Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:21]=[CH:20][C:6]([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH2:10][C:9]2([Cl:19])C=O)=[CH:5][CH:4]=1.N1CCCC[CH2:23]1.C(O)(=O)C.[C:32]([O:40][CH2:41][CH3:42])(=[O:39])[CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35]>C(O)C>[CH2:41]([O:40][C:32]([C:33](=[CH:23][C:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:8]([CH2:7][C:6]2[CH:20]=[CH:21][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[C:9]=1[Cl:19])[C:34]([O:36][CH2:37][CH3:38])=[O:35])=[O:39])[CH3:42]
Reactant: C1CCNCC1
Reactant: CCOC(=O)CC(=O)OCC
Reactant: COc1ccc(CN2c3ccccc3CC2(Cl)C=O)cc1
Solvent: CC(=O)O
Solvent: CCO
Product: CCOC(=O)C(=Cc1c(Cl)n(Cc2ccc(OC)cc2)c2ccccc12)C(=O)OCC
Reaction time: 72 h

Procedure:
To 460 mg of 1-(4-methoxybenzyl)-2-chloroindole-carbaldehyde, dissolved in 15 ml of a solvent which consisted of 5% piperidine and 2% acetic acid in absolute ethanol, was added 0.26 ml of diethyl malonate. After stirring for 3 days the solvent was removed by evaporation, and the product dissolved in 25 ml of ether plus 25 ml of 1N HCl. The organic phase was separated, and washed with 25 ml 1 N HCl, 25 ml water, 25 ml of saturated NaHCO3 solution, dried (MgSO4) and evaporated to give an oil. Purification by column chromatography (methylene chloride on silica 60) gave (15a) as an oil. 1H-NMR (CDCl3): 8.03 (s, 1H); 7.50 (m, 1H); 7.20 (m, 3H); 7.02 (d, 2H); 6.78 (d, 2H); 5.30 (s, 2H); 4.32 (q, 2H); 4.24 (q, 2H); 3.71 (s, 3H); 1.33 (t, 3H) 1.11 (t, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][N:3]=1.[F:9][C:10]([F:20])([F:19])[C:11]1[CH:18]=[CH:17][C:14]([CH:15]=O)=[CH:13][CH:12]=1.[OH:21][C:22]1[CH:23]=[CH:24][CH:25]=[C:26]2[C:31]=1[N:30]=[CH:29][CH:28]=[CH:27]2>CC#N.O>[CH3:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([NH:1][CH:15]([C:14]2[CH:17]=[CH:18][C:11]([C:10]([F:20])([F:19])[F:9])=[CH:12][CH:13]=2)[C:23]2[C:22]([OH:21])=[C:31]3[C:26]([CH:27]=[CH:28][CH:29]=[N:30]3)=[CH:25][CH:24]=2)[CH:7]=1
Reactant: O=Cc1ccc(C(F)(F)F)cc1
Reactant: Cc1ccnc(N)c1
Reactant: Oc1cccc2cccnc12
Solvent: CC#N
Solvent: O
Product: Cc1ccnc(NC(c2ccc(C(F)(F)F)cc2)c2ccc3cccnc3c2O)c1

Procedure:
The title compound was prepared by method B presented for the compound of Example 1 with the change that 2-amino-4-methyl-pyridine (Molar), 4-trifluoromethyl-benzaldehyde (Sigma) and 8-hydroxy-quinoline (Sigma) were used as starting materials. Product obtained: C23H18F3N3O; (MW; 409.1): yield 230 mg, (29.6%) m.p.: 104-107° C.; HPLC (CH3CN/H2O 70:30 Phenomenex C18 282 nm): Tr=7.61 min. 1H NMR 8 (DMSO) δ 2.18 (3H, s, CH3), 6.41(1H, d, J=5.1 Hz), 6.44 (1H, s, NH), 6.49 (1H, d, J=4.9 Hz), 7.07 (1H, d, J=9.2 Hz), 7.39 (1H, d, J=8.9 Hz), 7.49-7.54 (1H, m), 7.58 (2H, d, J=7.9 Hz), 7.63 (2H, d, J=8.3 Hz), 7.73 (1H, d, J=7.9 Hz), 7.85 (2H, d, J=7.9 Hz), 8.03-8.08 (1H, m), 8.12 (2H, d, J=8.5 Hz), 8.27 (1H, d, J=8.2 Hz). 8.81-8.86 (1H, m); 13C-NMR 8 (DMSO) δ 23.5 (CH3), 51.8 (NHCH), 109.5 (CH), 117.6 (CH), 121.8 (CH), 124.5 (Cq), 125.1 (CH), 125.6 2×CH), 126.8 (CH), 127.7 (2×CH), 127.8 (Cq), 130.1 (CH), 134.7 (Cq), 136.1 (CH), 138.1 (Cq), 148.2 (Cq), 148.5 (CH), 149.6 (Cq), 157.7 (CH), 161.6 (Cq), 166.3 (Cq).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][CH:3]=1.[CH2:9]([OH:13])[CH2:10][C:11]#[CH:12].Cl>C(N(CC)CC)C.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[OH:13][CH2:9][CH2:10][C:11]#[C:12][C:2]1[CH:7]=[CH:6][C:5]([C:12]#[C:11][CH2:10][CH2:9][OH:13])=[CH:4][CH:3]=1
