Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](/[CH:11]=[CH:12]/[C:13]([N:15]2[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=3[NH:17][C:16]2=[O:24])=[O:14])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].IC.[C:27]([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5](/[CH:11]=[CH:12]/[C:13]([N:15]2[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=3[N:17]([CH3:27])[C:16]2=[O:24])=[O:14])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(/C=C/C(=O)n2c(=O)[nH]c3ccccc32)cc1OC
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COc1ccc(/C=C/C(=O)n2c(=O)n(C)c3ccccc32)cc1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.8 %

Procedure:
A mixture of (E)-1-(3-(3,4-dimethoxyphenyl)acryloyl)-1H-benzo[d]imidazol-2(3H)-one (240 mg, 0.75 mmol), iodomethane (68 uL, 1.1 mmol) and K2CO3 (204 mg, 1.5 mmol) in DMF (5 mL) was stirred at room temperature overnight. The reaction was quenched with water and extracted with DCM. The combined organic phases were washed with brine, dried over sodium sulfate and the solvent removed under reduced pressure. The residue was purified by recrystallisation from EtOH to afford (E)-1-(3-(3,4-dimethoxyphenyl)acryloyl)-3-methyl-1H-benzo[d]imidazol-2(3H)-one (200 mg, 79%). 1H-NMR (400 MHz, CDCl3) δ 3.46 (s, 3H), 3.96 (s, 3H), 3.98 (s, 3H), 6.91 (d, J=8.4 Hz, 1H), 7.01 (dd, J=7.6, 0.8 Hz, 1H), 7.19-7.28 (m, 4H), 7.98 (d, J=15.6 Hz, 1H), 8.15 (d, J=15.6 Hz, 1H) 8.32 (dd, J=8.0, 0.8 Hz, 1H); LC-MS (ES-API); rt 9.05 min; m/z calculated for C19H18N2O4 [M+H]+ 339.1, found 339.0 and 361.0 ([M+Na]+).
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]([CH3:10])=[CH:5][C:6]=1[C:7](Cl)=[O:8].[BH4-].[Na+].Cl.O>O1CCCC1>[CH3:1][C:2]1[O:3][C:4]([CH3:10])=[CH:5][C:6]=1[CH2:7][OH:8]
Reactant: Cc1cc(C(=O)Cl)c(C)o1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(CO)c(C)o1
Temperature: 0 °C
Reaction time: 1 h
Yield: 95.5 %

Procedure:
A solution of 2,5-dimethylfuran-3-carbonyl chloride (5.0 g) in tetrahydrofuran (20 mL) was added dropwise to a suspension of sodium borohydride (3.4 g) in tetrahydrofuran (50 mL) at 0° C. and, after the completion of the dropwise addition, the mixture was stirred at 0° C. for 1 hr. The reaction mixture was treated with 1N hydrochloric acid, poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure to give the title compound (3.8 g, 100%) as an oil.
Reaction SMILES: [CH:1]([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:27][O:28][CH3:29])[C:10]([NH:12][C@@H:13]2[C:25](=[O:26])[N:15]3[C:16]([C:22]([OH:24])=[O:23])=[C:17]([CH2:20]Cl)[CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1)=[O:2].[CH3:30][N:31]1[CH2:36][CH2:35][N:34]([C:37](=[O:46])[C:38]2[CH:43]=[CH:42][C:41]([OH:44])=[C:40]([OH:45])[CH:39]=2)[CH2:33][CH2:32]1.C(OCC)(=O)C>CN(C)C=O>[CH:1]([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:27][O:28][CH3:29])[C:10]([NH:12][C@@H:13]2[C:25](=[O:26])[N:15]3[C:16]([C:22]([O-:24])=[O:23])=[C:17]([CH2:20][N+:31]4([CH3:30])[CH2:36][CH2:35][N:34]([C:37](=[O:46])[C:38]5[CH:43]=[CH:42][C:41]([OH:44])=[C:40]([OH:45])[CH:39]=5)[CH2:33][CH2:32]4)[CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1)=[O:2]
Reactant: CN1CCN(C(=O)c2ccc(O)c(O)c2)CC1
Reactant: CON=C(C(=O)N[C@@H]1C(=O)N2C(C(=O)O)=C(CCl)CS[C@H]12)c1csc(NC=O)n1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CON=C(C(=O)N[C@@H]1C(=O)N2C(C(=O)[O-])=C(C[N+]3(C)CCN(C(=O)c4ccc(O)c(O)c4)CC3)CS[C@H]12)c1csc(NC=O)n1
Temperature: 0 °C
Yield: 115.9 %

