Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:12][CH3:13])[CH:8]=2)[C:3]=1[O:14][C:15]1[CH:29]=[CH:28][C:18]([O:19][CH2:20][CH2:21][N:22]2[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)=[CH:17][CH:16]=1.[CH3:30][C:31]1[S:35][C:34](B(O)O)=[CH:33][CH:32]=1.CS(C)(=O)=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>[CH3:13][O:12][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[C:3]([O:14][C:15]1[CH:29]=[CH:28][C:18]([O:19][CH2:20][CH2:21][N:22]3[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]3)=[CH:17][CH:16]=1)=[C:2]([C:34]1[S:35][C:31]([CH3:30])=[CH:32][CH:33]=1)[CH:11]=[CH:10]2
Reactant: Cc1ccc(B(O)O)s1
Reactant: COc1ccc2c(Oc3ccc(OCCN4CCCCC4)cc3)c(Br)ccc2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CS(C)(=O)=O
Product: COc1ccc2c(Oc3ccc(OCCN4CCCCC4)cc3)c(-c3ccc(C)s3)ccc2c1
Reaction time: 6 h

Procedure:
To a 3-necked round bottom flask, add 1-(2-(4-(2-bromo-6-methoxynaphthalen-1-yloxy)phenoxy)ethyl)piperidine (25 mg, 75.9 μmol), 5-methylthiophen-2-ylboronic acid (20 mg, 140.86 μmol), tetrakis(triphenylphosphine)palladium (20 mg, 17.3 μmol), and dimethyl sulfone (DMSO) (2 mL). Purge the reaction vessel with nitrogen five times. Heat the mixture was at 100° C. for 6 hours, followed by 80° C. for 40 hours.
Reaction SMILES: [CH3:1][N:2]([CH3:24])[CH2:3][CH2:4][CH2:5][C:6]1[CH:23]=[CH:22][C:9]2[N:10]([CH2:19][O:20][CH3:21])[C:11](=[O:18])[C:12]3[CH:13]=[CH:14][CH:15]=[N:16][C:17]=3[C:8]=2[CH:7]=1>ClCCl.CO.[Pd]>[CH3:24][N:2]([CH3:1])[CH2:3][CH2:4][CH2:5][C:6]1[CH:23]=[CH:22][C:9]2[N:10]([CH2:19][O:20][CH3:21])[C:11](=[O:18])[C:12]3[CH2:13][CH2:14][CH2:15][NH:16][C:17]=3[C:8]=2[CH:7]=1
Reactant: COCn1c(=O)c2cccnc2c2cc(CCCN(C)C)ccc21
Agent: [Pd]
Solvent: ClCCl
Solvent: CO
Product: COCn1c(=O)c2c(c3cc(CCCN(C)C)ccc31)NCCC2
Temperature: 25 °C
Reaction time: 24 h
Yield: 50.7 %

Procedure:
The compound (110 mg, 0.67 mmol) prepared in step 8 was dissolved in dichloromethane/methanol (10 ml), added with 10%-palladium (11 mg). The resulting mixture was stirred for one day at room temperature under hydrogen gas. Once the reaction was completed, the solution was celite-filtered and the filtrate was concentrated to dryness. The residue was then purified by flash column chromatography (chloroform:methanol=10:1) to obtain the title compound (112 mg, yield: 99%, white solid).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([C:18]2[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=2)[S:5][C:6]=1[CH2:7][O:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[CH:11]=[CH:12][NH:13]2.[C:28]([O:32][C:33](=[O:37])[CH:34](Br)[CH3:35])([CH3:31])([CH3:30])[CH3:29].[H-].[Na+]>>[C:28]([O:32][C:33](=[O:37])[CH:34]([N:13]1[C:14]2[C:10](=[C:9]([O:8][CH2:7][C:6]3[S:5][C:4]([C:18]4[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:25])[F:26])=[CH:20][CH:19]=4)=[N:3][C:2]=3[CH3:1])[CH:17]=[CH:16][CH:15]=2)[CH:11]=[CH:12]1)[CH3:35])([CH3:31])([CH3:30])[CH3:29]
Reactant: CC(Br)C(=O)OC(C)(C)C
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1COc1cccc2[nH]ccc12
Agent: [H-]
Agent: [Na+]
Product: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1COc1cccc2c1ccn2C(C)C(=O)OC(C)(C)C

