Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][CH:4]([C:6]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=O)=[CH:8][CH:7]=1)[CH3:5])C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.[NH2:46][CH2:47][C:48]1[C:49]([OH:56])=[N:50][C:51]([CH3:55])=[CH:52][C:53]=1[CH3:54]>ClCCl.O>[OH:56][C:49]1[C:48]([CH2:47][NH:46][C:10](=[O:12])[C:9]2[CH:8]=[CH:7][C:6]([CH:4]([O:3][CH3:1])[CH3:5])=[CH:14][CH:13]=2)=[C:53]([CH3:54])[CH:52]=[C:51]([CH3:55])[N:50]=1
Reactant: CCOC(C)c1ccc(C(=O)O)cc1
Reactant: Cc1cc(C)c(CN)c(O)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: COC(C)c1ccc(C(=O)NCc2c(C)cc(C)nc2O)cc1
Temperature: 25 °C
Yield: 23.3 %

Procedure:
To the solution of 4-(1-ethoxyethyl)benzoic acid (162 mg, 0.9 mmol) in dichloromethane (80 mL) was added o-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (513 mg, 1.35 mmol) and triethylamine (273 mg, 2.7 mmol). then the 3-(aminomethyl)-4,6-dimethylpyridine-2-ol (137 mg, 0.9 mmol) was added, the solution was stirred at room temperature, water (80 mL) was added and washed 3 times, the organic layer was evaporated and purified by column chromatography (silica gel, dichloromethane/methanol=20:1) to give N-((2-hydroxy-4,6-dimethylpyridin-3-yl)methyl)-4-(1-methoxyethyl)benzamide (66 mg, 23%). LRMS (M+H+) m/z: calcd: 314.16. found 314; 1H-NMR (300 MHz, CD3OD) 1H-NMR (300 MHz, CD3OD) δ 1.379 (d, 3H), 2.241 (s, 3H), 2.368 (s, 3H), 3.207 (s, 3H), 4.368-4.389 (m, 1H), 4.497 (s, 2H), 6.110 (s, 1H), 7.377 (d, J=8.4 Hz, 2H), 7.779 (d, J=8.4 Hz, 2H).
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)[C:12]2C=CC=C[C:11]=2N=N1.[O:28]=[C:29]1[N:37](COCC[Si](C)(C)C)[C:32]2=[N:33][CH:34]=[CH:35][CH:36]=[C:31]2[C:30]21[O:56][C:48]1=NC=[C:51]([C:53]([OH:55])=O)[CH:52]=[C:47]1[CH2:46]2.Cl.[NH2:58][C@H:59]1[CH2:64][C@@H:63]([C:65]2[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=2)[C@@H:62]([CH3:71])[N:61]([CH2:72][C:73]([F:76])([F:75])[F:74])[C:60]1=[O:77].C(N(CC)C(C)C)(C)C>CN(C=O)C>[CH3:71][C@H:62]1[N:61]([CH2:72][C:73]([F:74])([F:75])[F:76])[C:60](=[O:77])[C@@H:59]([NH:58][C:53]([C:51]2[CH:11]=[CH:12][C:48]3[O:56][C:30]4([C:31]5[C:32](=[N:33][CH:34]=[CH:35][CH:36]=5)[NH:37][C:29]4=[O:28])[CH2:46][C:47]=3[CH:52]=2)=[O:55])[CH2:64][C@H:63]1[C:65]1[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=1
Reactant: C[Si](C)(C)CCOCN1C(=O)C2(Cc3cc(C(=O)O)cnc3O2)c2cccnc21
Reactant: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Reactant: C[C@@H]1[C@H](c2ccccc2)C[C@H](N)C(=O)N1CC(F)(F)F
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H]1[C@H](c2ccccc2)C[C@H](NC(=O)c2ccc3c(c2)CC2(O3)C(=O)Nc3ncccc32)C(=O)N1CC(F)(F)F
Temperature: 25 °C
Reaction time: 3 h

