Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[CH2:4][C:5]1[CH:10]=[CH:9][C:8](Br)=[CH:7][CH:6]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[CH2:50]([C:52]([C:71]1[CH:84]=[CH:83][C:74]([O:75][CH2:76][CH:77]([OH:82])[C:78]([CH3:81])([CH3:80])[CH3:79])=[C:73]([CH3:85])[CH:72]=1)([C:55]1[CH:60]=[CH:59][C:58](B2OC(C)(C)C(C)(C)O2)=[C:57]([CH3:70])[CH:56]=1)[CH2:53][CH3:54])[CH3:51].C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O>[CH3:1][O:2][C:3](=[O:12])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:58]2[CH:59]=[CH:60][C:55]([C:52]([CH2:50][CH3:51])([C:71]3[CH:84]=[CH:83][C:74]([O:75][CH2:76][CH:77]([OH:82])[C:78]([CH3:80])([CH3:81])[CH3:79])=[C:73]([CH3:85])[CH:72]=3)[CH2:53][CH3:54])=[CH:56][C:57]=2[CH3:70])=[CH:7][CH:6]=1
Reactant: COC(=O)Cc1ccc(Br)cc1
Reactant: CCC(CC)(c1ccc(OCC(O)C(C)(C)C)c(C)c1)c1ccc(B2OC(C)(C)C(C)(C)O2)c(C)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: Cc1ccccc1
Solvent: O
Product: CCC(CC)(c1ccc(OCC(O)C(C)(C)C)c(C)c1)c1ccc(-c2ccc(CC(=O)OC)cc2)c(C)c1
Temperature: 100 °C
Reaction time: 2.5 h
Yield: 97.1 %

Procedure:
(4-Bromo-phenyl)acetic acid methyl ester (Tetrahedron Letters 44 (2003) 331-334; 35 mg, 0.152 mmol), palladium acetate (2.2 mg, 0.010 mmol), 2-dicyclohexylphosphino-2′,6′-dimethoxy-1,1′-biphenyl (8.2 mg, 0.020 mmol), potassium phosphate (64 mg, 0.303 mmol) and water (0.2 mL) were added to a solution of 1-(4-{1-ethyl-1-[3-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-propyl}-2-methyl-phenoxy)-3,3-dimethyl-butan-2-ol (Example 31; 50 mg, 0.101 mmol) in toluene (2 mL). After replacement with nitrogen, the mixture was stirred at 100° C. for 2.5 hours. The reaction mixture was then poured into a saturated aqueous sodium bicarbonate solution, followed by extraction with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (hexane:ethyl acetate=4:1) to give the target compound as a colorless oil (50.7 mg, 99%).
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[CH2:6]([N:13]1[C:18](=[O:19])[CH:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:16](=O)[NH:15][C:14]1=[O:27])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>C(O)C>[CH2:6]([N:13]1[C:18](=[O:19])[C:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[C:16]([Cl:3])[NH:15][C:14]1=[O:27])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=C1NC(=O)N(Cc2ccccc2)C(=O)C1c1ccccc1
Solvent: CCO
Product: O=c1[nH]c(Cl)c(-c2ccccc2)c(=O)n1Cc1ccccc1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
To 64 ml of 50% ethanol, 300 ml (844 mmol) of phosphorus oxychloride was added drop by drop, with stirring under ice cooling conditions. To this solution, 120 g (380 mmol) of 3-benzyl-5-phenylpyrimidine-2,4,6(1H,3H)-trione was added little by little. This mixture was stirred at 50° C. for 30 minutes and then at 100° C. for 90 minutes. After cooling, the reaction mixture was poured into ice water and stirred for 1 hour. The resulting precipitate was collected by filtration, washed with water and n-hexane and dried to yield 112.89 g (94.7%, light white crystal) of the desired product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([P:9](=[O:14])([CH:12]=[CH2:13])[CH:10]=[CH2:11])=[CH:5][CH:4]=1.[CH3:15][NH2:16]>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([P:9]2(=[O:14])[CH2:12][CH2:13][N:16]([CH3:15])[CH2:11][CH2:10]2)=[CH:7][CH:8]=1
