Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(C1C=C(C)C=C(C(C)(C)C)C=1[OH:16])(C)(C)C.CN(CCCN1CN(CCCN(C)C)CN(CCCN(C)C)C1)C.[CH3:41][S:42][C:43]1[CH:48]=[CH:47][C:46]([N:49]=[C:50]=[O:51])=[CH:45][CH:44]=1.[C:52]([O:56][CH2:57][CH2:58][CH2:59]O)(=[O:55])[CH:53]=[CH2:54].[N-]=C=O>C(OCC)(=O)C>[C:52]([O:56][CH2:57][CH:58]([O:51][C:50](=[O:16])[NH:49][C:46]1[CH:47]=[CH:48][C:43]([S:42][CH3:41])=[CH:44][CH:45]=1)[CH3:59])(=[O:55])[CH:53]=[CH2:54]
Reactant: C=CC(=O)OCCCO
Reactant: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Reactant: CSc1ccc(N=C=O)cc1
Agent: CN(C)CCCN1CN(CCCN(C)C)CN(CCCN(C)C)C1
Agent: [N-]=C=O
Solvent: CCOC(C)=O
Product: C=CC(=O)OCC(C)OC(=O)Nc1ccc(SC)cc1
Temperature: 60 °C

Procedure:
0.02 g of 2,6-di-tert-butyl-4-methylphenol, 0.01 g of Desmorapid Z, 14.0 g of 4-(methylthio)phenyl isocyanate in 25 g of ethyl acetate were initially introduced into a 100 ml round-bottomed flask and heated to 60° C. Thereafter, 11.0 g of 3-hydroxypropyl acrylate were added dropwise and the mixture was kept further at 60° C. until the isocyanate content had fallen below 0.1%. Thereafter, the ethyl acetate was distilled off at 5 mbar and cooling was effected. The product was obtained as a light yellow liquid.
Reaction SMILES: [C:1]1([CH:8]=[CH:7][CH:6]=[C:4]([OH:5])[CH:3]=1)[OH:2].[C:9]1([CH2:15][C:16]([OH:18])=O)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.B(F)(F)F.P(Cl)(Cl)(Cl)(Cl)Cl.[CH3:29]N(C=O)C>>[OH:2][C:1]1[CH:3]=[C:4]2[C:6]([C:16](=[O:18])[C:15]([C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=3)=[CH:29][O:5]2)=[CH:7][CH:8]=1
Reactant: Oc1cccc(O)c1
Reactant: O=C(O)Cc1ccccc1
Reactant: CN(C)C=O
Agent: ClP(Cl)(Cl)(Cl)Cl
Agent: FB(F)F
Product: O=c1c(-c2ccccc2)coc2cc(O)ccc12
Temperature: 60 °C
Reaction time: 1 h
Yield: 91 %

Procedure:
Resorcinol (0.66 g, 6 mmol), phenylacetic acid (0.816 g, 6 mmol), and boron triflouride diethyletherate (5 ml) were heated to 85° C. for 90 mins. After this time the reaction was cooled and DMF (4 ml) was added. 30 min prior to the completion of the first stage, PCl5 (1.878 g, 9 mmol) was added to cool DMF (8 ml) and the mixture heated (60° C.) for 20 minutes. This was added to the solution from stage one, and the combined solution allowed to stir at room temperature for 1 hour. The reaction mixture was then poured into 1MHCl (100 ml). The precipitate formed was filtered and re-crystallized from methanol to give 7-Hydroxy-3-phenyl-chromen-4-one as a white solid (1.3 g, 91.0%); Rf 0.25 ethyl acetate/hexane (30/70)].
