Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:8]=[CH:7][C:6]([C:9](=O)[CH2:10][C:11](=O)[C:12]([F:15])([F:14])[F:13])=[CH:5][CH:4]=1.[NH2:20][C:21]1[C:25]([C:26]#[N:27])=[C:24]([CH3:28])[NH:23][N:22]=1>>[CH3:28][C:24]1[C:25]([C:26]#[N:27])=[C:21]2[N:20]=[C:9]([C:6]3[CH:7]=[CH:8][C:3]([C:2]([F:19])([F:18])[F:1])=[CH:4][CH:5]=3)[CH:10]=[C:11]([C:12]([F:15])([F:14])[F:13])[N:22]2[N:23]=1
Reactant: O=C(CC(=O)C(F)(F)F)c1ccc(C(F)(F)F)cc1
Reactant: Cc1[nH]nc(N)c1C#N
Product: Cc1nn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc2c1C#N
Yield: 63.2 %

Procedure:
Reaction of 1-(4-trifluoromethyl-phenyl)-4,4,4-trifluoro-butane-1,3-dione (284 mg, 1.0 mmol), prepared from commercially available 4-trifluoromethyl-acetophenone according to general procedure A, and commercially available 3-amino-4-cyano-5-methyl -pyrazole (122 mg, 1.0 mmol) according to general procedure B yielded the title compound as a light yellow solid (234 mg, 63%). MS (ISP) 371.1 [(M+H)+]; mp 184° C.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[C:16]([Cl:24])[N:15]=2)[CH2:10][C@@H:9]1[CH3:25])=O)(C)(C)C>C(Cl)Cl.C(O)(C(F)(F)F)=O>[Cl:24][C:16]1[N:15]=[C:14]([N:11]2[CH2:12][CH2:13][NH:8][C@@H:9]([CH3:25])[CH2:10]2)[CH:19]=[CH:18][C:17]=1[C:20]([F:23])([F:21])[F:22]
Reactant: C[C@H]1CN(c2ccc(C(F)(F)F)c(Cl)n2)CCN1C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@H]1CN(c2ccc(C(F)(F)F)c(Cl)n2)CCN1
Temperature: 25 °C
Yield: 78.4 %

Procedure:
A solution of 4-(6-chloro-5-trifluoromethyl-pyridin-2-yl)-2-(S)-methyl-piperazine-1-carboxylic acid tert-butyl ester (7.80 g, 26.4 mmol) was dissolved in CH2Cl2/TFA (50:50; 30 mL) and stirred at room temperature over night. The solvent was removed at reduced pressure and the resulting oil was taken up between alkaline water (NaOH) and CHCl3. The aqueous phase was extracted once with CHCl3, the combined organic phases were dried (MgSO4) and the solvent was evaporated at reduced pressure to yield 5.79 g (78%) of a light yellow oil. A NOE between the methylene protons at C-2 in the piperazine ring and the C3-hydrogen in the pyridine ring was observed. Purity 100% (HPLC). Fragmenting MS analysis supports the stated structure. HRMS m/z calcd for C11H13ClF3N3 (M)+ 279.0750. found 279.0751
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([C:15]([CH3:18])([CH3:17])[CH3:16])[C:13]=1[OH:14])[C:8](O)=[O:9])([CH3:4])[CH3:3].[NH3:19]>O1CCCC1>[CH3:1][C:2]([C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([C:15]([CH3:18])([CH3:17])[CH3:16])[C:13]=1[OH:14])[C:8]([NH2:19])=[O:9])([CH3:4])[CH3:3]
Reactant: CC(C)(C)c1cc(C(=O)O)cc(C(C)(C)C)c1O
Reactant: N
Solvent: C1CCOC1
Product: CC(C)(C)c1cc(C(N)=O)cc(C(C)(C)C)c1O
Temperature: 26 °C
Reaction time: 2 h