Reactant: C#CCCO
Reactant: Ic1ccc(I)cc1
Agent: Cl[Pd]Cl
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: OCCC#Cc1ccc(C#CCCO)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 95.2 %

Procedure:
First, 16.5 g of p-diiodobenzene and 8.0 g of 3-butyn-1-ol were dissolved in 200 ml of triethylamine, 0.35 g of bis(triphenylphosphine)palladium (II) chloride and 0.19 g of cuprous iodide were added thereto, and the reaction mixture was stirred under nitrogen gas flow at a room temperature for 3 hours. After the reaction was completed, an insoluble matter was filtered off and the filtrate was evaporated under a reduced pressure. To the residue was added a small amount of ethyl acetate, which was then evaporated under a reduced pressure. To the residue was added water, and the mixture was extracted with 100 ml of ethyl acetate. The extract was washed with a saturated sodium chloride aqueous solution and dried over magnesium sulfate. On the other hand the insoluble matter obtained above was acidified with 1N HCl and extracted with 100 ml of ethyl acetate, and the extract was washed with a saturated sodium chloride aqueous solution and dried over magnesium sulfate. This ethyl acetate layer was combined with the ethyl acetate layer obtained above, and the mixture was evaporated under a reduced pressure to obtain 10.2 g of 1,4-bis(4-hydroxy-1-butynyl)benzene as a yellow residue.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1CC=C[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[N+]1([O-])CC[O:21]CC1.[C:25]([OH:29])([CH3:28])(C)[CH3:26].S(=O)(O)[O-].[Na+]>O.CC(C)=O.[Os](=O)(=O)(=O)=O>[CH2:1]([O:8][C:9]([N:11]1[CH2:12][CH2:13][CH:26]([OH:21])[CH:25]([OH:29])[CH2:28]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)O
Reactant: O=C(OCc1ccccc1)N1CC=CCC1
Reactant: C[N+]1([O-])CCOCC1
Agent: O=[Os](=O)(=O)=O
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: O=C(OCc1ccccc1)N1CCC(O)C(O)C1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
31 (3.63 g, 16.7 mmol) is dissolved in 16 ml of a 1:1 mixture of water and acetone. After addition of N-methyl-morpholine-N-oxide (2.9 g, 24.8 mmol), a 1% solution of osmium tetroxide in tert. Butanol (7.23 ml, 0.28 mmol) is added. The mixture is stirred at room temperature for 20 h. Then 70 ml of a saturated sodium bisulfite solution is added. After 15 min stirring at room temperature, the reaction mixture is extracted with ethyl acetate. The organic layers are dried over sodium sulphate and evaporated. The crude product, 4.7 g of a yellow oil, is purified by Flash-chromatography (silica gel, ethyl acetate).
