Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][C:11]1[S:15][C:14]2[CH:16]=[CH:17][CH:18]=[CH:19][C:13]=2[C:12]=1[C:20]#[N:21])([O-])=O.[Sn](Cl)[Cl:23].Cl>CCO>[ClH:23].[CH:16]1[C:14]2[S:15][C:11]3[NH:10][C:5]4[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=4[N:1]=[C:20]([NH2:21])[C:12]=3[C:13]=2[CH:19]=[CH:18][CH:17]=1
Reactant: N#Cc1c(Nc2ccccc2[N+](=O)[O-])sc2ccccc12
Reactant: Cl[Sn]Cl
Agent: Cl
Solvent: CCO
Product: NC1=Nc2ccccc2Nc2sc3ccccc3c21
Temperature: 25 °C
Yield: 90.6 %

Procedure:
By using a method similar to the method of Example 532, combine 2-(2-nitro-phenylamino)-benzo[b]thiophene-3-carbonitrile (5.0 g, 17.0 mmol) and Tin(II) chloride (9.65 g, 51.0 mmol) in a mixed solvent of EtOH (50 mL) and 5.0 N HCl (50 mL), heat the suspension to reflux for 3 hours, cool to RT. The title compound 4.65 g (yield 91%) is obtained as a yellow solid by suction filtration. Mass spectrum: ACPI (m/e): 266.0 ((M+1-HCl); 1H NMR (300 MHz, DMSO-d6) ppm: 11.7 (br, 1H), 10.00 (br, 1H), 9.10 (br, 2H), 7.90–7.85 (m, 1H), 7.72–7.65 (m, 1H), 7.48–7.38 (m, 1H), 7.35–7.28 (m, 1H), 7.22–6.98 (m, 4H).
Reaction SMILES: [CH3:1][N:2]1[C@:6]2([CH2:18][C:9]3=[N:10][CH:11]=[C:12]([C:14]([O:16]C)=[O:15])[CH:13]=[C:8]3[CH2:7]2)[C:5](=[O:19])[NH:4][C:3]1=[O:20].[OH-].[Li+].Cl>C1COCC1.O>[CH3:1][N:2]1[C@:6]2([CH2:18][C:9]3=[N:10][CH:11]=[C:12]([C:14]([OH:16])=[O:15])[CH:13]=[C:8]3[CH2:7]2)[C:5](=[O:19])[NH:4][C:3]1=[O:20]
Reactant: COC(=O)c1cnc2c(c1)C[C@@]1(C2)C(=O)NC(=O)N1C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CN1C(=O)NC(=O)[C@]12Cc1cc(C(=O)O)cnc1C2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of methyl (6R)-3′-methyl-2′,5′-dioxo-5,7-dihydrospiro[cyclopenta[b]pyridine-6,4′-imidazolidine]-3-carboxylate (450 mg, 1.64 mmol) in THF (8 mL) and H2O (2 mL) was added 1 N aqueous lithium hydroxide (1.96 mL, 1.96 mmol). The reaction was stirred at ambient temperature for 2 h, adjusted to pH≈4 by addition of 1 N hydrochloric acid, and concentrated in vacuo to provide the title compound. MS: m/z=262.1 (M+1). 1H NMR (500 MHz, CD3OD) δ 8.96 (s, 1H), 8.24 (s, 1H), 3.54 (d, 1H, J=18.1 Hz), 3.52 (d, 1H, J=17.3 Hz), 3.40 (d, 1H, J=17.3 Hz), 3.39 (d, 1H, J=18.1 Hz), 2.71 (s, 3H).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([CH:13]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([O:23][CH3:24])[CH:21]=3)[CH2:16][CH2:15][CH2:14]2)=[O:12])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].CS(O[CH2:30][CH2:31][CH2:32][CH2:33][C:34]1[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=1)(=O)=O>>[CH:1]([C:4]1[CH:5]=[CH:6][C:7]([N:10]([CH2:30][CH2:31][CH2:32][CH2:33][C:34]2[CH:35]=[CH:36][C:37]([O:40][CH3:41])=[CH:38][CH:39]=2)[C:11]([CH:13]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([O:23][CH3:24])[CH:21]=3)[CH2:16][CH2:15][CH2:14]2)=[O:12])=[CH:8][CH:9]=1)([CH3:3])[CH3:2]
Reactant: COc1ccc(CCCCOS(C)(=O)=O)cc1
Reactant: COc1ccc2c(c1)C(C(=O)Nc1ccc(C(C)C)cc1)CCC2
Product: COc1ccc(CCCCN(C(=O)C2CCCc3ccc(OC)cc32)c2ccc(C(C)C)cc2)cc1
Yield: 34 %

