Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH2:11][C:12](O)=O)[C:2]([CH3:4])=[O:3].[NH2:15][C:16]1[C:17](=[O:38])[N:18]([CH2:35][CH2:36][CH3:37])[C:19](=[O:34])[N:20]([CH2:23][CH2:24][C:25]2[CH:30]=[CH:29][C:28]([N+:31]([O-:33])=[O:32])=[CH:27][CH:26]=2)[C:21]=1[NH2:22]>>[NH:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH2:11][C:12]1[NH:15][C:16]2[C:17](=[O:38])[N:18]([CH2:35][CH2:36][CH3:37])[C:19](=[O:34])[N:20]([CH2:23][CH2:24][C:25]3[CH:30]=[CH:29][C:28]([N+:31]([O-:33])=[O:32])=[CH:27][CH:26]=3)[C:21]=2[N:22]=1)[C:2]([CH3:4])=[O:3]
Reactant: CCCn1c(=O)c(N)c(N)n(CCc2ccc([N+](=O)[O-])cc2)c1=O
Reactant: CC(=O)Nc1ccccc1CC(=O)O
Product: CCCn1c(=O)c2[nH]c(Cc3ccccc3NC(C)=O)nc2n(CCc2ccc([N+](=O)[O-])cc2)c1=O

Procedure:
By the method of Example 2, 2-(acetamino)phenylacetic acid is reacted with 5,6-diamino-1-[2-(4-nitrophenyl)ethyl]-3-propyluracil (6) to yield 8-(2-acetaminobenzyl)-3-[2-(4-nitrophenyl)ethyl]-1-propylxanthine. By methods well known in the art, 8-(2-acetaminobenzyl)-3-[2-(4-nitrophenyl)ethyl]-1-propylxanthine is reduced with hydrazine hydrate or hydrogen gas in the presence of a palladium catalyst to yield 8-(2-acetaminobenzyl)-3-[2-(4-aminophenyl)ethyl]-1-propylxanthine.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][CH2:8][NH:9]2)=[CH:5][CH:4]=1.[S-:14][C:15]#[N:16].[K+].BrBr>CO>[S:14]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][C:3]=1[C:2]([F:1])([F:12])[F:13])[NH:9][CH2:8][CH2:7]2)[C:15]#[N:16]
Reactant: N#C[S-]
Reactant: FC(F)(F)c1ccc2c(c1)NCC2
Agent: BrBr
Agent: [K+]
Solvent: CO
Product: N#CSc1cc2c(cc1C(F)(F)F)NCC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.7 %

