Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1(Cl)[CH:8]2[CH:4]([CH:5]([CH2:9][CH2:10][CH2:11][CH2:12][CH:13]([O:16][CH3:17])[CH2:14][CH3:15])[CH2:6][CH2:7]2)[C:3]1=[O:18]>C(O)(=O)C.[Zn]>[CH3:17][O:16][CH:13]([CH2:14][CH3:15])[CH2:12][CH2:11][CH2:10][CH2:9][CH:5]1[CH:4]2[CH:8]([CH2:2][C:3]2=[O:18])[CH2:7][CH2:6]1
Reactant: CCC(CCCCC1CCC2C1C(=O)C2(Cl)Cl)OC
Agent: [Zn]
Solvent: CC(=O)O
Product: CCC(CCCCC1CCC2CC(=O)C12)OC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Zinc (4 g) is added to a stirred solution of 7,7-dichloro-4-(5-methoxyheptyl)bicyclo[3.2.0]heptan-6-one (2 g) in glacial acetic acid (120 ml). The solution is stirred at room temperature for one hour, then refluxed for 1 hour, after which time the mixture is filtered through a sintered glass funnel and the ether solution dried over anhydrous sodium sulfate. The solvent is removed under vacuum, leaving the crude product. Chromatography on silica gel yields 4-(5-methoxyheptyl)bicyclo [3.2.0]heptan-6-one (Formula IV, X=--(CH2)4 --CH(OCH3)--C2H5).
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[NH2:8].[CH2:9]1[CH2:15][S:12](=[O:14])(=[O:13])[O:11][CH2:10]1>O1CCCC1>[CH3:1][C@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH:8][CH2:10][CH2:9][CH2:15][S:12]([OH:14])(=[O:13])=[O:11]
Reactant: CC1CCCCC1N
Reactant: O=S1(=O)CCCO1
Solvent: C1CCOC1
Product: C[C@H]1CCCC[C@H]1NCCCS(=O)(=O)O
Temperature: 25 °C

Procedure:
To a solution of 2-methylcyclohexylamine (98% cis and trans isomers, 10.0 g, 88.3 mmol) in tetrahydrofuran (60 mL) was slowly added a solution of 1,3-propane sultone (10.5 g, 84.1 mmol) in THF (20 mL). The mixture was stirred at reflux for 2 hours. The reaction mixture was cooled to room temperature. The solid material was collected by filtration, washed with acetone (2×50 mL). The solid was dissolved in 50% EtOH/water (200 mL); and solution was treated with Dowex 50WX8 resin (15 g). The suspension stirred at room temperature for 15 min. The resin was removed by filtration. The filtrate was concentrated to half of the original volume on a rotary evaporator. The solid product slowly crystallized. The product was collected by filtration, washed with acetone (2×50 mL) and dried in a vacuum oven (50° C.), to afford compound DJ (10.4 g, 53%): 1H NMR (D2O, 500 MHz) δ ppm 3.15 (m, 1H), 3.03 (m, 1H), 2.88 (t, 2H, J=7.3 Hz), 2.76 (m, 1H), 1.98 (m, 3H), 1.68 (m, 2H), 1.51 (m, 2H), 1.18 (m, 3H), 1.01 (m, 1H), 0.92 (m, 3H). 13C NMR (D2O, 125 MHz) δ ppm 62.97, 48.16, 42.72, 34.77, 33.50, 27.57, 24.51, 24.23, 21.51, 17.80. ES-MS 234 (M-1).
Reaction SMILES: [CH2:1]([NH:6][C:7]1[CH:11]=[CH:10][S:9][CH:8]=1)[CH2:2][CH2:3][CH2:4][CH3:5].[C:12](Cl)(=[O:16])[C:13](Cl)=[O:14]>CCOCC>[CH2:1]([N:6]1[C:13](=[O:14])[C:12](=[O:16])[C:8]2[S:9][CH:10]=[CH:11][C:7]1=2)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CCCCCNc1ccsc1
Solvent: CCOCC
Product: CCCCCN1C(=O)C(=O)c2sccc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 531.2 %