Procedure:
By the reaction and treatment in the same manner as in Example 6 using N-(4-isopropylphenyl)-7-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.49 g) and 1-methanesulfonyloxy-4-(4-methoxyphenyl)butane (0.43 g) as starting materials, N-(4-isopropylphenyl)-N-[4-(4-methoxyphenyl)butyl]-7-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.25 g) was obtained.
Reaction SMILES: C([O:8][C:9]1[C:14](=[O:15])[N:13]2[CH:16]=[C:17]([CH2:20][N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)[CH:18]=[CH:19][C:12]2=[N:11][C:10]=1[C:27]1[O:28][C:29]([CH2:32][C:33]2[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=2)=[N:30][N:31]=1)C1C=CC=CC=1.[Si](I)(C)(C)C.N#N.[OH-].[Na+]>C(#N)C.O.CO>[F:39][C:36]1[CH:37]=[CH:38][C:33]([CH2:32][C:29]2[O:28][C:27]([C:10]3[N:11]=[C:12]4[CH:19]=[CH:18][C:17]([CH2:20][N:21]5[CH2:22][CH2:23][O:24][CH2:25][CH2:26]5)=[CH:16][N:13]4[C:14](=[O:15])[C:9]=3[OH:8])=[N:31][N:30]=2)=[CH:34][CH:35]=1
Reactant: O=c1c(OCc2ccccc2)c(-c2nnc(Cc3ccc(F)cc3)o2)nc2ccc(CN3CCOCC3)cn12
Agent: C[Si](C)(C)I
Agent: N#N
Agent: [Na+]
Solvent: CC#N
Solvent: O
Solvent: CO
Product: O=c1c(O)c(-c2nnc(Cc3ccc(F)cc3)o2)nc2ccc(CN3CCOCC3)cn12
Temperature: 25 °C
Reaction time: 2 h
Yield: 63.3 %

Procedure:
To a solution of the product of example 17 (34 mg, 0.065 mmol) in acetonitrile (7 ml), TMSI (0.08 ml, 0.516 mmol) was added dropwise in the presence of N2 at room temperature and then stirred at room temperature for 2 hours. Methanol (5 ml) was added to quench the reaction. Then the mixture was poured into water (15 ml) and 0.5 N sodium hydroxide solution was added dropwise to adjust the pH 8-9. The mixture was extracted with dichloromethane three times. The combined extracts were washed with aqueous sodium bisulfite and water, dried over anhydrous sodium sulfate and evaporated into dryness. The residue was recrystallized for a mixed solvent of DCM/PE to give the titled product (18 mg, 63.8%). 1H NMR (300 MHz, DMSO-d6) δ 2.43 (t, J=4.5 Hz, 4H), 3.54-3.62 (m, 6H), 4.43 (s, 2H), 7.16-7.25 (m, 2H), 7.39-7.46 (m, 2H), 7.59-7.68 (m, 2H), 8.66 (s, 1H), 10.55 (brs, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([CH2:19][N:20]1[CH:24]=[N:23][CH:22]=[N:21]1)([OH:18])[CH2:10][N:11]1[CH:15]=[N:14][C:13]([CH:16]=O)=[N:12]1.[Cl-].[CH3:26][O:27][C:28]1[CH:53]=[CH:52][C:31]([CH2:32][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[CH:30][CH:29]=1.C(=O)([O-])[O-].[K+].[K+]>CO>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([CH2:19][N:20]1[CH:24]=[N:23][CH:22]=[N:21]1)([OH:18])[CH2:10][N:11]1[CH:15]=[N:14][C:13]([CH:16]=[CH:32][C:31]2[CH:30]=[CH:29][C:28]([O:27][CH3:26])=[CH:53][CH:52]=2)=[N:12]1
Reactant: O=Cc1ncn(CC(O)(Cn2cncn2)c2ccc(F)cc2F)n1
Reactant: COc1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CO
Product: COc1ccc(C=Cc2ncn(CC(O)(Cn3cncn3)c3ccc(F)cc3F)n2)cc1
Reaction time: 20 h

