Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:23])[C:3]([N:5]1[CH2:9][CH:8]2[CH2:10][C:11]([CH2:16][CH:17]3[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)([N:13]=C=O)[CH2:12][CH:7]2[CH2:6]1)=[O:4].N>Cl>[CH3:23][N:2]([CH3:1])[C:3]([N:5]1[CH2:9][CH:8]2[CH2:10][C:11]([NH2:13])([CH2:16][CH:17]3[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]3)[CH2:12][CH:7]2[CH2:6]1)=[O:4]
Reactant: CN(C)C(=O)N1CC2CC(CC3CCCCC3)(N=C=O)CC2C1
Agent: Cl
Agent: N
Product: CN(C)C(=O)N1CC2CC(N)(CC3CCCCC3)CC2C1
Yield: 83.9 %

Procedure:
Upon cooling by an ice-water bath, to a solution of 10 mL of hydrochloric acid (8 N) was added dropwise 5-cyclohexylmethyl-5-isocyanato-hexahydro-cyclopenta[c]pyrrole-2-carboxylic acid dimethylamide 15e (0.65 g, 2.03 mmol). Then the ice-water bath was removed. The reaction mixture was reacted at 50° C. for 20 minutes. The reaction was monitored by TLC until the disappearance of the starting materials. The mixture was adjusted to pH>8 with concentrated ammonia and extracted with ethyl acetate (30 mL×5). The combined organic extracts were dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 5-amino-5-cyclohexylmethyl-hexahydro-cyclopenta[c]pyrrole-2-carboxylic acid dimethylamide 15f (0.5 g, yield 84%) as a grey oil.
Reaction SMILES: [OH:1][CH2:2][C:3]([C:6]1[CH:7]=[C:8]([OH:12])[CH:9]=[CH:10][CH:11]=1)([CH3:5])[CH3:4].C(=O)C1[C:15](=CC=CC=1)[OH:16]>>[OH:1][CH2:2][C:3]([C:6]1[CH:7]=[C:8]([OH:12])[C:9](=[CH:10][CH:11]=1)[CH:15]=[O:16])([CH3:5])[CH3:4]
Reactant: CC(C)(CO)c1cccc(O)c1
Reactant: O=Cc1ccccc1O
Product: CC(C)(CO)c1ccc(C=O)c(O)c1

Procedure:
The phenol (Step 5) was converted to the salicylaldehyde via a method similar to that described in Example 2, Step 1: mp 80.4–81.9° C. 1H NMR (CDCl3/300 MHz) 11.00 (s, 1H), 9.87 (s, 1H), 7.51 (d, 1H, J=8.3 Hz), 7.08 (dd, 1H, J=8.3 Hz, 1.4 Hz), 7.02 (d, 1H, J=1.4 Hz), 3.66 (s, 2H), 1.34 (s, 6H).
Reaction SMILES: [H-].[Na+].[C:3]([CH:11]1[C:20](=[O:21])[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[NH:13][CH2:12]1)(=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:22][C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=1)[CH2:26]Br>CN(C)C=O>[C:3]([C:11]1[C:20](=[O:21])[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]([CH2:22][C:23]2[CH:30]=[CH:29][CH:28]=[C:25]([CH3:26])[CH:24]=2)[CH:12]=1)(=[O:10])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: O=C(c1ccccc1)C1CNc2ccccc2C1=O
Reactant: Cc1cccc(CBr)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cccc(Cn2cc(C(=O)c3ccccc3)c(=O)c3ccccc32)c1

