Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[K+].[NH:3]1[CH:7]=[CH:6][CH:5]=[CH:4]1.Br[CH2:9][C:10]([O:12]CC)=[O:11].Cl>O.CS(C)=O>[N:3]1([CH2:9][C:10]([OH:12])=[O:11])[CH:7]=[CH:6][CH:5]=[CH:4]1
Reactant: CCOC(=O)CBr
Reactant: c1cc[nH]c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: O=C(O)Cn1cccc1
Reaction time: 1 h

Procedure:
To a mixture of potassium hydroxide (16.7 g) and dry DMSO (150 mL), pyrrole (5 g) was added dropwise at 20-25° C., with stirring under nitrogen atmosphere. Stirring was continued for 1 hr at 20-25° C. Ethyl bromoacetate (24.5 g) was added dropwise at 20-25° C. and stirring was continued for 2 hr. In the reaction mixture (150 mL) DM water was added and pH was made acidic (pH=3) with 20% HCl (50 mL). The reaction mixture was extracted with diethyl ether (2×100 mL). The combined organic extract was washed with DM water (100 mL), saturated brine (100 mL) and dried over Na2SO4. The solvent was evaporated to obtain pyrrol-1-yl-acetic acid.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][CH:4]=[C:3]1[C:12]([OH:14])=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC.[C:46]([C:50]1[CH:51]=[C:52]([CH:54]=[CH:55][CH:56]=1)[NH2:53])([CH3:49])([CH3:48])[CH3:47]>CN(C=O)C>[C:46]([C:50]1[CH:51]=[C:52]([NH:53][C:12]([C:3]2[C:2](=[O:1])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[NH:5][CH:4]=2)=[O:14])[CH:54]=[CH:55][CH:56]=1)([CH3:49])([CH3:47])[CH3:48]
Reactant: O=C(O)c1c[nH]c2ccccc2c1=O
Reactant: CC(C)(C)c1cccc(N)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)c1cccc(NC(=O)c2c[nH]c3ccccc3c2=O)c1
Temperature: 60 °C

