Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(O)(O)(=O)=O.[OH:6][NH:7][C:8]([CH3:15])([C:10]([NH:13][OH:14])([CH3:12])[CH3:11])[CH3:9].[CH:16]([C:18]1[CH:26]=[CH:25][C:21]([C:22]([OH:24])=[O:23])=[CH:20][CH:19]=1)=O>O>[OH:6][N:7]1[C:8]([CH3:15])([CH3:9])[C:10]([CH3:12])([CH3:11])[N:13]([OH:14])[CH:16]1[C:18]1[CH:26]=[CH:25][C:21]([C:22]([OH:24])=[O:23])=[CH:20][CH:19]=1
Reactant: CC(C)(NO)C(C)(C)NO
Reactant: O=Cc1ccc(C(=O)O)cc1
Agent: O=S(=O)(O)O
Solvent: O
Product: CC1(C)N(O)C(c2ccc(C(=O)O)cc2)N(O)C1(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 60.4 %

Procedure:
24.6 g of 2,3-bis-(hydroxyamino)-2,3-dimethylbutane sulfate was dissolved in 100 ml of water. After neutralized with 1M KHCO3 with cooling on ice, the solution was added with 15.0 g of p-formylbenzoic acid and was agitated overnight at room temperature. The precipitate was dried and 16.9 g of 1,3-dihydroxy-4,4,5,5-tetramethyl 2-(4-carboxyphenyl)imidazole (I) was obtained.
Reaction SMILES: [CH:1]1([N:5]2[C:9](=[O:10])[C:8]([NH:11]C(=O)OC(C)(C)C)=[C:7]([CH3:19])[N:6]2[CH3:20])[CH2:4][CH2:3][CH2:2]1.S(=O)(=O)(O)O>C(Cl)Cl.O>[NH2:11][C:8]1[C:9](=[O:10])[N:5]([CH:1]2[CH2:2][CH2:3][CH2:4]2)[N:6]([CH3:20])[C:7]=1[CH3:19]
Reactant: Cc1c(NC(=O)OC(C)(C)C)c(=O)n(C2CCC2)n1C
Agent: O=S(=O)(O)O
Solvent: O
Solvent: ClCCl
Product: Cc1c(N)c(=O)n(C2CCC2)n1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of tert-butyl (2-cyclobutyl-1,5-dimethyl-3-oxo-2,3-dihydro-1H-pyrazol-4-yl)carbamate in DCM (5 mL) was added sulfuric acid (0.034 mL, 0.634 mmol). The reaction mixture was stirred at room temperature overnight. Further sulfuric acid (0.068 mL, 1.268 mmol) was added to the reaction mixture and it was stirred for 2 hours. The resulting mixture was diluted with DCM and water and the layers separated. The aqueous layer was made basic by the dropwise addition of 2M NaOH (aq). The aqueous layer was extracted with DCM (×3) and the combined organic extracts were passed through a phase separating cartridge. The eluent was concentrated under reduced pressure to afford the title compound;
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[Cl:8][C:9]1[C:17]2[N:16]=[C:15]3[N:18]([C:22]4[CH:23]=[N:24][C:25]([O:29][CH3:30])=[CH:26][C:27]=4[CH3:28])[CH2:19][CH2:20][CH2:21][N:14]3[C:13]=2[C:12]([CH:31]([OH:34])[CH2:32][CH3:33])=[CH:11][CH:10]=1>N1C=CC=CC=1>[C:1]([O:34][CH:31]([C:12]1[C:13]2[N:14]3[CH2:21][CH2:20][CH2:19][N:18]([C:22]4[CH:23]=[N:24][C:25]([O:29][CH3:30])=[CH:26][C:27]=4[CH3:28])[C:15]3=[N:16][C:17]=2[C:9]([Cl:8])=[CH:10][CH:11]=1)[CH2:32][CH3:33])(=[O:3])[CH3:2]
Reactant: CCC(O)c1ccc(Cl)c2nc3n(c12)CCCN3c1cnc(OC)cc1C
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CCC(OC(C)=O)c1ccc(Cl)c2nc3n(c12)CCCN3c1cnc(OC)cc1C
Temperature: 25 °C
Reaction time: 19 h

