Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:12]([N:14]3[CH2:19][CH2:18][CH2:17][CH:16]([CH2:20]OS(C)(=O)=O)[CH2:15]3)=[O:13])[CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[F:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[N:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1.C(=O)([O-])[O-].[Cs+].[Cs+]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:12]([N:14]3[CH2:19][CH2:18][CH2:17][CH:16]([CH2:20][N:36]4[CH2:35][CH2:34][N:33]([C:28]5[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=5[F:26])[CH2:38][CH2:37]4)[CH2:15]3)=[O:13])[CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)OCC1CCCN(C(=O)C2(c3ccc(Cl)cc3)CCC2)C1
Reactant: Fc1ccccc1N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: O=C(N1CCCC(CN2CCN(c3ccccc3F)CC2)C1)C1(c2ccc(Cl)cc2)CCC1
Yield: 45.8 %

Procedure:
Compound 8 was prepared using the method described in Example 3, starting with compound 2 (1.0 g, 2.60 mmol), 1-(2-fluorophenyl)piperazine (0.51 g, 2.86 mmol), and cesium carbonate (1.27 g, 3.90 mmol) to give 8 (0.56 g, 46%); C27H33ClFN3O, LRMS (m/z)=471 (MH+).
Reaction SMILES: O[CH2:2][CH:3]1[CH2:6][C:5]([CH2:29][C:30]#[N:31])([N:7]2[CH:11]=[C:10]([C:12]3[C:13]4[CH:20]=[CH:19][N:18]([CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])[C:14]=4[N:15]=[CH:16][N:17]=3)[CH:9]=[N:8]2)[CH2:4]1.C(Br)(Br)(Br)[Br:33].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C([O-])(O)=O.[Na+]>CN(C=O)C.O>[Br:33][CH2:2][CH:3]1[CH2:6][C:5]([CH2:29][C:30]#[N:31])([N:7]2[CH:11]=[C:10]([C:12]3[C:13]4[CH:20]=[CH:19][N:18]([CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])[C:14]=4[N:15]=[CH:16][N:17]=3)[CH:9]=[N:8]2)[CH2:4]1
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C4(CC#N)CC(CO)C4)c3)ncnc21
Reactant: BrC(Br)(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C4(CC#N)CC(CBr)C4)c3)ncnc21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 86.7 %

Procedure:
To an ice-cooled mixture of 3-(hydroxymethyl)-1-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutylacetonitrile (1.0 g, 0.0023 mol) and carbon tetrabromide (1.1 g, 0.0034 mol) in DMF (7 mL) was added triphenylphosphine (0.90 g, 0.0034 mol) and the mixture was stirred at this temp. for 30 min. To the resulting dark brown solution was added saturated aq. NaHCO3 (5 mL) followed by water (5 mL) and the mixture was extracted with dichloromethane. The organic layers were combined, washed with water, dried over Na2SO4, concentrated and purified with combiflash (silica gel, 0-40% EtOAc/Hex) to give the desired product (1.0 g, 87%) as light yellow solid. LCMS calculated for C22H30BrN6OSi(M+H)+: 501.1: Found: 501.3.
Reaction SMILES: [C:1]1([C:7]2[O:8][C:9]([C:42]([F:45])([F:44])[F:43])=[C:10]([CH2:12][O:13][C:14](=[O:41])[C:15]3[CH:20]=[CH:19][C:18]([CH2:21][CH:22]([S:31][CH2:32][CH2:33][C:34]4[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=4)[C:23]([O:25]CC(Cl)(Cl)Cl)=[O:24])=[CH:17][CH:16]=3)[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O)(=O)C>C(Cl)Cl.[Zn]>[C:1]1([C:7]2[O:8][C:9]([C:42]([F:43])([F:45])[F:44])=[C:10]([CH2:12][O:13][C:14](=[O:41])[C:15]3[CH:16]=[CH:17][C:18]([CH2:21][CH:22]([C:23]([OH:25])=[O:24])[S:31][CH2:32][CH2:33][C:34]4[CH:35]=[CH:36][C:37]([F:40])=[CH:38][CH:39]=4)=[CH:19][CH:20]=3)[N:11]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(OCc1nc(-c2ccccc2)oc1C(F)(F)F)c1ccc(CC(SCCc2ccc(F)cc2)C(=O)OCC(Cl)(Cl)Cl)cc1
Agent: [Zn]
Solvent: CC(=O)O
Solvent: ClCCl
Product: O=C(OCc1nc(-c2ccccc2)oc1C(F)(F)F)c1ccc(CC(SCCc2ccc(F)cc2)C(=O)O)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 10.2 %

