Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([C:8](=[O:10])[CH3:9])[CH:7]=1.N1[CH2:16][CH2:15][CH2:14][CH2:13]1.C1(=O)CCC1>CO.O>[Cl:1][C:2]1[CH:7]=[C:6]2[C:5](=[CH:4][CH:3]=1)[O:11][C:13]1([CH2:16][CH2:15][CH2:14]1)[CH2:9][C:8]2=[O:10]
Reactant: C1CCNC1
Reactant: CC(=O)c1cc(Cl)ccc1O
Agent: O=C1CCC1
Solvent: CO
Solvent: O
Product: O=C1CC2(CCC2)Oc2ccc(Cl)cc21
Yield: 96.5 %

Procedure:
To a stirred solution of 5′-chloro-2′-hydroxy acetophenone (5.0 g, 29.308 mmol) in methanol (50 ml) was added pyrrolidine (4.16 g, 58.616 mmol) followed by cyclobutanone (4.1 g, 58.616 mmol) at room temperature. The reaction mixture was heated to reflux under nitrogen for 14 h. The solvent was evaporated under reduced pressure and the residue obtained was diluted with water (100 ml) and the mixture was acidified to pH 4.0. The mixture was extracted with chloroform (3×100 ml). The combined organic extracts were washed with water (100 ml), brine (50 ml) and dried over anhydrous sodium sulfate. The residue obtained after evaporation of the solvent was purified by silica gel column chromatography using 15% ethyl acetate in petroleum ether to give 6.3 g of the product as a white solid; 1H NMR (300 MHz, CDCl3) δ 1.69-1.88 (m, 5H), 1.96-2.04 (m, 1H), 2.88 (s, 2H), 6.91 (d, J=9.0 Hz, 1H), 7.38 (d, J=6.6 Hz, 1H), 7.76 (s, 1H).
Reaction SMILES: Br[C:2]1[CH:27]=[CH:26][C:5]2[N:6]([C:22]([CH3:25])([CH3:24])[CH3:23])[C:7]([C:9]3[CH:10]=[C:11]([CH2:20][OH:21])[CH:12]=[CH:13][C:14]=3[N:15]3[CH:19]=[N:18][CH:17]=[N:16]3)=[N:8][C:4]=2[CH:3]=1.[NH2:28][C:29]1[N:34]=[CH:33][C:32](B2OC(C)(C)C(C)(C)O2)=[CH:31][N:30]=1.C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C.CCOC(C)=O.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>[NH2:28][C:29]1[N:34]=[CH:33][C:32]([C:2]2[CH:27]=[CH:26][C:5]3[N:6]([C:22]([CH3:23])([CH3:25])[CH3:24])[C:7]([C:9]4[CH:10]=[C:11]([CH2:20][OH:21])[CH:12]=[CH:13][C:14]=4[N:15]4[CH:19]=[N:18][CH:17]=[N:16]4)=[N:8][C:4]=3[CH:3]=2)=[CH:31][N:30]=1
Reactant: CC1(C)OB(c2cnc(N)nc2)OC1(C)C
Reactant: CC(C)(C)n1c(-c2cc(CO)ccc2-n2cncn2)nc2cc(Br)ccc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)n1c(-c2cc(CO)ccc2-n2cncn2)nc2cc(-c3cnc(N)nc3)ccc21
Temperature: 110 °C
Yield: 61.9 %

