Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[S:3].Cl[CH2:6][C:7]1[CH2:11][CH2:10][CH2:9][C:8]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[F:18]>C(O)C>[F:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[C:8]12[CH2:9][CH2:10][CH2:11][CH:7]1[CH2:6][S:3][C:2]([NH2:4])=[N:1]2
Reactant: Fc1ccccc1C1=C(CCl)CCC1
Reactant: NC(N)=S
Solvent: CCO
Product: NC1=NC2(c3ccccc3F)CCCC2CS1
Temperature: 25 °C

Procedure:
Thiourea (2.60 g) was added to a solution of 1-(2-chloromethylcyclopent-1-enyl)-2-fluorobenzene obtained in Preparation Example 3-(4) (7.20 g) in ethanol (100 mL), and the mixture was stirred with heating under reflux for five hours. The reaction solution was cooled to room temperature and the solvent was evaporated under reduced pressure. The residual syrup was washed with heptane, followed by drying under reduced pressure. Trifluoroacetic acid (50.0 mL) and trifluoromethanesulfonic acid (10.0 mL) were added to the residue in an ice bath. Then, the reaction mixture was warmed to room temperature and stirred for four days. The reaction solution was poured into ice, diluted with ether and then neutralized with sodium bicarbonate, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. The drying agent was removed by filtration and the filtrate was concentrated under reduced pressure to obtain a residue. The residue was purified by NH-silica gel column chromatography to obtain the title compound (4.98 g).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[C:6]([NH:10][C@H:11]([C:13]2[N:18]=[C:17]3[CH:19]=[CH:20][N:21]([CH3:22])[C:16]3=[CH:15][C:14]=2[C:23]2[N:27]([CH3:28])[N:26]=[CH:25][CH:24]=2)[CH3:12])[N:5]=[C:4]([S:29][CH3:30])[N:3]=1.[OH-].[NH4+:32]>>[NH2:32][C:2]1[C:7]([C:8]#[N:9])=[C:6]([NH:10][C@H:11]([C:13]2[N:18]=[C:17]3[CH:19]=[CH:20][N:21]([CH3:22])[C:16]3=[CH:15][C:14]=2[C:23]2[N:27]([CH3:28])[N:26]=[CH:25][CH:24]=2)[CH3:12])[N:5]=[C:4]([S:29][CH3:30])[N:3]=1
Reactant: [NH4+]
Reactant: CSc1nc(Cl)c(C#N)c(N[C@@H](C)c2nc3ccn(C)c3cc2-c2ccnn2C)n1
Agent: [OH-]
Product: CSc1nc(N)c(C#N)c(N[C@@H](C)c2nc3ccn(C)c3cc2-c2ccnn2C)n1
Temperature: 85 °C

Procedure:
A mixture of (S)-4-chloro-6-((1-(1-methyl-6-(1-methyl-1H-pyrazol-5-yl)-1H-pyrrolo[3,2-b]pyridin-5-yl)ethyl)amino)-2-(methylthio)pyrimidine-5-carbonitrile (1.857 g, 4.23 mmol) and ammonium hydroxide (0.494 mL, 12.69 mmol) was heated at 85° C. in a microwave reactor for 12 hours. Additional ammonium hydroxide (0.494 mL, 12.69 mmol) was added. The reaction mixture was heated at 85° C. in a microwave reactor for 6 hours and then concentrated to give the title compound, which was used without further purification. ESI-MS m/z [M+H]+ calc'd for C20H21N9S, 420.16; found 420.4.
Reaction SMILES: I[C:2]1[C:3]([O:10][CH3:11])=[N:4][C:5]([O:8][CH3:9])=[N:6][CH:7]=1.[F:12][C:13]1[CH:14]=[N:15][CH:16]=[CH:17][C:18]=1B(O)O.C([O-])([O-])=O.[Na+].[Na+].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C(O)CC.CC([O-])=O.CC([O-])=O.[Pd+2]>[F:12][C:13]1[CH:14]=[N:15][CH:16]=[CH:17][C:18]=1[C:2]1[C:3]([O:10][CH3:11])=[N:4][C:5]([O:8][CH3:9])=[N:6][CH:7]=1
Reactant: OB(O)c1ccncc1F
Reactant: COc1ncc(I)c(OC)n1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CCCO
Product: COc1ncc(-c2ccncc2F)c(OC)n1
Yield: 93 %

