Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([OH:8])(=O)[CH2:2][CH2:3][C:4](O)=[O:5].Cl.[C:10](Cl)(=O)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]C>>[CH2:11]([CH:10]1[C:4](=[O:5])[CH2:3][CH2:2][C:1]1=[O:8])[CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: CCCCCCC(=O)Cl
Reactant: O=C(O)CCC(=O)O
Agent: Cl
Product: CCCCCC1C(=O)CCC1=O
Temperature: 80 °C

Procedure:
After charging succinic acid, the mixture was allowed stand to complete generation of HCl gas. Then, thereto was added 60 g (0.4 mol) of heptanoyl chloride, and the resulting mixture was heated at 80° C. for 8 hours. Since heptanoyl chloride is also fuming (HCl gas), measures were taken against corrosion of equipment in the peripheral environment at the time of weighing, but it was with difficulty. The mixture was cooled, poured onto 60 g of ice, and maintained at −10° C. for 10 hours, depositing a product as a solid. The product was subjected to suction filtration, washed with 10% NaCl water and toluene (20 ml×3 times), and dried, yielding 8.4 g (0.05 mol) of 2-pentyl-1,3-cyclopentanedione (a compound in which R1 represents an n-pentyl group in the above formula (3)). Yields were 20.8%, 50.0%, and 12.5% relative to AlCl3, succinic acid, and heptanoyl chloride, respectively. Simultaneously, wastewater containing a large amount of an aluminum-based and a chlorine-based compound was byproduced.
Reaction SMILES: N([O-])=[O:2].[Na+].[C:5]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)=[C:10](N)[CH:9]=1)(=[O:7])[CH3:6]>O.S(=O)(=O)(O)O>[C:5]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)=[C:10]([OH:2])[CH:9]=1)(=[O:7])[CH3:6]
Reactant: CC(=O)c1ccc(-c2ccc(F)cc2)c(N)c1
Reactant: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: CC(=O)c1ccc(-c2ccc(F)cc2)c(O)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of sodium nitrite (12.0 g.) in water (40 ml.) was added to a stirred solution of 4-acetyl-2-amino-4'-fluorobiphenyl (36.6 g.) in 5N sulphuric acid (480 ml.), whilst maintaining the temperature of the reaction mixture at 0° - 5°C. The reaction mixture was stirred at 0° - 5°C. for a further 1 hour. The resulting cold solution of diazonium salt was poured slowly into stirred refluxing 5N sulphuric acid (400 ml.). When the addition was complete, refluxing was continued for 0.5 hour. The resulting solution was poured into ice/water, causing the precipitation of a solid which was collected, dried and dissolved in ether. The ethereal solution was extracted with dilute aqueous sodium hydroxide and the extract was acidified to precipitate a product which was extracted into ether. The ethereal extract was washed with water, dried over anhydrous sodium sulphate, and evaporated to give a product which was recrystallized from light petroleum (b.p. 80° - 100°C.) to give the novel intermediate 4-acetyl-4'-fluoro-2-hydroxybiphenyl, m.p. 152° - 154°C. A mixture of this compound (36.5 g.), dimethyl sulphate (25.2 g.) and potassium carbonate (25 g.) in anhydrous acetone (200 ml.) was refluxed with stirring overnight. Acetone was removed by evaporation, the residue poured into water, and the resulting mixture extracted with ether. The ether extract was washed with dilute sodium hydroxide solution, then with water and dried over anhydrous sodium sulphate. Ether was removed by evaporation and the residue was distilled in vacuo to give a product, b.p. 142° - 144°C./0.2 mm. which solidified on cooling. This solid was recrystallized from light petroleum (b.p. 62° - 68°C.) to give the novel intermediate 4-acetyl-4'-fluoro-2-methoxybiphenyl, m.p. 75° - 77°C.
Reaction SMILES: [NH3:1].[CH3:2][C:3]1([CH3:16])[O:15][C:7]2[C:8]([CH3:14])=[N:9][CH:10]=[C:11]([CH:12]=[O:13])[C:6]=2[CH2:5][O:4]1.CO>C(O)(C)C.[O-2].[O-2].[Mn+4]>[CH3:2][C:3]1([CH3:16])[O:15][C:7]2[C:8]([CH3:14])=[N:9][CH:10]=[C:11]([C:12]([NH2:1])=[O:13])[C:6]=2[CH2:5][O:4]1
Reactant: Cc1ncc(C=O)c2c1OC(C)(C)OC2
Reactant: N
Agent: [Mn+4]
Agent: [O-2]
Solvent: CC(C)O
Solvent: CO
Product: Cc1ncc(C(N)=O)c2c1OC(C)(C)OC2
Temperature: 25 °C
Reaction time: 15 h
Yield: 69 %