Procedure:
(Benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (90 mg, 0.20 mmol) is added to a solution of 2′-oxo-1′,2′-dihydro-3H-spiro[benzofuran-2,3′-pyrrolo[2,3-b]pyridine]-5-carboxylic acid (described in Intermediate 2) (48 mg, 0.17 mmol), (3S,5S,6R)-3-amino-6-methyl-5-phenyl-1-(2,2,2-trifluoroethyl)piperidin-2-one hydrochloride (described in Intermediate 1, 54 mg, 0.17 mmol), and N,N-diisopropylethylamine (0.15 mL, 0.84 mmol) in DMF (3 mL), and the resulting mixture is stirred at ambient temperature for 3 h. The reaction mixture is then partitioned between saturated aqueous sodium bicarbonate solution (20 mL) and ethyl actetate (3×20 mL). The combined organic layers are washed with brine, dried over sodium sulfate, and concentrated in vacuo. The residue is purified by flash column chromatography on silica gel, eluting with a gradient of CH2Cl2:MeOH—100:0 to 90:10, to afford the title compound as a mixture of diastereomers.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([CH3:8])[C:5]([CH3:9])=[C:4]([CH3:10])[N:3]=1.[CH2:11]([N:13]([CH2:29][CH3:30])[S:14]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[S:23]([N:26]=[C:27]=[O:28])(=[O:25])=[O:24])(=[O:16])=[O:15])[CH3:12].C1N2CCN(CC2)C1>C(#N)C>[CH2:29]([N:13]([CH2:11][CH3:12])[S:14]([C:17]1[C:18]([S:23]([NH:26][C:27]([NH:1][C:2]2[N:7]=[C:6]([CH3:8])[C:5]([CH3:9])=[C:4]([CH3:10])[N:3]=2)=[O:28])(=[O:25])=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=1)(=[O:16])=[O:15])[CH3:30]
Reactant: Cc1nc(N)nc(C)c1C
Reactant: CCN(CC)S(=O)(=O)c1ccccc1S(=O)(=O)N=C=O
Agent: C1CN2CCN1CC2
Solvent: CC#N
Product: CCN(CC)S(=O)(=O)c1ccccc1S(=O)(=O)NC(=O)Nc1nc(C)c(C)c(C)n1

Procedure:
A mixture of 0.8 g of 2-amino-4,5,6-trimethylpyrimidine, 2.8 g of the crude sulfonyl isocyanate from Example 9 and a few crystals of DABCO in 25 ml of acetonitrile is stirred at room temperature for 16 hours. A small amount of unreacted aminopyrimidine is filtered off and the filtrate concentrated in-vacuo to give a hard glass. Crystallization from methanol gives N,N-diethyl-N'[4,5,6-trimethylpyrimidin-2-yl]aminocarbonyl-1,2-benzenedisulfonamide as a white solid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C:15]([OH:17])=O)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[CH3:18][O:19][C:20]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:21]=1[NH2:22].C1(N=C=NC2CCCCC2)CCCCC1>O1CCCC1.O1CCOCC1>[Cl:27][C:24]1[CH:25]=[CH:26][C:20]([O:19][CH3:18])([C:15]([CH2:14][C:11]2[CH:10]=[CH:9][C:8]([C:5]3[CH:4]=[CH:3][C:2]([OH:1])=[CH:7][CH:6]=3)=[CH:13][CH:12]=2)=[O:17])[CH:21]([CH:23]=1)[NH2:22]
Reactant: COc1ccc(Cl)cc1N
Reactant: O=C(O)Cc1ccc(-c2ccc(O)cc2)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: C1CCOC1
Solvent: C1COCCO1
Product: COC1(C(=O)Cc2ccc(-c3ccc(O)cc3)cc2)C=CC(Cl)=CC1N
Yield: 70 %

