Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([CH:3]1[CH2:29][CH:6]2[CH:7]([C:19]3[CH:24]=[CH:23][C:22]([O:25]COC)=[CH:21][CH:20]=3)[O:8][C:9]3[CH:10]=[CH:11][C:12]([O:15]COC)=[CH:13][C:14]=3[CH:5]2[CH2:4]1)[CH3:2].Cl.CCOC(C)=O.CCOC(C)=O.CCCCCC>C1COCC1>[CH2:1]([C@H:3]1[CH2:29][C@H:6]2[C@@H:7]([C:19]3[CH:20]=[CH:21][C:22]([OH:25])=[CH:23][CH:24]=3)[O:8][C:9]3[CH:10]=[CH:11][C:12]([OH:15])=[CH:13][C:14]=3[C@H:5]2[CH2:4]1)[CH3:2]
Reactant: CCC1CC2c3cc(OCOC)ccc3OC(c3ccc(OCOC)cc3)C2C1
Agent: Cl
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC[C@H]1C[C@@H]2[C@H](C1)c1cc(O)ccc1O[C@@H]2c1ccc(O)cc1
Yield: 66.7 %

Procedure:
Dissolve alkyl cyclopentane 38 (109 mg, 0.27 mmol) in THF (4 mL) then add 3 M HCl (1.0 mL). Stir the reaction at room temperature overnight. Dilute the reaction with EtOAc and wash with saturated aqueous sodium bicarbonate and brine. Extract the aqueous layer with EtOAc (1×). Combine the organic extracts, dry (Na2SO4), filter and concentrate in vacuo. Purify by flash chromatography (10 g SiO2, dry loading on 700 mg silica, 40 ml/min, 0-30% EtOAc/Hexane over 25 minutes and then 30% EtOAc/hexane for 7 minutes) to afford 56 mg (0.18 mmol, 68%) of alkyl cyclopentane 39 as a white solid. HRMS(ES+) calcd for C20H26NO3: 328.1913; found: 328.1906 (M+NH4). HPLC (Zorbax C18 column; 10 to 100% CH3CN/H2O for 10 min then 100% CH3CN for 5 min; 1 mL/min; tr 9.33 min).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=3[Cl:20])[N:11]=[C:10]([C:21]([NH:23][CH:24]3[CH2:29][CH2:28][N:27]([C:30]([O:32][C:33]4C=CC([N+]([O-])=O)=C[CH:34]=4)=[O:31])[CH2:26][CH2:25]3)=[O:22])[C:9]=2[CH3:42])=[CH:4][CH:3]=1.[H-].[Na+]>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=3[Cl:20])[N:11]=[C:10]([C:21]([NH:23][CH:24]3[CH2:25][CH2:26][N:27]([C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH2:28][CH2:29]3)=[O:22])[C:9]=2[CH3:42])=[CH:4][CH:3]=1
Reactant: Cc1c(C(=O)NC2CCN(C(=O)Oc3ccc([N+](=O)[O-])cc3)CC2)nn(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)N1CCC(NC(=O)c2nn(-c3ccc(Cl)cc3Cl)c(-c3ccc(Cl)cc3)c2C)CC1
Reaction time: 16 h

