Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][CH3:11])[N:5]=[C:4]([NH:12][CH2:13][CH2:14][CH3:15])[N:3]=1.[CH2:16]([O:23][NH:24][CH3:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[CH2:16]([O:23][N:24]([C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][CH3:11])[N:5]=[C:4]([NH:12][CH2:13][CH2:14][CH3:15])[N:3]=1)[CH3:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CCCNc1nc(Cl)nc(NCCC)n1
Reactant: CNOCc1ccccc1
Product: CCCNc1nc(NCCC)nc(N(C)OCc2ccccc2)n1
Yield: 29 %

Procedure:
2-Chloro-N-(4,6-bis-(n-propylamino)-[1,3,5]triazine (XXXIV) and O-benzyl-N-methyl-hydroxylamine (LII) were reacted as described in Example 13 to yield O-benzyl-N-(4,6-bis-propylamino-[1,3,5]triazin-2-yl)-N-methyl-hydroxylamine (LIII) (29% yield). 200 MHz 1H NMR (DMSO-d6, ppm) 7.52-7.28 (5H, m), 7.07-6.67 (2H, m), 4.93 (2H, s), 3.26-3.03 (7H, m), 1.58-1.39 (4H, m), 0.85 (6H, t, J=7.2 Hz). ESI-MS (m/z): 331 [M+H]+.
Reaction SMILES: [CH:1]12[O:10][CH:7]([CH2:8][CH2:9]1)[CH:6]1[CH:2]2[C:3](=[O:12])[CH2:4][C:5]1=O.P(Cl)(Cl)(Cl)(Cl)[Cl:14]>C(Cl)(Cl)Cl>[Cl:14][C:5]1[CH:6]2[CH:2]([CH:1]3[O:10][CH:7]2[CH2:8][CH2:9]3)[C:3](=[O:12])[CH:4]=1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: O=C1CC(=O)C2C3CCC(O3)C12
Solvent: ClC(Cl)Cl
Product: O=C1C=C(Cl)C2C3CCC(O3)C12
Yield: 139.7 %

Procedure:
To a solution of 10-oxa-tricyclo[5.2.1.0*2,6*]decane-3,5-dione (1.66 g, 10 mmol) in chloroform (20 ml) is added PCl5 (1.04 g, 5 mmol) in one portion. The reaction mixture is stirred and heated at reflux for 5 hours. The reaction mixture is evaporated to dryness. The crude product is purified by flash chromatography to give 5-chloro-10-oxa-tricyclo[5.2.1.0*2,6*]dec-4-en-3-one (1.29 g).
Reaction SMILES: Cl[C:2]1[C:3]2[N:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:4]=2[N:5]=[C:6]([NH:8][C:9](=[O:11])[CH3:10])[N:7]=1.ClC1N=C(Cl)C2N=[C:26]([C:28]3[CH:33]=CC(F)=CC=3)C=CC=2N=1>>[Cl:16][C:14]1[CH:13]=[CH:12][C:4]2[N:5]=[C:6]([NH:8][C:9](=[O:11])[CH3:10])[N:7]=[C:2]([CH:33]3[CH2:28][CH2:26]3)[C:3]=2[N:15]=1
Reactant: CC(=O)Nc1nc(Cl)c2nc(Cl)ccc2n1
Reactant: Fc1ccc(-c2ccc3nc(Cl)nc(Cl)c3n2)cc1
Product: CC(=O)Nc1nc(C2CC2)c2nc(Cl)ccc2n1