Reaction SMILES: [F:1][C:2]1[C:11]([F:12])=[C:10]2[C:5]([C:6]([OH:21])=[C:7]([C:16](OCC)=[O:17])[C:8](=[O:15])[C:9]2([CH3:14])[CH3:13])=[CH:4][CH:3]=1.Cl.[NH2:23][CH2:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26].C(N(C(C)C)C(C)C)C>O1CCOCC1>[F:1][C:2]1[C:11]([F:12])=[C:10]2[C:5]([C:6]([OH:21])=[C:7]([C:16]([NH:23][CH2:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])=[O:17])[C:8](=[O:15])[C:9]2([CH3:13])[CH3:14])=[CH:4][CH:3]=1
Reactant: CCOC(=O)C1=C(O)c2ccc(F)c(F)c2C(C)(C)C1=O
Reactant: CC(C)(C)OC(=O)CN
Agent: Cl
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)CNC(=O)C1=C(O)c2ccc(F)c(F)c2C(C)(C)C1=O
Temperature: 85 °C
Reaction time: 15 h
Yield: 86.9 %

Procedure:
A mixture of ethyl 7,8-difluoro-4-hydroxy-1,1-dimethyl-2-oxo-naphthalene-3-carboxylate (0.46 g, 1.6 mmol) and tert-butyl 2-aminoacetate hydrochloride (0.39 g, 2.3 mmol) in 2 mL dioxane was treated with N-ethyl-N-isopropylpropan-2-amine (0.60 g, 4.7 mmol). The mixture was warmed to 85° C. and stirred for 15 hours, M+Na=404, M−1=380. The mixture was then cooled to room temperature and concentrated in vacuo. The crude product was purified by column chromatography eluting with 10-30% EtOAc/hexane to give the title compound (0.53 g) as a pale yellow solid. MS (m/z)=404 (M+Na)+.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].Br[CH2:6][C:7]1[N:8]=[C:9]2[C:14](=[C:15]3[C:20]=1[CH:19]=[CH:18][CH:17]=[CH:16]3)[CH:13]=[CH:12][CH:11]=[CH:10]2>CC(C)=O>[N:1]([CH2:6][C:7]1[N:8]=[C:9]2[C:14](=[C:15]3[C:20]=1[CH:19]=[CH:18][CH:17]=[CH:16]3)[CH:13]=[CH:12][CH:11]=[CH:10]2)=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=[N-]
Reactant: BrCc1nc2ccccc2c2ccccc12
Agent: [Na+]
Solvent: CC(C)=O
Product: [N-]=[N+]=NCc1nc2ccccc2c2ccccc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Sodium azide (715 mg, 11.0 mmol) was added to a solution of the bromide 6 (301 mg, 1.10 mmol) in dry acetone (30 mL). The reaction mixture was stirred at ambient temperature for 1 hour, then heated to reflux for 2 hours. The reaction mixture was then allowed to cool to room temperature, the excess sodium azide was filtered off, and the solvent was removed under reduced pressure to yield the crude azide 7 as a light yellow crystalline solid, which was used immediately in the next step without further purification.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH:7]=O)=[CH:3][CH:2]=1.C(O)(=O)C.[CH2:13]([N:15]1[C:21](=[O:22])[C:20]([CH3:24])([CH3:23])[C:19](=[O:25])[N:18]([CH3:26])[C:17]2[CH:27]=[C:28]([O:31][CH2:32][CH2:33][CH2:34][NH:35][CH2:36][CH2:37][C:38]3[CH:39]=[N:40][CH:41]=[CH:42][CH:43]=3)[CH:29]=[CH:30][C:16]1=2)[CH3:14].[Na]>ClCCl.ClCCCl>[CH2:13]([N:15]1[C:21](=[O:22])[C:20]([CH3:24])([CH3:23])[C:19](=[O:25])[N:18]([CH3:26])[C:17]2[CH:27]=[C:28]([O:31][CH2:32][CH2:33][CH2:34][N:35]([CH2:36][CH2:37][C:38]3[CH:39]=[N:40][CH:41]=[CH:42][CH:43]=3)[CH2:7][C:4]3[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=3)[CH:29]=[CH:30][C:16]1=2)[CH3:14]
Reactant: CCN1C(=O)C(C)(C)C(=O)N(C)c2cc(OCCCNCCc3cccnc3)ccc21
Reactant: O=Cc1ccncc1
Agent: [Na]
Solvent: ClCCCl
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCN1C(=O)C(C)(C)C(=O)N(C)c2cc(OCCCN(CCc3cccnc3)Cc3ccncc3)ccc21
Reaction time: 0.5 h
Yield: 87.4 %

