Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Li])CCC.[F:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[NH:14][CH:15]=[CH:16][C:17]=2[C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)=[CH:9][CH:8]=1.O([Si:32]([CH:39]([CH3:41])[CH3:40])([CH:36]([CH3:38])[CH3:37])[CH:33]([CH3:35])[CH3:34])S(C(F)(F)F)(=O)=O>CCCCCC.O1CCCC1>[F:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]2[N:14]([Si:32]([CH:39]([CH3:41])[CH3:40])([CH:36]([CH3:38])[CH3:37])[CH:33]([CH3:35])[CH3:34])[CH:15]=[CH:16][C:17]=2[C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)=[CH:11][CH:12]=1
Reactant: CC(C)[Si](OS(=O)(=O)C(F)(F)F)(C(C)C)C(C)C
Reactant: Fc1ccc(-c2[nH]ccc2-c2ccncc2)cc1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(C)[Si](C(C)C)(C(C)C)n1ccc(-c2ccncc2)c1-c1ccc(F)cc1
Reaction time: 0.17 h
Yield: 100 %

Procedure:
31 ml (47.4 mmol) of a 1.57 N solution of butyllithium in hexane were added to a solution of 11.30 g (47.4 mmol) of 2-(4-fluorophenyl)-3-(pyridin-4-yl)-1H-pyrrole [prepared as described in step 7(i) above] in 300 ml of tetrahydrofuran at −78° C. and the mixture was stirred for 10 minutes. At the end of this time, 13.4 ml (49.8 mmol) of triisopropylsilyl triflate were added to the reaction mixture at the same temperature. After removal of the cooling bath, the mixture was stirred at room temperature for 30 minutes. 200 ml of water and 300 ml of a saturated aqueous solution of sodium hydrogencarbonate were then added to the reaction mixture before extracting with ethyl acetate. The organic extract was washed with water, dried over anhydrous sodium sulfate and then concentrated by evaporation under reduced pressure to give 18.70 g (quantitative yield) of the title compound as a reddish purple oil.
Reaction SMILES: [CH2:1]=[C:2]([C:4]1[CH:5]=[C:6]([CH:10]([CH3:14])[CH2:11][CH:12]=[O:13])[CH:7]=[CH:8][CH:9]=1)[CH3:3].[H][H]>[Pd].C(O)C>[CH3:3][CH:2]([C:4]1[CH:5]=[C:6]([CH:10]([CH3:14])[CH2:11][CH:12]=[O:13])[CH:7]=[CH:8][CH:9]=1)[CH3:1]
Reactant: [H][H]
Reactant: C=C(C)c1cccc(C(C)CC=O)c1
Agent: [Pd]
Solvent: CCO
Product: CC(C)c1cccc(C(C)CC=O)c1
Yield: 78 %

Procedure:
3-(3-Propen-2-ylphenyl)butanal, lb, (100 g) was hydrogenated over palladium on charcoal (5% wet, 1 gram) in 150 ml ethanol for 2.5 hours at 50 psi hydrogen using a Parr-shaker apparatus. The product mixture was decanted, filtered and the ethanol removed on a rotary evaporator to give 97 grams of a mixture which analyzed as 95.8% la, and 2% lb. The mixture was distilled to give 78.1 g pure la, b.p. 84° C./0.3 mm.Hg. Yield 78.0% la. IR and NMR spectra were compatible with the assigned structure. Odor: fresh, floral, melon having qualities found in lily-of-the-valley (muguet) and linden blossom. Odor value: 981,483; Odor threshold value: 0.07 ng/L. EXAMPLE III
Reaction SMILES: [CH2:1]([C:8]1[S:12][C:11]([NH2:13])=[N:10][C:9]=1[C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:29](Cl)(=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>C(OCC)(=O)C>[CH2:1]([C:8]1[S:12][C:11]([NH:13][C:29](=[O:36])[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[N:10][C:9]=1[C:14]1[CH:15]=[CH:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(-c2nc(N)sc2Cc2ccccc2)cc1
Reactant: O=C(Cl)c1ccccc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: COc1ccc(-c2nc(NC(=O)c3ccccc3)sc2Cc2ccccc2)cc1
Reaction time: 8 h
Yield: 57.6 %

