Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[N:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C:20]3[CH:21]=[C:22]([NH:26][CH2:27][CH:28]4[CH2:32][CH2:31][CH2:30][N:29]4[C:33]([O:35]C(C)(C)C)=O)[CH:23]=[CH:24][CH:25]=3)[CH2:14][CH2:13]2)[N:3]=1.Cl.ClC(Cl)(OC(=O)OC(Cl)(Cl)Cl)Cl.C(NC(C)C)(C)C>CO.CCOCC>[CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[N:12]2[CH2:13][CH2:14][N:15]([CH2:18][CH2:19][C:20]3[CH:21]=[C:22]([N:26]4[CH2:27][C@H:28]5[CH2:32][CH2:31][CH2:30][N:29]5[C:33]4=[O:35])[CH:23]=[CH:24][CH:25]=3)[CH2:16][CH2:17]2)[N:3]=1
Reactant: Cc1ccc2c(N3CCN(CCc4cccc(NCC5CCCN5C(=O)OC(C)(C)C)c4)CC3)cccc2n1
Agent: Cl
Agent: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CO
Solvent: CC(C)NC(C)C
Solvent: CCOCC
Product: Cc1ccc2c(N3CCN(CCc4cccc(N5C[C@H]6CCCN6C5=O)c4)CC3)cccc2n1
Reaction time: 0.5 h

Procedure:
A solution of (R)-(1,1-dimethylethyl 2-{[(3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}phenyl)amino]methyl}-1-pyrrolidinecarboxylate in methanol was treated with a solution of hydrogen chloride in ether (1 M). The resulting mixture was stirred 30 minutes then concentrated under vacuum and then loaded onto an ion-exchange cartridge (SCX-2) and eluted with methanol followed by ammonia in methanol (1 M). The combined basic fractions were concentrated under vacuum. The residue, (10 mg) was then dissolved in DCM (1 mL) and treated with triphosgene (23 mg, 0.3 eq.), diisopropylamine (4 uL, 3 eq.). The mixture was stirred for 1 h then concentrated under vacuum and purified by preparative mass-directed hplc to afford the title compound (3.1 mg).
Reaction SMILES: [NH4+].[C:2]([C:4](=[CH2:10])[CH2:5][CH2:6][C:7]([O-:9])=[O:8])#[N:3].Cl>>[C:2]([C:4](=[CH2:10])[CH2:5][CH2:6][C:7]([OH:9])=[O:8])#[N:3]
Reactant: C=C(C#N)CCC(=O)[O-]
Agent: Cl
Agent: [NH4+]
Product: C=C(C#N)CCC(=O)O
Temperature: -78 °C
Yield: 60 %

Procedure:
A 100-mL portion of the filtrate containing the 4-cyano-4-pentenoic acid ammonium salt product mixture described above was adjusted to pH 2.7 with 6N HCl, then saturated with sodium chloride and extracted with 4×100 mL of ethyl ether. The combined organic extracts were dried over magnesium sulfate, filtered, and the volume of the combined extracts reduced to 100 mL by rotary evaporation at reduced pressure at 28° C. To the ether solution was added 200 mL of hexane, and the resulting solution cooled to -78° C. The resulting white solid which crystallized was isolated by rapid vacuum filtration and washing with 100 mL of cold (5° C.) hexane. Residual solvent was removed under high vacuum (150 millitorr) to yield 9.80 g (60% isolated yield) of 4-cyano-4-pentenoic acid (m.p. 26.5°-27.0° C., stored at -20° C.).
Reaction SMILES: C[O:2][CH2:3][CH2:4][O:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][O:20][CH2:21][CH2:22][O:23][CH2:24][CH2:25][O:26][CH2:27][CH2:28][O:29][CH2:30]C1C=CC=CC=1>C(O)C.[Pd]>[CH3:30][O:29][CH2:28][CH2:27][O:26][CH2:25][CH2:24][O:23][CH2:22][CH2:21][O:20][CH2:19][CH2:18][O:17][CH2:16][CH2:15][O:14][CH2:13][CH2:12][O:11][CH2:10][CH2:9][O:8][CH2:7][CH2:6][O:5][CH2:4][CH2:3][OH:2]
Reactant: COCCOCCOCCOCCOCCOCCOCCOCCOCCOCc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: COCCOCCOCCOCCOCCOCCOCCOCCOCCO
Yield: 98.8 %