Procedure:
In analogy to the procedure described in example 1 b], 4-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy]-1H-indole (example 1 a]) was reacted with 2-bromo-propionic acid tert-butyl ester in the presence of sodium hydride to obtain [rac]-2-{4-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy]-indol-1-yl}-propionic acid tert-butyl ester as yellow oil.
Reaction SMILES: O[C@H:2]([C:22]1[CH:23]=[CH:24][C:25]2[O:30][C@H:29]([CH2:31][C:32]3[CH:37]=[CH:36][C:35]([O:38][CH2:39][C:40]4[CH:45]=[CH:44][CH:43]=[C:42]([F:46])[CH:41]=4)=[CH:34][CH:33]=3)[CH:28]=[CH:27][C:26]=2[CH:47]=1)[C@H:3]([O:19][CH2:20][CH3:21])[C:4]([N:6]1[C@@H:10]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:9][O:8][C:7]1=[O:18])=[O:5].C([SiH](CC)CC)C>FC(F)(F)C(O)=O.CCOCC>[CH2:20]([O:19][C@H:3]([C:4]([N:6]1[C@@H:10]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:9][O:8][C:7]1=[O:18])=[O:5])[CH2:2][C:22]1[CH:23]=[CH:24][C:25]2[O:30][C@H:29]([CH2:31][C:32]3[CH:33]=[CH:34][C:35]([O:38][CH2:39][C:40]4[CH:45]=[CH:44][CH:43]=[C:42]([F:46])[CH:41]=4)=[CH:36][CH:37]=3)[CH:28]=[CH:27][C:26]=2[CH:47]=1)[CH3:21]
Reactant: CCO[C@H](C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1)[C@H](O)c1ccc2c(c1)C=C[C@@H](Cc1ccc(OCc3cccc(F)c3)cc1)O2
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: CCOCC
Product: CCO[C@@H](Cc1ccc2c(c1)C=C[C@@H](Cc1ccc(OCc3cccc(F)c3)cc1)O2)C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1
Yield: 48.3 %

Procedure:
(R)-6-{(1R,2S)-1-Hydroxy-2-ethoxy-3-[(S)-4-benzyl-2-oxo-3-oxazolidinyl]-3-oxopropyl}-2-[4-(3-fluorobenzyloxy)benzyl]-2H-benzopyran (80 mg, 0.13 mmol) was dissolved in trifluoroacetic acid (2 ml) and triethylsilane (0.20 ml) was added. After 30 minutes the solution was diluted with ether, washed with water (2×) and saturated sodium bicarbonate (2×), dried over magnesium sulfate and concentrated. The product was purified by flash-chromatography (hexanes/ethyl acetate, 2:1) and obtained as an oil (39 mg).
Reaction SMILES: [C:1]1([CH2:7][C:8]([NH:10][CH:11]2[C:37](=[O:38])[N:13]3[C:14]([C:21]([O:23][CH:24]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)=[O:22])=[C:15]([CH2:19]Cl)[CH2:16][S:17](=[O:18])[C@H:12]23)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH:39]1[C:43]([SH:44])=[N:42][N:41]=[N:40]1.CN(C)C=O.Cl>C(N(CC)CC)C>[C:1]1([CH2:7][C:8]([NH:10][CH:11]2[C:37](=[O:38])[N:13]3[C:14]([C:21]([O:23][CH:24]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)=[O:22])=[C:15]([CH2:19][S:44][C:43]4[NH:42][N:41]=[N:40][N:39]=4)[CH2:16][S:17](=[O:18])[C@H:12]23)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cc1ccccc1)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CCl)CS(=O)[C@H]12
Reactant: Sc1nnn[nH]1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(Cc1ccccc1)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CSc3nnn[nH]3)CS(=O)[C@H]12
Temperature: 0 °C
Yield: 100.5 %

