Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([SH:10])=[CH:6][CH:5]=1.Br[C:12]1[S:16][C:15]([CH:17]=[O:18])=[CH:14][CH:13]=1>C1COCC1>[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([S:10][C:12]2[S:16][C:15]([CH:17]=[O:18])=[CH:14][CH:13]=2)=[CH:6][CH:5]=1
Reactant: Sc1ccc(Cl)cc1
Reactant: O=Cc1ccc(Br)s1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=Cc1ccc(Sc2ccc(Cl)cc2)s1
Reaction time: 0.17 h
Yield: 97.3 %

Procedure:
Sodium hydride (60%, 1.2 g, 30 mmol) is added to a solution of 4-chlorothiophenol (4.3 g, 30 mmol) in THF (30 mL). The resulting solution is stirred for 10 minutes then the solvent is removed in vacuo. Acetone (60 mL) is added followed by 5-bromothiophene-2-carboxaldehyde (3.0 mL, 25 mmol). The mixture is stirred at room temperature for 2 hours. The solvent is removed in vacuo and the resulting slurry diluted with CH2Cl2. This solution is washed three times with 1N NaOH then dried over MgSO4, filtered and concentrated in vacuo. The crude product is purified by flash column chromatography (gradient of 1 to 5% EtOAc in heptane) to give the desired product (6.2 g, 98%). 1H NMR (300 MHz, CDCl3) δ 7.13, 7.31-7.39, 7.63, 9.78.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]2[O:6][CH2:7][O:8][C:4]=2[C:3]=1[NH:11][C:12]1[C:20]2[C:19]3[CH2:21][NH:22][CH2:23][CH2:24][C:18]=3[NH:17][C:16]=2[N:15]=[CH:14][CH:13]=1.CCN(C(C)C)C(C)C.[C:34](Cl)(=[O:41])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>ClCCCl>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]2[O:6][CH2:7][O:8][C:4]=2[C:3]=1[NH:11][C:12]1[C:20]2[C:19]3[CH2:21][N:22]([C:34]([C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)=[O:41])[CH2:23][CH2:24][C:18]=3[NH:17][C:16]=2[N:15]=[CH:14][CH:13]=1
Reactant: Clc1ccc2c(c1Nc1ccnc3[nH]c4c(c13)CNCC4)OCO2
Reactant: O=C(Cl)c1ccccc1
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1ccccc1)N1CCc2[nH]c3nccc(Nc4c(Cl)ccc5c4OCO5)c3c2C1
Temperature: 25 °C
Yield: 10 %

Procedure:
(5-Chloro-benzo[1,3]dioxol-4-yl)-(6,7,8,9-tetrahydro-5H-dipyrido[2,3-b;3′,4′-d]pyrrol-4-yl)-amine (100 mg, 0.29 mmol) and DIEA (0.15 mL, 0.88 mmol) were dissolved in 1,2-dichloroethane (2 mL) and stirred at room temperature. Benzoyl chloride (0.03 mL, 0.35 mmol) was added dropwise, and the reaction was stirred for 1 h at room temperature. The reaction solution was concentrated. The crude material was dissolved in DMSO (3 mL) and filtered. The filtrate was purified directly via prep-LC-MS to provide 67 (13 mg, 10% yield) as a white fluffy solid. LC-MS (M+H=447, obsd.=447).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([OH:13])=[C:7]([CH:12]=1)[C:8]([O:10][CH3:11])=[O:9])#[N:2].C(=O)([O-])[O-].[K+].[K+].FC(F)(F)S(O[CH2:26][C:27]([F:30])([F:29])[F:28])(=O)=O>CC(C)=O>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([O:13][CH2:26][C:27]([F:30])([F:29])[F:28])=[C:7]([CH:12]=1)[C:8]([O:10][CH3:11])=[O:9])#[N:2]
Reactant: COC(=O)c1cc(C#N)ccc1O
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)c1cc(C#N)ccc1OCC(F)(F)F
Yield: 61.5 %

