Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:4][C:5]([NH:7][CH:8](O)[C:9]([OH:11])=[O:10])=[O:6])[CH:2]=[CH2:3].[S:13]1[CH:17]=[CH:16][C:15]2[CH:18]=[CH:19][CH:20]=[CH:21][C:14]1=2>FC(F)(F)C(O)=O>[CH2:1]([O:4][C:5]([N:7]([C:16]1[C:15]2[CH:18]=[CH:19][CH:20]=[CH:21][C:14]=2[S:13][CH:17]=1)[CH2:8][C:9]([OH:11])=[O:10])=[O:6])[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)NC(O)C(=O)O
Reactant: c1ccc2sccc2c1
Solvent: O=C(O)C(F)(F)F
Product: C=CCOC(=O)N(CC(=O)O)c1csc2ccccc12
Yield: 88 %

Procedure:
A solution of 5.15 g (29.4 mM) of DL N-allyloxycarbonyl-α-hydroxyglycine and 3.95 g (29.4 mM) of benzo[b]thiophene in 40 ml of trifluoroacetic acid was stirred at 22.5° C. for eighteen hours. The reaction mixture was then concentrated by evaporation under reduced pressure to given an oil, and the oil was dissolved in a mixture of 100 ml of ethyl acetate and 100 ml of water. The organic layer was separated, and the aqueous layer was extracted twice more with 50 ml portions of fresh ethyl acetate. The organic extracts were combined, washed with water, and then extracted twice with 100 ml portions of 10% aqueous sodium bicarbonate. The aqueous extracts were combined, added to 100 ml of fresh ethyl acetate, and acidified to pH 2.0 by the addition of conc. hydrochloric acid. The organic layer was separated and the aqueous acid layer was extracted with two 50 ml portions of fresh ethyl acetate. The organic portions were combined, dried, and the solvent was removed by evaporation to provide 7.55 g (88% yield) of N-allyloxycarbonyl-(3-benzothienyl)glycine.
Reaction SMILES: FC1C=CC(O)=C(C2C3C(=CC=CC=3)N(CCCCC)[C:9]2=[O:22])C=1.[Br:24][C:25]1[CH:26]=[CH:27][C:28]([OH:46])=[C:29]([CH:31]2[C:39]3[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=3)[N:33]([CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])[C:32]2=[O:45])[CH:30]=1>>[Br:24][C:25]1[CH:26]=[CH:27][C:28]([OH:46])=[C:29]([C:31]2([CH2:9][OH:22])[C:39]3[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=3)[N:33]([CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])[C:32]2=[O:45])[CH:30]=1
Reactant: CCCCCN1C(=O)C(c2cc(F)ccc2O)c2ccccc21
Reactant: CCCCCN1C(=O)C(c2cc(Br)ccc2O)c2ccccc21
Product: CCCCCN1C(=O)C(CO)(c2cc(Br)ccc2O)c2ccccc21

Procedure:
Following the procedure as described in PREPARATION 14C, and making non-critical variations to replace 3-(5-fluoro-2-hydroxyphenyl)-1-pentyl-1,3-dihydro-2H-indol-2-one with 3-(5-bromo-2-hydroxyphenyl)-1-pentyl-1,3-dihydro-2H-indol-2-one, the title compound was obtained: MS (ES+) m/z 386 (M−17), 388 (M−17), 426 (M+23), 428 (M+23).
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][NH:9][C:10]([C:12]2[S:13][CH:14]=[CH:15][CH:16]=2)=[O:11])[CH:5]=[CH:4][N:3]=[CH:2]1.[H-].[Na+].[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CN(C)C=O>[CH2:19]([N:9]([CH2:8][CH2:7][CH2:6][N:1]1[CH:5]=[CH:4][N:3]=[CH:2]1)[C:10]([C:12]1[S:13][CH:14]=[CH:15][CH:16]=1)=[O:11])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: BrCc1ccccc1
Reactant: O=C(NCCCn1ccnc1)c1cccs1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(c1cccs1)N(CCCn1ccnc1)Cc1ccccc1
Reaction time: 24 h