Procedure:
A flask charged with 4-oxo-1H-quinoline-3-carboxylic acid (38 mg, 0.20 mmol), HBTU (76 mg, 0.20 mmol), Et3N (61 mg, 84 μL, 0.60 mmol) and DMF (2 mL) was heated at 60° C. for 15 minutes. To the reaction mixture was then added 3-tert-butylaniline (29.98 mg, 0.2009 mmol) and the reaction mixture was stirred at 60° C. for an additional 30 minutes. The reaction mixture was cooled to room temperature, filtered and purified via reverse phase HPLC using 10 to 99% CH3CN in H2O to obtain N-(3-tert-butylphenyl)-4-oxo-1H-quinoline-3-carboxamide. 1H NMR (400 MHz, DMSO-d6) δ 12.94 (s, 1H), 12.45 (s, 1H), 8.89 (s, 1H), 8.34 (dd, J=1.1, 8.2 Hz, 1H), 7.84-7.80 (m, 1H), 7.76-7.71 (m, 2H), 7.62-7.53 (m, 2H), 7.29 (t, J=7.9 Hz, 1H), 7.15-7.12 (m, 1H), 1.31 (s, 9H). LC/MS: m/z 321.5 (M+H)+ at 1.8 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([CH2:11][N:12]3[C:16]4=[N:17][C:18]([C:21](=O)[CH3:22])=[CH:19][CH:20]=[C:15]4[N:14]=[N:13]3)=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.C([O-])(=O)C.[Na+].Cl.[NH2:30][OH:31]>C(O)C>[N:1]1[C:10]2[C:5](=[CH:6][C:7]([CH2:11][N:12]3[C:16]4=[N:17][C:18]([C:21](=[N:30][OH:31])[CH3:22])=[CH:19][CH:20]=[C:15]4[N:14]=[N:13]3)=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: NO
Reactant: CC(=O)c1ccc2nnn(Cc3ccc4ncccc4c3)c2n1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CC(=NO)c1ccc2nnn(Cc3ccc4ncccc4c3)c2n1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of example 208 (0.060 g, 0.197 mmol) in ethanol (1.3 ml), sodium acetate (0.016 g, 0.197 mmol) and hydroxylamine hydrochloride (0.013 g, 0.197 mmol) were added and stirred at RT for 12 h. The reaction mixture was concentrated and the residue was washed with bicarbonate solution, dichloromethane and dried under vacuum to afford the title compound as a ca. 9:1 mixture of two isomers. Off-white solid (0.030 g, 48%). M.P.: 259-261° C. 1H-NMR (δ ppm, DMSO-d6, 400 MHz): 11.95 (s, 0.9H), 11.28 (s, 0.1H), 8.88 (d, J=2.6 Hz, 1H), 8.74 (d, J=8.8 Hz, 0.1H), 8.61 (d, J=8.4 Hz, 0.1H), 8.52 (d, J=8.8 Hz, 0.9H), 8.36 (d, J=8.4 Hz, 0.9H), 8.00 (m, 3H), 7.81 (dd, J=8.4, 1.6 Hz, 1H), 7.53 (dd, J=8.3, 4.1 Hz, 1H), 6.24 (s, 0.2H), 6.15 (s, 1.8H), 2.74 (s, 0.3H), 2.30 (s, 2.7H).
Reaction SMILES: [C:1]1([C:15]([O-])=[C:11]([N+:12]([O-:14])=[O:13])[CH:10]=[C:6]([N+:7]([O-:9])=[O:8])[CH:5]=1)[N+:2]([O-:4])=[O:3].[NH4+].C(=O)([O-])[NH2:19].[NH4+].CN1CCCC1=O>O>[CH:5]1[C:1]([N+:2]([O-:4])=[O:3])=[C:15]([NH2:19])[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][C:6]=1[N+:7]([O-:9])=[O:8]
Reactant: NC(=O)[O-]
Reactant: O=[N+]([O-])c1cc([N+](=O)[O-])c([O-])c([N+](=O)[O-])c1
Agent: [NH4+]
Solvent: CN1CCCC1=O
Solvent: O
Product: Nc1c([N+](=O)[O-])cc([N+](=O)[O-])cc1[N+](=O)[O-]
Temperature: 100 °C
Reaction time: 20 h
Yield: 61.6 %

Procedure:
Ammonium picrate (0.92 g, 3.7 mmol), ammonium carbamate (7.78 g, 99.6 mmol) and dry N-methylpyrrolidinone (40 ml) are placed in a glass-lined, stainless steel reactor. The reactor is sealed and the reaction slurry is stirred with heating for 2 hr as the temperature increases from 25 to 175° C. (80 psi pressure). The temperature is maintained at 175° C. and stirring is continued for an additional 20 hr. The cooled reaction mixture is mixed with water (400 ml) and the insoluble material is collected, washed with water and dried to give 0.52 g (56%) picramide (Table 2, entry 2).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([OH:10])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].Br[C:12]1[CH:13]=[CH:14][C:15]([N+:18]([O-:20])=[O:19])=[N:16][CH:17]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CN(C)C=O>O>[N+:18]([C:15]1[CH:14]=[CH:13][C:12]([O:10][C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)=[CH:17][N:16]=1)([O-:20])=[O:19]
Reactant: O=[N+]([O-])c1cccc(O)c1
Reactant: O=[N+]([O-])c1ccc(Br)cn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1cccc(Oc2ccc([N+](=O)[O-])nc2)c1
Temperature: 50 °C
Reaction time: 15 h
Yield: 33 %

