Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[N:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH2:19][C:20]2[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=2)[CH:14]=1.[N:26]1[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([C:34]2[CH:39]=[CH:38][N:37]=[CH:36][N:35]=2)=[O:33])[CH:27]=1>C1COCC1>[N:26]1[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([C:34]2[CH:39]=[CH:38][N:37]=[CH:36][N:35]=2)([OH:33])[CH:19]([C:20]2[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=2)[C:15]2[CH:14]=[N:13][CH:18]=[CH:17][CH:16]=2)[CH:27]=1
Reactant: O=C(c1cccnc1)c1ccncn1
Reactant: c1cncc(Cc2cccnc2)c1
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: OC(c1cccnc1)(c1ccncn1)C(c1cccnc1)c1cccnc1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
In a flame dried flask under N2, diisopropylamine (0.079 mL, 0.56 mmol) was dissolved in THF (1 mL). The solution was cooled to 0° C. n-Butyl-lithium (2.5 M solution in hexanes, 0.215 mL, 0.54 mmol) was slowly added and the reaction was stirred at 0° C. for 15 min. A solution of 3-(pyridin-3-ylmethyl)pyridine (0.087 g, 0.51 mmol) in THF (1mL) was slowly added drop-wise. The reaction became dark red. After 10 min. a solution of pyridin-3-yl(pyrimidin-4-yl)methanone (0.099 g, 0.54 mmol, J. Heterocyclic Chem., 34, 17 (1997)) in THF (1 mL) was slowly added drop-wise. The reaction was stirred at 0° C. for 3 hr then removed from the ice bath. Sat. aq. NH4Cl (20 mL) was added and the reaction was stirred vigorously. The product was extracted with EtOAc (4×50 mL). The combined organics were dried over Na2SO4, filtered and concentrated to afford an oil which was purified by reverse phase HPLC (5-95% CH3CN/H2O+0.05% NH4OH). The fractions were combined and concentrated in vacuo to afford the title compound as a white solid. 1H NMR (CDCl3) δ 9.01 (d, 1H, J=1.22 Hz), 8.85 (d, 1H, J=1.95 Hz), 8.70 (d, 1H, J=5.37 Hz), 8.58 (d, 1H, J=2.19 Hz), 8.42 (dd, 1H, J=1.46 Hz), 8.38-8.33 (m, 3H), 7.94-7.87 (m, 2H), 7.70-7.67 (m, 1H), 7.07 (dd, 1H, J=1.22 Hz), 7.19-7.14 (m, 1H), 7.13-7.08 (m, 2H), 5.98 (s, 1H), 5.12 (s, 1H). HRMS m/z (M+H) Calculated: 356.1506, found: 356.1519.
Reaction SMILES: [Li+].C[Si]([N-][Si](C)(C)C)(C)C.[C:11]([OH:14])(=O)[CH3:12].N1C2C=CC=CC=2NC=1.[NH2:24][C:25]1[CH:32]=[CH:31][CH:30]=[CH:29][C:26]=1[C:27]#[N:28]>C1COCC1>[NH2:28][C:27]1[C:26]2[C:25](=[CH:32][CH:31]=[CH:30][CH:29]=2)[NH:24][C:11](=[O:14])[CH:12]=1
Reactant: CC(=O)O
Reactant: N#Cc1ccccc1N
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Agent: c1ccc2[nH]cnc2c1
Solvent: C1CCOC1
Product: Nc1cc(=O)[nH]c2ccccc12
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
LiHMDS (3-4 eq) was added to the benzimidazole acetate (1.0 eq) in THF (at a constant temperature ranging from −78° C. to 0C). After 20 minutes, a solution of the 2-aminobenzonitrile (1.1 eq) in THF was then added. The resulting mixture was allowed to warm to room temperature, stirred for 1-3 hours and was then heated to approx. 40° C.-65° C. (1 hour to 12 hours). The mixture was cooled to 0° C. and quenched with NH4Cl (aq, saturated). The aqueous phase was extracted with CH2Cl2 or EtOAc, and the organic extracts were collected, dried (Na2SO4), and filtered. Evaporation of the solvent under reduced pressure and purification of the residue by silica gel chromatography or HPLC provided the 4-amino quinolinone products.
