Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH2:5][CH:6]([C:15]([OH:17])=O)[CH2:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH3:2].CCN(C(C)C)C(C)C.[C:28]1([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH:33]=[CH:32][C:31]([CH2:34][CH2:35][NH2:36])=[CH:30][CH:29]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.Cl>CN(C=O)C>[CH2:1]([O:3][C:4](=[O:18])[CH2:5][CH:6]([C:15](=[O:17])[NH:36][CH2:35][CH2:34][C:31]1[CH:32]=[CH:33][C:28]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)=[CH:29][CH:30]=1)[CH2:7][C:8]([O:10][C:11]([CH3:12])([CH3:13])[CH3:14])=[O:9])[CH3:2]
Reactant: NCCc1ccc(-c2ccccc2)cc1
Reactant: CCOC(=O)CC(CC(=O)OC(C)(C)C)C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)CC(CC(=O)OC(C)(C)C)C(=O)NCCc1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of the compound of example 70 (1.55 g, 5.96 mmol) in anhydrous DMF (5 mL) was treated successively with DIEA (5.2 mL), 4-biphenylethyl amine (2.40 g, 11.92 mmol) and TBTU (2.76 g, 8.34 mmol). The reaction mixture was stirred for 24 h at room temperature. The reaction mixture was treated with HCl (1M, excess) and the mixture was extracted several times with ethyl acetate. The recombined organic layer was washed with brine, dried over sodium sulfate, filtered and evaporated. The residue was flashed with 30% ethyl acetate in hexanes and the desired product was obtained as a white solid. 1H-NMR(CDCl3, 400 MHz: 1.22(t, J=7.2, 3H); 1.42(s, 9H); 2.32-2.42(m, 2H); 2.60-2.75(m, 2H); 2.83(t, J=7.1 Hz, 2H); 3.02(m, 1H); 3.53(m, 2H); 4.11(m, 2H); 6.25(m, t, 5.1 Hz, 1H); 7.30(m, 3H); 7.43(m, 2H); 7.57(m, 4H).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][O:11][CH:10]([CH2:14][N:15]2[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=3[N:17]([C:24]([CH3:26])=[CH2:25])[C:16]2=[O:27])[CH2:9]1)C1C=CC=CC=1.Cl.CN1C2C=CC=CC=2N(CC2OCCNC2)C1=O>>[CH:24]([N:17]1[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[N:15]([CH2:14][CH:10]2[O:11][CH2:12][CH2:13][NH:8][CH2:9]2)[C:16]1=[O:27])([CH3:26])[CH3:25]
Reactant: C=C(C)n1c(=O)n(CC2CN(Cc3ccccc3)CCO2)c2ccccc21
Agent: Cl
Agent: Cn1c(=O)n(CC2CNCCO2)c2ccccc21
Product: CC(C)n1c(=O)n(CC2CNCCO2)c2ccccc21
Yield: 71.1 %

Procedure:
26 g of 4-benzyl-2-(1-isopropenyl-2,3-dihydro-benzimidazol-2-on-3-yl-methyl)-morpholine are treated as in part (a) of Example 2. After evaporation of the solvent under reduced pressure, a limpid oil is obtained, which crystallizes slowly. Recrystallization from isopropyl ether gives 14 g of 2-(1-isopropyl-2,3-dihydro-benzimidazol-2-on-3-yl-methyl)-morpholine, m.p. 95° C.
Reaction SMILES: [OH-].[K+].Cl[C:4]1[C:9]([C:10]#[N:11])=[CH:8][C:7]([C:12]2[CH:17]=[CH:16][N+:15]([O-:18])=[CH:14][CH:13]=2)=[CH:6][N:5]=1.O.[OH:20][CH2:21][CH:22]([CH2:24][OH:25])[OH:23]>>[C:10]([C:9]1[C:4]([O:20][CH2:21][CH:22]([OH:23])[CH2:24][OH:25])=[N:5][CH:6]=[C:7]([C:12]2[CH:17]=[CH:16][N+:15]([O-:18])=[CH:14][CH:13]=2)[CH:8]=1)#[N:11]
Reactant: N#Cc1cc(-c2cc[n+]([O-])cc2)cnc1Cl
Reactant: OCC(O)CO
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: N#Cc1cc(-c2cc[n+]([O-])cc2)cnc1OCC(O)CO