Procedure:
A mixture of 3-nitrophenol (7.76 g, 55.8 mmol), 5-bromo-2-nitropyridine (10.3 g, 50.7 mmol), cesium carbonate (24.8 g, 76.1 mmol) and N,N-dimethylformamide (150 mL) was stirred at 50° C. for 15 hr. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate and filtrated. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (NH silica gel, hexane/ethyl acetate=100/0→0/100) to give the title compound (4.37 g, 33%) as a yellow solid.
Reaction SMILES: [CH3:1][C:2]([F:7])([CH3:6])[C:3](O)=[O:4].O[N:9]=[C:10]([C:12]12[CH2:19][CH2:18][C:15]([C:20]3[N:24]([CH3:25])[C:23]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=4[C:32]([F:35])([F:34])[F:33])=[N:22][N:21]=3)([CH2:16][CH2:17]1)[CH2:14][CH2:13]2)[NH2:11]>CN(C=O)C>[F:7][C:2]([C:3]1[O:4][N:11]=[C:10]([C:12]23[CH2:19][CH2:18][C:15]([C:20]4[N:24]([CH3:25])[C:23]([C:26]5[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=5[C:32]([F:35])([F:34])[F:33])=[N:22][N:21]=4)([CH2:16][CH2:17]2)[CH2:14][CH2:13]3)[N:9]=1)([CH3:6])[CH3:1]
Reactant: CC(C)(F)C(=O)O
Reactant: Cn1c(-c2ccccc2C(F)(F)F)nnc1C12CCC(C(N)=NO)(CC1)CC2
Solvent: CN(C)C=O
Product: Cn1c(-c2ccccc2C(F)(F)F)nnc1C12CCC(c3noc(C(C)(C)F)n3)(CC1)CC2
Temperature: 100 °C
Reaction time: 8 h

Procedure:
A solution of 2-methyl-2-fluoropropionic acid (108 mg, 1.02 mmol) and 1′1′-carbonyldiimidazole (144 mg, 0.888 mmol) in anhydrous DMF (2.5 ml) was stirred at room temperature under nitrogen atmosphere for 30 min. To this was added N′-Hydroxy-4-{4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1,2,4-triazol-3-yl}bicyclo[2.2.2]octane-1-carboximidamide (1-G) (139.5 mg, 0.355 mmol) and the solution stirred overnight under N2. The reaction was heated for 1.5 hr at 100° C. in a heat block. DMF was removed in vacuo and the solid was redissolved in CH3CN (4 ml). The product was purified by C-18 reverse phase chromatography eluting with 10-90% CH3CN (0.1% TFA)/water (0.1% TFA). The solvent was removed and the residue taken up in DCM and free-based from saturated aqueous sodium bicarbonate solution. The organic layers were dried over MgSO4 and filtered. The solvent was replaced with CH3CN/water and lyophilized to afford 5-(1-fluoro-1-methylethyl)-3-(4-{4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1,2,4-triazol-3-yl}bicyclo[2.2.2]oct-1-yl)-1,2,4-oxadiazole (3-A) as a white solid. MS (ESI+)=464.13 (M+1). 1H NMR (500 MHz, CDCl3): δ 7.89-7.85 (m, 1H), 7.75-7.69 (m, 2H), 7.55 (t, 1H), 3.52 (s, 3H), 2.30 (dd, 6H), 2.15 (dd, 6H), 1.90 (s, 3H), 1.86 (s, 3H).
Reaction SMILES: [C:1]([OH:7])(=[O:6])[CH2:2][CH:3]([CH3:5])[CH3:4].[CH3:8][S:9][CH2:10]Cl.C(N(CC)CC)C>>[C:1]([O:7][CH2:8][S:9][CH3:10])(=[O:6])[CH2:2][CH:3]([CH3:5])[CH3:4]
Reactant: CSCCl
Reactant: CC(C)CC(=O)O
Solvent: CCN(CC)CC
Product: CSCOC(=O)CC(C)C

Procedure:
This product was prepared according to the procedure described in Example 1, by reacting isovaleric acid with chloromethyl methyl sulfide in the presence of one equivalent of triethylamine; b.p. 78°-79° C./12 mm Hg, n20 1.4496.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][O:17][C:18]3[CH:23]=[CH:22][NH:21][C:20](=[O:24])[N:19]=3)=[CH:11][CH:10]=2)=[CH:4][C:3]=1[C:25]([F:28])([F:27])[F:26].Cl.Cl[CH2:31][C:32]1[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:10]=[CH:11][C:12]([CH2:15][CH2:16][O:17][C:18]3[CH:23]=[CH:22][N:21]([CH2:31][C:32]4[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=4)[C:20](=[O:24])[N:19]=3)=[CH:13][CH:14]=2)=[CH:4][C:3]=1[C:25]([F:26])([F:28])[F:27]
Reactant: ClCc1cccnc1
Reactant: O=c1nc(OCCc2ccc(Oc3ccc(Cl)c(C(F)(F)F)c3)cc2)cc[nH]1
Agent: Cl
Product: O=c1nc(OCCc2ccc(Oc3ccc(Cl)c(C(F)(F)F)c3)cc2)ccn1Cc1cccnc1