Reaction SMILES: C1(C)C=CC=CC=1.[C:8]([C:10]1[CH:11]=[CH:12][C:13]2[C:23](=[C:24]3[CH2:29][CH2:28][N:27](C)[CH2:26][CH2:25]3)[C:18]3=[N:19][CH:20]=[CH:21][CH:22]=[C:17]3[CH2:16][CH2:15][C:14]=2[CH:31]=1)#[N:9].Cl[C:33]([O:35][CH2:36][CH3:37])=[O:34]>C(N(CC)CC)C>[C:8]([C:10]1[CH:11]=[CH:12][C:13]2[C:23](=[C:24]3[CH2:29][CH2:28][N:27]([C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH2:26][CH2:25]3)[C:18]3=[N:19][CH:20]=[CH:21][CH:22]=[C:17]3[CH2:16][CH2:15][C:14]=2[CH:31]=1)#[N:9]
Reactant: CN1CCC(=C2c3ccc(C#N)cc3CCc3cccnc32)CC1
Reactant: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCOC(=O)N1CCC(=C2c3ccc(C#N)cc3CCc3cccnc32)CC1
Yield: 75.2 %

Procedure:
Toluene (40 ml) was added to 1 g of 8-cyano-11-(1-methyl-4-piperidylidene)-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine to dissolve the latter, followed by the addition of 0.52 g of triethylamine and 1.92 g of ethyl chloroformate. The resulting mixture was refluxed for 2.5 hours. The mixture was cooled and washed with water. The organic layer was dried over anhydrous Na2SO4 and then filtered. The filtrate was concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column. The substance eluted with chloroform was recrystallized from n-hexane, whereby 0.89 g of 8-cyano-11-(1-ethoxycarbonyl-4-piperidylidene)-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine was obtained (yield: 75%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1.[C:15](Cl)(=[O:17])[CH3:16].O>C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:15](=[O:17])[CH3:16])=[CH:6][CH:7]=1
Reactant: CCOC(=O)CNc1ccc(F)cc1
Reactant: CC(=O)Cl
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)CN(C(C)=O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-((4-fluorophenyl)amino)acetate (1) (6.68 g, 33.9 mmol) in THF (84 mL) was added acetyl chloride (2.88 mL, 40.6 mmol) and the reaction was stirred overnight at room temperature. Water was added and the reaction was extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo to yield ethyl 2-(N-(4-fluorophenyl)acetamido)acetate (2) as an orange solid.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[C:12]([NH2:13])=[CH:11][C:10]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)=[CH:9][N:8]=2)[CH2:3][CH2:2]1.Cl[C:21]1[C:30]2[C:25](=[CH:26][C:27]([F:32])=[CH:28][C:29]=2[F:31])[N:24]=[C:23]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=2)[C:22]=1[CH3:39].Cl.O1CCOCC1>CN1C(=O)CCC1>[N:4]1([C:7]2[C:12]([NH:13][C:21]3[C:30]4[C:25](=[CH:26][C:27]([F:32])=[CH:28][C:29]=4[F:31])[N:24]=[C:23]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=4)[C:22]=3[CH3:39])=[CH:11][C:10]([N:14]3[CH2:15][CH2:16][O:17][CH2:18][CH2:19]3)=[CH:9][N:8]=2)[CH2:5][CH2:6][O:1][CH2:2][CH2:3]1
Reactant: Cc1c(-c2ccccn2)nc2cc(F)cc(F)c2c1Cl
Reactant: Nc1cc(N2CCOCC2)cnc1N1CCOCC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CN1CCCC1=O
Product: Cc1c(-c2ccccn2)nc2cc(F)cc(F)c2c1Nc1cc(N2CCOCC2)cnc1N1CCOCC1

Procedure:
