Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:9][CH:10]1[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH:11]1[F:23].C([BH3-])#N.[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(O)C.C(O)(=O)C>[CH2:1]([NH:9][CH:10]1[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:21])([CH3:20])[CH3:22])=[O:17])[CH2:12][CH:11]1[F:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC(N)C(F)C1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCC(NCc2ccccc2)C(F)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Benzaldehyde (34.0 g, 0.321 mol) was added to a solution of tert-butyl 4-amino-3-fluoropiperidine-1-carboxylate, 2.7 (70 g, 0.32 mol) and acetic acid (10 mL) in ethanol (500 mL) and stirred for 30 min at room temperature. Sodiumcyanoborohydride (26.23 g, 0.417 mol) was added and stirred for 3 h. Reaction was quenched with saturated sodium bicarbonate solution (200 mL) and extracted with dichloromethane (2×250 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was dissolved in a minimum amount of dichloromethane (200 mL) and pH adjusted to 3-4 by adding aqueous citric acid (124 g, 0.645 mol in 1000 mL water). Layers were separated and aqueous layer was washed with dichloromethane (3×250 mL). Separated aqueous layer pH was then adjusted to 9-10 by using saturated Na2CO3 and extract with diethyl ether (2×500 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated to obtain the crude product which was purified by as light yellow oil. The residue was purified by silica gel chromatography by eluting with 10-15% EtOAc/hexane to provide the desired product tert-butyl 4-(benzylamino)-3-fluoropiperidine-1-carboxylate, 2.8 (51 g, 51.52% yield). 1HNMR (400 MHz, CDCl3): δ 7.39-7.29 (m, 5H), 4.44-4.35 (m, 0.5H), 4.32-4-10 (m, 1.5H), 3.98-3.85 (m, 2H), 3.80 (d, 1H), 2.97-2.77 (m, 4H), 2.04-1.93 (m, 1H), 1.46 (s, 9H); LCMS: 92.34%, m/z=309.2 (M+1); HPLC: 95.46%; Chiral HPLC: 47.2% at 9.56 min. and 48.3% at 12.34 min. Column. AG/Chiral Pak AD-H/03, n-Hexane/EtOH (80:20).
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]([C:6]2[CH:11]=[C:10]([CH2:12][CH3:13])[C:9]([NH:14]C(=O)C)=[CH:8][CH:7]=2)=[CH:4][CH:3]=1.Cl>O1CCOCC1>[Cl:1][C:2]1[CH:19]=[CH:18][C:5]([C:6]2[CH:11]=[C:10]([CH2:12][CH3:13])[C:9]([NH2:14])=[CH:8][CH:7]=2)=[CH:4][CH:3]=1
Reactant: CCc1cc(-c2ccc(Cl)cc2)ccc1NC(C)=O
Agent: Cl
Solvent: C1COCCO1
Product: CCc1cc(-c2ccc(Cl)cc2)ccc1N
Yield: 97.1 %

Procedure:
To a solution of N-(4′-chloro-3-ethylbiphen-4-yl)acetamide (18 g, 0.06 mol) in dioxane (126 ml), is added concentrated hydrochloric acid (36 ml) and the reaction mixture is refluxed for 2 hours. The dioxane is evaporated under reduced pressure. The residue is diluted with water, the solution made basic by addition of 2N aqueous potassium hydroxide solution and extracted with ethyl acetate (3×500 ml). The organic extracts are combined and concentrated under reduced pressure to give 4′-chloro-3-ethylbiphen-4-ylamine (13.5 g).
Reaction SMILES: [Br:1][C:2]1[C:3]([N:18]2[CH2:23][CH2:22][CH:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:20][CH2:19]2)=[C:4]([C@H:10]([OH:17])[C:11]([O:13][CH:14]([CH3:16])[CH3:15])=[O:12])[C:5]([CH3:9])=[N:6][C:7]=1[CH3:8]>C(Cl)Cl>[Br:1][C:2]1[C:3]([N:18]2[CH2:23][CH2:22][CH:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:20][CH2:19]2)=[C:4]([C@H:10]([O:17][C:4]([CH3:10])([CH3:5])[CH3:3])[C:11]([O:13][CH:14]([CH3:16])[CH3:15])=[O:12])[C:5]([CH3:9])=[N:6][C:7]=1[CH3:8]
Reactant: Cc1nc(C)c([C@H](O)C(=O)OC(C)C)c(N2CCC(c3ccccc3)CC2)c1Br
Solvent: ClCCl
Product: Cc1nc(C)c([C@H](OC(C)(C)C)C(=O)OC(C)C)c(N2CCC(c3ccccc3)CC2)c1Br
Temperature: 25 °C
Reaction time: 18 h
Yield: 249.9 %