Procedure:
Compound 4t was prepared following the procedure outlined in Step 3 of Example 1 using 16 mg (0.4 mmol) of sodium hydride (60%), 75 mg (0.31 mmol) of 3-benzoyl-2,3-dihydro-1H-quinolin-4-one 3e, 3 mL of anhydrous dimethylformamide, 75.6 mg (0.40 mmol) of 3-methylbenzylbromide. The crude product 4t was purified by flash chromatography to yield 45 mg of colorless solid: LC-MSD, m/z for C24H19NO2, [M+H]+=354.4, [M+2H]+=355.4; Reverse phase HPLC (gradient acetonitrile 0.1% TFA 20-95% in 4 min) retention time=2.146 min; 1H NMR (400 MHz, CDCl3/HCl): δ 2.35 (s, 3H), 5.38 (s, 2H), 7.00 (d, 2H), 7.33 (d, 1H), 7.22-7.26 (m, 1H), 7.36-7.45 (m, 4H), 7.50-7.60 (m, 2H), 7.82-7.86 (m, 2H), 8.31 (s, 1H), 8.44-8.48 (m, 1H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1)#[N:2].N1C=CC=CC=1.[C:22](Cl)(=[O:30])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]>C1C=CC=CC=1>[C:22]([O:15][C:12]1[CH:13]=[CH:14][C:9]([C:6]2[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][CH:7]=2)=[CH:10][CH:11]=1)(=[O:30])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]
Reactant: CCCCCCCC(=O)Cl
Reactant: N#Cc1ccc(-c2ccc(O)cc2)cc1
Solvent: c1ccncc1
Solvent: c1ccccc1
Product: CCCCCCCC(=O)Oc1ccc(-c2ccc(C#N)cc2)cc1

Procedure:
0.390 G. of 4'-cyano-4-hydroxy-biphenyl are dissolved in 4.0 ml. of absolute pyridine and reacted with 0.390 g. of caprylic acid chloride as in Example 1. The 0.671 g. of yellowish crystals obtained according to the procedure described in Example 1 are dissolved in benzene and chromatographed on 40 g. of silica gel. Benzene elutes 0.586 g. of colorless crytals which are recrystallized from acetone-hexane up to constant melting point and clearing point. The pure 4'-cyano-4-biphenylyl octanoate obtained melts at 77.5°-77.9° and is liquid crystalline (monotrope) upon cooling to 74.1°. UV (EtOH): ε 272 = 26500.
Reaction SMILES: C1C(=O)N([I:8])C(=O)C1.[CH3:9][C:10]1[N:11]=[C:12]([C:15]2([CH3:19])[CH2:18][O:17][CH2:16]2)[NH:13][CH:14]=1>C(#N)C>[I:8][C:14]1[NH:13][C:12]([C:15]2([CH3:19])[CH2:16][O:17][CH2:18]2)=[N:11][C:10]=1[CH3:9]
Reactant: O=C1CCC(=O)N1I
Reactant: Cc1c[nH]c(C2(C)COC2)n1
Solvent: CC#N
Product: Cc1nc(C2(C)COC2)[nH]c1I
Temperature: 25 °C
Reaction time: 1 h
Yield: 93.2 %

Procedure:
NIS (2.61 g, 11.58 mmol) was added portion-wise to a solution of 4-methyl-2-(3-methyloxetan-3-yl)-1H-imidazole (compound 175.1, 1.76 g, 11.58 mmol) in acetonitrile (60 mL). The mixture was stirred at room temperature for 1 hour, then was partitioned between EtOAc (300 mL) and water (80 mL). The organic layer was washed with saturated sodium thiosulfate (50 mL), brine (50 mL), dried (MgSO4) and concentrated under reduced pressure to give the title compound as a light yellow solid (3.0 g, 93%). m/z (ES+) 279 (M+H)+.
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:39][CH2:38][CH:37]([CH2:40][C:41](O)=[O:42])[CH2:36][CH2:35]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:47][C:48]1([CH3:54])[CH2:53][CH2:52][CH2:51][NH:50][CH2:49]1>>[C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:39][CH2:38][CH:37]([CH2:40][C:41]([N:50]4[CH2:51][CH2:52][CH2:53][C:48]([CH3:54])([CH3:47])[CH2:49]4)=[O:42])[CH2:36][CH2:35]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC1(C)CCCNC1
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CC(=O)O)CC1
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CC(=O)N2CCCC(C)(C)C2)CC1