Prepared according to Procedure K, method 2 using 2,5-dimorpholinopyridin-3-amine (118 mg, 0.45 mmol; described herein), 4-chloro-5,7-difluoro-3-methyl-2-(pyridin-2-yl)quinoline (130 mg, 0.45 mmol; described herein), 4.0M hydrogen chloride in 1,4-dioxane (110 μL, 0.45 mmol), and NMP (450 μL). Purification afforded N-(2,5-di-4-morpholinyl-3-pyridinyl)-5,7-difluoro-3-methyl-2-(2-pyridinyl)-4-quinolinamine as a yellow solid. 1H NMR (500 MHz, chloroform-d) δ ppm 8.66-8.74 (1H, m), 7.85-7.94 (2H, m), 7.73 (1H, d, J=11.0 Hz), 7.57-7.66 (2H, m), 7.38 (1H, ddd, J=6.0, 4.9, 2.8 Hz), 7.02 (1H, ddd, J=13.4, 8.5, 2.6 Hz), 6.44 (1H, d, J=2.9 Hz), 3.86-3.98 (4H, m), 3.76-3.85 (4H, m), 2.91-3.47 (8H, m), 2.21 (3H, s). Mass Spectrum (ESI) m/e=519.0 (M+1).
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6]2[CH:8]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[S:10][C:5]=2[C:4](=[O:17])[N:3]1[CH:18]1[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]1.Cl[CH2:32][C:33]1[S:34][C:35]([CH3:38])=[CH:36][N:37]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:38][C:35]1[S:34][C:33]([CH2:32][N:7]2[C:6]3[CH:8]=[C:9]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)[S:10][C:5]=3[C:4](=[O:17])[N:3]([CH:18]3[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]3)[C:2]2=[O:1])=[N:37][CH:36]=1
Reactant: CC(C)(C)OC(=O)N1CCC(n2c(=O)[nH]c3cc(-c4ccccc4)sc3c2=O)CC1
Reactant: Cc1cnc(CCl)s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cnc(Cn2c(=O)n(C3CCN(C(=O)OC(C)(C)C)CC3)c(=O)c3sc(-c4ccccc4)cc32)s1

Procedure:
According to GP1 tert-butyl 4-(2,4-dioxo-6-phenyl-1,4-dihydrothieno[3,2-d]pyrimidin-3(2H)-yl)piperidine-1-carboxylate (855 mg; compound B50) is reacted with 2-(chloromethyl)-5-methyl-1,3-thiazole (366 mg; compound D12) in the presence of potassium carbonate (554 mg) in DMF (10 ml). Using WU1 the title compound is obtained as a solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:43])[NH:4][C@H:5]([C:14](=[O:42])[NH:15][CH2:16][CH2:17][CH2:18][CH2:19][C@H:20]([N:27]([S:32]([C:35]1[CH:40]=[CH:39][C:38]([NH2:41])=[CH:37][CH:36]=1)(=[O:34])=[O:33])[CH2:28][CH:29]([CH3:31])[CH3:30])[CH2:21][O:22][P:23]([OH:26])([OH:25])=[O:24])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1Br.C1C(C[C@H](N)C(O)=O)=CC=C([Br:56])C=1>>[CH3:1][O:2][C:3](=[O:43])[NH:4][C@H:5]([C:14](=[O:42])[NH:15][CH2:16][CH2:17][CH2:18][CH2:19][C@H:20]([N:27]([S:32]([C:35]1[CH:40]=[CH:39][C:38]([NH2:41])=[CH:37][CH:36]=1)(=[O:33])=[O:34])[CH2:28][CH:29]([CH3:30])[CH3:31])[CH2:21][O:22][P:23]([OH:26])([OH:25])=[O:24])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([Br:56])=[CH:9][CH:8]=1
Reactant: COC(=O)N[C@@H](Cc1ccccc1Br)C(=O)NCCCC[C@@H](COP(=O)(O)O)N(CC(C)C)S(=O)(=O)c1ccc(N)cc1
Reactant: N[C@@H](Cc1ccc(Br)cc1)C(=O)O
Product: COC(=O)N[C@@H](Cc1ccc(Br)cc1)C(=O)NCCCC[C@@H](COP(=O)(O)O)N(CC(C)C)S(=O)(=O)c1ccc(N)cc1
Yield: 28 %

Procedure:
This derivative was synthesized using the procedure described for the preparation of (1S,5S)-[1-{5-[(4-amino-benzenesulfonyl)-isobutyl-amino]-6-phosphonooxy-hexylcarbamoyl}-2-(2-bromo-phenyl)-ethyl]-carbamic acid methyl ester (example 4, steps A and B) using L-4-bromophenylalanine (Peptech Corp.) instead of L-2-bromophenylalanine. The desired material was obtained in 28% yield (25 mg)