Procedure:
5-Iodo-2,4-dimethoxy-pyrimidine (commercially available from Matrix, 905 mg, 3.4 mmol) was dissolved in degassed n-PrOH (24 ml) and then 3-fluoropyridine-4-boronic acid (715 mg, 5.1 mmol), Na2CO3 (721 mg, 6.8 mmol), PPh3 (84 mg, 0.34 mmol) and Pd(OAc)2 (40 mg) were added. The suspension was stirred at reflux for 1.5 hours. The solvent was evaporated under vacuum and the crude was partitioned between water and ethyl acetate. The organic phase was dried (Na2SO4) and evaporated. The crude was purified by flash chromatography with DCM-MeOH 98-2 and by SCX cartridge washing with MeOH and then collecting the product with MeOH—NH4OH (95-5) to give 750 mg of the title compound (93% yield).
Reaction SMILES: C(O[C:4]([N:6]1[CH2:20][CH2:19][CH:18]2[N:9]([CH:10]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:16]=3[CH2:17]2)[CH2:8][CH2:7]1)=O)C.[H-].COCCO[Al+2].[Na+].[Na+].[H-].[H-].[H-].[OH-].[Na+]>C1(C)C=CC=CC=1.C1C=CC=CC=1>[CH3:4][N:6]1[CH2:20][CH2:19][CH:18]2[N:9]([CH:10]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:16]=3[CH2:17]2)[CH2:8][CH2:7]1
Reactant: CCOC(=O)N1CCC2Cc3ccccc3C(c3ccccc3)N2CC1
Agent: COCCO[Al+2]
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: c1ccccc1
Product: CN1CCC2Cc3ccccc3C(c3ccccc3)N2CC1

Procedure:
A solution of 6.8 g of (7RS,12aRS)-1,2,3,4,5,7,12,12a-octahydro-7-phenyl-1,4-diazepino[1,7-b]isoquinoline-3-carboxylic acid ethyl ester in toluene was added dropwise slowly into a stirred and boiling mixture of 200 ml of toluene and 21.6 ml of 70% disodium (2-methoxyethoxy)aluminium hydride in benzene. The reaction mixture was refluxed for a further 30 minutes, and cooled to 0°. The complex and remaining reducing agent was decomposed by the slow dropwise addition of 60 ml of a 20% sodium hydroxide solution. The organic phase was separated off, washed with 100 ml of a 20% sodium hydroxide solution, then washed three times with water, then dried with magnesium sulphate, and finally concentrated to dryness to give the title compound (M.P. of maleate from methanol/ether 184°-186°).
Reaction SMILES: [CH3:1][O:2][C:3]([C@H:5]1[CH2:10][CH2:9][C@H:8]([CH2:11][NH:12][C:13](=[O:23])[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[N+:20]([O-])=O)[CH2:7][CH2:6]1)=[O:4].CC(O)=O.[H][H]>CO.[Pd]>[CH3:1][O:2][C:3]([C@H:5]1[CH2:6][CH2:7][C@H:8]([CH2:11][NH:12][C:13](=[O:23])[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[NH2:20])[CH2:9][CH2:10]1)=[O:4]
Reactant: COC(=O)[C@H]1CC[C@H](CNC(=O)c2ccccc2[N+](=O)[O-])CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: CC(=O)O
Product: COC(=O)[C@H]1CC[C@H](CNC(=O)c2ccccc2N)CC1

Procedure:
A solution 0.01 M of trans-4-[(2-Nitro-benzoylamino)-methyl]-cyclohexanecarboxylic acid methyl ester (1.8 g) in MeOH (550 mL) with ˜1% of glacial AcOH (5.5 mL) was submitted to continuous flow rate hydrogenation by H-Cube (ThalesNano®) using a 10% Pd/C cartridge (small cartridge, full hydrogen mode, flowrate of 1 mL/min). Finally, the solvent was removed under reduced pressure to obtain the titled compound as acetate salt (1.9 g, quantitative yield).
Reaction SMILES: [OH-].[Na+].[OH:3][C:4]1([CH3:33])[CH2:9][CH2:8][N:7]([C:10]2[N:15]=[C:14]([C:16]([NH:18][C:19]3[C:29]([CH3:30])=[CH:28][C:22]([C:23]([O:25]CC)=[O:24])=[CH:21][C:20]=3[CH3:31])=[O:17])[C:13]([CH3:32])=[CH:12][CH:11]=2)[CH2:6][CH2:5]1.CO>C1COCC1>[OH:3][C:4]1([CH3:33])[CH2:5][CH2:6][N:7]([C:10]2[N:15]=[C:14]([C:16]([NH:18][C:19]3[C:20]([CH3:31])=[CH:21][C:22]([C:23]([OH:25])=[O:24])=[CH:28][C:29]=3[CH3:30])=[O:17])[C:13]([CH3:32])=[CH:12][CH:11]=2)[CH2:8][CH2:9]1
Reactant: CCOC(=O)c1cc(C)c(NC(=O)c2nc(N3CCC(C)(O)CC3)ccc2C)c(C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1ccc(N2CCC(C)(O)CC2)nc1C(=O)Nc1c(C)cc(C(=O)O)cc1C
Reaction time: 1 h
Yield: 0 %

