Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1](/[CH:4]=[CH:5]/[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)([O-:3])=[O:2].[C:12]([O:19][CH3:20])(=[O:18])[CH2:13][C:14]([O:16][CH3:17])=[O:15]>C1(C)C=CC=CC=1>[CH3:17][O:16][C:14]([CH:13]([C@H:5]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH2:4][N+:1]([O-:3])=[O:2])[C:12]([O:19][CH3:20])=[O:18])=[O:15]
Reactant: O=[N+]([O-])/C=C/c1ccccc1
Reactant: COC(=O)CC(=O)OC
Solvent: Cc1ccccc1
Product: COC(=O)C(C(=O)OC)[C@@H](C[N+](=O)[O-])c1ccccc1
Temperature: -20 °C
Reaction time: 48 h

Procedure:
[(S,S)-N-(pentamethylbenzenesulfonyl)-1,2-diphenylethylenediamine](hexamethylbenzene)ruthenium (13.7 mg, 0.02 mmol, S/C=50), trans-β-nitrostyrene (149 mg, 1.0 mmol), dimethyl malonate (114 μl, 1.0 mmol) and toluene (1 ml) were added into Schlenk (20 ml) under an argon atmosphere, and stirred at −20° C. for 48 hours. The reaction solution was purified by flash column chromatography (hexane/acetone=80/20, SiO2), showing that the yield of the product was 93%. The optical purity was measured by HPLC (CHIRALPACK AD manufactured by Daicel Co., Ltd., hexane:2-propanol=90:10, flow rate 0.5 ml/min, detection by 210 mn), resulting to 94% ee.
Reaction SMILES: [OH:1][C:2]1[CH:19]=[C:18]2[C:5]([C@@:6]3([CH3:25])[C@H:15]([CH2:16][S:17]2(=[O:21])=[O:20])[C@:14]2([CH3:22])[C@H:9]([C:10]([CH3:24])([CH3:23])[CH2:11][CH2:12][CH2:13]2)[CH2:8][CH2:7]3)=[C:4]([C:26]([N:28]2[CH2:33][CH2:32][N:31](C(OC(C)(C)C)=O)[CH2:30][CH2:29]2)=[O:27])[CH:3]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[OH:1][C:2]1[CH:19]=[C:18]2[C:5]([C@@:6]3([CH3:25])[C@H:15]([CH2:16][S:17]2(=[O:21])=[O:20])[C@:14]2([CH3:22])[C@H:9]([C:10]([CH3:23])([CH3:24])[CH2:11][CH2:12][CH2:13]2)[CH2:8][CH2:7]3)=[C:4]([C:26]([N:28]2[CH2:29][CH2:30][NH:31][CH2:32][CH2:33]2)=[O:27])[CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)c2cc(O)cc3c2[C@]2(C)CC[C@H]4C(C)(C)CCC[C@]4(C)[C@H]2CS3(=O)=O)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC1(C)CCC[C@]2(C)[C@H]3CS(=O)(=O)c4cc(O)cc(C(=O)N5CCNCC5)c4[C@]3(C)CC[C@@H]12
Temperature: 25 °C
Reaction time: 18 h
Yield: 55 %

Procedure:
A mixture of tert-butyl 4-{[(1R,10R,11S,16S)-5-hydroxy-1,11,15,15-tetramethyl-8,8-dioxo-8λ6-thiatetracyclo[8.8.0.02,7.011,16]octadeca-2,4,6-trien-3-yl]-carbonyl}piperazine-1-carboxylate (99) (0.13 g, 0.23 mmol) and trifluoroacetic acid (1.0 mL, 13 mmol) in CH2Cl2 (10 mL) was stirred at room temperature under N2 for 18 h. The mixture was concentrated under reduced pressure, and basified with Et3N, dissolved in EtOAc and washed with water. The organic layer was separated and concentrated to dryness under reduced pressure to give (1R,10R,11S,16S)-5-hydroxy-1,11,15,15-tetramethyl-3-[(piperazin-1-yl)carbonyl]-8λ6-thiatetracyclo[8.8.0.02,7.011,16]octadeca-2,4,6-triene-8,8-dione (100) (0.06 g, 55%) as a brown solid. 1H NMR (CD3OD): δ 7.27 (d, 1H), 6.78 (d, 1H), 3.50 (m, 3H), 3.02 (m 2H), 2.90 (m, 2H), 2.53 (m, 1H), 2.16 (d, 1H), 1.88-1.14 (m, 14H), 1.00 (m, 5H), 0.90 (s, 3H), 0.86 (s, 3H). MS m/z 475 (C26H38N2O4S+H+).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10]Br)[CH3:2].C(N(CC)CC)C.[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([SH:27])=[CH:23][CH:22]=1>ClCCl>[CH2:1]([O:3][C:4](=[O:12])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][S:27][C:24]1[CH:25]=[CH:26][C:21]([Cl:20])=[CH:22][CH:23]=1)[CH3:2]
Reactant: CCOC(=O)CCCCCCBr
Reactant: Sc1ccc(Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)CCCCCCSc1ccc(Cl)cc1

