Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][O:8][CH2:9][C:10]([O:12]CC)=O)[CH:2]=1.[NH2:15][CH2:16][CH:17]([OH:29])[CH2:18][N:19]1[CH2:28][CH2:27][C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:20]1>CCO>[CH2:20]1[C:21]2[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:27][CH2:28][N:19]1[CH2:18][CH:17]([OH:29])[CH2:16][NH:15][C:10](=[O:12])[CH2:9][O:8][CH2:7][C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1
Reactant: CCOC(=O)COCc1cccnc1
Reactant: NCC(O)CN1CCc2ccccc2C1
Solvent: CCO
Product: O=C(COCc1cccnc1)NCC(O)CN1CCc2ccccc2C1
Temperature: 120 °C
Yield: 16.5 %

Procedure:
To a solution of Ethyl 2-(pyridin-3-ylmethoxy)acetate (100 mg, 0.51 mmol) in EtOH (0.5 ml) was added 1-amino-3-(3,4-dihydroisoquinolin-2(1H)-yl)propan-2-ol (105 mg, 0.51 mmol) at 28° C. The mixture was stirred at 120° C. under microwave heating for 1 hour until the reaction was completed by TLC. After evaporation of the solvent, the residue was purified by HPLC separation to give the title compound (30 mg, yield: 16.5%) as a white solid. LCMS: 356.2 [M+H]+. 1H NMR (MeOD, 400 MHz) δ 8.53 (s, 1H), 8.50 (d, J=4.8 Hz, 1H), 7.85 (d, J=8.0 Hz, 1H), 7.462 (dd, J1=4.8 Hz, J2=8.0 Hz, 1H), 7.19-7.03 (m, 4H), 4.58 (s, 2H), 4.02 (br. s, 3H), 3.72 (s, 2H), 3.42-3.36 (m, 2H), 2.93-2.83 (m, 4H), 2.62-2.61 (m, 2H).
Reaction SMILES: [C:1]([O:9][CH2:10][C@@H:11]1[C:15]([O:17][C:18](=[O:20])[CH3:19])([CH3:16])[C@:14]([F:22])([CH3:21])[CH:13]([N:23]2[CH:31]=[N:30][C:29]3[C:24]2=[N:25][CH:26]=[N:27][C:28]=3Cl)[O:12]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:33][C:34]1[CH:35]=[C:36]([CH:39]=[CH:40][CH:41]=1)[CH2:37][NH2:38].O>C(O)C>[C:1]([O:9][CH2:10][C@@H:11]1[C:15]([O:17][C:18](=[O:20])[CH3:19])([CH3:16])[C@:14]([F:22])([CH3:21])[CH:13]([N:23]2[CH:31]=[N:30][C:29]3[C:24]2=[N:25][CH:26]=[N:27][C:28]=3[NH:38][CH2:37][C:36]2[CH:39]=[CH:40][CH:41]=[C:34]([Cl:33])[CH:35]=2)[O:12]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)OC1(C)[C@@H](COC(=O)c2ccccc2)OC(n2cnc3c(Cl)ncnc32)[C@]1(C)F
Reactant: NCc1cccc(Cl)c1
Solvent: CCO
Solvent: O
Product: CC(=O)OC1(C)[C@@H](COC(=O)c2ccccc2)OC(n2cnc3c(NCc4cccc(Cl)c4)ncnc32)[C@]1(C)F
Yield: 61.4 %

