Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]2[N:6]=[CH:7][NH:8][C:4]=2[CH:3]=1.[O:11]1[CH2:16][CH2:15][N:14]([C:17]2[CH:22]=[CH:21][C:20]([C:23]3[NH:24][C:25]4[CH:31]=[C:30]([C:32]([O-:34])=O)[CH:29]=[CH:28][C:26]=4[N:27]=3)=[CH:19][CH:18]=2)[CH2:13][CH2:12]1>>[C:23]([C:20]1[CH:21]=[CH:22][C:17]([C:7]2[NH:6][C:5]3[CH:9]=[CH:10][C:2]([NH:1][C:32]([C:30]4[CH:29]=[CH:28][C:26]5[N:27]=[C:23]([C:20]6[CH:19]=[CH:18][C:17]([N:14]7[CH2:15][CH2:16][O:11][CH2:12][CH2:13]7)=[CH:22][CH:21]=6)[NH:24][C:25]=5[CH:31]=4)=[O:34])=[CH:3][C:4]=3[N:8]=2)=[CH:18][CH:19]=1)#[N:24]
Reactant: Nc1ccc2nc[nH]c2c1
Reactant: O=C([O-])c1ccc2nc(-c3ccc(N4CCOCC4)cc3)[nH]c2c1
Product: N#Cc1ccc(-c2nc3cc(NC(=O)c4ccc5nc(-c6ccc(N7CCOCC7)cc6)[nH]c5c4)ccc3[nH]2)cc1

Procedure:
Compound 298 was prepared according to the procedure similar to that described in Scheme V from 2-(4-cyano)phenyl)-5-aminobenzimidazole and 2-(4-morpholinophenyl)benzimidazole-5-carboxylate. [M+H]+ calcd for C32H25N7O2: 540.21; found: 539.97.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=O)[CH:16]([CH3:21])[CH2:17][C:18](O)=[O:19])=[CH:11][C:10]=1[N+:23]([O-:25])=[O:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[NH2:27][NH2:28].C(O)(=O)C>C(O)C>[CH2:1]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]([CH3:21])[CH2:17][C:18](=[O:19])[NH:27][N:28]=2)=[CH:11][C:10]=1[N+:23]([O-:25])=[O:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NN
Reactant: CC(CC(=O)O)C(=O)c1ccc(NCc2ccccc2)c([N+](=O)[O-])c1
Solvent: O
Solvent: CCO
Solvent: CC(=O)O
Product: CC1CC(=O)NN=C1c1ccc(NCc2ccccc2)c([N+](=O)[O-])c1
Temperature: 100 °C
Reaction time: 2 h

Procedure:
4-(4-Benzylamino-3-nitro-phenyl)-3-methyl-4-oxo-butyric acid E-4.1″ (939 mg; 2.74 mmol) is placed in 7 ml ethanol and treated with hydrazine hydrate (0.16 ml; 3.29 mmol) and acetic acid (78.58 μl; 1.37 mmol). The reaction mixture is heated up to 100° C. for 2 hours. Another portion of hydrazine hydrate (0.08 ml; 1.65 mmol) and 40 μl acetic acid are added and stirred for 2 hours at 100° C. After letting the reaction cooling to RT, the product precipitates. It is filtered off and washed with methanol and dried under reduced pressure.