Reactant: C=CP(=O)(C=C)c1ccc(OC)cc1
Reactant: CN
Product: COc1ccc(P2(=O)CCN(C)CC2)cc1
Temperature: 25 °C

Procedure:
(4-Methoxyphenyl)(divinyl) phosphine oxide (1.22 g, 5.88 mmol) and methylamine (0.53 mL, 6.18 mmol, 40% in water) was heated to 90° C. for 2 h. The reaction mixture was cooled to ambient temperature then extracted with DCM (3×). The combined organic extracts were dried (MgSO4) then concentrated in vacuo to afford the requisite product. MS: cal'd 240 (MH+), exp 240 (MH+)
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10](/[CH:17]=[CH:18]/[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2Br)=[N:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:26]([N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1)(=[O:28])[CH3:27].C(=O)([O-])[O-].[K+].[K+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C(OCC)(=O)C.O>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10](/[CH:17]=[CH:18]/[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[N:32]2[CH2:33][CH2:34][N:29]([C:26](=[O:28])[CH3:27])[CH2:30][CH2:31]2)=[N:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(=O)N1CCNCC1
Reactant: CC(C)(C)OC(=O)n1nc(/C=C/c2ccccc2Br)c2ccccc21
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: O
Product: CC(=O)N1CCN(c2ccccc2/C=C/c2nn(C(=O)OC(C)(C)C)c3ccccc23)CC1
Temperature: 121 °C
Reaction time: 0.17 h
Yield: 16.5 %

Procedure:
To a solution of (E)-3-[2-(2-bromophenyl)vinyl]indazole-1-carboxylic acid tert-butyl ester (0.23 g, 0.57 mmol) obtained in Step 2 in toluene (1.5 mL), 1-acetylpiperazine (0.15 g, 1.1 mmol), potassium carbonate (0.20 mg, 1.4 mmol), dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphane (0.068 g, 0.14 mmol) and tris(dibenzylideneacetone)dipalladium (0.052 g, 0.57 mmol) were sequentially added and, the mixture was stirred at 121° C. for 10 minutes under microwave (300 W) irradiation. The reaction mixture was added with water and ethyl acetate to separate the mixture into organic layer and aqueous layer and the organic layer was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=90/10 to 50/50) to obtain (E)-3-{2-[2-(4-acetylpiperazin-1-yl)phenyl]vinyl}indazol-1-carboxylic acid tert-butyl ester (0.042 g, 17%).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[O:10][CH3:11].[CH2:12](Br)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>C1C=CC=CC=1>[CH3:11][O:10][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:2]=1[O:1][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH:6]=[O:7]
Reactant: COc1cc(C=O)ccc1O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccccc1
Product: COc1cc(C=O)ccc1OCc1ccccc1
Yield: 92.6 %

Procedure:
A mixture of 4-hydroxy-3-methoxybenzaldehyde (100.0 g, 0.657 mole), benzyl bromide (112.4 g, 0.657 mole), and potassium carbonate (90.8 g, 0.657 mole) was heated overnight at reflux in 600 ml of dry acetonitrile (dried over 4A molecular sieves). The reaction mixture was stripped to dryness on a rotary evaporator. A white solid was obtained which was recrystallized form ethanol and dried in vacuo overnight at 80° C., to give 147.45 g (92.6% yield) of white crystalline product, mp 58°-63° C.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH2:14])(=[O:13])=[O:12])=[CH:7][C:6]=1[N:15]=[C:16]=[S:17])([CH3:3])[CH3:2].[NH3:18]>CO>[CH:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH2:14])(=[O:13])=[O:12])=[CH:7][C:6]=1[NH:15][C:16]([NH2:18])=[S:17])([CH3:3])[CH3:2]