Procedure:
To a refluxing mixture of acetone (20 mL), methyl 5-cyano-2-hydroxybenzoate (2.0 g, 11.3 mmol, Astatech) and potassium carbonate (3.1 g, 22.6 mmol) in a 40 mL sealed vial was added dropwise 2,2,2-trifluoroethyl trifluoromethanesulfonate (3.9 g, 16.9 mmol, TCI). The mixture was stirred at reflux overnight and then concentrated under reduced pressure. The residue was dissolved in water (50 mL) and dichloromethane (50 mL). The layers were separated and the aqueous layer was extracted with dichloromethane (3×50 mL). The combined organic extracts were dried (Na2SO4), filtered and concentrated to afford 1.8 g of crude methyl 5-cyano-2-(2,2,2-trifluoroethoxy)benzoate that was suspended in methanol/water (1:1, 100 mL) and treated with an aqueous solution of 5N sodium hydroxide (2.8 mL, 13.9 mmol). After stirring at 40° C. for 16 h, the reaction mixture was concentrated and then washed with methylene chloride. The aqueous layer was acidified to pH-2 with aqueous 2N HCl solution to precipitate the product. The precipitate was filtered and dried under reduced pressure to afford 1.1 g of a product mixture of the title compound with unreacted 5-cyano-2-hydroxybenzoic acid (5:2 ratio). MS (ESI+) m/z 263 (M+NH4)+.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1([OH:21])[C:18]2[C:13](=[CH:14][CH:15]=[C:16](I)[CH:17]=2)[NH:12][C:11]1=[O:20])[CH3:2].[CH3:22][N:23](C=O)C>[C-]#N.[Zn+2].[C-]#N.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:22]([C:16]1[CH:17]=[C:18]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11](=[O:20])[C:10]2([C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[O:3][CH2:1][CH3:2])[OH:21])#[N:23]
Reactant: CN(C)C=O
Reactant: CCOc1ccccc1C1(O)C(=O)Nc2ccc(I)cc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: CCOc1ccccc1C1(O)C(=O)Nc2ccc(C#N)cc21
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
37.2 g (94 mmol) of the product 1a and 11.1 g (94 mmol) of zinc cyanide in 300 ml of DMF were heated to 95° C. Then 1.6 g (1.38 mmol) of tetrakis(triphenylphosphine)palladium(0) were added in portions every 10 minutes. After 45 minutes, the reaction mixture was poured into ice-water and extracted with ethyl acetate. The organic phase was washed with saturated NaCl solution, dried and concentrated in vacuo. The residue obtained in this way crystallizes from a little ethyl acetate. 24 g of the product were obtained.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[C:9](=[O:18])[CH2:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12].[CH:19](=O)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.N1CCCCC1.C(O)(=O)C>C1C=CC=CC=1>[OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[C:9](/[C:10](=[CH:19]\[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)/[C:11]([O:13][C:14]([CH3:15])([CH3:17])[CH3:16])=[O:12])=[O:18]
Reactant: Cc1ccc(C(=O)CC(=O)OC(C)(C)C)c(O)c1
Reactant: O=Cc1ccccc1
Solvent: c1ccccc1
Solvent: CC(=O)O
Solvent: C1CCNCC1
Product: Cc1ccc(C(=O)/C(=C\c2ccccc2)C(=O)OC(C)(C)C)c(O)c1
Yield: 45.5 %

