Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11]2[N:14]=[C:15]([NH:17][C:18]([C:20]3[C:28]4[NH:27][C:26]([NH:29][C:30]([C:32]5[N:33]=[CH:34][C:35]6[C:40]([CH:41]=5)=[CH:39][CH:38]=[CH:37][CH:36]=6)=[O:31])=[N:25][C:24]=4[CH:23]=[CH:22][CH:21]=3)=[O:19])[S:16][C:10]=2[CH2:9]1)=O)(C)(C)C.Cl>CO>[N:14]1[C:11]2[CH2:12][CH2:13][NH:8][CH2:9][C:10]=2[S:16][C:15]=1[NH:17][C:18]([C:20]1[C:28]2[NH:27][C:26]([NH:29][C:30]([C:32]3[N:33]=[CH:34][C:35]4[C:40]([CH:41]=3)=[CH:39][CH:38]=[CH:37][CH:36]=4)=[O:31])=[N:25][C:24]=2[CH:23]=[CH:22][CH:21]=1)=[O:19]
Reactant: CC(C)(C)OC(=O)N1CCc2nc(NC(=O)c3cccc4nc(NC(=O)c5cc6ccccc6cn5)[nH]c34)sc2C1
Agent: Cl
Solvent: CO
Product: O=C(Nc1nc2cccc(C(=O)Nc3nc4c(s3)CNCC4)c2[nH]1)c1cc2ccccc2cn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 97.4 %

Procedure:
To a solution of 0.2 g (0.35 mmol) of 2-({2-[(isoquinoline-3-carbonyl)-amino]-3H-benzoimidazole-4-carbonyl}-amino)-6,7-dihydro-4H-thiazolo[5,4-c]pyridine-5-carboxylic acid tert-butyl ester in methanol (1 mL) was added HCl solution (5 mL, 4M HCl in 1,4-dioxane). The mixture was stirred at room temperature for 30 min. The conversion was checked by LCMS. After removal of the organic phase, the residue was diluted with DCM (50 mL) and the organic phase was washed with sat. aq. Na2CO3 solution, water, brine, dried over Na2SO4 and concentrated to afford 160 mg (100%) of isoquinoline-3-carboxylic acid [7-(4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-2-ylcarbamoyl)-1H-benzoimidazol-2-yl]-amide. LCMS: 470 (M+1)+.
Reaction SMILES: C(OC([N:8]1[CH2:11][CH:10]([NH:12][C:13]([NH:15][C:16]2[CH:25]=[CH:24][CH:23]=[C:22]3[C:17]=2[CH:18]=[CH:19][N:20]=[C:21]3[CH3:26])=[O:14])[CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>>[CH3:26][C:21]1[C:22]2[C:17](=[C:16]([NH:15][C:13]([NH:12][CH:10]3[CH2:9][NH:8][CH2:11]3)=[O:14])[CH:25]=[CH:24][CH:23]=2)[CH:18]=[CH:19][N:20]=1
Reactant: Cc1nccc2c(NC(=O)NC3CN(C(=O)OC(C)(C)C)C3)cccc12
Solvent: O=C(O)C(F)(F)F
Product: Cc1nccc2c(NC(=O)NC3CNC3)cccc12

Procedure:
The title compound was prepared from D6 by deprotection using trifluoroacetic acid in a similar manner to that described in WO 03/022809.
Reaction SMILES: Cl[C:2]1[CH:16]=[CH:15][C:5]2[C:6](=[O:14])[NH:7][C:8]3[C:13]([C:4]=2[CH:3]=1)=[CH:12][CH:11]=[CH:10][N:9]=3.[F:17][C:18]([F:27])([F:26])[C:19]1[CH:20]=[C:21]([CH:23]=[CH:24][CH:25]=1)[NH2:22]>>[F:17][C:18]([F:26])([F:27])[C:19]1[CH:20]=[C:21]([NH:22][C:2]2[CH:16]=[CH:15][C:5]3[C:6](=[O:14])[NH:7][C:8]4[C:13]([C:4]=3[CH:3]=2)=[CH:12][CH:11]=[CH:10][N:9]=4)[CH:23]=[CH:24][CH:25]=1
Reactant: Nc1cccc(C(F)(F)F)c1
Reactant: O=c1[nH]c2ncccc2c2cc(Cl)ccc12
Product: O=c1[nH]c2ncccc2c2cc(Nc3cccc(C(F)(F)F)c3)ccc12
Yield: 2.6 %

