Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH:8]=[O:9])=[CH:6][N:5]=[C:4]2[NH:10][CH:11]=[CH:12][C:3]=12.[H-].[Na+].[CH3:15][C:16]1[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=1>CN(C=O)C>[Cl:1][C:2]1[C:7]([CH:8]=[O:9])=[CH:6][N:5]=[C:4]2[N:10]([S:22]([C:19]3[CH:20]=[CH:21][C:16]([CH3:15])=[CH:17][CH:18]=3)(=[O:24])=[O:23])[CH:11]=[CH:12][C:3]=12
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: O=Cc1cnc2[nH]ccc2c1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)n2ccc3c(Cl)c(C=O)cnc32)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 86.7 %

Procedure:
To a suspension of 4-chloro-1H-pyrrolo[2,3-b]pyridine-5-carbaldehyde (2.00 g, 11.1 mmol, Adesis) in DMF (30 mL) was added NaH (60% dispersion in mineral oil, 0.500 g, 12.5 mmol) forming a yellow solution. The reaction mixture was stirred at ambient temperature for about 30 min then 4-methylbenzene-1-sulfonyl chloride (2.40 g, 12.6 mmol) was added. The reaction mixture was stirred at ambient temperature for about 30 min and poured into ice water (about 50 mL). The solid was collected via vacuum filtration, while washing with water (about 15 mL), and dried in a vacuum oven to give 4-chloro-1-tosyl-1H-pyrrolo[2,3-b]pyridine-5-carbaldehyde (3.22 g, 87%) as an off white solid: LC/MS (Table 1, Method b) Rt=2.56 min; MS m/z: 335 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:16])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])=[CH:4][CH:3]=1.[OH-].[K+]>C1(C)C(C)=CC=CC=1.CO>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:16])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])=[CH:4][CH:3]=1
Reactant: CCCCCCCC(=O)c1ccc(C)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: Cc1ccccc1C
Product: CCCCCCCC(O)c1ccc(C)cc1
Temperature: 140 °C
Reaction time: 2 h

Procedure:
Tris(triphenylphosphine)ruthenium (II) chloride (1.9 mg, 2 μmol, 0.5 mol %) and a chiral ligand (M=Ru, R=t-Bu, Ar=C6H5—, 1.3 μmol, 0.33 mol %) were dissolved in xylene (3 mL) under nitrogen atmosphere, and then heated and stirred for 2 h at 140° C. After the mixture was cooled to room temperature, p-methyloctanophenone (0.8 mmol), xylene (2 mL) and a solution of potassium hydroxide in methanol (0.8 mL, 0.2 M) were added thereto. Thereafter, the reaction system was placed in an autoclave, and stirred for 6 h under H2 (10 atm) at 50° C. The solvent was removed under reduced pressure, and the resultants were separated by column chromatography (silica gel column; eluent:ethyl acetate/petroleum ether=1/5). Accordingly, pure 1-(p-methylphenyl) octanol was obtained and the ee value (ee=99.0%) was measured by GC analysis.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:18]([O:19][CH3:20])=[CH:17][C:12]([C:13]([NH:15][OH:16])=[NH:14])=[C:11]([I:21])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:22](N(CC)CC)[CH3:23].C(Cl)(=O)C>O1CCCC1>[CH2:1]([O:8][C:9]1[C:18]([O:19][CH3:20])=[CH:17][C:12]([C:13]2[N:14]=[C:22]([CH3:23])[O:16][N:15]=2)=[C:11]([I:21])[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCN(CC)CC
Reactant: COc1cc(C(=N)NO)c(I)cc1OCc1ccccc1
Solvent: CC(=O)Cl
Solvent: C1CCOC1
Product: COc1cc(-c2noc(C)n2)c(I)cc1OCc1ccccc1
Reaction time: 1 h