Procedure:
A mixture of benzhydryl 7-(2-phenylacetamido)-3-chloromethyl-3-cephem-4-carboxylate-1-oxide (70.0 g), 1H-tetrazole-5-thiol (15.6 g) and N,N-dimethylformamide (700 ml) was stirred to give a homogeneous solution and thereto was added triethylamine (32.1 g), keeping the temperature at 20° to 30° C. The resulting solution was stirred for 40 minutes at room temperature. After the reaction mixture was added to ice water (2.8 l), the mixture was adjusted to pH 2.0 with 10% hydrochloric acid and then filtered. The filter cake was washed with water and dried over phosphorus pentoxide under reduced pressure to give benzhydryl 7-(2-phenylacetamido)-3-(1H-tetrazole-5-yl)thiomethyl-3-cephem-4-carboxylate-1-oxide (78.8 g).
Reaction SMILES: O=[C:2]([CH2:6][CH3:7])[C:3]([OH:5])=[O:4].[CH2:8]([C:10]1([CH2:16][CH3:17])[CH2:12][CH:11]1[C:13]([NH2:15])=[O:14])[CH3:9].C1(C)C=CC=CC=1>O>[CH2:8]([C:10]1([CH2:16][CH3:17])[CH2:12][CH:11]1[C:13]([NH:15]/[C:2](=[CH:6]\[CH3:7])/[C:3]([OH:5])=[O:4])=[O:14])[CH3:9]
Reactant: CCC(=O)C(=O)O
Reactant: CCC1(CC)CC1C(N)=O
Solvent: O
Solvent: Cc1ccccc1
Product: C/C=C(\NC(=O)C1CC1(CC)CC)C(=O)O
Yield: 9.7 %

Procedure:
A mixture of 2.3 g of 2-ketobutyric acid, 2.0 g of 2,2-diethylcyclopropanecarboxamide, and 25 ml of toluene was heated under reflux for 16 hrs with removal of H2O by a modified Dean-Stark trap containing molecular sieves (4A). No product precipitated upon cooling. Ether (25 ml) was added and the mixture was extracted with saturated NaHCO3 (3 times). The combined extracts were acidified with concentrated HCl. The gummy precipitate crystallized when triturated with water. Recrystallization from ethyl acetate gave 0.31 g of product, m.p. 129°-30°. The NMR spectrum was consistent with the desired structure.
Reaction SMILES: [CH2:1]([C:3]1[N:7]([C:8]2[N:16]=[C:15]3[C:11]([N:12]=[C:13]([C:18]4([OH:24])[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]4)[N:14]3[CH3:17])=[C:10]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)[N:9]=2)[C:6]2[CH:31]=[CH:32][CH:33]=[CH:34][C:5]=2[N:4]=1)[CH3:2].[OH:35][C:36]([CH3:41])([CH3:40])[C:37](O)=[O:38].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[CH2:1]([C:3]1[N:7]([C:8]2[N:16]=[C:15]3[C:11]([N:12]=[C:13]([C:18]4([OH:24])[CH2:19][CH2:20][N:21]([C:37](=[O:38])[C:36]([OH:35])([CH3:41])[CH3:40])[CH2:22][CH2:23]4)[N:14]3[CH3:17])=[C:10]([N:25]3[CH2:26][CH2:27][O:28][CH2:29][CH2:30]3)[N:9]=2)[C:6]2[CH:31]=[CH:32][CH:33]=[CH:34][C:5]=2[N:4]=1)[CH3:2]
Reactant: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C3(O)CCNCC3)n(C)c2n1
Reactant: CC(C)(O)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C3(O)CCN(C(=O)C(C)(C)O)CC3)n(C)c2n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 34.2 %

