Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.[F:3][C:4]1[CH:5]=[CH:6][C:7]2[N:11]=[C:10]([C@@H:12]([NH2:14])[CH3:13])[N:9]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:8]=2[C:21]=1[O:22][CH3:23].Cl[C:25]1[N:33]=[CH:32][N:31]=[C:30]2[C:26]=1[N:27]=[CH:28][N:29]2C1CCCCO1.CCN(C(C)C)C(C)C>CC(O)C.Cl.CO>[F:3][C:4]1[CH:5]=[CH:6][C:7]2[N:11]=[C:10]([C@@H:12]([NH:14][C:25]3[N:33]=[CH:32][N:31]=[C:30]4[C:26]=3[N:27]=[CH:28][NH:29]4)[CH3:13])[N:9]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:8]=2[C:21]=1[O:22][CH3:23]
Reactant: COc1c(F)ccc2nc([C@H](C)N)n(-c3ccccc3)c12
Reactant: Clc1ncnc2c1ncn2C1CCCCO1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Solvent: CO
Product: COc1c(F)ccc2nc([C@H](C)Nc3ncnc4[nH]cnc34)n(-c3ccccc3)c12
Temperature: 90 °C
Reaction time: 0.17 h
Yield: 63.7 %

Procedure:
To a solution of (S)-1-(6-fluoro-7-methoxy-1-phenyl-1H-benzoimidazol-2-yl)ethylamine dihydrochloride (0.16 g, 0.44 mmol) in IPA (3 mL) was added 6-chloro-9-(tetrahydropyran-2-yl)-9H-purine (139 mg, 0.58 mmol) and DIPEA (229 μL, 1.34 mmol) and the reaction mixture heated at 90° C. for 72 hours. The reaction mixture was concentrated in vacuo and the resultant residue was subjected to flash chromatography (SiO2, eluting with 0-10% methanol in EtOAc) to give a white solid: LCMS (Method C): RT=3.13 min, [M+H]+=488. The solid was dissolved in HCl in methanol (1.25 M, 5 mL) and the reaction mixture stirred at RT for 10 min. The reaction mixture was concentrated in vacuo and the resultant residue subjected to prep. HPLC (C18 phenomonix column, 10-90% MeCN in water 0.1% formic acid, 20 min gradient) to give 338 as a white solid (113 mg, 63%). 1H NMR 400 MHz δ (d6-DMSO): 8.10-8.00 (2H, m), 7.89-7.75 (1H, m), 7.66-7.29 (7H, m), 7.13-7.02 (1H, m), 5.38-5.17 (1H, m), 3.33 (3H, s), 1.48 (3H, d, J=6.8 Hz), LCMS (Method K): RT=3.40 min, [M+H]+=404
Reaction SMILES: [F:1][C:2]([F:42])([F:41])[C:3]1[CH:4]=[C:5]([C:13]([CH3:40])([CH3:39])[C:14]([N:16]([C:18]2[C:19]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=3[CH3:38])=[CH:20][C:21]([N:25]3[CH2:30][CH2:29][N:28]([CH3:31])[CH2:27][CH2:26]3)=[N+:22]([O-:24])[CH:23]=2)[CH3:17])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.C([O-])(O)=[O:44].[Na+].OS([O-])(=O)=O.OS(O[O-])(=O)=O.OS(O[O-])(=O)=O.[O-]S([O-])(=O)=O.[K+].[K+].[K+].[K+].[K+]>CO.O>[F:42][C:2]([F:1])([F:41])[C:3]1[CH:4]=[C:5]([C:13]([CH3:39])([CH3:40])[C:14]([N:16]([C:18]2[C:19]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=3[CH3:38])=[CH:20][C:21]([N:25]3[CH2:26][CH2:27][N+:28]([O-:44])([CH3:31])[CH2:29][CH2:30]3)=[N+:22]([O-:24])[CH:23]=2)[CH3:17])=[O:15])[CH:6]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:8]=1
Reactant: O=C([O-])O
Reactant: Cc1ccccc1-c1cc(N2CCN(C)CC2)[n+]([O-])cc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: O=S(=O)(O)O[O-]
Agent: O=S(=O)([O-])O
Agent: O=S(=O)([O-])[O-]
Solvent: O
Solvent: CO
Product: Cc1ccccc1-c1cc(N2CC[N+](C)([O-])CC2)[n+]([O-])cc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 57.4 %

