Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:8])=[N:4][CH:5]=[CH:6][CH:7]=1.[C:9]([NH:12][C:13]1[CH:17]=[CH:16][S:15][C:14]=1[C:18](O)=[O:19])(=O)[CH3:10].P(Cl)(Cl)Cl>N1C=CC=CC=1>[CH3:10][C:9]1[N:1]([C:2]2[C:3]([Cl:8])=[N:4][CH:5]=[CH:6][CH:7]=2)[C:18](=[O:19])[C:14]2[S:15][CH:16]=[CH:17][C:13]=2[N:12]=1
Reactant: Nc1cccnc1Cl
Reactant: CC(=O)Nc1ccsc1C(=O)O
Solvent: ClP(Cl)Cl
Solvent: c1ccncc1
Product: Cc1nc2ccsc2c(=O)n1-c1cccnc1Cl
Temperature: 105 °C
Yield: 31.5 %

Procedure:
To a mixture of pyridine (4 mL), 3-amino-2-chloropyridine (0.514 g, 4 mmol), and 3-acetamidothiophene-2-carboxylic acid (0.370 g, 4 mmol) was added phosphorus trichloride (0.02 mL, 2.3 mmol). The reaction was heated to 105° C. for 3 hours, cooled to ambient temperature and partitioned between ethyl acetate and water. Phases were separated and the aqueous layer was extracted with ethyl acetate. The combined organic phase was washed with water and brine, dried over sodium sulfate and concentrated to a greenish brown oil. This residue was flash chromatographed on silica gel (20×120 mm) eluting with 20-40% ethyl acetate/hexane to afford 0.350 g (63%) of 2-methyl-3-(2-chloropyrid-3-yl)-3H-thieno[3,2-d]pyrimidin-4-one as a yellow foam.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[C:5]([C:10]3[CH:11]=[C:12]([NH2:19])[C:13]4[CH:14]=[N:15][NH:16][C:17]=4[CH:18]=3)[CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[C:20]1([CH:28]=O)[C:21]([CH:26]=[O:27])=[CH:22][CH:23]=[CH:24][CH:25]=1>C(OCC)(=O)C.C(O)(=O)C>[NH:1]1[C:9]2[C:4](=[C:5]([C:10]3[CH:18]=[C:17]4[C:13]([CH:14]=[N:15][NH:16]4)=[C:12]([N:19]4[CH2:28][C:20]5[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=5)[C:26]4=[O:27])[CH:11]=3)[CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: Nc1cc(-c2cccc3[nH]ccc23)cc2[nH]ncc12
Reactant: O=Cc1ccccc1C=O
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: O=C1c2ccccc2CN1c1cc(-c2cccc3[nH]ccc23)cc2[nH]ncc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 13.6 %

Procedure:
A mixture of 6-(1H-indol-4-yl)-1H-indazol-4-amine (100 mg, 0.403 mmol) and 1,2-benzenedicarbaldehyde (54 mg, 0.403 mmol) in ethyl acetate (1 ml) and acetic acid (0.25 ml) was stirred under a nitrogen atmosphere at room temperature for 3 h then overnight at room temperature. The reaction mixture was diluted with ethyl acetate (20 ml) and washed with 5% sodium bicarbonate solution (10 ml). The phases were separated, and the aqueous phase was extracted with further ethyl acetate (20 ml). The combined organic extracts (which contained a small amount of insoluble solid) were dried over anhydrous sodium sulphate, filtered and evaporated to give a yellow foam. This was partially dissolved in ethyl acetate (20 ml) and pre-adsorbed on silica (1.5 g). This silica was then added to the top of a 20 g silica SPE cartridge. The cartridge was eluted on a Flashmaster (II) instrument using a gradient of 0-100% ethyl acetate in cyclohexane over 30 min. Appropriate fractions were combined and evaporated to give the title compound (20 mg) as a pale yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4](F)[CH:3]=1.[CH2:12]([NH2:14])[CH3:13]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([CH:3]=1)[NH:14][CH2:12][CH3:13]
Reactant: CCN
Reactant: O=[N+]([O-])c1ccc(Br)cc1F
Product: CCNc1cc(Br)ccc1[N+](=O)[O-]
Temperature: 50 °C
Reaction time: 2 h