Procedure:
In a 22 L Morton flask, 749 g (3.0 mol) of 3,5-bis(1,1-dimethylethyl)-4-hydroxybenzoic acid, 533 g (3.3 mol) carbonylcuiimidazole and tetrahydrofuran (THF) were combined and heated slowly to reflux and allowed to reflux for 2.5 hours. The reaction mixture was cooled to 26° C. and concentrated aqueous ammonia was added. Stirring was continued for 2 hours and the reaction mixture was allowed to stand overnight. The contents were transferred to a flask and rinsed with tetrahydrofuran (250 mL). The mixture was stirred, layers were separated, and the aqueous layer was saved. The organic layer was washed with brine (2.5 L) followed by brine/deionized (DI) water (1 L/1.5 L). The organic layer was washed with 9.7 M hydrochloric acid (HCl)/deionized water (0.25 L/2.25 L), followed by 9.7 M hydrochloric acid/deionized water (0.5 L/2.8 L), and 9.7 M hydrochloric acid/deionized water/brine (0.5 L/1.5 L/1.5 L). The organic layer was set aside while the combined aqueous layers were washed with tetrahydrofuran. The combined organic layers were washed with brine, dried with sodium sulfate (855 g) and filtered. The filtrate was evaporated to 1011 g of a wet (water), white solid. Methylene chloride was added and removed in vacuo. This procedure was repeated with ethyl acetate (6 L, then 2 L) to produce a solid residue (779 g). The residue was slurried in ethyl acetate and heptane, filtered, and dried in a vacuum oven to yield the desired amide (736 g, 98.7%) as a white solid
Reaction SMILES: [OH2:1].NN.[C:4]1(=O)[N:8]([CH:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:12][CH2:11][CH2:10]2)[C:7](=O)C2=CC=CC=C12>C(O)C>[NH2:8][CH2:9][CH2:10][CH2:11][O:1][C:16]1[CH:17]=[C:18]2[C:13]([CH2:12][CH2:11][CH2:10][CH:9]2[N:8]([CH3:7])[CH3:4])=[CH:14][CH:15]=1
Reactant: O
Reactant: O=C1c2ccccc2C(=O)N1C1CCCc2ccccc21
Agent: NN
Solvent: CCO
Product: CN(C)C1CCCc2ccc(OCCCN)cc21

Procedure:
85% hydrazine hydrate solution (3.2 ml) is added to a solution of the phthalimido tetrahydronaphthalene (about 15 g) obtained in the preceding step dissolved in absolute ethanol (160 ml). The stirred reaction mixture is refluxed for 3 hours, after which it is allowed to cool and the resulting precipitate removed by filtration. The clear yellow filtrate is evaporated in vacuo leaving a moist yellow solid, which is triturated in 5% aqueous HCl solution The resulting thick slurry is filtered and the clear filtrate made strongly alkaline with 50% sodium hydroxide solution, resulting in the formation of an oily precipitate. The precipitate is extracted with diethyl ether and the ether layers washed with saturated sodium chloride solution, dried over sodium sulfate, filtered and the filtrate evaporated in vacuo, yielding 7.8 g of a light amber oil. NMR and IR analysis indicate that this oil is the desired amino product, which is used without further treatment for the next reaction step.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][NH:4][C:5]([N:7]([CH2:17][CH:18]1[CH2:20][CH2:19]1)[CH:8]1[O:14][C@H:13]([CH2:15][OH:16])[C@@H:11]([OH:12])[C@H:9]1[OH:10])=[O:6].[N:21]([O-])=[O:22].[Na+]>>[Cl:1][CH2:2][CH2:3][N:4]([N:21]=[O:22])[C:5]([N:7]([CH2:17][CH:18]1[CH2:20][CH2:19]1)[CH:8]1[O:14][C@H:13]([CH2:15][OH:16])[C@@H:11]([OH:12])[C@H:9]1[OH:10])=[O:6]
Reactant: O=N[O-]
Reactant: O=C(NCCCl)N(CC1CC1)C1O[C@H](CO)[C@@H](O)[C@H]1O
Agent: [Na+]
Product: O=NN(CCCl)C(=O)N(CC1CC1)C1O[C@H](CO)[C@@H](O)[C@H]1O
Yield: 47.2 %

