Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1](=NC1C=CC=CC=1)=O.[NH2:10][CH:11]([CH:15]1[CH2:20][N:19]([C:21]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:18]=[N:17][CH2:16]1)[C:12]([NH2:14])=[O:13]>N1C=CC=CC=1>[C:22]1([C:21]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[N:19]2[CH2:20][CH:15]([C:11]3[C:12]([OH:13])=[N:14][S:1][N:10]=3)[CH2:16][N:17]=[CH:18]2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=S=Nc1ccccc1
Reactant: NC(=O)C(N)C1CN=CN(C(c2ccccc2)(c2ccccc2)c2ccccc2)C1
Solvent: c1ccncc1
Product: Oc1nsnc1C1CN=CN(C(c2ccccc2)(c2ccccc2)c2ccccc2)C1
Yield: 60 %

Procedure:
N-Thionylaniline (2.6 mL, 23.2 mmol) is added to amino(1-triphenylmethyl-1,4,5,6-tetrahydropyrimidin-5-yl)acetamide (1.64 g, 4.1 mmol) suspended in pyridine (25 ml). After heating at 90° C. for 48 hours the pyridine is evaporated, and the black residue partitioned between chloroform and water. The aqueous layer is lowered to pH 5 (HCl) and chromatographed (Dowex-50 W, 0.5 N ammonium hydroxide) to yield the product as a brown solid 1.05 g (61%) that can be further purified by chromatography (silica, methanol) and converted to a white crystalline hydrochloride salt, ms m/z=426.
Reaction SMILES: [NH2:1][CH:2]([CH2:5][C:6]([CH3:15])([CH3:14])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH2:3][OH:4].C([O-])([O-])=O.[K+].[K+].Br[C:23]#[N:24]>C1COCC1.CCOC(C)=O>[CH3:14][C:6]([CH3:15])([CH2:7][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[CH2:5][CH:2]1[CH2:3][O:4][C:23]([NH2:24])=[N:1]1
Reactant: CC(C)(Cc1ccccc1)CC(N)CO
Reactant: N#CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(Cc1ccccc1)CC1COC(N)=N1
Reaction time: 17 h
Yield: 54.3 %

Procedure:
To a stirred solution of (RS)-2-amino-4,4-dimethyl-5-phenyl-pentan-1-ol (0.97 g) at r.t. in THF (15 ml) under an argon atmosphere were added K2CO3 (0.78 g) and a solution of BrCN (0.59 g) in THF (10 ml). The mixture was stirred for 17 h. The suspension was diluted with EtOAc and washed with H2O. The aqueous phase was back-extracted with EtOAc. The combined organics were washed with brine, dried (MgSO4), filtered and concentrated. The crude product was purified by chromatography on Isolute® Flash-NH2 silica gel from Separtis (gradient: cyclohexane ->CH2Cl2->CH2Cl2/MeOH 9:1) to give (RS)-4-(2,2-dimethyl-3-phenylpropyl)-4,5-dihydro-oxazol-2-ylamine (0.59 g) as an off-white sticky solid. MS (ISP): 233.2 ([M+H]+))
Reaction SMILES: [H-].[Na+].O.[NH2:4][C:5]1[C:14]2[N:15]=[C:16]([CH:22]([CH2:24][CH2:25][CH2:26][CH3:27])[OH:23])[N:17]([CH2:18][CH:19]([CH3:21])[CH3:20])[C:13]=2[C:12]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[N:6]=1.N[C:29]1C2N=C(C(CCCC)O)N(CC(C)C)C=2C2C=CC=CC=2N=1.CI>>[CH3:29][O:23][CH:22]([C:16]1[N:17]([CH2:18][CH:19]([CH3:20])[CH3:21])[C:13]2[C:12]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[N:6]=[C:5]([NH2:4])[C:14]=2[N:15]=1)[CH2:24][CH2:25][CH2:26][CH3:27]
Reactant: CCCCC(O)c1nc2c(N)nc3ccccc3c2n1CC(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: O
Product: CCCCC(OC)c1nc2c(N)nc3ccccc3c2n1CC(C)C
Reaction time: 2 h
Yield: 16 %