Procedure:
The title compound was synthesized according to the procedure described for the preparation of Example 231 using 6 (50 mg, 0.22 mmol) and 3-(trifluoromethyl)aniline (0.04 mL, 0.33 mmol) to provide 239 (2 mg, 3% yield) as a brown solid. LC-MS (M+H=356, obsd.=356).
Reaction SMILES: [O:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4](=[O:5])[C:3]([C:12](O)=[O:13])=[C:2]1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.CS(Cl)(=O)=O.[CH2:26]([N:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>CN(C)C1C=CN=CC=1.ClCCl>[CH2:26]([N:33]1[CH2:38][CH2:37][N:36]([C:12]([C:3]2[C:4](=[O:5])[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[O:1][C:2]=2[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)=[O:13])[CH2:35][CH2:34]1)[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: O=C(O)c1c(-c2ccccc2)oc2ccccc2c1=O
Reactant: c1ccc(CN2CCNCC2)cc1
Agent: CN(C)c1ccncc1
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Product: O=C(c1c(-c2ccccc2)oc2ccccc2c1=O)N1CCN(Cc2ccccc2)CC1

Procedure:
6 g of flavone-3-carboxylic acid was converted into the mixed anhydride with 5.5 g 4-dimethylaminopyridine and 2.2 ml methanesulfonyl chloride in 50 ml absolute dichloromethane under the conditions described in Example 1 (a), and the mixed anhydride was then reacted with 4.42 ml N-benzylpiperazine as described in Example 1(b). The working up of the reaction mixture and the purification of the resulting crude title compound were carried out in the manner described in Example 1 (b). 9 g of 3-[(4-benzylpiperazin-1-yl)-carbonyl] flavone were obtained.
Reaction SMILES: [CH3:1][CH:2]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[C:3](=[O:5])[CH3:4].[BH4-].[Na+]>C(O)C>[CH3:1][CH:2]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH:3]([OH:5])[CH3:4]
Reactant: CCCCCCCCCCCCCCC(C)C(C)=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CCCCCCCCCCCCCCC(C)C(C)O
Reaction time: 2 h
Yield: 99.1 %

Procedure:
2 g (7.46 mmol) of 3-methyl-heptadecan-2-one are dissolved in 20 ml of ethanol and the solution is treated, at 0° C., with 0.28 g (7.46 mmol) of sodium borohydride. Stirring is continued for two hours at 0° C. and for two hours at room temperature. The mixture is subsequently concentrated under reduced pressure, the concentrate is taken up in cyclohexane/water, and the aqueous phase is extracted three times using cyclohexane. After the extract has been dried and concentrated, 2 g (99% of theory) of 3-methyl-heptadecan-2-ol are obtained as pure substance.
Reaction SMILES: NC(N)=S.Br[CH2:6][C:7]#[C:8][CH3:9].C[S:11]([C:14]1[CH2:18][C:17]([CH3:20])([CH3:19])[O:16][N:15]=1)(=O)=O.C(=O)([O-])[O-].[K+].[K+]>C(O)C>[CH2:6]([S:11][C:14]1[CH2:18][C:17]([CH3:20])([CH3:19])[O:16][N:15]=1)[C:7]#[C:8][CH3:9]
Reactant: CC1(C)CC(S(C)(=O)=O)=NO1
Reactant: CC#CCBr
Agent: NC(N)=S
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CC#CCSC1=NOC(C)(C)C1
Temperature: 25 °C
Yield: 59.7 %