Procedure:
4-[2-[2-(4-Fluoro-phenyl)-ethylsulfanyl]-2-(2,2,2-trichloro-ethoxycarbonyl)-ethyl]-benzoic acid 2-phenyl-5-trifluoromethyl-oxazol-4-ylmethylester (289 mg, 0.41 mmol) was dissolved in DCM (30 mL) and zinc (530 mg, 8.1 mmol) was added followed by acetic acid (2.5 mL, 41.6 mmol). The resulting suspension was stirred for 6 h at ambient temperature. After filtering off and washing the zinc with MeOH and EtOAc, the combined organic layers were extracted with water, dried (MgSO4) and evaporated under reduced pressure. The remaining crude product was purified by flash chromatography using Et2O/DCM/EtOAc 6:3:1 as the eluent to afford the title compound as a solid (yield: 24 mg, 10%). 1H NMR (400 MHz, CDCl3): δ 8.07 (d, 2H), 7.98 (d, 2H), 7.43-7.55 (m, 3H), 7.24 (d, 2H), 7.07 (m, 2H), 6.92 (t, 2H), 5.39 (s, 2H), 3.43 (t, 1H), 3.22 (dd, 1H), 2.75-2.99 (m, 5H). Mass spectrum: M+H+ 574.14, M−H+ 572.24.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:12]([CH3:13])=[CH:11][C:10]([N:14]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[C:15]2[C:24]3[C:19](=[CH:20][C:21]([CH2:25][OH:26])=[CH:22][CH:23]=3)[C:18](=[O:27])[N:17]([CH:28]([CH3:30])[CH3:29])[N:16]=2)=[N:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].I(C1C=CC=CC=1C(O)=O)(=O)=[O:39].S(=O)(=O)(O)N.Cl([O-])=O.[Na+]>CS(C)=O.C(Cl)Cl.O>[C:34]([O:33][C:31]([N:14]([C:10]1[CH:11]=[C:12]([CH3:13])[N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[N:9]=1)[C:15]1[C:24]2[C:19](=[CH:20][C:21]([C:25]([OH:39])=[O:26])=[CH:22][CH:23]=2)[C:18](=[O:27])[N:17]([CH:28]([CH3:29])[CH3:30])[N:16]=1)=[O:32])([CH3:35])([CH3:37])[CH3:36]
Reactant: Cc1cc(N(C(=O)OC(C)(C)C)c2nn(C(C)C)c(=O)c3cc(CO)ccc23)nn1C(=O)OC(C)(C)C
Reactant: O=C(O)c1ccccc1I(=O)=O
Agent: NS(=O)(=O)O
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: ClCCl
Solvent: O
Solvent: CS(C)=O
Product: Cc1cc(N(C(=O)OC(C)(C)C)c2nn(C(C)C)c(=O)c3cc(C(=O)O)ccc23)nn1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 24 h
Yield: 42.8 %