Procedure:
The mixture of 4-bromo-2-fluoro-1-nitrobenzene (5 g) and ethylamine (2 M in THF, 17.05 ml) was stirred at room temperature for 2 h and at 50° C. for 2 h. After concentration of the mixture, the residue was quenched with saturated NaHCO3 solution at room temperature and extracted with EtOAc. The organic layer was separated, washed with water and brine, dried over MgSO4 and concentrated in vacuo. The progress of the reaction was followed by NMR, but 4-bromo-2-fluoro-1-nitrobenzene was remained. The resulting residue was dissolved in EtOH (25 ml), and heated with potassium carbonate (6.28 g) and ethylamine (15.6 M in water, 1.47 ml) at 50° C. for 2 h. The resulting suspension was filtered. The precipitate was washed with EtOH and water and dried to give the title compound (4.45 g) as a pale yellow solid.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[CH:9][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:4]2[N:3]=1.Cl.[F:17][C:18]1[CH:19]=[CH:20][C:21]([C:29]([F:32])([F:31])[F:30])=[C:22]([C@H:24]2[CH2:28][CH2:27][CH2:26][NH:25]2)[CH:23]=1.C(N(C(C)C)CC)(C)C>C(O)(C)C>[F:17][C:18]1[CH:19]=[CH:20][C:21]([C:29]([F:32])([F:30])[F:31])=[C:22]([C@H:24]2[CH2:28][CH2:27][CH2:26][N:25]2[C:2]2[CH:7]=[CH:6][N:5]3[N:8]=[CH:9][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:4]3[N:3]=2)[CH:23]=1
Reactant: CCOC(=O)c1cnn2ccc(Cl)nc12
Reactant: Fc1ccc(C(F)(F)F)c([C@H]2CCCN2)c1
Agent: Cl
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1cnn2ccc(N3CCC[C@@H]3c3cc(F)ccc3C(F)(F)F)nc12
Temperature: 120 °C
Yield: 96.4 %

Procedure:
Ethyl 5-chloropyrazolo[1,5-a]pyrimidine-3-carboxylate (Preparation B, 0.51 g, 2.26 mmol), (R)-2-(5-fluoro-2-(trifluoromethyl)phenyl)pyrrolidine hydrochloride (0.610 g, 2.26 mmol) and diisopropylethylamine (1.12 mL, 6.78 mmol) were suspended in isopropanol (2.5 mL) and heated to 120° C. for 24 hours. The reaction mixture was purified by reverse phase chromatography eluting with 0-75% acetonitrile/water to yield the title compound (0.92 g, 96.4% yield). MS (apci) m/z=423.0.0 (M+H).
Reaction SMILES: [CH:1]1[C:11](=[C:12]([C:15]#[N:16])[C:13]#[N:14])[CH:10]=[CH:9][C:3](=[C:4]([C:7]#[N:8])[C:5]#[N:6])[CH:2]=1.C(#N)CC#N.C1(=O)CCC(=O)CC1>>[C:7]([C:4]([C:5]#[N:6])=[C:3]1[CH2:2][CH2:1][C:11](=[C:12]([C:15]#[N:16])[C:13]#[N:14])[CH2:10][CH2:9]1)#[N:8]
Reactant: N#CC(C#N)=c1ccc(=C(C#N)C#N)cc1
Agent: O=C1CCC(=O)CC1
Solvent: N#CCC#N
Product: N#CC(C#N)=C1CCC(=C(C#N)C#N)CC1