Procedure:
Ammonia gas was bubbled into a solution of 2,2,8-trimethyl-4H-[1,3]dioxino[4,5-c]pyridine-5-carbaldehyde (31.3 g, 151 mmol) in isopropyl alcohol (2.4 L) at 0° C. for about 30 minutes. Manganese (IV) dioxide (210 g, 7.96 mmol) was added, and the solution was stirred for about 15 hours at room temperature. Excess manganese (IV) dioxide was filtered through a celite pad and washed with isopropyl alcohol. The filtrate was evaporated and washed with diethyl ether, water, and then with methyl alcohol to give 2,2,8-trimethyl-4H-[1,3]dioxino[4,5-c]pyridine-5-carboxylic acid amide (78) (23.1 g, 69% yield) as a light yellow solid.
Reaction SMILES: [C:1](OC1C2C(=CC=CC=2)N(CCC)C1=O)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:23][C:24]1[CH:25]=[C:26]2[C:30](=[CH:31][CH:32]=1)[N:29]([CH2:33][CH2:34][CH2:35][CH:36]([CH3:38])[CH3:37])[C:28](=[O:39])[C:27]2=[O:40]>>[C:1]([O:40][CH:27]1[C:26]2[C:30](=[CH:31][CH:32]=[C:24]([CH3:23])[CH:25]=2)[N:29]([CH2:33][CH2:34][CH2:35][CH:36]([CH3:37])[CH3:38])[C:28]1=[O:39])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccc2c(c1)C(=O)C(=O)N2CCCC(C)C
Reactant: CCCN1C(=O)C(OC(=O)c2ccccc2)c2ccccc21
Product: Cc1ccc2c(c1)C(OC(=O)c1ccccc1)C(=O)N2CCCC(C)C