Procedure:
A mixture of 4.7 g. of N-[3-(1H-imidazol-1-yl)propyl]-2-thiophene carboxamide, 40 ml. of dimethylformamide, and 0.96 g. of 50% sodium hydride in oil was stirred for 2 hours and 2.62 g. of benzyl bromide was added. The mixture was stirred for 24 hours, concentrated to remove the dimethyl formamide, diluted with water and methylene chloride, and the layers separated. The organic layer was washed with water, dried over magnesium sulfate, and concentrated. The oil was twice washed with hexane and again concentrated. The desired product was obtained as an oil.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]([CH2:20][C:21]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22])([C:15]([O:17]CC)=[O:16])[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]>P([O-])([O-])([O-])=O.C(#N)C>[C:1]([O:5][C:6]([NH:8][C@@:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])([C:15]([OH:17])=[O:16])[CH2:20][C:21]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22])=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: CCOC(=O)C(CC(=O)OCc1ccccc1)(NC(=O)OC(C)(C)C)C(=O)OCC
Agent: O=P([O-])([O-])[O-]
Solvent: CC#N
Product: CCOC(=O)[C@](CC(=O)OCc1ccccc1)(NC(=O)OC(C)(C)C)C(=O)O
Temperature: 30 °C
Reaction time: 4 h

Procedure:
1.0 g of pig liver esterase produced by Sigma [PLE (27 kU/g), lyophilized product, product number: E3019] was dissolved in a 0.1 mol/L phosphate buffer adjusted to pH 7.5 (90 mL), and the solution was added with a solution of diethyl 2-t-butyloxycarbonylamino-2-(benzyloxycarbonylmethyl)malonate (1.0 g) dissolved in acetonitrile (10 mL). The mixture was stirred at 30° C. for 4 hours to produce the title compound. Optical purity measured by HPLC was 78.1% ee. After completion of the reaction, the reaction mixture was filtered by using a filtration aid (KC Floc 100) to remove the insoluble matter. The filtrate was cooled, and adjusted to pH 2 by adding 6 mol/L hydrochloric acid, then the objective substance was extracted with ethyl acetate, and the extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to obtain the title compound (1.0 g).
Reaction SMILES: [F:1][C:2](I)([F:4])[F:3].CN(C)P(=O)(N(C)C)N(C)C.[C:17]([C@@H:21]1[CH2:26][CH2:25][C@H:24]([NH:27][C:28]2[C:33](I)=[C:32]([CH2:35][CH3:36])[N:31]=[CH:30][N:29]=2)[CH2:23][CH2:22]1)([CH3:20])([CH3:19])[CH3:18]>[Cu].C(OCC)C>[C:17]([C@@H:21]1[CH2:22][CH2:23][C@H:24]([NH:27][C:28]2[C:33]([C:2]([F:4])([F:3])[F:1])=[C:32]([CH2:35][CH3:36])[N:31]=[CH:30][N:29]=2)[CH2:25][CH2:26]1)([CH3:20])([CH3:19])[CH3:18]
Reactant: FC(F)(F)I
Reactant: CCc1ncnc(N[C@H]2CC[C@@H](C(C)(C)C)CC2)c1I
Agent: [Cu]
Solvent: CCOCC
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCc1ncnc(N[C@H]2CC[C@@H](C(C)(C)C)CC2)c1C(F)(F)F
Temperature: 100 °C
Reaction time: 2 h

Procedure:
8.4 g of trifluoromethyl iodide and 5 g of copper powder were stirred with 20 ml of hexamethylphosphoric triamide in a stainless steel laboratory autoclave (Hastelloy) at 120° C. for 2.5 hours. The mixture was filtered with suction over Celite, under nitrogen, to remove the excess copper powder. 1.92 g (5 mmol) of 4-(cis-4-tert-butyl-cyclohexylamino)-6-ethyl-5-iodopyrimidine (Example 1) were added in order to dissolve the trifluoromethyl-copper complex, and the mixture was stirred under nitrogen at 100° C. for 2 hours. After cooling, 200 ml of diethyl ether were added, the precipitated copper salts were filtered off and the filtrate was extracted by stirring with water. The organic phase was dried and concentrated. The product was purified by filtration over a silica gel column (petroleum ether/ethyl acetate 7:3) to give 0.52 g (32% of theory) of product as a colorless oil.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:37])[CH2:10][N:11]([C:16](=[O:36])[C@H:17]([CH2:29][CH2:30][CH2:31][NH:32][C:33](=[NH:35])[NH2:34])[N:18]([N+:26]([O-:28])=[O:27])C(OC(C)(C)C)=O)[CH2:12][CH2:13][CH2:14][CH3:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:38].C(OCC)(=O)C.C(OCC)C>C(OCC)(=O)C>[ClH:38].[CH2:1]([O:8][C:9](=[O:37])[CH2:10][N:11]([C:16](=[O:36])[C@H:17]([CH2:29][CH2:30][CH2:31][NH:32][C:33](=[NH:34])[NH2:35])[NH:18][N+:26]([O-:28])=[O:27])[CH2:12][CH2:13][CH2:14][CH3:15])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCCN(CC(=O)OCc1ccccc1)C(=O)[C@H](CCCNC(=N)N)N(C(=O)OC(C)(C)C)[N+](=O)[O-]
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: CCCCN(CC(=O)OCc1ccccc1)C(=O)[C@H](CCCNC(=N)N)N[N+](=O)[O-]
Reaction time: 3 h

