Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O=S(Cl)[Cl:3].O[CH2:6][CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]([CH3:25])[CH2:16][CH2:17][CH2:18][CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)=[CH:11][CH:10]=1>N1C=CC=CC=1.C1C=CC=CC=1>[Cl:3][CH2:6][CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]([CH3:25])[CH2:16][CH2:17][CH2:18][CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)=[CH:11][CH:10]=1
Reactant: O=S(Cl)Cl
Reactant: CC(CCCC1CCCCC1)c1ccc(CCCO)cc1
Solvent: c1ccncc1
Solvent: c1ccccc1
Product: CC(CCCC1CCCCC1)c1ccc(CCCCl)cc1

Procedure:
Next, 0.82 g of Li[AlH4 ] was added to 50 ml of dried (C2H5)2O, and the resulting mixture was stirred. Thereto was gradually added 5 g of 4-[p-(2-hydroxycarbonylethyl)phenyl]pentylcyclohexane. Thereafter the thus obtained mixture was stirred for 5 hours, and filtered. The (C2H5)2O was distilled off from the filtrate, and the residue was recrystallized from n--C6H14 to obtain 4-[p-(3-hydroxypropyl)phenyl]pentylcyclohexane. The melting point of this compound was 70.7° to 72.5° C. To a mixture of 3.6 g of SOCl2, one drop of pyridine and 50 ml of benzene was added 4.3 g of the 4-[p-(3-hydroxypropyl)phenyl]pentylcyclohexane obtained above, and the resulting mixture was refluxed for 5 hours. Thereafter, the surplus SOCl2 was distilled off to obtain 4-[p-(3-chloropropyl)phenyl]pentylcyclohexane. The melting point of this compound was 70.7° to 72.5° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([CH2:31][CH3:32])[C:12]([NH:17][C@H:18]2[C@@H:22]([O:23][CH2:24][CH3:25])[CH2:21][N:20]([C:26]3S[CH:28]=[CH:29][N:30]=3)[CH2:19]2)=[N:13][C:14]=1[CH2:15][CH3:16].Br[C:34]1[CH:39]=CC=CN=1>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([CH2:31][CH3:32])[C:12]([NH:17][C@H:18]2[C@@H:22]([O:23][CH2:24][CH3:25])[CH2:21][N:20]([C:26]3[CH:39]=[CH:34][CH:28]=[CH:29][N:30]=3)[CH2:19]2)=[N:13][C:14]=1[CH2:15][CH3:16]
Reactant: CCO[C@H]1CN(c2nccs2)C[C@H]1Nc1nc(CC)c(-c2ccc(Cl)cc2Cl)nc1CC
Reactant: Brc1ccccn1
Product: CCO[C@H]1CN(c2ccccn2)C[C@H]1Nc1nc(CC)c(-c2ccc(Cl)cc2Cl)nc1CC

Procedure:
Following the procedure for the preparation of 5-(2,4-dichlorophenyl)-N-[(3R,4S)-4-ethoxy-1-(1,3-thiazol-2-yl)pyrrolidin-3-yl]-3,6-diethylpyrazin-2-amine but substituting 2-bromo pyridine provided the title compound as an amporphous solid: 1 H NMR (400 MHz, CDCl3) δ) 8.20, 7.50, 7.32, 7.28, 6.69, 6.53, 5.33, 4.92, 4.28, 4.05, 3.92–3.78, 3.58, 3.42, 2.73, 2.50, 1.33–1.25,1.16; HRMS (ESI) calcd for C25H29N5OCl2+H1 486.1827. found 486.1827.
Reaction SMILES: [CH3:1]/[C:2](/[CH:6]=[CH:7]/[C:8](/[F:21])=[C:9](\[CH3:20])/[CH:10]=[CH:11]/[C:12]1[C:16]([CH3:17])=[C:15]([CH3:18])[S:14][C:13]=1[CH3:19])=[CH:3]\[CH2:4][OH:5].O1CCC[CH2:23]1.[H-].[Na+].CN(C)C=O>O>[CH3:1]/[C:2](/[CH:6]=[CH:7]/[C:8](/[F:21])=[C:9](\[CH3:20])/[CH:10]=[CH:11]/[C:12]1[C:16]([CH3:17])=[C:15]([CH3:18])[S:14][C:13]=1[CH3:19])=[CH:3]\[CH2:4][O:5][CH3:23]
Reactant: C1CCOC1
Reactant: CC(/C=C/c1c(C)sc(C)c1C)=C(F)\C=C\C(C)=C\CO
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC/C=C(C)/C=C/C(F)=C(C)/C=C/c1c(C)sc(C)c1C
Temperature: 23 °C
Reaction time: 14 h
Yield: 52 %