Reaction SMILES: [CH2:1]([N:5]([CH2:16][CH2:17][CH2:18][CH3:19])[C:6]1[CH:13]=[CH:12][C:9]([CH:10]=O)=[C:8]([O:14][CH3:15])[CH:7]=1)[CH2:2][CH2:3][CH3:4].[C:20]([C:22]1[C:23](=[C:30]([C:33]#[N:34])[C:31]#[N:32])[O:24][C:25]([CH3:29])([CH3:28])[C:26]=1[CH3:27])#[N:21].C([O-])(=O)C.[NH4+]>C(O)C>[CH2:1]([N:5]([CH2:16][CH2:17][CH2:18][CH3:19])[C:6]1[CH:13]=[CH:12][C:9]([CH:10]=[CH:27][C:26]2[C:25]([CH3:28])([CH3:29])[O:24][C:23](=[C:30]([C:31]#[N:32])[C:33]#[N:34])[C:22]=2[C:20]#[N:21])=[C:8]([O:14][CH3:15])[CH:7]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CC1=C(C#N)C(=C(C#N)C#N)OC1(C)C
Reactant: CCCCN(CCCC)c1ccc(C=O)c(OC)c1
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CCO
Product: CCCCN(CCCC)c1ccc(C=CC2=C(C#N)C(=C(C#N)C#N)OC2(C)C)c(OC)c1
Temperature: 50 °C
Reaction time: 4 h
Yield: 94.5 %

Procedure:
In 5 ml of ethanol were dissolved 170 mg (0.65 mmol) of 4-dibutylamino-2-methoxybenzaldehyde and 141 mg (0.71 mmol) of 2-(3-cyano-4,5,5-trimethyl-2(5H)-furanylidene) propanedinitrile. To this mixture was added 50 mg of ammonium acetate, and the mixture was stirred at 50° C. for 4 hours. Ethanol was evaporated off and the residue was purified by silica gel column chromatography to give 273 mg of a dark brown crystal (yield: 95.1%; mp: 222-226° C.)
Reaction SMILES: [C:1]([C:9]1[S:13][C:12]2[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=2[C:10]=1[OH:18])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:19]1([CH2:25][CH2:26][NH2:27])[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1>>[N:19]1([CH2:25][CH2:26][NH:27]/[C:1](/[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[C:9]2\[C:10](=[O:18])[C:11]3[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=3[S:13]\2)[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1
Reactant: O=C(c1ccccc1)c1sc2ccccc2c1O
Reactant: NCCN1CCOCC1
Product: O=C1/C(=C(\NCCN2CCOCC2)c2ccccc2)Sc2ccccc21
Yield: 62 %

Procedure:
Prepared as in Example 35 from 2-benzoyl-benzo[b]thiophen-3-ol and 2-(4-morpholinyl)-ethylamine instead of ammonium acetate with a yield of 62% of theory.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=O)=[C:7]([N+:14]([O-:16])=[O:15])[CH:6]=1)=[O:4].[NH2:17][C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][N:19]=1>>[Cl:24][C:21]1[CH:22]=[CH:23][C:18]([NH:17][C:9](=[O:11])[C:8]2[CH:12]=[CH:13][C:5]([C:3]([O:2][CH3:1])=[O:4])=[CH:6][C:7]=2[N+:14]([O-:16])=[O:15])=[N:19][CH:20]=1
Reactant: COC(=O)c1ccc(C(=O)O)c([N+](=O)[O-])c1
Reactant: Nc1ccc(Cl)cn1
Product: COC(=O)c1ccc(C(=O)Nc2ccc(Cl)cn2)c([N+](=O)[O-])c1
Yield: 73.5 %

Procedure:
Using a similar procedure to that described in Example 1-A, 4-methoxycarbonyl-2-nitrobenzoic acid (1.87 g, 8.31 mmol) and 2-amino-5-chloropyridine (1.16 g, 9.14 mmol) afforded 2.05 g (74%) of the title compound.