Procedure:
To a stirred solution of ((2R,4R)-3-acetoxy-5-(6-chloro-9H-purin-9-yl)-4-fluoro-3,4-dimethyl-tetrahydrofuran-2-yl)methyl benzoate (about 0.4 g, 0.86 mmol) in ethanol (about 5 ml) was added 3-chlorobenzylamine (about 1.26 ml, 10.38 mmol) and refluxed for about 20 minutes. Completion of the reaction mixture monitored by thin-layer chromatography, water added to the reaction mixture and the aqueous layer was extracted with ethyl acetate and the combined organic layers were washed with brine and dried over sodium sulphate. Concentration under reduced pressure and purification by silica gel column chromatography using 40% ethyl acetate in hexane as eluent furnished title compound (0.30 g) as a colorless gummy mass. Yield: 61.2%; 1H NMR (300 MHz, CDCl3): δ 8.42 (s, 1H), 8.06-8.01 (m, 4H), 7.58-7.24 (m, 6H), 6.56 (d, 1H, J=22.8 Hz), 6.45 (bs, 1H), 4.84-4.78 (m, 3H), 4.49-4.42 (m, 1H), 2.17 (s, 3H), 1.89 (d, 3H, J=2.4 Hz), 1.46 (d, 3H, J=23.1 Hz); Mass: [M+1]+ 568 (50%), [M+Na]+ 590 (70%); IR cm−: 3782, 3414, 2929, 2294, 2177, 1619, 1274, 1061, 712; HPLC: 96%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@H:13]([OH:14])[C@@H:12]([OH:15])[C@H:11]([OH:16])[C@@H:10]([CH2:17][OH:18])[O:9]2)=[CH:4][C:3]=1[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[Br:33][CH2:34][CH2:35][O:36][CH2:37][CH2:38]Br>CN(C)C=O.O>[Br:33][CH2:34][CH2:35][O:36][CH2:37][CH2:38][O:26][C:23]1[CH:22]=[CH:21][C:20]([CH2:19][C:3]2[CH:4]=[C:5]([C@H:8]3[C@H:13]([OH:14])[C@@H:12]([OH:15])[C@H:11]([OH:16])[C@@H:10]([CH2:17][OH:18])[O:9]3)[CH:6]=[CH:7][C:2]=2[Cl:1])=[CH:25][CH:24]=1
Reactant: BrCCOCCBr
Reactant: OC[C@H]1O[C@@H](c2ccc(Cl)c(Cc3ccc(O)cc3)c2)[C@H](O)[C@@H](O)[C@@H]1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: OC[C@H]1O[C@@H](c2ccc(Cl)c(Cc3ccc(OCCOCCBr)cc3)c2)[C@H](O)[C@@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 21.7 %

Procedure:
To a stirred suspension of (2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-hydroxybenzyl)phenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol (intermediate D1) (100 mg, 0.26 mmol) in N,N-dimethylformamide (3 mL) and cesium carbonate (162 mg, 0.52 mmol) was added 1-bromo-2-(2-bromoethoxy)ethane (182 mg, 0.79 mmol). The mixture was stirred overnight at room temperature. The solution was diluted with water and the aqueous layer was extracted with ethyl acetate. The combined organic layers were concentrated under reduced pressure. The residue was purified by preparative TLC to give 30 mg of yellow oil (21% yield), which was used in the next step without purification.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[CH:9][C:10]([CH:11]=[O:12])=[C:4]2[N:3]=1.[O:13]1[CH2:18][CH2:17][N:16]([CH2:19][C:20]2[CH:21]=[C:22]([CH:24]=[CH:25][CH:26]=2)[NH2:23])[CH2:15][CH2:14]1.O>CN(C=O)C>[O:13]1[CH2:14][CH2:15][N:16]([CH2:19][C:20]2[CH:21]=[C:22]([NH:23][C:2]3[CH:7]=[CH:6][N:5]4[N:8]=[CH:9][C:10]([CH:11]=[O:12])=[C:4]4[N:3]=3)[CH:24]=[CH:25][CH:26]=2)[CH2:17][CH2:18]1
Reactant: Nc1cccc(CN2CCOCC2)c1
Reactant: O=Cc1cnn2ccc(Cl)nc12
Solvent: CN(C)C=O
Solvent: O
Product: O=Cc1cnn2ccc(Nc3cccc(CN4CCOCC4)c3)nc12
Temperature: 140 °C

Procedure:
To 5-chloropyrazolo[1,5-a]pyrimidine-3-carbaldehyde (30 mg, 0.166 mmol) in DMF was added 3-(morpholinomethyl)aniline (233 mg, 1.213 mmol). The mixture was heated in microwave for 40 minutes at 140° C. Water was added and the solid formed was isolated by filtration to yield 5-(3-(morpholinomethyl)phenylamino)pyrazolo[1,5-a]pyrimidine-3-carbaldehyde. LCMS (M+1=338)
Reaction SMILES: O[C@H:2]1[CH2:6][N:5]([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=2)=[O:8])[C@H:4]([CH2:20][S:21][C:22]2[N:26]([CH3:27])[N:25]=[N:24][N:23]=2)[CH2:3]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.[C:59]([SH:67])(=[O:66])[C:60]1[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=1>O1CCCC1.C(OCC)(=O)C>[C:59]([S:67][C@@H:2]1[CH2:6][N:5]([C:7]([O:9][CH2:10][C:11]2[CH:12]=[CH:13][C:14]([N+:17]([O-:19])=[O:18])=[CH:15][CH:16]=2)=[O:8])[C@H:4]([CH2:20][S:21][C:22]2[N:26]([CH3:27])[N:25]=[N:24][N:23]=2)[CH2:3]1)(=[O:66])[C:60]1[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=1
Reactant: O=C(S)c1ccccc1
Reactant: Cn1nnnc1SC[C@@H]1C[C@@H](O)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cn1nnnc1SC[C@@H]1C[C@H](SC(=O)c2ccccc2)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Reaction time: 0.5 h