Procedure:
A mixture of 6-trifluoromethylindoline (D1) (9.7 g, 52 mmol) and potassium thiocyanate (10.09 g, 104 mmol) in methanol (200 ml) was treated with a solution of bromine (2.82 ml, 55 mmol) in methanol (35 ml) dropwise over 0.5 h at −5-0° C. The reaction mixture was allowed to warm to room temperature and stirred overnight then evaporated to dryness. The residue was partitioned between aqueous K2CO3 (100 ml) and dichloromethane (3×100 ml). The combined extracts were dried (Na2SO4) and evaporated and the residue chromatographed, on silica using 2-30% ethyl acetate/petroleum ether as eluant to afford the title compound (9.1 g, 72%) as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[C:13]([C:19](=[O:29])[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[N+:26]([O-])=O)=[N:14][CH:15]=[C:16]([Cl:18])[CH:17]=2)(=[O:10])=[O:9])=[CH:4][C:3]=1[C:30]([F:33])([F:32])[F:31]>C(O)(=O)C.CCOC(C)=O.[Fe]>[NH2:26][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[C:19]([C:13]1[C:12]([NH:11][S:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([C:30]([F:33])([F:32])[F:31])[CH:4]=2)(=[O:10])=[O:9])=[CH:17][C:16]([Cl:18])=[CH:15][N:14]=1)=[O:29]
Reactant: O=C(c1ccccc1[N+](=O)[O-])c1ncc(Cl)cc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Agent: [Fe]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: Nc1ccccc1C(=O)c1ncc(Cl)cc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred suspension of Fe (176 mg, 3.15 mmol) in glacial acetic acid (5 mL) was added a solution 4-chloro-N-[5-chloro-2-(2-nitro-benzoyl)-pyridin-3-yl]-3-trifluoromethyl-benzenesulfonamide (410 mg, 0.788 mmol) in AcOH (5 mL) at 80° C. for 15 minutes. After complete addition the mixture was stirred at the same temperature for 30 minutes and the progress of the reaction was followed by LCMS. The reaction mixture was then cooled to room temperature and it was then diluted with EtOAc and filtered through a pad of Celite. The filtrate was concentrated under reduced pressure and residue was portioned between NaHCO3 and EtOAc. The organic portion was separated and the aqueous portion was extracted with EtOAc. The combined extracts were dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel to provide N-[2-(2-amino-benzoyl)-5-chloro-pyridin-3-yl]-4-chloro-3-trifluoromethyl-benzenesulfonamide. 1H NMR (400 MHz, CDCl3) δ 8.98 (s, 1 H), 8.42 (d, J=2.4 Hz, 1 H), 8.12 (d, J=2.0 Hz, 1 H), 7.93 (d, J=2.4 Hz, 1H), 7.64-7.61 (m, 1 H), 7.30-7.26 (m, 2 H), 7.03-7.00 (m, 1 H), 6.64 (d, J=8.4 Hz, 1 H), 6.47-6.43 (m, 1 H), 6.26 (s, 2H); Mass spectrum m/z: 490.0 (M+H).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([N:8]2[C:12]3[CH:13]=[CH:14][C:15]([C:17]#[N:18])=[CH:16][C:11]=3[N:10]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([Cl:28])[CH:21]=3)[C:9]2=[O:29])[CH2:4][CH2:3]1.[S:30](N)([NH2:33])(=[O:32])=[O:31]>COCCOC>[NH2:33][S:30]([NH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([N:8]2[C:12]3[CH:13]=[CH:14][C:15]([C:17]#[N:18])=[CH:16][C:11]=3[N:10]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([Cl:28])[CH:21]=3)[C:9]2=[O:29])[CH2:4][CH2:3]1)(=[O:32])=[O:31]
Reactant: NS(N)(=O)=O
Reactant: COc1ccc(Cn2c(=O)n([C@H]3CC[C@H](N)CC3)c3ccc(C#N)cc32)cc1Cl
Solvent: COCCOC
Product: COc1ccc(Cn2c(=O)n([C@H]3CC[C@H](NS(N)(=O)=O)CC3)c3ccc(C#N)cc32)cc1Cl

Procedure:
A mixture of 1-(trans-4-aminocyclohexyl)-3-(3-chloro-4-methoxybenzyl)-5-cyano-2,3-dihydro-1H-benzimidazol-2-one (90 mg) and sulfamide (42 mg) in ethylene glycol dimethyl ether (3 mL) was refluxed overnight. The mixture was concentrated in vacuo, and the residue was partitioned between chloroform and water. The separated organic layer was washed with an aqueous saturated sodium chloride solution, dried over magnesium sulfate, and concentrated in vacuo. The residue was subjected to a preparative thin-layer chromatography eluting with a mixture of chloroform and methanol (10:1). The obtained crystals were collected by filtration and washed with diethyl ether to give 1-(trans-4-aminosulfonamidocyclohexyl)-3-(3-chloro-4-methoxybenzyl)-5-cyano-2,3-dihydro-1H-benzimidazol-2-one (41 mg) as powders.
Reaction SMILES: O[Li].O.[CH2:4]([O:11][C:12]1[C:17](=[O:18])[N:16]([CH3:19])[C:15](SC)=[N:14][C:13]=1[C:22]([O:24]CC)=[O:23])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[CH3:27][CH2:28][OH:29]>>[CH2:4]([O:11][C:12]1[C:17](=[O:18])[N:16]([CH3:19])[C:15]([O:29][CH2:28][CH3:27])=[N:14][C:13]=1[C:22]([OH:24])=[O:23])[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: CCOC(=O)c1nc(SC)n(C)c(=O)c1OCc1ccccc1
Reactant: CCO
Agent: [Li]O
Solvent: O
Product: CCOc1nc(C(=O)O)c(OCc2ccccc2)c(=O)n1C
Temperature: 25 °C
Reaction time: 5 h
Yield: 99 %