Procedure:
To a mixture of 4-[2-(2-ethylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purin-8-yl]piperidin-4-ol (150 mg, 0.32 mmol), 2-hydroxyisobutyric acid (41 mg, 0.39 mmol) and DIPEA (68 μL, 0.39 mmol) in DCM (2 mL) was added HATU (149 mg, 0.39 mmol). The resulting mixture was allowed to stir at r.t. for 18 h then diluted with DCM and washed with sat. aq. NaHCO3. The organic phase was dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si-PCC, MeOH:EtOAc, 0-20%) affording 790 (60 mg, 34%). LCMS (method I): RT 3.09 min, [M+H]+ 549.3. 1H NMR (DMSO, 400 MHz): δ 8.02-8.01 (1 H, m), 7.64-7.63 (1 H, m), 7.27-7.23 (2 H, m), 5.84 (1 H, s), 5.42 (1 H, s), 4.25 (6 H, brd s), 3.98 (3 H, s), 3.77 (4 H, t, J=4.55 Hz), 3.60 (1 H, brd s), 3.2-3.24 (3 H, m), 2.11-2.10 (2 H, m), 2.06-1.94 (2 H, m), 1.38-1.30 (9 H, m)
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH:14]([N:22]([CH3:39])[C:23](=[O:38])[CH2:24][N:25]3[C:30]4[CH:31]=[C:32]([Cl:36])[C:33]([Cl:35])=[CH:34][C:29]=4[O:28][CH2:27][C:26]3=[O:37])[CH2:15][N:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[CH2:40]([S:42](Cl)(=[O:44])=[O:43])[CH3:41].C(N(CC)CC)C>ClCCl>[Cl:36][C:32]1[C:33]([Cl:35])=[CH:34][C:29]2[O:28][CH2:27][C:26](=[O:37])[N:25]([CH2:24][C:23]([N:22]([CH:14]([C:11]3[CH:12]=[CH:13][C:8]([C:5]4[CH:4]=[CH:3][C:2]([NH:1][S:42]([CH2:40][CH3:41])(=[O:44])=[O:43])=[CH:7][CH:6]=4)=[CH:9][CH:10]=3)[CH2:15][N:16]3[CH2:17][CH2:18][O:19][CH2:20][CH2:21]3)[CH3:39])=[O:38])[C:30]=2[CH:31]=1
Reactant: CN(C(=O)CN1C(=O)COc2cc(Cl)c(Cl)cc21)C(CN1CCOCC1)c1ccc(-c2ccc(N)cc2)cc1
Reactant: CCS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCS(=O)(=O)Nc1ccc(-c2ccc(C(CN3CCOCC3)N(C)C(=O)CN3C(=O)COc4cc(Cl)c(Cl)cc43)cc2)cc1
Reaction time: 0.25 h
Yield: 23.1 %

Procedure:
To a solution of N-[1-(4′-amino-4-biphenylyl)-2-(4-morpholinyl)ethyl]-2-(6,7-dichloro-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl)-N-methylacetamide (68 mg, 0.12 mmol) in dichloromethane (2 mL) was added ethanesulfonyl chloride (18.5 mg, 0.14 mmol). Triethylamine (24 mg, 0.24 mmol) was added, and the resultant mixture was stirred at room temperature for 2 h. The mixture was concentrated under reduced pressure, and the residue was purified by Gilson preparative HPLC (Xterra Prep RP, 30×100 mm, 45 mL/min, A: acetonitrile with 0.1% TFA B: water with 0.1% TFA, A: 25 to 55% over 15 min, UV detection at 214 nm) to give 18.3 mg (23%) of the title compound as an off white solid. MS (ES) m/e 661.1 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([C:11]([NH:13][CH:14]([C:16]2[NH:20][C:19]3[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:18]=3[N:17]=2)[CH3:15])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].[NH2:26][CH2:27][CH2:28][CH2:29][NH:30][CH2:31][CH3:32].C(N(C(C)C)CC)(C)C.ClCl>CS(C)=O>[NH2:26][CH2:27][CH2:28][CH2:29][N:30]([CH2:31][CH3:32])[C:4]([C:3]1[CH:7]=[CH:8][C:9]([C:11]([NH:13][CH:14]([C:16]2[NH:20][C:19]3[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:18]=3[N:17]=2)[CH3:15])=[O:12])=[CH:10][C:2]=1[Cl:1])=[O:5]
Reactant: CC(NC(=O)c1ccc(C(=O)O)c(Cl)c1)c1nc2cc(Cl)ccc2[nH]1
Reactant: CCNCCCN
Agent: ClCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CCN(CCCN)C(=O)c1ccc(C(=O)NC(C)c2nc3cc(Cl)ccc3[nH]2)cc1Cl