Procedure:
To a solution of (2S,4R)-4-hydroxy-2-(1-methyl-1H-tetrazol-5-yl)thiomethyl-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (1.23 g) and triphenylphosphine (1.23 g) in tetrahydrofuran (25 ml) was added dropwise a solution of diethyl azodicarboxylate (0.74 ml) in tetrahydrofuran (2 ml) under ice-cooling. After stirring at the same temperature for 30 minutes, to the solution was added thiobenzoic S-acid (0.55 ml) under ice-cooling. The mixture was stirred at the same temperature for 2 hours. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was dissolved in ethyl acetate (100 ml) and the solution was washed with saturated aqueous sodium hydrogen carbonate and saturated aqueous sodium chloride successively, dried over anhydrous magnesium sulfate, and evaporated in vacuo. The resulting residue was chromatographed on silica gel (100 g) eluting with a mixture of dichloromethane and acetone (19:1, V/V). The fractions containing the resired compound were collected and evaporated in vacuo to give (2S,4S)-4-benzoylthio-2-(1-methyl-1H-tetrazol- 5-yl)thiomethyl-1(4-nitrobenzyloxycarbonyl)pyrrolidine (1.61 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[NH:9][C:10]1[S:11][CH:12]=[C:13]([C:15]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=2)=[O:16])[N:14]=1.C(O)(=O)C.[Br:32]Br>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[NH:9][C:10]1[S:11][C:12]([Br:32])=[C:13]([C:15]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]([F:26])([F:27])[F:25])=[CH:20][CH:19]=2)=[O:16])[N:14]=1
Reactant: O=C(Nc1ccc(C(F)(F)F)cc1)c1csc(Nc2c(Cl)cccc2Cl)n1
Reactant: BrBr
Solvent: CC(=O)O
Product: O=C(Nc1ccc(C(F)(F)F)cc1)c1nc(Nc2c(Cl)cccc2Cl)sc1Br
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a 50-mL flask was added {2-[(2,6-dichlorophenyl)amino](1,3-thiazol-4-yl)}-N-[4-(trifluoromethyl)phenyl]-carboxamide, Example 63, (100 mg, 0.23 mmol), acetic acid (2.0 mL), and bromine (0.03 mL, 0.46 mmol, Aldrich). The reaction mixture was stirred at room temperature overnight, then concentrated in vacuo. The crude product was diluted with CH2Cl2 (50 mL), washed with satd NaHCO3 (2×), 1 M Na2S2O3 and brine, dried over Na2SO4, filtered and concentrated in vacuo. Purification by silica gel chromatography (12% EtOAc in hexane) provided the title product as an off-white solid. MS (ESI, pos. ion) m/z: 512 (M+1). MP: 151-162° C.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[CH:5][CH:6]=1.C([Li])(C)(C)C.CN1CCCN(C)C1=O.Br[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][O:30][Si](C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[S:3]1[CH:4]=[CH:5][CH:6]=[C:2]1[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][OH:30]
Reactant: CC(C)(C)[Si](C)(C)OCCCCCCCCBr
Reactant: Brc1cccs1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Agent: [Li]C(C)(C)C
Solvent: CN1CCCN(C)C1=O
Solvent: C1CCOC1
Product: OCCCCCCCCc1cccs1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred solution of 2-bromothiophene (0.341 g, 2.09 mmol) in tetrahydrofuran (30 ml) under argon at -78° was added t-butyl lithium (2.53 ml of a 1.7M solution) followed by 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (0.268 g, 2.09 mmol). To this mixture was added 1-bromo-8-t-butyldimethylsiloxyoctane (0.615 g, 1.90 mmol) in tetrahydrofuran (10 ml). After gradual warming followed by stirring at room temperature for 18 hours, the mixture was concentrated, taken up in ethyl ether and washed consecutively with cold 10% hydrochloric acid, saturated sodium bicarbonate, water, saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated to give a yellow oil. To this residue in tetrahydrofuran (20 ml) at 0° was added tetrabutylammonium fluoride (8.4 ml of a 1.0M solution). After stirring for 16 hours at room temperature, the mixture was concentrated, taken up in ethyl ether and washed with 10% hydrochloric acid, saturated sodium bicarbonate, water, saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated to give a yellow oil. Further purification by flash chromatography (silica, 30% ethyl acetate/hexane) gave the desired alcohol.
Reaction SMILES: O[C:2]1[C:3]2[C:10]([CH3:11])=[C:9]([CH3:12])[N:8]([CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:4]=2[N:5]=[CH:6][N:7]=1.O=P(Cl)(Cl)[Cl:22]>>[Cl:22][C:2]1[C:3]2[C:10]([CH3:11])=[C:9]([CH3:12])[N:8]([CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1c(C)n(Cc2ccccc2)c2ncnc(O)c12
Product: Cc1c(C)n(Cc2ccccc2)c2ncnc(Cl)c12
Temperature: 25 °C