Procedure:
Acetic anhydride (103 μL, 1.09 mmol) was added to a stirred solution of 1-[9-chloro-1-(6-methoxy-4-methylpyridin-3-yl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazol-6-yl]propan-1-ol (140 mg, 0.362 mmol) in pyridine (1.2 mL) at room temperature, and the mixture was stirred at room temperature for 19 hr. The mixture was concentrated in vacuo, diluted with saturated aqueous sodium hydrogen carbonate, and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 10-50% ethyl acetate/n-hexane gradient mixture. The filtrate was concentrated in vacuo to give the title compound as a colorless amorphous (89.9 mg, 0.210 mmol, 58%).
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].O.[C:6]1([CH3:12])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>>[N+:1]([C:9]1[CH:10]=[CH:11][C:6]([CH3:12])=[CH:7][CH:8]=1)([O-:4])=[O:2]
Reactant: Cc1ccccc1
Reactant: O=[N+]([O-])O
Solvent: O
Product: Cc1ccc([N+](=O)[O-])cc1

Procedure:
reacting toluene with nitric acid having an acid concentration of between about 60 and about 75 percent by weight, based upon the total amount of acid plus water, at a reaction temperature of between about 60° C. and about 75° C., and employing between about 3 and about 5 moles of nitric acid per mole of toluene, to produce mononitrotoluene,
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:9][N:10]([CH2:17][C:18]2[C:23]([CH:24]([CH3:26])[CH3:25])=[CH:22][CH:21]=[CH:20][N:19]=2)[CH:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1.C[Si]([N:31]=[C:32]=[O:33])(C)C>CC(O)C>[CH3:1][C:2]1[C:3]([CH2:9][N:10]([CH2:17][C:18]2[C:23]([CH:24]([CH3:26])[CH3:25])=[CH:22][CH:21]=[CH:20][N:19]=2)[CH:11]2[CH2:16][CH2:15][N:14]([C:32]([NH2:31])=[O:33])[CH2:13][CH2:12]2)=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: C[Si](C)(C)N=C=O
Reactant: Cc1cnc(CN(Cc2ncccc2C(C)C)C2CCNCC2)c(C)c1
Solvent: CC(C)O
Product: Cc1cnc(CN(Cc2ncccc2C(C)C)C2CCN(C(N)=O)CC2)c(C)c1
Yield: 72.8 %

Procedure:
(3,5-Dimethyl-pyridin-2-ylmethyl)-(3-isopropyl-pyridin-2-ylmethyl)-piperidin-4-yl-amine (145 mg, 0.41 mmol) was dissolved in i-PrOH (4 mL) and treated with trimethylsilylisocyanate (78 μL, 0.58 mmol) at room temperature for 16 hours. The solution was then concentrated under reduced pressure and dried in vacuo. The crude material was purified by column chromatography with silica gel (15:1:0.1 CH2Cl2/MeOH/NH4OH) to give COMPOUND 301 as a colorless oil (118 mg, 73%). 1H NMR (CDCl3) δ 0.93 (d, 6H, J=6.6 Hz), 1.66 (q, 2H, J=11.1 Hz), 1.89 (br d, 2H, J=12.3 Hz), 2.17 (s, 3H), 2.28 (s, 3H), 2.68 (br t, 3H, J=12.3 Hz), 2.82 (sept, 1H, J=6.6 Hz), 3.77 (s, 2H), 3.83 (s, 2H), 4.00 (br d, 2H, J=12.6 Hz), 4.45 (br, 2H(NH2)), 7.15 (m, 1H), 7.24 (s, 1H), 7.50 (d, 1H, J=7.2 Hz), 8.19 (s, 1H), 8.32 (d, 1H, J=3.6 Hz). 13C NMR (CDCl3) δ 17.91, 18.07, 23.21 (2C), 26.93 (2C), 27.00, 44.49 (2C), 53.97 (2C), 56.89, 122.79, 131.89, 132.84, 133.47, 138.68, 144.03, 145.03, 146.26, 154.10, 155.91, 157.78. ES-MS m/z 396 (M+H). Anal. Calcd. for C23H33N5O.0.8CH2Cl2: C, 67.39; H, 8.51; N, 17.08. Found: C, 67.33; H, 8.23; N, 17.27.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([OH:5])[CH3:4].[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14]Cl)=[CH:9][CH:8]=1.ClC1C=CC=CC=1>O>[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][NH:1][CH2:2][CH:3]([OH:5])[CH3:4])=[CH:9][CH:8]=1
Reactant: ClCCc1ccc(Cl)cc1
Reactant: CC(O)CN
Solvent: O
Solvent: Clc1ccccc1
Product: CC(O)CNCCc1ccc(Cl)cc1
Temperature: 85 °C
Reaction time: 2.5 h

