Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]3[CH:37]=[CH:36][C:17]([O:18][CH2:19][C:20]([C:28]4[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:29]=4[Cl:35])([OH:27])[CH2:21][N:22]4[CH:26]=[N:25][CH:24]=[N:23]4)=[CH:16][CH:15]=3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[C:38]1(=O)[O:43][C:41](=[O:42])[CH2:40][CH2:39]1>C(O)(=O)C>[Cl:35][C:29]1[CH:30]=[C:31]([Cl:34])[CH:32]=[CH:33][C:28]=1[C:20]([OH:27])([CH2:21][N:22]1[CH:26]=[N:25][CH:24]=[N:23]1)[CH2:19][O:18][C:17]1[CH:36]=[CH:37][C:14]([N:11]2[CH2:12][CH2:13][N:8]([C:5]3[CH:6]=[CH:7][C:2]([N:1]4[C:41](=[O:42])[CH2:40][CH2:39][C:38]4=[O:43])=[CH:3][CH:4]=3)[CH2:9][CH2:10]2)=[CH:15][CH:16]=1
Reactant: O=C1CCC(=O)O1
Reactant: Nc1ccc(N2CCN(c3ccc(OCC(O)(Cn4cncn4)c4ccc(Cl)cc4Cl)cc3)CC2)cc1
Solvent: CC(=O)O
Product: O=C1CCC(=O)N1c1ccc(N2CCN(c3ccc(OCC(O)(Cn4cncn4)c4ccc(Cl)cc4Cl)cc3)CC2)cc1
Yield: 71.8 %

Procedure:
A solution of 3-(4-[4-(4-aminophenyl)piperazin-1-yl]phenoxy)-2-(2,4-dichlorophenyl)-1-(1H-1,2,4-triazol-1-yl)propan-2-ol (see Preparation 1) (0.2 g, 0.37 mmole) and succinic anhydride (0.05 g, 0.5 mmole) in acetic acid (3 ml) was heated under reflux for 4 hours. The solution was cooled, the solvent removed by concentration under reduced pressure and the resulting gum triturated with isopropanol to provide a solid (0.165 g). Purification of this solid material by flash chromatography on silica gel eluting with methylene chloride (90):isopropanol (10):acetic acid (1) yielded, after collection and evaporation of appropriate fractions, the desired product, m.p. 212°-216° (0.072 g, 31%).
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:26][C:27]2[CH:39]=[CH:38][C:30]([C:31]([O:33]C(C)(C)C)=[O:32])=[CH:29][CH:28]=2)[C:7](/[CH:10]=[C:11]2\[N:12]([CH2:22][CH2:23][CH2:24][CH3:25])[C:13](=[O:21])[N:14]([CH2:17][CH2:18][CH2:19][CH3:20])[C:15]\2=[O:16])=[CH:8][N:9]=1)[CH2:2][CH2:3][CH3:4]>C(Cl)Cl.FC(F)(F)C(O)=O>[CH2:1]([C:5]1[N:6]([CH2:26][C:27]2[CH:39]=[CH:38][C:30]([C:31]([OH:33])=[O:32])=[CH:29][CH:28]=2)[C:7](/[CH:10]=[C:11]2\[N:12]([CH2:22][CH2:23][CH2:24][CH3:25])[C:13](=[O:21])[N:14]([CH2:17][CH2:18][CH2:19][CH3:20])[C:15]\2=[O:16])=[CH:8][N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1ncc(/C=C2/C(=O)N(CCCC)C(=O)N2CCCC)n1Cc1ccc(C(=O)OC(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCCc1ncc(/C=C2/C(=O)N(CCCC)C(=O)N2CCCC)n1Cc1ccc(C(=O)O)cc1
Reaction time: 3 h

