Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][CH2:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])=[CH:4][CH:3]=1.[C:17]1(=[O:23])[NH:21][C:20](=[O:22])[CH2:19][CH2:18]1.[CH2:24]=O>C(O)C>[C:20]1(=[O:22])[N:21]([CH2:24][NH:1][C:2]2[CH:3]=[CH:4][C:5]([O:6][CH2:7][C:8]([O:10][C:11]([CH3:13])([CH3:12])[CH3:14])=[O:9])=[CH:15][CH:16]=2)[C:17](=[O:23])[CH2:18][CH2:19]1
Reactant: CC(C)(C)OC(=O)COc1ccc(N)cc1
Reactant: O=C1CCC(=O)N1
Reactant: C=O
Solvent: CCO
Product: CC(C)(C)OC(=O)COc1ccc(NCN2C(=O)CCC2=O)cc1
Yield: 79.7 %

Procedure:
t-Butyl 4-aminophenoxyacetate (7.00 g, 31.4 mmol) and succinimide (3.11 g, 31.4 mmol) were added to ethanol (40 ml), and a 37% aqueous formaldehyde solution (2.55 g, 31.4 mmol) was added. The mixtue was refluxed under heating for 4 hours. Low boiling matters were distilled away from the reaction mixture under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate) to give 8.37 g of t-butyl 4-(succinimidomethylamino)phenoxyacetate as a yellow solid (84%). This solid (8.30 g, 26.0 mmol) was dissolved in dimethyl sulfoxide (50 ml) and sodium borohydride (989 mg, 26.0 mmol) was added, which was followed by stirring at 100° C. for 30 minutes. After cooling, water was poured into the reaction mixture and the mixture was extracted with diethyl ether. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. After filtration, low boiling matters were distilled away from the filtrate under reduced pressure and the residue was purified by silica gel column chromatography (n-hexane/ethyl acetate=1/1) to give 3.62 g of t-butyl 4-(methylamino)phenoxyacetate as a yellow oil (59%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH:13]([CH3:18])[C:14]([O:16][CH3:17])=[O:15])[C:10](O)=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN1CCOCC1.C(OC(Cl)=O)C(C)C.[C:34]([C:38]1[CH:43]=[CH:42][C:41]([NH2:44])=[C:40]([NH2:45])[CH:39]=1)([CH3:37])([CH3:36])[CH3:35]>C1COCC1>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:10]1[NH:44][C:41]2[CH:42]=[CH:43][C:38]([C:34]([CH3:37])([CH3:36])[CH3:35])=[CH:39][C:40]=2[N:45]=1)[CH:13]([CH3:18])[C:14]([O:16][CH3:17])=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccc(N)c(N)c1
Reactant: COC(=O)C(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CC(C)COC(=O)Cl
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: COC(=O)C(C)[C@H](NC(=O)OC(C)(C)C)c1nc2cc(C(C)(C)C)ccc2[nH]1
Temperature: -78 °C
Reaction time: 1 h
Yield: 57.6 %

