Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)=[CH:6][C:5]=1[C:16]1[CH:17]=[C:18]([CH:23]=[CH:24][N:25]=1)[C:19]([O:21]C)=[O:20])([O-:3])=[O:2].O.[OH-].[Li+]>O1CCCC1.O>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)=[CH:6][C:5]=1[C:16]1[CH:17]=[C:18]([CH:23]=[CH:24][N:25]=1)[C:19]([OH:21])=[O:20])([O-:3])=[O:2]
Reactant: COC(=O)c1ccnc(-c2cc(N3CCCCC3)ccc2[N+](=O)[O-])c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1ccnc(-c2cc(N3CCCCC3)ccc2[N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Into a 50-mL round-bottom flask, was placed a solution of methyl 2-(2-nitro-5-(piperidin-1-yl)phenyl)isonicotinate 1.1 g (1 g, 2.93 mmol, 1.00 equiv) in tetrahydrofuran/water (1:1) (20 mL), lithium hydroxide hydrate (1.26 g, 30.00 mmol, 10.23 equiv). The resulting solution was stirred overnight at 25° C. in an oil bath. The resulting mixture was concentrated under vacuum. The resulting solution was diluted with 10 mL of water. The resulting solution was extracted with 2×20 mL of ethyl acetate and the aqueous layers combined. The solution was adjusted to pH 5 with hydrochloric acid. The resulting solution was extracted with 2×50 mL of ethyl acetate and the organic layers combined, dried over anhydrous sodium sulfate, and concentrated under vacuum. This resulted in 0.8 g (83%) of 2-(2-nitro-5-(piperidin-1-yl)phenyl)isonicotinic acid as a yellow solid.
Reaction SMILES: Cl[C:2]1[C:3](Cl)=[C:4](Cl)[C:5](Cl)=[C:6]2[C:11](=[O:12])[O:10][C:8](=[O:9])[C:7]=12.[C:16]1([SH:22])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCCC1>[C:16]1([S:22][C:2]2[C:3]([S:22][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[C:4]([S:22][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:5]([S:22][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[C:6]3[C:11](=[O:12])[O:10][C:8](=[O:9])[C:7]=23)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Sc1ccccc1
Reactant: O=C1OC(=O)c2c(Cl)c(Cl)c(Cl)c(Cl)c21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: O=C1OC(=O)c2c(Sc3ccccc3)c(Sc3ccccc3)c(Sc3ccccc3)c(Sc3ccccc3)c21

Procedure:
30.88 g (108 millimols) of tetrachlorophthalic anhydride, 48.79 g (443 millimols) of thiophenol, 91.06 g (659 millimols) of potassium carbonate and 300 ml of tetrahydrofuran are stirred under reflux for 3 hours. The mixture is evaporated and the residue is taken up in methylene chloride/2N HCl solution. The organic phase is separated off, dried over sodium sulfate and evaporated. After recrystallisation from toluene/cyclohexane, 44.71 g (71% of theory) of tetrakis-(phenylthio)-phthalic anhydride are obtained; melting point 141°-2° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([C:29]([N:31]([CH2:35][CH2:36]O)[CH:32]([CH3:34])[CH3:33])=[O:30])=[N:11][C:12]([CH2:16][C:17]2([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=3)[CH2:21][CH2:20][CH2:19][CH2:18]2)=[N:13][C:14]=1[OH:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC1C(=O)N=C(CC2(C3C=CC(C(F)(F)F)=CC=3)CCCC2)N2CCN(C(C)C)C(=O)C=12)C1C=CC=CC=1>>[CH2:1]([O:8][C:9]1[C:14](=[O:15])[N:13]=[C:12]([CH2:16][C:17]2([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=3)[CH2:18][CH2:19][CH2:20][CH2:21]2)[N:11]2[CH2:36][CH2:35][N:31]([CH:32]([CH3:33])[CH3:34])[C:29](=[O:30])[C:10]=12)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)N(CCO)C(=O)c1nc(CC2(c3cccc(Cl)c3)CCCC2)nc(O)c1OCc1ccccc1