Procedure:
1,1-dimethylethyl Z-4-[[2-butyl-5-[(1,3-dibutyl-2,5-dioxo-4-imidazolidinylidene)methyl]-1H-imidazol-1-yl]methyl]benzoate (0.88 g, 1.64 mmol) was dissolved in methylene chloride (16 mL) and trifluoroacetic acid (16 mL). After stirring for 3 hours the reaction mixture was evaporated in vacuo. Dilute NaHCO3 was added to adjust the pH to 6 and extracted with ethyl acetate. This extract was dried over MgSO4 and then evaporated in vacuo and purified via chromatography (eluant methanol in chloroform).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:15]=[CH:16][C:17]=1[N+:18]([O-:20])=[O:19])[O:6][C:7]1[CH:8]=[C:9]([CH:12]=[CH:13][CH:14]=1)[C:10]#[N:11])=O.[CH2:21]([NH2:24])[CH2:22][CH3:23].C([O-])(O)=O.[Na+]>ClCCCl>[N+:18]([C:17]1[CH:16]=[CH:15][C:5]([O:6][C:7]2[CH:8]=[C:9]([CH:12]=[CH:13][CH:14]=2)[C:10]#[N:11])=[CH:4][C:3]=1[CH2:1][NH:24][CH2:21][CH2:22][CH3:23])([O-:20])=[O:19]
Reactant: N#Cc1cccc(Oc2ccc([N+](=O)[O-])c(C=O)c2)c1
Reactant: CCCN
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Product: CCCNCc1cc(Oc2cccc(C#N)c2)ccc1[N+](=O)[O-]
Temperature: 25 °C

Procedure:
Under N2, a mixture of 3-(3-formyl-4-nitrophenoxy)-benzonitrile (0.056 mol) and propylamine (0.059 mol) in DCE (450 mL) was stirred at room temperature, and then NaBH(OAC)3 (0.063 mol) was added, and the reaction mixture was stirred overnight at room temperature. A saturated NaHCO3 solution was added, and the layers were separated. The organic layer was dried, filtered off and the solvent was evaporated. The residue was purified over silica gel filter (eluent: 99:1 CH2Cl2:CH3OH). The purest product fractions were collected and the solvent was evaporated to yield the title compound as a residue.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)[O:5][CH2:6][C:7]([OH:9])=O.[N+]([O-])(O)=O.[O:17]([CH2:21][CH2:22][NH2:23])[N+:18]([O-:20])=[O:19]>CCCCCC>[O:17]([CH2:21][CH2:22][NH:23][C:7](=[O:9])[CH2:6][O:5][C:4]1[CH:10]=[CH:11][CH:12]=[C:2]([CH3:1])[CH:3]=1)[N+:18]([O-:20])=[O:19]
Reactant: NCCO[N+](=O)[O-]
Reactant: Cc1cccc(OCC(=O)O)c1
Solvent: CCCCCC
Solvent: O=[N+]([O-])O
Product: Cc1cccc(OCC(=O)NCCO[N+](=O)[O-])c1
Yield: 55.4 %