Procedure:
Thiourea (2.15 g, 28.21 mmol) was added to a solution of 1-bromo-2-butyne (2.47 ml, 28.21 mmol) in ethanol (69 ml) and the solution was heated under reflux for 1 hour 40 minutes. The mixture was allowed to cool to room temperature and 3-methanesulfonyl-5,5-dimethyl-4,5-dihydroisoxazole (5 g, 28.21 mmol) and potassium carbonate (4.28 g, 31.03 mmol) were added. The mixture was heated under reflux for 2 hours 35 minutes and allowed to cool to room temperature. The mixture was partitioned between water and ethyl acetate. The aqueous phase was extracted with ethyl acetate. The combined organic phases were washed with brine, dried over magnesium sulfate and concentrated. The residue was purified by chromatography on silica gel (eluent: ethyl acetate/hexane) to give the product (3.085 g, 60% yield) as a pale yellow oil. 1H-NMR (400 MHz, CDCl3): 1.42 (6H, s, Me), 1.83 (3H, t, Me), 2.81 (2H, s, CH2), 3.77 (2H, q, CH2).
Reaction SMILES: [C:1]([CH:5]([C:12]([OH:14])=[O:13])[CH2:6][C@@H:7]([C:9]([OH:11])=[O:10])[NH2:8])([CH3:4])([CH3:3])[CH3:2].[C:15]1(=O)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CN(C)C=O.C(O)(=O)C>[CH:15]1([NH:8][C@H:7]([C:9]([OH:11])=[O:10])[CH2:6][CH:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[C:12]([OH:14])=[O:13])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: O=C1CCCCCCC1
Reactant: CC(C)(C)C(C[C@H](N)C(=O)O)C(=O)O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: CC(C)(C)C(C[C@H](NC1CCCCCCC1)C(=O)O)C(=O)O
Reaction time: 8 h
Yield: 76.9 %

Procedure:
To a stirred suspension of γ-tert-butyl-L-glutamic acid (4.06 g, 20.0 mmol) and cyclooctanone (3.15 g, 25 mmol) in N,N-dimethylformamide/acetic acid (99:1, v/v, 50 mL) was added sodium triacetoxyborohydride (6.36 g, 30.0 mmol) in small portions and the mixture was stirred overnight. After evaporation of the solvent, the residue was dissolved in water (50 mL). The pH was adjusted to 9 with 2 N sodium hydroxide solution, followed by extraction with diethylether (50 mL). Subsequently, the pH of the aqueous layer was carefully adjusted to 2.5 using 1.0 N hydrochloric acid. Extraction with dichloromethane afforded an organic layer, which was dried (magnesium sulphate) and concentrated under reduced pressure, yielding 4.82 g (77%) of the title compound as a white solid. ESI-MS: 314.2 (M+H)+, 336.2 (M+Na)+. Rf (silica gel; ethyl acetate/pyridine/acetic acid/water 63:20:6:11, v/v): 0.80.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[O:11][CH3:12].[N:13]1[CH:18]=[CH:17][C:16](B(O)O)=[CH:15][CH:14]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC>[CH3:12][O:11][C:3]1[CH:4]=[CH:5][C:6]([N+:8]([O-:10])=[O:9])=[CH:7][C:2]=1[C:16]1[CH:17]=[CH:18][N:13]=[CH:14][CH:15]=1
Reactant: COc1ccc([N+](=O)[O-])cc1Br
Reactant: OB(O)c1ccncc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: COc1ccc([N+](=O)[O-])cc1-c1ccncc1

