Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH2:13][S:12][CH:11]2[N:8]([C:9](=[O:15])[CH:10]2[NH2:14])[C:7]=1[C:16]([OH:18])=[O:17])(=[O:3])[CH3:2].[Cl:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][C:28](Cl)=[O:29])=[CH:23][CH:22]=1>C(OC(=O)C)C>[C:1]([O:4][CH2:5][C:6]1[CH2:13][S:12][CH:11]2[N:8]([C:9](=[O:15])[CH:10]2[NH:14][C:28](=[O:29])[CH2:27][C:24]2[CH:25]=[CH:26][C:21]([CH2:20][Cl:19])=[CH:22][CH:23]=2)[C:7]=1[C:16]([OH:18])=[O:17])(=[O:3])[CH3:2]
Reactant: O=C(Cl)Cc1ccc(CCl)cc1
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)C(N)C2SC1
Solvent: CCOC(C)=O
Product: CC(=O)OCC1=C(C(=O)O)N2C(=O)C(NC(=O)Cc3ccc(CCl)cc3)C2SC1

Procedure:
A mixture of 1 g of 3-[(acetyloxy)methyl]-7-amino-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid and 1 g of p-chloromethylphenylacetyl chloride in 45 ml of ethylacetate is refluxed for about 2 hours after which the solvent is removed under vacuum yielding a yellow-brown amorphous product which is chromatographed on silica gel using benzene-acetone as the eluant to give 3-[(acetyloxy)-methyl]-7-[[2-[4-(chloromethyl)phenyl]acetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid. M.P. 164°-165° C. (dec.).
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([NH:5][C@H:6]2[CH2:10][CH2:9][N:8]([C:11]([C:13]3[S:14][CH:15]=[CH:16][N:17]=3)=[O:12])[CH2:7]2)[CH2:2]1.[I-].[Br:19][C:20]1[CH:21]=[C:22]2[C:27](=[CH:28][CH:29]=1)[CH2:26][N:25]([C:30](N1C=C[N+](C)=C1)=[O:31])[CH2:24][CH2:23]2.CCN(CC)CC.O>C(Cl)Cl>[Br:19][C:20]1[CH:21]=[C:22]2[C:27](=[CH:28][CH:29]=1)[CH2:26][N:25]([C:30]([N:1]1[CH2:2][CH:3]([NH:5][C@H:6]3[CH2:10][CH2:9][N:8]([C:11]([C:13]4[S:14][CH:15]=[CH:16][N:17]=4)=[O:12])[CH2:7]3)[CH2:4]1)=[O:31])[CH2:24][CH2:23]2
Reactant: C[n+]1ccn(C(=O)N2CCc3cc(Br)ccc3C2)c1
Reactant: O=C(c1nccs1)N1CC[C@H](NC2CNC2)C1
Agent: [I-]
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(c1nccs1)N1CC[C@H](NC2CN(C(=O)N3CCc4cc(Br)ccc4C3)C2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of compound 1g (di-HCl salt, 105 mg, 0.327 mmol) and compound 1j (162 mg, 0.36 mmol) in CH2Cl2 (2 mL) was added Et3N (0.09 mL, 0.65 mmol). The reaction was stirred room temperature overnight. To the reaction mixture was added water, and the resultant mixture was extracted with CH2Cl2. The organic layer was dried over Na2SO4 and concentrated. Purification by flash column chromatography (silica gel, 5% MeOH/EtOAc+0.5% TEA) gave compound 10 (136 m g). MS m/z (M+H+) 490, 492. 1H NMR (300 MHz, CDCl3): δ 7.90 (m, 1H), 7.54 (m, 1H), 7.31-7.28 (m, 2H), 6.96 (m, 1H), 4.42 (d, J=3 Hz, 2H), 4.31-4.16 (m, 3H), 3.96-3.68 (m, 4H), 3.53-3.40 (m, 3H), 2.83 (m, 2H), 2.12 (m, 1H), 1.84 (m, 1H).