Procedure:
4-Pyridinecarbaldehyde (1.18 ml, 12.5 mmol) and a catalytic amount of acetic acid were added to a 1,2-dichloroethane solution (40 ml) of 1-ethyl-3,3,5-trimethyl-7-[3-(2-pyridin-3-ylethylamino)propoxy]-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione (4.44 g, 10.5 mmol), and stirred for 30 minutes. Sodium triacetoxyhydroborate (3.33 g, 15.7 mmol) was added to the resulting mixture, and stirred at room temperature overnight. The reaction mixture was diluted with dichloromethane, washed with water and a saturated sodium chloride aqueous solution in this order, then dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (ethyl acetate:methanol=1:0→9:1). The purified product was concentrated under reduced pressure to thereby obtain 4.73 g (yield: 88%) of 1-ethyl-3,3,5-trimethyl-7-{3-[(2-pyridin-3-ylethyl)pyridin-4-ylmethylamino]propoxy}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione as a pale yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C@@H:9]([OH:14])[C:10]([O:12]C)=[O:11].[OH-].[Na+].Cl>CO>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C@@H:9]([OH:14])[C:10]([OH:12])=[O:11]
Reactant: COC(=O)[C@H](O)c1ccccc1OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccccc1[C@@H](O)C(=O)O
Temperature: 25 °C
Reaction time: 12 h
Yield: 62.4 %

Procedure:
To a solution of 19 g of methyl (2R)-2-(methoxyphenyl)-2-hydroxyethanoate (cf. Journal of Chemical Society, Parkintrans 1, 2253-2255 (1992)) in 50 ml of methanol, 50 ml of 3N aqueous sodium hydroxide solution was added, followed by 12 hours' stirring at room temperature. Distilling the methanol off under reduced pressure, the reaction liquid was acidified with 1N hydrochloric acid and extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate and the solvent was distilled off under reduced pressure, to provide 11 g of the title compound.
Reaction SMILES: [C:1]1([C:7]2[C:8]([C:16]3[CH:23]=[CH:22][C:19]([CH:20]=[O:21])=[CH:18][CH:17]=3)=[N:9][C:10]3[N:11]([CH:13]=[CH:14][N:15]=3)[CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.ClC[N+]12CC[N+]([F:34])(CC1)CC2.F[B-](F)(F)F>C(Cl)(Cl)Cl.O.ClCCl>[F:34][C:13]1[N:11]2[CH:12]=[C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[C:8]([C:16]3[CH:17]=[CH:18][C:19]([CH:20]=[O:21])=[CH:22][CH:23]=3)=[N:9][C:10]2=[N:15][CH:14]=1
Reactant: F[N+]12CC[N+](CCl)(CC1)CC2
Reactant: O=Cc1ccc(-c2nc3nccn3cc2-c2ccccc2)cc1
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: O
Solvent: ClC(Cl)Cl
Product: O=Cc1ccc(-c2nc3ncc(F)n3cc2-c2ccccc2)cc1
Temperature: 120 °C
Reaction time: 0.75 h

Procedure:
500 mg 4-(6-phenylimidazo[1,2-a]pyrimidin-7-yl)benzaldehyde (prepared as described under example 1) and 880 mg 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate are dissolved in 25 ml chloroform and heated under microwave irradiation to 120° C. After for 45 min and 4 h additional portions of 200 mg of 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate are added and heating continued at 120° C. The reaction is worked up after 5 h by diluting with water and extraction with dichloromethane. The combined organic layers are dried over Na2SO4 and the solvens evaporated. The crude material is purified on silica gel (dichloromethane/ethyl acetate.