Procedure:
A mixture of 1-(2,4-difluorophenyl)-2-(3-formyl-1,2,4-triazol-1-yl)-1-(1,2,4-triazol-1-ylmethyl)ethanol (0.6 g), p-methoxybenzyl-triphenylphosphonium chloride (1.68 g), potassium carbonate (0.5 g) and methanol (10 ml) was heated at 60°-70° for 2 hours, then left at room temperature for 20 hours. The reaction mixture was filtered, the separated solids were washed with methanol, and the combined organic solutions were evaporated to dryness. The residue was purified by medium pressure liquid chromatography on silica, eluting with chloroform, to give 1-(2,4-difluorophenyl)-2-[3-(4-methoxystyryl)-1,2,4-triazol-1-yl]-1-(1,2,4-triazol-1-ylmethyl)ethanol, m.p. 150°-152°.
Reaction SMILES: F[C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]2[C:3]=1[C:4](=[O:13])[NH:5][CH:6]=[N:7]2.[CH:14]([OH:17])([CH3:16])[CH3:15].[H-].[Na+].C(O)(=O)C>CN(C)C=O>[F:12][C:10]1[CH:9]=[C:8]2[C:3]([C:4](=[O:13])[NH:5][CH:6]=[N:7]2)=[C:2]([O:17][CH:14]([CH3:16])[CH3:15])[CH:11]=1
Reactant: CC(C)O
Reactant: O=c1[nH]cnc2cc(F)cc(F)c12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: CC(C)Oc1cc(F)cc2nc[nH]c(=O)c12
Temperature: 25 °C
Reaction time: 14 h
Yield: 95.1 %

Procedure:
5,7-Difluoroquinazolin-4(3H)one (2.73 g, 15 mmol) in dimethylformamide (20 ml) was reacted with isopropanol (1.26 ml, 16.4 mmol) and sodium hydride (1.8 g, 45 mmol) at 0° C. under argon. The mixture was stirred at ambient temperature for 14 hours, acidified with acetic acid and concentrated. The residue was washed with water and dried to yield 7-fluoro-5-isopropoxyquinazolin-4(3H)-one (3.17 g, 95% yield) as a beige solid:
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[CH3:11][N:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.C1COCC1>CCOC(C)=O>[CH3:11][N:12]1[CH2:17][CH2:16][N:15]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[N+:8]([O-:10])=[O:9])[CH2:14][CH2:13]1
Reactant: O=[N+]([O-])c1ccccc1F
Reactant: CN1CCNCC1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CN1CCN(c2ccccc2[N+](=O)[O-])CC1
Temperature: 60 °C
Reaction time: 24 h
Yield: 96.7 %

Procedure:
To a Kontes glass tube was added 2-fluoro-nitrobenzene (3.34 g, 23.7 mmol), 1-methyl-piperazine (3.90 mL, 35.6 mmol), and anhydrous THF (10 mL). The tube was sealed and the reaction mixture was allowed to stir at 60° C. for 1 day. The reaction solution was diluted with EtOAc (150 mL), washed with aq NaHCO3, dried over Na2SO4, filtered, and concentrated in vacuo to afford 5.07 g (97% yield) of the title product. MS (ES) 222.3 [M+H]+.
Reaction SMILES: [C:1]1([C@@H:7]([N:9]2[C:13](=[O:14])[CH2:12][C@H:11]([C:15]([OH:17])=[O:16])[CH2:10]2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(=O)(=O)(O)O.[CH3:23]O>>[C:1]1([C@@H:7]([N:9]2[C:13](=[O:14])[CH2:12][C@H:11]([C:15]([O:17][CH3:23])=[O:16])[CH2:10]2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CO
Reactant: C[C@@H](c1ccccc1)N1C[C@@H](C(=O)O)CC1=O
Agent: O=S(=O)(O)O
Product: COC(=O)[C@H]1CC(=O)N([C@@H](C)c2ccccc2)C1

