Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[C:17]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[C:9]([NH2:18])[C:8]=2[N:7]=[C:6]1[CH2:19][CH2:20][CH2:21][CH3:22].[C:23](Cl)(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CN1CCCC1=O>[NH2:18][C:9]1[C:8]2[N:7]=[C:6]([CH2:19][CH2:20][CH2:21][CH3:22])[N:5]([CH2:4][CH2:3][CH2:2][NH:1][C:23](=[O:30])[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:17]=2[C:16]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:10]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CCCCc1nc2c(N)nc3ccccc3c2n1CCCN
Solvent: CN1CCCC1=O
Product: CCCCc1nc2c(N)nc3ccccc3c2n1CCCNC(=O)c1ccccc1
Yield: 39.5 %

Procedure:
Under a nitrogen atmnosphere triethylamine (765 mg, 7.56 mmol) was added to a solution of 1-(3-aminopropyl)-2-butyl-1H-imidazo[4,5-c]quinolin-4-amine (1.50 g, 5.04 mmol) in 1-methyl-2-pyrrolidinone (50 mL). Benzoyl chloride (972 mg, 5.55 mmol) was added dropwise. When analysis by HPLC indicated that the reaction was complete, the reaction solution was poured into distilled water (500 mL). The pH was adjusted to 10 using solid potassium carbonate. A solid was isolated by filtration, rinsed with water and then dried in a vacuum oven. This material was stirred with chloroform (500 mL) and then filtered. The filtrate was loaded onto a silica gel column. The column was eluted with 1-5% methanol in chloroform. The purified material was dried in a vacuum oven to provide 800 mg of N-[3-(4-amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)propyl]benzamide as a solid, m.p. 189.4-190.0° C. Analysis: Calculated for C24H27N5O.0.82 H2O: % C, 69.25; % H, 6.93; % N, 16.82. Found: % C, 69.50; % H, 7.15; % N, 17.02.
Reaction SMILES: [C:1]([O:5][C:6]1[C:7]([CH:12]=O)=[N:8][CH:9]=[CH:10][N:11]=1)([CH3:4])([CH3:3])[CH3:2].[F:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[S:21]([CH2:23][CH:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1)=[O:22].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>ClCCl.C(OCC)(=O)C>[C:1]([O:5][C:6]1[C:7]([CH2:12][N:27]2[CH2:28][CH2:29][CH:24]([CH2:23][S:21]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[F:14])=[O:22])[CH2:25][CH2:26]2)=[N:8][CH:9]=[CH:10][N:11]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: O=S(CC1CCNCC1)c1ccccc1F
Reactant: CC(C)(C)Oc1nccnc1C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)(C)Oc1nccnc1CN1CCC(CS(=O)c2ccccc2F)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 52.2 %

Procedure:
After then dissolving 44 mg of 3-tert-butoxypyrazine-2-carboxaldehyde and 49 mg of the 4-[(2-fluorophenylsulfinyl)methyl]piperidine in 2 ml of dichloromethane, 65 mg of sodium triacetoxyborohydride was added and the mixture was stirred overnight at room temperature. A 1N sodium hydroxide solution was added to the reaction mixture and extraction was performed with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (solvent: ethyl acetate/methanol) to obtain the title compound (43 mg, 52% yield).
Reaction SMILES: C[O:2][C:3](=[O:36])[CH:4]([CH2:24][CH:25]=[CH:26][CH2:27][P:28]([O:33][CH2:34][CH3:35])([O:30][CH2:31][CH3:32])=[O:29])[CH2:5][C:6]([CH3:23])=[CH:7][CH2:8][C:9]1[C:10]([OH:22])=[C:11]2[C:15](=[C:16]([CH3:20])[C:17]=1[O:18][CH3:19])[CH2:14][O:13][C:12]2=[O:21].[OH-].[Li+]>C1COCC1.O>[CH2:31]([O:30][P:28]([CH2:27][CH:26]=[CH:25][CH2:24][CH:4]([CH2:5][C:6]([CH3:23])=[CH:7][CH2:8][C:9]1[C:10]([OH:22])=[C:11]2[C:15](=[C:16]([CH3:20])[C:17]=1[O:18][CH3:19])[CH2:14][O:13][C:12]2=[O:21])[C:3]([OH:36])=[O:2])([O:33][CH2:34][CH3:35])=[O:29])[CH3:32]
Reactant: CCOP(=O)(CC=CCC(CC(C)=CCc1c(O)c2c(c(C)c1OC)COC2=O)C(=O)OC)OCC
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCOP(=O)(CC=CCC(CC(C)=CCc1c(O)c2c(c(C)c1OC)COC2=O)C(=O)O)OCC
Temperature: 25 °C
Reaction time: 6 h
Yield: 93.3 %