Reactant: CC(C)Oc1ccc(S(N)(=O)=O)cc1N=C=S
Reactant: N
Solvent: CO
Product: CC(C)Oc1ccc(S(N)(=O)=O)cc1NC(N)=S
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Crude 4-isopropoxy-3-isothiocyanato-benzenesulfonamide (17.8 g, 65.2 mmol, example 2, step e) was treated with a 2 M solution of ammonia in MeOH (250 mL) and the resulting solution was stirred at room temperature for 18 h. The reaction mixture was then concentrated to about half the volume until a large amount of tan solid precipitated. The suspension was cooled to 0° C. for 30 minutes and was filtered. The solid was washed with methanol and ether to give the title compound as a cream colored solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[CH2:7][CH:8]([NH:13][C:14]([CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][NH:17]1)=[O:15])[CH:9]([OH:12])[CH2:10][F:11])([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.[C:32]1([C:38]2[S:39][CH:40]=[C:41]([C:43](O)=[O:44])[N:42]=2)[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C.C(OCC)(=O)C>[C:1]([O:5][C:6](=[O:22])[CH2:7][CH:8]([NH:13][C:14]([CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][N:17]1[C:43]([C:41]1[N:42]=[C:38]([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[S:39][CH:40]=1)=[O:44])=[O:15])[CH:9]([OH:12])[CH2:10][F:11])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)CC(NC(=O)C1CCCCN1)C(O)CF
Reactant: O=C(O)c1csc(-c2ccccc2)n1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)CC(NC(=O)C1CCCCN1C(=O)c1csc(-c2ccccc2)n1)C(O)CF
Reaction time: 0.5 h
Yield: 56.2 %

Procedure:
A stirred solution of [3S/R,4S/R,(2S)]-5-fluoro-4-hydroxy-3-[2-piperidinecarboxamido]-pentanoic acid tert-butyl ester (520 mg, 1.63 mmol), in DMF (9.7 ml) at room temperature was treated with DIPEA (311 μl, 1.80 mmol). The resulting mixture was allowed to stir for 30 min before being treated with 2-phenyl-thiazole-4-carboxylic acid (335 mg, 1.63 mmol) and TBTU (524 mg, 1.63 mmol). The mixture was stirred at room temperature for 16 hr and then diluted with ethyl acetate. The resulting solution was washed with 2 N HCl, saturated aq. NaHCO3, saturated aq. NaCl, dried (Na2SO4), filtered and concentrated to reveal an oil. The residue was purified by flash chromatography (60% ethyl acetate in hexane) to afford the sub-title compound as a colorless oil (463 mg, 56%): 1H NMR (400 MHz, CDCl3) δ 1.10-1.85 (15H, m), 2.22-2.89 (3H, m), 3.09-4.78 (6H, m), 5.20-5.43 (1H, m), 7.40-7.56 (3H, m), 7.81-8.11 (3H, m).
Reaction SMILES: [NH2:1][C@H:2]([C:13]([NH:15][CH2:16][CH2:17][CH2:18][CH2:19][NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[O:14])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.[NH:28]([C:53]([O:55][C:56]([CH3:59])([CH3:58])[CH3:57])=[O:54])[C@H:29]([C:45]([NH:47][C@H:48]([C:50](O)=[O:51])[CH3:49])=[O:46])[CH2:30][C:31]1[CH:36]=[CH:35][C:34]([O:37][CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)=[CH:33][CH:32]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>C(Cl)Cl.CN(C=O)C>[NH:28]([C:53]([O:55][C:56]([CH3:57])([CH3:59])[CH3:58])=[O:54])[C@H:29]([C:45]([NH:47][C@H:48]([C:50]([NH:1][C@H:2]([C:13]([NH:15][CH2:16][CH2:17][CH2:18][CH2:19][NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[O:14])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1)=[O:51])[CH3:49])=[O:46])[CH2:30][C:31]1[CH:36]=[CH:35][C:34]([O:37][CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)=[CH:33][CH:32]=1