Procedure:
A solution of aqueous 2N NaOH (5.00 ml) is added to a stirred solution of ethyl 4-[[6-(4-hydroxy-4-methyl-1-piperidyl)-3-methyl-pyridine-2-carbonyl]amino]-3,5-dimethyl-benzoate (0.27 g, 634.51 mmol) in THF:MeOH (10 ml:5 ml). After 1 hour at 50° C., the organic solvent is removed under reduced pressure and the residue is diluted with water, acidified to pH 6 with 5N HCl, and extracted with ethyl acetate. The organic layers are combined with aqueous layer and concentrated under reduced pressure. The solids are triturated with acetone/acetonitrile and filtered. The filtrate is dried over sodium sulfate, filtered, and concentrated under reduced pressure to afford the title compound as an off-white solid (0.11 g, 43.6%). Mass spectrum (m/z): 398.2 (M+1).
Reaction SMILES: [C:1]([OH:13])(=[O:12])[CH2:2][CH2:3][C:4]1[CH:11]=[CH:10][C:8]([OH:9])=[C:6]([OH:7])[CH:5]=1.[C:14](Cl)(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>N1C=CC=CC=1>[C:14]([O:7][C:6]1[CH:5]=[C:4]([CH2:3][CH2:2][C:1]([OH:13])=[O:12])[CH:11]=[CH:10][C:8]=1[O:9][C:14](=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C(O)CCc1ccc(O)c(O)c1
Reactant: O=C(Cl)c1ccccc1
Solvent: c1ccncc1
Product: O=C(O)CCc1ccc(OC(=O)c2ccccc2)c(OC(=O)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 105.8 %

Procedure:
3 g of dihydrocaffeic acid was dissolved in 20 ml of pyridine, and 5 g of benzoyl chloride was then gradually added thereto under cooling. After stirring at room temperature for 2 hours, the solvent was distilled off, and the resultant residue was then poured into 50 ml of ice water. This solution was neutralized with 6N hydrochloric acid and then extracted with 50 ml of chloroform twice. After washed with a saturated saline solution, the extracted material was dried over Glauber's salt, and the solvent was then distilled off under reduced pressure, thereby obtaining 6.8 g of 3-(3,4-dibenzoyloxyphenyl)propionic acid.
Reaction SMILES: [C:1]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:11]=2)[C:6]([OH:20])=[C:5]([C:21]([NH:23][CH2:24][CH2:25][C@H:26]([OH:30])[C:27]([OH:29])=[O:28])=[O:22])[N:4]=1)#[N:2].[CH3:31]O>OS(O)(=O)=O>[C:1]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:13][C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:11]=2)[C:6]([OH:20])=[C:5]([C:21]([NH:23][CH2:24][CH2:25][C@H:26]([OH:30])[C:27]([O:29][CH3:31])=[O:28])=[O:22])[N:4]=1)#[N:2]
Reactant: CO
Reactant: N#Cc1nc(C(=O)NCC[C@H](O)C(=O)O)c(O)c2ccc(Oc3ccccc3)cc12
Agent: O=S(=O)(O)O
Product: COC(=O)[C@@H](O)CCNC(=O)c1nc(C#N)c2cc(Oc3ccccc3)ccc2c1O