Procedure:
3-[tert-Butoxycarbonyl-(6-hydroxymethyl-3-isopropyl-4-oxo-3,4-dihydro-phthalazin-1-yl)-amino]-5-methyl-pyrazole-1-carboxylic acid tert-butyl ester (0.2 g, 0.39 mmol) was dissolved in DMSO (3 ml). To this was added 2-iodoxybenzoic acid (IBX) (0.22 g, 0.78 mmol) in one portion and the reaction mixture was stirred at RT for 24 hours. After this time, the reaction mixture was partitioned between EtOAc (20 ml) and water (20 ml), the organic layer was separated and washed with water (3×20 ml) before being dried (MgSO4), filtered and concentrated under vacuum. The resulting orange oil (0.197 g, 0.38 mmol) was dissolved in DCM (3 ml) and water (3 ml). To this was added sulfamic acid (0.037 g, 0.38 mmol) and the reaction mixture was stirred vigorously at 0° C. After 5 min, sodium chlorite (0.034 g, 0.38 mmol) was added in one portion and the mixture stirred for a further hour. After this time, the reaction mixture was diluted with DCM (20 ml) and washed with water (10 ml). The organic layer was separated, dried (MgSO4), filtered and concentrated under vacuum. The resulting residue was purified by flash column chromatography (elution: 50% heptane, 50% EtOAc to 100% EtOAc) to give the title compound (0.088 g, 44% yield) as a white solid. MS (ESI+)=(M+H)+ 528.41.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[C:5]([N:10]2[CH2:15][CH2:14][N:13]([C:16]([C:18]3[CH:26]=[CH:25][C:21]([C:22]([OH:24])=O)=[CH:20][CH:19]=3)=[O:17])[CH2:12][CH2:11]2)=[N:6][CH:7]=[CH:8][CH:9]=1)[CH3:2].[CH2:27]([NH:29][CH2:30][CH2:31][OH:32])[CH3:28]>>[CH2:27]([N:29]([CH2:30][CH2:31][OH:32])[C:22]([C:21]1[CH:20]=[CH:19][C:18]([C:16]([N:13]2[CH2:14][CH2:15][N:10]([C:5]3[C:4]([NH:3][CH2:1][CH3:2])=[CH:9][CH:8]=[CH:7][N:6]=3)[CH2:11][CH2:12]2)=[O:17])=[CH:26][CH:25]=1)=[O:24])[CH3:28]
Reactant: CCNCCO
Reactant: CCNc1cccnc1N1CCN(C(=O)c2ccc(C(=O)O)cc2)CC1
Product: CCNc1cccnc1N1CCN(C(=O)c2ccc(C(=O)N(CC)CCO)cc2)CC1
Yield: 72 %

Procedure:
By the same procedure as described in the example 1, synthesis was carried out starting with 4-[1-[3-(ethylamino)-2-pyridyl]piperazin-4-yl-carbonyl]benzoic acid and using 2-(ethylamino)ethanol. Then, the product was recrystallized using ethyl acetate and hexane to give the desired compound.
Reaction SMILES: [Br:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:8][CH:7]=1)[C:3]([OH:5])=O.O=S(Cl)Cl.[CH:20]1([CH2:26][O:27][C:28]2[CH:33]=[CH:32][C:31]([NH2:34])=[CH:30][CH:29]=2)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1.C(N(C(C)C)C(C)C)C>C1(C)C=CC=CC=1>[Br:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:8][CH:7]=1)[C:3]([NH:34][C:31]1[CH:30]=[CH:29][C:28]([O:27][CH2:26][CH:20]2[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]2)=[CH:33][CH:32]=1)=[O:5]
Reactant: CC(C)(C)c1ccc(C(Br)C(=O)O)cc1
Reactant: Nc1ccc(OCC2CCCCC2)cc1
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: O=S(Cl)Cl
Product: CC(C)(C)c1ccc(C(Br)C(=O)Nc2ccc(OCC3CCCCC3)cc2)cc1
Temperature: 90 °C
Reaction time: 1 h
Yield: 59.1 %