Procedure:
The experimental procedure of example 12 was repeated, except for the use of N-(4,6-dichloro-pyrido[3,2-d]pyrimidin-2-yl)-acetamide (a compound described in WO 2006/135993) instead of 2,4-dichloro-6-(4-fluoro-phenyl)-pyrido[3,2-d]pyrimidine. The resulting compound was characterized as follows: MS (m/z) 263.0 [M+H]+; HPLC Rt=2.24 minutes (Method B).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]=[CH:11][NH:10][C:9]=2[C:13]([NH2:15])=[O:14])=[CH:4][CH:3]=1.[F:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][C:18]=1[N:27]=[C:28]=[O:29]>O1CCCC1>[F:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][C:18]=1[NH:27][C:28](=[O:29])[NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:12]=[CH:11][NH:10][C:9]=2[C:13]([NH2:15])=[O:14])=[CH:6][CH:7]=1
Reactant: NC(=O)c1[nH]cnc1-c1ccc(N)cc1
Reactant: O=C=Nc1cc(C(F)(F)F)ccc1F
Solvent: C1CCOC1
Product: NC(=O)c1[nH]cnc1-c1ccc(NC(=O)Nc2cc(C(F)(F)F)ccc2F)cc1
Temperature: 20 °C
Reaction time: 16 h
Yield: 52.4 %

Procedure:
To 0.055 g (0.272 mmol) of 5-(4-aminophenyl)-3H-imidazole-4-carboxamide dissolved in 4 cm3 of tetrahydrofuran is added, at a temperature in the region of 20° C. under an argon atmosphere, 0.040 cm3 (0.272 mmol) of 2-fluoro-5-trifluoromethylphenyl isocyanate. After stirring for 16 hours at a temperature in the region of 20° C., the reaction mixture is filtered through a No. 3 sinter funnel. The solid obtained is washed successively with three times 2 cm3 of tetrahydrofuran and three times 2 cm3 of pentane and is then dried under reduced pressure (2.7 kPa) to give 0.058 g of 5-{4-[3-(2-fluoro-5-trifluoromethylphenyl)ureido]phenyl}-3H-imidazole-4-carboxamide in the form of a beige-coloured solid melting at 325° C.; 1H NMR (400 MHz, DMSO d6, δ in ppm) 6.98 (broad m, 1H); 7.30 (broad m, 1H); 7.40 (m, 1H); 7.49 (partially masked m, 1H); 7.51 (d, J=8.5 Hz, 2H); 7.71 (s, 1H); 7.82 (d, J=8.5 Hz, 2H); 8.62 (dd, J=2.0 and 7.5 Hz, 1H); 9.00 (broad s, 1H); 9.37 (broad s, 1H); 12.65 (broad m, 1H); EI: m/z=407: M+; m/z=205 [C8H3NOF4]+ base peak; m/z=179 [C7H5NF4]+.
Reaction SMILES: [CH3:1][NH:2][C@H:3]([C:5]([OH:7])=[O:6])[CH3:4].[CH2:8](O)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.O.[C:17]1([CH3:27])[CH:22]=[CH:21][C:20]([S:23]([OH:26])(=[O:25])=[O:24])=[CH:19][CH:18]=1.O>C1(C)C=CC=CC=1.CCOCC>[C:17]1([CH3:27])[CH:18]=[CH:19][C:20]([S:23]([OH:26])(=[O:24])=[O:25])=[CH:21][CH:22]=1.[CH2:8]([O:6][C:5](=[O:7])[C@H:3]([CH3:4])[NH:2][CH3:1])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: OCc1ccccc1
Reactant: CN[C@@H](C)C(=O)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCOCC
Product: CN[C@@H](C)C(=O)OCc1ccccc1

Procedure:
A suspension of 1.55 g (15.0 mmol) of (S)-N-methylalanine and 9.31 (90.0 mmol) of benzyl alcohol in 30 mL of toluene was treated with 3.00 g (15.8 mmol) of p-toluenesulfonic acid monohydrate. The mixture was heated for 19 hours under reflux with removal of water via a Dean-Stark trap. After cooling, the reaction solution was poured into 200 mL of ether, precipitating a yellow oil. The solvents were decanted and the residue was taken up into ethyl acetate and concentrated to yield a viscous, light yellow oil (141); TLC: Rf =0.34, 95:5:0.5 CH2Cl2 /MeOH/concentrated ammonium hydroxide; 1H NMR (300 MHz) consistent with structure.
Reaction SMILES: C1([C@@H](N[C:14]([CH3:28])=[CH:15][C:16]([O:18][C@@H:19]([C:24]([Cl:27])([Cl:26])[Cl:25])[CH:20]=[C:21]([CH3:23])[CH3:22])=[O:17])C)C2C(=CC=CC=2)C=CC=1.Cl.Br.[N+]([O-])(O)=[O:32].OP(O)(O)=O.OS(O)(=O)=O>O1CCCC1>[C:16]([O:18][C@@H:19]([C:24]([Cl:27])([Cl:26])[Cl:25])[CH:20]=[C:21]([CH3:23])[CH3:22])(=[O:17])[CH2:15][C:14]([CH3:28])=[O:32]
Reactant: CC(C)=C[C@@H](OC(=O)C=C(C)N[C@@H](C)c1cccc2ccccc12)C(Cl)(Cl)Cl
Reactant: O=[N+]([O-])O
Agent: Br
Agent: Cl
Agent: O=P(O)(O)O
Solvent: C1CCOC1
Product: CC(=O)CC(=O)O[C@H](C=C(C)C)C(Cl)(Cl)Cl