Procedure:
To a solution of 7-bromoheptanoic acid ethyl ester (2.5 mL, 12.8 mmol) and triethylamine (2 mL, 14.3 mmol) in dichloromethane (10 mL) was added 4-chlorothiophenol (1.86 g, 12.8 mmol) under an atmosphere of argon. The mixture was stirred at reflux for 2 hours after which it was concentrated under reduced pressure. The oil was dissolved in ethyl acetate (50 mL) and then washed successively with saturated aqueous sodium hydrogen carbonate (25 mL), distilled water (25 mL) and brine (25 mL). The organic layer was then dried over anhydrous MgSO4, filtered and concentrated under reduced pressure to give an yellow oil that was purified by flash chromatography (1:9 diethyl ether:40-60° C. petroleum ether). The title compound was obtained as a colourless oil (3.3 g, 87%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:30]=[CH:31][CH:32]=1)[C:5]([N:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH:8]1[C:13]1[O:14][C:15]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:17]=1)=[O:6].Br[CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36].C([O-])([O-])=O.[K+].[K+]>C(#N)C>[CH2:38]([O:37][C:35]([CH2:34][O:1][C:2]1[CH:3]=[C:4]([CH:30]=[CH:31][CH:32]=1)[C:5]([N:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH:8]1[C:13]1[O:14][C:15]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)=[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:17]=1)=[O:6])=[O:36])[CH3:39]
Reactant: CCOC(=O)CBr
Reactant: O=C(c1cccc(O)c1)N1CCCCC1c1nc(-c2ccccc2)c(-c2ccccc2)o1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)COc1cccc(C(=O)N2CCCCC2c2nc(-c3ccccc3)c(-c3ccccc3)o2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.8 %

Procedure:
A mixture of 1-(3-hydroxybenzoyl)-2-(4,5-diphenyl-2-oxazolyl)piperidine (100 mg), ethyl bromoacetate (61 mg), and K2CO3 (84 mg) in acetonitrile (1.0 ml) was stirred at room temperature overnight and partitioned between water and ethyl acetate. The organic layer was separated, washed with water and brine, dried over MgSO4, and evaporated in vacuo. The residue was chromatographed over silica gel to afford 1-[3-(ethoxycarbonylmethoxy)benzoyl]-2-(4,5-diphenyl-2-oxazolyl)piperidine (90 mg) as a colorless oil.
Reaction SMILES: [Br:1][CH:2]1[C:10]2[N:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=3)[N:8]=[C:7]([CH3:17])[C:6]=2[C:5](=O)[CH2:4][C:3]1([CH3:20])[CH3:19].Cl.[NH2:22][OH:23].C([O-])(=O)C.[Na+]>O1CCOCC1>[Br:1][CH:2]1[C:10]2[N:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=3)[N:8]=[C:7]([CH3:17])[C:6]=2[C:5](=[N:22][OH:23])[CH2:4][C:3]1([CH3:20])[CH3:19]
Reactant: Cc1nn(-c2ccccn2)c2c1C(=O)CC(C)(C)C2Br
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: C1COCCO1
Product: Cc1nn(-c2ccccn2)c2c1C(=NO)CC(C)(C)C2Br
Reaction time: 4 h
Yield: 44.5 %

