Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][O:8][C:9]1[CH:28]=[CH:27][C:12]([CH2:13][O:14][C:15]2[C:20]([C:21](OCC)=[S:22])=[CH:19][N:18]=[C:17]([CH3:26])[N:16]=2)=[CH:11][CH:10]=1>O1CCCC1.[O-2].[O-2].[Mn+4]>[CH3:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:13][O:14][C:15]2[C:20]([CH:21]=[S:22])=[CH:19][N:18]=[C:17]([CH3:26])[N:16]=2)=[CH:27][CH:28]=1
Reactant: CCOC(=S)c1cnc(C)nc1OCc1ccc(OC)cc1
Agent: [Mn+4]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: COc1ccc(COc2nc(C)ncc2C=S)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 100.7 %

Procedure:
An ice-cooled suspension of 1.6 g (42 mmol) of lithium aluminium hydride in 150 ml of tetrahydrofuran was treated slowly with a solution of 14 g (42 mmol) of ethyl 4-(4-methoxy-benzyloxy)-2-methylthiopyrimidine-5-carboxylate in 150 ml of tetrahydrofuran. After 15 minutes the reaction was quenched by the cautious addition of 1.5 ml of water, 0.8 ml of 2M aqueous sodium hydroxide and 2.3 ml of water. The resulting suspension was filtered through hyflo filter aid. The filtered solid was washed thoroughly with tetrahydrofuran and the combined filtrate and washings evaporated. The residue was partitioned between 200 ml of dichloromethane and 100 ml of water. The organic phase was dried over magnesium sulfate and filtered. To the filtrate was added a further 100 ml of dichloromethane which was then treated with 36 g (414 mmol) of manganese dioxide. The mixture was stirred at ambient temperature for 2 hours and filtered through hyflo filter aid. The filtrate was evaporated to give 11.6 g (95%) of 4-(4-methoxy-benzyloxy)-2-methylthiopyrimidine-5-carboxaldehyde as a pale yellow oil. [Mass spectrum (ESI) MH+ =291].
Reaction SMILES: [NH2:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:9])[NH2:8].[C:13]([NH:23][CH2:24][C:25]([OH:27])=O)([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14]>CN(C)C=O>[C:13]([NH:23][C@H:24]([C:25]([NH:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:8])[NH2:9])=[O:27])[CH2:16][CH:17]([CH3:22])[CH3:18])([O:15][CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)=[O:14]
Reactant: N=C(N)NCCC[C@H](N)C(=O)O
Reactant: O=C(O)CNC(=O)OCc1ccccc1
Solvent: CN(C)C=O
Product: CC(C)C[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@@H](CCCNC(=N)N)C(=O)O
Temperature: 25 °C
Reaction time: 24 h
Yield: 96 %