Reaction SMILES: [CH2:1]([C:6]1[CH:20]=[CH:19][C:9]([O:10][C:11]2[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=2)[CH:14]=O)=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH2:4][CH3:5].[S:21]1[CH2:27][C:25](=[O:26])[NH:24][C:22]1=[S:23]>C(O)(=O)C.C([O-])(=O)C.[Na+]>[CH2:1]([C:6]1[CH:20]=[CH:19][C:9]([O:10][C:11]2[CH:12]=[C:13]([CH:14]=[C:27]3[S:21][C:22](=[S:23])[NH:24][C:25]3=[O:26])[CH:16]=[CH:17][CH:18]=2)=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCCc1ccc(Oc2cccc(C=O)c2)cc1
Reactant: O=C1CSC(=S)N1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CCCCCc1ccc(Oc2cccc(C=C3SC(=S)NC3=O)c2)cc1
Yield: 61.9 %

Procedure:
The 3-(4-n-pentylphenoxy)benzaldehyde was coupled with rhodanine in acetic acid and sodium acetate essentially as described previously to yield 1.3 grams (61.9%) of the title product.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2[CH:8]=[CH:9][C:10]([CH:12]=O)=[CH:11][C:6]=2[N:5]([CH2:14]C)[C:4]1=[O:16])C.N[C@H](C(O)=O)C.[N+:23]([CH2:26][CH3:27])([O-:25])=[O:24]>C(O)CCC>[CH3:1][N:3]1[C:7]2[CH:8]=[CH:9][C:10]([CH:12]=[C:26]([N+:23]([O-:25])=[O:24])[CH3:27])=[CH:11][C:6]=2[N:5]([CH3:14])[C:4]1=[O:16]
Reactant: CC[N+](=O)[O-]
Reactant: CCn1c(=O)n(CC)c2cc(C=O)ccc21
Agent: C[C@H](N)C(=O)O
Solvent: CCCCO
Product: CC(=Cc1ccc2c(c1)n(C)c(=O)n2C)[N+](=O)[O-]
Temperature: 115 °C
Reaction time: 2 h

Procedure:
1,3-Dimethyl-2-oxo-2,3-dihydro-1H-benzoimidazole-5-carbaldehyde (2.48 g, 13.1 mmol, obtained using the same procedure used for 1,3-Diethyl-2-oxo-2,3-dihydro-1H-benzoimidazole-5-carbaldehyde) in n-butanol (25 mL) was treated with □-alanine (298.0 mg) and nitroethane (1.85 mL). The mixture was heated to 115° C. for 4 hours, more nitroethane (0.5 mL) was added and the heating was continued for 2 hours. The reaction was allowed to cool, was filtered and washed with ether then dried to give 1,3-Dimethyl-5-(2-nitro-propenyl)-1,3-dihydro-benzoimidazol-2-one (2.229 g).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH:8]([CH3:10])[CH3:9])[CH:5]=[CH:4][C:3]=1[C:11]1([NH:22][C:23](=[O:28])[CH2:24][CH2:25][CH2:26][CH3:27])[C:19](=[O:20])[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]1=[O:21].C(N(CC)CC)C.[C:36](Cl)(=[O:41])[C:37]([CH3:40])([CH3:39])[CH3:38]>C(Cl)Cl>[O:21]=[C:12]1[C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:19](=[O:20])[C:11]1([C:3]1[CH:4]=[CH:5][C:6]([CH:8]([CH3:10])[CH3:9])=[CH:7][C:2]=1[O:1][C:36](=[O:41])[C:37]([CH3:40])([CH3:39])[CH3:38])[NH:22][C:23](=[O:28])[CH2:24][CH2:25][CH2:26][CH3:27]
Reactant: CC(C)(C)C(=O)Cl
Reactant: CCCCC(=O)NC1(c2ccc(C(C)C)cc2O)C(=O)c2ccccc2C1=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCC(=O)NC1(c2ccc(C(C)C)cc2OC(=O)C(C)(C)C)C(=O)c2ccccc2C1=O
Reaction time: 2 h
Yield: 91.3 %

Procedure:
A solution of pentanoic acid [2-(2-hydroxy-4-isopropyl-phenyl)-1,3-dioxo-indan-2-yl]-amide (0.10 g, 0.26 mmol) in anhydrous methylene chloride (10 ml) was added triethylamine (0.03 g, 0.31 mmol) and pivaloyl chloride (0.047 g, 0.39 mmol) and then stirred for 2 hrs. The reaction mixture was concented and extracted with ethylacetate. The concentrated organic layer was purified using silica gel column chromatography (ethylacetate:hexane=1:4) to afford the title compound (0.11 g, 91%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([S:9]([N:12]=[C:13]=[O:14])(=[O:11])=[O:10])[CH:5]=[CH:6][C:7]=1[CH3:8].[NH2:15][C:16]1[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:17]=1[C:18]([OH:20])=O>>[Cl:25][C:23]1[CH:24]=[C:16]2[C:17]([C:18](=[O:20])[N:12]([S:9]([C:4]3[CH:5]=[CH:6][C:7]([CH3:8])=[C:2]([CH3:1])[CH:3]=3)(=[O:11])=[O:10])[C:13](=[O:14])[NH:15]2)=[CH:21][CH:22]=1
Reactant: Cc1ccc(S(=O)(=O)N=C=O)cc1C
Reactant: Nc1cc(Cl)ccc1C(=O)O
Product: Cc1ccc(S(=O)(=O)n2c(=O)[nH]c3cc(Cl)ccc3c2=O)cc1C
Yield: 18.9 %

Procedure:
582 mg (2.76 mmol) of 3,4-dimethylbenzenesulfonylisocyanate and 473 mg (2.76 mmol) of 2-amino-4-chlorobenzoic acid were treated in the same way as in Example 1 to obtain 190 mg of the above-identified compound (yield 18.9%). Properties: colorless crystal, Melting point: >250° C., PMR (δppm, DMSO-d6): 2.33 (6H,s), 7.12 (1H,s), 7.23 (1H,d), 7.43 (1H,d), 7.84-7.91 (3H,m), 11.64 (1H,br).