Procedure:
Prepared analogously to Example 1d from rac.-2-chloro-4-{N-[1-(5-chloro-1H-benzimidazol-2-yl)ethyl]aminocarbonyl}benzoic acid, N-(3-aminopropyl)ethylamine, PFTU, and diisopropylethylamine in DMSO at ambient temperature. HPLC-MS results: retention time: 3.82 minutes; C22H25Cl2N5O2 (462.38); mass spectrum: (M−H)−=461/463/465 (chlorine isotope).
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][NH:8][CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[CH3:18][N:19]([CH3:24])[S:20](Cl)(=[O:22])=[O:21]>C1COCC1>[CH3:18][N:19]([CH3:24])[S:20]([N:8]1[CH2:9][CH2:10][C:5]2([O:4][CH2:3][CH2:2][O:1]2)[CH2:6][CH2:7]1)(=[O:22])=[O:21]
Reactant: CN(C)S(=O)(=O)Cl
Reactant: C1CC2(CCN1)OCCO2
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CN(C)S(=O)(=O)N1CCC2(CC1)OCCO2
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.3 %

Procedure:
To a solution of 1,4-dioxa-8-azaspiro[4,5]decane (5.0 g, 35 mmol) in THF (25 mL) was added triethylamine (5 mL, 36 mmol) followed by N,N-dimethylsulfamoyl chloride (3.7 mL, 35 mmol). The resulting white mixture was stirred at room temperature for 1 h. The solids were removed by filtration and the solution was concentrated to give the title compound as a white solid (8.7 g, 100% yield). 1H NMR (300 MHz, CDCl3) δ: 3.93 (4H, s), 3.35 (4H, t, J=5.8 Hz), 2.78 (6H, s), 1.73 (4H, t, J=5.8 Hz). LCMS (M+H) calcd for C9H19N2O4S: 251.10; found: 251.24.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:12]=[C:13]([CH:15]=[O:16])[CH:14]=1)[C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6].C[Si](C)(C)[C:19]([F:22])([F:21])[F:20].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.Cl>C1COCC1.COC(C)(C)C>[Br:1][C:2]1[CH:3]=[C:4]([CH:12]=[C:13]([CH:15]([OH:16])[C:19]([F:22])([F:21])[F:20])[CH:14]=1)[C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6]
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: CC(C)(C)OC(=O)c1cc(Br)cc(C=O)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [F-]
Solvent: COC(C)(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)c1cc(Br)cc(C(O)C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of tert-butyl 3-bromo-5-formylbenzoate (Merck patent case No. 22407 PV; 5.7 g, 20.0 mmol) in THF (133 mL) at 0° C. were added trimethyl(trifluoromethyl)silane (4.44 mL, 30.0 mmol) and activated 4 Å molecular sieves. Tetrabutylammonium fluoride (1.0 M in THF; 6.0 mL, 6.0 mmol) was added dropwise. The reaction mixture was warmed to ambient temperature. After 3 h, aqueous 1N HCl (25 mL) and tert-butyl methyl ether (100 mL) were added. The organic layer was separated, washed with brine, dried over sodium sulfate, filtered and concentrated.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]([C:11]2[NH:12][CH:13]=[C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[N:15]=2)=[O:10])[CH:6]=[CH:7][CH:8]=1.C(=O)([O-])[O-].[K+].[K+].C1OCCOCCOCCOCCOCCOC1.[CH2:46](Br)[CH2:47][CH:48]=[CH2:49]>CN(C=O)C.O>[CH2:49]([N:12]1[CH:13]=[C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:15]=[C:11]1[C:9]([C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=1)=[O:10])[CH2:48][CH:47]=[CH2:46]
Reactant: COc1cccc(C(=O)c2nc(-c3ccccc3)c[nH]2)c1
Reactant: C=CCCBr
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C=CCCn1cc(-c2ccccc2)nc1C(=O)c1cccc(OC)c1
Temperature: 80 °C
Reaction time: 5 h
Yield: 93 %