Procedure:
The isobutylene gas was bubbled into a nitrogen purged, cooled (0° C.) solution of (S)-isopropyl 2-(5-bromo-2,6-dimethyl-4-(4-phenylpiperidin-1-yl)pyridin-3-yl)-2-hydroxyacetate (1.95 g, 1.5 mmol) and 0.6 mL of 70% HClO4 in DCM (25 mL) for 20 min. The reaction mixture was allowed to warm to rt and stirred for 18 h in a pressure sealed vessel, diluted with DCM, washed with 1M Na2CO3 solution, and dried over MgSO4. The crude product was charged (DCM) to a 80 g ISCO silica gel cartridge and gradient elution (5-50% EtOAc/hexanes) using an Isolera chromatography station gave (S)-isopropyl 2-(5-bromo-2,6-dimethyl-4-(4-phenylpiperidin-1-yl)pyridin-3-yl)-2-(tert-butoxy)acetate 970 mg (44.4%) as a mixture of diastereomers. 1H NMR (500 MHz, DMSO-d6) δ 7.36-7.33 (m, 2H), 7.29-7.28 (m, 2H), 7.23-7.20 (m, 1H), 6.26 (s, 1H), 4.95-4.90 (m, 1H), 3.98 (br. s, 1H), 3.41 (br. s, 1H), 3.12 (br. s, 1H), 2.98 (br. s, 1H), 2.71 (br. s, 1H), 2.51 (s, 3H), 2.44 (s, 3H), 1.93 (br. s, 1H), 1.82-1.75 (m, 3H), 1.18 (s, 9H), 1.15 (d, J=6.2 Hz, 3H), 1.07 (d, J=5.9 Hz, 3H). UPLC (M+H)=519.2.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:10])[CH3:9])=[CH:4][CH:3]=1.N1C=CN=C1.[CH3:16][C:17]([Si:20](Cl)([CH3:22])[CH3:21])([CH3:19])[CH3:18]>CN(C=O)C.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([O:10][Si:20]([C:17]([CH3:19])([CH3:18])[CH3:16])([CH3:22])[CH3:21])[CH3:9])=[CH:4][CH:3]=1
Reactant: CC(O)c1ccc(Br)cc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: CC(O[Si](C)(C)C(C)(C)C)c1ccc(Br)cc1
Reaction time: 8 h
Yield: 92.9 %

Procedure:
To a solution of 1-(4-bromophenyl)ethan-1-ol (2.8 g, 13.93 mmol) and imidazole (2.84 g, 41.79 mmol) in DMF (35 mL) was added TBDMSCl (4.18 g, 27.86 mmol) at r.t., and the reaction was stirred overnight. The reaction was diluted with water (70 mL) and extracted with EtOAc (50 mL×3). Organics were washed with brine (50 mL), dried (Na2SO4), and concentrated. The residue was purified by silica gel chromatography (PE:EtOAc=100:1) to give 4.08 g (95%) of the title compound as a colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([S:8]([CH3:11])(=[O:10])=[O:9])[CH:5]=[C:4]([F:12])[C:3]=1[NH:13][C@H:14]1[CH2:19][CH2:18][CH2:17][N:16]([CH:20]2[CH2:25][CH2:24][N:23](C(OC(C)(C)C)=O)[CH2:22][CH2:21]2)[C:15]1=[O:33].Cl.C(Cl)[Cl:36]>CO>[ClH:36].[F:12][C:4]1[CH:5]=[C:6]([S:8]([CH3:11])(=[O:10])=[O:9])[CH:7]=[C:2]([F:1])[C:3]=1[NH:13][C@H:14]1[CH2:19][CH2:18][CH2:17][N:16]([CH:20]2[CH2:21][CH2:22][NH:23][CH2:24][CH2:25]2)[C:15]1=[O:33]
Reactant: ClCCl
Reactant: CC(C)(C)OC(=O)N1CCC(N2CCC[C@H](Nc3c(F)cc(S(C)(=O)=O)cc3F)C2=O)CC1
Agent: Cl
Solvent: CO
Product: CS(=O)(=O)c1cc(F)c(N[C@H]2CCCN(C3CCNCC3)C2=O)c(F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.5 %