Procedure:
Following a similar treatment to that in Example 2 and using 0.71 g of 3-methylphenoxyacetic acid and 0.6 g of 2-nitroxyethylamine nitrate, 0.50 g of the title compound was obtained as colorless powdery crystals (solvent for recrystallization; hexane).
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[C:7]([O:9][CH2:10][CH2:11][Si:12]([CH3:15])([CH3:14])[CH3:13])[C:6]([C:16]([OH:18])=O)=[CH:5][N:4]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.O.[NH2:32][NH2:33].O>C1COCC1>[CH3:1][S:2][C:3]1[N:8]=[C:7]([O:9][CH2:10][CH2:11][Si:12]([CH3:15])([CH3:14])[CH3:13])[C:6]([C:16]([NH:32][NH2:33])=[O:18])=[CH:5][N:4]=1
Reactant: NN
Reactant: CSc1ncc(C(=O)O)c(OCC[Si](C)(C)C)n1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: C1CCOC1
Product: CSc1ncc(C(=O)NN)c(OCC[Si](C)(C)C)n1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
2-Methylthio-4-(2-trimethylsilylethoxy)pyrimidine-5-carboxylic acid (9.73 g) obtained in Step 2 was dissolved in THF (100 mL), carbonyldiimidazole (5.5 g) was added thereto, followed by stirring at room temperature for 1.5 hours. Then, hydrazine monohydrate (4.70 mL) was added dropwise to the reaction mixture, and the resulting mixture was stirred at room temperature for 2.5 hours. After completion of the reaction was confirmed by thin-layer chromatography, water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was sequentially washed with a saturated aqueous sodium hydrogencarbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the mixture was dried under reduced pressure to give crude 2-methylthio-4-(2-trimethylsilylethoxy)pyrimidine-5-carbohydrazide [Compound (E) in which R1 is 2-trimethylsilylethoxy].
Reaction SMILES: [O:1]1CCO[CH:2]1[CH2:6][N:7]1[C:16]2[C:11](=[C:12]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9][C:8]1=[O:25]>FC(F)(F)C(O)=O>[CH2:18]([O:17][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:11]=1[CH:10]=[CH:9][C:8](=[O:25])[N:7]2[CH2:6][CH:2]=[O:1])[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: O=c1ccc2c(OCc3ccccc3)cccc2n1CC1OCCO1
Solvent: O=C(O)C(F)(F)F
Product: O=CCn1c(=O)ccc2c(OCc3ccccc3)cccc21
Temperature: 25 °C
Reaction time: 72 h

Procedure:
750 mg of 1-(1,3-dioxolan-2-ylmethyl)-5-benzyloxyquinolin-2(1H)-one was dissolved in 3 mL of 90% aqueous trifluoroacetic acid solution, and stirred at room temperature for 3 days. The solvent was removed under reduced pressure, and after it was alkalized by aqueous saturated sodium hydrogen carbonate solution, it was extracted with ethyl acetate. The organic layer was washed sequentially with water and aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure to give (5-benzyloxy-2-oxoquinolin-1(2H)-yl)acetaldehyde as a pale yellow solid. (2) To 25 mL of a chloroform solution containing (5-benzyloxy-2-oxoquinolin-1(2H)-yl)acetaldehyde and 877 mg of tert-butyl (2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(piperidin-4-yl)carbamate, 144 μL of acetic acid was added, and stirred at room temperature for 1 hour. To the reaction mixture, 811 mg of sodium triacetoxyborohydride was added, and stirred for 1.5 hours. Aqueous saturated sodium hydrogen carbonate solution was added, the organic layer was separated. The organic layer was washed with aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by silica gel column chromatography [Silica Gel; Kanto Chemical Co., Inc., Silica Gel 60, eluent; chloroform:methanol=100:1], to give 592 mg of tert-butyl (2,3-dihydro-1,4-benzodioxin-6-ylmethyl) (1-(2-(5-benzyloxy-2-oxoquinolin-1(2H)-yl)ethyl)piperidin-4-yl)carbamate as a pale brown foam.
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5][C:6]1[CH:15]=[C:14]2[C:9]([CH2:10][CH2:11][N:12]([CH2:16][CH2:17][CH2:18][CH2:19][NH:20][C:21](=[O:34])[C:22]3[CH:27]=[CH:26][C:25]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)=[CH:24][CH:23]=3)[CH2:13]2)=[CH:8][CH:7]=1)=[O:4].S(=O)(=O)(O)O.[CH2:40](O)C>>[CH2:1]([O:2][C:3]([CH2:5][C:6]1[CH:15]=[C:14]2[C:9]([CH2:10][CH2:11][N:12]([CH2:16][CH2:17][CH2:18][CH2:19][NH:20][C:21](=[O:34])[C:22]3[CH:23]=[CH:24][C:25]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)=[CH:26][CH:27]=3)[CH2:13]2)=[CH:8][CH:7]=1)=[O:4])[CH3:40]
Reactant: CCO
Reactant: COC(=O)Cc1ccc2c(c1)CN(CCCCNC(=O)c1ccc(-c3ccccc3)cc1)CC2
Agent: O=S(=O)(O)O
Product: CCOC(=O)Cc1ccc2c(c1)CN(CCCCNC(=O)c1ccc(-c3ccccc3)cc1)CC2
Yield: 56 %