Procedure:
(3S)-1-((S)-1-Phenylethyl)-5-oxo-3-pyrrolidinecarboxylic acid (666 g, optical purity not less than 99%) was dissolved in methanol (6 l), and conc. sulfuric acid (15 ml) was added at room temperature. The mixture was stirred at refluxing temperature for 7 hr. Methanol was evaporated, and the residue was extracted with ethyl acetate. The organic layer was washed with sodium hydrogencarbonate, dried over magnesium sulfate and concentrated under reduced pressure to give 738 g of methyl (3S)-1-((S)-1-phenylethyl)-5-oxo-3-pyrrolidine-carboxylate.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[CH:4][C:3]=1CO.S(Cl)(Cl)(=O)=O.[C:16]([Cl:20])(Cl)([Cl:18])[Cl:17]>>[Cl:8][C:6]1[CH:7]=[C:2]([Cl:1])[C:3]([C:16]([Cl:20])([Cl:18])[Cl:17])=[CH:4][N:5]=1
Reactant: ClC(Cl)(Cl)Cl
Reactant: OCc1cnc(Cl)cc1Cl
Solvent: O=S(=O)(Cl)Cl
Product: Clc1cc(Cl)c(C(Cl)(Cl)Cl)cn1
Yield: 12 %

Procedure:
To a solution of (4,6-dichloropyridin-3-yl)methanol (7 g, 39 mmol) in CCl4 (200 mL), was added sulfuryl dichloride (120 mL) dropwise with stirring. The resulting solution was heated at reflux overnight. The mixture was concentrated and the pH was adjusted to pH 8 by the addition of NaHCO3 (2N). The resulting solution was extracted with EtOAc (2×100 mL) and the organic layers were combined and dried over Na2SO4. The residue was purified by silica gel column chromatography to afford 1.2 g (12%) of 2,4-dichloro-5-(trichloromethyl)pyridine.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[C:8]([N+:15]([O-])=O)=[CH:7][C:6]=1[O:18][CH3:19])([CH3:4])([CH3:3])[CH3:2].C([O-])=O.[NH4+]>CCO.[Pd]>[C:1]([C:5]1[CH:10]=[C:9]([C:11]([F:14])([F:12])[F:13])[C:8]([NH2:15])=[CH:7][C:6]=1[O:18][CH3:19])([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1cc([N+](=O)[O-])c(C(F)(F)F)cc1C(C)(C)C
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: COc1cc(N)c(C(F)(F)F)cc1C(C)(C)C
Yield: 95.9 %

Procedure:
To a refluxing solution of 1-tert-butyl-2-methoxy-5-(trifluoromethyl)-4-nitrobenzene (473 mg, 1.7 mmol) and ammonium formate (473 mg, 7.3 mmol) in EtOH (10 mL) was added 10% Pd—C (200 mg). The mixture was refluxed for 1 h, cooled and filtered through Celite. The solvent was removed by evaporation to give 1-tert-butyl-2-methoxy-5-(trifluoromethyl)-4-aminobenzene (C-18) (403 mg, 95%). 1H NMR (400 MHz, CDCl3) δ 7.19 (s, 1H), 6.14 (s, 1H), 4.02 (bs, 2H), 3.74 (s, 3H), 1.24 (s, 9H).
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:19])[CH:11]=[CH:12]C2C=CC=CC=2)=[C:5]([CH3:20])[CH:4]=1.[Cl-].[Al+3].[Cl-].[Cl-].ClC1C=CC=CC=1.O>CCCCCC>[OH:2][C:3]1[CH:8]=[C:7]2[C:6](=[C:5]([CH3:20])[CH:4]=1)[NH:9][C:10](=[O:19])[CH:11]=[CH:12]2
Reactant: COc1ccc(NC(=O)C=Cc2ccccc2)c(C)c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: Clc1ccccc1
Solvent: CCCCCC
Solvent: O
Product: Cc1cc(O)cc2ccc(=O)[nH]c12
Temperature: 125 °C
Reaction time: 1 h