Reaction SMILES: C[O:2][C:3](=[O:24])[C:4]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][CH:7]=[CH:6][C:5]=1[NH:13][CH2:14][CH2:15][NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18].[OH-].[Li+]>C1COCC1.O.C(OCC)(=O)C>[C:20]([O:19][C:17]([NH:16][CH2:15][CH2:14][NH:13][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]([N+:10]([O-:12])=[O:11])[C:4]=1[C:3]([OH:24])=[O:2])=[O:18])([CH3:23])([CH3:21])[CH3:22]
Reactant: COC(=O)c1c(NCCNC(=O)OC(C)(C)C)cccc1[N+](=O)[O-]
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCCNc1cccc([N+](=O)[O-])c1C(=O)O
Temperature: 50 °C
Yield: 95.8 %

Procedure:
To a solution of 2-(2-tert-butoxycarbonylaminoethylamino)-6-nitro-benzoic acid methylester (0.26 g, 0.00077 mol) in THF-water (3:1, 20 mL) under nitrogen was added lithium hydroxide (0.14 g, 0.00326 mol) as a solid in one portion. The reaction mixture was heated at 50° C. for 5 h then cooled to room temperature overnight. The mixture was diluted with ethyl acetate (10 mL) and washed with 10% aqueous HCl, water, and brine. The organic phase was dried over magnesium sulfate, filtered and concentrated in vacuo to a yellow oil which was purified by ISCO chromatography on silica gel using 15-50% ethyl acetate-hexane to give product as a pale yellow oil 2-(2-tert-butoxycarbonylaminoethylamino)-6-nitro-benzoic acid (0.24 g, 96%). 1H NMR (400 MHz, CDCl3) δ 11.8 (s, 1H), 7.57 (t, 1H, J=7.8 Hz), 7.05 (d, 1H, J=7.8 Hz), 6.81 (d, 1H, J=7.8 Hz), 6.73 (s, 1H), 4.5 (s, 1H), 3.47 (m, 2H), 3.19 (m, 2H), 1.47 (s, 9H); MS (m/e) 326 (M+1).
