Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:19]2[S:23][C:22]([C:24](O)([CH3:26])[CH3:25])=[N:21][CH:20]=2)[CH:5]=[C:6]([NH:8][C:9]2[N:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[CH:11][N:10]=2)[CH:7]=1.[SiH](CC)(CC)CC.C(O)(C(F)(F)F)=O>C(Cl)Cl.C(OCC)(=O)C>[CH3:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[N:14]=[C:13]([C:15]([F:16])([F:18])[F:17])[CH:12]=[CH:11][N:10]=2)[CH:5]=[C:4]([C:19]2[S:23][C:22]([CH:24]([CH3:26])[CH3:25])=[N:21][CH:20]=2)[CH:3]=1
Reactant: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnc(C(C)(C)O)s2)c1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnc(C(C)C)s2)c1
Temperature: 60 °C
Yield: 56 %

Procedure:
To a stirred solution of 2-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]propan-2-ol (Example 4, 58 mg, 0.15 mmol) in DCM (1.5 mL) were added Et3SiH (0.18 mL, 1.1 mmol) and TFA (0.17 mL, 2.2 mmol). The reaction mixture was heated to 60° C. for 3 hr. Additional Et3SiH (0.18 mL) and TFA (0.11 mL) were added and the reaction was then heated to 80° C. for 1 d. The mixture was cooled to room temperature, diluted with ethyl acetate (75 mL) and washed with saturated aqueous NaHCO3 solution, water, and brine. The solution was dried over anhydrous sodium sulfate, concentrated, and purified by flash chromatography to give N-{3-methyl-5-[2-(1-methylethyl)-1,3-thiazol-5-yl]phenyl}-4-(trifluoromethyl)pyrimidin-2-amine (31.7 mg, 0.084 mmol, 57.3% yield) as a white solid. APCI: [M+H]+ m/z 379.1. 1H NMR (500 MHz, DMSO-d6) δ 10.25 (s, 1H), 8.83 (d, J=4.9, 1H), 7.98 (s, 1H), 7.93 (s, 1H), 7.44 (s, 1H), 7.28 (d, J=4.9, 1H), 7.14 (s, 1H), 3.27 (dt, J=6.9, 13.7, 1H), 2.31 (s, 3H), 1.34 (d, J=6.9, 61-1). rhSYK activity=+++
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:8]1([C:14]2([CH3:21])[O:20][CH:15]2[C:16]([O:18][CH3:19])=[O:17])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>>[O:7]([C:14]([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)([CH3:21])[CH:15]([OH:20])[C:16]([O:18][CH3:19])=[O:17])[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Oc1ccccc1
Reactant: COC(=O)C1OC1(C)c1ccccc1
Product: COC(=O)C(O)C(C)(Oc1ccccc1)c1ccccc1

Procedure:
28.2 g (0.3 mol) of phenol and 19.2 g (0.1 mol) of methyl 3-phenyl-2,3-epoxybutyrate are heated together for 6 hours at 100° C. After the excess phenol has been distilled off under greatly reduced pressure and the residue has been purified by chromatography over silica gel using a hexane/ethyl acetate mixture, 17.9 g of a slightly yellow oil are obtained.
Reaction SMILES: C[O:2][C:3](=[O:29])[CH2:4][NH:5][C:6]([C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([O:18][Si:19]([CH:26]([CH3:28])[CH3:27])([CH:23]([CH3:25])[CH3:24])[CH:20]([CH3:22])[CH3:21])[CH:16]=2)[CH:11]=[CH:10][CH:9]=1)=[O:7].O.[OH-].[Li+:32].Cl>C1COCC1.O>[Li+:32].[CH:26]([Si:19]([CH:20]([CH3:22])[CH3:21])([CH:23]([CH3:25])[CH3:24])[O:18][C:15]1[CH:16]=[C:17]2[C:12]([CH:11]=[CH:10][CH:9]=[C:8]2[C:6]([NH:5][CH2:4][C:3]([O-:29])=[O:2])=[O:7])=[CH:13][CH:14]=1)([CH3:27])[CH3:28]
Reactant: COC(=O)CNC(=O)c1cccc2ccc(O[Si](C(C)C)(C(C)C)C(C)C)cc12
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)[Si](Oc1ccc2cccc(C(=O)NCC(=O)[O-])c2c1)(C(C)C)C(C)C
Reaction time: 0.5 h

