Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[C:5](SC#N)=[N:6][C:7]([NH:10][CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[N:8][CH:9]=1)([O-:3])=[O:2].[NH2:22][CH2:23][C@H:24]1[CH2:29][CH2:28][C@H:27]([NH:30]C(=O)OC(C)(C)C)[CH2:26][CH2:25]1>C(Cl)Cl>[NH2:30][C@H:27]1[CH2:28][CH2:29][C@H:24]([CH2:23][NH:22][C:5]2[C:4]([N+:1]([O-:3])=[O:2])=[CH:9][N:8]=[C:7]([NH:10][CH2:11][CH2:12][C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:6]=2)[CH2:25][CH2:26]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](CN)CC1
Reactant: N#CSc1nc(NCCc2ccccc2)ncc1[N+](=O)[O-]
Solvent: ClCCl
Product: N[C@H]1CC[C@H](CNc2nc(NCCc3ccccc3)ncc2[N+](=O)[O-])CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 38.9 %

Procedure:
To a solution of the above (5-nitro-4-thiocyanato-pyrimidin-2-yl)-phenethyl-amine (75 mg, 0.25 mmol) in CH2Cl2 was added tert-butyl trans-4-aminomethylcyclohexylcarbamate (114 mg, 0.5 mmol). The reaction mixture was stirred at room temperature for 16 h and concentrated in vacuo. The resulting residue was then diluted with CH2Cl2 (1 mL) and TFA (0.5 mL) was added. The mixture was stirred at room temperature for 4 h and concentrated in vacuo. The resulting residue was purified by preparative LCMS to afford 36 mg (39%) of the title compound, m/z 371.6 [M+1]+.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([N:8]([CH3:16])[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:5]=[C:4]([O:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=2)[N:3]=1.CCCCCC.[Li]CCCC.[C:39](=[O:41])=[O:40]>C(OCC)C>[CH3:16][N:8]([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:6]1[CH:5]=[C:4]([O:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=2)[N:3]=[C:2]([C:39]([OH:41])=[O:40])[CH:7]=1
Reactant: CN(Cc1ccccc1)c1cc(Br)nc(Oc2cccc(C(F)(F)F)c2)c1
Reactant: O=C=O
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Product: CN(Cc1ccccc1)c1cc(Oc2cccc(C(F)(F)F)c2)nc(C(=O)O)c1
Reaction time: 0.17 h

Procedure:
2.00 g (0.0046 mol) of 2-bromo-4-{methyl(phenylmethyl)amino}-6-{3-(trifluoromethyl)phenoxy} pyridine was dissolved in about 100 ml of diethyl ether. While cooling the obtained suspension in a dry ice-acetone bath in an argon atmosphere, 2.2 ml of a 1.6M-hexane solution of BuLi (0.0023×1.5 mol) was added thereto, followed by stirring the suspension for about 10 minutes. After an interior of reactor was replaced with carbon dioxide gas, the reaction solution was removed from the bath and stirred at room temperature for about one hour. The reaction solution was mixed with about 10 ml of a 1N-HCl aqueous solution, and then distributed in ethyl acetate-water, followed by washing with saturated brine. The organic phase of the obtained solution was dried with anhydrous sodium sulfate, concentrated and subjected to silica gel column chromatography (eluting solution: ethyl acetate/hexane) to remove a main fraction therefrom. The fraction was concentrated, thereby obtaining an aimed product.
Reaction SMILES: CN(C)[CH:3]=[O:4].P(Cl)(Cl)(Cl)=O.[I-].[CH2:12]([C:16]1([CH2:27][CH:28]([CH3:30])[CH3:29])[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[N+:18]([CH3:25])=[C:17]1[CH3:26])[CH:13]([CH3:15])[CH3:14].C>O>[CH2:12]([C:16]1([CH2:27][CH:28]([CH3:30])[CH3:29])[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[N:18]([CH3:25])[C:17]1=[CH:26][CH:3]=[O:4])[CH:13]([CH3:15])[CH3:14]
Reactant: CN(C)C=O
Reactant: CC1=[N+](C)c2ccccc2C1(CC(C)C)CC(C)C
Agent: C
Agent: [I-]
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Product: CC(C)CC1(CC(C)C)C(=CC=O)N(C)c2ccccc21
Temperature: 25 °C

