Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ClCC1C=CC(O[CH2:10][O:11][CH2:12][CH2:13][Si:14]([CH3:17])([CH3:16])[CH3:15])=CC=1.O[C:19]1[CH:28]=[CH:27][C:22]([C:23]([O:25][CH3:26])=[O:24])=[CH:21][CH:20]=1>>[CH3:15][Si:14]([CH3:17])([CH3:16])[CH2:13][CH2:12][O:11][CH2:10][C:19]1[CH:28]=[CH:27][C:22]([C:23]([O:25][CH3:26])=[O:24])=[CH:21][CH:20]=1
Reactant: C[Si](C)(C)CCOCOc1ccc(CCl)cc1
Reactant: COC(=O)c1ccc(O)cc1
Product: COC(=O)c1ccc(COCC[Si](C)(C)C)cc1

Procedure:
The 1-chloromethyl-4-(2-trimethylsilanyl-ethoxymethoxy)-benzene used at the alkylating agent was prepared in analogy to Example 5 (a)--(c) from methyl 4-hydroxybenzoate by introducing the SEM group to give methyl 4-(2-trimethylsilanylethoxymethyl)-benzoate. Subsequent reduction with lithium aluminium hydride gave [4-(2-trimethylsilanylethoxy-methoxy)-phenyl]-methanol and chlorination of this gave 1-chlormethyl-4-(2-trimethylsilanyl-ethoxymethoxy)-benzene as a colourless oil; MS:272 (M)+.
Reaction SMILES: FC(F)(F)C(O)=O.C(OC(=O)[NH:14][C@@H:15]1[C:23]2[C:18](=[CH:19][CH:20]=[C:21]([N:24]=[C:25]([NH:27][CH2:28][CH2:29][C:30]3[CH:35]=[CH:34][C:33]([F:36])=[C:32]([F:37])[CH:31]=3)[CH3:26])[CH:22]=2)[CH2:17][C@H:16]1[OH:38])(C)(C)C.O=C1CCC(=O)N1O[C:48]([C:50]1[CH:55]=[CH:54][C:53]([C:56]2[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=2)=[CH:52][C:51]=1[F:62])=[O:49].C(N(CC)CC)C>C(Cl)Cl>[F:37][C:32]1[CH:31]=[C:30]([CH:35]=[CH:34][C:33]=1[F:36])[CH2:29][CH2:28][NH:27][C:25](=[N:24][C:21]1[CH:22]=[C:23]2[C:18]([CH2:17][C@@H:16]([OH:38])[C@@H:15]2[NH:14][C:48]([C:50]2[CH:55]=[CH:54][C:53]([C:56]3[CH:57]=[CH:58][CH:59]=[CH:60][CH:61]=3)=[CH:52][C:51]=2[F:62])=[O:49])=[CH:19][CH:20]=1)[CH3:26]
Reactant: CC(=Nc1ccc2c(c1)[C@@H](NC(=O)OC(C)(C)C)[C@H](O)C2)NCCc1ccc(F)c(F)c1
Reactant: O=C(ON1C(=O)CCC1=O)c1ccc(-c2ccccc2)cc1F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Product: CC(=Nc1ccc2c(c1)[C@@H](NC(=O)c1ccc(-c3ccccc3)cc1F)[C@H](O)C2)NCCc1ccc(F)c(F)c1
Reaction time: 0.5 h
Yield: 1.6 %