Procedure:
Sodium hydride (0.32 g; 10.1 mmol) was added to a suspension of 4-amino-α-butyl-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinoline-2-methanol (3 g; 9.2 mmol, Example 60) and the resulting mixture was stirred for about 2 hours. Methyl iodide (0.82 mL; 13.8 mmol) was added to the mixture and stirring was continued overnight. Thin layer chromatography indicated that the reaction was incomplete so sodium hydride (0.25 g) was added followed two hours later by methyl iodide (1 mL). The reaction was stirred for several additional hours then quenched with water and diluted with ethyl acetate. The organic layer was separated, washed with water, dried over magnesium sulfate and concentrated under vacuum to provide an oil. The oil was purified by silica gel chromatography (1-3% methanol in methylene chloride as eluent) to provide 0.5 g of a solid, m.p. 125-128° C. Analysis: Calculated: C, 70.55; H, 8.3; %N, 16.5; Found: C, 70.2; H, 8.3; N, 16.0.
Reaction SMILES: C1CCC(N=C=NC2CCCCC2)CC1.[NH2:16][CH:17]([CH2:21][CH3:22])[C:18](O)=[O:19].[CH2:23]([NH:30][CH2:31][C:32](OCC)=[O:33])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:21]([C@@H:17]1[NH:16][C:32](=[O:33])[CH2:31][N:30]([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:18]1=[O:19])[CH3:22]
Reactant: CCC(N)C(=O)O
Reactant: CCOC(=O)CNCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC[C@@H]1NC(=O)CN(Cc2ccccc2)C1=O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of DCC (5.07 g) in DCM (140 mL) at 0° C. was added N—BOC-L-□-aminobutyric acid (5 g) followed by ethyl JV-benzylglycinate (4.6 mL) dropwise. The resulting solution was stirred at 0° C. for 2 h and RT 1 h, filtered and the concentrated to give an oil. This was dissolved in DCM (100 mL) and TFA (100 ml) and stirred for 1 h. The solution was concentrated under reduced pressure. The residue was stirred in saturated aq NaHCO3 (125 ml) and EtOAc (125 ml) for 6 h. The organics were separated, dried (Na2SO4), and concentrated to give the sub title compound as a white solid. (5.68 g).
Reaction SMILES: [Cl:1]C1C=C(C2(CC#N)CCCC2)C=CC=1.[ClH:16].FC(F)(F)[C:19]1[CH:24]=[CH:23][C:22]([C:25]2([CH2:30][C:31]([NH2:33])=[NH:32])[CH2:29][CH2:28][CH2:27][CH2:26]2)=[CH:21][CH:20]=1>>[ClH:1].[Cl:16][C:24]1[CH:23]=[C:22]([C:25]2([CH2:30][C:31]([NH2:33])=[NH:32])[CH2:29][CH2:28][CH2:27][CH2:26]2)[CH:21]=[CH:20][CH:19]=1
Reactant: N#CCC1(c2cccc(Cl)c2)CCCC1
Reactant: N=C(N)CC1(c2ccc(C(F)(F)F)cc2)CCCC1
Agent: Cl
Product: N=C(N)CC1(c2cccc(Cl)c2)CCCC1