Procedure:
300 mg Potassium hydroxide is dissolved in 15 ml glycerin with heating and 1 g 2-chloro-3-cyano-5,4'-bipyridine-1'-oxide is subsequently added. The reaction mixture is heated for 3 hours at 80° C.-90° C. with stirring, allowed to cool and treated with water. The precipitate obtained is filtered off with suction. Yield: 2 g (89.5% of the theoretical yield), having a melting point of 194° C.-196° C.
Reaction SMILES: [CH2:1]([CH:5]1[C:9](=[O:10])[C:8]2[CH:11]=[C:12]([N+:15]([O-:17])=[O:16])[CH:13]=[CH:14][C:7]=2[O:6]1)[CH2:2][CH2:3][CH3:4].[BH4-].[Na+]>C(O)C.O>[CH2:1]([CH:5]1[CH:9]([OH:10])[C:8]2[CH:11]=[C:12]([N+:15]([O-:17])=[O:16])[CH:13]=[CH:14][C:7]=2[O:6]1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCC1Oc2ccc([N+](=O)[O-])cc2C1=O
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCCCC1Oc2ccc([N+](=O)[O-])cc2C1O
Temperature: 0 °C

Procedure:
700 mg of 2-(n-butyl)-5-nitro-3(2H)-benzofuranone were introduced into 10 ml of ethanol in a 50 ml flask and cooled to 0° C. A solution of 130 mg of NaBH4 in 5 ml of ethanol was added dropwise thereto, an intense red coloration immediately appearing. The mixture was allowed to reach room temperature and was then briefly heated to reflux. After cooling to room temperature, the reaction mixture was taken up in water and dichloromethane, the organic phase was separated off, and the aqueous phase was extracted once more with dichloromethane. Drying of the combined organic phases over sodium sulphate, removal of the solvent in vacuo and column chromatography (eluent: hexane:ethyl acetate=5:1) resulted in 400 mg (57% of theory) of 2-(n-butyl)-5-nitro-2,3-dihydrobenzofuran-3-ol.
Reaction SMILES: [CH3:1][C:2]([CH3:12])=[CH:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][CH:5]=1.CC(C)([O-])C.[K+].[CH:19]([Cl:22])(Cl)[Cl:20]>CCCCC>[Cl:20][C:19]1([Cl:22])[C:2]([CH3:12])([CH3:1])[CH:3]1[C:4]1[CH:5]=[CH:6][C:7]([O:10][CH3:11])=[CH:8][CH:9]=1
Reactant: ClC(Cl)Cl
Reactant: COc1ccc(C=C(C)C)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCCCC
Product: COc1ccc(C2C(C)(C)C2(Cl)Cl)cc1

Procedure:
p-(2,2-Dichloro-3,3-dimethylcyclopropyl)anisole was prepared from 58.3 g. of p-(2,2-dimethylvinyl)anisole, 102 g. of potassium t-butoxide, 180 ml. of chloroform and 1800 ml. of pentane according to the procedure described above in Example 1, part (b). The product was recrystallized from hexane to produce p-(2,2-dichloro-3,3-dimethylcyclopropyl)anisole in the form of colorless needles, m.p. 54.5°-57°C.
Reaction SMILES: [CH:1]1([C:4](O)=O)[CH2:3][CH2:2]1.Cl.Cl.[C:9]1([NH2:16])[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[NH2:15].[OH-].[Na+]>O>[CH:1]1([C:4]2[NH:15][C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[N:16]=2)[CH2:3][CH2:2]1
Reactant: O=C(O)C1CC1
Reactant: Nc1ccccc1N
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: c1ccc2[nH]c(C3CC3)nc2c1
Temperature: 160 °C
Yield: 13 %