Procedure:
A flask was charged with (S)-tert-butyl 3-(2,6-difluoro-4-(methylsulfonyl)phenylamino)-2-oxo-1,4′-bipiperidine-1′-carboxylate (1.2 g, 2.46 mmol), HCl (6.15 mL, 24.6 mmol), DCM (25 mL), and methanol (1 mL). The reaction mixture was stirred at ambient temperature overnight. The organic solvents were removed under reduced pressure to afford (S)-3-(2,6-difluoro-4-(methylsulfonyl)phenylamino)-[1,4′-bipiperidin]-2-one hydrochloride (0.986 g, 94.5% yield). Mass spectrum (apci) m/z=388.2 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:3]=1[NH:4][C:5](=[O:9])[CH2:6][C:7]#[N:8].CO[CH:17](OC)[N:18]([CH3:20])[CH3:19]>>[C:7]([C:6](=[CH:17][N:18]([CH3:20])[CH3:19])[C:5]([NH:4][C:3]1[CH:10]=[C:11]([Cl:14])[CH:12]=[CH:13][C:2]=1[Cl:1])=[O:9])#[N:8]
Reactant: N#CCC(=O)Nc1cc(Cl)ccc1Cl
Reactant: COC(OC)N(C)C
Product: CN(C)C=C(C#N)C(=O)Nc1cc(Cl)ccc1Cl

Procedure:
As for Example 1, 2',5'-dichloro-2-cyanoacetanilide, as a white crystalline product, m.p. 190.5°-191.5° C. (prepared by the procedure described in U.S. Pat. No. 3,116,312), is heated with N,N-dimethylformamide dimethylacetal to yield 2-cyano-2',5'-dichloro-3-dimethylaminoacrylanilide as colorless needles, m.p. 175°-176° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[NH:7][CH:8]([C:10]1[CH:15]=[CH:14][C:13](Br)=[CH:12][CH:11]=1)[CH3:9])([CH3:4])([CH3:3])[CH3:2].CN(C1CCCCC1)C1CCCCC1.C(P(C(C)(C)C)C(C)(C)C)(C)(C)C.[C:45]([O:49][CH2:50][CH3:51])(=[O:48])[CH:46]=[CH2:47]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O.O1CCOCC1>[CH2:50]([O:49][C:45](=[O:48])[CH:46]=[CH:47][C:13]1[CH:14]=[CH:15][C:10]([CH:8]([NH:7][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:17])[CH3:9])=[CH:11][CH:12]=1)[CH3:51]
Reactant: C=CC(=O)OCC
Reactant: CC(NC(=O)OC(C)(C)C)c1ccc(Br)cc1
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: CN(C1CCCCC1)C1CCCCC1
Solvent: O
Solvent: C1COCCO1
Product: CCOC(=O)C=Cc1ccc(C(C)NC(=O)OC(C)(C)C)cc1
Temperature: 80 °C