Procedure:
To a sealed vial is added [3-(5-bromo-1-tert-butyl-1H-benzoimidazol-2-yl)-4-[1,2,4]triazol-1-yl-phenyl]methanol (47 mg, 0.11 mmol) in DMF (2 mL), followed by the addition of 2-aminopyrimidine-5-boronic acid pinacol ester (29 mg, 0.13 mmol) and tetrakis(triphenylphosphine)palladium(0) (13 mg, 0.011 mmol) and 2M aqueous Na2CO3 (0.25 mL, 0.5 mmol). The reaction mixture is heated under argon at 110° C. for 2 hours. The residue is diluted with EtOAc (10 mL), washed with brine (10 mL), and dried under anhydrous Na2SO4 (500 mg). The mixture is filtered and is concentrated. The residue is purified by silica gel flash chromatography with 0-10% 2M NH3 in MeOH/CH2Cl2 as the eluent. The product fractions are collected and concentrated to afford the title compound (30 mg, 62%). LCMS (ESMS): m/z 441.32 (M++1)
Reaction SMILES: [C:1]([C:4]1[C:5]([NH:13][C:14]2[CH:23]=[CH:22][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][C:15]=2[O:24][CH3:25])=[N:6][C:7]([S:11][CH3:12])=[N:8][C:9]=1Cl)(=[O:3])[NH2:2].[OH-].[NH4+:27].O>CS(C)=O>[NH2:27][C:9]1[N:8]=[C:7]([S:11][CH3:12])[N:6]=[C:5]([NH:13][C:14]2[CH:23]=[CH:22][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][C:15]=2[O:24][CH3:25])[C:4]=1[C:1](=[O:3])[NH2:2]
Reactant: [NH4+]
Reactant: COC(=O)c1ccc(Nc2nc(SC)nc(Cl)c2C(N)=O)c(OC)c1
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: COC(=O)c1ccc(Nc2nc(SC)nc(N)c2C(N)=O)c(OC)c1
Temperature: 100 °C

Procedure:
To a solution of the product of Example 10A (1.3 g, 3.4 mmol) in dimethylsulfoxide (50 mL) was added ammonium hydroxide (5.2 mL, 34 mmol). The mixture was heated to 100° C. for 4 hours and was allowed to cool to ambient temperature. Water (50 mL) was added and the precipitate was filtered and washed with ethanol (20 mL) to give the title compound. MS: 364 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][C:10]([N:13]2[C:18](=[O:19])[CH:17]=[CH:16][NH:15][C:14]2=[O:20])=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].[CH3:21]N(C)C=O>>[Cl:1][C:2]1[CH:12]=[CH:11][C:10]([N:13]2[C:18](=[O:19])[CH:17]=[CH:16][N:15]([CH3:21])[C:14]2=[O:20])=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCOC(=O)c1cc(-n2c(=O)cc[nH]c2=O)ccc1Cl
Reactant: CN(C)C=O
Product: CCOC(=O)c1cc(-n2c(=O)ccn(C)c2=O)ccc1Cl

Procedure:
using ethyl 2-chloro-5-[3,6-dihydro-2,6-dioxo-1(2H)-pyrimidinyl]-benzoate in dimethylformamide there is obtained ethyl 2-chloro-5-[3,6-dihydro-3-methyl-2,6-dioxo-1(2H)-pyrimidinyl]-benzoate, m.p. 147°-148° C.,
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([OH:7])[CH2:3][CH2:2]1.[H-].[Na+].[F:10][C:11]([F:39])([F:38])[C:12]1[CH:13]=[C:14]([CH:35]=[CH:36][CH:37]=1)[CH2:15][NH:16][C:17](=[O:34])[C:18]1[CH:23]=[CH:22][N:21]=[C:20]([C:24]2[CH:29]=[C:28](F)[CH:27]=[CH:26][C:25]=2[N+:31]([O-:33])=[O:32])[CH:19]=1>CN(C)C=O.C(OCC)(=O)C>[F:38][C:11]([F:10])([F:39])[C:12]1[CH:13]=[C:14]([CH:35]=[CH:36][CH:37]=1)[CH2:15][NH:16][C:17](=[O:34])[C:18]1[CH:23]=[CH:22][N:21]=[C:20]([C:24]2[CH:29]=[C:28]([O:7][CH:4]3[CH2:5][CH2:6][O:1][CH2:2][CH2:3]3)[CH:27]=[CH:26][C:25]=2[N+:31]([O-:33])=[O:32])[CH:19]=1
Reactant: OC1CCOCC1
Reactant: O=C(NCc1cccc(C(F)(F)F)c1)c1ccnc(-c2cc(F)ccc2[N+](=O)[O-])c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(NCc1cccc(C(F)(F)F)c1)c1ccnc(-c2cc(OC3CCOCC3)ccc2[N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 114 %