Procedure:
To N-(4-methoxy-2-methylphenyl)cinnamamide (28.33 g, 0.106M), aluminum chloride (70.5 g, 529 mmol) and chlorobenzene (175 ml) were added, and the mixture was stirred in a bath of 125° C. for 1 hour. Thereafter, the mixture was cooled and poured into ice--water, to which n-hexane was added. The insoluble matter was collected by filtration, and washed with chloroform. As a result, 15.0 of 6-hydroxy-8-methylcarbostyril was obtained as brown crystals (80.8%).
Reaction SMILES: [CH3:1][C:2]1[CH:28]=[C:27]([CH3:29])[CH:26]=[CH:25][C:3]=1[CH2:4][N:5]1[C:13]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)=[C:12]2[C:7]([C:8]([C:21]([O:23]C)=[O:22])=[CH:9][CH:10]=[CH:11]2)=[N:6]1.[OH-].[Na+].Cl>CO>[CH3:1][C:2]1[CH:28]=[C:27]([CH3:29])[CH:26]=[CH:25][C:3]=1[CH2:4][N:5]1[C:13]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)=[C:12]2[C:7]([C:8]([C:21]([OH:23])=[O:22])=[CH:9][CH:10]=[CH:11]2)=[N:6]1
Reactant: COC(=O)c1cccc2c(-c3ccc(F)cc3)n(Cc3ccc(C)cc3C)nc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1ccc(Cn2nc3c(C(=O)O)cccc3c2-c2ccc(F)cc2)c(C)c1
Temperature: 50 °C
Reaction time: 1 h
Yield: 0.5 %

Procedure:
A solution of methyl 2-(2,4-dimethylbenzyl)-3-(4-fluorophenyl)-2H-indazole-7-carboxylate (0.195 g, 0.5 mmol) in 5 mL methanol was treated with 1 mL of 1N NaOH and stirred at 50° C. for 1 hour. The solution was neutralized with dilute HCl and partitioned with ethyl acetate and H2O. The organic phase was dried (Na2SO4) and concentrated in vacuo to give 0.95 mg of the title compound as a yellow solid.
Reaction SMILES: [Br:1][C:2]1[C:3]([Cl:11])=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=O.[F:12][C:13]([F:23])([F:22])[S:14][C:15]1[N:20]=[CH:19][C:18]([NH2:21])=[CH:17][CH:16]=1>>[Br:1][C:2]1[C:3]([Cl:11])=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([NH:21][C:18]1[CH:19]=[N:20][C:15]([S:14][C:13]([F:23])([F:22])[F:12])=[CH:16][CH:17]=1)=[O:9]
Reactant: O=C(O)c1cnc(Cl)c(Br)c1
Reactant: Nc1ccc(SC(F)(F)F)nc1
Product: O=C(Nc1ccc(SC(F)(F)F)nc1)c1cnc(Cl)c(Br)c1

Procedure:
The title compound was prepared in an analogous fashion to that described in Stage 169.2 using 5-bromo-6-chloronicotinic acid and 6-(trifluoromethylthio)pyridin-3-amine to afford an off-white powder. HPLC (Condition 4) tR=6.43 min, UPLC-MS (Condition 3) tR=1.15 min, m/z=411.9 [M−H]−.
Reaction SMILES: [OH:1][C:2]1[C:3]([C:12](=[O:14])[CH3:13])=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.C(N(CC)CC)C.[C:22]1([CH3:32])[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1>ClCCl>[C:12]([C:3]1[C:2]([O:1][S:28]([C:25]2[CH:26]=[CH:27][C:22]([CH3:32])=[CH:23][CH:24]=2)(=[O:30])=[O:29])=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1)(=[O:14])[CH3:13]
Reactant: CC(=O)c1nc2ccccc2cc1O
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)c1nc2ccccc2cc1OS(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 99.9 %