Procedure:
A solution of (2S)-2-[(tert-butoxycarbonyl)amino]-4-methoxy-3-methyl-4-oxobutanoic acid (Preparation 62, 8.45 g, 32.3 mmol) in THF (300 mL) was cooled to −78° C. and NMM (5.3 mL, 48.5 mmol) was added followed by a solution of isobutylchloroformate (4.44 mL, 34 mmol) in THF (20 mL) dropwise over 30 minutes. The resulting solution was added to a solution of 4-tert-butyl-1,2-diaminobenzene (5.95 g, 36.22 mmol) in THF (100 mL) via cannula at −78° C. The reaction was stirred at −78° C. for 1 hour, then allowed to warm to room temperature for 3 hours. The reaction was concentrated in vacuo and diluted with EtOAc (300 mL). The solution was washed with saturated aqueous NaHCO3 solution (2×100 mL), brine (3×100 mL), dried over Na2SO4 and concentrated in vacuo. The residue was dissolved in AcOH (150 mL) and stirred at room temperature for 4 days. The reaction was evaporated to dryness azeotroping with dioxane. The residue was purified using reverse phase column chromatography eluting with 5-40% MeCN in 0.1% formic acid in water. The acetonitrile was evaporated and the remaining aqueous solution was basified with saturated aqueous NaHCO3 solution. The product was extracted with EtOAc, dried over Na2SO4 and concentrated in vacuo. The crude residue was purified using silica gel column chromatography eluting with DCM/TBME 9/1 to afford the title compound as a yellow solid (7.25 g, 58%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([CH:10]=[CH:11][C:12]([CH3:22])=[CH:13][CH:14]=[CH:15][C:16]([CH3:21])=[CH:17][C:18]([OH:20])=[O:19])=[C:5]([CH3:23])[C:4]=1[CH3:24].P(Cl)(Cl)Cl.N1C=C[CH:32]=[CH:31][CH:30]=1.C(O)C#C>O1CCCC1.O>[CH2:32]([O:19][C:18](=[O:20])[CH:17]=[C:16]([CH3:21])[CH:15]=[CH:14][CH:13]=[C:12]([CH3:22])[CH:11]=[CH:10][C:6]1[C:7]([CH3:9])=[CH:8][C:3]([O:2][CH3:1])=[C:4]([CH3:24])[C:5]=1[CH3:23])[C:31]#[CH:30]
Reactant: c1ccncc1
Reactant: COc1cc(C)c(C=CC(C)=CC=CC(C)=CC(=O)O)c(C)c1C
Agent: C#CCO
Solvent: O
Solvent: C1CCOC1
Solvent: ClP(Cl)Cl
Product: C#CCOC(=O)C=C(C)C=CC=C(C)C=Cc1c(C)cc(OC)c(C)c1C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
20 g of 9-(4-methoxy-2,3,6-trimethyl-phenyl)-3,7-dimethyl-nona-2,4,6,8-tetraen-1-oic acid are dissolved in 200 ml of tetrahydrofuran. After the addition of 5.5 ml of phosphorus trichloride, the solution is stirred for 2 hours at room temperature, cooled to 0° C. and treated firstly with 50 ml of pyridine and then dropwise at 0°-5° C. with 50 ml of propargyl alcohol. The mixture is stirred for 2 hours at room temperature and then diluted with water. The organic phase is washed successively with water, dilute hydrochloric acid and a 2% aqueous sodium bicarbonate solution, dried over sodium sulphate and evaporated. There is obtained 9-(4-methoxy-2,3,6-trimethyl-phenyl)-3,7-dimethyl-nona-2,4,6,8-tetraen-1-oic acid propargyl ester which melts at 94°-95° C. after absorption on aluminium oxide using benzene as the eluent.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([OH:29])[C:9]1[S:13][C:12]([NH:14][C:15]([C:17]2([C:20]3[CH:28]=[CH:27][C:23]4[O:24][CH2:25][O:26][C:22]=4[CH:21]=3)[CH2:19][CH2:18]2)=[O:16])=[N:11][CH:10]=1.[C:30]1(C)C=CC(S(O)(=O)=O)=CC=1.CO>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([O:29][CH3:30])[C:9]1[S:13][C:12]([NH:14][C:15]([C:17]2([C:20]3[CH:28]=[CH:27][C:23]4[O:24][CH2:25][O:26][C:22]=4[CH:21]=3)[CH2:18][CH2:19]2)=[O:16])=[N:11][CH:10]=1
Reactant: O=C(Nc1ncc(C(O)c2ccccc2Cl)s1)C1(c2ccc3c(c2)OCO3)CC1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: CO
Product: COC(c1cnc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)s1)c1ccccc1Cl

