Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S([O-])([O-])=O.[Na+].[Na+].C(=O)(O)[O-].[Na+].[F:12][C:13]([F:25])([F:24])[C:14]1[CH:15]=[C:16]([S:20](Cl)(=[O:22])=[O:21])[CH:17]=[CH:18][CH:19]=1.[OH-].[Na+].[CH2:28](C(Br)C(O)=O)C>O>[CH3:28][S:20]([C:16]1[CH:17]=[CH:18][CH:19]=[C:14]([C:13]([F:25])([F:24])[F:12])[CH:15]=1)(=[O:22])=[O:21]
Reactant: O=S(=O)(Cl)c1cccc(C(F)(F)F)c1
Reactant: CCC(Br)C(=O)O
Agent: O=C([O-])O
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: O
Product: CS(=O)(=O)c1cccc(C(F)(F)F)c1
Yield: 22.3 %

Procedure:
A suspension of sodium sulfite (3.0 g, 24 mmol), sodium bicarbonate (3.7 g; 44 mmol and 3-trifluormethylbenzenesulfonylchloride (5.0 g; 20 mmol) in 70 mL water, was heated at 75° C. for 1 hour. Then 5 mL 50% aqueous sodium hydroxide to solution and ethyl bromoacetic acid (2.65 mL; 22 mmol) was added and the mixture was refluxed for 30 hours. Then the mixture was extracted with dichloromethane and concentrated to provide 1 g (4.46 mmol; 20% yield) of 1-methanesulfonyl-3-trifluoromethylbenzene as a solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[CH:14][CH:15]=3)[N:10]([C:17]3[CH:18]=[C:19]([CH:25]=[CH:26][CH:27]=3)[O:20][CH2:21][C:22]([OH:24])=O)[N:9]=2)=[CH:4][CH:3]=1.[CH3:28][N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[CH:14][CH:15]=3)[N:10]([C:17]3[CH:18]=[C:19]([CH:25]=[CH:26][CH:27]=3)[O:20][CH2:21][C:22]([N:32]3[CH2:33][CH2:34][N:29]([CH3:28])[CH2:30][CH2:31]3)=[O:24])[N:9]=2)=[CH:6][CH:7]=1
Reactant: CN1CCNCC1
Reactant: O=C(O)COc1cccc(-n2nc(-c3ccc(F)cc3)c3cccnc32)c1
Product: CN1CCN(C(=O)COc2cccc(-n3nc(-c4ccc(F)cc4)c4cccnc43)c2)CC1

Procedure:
By conducting reactions and treatments in the same manner as in Examples 36 and 37, using 3-[3-(4-fluorophenyl)-1H-pyrazolo[3,4-b]pyridin-1-yl]phenoxyacetic acid and 4-methylpiperazine, there was obtained 1-{3-[3-(4-fluorophenyl)-1H-pyrazolo[3,4-b]pyridin-1-yl]phenoxyacetyl}-4-methylpiperazine, m.p. 132°-135° C.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:6][CH:5]=1)([O-:3])=[O:2].[H-].[Na+].[CH3:18]I.O>CN(C)C=O.C1(C)C=CC=CC=1>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH:10]([CH3:18])[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: CI
Reactant: CCOC(=O)Cc1ccc([N+](=O)[O-])cc1
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C(C)c1ccc([N+](=O)[O-])cc1

Procedure:
To the solution of 52 g of ethyl 4-nitrophenylacetate in 350 ml dimethylformamide-toluene (1:1), 9.5 g of 50% sodium hydride in mineral oil are added portionwise while stirring and cooling. After 11/2 hours stirring at room temperature, 26 g methyl iodide are added dropwise and the mixture is stirred overnight at room temperature. The mixture is carefully combined with water, extracted with diethyl ether, the extract dried, filtered and evaporated. The residue is taken up in 100 ml ethanol, the solution seeded with a few crystals starting material and allowed to stand in the cold. The precipitate formed is filtered off and the filtrate evaporated, to yield the ethyl α-(4-nitrophenyl)-propionate.
Reaction SMILES: N[C@H](C=O)CCSC.C([O-])(=O)CC(CC([O-])=O)(C([O-])=O)O.[C:22]([O-:27])(=O)[C:23]([CH3:25])=[O:24].[Na+].C(=O)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>C(O)C>[C:30]1([CH2:25][C:23]([CH2:22][OH:27])=[O:24])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: O=Cc1ccccc1
Reactant: CC(=O)C(=O)[O-]
Agent: CSCC[C@H](N)C=O
Agent: O=C([O-])CC(O)(CC(=O)[O-])C(=O)[O-]
Agent: [Na+]
Solvent: CCO
Product: O=C(CO)Cc1ccccc1
Temperature: 5 °C
Reaction time: 24 h
Yield: 24.4 %