Procedure:
1.74 g (10.00 mM) of arginine are suspended in 25 ml of dimethylformamide, the solution is added with 4,25 g (11.00 mM) of p-nitrophenyl ester of carbobenzoxy-glycine, the mixture is stirred at room temperature for one day. Dimethylformamide is evaporated, the residue is dissolved in 5 ml of methanol and added with 300 ml of ether. The resulting precipitate is filtered-off, washed with ether on the filter and dried in a vacuum desiccator to give 4.05 g (96%) of carbobenzoxy-leucyl-arginine, m.p. 126°-130° C.
Reaction SMILES: [Cl-:1].[OH:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C@H:10]([NH3+:15])[C:11]([O:13][CH3:14])=[O:12])=[CH:5][C:4]=1[O:16][C:17](=[O:20])[NH:18][CH3:19].[CH2:21]([O:23]CC)[CH3:22]>C(O)(=O)C>[Cl-:1].[C:21]([O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C@H:10]([NH3+:15])[C:11]([O:13][CH3:14])=[O:12])=[CH:5][C:4]=1[O:16][C:17](=[O:20])[NH:18][CH3:19])(=[O:23])[CH3:22]
Reactant: CCOCC
Reactant: CNC(=O)Oc1cc(C[C@H]([NH3+])C(=O)OC)ccc1O
Agent: [Cl-]
Solvent: CC(=O)O
Product: CNC(=O)Oc1cc(C[C@H]([NH3+])C(=O)OC)ccc1OC(C)=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
(S)-2-(4-Hydroxy-3-methylcarbamoyloxyphenyl)-1-methoxycarbonylethylammonium chloride (1.68 g, 6.26 mM) was dissolved in acetic acid (25 ml). HCl (g) was bubbled through the reaction mixture for 5 minutes before adding acetyl chloride (4.45 ml, 62.6 mM) dropwise. The reaction mixture was stirred at room temperature for 2 h. The mixture was concentrated to approximately half of its initial reaction volume. Diethyl ether was added to afford a solid. The solvent was evaporated and the residue was triturated with diethyl ether. The product was collected by filtration and dried under vacuum to constant weight to afford (S)-2-(4-Acetoxy-3-methylcarbamoyloxy-phenyl)-1-methoxycarbonyl-ethyl-ammonium chloride as a solid, 1.55 g. 1H-NMR (500 MHz, DMSO-d6): δ=2.23 (s, 3H), 2.65 (d, J=4.6 Hz, 3H), 3.08-3.11 (m, J=14.35 Hz, 7.1 Hz, 1H), 3.14-3.17 (m, J=14.15 Hz, 5.9 Hz, 1H), 3.68 (s, 3H), 4.28 (t, 1H, CH), 7.10-7.17 (m, 3H), 7.70 (q, J=4.55 Hz, 1H), 8.59 (s, 3H). HPLC/MS (Method A) retention time 2.85 min, m/z 311 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:9][O:8][B:7]([OH:10])[C:6]=2[CH:11]=1.[NH:12]1[C:20]2[C:15](=[CH:16][C:17]([S:21](Cl)(=[O:23])=[O:22])=[CH:18][CH:19]=2)[CH:14]=[N:13]1.O>N1C=CC=CC=1>[OH:10][B:7]1[C:6]2[CH:11]=[C:2]([NH:1][S:21]([C:17]3[CH:16]=[C:15]4[C:20](=[CH:19][CH:18]=3)[NH:12][N:13]=[CH:14]4)(=[O:23])=[O:22])[CH:3]=[CH:4][C:5]=2[CH2:9][O:8]1
Reactant: O=S(=O)(Cl)c1ccc2[nH]ncc2c1
Reactant: Nc1ccc2c(c1)B(O)OC2
Solvent: O
Solvent: c1ccncc1
Product: O=S(=O)(Nc1ccc2c(c1)B(O)OC2)c1ccc2[nH]ncc2c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 6-amino-3H-benzo[c][1,2]oxaborol-1-ol (0.385 g, 2.07 mmol) in anhydrous pyridine (30 mL) at 5° C. was added 1H-indazole-5-sulfonyl chloride (0.45 g, 2.07 mmol) and the resulting orange solution stirred at room temperature for 0.5 h. The reaction was warmed to 50° C. for 2 h and then the pyridine was removed under reduced pressure to afford a sticky residue. This was treated with water (40 mL) and sonicated for 5 h at 70° C. The fine precipitate that formed was collected by filtration, washed with water and dried in vacuo generating 0.402 g (59%) of the title compound as a yellowish orange solid. mp 222° C.; 1H NMR (400 MHz, DMSO-d6) δ (ppm): 10.21 (s, 1H), 9.19 (s, 1H), 8.24 (s, 2H), 7.67 (s, 2H), 7.48 (d, J=1.2 Hz, 1H), 7.22 (d, J=8.0 Hz, 1H), 7.17 (dd, J=8.2, 2.0 Hz, 1H), 4.84 (s, 2H); MS (ESI) m/z=330 (M+1, positive); HPLC purity: 97.30% (MaxPlot 200-400 nm), 97.30% (220 nm).
Reaction SMILES: C([O:5][C:6]([CH2:8][O:9][CH2:10][CH:11]([NH:13][C:14]1[CH:24]=[CH:23][C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:16][C:15]=1[Cl:25])[CH3:12])=[O:7])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[Cl:25][C:15]1[CH:16]=[C:17]([CH:23]=[CH:24][C:14]=1[NH:13][CH:11]([CH3:12])[CH2:10][O:9][CH2:8][C:6]([OH:7])=[O:5])[C:18]([O:20][CH2:21][CH3:22])=[O:19]
Reactant: CCOC(=O)c1ccc(NC(C)COCC(=O)OC(C)(C)C)c(Cl)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1ccc(NC(C)COCC(=O)O)c(Cl)c1