Procedure:
A solution of 0.400 g. (1.31 mmole) of 2E,4E,6Z,8E-3,7-dimethyl-6-fluoro-9-(2,4,5-trimethyl-3-thienyl)-2,4,6,8-nonatetraen-1-ol in 5 ml. of tetrahydrofuran was added to a suspension of 0.11 g. (2.6 mmole) of a 56% sodium hydride dispersion in a mixture of 10 ml. of dry tetrahydrofuran and 20 ml. of dry dimethylformamide. This reaction mixture was stirred at 23° C. for 14 hours, poured into water and extracted with ether-hexane (1:1 parts by volume). The extracts were washed with water, dried with magnesium sulfate, filtered and evaporated to give an orange product which was crystallized from ether-hexane (1:4 parts by volume) to give 220 mg. (52% yield) of 2E,4E,6Z,8E-3,7-dimethyl-6-fluoro-9-(2,4,5-trimethyl-3-thienyl)-1-methoxy-2,4,6,8-nonatetraene as a light orange solid, m.p. 117°-118° C.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([C:10]2[CH:15]=[CH:14][C:13]([CH:16]([CH3:25])[CH2:17][NH:18][S:19]([CH:22]([CH3:24])[CH3:23])(=[O:21])=[O:20])=[CH:12][CH:11]=2)[CH:7]=[CH:8][CH:9]=1)(=[O:3])[CH3:2].[BH4-].[Na+]>C(O)C>[OH:3][CH:1]([C:4]1[CH:5]=[C:6]([C:10]2[CH:15]=[CH:14][C:13]([CH:16]([CH3:25])[CH2:17][NH:18][S:19]([CH:22]([CH3:24])[CH3:23])(=[O:21])=[O:20])=[CH:12][CH:11]=2)[CH:7]=[CH:8][CH:9]=1)[CH3:2]
Reactant: CC(=O)c1cccc(-c2ccc(C(C)CNS(=O)(=O)C(C)C)cc2)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CC(O)c1cccc(-c2ccc(C(C)CNS(=O)(=O)C(C)C)cc2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 59.3 %

Procedure:
To a solution of 0.5 g (1.4 mmol) of material from Example 132 in 5 mL of ethyl alcohol was added 0.05 g (1.4 mmol) of sodium borohydride. The mixture was stirred at ambient temperature for 2 hr, concentrated in vacuo and then 10 mL of ethyl acetate and 10 mL of water was added. The organic layer was separated and the aqueous layer was extracted three times with 5 mL each of ethyl acetate. The combined organic extracts were dried (MgSO4), filtered and concentrated in vacuo. Chromatography (40 g of silica gel, 50% ethyl acetate/hexane) of the residue afforded 0.3 g (65%) of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[C:9]([C:31]3[CH:32]=[N:33][NH:34][CH:35]=3)=[N:10][N:11](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[C:7]=2[CH:6]=[CH:5][N:4]=1.Br[CH2:37][CH:38]1[CH2:40][C:39]1([F:42])[F:41]>>[F:41][C:39]1([F:42])[CH2:40][CH:38]1[CH2:37][N:34]1[CH:35]=[C:31]([C:9]2[C:8]3[C:3]([O:2][CH3:1])=[N:4][CH:5]=[CH:6][C:7]=3[NH:11][N:10]=2)[CH:32]=[N:33]1
Reactant: COc1nccc2c1c(-c1cn[nH]c1)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: FC1(F)CC1CBr
Product: COc1nccc2[nH]nc(-c3cnn(CC4CC4(F)F)c3)c12
Yield: 55 %