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:7])[CH2:5][NH2:6].[C:8]([C:11]1[CH:42]=[C:41]2[C:14]([CH2:15][C:16]3[C:20]([C:21](=[O:34])[CH:22]([C:32]#[N:33])[C:23]([NH:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)=[O:24])=[N:19][N:18]([C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)[C:17]=32)=[CH:13][CH:12]=1)(O)=[O:9].C1(N=C=NC2CCCCC2)CCCCC1.CN(CCO)C>C(#N)C.C(N(CC)CC)C>[CH3:2][O:3][C:4](=[O:7])[CH2:5][NH:6][C:8]([C:11]1[CH:42]=[C:41]2[C:14]([CH2:15][C:16]3[C:20]([C:21](=[O:34])[CH:22]([C:32]#[N:33])[C:23](=[O:24])[NH:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)=[N:19][N:18]([C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)[C:17]=32)=[CH:13][CH:12]=1)=[O:9]
Reactant: N#CC(C(=O)Nc1ccccc1)C(=O)c1nn(-c2ccccc2)c2c1Cc1ccc(C(=O)O)cc1-2
Reactant: COC(=O)CN
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)CCO
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COC(=O)CNC(=O)c1ccc2c(c1)-c1c(c(C(=O)C(C#N)C(=O)Nc3ccccc3)nn1-c1ccccc1)C2
Temperature: 25 °C
Yield: 45.2 %

Procedure:
Glycine methyl ester hydrochloride (0.7 g) suspended in anhydrous acetonitrile (250 ml) is treated with triethylamine (0.56 g) under stirring at room temperature. To the suspension first 3-(7-carboxy-1,4-dihydro-1-phenyl-indeno[1,2-c]pyrazole-3-yl)-2-cyano-3-oxo-N-phenyl-propanamide (2.3 g) and the dicyclohexylcarbodiimide (1.25 g) are added. The reaction mixture is kept under stirring at room temperature for 4 hours and then is basified to pH 8 by adding dimethylaminoethanol. The precipitate is filtered, washed with acetonitrile and then eliminated. The organic solution is concentrated in vacuo to a small volume, diluted with water, acidified to pH 2 with 1N HCl and then basified to pH 8 with 1N NaOH. The obtained precipitate is filtered, washed with water, dissolved in chloroform and washed with 1N HCl and then with water until neutral. The organic solution is evaporated in vacuo to dryness and the residue is purified over a SiO2 column using CHCl3 /methanol 90/10 as eluent. Final crystallization from CH2Cl 2 /ethyl acetate yields 1.2 g of pure N-[1,4-dihydro-1-phenyl-3-(2-phenylcarbamoyl-cyano-acetyl)indeno[1,2-c]pyrazol-7-yl] carbonyl-glycine methyl ester.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:18]=[CH:19][C:20]4[O:26][CH2:25][CH2:24][NH:23][CH2:22][C:21]=4[CH:27]=3)[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].CCN(C(C)C)C(C)C.Br[CH2:38][CH2:39][CH2:40][C:41]([O:43][CH2:44][CH3:45])=[O:42]>C(#N)C.CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:18]=[CH:19][C:20]4[O:26][CH2:25][CH2:24][N:23]([CH2:38][CH2:39][CH2:40][C:41]([O:43][CH2:44][CH3:45])=[O:42])[CH2:22][C:21]=4[CH:27]=3)[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10]
Reactant: CCOC(=O)CCCBr
Reactant: CC(C)Oc1ccc(-c2nc(-c3ccc4c(c3)CNCCO4)no2)cc1Cl
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)CCCN1CCOc2ccc(-c3noc(-c4ccc(OC(C)C)c(Cl)c4)n3)cc2C1
Temperature: 80 °C
Yield: 58.8 %

Procedure:
7-(5-{3-Chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-2,3,4,5-tetrahydro-1,4-benzoxazepine (0.105 g, 0.272 mmol) was stirred in acetonitrile (2 ml). DIPEA (0.095 ml, 0.544 mmol) and ethyl 4-bromobutanoate (0.058 ml, 0.408 mmol) were added and the reaction mixture heated at 80° C. under Argon for 5 hours. Additional DIPEA (0.095 ml, 0.544 mmol) and ethyl 4-bromobutanoate (0.058 ml, 0.408 mmol) were added and the reaction mixture heated at 80° C. overnight. Then the reaction mixture was dissolved in EtOAc (20 ml), washed with NaHCO3 (aq) (15 ml×3) and with water (15 ml×3) and the organics dried (MgSO4) and evaporated. The crude was purified by flash chromatography eluting with EtOAc/iso-Hexane 20/30% (Biotage column), and evaporated to give the title compounds as an oil (80 mg). MS (ES): C26H3035ClN3O5 requires 499; found 500 [M+H]+.