Reaction SMILES: CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:25][C:26]([CH3:39])([CH3:38])[CH2:27][CH2:28][N:29]1[CH2:34][CH2:33][CH:32]([C:35]([OH:37])=O)[CH2:31][CH2:30]1.CCN(C(C)C)C(C)C.[NH2:49][CH2:50][C:51]1[CH:67]=[CH:66][C:54]([C:55]([N:57]([C:59]2[CH:64]=[CH:63][C:62]([Cl:65])=[CH:61][CH:60]=2)[CH3:58])=[O:56])=[CH:53][C:52]=1[CH3:68]>CN(C=O)C.CCOC(C)=O>[Cl:65][C:62]1[CH:63]=[CH:64][C:59]([N:57]([CH3:58])[C:55]([C:54]2[CH:66]=[CH:67][C:51]([CH2:50][NH:49][C:35]([CH:32]3[CH2:31][CH2:30][N:29]([CH2:28][CH2:27][C:26]([CH3:25])([CH3:39])[CH3:38])[CH2:34][CH2:33]3)=[O:37])=[C:52]([CH3:68])[CH:53]=2)=[O:56])=[CH:60][CH:61]=1
Reactant: Cc1cc(C(=O)N(C)c2ccc(Cl)cc2)ccc1CN
Reactant: CC(C)(C)CCN1CCC(C(=O)O)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1cc(C(=O)N(C)c2ccc(Cl)cc2)ccc1CNC(=O)C1CCN(CCC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 83 %

Procedure:
HBTU (296 mg, 0.78 mmol) was added to a solution of 1-(3,3-dimethyl-butyl)-piperidine-4-carboxylic acid from Example E15 (182 mg, 0.73 mmol) in DMF (5 ml) and DIEA (0.272 ml, 1.56 mmol). The mixture was stirred at room temperature for 2 h then 4-aminomethyl-N-(4-chloro-phenyl)-3,N-dimethyl-benzamide from Example E115.2 (150 mg, 0.52 mmol) was added. The mixture was stirred for 2 h at room temperature then diluted with EtOAc, washed with saturated NaHCO3 then brine, dried and concentrated in vacuo. The residue was purified by preparative HPLC (eluant; 0.5% 35% ammonia:9.5% methanol:90% dichloromethane) to give a white powder identified as the title compound (209 mg, 83%).
Reaction SMILES: [C:1]([Si:5]([CH3:27])([CH3:26])[O:6][C@@H:7]([C@H:9]1[C:15](=[O:16])[N:14]2[C@@H:10]1[C@@H:11]([CH3:25])[C:12]([S:23][CH3:24])=[C:13]2[C:17]([O:19][CH2:20][CH:21]=[CH2:22])=[O:18])[CH3:8])([CH3:4])([CH3:3])[CH3:2].[OH:28]O>CC(C)=O.C(O)C.C(OCC)(=O)C>[Si:5]([O:6][C@@H:7]([C@H:9]1[C:15](=[O:16])[N:14]2[C@@H:10]1[C@@H:11]([CH3:25])[C:12]([S:23]([CH3:24])=[O:28])=[C:13]2[C:17]([O:19][CH2:20][CH:21]=[CH2:22])=[O:18])[CH3:8])([C:1]([CH3:3])([CH3:2])[CH3:4])([CH3:27])[CH3:26]
Reactant: C=CCOC(=O)C1=C(SC)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O[Si](C)(C)C(C)(C)C)C(=O)N12
Reactant: OO
Solvent: CCO
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: C=CCOC(=O)C1=C(S(C)=O)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O[Si](C)(C)C(C)(C)C)C(=O)N12
Reaction time: 96 h

Procedure:
To a solution of allyl (4R,5S,6S)-6-[(1R)-1-(tertbutyldimethylsilyloxy)ethyl] -4-methyl-3-methylthio-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (31.4 mg) in a mixture of acetone (1.0 ml) and ethanol (0.1 ml) was added a 30% aqueous solution of hydrogen peroxide (0.2 ml). The reaction was allowed to stand at ambient temperature for 4 days. The mixture was diluted with ethyl acetate, washed with water, 5% aqueous sodium thiosulfate solution, brine, and dried. The solvent was removed off under reduced pressure and the residue was purified by silica gel column chromatography [ethyl acetate-n-hexane (1:3, V/V)] to afford allyl (4R,5S,6S)-6-[(1R)-1-(tert-butyldimethylsilyloxy)ethyl]-4-methyl-3-methylsulfinyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (10.1 mg).
Reaction SMILES: [C:1]([C:3]1[N:7]([CH2:8][CH2:9][CH3:10])[N:6]=[C:5]([CH3:11])[C:4]=1[NH:12][C:13](=O)[CH3:14])#[N:2].[OH:16]O.O.[OH-].[Na+]>C(O)(=O)C>[CH3:11][C:5]1[C:4]2[N:12]=[C:13]([CH3:14])[N:2]=[C:1]([OH:16])[C:3]=2[N:7]([CH2:8][CH2:9][CH3:10])[N:6]=1
Reactant: OO
Reactant: CCCn1nc(C)c(NC(C)=O)c1C#N
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: CCCn1nc(C)c2nc(C)nc(O)c21
Temperature: 80 °C
Yield: 66 %

Procedure:
The above acetamide (16 g, 0.085 mol) is added in portions with stirring at 80° C. to a solution prepared by adding 24 ml of 30% hydrogen peroxide to 200 ml water containing 6 g (0.015 mol) of sodium hydroxide. After stirring at 80° C. for five hours, the mixture is cooled, acidified with acetic acid, and filtered to give 11.6 g (66%) of the title compound, mp 196°-198° C.