Procedure:
To a solution of N-pentylthiophen-3-amine (7.30 g, 4.30 mmol) in ether (50.0 mL) was added a solution of oxalyl chloride (6.00 mL, 42.0 mmol) in ether (50.0 mL) slowly at −10° C. The reaction mixture was stirred at ambient temperature for 3 h and quenched with cold water. The organic layer was separated, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to dryness. The residue was subjected to column chromatography to afford the title compound (5.10 g, 53%): MS (ES+) m/z 246.3 (M+23).
Reaction SMILES: [CH3:1][N:2]([CH3:32])[CH2:3][CH2:4][CH2:5][NH:6]C(C1C=C(C2C=CC(CSCCOC3C=CC=CC=3)=CC=2)C=CC=1)=O.[O:33]([CH2:40][CH2:41][S:42][CH2:43][C:44]1[CH:45]=[C:46]([C:50]2[CH:55]=[CH:54][C:53]([C:56](O)=[O:57])=[CH:52][CH:51]=2)[CH:47]=[CH:48][CH:49]=1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.CN(C)CCCN>C1COCC1>[CH3:1][N:2]([CH3:32])[CH2:3][CH2:4][CH2:5][NH:6][C:56]([C:53]1[CH:52]=[CH:51][C:50]([C:46]2[CH:47]=[CH:48][CH:49]=[C:44]([CH2:43][S:42][CH2:41][CH2:40][O:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[CH:45]=2)=[CH:55][CH:54]=1)=[O:57]
Reactant: CN(C)CCCNC(=O)c1cccc(-c2ccc(CSCCOc3ccccc3)cc2)c1
Reactant: O=C(O)c1ccc(-c2cccc(CSCCOc3ccccc3)c2)cc1
Agent: CN(C)CCCN
Solvent: C1CCOC1
Product: CN(C)CCCNC(=O)c1ccc(-c2cccc(CSCCOc3ccccc3)c2)cc1

Procedure:
3′-(2-Phenoxy-ethylsulfanylmethyl)-bipheny-4-carboxylic acid (3-dimethylamino-propyl)-amide was synthesized as described for 4′-(2-phenoxy-ethylsulfanylmethyl)-biphenyl-3-carboxylic acid (3-dimethylamino-propyl)-amide. 3′-(2-Phenoxy-ethylsulfanylmethyl)-biphenyl-4carboxylic acid (0.80 g, 2.19 mmol, 1 eq.) in anhydrous THF was treated with 1,1-carbonyldiimidazole (0.36 g, 2.23 mmol, 1.02 eq.) and 3-(dimethylamino)propylamine (0.27 g, 2.63 mmol, 1.2 eq.). When complete, the reaction was worked up as described leaving a yellow oil.
Reaction SMILES: Cl[CH2:2][C:3]1[C:7]([CH2:8]Cl)=[C:6]([CH3:10])[S:5][C:4]=1[CH3:11].[C:12]1([CH3:22])[CH:17]=[CH:16][C:15]([S:18]([NH2:21])(=[O:20])=[O:19])=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:11][C:4]1[S:5][C:6]([CH3:10])=[C:7]2[CH2:8][N:21]([S:18]([C:15]3[CH:16]=[CH:17][C:12]([CH3:22])=[CH:13][CH:14]=3)(=[O:19])=[O:20])[CH2:2][C:3]=12
Reactant: Cc1sc(C)c(CCl)c1CCl
Reactant: Cc1ccc(S(N)(=O)=O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)N2Cc3c(C)sc(C)c3C2)cc1
Yield: 63.6 %

Procedure:
A solution of 10 g (0.048 mol) of 3,4-bis(chloromethyl)-2,5-dimethylthiophene and 8.22 g of p-toluenesulphonamide in 600 ml of dry dimethylformamide is added dropwise, over 6 h, to a stirred suspension, heated to 100°-110° C., of 180 g of potassium carbonate in 900 ml of dimethylformamide. After the end of the addition, the mixture is maintained at the same temperature for 30 min, and then filtered. The solid is washed with dimethylformamide. The filtrate is concentrated under vacuum, and the residue is treated with 100 ml of ethanol, and filtered. The solid residue remaining is washed with ethanol and dried. 9.39 g of product are obtained. Melting point: 163°-164° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C:11](=O)[CH:10]2[O:14][CH2:15][C:16]([O:19][CH3:20])([O:17][CH3:18])[CH:9]12)=[O:7])([CH3:4])([CH3:3])[CH3:2].B1C2CCCC1CCC2.C1C[O:33][CH2:32]C1>>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]([CH2:32][OH:33])[CH:10]2[O:14][CH2:15][C:16]([O:17][CH3:18])([O:19][CH3:20])[CH:9]12)=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: C1CCOC1
Reactant: COC1(OC)COC2C(=O)CN(C(=O)OC(C)(C)C)C21
Agent: B1C2CCCC1CCC2
Product: COC1(OC)COC2C(CO)CN(C(=O)OC(C)(C)C)C21
Yield: 86 %