Procedure:
Prepared according to general procedure A using tert-butyl 3-(2-hydroxy-4-methyphenyl)-3-oxopropanoate (250 mg, 1.0 mmol), benzaldehyde (100 μL, 1.00 mmol), 12.0 mL benzene, piperidine (10 μL, 0.10 mmol) and glacial acetic acid (5.7 μL, 0.10 mmol), refluxed for 3 h. Purified via recrystallization from hexanes/CH2Cl2, yielding 154 mg (46%) of white solid. mp=92-95° C.; IR (film) 2977.9; 1718.2; 1627.9; 1155.0 cm−1; 1H NMR (500 MHz, CDCl3) δ 11.95 (bs, 1H), 7.82 (s, 1H), 7.40 (d, J=9.6 Hz, 1H), 7.36-7.29 (m, 5H), 6.83 (s, 1H), 6.61 (d, J=8.0 Hz, 1H), 2.34 (s, 3H), 1.41 (s, 9H); 13C NMR (125 MHz, CDCl3) δ 200.8, 163.9, 163.0, 149.0, 142.0, 133.0, 131.8, 131.7, 130.6, 130.3, 129.1, 120.9, 118.5, 118.0, 82.7, 28.1, 22.3; LRMS (electrospray): Mass calculated for C21H22O4 [M]+, 338.15. Found [M+23]+, 361.2. An NOE difference experiment was conducted for this compound and a positive NOE was seen for the alkene proton when the tert-butyl signal was irradiated and a positive NOE was seen for the tert-butyl signal upon irradiation of the alkene proton.
Reaction SMILES: [F:1][C:2]([F:15])([CH:12]([F:14])[F:13])[CH2:3][C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1C=O.[F:16][C:17]1[CH:18]=[C:19]2[C:26](=[CH:27][CH:28]=1)[C:22]([CH2:23][CH2:24][NH2:25])=[CH:21][NH:20]2.[CH:29](O)(C)C>>[F:16][C:17]1[CH:18]=[C:19]2[C:26]([C:22]([CH2:23][CH2:24][NH:25][CH2:29][C:10]3[CH:9]=[CH:8][CH:5]=[C:4]([CH2:3][C:2]([F:1])([F:15])[CH:12]([F:13])[F:14])[CH:11]=3)=[CH:21][NH:20]2)=[CH:27][CH:28]=1
Reactant: NCCc1c[nH]c2cc(F)ccc12
Reactant: CC(C)O
Reactant: O=Cc1ccccc1CC(F)(F)C(F)F
Product: Fc1ccc2c(CCNCc3cccc(CC(F)(F)C(F)F)c3)c[nH]c2c1
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
Combine isopropanol (500 g), 2,2,3,3-tetrafluoropropylbenzaldehyde (116.8 g), and 6-fluorotryptamine (1.15 equiv.). Heat to reflux over about 1.5 hour. After 30 minutes at the reflux, distill and over 30 minutes collect about 380 g of distillate. Cool the reaction mixture to 50° C. and add NaBH4 (19.71 g) in one portion. After 1 hour at 50° C., slowly add water over 15 minutes and allow the resulting solution to cool to room temperature overnight. Distill the isopropanol under reduced pressure to give a residue and extract with dichloromethane, combine organic layers, and treat with 1N aqueous HCl (650 mL) to give a solid. Stir the heavy suspension for 2 hours at 20-25° C. Collect the solid by filtration, wash with dichloromethane and dry at 50° C. under vacuum overnight to afford title compound.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:11])[C:6](=[O:12])[CH2:5]2.[Br:13][CH2:14][CH2:15][CH2:16]Br.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>C(Cl)Cl.C(C(C)=O)C>[Br:13][CH2:14][CH2:15][CH2:16][O:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:11])[C:6](=[O:12])[CH2:5]2
Reactant: CN1C(=O)Cc2cc(O)ccc21
Reactant: BrCCCBr
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCC(C)=O
Solvent: ClCCl
Product: CN1C(=O)Cc2cc(OCCCBr)ccc21

Procedure:
A mixture of 11.9 g of 5-hydroxy-1-methyl-2-indolinone, 29.2 g of 1,3-dibromopropane, 11 g of potassium carbonate, 1 g of potassium iodide and 75 ml of ethylmethyl ketone is refluxed for 20 hours. The mixture is then diluted with 300 ml of methylene dichloride, washed with water and the solvent is removed under reduced pressure.
Reaction SMILES: [C:1]([CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][C:14](=O)[CH3:15])=[CH:9][CH:8]=1)([O:3][CH3:4])=[O:2].[CH3:17][O:18][CH:19]([C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[C:23]=1[F:29])[CH2:20][NH2:21].[H][H]>CO.[Pt]>[C:1]([CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH:14]([NH:21][CH2:20][CH:19]([O:18][CH3:17])[C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[C:23]=2[F:29])[CH3:15])=[CH:9][CH:8]=1)([O:3][CH3:4])=[O:2]
Reactant: COC(CN)c1cccc(F)c1F
Reactant: COC(=O)COc1ccc(CC(C)=O)cc1
Reactant: [H][H]
Agent: [Pt]
Solvent: CO
Product: COC(=O)COc1ccc(CC(C)NCC(OC)c2cccc(F)c2F)cc1