Procedure:
1-Benzo[1,3]dioxol-5-yl-cyclopropanecarboxylic acid [5-[(2-chloro-phenyl)-hydroxy-methyl]-thiazol-2-yl]-amide (25 mg, 0.058 mmol) was placed in 1 mL of toluene with p-toluenesulfonic acid (14 mg, 0.073 mmol). Methanol (3.0 L, 0.075 mmol) was added and the solution was subjected to microwave irradiation for 5 minutes at 150° C. The mixture was then evaporated to dryness and purified by reverse-phase preparative liquid chromatography to yield the pure product. (6.0 mg, 0.013 mol, 22%). ESI-MS m/z calc. 515.1. found; 443.3 (M+1)+ Retention time 3.72 minutes. 1H NMR (400 MHz, CD3CN) δ 1.23-1.30 (m, 2H), 1.56-1.67 (m, 2H), 3.38 (s, 3H), 5.88 (s, 1H), 5.99 (s, 2H), 6.84 (d, J=6.2 Hz, 1H), 6.92-6.98 (m, 2H), 7.26 (s, 1H), 7.33-7.38 (m, 1H), 7.41-7.48 (m, 2H), 7.62-7.71 (m, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[CH:3]=1.[N+:9]([O-])([O-:11])=[O:10].[NH4+]>S(=O)(=O)(O)O>[Br:1][C:2]1[CH:3]=[C:4]([Br:8])[CH:5]=[CH:6][C:7]=1[N+:9]([O-:11])=[O:10]
Reactant: O=[N+]([O-])[O-]
Reactant: Brc1cccc(Br)c1
Agent: O=S(=O)(O)O
Agent: [NH4+]
Product: O=[N+]([O-])c1ccc(Br)cc1Br
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 64.1 %

Procedure:
To an ice-cold solution of 1,3-dibromobenzene (10 g, 42.4 mmol) in concentrated sulfuric acid (200 mL) was added ammonium nitrate (3.39 g, 42.4 mmol) portionwise. The reaction mixture was stirred at 0° C. for 15 min, then it was poured onto an ice-water mixture. The aqueous mixture was extracted with dichloromethane (2×). The combined organic layers were washed with water then a saturated aqueous solution of sodium bicarbonate (2×), dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was triturated with hexane, filtered, and dried in vacuo to give 7.63 g of 2,4-dibromo-1-nitro-benzene as a yellow solid (64% yield): 1H NMR (CDCl3) δ 7.62 (dd, 1H), 7.78 (d, 1H), 7.95 (d, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=[O:8])[C:5]([OH:11])=[CH:4][CH:3]=1.C1C(=O)N([I:19])C(=O)C1.C(OCC)(=O)C>CN(C=O)C>[Cl:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=[O:8])[C:5]([OH:11])=[C:4]([I:19])[CH:3]=1
Reactant: O=C(O)c1cc(Cl)ccc1O
Reactant: O=C1CCC(=O)N1I
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(O)c1cc(Cl)cc(I)c1O
Temperature: 60 °C
Reaction time: 20 h

Procedure:
5-Chlorosalicylic acid (20 g, 115.8 mmol) is dissolved in DMF (100 mL). To this solution is added NIS (26.1 g, 116.0 mmol) which causes the reaction to warm up to 60° C. The reaction is stirred at room temperature for 20 hours. At this point ethyl acetate (100 mL) is added and the solution washed with 0.1N HCl (100 mL). The organic phase is then washed with water (3×100 mL), dried with sodium sulfate and evaporated under reduced pressure to yield 5-yield 5-chloro-3-iodosalicylic acid as off-white solid. (mp 160°-163° C.)
Reaction SMILES: [NH:1]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C@H:2]([C:7]([NH:9][C@H:10]([C:15]([NH:17][CH2:18][C:19]([O:21]CC)=[O:20])=[O:16])[CH2:11][CH:12]([CH3:14])[CH3:13])=[O:8])[CH2:3][CH2:4][S:5][CH3:6].[OH-].[Na+].Cl>CO>[NH:1]([C:24]([O:26][C:27]([CH3:29])([CH3:28])[CH3:30])=[O:25])[C@H:2]([C:7]([NH:9][C@H:10]([C:15]([NH:17][CH2:18][C:19]([OH:21])=[O:20])=[O:16])[CH2:11][CH:12]([CH3:14])[CH3:13])=[O:8])[CH2:3][CH2:4][S:5][CH3:6]
Reactant: CCOC(=O)CNC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCSC)NC(=O)OC(C)(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CSCC[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](CC(C)C)C(=O)NCC(=O)O