Procedure:
The olefin 1e (524 mg, 1.84 mmol) was dissolved in dry THF (70 mL). 9-BBN-H (0.5 M in THF) (7.34 mL, 3.67 mmol) was added and the solution was stirred over night. The solvent was removed by rotary evaporation and redissolved in THF (20 mL). MeOH (10 mL) was slowly added to the solution and when the gas evolution had ceased, H2O (20 mL) was added to the solution followed by NaBO3. The solution was filtered after it had been stirred for 18 hrs and the filtrate was diluted with EtOAc (70 mL) and washed with brine (2*50 mL). The organic phase was dried with Na2SO4, filtered and the solvent was evaporated in vacuo. The crude product was purified by flash chromatography (heptane: ethyl acetate 2:1) which gave the title compound (477 mg, 86%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][OH:10])=[CH:4][CH:3]=1.[H-].[Na+].[CH3:13]I.O>CN(C)C=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][O:10][CH3:13])=[CH:4][CH:3]=1
Reactant: OCCc1ccc(Br)cc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COCCc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 56.1 %

Procedure:
2-(4-Bromophenyl)ethanol (2.0 g) was dissolved in N,N-dimethylformamide (50 mL), and sodium hydride (60% in oil) (0.44 g) was added under ice-cooling. After gradually warming to room temperature, the mixture was stirred for 2 hr, and methyl iodide (2.1 g) was added again under ice-cooling. After gradually warming to room temperature, the mixture was stirred overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent; hexane:ethyl acetate=20:1 to 10:1) to give the title compound (1.2 g) as a colorless oil.
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[CH:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:5]2[C:13]([CH3:20])=[C:14]([NH2:19])[C:15]([CH3:18])=[C:16]([CH3:17])[C:4]=2[O:3]1.Cl[CH2:23][C:24]1[CH:29]=[C:28]([O:30][CH3:31])[C:27]([O:32][CH3:33])=[CH:26][C:25]=1[CH2:34]Cl.C(=O)([O-])[O-].[Na+].[Na+]>O1CCCC1.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH3:33][O:32][C:27]1[CH:26]=[C:25]2[C:24](=[CH:29][C:28]=1[O:30][CH3:31])[CH2:23][N:19]([C:14]1[C:15]([CH3:18])=[C:16]([CH3:17])[C:4]3[O:3][C:2]([CH3:21])([CH3:1])[CH:6]([C:7]4[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=4)[C:5]=3[C:13]=1[CH3:20])[CH2:34]2
Reactant: Cc1c(C)c2c(c(C)c1N)C(c1ccccc1)C(C)(C)O2
Reactant: COc1cc(CCl)c(CCl)cc1OC
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: C1CCOC1
Product: COc1cc2c(cc1OC)CN(c1c(C)c(C)c3c(c1C)C(c1ccccc1)C(C)(C)O3)C2
Temperature: 25 °C
Yield: 25.5 %

Procedure:
To a solution of 2,2,4,6,7-pentamethyl-3-phenyl-2,3-dihydro-1-benzofuran-5-amine (1.00 g, 3.56 mmol) in tetrahydrofuran (30 ml) were added 1,2-bis(chloromethyl)-4,5-dimethoxybenzene (889.1 mg, 3.78 mmol), sodium carbonate (1.15 g, 10.85 mmol), and tetrabutylammonium iodide (701.4 mg, 1.90 mmol) and the mixture was refluxed with heating for 21 hours. The reaction mixture was cooled down to room temperature and then poured into ice water. The product was extracted twice with ethyl acetate. The combined extracts were washed with an aqueous saturated solution of sodium hydrogen carbonate, dried on magnesium sulfate, filtered, and then concentrated under reduced pressure. The residue was subjected to column chromatography on silica gel to obtain 403 mg (26% yield) of the title compound. Melting point: 154-157° C. (Ethyl acetate)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2([C:27]3[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:28]=3[F:34])[CH2:16][CH2:15][CH:14]([CH2:17][C:18]([C:20]3[O:21][CH:22]=[CH:23][C:24]=3[CH:25]=O)=[O:19])[CH2:13][CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[NH:35]1[CH2:40][CH2:39][O:38][CH2:37][CH2:36]1.C([BH3-])#N.[Na+].Cl>CO.C(OCC)C.[OH-].[Na+]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([C:11]2([C:27]3[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:28]=3[F:34])[CH2:16][CH2:15][CH:14]([CH2:17][C:18]([C:20]3[O:21][CH:22]=[CH:23][C:24]=3[CH2:25][N:35]3[CH2:40][CH2:39][O:38][CH2:37][CH2:36]3)=[O:19])[CH2:13][CH2:12]2)(=[O:10])=[O:9])=[CH:6][CH:7]=1
Reactant: O=Cc1ccoc1C(=O)CC1CCC(c2cc(F)ccc2F)(S(=O)(=O)c2ccc(Cl)cc2)CC1
Reactant: C1COCCN1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCOCC
Solvent: CO
Product: O=C(CC1CCC(c2cc(F)ccc2F)(S(=O)(=O)c2ccc(Cl)cc2)CC1)c1occc1CN1CCOCC1
Temperature: 25 °C
Reaction time: 20 h
Yield: 22.8 %