Procedure:
To a cooled (5° C.) solution of 1-(3-Hydroxy-quinolin-2-yl)-ethanone (1.96 g, 10.5 mmol) in 100 mL dichloromethane was added triethylamine (1.59 g, 2.19 mL. 15.75 mmol). After 10 minutes p-toluenesulfonyl chloride (2.191 g, 11.5 mmol) was added and the mixture was stirred at room temperature for 18 hours. The mixture was washed with 1N HCl, water, and brine, dried (MgSO4) and concentrated under reduced pressure to afford 3.58 g of toluene-4-sulfonic acid 2-acetyl-quinolin-3-yl ester.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7]Cl)=[CH:5][CH:4]=1.[OH:11][CH2:12][CH2:13][N:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1.C(N(CC)CC)C>C(O)C>[OH:11][CH2:12][CH2:13][N:14]1[CH2:19][CH2:18][N:17]([CH2:7][C:6]2[CH:9]=[CH:10][C:3]([S:2][CH3:1])=[CH:4][CH:5]=2)[CH2:16][CH2:15]1
Reactant: CSc1ccc(CCl)cc1
Reactant: OCCN1CCNCC1
Solvent: CCN(CC)CC
Solvent: CCO
Product: CSc1ccc(CN2CCN(CCO)CC2)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 71.6 %

Procedure:
A mixture of 4-(methylthio)benzyl chloride (28.6 g), 1-(2-hydroxyethyl)piperazine (21.6 g), triethylamine (16.8 g), and ethanol (250 ml) is stirred at room temperature for 5 hours. The ethanol is then removed in vacuo and water added to the residue. The product is extracted with ether, dried, and the ether evaporated to give 31.6 g of 1-(2-hydroxyethyl)-4-[4-(methylthio)benzyl] piperazine as an orange oil, suitable for use in the next reaction.
Reaction SMILES: Cl[C:2]1[S:6][C:5]([C:7]([O:9][CH3:10])=[O:8])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].[Cl:14][C:15]1[CH:16]=[N+:17]([O-:23])[CH:18]=[C:19]([Cl:22])[C:20]=1[SH:21]>>[Cl:14][C:15]1[CH:16]=[N+:17]([O-:23])[CH:18]=[C:19]([Cl:22])[C:20]=1[S:21][C:2]1[S:6][C:5]([C:7]([O:9][CH3:10])=[O:8])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12]
Reactant: [O-][n+]1cc(Cl)c(S)c(Cl)c1
Reactant: COC(=O)c1cc([N+](=O)[O-])c(Cl)s1
Product: COC(=O)c1cc([N+](=O)[O-])c(Sc2c(Cl)c[n+]([O-])cc2Cl)s1

Procedure:
Prepared according to the procedure described for example 18 from methyl 5-chloro-4-nitrothiophene-2-carboxylate (500 mg, 2.26 mmol) and 3,5-dichloro-4-mercaptopyridine 1-oxide (441 mg, 2.26 mmol) from step A of example 18. The titled product was obtained as a solid (250 mg, 29% yield). The crude was used as such for the next step transformation.
Reaction SMILES: FC(F)(F)C(O)=O.[I:8][CH:9]([O:12][C:13](=[O:17])[C@H:14]([CH3:16])[NH2:15])[C:10]#[CH:11].C(N(CC)CC)C.[C:25]([O:29][C:30]([NH:32][CH2:33][C:34](O)=[O:35])=[O:31])([CH3:28])([CH3:27])[CH3:26].O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>ClCCl>[I:8][CH:9]([O:12][C:13](=[O:17])[C@H:14]([CH3:16])[NH:15][C:34](=[O:35])[CH2:33][NH:32][C:30]([O:29][C:25]([CH3:27])([CH3:26])[CH3:28])=[O:31])[C:10]#[CH:11]
Reactant: C#CC(I)OC(=O)[C@H](C)N
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C#CC(I)OC(=O)[C@H](C)NC(=O)CNC(=O)OC(C)(C)C
Reaction time: 17 h
Yield: 70 %

