Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([NH2:9])=[N:5][CH:6]=[CH:7][CH:8]=1.Br[CH2:11][C:12](=O)[CH:13]([CH3:15])[CH3:14].C(=O)([O-])O.[Na+]>C(O)C>[CH:13]([C:12]1[N:9]=[C:4]2[C:3]([O:2][CH3:1])=[CH:8][CH:7]=[CH:6][N:5]2[CH:11]=1)([CH3:15])[CH3:14]
Reactant: CC(C)C(=O)CBr
Reactant: COc1cccnc1N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: COc1cccn2cc(C(C)C)nc12
Temperature: 110 °C
Reaction time: 13 h
Yield: 49 %

Procedure:
[step 1] Commercially available 3-methoxypyridin-2-amine (1.0 g, 8.06 mmol) was dissolved in ethanol (8.1 mL), 1-bromo-3-methylbutan-2-one (Organic Syntheses, 1976, vol. 55, p 24; 1.46 g, 8.86 mmol) was added, and the mixture was stirred at 110° C. for 13 hr. To the mixture was added saturated aqueous sodium hydrogen carbonate, and the mixture was extracted 3 times with chloroform. The combined organic layers were dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=100/0 v/v-30/70 v/v) to give 2-isopropyl-8-methoxyimidazo[1,2-a]pyridine (746 mg, 49%).
Reaction SMILES: [CH3:1][N:2]1[CH2:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[NH:5][CH:4]([CH2:13][C:14]([O:16][CH3:17])=[O:15])[C:3]1=[O:18].[Br:19]N1C(=O)CCC1=O>C(Cl)Cl>[Br:19][C:10]1[CH:11]=[CH:12][C:6]2[NH:5][CH:4]([CH2:13][C:14]([O:16][CH3:17])=[O:15])[C:3](=[O:18])[N:2]([CH3:1])[CH2:8][C:7]=2[CH:9]=1
Reactant: COC(=O)CC1Nc2ccccc2CN(C)C1=O
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Product: COC(=O)CC1Nc2ccc(Br)cc2CN(C)C1=O
Temperature: 28 °C
Reaction time: 1 h
Yield: 93 %

Procedure:
Methyl 2,3,4,5-tetrahydro-4-methyl-3-oxo-1H-1,4-benzodiazepine-2-acetate (100 g, 0.4 mole) and n-Bu4 N Br (13 g, 0.04 mole) were added to CH2Cl2 (1.0 liter) and refluxed for 0.5 hr. The reaction mixture was cooled to 28° C. and N-Bromosuccinimide added in small portions (72.8 g, 0.41 mole). The reaction was stirred at ambient temperature for 1.0 hr then washed with 5% NaHCO3 solution (400 ml) then water (2×400 ml) CH2Cl2 (800 ml) was replaced with hexane (800 ml) via ‘put and take’ distillation, the resulting slurry was cooled, filtered and washed with hexane. The product was dried in vacuo to yield the title compound (123 g, 93%). HPLC analysis showed 0.7% residual starting material and 0.7% 7,9-dibromide.