Procedure:
Cyclopropanecarboxylic acid (4 g, 52 mmol) was treated with phenylenediamine bis-hydrochloride (1 eq) and polyphosphosphoric acid (52 mL) and heated to 160° C. for 6 h. The reaction was cooled to 0° C. and diluted with water, then basified with NaOH (50% aqueous) until pH>10. The solution was extracted with ethyl acetate, dried (MgSO4), filtered and concentrated, purified by flash chromatography (100% ethyl acetate) giving 2-cyclopropylbenzimidazole (1.1 g, 13%). MS found: (M+H)+=159.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH:5]([O:15][CH2:16][CH3:17])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][C:8]=1[CH3:14])[CH3:2].Cl[CH2:20][C:21]1[N:22]=[C:23]([C:27]2[CH:32]=[C:31]([CH3:33])[CH:30]=[C:29]([CH3:34])[CH:28]=2)[O:24][C:25]=1[CH3:26].CC1C=C(C=C(C)C=1)C=O.O=P(Cl)(Cl)Cl.C(=O)([O-])[O-].[Cs+].[Cs+].[I-].[K+]>>[CH2:1]([O:3][C:4](=[O:18])[CH:5]([O:15][CH2:16][CH3:17])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:20][C:21]2[N:22]=[C:23]([C:27]3[CH:28]=[C:29]([CH3:34])[CH:30]=[C:31]([CH3:33])[CH:32]=3)[O:24][C:25]=2[CH3:26])=[CH:9][C:8]=1[CH3:14])[CH3:2]
Reactant: CCOC(=O)C(Cc1ccc(O)cc1C)OCC
Reactant: Cc1cc(C)cc(-c2nc(CCl)c(C)o2)c1
Agent: Cc1cc(C)cc(C=O)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O=P(Cl)(Cl)Cl
Product: CCOC(=O)C(Cc1ccc(OCc2nc(-c3cc(C)cc(C)c3)oc2C)cc1C)OCC

Procedure:
In analogy to the procedure described in example 1 f], [rac]-2-ethoxy-3-(4-hydroxy-2-methyl-phenyl)-propionic acid ethyl ester (example 34 b]) was reacted with 4-chloromethyl-2-(3,5-dimethyl-phenyl)-5-methyl-oxazole (prepared from 3,5-dimethyl-benzaldehyde and diacetyl monoxyme followed by treatment with POCl3 in analogy to the procedures described in examples 2 a] and b]) in the presence of cesium carbonate and potassium iodide to yield [rac]-3-{4-[2-(3,5-dimethyl-phenyl)-5-methyl-oxazol-4-ylmethoxy]-2-methyl-phenyl}-2-ethoxy-propionic acid ethyl ester as colorless liquid.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([OH:8])=O.CN(C=O)C.C(Cl)(=O)C(Cl)=O.[C:20]([NH2:24])([CH3:23])([CH3:22])[CH3:21]>C(Cl)Cl.C1COCC1>[C:20]([NH:24][C:6]([C:2]1[O:1][CH:5]=[CH:4][CH:3]=1)=[O:8])([CH3:23])([CH3:22])[CH3:21]
Reactant: O=C(O)c1ccco1
Reactant: CC(C)(C)N
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(C)(C)NC(=O)c1ccco1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a slurry of furan-2-carboxylic acid (10.0 g, 89 mmol) in 100 mL DCM at 0° C. under nitrogen was added DMF (0.069 ml, 0.89 mmol) and oxalyl chloride (9.9 ml, 112 mmol) slowly in small portions over 5 min. The reaction was allowed to warm to ambient temperature. After 3 h, the clear solution was concentrated in vacuo and the resulting oil was dissolved in 75 mL THF and cooled to 0° C. A solution of tert-butylamine (28 ml, 268 mmol) in 25 mL THF was added dropwise over 1 h. The bath was allowed to expire and the slurry was stirred over the weekend. The reaction was concentrated in vacuo and partitioned between 1N NaOH and DCM. The aqueous layer was extracted twice with DCM. The combined organic layers were concentrated in vacuo to give N-tert-butylfuran-2-carboxamide as a white solid. MS m/z=168 [M+H]+. Calc'd for C9H13NO2: 167.2.
Reaction SMILES: [CH3:1][C:2]([CH3:32])([CH3:31])[C:3](=[O:30])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([C:17]2[CH:18]=[CH:19][C:20]3[CH:24]=[C:23]([C:25](O)=[O:26])[S:22][C:21]=3[CH:28]=2)([CH2:15][CH3:16])[CH2:13][CH3:14])=[CH:8][C:7]=1[CH3:29].C(Cl)CCl.Cl.[CH3:38][NH:39][CH3:40]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:38][N:39]([CH3:40])[C:25]([C:23]1[S:22][C:21]2[CH:28]=[C:17]([C:12]([C:9]3[CH:10]=[CH:11][C:6]([O:5][CH2:4][C:3](=[O:30])[C:2]([CH3:32])([CH3:31])[CH3:1])=[C:7]([CH3:29])[CH:8]=3)([CH2:15][CH3:16])[CH2:13][CH3:14])[CH:18]=[CH:19][C:20]=2[CH:24]=1)=[O:26]
Reactant: CNC
Reactant: CCC(CC)(c1ccc(OCC(=O)C(C)(C)C)c(C)c1)c1ccc2cc(C(=O)O)sc2c1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCCl
Solvent: ClCCl
Product: CCC(CC)(c1ccc(OCC(=O)C(C)(C)C)c(C)c1)c1ccc2cc(C(=O)N(C)C)sc2c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 90.9 %