Procedure:
To 10 mL of dry dimethylformamide in a flask cooled with an ice bath was added dropwise with stirring phosphoryl chloride (1.76 g, 0.0115 mole). After a few minutes 3,3-diisobutyl-1,2-dimethyl-(3H)-indolium iodide (3.85 g, 0.01 mole) was added portionwise over 5 min. The resulting solution was allowed to stir at room temperature for at least 3 hours. This solution was then slowly poured into 250 mL of water stirring in a beaker. After a few minutes 3,3-diisobutyl-2-dimethylaminovinyl-1-methyl-(3H)-indolium iodide separated as its monohydrate via elemental analysis and NMR of a small sample which was removed. This aqueous suspension was then heated to boiling with stirring to dissolve this intermediate product giving a yellow solution with a little purple scum floating on the top. A little Norit was added and after a minute or so the solution was filtered. The yellow filtrate was made strongly basic with 20% sodium hydroxide solution and stirred with warming at 50°-60° C. for a few minutes. The formylmethylene product separated and slowly became crystalline. After cooling to room temperature, the product was filtered, washed well with water, and dried to give 2.3 g (80.6%). The IR and NMR were good. (MW 285.43)
Reaction SMILES: [CH2:1]([C:5]1[C:9](/[CH:10]=[CH:11]/[C:12]2[S:13][C:14]([C:18]([OH:20])=O)=[C:15]([CH3:17])[N:16]=2)=[C:8]([CH3:21])[O:7][N:6]=1)[CH2:2][CH2:3][CH3:4].[CH3:22][CH:23]([NH2:28])[C:24]([F:27])([F:26])[F:25]>>[F:25][C:24]([F:27])([F:26])[C@H:23]([NH:28][C:18]([C:14]1[S:13][C:12](/[CH:11]=[CH:10]/[C:9]2[C:5]([CH2:1][CH2:2][CH2:3][CH3:4])=[N:6][O:7][C:8]=2[CH3:21])=[N:16][C:15]=1[CH3:17])=[O:20])[CH3:22]
Reactant: CC(N)C(F)(F)F
Reactant: CCCCc1noc(C)c1/C=C/c1nc(C)c(C(=O)O)s1
Product: CCCCc1noc(C)c1/C=C/c1nc(C)c(C(=O)N[C@H](C)C(F)(F)F)s1
Yield: 46 %

Procedure:
As described for example 104, 2-[(E)-2-(3-butyl-5-methyl-isoxazol-4-yl)-vinyl]-4-methyl-thiazole-5-carboxylic acid (153 mg, 0.5 mmol) was converted, using L-2,2,2,-trifluoro-1-(methyl)ethylamine instead of rac-2-amino-1-butanol, to the title compound (92 mg, 46%) which was obtained as a white solid after purification by chromatography (silica, 50 to 100% ethyl acetate in heptane and recrystallization from ethyl acetate/heptane. MS: m/e=402.3 [M+H]+.
Reaction SMILES: Cl[C:2]1[N:6]([CH3:7])[C:5]2[CH:8]=[CH:9][CH:10]=[CH:11][C:4]=2[N:3]=1.[CH:12]1[C:17]([OH:18])=[CH:16][CH:15]=[C:14]([Br:19])[CH:13]=1>C(N(CC)CC)C>[Br:19][C:14]1[CH:15]=[CH:16][C:17]([O:18][C:2]2[N:6]([CH3:7])[C:5]3[CH:8]=[CH:9][CH:10]=[CH:11][C:4]=3[N:3]=2)=[CH:12][CH:13]=1
Reactant: Oc1ccc(Br)cc1
Reactant: Cn1c(Cl)nc2ccccc21
Solvent: CCN(CC)CC
Product: Cn1c(Oc2ccc(Br)cc2)nc2ccccc21
Temperature: 120 °C
Reaction time: 6 h
Yield: 24.4 %