Procedure:
A mixture of 2-[4-(diethoxy-phosphoryl)-but-2-enyl]-6-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-4-methyl-hex-4-enoic acid methyl ester 4C (33 mg, 0.063 mmol) and lithium hydroxide (44 mg) in a mixture of THF (6 mL) and water (1 mL) was stirred at room temperature for 6 hours. The organic solvent was removed and the residue was partitioned between ethyl acetate and 5% aqueous sodium bicarbonate. The aqueous layer was acidified with 2 N HCl and extracted with ethyl acetate. The ethyl acetate extract was concentrated, affording 2-[4-(diethoxy-phosphoryl)-but-2-enyl]-6-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-4-methyl-hex-4-enoic acid 4D as an oil (30 mg, 100%); 1H NMR (300 MHz, CDCl3) δ 1.27 (m, 6H), 1.79 (s, 3H), 2.0-2.7 (m, 8H), 3.37 (d, J=6.6 Hz), 3.75 (s, 3H), 4.08 (m, 4H), 5.19 (s, 2H), 5.25 (m, 1H), 5.44 (m, 1H), 5.55 (m, 1H), 5.45 (m, 2H) ppm.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[C:23]([OH:26])[CH:24]=3)[CH:19]=[CH:18][CH:17]=2)=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:34][S:35](Cl)(=[O:37])=[O:36]>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[C:23]([O:26][S:35]([CH3:34])(=[O:37])=[O:36])[CH:24]=3)[CH:19]=[CH:18][CH:17]=2)=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)c2cccc3ccc(O)cc23)CC1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(C(=O)c2cccc3ccc(OS(C)(=O)=O)cc23)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of the product from Step E (426 mg, 1.19 mmol) in 5 mL of DMF at 0° C. was added triethylamine (0.532 mL, 3.82 mmol), followed by methanesulfonyl chloride (0.212 mL, 2.73 mmol). The reaction was stirred at room temperature overnight, then partitioned between EtOAc and 50% NaHCO3 solution. The organic layer was washed with water and brine, dried (MgSO4), filtered, and concentrated in vacuo. The product was isolated as a yellow gum which was used without further purification.
Reaction SMILES: C(OC1N[CH2:6][CH2:7][N:8]=1)C.[OH-:9].[Na+].S>O>[NH2:8][C@H:7]([C:6]([OH:9])=[O:9])[CH2:7][CH2:6][O:9][NH:8][C:7]([CH3:6])=[NH:8]
Reactant: [OH-]
Reactant: CCOC1=NCCN1
Agent: S
Agent: [Na+]
Solvent: O
Product: CC(=N)NOCC[C@H](N)C(=O)O
Yield: 16 %

Procedure:
The ethylene analog of canavanine 8, was obtained by treatment of the copper salt of L-canaline (1 mmol, 7), prepared as described for 4, with 2-ethoxyimidazoline (240 mg, 1.8 mmol) in water (5 mL) at 45° C. for 4 days. After adjusting the solution to pH 5.0 with 1N NaOH, hydrogen sulfide was bubbled through for 5 min. The acidic reaction mixture was filtered and the filtrate adjusted to pH 3.4 with 1N NaOH. This solution was applied to a 25 cm3 column of Dowex 50×8 (NH4+) and the resin was washed with distilled water (500 mL) followed by 0.2N NH4OH (400 mL). The ammonia wash was evaporated to dryness by rotary evaporation in vacuo, and the resulting residue was purified by cellulose column chromatography (25×1 cm) by elution with n-BuOH:AcOH:H2O (4:1:1). Fractions containing 8 were combined and the solvent was removed by rotary evaporation in vacuo to give pure 8 (29 mg, 16%) as a glassy solid; [α]D23 =+9.6° (c=2.4, H2O); 1H-NMR (D2O): δ4.08-4.17 (m, 2H, 4-CH2), 3.90 (t, J=6.0 Hz, 1H, 2-CH), 3.80 (s, 4H, NCH2CH2N), 2.27 (dt, J=6.0 Hz, 2H, 3-CH2) ppm; 13C-NMR (CDCl3): δ176.66 (C-1), 164.09 (C=N), 75.72 (C-4), 54.99 (C-2), 45.75 (2×NCH2), 31.51 (C-3) ppm; HRFABMS calcd. for C7H14N4O3 203.1144 (MH+), found 203.1128.
Reaction SMILES: [O:1]=[C:2]1[C@@H:5]([NH:6]C(=O)OCC2C=CC=CC=2)[C@@H:4]([CH2:17][N:18]2[CH2:22][CH2:21][O:20][C:19]2=[O:23])[NH:3]1>CCO.CO.[Pd]>[NH2:6][C@@H:5]1[C:2](=[O:1])[NH:3][C@@H:4]1[CH2:17][N:18]1[CH2:22][CH2:21][O:20][C:19]1=[O:23]
Reactant: O=C(N[C@@H]1C(=O)N[C@@H]1CN1CCOC1=O)OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Solvent: CO
Product: N[C@@H]1C(=O)N[C@@H]1CN1CCOC1=O