Procedure:
To a stirred solution of 26.0 g of NG -nitro-N2 -(tertbutoxycarbonyl)-L-arginyl-N-butylglycine benzyl ester in 50 ml of ethyl acetate was added 80 ml of 10% dry HCl-ethyl acetate at 0° C. After 3 hours, to this solution was added 200 ml of dry ethyl ether to precipitate a viscous oily product. This was filtered and washed with dry ethyl ether to give 20.8 g of NG -nitro-L-arginyl-N-butylglycine benzyl ester hydrochloride as an amorphous solid.
Reaction SMILES: Cl[CH2:2][C@H:3]1[O:7][C@@H:6]([N:8]2[C:17]3[N:16]=[CH:15][N:14]=[C:12]([NH2:13])[C:11]=3[N:10]=[C:9]2[CH3:18])[C@H:5]([OH:19])[C@@H:4]1[OH:20].[CH3:21][S-:22].[Na+]>CN(C=O)C>[CH3:21][S:22][CH2:2][C@H:3]1[O:7][C@@H:6]([N:8]2[C:17]3[N:16]=[CH:15][N:14]=[C:12]([NH2:13])[C:11]=3[N:10]=[C:9]2[CH3:18])[C@H:5]([OH:19])[C@@H:4]1[OH:20]
Reactant: C[S-]
Reactant: Cc1nc2c(N)ncnc2n1[C@@H]1O[C@H](CCl)[C@@H](O)[C@H]1O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CSC[C@H]1O[C@@H](n2c(C)nc3c(N)ncnc32)[C@H](O)[C@@H]1O

Procedure:
A solution of 3a (200 mg, 0.66 mmol) and sodium thiomethoxide (47 mg, 0.67 mmol) in 2 mL of anhydrous DMF was stirred for 2 days at room temperature and then concentrated to dryness. The crude product was purified by column chromatography using chloroform:methanol (7:1) as eluent. The desired fractions were collected, concentrated and dried in vacuo: yield 102 mg (49%); MS m/z 312 (M+H)+; 1HNMR (DMSO-d6) δ 8.09 (s, 1H, H-2), 7.12 (bs, 2H, 6-NH2), 5.77 (d, 1H, H-1′, J1′,2′=5.7 Hz), 5.38 (bd, 1H, OH-2′, J2′-2′OH=4.4 Hz), 5.31 (d, 1H, OH-3′, J3′-3′OH=4.2 Hz), 5.15 (bddd, 1H, H-2′, J1′,2′=5.7 Hz, J2′,3′=5.7 Hz, J2′-2′OH=4.4 Hz), 4.20 (ddd, 1H, H-3′, J2′,3′=5.7 Hz, J3′,4′=3.6 Hz, J3′-3′OH=4.2 Hz), 3.97-4.05 (m, 1H, H-4′), 2.74-2.92 (m, 2H, 5′-CH2), 2.54 (s, 3H, 8-CH3), 2.03 (s, 3H, S—CH3).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.Cl[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=2)=[CH:4][CH:3]=1
Reactant: Clc1ccccn1
Reactant: Oc1ccc(S)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Oc1ccc(Sc2ccccn2)cc1
Temperature: 75 °C
Yield: 91.8 %

