Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[Al](C)C.[N+:5]([C:8]1[CH:9]=[C:10]([CH:12]=[CH:13][C:14]=1[CH3:15])[NH2:11])([O-:7])=[O:6].C[O:17][C:18](=O)[C:19]1[CH:24]=[CH:23][C:22]([CH2:25][N:26]2[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]2)=[CH:21][CH:20]=1.C(C(C(C([O-])=O)O)O)([O-])=O.[Na+].[K+]>C1(C)C=CC=CC=1.C(Cl)Cl.COC(C)(C)C>[CH3:15][C:14]1[CH:13]=[CH:12][C:10]([NH:11][C:18](=[O:17])[C:19]2[CH:20]=[CH:21][C:22]([CH2:25][N:26]3[CH2:27][CH2:28][N:29]([CH3:32])[CH2:30][CH2:31]3)=[CH:23][CH:24]=2)=[CH:9][C:8]=1[N+:5]([O-:7])=[O:6]
Reactant: Cc1ccc(N)cc1[N+](=O)[O-]
Reactant: COC(=O)c1ccc(CN2CCN(C)CC2)cc1
Agent: C[Al](C)C
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: COC(C)(C)C
Solvent: ClCCl
Product: Cc1ccc(NC(=O)c2ccc(CN3CCN(C)CC3)cc2)cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of trimethylaluminium (2M in toluene, 1.3 ml, 2.6 mmol) is added over a period of 5 min to a solution of 3-nitro-4-methyl-aniline (152 mg, 1.00 mmol) and 4-(4-methyl-piperazin-1-ylmethyl)-benzoic acid methyl ester (248 mg, 1.00 mmol) in toluene (3.0 ml) at 45° C. under an atmosphere of argon. After gas evolution ceases, the dark brown reaction mixture is stirred 30 min before being cooled to 0° C. An aqueous saturated solution of potassium-sodium tartrate (20 ml), t-butyl methyl ether (15 ml) and methylene chloride (10 ml) are added sequentially. The organic phase is separated and washed with aqueous saturated NaHCO3 (10 ml) and aqueous saturated NaCl (10 ml). The aqueous phases are back-extracted with t-butyl methyl ether (2×15 ml). The organic phases are combined, dried over MgSO4 and concentrated in vacuo to give 383 mg (96 area % by HPLC) of the title compound as pale yellow crystals.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10]3=[CH:12][S:13][CH:14]=[C:9]3[C:8](SC)=[N:7][C:6]=2[CH:17]=1.O.[C:19]1([N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(O)(=O)C>[OH:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10]3=[CH:12][S:13][CH:14]=[C:9]3[C:8]([N:28]3[CH2:29][CH2:30][N:25]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH2:26][CH2:27]3)=[N:7][C:6]=2[CH:17]=1
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: CSC1=Nc2cc(O)ccc2Nc2cscc21
Solvent: O
Solvent: CC(=O)O
Product: Oc1ccc2c(c1)N=C(N1CCN(c3ccccc3)CC1)c1cscc1N2

Procedure:
A solution of 7-hydroxy-10-(methylthio)-4H-thieno[3,4-b][1,5]benzodiazepine in excess N-phenylpiperazine and glacial acetic acid is heated at 140°-160°C. for 2 days. The solution is poured into water and the product is collected.