Reaction SMILES: [H-].[Na+].[C:3]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:4][C:5]([CH3:7])=[O:6].[Li]CCCC.[S:17]1[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[N:19]=[C:18]1[N:26]1[C:30]([C:31]2[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=2)=[C:29](/[CH:38]=[CH:39]/[CH:40]=[O:41])[C:28]([CH:42]([CH3:44])[CH3:43])=[N:27]1>C1COCC1>[S:17]1[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[N:19]=[C:18]1[N:26]1[C:30]([C:31]2[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=2)=[C:29](/[CH:38]=[CH:39]/[CH:40]([OH:41])[CH2:7][C:5](=[O:6])[CH2:4][C:3]([O:9][CH2:10][CH3:11])=[O:8])[C:28]([CH:42]([CH3:44])[CH3:43])=[N:27]1
Reactant: CC(C)c1nn(-c2nc3ccccc3s2)c(-c2ccc(F)cc2)c1/C=C/C=O
Reactant: CCOC(=O)CC(C)=O
Agent: [H-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)CC(=O)CC(O)/C=C/c1c(C(C)C)nn(-c2nc3ccccc3s2)c1-c1ccc(F)cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 87 %

Procedure:
To a hexane washed suspension of NaH (1.23 g, 30.7 mmol) in THF (20 mL) at 0° C. under an inert atmosphere, was added a solution of ethyl acetoacetate (3.66 mL, 28.7 mmol) in THF (20 mL). The resulting clear solution was stirred at 0° C. for 15 minutes before n-BuLi (13.1 mL, 28.7 mmol) was added dropwise. This orange solution was stirred at 0° C. for 15 minutes before it was cooled to -78° C. and a solution of the unsaturated aldehyde (7.50 g, 19.2 mmol, Step E) in THF (100 mL) was added dropwise. The reaction was stirred at -78° C. for 1 hour and then it was quenched by adding 4 mL glacial acetic acid and removing the cooling bath. The reaction mixture was partitioned between Et2O and saturated aqueous K2CO3 solution. The organic extracts were dried (MgSO4) and evaporated to give an orange solid. Recrystallization from hexanes gave 8.71 g (87%) of product as a pale yellow orange solid.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3]([NH2:6])=[N:2]1.[C:7](OCC)(=[O:14])[CH2:8][C:9](OCC)=[O:10].CC[O-].[Na+]>CCO>[N:1]1[N:2]2[C:7]([OH:14])=[CH:8][C:9]([OH:10])=[N:6][C:3]2=[CH:4][CH:5]=1
Reactant: Nc1cc[nH]n1
Reactant: CCOC(=O)CC(=O)OCC
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: Oc1cc(O)n2nccc2n1
Temperature: 80 °C
Yield: 76.6 %

Procedure:
To 1H-pyrazol-3-amine (12.3 g, 148.0 mmol) in EtOH (50 mL) was added diethyl malonate (25.0 mL, 164.7 mmol), 21 wt % NaOEt in EtOH (110 mL, 294.6 mmol) and additional EtOH (50 mL). The resulting mixture was then heated at 80° C. under an atmosphere of argon for 16 hours, at which time the reaction was allowed to cool to room temperature. The reaction mixture was then concentrated in vacuo until almost dry, before H2O (500 mL) was added. Vigorous stirring aided the dissolving of solids, at which time conc. HCl was added until pH˜2 was attained (solid precipitate formed). The precipitate was collected and dried by vacuum filtration giving pyrazolo[1,5-a]pyrimidine-5,7-diol as a tan solid (17.13 g, 113.4 mmol, 77%).