Procedure:
Was made in a similar way to 2-oxo-1-propylindolin-3-yl benzoate starting from 5-methyl-1-(4-methylpentyl)indoline-2,3-dione. 1H-NMR δ 8.11 (d, 2H), 7.58 (dt, 1H), 7.45 (m, 2H), 7.25 (s, 1H), 7.15 (dd, 1H), 6.77 (d, 1H), 6.17 (s, 1H), 3.70 (m, 2H), 2.31 (s, 3H), 1.73 (m, 2H), 1.61 (m, 1H), 1.29 (m, 2H), 0.90 (d, 6H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:12]2[N:13]=[CH:14][N:15]=[C:16]([N:17]3[CH2:24][C:21]4([CH2:23][CH2:22]4)[N:20]([S:25](=[O:36])(=[O:35])[NH:26][CH2:27][CH2:28][C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[CH2:19][CH2:18]3)[C:11]=2[CH:10]=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:44][CH3:45].O>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[C:12]2[N:13]=[CH:14][N:15]=[C:16]([N:17]3[CH2:24][C:21]4([CH2:23][CH2:22]4)[N:20]([S:25](=[O:35])(=[O:36])[N:26]([CH2:27][CH2:28][C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[CH2:2][CH2:1][CH2:3][C:45]4[CH:44]=[CH:12][CH:11]=[CH:10][CH:9]=4)[CH2:19][CH2:18]3)[C:11]=2[CH:10]=[CH:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)n1ccc2c(N3CCN(S(=O)(=O)NCCc4ccccc4)C4(CC4)C3)ncnc21
Reactant: CCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)n1ccc2c(N3CCN(S(=O)(=O)N(CCCc4ccccc4)CCc4ccccc4)C4(CC4)C3)ncnc21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
4-(4-Phenethylsulfamoyl-4,7-diaza-spiro[2.5]oct-7-yl)-pyrrolo[2,3-d]pyrimidine-7-carboxylic acid tert-butyl ester (intermediate 6) (0.1 mmol) was dissolved in dry DMF (0.5 mL) and added Cs2CO3 (0.12 mmol) and bromo-ethane (0.12 mmol). Stirred at rt for 16 h and then added H2O (2 mL). Extracted with EtOAc (3×2 mL) and the combined organic phases were concentrated in vacuo. The residual oil was treated with TFA (1 mL) at rt for 3 h. The pure compound was obtained by standard preparative HPLC purification of the reaction mixture.
Reaction SMILES: [Si]([O:8][CH:9]1[CH2:18][C:17]2[C:16]([NH:19][C:20]([NH2:22])=[S:21])=[CH:15][CH:14]=[CH:13][C:12]=2[CH2:11][CH2:10]1)(C(C)(C)C)(C)C.Br[CH:24]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH:25](OC)OC>CCO.Cl>[C:30]1([C:24]2[S:21][C:20]([NH:19][C:16]3[CH:15]=[CH:14][CH:13]=[C:12]4[C:17]=3[CH2:18][CH:9]([OH:8])[CH2:10][CH2:11]4)=[N:22][CH:25]=2)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: COC(OC)C(Br)c1ccccc1
Reactant: CC(C)(C)[Si](C)(C)OC1CCc2cccc(NC(N)=S)c2C1
Agent: Cl
Solvent: CCO
Product: OC1CCc2cccc(Nc3ncc(-c4ccccc4)s3)c2C1
Temperature: 25 °C

Procedure:
A mixture of the product of Example 24A (200 mg, 0.594 mmol) and the product of Example 24B (146 mg, 0.596 mmol) was refluxed for 2 hours in a mixture of EtOH (6 mL) and 1N HCl (1 mL). After cooling to room temperature, the mixture was quenched with saturated NaHCO3 solution and was extracted with EtOAc. The extracts were dried over Na2SO4, filtered evaporated under reduced pressure, and chromatographed on silica gel (95:5 to 92:8 CH2Cl2:CH3OH eluant). The title compound was afforded as a pale tan solid, 53 mg (28%). 1H NMR (DMSO-d6) δ 9.29 (s, 1H), 7.57 (m, 2H), 7.46-7.49 (m, 2H), 7.33-7.38 (m, 2H), 7.22 (m, 1H), 7.10 (m, 1H), 6.88 (d, J=7.4 Hz, 1H), 4.82 (d, J=4.0 Hz, 1H), 3.82 (m, 1H), 2.71-2.98 (m, 4H), 1.83-1.93 (m, 1H), 1.57-1.66 (m, 1H). MS (ESI+) m/z 323 (M+H). Anal. calcd. For C19H18N2OS: C, 70.78; H, 5.63; N, 8.69. Found: C, 70.91; H, 5.37; N, 8.33.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:18]=[CH:17][CH:16]=[CH:15][C:5]=1[CH2:6][CH:7]1[CH2:12][CH2:11][CH:10]([CH2:13][OH:14])[CH2:9][CH2:8]1.[F:19][C:20]1[CH:27]=[CH:26][CH:25]=[C:24](F)[C:21]=1[C:22]#[N:23]>CN(C)C=O>[F:19][C:20]1[CH:27]=[CH:26][CH:25]=[C:24]([O:14][CH2:13][CH:10]2[CH2:9][CH2:8][CH:7]([CH2:6][C:5]3[CH:15]=[CH:16][CH:17]=[CH:18][C:4]=3[F:3])[CH2:12][CH2:11]2)[C:21]=1[C:22]#[N:23]
Reactant: OCC1CCC(Cc2ccccc2F)CC1
Reactant: N#Cc1c(F)cccc1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1c(F)cccc1OCC1CCC(Cc2ccccc2F)CC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 97.5 %