Reaction SMILES: [CH2:1]([Li])CCC.[Br:6][C:7]1[CH:14]=[CH:13][C:10]([CH:11]=O)=[C:9]([F:15])[CH:8]=1>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCCC1>[Br:6][C:7]1[CH:14]=[CH:13][C:10]([CH:11]=[CH2:1])=[C:9]([F:15])[CH:8]=1
Reactant: [Li]CCCC
Reactant: O=Cc1ccc(Br)cc1F
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Product: C=Cc1ccc(Br)cc1F
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
To a suspension of methyltriphenylphosphonium bromide (1.1 eq) in tetrahydrofuran (0.13M) at −78° C., was added n-butyllithium (2.5M in hexanes, 1.1 eq) dropwise over 20 min. The reaction mixture was stirred at −78° C. for 15 min, warm to 0° C., stirred for 15 min and cooled back to −78° C. A solution of 4-bromo-2-fluoro-benzaldehyde (1 eq) in 100 mL THF was added dropwise over 30 min. Final mixture was allowed to warm slowly to rt and stirred for 1 h. The resulting mixture was quenched with a saturated NH4Cl solution and diluted with 2 volume of hexane. The organic extract was washed with brine, dried over MgSO4, filtered and concentrated. The residue was diluted with Hexane/EtOAc (9:1) and filtered on a pad of Silica gel. The fractions were combined and concentrated to afford the desired material
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:30]#[C:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[CH:8][C:9]=1[N:10]([CH:20]1[CH2:29][CH2:28][C:23]2(OCC[O:24]2)[CH2:22][CH2:21]1)[C:11]([C@@H:13]1[CH2:18][CH2:17][C:16]([CH3:19])=[CH:15][CH2:14]1)=[O:12])=[O:4].Cl.C(OCC)(=O)C>C1COCC1>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:30]#[C:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[CH:8][C:9]=1[N:10]([C:11]([C@@H:13]1[CH2:18][CH2:17][C:16]([CH3:19])=[CH:15][CH2:14]1)=[O:12])[CH:20]1[CH2:21][CH2:22][C:23](=[O:24])[CH2:28][CH2:29]1)=[O:4]
Reactant: COC(=O)c1sc(C#CC(C)(C)C)cc1N(C(=O)[C@H]1CC=C(C)CC1)C1CCC2(CC1)OCCO2
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)c1sc(C#CC(C)(C)C)cc1N(C(=O)[C@H]1CC=C(C)CC1)C1CCC(=O)CC1
Temperature: 45 °C
Reaction time: 2 h
Yield: 95.2 %

Procedure:
5-(3,3-Dimethyl-but-1-ynyl)-3-[(1,4-dioxa-spiro[4.5]dec-8-yl)-((1R)-4-methyl-cyclohex-3-enecarbonyl)-amino]-thiophene-2-carboxylic acid methyl ester 506 (219 mg, 0.438 mmol) was dissolved in THF (3.5 mL) and treated with 4M HCl (1.75 mL, 7.01 mmol). The reaction mixture was heated to 45° C. and stirred 2 h. Ethyl acetate was added and the organic layer was separated then washed with water, sodium bicarbonate (sat aq), water, and brine. The organic layer was dried over sodium sulfate, filtered and concentrated to 0.190 g (95% yield) of the desired 5-(3,3-dimethyl-but-1-ynyl)-3-[((1R)-4-methyl-cyclohex-3-enecarbonyl)-(4-oxo-cyclohexyl)-amino]-thiophene-2-carboxylic acid methyl ester 507 as a white foam.