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5](=O)[CH:6]([C:9]1[CH:14]=[CH:13][C:12](C)=[CH:11][CH:10]=1)[C:7]#[N:8])C.O.[NH2:18][NH2:19].[C:20]([OH:23])(=O)C>C(O)C>[CH3:1][O:3][CH2:4][C:5]1[C:6]([C:9]2[CH:10]=[CH:11][C:12]([O:23][CH3:20])=[CH:13][CH:14]=2)=[C:7]([NH2:8])[NH:19][N:18]=1
Reactant: NN
Reactant: CCOCC(=O)C(C#N)c1ccc(C)cc1
Reactant: CC(=O)O
Solvent: O
Solvent: CCO
Product: COCc1n[nH]c(N)c1-c1ccc(OC)cc1
Temperature: 80 °C
Yield: 90 %

Procedure:
4-Ethoxy-2-(4-methylphenyl)-3-oxobutanenitrile (1.493 g) is dissolved in ethanol (150 mL) and hydrazine hydrate (˜40%, 7.8 mL, 2 eq) and acetic acid (5.9 mL, 2 eq) are slowly added. The reaction mixture is stirred at 80° C.90° C. for 1 hour under reflux. Upon completion of the reaction, ethanol is removed under reduced pressure. After the reaction is terminated by adding saturated aq. NaHCO3, the reaction mixture is extracted 3 times with ethyl acetate. The organic layer is washed with water and dehydrated with MgSO4. After concentration under reduced pressure, the produced solid is recrystallized with Hx:EA:MC=20:1:0.1 to obtain the target compound (90%). 1H NMR (CDCl3, 300 MHz): δ 7.25 (m, 2H), 6.95 (m, 2H), 4.43 (s, 3H), 3.82 (s, 3H), 3.38 (s, 3H).
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[N:9]#[C:10][NH2:11].[C:12](=[O:15])([O-:14])[O-:13].[Na+].[Na+]>O>[C:12](=[O:13])([OH:15])[OH:14].[C:3]1([NH:2][C:10]([NH2:11])=[NH:9])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: Nc1ccccc1
Reactant: N#CN
Reactant: O=C([O-])[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: N=C(N)Nc1ccccc1
Product: O=C(O)O
Temperature: 85 °C
Reaction time: 2 h
Yield: 92.7 %

Procedure:
88.5 g (0.78 mol) aqueous HCl (32% by weight) are added to 93.1 g aniline (1.0 mol) until the pH value reaches 2.0. Over the course of 1 hour, 92.4 g (1.1 mol) of a 50% aqueous cyanamide solution are run into the reaction mixture at 85° C. Towards the end of the cyanamide addition, a further 22.1 g (0.19 mol) aqueous HCl (32%) are added, which returns the pH to 2.4 to 2.7. After stirring for 2 hours at 85° C., the mixture is allowed to cool to 60° C. and a solution of 63.6 g (0.6 mol) sodium carbonate in 170 ml water is added over a 30 minute period. The crystalline precipitate is filtered after cooling to 5° C. 163 g phenylguanidine carbonate are produced, containing 76.7% phenylguanidine free base, which corresponds to a 92.7% yield based on aniline. The melting point (decomposition) is 147° to 150° C.