Procedure:
To a mixture of 4-benzyloxy-N-hydroxy-2-iodo-5-methoxy-benzamidine (reference example 3-1) (35 g), triethylamine (31 mL) and tetrahydrofuran (31 mL) was added acetyl chloride (8.2 mL) under ice-bath cooling. The mixture was stirred at the same temperature for 1 hour. Insoluble materials were removed by filtration. To the filtrate was added tetrabutylammonium fluoride (1 mol/L tetrahydrofuran solution, 89 mL). After stirring at the same temperature for 2 hours, water and ethylacetate were added to the mixture. The separated organic layer was washed with 1 mol/L hydrochloric acid, a 1 mol/L aqueous solution of sodium hydroxide, an aqueous solution of sodium bicarbonate and brine successively, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was triturated with methanol to give the title compound (31.5 g).
Reaction SMILES: [C:1]([CH:4]1[C:16]2[NH:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:8]=2[CH2:7][CH2:6][NH:5]1)(=[O:3])[CH3:2].[H-].[Na+].[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CN(C)C=O>[C:1]([CH:4]1[C:16]2[N:15]([CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:8]=2[CH2:7][CH2:6][NH:5]1)(=[O:3])[CH3:2]
Reactant: BrCc1ccccc1
Reactant: CC(=O)C1NCCc2c1[nH]c1ccccc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)C1NCCc2c1n(Cc1ccccc1)c1ccccc21
Reaction time: 1 h

Procedure:
2 acetyl-9 benzyl-1,2,3,4-tetrahydro-β-carboline was prepared as follows: Under a nitrogen atmosphere, 8.0 mmol of 2 acetyl-1,2,3,4-tetrahydro-β-carboline (1.71 was dissolved in 4Q mL dry dimethylformamide (DMF). The solution was stirred over ice, and NaH (2 g) was added under N2. The suspension was stirred for 1 hour, and then benzylbromide (9.2 mmol, 1.56 was slowly to the cooled suspension. After a further 2 hours of stirring at ambient temperature, the mixture was filtered and the filtrate added to 320 mL 0.1 N HCl. Crude 2-acetyl- 9-benzyl-1,2,3,4-tetrahydro-β-carboline separated as an oil. The oil was collected by centrifugation, washed with water, and dried over anhydrous MgSO:. The product was purified by standard chromatographic procedures using a 60:40 mixture of ether:hexane.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:11]=[C:12]([N:17]2[CH2:26][CH2:25][C:20]3(OCC[O:21]3)[CH2:19][CH2:18]2)[CH:13]=[CH:14][C:15]=1[Cl:16].OS(O)(=O)=O.C([O-])([O-])=O.[Na+].[Na+]>O>[NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:11]=[C:12]([N:17]2[CH2:26][CH2:25][C:20](=[O:21])[CH2:19][CH2:18]2)[CH:13]=[CH:14][C:15]=1[Cl:16]
Reactant: Clc1ccc(N2CCC3(CC2)OCCO3)cc1-c1nc2ccccc2[nH]1
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: O=C1CCN(c2ccc(Cl)c(-c3nc4ccccc4[nH]3)c2)CC1
Temperature: 25 °C
Reaction time: 72 h
Yield: 90.6 %