Procedure:
2.5 g of 4-hydroxy-5,6-dimethyl-7-benzyl-pyrrolo[2,3-d]pyrimidine are boiled at reflux with 20 ml of POCl3 for 2.5 hours. The brown solution is cooled to RT and poured onto ice-water. The brownish precipitate is filtered off with suction and dissolved in ethyl acetate. The ethyl acetate phase is washed with water, dried and concentrated in a rotary evaporator until white crystals form. 4-Chloro-5,6-dimethyl-7-benzyl-pyrrolo[2,3-d]-pyrimidine is obtained in the form of white crystals having a melting point of 115-116° C.
Reaction SMILES: [F:1][C:2]([F:40])([F:39])[C:3]1[CH:4]=[C:5]([CH:32]=[C:33]([C:35]([F:38])([F:37])[F:36])[CH:34]=1)[CH2:6][N:7]([CH2:14][C:15]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:17][C:16]=1[CH:25]([CH:27]1[CH2:31][CH2:30][CH2:29][CH2:28]1)[OH:26])[C:8]1[N:9]=[N:10][N:11]([CH3:13])[N:12]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.CCOCC.[OH-].[Na+]>C(Cl)Cl>[F:40][C:2]([F:1])([F:39])[C:3]1[CH:4]=[C:5]([CH:32]=[C:33]([C:35]([F:36])([F:37])[F:38])[CH:34]=1)[CH2:6][N:7]([CH2:14][C:15]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:17][C:16]=1[C:25]([CH:27]1[CH2:31][CH2:30][CH2:29][CH2:28]1)=[O:26])[C:8]1[N:9]=[N:10][N:11]([CH3:13])[N:12]=1
Reactant: Cn1nnc(N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)Cc2cc(C(F)(F)F)ccc2C(O)C2CCCC2)n1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: ClCCl
Product: Cn1nnc(N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)Cc2cc(C(F)(F)F)ccc2C(=O)C2CCCC2)n1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 93.2 %