Procedure:
(3-Methoxyphenyl)(4-phenyl-1H-imidazol-2-yl)methanone (278 mg, 1.00 mmol) was dissolved in DMF (3 ml), and thereto were added potassium carbonate (207 mg, 1.50 mmol), 18-crown-6 (26.4 mg, 0.100 mmol), 3-butenyl bromide (162 mg, 1.20 mmol), and the mixture was stirred at 80° C. for 5 hours. The reaction solution was cooled to room temperature, and thereto was added water. The mixture was extracted with ethyl acetate, and the solvent was evaporated under reduced pressure. The resulting residue was subjected to azeotropic distillation with toluene to give the title compound (309 mg, 93%).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[NH2:6][C:7]1[CH:8]=[C:9]([CH2:15][CH2:16][NH:17][C:18](=[O:23])[C:19]([F:22])([F:21])[F:20])[CH:10]=[CH:11][C:12]=1[O:13][CH3:14].C(N(CC)CC)C>ClCCl>[F:20][C:19]([F:21])([F:22])[C:18]([NH:17][CH2:16][CH2:15][C:9]1[CH:10]=[CH:11][C:12]([O:13][CH3:14])=[C:7]([NH:6][S:2]([CH3:1])(=[O:4])=[O:3])[CH:8]=1)=[O:23]
Reactant: CS(=O)(=O)Cl
Reactant: COc1ccc(CCNC(=O)C(F)(F)F)cc1N
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(CCNC(=O)C(F)(F)F)cc1NS(C)(=O)=O
Reaction time: 18 h
Yield: 93.4 %

Procedure:
Methanesulphonyl chloride (5.75 g, 0.05 moles) in dry dichloromethane (50 ml) was added dropwise with stirring to N-[2-(3-amino-4-methoxyphenyl)ethyl]-2,2,2-trifluoro acetamide (13.1 g, 0.05 moles) and triethylamine (10.1 g, 7.5 ml, 0.1 mole) in dry dichloromethane (250 ml). Stirring was continued at 20° for 18 hr and the solution was then washed with dilute hydrochloric acid, saturated sodium bicarbonate solution and water, dried and evaporated. The residue on recrystallisation from benzene gave the sub-title compound (15.9 g) as ivory-coloured plates mp 129°-130°.
Reaction SMILES: [C:1]1([C:7]2[CH:11]=[C:10]([C:12](=[O:17])[CH2:13][CH:14]([CH3:16])[CH3:15])[O:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[NH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1.C=O>>[C:1]1([C:7]2[CH:11]=[C:10]([C:12](=[O:17])[CH:13]([CH2:24][N:19]3[CH2:20][CH2:21][CH2:22][CH2:23]3)[CH:14]([CH3:15])[CH3:16])[O:9][N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)CC(=O)c1cc(-c2ccccc2)no1
Reactant: C1CCNCC1
Agent: C=O
Agent: Cl
Product: CC(C)C(CN1CCCC1)C(=O)c1cc(-c2ccccc2)no1

Procedure:
From 1.5 g (6.6 mmol) of 3-phenyl-5-(3-methylbutyryl)isoxazole prepared above in the procedure (2), 0.84 g (7.9 mmol) of piperidine hydrochloride, and 0.26 g (8.7 mmol) of paraformaldehyde, the free base of 3-phenyl-5-{2-(1-pyrrolidinylmethyl)-3-methylbutyryl}isoxazole was obtained as crystals in a manner similar to Example 28.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][N:6]([CH2:16][C:17]1[C:18]([NH2:24])=[N:19][CH:20]=[C:21]([Br:23])[CH:22]=1)[CH2:7][CH2:8][CH2:9][N:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1)C.[H-].[Na+]>CS(C)=O.O>[Br:23][C:21]1[CH:20]=[N:19][C:18]2[NH:24][C:4](=[O:3])[CH2:5][N:6]([CH2:7][CH2:8][CH2:9][N:10]3[CH2:15][CH2:14][O:13][CH2:12][CH2:11]3)[CH2:16][C:17]=2[CH:22]=1
Reactant: CCOC(=O)CN(CCCN1CCOCC1)Cc1cc(Br)cnc1N
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: O=C1CN(CCCN2CCOCC2)Cc2cc(Br)cnc2N1
Temperature: 25 °C
Reaction time: 8 h
Yield: 55.1 %