Procedure:
Prepared according to the general procedure described in Example 86, by reacting 4-methoxy-3-(1H-pyrazol-4-yl)-1-trityl-1H-pyrazolo[4,3-c]pyridine with 1-bromomethyl-2,2-difluorocyclopropane to give the title compound (29.4 mg, 55% over two steps). LC-MS (Method G): m/z=306.0 [M+H]+, 3.49 min. 1H-NMR (400 MHz, DMSO): δ 13.28 (s, 1H), 8.34 (s, 1H), 8.04 (s, 1H), 7.86 (d, J=5.8, 1H), 7.09 (d, J=5.9, 1H), 4.43-4.26 (m, 2H), 4.06 (s, 3H), 2.37-2.23 (m, 1H), 1.79-1.67 (m, 1H), 1.60-1.49 (m, 1H).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([F:8])=[N:6][CH:7]=1.C([Sn](CCCC)(CCCC)[C:14]1[S:15][CH:16]=[CH:17][N:18]=1)CCC>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:8][C:5]1[N:6]=[CH:7][C:2]([C:14]2[S:15][CH:16]=[CH:17][N:18]=2)=[CH:3][CH:4]=1
Reactant: Fc1ccc(Br)cn1
Reactant: CCCC[Sn](CCCC)(CCCC)c1nccs1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Product: Fc1ccc(-c2nccs2)cn1
Temperature: 100 °C
Yield: 77.7 %

Procedure:
To a solution of 5-bromo-2-fluoropyridine (0.5 g, 2.857 mmol) in DMF (6 mL), 2-(tributylstannyl)thiazole (1.3 mL, 4.285 mmol) and Pd(PPh3)2Cl2(0.2 mg, 0.2857 mmol) were added under argon. The mixture was degassed with argon for 10 min and heated to 100° C. for 30 min. The reaction mixture was filtered through Celite® reagent and the filtrate was diluted with EtOAc (2×100 mL) and water (100 mL). The organic layer was separated, dried over Na2SO4, filtered and concentrated under reduced pressure to obtain crude product. The crude product was purified by Biotage IsoleraOne® column (5% ethyl acetate in hexane) to obtain 2-(6-fluoropyridin-3-yl) thiazole as off-white solid (0.4 g, 80% yield). 1H NMR (400 MHz, DMSO-d6): δ 8.80 (s, 1H), 8.52-8.47 (m, 1H), 7.98 (d, 1H), 7.87 (d, 1H), 7.33 (dd, 1H); LC-MS m/z calculated for [M+11]+181.02. found 180.8.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([S:9][CH2:10][C:11]([OH:13])=O)[N:3]=1.C(Cl)(=O)C(Cl)=O.[CH2:20]([CH2:22][NH2:23])[OH:21]>C1C=CC=CC=1.C(Cl)(Cl)Cl>[Cl:8][C:6]1[CH:7]=[C:2]([Cl:1])[N:3]=[C:4]([S:9][CH2:10][C:11]([NH:23][CH2:22][CH2:20][OH:21])=[O:13])[N:5]=1
Reactant: NCCO
Reactant: O=C(O)CSc1nc(Cl)cc(Cl)n1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: c1ccccc1
Product: O=C(CSc1nc(Cl)cc(Cl)n1)NCCO
Temperature: 40 °C
Reaction time: 0.17 h