Procedure:
9.5 ml of 0.1 M citric acid and 40.5 ml of 0.1 M tri-sodium citrate were diluted to 100 ml to give a pH 6 citrate buffer solution. (Ref.: Buffers for pH and Metal Ion Control, D. D. Perrin and B. Dempsey, Publ. John Wiley and Sons, pg 103). Petroleum spirit (40 ml), ethanol (0.5 ml), the pH 6 citrate buffer (5 ml) and sodium pyruvate (2.5 g, 23 mmol) were stirred at room temperature for 1 h. Benzaldehyde (127 mg, 1.2 mmol) and baker's yeast (5 g) were then added and the reaction stirred at 5° C. for 24 h. The mixture was then filtered and yeast washed with diethyl ether. After removal of the solvent in vacuo the product was purified by flash distillation (200° C./1 mm) to give phenylacetylcarbinol (44 mg, 24%). The GC of the product showed pure PAC (11.88 min.). Chiral GC showed a ratio of 97.5:2.5, 95% ee.
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[C:9]2[C:5]([CH2:6][C:7]([CH:14]3[CH2:18][CH2:17][CH2:16][CH2:15]3)([CH3:13])[C:8]2=[O:12])=[CH:4][C:3]=1[OH:19].C(=O)([O-])[O-].[K+].[K+].[F:26][C:27]([F:33])([F:32])[S:28](Cl)(=[O:30])=[O:29]>CN(C)C=O>[F:26][C:27]([F:33])([F:32])[S:28]([O:19][C:3]1[CH:4]=[C:5]2[C:9](=[C:10]([Cl:11])[C:2]=1[Cl:1])[C:8](=[O:12])[C:7]([CH:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1)([CH3:13])[CH2:6]2)(=[O:30])=[O:29]
Reactant: CC1(C2CCCC2)Cc2cc(O)c(Cl)c(Cl)c2C1=O
Reactant: O=S(=O)(Cl)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC1(C2CCCC2)Cc2cc(OS(=O)(=O)C(F)(F)F)c(Cl)c(Cl)c2C1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.7 %

Procedure:
A mixture of (+)-6,7-dichloro-2-cyclopentyl-2,3-dihydro-5-hydroxy-2-methyl-1H-inden-1-one (25.05 g, 0.0837 mole) and potassium carbonate (35.4 g. 0.256 mole) in dimethylformamide (100 ml.) is stirred at 25° C. for 1 hour, cooled to 0° C. then treated with trifluoromethanesulfonyl chloride (10.5 ml., 0.984 mole) over a 3 minute period. The reaction mixture is stirred at 25° C. for 1 hour, poured into ice water (700 ml.) extracted with ether, washed with water and brine and dried over MgSO4. The ether is evaporated at reduced pressure to give 34.2 g of (+) (+)-(6,7-dichloro-2-cyclopentyl-2,3-dihydro-2-methyl-1-oxo-1H-inden-5-yl) trifluoromethanesulfonate which melts at 104°-6° C. and is used in Step B without further purification.
Reaction SMILES: [Cl-].[C:2](Cl)(=[O:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:11][N:12]1[CH:16]=[CH:15][CH:14]=[C:13]1[CH2:17][C:18]#[N:19].Cl>C(Cl)Cl>[C:2]([C:16]1[N:12]([CH3:11])[C:13]([CH2:17][C:18]#[N:19])=[CH:14][CH:15]=1)(=[O:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Cn1cccc1CC#N
Agent: Cl
Agent: [Cl-]
Solvent: ClCCl
Product: Cn1c(CC#N)ccc1C(=O)c1ccccc1
Temperature: 0 °C