Procedure:
To a solution of (S)-4-(1-cyano-4-hydroxy-7-phenoxyisoquinoline-3-carboxamido)-2-hydroxybutanoic acid (73 mg, 0.18 mmol) in anhydrous MeOH (25 mL) was added concentrated H2SO4 (3 drops). The resulting mixture was heated to reflux for 20 hours. The volatiles were removed in vacuo and the residue was purified by flash chromatography (0-30% EtOAc/CH2Cl2) to give the title compound in 54 mg. MS: (−) m/z 420.26 (M−1).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[CH:12][C:13]3[N:19]([CH:20]=[O:21])[CH2:18][CH2:17][C:16]([C:22]([O:24]C)=[O:23])=[CH:15][C:14]=3[CH:26]=2)=[CH:6][CH:5]=1)[CH3:2].[OH-].[Na+]>CO.C1COCC1>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[CH:12][C:13]3[N:19]([CH:20]=[O:21])[CH2:18][CH2:17][C:16]([C:22]([OH:24])=[O:23])=[CH:15][C:14]=3[CH:26]=2)=[CH:6][CH:5]=1)[CH3:2]
Reactant: CCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCN3C=O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCOc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCN3C=O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.8 %

Procedure:
In methanol (25 ml) and THF (30 ml) was dissolved methyl 7-(4-ethoxyphenyl)-1-formyl-2,3-dihydro-1H-1-benzazepine-4-carboxylate (0.24 g). To the solution was added 1N sodium hydroxide solution (5 ml) and the mixture was stirred at room temperature overnight and concentrated. To the residue was added water, and the mixture was neutralized with 1N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried with anhydrous magnesium sulfate, and the solvent was evaporated to give 7-(4-ethoxyphenyl)-1-formyl-2,3-dihydro-1H-1-benzazepine-4-carboxylic acid (0.23 g) as pale yellow crystals.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[C:54]1[CH:59]=[C:58]([CH3:60])[CH:57]=[CH:56][C:55]=1[O:61][CH3:62].[NH:63]1[CH2:68][CH2:67][NH:66][CH2:65][CH2:64]1>C1(C)C=CC=CC=1>[CH3:62][O:61][C:55]1[CH:56]=[CH:57][C:58]([CH3:60])=[CH:59][C:54]=1[N:63]1[CH2:68][CH2:67][NH:66][CH2:65][CH2:64]1
Reactant: COc1ccc(C)cc1Br
Reactant: C1CNCCN1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: Cc1ccccc1
Product: COc1ccc(C)cc1N1CCNCC1
Yield: 67.1 %

Procedure:
15 mg (0.016 mmol, 0.027 eq) Tris(dibenzylidene-acetone)dipalladium (0) (Pd2dba3), 27 mg (0.043 mmol, 0.072 eq) racemic-2,2′-Bis(diphenylphosphino)-1,1′-binaphthyl [(±)-BINAP] and 450 mg (1.38 mmol, 2.3 eq) cesium carbonate were combined in a microwave vial. 1.5 mL anhydrous toluene was added, followed by 121 mg (0.60 mmol, 1.0 eq) 2-bromo-4-methylanisole and 207 mg (2.40 mmol, 4.0 eq) piperazine. The vial was flushed with nitrogen prior to being microwaved at 140° C. for 30 minutes. The reaction mixture was diluted with 3.0 mL DMSO:methanol (1:1), filtered and purified by reverse-phase HPLC (2-99% CH3CN in 0.085% TFA (aq), 50 mL/min, 3×1.5 mL injected). Yield=83 mg (43%) of 1-(2-Methoxy-5-methyl-phenyl)-piperazine as a pale yellow oil (isolated as the mono-TFA salt);
Reaction SMILES: [O:1]1[CH:5]=[N:4][N:3]=[C:2]1[C@H:6]([NH:9][CH:10]1[CH2:14][CH2:13][CH2:12][CH2:11]1)[CH2:7][CH3:8].C([O-])(O)=O.[Na+].[Cl:20][C:21]1[N:26]=[C:25](Cl)[C:24]([N+:28]([O-:30])=[O:29])=[CH:23][N:22]=1>C1COCC1.CCOC(C)=O.[Cl-].[Na+].O>[Cl:20][C:21]1[N:26]=[C:25]([N:9]([CH:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)[C@@H:6]([C:2]2[O:1][CH:5]=[N:4][N:3]=2)[CH2:7][CH3:8])[C:24]([N+:28]([O-:30])=[O:29])=[CH:23][N:22]=1
Reactant: O=[N+]([O-])c1cnc(Cl)nc1Cl
Reactant: CC[C@@H](NC1CCCC1)c1nnco1
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC[C@H](c1nnco1)N(c1nc(Cl)ncc1[N+](=O)[O-])C1CCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 29.8 %