Procedure:
A solution of 10 gm (44 millimols) of 4-hydroxy-4'-biphenyl-acetic acid (see W. H. Linnell and H. J. Smith, J. Chem. Soc. 1959,557) in a mixture of 33 ml of tetrahydrofuran and 162 ml of absolute dioxane were added at 0° C to a solution of 4.63 gm (29.4 millimols) of 2-methoxy-5-chloroaniline (m.p. 83°-85° C) in 40 ml of absolute dioxane, and the mixed solution was subsequently admixed with a solution of 9.1 gm (44 millimols) of N,N'-dicyclohexyl-carbodiimide in 20 ml of dioxane. After 20 hours of reaction time at 0° C, the dicyclohexylurea was filtered off and the solvent was distilled off. The residue was dissolved in 700 ml of chloroform, the solution was washed several times with 2N hydrochloric acid and water, dried over sodium sulfate, and the organic phase was evaporated in vacuo. The light brown, viscous crude product was purified on a silicagel column with toluene/acetic acid (4:1 ) as the eluant. Yield: 70% of theory; m.p. 165°-168° C.
Reaction SMILES: [C:1]([O:7][CH2:8][CH2:9][Si:10]([CH3:13])([CH3:12])[CH3:11])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[N:14]([O-])=[O:15].[Na+]>C(O)(=O)C.O.C(OCC)(=O)C>[N:14](=[C:2]([C:3]([CH3:5])=[O:4])[C:1]([O:7][CH2:8][CH2:9][Si:10]([CH3:11])([CH3:13])[CH3:12])=[O:6])[OH:15]
Reactant: CC(=O)CC(=O)OCC[Si](C)(C)C
Reactant: O=N[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: O
Product: CC(=O)C(=NO)C(=O)OCC[Si](C)(C)C
Temperature: 25 °C
Yield: 57.6 %

Procedure:
To a solution of 18.24 gm (90.3 mMol) 2-(trimethylsilyl)-ethyl acetoacetate in 10 mL acetic acid at −4° C. was added a solution of 6.85 gm (99.3 mMol) sodium nitrite in 30 mL of water dropwise over 15 minutes. The reaction mixture was allowed to warm to room temperature while stirring. After 2 hours the reaction mixture was diluted with 100 mL ethyl acetate and washed twice with 50 mL portions of saturated aqueous sodium chloride. The organic phase was dried over sodium sulfate and concentrated under reduced pressure. The residual was dissolved in toluene and concentrated under reduced pressure twice to azeotropically remove any remaining acetic acid. The residual oil was finally subjected to flash silica gel chromatography, eluting with hexane containing 30% ethyl acetate. Fractions shown to contain product were combined and concentrated under reduced pressure to provide 12.04 gm (58%) of the desired compound as a colorless oil.
Reaction SMILES: N[C:2]1[NH:3][C:4](=O)[C:5]2CC(C)[CH2:8][C:6]=2[N:7]=1.[O-:13][CH2:14][CH3:15].[Na+].C(C(CC(OCC)OCC)C(OCC)=O)#[N:18]>>[CH3:8][C:6]1[NH:7][C:2]2=[N:3][CH:4]=[CH:5][C:15]2=[C:14]([OH:13])[N:18]=1
Reactant: CC1Cc2nc(N)[nH]c(=O)c2C1
Reactant: CCOC(=O)C(C#N)CC(OCC)OCC
Reactant: CC[O-]
Agent: [Na+]
Product: Cc1nc(O)c2ccnc-2[nH]1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Acetamidine hydrochloride (2, 0.05 mol, 4.7 g) was added to the 0.1 M sodium ethoxide solution (75 ml) and kept stirring under room temperature for 0.5 h. After removing the formed sodium chloride by filtration, the filtrate was added the ethyl α-cyano-γ,γ-diethoxybutyrate (1, 0.05 mol, 11.5 g) and the solution was heated under reflux for 5 h. After the removal of most solvent under vacuum, acetic acid was added to adjust the pH to 7.0 and 10.8 g precipitation as white powder. Ethanol (110 ml) with concentrated sulfuric acid (2 ml) was added to the collected powder and was refluxed for 2 h. By the end of the reaction an equal volume of water was added and kept at 4° C. overnight. The pyrrolopyrimidine 3 precipitated as white powder (2.1 g) was used for next step without further purification.
Reaction SMILES: [OH:1][CH:2]([C:4]1[CH:8]=[CH:7][S:6][CH:5]=1)[CH3:3].[Br:9]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Br:9][C:5]1[S:6][CH:7]=[CH:8][C:4]=1[CH:2]([OH:1])[CH3:3]
Reactant: CC(O)c1ccsc1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: CC(O)c1ccsc1Br
Reaction time: 2 h