Procedure:
To a chilled suspension of 9.7 g. (0.07 mole) of alumonum chloride in 45 ml. methylene chloride is added 9 ml. (0.07 mole) benzoyl chloride. The resulting solution is added dropwise to a solution of 1-methylpyrrole-2-acetonitrile in 30 ml. methylene chloride while cooling externally with an ammonium chloride ice bath (temperature below 5° C.). After the addition is complete, the reaction mixture is stirred at 0° C. for fifteen minutes and then poured into ice acidified with 3N hydrochloric acid. The acidic fraction is extracted three times with methylene chloride. The organic fractions are combined and washed consecutively with N,N-dimethyl-1,3-propanediamine and 3N hydrochloric acid. The organic solution is dried over anhydrous magnesium sulfate. The solvent is then evaporated off to yield an oily residue which is column chromatographed on neutral alumina using hexane, benzene and ethylacetate as successive solvents. The first few fractions having ultraviolet absorption in the 240-260 mμ range contain the desired product. These fractions are combined, the solvent evaporated off, and the oily residue, when triturated with methanol, yields the crystalline product, 5-benzoyl-1-methylpyrrole-2-acetonitrile, m.p. 106-108° C.
Reaction SMILES: [CH3:1][N:2]([CH3:6])[CH2:3][C:4]#[CH:5].Br[C:8]1[CH:9]=[C:10]2[C:14](=[C:15]([Cl:17])[CH:16]=1)[C:13](=[O:18])[N:12]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[CH:22][CH:21]=1)[CH2:11]2.C(Cl)(Cl)Cl.CO>C(NC(C)C)(C)C.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>[Cl:17][C:15]1[CH:16]=[C:8]([C:5]#[C:4][CH2:3][N:2]([CH3:6])[CH3:1])[CH:9]=[C:10]2[C:14]=1[C:13](=[O:18])[N:12]([CH2:19][C:20]1[CH:21]=[CH:22][C:23]([O:26][C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)=[CH:24][CH:25]=1)[CH2:11]2
Reactant: C#CCN(C)C
Reactant: O=C1c2c(Cl)cc(Br)cc2CN1Cc1ccc(Oc2ccccc2)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: ClC(Cl)Cl
Solvent: CC(C)NC(C)C
Solvent: CO
Product: CN(C)CC#Cc1cc(Cl)c2c(c1)CN(Cc1ccc(Oc3ccccc3)cc1)C2=O
Temperature: 100 °C
Reaction time: 2 h
Yield: 78.7 %

Procedure:
A mixture of dimethyl-prop-2-ynyl-amine (0.036 mL, 0.32 mmol), 5-bromo-7-chloro-2-(4-phenoxy-benzyl)-2,3-dihydro-isoindol-1-one (0.120 g, 0.28 mmol), PdCl2(PPh3)2 (0.011 g, 0.015 mmol), and CuI (0.0028 g, 0.015 mmol) in diisopropyl amine (4 mL) was stirred at 100° C. for 2 h. Workup and silica gel column chromatography using 10:1 CHCl3-MeOH afforded 7-chloro-5-(3-dimethylamino-prop-1-ynyl)-2-(4-phenoxy-benzyl)-2,3-dihydro-isoindol-1-one (0.095 g, 79%). 1H NMR (300 MHz, CDCl3): δ (ppm) 2.36 (s, 6H), 3.46 (s, 2H), 4.23 (s, 2H), 4.76 (s, 2H), 6.93-7.38 (m, 10H), 7.43 (s, 1H).
Reaction SMILES: [C:1](ON=O)([CH3:4])(C)[CH3:2].[F:8][CH:9]([F:29])[C:10]1[N:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[C:13]([C:20](=[O:23])[S:21][CH3:22])=[C:12]([NH2:24])[C:11]=1[C:25](=[O:28])[S:26][CH3:27].N#N.Cl.ClC1C=CN=CC=1.C(N(CC)CC)C.C1(N)CC1>CC#N.CN(C=O)C.O.CCOCC>[F:29][CH:9]([F:8])[C:10]1[N:15]=[C:14]([C:16]([F:19])([F:17])[F:18])[C:13]([C:20](=[O:23])[S:21][CH3:22])=[C:12]([NH:24][CH:4]2[CH2:1][CH2:2]2)[C:11]=1[C:25](=[O:28])[S:26][CH3:27]
Reactant: CC(C)(C)ON=O
Reactant: CSC(=O)c1c(C(F)F)nc(C(F)(F)F)c(C(=O)SC)c1N
Agent: Cl
Agent: Clc1ccncc1
Agent: N#N
Solvent: CCN(CC)CC
Solvent: O
Solvent: CC#N
Product: CSC(=O)c1c(C(F)F)nc(C(F)(F)F)c(C(=O)SC)c1NC1CC1
Reaction time: 18 h
Yield: 63.8 %