Procedure:
3.1 g of 1-(2-chloroethyl)-3-cyclopropylmethyl-3-(D-ribofuranosyl)urea and 1.5 g of sodium nitrite are treated in the same manner as described in Example 41. 1.6 g of 1-(2-chloroethyl)-1-nitroso-3-cyclopropylmethyl-3-(D-ribofuranosyl)-urea are thereby obtained as yellow liquid.
Reaction SMILES: CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[CH3:22][C:23]1[O:27][C:26](=[O:28])[O:25][C:24]=1[CH2:29][O:30][C:31](=[O:52])[C@H:32]([OH:51])[CH2:33][N:34]([CH2:36][C:37]1[CH:42]=[CH:41][C:40]([C:43]2[CH:48]=[C:47]([Cl:49])[CH:46]=[CH:45][C:44]=2[F:50])=[CH:39][CH:38]=1)[NH2:35].[F:53][C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][C:55]=1[C:60]1[CH:64]=[C:63]([C:65](O)=[O:66])[O:62][N:61]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:22][C:23]1[O:27][C:26](=[O:28])[O:25][C:24]=1[CH2:29][O:30][C:31](=[O:52])[C@H:32]([OH:51])[CH2:33][N:34]([CH2:36][C:37]1[CH:38]=[CH:39][C:40]([C:43]2[CH:48]=[C:47]([Cl:49])[CH:46]=[CH:45][C:44]=2[F:50])=[CH:41][CH:42]=1)[NH:35][C:65]([C:63]1[O:62][N:61]=[C:60]([C:55]2[CH:56]=[CH:57][CH:58]=[CH:59][C:54]=2[F:53])[CH:64]=1)=[O:66]
Reactant: O=C(O)c1cc(-c2ccccc2F)no1
Reactant: Cc1oc(=O)oc1COC(=O)[C@H](O)CN(N)Cc1ccc(-c2cc(Cl)ccc2F)cc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1oc(=O)oc1COC(=O)[C@H](O)CN(Cc1ccc(-c2cc(Cl)ccc2F)cc1)NC(=O)c1cc(-c2ccccc2F)no1
Temperature: 25 °C
Reaction time: 5 h
Yield: 37.8 %

Procedure:
EDCI (92 mg, 480 μmol) and HOBT (65 mg, 480 μmol) were added to a solution of (R)-3-[N-(5′-chloro-2′-fluorobiphenyl-4-ylmethyl)hydrazino]-2-hydroxypropionic acid 5-methyl-2-oxo-[1,3]dioxol-4-ylmethyl ester (108 mg, 240 μmol) and 3-(2-fluorophenyl)isoxazole-5-carboxylic acid (50 mg, 240 μmol) in DMF (20 mL). DIPEA (62 mg, 480 μmol) was added and the mixture was stirred for 5 hours at room temperature. The mixture was washed with saturated aqueous NaCl (2×30 mL) and extracted with EtOAc (2×50 mL). The combined organic layers were dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography (hexanes/EtOAc=1:1) to yield the title compound as a white solid (58 mg). LC-MS: 640.2 [M+H]+. 1H-NMR: (CDCl3) 2.07 (s, 3H), 3.43 (br, 2H), 4.4-4.2 (m, 2H), 4.3 (br, 1H), 4.94-4.86 (m, 2H), 7.24-6.85 (m, 5H), 7.97-7.27 (m, 8H).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[NH2:7][C@@H:8]([CH3:11])[CH2:9][OH:10].Br[CH2:13][CH2:14][CH2:15][CH2:16]Br>C(#N)C.ClCCl>[N:7]1([C@@H:8]([CH3:11])[CH2:9][OH:10])[CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: C[C@H](N)CO
Reactant: BrCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: ClCCl
Product: C[C@@H](CO)N1CCCC1
Temperature: 25 °C