Procedure:
hydrolyzing the recovered (R)-3-methyl-1-trichloromethylbut-2-en-1-yl (S)-3-[N-(1-(1-naphthyl)ethyl)amino]but-2-enoate in a mixture of tetrahydrofuran and aqueous mineral acid selected from HCl, HBr, HNO3, H3PO4, and H2SO4, about 1-20 equivalents of 0.1 to 4 N aqueous mineral acid being employed for each equivalent of (R)-3-methyl-1-trichloromethylbut-2-en-1-yl (S)-3-[N-(1-(1-naphthyl)ethyl)amino]but-2-enoate.
Reaction SMILES: [OH:1][C:2]1[C:3]([C:12]([N:14]([O:16][CH3:17])[CH3:15])=[O:13])=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.[Cl:18]N1C(=O)CCC1=O>C(O)(=O)C>[Cl:18][C:5]1[CH:4]=[C:3]([C:12]([N:14]([O:16][CH3:17])[CH3:15])=[O:13])[C:2]([OH:1])=[C:11]2[C:6]=1[CH:7]=[CH:8][CH:9]=[N:10]2
Reactant: CON(C)C(=O)c1ccc2cccnc2c1O
Reactant: O=C1CCC(=O)N1Cl
Solvent: CC(=O)O
Product: CON(C)C(=O)c1cc(Cl)c2cccnc2c1O
Temperature: 100 °C
Yield: 81.6 %

Procedure:
To a stirred solution of 8-hydroxy-N-methoxy-N-methylquinoline-7-carboxamide (5.00 g, 21.5 mmol) in acetic acid (100 mL) was added N-chlorosuccinimide (3.16 g, 23.7 mmol) and the resulting mixture heated at 100° C. for 18 hours. After allowing the mixture to cool to ambient temperature, the reaction mixture was concentrated in vacuo, then neutralized with saturated sodium bicarbonate, and then extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, and then concentrated to dryness under reduced pressure. The residue was purified on silica gel, eluting with 0 to 10% methanol in dichloromethane, to give the desired product (4.68 g, 81%). LCMS calculated for C12H12ClN2O3(M+H)+: m/z=267.1; found: 267.0. 1H NMR (DMSO-d6, 400 MHz) δ 90.4 (1H, dd, J=4.0 and 1.2 Hz), 8.61 (1H, dd, J=8.8 and 1.6 Hz), 7.92 (1H, s), 7.80 (1H, dd, J=8.8 and 4.4 Hz), 3.45 (3H, s), 3.30 (4H, br s) ppm.
Reaction SMILES: [CH3:1][C:2]([CH3:9])([CH3:8])[CH2:3][CH2:4][C:5]([OH:7])=O.C(N(CC)CC)C.ClC(OCC(C)C)=O.[CH2:25]([NH:27][CH2:28][CH2:29][CH2:30][CH:31]([C:33]1[CH:38]=[CH:37][C:36]([NH:39][S:40]([CH3:43])(=[O:42])=[O:41])=[CH:35][CH:34]=1)[OH:32])[CH3:26].Cl>C1COCC1>[CH2:25]([N:27]([C:5](=[O:7])[CH2:4][CH2:3][C:2]([CH3:1])([CH3:9])[CH3:8])[CH2:28][CH2:29][CH2:30][CH:31]([C:33]1[CH:34]=[CH:35][C:36]([NH:39][S:40]([CH3:43])(=[O:41])=[O:42])=[CH:37][CH:38]=1)[OH:32])[CH3:26]
Reactant: CCNCCCC(O)c1ccc(NS(C)(=O)=O)cc1
Reactant: CC(C)(C)CCC(=O)O
Agent: CC(C)COC(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCN(CCCC(O)c1ccc(NS(C)(=O)=O)cc1)C(=O)CCC(C)(C)C
Reaction time: 1.5 h
Yield: 78.9 %