Procedure:
Prepared analogously to Example 1g from ethyl 4-[2-(tert.-butoxycarbonylmethoxy)-1-methyl-ethylamino]-3-chloro-benzoate and trifluoroacetic acid in dichloromethane.
Reaction SMILES: [Cl:1][S:2]([N:5]=[C:6]=[O:7])(=[O:4])=[O:3].[C:8]([OH:12])([CH3:11])([CH3:10])[CH3:9]>ClCCl>[Cl:1][S:2]([NH:5][C:6](=[O:7])[O:12][C:8]([CH3:11])([CH3:10])[CH3:9])(=[O:4])=[O:3]
Reactant: O=C=NS(=O)(=O)Cl
Reactant: CC(C)(C)O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NS(=O)(=O)Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of chlorosulfonyl isocyanate (9.2 μL, 0.11 mmol) in dichloromethane (0.24 mL), at 0° C. and under a nitrogen atmosphere, was added tert-butyl alcohol (10 μL, 0.11 mmol) in a dropwise fashion. The solution was allowed to stir at room temperature for 1 hour to obtain a solution of tert-butyl [chlorosulfonyl]carbamate.
Reaction SMILES: [C:1]([C:3]([C:14](=[O:30])[N:15]([CH2:26][CH2:27][CH2:28][CH3:29])[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=1)=[CH:4][NH:5][C:6](=[NH:13])[N:7]1[CH2:11][CH2:10][NH:9][C:8]1=[O:12])#[N:2]>C(O)(=O)C>[CH2:26]([N:15]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:23])([F:24])[F:25])[CH:17]=1)[C:14]([C:3]1[C:1]([NH2:2])=[N:13][C:6]([N:7]2[CH2:11][CH2:10][NH:9][C:8]2=[O:12])=[N:5][CH:4]=1)=[O:30])[CH2:27][CH2:28][CH3:29]
Reactant: CCCCN(C(=O)C(C#N)=CNC(=N)N1CCNC1=O)c1cccc(C(F)(F)F)c1
Solvent: CC(=O)O
Product: CCCCN(C(=O)c1cnc(N2CCNC2=O)nc1N)c1cccc(C(F)(F)F)c1
Yield: 47.2 %

Procedure:
As in Example 51, 1.80 g (4.26 mmol) of 1-cyano-1-[N-butyl-N-(3-trifluoromethylphenyl)carbamoyl]-2-[imino(2-oxo-1-imidazolidinyl)methylamino]ethene (compound II, R1, R2, R3, R5, R6 =H; R4 =n-C4H9) and 4.7 ml of glacial acetic acid were stirred at 60° for 4 hours and subsequently worked up. 0.85 g (=47.3% yield) of pure 4-amino-2-(2-oxo-1-imidazolidinyl)pyrimidine-5-carboxylic acid N-butyl-N-(3-trifluoromethylphenyl)amide was obtained, melting point 234°-235°.
Reaction SMILES: Br[C:2]1[S:3][C:4]([S:7][CH2:8][C:9]([NH:11][CH2:12][C@@H:13]2[O:18][CH2:17][CH2:16][N:15]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=3)[CH2:14]2)=[O:10])=[CH:5][CH:6]=1.[N:28]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1.C(=O)([O-])O.[Na+]>COCCOC.O>[Cl:27][C:22]1[CH:21]=[C:20]([CH:25]=[CH:24][C:23]=1[Cl:26])[CH2:19][N:15]1[CH2:16][CH2:17][O:18][C@@H:13]([CH2:12][NH:11][C:9](=[O:10])[CH2:8][S:7][C:4]2[S:3][C:2]([C:31]3[CH:32]=[CH:33][N:28]=[CH:29][CH:30]=3)=[CH:6][CH:5]=2)[CH2:14]1
Reactant: OB(O)c1ccncc1
Reactant: O=C(CSc1ccc(Br)s1)NC[C@H]1CN(Cc2ccc(Cl)c(Cl)c2)CCO1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: O=C(CSc1ccc(-c2ccncc2)s1)NC[C@H]1CN(Cc2ccc(Cl)c(Cl)c2)CCO1
Temperature: 100 °C
Reaction time: 8 h
Yield: 18.1 %