Procedure:
A mixture of 7-bromo-1-(2-pyridyl)-3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-indazole (0.3 g, 0.9 mmol), prepared as described in example 4, hydroxylamine hydrochloride (0.37 g, 4.5 mmol), and sodium acetate (0.44 g, 5.4 mmol) in 1,4-dioxane (50 ml) was heated under reflux for about 4 hours. Additional hydroxylamine hydrochloride (0.123 g, 1.6 eq) and sodium acetate (0.146 g, 2 eq) were added and heating was continued for further 4 hours. The reaction mixture was poured onto ice/water and extracted with dichloromethane. The combined organic layers were washed with brine, dried over sodium sulfate and evaporated. The residue was chromatographed on silica gel (cyclohexane:ethyl acetate=90:10) to give the title compound as a colourless solid (0.14 g, 45%): m.p. 195-196° C.
Reaction SMILES: [CH2:1]([C:8]1[CH:24]=[CH:23][C:11]2[C:12](=[O:22])[CH:13]=[C:14]([CH2:16][CH2:17][C:18]([O:20]C)=[O:19])[O:15][C:10]=2[C:9]=1[CH2:25][CH2:26][CH3:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)C.C(=O)([O-])[O-].[Na+].[Na+]>O>[CH2:1]([C:8]1[CH:24]=[CH:23][C:11]2[C:12](=[O:22])[CH:13]=[C:14]([CH2:16][CH2:17][C:18]([OH:20])=[O:19])[O:15][C:10]=2[C:9]=1[CH2:25][CH2:26][CH3:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCc1c(Cc2ccccc2)ccc2c(=O)cc(CCC(=O)OC)oc12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCCc1c(Cc2ccccc2)ccc2c(=O)cc(CCC(=O)O)oc12
Yield: 72.8 %

Procedure:
Methyl 3-[7-benzyl-4-oxo-8-propyl-4H-1-benzopyran-2-yl]propionate (1.0 g) was refluxed with ethanol (50 ml) containing 10% aqueous sodium carbonate solution (10 ml) for 30 minutes. The mixture was diluted with water, washed with ethyl acetate, and acidified to give a solid, which crystallised from ethanol to give the propionic acid (0.7 g), mp 160°-161°.
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([N:12]2[CH2:17][CH:16]([CH3:18])[O:15][CH:14]([CH3:19])[CH2:13]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:20].[CH3:21][C:22]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)([CH3:27])[CH2:23][C:24](O)=[O:25]>>[CH3:18][CH:16]1[O:15][CH:14]([CH3:19])[CH2:13][N:12]([C:10]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3](=[O:20])[N:2]([NH:1][C:24](=[O:25])[CH2:23][C:22]([CH3:21])([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH3:27])[N:11]=2)[CH2:17]1
Reactant: CC(C)(CC(=O)O)c1ccccc1
Reactant: CC1CN(c2nn(N)c(=O)c3ccccc23)CC(C)O1
Product: CC1CN(c2nn(NC(=O)CC(C)(C)c3ccccc3)c(=O)c3ccccc23)CC(C)O1

Procedure:
The product from Example 60A and 3-methyl-3-phenylbutanoic acid were processed using a method similar to that described in Example 10C to afford the title compound. 1H NMR (400 MHz, DMSO-d6) δ 11.13 (s, 1H), 8.30 (d, J=7.5, 1H), 8.03-7.92 (m, 2H), 7.92-7.84 (m, 1H), 7.44 (dd, J=8.4, 1.1, 2H), 7.32 (dd, J=10.5, 5.0, 2H), 7.19 (dd, J=10.4, 4.2, 1H), 3.91-3.83 (m, 2H), 3.30 (m, 2H, buried), 2.57 (s, 2H), 2.45-2.36 (m, 2H), 1.46 (s, 6H), 1.13 (d, J=6.3, 6H); MS (DCI+) M/Z 452 (M+HN4)+.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1)#[N:2].[Cl:10][C:11]1[C:12](F)=[CH:13][C:14]2[O:19][CH:18]([C:20]([F:23])([F:22])[F:21])[C:17]([C:24]([O:26]CC)=[O:25])=[CH:16][C:15]=2[CH:29]=1>>[Cl:10][C:11]1[C:12]([O:9][C:6]2[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=2)=[CH:13][C:14]2[O:19][CH:18]([C:20]([F:22])([F:21])[F:23])[C:17]([C:24]([OH:26])=[O:25])=[CH:16][C:15]=2[CH:29]=1
Reactant: CCOC(=O)C1=Cc2cc(Cl)c(F)cc2OC1C(F)(F)F
Reactant: N#Cc1ccc(O)cc1
Product: N#Cc1ccc(Oc2cc3c(cc2Cl)C=C(C(=O)O)C(C(F)(F)F)O3)cc1