Procedure:
A stirred, ice-cooled solution of 7-methoxycarbonylmethyl-2-(4-(4-phenylbenzoylamino)butyl)-1,2,3,4-tetrahydroisoquinoline (0.202 g, 0.46 mmol) in ethanol (10 ml) was treated with concentrated sulfuric acid (0.53 ml, 0.53 mmol). The mixture was heated at reflux for 2 h. The solvent was evaporated in vacuo and the residue was dissolved in ethyl acetate (30 ml) and saturated aqueous sodium bicarbonate solution (30 ml). The organic phase was separated and washed with brine. Drying (Na2SO4) and evaporation in vacuo afforded an orange oil which was chromatographed on silica using 50-100% ethyl acetate-pentane gradient elution to afford the title compound as a colourless oil (120 mg, 56%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:10]#[C:11][CH2:12][NH:13][S:14]([CH3:17])(=[O:16])=[O:15])=[CH:8][CH:9]=1)=[O:4]>CCOC(C)=O.CO.[Pd]>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([CH2:10][CH2:11][CH2:12][NH:13][S:14]([CH3:17])(=[O:15])=[O:16])=[CH:8][CH:9]=1)=[O:4]
Reactant: COC(=O)c1ccc(C#CCNS(C)(=O)=O)s1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(CCCNS(C)(=O)=O)s1
Yield: 97.6 %

Procedure:
A solution of 5-(3-methanesulfonylamino-prop-1-ynyl)-thiophene-2-carboxylic acid methyl ester (3.0 g, 10.9 mmol) in EtOAc (100 mL) and MeOH (50 mL) was hydrogenated with 10% Pd/C (680 mg) at 50 psi for 7 h. The solution was filtered through a pad of Celite with the aid of MeOH and was concentrated in vacuo to provide the title compound as an off-white solid (2.95 g). 1H NMR (300 MHz, CDCl3) δ 7.62 (d, 1H), 7.23 (d, 1H), 4.29 (m, 1H), 3.85 (s, 3H), 3.18 (q, 2H), 2.93 (m, 5H), 1.96 (m, 2H).
Reaction SMILES: Br[C:2]1[CH:16]=[CH:15][C:5]2[CH:6]=[CH:7][N:8]3[CH:14]=[CH:13][CH:12]=[C:9]3[C:10](=[O:11])[C:4]=2[CH:3]=1.Cl.[CH3:18][N:19](C)C=O>>[C:18]([C:2]1[CH:16]=[CH:15][C:5]2[CH:6]=[CH:7][N:8]3[CH:14]=[CH:13][CH:12]=[C:9]3[C:10](=[O:11])[C:4]=2[CH:3]=1)#[N:19]
Reactant: O=c1c2cc(Br)ccc2ccn2cccc12
Reactant: CN(C)C=O
Agent: Cl
Product: N#Cc1ccc2ccn3cccc3c(=O)c2c1
Reaction time: 0.5 h

Procedure:
A stirred mixture of 1 gm. of 9-bromo-11H-pyrrolo[2,1-b][3]benzazepin-11-one, 1 gm. of cuprous cyanide and 5 ml. of dimethylformamide is heated to reflux for 5 hr. The mixture is then poured into a solution of 4 gm. of ferric chloride hydrate in 25 ml. of 2N hydrochloric acid. After stirring the resulting mixture at 60° for 30 min., it is extracted with 3 × 50 ml. of ethyl acetate, the organic extracts washed with 3 × 100 ml. of water and dried over Na2SO4. Evaporation of the dried solution yields 9-cyano-11H-pyrrolo[2,1-b][3]benzazepin-11-one, m.p. 213°-217° C.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][CH2:5][C:4]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)([C:8]#[N:9])[CH2:3]1.[CH2:16](O)[CH2:17][OH:18].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>C1C=CC=CC=1>[CH2:16]1[CH2:17][O:18][C:2]2([CH2:7][CH2:6][CH2:5][C:4]([C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=3)([C:8]#[N:9])[CH2:3]2)[O:1]1
Reactant: OCCO
Reactant: N#CC1(c2ccccc2)CCCC(=O)C1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: c1ccccc1
Product: N#CC1(c2ccccc2)CCCC2(C1)OCCO2
Temperature: 111 °C
Reaction time: 8 h
Yield: 48 %