Procedure:
Into a 250-mL round-bottom flask equipped with a magnetic stir bar, a thermocouple, a condenser, and a nitrogen bubbler vented to a caustic scrubber, was charged 1-aminopropan-2-ol (60.0 g, 799 mmol). The mixture was heated to 85° C. and the product from Step A was added while maintaining the reaction temperature below 98° C. Upon completion of the addition the reaction mixture was stirred at 90 to 95° C. for 2.5 h. Chlorobenzene (50 mL) and water (25 mL) were added and the mixture was stirred at 70 to 75° C. for 15 min. The phases were allowed to separate and the lower organic phase was removed. The upper aqueous phase was extracted with chlorobenzene (2×25 mL) at 70 to 75° C. The combined organic phases were washed with water (2×25 mL) at 70 and 75° C. and 87.5 g of solvent was removed by distillation under reduced pressure at 60° C. (bath). The residue was diluted with chlorobenzene (125 mL). The resulting orange solution, which contained 0.032% water by Karl Fischer titration, was stirred overnight at 45° C. (bath).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]=[CH:10]2)=[CH:5][CH:4]=1.CC[O:20]CC>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([N:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH2:11][C:10]2=[O:20])=[CH:7][CH:8]=1
Reactant: CCOCC
Reactant: COc1ccc(-n2ccc3ccccc32)cc1
Product: COc1ccc(N2C(=O)Cc3ccccc32)cc1

Procedure:
Omitting the final chromatography, but triturating the crude product three times with ether, 1-(4-methoxyphenyl)indole (18.1 g, 81 mmoles) was converted to title product, 12.0 g, m.p. 115°-117° C., pnmr/CDCl3 /TMS/delta: 3.65 (s, 2H), 3.8 (s, 3H), 6.6-7.4 (m, 8H).
Reaction SMILES: N(OCCC(C)C)=O.N[C:10]1[CH:29]=[C:28]([F:30])[C:27]([N:31]2[C:36](=[O:37])[CH:35]=[C:34]([C:38]([F:41])([F:40])[F:39])[N:33]([CH3:42])[C:32]2=[O:43])=[CH:26][C:11]=1[O:12][C:13]1[C:14]([O:20][CH2:21][C:22]([O:24][CH3:25])=[O:23])=[N:15][C:16]([Cl:19])=[CH:17][CH:18]=1.[ClH:44]>[Cu]Cl.[Cu](Cl)Cl.C(#N)C>[Cl:44][C:10]1[CH:29]=[C:28]([F:30])[C:27]([N:31]2[C:36](=[O:37])[CH:35]=[C:34]([C:38]([F:40])([F:41])[F:39])[N:33]([CH3:42])[C:32]2=[O:43])=[CH:26][C:11]=1[O:12][C:13]1[C:14]([O:20][CH2:21][C:22]([O:24][CH3:25])=[O:23])=[N:15][C:16]([Cl:19])=[CH:17][CH:18]=1
Reactant: Cl
Reactant: COC(=O)COc1nc(Cl)ccc1Oc1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c(F)cc1N
Agent: Cl[Cu]
Agent: Cl[Cu]Cl
Agent: CC(C)CCON=O
Solvent: CC#N
Product: COC(=O)COc1nc(Cl)ccc1Oc1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c(F)cc1Cl
Reaction time: 1 h