Procedure:
To a solution of 7β-[2-(2-formamidothiazol-4-yl)-2-methoxyiminoacetamido]-3-chloromethyl-3-cephem-4-carboxylic acid (syn isomer) (920 mg) in N,N-dimethylformamide (5 ml) was added 1-methyl-4-(3,4-dihydroxybenzoyl)piperazine (945 mg) at 0° C. and the mixture was stirred at 0° C. for 3. 5 hours. The mixture was added dropwise to ethyl acetate (200 ml) under stirring and the pulverized product was collected by filtration and washed with ethyl acetate to give 7β-[2-(2-formamidothiazol-4-yl) -2-methoxyiminoacetamido]-3-[1-methyl-4(3,4-dihydroxybenzoyl) -1-piperazinio]methyl-3-cephem-4-carboxylate (syn isomer) (1.53 g) .
Reaction SMILES: [CH2:1]([O:6][C:7]1[CH:8]=[C:9]([CH:13]=[C:14]([O:16][CH2:17][CH:18]=[C:19]([CH3:21])[CH3:20])[CH:15]=1)[C:10]([OH:12])=O)[CH:2]=[C:3]([CH3:5])[CH3:4].[NH2:22][CH2:23][CH:24]1[CH2:28][CH2:27][CH2:26][N:25]1[CH2:29][CH3:30]>>[CH2:29]([N:25]1[CH2:26][CH2:27][CH2:28][CH:24]1[CH2:23][NH:22][C:10](=[O:12])[C:9]1[CH:13]=[C:14]([O:16][CH2:17][CH:18]=[C:19]([CH3:21])[CH3:20])[CH:15]=[C:7]([O:6][CH2:1][CH:2]=[C:3]([CH3:4])[CH3:5])[CH:8]=1)[CH3:30]
Reactant: CCN1CCCC1CN
Reactant: CC(C)=CCOc1cc(OCC=C(C)C)cc(C(=O)O)c1
Product: CCN1CCCC1CNC(=O)c1cc(OCC=C(C)C)cc(OCC=C(C)C)c1
Yield: 39 %

Procedure:
In a manner identical to Example 15, 3,5-diprenyloxybenzoic acid(1.45 g) was subjected to a condensation reaction with 2-aminomethyl-1-ethylpyrrolidine (0.7 ml), thereby yielding 0.78 g(39%) of the aimed compound.
Reaction SMILES: N1C=CC=CC=1.[C:7](Cl)(=[O:9])[CH3:8].[NH2:11][C:12]1[C:25]2[N:24]([CH3:26])[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17](=[O:27])[C:16]=2[C:15]([O:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[CH:14][CH:13]=1>C(Cl)(Cl)Cl>[C:7]([NH:11][C:12]1[C:25]2[N:24]([CH3:26])[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17](=[O:27])[C:16]=2[C:15]([O:28][C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)=[CH:14][CH:13]=1)(=[O:9])[CH3:8]
Reactant: Cn1c2ccccc2c(=O)c2c(Oc3ccccc3)ccc(N)c21
Reactant: CC(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: CC(=O)Nc1ccc(Oc2ccccc2)c2c(=O)c3ccccc3n(C)c12
Temperature: 25 °C
Reaction time: 6 h