Procedure:
Into a 50-mL round bottom flask, was placed a solution of tetrahydro-2H-pyran-4-ol (220 mg, 2.11 mmol, 3.00 equiv, 98%) in N,N-dimethylformamide (5 mL). This was followed by the addition of sodium hydride (86 mg, 3.58 mmol, 5.00 equiv), in portions at room temperature. The resulting solution was stirred for 10 min at room temperature. To this was added N-(3-(trifluoromethyl)benzyl)-2-(5-fluoro-2-nitrophenyl)isonicotinamide (300 mg, 0.70 mmol, 1.00 equiv, 98%). Then the resulting solution was stirred for an additional 2 h at 80° C. in an oil bath. The resulting solution was diluted with 200 mL of ethyl acetate, and washed with 2×30 mL of brine. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column and eluted with ethyl acetate/methanol (20/1). The product was obtained as 400 mg (97%) of a brown oil.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH2:3][C@@H:2]1[C:6]([OH:8])=O.C(Cl)(=O)C(Cl)=O.Cl.Cl.[CH2:17]([N:24]1[CH2:29][CH2:28][CH:27]([NH2:30])[CH2:26][CH2:25]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(N(CC)CC)C>C(Cl)Cl>[CH2:17]([N:24]1[CH2:29][CH2:28][CH:27]([NH:30][C:6]([C@H:2]2[CH2:3][CH2:4][CH2:5][O:1]2)=[O:8])[CH2:26][CH2:25]1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: O=C(O)[C@H]1CCCO1
Reactant: NC1CCN(Cc2ccccc2)CC1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NC1CCN(Cc2ccccc2)CC1)[C@H]1CCCO1
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.1 %

Procedure:
A solution of (R)-tetrahydro-2-furoic acid (58.5 g, 504 mmol) and oxalyl chloride (86 mL, 1.0 mol) in 100 mL CH2Cl2 were refluxed for 2 hours in a flask equipped with a CaCl2 guard tube. After the solution was cooled to room temperature the solvents and excess oxalyl chloride were removed by evaporation under reduced pressure. The resulting acid chloride was dissolved in 200 mL CH2Cl2 and added dropwise to a solution of 1-benzyl-4-amino piperidine dihydrochloride (142 g, 539 mmol) and triethylamine (240 mL, 1.7 mol) in 300 mL CH2Cl2 cooled in an ice bath. The resulting mixture was stirred for 2 hours at room temperature and subsequently washed twice with 300 mL portions of 5% aq. NaHCO3 and 300 mL saturated aq. NaCl solution, dried over Na2SO4, filtered, and evaporated to dryness under reduced pressure. The solid residue was triturated with 500 mL heptanes, collected by filtration, and washed twice with 200 mL portions of heptanes. The solid was air-dried at 45° C. to yield (R)-tetrahydrofuran-2-carboxylic acid (1-benzyl-piperidin-4-yl)-amide (128 g, 88%) as an off-white solid. 1H-NMR (300 MHz, CDCl3): δ 7.35-7.20 (m, 5H), 6.58 (bs, 1H), 4.29 (dd, J=5.9, 8.4 Hz, 1H), 3.92-3.77 (m, 2H), 3.48 (s, 2H), 2.82-2.74 (m, 2H), 2.32-2.21 (m, 1H), 2.19-1.95 (m, 3H), 1.94-1.78 (m, 4H), 1.58-1.40 (m, 2H) ppm.
Reaction SMILES: N(C(OC(C)(C)C)=O)[C@H](C([NH:9][C@H:10]([C:18]([N:20]1[CH2:27][CH2:26][CH2:25][C@H:21]1[C:22]([OH:24])=[O:23])=[O:19])[CH2:11][S:12][CH2:13][NH:14][C:15]([CH3:17])=[O:16])=O)CC(=O)N.N(C(OC(C)(C)C)=O)[C@H](C(N1CCC[C@H]1C(O)=O)=O)CSCNC(C)=O.[ClH:61].CC(O)=O>CN(C=O)C>[NH2:9][C@H:10]([C:18]([N:20]1[CH2:27][CH2:26][CH2:25][C@H:21]1[C:22]([OH:24])=[O:23])=[O:19])[CH2:11][S:12][CH2:13][NH:14][C:15]([CH3:17])=[O:16].[ClH:61]
Reactant: CC(=O)NCSC[C@H](NC(=O)[C@H](CC(N)=O)NC(=O)OC(C)(C)C)C(=O)N1CCC[C@H]1C(=O)O
Agent: CC(=O)NCSC[C@H](NC(=O)OC(C)(C)C)C(=O)N1CCC[C@H]1C(=O)O
Agent: Cl
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: CC(=O)NCSC[C@H](N)C(=O)N1CCC[C@H]1C(=O)O