Reaction SMILES: [CH3:1][CH:2]([CH3:21])[CH2:3][CH2:4][NH:5][C:6]([C:8]1[S:12][C:11]([N:13]2[CH2:20][C:19]3[CH2:18][NH:17][CH2:16][C:15]=3[CH2:14]2)=[N:10][CH:9]=1)=[O:7].FC(F)(F)C([O-])=O.C(N(CC)CC)C.[F:36][C:37]([F:48])([F:47])[C:38]1[CH:46]=[CH:45][CH:44]=[CH:43][C:39]=1[C:40](Cl)=[O:41]>CN(C=O)C>[CH3:1][CH:2]([CH3:21])[CH2:3][CH2:4][NH:5][C:6]([C:8]1[S:12][C:11]([N:13]2[CH2:14][C:15]3[CH2:16][N:17]([C:40](=[O:41])[C:39]4[CH:43]=[CH:44][CH:45]=[CH:46][C:38]=4[C:37]([F:36])([F:47])[F:48])[CH2:18][C:19]=3[CH2:20]2)=[N:10][CH:9]=1)=[O:7]
Reactant: CC(C)CCNC(=O)c1cnc(N2CC3=C(CNC3)C2)s1
Reactant: O=C(Cl)c1ccccc1C(F)(F)F
Agent: O=C([O-])C(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)CCNC(=O)c1cnc(N2CC3=C(CN(C(=O)c4ccccc4C(F)(F)F)C3)C2)s1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
N-(3-Methylbutyl)-2-(3,4,5,6-tetrahydro-1H-pyrrolo[3,4-c]pyrrol-2-yl)thiazole-5-carboxamide, trifluoroacetate (220 mg, 0.52 mmol) and triethylamine (0.22 ml, 1.57 mmol) were dissolved in 10 ml of DMF and admixed in an ice bath with 2-trifluoromethylbenzoyl chloride (218 mg, 1.04 mmol). The mixture was stirred further for 1 h and allowed to warm to room temperature, and concentrated, water and ethyl acetate were added and the organic phase was removed, concentrated and purified by preparative HPLC (PR18, acetonitrile/water 0.1% TFA). Yield: 25 mg (10%), M+H+: 479.06.
Reaction SMILES: [C:1]1([CH:7]2[C:12]3[N:13]=[C:14]([NH:16][C:17]4[CH:25]=[CH:24][C:20]([C:21]([OH:23])=O)=[CH:19][CH:18]=4)[S:15][C:11]=3[CH2:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:26](N1C=CN=C1)(N1C=CN=C1)=[O:27].[OH-].[NH4+:39]>CN(C)C=O>[CH3:26][O:27][C:24]1[CH:25]=[C:17]([NH:16][C:14]2[S:15][C:11]3[CH2:10][CH2:9][CH2:8][CH:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[C:12]=3[N:13]=2)[CH:18]=[CH:19][C:20]=1[C:21]([NH2:39])=[O:23]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: [NH4+]
Reactant: O=C(O)c1ccc(Nc2nc3c(s2)CCCC3c2ccccc2)cc1
Agent: [OH-]
Solvent: CN(C)C=O
Product: COc1cc(Nc2nc3c(s2)CCCC3c2ccccc2)ccc1C(N)=O
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 82.9 %

Procedure:
A solution of 4-(4-phenyl-4,5,6,7-tetrahydro-benzothiazol-2-ylamino)-benzoic acid (810 mg, 2.1 mmol) and 1,1′-carbonyldiimidazol (463 mg, 2.8 mmol) in dimethylformamide (15 mL) was stirred for 30 minutes at 50° C. The solution was cooled to 0° C. and 25% aqueous ammonium hydroxide solution (1.6 mL, 21.3 mmol) was added slowly. The reaction mixture was stirred for 45 minutes at room temperature. The reaction was poured onto water, stirred for 15 minutes and the solid was filtered off, washed with water and dried to yield the title compound (661 mg, 82%) as an off-white solid. mp 243-246° C. MS ISP (m/e): 380.4 (100) [(M+H)+].