Procedure:
2-(1-(3-Chlorophenyl)-cyclopentyl)-acetamidine hydrochloride (499) was synthesized from 2-(1-(3-chlorophenyl)cyclopentyl)acetonitrile (498) following the procedure described for HCl-salt of 2-[1-(4-trifluoromethyl-phenyl)-cyclopentyl]-acetamidine hydrochloride (242).
Reaction SMILES: [CH:1]1([NH:4][C:5]2[CH:6]=[C:7]([O:26][CH2:27][CH2:28][O:29][CH3:30])[CH:8]=[C:9]3[C:13]=2[N:12]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:11]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:10]3)[CH2:3][CH2:2]1.[N:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[S:37](Cl)(=[O:39])=[O:38]>N1C=CC=CC=1>[CH:1]1([N:4]([S:37]([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][N:31]=2)(=[O:39])=[O:38])[C:5]2[CH:6]=[C:7]([O:26][CH2:27][CH2:28][O:29][CH3:30])[CH:8]=[C:9]3[C:13]=2[N:12]([C:14]([O:16][C:17]([CH3:19])([CH3:18])[CH3:20])=[O:15])[CH:11]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:10]3)[CH2:2][CH2:3]1
Reactant: CCOC(=O)C1Cc2cc(OCCOC)cc(NC3CC3)c2N1C(=O)OC(C)(C)C
Reactant: O=S(=O)(Cl)c1ccccn1
Solvent: c1ccncc1
Product: CCOC(=O)C1Cc2cc(OCCOC)cc(N(C3CC3)S(=O)(=O)c3ccccn3)c2N1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 67 %

Procedure:
To a mixture of 1-tert-butyl 2-ethyl 7-(cyclopropylamino)-5-(2-methoxyethoxy)indoline-1,2-dicarboxylate (1.9 g) and pyridine (3 mL) was added a mixture of 2-pyridylsulfonyl chloride (1.2 g) and pyridine (2 mL) at 0° C., and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with ethyl acetate and water. The organic layer was washed with aqueous 10% aqueous citric acid solution, aqueous sodium bicarbonate solution and saturated brine, dried over anhydrous sodium sulfate, and filtered, and the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give the title compound (1.70 g, yield 67%) as a pale-yellow oil from a fraction eluted with ethyl acetate-hexane (9:1, volume ratio). MS: 562 (MH+).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]([OH:10])=O)[CH:5]=[CH:4][CH:3]=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.CCN(C(C)C)C(C)C.[NH:44]1[C:52]2[C:47](=[C:48]([C:53]3[CH:54]=[C:55]([NH2:62])[C:56]4[CH:57]=[N:58][NH:59][C:60]=4[CH:61]=3)[CH:49]=[CH:50][CH:51]=2)[CH:46]=[CH:45]1>CN(C=O)C>[Cl:1][C:2]1[N:7]=[C:6]([C:8]([NH:62][C:55]2[CH:54]=[C:53]([C:48]3[CH:49]=[CH:50][CH:51]=[C:52]4[C:47]=3[CH:46]=[CH:45][NH:44]4)[CH:61]=[C:60]3[C:56]=2[CH:57]=[N:58][NH:59]3)=[O:10])[CH:5]=[CH:4][CH:3]=1
Reactant: Nc1cc(-c2cccc3[nH]ccc23)cc2[nH]ncc12
Reactant: O=C(O)c1cccc(Cl)n1
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: O=C(Nc1cc(-c2cccc3[nH]ccc23)cc2[nH]ncc12)c1cccc(Cl)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 25.9 %