Procedure:
A solution of nonaethylene glycol benzyl methyl ether (10 g, 19.3 mmol) in ethanol (200 mL) was shaken with 10% palladium on activated charcal (Aldrich, 1.0 g) under hydrogen (50 psi) on a Parr apparatus for 3 h. The catalyst was filtered off (Celite), and the filtrate was concentrated in vacuo and dried by evaporation of toluene to provide nonaethylene glycol monomethyl ether as an oil (8.17 g, 99%). 1H-NMR (300 MHz, DMSO-d6) δ: 4.56 (t, 1H OH), 3.60-3.35 (m, 36H, 18 OCH2), 3.22 (s, 3H, CH3).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[NH:6][C:7]3[C:12]([C:13]=2[CH:14]=1)=[CH:11][CH:10]=[CH:9][CH:8]=3.C1([C:21]2[C:33]3[NH:32][C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[C:25]=3[CH:24]=[C:23](B(O)O)[CH:22]=2)C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(COC)OC>[C:2]1([N:6]2[C:5]3[CH:4]=[CH:3][C:2]([C:23]4[CH:22]=[CH:21][C:33]5[NH:32][C:31]6[C:26]([C:25]=5[CH:24]=4)=[CH:27][CH:28]=[CH:29][CH:30]=6)=[CH:14][C:13]=3[C:12]3[C:7]2=[CH:8][CH:9]=[CH:10][CH:11]=3)[CH:3]=[CH:4][CH:5]=[CH:13][CH:14]=1
Reactant: Brc1ccc2[nH]c3ccccc3c2c1
Reactant: OB(O)c1cc(-c2ccccc2)c2[nH]c3ccccc3c2c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: COCCOC
Product: c1ccc(-n2c3ccccc3c3cc(-c4ccc5[nH]c6ccccc6c5c4)ccc32)cc1
Temperature: 25 °C
Yield: 77.8 %

Procedure:
A mixed solution of 20.9 g of 3-bromocarbazole, 15.0 g of phenylcarbazole-3-boronic acid, 366 mg of palladium acetate, 300 mg of tris(2-methylphenyl)phosphine, 105 ml of a 2M aqueous potassium carbonate solution and 260 ml of dimethoxyethane was refluxed for 6 hours under a nitrogen flow. The solution was cooled to room temperature, and then extracted with 500 ml of toluene. The organic layer was washed with 100 ml of water twice, dried over magnesium sulfate, and then evaporated. The resultant concentrate was purified by silica gel column chromatography and then vacuum-dried to obtain 13.5 g of 9-phenyl-9H,9′H-3,3′-bicarbazole.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:4][C:3]=1[CH2:15][NH:16][C:17]1[C:18]([F:32])=[C:19]([CH:28]=[CH:29][C:30]=1[F:31])[O:20][CH2:21][C:22]([O:24]C(C)C)=[O:23].[Li+].[OH-].O>C1COCC1>[CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:4][C:3]=1[CH2:15][NH:16][C:17]1[C:18]([F:32])=[C:19]([CH:28]=[CH:29][C:30]=1[F:31])[O:20][CH2:21][C:22]([OH:24])=[O:23]
Reactant: Cc1cc(-c2ccccc2)cc(CNc2c(F)ccc(OCC(=O)OC(C)C)c2F)c1C
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(-c2ccccc2)cc(CNc2c(F)ccc(OCC(=O)O)c2F)c1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 80.5 %