Procedure:
A stirred mixture of 2-bromo-4-nitroanisole (7.6 g, 32.7 mmol), 4-pyridineboronic acid (4.07 g, 33 mmol) and powdered sodium carbonate (13.8 g, 5 equivalents) in 1:1 1,2-dimethoxyethane:water (1,360 ml) was degassed for 0.5 hr, by the passage of a stream of argon. Tetrakistriphenylphosphine palladium (0) (1.35 g) was added, and the mixture was cooled, the solvents evaporated under reduced pressure to approximately half-volume, and the aqueous residue was acidified with 5N hydrochloric acid and washed with ethyl acetate. The acid phase was then basified with solid potassium carbonate, and extracted into ethyl acetate, the organic phase was dried (Na2SO4) and evaporated under reduced pressure to give the title compound (D36) as a pale yellow solid (3.4 g, 45%).
Reaction SMILES: [CH3:1][N:2]([C:10]1[CH:11]=[N:12][N:13]([C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)[CH:14]=1)[C:3](=[O:9])[O:4][C:5]([CH3:8])([CH3:7])[CH3:6].[Br:21]N1C(=O)CCC1=O>ClC(Cl)C>[Br:21][C:14]1[N:13]([C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)[N:12]=[CH:11][C:10]=1[N:2]([CH3:1])[C:3](=[O:9])[O:4][C:5]([CH3:8])([CH3:6])[CH3:7]
Reactant: O=C1CCC(=O)N1Br
Reactant: CN(C(=O)OC(C)(C)C)c1cnn(-c2cccnc2)c1
Solvent: CC(Cl)Cl
Product: CN(C(=O)OC(C)(C)C)c1cnn(-c2cccnc2)c1Br
Temperature: 50 °C
Reaction time: 8 h
Yield: 99.5 %

Procedure:
To tert-butyl methyl(1-(pyridin-3-yl)-1H-pyrazol-4-yl)carbamate (0.200 g, 0.729 mmol) in dichloroethane (3.65 ml) was added 1-bromopyrrolidine-2,5-dione (0.260 g, 1.458 mmol) and the reaction was stirred overnight at 50° C. The reaction was concentrated, diluted with dichloromethane, and washed with water and saturated aqueous sodium thiosulfate. The organic phase was concentrated to give tert-butyl 5-bromo-1-(pyridin-3-yl)-1H-pyrazol-4-yl(methyl)carbamate (256 mg, 0.725 mmol, 99%) as a brown oil: IR (thin film) 1697 cm−1; 1H NMR (400 MHz, CDCl3) δ 8.89 (s, 1H), 8.68 (d, J=4.1 Hz, 1H), 7.93 (ddd, J=8.2, 2.5, 1.5 Hz, 1H), 7.69 (s, 1H), 7.46 (dd, J=8.1, 4.8 Hz, 1H), 3.22 (s, 3H), 1.44 (s, 9H); ESIMS m/z 352 ([M−H]−).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([S:25]([O-:28])(=[O:27])=[O:26])[C:7]([CH:10]=[CH:11][C:12]2[C:13]([S:21]([O-:24])(=[O:23])=[O:22])=[CH:14][C:15]([N+:18]([O-])=O)=[CH:16][CH:17]=2)=[CH:8][CH:9]=1)([O-])=O.[Na+:29].[Na+].OS(O)(=O)=O>[Pt].O>[NH2:1][C:4]1[CH:5]=[C:6]([S:25]([O-:28])(=[O:27])=[O:26])[C:7]([CH:10]=[CH:11][C:12]2[C:13]([S:21]([O-:24])(=[O:23])=[O:22])=[CH:14][C:15]([NH2:18])=[CH:16][CH:17]=2)=[CH:8][CH:9]=1.[Na+:29].[Na+:29]
Reactant: O=[N+]([O-])c1ccc(C=Cc2ccc([N+](=O)[O-])cc2S(=O)(=O)[O-])c(S(=O)(=O)[O-])c1
Agent: [Pt]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: Nc1ccc(C=Cc2ccc(N)cc2S(=O)(=O)[O-])c(S(=O)(=O)[O-])c1