Procedure:
9.98 g of BOC-Met-Leu-Gly-OEt are dissolved in 300 ml of methanol. 57 ml of 0.59 N sodium hydroxide solution are added over the course of 45 minutes at room temperature and the mixture is stirred for a further hour. Thereafter the pH-value is adjusted to 7 with 0.68 N hydrochloric acid and the solution is evaporated to dryness. The residue is dissolved in ethyl acetate and water and the pH-value is brought to 2 by means of 0.68 N hydrochloric acid. The aqueous phase is extracted by shaking with ethyl acetate. The combined ethyl acetate phases are washed with sodium chloride solution, dried and evaporated. The residue is crystallised from ethyl acetate-hexane.
Reaction SMILES: [Cl:1][CH2:2][C@@H:3]([OH:21])[CH2:4][C@@H:5]([OH:20])[CH2:6][C:7]([O:9][C:10]([CH3:19])([CH3:18])[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:8].CO[C:24](OC)([CH3:26])[CH3:25].CS(O)(=O)=O>CC(C)=O.C(OCC)(=O)C>[Cl:1][CH2:2][C@H:3]1[O:21][C:24]([CH3:26])([CH3:25])[O:20][C@@H:5]([CH2:6][C:7]([O:9][C:10]([CH3:18])([CH3:19])[CH2:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[O:8])[CH2:4]1
Reactant: CC(C)(Cc1ccccc1)OC(=O)C[C@H](O)C[C@H](O)CCl
Reactant: COC(C)(C)OC
Agent: CS(=O)(=O)O
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: CC(C)(Cc1ccccc1)OC(=O)C[C@H]1C[C@@H](CCl)OC(C)(C)O1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The crude compound (3R,5S)-2-methyl-1-phenylpropan-2-yl 6-chloro-3,5-dihydroxy-hexanoate (21.1 g) prepared in Example 3 was dissolved in acetone (210 ml), and 2,2-dimethoxypropane (65.6 ml) and methanesulfonic acid (0.2 ml) were added dropwise thereto, followed by stirring at room temperature for 2 hours. The reaction liquid was diluted with ethyl acetate (320 ml) and washed successively with a saturated sodium bicarbonate aqueous solution (320 ml), a saturated sodium chloride aqueous solution (320 ml) and purified water (320 ml). The separated organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure to give the crude title compound (23.7 g).
Reaction SMILES: C(Cl)CCl.[CH3:5][C:6]1([CH3:22])[C:10]([CH3:12])([CH3:11])[O:9][B:8]([C:13]2[CH:21]=[CH:20][C:16]([C:17]([OH:19])=O)=[CH:15][CH:14]=2)[O:7]1.[CH3:23][O:24][CH2:25][CH2:26][NH:27][CH3:28].C1C=C2N=NN(O)C2=CC=1.O>O.CN(C=O)C>[CH3:23][O:24][CH2:25][CH2:26][N:27]([CH3:28])[C:17](=[O:19])[C:16]1[CH:15]=[CH:14][C:13]([B:8]2[O:9][C:10]([CH3:11])([CH3:12])[C:6]([CH3:5])([CH3:22])[O:7]2)=[CH:21][CH:20]=1
Reactant: CC1(C)OB(c2ccc(C(=O)O)cc2)OC1(C)C
Reactant: CNCCOC
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: O
Product: COCCN(C)C(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Reaction time: 72 h
Yield: 18 %