Procedure:
Under nitrogen atmosphere, 127 g of 4-hydroxythiophenol, 112 g of chloropyridine, and 140 g of potassium carbonate were mixed. To the mixture was added 250 mL of dimethylformamide. The resultant was stirred, heated to 75° C. and further heated at 10° C. for 5 hours. At the time when the reaction completed substantially, the resultant was poured into 1.5 L of water. The precipitated crystals were collected by filtration, washed with water, and dried (yielded amount 184 g, and yield 91.8%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=O)[O:5][CH:6]=1.[NH:9]1[CH2:13][CH2:12][CH2:11][CH2:10]1.C(Cl)Cl.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CCOC(C)=O>[Br:1][C:2]1[CH:3]=[C:4]([CH2:7][N:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)[O:5][CH:6]=1
Reactant: O=Cc1cc(Br)co1
Reactant: C1CCNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: Brc1coc(CN2CCCC2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 61 %

Procedure:
To a solution of 4-bromofuran-2-carbaldehyde (500 mg, 2.85 mmol) and pyrrolidine (0.47 mL, 5.74 mmol) and CH2Cl2 (10 mL) was added sodium triacetoxyborohydride (1.2 g, 5.71 mmol). The mixture was stirred at room temperature overnight. The resulting mixture was diluted with EtOAc (100 mL) and the organic layer was washed with brine then dried (Na2SO4), filtered and concentrated. The residue was purified by column chromatography (silica, 0-5% MeOH in CH2Cl2) to afford the sub-title compound (400 mg, 61%).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[C:8]([CH:10]=[CH2:11])[CH:7]=[CH:6][C:5]=1[N+:12]([O-:14])=[O:13])[CH3:2].[CH3:15][N:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1>CC(O)C>[CH2:1]([O:3][C:4]1[CH:9]=[C:8]([CH2:10][CH2:11][N:19]2[CH2:20][CH2:21][N:16]([CH3:15])[CH2:17][CH2:18]2)[CH:7]=[CH:6][C:5]=1[N+:12]([O-:14])=[O:13])[CH3:2]
Reactant: C=Cc1ccc([N+](=O)[O-])c(OCC)c1
Reactant: CN1CCNCC1
Solvent: CC(C)O
Product: CCOc1cc(CCN2CCN(C)CC2)ccc1[N+](=O)[O-]
Temperature: 120 °C
Yield: 87.6 %

Procedure:
To 5-ethenyl-2-nitrophenyl ethyl ether (0.53 g, 2.74 mmol) in 10 mL of iPrOH was added, 1-methylpiperazine (0.41 g, 4.11 mmol). The mixture was heated to 120° C. for 2 h. The solvent was rotovaped down and the crude product was purified by flash chromatography to give the title compound of step C (0.708 g, 2.4 mmol, 88%). 1H NMR (400 MHz, CDCl3) δ ppm 7.75 (d, J=8.42 Hz, 1H), 6.90 (d, J=1.47 Hz, 1H), 6.82 (dd, J=8.42, 1.47 Hz, 1H), 4.15 (q, J=6.96 Hz, 2H), 2.78-2.83 (m, 2H), 2.33-2.88 (m, 10H), 2.30 (s, 3H), 1.46 (t, J=6.96 Hz, 3H).
Reaction SMILES: Br[CH2:2][CH2:3][N:4]([N:13]1[CH:17]=[N:16][N:15]=[CH:14]1)[C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[CH:7][CH:6]=1.[OH:18][C:19]1[CH:24]=[CH:23][C:22]([SH:25])=[CH:21][CH:20]=1.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C=O)C.O>[OH:18][C:19]1[CH:24]=[CH:23][C:22]([S:25][CH2:2][CH2:3][N:4]([N:13]2[CH:17]=[N:16][N:15]=[CH:14]2)[C:5]2[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[CH:7][CH:6]=2)=[CH:21][CH:20]=1
Reactant: Oc1ccc(S)cc1
Reactant: N#Cc1ccc(N(CCBr)n2cnnc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1ccc(N(CCSc2ccc(O)cc2)n2cnnc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 4-[(2-bromo-ethyl)-[1,2,4]triazol-4-yl-amino]-benzonitrile (CAB03031, 146 mg, 0.50 mmol), 4-hydroxythiophenol (126 mg, 1.0 mmol) and potassium carbonate (138 mg, 1.0 mmol) in DMF (10 mL) was stirred overnight at room temperature. The mixture was transferred into a separation funnel and ethyl acetate (50 mL) and water (50 mL) were added. The organic layer was separated, washed with brine (30 mL), dried over sodium sulphate and concentrated under reduced pressure. The residue was crystallised from methanol. Yield: 116 mg (69%) colourless crystals. 1H-NMR (400 MHz, d6-DMSO) δ=2.99 (t, J=7.0 Hz, 2H), 3.93 (t, J=7.0 Hz, 2H), 6.48 (d,=9.0 Hz, 2H), 6.73 (d, J=8.6 Hz, 2H), 7.21 (d, J=8.6 Hz, 2H), 7.68 (d, J=9.0 Hz, 2H), 8.89 (s, 2H), 9.66 (s, 1H, —OH). 13C-NMR (100 MHz, d6-DMSO) δ=30.62, 53.07, 102.92, 113.36, 116.86, 119.59, 122.71, 134.07, 134.49, 144.07, 151.17, 157.83. LRMS (FAB+): 338.2 (100, [M+H]+). Found: C 60.6, H 4.57, N 20.6%; C17H15N5OS (337.4) requires C 60.52, H 4.48, N 20.76%.
Reaction SMILES: [CH3:1][N:2]([CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10](/[C:13](/[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[C:14](\[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)/[CH2:15][CH2:16][Cl:17])=[CH:9][CH:8]=1)[CH3:3].[CH3:30][S:31]([OH:34])(=[O:33])=[O:32]>C(OCC)C>[CH3:1][N:2]([CH2:4][CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10](/[C:13](/[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[C:14](\[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)/[CH2:15][CH2:16][Cl:17])=[CH:11][CH:12]=1)[CH3:3].[S:31]([O-:34])(=[O:33])(=[O:32])[CH3:30]
Reactant: CS(=O)(=O)O
Agent: CN(C)CCOc1ccc(/C(=C(/CCCl)c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Product: CS(=O)(=O)[O-]
Temperature: 25 °C