Reaction SMILES: CNCCN(C)C.[Li]CCCC.[O:13]1[CH:17]=[CH:16][C:15]([CH:18]=[O:19])=[CH:14]1.Cl[C:21]([O:23][CH2:24][CH3:25])=[O:22].Cl>O1CCCC1>[C:21]([C:14]1[O:13][CH:17]=[CH:16][C:15]=1[CH:18]=[O:19])([O:23][CH2:24][CH3:25])=[O:22]
Reactant: O=Cc1ccoc1
Reactant: CCOC(=O)Cl
Agent: CNCCN(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCOC(=O)c1occc1C=O
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
To a suspension of 7.02 g (68.7 mmol) of N,N'-trimethylethylene diamine in 100 ml of anhydrous tetrahydrofuran (chilled to -78° C.) was added 44.6 ml (71.4 mmol) of 1.6M n-BuLi in hexanes. A dark yellow solution was formed. The solution was stirred at -78° C. under a blanket of argon for 15 minutes. To the solution was added 6.24 g (64.9 mmol) of distilled 3-furaldehyde and the solution was stirred at -78° C. for 20 minutes. To this solution was added 55.0 ml (71.4 mmol) of 1.3M solution of BuLi in hexanes and the solution was stirred at -78° C. for 3 hours. The anion formed was transfered via cannula onto a solution of 7.75 g (6.8 ml, 71.4 mmol) of ethyl chloroformate in 20 ml of anhydrous tetrahydrofuran (chilled to -78° C.). The resulting solution was allowed to warm to room temperature and stirred overnight (16.33 h). The solution was poured onto 1:10 10% HCl: ice (v/v) and the layers were separated. The aqueous layer was extracted with ether and the organic phases combined, dried over MgSO4, filtered and concentrated in vacuo to yield a brown oil. Purification by flash chromatography (silica gel, 5% ethyl acetate in hexane) yielded the title compound as a white solid.
Reaction SMILES: C(OC(N(C(OC(C)(C)C)=O)[C:9]1[S:10][C:11]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[C:12]([C:14](=[O:17])[CH2:15][CH3:16])[N:13]=1)=O)(C)(C)C.[ClH:30].C(OCC)(=O)C.N(OC(C)(C)C)=O>CO.[Cu](Cl)Cl>[Cl:30][C:9]1[S:10][C:11]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[C:12]([C:14](=[O:17])[CH2:15][CH3:16])[N:13]=1
Reactant: CCOC(=O)c1sc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)nc1C(=O)CC
Reactant: Cl
Agent: Cl[Cu]Cl
Agent: CC(C)(C)ON=O
Solvent: CO
Solvent: CCOC(C)=O
Product: CCOC(=O)c1sc(Cl)nc1C(=O)CC
Temperature: 50 °C
Reaction time: 0.83 h

Procedure:
Ethyl 2-[bis(tert-butoxycarbonyl)amino]-4-propanoyl-1,3-thiazole-5-carboxylate obtained in Example (62f) (270.5 mg, 0.63 mmol) was dissolved in methanol (2 mL). A 4 N hydrochloric acid/ethyl acetate solution (6 mL) was added, and the mixture was stirred at 50° C. for 50 minutes. The reaction solution was washed with saturated aqueous sodium bicarbonate solution, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The same operation as in Example (22c) was performed using the resulting crude product, copper chloride (96 mg, 0.71 mmol) and tert-butyl nitrite (86 μL, 0.72 mmol), to obtain 49.0 mg of the title compound as a colorless oily substance (31%).