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[C:11]([C:13]2[C:21]3[C:16](=[N:17][CH:18]=[C:19]([C:22]4[CH:27]=[CH:26][C:25]([N:28]5[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]5)=[CH:24][CH:23]=4)[CH:20]=3)[N:15]([S:34]([C:37]3[CH:43]=[CH:42][C:40]([CH3:41])=[CH:39][CH:38]=3)(=[O:36])=[O:35])[CH:14]=2)[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:44][C@H:45]1[CH2:47][O:46]1.CCN(C(C)C)C(C)C>C(O)C>[CH2:1]([N:8]1[CH:12]=[C:11]([C:13]2[C:21]3[C:16](=[N:17][CH:18]=[C:19]([C:22]4[CH:23]=[CH:24][C:25]([N:28]5[CH2:29][CH2:30][N:31]([CH2:44][C@@H:45]([OH:46])[CH3:47])[CH2:32][CH2:33]5)=[CH:26][CH:27]=4)[CH:20]=3)[N:15]([S:34]([C:37]3[CH:38]=[CH:39][C:40]([CH3:41])=[CH:42][CH:43]=3)(=[O:35])=[O:36])[CH:14]=2)[CH:10]=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[C@H]1CO1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4ccccc4)c3)c3cc(-c4ccc(N5CCNCC5)cc4)cnc32)cc1
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4ccccc4)c3)c3cc(-c4ccc(N5CCN(C[C@H](C)O)CC5)cc4)cnc32)cc1
Yield: 62.1 %

Procedure:
Using similar reaction conditions as described in step-i of example-82A, 3-(1-benzyl-1H-pyrazol-4-yl)-5-(4-(piperazin-1-yl)phenyl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine (175 mg. 0.249 mmol) was alkylated using (S)-2-methyloxirane (27 mg, 0.498 mmol), DIPEA (129 mg, 0.996 mmol) and ethanol (5 mL) to get 100 mg (62.1% yield) of the titled compound. MS: m/z=647.2 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=2[F:16])[CH:5]=[CH:4][C:3]=1[C:17]([C:19]1[CH:24]=[C:23]([C:25]2[N:26]=[N:27][N:28]([CH2:30][CH2:31]OC3CCCCO3)[CH:29]=2)[CH:22]=[CH:21][C:20]=1[CH3:39])=[O:18].ClC1C=C(NC2C=CC(F)=CC=2F)C=CC=1C(C1C=C(C#C)C=CC=1C)=O.N(CC[CH2:72][O:73][CH:74]1[CH2:79][CH2:78][CH2:77][CH2:76][O:75]1)=[N+]=[N-]>>[Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=2[F:16])[CH:5]=[CH:4][C:3]=1[C:17]([C:19]1[CH:24]=[C:23]([C:25]2[N:26]=[N:27][N:28]([CH2:30][CH2:31][CH2:72][O:73][CH:74]3[CH2:79][CH2:78][CH2:77][CH2:76][O:75]3)[CH:29]=2)[CH:22]=[CH:21][C:20]=1[CH3:39])=[O:18]
Reactant: Cc1ccc(-c2cn(CCOC3CCCCO3)nn2)cc1C(=O)c1ccc(Nc2ccc(F)cc2F)cc1Cl
Reactant: [N-]=[N+]=NCCCOC1CCCCO1
Agent: C#Cc1ccc(C)c(C(=O)c2ccc(Nc3ccc(F)cc3F)cc2Cl)c1
Product: Cc1ccc(-c2cn(CCCOC3CCCCO3)nn2)cc1C(=O)c1ccc(Nc2ccc(F)cc2F)cc1Cl

Procedure:
The reaction was carried out similarly as described in the preparation of compound 101, using compound 407 (0.44 mmol) and compound 409 (0.44 mmol). The crude product was purified by continuous gradient flash chromatography using EtOAc/petroleum ether (40-60) 10:90 to 50:50 as the eluent to afford the title compound as colourless foam.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:5]=[CH:6][C:7]([OH:10])=[CH:8][CH:9]=1)=[O:3].C(=O)([O-])[O-].[K+].[K+].N#N.Br[CH2:20][CH2:21][CH2:22][OH:23]>C1OCCOCCOCCOCCOCCOC1.CC(C)=O>[OH:23][CH2:22][CH2:21][CH2:20][O:10][C:7]1[CH:8]=[CH:9][C:4]([C:2](=[O:3])[CH3:1])=[CH:5][CH:6]=1