Procedure:
First, isoamyl nitrite is added dropwise to a mixture of methyl [3-{2-amino-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}-6-chloro-2-pyridyloxy]acetate, copper(I) chloride, copper(II) chloride, and acetonitrile at room temperature, and the mixture is stirred for 1 hour. The reaction mixture is poured into 2% hydrochloric acid, and the mixture is extracted with ethyl acetate. The organic layer is washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated. The residue is subjected to silica gel column chromatography to give methyl [3-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}-6-chloro-2-pyridyloxy]acetate (compound a-108).
Reaction SMILES: [NH2:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][CH3:15])[CH:7]=1)[CH2:3][CH2:4][OH:5].[C:16]1(=O)[O:21][C:19](=[O:20])[C:18]2=[CH:22][CH:23]=[CH:24][CH:25]=[C:17]12>CCOCC>[C:16]1(=[O:21])[N:1]([CH:2]([C:6]2[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][CH3:15])[CH:7]=2)[CH2:3][CH2:4][OH:5])[C:19](=[O:20])[C:18]2=[CH:22][CH:23]=[CH:24][CH:25]=[C:17]12
Reactant: O=C1OC(=O)c2ccccc21
Reactant: COc1ccc(C(N)CCO)cc1OC
Solvent: CCOCC
Product: COc1ccc(C(CCO)N2C(=O)c3ccccc3C2=O)cc1OC
Reaction time: 0.08 h
Yield: 73.2 %

Procedure:
A mixture of 3-amino-3-(3',4'-dimethoxyphenyl)-propan-1-ol (1.11 grams, 5 mmol) and phthalic anhydride (0.74 grams, 5 mmol) were melted together and stirred for 5 minutes. After cooling, a green/yellow glassy semi solid formed which was stirred in ether to afford 1.62 g (95%) of crude product as a white solid. The crude product was purified by flash chromatography (silica gel, 40% ethyl acetate/methylene chloride) to afford 1.25 grams (73%) of product as a white solid. 1H NMR (CDCl3)δ7.85-7.63 (m, 4H), 7.18-7.07 (m , 2H), 6.86-6.76 (m, 1H), 5.62-5.49(m, 1H), 3.88 (s, 3H), 3.85 (s, 3H), 3.79-3.63 (m, 2H), 2.89-2.71 (m, 1H), 2.64-2.47 (m, 1H), 1.87-1.73 (br m, 1H). 13C NMR (CDCl3)δ168.5, 148.8, 148.6, 133.9, 131.8, 131.7, 123.2, 120.7, 111.6, 110.8, 59.8, 55.0, 55.8, 51.4, 33.9. Anal. Calcd. for C19 H19NO5. Theoretical: C, 66.85; H, 5.61 ;N, 4.10. Found: C, 66.70; H, 5.60; N, 4.06. HPLC 100%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]#[CH:9].[F:10][C:11]([F:32])([F:31])[C:12]1[CH:13]=[C:14]([CH:24]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:26]=1)[CH2:15][N:16]1[C:20]([Cl:21])=[C:19]([CH:22]=[O:23])[N:18]=[N:17]1.O.Cl>C1COCC1.C[Mg]Br>[F:30][C:27]([F:28])([F:29])[C:25]1[CH:24]=[C:14]([CH:13]=[C:12]([C:11]([F:10])([F:32])[F:31])[CH:26]=1)[CH2:15][N:16]1[C:20]([Cl:21])=[C:19]([CH:22]([OH:23])[C:9]#[C:8][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])[N:18]=[N:17]1
Reactant: C#Cc1ccccc1Cl
Reactant: O=Cc1nnn(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1Cl
Agent: C[Mg]Br
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: OC(C#Cc1ccccc1Cl)c1nnn(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1Cl
Reaction time: 0.67 h