Procedure:
Potassium carbonate (41.4 g, 0.30 moles) was added to a solution of (S)-(+)-2-amino-1-propanol (11.27 g, 0.15 moles, Aldrich) in anhydrous acetonitrile (1.5 L) then 1,4-dibromobutane (17.9 mL, 0.15 moles, Aldrich) was added. The resulting mixture was refluxed for 24 hours then cooled to room temperature and filtered. The filtrate was concentrated under vacuum to a straw-colored solid which was dissolved in dichloromethane (150 mL) and again concentrated under vacuum to afford a straw-colored solid. This crude material, believed to be a mixture of the hydrobromide salt and the free base of the product, was again dissolved in dichloromethane (200 mL). Solid potassium carbonate and the mixture was stirred vigorously for 3 hours then filtered and concentrated under vacuum to afford a straw-colored solid. This solid, believed to still be partially the hydrobromide salt, was partitioned between dichloromethane (150 mL) and saturated aqueous potassium carbonate (50 mL). The layers (upper layer organic, lower layer aqueous) were separated and the aqueous layer was extracted with dichloromethane (2×100 mL). The combined organic layers were dried over magnesium sulfate, filtered and evaporated to an amber oil. This crude product was purified by short-path vacuum distillation to afford the title compound as a colorless liquid (bp 53–54.5° C. at 1.5 mm Hg). NMR: (CDCl3, 600 MHz) δ 3.59 & 3.36 (2H, 2 dd, J=4, 10 Hz, H1), 2.64–2.72 (1H, m, H2), 2.54–2.62 (4H, m, H2′ & H5′), 1.72–1.80 (4H, m, H3′ & H4′),1.04 (3H, d, J=7 Hz, H3); MS (electrospray): m/e 130 (M+H), 112 (M−OH). [α]D+0.9°
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[N:11]=[CH:10][C:9](=[O:12])[NH:8][C:7]=2[N:13]=1.[H-].[Na+].[N+](C1C=C(S(O[CH2:29][C@H:30]2[O:32][CH2:31]2)(=O)=O)C=CC=1)([O-])=O.O>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[N:11]=[CH:10][C:9](=[O:12])[N:8]([CH2:29][C@@H:30]3[CH2:31][O:32]3)[C:7]=2[N:13]=1
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)OC[C@@H]2CO2)c1
Reactant: COc1ccc2ncc(=O)[nH]c2n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc2ncc(=O)n(C[C@@H]3CO3)c2n1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 75.7 %

Procedure:
In dimethylformamide (140 ml) was dissolved 6-methoxypyrido[2,3-b]pyrazin-3(4H)-one (5.0 g, 28.22 mmol), and sodium hydride (1.35 g, 31.04 mmol) was then added to the solution under cooling on ice. The obtained mixture was stirred at room temperature for 1.5 hours. The reaction solution was cooled on ice again, and (S)-glycidyl 3-nitrobenzenesulfonate (8.78 g, 33.86 mmol) was then added thereto. While slowly raising the temperature to room temperature, the mixture was stirred for 15 hours. Thereafter, water was added to the reaction solution, and it was then extracted with ethyl acetate. The resultant was washed with saturated sodium chloride solution, and it was then dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the obtained residue was then purified by silica gel column chromatography (hexane/ethyl acetate) to yield 4.98 g (76%) of the above-captioned compound in the form of a white solid.
Reaction SMILES: [H-].[Na+].[CH3:3][S:4]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])(=[O:6])=[O:5].[CH2:13]([O:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][CH2:28]I)=[CH:23][CH:22]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CN(C=O)C>[CH2:13]([O:20][C:21]1[CH:22]=[CH:23][C:24]([CH2:27][CH2:28][CH:7]([S:4]([CH3:3])(=[O:6])=[O:5])[C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:25][CH:26]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CCOC(=O)CS(C)(=O)=O
Reactant: ICCc1ccc(OCc2ccccc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(CCc1ccc(OCc2ccccc2)cc1)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.5 %

Procedure:
Sodium hydride (1.80 g, 45 mmol, 60% in mineral oil) was added in three portions to a solution of ethyl (methylsulfonyl)acetate (6.70 g, 40.3 mmol) in DMF (200 mL) at 0° C. The reaction was allowed to warm to room temperature and stirred for 1 hour. 1-(Benzyloxy)-4-(2-iodoethyl)benzene was added to the solution and the reaction was stirred overnight at rt. The reaction was quenched with 1N aqueous HCl (200 mL) and extracted with ethyl acetate (3×100 mL). The combined organics were dried (MgSO4), filtered and concentrated in vacuo. Chromatography on a Biotage 40 L column using 1:4 ethyl acetate in heptane afforded the title compound as a white solid (13.13 g, 86.5%). LC-MS m/z 375.2 (M−1). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.34 (t, J=7.03 Hz, 3H) 2.31-2.47 (m, 2H) 2.55-2.68 (m, 1H) 2.70-2.80 (m, 1H) 3.00 (s, 3H) 3.66-3.80 (m, 1H) 4.18-4.38 (m, 2H) 5.06 (s, 2H) 6.92 (d, J=8.59 Hz, 2H) 7.09 (d, J=8.59 Hz, 2H) 7.31-7.47 (m, 5H).
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5]1[CH:20]=[CH:19][C:8]([O:9][C:10]2[CH:17]=[CH:16][C:15]([I:18])=[CH:14][C:11]=2[CH:12]=[O:13])=[CH:7][CH:6]=1.[C:21]([Si:25]([CH3:28])([CH3:27])Cl)([CH3:24])([CH3:23])[CH3:22].N1C=CN=C1>CN(C)C=O>[C:21]([Si:25]([CH3:28])([CH3:27])[O:1][CH2:2][CH2:3][O:4][C:5]1[CH:6]=[CH:7][C:8]([O:9][C:10]2[CH:17]=[CH:16][C:15]([I:18])=[CH:14][C:11]=2[CH:12]=[O:13])=[CH:19][CH:20]=1)([CH3:24])([CH3:23])[CH3:22]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O=Cc1cc(I)ccc1Oc1ccc(OCCO)cc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCCOc1ccc(Oc2ccc(I)cc2C=O)cc1
Yield: 96.2 %