Procedure:
To a solution of N-[7-(triisopropylsilyloxy)naphthalene-1-carbonyl]glycine methyl ester, as described above in Step C, (175 mg, 0.42 mmol) in 4:1 THF/water (5 mL) at ambient temperature was added lithium hydroxide monohydrate (18 mg, 0.44 mmol). After 30 min, the solution was adjusted to pH 7 with 1.0 N hydrochloric acid and concentrated in vacuo. The residue was concentrated from toluene in vacuo (3×10 mL) to give the titled product.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[CH3:12][N:13]1[CH:18]=[C:17]([S:19][CH3:20])[C:16](=[O:21])[C:15]2[S:22][CH:23]=[CH:24][C:14]1=2>ClCCl>[CH3:12][N:13]1[CH:18]=[C:17]([S:19]([CH3:20])=[O:9])[C:16](=[O:21])[C:15]2[S:22][CH:23]=[CH:24][C:14]1=2
Reactant: CSc1cn(C)c2ccsc2c1=O
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: Cn1cc(S(C)=O)c(=O)c2sccc21
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of 3-chloroperbenzoic acid (85%; 1.63 g) in dichloromethane (60 ml) can be added dropwise during 20 minutes to a stirred solution of 4-methyl-6-methylthiothieno[3,2-b]pyrid-7(4H)-one (2.0 g) in dichloromethane (60 ml) at 0° C.-5° C. After 4 hours, more 3-chloroperbenzoic acid (0.15 g) in dichloromethane (10 ml) can be added and the mixture stirred overnight at ambient temperature. More 3-chloroperbenzoic acid (0.15 g) in dichloromethane (10 ml) can be added and the mixture can again be stirred overnight at ambient temperature. The resulting solution can be extracted with saturated aqueous sodium bicarbonate solution (5×150 ml) and saturated aqueous sodium chloride solution (1×150 ml) and the organic phase can be discarded. The aqueous extracts are combined and extracted with dichloromethane (5×100 ml). The organic extracts are combined, dried over anhydrous magnesium sulphate and evaporated to give a solid product. This product can be crystallised from industrial methylated spirit to give the compound 4-methyl-6-methylsulphinylthieno [3,2-b]pyrid-7(4H)-one, m.p. 174° C.-176° C.
Reaction SMILES: [OH:1][C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[C:5]([OH:12])=[CH:4][CH:3]=1.[CH3:13][O:14]C(Cl)Cl.Cl>ClCCl.[Ti](Cl)(Cl)(Cl)Cl>[OH:1][C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[C:5]([OH:12])=[CH:4][C:3]=1[CH:13]=[O:14]
Reactant: COC(Cl)Cl
Reactant: Oc1ccc(O)c2c1CCCC2
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: Cl
Solvent: ClCCl
Product: O=Cc1cc(O)c2c(c1O)CCCC2
Yield: 60 %

Procedure:
To a solution of 1,4-dihydroxy-5,6,7,8-tetrahydronaphthalene (1.640 g, 0.010 mol) in dichloromethane (50 ml) was added titanium tetrachloride (5.69 g, 0.03 mol). Then 1,1-dichlorodimethyl ether (1.73 g, 0.015 mol) was added dropwise under vigorous stirring and the reaction mixture stirred for another 3 h at room temperature. Finally 5% hydrochloric acid (10 ml) was added under ice-cooling. The organic phase was separated and the residual aqueous phase repeatedly extracted with ether. The combined organic phases are washed with saturated saline solution, dried over sodium sulfate and evaporated under vacuum. The residue was crystallized from benzene or alternatively submitted to flash chromatography on silica gel with benzene/ethylacetate 85:15 to afford pure title compound in about 60% yield (1.080 g), mp 145° C.
Reaction SMILES: [CH3:1][C:2]1[C:3]([O:13][CH:14]([CH3:16])[CH3:15])=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10](=[O:12])[NH:9][CH2:8][CH2:7]2.[H-].[Na+].[CH2:19]([O:26][C:27]1[C:32]([CH2:33]Cl)=[C:31]([CH3:35])[CH:30]=[C:29]([CH3:36])[N:28]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>O1CCCC1>[CH2:19]([O:26][C:27]1[C:32]([CH2:33][N:9]2[CH2:8][CH2:7][C:6]3[C:11](=[C:2]([CH3:1])[C:3]([O:13][CH:14]([CH3:16])[CH3:15])=[CH:4][CH:5]=3)[C:10]2=[O:12])=[C:31]([CH3:35])[CH:30]=[C:29]([CH3:36])[N:28]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: Cc1cc(C)c(CCl)c(OCc2ccccc2)n1
Reactant: Cc1c(OC(C)C)ccc2c1C(=O)NCC2
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cc(C)c(CN2CCc3ccc(OC(C)C)c(C)c3C2=O)c(OCc2ccccc2)n1
Temperature: 50 °C
Yield: 73.9 %