Procedure:
To a mechanically stirred mixture of 0.78 g (0.006 mol) of CuCl2, and 0.75 g (0.007 mol) of t-butylnitrite in 40 ml of CH3CN at 25° C. was added dropwise a solution of 1.7 g (0.0047 mol) of product of Example 191 in 10 ml of CHhd 3CN. Evolution of N2 was observed and reaction mixture was stirred for 18 hours. The crude mixture was poured into 3.7% HCl(aq), and extracted with diethyl ether. The ether phase was washed with H2O and dried (MgSO4). The dry ether phase was concentrated in vacuo to 1.55 g (0.004 mol) of the 4-chloropyridine as a yellow solid. To a magnetically stirred solution of 1.55 g (0.004 mol) of this yellow solid, and 0.50 g (0.005 mol) of triethylamine in 40 ml of DMF at 25° C. was added dropwise 0.28 g (0.005 mol) of cyclopropylamine. After 18 hours the reaction mixture was poured into H2O, and extracted with diethyl ether. The ether phace was washed with H2O, dried (MgSO4), and concentrated in vacuo affording 1.2 g of a brown solid. The crude was purified by preparatory centrifugally-accelerated radical thin-layer chromatography in 10% EtOAc/cyclohexane yielding 0.4 g (25%) of product as a yellow solid; mp 85°-86° C.
Reaction SMILES: N(CC)CC.CC([NH:10][CH2:11][CH:12]([OH:22])[C:13]1[CH:14]=[CH:15][C:16]([OH:21])=[C:17]([CH2:19][OH:20])[N:18]=1)(C)C>CO>[OH:20][CH2:19][C:17]1[C:16]([OH:21])=[CH:15][CH:14]=[C:13]([CH:12]([OH:22])[CH2:11][NH2:10])[N:18]=1
Reactant: CC(C)(C)NCC(O)c1ccc(O)c(CO)n1
Solvent: CO
Solvent: CCNCC
Product: NCC(O)c1ccc(O)c(CO)n1