Procedure:
1-(4-Carbomethoxymethoxyphenyl)propan-2-one (2.20 g) and 2-methoxy-2-(2,3-difluorophenyl)ethanamine (1.87 g) in methanol (50 ml) was hydrogenated in the presence of platinum (from platinum oxide, 50 mg) until hydrogen uptake ceased. The solution was filtered through diatomaceous earth, and the solvent removed under reduced pressure. Chromatography of the residue on silica-gel eluting with 2% methanol in dichloromethane gave the title compound as an oil. The product was used in Example 54 without further purification.
Reaction SMILES: [CH3:1][C@H:2]1[O:7][C@@H:6]([CH3:8])[CH2:5][N:4]([C:9]2[CH:18]=[CH:17][C:12]([C:13]([NH:15][NH2:16])=[O:14])=[CH:11][CH:10]=2)[CH2:3]1.[CH3:19][O:20][C:21]([C:23]1[CH:31]=[CH:30][C:26]([C:27](Cl)=[O:28])=[CH:25][CH:24]=1)=[O:22].N1C=CC=CC=1.O>O1CCCC1>[CH3:19][O:20][C:21](=[O:22])[C:23]1[CH:31]=[CH:30][C:26]([C:27]([NH:16][NH:15][C:13](=[O:14])[C:12]2[CH:11]=[CH:10][C:9]([N:4]3[CH2:3][C@H:2]([CH3:1])[O:7][C@H:6]([CH3:8])[CH2:5]3)=[CH:18][CH:17]=2)=[O:28])=[CH:25][CH:24]=1
Reactant: COC(=O)c1ccc(C(=O)Cl)cc1
Reactant: C[C@@H]1CN(c2ccc(C(=O)NN)cc2)C[C@H](C)O1
Solvent: C1CCOC1
Solvent: c1ccncc1
Solvent: O
Product: COC(=O)c1ccc(C(=O)NNC(=O)c2ccc(N3C[C@@H](C)O[C@@H](C)C3)cc2)cc1
Temperature: 0 °C
Reaction time: 6 h
Yield: 87.7 %

Procedure:
A mixture of 4-(cis-2,6-dimethylmorpholin-4-yl)benzoic acid hydrazide (458 mg), 4-methoxycarbonylbenzoyl chloride (622 mg) and pyridine (5 ml) in tetrahydrofuran (10 ml) was stirred for 6 hours at 0° C. The reaction mixture was added to water. The resulting precipitates were filtered, washed with water and dried to give 4-[N′-[4-(cis-2,6-dimethylmorpholin-4-yl)benzoyl]hydrazinocarbonyl]benzoic acid methyl ester (662.8 mg).
Reaction SMILES: C=C1OCC2C(OC(C)(C)O2)CO1.Br[CH2:15][CH:16]1[O:25][CH2:24][CH:23]2[CH:19]([O:20][C:21]([CH3:28])([CH:26]=[CH2:27])[O:22]2)[CH2:18][O:17]1>>[CH2:15]=[C:16]1[O:17][CH2:18][CH:19]2[CH:23]([O:22][C:21]([CH3:28])([CH:26]=[CH2:27])[O:20]2)[CH2:24][O:25]1
Reactant: C=CC1(C)OC2COC(CBr)OCC2O1
Agent: C=C1OCC2OC(C)(C)OC2CO1
Product: C=CC1(C)OC2COC(=C)OCC2O1
Yield: 43.2 %