Procedure:
To a solution of isopropyl 2-[3-[(2,3-dimethyl-5-phenyl-phenyl)methylamino]-2,4-difluoro-phenoxy]acetate (110 mg, 0.25 mmol, 1.0 eq) in THF (4 mL) was added LiOH (52 mg, 1.2 mmol, 5 eq) and water (3 mL) and the reaction mixture stirred at room temperature for 1 h. The THF was removed under reduced pressure and the remaining aqueous solution was adjusted to pH 4-5 by addition of 1M HCl. The mixture was extracted with EtOAc and the combined organic extracts washed with water and brine, dried (Na2SO4), filtered and evaporated in vacuo to give the title compound as a yellow oil (80 mg, 80%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=2)[N:9]2[CH2:14][CH2:13][N:12]([CH2:15][C:16]([O:18]C)=[O:17])[C:11](=[O:20])[CH2:10]2)=[CH:4][CH:3]=1.O.[OH-].[Li+]>C1COCC1.CO.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([C:21]2[CH:22]=[CH:23][C:24]([Cl:27])=[CH:25][CH:26]=2)[N:9]2[CH2:14][CH2:13][N:12]([CH2:15][C:16]([OH:18])=[O:17])[C:11](=[O:20])[CH2:10]2)=[CH:6][CH:7]=1
Reactant: COC(=O)CN1CCN(C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)CC1=O
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)CN1CCN(C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)CC1=O
Reaction time: 8 h
Yield: 88 %

Procedure:
To a solution of methyl 2-(4-(bis(4-chlorophenyl)methyl)-2-oxopiperazin-1-yl)acetate (160 mg, 393 μmol) in THF/MeOH/H2O=5:5:1 (5.5 mL) was added lithium hydroxide monohydrate (49.5 mg, 1.179 mmol) and the resulting solution was stirred overnight. The solvent was evaporated, diluted with water, adjusted to pH=5 with 10% HCl, extracted with DCM, dried over Na2SO4, filtered and evaporated to dryness under high vacuum. The residue was loaded onto flash column (SiO2, DCM to DCM/MeOH=100:5 to 100:10 to 100:15 to 100:20) to give 2-(4-(bis(4-chlorophenyl)methyl)-2-oxopiperazin-1-yl)acetic acid (136 mg) as a white solid.
Reaction SMILES: OS(O)(=O)=O.[CH3:6][C:7](=[CH2:9])[CH3:8].[CH2:10]([O:17][C:18]([NH:20][C:21](=[O:27])[C@@H:22]([C@H:24]([CH3:26])[OH:25])[NH2:23])=[O:19])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(=O)=O.CC(C)=O>C(Cl)Cl>[CH2:10]([O:17][C:18]([NH:20][C:21](=[O:27])[C@@H:22]([C@H:24]([CH3:26])[O:25][C:7]([CH3:9])([CH3:8])[CH3:6])[NH2:23])=[O:19])[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: C=C(C)C
Reactant: C[C@H](O)[C@@H](N)C(=O)NC(=O)OCc1ccccc1
Agent: O=C=O
Agent: O=S(=O)(O)O
Solvent: ClCCl
Solvent: CC(C)=O
Product: C[C@H](OC(C)(C)C)[C@@H](N)C(=O)NC(=O)OCc1ccccc1
Reaction time: 96 h
Yield: 90.3 %