Procedure:
To a stirred solution of 3-(1-hydroxyethyl)thiophene (61.4 g, 0.48 mol) in carbon tetrachloride (550 ml) was added N-bromosuccinimide (89.4 g, 0.504 mol) portionwise over 11/2 hours at 40° C. Stirring was continued for an additional 2 hours at ambient temperature. The reaction mixture was filtered and the filtrate was washed with water, saturated NaHCO3 and again with water. The solution
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:17])[NH:4][C:5](=[O:16])[N:6]([CH2:9][CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)[C:7]=1[NH2:8].[CH:18](Cl)(Cl)Cl.CCOCC>C(O)=O>[CH:10]1([CH2:9][N:6]2[C:7]3[N:8]=[CH:18][NH:1][C:2]=3[C:3](=[O:17])[NH:4][C:5]2=[O:16])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: Nc1c(N)n(CC2CCCCC2)c(=O)[nH]c1=O
Reactant: ClC(Cl)Cl
Solvent: O=CO
Solvent: CCOCC
Product: O=c1[nH]c(=O)n(CC2CCCCC2)c2nc[nH]c12

Procedure:
2 g of 5,6-diamino-1-cyclohexylmethyl-2,4-(1H,3H)-pyrimidine dione (XXII) was refluxed in 10 ml of formic acid for 1 h. 5 ml of chloroform was added and ether was then added slowly. The received crystals were filtered off. Yield 2.1 g (XXIII). The amide (XXIII) was refluxed in 15 ml of 2N NaOH for 1 hour and then neutralized with 5N HCl. Yield 1.7 g (XXIV) NMR (see Table I). ##STR12##
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][C:5]=12.C=O.CC1(C)O[C:18](=O)[CH2:17][C:16](=[O:21])[O:15]1.O>C(#N)C>[N:1]1[CH:2]=[C:3]([CH2:18][CH2:17][C:16]([OH:21])=[O:15])[N:4]2[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][C:5]=12
Reactant: c1cn2c(n1)CCCCC2
Reactant: CC1(C)OC(=O)CC(=O)O1
Agent: C=O
Solvent: O
Solvent: CC#N
Product: O=C(O)CCc1cnc2n1CCCCC2