Reaction SMILES: [F:1][C:2]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:3]=1[CH2:4][N:5]1[C:14]([C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=2)=[CH:13][C:12]2[C:7](=[CH:8][C:9]([F:22])=[CH:10][CH:11]=2)[C:6]1=[O:23].[C:29]1(B(O)O)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C(N(CC)CC)C>C(Cl)Cl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[F:1][C:2]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:3]=1[CH2:4][N:5]1[C:14]([C:15]2[CH:16]=[CH:17][C:18]([O:21][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[CH:19][CH:20]=2)=[CH:13][C:12]2[C:7](=[CH:8][C:9]([F:22])=[CH:10][CH:11]=2)[C:6]1=[O:23]
Reactant: O=c1c2cc(F)ccc2cc(-c2ccc(O)cc2)n1Cc1ccc(F)cc1F
Reactant: OB(O)c1ccccc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=c1c2cc(F)ccc2cc(-c2ccc(Oc3ccccc3)cc2)n1Cc1ccc(F)cc1F
Reaction time: 0.17 h
Yield: 45 %

Procedure:
To a solution of 2-(2,4-difluorobenzyl)-7-fluoro-3-(4-hydroxyphenyl)-2H-isoquinolin-1-one (54 mg, 0.14 mmol), a compound of formula (Id), in CH2Cl2 (8 mL) was added phenylboronic acid (35 mg, 0.28 mmol), copper (II) acetate (51 mg, 0.28 mmol), and powdered activated 4 Å molecular sieves (500 mg). The mixture was stirred for 10 minutes then treated with triethylamine (99 μL, 0.71 mmol). The resulting suspension was stirred for 72 hours at ambient temperature. The mixture was then filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by preparative thin-layer chromatography on silica gel eluting with 25% EtOAc/hexanes to afford 2-(2,4-difluorobenzyl)-7-fluoro-3-(4-phenoxyphenyl)-2H-isoquinolin-1-one, a compound of formula (Id), (29 mg, 45% yield) as a white solid. 1H-NMR (400 MHz, CDCl3): δ 8.11 (1H, dd, J=9.4, 2.8 Hz), 7.52 (1H, dd, J=8.6, 5.1 Hz), 7.45-7.36 (3H, m), 7.19-7.14 (1H, m), 7.14-7.09 (2H, m), 7.08-7.03 (2H, m), 7.02-6.93 (3H, m), 6.78-6.72 (1H, m), 6.70-6.64 (1H, m), 6.47 (1H, s), 5.24 (2H, s) ppm.
Reaction SMILES: C(O)(=O)C.[F:5][C:6]1[CH:11]=[C:10]([N+:12]([O-])=O)[C:9]([O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[OH:22])=[CH:8][C:7]=1[NH:23][C:24](=[O:26])[CH3:25].C(OCC)(=O)C>[Fe].O>[NH2:12][C:10]1[C:9]([O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[OH:22])=[CH:8][C:7]([NH:23][C:24](=[O:26])[CH3:25])=[C:6]([F:5])[CH:11]=1
Reactant: CC(=O)Nc1cc(Oc2ccccc2O)c([N+](=O)[O-])cc1F
Agent: [Fe]
Solvent: CC(=O)O
Solvent: O
Solvent: CCOC(C)=O
Product: CC(=O)Nc1cc(Oc2ccccc2O)c(N)cc1F
Temperature: 80 °C
Yield: 82.3 %

Procedure:
Into a mixture of 25 ml of acetic acid and 25 ml of water was added 9.5 g of an iron powder, and the mixture was heated to 80° C. Into the mixture was added dropwise a solution composed of 10.0 g of N-[2-fluoro-5-(2-hydroxyphenoxy)-4-nitrophenyl]acetamide and 100 ml of ethyl acetate. The mixture was heated for 1 hour under reflux, then, poured into water, extracted with ethyl acetate, the organic layer was washed with water, and washed with saturated aqueous sodium bicarbonate, dried over magnesium sulfate, and concentrated to obtain 7.42 g of N-[4-amino-2-fluoro-5-(2-hydroxyphenoxy)phenyl]acetamide.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:17]=[C:16]([C:18]([OH:20])=O)[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]=2)=[CH:4][CH:3]=1.Cl.[OH:22][C:23]1[C:32]([CH3:33])=[CH:31][CH:30]=[C:29]2[C:24]=1[CH2:25][CH2:26][NH:27][CH2:28]2>>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:17]=[C:16]([C:18]([N:27]3[CH2:26][CH2:25][C:24]4[C:29](=[CH:30][CH:31]=[C:32]([CH3:33])[C:23]=4[OH:22])[CH2:28]3)=[O:20])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]=2)=[CH:6][CH:7]=1
Reactant: Cc1ccc(-c2nc(C(=O)O)c3ccccc3n2)cc1
Reactant: Cc1ccc2c(c1O)CCNC2
Agent: Cl
Product: Cc1ccc(-c2nc(C(=O)N3CCc4c(ccc(C)c4O)C3)c3ccccc3n2)cc1
Yield: 30 %

Procedure:
Reaction of 2-(4-methylphenyl)quinazoline-4-carboxylic acid with 5-hydroxy-6-methyl-1,2,3,4-tetrahydroisoquinoline hydrochloride gave compound 16 (30% yield) as a white solid. 1H NMR (300 MHz, CDCl3) δ 2.25 and 2.28 (2s, 3H), 2.48 (s, 3H), 2.81 and 3.05 (2t, 2H), 3.60 and 4.23 (2t, 2H), 4.50 and 5.09 (2s, 2H), 6.36-6.92 (m, 2H), 7.08 (2d, 1H), 7.37-7.64 (m, 3H), 7.97-8.06 (m, 2H), 8.37 (m, 1H), 8.60 (m, 2H); MS (ESI) m/z 410 ([M+H]+).
Reaction SMILES: [CH3:1][N:2]([CH3:15])[C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:14])[CH2:8]2)=[O:4].[O:16]=[C:17]1[C:22]2=[CH:23][NH:24][C:25]([CH:26]=O)=[C:21]2[CH2:20][CH2:19][NH:18]1.N1CCCCC1>C(O)C>[CH3:1][N:2]([CH3:15])[C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:14])[C:8]2=[CH:26][C:25]1[NH:24][CH:23]=[C:22]2[C:21]=1[CH2:20][CH2:19][NH:18][C:17]2=[O:16])=[O:4]
Reactant: O=Cc1[nH]cc2c1CCNC2=O
Reactant: CN(C)C(=O)c1ccc2c(c1)CC(=O)N2
Solvent: CCO
Solvent: C1CCNCC1
Product: CN(C)C(=O)c1ccc2c(c1)C(=Cc1[nH]cc3c1CCNC3=O)C(=O)N2
Temperature: 80 °C

Procedure:
A mixture of 2-oxo-2,3-dihydro-1H-indole-5-carboxylic acid dimethylamide (40.8 mg, 0.2 mmol), 4-oxo-4,5,6,7-tetrahydro-2H-pyrrolo[3,4-c]pyridine-1-carbaldehyde (1 eq.) and 0.1 mL of piperidine in ethanol (1 mL) was heated in a sealed tube at 80° C. for 3 hours. The precipitate was collected by vacuum filtration, washed with ethanol and dried to give the title compound as a yellow solid.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[CH:9]=[C:8]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][CH:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)=[C:13]([C:26]([F:29])([F:28])[F:27])[CH:12]=3)[N:7]=[C:6]([C:30]#[N:31])[C:5]=2[N:4]=[N:3]1.[C:32](Cl)(=[O:34])[CH3:33].C(N(C(C)C)C(C)C)C>ClCCl.CO>[C:32]([N:23]1[CH2:22][CH2:21][CH:20]([CH2:19][CH2:18][O:17][C:14]2[CH:15]=[CH:16][C:11]([C:8]3[N:7]=[C:6]([C:30]#[N:31])[C:5]4[N:4]=[N:3][N:2]([CH3:1])[C:10]=4[CH:9]=3)=[CH:12][C:13]=2[C:26]([F:29])([F:28])[F:27])[CH2:25][CH2:24]1)(=[O:34])[CH3:33]