Procedure:
To 4-nitrophenyl 4-[5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-amido]piperidine-1-carboxylate (0.02 mmol, 1 eq.) and appropriate alcohol (0.5 mL) in THF (2 mL) was added sodium hydride 60% dispersion in mineral oil (4 mg, 0.1 mmol, 5 eq.). The reaction was stirred for 16 h and quenched with acetic acid. The reaction was concentrated in vacuo. The crude material was purified by column chromatography 0-100% ethyl acetate/hexanes to yield desired product.
Reaction SMILES: [CH2:1]([C:8]1[C:13](I)=[CH:12][CH:11]=[C:10]([N:15]2[CH2:19][C@H:18]([OH:20])[C@H:17]([O:21][CH:22]([CH3:24])[CH3:23])[CH2:16]2)[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:25]([C@:27]1([OH:35])[CH:32]2[CH2:33][CH2:34][N:29]([CH2:30][CH2:31]2)[CH2:28]1)#[CH:26].C(N(CC)CC)C.N>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CN(C)C=O>[CH2:1]([C:8]1[C:13]([C:26]#[C:25][C@:27]2([OH:35])[CH:32]3[CH2:33][CH2:34][N:29]([CH2:30][CH2:31]3)[CH2:28]2)=[CH:12][CH:11]=[C:10]([N:15]2[CH2:19][C@H:18]([OH:20])[C@H:17]([O:21][CH:22]([CH3:24])[CH3:23])[CH2:16]2)[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)O[C@@H]1CN(c2ccc(I)c(Cc3ccccc3)n2)C[C@@H]1O
Reactant: C#C[C@@]1(O)CN2CCC1CC2
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: N
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)O[C@@H]1CN(c2ccc(C#C[C@@]3(O)CN4CCC3CC4)c(Cc3ccccc3)n2)C[C@@H]1O
Temperature: 75 °C
Reaction time: 2 h
Yield: 34.4 %

Procedure:
A mixture of 464 mg of 2-benzyl-6-(cis-3-isopropyloxy-4-hydroxypyrrolidine-1-yl)-3-iodopyridine, 176 mg of (3R)-3-ethynyl-3-quinuclidinol, 122 mg of tetrakis(triphenylphosphine)palladium (0), 10 mg of cuprous iodide, 0.44 ml of triethylamine and 5.0 ml of N,N-dimethylformamide was heated under stirring at 75° C. for 2 hours in a nitrogen atmosphere. The reaction solution was poured into aqueous dilute ammonia, and then extracted with ethyl acetate. The extract was washed with brine and the solvent was removed. The residue was subjected to NH-silica gel (Fuji Silicia) column chromatography and eluted with hexane/ethyl acetate (1:1) and then with ethyl acetate/methanol (20:1), to give 168 mg of the target compound.
Reaction SMILES: F[C:2]1[C:7](/[CH:8]=[CH:9]\[C:10]2[C:11](F)=[N:12][CH:13]=[CH:14][CH:15]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[CH:17]1([NH2:20])[CH2:19][CH2:18]1>>[CH:17]1([N:20]2[C:2]3[N:3]=[CH:4][CH:5]=[CH:6][C:7]=3[CH:8]=[CH:9][C:10]3[CH:15]=[CH:14][CH:13]=[N:12][C:11]2=3)[CH2:19][CH2:18]1
Reactant: NC1CC1
Reactant: Fc1ncccc1/C=C\c1cccnc1F
Product: C1=Cc2cccnc2N(C2CC2)c2ncccc21
Temperature: 125 °C
Yield: 54.9 %

Procedure:
A mixture of Z-1,2-di-(2-fluoropyridinyl)ethylene (0.436 g) and cyclopropylamine (2 g) was heated at 125° C. in a sealed tube for 12 hours. The mixture was cooled and fractionated directly over silica gel to give 11-cyclopropyl-dipyrido[2,3-b:3',2'-f]azepine (0.258 g), mp 184°-185° C.
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:22])[C:6]2[CH:11]=[CH:10][C:9]([B:12]3[O:16]C(C)(C)C(C)(C)[O:13]3)=[CH:8][C:7]=2[CH3:21])CC1.I([O-])(=O)(=O)=O.[Na+].Cl>CC(C)=O>[CH3:21][C:7]1[CH:8]=[C:9]([B:12]([OH:16])[OH:13])[CH:10]=[CH:11][C:6]=1[C:5](=[O:22])[NH:4][CH3:1]
Reactant: Cc1cc(B2OC(C)(C)C(C)(C)O2)ccc1C(=O)NC1CC1
Agent: Cl
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: CC(C)=O
Product: CNC(=O)c1ccc(B(O)O)cc1C
Temperature: 40 °C
Reaction time: 2 h
Yield: 112.8 %