Procedure:
4-Methylene-9-methyl-9-vinyl-3,5,8,10-tetraoxabicyclo[5.3.0]decane was prepared in a similar way to 4-methylene-9,9-dimethyl-3,5,8,10-tetraoxabicyclo[5.3.0]decane starting from 115.7 mmol (35 g) of 4-bromomethyl-9-methyl-9-vinyl-3,5,8, 10-tetraoxabicyclo[5.3.0]decane, fractional distillation giving 10 g (43.2% yield) at 62° C. (0.1 mbar).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=3)([CH:12]3[CH2:17][CH2:16][CH2:15][NH:14][CH2:13]3)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[Cl:33][C:34]1[CH:35]=[C:36]([N:40]=[C:41]=[O:42])[CH:37]=[CH:38][CH:39]=1>ClCCl>[Cl:33][C:34]1[CH:35]=[C:36]([NH:40][C:41]([N:14]2[CH2:15][CH2:16][CH2:17][CH:12]([C:6]3([CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=4)[C:5]4[C:9](=[CH:10][C:2]([Cl:1])=[CH:3][CH:4]=4)[NH:8][C:7]3=[O:11])[CH2:13]2)=[O:42])[CH:37]=[CH:38][CH:39]=1
Reactant: O=C1Nc2cc(Cl)ccc2C1(Cc1cccc(Cl)c1)C1CCCNC1
Reactant: O=C=Nc1cccc(Cl)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Nc1cccc(Cl)c1)N1CCCC(C2(Cc3cccc(Cl)c3)C(=O)Nc3cc(Cl)ccc32)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of rac-6-chloro-3-(3-chloro-benzyl)-3-piperidin-3-yl-1,3-dihydro-indol-2-one (50 mg, 0.13 mmol) (from Example 25a supra) in dichloromethane (3 mL) was added triethylamine (20 mg, 0.19 mmol) (Aldrich), followed by the addition of 3-chloro-phenyl isocyanate (24 mg, 0.16 mmol) (Aldrich). The mixture was stirred at room temperature for 30 minutes. The mixture was partitioned between dichlormethane and water. The aqueous layer was extracted with dichlormethane. The combined organic layers were washed with water, brine, dried over Na2SO4 and concentrated. The residue was purified by chromatography to give rac-3-[6-chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-piperidine-1-carboxylic acid (3-chloro-phenyl)-amide as a white solid. (Yield 32 mg, 46%).
Reaction SMILES: [Na].[C:2](OCC)(=[O:9])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[O-]CC.[Na+].C(O[C:20](=[O:27])[CH:21]=[C:22]([NH2:26])[CH:23]1[CH2:25][CH2:24]1)C>C(O)C.O>[CH2:7]([O:6][C:4](=[O:5])[C:3]1[C:20]([OH:27])=[CH:21][C:22]([CH:23]2[CH2:24][CH2:25]2)=[N:26][C:2]=1[OH:9])[CH3:8]
Reactant: CCOC(=O)C=C(N)C1CC1
Reactant: CCOC(=O)CC(=O)OCC
Agent: CC[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1c(O)cc(C2CC2)nc1O
Temperature: 60 °C
Reaction time: 8 h
Yield: 59.6 %

Procedure:
Sodium metal (8.1 g, 119 mmol) was cut into small pieces and added portionwise to stirred ethanol (120 mL) at room temperature under a nitrogen atmosphere. The mixture was then stirred at 60° C. under N2 overnight to ensure complete dissolution of the metal. Diethyl malonate (18.1 ml, 119 mmol) was added to the sodium ethoxide solution at 60° C. and the mixture was stirred at 60° C. under N2 for 1 h. A solution 3-Amino-3-cyclopropyl-acrylic acid ethyl ester (10.3 g, 40 mmol) in ethanol (10 mL) was added dropwise at 60° C. and the mixture was heated at reflux under N2 for 5 days to give an orange suspension. The mixture was allowed to cool to room temperature and the resulting solid collected by filtration. The filtrate was concentrated in vacuo to give more solid. The combined solids were dissolved in water (150 mL) and the solution washed with EtOAc (150 mL). The aqueous was acidified to pH2 using concentrated HCl causing a white solid to precipitate. The solid was collected by filtration, washed with cold water and then Et2O, and then dried in vacuo at 40° C. overnight to give the title product (5.32 g) as a fine white solid. The filtrate was concentrated in vacuo to half its volume causing more product to precipitate. This second crop of solid was collected by filtration, washed with water and Et2O and dried in vacuo at 40° C. to give a further 0.35 g of the title compound as a pale beige solid.
Reaction SMILES: B(F)(F)F.[CH3:5][CH2:6][O:7]CC.[C:10]([O:13][C@H:14]1[O:31][C@H:30]([CH2:32][O:33][C:34](=O)[CH3:35])[C@@H:25]([O:26][C:27](=[O:29])[CH3:28])[C@H:20]([O:21][C:22](=[O:24])[CH3:23])[C@@H:15]1[O:16]C(=O)C)(=[O:12])[CH3:11].[CH2:37](O)C#C.C(=O)([O-])[O-].[K+].[K+]>ClCCl>[C:6]([O:31][C@H:30]1[C@@H:25]([O:26][C:27](=[O:29])[CH3:28])[C@H:20]([O:21][C:22](=[O:24])[CH3:23])[C@@H:15]([CH2:14][O:13][C:10](=[O:12])[CH3:11])[O:16][C@@H:32]1[O:33][CH2:34][C:35]#[CH:37])(=[O:7])[CH3:5]
Reactant: CCOCC
Reactant: C#CCO
Reactant: CC(=O)OC[C@H]1O[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: FB(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: C#CCO[C@H]1O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 0 °C
Reaction time: 96 h
Yield: 100.1 %