Procedure:
Boc-Asn-Cys(Acm)-Pro-OH (XIII) is obtained by deblocking XII in HCl/HOAc att room temperature, dissolving the thus obtained raw H-Cys(Acm)-Pro-OH.HCl in DMF and neutralizing it with Et3N, and adding Boc-Asn-ONp (Novabiochem, Laufelingen, CH) at -5° C. while keeping pH neutral. XIII is isolated in 81% yield. [α]D20 =-77.1° (1 g/100 ml DMF). The tetrapeptide derivative X is prepared from XIII and Boc-Gln-ONp (Novabiochem, Laufelingen, CH) in a way corresponding to the preparation of XIII from XII and Boc-Asn-ONp. Yield 78.5%; [α]D20 =-89.7° (1 g/100 ml H2O).
Reaction SMILES: [CH2:1]([N:3]([CH2:6][CH:7]1[CH2:12][CH2:11][CH2:10][NH:9][CH2:8]1)[CH2:4][CH3:5])[CH3:2].Cl[CH2:14][C:15]([N:17]1[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[C:21](=[O:28])[NH:20][C:19]2[CH:29]=[CH:30][CH:31]=[N:32][C:18]1=2)=[O:16].C(=O)([O-])[O-]>CN(C)C=O>[CH2:1]([N:3]([CH2:6][CH:7]1[CH2:12][CH2:11][CH2:10][N:9]([CH2:14][C:15]([N:17]2[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[C:21](=[O:28])[NH:20][C:19]3[CH:29]=[CH:30][CH:31]=[N:32][C:18]2=3)=[O:16])[CH2:8]1)[CH2:4][CH3:5])[CH3:2]
Reactant: O=C1Nc2cccnc2N(C(=O)CCl)c2ccccc21
Reactant: CCN(CC)CC1CCCNC1
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: CCN(CC)CC1CCCN(CC(=O)N2c3ccccc3C(=O)Nc3cccnc32)C1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A solution of 3-[(diethylamino)-methyl]piperidine (4.6 g, 0.027 mol) in dry dimethylformamide (10 ml) is added dropwise over 2 hours to a suspension of 11-chloroacetyl-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one (5.2 g, 0.0181 mol) in anhydrous dimethylformamide (25 ml), then the resulting mixture is stirred for a further 6 hours at ambient temperature and left to stand overnight. The mixture is stirred into ice (200 g), made alkaline with postassium carbonate and extracted exhaustively with dichloromethane. The combined dichloromethane extracts are washed once with water (20 ml), dried over magnesium sulphate and concentrated by evaporation in vacuo. After recrystallization from ethyl acetate, colorless crystals (4.5 g) are obtained, mp. 199°-200° C.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[N:11]=[CH:10][CH:9]=[C:8]2[NH:13][C:14]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:15]=1[C:16]([O:18][CH3:19])=[O:17].[CH3:27][N:28]([CH:30](O)C)[CH3:29]>>[F:26][C:2]([F:1])([F:25])[C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[N:11]=[CH:10][CH:9]=[C:8]2[NH:13][C:14]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:15]=1[C:16]([O:18][CH2:19][CH2:27][N:28]([CH3:30])[CH3:29])=[O:17]
Reactant: CC(O)N(C)C
Reactant: COC(=O)c1cc(F)ccc1Nc1ccnc2c(C(F)(F)F)cccc12
Product: CN(C)CCOC(=O)c1cc(F)ccc1Nc1ccnc2c(C(F)(F)F)cccc12