Reactant: C[C@H](NC(=O)[C@H](Cc1ccc(OCc2ccccc2)cc1)NC(=O)OC(C)(C)C)C(=O)O
Reactant: CC(C)(C)OC(=O)NCCCCNC(=O)[C@@H](N)Cc1c[nH]c2ccccc12
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: C[C@H](NC(=O)[C@H](Cc1ccc(OCc2ccccc2)cc1)NC(=O)OC(C)(C)C)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)NCCCCNC(=O)OC(C)(C)C

Procedure:
compound SP305R. Same procedure as above with Trp-NH(CH2)4NHBoc (204.6 mg, 0.546 mmol), N-Boc-Tyr(Bn)-Ala-OH (242 mg, 0.546 mmol), EDC (116 mg, 0.61 mmol) and HOBt (82.2 mg, 0.61 mmol) in CH2Cl2/DMF (2.2 mL, 1/1). The crude tripeptide (282 mg) can be recrystallized from hot THF to give a white solid as an analytical sample (89.1 mg, 31.5%). 1H NMR (300 MHz, DMSO-d6) δ 1.18-1.4 (m, 7H, 2 CH2 putrescine, CH3), 1.28 (s, 9H, (CH3)3), 1.37 (s, 9H, (CH3)3), 2.61 (m, 1H, CH2 Tyr or Trp), 2.85-3.1 (m, 7H, CH2 Tyr, CH2 Trp, 2 CH2 putrescine), 4.08 (m, 1H, CHα), 4.29 (m, 1H, CHα), 4.45 (m, 1H, CHα), 5.03 (s, 2H, CH2 (Bn)), 6.73 (m, 1H), 6.87-7.43 (m, 14 aromatic H), 7.56 (d, J=7.7 Hz, 1H), 7.83 (m, 1H), 7.99 (m, 2H), 10.8 (s, 1NH). 13C NMR (75 MHz, DMSO-d6) δ 18.2 (CH3), 26.2, 26.8 (2 CH2 putrescine), 28.1 (CH2 Trp), 28.2 ((CH3)3), 36.3 (CH2 Tyr), 38.2, 39.2 (2 CH2 putrescine), 48.2, 53.4, 55.8 (CHα Ala, Tyr, Trp), 69 (CH2 (Bn)), 77.3, 78 (2 C(CH3)3), 109.8, 111.1, 114.2, 118.1, 118.4, 120.7, 123.4, 127.3, 127.5, 127.7, 128.3, 130.1, 130.3, 136, 137.2 (19 aromatic C), 155.2, 155.5, 156.8 (Car-O, 2 CO carbamate), 170.7, 171.4, 171.8 (3 CO amide). Anal. Calcd. for C44H58N6O8: C, 66.14; H, 7.32; N, 10.52. Found: C, 65.89; H, 7.34; N, 10.77.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[CH:12]=2)[CH:9]=[O:10])[CH:5]=[CH:6][CH:7]=1.[OH-].[Na+].[Br:20][CH2:21][CH2:22]Br>ClCCl.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.[Cl-].[Na+].O>[Br:20][CH2:21][CH2:22][O:10][CH:9]=[C:8]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[CH:12]=1)[C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=1
Reactant: O=CC(c1cccc(F)c1)c1cccc(F)c1
Reactant: BrCCBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Cl-]
Solvent: O
Solvent: ClCCl
Product: Fc1cccc(C(=COCCBr)c2cccc(F)c2)c1
Reaction time: 20 h
Yield: 94.4 %

Procedure:
bis(3-Fluorophenyl)acetaldehyde (4.82 g, 0.0208 mol) was dissolved in dichloromethane (50 ml) and tetra-n-butylammonium bromide (0.67 g, 0.00208 mol) was added. 12 N sodium hydroxide solution (50 ml) and 1,2-dibromoethane (17.9 ml, 0.208 mol) were introduced and the mixture was stirred vigorously at room temperatue for 20 h. Dichloromethane (100 ml) and saturated brine (50 ml) were added, and the phases were separated. The aqueous phase was extracted further with dichloromethane (50 ml) and the combined dichloromethane extracts were washed with water (2×75 ml) and saturated brine (50 ml). Drying of the dichloromethane solution (Na2SO4) and evaporation provided 1-(2-(2-bromoethoxy)-1-(3-fluoro-phenyl)ethenyl)-3-fluorobenzene as an oil (6.66 g, 95%).