Procedure:
The title compound was prepared from 4-cyanophenol and ethyl 6-chloro-7-fluoro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylate (Example 183, Step 2) via a procedure similar to that described in Example 183, Steps 3 and 4: mp 212.5-215.7° C. 1H NMR (acetone-d6 /300 MHz) 7.96 (s, 1H), 7.90 (d, 2H, J=8.9 Hz), 7.81 (s, 1H), 7.27 (d, 2H, J=8.9 Hz), 6.96 (s, 1H), 5.90 (q, 1H, J=7.0 Hz). 19F NMR (acetone-d6 /282 MHz) -79.4 (d, J=7.2 Hz). FABLRMS m/z 396 (M+H). ESHRMS m/z 413.0544 (M+NH4. Calc'd 413.0516). Anal. Calc'd for C18H9ClF3NO4 : C, 54.63; H, 2.29; N, 3.54; Cl, 8.96. Found: C, 54.40; H, 2.18; N 3.30; Cl, 9.20.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[C:9]([O:11][CH2:12][C:13]([CH2:54][O:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH2:71][CH2:72][CH3:73])([CH2:34][O:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH3:53])[CH2:14][O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[CH:8]=[CH:7][C:4]=1[CH:5]=O.Cl.[NH2:75][OH:76].C(N(CC)CC)C>ClCCl>[CH3:1][O:2][C:3]1[CH:10]=[C:9]([O:11][CH2:12][C:13]([CH2:54][O:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH2:71][CH2:72][CH3:73])([CH2:34][O:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH3:53])[CH2:14][O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[CH:8]=[CH:7][C:4]=1[CH:5]=[N:75][OH:76]
Reactant: NO
Reactant: CCCCCCCCCCCCCCCCCCOCC(COCCCCCCCCCCCCCCCCCC)(COCCCCCCCCCCCCCCCCCC)COc1ccc(C=O)c(OC)c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCCCCCCCCCCCCCOCC(COCCCCCCCCCCCCCCCCCC)(COCCCCCCCCCCCCCCCCCC)COc1ccc(C=NO)c(OC)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 83.7 %

Procedure:
2-Methoxy-4-[2′,2′,2′-tris(octadecyloxymethyl)ethoxy]benzaldehyde (50 mg, 0.049 mmol) was dissolved in dichloromethane (1 ml), hydroxylamine hydrochloride (18 mg, 0.26 mmol) and triethylamine (51 μl, 0.37 mmol) were added, and the mixture was stirred at room temperature for 4 hr. The solvent was evaporated, and the residue was precipitated with acetonitrile to give 2-methoxy-4-[2,2,2-tris(octadecyloxymethyl)ethoxy]benzaldoxime (43 mg, 0.041 mmol, 85%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH2:10][O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH2:18][CH2:19][CH2:20][C:21]2[CH:30]=[CH:29][C:24]([C:25]([O:27][CH3:28])=[O:26])=[CH:23][CH:22]=2)[CH:7]=[CH:8][CH:9]=1)([O-])=O.O.O.[Sn](Cl)Cl.C(=O)(O)[O-].[Na+].[CH2:41]([OH:43])[CH3:42]>>[CH3:42][C:41]([NH:1][C:4]1[CH:5]=[C:6]([CH2:10][O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH2:18][CH2:19][CH2:20][C:21]2[CH:30]=[CH:29][C:24]([C:25]([O:27][CH3:28])=[O:26])=[CH:23][CH:22]=2)[CH:7]=[CH:8][CH:9]=1)=[O:43]
Reactant: COC(=O)c1ccc(CCCc2ccccc2OCc2cccc([N+](=O)[O-])c2)cc1
Reactant: CCO
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: COC(=O)c1ccc(CCCc2ccccc2OCc2cccc(NC(C)=O)c2)cc1
Temperature: 70 °C