Procedure:
The resultant product (500 mg) of Example 31 and 4-pyridylboronic acid (250 mg) were dissolved in a mixed solvent of ethylene glycol dimethyl ether (25 mL) and water (5 mL), sodium hydrogen carbonate (500 mg) and tetrakistriphenylphosphine palladium (60 mg) were added, and the mixture was stirred overnight at 100° C. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography using a mixed solvent of chloroform and methanol as an eluent. The solvent was evaporated from the eluent, and the obtained residue was recrystallized from ethyl acetate to give the title compound (90 mg) as a pale-brown powder.
Reaction SMILES: [C:1]([CH2:3][N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([I:13])[CH:11]=2)[CH:6]=[C:5]1[C:14](OCC)=O)#[N:2].[H-].[Al+3].[Li+].[H-].[H-].[H-].C(C(C(C([O-])=O)O)O)([O-])=O.[Na+].[K+].C(OCC)(=O)C>CCOCC>[I:13][C:10]1[CH:9]=[CH:8][C:7]2[CH:6]=[C:5]3[CH2:14][NH:2][CH2:1][CH2:3][N:4]3[C:12]=2[CH:11]=1
Reactant: CCOC(=O)c1cc2ccc(I)cc2n1CC#N
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: Ic1ccc2cc3n(c2c1)CCNC3
Temperature: 25 °C
Reaction time: 18 h
Yield: 31.5 %

Procedure:
Ethyl 1-(cyanomethyl)-6-iodoindole-2-carboxylate (1.77 g, 5 mmol) was added portion-wise over 2 min to a stirred suspension of lithium aluminium hydride (0.48 g, 13 mmol) in ether (50 mL) at 0° C. under Ar. The reaction was then heated to reflux and stirred for 18 h. After allowing to cool to room temperature the mixture was poured into a mixture of saturated aqueous potassium sodium tartrate solution (150 mL) and ethyl acetate (100 mL). The mixture was filtered through celite and the biphasic filtrate was separated. The aqueous layer was extracted with ethyl acetate (2×50 mL) and the combined organic extracts were washed with brine (1×75 mL), dried (magnesium sulfate), filtered and the solvent removed under vacuum to leave a crude oil. The oil was purified by flash column chromatography [SiO2; ethyl acetate-methanol, (9:1)] to give the product as a yellow solid (0.47 g, 32%, contains 15% of de-iodinated material). IR νmax (Nujol)/cm−1 3306, 2924, 2855, 1882, 1735, 1664, 1598, 1527, 1460, 1410, 1378, 1356, 1338, 1322, 1298, 1282, 1246, 1218, 1202, 1170, 1143, 1116, 1045, 1001, 984, 943, 919, 876, 840, 814, 773, 740, 698, 637, 617, 589, 522 and 488; NMR δH (400 MHz; CDCl3) 7.60 (1H, m), 7.35–7.37 (1H, m), 7.28 (1H, d, J 7.8 Hz), 6.15 (1H, m), 4.19 (2H, m), 3.94 (2H, t, J 5.8 Hz), 3.33 (2H, t, J 5.8 Hz), 1.79 (1H, br. s).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:23]#[N:24])=[C:4]([CH:20]=[CH:21][CH:22]=1)[O:5][CH2:6][C@H:7]([NH:9]C(=O)OCC1C=CC=CC=1)[CH3:8].O=[C:26]([CH3:33])[CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29]>>[NH2:24][C:23]1[C:3]2[C:2](=[CH:22][CH:21]=[CH:20][C:4]=2[O:5][CH2:6][C@H:7]([NH2:9])[CH3:8])[N:1]=[C:26]([CH3:33])[C:27]=1[C:28]([O:30][CH2:31][CH3:32])=[O:29]
Reactant: CCOC(=O)CC(C)=O
Reactant: C[C@H](COc1cccc(N)c1C#N)NC(=O)OCc1ccccc1
Product: CCOC(=O)c1c(C)nc2cccc(OC[C@@H](C)N)c2c1N