Procedure:
Triethylamine (18 mL) was added to a mixture of 2-chloro-1-methyl-1H-benzimidazole (7.2 g) and p-bromophenol (22.5 g) at room temperature. The mixture was stirred at 120° C. for 6 h. The mixture was quenched with water at room temperature and extracted with EtOAc. The organic layer was separated, washed with 1 N NaOH aq. and brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by column chromatography (NH silica gel, eluted with 10%-15% EtOAc in hexane) to give 2-(4-bromophenoxy)-1-methyl-1H-benzimidazole (3.2 g) as colorless crystals.
Reaction SMILES: [CH2:1](OC1C=C(CC(O)=O)C=C(C2C=CC(C(F)(F)F)=CC=2)C=1)[C:2]1C=CC=C[CH:3]=1.[N:29]1([S:34]([C:37]2[CH:64]=[CH:63][C:40]([CH2:41][O:42][C:43]3[CH:44]=[C:45]([CH2:59][C:60]([OH:62])=[O:61])[CH:46]=[C:47]([C:49]4[CH:54]=[CH:53][C:52]([C:55]([F:58])([F:57])[F:56])=[CH:51][CH:50]=4)[CH:48]=3)=[CH:39][CH:38]=2)(=[O:36])=[O:35])[CH2:33][CH2:32][CH2:31][CH2:30]1.C(O)C1C=CC=CC=1.N1(S(C2C=CC(CO)=CC=2)(=O)=O)CCCC1>>[N:29]1([S:34]([C:37]2[CH:38]=[CH:39][C:40]([CH2:41][O:42][C:43]3[CH:44]=[C:45]([CH:59]([CH2:1][CH2:2][CH3:3])[C:60]([OH:62])=[O:61])[CH:46]=[C:47]([C:49]4[CH:54]=[CH:53][C:52]([C:55]([F:57])([F:58])[F:56])=[CH:51][CH:50]=4)[CH:48]=3)=[CH:63][CH:64]=2)(=[O:35])=[O:36])[CH2:33][CH2:32][CH2:31][CH2:30]1
Reactant: O=C(O)Cc1cc(OCc2ccccc2)cc(-c2ccc(C(F)(F)F)cc2)c1
Reactant: O=C(O)Cc1cc(OCc2ccc(S(=O)(=O)N3CCCC3)cc2)cc(-c2ccc(C(F)(F)F)cc2)c1
Agent: O=S(=O)(c1ccc(CO)cc1)N1CCCC1
Solvent: OCc1ccccc1
Product: CCCC(C(=O)O)c1cc(OCc2ccc(S(=O)(=O)N3CCCC3)cc2)cc(-c2ccc(C(F)(F)F)cc2)c1

Procedure:
Procedure as for example 110 replacing (5-benzyloxy-4′-trifluoromethyl-biphenyl-3-yl)-acetic acid with 5-[4-(pyrrolidine-1-sulfonyl)-benzyloxy]-4′-trifluoromethyl-biphenyl-3-yl-acetic acid, itself made according to the procedure of example 9 replacing benzyl alcohol with 4-(pyrrolidine-1-sulfonyl)-benzyl alcohol, afforded 2-{5-[4-(pyrrolidine-1-sulfonyl)-benzyloxy]-4′-trifluoromethyl-biphenyl-3-yl}-pentanoic acid, LC method B, retention time 12.6 min.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:11][C:10]=1[OH:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:25][C:26]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:27].C(=O)([O-])O.[K+].C1OCCOCCOCCOCCOCCOC1>C(#N)C>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:11][C:10]=1[O:23][CH2:25][C:26]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Oc1cc(OCc2ccccc2)ccc1OCc1ccccc1
Reactant: O=C(CBr)c1ccccc1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])O
Agent: [K+]
Solvent: CC#N
Product: O=C(COc1cc(OCc2ccccc2)ccc1OCc1ccccc1)c1ccccc1
Temperature: 22 °C

Procedure:
A mixture of 2,5-bis(benzyloxy)phenol (0.28 g), 2-bromoacetophenone (0.22 g), potassium hydrogen-carbonate (0.25 g) and 18-Crown-6 (3 mg) in acetonitrile (4.2 ml) was stirred at 22° C. for one week. The mixture was filtered and evaporated to dryness under reduced pressure. The residue was triturated with the mixture of ether (8.2 ml) and water (1.4 ml) at the ice bath temperature. The product was collected by filtration, washed with cold ether and dried under reduced pressure. Yield is 0.14 g. 1H NMR (DMSO-d6) δ: 4.98 (s, 2H), 5.06 (s, 2H), 5.58 (s, 2H), 6.51 (dd, J 8.9, 2.3 Hz, 1H), 6.68 (d, J 2.3 Hz, 1H), 6.94 (d, J 8.9 Hz, 1H), 7.28-8.03 (m, 15H).
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].[CH3:14][O-:15].[Na+]>CO.O>[N+:11]([C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([N+:8]([O-:10])=[O:9])[C:2]=1[O:15][CH3:14])([O-:13])=[O:12]
Reactant: C[O-]
Reactant: O=[N+]([O-])c1cccc([N+](=O)[O-])c1Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COc1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Reaction time: 8 h
Yield: 95 %