Procedure:
Dissolve 1-chloro-2-ethynyl-benzene (22.1 g, 162 mmol) in THF (300 mL) and slowly add methyl magnesium bromide (50 mL, 3.0 M in ether). Stir solution at RT for 40 min, then add a solution of 1-(3,5-bis-trifluoromethyl-benzyl)-5-chloro-1H-[1,2,3]triazole-4-carbaldehyde (29.6 g, 82.8 mmol) in THF (160 ml). Stir resulting solution at RT for 2 h then pour into cold water (500 mL) and 1N HCl (150 mL) and extract with EtOAc (3×200 mL). Combine the organic phases and wash with saturated NaHCO3 (200 mL) and brine (200 mL) then dry, filter, and concentrate. Purify the crude material by triturating with 30% ether/hexanes to give the title compound. MS (IS) 494.0 (M+1), MS (ES−) 492.0 (M−1); 1H NMR (400 MHz, CDCl3) δ 7.87 (s, 1H), 7.79 (s, 2H), 7.47 (dd, 1H, J=1.9, 7.3), 7.37 (dd, 1H, J=1.4, 7.9), 7.25 (dt, 1H, J=2.0, 7.3), 7.19 (dt, 1H, J=1.5, 7.3), 5.92 (d, 1H, J=6.7), 5.62 (s, 2H), 2.79 (d, 1H, J=6.4).
Reaction SMILES: [C:1]1([SH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Cl[CH2:11][C:12]1[C:17]([CH3:18])=[CH:16][C:15]([CH3:19])=[CH:14][C:13]=1[C:20]1[CH:25]=[CH:24][C:23]([F:26])=[C:22]([CH3:27])[CH:21]=1>CN(C=O)C>[F:26][C:23]1[CH:24]=[CH:25][C:20]([C:13]2[CH:14]=[C:15]([CH3:19])[CH:16]=[C:17]([CH3:18])[C:12]=2[CH2:11][S:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[CH:21][C:22]=1[CH3:27]
Reactant: Sc1ccccc1
Reactant: Cc1cc(C)c(CCl)c(-c2ccc(F)c(C)c2)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc(C)c(CSc2ccccc2)c(-c2ccc(F)c(C)c2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 98.6 %

Procedure:
Thiophenol (1.4 ml, 13.6 mmoles) was added dropwise to a stirred suspension of sodium hydride (0.653 g, 13.6 mmoles) in dry DMF under an atmosphere of nitrogen. The mixture was then heated at 50° C. for 30 minutes until all of the sodium hydride was consumed and hydrogen evolution ceased. To this solution was added a solution of 2-chloromethyl-4'-fluoro-3,3',5-trimethyl-1,1'-biphenyl (3.27 g crude, approximately 11.3 mmoles) in 8 ml of dry DMF and the mixture was heated at 50° with stirring for 30 minutes. The reaction was cooled to room temperature and partitioned between ether (200 ml) and dilute sodium hydroxide solution (50 ml). The ether solution was extracted with dilute sodium hydroxide solution (50 ml) again, then extracted with dilute sodium chloride solution (2×100 ml). The ether solution was then dried (MgSO4), filtered, and the solvent was evaporated to leave 3.75 g of product. This material was purified by flash chromatography on silica gel with a 60×150 mm column eluting with methylene chloride/hexane, 1/4 (v:v) to give 3.1 g of the title compound, m.p. 72°-74° C.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:18][CH:17]=2)[CH2:10][CH2:9]1)C1C=CC=CC=1.[H][H]>[Pd].C(O)C>[N:11]1([CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:18][CH:17]=2)[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1
Reactant: [H][H]
Reactant: CCOC(=O)CCc1ccc(CCN2CCN(Cc3ccccc3)CC2)cc1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)CCc1ccc(CCN2CCNCC2)cc1