Procedure:
In an 18 mL vial, sodium hydride was suspended in 2 mL dry dimethylformamide and chilled to 0° C. under nitrogen flow. 4-(2-Fluorobenzyl)cyclohexylmethanol (155 mg; 0.7 mmol) was added over 2 minutes and warmed to room temperature for 2 hours. Mixture was then added to a 0° C. mixture of 2,6-difluorobenzonitrile (97 mg; 0.7 mmol) in 2 mL of dimethylformamide over 1 minute and mixture continued to stir an additional 2 hours. Mixture was quenched over 10 g of ice and extracted 3× ethyl acetate 20 mL each. Combined organics were washed 5× water, brine and dried over MgSO4. Colorless oil was obtained and purified by flash chromatography (20:1) with 0-5% ethyl acetate in hexanes to give 233 mg of title compound. (98% yield).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:5]2[S:10][C:9](I)=[CH:8][C:6]=2[N:7]=1.[CH:18]([C:20]1[CH:21]=[C:22](B(O)O)[CH:23]=[CH:24][CH:25]=1)=[O:19]>C([O-])([O-])=O.[Na+].[Na+].C(#N)C.C(OCC)(=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:1][C:2]1[N:3]=[C:4]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:5]2[S:10][C:9]([C:24]3[CH:25]=[C:20]([CH:21]=[CH:22][CH:23]=3)[CH:18]=[O:19])=[CH:8][C:6]=2[N:7]=1
Reactant: Clc1nc(N2CCOCC2)c2sc(I)cc2n1
Reactant: O=Cc1cccc(B(O)O)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: O=Cc1cccc(-c2cc3nc(Cl)nc(N4CCOCC4)c3s2)c1
Yield: 35 %

Procedure:
2-Chloro-6-iodo-4-morpholinothieno[3,2-d]pyrimidine 19 (300 mg), 130 mg of 3-formylbenzeneboronic acid and 55 mg of Bis(triphenylphosphine)palladium(II) dichloride in 0.6 mL of 1M Na2CO3 and 0.6 mL of acetonitrile was heated to 100° C. in the microwave reactor for 15 min. The reaction mixture was diluted with ethyl acetate (60 mL), and then washed with H2O (40 mL). The organic layer was dried over MgSO4, filtered and evaporated. The residue was purified by ISCO CombiFlash (0-40% ethyl acetate/hexane) to yield 99 mg of 3-(2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)benzaldehyde.
Reaction SMILES: C(N=S(C1C=CC(CN2C(=O)C3C(=CC=CC=3)C2=O)=CC=1)(C)=[O:5])#N.[C:25]([N:27]=[S:28]([C:32]1[CH:49]=[CH:48][C:35]([CH2:36][N:37]2[C:45](=[O:46])[C:44]3[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=3)[C:38]2=[O:47])=[CH:34][CH:33]=1)[CH:29]([CH3:31])[CH3:30])#[N:26]>>[C:25]([N:27]=[S:28]([C:32]1[CH:49]=[CH:48][C:35]([CH2:36][N:37]2[C:45](=[O:46])[C:44]3[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=3)[C:38]2=[O:47])=[CH:34][CH:33]=1)([CH:29]([CH3:31])[CH3:30])=[O:5])#[N:26]
Reactant: CC(C)S(=NC#N)c1ccc(CN2C(=O)c3ccccc3C2=O)cc1
Reactant: CS(=O)(=NC#N)c1ccc(CN2C(=O)c3ccccc3C2=O)cc1
Product: CC(C)S(=O)(=NC#N)c1ccc(CN2C(=O)c3ccccc3C2=O)cc1