Procedure:
EDC (310 mg, 1.6 mmol) was added to DMF (4 mL) solution of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid (200 mg, 0.81 mmol), 2-methoxy-N-methylethanamine (144 mg, 1.6 mmol), TEA (0.23 mL, 1.6 mmol) and HOBT hydrate (247 mg, 1.60 mmol). After 3 days at room temperature, the reaction mixture was diluted in water (15 mL), extracted with DCM (3×10 mL), the combined organic portions dried over Na2SO4, filtered, concentrated under reduced pressure and purified by reverse phase HPLC (Phenomemenx Luna AXIA 5 micron C18, 21.2×100, UV at 220 nm, 10 to 70% B over 30 minutes with 10 minute hold time, solvent A: 90% water/ACNl/0.1% TFA, solvent B:90% ACN/water/0.1% TFA, Flow rate 20 mL/min; detector at 254) to isolate Compound B172a (47 mg, 18% yield) as a clear oil. HPLC: RT=0.96 min (LCMS Method M). MS (ES): m/z=319.7 [M+H]+. 1H NMR (500 MHz, CHLOROFORM-d) δ 9.45-8.71 (m, 1H), 7.85 (d, J=7.2 Hz, 2H), 7.40 (d, J=8.0 Hz, 2H), 3.89-3.64 (m, 2H), 3.42 (d, J=12.1 Hz, 3H), 3.34-3.12 (m, 3H), 3.04 (s, 2H), 1.36 (s, 12H).
Reaction SMILES: [CH2:1]([C:8]1[S:9][C:10]([CH3:31])=[C:11]([CH3:30])[C:12]=1[C:13]([C:15]1[CH:20]=[C:19]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:18]([O:27]C)=[C:17]([CH3:29])[CH:16]=1)=[O:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B(Br)(Br)Br.C(Cl)Cl>>[CH2:1]([C:8]1[S:9][C:10]([CH3:31])=[C:11]([CH3:30])[C:12]=1[C:13]([C:15]1[CH:20]=[C:19]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:18]([OH:27])=[C:17]([CH3:29])[CH:16]=1)=[O:14])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1c(C)cc(C(=O)c2c(Cc3ccccc3)sc(C)c2C)cc1-c1ccccc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Cc1cc(C(=O)c2c(Cc3ccccc3)sc(C)c2C)cc(-c2ccccc2)c1O
Yield: 76.5 %

Procedure:
The title compound was prepared according to the procedure in Example 5, step 3 using (2-benzyl-4,5-dimethyl-thiophen-3-yl)-(5-methyl-6-methoxy-biphen-3-yl)-methanone (1.68 g, 4.09 mmol) and 1M boron tribromide/CH2Cl2 (8.58 mL). Purification on Biotage KP-Sil eluting with 15% acetone/hexane gave 1.29 g (80%) of the title compound. 1H NMR (DMSO-d6) δ1.83 (s, 3H), 2.17 (s, 3H), 2.25 (s, 3H), 3.85 (s, 2H), 7.07-7.10 (m, 2H), 7.14-7.26 (m, 3H), 7.33-7.43 (m, 6H), 7.54 (d, 1H), 9.31 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([O:8][CH:9]2[CH2:14][CH2:13][N:12]([C:15](OC(C)(C)C)=O)[CH2:11][CH2:10]2)=[CH:4][CH:3]=1.[CH3:22][C:23]1(C)[CH2:25][O:24]1>ClCCl.FC(F)(F)C(O)=O>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([O:8][CH:9]2[CH2:10][CH2:11][N:12]([CH2:15][C:23]([CH3:25])([OH:24])[CH3:22])[CH2:13][CH2:14]2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(Cl)nc2)CC1
Reactant: CC1(C)CO1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(O)CN1CCC(Oc2ccc(Cl)nc2)CC1
Reaction time: 3 h
Yield: 85 %