Reaction SMILES: [OH:1][N:2]=[C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][O:13]/[N:14]=[C:15](\[C:22]2[N:26]([CH3:27])[C:25](=[O:28])[O:24][N:23]=2)/[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:7]=1)[CH3:4].I[CH2:30][CH:31]1[CH2:33][CH2:32]1.C(=O)([O-])[O-].[Cs+].[Cs+].[I-].[K+]>CN(C=O)C.O>[CH:31]1([CH2:30][O:1][N:2]=[C:3]([NH:5][C:6]2[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][O:13]/[N:14]=[C:15](\[C:22]3[N:26]([CH3:27])[C:25](=[O:28])[O:24][N:23]=3)/[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[N:7]=2)[CH3:4])[CH2:33][CH2:32]1
Reactant: CC(=NO)Nc1cccc(CO/N=C(/c2ccccc2)c2noc(=O)n2C)n1
Reactant: ICC1CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=NOCC1CC1)Nc1cccc(CO/N=C(/c2ccccc2)c2noc(=O)n2C)n1
Temperature: 60 °C
Reaction time: 8 h
Yield: 11.7 %

Procedure:
A solution of N′-hydroxy-N-{6-[({[(Z)-(4-methyl-5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)(phenyl)methylene]amino}oxy)methyl]pyridin-2-yl}ethanimidamide (150 mg, 0.392 mmol, 1 eq), iodomethylcyclopropane (0.069 ml, 0.588 mmol, 1.5 eq) and cesium carbonate (191 mg, 0.588 mmol, 1.5 eq) in DMF (3 ml) was stirred at 80° C. for 7 h and overnight at room temperature. Iodomethylcyclopropane (0.069 ml, 0.588 mmol, 1.5 eq), cesium carbonate (191 mg, 0.588 mmol, 1.5 eq) and potassium iodide (0.1 eq) were then added and the mixture was stirred at 60° C. for 8 h. Water was added and the mixture was extracted with ethyl acetate. The organics were combined, dried over MgSO4 and evaporated. The residue was purified by chromatography on silica gel to afford N′-(cyclopropylmethoxy)-N-{6-[({[(Z)-(4-methyl-5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)(phenyl)methylene]amino}oxy)methyl]pyridin-2-yl}ethanimidamide (20 mg, 10% yield) as a transparent oil.
Reaction SMILES: N#N.[C:3]1([P:9]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[N-:22]([S:30]([C:33]([F:36])([F:35])[F:34])(=[O:32])=[O:31])[S:23]([C:26]([F:29])([F:28])[F:27])(=[O:25])=[O:24].C1(=O)O[CH2:40][CH2:39][O:38]1>CO>[F:36][C:33]([F:34])([F:35])[S:30]([N-:22][S:23]([C:26]([F:27])([F:28])[F:29])(=[O:24])=[O:25])(=[O:31])=[O:32].[OH:38][CH2:39][CH2:40][P+:9]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1)([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: O=C1OCCO1
Agent: N#N
Agent: O=S(=O)([N-]S(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: CO
Product: OCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 60 °C

Procedure:
In a reactor wherein air was replaced by N2, 300.0 g of (1.1 mol) triphenyl phosphine and 500 mL of methanol were added and heated to 60° C. 321.8 g (1.1 mol) of trifluoromethanesulfonimide was then added dropwise under strong stirring, and 176.0 g (2.0 mol) of ethylene carbonate was also added after a half hour of reaction. The reaction mixture was transferred to an autoclave, wherein air was removed prior to heating. After 4 hours of reaction at temperature of 160° C. and at pressure of from 1.4 MPa to 1.5 MPa, the crude product was obtained after distilling off the unreacted materials and solvent. 616.3 g of 2-hydroxyethyl triphenyl phosphonium bis(trifluoromethyl sulfonyl) amide was obtained after washing and drying at 60° C. and 0.1 kPa for 4 hours.
