Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[CH:9][S:8][C:4]=2[N:5]=[CH:6][N:7]=1.[NH:17]1[CH2:22][CH2:21][CH:20]([C:23]([OH:25])=[O:24])[CH2:19][CH2:18]1.C(N(CC)CC)C>C(O)C>[C:11]1([C:10]2[C:3]3[C:2]([N:17]4[CH2:22][CH2:21][CH:20]([C:23]([OH:25])=[O:24])[CH2:19][CH2:18]4)=[N:7][CH:6]=[N:5][C:4]=3[S:8][CH:9]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Clc1ncnc2scc(-c3ccccc3)c12
Reactant: O=C(O)C1CCNCC1
Solvent: CCO
Solvent: CCN(CC)CC
Product: O=C(O)C1CCN(c2ncnc3scc(-c4ccccc4)c23)CC1
Temperature: 140 °C
Yield: 101.4 %

Procedure:
4-Chloro-5-phenylthieno[2,3-d]pyrimidine (1.5 g, 6.1 mmol), piperidine-4-carboxylic acid (0.86 g, 6.7 mmol) and triethylamine (2.6 mL, 18 mmol) were suspended in dry ethanol (15 mL). The reaction was heated at 140° C. in a microwave for 10 min. The reaction was partitioned between water and DCM. The product was purified by column chromatography using a gradient of 10% methanol in DCM to 100% methanol to give the target compound as an off-white solid (yield=2.1 g). LCMS [M+H]+=440; RT=4.04 min.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4](S(C)(=O)=O)[N:3]=1.[C:19]1([C:25]([N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)=[O:26])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>COCCOC>[NH2:1][C:2]1[N:3]=[C:4]([N:30]2[CH2:31][CH2:32][N:27]([C:25](=[O:26])[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:28][CH2:29]2)[C:5]([C:13]#[N:14])=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[N:7]=1
Reactant: O=C(c1ccccc1)N1CCNCC1
Reactant: CS(=O)(=O)c1nc(N)nc(-c2ccco2)c1C#N
Solvent: COCCOC
Product: N#Cc1c(-c2ccco2)nc(N)nc1N1CCN(C(=O)c2ccccc2)CC1

Procedure:
From 2-amino-4-furan-2-yl-6-methanesulfonyl-pyrimidine-5-carbonitrile and phenyl-piperazin-1-ylmethanone in DME. ES-MS m/e (%): 397 (M+Na+, 25),375 (M+H+, 100).
Reaction SMILES: C1CCN2C(=NCCC2)CC1.[CH3:12][O:13][C:14]1[CH:21]=[CH:20][C:17]([CH:18]=[O:19])=[CH:16][CH:15]=1.[N:22]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:23]>ClCCl>[OH:23][N:22]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:18](=[O:19])[C:17]1[CH:20]=[CH:21][C:14]([O:13][CH3:12])=[CH:15][CH:16]=1
Reactant: O=Nc1ccccc1
Reactant: COc1ccc(C=O)cc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Product: COc1ccc(C(=O)N(O)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
DBU (7.61 mg, 0.05 mmol) was added under argon to a solution of 4-methoxybenzaldehyde (136 mg, 1 mmol), nitrosobenzene (107 mg, 1 mmol) and catalyst (18.15 mg, 0.05 mmol) in dichloromethane (5 mL). The reaction mixture was stirred at room temperature for 10 min. The solvent was removed under vacuum, and the residue was purified by flash silica gel column chromatography using hexane and ethyl acetate as the eluents.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[C:4]([C:14]([F:17])([F:16])[F:15])[CH:3]=1>[Pt]>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[NH:5][CH:4]([C:14]([F:17])([F:15])[F:16])[CH2:3][CH2:2]2
Reactant: COc1ccc2nc(C(F)(F)F)cc(Cl)c2c1
Agent: [Pt]
Product: COc1ccc2c(c1)CCC(C(F)(F)F)N2