Procedure:
A 300 ml steel autoclave is charged with 48 g of sodium 4,4'-dinitrostilbene-2,2'-disulfonate, 174 g of water, 0.15 ml of 0.5 M H2SO4, 1.4 g of activated carbon, 64 mg of 5% Pt/C and 12 mg of NH4VO3. The autoclave is closed and flushed with nitrogen. The hydrogenation is carried out at 70° C. with the controlled addition of hydrogen of 2.5 NI/h (max. 4-5 bar hydrogen). After the hydrogenation is terminated, the autoclave is rendered inert, the catalyst is filtered off and the reaction mixture is analysed with HPLC. The results are listed in Table 3.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]([N:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:12])[C:5]([OH:7])=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)CC)(C)C.[Cl:49][C:50]1[CH:63]=[CH:62][C:53]2[NH:54][C:55]([C@@H:57]([NH2:61])[CH2:58][CH2:59][CH3:60])=[N:56][C:52]=2[CH:51]=1.ClCl>O1CCCC1.ClCCl.C(O)C>[Cl:49][C:50]1[CH:63]=[CH:62][C:53]2[NH:54][C:55]([C@@H:57]([NH:61][C:5](=[O:7])[C:4]3[CH:8]=[CH:9][C:10]([C:11]([N:13]4[CH2:17][CH2:16][CH2:15][CH2:14]4)=[O:12])=[C:2]([CH3:1])[CH:3]=3)[CH2:58][CH2:59][CH3:60])=[N:56][C:52]=2[CH:51]=1
Reactant: Cc1cc(C(=O)O)ccc1C(=O)N1CCCC1
Reactant: CCC[C@H](N)c1nc2cc(Cl)ccc2[nH]1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: ClCl
Agent: F[B-](F)(F)F
Solvent: C1CCOC1
Solvent: CCO
Solvent: ClCCl
Product: CCC[C@H](NC(=O)c1ccc(C(=O)N2CCCC2)c(C)c1)c1nc2cc(Cl)ccc2[nH]1
Yield: 60 %

Procedure:
Prepared analogously to Example 1g from 3-methyl-4-(pyrrolidin-1-ylcarbonyl)benzoic acid, TBTU, diisopropylethylamine, and (S)-1-(5-chloro-1H-benzimidazol-2-yl)butylamine in tetrahydrofuran. Yield: 60%; Rf value: 0.36 (silica gel; dichloromethane/ethanol=9:1); C24H27ClN4O2 (438.96); mass spectrum: (M+H)+=439/441 (chlorine isotope).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH3:24])[C:6]([NH:12][S:13]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)(=[O:15])=[O:14])=[C:7]([CH:11]=1)[C:8]([OH:10])=[O:9])#[N:2].[CH2:25](Br)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>CCOCC>[CH2:25]([C:4]1[C:3]([C:1]#[N:2])=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[C:6]([NH:12][S:13]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)(=[O:15])=[O:14])[C:5]=1[CH3:24])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: BrCc1ccccc1
Reactant: COc1ccc(S(=O)(=O)Nc2c(C)cc(C#N)cc2C(=O)O)cc1
Solvent: CCOCC
Product: COc1ccc(S(=O)(=O)Nc2c(C(=O)O)cc(C#N)c(Cc3ccccc3)c2C)cc1
Yield: 51 %