Procedure:
To a stirring solution of bromo-(4-tert-butyl-phenyl)-acetic acid (1.2 g, 4.43 mmol) in toluene (20 mL) was added SOCl2 (0.8 mL, 11.1 mmol). The mixture was stirred at 90° C. for 1 hr and concentrated under reduced pressure. This crude product was dissolved into toluene (20 ml), and 4-cyclohexylmethoxy-phenylamine (0.91 g, 4.43 mmol) and ethyl-diisopropyl-amine (0.85 mL, 4.87 mmol) were added at room temperature. The reaction mixture was stirred at room temperature for 1 hr. The reaction mixture was quenched with water and diluted with EtOAc. The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel, eluting with ethyl acetate-hexanes (3:7) to afford 2-bromo-2-(4-tert-butyl-phenyl)-N-(4-cyclohexylmethoxy-phenyl)-acetamide as a brown oil (1.2 g, 59%): 1H NMR (300 MHz, DMSO-d6): δ 10.35 (s, 1H) 7.49 (m, 6H), 6.87 (d, J=9.3 Hz, 2H), 5.74 (s, 1H), 3.75 (d, J=6.3 Hz, 2H), 1.69 (m, 6H), 1.27 (m, 12H), 1.09 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([NH:8][CH:9]=[O:10])=[C:6](Cl)[N:5]=[CH:4][N:3]=1.[NH2:12][O:13][CH2:14][CH2:15][CH2:16][P:17](=[O:24])([O:21][CH2:22][CH3:23])[O:18][CH2:19][CH3:20].C(N(CC)CC)C>O1CCOCC1>[Cl:1][C:2]1[C:7]([NH:8][CH:9]=[O:10])=[C:6]([NH:12][O:13][CH2:14][CH2:15][CH2:16][P:17]([O:18][CH2:19][CH3:20])([O:21][CH2:22][CH3:23])=[O:24])[N:5]=[CH:4][N:3]=1
Reactant: O=CNc1c(Cl)ncnc1Cl
Reactant: CCOP(=O)(CCCON)OCC
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CCOP(=O)(CCCONc1ncnc(Cl)c1NC=O)OCC
Temperature: 100 °C
Yield: 82.2 %

Procedure:
A mixture of 4,6-dichloro-5-formamidopyrimidine (2.82 g, 14.6 mmol), diethyl 3-(aminooxy)propylphosphonate (3.1 g, 14.6 mmol) and triethylamine (3.1 ml, 22.3 mmol) in dioxan (40 ml) was heated at 100° C. for 4 hours. The solution was cooled to ambient temperature, filtered, and the filtrate evaporated to give a yellow oil. The oil was purified by column chromatography on silica gel (eluting with chloroform: methanol 97:3) to give the title compound as a yellow oil (4.4 g, 74%). 1H NMR: δH (CDCl3) 1.3 (6H, t, J=7Hz, (OCH2CH3)2), 1.6-2.5 (4H, m, CH2CH2P), 3.9-4.5 (6H, m, N--OCH2, (OCH2CH3)2), 7.3-9.3 (3H, broad, --NHCHO, --NH--OCH2).
Reaction SMILES: [C:1]([O-:4])(=[O:3])[CH3:2].[NH4+:5].[C:6]([OH:9])(=O)[CH3:7]>>[C:1]([O-:4])(=[O:3])[CH3:2].[NH4+:5].[O:9]1[CH:6]=[CH:7][N:5]=[CH:1]1
Reactant: CC(=O)O
Agent: CC(=O)[O-]
Agent: [NH4+]
Product: c1cocn1