Procedure:
Using the process of Example 13, methyl 2-(8-trifluoromethyl-4-quinolinylamino)-5-fluoro-benzoate and dimethylamino-ethanol were reacted to form 2-dimethylaminoethyl 2-(8-trifluoromethyl-4-quinolinylamino)-5-fluorobenzoate which was then dissolved in ethanol. Dry hydrogen chloride in ethanol was added to the solution and anhydrous ether was added to effect precipitation. The mixture was vacuum filtered and the crystals were washed and dried to obtain 2-dimethylamino-ethyl 2-(8-trifluoromethyl-4-quinolinylamino)-5-fluoro-benzoate hydrochloride melting at 220° C.
Reaction SMILES: [N:1]#[C:2][NH2:3].Cl.C([NH:9][C:10]([NH:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][CH:15]=1)=[O:11])(C)(C)C>O>[C:14]([N:12]([CH2:13][C:14]1[CH:15]=[CH:16][C:17]([NH:20][C:2]([NH2:3])=[NH:1])=[CH:18][CH:19]=1)[C:10]([NH2:9])=[O:11])([CH3:19])([CH3:15])[CH3:13]
Reactant: N#CN
Reactant: CC(C)(C)NC(=O)NCc1ccc(N)cc1
Agent: Cl
Solvent: O
Product: CC(C)(C)N(Cc1ccc(NC(=N)N)cc1)C(N)=O
Temperature: 62.5 °C
Reaction time: 2 h
Yield: 142.1 %

Procedure:
Cyanamide (100 g, 2.4 mol) was placed in a 500 mL round bottom flask and heated to 60-65° C. until the material completely melted. N-tert-butyl-N′-4-aminobenzylurea hydrochloride, (25.3 g, 97.8 mmol) was then added directly to the liquid cyanamide and the resulting yellow solution was stirred at 60-65° C. an additional two hours. Water (100 mL) was subsequently added to the solution followed by cooling to room temperature. The aqueous solution was washed with ethyl ether (1 L) followed by back extraction of the organic phase with water (2×, 100 mL). The combined aqueous layers were again washed with ethyl ether (500 mL) and the aqueous solution cooled in an ice water bath followed by basification with aqueous sodium hydroxide (10M, 100 mL). The resulting insoluble oil slowly crystalized and was collected by filtration. The material then was washed with water and dried in vacuo to give N-tert-butyl-N-4-guanidinobenzylurea (18.3 g, 70.8%) as a colorless crystalline solid.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[CH:5][N:6]=1.O.O.O.[F:10][C:11]([F:19])([F:18])[C:12]([C:14]([F:17])([F:16])[F:15])=[O:13]>C(OCC)(=O)C>[NH2:1][C:2]1[S:3][C:4]([C:12]([OH:13])([C:14]([F:17])([F:16])[F:15])[C:11]([F:19])([F:18])[F:10])=[CH:5][N:6]=1
Reactant: O=C(C(F)(F)F)C(F)(F)F
Reactant: Nc1nccs1
Solvent: CCOC(C)=O
Solvent: O
Product: Nc1ncc(C(O)(C(F)(F)F)C(F)(F)F)s1
Temperature: 100 °C
Yield: 73.1 %