Procedure:
17 N-[(1R)-1-(1,3,4-oxadiazol-2-yl)propyl]cyclopentanamine (199 mg, 1.019 mmol) in anhydrous THF (3.980 mL) was treated with NaHCO3 (342.4 mg, 4.076 mmol) then 2,4-dichloro-5-nitro-pyrimidine (197.7 mg, 1.019 mmol). The reaction was stirred overnight at ambient temperature. The reaction was further stirred at 45° C. for 10 hours, diluted with EtOAc/Brine and extracted EtOAc (×3). The combined organic extracts were dried over MgSO4 and concentrated under reduced pressure. The residue was purified by column chromatography (30% EtOAc/petrol) to give the sub-tilte compound as a pale yellow oil (107 mg, 30%); 1H NMR (400.0 MHz, CDCl3) d 1.03 (3H, t), 1.45-2.80 (10H, m), 3.55 (1H, m), 4.39 (1H, m), 8.31 (1H, s), 8.60 (1H, s); MS ES (+) 353.1.
Reaction SMILES: [F:1][C:2]([F:36])([F:35])[C:3]1[CH:4]=[C:5]([C:13]([CH3:34])([CH3:33])[C:14]([N:16]([C:18]2[CH:19]=[N:20][C:21](Cl)=[CH:22][C:23]=2[C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=2[CH3:31])[CH3:17])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[CH3:37][C:38]([O:41][C:42]([NH:44][C@H:45]([CH2:50][C:51]#[CH:52])[C:46]([O:48][CH3:49])=[O:47])=[O:43])([CH3:40])[CH3:39].C(NC(C)C)(C)C>C(N(CC)CC)C.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[F:1][C:2]([F:36])([F:35])[C:3]1[CH:4]=[C:5]([C:13]([CH3:34])([CH3:33])[C:14]([N:16]([CH3:17])[C:18]2[C:23]([C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=3[CH3:31])=[CH:22][C:21]([C:52]#[C:51][CH2:50][C@@H:45]([NH:44][C:42]([O:41][C:38]([CH3:40])([CH3:39])[CH3:37])=[O:43])[C:46]([O:48][CH3:49])=[O:47])=[N:20][CH:19]=2)=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: Cc1cc(F)ccc1-c1cc(Cl)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: C#CC[C@@H](NC(=O)OC(C)(C)C)C(=O)OC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC(C)NC(C)C
Solvent: O
Solvent: CCN(CC)CC
Product: COC(=O)[C@@H](CC#Cc1cc(-c2ccc(F)cc2C)c(N(C)C(=O)C(C)(C)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)cn1)NC(=O)OC(C)(C)C
Yield: 168.5 %