Procedure:
The title compound is prepared in analogy to preparation 6c, substituting 2-(4-(N-cyano-S-methylsulfinimidoyl)benzyl)isoindoline-1,3-dione with 2-(4-(N-cyano-S-isopropylsulfinimidoyl)benzyl)isoindoline-1,3-dione (preparation 14a). ESI mass spectrum: [M+H]+=368; r.t. HPLC: 3.42 min (LCMS-FA-8).
Reaction SMILES: Br[C:2]1[N:6]2[CH:7]=[CH:8][N:9]=[CH:10][C:5]2=[CH:4][CH:3]=1.Cl.[NH2:12][CH2:13][CH2:14][SH:15].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[NH2:12][CH2:13][CH2:14][S:15][C:2]1[N:6]2[CH:7]=[CH:8][N:9]=[CH:10][C:5]2=[CH:4][CH:3]=1
Reactant: NCCS
Reactant: Brc1ccc2cnccn12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: NCCSc1ccc2cnccn12
Temperature: 0 °C
Yield: 76.5 %

Procedure:
To the solution of 2.0 g of 6-bromopyrrolo[1,2-a]pyrazine prepared in Preparation Example 7 dissolved in 20 ml of dimethylformamide were added 1.8 g of 2-aminoethanethiol hydrochloride and 1.0 g of potassium carbonate. The reaction mixture was refluxed for 5 hours, poured into 100 ml of ice-water and then extracted with ethyl acetate (50 ml×3). The organic layer was isolated and concentrated to dryness; and the residue was chromatographed over silica gel to obtain 1.5 g of title compound.
Reaction SMILES: [C:1]([C:3]1[C:4](=[O:26])[N:5]([CH2:24][CH3:25])[C:6](=[O:23])[C:7](=NC2C=CC(N(CC)CCO)=CC=2)[C:8]=1[CH3:9])#[N:2].Cl.[OH2:28]>>[C:1]([C:3]1[C:4](=[O:26])[N:5]([CH2:24][CH3:25])[C:6](=[O:23])[C:7](=[O:28])[C:8]=1[CH3:9])#[N:2]
Reactant: O
Reactant: CCN1C(=O)C(=Nc2ccc(N(CC)CCO)cc2)C(C)=C(C#N)C1=O
Agent: Cl
Product: CCN1C(=O)C(=O)C(C)=C(C#N)C1=O

Procedure:
1.02 g of 3-Cyano-1-ethyl-4-methyl-5-[4-(N-ethyl-N-hydroxyethylamino)phenylimino]-pyridine-2,6-dione (prepared as described in German Offenlegungsschrift No. 2808825) is stirred in 7 ml of water, and concentrated hydrochloric acid is slowly added until the blue dye had disappeared. A pale yellow solid precipitates, and is filtered off and recrystallised from ethyl acetate/petrol, yield 0.32 g, m.p. 159°-160° C. This is the compound of formula (4).
Reaction SMILES: Cl.[NH:2]([C:4]1[CH:14]=[CH:13][C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][CH:5]=1)N.[CH:15](=O)[CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]>C(O)C.O>[CH2:17]([C:16]1[C:14]2[C:4](=[CH:5][CH:6]=[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH:13]=2)[NH:2][CH:15]=1)[CH2:18][CH2:19][CH3:20]
Reactant: CCCCCC=O
Reactant: CCOC(=O)c1ccc(NN)cc1
Agent: Cl
Solvent: O
Solvent: CCO
Product: CCCCc1c[nH]c2ccc(C(=O)OCC)cc12
Temperature: 100 °C
Yield: 7.1 %