Procedure:
A solution of [(2-amino-5-bromo-pyridin-3-ylmethyl)-(3-morpholin-4-yl-propyl)amino]acetic acid ethyl ester (11.8 g, 28.3 mmol) in DMSO (200 mL) was treated with NaH (60% dispersion in mineral oil, 1.13 g, 28.3 mmol). After stirring at room temperature overnight, the mixture was diluted with H2O (400 mL) and then extracted with EtOAc (7×250 mL). The combined organic layers were washed with H2O (2×200 mL) and brine (200 mL), dried over Na2SO4, filtered and the solvent was removed in vacuo. Purification by flash column chromatography (silica gel, CH2Cl2/MeOH, 97:3 to 96:4) gave the title compound (5.76 g, 55%) as an off-white powder: MS (ESI) m/e 369 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:14]([OH:16])=O)[CH2:10][CH:9]2[C:11](O)=[O:12])=[CH:4][CH:3]=1.[NH3:17]>>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]23[CH2:10][CH:9]2[C:11](=[O:12])[NH:17][C:14]3=[O:16])=[CH:4][CH:3]=1
Reactant: N
Reactant: Nc1ccc(C2(C(=O)O)CC2C(=O)O)cc1
Product: Nc1ccc(C23CC2C(=O)NC3=O)cc1

Procedure:
In a glass bomb tube, 2.3 g of 1-(4-aminophenyl)-1,2-cyclopropanedicarboxylic acid are stirred in 80 ml of approx. 1N methanolic ammonia solution for 7 days at 100° C. The reaction mixture is evaporated to dryness and the residue is chromatographed over silica gel with hexane/ethyl acetate (4:6). Recrystallisation from ethanol affords white crystals of the title compound, which is identical with the title compound of Example 1.
Reaction SMILES: O.[OH-].[Li+].C[O:5][C:6](=[O:40])[C@H:7]([CH2:15][C:16]1[CH:21]=[C:20]([I:22])[C:19]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][C:28]([O:31][C:32]3[CH:37]=[CH:36][C:35]([OH:38])=[CH:34][CH:33]=3)=[CH:27][CH:26]=2)=[C:18]([I:39])[CH:17]=1)[NH:8]C(=O)C(F)(F)F.Cl>O1CCCC1.O>[OH:38][C:35]1[CH:34]=[CH:33][C:32]([O:31][C:28]2[CH:29]=[CH:30][C:25]([CH2:24][O:23][C:19]3[C:18]([I:39])=[CH:17][C:16]([CH2:15][C@@H:7]([C:6]([OH:40])=[O:5])[NH2:8])=[CH:21][C:20]=3[I:22])=[CH:26][CH:27]=2)=[CH:37][CH:36]=1
Reactant: COC(=O)[C@H](Cc1cc(I)c(OCc2ccc(Oc3ccc(O)cc3)cc2)c(I)c1)NC(=O)C(F)(F)F
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: N[C@@H](Cc1cc(I)c(OCc2ccc(Oc3ccc(O)cc3)cc2)c(I)c1)C(=O)O
Temperature: 25 °C
Reaction time: 16 h
Yield: 94 %