Procedure:
In a manner similar to the method described in Example 60b, 2-[4-(2-hydroxy-ethoxy)-phenoxy]-5-iodo-benzaldehyde (3.8 g, 9.8 mmol) was reacted with tert-butyldimethylchlorosilane (1.8 g, 12 mmol) and imidazole in N,N-dimethylformamide to give 2-{4-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-phenoxy}-5-iodo-benzaldehyde as a white solid (Yield 4.7 g, 95%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([N:11]=[C:12]=[O:13])=[CH:7][C:6]=1[S:14]([N:17]=[C:18]=[O:19])(=[O:16])=[O:15])=[O:4].[NH2:20][C:21]1[N:26]=[C:25]([O:27][CH3:28])[N:24]=[C:23]([CH3:29])[N:22]=1>C(#N)C>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([N:11]=[C:12]=[O:13])=[CH:7][C:6]=1[S:14]([NH:17][C:18]([NH:20][C:21]1[N:26]=[C:25]([O:27][CH3:28])[N:24]=[C:23]([CH3:29])[N:22]=1)=[O:19])(=[O:15])=[O:16])=[O:4]
Reactant: COc1nc(C)nc(N)n1
Reactant: COC(=O)c1ccc(N=C=O)cc1S(=O)(=O)N=C=O
Solvent: CC#N
Product: COC(=O)c1ccc(N=C=O)cc1S(=O)(=O)NC(=O)Nc1nc(C)nc(OC)n1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To 27 g of 2-methoxycarbonyl-5-isocyanatobenzenesulfonylisocyanate in 250 ml of anhydrous acetonitrile is added in small portions at ambient temperatures, 14 g of 2-amino-4-methoxy-6-methyl-1,3,5-triazine, the mixture is then stirred at ambient temperature for 16 hours. The resultant product, a white precipitate is removed by filtration and dried in vacuo.
Reaction SMILES: [N+:1]([C:4]1[CH:31]=[CH:30][C:7]([O:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]([N:18]3[CH2:23][CH2:22][N:21]([CH2:24][CH2:25][N:26]4[CH2:29][CH2:28][CH2:27]4)[CH2:20][CH2:19]3)=[O:17])[CH:10]=2)=[CH:6][CH:5]=1)([O-])=O>O1CCCC1.CO.[C].[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([O:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]([N:18]3[CH2:23][CH2:22][N:21]([CH2:24][CH2:25][N:26]4[CH2:29][CH2:28][CH2:27]4)[CH2:20][CH2:19]3)=[O:17])[CH:10]=2)=[CH:30][CH:31]=1
Reactant: O=C(Nc1cc(Oc2ccc([N+](=O)[O-])cc2)ccn1)N1CCN(CCN2CCC2)CC1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: Nc1ccc(Oc2ccnc(NC(=O)N3CCN(CCN4CCC4)CC3)c2)cc1
Reaction time: 22 h
Yield: 61.7 %

Procedure:
4-[2-(Azetidin-1-yl)ethyl]piperazine-1-carboxylic acid [4-(4-nitrophenoxy)pyridin-2-yl]amide (122 mg) was dissolved in tetrahydrofuran (3 ml) and methanol (3 ml). 10% Palladium carbon (61 mg) was added, followed by stirring under a hydrogen atmosphere for 22 hrs. The reaction mixture was filtered to remove the catalyst, and the catalyst was washed with methanol. The filtrate was concentrated under reduced pressure to give a residue, which was then purified by silica gel column chromatography (Fuji Silysia NH, eluent; ethyl acetate:methanol=9:1). Fractions containing the target compound were concentrated to give a crude product of the titled compound (70 mg) as a pale yellow oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][O:11][CH:10]([C:14]2[CH:19]=[CH:18][C:17]([NH2:20])=[C:16](F)[CH:15]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].BrC1C=CC(C(Cl)=O)=C([F:32])C=1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][O:11][CH:10]([C:14]2[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][C:15]=2[F:32])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C(Cl)c1ccc(Br)cc1F
Reactant: CC(C)(C)OC(=O)N1CCOC(c2ccc(N)c(F)c2)C1
Product: CC(C)(C)OC(=O)N1CCOC(c2ccc(N)cc2F)C1

