Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:5][C:6]([C@@H:8]([C@@H:20]([CH2:29][CH:30]1[CH2:34][CH2:33][CH2:32][CH2:31]1)[C:21]([N:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1)=[O:22])[CH2:9][N:10]1[C:14](=[O:15])[C:13]([CH3:17])([CH3:16])[N:12]([CH3:18])[C:11]1=[O:19])=[O:7])(C)(C)C.Br>C(O)(=O)C.C(Cl)Cl>[C:6]([C@H:8]([C@@H:20]([CH2:29][CH:30]1[CH2:34][CH2:33][CH2:32][CH2:31]1)[C:21]([N:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1)=[O:22])[CH2:9][N:10]1[C:14](=[O:15])[C:13]([CH3:17])([CH3:16])[N:12]([CH3:18])[C:11]1=[O:19])([OH:7])=[O:5]
Reactant: CN1C(=O)N(C[C@@H](C(=O)OC(C)(C)C)[C@@H](CC2CCCC2)C(=O)N2CCCCC2)C(=O)C1(C)C
Agent: Br
Solvent: ClCCl
Solvent: CC(=O)O
Product: CN1C(=O)N(C[C@H](C(=O)O)[C@@H](CC2CCCC2)C(=O)N2CCCCC2)C(=O)C1(C)C
Reaction time: 4 h

Procedure:
A solution of 15.11 g of the 9:1 mixture from Example 4 in 15 ml of acetic acid was treated at 0° with 15 ml of 33% hydrogen bromide in acetic acid and stirred at 0° for 4 hrs. The solution was diluted with methylene chloride, washed with water and the organic phase was dried, filtered and evaporated. The residue was crystallized from 26 ml of tert-butyl methyl ether and 26 ml of hexane, after which 6.90 g (70%) of diastereomer-pure (de>98%) 1-[2(R)-[1(R)-carboxy-2-(3,4,4,-trimethyl-2,5-dioxo-1-imidazolidinyl)ethyl]-3-cyclopentylpropionyl]piperidine (IX), m.p. 111-114°, was obtained. IR (KBr): 1770m and 1715s (C═O).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:12][C:13]3[CH:26]=[CH:25][C:16]([C:17]([N:19]4[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]4)=[O:18])=[CH:15][CH:14]=3)=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.[Br:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[N:34]=[C:35]=[O:36]>>[Br:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[NH:34][C:35]([N:22]1[CH2:21][CH2:20][N:19]([C:17](=[O:18])[C:16]2[CH:25]=[CH:26][C:13]([NH:12][C:6]3[C:5]4[C:10](=[CH:11][C:2]([Cl:1])=[CH:3][CH:4]=4)[N:9]=[CH:8][CH:7]=3)=[CH:14][CH:15]=2)[CH2:24][CH2:23]1)=[O:36]
Reactant: O=C=Nc1ccccc1Br
Reactant: O=C(c1ccc(Nc2ccnc3cc(Cl)ccc23)cc1)N1CCNCC1
Product: O=C(Nc1ccccc1Br)N1CCN(C(=O)c2ccc(Nc3ccnc4cc(Cl)ccc34)cc2)CC1

Procedure:
In the manner given in Example 23, 4-[4-[[7-chloro-4-quinolinyl]amino]benzoyl]piperazine is reacted with o-bromophenyl isocyanate to give 1-[[(2-bromophenyl)amino]carbonyl]-4-[4-[[7-chloro-4-quinolinyl]amino]benzoyl]piperazine.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([S:8](Cl)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.[NH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C.O>[Br:1][C:2]1[CH:3]=[C:4]([S:8]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1
Reactant: O=S(=O)(Cl)c1cccc(Br)c1
Reactant: Nc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: O=S(=O)(Nc1ccccc1)c1cccc(Br)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.5 %