Procedure:
1.3 ml (16 mmol) of pyridine and 0.28 (4 mmol) of acetyl chloride are added to a solution of 0.7 g (2 mmol) of 4-amino-N-methyl-1-phenoxyacridone in 20 ml of chloroform, and the mixture is stirred at room temperature for 6 hours. The solution is washed with hydrochloric acid (18%), water and saturated aqueous sodium chloride solution, dried using sodium sulphate and evaporated. The residue is washed with diethyl ether nad filtered off. Yield: 0.6 g (83%) melting point: 252°-254° C.
Reaction SMILES: [CH3:1][S:2]([C:5]1[O:6][C:7]2[C:13]([O:14][CH3:15])=[CH:12][CH:11]=[CH:10][C:8]=2[CH:9]=1)(=[O:4])=[O:3].[Br:16]N1C(=O)CCC1=O>C(#N)C>[Br:16][C:10]1[C:8]2[CH:9]=[C:5]([S:2]([CH3:1])(=[O:4])=[O:3])[O:6][C:7]=2[C:13]([O:14][CH3:15])=[CH:12][CH:11]=1
Reactant: COc1cccc2cc(S(C)(=O)=O)oc12
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Product: COc1ccc(Br)c2cc(S(C)(=O)=O)oc12
Yield: 109.2 %

Procedure:
Prepared from 2-methanesulfonyl-7-methoxybenzofuran (0.50 g) and N-bromosuccinimide (0.39 g) in acetonitrile (30 ml). Purification by flash chromatography on silica eluting with 50% ethyl acetate in hexane gave the title compound as a white solid (0.73 g).
Reaction SMILES: [Cl:1][C:2]([Cl:16])([C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][CH:8]=1)[C:3](OC)=[O:4].[NH3:17]>ClCCl.O>[Cl:1][C:2]([Cl:16])([C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][CH:8]=1)[C:3]([NH2:17])=[O:4]
Reactant: N
Reactant: COC(=O)C(Cl)(Cl)c1ccc([N+](=O)[O-])cc1
Solvent: ClCCl
Solvent: O
Product: NC(=O)C(Cl)(Cl)c1ccc([N+](=O)[O-])cc1
Yield: 63 %

Procedure:
A solution of methyl 2,2-dichloro-2-(4-nitrophenyl)acetate (1.36 parts) in dichloromethane (13.6 parts) was stirred with concentrated ammonia solution (10 parts) at 25° C. for 24 hours before diluting the reaction mixture with water (50 parts) and extracting with dichloromethane. The dichloromethane extracts were washed with water and evaporated to give 2,2-dichloro-2-(4-nitrophenyl)acetamide (0.86 parts, 63,4%) (1Hnmr in D6 dimethylsulphoxide 87.95 medium (2H), 88,23 broad (2H), δ8.35 medium (2H)).
Reaction SMILES: Cl.[CH2:2]([N:9]1[CH2:16][CH:15]2[CH:11]([CH2:12][NH:13][CH2:14]2)[CH2:10]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl[C:18]1[CH:19]=[CH:20][C:21]2[N:22]([C:24]([C:27]([Cl:30])([F:29])[F:28])=[N:25][N:26]=2)[N:23]=1>>[CH2:2]([N:9]1[CH2:10][CH:11]2[CH2:12][N:13]([C:18]3[CH:19]=[CH:20][C:21]4[N:22]([C:24]([C:27]([Cl:30])([F:29])[F:28])=[N:25][N:26]=4)[N:23]=3)[CH2:14][CH:15]2[CH2:16]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: FC(F)(Cl)c1nnc2ccc(Cl)nn12
Reactant: c1ccc(CN2CC3CNCC3C2)cc1
Agent: Cl
Product: FC(F)(Cl)c1nnc2ccc(N3CC4CN(Cc5ccccc5)CC4C3)nn12
Yield: 66 %