Reaction SMILES: [C:1]([CH2:4][CH2:5][CH2:6][N:7]([CH3:66])[C@H:8]([C:12]([NH:14][C@H:15]([C:19]([N:21]([C@@H:23]([C@@H:62]([CH3:65])[CH2:63][CH3:64])[C@H:24]([O:60][CH3:61])[CH2:25][C:26]([N:28]1[CH2:32][CH2:31][CH2:30][C@H:29]1[C@H:33]([O:58][CH3:59])[C@@H:34]([CH3:57])[C:35]([NH:37][C@@H:38]([C@H:49]([C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1)[CH3:50])[C:39]([O:41][CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)=[O:40])=[O:36])=[O:27])[CH3:22])=[O:20])[CH:16]([CH3:18])[CH3:17])=[O:13])[CH:9]([CH3:11])[CH3:10])(O)=[O:2].Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.[O:99]=[C:100]1[CH:104]=[CH:103][C:102](=[O:105])[N:101]1[CH2:106][CH2:107][CH2:108][CH2:109][CH2:110][C:111]([NH:113][NH2:114])=[O:112]>CN(C=O)C>[O:105]=[C:102]1[CH:103]=[CH:104][C:100](=[O:99])[N:101]1[CH2:106][CH2:107][CH2:108][CH2:109][CH2:110][C:111]([NH:113][NH:114][C:1](=[O:2])[CH2:4][CH2:5][CH2:6][N:7]([CH3:66])[C@H:8]([C:12]([NH:14][C@H:15]([C:19]([N:21]([C@@H:23]([C@@H:62]([CH3:65])[CH2:63][CH3:64])[C@H:24]([O:60][CH3:61])[CH2:25][C:26]([N:28]1[CH2:32][CH2:31][CH2:30][C@H:29]1[C@H:33]([O:58][CH3:59])[C@@H:34]([CH3:57])[C:35]([NH:37][C@@H:38]([C@H:49]([C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1)[CH3:50])[C:39]([O:41][CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)=[O:40])=[O:36])=[O:27])[CH3:22])=[O:20])[CH:16]([CH3:17])[CH3:18])=[O:13])[CH:9]([CH3:10])[CH3:11])=[O:112]
Reactant: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@H](C(=O)OCc1ccccc1)[C@@H](C)c1ccccc1)OC)N(C)C(=O)[C@@H](NC(=O)[C@H](C(C)C)N(C)CCCC(=O)O)C(C)C
Reactant: NNC(=O)CCCCCN1C(=O)C=CC1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@H](C(=O)OCc1ccccc1)[C@@H](C)c1ccccc1)OC)N(C)C(=O)[C@@H](NC(=O)[C@H](C(C)C)N(C)CCCC(=O)NNC(=O)CCCCCN1C(=O)C=CC1=O)C(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
5.8 mg (6.3 μmol) of N-(3-carboxypropyl)-N-methyl-L-valyl-N-[(3R,4S,5S)-1-{(2S)-2-[(1R,2R)-3-{[(2S,3S)-1-(benzyloxy)-1-oxo-3-phenylbutan-2-yl]amino}-1-methoxy-2-methyl-3-oxopropyl]pyrrolidin-1-yl}-3-methoxy-5-methyl-1-oxoheptan-4-yl]-N-methyl-L-valinamide were dissolved in 943 μl of DMF and then admixed with 3.6 mg (19 μmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, 2.9 mg (19 μmol) of 1-hydroxy-1H-benzotriazole hydrate, 2.2 μl of N,N-diisopropylethylamine and with 6.6 mg (25 μmol) of commercially available 6-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)hexanehydrazide. The mixture was stirred at RT overnight and then concentrated under high vacuum. The remaining residue was purified by means of preparative HPLC. Thus, 4.5 mg (64% of theory) of the title compound were obtained as a colourless foam.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([O:10][CH2:11][CH3:12])[N:5]=[C:4]([C:13]([OH:15])=O)[CH:3]=1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.Cl.[NH2:39][CH2:40][CH2:41][S:42]([CH2:45]CN)(=[O:44])=[O:43].C(N(C(C)C)CC)(C)C>CN(C)C(=O)C>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([O:10][CH2:11][CH3:12])[N:5]=[C:4]([C:13]([NH:39][CH2:40][CH2:41][S:42]([CH3:45])(=[O:44])=[O:43])=[O:15])[CH:3]=1