Procedure:
In a manner analogous to the method described in example 163, {1-[(4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl]-piperidin-4-yl}-acetic acid was reacted with 3,3-dimethylpiperidine (Chmsrv-As) to give the title product. LC-MS (ES+) 760 [(M+H)+].
Reaction SMILES: [SH:1][C:2]1[N:7]=[CH:6][CH:5]=[CH:4][N:3]=1.F[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N+:15]([O-:17])=[O:16].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[N+:15]([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[S:1][C:2]1[N:7]=[CH:6][CH:5]=[CH:4][N:3]=1)([O-:17])=[O:16]
Reactant: O=[N+]([O-])c1ccccc1F
Reactant: Sc1ncccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccccc1Sc1ncccn1
Yield: 83.1 %

Procedure:
A mixture of 2 mercaptopyrimidine (2.00 g, 17.8 mmol), 1-fluoro-2-nitrobenzene (2.50 g, 17.8 mmol) and potassium carbonate (2.46 g, 17.8 mmol) in DMF (15 mL) was stirred under reflux for 2 h. After removal of DMF, the residue was dissolved in DCM and washed with NaOH (5%, 3×20 mL) and brine. The organic layer was dried (MgSO4), filtered and evaporated to give 2-(2-nitro-phenylsulfanyl)-pyrimidine (3.45 g, 83%) as a yellow solid which was used in the next step without further purification. LC/MS (APCI) tr=3.66 min, m/z 379.28 (39), 233.98 (M++H, 100). HPLC tr=2.22 min (99.67%) 1H NMR (270 MHz, CDCl3) δ 7.03 (1H, t, J=4.7 Hz, Pyrimidine-H), 7.51-7.64 (2H, m, ArH), 7.80 (1H, dd, J=7.7, 1.5 Hz, ArH), 8.03 (1H, dd, J=7.7, 2.0 Hz, ArH) and 8.48 (2H, d, J=4.7 Hz, Pyrimidine-H).
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@@H:3]1[N:8]1[C:12]2=[C:13]3[CH:19]=[CH:18][N:17](COCC[Si](C)(C)C)[C:14]3=[N:15][CH:16]=[C:11]2[N:10]([CH2:28][C:29]#[N:30])[C:9]1=[O:31].B(F)(F)F.CCOCC.C([O-])(=O)C.[Na+]>ClCCl>[CH3:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@@H:3]1[N:8]1[C:12]2=[C:13]3[CH:19]=[CH:18][NH:17][C:14]3=[N:15][CH:16]=[C:11]2[N:10]([CH2:28][C:29]#[N:30])[C:9]1=[O:31]
Reactant: C[C@@H]1CCCC[C@@H]1n1c(=O)n(CC#N)c2cnc3c(ccn3COCC[Si](C)(C)C)c21
Agent: CC(=O)[O-]
Agent: FB(F)F
Agent: [Na+]
Solvent: CCOCC
Solvent: ClCCl
Product: C[C@@H]1CCCC[C@@H]1n1c(=O)n(CC#N)c2cnc3[nH]ccc3c21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 22.7 %