Procedure:
To a solution of 5-(2-(3,5-bis(trifluoromethyl)phenyl)-N,2-dimethylpropanamido)-2-(4-methylpiperazin-1-yl)-4-(o-tolyl)pyridine 1-oxide (3 g, 5.05 mmol) and NaHCO3 (0.354 g, 12.66 mmol) in 60 mL of MeOH and 15 mL of H2O were added potassium monopersulfate triple salt (1.62 g, 26.25 mmol) at room temperature during 15 min. After stirring for 4 hrs at room temperature under N2 atmosphere, the reaction mixture was concentrated in vacuo and purified by flash chromatography (eluent: MeOH). The product was dissolved into DCM, the formed solid was filtered off, and the solution was concentrated under reduced pressure to afford 1.77 g 4-(5-(2-(3,5-bis(trifluoromethyl)phenyl)-N,2-dimethylpropanamido)-1-oxido-4-(o-tolyl)pyridin-2-yl)-1-methylpiperazine 1-oxide as a white solid (Yield: 57.4%). 1HNMR (CDCl3, 400 MHz) δ 8.06 (s, 1H), 7.78 (s, 1H), 7.60 (s, 2H), 7.37˜7.20 (m, 4H), 6.81 (s, 1H), 3.89 (s, 21H), 3.74 (m, 4H), 3.31 (m, 5H), 2.48 (s, 3H), 2.18 (s, 3H), 1.36 (s, 6H).
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([O:21][C:22]([F:25])([F:24])[F:23])[CH:5]=[C:6]2[C:11]=1[O:10][CH:9]([C:12]([F:15])([F:14])[F:13])[C:8]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:7]2.[C:26]1(B(O)O)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C([O-])(O)=O.[Na+]>C1(C)C=CC=CC=1.O.[Cl-].[Na+].O.CC([O-])=O.CC([O-])=O.[Pd+2].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.CCO>[C:26]1([C:2]2[CH:3]=[C:4]([O:21][C:22]([F:24])([F:23])[F:25])[CH:5]=[C:6]3[C:11]=2[O:10][CH:9]([C:12]([F:14])([F:15])[F:13])[C:8]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:7]3)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: OB(O)c1ccccc1
Reactant: CCOC(=O)C1=Cc2cc(OC(F)(F)F)cc(I)c2OC1C(F)(F)F
Agent: [Pd+2]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: O
Product: CCOC(=O)C1=Cc2cc(OC(F)(F)F)cc(-c3ccccc3)c2OC1C(F)(F)F
Temperature: 25 °C
Reaction time: 21 h