Procedure:
To a stirred solution of the product of Example 143 (100 mg, 0.19 mmol) in methanol (2.5 mL) was added morpholine (100 μL, 1.7 mmol) and sodium cyanoborohydride (9 mg, 0.19 mmol) followed by hydrochloric acid (3M solution in methanol, 0.3 mL) dropwise. The reaction was stirred at room temperature for 20 hours then diluted with diethyl ether and 4N aqueous sodium hydroxide. The organic layer was washed with water, dried (MgSO4) and evaporated to dryness, yielding a yellow oil which was purified by column chromatography on silica eluting with 1:1:1 iso-hexane:dichloromethane:ethyl acetate +1% triethylamine to yield the desired product as a white solid (25 mg).
Reaction SMILES: [CH:1]1[C:14]2[C:5](=[CH:6][C:7]3[C:12]([C:13]=2[C:15](Cl)=[O:16])=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH:4]=[CH:3][CH:2]=1.[CH2:18]([NH:21][CH2:22][CH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1)[C:19]#[CH:20].[O-2].[Mg+2]>O1CCCC1>[CH:23]1([CH2:22][N:21]([CH2:18][C:19]#[CH:20])[C:15]([C:13]2[C:14]3[C:5]([CH:6]=[C:7]4[C:12]=2[CH:11]=[CH:10][CH:9]=[CH:8]4)=[CH:4][CH:3]=[CH:2][CH:1]=3)=[O:16])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: C#CCNCC1CCCCC1
Reactant: O=C(Cl)c1c2ccccc2cc2ccccc12
Agent: [Mg+2]
Agent: [O-2]
Solvent: C1CCOC1
Product: C#CCN(CC1CCCCC1)C(=O)c1c2ccccc2cc2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.6 %

Procedure:
A solution of 12.66 g of 9-anthroyl chloride in 50 ml of tetrahydrofuran is added dropwise to a stirred mixture of 8.69 g of N-propargylcyclohexylmethylamine and 9 g of magnesium oxide in 80 ml of tetrahydrofuran. After stirring at room temperature overnight, the mixture is filtered and the filtrate is concentrated to dryness. The residue is taken up in methylene chloride and washed, in turn, with dilute sulfuric acid, water, and dilute sodium hydroxide solution, and dried. Removal of the solvent gives 14.7 g of N-cyclohexylmethyl-N-propargyl-9-anthramide as an oil. It is dissolved in 100 ml of p-xylene and the mixture is heated under reflux for three hours. The solvent is removed, and the residue is heated under reflux with 60 ml of tetrahydrofuran and 60 ml of 15% aqueous sodium hydroxide solution for one hour. The mixture is concentrated to a small volume, diluted with water and filtered. The solid is washed with dilute alkali and water, dried, and crystallized from toluene to give 6.68 g of 2-cyclohexylmethyl-3,5-dihydro-5,9b-o-benzenobenz[e]isoindol-1(2H)-one; nmr spectrum: τ 2.3-3.4 (m, 9); 4.8 (d, J = 6Hz, 1) 5.9 (d, J = 2Hz, 2); 6.6 (d, J = 6.5 Hz, 2) and 8.0-9.2 (m, 11).
Reaction SMILES: C1(C2CCNCC2)C=CC=CC=1.C(Br)CO.[C:17]1([CH:23]2[CH2:28][CH2:27][N:26]([CH2:29][CH2:30][OH:31])[CH2:25][CH2:24]2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[CH2:32]=[C:33]1[O:37][C:35](=[O:36])[CH2:34]1>>[C:35]([O:31][CH2:30][CH2:29][N:26]1[CH2:25][CH2:24][CH:23]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:28][CH2:27]1)(=[O:36])[CH2:34][C:33]([CH3:32])=[O:37]
Reactant: OCCN1CCC(c2ccccc2)CC1
Reactant: C=C1CC(=O)O1
Agent: OCCBr
Agent: c1ccc(C2CCNCC2)cc1
Product: CC(=O)CC(=O)OCCN1CCC(c2ccccc2)CC1