Procedure:
4-Chloro-6-methoxy-2-trifluoromethylquinoline was reduced with platinum on carbon to give 6-methoxy-2-trifluoromethyltetrahydroquinoline. .
Reaction SMILES: C[O:2][C:3](=[O:24])[CH2:4][N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[N:8][C:7]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)=[N:6]1.[Li+].[OH-].Cl>O1CCOCC1.O>[F:23][C:20]1[CH:21]=[CH:22][C:17]([C:7]2[N:8]=[C:9]([C:10]3[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=3)[N:5]([CH2:4][C:3]([OH:24])=[O:2])[N:6]=2)=[CH:18][CH:19]=1
Reactant: COC(=O)Cn1nc(-c2ccc(F)cc2)nc1-c1ccc(F)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)Cn1nc(-c2ccc(F)cc2)nc1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 98.3 %

Procedure:
30.8 g of (3,5-bis-(4-fluoro-phenyl)-(1,2,4)triazol-1-yl)-acetic acid methyl ester was dissolved in 250 mL dioxane and a solution of 2.4 g LiOH in 250 mL of water was added. The mixture was stirred for 24 h at RT. The mixture was acidified with HCl-solution. The precipitate was filtered to give 29 g of the desired product. Rt: 1.28 min (method B), (M+H)+: 316
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:4]([F:20])=[C:5]([O:10][C:11]2[CH:16]=[C:15]([C:17]#[N:18])[CH:14]=[C:13]([Cl:19])[N:12]=2)[C:6]([Cl:9])=[CH:7][CH:8]=1.[Cl:21][C:22]1[N:23]=[CH:24][N:25](COCC[Si](C)(C)C)[C:26]=1[C:27](O)=[O:28].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C1COCC1>[Cl:21][C:22]1[N:23]=[CH:24][NH:25][C:26]=1[C:27]([NH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([Cl:9])=[C:5]([O:10][C:11]2[CH:16]=[C:15]([C:17]#[N:18])[CH:14]=[C:13]([Cl:19])[N:12]=2)[C:4]=1[F:20])=[O:28]
Reactant: C[Si](C)(C)CCOCn1cnc(Cl)c1C(=O)O
Reactant: N#Cc1cc(Cl)nc(Oc2c(Cl)ccc(CN)c2F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1cc(Cl)nc(Oc2c(Cl)ccc(CNC(=O)c3[nH]cnc3Cl)c2F)c1
Yield: 86.7 %

Procedure:
2-{[3-(aminomethyl)-6-chloro-2-fluorophenyl]oxy}-6-chloro-4-pyridinecarbonitrile (0.056 g, 0.181 mmol), 4-chloro-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-imidazole-5-carboxylic acid (0.05 g, 0.181 mmol) and DIPEA (0.063 mL, 0.361 mmol) were combined in THF (2 mL) and treated with HATU (0.076 g, 0.199 mmol) at 25° C. for 6 h with stirring. The reaction mixture was concentrated to dryness, dissolved in DCM, washed with saturated aqueous NaHCO3, dried over MgSO4, filtered and concentrated to dryness. The residue was dissolved in DCM (2.5 mL) and treated with TFA (2.5 mL) at 25° C. for 16 h. The reaction mixture was concentrated to dryness, dissolved in DCM, washed with saturated aqueous NaHCO3, dried over MgSO4, filtered and concentrated to dryness. The resultant solid was triturated with boiling IPA, cooled in an ice bath and filtered to give 4-chloro-N-({4-chloro-3-[(6-chloro-4-cyano-2-pyridinyl)oxy]-2-fluorophenyl}methyl)-1H-imidazole-5-carboxamide (0.069 g, 0.157 mmol, 87% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 13.18 (br. s., 1H), 8.28 (br. s., 1H), 7.99 (s, 1H), 7.95 (s, 1H), 7.78 (s, 1H), 7.49 (d, J=8.38 Hz, 1H), 7.30-7.41 (m, 1H), 4.46-4.61 (m, 2H). LC-MS (ES−) m/z 438.02, 440.05, 442.05 [M−1]. LC-MS (ES+) m/z 439.93, 441.90, 443.94 [M+H]
Reaction SMILES: O[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:21](=[O:22])[N:12]3[CH2:13][NH:14][C:15]4[CH:16]=[CH:17][CH:18]=[CH:19][C:20]=4[C:11]3=[N:10]2)=[CH:5][CH:4]=1.O=S(Cl)[Cl:25]>>[Cl:25][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:21](=[O:22])[N:12]3[CH2:13][NH:14][C:15]4[CH:16]=[CH:17][CH:18]=[CH:19][C:20]=4[C:11]3=[N:10]2)=[CH:5][CH:4]=1
Reactant: O=S(Cl)Cl
Reactant: O=c1n(-c2ccc(CO)cc2)nc2n1CNc1ccccc1-2
Product: O=c1n(-c2ccc(CCl)cc2)nc2n1CNc1ccccc1-2
Temperature: 50 °C