Procedure:
It is known to prepare 7,7,8,8-tetracyanoquinodimethane, for example, by subjecting malononitrile and 1,4-cyclohexane-dione to a condensation reaction to obtain 1,4-bis(dicyanomethylene)cyclohexane, and oxidizing the cyclohexane in pyridine with N-bromosuccinimide or bromine.
Reaction SMILES: C[CH2:2][CH2:3][CH:4](N)[C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6].[Br:13][C:14]1[CH:15]=[CH:16][C:17](F)=[C:18]([CH:21]=1)[CH:19]=[O:20].C(=O)([O-])[O-].[K+].[K+].O.[CH3:30][N:31](C=O)C>>[Br:13][C:14]1[CH:15]=[CH:16][C:17]([N:31]([CH2:2][CH2:3][CH2:4][C:5]([O:7][C:8]([CH3:9])([CH3:10])[CH3:11])=[O:6])[CH3:30])=[C:18]([CH:19]=[O:20])[CH:21]=1
Reactant: CN(C)C=O
Reactant: O=Cc1cc(Br)ccc1F
Reactant: CCCC(N)C(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CN(CCCC(=O)OC(C)(C)C)c1ccc(Br)cc1C=O
Temperature: 70 °C
Reaction time: 60 h
Yield: 90 %

Procedure:
In DMF (5.0 ml) was dissolved tert-butyl 4-methyl-aminobutyrate (1050 mg), and to the mixture was added at room temperature a solution of 5-bromo-2-fluorobenzaldehyde (1025 mg) in DMF (1.0 ml) and then potassium carbonate (837 mg). The mixture was stirred at 70° C. for 60 hours, and to the mixture was added at room temperature water (50 ml). The mixture was extracted with ethyl acetate (50 ml×3), and the organic layer was washed with saturated brine (50 ml×3) and dried with anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified with silica gel column chromatography (75 g, hexane:ethyl acetate=10:1) to give tert-butyl 4-(4-bromo-2-formyl-N-methylanilino)butyrate (1620 mg, 90%).
Reaction SMILES: [BH4-].[Na+].[C:3]([C:6]1[CH:14]=[C:13]2[C:9]([C:10]([C:19]([NH2:21])=[O:20])=[C:11]([NH:15][C:16]([NH2:18])=[O:17])[NH:12]2)=[CH:8][CH:7]=1)(=[O:5])[CH3:4].O>O1CCCC1>[NH2:18][C:16]([NH:15][C:11]1[NH:12][C:13]2[C:9]([C:10]=1[C:19]([NH2:21])=[O:20])=[CH:8][CH:7]=[C:6]([CH:3]([OH:5])[CH3:4])[CH:14]=2)=[O:17]
Reactant: CC(=O)c1ccc2c(C(N)=O)c(NC(N)=O)[nH]c2c1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(O)c1ccc2c(C(N)=O)c(NC(N)=O)[nH]c2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 21.2 %

Procedure:
Sodium borohydride (10 mg, 0.26 mmol) was added to a solution of 6-acetyl-2-aminocarbonylaminoindole-3-carboxamide (Compound 14-1,14 mg, 0.054 mmol) in anhydrous tetrahydrofuran (2 mL) under ice-cooling, and the mixture was stirred at room temperature for 1 hour. Water (5 mL) was added to the reaction mixture, and the whole was extracted with ethyl acetate (20 mL). The organic layer was washed with brine (5 mL), and dried over anhydrous magnesium sulfate. After the solvent was evaporated under reduced pressure, the resultant solid was washed with diethyl ether (2 mL) and dried under reduced pressure to give the title compound (3 mg) as a colorless solid (yield 22%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1.Cl[C:11]1[CH:12]=[CH:13][C:14]([N+:26]([O-:28])=[O:27])=[C:15]([N:17]([CH3:25])[C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH:16]=1.[H-].[Na+]>CN(C)C=O>[CH3:25][N:17]([C:15]1[CH:16]=[C:11]([O:9][C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[CH:12]=[CH:13][C:14]=1[N+:26]([O-:28])=[O:27])[C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21]
Reactant: CN(C(=O)OC(C)(C)C)c1cc(Cl)ccc1[N+](=O)[O-]
Reactant: COc1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(Oc2ccc([N+](=O)[O-])c(N(C)C(=O)OC(C)(C)C)c2)cc1
Yield: 85.7 %