Procedure:
To a solution of {1-[(1S,2R)-2-methylcyclohexyl]-2-oxo-6-{[2-(trimethylsilyl)ethoxy]methyl}-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-3(2H)-yl}acetonitrile (25 mg) in dichloromethane (1 mL) was added boron trifluoride etherate (35.7 μl) dropwise at 4° C. The mixture was stirred at ambient temperature for 0.5 hour. To the mixture was added 5.5M sodium acetate aqueous solution (0.207 mL) and the mixture was stirred at 80° C. for 4 hours. The mixture was extracted with chloroform and washed with water. The extract was dried over MgSO4, filtrated and concentrated under reduced pressure. The residue was purified by column chromatography on NH silica gel with EtOAc and n-hexane (50:50 to 95:5) to give {1-[(1S,2R)-2-methylcyclohexyl]-2-oxo-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-3(2H)-yl}acetonitrile (4 mg) as a white powder.
Reaction SMILES: Br[C:2]1[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[C:6]([Cl:13])=[CH:5][C:3]=1[NH2:4].[CH3:14][Si:15]([C:18]#[CH:19])([CH3:17])[CH3:16].C(N(CC)CC)C>C(OCC)C>[Cl:13][C:6]1[C:7]([C:9]([F:12])([F:11])[F:10])=[CH:8][C:2]([C:19]#[C:18][Si:15]([CH3:17])([CH3:16])[CH3:14])=[C:3]([CH:5]=1)[NH2:4]
Reactant: Nc1cc(Cl)c(C(F)(F)F)cc1Br
Reactant: C#C[Si](C)(C)C
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: C[Si](C)(C)C#Cc1cc(C(F)(F)F)c(Cl)cc1N
Temperature: 60 °C
Reaction time: 9 h
Yield: 92 %

Procedure:
A mixture of 2-bromo-5-chloro-4-(trifluoromethyl)aniline (17.1 g), trimethylsilylacetylene (14.8 ml), bistriphenylphosphinepalladium dichloride (816 mg) and triethylamine (115 ml) was stirred at 60° C. for 9 hr. The reaction mixture was ice-cooled, diethyl ether was added and the mixture was filtered through a celite (trademark) filter. The filtrate was evaporated under reduced pressure to give a brown oil. The oil was purified by silica gel column chromatography (elution solvent:ethyl acetate-hexane (1:20-1:10)) to give 5-chloro-4-(trifluoromethyl)-2-[(trimethylsilyl)ethynyl]aniline (16.5 g, yield 92%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]=[O:10])=[CH:4][C:3]=1[C:11]([F:14])([F:13])[F:12].[CH:15]1[C:20]([NH2:21])=[CH:19][CH:18]=[C:17]([NH2:22])[CH:16]=1>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:21][C:20]2[CH:15]=[CH:16][C:17]([NH2:22])=[CH:18][CH:19]=2)=[O:10])=[CH:4][C:3]=1[C:11]([F:12])([F:13])[F:14]
Reactant: Nc1ccc(N)cc1
Reactant: O=C=Nc1ccc(Cl)c(C(F)(F)F)c1
Solvent: ClCCl
Product: Nc1ccc(NC(=O)Nc2ccc(Cl)c(C(F)(F)F)c2)cc1
Reaction time: 1 h
Yield: 97.2 %

Procedure:
To a solution of 4-chloro-3-(trifluoromethyl)phenyl isocyanate (2.27 g, 10.3 mmol) in CH2Cl2 (308 mL) was added p-phenylenediamine (3.32 g, 30.7 mmol) in one part. The resulting mixture was stirred at room temp. for 1 h, treated with CH2Cl2 (100 mL), and concentrated under reduced pressure. The resulting pink solids were dissolved in a mixture of EtOAc (110 mL) and MeOH (15 mL), and the clear solution was washed with a 0.05 N HCl solution. The organic layer was concentrated under reduced pressure to afford impure N-(4-chloro-3-(trifluoromethyl)phenyl)-N′-(4-aminophenyl)urea (3.3 g): TLC (100% EtOAc) Rf 0.72.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:3]=1[C:4]([N:6]1[CH2:17][CH2:16][C:9]2[N:10]=[N:11][C:12]([NH:14][NH2:15])=[CH:13][C:8]=2[CH2:7]1)=[O:5].[CH3:23][C:24]([CH3:26])=O>>[Cl:1][C:2]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:3]=1[C:4]([N:6]1[CH2:17][CH2:16][C:9]2[N:10]=[N:11][C:12]([NH:14][N:15]=[C:24]([CH3:26])[CH3:23])=[CH:13][C:8]=2[CH2:7]1)=[O:5]
Reactant: CC(C)=O
Reactant: NNc1cc2c(nn1)CCN(C(=O)c1ccc(Cl)cc1Cl)C2
Product: CC(C)=NNc1cc2c(nn1)CCN(C(=O)c1ccc(Cl)cc1Cl)C2