Procedure:
A solution of 2-[3,5-bis(trifluoromethyl)phenyl]-N-[6-chloro-4-(4-fluoro-2-methylphenyl)-3-pyridinyl]-N,2-dimethylpropanamide (WO2005/002577, 1.05 g, 1.97 mmol), methyl (2R)-2-({[(1,1-dimethylethyl)oxy]carbonyl}amino)-4-pentynoate (Intermediate 11, 1.343 g, 5.91 mmol), Pd(PPh3)2Cl2 (69 mg, 0.098 mmol), copper(I) iodide (19 mg, 0.100 mmol) and triphenylphoshine (52 mg, 0.198 mmol) in triethylamine (2 ml)/diisopropylamine (8 ml) was heated at 100° C. under microwave irradiation for 30 min. This reaction was carried out three times always using the amounts of reagents reported above. The reaction mixtures were combined and evaporated to dryness. The final reaction crude was taken-up in water (50 ml) and extracted with DCM (3×50 ml). The organic phases were collected, dried over sodium sulphate and concentrated. Purification on Si (SP1, 65M column) with Cyclohexane/EtOAc [from Cyclohexane 100 to Cyclohexane/EtOAc 70/30 in 4CV and then Cyclohexane/EtOAc 70/30] elution afforded the title compound (2.4 g, 3.32 mmol, 56.1% yield) as a yellow-brown solid. UPLC: Rt 1.02 min, m/z 724 [M+H+]. Chiral analysis, chromatographic conditions: [Column Chiralpak AD-H (25×0.46 cm); mobile phase: n-hexane/Ethanol 70/30% v/v; Flow rate 0.8 ml/min; DAD 210-340 nm, CD 250] Rt 13.43 min, 99.2% e.e.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[C:11]3[C:18]([CH3:19])=[CH:17][O:16][C:12]=3[N:13]=[CH:14][N:15]=2)=[CH:5][CH:4]=1.[H-].[Na+].S(OC)(O[CH3:26])(=O)=O.Cl>CO.C(Cl)(Cl)Cl.CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([N:9]([CH3:26])[C:10]2[C:11]3[C:18]([CH3:19])=[CH:17][O:16][C:12]=3[N:13]=[CH:14][N:15]=2)=[CH:7][CH:8]=1
Reactant: COS(=O)(=O)OC
Reactant: COc1ccc(Nc2ncnc3occ(C)c23)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: COc1ccc(N(C)c2ncnc3occ(C)c23)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a 25 mL round bottom flask was weighed 7 (51 mg, 0.2 mmol) and was added DMF (2 mL) to afford a solution. The flask was purged with argon for five min followed by cooling down to 0° C. using ice bath. Sodium hydride (14.4 mg, 0.6 mmol) was added to the solution at 0° C. The solution was stirred for 30 min at 0° C. under argon atmosphere. Dimethyl sulfate (75.7 mg; ≈57 μl; 0.6 mmol) was injected to the reaction mixture and the flask was warmed to room temperature. The mixture was stirred at room temperature for another 3 h at the end of which 1 N Hydrochloric acid (5 mL) was added carefully to quench the reaction followed by water (20 mL) to afford a precipitate. Product was extracted using ethyl acetate (10 mL×2). Combined organic extracts were washed with brine (10 mL) dried (anhydrous sodium sulfate) and concentrated under reduced pressure. Silica gel (200 mg) was added and solvent evaporated to afford a plug. Column chromatography by elution with hexanes:ethyl acetate (5:1) afforded AAG16 (20 mg; 37%) as light brown semisolid; which was triturated withl hexanes to afford light brown solid. TLC Rf0.79 (CHCl3:MeOH, 10:1); mp 84-85.6° C.; 1HNMR (400 MHz) (DMSO-d6): δ 1.036-1.039 (d, 3H, CH3, J=1.2 Hz); 3.423 (s, 3H, NCH3), 3.752 (s, 3H, OCH3), 6.944-6.967 (d, 2H, C6H4, J=9.2 Hz), 7.176-7.199 (d, 2H, C6H4, J=9.2 Hz), 7.505-7.508 (d, 1H, C6-CH, J=1.2 Hz), 8.234 (s, 1H, C2-CH). Anal. Calcd for C15H15N3O2.0.28 C6H14.0.05 HCl: C, 67.84; H, 6.48; N, 14.22; Found: C, 67.89; H, 6.18; N, 14.06.
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[CH:9]=[C:8]([C:10]([NH:12][NH2:13])=[O:11])[CH:7]=[CH:6][C:5]=12.[CH3:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][C:24](O)=O)=[CH:18][C:17]=1[C:27]([F:30])([F:29])[F:28]>>[CH3:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][C:24]2[O:11][C:10]([C:8]3[CH:7]=[CH:6][C:5]4[N:4]([CH:3]=[CH:2][N:1]=4)[CH:9]=3)=[N:12][N:13]=2)=[CH:18][C:17]=1[C:27]([F:28])([F:30])[F:29]
Reactant: NNC(=O)c1ccc2nccn2c1
Reactant: COc1ccc(CCC(=O)O)cc1C(F)(F)F
Product: COc1ccc(CCc2nnc(-c3ccc4nccn4c3)o2)cc1C(F)(F)F
Yield: 38 %

Procedure:
In the same manner as in Example 14 and using imidazo[1,2-a]pyridine-6-carbohydrazide instead of 1H-benzotriazole-5-carbohydrazide and 3-[4-methoxy-3-(trifluoromethyl)phenyl]propionic acid instead of 3-(3-cyanophenyl)propionic acid, the title compound (yield 38%) was obtained as colorless crystals.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][CH2:5][NH:6][C:7]1[S:8][C:9]([C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:13])=[CH:10][N:11]=1.[C:20](Cl)(=[O:25])[CH2:21][CH2:22][CH2:23][CH3:24].CCN(CC)CC>CO.C(Cl)Cl>[C:12]([C:9]1[S:8][C:7]([NH:6][CH2:5][CH2:4][CH2:3][NH:2][C:20](=[O:25])[CH2:21][CH2:22][CH2:23][CH3:24])=[N:11][CH:10]=1)(=[O:13])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: NCCCNc1ncc(C(=O)c2ccccc2)s1
Reactant: CCCCC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CO
Solvent: CCN(CC)CC
Product: CCCCC(=O)NCCCNc1ncc(C(=O)c2ccccc2)s1
Temperature: 25 °C
Reaction time: 16 h
Yield: 43.4 %