Procedure:
A mixture of methyl 4-[3-(2-(3-nitrophenylmethyloxy)-phenyl)propyl]benzoate (0.25 g), tin (II) chloride dihydrate (0.7 g) in ethanol (10 ml) was heated at 70° C. for 45 minutes, cooled and poured onto ice. The pH of the solution was adjusted to 8 with sodium bicarbonate and extracted with ethyl acetate (2×50 ml). The combined organics were washed with brine (50 ml), dried (magnesium sulphate), filtered and evaporated. The residue was purified by subjecting to chromatography on silica gel using ethyl acetate hexane (1:9) as eluant. There was thus obtained methyl 4-[3-(2-(3-aminophenylmethyloxy)phenyl)propyl]benzoate (185 mg). b: - Methyl 4-[3-(2-(3-methylcarbonylaminophenylmethyloxy)-phenyl) propyl]benzoate was prepared from methyl 4-[3-(2-(3-amino-phenylmethyloxy)phenyl)propyl]benzoate (preparation described in note a) as follows:
Reaction SMILES: CC(C)([O-])C.[K+].[P:7]([O-:24])([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[CH2:25](Br)[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36].Cl>CN(C=O)C.C1COCC1>[CH2:36]([P:7]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)(=[O:24])[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH3:25]
Reactant: CCCCCCCCCCCCBr
Reactant: [O-]P(OCc1ccccc1)OCc1ccccc1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCP(=O)(OCc1ccccc1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of potassium t-butoxide (6.16 g, 55 mmol), in dry DMF (50 mL), under an argon atmosphere was added dropwise via syringe a solution of dibenzyl phosphite (13.1 g, 50 mmol) in dry DMF (5 mL), and the reaction mixture was stirred at room temperature for 20 min. Then a solution of lauryl bromide (18.6 g, 75 mmol) in dry THF (15 mL), was added dropwise under argon atmosphere, and the mixture was stirred at room temperature for an additional 1 h. After completion of the reaction, the mixture was neutralized with dilute HCl (40 mL) and extracted with ethyl acetate (200 mL), the organic phase was dried, concentrated, and purified by flash chromatography to afford the pure dibenzyl phosphate 14 as a colorless oil (Rf 0.46, silica, ethyl acetate and hexane, 1:2, 10.5 g, 50%).
Reaction SMILES: Cl.[NH2:2][OH:3].[OH-].[Na+].[C:6]1(=O)[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8][CH2:7]1>O.C(O)C>[C:6]1(=[N:2][OH:3])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8][CH2:7]1
Reactant: O=C1CCc2ccccc21
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: ON=C1CCc2ccccc21
Temperature: 25 °C