Procedure:
In a similar manner to that described in Reference Example 6, a reaction was carried out using 4-methoxyphenol (5.0 g), t-butyl N-(5-chloro-2-nitrophenyl)-N-methylcarbamate (10.9 g), sodium hydride (55 wt. %, 2.2 g) and anhydrous N,N-dimethylformamide (120 ml) and the reaction mixture was purified to give the title compound (12.2 g).
Reaction SMILES: [F:1][C:2]1[C:3](=[O:9])[NH:4][C:5](=[O:8])[NH:6][CH:7]=1.[C:10](Cl)(=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>N1C=CC=CC=1.O1CCOCC1>[C:10]([N:4]1[C:3](=[O:9])[C:2]([F:1])=[CH:7][NH:6][C:5]1=[O:8])(=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=c1[nH]cc(F)c(=O)[nH]1
Reactant: O=C(Cl)c1ccccc1
Solvent: c1ccncc1
Solvent: C1COCCO1
Product: O=C(c1ccccc1)n1c(=O)[nH]cc(F)c1=O
Temperature: 0 °C
Yield: 32 %

Procedure:
2.6 g (0.02 mole) of 5-fluorouracil was suspended in 10 ml of absolute pyridine and 10 ml of absolute dioxane, and the suspension was warmed to 80° C and stirred. 5.6 g (0.04 mole) of benzoyl chloride was then added dropwise thereto followed by stirring at 80° C for 1.5 hours to allow the mixture to react. After completion of the reaction, the reaction mixture was poured into ice-water followed by stirring, and the thus precipitated solid was filtered, washed with water and then dissolved in benzene while hot (80° C). Any insoluble matter was removed by filtration, and the filtrate allowed to cool to precipitate crystals, which were recovered by filtration to obtain 1.5 g of 3-N-benzoyl-5-fluorouracil in a yield of 32% (the filtrate was set aside). Melting Point: 170° C.
Reaction SMILES: FC(F)(F)C(O)=O.[CH:8]1([CH2:14][CH2:15][CH2:16][C@@H:17]([C:22]2[O:26][N:25]=[C:24]([C:27]([N:29]3[CH2:32][CH:31]([N:33]4[CH2:38][CH2:37][O:36][CH2:35][CH2:34]4)[CH2:30]3)=[O:28])[N:23]=2)[CH2:18][C:19]([OH:21])=O)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1.CN1CCOCC1.ClC(OCC(C)C)=O.Cl.[NH2:55][OH:56]>CN(C)C=O>[CH:8]1([CH2:14][CH2:15][CH2:16][C@@H:17]([C:22]2[O:26][N:25]=[C:24]([C:27]([N:29]3[CH2:32][CH:31]([N:33]4[CH2:34][CH2:35][O:36][CH2:37][CH2:38]4)[CH2:30]3)=[O:28])[N:23]=2)[CH2:18][C:19]([NH:55][OH:56])=[O:21])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]1
Reactant: NO
Reactant: O=C(O)C[C@@H](CCCC1CCCCC1)c1nc(C(=O)N2CC(N3CCOCC3)C2)no1
Agent: CC(C)COC(=O)Cl
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: O=C(C[C@@H](CCCC1CCCCC1)c1nc(C(=O)N2CC(N3CCOCC3)C2)no1)NO
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 12.4 %