Agent: CC(C)N1CCn2c(CC3(c4ccc(C(F)(F)F)cc4)CCCC3)nc(=O)c(OCc3ccccc3)c2C1=O
Product: CC(C)N1CCn2c(CC3(c4cccc(Cl)c4)CCCC3)nc(=O)c(OCc3ccccc3)c2C1=O

Procedure:
9-(Benzyloxy)-6-((1-(3-chlorophenyl)cyclopentyl)methyl)-2-isopropyl-3,4-dihydro-1H-pyrazino[1,2-c]pyrimidine-1,8(2H)-dione (504) was synthesized as a white solid from 5-(benzyloxy)-2-((1-(3-)cyclopentyl)methyl)-6-hydroxy-N-(2-hydroxyethyl)-N-isopropylpyrimidine-4-carboxamide (503) following the procedure described for 9-benzyloxy-6-[1-(4-trifluoromethyl-phenyl)-cyclopentylmethyl]-2-isopropyl-3,4-dihydro-2H-pyrazino[1,2-c]pyrimidine-1,8-dione (247).
Reaction SMILES: [I:1][C:2]1[C:3]([OH:12])=[C:4]([O:10][CH3:11])[CH:5]=[C:6]([CH:9]=1)[CH:7]=[O:8].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22]>CC(C)=O>[I:1][C:2]1[CH:9]=[C:6]([CH:7]=[O:8])[CH:5]=[C:4]([O:10][CH3:11])[C:3]=1[O:12][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22]
Reactant: COc1cc(C=O)cc(I)c1O
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Product: CCOC(=O)COc1c(I)cc(C=O)cc1OC
Reaction time: 1 h
Yield: 48.8 %

Procedure:
To a solution of 5-iodovanilline (502 mg, 1.8 mmol) in acetone (25 mL) was added cesium carbonate (766 mg, 2.35 mmol), followed by ethyl bromoacetate (0.30 mL, 2.7 mmol). The mixture was refluxed in acetone under stirring for 1 hour. After evaporation of acetone under reduced pressure, 100 mL of water were added and the mixture was extracted with dichloromethane (200 mL). The organic phase was washed with brine (100 mL), dried over magnesium sulfate and concentrated under vacuum. The residue was purified by column chromatography over silica gel (eluent: dichloromethane) to give 320 mg of a yellow solid (49% yield). 1H NMR (250 MHz, CD3COCD3): δ 1.28 (t, J=7.2 Hz, 3H), 3.97 (s, 3H), 4.23 (q, J=7.2 Hz, 2H), 4.85 (s, 2H), 7.55 (s, 1H), 7.95 (s, 1H), 9.89 (s, 1H). 13C NMR (126 MHz, CD3COCD3): δ 15.2, 57.4, 62.1, 70.5, 92.4, 113.9, 135.1, 135.5, 153.1 (2C), 169.4, 169.5, 191.0.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=1)[C:12](O)=[O:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].B>C1COCC1>[OH:13][CH2:12][C:11]1[CH:10]=[C:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:3])([CH3:2])[CH3:4])[CH:17]=[CH:16][CH:15]=1
Reactant: CC(C)(C)OC(=O)Nc1cccc(C(=O)O)c1
Agent: B
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1cccc(CO)c1
Temperature: 0 °C
Reaction time: 6 h
Yield: 85.7 %

Procedure:
3-(tert-Butoxy-carbonylamino)benzoic acid (3.00 g, 12.6 mmol) was dissolved in THF (30 mL) and cooled to 0° C. A 1 M borane:THF solution (12.7 mL, 12.7 mmol) was slowly added to the reaction. The solution was then allowed to slowly warm to room temperature and stirred for six hours. The reaction was then quenched with a 50% AcOH:water mixture (2 mL). Next, the mixture was concentrated to reduced volume and poured into a saturated sodium bicarbonate solution (75 mL). The mixture was then extracted with EtOAc (2×250 mL). The organic layers were combined and washed with saturated sodium bicarbonate solution (1×75 mL), brine (1×75 mL), and then dried over magnesium sulfate. The filtrate was concentrated, and the residue was purified by medium pressure chromatography (silica gel, 0 to 5% MeOH:DCM) to give 27.1 (2.41 g). MS ESI (pos.) m/e 241.1 (M+18). 1H NMR (400 MHz, DMSO-d6) δ ppm 9.28 (1H, s), 7.48 (1H, s), 7.26 (1H, d, J=8.6 Hz), 7.17 (1H, t, J=7.8 Hz), 6.89 (1H, d, J=7.4 Hz), 5.12 (1H, t, J=5.7 Hz), 4.42 (2H, d, J=5.5 Hz), 1.47 (9H, s)
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:18])[CH2:15][CH2:16][CH3:17])[C:11]([Cl:19])=[CH:10][C:9]=1[NH:20][C:21](=[O:44])[CH2:22][C:23](=O)[C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([N:30]2[C:34]([CH2:35][O:36]C3CCCCO3)=[N:33][CH:32]=[N:31]2)[CH:25]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:19][C:11]1[C:12]([N:14]([CH3:18])[CH2:15][CH2:16][CH3:17])=[CH:13][C:8]2[N:7]=[C:23]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([N:30]4[C:34]([CH2:35][OH:36])=[N:33][CH:32]=[N:31]4)[CH:25]=3)[CH2:22][C:21](=[O:44])[NH:20][C:9]=2[CH:10]=1
Reactant: CCCN(C)c1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-n3ncnc3COC3CCCCO3)c2)cc1Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCN(C)c1cc2c(cc1Cl)NC(=O)CC(c1cccc(-n3ncnc3CO)c1)=N2

Procedure:
The title compound was prepared from (RS)-[4-chloro-5-(methyl-propyl-amino)-2-(3-oxo-3-{3-[5-(tetrahydro-pyran-2-yloxymethyl)-[1,2,4]triazol-1-yl]-phenyl}-propionylamino)-phenyl]-carbamic acid tert-butyl ester (Example M114) (1.47 g, 2.29 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a pale yellow solid (1.0 g, 99%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[C:7]([CH2:12][CH:13]=[CH2:14])[CH:6]=1)[CH3:2].[H][H]>[Pd].C(O)C>[CH2:1]([O:3][C:4](=[O:15])[C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[C:7]([CH2:12][CH2:13][CH3:14])[CH:6]=1)[CH3:2]
Reactant: [H][H]
Reactant: C=CCc1cc(C(=O)OCC)ccc1O
Agent: [Pd]
Solvent: CCO
Product: CCCc1cc(C(=O)OCC)ccc1O
Yield: 115.4 %

Procedure:
A mixture of ethyl-3-allyl-4-hydroxybenzoate (4.12 g), palladium on carbon (10% w/w) and ethanol (100 ml) was stirred under an atmosphere of hydrogen until 500 ml of hydrogen had been consumed. The mixture was filtered and the filtrate was evaporated. The residue was purified by flash chromatography on silica gel using 4:1 (v/v) n-pentane/ethyl acetate as eluent to give ethyl-3-propyl-4-hydroxybenzoate (4.8 g) as a solid, m.p. 78°-79° C.; microanalysis, found: C, 69.2; H, 8.1%; C12H16O3 requires: C, 69.2; H, 7.74%; NMR (CDCl3): 0.97(3H,t), 1.38(3H,t), 1.67(2H,m), 2.60(2H,t), 4.35(2H,q), 5.71(1H,s), 6.79(1H,d) and 7.75-7.87(2H,m); m/z 209(M+H).