Procedure:
To a magnetically stirred, anhydrous dichloromethane (30 ml.) solution of L-alanine iodopropargyl ester trifluoroacetate (Compound #8) (2.30 g., 6.27 mmole) held at 0° C. with an ice-bath was added triethylamine (0.96 ml., 6.89 mmole), followed by N-t-butoxycarbonylglycine (1.10 g., 6.28 mmole), 1-hydroxybenzotriazole hydrate (0.85 g., 6.29 mmole) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.56 g., 8.14 mmole). The reaction mixture was held at 0°-7° C. for 17 hours. The resultant solution was transferred to a separatory funnel and diluted to an approximate volume of 100 ml. with dichloromethane, then washed successively with 3×50 ml. of water, 3×50 ml. of 10% aqueous potassium hydrogen sulfate, 3×50 ml. of saturated aqueous sodium bicarbonate, 3×50 ml. of water and a final wash with 50 ml. of saturated aqueous sodium chloride. The organic layer was dried with magnesium sulfate, filtered and concentrated in vacuo with a rotary evaporator to give 1.80 g. (70% yield) of the desired N-t-butoxycarbonylglycyl-L-alanine iodopropargyl ester as a dry white foam. 1H-NMR (200 MHz, CDCl3) δ=1.45 ppm, d, 3H; 1.45, 1.72, two s, 9H; 3.82, d, 2H; 4.63, m, 1H; 4.87, s, 2H; 5.17, broad m, 1H; 6.67, d, 1H.
Reaction SMILES: Br[C:2]1[CH:17]=[CH:16][C:5]([O:6][C:7]2[C:13]([CH3:14])=[CH:12][C:10]([NH2:11])=[C:9]([CH3:15])[CH:8]=2)=[CH:4][CH:3]=1.[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>C(O)CCC.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>[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([C:2]2[CH:17]=[CH:16][C:5]([O:6][C:7]3[C:13]([CH3:14])=[CH:12][C:10]([NH2:11])=[C:9]([CH3:15])[CH:8]=3)=[CH:4][CH:3]=2)=[CH:22][CH:21]=1
Reactant: COc1ccc(B(O)O)cc1
Reactant: Cc1cc(Oc2ccc(Br)cc2)c(C)cc1N
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: [Cs+]
Solvent: CCCCO
Solvent: O
Product: COc1ccc(-c2ccc(Oc3cc(C)c(N)cc3C)cc2)cc1
Temperature: 80 °C
Reaction time: 16 h
Yield: 79.7 %

Procedure:
Under argon, 0.50 g (1.7 mmol) of 4-(4-bromophenoxy)-2,5-dimethylaniline and 0.34 g (2.2 mmol) of 4-methoxyphenylboronic acid are dissolved in 10 ml of 1-butanol and the solution is admixed with 2.23 g (6.8 mmol) of cesium carbonate, 39.5 mg (0.03 mmol) of tetrakis(triphenylphosphine)palladium(0) and 2.5 ml of water. The reaction mixture is stirred at 80° C. for 16 h, poured into water and extracted repeatedly with ethyl acetate. The combined organic phases are dried over Na2SO4 and filtered and the solvent is removed under reduced pressure. This is followed by purification by column chromatography (0.44 g, purity 99.0%, yield 79.7%, log P (pH 2.3)=3.06).
Reaction SMILES: [Si:1](Cl)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:19][C:20]1([CH2:33][CH2:34][OH:35])[CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:22][CH2:21]1.C(N(CC)CC)C.[Cl-].[NH4+]>ClCCl>[Si:1]([O:35][CH2:34][CH2:33][C:20]1([OH:19])[CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]([CH3:31])([CH3:30])[CH3:32])=[O:27])[CH2:22][CH2:21]1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC(O)(CCO)CC1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(O)(CCO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)CC1
Temperature: 0 °C
Reaction time: 12 h