Procedure:
To a suspension of (4,6-dichloro-2-pyrimidinyl-thio)-acetic acid (2.390 g.) in anhydrous benzene (24 ml.), 1.27 ml. of oxalyl chloride in anhydrous benzene (6 ml.) was added at room temperature. The reaction mixture was heated, with agitation, to 40° C., for 30 minutes and held for another 10 minutes at 60° C. The solvent was evaporated under vacuum to give an oily residue, which was taken up again in anhydrous chloroform (50 ml.). The chloroform solution was added drop by drop to a solution of ethanolamine (1.1 ml.) in anhydrous chloroform (40 ml.) while the temperature was kept at about 15° C. The mixture was held at ambient temperature for 60 minutes and the separated solid was then filtered off. The filtrate was evaporated under vacuum to obtain a residue which was crystallised from ethyl acetate/hexane (1.5 g.), m.p. 95°-96° C.
Reaction SMILES: C([O:3][C:4](=[O:18])[C:5]1[C:10]([O:11][CH2:12][CH3:13])=[CH:9][C:8]([C:14]([CH3:17])([CH3:16])[CH3:15])=[N:7][CH:6]=1)C.[OH-].[K+]>C(O)C.O>[C:14]([C:8]1[CH:9]=[C:10]([O:11][CH2:12][CH3:13])[C:5]([C:4]([OH:18])=[O:3])=[CH:6][N:7]=1)([CH3:17])([CH3:15])[CH3:16]
Reactant: CCOC(=O)c1cnc(C(C)(C)C)cc1OCC
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCOc1cc(C(C)(C)C)ncc1C(=O)O
Temperature: 80 °C
Reaction time: 1 h

Procedure:
6-tert-Butyl-4-ethoxy-nicotinic acid ethyl ester (100 mg, 0.4 mmol) was dissolved in ethanol. Potassium hydroxide (46 mg, 0.8 mmol) in 1 mL of water was added. It was stirred at 80° C. for 1 hr, checked by thin layer chromatography and LC-MS until the reaction was completed. The mixture was concentrated at high vacuum and dried overnight to give 6-tert-butyl-4-ethoxy-nicotinic acid as a white solid which was used in the next reaction with out further purification. The 6-tert-butyl-4-ethoxy-nicotinic acid was heated at 70° C. in 3 mL of SOCl2 for 2 hrs. The reaction mixture containing 6-tert-butyl-4-ethoxy-nicotinoyl chloride was concentrated to dryness then suspended in tetrahydrofuran (6 mL) with 0.1 mL of triethylamine and used for the next reaction immediately.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[N:9][CH:10]=2)[NH:5][CH:4]([CH3:12])[CH2:3]1.C(N(CC)CC)C.[C:20](OC(=O)C)(=[O:22])[CH3:21]>ClCCl>[C:20]([N:5]1[C:6]2[C:11](=[CH:10][N:9]=[CH:8][CH:7]=2)[C:2](=[O:1])[CH2:3][CH:4]1[CH3:12])(=[O:22])[CH3:21]
Reactant: CC1CC(=O)c2cnccc2N1
Reactant: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)N1c2ccncc2C(=O)CC1C
Temperature: 40 °C
Reaction time: 8 h

Procedure:
[Step 4] 30 mg of the 4-oxo-2-methyl-2,3-dihydro-1H-[1,6]naphthyridine were dissolved in 2 mL of dichloromethane followed by adding 0.1 mL of triethylamine and 35 μL of acetic anhydride and stirring overnight at 40° C. Following completion of the reaction, the solution was concentrated under reduced pressure and the resulting residue was purified using silica gel chromatography (ethyl acetate) to obtain 7 mg of 1-acetyl-4-oxo-2-methyl-2,3-dihydro-1H-[1,6]naphthyridine in the form of a pale yellow oil (18%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[C:7]([OH:13])=[CH:6][C:5]2=[O:14].C(=O)(O)[O-:16].[Na+].OO>O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[C:7]([OH:13])=[C:6]([OH:16])[C:5]2=[O:14]
Reactant: O=C([O-])O
Reactant: O=C1C=C(O)C(=O)c2ccc(Cl)cc21
Agent: OO
Agent: [Na+]
Solvent: O
Product: O=C1C(O)=C(O)C(=O)c2cc(Cl)ccc21