Reaction SMILES: [N+:1]([C:4]1[CH:31]=[CH:30][C:7]([CH2:8][O:9][C:10]([N:12]2[CH2:16][C@@H:15]([S:17][C:18](=[O:20])[CH3:19])[CH2:14][C@H:13]2[CH2:21][O:22][Si](C(C)(C)C)(C)C)=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].Cl>CO.C(OCC)(=O)C>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:8][O:9][C:10]([N:12]2[CH2:16][C@@H:15]([S:17][C:18](=[O:20])[CH3:19])[CH2:14][C@H:13]2[CH2:21][OH:22])=[O:11])=[CH:30][CH:31]=1)([O-:3])=[O:2]
Reactant: CC(=O)S[C@H]1C[C@@H](CO[Si](C)(C)C(C)(C)C)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Agent: Cl
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(=O)S[C@H]1C[C@@H](CO)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
(2S,4S)-1-(p-Nitrobenzyloxycarbonyl)-2-t-butyldimethylsilyloxymethyl-4-acetylthiopyrrolidine (0.85 g) was dissolved in methanol (8.5 ml), and 0.85 ml of 6N hydrochloric acid was added thereto. The resulting mixture was stirred at room temperature for 2.5 hours, diluted with ethyl acetate, washed with water, dried over anhydrous magnesium sulfate and distilled to remove the solvent. Recrystallization of the residue from diethyl ether gave (2S,4S)-1-(p-nitrobenzyloxycarbonyl)-2-hydroxymethyl-4-acetylthiopyrrolidine.
Reaction SMILES: [CH3:1][C:2]1([CH2:7][CH2:8][C:9]([O:11][CH3:12])=[O:10])[S:6][CH2:5][CH2:4][S:3]1.[C:13](=O)([O:16]C)[O:14][CH3:15].[H-].[Na+].Cl.[Cl-].[Na+]>O1CCCC1>[CH3:12][O:11][C:9](=[O:10])[CH:8]([CH2:7][C:2]1([CH3:1])[S:3][CH2:4][CH2:5][S:6]1)[C:13]([O:14][CH3:15])=[O:16]
Reactant: COC(=O)OC
Reactant: COC(=O)CCC1(C)SCCS1
Agent: Cl
Agent: [Cl-]
Agent: [H-]
Solvent: C1CCOC1
Product: COC(=O)C(CC1(C)SCCS1)C(=O)OC
Temperature: 25 °C
Yield: 47 %

Procedure:
A mixture of about 160 g of methyl 2-methyl-1,3-dithiolane-2-propanoate, about 174.63 g of dimethyl carbonate, about 74.41 g of sodium hydride and about 1000 ml of tetrahydrofuran was refluxed for about 19 hours under argon. The mixture was cooled to room temperature, added to a mixture of ice and dilute hydrochloric acid (about 1N) with stirring and saturated with sodium chloride. The organic layer was washed with saturated sodium bicarbonate then saturated sodium chloride, dried and the solvent removed. The residue was dissolved in ether, treated with charcoal, filtered through silica gel and the solvent removed. The residue was distilled via a Kugelrohr collecting the major fraction at about 180°-190° C., at about 0.5 mm giving about 96.26 g of the desired title product as a yellow oil.