Procedure:
Add 5 mL of trifluoroacetic acid to (R)-(6-(1-((3,4-difluorobenzyl)methylamino)ethylideneamino)-2(R)-hydroxyindan-1-yl)carbamic acid tert-butyl ester (180 mg, 4.04 mmol) and stir for 30 minutes. Remove solvent under reduced pressure. Dissolve the residue in 15 mL of CH2Cl2. Then add 3-fluorobiphenyl-4-carboxylic acid 2,5-dioxopyrrolidin-1-yl ester (150 mg, 4.79 mmol) and triethylamine (0.6 mL, 4.0 mmol) to the solution and stir for 12 hours. Pour the mixture into methylene chloride, wash with water, dry with Na2SO4, and then concentrate. Purify the residue by column chromatography (silica gel, 3% MeOH in CH2Cl2) to give 35 mg of the title compound as a white solid in 16% yield: 1H NMR (CD3OD) δ 7.88 (2H, t, J=8.0 Hz), 7.7 (2H, d, J=8.4 Hz), 7.60 (2H, dd, J=8.0, 1.2 Hz), 7.47-7.55 (3H, m), 7.43-7.47 (1H, m), 7.21-7.32 (2H, m), 7.18 (1H, d, J=8.0 Hz), 7.11-7.14 (1H, m), 6.71 (2H, dd, J=10.0, 1.2 Hz), 5.47 (1H, d, J=6.8 Hz), 4.69 (2H, s), 4.54 (1H, q, J=7.2 Hz), 4.54 (1H, q, J=6.4 Hz), 3.29 (1H, q, J=7.2 Hz), 3.07 (3H, s), 2.88 (1H, q, J=7.8 Hz), 1.99 (3H, s); MS 544 (MH+).
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=3)([C:14]3[S:15][CH:16]=[CH:17][N:18]=3)O)[CH:10]=2)[N:5]=[C:4]([O:26]C(C)(C)C)[CH:3]=1.Cl.Cl[Sn]Cl.O>CC(O)=O>[Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH:12]([C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=3)[C:14]3[S:15][CH:16]=[CH:17][N:18]=3)[CH:10]=2)[N:5]=[C:4]([OH:26])[CH:3]=1
Reactant: CC(C)(C)Oc1cc(Br)c2cc(C(O)(c3ccc(Cl)cc3)c3nccs3)ccc2n1
Agent: Cl
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CC(=O)O
Product: Oc1cc(Br)c2cc(C(c3ccc(Cl)cc3)c3nccs3)ccc2n1
Temperature: 100 °C
Reaction time: 0.67 h

Procedure:
Into a 250-mL round-bottom flask, was placed [4-bromo-2-(tert-butoxy)quinolin-6-yl](4-chlorophenyl)1,3-thiazol-2-ylmethanol (5.5 g, 10.92 mmol, 1.00 equip), AcOH (78 mL), hydrogen chloride (13 mL), and SnCl2.2 H2O (7.4 g, 32.80 mmol, 3.00 equip). The resulting solution was stirred for 40 min at 100° C. The resulting mixture was concentrated under vacuum. The resulting solution was diluted with water (200 mL). The resulting solution was extracted with DCM (3×200 mL) and the organic layers combined. The resulting mixture was washed with water (2×200 mL). The resulting mixture was dried over anhydrous sodium sulfate. The residue was applied onto a silica gel column with dichloromethane:methanol (10:1) to yield 4-bromo-6-[(4-chlorophenyl)(1,3-thiazol-2-yl)methyl]quinolin-2-ol as a white solid. (ES, m/z): [M+N]+ 433
Reaction SMILES: CC(C)([O-])C.[K+].[OH:7][CH2:8][C@H:9]([C@@H:11]1[C@:28]2([CH3:29])[C@H:14]([C@H:15]3[C@H:25]([CH2:26][CH2:27]2)[C@:23]2([CH3:24])[C:18](=[CH:19][C:20](=[O:30])[CH2:21][CH2:22]2)[CH2:17][CH2:16]3)[CH2:13][CH2:12]1)[CH3:10].C(C(CCCC)C[O:35][N+:36]([O-])=[O:37])C>C(O)(C)(C)C>[OH:7][CH2:8][C@H:9]([C@@H:11]1[C@:28]2([CH3:29])[C@H:14]([C@H:15]3[C@H:25]([CH2:26][CH2:27]2)[C@:23]2([CH3:24])[C:18](=[C:19]([N+:36]([O-:37])=[O:35])[C:20](=[O:30])[CH2:21][CH2:22]2)[CH2:17][CH2:16]3)[CH2:13][CH2:12]1)[CH3:10]
Reactant: C[C@H](CO)[C@H]1CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Reactant: CCCCC(CC)CO[N+](=O)[O-]
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Product: C[C@H](CO)[C@H]1CC[C@H]2[C@@H]3CCC4=C([N+](=O)[O-])C(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Potasium tert-butoxide (7.6 g, 67.8 mM) and (20S)-20-hydroxymethylpregn-4-en-3-one (6.6 g, 20 mM) are combined in tert-butanol and heated at reflux temperature for 120 minutes. 2-ethylhexylnitrate (3.56 ml, 20 mM) is then added in one continuous portion. After 10 minutes, the reaction vessel is cooled to room temperature. The reaction is then quenched with acetic acid (9 ml) and stirred overnight. After diluting with dichloromethane (200 mL), the solids are removed, washed, and combined with the washing residue and subsequently purified as described in Example 1 to give crystallized (20S)-20-hydroxymethyl-4-nitropregn-4-en-3-one.
Reaction SMILES: [Br:1][C:2]1[C:3]([F:14])=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7](C(=O)C)[N:6]=[CH:5]2>Cl.CO>[Br:1][C:2]1[C:3]([F:14])=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[CH:5]2
Reactant: CC(=O)n1ncc2c(F)c(Br)ccc21
Agent: Cl
Solvent: CO
Product: Fc1c(Br)ccc2[nH]ncc12