Procedure:
The mixture of 3-oxo-1-phenylcyclohexanecarbonitrile (2.62 g), ethylene glycol (3.65 mL) and pyridinium p-toluene sulfonate (1 spatula) in benzene (40 mL) was stirred at 111° C. with Dean-Stark apparatus overnight. After cooling down to room temperature, the mixture was washed with saturated sodium bicarbonate and the organic layer was separated. The aqueous layer was extracted with dichloromethane 3 times and the combined organic layers were dried over magnesium sulfate, filtered and concentrated under vacuum. The crude material was purified by Flash Chromatography with from 25% ethyl acetate/75% hexane to 30% ethyl acetate/70% hexane over 20 minutes. The title compound was obtained as a white solid (1.66 g, 48% yield in 2 steps). 1H NMR (400 MHz, CDCl3) δ 1.56 (1H, dt, J=4, 16 Hz), 1.70-1.79 (1H, m), 1.89-1.96 (3H, m), 2.06-2.28 (3H, m), 3.89-3.97 (2H, m), 4.03-4.12 (2H, m), 7.28-7.32 (1H, m), 7.36-7.39 (2H, m), 7.48-7.51 (2H, m). HPLC purity (retention time): 95% (1.62 min, method C). MS: 266.37 (M+Na+).
Reaction SMILES: [N:1]1([C:6]2[CH:11]=[C:10]([NH2:12])[C:9]([NH2:13])=[C:8]([CH3:14])[CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[Cl:15][C:16]1[C:21]([CH:22]=O)=[C:20]([Cl:24])[N:19]=[CH:18][N:17]=1>CO>[Cl:15][C:16]1[C:21]([C:22]2[NH:12][C:10]3[CH:11]=[C:6]([N:1]4[CH:5]=[CH:4][N:3]=[CH:2]4)[CH:7]=[C:8]([CH3:14])[C:9]=3[N:13]=2)=[C:20]([Cl:24])[N:19]=[CH:18][N:17]=1
Reactant: O=Cc1c(Cl)ncnc1Cl
Reactant: Cc1cc(-n2ccnc2)cc(N)c1N
Solvent: CO
Product: Cc1cc(-n2ccnc2)cc2[nH]c(-c3c(Cl)ncnc3Cl)nc12
Temperature: 25 °C
Reaction time: 14 h
Yield: 54.3 %

Procedure:
To a solution of 5-imidazol-1-yl-3-methyl-benzene-1,2-diamine (180 mg, 0.96 mmol) in methanol (4 mL) was added a solution of 4,6-dichloro-pyrimidine-5-carbaldehyde (183 mg, 0.96 mmol) in methanol (1 mL). The reaction mixture was stirred at room temperature for 14 h. After concentration, the residue was purified by flash column chromatography (5% methanol/CH2Cl2) to yield the title compound (180 mg, 55%). LCMS (M+H)+ m/z 344 (t=1.31 min.).
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[C:6]([N:9]2[CH2:14][CH2:13][S:12](=[O:16])(=[O:15])[CH2:11][CH2:10]2)=[C:5]2[C:17](=[O:33])[N:18]([CH2:21][CH2:22][C:23]3[CH:32]=[CH:31][C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[N:24]=3)[C:19](=O)[C:4]2=[CH:3]1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:43])=CC=1>C1(C)C=CC=CC=1>[CH3:1][N:2]1[C:7](=[O:8])[C:6]([N:9]2[CH2:14][CH2:13][S:12](=[O:16])(=[O:15])[CH2:11][CH2:10]2)=[C:5]2[C:17](=[O:33])[N:18]([CH2:21][CH2:22][C:23]3[CH:32]=[CH:31][C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[N:24]=3)[C:19](=[S:43])[C:4]2=[CH:3]1
Reactant: Cn1cc2c(c(N3CCS(=O)(=O)CC3)c1=O)C(=O)N(CCc1ccc3ccccc3n1)C2=O
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: Cn1cc2c(c(N3CCS(=O)(=O)CC3)c1=O)C(=O)N(CCc1ccc3ccccc3n1)C2=S
Temperature: 120 °C
Reaction time: 16 h
Yield: 120.9 %