Procedure:
Concentrated H2SO4 (0.1 ml) and isobutylene (35 ml, 390 mmol) are added to a suspension of N-benzyloxycarbonyl-D-threonineamide (4.2 g, 16.6 mmol) in methylene chloride (35 ml) kept in a pressure resistant vessel cooled with dry ice/acetone. The reaction vessel is sealed and the temperature is allowed to raise up to the room value. After 4 days, excess isobutylene is evaporated off and the organic solution is washed with aqueous 5% Na2CO3 (3×30 ml), 5% citric acid (20 ml) and then with water up to pH 6. The organic phase is dried over MgSO4 and concentrated to dryness yielding the compound of the title as a clear oil (4.62 g, 90%).
Reaction SMILES: FC1C=CC(S([N:11]([S:17]([C:20]2[CH:25]=[CH:24][C:23]([N:26]3[CH2:30][CH2:29][C@@H:28](O)[C:27]3=[O:32])=[CH:22][CH:21]=2)(=[O:19])=[O:18])[C:12]2[S:13][CH:14]=[CH:15][N:16]=2)(=O)=O)=CC=1.CCN(C(C)C)C(C)C.S(OS(C(F)(F)F)(=O)=O)(C(F)(F)F)(=O)=O.[Cl:57][C:58]1[CH:63]=[CH:62][C:61]([CH:64]2[CH2:68][CH2:67][NH:66][CH2:65]2)=[CH:60][C:59]=1[CH3:69].N1CCOCC1.C([O-])(O)=O.[Na+]>C(Cl)Cl>[Cl:57][C:58]1[CH:63]=[CH:62][C:61]([CH:64]2[CH2:68][CH2:67][N:66]([C@H:28]3[CH2:29][CH2:30][N:26]([C:23]4[CH:22]=[CH:21][C:20]([S:17]([NH:11][C:12]5[S:13][CH:14]=[CH:15][N:16]=5)(=[O:19])=[O:18])=[CH:25][CH:24]=4)[C:27]3=[O:32])[CH2:65]2)=[CH:60][C:59]=1[CH3:69]
Reactant: Cc1cc(C2CCNC2)ccc1Cl
Reactant: O=C1[C@H](O)CCN1c1ccc(S(=O)(=O)N(c2nccs2)S(=O)(=O)c2ccc(F)cc2)cc1
Agent: O=C([O-])O
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCN1
Solvent: ClCCl
Product: Cc1cc(C2CCN([C@H]3CCN(c4ccc(S(=O)(=O)Nc5nccs5)cc4)C3=O)C2)ccc1Cl
Temperature: -20 °C
Reaction time: 1 h
Yield: 73.3 %

Procedure:
Synthesized according to General Procedure 9. To a stirred suspension of [(R)-4-fluoro-N-(4-(3-hydroxy-2-oxopyrrolidin-1-yl)phenylsulfonyl]-N-(thiazol-2-yl)benzenesulfonamide (500 mg, 1.01 mmol) in anhydrous DCM (10 mL) under nitrogen at −20° C. was added DIEA (0.88 mL, 5.03 mmol) followed by the dropwise addition of triflic anhydride (0.22 mL, 1.31 mmol) over 5 min. After stirring for 15 minutes at −20° C. a solution of 3-(4-chloro-3-methylphenyl)pyrrolidine (197 mg, 1.01 mmol) in anhydrous DCM (1 mL) was added dropwise over 5 minutes. The reaction mixture was continued to stir at −20° C. for 1 hour. Morpholine (0.35 mL, 4.02 mmol) was added and the reaction mixture was stirred at −20° C. for 1.5 hours. The reaction mixture was then poured into saturated aqueous NaHCO3 (10 mL), DCM (5 mL) was added and the phases were separated. The aqueous phase was extracted with DCM (5 mL). The organic portions were combined and washed with saturated aqueous NaHCO3 (5×5 ml). The organic layer was washed with brine (5 mL), dried over MgSO4 and absorbed onto Celite. Purification by silica gel column chromatography (1-5% MeOH in DCM) afforded 4-[(3′S)-3-(4-chloro-3-methylphenyl]-2′-oxo-1,3′-bipyrrolidin-1′-yl)-N-(thiazol-2-yl)benzenesulfonamide as a white solid (385 mg, 0.74 mmol, 74% yield). LC/MS (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)), m/z: M+1 obs=517.0; tR=1.11 min.
Reaction SMILES: [CH:1]1[CH2:5][CH:4]=[CH:3][CH:2]=1.[CH3:6][C:7]([CH:10]=O)([CH3:9])[CH3:8].N1CCCC1>CO>[C:7]([C:10]1[C:2](=[CH2:3])[CH:1]=[CH:5][CH:4]=1)([CH3:9])([CH3:8])[CH3:6]
Reactant: C1=CCC=C1
Reactant: CC(C)(C)C=O
Solvent: C1CCNC1
Solvent: CO
Product: C=C1C=CC=C1C(C)(C)C