Procedure:
A solution of 2.0 g., (0.005 mole) of 2-acetoxymethyl-3-acetoxy-6-(1-acetoxy-2-N-acetyl-tert-butylaminoethyl)pyridine in 50 ml. of methanol containing 1 ml. of concentrated hydrochloric acid was heated to reflux for 12 hours. The solvents were removed in vacuo and the residue recrystallized frcm ethyl acetate to give pirbuterol hydrochloride (900 mg., 58%) m.p. 172°-175° C. (dec.), NMR and tlc in 6:3:1 EtOAz: CH3OH: Et2NH identical to pirbuterol. Prolonged heating results in the formation of 2-hydroxymethyl-3-hydroxy-6-(1-hydroxy-2-aminoethyl)pyridine, m.p. 184°-186° dec.
Reaction SMILES: [C:1]([NH:4][C@H:5]([C:25]([OH:27])=[O:26])[CH2:6][C:7]1[CH:14]=[C:12]([I:13])[C:11]([O:15][C:16]2[CH:23]=[C:21]([I:22])[C:20]([OH:24])=[C:18]([I:19])[CH:17]=2)=[C:9]([I:10])[CH:8]=1)(=[O:3])[CH3:2].O[N:29]1[C:33](=O)[CH2:32][CH2:31][C:30]1=[O:35].NCCC[CH2:40][CH2:41][C:42]([OH:44])=[O:43].C(=O)(O)[O-].[Na+].Cl>CN(C)C=O.O1CCCC1.O>[C:1]([NH:4][C@H:5]([C:25]([OH:27])=[O:26])[CH2:6][C:7]1[CH:14]=[C:12]([I:13])[C:11]([O:15][C:16]2[CH:17]=[C:18]([I:19])[C:20]([OH:24])=[C:21]([I:22])[CH:23]=2)=[C:9]([I:10])[CH:8]=1)(=[O:3])[CH3:2].[C:42]([CH2:41][CH2:40][CH2:31][CH2:32][CH2:33][NH:29][CH:30]=[O:35])([OH:44])=[O:43]
Reactant: NCCCCCC(=O)O
Reactant: O=C1CCC(=O)N1O
Agent: CC(=O)N[C@@H](Cc1cc(I)c(Oc2cc(I)c(O)c(I)c2)c(I)c1)C(=O)O
Agent: Cl
Agent: O=C([O-])O
Solvent: O
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: O=CNCCCCCC(=O)O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
N-acetyl-L-thyroxine (Anal. Biochem., 33 (1970) 67) (1.0 g, 1.22 mmole) and N-hydroxysuccinimide (0.148 g, 1.28 mmole) are dissolved in 2 ml of dimethylformamide and 3 ml of tetrahydrofuran. Dicychlohexylcarbodiimide (0.264 g=1.28 mmole) is then added all at once and the reaction mixture stirred at room temperature for 4 hours. The dicyclohexylurea is removed by filtration and to the filtrate is added a solution of 6-aminocaproic acid (160 mg, 1.22 mmole) and sodium bicarbonate (204 mg, 2.44 mmole) in 1 ml of water. After stirring 2 hours the reaction mixture is acidified to pH 3 with 2 N HCl and extracted with methylene chloride. The organic extract is dried over magnesium sulfate and evaporated to the crude amide. Purification of the product is achieved by dissolving the crude material in methylene chloride containing a trace of methanol and precipitating the product with ether/hexane (75:25). The procedure is repeated two times to give 223 mg (23%) of pure product. It shows a single spot on TLC in 8% methanol in chloroform. The compound has the formula C22H24N2O6I4 and the following structure ##STR3##
Reaction SMILES: [OH:1][C@@H:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C@H:3]1[O:12][C:13](=[O:20])[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16].N1C=CN=C1.[Si:26](Cl)([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27]>ClCCl.CN(C1C=CC=CN=1)C>[CH2:18]([O:17][C:15](=[O:16])[CH2:14][C:13]([O:12][C@@H:3]1[CH:4]=[CH:5][C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C@H:2]1[O:1][Si:26]([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27])=[O:20])[CH3:19]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CCOC(=O)CC(=O)O[C@@H]1C=Cc2ccccc2[C@H]1O
Agent: CN(C)c1ccccn1
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CCOC(=O)CC(=O)O[C@@H]1C=Cc2ccccc2[C@H]1O[Si](C)(C)C(C)(C)C
Yield: 89.6 %