Procedure:
A mixture of ethyl 8-iodo-6-(trifluoromethoxy)-2-(trifluoromethyl)-2H-chromene-3-carboxylate prepared as in Example 21a, Step 2 (0.500 g, 1.04 mmole), phenylboronic acid (133 mg, 1.09 mmole), Pd(OAc)2 (7.00 mg, 0.031 mmole), triphenyl phosphine (24.4 mg, 0.093 mmole), and NaHCO3 (132 mg, 1.25 mmole) in toluene (25 mL) and H2O (5 mL) was stirred at room temperature for 21 hrs and was then refluxed for 1 h. Pd(PPh3)4 (120 mg, 0.104 mmole) was added and the mixture was refluxed for 1.5 hrs. LCMS indicated that the product was increased slightly. Additional Pd(PPh3)4 (120 mg, 0.104 mmole), NaHCO3 (132 mg, 1.25 mmole) and phenylboronic acid (133 mg, 1.09 mmole) and EtOH (10 mL) to above mixture and the mixture was refluxed overnight. After cooling, the mixture was then poured into brine (100 mL) and extracted with EtOAc (100 mL). The EtOAc layer was separated, dried over MgSO4 and filtered. The crude product was purified by silica chromatography (0-10% EtOAc—hexanes) to give 336 mg (85%, yield) of the product as an off-white solid: EIHRMS m/z 432.0807 (M+, C20H14F6O4, Calc'd 432.0796).
Reaction SMILES: [I:1][C:2]1[CH:14]=[N:13][C:5]2[NH:6][C:7]([CH3:12])([CH3:11])[C:8](=[O:10])[NH:9][C:4]=2[CH:3]=1.[F:15][C:16]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:17]=1[CH2:18]Br>>[F:15][C:16]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:17]=1[CH2:18][N:9]1[C:8](=[O:10])[C:7]([CH3:11])([CH3:12])[NH:6][C:5]2[N:13]=[CH:14][C:2]([I:1])=[CH:3][C:4]1=2
Reactant: Fc1ccc(F)c(CBr)c1
Reactant: CC1(C)Nc2ncc(I)cc2NC1=O
Product: CC1(C)Nc2ncc(I)cc2N(Cc2cc(F)ccc2F)C1=O
Yield: 98 %

Procedure:
7-Iodo-3,3-dimethyl-3,4-dihydro-1H-pyrido[2,3-b]pyrazin-2-one (237 mg) was reacted with 2,5-difluorobenzyl bromide as in General Procedure 1 to give the title compound as a white solid (98% yield). M.p. 198-201° C., LCMS: m/z=430.00 (M+H+), 1H-NMR (DMSO-d6, 400 MHz) δ 1.36 (s, 6H), 5.12 (s, 2H), 6.79-6.83 (m, 1H), 7.15-7.22 (m, 1H), 7.28-7.32 (m, 1H), 7.31 (s, 1H), 7.40 (s, 1H), 7.90 (s, 1H).
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH3:6][N:7]([CH3:49])[CH2:8][CH2:9][CH2:10][C:11]1(O)[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[CH2:15][O:14][C:13]2[CH:22]=[CH:23][C:24]([CH2:26][CH2:27][O:28][C:29]([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[CH:25][C:12]1=2>N1C=CC=CC=1>[CH3:49][N:7]([CH3:6])[CH2:8][CH2:9][CH:10]=[C:11]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[CH2:15][O:14][C:13]2[CH:22]=[CH:23][C:24]([CH2:26][CH2:27][O:28][C:29]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)([C:42]3[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=3)[C:36]3[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=3)=[CH:25][C:12]1=2
Reactant: CN(C)CCCC1(O)c2ccccc2COc2ccc(CCOC(c3ccccc3)(c3ccccc3)c3ccccc3)cc21
Solvent: O=P(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: CN(C)CCC=C1c2ccccc2COc2ccc(CCOC(c3ccccc3)(c3ccccc3)c3ccccc3)cc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 70.5 %

Procedure:
In this process, 1.2 g of 11-(3-dimethylaminopropyl)-11-hydroxy-2-(2-triphenylmethyloxyethyl)-6,11-dihydrodibenz[b,e]oxepin is dissolved in 50 ml of pyridine. To the solution is dropwise added 0.8 g of phosphorusoxychloride under a nitrogen atmosphere and ice-cooling. After stirring the mixture at room temperature for one hour, the solvent is distilled away under reduced pressure. The residue is extracted with 100 ml of methylene chloride, and washed with saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution in order. After drying the mixture over anhydrous sodium sulfate, the solvent is distilled away under reduced pressure. The resultant residue is purified by column chromatography on silica gel (eluent: hexane:ethylacetate:triethylamine=10:10:1 ) to obtain 0.82 g of the desired product as a colorless oily matter.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[CH:14][CH:15]=3)[N:10]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([OH:23])[CH:18]=3)[N:9]=2)=[CH:4][CH:3]=1.[CH2:24]([N:26]([CH2:31][CH3:32])[C:27](=[O:30])[CH2:28]Br)[CH3:25].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:24]([N:26]([CH2:31][CH3:32])[C:27](=[O:30])[CH2:28][O:23][C:19]1[CH:20]=[CH:21][CH:22]=[C:17]([N:10]2[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:16]3[C:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)=[N:9]2)[CH:18]=1)[CH3:25]
Reactant: Oc1cccc(-n2nc(-c3ccc(F)cc3)c3cccnc32)c1
Reactant: CCN(CC)C(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCN(CC)C(=O)COc1cccc(-n2nc(-c3ccc(F)cc3)c3cccnc32)c1
Temperature: 60 °C
Reaction time: 5 h
Yield: 40.9 %