Procedure:
4-Phenylpiperidine was reacted with ethylene bromohydrin in the same manner as Reference Example 5, and the resulting oily 4-phenyl-1-piperidineethanol was further reacted with diketene to give 2-(4-phenylpiperidino)ethyl acetoacetate as an oil.
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([S:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)(=[O:14])=[O:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:21].[CH3:22][O:23][C:24]1[CH:25]=[C:26]([CH2:30][C:31](O)=[O:32])[CH:27]=[CH:28][CH:29]=1>>[CH3:22][O:23][C:24]1[CH:25]=[C:26]([CH2:30][C:31]([NH:1][N:2]2[N:11]=[C:10]([S:12]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)(=[O:14])=[O:13])[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]2=[O:21])=[O:32])[CH:27]=[CH:28][CH:29]=1
Reactant: COc1cccc(CC(=O)O)c1
Reactant: Nn1nc(S(=O)(=O)c2ccccc2)c2ccccc2c1=O
Product: COc1cccc(CC(=O)Nn2nc(S(=O)(=O)c3ccccc3)c3ccccc3c2=O)c1

Procedure:
The product from Example 68B and 2-(3-methoxyphenyl)acetic acid were processed using a method similar to that described in Example 10C to afford the title compound. 1H NMR (400 MHz, DMSO-d6) δ 11.85 (s, 1H), 8.56 (d, J=8.1, 1H), 8.38 (dd, J=8.0, 0.9, 1H), 8.15-8.06 (m, 1H), 8.05-7.96 (m, 3H), 7.84-7.76 (m, 1H), 7.72-7.62 (m, 2H), 7.26 (t, J=7.9, 1H), 6.95-6.88 (m, 1H), 6.85 (dd, J=8.2, 2.6, 2H), 3.77 (s, 3H), 3.64 (s, 2H); MS (ESI+) M/Z 467 (M+NH4)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:37])[CH:4]([C:9]1[CH:10]=[C:11]([C:23]2[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[C:25]([C:33]([F:36])([F:35])[F:34])[CH:24]=2)[CH:12]=[C:13](OS(C(F)(F)F)(=O)=O)[CH:14]=1)[CH2:5][CH:6]([CH3:8])[CH3:7].[F:38][C:39]1[CH:45]=[CH:44][C:42]([NH2:43])=[C:41]([C:46]([F:49])([F:48])[F:47])[CH:40]=1>>[CH3:1][O:2][C:3](=[O:37])[CH:4]([C:9]1[CH:10]=[C:11]([C:23]2[CH:28]=[C:27]([C:29]([F:31])([F:30])[F:32])[CH:26]=[C:25]([C:33]([F:34])([F:35])[F:36])[CH:24]=2)[CH:12]=[C:13]([NH:43][C:42]2[CH:44]=[CH:45][C:39]([F:38])=[CH:40][C:41]=2[C:46]([F:47])([F:48])[F:49])[CH:14]=1)[CH2:5][CH:6]([CH3:8])[CH3:7]
Reactant: Nc1ccc(F)cc1C(F)(F)F
Reactant: COC(=O)C(CC(C)C)c1cc(OS(=O)(=O)C(F)(F)F)cc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1
Product: COC(=O)C(CC(C)C)c1cc(Nc2ccc(F)cc2C(F)(F)F)cc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1
Yield: 46 %