Procedure:
Under nitrogen atmosphere, boron trifluoride ethyl etherate (7.90 mL, 64 mmol, 5 equiv) was added dropewise at 0° C. to a solution of α-D-mannopyranose pentaacetate (5 g, 12.8 mmol) and propargyl alcohol (2.98 mL, 51.2 mmol, 4 equiv) in anhydrous dichloromethane (150 mL) and the solution was stirred at 0° C. for 4 days. Anhydrous potassium carbonate (8 g) was added and the reaction mixture was stirred for further 1 h and filtered. The filtrate was diluted with dichloromethane (200 mL), washed with water (3×200 mL), dried over Na2SO4, filtered and concentrated to afford 2-propynyl 2,3,4,6-tetra-O-acetyl-α-D-mannopyranoside (4.95 g, quantitative yield) as a brown oil which was used without further purification. 1H NMR (400 MHz, CDCl3): δ=5.38-5.20 (m, 3H, H2,3,4), 5.02 (d, J=1.6 Hz, 1H, H1), 4.27 (dd, J=5.2, 12.2 Hz, 1H, H6), 4.26 (d, J=2.4 Hz, 2H, OCH2C≡CH), 4.10 (dd, J=2.5, 12.2 Hz, 1H, H6), 4.45-3.72 (m, 1H, H5), 2.46 (t, J=2.4 Hz, 1H, C≡CH), 2.15, 2.09, 2.03, 1.98 (4s, 4×3H, OCOCH3); 13C NMR (100.6 MHz, CDCl3): δ=170.7, 170.0, 169.9 and 169.8 (OCOCH3), 96.4 (CO, 78.0 (C≡C—H), 75.7 (C≡C—H), 69.5 (C5), 69.1 (C4), 69.0 (C3), 66.2 (C2), 62.5 (C6), 55.1 (OCH2C≡C—H), 20.9, 20.8×2 and 20.7 (OCOCH3); MS (ESI): m/z=409.0 [M+Na]+.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[C:7]([OH:12])[CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][CH:3]=1.[Br:13][C:14]1[CH:15]=[C:16]([CH:19]=[C:20]([O:24][CH3:25])[C:21]=1[O:22][CH3:23])[CH:17]=O.[C:26](#[N:30])[CH2:27][C:28]#[N:29].C1N2CCN(CC2)C1>C(O)C.O>[NH2:30][C:26]1[O:1][C:2]2[C:3]([CH:17]([C:16]3[CH:19]=[C:20]([O:24][CH3:25])[C:21]([O:22][CH3:23])=[C:14]([Br:13])[CH:15]=3)[C:27]=1[C:28]#[N:29])=[CH:4][CH:5]=[C:6]1[C:7]([OH:12])=[CH:8][CH:9]=[CH:10][C:11]=21
Reactant: Oc1cccc2c(O)cccc12
Reactant: N#CCC#N
Reactant: COc1cc(C=O)cc(Br)c1OC
Agent: C1CN2CCN1CC2
Solvent: O
Solvent: CCO
Product: COc1cc(C2C(C#N)=C(N)Oc3c2ccc2c(O)cccc32)cc(Br)c1OC
Temperature: 80 °C
Reaction time: 18 h

Procedure:
1,5-Dihydroxy-naphthalene (704 mg, 4.4 mmol), 3-bromo-4,5-dimethoxy-benzaldehyde (1077 mg, 4.4 mmol) and malononitrile (295 mg, 4.4 mmol) were taken in 40 ml ethanol at room temperature, charged with DABCO (triethylenediamine) (48.4 μl, 1.46 mmol) and then stirred at 80° C. under LC-MS control for 18 h. The reaction mixture was then cooled down to room temperature. The mixture was diluted with water to about 100 ml, stirred at room temperature for 1 h and the precipitates were separated by filtration. It was washed well with 50% aqueous ethanol and dried under vacuum (1.18 g, 2.6 mmol, 59%).
Reaction SMILES: [CH2:1]([N:8]1[C:12]2[C:13](=[O:33])[N:14]([CH2:31][CH3:32])[C:15]3[N:16]([N:17]=[C:18]([CH2:20][O:21]CC4C=CC(OC)=CC=4)[N:19]=3)[C:11]=2[N:10]=[C:9]1[CH:34]1[CH2:38][CH2:37][CH2:36][CH2:35]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>ClCCl>[CH2:1]([N:8]1[C:12]2[C:13](=[O:33])[N:14]([CH2:31][CH3:32])[C:15]3[N:16]([N:17]=[C:18]([CH2:20][OH:21])[N:19]=3)[C:11]=2[N:10]=[C:9]1[CH:34]1[CH2:35][CH2:36][CH2:37][CH2:38]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCn1c(=O)c2c(nc(C3CCCC3)n2Cc2ccccc2)n2nc(COCc3ccc(OC)cc3)nc12
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: ClCCl
Solvent: O
Product: CCn1c(=O)c2c(nc(C3CCCC3)n2Cc2ccccc2)n2nc(CO)nc12
Yield: 93.8 %