Procedure:
To a solution of 6,7,8,9-tetrahydro-5H-imidazo[1,2-a]azepine in acetonitrile are added aqueous formaldehyde solution and 2,2-dimethyl-1,3-dioxane-4,6-dione with stirring and the mixture is heated for 4 hours. After the completion of the reaction, the reaction mixture is poured into water and the mixture is extracted with chloroform, washed with water, and dried over magnesium sulfate. The solution is concentrated under reduced pressure and the resulting 2,2-dimethyl-5-(6,7,8,9-tetrahydro-5H-imidazo[1,2-a]azepin-3-ylmethyl)-1,3-dioxane-4,6-dione is dissolved in pyridine with sting. Water and copper powder are added and the mixture is refluxed under heating for 3 hours. After the completion of the reaction, the reaction mixture is filtered while it is hot and the solvent is evaporated under reduced pressure to give 3-(6,7,8,9-tetrahydro-5H-imidazo[1,2-a]azepin-3-yl)propionic acid. To a solution of this compound in dimethylformamide are added 4-(4-chlorophenyl)piperidine, triethylamine and cyanophosphonic acid diester and the mixture is stirred at room temperature. After the completion of the reaction, the reaction mixture is poured into water and the mixture is extracted with chloroform, washed with water, and dried over magnesium sulfate. The solution is concentrated under reduced pressure and the resulting 1-(4-(4-chlorophenyl)piperidin-1-yl)-3-(6,7,8,9-tetrahydro-5H-imidazo[1,2-a]azepin-3-yl)propan-1-one is dissolved in tetrahydrofuran and lithium aluminum hydride is added under ice-cooling with stirring and the mixture is stirred at room temperature for 1 hour. After the completion of the reaction, the reaction mixture is poured into water and the mixture is extracted with chloroform, washed with water, and dried over magnesium sulfate. The solution is concentrated under reduced pressure and the obtained residue is subjected to silica gel column chromatography to give 3-(3-(4-(4-chlorophenyl)piperidin-1-yl)propyl)-6,7,8,9-tetrahydro-5H-imidazo[1,2-a]azepine.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([N:8]2[CH2:21][CH2:20][N:11]3[C:12]4[CH2:13][CH2:14][CH2:15][CH2:16][C:17]=4[C:18]([F:19])=[C:10]3[C:9]2=[O:22])[C:3]=1[CH2:23][OH:24].ClCCl.[C:28](Cl)(=[O:30])[CH3:29]>C(N(CC)CC)C>[C:28]([O:24][CH2:23][C:3]1[C:4]([N:8]2[CH2:21][CH2:20][N:11]3[C:12]4[CH2:13][CH2:14][CH2:15][CH2:16][C:17]=4[C:18]([F:19])=[C:10]3[C:9]2=[O:22])=[N:5][CH:6]=[CH:7][C:2]=1[Cl:1])(=[O:30])[CH3:29]
Reactant: CC(=O)Cl
Reactant: O=C1c2c(F)c3c(n2CCN1c1nccc(Cl)c1CO)CCCC3
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)OCc1c(Cl)ccnc1N1CCn2c3c(c(F)c2C1=O)CCCC3
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 89.8 %

Procedure:
A round-bottomed flask was charged with 231a (600 mg, 1.72 mmol), dichloromethane (50 mL), and triethylamine (5 mL). The solution was stirred at 0° C. for 0.5 h and acetyl chloride (135 mg, 1.72 mmol) was added slowly. The mixture was stirred at 0° C. for another 2.5 h. It was then evaporated under reduced pressure. The residue was purified by silica-gel column chromatography eluting with 9:1 petroleum ether/ethyl acetate to afford 231b (605 mg, 90%) as a yellow solid. MS-ESI: [M+H]+ 392.1
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[CH3:8].C(=O)([O-])O.[Na+].[C:15]([C:17]1([C:20]2[CH:21]=[C:22]([CH:26]=[CH:27][CH:28]=2)[C:23](Cl)=[O:24])[CH2:19][CH2:18]1)#[N:16]>O1CCCC1>[C:15]([C:17]1([C:20]2[CH:21]=[C:22]([CH:26]=[CH:27][CH:28]=2)[C:23]([NH:1][C:2]2[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=2[CH3:8])=[O:24])[CH2:18][CH2:19]1)#[N:16]
Reactant: N#CC1(c2cccc(C(=O)Cl)c2)CC1
Reactant: Cc1ccc(O)cc1N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1ccc(O)cc1NC(=O)c1cccc(C2(C#N)CC2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 87 %