Procedure:
To a 100 ml three-necked flask were added 0.50 g (1.69 mmol) 5-benzyl-4-(4-methoxy-phenyl)-thiazol-2-ylamine prepared in Example 1, 1.42 g (10.12 mmol) triethylamine and 40 ml ethyl acetate, and then added dropwise 0.48 g (3.38 mmol) benzoyl chloride dissolved in 10 ml ethyl acetate. The resulting mixture was magnetically stirred overnight at room temperature, filtrated, washed with ethyl acetate, the filtrate was washed with 1N aqueous sodium hydroxide solution, then washed with water until neutrality, dried over anhydrous sodium sulfate, filtered and concentrated under a reduced pressure to give a crude product, which was subjected to a silica gel column chromatography eluted with petroleum ether/ethyl acetate (5:1) to obtain a 0.39 g product as a white solid in a yield of 57.4%, mp: 146-147 └. 1H-NMR (CDCl3, 400 MHz) δ: 3.88 (3H, s, OCH3), 4.20 (2H, s, CH2), 7.01 (2H, d, J=8.72 Hz, ArH), 7.31 (2H, d, J=8.72 Hz, ArH), 7.42˜7.65 (7H, m, 6ArH+CONH), 8.09 (2H, d, J=7.28 Hz, ArH), 8.17 (2H, d, J=7.28 Hz, ArH); EI-MS m/e (%): 400.0 (M+, 94), 104.9 (100); HREI-MS Calcd. for C24H20N2O2S: 400.1245. found: 400.1235.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[C:7]2[OH:12].[C:13]1([CH3:23])[CH:18]=[CH:17][C:16]([S:19](Cl)(=[O:21])=[O:20])=[CH:15][CH:14]=1>N1C=CC=CC=1>[C:13]1([CH3:23])[CH:18]=[CH:17][C:16]([S:19]([NH:1][C:2]2[CH:11]=[CH:10][CH:9]=[C:8]3[C:3]=2[CH:4]=[CH:5][CH:6]=[C:7]3[OH:12])(=[O:21])=[O:20])=[CH:15][CH:14]=1
Reactant: Nc1cccc2c(O)cccc12
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)Nc2cccc3c(O)cccc23)cc1
Yield: 96 %