Procedure:
The title compound was prepared in 46% yield from 4-methyl-2-(5-trifluoromethanesulfonyloxy-3′,5′-bis-trifluoromethyl-biphenyl-3-yl)-pentanoic acid methyl ester (prepared in Example 43, step (a)) and 4-fluoro-2-trifluoromethyl-aniline under the conditions described in Example 37, step (b).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][S:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=1.[OH:12]O>C(O)=O.O>[Cl:1][CH2:2][CH2:3][CH2:4][S:5]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=1)=[O:12]
Reactant: ClCCCSc1ccccn1
Reactant: OO
Solvent: O=CO
Solvent: O
Product: O=S(CCCCl)c1ccccn1
Temperature: 25 °C
Reaction time: 3 h
Yield: 56.5 %

Procedure:
2-(3-Chloropropyl)thiopyridine (4.4 g) prepared in Reference Example 3 is dissolved in formic acid (40 ml). 30% Aqueous hydrogen peroxide (2.7 g) is added to the solution and the mixture is stirred at room temperature for 3 hours. The mixture is allowed to stand at room temperature for overnight, diluted with water and extracted with chloroform. The chloroform solution is washed with water, saturated aqueous sodium bicarbonate and saturated aqueous sodium chloride and dried over magnesium sulfate. Chloroform is distilled off and the residue is purified by column chromatography (Kieselgel 60). The column is eluted with chloroform-methanol (50:1) to obtain 2-pyridyl 3-chloropropyl sulfoxide (2.7 g) as colorless liquid.
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[CH:5][C:6]([F:12])=[C:7]([CH2:9][CH2:10][OH:11])[CH:8]=1.FC(F)(F)C(O)=O.[CH:20]([C:23]1[S:24][CH:25]=[C:26]([C:28]([N:30]2[CH2:35][C:34]3([CH2:40][CH2:39][NH:38][CH2:37][CH2:36]3)[O:33][CH2:32][CH2:31]2)=[O:29])[N:27]=1)([CH3:22])[CH3:21].C(=O)([O-])[O-].[K+].[K+]>C(O)C>[F:12][C:6]1[CH:5]=[CH:4][C:3]([CH2:2][N:38]2[CH2:39][CH2:40][C:34]3([O:33][CH2:32][CH2:31][N:30]([C:28]([C:26]4[N:27]=[C:23]([CH:20]([CH3:21])[CH3:22])[S:24][CH:25]=4)=[O:29])[CH2:35]3)[CH2:36][CH2:37]2)=[CH:8][C:7]=1[CH2:9][CH2:10][OH:11]
Reactant: CC(C)c1nc(C(=O)N2CCOC3(CCNCC3)C2)cs1
Reactant: OCCc1cc(CBr)ccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: CCO
Product: CC(C)c1nc(C(=O)N2CCOC3(CCN(Cc4ccc(F)c(CCO)c4)CC3)C2)cs1
Reaction time: 8 h

Procedure:
2-(5-(Bromomethyl)-2-fluorophenyl)ethanol (example 47A, step a) (5.2 g) was added to a suspension of (2-isopropylthiazol-4-yl)(1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)methanone trifluoroacetate (example 22, step b) (9.4 g) and potassium carbonate (6.8 g) in ethanol (75 mL). The resulting mixture was stirred overnight and filtered. The filter cake was washed with ethanol (50 mL) and the combined filtrate and washings were evaporated. The residue was partioned between water (100 mL) and ethyl acetate (250 mL). The layers were separated and the organic washed with brine (100 mL), dried over sodium sulphate, filtered and evaporated. Purification was by silica gel chromatography eluting with 95:5 ethyl acetate:triethylamine gradient. The fractions containing product were combined and evaporated to give to the subtitled compound as a yellow gum. Yield 7.9 g.
Reaction SMILES: [C:1]1(=[O:11])[NH:5][C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[K].[Cl:13]Cl>C(Cl)Cl>[Cl:13][N:5]1[C:1](=[O:11])[C:2]2=[CH:10][CH:9]=[CH:8][CH:7]=[C:3]2[C:4]1=[O:6]
Reactant: ClCl
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: ClCCl
Product: O=C1c2ccccc2C(=O)N1Cl
Temperature: 0 °C
Yield: 88 %