Procedure:
A mixture of 2-[4-(hydroxymethyl)-phenyl]-5,6-dihydro-1,2,4-triazolo[4,3-c]-quinazolin-3-one (Compound 19) (500 mg, 1.6 mmol) and excess SOCl2 was heated at 50° C for 1 hour. SOCl2 was evaporated under reduced pressure and the residue was washed with ether to afford 2-[4-(chloromethyl)-phenyl]-5,6-dihydro-1,2,4-triazolo[4,3-c]-quinazolin-3-one (Compound 20).
Reaction SMILES: O[C:2]1([CH2:26][I:27])[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:18][C@H:17]([CH2:19][NH:20][C:21](=[O:23])[CH3:22])[O:16][C:15]3=[O:24])=[CH:10][C:9]=2[F:25])[CH2:4][CH2:3]1.CCN(S(F)(F)[F:34])CC>ClCCl>[F:34][C:2]1([CH2:26][I:27])[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:18][C@H:17]([CH2:19][NH:20][C:21](=[O:23])[CH3:22])[O:16][C:15]3=[O:24])=[CH:10][C:9]=2[F:25])[CH2:4][CH2:3]1
Reactant: CC(=O)NC[C@H]1CN(c2ccc(N3CCC(O)(CI)CC3)c(F)c2)C(=O)O1
Reactant: CCN(CC)S(F)(F)F
Solvent: ClCCl
Product: CC(=O)NC[C@H]1CN(c2ccc(N3CCC(F)(CI)CC3)c(F)c2)C(=O)O1
Yield: 80 %

Procedure:
The title compound was prepared by reacting (S)-N-{3-[4-(4-hydroxy-4-iodomethylpiperidin-1-yl)-3-fluorophenyl]-2-oxo-oxazolidin-5-ylmethyl}-acetamide (1.01 mmol) with DAST (1.32 mmol) in dichloromethane (10 ml) at a temperature 0° C. for one hour and by purifying the compound by silica gel column chromatography in 80% yield.
Reaction SMILES: [Br:1][C:2]1[O:6][C:5]([C:7]([OH:9])=O)=[CH:4][CH:3]=1.[NH2:10][C:11]1[CH:12]=[C:13]([CH:18]=[CH:19][CH:20]=1)[O:14][CH2:15][C:16]#[N:17]>>[C:16]([CH2:15][O:14][C:13]1[CH:12]=[C:11]([NH:10][C:7]([C:5]2[O:6][C:2]([Br:1])=[CH:3][CH:4]=2)=[O:9])[CH:20]=[CH:19][CH:18]=1)#[N:17]
Reactant: O=C(O)c1ccc(Br)o1
Reactant: N#CCOc1cccc(N)c1
Product: N#CCOc1cccc(NC(=O)c2ccc(Br)o2)c1

Procedure:
5-Bromo-furan-2-carboxylic acid (325 mg, 1.70 mmol) was coupled to (3-amino-phenoxy)-acetonitrile (172) (250 mg, 1.69 mmol) using Method C. The residue was purified by column chromatography eluting with a stepped gradient of 10-30% EtOAc in heptane to give the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:12]=[CH:11][C:5]([CH:6]=[CH:7][C:8](O)=[O:9])=[CH:4][CH:3]=1.S(Cl)([Cl:15])=O>>[Br:1][C:2]1[CH:12]=[CH:11][C:5]([CH:6]=[CH:7][C:8]([Cl:15])=[O:9])=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)C=Cc1ccc(Br)cc1
Product: O=C(Cl)C=Cc1ccc(Br)cc1