Procedure:
6-{1-[4-(3,3-Dimethyl-2-oxo-butoxy)-3-methyl-phenyl]-1-ethyl-propyl}-benzo[b]thiophene-2-carboxylic acid (290 mg, 0.642 mmol) in CH2Cl2 (5.0 mL) is treated with DMAP (235 mg, 1.93 mmol) and EDC (184 mg, 0.962 mmol). The mixture is stirred for 15 min at RT, and dimethylamine hydrochloride (78 mg, 0.962 mmol) is added. The reaction is stirred for 18 h and quenched with aqueous NH4Cl (5.0 mL). The organic layer is loaded onto a silica gel column and purified with 50% EtOAc/Hex to afford the title compound (280 mg, 91%).
Reaction SMILES: [CH:1]([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:35][O:36][CH2:37][C:38](O)=[O:39])[C:10]([NH:12][CH:13]2[C:33](=[O:34])[N:15]3[C:16]([C:20]([O:22][CH2:23][C:24]4[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][CH:25]=4)=[O:21])=[CH:17][CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1)=[O:2].C[N+:42](C)=CCl.[Cl-].P(Cl)(Cl)(Cl)=O.N.Cl>O1CCCC1.O.CN(C)C=O>[CH:1]([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:35][O:36][CH2:37][C:38](=[O:39])[NH2:42])[C:10]([NH:12][CH:13]2[C:33](=[O:34])[N:15]3[C:16]([C:20]([O:22][CH2:23][C:24]4[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][CH:25]=4)=[O:21])=[CH:17][CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1)=[O:2]
Reactant: O=CNc1nc(C(=NOCC(=O)O)C(=O)NC2C(=O)N3C(C(=O)OCc4ccc([N+](=O)[O-])cc4)=CCS[C@H]23)cs1
Reactant: C[N+](C)=CCl
Agent: Cl
Agent: N
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: O
Product: NC(=O)CON=C(C(=O)NC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=CCS[C@H]12)c1csc(NC=O)n1
Reaction time: 0.5 h