Procedure:
A catalytic amount of molecular sieves powder (4A) was added to a mixture of 2-aminothiazole 200 mg (2 mmol) and hexafluoroacetone trihydrate (880 mg, 4 mmol). The mixture was heated at 100° C. for 8 h. Ethyl acetate was added and the mixture was filtered. Organic solvents were evaporated under reduced pressure. The residue was recrystallized in THF and hexanes to afford the title product (389 mg) as a white solid. 1H NMR (DMSO-d6) δ7.12 (s, 1H), 7.45 (brs, 2H), 8.85 (s, 1H); ESIMS: m/z 267 (M+H).
Reaction SMILES: [CH2:1]([C:8]1([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH2:1]([C:8]1([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:9][CH2:10][NH:11][CH2:12][CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C1(Cc2ccccc2)CCN(C(=O)OC(C)(C)C)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)C1(Cc2ccccc2)CCNCC1
Yield: 71.8 %

Procedure:
A solution of 1-tert-butyl 4-ethyl 4-benzylpiperidine-1,4-dicarboxylate (step 2, 4.5 g, 12.96 mmol) in DCM (50 ml) was cooled to 0° C. After ten minutes, trifluoroacetic acid (6.0 g) was added and stirred the reaction at room temperature for about 6 hours. After completion of the reaction (monitored by TLC), the reaction mixture was neutralized with sat. NaHCO3, extracted with DCM, dried over Na2SO4 and concentrated under reduced pressure to furnish the title compound (2.3 g) as a light yellow liquid. 1H NMR (300 MHz, CDCl3): 1.19-1.24 (t, 3H); 1.48-1.58 (m, 2H); 2.14-2.18 (m, 2H); 2.64-2.73 (m, 2H); 2.86 (s, 2H); 3.01-3.07 (m, 4H); 4.10-4.17 (m, 2H); 7.07-7.10 (m, 2H); 7.24-7.30 (m, 3H); ES Mass: 248 (100%) [M+1].
Reaction SMILES: [CH:1]1([CH:7]([NH:25][C:26]2[CH:34]=[CH:33][C:29]([C:30](O)=[O:31])=[CH:28][CH:27]=2)[C:8]2[CH:12]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([O:19][C:20]([F:23])([F:22])[F:21])=[CH:15][CH:14]=3)[O:10][C:9]=2[CH3:24])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:35][NH:36][CH2:37][CH2:38][C:39]([O:41]CC)=[O:40]>>[CH:1]1([CH:7]([NH:25][C:26]2[CH:27]=[CH:28][C:29]([C:30]([N:36]([CH3:35])[CH2:37][CH2:38][C:39]([OH:41])=[O:40])=[O:31])=[CH:33][CH:34]=2)[C:8]2[CH:12]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([O:19][C:20]([F:22])([F:23])[F:21])=[CH:15][CH:14]=3)[O:10][C:9]=2[CH3:24])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCOC(=O)CCNC
Reactant: Cc1oc(-c2ccc(OC(F)(F)F)cc2)cc1C(Nc1ccc(C(=O)O)cc1)C1CCCCC1
Product: Cc1oc(-c2ccc(OC(F)(F)F)cc2)cc1C(Nc1ccc(C(=O)N(C)CCC(=O)O)cc1)C1CCCCC1
Yield: 95.7 %