Reactant: NCCS(=O)(=O)CCN
Reactant: CCOc1nc(C(=O)O)cc(N)c1C#N
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: CCOc1nc(C(=O)NCCS(C)(=O)=O)cc(N)c1C#N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a 20 mL vial a solution of Example 104A (32.5 mg, 0.16 mmol) dissolved in N,N-dimethylacetamide (0.8 mL) was added, followed by the addition of O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium tetrafluoroborate (50.4 mg, 0.16 mmol) dissolved in N,N-dimethylacetamide (0.8 mL). Then, 2-aminoethylsulfone hydrocloride (30.3 mg, 0.19 mmol) dissolved in N,N-dimethylacetamide (0.6 mL) was added followed by the addition of diisopropyl ethyl amine (57.9 uL, 0.31 mmol) dissolved in N,N-dimethylacetamide (0.8 mL). The mixture was shaken at room temperature overnight. The reaction was checked by LC/MS and concentrated to dryness. The residue was dissolved in 1:1 dimethyl sulfoxide/methanol and purified by reverse phase (0-70% CH3CN in 10 mM aq. ammonium acetate) to give the titled compound. 1H NMR (500 MHz, DMSO-d6) δ ppm 1.26-1.38 (m, 3H) 2.93-3.08 (m, 3H) 3.29-3.47 (m, 2H) 3.72-3.80 (m, 2H) 4.30-4.61 (m, 2H) 7.05-7.09 (m, 1H); MS (ESI) positive ion 313 (M+H).
Reaction SMILES: N[CH:2]([OH:4])[CH3:3].Br[CH2:6][C:7]1[C:8](=[O:36])[N:9]([C:13]2[CH:18]=[CH:17][C:16]([N:19]3[CH2:23][C@H:22]([CH2:24][NH:25][C:26]([C:28]4[S:29][C:30]([Cl:33])=[CH:31][CH:32]=4)=[O:27])[O:21][C:20]3=[O:34])=[CH:15][C:14]=2[CH3:35])[CH:10]=[CH:11][CH:12]=1.O.C[N:39](C=O)C>>[Cl:33][C:30]1[S:29][C:28]([C:26]([NH:25][CH2:24][C@@H:22]2[O:21][C:20](=[O:34])[N:19]([C:16]3[CH:17]=[CH:18][C:13]([N:9]4[CH:10]=[CH:11][CH:12]=[C:7]([CH2:6][NH:39][CH2:3][CH2:2][OH:4])[C:8]4=[O:36])=[C:14]([CH3:35])[CH:15]=3)[CH2:23]2)=[O:27])=[CH:32][CH:31]=1
Reactant: Cc1cc(N2C[C@H](CNC(=O)c3ccc(Cl)s3)OC2=O)ccc1-n1cccc(CBr)c1=O
Reactant: CN(C)C=O
Reactant: CC(N)O
Solvent: O
Product: Cc1cc(N2C[C@H](CNC(=O)c3ccc(Cl)s3)OC2=O)ccc1-n1cccc(CNCCO)c1=O
Reaction time: 0.5 h

Procedure:
At −10° C., 38 mg (0.63 mmol) of aminoethanol are added to a solution of 56 mg (0.11 mmol) of the compound from Example 11A in 1 ml of DMF. After 30 min at −10° C., the mixture is added to water and then extracted three times with ethyl acetate. The organic phases are combined and then freed from the solvent under reduced pressure. The product is purified by preparative HPLC using an acetonitrile/water mixture. This gives 14.5 mg (26% of theory) of the desired product.