Procedure:
To a 0° C. solution of 8-methyl-7-(propan-2-yloxy)-3,4-dihydroisoquinolin-1(2H)-one (107a, 30 mg, 0.14 mmol) in tetrahydrofuran (0.46 mL) was added 60% sodium hydride (18 mg, 0.45 mmol). After 30 minutes 2-(benzyloxy)-3-(chloromethyl)-4,6-dimethylpyridine (Cpd Z, 43 mg, 0.16 mmol) was added and the resulting mixture was heated at 50° C. for 16 hours. The reaction mixture was quenched with water (1 mL) then extracted with ethyl acetate (20 mL), washed with brine (2 mL), dried over sodium sulfate, filtered, then concentrated under vacuum. The residue was purified by column chromatography (EtOAc/heptanes, 0-100), to give 2-{[2-(benzyloxy)-4,6-dimethylpyridin-3-yl]methyl}-8-methyl-7-(propan-2-yloxy)-3,4-dihydroisoquinolin-1(2H)-one (107b, 46 mg, 76%) as a colorless oil.
Reaction SMILES: C([O:8][C:9]1[C:10](=[O:21])[CH:11]=[C:12]([CH3:20])[N:13]([CH2:15][C:16]([F:19])([F:18])[F:17])[CH:14]=1)C1C=CC=CC=1.[ClH:22]>C(O)(C)C>[ClH:22].[OH:8][C:9]1[C:10](=[O:21])[CH:11]=[C:12]([CH3:20])[N:13]([CH2:15][C:16]([F:17])([F:18])[F:19])[CH:14]=1
Reactant: Cc1cc(=O)c(OCc2ccccc2)cn1CC(F)(F)F
Agent: Cl
Solvent: CC(C)O
Product: Cc1cc(=O)c(O)cn1CC(F)(F)F
Temperature: 110 °C
Yield: 65 %

Procedure:
5-(Benzyloxy)-2-methyl-1-(2,2,2-trifluoroethyl)pyridin-4(1H)-one (45.8 g, 164 mmol) was mixed with 6N HCl (100 mL) and isopropanol (20 mL). The mixture was heated at 110° C. oil bath for 8 hours and then concentrated by rotary evaporator. The residue was triturated with acetone and ether to give 5-hydroxy-2-methyl-1-(2,2,2-trifluoroethyl)pyridin-4(1H)-one hydrochloride (24.5 g). Yield=65%; 1H NMR (MeOD-D4, 90 MHz) δ (ppm): 8.18 (s, 1H), 7.21 (s, 1H), 5.31 (q, J=8.2 Hz, 2H) and 2.67 (s, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:31])/[CH:5]=[C:6](\[CH3:30])/[CH:7]=[CH:8]/[C:9](/[F:29])=[C:10](\[C:12]1[CH:13]=[C:14]([CH:26]([CH3:28])[CH3:27])[CH:15]=[C:16]2[C:21]=1[N:20]([CH2:22][CH3:23])[CH2:19][CH2:18][C:17]2([CH3:25])[CH3:24])/[CH3:11])[CH3:2].[CH2:32](O)C.[OH-].[Na+]>C1COCC1>[CH2:1]([O:3][C:4](=[O:31])/[CH:5]=[C:6](\[CH3:30])/[CH:7]=[CH:8]/[C:9](/[F:29])=[C:10](\[C:12]1[CH:13]=[C:14]([CH:26]([CH3:27])[CH3:28])[CH:15]=[C:16]2[C:21]=1[N:20]([CH2:22][CH2:23][CH3:32])[CH2:19][CH2:18][C:17]2([CH3:25])[CH3:24])/[CH3:11])[CH3:2]
Reactant: CCO
Reactant: CCOC(=O)/C=C(C)/C=C/C(F)=C(/C)c1cc(C(C)C)cc2c1N(CC)CCC2(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCCN1CCC(C)(C)c2cc(C(C)C)cc(/C(C)=C(F)\C=C\C(C)=C\C(=O)OCC)c21
Temperature: 50 °C