Procedure:
0.200 g (1.00 mmol) of commercially available 2-chloro-1,3-dinitrobenzene was dissolved in a warm solution of 15 ml methanol and 0.223 g (4.13 mmol) of NaOMe. The reaction was stirred overnight with continued warming. The residue was dissolved in water after evaporation of the solvent. The aqueous solution was extracted with dichloromethane, dried and evaporated under reduced pressure to give 0.187 g of 2,6-dinitroanisole (95%) as yellow flakes. 1H NMR (CDCl3) δ 8.06 (d, J=8.2 Hz, 2H, Ar—H), 7.38 (t, J=8.2 Hz, 1H, Ar—H), 4.09 (s, 3H, O—CH3). 13C NMR (CDCl3) δ 148.0, 129.4, 124.2, 65.1.
Reaction SMILES: [F:1][CH:2]([F:17])[O:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][CH:11]([F:13])[F:12])=[CH:6][C:5]=1[N+:14]([O-])=O.[H][H]>[Ni].O1CCOCC1>[F:1][CH:2]([F:17])[O:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][CH:11]([F:13])[F:12])=[CH:6][C:5]=1[NH2:14]
Reactant: [H][H]
Reactant: O=[N+]([O-])c1cc(OC(F)F)ccc1OC(F)F
Agent: [Ni]
Solvent: C1COCCO1
Product: Nc1cc(OC(F)F)ccc1OC(F)F
Yield: 98.9 %

Procedure:
A mixture of 12.6 g of 2.5-bis(difluoromethoxy)nitrobenzene, 1.3 g of Raney-nickel catalyst and 130 ml of dioxane is agitated in a hydrogen atmosphere for 15 hours at a temperature of 20°-25° C. The hydrogen consumption is 3.34 liters. After removal of the catalyst the mixture is evaporated to dryness, yielding 11.0 g of crude 2.5-bis(difluoromethoxy) aniline in form of a yellow-brown oil.
Reaction SMILES: F[C:2]1[C:7]([O:8][CH2:9][O:10][CH3:11])=[C:6]([CH3:12])[CH:5]=[CH:4][C:3]=1[O:13][CH2:14][O:15][CH3:16].[CH:17]1([C:20]#[N:21])[CH2:19][CH2:18]1.C[Si](N([K])[Si](C)(C)C)(C)C>C1(C)C=CC=CC=1>[CH3:11][O:10][CH2:9][O:8][C:7]1[C:6]([CH3:12])=[CH:5][CH:4]=[C:3]([O:13][CH2:14][O:15][CH3:16])[C:2]=1[C:17]1([C:20]#[N:21])[CH2:19][CH2:18]1
Reactant: N#CC1CC1
Reactant: COCOc1ccc(C)c(OCOC)c1F
Agent: C[Si](C)(C)N([K])[Si](C)(C)C
Solvent: Cc1ccccc1
Product: COCOc1ccc(C)c(OCOC)c1C1(C#N)CC1
Temperature: 105 °C
Yield: 42.7 %