Procedure:
In 75 ml of dimethylformamide were suspended 5.0 g of 3-(4-fluorophenyl)-1-(3-hydroxyphenyl)-1H-pyrazolo[3,4-b]pyridine, 3.5 g of N,N-diethylbromoacetamide and 2.5 g of potassium carbonate. The mixture was stirred at 60° C. for 5 hours. After the solvent was distilled off under reduced pressure, the residue was extracted with ethyl acetate-water. The organic layer was concentrated. Isopropyl ether was added to the residue for crystallization. The obtained crude crystals were recrystallized from ethyl acetate to give 2.8 g of N,N-diethyl-3-[3-(4-fluorophenyl)-1H-pyrazolo[3,4-b]pyridin-1yl]phenoxyacetamide, m.p. 102°-105° C.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[CH:4][C:3]=1[OH:9].[C:10](N1C=CN=C1)(N1C=CN=C1)=[O:11]>C1COCC1>[OH:9][C:3]1[C:2]2[NH:1][C:10](=[O:11])[NH:8][C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: Nc1cccc(O)c1N
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: O=c1[nH]c2cccc(O)c2[nH]1
Reaction time: 8 h
Yield: 53.3 %

Procedure:
A mixture of 2,3-diamino-phenol (50 mg; 0.4 mmol) and 1,1′-carbonyl-diimidazole (65 mg; 0.4 mmol) in THF (5 ml) was stirred overnight. The crude product was purified by chromatography and by washed with water, to give pure 4-hydroxy-1,3-dihydro-benzoimidazole-2-one (32 mg; 53%). 1H NMR (DMSO-d6): 10.42 and 10.31 (s each, 2H), 9.46 (s, 1H), 6.70 (t, J=8.0 Hz; 1H), 6.41 (dd, J=0.8, 8.2 Hz; 1H), 6.40 (d, J=8.0 Hz).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4]([NH2:11])[N:3]=1.[F:12][C@@H:13]1[C@H:17]([OH:18])[C@@H:16]([CH2:19][OH:20])[O:15][C@H:14]1N1C=CC(=O)NC1=O.[N-]=[N+]=[N-].[K+].[C@@H]1(N2C=C(C)C(=O)NC2=O)O[C@H](CO)[C@@H](O)C1>P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:14]2[O:15][C@H:16]([CH2:19][OH:20])[C@@H:17]([OH:18])[C@H:13]2[F:12])=[C:4]([NH2:11])[N:3]=1
Reactant: Nc1nc(N)c2[nH]cnc2n1
Reactant: O=c1ccn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2F)c(=O)[nH]1
Agent: Cc1cn([C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)[nH]c1=O
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Product: Nc1nc(N)c2ncn([C@@H]3O[C@H](CO)[C@@H](O)[C@H]3F)c2n1
Temperature: 37 °C
Yield: 94.9 %