Procedure:
A solution of 4-bromocinnamic acid (5.03 g, 22.2 mmol) in thionyl chloride (SOCl2) (15 mL) was stirred at 23° C. for 16 h, and then heated at reflux for a further 2 h. The solvents were evaporated in vacuo and the residue azeotroped with toluene (×3) to yield 4-bromocinnamoyl chloride as an orange-brown solid in quantitative yield.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:12])[CH3:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH:13]([C:15]1[CH:24]=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][CH:16]=1)=O.N1CCCCC1>C(O)C>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([C:10](=[O:12])[CH:11]=[CH:13][C:15]2[CH:24]=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][CH:16]=2)=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: CC(=O)c1ccc([N+](=O)[O-])cc1
Reactant: COC(=O)c1ccc(C=O)cc1
Solvent: CCO
Solvent: C1CCNCC1
Product: COC(=O)c1ccc(C=CC(=O)c2ccc([N+](=O)[O-])cc2)cc1
Yield: 77.2 %

Procedure:
To a mixture of 16.5 g of 1-(4-nitrophenyl)ethanone, 16.4 g of methyl 4-formylbenzoate and 100 mL of ethanol was added dropwise 4.0 mL of piperidine at room temperature, followed by heating under reflux for 8 hours. The precipitate was collected by filtration, thereby obtaining 24.6 g of a crude product. The crude product was suspended in 100 mL of ethanol, followed by heating under reflux for 6 hours. The precipitate was collected by filtration, thereby obtaining 24.0 g of methyl 4-[3-(4-nitrophenyl)-3-oxoprop-1-en-1-yl]benzoate.
Reaction SMILES: [N:1]1([CH:6]2[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.F[C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=1>>[N+:19]([C:16]1[CH:17]=[CH:18][C:13]([N:9]2[CH2:10][CH2:11][CH:6]([N:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)[CH2:7][CH2:8]2)=[CH:14][CH:15]=1)([O-:21])=[O:20]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: C1CCN(C2CCNCC2)C1
Product: O=[N+]([O-])c1ccc(N2CCC(N3CCCC3)CC2)cc1

Procedure:
The compound was prepared from 4-pyrrolidin-1-yl-piperidine (Aldrich) and 4-fluoro-nitrobenzene (Aldrich) following the procedure used in Example 1. MS (m+H)+: 276.
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][C:2]1=[O:11].CO[CH:14](OC)[N:15]([CH3:17])[CH3:16]>>[CH3:14][N:15]([CH:17]=[C:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][C:2]1=[O:11])[CH3:16]
Reactant: COC(OC)N(C)C
Reactant: O=C1CCc2ccccc2C1
Product: CN(C)C=C1C(=O)CCc2ccccc21

Procedure:
Heat 8.0 ml of 2-tetralone and 12.0 ml of dimethylformamide dimethyl acetal under reflux at 80° for 11/2 hours. Concentrate the reaction mixture in vacuo. Dissolve the residue in hot methanol, add charcoal, filter, and concentrate the filtrate in vacuo to give the title compound, an amber oil.
Reaction SMILES: Br.[N:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[O:19][C:18]([NH2:20])=[N:17][N:16]=3)=[CH:11][CH:10]=2)[CH:3]=1.[F:21][C:22]([F:33])([F:32])[C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=1)[C:26](Cl)=[O:27]>N1C=CC=CC=1.CO>[N:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][C:9]2[CH:10]=[CH:11][C:12]([C:15]3[O:19][C:18]([NH:20][C:26](=[O:27])[C:25]4[CH:29]=[CH:30][CH:31]=[C:23]([C:22]([F:21])([F:32])[F:33])[CH:24]=4)=[N:17][N:16]=3)=[CH:13][CH:14]=2)[CH:3]=1
Reactant: O=C(Cl)c1cccc(C(F)(F)F)c1
Reactant: Nc1nnc(-c2ccc(Oc3cccnc3)cc2)o1
Agent: Br
Solvent: c1ccncc1
Solvent: CO
Product: O=C(Nc1nnc(-c2ccc(Oc3cccnc3)cc2)o1)c1cccc(C(F)(F)F)c1
Reaction time: 3 h
Yield: 23.5 %