Procedure:
6-benzyl-7-cyclopentyl-4-ethyl-2-[(4-methoxybenzyloxy)methyl]-imidazo[4,5-e]-s-triazolo[1,5-a]pyrimidin-5-one (1.03 g) is dissolved in 20 ml of dichloromethane and 1.2 ml of water are added. At ambient temperature, 2,3-dichloro-5,6-dicyanobenzoquinone (DDQ, 0.68 g) is added with stirring and the mixture is stirred for a further 4 hours. After the 2,3-dichloro-5,6-dicyanobenzoquinone precipitate has been separated off, the remaining solution is washed with saturated aqueous sodium hydrogen carbonate solution and saturated aqueous sodium chloride solution and dried over sodium sulphate. The solvent is distilled of and the residue remaining is crystallised from diethyl ether. 0.74 g of 6-benzyl-7-cyclopentyl-4-ethyl-2-hydroxymethyl-imidazo[4,5-e]-s-triazolo[1,5-a]pyrimidin-5-one are obtained in the form of slightly reddish crystals which can be used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([CH2:9]I)=[CH:4][N:3]=1.[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([NH2:19])=[CH:15][CH:14]=1.[OH-].[Na+]>C1(C)C=CC=CC=1.O>[Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([CH2:9][NH:19][C:16]2[CH:17]=[CH:18][C:13]([O:12][CH3:11])=[CH:14][CH:15]=2)=[CH:4][N:3]=1
Reactant: COc1ccc(N)cc1
Reactant: Clc1ncc(CI)c(Cl)n1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O
Product: COc1ccc(NCc2cnc(Cl)nc2Cl)cc1
Reaction time: 0.5 h

Procedure:
A 500-mL, three-necked flask equipped with a magnetic stirrer, thermometer, and nitrogen-inlet bubbler was charged with a solution of 2,4-dichloro-5-(iodomethyl)pyrimidine (85 g, ca. 253.2 mmol) (from Example 1c supra) in toluene (13.7 mL) from the previous step and toluene (96.3 mL, thus, a total of ca. 110 mL of toluene). After cooling with an ice-water bath, p-anisidine (31.18 g, 253.2 mmol) (Aldrich) was added. After stirring for 30 minutes, a solution of sodium hydroxide (13.54 g, 331.7 mmol) in water (50 mL) was added dropwise over 8 minutes, while maintaining the temperature of the reaction mixture at 10–15° C. hexanes (55 mL) was added and the mixture was stirred at 10–15° C. for 45 minutes, then at room temperature for 22 hours to give a slurry. TLC analysis of the supernatant indicated complete reaction. The slurry was diluted with water (100 mL) and the solid was collected by filtration, washed with cold water and cold (−50° C.) methanol (100 mL), and dried by suction to give [(2,4-dichloropyrimidin-5-yl)methyl](4-methoxyphenyl)amine as an off-white solid, 97% pure by HPLC analysis. (Yield 59.87 g, 83.2%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]([OH:10])=O.[CH:11]([NH2:13])=O>O>[N:1]1[C:2]2[CH:3]=[N:4][CH:5]=[CH:6][C:7]=2[C:8](=[O:10])[NH:13][CH:11]=1
Reactant: NC=O
Reactant: Nc1cnccc1C(=O)O
Solvent: O
Product: O=c1[nH]cnc2cnccc12
Reaction time: 1 h

Procedure:
A mixture of 4 g of 3-amino-pyridine-4-carboxylic acid in 15 mL of formamide was heated in an oil bath to 160°-180° C. After one hour the mixture was allowed to cool. Then, the mixture was slurried in 25 mL of water and filtered. The product was recrystallized from water. Yield 3.3 g. M.P. 317° C. (with sublimation).