Procedure:
6-Chloro-2-pyridinecarboxylic acid (available from Fluorochem, 2540 mg, 16.1 mmol) and O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (6130 mg, 16.1 mmol) were dissolved in DMF (40 ml) and DIPEA (8.44 ml) was added. The mixture was stirred at room temperature for 30 mins then 6-(1H-indol-4-yl)-1H-indazol-4-amine (2000 mg, 8.06 mmol) was added and the mixture stirred at room temperature overnight. The reaction mixture was concentrated in vacuo to ˜15 ml which was added to 4×50 g aminopropyl cartridges which had been preconditioned with MeOH. The reaction mixture remained on the cartridges for 3 h before being eluted with MeOH. The fractions were combined and the solvent was removed in vacuo to give a brown oil which was purified by chromatography on silica gel (2×100 g cartridges) eluting with 0-25% MeOH in dichloromethane over 40 mins. Appropriate fractions were combined and the solvent was removed in vacuo to give the title compound (809 mg) as an orange solid.
Reaction SMILES: [C:1]([CH:4]1[C:11](=[CH2:12])[CH2:10][S:9][CH:8]2[N:5]1[C:6](=[O:21])[CH:7]2[NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])([OH:3])=[O:2].[C:22]1([C:28]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[N+]=[N-])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C(OCC)(=O)C>[CH:28]([O:2][C:1]([CH:4]1[C:11](=[CH2:12])[CH2:10][S:9][CH:8]2[N:5]1[C:6](=[O:21])[CH:7]2[NH:13][C:14]([O:16][C:17]([CH3:18])([CH3:20])[CH3:19])=[O:15])=[O:3])([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: [N-]=[N+]=C(c1ccccc1)c1ccccc1
Reactant: C=C1CSC2C(NC(=O)OC(C)(C)C)C(=O)N2C1C(=O)O
Solvent: CCOC(C)=O
Product: C=C1CSC2C(NC(=O)OC(C)(C)C)C(=O)N2C1C(=O)OC(c1ccccc1)c1ccccc1
Yield: 66.2 %

Procedure:
2-Carboxy-7-tert.-butoxycarbonylamino-3-methylene-8-oxo-5-thia-1-aza-bicyclo[4.2.0]octane (21.3 g) is esterified with diphenyldiazomethane (11.2 g) in accordance with the procedure of Example 1. 2-Benzhydryloxycarbonyl-7-tert.-butoxycarbonylamino-3-methylene-8-oxo-5-thia-1-aza-bicyclo[4.2.0]octane (18.35 g) is obtained in the form of white crystals (m.p.=135°-7° C. after recrystallisation from ethyl acetate).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]2[N:13]([C:14](OC3C=CC([N+]([O-])=O)=CC=3)=[O:15])[C:12]([O:26]C)=[N:11][C:10]([CH3:28])=[C:9]2[C:29]([O:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[O:30])[CH:5]=[CH:6][CH:7]=1.[C:39]1([CH:45]([C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)[CH2:46][CH2:47][NH2:48])[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>C(#N)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]2[C:9]([C:29]([O:31][CH2:32][C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=3)=[O:30])=[C:10]([CH3:28])[NH:11][C:12](=[O:26])[N:13]2[C:14](=[O:15])[NH:48][CH2:47][CH2:46][CH:45]([C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=2)[C:49]2[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: COC1=NC(C)=C(C(=O)OCc2ccccc2)C(c2cccc(Cl)c2)N1C(=O)Oc1ccc([N+](=O)[O-])cc1
Reactant: NCCC(c1ccccc1)c1ccccc1
Solvent: CC#N
Product: CC1=C(C(=O)OCc2ccccc2)C(c2cccc(Cl)c2)N(C(=O)NCCC(c2ccccc2)c2ccccc2)C(=O)N1
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
10 ml of acetonitrile was added to a mixture of 200 mg (0.373 mmol) of 5-benzyl 1-(4-nitrophenyl) 6-(3-chlorophenyl)-2-methoxy-4-methyl-6H-pyrimidine-1,5-dicarboxylate and 78.9 mg (0.373 mmol) of 3,3-diphenylpropylamine, and they were stirred at 60° C. for 30 minutes. The solvent was evaporated under reduced pressure to obtain the title compound.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].[C:9](#[N:12])[CH:10]=[CH2:11]>C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[I:1][C:2]1[CH:3]=[C:4]([NH:5][CH2:11][CH2:10][C:9]#[N:12])[CH:6]=[CH:7][CH:8]=1
Reactant: Nc1cccc(I)c1
Reactant: C=CC#N
Agent: [Cu+2]
Agent: CC(=O)[O-]
Product: N#CCCNc1cccc(I)c1
Yield: 37 %