Procedure:
5-[4-(Pyridin-3-yloxy)phenyl]-1,3,4-oxadiazol-2-amine hydrobromide salt (167.5 mg, 0.5 mmol) was suspended in 2 mL of anhydrous pyridine. 3-Trifluoromethylbenzoyl chloride (156.4 mg, 0.75 mmol) was added to the solution. The reaction mixture formed an orange-red solution with a small amount of white precipitate. It was left to stir for 3 hours. Then it was diluted with ca. 1 mL of MeOH, filtered through 0.22 u syringe filter and purified by reverse phase preparative HPLC using acetonitrile/water mixture containing 0.01% of TFA. Fractions, containing the product, were combined and partitioned between ca. 40 mL of EtOAc and ca. 40 mL of saturated aqueous NaHCO3. The EtOAc layer was washed with brine, dried over anhydrous sodium sulfate and filtered. Solvent was removed in vacuo to give the title product as a yellow solid (50.0 mg). Yield 23.4%.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:14])[N:4]([CH2:12][CH3:13])[C:5](=[O:11])[N:6]([CH2:9][CH3:10])[C:7]=1[NH2:8].[CH3:15][O:16][C:17]1[CH:18]=[C:19]([CH:25]=[C:26]2[O:30][CH2:29][O:28][C:27]=12)[CH:20]=[CH:21][C:22](O)=O>>[CH2:12]([N:4]1[C:3](=[O:14])[C:2]2[NH:1][C:22](/[CH:21]=[CH:20]/[C:19]3[CH:25]=[C:26]4[O:30][CH2:29][O:28][C:27]4=[C:17]([O:16][CH3:15])[CH:18]=3)=[N:8][C:7]=2[N:6]([CH2:9][CH3:10])[C:5]1=[O:11])[CH3:13]
Reactant: CCn1c(N)c(N)c(=O)n(CC)c1=O
Reactant: COc1cc(C=CC(=O)O)cc2c1OCO2
Product: CCn1c(=O)c2[nH]c(/C=C/c3cc(OC)c4c(c3)OCO4)nc2n(CC)c1=O
Yield: 12.4 %

Procedure:
Substantially the same procedure as in Example 7 was repeated using 2.50 g (12.6 mmol) of 5,6-diamino-1,3-diethyluracil and 3.31 g (14.9 mmol) of 3-methoxy-4,5-methylenedioxycinnamic acid. Then, the resultant crude crystals were recrystallized from tetrahydrofuran/water to give 600 mg (yield 53%) of Compound 169 as a white powder.
Reaction SMILES: [OH:1][NH:2][C:3](=[O:9])[O:4][C:5]([CH3:8])([CH3:7])[CH3:6].Br[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].C1CCN2C(=NCCC2)CC1>CC#N>[C:5]([O:4][C:3](=[O:9])[NH:2][O:1][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])([CH3:8])([CH3:7])[CH3:6]
Reactant: CC(C)(C)OC(=O)NO
Reactant: CCCCCBr
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: CCCCCONC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 12 h
Yield: 100.8 %