Procedure:
To a dried round bottom flask, 7 (270 mg, 0.98 mmol), imidazole (134 mg, 1.96 mmol), dimethylaminopyridine (6 mg, 0.05 mmol) were dissolved in dichloromethane (4 mL). Tert-butyldimethylsilyl chloride (222 mg, 1.47 mmol) was then added portionwise and allowed to react for 24 hours. The reaction was then quenched with water, extracted with dichloromethane, dried over Na2SO4 and concentrated in vacuo. Flash chromatography (10% ethyl acetate in hexanes) gave a colourless oil 8 (343 mg, 90%). Rf=0.48 on silica gel (10% ethyl acetate:hexanes. IR (KBr, cm−1) 2983 (w), 1731 (s), 1453 (w), 1370 (m), 1150 (s), 1031 (m); 1H NMR (400 MHz, CDCl3) δ7.41-7.39 (1H, m), 7.24-7.22 (2H, m), 7.07-7.05 (1H, m), 6.47 (1H, dd, J=9.9, 1.8 Hz), 5.83 (1H, dd, J=9.7, 2.7 Hz), 5.60 (1H, ddd, J=9.3, 2.9, 2.0 Hz), 5.00 (1H, dd, J=9.3, 0.5 Hz), 4.22-4.15 (2H, m), 3.40 (2H, dd, J=19.6, 16.0 Hz), 1.57 (1H, s), 1.25 (3H, t, J=7.1 Hz), 0.92 (9H, s), 0.13 (3H, s), 0.09 (3H, s); 13C NMR (400 MHz, CDCl3) δ166.3, 166.2 136.2, 132.1, 129.4, 128.0, 127.9, 126.5, 125.9, 125.7, 76.4, 71.6, 61.6, 41.7, 25.8, 18.1, 14.0, −4.3, −4.5. HRMS calcd for C17H21O5Si (M+-C4H9): 333.1158. Found: 333.1149.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[C:13]2[C:8](=[N:9][CH:10]=[N:11][C:12]=2[NH:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=3)=[C:17]([CH3:29])[CH:16]=2)[NH:7][N:6]=1.[NH:30]1[CH2:34][CH2:33][CH2:32][CH2:31]1>>[CH3:29][C:17]1[CH:16]=[C:15]([NH:14][C:12]2[N:11]=[CH:10][N:9]=[C:8]3[NH:7][N:6]=[C:5]([O:4][CH2:3][CH2:2][N:30]4[CH2:34][CH2:33][CH2:32][CH2:31]4)[C:13]=23)[CH:20]=[CH:19][C:18]=1[O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=1
Reactant: Cc1cc(Nc2ncnc3[nH]nc(OCCCl)c23)ccc1OCc1ccccn1
Reactant: C1CCNC1
Product: Cc1cc(Nc2ncnc3[nH]nc(OCCN4CCCC4)c23)ccc1OCc1ccccn1
Yield: 40 %

Procedure:
The procedure described in Example 23 was repeated using 3-(2-chloroethoxy)-N-[3-methyl-4-(pyridin-2-ylmethoxy)phenyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (prepared as described in Example 14) and pyrrolidine to give the title compound in 40% yield; NMR Spectrum: 1.66 (s, 4H), 2.25 (s, 3H), 2.54 (s, 4H), 2.86 (t, 2H), 4.40 (t, 2H), 5.19 (s, 2H), 6.97 (d, 1H), 7.34 (t, 1H), 7.44 (s+d, 2H), 7.54 (d, 1H), 7.84 (t, 1H), 8.23 (s, 1H), 8.49 (s, 1H), 8.59 (d, 1H); Mass Spectrum: 446 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)[CH2:11][C:10]([C:20](=[N:32][OH:33])[NH:21][C:22]3[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=3)=[N:9]2)=[CH:4][CH:3]=1.[CH3:34][N:35]=[C:36]=[O:37].C(N(CC)CC)C.O>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]([C:13]3[CH:14]=[CH:15][C:16]([F:19])=[CH:17][CH:18]=3)[CH2:11][C:10]([C:20](=[N:32][O:33][C:36]([NH:35][CH3:34])=[O:37])[NH:21][C:22]3[CH:27]=[CH:26][C:25]([C:28]([F:30])([F:31])[F:29])=[CH:24][CH:23]=3)=[N:9]2)=[CH:4][CH:3]=1
Reactant: ON=C(Nc1ccc(C(F)(F)F)cc1)C1=NN(c2ccc(Cl)cc2)C(c2ccc(F)cc2)C1
Reactant: CN=C=O
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CNC(=O)ON=C(Nc1ccc(C(F)(F)F)cc1)C1=NN(c2ccc(Cl)cc2)C(c2ccc(F)cc2)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 54.9 %