Procedure:
A suspension of 5-methyl-7-(1,1-dioxo-thiomorpholin-4-yl)-2-(2-quinolin-2-yl-ethyl)-5H-pyrrolo[3,4-c]pyridine-1,3,6-trione (0.8 g, 1.715 mmol, see Example 3) in toluene (30 ml) was heated to 120° C., Lawesson's reagent (0.347 g, 0.857 mmol) was added and the reaction was stirred at 120° C. for 16 h. The solvent was removed and the resulting mixture was purified on a silica column (DCM/MeOH=50:1) to afford the title compound (0.5 g, 60% yield).
Reaction SMILES: [S:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]=[C:2]1[SH:10].[OH-].[Na+].Cl[CH:14]([F:16])[F:15].Cl>O1CCOCC1.O>[F:15][CH:14]([F:16])[S:10][C:2]1[S:1][C:9]2[C:4]([N:3]=1)=[N:5][CH:6]=[CH:7][CH:8]=2
Reactant: FC(F)Cl
Reactant: Sc1nc2ncccc2s1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: FC(F)Sc1nc2ncccc2s1
Temperature: 70 °C
Yield: 33 %

Procedure:
A solution of thiazolo[4,5-b]pyridine-2-thiol (2.0 g, 12 mmol) in dioxane is treated with a solution of sodium hydroxide (4.8 g, 120 mmol) in water, heated to 70° C., treated with a steady stream of chlorodifluoromethane for 75 minutes, and poured onto ice. The resultant aqueous mixture is acidified with concentrated hydrochloric acid and extracted with dichloromethane. The organic extract is dried over anhydrous sodium sulfate and concentrated in vacuo to obtain a residue. Column chromatography of the residue using silica gel and several ethyl acetate/hexanes solutions gives the title product as a light yellow solid (0.86 g, 33% yield, mp 41-43° C.).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([N+:13]([O-])=O)[CH:7]=[C:8]2[C:12]=1[NH:11][CH:10]=[CH:9]2)(=[O:3])[CH3:2]>CO.[Pd]>[C:1]([C:4]1[CH:5]=[C:6]([NH2:13])[CH:7]=[C:8]2[C:12]=1[NH:11][CH:10]=[CH:9]2)(=[O:3])[CH3:2]
Reactant: CC(=O)c1cc([N+](=O)[O-])cc2cc[nH]c12
Agent: [Pd]
Solvent: CO
Product: CC(=O)c1cc(N)cc2cc[nH]c12
Yield: 81.3 %

Procedure:
A solution of 7-acetyl-5-nitroindole (0.2 g, 1.2 mmol) and 10% Pd/C (30 mg) in 20 mL of MeOH was stirred at reflux for 1 h. The reaction mixture was filtered and concentrated in vacuo, yielding oil (0.17 g, >95%), which was characterized by NMR and subjected to the following reaction without further purification.
Reaction SMILES: [C:1]1([CH3:9])[CH:6]=[CH:5][C:4]([CH:7]=[O:8])=[CH:3][CH:2]=1.S(=O)(O)[O-].[Na+].[N+:15]([CH2:18][CH2:19][CH3:20])([O-:17])=[O:16].[OH-].[Na+]>C(O)C.O>[N+:15]([CH:18]([CH2:19][CH3:20])[CH:7]([C:4]1[CH:5]=[CH:6][C:1]([CH3:9])=[CH:2][CH:3]=1)[OH:8])([O-:17])=[O:16]
Reactant: CCC[N+](=O)[O-]
Reactant: Cc1ccc(C=O)cc1
Agent: O=S([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCC(C(O)c1ccc(C)cc1)[N+](=O)[O-]