Procedure:
To a mixture of [1-(4-bromo-phenyl)-ethyl]-carbamic acid tert-butyl ester (3.0 g, 10 mmol), tris(dibenzylideneacetone)dipalladium (0.55 g, 0.6 mmol), and N -methyldicyclohexylamine (2.1 mL, 10 mmol) was purged nitrogen followed by the addition of 1,4-dioxane (20 mL) and tri-tert-butylphospine (0.24 g, 1.2 mmol). The mixture was again purged with nitrogen and the ethyl acrylate (2.16 mL, 20 mmol) was added. The mixture was heated to 80° C. for 30 min, poured into water (100 mL) and extracted with ethyl acetate (150 mL). The organic layer was separated, washed again with water, dried over magnesium sulfate, concentrated and chromatographed on silica gel using 2:1 hexanes/ethyl acetate to afford a light-brown oil. M+1=320.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]([C:12]2[CH:17]=[CH:16][C:15]([NH:18][C:19](=[O:21])[CH3:20])=[CH:14][C:13]=2[CH3:22])=[O:11])=[CH:4][C:3]=1[CH3:23].[O:24]1[CH:29]=[CH:28][CH2:27][CH2:26][CH2:25]1>C(Cl)Cl>[CH3:22][C:13]1[CH:14]=[C:15]([NH:18][C:19](=[O:21])[CH3:20])[CH:16]=[CH:17][C:12]=1[C:10](=[O:11])/[CH:9]=[CH:8]/[C:5]1[CH:6]=[CH:7][C:2]([O:1][CH:25]2[CH2:26][CH2:27][CH2:28][CH2:29][O:24]2)=[C:3]([CH3:23])[CH:4]=1
Reactant: CC(=O)Nc1ccc(C(=O)/C=C/c2ccc(O)c(C)c2)c(C)c1
Reactant: C1=COCCC1
Solvent: ClCCl
Product: CC(=O)Nc1ccc(C(=O)/C=C/c2ccc(OC3CCCCO3)c(C)c2)c(C)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 63.5 %

Procedure:
To a solution of (E)-N-(4-(3-(4-hydroxy-3-methylphenyl)acryloyl)-3-methylphenyl)acetamide (100 mg, 0.32 mmol) in DCM was added 300 mg of H2SO4/SiO2 (cat. amount), and 3,4-dihydro-2H-pyran (500 mg, 5.9 mmol). The reaction mixture was stirred for 1 h at room temperature. The resulting slurry was filtered, concentrated under reduced pressure, and the product was purified by column chromatography (EtOAc/Hex, 10% to 50% gradient), resulting in 80 mg (78%) of the title compound. MS (EI) for C24H27NO4: 394 (MH+).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([N:8]2[CH2:13][C@H:12]([CH3:14])[NH:11][C@H:10]([CH3:15])[CH2:9]2)[CH:5]=[CH:4][N:3]=1.[C:16](=[NH:29])([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[CH3:15][C@H:10]1[NH:11][C@@H:12]([CH3:14])[CH2:13][N:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([N:29]=[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH:7]=2)[CH2:9]1
Reactant: N=C(c1ccccc1)c1ccccc1
Reactant: C[C@@H]1CN(c2ccnc(Cl)c2)C[C@H](C)N1
Product: C[C@@H]1CN(c2ccnc(N=C(c3ccccc3)c3ccccc3)c2)C[C@H](C)N1