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[S:10][C:11]3[CH2:12][CH2:13][O:14][C:15]4[CH:22]=[C:21]([CH2:23][NH2:24])[CH:20]=[CH:19][C:16]=4[C:17]=3[N:18]=2)=[N:7][C:6]([CH3:25])=[N:5]1)([CH3:3])[CH3:2].C(N(CC)CC)C.[N:33]([CH2:36][CH3:37])=[C:34]=[O:35]>O1CCCC1>[CH2:36]([NH:33][C:34]([NH:24][CH2:23][C:21]1[CH:20]=[CH:19][C:16]2[C:17]3[N:18]=[C:9]([C:8]4[N:4]([CH:1]([CH3:3])[CH3:2])[N:5]=[C:6]([CH3:25])[N:7]=4)[S:10][C:11]=3[CH2:12][CH2:13][O:14][C:15]=2[CH:22]=1)=[O:35])[CH3:37]
Reactant: Cc1nc(-c2nc3c(s2)CCOc2cc(CN)ccc2-3)n(C(C)C)n1
Reactant: CCN=C=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCNC(=O)NCc1ccc2c(c1)OCCc1sc(-c3nc(C)nn3C(C)C)nc1-2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of C-[2-(2-Isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl]-methylamine 532 (0.050 g, 0.00014 mol) in tetrahydrofuran (1.0 mL) was added triethylamine (0.0588 mL, 0.000422 mol) then isocyanatoethane (0.110 mL, 0.00141 mol). The reaction was stirred at room temperature overnight, quenched with a small amount of methanol and concentrated in vacuo. The crude was precipitated from MeOH/H2O to give 525. MS (ESI+) 427.1
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:26])[C:5]([OH:25])([C:21]([F:24])([F:23])[F:22])[CH2:6][C:7]([C:10]1[CH:15]=[C:14]([F:16])[CH:13]=[C:12](CC=C)[C:11]=1[OH:20])([CH3:9])[CH3:8])[CH3:2].O.C[N+]1([O-])CC[O:32]CC1.[CH3:36][C:37]([CH3:39])=[O:38]>O.[Os](=O)(=O)(=O)=O>[CH2:1]([O:3][C:4](=[O:26])[C:5]([OH:25])([C:21]([F:24])([F:23])[F:22])[CH2:6][C:7]([C:10]1[CH:15]=[C:14]([F:16])[CH:13]=[C:12]([CH2:36][CH:37]([OH:38])[CH2:39][OH:32])[C:11]=1[OH:20])([CH3:9])[CH3:8])[CH3:2]
Reactant: C=CCc1cc(F)cc(C(C)(C)CC(O)(C(=O)OCC)C(F)(F)F)c1O
Reactant: C[N+]1([O-])CCOCC1
Reactant: CC(C)=O
Agent: O=[Os](=O)(=O)=O
Solvent: O
Product: CCOC(=O)C(O)(CC(C)(C)c1cc(F)cc(CC(O)CO)c1O)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
4-(3-Allyl-5-fluoro-2-hydroxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-valeric acid ethyl ester (4.9 g, 12.95 mmol) in acetone (214 ml) and water (32 ml) are mixed with N-methylmorpholine oxide-hydrate (1.75 g, 12.95 mmol) and 0.4 ml of osmium tetroxide solution (2.5% by weight in tert-butanol) while being cooled with ice. After 30 minutes at 2° C. and 16 hours at room temperature, the batch is mixed with another 0.3 ml of osmium tetroxide solution and stirred for 3 days at room temperature. For working-up, acetone is distilled off in a rotary evaporator, the residue is taken up in ethyl acetate (200 ml) and water (150 ml), and the phases are separated. The aqueous phase is extracted twice more with ethyl acetate, the combined ethyl acetate extracts are washed with saturated NaCl solution, dried (Na2SO4) and concentrated by evaporation. Column chromatography on silica gel with hexane-ethyl acetate yields 5.27 g of 4-(3-(2,3-dihydroxypropyl)-5-fluoro-2-hydroxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-valeric acid ethyl ester. The latter (5.2 g, 12.6 mmol) is stirred with sodium periodate (5.39, 25.2 mmol) in THF (75 ml) and water (12.5 ml) for 24 hours under nitrogen. The batch is concentrated by evaporation, and the aqueous residue is extracted three times with ethyl acetate. The combined organic phases are washed with saturated NaCl solution, dried (Na2SO4) and concentrated by evaporation in a vacuum. Column chromatography on silica gel with hexane-ethyl acetate yields 4.3 g of 4-(5-fluoro-2-hydroxy-2,3-dihydrobenzofuran-7-yl)-2-hydroxy-4-methyl-2-trifluoromethyl-valeric acid ethyl ester. 