Procedure:
A solution of 1.2 g of crude 6-(2,4-dichlorobenzoyl)-3-hydrazino-5,6,7,8-tetrahydropyrido[4,3-c]pyridazine in 5 cc of acetone is heated on a water bath for 5 minutes. The title compound has a M.P. of 211°-214° (decomp., from methanol).
Reaction SMILES: [N+:1]([C:4]1[CH:23]=[CH:22][C:7]([CH2:8][O:9][C:10]([C:12]2[N:13]=[C:14]([N:17]3[CH2:20][CH:19]([OH:21])[CH2:18]3)[S:15][CH:16]=2)=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:24][S:25](Cl)(=[O:27])=[O:26].C(N(CC)CC)C>C(Cl)Cl>[N+:1]([C:4]1[CH:23]=[CH:22][C:7]([CH2:8][O:9][C:10]([C:12]2[N:13]=[C:14]([N:17]3[CH2:20][CH:19]([O:21][S:25]([CH3:24])(=[O:27])=[O:26])[CH2:18]3)[S:15][CH:16]=2)=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=C(OCc1ccc([N+](=O)[O-])cc1)c1csc(N2CC(O)C2)n1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OC1CN(c2nc(C(=O)OCc3ccc([N+](=O)[O-])cc3)cs2)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 98.9 %

Procedure:
To a solution of 1-(4-p-nitrobenzyloxycarbonyl-1,3-thiazol-2-yl)-3-hydroxyazetidine (648 mg, 1.93 mmol) (obtained as described in Reference Example 2(6)) in methylene chloride (20 ml) were added methanesulfonyl chloride (0.31 ml, 3.95 mmol) and triethylamine (0.55 ml, 3.95 mmol) in an ice bath. After stirring the mixture in the ice bath for 10 minutes, the mixture was stirred at room temperature for 3 hours. After checking the completion of the reaction, the reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium hydrogencarbonate solution. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was recrystallized from a mixture of n-hexane and ethyl acetate to afford 1-(4-p-nitrobenzyloxycarbonyl-1,3-thiazol-2-yl)-3-methanesulfonyloxyazetidine (789 mg, yield 99%) as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:10])[NH2:9])=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:11][C:12]1[CH:13]=[C:14](B(O)O)[CH:15]=[CH:16][CH:17]=1.C(N(CC)CC)C>ClCCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[C:1]([O:5][C:6]([N:8]([CH3:10])[NH:9][C:16]1[CH:15]=[CH:14][CH:13]=[C:12]([F:11])[CH:17]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: OB(O)c1cccc(F)c1
Reactant: CN(N)C(=O)OC(C)(C)C
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: CN(Nc1cccc(F)c1)C(=O)OC(C)(C)C
Temperature: 60 °C
Yield: 39.2 %