Procedure:
To a solution of (2-{[(3,5-bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino]-methyl}-4-trifluoromethyl-phenyl)-cyclopentyl-methanol (44,5 mg, 0.077 mmol) in methylene chloride (1.0 mL) at room temperature was added Dess-Martin periodinane reagent (35.7 mg, 0.084 mmol). The mixture was stirred at room temperature for 1.5 hours. Ether and 1N sodium hydroxide was added. The mixture was extracted with ethyl acetate. Combined organic layers were washed with brine, dried over sodium sulfate and concentrated in vacuo to yield a pale yellow oil (41.6 mg, 94%). 1H NMR (400 MHz, CDCl3) δ ppm 1.58-1.72 (m, 4H) 1.75-1.88 (m, 4H) 3.48-3.58 (m, 1H) 4.18 (s, 3H) 4.81 (s, 2H) 4.88 (s, 2H) 7.53 (s, 1H) 7.57 (d, J=8.30 Hz, 1H) 7.66 (s, 2H) 7.71 (d, 1H) 7.73 (s, 1H). MS (ES+) Calc: 579.2, Found: 580.4 (M+1).
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7](=[N:14][O:15][CH2:16][C:17]2[N:22]=[C:21]([NH2:23])[CH:20]=[CH:19][CH:18]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:5][N:4]=[N:3]1.N1C=CC=CC=1.[C:30](=[O:37])(Cl)[S:31][CH2:32][CH2:33][CH2:34][CH3:35]>ClCCl>[CH3:1][N:2]1[C:6]([C:7](=[N:14][O:15][CH2:16][C:17]2[N:22]=[C:21]([NH:23][C:30](=[O:37])[S:31][CH2:32][CH2:33][CH2:34][CH3:35])[CH:20]=[CH:19][CH:18]=2)[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)=[N:5][N:4]=[N:3]1
Reactant: Cn1nnnc1C(=NOCc1cccc(N)n1)c1ccccc1
Reactant: CCCCSC(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCCSC(=O)Nc1cccc(CON=C(c2ccccc2)c2nnnn2C)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 38 %

Procedure:
To a stirred solution of 6-[({[(1-methyl-1H-tetrazol-5-yl)(phenyl)methylene]amino}oxy)methyl]pyridin-2-amine (150.0 mg, 0.485 mmol) in dichloromethane (5 mL), under argon atmosphere, were added pyridine (0.078 mL, 0.97 mmol) and S-butyl carbonochloridothioate (133 mg, 0.87 mmol) at room temperature. After stirring at room temperature overnight, the reaction mixture was diluted with dichloromethane (50 mL), filtered through “Chem Elut” cartridge, washed with dichloromethane (50 mL) and the filtrate was concentrated in vacuo yielding to S-butyl {6-[({[(1-methyl-1H-tetrazol-5-yl)(phenyl)methylene]amino}oxy)methyl]pyridin-2-yl}carbamothioate as a honey [82 mg, yield 38%; HPLC/MS m/z=426 (M+H); logP(HCOOH)=4.25].
Reaction SMILES: I[CH2:2][CH3:3].[Br:4][C:5]1[C:10]([OH:11])=[CH:9][CH:8]=[CH:7][N:6]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Br:4][C:5]1[C:10]([O:11][CH2:2][CH3:3])=[CH:9][CH:8]=[CH:7][N:6]=1
Reactant: Oc1cccnc1Br
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOc1cccnc1Br
Reaction time: 3.25 h

Procedure:
Iodoethane (26 ml) is added to a mixture of 2-bromo-3-pyridinol (Aldrich, 22.75 g), potassium carbonate anhydrous (32.541 g) and DMF (258 ml). The mixture is stirred at 80-85° for 3.25 hr, at which time the mixture is cooled in an ice water bath and potassium carbonate is then filtered off and washed with dichloromethane. The filtrate is concentrated under reduced pressure and the residue is dissolved in ethyl acetate (570 ml) and washed with water (300 ml). The aqueous layer is backwashed with ethyl acetate (500 ml) and each of the organic phases are washed with saline (114 ml). The organic phases are combined, dried with magnesium sulfate and concentrated under reduced pressure. The crude material is chromatographed (silica gel; eluting with ethyl acetate/hexane (20/80) to give 2-bromo-3-ethoxypyridine (XXVIIIa, Chart G), MS (m/z) 201, 203; IR (neat) 1448, 1294, 1389, 1420 and 1205 cm-1.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][NH:5][C:6]1[CH:11]=[C:10]([CH3:12])[N:9]=[C:8]2[CH:13]=[N:14][NH:15][C:7]=12.[C:16](Cl)(=[O:18])[CH3:17].[OH-].[Na+]>O>[C:16]([O:1][CH2:2][CH2:3][CH2:4][NH:5][C:6]1[CH:11]=[C:10]([CH3:12])[N:9]=[C:8]2[CH:13]=[N:14][NH:15][C:7]=12)(=[O:18])[CH3:17]
Reactant: Cc1cc(NCCCO)c2[nH]ncc2n1
Reactant: CC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(=O)OCCCNc1cc(C)nc2cn[nH]c12