Reaction SMILES: S(Cl)([Cl:3])=O.[PH:5](=[O:8])([OH:7])[OH:6].[CH2:9]([C:11]([CH2:39][CH3:40])([CH:13](O)[C:14]1[N:18]=[CH:17][N:16]([C:19]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:15]=1)[CH3:12])[CH3:10]>N1C=CC=CC=1>[PH:5](=[O:6])([OH:8])[OH:7].[CH2:9]([C:11]([CH2:39][CH3:40])([CH:13]([Cl:3])[C:14]1[N:18]=[CH:17][N:16]([C:19]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:15]=1)[CH3:12])[CH3:10]
Reactant: CCC(C)(CC)C(O)c1ncn(C(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reactant: O=S(Cl)Cl
Agent: O=[PH](O)O
Solvent: c1ccncc1
Product: CCC(C)(CC)C(Cl)c1ncn(C(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Thionyl chloride (20 ml) was added dropwise to a stirred solution of diethyl 3-hydroxy-3(1-trityl-1,2,4-triazol-3-yl)propane phosphonate (1.0 g, prepared as described in Example 24) in pyridine (10 ml), whilst maintaining the temperature below 5° C. The mixture was allowed to warm to room temperature, stirred for three hours, then evaporated under reduced pressure. The residue was dissolved in ethyl acetate, washed with water and brine, dried over magnesium sulphate and evaporated under reduced pressure. This residue was chromatographed on silica, using dichloromethane-ethanol (49:1) as eluant, to give diethyl 3-chloro-3(1-trityl-1,2,4-triazol-3-yl)propane phosphonate (0.64 g, m.p. 123°-124° C.). NMR (CDCl3): δ1.3(6H,t), 1.8-2.1(2H,m), 2.4-2.6(2H,m), 4.1(4H,m), 5.1(1H,t), 7.1(6H,m), 7.4(9H,m), 7.95(1H,s). M/S: M+ 523,525.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([CH:10]([CH3:12])[CH3:11])[CH:3]=1.[Li]CCCC.CCCCCC.CN([CH:27]=[O:28])C.Cl>C1COCC1>[CH:10]([C:4]1[CH:3]=[C:2]([CH:7]=[C:6]([O:8][CH3:9])[CH:5]=1)[CH:27]=[O:28])([CH3:12])[CH3:11]
Reactant: CN(C)C=O
Reactant: COc1cc(Br)cc(C(C)C)c1
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COc1cc(C=O)cc(C(C)C)c1
Reaction time: 0.08 h

Procedure:
A solution of 1-bromo-3-isopropyl-5-methoxy-benzene (1.06 g, 4.63 mmol) in dry THF (10 mL) was cooled to −78° C. under nitrogen atmosphere. A 1.6 M solution of nBuLi in hexane (2.9 mL, 4.63 mmol) was added at once, followed within 1 min by DMF (0.356 mL, 4.63 mmol). After 1 min the mixture was poured onto 10 mL 1N aq. HCl, stirred for 5 min and extracted with TBME. The organic phase was washed with brine, dried with MgSO4 and evaporated to give the title compound sufficiently pure for further use: TLC (AcOEt-hexane 1:9) Rf=0.40; HPLC RtH1=2.97 min; ESIMS [M+H]+=179; 1H NMR (400 MHz, CDCl3): δ 9.95 (s, 1H), 7.36 (s, 1H), 7.22 (s, 1H), 7.05 (s, 1H), 3.85 (s, 3H), 2.96 (heptet, 1H), 1.29 (d, 6H).