Procedure:
A solution of 1.2 gm 6- chloro-2-hydroxy-1,4-naphthoquinone (or 7-chloro or mixture thereof) and 0.48 g sodium bicarbonate in 58 ml of water is cooled to 5° C. and 2.3 ml of 30% hydrogen peroxide is added in one portion. The mixture is then stirred at 22° C. for 16 hours where the red crystalline product (0.24 g) is removed by filtration and crystallized from water:methanol (2:1) giving the 6-chloro-2,3-dihydroxy-1,4-naphthoquinone, m.p. 228°-229° C.
Reaction SMILES: O[C@@H:2]([CH3:22])[C@H:3]([NH:7][C:8]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:9])[C:4]([OH:6])=[O:5].CCN(CC)CC.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>C(Cl)Cl>[C:16]1([CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][O:10][C:8](=[O:9])[NH:7][C@@H:3]2[C:4](=[O:6])[O:5][C@H:2]2[CH3:22])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: C[C@H](O)[C@H](NC(=O)OCCCCCc1ccccc1)C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@@H]1OC(=O)[C@H]1NC(=O)OCCCCCc1ccccc1
Temperature: 0 °C
Reaction time: 15 h
Yield: 67.7 %

Procedure:
Under nitrogen atmosphere at 0° C., to a stirred mixture of (2S,3S)-3-hydroxy-2-(5-phenylpentoxycarbonylamino)-butanoic acid (0.35 g, 1.13 mmol) in dry CH2Cl2 (35 mL), Et3N (0.47 mL, 3.39 mmol) and subsequently TBTU (0.43 g, 1.35 mmol) were added. The mixture was left stirring 1 h at 0° C. and 15 h at rt. Upon full conversion of the starting material, the organics were removed under reduced pressure, and the resulting crude product absorbed over silica gel and purified by typical column chromatography, eluting with Cy/AcOEt (from 100:0 to 0:100) to afford the title compound (0.223 g, 76%), as white solid. MS (ESI) m/z: 292 [M−H]+; (ESI) m/z: 290 [M−H]−. 1H NMR (DMSO-d6): δ 1.28-1.39 (m, 2H), 1.48 (d, J=6.1 Hz, 3H), 1.54-1.65 (m, 4H), 2.57 (t, J=8.4, 16.2 Hz, 2H), 4.00 (t, J=6.6 Hz, 2H), 4.64-4.80 (m, 2H), 7.14-7.23 (m, 3H), 7.23-7.33 (m, 2H), 8.05 (d, J=7.9 Hz, 1H).
Reaction SMILES: [CH:1]([C@:3]12[CH2:41][CH2:40][C@@H:39]([C:42]([CH3:44])=[CH2:43])[C@@H:4]1[C@@H:5]1[C@@:18]([CH3:21])([CH2:19][CH2:20]2)[C@@:17]2([CH3:22])[C@@H:8]([C@:9]3([CH3:38])[C@@H:14]([CH2:15][CH2:16]2)[C:13]([CH3:24])([CH3:23])[C:12]([C:25]2[CH:37]=[CH:36][C:28]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])=[CH:27][CH:26]=2)=[CH:11][CH2:10]3)[CH2:7][CH2:6]1)=O.C(O)(=O)C.[NH2:49][CH2:50][CH:51]1[CH2:55][CH2:54][CH2:53][N:52]1[CH2:56][CH3:57].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.C([O-])(O)=O.[Na+]>[CH2:56]([N:52]1[CH2:53][CH2:54][CH2:55][CH:51]1[CH2:50][NH:49][CH2:1][C@:3]12[CH2:41][CH2:40][C@@H:39]([C:42]([CH3:44])=[CH2:43])[C@@H:4]1[C@@H:5]1[C@@:18]([CH3:21])([CH2:19][CH2:20]2)[C@@:17]2([CH3:22])[C@@H:8]([C@:9]3([CH3:38])[C@@H:14]([CH2:15][CH2:16]2)[C:13]([CH3:23])([CH3:24])[C:12]([C:25]2[CH:26]=[CH:27][C:28]([C:29]([O:31][C:32]([CH3:33])([CH3:34])[CH3:35])=[O:30])=[CH:36][CH:37]=2)=[CH:11][CH2:10]3)[CH2:7][CH2:6]1)[CH3:57]
Reactant: C=C(C)[C@@H]1CC[C@]2(C=O)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC(C)(C)C)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Reactant: CCN1CCCC1CN