Procedure:
To a mixture of ethyl 4-hydrazinobenzoate hydrochloride (10 gm) in ethanol:water (5:1 100 mL) was added hexanal (4.62 gm). The mixture was refluxed at 100° C. for 3 h. The solvents were removed and toluene (100 mL) and p-toluene sulfonic acid (0.1 g) were added. The mixture was refluxed at 120° C. for 18 h, cooled to room temperature and concentrated under reduced pressure. Column chromatography on silica gel (100 mL) using 90:9:1 (hexanes: methylene chloride: ethyl acetate) as eluent to give 0.8 g of the title compound: 1H NMR (CDCl3) δ 0.957, 1.44, 1.72, 2.78, 4.40, 7.02, 7.34, 7.90, 8.13, 8.38.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1[C:13]([C:23](O)=[O:24])=[N:14][C:15]2[C:20]([CH:21]=1)=[CH:19][CH:18]=[C:17]([Br:22])[CH:16]=2)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:26][C:27]1[CH:28]=[N:29][CH:30]=[CH:31][C:32]=1[N:33]1[CH2:38][C@H:37]([CH3:39])[C@H:36]([N:40]2[CH:44]=[CH:43][N:42]=[N:41]2)[C@H:35]([NH:45][C:46](=[O:52])[O:47][C:48]([CH3:51])([CH3:50])[CH3:49])[CH2:34]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[Br:22][C:17]1[CH:16]=[C:15]2[C:20]([CH:21]=[C:12]([NH:11][C:9](=[O:10])[O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[C:13]([C:23]([NH:26][C:27]3[CH:28]=[N:29][CH:30]=[CH:31][C:32]=3[N:33]3[CH2:38][C@H:37]([CH3:39])[C@H:36]([N:40]4[CH:44]=[CH:43][N:42]=[N:41]4)[C@H:35]([NH:45][C:46]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:52])[CH2:34]3)=[O:24])=[N:14]2)=[CH:19][CH:18]=1
Reactant: O=C(Nc1cc2ccc(Br)cc2nc1C(=O)O)OCc1ccccc1
Reactant: C[C@H]1CN(c2ccncc2N)C[C@@H](NC(=O)OC(C)(C)C)[C@H]1n1ccnn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H]1CN(c2ccncc2NC(=O)c2nc3cc(Br)ccc3cc2NC(=O)OCc2ccccc2)C[C@@H](NC(=O)OC(C)(C)C)[C@H]1n1ccnn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 131 %

Procedure:
To a mixture of 3-{[(benzyloxy)carbonyl]amino}-7-bromoquinoline-2-carboxylic acid (47 mg, 0.12 mmol), tert-butyl [(3R,4S,5S)-1-(3-aminopyridin-4-yl)-5-methyl-4-(1H-1,2,3-triazol-1-yl)piperidin-3-yl]carbamate (40 mg, 0.11 mmol), and HATU (100 mg, 0.27 mmol), in DMF (0.4 mL), DIPEA (0.056 mL, 0.32 mmol) was added. The reaction mixture was stirred at room temperature for 2 h then concentrated under reduced pressure. After concentration, the residue was purified by flash chromatography on silica using a CombiFlash® apparatus (0-100% EtOAc in hexanes) to give the sub-title compound as a light yellow powder (109 mg). LCMS calc. for C36H39BrN9O5 (M+H)+: m/z=756.2. Found: 756.3.
Reaction SMILES: [NH:1]1[C:55](=[O:56])[C@@H:51]([CH:52]([CH3:54])[CH3:53])[NH:50][C:48](=[O:49])[C@H:40]([CH2:41][C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[NH:39][C:37](=[O:38])[C@H:32]([CH2:33][C:34](=[O:36])[OH:35])[NH:31][C:29](=[O:30])[CH2:28][CH2:27][NH:26][C:24](=[O:25])[C@@H:2]1[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:23])[NH:8]S(C1C(C)=C(C)C(OC)=CC=1C)(=O)=O>C(O)(C(F)(F)F)=O.ClCCl.C1(S)C=CC=CC=1>[NH:1]1[C:55](=[O:56])[C@@H:51]([CH:52]([CH3:54])[CH3:53])[NH:50][C:48](=[O:49])[C@H:40]([CH2:41][C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[NH:39][C:37](=[O:38])[C@H:32]([CH2:33][C:34](=[O:35])[OH:36])[NH:31][C:29](=[O:30])[CH2:28][CH2:27][NH:26][C:24](=[O:25])[C@@H:2]1[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:8])[NH2:23]
Reactant: COc1cc(C)c(S(=O)(=O)NC(=N)NCCC[C@@H]2NC(=O)[C@@H](C(C)C)NC(=O)[C@H](Cc3ccccc3)NC(=O)[C@H](CC(=O)O)NC(=O)CCNC2=O)c(C)c1C
Agent: Sc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)[C@H]1NC(=O)[C@H](Cc2ccccc2)NC(=O)[C@H](CC(=O)O)NC(=O)CCNC(=O)[C@H](CCCNC(=N)N)NC1=O
Reaction time: 4 h