Reactant: OCCCBr
Reactant: CC(=O)c1ccc(O)cc1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: N#N
Agent: O=C([O-])[O-]
Solvent: CC(C)=O
Product: CC(=O)c1ccc(OCCCO)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 105.1 %

Procedure:
4-hydroxyacetophenone (10.0 g, 73.5 mmol), 18-crown-6 (0.2912 g, 1.1 mmol) and potassium carbonate (13.2 g, 95.5 mmol) were taken in a two neck round bottom flask equipped with a stir bar. The flask was vacuumed and refilled with N2 three times. Acetone (22 mL) was added through syringe and needle. The mixture was stirred at room temperature for 30 minutes, followed by addition of 1-bromo-3-propanol (7.8 mL, 88.1 mmol). The mixture was refluxed for 24 hours and then filtered. Acetone was removed under vacuum to yield the crude product (15.0 g) which was used in the next step without purification. Purification can be performed by column chromatography (30% ethyl acetate and 70% hexane): mp 37-41° C.; 1H NMR (500 MHz, DMSO-d6) δ 1.86-1.91 (m, 2H), 2.50 (s, 3H, overlap with DMSO), 3.56 (m, 2H), 4.13 (t, J=6.36 Hz, 2H), 4.55 (t, J=5.14 Hz, 1H), 7.03 (d, J=8.80 Hz, 2H), 7.92 (d, J=9.05 Hz, 2H); 13C NMR (125 MHz, DMSO-d6) δ 26.3 (s), 31.9 (s), 57.1 (s), 64.9(s), 114.1(s), 129.7 (s), 130.3 (d), 162.5 (s), 196.1 (s); IR (ATR) ν 3439, 2941, 1654, 1595, 1255, 1170, 1056, 948, 827 cm-1; MS (ESI) m/z calc for C11H14NaO3 [MNa]+ 217.1, found 216.8. NMR results were consistent with the previously reported characterization in CDCl3.4
Reaction SMILES: [CH3:1][Si](C=[N+]=[N-])(C)C.[C:8]([O:12][C:13]([N:15]([CH3:33])[CH2:16][CH2:17][O:18][CH2:19][CH2:20][O:21][CH2:22][CH2:23][O:24][CH2:25][CH2:26][O:27][CH2:28][CH2:29][C:30]([OH:32])=[O:31])=[O:14])([CH3:11])([CH3:10])[CH3:9].C(O)(=O)C>CCCCCC.CO>[C:8]([O:12][C:13]([N:15]([CH3:33])[CH2:16][CH2:17][O:18][CH2:19][CH2:20][O:21][CH2:22][CH2:23][O:24][CH2:25][CH2:26][O:27][CH2:28][CH2:29][C:30]([O:32][CH3:1])=[O:31])=[O:14])([CH3:11])([CH3:10])[CH3:9]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: CN(CCOCCOCCOCCOCCC(=O)O)C(=O)OC(C)(C)C
Solvent: CCCCCC
Solvent: CC(=O)O
Solvent: CO
Product: COC(=O)CCOCCOCCOCCOCCN(C)C(=O)OC(C)(C)C
Reaction time: 2 h

Procedure:
2 ml of a 2M solution of trimethylsilyldiazomethane in hexane are added to a solution, cooled to 0° C., of 500 mg of 3-[2-(2-{2-[2-((tert-butoxycarbonyl)(methyl)amino)ethoxy]ethoxy}ethoxy)ethoxy]propanoic acid in 4.8 ml of MeOH. After 2 h, the mixture is neutralized by addition of 120 μl of acetic acid and then concentrated under RP, and the residue is purified by flash chromatography on silica (Analogix Super Flash SiO2 SF25-40 g) using a gradient from 0 to 5% of methanol in DCM. 400 mg of methyl 3-[2-(2-{2-[2-((tert-butoxycarbonyl)(methyl)amino)ethoxy]ethoxy}ethoxy)ethoxy]propanoate are thus obtained.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[CH:9]1([CH2:15]C2C=CC=CC=2O)[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.C1(C)C=CC=CC=1>O1CCCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:15][CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)=[CH:4][CH:3]=1
Reactant: Oc1ccccc1CC1CCCCC1
Reactant: Oc1ccc(Br)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: Brc1ccc(OCC2CCCCC2)cc1
Yield: 54.6 %

Procedure:
To a solution of 4-bromophenol (6.0 g, 34.7 mmol), cyclohexylmethylphenol (4.3 ml, 34.7 mmol) and triphenylphosphine (9.1 g, 34.7 mmol) in tetrahydrofuran (100 ml) was added slowly a 40% solution of diethyl azodicarboxylate in toluene (15.1 ml, 34.7 mmol) in portions at 0° C. with stirring, and then the resulting mixture was stirred at room temperature for 3 hours. After stirring, the reaction mixture was evaporated in vacuo, and hexane was added to the residue. After filtration, the filtrate was evaporated in vacuo once again, and the residue was purified by chromatography on a silica gel column using a mixed solvent of ethyl acetate and hexane (1:20) as the eluent to afford 1-bromo-4-(cyclohexylmethoxy)benzene (5.1 g, yield: 54%).
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][C@@H:9]([CH2:13][CH2:14][CH2:15][CH2:16][N:17]([C:34]([O:36][CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)=[O:35])[CH2:18][C@H:19]([OH:33])[CH2:20][CH2:21][NH:22][C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24])[C:10]([OH:12])=[O:11].[O:44]1[CH:49]=[CH:48][CH2:47][CH2:46][CH2:45]1>C(Cl)(Cl)Cl>[NH2:8][C@@H:9]([CH2:13][CH2:14][CH2:15][CH2:16][N:17]([C:34]([O:36][CH2:37][C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1)=[O:35])[CH2:18][C@H:19]([O:33][CH:45]1[CH2:46][CH2:47][CH2:48][CH2:49][O:44]1)[CH2:20][CH2:21][NH:22][C:23]([O:25][CH2:26][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)=[O:24])[C:10]([OH:12])=[O:11]
Reactant: N[C@@H](CCCCN(C[C@H](O)CCNC(=O)OCc1ccccc1)C(=O)OCc1ccccc1)C(=O)O
Reactant: C1=COCCC1
Solvent: ClC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Product: N[C@@H](CCCCN(C[C@@H](CCNC(=O)OCc1ccccc1)OC1CCCCO1)C(=O)OCc1ccccc1)C(=O)O
Reaction time: 16 h
Yield: 51.9 %

Procedure:
Trifluoroacetic acid (164 mg, 1.44 mmol) was added to a solution of 17a (360 mg, 0.72 mmol) in CHCl3 (7 mL). The solution was concentrated in vacuo. The resultant oil was dissolved in CH2Cl2 (20 mL), and 3,4-dihydro-2H-pyran (69 mg, 75 μL, 0.83 mmol) was added at room temperature. The reaction progress was monitored by TLC, and six additional portions of 3,4-dihydro-2H-pyran (69 mg each) were added over the next 31 hours. The reaction mixture was stirred for an additional 16 hours and concentrated in vacuo. The oil was dissolved in water (4 mL) and methanol (8 mL), then adjusted to pH 7 with saturated NaHCO3 solution. The solution was concentrated, and the crude oil was purified by chromatography on a C-18 column (30% acetone/water, followed by 55% acetone/water) to give 18a (219 mg, 52%) as a colorless oil: 1H NMR δ 1.20-1.98 (m, 14H), 3.06-3.56 (m, 8H), 3.68-4.02 (m, 2H), 4.33-4.62 (m, 1H), 5.06 (s, 2H), 5.11 (s, 2H), 7.24-7.36 (m, 10H); 13C NMR δ 20.7, 21.1, 21.7, 23.6, 26.3, 26.5, 32.0, 32.5, 34.2, 38.1, 38.5, 52.0, 56.2, 64.2, 65.2, 67.3, 68.3, 74.9, 100.1, 101.6, 128.79, 128.96, 129.02, 129.10, 129.20, 129.47, 129.56, 129.62, 138.3, 138.5, 158.0, 158.7, 174.8; HRMS m/z calcd for C31H43N3NaO8 608.2948, found 608.2954.
Reaction SMILES: [C:1]1([CH2:7][C:8]([O:10]C2CCCCO2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.BrCCCCCBr.[H-].[Na+].Cl>CN(C)P(=O)(N(C)C)N(C)C.O1CCOCC1.O.C(OCC)(=O)C>[C:1]1([CH2:7][C:8]([OH:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cc1ccccc1)OC1CCCCO1
Agent: BrCCCCCBr
Agent: Cl
Agent: [H-]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: O=C(O)Cc1ccccc1
Reaction time: 0.25 h
Yield: 71.4 %

Procedure:
The crude tetrahydro-2H-pyran-2-yl 2-phenylacetate (E5) (0.581 g, 4.26 mmol)) and 1,5-dibromopentane (1.474 g, 6.41 mmol) were dissolved in dry hexamethylphosphoric triamide (6 ml) and the mixture was cooled in an ice bath. To the cooled solution 60% suspension of NaH in mineral oil (0.507 g, 12.67 mmol) was added and the reaction mixture was stirred at ice bath temperature for 15 minutes and at room temperature for 5 hours. The reaction mixture was diluted with dioxane (20 ml) and water (15 ml), and the pH of the reaction medium was brought to pH 1 with conc. HCl (3 ml). The reaction mixture was stirred for 20 minutes and poured into ethyl acetate (75 ml). The organic layer was washed with a mixture of 2 N HCl and brine, 1:1 (2×50 ml), brine (50 ml), and dried (Na2SO4). The solvents were evaporated and the residue was chromatographed on silicagel (50 g) with benzene-ethyl acetate-acetic acid (9:1:0.1) as eluent to give a crude product. The product was re-chromatographed on silicagel (50 g) with petroleum ether-ethyl acetate-acetic acid (8:2:0.1) as eluent to give the title compound (0.414 g, 47% based on E4) as a white solid. 