Procedure:
3-Bromobenzenesulfonyl chloride (51a) (1.0 g, 3.9 mmol) was added to a mixture of aniline (0.47 g, 5.1 mmol) in acetonitrile (10 ml) and sodium carbonate (1.3 g, 12.3 mmol) in water (10 ml). The mixture was stirred at ambient temperature for 1 hour and the reaction product was extracted with ethyl acetate (30 ml). The extract was dried (Na2SO4) and solvents were removed under reduced pressure to give the title compound (1.15 g, 94%) as an oil witch solidified upon standing. M.p. 98-100° C. 1H NMR (DMSO-d6, HMDSO) δ: 6.94-7.48 (5H, m, C6H5); 7.50-7.96 (4H, m, C6H4); 10.36 (1H, s, NH).
Reaction SMILES: [OH:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[O:26][CH3:27])=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:3]1.Cl[CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[C:39]([O:43][CH3:44])[C:38]=1[O:45][CH2:46][CH2:47][CH2:48][O:49][CH3:50]>>[CH3:27][O:26][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[CH2:19][O:18][CH2:17][CH2:16][CH2:15][O:14][C:11]1[CH:12]=[CH:13][C:8]([CH:7]2[CH2:6][CH2:5][N:4]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:3][CH:2]2[O:1][CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[C:39]([O:43][CH3:44])[C:38]=2[O:45][CH2:46][CH2:47][CH2:48][O:49][CH3:50])=[CH:9][CH:10]=1
Reactant: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2O)cc1
Reactant: COCCCOc1c(CCl)cccc1OC
Product: COCCCOc1c(COC2CN(C(=O)OC(C)(C)C)CCC2c2ccc(OCCCOCc3ccccc3OC)cc2)cccc1OC

Procedure:
Analogously to Method D, 0.417 g of tertbutyl 3-hydroxy-4-{4-[3-(2-methoxybenzyloxy)-propoxy]phenyl}piperidine-1-carboxylate and 0.278 g of 1-chloromethyl-3-methoxy-2-(3-methoxypropoxy)benzene are reacted. The title compound is obtained as a colourless oil. Rf=0.17 (1:2 EtOAc-heptane); Rt=6.19.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH:7]([O:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][C:20]([OH:22])=O)=[CH:14][CH:13]=1)[CH2:6][CH2:5]2.[CH3:23][S:24]([NH2:27])(=[O:26])=[O:25].Cl.C(N=C=NCCCN(C)C)C.O>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH:7]([O:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][C:20]([NH:27][S:24]([CH3:23])(=[O:26])=[O:25])=[O:22])=[CH:14][CH:13]=1)[CH2:6][CH2:5]2
Reactant: O=C(O)CCc1ccc(OC2CCc3cc(Cl)ccc32)cc1
Reactant: CS(N)(=O)=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: O
Solvent: ClCCl
Product: CS(=O)(=O)NC(=O)CCc1ccc(OC2CCc3cc(Cl)ccc32)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 26.7 %

Procedure:
To a solution of 4-[(5-chloro-2,3-dihydro-1H-inden-1-yl)oxy]benzenepropanoic acid (0.3 g, 0.95 mmol) in dichloromethane (10 mL) were added methanesulfonamide (90 mg, 0.95 mmol), N,N-dimethylaminopyridine (0.12 g, 0.95 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.17 mL, 0.95 mmol), and the mixture was stirred at room temperature for 15 hrs. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water, concentrated under reduced pressure to give the title compound (0.10 g, yield 30%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([C:13]1[O:14][C:15]3[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=3[CH:17]=1)[CH:7]=[CH:6]2.[C:22]([CH2:26][C:27](Cl)=[O:28])([CH3:25])([CH3:24])[CH3:23].[Sn](Cl)(Cl)(Cl)Cl>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([C:13]1[O:14][C:15]3[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=3[C:17]=1[C:27](=[O:28])[CH2:26][C:22]([CH3:25])([CH3:24])[CH3:23])[CH:7]=[CH:6]2
Reactant: CC(C)(C)CC(=O)Cl
Reactant: COc1ccc2cc(-c3cc4ccccc4o3)ccc2c1
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Product: COc1ccc2cc(-c3oc4ccccc4c3C(=O)CC(C)(C)C)ccc2c1