Procedure:
Tetrahydrofuran (24 ml.) and 4-nitrobenzyl 7-[2-(2-formamidothiazol-4-yl)-2-carboxymethoxyiminoacetamido]-3-cephem-4-carboxylate (syn isomer, 3.07 g.) were added to Vilsmeier reagent prepared from N,N-dimethylformamide (0.0756 g.) and phosphoryl chloride (1.59 g.) in tetrahydrofuran (6 ml.) at -10° t -5° C. and then stirred at the same temperature for 30 minutes. The solution was added dropwise to a mixture of tetrahydrofuran (50 ml.) and water (25 ml.) at -5° to 0° C. while keeping at pH 9 to 9.5 with aqueous ammonia, and stirred for 20 minutes at pH 7.5 After adjusting the resultant solution to pH 2.0 with 10% hydrochloric acid, tetrahydrofuran was removed in vacuo. Water was added to the residue and extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride twice, an aqueous solution of sodium bicarbonate five times and a saturated aqueous solution of sodium chloride twice in turn, dried over magnesium sulfate and then concentrated in vacuo. The residue was pulverized with diethyl ether, collected by filtration and dried to give 4-nitrobenzyl 7-[2-(2-formamidothiazol-4-yl)-2-carbamoylmethoxyiminoacetamido]-3-cephem-4-carboxylate (syn isomer, 1.8 g.).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([OH:8])=O.[F:9][C:10]([F:37])([F:36])[C:11]([CH2:31][NH:32][CH2:33][CH2:34][CH3:35])([OH:30])[CH2:12][NH:13][C:14]1[CH:22]=[CH:21][CH:20]=[C:19]2[C:15]=1[CH:16]=[N:17][N:18]2[C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=1>>[CH2:33]([N:32]([CH2:31][C:11]([CH2:12][NH:13][C:14]1[CH:22]=[CH:21][CH:20]=[C:19]2[C:15]=1[CH:16]=[N:17][N:18]2[C:23]1[CH:24]=[CH:25][C:26]([F:29])=[CH:27][CH:28]=1)([OH:30])[C:10]([F:9])([F:36])[F:37])[C:6]([C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)=[O:8])[CH2:34][CH3:35]
Reactant: CCCNCC(O)(CNc1cccc2c1cnn2-c1ccc(F)cc1)C(F)(F)F
Reactant: O=C(O)c1cccs1
Product: CCCN(CC(O)(CNc1cccc2c1cnn2-c1ccc(F)cc1)C(F)(F)F)C(=O)c1cccs1

Procedure:
Prepared similarly to Example 1 from 2-thiophenecarboxylic acid and 1,1,1-trifluoro-3-{[1-(4-fluorophenyl)-1H-indazol-4-yl]amino}-2-[(propylamino)methyl]-2-propanol.
Reaction SMILES: [CH3:1][C:2](=[CH:4][CH:5]=[C:6]([CH3:8])[CH3:7])[CH3:3].[C:9]([O:15][CH2:16][CH3:17])(=[O:14])[CH2:10][C:11]([CH3:13])=[O:12]>>[C:9]([C:10]1[C:2]([CH3:3])([CH3:1])[CH:4]([CH2:5][CH:6]([CH3:8])[CH3:7])[O:12][C:11]=1[CH3:13])([O:15][CH2:16][CH3:17])=[O:14]
Reactant: CC(C)=CC=C(C)C
Reactant: CCOC(=O)CC(C)=O
Product: CCOC(=O)C1=C(C)OC(CC(C)C)C1(C)C