Procedure:
A solution of (3R)-6-cyclohexyl-3-(3-{[3-(4-morpholinyl)-1-azetidinyl]carbonyl}-1,2,4-oxadiazol-5-yl)hexanoic acid trifluoroacetate (Preparation 28) (1173 mg, 2.70 mmol) and N-methylmorpholine (327 μl, 2.97 mmol) in N,N-dimethylformamide (25 ml) was cooled to 0° C., treated dropwise with isobutyl chloroformate (386 μl, 2.97 mmol) and stirred under a nitrogen atmosphere at 0° C. for 45 minutes. Hydroxylamine hydrochloride (564 mg, 8.11 mmol) was then added followed by further N-methylmorpholine (891 μl, 8.11 mmol) and the mixture was stirred for 18 hours being allowed to warm to room temperature over this time. The solvent was removed under reduced pressure and the residue dissolved in a saturated aqueous solution of sodium carbonate. The pH of the solution was adjusted to 9 by dropwise addition of acetic acid. Water was added (75 ml) and the product was then extracted with ethyl acetate (×2). The combined organic phases were washed with brine, dried over anhydrous sodium sulphate, filtered and the solvent removed under reduced pressure. The residue was purified by column chromatography on silica gel eluting with a gradient system of dichloromethane:methanol:0.88 ammonia (90:10:1) then dichloromethane:methanol:0.88 ammonia (80:20:2). The product was further purified by HPLC to afford the title compound as a white solid (151 mg)
Reaction SMILES: [CH:1]([C:4]1[C:5]([O:13][CH2:14][CH2:15][CH3:16])=[C:6]([CH:10]=[CH:11][CH:12]=1)[CH2:7]CN)([CH3:3])[CH3:2].[C:17](Cl)(=[O:20])[CH:18]=[CH2:19].[CH2:22]([N:24](CC)CC)C>C(Cl)Cl>[CH:1]([C:4]1[C:5]([O:13][CH2:14][CH2:15][CH3:16])=[C:6]([CH:10]=[CH:11][CH:12]=1)[CH2:7][N:24]([CH3:22])[C:17](=[O:20])[CH:18]=[CH2:19])([CH3:2])[CH3:3]
Reactant: CCN(CC)CC
Reactant: CCCOc1c(CCN)cccc1C(C)C
Reactant: C=CC(=O)Cl
Solvent: ClCCl
Product: C=CC(=O)N(C)Cc1cccc(C(C)C)c1OCCC
Reaction time: 0.08 h
Yield: 88.6 %

Procedure:
To a solution of (3-isopropyl-2-propoxybenzyl)methylamine (1.00 g, 4.51 mmol) in CH2Cl2 (40 mL) was added acryloyl chloride (0.43 mL, 4.96 mmol) drop-wise. After stirring for five minutes, triethylamine (0.69 mL, 4.96 mmol) was added and the solution was stirred for 5 hours. The solution was diluted with CH2Cl2 (50 mL), washed with H2O (3×50 mL) and brine (2×100 mL), dried (Na2SO4) and concentrated to yield the title compound (1.10 g, 88%) as a light yellow oil and a mixture of amide rotamers: 1H NMR (300 MHz, DMSO-d6) δ 7.23-7.19 (m, 1H), 7.10-7.06 (m, 1H), 6.86-6.80 (m, 2H), 6.20-6.13 (m, 1H), 5.61-5.79 (m, 1H), 4.68-4.61 (m, 2H), 3.71-3.67 (m, 2H), 3.34-3.26 (m, 1H), 3.01-2.88 (m, 3H), 1.78-1.76 (m, 2H), 1.19-1.17 (m, 6H), 1.06-1.00 (m, 3H).
Reaction SMILES: [NH2:1][C@H:2]([C:8]([NH:10][C@H:11]([C:17]([OH:19])=[O:18])[CH2:12][CH2:13][C:14]([OH:16])=[O:15])=[O:9])[CH2:3][CH2:4][C:5](=[O:7])[OH:6].[C:20](Cl)(=[O:38])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37]>>[C:20]([NH:1][C@H:2]([C:8]([NH:10][C@H:11]([C:17]([OH:19])=[O:18])[CH2:12][CH2:13][C:14]([OH:16])=[O:15])=[O:9])[CH2:3][CH2:4][C:5](=[O:6])[OH:7])(=[O:38])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37]
Reactant: N[C@@H](CCC(=O)O)C(=O)N[C@@H](CCC(=O)O)C(=O)O
Reactant: CCCCCCCCCCCCCCCCCC(=O)Cl
Product: CCCCCCCCCCCCCCCCCC(=O)N[C@@H](CCC(=O)O)C(=O)N[C@@H](CCC(=O)O)C(=O)O
Yield: 89.3 %