Procedure:
A mixture of 2-benzylhexahydropyrrolo[3,4-c]pyrrole hydrochloride and 6-chloro-3-[chloro(difluoro)methyl]-[1,2,4]triazolo[4,3-b]pyridazine was allowed to react by an analogous method to Example 331 to give 6-(5-benzylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-3-[chloro(difluoro)methyl][1,2,4]triazolo[4,3-b]pyridazine in 66% yield.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([Cl:14])=[CH:9][C:8]=2[Cl:15])[N:5]=[C:4]([OH:16])[CH:3]=1.[C:17]1(=O)[O:22][C:20](=[O:21])[C:19]2=[CH:23][CH:24]=[CH:25][CH:26]=[C:18]12.O>C(O)(=O)C>[OH:16][C:4]1[CH:3]=[C:2]([N:1]2[C:20](=[O:21])[C:19]3=[CH:23][CH:24]=[CH:25][CH:26]=[C:18]3[C:17]2=[O:22])[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([Cl:14])=[CH:9][C:8]=2[Cl:15])[N:5]=1
Reactant: Nc1cc(O)nn1-c1c(Cl)cc(Cl)cc1Cl
Reactant: O=C1OC(=O)c2ccccc21
Solvent: O
Solvent: CC(=O)O
Product: O=C1c2ccccc2C(=O)N1c1cc(O)nn1-c1c(Cl)cc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 4.50 g (18.0 mmol) of the compound of Step A and 2.81 g (19.0 mmol) of phthalic anhydride in 40 mL of glacial acetic acid was refluxed for 4 hours and stirred overnight at room temperature. About two volumes of water were added dropwise and the resulting solid was filtered and washed with water. The damp solid was taken up in a little ethanol, filtered and washed with a little ethanol and ether, and air dried to give the title compound, 5.1 g (69%), m.p. 295°-298° C. (dec). Anal. Calcd. for C17H8O3N3Cl3 : C, 49.97; H, 1.97; N, 10.28. Found: C, 49.28; H, 1.95; N, 10.06.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[S:3]([O:6]S(C(F)(F)F)(=O)=O)(=[O:5])=[O:4].O[C:17]1[CH:26]=[C:25]2[C:20]([CH2:21][CH2:22][N:23]([CH2:27][CH2:28][CH2:29][CH2:30][NH:31][C:32](=[O:41])/[CH:33]=[CH:34]/[C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[CH2:24]2)=[CH:19][CH:18]=1>N1C=CC=CC=1.S([O-])([O-])(=O)=O.[Cu+2]>[C:35]1(/[CH:34]=[CH:33]/[C:32]([NH:31][CH2:30][CH2:29][CH2:28][CH2:27][N:23]2[CH2:22][CH2:21][C:20]3[C:25](=[CH:26][C:17]([O:6][S:3]([C:2]([F:15])([F:14])[F:1])(=[O:5])=[O:4])=[CH:18][CH:19]=3)[CH2:24]2)=[O:41])[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: O=C(/C=C/c1ccccc1)NCCCCN1CCc2ccc(O)cc2C1
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Solvent: c1ccncc1
Product: O=C(/C=C/c1ccccc1)NCCCCN1CCc2ccc(OS(=O)(=O)C(F)(F)F)cc2C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 36.3 %