Procedure:
To a stirred solution of 20.22 g (67 mmol) N-cyclopropyl-2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide in acetone (300 mL) were added 43.08 g (201 mmol) sodium periodate 134 mL ammonium acetate (134 mmol, 1M in water) and the mixture was stirred for 3 h at rt and 2 h at 40° C. 4 N HCl was added (32 mL) and the organic phase was removed in vaccuo. The mixture was extracted with ethyl acetate, and the organic phase was washed with water, dried and removed in vaccuo to yield 14.59 g (94.2%) of the title compound. 1H-NMR (400 MHz, DMSO-d6), δ [ppm]=0.44-0.52 (2H), 0.59-0.67 (2H), 2.26 (3H), 2.78 (1H), 7.18 (1H), 7.53-7.61 (2H), 8.01 (2H), 8.19 (1H).
Reaction SMILES: Br[C:2](Br)=[CH:3][C:4]1[C:9]([CH2:10][CH3:11])=[C:8]([O:12][CH3:13])[CH:7]=[CH:6][C:5]=1[CH2:14][CH3:15].[CH2:17]([NH2:20])[CH2:18][NH2:19]>>[CH2:10]([C:9]1[C:8]([O:12][CH3:13])=[CH:7][CH:6]=[C:5]([CH2:14][CH3:15])[C:4]=1[CH2:3][C:2]1[NH:19][CH2:18][CH2:17][N:20]=1)[CH3:11]
Reactant: NCCN
Reactant: CCc1ccc(OC)c(CC)c1C=C(Br)Br
Product: CCc1ccc(OC)c(CC)c1CC1=NCCN1

Procedure:
2-(2,6-Diethyl-3-methoxy-benzyl)-4,5-dihydro-1H-imidazole was prepared from 2-(2,2-dibromo-vinyl)-1,3-diethyl-4-methoxy-benzene and ethylenediamine in analogy to Example 1e): yellow crystals; MS (ISP): 247.4 ([M+H]+, 100%).
Reaction SMILES: [I:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3C(=[CH:7][CH:8]=[CH:9][CH:10]=3)C[C:4]=2[CH:3]=1.[CH3:15][C:16]([CH3:19])([O-])[CH3:17].[K+].CI>CS(C)=O.O1CCCC1>[CH3:15][C:16]1([CH3:19])[C:4]2[CH:3]=[C:2]([I:1])[CH:14]=[CH:13][C:12]=2[C:11]2[C:17]1=[CH:7][CH:8]=[CH:9][CH:10]=2
Reactant: CC(C)(C)[O-]
Reactant: Ic1ccc2c(c1)Cc1ccccc1-2
Agent: [K+]
Solvent: CI
Solvent: C1CCOC1
Solvent: CS(C)=O
Product: CC1(C)c2ccccc2-c2ccc(I)cc21
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
20 parts of 2-iodofluorene was dissolved in a mixed solution of 114 parts of dimethyl sulfoxide (DMSO) and 23 parts of tetrahydrofuran (THF), and the thus obtained mixture was then stirred at 25° C. for 10 minutes. Thereafter, while stirring, 8.7 parts of potassium-tert-butoxide was added to the mixture. Twenty minutes later, 13.2 parts of methyl iodide was added to the mixture, and further twenty minutes later, 8.7 parts of potassium-tert-butoxide was added thereto. Further, twenty minutes later, 13.2 parts of methyl iodide was added thereto, and the obtained mixture was then stirred at 25° C. for 2 hours. After completion of the stirring, the THF was distilled away from the reaction solution, and it was then extracted with toluene-water. The toluene phase was dried over magnesium sulfate, and the toluene was then distilled away, thereby obtaining a brown tarry solid. This brown tarry solid was separated and purified by column chromatography (hexane-ethyl acetate) to obtain 21 parts of 9,9-dimethyl-2-iodofluorene in the form of a colorless crystal.
Reaction SMILES: [ClH:1].[CH3:2][N:3]1[C:7]2[CH:8]=[C:9]([S:12][CH3:13])[CH:10]=[CH:11][C:6]=2[N:5]=[C:4]1[CH2:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][CH:23]([CH3:28])[C:24]([O:26]C)=[S:25])=[CH:18][CH:17]=1.Cl>O1CCOCC1>[ClH:1].[CH3:2][N:3]1[C:7]2[CH:8]=[C:9]([S:12][CH3:13])[CH:10]=[CH:11][C:6]=2[N:5]=[C:4]1[CH2:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][CH:23]([CH3:28])[C:24]([OH:26])=[S:25])=[CH:18][CH:17]=1
Reactant: COC(=S)C(C)Cc1ccc(OCc2nc3ccc(SC)cc3n2C)cc1
Agent: Cl
Solvent: C1COCCO1
Product: CSc1ccc2nc(COc3ccc(CC(C)C(O)=S)cc3)n(C)c2c1
Yield: 90.2 %