Procedure:
In a 12 l four-necked flask fitted with a mechanical stirrer, a reflux condenser and a thermometer was placed 3.6 l of deionized water. Hydroxylamine hydrochloride was added. A clear, colorless solution formed (pH 2.5) to which was added 475 ml of 50% sodium hydroxide which had been diluted to 2.4 l with deionized water (pH 6.2). 1-Indanone was dissolved in 2.4 l of 3A anhydrous ethanol and added to the flask. The slightly turbid solution was heated at reflux for 15 minutes. A white solid started to precipitate at 39° C. The mixture was cooled to room temperature and then in an ice-water bath. The product was filtered off and washed with three 2 l portions of chilled water. The product was dried in a vacuum oven at 46° C. A white fluffy solid was obtained.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][CH3:5].[H-].[Na+].[I:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]2[N:21]=[CH:20][CH:19]=[CH:18][N:17]=2)=[CH:11][CH:10]=1>CN(C=O)C.[Cl-].[Na+].O>[I:8][C:9]1[CH:10]=[CH:11][C:12]([N:15]([CH2:2][CH2:3][O:4][CH3:5])[C:16]2[N:17]=[CH:18][CH:19]=[CH:20][N:21]=2)=[CH:13][CH:14]=1
Reactant: COCCBr
Reactant: Ic1ccc(Nc2ncccn2)cc1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COCCN(c1ccc(I)cc1)c1ncccn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Under an argon atmosphere, 2-bromoethylmethyl ether (0.14 ml) and sodium hydride (48 mg) were added to a solution of N-(4-iodophenyl)pyrimidin-2-amine (300 mg) in anhydrous DMF (1 ml), and the resulting mixture was stirred at room temperature overnight. Saturated brine was added to the reaction solution and the resulting mixture was extracted with chloroform, followed by drying the organic layer over anhydrous sodium sulfate. After removing anhydrous sodium sulfate by filtration, the filtrate was concentrated. The residue was purified by column chromatography (silica gel, eluent: hexane/chloroform=1/10) to obtain N-(4-iodophenyl)-N-(2-methoxyethyl)pyrimidin-2-amine (233 mg). NMR (H1, CDCl3): δ 3.32(3H, s), 3.63 (2H, t, J=5.9 Hz), 4.14 (2H, t, J=5.9 Hz), 6.59 (1H, t, J=4.9 Hz), 7.09-7.13 (2H, m), 7.70-7.73 (2H, m), 8.32 (2H, d, J=4.9 Hz)
Reaction SMILES: [CH:1]1([N:6]2[C:10]3=[N:11][C:12]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][CH:23]=[CH2:24])[C:17]=4O)=[N:13][C:14](=[O:15])[C:9]3=[C:8]([CH2:26][CH3:27])[NH:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.S(=O)(=O)(O)[OH:29]>C(O)(=O)C>[CH:1]1([N:6]2[C:10]3=[N:11][C:12]([C:16]4[CH:21]=[CH:20][C:19]5[O:29][CH:23]([CH3:24])[CH2:22][C:18]=5[CH:17]=4)=[N:13][C:14](=[O:15])[C:9]3=[C:8]([CH2:26][CH3:27])[NH:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=S(=O)(O)O
Reactant: C=CCc1cccc(-c2nc3n(C4CCCC4)[nH]c(CC)c-3c(=O)n2)c1O
Solvent: CC(=O)O
Product: CCc1[nH]n(C2CCCC2)c2nc(-c3ccc4c(c3)CC(C)O4)nc(=O)c1-2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of 1-cyclopentyl-3-ethyl-6-[2-hydroxy-3-(2-propenyl)phenyl]pyrazolo[3,4-d]pyrimidin-4-one (1.0 g) in acetic acid (15 ml) was added sulfuric acid (15 ml) while cooling in an ice bath. The reaction mixture was warmed to room temperature and stirred overnight. The reaction mixture was poured into ice/water, a precipitate formed which was collected by filtration and washed with water. The product was purified by recrystallization from ether, followed by column chromatography on silica gel eluting with 25% EtOAc/hexane to afford 0.5 g of 1-cyclopentyl-3-ethyl-6-[2-methyl-2,3-dihydrobenzo[b]furan-5-yl]pyrazolo[3,4-d]pyrimidin-4-one, m.p. 164-165° C.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:13]=[C:12]2[C:8]([CH:9]=[CH:10][N:11]2[CH2:14][CH2:15][CH2:16][O:17][CH3:18])=[CH:7][CH:6]=1)=[O:4].[OH-].[Na+]>CO>[CH3:18][O:17][CH2:16][CH2:15][CH2:14][N:11]1[C:12]2[C:8](=[CH:7][CH:6]=[C:5]([C:3]([OH:4])=[O:2])[CH:13]=2)[CH:9]=[CH:10]1
Reactant: COCCCn1ccc2ccc(C(=O)OC)cc21
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COCCCn1ccc2ccc(C(=O)O)cc21
Reaction time: 3 h

Procedure:
To a solution of 1-(3-methoxy-propyl)-1H-indole-6-carboxylic acid methyl ester (7 g, 28.5 mmol) in MeOH (50 mL) is added NaOH 2N (28.5 mL), and the mixture is stirred for 3 h. The solvent is concentrated and the remaining aqueous residue is acidified with HCl 1N and extracted twice with CH2Cl2. The combined organic extracts are dried over Na2SO4, filtered and concentrated to give title product. TLC, Rf (c-hexane/AcOEt 2:1)=0.25. MS (LC-MS): 232.0 [M+H]+, tR (HPLC, Macherey-Nagel Nucleosil C18 column, 10-100% CH3CN/H2O/5 min, 100% CH3CN/3 min, flow: 1.5 ml/min): 5.04 min.
Reaction SMILES: FC(F)(F)S(O[C:7]1[N:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]=[C:10]2[CH:16]1[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]1)(=O)=O.[F:25][C:26]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:29](B(O)O)=[CH:28][CH:27]=1>>[F:25][C:26]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:29]([C:7]2[N:8]=[C:9]3[C:13](=[CH:14][CH:15]=2)[NH:12][CH:11]=[C:10]3[CH:16]2[CH2:17][CH2:18][N:19]([CH3:22])[CH2:20][CH2:21]2)=[CH:28][CH:27]=1
Reactant: CN1CCC(c2c[nH]c3ccc(OS(=O)(=O)C(F)(F)F)nc23)CC1
Reactant: OB(O)c1ccc(F)c2ccccc12
Product: CN1CCC(c2c[nH]c3ccc(-c4ccc(F)c5ccccc45)nc23)CC1
Yield: 84.5 %