Procedure:
To a stirred solution of tert-butyl 4-((6-chloropyridin-3-yl)oxy)piperidine-1-carboxylate (1.0 g, 3.2 mmol) in dichloromethane (10 mL), trifluoroacetic acid (3 mL) was added at 0° C. and stirred for 3 h. The reaction mixture was concentrated in vacuo and resultant residue was dissolved in MeOH (5 mL), 2,2-dimethyloxirane (0.246 g, 3.2 mmol) was added and stirred at room temperature for 10-12 h. The reaction mixture was concentrated in vacuo to give the title product (0.775, 85%); MS: 285.0 (M+1).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([C:7]2[S:11][CH:10]=[C:9]([C:12]([OH:14])=O)[CH:8]=2)[CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.CN(C(ON1N=N[C:34]2[CH:35]=[CH:36][CH:37]=[N:38][C:33]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.N1CCCCC1>CN(C=O)C>[N:38]1([C:12]([C:9]2[CH:8]=[C:7]([CH:4]3[CH2:3][CH2:2][O:1][CH2:6][CH2:5]3)[S:11][CH:10]=2)=[O:14])[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37]1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: O=C(O)c1csc(C2CCOCC2)c1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: C1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1csc(C2CCOCC2)c1)N1CCCCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 53 %

Procedure:
5-(Tetrahydro-pyran-4-yl)-thiophene-3-carboxylic acid (0.107 g, 0.5 mmol) was dissolved in DMF (2 mL). DIPEA (1.0 mmol), HATU (0.5 mmol) and piperidine (0.5 mmol) were added and the reaction stirred at room temperature for 1 hour. The reaction was then partitioned between ethyl acetate and water and the organic solution separated and dried over magnesium sulphate, filtered and the solvent evaporated. The product was purified by HPLC, eluting with 40%-90% acetonitrile in water (0.1% formic acid) over 30 minutes. The fractions containing the desired product were concentrated under vacuum to give the title compound (74 mg). LCMS m/z 280.22 [M+H]+ RT=8.77 min (Analytical Method 1). 1H NMR δ (ppm)(CHCl3-d): 7.25 (s, 1H), 6.9 (t, 1H), 4.1-4.0 (m, 2H), 3.6 (m, 4H), 3.5 (m, 2H), 3.1-3.0 (m, 1H), 1.95-1.6 (m, 10H).
Reaction SMILES: CCCCCC.[CH2:7]([C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][CH:26]=1)[CH:23]=[C:22]([O:27][CH3:28])[CH:21]=[CH:20]2)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[CH3:29][S:30]SC.[Cl-].[NH4+]>C1COCC1>[CH2:7]([C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][CH:26]=1)[CH:23]=[C:22]([O:27][CH3:28])[C:21]([S:30][CH3:29])=[CH:20]2)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCCCc1ccc2cc(OC)ccc2c1
Reactant: CSSC
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCCCCCCCCCc1ccc2cc(OC)c(SC)cc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 110.3 %