Procedure:
Trifluoromethanesulfonic anhydride (0.26 ml, 1.52 mmol) was added dropwise with stirring to an ice cooled solution of (E)-7-hydroxy-2-(4-(3-phenylpropenoyl)aminobutyl)-1,2,3,4-tetrahydroisoquinoline (0.41 g, 1.17 mmol) in anhydrous pyridine (5 ml). After stirring at room temperature for 18 h the reaction mixture was poured into 10% aqueous copper (II) sulfate (100 ml). The mixture was extracted with ethyl acetate (2×75 ml). Combined extracts were washed with 10% aqueous copper (II) sulfate (2×50 ml), water (50 ml), dried (Na2SO4) and evaporated in vacuo. The residue was chromatographed on silica using 10-100% ethyl acetate-hexane gradient elution to afford the title compound (0.205 g, 43%).
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[NH2:5][C:6]1[CH:7]=[CH:8][C:9]([S:58]([CH:61]2[CH2:63][CH2:62]2)(=[O:60])=[O:59])=[C:10]([CH2:12][N:13]([CH3:57])[C:14]([CH:16]([NH:30][C:31]2[CH:32]=[C:33]3[C:38](=[CH:39][C:40]=2[F:41])[C:37]([N:42]([C:50]([O:52][C:53]([CH3:56])([CH3:55])[CH3:54])=[O:51])[C:43](=[O:49])[O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[N:36][CH:35]=[CH:34]3)[C:17]2[CH:22]=[C:21]([O:23][CH3:24])[C:20]([C@@H:25]([CH3:28])[CH2:26][OH:27])=[CH:19][C:18]=2[F:29])=[O:15])[CH:11]=1>C(#N)C.C(Cl)Cl>[C:45]([O:44][C:43]([N:42]([C:37]1[C:38]2[C:33](=[CH:32][C:31]([NH:30][C@H:16]3[C:14](=[O:15])[N:13]([CH3:57])[CH2:12][C:10]4[CH:11]=[C:6]([CH:7]=[CH:8][C:9]=4[S:58]([CH:61]4[CH2:62][CH2:63]4)(=[O:59])=[O:60])[NH:5][C:1](=[O:2])[O:27][CH2:26][C@H:25]([CH3:28])[C:20]4[C:21]([O:23][CH3:24])=[CH:22][C:17]3=[C:18]([F:29])[CH:19]=4)=[C:40]([F:41])[CH:39]=2)[CH:34]=[CH:35][N:36]=1)[C:50](=[O:51])[O:52][C:53]([CH3:54])([CH3:55])[CH3:56])=[O:49])([CH3:47])([CH3:48])[CH3:46]
Reactant: COc1cc(C(Nc2cc3ccnc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c3cc2F)C(=O)N(C)Cc2cc(N)ccc2S(=O)(=O)C2CC2)c(F)cc1[C@@H](C)CO
Reactant: O=C(Cl)Cl
Solvent: ClCCl
Solvent: CC#N
Product: COc1cc2c(F)cc1[C@@H](C)COC(=O)Nc1ccc(S(=O)(=O)C3CC3)c(c1)CN(C)C(=O)[C@@H]2Nc1cc2ccnc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c2cc1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 13.1 %

Procedure:
Phosgene (87 mg, 0.176 mmol) was added dropwise to a solution of 25D (148 mg, 0.176 mmol) in acetonitrile (2.5 mL)/CH2Cl2 (2.5 mL) at 0° C. The mixture was stirred at rt for 30 min. Ar was bubbled though the solution (10 min) to remove excess phosgene, and then the mixture was added to a solution of TEA (0.123 mL, 0.881 mmol) in CH2Cl2 (25 mL) at 40° C. over 5 h. The reaction was stirred at rt overnight, quenched with H2O (1 mL) and MeOH (5 mL) and then concentrated. The crude product was purified by flash chromatography (loading in chloroform, 0% to 100% ethyl acetate in hexane over 15 min using a 12 g silica gel cartridge). The diastereomers were separated by a prep chiral HPLC (R,R-Whelk-O column 21.1×250 mm) to give 25E (20 mg, 0.023 mmol, 13.11% yield).
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([C:12]2[S:16][C:15]([NH:17][C:18](=[O:20])[CH3:19])=[N:14][C:13]=2[CH3:21])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].FC1C=C(C=CC=1[C:31]([F:34])([F:33])[F:32])C=O>>[CH3:11][S:8]([C:7]1[CH:6]=[CH:5][C:4]([C:12]2[S:16][C:15]([NH:17][C:18](=[O:20])[CH3:19])=[N:14][C:13]=2[CH3:21])=[CH:3][C:2]=1[C:31]([F:34])([F:33])[F:32])(=[O:10])=[O:9]
Reactant: CC(=O)Nc1nc(C)c(-c2ccc(S(C)(=O)=O)c(F)c2)s1
Reactant: O=Cc1ccc(C(F)(F)F)c(F)c1
Product: CC(=O)Nc1nc(C)c(-c2ccc(S(C)(=O)=O)c(C(F)(F)F)c2)s1

Procedure:
The title compound is prepared by an analogous procedure to N-[5-(3-fluoro-4-methane-sulfonyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide (Example 64) by replacing 3,4-difluoro-benzaldehyde with 3-fluoro-4-trifluoromethylbenzaldehyde.
Reaction SMILES: [CH3:1][N:2]([CH2:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:3]1[C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[N:5][C:6]2[C:11]([N:12]=1)=[CH:10][C:9]([C:13]([O:15]C)=[O:14])=[CH:8][CH:7]=2.[OH-].[Na+]>CO.O>[CH3:1][N:2]([CH2:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:3]1[C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[N:5][C:6]2[C:11]([N:12]=1)=[CH:10][C:9]([C:13]([OH:15])=[O:14])=[CH:8][CH:7]=2
Reactant: COC(=O)c1ccc2nc(-c3ccccc3)c(N(C)CCc3ccccc3)nc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CN(CCc1ccccc1)c1nc2cc(C(=O)O)ccc2nc1-c1ccccc1