Procedure:
Tert-butyl hydroxycarbamate (2.1 g, 15.77 mmol, 1 eq.) was dissolved in MeCN and bromopentane (2.73 g, 18.13 mmol, 1.15 eq.) was added followed by DBU (2.52 g, 16.56 mmol, 1.05 eq.). The reaction was stirred at room temperature for 12 h and quenched with 0.1N HCl, extracted with EtOAc, dried over MgSO4, and concentrated. The residue was purified by chromatography on silica gel to give tert-butyl(pentyloxy)carbamate (3.23 g, 91% yield) as a clear oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH2:9][C@H:10]([C@H:13]([CH2:24]O)[CH2:14][C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[C:17]([O:22][CH3:23])[CH:16]=2)[CH2:11][OH:12])[CH:6]=[CH:5][C:4]=1[OH:26].[Cl-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1.C(#N)C>[CH2:9]([CH:10]1[CH:13]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[C:17]([O:22][CH3:23])[CH:16]=2)[CH2:24][O:12][CH2:11]1)[C:7]1[CH:6]=[CH:5][C:4]([OH:26])=[C:3]([O:2][CH3:1])[CH:8]=1
Reactant: COc1cc(C[C@@H](CO)[C@H](CO)Cc2ccc(O)c(OC)c2)ccc1O
Agent: [Cl-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CC#N
Product: COc1cc(CC2COCC2Cc2ccc(O)c(OC)c2)ccc1O
Temperature: 40 °C
Reaction time: 5.5 h
Yield: 81 %

Procedure:
(−) secoisolariciresinol (100 mg,) was dissolved in THF (5 ml) and to it was added a solution of triphenyl phosphine chloride in acetonitrile (1 ml) and the mixture was stirred at 0-80° C. for 1-10 hours. After completion of the reaction, the reaction mixture was concentrated under vacuum and the residue thus obtained was chromatographed over florosil column. Elution of the column with 30% EtOAC in pet. ether gave (−-3,4-divanillyl tetrahydrofuran (77 mg), m.p. 114-116° C.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH3:6][O:7][C:8]1[C:13]([NH2:14])=[CH:12][C:11]([CH2:15][S:16](/[CH:19]=[CH:20]/[C:21]2[C:26]([O:27][CH3:28])=[CH:25][C:24]([O:29][CH3:30])=[CH:23][C:22]=2[O:31][CH3:32])(=[O:18])=[O:17])=[CH:10][N:9]=1>N1C=CC=CC=1>[CH3:6][O:7][C:8]1[C:13]([NH:14][S:2]([CH3:1])(=[O:4])=[O:3])=[CH:12][C:11]([CH2:15][S:16](/[CH:19]=[CH:20]/[C:21]2[C:26]([O:27][CH3:28])=[CH:25][C:24]([O:29][CH3:30])=[CH:23][C:22]=2[O:31][CH3:32])(=[O:18])=[O:17])=[CH:10][N:9]=1
Reactant: COc1cc(OC)c(/C=C/S(=O)(=O)Cc2cnc(OC)c(N)c2)c(OC)c1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: COc1cc(OC)c(/C=C/S(=O)(=O)Cc2cnc(OC)c(NS(C)(=O)=O)c2)c(OC)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 31.7 %

Procedure:
Methanesulfonyl chloride (0.048 mL, 0.31 mmol) was added dropwise into the solution of (E)-2-methoxy-5-((2,4,6-trimethoxystyrylsulfonyl)methyl)pyridin-3-amine (111 mg, 0.28 mmol) in dry pyridine (7 mL) on an ice bath. After warming up to room temperature the mixture was stirred overnight. After evaporated to dryness, the residue was purified by silica gel chromatography, eluting with PE/EtOAc (1:2 v/v) to afford pure product as a white solid (42 mg, 32%) 1H-NMR (Acetone-do): δ 2.98 (s, 3H, CH3), 3.90 (s, 3H, OCH3), 3.93 (s, 6H, 2×OCH3), 3.97 (s, 3H, OCH3), 4.38 (s, 2H, CH2), 6.31 (s, 2H, Ph-H), 7.19 (d, 1H, J=15.6 Hz, CH), 7.71 (d, 1H, J=15.6 Hz, CH), 7.85 (d, 1H, J=2.0 Hz, Py-H), 7.97 (d, 1H, J=2.0 Hz, Py-H); 13C-NMR (Acetone-d6): δ 38.78, 53.30, 55.08, 55.53, 57.36, 90.67, 103.24, 119.44, 121.70, 123.17, 130.21, 134.70, 143.67, 154.11, 161.54, 164.28; HR-MS (ESI+) m/z 473.1115 [M+H]+ C19H24N2O832 requires 472.0974.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C@H:9]([C:11]2[N:20]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:19](=[O:27])[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][C:17]=3[Cl:28])[N:12]=2)[CH3:10])[C:3]=1I.[C:30]1([C:36]#[CH:37])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>C1COCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C@H:9]([C:11]2[N:20]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:19](=[O:27])[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][C:17]=3[Cl:28])[N:12]=2)[CH3:10])[C:3]=1[C:37]#[C:36][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: C[C@H](Nc1ncnc(N)c1I)c1nc2cccc(Cl)c2c(=O)n1-c1ccccc1
Reactant: C#Cc1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: C1CCOC1
Product: C[C@H](Nc1ncnc(N)c1C#Cc1ccccc1)c1nc2cccc(Cl)c2c(=O)n1-c1ccccc1
Temperature: 70 °C
Reaction time: 2 h