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: C=C(C)[C@@H]1CC[C@]2(CNCC3CCCN3CC)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC(C)(C)C)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of tert-butyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-formyl-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate (0.1 g, 0.167 mmol) in DCE (2 ml) was added acetic acid (1M in DCM) (0.167 ml, 0.167 mmol) and 2-(aminomethyl)-1-ethylpyrrolidine (0.029 ml, 0.200 mmol). The mixture was stirred for 15 minutes at rt and sodium triacetoxyborohydride (0.071 g, 0.334 mmol) was added. The mixture was stirred at rt for 1.5 h then an additional 0.1 g of sodium triacetoxyborohydride was added and the mixture was stirred at rt overnight. After 24 h of stirring, some starting material still remained by TLC. To the mixture was added acetic acid (1M in DCM) (0.167 ml, 0.167 mmol), 2-(aminomethyl)-1-ethylpyrrolidine (0.029 ml, 0.200 mmol), and sodium triacetoxyborohydride (0.071 g, 0.334 mmol). The mixture was stirred at rt for an additional 19 h then was diluted with 7 ml of sat. NaHCO3. The mixture was extracted with dichloromethane (3×7 ml) and the combined organic layers were dried with Na2SO4. The drying agent was removed by filtration and the filtrate was concentrated under reduced pressure. The mixture was purified by flash chromatography using a 0-10% MeOH in dichloromethane gradient. Two products were isolated as white foams. LC/MS indicated the same mass for both, with different retention times. 1H NMR confirmed that two diastereomers were isolated. 44 mg of diastereomer 1 (less polar spot by TLC) was isolated while 55 mg of diastereomer 2 (more polar spot) was isolated. Diastereomer 1: LCMS: m/e 711.4 (M+H)+, 3.34 min (method 6). Diastereomer 2: LCMS: m/e 711.6 (M+H)+, 3.27 min (method 6).
Reaction SMILES: [F:1][S:2]([F:13])([F:12])([F:11])([F:10])[C:3]1[CH:9]=[CH:8][C:6](N)=[CH:5][CH:4]=1.[OH:14]S(O)(=O)=O.N([O-])=O.[Na+]>O>[F:1][S:2]([F:13])([F:12])([F:11])([F:10])[C:3]1[CH:9]=[CH:8][C:6]([OH:14])=[CH:5][CH:4]=1
Reactant: Nc1ccc(S(F)(F)(F)(F)F)cc1
Reactant: O=S(=O)(O)O
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: Oc1ccc(S(F)(F)(F)(F)F)cc1
Temperature: 0 °C
Reaction time: 0.58 h

Procedure:
40.00 g of 4-pentafluorosulfanylaniline were suspended in 500 ml of a 35% aqueous H2SO4 solution and a solution of 13.85 g of NaNO2 in 30 ml of water was added dropwise at 0° C. over a period of 10 minutes. Subsequently, the mixture was stirred at 0° C. for 35 minutes, then a solution, at 0° C., of 171.10 g of Cu(NO3)2 in 200 ml of water was poured in and, directly thereafter, 26.11 g of Cu2O were added in portions. The mixture is stirred at RT for a further 2 hours, then extraction is effected 3 times with 200 ml each time of CH2Cl2. Drying was effected over MgSO4 and the solvent was removed under reduced pressure. 38.00 g of a pale yellow oil were obtained which was used further without purification.
Reaction SMILES: I[CH2:2][CH2:3][CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[N:7]([CH3:14])[C:6]1=[O:15].[Cl:16][C:17]1[CH:32]=[CH:31][C:20]2[N:21]([CH:25]3[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]3)[C:22](=[O:24])[NH:23][C:19]=2[CH:18]=1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O>[Cl:16][C:17]1[CH:32]=[CH:31][C:20]2[N:21]([CH:25]3[CH2:26][CH2:27][N:28]([CH2:2][CH2:3][CH2:4][N:5]4[C:9]5[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=5[N:7]([CH3:14])[C:6]4=[O:15])[CH2:29][CH2:30]3)[C:22](=[O:24])[NH:23][C:19]=2[CH:18]=1
Reactant: O=c1[nH]c2cc(Cl)ccc2n1C1CCNCC1
Reactant: Cn1c(=O)n(CCCI)c2ccccc21
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1c(=O)n(CCCN2CCC(n3c(=O)[nH]c4cc(Cl)ccc43)CC2)c2ccccc21
Reaction time: 2 h
Yield: 43 %