Procedure:
Into a 50-mL round-bottom flask, was placed a solution of methyl 3-(methyl(phenethyl)amino)-2-phenylquinoxaline-6-carboxylate (144.7 mg, 0.35 mmol, 1.00 equiv, 96%) in methanol (20 mL). This was followed by the dropwise addition of a solution of sodium hydroxide (72.9 mg, 1.82 mmol, 5.00 equiv) in water (2 mL) with stirring. The resulting solution was stirred overnight at 50° C. in an oil bath. Then it was concentrated under vacuum and diluted with 10 ml of water. The pH value of the aqueous solution was adjusted to 3-4 with 1N aq. hydrogen chloride. The resulting solid was collected by filtration and washed with methanol. This resulted in 52.6 mg (38%) of 3-(methyl(phenethyl)amino)-2-phenylquinoxaline-6-carboxylic acid as a yellow solid.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][O:8][C:9]2[CH:10]=[C:11]([O:15][S:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[Cl:25])(=[O:18])=[O:17])[CH:12]=[CH:13][CH:14]=2)[CH2:3][CH2:2]1.C(N(CC)CC)C.[NH2:33][N:34]=[CH:35]S(O)(=O)=O>CN(C=O)C>[NH2:33][N:34]=[CH:35][N:1]1[CH2:6][CH2:5][CH:4]([CH2:7][O:8][C:9]2[CH:10]=[C:11]([O:15][S:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[Cl:25])(=[O:17])=[O:18])[CH:12]=[CH:13][CH:14]=2)[CH2:3][CH2:2]1
Reactant: NN=CS(=O)(=O)O
Reactant: O=S(=O)(Oc1cccc(OCC2CCNCC2)c1)c1ccccc1Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: NN=CN1CCC(COc2cccc(OS(=O)(=O)c3ccccc3Cl)c2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 49.5 %

Procedure:
A solution of 2-chlorobenzenesulfonic acid 3-[(piperidin-4-yl)methoxy]phenyl ester (191 mg, 0.5 mmol), as prepared in the preceding step, in DMF (10 mL) containing triethylamine (0.2 mL) and aminoiminomethanesulfonic acid (124 mg, 1.0 mmol) was stirred at room temperature overnight. The DMF was concentrated in vacuo and the residue was purified by flash column chromatography (90: 10 methylene chloride:methanol saturated with NH3) to give the title compound as a white foam (105 mg, 49%). 1H-NMR (300 MHz, CDCl3 /DMSO)-d6) δ 1.38 (m, 2H), 1.88 (d, 2H), 2.08 (m, 1H), 3.00 (t, 2H), 3.79 (d, 2H), 4.05 (dd, 2H), 6.61 (dd, 1H) 6.77 (t, 1H), 6.79 (dd, 1H), 7.20 (t, 1H), 7.37 (bs, 3H), 7.50 (m, 1H), 7.92 (d, 2H). Mass spectrum (MALDI-TOF, sinapinic acid matrix) calcd. for C19H22 N3O4SCl: 424.1(M+H), 446.1 (M+Na), Found: 424.3, 446.6
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:10].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[Cl:21][C:22]1[N:27]=[CH:26][C:25]2[C:28](=O)[O:29][CH:30]([CH2:31][CH3:32])[C:24]=2[CH:23]=1.Cl>C1COCC1>[Cl:21][C:22]1[N:27]=[CH:26][C:25]2[C:28](=[C:3]3[C:4]4[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=4)[NH:1][C:2]3=[O:10])[O:29][CH:30]([CH2:31][CH3:32])[C:24]=2[CH:23]=1
Reactant: O=C1Cc2ccccc2N1
Reactant: CCC1OC(=O)c2cnc(Cl)cc21
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Product: CCC1OC(=C2C(=O)Nc3ccccc32)c2cnc(Cl)cc21
Temperature: 95 °C
Reaction time: 4.5 h
Yield: 67.4 %