Reaction SMILES: [CH3:1][C:2]1[CH:14]=[C:13]([C:15]2[CH2:19][C@:18]([C:24]3[CH:29]=[C:28]([Cl:30])[C:27]([Cl:31])=[C:26]([Cl:32])[CH:25]=3)([C:20]([F:23])([F:22])[F:21])[O:17][N:16]=2)[CH:12]=[CH:11][C:3]=1[C:4]([O:6]C(C)(C)C)=[O:5].FC(F)(F)C(O)=O>ClCCl>[CH3:1][C:2]1[CH:14]=[C:13]([C:15]2[CH2:19][C@:18]([C:24]3[CH:29]=[C:28]([Cl:30])[C:27]([Cl:31])=[C:26]([Cl:32])[CH:25]=3)([C:20]([F:23])([F:22])[F:21])[O:17][N:16]=2)[CH:12]=[CH:11][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: Cc1cc(C2=NO[C@@](c3cc(Cl)c(Cl)c(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(C2=NO[C@@](c3cc(Cl)c(Cl)c(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)O

Procedure:
To a solution of tert-butyl 2-methyl-4-[(5S)-5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4H-isoxazol-3-yl]benzoate (64.87 mmol, 33 g) in dichloromethane (300 mL) was added trifluoroacetic acid (389.2 mmol, 44.6 g) at 0° C. After addition the reaction was brought to room temperature and the mixture stirred over night after which time LC-MS analysis showed a complete conversion. The crude mixture was concentrated and the residue dissolved in 300 mL of ethylacetate, washed with brine, dried over MgSO4 and evaporated to yield crude title product which was purified over a silica gel column (eluent: CH2Cl2/EtOAc) to obtain the desired product as pale yellow foam. LCMS (Method GR) RT 1.23 min, [M+H]+ 450/452; 1H-NMR (CDCl3, 400 MHz): 2.7 (s, 3H), 3.70 (d, 2H), 4.10 (d, 2H), 7.60 (s, 3H), 7.01 (d, 1H), 8.15 (d, 2H), 7.01 (d, 1H), 8.15 (d, 2H), 11.40 (s, 1H); 19F-NMR (CDCl3, 376 MHz): −79.38.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[C@H:4]([NH:8][S:9]([C:12]1[CH:21]=[CH:20][C:15]2[N:16]=[C:17](Cl)[S:18][C:14]=2[CH:13]=1)(=[O:11])=[O:10])[CH:5]([CH3:7])[CH3:6].C([O-])([O-])=O.[K+].[K+].[C:29]1([SH:35])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.O.C(OC(=O)C)C>CC#N>[CH3:1][O:2][C:3](=[O:22])[C@H:4]([NH:8][S:9]([C:12]1[CH:21]=[CH:20][C:15]2[N:16]=[C:17]([S:35][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[S:18][C:14]=2[CH:13]=1)(=[O:11])=[O:10])[CH:5]([CH3:7])[CH3:6]
Reactant: COC(=O)[C@H](NS(=O)(=O)c1ccc2nc(Cl)sc2c1)C(C)C
Reactant: Sc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)[C@H](NS(=O)(=O)c1ccc2nc(Sc3ccccc3)sc2c1)C(C)C

Procedure:
(2R)-3-methyl-2-[(2-chlorobenzthiazol-6-sulfonyl)amino]butanoic acid methylester (0.154 mg, 0.44 mmol) prepared in a similar manner as in Example 20 was dissolved in MeCN (3 mL) and added solid K2CO3 (0.1 mg, 1.6 equi.). Thiophenol (0.055 mL, 1.2 equi.) was also added and the reaction solution was refluxed for 3 hours. When starting material was disappeared, H2O/ethylacetate (5 mL/10 mL) was added for extraction of product. The extracted product in organic phase was washed with NaCl solution, dried over MgSO4 and distilled under reduced pressure. The extracted product was crystallized with n-hexane/ethylacetate (3/1) solution to prepare the titled compound, (2R)-3-methyl-2-[(2-phenylthiobenzthiazol-6-sulfonyl)amino]butanoic acid methylester (190 mg, 99%).