Procedure:
An alternative synthetic route to oxazole tailpiece is shown in Reaction Scheme 24. Carboxylic acid (106) is condensed with 2-bromo-3-oxopentanoate (preferably methyl ester) (107) to give ketoester (108). The latter is converted to an intermediate enamine (109) by treatment with anhydrous ammonium acetate. Subsequent cyclization of compound (109) in acetic acid in the presence of anhydrous ammonium acetate gives compound (110). The use of anhydrous ammonium acetate obtained by azeotropic evaporation with ethanol eliminates water in the reaction, which causes decarboxylation of compound (110). Additionally, some of the water liberated in the reaction is removed at the enamine stage. These modifications along with a simplified isolation procedure lead to higher yields of oxazole (110).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][NH2:8])=[CH:5][CH:4]=1>O1CCCC1>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][N:8]=[CH:5][CH:6]([CH3:9])[CH3:7])=[CH:5][CH:4]=1
Reactant: COc1ccc(CN)cc1
Solvent: C1CCOC1
Product: COc1ccc(CN=CC(C)C)cc1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
Isobutylaldehyde (2.8 ml) was dissolved in tetrahydrofuran (10 ml), and the solution was added with 4-methoxybenzylamine (1 ml) and then stirred at 60° C. for 2 hours. The imine generation was observed by 1H-NMR, and then the reaction mixture was concentrated under reduced pressure to obtain crude (4-methoxybenzyl)-N-(2-methylpropylidene)amine.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[O:12][C@H:13]([CH2:15][CH3:16])[CH3:14])[C:6]([OH:8])=O.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.CC(C)CC1C=CC(C2O[N:45]=[C:44]([C:47]3[CH:52]=[CH:51][C:50]([CH2:53][OH:54])=[CH:49][CH:48]=3)[N:43]=2)=CC=1>CN(C=O)C>[CH3:14][C@H:13]([O:12][C:11]1[CH:10]=[CH:9][C:5]([C:6]2[O:8][N:45]=[C:44]([C:47]3[CH:52]=[CH:51][C:50]([CH2:53][OH:54])=[CH:49][CH:48]=3)[N:43]=2)=[CH:4][C:3]=1[C:2]([F:1])([F:18])[F:17])[CH2:15][CH3:16]
Reactant: CC[C@H](C)Oc1ccc(C(=O)O)cc1C(F)(F)F
Reactant: CC(C)Cc1ccc(-c2nc(-c3ccc(CO)cc3)no2)cc1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CC[C@H](C)Oc1ccc(-c2nc(-c3ccc(CO)cc3)no2)cc1C(F)(F)F
Temperature: 80 °C
Yield: 59.1 %

Procedure:
A solution of 600 mg (2.2 mmol) of 3-trifluoromethyl-4-(2-(S)-methylpropyloxy)benzoic acid (from Step B), 542 mg (2.2 mmol) of EDC and 357 mg (2.2 mmol) of HOBT in 6 mL of DMF were stirred at rt for 1 h. The reaction was subsequently treated with 350 mg (2.2 mmol) of N-hydroxy-4-(hydroxymethyl)benzamidine (from Aldehyde 1, Step A) and heated to 80° C. for 12 h. The reaction mixture was cooled and purified via chromatography on a Biotage 40M cartridge using 2:1 v/v hexanes/EtOAc as the eluant affording 510 mg of the title compound: 1H NMR (500 MHz) δ 1.01 (t, J=7.3, 3H), 1.38 (d, J=5.9, 3H), 1.73–1.83 (m, 2H), 4.55 (septet, 1H), 4.79 (s, 2H), 7.12 (d, J=8.9, 1H), 7.51 (d, J=8.2, 2H), 8.15 (d, J=8.2, 2H), 8.30 (d, J=8.9, 1H), 8.43 (s, 1H).
Reaction SMILES: [O:1]1[CH:5]=[C:4]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[S:12](Cl)(=[O:14])=[O:13])[CH:3]=[N:2]1.[OH-].[NH4+:17]>O1CCCC1>[O:1]1[CH:5]=[C:4]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[S:12]([NH2:17])(=[O:14])=[O:13])[CH:3]=[N:2]1
Reactant: [NH4+]
Reactant: O=S(=O)(Cl)c1ccccc1-c1cnoc1
Agent: [OH-]
Solvent: C1CCOC1
Product: NS(=O)(=O)c1ccccc1-c1cnoc1

Procedure:
By the procedure of Example 5, 15 g of 2-(isoxazol-4-yl)benzensulfonyl chloride prepared in Example 12 was reacted with 30 ml of concentrated ammonium hydroxide in 150 ml of tetrahydrofuran to give, after recrystallization from 2-propanol, 11 g of the title compound; m.p. 165°-167° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2([CH2:16][CH2:17][CH3:18])[CH2:14][CH2:13][CH2:12][CH2:11][C:10]2=[O:15])[CH:6]=[CH:7][CH:8]=1.[Br:19]Br>C(Cl)(Cl)Cl>[Br:19][CH:11]1[C:10](=[O:15])[C:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=2)([CH2:16][CH2:17][CH3:18])[CH2:14][CH2:13][CH2:12]1
Reactant: CCCC1(c2cccc(OC)c2)CCCCC1=O
Reactant: BrBr
Solvent: ClC(Cl)Cl
Product: CCCC1(c2cccc(OC)c2)CCCC(Br)C1=O
Temperature: 50 °C
Reaction time: 1 h
Yield: 94.5 %