Procedure:
Following the procedure described in Step 2 of Example 1, the title compound was prepared from 2-(6-methoxy-2-naphthyl)-1-benzofuran (3.00 g, 10.9 mmol), t-butyl acetyl chloride (2.3 mL, 16 mmol), and tin (IV) chloride (1.7 mL, 14 mmol) in chloroform (60 mL). The reaction mixture was refluxed for 24 hours. Purification by HPLC using 7-8% ethyl acetate in hexane as the mobile phase yielded a yellow solid (1.09 g), mp ˜140° C. 1HNMR (200 MHz, DMSO-d6): δ8.35 (s, 1H), 7.9-8.1 (m, 3H), 7.7-7.85 (m, 2H), 7.35-7.5 (m, 3H), 7.3 (d, 1H, J=9.0 Hz), 3.95 (s, 3H), 2.75 (s, 2H), and 0.85 ppm (s, 9H).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[C:4](Cl)[C:3]=1[N+:9]([O-:11])=[O:10].[CH2:12]([CH2:14][NH2:15])[OH:13]>>[OH:13][CH2:12][CH2:14][NH:15][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([NH:15][CH2:14][CH2:12][OH:13])[C:3]=1[N+:9]([O-:11])=[O:10]
Reactant: O=[N+]([O-])c1c(Cl)cccc1Cl
Reactant: NCCO
Product: O=[N+]([O-])c1c(NCCO)cccc1NCCO
Temperature: 98 °C

Procedure:
0.25 mole (48 g) of 2,6-dichloronitrobenzene, prepared according to the method described by Alexander McKillop and Jonathan A. Tarbin in Tetrahedron Letters, Vol. 24 No. 14, page 1505 (1983), is added to 200 ml of ethanolamine. The mixture is heated to 98° C. for 8 hours. The reaction mixture is poured onto ice. After phase separation, the precipitate is taken up in the minimum quantity of ethanol, with stirring. After dilution with a mixture of ice and water, the expected product is filtered off, washed with water and then recrystallized from ethanol. It is identical with the product prepared in Example 1.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1)#[N:2].[OH-].[Na+].Cl[CH2:19][CH2:20][CH2:21][OH:22]>C(O)C>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:19][CH2:20][CH2:21][OH:22])=[CH:11][CH:10]=2)=[CH:7][CH:8]=1)#[N:2]
Reactant: N#Cc1ccc(-c2ccc(O)cc2)cc1
Reactant: OCCCCl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: N#Cc1ccc(-c2ccc(OCCCO)cc2)cc1
Temperature: 80 °C
Reaction time: 0.17 h
Yield: 20.6 %