Procedure:
To a solution of 0.75 g (0.0015 mol) of the product obtained from Example 4 dissolved in 15 mL tetrahydrofuran was added 0.097 g (0.0017 mol) of methyl isocyanate and 0.20 g (0.002 mol) of triethylamine. The reaction mixture was stirred at room temperature for 18 hours, poured into cold water (50 mL) and extracted with ethyl acetate (3×50 mL). The ethyl acetate layer was washed with brine (100 mL), dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to afford 0.44 g of a white solid, mp 75° C. to 77° C.
Reaction SMILES: Cl.[CH3:2][C:3]1[NH:8][C:7]2[CH:9]=[N:10][CH:11]=[CH:12][C:6]=2[NH:5][N:4]=1.[F:13][C:14]([F:25])([F:24])[C:15]([O:17][C:18](=[O:23])[C:19]([F:22])([F:21])[F:20])=[O:16]>FC(F)(F)C(O)=O>[F:13][C:14]([F:25])([F:24])[C:15]([OH:17])=[O:16].[F:22][C:19]([F:20])([F:21])[C:18]([N:5]1[C:6]2[CH:12]=[CH:11][N:10]=[CH:9][C:7]=2[NH:8][C:3]([CH3:2])=[N:4]1)=[O:23]
Reactant: CC1=NNc2ccncc2N1
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Product: CC1=NN(C(=O)C(F)(F)F)c2ccncc2N1
Temperature: 25 °C
Reaction time: 3 h
Yield: 75.4 %

Procedure:
3.7 g (0.02 moles) of 3-methyl-1,4-dihydropyrido[3,4-e]-as-triazine hydrochloride are dissolved in 100 ml of trifluoroacetic acid, and the solution is maintained at room temperature for 2 hours. Thereafter 22.4 ml (0.08 moles) of trifluoroacetic acid anhydride are added to the mixture, and the reaction is conducted for additional 3 hours at 20° to 30° C. The reaction mixture is processed to obtain 5.4 g (75.5%) of 1-trifluoroacetyl-3-methyl-1,4-dihydropyrido[3,4-e]-as-triazine trifluoroacetate; m.p.: 208°-209° C.
Reaction SMILES: [N:1]1[C:2]([C:13]([O:15]CC)=O)=[CH:3][N:4]2[C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=3[S:6][C:5]=12.[BH4-].[Li+].Cl.[C:21](=O)(O)[O-:22].[Na+]>CCO>[CH3:21][O:22][C:10]1[CH:11]=[CH:12][C:7]2[S:6][C:5]3=[N:1][C:2]([CH2:13][OH:15])=[CH:3][N:4]3[C:8]=2[CH:9]=1
Reactant: CCOC(=O)c1cn2c(n1)sc1ccccc12
Reactant: O=C([O-])O
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: CCO
Product: COc1ccc2sc3nc(CO)cn3c2c1
Temperature: 50 °C
Yield: 96.4 %

Procedure:
A mixture of 4.0 g of ethyl imidazo[2,1-b]benzothiazole-2-carboxylate in dry T.H.F. was stirred with 1.5 g of lithium borohydride for 48 hours at room temperature under dry nitrogen. The mixture was treated with an excess of 2N hydrochloric acid and warmed to 50° C. for 2 hours to decompose the complex. The mixture was made alkaline with aqueous sodium bicarbonate and extracted with ethyl acetate. The extracts were dried over magnesium sulfate and evaporated to dryness under reduced pressure to obtain 3.27 g (96.4% yield) of 6-methoxy-imidazo[2,1-b]benzothiazole-2-methanol as a colorless solid melting at 189° to 190° C. (EtOH).
Reaction SMILES: [H-].[Na+].CN(C)C=O.[CH3:8][CH:9]([O:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[C:29]3[C:24](=[N:25][CH:26]=[CH:27][CH:28]=3)[NH:23][N:22]=2)=[CH:17][CH:16]=1)[CH2:10][N:11]([CH3:13])[CH3:12].Cl[CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33]>C1(C)C=CC=CC=1.O>[CH3:8][CH:9]([O:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[C:29]3[C:24](=[N:25][CH:26]=[CH:27][CH:28]=3)[N:23]([CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[N:22]=2)=[CH:17][CH:16]=1)[CH2:10][N:11]([CH3:13])[CH3:12]
Reactant: CCOC(=O)CCl
Reactant: CC(CN(C)C)Oc1ccc(-c2n[nH]c3ncccc23)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: Cc1ccccc1
Product: CCOC(=O)Cn1nc(-c2ccc(OC(C)CN(C)C)cc2)c2cccnc21
Reaction time: 0.25 h