Procedure:
2,6-Diaminopurine (Pacific Chemical Laboratories, 2.0 g, 12.7 mmoles) and 1-(2-deoxy-2-fluoro-β-D-ribofuranosyl)uracil (0.8 g; 3.3 mmoles) which may be prepared according to J. F. Codington et al., (J. Org. Chem. 29:558, 1964) were suspended to 500 ml of 5 mM potassium phosphate buffer, pH 7.0, which contained 0.04% (w/v) potassium azide. Thymidine phosphorylase (41,700 I.U.) and purine nucleoside phosphorylase (83,300 I.U.) (T. A. Krenitsky et al., Biochemistry 20:3615, 1981 and U.S. Pat. No. 4,381,344) which had been absorbed onto 10.5 g of DEAE-cellulose (25 ml) were added and the suspension shaken at 37° C. After 24 hours 2.0 g of 1,6-diaminopurine was added and the temperature increased to 50° C. After another 24 hours the reaction was filtered. The filter cake was washed with water and the filtrates combined and the solvent removed under vacuum. The residue was dissolved in hot water and the pH adjusted to pH 9.4 with NH4OH. The solution was applied to a 2.5×13 cm column of anion exchange resin (Bio-Rad AG1X2-hydroxide form). After washing the column with water, the product was eluted with methanol/water (9/1). Product containing fractions were combined and the solvent removed under vacuum. The residue was treated as above. Product containing fractions were combined and the solvent removed under vacuum. The residue was dissolved in water and lyophilization yielded 0.89 g of title compound that analyzed as a 0.5 hydrate.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][NH:10][C:11]([C:13]2[N:14]([CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([C:31]#[N:32])[CH:26]=3)[C:15]3[C:20]([CH:21]=2)=[C:19]([O:22][CH3:23])[CH:18]=[CH:17][CH:16]=3)=[O:12])=[CH:4][CH:3]=1.Cl.[NH2:34][OH:35].C(N(CC)CC)C>C(O)C>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][NH:10][C:11]([C:13]2[N:14]([CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([C:31](=[NH:32])[NH:34][OH:35])[CH:26]=3)[C:15]3[C:20]([CH:21]=2)=[C:19]([O:22][CH3:23])[CH:18]=[CH:17][CH:16]=3)=[O:12])=[CH:4][CH:3]=1
Reactant: COc1cccc2c1cc(C(=O)NCCc1ccc(O)cc1)n2Cc1cccc(C#N)c1
Reactant: NO
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: COc1cccc2c1cc(C(=O)NCCc1ccc(O)cc1)n2Cc1cccc(C(=N)NO)c1
Yield: 63 %

Procedure:
The starting material 1-(3-cyano-benzyl)-4-methoxy-1H-indole-2-carboxylic acid 2-(4-hydroxyphenyl)ethyl amide (example 25/1) was dissolved in ethanol and hydroxylamine hydrochloride and triethylamine were added. After reflux for 5 h the reaction mixture was concentrated in vacuo and partitioned between dichloromethane and water. The organic layer was separated, dried over magnesium sulfate, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel with dichloromethane/methanol 19:1 to give 63% of the desired product, which solidified under water. M.p. 173-175° C. (dec.). MS: 459.3 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([NH:13][C:14](=[O:18])OCC)=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH3:19])[CH:9]=2)[N:4]=1.[C:20]([C:23]1[CH:28]=[CH:27][C:26]([N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)=[CH:25][CH:24]=1)(=[O:22])[CH3:21]>>[CH3:1][O:2][C:3]1[C:12]([NH:13][C:14]([N:32]2[CH2:31][CH2:30][N:29]([C:26]3[CH:25]=[CH:24][C:23]([C:20](=[O:22])[CH3:21])=[CH:28][CH:27]=3)[CH2:34][CH2:33]2)=[O:18])=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH3:19])[CH:9]=2)[N:4]=1
Reactant: CC(=O)c1ccc(N2CCNCC2)cc1
Reactant: CCOC(=O)Nc1nc2cc(C)ccc2nc1OC
Product: COc1nc2ccc(C)cc2nc1NC(=O)N1CCN(c2ccc(C(C)=O)cc2)CC1
Yield: 87 %