Reaction SMILES: C1(S([N:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]([C:19]3[N:24]=[CH:23][C:22]([NH:25][C@@H:26]4[CH:33]5[CH2:34][N:29]6[CH2:30][CH:31]([CH2:35][CH:27]4[CH2:28]6)[CH2:32]5)=[CH:21][CH:20]=3)=[CH:11]2)(=O)=O)C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+]>CO>[NH:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]([C:19]2[N:24]=[CH:23][C:22]([NH:25][C@@H:26]3[CH:33]4[CH2:34][N:29]5[CH2:30][CH:31]([CH2:35][CH:27]3[CH2:28]5)[CH2:32]4)=[CH:21][CH:20]=2)=[CH:11]1
Reactant: O=S(=O)(c1ccccc1)n1cc(-c2ccc(NC3C4CC5CC3CN(C5)C4)cn2)c2ccccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: c1ccc2c(-c3ccc(NC4C5CC6CC4CN(C6)C5)cn3)c[nH]c2c1

Procedure:
A solution of the product of Example 162A (50 mg, 0.103 mmol) and potassium carbonate (34 mg, 0.25 mmol) in methanol (3 mL) was heated to reflux for 90 minutes. After cooling, the solvent was removed, the residue was dissolved in water, and the mixture was extracted with ethyl acetate (3×). The combined extracts were washed with brine, dried (Na2SO4), filtered and concentrated to afford the free base of the title compound: 1H NMR (300 MHz, methanol-D4) δ ppm 1.68 (s, 1H), 1.86 (d, J=14.9 Hz, 2H), 1.96 (s, 2H), 2.29 (d, J=12.2 Hz, 2H), 3.09-3.29 (m, 8H), 3.81 (s, 1H), 7.01-7.24 (m, 3H), 7.40 (d, J=7.1 Hz, 1H), 7.50-7.61 (m, 2H), 7.98 (d, J=7.5 Hz, 1H), 8.07 (d, J=2.4 Hz, 1H). MS (DCI/NH3) m/z=345 (M+H)+.
Reaction SMILES: [C:1]([C:3]1[C:11]2[C:10]([N:12]3[CH2:17][CH2:16][CH:15]([NH:18][C:19](=[O:26])[C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[CH2:14][CH2:13]3)=[N:9][CH:8]=[N:7][C:6]=2[N:5](COCC[Si](C)(C)C)[CH:4]=1)#[N:2]>CC#N>[C:1]([C:3]1[C:11]2[C:6]([NH:7][CH:8]=[N:9][C:10]=2[N:12]2[CH2:13][CH2:14][CH:15]([NH:18][C:19](=[O:26])[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:16][CH2:17]2)=[N:5][CH:4]=1)#[N:2]
Reactant: C[Si](C)(C)CCOCn1cc(C#N)c2c(N3CCC(NC(=O)c4ccccc4)CC3)ncnc21
Solvent: CC#N
Product: N#Cc1cnc2[nH]cnc(N3CCC(NC(=O)c4ccccc4)CC3)c1-2
Temperature: 80 °C

Procedure:
N-{1-[5-cyano-7-({[2-(trimethylsilyl)ethyl]oxy}methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-4-piperidinyl}benzamide D44 (69 mg) and LiBF4 (85 mg, 0.9 mmol) were dissolved in MeCN (10 ml) and then the reaction mixture was heated at 80° C. for 16 hours.
Reaction SMILES: [CH:1]1([CH2:4][N:5]([CH2:15][CH2:16][CH3:17])[C:6]2[N:11]=[CH:10][N:9]=[C:8]([C:12]([OH:14])=O)[CH:7]=2)[CH2:3][CH2:2]1.C(N(C(C)C)CC)(C)C.ClC(OC)=O.[CH3:32][C:33]1[N:34]([C:38]2[CH:39]=[C:40]([CH:42]=[CH:43][CH:44]=2)[NH2:41])[CH:35]=[CH:36][N:37]=1>C(Cl)Cl>[CH:1]1([CH2:4][N:5]([CH2:15][CH2:16][CH3:17])[C:6]2[N:11]=[CH:10][N:9]=[C:8]([C:12]([NH:41][C:40]3[CH:42]=[CH:43][CH:44]=[C:38]([N:34]4[CH:35]=[CH:36][N:37]=[C:33]4[CH3:32])[CH:39]=3)=[O:14])[CH:7]=2)[CH2:2][CH2:3]1
Reactant: CCCN(CC1CC1)c1cc(C(=O)O)ncn1
Reactant: Cc1nccn1-c1cccc(N)c1