Procedure:
To a suspension of 8-[3-(1H-benzoimidazol-2-yl)-4-chloro-phenyl]-1,4-dioxa-8-aza-spiro[4.5]decane (2.00 g, 5.42 mmol) in water (50 mL) was added H2SO4 (2.50 mL) dropwise and the resulting solution was stirred for 72 h at room temperature. The solution was neutralized with Na2CO3 and the oil obtained solidified on standing in water. The precipitate was filtered and dried to obtain 1.60 g (90%) of the title compound.
Reaction SMILES: [OH-:1].[Na+].OO.[C:5]([C:7]1[N:12]=[CH:11][C:10]([NH:13][C@@H:14]2[CH2:19][CH2:18][CH2:17][CH2:16][C@@H:15]2[NH:20]C(=O)OC(C)(C)C)=[CH:9][C:8]=1[NH:28][C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([N:35]2[N:39]=[CH:38][CH:37]=[N:36]2)[N:30]=1)#[N:6].[C:40]([OH:46])([C:42]([F:45])([F:44])[F:43])=[O:41]>C(Cl)Cl.CS(C)=O>[OH:46][C:40]([C:42]([F:45])([F:44])[F:43])=[O:41].[NH2:20][C@H:15]1[CH2:16][CH2:17][CH2:18][CH2:19][C@H:14]1[NH:13][C:10]1[CH:9]=[C:8]([NH:28][C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([N:35]3[N:39]=[CH:38][CH:37]=[N:36]3)[N:30]=2)[C:7]([C:5]([NH2:6])=[O:1])=[N:12][CH:11]=1
Reactant: [OH-]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCC[C@H]1Nc1cnc(C#N)c(Nc2cccc(-n3nccn3)n2)c1
Agent: OO
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CS(C)=O
Solvent: ClCCl
Product: NC(=O)c1ncc(N[C@@H]2CCCC[C@@H]2N)cc1Nc1cccc(-n2nccn2)n1
Reaction time: 0.5 h

Procedure:
Dioxane (1.06 mL), 6-(2H-1,2,3-triazol-2-yl)pyridin-2-amine (51 mg, 0.32 mmol) and cesium carbonate (311 mg, 0.955 mmol) were added to tert-butyl {(1S,2R)-2-[(5-bromo-6-cyanopyridin-3-yl)amino]cyclohexyl}carbamate (PrepEx 1.1) (94 mg, 0.32 mmol) in a scintillation vial. The vial was purged and flushed with argon three times before Pd2 dba3 (29 mg, 0.032 mmol) and Xantphos (28 mg, 0.048 mmol) were added. The vial was purged and flushed 3 times with argon before the vial was sealed and heated to 80° C. After 16 hours, the reaction mixture was cooled to room temperature, filtered through CELITE (washed with dichloromethane), and diluted with water. The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (10-70% acetone in hexanes, linear gradient) to afford tert-butyl {(1S,2R)-2-[(6-cyano-5-{[6-(2H-1,2,3-triazol-2-yl)pyridin-2-yl]amino}pyridin-3-yl)amino]cyclohexyl}carbamate. The isolated solids were dissolved in DCM (1 mL) and TFA (1 mL), and stirred at room temperature. After 30 minutes, the reaction mixture was concentrated under reduced pressure. The residue was dissolved in DMSO (1 mL). To this solution was added sodium hydroxide (4.0 M in water, 0.1 mL, 0.4 mmol) and hydrogen peroxide (30 wt % in water, 0.050 mL, 0.49 mmol). The reaction mixture was stirred at room temperature until complete conversion of the nitrile intermediate was observed by LCMS. The reaction mixture was diluted with DMSO and filtered. The filtrate was purified directly by reverse phase HPLC (acetonitrile/water with 0.1% TFA, linear gradient) to afford 5-{[(1R,2S)-2-aminocyclohexyl]amino}-3-{[6-(2H-1,2,3-triazol-2-yl)pyridin-2-yl]amino}pyridine-2-carboxamide TFA salt. MS ESI calc'd. for C19H24N9O [M+H]+ 394. found 394. 1H NMR (500 MHz, CD3OD) δ 9.20 (s, 1H), 8.07 (s, 2H), 7.83 (t, J=8.0 Hz, 1H), 7.80 (d, J=2.5 Hz, 1H), 7.55 (d, J=7.5 Hz, 1H), 6.87 (d, J=7.8 Hz, 1H), 4.38 (s, 1H), 3.75-3.67 (m, 1H), 2.01-1.66 (m, 6), 1.66-1.51 (m, 2H).
Reaction SMILES: [CH2:1]([O:11][C:12]1[CH:17]=[CH:16][C:15](I)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[C:19]([C:21]1[CH:26]=[CH:25][C:24]([C:27]#[CH:28])=[CH:23][CH:22]=1)#[CH:20]>>[CH2:1]([O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:20]#[C:19][C:21]1[CH:26]=[CH:25][C:24]([C:27]#[C:28][C:17]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[O:11][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])=[CH:23][CH:22]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: C#Cc1ccc(C#C)cc1
Reactant: CCCCCCCCCCOc1ccc(I)cc1
Product: CCCCCCCCCCOc1ccccc1C#Cc1ccc(C#Cc2ccccc2OCCCCCCCCCC)cc1