Procedure:
A stirred solution of 4,4-dimethylpentanoic acid (2.07 g, 0.0159 mol) and triethylamine (2.28 ml, 0.0163 mol) in THF (120 ml) was cooled to -8° C. and treated dropwise with isobutyl chloroformate (2.12 ml, 0.0163 mol). The mixture was kept at -8° C. for 1.5 hour and treated with a mixture of the product from Example 7 Step II (4.0 g, 0.014 mol), triethylamine (2.28 ml, 0.0163 mol) and THF (160 ml). This mixture was kept at -8° C. for 1.5 hour and then treated slowly with 1N HCl (158 ml) and extracted with EtOAc. The extract was washed with water, dilute NaHCO3 and water, dried (MgSO4) and concentrated to give 4.4 g of N-(4-(4-(ethyl(4,4-dimethylpentanoyl)amino)-1-hydroxybutyl)phenyl)methanesulfonamide. The mass spectrum had m/z 398 (M+).
Reaction SMILES: F[B-](F)(F)F.[CH3:6][O+](C)C.[C:10]([N:13]1[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([Cl:22])[CH:20]=2)[C:15](=[C:23]([OH:31])[C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([I:30])[CH:25]=2)[C:14]1=[O:32])(=[O:12])[CH3:11].C(N(C(C)C)C(C)C)C>ClCCl>[C:10]([N:13]1[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([Cl:22])[CH:20]=2)[C:15](=[C:23]([O:31][CH3:6])[C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([I:30])[CH:25]=2)[C:14]1=[O:32])(=[O:12])[CH3:11]
Reactant: CC(=O)N1C(=O)C(=C(O)c2cccc(I)c2)c2ccc(Cl)cc21
Reactant: C[O+](C)C
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=C1C(=O)N(C(C)=O)c2cc(Cl)ccc21)c1cccc(I)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A little at a time, 2.36 g of trimethyloxonium tetrafluoroborate are added to a solution of 3.52 g of 1-acetyl-3-[1-hydroxy-1-(3-iodophenyl)methylene]-6-chloro-2-indolinone (starting material VI) and 2.72 ml of ethyldiisopropylamine in 80 ml of dichloromethane, and the mixture is stirred at room temperature for one hour. Another 1.4 ml of ethyldiisopropylamine and 1.2 g of trimethyloxonium tetrafluoroborate are added, and the mixture is stirred at room temperature for another two hours. The mixture is then extracted with water and the organic phase is dried over magnesium sulphate and evaporated to dryness. The residue is recrystallized from ether and dried at 80° C. under reduced pressure.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[C:5]1[CH:10]=[C:9](Br)[CH:8]=[N:7][C:6]=1[NH:12][CH3:13])[CH3:2].[Cl-].[Li+].[CH:17]([Sn](CCCC)(CCCC)CCCC)=[CH2:18]>CS(C)=O.[Cu]Cl.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:1]([O:3][C:4](=[O:14])[C:5]1[CH:10]=[C:9]([CH:17]=[CH2:18])[CH:8]=[N:7][C:6]=1[NH:12][CH3:13])[CH3:2]
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: CCOC(=O)c1cc(Br)cnc1NC
Agent: Cl[Cu]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Solvent: CS(C)=O
Product: C=Cc1cnc(NC)c(C(=O)OCC)c1
Reaction time: 18 h
Yield: 89.5 %