Reaction SMILES: CS(O[CH:6]([CH2:14][CH2:15][CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:7]([CH3:13])([CH3:12])[C:8]([O:10][CH3:11])=[O:9])(=O)=O.[CH3:24][O:25][C:26]1[CH:31]=[CH:30][C:29]([SH:32])=[CH:28][CH:27]=1.C(=O)([O-])[O-].[K+].[K+]>CO>[CH3:24][O:25][C:26]1[CH:31]=[CH:30][C:29]([S:32][CH:6]([CH2:14][CH2:15][CH2:16][CH2:17][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:7]([CH3:12])([CH3:13])[C:8]([O:10][CH3:11])=[O:9])=[CH:28][CH:27]=1
Reactant: COC(=O)C(C)(C)C(CCCCc1ccccc1)OS(C)(=O)=O
Reactant: COc1ccc(S)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: COC(=O)C(C)(C)C(CCCCc1ccccc1)Sc1ccc(OC)cc1
Temperature: 60 °C
Yield: 23.6 %

Procedure:
Methyl 3-methanesulfonyloxy-2,2-dimethyl-7-phenylheptanoate (7.7 g, 23 mmol) and 4-methoxybenzenethiol (5.5 mL, 45 mmol) are dissolved in MeOH (40 mL) and potassium carbonate (4.8 g, 35 mmol) is added and the reaction is heated at 60° C. for 24 hours. The solvent is removed in vacuo and CH2Cl2 (100 mL) added and then washed with NaHCO3 (60 mL), 1 N HCl (60 mL) and brine (100 mL). The solvent is removed in vacuo and the residue purified by column chromatography (silica, 40% petroleum ether in CH2Cl2) to yield methyl 3-(4-methoxyphenylsulfanyl)-2,2-dimethyl-7-phenylheptanoate (2.1 g, 24%). 1H NMR (300 MHz, CDCl3) δ 7.36-7.33 (m, 2H), 7.29-7.12 (m, 5H), 6.82-6.79 (m, 2H), 3.79 (s, 3H), 3.55 (s, 3H), 3.18-3.15 (m, 1H), 2.60-2.53 (m, 2H), 1.85-1.73 (m, 1H), 1.57-1.40 (m, 5H), 1.26 (s, 3H), 1.20 (s, 3H); MS (FAB) m/e 386 (M+).
Reaction SMILES: [NH2:1][CH:2]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][C:20]([F:25])([F:24])[CH:21]([F:23])[F:22])[CH:14]=1)[CH:3]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)[OH:4].[C:26]1([C:37](O)=[O:38])[CH:27]=[CH:28][CH:29]=[C:30]2[CH2:36][CH2:35][CH2:34][CH:33]=[CH:32][C:31]=12.Cl.C(N=C=NCCCN(C)C)C.O.ON1C2C=CC=CC=2N=N1>C(#N)C.O>[OH:4][CH:3]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)[CH:2]([NH:1][C:37]([C:26]1[CH:27]=[CH:28][CH:29]=[C:30]2[CH2:36][CH2:35][CH2:34][CH:33]=[CH:32][C:31]=12)=[O:38])[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][C:20]([F:24])([F:25])[CH:21]([F:22])[F:23])[CH:14]=1
Reactant: O=C(O)c1cccc2c1C=CCCC2
Reactant: NC(Cc1cccc(OC(F)(F)C(F)F)c1)C(O)c1ccc(O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CC#N
Solvent: O
Product: O=C(NC(Cc1cccc(OC(F)(F)C(F)F)c1)C(O)c1ccc(O)cc1)c1cccc2c1C=CCCC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-{(1RS,2SR)-2-amino-1-hydroxy-3-[3-(1,1,2,2-tetrafluoroethoxy)phenyl]propyl}phenol (125 mg, 0.35 mmol) in acetonitrile (30 ml) were added 6,7-dihydro-5H-benzo[a]cycloheptene-1-carboxylic acid (66 mg, 0.35 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (100 mg, 0.52 mmol) and 1-hydroxybenzotriazole hydrate (53 mg, 0.35 mmol), and the mixture was stirred overnight at room temperature. The reaction solution was diluted with water (100 ml) and extracted with ethyl acetate (100 ml×2). The extract was washed successively with 1N hydrochloric acid, saturated aqueous sodium hydrogen carbonate and saturated brine, dried (anhydrous magnesium sulfate) and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1) and recrystallized from chloroform-hexane to give the objective substance (162 mg, 88%).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH2:6]([O:9][C:10]([N:12]1[CH2:16][C@@H:15]([S:17][C:18]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:14][C@H:13]1[CH2:37][OH:38])=[O:11])[CH:7]=[CH2:8].C(N(CC)CC)C>C(Cl)Cl>[CH2:6]([O:9][C:10]([N:12]1[CH2:16][C@@H:15]([S:17][C:18]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:14][C@H:13]1[CH2:37][O:38][S:2]([CH3:1])(=[O:4])=[O:3])=[O:11])[CH:7]=[CH2:8]