Procedure:
A solution of 1 mole 5-amino-1-naphthol in dry pyridine was stirred at 0°C and treated portionwise with 1 mole of p-toluenesulfonyl chloride. When analysis showed that the 5-amino-1-naphthol was consumed the reaction mixture was poured onto a sufficient quantity of aqueous hydrogen chloride to neutralize the excess pyridine and allow separation of the product as a fine powder which was filtered, washed with water, and recrystallized from ethanol to obtain (96% yield) analytically pure 5-p-toluenesulfonamido-1-naphthol having a melting point of 182°-194°C. Next, 2.58 g. (4.00 mmol) of 4-(m-aminophenylsulfonamido)-N-[4-(2,4-di-tert-pentylphenoxy)butyl]-1-hydroxy-2-naphthamide were dissolved in 10 ml. dry pyridine and treated with 50 ml. 5:1 acid and 10 ml. concentrated hydrochloric acid. The clear solution was cooled to 0°C. and treated with a solution of 284 mg. (4.00 mmol) sodium nitrite in 3 ml. of ice water. The resulting orange solution was added rapidly to a solution of 1.25 g. (4.00 mmol) of the above sulfonamidonaphthol dissolved in 8 ml. dry pyridine and 50 ml. 5:1 acid, and cooled to 5°C. The orange dye formed immediately. After 40 minutes at 5°-10°, the dye was precipitated by adding 300 ml. ice water and adjusting the pH to 2 with concentrated HCl. The orange powder obtained by filtration was washed with 8 liters of water and dried to give 3.31 g. Compound 12. This compound was tested in a manner similar to that of Example 12A and the released dye was found to have a λ max of 555 nm. The Dmax of transferred image was 0.97.
Reaction SMILES: [C:1]12[C:12]([NH:13][CH:14]3[CH2:19][CH2:18][CH:17]([NH2:20])[CH2:16][CH2:15]3)=[N:11][CH:10]=[N:9][C:8]=1[S:7][C:6]1[CH2:5][CH2:4][CH2:3][C:2]2=1.Br[CH2:22][CH2:23][F:24].CCN(C(C)C)C(C)C>CC#N>[F:24][CH2:23][CH2:22][NH:20][CH:17]1[CH2:18][CH2:19][CH:14]([NH:13][C:12]2[C:1]3[C:2]4[CH2:3][CH2:4][CH2:5][C:6]=4[S:7][C:8]=3[N:9]=[CH:10][N:11]=2)[CH2:15][CH2:16]1
Reactant: NC1CCC(Nc2ncnc3sc4c(c23)CCC4)CC1
Reactant: FCCBr
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: FCCNC1CCC(Nc2ncnc3sc4c(c23)CCC4)CC1
Temperature: 70 °C
Reaction time: 7 h
Yield: 82.5 %

Procedure:
Reference: For the preparation of the starting material compound 1, see Example 147. Into a 100-mL round-bottom flask, a solution of 1-N-[7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-12-yl]cyclohexane-1,4-diamine (250 mg, 0.87 mmol, 1.00 equiv) in CH3CN (15 mL) was added 1-bromo-2-fluoroethane (220 mg, 1.73 mmol, 2.00 equiv) and DIPEA (200 mg, 1.74 mmol, 2.00 equiv) at room temperature under nitrogen. The resulting solution was stirred for 7 h at 70° C. in an oil bath. After completion, the resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with dichloromethane/methanol (20:1) to give 240 mg (83%) of the desired 1-N-(2-fluoroethyl)-4-N-[7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-12-yl]cyclohexane-1,4-diamine as a light yellow solid. MS (ES, m/z): 334 [M+H]+.
Reaction SMILES: O.[C:2]1([OH:10])[CH:9]=[C:7]([CH3:8])[CH:6]=[C:4]([OH:5])[CH:3]=1.[N+:11]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[S:20](Cl)(=[O:22])=[O:21])([O-:13])=[O:12]>C([O-])(O)=O.[Na+].C(OCC)C.O>[CH3:8][C:7]1[CH:9]=[C:2]([O:10][S:20]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[N+:11]([O-:13])=[O:12])(=[O:21])=[O:22])[CH:3]=[C:4]([OH:5])[CH:6]=1
Reactant: Cc1cc(O)cc(O)c1
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Product: Cc1cc(O)cc(OS(=O)(=O)c2ccccc2[N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.7 %