Procedure:
The title compound was prepared in a similar manner to cis-1-(2-chloro-4-pyridinyl)-3,5-dimethylpiperazine (D19) using cis-1-(2-chloro-4-pyridinyl)-3,5-dimethylpiperazine (D19) and benzophenone imine as the starting materials. MS (ES+) m/e 371 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:29]=[CH:28][C:5]([C:6]([N:8]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[C:12]3=[N:19][N:20]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:21]=[C:11]3[CH2:10][CH2:9]2)=[O:7])=[CH:4][CH:3]=1.C(N(CC)CC)C.[Cl:37][C:38]1[CH:46]=[C:45]([Cl:47])[CH:44]=[CH:43][C:39]=1[C:40](Cl)=[O:41]>C(Cl)Cl>[Cl:37][C:38]1[CH:46]=[C:45]([Cl:47])[CH:44]=[CH:43][C:39]=1[C:40]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([N:8]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[C:12]3=[N:19][N:20]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:21]=[C:11]3[CH2:10][CH2:9]2)=[O:7])=[CH:28][CH:29]=1)=[O:41]
Reactant: O=C(Cl)c1ccc(Cl)cc1Cl
Reactant: CCOC(=O)Cn1cc2c(n1)-c1ccccc1N(C(=O)c1ccc(N)cc1)CC2
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)Cn1cc2c(n1)-c1ccccc1N(C(=O)c1ccc(NC(=O)c3ccc(Cl)cc3Cl)cc1)CC2
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred solution of 0.940 g of ethyl 6-(4-aminobenzoyl)-5,6-dihydropyrazolo[4,3-d][1]benzazepine-2(4H)-acetate in 25 ml of methylene chloride is added 369 μl of triethylamine followed by the dropwise addition of 373 μl of 2,4-dichlorobenzoyl chloride in 3.5 ml of methylene chloride. The reaction mixture is stirred at room temperature for 18 hours, washed with water, saturated NaHCO3, brine and the organic layer treated with activated carbon, and filtered through is MgSO4. The filtrate is concentrated in vacuo to a residue which is purified by flash chromatography on silica gel using 25% ethyl acetate in methylene chloride to give 380 mg of the desired product as white crystals, m.p. 164°-167° C. The mother liquors are combined, evaporated in vacuo to a residue which is dissolved in 25% ethyl acetate in chloroform to give 535 mg of off-white solid, m.p. 160°-163.5° C.
Reaction SMILES: [CH:1]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[CH2:4][N:3]([C:10]([CH2:12][N:13]1[C:19]3[C:20]([CH3:24])=[CH:21][CH:22]=[CH:23][C:18]=3[C:17]([CH2:25]O)=[N:16][CH:15]([NH:27][C:28]([NH:30][C:31]3[CH:36]=[CH:35][CH:34]=[C:33]([CH3:37])[CH:32]=3)=[O:29])[C:14]1=[O:38])=[O:11])[CH2:2]2.C(N(C(C)C)CC)(C)C.[CH3:48][S:49](Cl)(=O)=O.[Na]>C(Cl)Cl.O1CCCC1.C(OCC)(=O)C.CO.C(Cl)(Cl)Cl>[CH:1]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[CH2:4][N:3]([C:10]([CH2:12][N:13]1[C:19]3[C:20]([CH3:24])=[CH:21][CH:22]=[CH:23][C:18]=3[C:17]([CH2:25][S:49][CH3:48])=[N:16][CH:15]([NH:27][C:28]([NH:30][C:31]3[CH:36]=[CH:35][CH:34]=[C:33]([CH3:37])[CH:32]=3)=[O:29])[C:14]1=[O:38])=[O:11])[CH2:2]2
Reactant: Cc1cccc(NC(=O)NC2N=C(CO)c3cccc(C)c3N(CC(=O)N3CC4CCC(CC4)C3)C2=O)c1
Reactant: CS(=O)(=O)Cl
Agent: [Na]
Solvent: CO
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: CSCC1=NC(NC(=O)Nc2cccc(C)c2)C(=O)N(CC(=O)N2CC3CCC(CC3)C2)c2c(C)cccc21
Temperature: 2.5 °C

Procedure:
To a mixture of N-[(3RS)-1-(3-azabicyclo[3.2.2]non-3-yl)carbonylmethyl-5-hydroxymethyl-9-methyl-2-oxo-2,3-dihydro-1H-1,4-benzodiazepin-3-yl]-N′-(3-methylphenyl)urea (147 mg) and diisopropylethylamine (55.1 mg) in methylene chloride (2 ml) was added dropwise a solution of methanesulfonyl chloride (48.7 mg) in methylene chloride (1 ml) under stirring and cooling at 0-5° C. in an ice-bath. The mixture was stirred for 1.5 hours under the same conditions. The reaction mixture was evaporated in vacuo to afford a residue, which was dissolved in tetrahydrofuran (2 ml) and cooled in an ice-bath. To the solution prepared above was added 15% aqueous solution of sodium methylmercaptide (0.5 g). The mixture was stirred under cooling for 0.5 hour and at ambient temperature for 2 hours. The reaction mixture was evaporated in vacuo to afford a residue, which was dissolved in ethyl acetate and washed with water twice. The separated organic layer was dried over magnesium sulfate and evaporated in vacuo to afford an amorphous mass, which was subjected to preparative thin-layer chromatography on silica gel developing with a mixture of chloroform and methanol (10:1) to give N-[(3RS)-1-(3-azabicyclo[3.2.2]non-3-yl)carbonylmethyl-5-methylthiomethyl-9-methyl-2-oxo-2,3-dihydro-1H-1,4-benzodiazepin-3-yl]-N′-(3-methyphenyl)urea as an amorphous mass. This was triturated in diisopropyl ether and collected by filtration to give a crystalline powder (71.9 mg, 41.7% yield).
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([N:8]2[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)[S:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[O:20]=[CH:21][C:22]1[CH:30]=[CH:29][C:27]([OH:28])=[C:24]([O:25][CH3:26])[CH:23]=1.CN(C)C=O>O>[CH3:26][O:25][C:24]1[CH:23]=[C:22]([CH:30]=[CH:29][C:27]=1[O:28][CH2:2][C:3]1[N:4]=[C:5]([N:8]2[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)[S:6][CH:7]=1)[CH:21]=[O:20]
Reactant: ClCc1csc(N2CCCCC2)n1
Reactant: COc1cc(C=O)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(C=O)ccc1OCc1csc(N2CCCCC2)n1
Temperature: 80 °C
Reaction time: 2 h
Yield: 87.6 %