Procedure:
Prepared as in Example 2a from (R)-benzyl (1-(3-amino-2-cyanophenoxy)propan-2-yl)-carbamate (Example 86c) and ethyl 3-oxobutanoate as brown solid. MS 304 (MH+).
Reaction SMILES: [CH:1]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](O)=[CH:5][CH:4]=1)=[O:2].C(C1C=CC2C(=CC=CC=2)C=1O)=[O:15].C(C1C=C(O)C2C(C=1)=CC=CC=2)=O>>[CH:1]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:4]=1[OH:15])=[O:2]
Reactant: O=Cc1ccc(O)c2ccccc12
Reactant: O=Cc1ccc2ccccc2c1O
Agent: O=Cc1cc(O)c2ccccc2c1
Product: O=Cc1c(O)ccc2ccccc12

Procedure:
4-formyl-1-naphthol; 2-formyl-1-naphthol; 3-formyl-1-naphthol; and 2-anthrol-1-aldehyde.
Reaction SMILES: [NH2:1][CH:2]1[CH2:9][CH2:8][CH2:7][CH2:6][NH:5][C:3]1=[O:4].C(N(CC)CC)C.F[C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=1>CN(C)C=O>[N+:24]([C:21]1[CH:22]=[CH:23][C:18]([NH:1][CH:2]2[CH2:9][CH2:8][CH2:7][CH2:6][NH:5][C:3]2=[O:4])=[CH:19][CH:20]=1)([O-:26])=[O:25]
Reactant: NC1CCCCNC1=O
Reactant: O=[N+]([O-])c1ccc(F)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C1NCCCCC1Nc1ccc([N+](=O)[O-])cc1
Reaction time: 48 h
Yield: 28 %

Procedure:
5 g (39 mmol) of α-amino-ε-caprolactam are dissolved in 50 ml of dimethylformamide and 5.5 ml (1 eq) of triethylamine in a 100 ml three-necked flask equipped with a reflux condenser and a thermometer. 4.1 ml (1.5 eq) of 4-fluoronitrobenzene are then run into the reaction mixture, which is subsequently brought to a temperature of 70° C. for 48 hours. The mixture is cooled and is then precipitated from water. An orangy-yellow precipitate is isolated by filtration and is then purified on a silica column (eluent: dichloromethane 95/methanol 5). 2.7 g of a yellow product are obtained, i.e. a final yield of 28%.
Reaction SMILES: C(N(C(C)C)CC)(C)C.[CH3:10][O:11][C:12]1[CH:13]=[C:14](/[CH:24]=[CH:25]/[C:26]([OH:28])=[O:27])[CH:15]=[CH:16][C:17]=1[N:18]1[CH:22]=[C:21]([CH3:23])[N:20]=[CH:19]1.[F:29][C:30]1[CH:39]=[CH:38][C:33]([C:34](=[O:37])[CH2:35]Br)=[CH:32][CH:31]=1.O.C(=O)(O)[O-].[Na+]>CN(C=O)C.C(OCC)(=O)C>[CH3:10][O:11][C:12]1[CH:13]=[C:14](/[CH:24]=[CH:25]/[C:26]([O:28][CH2:35][C:34]([C:33]2[CH:38]=[CH:39][C:30]([F:29])=[CH:31][CH:32]=2)=[O:37])=[O:27])[CH:15]=[CH:16][C:17]=1[N:18]1[CH:22]=[C:21]([CH3:23])[N:20]=[CH:19]1
Reactant: COc1cc(/C=C/C(=O)O)ccc1-n1cnc(C)c1
Reactant: O=C(CBr)c1ccc(F)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1cc(/C=C/C(=O)OCC(=O)c2ccc(F)cc2)ccc1-n1cnc(C)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 75.3 %