Procedure:
To a stirred solution of LiOH.H2O (1.26 g, 30 mmol) in EtOH (100 mL) at 40° C. was added ethyl 5-(benzyloxy)-1-methyl-2-(methylthio)-6-oxo-1,6-dihydropyrimidine-4-carboxylate (prepared according to the procedure in WO2004062613) (6.7 g, 20 mmol). The resulting reaction mixture was stirred at room temperature for 5 h then concentrated. The residue was taken up in aq. HCl (50 mL) and extracted with EtOAc (2×100 mL). The combined organic fractions were dried (Na2SO4), filtered and concentrated to give the desired product (6 g, 99% yield) as off-white solid which was used in the next step without purification.
Reaction SMILES: [C:1]([C:5]1[CH:14]=[C:13]2[C:8]([C:9](C)=[C:10]([CH2:15][N:16]3[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)[CH2:11][CH2:12]2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl.N1CCCCC1.C(C1C=C2C(=CC=1)C(=[O:44])CCC2)(C)(C)C.C=O>C(O)C.Cl>[C:1]([C:5]1[CH:14]=[C:13]2[C:8](=[CH:7][CH:6]=1)[C:9](=[O:44])[CH:10]([CH2:15][N:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1)[CH2:11][CH2:12]2)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccc2c(c1)CCCC2=O
Reactant: CC1=C(CN2CCCCC2)CCc2cc(C(C)(C)C)ccc21
Agent: C=O
Agent: Cl
Solvent: CCO
Solvent: C1CCNCC1
Product: CC(C)(C)c1ccc2c(c1)CCC(CN1CCCCC1)C2=O
Yield: 83 %

Procedure:
This Example illustrates the preparation of 7-tert-butyl-4-methyl-3-piperidinomethyl,1,2-dihydronaphthalene (Compound number 3 of Table I). Piperidine hydrochloride (12.6 g 0.103 mol), 6-tert-butyl-1,2,3,4-tetrahydronaphthalen-1-one (80.0 g, 0.04 mol) and paraformaldehyde (2.64 g, 0.088 mol) were refluxed in ethanol (200 ml) with concentrated hydrochloric acid (1 ml) as a catalyst for 48 hours. The reaction mixture was concentrated under reduced pressure and the residue dissolved in water then extracted with diethyl ether. The resulting aqueous solution was neutralized with sodium bicarbonate and extracted with diethyl ether (2×200 ml); the ethereal extracts were dried over magnesium sulphate and concentrated under reduced pressure to give 6-tert-butyl-2-piperidinomethyl-1,2,3,4-tetrahydronaphthalen-1-one (10.0 g 83% yield) melting at 47°-9°.
Reaction SMILES: C([Al:5]([CH2:10][CH:11]([CH3:13])[CH3:12])[CH2:6][CH:7]([CH3:9])[CH3:8])C(C)C.[C:14]1([OH:20])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C1(C)C=CC=CC=1>[O:20]([Al:5]([CH2:6][CH:7]([CH3:8])[CH3:9])[CH2:10][CH:11]([CH3:12])[CH3:13])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: Oc1ccccc1
Reactant: CC(C)C[Al](CC(C)C)CC(C)C
Solvent: Cc1ccccc1
Product: CC(C)C[Al](CC(C)C)Oc1ccccc1

Procedure:
In a manner analogous to that described in Example 1, triisobutylaluminum and phenol are reacted in absolute toluene to give phenoxy-diisobutylaluminum and this is then reacted with pyridine-N-oxide-2-thiol to give the title compound. The isolation of the product is carried out in an analogous manner. The yield of phenoxy-bis(2-pyridinethiolato)aluminum N,N'-dioxide, a white solid, is 98% of theory. Melting point: 240°-241° C. (with decomposition).
Reaction SMILES: C[N:2](C)[CH:3]=[CH:4][C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[N:8]=1)=O.[C:23]1([NH:29]N)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>CO>[CH3:21][O:20][C:17]1[CH:18]=[CH:19][C:14]([N:9]2[CH:10]=[CH:11][C:12](=[O:13])[C:7]([C:5]3[N:29]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[N:2]=[CH:3][CH:4]=3)=[N:8]2)=[CH:15][CH:16]=1
Reactant: NNc1ccccc1
Reactant: COc1ccc(-n2ccc(=O)c(C(=O)C=CN(C)C)n2)cc1
Solvent: CO
Product: COc1ccc(-n2ccc(=O)c(-c3ccnn3-c3ccccc3)n2)cc1
Yield: 17 %