Procedure:
A mixture of 1-(4-chloromethyl-1,3-thiazol-2-yl)piperidine (1.00 g), potassium carbonate (0.64 g), vanillin (0.70 g) and N,N-dimethylformamide (30 mL) was stirred at 80° C. for 2 hrs. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to give 3-methoxy-4-[(2-piperidin-1-yl-1,3-thiazol-4-yl)methoxy]benzaldehyde as colorless crystals (1.34 g, 88%) from a fraction eluted with ethyl acetate-hexane (1:1, v/v). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 129-130° C.
Reaction SMILES: [C:1]1([N:10]=[C:11]=[S:12])[CH:6]=[CH:5][CH:4]=[C:3]([N:7]=[C:8]=[S:9])[CH:2]=1.[CH:13]([NH:16][CH:17]([CH3:19])[CH3:18])([CH3:15])[CH3:14]>C(#N)C>[C:3]1([NH:7][C:8]([N:16]([CH:17]([CH3:19])[CH3:18])[CH:13]([CH3:15])[CH3:14])=[S:9])[CH:4]=[CH:5][CH:6]=[C:1]([NH:10][C:11]([N:16]([CH:17]([CH3:19])[CH3:18])[CH:13]([CH3:15])[CH3:14])=[S:12])[CH:2]=1
Reactant: CC(C)NC(C)C
Reactant: S=C=Nc1cccc(N=C=S)c1
Solvent: CC#N
Product: CC(C)N(C(=S)Nc1cccc(NC(=S)N(C(C)C)C(C)C)c1)C(C)C

Procedure:
To a solution of 3.84 g. of 1,3-phenylenediisothiocyanate in 100ml. of acetonitrile is added 4.4 g. of diisopropylamine and the mixture is refluxed for 3 hours. The solvent is removed in vacuo and the residue is crystallized from acetonitrile to yield 3.5 g. of the title compound, melting point 128°-129° C.
Reaction SMILES: [CH2:1]([C:14]1[NH:18][CH:17]=[C:16]([C:19]([OH:21])=[O:20])[CH:15]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].C(Cl)(=O)OCC.C(N(CC)CC)C.[Br:35][CH2:36][CH2:37]O.Cl>O1CCCC1>[CH2:1]([C:14]1[NH:18][CH:17]=[C:16]([C:19]([O:21][CH2:37][CH2:36][Br:35])=[O:20])[CH:15]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: OCCBr
Reactant: CCCCCCCCCCCCCc1cc(C(=O)O)c[nH]1
Agent: CCOC(=O)Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCCc1cc(C(=O)OCCBr)c[nH]1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 52.4 %