Procedure:
Ethyl N-(2-methoxy-6-methylquinoxalin-3-yl)carbamate and 1-(4-acetylphenyl)piperazine were reacted by the same way with the example 43 to obtain the titled compound (yield, 87%). 1H NMR (300 MHz, CDCl3): δ 2.45-2.53 (m, 6H), 3.47 (s, 4H), 3.81 (s, 3H), 3.87-4.13 (m, 4H), 6.88 (d, J=8.7 Hz, 2H), 7.22-7.36 (m, 2H), 7.56-7.76 (m, 2H), 7.90 (d, J=8.7 Hz, 2H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[N:11]([CH2:29][CH:30]([CH3:32])[CH3:31])[C:12](=[O:28])[C:13]2[C:18]([C:19]=1[C:20]1[S:21][CH:22]=[CH:23][CH:24]=1)=[CH:17][C:16]([C:25]([OH:27])=O)=[CH:15][CH:14]=2)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.C([N:36]=C=NCCCN(C)C)C.[NH4+].ON1C2C=CC=CC=2N=N1.O>CN(C)C=O>[C:1]([O:5][C:6](=[O:7])[NH:8][CH2:9][C:10]1[N:11]([CH2:29][CH:30]([CH3:31])[CH3:32])[C:12](=[O:28])[C:13]2[C:18]([C:19]=1[C:20]1[S:21][CH:22]=[CH:23][CH:24]=1)=[CH:17][C:16]([C:25]([NH2:36])=[O:27])=[CH:15][CH:14]=2)([CH3:2])([CH3:4])[CH3:3]
Reactant: CC(C)Cn1c(CNC(=O)OC(C)(C)C)c(-c2cccs2)c2cc(C(=O)O)ccc2c1=O
Reactant: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Agent: [NH4+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)Cn1c(CNC(=O)OC(C)(C)C)c(-c2cccs2)c2cc(C(N)=O)ccc2c1=O
Yield: 94.6 %

Procedure:
A solution of 3-{[(tert-butoxycarbonyl)amino]methyl}-2-isobutyl-1-oxo-4-(2-thienyl)-1,2-dihydro-6-isoquinolinecarboxylic acid (0.59 g, 1.3 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.50 g, 2.6 mmol) and 1-hydroxybenzotriazole ammonium salt (0.40 g, 2.6 mmol) in N,N-dimethylformamide (10 ml) was stirred at room temperature for 2 h. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting crystals were recrystallized from tetrahydrofuran-diisopropyl ether to give tert-butyl[6-(aminocarbonyl)-2-isobutyl-1-oxo-4-(2-thienyl)-1,2-dihydro-3-isoquinolinyl]methylcarbamate (0.56 g, 94.9%) as crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[O:17][CH3:18])=[CH2:10].[C:19]1(C)C=CC=CC=1.C1(OC)C=CC=CC=1.COCCO[AlH2-]OCCOC.[Na+]>CCCCCC>[CH3:18][O:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[C:9]([C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[O:2][CH3:1])([CH3:19])[CH3:10]
Reactant: C=C(c1ccccc1OC)c1ccccc1OC
Reactant: Cc1ccccc1
Agent: COCCO[AlH2-]OCCOC
Agent: [Na+]
Solvent: CCCCCC
Solvent: COc1ccccc1
Product: COc1ccccc1C(C)(C)c1ccccc1OC