Procedure:
2,5-Dimethyl-2,4-hexadiene and ethyl acetoacetate were reacted utilizing the oxidative addition procedure to obtain 4-carbethoxy-2-(2-methyl-1-propenyl)-3,3,5-trimethyl-2,3-dihydrofuran. Manganese (III) acetate obtained by the reaction potassium permanganate (19.75 grams) and manganese (II) acetate (122.5 grams) in 250 mls acetic acid was employed for the oxidation. The 2,5-dimethyl-2,4-hexadiene (27.5 gram) and ethyl acetoacetate (32.5 grams) were reacted in the presence of 0.5 grams cupric acetate catalyst. 4Carbethoxy-2-(2-methyl-1-propenyl)-3,3,5-trimethyl-2,3-dihydrofuran was recovered (61% yield) and hydrogenated in ethanol using a supported palladium catalyst (5% Pd on carbon) to obtain 4-carbethoxy-2-(2-methylpropyl)-3,3,5-trimethyl-2,3-dihydrofuran. Essentially pure (97+%) 4-carbethoxy-2-(2-methylpropyl)-3,3,5-trimethyl-2,3-dihydrofuran (B.P. 136° C. @9.2 mm Hg; nD23° 1.4642) was obtained upon distillation of the crude product. The product had a green vegetable odor. The structure of the product ##STR23## was confirmed by infrared and nuclear magnetic resonance.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[CH:15][O:16]C)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])=[CH:4][N:3]=1.Cl>O1CCCC1>[Cl:1][C:2]1[N:3]=[CH:4][C:5]([CH:8]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[CH:15]=[O:16])=[CH:6][CH:7]=1
Reactant: CCCCCCC(=COC)c1ccc(Cl)nc1
Agent: Cl
Solvent: C1CCOC1
Product: CCCCCCC(C=O)c1ccc(Cl)nc1
Temperature: 50 °C

Procedure:
2-Chloro-5-(1-methoxymethylene-heptyl)-pyridine is dissolved into anhydrous tetrahydrofuran (20 mL) and concentrated hydrochloric acid (2 mL) are added with stirring under nitrogen. The reaction is heated to 50° C. and monitored by HPLC. Upon complete consumption of starting material, the reaction is carefully neutralized with sodium hydroxide, extracted with diethyl ether, washed, dried, and concentrated. The 2-(6-Chloro-pyridin-3-yl)-octanal (1.02 g, 4.26 mmol), 32% two steps, is obtained in purified form after flash column chromatography.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([O:8]C(=O)C)=[CH:4][CH:3]=1.[F:12][C:13](I)([F:36])[C:14]([F:35])([F:34])[C:15]([F:33])([F:32])[C:16]([F:31])([F:30])[C:17]([F:29])([F:28])[C:18]([F:27])([F:26])[C:19]([F:25])([F:24])[C:20]([F:23])([F:22])[F:21].O.CCOCC>CS(C)=O.[Cu].II>[F:24][C:19]([F:25])([C:20]([F:21])([F:22])[F:23])[C:18]([F:26])([F:27])[C:17]([F:28])([F:29])[C:16]([F:30])([F:31])[C:15]([F:33])([F:32])[C:14]([F:35])([F:34])[C:13]([F:12])([F:36])[C:2]1[CH:3]=[CH:4][C:5]([OH:8])=[CH:6][CH:7]=1
Reactant: FC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)I
Reactant: CC(=O)Oc1ccc(I)cc1
Agent: [Cu]
Agent: II
Solvent: CS(C)=O
Solvent: CCOCC
Solvent: O
Product: Oc1ccc(C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)cc1
Temperature: 105 °C
Yield: 66.7 %