1H NMR (CDCl3, HMDSO) δ: 1.04-2.01 (8H, m); 2.19-2.62 (2H, m); 7.09-7.55 (5H, m), 10.29 (1H, br s).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][C:3]=1[NH:4][CH2:5][CH:6]=[O:7].C(=O)([O-])[O-].[Na+].[Na+].C1C=CC=CC=1.[Cl:25][CH:26]([CH3:30])[C:27](Cl)=[O:28]>O>[Cl:25][CH:26]([CH3:30])[C:27]([N:4]([CH2:5][CH:6]=[O:7])[C:3]1[CH:8]=[C:9]([Cl:12])[CH:10]=[CH:11][C:2]=1[CH3:1])=[O:28]
Reactant: CC(Cl)C(=O)Cl
Reactant: Cc1ccc(Cl)cc1NCC=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: O
Product: Cc1ccc(Cl)cc1N(CC=O)C(=O)C(C)Cl
Temperature: 25 °C

Procedure:
The dimethyl acetal of 2-(2-methyl-5-chloroanilino)-acetaldehyde (0.1 mole), sodium carbonate (0.06 mole) dissolved in water (50 ml) and benzene (50 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and cooling means. The mixture is cooled to a temperature of about 0° C. and α-chloropropionyl chloride (0.11 mole) is incrementally added with stirring. After the addition is completed stirring is continued and the reaction mixture is permitted to warm to room temperature. After this time the mixture is filtered, washed with dilute hydrochloric acid and stripped of solvent to yield the desired product the dimethyl acetal of 2-(N-α-chloropropionyl-2-methyl-5-chloroanilino)-acetaldehyde.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].Cl.[NH2:13][C:14]1[CH:20]=[CH:19][C:17]([OH:18])=[CH:16][C:15]=1O.[OH-].[Na+].C1COCC1>CO.O>[Cl:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4]1[O:5][C:15]2[CH:16]=[C:17]([OH:18])[CH:19]=[CH:20][C:14]=2[N:13]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1Cl
Reactant: Nc1ccc(O)cc1O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: Oc1ccc2nc(-c3ccc(Cl)cc3Cl)oc2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 26.4 %

Procedure:
9.9 ml (70.5 mmol) of 2,4-dichlorobenzoyl chloride and 2.0 g (12.4 mmol) of 4-aminoresorcinol hydrochloride were introduced into a three-necked flask provided with a thermometer and a cooling condenser, and the mixture was heated at 172° to 247° C. for 1 hour, then excessive acid chloride was removed by distillation. To the residue, 6.47 g (161.8 mmol) of NaOH, 60 ml of THF, 60 μl of water and 30 ml of methanol were added, and the mixture was stirred at room temperature for about 2 hours. The reaction solution was extracted with ethyl acetate, the extract was washed with saturated sodium chloride water solution, and ethyl acetate was distilled off. Recrystallizing the residue with water/methanol/THF and drying the crystal, there was obtained 915 mg (3.27 mmol) of 2-(2,4-dichlorophenyl)-6-hydroxybenzoxazole. The yield was 26.3%.