Reaction SMILES: CN([C:4]([O:8][N:9]1N=NC2C=CC=N[C:10]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[C:25]([O:29][C:30]([N:32]1[CH2:36][CH2:35][CH:34]([C:37]([OH:39])=O)[CH2:33]1)=[O:31])([CH3:28])([CH3:27])[CH3:26].Cl.CNOC.C(N(CC)CC)C>C(Cl)Cl>[CH3:4][O:8][N:9]([CH3:10])[C:37]([CH:34]1[CH2:35][CH2:36][N:32]([C:30]([O:29][C:25]([CH3:26])([CH3:27])[CH3:28])=[O:31])[CH2:33]1)=[O:39]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)C1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CNOC
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CON(C)C(=O)C1CCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
HATU (4.56 g, 12.0 mmol) was added to 1-(tert-butoxycarbonyl)pyrrolidine-3-carboxylic acid (2.15 g, 10.0 mmol), N,O-dimethylhydroxylamine hydrochloride (1.17 g, 12.0 mmol), and triethylamine (30.0 mmol) in DCM (50.0 mL), and the resulting mixture was allowed to stir at rt. After 12 h, the reaction mixture was diluted with DCM, and the combined organics were washed with water and brine, dried (sodium sulfate) and concentrated in vacuo to afford the title compound i-19a. m/z (ES) 259 (MH)+.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][N:6]2[C:9]([C:12]3[CH:21]=[CH:20][C:19]4[C:14](=[C:15]([N:22]5[CH2:27][CH2:26][CH:25]([CH2:28][NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[CH2:24][CH2:23]5)[CH:16]=[CH:17][CH:18]=4)[N:13]=3)=[N:10][N:11]=[C:5]2[CH:4]=1)=O.[CH2:37]([NH2:39])[CH3:38].CC(O)=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl.CO>[CH2:37]([NH:39][CH2:1][C:3]1[CH:8]=[CH:7][N:6]2[C:9]([C:12]3[CH:21]=[CH:20][C:19]4[C:14](=[C:15]([N:22]5[CH2:27][CH2:26][CH:25]([CH2:28][NH:29][C:30](=[O:36])[O:31][C:32]([CH3:34])([CH3:35])[CH3:33])[CH2:24][CH2:23]5)[CH:16]=[CH:17][CH:18]=4)[N:13]=3)=[N:10][N:11]=[C:5]2[CH:4]=1)[CH3:38]
Reactant: CCN
Reactant: CC(C)(C)OC(=O)NCC1CCN(c2cccc3ccc(-c4nnc5cc(C=O)ccn45)nc23)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: CO
Product: CCNCc1ccn2c(-c3ccc4cccc(N5CCC(CNC(=O)OC(C)(C)C)CC5)c4n3)nnc2c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To tert-butyl (1-(2-(7-formyl-[1,2,4]triazolo[4,3-a]pyridin-3-yl)quinolin-8-yl)piperidin-4-yl)methylcarbamate (Example 11, steps A-K; 10 mg, 0.021 mmol) in DCM/MeOH (1 mL/1 mL) was added EtNH2 (0.1 mL, 2M in THF) and HOAc (0.2 mL), followed by NaB(OAc)3H (13 mg, 0.062 mmol). The reaction mixture was stirred for 5 hours at ambient temperature and then concentrated. The crude material was purified by silica gel chromatography (DCM/MeOH/NH4OH 20:1:0.1) to provide the desired product (4 mg). MS APCI (+) m/z 343 (M+1) detected.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:12])=[C:4]([C:8]([Br:11])=[CH:9][CH:10]=1)[CH:5]=[N:6][OH:7].[CH2:13]=[CH2:14].[O-]Cl.[Na+]>C(Cl)Cl>[Br:1][C:2]1[C:3]([CH3:12])=[C:4]([C:5]2[CH2:14][CH2:13][O:7][N:6]=2)[C:8]([Br:11])=[CH:9][CH:10]=1
Reactant: C=C
Reactant: Cc1c(Br)ccc(Br)c1C=NO
Agent: [Na+]
Agent: [O-]Cl
Solvent: ClCCl
Product: Cc1c(Br)ccc(Br)c1C1=NOCC1
Reaction time: 8 h

Procedure:
68 g (0.23 mol) of 3,6-dibromo-2-methylbenzaldoxime are dissolved in 750 ml of methylene chloride in a pressure container. 20 g of ethylene are applied, and 620 g of a 12.5% strength solution of NaOCl are then pumped in at room temperature, and the mixture is stirred overnight. The pressure vessel is vented, and the organic phase is then separated off, washed once with 250 ml of water and dried, and the solvent is removed under reduced pressure. This gives 77 g of product (95% pure) (99% of theory).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([CH2:7][CH2:8][C:9]([O:11][CH3:12])=[O:10])[CH:4]=[N:3]1.[CH:13](OC)=[O:14].CC([O-])(C)C.[K+]>C1COCC1>[CH:13]([CH:8]([CH2:7][C:5]1[CH:4]=[N:3][N:2]([CH3:1])[CH:6]=1)[C:9]([O:11][CH3:12])=[O:10])=[O:14]