Procedure:
Into a 300 ml flask, 20 g (102.4 mmol) of 4-cyano-4'-hydroxybiphenyl, 140 ml of ethanol and a NaOH aqueous solution (7.48 g (132.2 mmol) of NaOH/40 ml of water) were added. The mixture was stirred at 80° C. for 10 minutes, and then 10.66 g (112.8 mmol) of 3-chloro-1-propanol was added thereto. The mixture was heated and refluxed for 18 hours. Ethanol was distilled off. Then, 300 ml of water was added to the reaction solution, and the mixture was neutralized with hydrochloric acid. Precipitated crystals were collected by filtration. Then, 1200 ml of toluene was added thereto, and the toluene layer was washed with water and a saturated sodium chloride aqueous solution and then dried over anhydrous sodium sulfate. Further, the solvent was distilled off under reduced pressure, and the residue was recrystallized from ethanol to obtain 5.34 g (yield: 21%) of 4-cyano-4'-(3-hydroxypropoxy)biphenyl (7) as colorless crystals.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.C([Li])CCC.[CH:13]([CH:15]1[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]1)=[O:14]>C1COCC1>[OH:14][CH:13]([C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1)[CH:15]1[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]1
Reactant: Brc1cccnc1
Reactant: CC(C)(C)OC(=O)N1CCC(C=O)CC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(C(O)c2cccnc2)CC1
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
3-Bromopyridine (116 μL, 1.20 mmol) was added slowly dropwise to a stirred suspension of n-butyllithium (480 μL of a 2.5 M hexanes solution, 1.20 mmol) in THF (1.00 mL) at −78° C. After 15 min, tert-butyl 4-formylpiperidine-1 -carboxylate (213 mg, 1.00 mmol) was added, and the resulting mixture was allowed to stir at −78° C. After 1 h, the reaction was quenched with 1.0 M HCl, poured into satd. aq. NaHCO3 and extracted with EtOAc. The combined organics were washed with brine, dried (sodium sulfate) and concentrated in vacuo. Purification of the crude residue by flash chromatography on silica gel (gradient elution; 10%-100% EtOAc/DCM as eluent) afforded the title compound i-16a. 1H NMR (500 MHz, CDCl3): δ 8.55 (m, 2H), 7.70 (d, 1H, J=8.0 Hz), 7.32 (dd, 1H, J=4.9, 7.4 Hz), 4.49 (m, 1H), 4.15 (m, 4H), 2.65 (m, 2H), 1.83 (m, 1H), 1.79 (m, 1H), 1.46 (s, 9H), 1.31 (m, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:14](=[O:16])[CH3:15])[CH:5]=[C:6]([S:8]([F:13])([F:12])([F:11])([F:10])[F:9])[CH:7]=1.[C:17](O)(=[O:23])[CH2:18][CH2:19][C:20](O)=[O:21]>>[C:14]([C:4]1[CH:3]=[C:2]([N:1]2[C:20](=[O:21])[CH2:19][CH2:18][C:17]2=[O:23])[CH:7]=[C:6]([S:8]([F:13])([F:9])([F:10])([F:11])[F:12])[CH:5]=1)(=[O:16])[CH3:15]
Reactant: O=C(O)CCC(=O)O
Reactant: CC(=O)c1cc(N)cc(S(F)(F)(F)(F)F)c1
Product: CC(=O)c1cc(N2C(=O)CCC2=O)cc(S(F)(F)(F)(F)F)c1
Temperature: 130 °C
Reaction time: 8 h
Yield: 16.1 %

Procedure:
1-[3-Amino-5-(pentafluorosulfanyl)phenyl]ethanone (200 mg) was mixed with succinic acid (90 mg) in a flask, and then polyphosphoric acid (10 ml) was added. The mixture was heated to 130° C. for 8 h while stirring and, after leaving to stand overnight, further succinic acid (50 mg) was added and the mixture was heated to 130° C. for a further 4 h. After cooling, the mixture was stirred into ice-water and the aqueous solution was extracted five times with ethyl acetate. The combined extracts were washed with saturated sodium hydrogencarbonate solution, dried over magnesium sulfate, filtered and concentrated. The residue was purified by means of preparative HPLC. The product-containing fractions were combined, freed of the acetonitrile, admixed with saturated sodium hydrogencarbonate solution and extracted three times with ethyl acetate. The combined extracts were dried over magnesium sulfate, filtered and concentrated. 42 mg of the desired compound were obtained.
Reaction SMILES: [F:1][C:2]1([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)[CH2:7][CH2:6][N:5](C(OC(C)(C)C)=O)[CH2:4][CH2:3]1.[ClH:21]>C(OCC)(=O)C>[ClH:21].[F:1][C:2]1([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)[CH2:3][CH2:4][NH:5][CH2:6][CH2:7]1
Reactant: CC(C)(C)OC(=O)N1CCC(F)(c2ccccn2)CC1
Agent: Cl
Solvent: CCOC(C)=O
Product: FC1(c2ccccn2)CCNCC1
Reaction time: 1 h