Procedure:
To (S)-2-(1-(6-amino-5-iodopyrimidin-4-ylamino)ethyl)-5-chloro-3-phenylquinazolin-4(3H)-one (58 mg, 0.11 mmol) (prepared according to the procedure in Example 5A) in THF (5 mL) was added Pd(PPh3)2Cl2 (2 mg, 2.5%), CuI (1 mg, 5%), TEA (0.1 mL, 0.16 mmol), and phenylacetylene (20 mg 0.16 mmol). After stirring at 70° C. for 2 hours, the solvent was stripped. The residue was purified on silica with 0 to 10% MeOH in DCM to give material that required further purification. Purification on silica with 0 to 100% EtOAc in hexanes gave (S)-2-(1-(6-amino-5-(phenylethynyl)pyrimidin-4-ylamino)ethyl)-5-chloro-3-phenylquinazolin-4(3H)-one. 1H NMR (400 MHz, DMSO-D6) δ 7.88 (s, 1H), 7.78 (t, J=8.0 Hz, 1H), 7.88 (dt, J=6.8, 1.6 Hz, 2H), 7.59-7.41 (m, 10H), 6.92 (d, J=7.0 Hz, 1H), 6.75 (bs, 2H), 4.73 (p, J=6.8 Hz, 1H), 1.35 (d, J=6.7 Hz, 3H). ES/MS m/z=493.1 (M+H+).
Reaction SMILES: C(C1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[CH:6][C:5]=1[OH:14])(=O)C.N1CC[O:18]CC1>C1(C)C=CC=CC=1>[O:18]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7][CH2:6][CH:5]1[OH:14]
Reactant: C1COCCN1
Reactant: CC(=O)c1c(O)ccc2ccccc12
Solvent: Cc1ccccc1
Product: OC1CCc2ccccc2O1
Reaction time: 5 h

Procedure:
A solution was prepared by dissolving 10 g (0.054 mole) of 1-acetyl-2-naphthol, 8.29 g (0.06 mole) of bicyclo [3.3.1]9-nonylidene and 8.7 g (0.10 mole) of morpholine in 300 cc of toluene, and the solution was boiled for 5 hours and water was separated. After termination of the reaction, toluene was removed under reduced pressure and the remaining chromanone compound was recrystallized from acetone. Then, the chromanone compound was dissolved in 200 cc of methanol and lithium aluminum hydride was added to the solution to form a chromanol compound. Then, 6.49 g of this chromanol compound was heated at 170° to 180° C. together with anhydrous copper sulfate in a carbon dioxide current for 10 minutes, and the obtained brown viscous liquid was purified by the chromatography on silica gel to obtain 5.8 g of a chromene compound represented by the following formula: ##STR159##
Reaction SMILES: [ClH:1].[C:2]([CH:5]1[CH:10]2[CH2:11][CH2:12][N:7]([CH2:8][CH2:9]2)[CH2:6]1)(=O)[CH3:3].Cl.[CH3:14][O:15][NH2:16]>CO>[ClH:1].[CH3:14][O:15][N:16]=[C:2]([CH:5]1[CH:10]2[CH2:11][CH2:12][N:7]([CH2:8][CH2:9]2)[CH2:6]1)[CH3:3]
Reactant: CC(=O)C1CN2CCC1CC2
Reactant: CON
Agent: Cl
Solvent: CO
Product: CON=C(C)C1CN2CCC1CC2
Yield: 67.9 %