Procedure:
To a solution of 3-[3-(dimethylamino)prop-2-enoyl]-1-(4-methoxyphenyl)pyridazin-4(1H)-one (crude 640 mg, 2.14 mmol) in 20 mL of methanol was added phenylhydrazine (347 mg, 3.21 mmol). The mixture was refluxed for 4 h and concentrated. The residue was dissolved in dichloromethane (20 mL), washed with 1N HCl aqueous solution and brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by prep-HPLC to give 1-(4-methoxyphenyl)-3-(1-phenyl-1H-pyrazol-5-yl)pyridazin-4(1H)-one (127 mg, 17% for two steps) as a yellow solid.
Reaction SMILES: [C:1]([NH:7][C:8]1[S:9][CH:10]=[C:11]([CH2:13]Cl)[N:12]=1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[NH:15]1[CH2:20][CH2:19][CH:18]([C:21]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[NH:23][CH:22]=2)[CH2:17][CH2:16]1.C(=O)([O-])O.[Na+].[I-].[Na+]>CN(C)C=O>[NH:23]1[C:24]2[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:21]([CH:18]2[CH2:19][CH2:20][N:15]([CH2:13][C:11]3[N:12]=[C:8]([NH:7][C:1](=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3])[S:9][CH:10]=3)[CH2:16][CH2:17]2)=[CH:22]1
Reactant: CC(C)(C)C(=O)Nc1nc(CCl)cs1
Reactant: c1ccc2c(C3CCNCC3)c[nH]c2c1
Agent: O=C([O-])O
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)C(=O)Nc1nc(CN2CCC(c3c[nH]c4ccccc34)CC2)cs1
Yield: 41.6 %

Procedure:
A mixture of 2-pivaloylamino-4-chloromethylthiazole (0.42 g), 3-(4-piperidyl)indole (0.34 g), sodium hydrogen carbonate (0.23 g), N,N-dimethylformamide (4.2 ml) and a trace amount of sodium iodide was stirred at 50° C. for 2 hours. The insoluble material was filtered off and the filtrate was washed with a mixture of chloroform and methanol (10:1 V/V). The washings and the filtrate were combined and concentrated under reduced pressure. The residue was subjected to column chromatography on silica gel and recrystallized from ethanol to give 4-[4-(3-indolyl)piperidinomethyl]-2-pivaloylaminothiazole (280 mg).
Reaction SMILES: [CH3:1][O:2][CH:3]([CH2:6][O:7][C:8]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH2:4][OH:5].C(N(CC)CC)C.[C:34]1([CH3:44])[CH:39]=[CH:38][C:37]([S:40](Cl)(=[O:42])=[O:41])=[CH:36][CH:35]=1.Cl>C(Cl)Cl>[CH3:1][O:2][CH:3]([CH2:4][O:5][S:40]([C:37]1[CH:38]=[CH:39][C:34]([CH3:44])=[CH:35][CH:36]=1)(=[O:42])=[O:41])[CH2:6][O:7][C:8]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COC(CO)COC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(COC(c1ccccc1)(c1ccccc1)c1ccccc1)COS(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 17 h
Yield: 89.4 %

Procedure:
In 40 ml of methylene chloride were dissolved 3.484 g (10 mmole) of the alcohol derivative as synthesized in (i) and 3.036 g (30 mmole) of triethylamine, and 2.478 g (13 mmole) of p-toluenesulfonyl chloride was added to the solution under ice-cooling. The reaction solution was stirred at room temperature for 17 hours, treated with 1N hydrochloric acid and extracted with chloroform. The organic layer was dried over magnesium sulfate and the solvent was distilled off under reduced pressure. The resulting crude product was purified by column chromatography [silica gel: 170 g; eluent: n-hexane/ethyl acetate=5/1 to 3/1] to give 4.491 g (89.4%) of the objective compound as a colorless solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([NH2:16])[CH2:11][C:10]3([O:15][CH2:14][CH2:13][O:12]3)[CH2:9]2)=[CH:4][CH:3]=1.[O:17]=[C:18]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:20](=[O:27])N1C(OCC)=O>C(Cl)(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([N:16]3[C:18](=[O:17])[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[C:20]3=[O:27])[CH2:11][C:10]3([O:12][CH2:13][CH2:14][O:15]3)[CH2:9]2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)N1C(=O)c2ccccc2C1=O
Reactant: NC1(c2ccc(Br)cc2)CC2(C1)OCCO2
Solvent: ClC(Cl)Cl
Product: O=C1c2ccccc2C(=O)N1C1(c2ccc(Br)cc2)CC2(C1)OCCO2
Temperature: 70 °C
Reaction time: 8 h