Reactant: CC(=O)Cl
Reactant: Cn1nnc2c(C#N)nc(-c3ccc(OCCC4CCNCC4)c(C(F)(F)F)c3)cc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CO
Product: CC(=O)N1CCC(CCOc2ccc(-c3cc4c(nnn4C)c(C#N)n3)cc2C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1-Methyl-6-(4-(2-(piperidin-4-yl)ethoxy)-3-(trifluoromethyl)phenyl)-1H-[1,2,3]triazolo[4,5-c]pyridine-4-carbonitrile (50 mg), acetyl chloride (0.041 ml), and N-ethyl-N-isopropylpropan-2-amine (0.096 ml) were combined in dichloromethane (1 ml) and the reaction mixture stirred at room temperature for 2 hours. Washed with water the organic layer was separated, dried, and blown down to afford crude product. Solid was suspended in methanol and filtered off to afford the title compound (29.1 mg).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=1.ClCCCl.CC(O)(C)C.[NH2:22][C:23]1[CH:28]=[CH:27][C:26]([CH:29]2[CH2:34][CH2:33][N:32]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:31][CH2:30]2)=[C:25]([F:42])[CH:24]=1.CCN(CC)CC>CO.[Cl-].[Zn+2].[Cl-]>[Cl:8][C:6]1[C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=[C:2]([NH:22][C:23]2[CH:28]=[CH:27][C:26]([CH:29]3[CH2:34][CH2:33][N:32]([C:35]([O:37][C:38]([CH3:40])([CH3:39])[CH3:41])=[O:36])[CH2:31][CH2:30]3)=[C:25]([F:42])[CH:24]=2)[N:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(N)cc2F)CC1
Reactant: FC(F)(F)c1cnc(Cl)nc1Cl
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CC(C)(C)O
Solvent: CCN(CC)CC
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(Nc3ncc(C(F)(F)F)c(Cl)n3)cc2F)CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Zinc(II) chloride (1.0 M in Et2O; 1.08 mL, 1.08 mmol) was added to a solution of 2,4-dichloro-5-(trifluoromethyl)pyrimidine (0.216 g, 0.994 mmol) in 1:1 DCE/t-BuOH (8 mL) at 0° C. under a nitrogen atmosphere. The resulting mixture was stirred for 1 hour at 0° C. then tert-butyl 4-(4-amino-2-fluorophenyl)piperidine-1-carboxylate (A28) (0.266 g, 0.904 mmol) in 1:1 DCE/t-BuOH (8 mL) was added. A solution of Et3N (0.139 mL, 0.994 mmol) in 1:1 DCE/t-BuOH (5 mL) was then added dropwise at 0° C. and the resulting mixture was vigorously stirred for a further 30 minutes at 0° C., then at room temperature for 18 hours. The volatiles removed in vacuo to afford a brown residue which was purified by silica gel column chromatography (Biotage Isolera, 25 g SiO2 Cartridge, 0-20% EtOAc in petroleum benzine 40-60° C.) to yield a pale yellow solid. The solid was suspended in MeOH (15 mL) and water (15 mL) and the resulting suspension filtered to afford the title compound A29 as a white solid (0.363 g, 85%); 1H NMR (400 MHz, CDCl3) δ 8.59 (s, 1H), 7.59-7.47 (m, 2H), 7.20-7.14 (m, 1H), 4.37-4.14 (m, 2H), 2.98 (tt, J=12.1, 3.4 Hz, 1H), 2.83 (t, J=11.7 Hz, 2H), 1.80 (d, J=12.8 Hz, 2H), 1.71-1.55 (m, 3H), 1.48 (s, 9H). LCMS-A: rt 6.902 min; m/z 473.1 [M−H]−.