Procedure:
Prepared in an analogous manner to example 4, step 3 using benzyl ((3S,4R)-2-oxo-4-((2-oxooxazolidin-3-yl)methyl)azetidin-3-yl)carbamate (96 mg, 0.30 mmol) and Pd/C 10% Degussa type 101 (10%, 64 mg) in EtOH:MeOH (4:1, 1.5 mL) for 1 h. The crude residue was used as such in following step. LCMS: Rt=0.11 min, m/z=186.0 (M+1) Method 2m_acidic.
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][O:6][CH2:7][CH2:8][OH:9])[CH3:2].C(=O)(OCC)O[CH2:12][CH3:13].[Mg].[Al]>>[CH2:1]([O:3][CH2:4][CH2:5][O:6][CH2:7][CH2:8][O:9][CH2:12][CH3:13])[CH3:2]
Reactant: CCOCCOCCO
Reactant: CCOC(=O)OCC
Agent: [Al]
Agent: [Mg]
Product: CCOCCOCCOCC
Reaction time: 1 h

Procedure:
A mixture of 2-(2-ethoxyethoxy)ethanol (1 mole) and diethyl carbonate (3 mole) was passed through 11.5 grams of a magnesium:aluminum mixed metal oxide (3/16 inch pellets, Mg/Al 3:1) at a temperature of 225° C. and at a liquid feed rate of 0.29 milliliters/minute. After a period of one hour, a total of 30.2 grams of liquid was collected. Analysis was performed by capillary gas chromatography (FID) using a DB-1701 column. The results were (area %) as follows:
Reaction SMILES: [CH2:1]([O:8][CH:9]1[CH2:12][C:11]([NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])([C:13]([O:15]CCC(C)C)=[O:14])[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].O>CO>[CH2:1]([O:8][CH:9]1[CH2:12][C:11]([NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])([C:13]([OH:15])=[O:14])[CH2:10]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)CCOC(=O)C1(NC(=O)OC(C)(C)C)CC(OCc2ccccc2)C1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)NC1(C(=O)O)CC(OCc2ccccc2)C1
Temperature: 0 °C

Procedure:
A 45.28 g (115.7 mmol) portion of 1-benzyloxy-3-(tert-butoxycarbonylamino)-3-isoamyloxycarbonylcyclobutane was dissolved in 300 ml of methanol to which, while cooling in an ice bath with stirring, was subsequently added dropwise 127 ml (127.2 mmol) of 1 N sodium hydroxide in 10 minutes. After 10 minutes of stirring, the ice bath was detached and the reaction mixture was stirred at room temperature for 5 hours. This was mixed with 200 ml of water, and methanol was evaporated under a reduced pressure. The thus obtained residue was mixed with ether to effect separation of layers, the resulting aqueous layer was extracted with diethyl ether, and the ether layer was extracted with water. The aqueous layers were combined, acidified with 10% citric acid while cooling in an ice bath with stirring and then mixed with ethyl acetate to effect separation of layers. The resulting organic layer was washed with saturated brine, and the aqueous layer was further extracted with ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate and then filtered, and the solvent was evaporated under a reduced pressure to give 37.24 g (quantitative) of the title compound. This compound was used in the following reaction without purification.
Reaction SMILES: NN.[F:3][CH2:4][C:5]1[CH:6]=[C:7]([N:11]([CH2:13][C:14]([O:16]C)=O)[NH2:12])[CH:8]=[CH:9][CH:10]=1.[O-:18][C:19]#[N:20].[Na+].FC(F)(F)C(O)=O.C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1>[F:3][CH2:4][C:5]1[CH:6]=[C:7]([N:11]2[CH2:13][C:14](=[O:16])[NH:20][C:19](=[O:18])[NH:12]2)[CH:8]=[CH:9][CH:10]=1
Reactant: N#C[O-]
Reactant: COC(=O)CN(N)c1cccc(CF)c1
Agent: NN
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: O=C1CN(c2cccc(CF)c2)NC(=O)N1
Reaction time: 2.25 h
Yield: 78 %