Reaction SMILES: CO[C:3]1([C:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:16]=[CH:15][CH:14]=2)[C:11]2[C:6](=[C:7](Br)[CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4]1.[C:23]1([C:33]2[C:41]3[C:36](=[C:37]([OH:42])[CH:38]=[CH:39][CH:40]=3)[CH2:35][CH:34]=2)[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][CH:24]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1N(C)C)(C)(C)C>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].O.C1(C)C=CC=CC=1>[C:23]1([C:33]2[C:41]3[C:36](=[C:37]([O:42][C:7]4[CH:8]=[CH:9][CH:10]=[C:11]5[C:6]=4[CH2:5][CH:4]=[C:3]5[C:13]4[C:22]5[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=5)[CH:16]=[CH:15][CH:14]=4)[CH:38]=[CH:39][CH:40]=3)[CH2:35][CH:34]=2)[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][CH:24]=1
Reactant: Oc1cccc2c1CC=C2c1cccc2ccccc12
Reactant: COC1(c2cccc3ccccc23)CCc2c(Br)cccc21
Agent: [Pd]
Agent: CN(C)c1ccccc1-c1ccccc1P(C(C)(C)C)C(C)(C)C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Solvent: O
Product: C1=C(c2cccc3ccccc23)c2cccc(Oc3cccc4c3CC=C4c3cccc4ccccc34)c2C1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
Under an argon atmosphere, to a mixture of 5.50 g (15.6 mmol) of 4-bromo-1-(1-naphthyl)-2,3-dihydro-1H-inden-1-yl methyl ether, 4.00 g (15.5 mmol) of 3-(1-naphthyl)-1H-inden-7-ol, 6.60 g (31.1 mmol) of K3PO4, and 150 ml of toluene, a mixture of 183 mg (0.32 mmol) of Pd(dba)2 and 212 mg (0.62 mmol) of N-{2′-[di(tert-butyl)phosphino][1,1′-biphenyl]-2-yl}-N,N-dimethylamine was added. The resulting mixture was stirred for 8 hours at 100° C. Then, 300 ml of water was added, the organic layer was separated, and the aqueous layer was extracted with 3×75 ml of CH2Cl2. The combined extract was dried over Na2SO4 and evaporated to dryness. The crude 1-(1-methoxy-4-{[1-methoxy-1-(1-naphthyl)-2,3-dihydro-1H-inden-4-yl]oxy}-2,3-dihydro-1H-inden-1-yl)naphthalene was purified using a short column with Silica Gel 60 (40-63 μm, d 50 mm, l 70 mm, eluant: CH2Cl2). This product was demethoxylated in a mixture of 170 ml of 16 M HCl and 170 ml of methanol for 7 hours at reflux. The crude product was extracted with 3×150 ml of CH2Cl2. The combined extract was washed with 2×100 ml of water, dried over K2CO3, and evaporated to dryness. The analytically pure product was obtained by flash chromatography on Silica Gel 60 (40-63 μm, d 35 mm, l 300 mm, eluant:hexanes-CH2Cl2=5:1). Yield, 2.65 g (34%) of a white solid.
Reaction SMILES: [NH2:1][C@H:2]([C:9]([O:11]C(C)(C)C)=[O:10])[CH2:3][O:4]C(C)(C)C.C(OC([N:23]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:25]([CH2:32][CH:33]([NH:37][C:38](=[O:79])[CH:39]([NH:48][C:49](=[O:78])[CH:50]([S:58]C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH2:51][C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=2)[CH2:40][C:41]([O:43]C(C)(C)C)=[O:42])[C:34](O)=[O:35])=[CH:24]1)=O)(C)(C)C>>[C:9]([CH:2]([NH:1][C:34]([CH:33]([NH:37][C:38](=[O:79])[CH:39]([NH:48][C:49](=[O:78])[CH:50]([SH:58])[CH2:51][C:52]1[CH:53]=[CH:54][CH:55]=[CH:56][CH:57]=1)[CH2:40][C:41]([OH:43])=[O:42])[CH2:32][C:25]1[C:26]2[C:31](=[CH:30][CH:29]=[CH:28][CH:27]=2)[NH:23][CH:24]=1)=[O:35])[CH2:3][OH:4])([OH:11])=[O:10]
Reactant: CC(C)(C)OC[C@H](N)C(=O)OC(C)(C)C
Reactant: CC(C)(C)OC(=O)CC(NC(=O)C(Cc1ccccc1)SC(c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)NC(Cc1cn(C(=O)OC(C)(C)C)c2ccccc12)C(=O)O
Product: O=C(O)CC(NC(=O)C(S)Cc1ccccc1)C(=O)NC(Cc1c[nH]c2ccccc12)C(=O)NC(CO)C(=O)O

Procedure:
The title compound was prepared by condensing H-Ser(But)OBut with the protected dipeptide of Example 88, followed by deprotection and purification by HPLC (40%): (Pos. FAB)? (MH+).