Reaction SMILES: Br[C:2]1[S:6][C:5]([C:7]2[N:8]=[C:9]3[CH:14]=[N:13][CH:12]=[CH:11][N:10]3[C:15]=2[NH:16][C:17]([CH3:24])([CH3:23])[CH2:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:4][CH:3]=1.[C:25]1([C:31]#[CH:32])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(N(CC)CC)C.C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C.CC(=O)OCC.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>[C:25]1([C:31]#[C:32][C:2]2[S:6][C:5]([C:7]3[N:8]=[C:9]4[CH:14]=[N:13][CH:12]=[CH:11][N:10]4[C:15]=3[NH:16][C:17]([CH3:24])([CH3:23])[CH2:18][C:19]([CH3:21])([CH3:20])[CH3:22])=[CH:4][CH:3]=2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: CC(C)(C)CC(C)(C)Nc1c(-c2ccc(Br)s2)nc2cnccn12
Reactant: C#Cc1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC(C)(C)CC(C)(C)Nc1c(-c2ccc(C#Cc3ccccc3)s2)nc2cnccn12
Temperature: 50 °C
Reaction time: 16 h
Yield: 87.8 %

Procedure:
3.65 g (9.0 mmol) of [2-(5-bromothiophen-2-yl)-imidazo[1,2-a]pyrazin-3-yl]-(1,1,3,3-tetra-methyl-butyl)-amine were dissolved together with 1.18 ml (10.8 mmol) of phenylacetylene, 0.16 g (0.23 mmol) of bis(triphenylphosphine)-palladium(II) chloride and 0.08 g (0.45 mmol) of copper(I) iodide in DMF (30 ml). After addition of 2.50 ml (18.00 mmol) of triethylamine, the mixture was stirred at 50° C. for 16 h. The reaction solution was then diluted with EA and combined with a sat. aq. sodium carbonate solution. The phases were separated and the aqueous phase extracted with EA. The combined organic phases were washed 2× with a sat. aq. sodium carbonate solution and dried over magnesium sulfate. After filtration and removal of the solvents under a vacuum, column chromatography (EA/DIPE/DCM 3:3:4) was carried out with the group, after which 3.38 g (7.9 mmol, 88% of theoretical) of [2-(5-phenylethynyl-thiophen-2-yl)-imidazo[1,2-a]pyrazin-3-yl]-(1,1,3,3-tetramethyl-butyl)-amine were obtained.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1.[Cl:10][C:11]1[CH:16]=[C:15]([Cl:17])[C:14]([O:18][CH3:19])=[CH:13][C:12]=1[NH:20][C:21]1[C:26]([C:27]#[N:28])=[CH:25][N:24]=[C:23]2[CH:29]=[C:30]([C:32]3[CH:37]=[CH:36][C:35]([CH:38]=O)=[CH:34][CH:33]=3)[S:31][C:22]=12.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl.CN(C)C=O.C(O)(=O)C>[Cl:10][C:11]1[CH:16]=[C:15]([Cl:17])[C:14]([O:18][CH3:19])=[CH:13][C:12]=1[NH:20][C:21]1[C:26]([C:27]#[N:28])=[CH:25][N:24]=[C:23]2[CH:29]=[C:30]([C:32]3[CH:37]=[CH:36][C:35]([CH2:38][N:7]4[CH2:8][CH2:9][N:4]([CH2:3][CH2:2][OH:1])[CH2:5][CH2:6]4)=[CH:34][CH:33]=3)[S:31][C:22]=12
Reactant: OCCN1CCNCC1
Reactant: COc1cc(Nc2c(C#N)cnc3cc(-c4ccc(C=O)cc4)sc23)c(Cl)cc1Cl
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Solvent: ClCCl
Product: COc1cc(Nc2c(C#N)cnc3cc(-c4ccc(CN5CCN(CCO)CC5)cc4)sc23)c(Cl)cc1Cl
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 35.2 %

Procedure:
4-(2-Hydroxyethyl)piperazine (104 mg, 0.80 mmol) is added to a suspension of 7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-(4-formylphenyl)thieno[3,2-b]pyridine-6-carbonitrile (227 mg, 0.50 mmol) in 15 mL of dichloromethane and 1 mL of N,N-dimethylformamide. The reaction mixture is cooled to 0° C. and sodium triacetoxyborohydride (800 mg, 3.8 mmol) is added. After stirring at 0° C. for 1.5 hours, 2 drops of acetic acid are added and the reaction mixture is allowed to warm to room temperature and stirred overnight. The reaction is quenched by the addition of water and then partitioned between aqueous sodium bicarbonate and dichloromethane. The organic layer is dried over sodium sulfate, filtered and concentrated in vacuo. The residue is purified by flash column chromatography eluting with 10% methanol in dichloromethane to provide 100 mg of 7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-(4-{[4-(2-hydroxyethyl)piperazin-1-yl]methyl}phenyl)thieno[3,2-b]pyridine-6-carbonitrile as white crystals, mp 189–190° C.; 1H NMR (DMSO-d6) δ 2.27–2.44 (m, 10H), 3.41–3.50 (m, 4H), 3.85 (s, 3H), 4.36 (s, 1H), 7.37 (s, 1H), 7.40 (d, J=8 Hz, 2H), 7.67 (d, J=8 Hz, 2H), 7.76 (s, 1H), 7.89 (s, 1H), 8.60 (s, 1H), 9.74 (s, 1H); MS 566.3 (M−H)−.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][C:7]#[N:8])=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:18](OC(=O)C)(=[O:20])[CH3:19]>ClCCl.C(OCC)(=O)C>[C:18]([NH:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][C:7]#[N:8])=[CH:4][CH:3]=1)(=[O:20])[CH3:19]
Reactant: N#CCc1ccc(N)cc1
Reactant: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(=O)Nc1ccc(CC#N)cc1
Temperature: 0 °C
Reaction time: 18 h

Procedure:
To a cooled (0° C.) and stirred solution of 4-aminobenzyl cyanide (2.38 g, 18.04 mmol) in anhydrous dichloromethane (30 ml) was added anhydrous triethylamine (7.54 ml, 54.12 mmol) followed by acetic anhydride (2.56 ml, 27.06 mmol) under nitrogen. The mixture was allowed to warm to room temperature and it was stirred for 18 h before it was diluted with ethyl acetate (150 ml) and-washed with 10% aqueous sodium bicarbonate (100 ml), 2M hydrochloric acid (50 ml), brine (50 ml), then dried (MgSO4) and concentrated to give 4-(acetylamino)benzyl cyanide as an orange solid. The crude nitrile (2.8 g) was dissolved in absolute ethanol (200 ml) and chloroform (4 ml) and it was hydrogenated at 50 psi over platinum (IV) oxide for 16 h. The catalyst was filtered off, washed with ethanol and the filtrate was concentrated under vacuum. The residue was dissolved in 2M sodium hydroxide (30 ml) and the product was extracted with dichloromethane (4×150 ml), then dried (Na2SO4) and concentrated. Flash chromatography of the residue (silica gel, dichloromethane/methanol/ammonia, 85:15:1.5) gave 2.3 g (80%) of the title compound as a yellow solid. δ (360 MHz, CDCl3) 2.16 (3H, s), 2.71 (2H, t, J=6.8 Hz), 2.94 (2H, t, J=6.8 Hz), 7.14 (2H, d, J=8.3 Hz), 7.26 (1H, br s), 7.41 (2H, d, J=8.3 Hz).