Procedure:
13at) 4.38 g of 3-iodoaniline, 1.06 g of acrylonitrile and 0.5 g of copper-(II)acetate are mixed and held at 70° for 5 hrs. The mixture is chromatographed on silica gel with ethyl acetate/cyclohexane 1:4 and yields 2.01 g of 3-(3-iodo-phenylamino)-propionitrile as a brown oil. Yield: 37%. Mass spectrum: peak inter alia at m/e : 272 (M+, 50%), 232 (100%); 105 (35%).
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH:6]=[C:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([N+:17]([O-:19])=[O:18])[CH:15]=3)[NH:10][CH:9]=2)[CH2:4][CH2:3]1.CN(C)C=O.C(=O)([O-])[O-].[Na+].[Na+].Cl[CH2:32][CH:33]1[CH2:35][CH2:34]1>O>[CH:33]1([CH2:32][N:2]2[CH2:3][CH:4]=[C:5]([C:8]3[C:16]4[C:11](=[CH:12][CH:13]=[C:14]([N+:17]([O-:19])=[O:18])[CH:15]=4)[NH:10][CH:9]=3)[CH2:6][CH2:7]2)[CH2:35][CH2:34]1
Reactant: ClCC1CC1
Reactant: O=[N+]([O-])c1ccc2[nH]cc(C3=CCNCC3)c2c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1ccc2[nH]cc(C3=CCN(CC4CC4)CC3)c2c1
Temperature: 70 °C
Reaction time: 23 h

Procedure:
A mixture of 11.88 g of 3-(1,2,3,6-tetrahydro-4-pyridinyl)-5-nitro-1H-indole hydrochloride, 148 ml of dimethylformamide, 12.72 g of sodium carbonate and 4.8 ml of chloromethylcyclopropane was stirred at 70° C. under an inert atmosphere for 23 hours and the mixture was cooled. 450 ml of distilled water were added to the mixture which was then stirred for one hour and was vacuum filtered. The recovered product was rinsed with water and dried to obtain 10.8 g of raw product. The latter was chromatographed over silica gel and was eluted with a 6-3-1 chloroform-acetone-triethylamine mixture to obtain 8.3 g of 3-(1-cyclopropylmethyl-1,2,3,6-tetrahydro-4-pyridinyl)-5-nitro-1H-indole melting at 187°-188° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]=[C:9]=[O:10])[CH:5]=[CH:6][CH:7]=1.Cl.[NH2:12][CH2:13][C:14]1[CH:22]=[CH:21][CH:20]=[C:19]2[C:15]=1[CH2:16][N:17]([CH:24]1[CH2:29][CH2:28][C:27](=[O:30])[NH:26][C:25]1=[O:31])[C:18]2=[O:23].C(N(CC)CC)C>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]([NH:12][CH2:13][C:14]2[CH:22]=[CH:21][CH:20]=[C:19]3[C:15]=2[CH2:16][N:17]([CH:24]2[CH2:29][CH2:28][C:27](=[O:30])[NH:26][C:25]2=[O:31])[C:18]3=[O:23])=[O:10])[CH:5]=[CH:6][CH:7]=1
Reactant: NCc1cccc2c1CN(C1CCC(=O)NC1=O)C2=O
Reactant: O=C=Nc1cccc(Cl)c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C1CCC(N2Cc3c(CNC(=O)Nc4cccc(Cl)c4)cccc3C2=O)C(=O)N1
Temperature: 5 °C
Reaction time: 0.17 h
Yield: 89.2 %