Reaction SMILES: [F:1][CH2:2][C:3]([N:14]1[C:18](=[O:19])[C:17]2=[CH:20][CH:21]=[CH:22][CH:23]=[C:16]2[C:15]1=[O:24])([CH2:6][CH2:7][CH2:8]OS(C)(=O)=O)[C:4]#[N:5].[I-:25].[Na+]>CC(C)=O.CCOCC>[F:1][CH2:2][C:3]([N:14]1[C:18](=[O:19])[C:17]2=[CH:20][CH:21]=[CH:22][CH:23]=[C:16]2[C:15]1=[O:24])([CH2:6][CH2:7][CH2:8][I:25])[C:4]#[N:5]
Reactant: [I-]
Reactant: CS(=O)(=O)OCCCC(C#N)(CF)N1C(=O)c2ccccc2C1=O
Agent: [Na+]
Solvent: CC(C)=O
Solvent: CCOCC
Product: N#CC(CF)(CCCI)N1C(=O)c2ccccc2C1=O
Reaction time: 0.5 h

Procedure:
A solution of 2-fluoromethyl-2-phthalimido-5-methanesulfonyloxypentanenitrile (42 g) and sodium iodide (35.7 g) in acetone (600 ml) is stirred and heated under reflux. After about 1/2 hour, the mixture solidifies. Acetone (500 ml) is added, and refluxing and stirring is continued overnight. The salts are removed by filtration and washed several times with acetone. The acetone is evaporated to give a residue which is dissolved in ether (1.5 l). The ether solution is washed subsequently with water (2×), sodium sulfite solution, and water again (3×). After drying (MgSO4) and evaporating the ether, 2-fluoromethyl-2-phthalimido-5-iodopentanenitrile is obtained as an oil (34.1 g).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[N:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.O1CCCC1.[CH3:16][N:17]1[CH:21]=[C:20](B2OC(C)(C)C(C)(C)O2)[CH:19]=[N:18]1>C(=O)([O-])[O-].[K+].[K+].O.[I-].C([N+](CCCC)(CCCC)CCCC)CCC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:16][N:17]1[CH:21]=[C:20]([C:2]2[CH:3]=[C:4]3[CH:5]=[CH:6][NH:7][C:8]3=[N:9][CH:10]=2)[CH:19]=[N:18]1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: Brc1cnc2[nH]ccc2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Solvent: C1CCOC1
Solvent: O
Product: Cn1cc(-c2cnc3[nH]ccc3c2)cn1
Temperature: 70 °C
Reaction time: 8 h

Procedure:
To 5-bromo-7-azaindole (44, 1.04 g, 5.28 mmol) in 1.00M potassium carbonate in water (15.8 mL) and tetrahydrofuran (50.0 mL) were added 1-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (546, 1.65 g, 7.92 mmol), Tetrakis(triphenylphosphine)palladium(0) (0.305 mg, 0.26 mmol) and tetra-n-butylammonium iodide (0.20 g, 0.53 mmol). The reaction mixture was stirred at 70° C. overnight. The reaction mixture was poured into water and the organic layer was washed with brine, dried over sodium sulfate, and concentrated. The residue was purified with silica gel column chromatography eluting with 25% ethyl acetate in hexane to provide a light yellow solid (547, 670 mg, 64.0%). MS (ESI)[M+H+]+=199.4.
Reaction SMILES: CS[C:3]1[N:8]=[C:7]([NH:9][CH:10]([CH3:12])[CH3:11])[C:6]([N+:13]([O-:15])=[O:14])=[C:5]([NH:16][CH:17]([CH2:20][CH3:21])[CH2:18][CH3:19])[N:4]=1.[CH2:22]([N:24](CC)[CH2:25]C)C.CNC>CCCCCC.CC(C)=O>[CH3:22][N:24]([CH3:25])[C:3]1[N:8]=[C:7]([NH:9][CH:10]([CH3:12])[CH3:11])[C:6]([N+:13]([O-:15])=[O:14])=[C:5]([NH:16][CH:17]([CH2:20][CH3:21])[CH2:18][CH3:19])[N:4]=1
Reactant: CCC(CC)Nc1nc(SC)nc(NC(C)C)c1[N+](=O)[O-]
Reactant: CCN(CC)CC
Agent: CNC
Solvent: CCCCCC
Solvent: CC(C)=O
Product: CCC(CC)Nc1nc(N(C)C)nc(NC(C)C)c1[N+](=O)[O-]
Reaction time: 16 h

Procedure:
15.6 g of 2-methylmercapto-4-isopropylamino-5-nitro-6-(3-pentyl-amino)-pyrimidine (0.05 mol) are dissolved in 250 ml of alcohol. Then 20 ml of triethylamine and 3 g of dimethylamine are added. The reaction mixture is kept for 16 hours under high pressure (12 bar) at 100° C, until no more starting material can be detected in a thin-layer chromatogram (silica gel. hexane/acetone 5:1). The mixture is evaporated, the residue is treated with water and extracted twice with ether. The ethereal extracts are dried over MgSO4, filtered and evaporated, to yield 13.5 g of 2-dimethylamino-4-isopropylamino-5-nitro-6-(3-pentylamino)-pyrimidine; b.p. 160° C/0.001 Torr.