Agent: COC(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCCN(CC1CC1)c1cc(C(=O)Nc2cccc(-n3ccnc3C)c2)ncn1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A cooled (0° C.) solution of 6-(cyclopropylmethyl(propyl)amino)pyrimidine-4-carboxylic acid (Intermediate 21, 112 mg; 0.45 mmol) in DCM was treated with diisopropylethylamine (78.4 mL; 0.52 mmol) and methyl chloroformate (36.2 mL; 0.47 mmol). After stirring at 0° C. for 15 minutes, 3-(2-methyl-1H-imidazol-1-yl)aniline (Maybridge, 117 mg; 0.67 mmol) was added and the mixture stirred for 72 hours. The solvent was evaporated and the compound purified by preparative HPLC to give the title compound as a white solid.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([C:14]2[O:18][N:17]=[C:16]([CH3:19])[N:15]=2)[CH:6]=[C:7]([N+:11]([O-:13])=[O:12])[C:8]=1[O:9]C.B(Br)(Br)Br.C(O)C>C(Cl)Cl>[CH3:19][C:16]1[N:15]=[C:14]([C:5]2[CH:4]=[C:3]([OH:2])[C:8]([OH:9])=[C:7]([N+:11]([O-:13])=[O:12])[CH:6]=2)[O:18][N:17]=1
Reactant: COc1cc(-c2nc(C)no2)cc([N+](=O)[O-])c1OC
Agent: BrB(Br)Br
Solvent: CCO
Solvent: ClCCl
Product: Cc1noc(-c2cc(O)c(O)c([N+](=O)[O-])c2)n1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
2.5 g of 5-(3,4-dimethoxy-5-nitrophenyl)-3-methyl-1,2,4-oxadiazole are dissolved in 70 ml of methylene chloride. After cooling to -60° there is added dropwise thereto within 20 minutes while stirring a solution of 23.62 g of boron tribromide in 50 ml of methylene chloride, whereupon the mixture is held at the reflux temperature for 48 hours. After cooling to -60°, the mixture is treated with 60 ml of ethanol and subsequently stirred at room temperature for 30 minutes. The yellow solution is evaporated to dryness, whereupon the residue is treated three times with 100 ml of toluene/ethanol (1:1) each time and the solvent is distilled each time. After crystallization from ethanol, there is obtained 5-(3-methyl-1,2,4-oxadiazol-5- yl)-3-nitropyrocatechol in the form of yellow crystals of m.p. 201°-202°.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:41])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:27]=[C:26]([C:28]3[CH:32]=[CH:31][S:30][CH:29]=3)[CH:25]=[C:24](I)[CH:23]=2)[C:10]=1[CH2:34][CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37])[CH3:2].[O:42]1[C:46]2[CH:47]=[CH:48][C:49](B(O)O)=[CH:50][C:45]=2[O:44][CH2:43]1.C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.C(O)C.O.C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:1]([O:3][C:4](=[O:41])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:27]=[C:26]([C:28]3[CH:32]=[CH:31][S:30][CH:29]=3)[CH:25]=[C:24]([C:49]3[CH:48]=[CH:47][C:46]4[O:42][CH2:43][O:44][C:45]=4[CH:50]=3)[CH:23]=2)[C:10]=1[CH2:34][CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37])[CH3:2]
Reactant: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(I)cc(-c3ccsc3)c2)c1CCC(=O)OCC
Reactant: OB(O)c1ccc2c(c1)OCO2
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(-c3ccsc3)cc(-c3ccc4c(c3)OCO4)c2)c1CCC(=O)OCC
Temperature: 80 °C
Reaction time: 0.08 h
Yield: 53.5 %

Procedure:
A solution of 4-{3-[6-(3-iodo-5-thiophen-3-yl-phenoxy)-hexyl]-2-(2-ethoxycarbonyl-ethyl)-phenoxy}-butyric acid ethyl ester (2.13 g, 3.06 mmol) in dimethoxyethane (75 mL) was stirred for 5 minutes at room temperature under nitrogen atmosphere. Then, tetrakis(triphenylphosphine)palladium(0) (1.06 g, 0.92 mmol) was added at room temperature and the resulting light yellow solution was heated to 80° C. and stirred for 5 minutes. At this period, a solution of benzo[1,3]dioxol-5-yl-boronic acid (1.53 g, 9.2 mmol) in ethanol (75 mL) was added followed by a solution of sodium carbonate (975 mg, 9.2 mmol) in water (6.0 mL). The resulting light yellow suspension was stirred for 24 h at reflux. Then, the