Procedure:
6,-tert-butyl-fulvene was prepared analogously by reaction of cyclopentadiene (31.7 g, 480 mmole), pivaldehyde (19.825 g, 230 mmol), and pyrrolidine (25 ml, 300 mmole) in methanol (250 ml). The yellow oil is kugel-rohr distilled at 70° C. and <1 torr yielding a bright yellow oil; 20.5 g (66.4%).
Reaction SMILES: Cl[CH2:2][N:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[N:5]=[N:4]1.O.[S-2:13].[Na+].[Na+].O>C(O)C>[N:3]1([CH2:2][S:13][CH2:2][N:3]2[C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=3[N:5]=[N:4]2)[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[N:5]=[N:4]1
Reactant: [S-2]
Reactant: ClCn1nnc2ccccc21
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: c1ccc2c(c1)nnn2CSCn1nnc2ccccc21
Temperature: 25 °C
Reaction time: 20 h
Yield: 86.5 %

Procedure:
1-(Chloromethyl)benzotriazole (20.4 g), prepared above, and sodium sulfide monohydrate (14.4 g) in anhydrous ethanol (75 ml) were stirred overnight (20 hours) at room temperature. Water (240 ml) was added to the reaction mixture. The precipitate was filtered, washed with water to remove inorganic salts and dried. Crystallization from ethanol gave 15.6 g (88%) of desired product (Compound 1); m.p. 179°-181° C. (lit. 182°-184° C.). Thin Layer Chromotography in (CHCl3 /Ethyl acetate) showed only one spot.
Reaction SMILES: [CH2:1]([O:5][C:6]([NH:8][C:9]([CH3:22])([CH3:21])[CH2:10][CH2:11][C:12]1[CH:20]=[CH:19][C:15]([C:16]([OH:18])=O)=[CH:14][CH:13]=1)=[O:7])[CH2:2][CH2:3][CH3:4].N1CCCCC1.ON1[C:34]2[CH:35]=[CH:36][CH:37]=C[C:33]=2[N:32]=[N:31]1.C(N(C(C)C)CC)(C)C.CN(CCCN=C=NCC)C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(Cl)Cl.C(OCC)(=O)C>[N:32]1([NH:31][C:16](=[O:18])[C:15]2[CH:14]=[CH:13][C:12]([CH2:11][CH2:10][C:9]([CH3:22])([NH:8][C:6]([O:5][CH2:1][CH2:2][CH2:3][CH3:4])=[O:7])[CH3:21])=[CH:20][CH:19]=2)[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1
Reactant: On1nnc2ccccc21
Reactant: CCCCOC(=O)NC(C)(C)CCc1ccc(C(=O)O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCNCC1
Product: CCCCOC(=O)NC(C)(C)CCc1ccc(C(=O)NN2CCCCC2)cc1
Reaction time: 1 h