Procedure:
2-(3-Methoxy-phenyl)-2-propyl-cyclohexanone (100 mg, 0.41 mmol) was dissolved in chloroform (1 mL). To this solution bromine (68.1 mg, 0.43 mmol) in chloroform (0.5 mL) was added drop wise at −11° C. The reaction was stirred at 5° C. for 1½ hours, at room temperature for 1 hour and at 50° C. for 1 hour. The solvent was removed under reduced pressure to yield the crude title compound (126 mg) which was used directly in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([S:14](Cl)(=[O:16])=[O:15])[CH:11]=[CH:12][CH:13]=2)=[CH:4][CH:3]=1.[NH2:18][C:19]1[CH:27]=[C:23]([C:24]([OH:26])=[O:25])[C:22]([OH:28])=[CH:21][CH:20]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([S:14]([NH:18][C:19]3[CH:20]=[CH:21][C:22]([OH:28])=[C:23]([CH:27]=3)[C:24]([OH:26])=[O:25])(=[O:16])=[O:15])[CH:9]=2)=[CH:4][CH:3]=1
Reactant: Nc1ccc(O)c(C(=O)O)c1
Reactant: O=S(=O)(Cl)c1cccc(-c2ccc(Cl)cc2)c1
Product: O=C(O)c1cc(NS(=O)(=O)c2cccc(-c3ccc(Cl)cc3)c2)ccc1O
Yield: 33 %

Procedure:
The product was prepared according to General Procedure 1, described in Example 1, with [[3-(4-chlorophenyl)phenyl]sulfonyl chloride (16 mg, 0.055 mmol) and 5-aminosalicylic acid (7.7 mg, 0.050 mmol) using a modified reaction temperature of 60° C. The title compound was obtained in 33% yield (6.7 mg). MS (ESI+) calcd mass for C19H14ClNO5S 403.028121, found 403.028561.
Reaction SMILES: [O:1]=[S:2]1(=[O:30])[C:8]2[CH:9]=[C:10]([O:13]C)[CH:11]=[CH:12][C:7]=2[N:6]([C:15]2[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][CH:16]=2)[CH2:5][C:4]([CH2:26][CH2:27][CH2:28][CH3:29])([CH2:22][CH2:23][CH2:24][CH3:25])[CH2:3]1.C[S-].[Na+].C(O)(=O)C.O>CN(C=O)C>[O:30]=[S:2]1(=[O:1])[C:8]2[CH:9]=[C:10]([OH:13])[CH:11]=[CH:12][C:7]=2[N:6]([C:15]2[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][CH:16]=2)[CH2:5][C:4]([CH2:26][CH2:27][CH2:28][CH3:29])([CH2:22][CH2:23][CH2:24][CH3:25])[CH2:3]1
Reactant: CCCCC1(CCCC)CN(c2ccc(N)cc2)c2ccc(OC)cc2S(=O)(=O)C1
Agent: C[S-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Solvent: O
Product: CCCCC1(CCCC)CN(c2ccc(N)cc2)c2ccc(O)cc2S(=O)(=O)C1
Yield: 67.6 %