Procedure:
A mixture of 2-(4-bromophenyl)-5,8-dioxaspiro[3.4]octan-2-amine (7-1) (2.7 g, 9.50 mmol), ethyl 1,3-dioxo-1,3-dihydro-2H-isoindole-2-carboxylate (4.2 g, 19.0 mmol), and TEA (5.3 mL, 38.0 mmol) in CHCl3 (50 mL) was stirred at 70° C. for overnight. The solvent was evaporated under reduced pressure, and to the residue was added MeOH. The resulting solid was collected by filtration to give 2-[2-(4-bromophenyl)-5,8-dioxaspiro[3.4]oct-2-yl]-1H-isoindole-1,3(2H)-dione (7-2) as a colorless solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11](=O)[CH3:12])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].Cl.[N+:15]([C:18]1[CH:26]=[CH:25][C:21]([CH2:22][O:23][NH2:24])=[CH:20][CH:19]=1)([O-:17])=[O:16]>>[N+:15]([C:18]1[CH:19]=[CH:20][C:21]([CH2:22][O:23]/[N:24]=[C:11](/[C:5]2[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=2)\[CH3:12])=[CH:25][CH:26]=1)([O-:17])=[O:16]
Reactant: COc1ccc(C(C)=O)cc1OC
Reactant: NOCc1ccc([N+](=O)[O-])cc1
Agent: Cl
Product: COc1ccc(/C(C)=N/OCc2ccc([N+](=O)[O-])cc2)cc1OC
Yield: 80.8 %

Procedure:
3′,4′-Dimethoxyacetophenone (23) (150 g, 0.832 mmol) was condensed with compound 19 (187 mg, 0.914 mmol) according to the general procedure II-A defined above. After being heated for 3 h the mixture was cooled and the resulting solid filtered off and washed with cold isopropanol (3.0 mL) to afford the title compound CP30257 (222 mg, 81%) as a white solid, m.p. 118.4-121.0° C.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:4]=[C:5]([C:9]2[C:13]([NH2:14])=[C:12]([C:15](O)=[O:16])[S:11][N:10]=2)[CH:6]=[CH:7][CH:8]=1.C(N1C=CN=C1)([N:22]1C=CN=C1)=O.[OH-].[NH4+]>CN(C=O)C>[F:1][C:2]([F:19])([F:18])[C:3]1[CH:4]=[C:5]([C:9]2[C:13]([NH2:14])=[C:12]([C:15]([NH2:22])=[O:16])[S:11][N:10]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: Nc1c(-c2cccc(C(F)(F)F)c2)nsc1C(=O)O
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: [NH4+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: NC(=O)c1snc(-c2cccc(C(F)(F)F)c2)c1N
Temperature: 0 °C
Reaction time: 2.25 h