Procedure:
Then, 1-decyloxy-4-iodobenzene and 1,4-diethynylbenzene are reacted to obtain 1,4-bis(decyloxyphenylethynyl)benzene as shown in the following reaction formula (38).
Reaction SMILES: [C:1]([OH:4])(=[O:3])[CH3:2].[N:5]([C:8]1[C:28](=[O:29])[CH2:27][CH2:26][C@@:25]2([CH3:30])[C:9]=1[CH2:10][CH2:11][C@@H:12]1[C@@H:24]2[CH2:23][CH2:22][C@@:21]2([CH3:31])[C@H:13]1[CH2:14][CH2:15][C@@H:16]2[C@H:17]([CH3:20])[CH2:18][OH:19])=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O1CCCC1>O>[C:1]([OH:4])(=[O:3])[CH3:2].[NH2:5][C:8]1[C:28](=[O:29])[CH2:27][CH2:26][C@@:25]2([CH3:30])[C:9]=1[CH2:10][CH2:11][C@@H:12]1[C@@H:24]2[CH2:23][CH2:22][C@@:21]2([CH3:31])[C@H:13]1[CH2:14][CH2:15][C@@H:16]2[C@H:17]([CH3:20])[CH2:18][OH:19]
Reactant: C[C@H](CO)[C@H]1CC[C@H]2[C@@H]3CCC4=C(N=[N+]=[N-])C(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: O
Product: C[C@H](CO)[C@H]1CC[C@H]2[C@@H]3CCC4=C(N)C(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Yield: 80 %

Procedure:
A stirred mixture of (20S)-4-azido-21-hydroxy-20-methylpregn-4-en-3-one acetate (1.4 g, 3.39 mmole), triphenylphosphine (1.08 g), tetrahydrofuran (25 mL) and water (7 mL) was heated at reflux temperature under argon for 18 hours. The solvents were removed from the cooled reaction and the residue was purified by flash chromatography to give (20S)-4-amino-21-hydroxy-20-methylpregn-4-en-3-one acetate (1.1 g, 84%). IR 3470, 3366, 1732, 1674, 1618, 1584, 1254 cm-1 ; MS (CI) 388 (100%, M+1), 328 (70% M+1-AcOH); 1H NMR (CDCl3) δ 0.72 (3H, s, C18 -Me), 1.00 (d, C22 -Me), 1.14 (s, C19 -Me), 2.04 (s, Ac-Me), 3.43 (2H, v br, NH2), 3.76 (1H, dd, 1/2 C21 -CH2), 4.07 (1 H, dd, 1/2 C21 -CH2). This compound has the following structure: ##STR8##
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]([CH:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=1)[CH3:14])[C:7]2=[O:12].[F:21][C:22]1[C:27]([C:28]([F:31])([F:30])[F:29])=[CH:26][CH:25]=[CH:24][C:23]=1[CH2:32][C:33](O)=[O:34].F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C=O)C>[F:21][C:22]1[C:27]([C:28]([F:30])([F:31])[F:29])=[CH:26][CH:25]=[CH:24][C:23]=1[CH2:32][C:33]([NH:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]([CH:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=1)[CH3:14])[C:7]2=[O:12])=[O:34]
Reactant: O=C(O)Cc1cccc(C(F)(F)F)c1F
Reactant: CC(c1ccccn1)n1ccc2c(N)cccc2c1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(c1ccccn1)n1ccc2c(NC(=O)Cc3cccc(C(F)(F)F)c3F)cccc2c1=O
Temperature: 50 °C
Reaction time: 16 h