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:7]2[CH:8]=[C:9]([C:12]#[N:13])[CH:10]=[CH:11][C:6]2=[N:5][CH:4]=1.[H-].[Na+].CI.[C:18]([O-])([O-])=O.[Na+].[Na+]>C1COCC1>[CH3:18][O:1][CH2:2][C:3]1[N:7]2[CH:8]=[C:9]([C:12]#[N:13])[CH:10]=[CH:11][C:6]2=[N:5][CH:4]=1
Reactant: N#Cc1ccc2ncc(CO)n2c1
Reactant: O=C([O-])[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: C1CCOC1
Product: COCc1cnc2ccc(C#N)cn12
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 3-(hydroxymethyl)-imidazo[1,2-a]pyridine-6-carbonitrile (7-2) (346 mg, 2 mmol) in 20 mL of THF was added sodium hydride (240 mg, 60% in oil) at 0° C. The reaction mixture was stirred at 0° C. for 1 h, then methyl iodide (615 mg, 4.3 mmol) was added. The reaction was stirred at room temperature overnight. The mixture was treated with aqueous Na2CO3, then concentrated. The residue was diluted with water and extracted with EtOAc. The combined organics were dried over Na2SO4 and concentrated to afford the title compound (300 mg). MS (m/z): 188.0 (M+H)+
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[CH:8][C:7](B2OC(C)(C)C(C)(C)O2)=[C:6]([CH3:19])[CH:5]=1.FC(F)(F)S(O[C:27]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH2:30][CH2:29][CH:28]=1)(=O)=O>>[CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[CH:8][C:7]([C:30]2[C:31]3[C:36](=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH2:27][CH2:28][CH:29]=2)=[C:6]([CH3:19])[CH:5]=1
Reactant: O=S(=O)(OC1=CCCc2ccccc21)C(F)(F)F
Reactant: COC(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)c(C)c1
Product: COC(=O)c1ccc(C2=CCCc3ccccc32)c(C)c1
Yield: 97.3 %

Procedure:
3-Methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzoic acid methyl ester of Example 28, Step A (5.00 g, 18.1 mmol) and 3,4-dihydronaphthalen-1-yl trifluoromethanesulfonate (5.54 g, 19.9 mmol) were reacted in the manner of Example 1, Step F. Purification by flash column chromatography on silica gel, eluting with 10% ethyl acetate in hexane, afforded the title compound (4.90 g) as a light yellow oil.
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[NH:7][C:8]([CH2:24][OH:25])([CH2:22][OH:23])[CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[C:13]([C:18]([F:21])([F:20])[F:19])[CH:12]=1)([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[C:33]1([CH2:39][CH2:40][CH2:41][CH2:42][CH2:43]Br)[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.O>CN(C)C=O>[C:1]([O:5][C:6](=[O:26])[NH:7][C:8]([CH2:22][OH:23])([CH2:24][OH:25])[CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:43][CH2:42][CH2:41][CH2:40][CH2:39][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[C:13]([C:18]([F:20])([F:19])[F:21])[CH:12]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: BrCCCCCc1ccccc1
Reactant: CC(C)(C)OC(=O)NC(CO)(CO)CCc1ccc(O)c(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC(CO)(CO)CCc1ccc(OCCCCCc2ccccc2)c(C(F)(F)F)c1
Temperature: 80 °C
Reaction time: 6 h
Yield: 106.4 %

Procedure:
Compound 3-6 (380 mg) was dissolved in N,N-dimethylformamide (10 ml), potassium carbonate (277 mg) and 5-phenylpentylbromide (281 mg) were added, and the mixture was stirred at 80° C. for 6 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give the object product (560 mg) as a colorless oil.