Procedure:
One gram of 3-(3-trifluoromethylphenyl)-4-amino-5-isothiazolecarboxylic acid and 0.7 g. of carbonyldiimidazole were dissolved in 25 ml. of DMF at ambient temperature. The solution was stirred for 2.25 hours; 3 ml. of 14 N aqueous ammonium hydroxide were added and the resulting mixture stirred overnight at ambient temperature after which time it was poured into an ice-water mixture. 3-(3-Trifluoromethylphenyl)-4-amino-5-isothiazolecarboxamide formed in the above reaction precipitated and the precipitate was collected by filtration and was dried. 3-(3-Trifluoromethylphenyl)-4-amino-5-isothiazole carboxamide, thus prepared and purified, melted at about 124° C. after recrystallization from an ethyl acetate-hexane solvent mixture; yield 0.4 g.
Reaction SMILES: [Cl-:1].[CH2:2]([O:4][C:5](=[O:14])[CH2:6][C:7](=[O:13])[C:8]([CH3:12])([CH3:11])[CH:9]=[CH2:10])[CH3:3]>C(Cl)(Cl)Cl>[CH2:2]([O:4][C:5](=[O:14])[CH:6]([Cl:1])[C:7](=[O:13])[C:8]([CH3:12])([CH3:11])[CH:9]=[CH2:10])[CH3:3]
Reactant: [Cl-]
Reactant: C=CC(C)(C)C(=O)CC(=O)OCC
Solvent: ClC(Cl)Cl
Product: C=CC(C)(C)C(=O)C(Cl)C(=O)OCC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 92.6 %

Procedure:
Sulftiryl chloride (0.84 ml, 10.4 mmol) was added to a cooled (0°) solution of 4,4-dimethyl-3-oxo-hex-5-enoic acid ethyl ester (1.83 g, 9.93 mmol) in chloroform (7 ml). The resulting mixture was allowed to warm to room temperature and stir for 30 min, after which it was heated under reflux for 2 h. After cooling to room temperature the reaction mixture was diluted with chloroform, then was washed with sodium bicarbonate, water then brine. The organic phase was dried and evaporated to afford, as a brown oil, 2-chloro-4,4-dimethyl-3-oxo-hex-5-enoic acid ethyl ester (2.01 g, 93%). (Hayashi et al., J Org. Chem., 65:8402-8405 (2000).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]([O:14]CC)=[O:13])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[CH2:17]([O:20][C:21]1[C:26]([C:27]([CH3:30])([CH3:29])[CH3:28])=[CH:25][C:24]([C:31]([CH3:34])([CH3:33])[CH3:32])=[CH:23][C:22]=1B(O)O)[CH2:18][CH3:19]>>[C:27]([C:26]1[C:21]([O:20][CH2:17][CH2:18][CH3:19])=[C:22]([C:2]2[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[C:4]([CH:10]=[CH:11][C:12]([OH:14])=[O:13])[CH:3]=2)[CH:23]=[C:24]([C:31]([CH3:34])([CH3:33])[CH3:32])[CH:25]=1)([CH3:30])([CH3:28])[CH3:29]
Reactant: CCOC(=O)C=Cc1ccc(OC)c(Br)c1
Reactant: CCCOc1c(B(O)O)cc(C(C)(C)C)cc1C(C)(C)C
Product: CCCOc1c(-c2cc(C=CC(=O)O)ccc2OC)cc(C(C)(C)C)cc1C(C)(C)C
Yield: 80.8 %

Procedure:
In a manner similar to that of Example 1(c), by reaction of 1.0 g (3.5 mmol) of ethyl 3-(3-bromo-4-methoxyphenyl)acrylate obtained in Example 13(d) with 1.54 g (5.26 mmol) of 2-propyloxy-3,5-di-tert-butylphenylboronic acid obtained in Example 39(b), 1.20 g (76%) of the expected compound was obtained in the form of a white powder having a melting point of 107°-109° C.
Reaction SMILES: [NH2:1][C@H:2]([C:10]([NH:12][C:13]1[CH:21]=[CH:20][C:16]([N+:17]([O-:19])=[O:18])=[CH:15][CH:14]=1)=[O:11])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:9])[NH2:8].[BrH:22].Br.CCN(C(C)C)C(C)C.[NH:33]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:34][C:35](O)=[O:36]>CN(C=O)C>[NH:33]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:34][C:35]([NH:1][C@H:2]([C:10]([NH:12][C:13]1[CH:14]=[CH:15][C:16]([N+:17]([O-:19])=[O:18])=[CH:20][CH:21]=1)=[O:11])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:8])[NH2:9])=[O:36].[BrH:22]
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: N=C(N)NCCC[C@H](N)C(=O)Nc1ccc([N+](=O)[O-])cc1
Agent: Br
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NCC(=O)N[C@@H](CCCNC(=N)N)C(=O)Nc1ccc([N+](=O)[O-])cc1
Reaction time: 1 h
Yield: 75 %