Procedure:
To a flame dried flask under a nitrogen atmosphere was added N-butyloxycarbonyl-4-(3-methyl-3-aminobutyl)benzoic acid (500 mg), piperidine (0.161 mL, 1.0 eq.), 1-hydroxybenzotriazole (47 mg, 1.0 eq.), diisopropylethylamine (0.2 mL, 3.5 eq.), and 25 mL of methylene chloride. A solution of (dimethylaminopropyl)ethyl carbodiimide in 20 mL of methylene chloride was then added and the resulting solution was allowed to stir for 1 hour before diluting with ethyl acetate. This mixture was acidified with 10% aqueous citric acid. The organics were washed twice each with saturated aqueous sodium bicarbonate and brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was taken up in ethyl acetate and was washed twice with 10% aqueous sodium bicarbonate, once with brine, dried over sodium sulfate, filtered, and concentrated in vacuo to give the title compound.
Reaction SMILES: [Mg].C([Mg])CCC.[NH:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[CH:8]1.[N+:16]([C:19]1[CH:20]=[C:21]([CH:25]=[CH:26][CH:27]=1)[C:22](Cl)=[O:23])([O-:18])=[O:17].[Cl-].[NH4+]>C1(C)C=CC=CC=1.C(N(CC)CC)C>[N+:16]([C:19]1[CH:20]=[C:21]([CH:25]=[CH:26][CH:27]=1)[C:22]([C:9]1[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[NH:7][CH:8]=1)=[O:23])([O-:18])=[O:17]
Reactant: O=C(Cl)c1cccc([N+](=O)[O-])c1
Reactant: c1ccc2[nH]ccc2c1
Agent: CCCC[Mg]
Agent: [Cl-]
Agent: [Mg]
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: O=C(c1cccc([N+](=O)[O-])c1)c1c[nH]c2ccccc12
Temperature: 37.5 °C
Reaction time: 1 h
Yield: 80.3 %

Procedure:
Magnesium (2.08 g), toluene (40 ml), triethylamine (10.4 g) were put into a 3″ diameter flask, and the internal temperature was raised to 30 to 45° C. A solution of 1-iodebutane (18.9 g) in toluene was added under stirring at an internal temperature of 30 to 45° C. After stirring for two hours at the same temperature, the temperature was lowered to 0 to 5° C., thereby preparing a solution of iode n-butylmagnesium in toluene. To this prepared Grignard reagent, indole (10.0 g) dissolved beforehand in toluene (25 ml) was added at an internal temperature of 0 to 10° C., and a reaction was carried out for about one hour at the same temperature to synthesize iodeindole-1-ylmagnesium. Then, m-nitrobenzoyl chloride (15.8 g) and toluene (60 ml) were put into another 3″ diameter flask, and the internal temperature was lowered to below −15° C. The slurry of the iodeindole-1-ylmagnesium prepared previously was added to the solution of this acid chloride while keeping the internal temperature at −15 to −10° C., and the mixture was stirred for more one hour at the same temperature. The internal temperature was then raised further to 20 to 25° C., and the mixture was stirred for one hour. After this reaction, the mixture was added to an aqueous ammonium chloride solution (16 g, 60 ml) prepared beforehand in another 3″ diameter flask at 10° C. or less to carry out quenching. Acetone (220 ml) was added thereto, the internal temperature was raised to 50 to 65° C., and dissolution was carried out, followed by separation. The organic layer of the upper layer was then collected and cleaned with an aqueous 5% sodium hydrogencarbonate solution at the same temperature. The solvent was evaporated so as to be concentrated to about 50 ml. After cooled to an internal temperature of 2 to 10° C., a precipitated crystal was filtered. The filtered crystal was cleaned with toluene (10 ml) and dried to obtain a crystal of 3-m-nitrobenzoylindole (18.2 g) (80.0% yield).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([NH:7][C:8]2[O:9][C:10]3[C:11](=[C:13]([C:17]([OH:19])=O)[CH:14]=[CH:15][CH:16]=3)[N:12]=2)=[CH:3][CH:2]=1.Cl.Cl.[NH2:22][C@H:23]1[CH:28]2[CH2:29][CH2:30][N:25]([CH2:26][CH2:27]2)[CH2:24]1>>[N:25]12[CH2:24][C@@H:23]([NH:22][C:17]([C:13]3[CH:14]=[CH:15][CH:16]=[C:10]4[O:9][C:8]([NH:7][C:4]5[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=5)=[N:12][C:11]=34)=[O:19])[CH:28]([CH2:29][CH2:30]1)[CH2:27][CH2:26]2
Reactant: O=C(O)c1cccc2oc(Nc3ccncc3)nc12
Reactant: N[C@@H]1CN2CCC1CC2
Agent: Cl
Product: O=C(N[C@@H]1CN2CCC1CC2)c1cccc2oc(Nc3ccncc3)nc12