Procedure:
To a solution (20 ml) of 1.47 g (5.0 mmol) of 5-tridecylpyrrole-3-carboxylic acid in tetrahydrofuran were added 0.60 g (5.53 mmol) of ethyl chlorocarbonate and 0.60 g (5.94 mmol) of triethylamine, and the whole was stirred at room temperature for 10 minutes. After adding 1.88 g (15 mmol) of 2-bromoethanol, the mixture was heated under reflux for 1.5 hours. After further addition of 0.94 (7.5 mmol) of 2-bromoethanol, the mixture was heated under reflux for 9 hours. The resulting mixture was cooled, acidified with a diluted hydrochloric acid and extracted with ethyl acetate. The extract was washed with water and dried over magnesium sulfate. A removal of the solvent under reduced pressure afforded an oily product, which was purified by subjecting it to column chromatography over silica gel (eluent: ethyl acetate/hexane=1/10) to obtain 1.05 g (53% yield) of 2-bromoethyl 5-tridecylpyrrole-3-carboxylate, m.p. 67°-69.5° C.
Reaction SMILES: [C:1]([O:4][C@:5]1([C@:26]2([CH3:27])[C@H:12]([C@H:13]3[C@:23]([F:29])([C@@H:24]([OH:28])[CH2:25]2)[C@:21]2([CH3:22])[C:16](=[CH:17][C:18](=[O:30])[CH2:19][CH2:20]2)[C@@H:15]([CH3:31])[CH2:14]3)[CH2:11][C@H:10]1[CH3:32])[C:6](=[O:9])[CH2:7][OH:8])(=[O:3])[CH3:2].[C:33](OC(=O)C)(=[O:35])[CH3:34]>N1C=CC=CC=1>[C:1]([O:4][C@:5]1([C@:26]2([CH3:27])[C@H:12]([C@H:13]3[C@:23]([F:29])([C@@H:24]([OH:28])[CH2:25]2)[C@:21]2([CH3:22])[C:16](=[CH:17][C:18](=[O:30])[CH2:19][CH2:20]2)[C@@H:15]([CH3:31])[CH2:14]3)[CH2:11][C@H:10]1[CH3:32])[C:6](=[O:9])[CH2:7][O:8][C:33](=[O:35])[CH3:34])(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@]1(C(=O)CO)[C@H](C)C[C@H]2[C@@H]3C[C@H](C)C4=CC(=O)CC[C@]4(C)[C@@]3(F)[C@@H](O)C[C@@]21C
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)OCC(=O)[C@@]1(OC(C)=O)[C@H](C)C[C@H]2[C@@H]3C[C@H](C)C4=CC(=O)CC[C@]4(C)[C@@]3(F)[C@@H](O)C[C@@]21C

Procedure:
A solution of 650 mg of 17α-acetoxy-9α-fluoro-11β,21-dihydroxy-6α,16α-dimethyl-4-pregnene-3,20-dione in 6.5 ml of pyridine and 3.2 ml of acetic anhydride is stirred for 2 hours at room temperature and poured on an ice water-sodium chloride solution. The mixture is filtered off and worked up as usual. After crystallization from hexane/ethyl acetate, 430 mg of 17α,21-diacetoxy-9α-monofluoro-11β-hydroxy-6α,16α-dimethyl-4-pregnene-3,20-dione is isolated, mp 194°-195° C.
Reaction SMILES: [C:1]([C:3]1([OH:11])[CH:8]2[CH2:9][CH2:10][N:5]([CH2:6][CH2:7]2)[CH2:4]1)#[CH:2].[CH2:12]([O:16][C:17]1[CH:22]=[CH:21][C:20](I)=[CH:19][CH:18]=1)[CH2:13][CH2:14][CH3:15].C(N(CC)CC)C>C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Cu]I.CN(C)C=O>[CH2:12]([O:16][C:17]1[CH:22]=[CH:21][C:20]([C:2]#[C:1][C:3]2([OH:11])[CH:8]3[CH2:9][CH2:10][N:5]([CH2:6][CH2:7]3)[CH2:4]2)=[CH:19][CH:18]=1)[CH2:13][CH2:14][CH3:15]
Reactant: C#CC1(O)CN2CCC1CC2
Reactant: CCCCOc1ccc(I)cc1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCCCOc1ccc(C#CC2(O)CN3CCC2CC3)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 33.7 %