Procedure:
A mixture of 57 g. (0.126 mole) ethyl 3-{4-[2-(1-benzylpiperazin-4-yl)-ethyl]-phenyl}-propionate and 200 ml. ethanol is hydrogenated, with the addition of 10% palladium-charcoal, at 50° C. and 50 bar hydrogen pressure in a shaking autoclave, then allowed to cool and filtered. After evaporation, the residue is dissolved in diethyl ether. The dihydrochloride is now precipitated out by adding hydrogen chloride-containing diethyl ether. The dihydrochloride is triturated with ethanol and filtered off with suction. Yield 31.0 g. (68% of theory) ethyl 3-{4-[2-(piperazin-1-yl)-ethyl]-phenyl}-propionate dihydrochloride; m.p. 243°-244° C.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[NH2:8][CH2:9][CH2:10][N:11]1[CH2:16][CH2:15][CH:14]([NH:17][C:18]2[N:19]([CH2:27][C:28]3[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=3)[C:20]3[C:25]([N:26]=2)=[CH:24][N:23]=[CH:22][N:21]=3)[CH2:13][CH2:12]1.C(=O)([O-])O.[Na+]>C(O)C>[F:34][C:31]1[CH:30]=[CH:29][C:28]([CH2:27][N:19]2[C:18]([NH:17][CH:14]3[CH2:13][CH2:12][N:11]([CH2:10][CH2:9][NH:8][C:2]4[N:7]=[CH:6][CH:5]=[CH:4][N:3]=4)[CH2:16][CH2:15]3)=[N:26][C:25]3[C:20]2=[N:21][CH:22]=[N:23][CH:24]=3)=[CH:33][CH:32]=1
Reactant: NCCN1CCC(Nc2nc3cncnc3n2Cc2ccc(F)cc2)CC1
Reactant: Clc1ncccn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: Fc1ccc(Cn2c(NC3CCN(CCNc4ncccn4)CC3)nc3cncnc32)cc1
Yield: 67 %

Procedure:
A mixture of 1.7 parts of 2-chloropyrimidine, 5.5 parts of N-[1-(2-aminoethyl)-4-piperidinyl]-9-[(4-fluorophenyl)methyl]-9H-purin-8-amine, 1.5 parts of sodium hydrogen carbonate and 160 parts of ethanol was stirred and refluxed for 20 hours. The reaction mixture was evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (95:5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from acetonitrile, yielding 4.5 parts (67%) of 9-[(4-fluorophenyl)methyl]-N-[1-[2-(2-pyrimidinylamino)ethyl]-4-piperidinyl]-9H-purin-8-amine; mp. 164.1° C. (compound 164).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][C:9]=2[Cl:15])=[C:6]([N:16]2[CH2:21][CH2:20][CH:19]([CH3:22])[CH2:18][CH2:17]2)[N:5]2[N:23]=[CH:24][N:25]=[C:4]2[N:3]=1.O.COC(C)(C)C.[CH3:33][N:34](C)C=O>[C-]#N.C([N+](CC)(CC)CC)C>[C:33]([C:2]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][C:9]=2[Cl:15])=[C:6]([N:16]2[CH2:21][CH2:20][CH:19]([CH3:22])[CH2:18][CH2:17]2)[N:5]2[N:23]=[CH:24][N:25]=[C:4]2[N:3]=1)#[N:34]
Reactant: CC1CCN(c2c(-c3ccc(F)cc3Cl)c(Cl)nc3ncnn23)CC1
Reactant: CN(C)C=O
Agent: CC[N+](CC)(CC)CC
Agent: [C-]#N
Solvent: O
Solvent: COC(C)(C)C
Product: CC1CCN(c2c(-c3ccc(F)cc3Cl)c(C#N)nc3ncnn23)CC1
Temperature: 22.5 °C
Reaction time: 16 h