Procedure:
3-Chlorophenyl isocyanate (0.4 g, 2.7 mmol) was added to a stirred suspension of 3-(4-aminomethyl-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione hydrochloride (0.7 g, 2.1 mmol) and triethylamine (0.3 g, 2.9 mmol) in THF (30 mL) at 5-10° C. After stirring at 5° C. for 10 minutes, the mixture was stirred at room temperature overnight. The reaction was quenched with methanol (1 mL) and then concentrated. The residue was stirred with 1N HCl (30 mL) for 1 hour and filtered. The solid was slurried with hot methanol (15 mL) to give 1-(3-chloro-phenyl)-3-[2-(2,6-dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-urea (0.8 g, 91%): mp 250-252° C.; 1H NMR (DMSO-d6) δ 2.00-2.05 (m, 1H), 2.37-2.65 (m, 2H), 2.86-2.98 (m, 1H), 4.37 (d, J=5.3 Hz, 2H, CH2), 4.44 (d, J=17.2 Hz, 1H), 4.51 (d, J=17.3 Hz, 1H), 5.11-5.18 (dd, J=4.9 and 13.1 Hz, 1H, CH), 6.82 (t, J=5.4 Hz, 1H, NH), 6.92-6.95 (m, 1H, Ar), 7.18-7.27 (m, 2H, Ar), 7.48-7.65 (m, 4H, Ar), 8.84 (s, 1H, NH), 11.01 (s, 1H, NH); 13C NMR (DMSO-d6) δ 22.57, 31.18, 39.68, 46.20, 51.59, 116.15, 117.13, 120.78, 121.57, 128.30, 130.21, 130.35, 131.64, 133.06, 135.37, 139.90, 141.86, 154.99, 168.07, 171.00, 172.82; Anal. calcd. for C21H19N4O4Cl: C, 59.09; H, 4.49; N, 13.13; Cl, 8.31. Found: C, 59.06; H, 4.39; N, 13.24; Cl, 7.95.
Reaction SMILES: [CH2:1]([S:8][C:9]1[CH:14]=[N:13][N:12]([CH3:15])[C:11](=[O:16])[C:10]=1[Cl:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC1C=CC=C(C(OO)=[O:26])C=1>ClCCl>[CH2:1]([S:8]([C:9]1[CH:14]=[N:13][N:12]([CH3:15])[C:11](=[O:16])[C:10]=1[Cl:17])=[O:26])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cn1ncc(SCc2ccccc2)c(Cl)c1=O
Solvent: ClCCl
Product: Cn1ncc(S(=O)Cc2ccccc2)c(Cl)c1=O
Temperature: -20 °C
Reaction time: 1 h
Yield: 77.2 %

Procedure:
16.0 g (60.0 millimoles) of 5-benzylthio-4-chloro-2-methylpyridazin-3(2H)-one from Method 4 were dissolved in 200 ml of dichloromethane, the solution was cooled to -20° C. and a solution of 11.4 g (66.1 millimoles) of m-chloroperbenzoic acid in dichloromethane was added dropwise. Stirring was continued for 1 hour at -10° C., and then overnight at room temperature. The reaction solution was washed three times with saturated NaHCO3 solution and once with water, dried and evaporated down, and the residue was triturated with diethyl ether and then filtered off under suction to give 13.1 g (77%) of a product of melting point 129°-131° C. (active ingredient no. 2 a).
Reaction SMILES: [C:1]([O:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][N:15]1[C:23]2[C:22](Cl)=[N:21][CH:20]=[N:19][C:18]=2[CH:17]=[CH:16]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:25][C:26]1[CH:45]=[CH:44][C:29]([O:30][C:31]2[CH:43]=[CH:42][C:34]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])=[CH:33][CH:32]=2)=[C:28]([Cl:46])[CH:27]=1>C(O)(C)C>[C:1]([O:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][N:15]1[C:23]2[C:22]([NH:25][C:26]3[CH:45]=[CH:44][C:29]([O:30][C:31]4[CH:43]=[CH:42][C:34]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])=[CH:33][CH:32]=4)=[C:28]([Cl:46])[CH:27]=3)=[N:21][CH:20]=[N:19][C:18]=2[CH:17]=[CH:16]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)c1ccc(Oc2ccc(N)cc2Cl)cc1
Reactant: O=C(OCCOCCn1ccc2ncnc(Cl)c21)c1ccccc1
Solvent: CC(C)O
Product: CC(C)(C)OC(=O)c1ccc(Oc2ccc(Nc3ncnc4ccn(CCOCCOC(=O)c5ccccc5)c34)cc2Cl)cc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 58 %