Procedure:
The hydrazine (Intermediate 55, 1.5 g, 7.1 mmol) was dissolved in dry toluene (30 ml) under nitrogen at room temperature. Sodium cyanate (1.6 g, 24.6 mmol) was added followed by trifluoroacetic acid (1.7 ml, 22,1 mmol). The reaction was stirred for 2.25 h after which the reaction was poured into saturated sodium bicarbonate solution (100 ml) and extracted with ethyl acetate (4×(100 ml). The combined extracts were dried (Na2SO4) and concentrated in vacuo to give a white solid. The crude material was triturated with ether (2×100 ml) to give the title compound (Intermediate 56, 1.41 g, 78%) as a colourless powder, m.p. 169°-70°.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[H-].[Na+].[OH:11][C:12]1[CH:17]=[CH:16][O:15][CH2:14][CH:13]=1>CN(C)C=O.[Cl-].[Na+].O>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([O:11][CH:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[N:3][CH:4]=1
Reactant: Brc1ccc(Br)nc1
Reactant: OC1=CCOC=C1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Brc1ccc(OC2CCOCC2)nc1
Temperature: 0 °C
Yield: 87.2 %

Procedure:
A solution of 2,5-dibromopyridine (9.5 g, 40 mmol) in N,N-dimethylformamide (100 mL) was treated with sodium hydride (60% dispersion in mineral oil, 2.4 g, 60 mmol). The mixture was cooled to 0° C. and 4-hydroxypyran (3.8 mL, 40 mmol) was added slowly. The resultant mixture was stirred at room temperature for 24 hours, then was added to dilute brine solution and was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, was filtered, and the solvent was removed in vacuo. The residue was purified by silica gel chromatography (40:1 hexanes-ethyl acetate) to afford 9.0 g (87% yield) of the title compound. 13C NMR (100 MHz, CDCl3) d 162.0, 147.6, 141.5, 113.5, 111.7, 70.3, 65.7, 32.1; MS (AP/Cl) 258.2, 260.2 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13](=[O:14])[C:12](=[N:15][NH:16][C:17]3[C:18]([OH:32])=[C:19]([C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([OH:31])=[O:30])[CH:24]=4)[CH:20]=[CH:21][CH:22]=3)[C:11]([CH3:33])=[N:10]2)[CH:5]=[CH:6][C:7]=1[CH3:8].[CH2:34]([CH2:36][NH2:37])[OH:35]>O>[CH3:8][C:7]1[CH:6]=[CH:5][C:4]([N:9]2[N:10]=[C:11]([CH3:33])/[C:12](=[N:15]/[NH:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([OH:31])=[O:30])[CH:24]=4)[C:18]=3[OH:32])/[C:13]2=[O:14])=[CH:3][C:2]=1[CH3:1].[CH2:36]([NH2:37])[CH2:34][OH:35]
Reactant: CC1=NN(c2ccc(C)c(C)c2)C(=O)C1=NNc1cccc(-c2cccc(C(=O)O)c2)c1O
Solvent: NCCO
Solvent: O
Product: CC1=NN(c2ccc(C)c(C)c2)C(=O)/C1=N\Nc1cccc(-c2cccc(C(=O)O)c2)c1O
Reaction time: 1 h