Procedure:
To a solution of acetic acid 4-iodo-phenyl ester (9 gm, 0.0366 mol) in anhydrous DMSO (75 mL) was added copper powder (5.8 g, 0.091 mol), perfluorooctyl iodide (25 g, 0.046 mol) and iodine (130 mg). The reaction mixture was heated to 105° C. for 18 hr, cooled, combined with 100 ml water and 50 ml ether and filtered to remove insoluble copper salts. The organic and aqueous layers in the filtrate were separated, and the aqueous layer extracted twice with ether (2×100 mL). The combined organics were washed with water and brine, dried over MgSO4, and concentrated. To a solution of the crude product in 50 mL methanol was added 1.5 mL 10N HCl. The mixture was refluxed on a steam bath for 1 hr to hydrolyze the acetate completely to the phenol. After cooling to room temperature, the reaction mixture was poured into a separatory funnel containing 100 mL water, and extracted with ether (3×75 mL). The combined organics were washed with water and brine and dried over MgSO4. Recrystallization of the crude concentrate gave 12.5 g of the phenol at 99% purity by HPLC as a waxy solid mp 63-68° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:11][S:12]([C:15]2[CH:20]=[C:19]([CH3:21])[C:18]([CH3:22])=[C:17]([CH3:23])[CH:16]=2)(=[O:14])=[O:13])=[O:10])=[CH:4][CH:3]=1.FC(F)(F)C1C=CC(NC(NS(C2C=C(C)C(C)=C(C)C=2)(=O)=O)=O)=CC=1.[Cl:50]C1C=C(NC(NS(C2C=C(C)C(C)=C(C)C=2)(=O)=O)=O)C=CC=1Cl.ClC1C=CC(NC(NS(C2C=C(Cl)C(Cl)=C(Cl)C=2)(=O)=O)=O)=CC=1.ClC1C=CC(NC(NS(C2C=C(Cl)C(N)=C(Cl)C=2)(=O)=O)=O)=CC=1.ClC1C=CC(NC(NS(C2C=C(C)C(Cl)=C(C)C=2)(=O)=O)=O)=CC=1.ClC1C=CC(NC(NS(C2C=C(C)C(OC)=C(C)C=2)(=O)=O)=O)=CC=1.ClC1C=CC(NC(NS(C2C=C(OC)C(OC)=C(OC)C=2)(=O)=O)=O)=CC=1.ClC1C=CC(NC(NS(C2C=C(Br)C(NC)=C(Br)C=2)(=O)=O)=O)=CC=1>>[Cl:50][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:11][S:12]([C:15]2[CH:20]=[C:19]([CH3:21])[C:18]([CH3:22])=[C:17]([CH3:23])[CH:16]=2)(=[O:14])=[O:13])=[O:10])=[CH:4][CH:3]=1
Reactant: Cc1cc(S(=O)(=O)NC(=O)Nc2ccc(Br)cc2)cc(C)c1C
Reactant: Cc1cc(S(=O)(=O)NC(=O)Nc2ccc(Cl)c(Cl)c2)cc(C)c1C
Agent: CNc1c(Br)cc(S(=O)(=O)NC(=O)Nc2ccc(Cl)cc2)cc1Br
Agent: COc1c(C)cc(S(=O)(=O)NC(=O)Nc2ccc(Cl)cc2)cc1C
Agent: COc1cc(S(=O)(=O)NC(=O)Nc2ccc(Cl)cc2)cc(OC)c1OC
Product: Cc1cc(S(=O)(=O)NC(=O)Nc2ccc(Cl)cc2)cc(C)c1C

Procedure:
N-[[(4-bromophenyl)amino]carbonyl]-3,4,5-trimethylbenzenesulfonamide; N-[[(4-trifluoromethylpheny)amino]carbonyl]-3,4,5-trimethylbenzenesulfonamide; N-[[(3,4-dichlorophenyl)amino]carbonyl]-3,4,5-trimethylbenzenesulfonamide; N-[[(4-chlorophenyl)amino]carbonyl]-3,4,5-trichlorobenzene sulfonamide; N-[[(4-chlorophenyl)amino]carbonyl]-4-amino-3,5-dichlorobenzenesulfonamide; N-[[(4-chlorophenyl)amino]-carbonyl]-4-chloro-3,5-dimethylbenzenesulfonamide; N-[[(4-chlorophenyl)amino]carbonyl]-4-(N,N,dimethylamino)3,5-dichlorobenzene-sulfonamide; N-[[(4-chlorophenyl)amino]carbonyl]-3,5-dimethyl-4-methoxybenzenesulfonamide; N-[[(4-chlorophenyl)amino]carbonyl]-3,4,5-trimethoxylbenzenesulfonamide; N-[[(4-chlorophenyl)amino]carbonyl]-3,5-dibromo-4-(N-methylamino)benzenesulfonamide; and pharmaceutically acceptable salts thereof.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:8][CH2:9][CH:10]2[CH2:12][CH2:11]2)[N:3]=1.[C:13]([O:17][C:18]([NH:20][CH2:21][C:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][CH:23]=1)=[O:19])([CH3:16])([CH3:15])[CH3:14].C(=O)([O-])[O-].[K+].[K+].[OH-].[Na+]>C1(C)C=CC=CC=1.O.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.C(O)C>[CH:10]1([CH2:9][NH:8][C:4]2[N:3]=[C:2]([C:25]3[CH:26]=[CH:27][C:22]([CH2:21][NH:20][C:18]([O:17][C:13]([CH3:14])([CH3:16])[CH3:15])=[O:19])=[CH:23][CH:24]=3)[CH:7]=[CH:6][N:5]=2)[CH2:12][CH2:11]1
Reactant: Clc1ccnc(NCC2CC2)n1
Reactant: CC(C)(C)OC(=O)NCc1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)NCc1ccc(-c2ccnc(NCC3CC3)n2)cc1
Temperature: 25 °C
Yield: 91 %