Procedure:
A mixture of 5-chloro-6-(2-chloro-4-fluorophenyl)-7-(4-methylpiperidin-1-yl)-[1,2,4]-triazolo-[1,5-a]-pyrimidine (0.1 mol) and tetraethylammonium cyanide (0.25 mol) in 750 ml Dimethylformamide (DMF) was stirred for 16 hours at 20 to 25° C. To this mixture was added water and methyl-tert. butylether (MTBE), the organic phase was separated, washed with water, dried and filtered. The filtrate was evaporated and the residue was purified by column chromatography to yield 5.91 g of the title compound of mp. 247° C.
Reaction SMILES: C(O[CH:5]([C:28]1[CH:29]=[CH:30][C:31]2[N:35]=[C:34]3[S:36][CH:37]=[CH:38][N:33]3[C:32]=2[CH:39]=1)[C:6]1(Br)[C:12](=[O:13])[N:11]2[C@@H:7]1[S:8][CH:9]=[C:10]2[C:14]([O:16]CC1C=CC([N+]([O-])=O)=CC=1)=[O:15])(=O)C.[H][H]>C1COCC1.P([O-])([O-])([O-])=O>[O:13]=[C:12]1[N:11]2[C@H:7]([S:8][CH:9]=[C:10]2[C:14]([OH:16])=[O:15])/[C:6]/1=[CH:5]\[C:28]1[CH:29]=[CH:30][C:31]2[N:35]=[C:34]3[S:36][CH:37]=[CH:38][N:33]3[C:32]=2[CH:39]=1
Reactant: CC(=O)OC(c1ccc2nc3sccn3c2c1)C1(Br)C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=CS[C@@H]21
Reactant: [H][H]
Agent: O=P([O-])([O-])[O-]
Solvent: C1CCOC1
Product: O=C(O)C1=CS[C@@H]2/C(=C\c3ccc4nc5sccn5c4c3)C(=O)N12
Yield: 9.3 %

Procedure:
4-nitrobenzyl (5R)-6-[(acetyloxy)([1,3]thiazolo[3,2-a]benzimidazol-6-yl)methyl]-6-bromo-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (630 mg, 1 mmol) was suspended in 20 ml THF and 20 ml pH=6.5 aqueous phosphate buffer. The mixture was then subjected to 45 psi hydrogen for two hours. Then it was filtered through a pad of celite and concentrated in vacuo to remove most of the THF. The solution was then cooled to zero degree and basified to pH=8 with 1 N sodium hydroxide. Then it was purified via reverse phase HPLC using 1 liter of water followed by 5%˜25% acetonitrile and water. Water was then removed through concentrate in vacuo and 33 mg of product (Yield 8%) was collected. MP: >250° C.;
Reaction SMILES: [CH3:1][C@H:2]1[NH:7][CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3]1.CCN(C(C)C)C(C)C.[F:24][C:25]([F:38])([F:37])[O:26][C:27]1[CH:32]=[CH:31][C:30]([S:33](Cl)(=[O:35])=[O:34])=[CH:29][CH:28]=1.Cl>C(Cl)Cl>[CH3:1][C@H:2]1[N:7]([S:33]([C:30]2[CH:29]=[CH:28][C:27]([O:26][C:25]([F:24])([F:37])[F:38])=[CH:32][CH:31]=2)(=[O:35])=[O:34])[CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:13])([CH3:12])[CH3:14])=[O:9])[CH2:3]1
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)CCN1
Reactant: O=S(=O)(Cl)c1ccc(OC(F)(F)F)cc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C[C@@H]1CN(C(=O)OC(C)(C)C)CCN1S(=O)(=O)c1ccc(OC(F)(F)F)cc1