Procedure:
Orcinol monohydrate (4.27 g, 30.0 mmol) and 2-nitrobenzenesulfonyl chloride (6.65 g, 30.0 mmol) were mixed in saturated aqueous NaHCO3 (100 mL) and diethyl ether (100 mL). The biphasic mixture was stirred vigorously at ambient temperature overnight. The reaction mixture was diluted with water (150 mL) and extracted into ethyl acetate (3×100 mL). The organic phase was washed with brine (2×100 mL) and dried over Na2SO4. After removing the solvent in vacuo, the residue was purified by flash column chromatography (dichloromethane to 5% ethyl acetate in dichloromethane) to give the title compound as a pale yellow solid (6.10 g, 73%). 1H-NMR (300 MHz, CDCl3) δ 8.09 (d, J=7.8 Hz, 1H), 7.85 (m, 2H), 7.71 (m, 1H), 6.62 (s, 1H), 6.59 (s, 1H), 6.51 (s, 1H), 5.06 (s, 1H), 2.26 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][NH2:10])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:18][CH2:19][CH2:20][N:21]1[C:25](=[O:26])[C:24]2=[CH:27][CH:28]=[CH:29][CH:30]=[C:23]2[C:22]1=[O:31]>CC#N>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][NH:10][CH2:18][CH2:19][CH2:20][N:21]2[C:25](=[O:26])[C:24]3=[CH:27][CH:28]=[CH:29][CH:30]=[C:23]3[C:22]2=[O:31])=[CH:4][CH:3]=1
Reactant: O=C1c2ccccc2C(=O)N1CCCBr
Reactant: NCCc1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=C1c2ccccc2C(=O)N1CCCNCCc1ccc(Cl)cc1
Reaction time: 16 h
Yield: 66.5 %

Procedure:
To a mixture of 2-(4-chlorophenyl)ethylamine (1.56 g, 10 mmol) and potassium carbonate (2.8 g, 20 mmol) in CH3CN (50 ml) was added N-(3-bromopropyl)phthalimide (3.0 g, 11 mmol). The mixture was refluxed under stirring for 16 h, and then filtered. The filtrate was concentrated under vacuum to dryness, and the residue was chromatographed on silica gel (eluting with 2.5% methanol/chloroform) to afford N-[3-[2-(4-chlorophenyl)ethylamino]propyl]phthalimide (2.28 g, 67%): MS(FD) m/e 343 [M+H]+; 1H NMR (400 MHz, CDCl3) δ 7.84 (m, 2H), 7.71 (m, 2H), 7.24 (d, J=8.3 Hz, 2H), 7.11 (d, J=8.3 Hz, 2H), 3.74 (d, J=6.8 Hz, 2H), 2.82 (t, J=6.8 Hz, 2H), 2.73 (t, J=6.8 Hz, 2H), 2.66 (t, J=6.8 Hz, 2H), 1.84 (m, 2H).
Reaction SMILES: Cl.Cl.[NH2:3][C@@H:4]([CH2:14][C:15]1[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=1)[C:5]([N:7]1[CH2:12][CH2:11][CH:10]([OH:13])[CH2:9][CH2:8]1)=[O:6].[Cl:21][C:22]1[CH:23]=[C:24]2[C:28](=[CH:29][CH:30]=1)[NH:27][C:26]([C:31](O)=[O:32])=[CH:25]2>>[OH:13][CH:10]1[CH2:11][CH2:12][N:7]([C:5](=[O:6])[C@@H:4]([NH:3][C:31]([C:26]2[NH:27][C:28]3[C:24]([CH:25]=2)=[CH:23][C:22]([Cl:21])=[CH:30][CH:29]=3)=[O:32])[CH2:14][C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)[CH2:8][CH2:9]1
Reactant: N[C@@H](Cc1cccnc1)C(=O)N1CCC(O)CC1
Reactant: O=C(O)c1cc2cc(Cl)ccc2[nH]1
Agent: Cl
Product: O=C(N[C@@H](Cc1cccnc1)C(=O)N1CCC(O)CC1)c1cc2cc(Cl)ccc2[nH]1