Procedure:
To a solution of 5-amino-2-(1-(pyridin-2-yl)ethyl)isoquinolin-1(2H)-one (100 mg, 0.0004 mol) in N,N-Dimethylformamide (1 mL, 0.01 mol) was added 2-(2-fluoro-3-(trifluoromethyl)phenyl)acetic acid (178 mg, 0.000801 mol), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (468.3 mg, 0.001232 mol) and N,N-diisopropylethylamine (300 uL, 0.002 mol). The reaction mixture was stirred for 16 hours at 50° C. LC/MS indicated that the reaction was completed. The DMF reaction solution was directly applied to prep. HPLC. The final product was obtained as a solid (102.4 mg). MS m/z=470.3 (M+1). 1H NMR (DMSO) δ 10.17 (s, 1 H), 8.54 (d, J=6.4 Hz, 1 H), 8.10 (d, J=8.0 Hz, 1 H), 7.82 (dd, J=7.8, 0.7 Hz, 1 H), 7.78 (td, J=9.5, 1.8 Hz, 2 H), 7.70 (t, J=7.1 Hz, 1 H), 7.55 (d, J=7.8 Hz, 1 H), 7.48 (t, J=7.9 Hz, 1 H), 7.40 (t, J=7.7 Hz, 1 H), 7.35 (d, J=8.0 Hz, 1 H), 7.31 (qd, J=4.8, 0.9 Hz, 1 H), 6.74 (d, J=7.8 Hz, 1 H), 6.28 (q, J=7.2 Hz, 1 H), 3.98 (s, 2 H), 1.78 (d, J=7.2 Hz, 3 H).
Reaction SMILES: [OH-].[Na+].[C:3]1([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:8]=[CH:7][C:6]([C:9]2[S:13][C:12]([C:14]([O:16]C)=[O:15])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1>O.C1COCC1.CO>[C:3]1([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:8]=[CH:7][C:6]([C:9]2[S:13][C:12]([C:14]([OH:16])=[O:15])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1
Reactant: COC(=O)c1ccc(-c2ccc(-c3ccccc3)cc2)s1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1ccc(-c2ccc(-c3ccccc3)cc2)s1
Temperature: 25 °C
Reaction time: 14 h
Yield: 80.9 %

Procedure:
A solution of sodium hydroxide in water (2N, 50 mL) was added to a suspension of compound 1022 (3.5 g, 11.9 mmol) in THF (50 mL) and methanol (50 mL). The reaction mixture was stirred at room temperature for 14 hours and then concentrated to approximately 1/10 of its original volume (15 mL). The concentrated solution was adjusted to pH 2-3 using 2N aqueous hydrochloric acid solution and extracted with a mixture of DCM and ethanol (7:3 ratio, 200 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated to give the compound 1023 (2.7 g). 1H NMR (CDCl3, 300 MHz) δ 7.39-7.41 (d, 1H), 7.46-7.51 (m, 2H), 7.63-7.64 (d, 1H), 7.71-7.85 (m, 7H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH2:11][CH2:10][NH:9]2)=[CH:4][CH:3]=1.[F:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]=[C:26]=[O:27])=[CH:21][CH:20]=1>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH2:11][CH2:10][N:9]2[C:26]([NH:25][C:22]2[CH:23]=[CH:24][C:19]([F:18])=[CH:20][CH:21]=2)=[O:27])=[CH:4][CH:3]=1
Reactant: O=C=Nc1ccc(F)cc1
Reactant: Clc1ccc(C2NCCc3ccccc32)cc1
Solvent: ClCCl
Product: O=C(Nc1ccc(F)cc1)N1CCc2ccccc2C1c1ccc(Cl)cc1
Reaction time: 3 h