Procedure:
A solution of 5-bromo-2-methylamino-nicotinic acid ethyl ester (100 mg, 0.39 mmol), lithium chloride (98 mg, 2.32 mmol), copper(I)chloride (191 mg, 1.93 mmol), vinyl tributyl tin (151 mg, 0.46 mmol), and tetrakis(triphenylphosphine)palladium(0) (45 mg, 39 μmol) in methyl sulfoxide (3.1 mL) was stirred at 65° C., then after 4 h another portion of vinyl tributyl tin (141 mg, 0.46 mmol) was added, and stirring was continued for 18 h. After cooling, the reaction mixture was partitioned between sat. aq. ammonium chloride solution and diethyl ether, the organic layer was washed with water, dried (MgSO4), and evaporated. Chromatography (SiO2, heptane-ethyl acetate gradient) afforded the title compound (72 mg, 91%). Yellow liquid, MS (ISP): 207.1 (M+H)+.
Reaction SMILES: Cl.[NH2:2][C@H:3]([C:14]([OH:16])=[O:15])[CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][CH:6]=1.N[C@@H](C(O)=O)CC1C2C(=CC=CC=2)NC=1.C([S:40][C@H:41]([CH2:45][C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)[C:42](O)=[O:43])(=O)C1C=CC=CC=1.C(S[C@@H](CC1C=CC=CC=1)C(O)=O)(=O)C1C=CC=CC=1>>[SH:40][CH:41]([CH2:45][C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)[C:42]([NH:2][C@H:3]([C:14]([OH:16])=[O:15])[CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][CH:6]=1)=[O:43]
Reactant: N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O
Reactant: O=C(S[C@H](Cc1ccccc1)C(=O)O)c1ccccc1
Agent: Cl
Agent: N[C@H](Cc1c[nH]c2ccccc12)C(=O)O
Agent: O=C(S[C@@H](Cc1ccccc1)C(=O)O)c1ccccc1
Product: O=C(N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O)C(S)Cc1ccccc1

Procedure:
The operation is carried out as in Stage 1 of Example 24 using, instead of the hydrochloride of the methyl ester of L-Tryptophan, the hydrochloride of the methyl ester of D-Tryptophan and, instead of (R)-2-(benzoylthio)-3-phenylpropanoic acid, (S)-2-(benzoylthio)-3-phenylpropanoic acid (prepared according the same reference). After purification by chromatography on silica with a methylene chloride-ethyl acetate: 95-5 mixture as eluant, 564 mg of expected product (SR isomer) (colourless foam) is obtained.
Reaction SMILES: [C:1]1([NH:7][C:8]([C:10]2[O:14][C:13]([CH2:15][CH:16]([CH:24]([NH:26][CH2:27]/[CH:28]=[CH:29]/[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH3:25])[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[CH:12][CH:11]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:36]([O:40][C:41]([CH:43]1[CH2:47][C:46](=[O:48])[O:45][CH:44]1[C:49](O)=[O:50])=[O:42])([CH3:39])([CH3:38])[CH3:37].C(N(CC)CC)C.[Cl-].ClC1N(C)CC[NH+]1C>C(Cl)(Cl)Cl.O>[C:20]([O:19][C:17]([CH:16]([CH2:15][C:13]1[O:14][C:10]([C:8](=[O:9])[NH:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[CH:11][CH:12]=1)[CH:24]([N:26]([CH2:27]/[CH:28]=[CH:29]/[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)[C:49]([CH:44]1[CH:43]([C:41]([O:40][C:36]([CH3:38])([CH3:37])[CH3:39])=[O:42])[CH2:47][C:46](=[O:48])[O:45]1)=[O:50])[CH3:25])=[O:18])([CH3:23])([CH3:22])[CH3:21]
Reactant: CC(NC/C=C/c1ccccc1)C(Cc1ccc(C(=O)Nc2ccccc2)o1)C(=O)OC(C)(C)C
Reactant: CC(C)(C)OC(=O)C1CC(=O)OC1C(=O)O
Agent: CN1CC[NH+](C)C1Cl
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Solvent: O
Product: CC(C(Cc1ccc(C(=O)Nc2ccccc2)o1)C(=O)OC(C)(C)C)N(C/C=C/c1ccccc1)C(=O)C1OC(=O)CC1C(=O)OC(C)(C)C
Reaction time: 1 h