Procedure:
2-fluoro-1,3-bis(methoxymethoxy)-4-methyl-benzene (Intermediate 34, 17.5 g, 76.011 mmol) and cyclopropanecarbonitrile (22.625 g, 337.23 mmol) were warmed under stirring to 105° C. A solution of [bis(trimethylsilyl)amino]potassium 0.5M in Toluene (275 ml) was slowly added for 1 hour to the previous solution. The reaction mixture was stirred for 6 hour at the same temperature. After cooling the solid was filtered off and the filtrate was partitioned between Brine (200 ml) and ethyl acetate (300 ml). The aqueous layer was re-extracted with ethyl acetate (200 ml) and combined organic layers were dried (Na2SO4), filtered and evaporated (the temperature during the concentration was ˜60° C. for removing the excess of cyclopropane carbonitrile). The residue was triturated with isopropanol (25 ml) and the solid collected and dried to afford the title compound (9.0 g) as white solid.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:12]2[O:13][C:14]3[CH:20]=[CH:19][C:18](Br)=[CH:17][C:15]=3[N:16]=2)[C:7]([O:10][CH3:11])=[CH:8][CH:9]=1)([O-:3])=[O:2].[CH2:22]1[O:30][C:29]2[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][C:24]=2[O:23]1>>[N+:1]([C:4]1[CH:5]=[C:6]([C:12]2[O:13][C:14]3[CH:20]=[CH:19][C:18]([C:27]4[CH:26]=[CH:25][C:24]5[O:23][CH2:22][O:30][C:29]=5[CH:28]=4)=[CH:17][C:15]=3[N:16]=2)[C:7]([O:10][CH3:11])=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: COc1ccc([N+](=O)[O-])cc1-c1nc2cc(Br)ccc2o1
Reactant: OB(O)c1ccc2c(c1)OCO2
Product: COc1ccc([N+](=O)[O-])cc1-c1nc2cc(-c3ccc4c(c3)OCO4)ccc2o1

Procedure:
Prepared by the method of Example 15d), from 2-(3-nitro-6-methoxyphenyl)-5-bromobenzoxazole (400 mg, 1.14 mmol) and 3,4-methylenedioxyphenylboronic acid (285 mg, 1.71 mmol) the subtitle compound was obtained (270 mg, 48%). The product was used directly in the next step without purification.
Reaction SMILES: [NH:1]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH2:2][C:3]([OH:5])=O.[NH2:13][CH2:14][C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16].C1CCC(N=C=NC2CCCCC2)CC1>ClCCl>[NH:1]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH2:2][C:3]([NH:13][CH2:14][C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16])=[O:5]
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: NCC(=O)OCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCC(=O)NCC(=O)OCc1ccccc1

Procedure:
A 10-20% excess of BOC-Gly-OH is coupled to the H-Gly-O-Bzl with DCC in dichloromethane for one hour. The solution is filtered and the solvent is removed on a rotary evaporator. The residue is taken up in ethyl acetate and washed successively with 1M KHSO4, water, saturated NaHCO3 solution, and water. The ethyl acetate solution is dried over MgSO4, filtered, and the solvent is removed on a rotary evaporator to form BOC-Gly-Gly-O-Bzl as a semisolid oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([S:11][CH2:12][C@@H:13]2[C@:22]3([CH3:23])[C@H:17]([C:18]([CH3:25])([CH3:24])[CH2:19][CH2:20][CH2:21]3)[CH2:16][CH2:15][C@@:14]2([CH3:27])O)[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.Cl[Sn](Cl)(Cl)Cl.O>C(Cl)Cl>[CH3:10][O:9][C:7]1[CH:8]=[C:3]([O:2][CH3:1])[CH:4]=[C:5]2[C:6]=1[C@@:14]1([CH3:27])[C@H:13]([CH2:12][S:11]2)[C@:22]2([CH3:23])[C@H:17]([C:18]([CH3:24])([CH3:25])[CH2:19][CH2:20][CH2:21]2)[CH2:16][CH2:15]1
Reactant: COc1cc(OC)cc(SC[C@@H]2[C@@]3(C)CCCC(C)(C)[C@@H]3CC[C@@]2(C)O)c1
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: ClCCl
Solvent: O
Product: COc1cc(OC)c2c(c1)SC[C@@H]1[C@@]3(C)CCCC(C)(C)[C@@H]3CC[C@@]21C
Temperature: 0 °C
Reaction time: 2 h
Yield: 80.6 %