Procedure:
1 g (2.19 mmol) of H-L-Arg-pNA.2HBr is dissolved in 10 ml of DMF, and 0.854 ml (6.57 mmol) of DIEA is then added. In another vessel, a solution of 384 mg (2.19 mmol) of Boc-Gly-OH in 5 ml of DMF is neutralized with 0.285 ml of DIEA. The two solutions obtained in this way are mixed and 970 mg of Bop are added to the resulting medium, the latter being kept at RT; also, the pH is kept at a value of between 7 and 8 by the addition of small portions of DIEA throughout the reaction. After one hour, the reaction has completely finished and the reaction medium is evaporated to dryness under vacuum; the evaporation residue is taken up with an AcOEt/MeOH mixture and extracted with a 0.5M aqueous solution of NaHCO3. The organic phase is dried over sodium sulfate, concentrated under vacuum and then precipitated in ether (MeOMe or EtOEt) to give 874 mg (yield: 75%) of the expected product.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](/[CH:9]=[CH:10]/[C:11]([N:13]2[CH2:19][CH2:18][C:17](=[O:20])[N:16]([CH2:21][CH:22]3[CH2:24][O:23]3)[CH2:15][CH2:14]2)=[O:12])[CH:5]=[CH:6][C:7]=1[F:8].[NH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1>>[F:1][C:2]1[CH:3]=[C:4](/[CH:9]=[CH:10]/[C:11]([N:13]2[CH2:19][CH2:18][C:17](=[O:20])[N:16]([CH2:21][CH:22]([OH:23])[CH2:24][N:25]3[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)[CH2:15][CH2:14]2)=[O:12])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: O=C(/C=C/c1ccc(F)c(F)c1)N1CCC(=O)N(CC2CO2)CC1
Reactant: C1CCNCC1
Product: O=C(/C=C/c1ccc(F)c(F)c1)N1CCC(=O)N(CC(O)CN2CCCCC2)CC1

Procedure:
In analogy to the procedure described for example 166B, (rac)-1-[(E)-3-(3,4-difluoro-phenyl)-acryloyl]-4-oxiranylmethyl-[1,4]diazepan-5-one and piperidine gave the title compound as light yellow viscous oil. MS: 422.2 (MH+).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:32][C:33]1[CH:34]=[C:35]([CH:39]=[CH:40][CH:41]=1)[C:36]([OH:38])=[O:37])[S:9]([C:12]1[CH:17]=[C:16]([C:18]([NH:20][N:21]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH2:23][CH:22]2[CH3:30])=[O:19])[CH:15]=[CH:14][C:13]=1[Cl:31])(=[O:11])=[O:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[CH2:43][O:44]/[N:45]=[N+:46](/[N:48]([CH2:51][CH3:52])[CH2:49][CH3:50])\[O-:47]>>[C:1]([O:5][C:6]([N:8]([CH2:32][C:33]1[CH:34]=[C:35]([CH:39]=[CH:40][CH:41]=1)[C:36]([O:38][CH2:43][O:44]/[N:45]=[N+:46](\[O-:47])/[N:48]([CH2:51][CH3:52])[CH2:49][CH3:50])=[O:37])[S:9]([C:12]1[CH:17]=[C:16]([C:18]([NH:20][N:21]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH2:23][CH:22]2[CH3:30])=[O:19])[CH:15]=[CH:14][C:13]=1[Cl:31])(=[O:10])=[O:11])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCN(CC)/[N+]([O-])=N/OCCl
Reactant: CC1Cc2ccccc2N1NC(=O)c1ccc(Cl)c(S(=O)(=O)N(Cc2cccc(C(=O)O)c2)C(=O)OC(C)(C)C)c1
Product: CCN(CC)/[N+]([O-])=N/OCOC(=O)c1cccc(CN(C(=O)OC(C)(C)C)S(=O)(=O)c2cc(C(=O)NN3c4ccccc4CC3C)ccc2Cl)c1

Procedure:
The product obtained in Step C of Example 1 is reacted with N—[(Z)-(chloromethoxy)-NNO-azoxy]-N-ethylethanamine in accordance with the process conditions described in Step D of Example 1. The title product is obtained in the form of a yellow solid after chromatography on a silica column using as eluant a 65/35 n-heptane/ethyl acetate mixture.