Procedure:
1,1-Dioxo-3,3-dibutyl-5-(4-aminophenyl)-8-methoxy-2,3,4,5-tetrahydro-1,5-benzothiazepine (Method 105; 918 mg, 2.13 mmol) was dissolved in DMF (dry, 20 ml). Sodium thiomethoxide (810 mg, 11.6 mmol) was added. The reaction mixture was treated at 100–120° C. for four hours then room temperature overnight. Acetic acid (3 ml) was added and the mixture was flushed with nitrogen (g) and the gas was lead through a flask containing sodium hypochlorite in order to destroy the methyl mercaptan formed. Water was added and the water layer was extracted two times with EtOAc. The combined organic layer was washed with brine, dried, filtered and evaporated under reduced pressure. The mixture contained DMF so toluene and brine was added (everything didn't dissolved). The water layer was extracted two times with toluene. The combined organic layers were washed once with brine. The separation funnel was washed with EtOAc in order to dissolve everything. The toluene and EtOAc solutions were combined, dried, filtered and evaporated under reduced pressure. The residue was purified by flash chromatography using DCM:EtOAc, 7:3 as eluent to give the title compound 0.6 g (27%). M/z 417.4.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:12](Br)=[CH:11][C:10]=1[C:24]([N:26]1[CH2:34][C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH2:27]1)=[O:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:35][C:36]([F:41])([F:40])C([O-])=O.[Na+]>[Cu]I>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:12]([C:36]([F:41])([F:40])[F:35])=[CH:11][C:10]=1[C:24]([N:26]1[CH2:34][C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH2:27]1)=[O:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C([O-])C(F)(F)F
Reactant: O=C(c1cc(Br)c(OCc2ccccc2)cc1OCc1ccccc1)N1Cc2ccccc2C1
Agent: [Cu]I
Agent: [Na+]
Product: O=C(c1cc(C(F)(F)F)c(OCc2ccccc2)cc1OCc1ccccc1)N1Cc2ccccc2C1
Temperature: 150 °C
Yield: 29.3 %

Procedure:
A mixture of (2,4-bis-benzyloxy-5-bromo-phenyl)-(1,3-dihydro-isoindol-2-yl)-methanone (491 mg, 0.95 mmol), sodium trifluoroacetate (649 mg, 4.8 mmol) and copper (I) iodide (364 mg, 1.91 mmol) were dried under vacuum (0.04 mbar) for 6 hours. The flask was flushed with nitrogen, DMF (5 mL) was added and the mixture heated at 150° C. for 17 hours. After cooling to r.t., the mixture was diluted with DCM (100 mL) and filtered through Celite, rinsing with DCM. The filtrate was concentrated to dryness and the residue was partially purified by flash chromatography on silica (ethyl acetate/petrol gradient, 0-20%). The purest fraction was recrystallised from methanol to afford the title compound as a white solid (140 mg, 29%). 1H NMR (methanol-d4) 7.60 (1H, s), 7.48-7.44 (2H, m), 7.40 (2H, t), 7.37-7.21 (m, 9H), 7.17 (1H, d), 7.02 (1H, s), 5.29 (2H, s), 5.24 (2H, s), 4.88 (2H, s), 4.62 (2H, s). MS: [M+H]+ 504.
Reaction SMILES: [Si]([O:18][C:19]1[CH:62]=[CH:61][C:22]([O:23][CH2:24][C@@H:25]([OH:60])[CH2:26][NH:27][CH2:28][CH2:29][C:30]2[CH:59]=[CH:58][C:33]([NH:34][CH:35]3[CH2:40][CH2:39][N:38]([C:41]([NH:43][CH2:44][CH:45]([C:52]4[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=4)[C:46]4[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=4)=[O:42])[CH2:37][CH2:36]3)=[CH:32][CH:31]=2)=[CH:21][CH:20]=1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1>C(Cl)(Cl)Cl.CO>[C:46]1([CH:45]([C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=2)[CH2:44][NH:43][C:41]([N:38]2[CH2:39][CH2:40][CH:35]([NH:34][C:33]3[CH:58]=[CH:59][C:30]([CH2:29][CH2:28][NH:27][CH2:26][C@H:25]([OH:60])[CH2:24][O:23][C:22]4[CH:61]=[CH:62][C:19]([OH:18])=[CH:20][CH:21]=4)=[CH:31][CH:32]=3)[CH2:36][CH2:37]2)=[O:42])[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=1
Reactant: CC(C)(C)[Si](Oc1ccc(OC[C@@H](O)CNCCc2ccc(NC3CCN(C(=O)NCC(c4ccccc4)c4ccccc4)CC3)cc2)cc1)(c1ccccc1)c1ccccc1
Solvent: CO
Solvent: ClC(Cl)Cl
Product: O=C(NCC(c1ccccc1)c1ccccc1)N1CCC(Nc2ccc(CCNC[C@H](O)COc3ccc(O)cc3)cc2)CC1
Yield: 63.6 %