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][S:6][CH2:7][C:8]1[C:16]2[C:15]3[CH:17]=[CH:18][C:19]([Cl:21])=[CH:20][C:14]=3[O:13][C:12]=2[CH:11]=[CH:10][CH:9]=1)C.CO.[NH3:25]>>[Cl:21][C:19]1[CH:18]=[CH:17][C:15]2[C:16]3[C:8]([CH2:7][S:6][CH2:5][C:4]([NH2:25])=[O:3])=[CH:9][CH:10]=[CH:11][C:12]=3[O:13][C:14]=2[CH:20]=1
Reactant: N
Reactant: CCOC(=O)CSCc1cccc2oc3cc(Cl)ccc3c12
Solvent: CO
Product: NC(=O)CSCc1cccc2oc3cc(Cl)ccc3c12
Temperature: 45 °C
Reaction time: 1 h

Procedure:
A suspension of 2-(7-chlorodibenzofuran-1-ylmethylsulfanyl)acetic acid ethyl ester (Compound Ic; 3.77 g, 11.8 mmole) in 50 ml 7N methanol/ammonia was stirred at 45° C. for one hour, and then at RT for 2 days. The suspension was filtered, washed by methanol, dried in vacuum to give 2.56 g of white solid.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][C:4](=[C:7]([CH3:10])[CH2:8][OH:9])[CH2:3][CH2:2]1>CCCCCC.ClCCl.ClCCl.[O-2].[O-2].[Mn+4]>[O:1]1[CH2:6][CH2:5][C:4](=[C:7]([CH3:10])[CH:8]=[O:9])[CH2:3][CH2:2]1
Reactant: CC(CO)=C1CCOCC1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Solvent: CCCCCC
Product: CC(C=O)=C1CCOCC1
Temperature: 25 °C
Reaction time: 40 h
Yield: 101.4 %

Procedure:
To a suspension of 23 g (0.265 mmol) of activated manganese dioxide in a mixture of hexane-dichloromethane (20 mL+70 mL) was added a solution of 2.0 g (14.07 mmol) of 2-(tetrahydropyran-4-ylidene)propan-1-ol obtained in the above 2) in dichloromethane (4 mL), and stirred for 40 hours at 25° C. Upon filtration of the mixture and subsequent concentration of the filtrate, 2.0 g (yield 100%) of 2-(tetrahydropyran-4-ylidene)propionaldehyde (VII-15) was obtained as colorless liquid. Its physical properties are shown below.
Reaction SMILES: F[C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][C:3]=1[N+:13]([O-:15])=[O:14].[CH:16]([C:19]1[NH:20][CH:21]=[CH:22][N:23]=1)([CH3:18])[CH3:17].C(N(CC)C(C)C)(C)C>C(#N)C>[CH:16]([C:19]1[N:20]([C:2]2[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][C:3]=2[N+:13]([O-:15])=[O:14])[CH:21]=[CH:22][N:23]=1)([CH3:18])[CH3:17]
Reactant: CCOC(=O)c1ccc(F)c([N+](=O)[O-])c1
Reactant: CC(C)c1ncc[nH]1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CCOC(=O)c1ccc(-n2ccnc2C(C)C)c([N+](=O)[O-])c1
Yield: 81.7 %

Procedure:
A mixture of ethyl 4-fluoro-3-nitrobenzoate 4.26 g, 2-isopropylimidazole 2.20 g, N,N-diisopropylethylamine 5.2 mL and acetonitrile 40 mL was heated under reflux for 24 hours. After distilling the solvent off, water was added to the residue and extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate and removed of the solvent by distillation, to provide 4.95 g of the title compound.