Reaction SMILES: Cl.Cl.[NH2:3][CH:4]1[CH2:9][CH2:8][N:7]([CH2:10][CH2:11][CH2:12][O:13][C:14]2[CH:27]=[CH:26][C:17]3[C:18]4[CH2:25][CH2:24][CH2:23][C:19]=4[C:20](=[O:22])[O:21][C:16]=3[CH:15]=2)[CH2:6][CH2:5]1.C(=O)(O)[O-].[Na+].[N+:33]([C:36]1[CH:44]=[CH:43][C:39]([C:40](Cl)=[O:41])=[CH:38][CH:37]=1)([O-:35])=[O:34]>ClCCl>[N+:33]([C:36]1[CH:37]=[CH:38][C:39]([C:40]([NH:3][CH:4]2[CH2:9][CH2:8][N:7]([CH2:10][CH2:11][CH2:12][O:13][C:14]3[CH:27]=[CH:26][C:17]4[C:18]5[CH2:25][CH2:24][CH2:23][C:19]=5[C:20](=[O:22])[O:21][C:16]=4[CH:15]=3)[CH2:6][CH2:5]2)=[O:41])=[CH:43][CH:44]=1)([O-:35])=[O:34]
Reactant: NC1CCN(CCCOc2ccc3c4c(c(=O)oc3c2)CCC4)CC1
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: O=C(NC1CCN(CCCOc2ccc3c4c(c(=O)oc3c2)CCC4)CC1)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
A mixture of 4.15 g. (0.01 mole) 7-[3-(4-aminopiperidino)-propoxy]-2,3-dihydrocyclopenta[c][1]benzopyran-4(1H)-one dihydrochloride, 2.5 g. sodium bicarbonate and 60 ml. dichloromethane is mixed, while cooling with ice, with a solution of 1.86 g. (0.01 mole) 4-nitrobenzoyl chloride in 20 ml. dichloromethane. The reaction mixture is stirred for 14 hours at ambient temperature, filtered and the precipitate washed with water and dichloromethane and purified by chromatography on silica gel (elution agent dichloromethane:methanol, 9:1 v/v). There are obtained 2.5 g. (51% of theory) of the desired compound; m.p. 212°-213° C.
Reaction SMILES: [C:1]([NH:4][C:5]1[C:13]2[C:8](=[C:9]([Cl:14])[CH:10]=[CH:11][CH:12]=2)[NH:7][C:6]=1[C:15](N(OC)C)=[O:16])(=[O:3])[CH3:2].[C:21]1([Li])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(OCC)C.O1CCCC1>[C:1]([NH:4][C:5]1[C:13]2[C:8](=[C:9]([Cl:14])[CH:10]=[CH:11][CH:12]=2)[NH:7][C:6]=1[C:15](=[O:16])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)(=[O:3])[CH3:2]
Reactant: CON(C)C(=O)c1[nH]c2c(Cl)cccc2c1NC(C)=O
Reactant: [Li]c1ccccc1
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(=O)Nc1c(C(=O)c2ccccc2)[nH]c2c(Cl)cccc12
Temperature: 0 °C
Reaction time: 1 h
Yield: 26 %

Procedure:
To a solution of 3-acetylamino-7-chloro-2-[(N-methoxy-N-methylamino)carbonyl]indole (step 4, 321 mg, 1.08 mmol) in diethyl ether-tetrahydrofuran (1:1, 10 ml) was added phenyl lithium (1M solution in cyclohexane, 5.4 ml, 5.42 mmol) at −78° C. After stirring for 1 h, the mixture was allowed to warm to 0° C. and stirred for an additional 2 h. The mixture was quenched with saturated aqueous ammonium chloride (20 ml) and extracted with ether (150 ml). The organic layer was washed with water (50 ml) and dried (MgSO4). Removal of solvent gave an oily residue. Purification by flash column chromatography eluting with ethyl acetate/hexane (1:3) afforded yellow crystals. Recrystallization from ethyl acetate gave 87 mg, (26%) of the title compound. m.p.: 185-188° C. IR (KBr) ν: 3240, 1690, 1628, 1543, 1375, 1315, 1250, 725 cm1 1H-NMR (CDCl3) δ: 9.77 (1 H, br s), 8.36 (1 H, br s), 8.18 (1 H, d, J=8.6 Hz), 7.87-7.83 (2 H, m), 7.71-7.57 (3 H, m), 7.40 (1 H, dd, J=1.0, 7.6 Hz), 7.10 (1 H, dd, J=7.6, 8.4 Hz), 2.26 (3 H, s).