Procedure:
To a solution of toremifene base (1.094 g, 0.0027 moles) and refluxing diethyl ether (15 ml) was slowly added methanesulfonic acid (190 μl, 0.0029 moles). The refluxing mixture was stirred for a while and cooled to room temperature. The mixture was stirred additional 30 min. After filtration the mesylate of toremifene was obtained (yield 95%) having melting point of 185° C. 1H-NMR (d6-DMSO) d 7.41 (t, 2H), 7.35-7.27 (m, 3H), 7.27-7.12 (m, 5H), 6.81 (d, 2H), 6.69 (d, 2H), 4.18 (t, 2H), 3.43 (t, 4H), 2.85 (t, 2H), 2.82 (s, 6H), 2.32 (s, 3H).
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)/[C:5](=[N:12]/[S:13]([C:16]2S[CH:18]=[CH:19][CH:20]=2)(=[O:15])=[O:14])/[CH:4]=[C:3]1[S:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24].[Cl:28][C:29]1C=CC(CS(N)(=O)=O)=[CH:31][CH:30]=1>C1COCC1.Cl[Ti](Cl)(Cl)Cl>[Cl:28][C:29]1[CH:18]=[CH:19][C:20]([CH2:16][S:13]([N:12]=[C:5]2[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[C:2](=[O:1])[C:3]([S:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:4]2)(=[O:14])=[O:15])=[CH:31][CH:30]=1
Reactant: CCOC(=O)CSC1=C/C(=N\S(=O)(=O)c2cccs2)c2ccccc2C1=O
Reactant: NS(=O)(=O)Cc1ccc(Cl)cc1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: C1CCOC1
Product: CCOC(=O)CSC1=CC(=NS(=O)(=O)Cc2ccc(Cl)cc2)c2ccccc2C1=O

Procedure:
5.2.21 Ethyl 2-(4-(4-chlorobenzylsulfonylimino)-1-oxo-1,4-dihydronaphthalen-2-ylthio)-acetate (8g) was prepared according to the procedure for 8a except using (4-chlorophenyl)methanesulfonamide, TiCl4.2THF and THF as solvent. The title compound 130 mg (56%) was obtained according to the workup procedure for 12a as a yellow solid, m.p.: ° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]([N:11]2[CH2:16][CH2:15][CH2:14][C@H:13]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH2:12]2)=[C:4]2[CH2:10][CH2:9][CH2:8][C:5]2=[N:6][CH:7]=1.[F:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[C:27]=1[C:33]1[S:34][CH:35]=[C:36]([C:38](O)=[O:39])[N:37]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[F:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[C:27]=1[C:33]1[S:34][CH:35]=[C:36]([C:38]([NH:1][C:2]2[C:3]([N:11]3[CH2:16][CH2:15][CH2:14][C@H:13]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:21])([CH3:23])[CH3:22])[CH2:12]3)=[C:4]3[CH2:10][CH2:9][CH2:8][C:5]3=[N:6][CH:7]=2)=[O:39])[N:37]=1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCN(c2c(N)cnc3c2CCC3)C1
Reactant: O=C(O)c1csc(-c2c(F)cccc2F)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@H]1CCCN(c2c(NC(=O)c3csc(-c4c(F)cccc4F)n3)cnc3c2CCC3)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 49.2 %