Procedure:
A solution of 1,3-dihydro-indol-2-one (650 mg, 4.77 mmol.) in THF (10 mL) is cooled to 0° C. under an argon atmosphere and treated with a solution of lithium bis(trimethylsilyl)amide (9.6 mL of a 1 M solution in THF, 9.6 mmol) dropwise. The ice bath is removed and 6-chloro-1-ethyl-1H-furo[3,4-c]pyridin-3-one (630 mg, 3.18 mmol) is added directly as a solid. The resulting solution is stirred for 4.5 h. The reaction mixture is poured into aqueous 10% HCl solution (100 mL) and stirred at room temperature for 10 min and then heated at 90-100° C. for 2 h. The reaction mixture is cooled to room temperature for 36 h during which time a precipitate formed. The precipitate which formed is collected by filtration and dried to give the title compound as an orange solid (670 mg, 67%).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[C:5]2[OH:12].OS(O)(=O)=O.[N+:18]([O-])([O-:20])=[O:19].[K+]>>[Cl:1][C:2]1[N:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([N+:18]([O-:20])=[O:19])=[C:5]2[OH:12]
Reactant: O=[N+]([O-])[O-]
Reactant: Oc1ccnc2ccc(Cl)nc12
Agent: O=S(=O)(O)O
Agent: [K+]
Product: O=[N+]([O-])c1cnc2ccc(Cl)nc2c1O
Temperature: 100 °C
Yield: 90 %

Procedure:
6-chloro-1,5-naphthyridin-4-ol (1.45 g, 8 mmol) was added to ice-cooled conc. H2SO4 (15 mL) and followed by the addition of KNO3 (1.62 g, 16 mmol) slowly at 0° C. The mixture was heated to 100° C. for 1 h, and then was poured into ice-water. The precipitate was collected and dried in vacuo to afford 6-chloro-3-nitro-1,5-naphthyridin-4-ol as a solid in 90% yield (1.97 g).
Reaction SMILES: Cl[C:2]1[N:11]=[CH:10][C:9]2[N:8]([CH3:12])[C:7](=[O:13])[CH2:6][N:5]([CH:14]([CH3:16])[CH3:15])[C:4]=2[N:3]=1.[N+:17]([C:20]1[CH:21]=[C:22]([NH2:30])[CH:23]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:25]=1)([O-:19])=[O:18].Cl>O.O1CCOCC1>[CH:14]([N:5]1[C:4]2[N:3]=[C:2]([NH:30][C:22]3[CH:23]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:25]=[C:20]([N+:17]([O-:19])=[O:18])[CH:21]=3)[N:11]=[CH:10][C:9]=2[N:8]([CH3:12])[C:7](=[O:13])[CH2:6]1)([CH3:16])[CH3:15]
Reactant: CC(C)N1CC(=O)N(C)c2cnc(Cl)nc21
Reactant: Nc1cc([N+](=O)[O-])cc(C(F)(F)F)c1
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Product: CC(C)N1CC(=O)N(C)c2cnc(Nc3cc([N+](=O)[O-])cc(C(F)(F)F)c3)nc21
Temperature: 25 °C
Yield: 49 %