Procedure:
The title compound was prepared by a procedure similar to that described for E1 starting from 4-{[2-(4-{[4-chloro-3-(trifluoromethyl)phenyl]oxy}phenyl)ethyl]oxy}-2(1H)-pyrimidinone and 3-(chloromethyl)pyridine hydrochloride. LC-MS (ESI): m/z 502 [M+H]+; 4.30 min (ret time).
Reaction SMILES: [CH2:1]([C:6]1[CH:7]=[C:8]([OH:23])[C:9]([CH:13]([CH:15]2[CH2:20][CH2:19][CH2:18][O:17][C:16]2([CH3:22])[CH3:21])[CH3:14])=[C:10]([OH:12])[CH:11]=1)[CH2:2][CH2:3][CH2:4][CH3:5].C1(C)C=CC(S(O)(=O)=O)=CC=1.[NH+]1C=CC=CC=1>C1(C)C=CC=CC=1.CCOC(C)=O>[OH:12][C:10]1[C:9]2[CH:13]([CH3:14])[CH:15]([CH2:20][CH2:19][CH2:18][OH:17])[C:16]([CH3:21])([CH3:22])[O:23][C:8]=2[CH:7]=[C:6]([CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])[CH:11]=1
Reactant: CCCCCc1cc(O)c(C(C)C2CCCOC2(C)C)c(O)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: c1cc[nH+]cc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CCCCCc1cc(O)c2c(c1)OC(C)(C)C(CCCO)C2C
Temperature: 25 °C
Yield: 36.2 %

Procedure:
A solution of 9.4 g of 5-Pentyl-2-[1-(tetrahydro-2,2-dimethyl-2H-pyran-3-yl)ethyl]-1,3-benzenediol in 400 mL of toluene containing a catalytic amount of pyridinium para-toluenesulfonic acid (Aldrich) was heated to 60° C. under argon for 2 hr. The reaction was cooled to RT, diluted with EtOAc, washed with 0.1N aq. HCl (×2), water (×2), sat. aq. NaHCO3, dried and evaporated under reduced pressure. The material obtained was purified by extensive chromatography to give 3.4 g (35%) of rac-3,4-Dihydro-5-hydroxy-2,2,4-trimethyl-7-pentyl-2H-1-benzopyran-3-propanol as a pale yellow amorphous solid. HR EI MS: Calc M+, 320.2351; Observed, 320.2377. Ratio of 3:1 diastereoisomers as shown by 1 H-NMR.
Reaction SMILES: C(O)(C(F)(F)F)=O.[CH3:8][NH:9][C:10]1[N:15]=[CH:14][C:13]([C:16]2[N:17]=[C:18]([N:33]3[CH2:38][CH2:37][O:36][CH2:35][CH2:34]3)[C:19]3[S:24][C:23]([CH2:25][N:26]4[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]4)=[C:22]([CH3:32])[C:20]=3[N:21]=2)=[CH:12][N:11]=1.[C:39](O)(=[O:43])[C@H:40]([CH3:42])[OH:41]>>[OH:41][C@@H:40]([CH3:42])[C:39]([N:29]1[CH2:30][CH2:31][N:26]([CH2:25][C:23]2[S:24][C:19]3[C:18]([N:33]4[CH2:34][CH2:35][O:36][CH2:37][CH2:38]4)=[N:17][C:16]([C:13]4[CH:14]=[N:15][C:10]([NH:9][CH3:8])=[N:11][CH:12]=4)=[N:21][C:20]=3[C:22]=2[CH3:32])[CH2:27][CH2:28]1)=[O:43]
Reactant: CNc1ncc(-c2nc(N3CCOCC3)c3sc(CN4CCNCC4)c(C)c3n2)cn1
Reactant: C[C@H](O)C(=O)O
Solvent: O=C(O)C(F)(F)F
Product: CNc1ncc(-c2nc(N3CCOCC3)c3sc(CN4CCN(C(=O)[C@H](C)O)CC4)c(C)c3n2)cn1