Procedure:
IPEA (0.28 mL) was added to a solution of (E)-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]acrylic acid (200 mg) and 4-fluorophenacyl bromide (185 mg) in DMF (3 mL), and the reaction solution was stirred at room temperature for one hour. Ethyl acetate and saturated sodium bicarbonate water were added to the reaction solution, and the organic layer was separated. The resulting organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was suspended in diethyl ether, and the solid was collected by filtration to obtain 230 mg of the title compound. The property values of the compound are as follows.
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([CH:13]=[CH:14][N:15]=[C:16]3[Cl:19])=[CH:11][CH:10]=2)[C:4]1=[O:20].C(N(CC)CC)C.[S:28]1[C:36]2[C:31](=[N:32][CH:33]=[CH:34][CH:35]=2)[CH:30]=[C:29]1[S:37](Cl)(=[O:39])=[O:38]>CC#N>[Cl:19][C:16]1[C:17]2[C:12](=[CH:11][CH:10]=[C:9]([CH2:8][N:5]3[CH2:6][CH2:7][C@H:3]([NH:2][S:37]([C:29]4[S:28][C:36]5[C:31](=[N:32][CH:33]=[CH:34][CH:35]=5)[CH:30]=4)(=[O:38])=[O:39])[C:4]3=[O:20])[CH:18]=2)[CH:13]=[CH:14][N:15]=1
Reactant: O=S(=O)(Cl)c1cc2ncccc2s1
Reactant: N[C@H]1CCN(Cc2ccc3ccnc(Cl)c3c2)C1=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: O=C1[C@@H](NS(=O)(=O)c2cc3ncccc3s2)CCN1Cc1ccc2ccnc(Cl)c2c1
Reaction time: 8 h
Yield: 33.3 %

Procedure:
To a solution of 3-(S)-amino-1-(1-chloro-isoquinolin-7-ylmethyl)-pyrrolidin-2-one hydrochloride (0.15 g, 0.48 mmol) suspended in CH3CN (2.5 mL) is added triethylamine (0.23 mL, 1.6 mmol) followed by thieno[3,2-b]pyridine-2-sulfonyl chloride (0.14 g, 0.55 mmol). The mixture is stirred overnight, then concentrated. The residue is diluted with CH2Cl2 and washed with saturated NaHCO3 and brine. The organic layer is dried over MgSO4, filtered and concentrated to dryness. The crude product is purified by column chromatography eluting with 5% MeOH/CH2Cl2 to give the title compound (0.076 g, 0.16 mmol) as a light yellow solid.
Reaction SMILES: C([O:3][C:4](=[O:30])[CH2:5][N:6]([CH2:20][CH2:21][NH:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C:7](=[O:19])[CH2:8][CH2:9][N:10]1[CH:18]=[C:16]([CH3:17])[C:14](=[O:15])[NH:13][C:11]1=[O:12])C.[OH-].[Na+]>CO>[C:23]([NH:22][CH2:21][CH2:20][N:6]([C:7](=[O:19])[CH2:8][CH2:9][N:10]1[CH:18]=[C:16]([CH3:17])[C:14](=[O:15])[NH:13][C:11]1=[O:12])[CH2:5][C:4]([OH:30])=[O:3])([O:25][C:26]([CH3:28])([CH3:29])[CH3:27])=[O:24]
Reactant: CCOC(=O)CN(CCNC(=O)OC(C)(C)C)C(=O)CCn1cc(C)c(=O)[nH]c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1cn(CCC(=O)N(CCNC(=O)OC(C)(C)C)CC(=O)O)c(=O)[nH]c1=O
Reaction time: 1 h