Procedure:
A mixture of N-methyl-hydrazinecarboxylic acid tert-butyl ester (Intermediate 1; 570 mg, 4.1 mmol), 3-fluorophenylboronic acid (Aldrich; 673 mg, 4.6 mmol), copper(II) acetate (750 mg, 4.1 mmol) and triethylamine (1.4 mL, 10.0 mmol) in 1,2-dichloroethane (20 mL) was heated in an oil bath at 60° C. for 1.5 h. The mixture was allowed to cool, and it was then adsorbed onto silica gel and purified by chromatography using an ISCO 120 g column, eluting with 10-20% ethyl acetate/hexanes, to give N′-(3-fluoro-phenyl)-N-methyl-hydrazinecarboxylic acid tert-butyl ester (386 mg, 39%) as a pale yellow oil.
Reaction SMILES: [OH-].[Na+].[CH3:3][N:4]1[CH:8]=[C:7]([C:9]2[CH:32]=[CH:31][C:12]3[N:13]([C:16]4[CH:17]=[C:18]([NH:27]C(=O)C)[CH:19]=[C:20]([N:22]5[CH:26]=[CH:25][CH:24]=[CH:23]5)[CH:21]=4)[CH:14]=[N:15][C:11]=3[CH:10]=2)[N:6]=[N:5]1>C(O)C.C(OCC)(=O)C>[CH3:3][N:4]1[CH:8]=[C:7]([C:9]2[CH:32]=[CH:31][C:12]3[N:13]([C:16]4[CH:17]=[C:18]([CH:19]=[C:20]([N:22]5[CH:26]=[CH:25][CH:24]=[CH:23]5)[CH:21]=4)[NH2:27])[CH:14]=[N:15][C:11]=3[CH:10]=2)[N:6]=[N:5]1
Reactant: CC(=O)Nc1cc(-n2cccc2)cc(-n2cnc3cc(-c4cn(C)nn4)ccc32)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CCOC(C)=O
Product: Cn1cc(-c2ccc3c(c2)ncn3-c2cc(N)cc(-n3cccc3)c2)nn1
Yield: 73 %

Procedure:
A mixture of 20% sodium hydroxide (5 ml) and the compound of Example 99 (1.0 g, 2.52 mmol) in 10 ml ethanol was heated at 100° C. for 3 h. The mixture was diluted with ethyl acetate (100 ml) and the organic layer was washed with water (50 ml) and brine (25 ml). The solvent was removed under reduced pressure and the residue was purified by column chromatography over silica gel to afford the product in 73% yield (0.65 g). LC-MS (ESI): Calculated mass: 355.4; Observed mass: 356.3 [M+H]+ (rt: 0.49 min).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH3:12])[C:5]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20][C:21]([OH:23])=[O:22])=[CH:16][C:15]=2[O:24]C)=[C:4]([CH3:26])[N:3]=1.[CH3:27]O.Cl>C(Cl)Cl.B(Br)(Br)Br.O1CCOCC1>[NH2:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH3:12])[C:5]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20][C:21]([O:23][CH3:27])=[O:22])=[CH:16][C:15]=2[OH:24])=[C:4]([CH3:26])[N:3]=1
Reactant: CCCCNc1nc(N)nc(C)c1Cc1ccc(CC(=O)O)cc1OC
Reactant: CO
Agent: BrB(Br)Br
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: CCCCNc1nc(N)nc(C)c1Cc1ccc(CC(=O)OC)cc1O
Reaction time: 5 h

Procedure:
To the product from example 72 step (i) (550 mg) in DCM (20 mL), BBr3 (0.29 ml) was added dropwise and the reaction mixture stirred for 5 h. MeOH (4 mL) was added followed by 4M HCl in dioxane (0.5 mL) and stirred for 16 h and the solvents evaporated. The residue was purified by RPHPLC to give the title compound as a white solid, 8 mg.
Reaction SMILES: [ClH:1].C([O:9][C:10]1[CH:11]=[C:12]([NH:24][C:25]([NH:27][CH3:28])=[NH:26])[CH:13]=[CH:14][C:15]=1[O:16]CC1C=CC=CC=1)C1C=CC=CC=1>[Pd].C(O)C>[ClH:1].[OH:9][C:10]1[CH:11]=[C:12]([NH:24][C:25]([NH:27][CH3:28])=[NH:26])[CH:13]=[CH:14][C:15]=1[OH:16]
Reactant: CNC(=N)Nc1ccc(OCc2ccccc2)c(OCc2ccccc2)c1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: CNC(=N)Nc1ccc(O)c(O)c1
Reaction time: 4 h