Procedure:
A mixture of 5 parts of 1,3-dihydro-1-(3-iodopropyl)-3-methyl-2H-benzimidazol-2-one, 3.75 parts of 5-chloro-1,3-dihydro-1-(4-piperidinyl)-2H-benzimidazol-2-one, 2,65 parts of sodium carbonate and 22.5 parts of N,N-dimethylformamide is stirred at 70°-80° C. for 2 hours. The reaction mixture is cooled, poured onto water and the precipitated product is filtered off. It is dissolved in trichloromethane. The solution is dried, filtered and evaporated. The residue is crystallized from 4-methyl-2-pentanone, yielding 3 parts (43%) of 5-chloro-1-{1-[3-(1,3-dihydro-3-methyl-2-oxo-2H-benzimidazol-1-yl)propyl]-4-piperidinyl}-1,3-dihydro-2H-benzimidazol-2-one; mp. 166.5° C.
Reaction SMILES: B(Br)(Br)[Br:2].S(O[CH2:10][CH2:11][CH2:12][CH2:13][CH:14]1[C:23]2[C:18](=[CH:19][C:20]([O:24]C)=[CH:21][CH:22]=2)[CH2:17][CH2:16][C:15]1([C:27]1[CH:32]=[CH:31][C:30]([O:33]C)=[CH:29][CH:28]=1)[CH3:26])(C)(=O)=O.O>C(Cl)Cl>[Br:2][CH2:10][CH2:11][CH2:12][CH2:13][CH:14]1[C:23]2[C:18](=[CH:19][C:20]([OH:24])=[CH:21][CH:22]=2)[CH2:17][CH2:16][C:15]1([C:27]1[CH:32]=[CH:31][C:30]([OH:33])=[CH:29][CH:28]=1)[CH3:26]
Reactant: BrB(Br)Br
Reactant: COc1ccc(C2(C)CCc3cc(OC)ccc3C2CCCCOS(C)(=O)=O)cc1
Solvent: ClCCl
Solvent: O
Product: CC1(c2ccc(O)cc2)CCc2cc(O)ccc2C1CCCCBr
Temperature: -60 °C