4.1 g (10.78 mmol) thereof in methanol (150 ml) is dissolved, the solution is mixed in portions with sodium borohydride (586 mg, 15 mmol), and it is stirred for 30 minutes at room temperature. A pH of 7.5 is set with acetic acid, and the reaction mixture is concentrated by evaporation. The residue is taken up in ethyl acetate (200 ml) and saturated NaHCO3 solution (75 ml), the phases are separated, the organic phase is washed with saturated NaCl solution, dried (Na2SO4) and concentrated by evaporation in a vacuum, whereby 4.01 g of product accumulates.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][NH:13][CH2:14][C:15]2[CH:16]=[CH:17][C:18]3[O:22][CH2:21][CH2:20][C:19]=3[CH:23]=2)[CH:7]=1.[CH3:25][S:26](Cl)(=[O:28])=[O:27]>C(N(CC)CC)C>[CH3:1][O:2][C:3](=[O:24])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][N:13]([CH2:14][C:15]2[CH:16]=[CH:17][C:18]3[O:22][CH2:21][CH2:20][C:19]=3[CH:23]=2)[S:26]([CH3:25])(=[O:28])=[O:27])[CH:7]=1
Reactant: COC(=O)CCc1cccc(CNCc2ccc3c(c2)CCO3)c1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Product: COC(=O)CCc1cccc(CN(Cc2ccc3c(c2)CCO3)S(C)(=O)=O)c1

Procedure:
The title compound of Step B was prepared following the method described in Step B of Example 1 from 3-(3-{[(2,3-dihydro-benzofuran-5-ylmethyl)-amino]-methyl}-phenyl)-propionic acid methyl ester of Step A and methanesulfonyl chloride using triethylamine in place of N,N-diisopropylethylamine. 1H NMR (400 MHz, CDCl3) δ 7.27 (m, 2H), 7.14 (m, 3H), 6.98 (d, 1H), 6.73 (d, 1H), 4.57 (t, 2H), 4.29 (s, 2H), 4.24 (s, 2H), 3.66 (s, 3H), 3.19 (t, 2H), 2.94 (t, 2H), 2.75 (s, 3H), 2.61 (t, 2H).
Reaction SMILES: [C:1]1([CH:7](C2C=CC(C)=CC=2)[CH2:8][CH:9]=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[S:18](=[O:22])(=O)(O)[OH:19].Cl.[NH2:24][C:25]1[CH:30]=[CH:29][C:28]([CH2:31][CH2:32][O:33][C:34]2[CH:39]=[CH:38][C:37]([CH2:40][C@H:41]([O:45][CH2:46][CH3:47])[C:42]([OH:44])=[O:43])=[CH:36][CH:35]=2)=[CH:27][CH:26]=1.[BH4-].[Na+]>O1CCCC1.ClCCl.CO>[CH2:46]([O:45][C@@H:41]([CH2:40][C:37]1[CH:38]=[CH:39][C:34]([O:33][CH2:32][CH2:31][C:28]2[CH:27]=[CH:26][C:25]([NH:24][CH2:9][CH2:8][CH:7]([S:18]([C:4]3[CH:5]=[CH:6][C:1]([CH3:7])=[CH:2][CH:3]=3)(=[O:22])=[O:19])[C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[CH:30][CH:29]=2)=[CH:35][CH:36]=1)[C:42]([OH:44])=[O:43])[CH3:47]
Reactant: Cc1ccc(C(CC=O)c2ccccc2)cc1
Reactant: O=S(=O)(O)O
Reactant: CCO[C@@H](Cc1ccc(OCCc2ccc(N)cc2)cc1)C(=O)O
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Solvent: C1CCOC1
Product: CCO[C@@H](Cc1ccc(OCCc2ccc(NCCC(c3ccccc3)S(=O)(=O)c3ccc(C)cc3)cc2)cc1)C(=O)O
Temperature: 0 °C
Yield: 131.7 %

Procedure:
3-Phenyl-3-(4-methylphenyl)propionaldehyde (0.166 g; 0.57 mmole) was dissolved in tetrahydrofurane(3 ml) and sulfuric acid (4 M; 0.041 ml; 0.164 mmole) was added under stirring, followed by addition of 3-{4-[2-(4-aminophenyl)ethoxy]phenyl}-(S)-2-ethoxypropanoic acid hydro chloride (described in Example 56a) (0.2 g; 0.547 mmole) dissolved in tetrahydrofurane(2 ml). The reaction mixture was stirred for 10 minutes, then cooled to 0° C. in an ice-bath and sodium borohydride (0.042 g; 1.10 mmole) was added. After addition, the cooling bath was removed. The mixture was stirred overnight and then evaporated to remove tetrahydrofurane. Ethyl acetate and water were added into the residue and the organic phase was separated, washed with brine, dried with magnesium sulfate. The solvent was then evaporated. Chromatography on silica gel (Isolute, SI ) using dichloromethane and then methanol (1%) in dichloromethane as eluant gave 0.13 g (40% yield) of (S)-2-ethoxy-3-(4-{2-[4-({3-[(4-methylphenyl)sulfonyl]-3-phenyl-(R/S)-propyl}amino)phenyl]ethoxy}phenyl)propanoic acid.