Procedure:
To a solution of (1R,2R,4aS,8aS)-1-{[(3,5-dimethoxyphenyl)sulfanyl]-methyl}-2,5,5,8a-tetramethyl-decahydronaphthalen-2-ol (21) (1.0 g, 2.55 mmol) in CH2Cl2 (50 mL) was added dropwise SnCl4 (1 M in CH2Cl2, 10.2 mL, 10.19 mmol) at −78° C. over 5 min. After complete addition, the reaction mixture was allowed to warm to 0° C. for 1 h, then room temperature for 2 h. Water (20 mL) was added at room temperature followed by CH2Cl2 (50 mL). The organic layer was separated, dried (Na2SO4), and concentrated. Trituration with MeOH gave (1R,10R,11S,16S)-3,5-dimethoxy-1,11,15,15-tetramethyl-8-thiatetracyclo[8.8.0.02,7.011,16]octadeca-2,4,6-triene (Compound No. 22) (0.77 g, 81%) as a white solid. 1H NMR (CDCl3): δ 6.22 (d, 1H), 6.18 (d, 1H), 3.78 (s, 3H), 3.78 (s, 3H), 3.25 (m, 1H), 2.90 (m, 1H), 2.78 (m, 1H), 1.84-1.38 (m, 7H), 1.37 (s, 3H), 1.36-1.00 (m, 3H), 0.95 (s, 3H), 0.90 (m, 1H), 0.85 (s, 3H), 0.85 (s, 3H). MS m/z 375 (C23H34O2S+H+).
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:5]([CH:6]=[CH:7][C:8]([OH:10])=[O:9])=[CH:4][CH:3]=1.[I-].[K+].[OH-].[K+].Cl[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][OH:24]>C(O)C.O>[OH:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][O:1][C:2]1[CH:3]=[CH:4][C:5]([CH:6]=[CH:7][C:8]([OH:10])=[O:9])=[CH:11][CH:12]=1
Reactant: O=C(O)C=Cc1ccc(O)cc1
Reactant: OCCCCCCCl
Agent: [I-]
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)C=Cc1ccc(OCCCCCCO)cc1
Temperature: 35 °C

Procedure:
To a mixture of 24.62 g (0.15 mole) 4-hydroxycinnamic acid and 0.29 g (1.65 mmole) of potassium iodide in 60 ml of ethanol were added under a nitrogen atmosphere in 10 min a solution of 20.72 g (0.314 mole) of potassium hydroxide in 60 ml of water using a dropping funnel. The resulting solution was heated to 30-40° C. and 6-chlorohexanol (22.54 g, 0.165 mole) was then added in about 10 min. The solution was then refluxed overnight. After cooling, 70 ml of water were added to the solid reaction mixture, and the ethanol was removed using a rotary evaporator. The residue was cooled in an ice/water bath and 70 ml of conc. hydrochloric acid were added under stirring. The solid was collected and washed with water. Then the solid was stirred at 50° C. with 250 ml of acetone. After drying at 100° C. in vacuo 24.5 g (62%) of product 13 were obtained.
Reaction SMILES: CI.[C:3]([O:7][C:8]([N:10]1[CH2:16][CH2:15][CH2:14][N:13]([C:17]2[CH:22]=[CH:21][C:20]([NH:23][S:24]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)(=[O:26])=[O:25])=[C:19]([NH:33][S:34]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)(=[O:36])=[O:35])[CH:18]=2)[CH2:12][CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4].[C:43]([O-])([O-])=O.[K+].[K+]>CC(C)=O>[C:3]([O:7][C:8]([N:10]1[CH2:16][CH2:15][CH2:14][N:13]([C:17]2[CH:22]=[CH:21][C:20]([NH:23][S:24]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)(=[O:25])=[O:26])=[C:19]([N:33]([CH3:43])[S:34]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)(=[O:35])=[O:36])[CH:18]=2)[CH2:12][CH2:11]1)=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)OC(=O)N1CCCN(c2ccc(NS(=O)(=O)c3ccccc3)c(NS(=O)(=O)c3ccccc3)c2)CC1
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: CN(c1cc(N2CCCN(C(=O)OC(C)(C)C)CC2)ccc1NS(=O)(=O)c1ccccc1)S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
MeI (45 μL, 0.72 mmol) was added to a mixture of N-{4-(4-t-butyloxycarbonyl-1,4-diazepan-1-yl)-2-[(phenylsulfonyl)amino]phenyl}benzenesulfonamide (0.189 g, 0.36 mmol) and K2CO3 (0.124, 0.90 mmol) in acetone (25 mL). The mixture was stirred at r.t. for 2 h, filtered and the solvent was removed. Purification by column chromatography (DCM/MeOH/heptane 4:1:15) gave N-{4-(4-t-butyloxycarbonyl-1,4-diazepan-1-yl)-2-[methyl(phenylsulfonyl)-amino]phenyl}benzenesulfonamide as a colourless oil. Boc-deprotection was carried out by dissolving the compound in small amount of MeOH and adding HCl/ether. The solvent was removed and the residue was recrystallized from MeOH/ether to give 62.7 mg of product M+ 1 501.3 Calcd 501.16.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[OH:11])[C:5]([OH:7])=[O:6].[CH3:12][O:13][C:14]([C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][CH:25]=1)[CH:22]=[C:21]([C:26](O)=[O:27])[CH:20]=[CH:19]2)=[O:15]>C(Cl)Cl.N1C=CC=CC=1>[OH:11][C:10]1[CH:9]=[CH:8][C:4]([C:5]([OH:7])=[O:6])=[CH:3][C:2]=1[NH:1][C:26]([C:21]1[CH:20]=[CH:19][C:18]2[C:23](=[CH:24][CH:25]=[C:16]([C:14]([O:13][CH3:12])=[O:15])[CH:17]=2)[CH:22]=1)=[O:27]
Reactant: COC(=O)c1ccc2cc(C(=O)O)ccc2c1
Reactant: Nc1cc(C(=O)O)ccc1O
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)c1ccc2cc(C(=O)Nc3cc(C(=O)O)ccc3O)ccc2c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 24.8 %