Procedure:
To a solution of 1-(4-chlorophenyl)-1,2,3,4-tetrahydroisoquinoline (150 mg, 615 μmol) in CH2Cl2 (2.0 mL) at RT was added 1-fluoro-4-isocyanatobenzene (85.8 μL, 739 μmol). The reaction was stirred 3 h and then directly purified by reverse phase HPLC to give the title compound as a white solid. MS (ESI pos. ion) m/z: 381 (M+1).
Reaction SMILES: [CH3:1][C:2]([CH:4]=O)=O.[NH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[NH2:13]>>[CH3:1][C:2]1[CH:4]=[N:13][C:8]2[C:7](=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:6]=1
Reactant: CC(=O)C=O
Reactant: Nc1ccccc1N
Product: Cc1cnc2ccccc2n1

Procedure:
Methylglyoxal was estimated by derivatization of methylglyoxal with 1,2-diaminobenzene to produce 2-methylquinoxaline according to the method of Cordeiro and Freire (1996) with some modifications.
Reaction SMILES: [CH2:1]([C:8]1[C:16]([C:17]2[CH:22]=[CH:21][N:20]=[C:19]([NH:23][CH:24]3[CH2:28][CH2:27][CH2:26][CH2:25]3)[N:18]=2)=[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][N:10]2[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([N-]C(C)C)(C)C.[Li+].C(Cl)(Cl)(Cl)[Cl:38]>O1CCCC1>[CH2:1]([C:8]1[C:16]([C:17]2[CH:22]=[CH:21][N:20]=[C:19]([NH:23][CH:24]3[CH2:25][CH2:26][CH2:27][CH2:28]3)[N:18]=2)=[C:11]2[CH:12]=[CH:13][CH:14]=[C:15]([Cl:38])[N:10]2[N:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(Cc2nn3ccccc3c2-c2ccnc(NC3CCCC3)n2)cc1
Reactant: ClC(Cl)(Cl)Cl
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Clc1cccc2c(-c3ccnc(NC4CCCC4)n3)c(Cc3ccccc3)nn12
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 26.5 %

Procedure:
To a cold (−78° C.) solution of 4-(2-benzylpyrazolo[1,5-a]pyridin-3-yl)-N-cyclopentyl-2-pyrimidinamine (207 mg, 0.560 mmol) in tetrahydrofuran (7 mL) was added lithium diisopropylamide (17.5 mL, 0.16 M in tetrahydrofuran, 2.80 mmol). The reaction mixture was stirred at −78° C. for 45 minutes, then carbon tetrachloride (542 μl, 5.60 mmol) was added. The reaction mixture was stirred for an additional 30 minutes at −78° C. The reaction mixture was quenched with water, warmed to room temperature, and extracted with ethyl acetate. The organic layer was washed with water and brine, then dried over magnesium sulfate. Filtration and concentration, followed by flash chromatography (4:1 hexanes:ethyl acetate) provided 4-(2-benzyl-7-chloropyrazolo[1,5-a]pyridin-3-yl)-N-cyclopentyl-2-pyrimidinamine (60 mg, 27%) as a yellow solid. 1H NMR (CDCl3) δ 8.35 (d, 1H), 8.21 (d, 1H), 7.35–7.16 (m, 6H), 7.04 (d, 1H), 6.64 (d, 1H), 5.20 (d, 1H), 4.60 (s, 2H), 4.37 (m, 1H), 2.09 (m, 2H), 1.82–1.48 (m, 6H); MS m/z 404 (M+1).
Reaction SMILES: S(Cl)([Cl:3])=O.[C:5]1([NH:11][C:12](=[O:22])[NH:13][C:14]2[CH:21]=[CH:20][C:17]([CH2:18]O)=[CH:16][CH:15]=2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>ClCCl>[C:5]1([NH:11][C:12](=[O:22])[NH:13][C:14]2[CH:21]=[CH:20][C:17]([CH2:18][Cl:3])=[CH:16][CH:15]=2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(Nc1ccccc1)Nc1ccc(CO)cc1
Solvent: ClCCl
Product: O=C(Nc1ccccc1)Nc1ccc(CCl)cc1
Temperature: 40 °C
Reaction time: 1 h