Procedure:
Lithium hydroxide monohydrate (47 mg, 1.12 mmol) was added to a solution of N-trifluoroacetyl-O-[4-(4-hydroxy-phenoxy)benzyl]-3,5-diiodo-L-tyrosine methyl ester (235 mg, 0.317 mmol) in tetrahydrofuran (2 ml)-water (1 ml) under ice cooling and the mixture was reacted at room temperature for 7.5 hrs., and then at 0-5° C. for 16 hrs. The reaction mixture was diluted with water, adjusted to pH 4-5 under ice cooling with 1N hydrochloric acid (0.79 ml) and stirred at room temperature for 1.5 hrs. The precipitates were collected by filtration, washed with water and ethanol in turn and dried to give O-[4-(4-hydroxyphenoxy)benzyl]-3,5-diiodo-L-tyrosine (188 mg, 90%) as pale yellow crystals.
Reaction SMILES: O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.[Cl:15][C:16]1[CH:17]=[C:18]([CH2:22][C:23]([OH:25])=O)[CH:19]=[CH:20][CH:21]=1.[Cl:26][C:27]1[S:28][CH:29]=[CH:30][CH:31]=1.ClCCCl>CCOCC>[Cl:15][C:16]1[CH:17]=[C:18]([CH2:22][C:23]([C:29]2[S:28][C:27]([Cl:26])=[CH:31][CH:30]=2)=[O:25])[CH:19]=[CH:20][CH:21]=1
Reactant: O=C(O)Cc1cccc(Cl)c1
Reactant: Clc1cccs1
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: ClCCCl
Solvent: CCOCC
Product: O=C(Cc1cccc(Cl)c1)c1ccc(Cl)s1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a 500-mL round-bottomed flask was added silica gel 60 (21 g, 350 mmol) and the flask was heated with a heat gun under high vacuum for 30 min. The system was cooled to room temperature and phosphorus pentoxide (8.75 mL, 148 mmol) was added. The mixture was stirred at 110° C. (oil bath) under high vacuum for 120 min. The mixture was allowed to cool to room temperature. 3-chlorophenylacetic acid (15.6 g, 91 mmol), 2-chlorothiophene (33.8 mL, 366 mmol) and DCE (50 mL) were added. The reaction mixture was stirred at reflux for 4 hours. LCMS analysis showed the reaction was complete. The reaction mixture was allowed to cool to room temperature. The reaction mixture was diluted with ether (300 mL) and filtered. The organic solution was concentrated under reduced pressure. The residue was triturated with hexane to afford the title compound as an off-white solid. The hexane mother liquid was concentrated and purified by flash chromatography (SiO2, 0 to 30% EtOAc/Hex, a gradient elution) provided another batch of the title compounde as a light yellow solid. Mass Spectrum (ESI) m/z=271 (M+1).
Reaction SMILES: [OH:1][C:2]1[C:7]2[C:8]([O:11][CH2:12][CH:13]3[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]3)=[N:9][O:10][C:6]=2[CH:5]=[CH:4][CH:3]=1.[C:26]([O:29][CH2:30][C@H:31]1[CH2:36][CH2:35][C@H:34](O)[CH2:33][CH2:32]1)(=[O:28])[CH3:27].OCCC1CCN(C(OC(C)(C)C)=O)CC1>>[C:26]([O:29][CH2:30][C@@H:31]1[CH2:36][CH2:35][C@H:34]([O:1][C:2]2[C:7]3[C:8]([O:11][CH2:12][CH:13]4[CH2:14][CH2:15][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:17][CH2:18]4)=[N:9][O:10][C:6]=3[CH:5]=[CH:4][CH:3]=2)[CH2:33][CH2:32]1)(=[O:28])[CH3:27]
Reactant: CC(=O)OC[C@H]1CC[C@H](O)CC1
Reactant: CC(C)(C)OC(=O)N1CCC(COc2noc3cccc(O)c23)CC1
Agent: CC(C)(C)OC(=O)N1CCC(CCO)CC1
Product: CC(=O)OC[C@H]1CC[C@@H](Oc2cccc3onc(OCC4CCN(C(=O)OC(C)(C)C)CC4)c23)CC1

Procedure:
The title compound was prepared according to the procedure described in Step 2 of EXAMPLE 7 using tert-butyl 4-{[(4-hydroxy-1,2-benzisoxazol-3-yl)oxy]methyl}piperidine-1-carboxylate (EXAMPLE 17, step 2) and (trans-4-hydroxycyclohexyl)methyl acetate (EXAMPLE 46, Step 1) instead of 4-(benzyloxy)-1,2-benzisoxazol-3-ol and tert-butyl 4-(2-hydroxyethyl)piperidine-1-carboxylate.