Procedure:
tert-Butyl [(3S)-1-(3-amino-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)piperidin-3-yl]carbamate (5.0 mg, 0.015 mmol) was mixed with 2-(2,6-difluorophenyl)-1,3-thiazole-4-carboxylic acid (Example 2, step 2, 4.4 mg, 0.018 mmol), HATU (14 mg, 0.038 mmol), DMF (0.035 mL) and DIPEA (5.8 mg, 0.045 mmol). The reaction mixture was stirred at room temperature for 1 h. The mixture was filtered, concentrated and purified by preparative LC-MS (XBridge™ preparative C18 5 μm 30×10 mm OBD™ column, flow rate 60 mL/min., eluting with a gradient of MeCN and water with 0.15% NH4OH) to give the sub-title compound as a colorless gum (4.1 mg, 49%). LCMS calc. for C28H32F2N5O3S (M+H)+: m/z=556.2. Found: 556.1.
Reaction SMILES: O=[CH:2][C@@H:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4].[CH2:13]([NH:21][CH2:22][CH2:23][CH2:24][NH2:25])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]>>[CH2:13]([NH:21][CH2:22][CH2:23][CH2:24][NH:25][CH2:2][C@@H:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: CCCCCCCCNCCCN
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Product: CCCCCCCCNCCCNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO

Procedure:
The product was made from D-glucose and 3-octylamino-propylamine comparable as in Example A.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:21]=1[C:20](=O)[C@H:19]1[C@@H:14]2[CH2:15][NH:16][CH2:17][CH2:18]1.[SiH](CC)(CC)CC.FC(F)(F)C(O)=O>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:21]=1[CH2:20][C@H:19]1[C@@H:14]2[CH2:15][NH:16][CH2:17][CH2:18]1
Reactant: O=C1c2c(-c3ccc(Cl)cc3Cl)cccc2[C@H]2CNCC[C@@H]12
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: Clc1ccc(-c2cccc3c2C[C@@H]2CCNC[C@H]32)c(Cl)c1

Procedure:
The title compound was prepared as a white solid (22 mg, 0.069) by following the procedures of example 5 from cis-8-(2,4-dichloro-phenyl)-1,2,3,4,4a,9a-hexahydro-3-aza-fluoren-9-one (51 mg, 0.15 mmol), Et3SiH (79 mg, 0.68 mmol) and trifluoroacetic acid (175 mg, 1.5 mmol): MS (ES) 318.1 (M+H).
Reaction SMILES: [OH-].[Na+].C(CCCC(O)=O)CCCC(O)[CH:8]([OH:16])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][OH:15].[Na].I([O-])(=O)(=O)=O.[Na+].C(=O)(O)[O-].[Na+]>O.ClCCl>[OH:16][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH:14]=[O:15]
Reactant: O=C(O)CCCCCCCC(O)C(O)CCCCCCO
Agent: O=C([O-])O
Agent: [Na+]
Agent: [Na]
Solvent: O
Solvent: ClCCl
Product: O=CCCCCCCO