Procedure:
A mixture of 11.9 mg (0.04 mmol) [2-(3-Amino-propylamino)-thiazol-5-yl]-phenyl-methanone hydrochloride, 5.8 mg (0.048 mmol) pentanoyl chloride and 39 ul (0.28 mmol) NEt3 in 1 ml methanol and 0.5 ml DCM was stirred at room temperature for 16 h. After evaporation to dryness the residue was taken up in 1.5 ml MeOH/formic acid 1/1 and subjected to preparative HPLC separation on reversed phase eluting with an acetonitrile/water gradient. Evaporation of product fractions yielded 6 mg (43%) of the title compound.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:12]=[C:11]2[C:7]([C:8]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[N:9][NH:10]2)=[CH:6][CH:5]=1.I[CH3:20].O>C1COCC1>[Cl:3][C:4]1[CH:12]=[C:11]2[C:7]([C:8]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[N:9][N:10]2[CH3:20])=[CH:6][CH:5]=1
Reactant: CCOC(=O)Cc1n[nH]c2cc(Cl)ccc12
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)Cc1nn(C)c2cc(Cl)ccc12
Reaction time: 0.5 h
Yield: 100 %

Procedure:
Sodium hydride (24 mg, 0.602 mmol, 60% in oil) was added to ethyl (6-chloro-1H-indazol-3-yl)acetate (Preparation 168, 120 mg, 0.502 mmol) in THF (4 mL) at 0° C. and the mixture was stirred for 30 minutes. Then iodomethane (0.09 mL, 1.508 mmol) was added. The mixture was stirred at room temperature for 30 mins then water (4 mL) was added. The mixture was evaporated in vacuo and the aqueous residue was acidified with aqueous HCl (6 M). This was extracted with ethyl acetate (10 mL) and the organic phase was dried over sodium sulphate and evaporated in vacuo to afford the title compound as a white solid in 100% yield, 150 mg.
Reaction SMILES: C([O:8][N:9]([C:16](=[O:48])[CH2:17][CH2:18][CH2:19][CH2:20][N:21]([O:40]CC1C=CC=CC=1)[C:22](=[O:39])[CH2:23][CH2:24][CH2:25][CH2:26][N:27]([O:31]CC1C=CC=CC=1)[C:28](=[O:30])[CH3:29])[CH2:10][CH2:11][CH2:12][CH2:13][C:14]#[N:15])C1C=CC=CC=1.[ClH:49]>CO.[Pd]>[ClH:49].[OH:8][N:9]([C:16](=[O:48])[CH2:17][CH2:18][CH2:19][CH2:20][N:21]([OH:40])[C:22](=[O:39])[CH2:23][CH2:24][CH2:25][CH2:26][N:27]([OH:31])[C:28](=[O:30])[CH3:29])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][NH2:15]
Reactant: CC(=O)N(CCCCC(=O)N(CCCCC(=O)N(CCCCC#N)OCc1ccccc1)OCc1ccccc1)OCc1ccccc1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CC(=O)N(O)CCCCC(=O)N(O)CCCCC(=O)N(O)CCCCCN
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Compound (9) (1.000 g, 1,522 mmol) was dissolved in CH3OH (210 mL), followed by addition of 0.1N HCl (from concentrated HCl and methanol, 16.75 mL, 1.675 mmol) and 10% Pd-C (0.6 g). The mixture was stirred under H2 (1 atm) at room temperature overnight. The catalyst was filtered and the solvent was removed. The residue was purified by Sephadex LH-20 column chromatography, eluting with 15% MeOH/toluene, to generate 560 mg (86%) of [A] as a colorless solid: NMR (CD3OD) δ 1.30-1.97 (m, 14H), 2.17 (s, 3H), 2.60 (t, 4H, J=6), 3.00 (t, 2H, J=6), 3.70 (t, 6H, J=6). Anal. (C17H35ClN4O6) C, H, N.