Procedure:
A suspension of 1-(5-Bromo-4-fluoroindazol-1-yl)ethanone (13 mmol) in 10% HCl (40 mL) and methanol (10 mL) was heated at reflux until clear (ca. 1 h). The hot solution was filtered, cooled and pH was neutralized by the addition of NaOH solution (3N). The resultant white precipitate was collected via filtration and the solid was dried in vacuum to give 5-bromo-4-fluoro-1H-indazole.
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([CH3:7])=[C:4]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([O:15]C)=[CH:11][CH:10]=2)[CH:3]=1.B(Br)(Br)Br.Cl>C(Cl)Cl>[Br:1][C:2]1[S:6][C:5]([CH3:7])=[C:4]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)[CH:3]=1
Reactant: COc1ccc(Cc2cc(Br)sc2C)cc1
Agent: BrB(Br)Br
Agent: Cl
Solvent: ClCCl
Product: Cc1sc(Br)cc1Cc1ccc(O)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 61.1 %

Procedure:
To a solution of bromide 10 (9.7 g, 32.6 mmol) in CH2Cl2 (100 mL) was added boron tribromide (40 mL, 39.2 mmol, 1M in CH2Cl2) dropwise at 0° C. The mixture was warmed up to room temperature slowly and stirred at room temperature for 3 hours. To the mixture was added aq. 1N HCl solution (200 mL) dropwise at 0° C. The mixture was extracted with CH2Cl2 (150 mL×2). The combined organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by silica column chromatography (Biotage) to provide the desired product 12 (5.64 g, 61%).
Reaction SMILES: [Cl:1][CH2:2][C:3](=[O:8])[CH2:4][C:5](Cl)=[O:6].[C:9]1([CH3:17])[CH:14]=[C:13]([CH3:15])[CH:12]=[C:11]([CH3:16])[CH:10]=1>FC(F)(F)S([O-])(=O)=O.[Sc+3].FC(F)(F)S([O-])(=O)=O.FC(F)(F)S([O-])(=O)=O.O>[Cl:1][CH2:2][C:3](=[O:8])[CH2:4][C:5]([C:10]1[C:11]([CH3:16])=[CH:12][C:13]([CH3:15])=[CH:14][C:9]=1[CH3:17])=[O:6]
Reactant: O=C(Cl)CC(=O)CCl
Reactant: Cc1cc(C)cc(C)c1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Sc+3]
Solvent: O
Product: Cc1cc(C)c(C(=O)CC(=O)CCl)c(C)c1
Temperature: 24 °C
Reaction time: 48 h

Procedure:
4-Chloroacetoacetyl chloride (35% strength solution in dichloromethane, 26.2 g, 59 mmol), mesitylene (7.4 g, 59 mmol, and scandium trifluoro-methanesulphonate (2.6 g, 5.1 mmol) were introduced at 20° C. The reaction mixture was then stirred at 24° C. for a total of 2 days. It was then hydrolysed with water (10 ml). The organic phase was concentrated, and the residue was dried in a high vacuum. 9.1 g of crude product were obtained.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:12]([Cl:23])=[CH:11][C:10]=1[C:24]1[O:28][N:27]=[C:26]([C:29]([O:31]CC)=[O:30])[CH:25]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO.[Li+].[OH-]>O>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:12]([Cl:23])=[CH:11][C:10]=1[C:24]1[O:28][N:27]=[C:26]([C:29]([OH:31])=[O:30])[CH:25]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1cc(-c2cc(Cl)c(OCc3ccccc3)cc2OCc2ccccc2)on1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1cc(-c2cc(Cl)c(OCc3ccccc3)cc2OCc2ccccc2)on1
Reaction time: 24 h