Procedure:
To a solution of (2E,4E,6E)-7-(1-ethyl-6-isopropyl-4,4-dimethyl-1,2,3,4-tetrahydro-quinolin-8-yl)-6-fluoro-3-methyl-octa-2,4,6-trienoic acid ethyl ester (Compound 24, 117 mg, 2.74 mmol) and 5 ml of ethanol and 1 ml of THF was added 2 ml of 1 M NaOH(aq). The reaction was heated to 50° C. for 4 hours. The excess alcohol was removed by evaporation. The residue was neutralized with saturated NH4Cl to pH=7 then extracted with ethyl acetate (3×10 ml). The combined organic layers were washed with water, and brine, dried over Na2SO4 and concentrated to give the crude acid as a residue. This was purified by column chromatography (silica, first using 100% hexane, followed by 5:95 ethyl acetate:hexane, then 1:1 ethyl acetate:hexane) to yield a yellow oil. The resulting yellow oil was recrystallized from acetonitrile to produce the title compound as a yellow solid.
Reaction SMILES: [NH2:1][S:2]([C:5]1[C:13]2[O:12][C:11]([CH3:15])([CH3:14])[CH2:10][C:9]=2[CH:8]=[CH:7][CH:6]=1)(=[O:4])=[O:3].[Br:16][CH:17]([CH3:21])[C:18](Cl)=[O:19]>>[CH3:14][C:11]1([CH3:15])[CH2:10][C:9]2[CH:8]=[CH:7][CH:6]=[C:5]([S:2]([NH:1][C:18](=[O:19])[CH:17]([Br:16])[CH3:21])(=[O:4])=[O:3])[C:13]=2[O:12]1
Reactant: CC1(C)Cc2cccc(S(N)(=O)=O)c2O1
Reactant: CC(Br)C(=O)Cl
Product: CC(Br)C(=O)NS(=O)(=O)c1cccc2c1OC(C)(C)C2
Temperature: 25 °C

Procedure:
A stirred slurry of 0.39 gram (0.0017 mole) of 7-aminosulfonyl-2,3-dihydro-2,2-dimethylbenzofuran and 1 ml of 2-bromopropionyl chloride was heated at 96° for 35 minutes, then at reflux for 30 minutes. The reaction mixture was cooled to ambient temperature and washed repeatedly with petroleum ether to remove excess acid chloride. The residue was 0.53 gram of N-(2,3-dihydro-2,2-dimethylbenzofuran-7-yl)sulfonyl-2-bromopropionamide; m.p. 224°-226° C.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:11]=[CH:10][C:6]=1[C:7]([OH:9])=O)[CH2:2][CH3:3].C(OC([NH:25][CH2:26][C:27]1[CH:28]=[C:29]([CH2:35][CH:36]([O:40][CH:41]([CH3:43])[CH3:42])[C:37]([O-:39])=[O:38])[CH:30]=[CH:31][C:32]=1[O:33][CH3:34])=O)(C)(C)C>>[CH:41]([O:40][CH:36]([CH2:35][C:29]1[CH:30]=[CH:31][C:32]([O:33][CH3:34])=[C:27]([CH2:26][NH:25][C:7](=[O:9])[C:6]2[CH:10]=[CH:11][C:12]([C:14]([F:17])([F:16])[F:15])=[CH:13][C:5]=2[O:4][CH2:1][CH2:2][CH3:3])[CH:28]=1)[C:37]([OH:39])=[O:38])([CH3:43])[CH3:42]
Reactant: CCCOc1cc(C(F)(F)F)ccc1C(=O)O
Reactant: COc1ccc(CC(OC(C)C)C(=O)[O-])cc1CNC(=O)OC(C)(C)C
Product: CCCOc1cc(C(F)(F)F)ccc1C(=O)NCc1cc(CC(OC(C)C)C(=O)O)ccc1OC