Procedure:
A solution of tert-butyl 4-fluoro-4-pyridin-2-ylpiperidine-1-carboxylate (0.075 g, 0.27 mmoL) in 10 mL of ethyl acetate was saturated with gaseous hydrochloric acid. After 1 hr, the mixture was concentrated in vacuo to provide 2-(4-fluoropiperidin-4-yl)pyridine hydrochloride that gave a mass ion (ES+) of 181.1 for [M+H]+
Reaction SMILES: [OH:1][C@H:2]1[CH2:16][CH:15]=[C:14]2[C@:4]([CH3:17])([CH2:5][C:6]3[C:7](=[CH:13]2)[O:8][C:9](=[O:12])[C:10]=3[CH3:11])[C@H:3]1[CH3:18].[C:19](Cl)(=[O:22])[CH2:20][CH3:21]>>[C:19]([O:1][C@H:2]1[CH2:16][CH:15]=[C:14]2[C@:4]([CH3:17])([CH2:5][C:6]3[C:7](=[CH:13]2)[O:8][C:9](=[O:12])[C:10]=3[CH3:11])[C@H:3]1[CH3:18])(=[O:22])[CH2:20][CH3:21]
Reactant: CCC(=O)Cl
Reactant: CC1=C2C[C@@]3(C)C(=CC[C@H](O)[C@@H]3C)C=C2OC1=O
Product: CCC(=O)O[C@H]1CC=C2C=C3OC(=O)C(C)=C3C[C@]2(C)[C@H]1C

Procedure:
The title compound was prepared in the same manner as in Example B2, except that the compound prepared in Example B1 (2) Method B was reacted with propionyl chloride.
Reaction SMILES: [F:1][C:2]([F:6])([F:5])[S:3]Cl.[Cl:7][CH2:8][CH2:9][CH2:10][C:11]1[C:12]([F:32])=[C:13]([C:18]([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[C:22]([CH2:27][CH2:28][CH2:29][Cl:30])[C:21]=2[F:31])=[O:19])[CH:14]=[CH:15][C:16]=1[F:17]>C(Cl)Cl>[Cl:30][CH2:29][CH2:28][CH:27]([C:22]1[C:21]([F:31])=[C:20]([C:18]([C:13]2[CH:14]=[CH:15][C:16]([F:17])=[C:11]([CH:10]([S:3][C:2]([F:6])([F:5])[F:1])[CH2:9][CH2:8][Cl:7])[C:12]=2[F:32])=[O:19])[CH:25]=[CH:24][C:23]=1[F:26])[S:3][C:2]([F:6])([F:5])[F:1]
Reactant: O=C(c1ccc(F)c(CCCCl)c1F)c1ccc(F)c(CCCCl)c1F
Reactant: FC(F)(F)SCl
Solvent: ClCCl
Product: O=C(c1ccc(F)c(C(CCCl)SC(F)(F)F)c1F)c1ccc(F)c(C(CCCl)SC(F)(F)F)c1F
Temperature: 25 °C
Reaction time: 108 h
Yield: 51.9 %

Procedure:
75 g (0.55 mol) of trifluoromethylsulphenyl chloride are added at 20 to 25° C. with stirring to a solution of 43 g (0.2 mol) of 3-chloropropyl-2,4-difluorophenyl ketone in 100 ml of methylene chloride. The mixture is stirred at room temperature for 108 hours and then concentrated by stripping off the solvent under reduced pressure. 63 g of (3-chloro-1-trifluoromethylmercapto-propyl)-2,4-difluorophenyl ketone are obtained.
Reaction SMILES: [Br:1][C@@H:2]([CH2:5][CH2:6][OH:7])[CH2:3][OH:4].C(N(CC)CC)C.[CH3:15][S:16](Cl)(=[O:18])=[O:17]>C(Cl)Cl>[Br:1][C@@H:2]([CH2:5][CH2:6][O:7][S:16]([CH3:15])(=[O:18])=[O:17])[CH2:3][O:4][S:16]([CH3:15])(=[O:18])=[O:17]
Reactant: CS(=O)(=O)Cl
Reactant: OCC[C@H](Br)CO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCC[C@H](Br)COS(C)(=O)=O
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 78 %