Procedure:
The procedure of Example 1 was followed for the reaction of 120 g of p-tolualdehyde and 114 g of sodium bisulfite with 178 g of 1-nitropropane and 80 g of sodium hydroxide. Water and ethanol were the solvents. The product obtained was a clear, yellow liquid weighing 100 g; ir (film) 2.8 (s), 3.4 (m), 6.5 (s), 7.3 (m), 9.7 (m), 12.2 (s) microns.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[F:14])[N:5]=[C:4]2[N:15]([CH3:19])[N:16]=[C:17]([CH3:18])[C:3]=12.[NH2:20][C:21]1[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=1>C(O)(C)C.Cl.O1CCOCC1>[F:14][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[C:6]1[N:5]=[C:4]2[N:15]([CH3:19])[N:16]=[C:17]([CH3:18])[C:3]2=[C:2]([NH:20][C:21]2[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=2)[N:7]=1
Reactant: Nc1ccncc1
Reactant: Cc1nn(C)c2nc(-c3ccccc3F)nc(Cl)c12
Agent: Cl
Solvent: C1COCCO1
Solvent: CC(C)O
Product: Cc1nn(C)c2nc(-c3ccccc3F)nc(Nc3ccncc3)c12
Temperature: 80 °C
Yield: 81 %

Procedure:
4-Chloro-6-(2-fluoro-phenyl)-1,3-dimethyl-1H-pyrazolo[3,4-d]pyrimidine (84 mg, 0.304 mmole) and 4-aminopyridine (57 mg, 0.608 mmole) were combined in 4 ml isopropanol, 3 drops 4M HCl/dioxane were added and the reaction mixture heated to 80° C. for 5 hours. The reaction mixture was cooled and the product was filtered to obtain 83 mg after vacuum drying (yield: 81%).
Reaction SMILES: C(N(CC)C(C)C)(C)C.[OH:10][C:11]1[CH:21]=[CH:20][CH:19]=[C:13]2[C:14]([O:16][C:17](=[O:18])[C:12]=12)=[O:15].[CH3:22][O:23][CH2:24]Cl>ClC(Cl)C>[CH3:22][O:23][CH2:24][O:10][C:11]1[CH:21]=[CH:20][CH:19]=[C:13]2[C:14]([O:16][C:17](=[O:18])[C:12]=12)=[O:15]
Reactant: O=C1OC(=O)c2c(O)cccc21
Reactant: COCCl
Solvent: CC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: COCOc1cccc2c1C(=O)OC2=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 99.2 %

Procedure:
N,N-Diisopropylethylamine (4.39 g, 34.0 mmol) was added to a solution of 3-hydroxyphthalic anhydride (5.0 g, 30.5 mmol) in dichloroethane (60 ml), then chloromethyl methyl ether (2.57 g, 32.0 mmol) was dropped thereinto under cooling with ice water and the mixture was returned to room temperature and stirred for 1 hour. Then N,N-diisopropylethylamine (2.20 g, 17.0 mmol) and chloromethyl methyl ether (1.28 g, 16.0 mmol) were further added thereto followed by stirring for 1 hour. After the reaction, the solvent was evaporated and the residue was diluted with water followed by extracting with ether. The organic layer was washed with water and a saturated sodium chloride solution successively and dried over anhydrous magnesium sulfate and the solvent was evaporated therefrom to provide 6.3 g (yield 99%) of 3-methoxymethyloxyphthalic anhydride as colorless oil.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[CH:5](Br)[C:6]1[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=1)[CH3:2].[CH2:14]([NH2:19])[C:15]([CH3:18])([CH3:17])[CH3:16].CCN(CC)CC>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:13])[CH:5]([NH:19][CH2:14][C:15]([CH3:18])([CH3:17])[CH3:16])[C:6]1[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=1)[CH3:2]
Reactant: CCOC(=O)C(Br)c1cccnc1
Reactant: CC(C)(C)CN
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)C(NCC(C)(C)C)c1cccnc1
Yield: 39.2 %