Procedure:
In analogy to (RS)-2-(4-Amino-3-fluoro-phenyl)-morpholine-4-carboxylic acid tert-butyl ester (Example 1, steps a-g) using 4-bromo-2-fluorobenzoyl chloride (CAS 151982-51-3) instead of 4-bromo-3-fluorobenzoyl chloride.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[N:8]([C:9]([C:11]2[N:12]=[C:13]([CH3:23])[S:14][C:15]=2[C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)=[O:10])[CH2:7][C@H:6]2[C@@H:4]1[CH2:5]2.[Cl:24][C:25]1[CH:33]=[CH:32][C:28]([C:29](O)=[O:30])=[CH:27][CH:26]=1>>[Cl:24][C:25]1[CH:33]=[CH:32][C:28]([C:29]([NH:1][CH2:2][C@H:3]2[N:8]([C:9]([C:11]3[N:12]=[C:13]([CH3:23])[S:14][C:15]=3[C:16]3[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=3)=[O:10])[CH2:7][C@H:6]3[C@@H:4]2[CH2:5]3)=[O:30])=[CH:27][CH:26]=1
Reactant: O=C(O)c1ccc(Cl)cc1
Reactant: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CN)c1
Product: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CNC(=O)c2ccc(Cl)cc2)c1

Procedure:
prepared by reaction of ((1S,2S,5R)-2-Aminomethyl-3-aza-bicyclo[3.1.0]hex-3-yl)-(2-methyl-5-m-tolyl-thiazol-4-yl)-methanone with 4-Chloro-benzoic acid.
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:14][OH:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:16][O:17][C:18](=[O:27])[CH2:19][C:20]1[CH:25]=[CH:24][C:23](O)=[CH:22][CH:21]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[CH3:16][O:17][C:18](=[O:27])[CH2:19][C:20]1[CH:21]=[CH:22][C:23]([O:15][CH2:14][C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[O:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:24][CH:25]=1
Reactant: OCc1ccccc1Oc1ccccc1
Reactant: COC(=O)Cc1ccc(O)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)Cc1ccc(OCc2ccccc2Oc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of (2-phenoxyphenyl)methanol (1.43 g) in tetrahydrofuran (25 ml), 1.19 g of methyl(4-hydroxyphenyl)acetate, 2.82 g of triphenylphosphine, and 4.86 ml of diethyl azodicarboxylate (45% toluene solution) were added, and the reaction solution was stirred at room temperature for 30 minutes. The reaction solvent was distilled off under reduced pressure, and the residue obtained was purified by silica gel column chromatography (eluent: ethyl acetate/hexane (5:95-30:70)) to afford the title compound as a colorless oil.
Reaction SMILES: B(F)(F)F.CCOCC.[CH2:10]([SH:13])[CH2:11][SH:12].[CH2:14]([O:16][C:17](=[O:26])[C@@H:18]([O:22][C:23](=[O:25])[CH3:24])[CH2:19][CH:20]=O)[CH3:15]>ClCCl>[CH2:14]([O:16][C:17](=[O:26])[C@@H:18]([O:22][C:23](=[O:25])[CH3:24])[CH2:19][CH:20]1[S:13][CH2:10][CH2:11][S:12]1)[CH3:15]
Reactant: CCOC(=O)[C@H](CC=O)OC(C)=O
Reactant: SCCS
Agent: FB(F)F
Solvent: CCOCC
Solvent: ClCCl
Product: CCOC(=O)[C@H](CC1SCCS1)OC(C)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 145 %