Reaction SMILES: [NH:1]1[CH:5]=[N:4][N:3]=[N:2]1.[OH-].C([N+](CCCC)(CCCC)CCCC)CCC.F[C:25]1[C:26]([C:31]#[N:32])=[N:27][CH:28]=[CH:29][CH:30]=1>CN(C=O)C>[N:1]1([C:25]2[C:26]([C:31]#[N:32])=[N:27][CH:28]=[CH:29][CH:30]=2)[CH:5]=[N:4][N:3]=[N:2]1
Reactant: c1nnn[nH]1
Reactant: N#Cc1ncccc1F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [OH-]
Solvent: CN(C)C=O
Product: N#Cc1ncccc1-n1cnnn1
Temperature: 25 °C
Reaction time: 96 h

Procedure:
To a stirred solution of tetrazole (1.0 g; 14 mmol) in DMF (150 mL) was added 40% aqueous tetrabutylammonium hydroxide (7.8 g; 12 mmol). The solvent was removed under reduced pressure. To ensure removal of all the water from the tetrabutylammonium hydroxide solution, the residue was redissolved in DMF and the solution was evaporated under reduced pressure. This procedure was repeated a total of three times. The residue was then dissolved in DMF (60 mL) and 3-fluoro-2-cyanopyridine (1.5 g; 12 mmol) was added. The reaction was stirred at ambient temperature under inert atmosphere for four days, at which time hplc analysis indicated about 65% conversion of the 3-fluoro-2-cyanopyridine to new products. The solvent was removed under reduced pressure and the residue was partitioned between EtOAc and water. The EtOAc layer was separated, dried over anhydrous MgSO4, and filtered. The solvent was removed under reduced pressure and the residue was purified by flash chromatography using a gradient elution of 1:4 to 100:0 EtOAc:hexanes to give 3-(tetrazol-1-yl)cyanopyridine as a white crystalline solid (TLC Rf=0.5, 1:1 EtOAc-hexanes; hplc retention time =2.04 min, method X; 1H NMR (CDCl3) δ9.42 (s, 1H), 8.94 (dd, J=1.3, 4.6 Hz, 1H), 8.31 (dd, J=1.3, 8.4 Hz, 1H), 7.87 (dd, J=4.6, 8.4 Hz, 1H).
Reaction SMILES: C[C:2]1([C:10]([OH:12])=[O:11])[CH2:7][CH2:6][C:5]([CH3:9])([CH3:8])[CH2:4][CH2:3]1.[CH:13](NC(C)C)(C)C.[Li].[CH3:21][O:22][C:23](Cl)=[O:24]>C1COCC1>[CH3:8][C:5]1([CH3:9])[CH2:6][CH2:7][C:2]([C:10]([O:12][CH3:13])=[O:11])([C:23]([O:22][CH3:21])=[O:24])[CH2:3][CH2:4]1
Reactant: CC1(C)CCC(C)(C(=O)O)CC1
Reactant: COC(=O)Cl
Reactant: CC(C)NC(C)C
Agent: [Li]
Solvent: C1CCOC1
Product: COC(=O)C1(C(=O)OC)CCC(C)(C)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 36192700 %

Procedure:
A solution of methyl 4,4-dimethyl-cyclohexane carboxylic acid (7.17 g, 42.2 mmol) in THF (15 mL) was added dropwise to a solution of lithium diisopropylamine (6.84 g, 63.3 mmol) in THF (60 mL) at −78° C. After stirring for 1 h at the same temperature, a solution of methylchloroformate (6.0 g, 63.3 nmol) in THF (15 mL) was added slowly and the mixture was allowed to warm to room temperature. After 18 h the reaction mixture was quenched with saturated aqueous NH4Cl solution (150 mL) and the aqueous residue was extracted with EtOAc (100 mL×5). The combined organic layers were dried (MgSO4). After removal of the solvent under reduced pressure, purification by flash column chromatography using an eluting system of hexane/EtOAc (95:5) yielded the title compound as a clear colorless liquid (5.23 g, 54%). MH+229.