Procedure:
A mixture of methyl 3-[4-(1-methyl-6-methylthio-1H-benzimidazol-2-ylmethoxy)phenyl]-2-methylthiopropionate hydrochloride (5.75 g), concentrated hydrochloric acid (100 ml) and 1,4-dioxane (100 ml) was heated at reflux for 90 minutes. The reaction mixture was concentrated to dryness. To the residue was added tetrahydrofuran and the mixture was irradiated with ultrasonic waves. The insoluble material was isolated by filtration, washed with ethyl acetate, dissolved in N,N-dimethylformamide and reprecipitated with ether to afford the title compound (5.02 g, mp 193-196° C.).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.C(N(C(C)C)CC)(C)C.Cl[C:23](OCC)=[O:24].[F:28][C:29]1[CH:36]=[C:35]([Br:37])[CH:34]=[CH:33][C:30]=1[CH2:31][NH2:32]>O1CCCC1.C(OCC)(=O)C>[Br:37][C:35]1[CH:34]=[CH:33][C:30]([CH2:31][N:32]2[C:4](=[O:6])[C:3]3[CH:7]=[CH:8][C:9]([O:11][CH3:12])=[CH:10][C:2]=3[O:1][C:23]2=[O:24])=[C:29]([F:28])[CH:36]=1
Reactant: NCc1ccc(Br)cc1F
Reactant: CCOC(=O)Cl
Reactant: COc1ccc(C(=O)O)c(O)c1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc2c(=O)n(Cc3ccc(Br)cc3F)c(=O)oc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 36.5 %