Procedure:
To a two-layer solution of 3-amino-4-methylphenol (5.92 g, 48.0 mmol) in tetrahydrofuran (40 mL )/1N aqueous sodium hydrogen carbonate solution (54 mL) was added a solution of 3-(1-cyanocyclopropyl)benzoyl chloride synthesized above in tetrahydrofuran (20 mL), and the mixture was stirred at room temperature for 2 hr. Since the pH of the reaction mixture was 4-5, sodium hydrogen carbonate (900 mg, 10.7 mmol) was added to the mixture to adjust the pH to 8-9, and the reaction mixture was further stirred at room temperature for 1 hr. The aqueous layer was separated, and extracted with ethyl acetate (150 mL). The combined organic layer was washed with saturated brine (150 mL), and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. Ethyl acetate (25 mL)/hexane (50 mL) was added to the obtained suspension, and the mixture was stirred at room temperature for 20 min. The precipitate was collected by filtration, washed repeatedly with diisopropyl ether/hexane (1:1), and air-dried to give the title compound (12.2 g, 87%) as a pale-yellow powder.
Reaction SMILES: [C:1]([O:9][C@H:10]([CH2:15][C:16]1[CH:21]=[C:20]([Cl:22])[C:19]([NH2:23])=[C:18]([CH3:24])[C:17]=1[CH2:25][O:26][C:27](=[O:29])[CH3:28])[C:11]([O:13][CH3:14])=[O:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(C)C=CC=CC=1.C(O)(=O)C.[N:41](OCCC(C)C)=O.C([O-])(=O)C.[K+]>>[C:1]([O:9][C@H:10]([CH2:15][C:16]1[C:17]([CH2:25][O:26][C:27](=[O:29])[CH3:28])=[C:18]2[C:19](=[C:20]([Cl:22])[CH:21]=1)[NH:23][N:41]=[CH:24]2)[C:11]([O:13][CH3:14])=[O:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)CCON=O
Reactant: COC(=O)[C@@H](Cc1cc(Cl)c(N)c(C)c1COC(C)=O)OC(=O)c1ccccc1
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: COC(=O)[C@@H](Cc1cc(Cl)c2[nH]ncc2c1COC(C)=O)OC(=O)c1ccccc1
Reaction time: 0.25 h
Yield: 88 %

Procedure:
(R)-3-(2-(acetoxymethyl)-4-amino-5-chloro-3-methylphenyl)-1-methoxy-1-oxopropan-2-yl benzoate (16.33 g, 38.9 mmol) in toluene (100.0 ml, 939 mmol) was added acetic acid (5.0 ml, 87 mmol) followed by isoamyl nitrite (5.76 ml, 42.8 mmol) at 0° C. After 15 min, potassium acetate (7.64 g, 78 mmol) was added and the reaction mixture was stirred for 12 h. The solvent was removed and the crude product was dissolved in dichloromethane (250 mL) and washed with aqueous NaHCO3. The solvent was dried (Na2SO4), evaporated and the crude product was purified by flash chromatography using 40% EtOAc in hexane to give (R)-3-(4-(acetoxymethyl)-7-chloro-1H-indazol-5-yl)-1-methoxy-1-oxopropan-2-yl benzoate in 88% yield. MS (ESI) 453 (M+Na); Rf=2.46.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:17])[C@H:9]([C:14]([OH:16])=O)[CH2:10][CH:11]([CH3:13])[CH3:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)C(C)C)(C)C.Cl.CN(C)O.CN([C:35]([O:39][N:40]1N=NC2C=CC=C[C:41]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.CCOC(C)=O>[C:1]([O:5][C:6](=[O:7])[N:8]([C@H:9]([C:14](=[O:16])[N:40]([O:39][CH3:35])[CH3:41])[CH2:10][CH:11]([CH3:12])[CH3:13])[CH3:17])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)C[C@@H](C(=O)O)N(C)C(=O)OC(C)(C)C
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: CN(C)O
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CON(C)C(=O)[C@H](CC(C)C)N(C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
N-tert-butoxycarbonyl-N-methyl-L-leucine (5.0 g, 20.4 mmol) was dissolved in DMF (100 mL), treated with treated with N,N-diisopropylethylamine (28 mL, 163 mmol), N,N-dimethylhydroxylamine hydrochloride salt (2.0 g, 20.4 mmol), and HBTU (7.73 g, 20.4 mmol), then stirred overnight at room temperature. The reaction was diluted with EtOAc (500 mL), washed with saturated bicarbonate solution and brine, dried over Na2SO4, and concentrated to give the desired product as an oil; MS: 289.2 (M+1 for C14H28N2O4); TLC (SiO2) Rf 0.39 (8% MeOH/CH2Cl2), visualized with ninhydrin.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[CH3:10][C:11]1([CH3:19])[O:16][C:15](=[O:17])[CH2:14][C:13](=[O:18])[O:12]1.[CH3:20]OC(OC)OC>C(O)C>[CH3:10][C:11]1([CH3:19])[O:16][C:15](=[O:17])[C:14](=[CH:20][NH:1][C:2]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=2)[C:13](=[O:18])[O:12]1
Reactant: COC(OC)OC
Reactant: N#Cc1ccc(N)cc1
Reactant: CC1(C)OC(=O)CC(=O)O1
Solvent: CCO
Product: CC1(C)OC(=O)C(=CNc2ccc(C#N)cc2)C(=O)O1
Yield: 97 %