Procedure:
42 g (354 mmol) of thionyl chloride were added dropwise at 30° C. to a suspension of 42.8 g (177 mmol) of 4-(3-phenylureido)benzyl alcohol in 500 ml of dichloromethane. The mixture was subsequently stirred at 40° C. for 1 hour. After completion of the evolution of gas, the mixture was allowed to cool to room temperature. The precipitated product was filtered off with suction and washed with dichloromethane. Yield: 44.26 g (96%).
Reaction SMILES: [CH3:1][C:2]([CH3:32])([CH3:31])[C:3]([C:5]1[C:13]2[C:8](=[N:9][CH:10]=[C:11]([NH:14][C:15]3[CH:22]=[CH:21][C:18]([CH:19]=O)=[CH:17][CH:16]=3)[N:12]=2)[N:7]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[CH:6]=1)=[O:4].[O:33]=[C:34]([N:38]1[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]1)[CH2:35][C:36]#[N:37].N1CCCCC1>CO>[CH3:1][C:2]([CH3:32])([CH3:31])[C:3]([C:5]1[C:13]2[C:8](=[N:9][CH:10]=[C:11]([NH:14][C:15]3[CH:22]=[CH:21][C:18]([CH:19]=[C:35]([C:34]([N:38]4[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]4)=[O:33])[C:36]#[N:37])=[CH:17][CH:16]=3)[N:12]=2)[N:7]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:28])[CH3:29])[CH:6]=1)=[O:4]
Reactant: CC(C)(C)C(=O)c1cn(COCC[Si](C)(C)C)c2ncc(Nc3ccc(C=O)cc3)nc12
Reactant: N#CCC(=O)N1CCCCC1
Solvent: CO
Solvent: C1CCNCC1
Product: CC(C)(C)C(=O)c1cn(COCC[Si](C)(C)C)c2ncc(Nc3ccc(C=C(C#N)C(=O)N4CCCCC4)cc3)nc12
Reaction time: 5 h
Yield: 59.6 %

Procedure:
To a 20 ml vial 4-[[7-(2,2-dimethylpropanoyl)-5-(2-trimethylsilylethoxymethyl)-pyrrolo[2,3-b]pyrazin-2-yl]amino]benzaldehyde (35 mg, 0.0800 mmol), 3-oxo-3-(1-piperidyl)propanenitrile (18.01 mg, 0.1200 mmol), piperdine (0.02 ml, 0.15 mmol) and 3-oxo-3-(1-piperidyl)propanenitrile (18.01 mg, 0.12 mmol), were taken in methanol (5 ml). To this reaction mixture, piperdine (0.02 ml, 0.15 mmol) was added drop wise at RT. After completion of the addition, the reaction mixture was stirred for 5 hrs. Ethanol was evaporated, the residue was loaded on silica gel column and elution with CH2Cl2 to MeOH 0-2, 3% yielded 28 mg of 3-[4-[[7-(2,2-dimethylpropanoyl)-5-(2-trimethylsilylethoxymethyl)pyrrolo[2,3-b]pyrazin-2-yl]amino]phenyl]-2-(piperidine-1-carbonyl)prop-2-enenitrile.
Reaction SMILES: C1([As](C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C([Sn](CCCC)(CCCC)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=1)CCC.[CH2:39]([N:45]1[CH2:50][CH:49]2[CH:47]([C:48]2([C:52]2[CH:57]=[CH:56][CH:55]=[C:54](I)[CH:53]=2)[CH3:51])[C:46]1=[O:59])[CH2:40][CH2:41][CH2:42][CH2:43][CH3:44]>O1CCCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:39]([N:45]1[CH2:50][CH:49]2[CH:47]([C:48]2([CH3:51])[C:52]2[CH:57]=[CH:56][CH:55]=[C:54]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=3)[CH:53]=2)[C:46]1=[O:59])[CH2:40][CH2:41][CH2:42][CH2:43][CH3:44]
Reactant: CCCCCCN1CC2C(C1=O)C2(C)c1cccc(I)c1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: c1ccc([As](c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCCCCCN1CC2C(C1=O)C2(C)c1cccc(-c2ccccn2)c1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 101.2 %