Procedure:
A solution of 2-hydroxy-4-methoxybenzoic acid (2.04 g, 12.2 mmol) in tetrahydrofuran (20 mL, 0.6 M)was cooled to 0° C. After being treated with diisopropylethylamine (4.4 mL, 25.3 mmol), and ethyl chloroformate (2.4 mL, 25.1 mmol), the mixture was stirred at room temperature for 1 h and subsequently treated with a solution of 2-fluoro-4-bromobenzylamine (2.92 g, 12.1 mmol) and diisopropylethylamine (4.4 mL, 25.3 mmol) in tetrahydrofuran (15 mL). After stirring at room temperature for 22 h, the reaction mixture was diluted ethyl acetate and successively washed with 2 N HCl, saturated aq NaHCO3 and saturated aq NaCl. The organic layer was dried over Na2SO4, filtered and concentrated. The crude solid was purified by recrystallization with heptane and ethyl acetate to give 3-(4-bromo-2-fluoro-benzyl)-7-methoxy benzo[e][1,31 oxazine-2,4-dione (1.68 g, 36%): 1H NMR (DMSO-d6, 300 MHz) δ 7.87 (d, J=8.4 Hz, 1 H), 7.53 (dd, J1=10.5 Hz, J2=1.1 Hz, 1 H), 7.33–7.34 (m, 2 H), 7.03–6.99 (m, 2 H), 5.02 (s, 2 H), 3.87 (s, 3 H).
Reaction SMILES: [OH-:1].[Na+].O.BrBr.[Br:6][C:7]1[S:11][C:10]([C:12](=[O:14])C)=[CH:9][C:8]=1[Cl:15]>O1CCOCC1>[Br:6][C:7]1[S:11][C:10]([C:12]([OH:14])=[O:1])=[CH:9][C:8]=1[Cl:15]
Reactant: [OH-]
Reactant: CC(=O)c1cc(Cl)c(Br)s1
Agent: BrBr
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)c1cc(Cl)c(Br)s1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
Sodium hydroxide (50% in water) (5.82 ml, 110 mmol) was added to water (15 ml), and the mixture was chilled to 0° C. Bromine solution (1.669 ml, 32.6 mmol) was added, followed by dropwise addition of a solution of 1-(5-bromo-4-chlorothiophen-2-yl)ethanone (2.4 g, 10.02 mmol) in dioxane (18 ml). The mixture was stirred for 1.5 hours at room temperature, washed with dichloromethane, and then the aqueous phase was adjusted to pH 1 using 4N aqueous HCl. The precipitated solid was collected by filtration to give the title compound.
Reaction SMILES: C([Li])(C)(C)C.C(OC([N:13]1[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([F:22])[CH:20]=2)[CH2:15][CH2:14]1)=O)(C)(C)C.[O:23]1CCC[CH2:24]1>>[F:22][C:19]1[C:20]([CH:24]=[O:23])=[C:21]2[C:16]([CH2:15][CH2:14][NH:13]2)=[CH:17][CH:18]=1
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(F)cc21
Reactant: C1CCOC1
Agent: [Li]C(C)(C)C
Product: O=Cc1c(F)ccc2c1NCC2
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 42 %

Procedure:
Add tert-butyllithium (21.13 ml, 35.93 mmol, 1.7 M solution in heptane) to a solution of 1-(tert-butoxycarbonyl)-2,3-dihydro-6-fluoroindole (3.28 g, 13.82 mmol) in anhydrous tetrahydrofuran (100 ml) at −78 C. Stir for 20 minutes, quench with excess dimethylformamide, and stir for 1 hour at −78 C. Warm to room temperature, add saturated aqueous ammonium chloride, and extract with ethyl acetate. Concentrate the combined organic phases under reduced pressure and subject the residue to silica gel chromatography to provide the desired compound as a bright yellow solid (0.91 g, 42%).
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([S:12]([N:15]2[CH2:20][CH2:19][N:18]([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=3[C:28]([F:31])([F:30])[F:29])[CH2:17][C@H:16]2[CH3:32])(=[O:14])=[O:13])=[CH:4][CH:3]=1.[C:33]([O:37][C:38]([N:40]1[CH2:45][CH2:44][N:43](C)[CH2:42][CH2:41]1)=[O:39])([CH3:36])([CH3:35])[CH3:34].CC(C)([O-])C.[Na+].C1(C)C=CC=CC=1>ClCCl.C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[F:27][C:24]1[CH:25]=[CH:26][C:21]([N:18]2[CH2:19][CH2:20][N:15]([S:12]([C:5]3[C:6]4[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=4)[C:2]([N:43]4[CH2:42][CH2:41][N:40]([C:38]([O:37][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:39])[CH2:45][CH2:44]4)=[CH:3][CH:4]=3)(=[O:14])=[O:13])[C@H:16]([CH3:32])[CH2:17]2)=[C:22]([C:28]([F:31])([F:30])[F:29])[CH:23]=1
Reactant: C[C@@H]1CN(c2ccc(F)cc2C(F)(F)F)CCN1S(=O)(=O)c1ccc(Br)c2ccccc12
Reactant: CN1CCN(C(=O)OC(C)(C)C)CC1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: C[C@@H]1CN(c2ccc(F)cc2C(F)(F)F)CCN1S(=O)(=O)c1ccc(N2CCN(C(=O)OC(C)(C)C)CC2)c2ccccc12
Yield: 66.9 %