Procedure:
A mixture of 4-amino-benzonitrile (12.5 g, 0.106 mol), 2,2-dimethyl-[1,3]dioxane-4,6-dione (18.3 g, 0.127 mol) and trimethylorthoformate (16 ml) in ethanol (100 ml) was refluxed for 3 hours. After cooling the solid was filtered off, washed with ethanol and air dried. The product was obtained as an off-white solid (27.9 g, 97%).
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([N:15]1[CH2:20][CH2:19][CH:18]([NH:21][C:22]2[C:27]([NH:28][C:29](=[O:36])[CH2:30][CH:31]3[CH2:35][CH2:34][CH2:33][CH2:32]3)=[CH:26][N:25]=[C:24]3[N:37]([S:40]([C:43]4[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=4)(=[O:42])=[O:41])[CH:38]=[CH:39][C:23]=23)[CH2:17][CH2:16]1)=O)(C)(C)C.[C:49](#[N:52])[CH:50]=[CH2:51]>C(Cl)Cl>[C:43]1([S:40]([N:37]2[C:24]3=[N:25][CH:26]=[C:27]([NH:28][C:29](=[O:36])[CH2:30][CH:31]4[CH2:32][CH2:33][CH2:34][CH2:35]4)[C:22]([NH:21][CH:18]4[CH2:19][CH2:20][N:15]([CH2:51][CH2:50][C:49]#[N:52])[CH2:16][CH2:17]4)=[C:23]3[CH:39]=[CH:38]2)(=[O:41])=[O:42])[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2c(NC(=O)CC3CCCC3)cnc3c2ccn3S(=O)(=O)c2ccccc2)CC1
Reactant: C=CC#N
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#CCCN1CCC(Nc2c(NC(=O)CC3CCCC3)cnc3c2ccn3S(=O)(=O)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 158 %

Procedure:
Trifluoroacetic acid (2 ml) was added to a solution of 4-[1-benzenesulfonyl-5-(2-cyclopentyl-acetylamino)-1H-pyrrolo[2,3-b]pyridin-4-ylamino]-piperidine-1-carboxylic acid tert-butyl ester (0.421 g, 0.724 mmol) in CH2Cl2 (10 ml) at 25° C. The reaction mixture was stirred at 25° C. for 30 min, then was concentrated under reduced pressure. The residue was partitioned between half-saturated NaHCO3 (100 ml) and EtOAc (2×100 ml) and the combined organic layers were dried over MgSO4 and filtered. The filtrate was concentrated under reduced pressure and the residue was dissolved in DMF (8 ml) at 25° C. Acrylonitrile (1.0 ml, 0.200 mmol) was added and the reaction mixture was stirred at 25° C. for 18 h, then was concentrated under reduced pressure. The residue was partitioned between water (100 ml) and EtOAc (2×100 ml). The combined organic layers were dried over MgSO4, filtered, and the filtrate was concentrated under reduced pressure. Purification of the residue by column chromatography on silica gel (gradient: 0 to 7% CH3OH in CH2Cl2) afforded N-{1-benzenesulfonyl-4-[1-(2-cyano-ethyl)-piperidin-4-ylamino]-1H-pyrrolo[2,3-b]pyridin-5-yl}-2-cyclopentyl-acetamide (0.169 g, 63%) as a white foam. LCMS (Method G, ESI): RT=0.70 min, m+H=535.4. This material was used in the next step below without additional characterization.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH3:12])[CH:6]=[CH:5]2.C1C(=O)N([Cl:20])C(=O)C1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH2:12][Cl:20])[CH:6]=[CH:5]2
Reactant: Cc1ccc2cc(Br)ccc2n1
Reactant: O=C1CCC(=O)N1Cl
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: c1ccccc1
Product: ClCc1ccc2cc(Br)ccc2n1
Temperature: 80 °C