Procedure:
In the same manner as described in Example 177, 4.5 g (13 mmol) of the product of Example 180 and 5 mL of benzylbromide provided 3.5 g (51%) of the desired product as brown solid after trituration with ether. m.p. 123° C.; Electrospray Mass Spec 527 (M+H).
Reaction SMILES: CS[C:3](=[C:6]([C:9]#[N:10])[C:7]#[N:8])[S:4][CH3:5].[CH3:11][C:12]1[N:13]=[CH:14][NH:15][C:16]=1[CH2:17][S:18][CH2:19][CH2:20][NH2:21]>C(O)C>[C:9]([C:6]([C:7]#[N:8])=[C:3]([S:4][CH3:5])[NH:21][CH2:20][CH2:19][S:18][CH2:17][C:16]1[NH:15][CH:14]=[N:13][C:12]=1[CH3:11])#[N:10]
Reactant: CSC(SC)=C(C#N)C#N
Reactant: Cc1nc[nH]c1CSCCN
Solvent: CCO
Product: CSC(NCCSCc1[nH]cnc1C)=C(C#N)C#N
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Bis(methylthio)methylenemalononitrile [prepared according to the procedure described in Chem. Ber., 95, 2861 (1962)] (9.94 g, 58.4 mmole) was added with stirring to a solution of 2-[(4-methyl-1H-imidazol-5-yl)methylthio]ethylamine (10.0 g, 58.4 mmole) in 100 ml of absolute ethanol. After stirring at room temperature for 90 minutes, the solvent was removed by evaporation under reduced pressure, and the residue placed on silica gel and chromatographed to yield the title compound (15.65 g).
Reaction SMILES: Br[C:2]1[O:3][C:4]2[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:5]=2[N:6]=1.[NH2:13][C:14]1[CH:19]=[CH:18][C:17](B2OC(C)(C)C(C)(C)O2)=[CH:16][N:15]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:12][O:11][C:9]1[CH:8]=[CH:7][C:5]2[N:6]=[C:2]([C:17]3[CH:18]=[CH:19][C:14]([NH2:13])=[N:15][CH:16]=3)[O:3][C:4]=2[CH:10]=1
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Reactant: COc1ccc2nc(Br)oc2c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: COc1ccc2nc(-c3ccc(N)nc3)oc2c1
Temperature: 80 °C
Reaction time: 2 h
Yield: 32.1 %

Procedure:
2-Bromo-6-methoxy-1,3-benzoxazole (0.877 mmol), 2-amino-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine (1.3 mmol), K2CO3 2M aq. (3.5 mmol) and Pd(dppf)Cl2 (0.022 mmol) were mixed in DMF (5 ml) and stirred at 80° C. for 2 h. The solvents were evaporated under reduced pressure and the crude product was subjected to flash column chromatography followed by purification using reverse phase HPLC to afford the title compound as a white solid (68 mg). 1H NMR δ ppm 8.67 (br. s, 1H) 8.12-7.91 (m, 1H) 7.69-7.51 (m, 1H) 7.34 (br. s, 1H) 6.89-7.00 (m, 1H) 6.75 (br. s, 2H) 6.43-6.65 (m, 1H) 3.84 (s, 3H); MS m/z 242 (M+H).
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[CH2:3][O:4][C:5]1[N:10]=[C:9]([CH2:11]O)[CH:8]=[CH:7][CH:6]=1.S(Cl)([Cl:17])=O>C(Cl)Cl>[Cl:17][CH2:11][C:9]1[CH:8]=[CH:7][CH:6]=[C:5]([O:4][CH2:3][C:2]([F:14])([F:13])[F:1])[N:10]=1
Reactant: O=S(Cl)Cl
Reactant: OCc1cccc(OCC(F)(F)F)n1
Solvent: ClCCl
Product: FC(F)(F)COc1cccc(CCl)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100.1 %

Procedure:
A mixture of (6-(2,2,2-trifluoroethoxy)pyridin-2-yl)methanol (0.32 g, 1.55 mmol, Step-3), and thionyl chloride (0.23 mL, 3.10 mmol) in DCM (16 mL) is stirred at rt for 1 hour. The organic solvent is concentrated under reduced pressure and dried to give 0.35 g (>99% yield) of the title compound as yellow oil. This material is used for the next reaction (Step-5) without further purification.
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([N+:11]([O-])=O)[C:6]=1[CH3:14].[H][H]>[Ni].CO>[OH:1][CH2:2][CH2:3][NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([NH2:11])[C:6]=1[CH3:14]
Reactant: Cc1c(NCCO)cccc1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Ni]
Solvent: CO
Product: Cc1c(N)cccc1NCCO