Procedure:
The crude TFA salt of N-methyl-5-(7-methyl-4-morpholino-6-((piperazin-1-yl)methyl)thieno[3,2-d]pyrimidin-2-yl)pyrimidin-2-amine was reacted with L-lactic acid via General Procedure B to give 24.5 mg of 389 after reverse phase HPLC purification. MS (Q1) 513.3 (M)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH:9][C:10](=[O:22])[C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[N:13][C:12]=2[CH3:21])[CH:5]=[CH:6][C:7]=1[Cl:8].[Cl:23][C:24]1[CH:25]=[C:26]([CH:30]=[CH:31][CH:32]=1)[C:27](Cl)=[O:28]>>[Cl:8][C:7]1[CH:6]=[CH:5][C:4]([NH:9][C:10](=[O:22])[C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[N:13][C:12]=2[CH3:21])=[CH:3][C:2]=1[NH:1][C:27](=[O:28])[C:26]1[CH:30]=[CH:31][CH:32]=[C:24]([Cl:23])[CH:25]=1
Reactant: O=C(Cl)c1cccc(Cl)c1
Reactant: Cc1nc(C(F)(F)F)ccc1C(=O)Nc1ccc(Cl)c(N)c1
Product: Cc1nc(C(F)(F)F)ccc1C(=O)Nc1ccc(Cl)c(NC(=O)c2cccc(Cl)c2)c1

Procedure:
N-(3-amino-4-chlorophenyl)-2-methyl-6-(trifluoromethyl)nicotinamide (0.182 mmol) was used in general procedure 1 with 3-chlorobenzoyl chloride (0.228 mmol). The product was purified by RP-HPLC to give N-(4-chloro-3-(3-chlorobenzoamido)phenyl)-2-methyl-6-(trifluoromethyl)-nicotinamide. MS (Q1) 469 (M)+
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:16])[C@H:10]([C@H:12]([CH2:14][CH3:15])[CH3:13])[NH2:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:17]1[CH2:23][S:20](=[O:22])(=[O:21])[O:19][CH2:18]1>C(#N)C>[CH2:1]([O:8][C:9]([C@@H:10]([NH:11][CH2:18][CH2:17][CH2:23][S:20]([OH:22])(=[O:21])=[O:19])[CH:12]([CH3:13])[CH2:14][CH3:15])=[O:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S1(=O)CCCO1
Reactant: CC[C@H](C)[C@H](N)C(=O)OCc1ccccc1
Solvent: CC#N
Product: CCC(C)[C@H](NCCCS(=O)(=O)O)C(=O)OCc1ccccc1
Temperature: 25 °C
Yield: 39.1 %

Procedure:
To a solution of L-isoleucine benzylester (1.41 g, 6.4 mmol) in acetonitrile (12 mL) was added 1,3-propane sultone (706 mg, 5.8 mmol). The solution was stirred at reflux for 2 hours. The reaction mixture was cooled to room temperature. The solid was filtered and washed with acetone (2×20 mL). The solid material was dissolved in 50% EtOH/water (50 mL). Dowex Marathon C ion exchange resin (strongly acidic, 10 g) was added to the solution. The suspension was stirred for 15 minutes before the resin was removed by filtration. The filtrate was evaporated under reduced pressure and lyophilized affording the title compound (778 mg, 39%). 1H NMR (D2O, 500 MHz) δ ppm 7.49 (m, 5H), 5.42 (d, 1H, J=11.7 Hz), 5.31 (d, 1H, J=11.7 Hz), 3.24 (m, 2H), 2.98 (m, 2H), 2.13 (m, 3H), 1.46 (m, 1H), 1.34 (m, 1H), 0.93 (m, 6H). 13C (D2O, 125 MHz) δ ppm 168.53, 134.69, 129.28, 129.22, 129.06, 68.86, 64.45, 48.12, 46.56, 36.21, 25.97, 21.31, 13.73, 11.05. [α]D=−1.5° (c=0.0031 in water), ES-MS 342 (M−1).
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[Cl:6][C:7]1[CH:8]=[C:9]([CH:13]=[C:14]([Cl:16])[CH:15]=1)[N:10]([CH3:12])[CH3:11].[C:17]([O-])(=[O:19])C.[Na+]>CN(C)C=O>[Cl:6][C:7]1[CH:8]=[C:9]([N:10]([CH3:12])[CH3:11])[CH:13]=[C:14]([Cl:16])[C:15]=1[CH:17]=[O:19]
Reactant: CC(=O)[O-]
Reactant: CN(C)c1cc(Cl)cc(Cl)c1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: CN(C)c1cc(Cl)c(C=O)c(Cl)c1
Temperature: 100 °C