Procedure:
A mixture of 2-[2-(4-chloro-5H-pyrrolo[3,2-d]pyrimidin-5-yl)ethoxy]ethyl benzoate (1.46 g), tert-butyl 4-(4-amino-2-chlorophenoxy)benzoate (1.35 g) and isopropyl alcohol (30 mL) was stirred at 80° C. overnight. The reaction mixture was concentrated under reduced pressure, water and saturated aqueous sodium hydrogen carbonate solution were added, and the mixture was extracted with ethyl acetate. The ethyl acetate layer washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was subjected to silica gel column chromatography (eluent, ethyl acetate). The object fraction was concentrated under reduced pressure and the residue was crystallized from ethyl acetate-diethyl ether to give the title compound (1.54 g) as a white powder.
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[N:7]([C:9]([C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([Cl:23])[CH:17]=1)([CH2:13][NH:14][CH3:15])[CH2:10][CH:11]=[CH2:12])[CH3:8])([CH3:4])([CH3:3])[CH3:2].N1C=CC=CC=1.ClC(F)(F)C([O:35][C:36](=O)[C:37]([F:40])([F:39])[Cl:38])=O.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[C:1]([O:5][C:6](=[O:24])[N:7]([C:9]([CH2:13][N:14]([C:36](=[O:35])[C:37]([Cl:38])([F:40])[F:39])[CH3:15])([C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([Cl:23])[CH:17]=1)[CH2:10][CH:11]=[CH2:12])[CH3:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: O=C(OC(=O)C(F)(F)Cl)C(F)(F)Cl
Reactant: C=CCC(CNC)(c1ccc(Cl)c(Cl)c1)N(C)C(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: c1ccncc1
Product: C=CCC(CN(C)C(=O)C(F)(F)Cl)(c1ccc(Cl)c(Cl)c1)N(C)C(=O)OC(C)(C)C
Reaction time: 0.83 h
Yield: 46 %

Procedure:
tert-Butyl[1-(3,4-dichlorophenyl)-1-methylaminomethyl-3-butenyl]methylcarbamate (500 mg) produced in Example 4 was dissolved in methylene chloride (10 mL). Under cooling with ice, pyridine (163 μL) and chlorodifluoroacetic acid anhydride (350 μL) were added thereto. Under cooling with ice, the mixture was stirred for 50 minutes. Saturated aqueous sodium bicarbonate was added to the reaction mixture, and the resultant mixture was extracted with methylene chloride. The organic layer was washed with saturated brine, dried over sodium sulfate anhydrate, and concentrated under reduced pressure. The residue was purified through silica gel column chromatography (n-hexane:ethyl acetate=4:1), to thereby give the title compound (300 mg, 46%).
Reaction SMILES: [C:1]1([CH3:22])[C:2]([S:7]([N:10]([CH2:18][C:19](O)=[O:20])[C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=2)(=[O:9])=[O:8])=[CH:3][CH:4]=[CH:5][CH:6]=1.[CH2:23]([NH:25][CH2:26][C:27]1[S:28][CH:29]=[CH:30][N:31]=1)[CH3:24]>>[CH2:23]([N:25]([CH2:26][C:27]1[S:28][CH:29]=[CH:30][N:31]=1)[C:19](=[O:20])[CH2:18][N:10]([S:7]([C:2]1[C:1]([CH3:22])=[CH:6][CH:5]=[CH:4][CH:3]=1)(=[O:8])=[O:9])[C:11]1[CH:12]=[CH:13][C:14]([CH3:17])=[CH:15][CH:16]=1)[CH3:24]
Reactant: Cc1ccc(N(CC(=O)O)S(=O)(=O)c2ccccc2C)cc1
Reactant: CCNCc1nccs1
Product: CCN(Cc1nccs1)C(=O)CN(c1ccc(C)cc1)S(=O)(=O)c1ccccc1C