Procedure:
To a mixture of 3′-{N′-[1-(3,4-dimethylphenyl)-3-methyl-5-oxo-1,5-dihydro-pyrazol-4-ylidene]hydrazino}-2′-hydroxybiphenyl-3-carboxylic acid (2 g) in water (40 mL), ethanolamine (2.5 g) was added and heated to about reflux temperature for about 2 hours. The mixture was cooled to about 0° C. to about 10° C. and stirred for about 1 hour. The reaction mixture was filtered, washed with water (10 mL) and dried in an oven at about 55° C. to about 60° C. for about 12 hours to get purple solid.
Reaction SMILES: [CH2:1]([C:5]1(C=O)[NH:9][CH:8]=[CH:7][N:6]1[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[Cl:17])[CH2:2][CH2:3][CH3:4].C[Li].[O:22]1CC[CH2:24][CH2:23]1>>[CH2:1]([C:5]1[N:6]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[Cl:17])[C:7]([CH:23]([OH:22])[CH3:24])=[CH:8][N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: C1CCOC1
Reactant: CCCCC1(C=O)NC=CN1Cc1ccccc1Cl
Agent: [Li]C
Product: CCCCc1ncc(C(C)O)n1Cc1ccccc1Cl
Temperature: -78 °C
Reaction time: 1.5 h
Yield: 92 %

Procedure:
A solution of 2-n-butyl-1-(2-chlorophenyl)methyl-1H- imidazol-carboxaldehyde (Example 1 (iii)) (1.1 g, 3.97 mmol) was dissolved in dry tetrahydrofuran (15 mL), cooled to -78° C. under argon and a solution of methyl lithium (3.64 ml of 1.2M in diethyl ether, 4.57 mmol) was added dropwise. The mixture was stirred for 1.5 hours, quenched with ammonium chloride solution, warmed to ambient temperature and extracted with ethyl acetate. The washed, dried, concentrated product was flashed chromatographed over silica gel with ethyl acetate to provide 1.07 g (92%) of 2-n-butyl-1-(2-chlorophenyl)methyl-5-(a-hydroxy) ethyl-1H-imidazole.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([Cl:14])=[CH:9][C:8]=2[Cl:15])[N:5]=[C:4]([CH:16]2[CH2:18][CH2:17]2)[C:3]=1[C:19]([NH2:21])=[O:20].[OH:22][C:23]1[CH:24]=[C:25]([CH2:31][C:32](OCC)=O)[CH:26]=[CH:27][C:28]=1[O:29][CH3:30].[O-]CC.[Na+]>C(O)C>[Cl:13][C:12]1[CH:11]=[C:10]([Cl:14])[CH:9]=[C:8]([Cl:15])[C:7]=1[N:6]1[C:2]2=[N:1][C:32]([CH2:31][C:25]3[CH:26]=[CH:27][C:28]([O:29][CH3:30])=[C:23]([OH:22])[CH:24]=3)=[N:21][C:19](=[O:20])[C:3]2=[C:4]([CH:16]2[CH2:17][CH2:18]2)[NH:5]1
Reactant: NC(=O)c1c(C2CC2)nn(-c2c(Cl)cc(Cl)cc2Cl)c1N
Reactant: CCOC(=O)Cc1ccc(OC)c(O)c1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: COc1ccc(Cc2nc3n(-c4c(Cl)cc(Cl)cc4Cl)[nH]c(C4CC4)c-3c(=O)n2)cc1O
Temperature: 25 °C
Reaction time: 18 h
Yield: 22.3 %

Procedure:
To a stirred solution of 146 mg (0.42 mmol) of 5-amino-3-cyclopropyl-1-(2,4,6-trichlorophenyl)pyrazole-4-carboxamide in 6 mL of absolute ethanol was added 533 mg (2.53 mmol) of ethyl 3-hydroxy-4-methoxyphenylacetate followed by 1.91 mL (5.1 mmol) of 2.66 M sodium ethoxide in ethanol. The solution was stirred 18 h at reflux, and the heating mantle was then removed. The reaction was treated with 5 mL of 10% aq. HOAc, cooled to ambient temperature, and filtered. The filtrate was washed with 6 mL of 1:1 water-methanol then 6 mL of 1:1 ether-hexanes. The off-white solid was briefly air-dried to give 46 mg (22%) of 1-(2,4,6-trichlorophenyl)-3-cyclopropyl-6-(3-hydroxy-4-methoxybenzyl)pyrazolo[3,4-d]pyrimidin-4-one. Mass Spec.: 489 (M−H)−.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:7]=[C:8]([O:10][CH3:11])[CH:9]=1)[NH2:6].[C:12](Cl)(Cl)=[O:13]>C1(C)C=CC=CC=1>[CH3:11][O:10][C:8]1[CH:7]=[C:5]([N:6]=[C:12]=[O:13])[CH:4]=[C:3]([O:2][CH3:1])[CH:9]=1
Reactant: COc1cc(N)cc(OC)c1
Reactant: O=C(Cl)Cl
Solvent: Cc1ccccc1
Product: COc1cc(N=C=O)cc(OC)c1
Temperature: 25 °C
Yield: 96.9 %