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[C:5]([CH3:13])[N:4]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][NH2:22])=[CH:16][CH:15]=2)[N:3]=1.ClCCl.C(N(CC)CC)C.[C:33](Cl)(=[O:41])[O:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>O>[CH3:1][C:2]1[C:6]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[C:5]([CH3:13])[N:4]([C:14]2[CH:15]=[CH:16][C:17]([CH2:20][CH2:21][NH:22][C:33](=[O:41])[O:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)=[CH:18][CH:19]=2)[N:3]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: Cc1nn(-c2ccc(CCN)cc2)c(C)c1-c1ccccc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1nn(-c2ccc(CCNC(=O)Oc3ccccc3)cc2)c(C)c1-c1ccccc1
Reaction time: 1 h
Yield: 81.9 %

Procedure:
To a stirred solution of 2-[4-(3,5-dimethyl-4-phenyl-1H-pyrazol-1-yl)phenyl]ethylamine (step 3 of Example 14, 1.36 g, 4.66 mmol), dichloromethane (30 m]L) and triethylamine (0.78 mL, 5.60 mmol) was added phenyl chlorocarbonate (0.64 mL, 5.13 mmol) slowly at room temperature. After 1 h, the mixture was poured into water and extracted with dichloromethane. The organic fraction was dried over MgSO4 and concentrated under reduced pressure. The residue was purified by silica-gel column chromatography eluting with hexane/ethyl acetate (2:1) to afford 1.57 g (82%) of the title compound as white solids: MS (ESI) m/z 412 [M+H]+, 1H-NMR (CDCl3) δ 7.48-7.10 (14H, m), 5.06 (1H, br.s), 3.60-3.53 (2H, m), 2.96 (2H, t, J=6.8 Hz), 2.34 (3H, s), 2.31 (3H, s).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1.C1C=C(Cl)C=C(C(OO)=[O:17])C=1.CCOC(C)=O>C(Cl)(Cl)Cl>[CH3:1][C:2]1[CH:3]=[N+:4]([O-:17])[CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1cncc(C)c1
Solvent: ClC(Cl)Cl
Solvent: CCOC(C)=O
Product: Cc1cc(C)c[n+]([O-])c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 93.4 %

Procedure:
To a solution of 3,5-dimethylpyridine (85 g, 0.8 mol) in CHCl3 (1500 mL) was added m-CPBA (180 g, 0.88 mol) in portions at 0° C. Then the mixture was stirred at room temperature for 18 hr. TLC (petroleum ether:EtOAc=1:1) showed the starting material was consumed almost. After diluting with CH2Cl2 (1200 mL), the solution was washed with Na2S2O3(aq.) (600 mL), NaHCO3(aq.) (600 mL) and brine (600 mL). The resulting material was dried over Na2SO4 and concentrated in vacuo to give crude material which was purified by chromatography on silica gel with EtOAc:CH2Cl2=4:1 to afford 3,5-dimethylpyridine 1-oxide (92 g, 93%) as light yellow solid.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[Br:6][CH2:7][CH2:8][CH2:9]Br.[H-].[Na+]>C1COCC1>[Br:6][CH2:7][CH2:8][CH2:9][N:1]1[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: BrCCCBr
Reactant: c1c[nH]cn1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: BrCCCn1ccnc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 30 %

Procedure:
To a stirred solution of imidazole (500 mg, 7.35 mmol) and 1,3-dibromopropane (2.2 mL, 22.0) in THF (35 mL) was added 60% NaH (356 mg, 8.82 mmol), and the resultant mixture was refluxed for 1H and stirred at room temperature overnight. The mixture was quenched with H2O (25 mL) and diluted with CH2Cl2 (40 mL). The aqueous phase was separated and extracted with CH2Cl2 (3×15 mL). The combined organic extracts were dried (Na2SO4), filtered, and concentrated to dryness. Purification by flash chromatography on silica gel (CH2Cl2/MeOH, 97:3) provided 1-(3-Bromo-propyl)-1H-imidazole (410 mg, 30%) as a colorless oil. 1H NMR (CDCl3) δ 2.20-2.34 (m, 2H), 3.31 (t, 2H, J=6.3 Hz), 4.16 (t, 2H, J=6.2 Hz), 6.93 (s, 1H), 7.08 (s, 1H), 7.51 (s, 1H).