Procedure:
1,1-Bis(2-methoxyphenyl)ethene (15.6 g), toluene (35 ml) and anisole (35 ml) were combined in a flask and 35 ml of a 3.7M hexane solution of Red-Al was added. The mixture was heated to reflux with stirring whereupon it turned dark red. After 2 hours the heat was removed and the mixture was allowed to stir overnight. The excess hydride reagent was carefully quenched with 1.0N hydrochloric acid. The mixture was then diluted with ether and the ethereal solution separated, dried over magnesium sulfate, filtered, and concentrated by evaporation under reduced pressure to obtain a golden-brown oil. This was triturated with hexane to obtain 3.70 of the title compound. The proton and carbon NMR spectra were consistent with the assigned structure.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[C:7]1[CH:12]=[CH:11][C:10]([C:13]#[C:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[C:9](Cl)[CH:8]=1)([CH3:4])([CH3:3])[CH3:2].Cl.[NH:24]([C:26]1[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=1)[NH2:25].C([O-])([O-])=O.[Cs+].[Cs+]>>[C:1]([O:5][C:6]([C:7]1[CH:12]=[CH:11][C:10]2[C:9]([CH:8]=1)=[N:25][N:24]([C:26]1[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=1)[C:13]=2[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:22])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)c1ccc(C#Cc2ccccc2)c(Cl)c1
Reactant: NNc1ccncc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CC(C)(C)OC(=O)c1ccc2c(Cc3ccccc3)n(-c3ccncc3)nc2c1
Yield: 54.3 %

Procedure:
The reaction was performed according to example 1 using 156.4 mg 3-chloro-4-phenylethynyl-benzoic acid tert-butyl ester, 101.9 mg 4-hydrazinopyridine hydrochloride (1.4 equiv.) and 456.2 mg Cs2CO3 (2.8 equiv.) with a reaction time of 2 hours at 110° C. This afforded 104.7 mg (54%) of the title compound. 1H-NMR (DMSO-d6) δ 1.58 (s, 9H), 4.66 (s, 2H), 6.98 (d, 2H, J=7.4 Hz), 7.15-7.24 (m, 3H), 7.51 (dd, 1H, J=8.8, 1.3 Hz), 7.69-7.73 (m, 3H), 8.30 (s, 1H), 8.77 (dd, 2H, J=4.6, 1.6 Hz); HRMS (FAB): Calculated for C24H24N3O2 (M+H+) 386.1869, found 386.1864.
Reaction SMILES: [C:1]1([CH2:11][CH:12]2[N:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]3=[N:14][C:13]2=[S:21])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.Br[CH2:23][CH2:24][CH2:25][C:26]([O:28][CH3:29])=[O:27].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.ClCCl>[CH3:29][O:28][C:26](=[O:27])[CH2:25][CH2:24][CH2:23][S:21][CH:13]1[CH:12]([CH2:11][C:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:4]=[CH:3][CH:2]=2)[N:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]2=[N:14]1
Reactant: S=C1N=C2C=CC=CN2C1Cc1cccc2ccccc12
Reactant: COC(=O)CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: ClCCl
Product: COC(=O)CCCSC1N=C2C=CC=CN2C1Cc1cccc2ccccc12
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 75 mg (0.26 mmol) of 3-naphthalen-1-ylmethyl-imidazo[1,2-a]pyridine-2-thione and 70 mg (0.39 mmol) of methyl 4-bromobutyrate and 72 mg (0.52 mmol) of potassium carbonate in 3 mL of 50% acetone in dichloromethane is stirred at room temperature for 18 h. The mixture is concentrated in vacuo and the residue is purified by flash chromatography on silica gel eluting with 50˜75% ethyl acetate in hexanes to give the desired compound.
Reaction SMILES: [C:1]1([CH3:21])[CH:6]=[CH:5][C:4]([S:7]([NH:10][C@H:11]([C:17](OC)=[O:18])[CH2:12][C:13](OC)=[O:14])(=[O:9])=[O:8])=[CH:3][CH:2]=1.[BH4-].[Na+].[Li+].[Cl-].Cl>O1CCCC1>[C:1]1([CH3:21])[CH:2]=[CH:3][C:4]([S:7]([NH:10][C@@H:11]([CH2:12][CH2:13][OH:14])[CH2:17][OH:18])(=[O:9])=[O:8])=[CH:5][CH:6]=1
Reactant: COC(=O)C[C@H](NS(=O)(=O)c1ccc(C)cc1)C(=O)OC
Agent: Cl
Agent: [BH4-]
Agent: [Cl-]
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)N[C@H](CO)CCO)cc1
Temperature: 0 °C
Reaction time: 62 h