Procedure:
A mixture of 3,5-dimethoxyaniline (1.5 g) in toluene (20 ml) was dropwise added to a toluene solution containing 10 g of phosgene at 10° to 20° C. The resulting mixture was gradually heated and, after being refluxed for 30 minutes, cooled to room temperature. The solvent was removed by distillation under reduced pressure to give 3,5-dimethoxyphenyl isocyanate (1.7 g). The thus obtained crude substance was added to a toluene solution (50 ml) containing triethylamine (1 g) and propargyl alcohol (2 g). The resultant mixture was allowed to stand at room temperature for 12 hours, poured into ice-water and extracted with ethyl acetate. The extract was washed with water, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by recrystallization from toluene to give propargyl N-(3,5-dimethoxyphenyl)carbamate (1.7 g) in a yield of 75 % (calculated from the starting 3,5-dimethoxyaniline). M.P., 139.5°-140.5° C.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([S:12]([NH:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)(=[O:14])=[O:13])[C:9]([O:24]C)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2>C(Cl)Cl>[Cl:1][C:2]1[CH:11]=[C:10]([S:12]([NH:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)(=[O:13])=[O:14])[C:9]([OH:24])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: COc1c(S(=O)(=O)NCc2ccc(Cl)cc2)cc(Cl)c2cccnc12
Solvent: ClCCl
Product: O=S(=O)(NCc1ccc(Cl)cc1)c1cc(Cl)c2cccnc2c1O

Procedure:
Under N2, a flame-dried, 50-mL, two-necked flask is charged with 5-chloro-N-[(4-chlorophenyl)methyl]-8-methoxy-7-quinolinesulfonamide (0.322 g), which is the first title compound of Preparation 9, and CH2Cl2 (20 mL) and is cooled in a dry ice/acetone bath. 1.0 M BBr3 (1.05 mL) is added dropwise. The cooling bath is removed and the reaction mixture is allowed to stir for 1.5 hrs. It is then poured into 75 mL 5% NaHCO3 aqueous solution, and the layers are separated. The aqueous layer is extracted twice with CH2Cl2. The combined organic layers are washed with H2O and then brine, dried over MgSO4, filtered and concentrated to a brown residue. Purification by column chromatography (elution with 2-5% MeOH/ CH2Cl2 with <1% AcOH) yields 0.037 g of the title compound as a pale yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]2[C:14]3[CH:15]=[C:16]([C:19]4[O:23][C:22]([NH2:24])=[N:21][N:20]=4)[CH:17]=[CH:18][C:13]=3[O:12][CH:11]=2)[CH:5]=[CH:6][C:7]=1[S:8][CH3:9].CN(C)C=[O:28]>>[Cl:1][C:2]1[CH:3]=[C:4]([C:10]2[C:14]3[CH:15]=[C:16]([C:19]4[O:23][C:22]([NH2:24])=[N:21][N:20]=4)[CH:17]=[CH:18][C:13]=3[O:12][CH:11]=2)[CH:5]=[CH:6][C:7]=1[S:8]([CH3:9])=[O:28]
Reactant: CSc1ccc(-c2coc3ccc(-c4nnc(N)o4)cc23)cc1Cl
Reactant: CN(C)C=O
Product: CS(=O)c1ccc(-c2coc3ccc(-c4nnc(N)o4)cc23)cc1Cl
Yield: 84 %