Procedure:
To 800 ml. of methylene chloride were added 50 grams (270 mmoles) of potassium phthalimide. The resulting slurry was chilled to 0° C. To a jacketed flask maintained immediately above the main reaction vessel were added 200 ml. of methylene chloride. The methylene chloride was saturated with chlorine and was maintained at a temperature of -5° C. to 0° C. The flask containing the chlorinesaturated methylene chloride was equipped with a dry-ice trap to ensure that none of the reagent escaped. The chlorine-saturated methylene chloride then was added to the potassium phthalimide mixture as rapidly as possible by means of a tube which extended below the surface of the potassium phthalimide slurry. Addition was completed in less than 30 seconds. During addition, the temperature of the mixture increased from 0° C. to 10° C. The resulting mixture had a greenish-yellow color which persisted. The mixture was allowed to warm to 20° C. over a two hour period. Some undissolved lumps of potassium phthalimide were noted in the mixture. The resulting potassium chloride percipitate was removed by filtration, and the filtrate was evaporated in vacuo to a slush. Heptane (about 400 ml.) was added, and the mixture was filtered. The collected N-chlorophthalimide was reslurried in about 500 ml. of water and vacuum-dried to afford 42.9 grams (88% yield) of N-chlorophthalimide.
Reaction SMILES: B(Cl)([C@H]1[C@H](C)[C@@H]2C(C)(C)[C@@H](C2)C1)[C@H]1[C@H](C)[C@@H]2C(C)(C)[C@@H](C2)C1.[CH2:23]([Mg]Br)[CH:24]=[CH2:25].[CH:28](=[O:40])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39].C(=O)C.C([O-])(=O)C.[Na+].OO>C(OCC)C>[CH2:25]=[CH:24][CH2:23][C@H:28]([OH:40])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39]
Reactant: C=CC[Mg]Br
Reactant: CCCCCCCCCCCC=O
Agent: CC(=O)[O-]
Agent: CC=O
Agent: C[C@@H]1[C@H]2C[C@@H](C[C@H]1B(Cl)[C@@H]1C[C@@H]3C[C@H]([C@H]1C)C3(C)C)C2(C)C
Solvent: CCOCC
Product: C=CC[C@H](O)CCCCCCCCCCC
Temperature: -40 °C
Reaction time: 0.5 h
Yield: 75 %

Procedure:
In a 250-ml round bottom flask equipped with septum inlet, bent tube adapter and magnetic stirring bar is placed (-)-B-chlorodiisopinocampheylborane (99% ee, 9.6 g, 30 mM derived from (+)-α-pinene). The reagent (purchased from Aldrich Chemical Co., 940 West Saint Paul Ave., Milwaukee, Wis. 53233), and 30 ml of anhydrous ether were placed under a nitrogen atmosphere. The mixture was cooled to -40° C. and then treated with allylmagnesium bromide (1.1M 22.7 ml, 25 mM). The reaction mixture was then allowed to warm to room temperature. Meanwhile, dodecanal (redistilled, 4.41 ml, 20 mM) was dissolved in 10 ml of anhydrous ethyl ether and cooled to ice-bath temperature (5° C.). The resulting allyldiisopinocampheylborane was cooled to -78° C. after stirring at room temperature for 30 minutes; dodecanal was then slowly added keeping the mixture at -78° C. The mixture was then allowed to warm to room temperature in the same bath overnight. The resulting mixture was cooled to 5° C. and then acetaldehyde (10 ml, 180 mM) was slowly added, with stirring. The mixture was further stirred at room temperature for 18 hours. The resulting organoborane was then oxidized at 5° C. with sodium acetate (20 ml, 60 mM), and hydrogen peroxide (30%, 10 ml). The addition of H2O2 generates an exothermic reaction. The mixture was extracted with diethylether (Et2O) (3×20 ml), and the combined ether extracts were washed with water and a saturated solution of sodium chloride. The extract was dried over anhydrous magnesium sulfate, filtered and the solvent removed. The residue was chromatographed on silical gel (1:15 ethyl acetate/hexane). The pure fractions, as determined by thin layer chromatography (TLC) were pooled, made free of solvents and distilled to provide (R)-1-pentadecen-4-ol (3), a colorless oil with a bp 96° C., 0.5 mm of Hg, 3.39 g, 75% yield. Analysis of the prepared (R)-1-pentadecen-4-ol (3): IR(neat) 3350, 2900, 2860, 1640, 910 cm-1. 1H NMR (CDCl3) δ 0.89 (t, 3H, J=6.4 Hz), 1.28 (bs, 16H), 1.47 (bs, 2H), 2.15 (m, 1H), 2.3 (bm, 1H), 3.65 (bq, 1H), 5.11 (s, 1H), 5.16 (d, 1H), 5.84 (m, 1H).