Procedure:
Slurry 4-chloro-2-(cyclopropylmethyl-amino)-pyrimidine (155 mg, 0.62 mmol), [4-(N-tert-butoxycarbonyl-aminomethyl)phenyl]boronic acid (160 mg, 0.86 mmol), and tetrakis(triphenylphosphine)palladium(0) (36 mg, 0.031 mmol) in toluene (3 mL). Add ethanol (0.5 mL) followed by potassium carbonate (175 mg, 1.24 mmol) dissolved in water (300 μL). Irradiate in microwave (300 watts) at 120° C. for 60 min. Cool to room temperature, pour reaction mixture into water (100 mL) containing 1N NaOH (25 mL) and extract with DCM (3×50 mL). Wash the combined organic extracts with brine, dry over MgSO4, filter and concentrate in vacuo. Purify by chromatography on silica gel (12 g) eluting with hexane/EtOAc (4:1 to 3:7 over 30 min; 30 mL/min) to obtain the desired intermediate (200 mg, 90%) as a light yellow solid. MS (ES+) m/z: 355 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C@@H:6]([NH:15][C@@H:16]1[C:22](=[O:23])[N:21]([CH2:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[C:20]2[CH:32]=[CH:33][CH:34]=[CH:35][C:19]=2[S:18][CH2:17]1)[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:5])[CH3:2].ClC1C=CC=C(C(OO)=[O:44])C=1.[OH-].[Na+]>C(Cl)Cl>[CH2:1]([O:3][C:4]([C@@H:6]([NH:15][C@@H:16]1[C:22](=[O:23])[N:21]([CH2:24][C:25]([O:27][C:28]([CH3:29])([CH3:30])[CH3:31])=[O:26])[C:20]2[CH:32]=[CH:33][CH:34]=[CH:35][C:19]=2[S:18](=[O:44])[CH2:17]1)[CH2:7][CH2:8][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)=[O:5])[CH3:2]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCOC(=O)[C@H](CCc1ccccc1)N[C@H]1CSc2ccccc2N(CC(=O)OC(C)(C)C)C1=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CCOC(=O)[C@H](CCc1ccccc1)N[C@H]1CS(=O)c2ccccc2N(CC(=O)OC(C)(C)C)C1=O
Reaction time: 0.5 h

Procedure:
A solution of 1 g of tert-butyl 3(R)-[1(S)-ethoxycarbonyl-3-phenylpropyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetate obtained in Example 1 in 100 ml of methylene chloride is added 0.51 g of m-chloroperbenzoic acid. After stirring for 30 minutes, 0.15 g of m-chloroperbenzoic acid is added, and stirring is continued for further 30 minutes. Fifty ml of 1N aqueous sodium hydroxide is added to the mixture, and the methylene chloride layer is separated, washed with water and concentrated under reduced pressure to yield tert-butyl 3(R)-[1(S)-ethoxycarbonyl-3-phenylpropyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetate 1-oxide as a mixture of two stereoisomers. Separation by silica gel column chromatography yields 0.3 g of one isomer and 0.5 g of another isomer. Both are obtained as colorless oil. Mass spectrum of each isomer shows the peak due to molecular ion at 514.