Procedure:
In the same manner as in Example 140 and using 5-[3-[3-chloro-4-(methylthio)phenyl]-1-benzofuran-5-yl]-1,3,4-oxadiazol-2-amine instead of 2-methyl-5-[3-[4-(methylthio)phenyl]-1-benzofuran-5-yl]-1,3,4-oxadiazole and using N,N-dimethylformamide instead of dichloromethane, the title compound (yield 84%) was obtained as colorless crystals.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].Cl.[NH2:18][OH:19]>CCO>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12](/[C:13](=[N:18]/[OH:19])/[NH2:14])=[CH:15][CH:16]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCCCCOc1ccc(C#N)cc1
Reactant: NO
Agent: Cl
Solvent: CCO
Product: CCCCCCCOc1ccc(/C(N)=N/O)cc1
Temperature: 85 °C
Yield: 91.2 %

Procedure:
Prepared using General Procedure 2: To a stirring solution of 4-(heptyloxy)benzonitrile (1.0 g, 4.6 mmol) in EtOH (15 mL) were added hydroxylamine hydrochloride (0.96 g, 13.8 mmol) and TEA (2.22 g, 23.0 mmol). The reaction was heated to 85° C. for 2 h. The solvent was removed under reduced pressure and the residue was diluted with water (20 mL) and extracted with DCM (3×10 mL). The combined organic layers were concentrated under reduced pressure. The crude material was crystallized from isopropanol (20 mL) to afford 1.05 g (91%) of (Z)-4-(heptyloxy)-N′-hydroxybenzimidamide as a white solid. LCMS-ESI (m/z) calculated for C14H22N2O2: 250.2. found 251.3 [M+H]+, tR=1.70 min (Method 1). 1H NMR (400 MHz, CDCl3) δ 9.45 (s, 1H), 7.59 (d, J=8.6 Hz, 2H), 6.93 (t, J=14.7 Hz, 2H), 5.82-5.48 (m, 2H), 3.97 (t, J=6.5 Hz, 2H), 1.83-1.55 (m, 2H), 1.56-1.05 (m, 8H), 0.87 (t, J=6.7 Hz, 3H). 13C NMR (101 MHz CDCl3) δ 159.19, 150.53, 126.64, 125.55, 113.87, 67.40, 31.21, 28.62, 28.40, 25.44, 22.02, 13.92.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([CH3:17])[C:5]2[CH:11]=[C:10]([C:12]#[CH:13])[C:9](=[O:14])[N:8]([CH2:15][CH3:16])[C:6]=2[N:7]=1.[N-:18]=[N+:19]=[N-:20].[Na+].[Cl-].[NH4+]>CN(C=O)C>[NH2:1][C:2]1[N:3]=[C:4]([CH3:17])[C:5]2[CH:11]=[C:10]([C:12]3[NH:20][N:19]=[N:18][CH:13]=3)[C:9](=[O:14])[N:8]([CH2:15][CH3:16])[C:6]=2[N:7]=1
Reactant: [N-]=[N+]=[N-]
Reactant: C#Cc1cc2c(C)nc(N)nc2n(CC)c1=O
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCn1c(=O)c(-c2cnn[nH]2)cc2c(C)nc(N)nc21
Temperature: 120 °C
Reaction time: 48 h
Yield: 5.8 %

Procedure:
Anhydrous DMF (5.0 mL) was added to a flask charged with 2-amino-8-ethyl-6-ethynyl-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one (0.204 g, 0.894 mmol), sodium azide (0.070 g, 1.07 mmol), and ammonium chloride (0.057 g, 1.07 mmol). The reaction was capped under nitrogen and heated to 120° C. After 48 h, the reaction was cooled to room temperature and concentrated in vacuo. The residue was purified on reverse phase HPLC (acetonitrile:water 0.1% TFA, 20-60% gradient). The fractions containing product were collected and concentrated to one half volume and poured into saturated NaHCO3 (50 mL). The aqueous phase was washed trice with ethyl acetate (50 mL) and dried over Na2SO4, filtered, and concentrated in vacuo. The residue was triturated with methylene chloride and ethyl acetate to afford 2-amino-8-ethyl-4-methyl-6-(1H-1,2,3-triazol-5-yl)pyrido[2,3-d]pyrimidin-7(8H)-one (14 mg, 6% yield) as a light yellow solid: 1H NMR (400 MHz, DMSO-d6): δ 8.55 (bs, 1H), 8.41 (bs, 1H), 7.32 (bs, 2H), 4.37 (q, J=7.2 Hz, 2H), 2.60 (s, 3H), 1.21 (t, J=7.2 Hz, 3H); MS (EI) for C12H13N7O: 272.0 (MH+).