Procedure:
A molar solution of boron tribromide in methylene chloride (27.6 ml.) was added to a stirred solution of (1RS,2RS)-1,2,3,4-tetrahydro-1-(4-mesyloxybutyl)-6-methoxy-2-p-methoxyphenyl-2-methylnaphthalene (Example 1; 2.3 g.) in methylene chloride (30 ml.) which was cooled to -60° C. under an atmosphere of argon, and the mixture was allowed to warm up to laboratory temperature and then poured into iced water. The mixture was extracted with ethyl acetate and the extract was dried and evaporated to dryness. The residue was purified by chromatography on a silica gel column using a 9:1 v/v mixture of toluene and ethyl acetate as eluent. There were thus separately obtained the (1RS, 2RS)- and (1RS,2SR)-isomers of 1-(4-bromobutyl)-2-p-hydroxyphenyl- 2-methyl-1,2,3,4-tetrahydronaphth-6-ol.
Reaction SMILES: [CH3:1][N:2]([CH2:17][CH:18]([C:25]1[CH:30]=[CH:29][C:28]([Cl:31])=[C:27]([Cl:32])[CH:26]=1)[CH2:19][CH2:20]S(C)(=O)=O)[C:3](=[O:16])[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[C:6]([O:14][CH3:15])[CH:5]=1.I.[NH:34]1[C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][C:37]=2[N:36]=[C:35]1[C:43]([CH:45]1[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]1)=[O:44]>>[CH3:1][N:2]([CH2:17][CH:18]([C:25]1[CH:30]=[CH:29][C:28]([Cl:31])=[C:27]([Cl:32])[CH:26]=1)[CH2:19][CH2:20][N:48]1[CH2:49][CH2:50][CH:45]([C:43]([C:35]2[NH:34][C:38]3[CH:39]=[CH:40][CH:41]=[CH:42][C:37]=3[N:36]=2)=[O:44])[CH2:46][CH2:47]1)[C:3](=[O:16])[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[C:6]([O:14][CH3:15])[CH:5]=1
Reactant: O=C(c1nc2ccccc2[nH]1)C1CCNCC1
Reactant: COc1cc(C(=O)N(C)CC(CCS(C)(=O)=O)c2ccc(Cl)c(Cl)c2)cc(OC)c1OC
Agent: I
Product: COc1cc(C(=O)N(C)CC(CCN2CCC(C(=O)c3nc4ccccc4[nH]3)CC2)c2ccc(Cl)c(Cl)c2)cc(OC)c1OC

Procedure:
Prepare by the method of Example 1.7 using N-methyl-N-(2-(3,4-dichlorophenyl)-4-methanesulfonylbutyl)-3,4,5-trimethoxybenzamide and 4-(1H-benzimidazole-2-carbonyl)piperidine hydriodic acid salt to give the title compound.
Reaction SMILES: [C:1]([NH:4][C:5]1[N:9]([C:10]2[CH:15]=[C:14]([SH:16])[C:13]([CH3:17])=[CH:12][C:11]=2[F:18])[N:8]=[C:7]([O:19][CH2:20][C:21]([F:27])([F:26])[C:22]([F:25])([F:24])[F:23])[CH:6]=1)(=[O:3])[CH3:2].C(=O)([O-])[O-].[Na+].[Na+].FC(F)(F)C(F)(F)C(F)(F)C(F)(F)S(O[CH2:43][C:44]([Cl:47])([F:46])[F:45])(=O)=O>CN(C)C=O>[C:1]([NH:4][C:5]1[N:9]([C:10]2[CH:15]=[C:14]([S:16][CH2:43][C:44]([Cl:47])([F:46])[F:45])[C:13]([CH3:17])=[CH:12][C:11]=2[F:18])[N:8]=[C:7]([O:19][CH2:20][C:21]([F:27])([F:26])[C:22]([F:25])([F:24])[F:23])[CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1cc(OCC(F)(F)C(F)(F)F)nn1-c1cc(S)c(C)cc1F
Reactant: O=S(=O)(OCC(F)(F)Cl)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)Nc1cc(OCC(F)(F)C(F)(F)F)nn1-c1cc(SCC(F)(F)Cl)c(C)cc1F
Temperature: 25 °C
Reaction time: 12 h
Yield: 70 %

Procedure:
Then, 1.5 g of 5-acetylamino-1-(2-fluoro-4-methyl-5-mercaptophenyl)-3-(2,2,3,3,3-pentafluoropropoxy)pyrazole was dissolved in 20 mL of dimethylformamide, and 0.32 g of sodium carbonate and 1.5 g of 2-chloro-2,2-difluoroethyl nonafluorobutanesulfonate were added, followed by stirring at room temperature for 12hours. Then, extraction with ethyl acetate was carried out, the organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, the obtained residue was purified by silica gel column chromatography (developing solvent ethyl acetate:hexane=1:4) to obtain 1.3 g of 5-acetylamino-1-{2-fluoro-4-methyl-5-(2-chloro-2,2-difluoroethylthio)phenyl}-3-(2,2,3,3,3-pentafluoropropoxy)pyrazole.