Procedure:
Following general procedure GP-C1, a mixture of 2-(pyridin-4-ylamino)benzoxazole-4-carboxylic acid and (S)-(−)-3-aminoquinuclidine dihydrochloride were coupled to provide (S)—N-(quinuclidine-8-yl)-2-(pyridin-4-ylamino)benzoxazole-4-carboxamide, which was converted to the dihydrochloride salt following general procedure GP-D1. 1H NMR and MS consistent.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH3:13])=[C:11]([C:14](OCC)=[O:15])[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].Cl>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:12]([CH3:13])=[C:11]([CH2:14][OH:15])[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1cnn(-c2ccc(Cl)cc2)c1C
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Product: Cc1c(CO)cnn1-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 91 %

Procedure:
To a solution of 3.2 g of ethyl 1-(4-chlorophenyl)-5-methyl-1H-pyrazole-4-carboxylate, 0.46 g of lithium aluminum hydride was added, followed by stirring for 1.5 hours at room temperature. The reaction mixture was added with a 5% aqueous solution of hydrochloric acid and then extracted with ethyl acetate. The extract was washed with an aqueous solution of sodium chloride, dried over magnesium sulfate and then filtered. The filtrate was concentrated under reduced pressure. The residue was subjected to chromatography on a silica gel column and then purified using gradient elution with hexane-ethyl acetate, whereby 2.45 g of the title compound were obtained (yield: 91%).
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH2:3][C@@H:2]1[CH2:6][O:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[C:13](=[O:17])[CH2:12][CH2:11]2.[C:18]([O:21]C(=O)C)(=[O:20])[CH3:19].C([O-])(=O)C.[Pb+2].C([O-])(=O)C.C(=O)([O-])[O-].[Na+].[Na+]>C(O)(=O)C>[O:17]=[C:13]1[C:14]2[C:10](=[CH:9][C:8]([O:7][CH2:6][C@H:2]3[CH2:3][CH2:4][CH2:5][O:1]3)=[CH:16][CH:15]=2)[CH2:11][CH:12]1[O:21][C:18](=[O:20])[CH3:19]
Reactant: O=C1CCc2cc(OC[C@H]3CCCO3)ccc21
Reactant: CC(=O)OC(C)=O
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(=O)OC1Cc2cc(OC[C@H]3CCCO3)ccc2C1=O
Temperature: 100 °C
Reaction time: 48 h

Procedure:
A mixture of 5-[(R)-1-(tetrahydrofuran-2-yl)methoxy]-indan-1-one (1.25 g), acetic anhydride (3 mL), lead acetate (3.58 g) and acetic acid (3 mL) was stirred for 48 h at 100° C. After adding sodium carbonate solution it was extracted with ether, dried over magnesium sulfate and concentrated. The residue was chromatographed on silica gel. In this way the product was obtained with molecular weight 290.32 (C16H18O5); MS (ESI): 291 (M+H+).
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[CH3:10][O:11][C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][CH:21]=1)[C:18]([OH:22])=[C:17]([C:23]1[CH:28]=[CH:27][C:26]([S:29][CH3:30])=[CH:25][CH:24]=1)[CH:16]=[CH:15]2.[H-].[Na+].C(OCC)(=O)C>CN1CCCC1=O>[CH3:10][O:11][C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][CH:21]=1)[C:18]([O:22][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1)=[C:17]([C:23]1[CH:28]=[CH:27][C:26]([S:29][CH3:30])=[CH:25][CH:24]=1)[CH:16]=[CH:15]2
Reactant: O=Cc1ccc(F)cc1
Reactant: COc1ccc2c(O)c(-c3ccc(SC)cc3)ccc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: COc1ccc2c(Oc3ccc(C=O)cc3)c(-c3ccc(SC)cc3)ccc2c1
Temperature: 25 °C
Yield: 31.9 %