Procedure:
A mixture of ethyl 5-(2,4-bis(benzyloxy)-5-chlorophenyl)isoxazole-3-carboxylate (200 mg, 0.43 mmol), methanol (10 ml), water (6-7 ml), and LiOH (16 mg, 0.65 mmol) was allowed to stand at 50-60° C. for 24 h. The solution was concentrated under vacuo to remove methanol, and the remaining aqueous solution was extracted with Et2O to remove traces of unreacted starting material. The aqueous solution was acidified with 1 M HCl and extracted with three portions of AcOEt. The combined organic extracts were washed with saturated aqueous sodium chloride and dried over sodium sulfate. Removal of the solvent under reduced pressure afforded a residue, which was chromatographed on silica gel (DCM/methanol: 9/1).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C@H:9]([CH:14]2[CH2:17][N:16]([C@@H:18]([C:27]3[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=3)[C:19]3[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=3)[C:22]#[N:23])[CH2:15]2)[C:10]([F:13])([CH3:12])[CH3:11])[CH:5]=[C:6]([F:8])[CH:7]=1.[CH3:34][N:35](C=O)C>[C-]#N.[C-]#N.[Zn+2].C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[Cl:33][C:30]1[CH:29]=[CH:28][C:27]([C@@H:18]([C:19]2[CH:26]=[CH:25][CH:24]=[C:21]([C:22]#[N:23])[CH:20]=2)[N:16]2[CH2:17][CH:14]([C@@H:9]([C:4]3[CH:3]=[C:2]([CH:7]=[C:6]([F:8])[CH:5]=3)[C:34]#[N:35])[C:10]([F:13])([CH3:11])[CH3:12])[CH2:15]2)=[CH:32][CH:31]=1
Reactant: CC(C)(F)[C@H](c1cc(F)cc(Br)c1)C1CN([C@@H](c2ccc(Cl)cc2)c2cccc(C#N)c2)C1
Reactant: CN(C)C=O
Agent: [Fe+2]
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: CC(C)(F)[C@H](c1cc(F)cc(C#N)c1)C1CN([C@@H](c2ccc(Cl)cc2)c2cccc(C#N)c2)C1
Temperature: 140 °C

Procedure:
A suspension of 143 mg (0.27 mmole) of 3-[(S)-{3-[(1S)-1-(3-bromo-5-fluorophenyl)-2-fluoro-2-methylpropyl]azetidin-1-yl}(4-chlorophenyl)methyl]benzonitrile, 0.026 mg (0.216 mmole) of Zn(CN)2, 5 mg (0.005 mmole) of tris(dibenzylideneacetone)dipalladium(0) and 8 mg (0.014 mmole) of 1,1′-Bis(diphenylphosphino)ferrocene in 2.5 mL of dry DMF was degassed for 1 h at rt. Then the solution was heated at 140° C. for 17 h. The solution was concentrated under high vacuum and then was partitioned between 20 mL ether, 20 mL ethyl acetate and 10 mL water. The layers were separated and the aqueous layer was washed with two 20 mL portions of 1:1 ether-ethyl acetate. The combined organic layers were dried over Na2SO4 and concentrated. The residue was purified by preparatory TLC using 20% ethyl acetate-hexane to afford the title compound; Mass Spectrum: m/e=476 (M+1, 35Cl), 478 (M+1, 37Cl).
Reaction SMILES: C(O[C:4](=O)[NH:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH:7]1[OH:12])C.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[CH3:4][NH:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH:7]1[OH:12]
Reactant: CCOC(=O)NC1CCCCC1O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CNC1CCCCC1O
Temperature: 65 °C
Yield: 83.7 %

Procedure:
To a solution of (2-hydroxy-cyclohexyl)-carbamic acid ethyl ester (2.06 g, 11.0 mmol, 1.0 eq.) in THF (80 mL) was added LiAlH4 (1.09 g, 28.7 mmol, 2.6 eq.) and the resulting mixture was heated at 65° C. for 2 h. The reaction mixture was cooled to 0° C., quenched with water, and the separated aqueous phase was extracted with 3×EtOAc. The combined organic phase was dried over MgSO4, filtered and concentrated to give 2-methylamino-cyclohexanol (1.19 g, 84%).
Reaction SMILES: [CH2:1]([O:8][NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[I-].[Na+].[H-].[Na+].Cl[CH:22]([CH3:27])[CH2:23][CH2:24][C:25]#[N:26]>CN(C)C=O>[CH2:1]([O:8][N:9]([CH2:27][CH2:22][CH2:23][CH2:24][C:25]#[N:26])[C:10](=[O:16])[O:11][C:12]([CH3:13])([CH3:15])[CH3:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)NOCc1ccccc1
Reactant: CC(Cl)CCC#N
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N(CCCCC#N)OCc1ccccc1
Temperature: 85 °C
Reaction time: 3.5 h