Procedure:
To a solution of 1,1-dimethylethyl(3R)-3-methyl-1-piperazinecarboxylate (605 mg, 2.56 mmol) in DCM (20 ml) was added DIPEA (1.12 ml, 6.39 mmol) and then portionwise 4-[(trifluoromethyl)oxy]benzenesulfonyl chloride (0.455 ml, 2.68 mmol) at room temp and the resultant mixture stirred under Ar for 16 h. DCM (75 ml) and a 1M HCl solution (75 ml) were added, the layers were separated and the organic layer was then washed with 2M NaOH solution (75 ml), the organic layers were separated, dried (MgSO4) and concentrated to dryness. 1,1-Dimethylethyl(3R)-3-methyl-4-({4-[(trifluoromethyl)oxy]phenyl}sulfonyl)-1-piperazinecarboxylate was isolated as a slowly crystallizing white solid.
Reaction SMILES: C[O-].[Na+].[C:4]([CH2:6][C:7]([NH2:9])=[O:8])#[N:5].[Cl:10][C:11]1[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[C:12]=1[C:13]([C:15]1[CH:24]=[CH:23][C:18]([CH2:19][N:20]=[N+:21]=[N-:22])=[CH:17][CH:16]=1)=[O:14].C(O)(=O)C>C(O)C>[NH2:5][C:4]1[N:20]([CH2:19][C:18]2[CH:17]=[CH:16][C:15]([C:13](=[O:14])[C:12]3[C:25]([Cl:29])=[CH:26][CH:27]=[CH:28][C:11]=3[Cl:10])=[CH:24][CH:23]=2)[N:21]=[N:22][C:6]=1[C:7]([NH2:9])=[O:8]
Reactant: [N-]=[N+]=NCc1ccc(C(=O)c2c(Cl)cccc2Cl)cc1
Reactant: N#CCC(N)=O
Agent: C[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Product: NC(=O)c1nnn(Cc2ccc(C(=O)c3c(Cl)cccc3Cl)cc2)c1N
Reaction time: 0.17 h
Yield: 4.9 %

Procedure:
A stirred, 65° C. mixture of sodium methoxide (330 mg, 6.11 mmol) in absolute ethanol (20 ml) was treated with 2-cyanoacetamide (527 mg, 6.27 mmol) and kept 10 minutes. The resulting suspension was treated with 4-(2,6-dichlorobenzoyl)benzyl azide (1.6 g, 5.2 mmol), refluxed 2 hours, cooled, treated with glacial acetic acid (600 μl, 629 mg, 10.5 mmol), and evaporated to dryness under vacuum. The residue was chromatographed on a column of silica gel (100 g) eluted with 19:1 (v/v) dichloromethane-methanol to provide 100 mg (5%) 5-amino-1-(4-[2,6-dichlorobenzoyl]benzyl)-1,2,3-triazole-4-carboxamide, m.p. 165°-167° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][C:9]([CH3:18])([CH3:17])[C:10]([O:12]C(C)(C)C)=[O:11])=[CH:6][C:5]([Cl:19])=[CH:4][N:3]=1.FC(F)(F)C(O)=O>ClCCl>[Cl:1][C:2]1[C:7]([O:8][C:9]([CH3:17])([CH3:18])[C:10]([OH:12])=[O:11])=[CH:6][C:5]([Cl:19])=[CH:4][N:3]=1
Reactant: CC(C)(C)OC(=O)C(C)(C)Oc1cc(Cl)cnc1Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(Oc1cc(Cl)cnc1Cl)C(=O)O
Reaction time: 8 h
Yield: 125.5 %

Procedure:
To a dichloromethane solution (157 ml) of tert-butyl 2-[(2,5-dichloropyridin-3-yl)oxy]-2-methylpropionate (79.1 g) was added at 0° C. trifluoroacetic acid (157 ml). The reaction solution was brought back to room temperature, stirred overnight, and then concentrated under reduced pressure. The residue was dissolved in ethyl acetate, washed sequentially with water and saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was azeotroped with toluene to afford 2-[(2,5-dichloropyridin-3-yl)oxy]-2-methylpropionic acid (81.1 g).