Reaction SMILES: [NH2:1][C:2]1[C:11]([Br:12])=[C:10]2[C:5]([C:6](=[O:23])[C:7]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)=[C:8]([CH:13]([CH3:15])[CH3:14])[O:9]2)=[CH:4][CH:3]=1.[C:24](Cl)(Cl)=[O:25].C(N(CC)CC)C.[CH2:35]([OH:42])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>C(Cl)Cl.C1(C)C=CC=CC=1>[CH2:35]([O:42][C:24](=[O:25])[NH:1][C:2]1[C:11]([Br:12])=[C:10]2[C:5]([C:6](=[O:23])[C:7]([C:16]3[CH:17]=[CH:18][C:19]([Cl:22])=[CH:20][CH:21]=3)=[C:8]([CH:13]([CH3:14])[CH3:15])[O:9]2)=[CH:4][CH:3]=1)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: OCc1ccccc1
Reactant: CC(C)c1oc2c(Br)c(N)ccc2c(=O)c1-c1ccc(Cl)cc1
Reactant: O=C(Cl)Cl
Solvent: Cc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)c1oc2c(Br)c(NC(=O)OCc3ccccc3)ccc2c(=O)c1-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A stirred solution of 7-amino-8-bromo-3-(4-chlorophenyl)-2-isopropyl-chromen-4-one (0.242 g, 0.62 mmol) in anhydrous methylene chloride (5 ml) is treated with a 20% solution of phosgene in toluene (0.5 ml). After 3 h, triethylamine (0.12 g, 0.17 ml, 1.24 mmol, 2 eq.) is added, followed by benzyl alcohol (0.067 g, 0.064 ml, 0.62 mmol), and the solution is stirred at room temperature overnight. The solution is diluted with methylene chloride and washed with water. The organic layer is dried (magnesium sulfate) and filtered, and the solvent is removed by evaporation in vacuo. The resulting solid is purified by flash chromatography (cyclohexane/ethyl acetate=9:1) to afford the title compound as a pale yellow solid.
Reaction SMILES: [Cl:1][C:2]1[C:6]([Cl:7])=[C:5]([CH3:8])[NH:4][C:3]=1[C:9]([NH:11][CH:12]1[CH2:17][CH2:16][N:15]([C:18]2[N:23]=[C:22]([O:24][CH2:25][CH3:26])[N:21]=[C:20]([C:27]([OH:29])=O)[CH:19]=2)[CH2:14][CH2:13]1)=[O:10].Cl.[O:31]([NH2:33])[CH3:32]>>[Cl:1][C:2]1[C:6]([Cl:7])=[C:5]([CH3:8])[NH:4][C:3]=1[C:9]([NH:11][CH:12]1[CH2:17][CH2:16][N:15]([C:18]2[N:23]=[C:22]([O:24][CH2:25][CH3:26])[N:21]=[C:20]([C:27]([NH:33][O:31][CH3:32])=[O:29])[CH:19]=2)[CH2:14][CH2:13]1)=[O:10]
Reactant: CCOc1nc(C(=O)O)cc(N2CCC(NC(=O)c3[nH]c(C)c(Cl)c3Cl)CC2)n1
Reactant: CON
Agent: Cl
Product: CCOc1nc(C(=O)NOC)cc(N2CCC(NC(=O)c3[nH]c(C)c(Cl)c3Cl)CC2)n1

Procedure:
The title compound was synthesised by an analogous method to Example 8 starting from 6-(4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}piperidin-1-yl)-2-ethoxypyrimidine-4-carboxylic acid (Example 312) and methoxylamine hydrochloride.