Procedure:
Production Example 1 was repeated using 20.0 g (0.072 mols) of α-glutamylglutamic acid and 21.9 g (0.072 mols)of stearoyl chloride to give 34.9 g of N-(N'-stearoyl-α-glutamyl)glutamic acid in a yield of 89%. This solid was analyzed by infrared spectrophotometry. A peak diagnostic of an amide group was observed at 1,650 cm-1 and a peak diagnostic of a carboxyl group was observed at 1,730 cm-1, respectively.
Reaction SMILES: N1[C:2](=[O:10])N=C2C=CC=CC=12.[C:11]([NH:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]#[N:22])=[CH:17][C:16]=1[NH2:23])(=[O:13])[CH3:12]>C(#N)C>[C:21]([C:18]1[CH:19]=[CH:20][C:15]2[N:14]([C:11](=[O:13])[CH3:12])[C:2](=[O:10])[NH:23][C:16]=2[CH:17]=1)#[N:22]
Reactant: O=C1N=c2ccccc2=N1
Reactant: CC(=O)Nc1ccc(C#N)cc1N
Solvent: CC#N
Product: CC(=O)n1c(=O)[nH]c2cc(C#N)ccc21
Temperature: 77 °C

Procedure:
6—Cyano-3N-acetylbenzimidazolone (1.47 mmol, 0.29 g) which was synthesized similarly to its benzimidazolone analog except that 1N-acetyl-2-amino-4-cyanoaniline was used as starting material and 3-(4-biphenyl)-1,2-propen-3-one (1.37 mmol, 0.29 g) were combined in 15 mL of acetonitrile to form a suspension. The reaction mixture was warmed to 77° C. and heated for 24 h. The reaction mixture was concentrated and the resulting residue was purified by standard chromatographic technique to give crude 1-(4-biphenylcarbonyl)ethyl-6-cyano- 3N-acetylbenzimidazolinone. The crude material was subjected to Pinner conditions followed by reaction with ammonium carbonate to give the title compound 1-(4- biphenylcarbonyl)ethyl-6-amidinobenzimidazolinone. LRMS: m/z 385 (M+H,100). HRMS: calcd for C23H21N4O2, 385.166451; found, 385.167149.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:20])[C:10]2[CH:15]=[C:14]([N+:16]([O-])=O)[CH:13]=[CH:12][C:11]=2[CH3:19])=[CH:4][CH:3]=1.CC1C(O)=C(C=O)C(COP(O)(O)=O)=CN=1.O>[Ni].C(Cl)Cl.CCO>[NH2:16][C:14]1[CH:13]=[CH:12][C:11]([CH3:19])=[C:10]([CH:15]=1)[C:9]([NH:8][C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=1)=[O:20]
Reactant: Cc1ccc([N+](=O)[O-])cc1C(=O)Nc1ccc(Br)cc1
Agent: [Ni]
Agent: Cc1ncc(COP(=O)(O)O)c(C=O)c1O
Solvent: ClCCl
Solvent: CCO
Solvent: O
Product: Cc1ccc(N)cc1C(=O)Nc1ccc(Br)cc1