Procedure:
2-Chloro-8-isopropyl-5-methyl-7,8-dihydro-5H-pteridin-6-one of (2 g; 8.30 mmol) and 3-nitro-5-trifluoromethyl-phenylamine (1.71 g; 8.30 mmol) were diluted in 10 ml of water and 10 ml of 1,4-dioxane. 2 ml of HCl 37% were added. The reaction mixture was refluxed 48 h, then cooled to room temperature. The desired product precipitated from the reaction mixture, so, it was filtered, washed with water and dried in vacuo. Recrystallisation with 1,4-dioxane/water 1:1 gave 1.65 g (4.04 mmol; 49% yield) of white-yellow powder.
Reaction SMILES: [N:1]([CH2:4][C:5]1[CH:13]=[CH:12][C:8]([C:9](O)=[O:10])=[CH:7][CH:6]=1)=[N+:2]=[N-:3].S(Cl)([Cl:16])=O>C(Cl)Cl.CN(C=O)C>[N:1]([CH2:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([Cl:16])=[O:10])=[CH:7][CH:6]=1)=[N+:2]=[N-:3]
Reactant: O=S(Cl)Cl
Reactant: [N-]=[N+]=NCc1ccc(C(=O)O)cc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: [N-]=[N+]=NCc1ccc(C(=O)Cl)cc1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a solution of p-azidomethylbenzoic acid (1.063 g, 6.00 mmol) in CH2Cl2 (60 ml) at room temperature were added dropwise thionyl chloride (1 ml, excess) and DMF (5 drops). The mixture was stirred at room temperature for 2.5 h and evaporated, yielding 1.13 g of title compound as a light yellow oil: 1Hmr (CDCl3) δ: 4.48 (2H, s, --CH2N3), 7.38-7.52-8.07-8.22 ppm (4H, A2 'B2 ', aromatic Hs); ir (neat) νmax : 2090 (--N3) and 1750 cm-1 (br. --COCl). This material was used in the next step without further purification.
Reaction SMILES: Br[CH2:2][C:3](=O)[C:4]([O:6][CH2:7][CH3:8])=[O:5].[CH:10]1([C:13](=[S:15])[NH2:14])[CH2:12][CH2:11]1>C(O)C>[CH:10]1([C:13]2[S:15][CH:2]=[C:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])[N:14]=2)[CH2:12][CH2:11]1
Reactant: CCOC(=O)C(=O)CBr
Reactant: NC(=S)C1CC1
Solvent: CCO
Product: CCOC(=O)c1csc(C2CC2)n1
Yield: 23.1 %

Procedure:
A mixture of ethyl bromopyruvate (3.6 g), cyclopropanethioamide (2.2 g) and ethanol (30 ml) was refluxed for two hours. The reaction mixture was cooled, then ethanol was distilled off under reduced pressure. To the residue was added water (30 ml), which was subjected to extraction with ethyl acetate (50 ml) twice. The extract solution was washed with water (30 ml), followed by drying over magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was subjected to a silica gel chromatography (2.5×30 cm), eluting with ethyl acetate-hexane (1:3). The desired fraction was concentrated to give ethyl 2-cyclopropyl-4-thiazolcarboxylate (0.84 g) as pale yellow needles.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH:10]([OH:13])[CH2:9]1)=O)(C)(C)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl:33][C:34]1[CH:39]=[CH:38][C:37](O)=[CH:36][CH:35]=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[Cl:33][C:34]1[CH:39]=[CH:38][C:37]([O:13][CH:10]2[CH2:11][CH2:12][NH:8][CH2:9]2)=[CH:36][CH:35]=1
Reactant: Oc1ccc(Cl)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(O)C1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Clc1ccc(OC2CCNC2)cc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 87.9 %

Procedure:
3-Hydroxy-pyrrolidine-1-carboxylic acid tert butyl ester (2.1 g, 9.9 mmol) and triphenyl phosphine (2.59 g, 9.9 mmol) were dissolved in dry THF (35 ml) under nitrogen. The solution was cooled to 0° C. and 4-chlorophenol (1.28 g, 9.9 mmol) dissolved in dry THF (10 ml) was added followed by diethyl azodicarboxylate (DEAD) (1.55 ml, 9.9 mmol). After 15 minutes the ice bath was removed and the reaction was stirred overnight. The reaction mixture was concentrated under reduced pressure and the residue was stirred with ether. The solid triphenyl phosphine oxide was filtered off. The solution was washed three times with sodium hydroxide (1M) and concentrated. The BOC-protected product was purified by flash chromatography on silica using EtOAc/heptane as eluant. It was dissolved in dichloromethane (35 ml) and trifluoroacetic acid (17 ml). The reaction mixture was stirred at room temperature overnight, concentrated and purified by flash chromatography on silica (MeOH:CHCl3:NH3, 100:100:1) to give the subtitle compound (1.72 g, 88%).