Procedure:
Phosphoryl chloride (0.56 cm3, 6.1 mmol) was added dropwise to cooled N,N-dimethyl formamide (4 cm3) under nitrogen. 3,5-dichloro-N,N-dimethylaniline (1.16 g, 6.1 mmol) was then added to the solution which was then heated under nitrogen at 100° C. for 3 h. The solution was cooled, poured onto ice (6 g) and the mixture adjusted to pH 6 by addition of a saturated solution of sodium acetate. The suspended solid was collected and recrystallised from ethyl acetate-petroleum spirit 60°-80° C. mixture giving pale yellow needles of 2,6-dichloro-4-dimethylaminobenzaldehyde (0.8 g) mp 169°-71° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9](=[O:16])[N:10]2[CH2:13][CH:14]=C)=[N:5][CH:4]=1.I([O-])(=O)(=O)=[O:18].[Na+]>O1CCOCC1.O.[Os](=O)(=O)(=O)=O>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9](=[O:16])[N:10]2[CH2:13][CH:14]=[O:18])=[N:5][CH:4]=1
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: C=CCn1c(=O)ccc2ncc(OC)cc21
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: COc1cnc2ccc(=O)n(CC=O)c2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
7-(Methoxy)-1-(2-propen-1-yl)-1,5-naphthyridin-2(1H)-one (5.046 g, 23.361 mmol) was dissolved in 1,4-dioxane (100 mL) and water (100 mL). Sodium periodate (12.49 g, 58.402 mmol) was added, followed by osmium tetroxide (5 mL of 4% aqueous solution). The mixture stirred at rt for 1 h, water (200 ml) was added the mixture was stirred for a further 1 h. The reaction was concentrated to about 300 ml and extracted with 20% MeOH/DCM (3×400 ml). The organic extracts were combined, dried over anhydrous magnesium sulphate, filtered and evaporated under reduced pressure to give [7-(methoxy)-2-oxo-1,5-naphthyridin-1(2H)-yl]acetaldehyde (as the methyl hemiacetal) as a yellow solid (3.807 g, 75%).
Reaction SMILES: [C:1]1([CH:8]=[CH:7][CH:6]=[C:4]([OH:5])[CH:3]=1)[OH:2].[CH2:9]([CH:11]1[CH2:16][CH2:15][CH:14](O)[CH2:13][CH2:12]1)[CH3:10].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1>[CH2:9]([CH:11]1[CH2:16][CH2:15][CH:14]([O:2][C:1]2[CH:3]=[C:4]([OH:5])[CH:6]=[CH:7][CH:8]=2)[CH2:13][CH2:12]1)[CH3:10]
Reactant: CCC1CCC(O)CC1
Reactant: Oc1cccc(O)c1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCC1CCC(Oc2cccc(O)c2)CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 27 %