reaction mixture was cooled to room temperature and diluted with water (100 mL) and ethyl acetate (100 mL). The two layers were separated and the aqueous layer was extracted with ethyl acetate (2×100 mL) and the combined organic extracts were washed with water (300 mL) and brine solution (300 mL). The organic layer was dried over anhydrous magnesium sulfate and filtration of the drying agent and removal of the solvent in vacuo gave the colored residue which was purified by using an ISCO 120 column, eluting with 0-20% ethyl acetate in hexanes to afford 4-{3-[6-(3-benzo[1,3]dioxol-5-yl-5-thiophen-3-yl-phenoxy)-hexyl]-2-(2-ethoxycarbonyl-ethyl)-phenoxy}-butyric acid ethyl ester (1.125 g, 53.5%) as a light brown viscous oil: ES(+)-HRMS m/e calculated for C40H46O8S (M+Na)+ 709.2805, found 709.2808.
Reaction SMILES: C([Li])(C)(C)C.Br[C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=1.I[C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][CH:25]=1)[NH:22][C:21](=[O:26])[CH:20]=[CH:19]2>CCCCC.O1CCCC1.[Cl-].[Zn+2].[Cl-].[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:14][O:13][C:10]1[CH:11]=[CH:12][C:7]([C:16]2[CH:17]=[C:18]3[C:23](=[CH:24][CH:25]=2)[NH:22][C:21](=[O:26])[CH:20]=[CH:19]3)=[CH:8][CH:9]=1
Reactant: COc1ccc(Br)cc1
Reactant: O=c1ccc2cc(I)ccc2[nH]1
Agent: [Pd]
Agent: [Cl-]
Agent: [Li]C(C)(C)C
Solvent: CCCCC
Solvent: C1CCOC1
Product: COc1ccc(-c2ccc3[nH]c(=O)ccc3c2)cc1
Temperature: 25 °C

Procedure:
A solution of t-butyl lithium (9.0 cm3 of a 2.0M solution in n-pentane) was added at -70° to a stirred solution of 4-bromoanisole (1.13 cm3) in tetrahydrofuran (THF) (20 cm3) under nitrogen. After 10 minutes a solution of anhydrous zinc chloride (1.23 g) in THF (10 cm3) was added and the mixture was allowed to warm to room temperature over 0.5 hour. A mixture of 6-iodo-2-(1H)-quinolone (0.813 g) and tetrakis(triphenylphosphine) palladium (0) (0.03 g) was added and the mixture was heated under reflux for 2 hours. Volatile material was then removed in vacuo and the residue was partitioned between chloroform:methanol, 9:1 (100 cm3) and a solution of ethylenediaminetetraacetic acid disodium salt (7 g) in water (100 cm3). The aqueous phase was further extracted with chloroform:methanol, 9:1 (3×100 cm3), and the combined and dried (MgSO4) organic extracts were evaporated to give an oily solid which was triturated with ethyl acetate. Recrystallization of the residue from ethyl acetate-methanol-chloroform afforded the title compound, m.p. 262°-264° (0.359 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[CH:9]=[C:8]([C:15](=[O:18])[CH2:16][CH3:17])[CH:7]=[CH:6]2.[Br-:19].[Br-].[Br-].C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1>>[Br:19][CH:16]([CH3:17])[C:15]([C:8]1[CH:7]=[CH:6][C:5]2[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=2)[CH:9]=1)=[O:18]
Reactant: CCC(=O)c1ccc2cc(OC)c(OC)cc2c1
Reactant: [Br-]
Agent: C[N+](C)(C)c1ccccc1
Product: COc1cc2ccc(C(=O)C(C)Br)cc2cc1OC
Yield: 84 %

Procedure:
From 1-(6,7-dimethoxy-2-naphthyl)-1-propanone and phenyl trimethyl ammonium tribromide through 2-bromo-1-(6,7-dimethoxy-2-naphthyl)-1-propanone (yield 84%; m.p. 122°-124° C.) which is then reacted with 4-(2-oxo-1-benzimidazolinyl)-1-piperidine followed by reduction with LiAlH4. Yield 55%; m.p. 246°-248° C. J=9.5 Hz.