Procedure:
A hexane solution of 1.57 Mn—BuLi (28 ml, 44 mmol) was added to a THF (100 ml) solution of 6-n-decyl-2-methoxynaphthalene (compound (3)-64) (12 g, 40 mmol) at −78° C., and the solution was stirred at room temperature for 1 hour. Dimethyl disulfide (4.4 ml, 48 mmol) was added to the solution at −78° C., and the solution was stirred at room temperature for 18 hours. The reaction solution was added to a saturated ammonium chloride aqueous solution (50 ml), and extracted with ether (30 ml×3). The extracted solutions obtained by repeating the extraction 3 times were collected, washed with a saturated saline water (30 ml×3), and dried with MgSO4. The dried product was condensed with an evaporator to obtain 6-n-decyl-3-methylthio-2-methoxynaphthalene (compound (4)-64) (15.2 g, quantitative) as a yellow oil. The compound can be used in the subsequent reaction without performing further refining.
Reaction SMILES: [Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([O:9][CH3:10])=[CH:4][C:3]=1[CH2:11][OH:12].[H-].[Na+].Br[CH2:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18]>CN(C=O)C.O>[C:20]([O:19][C:17](=[O:18])[CH2:16][O:12][CH2:11][C:3]1[CH:4]=[C:5]([O:9][CH3:10])[CH:6]=[C:7]([CH3:8])[C:2]=1[Br:1])([CH3:23])([CH3:22])[CH3:21]
Reactant: COc1cc(C)c(Br)c(CO)c1
Reactant: CC(C)(C)OC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(C)c(Br)c(COCC(=O)OC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.6 %

Procedure:
A solution of (2-bromo-5-methoxy-3-methyl-phenyl)-methanol ((Example 192: step c) 0.800 g, 3.46 mmol) in DMF (10 mL) was cooled to 0° C. and treated with NaH (0.100 g of 95% dispersion, 4.15 mmol) and allowed to warm to room temperature 30 min. The mixture was then treated with tert-butyl bromoacetate (0.614 mL, 4.15 mmol) and stirred at room temperature 1 h. The reaction was diluted with water and extracted with EtOAc (2×125 mL). The combined organic layers were washed well with water (3×300 mL), dried over MgSO4, and concentrated in vacuo to afford the product (2-bromo-5-methoxy-3-methyl-benzyloxy)-acetic acid tert-butyl ester (1.19 g, 98%) as a yellow oil. 1H NMR (CDCl3): δ 6.967 (d, 1H, J=2.8 Hz), 6.745 (d, 1H, J=3.2 Hz), 4.683 (s, 2H), 4.086 (s, 2H), 3.794 (s, 3H), 2.380 (s, 3H), 1.496 (s, 9H).
Reaction SMILES: [OH:1][C:2]([CH3:21])([CH3:20])[CH2:3][CH2:4][CH2:5][C@H:6]([C@H:8]1[CH2:17][CH2:16][CH2:15][C@@H:14]2[C@:9]1([CH3:19])[CH2:10][CH2:11][CH2:12][C:13]2=[O:18])[CH3:7].[CH3:22][Si:23](C1NC=CN=1)([CH3:25])[CH3:24].C[Si](Cl)(C)C.N1C=CN=C1>O1CCCC1>[CH3:7][C@@H:6]([C@H:8]1[CH2:17][CH2:16][CH2:15][C@@H:14]2[C@:9]1([CH3:19])[CH2:10][CH2:11][CH2:12][C:13]2=[O:18])[CH2:5][CH2:4][CH2:3][C:2]([CH3:20])([O:1][Si:23]([CH3:25])([CH3:24])[CH3:22])[CH3:21]
Reactant: C[Si](C)(C)c1ncc[nH]1
Reactant: C[C@H](CCCC(C)(C)O)[C@H]1CCC[C@H]2C(=O)CCC[C@]12C
Agent: C[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: C1CCOC1
Product: C[C@H](CCCC(C)(C)O[Si](C)(C)C)[C@H]1CCC[C@H]2C(=O)CCC[C@]12C
Temperature: 0 °C