Procedure:
(S)-2-Amino-1-(4-hydroxy-piperidin-1-yl)-3-pyridin-3-yl-propan-1-one dihydrochloride (0.8 mmol) and 5-chloro-1H-indole-2-carboxylic acid (0.7 mmol) were coupled according to Procedure A (0-25° C. reaction temperature) and the product purified by chromatography on silica gel eluted with 1-16% ethanol in dichloromethane. Yield 26 mg, 8%; HPLC (50/50) 5.02 minutes (99%); PBMS 427/429 (MH+, 100%);
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:15]=[C:14]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:10]=1[C:11](O)=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:34][C:35]1[CH:36]=[C:37]([CH2:41][C:42]([NH:44][NH2:45])=[O:43])[CH:38]=[CH:39][CH:40]=1>>[OH:34][C:35]1[CH:36]=[C:37]([CH2:41][C:42]([NH:44][NH:45][C:11](=[O:12])[C:10]2[C:14]([O:26][CH2:27][C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)=[CH:15][C:16]([O:18][CH2:19][C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)=[CH:17][C:9]=2[O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:43])[CH:38]=[CH:39][CH:40]=1
Reactant: O=C(O)c1c(OCc2ccccc2)cc(OCc2ccccc2)cc1OCc1ccccc1
Reactant: NNC(=O)Cc1cccc(O)c1
Product: O=C(Cc1cccc(O)c1)NNC(=O)c1c(OCc2ccccc2)cc(OCc2ccccc2)cc1OCc1ccccc1
Yield: 40 %

Procedure:
The coupling of 2,4,6-tribenzyloxybenzoic acid to (3-hydroxyphenyl)acetohydrazide is carried out analogously to Example 2.5, giving N′-[2-(3-hydroxyphenyl)acetyl]-2,4,6-tribenzyloxybenzohydrazide, yield 40%; m.p. 154-155°.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[Ca+2].[CH3:17][NH:18][S:19](Cl)(=[O:21])=[O:20]>C(#N)C>[CH3:17][NH:18][S:19]([NH:1][C:2]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1)(=[O:21])=[O:20]
Reactant: COC(=O)c1cccnc1N
Reactant: CNS(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: CC#N
Product: CNS(=O)(=O)Nc1ncccc1C(=O)OC
Reaction time: 15 h

Procedure:
Methyl 2-amino-3-pyridine carboxylate (15.2 grams; 0.1 mole), calcium carbonate (13.0 grams; 0.1 mole) and methylsulfamoyl chloride (13.0 grams; 0.1 mole) were mixed with 200 ml of acetonitrile and the resulting reaction mixture stirred at ambient temperatures for a period of about 15 hours. Following the reaction period, the reaction mixture was filtered and the solvent removed in vacuo. The semi-solid residue thus obtained was extracted with ethanol. A white crystalline precipitate, obtained by filtering the extract solution, was recrystallized from ethanol and the desired title compound having a melting point of 133° C.-139° C. was obtained.
Reaction SMILES: C([O:8][C:9]1[C:17]([O:18][CH3:19])=[CH:16][C:12]([C:13]([OH:15])=[O:14])=[CH:11][C:10]=1[F:20])C1C=CC=CC=1.CO>[C].[Pd].C(OCC)(=O)C>[F:20][C:10]1[CH:11]=[C:12]([CH:16]=[C:17]([O:18][CH3:19])[C:9]=1[OH:8])[C:13]([OH:15])=[O:14]
Reactant: COc1cc(C(=O)O)cc(F)c1OCc1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: COc1cc(C(=O)O)cc(F)c1O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To 4-benzyloxy-3-fluoro-5-methoxybenzoic acid were added 20 ml of methanol, 20 ml of ethyl acetate and 50 mg of 10% palladium-carbon and the mixture was stirred at room temperature for 4 hours under hydrogen atmosphere. Then, the reaction mixture was filtered through Celite. The filtrate was concentrated under reduced pressure to obtain 4.5 g of 3-fluoro-4-hydroxy-5-methoxybenzoic acid represented by the formula:
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Br[CH2:8][C:9]1[CH:14]=[C:13]([C:15]([O:17][CH3:18])=[O:16])[CH:12]=[CH:11][C:10]=1[C:19]1[CH:24]=[C:23]([O:25][CH3:26])[CH:22]=[CH:21][C:20]=1[F:27].C([O-])([O-])=O.[Cs+].[Cs+].CCOC(C)=O>CS(C)=O>[F:27][C:20]1[CH:21]=[CH:22][C:23]([O:25][CH3:26])=[CH:24][C:19]=1[C:10]1[CH:11]=[CH:12][C:13]([C:15]([O:17][CH3:18])=[O:16])=[CH:14][C:9]=1[CH2:8][N:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C1CCNCC1
Reactant: COC(=O)c1ccc(-c2cc(OC)ccc2F)c(CBr)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: COC(=O)c1ccc(-c2cc(OC)ccc2F)c(CN2CCCCC2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 76 %