Procedure:
1-(3',4'-Dihydroxyphenyl)-3-methylguanidine hydrochloride is prepared from a mixture of 28 gm (0.07 mole) of the 1-(3',4'-dibenzyloxyphenyl)-3-methylguanidine hydrochloride (prepared in Example I), 1.0 gm of 5 percent palladium on charcoal, and 250 ml of ethyl alcohol. The mixture was shaken under an initial hydrogen pressure of 50 psi and, after 4 hours of agitation, the reaction mixture was filtered and the filtrate evaporated to a thick residue which solidified after standing 2 hours. This solid was purified by recrystallization from a mixture of ethyl alcohol and ether (3:2 ratio). The resulting white crystalline solid melted at 185-8° C and the infrared spectrum was consistent with the assigned structure.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:30][C:31]([O:33]C)=O)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][S:18]([C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[C:22]=4[Cl:28])(=[O:20])=[O:19])=[C:13]([F:29])[CH:12]=3)[C:3]=12.[CH3:35][N:36]([CH3:40])[CH2:37][CH2:38][NH2:39]>>[CH3:35][N:36]([CH3:40])[CH2:37][CH2:38][NH:39][C:31](=[O:33])[CH2:30][N:8]1[C:4]2=[N:5][CH:6]=[N:7][C:2]([NH2:1])=[C:3]2[C:10]([C:11]2[CH:16]=[CH:15][C:14]([NH:17][S:18]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[C:22]=3[Cl:28])(=[O:19])=[O:20])=[C:13]([F:29])[CH:12]=2)=[N:9]1
Reactant: CN(C)CCN
Reactant: COC(=O)Cn1nc(-c2ccc(NS(=O)(=O)c3cccc(Cl)c3Cl)c(F)c2)c2c(N)ncnc21
Product: CN(C)CCNC(=O)Cn1nc(-c2ccc(NS(=O)(=O)c3cccc(Cl)c3Cl)c(F)c2)c2c(N)ncnc21

Procedure:
The representative procedure for amide formation was used in the reaction of methyl 2-[4-amino-3-(4-{[(2,3-dichlorophenyl)sulfonyl]amino}-3-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]acetate (0.035 g, 0.067 mmol) with N,N-dimethylethylenediamine (1 mL). Purification by preparative HPLC (25 to 100% acetonitrile in 0.1 M aqueous ammonium acetate over 20 min at 21 mL/min using an 8μ Hypersil HS C18, 250×21 mm column, Rt 6.85-7.45 min) afforded N1-[2-(dimethylamino)ethyl]-2-[4-amino-3-(4-{[(2,3-dichlorophenyl)sulfonyl]amino)-3-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl}acetamide as an off-white solid (0.008 g, 0.014 mmol): 1H NMR (DMSO-d6, 400 MHz) δ 10.20 (br, 1H), 8.22 (m, 2H), 7.96 (d, 1H), 7.80 (d, 1H), 7.45 (t, 1H), 7.31 (m, 3H), 6.90 (br, 2H), 4.96 (s, 2H), 3.40 (m, 2H), 2.75 (m, 2H), 2.07 (s, 6H); MS: (M−H)− 579.
Reaction SMILES: [CH2:1]1[O:5][C:4]2[CH:6]=[C:7]([CH2:10][CH2:11][NH2:12])[CH:8]=[CH:9][C:3]=2[O:2]1.[C:13]1(=O)[O:18][C:16](=[O:17])[C:15]2=[CH:19][CH:20]=[CH:21][CH:22]=[C:14]12>C(O)(=O)C>[CH2:1]1[O:2][C:3]2[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][N:12]3[C:16](=[O:17])[C:15]4=[CH:19][CH:20]=[CH:21][CH:22]=[C:14]4[C:13]3=[O:18])=[CH:6][C:4]=2[O:5]1
Reactant: O=C1OC(=O)c2ccccc21
Reactant: NCCc1ccc2c(c1)OCO2
Solvent: CC(=O)O
Product: O=C1c2ccccc2C(=O)N1CCc1ccc2c(c1)OCO2