Reaction SMILES: [C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[C:8]([C:17]2[S:18][CH:19]=[C:20]([CH2:22][C:23](O)=[O:24])[N:21]=2)[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[N:26]1([C:31]2[CH:32]=[C:33]([CH2:37][NH2:38])[CH:34]=[CH:35][CH:36]=2)[CH:30]=[CH:29][N:28]=[CH:27]1>>[C:1]([N:5]1[C:9]([C:10]2[CH:11]=[CH:12][C:13]([F:16])=[CH:14][CH:15]=2)=[C:8]([C:17]2[S:18][CH:19]=[C:20]([CH2:22][C:23]([NH:38][CH2:37][C:33]3[CH:34]=[CH:35][CH:36]=[C:31]([N:26]4[CH:30]=[CH:29][N:28]=[CH:27]4)[CH:32]=3)=[O:24])[N:21]=2)[CH:7]=[N:6]1)([CH3:3])([CH3:2])[CH3:4]
Reactant: CC(C)(C)n1ncc(-c2nc(CC(=O)O)cs2)c1-c1ccc(F)cc1
Reactant: NCc1cccc(-n2ccnc2)c1
Product: CC(C)(C)n1ncc(-c2nc(CC(=O)NCc3cccc(-n4ccnc4)c3)cs2)c1-c1ccc(F)cc1

Procedure:
Using 2-(2-(1-tert-butyl-5-(4-fluorophenyl)-1H-pyrazol-4-yl)thiazol-4-yl)acetic acid and (3-(1H-imidazol-1-yl)phenyl)methanamine and by reaction and purification in the same manner as in the method described in Example 1, step 7, the title compound was obtained.
Reaction SMILES: [O:1]=[O+][O-].[CH2:4]([CH:8]1[CH2:16][C:15]2[C:10](=[CH:11][C:12]([C:17]([O:19][CH3:20])=[O:18])=[CH:13][CH:14]=2)[C:9]1=[O:21])[CH:5]=CC>ClCCl>[O:1]=[CH:5][CH2:4][CH:8]1[CH2:16][C:15]2[C:10](=[CH:11][C:12]([C:17]([O:19][CH3:20])=[O:18])=[CH:13][CH:14]=2)[C:9]1=[O:21]
Reactant: O=[O+][O-]
Reactant: CC=CCC1Cc2ccc(C(=O)OC)cc2C1=O
Solvent: ClCCl
Product: COC(=O)c1ccc2c(c1)C(=O)C(CC=O)C2
Reaction time: 0.75 h
Yield: 45 %

Procedure:
An ozone stream (3 g ozone/hour) was conducted for 45 minutes while stirring through a solution, cooled to -70°, of 10.5 g of (RS)-2-(2-buten-1-yl)-6-methoxycarbonyl-1-indanone in 150 ml of anhydrous dichloromethane. Subsequently, the mixture was flushed with oxygen for 5 minutes and with argon for 10 minutes. After the addition of 4.74 ml of dimethyl sulfide, the mixture was stirred at room temperature for 18 hours. The reaction mixture was evaporated in a vacuum and purified by column chromatography on silica get (diethyl ether). By recrystallization of the resulting solid, there were obtained 4.5 g (45%) of (RS)-2-(2-oxoethyl)-6-methoxycarbonyl-1-indanone as a light yellow solid with m.p. 92°.