Procedure:
N-(N′-Boc-aminoethyl)-N-[(1-thyminyl)propanoyl]glycine ethyl ester (0.83 g, 0.00195 mol) was dissolved in methanol (25 ml). Sodium hydroxide (25 ml; 2 M) was added. The solution was stirred for 1 h. The methanol was removed by evaporation, in vacuo, and the pH adjusted to 2 with 4 M hydrochloric acid at 0° C. The product was isolated by filtration, washed with ether (3×15 ml), and dried over sicapent, in vacuo. Yield 0.769 g, 99%). M.p. 213° C. (decomp.).
Reaction SMILES: [H-].[Na+].[I:3][C:4]1[CH:5]=[N:6][NH:7][CH:8]=1.[C:9]([O:13][C:14]([N:16]1[CH2:21][CH2:20][CH:19](OS(C)(=O)=O)[CH2:18][CH2:17]1)=[O:15])([CH3:12])([CH3:11])[CH3:10]>CN(C=O)C>[I:3][C:4]1[CH:5]=[N:6][N:7]([CH:19]2[CH2:20][CH2:21][N:16]([C:14]([O:13][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:15])[CH2:17][CH2:18]2)[CH:8]=1
Reactant: CC(C)(C)OC(=O)N1CCC(OS(C)(=O)=O)CC1
Reactant: Ic1cn[nH]c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(n2cc(I)cn2)CC1
Temperature: 4 °C
Reaction time: 1 h
Yield: 66 %

Procedure:
NaH (1.2 eq., 0.68 mmol) was added portionwise to a stirred solution of 4-iodopyrazole (0.57 mmol) in DMF (2 L) at 4° C. The resulting mixture was stirred for 1 hour at 4° C. and 4-methanesulfonyloxy-piperidine-1-carboxylic acid tert-butyl ester, compound 2 (1.1 eq., 0.63 mmol) was then added. The resulting mixture was heated to 100° C. for 12 h. The reaction was quenched with H2O and extracted with EtOAc several times. The combined organic layers were dried, filtered, and concentrated to afford an orange oil. The residue was purified by silica gel chromatography (eluting with 5% EtOAc in pentane) to give compound 3 as a white solid (140 g, 66%).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[O:5][C:4](=[O:12])[C:3]=1[CH2:13][C:14]1[CH:22]=[CH:21][CH:20]=[CH:19][C:15]=1[C:16]([OH:18])=[O:17].S(=O)(=O)(O)O.[CH3:28]O>O>[CH3:28][O:17][C:16](=[O:18])[C:15]1[CH:19]=[CH:20][CH:21]=[CH:22][C:14]=1[CH2:13][C:3]1[C:4](=[O:12])[O:5][C:6]2[C:11]([C:2]=1[OH:1])=[CH:10][CH:9]=[CH:8][CH:7]=2
Reactant: CO
Reactant: O=C(O)c1ccccc1Cc1c(O)c2ccccc2oc1=O
Agent: O=S(=O)(O)O
Solvent: O
Product: COC(=O)c1ccccc1Cc1c(O)c2ccccc2oc1=O
Temperature: 25 °C

Procedure:
A solution of 2-(4-Hydroxy-2-oxo-2H-chromen-3-ylmethyl)-benzoic acid in MeOH with a catalytic amount of conc. sulfuric acid was heated to reflux for 5 hours, cooled to room temperature, diluted with water and extracted with EtOAc. The organic layer was dried over MgSO4 and conc. in vacuo to give 2-(4-Hydroxy-2-oxo-2H-chromen-3-ylmethyl)-benzoic acid methyl ester as white solid. MS: 309[M-H].
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[CH2:5][C:6]1[NH:7][C:8](=[O:16])[C:9]([C:14]#[N:15])=[C:10](SC)[N:11]=1.[CH2:20]([NH2:23])[CH2:21][CH3:22]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[CH2:5][C:6]1[NH:7][C:8](=[O:16])[C:9]([C:14]#[N:15])=[C:10]([NH:23][CH2:20][CH2:21][CH3:22])[N:11]=1
Reactant: CCCN
Reactant: CSc1nc(Cc2cccc(Cl)c2)[nH]c(=O)c1C#N
Product: CCCNc1nc(Cc2cccc(Cl)c2)[nH]c(=O)c1C#N