Reactant: COC=O
Reactant: COC(=O)CCc1cnn(C)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COC(=O)C(C=O)Cc1cnn(C)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 41.8 %

Procedure:
A solution of methyl 3-(1-methyl-1H-pyrazol-4-yl)propanoate (18.7 g, 111 mmol) and methyl formate (14.02 g, 233 mmol) in dry THF (20 ml) was added dropwise over 2 h to a stirred, ice-cooled suspension of t-BuOK (31.2 g, 278 mmol) in dry THF (160 ml) under argon. The mixture was then allowed to warm to room temperature and stirred for 16 h. The solvents were removed in vacuo, and the residue was dissolved in water (50 ml). The solution was extracted with ethyl acetate (30 ml×2), and the aqueous phase was neutralized with 1M HCl to pH˜5. The solid was collected. The filtrate was extracted with ethyl acetate (40 ml×2), dried over Na2SO4, filtered and concentrated in vacuo. The solids were combined to give the title compound as a white solid (9.1 g, 39.8% yield). LCMS: rt=1.05 min, [M+H+]=197
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:11][CH:10]=[C:9]([CH2:12][NH2:13])[O:8][C:7]=2[CH:14]=1.[CH2:15]([N:18]=[C:19]=[O:20])[CH2:16][CH3:17].[N-]=C=O>C1(C)C=CC=CC=1.O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:11][CH:10]=[C:9]([CH2:12][NH:13][C:19]([NH:18][CH2:15][CH2:16][CH3:17])=[O:20])[O:8][C:7]=2[CH:14]=1
Reactant: CCCN=C=O
Reactant: COc1ccc2c(c1)OC(CN)=CO2
Agent: [N-]=C=O
Solvent: O
Solvent: Cc1ccccc1
Product: CCCNC(=O)NCC1=COc2ccc(OC)cc2O1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
The amine obtained in Step C of Example 24 is dissolved in 16 ml of anhydrous toluene; 0.78 g (9.17 mmol) of n-propyl isocyanate is then added to the medium. After 4 hours of stirring under an inert atmosphere and at ambient temperature, the excess of isocyanate is neutralised with a few drops of water. The solvent is then evaporated in vacuo. The residue obtained is purified on a silica column (eluant: MeOH/CH2Cl2: 10/90) to yield the title urea in the form of a white solid.
Reaction SMILES: [CH2:1]([C:8]1[CH:13]=[C:12]([CH3:14])[N:11]=[C:10]([NH:15][CH:16]2[CH2:21][CH2:20][N:19]([C:22]#[N:23])[CH2:18][CH2:17]2)[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:24](=[N:27][OH:28])(N)[CH3:25]>CCOC(C)=O.C1COCC1.O.[Cl-].[Zn+2].[Cl-]>[CH2:1]([C:8]1[CH:13]=[C:12]([CH3:14])[N:11]=[C:10]([NH:15][CH:16]2[CH2:21][CH2:20][N:19]([C:22]3[O:28][N:27]=[C:24]([CH3:25])[N:23]=3)[CH2:18][CH2:17]2)[N:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(N)=NO
Reactant: Cc1cc(Cc2ccccc2)nc(NC2CCN(C#N)CC2)n1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1cc(Cc2ccccc2)nc(NC2CCN(c3nc(C)no3)CC2)n1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 4-(4-benzyl-6-methyl-pyrimidin-2-ylamino)-piperidine-1-carbonitrile (135 mg, 0.44 mmol) and acetamidoxime (39 mg, 0.53 mmol) in EtOAc (1 mL) and THF (1 mL) was added within 10 minutes a solution of zinc chloride (73 mg, 0.53 mmol) in EtOAc (1 mL). After stirring at room temperature for 4 hours the reaction was heated to reflux over night under nitrogen. The reaction was diluted with water and extracted twice with ethyl acetate. The combined organic layers were washed with saturated aqueous NaCl solution, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using CH2Cl2/MeOH 19:1 (v/v) as eluent. The title compound was obtained as a colorless gum (98 mg, 61%).