Procedure:
A solution of 0.28 g of cyclo-(Arg(Mtr)-β-Ala-Asp-Phe-D-Val) [obtainable by cyclization according to Ex. 1] in 8.4 ml of TFA, 1.7 ml of dichloromethane and 0.9 ml of thiophenol is allowed to stand at room temperature for 4 hours, then concentrated and, after diluting with water, freeze-dried. Gel filtration on Sephadex G 10 (acetic acid/water 1:1) and subsequent purification by preparative HPLC under the conditions indicated give cyclo-(Arg-β-Ala-Asp-Phe-D-Val); RT=17.0; M+ 589.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][CH:5]=[C:6]2[CH:10]=[C:9]([C:11]([O:13][CH3:14])=[O:12])[NH:8][C:7]=12.[S:15]1[CH:19]=[CH:18][CH:17]=[C:16]1[S:20](Cl)(=[O:22])=[O:21].CN(C)C(=O)C>C(OCC)(=O)C>[S:15]1[CH:19]=[CH:18][CH:17]=[C:16]1[S:20]([NH:1][C:2]1[N:3]=[CH:4][CH:5]=[C:6]2[CH:10]=[C:9]([C:11]([O:13][CH3:14])=[O:12])[NH:8][C:7]=12)(=[O:22])=[O:21]
Reactant: COC(=O)c1cc2ccnc(N)c2[nH]1
Reactant: O=S(=O)(Cl)c1cccs1
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: COC(=O)c1cc2ccnc(NS(=O)(=O)c3cccs3)c2[nH]1
Yield: 1.5 %

Procedure:
A mixed solution of methyl 7-amino-1H-pyrrolo[2,3-c]pyridine-2-carboxylate (0.40 g), thiophene-2-sulfonyl chloride (0.48 g) and N,N-dimethylacetamide (20 ml) was stirred at 120° C. for 18 hr. The reaction solution was diluted with ethyl acetate, washed with aqueous sodium hydrogencarbonate solution, water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (ethyl acetate:hexane=2:8-1:1) to give the title compound (10.5 mg, yield 1.5%) as pale-yellow crystals. melting point 159-160° C.
Reaction SMILES: [CH3:1][S:2][C:3](SC)=[CH:4][N+:5]([O-:7])=[O:6].[CH3:10][NH:11][CH3:12]>CCO>[CH3:10][N:11]([CH3:12])[C:3]([S:2][CH3:1])=[CH:4][N+:5]([O-:7])=[O:6]
Reactant: CSC(=C[N+](=O)[O-])SC
Reactant: CNC
Solvent: CCO
Product: CSC(=C[N+](=O)[O-])N(C)C

Procedure:
In 50 ml of EtOH was dissolved 3.3 g of 1,1-bis(methylthio)-2-nitroethylene and 2.2 ml of a 40% aqueous solution of dimethylamine was added dropwise in 2 portions at 30-minute intervals under refluxing. After completion of dropwise addition, the mixture was further refluxed for 30 minutes. Then, the EtOH was distilled off and the residue was subjected to silica gel column chromatography using CHCl3 --MeOH (20:1) as an eluent. The procedure gave 1.0 g of 1-dimethylamino-1-methylthio-2-nitroethylene as a yellow oil.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:21]=[CH:22][C:23]=1[N+:24]([O-])=O)[NH:7][C:8](=[O:20])[C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH:19]=[CH:18][N:17]=[CH:16]2)=[CH:11][CH:10]=1)([O-])=O.[CH3:27][O:28][C:29]1[CH:36]=[CH:35][C:32]([CH:33]=O)=[CH:31][CH:30]=1>>[N:15]1([C:12]2[CH:13]=[CH:14][C:9]([C:8]([NH:7][C:6]3[CH:21]=[CH:22][C:23]4[NH:24][C:33]([C:32]5[CH:35]=[CH:36][C:29]([O:28][CH3:27])=[CH:30][CH:31]=5)=[N:1][C:4]=4[CH:5]=3)=[O:20])=[CH:10][CH:11]=2)[CH:19]=[CH:18][N:17]=[CH:16]1
Reactant: O=C(Nc1ccc([N+](=O)[O-])c([N+](=O)[O-])c1)c1ccc(-n2ccnc2)cc1
Reactant: COc1ccc(C=O)cc1
Product: COc1ccc(-c2nc3cc(NC(=O)c4ccc(-n5ccnc5)cc4)ccc3[nH]2)cc1