Procedure:
O-Trifluoromethanesulfonyl-3-(1-methylpiperidin-4-yl)-5-hydroxy-4-aza-1H-indole (160 mg, 0.441 mmol) and 4-fluoronaphth-1-ylboronic acid (134 mg, 0.71 mmol) were converted to 134 mg of the title compound by the procedure of Example 3. (85%). MS(FD) m/e 359.8 (M+). EA calculated for C23H22FN3: C, 76.88; H, 6.13; N, 11.70. Found: C, 77.15; H, 6.21; N, 11.62.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][CH2:9][O:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3([CH2:23][NH:24][C:25](=O)[CH3:26])[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[CH:13][CH:12]=2)[CH2:6][CH2:5][S:4][CH2:3][CH2:2]1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>>[N:1]1([CH2:7][CH2:8][CH2:9][O:10][C:11]2[CH:12]=[CH:13][C:14]([C:17]3([CH2:23][NH:24][CH2:25][CH3:26])[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[CH:15][CH:16]=2)[CH2:6][CH2:5][S:4][CH2:3][CH2:2]1
Reactant: CC(=O)NCC1(c2ccc(OCCCN3CCSCC3)cc2)CCOCC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: CCNCC1(c2ccc(OCCCN3CCSCC3)cc2)CCOCC1
Yield: 44 %

Procedure:
The title compound (492 mg, 44%) was prepared using N-({4-[4-(3-thiomorpholin-4-ylpropoxy)phenyl]tetrahydro-2H-pyran-4-yl}methyl)acetamide and lithium aluminium hydride similarly to the procedure used for example 142. 1H NMR (400 MHz, CDCl3) δ 0.96 (t, 3H), 1.88-1.98 (m, 4H), 2.11-2.15 (m, 2H), 2.49 (q, 2H), 2.55 (t, 2H), 2.68-2.74 (m, 10H), 3.55 (t, 2H), 3.74-3.79 (m, 2H), 4.00 (t, 2H), 6.89 (d, 2H), 7.22 (d, 2H). LRMS APCI+ m/z 379 [MH]+.
Reaction SMILES: [C:1]([CH2:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9](=[O:25])[CH:10]=[C:11]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([O:23][CH3:24])[CH:16]=3)[O:12]2)=[C:7]([O:26][CH3:27])[CH:6]=1)#[N:2].[Cl-].[NH4+].[N-:30]=[N+:31]=[N-:32].[Na+]>CN(C=O)C>[NH:30]1[C:1]([CH2:3][O:4][C:5]2[CH:14]=[C:13]3[C:8]([C:9](=[O:25])[CH:10]=[C:11]([C:15]4[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([O:23][CH3:24])[CH:16]=4)[O:12]3)=[C:7]([O:26][CH3:27])[CH:6]=2)=[N:2][N:32]=[N:31]1
Reactant: COc1ccc(-c2cc(=O)c3c(OC)cc(OCC#N)cc3o2)cc1OC
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(-c2cc(=O)c3c(OC)cc(OCc4nnn[nH]4)cc3o2)cc1OC
Temperature: 25 °C
Reaction time: 3 h
Yield: 57.9 %

Procedure:
7-(cyanomethyloxy)-3′,4′,5-trimethoxy flavone (0.3 g, 0.82 mmol) obtained in Step 2, ammonium chloride (0.13 g, 2.45 mmol) and sodium azide (0.08 g, 1.23 mmol) were dissolved in N,N′-dimethylformamide (6 mL). After the reaction was carried out at 120° C. for 3 hours, the reaction solution was cooled to room temperature. The resulting solids were filtered and washed with ethyl acetate and n-hexane. The washed solids were dissolved in a 3:1 mixed solvent of chloroform and methanol and dried over anhydrous sodium sulfate to remove the solvent. The resulting residue was recrystallized from a 1:1 mixed solvent of ethyl acetate and chloroform to give 0.195 g (yield: 58%) of the title compound.