Procedure:
10 g of the 2-(β-hydroxyethylamino)-6-nitro-toluene prepared under Example 3, stage 2 are transferred to a stainless steel autoclave together with 200 ml of methanol, about 2 g of Raney nickel are added, and catalytic reduction is carried out with hydrogen under a hydrogen pressure of 20 bar at 70° C. in the course of 6 hours. After the catalyst has been removed, the mother liquor is concentrated and the product is isolated and dried.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([N:12]2[CH2:16][CH2:15][S:14][CH:13]2[C:17]([OH:19])=O)=[O:11])[CH:5]=[C:6]([Cl:8])[CH:7]=1>Cl>[Cl:8][C:6]1[CH:5]=[C:4]([N:9]2[C:17](=[O:19])[CH:13]3[S:14][CH2:15][CH2:16][N:12]3[C:10]2=[O:11])[CH:3]=[C:2]([Cl:1])[CH:7]=1
Reactant: O=C(O)C1SCCN1C(=O)Nc1cc(Cl)cc(Cl)c1
Agent: Cl
Product: O=C1C2SCCN2C(=O)N1c1cc(Cl)cc(Cl)c1
Yield: 87.2 %

Procedure:
A mixture of 13.0 g of 3-(3,5-dichlorophenylcarbamoyl)thiazolidine-2-carboxylic acid thus obtained and 50 ml of concentrated hydrochloric acid was stirred at 120° C. for 2 hours. Then the reaction mixture was cooled and filtered to separate the precipitate, followed by recrystallization from a mixed solvent of ethyl acetate and n-hexane to give 10.7 g (yield 86.9%) of 6-(3,5-dichlorophenyl)perhydroimidazo[5,1-b]thiazole-5,7-dion (Compound No. 1). Its melting point and Elementary Analysis were as given in table 1.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([N+:11]([O-:13])=[O:12])[CH:3]=1.[N+:14]([C:17]1[CH:25]=[CH:24][C:20]([C:21](Cl)=[O:22])=[CH:19][CH:18]=1)([O-:16])=[O:15]>>[N+:14]([C:17]1[CH:18]=[CH:19][C:20]([C:21]([NH:1][C:2]2[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([N+:11]([O-:13])=[O:12])[CH:3]=2)=[O:22])=[CH:24][CH:25]=1)([O-:16])=[O:15]
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Reactant: Nc1ccc(C(=O)O)c([N+](=O)[O-])c1
Product: O=C(Nc1ccc(C(=O)O)c([N+](=O)[O-])c1)c1ccc([N+](=O)[O-])cc1

Procedure:
4-(4-Nitrobenzoylamino)-2-nitrobenzoic acid was prepared as described in Example 3 from 20.0 g (0.11 mol) of 4-amino-2-nitrobenzoic acid and 22.4 g (0.121 mol) of 4-nitrobenzoyl chloride. The product was reprecipitated from THF/H2O.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:9][CH3:10])[C:4]1[CH:8]=[CH:7][S:6][CH:5]=1.CCOCC.C([Li])CCC.[F:21][C:22]1[CH:29]=[CH:28][CH:27]=[CH:26][C:23]=1[CH:24]=[O:25]>O1CCCC1>[CH3:1][O:2][CH:3]([O:9][CH3:10])[C:4]1[CH:8]=[CH:7][S:6][C:5]=1[CH:24]([C:23]1[CH:26]=[CH:27][CH:28]=[CH:29][C:22]=1[F:21])[OH:25]
Reactant: COC(OC)c1ccsc1
Reactant: O=Cc1ccccc1F
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOCC
Product: COC(OC)c1ccsc1C(O)c1ccccc1F
Temperature: 25 °C