Procedure:
Piperidine (commercially available from Aldrich) (0.038 g, 0.44 mmol) was added to a solution of 66.63B (0.13 g, 0.37 mmol) in DMSO (3 mL). Cs2CO3 (0.18 g, 0.55 mmol) was then added to the reaction and it was stirred at room temperature for 1 hour. EtOAc (100 mL) was added and the organic phase was washed with water and brine and dried over anhydrous sodium sulfate. After removing solvent, the residue was purified by flash chromatography (silica gel, 1:1 EtOAc/DCM) and gave 66.64A (100 mg) in 76% yield. MS ESI (pos.) m/e: 358 (M+H)+.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[C:8]([C@@H:14]3[CH2:18][NH:17][CH2:16][C@:15]3([CH2:20][OH:21])[CH3:19])[CH:9]=[CH:10][C:11]=2[O:12][CH3:13])[CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.[CH2:31]([O:38][CH2:39][C:40](Cl)=[O:41])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.[Li+].[OH-]>O>[CH2:31]([O:38][CH2:39][C:40]([N:17]1[CH2:18][C@@H:14]([C:8]2[CH:9]=[CH:10][C:11]([O:12][CH3:13])=[C:6]([O:5][CH2:4][CH:1]3[CH2:3][CH2:2]3)[CH:7]=2)[C@@:15]([CH2:20][OH:21])([CH3:19])[CH2:16]1)=[O:41])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: O=C(Cl)COCc1ccccc1
Reactant: COc1ccc([C@@H]2CNC[C@@]2(C)CO)cc1OCC1CC1
Agent: [Li+]
Agent: [OH-]
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: COc1ccc([C@@H]2CN(C(=O)COCc3ccccc3)C[C@@]2(C)CO)cc1OCC1CC1
Temperature: 0 °C
Reaction time: 18 h