Procedure:
To a solution of tert-butyl benzyloxycarbamate in anhydrous dimethylformamide were added 5 mol % of sodium iodide and portionwise 1.36 eq. of sodium hydride (60% dispersion in mineral oil). The mixture was stirred at room temperature for 15 min. before 1.05 eq. of 4-chlorovaleronitrile were added. The mixture was heated to 85° C. and stirred for 3.5 h. After cooling to room temperature the mixture was quenched with water and extracted with diethyl ether. The combined organic phases were concentrated and washed with half saturated aq. sodium thiosulfate, water and brine. The organic phase was dried over sodium sulfate, filtered and concentrated under reduced pressure. The oily residue was washed with petroleum ether and dried under high vacuum to yield Tert-butyl benzyloxy(4-cyanobutyl)carbamate as a light yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:10](/[CH:11]=[C:12]3\[O:13][C:14]4[C:21]([CH2:22][N:23]5[CH2:28][CH2:27][N:26](C(OC(C)(C)C)=O)[CH2:25][CH2:24]5)=[C:20]([OH:36])[CH:19]=[CH:18][C:15]=4[C:16]\3=[O:17])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[ClH:37]>C(Cl)Cl.O1CCOCC1>[ClH:37].[ClH:37].[ClH:37].[Br:1][C:2]1[CH:3]=[C:4]2[C:10](/[CH:11]=[C:12]3\[O:13][C:14]4[C:21]([CH2:22][N:23]5[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]5)=[C:20]([OH:36])[CH:19]=[CH:18][C:15]=4[C:16]\3=[O:17])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2c(O)ccc3c2O/C(=C\c2c[nH]c4ncc(Br)cc24)C3=O)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: O=C1/C(=C/c2c[nH]c3ncc(Br)cc23)Oc2c1ccc(O)c2CN1CCNCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 78 %

Procedure:
A solution of tert-butyl (Z)-4-({2-[(5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-6-hydroxy-3-oxo-2,3-dihydrobenzofuran-7-yl}methyl)piperazine-1-carboxylate (0.018 g, 0.032 mmol) in methylene chloride (2.0 mL) was added with a 4 M solution of hydrogen chloride in 1,4-dioxane (2.0 mL), and then the mixture was stirred at room temperature for 2 hours. The mixture was azeotroped twice with toluene under reduced pressure, and then the residual solid was suspended in a mixed solvent of methylene chloride and diethyl ether and thereby washed to obtain (Z)-2-[(5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-6-hydroxy-7-(piperazin-1-ylmethyl)benzofuran-3(2H)-one trihydrochloride (0.014 g, 78%).
Reaction SMILES: CC[C@@]1(O)C(=O)[O:7]CC2C(N3C(=CC1=2)C1N=C2C(C=CC=C2)=CC=1C3)=O.[CH2:27]1[CH2:32][CH2:31][CH:30]([N:33]=[C:34]=[N:35][CH:36]2[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]2)[CH2:29][CH2:28]1>CN(C1C=CN=CC=1)C.CN(C=O)C>[CH:36]1([NH:35][C:34](=[O:7])[NH:33][CH:30]2[CH2:29][CH2:28][CH2:27][CH2:32][CH2:31]2)[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: CC[C@@]1(O)C(=O)OCc2c1cc1n(c2=O)Cc2cc3ccccc3nc2-1
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Product: O=C(NC1CCCCC1)NC1CCCCC1
Temperature: 25 °C
Reaction time: 84 h