Procedure:
4-[4-(2-{[(2S)-3-(4-{[tert-Butyl(diphenyl)silyl]oxy}phenoxy)-2-hydroxypropyl]amino}ethyl)anilino]-N-(2,2-diphenylethyl)-1-piperidinecarboxamide (0.20 g, 0.236 mmol) was reacted according to Procedure H (eluant: 5:1 chloroform-methanol containing 1% ammonium hydroxide) to give the title compound (0.095 g, 0.15 mmol)
Reaction SMILES: C[O:2][C:3](=[O:39])[C@@H:4]([NH:14][C:15]([C:17]1[S:18][C:19]([C:28](=[O:38])[NH:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([OH:37])[CH:32]=2)=[CH:20][C:21]=1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:16])[CH2:5][NH:6][C:7]([C:9]1[S:10][CH:11]=[CH:12][CH:13]=1)=[O:8].O.[OH-].[Li+].Cl>C1COCC1.O>[OH:37][C:33]1[CH:32]=[C:31]([CH:36]=[CH:35][CH:34]=1)[CH2:30][NH:29][C:28]([C:19]1[S:18][C:17]([C:15]([NH:14][C@@H:4]([CH2:5][NH:6][C:7]([C:9]2[S:10][CH:11]=[CH:12][CH:13]=2)=[O:8])[C:3]([OH:39])=[O:2])=[O:16])=[C:21]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:20]=1)=[O:38]
Reactant: COC(=O)[C@H](CNC(=O)c1cccs1)NC(=O)c1sc(C(=O)NCc2cccc(O)c2)cc1-c1ccccc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(NC[C@H](NC(=O)c1sc(C(=O)NCc2cccc(O)c2)cc1-c1ccccc1)C(=O)O)c1cccs1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of (S)-2-{[5-(3-Hydroxy-benzylcarbamoyl)-3-phenyl-thiophene-2-carbonyl]-amino}-3-[(thiophene-2-carbonyl)-amino]-propionic acid methyl ester (40 mg, 0.07 mmol) in THF (2 mL) was added a solution of lithium hydroxide monohydrate (30 mg, 0.71 mmol) in water (3 mL). The mixture was then stirred at room temperature 4 h. The mixture was then acidified with 1N HCl and extracted with EtOAc (×3). The extracts were combined, washed with water and brine, dried over sodium sulfate, filtered, and evaporated to pure product, 20.9 mg (68%). MS m/e 549.1 (M+H+).
Reaction SMILES: [CH:1]([N:4]1[C:8](=[O:9])[C:7]2=[CH:10][C:11]([N+:14]([O-])=O)=[CH:12][CH:13]=[C:6]2[C:5]1=[O:17])([CH3:3])[CH3:2]>C1COCC1.CN(C=O)C.[Pd]>[CH:1]([N:4]1[C:8](=[O:9])[C:7]2=[CH:10][C:11]([NH2:14])=[CH:12][CH:13]=[C:6]2[C:5]1=[O:17])([CH3:3])[CH3:2]
Reactant: CC(C)N1C(=O)c2ccc([N+](=O)[O-])cc2C1=O
Agent: [Pd]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CC(C)N1C(=O)c2ccc(N)cc2C1=O
Yield: 99.1 %

Procedure:
N-Isopropyl-4-nitrophthalimide (10.0 g, 43.0 mmol) was dissolved in a mixture of THF (200 mL) and DMF (100 mL). 10% Palladium catalyst on carbon (1,0 g, 50% wet weight) was added and the mixture was hydrogenated in a low-pressure apparatus (1 atm.) overnight. The catalyst was then removed by filtering the mixture through a short pad of celite. The filtrate was evaporated to dryness to afford a quantitative yield (8.70 g) of pure N-isopropyl-4-aminophthalimide.