Procedure:
Dimethyl N-(p-toluenesulfonyl)-L-aspartate, (2.0 g; J. M. Theobald, M. W. Williams, G. T. Young, J. Chem. Soc., 1927 (1963)) was dissolved in tetrahydrofuran (20 mL) and NaBH4 (1.5 g) and LiCl (1.5 g) added and the mixture stirred at 0° C. for 60 to 64 hours. Ten percent hydrochloric acid (10 mL) was slowly added (caution!gas evolution) and the mixture extracted with ethyl acetate (3×20 mL). The combined organic extracts were concentrated and the residue dried under vacuum to give (S)-2-(p-toluene-sulfonylamino)-1,4-butanediol, 2, as an off-white solid (1.95 g; HPLC: 97.7%).
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][C:3]=1[CH:4]=[O:5].[CH2:14]([O:16][C:17](=[O:36])[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21](B2OC(C)(C)C(C)(C)O2)[CH:20]=1)[CH3:15]>>[CH2:14]([O:16][C:17](=[O:36])[CH2:18][C:19]1[CH:20]=[C:21]([C:2]2[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][C:3]=2[CH:4]=[O:5])[C:22]([O:25][CH3:26])=[CH:23][CH:24]=1)[CH3:15]
Reactant: CCOC(=O)Cc1ccc(OC)c(B2OC(C)(C)C(C)(C)O2)c1
Reactant: O=Cc1cc(C(F)(F)F)ccc1Br
Product: CCOC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2C=O)c1

Procedure:
Prepared according to the procedure described in Example 1, Step 4, using the following starting materials: 2-bromo-5-(trifluoromethyl)benzaldehyde and [4-methoxy-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-acetic acid ethyl ester.
Reaction SMILES: [CH3:1][C@H:2]1[C@:14]23[CH:17]=[C:18]([CH3:21])[C@H:19]([OH:20])[C@@:13]2([OH:22])[C@H:12]([OH:23])[C:11]([CH2:24][OH:25])=[CH:10][C@H:9]([C:15]3=[O:16])[C@@H:5]2[C:6]([CH3:8])([CH3:7])[C@@H:4]2[CH2:3]1.O.[C:27]1(C)[CH:32]=CC(S(O)(=O)=O)=C[CH:28]=1>CC(C)=O>[CH3:1][C@H:2]1[C:14]23[CH:17]=[C:18]([CH3:21])[C@H:19]([OH:20])[C@@:13]2([OH:22])[C@H:12]2[C:11]([CH2:24][O:25][C:27]([CH3:32])([CH3:28])[O:23]2)=[CH:10][CH:9]([C:15]3=[O:16])[CH:5]2[C:6]([CH3:8])([CH3:7])[CH:4]2[CH2:3]1
Reactant: CC1=C[C@]23C(=O)[C@@H](C=C(CO)[C@@H](O)[C@]2(O)[C@H]1O)[C@H]1[C@@H](C[C@H]3C)C1(C)C
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)=O
Solvent: O
Product: CC1=CC23C(=O)C(C=C4COC(C)(C)O[C@H]4[C@]2(O)[C@H]1O)C1C(C[C@H]3C)C1(C)C

Procedure:
Ingenol is reacted with p-toluenesulphonic acid hydrate and acetone to give ingenol-5,20-acetonide according to the procedure of Opferkuch et al. (1981). Ingenol-5,20-acetonide is converted to the ingenol 3-acylate by treatment with the appropriate acyl chloride and 4-(N,N-dimethylamino)pyridine or pyridine in toluene or benzene, or treatment with the appropriate acid, an alkylpyridinium salt and tributylamine in toluene then treatment with methanolic perchloric acid according to the procedure of Sorg et al. (1982). The ingenol 3-acylate could be converted to the 20-chloro-20-deoxyingenol 3-acylate 5-benzoate by the method of Example 15.