Procedure:
The preparation is preferably carried out in the following way: The starting camptothecin compound, preferably 2 to 10 molar equivalent of the reacting aromatic acid of the general formula C6R2-6COOH, preferably 2 to 8 molar equivalent of DCC, and a catalytic amount of DMAP are added to about 60-100 ml DMF in a 250 ml round-bottomed flask equipped with a mechanical stirrer. The mixture is stirred at room temperature under nitrogen gas for 72-96 hr. Dicyclohexyl urea formed is removed by filtration. The filtrate is poured onto 500-800 ml ice water while stirring. The crude product is collected by filtration, air-dried at room temperature, then separated by column chromatography with THF-C2H2 (from 1:7 to 1:15) as eluent. The pure ester prodrug is obtained as white or yellow powders after precipitation from petroleum ether. Reaction yields can range from 5 to 98%.
Reaction SMILES: [P:1]([O-:6])([O:4][CH3:5])[O:2][CH3:3].C(N(CC)CC)C.[CH:14](/[C:22]1[C:30]2[C:25](=[CH:26][CH:27]=[C:28](OS(C(F)(F)F)(=O)=O)[CH:29]=2)[NH:24][N:23]=1)=[CH:15]\[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CN(C)C=O.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>[CH3:3][O:2][P:1]([C:28]1[CH:29]=[C:30]2[C:25](=[CH:26][CH:27]=1)[NH:24][N:23]=[C:22]2/[CH:14]=[CH:15]/[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)(=[O:6])[O:4][CH3:5]
Reactant: O=S(=O)(Oc1ccc2[nH]nc(/C=C/c3ccccc3)c2c1)C(F)(F)F
Reactant: COP([O-])OC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COP(=O)(OC)c1ccc2[nH]nc(/C=C/c3ccccc3)c2c1
Temperature: 85 °C
Yield: 6.4 %

Procedure:
40.7 μl (1.09 eq; 0.444 mmol) of dimethyl phosphite, 61.9 μl (1.09 eq; 0.444 mmol) of triethylamine and 18.8 mg (0.04 eq; 0.016 mmol) of tetrakis(triphenylphosphine)palladium(0) are stirred under an argon atmosphere for 15 minutes. 150 mg (1 eq; 0.407 mmol) of trifluoromethanesulfonic acid 3-((E)-styryl)-1H-indazol-5-yl ester in solution in 5 ml of dimethylformamide are added. The medium is heated at 85° C. overnight. 41 μl of dimethylphosphite, 62 μl of triethylamine and 20 mg of tetrakis(triphenylphosphine)palladium(0) are added to the medium, which is heated for a further two hours. 100 μl of dimethylphosphite, 100 μl of triethylamine and 30 mg of tetrakis(triphenylphosphine)palladium(0) are then added to the medium, which is heated overnight at 105° C. After filtration of the catalyst through filter paper, the solvent is evaporated off under reduced pressure in a rotary evaporator. The reaction crude is purified by LC/MS to obtain 8.6 mg of [3-((E)-styryl)-1H-indazol-5-yl]phosphonic acid dimethyl ester, along with 27.2 mg of [3-((E)-styryl)-1H-indazol-5-yl]phosphonic acid monomethyl ester (Example 13).
Reaction SMILES: [OH:1][C:2]1[CH:26]=[CH:25][C:5]([O:6][C:7]2[CH:8]=[CH:9][C:10]([N+:22]([O-])=O)=[C:11]([N:13]([CH3:21])[C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH:12]=2)=[C:4]([CH3:27])[C:3]=1[CH3:28]>[Pd].CO>[NH2:22][C:10]1[CH:9]=[CH:8][C:7]([O:6][C:5]2[CH:25]=[CH:26][C:2]([OH:1])=[C:3]([CH3:28])[C:4]=2[CH3:27])=[CH:12][C:11]=1[N:13]([CH3:21])[C:14](=[O:20])[O:15][C:16]([CH3:17])([CH3:18])[CH3:19]
Reactant: Cc1c(O)ccc(Oc2ccc([N+](=O)[O-])c(N(C)C(=O)OC(C)(C)C)c2)c1C
Agent: [Pd]
Solvent: CO
Product: Cc1c(O)ccc(Oc2ccc(N)c(N(C)C(=O)OC(C)(C)C)c2)c1C
Yield: 91.8 %