Procedure:
[4-(S)-(3-Cyclopropylmethoxy-4-methoxyphenyl)-3-(S)-methylpyrrolidin-3-yl]methanol (100 mg, 0.34 mmol) was dissolved in CH2C2 (1.7 mL), and the solution was cooled to 0° C. DIEA (144 μL, 0.82 mmol) was added, followed by benzyloxyacetyl chloride (114 μL, 0.72 mmol). The reaction was allowed to warm to room temperature slowly and stirred for 18 hours. Water was added (0.25 mL) and the reaction was stirred for 1.5 hours. CH2C2 was added and the mixture was washed once with water, twice with 1N HCl, once with water, twice with 6% NaHCO3, then dried over Na2SO4 and concentrated in vacuo. The residue was dissolved in THF (1 mL) and cooled to 0° C. A solution of LiOH in water (1.36M, 1 mL, 1.36 mmol) was added and the hydrolysis was allowed to proceed at 0° C. for 4 hours. The reaction mixture was quenched with saturated NH4Cl, and the THF was removed by concentration in vacuo. The residue was resuspended in CH2C2, and washed twice with 6%. NaHCO3, dried over Na2SO4 and concentrated in vacuo.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:9]2[C:14]3[S:15](=[O:19])(=[O:18])[CH2:16][CH2:17][C:13]=3[NH:12][C:11]3[CH2:20][O:21][CH2:22][C:23](=[O:24])[C:10]2=3)[CH:5]=[CH:6][C:7]=1[F:8].CC(C)([O-])C.[K+].Cl[C:32]([O:34][CH:35]1[CH:40]([C:41]([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)([CH3:43])[CH3:42])[CH2:39][CH2:38][CH:37]([CH3:50])[CH2:36]1)=[O:33].C1(C(C)(C)C2CCC(C)CC2O)C=CC=CC=1>C1COCC1.C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([CH:9]2[C:14]3[S:15](=[O:18])(=[O:19])[CH2:16][CH2:17][C:13]=3[N:12]([C:32]([O:34][C@@H:35]3[CH2:36][C@H:37]([CH3:50])[CH2:38][CH2:39][C@H:40]3[C:41]([CH3:42])([C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)[CH3:43])=[O:33])[C:11]3[CH2:20][O:21][CH2:22][C:23](=[O:24])[C:10]2=3)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: O=C1COCC2=C1C(c1ccc(F)c(Br)c1)C1=C(CCS1(=O)=O)N2
Reactant: CC1CCC(C(C)(C)c2ccccc2)C(OC(=O)Cl)C1
Agent: CC(C)(C)[O-]
Agent: CC1CCC(C(C)(C)c2ccccc2)C(O)C1
Agent: [K+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: C[C@@H]1CC[C@@H](C(C)(C)c2ccccc2)[C@H](OC(=O)N2C3=C(C(=O)COC3)C(c3ccc(F)c(Br)c3)C3=C2CCS3(=O)=O)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of the product from Example 11D (1.58 g, 3.7 mmol) in THF (40 mL) at 0° C. under a nitrogen atmosphere was added a 1M solution of potassium tert-butoxide in THF (4.1 mL) dropwise over 5 minutes. The mixture was stirred at ambient temperature for 30 minutes, cooled to 0° C., treated with a solution of 8-phenylmenthol chloroformate prepared from (−)-8-phenylmenthol as described in (Yamamoto, Y., J. Amer. Chem. Soc. (1992), 114, 121-125) (1.31 g, 4.4 mmol) in THF (20 mL) over 5 minutes, stirred at ambient temperature for 16 hours, diluted with methylene chloride (150 mL) and washed with aqueous sodium bicarbonate (30 mL). The layers were separated and the aqueous layer was extracted with methylene chloride (50 mL). The combined organic layers were dried (MgSO4), filtered and concentrated. The residue was purified by flash chromatography over silica gel (3:2:1 chloroform/hexanes/diethyl ether) to provide 0.98 g of the less polar diasteriomer.
Reaction SMILES: [C:1]1([CH3:17])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10][CH2:9][NH:8]1.[C:18]([O:22][C:23](=[O:27])[C@H:24](Br)[CH3:25])([CH3:21])([CH3:20])[CH3:19]>C(#N)C.C(OCC)(=O)C.C(=O)(O)[O-].[Na+]>[C:18]([O:22][C:23](=[O:27])[C@@H:24]([N:8]1[CH2:9][CH2:10][C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:7]1[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=1[CH3:17])[CH3:25])([CH3:21])([CH3:20])[CH3:19]
Reactant: Cc1ccccc1C1NCCc2ccccc21
Reactant: C[C@@H](Br)C(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: Cc1ccccc1C1c2ccccc2CCN1[C@@H](C)C(=O)OC(C)(C)C
Temperature: 85 °C
Reaction time: 16 h