Procedure:
A mixture of (2R)-1-[(4-bromo-1-naphthyl)sulfonyl]-4-[4-fluoro-2-(trifluoromethyl)phenyl]-2-methylpiperazine (250 mg, 0.47 mmol), 4-methyl-piperazine-1-carboxylic acid tert-butyl ester (175.1 mg, 0.94 mmol), tris(dibenzylidineacetone)dipalladium (0) (4.3 mg, 0.0047 mmol), rac-2,2′-bis(diphenylphosphino)-1,1′-binaphtyl (8.78 mg, 0.014 mmol) and sodium tert-butoxide (56.5 mg, 0.59 mmol) were charged to a microwave vial. Toluene (3.0 mL) was introduced under nitrogen atmosphere and the reaction mixture was irradiated at 110° C. for 35 minutes. Reaction was complete as determined by TLC. Reaction mixtures was diluted with dichloromethane, washed with water, saturated brine then dried over Na2SO4 and concentrated. The crude product was purified via flash column chromatography to yield tert-butyl 4-[4-({(2R)-4-[4-fluoro-2-(trifluoromethyl)phenyl]-2-methylpiperazin-1-yl}sulfonyl)-1-naphthyl]piperazine-1-carboxylate as yellow gum (200.1 mg, 66.9% yield).
Reaction SMILES: Cl.[C:2]1([S:8]([C:11]2[CH:23]=[CH:22][C:14]3[O:15][C@@H:16]([CH2:19][NH:20][CH3:21])[CH2:17][O:18][C:13]=3[CH:12]=2)(=[O:10])=[O:9])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CO>[C:2]1([S:8]([C:11]2[CH:23]=[CH:22][C:14]3[O:15][C@H:16]([CH2:19][NH:20][CH3:21])[CH2:17][O:18][C:13]=3[CH:12]=2)(=[O:10])=[O:9])[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CNC[C@H]1COc2cc(S(=O)(=O)c3ccccc3)ccc2O1
Agent: Cl
Solvent: CO
Product: CNC[C@@H]1COc2cc(S(=O)(=O)c3ccccc3)ccc2O1

Procedure:
Following the same procedure, (6-benzenesulfonyl-2,3-dihydro-benzo[1,4]dioxin-2-(S)-yl-methyl)-methyl amine hydrochloride salt was also prepared: MS; (M+H)+ 320, m. p. 209.0-212.0° C., [α]=−44° (methanol; c=0.5).
Reaction SMILES: C(OC([NH:8][C@H:9]([C:16]([NH:18][C@@H:19]([CH2:32][CH:33]1[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1)[C@@H:20]([OH:31])[CH2:21][C@@H:22]([C:27]([OH:30])([CH3:29])[CH3:28])[C:23]([NH:25][CH3:26])=[O:24])=[O:17])[CH2:10][C:11]1[N:12]=[CH:13][S:14][CH:15]=1)=O)(C)(C)C.Cl.[CH2:40]([C@H:47]([CH2:51][C:52](=[O:54])[CH3:53])[C:48]([OH:50])=O)[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1.P(C#N)(OCC)(OCC)=O.C(N(CC)CC)C>O1CCOCC1>[CH2:40]([C@H:47]([CH2:51][C:52](=[O:54])[CH3:53])[C:48]([NH:8][C@H:9]([C:16]([NH:18][CH:19]([CH2:32][CH:33]1[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38]1)[CH:20]([OH:31])[CH2:21][CH:22]([C:27]([OH:30])([CH3:28])[CH3:29])[C:23]([NH:25][CH3:26])=[O:24])=[O:17])[CH2:10][C:11]1[N:12]=[CH:13][S:14][CH:15]=1)=[O:50])[C:41]1[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=1
Reactant: CC(=O)C[C@@H](Cc1ccccc1)C(=O)O
Reactant: CNC(=O)[C@@H](C[C@H](O)[C@H](CC1CCCCC1)NC(=O)[C@H](Cc1cscn1)NC(=O)OC(C)(C)C)C(C)(C)O
Agent: CCOP(=O)(C#N)OCC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CNC(=O)C(CC(O)C(CC1CCCCC1)NC(=O)[C@H](Cc1cscn1)NC(=O)[C@@H](CC(C)=O)Cc1ccccc1)C(C)(C)O
Reaction time: 3 h
Yield: 72.9 %