Procedure:
In a four necked flask (2 L) sufficiently dried, substituted with nitrogen, and equipped with a dropping funnel, Dimroth condenser tube, thermometer and stirring blade, resorcinol (72 g, 0.65 mol), 4-ethylcyclohexanol (92 g, 0.72 mol) and triphenylphosphine (185 g, 0.70 mol) were dissolved in dried tetrahydrofuran (700 ml) under a nitrogen gas stream, and a mixed solution of diisopropyl azodicarboxylate (132 g, 0.65 mol) and dried tetrahydrofuran (180 ml) was dropped for 1 hour while cooling with an iced saline solution. Next, it was stirred at room temperature for 12 hours. After the reaction terminated, 30% hydrogen peroxide (140 ml) was dropped through the dropping funnel for 10 minutes, then the reaction solution was dissolved in 1 L toluene, and washed three times with 500 ml water. Toluene was distilled away by evaporation, and the residue was purified by column chromatography using hexane and ethyl acetate as developing solvents, to obtain a red brown objective product (hereinafter, referred to as R-3A) (38.5 g, 27% yield, 99% GC purity).
Reaction SMILES: [C:1]1([C@@H:7]([NH:9][C:10]2[N:15]=[C:14]([N:16]3[C:20]4[CH:21]=[CH:22][C:23]([C:25]5[N:26]=[N:27][C:28](Cl)=[CH:29][CH:30]=5)=[CH:24][C:19]=4[N:18]=[CH:17]3)[CH:13]=[CH:12][N:11]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:32][NH:33][CH3:34]>C(O)C>[C:1]1([C@@H:7]([NH:9][C:10]2[N:15]=[C:14]([N:16]3[C:20]4[CH:21]=[CH:22][C:23]([C:25]5[N:26]=[N:27][C:28]([N:33]([CH3:34])[CH3:32])=[CH:29][CH:30]=5)=[CH:24][C:19]=4[N:18]=[CH:17]3)[CH:13]=[CH:12][N:11]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CNC
Reactant: C[C@H](Nc1nccc(-n2cnc3cc(-c4ccc(Cl)nn4)ccc32)n1)c1ccccc1
Solvent: CCO
Product: C[C@H](Nc1nccc(-n2cnc3cc(-c4ccc(N(C)C)nn4)ccc32)n1)c1ccccc1
Temperature: 60 °C

Procedure:
2-[(S)-1-phenylethylamino]-4-[5-(6-chloropyridazin-3-yl)benzimidazol-1-yl]pyrimidine (13.2 mg) was mixed with 33% dimethylamine in ethanol (1 mL) in a sealed tube, the system heated to 60° C. for 15 h. The mixture was cooled, concentrated and the residue purified on silica gel (2.5%MeOH in CH2Cl2) to yield 11.2 mg of the title compound. 1H NMR (500 MHz, CDCl3): δ 8.51 (br s, 1H); 8.41 (d, J=5.5 Hz, 1H); 8.27 (s, 1H); 8.19 (br s, 1H); 7.89 (br s, 1H); 7.73 (d, J=9.6 Hz, 1H); 7.46 (m, 2H); 7.41 (t, J=7.5 Hz, 2H); 7.30 (m, 1H); 6.93 (d, J=1H); 6.81 (d, J=5.5 Hz, 1H); 5.80 (br s, 1H); 5.22 (br s, 1H); 3.26 (s, 6H); 1.65 (d, J=6.9 Hz, 3H). Mass spectrum (ESI) 437.4 (M+1).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:8]([CH3:11])=[C:7]2[C:3]=1[CH2:4][CH:5]([C:12]([O:14][CH3:15])=[O:13])[NH:6]2.OO.[C:18](=O)([O-])[O-:19].[K+].[K+].S(OC)(OC)(=O)=O>CO>[CH3:18][O:19][N:6]1[C:7]2[C:3](=[C:2]([CH3:1])[CH:10]=[CH:9][C:8]=2[CH3:11])[CH:4]=[C:5]1[C:12]([O:14][CH3:15])=[O:13]
Reactant: O=C([O-])[O-]
Reactant: COC(=O)C1Cc2c(C)ccc(C)c2N1
Agent: OO
Agent: [K+]
Solvent: CO
Solvent: COS(=O)(=O)OC
Product: COC(=O)c1cc2c(C)ccc(C)c2n1OC
Temperature: 0 °C
Reaction time: 3 h
Yield: 35 %