Procedure:
Using 2-propoxy-4-(trifluoromethyl)benzoic acid and 3-[3-([(tert-butoxycarbonyl)amino]methyl)-4-methoxyphenyl]-2-isopropoxypropanoate, 2-isopropoxy-3-[4-methoxy-3-([2-propoxy-4-(trifluoromethyl)benzoyl]aminomethyl)phenyl]propanoic acid was obtained in the same method as in Example 38).
Reaction SMILES: C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.[O:35]1[CH2:40][CH2:39][N:38]([C:41]2[C:46]([NH2:47])=[CH:45][C:44]([N:48]3[CH2:53][CH2:52][O:51][CH2:50][CH2:49]3)=[CH:43][N:42]=2)[CH2:37][CH2:36]1.Cl[C:55]1[C:64]2[C:59](=[C:60]([F:66])[CH:61]=[C:62]([F:65])[CH:63]=2)[N:58]=[C:57]([C:67]2[CH:72]=[CH:71][CH:70]=[CH:69][N:68]=2)[C:56]=1[CH3:73].CC(C)([O-])C.[Na+]>C1(C)C=CC=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[O:35]1[CH2:40][CH2:39][N:38]([C:41]2[C:46]([NH:47][C:55]3[C:64]4[C:59](=[C:60]([F:66])[CH:61]=[C:62]([F:65])[CH:63]=4)[N:58]=[C:57]([C:67]4[CH:72]=[CH:71][CH:70]=[CH:69][N:68]=4)[C:56]=3[CH3:73])=[CH:45][C:44]([N:48]3[CH2:49][CH2:50][O:51][CH2:52][CH2:53]3)=[CH:43][N:42]=2)[CH2:37][CH2:36]1
Reactant: Cc1c(-c2ccccn2)nc2c(F)cc(F)cc2c1Cl
Reactant: Nc1cc(N2CCOCC2)cnc1N1CCOCC1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: Cc1ccccc1
Product: Cc1c(-c2ccccn2)nc2c(F)cc(F)cc2c1Nc1cc(N2CCOCC2)cnc1N1CCOCC1

Procedure:
The Buchwald coupled product was prepared according to Procedure H using dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine (0.026 g, 0.055 mmol), 2,5-dimorpholinopyridin-3-amine (0.109 g, 0.41 mmol), 4-chloro-6,8-difluoro-3-methyl-2-(pyridin-2-yl)quinoline (0.1 g, 0.34 mmol), Pd2dba3 (0.013 g, 0.014 mmol) and sodium tert-butoxide (0.083 g, 0.86 mmol) in toluene (3.4 mL) at 120° C. for 3 h. The crude product was purified by column chromatography on basic alumina (0 to 50% hexanes/EtOAc) to give the desired product N-(2,5-dimorpholinopyridin-3-yl)-6,8-difluoro-3-methyl-2-(pyridin-2-yl)quinolin-4-amine. 1H NMR (400 MHz, CDCl3-d) δ ppm 8.73 (1H, dd, J=1.6, 1.2 Hz), 7.89-8.00 (2H, m), 7.62 (1H, d, J=2.5 Hz), 7.40 (1H, ddd, J=7.4, 4.9, 1.4 Hz), 7.21-7.26 (2H, m), 6.70 (1H, br. s.), 6.19 (1H, m), 3.95-3.93 (4H, br. s.), 3.77-3.75 (4H, br. s.), 3.25 (4H, br s), 2.9-2.95 (4H, m), 2.44 (3H, s). Mass Spectrum (ESI) m/e=519.2 (M+1).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([CH:6]=[CH:7][C:8]([OH:10])=O)=[CH:2]1.C(N(CC)CC)C.ClC(OCC(C)C)=O.[N-:26]=[N+:27]=[N-:28].[Na+]>CC(C)=O.O>[O:1]1[CH:5]=[CH:4][C:3]([CH:6]=[CH:7][C:8]([N:26]=[N+:27]=[N-:28])=[O:10])=[CH:2]1
Reactant: O=C(O)C=Cc1ccoc1
Reactant: [N-]=[N+]=[N-]
Agent: CC(C)COC(=O)Cl
Agent: [Na+]
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Solvent: O
Product: [N-]=[N+]=NC(=O)C=Cc1ccoc1
Temperature: 1 °C
Reaction time: 0.5 h