Procedure:
In analogy to the preparation of Example 1, 100 mg (0.34 mmol) of 2-(3-chlorobenzyl)-4-(methyl-sulphanyl)-6-oxo-1,6-dihydropyrimidine-5-carbonitrile are reacted with 203 mg (3.43 mmol) of n-propylamine to give 12 mg (12% of theory) of the title compound.
Reaction SMILES: [NH:1]1[C:5]2=[CH:6][N:7]=[CH:8][CH:9]=[C:4]2[C:3]([C:10](=O)[CH3:11])=[CH:2]1.C(O)(C(F)(F)F)=O>>[CH2:10]([C:3]1[C:4]2[C:5](=[CH:6][N:7]=[CH:8][CH:9]=2)[NH:1][CH:2]=1)[CH3:11]
Reactant: CC(=O)c1c[nH]c2cnccc12
Solvent: O=C(O)C(F)(F)F
Product: CCc1c[nH]c2cnccc12
Temperature: 25 °C
Reaction time: 18 h
Yield: 96.7 %

Procedure:
To a solution of 1-(1H-pyrrolo[2,3-c]pyridin-3-yl)-ethanone (1.53 g, 9.55 mmol) in TFA (29 mL) triethylsilane (6.88 g, 59.21 mmol) is added and stirred at rt for 18 h. The mixture is concentrated and extracted with EtOAc. The organic layer is washed with 2 N aqueous KOH, dried (Na2SO4), filtered and evaporated. The residue is chromatographed through silica gel eluting with 10% MeOH in DCM to afford 3-ethyl-1H-pyrrolo[2,3-c]pyridine (1.35 g, 97%). MS: 147 (M+H); 1H NMR (300 MHz, CDCl3): δ 13.3 (broad, N—H) 9.46 (s, 1H), 8.04 (s, 1H), 7.71-7.88 (m, 2H), 2.88 (q, 2H), 1.39 (t, 3H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([NH:13][NH2:14])=[O:12])=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:15](Cl)(=O)[O:16]CC.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.C[Si](C)(C)O[Si](C)(C)C>O.ClC1C=CC=CC=1Cl.CN(C)C(=O)C>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:10][C:11]2[O:12][C:15](=[O:16])[NH:14][N:13]=2)=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: CCOC(=O)Cl
Reactant: NNC(=O)Cc1ccc([N+](=O)[O-])cc1
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: CC(=O)N(C)C
Solvent: O
Solvent: Clc1ccccc1Cl
Product: O=c1[nH]nc(Cc2ccc([N+](=O)[O-])cc2)o1
Temperature: 25 °C
Reaction time: 1 h
Yield: 51.2 %

Procedure:
A mixture of 2-(4-nitrophenyl)acetohydrazide (0.50 g), ethyl chlorocarbonate (0.34 g) and N,N-dimethylacetamide (10 mL) was stirred at room temperature for 1 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous magnesium sulfate, and concentrated to give colorless crystals. A mixture of the obtained crystals, diphosphorus pentaoxide (1.50 g), hexamethyldisiloxane (2.96 g) and 1,2-dichlorobenzene (10 mL) was stirred at 160° C. for 2 hrs. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous magnesium sulfate, and concentrated to give 5-(4-nitrobenzyl)-1,3,4-oxadiazol-2(3H)-one as pale-yellow crystals (0.29 g, yield 50%). Recrystallization thereof from ethyl acetate-hexane gave pale-yellow prism crystals. melting point: 170-171° C.