Procedure:
Prepared analogously to example 2e with N-(4-bromo-phenyl)-2-methyl-5-nitro-benzamide (0.18 g; 0.54 mmol) and Ra-Ni (20 mg), 3 bar H2. Yield: 0.14 g (85%) MS: [m+H]+=305; HPLC Rt=1.2 min (Method MC-1); TLC (silica gel; DCM/EtOH 95/5) Rf=0.3
Reaction SMILES: [C:1]([CH2:5][O:6][CH:7]([N:9]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[N:11]=[C:10]1[C:18]([CH:20]1[CH2:25][CH2:24][N:23](C(OC(C)(C)C)=O)[CH2:22][CH2:21]1)=[O:19])[CH3:8])([O:3][CH3:4])=[O:2].FC(F)(F)C(O)=O.C(=O)([O-])O.[Na+]>>[C:1]([CH2:5][O:6][CH:7]([N:9]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[N:11]=[C:10]1[C:18]([CH:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1)=[O:19])[CH3:8])([O:3][CH3:4])=[O:2]
Reactant: COC(=O)COC(C)n1c(C(=O)C2CCN(C(=O)OC(C)(C)C)CC2)nc2ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)COC(C)n1c(C(=O)C2CCNCC2)nc2ccccc21
Temperature: 25 °C

Procedure:
Mix 1-[(1-carbomethoxy methoxy ethyl)-1H-benzimidazol-2-yl][1-(t-butyloxycarbonyl)-4-piperidinyl]methanone (11.9 g, 26.67 mmol) and trifluoroacetic acid (75 mL). Stir at room temperature until the reaction is complete. Pour onto water and carefully neutralize with solid sodium hydrogen carbonate. Extract into ethyl acetate (2×), wash with brine and dry (MgSO4). Evaporate the solvent in vacuo and purify by chromatography to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:21]2[CH:22]=[N:23][N:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=23)=[N:4][C:5]([NH:8][C:9]2[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[C:12](F)=[CH:11][C:10]=2[O:19][CH3:20])=[N:6][CH:7]=1.[CH3:30][NH:31][CH2:32][CH2:33][N:34]1[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1.CCN(C(C)C)C(C)C>CC(N(C)C)=O.CO>[Cl:1][C:2]1[C:3]([C:21]2[CH:22]=[N:23][N:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=23)=[N:4][C:5]([NH:8][C:9]2[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[C:12]([N:31]([CH3:30])[CH2:32][CH2:33][N:34]3[CH2:39][CH2:38][O:37][CH2:36][CH2:35]3)=[CH:11][C:10]=2[O:19][CH3:20])=[N:6][CH:7]=1
Reactant: COc1cc(F)c([N+](=O)[O-])cc1Nc1ncc(Cl)c(-c2cnn3ccccc23)n1
Reactant: CNCCN1CCOCC1
Solvent: CO
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(N(C)CCN2CCOCC2)c([N+](=O)[O-])cc1Nc1ncc(Cl)c(-c2cnn3ccccc23)n1
Temperature: 140 °C
Yield: 106.1 %

Procedure:
5-Chloro-N-(4-fluoro-2-methoxy-5-nitrophenyl)-4-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-2-amine (Intermediate 20, 311 mg, 0.75 mmol), N-methyl-2-morpholinoethanamine (130 mg, 0.90 mmol) and DIPEA (0.157 mL, 0.90 mmol) were dissolved in DMA (3 mL) and sealed into a microwave tube. The mixture was heated to 140° C. for 0.75 h in the microwave then cooled to r.t. The mixture was then diluted with CH3OH and purified by ion exchange chromatography, using an SCX column and eluting with 1:1 7N methanolic ammonia in CH2Cl2. Appropriate fractions were combined and concentrated in vacuo to give the title compound (429 mg, 106%) as an orange solid which was used without further purification; 1H NMR: 2.36 (4H, s), 2.54 (2H, m), 2.89 (3H, s), 3.34 (2H, m), 3.49 (4H, m), 3.91 (3H, s), 6.81 (1H, s), 7.15 (1H, m), 7.35 (1H, t), 8.16 (1H, s), 8.45 (2H, m), 8.76 (1H, s), 8.86 (1H, d), 8.96 (1H, s); m/z: ES+ MH+ 539.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:20]([NH:22][C@H:23]([C:30]([NH:32]N)=[O:31])[CH2:24][C:25]1[N:29]=[CH:28][NH:27][CH:26]=1)=[O:21])[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.N(OCCC(C)C)=O.CN1CCOCC1.N[C@H:51]([CH2:56][OH:57])[CH2:52][CH:53]([CH3:55])[CH3:54]>O1CCOCC1.CN(C)C=O>[CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:20]([NH:22][C@H:23]([C:30]([NH:32][C@H:51]([CH2:56][OH:57])[CH2:52][CH:53]([CH3:55])[CH3:54])=[O:31])[CH2:24][C:25]1[N:29]=[CH:28][NH:27][CH:26]=1)=[O:21])[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)C[C@H](N)CO
Reactant: NNC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1
Agent: CC(C)CCON=O
Agent: Cl
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Solvent: C1COCCO1
Product: CC(C)C[C@@H](CO)NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1
Temperature: -60 °C