Procedure:
To 6-Bromo-2-methyl-quinoline (2.4 g, 11.0 mmol) in benzene (20 mL) at room temperature was added NCS (1.44 g, 11.0 mmol) and catalytic benzoyl peroxide, and the reaction was heated to 80° C. for 1 hour. After cooling to room temperature, the mixture was concentrated and purified by silica gel chromatography (0-50% EtOAc in hexanes) to give the desired product, 4a.
Reaction SMILES: C(O)(=O)C.[Cl:5][C:6]1[CH:7]=[N:8][N:9]([C:11]([CH3:18])([CH3:17])[C:12](=[NH:16])OCC)[CH:10]=1.[NH2:19][C:20]1[CH:21]=[CH:22][C:23]([N:27]2[CH2:32][CH2:31][CH2:30][C@@H:29]([C:33]([N:35]3[CH2:39][CH2:38][CH2:37][CH2:36]3)=[O:34])[CH2:28]2)=[N:24][C:25]=1N>C(O)C>[Cl:5][C:6]1[CH:7]=[N:8][N:9]([C:11]([C:12]2[NH:16][C:25]3=[N:24][C:23]([N:27]4[CH2:32][CH2:31][CH2:30][C@@H:29]([C:33]([N:35]5[CH2:39][CH2:38][CH2:37][CH2:36]5)=[O:34])[CH2:28]4)=[CH:22][CH:21]=[C:20]3[N:19]=2)([CH3:17])[CH3:18])[CH:10]=1
Reactant: CCOC(=N)C(C)(C)n1cc(Cl)cn1
Reactant: Nc1ccc(N2CCC[C@@H](C(=O)N3CCCC3)C2)nc1N
Solvent: CCO
Solvent: CC(=O)O
Product: CC(C)(c1nc2ccc(N3CCC[C@@H](C(=O)N4CCCC4)C3)nc2[nH]1)n1cc(Cl)cn1
Yield: 25 %

Procedure:
Acetic acid (2.9 mL, 48.58 mmol) and ethyl 2-(4-chloro-1H-pyrazol-1-yl)-2-methylpropanimidate (Intermediate 54) were added to a solution of (R)-(1-(5,6-diaminopyridin-2-yl)piperidin-3-yl)(pyrrolidin-1-yl)methanone in ethanol, prepared in the previous step. The reaction mixture was heated at reflux for 18 h. The mixture was concentrated and the residue was partitioned between ethyl acetate and water. The organic layer was dried over sodium sulfate, filtered and concentrated. The crude material was purified via column chromatography (100-200 mesh silica gel, 5% methanol in ethyl acetate) to afford the title compound (530 mg, 25% yield over 2 steps). 1H NMR (500 MHz, CDCl3) δ 1.53-1.65 (m, 1H) 1.74-2.00 (m, 7H) 2.10 (s, 6H) 2.58-2.70 (m, 1H) 2.88-2.93 (m, 1H) 3.01-3.09 (m, 1H) 3.40-3.50 (m, 3H) 3.55-3.63 (m, 1H) 4.22 (d, 1H) 4.43 (d, 1H) 6.63 (d, 1H) 7.57 (d, 2H) 7.79 (d, 1H) 10.08 (br s, 1H). MS (ES+APCI) (M+H) 442.2; LCMS retention time 2.216 min (Method N1).