Procedure:
Boron trifluoride etherate (1.15 g, 81 mmol) was added to a stirred solution of 1,2-ethanedithiol (0.34 g, 3.65 mmol) and (S)-2-acetoxy-4-oxobutanoic acid ethyl ester (0.46 g, 2.4 mmol) in dichloromethane (20 ml) at 0°. The mixture was stirred at room temperature overnight and ice/water added. The organic layer was separated, dried (MgSO4) and the solvent evaporated to give the sub-title compound (0.92 g).
Reaction SMILES: C[O:2][P:3]([CH:7]=[CH:8][C:9]([CH3:26])=[CH:10][CH2:11][C:12]1[C:13]([OH:25])=[C:14]2[C:18](=[C:19]([CH3:23])[C:20]=1[O:21][CH3:22])[CH2:17][O:16][C:15]2=[O:24])(=[O:6])[O:4]C.N1C(C)=CC=CC=1C.C[Si](Br)(C)C>C(#N)C>[OH:25][C:13]1[C:12]([CH2:11][CH:10]=[C:9]([CH3:26])[CH:8]=[CH:7][P:3](=[O:2])([OH:6])[OH:4])=[C:20]([O:21][CH3:22])[C:19]([CH3:23])=[C:18]2[C:14]=1[C:15](=[O:24])[O:16][CH2:17]2
Reactant: COc1c(C)c2c(c(O)c1CC=C(C)C=CP(=O)(OC)OC)C(=O)OC2
Agent: C[Si](C)(C)Br
Solvent: CC#N
Solvent: Cc1cccc(C)n1
Product: COc1c(C)c2c(c(O)c1CC=C(C)C=CP(=O)(O)O)C(=O)OC2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of [5-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-3-methyl-penta-1,3-dienyl]-phosphonic acid dimethyl ester 2B (22 mg, 0.057 mmol) and 2,6-lutidine (0.22 mL, 1.71 mmol) in acetonitrile was added trimethylsilyl bromide (0.183 mL, 1.71 mmol) at 0° C. The mixture was allowed to warm to room temperature and stirred for 1 hour. The reaction was quenched with methanol at 0° C., and the resulting mixture was concentrated. The residue was purified by preparative reverse-phase HPLC to afford, after removal of the solvent, [5-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-3-methyl-penta-1,3-dienyl]-phosphonic acid 2C as a solid (13 mg, 65%); 1H NMR (300 MHz, CD3OD) δ 1.91 (s, 3H), 2.10 (s, 3H), 3.55 (d, J=6.6 Hz, 2H), 3.75 (s, 3H), 5.2 (s, 2H), 5.6-5.8 (m, 2H), 6.9 (m, 1H) ppm.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]([C:15](=[O:17])[CH3:16])=[C:13]([O:18][CH3:19])[C:12]([O:20][C:21]2[C:29]([CH3:30])=[CH:28][C:27]([N:31]([CH2:39][C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)=[C:26]3[C:22]=2[CH2:23][CH2:24][CH2:25]3)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:46][Li].[Cl-].[NH4+]>O1CCCC1.C(OCC)C>[CH2:1]([O:8][C:9]1[C:14]([C:15]([OH:17])([CH3:46])[CH3:16])=[C:13]([O:18][CH3:19])[C:12]([O:20][C:21]2[C:29]([CH3:30])=[CH:28][C:27]([N:31]([CH2:39][C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[CH2:32][C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=3)=[C:26]3[C:22]=2[CH2:23][CH2:24][CH2:25]3)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1c(Oc2c(C)cc(N(Cc3ccccc3)Cc3ccccc3)c3c2CCC3)ccc(OCc2ccccc2)c1C(C)=O
Reactant: [Li]C
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: COc1c(Oc2c(C)cc(N(Cc3ccccc3)Cc3ccccc3)c3c2CCC3)ccc(OCc2ccccc2)c1C(C)(C)O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 1-[6-benzyloxy-3-(7-dibenzylamino-5-methylindan-4-yloxy)-2-methoxyphenyl]ethanone (13.3 g) in tetrahydrofuran (100 mL) was added dropwise a 1.14 mol/L solution of methyllithium in diethyl ether (30 mL) under an argon atmosphere at −78° C. The mixture was stirred for 30 min, and then warmed up to room temperature gradually. To the dark-red reaction mixture was added a saturated aqueous solution of ammonium chloride (40 mL). The reaction mixture was stirred for 10 min. The organic solvent was evaporated under reduced pressure to dryness. The residue was extracted with ethyl acetate. The organic layer was washed with brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to dryness to give 2-[6-benzyloxy-3-(7-dibenzylamino-5-methylindan-4-yloxy)-2-met hoxyphenyl]-propane-2-ol (13.9 g).