Procedure:
To a solution of 0.91 g. (2 mmole) of N-benzyloxycarbonyl-L-phenylalanyl-L-histidine hydrazide in 32 ml. of dimethylformamide was added 1.64 ml. of a 4.1N solution of hydrogen chloride in dioxane. The mixture was cooled to -60° C., and there was added 0.4 ml. of isopentyl nitrite. The temperature of the resulting mixture was then raised to -20° C. After confirming the disappearance of the hydrazide, the temperature of the mixture was lowered to -60° C., and then the mixture was neutralized by the addition of 0.8 g. of N-methylmorpholine. To the mixture was added 0.28 g. (2.4 mmole) of L-leucinol and the mixture was stirred at 4° C. for 23 hours; the solvent was then removed by distillation under reduced pressure, and water was added to the residue to form a colourless precipitate, which was separated by filtration and washed thoroughly with water and then with ethyl acetate. There was obtained 0.94 g. of the desired compound as a white powdery solid, melting at 181°-183° C.; [α]22 -19.4° (C=0.5, methanol).
Reaction SMILES: [O:1]=[C:2]1[NH:6][C:5](=[O:7])/[C:4](=[CH:8]\[C:9]2[CH:28]=[CH:27][C:12]([O:13][CH2:14][CH2:15][O:16][C:17]3[CH:26]=[CH:25][C:20]([C:21]([O:23]C)=[O:22])=[CH:19][CH:18]=3)=[CH:11][CH:10]=2)/[S:3]1.CO.O.[OH-].[Li+].Cl>C1COCC1.O>[O:1]=[C:2]1[NH:6][C:5](=[O:7])/[C:4](=[CH:8]\[C:9]2[CH:10]=[CH:11][C:12]([O:13][CH2:14][CH2:15][O:16][C:17]3[CH:26]=[CH:25][C:20]([C:21]([OH:23])=[O:22])=[CH:19][CH:18]=3)=[CH:27][CH:28]=2)/[S:3]1
Reactant: COC(=O)c1ccc(OCCOc2ccc(/C=C3/SC(=O)NC3=O)cc2)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: O=C1NC(=O)/C(=C\c2ccc(OCCOc3ccc(C(=O)O)cc3)cc2)S1
Temperature: 60 °C
Yield: 22.6 %

Procedure:
To a solution of methyl ester 356 (647 mg, 1.62 mmol) in THF (15 mL) was added methanol (2 mL), water (2 mL) and lithium hydroxide monohydrate (340 mg, 8.11 mmol). The mixture was heated at 60° C. for 1 hour, acidified with 10% HCl solution and extracted with ethyl acetate. The organic extract was dried over MgSO4, filtered, and evaporated to afford the title compound (141 mg, 22%). 1H NMR: (MeOD-d4) δ (ppm): 7.97 (d, J=8.8 Hz, 2H), 7.75 (s, 1H), 7.53 (d, J=8.8 Hz, 2H), 7.12 (d, J=8.8 Hz, 2H), 7.04 (d, J=8.8 Hz, 2H), 4.44 (4H, bs). LRMS (ESI): (calc.) 385.4; (found) 392.3 (MLi)+.