Procedure:
To tris(dibenzylideneacetone)dipalladium (0) (4.4 mg, 4.80 μmol) in tetrahydrofuran (1 ml) at room temperature was added triphenylarsine (5.9 mg, 19.2 μmol). After 5 min, 2-(tributylstannyl)pyridine (0.10 g, 0.29 mmol) in tetrahydrofuran (1 ml) was added followed by 3-hexyl-6-(3-iodophenyl)-6-methyl-3-azabicyclo[3.1.0]hexan-2-one (Preparation 67, 77 mg, 0.19 mmol) in tetrahydrofuran (1 ml). The reaction mixture was stirred at room temperature for 16 h and then refluxed for 2 h. The cooled reaction mixture was concentrated in vacuo and chromatographed on silica gel eluting with hexane:ethyl acetate (1:1 then 0:1) to give the title compound as a colourless oil (67 mg, 100%).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:16]([OH:18])=O)=[N:4][C:5]([C:8]2[C:13]([F:14])=[CH:12][CH:11]=[CH:10][C:9]=2[F:15])=[CH:6][N:7]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[C:52]([O:55][CH:56]1[C:60]2=[N:61][CH:62]=[C:63]([NH2:79])[C:64]([N:65]3[CH2:70][CH2:69][CH2:68][C@H:67]([NH:71][C:72]([O:74][C:75]([CH3:78])([CH3:77])[CH3:76])=[O:73])[CH2:66]3)=[C:59]2[CH2:58][CH2:57]1)(=[O:54])[CH3:53]>ClCCCl>[C:52]([O:55][CH:56]1[C:60]2=[N:61][CH:62]=[C:63]([NH:79][C:16]([C:3]3[C:2]([NH2:1])=[N:7][CH:6]=[C:5]([C:8]4[C:9]([F:15])=[CH:10][CH:11]=[CH:12][C:13]=4[F:14])[N:4]=3)=[O:18])[C:64]([N:65]3[CH2:70][CH2:69][CH2:68][C@H:67]([NH:71][C:72]([O:74][C:75]([CH3:78])([CH3:77])[CH3:76])=[O:73])[CH2:66]3)=[C:59]2[CH2:58][CH2:57]1)(=[O:54])[CH3:53]
Reactant: CC(=O)OC1CCc2c1ncc(N)c2N1CCC[C@H](NC(=O)OC(C)(C)C)C1
Reactant: Nc1ncc(-c2c(F)cccc2F)nc1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: CC(=O)OC1CCc2c1ncc(NC(=O)c1nc(-c3c(F)cccc3F)cnc1N)c2N1CCC[C@H](NC(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 41.2 %

Procedure:
To a pre-stirred solution of 3-amino-6-(2,6-difluorophenyl)pyrazine-2-carboxylic acid (18 mg, 0.070 mmol), HATU (32 mg, 0.084 mmol), and DIPEA (36 μL, 0.21 mmol) in 1,2-dichloroethane (0.3 mL) was added a solution of 3-amino-4-{(3S)-3-[(tert-butoxycarbonyl)amino]piperidin-1-yl}-6,7-dihydro-5H-cyclopenta[b]pyridin-7-yl acetate (38 mg, 0.097 mmol) in 1,2-dichloroethane (0.5 mL). The resulting solution was stirred at ambient temperature for 3 h. The crude reaction mixture was concentrated under reduced pressure and the residue was purified by flash chromatography (20 g silica gel column, eluting with 0-10% MeOH in DCM) to afford the sub-title compound (18 mg, 41%). LC/MS (ESI) calc. for C31H36F2N2O5(M+H)+: m/z=624.3. found: 624.1.