Procedure:
Add 4-fluoro-benzaldehyde (2.20 mL, 20.3 mmol) to a solution of 6-methoxy-2-(4-methylsulfanyl-phenyl)-naphthalen-1-ol (3.0 g, 10.1 mmol) and 60% sodium hydride (400 mg, 10.1 mmol) in 1-methyl-2-pyrrolidinone (30 mL). Heat the reaction to 170° C. for 70 minutes, then cool to ambient temperature. Dilute the reaction with ethyl acetate (200 mL) and wash twice with 5% aqueous lithium chloride (500 mL), brine, 1N aqueous hydrochloric acid, dry with solid magnesium sulfate and chromatograph on silica gel with dichloromethane/hexane mixtures to give 1.29 g of 4-[6-methoxy-2-(4-methylsulfanyl-phenyl)-naphthalen-1-yloxy]-benzaldehyde (32%).
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH2:14][CH2:13][N:12]([C:15]3[N:20]=[CH:19][N:18]([CH2:21][C:22]4[S:23][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:25][CH:26]=4)[C:17](=[O:31])[N:16]=3)[CH2:11][CH:10]=2)O1.C([O:36][C:37]1[CH:42]=[C:41](Br)[CH:40]=[CH:39][C:38]=1[F:44])(=O)C>>[F:44][C:38]1[CH:39]=[CH:40][C:41]([C:9]2[CH2:14][CH2:13][N:12]([C:15]3[N:20]=[CH:19][N:18]([CH2:21][C:22]4[S:23][C:24]([C:27]([F:29])([F:30])[F:28])=[CH:25][CH:26]=4)[C:17](=[O:31])[N:16]=3)[CH2:11][CH:10]=2)=[CH:42][C:37]=1[OH:36]
Reactant: CC(=O)Oc1cc(Br)ccc1F
Reactant: CC1(C)OB(C2=CCN(c3ncn(Cc4ccc(C(F)(F)F)s4)c(=O)n3)CC2)OC1(C)C
Product: O=c1nc(N2CC=C(c3ccc(F)c(O)c3)CC2)ncn1Cc1ccc(C(F)(F)F)s1
Yield: 35 %

Procedure:
The synthesis was performed using a crude product obtained by synthesis using 4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridin-1(2H)-yl]-1-{[5-(t rifluoromethyl)thiophen-2-yl]methyl}-1,3,5-triazin-2(1H)-one synthesized in Reference Synthesis Example 346 and 5-bromo-2-fluorophenyl acetate in a similar manner to Reference Synthesis Example 139, in a similar manner to Reference Synthesis Example 2 (two step yield 35%).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH2:10][C:11]2[C:16]([CH3:17])=[CH:15][CH:14]=[CH:13][C:12]=2[CH3:18])[C:4]=1[CH3:19].[C-:20]#[N:21].[Na+]>CN(C=O)C.CCOC(C)=O>[CH3:18][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]([CH3:17])[C:11]=1[CH2:10][O:9][C:5]1[C:4]([CH3:19])=[C:3]([CH2:2][C:20]#[N:21])[CH:8]=[CH:7][CH:6]=1
Reactant: [C-]#N
Reactant: Cc1cccc(C)c1COc1cccc(CBr)c1C
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1cccc(C)c1COc1cccc(CC#N)c1C

Procedure:
The solution of 1-(bromomethyl)-3-(2,6-dimethylbenzyloxy)-2-methylbenzene (Step D, 4.28 g, 13.41 mmol) and NaCN (0.789 g, 16.10 mmol) in dry DMF (20 ml) was heated at 120° C. for 3 hours then cooled and diluted with EtOAc (50 ml). The organic layer was washed with water (30 ml), brine, dried over Na2SO4, filtered, concentrated, and purified by flash chromatography on a silica gel column (hex: ethyl acetate 4:1) to give the title compound.