Procedure:
Compound 209 was prepared according to the procedure similar to that described in Scheme III from 3,4-dinitro-N-(4-imidazol-1-ylbenzoyl)aniline and 4-methoxybenzaldehyde. [M+H]+ calcd for C24H19N5O2: 410.05; found: 410.00.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][C:18]=1[O:19][CH3:20])[C:5]([NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[CH:11]=[C:10]([CH3:15])[CH:9]=1)=[O:6].[CH3:21][C:22]1[CH:23]=[C:24]([N:28]=[C:29]=[S:30])[CH:25]=[CH:26][CH:27]=1>>[CH3:15][C:10]1[CH:9]=[C:8]([NH:7][C:5](=[O:6])[C:4]2[CH:16]=[CH:17][C:18]([O:19][CH3:20])=[C:2]([NH:1][C:29]([NH:28][C:24]3[CH:23]=[C:22]([CH3:21])[CH:27]=[CH:26][CH:25]=3)=[S:30])[CH:3]=2)[CH:13]=[C:12]([CH3:14])[CH:11]=1
Reactant: COc1ccc(C(=O)Nc2cc(C)cc(C)c2)cc1N
Reactant: Cc1cccc(N=C=S)c1
Product: COc1ccc(C(=O)Nc2cc(C)cc(C)c2)cc1NC(=S)Nc1cccc(C)c1
Yield: 48.6 %

Procedure:
Prepared according to the procedure described for Example 102 using 3-amino-N-(3,5-dimethylphenyl)-4-methoxy-benzamide from Example 11 (0.542 g, 2.01 mmol) and 3-methylphenyl isothiocyanate (0.28 mL, 2.07 mmol) to afford the product (0.41 g); m.p. 188-189° C.
Reaction SMILES: CS(C)=O.[H-].[Na+].[I-].[CH3:8][S+](C)C.[CH3:12][C:13]1[CH:20]=[CH:19][C:16]([CH:17]=[O:18])=[CH:15][N:14]=1>C1COCC1>[CH3:12][C:13]1[CH:20]=[CH:19][C:16]([CH:17]2[CH2:8][O:18]2)=[CH:15][N:14]=1
Reactant: C[S+](C)C
Reactant: Cc1ccc(C=O)cn1
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: C1CCOC1
Product: Cc1ccc(C2CO2)cn1
Temperature: 65 °C
Reaction time: 0.17 h
Yield: 137.9 %

Procedure:
DMSO (4 mL) was added to NaH 60% dispersion in oil (0.314 g, 7.8 mmol, 1.3 eq.) and heated it to 65° C. for 1 h. THF (10 mL) was added at the same temperature and heated for another min. After 10 min, reaction mixture was cooled to 0° C. Trimethylsulfonium iodide (1.2 g, 5.9 mmol, 1 eq.) was added and stirred for 10 min and solution of 6-methylnicotinaldehyde (0.720 g, 5.9 mmol, 1 eqv) in THF was added dropwise. After complete of addition, reaction mixture was stirred at RT for 2 h. Product was detected by LCMS. Reaction mixture was poured in ice water. Product was extracted in diethyl ether (4×50 mL), dried over sodium sulfate and concentrated under vacuum at 25° C. to get product 2-methyl-5-(oxiran-2-yl)pyridine (1.1 g).