Procedure:
prepared by reaction of [(toluene-2-sulfonyl)-p-tolyl-amino]-acetic acid with ethyl-thiazol-2-ylmethyl-amine
Reaction SMILES: [C:1]([NH:8][CH2:9][C:10]1[CH:25]=[CH:24][C:13]([C:14]([NH:16][CH:17]([CH2:22]O)[C:18]([O:20][CH3:21])=[O:19])=[O:15])=[CH:12][CH:11]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CC[N+](S(N=C(OC)[O-])(=O)=O)(CC)CC>C1COCC1>[C:1]([NH:8][CH2:9][C:10]1[CH:11]=[CH:12][C:13]([C:14]2[O:15][CH2:22][CH:17]([C:18]([O:20][CH3:21])=[O:19])[N:16]=2)=[CH:24][CH:25]=1)([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2]
Reactant: COC(=O)C(CO)NC(=O)c1ccc(CNC(=O)OC(C)(C)C)cc1
Agent: CC[N+](CC)(CC)S(=O)(=O)N=C([O-])OC
Solvent: C1CCOC1
Product: COC(=O)C1COC(c2ccc(CNC(=O)OC(C)(C)C)cc2)=N1
Temperature: 60 °C
Reaction time: 2 h
Yield: 97.1 %

Procedure:
To a solution of methyl 2-[4-(N-Boc-aminomethyl)benzoylamino]-3-hydroxypropionate (32.0 g, 90.8 mmol) in THF (150 ml) was added Burgess' Reagent (26.0 g, 109 mmol) and 3 Å molecular sieves (1 g). The reaction was allowed to stir at 60° C. for 2 h. The reaction mixture was cooled to room temperature and concentrated in vacuo. The crude product was dissolved in dichloromethane and purified by flash chromatography over silica gel with ethyl acetate/dichloromethane (1/1) to give methyl 2-[4-(N-Boc-aminomethyl)-phenyl]-4,5-dihydrooxazol-4-ylcarboxylate (29.5 g, 88.2 mmol) as a pale tan oil.
Reaction SMILES: [O:1]=[C:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH:11]=[O:12])[CH:8]=2)[NH:3]1.S([CH2:23][N+:24]#[C-:25])(C1C=CC(C)=CC=1)(=O)=O.C(=O)([O-])[O-].[K+].[K+]>CO>[O:12]1[C:11]([C:7]2[CH:8]=[C:9]3[C:4](=[CH:5][CH:6]=2)[NH:3][C:2](=[O:1])[CH2:10]3)=[CH:25][N:24]=[CH:23]1
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Reactant: O=Cc1ccc2c(c1)CC(=O)N2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: O=C1Cc2cc(-c3cnco3)ccc2N1
Yield: 52.6 %

Procedure:
A mixture of 2-oxoindoline-5-carbaldehyde (60 mg, 0.38 mmol), tosylmethyl isocyanide (145 mg, 0.75 mmol) and potassium carbonate (103 mg, 0.75 mmol) in methanol (20 mL) was heated at reflux for 2 h. The mixture was concentrated in vacuo and diluted with an aqueous saturated solution of sodium hydrogencarbonate and extracted with methylene chloride. The combined organic layers were dried (Na2SO4) and evaporated in vacuo. The crude product was purified on a silica gel column using heptane/ethyl acetate, (1:4), as the eluent to give 40 mg (53% yield) of the title compound: 1H NMR (DMSO-d6, 300 M ) δ 10.54 (br s, 1 H), 8.36 (br s, 1 H), 7.64-7.44 (m, 3 H), 6.89 (d, J=8 Hz, 1 H), 3.54 (br s, 2 H).