Procedure:
A solution of 70 g (0.414 mol) (S)-2-bromo-1,4-butanediol in 1.5 liters methylene chloride was cooled in ice and 173 ml (1.24 mol) triethylamine (dried over potassium hydroxide) was added to give a clear solution. To this was added dropwise over 80 minutes at 5° to 15° C., 96 ml (1.24 mol) methanesulfonyl chloride. The mixture was then stirred at room temperature for 2.5 hours, washed 2×750 ml with water and 1×750 ml brine, dried (MgSO4), and the solvent evaporated to give an amber oil which was purified by chromatography on a 140 mm×25 cm silica gel column, eluting with 9:1 chloroformethyl acetate. The product fractions were combined and solvent evaporated to give 105 g (97%) of the title compound as a waxy white solid; [alpha]D =-34.49° (c=5 in CHCl3).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C:10](=[O:13])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[P:14]([O-:21])([O:18][CH2:19][CH3:20])[O:15][CH2:16][CH3:17]>>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C:10]([P:14](=[O:21])([O:18][CH2:19][CH3:20])[O:15][CH2:16][CH3:17])([OH:13])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)C1
Reactant: CCOP([O-])OCC
Product: CCOP(=O)(OCC)C1(O)CCN(C(=O)OC(C)(C)C)C1
Temperature: 100 °C
Reaction time: 1.5 h
Yield: 53.4 %

Procedure:
A mixture of 1.9 g (10.3 mmol) of 1-tert-butoxycarbonyl-3-oxopyrrolidine (from Step B), 1.3 mL (10.3 mmol) of diethyl phosphite and 1.4 mL (10.3 mmol) of TEA was stirred at 100° C. for 1.5 h. Volatiles were removed under reduced pressure. The residue was purified on a 40M Biotage column using 13:7 v/v hexane/acetone as the eluant to afford 1.78 g (53%) of the title compound as a yellow oil: RF: 0.16 (7:3 v/v hexane/acetone); 1H-NMR (500 MHz) δ 1.33 (t, J=7.0, 6H), 1.45 (s, 9H), 2.08 (m, 1H), 2.18 (m, 1H), 3.47-3.64 (m, 4H), 4.13-4.22 (m, 4H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[S:9][C:10]3[CH:16]=[C:15]([O:17][CH2:18][CH2:19][CH2:20][F:21])[CH:14]=[CH:13][C:11]=3[CH:12]=2)[CH:5]=[CH:4][N:3]=1.[CH3:22][OH:23].C[O-].[Na+]>>[CH3:22][O:23][C:2]1[N:7]=[C:6]([C:8]2[S:9][C:10]3[CH:16]=[C:15]([O:17][CH2:18][CH2:19][CH2:20][F:21])[CH:14]=[CH:13][C:11]=3[CH:12]=2)[CH:5]=[CH:4][N:3]=1
Reactant: CO
Reactant: FCCCOc1ccc2cc(-c3ccnc(Cl)n3)sc2c1
Agent: C[O-]
Agent: [Na+]
Product: COc1nccc(-c2cc3ccc(OCCCF)cc3s2)n1
Yield: 107.1 %