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7]1=[N:11][C:12]([CH3:14])=[N:13][N:6]1[C:5]2([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)N.C(O)(=[O:24])C>CO>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([C:7]2[N:11]=[C:12]([CH3:14])[NH:13][N:6]=2)=[C:4]([CH:3]=1)[C:5]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:24]
Reactant: CC(=O)O
Reactant: Cc1nc2n(n1)C(N)(c1ccccc1)c1cc(Cl)ccc1-2
Solvent: CO
Product: Cc1nc(-c2ccc(Cl)cc2C(=O)c2ccccc2)n[nH]1

Procedure:
Ten milligrams of 7-chloro-2-methyl-5-phenyl-5H-[1,2,4]triazolo-[5,1-a]-isoindol-5-amine (as prepared in Example 1) are refluxed for 10 minutes in 2 ml of 50% aqueous methanol containing a drop of acetic acid. The methanol is removed under vacuum and the aqueous residue made basic with 10% NaOH. The aqueous solution is washed with chloroform, neutralized with 10% HCl and extracted with chloroform. The chloroform solution is evaporated to dryness and the residue is recrystallized from a water-ethanol mixture, m.p. 149° to 150°.
Reaction SMILES: [O:1]1[C:3]2([CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]2)[CH2:2]1.[N-:16]=[N+:17]=[N-:18].[Na+]>O1CCOCC1.O>[N:16]([CH2:2][C:3]1([OH:1])[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1)=[N+:17]=[N-:18]
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CO2
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCC(O)(CN=[N+]=[N-])CC1
Yield: 94.7 %

Procedure:
To a solution of the compound prepared in Example 255 (0.500 g) in dioxane (31 mL) and water (3 mL) was treated with sodium azide (0.143 g) at room temperature. The mixture was refluxed overnight. The solvent was evaporated in vacuo and the residue was distributed between ethyl acetate and water. The aqueous layer was extracted with more ethyl acetate, dried and evaporated in vacuo to obtain the title compound (0.534 g) having the following physical data.
Reaction SMILES: Br[CH2:2][C:3]#[N:4].C(N(C(C)C)C(C)C)C.[CH:14]([S:17][C:18](=[O:31])[CH2:19][C@H:20]([NH:24][C:25](=[O:30])[CH2:26][CH2:27][CH:28]=[CH2:29])[C:21]([OH:23])=[O:22])([CH3:16])[CH3:15].[Cl-].[NH4+]>CN(C=O)C>[CH:14]([S:17][C:18](=[O:31])[CH2:19][C@H:20]([NH:24][C:25](=[O:30])[CH2:26][CH2:27][CH:28]=[CH2:29])[C:21]([O:23][CH2:2][C:3]#[N:4])=[O:22])([CH3:16])[CH3:15]
Reactant: N#CCBr
Reactant: C=CCCC(=O)N[C@@H](CC(=O)SC(C)C)C(=O)O
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C=CCCC(=O)N[C@@H](CC(=O)SC(C)C)C(=O)OCC#N
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 70.4 %

Procedure:
2-Bromoacetonitrile (0.510 ml, 7.32 mmol) and N-ethyl-N-isopropylpropan-2-amine (0.153 ml, 0.878 mmol) were added to a solution of (S)-4-(isopropylthio)-4-oxo-2-(pent-4-enamido)butanoic acid (Compound 1f-IB) (200 mg, 0.732 mmol) in DMF (1 ml), and the mixture was stirred at room temperature for 30 minutes. A saturated aqueous ammonium chloride solution (1 ml) was added to the reaction mixture, after which the mixture was extracted with ethyl acetate and the organic layer was washed with water. The organic extract was then dried over magnesium sulfate. Following concentration under reduced pressure, the resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate=100/0→60/40) to afford (S)-cyanomethyl 4-(isopropylthio)-4-oxo-2-(pent-4-enamido)butanoate (Compound 1g-IB) (161 mg, 70%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13](=[O:14])[C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:11][N:10]([CH3:21])[CH:9]=2)[CH:5]=[CH:6][CH:7]=1.N1C=CC=C[C:23]1=O.[F:29][C:30]([F:37])([F:36])[S:31]([O:34]C)(=[O:33])=[O:32]>C(Cl)(Cl)Cl>[F:29][C:30]([F:37])([F:36])[S:31]([O-:34])(=[O:33])=[O:32].[Br:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[N+:10]([CH3:21])[CH:11]=[C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:13]=2[O:14][CH3:23])[CH:5]=[CH:6][CH:7]=1
Reactant: O=c1cccc[nH]1
Reactant: Cn1cc(-c2ccccc2)c(=O)c(-c2cccc(Br)c2)c1
Reactant: COS(=O)(=O)C(F)(F)F
Solvent: ClC(Cl)Cl
Product: COc1c(-c2ccccc2)c[n+](C)cc1-c1cccc(Br)c1
Product: O=S(=O)([O-])C(F)(F)F
Reaction time: 8 h

Procedure:
A 10 g. portion of 3-(3-bromophenyl)-1-methyl-5-phenyl-4(1H)-pyridinone was made from 22 g. of the corresponding 2-propane as described in Example 1. A 3.4 g. portion of the intermediate pyridinone was dissolved in chloroform and 1.8 g. of methyl trifluoromethanesulfonate was added. The reaction mixture was allowed to stand overnight, and the volatile portions were then evaporated under vacuum. The residue was identified as 3-(3-bromophenyl)-4-methoxy-1-methyl-5-phenylpyridinium trifluoromethanesulfonate, molecular weight 339 by mass spectroscopy.
Reaction SMILES: [N+](C1C=CC(C[O:11][C:12]([C:14]2[N:15]3[CH:18]([CH:19]([CH3:35])[C:20]=2[S:21][CH:22]2[CH2:26][CH:25]([CH2:27][O:28][C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[O:24][CH2:23]2)[CH:17]([CH:36]([OH:38])[CH3:37])[C:16]3=[O:39])=[O:13])=CC=1)([O-])=O.C(=O)(O)[O-].[Na+:44].O>[Pd].O1CCOCC1>[Na+:44].[OH:38][CH:36]([CH:17]1[C:16](=[O:39])[N:15]2[CH:18]1[CH:19]([CH3:35])[C:20]([S:21][CH:22]1[CH2:26][CH:25]([CH2:27][O:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[O:24][CH2:23]1)=[C:14]2[C:12]([O-:13])=[O:11])[CH3:37]
Reactant: CC(O)C1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(SC3COC(COc4ccccc4)C3)C(C)C12
Agent: [Pd]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CC(O)C1C(=O)N2C(C(=O)[O-])=C(SC3COC(COc4ccccc4)C3)C(C)C12

Procedure:
The title compound is prepared by the procedure of Example 18 using 0.320 gof product from Example 25, 0,054 g of sodium bicarbonate, 3.5 ml of water,8.3 ml of dioxane and 0.166 g of 10% palladium/carbon to give 0.052 g of the desired product.