Procedure:
A solution of 24 mg (0.08 mMol) of (4aR,5R,8aR)-5-[(R)-5-Hydroxy-1,5-dimethyl-hexyl]-4a-methyl-octahydro-naphtalen-1-one in 0.5 ml of tetrahydrofuran is cooled under stirring and Argon atmosphere to 0°. The reaction mixture is stirred for an additional hour after addition of 12 μl (0.08 mMol) of trimethylsilylimidazole, of 5.1 μl (0.04 mMol) of trimethylsilylchloride and of 2.8 mg (0.04 mMol) of imidazole. The reaction mixture is poured into ice water, extracted three times with diethylether, the combined organic extracts are washed twice with brine and dried over Na2SO4. The organic solvent is evaporated in vacuo and the residue is chromatographed over 5 g of silicagel with hexane/diethylether 9/1 to yield 25 mg of pure, oily (4aR,5R,8aR)-5-[(R)-1,5-Dimethyl-5-trimethylsilanyloxy-hexyl]-4a-methyl -octahydro-naphtalen-1-one
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:6]=1[Cl:12].[OH:13][C:14]1[CH:15]=[C:16]([CH2:22][CH:23]([O:29][CH:30]([CH3:32])[CH3:31])[C:24]([O:26]CC)=[O:25])[CH:17]=[CH:18][C:19]=1[O:20][CH3:21]>>[Cl:12][C:6]1[CH:7]=[C:8]([Cl:11])[CH:9]=[CH:10][C:5]=1[O:4][CH2:3][CH2:2][O:13][C:14]1[CH:15]=[C:16]([CH2:22][CH:23]([O:29][CH:30]([CH3:32])[CH3:31])[C:24]([OH:26])=[O:25])[CH:17]=[CH:18][C:19]=1[O:20][CH3:21]
Reactant: CCOC(=O)C(Cc1ccc(OC)c(O)c1)OC(C)C
Reactant: Clc1ccc(OCCBr)c(Cl)c1
Product: COc1ccc(CC(OC(C)C)C(=O)O)cc1OCCOc1ccc(Cl)cc1Cl

Procedure:
Using 1-(2-bromoethoxy)-2,4-dichlorobenzene and ethyl 3-(3-hydroxy-4-methoxyphenyl)-2-isopropoxypropanoate, the title compound was obtained in the same manner as described in Example 33c).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([SH:13])=[CH:9][C:8]=1[CH3:14])[CH3:2].[Br:16][C:17]1[C:18](Br)=[C:19]([OH:23])[CH:20]=[CH:21][CH:22]=1.C(N(CC)CC)C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CN1C(=O)CCC1>[CH2:1]([O:3][C:4](=[O:15])[CH3:5])[CH3:2].[Br:16][C:17]1[CH:22]=[C:21]([S:13][C:10]2[CH:11]=[CH:12][C:7]([O:6][CH2:5][C:4]([OH:3])=[O:15])=[C:8]([CH3:14])[CH:9]=2)[CH:20]=[C:19]([OH:23])[CH:18]=1
Reactant: Oc1cccc(Br)c1Br
Reactant: CCOC(=O)COc1ccc(S)cc1C
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CCN(CC)CC
Solvent: CN1CCCC1=O
Product: CCOC(C)=O
Product: Cc1cc(Sc2cc(O)cc(Br)c2)ccc1OCC(=O)O
Temperature: 105 °C
Reaction time: 1 h

Procedure:
(2-Methyl-4-mercapto-phenoxy)-acetic acid ethyl ester (6 g; 26.51 mmol), dibromophenol (8.68 g; 34.47 mmol), tris(dibenzylideneacetone)dipalladium (0) (0.97 g; 1.06 mmol), and 1,1′-bis-(diphenylphosphineo)ferrocene (0.88 g; 1.59 mmol) were added to a dry reaction flask under an atmosphere of nitrogen. Triethylamine (10.73 mL, 106 mmol) and NMP (20 mL) were added, and the reaction mixture was stirred in a microwave oven for 1 h at 105° C. A 5% aqueous citric acid solution (150 mL) was added to the reaction mixture, which was extracted with ethyl acetate (4×100 mL). The pooled organic phases were washed twice with water (30 mL), dried and evaporated in vacuo. The crude reaction product was purified by flash chromatography (heptane: ethyl acetate (10:1→7:3). Yield 6.5 g. HPLC-MS: m/z: 397.3 (M+); Rt: 2.33 min.