Reaction SMILES: CCN(C(C)C)C(C)C.[NH2:10][C:11]1[N:12]=[CH:13][C:14]([C:21]2[CH:31]=[CH:30][C:24]([C:25]([N:27]([CH3:29])[CH3:28])=[O:26])=[CH:23][CH:22]=2)=[N:15][C:16]=1[C:17]([NH:19][NH2:20])=[O:18].Cl[C:33](Cl)([O:35]C(=O)OC(Cl)(Cl)Cl)Cl>C(Cl)Cl>[NH2:10][C:11]1[N:12]=[CH:13][C:14]([C:21]2[CH:22]=[CH:23][C:24]([C:25]([N:27]([CH3:28])[CH3:29])=[O:26])=[CH:30][CH:31]=2)=[N:15][C:16]=1[C:17]1[O:18][C:33](=[O:35])[NH:20][N:19]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CN(C)C(=O)c1ccc(-c2cnc(N)c(C(=O)NN)n2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CN(C)C(=O)c1ccc(-c2cnc(N)c(-c3n[nH]c(=O)o3)n2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 98 %

Procedure:
DIPEA (86.08 mg, 116.0 μL, 0.6660 mmol) was added to a solution of 4-(5-amino-6-(hydrazinecarbonyl)pyrazin-2-yl)-N,N-dimethylbenzamide (100 mg, 0.3330 mmol) in DCM (6.500 mL) under nitrogen. A solution of triphosgene (39.53 mg, 0.1332 mmol) in DCM (100.0 μL) was then added dropwise to the stirred solution. The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was filtered and the solid obtained dried under vacuum to yield the product (106. g mg, 98% yield); 1H NMR (400.0 MHz, DMSO) d 2.96 (s, 3H), 3.00 (s, 3H), 7.33 (br s, 2H), 7.52 (d, 2H), 8.09 (d, 2H), 8.89 (s, 1H) and 12.98 (br s, 1H) ppm; MS (ES+) 327.12
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([C:12]#[N:13])[CH:8]=[N:9]2)=[CH:4][CH:3]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C(=O)([O-])[O-].[Cs+].[Cs+].[O:62]=[C:63]1[NH:68][CH2:67][CH2:66][N:65]([C:69]([O:71][C:72]([CH3:75])([CH3:74])[CH3:73])=[O:70])[CH2:64]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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:12]([C:7]1[CH:8]=[N:9][C:10]2[C:5]([CH:6]=1)=[CH:4][CH:3]=[C:2]([N:68]1[CH2:67][CH2:66][N:65]([C:69]([O:71][C:72]([CH3:74])([CH3:73])[CH3:75])=[O:70])[CH2:64][C:63]1=[O:62])[CH:11]=2)#[N:13]
Reactant: N#Cc1cnc2cc(Cl)ccc2c1
Reactant: CC(C)(C)OC(=O)N1CCNC(=O)C1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: CC(C)(C)OC(=O)N1CCN(c2ccc3cc(C#N)cnc3c2)C(=O)C1
Temperature: 100 °C

Procedure:
To a 25 mL flask was added a stir bar, 7-chloroquinoline-3-carbonitrile (0.15 g, 0.79 mmol), Pd2 dba3 (0.072 g, 0.08 mmol), Xantphos (0.090 g, 0.16 mmol), cesium carbonate (0.36 g, 1.13 mmol) and tert-butyl 3-oxopiperazine-1-carboxylate (0.31 g, 1.6 mmol). The resulting mixture was degassed and purged with N2 (3×). To the flask was added 1,4 dioxane (10 mL). The resulting reaction mixture was then refluxed at 100° C. for overnight. Analysis of the reaction mixture by LC indicated that reaction had gone to completion. The solution was concentrated in vacuo and the resulting crude was dissolved in EtOAc and washed with brine, then dried over Na2SO4, filtered and concentrated in vacuo. The crude residue was then subjected for purification by silica gel column chromatography (10% MeOH in DCM) to provide the title product.