Procedure:
2-(2-Methoxypyrimidine-4-yl)-6-(3-fluoropropoxy)benzothiophene (1-37, 75 mg, 99%) was prepared in the same manner as in Example 34 as a yellow solid using 2-(2-chloropyrimidine-4-yl)-6-(3-fluoropropoxy)benzothiophene (105c, 70 mg, 0.22 mmol) obtained in Preparation Example 21 and a 0.5 M sodium methoxide methanol solution (0.66 mL, 0.33 mmol).
Reaction SMILES: C(=O)([O-])[O-].[Ca+2].[CH3:6][C:7]1[CH:8]=[C:9]([CH:11]=[C:12]([CH3:21])[C:13]=1[S:14]([CH2:17][N+:18]([O-:20])=[O:19])(=[O:16])=[O:15])[NH2:10].[F:22][C:23]1[CH:28]=[CH:27][C:26]([S:29](Cl)(=[O:31])=[O:30])=[CH:25][CH:24]=1.O>O1CCCC1>[CH3:21][C:12]1[CH:11]=[C:9]([NH:10][S:29]([C:26]2[CH:27]=[CH:28][C:23]([F:22])=[CH:24][CH:25]=2)(=[O:31])=[O:30])[CH:8]=[C:7]([CH3:6])[C:13]=1[S:14]([CH2:17][N+:18]([O-:20])=[O:19])(=[O:15])=[O:16]
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Reactant: Cc1cc(N)cc(C)c1S(=O)(=O)C[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(NS(=O)(=O)c2ccc(F)cc2)cc(C)c1S(=O)(=O)C[N+](=O)[O-]
Yield: 36.4 %

Procedure:
1.65 g (16.5 mmol) of calcium carbonate are added to a solution of 2.0 g (8.19 mmol) of 3,5-dimethyl-4-[(nitromethyl)sulphonyl]aniline in 40 ml of anhydrous tetrahydrofuran, followed by portionwise addition of 2.4 g (12.3 mmol) of 4-fluorobenzenesulphonyl chloride. The reaction medium is refluxed for 50 hours. After cooling, it is poured into 200 ml of water and extracted with 3 times 100 ml of methylene chloride. The combined organic extracts are washed with 100 ml of water, dried over sodium sulphate and concentrated to dryness under reduced pressure. The oily residue obtained is purified by chromatography on a column of silica (eluent: methylene chloride) and recrystallization from a mixture of hexane and ethyl acetate, to give 1.2 g (36%) of N-[3,5-dimethyl-4-[(nitromethyl)sulphonyl]phenyl]-4-fluorobenzenesulphonamide.
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[N:4][CH:3]=1.[C:12](=[O:15])([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Pd]>[CH:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:2]([C:6]2[CH:11]=[CH:10][C:9]([CH2:12][OH:15])=[CH:8][CH:7]=2)=[CH:3][N:4]=1
Reactant: Brc1cncc2ccccc12
Reactant: O=C([O-])[O-]
Agent: [Pd]
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: OCc1ccc(-c2cncc3ccccc23)cc1

Procedure:
Under an argon atmosphere, a mixture of 1.09 g (7.2 mmol) of (4-hydroxymethyl)phenylboronic acid, 1.24 g (6 mmol) of 4-bromoisoquinoline and 0.28 g (0.24 mmol) of palladium tetrakis(triphenylphosphine) in 50 ml of toluene and 10 ml of aqueous sodium carbonate solution (2M) is heated at reflux overnight. The filtrate is concentrated under reduced pressure and the residue is taken up in 150 ml of ethyl acetate and 40 ml of water. After the phases have settled and been separated, the organic phase is washed in succession with 20 ml of water and 20 ml of saturated aqueous sodium chloride solution. It is dried over sodium sulphate and the filtrate is concentrated under reduced pressure. The residue is purified by chromatography on silica gel, eluting with a 60/40 then 40/60 mixture of cyclohexane and ethyl acetate. This gives 1.12 g of a white solid.
Reaction SMILES: [CH2:1]([C@@:4]12[C@@H:21]3[C@H:12]([C@H:13]4[C@@:17]([CH2:19][CH2:20]3)([CH3:18])[C:16](=[O:22])[CH2:15][CH2:14]4)[CH2:11][CH2:10][C:9]1=[CH:8][C:7](=[O:23])[CH2:6][CH2:5]2)[C:2]#[CH:3]>O1CCOCC1.CCOCC>[CH2:1]([C@@:4]12[C@@H:21]3[C@H:12]([C@H:13]4[C@@:17]([CH2:19][CH2:20]3)([CH3:18])[C:16](=[O:22])[CH2:15][CH2:14]4)[CH2:11][CH2:10][C:9]1=[CH:8][C:7](=[O:23])[CH:6]=[CH:5]2)[C:2]#[CH:3]
Reactant: C#CC[C@]12CCC(=O)C=C1CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Solvent: C1COCCO1
Solvent: CCOCC
Product: C#CC[C@]12C=CC(=O)C=C1CC[C@H]1[C@@H]3CCC(=O)[C@@]3(C)CC[C@@H]12