Procedure:
To 3-thiophenecarboxaldehyde dimethyl acetal (11.9 g) and ether (180 ml) was added n-butyllithium (31.0 ml, 2.5M in hexanes) at a rate so as to maintain gentle reflux of the solvent. The mixture was heated under reflux for 0.5 hr, cooled to ambient temperature, diluted with tetrahydrofuran (50 ml), was cooled to -78° C., and 2-fluorobenzaldehyde (8.50 ml) in tetrahydrofuran (90 ml) was added. The reaction mixture was allowed to warm to ambient temperature over several hrs and was quenched with dilute aqueous ammonium chloride solution and ether. The layers were separated and the organic layer was washed with dilute aqueous ammonium chloride solution. The combined aqueous layers were back-extracted with ether, and the combined organic layers were washed with brine, dried over anhydrous potassium carbonate, and filtered. Concentration of the residue afforded 3-(dimethoxymethyl)-α-(2-fluorophenyl)-2-thiophenemethanol.
Reaction SMILES: [C:1]([N:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][C:13]([Cl:20])=[C:14]([Cl:19])[CH:15]=2)[CH:10]1[C:21]#[N:22])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:23][O:24][C:25]1[CH:26]=[C:27]([CH:30]=[C:31]([O:35][CH3:36])[C:32]=1[O:33][CH3:34])[CH2:28]Cl.[OH-].[Na+].O>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.C1(C)C=CC=CC=1.C(Cl)Cl>[C:1]([N:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][C:13]([Cl:20])=[C:14]([Cl:19])[CH:15]=2)[C:10]1([CH2:28][C:27]1[CH:30]=[C:31]([O:35][CH3:36])[C:32]([O:33][CH3:34])=[C:25]([O:24][CH3:23])[CH:26]=1)[C:21]#[N:22])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N#CC1c2cc(Cl)c(Cl)cc2C=CN1C(=O)c1ccccc1
Reactant: COc1cc(CCl)cc(OC)c1OC
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: ClCCl
Product: COc1cc(CC2(C#N)c3cc(Cl)c(Cl)cc3C=CN2C(=O)c2ccccc2)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of 1.7 g (5.17 mmole) of 2-benzoyl-6,7-dichloro-1-cyano-1,2-dihydroisoquinoline, 1.16 g (5.37 mmole) of 3,4,5-trimethoxybenzyl chloride and 0.118 g (0.517 mmole) of benzyltriethylammonium chloride in 25 ml of toluene, under nitrogen, was added 7.2 ml of 50% sodium hydroxide solution. The mixture was stirred vigorously at ambient temperature for 2 hours, and then 25 ml of water and 25 ml of methylene chloride was added. The organic layer was separated, washed with water, dried over magnesium sulphate and concentrated to give 2-benzoyl-1-(3,4,5-trimethoxybenzyl)-6,7-dichloro-1-cyano-1,2-dihydroisoquinoline, m.p. 193°-195° C., after recrystallization from acetonitrile.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[C:5]([N+:15]([O-:17])=[O:16])=[C:4]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:3]=1.C(=O)([O-])[O-].[K+].[K+].[N:30]1[C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=2[NH:32][CH:31]=1>C1COCC1.C(OCC)(=O)C>[N:30]1([C:2]2[N:7]=[C:6]([NH:8][CH:9]3[CH2:14][CH2:13][O:12][CH2:11][CH2:10]3)[C:5]([N+:15]([O-:17])=[O:16])=[C:4]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[N:3]=2)[C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=2[N:32]=[CH:31]1
Reactant: c1ccc2[nH]cnc2c1
Reactant: O=[N+]([O-])c1c(NC2CCOCC2)nc(Cl)nc1-c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1c(NC2CCOCC2)nc(-n2cnc3ccccc32)nc1-c1ccccc1
Temperature: 70 °C
Reaction time: 2.5 h
Yield: 38.4 %

Procedure:
To 100 mg (0.3 mmol) of 2-chloro-5-nitro-6-phenyl-N-(tetrahydro-2H-pyran-4-yl)pyrimidin-4-amine in 5 mL of THF was added potassium carbonate (213 mg, 1.54 mmol, 5.1 equiv.), followed by benzimidazole (106 mg, 0.9 mmol, 3 equiv.) and the reaction mixture was stirred at 70° C. After 2.5 h, heating was discontinued; the reaction mixture was diluted with 70 mL of ethyl acetate, was washed with water and dried (anhydrous MgSO4). The solvent was removed in vacuo and the residue purified by column chromatography (silica gel, elution with 4/1 hexanes/ethyl acetate) to give the desired product (48 mg, 38% yield). LC-MS: tR=7.35 min, MS (EI) m/z 417.2 (MH)+.