Procedure:
86 mg of tert-butyl (2RS,3RS)-2-{5-(phenylcarbamoyl)-2-furylmethyl}-3-{(E)-3-phenyl-2-propenylamino}butanoate prepared in Reference Example 3, 46 mg of (2RS,3RS)-3-(tert-butoxycarbonyl)-5-oxotetrahydrofuran-2-carboxylic acid prepared in Reference Example 6 and 140 μl of triethylamine were dissolved in 2 ml of chloroform and stirred with 41 mg of 2-chloro-1,3-dimethylimidazolinium chloride in 1 ml of chloroform under cooling with ice for 10 minutes and then at room temperature for 1 hour. The reaction solution was poured into water and extracted with ethyl acetate, and the organic layer was dried over anhydrous magnesium sulfate. The desiccant was filtered off, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography [hexane/ethyl acetate=10/1→2/1] to give 124 mg (stoichiometric yield) of the title compound as a colorless oily substance.
Reaction SMILES: [NH2:1][CH:2]([C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[C:11]([Cl:16])[CH:10]=1)[CH2:3][C:4]([O:6]CC)=[O:5].[CH2:17]([O:24][CH2:25][CH:26]([NH:30][C:31]([O:33][CH2:34][CH2:35][CH2:36][NH:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][N:39]=1)=[O:32])[C:27](O)=[O:28])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[CH2:17]([O:24][CH2:25][CH:26]([NH:30][C:31]([O:33][CH2:34][CH2:35][CH2:36][NH:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][N:39]=1)=[O:32])[C:27]([NH:1][CH:2]([C:9]1[CH:10]=[C:11]([Cl:16])[CH:12]=[C:13]([Cl:15])[CH:14]=1)[CH2:3][C:4]([OH:6])=[O:5])=[O:28])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C(NC(COCc1ccccc1)C(=O)O)OCCCNc1ccccn1
Reactant: CCOC(=O)CC(N)c1cc(Cl)cc(Cl)c1
Product: O=C(O)CC(NC(=O)C(COCc1ccccc1)NC(=O)OCCCNc1ccccn1)c1cc(Cl)cc(Cl)c1

Procedure:
Analogously to Example 2, ethyl 3-amino-3-(3,5-dichlorophenyl)propionate is reacted with 3-benzyloxy-2-[3-(pyridin-2-ylamino)propoxycarbonylamino]-propionic acid and purified by preparative HPLC, giving 3-{3-benzyloxy-2-[3-(pyridin-2-ylamino)propoxycarbonylamino]propanoylamino}-3-(3,5-dichlorophenyl)propionic acid, RT 1.598 min, FAB-MS (M+H)+ 590.
Reaction SMILES: [CH2:1]([C:5]1[O:9][C:8]2[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=2[CH:6]=1)[CH2:2][CH2:3][CH3:4].[CH3:14][O:15][C:16]1[S:20][C:19]([C:21](Cl)=[O:22])=[CH:18][CH:17]=1.Cl[Sn](Cl)(Cl)Cl>C(Cl)(Cl)Cl>[CH2:1]([C:5]1[O:9][C:8]2[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=2[C:6]=1[C:21]([C:19]1[S:20][C:16]([O:15][CH3:14])=[CH:17][CH:18]=1)=[O:22])[CH2:2][CH2:3][CH3:4]
Reactant: COc1ccc(C(=O)Cl)s1
Reactant: CCCCc1cc2ccccc2o1
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Product: CCCCc1oc2ccccc2c1C(=O)c1ccc(OC)s1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
3.0 g (17.2 mmol) 2-butylbenzo[b]furan were dissolved in 30 ml abs. chloroform, the solution was cooled to 0° C., and reacted with 3.6 g (20.4 mmol) 5-methoxy-2-thiophenecarbonyl chloride, dissolved in 5 ml abs. chloroform, and then, at a temperature between 0° and 3° C., 2.8 ml SnCl4 were added dropwise. Stirring for 2 hours at 0° C. followed. The reaction mixture was evacuated under ice-cooling over 50 ml 2N HCl, the phases were separated and the aqueous phase thoroughly extracted with ether. The chloroform and ether phases were each washed with 50 ml 2N NaOH, combined, dried over sodium sulphate and evaporated. The crude product was quickly distilled.
Reaction SMILES: [C:1]1([C:7](=[O:17])[CH2:8][C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:18]([NH:20][C:21](=[O:24])[CH:22]=[CH2:23])O>>[C:11]1([C:9](=[O:10])[CH:8]([CH2:18][NH:20][C:21](=[O:24])[CH:22]=[CH2:23])[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[O:17])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=C(CC(=O)c1ccccc1)c1ccccc1
Reactant: C=CC(=O)NCO
Product: C=CC(=O)NCC(C(=O)c1ccccc1)C(=O)c1ccccc1