Reaction SMILES: [H-].[Na+].[CH3:3][CH:4]([O:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH:15]([CH3:18])[CH2:16][CH3:17])=[CH:10][CH:9]=1)[CH2:5][OH:6].Cl[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=1>O1CCCC1.CN(C)P(N(C)C)(N(C)C)=O>[CH3:3][CH:4]([O:7][C:8]1[CH:9]=[CH:10][C:11]([O:14][CH:15]([CH3:18])[CH2:16][CH3:17])=[CH:12][CH:13]=1)[CH2:5][O:6][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=1
Reactant: Clc1ccccn1
Reactant: CCC(C)Oc1ccc(OC(C)CO)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: C1CCOC1
Product: CCC(C)Oc1ccc(OC(C)COc2ccccn2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of sodium hydride (0.08 g) in 5 ml of tetrahydrofuran (THF) and 2 ml of hexamethylphosphoramide (HMPA), cooled in an ice bath, is added, dropwise, 2-methyl-2-[4-(1-methylpropoxy)phenoxy]ethanol (0.63 g). The mixture is stirred at RT for 2 hours, after which a solution of 2-chloropyridine (0.38 g) in 5 ml of THF is added and the mixture is stirred at 60° for 3 hours. The THF is then removed by rotoevaporation and the residue is purified by column chromatography on silica gel to give the product, 2-{2-methyl-2-[4-(1-methylpropoxy)phenoxy]ethoxy}pyridine, MS m/e 302 (M+).
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][C:5]([B:8]([OH:10])[OH:9])=[CH:4][CH:3]=1.Br[CH2:12][C:13]1[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=1[C:15]#[N:16].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C>[C:15]([C:14]1[CH:17]=[CH:18][CH:19]=[CH:20][C:13]=1[CH2:12][S:1][C:2]1[CH:7]=[CH:6][C:5]([B:8]([OH:10])[OH:9])=[CH:4][CH:3]=1)#[N:16]
Reactant: OB(O)c1ccc(S)cc1
Reactant: N#Cc1ccccc1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: N#Cc1ccccc1CSc1ccc(B(O)O)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 61 %

Procedure:
A suspension of (4-mercaptophenyl)boronic acid (0.847 g, 5.50 mmol), 2-(bromomethyl)benzonitrile (1.62 g, 8.25 mmol) and potassium carbonate (2.28 g, 16.5 mmol) in N,N-dimethylformamide (10 mL) was stirred at room temperature for 30 min. The reaction mixture was diluted with ethyl acetate, washed twice with water and once with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was washed with hexane/ethyl acetate (2/1) and recrystallized from hexane/ethyl acetate to give the title compound (903 mg, yield 61%) as colorless crystals.
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([CH2:7][C@@H:8]([C:21]([OH:23])=[O:22])[CH2:9][C:10]([C@@H:12]([NH2:20])[CH2:13][CH2:14][CH2:15][N:16]=[C:17]([NH2:19])[NH2:18])=[O:11])=[CH:3][CH:2]=1.Cl.[C:25](Cl)(=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(=O)([O-])[O-].[Na+].[Na+].Cl>O.C(OCC)C>[C:25]([NH:20][CH:12]([CH2:13][CH2:14][CH2:15][NH:16][C:17]([NH2:19])=[NH:18])[C:10](=[O:11])[CH2:9][CH:8]([CH2:7][C:4]1[CH:5]=[CH:6][CH:1]=[CH:2][CH:3]=1)[C:21]([OH:23])=[O:22])(=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: NC(N)=NCCC[C@H](N)C(=O)C[C@@H](Cc1ccccc1)C(=O)O
Reactant: O=C(Cl)c1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Product: N=C(N)NCCCC(NC(=O)c1ccccc1)C(=O)CC(Cc1ccccc1)C(=O)O
Reaction time: 0.5 h

Procedure:
Arphamenine A hydrochloride (200 mg) was dissolved in 1 ml of water, and to the resulting solution were added 98 μl of benzoyl chloride and 119 mg of sodium carbonate, each in 1/5 portions at 30 minutes-interval and totally five times, under ice-cooling and stirring. After the reaction was completed, the reaction mixture was adjusted to pH 7.0 with 1N HCl, followed by addition of ethyl ether thereto. The precipitate as formed was washed with water and dried to give 225 mg of the titled compound as a colorless powder. This product gave a value of m/z 425 (MH+) in mass spectrometry.