Procedure:
A mixture of (+) 3-ethynyl-3-hydroxyquinuclidine (180 mg), 4-butoxyiodobenzene (330 mg), bis(triphenylphosphine)-palladium (II) chloride (42 mg),copper (I) iodide (21 mg), triethylamine (2.5 ml) and dimethylformamide (5 ml) was stirred under argon at ambient temperature for 4 hours. The triethylamine and dimethylformamide were removed by evaporation. A solution of 2M sodium hydroxide (10 ml) was added and the mixture extracted with dichloromethane (3×10 ml). The combined organic extracts were washed with water (10 ml), dried (MgSO4) and evaporated to a gum. This gum was further purified by flash column chromatography on silica gel using a mixture of 5% methanol in dichloromethane containing 1% ammonia (density, 0.88 g(cm3) as eluent, followed by crystallisation from ethyl acetate to give (+)-3-[2-(4-butoxyphenyl)ethynyl)-3-hydroxyquinuclidine (120 mg) as a solid, m.p. 115°-116° C.; microanalysis, found C, 75.4; H, 8.4; N, 4.5%; C19H25NO2 0.2H2O requires: C,75.35; H, 8.39, N, 4.63%; NMR: 0.86-0.99(3H,t), 1.2-1.5(3H,m), 1.5-1.71(3H,m), 1.72-1.97(3H,m), 2.6-2.72(4H,m), 2.75-2.85(1H,d), 3.0-3.1(1H,d), 3.9-4.01(2H,t), 5.15(1H,s), 6.85-6.95(2H,d), 7.27-7.37(2H,d); m/z 300(M+H) α=[+26.6]58921 (c=1; methanol).
Reaction SMILES: [ClH:1].[CH2:2]([O:4][C:5]([C:7]1[S:11][C:10]2[CH:12]=[CH:13][CH:14]=[C:15]([N:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)[C:9]=2[CH:8]=1)=[O:6])[CH3:3].Br[CH2:23][CH2:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(=O)(O)[O-].[Na+]>CS(C)=O>[ClH:1].[CH2:2]([O:4][C:5]([C:7]1[S:11][C:10]2[CH:12]=[CH:13][CH:14]=[C:15]([N:16]3[CH2:17][CH2:18][N:19]([CH2:23][CH2:24][CH2:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[CH2:20][CH2:21]3)[C:9]=2[CH:8]=1)=[O:6])[CH3:3]
Reactant: BrCCCc1ccccc1
Reactant: CCOC(=O)c1cc2c(N3CCNCC3)cccc2s1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CS(C)=O
Product: CCOC(=O)c1cc2c(N3CCN(CCCc4ccccc4)CC3)cccc2s1
Yield: 26.9 %

Procedure:
In an analogous manner to example 6, the title compound (0.99 g) as a tan solid, mp 210.5°-213° C., is prepared from ethyl-4-(1-piperazinyl)-benzo[b]thiophene-2-carboxylate monohydrochloride (2.40 g, 8.27 mmol, prepared in example 5), dry dimethyl sulfoxide (45 mL), 1-bromo-3-phenylpropane (1.20 mL, 8.27 mmol) and sodium bicarbonate (0.69 g, 8.27 mmol). Recrystallize the title compound from warm methanol (10 mL); 1H NMR (DMSO-d6) δ 11.05 (bs), 7.76 (1H, d, J=8.2 Hz), 7.49 (1H, t, J=7.9 Hz), 7.28 (5H, m), 7.06 (1H, d, J=7.6 Hz), 4.37 (2H, q, J=7.2 Hz) 3.62 (2H, bd), 3.53 (2H, bd), 3.32 (4H, m), 3.18 (2H, m), 2.69 (2H, m), 1.34 (3H, t, J=7.1 Hz); 13C NMR (DMSO-d6) δ 161.86, 148.25, 142.82, 140.49, 132.62, 131.96, 128.41, 128.33, 128.23, 127.86, 126.11, 117.96, 113.65, 61.49, 55.24, 51.03, 48.76, 32.07, 24.71, 14.16; IR (KBr) 2970, 1709, 1284, 1258 cm-1 ; CI/MS (CH4) 409(100%), 408(75%). IC50 =239 nM (5HT1ABinding Affinity) IC50 =551 nM (5HT1DBinding Affinity)