Procedure:
In an oven-dried three-necked flask were placed a mixture of 3-(furan-3-yl)prop-2-enoic acid (20.0 g, 145 mmol) and dry triethylamine (17.2 g, 171 mmol) in acetone (200 mL, dried over anhydrous MgSO4). The mixture was cooled to 0 to 2° C. To the cold mixture, isobutyl chloroformate (25.2 mL, 193 mmol) was added at 0° C. The mixture was stirred at 0 to 2° C. for 30 min, then a solution of sodium azide (14.0 g, 215 mmol) in water (60 mL) was added slowly at 0° C. The reaction mixture was stirred for 1 h at the same temperature. It was quenched with an ice-water (500 mL) and the title azide was extracted with toluene (4×100 mL), dried over an anhydrous sodium sulfate and filtered. The filtrate containing the crude title compound was used as such for the next reaction.
Reaction SMILES: [Si:1](Cl)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Br:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]([OH:19])([CH3:18])[CH3:17])=[CH:12][CH:11]=1.N1C=CN=C1>CN(C=O)C>[Br:9][C:10]1[CH:11]=[CH:12][C:13]([C:16]([CH3:18])([O:19][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])[CH3:17])=[CH:14][CH:15]=1
Reactant: CC(C)(O)c1ccc(Br)cc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(O[Si](C)(C)C(C)(C)C)c1ccc(Br)cc1
Yield: 45.4 %

Procedure:
tert-Butyldimethylsilyl chloride (2.10 g, 14 mmol) was added to a mixture of 2-(4-bromophenyl)-propan-2-ol (2.0 g, 9.3 mmol) and imidazole (0.95 g 14 mmol) in DMF (30 mL) and the resultant mixture was stirred at 80° C. for 24 h. The mixture was concentrated to one third of the original volume then diluted with water (50 mL) and extracted with diethyl ether (3×50 mL). The combined organic layer was dried over anhydrous sodium sulfate, filtered and evaporated in vacuo. The resultant residue was purified by chromatography (silica, 50 g column, Si-SPE, 0-5% diethyl ether in pentane) to afford the title compound as a colourless oil (1.39 g, 46%). 1H NMR (MeOD, 400 MHz): 7.46-7.37 (m, 4H); 1.56 (s, 6H); 0.95-0.91 (m, 9H); 0.06 (s, 6H).
Reaction SMILES: [C:1]1([CH:7]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:8][CH2:9][N:10]([CH2:22][CH2:23][N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][OH:21])[CH:15]=2)=[O:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>[O-2].[Mn+2].C(Cl)(Cl)Cl>[C:1]1([CH:7]([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH2:8][CH2:9][N:10]([CH2:22][CH2:23][N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH:20]=[O:21])[CH:15]=2)=[O:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Nc1cccc(CO)c1)N(CCC(c1ccccc1)c1ccccc1)CCN1CCOCC1
Agent: [Mn+2]
Agent: [O-2]
Solvent: ClC(Cl)Cl
Product: O=Cc1cccc(NC(=O)N(CCC(c2ccccc2)c2ccccc2)CCN2CCOCC2)c1
Yield: 84 %