Procedure:
2.3 g of 3-acetyl quinuclidine hydrochloride (Helv. Chim. Acta (1963) 229, 2658) and 1.02 g of O-methylhydroxylamine hydrochloride are heated for 20 minutes to reflux in 30 cm3 of methanol. The solvent is evaporated and the residue is chromatographed on silica (eluant: chloroform-methanol 7-3). After crystallization from ethanol and from ether, 1.8 g of expected product is obtained. M.p.=186°-188° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:16])=[CH:4][C:5]([N+:13]([O-])=O)=[C:6]([NH:8][CH2:9][C:10](O)=[O:11])[CH:7]=1.O.O.[Sn](Cl)Cl>C(O)C>[Cl:1][C:2]1[CH:7]=[C:6]2[C:5](=[CH:4][C:3]=1[CH3:16])[NH:13][C:10](=[O:11])[CH2:9][NH:8]2
Reactant: Cc1cc([N+](=O)[O-])c(NCC(=O)O)cc1Cl
Agent: Cl[Sn]Cl
Solvent: CCO
Solvent: O
Product: Cc1cc2c(cc1Cl)NCC(=O)N2
Temperature: 25 °C
Yield: 31.2 %

Procedure:
A solution of N-(5'-chloro-4'-methyl-2'-nitrophenyl)glycine (1.000 g, 4.088 mmol, as prepared above) and tin (II) chloride dihydrate (2.767 g, 12.26 mmol, Aldrich, used as received) in ethanol (20.0 mL) was refluxed for 30 min. It was then cooled to room temperature and the precipitated solid was filtered, washed with ethanol (4.0 mL), and dried under vacuum to yield 0.251 g (31%) of the title compound as a yellow powder; 1H NMR (DMSO-d6): δ2.093 (s, 3H), 3.657 (d, 2H, J=1.5 Hz), 5.984 (s, 1H), 6.583 (s, 1H), 6.632 (s, 1H), 10.253 (s, 1H).
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1.[H-].[Na+].Br[CH:13]([C:15]1[N:20]2[N:21]=[CH:22][N:23]=[C:19]2[N:18]=[CH:17][CH:16]=1)[CH3:14]>COCCOC>[CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH:13]([C:15]2[N:20]3[N:21]=[CH:22][N:23]=[C:19]3[N:18]=[CH:17][CH:16]=2)[CH3:14])=[CH:5][CH:4]=1
Reactant: CSc1ccc(O)cc1
Reactant: CC(Br)c1ccnc2ncnn12
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: CSc1ccc(OC(C)c2ccnc3ncnn23)cc1
Reaction time: 0.5 h

Procedure:
A solution of 4-(methylthio)phenol (2.80 g) in dry 1,2-dimethoxyethane was added slowly to a stirred suspension of sodium hydride (0.87 g) in dry 1,2-dimethoxyethane (50 ml). The mixture was stirred for 30 minutes, then a solution of 7-(1-bromoethyl)-1,2,4-triazolo[1,5-a]pyrimidine (4.54 g, prepared in a similar manner to that described in Example 6 above) in dry 1,2-dimethoxyethane (150 ml) was added dropwise. The reaction mixture was stirred overnight at room temperature. The sodium bromide was removed from the mixture by filtration. The solvent was evaporated from the mixture and the residue was dissolved in dichloromethane and washed with 200 ml of a 5% aqueous solution of sodium hydroxide followed by water. The organic layer was dried over magnesium sulphate. Evaporation of the solvent afforded a crude product which was purified by column chromatography on silica gel using as eluent a mixture of ethyl acetate and petroleum ether (in the ratio 4:6 respectively), followed by recrystallisation from a mixture of ethyl acetate and hexane, to give 7-{1-[4-(methylthio)phenoxy]ethyl}-1,2,4-triazolo[1,5-a]pyrimidine. Yield 3.66 g, (m.p. 84°-86° C.).