Reaction SMILES: [C:1]([CH:4]1[CH2:9][N:8]([S:10]([C:13]2[CH:22]=[CH:21][C:20]3[C:15](=[CH:16][CH:17]=[C:18]([Cl:23])[CH:19]=3)[CH:14]=2)(=[O:12])=[O:11])[CH2:7][CH2:6][N:5]1[C:24]([C:26]1[CH:31]=[CH:30][C:29]([C:32]2[CH:37]=[CH:36][N+:35]([O-:38])=[CH:34][CH:33]=2)=[CH:28][CH:27]=1)=[O:25])([OH:3])=O.[CH3:39][N:40]([CH3:44])[CH2:41][CH2:42][NH2:43]>>[Cl:23][C:18]1[CH:19]=[C:20]2[C:15](=[CH:16][CH:17]=1)[CH:14]=[C:13]([S:10]([N:8]1[CH2:7][CH2:6][N:5]([C:24]([C:26]3[CH:27]=[CH:28][C:29]([C:32]4[CH:37]=[CH:36][N+:35]([O-:38])=[CH:34][CH:33]=4)=[CH:30][CH:31]=3)=[O:25])[CH:4]([C:1]([NH:43][CH2:42][CH2:41][N:40]([CH3:44])[CH3:39])=[O:3])[CH2:9]1)(=[O:12])=[O:11])[CH:22]=[CH:21]2
Reactant: CN(C)CCN
Reactant: O=C(O)C1CN(S(=O)(=O)c2ccc3cc(Cl)ccc3c2)CCN1C(=O)c1ccc(-c2cc[n+]([O-])cc2)cc1
Product: CN(C)CCNC(=O)C1CN(S(=O)(=O)c2ccc3cc(Cl)ccc3c2)CCN1C(=O)c1ccc(-c2cc[n+]([O-])cc2)cc1

Procedure:
In a similar manner to Example 4 except for the use of 4-[4-[[2-carboxy-4-[(6-chloronaphthalen-2-yl)sulfonyl]piperazin-1-yl]carbonyl]phenyl]pyridine N-oxide and 2-(dimethylamino)ethylamine as the raw materials, the reaction was conducted, whereby the title compound was obtained.
Reaction SMILES: [CH:1](/[CH:4]1[O:8][C@H:7]([C:9]([O:11][CH:12]([CH3:14])[CH3:13])=[O:10])[C@@H:6]([C:15]([O:17][CH:18]([CH3:20])[CH3:19])=[O:16])[O:5]1)=[CH:2]\[CH3:3].[CH2:21]([Zn]CC)C.ICI>>[CH3:3][C@H:2]1[CH2:21][C@@H:1]1[CH:4]1[O:5][C@H:6]([C:15]([O:17][CH:18]([CH3:20])[CH3:19])=[O:16])[C@@H:7]([C:9]([O:11][CH:12]([CH3:14])[CH3:13])=[O:10])[O:8]1
Reactant: CC[Zn]CC
Reactant: C/C=C/C1O[C@H](C(=O)OC(C)C)[C@@H](C(=O)OC(C)C)O1
Solvent: ICI
Product: CC(C)OC(=O)[C@H]1OC([C@H]2C[C@@H]2C)O[C@@H]1C(=O)OC(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 89 %

Procedure:
To a −20° C. solution of intermediate diisopropyl (4S,5S)-2-[(1E)-prop-1-enyl]-1,3-dioxolane-4,5-dicarboxylate (4.10 g, 14.32 mmol) in 60 mL hexanes was added 1M diethylzinc in hexanes (42.96 mL, 42.96 mmol). Diiodomethane (6.92 mL, 85.92 mmol) was added dropwise with vigorous stirring. After 1 h at −20° C., the reaction was refrigerated at −5° C. After 17 h at −5° C., the reaction was stirred at 0° C. for an additional 5 h and then quenched with cold saturated ammonium chloride solution (100 mL) and extracted with Et2O (100 mL×3). The combined organics were washed w/aqueous sodium thiosulfate (100 mL) and brine (100 mL), filtered, dried over Na2SO4, filtered again and concentrated in vacuo. Purification by normal phase chromatography (10->30% EtOAc/hexanes) yielded 3.85 g (89%) of diisopropyl (4S,5S)-2-[(1S,2S)-2-methylcyclopropyl]-1,3-dioxolane-4,5-dicarboxylate as a yellow oil. 1H NMR (CDCl3, 400 MHz) 5.12 (m, 2H); 4.78 (d, J=6.41 Hz, 1H); 4.66 (d, J=4.21 Hz, 1H); 4.57 (d, J=4.22 Hz, 1H); 1.30 (m, 12H); 1.09 (d, J=5.68 Hz, 3H); 0.94 (m, 2H); 0.67 (m, 1H); 0.39 (m, 1H); LC/MS [M+H]+=301.