Procedure:
A mixture or 192 mg (0.35 mmoles) of (2S, 4S, 5S)-5-[N-(t-butoxycarbonyl)-3-(4-thiazolyl)-L-alanyl]amino-6-cyclohexyl-4-hydroxy-2-(1-hydroxy-1-methylethyl)-N-methylhexanamide [prepared as described in Example 9(a)] in 2 ml of a 4N solution of hydrogen chloride in dioxane was stirred at room temperature under an atmosphere of nitrogen for 30 minutes. At the end of this time, the reaction mixture was concentrated by evaporation under reduced pressure. Diethyl ether was added to the residue, and the solvent was again removed by distillation under reduced pressure. The same operation was repeated, in total, three times. The resulting residue was dried by evaporation under reduced pressure for 8 hours, and was then suspended in 5 ml of anhydrous tetrahydrofuran. 86 mg (0.42 mmoles) of 2(R)-benzyl-4-oxopentanoic acid (prepared as described in Preparation 20) were then added to the suspension, after which 0.06 ml (0.40 mmoles) of diethyl cyanophosphate and 0.16 ml (1.15 mmoles) of triethylamine were added to the mixture, whilst ice-cooling and under an atmosphere of nitrogen. The mixture was then stirred for 3 hours, after which the solvent was removed by distillation under reduced pressure, and the resulting residue was purified by silica gel thin layer chromatography (using an 8:1 by volume mixture of methylene chloride and methanol as the developing solvent), to give 164 mg (yield 74%) of the title compound as an amorphous substance.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:30])[CH2:5][CH2:6][CH2:7][C:8](=[O:29])[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]Br)=[C:11]([CH2:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH:10]=1)[CH3:2].[OH:31][C:32]1[CH:42]=[CH:41][C:35]2[C:36](=[O:40])[CH2:37][CH2:38][O:39][C:34]=2[C:33]=1[CH2:43][CH2:44][CH3:45].C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[CH2:1]([O:3][C:4](=[O:30])[CH2:5][CH2:6][CH2:7][C:8](=[O:29])[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:31][C:32]2[CH:42]=[CH:41][C:35]3[C:36](=[O:40])[CH2:37][CH2:38][O:39][C:34]=3[C:33]=2[CH2:43][CH2:44][CH3:45])=[C:11]([CH2:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH:10]=1)[CH3:2]
Reactant: CCOC(=O)CCCC(=O)c1ccc(CCCCCCBr)c(CCC(=O)OCC)c1
Reactant: CCCc1c(O)ccc2c1OCCC2=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCCc1c(OCCCCCCc2ccc(C(=O)CCCC(=O)OCC)cc2CCC(=O)OCC)ccc2c1OCCC2=O
Temperature: 89 °C
Yield: 91.5 %

Procedure:
A mixture of 0.43 g (0.89 mmol) of 4-(6-bromohexyl)-3-(3-ethoxy-3-oxopropyl)-δ-oxobenzenepentanoic acid ethyl ester from the preceding example, 0.188 g (0.91 mmol) of 2,3-dihydro-7-hydroxy-8-propyl-4H-1-benzopyran-4-one and 0.398 g (2.88 mmol) of anhydrous granular potassium carbonate in 10 mL of 2-butanone was stirred and heated at 89° C. for 19.3 hr. The mixture was filtered with suction and the solid was washed with ether and ethyl acetate. The filtrate was concentrated in vacuo and the crude product was flash chromatographed on 80 g of silica gel, eluting with hexane-ethyl acetate (5:2). There was obtained 0.496 g (91.5%) of the title compound as a colorless oil.
Reaction SMILES: [CH:1]1[C:10]2[C:9]3([C:15]([O:17]CC)=[O:16])[CH2:11][CH:12]=[CH:13][CH2:14][CH:8]3[CH2:7][S:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.C[Si](C)(C)[O-].[K+]>O1CCCC1.CCCCCCC>[CH:1]1[C:10]2[C:9]3([C:15]([OH:17])=[O:16])[CH2:11][CH:12]=[CH:13][CH2:14][CH:8]3[CH2:7][S:6][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)C12CC=CCC1CSc1ccccc12
Agent: C[Si](C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCCCCCC
Product: O=C(O)C12CC=CCC1CSc1ccccc12
Yield: 68.1 %