Procedure:
In a similar manner to that described in Reference Example 7, a reaction was carried out using t-butyl N-[5-(4-hydroxy-2,3-dimethylphenoxy)-2-nitrophenyl]-N-methylcarbamate (1.90 g), palladium on carbon (10%, 0.20 g) and methanol (20 ml) and the reaction mixture was purified to give the title compound (1.61 g).
Reaction SMILES: C([O:4][C:5]1[CH:6]=[CH:7][C:8]([N+:18]([O-:20])=[O:19])=[C:9]([CH:17]=1)[C:10]([N:12]=[S:13]([CH3:16])([CH3:15])=[O:14])=[O:11])(=O)C.[OH-].[Na+].Cl>CO>[OH:4][C:5]1[CH:6]=[CH:7][C:8]([N+:18]([O-:20])=[O:19])=[C:9]([CH:17]=1)[C:10]([N:12]=[S:13]([CH3:16])([CH3:15])=[O:14])=[O:11]
Reactant: CC(=O)Oc1ccc([N+](=O)[O-])c(C(=O)N=S(C)(C)=O)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CS(C)(=O)=NC(=O)c1cc(O)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A solution of 30.0 g of N-(5-acetoxy-2-nitrobenzoyl)-S,S-dimethyl-sulphoximine in 500 ml of methanol is treated with 150 ml of 2N sodium hydroxide and the mixture is stirred at room temperature for 20 minutes. The resulting solution is then adjusted to about pH 4 with 100 ml of 2N hydrochloric acid and the methanol is distilled off under reduced pressure. The residue is saturated with sodium chloride solution and extracted with ethyl acetate, and the organic phase is dried and evaporated. The crystalline residue is then recrystallized from hot ethyl acetate. There is obtained N-(5-hydroxy-2-nitrobenzoyl)-S,S-dimethyl-sulphoximine as yellow crystals, m.p. 146°-149° C.; 1H-NMR (CMSO): 7.90 (d,1H), 6.95 (d,1H), 6.90 (q,1H), 3.44 (s,6H).
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([Cl:11])[N:3]=1.[Cl:12][C:13]1[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=1B(O)O.C([O-])([O-])=O.[Na+].[Na+]>C1COCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:12][C:13]1[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=1[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([Cl:11])[N:3]=1
Reactant: OB(O)c1ccc(Cl)cc1Cl
Reactant: O=[N+]([O-])c1ccc(Cl)nc1Cl
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(Cl)nc1-c1ccc(Cl)cc1Cl
Temperature: 25 °C

Procedure:
1 mmol 2,6-dichloro-3-nitropyridine, 1.05 mmol of 2,4-dichlorobenzeneboronic acid, and 3 mmol of Na2CO3, were dissolved in 1.5 ml THF and 0.5 ml water and purged with nitrogen. 0.05 mmol of [1,1′-Bis(diphenylphosphino)ferrocene]dichloro-palladium(II) was added to reaction and stirred at room temperature under nitrogen for fourteen hours. The reaction mixture was concentrated in vacuo and diluted with water and ethyl acetate. The solution was extracted three times with ethyl acetate, dried over sodium sulfate, and purified by column chromatography eluting with 10% ethylacetate 90% hexanes to obtain 2-(2,4-dichlorophenyl)-6-chloro-3-nitropyridine.
Reaction SMILES: [ClH:1].[NH:2]([C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]3[N:21]=[CH:20][NH:19][C:17]3=2)[N:12]=[C:11]([CH3:22])[CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH2:23]([N:25](CC)[C:26]1C=CC(N)=C[CH:27]=1)[CH3:24]>C(O)C>[ClH:1].[CH2:23]([N:25]([CH2:26][CH3:27])[C:6]1[CH:7]=[CH:8][C:3]([NH:2][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]4[N:21]=[CH:20][NH:19][C:17]4=3)[N:12]=[C:11]([CH3:22])[CH:10]=2)=[CH:4][CH:5]=1)[CH3:24]
Reactant: CCN(CC)c1ccc(N)cc1
Reactant: Cc1cc(Nc2ccccc2)c2c(ccc3nc[nH]c32)n1
Agent: Cl
Solvent: CCO
Product: CCN(CC)c1ccc(Nc2cc(C)nc3ccc4nc[nH]c4c23)cc1

Procedure:
A mixture of 26.4 g. (0.122 m.) of the compound of Example I, C. 20 g. (0.122 m.) of N,N-diethyl-p-phenylenediamine and 200 ml. of ethanol was stirred and heated at reflux overnight. The solution was concentrated in vacuo to give 43 g. m.p. 293°-295°. The crude product was recrystallized from 500 ml. of MeOH and precipitated with the addition of 500 ml. of ether. The yield after oven-drying (100°) was 33 g. m.p. 297°-299°.