Procedure:
The title compound was prepared from 7(3-hydroxypropylamino)-5-methyl-1H-pyrazolo[4,3-b]pyridine (1.125 g) and acetyl chloride by the general method of Example 4 with the following addition. After removal of solvents under reduced pressure the crude reaction mixture was dissolved in water and brought to pH 9 with 10% sodium hydroxide. The resulting solid was collected and dried before purifying by column chromatography under the conditions used for Example 4. A clear gum was obtained which on trituration with ether gave the title compound as a white solid, m.p. 115°-119° C.
Reaction SMILES: [C:1]([S:9][CH2:10][C:11]([OH:13])=[O:12])(=[S:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)(Cl)=O.[CH3:18]O>>[CH3:18][O:12][C:11](=[O:13])[CH2:10][S:9][C:1](=[S:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)CSC(=S)c1ccccc1
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)CSC(=S)c1ccccc1
Yield: 97 %

Procedure:
Add a solution of thiobenzoylsulfanylacetic acid (5.5 g, 26.0 mmol) in methanol (100 mL) and to a solution of thionyl chloride (52 mL) at room temperature under nitrogen and heat the mixture at reflux for 12 hours. Remove the solvent under reduced pressure, dissolve the residue in ethyl acetate (200 mL), wash with saturated NaHCO3 (200 mL) and brine (200 mL) solutions, and dry over sodium sulfate. Remove the solvent under reduced pressure to provide thiobenzoylsulfanylacetic acid methyl ester (5.7 g, 97%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](/[CH:13]=[CH:14]/[C:15](=[O:17])[CH3:16])[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].O.[C:19]([OH:23])(=[O:22])[CH:20]=O>C(O)(=O)C.O>[O:17]=[C:15](/[CH:14]=[CH:13]/[C:5]1[CH:6]=[C:7]([O:11][CH3:12])[C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=1)/[CH:16]=[CH:20]/[C:19]([OH:23])=[O:22]
Reactant: COc1cc(/C=C/C(C)=O)cc(OC)c1OC
Reactant: O=CC(=O)O
Solvent: CC(=O)O
Solvent: O
Product: COc1cc(/C=C/C(=O)/C=C/C(=O)O)cc(OC)c1OC

Procedure:
A solution of 5 g (21 mmol) of (E)-4-(3,4,5-trimethoxyphenyl)but-3-en-2-one and 2 g (21.7 mmol) of glyoxylic acid monohydrate in 5.2 ml of acetic acid was heated at reflux for 20 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic phase was extracted twice with 3N sodium hydroxide solution. The combined aqueous phases were treated with 3N hydrochloric acid to produce a strongly acidic reaction and extracted twice with ethyl acetate. The combined organic phases were dried over magnesium sulphate and concentrated. Crystallization of the residue from methylene chloride/ether yielded (E,E)-4-oxo-6-(3,4,5-trimethoxyphenyl)-2,5-hexadienoic acid of melting point 152°-154°.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][C:3]=1[O:9][CH2:10][CH:11]1[CH2:15][CH2:14][CH2:13][N:12]1[CH3:16].[CH3:17][S:18]([N:21]([CH3:45])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[C:28]1[N:36]2[C:31]([CH:32]=[N:33][C:34](OS(C(F)(F)F)(=O)=O)=[N:35]2)=[CH:30][CH:29]=1)(=[O:20])=[O:19]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:34]2[N:33]=[CH:32][C:31]3=[CH:30][CH:29]=[C:28]([C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=4[N:21]([CH3:45])[S:18]([CH3:17])(=[O:20])=[O:19])[N:36]3[N:35]=2)=[CH:4][C:3]=1[O:9][CH2:10][CH:11]1[CH2:15][CH2:14][CH2:13][N:12]1[CH3:16]
Reactant: CN1CCCC1COc1cc(N)ccc1Cl
Reactant: CN(c1ccccc1-c1ccc2cnc(OS(=O)(=O)C(F)(F)F)nn12)S(C)(=O)=O
Product: CN1CCCC1COc1cc(Nc2ncc3ccc(-c4ccccc4N(C)S(C)(=O)=O)n3n2)ccc1Cl