Procedure:
To a solution of the product from Example 18 (7.36 g) in tetrahydrofuran (200 ml) was added potassium trimethylsilanolate (5.30 g). The solution was refluxed for 7 hours then diluted with heptane and filtered. The precipitated solid was dissolved in water/ethyl acetate and acidified with dilute hydrochloric acid. The organic phase was washed with water then extracted with dilute sodium hydroxide (x2). The aqueous layer was washed with ethyl acetate then layered with fresh ethyl acetate and acidified. The solution was washed with water and dried (Na2SO4) and evaporated to a oil which was triturated with ethyl acetate/heptane to give the title compound as a cream colored solid (4.5 g), mp 152°-155° C. and a darker colored second crop (1.7 g) combined yield 94%.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][AlH2-:6][O:7][CH2:8][CH2:9][O:10][CH3:11].[Na+:12].[CH3:13][O:14][C:15]1[CH:16]=[C:17]([CH2:23][CH2:24][O:25]/[C:26](=N/[H])/[C:27](Cl)(Cl)[Cl:28])[CH:18]=[CH:19][C:20]=1[O:21][CH3:22].[CH:33]([NH2:36])([CH3:35])C.[C:37]1(C)[CH:42]=CC=[CH:39][CH:38]=1>>[CH3:11][O:10][CH2:9][CH2:8][O:7][AlH2-:6][O:5][CH2:4][CH2:3][O:2][CH3:1].[Na+:12].[ClH:28].[CH3:13][O:14][C:15]1[CH:16]=[C:17]([CH2:23][CH2:24][O:25][C@@H:26]2[CH2:27][CH2:39][CH2:38][CH2:37][C@H:42]2[N:36]2[CH2:33][CH2:35][C@@H:9]([OH:10])[CH2:8]2)[CH:18]=[CH:19][C:20]=1[O:21][CH3:22]
Reactant: [H]/N=C(/OCCc1ccc(OC)c(OC)c1)C(Cl)(Cl)Cl
Reactant: Cc1ccccc1
Reactant: CC(C)N
Agent: COCCO[AlH2-]OCCOC
Agent: [Na+]
Product: COc1ccc(CCO[C@@H]2CCCC[C@H]2N2CC[C@@H](O)C2)cc1OC
Product: Cl

Procedure:
To a refluxing solution of Red-Al (65 wt % in toluene, 1.86 g, 1.80 mL, 6 mmol, Aldrich cat #19, 619-3) in toluene (2 mL) was added dropwise (over 5 min) a solution of crude (36) in toluene (3 mL). After the resultant solution was refluxed for 1 h, TLC analysis (EtOAc-hexanes, 2:1 v/v, +0.5% v/v iPrNH2) revealed the absence of (36) and the appearance of a new polar spot (reduction of (36) with Red-Al at room temperature provided a very complex mixture (HPLC) from which (19) could not be isolated). The cooled (0° C.) reaction mixture was cautiously quenched by addition of 6M aq NaOH (3 mL). After separation of the layers, the organic layer was dried over anhydrous MgSO4 and concentrated in vacuo to give (19) free base as an oil (195 mg, 37% yield). Alternatively, the reduction of (36) was performed using LiAlH4.THF2 1.0M in toluene (3 mL, 3 mmol, Aldrich cat #243949) at room temperature. After carefully quenching the reaction by successive addition of water (100 μl), 6M aq NaOH (100 μL) and water (300 μL), the free base of (19) (423 mg, 80% yield) was obtained.