Procedure:
1,3-Diphenyl-2-(acrylamidomethyl)-propane-1,3-dione was prepared from 143 g of 1,3-diphenylpropane-1,3-dione and 64.8 g of N-methylolacrylamide similarly to the method described in Synthesis Example I.
Reaction SMILES: [CH2:1]([O:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C:10]1([C:28]1[CH:29]=[CH:30][C:31]2[N:32]([CH:34]=[CH:35][N:36]=2)[CH:33]=1)[C:15]([S:18]CC1C=CC(OC)=CC=1)=[N:16][CH3:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O.C(=O)([O-])O.[Na+]>ClCCl>[CH2:1]([O:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C:10]1([C:28]1[CH:29]=[CH:30][C:31]2[N:32]([CH:34]=[CH:35][N:36]=2)[CH:33]=1)[C:15](=[S:18])[NH:16][CH3:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN=C(SCc1ccc(OC)cc1)C1(c2ccc3nccn3c2)CCCCC1OCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: COc1ccccc1
Product: CNC(=S)C1(c2ccc3nccn3c2)CCCCC1OCc1ccccc1
Reaction time: 1 h
Yield: 79 %

Procedure:
500 mg of the 2-benzyloxy-1-(imidazo[1,2-a]-pyridin-6-yl)-1-((4-methoxybenzylthio)(methylimino)methyl)cyclohexane prepared in the Preparative Example 4 was dissolved in 5 ml of dichloromethane, followed by the addition of 1 ml of anisole. The obtained mixture was cooled with ice, followed by the gradual addition of 5 ml of trifluoroacetic acid. The obtained mixture was stirred for one hour, followed by the addition of a saturated aqueous solution of sodium hydrogencarbonate. The obtained mixture was extracted with chloroform. The organic phase was dried over anhydrous sodium sulfate and distilled to remove the solvent. The obtained residue was purified by silica gel column chromatography [solvent: dichloromethane/methanol (50:1)]. The obtained oil was crystallized from ether and the obtained crystal was recovered by filtration. Thus, 300 mg of the title compound was obtained as a white powder (yield 79%).
Reaction SMILES: [I:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.C([CH2:13][S:14]([CH2:17][S:18]([CH2:21][C:22](O)=O)(=[O:20])=[O:19])(=[O:16])=[O:15])(O)=O>C(O)(=O)C>[I:1][C:2]1[CH:9]=[CH:8][C:5](/[CH:6]=[CH:13]/[S:14]([CH2:17][S:18](/[CH:21]=[CH:22]/[C:5]2[CH:8]=[CH:9][C:2]([I:1])=[CH:3][CH:4]=2)(=[O:20])=[O:19])(=[O:16])=[O:15])=[CH:4][CH:3]=1
Reactant: O=C(O)CS(=O)(=O)CS(=O)(=O)CC(=O)O
Reactant: O=Cc1ccc(I)cc1
Solvent: CC(=O)O
Product: O=S(=O)(/C=C/c1ccc(I)cc1)CS(=O)(=O)/C=C/c1ccc(I)cc1
Yield: 78 %