Procedure:
A solution of 21.50 ml (82.50 mmol) of tert-butyldiphenylsilyl chloride in 15 ml of dichloromethane is added dropwise, under an inert atmosphere, to a solution of 18.4 g (75 mmol) of tert-butyl 4-hydroxy-4-(2-hydroxyethyl)-1-piperidinecarboxylate, obtained in step 12.1, and 11.60 ml (82.50 mmol) of triethylamine in 100 ml of dichloromethane, cooled to about 0° C. The mixture is allowed to warm to room temperature and stirring is then continued for 12 hours. Saturated aqueous ammonium chloride solution is added to the reaction medium. The aqueous phase is separated out and extracted twice with dichloromethane, the combined organic phases are washed with saturated aqueous sodium chloride solution and dried over sodium sulfate, and the filtrate is concentrated under reduced pressure. The residue thus obtained is purified by chromatography on silica gel, eluting with a 10/90 and then 20/80 mixture of ethyl acetate and cyclohexane.
Reaction SMILES: C[O:2][C:3](=O)[C@H:4]([CH2:10][CH2:11][CH2:12][CH2:13][NH:14][C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16])[NH:5][C:6](=[O:9])[CH2:7][NH2:8]>CO.N>[CH2:18]([O:17][C:15]([NH:14][CH2:13][CH2:12][CH2:11][CH2:10][CH:4]1[NH:5][C:6](=[O:9])[CH2:7][NH:8][C:3]1=[O:2])=[O:16])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: COC(=O)[C@H](CCCCNC(=O)OCc1ccccc1)NC(=O)CN
Agent: N
Solvent: CO
Product: O=C1CNC(=O)C(CCCCNC(=O)OCc2ccccc2)N1
Reaction time: 72 h
Yield: 13.2 %

Procedure:
The Nα-glycyl-Nε-carbobenzoxy-L-lysine methyl ester prepared as described in Example 1 was dissolved in methanol previously saturated with ammonia (300 ml.) and allowed to stand for 3 days in a sealed flask at ambient temperature. The solvent was removed in vacuo and the residual solid recrystallised from absolute ethanol to give the title compound as colourless needles (1 g.) m.p. 210°C. (Found: C, 59.9; H, 6.7; N, 13.5. C16H21N3O4 requires: C, 60.1; H, 6.5; N, 13.2%).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][C:3]=1[CH3:11].Cl.[CH3:13][NH:14][O:15][CH3:16].N1C=CC=CC=1.C([O-])([O-])=O.[Na+].[Na+]>S(Cl)(Cl)=O.ClCCl.C(#N)C>[CH3:16][O:15][N:14]([CH3:13])[C:6](=[O:7])[C:5]1[CH:9]=[CH:10][C:2]([Br:1])=[C:3]([CH3:11])[CH:4]=1
Reactant: Cc1cc(C(=O)O)ccc1Br
Reactant: CNOC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: CON(C)C(=O)c1ccc(Br)c(C)c1
Temperature: 25 °C
Yield: 99.4 %

Procedure:
A stirred suspension of 4-bromo-3-methylbenzoic acid (5.0 g, 0.023 mole) in thionyl chloride (20 ml) was heated under reflux for 2 hours, then concentrated in vacuo. The residual acid chloride was dissolved in dichloromethane (100 ml) and added dropwise over 10 minutes to a stirred solution of N,O-dimethylhydroxylamine hydrochloride (2.4 g, 0.025 mole) and pyridine (5.6 ml, 0.069 mole) in dichloromethane (150 ml) and acetonitrile (20 ml) at -20° C. The reaction mixture was allowed to warm to room temperature over 3 hours then treated with 10% Na2CO3 solution and extracted with dichloromethane. The extract was dried (Na2SO4) and concentrated in vacuo to afford the title compound as a pale yellow oil (5.9 g, 100%).