Procedure:
An operation similar to that in Example 1 (4) was performed using 4-[(cyclohexyl{2-methyl-5-[4-(trifluoromethoxy)phenyl]-3-furyl}methyl)amino]benzoic acid (355 mg) as well as ethyl 3-(methylamino)propanoate (118 mg) to give the title compound (401 mg, 96%) as an amorphous compound.
Reaction SMILES: BrC1C(N2CCN(C(NC3C=CC=CC=3)=O)CC2)=C2N=C(C3C=CC(N(C)C)=CC=3)NC2=NC=1.[Cl:35][C:36]1[C:37]([N:46]2[CH2:51][CH2:50][N:49]([CH2:52][C:53]3[CH:54]=[N:55][CH:56]=[CH:57][CH:58]=3)[CH2:48][CH2:47]2)=[C:38]([N+:43]([O-])=O)[C:39]([NH2:42])=[N:40][CH:41]=1.[O-]S(S([O-])=O)=O.[Na+].[Na+].[C:67]([O:71][C:72]([N:74]1[CH2:79][CH2:78][N:77]([C:80]2[CH:85]=[CH:84][C:83]([CH:86]=O)=[CH:82][CH:81]=2)[CH2:76][CH2:75]1)=[O:73])([CH3:70])([CH3:69])[CH3:68]>C(O)C.CN(C=O)C>[Cl:35][C:36]1[C:37]([N:46]2[CH2:51][CH2:50][N:49]([CH2:52][C:53]3[CH:54]=[N:55][CH:56]=[CH:57][CH:58]=3)[CH2:48][CH2:47]2)=[C:38]2[N:43]=[C:86]([C:83]3[CH:82]=[CH:81][C:80]([N:77]4[CH2:76][CH2:75][N:74]([C:72]([O:71][C:67]([CH3:70])([CH3:69])[CH3:68])=[O:73])[CH2:79][CH2:78]4)=[CH:85][CH:84]=3)[NH:42][C:39]2=[N:40][CH:41]=1
Reactant: Nc1ncc(Cl)c(N2CCN(Cc3cccnc3)CC2)c1[N+](=O)[O-]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(C=O)cc2)CC1
Agent: CN(C)c1ccc(-c2nc3c(N4CCN(C(=O)Nc5ccccc5)CC4)c(Br)cnc3[nH]2)cc1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(-c3nc4c(N5CCN(Cc6cccnc6)CC5)c(Cl)cnc4[nH]3)cc2)CC1
Reaction time: 6 h
Yield: 32.8 %

Procedure:
This was prepared using the same procedure as for 4-(6-bromo-2-(4-(dimethylamino)phenyl)-3H-imidazo[4,5-b]pyridin-7-yl)-N-phenylpiperazine-1-carboxamide, but here using 5-chloro-3-nitro-4-(4-(pyridin-3-ylmethyl)piperazin-1-yl)pyridin-2-amine (20 mg, 0.057 mmol), DMF (0.15 mL), ethanol (0.85 mL), 1M Na2S2O4 (3 eq, 0.17 mmol, 0.17 mL) and 4-(4-formylphenyl)piperazine-1-carboxylic acid tert-butyl ester (1.1 eq, 0.063 mmol, 20 mg). After 6 h, concentration in vacuo and purification by preparative tlc (CH2Cl2-MeOH, 9:1) gave the product (11 mg, 41%) as a colourless solid; δH (500 MHz, DMSO-d6) 1.43 (s, 9H, C(CH3)3), 7.08 (d, J=9.0 Hz, 2H, phenyl H-3 & H-5), 7.55 (dd, J=8.5, 4.4 Hz, 1H, pyridine H-5), 7.99 (d, br, J=8.4 Hz, 1H, pyridine H-4), 8.03 (d, J=9.0 Hz, 2H, phenyl H-2 & H-6), 8.14 (s, 1H, imidazo[4,5-b]pyridine H-5), 8.69 (d, J=4.4 Hz, 1H, pyridine H-6), 8.75 (s, br, 1H, pyridine H-2), 13.36 (s, br, 1H, imidazo[4,5-b]pyridine NH);
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:10]([O:11]C(=O)C)[C@H:9]([O:15]C(=O)C)[C@@H:8]([CH2:19][O:20]C(=O)C)[O:7][C@H:6]1[O:24][C:25]1[C:33]2[C:32]([CH2:34][CH2:35][C:36]3[CH:41]=[CH:40][C:39]([C:42](O)=[O:43])=[CH:38][CH:37]=3)=[CH:31][S:30][C:29]=2[CH:28]=[CH:27][CH:26]=1)(=O)C.Cl.[NH2:46][CH2:47][C:48]([NH2:50])=[O:49].OCCN1CCNCC1>>[C:48]([CH2:47][NH:46][C:42]([C:39]1[CH:38]=[CH:37][C:36]([CH2:35][CH2:34][C:32]2[C:33]3[C:25]([O:24][C@@H:6]4[O:7][C@H:8]([CH2:19][OH:20])[C@@H:9]([OH:15])[C@H:10]([OH:11])[C@H:5]4[OH:4])=[CH:26][CH:27]=[CH:28][C:29]=3[S:30][CH:31]=2)=[CH:41][CH:40]=1)=[O:43])(=[O:49])[NH2:50]
Reactant: CC(=O)OC[C@H]1O[C@@H](Oc2cccc3scc(CCc4ccc(C(=O)O)cc4)c23)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: NCC(N)=O
Agent: Cl
Agent: OCCN1CCNCC1
Product: NC(=O)CNC(=O)c1ccc(CCc2csc3cccc(O[C@@H]4O[C@H](CO)[C@@H](O)[C@H](O)[C@H]4O)c23)cc1