Procedure:
A solution of 4-iodobenzaldehyde (2 mmol) and carboxymethane-sulfonylmethanesulfonyl-acetic acid (1 mmol) in acetic acid (10 mL) was subjected to General Procedure 1, to yield the title compound in 78% yield. m.p. 253-255° C.
Reaction SMILES: [CH3:1][N:2]1[CH2:10][C:9]2[C:8]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][C@@H:12]3[CH3:17])=[N:7][C:6]([C:18]3[CH:23]=[CH:22][C:21]([NH:24][C:25](=O)[O:26]C4C=CC=CC=4)=[CH:20][CH:19]=3)=[N:5][C:4]=2[CH2:3]1.[F:34][C:35]1[CH:41]=[CH:40][C:38]([NH2:39])=[CH:37][CH:36]=1>>[F:34][C:35]1[CH:41]=[CH:40][C:38]([NH:39][C:25]([NH:24][C:21]2[CH:22]=[CH:23][C:18]([C:6]3[N:7]=[C:8]([N:11]4[CH2:16][CH2:15][O:14][CH2:13][C@@H:12]4[CH3:17])[C:9]4[CH2:10][N:2]([CH3:1])[CH2:3][C:4]=4[N:5]=3)=[CH:19][CH:20]=2)=[O:26])=[CH:37][CH:36]=1
Reactant: C[C@H]1COCCN1c1nc(-c2ccc(NC(=O)Oc3ccccc3)cc2)nc2c1CN(C)C2
Reactant: Nc1ccc(F)cc1
Product: C[C@H]1COCCN1c1nc(-c2ccc(NC(=O)Nc3ccc(F)cc3)cc2)nc2c1CN(C)C2

Procedure:
Method as described for example 51 using intermediate 10 and 4-fluoroaniline as starting materials. Purified by prep. LCMS (high pH).
Reaction SMILES: [CH3:1][N:2]1[C:6]2=[N:7][CH:8]=[CH:9][CH:10]=[C:5]2[N:4]=[C:3]1S(C)(=O)=O.[CH2:15]([N:17]1[C:25]2[C:20](=[N:21][CH:22]=[C:23]([O:26][CH3:27])[CH:24]=2)[N:19]([C:28]2[CH:33]=[CH:32][C:31]([OH:34])=[CH:30][CH:29]=2)[C:18]1=[O:35])[CH3:16].[H-].[Na+]>CN(C=O)C>[CH2:15]([N:17]1[C:25]2[C:20](=[N:21][CH:22]=[C:23]([O:26][CH3:27])[CH:24]=2)[N:19]([C:28]2[CH:33]=[CH:32][C:31]([O:34][C:3]3[N:2]([CH3:1])[C:6]4=[N:7][CH:8]=[CH:9][CH:10]=[C:5]4[N:4]=3)=[CH:30][CH:29]=2)[C:18]1=[O:35])[CH3:16]
Reactant: Cn1c(S(C)(=O)=O)nc2cccnc21
Reactant: CCn1c(=O)n(-c2ccc(O)cc2)c2ncc(OC)cc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCn1c(=O)n(-c2ccc(Oc3nc4cccnc4n3C)cc2)c2ncc(OC)cc21
Temperature: 150 °C
Reaction time: 2 h
Yield: 15.5 %

Procedure:
To a solution of 3-methyl-2-(methylsulfonyl)-3H-imidazo[4,5-b]pyridine (67 mg) and 1-ethyl-3-(4-hydroxyphenyl)-6-methoxy-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (75 mg) in DMF (3 mL) was added NaH (13 mg) at room temperature, and the mixture was stirred at 150° C. under microwave irradiation for 2 h. The mixture was partitioned between water and AcOEt. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography (dry charge, NH silica gel, eluted with 50%-100% AcOEt in hexane) and column chromatography (dry charge, silica gel, eluted with 50%-100% AcOEt in hexane), and recrystallized from MeOH to give 1-ethyl-6-methoxy-3-{4-[(3-methyl-3H-imidazo[4,5-b]pyridin-2-yl)oxy]phenyl}-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (17 mg) as white crystals.