Procedure:
Bromopyridin-3-yl-acetic acid ethyl ester (2.54 g; 10.2 mmol), prepared in a manner similar to preparation 340, was reacted in refluxing CH2Cl2, overnight with neopentylamine (4.83 mL; 41.0 mmol; 4 equiv) and Et3N (5.8 mL; 41.0 mmol; 4 equiv). The reaction solution was evaporated to dryness, dissolved in CH2Cl2, washed five times with saturated NaHCO3(aq), washed once with saturated NaCl (aq), dried with Na2SO4, filtered, and concentrated in vacuo. The resulting brown oil was purified with silica gel chromatography in a 3×25 cm glass column using a 0.5% methanol/chloroform (v/v) mobile phase. A second column purification with 100% chloroform followed by 1% methanol/chloroform (v/v) produced pure product as a yellow oil (1.0 g; 40% yield).
Reaction SMILES: [CH:1]#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[CH2:9]([O:11][C:12](=[O:16])/[CH:13]=[CH:14]\I)[CH3:10]>>[C:12]([O:11][CH2:9][CH3:10])(=[O:16])/[CH:13]=[CH:14]\[C:1]#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCOC(=O)/C=C\I
Reactant: C#CCCCCCC
Product: CCCCCCC#C/C=C\C(=O)OCC

Procedure:
The general procedure was used to convert n-octyne and (Z)-ethyl-3-iodoacrylate to the title product. Purification by flash chromatography (5% ethyl acetate in hexane as the eluent) gave the analytically pure product as a light yellow oil (401 mg, 96% yield). 1H NMR (400 MHz, CDCl3) δ 6.13 (dt, J=10.82, 1H), 6.02 (d, J=10.96, 1H), 4.21 (q, 2H), 2.44 (m, 2H), 1.58 (p, 2H), 1.42 (m, 2H), 1.30-1.28 (m, 7H), 0.89 (t, 3H). 13C NMR (100 MHz, CDCl3) δ 164.87, 127.34, 123.89, 104.17, 77.66, 60.18, 31.30, 28.60, 28.36, 22.49, 20.07, 14.21, 13.99. Anal. Calcd. for C13H20O2: C, 74.96; H, 9.68; Found C, 74.96; H, 9.56.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]2[CH2:16][C:15](=O)[CH:14]=[C:13]([O:18]CC)[CH2:12]2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[BH4-].[Na+].Cl.C(OCC)(=O)C>C(O)C.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]2[CH2:12][C:13](=[O:18])[CH:14]=[CH:15][CH2:16]2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: CCOC1=CC(=O)CC(c2ccc(OC)c(OC)c2)C1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(C)=O
Product: COc1ccc(C2CC=CC(=O)C2)cc1OC
Temperature: 60 °C
Reaction time: 1.5 h
Yield: 48.2 %

Procedure:
5-(3,4-Dimethoxyphenyl)-3-ethoxy-2-cyclohexen-1-one (16.7 g) was dissolved in ethanol (260 ml), and then sodium borohydride (6.88 g) was gradually added and the mixture was stirred at 60° C. for 1.5 hours. After distilling off the reaction solvent under reduced pressure, and subsequent pouring over of ice water, extraction with ethyl acetate and drying with anhydrous magnesium sulfate, the solvent was concentrated under reduced pressure to produce a yellow oily substance. The oily substance was dissolved in ethyl acetate (20 ml), 4 N HCl-ethyl acetate solution (50 ml) was added and the mixture was stirred at room temperature for 13 hours. The reaction solution was washed with saturated sodium bicarbonate water and saturated saline and dried with anhydrous magnesium sulfate, after which the solvent was distilled off under reduced pressure to produce a yellow oily substance which was then purified by silica gel column chromatography (n-hexane:ethyl acetate=2:1). The resulting crystals were washed with diethyl ether to give 6.76 g of 5-(3,4-dimethoxyphenyl)-2-cyclohexen-1-one (48.1%).