Reactant: CS(=O)(=O)Cl
Reactant: C=CCOC(=O)N1C[C@@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)C[C@H]1CO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CCOC(=O)N1C[C@@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)C[C@H]1COS(C)(=O)=O
Reaction time: 0.5 h
Yield: 94 %

Procedure:
A solution of methanesulfonyl chloride (20.5 ml, 265 mmol) in methylene chloride (20 ml) was dropwise added to a solution of (2S,4S)-N-allyloxycarbonyl-2-hydroxymethyl-4-tritylthiopyrrolidine (119 g, 259 mmol, compound of Reference Example 3-1 of Japanese Patent Application No. 192,093/1990) and triethylamine (40.3 ml, 289 mmol) in methylene chloride (1 l) under cooling with ice, and the mixture was stirred at the same temperature for 30 minutes. The reaction solution was washed sequentially with water (500 ml), a saturated sodium hydrogen carbonate aqueous solution (250 ml) and a saturated sodium chloride aqueous solution (250 ml), then dried over anhydrous sodium sulfate and concentrated. To the residue, ethyl acetate (30 ml) and diisopropyl ether (270 ml) were added, and the precipitated crystals were collected by filtration to obtain (2S,4S)-N-allyloxycarbonyl-2-methanesulfonyloxymethyl-4-tritylthiopyrrolidine (130.8 g, yield: 94%).
Reaction SMILES: ON1C2C=CC=CC=2N=N1.[NH:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]([CH2:20][CH2:21][CH2:22][NH2:23])=[CH:12]1.CN1CCOCC1.Cl.[CH3:32][N:33]([CH3:50])[C:34]1([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[CH2:39][CH2:38][C:37](=[CH:40][C:41](O)=[O:42])[CH2:36][CH2:35]1.C1(N=C=NC2CCCCC2)CCCCC1.[OH-].[Na+]>CN(C)C=O.O>[CH3:50][N:33]([CH3:32])[C:34]1([C:44]2[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=2)[CH2:39][CH2:38][C:37](=[CH:40][C:41]([NH:23][CH2:22][CH2:21][CH2:20][C:13]2[C:14]3[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=3)[NH:11][CH:12]=2)=[O:42])[CH2:36][CH2:35]1
Reactant: NCCCc1c[nH]c2ccccc12
Reactant: CN(C)C1(c2ccccc2)CCC(=CC(=O)O)CC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CN(C)C1(c2ccccc2)CCC(=CC(=O)NCCCc2c[nH]c3ccccc23)CC1
Temperature: 0 °C
Reaction time: 144 h
Yield: 60 %

Procedure:
1-Hydroxybenzotriazole (819 mg, 6.0 mmol), 3-(1H-indol-3-yl)propylamine (522 mg, 3.0 mmol) and N-methylmorpholine (0.666 ml, 6.0 mmol) were added to a solution of (4-dimethylamino-4-phenylcyclohexylidene)acetic acid hydrochloride (887 mg, 3.0 mmol) in dry dimethylformamide (10 ml) under argon. The solution was cooled to 0° C. and dicyclohexylcarbodiimide (1.25 g, 6.0 mmol) was added. The reaction mixture was stirred at RT for 6 d. Working up of the mixture was carried out by separating off the urea which had precipitated out and introducing the filtrate into a mixture of saturated NaCl solution (40 ml) and saturated NaHCO3 solution (10 ml). Still further urea thereby precipitated out and was separated off. The aqueous phase was diluted with water (400 ml), 5 M sodium hydroxide solution (5 ml, 25 mmol) was added and the mixture was stored at 5° C. for 3 d. The product thereby precipitated out as a beige-coloured solid in a yield of 60% (742 mg) with an m.p. of 85-87° C.