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[N:14]=[C:13]([NH:15][C:16]3[NH:20][N:19]=[C:18]([CH:21]4[CH2:23][CH2:22]4)[CH:17]=3)[CH:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1.[F:24][C:25]([F:36])([F:35])[C:26]1[CH:27]=[C:28]([N:32]=[C:33]=[O:34])[CH:29]=[CH:30][CH:31]=1>C(Cl)Cl>[CH:21]1([C:18]2[CH:17]=[C:16]([NH:15][C:13]3[CH:12]=[CH:11][N:10]=[C:9]([NH:8][C:4]4[CH:3]=[C:2]([NH:1][C:33]([NH:32][C:28]5[CH:29]=[CH:30][CH:31]=[C:26]([C:25]([F:24])([F:35])[F:36])[CH:27]=5)=[O:34])[CH:7]=[CH:6][CH:5]=4)[N:14]=3)[NH:20][N:19]=2)[CH2:23][CH2:22]1
Reactant: O=C=Nc1cccc(C(F)(F)F)c1
Reactant: Nc1cccc(Nc2nccc(Nc3cc(C4CC4)n[nH]3)n2)c1
Solvent: ClCCl
Product: O=C(Nc1cccc(Nc2nccc(Nc3cc(C4CC4)n[nH]3)n2)c1)Nc1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A solution of N2-(3-aminophenyl)-N4-(3-cyclopropyl-1H-pyrazol-5-yl)pyrimidine-2,4-diamine (0.014 g, 0.046 mmol) in CH2Cl2 (10 mL) was cooled in an ice-water bath. To this 3-(trifluoromethyl)phenyl isocyanate (0.006 mL, 0.046 mmol) diluted in CH2Cl2 (5 mL) was added drop wise. The reaction was allowed to warm to room temperature and left stirring for 12 hours. The reaction proceeded until completion as judged by TLC and LC-MS. The reaction mixture was concentrated in vacuo, resuspended in 50:50 H20-CH3CN, and purified on a C18 column in CH3CN/H20/0.1% TFA (1-100% gradient) to afford AD77. ESI-MS m/z [M+H]+ found 495.4, calculated 495.2.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([NH:12][C:13]([CH:15]3[CH2:17][CH2:16]3)=[O:14])[N:8]=[CH:9]2)=[CH:4][CH:3]=1.[CH3:18][C:19]1[CH:27]=[CH:26][C:22]([C:23]([OH:25])=[O:24])=[CH:21][C:20]=1B1OC(C)(C)C(C)(C)O1.C(=O)([O-])[O-].[K+].[K+].O1CCOCC1.O.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.Cl[Pd]Cl>[CH:15]1([C:13]([NH:12][C:7]2[N:8]=[CH:9][C:10]3[C:5]([CH:6]=2)=[CH:4][CH:3]=[C:2]([C:20]2[CH:21]=[C:22]([CH:26]=[CH:27][C:19]=2[CH3:18])[C:23]([OH:25])=[O:24])[CH:11]=3)=[O:14])[CH2:17][CH2:16]1
Reactant: O=C(Nc1cc2ccc(Br)cc2cn1)C1CC1
Reactant: Cc1ccc(C(=O)O)cc1B1OC(C)(C)C(C)(C)O1
Agent: Cl[Pd]Cl
Agent: CN(C)c1ccc(P(C(C)(C)C)C(C)(C)C)cc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: O
Solvent: C1COCCO1
Product: Cc1ccc(C(=O)O)cc1-c1ccc2cc(NC(=O)C3CC3)ncc2c1
Temperature: 90 °C
Yield: 93 %

Procedure:
A mixture of N-(7-bromoisoquinolin-3-yl)cyclopropanecarboxamide (0.3305 g, 1.135 mmol), 4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid (0.3782 g, 1.443 mmol), potassium carbonate (0.3196 g, 2.312 mmol), and bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (81.9 mg, 0.116 mmol) in 1,4-dioxane (5.0 mL, 64 mmol) and water (0.5 mL, 30 mmol) was heated at 90° C. for 2 hours. The reaction mixture was cooled to room temperature, acidified with 10% aqueous citric acid, and extracted twice with ethyl acetate. The combined organic extracts were reduced in volume under evaporation and the product collected via filtration as a white precipitate and dried under vacuum to yield 365.5 mg (91%) of 3-(3-(cyclopropanecarboxamido)isoquinolin-7-yl)-4-methylbenzoic acid. LCMS (ESI): M+H=347.2; 1H NMR (400 MHz, DMSO-d6) δ 10.90 (s, 1H), 9.19 (s, 1H), 8.50 (s, 1H), 8.04 (s, 1H), 7.93 (d, J=8.6 Hz, 1H), 7.89-7.83 (m, 2H), 7.72 (d, J=8.5 Hz, 1H), 7.45 (d, J=7.7 Hz, 1H), 2.34 (s, 3H), 2.14-2.02 (m, 1H), 0.85 (m, 4H).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2([OH:31])[CH2:20][CH2:19][N:18](C(OCC3C=CC=CC=3)=O)[CH2:17][CH2:16]2)=[CH:11][CH:10]=1)C1C=CC=CC=1>[Pd].CO>[OH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2([OH:31])[CH2:16][CH2:17][NH:18][CH2:19][CH2:20]2)=[CH:11][CH:10]=1
Reactant: O=C(OCc1ccccc1)N1CCC(O)(c2ccc(OCc3ccccc3)cc2)CC1
Agent: [Pd]
Solvent: CO
Product: Oc1ccc(C2(O)CCNCC2)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 66.6 %

Procedure:
10% Palladium on carbon (3.44 g, 3.23 mmol) was added to benzyl 4-[4-(benzyloxy)phenyl]-4-hydroxypiperidine-1-carboxylate (13.49 g, 32.31 mmol) in MeOH (146 mL). The resulting mixture was stirred at room temperature for 20 hours under an atmosphere of hydrogen. The reaction mixture was filtered and evaporated to afford crude product. The crude material was triturated with DCM (100 mL) and MeOH (50 mL) to give a solid which was collected by filtration and dried under vacuum to give 4-(4-hydroxyphenyl)piperidin-4-ol (4.16 g, 66.6%). The preparation of 4-(4-hydroxyphenyl)piperidin-4-ol is also described in Journal of Medicinal Chemistry (2000), 43(5), 984-994.
Reaction SMILES: Cl.[Br:2][C:3]1[CH:4]=[C:5]([C@H:9]([NH2:11])[CH3:10])[CH:6]=[N:7][CH:8]=1.C(N(CC)C(C)C)(C)C.[C:21](Cl)(=[O:23])[CH3:22]>C(Cl)Cl>[Br:2][C:3]1[CH:4]=[C:5]([C@H:9]([NH:11][C:21](=[O:23])[CH3:22])[CH3:10])[CH:6]=[N:7][CH:8]=1
Reactant: C[C@@H](N)c1cncc(Br)c1
Reactant: CC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N[C@H](C)c1cncc(Br)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a vial is added (1R)-1-(5-bromo(3-pyridyl))ethylamine HCl (500 mg, 2.1 mmol) in 2.5 ml of DCM, followed by the addition of N,N-diisopropylethylamine (816 mg, 2.52 mmol). Then acetyl chloride 1M in DCM solution (2.5 ml, 2.5 mmol) is added at 0° C. The reaction mixture is stirred at room temperature for 2 hours. The reaction mixture is diluted with DCM, washed with water, brine, dried over anhydrous Na2SO4, filtered and concentrated to give the crude product. Purification by the flash column chromatography affords 273 mg of N-[(R)-1-(5-bromo-pyridin-3-yl)-ethyl]-acetamide.