Procedure:
A flask was charged with 1.0 g (4.9 mmol) of methyl 4,7-dimethylindoline-2-carboxylate and 64 mg (0.193 mmol) of sodium tungstate-dihydrate, and the air in the reaction system was substituted with nitrogen. After 15 ml of methanol was added and the reaction mixture was cooled to 0° C., 1.25 g of 30% aqueous hydrogen peroxide solution was added and the reaction mixture was stirred for 3 hours. Then 1.1 g of potassium carbonate and 0.68 g of dimethyl sulfate were added dropwise and the reaction mixture was stirred at 0° C. for 1 hour. The reaction mixture was added dropwise to ice water and extracted with 15 ml of ethyl acetate three times. The ethyl acetate layers were combined, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The crystals thus obtained were purified by silica gel column chromatography to provide 400 mg of white crystals. Yield: 36% m.p.: 90°-91° C.; 1H-NMR (300 MHz, CDCl3 /TMS; δppm): 7.16 (s, 1H), 7.00 (d, 1H), 6.82 (d, 1H), 4.11 (s, 3H), 3.94 (s, 3H), 2.68 (s, 3H), 2.48 (s,3H)
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]([C:24]3[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=3)=[C:10]([C:19](OCC)=[O:20])[C:11]([C:12]3[CH:13]=[N:14][CH:15]=[C:16]([CH3:18])[CH:17]=3)=[C:6]2[CH:5]=[N:4]1)[CH3:2].[H-].C([Al+]CC(C)C)C(C)C>C(Cl)Cl.C1(C)C=CC=CC=1>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]([C:24]3[CH:25]=[CH:26][C:27]([O:30][CH3:31])=[CH:28][CH:29]=3)=[C:10]([CH2:19][OH:20])[C:11]([C:12]3[CH:13]=[N:14][CH:15]=[C:16]([CH3:18])[CH:17]=3)=[C:6]2[CH:5]=[N:4]1)[CH3:2]
Reactant: CCOC(=O)c1c(-c2ccc(OC)cc2)nc2c(cnn2CC)c1-c1cncc(C)c1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CCn1ncc2c(-c3cncc(C)c3)c(CO)c(-c3ccc(OC)cc3)nc21
Temperature: -78 °C
Reaction time: 1.5 h
Yield: 26.5 %

Procedure:
To a stirred solution of ethyl 1-ethyl-6-(4-methoxyphenyl)-4-(5-methyl-3-pyridyl)-1H-pyrazolo[3,4-b]pyridine-5-carboxylate (88 mg) in DCM (3 ml) was added 1N diisobutylaluminum hydride in toluene (0.63 ml) at −78° C. and the reaction mixtrue was stirred at −78° C. for 1.5 hours. Another 1N diisobutylaluminum hydride in toluene (0.31 ml) was added at −78° C. and the reaction mxitrue was stirred at −78° C. for 2.5 hours. The reaction mixture was quenched with brine, filtrated through celite pad, and the filtrate was concentrated in vacuo. The residue-was purified by preparative thin layer chromatography eluting with a mixture of CHCl3 and MeOH (9:1) to give [1-ethyl-6-(4-methoxyphenyl)-4-(5-methyl-3-pyridyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]methanol (21 mg) as a light yellow oil.
Reaction SMILES: I[C:2]1[CH:12]=[CH:11][C:5]([C:6]([N:8]([CH3:10])[CH3:9])=[O:7])=[CH:4][CH:3]=1.[CH2:13]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][NH:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:14]#[CH:15]>>[CH3:9][N:8]([CH3:10])[C:6](=[O:7])[C:5]1[CH:11]=[CH:12][C:2]([C:15]#[C:14][CH2:13][O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][NH:23][CH2:24][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)=[CH:3][CH:4]=1
Reactant: C#CCOCCCCCCNCc1ccccc1
Reactant: CN(C)C(=O)c1ccc(I)cc1
Product: CN(C)C(=O)c1ccc(C#CCOCCCCCCNCc2ccccc2)cc1
Yield: 83 %

Procedure:
From 4-iodo-N,N-dimethylbenzamide (2.5 g) and N-[6-[(2-propynyl)oxy]- hexyl]benzenemethanamine (2.23 g). FCC purification eluting with ethyl acetate-triethylamine (100:1) gave the title compound as an orange oil (2.96 g), t.l.c. (Ethyl acetate+few drops triethylamine) Rf 0.15.