Procedure:
Forty-one g of 3,4,-methylenedioxyphenethylamine (0.25 moles) was refluxed with 36 g of phthalic anhydride (0.28 moles) and 65 ml. of acetic acid for 2.5 hours. The mixture was cooled whereupon it solidified. The solid mass was broken up and triturated with water and the solid recovered by filtration. Recrystallization from 300 ml of acetic acid and 125 ml of water gave white crystals of the above-named product, m.p. 139°-140.5°.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4](Cl)[N:3]=1.[CH3:12][O:13][C:14](=[O:22])[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([NH2:21])[CH:16]=1.C(O)(C)C>C(O)CCCC>[CH3:12][O:13][C:14](=[O:22])[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([NH:21][C:4]2[N:3]=[C:2]([Cl:1])[N:10]=[C:9]3[C:5]=2[N:6]=[CH:7][NH:8]3)[CH:16]=1
Reactant: COC(=O)c1cccc(N)c1
Reactant: Clc1nc(Cl)c2[nH]cnc2n1
Solvent: CC(C)O
Solvent: CCCCCO
Product: COC(=O)c1cccc(Nc2nc(Cl)nc3[nH]cnc23)c1
Temperature: 75 °C
Reaction time: 8 h
Yield: 92.9 %

Procedure:
To a solution of 2,6-dichloropurine (17 g, 90 mmol) in 300 ml of 1-pentanol are added 37.8 g (250 mmol) of methyl-3-aminobenzoate and stirred for 8 hours at 75° C. After cooling to RT, 200 ml of isopropanol is added and the mixture is stirred for 1 h. After filtration, the precipitate is taken up into MeOH/H2O and treated with NaHCO3 to pH >8. After filtration, the product ist washed with H2O and MeOH and dried to obtain 25.4 g (93% yield) of 3-(2-chloro-9H-purin-6-yl-amino)-benzoic acid methyl ester, Rf=0.5; (CH2Cl2/MeOH (9/1)); m.p. 242° C.; ESI-MS: 304 (M+H)+.
Reaction SMILES: [N:1]([CH2:10][C:11]([OH:13])=O)([CH2:6][C:7]([OH:9])=[O:8])[CH2:2][C:3]([OH:5])=[O:4].C(OC(=O)C)(=O)C.[Br:21][C:22]1[CH:28]=[CH:27][C:25]([NH2:26])=[CH:24][C:23]=1[CH3:29]>N1C=CC=CC=1>[Br:21][C:22]1[CH:28]=[CH:27][C:25]([NH:26][C:11](=[O:13])[CH2:10][N:1]([CH2:2][C:3]([OH:5])=[O:4])[CH2:6][C:7]([OH:9])=[O:8])=[CH:24][C:23]=1[CH3:29]
Reactant: O=C(O)CN(CC(=O)O)CC(=O)O
Reactant: Cc1cc(N)ccc1Br
Solvent: c1ccncc1
Solvent: CC(=O)OC(C)=O
Product: Cc1cc(NC(=O)CN(CC(=O)O)CC(=O)O)ccc1Br
Temperature: 100 °C
Yield: 54.9 %

Procedure:
A slurry of 9.56 g of nitrilotriacetic acid in 80 ml of dry pyridine (dried over molecular sieves) is heated to 55° C. Acetic anhydride (7.66 g) is added and the solution is heated to 100° C. After heating for 0.5 hour, the solution is cooled to 55° C. and 9.30 g of 4-bromo-3-methylaniline is added with a 5 ml pyridine rinse. The solution is heated at 100° C. for 1.0 hour. The reaction is cooled and rotary evaporated to a pasty solid which is dissolved in 120 ml of aqueous ammonium hydroxide (30 ml concentrated ammonium hydroxide/90 ml distilled water). The clear brown solution is extracted with two 100 ml portions of methylene chloride and neutralized to pH 3 with 35 ml of concentrated HCl. The white solid is filtered, washed with three 25 ml portions of cold distilled water, and dried under vacuum for 2.75 hours at 60° C. The crude product (12.9 g) is recrystallized from 360 ml of 50% ethanol to give 9.85 g of product, melting point 206.5°-209.0° C.