Reaction SMILES: [O-:1][C:2]#[N:3].[K+].[NH2:5][CH2:6][C:7]1[O:11][C:10]([C:12]2[N:13]=[C:14]([NH:17][C:18]([NH2:20])=[S:19])[S:15][CH:16]=2)=[CH:9][CH:8]=1.Cl>O.CN(C)C=O>[NH:17]([C:14]1[S:15][CH:16]=[C:12]([C:10]2[O:11][C:7]([CH2:6][NH:5][C:2]([NH2:3])=[O:1])=[CH:8][CH:9]=2)[N:13]=1)[C:18]([NH2:20])=[S:19]
Reactant: NCc1ccc(-c2csc(NC(N)=S)n2)o1
Reactant: N#C[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: NC(=O)NCc1ccc(-c2csc(NC(N)=S)n2)o1
Temperature: 25 °C
Reaction time: 16 h
Yield: 91.9 %

Procedure:
A solution of potassium cyanate (9.6 g) in water (50 ml) was added to a mixture of 4-(5-aminomethylfuran-2-yl)-2-thioureidothiazole (10.0 g) in N,N-dimethylformamide (80 ml) and 1N-hydrochloric acid (78.6 ml), and the mixture was stirred for 16 hours at ambient temperature. To the reaction mixture was added a water (100 ml) and isolated precipitate was collected by filtration to give 2-thioureido-4-(5-ureidomethylfuran-2-yl)thiazole (10.74 g).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH2:8][N:9]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[C:12](=[O:19])[O:11][C:10]2=[O:20])[CH:5]=[CH:4][N:3]=1.[C:21]([O:26][CH2:27][CH2:28][N:29]=[C:30]=[O:31])(=[O:25])[C:22]([CH3:24])=[CH2:23]>N1C=CC=CC=1>[O:20]=[C:10]1[N:9]([CH2:8][C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:1][C:30](=[O:31])[NH:29][CH2:28][CH2:27][O:26][C:21](=[O:25])[C:22]([CH3:24])=[CH2:23])[CH:7]=2)[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[C:12](=[O:19])[O:11]1
Reactant: Nc1cc(Cn2c(=O)oc(=O)c3ccccc32)ccn1
Reactant: C=C(C)C(=O)OCCN=C=O
Solvent: c1ccncc1
Product: C=C(C)C(=O)OCCNC(=O)Nc1cc(Cn2c(=O)oc(=O)c3ccccc32)ccn1
Temperature: 40 °C
Reaction time: 2 h

Procedure:
To a stirred solution of 1-(2-amino-pyridin-4-ylmethyl)-1H-benzo[d][1,3]oxazine-2,4-dione (1.2 g, see preparation 7b) in pyridine was added isocyanatoethyl methacrylate (0.76 ml). The reaction mixture was heated to 40° C. and stirred for 2 hours. More isocyanatoethyl methacrylate (0.1 ml) was added and stirring was continued for 2 hours. The solvent was evaporated under reduced pressure and EtOAc (10 ml) was added to the residue. On scraping a solid material formed, that was isolated by filtration and dried in vacuo, affording 2-methyl-acrylic acid 2-{3-[4-(2,4-dioxo-4H-benzo[d][1,3]oxazin-1-ylmethyl)-pyridin-2-yl]-ureido}-ethyl ester (1.78 g). Step 2: This anhydride intermediate was converted into the title compound by reaction with O-(4-cyanobenzyl)hydroxylamine hydrochloride (see preparation 10), using general procedure 1A. 13C-NMR (DMSO-d6) δ 167.5, 166.5, 154.8, 153.7, 151.4, 148.6, 146.6, 141.9, 135.8, 132.8, 132.3, 129.2, 128.1, 125.9, 118.8, 115.4, 114.9, 113.0, 111.6, 110.9, 109.4, 76.1, 63.7, 45.4, 38.0, 18.0.