Procedure:
Prepared by following a procedure analagous to Example 1220c by using 4-Chloro-3-(1-methyl-pyrrolidin-2-ylmethoxy)-phenylamine and Trifluoro-methanesulfonic acid 7-[2-(methanesulfonyl-methyl-amino)-phenyl]-pyrrolo[2,1-f][1,2,4]triazin-2-yl ester. 1H-NMR (DMSO) δ 9.7 (brs, 1H), 9.6 (s, 1H), 9 (s, 1H), 7.8 (m, 1H), 7.7 (m, 1H), 7.5 (m, 3H), 7.3 (d, 1H), 7.2 (d, J=8.7 Hz , 1H), 7.0 (m, 2H), 3.8 (m, 1H), 3.6 (m, 1H), 3.5 (m, 1H), 3.1 (s, 3H), 3 (s, 3H), 2.8 (s, 3H), 2.2 (m, 1H), 2.0 (m, 1H), 1.9 (m, 1H), 1.7 (m, 1H); LC/MS (ESI+): 541 (M+H).
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:12]=[CH:13][C:14]=2[O:15][CH3:16])[CH:10]=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[NH2:18][OH:19].O>N1C=CC=CC=1>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:12]=[CH:13][C:14]=2[O:15][CH3:16])[CH:10]=[N:18][OH:19])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1ccc(C=O)cc1OC1CCCC1
Reactant: NO
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: COc1ccc(C=NO)cc1OC1CCCC1
Temperature: 25 °C
Yield: 104.9 %

Procedure:
3-cyclopentyloxy-4-methoxybenzaldehyde (13.00 g, 59.02 mM) and hydroxylamine hydrochloride (8.46 g, 118.04 mM) were dissolved in pyridine (120 ml) and the resultant mixture was heated to reflux for 23 hours. The solution obtained was cooled to room temperature, water (100 ml) was added, then the solution was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, then the solvent was removed in vacuo to obtain a green oily residue. The residue was purified by flash chromatography (SiO2: eluted by 20% ethyl acetate/hexane). The solvent was removed in vacuo and the resultant product was dried to obtain 3-cyclopentyloxy-4-methoxybenzaldehyde oxime 14.57 g as a colorless oil. The 3-cyclopentyloxy-4-methoxybenzaldehyde oxime (14.57 g) thus obtained was dissolved in acetic acid (130 ml) and the resultant mixture was heated to reflux for 22 hours. The solution obtained was ice cooled, then a saturated sodium hydrogencarbonate solution was added to neutralize it. The solution was extracted with ethyl acetate, the organic layer was dried over anhydrous magnesium sulfate, and the solvent was removed in vacuo to obtain a red solid residue. The residue was purified by flash chromatography (SiO2: eluted by 25% ethyl acetate/hexane). The solvent was removed in vacuo and the result dried to obtain 3-cyclopentyloxy-4-methoxybenzonitrile 9.60 g (yield 75.2%) as a yellow-green oil.
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]1[C:9](=[O:10])[N:8]2[C:11]([CH3:15])=[CH:12][CH:13]=[CH:14][C:7]2=[N:6][C:5]=1[CH3:16].[Cl:17][C:18]1[CH:19]=[C:20]([N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[CH:21]=[CH:22][CH:23]=1>C1(C)C=CC=CC=1>[Cl:17][C:18]1[CH:19]=[C:20]([N:24]2[CH2:29][CH2:28][N:27]([CH2:2][CH2:3][C:4]3[C:9](=[O:10])[N:8]4[C:11]([CH3:15])=[CH:12][CH:13]=[CH:14][C:7]4=[N:6][C:5]=3[CH3:16])[CH2:26][CH2:25]2)[CH:21]=[CH:22][CH:23]=1
Reactant: Cc1nc2cccc(C)n2c(=O)c1CCCl
Reactant: Clc1cccc(N2CCNCC2)c1
Solvent: Cc1ccccc1
Product: Cc1nc2cccc(C)n2c(=O)c1CCN1CCN(c2cccc(Cl)c2)CC1
Yield: 34.8 %

Procedure:
A mixture of 2.4 g of 3-(2-chloroethyl)-2,6-dimethy-4H-pyrido[1,2-a]pyrimidin-4-one, 5.9 g of 1-(m-chlorophenyl)piperazine and 25 ml of toluene was refluxed with heating for 30 hours. The reaction mixture was then treated in the same manner as in Example 1, and the obtained crude crystals were recrystallized from isopropyl alcohol to give 1.4 g of the desired compound as pale yellow needles, m.p. 116.5° - 117.5°C.