Procedure:
Racemic 1-o-tolyl-3,4-dihydro-1H-isoquinoline (0.67 g, 3.00 mmol) is added to a solution of (R)-(+)-2-bromo-propionic acid tert-butyl ester (0.50 g, 2.39 mmol) in acetonitrile (10 mL) and the mixture was stirred at 85° C. for 16 hours. After cooling to room temperature the reaction is diluted with ethyl acetate (100 mL) and saturated sodium bicarbonate (100 mL) and the organic layer isolated, washed with water (2×100 mL), brine (1×100 mL), and dried over magnesium sulfate. Filtration and concentration are followed by flash chromatography on SiO2 using 40:1 hexane:ethyl ether to afford 2-(S)-(1-o-tolyl-3,4-dihydro-1H-isoquinolin-2-yl)-propionic acid tert-butyl ester as a colorless syrup. C. 2-(S)-[1-(S)-o-tolyl-3,4-dihydro-1H-isoquinolin-2-yl]-propionic acid
Reaction SMILES: C(O)(=O)C.[Br:5][C:6]1[CH:11]=[C:10]([CH3:12])[CH:9]=[CH:8][N:7]=1.[Br:13]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:5][C:6]1[CH:11]=[C:10]([CH2:12][Br:13])[CH:9]=[CH:8][N:7]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccnc(Br)c1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: CC(=O)O
Solvent: ClC(Cl)(Cl)Cl
Product: BrCc1ccnc(Br)c1
Temperature: 50 °C
Yield: 28.3 %

Procedure:
0.073 ml of acetic acid is added to a solution of 0.172 g of 2-bromo-4-methylpyridine in 2.5 ml of carbon tetrachloride, under an inert atmosphere of argon at a temperature in the region of 20° C. The mixture brought, with stirring, to a temperature of 50° C. 0.356 g of N-bromosuccinimide and 0.048 g of benzoyl peroxide are added successively at this temperature. The mixture is maintained at 80° C. for about 18 hours. After cooling, the reaction medium is placed on a cartridge 20 mm in diameter packed with 10 g of 20-40 μm silica not conditioned beforehand, and then eluted with dichloromethane at a flow rate of 5 ml/minute. The fractions between 30 and 40 ml are concentrated to dryness under reduced pressure. 0.071 g of 2-bromo-4-(bromomethyl)pyridine is thus obtained.
Reaction SMILES: [C:1]([C:5]1[CH:15]=[CH:14][C:8]([O:9][CH2:10][C:11]([OH:13])=O)=[CH:7][C:6]=1[O:16][CH2:17][CH2:18][O:19][CH3:20])([CH3:4])([CH3:3])[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.Cl.[NH2:34][CH2:35][C:36]1[CH:41]=[CH:40][C:39]([NH:42][S:43]([CH3:46])(=[O:45])=[O:44])=[C:38]([F:47])[CH:37]=1.C(N(CC)CC)C>O1CCCC1>[C:1]([C:5]1[CH:15]=[CH:14][C:8]([O:9][CH2:10][C:11]([NH:34][CH2:35][C:36]2[CH:41]=[CH:40][C:39]([NH:42][S:43]([CH3:46])(=[O:45])=[O:44])=[C:38]([F:47])[CH:37]=2)=[O:13])=[CH:7][C:6]=1[O:16][CH2:17][CH2:18][O:19][CH3:20])([CH3:2])([CH3:3])[CH3:4]
Reactant: COCCOc1cc(OCC(=O)O)ccc1C(C)(C)C
Reactant: CS(=O)(=O)Nc1ccc(CN)cc1F
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COCCOc1cc(OCC(=O)NCc2ccc(NS(C)(=O)=O)c(F)c2)ccc1C(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 46.2 %

Procedure:
To a tetrahydrofuran (THF) (3 ml) solution of [4-tert-butyl-3-(2-methoxyethoxy)phenoxy]acetic acid (100 mg, 0.35 mmol) was added 1,1′-carbonyl-diimidazole (63 mg, 0.39 mmol) and the mixture was stirred for 1 hour at ambient temperature. To the mixture was added N-[4-(aminomethyl)-2-fluorophenyl]methanesulfonamide hydrochloride (99 mg, 0.39 mmol) and triethyl amine (150 ul, 1.1 mmol) and the mixture was stirred for 1 hour at ambient temperature. After filtration to separate solvent and the resulting percipitate, the solvent was removed under reduced pressure to give a residue, which was applied to a silica gel chromatography column and eluted with ethyl acetate/hexane=1/1 to furnish 78 mg (46% yield) of the title compound as a white solid.