Procedure:
Sodium hydroxide (13.2 g.) in water (660 ml.) was added to aleuritic acid (100 g.)and the suspension stirred at 0° to 10° C. To the resulting suspension of sodium aleuritate was added sodium periodate (80 g.) in water (800 ml.) over 1 hour, without allowing the temperature to rise above 15° C. Dichloromethane (200 ml.) was then added and the mixture stirred for a further 2.5 hours at 15° C. A further amount of dichloromethane (300 ml.) and saturated aqueous sodium bicarbonate (100 ml.) were added and the mixture vigorously stirred. The precipitated sodium iodate was removed by filtration and the dichloromethane layer separated. The aqueous phase was washed with dichloromethane (500 ml.) and the combined dichloromethane extracts dried over anhydrous magnesium sulphate. Removal of the dichloromethane in vacuo below 40° C. gave 7-hydroxyheptanal (43 g.), νmax 3400 cm-1, 2700 cm-1, 1710 cm-1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[C:12]([C:14](=[O:33])[NH:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][N:24]3[C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[CH:26]=[CH:25]3)[CH:11]=[C:10]([C:34]3[CH:39]=[CH:38][CH:37]=[C:36]([Cl:40])[CH:35]=3)[C:9]=2[O:41][CH2:42][CH2:43][CH2:44][CH2:45][C:46]([O:48]CC)=[O:47])[CH:5]=[CH:6][CH:7]=1.[OH-].[K+]>C1COCC1.CO>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[C:12]([C:14](=[O:33])[NH:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][N:24]3[C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[CH:26]=[CH:25]3)[CH:11]=[C:10]([C:34]3[CH:39]=[CH:38][CH:37]=[C:36]([Cl:40])[CH:35]=3)[C:9]=2[O:41][CH2:42][CH2:43][CH2:44][CH2:45][C:46]([OH:48])=[O:47])[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)CCCCOc1c(-c2cccc(Cl)c2)cc(C(=O)NCCCCCCCCn2ccc3ccccc32)cc1-c1cccc(Cl)c1
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)CCCCOc1c(-c2cccc(Cl)c2)cc(C(=O)NCCCCCCCCn2ccc3ccccc32)cc1-c1cccc(Cl)c1
Reaction time: 18 h
Yield: 63.4 %

Procedure:
A mixture of 5-[3,3″-Dichloro-5′-(8-indol-1-yl-octylcarbamoyl)-[1,1′;3′,1″]terphenyl-2′-yloxy]-pentanoic acid, ethyl ester (0.409 g, 0.573 mmol) and 1N KOH (1.15 ml) in THF (6 ml) and methanol (3 ml) was stirred under nitrogen. After ˜18 h, the reaction mixture was concentrated in vac. The residue was suspended in water (25 ml) and acidified with 2 N HCl (1.15 ml) then extracted with EtOAc (3×25 ml). The combined organics were washed with water (3×10 ml), brine (2×10 ml), dried over Na2SO4, filtered and the filtrate concentrated in vac and dried. The residue was purified by preparatory plate chromatography (50% EtOAc/Hex) to give the title compound as a light yellow foam (0.249 g, 63%); dec. >50° C.; 1H NMR (400 MHz, DMSO-d6) δ 1.12–1.32 (m, 12H), 1.44–1.53 (m, 2H), 1.67–1.76 (m, 2H), 1.87 (t, J=7.0 Hz, 2H), 3.16–3.27 (m, 4H), 4.12 (t, J=7.0 Hz, 2H), 6.37–6.38 (m, 1H), 6.94–6.99 (m, 1H), 7.06–7.10 (m, 1H), 7.31 (d, J=3.1 Hz, 1H), 7.40–7.52 (m, 6H), 7.56–7.59 (m, 2H), 7.66–7.69 (m, 2H), 7.87 (s, 2H), 8.52 (t, J=5.7 Hz, 1H), 11.85 (s, 1H); IR (KBr) 3400, 2940, 1710, 1630, 1550, 1220 cm−1; mass spectrum [(+)APCI], m/z 685 (M+H)+; Anal. Calcd. for C40H42Cl2N2O4: C, 70.07; H, 6.17; N, 4.09. Found: C, 69.66; H, 6.17; N, 3.85.
Reaction SMILES: [Cl:1][CH:2]=[C:3]([O:9]C1C=CC(Cl)=CC=1)[C:4]([CH3:8])([CH3:7])[CH:5]=[CH2:6]>C(O)=O.Cl>[Cl:1][CH2:2][C:3](=[O:9])[C:4]([CH3:8])([CH3:7])[CH:5]=[CH2:6]
Reactant: C=CC(C)(C)C(=CCl)Oc1ccc(Cl)cc1
Agent: Cl
Solvent: O=CO
Product: C=CC(C)(C)C(=O)CCl
Yield: 84.2 %

Procedure:
5.16 g (20 mmols) of 1-chloro-3,3-dimethyl-2-(p-chlorophenoxy)-1,4-pentadiene, prepared according to Example A2(a) above, are warmed to 50° C. in a mixture of 20 ml of formic acid and 2 ml of concentrated hydrochloric acid, during the course of 2 hours. The working-up corresponding to Example B1(a) yields 2.47 g of 1-chloro-3,3-dimethyl-pent-4-en-2-one, which are 84% of theory.