Procedure:
A mixture of 150 mg of 10-(2-propynyl)-estr-4-ene-3,17-dione, and 300 mg of dichlorodicyanoquinone in 10 ml of dioxane is refluxed for 20 hours. The mixture is cooled and diluted with ether and then washed with aqueous sodium carbonate and dried. The solvent is evaporated and the residue is chromatographed on silica gel in ethyl acetate/hexane to give 10-(2-propynyl)-estra-1,4-diene-3,17-dione melting at about 200°-201° C. This compound has the following structural formula ##STR11##
Reaction SMILES: CS(O[CH2:6][C:7]1[C:12]([Cl:13])=[CH:11][CH:10]=[C:9]([NH:14][C:15](=[O:17])[CH3:16])[C:8]=1[F:18])(=O)=O.[C-:19]#[N:20].[Na+].O>CS(C)=O>[Cl:13][C:12]1[CH:11]=[CH:10][C:9]([NH:14][C:15](=[O:17])[CH3:16])=[C:8]([F:18])[C:7]=1[CH2:6][C:19]#[N:20]
Reactant: [C-]#N
Reactant: CC(=O)Nc1ccc(Cl)c(COS(C)(=O)=O)c1F
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CC(=O)Nc1ccc(Cl)c(CC#N)c1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.5 %

Procedure:
A solution of 3-acetamido-6-chloro-2-fluorobenzyl methanesulfonate (1.31 g, 3.54 mmol) in DMSO (10 mL) was treated with sodium cyanide (0.868 g, 17.72 mmol), stirred at RT overnight, treated with water and extracted with EtOAc (2×). The combined organics were washed with brine, dried over Na2SO4, concentrated to dryness and purified via silica gel chromatography (EtOAc/Hex) to afford N-(4-chloro-3-(cyanomethyl)-2-fluorophenyl)acetamide (630 mg, 78% yield) as a yellow solid. MS (ESI) m/z: 227.0 [M+H]+.
Reaction SMILES: [NH3:1].[F:2][C:3]1[C:8]([CH:9]([CH3:13])[C:10](Cl)=[O:11])=[C:7]([F:14])[C:6]([F:15])=[C:5]([F:16])[C:4]=1[F:17]>O>[F:2][C:3]1[C:8]([CH:9]([CH3:13])[C:10]([NH2:1])=[O:11])=[C:7]([F:14])[C:6]([F:15])=[C:5]([F:16])[C:4]=1[F:17]
Reactant: N
Reactant: CC(C(=O)Cl)c1c(F)c(F)c(F)c(F)c1F
Solvent: O
Product: CC(C(N)=O)c1c(F)c(F)c(F)c(F)c1F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To an ice-cooled 10 ml of concentrated aqueous ammonia, was added dropwise 2.5 g of (-)-2-(pentafluorophenyl)-propanoyl chloride obtained in Example 5. After stirring for 30 minutes at room temperature, the reaction mixture was diluted with water, extracted with ethyl acetate and then dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and the subsequent recrystallization from a hexane-ether mixed solvent gave 1.92 g of (-)-2-(pentafluorophenyl)propaneamide as colorless needles having the aforementioned physical properties.