Procedure:
105.2 mg (0.222 mmol, 1 eq.) of 1-(3,3-diphenylpropyl)-3-(3-hydroxymethylphenyl)-1-(2-morpholin-4-ylethyl)urea (obtained in Example 60), 6 mL of chloroform, and 193 mg (2.22 mmol, 10 eq.) of manganese oxide are introduced in succession into a 50 mL flask under an argon atmosphere while stirring. The mixture is heated under reflux for one night, then the reaction medium is filtered over Celite®. After rinsing with dichloromethane then concentrating to dryness, the crude reaction product is purified by flash chromatography over silica gel (elution gradient: CH2Cl2/AcOEt 4/1 then 1/1), leading to the desired aldehyde in a yield of 84%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1.[CH3:10][O:11][C:12](=[O:21])[C:13]1[CH:18]=[CH:17][C:16](Br)=[CH:15][C:14]=1[CH3:20].C(=O)([O-])[O-].[K+].[K+]>C(OCC)C.[Cu]>[CH3:10][O:11][C:12](=[O:21])[C:13]1[CH:18]=[CH:17][C:16]([O:9][C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)=[CH:15][C:14]=1[CH3:20]
Reactant: COC(=O)c1ccc(Br)cc1C
Reactant: COc1ccc(O)cc1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Product: COC(=O)c1ccc(Oc2ccc(OC)cc2)cc1C
Temperature: 200 °C
Reaction time: 12 h
Yield: 28.2 %

Procedure:
A mixture of 4-methoxyphenol (12 grams, 52.4 mmol), 4-bromo-2-methylbenzoic acid methyl ester (12 grams, 52 mmol), potassium carbonate (14.5 grams, 105 mmol) and copper powder (3.3 grams, 52 mmol) was stirred at 200° C. for 12 hours. The mixture was cooled to 25° C., diluted with diethylether, and the organic phase was washed twice with water, dried over magnesium sulfate, filtered and concentrated in vacuo. Purification by silica gel chromatography (5% ether in hexanes) afforded 4.0 grams of 4-(4-Methoxy-phenoxy)-2-methyl-benzoic acid methyl ester. MS: 273.2 [M+H]+
Reaction SMILES: C[O:2][C:3](=[O:40])[CH:4]([NH:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:5][S:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][C:16]([C:19]3[C:24]4[O:25][C:26]5[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=5[C:23]=4[CH:22]=[CH:21][CH:20]=3)=[CH:15][CH:14]=2)=[CH:9][CH:8]=1.[OH-].[K+].Cl>C1COCC1.CO.C(OCC)(=O)C>[C:36]([O:35][C:33]([NH:32][CH:4]([CH2:5][S:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][C:16]([C:19]3[C:24]4[O:25][C:26]5[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=5[C:23]=4[CH:22]=[CH:21][CH:20]=3)=[CH:15][CH:14]=2)=[CH:9][CH:8]=1)[C:3]([OH:40])=[O:2])=[O:34])([CH3:39])([CH3:37])[CH3:38]
Reactant: COC(=O)C(CSc1ccc(-c2ccc(-c3cccc4c3oc3ccccc34)cc2)cc1)NC(=O)OC(C)(C)C
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC(CSc1ccc(-c2ccc(-c3cccc4c3oc3ccccc34)cc2)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 75.5 %

Procedure:
A solution of 2-tert-Butoxycarbonylamino-3-(4′-dibenzofuran-4-yl-biphen-4-ylsulfanyl)-propanoic acid methyl ester (0.150 g, 0.27 mmol) in THF (2 mL) and methanol (2 mL) was cooled to 0° C. and treated with 2 N KOH (1.0 mL). After stirring at room temperature for 1 h the solution was acidified with 10% HCl to pH 2 and diluted with ethyl acetate (25 mL). After being seperated, the aqueous layer was extracted with ethyl acetate (3×15 mL) and the combined organic layers were dried over MgSO4 and concentrated. Purification by flash column chromatography (2-5% methanol in dichloromethane) provided 2-tert-Butoxycarbonylamino-3-(4′-dibenzofuran-4-yl-biphen-4-ylsulfanyl)-propanoic acid (110 mg, 75%) as white solid. 1H NMR (CDCl3), δ 8.18 (d, J=7 Hz, 2 H), 8.14 (dd, J=1, 7 Hz, 2 H), 7.98 (d, J=9 Hz, 2 H), 7.82 (d, J=9 Hz, 2 H), 7.72 (m, 4 H), 7.51 (m, 3 H), 3.90 (m, 1 H), 3.48 (dd, J=4, 12 Hz, 1 H), 3.30 (m, 1H), 1.47 (s, 9 H). LCMS 440 (M+−100).