Procedure:
In 40 ml of toluene was suspended 2.3 g of 60% sodium hydride, and 40 ml of dimethylformamide was added to the suspension under ice-cooling. Thereto was added in the two or three times divided manner 14.8 g of 3-[4-(1-methyl-2-dimethylaminoethoxy)phenyl]-1H-pyrazolo[3,4-b]pyridine. After the mixture was stirred for 15 minutes, a solution of 7.0 g of ethyl chloroacetate in 70 ml of toluene was added dropwise. The mixture was stirred at room temperature for 1 hour, and then it was stirred at 40° C. for 1 hour. After cooling, water was added. The toluene layer was separated, washed with water and dried. Toluene was distilled off. The residue was purified by chromatography to give ethyl 3-[4-(1-methyl-2-dimethylaminoethoxy)phenyl]-1H-pyrazolo[3,4-b]-pyridin-1-ylacetate in an oily form.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([S:9]([NH:12][C:13]2[C:18]([O:19][CH3:20])=[N:17][CH:16]=[CH:15][N:14]=2)(=[O:11])=[O:10])[CH:6]=[CH:7][CH:8]=1.C([N-]C(C)C)(C)C.[Li+].C(NC(C)C)(C)C.C([Li])CCC.[Cl:41]C(Cl)(Cl)C(Cl)(Cl)Cl>O1CCCC1>[Cl:41][C:4]1[C:3]([O:2][CH3:1])=[CH:8][CH:7]=[CH:6][C:5]=1[S:9]([NH:12][C:13]1[C:18]([O:19][CH3:20])=[N:17][CH:16]=[CH:15][N:14]=1)(=[O:11])=[O:10]
Reactant: COc1cccc(S(=O)(=O)Nc2nccnc2OC)c1
Reactant: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: COc1cccc(S(=O)(=O)Nc2nccnc2OC)c1Cl
Yield: 46.1 %

Procedure:
Prepared as for Example 130, 3-methoxy-N-(3-methoxy-2-pyrazinyl)benzenesulphonamide (Example 132a) (0.295 g), lithium di-iso-propylamide (prepared from di-iso-propylamine (0.30 g) and n-butyl lithium (0.96 mL of a 2.5M solution in hexanes)) and hexachloroethane (0.994 g) in anhydrous tetrahydrofuran (20 mL) afforded the titled compound (0.152 g) as a white solid after re-crystallisation from tert-butyl methylether.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([CH:15]([CH3:24])[CH2:16][NH:17][S:18]([CH:21]([CH3:23])[CH3:22])(=[O:20])=[O:19])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1)=[O:2].[CH3:25][Mg]Br>O1CCCC1.C(OCC)C.O>[OH:2][CH:1]([C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:14]=[CH:13][C:12]([CH:15]([CH3:24])[CH2:16][NH:17][S:18]([CH:21]([CH3:23])[CH3:22])(=[O:19])=[O:20])=[CH:11][CH:10]=2)=[CH:7][CH:8]=1)[CH3:25]
Reactant: CC(CNS(=O)(=O)C(C)C)c1ccc(-c2ccc(C=O)cc2)cc1
Reactant: C[Mg]Br
Solvent: CCOCC
Solvent: O
Solvent: C1CCOC1
Product: CC(O)c1ccc(-c2ccc(C(C)CNS(=O)(=O)C(C)C)cc2)cc1
Reaction time: 16 h
Yield: 74 %

Procedure:
To a solution of 0.2 g (0.4 mmol) of material from Example 45 in 3 mL of tetrahydrofuran at ambient temperature was added 0.3 mL (0.9 mmol) of a 3.0M solution of methylmagnesium bromide in ethyl ether. The mixture was stirred for 16 hours, diluted with 5 mL of water and extracted four times with 5 mL each of ethyl acetate. The combined organics were dried (MgSO4), filtered and concentrated in vacuo. Chromatography (10 g silica gel, 45% ethyl acetate/hexane) of the residue afforded 0.1 g (74%) of the title compound.