Procedure:
A solution of 3-amino-4-hydroxybenzoic acid (0.142 g, 0.927 mmol) and the acyl chloride prepared from acid 74 (in 84% yield) (0.259 g, 1.019 mmol) in DCM (5 ml) and pyridine (6 ml) was stirred at room temperature for under at for 24 h. The solvent was removed under reduced pressure. HCl (aq, 4 M, 6 ml) was added and the precipitate was filtered, washed with water (10 ml) and dried under vacuum. Trituration with methanol (15 ml) and acetone (10 ml) afforded 75 as an off-white solid (0.084 g, 0.230 mml, 25%). 1H NMR (400 MHz, DMSO-d6) δ 3.92 (3H, s), 7.00 (1H, d, J 8.4 Hz), 7.67 (1H, d, J 8.8 Hz), 8.04-8.10 (2H, m), 8.16-8.27 (2H, m), 8.33 (1H, s), 8.70-8.66 (2H, m), 9.80 (1H, s), 10.55 (1H, bs). 13C NMR (100 MHz, DMSO-d6) δ 53.09, 116.18, 122.59, 125.94, 126.45, 126.26, 126.80, 128.45, 128.48, 129.19, 130.35, 130.40, 130.93, 134.13, 134.66, 134.94, 154.61, 165.85, 166.84, 167.73. νmax (solid)/(cm−1) 3059, 1716, 1666, 1592, 1541, 1283, 1247, 1132, 759.
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][C:6]2[C:9]([C:20]3[O:24][N:23]=[C:22]([CH3:25])[N:21]=3)=[C:10]([NH:12]C(=O)OC(C)(C)C)[S:11][C:5]=2[CH2:4]1)[CH3:2].FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:1]([N:3]1[CH2:8][CH2:7][C:6]2[C:9]([C:20]3[O:24][N:23]=[C:22]([CH3:25])[N:21]=3)=[C:10]([NH2:12])[S:11][C:5]=2[CH2:4]1)[CH3:2]
Reactant: CCN1CCc2c(sc(NC(=O)OC(C)(C)C)c2-c2nc(C)no2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCN1CCc2c(sc(N)c2-c2nc(C)no2)C1
Temperature: 25 °C
Reaction time: 24 h
Yield: 59.9 %

Procedure:
To a solution of compound I2 (87.0 mg, 0.240 mmol) in anhydrous methylene chloride (3 mL) was added trifluoroacetic acid (3 mL) at 0° C. The reaction mixture was warmed to room temperature and stirred for 24 h. After this time, the reaction mixture was concentrated under reduced pressure. The resulting residue was dissolved in methylene chloride (50 mL), washed with saturated aqueous sodium bicarbonate (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by flash column chromatography on silica gel eluting with methylene chloride to methanol/methylene chloride (1:19) to afford compound I3 as a yellow solid (38 mg, 60%): 1H NMR (500 MHz, CDCl3) δ 6.17 (bs, 2H), 3.48 (s, 2H), 2.99-2.96 (m, 2H), 2.82-2.79 (m, 2H), 2.62 (q, J=7.0 Hz, 2H), 2.39 (s, 3H), 1.18 (t, J=7.0 Hz, 3H). MS (M+H) 265.