Procedure:
The title compound was prepared in a similar manner to that described in Example 90 using 4-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-3-[2-(4-carboxyphenyl)ethyl]-benzo[b]thiophene and glycinamide hydrochloride instead of 4-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-3-[2-(4-{2-[1-carboxy-1-(methyl)ethylcarbamoyl]ethyl}phenyl)ethyl]-benzofuran and 1-(2-hydroxyethyl)piperazine, respectively.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][CH2:10][OH:11].[O:12]=[C:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:15][CH2:14]1>>[OH:12][C:13]1([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[CH2:8][CH2:9][CH2:10][OH:11])[CH2:14][CH2:15][N:16]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:17][CH2:18]1
Reactant: CCOC(=O)N1CCC(=O)CC1
Reactant: OCCCc1ccccc1Br
Product: CCOC(=O)N1CCC(O)(c2ccccc2CCCO)CC1

Procedure:
The title compound was prepared according to the procedure described in step 2 of example 36 from 3-(2-bromophenyl)propan-1-ol (J. Am. Chem. Soc. 2003, 125, 3509.) and ethyl 4-oxopiperidine-1-carboxylate:
Reaction SMILES: [C:1]([CH2:5][C:6]([O:8][CH3:9])=[O:7])(=O)[CH2:2][CH3:3].Cl.[CH2:11]([O:18][NH2:19])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C([O-])(=O)C.[K+]>CO.O>[CH2:11]([O:18][N:19]=[C:1]([CH2:2][CH3:3])[CH2:5][C:6]([O:8][CH3:9])=[O:7])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CCC(=O)CC(=O)OC
Reactant: NOCc1ccccc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [K+]
Solvent: CO
Solvent: O
Product: CCC(CC(=O)OC)=NOCc1ccccc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 100 %

Procedure:
To a solution of 26.03 g (0.2 mol) of methyl propionylacetate in 300 ml of methanol, 100 ml of water and 35.12 g (0.22 mol) of benzyloxyamine hydrochloride, 19.69 g (0.24 mol) of potassium acetate were added and the mixture was stirred for 15 hours at room temperature. After distilling methanol off under reduced pressure, followed by adding 200 ml of water and extracting three times with 200 ml of ethyl acetate, the mixture was washed with water and a saturated aqueous sodium chloride and then dried over with anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 47.06 g (yield: 100%) of a crude methyl 3-benzyloxyiminovalerate as a colorless oil.