Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7]([F:9])[C:6]([F:10])=[CH:5][C:3]=1[NH2:4].[CH3:11][S:12][CH3:13].ClN1C(=O)CCC1=O.[OH-].[Na+]>C(N(CC)CC)C.ClCCl>[CH3:11][S:12][CH2:13][C:5]1[C:6]([F:10])=[C:7]([F:9])[CH:8]=[C:2]([F:1])[C:3]=1[NH2:4]
Reactant: CSC
Reactant: Nc1cc(F)c(F)cc1F
Agent: O=C1CCC(=O)N1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CSCc1c(N)c(F)cc(F)c1F
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To 2,4,5-trifluoroaniline (35.0 g) are added anhydrous dichloromethane (530 ml) and dimethyl sulfide (24.6 ml) and the mixture is cooled to 0° C. Thereto N-chlorosuccinimide (38.2 g) is gradually added below 5° C. After the mixture is stirred at the same temperature for 15 minutes, triethylamine (47.7 ml) is gradually added. After reflux for 12 hours, the resultant is made alkaline with 5 % aqueous sodium hydroxide solution, extracted with dichloromethane, and the extract is dried over sodium sulfate and concentrated. The residue is purified with column chlomatography (silica-gel, dichloromethane: n-hexane=1:4) to give 2-methylthiomethyl-3,4,6-trifluoroaniline (22.3 g).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:32])[CH2:5][CH:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:31])[C:13]([CH3:30])([CH3:29])[CH:14]([CH2:27][CH3:28])[NH:15][C:16](=[O:26])[C:17]2[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[CH:19][C:18]=2[F:25])[CH2:8][CH2:7]1)[CH3:2].[NH:33]1[CH2:37][CH2:36][CH2:35][CH2:34]1>>[CH2:1]([O:3][C:4](=[O:32])[CH2:5][CH:6]1[CH2:7][CH2:8][N:9]([C:12](=[O:31])[C:13]([CH3:30])([CH3:29])[CH:14]([CH2:27][CH3:28])[NH:15][C:16](=[O:26])[C:17]2[CH:22]=[CH:21][C:20]([C:23]([N:33]3[CH2:37][CH2:36][CH2:35][CH2:34]3)=[NH:24])=[CH:19][C:18]=2[F:25])[CH2:10][CH2:11]1)[CH3:2]
Reactant: C1CCNC1
Reactant: CCOC(=O)CC1CCN(C(=O)C(C)(C)C(CC)NC(=O)c2ccc(C#N)cc2F)CC1
Product: CCOC(=O)CC1CCN(C(=O)C(C)(C)C(CC)NC(=O)c2ccc(C(=N)N3CCCC3)cc2F)CC1
Yield: 25 %

Procedure:
The same procedure as in Example 45 was performed with ethyl-N-(N-(4-cyano-2-fluorobenzoyl)-β-ethyl-α,α-dimethyl-β-alanyl)-4-piperidineacetate (1.4 g, 3.1 mmol) by using pyrrolidine (2.6 ml) as an amine to yield the titled compound (398 mg, 25%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[C@H:10]([O:12][C:13]1[C:14]2[O:22][CH:21]=[C:20]([C:23]3[CH2:24][CH2:25][NH:26][CH2:27][CH:28]=3)[C:15]=2[CH:16]=[N:17][C:18]=1[NH2:19])[CH3:11].C(=O)([O-])[O-].[Cs+].[Cs+].C[O:36][C:37](=[O:40])[CH2:38]Cl>CN(C=O)C>[NH2:19][C:18]1[N:17]=[CH:16][C:15]2[C:20]([C:23]3[CH2:24][CH2:25][N:26]([CH2:38][C:37]([OH:40])=[O:36])[CH2:27][CH:28]=3)=[CH:21][O:22][C:14]=2[C:13]=1[O:12][C@@H:10]([C:3]1[C:4]([Cl:9])=[CH:5][CH:6]=[C:7]([F:8])[C:2]=1[Cl:1])[CH3:11]
Reactant: C[C@@H](Oc1c(N)ncc2c(C3=CCNCC3)coc12)c1c(Cl)ccc(F)c1Cl
Reactant: COC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: C[C@@H](Oc1c(N)ncc2c(C3=CCN(CC(=O)O)CC3)coc12)c1c(Cl)ccc(F)c1Cl
Temperature: 40 °C
Reaction time: 0.17 h

Procedure:
A mixture of 7-[(R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy]-3-(1,2,3,6-tetrahydropyridin-4-yl)-furo[3,2-c]pyridine-6-ylamine (150.0 mg, 0.355 mmol), cesium carbonate (463 mg, 1.42 mmol) and DMF (4 mL) at rt was charged with chloroacetic acid methyl ester (37 μL, 0.43 mmol) and heated to 40° C. overnight. The solvent was removed in vacuo, and the material was dry-loaded onto silica gel for column chromatography, eluting with 2-5% MeOH/DCM. The fractions containing the pure ester were concentrated in vacuo and redissolved in EtOH (4 mL). The solution was charged with 2M aq. LiOH (0.9 mL) at rt, and stirred for 10 min. The solvents were removed in vacuo to afford the title compound as an orange solid. MS (ES+): m/z 497.97 (100) [MH+]. HPLC: tR=2.36 min (ZQ3, polar—5 min).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][CH:3]=1.[Mg].[O:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH:11]1[O:16][C@H:17]([CH3:26])[C:18](N1CCOCC1)=[O:19].[Cl-].[NH4+]>O1CCCC1.O>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([C:18](=[O:19])[C@H:17]([O:16][CH:11]2[CH2:12][CH2:13][CH2:14][CH2:15][O:10]2)[CH3:26])=[CH:3][CH:4]=1
Reactant: C[C@@H](OC1CCCCO1)C(=O)N1CCOCC1
Reactant: Clc1ccc(Br)cc1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Product: C[C@@H](OC1CCCCO1)C(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Yield: 235.1 %

Procedure:
To a solution of 1-bromo-4-chlorobenzene (20 g) in tetrahydrofuran (260 ml) was added magnesium (turnings, 7.47 g). The mixture was vigorously stirred at room temperature. When the temperature of the mixture reached 40° C., the reaction vessel was cooled in a water bath. A solution of 1-bromo-4-chlorobenzene (38.9 g) in tetrahydrofuran (90 ml), was added dropwise to the mixture at 34°-40° C., followed by stirring for an hour at 30° C. To the mixture was added dropwise a solution of 4-[(2R)-2-(3,4,5,6-tetrahydro-2H-pyran-2-yloxy)propionyl]morpholine (60 g) in tetrahydrofuran (60 ml) over the period of 15 minutes at 0° C. The mixture was stirred for 3 hours at room temperature. To the reaction mixture were added a saturated aqueous ammonium chloride solution (120 ml) and water (100 ml). The mixture was extracted with ethyl acetate (500 ml). The organic layer was washed with water, dried over magnesium sulfate and distilled under reduced pressure. The residue was purified by silica gel column chromatography (silica gel 900 g, eluent: hexane/ethyl acetate=30:1→10:1) to give (2R)-4'-chloro-2-(3,4,5,6-tetrahydro-2H-pyran-2-yloxy)propiophenone (66 g) as a pale yellow oily substance.
Reaction SMILES: [NH2:1][C@H:2]([C:4]1[N:5]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:6](=[O:15])[C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[CH:9][C:8]=2Cl)[CH3:3].[CH3:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([CH2:30][NH2:31])=[CH:26][CH:25]=1.C(N(C(C)C)CC)(C)C>CN1C(=O)CCC1>[NH2:1][C@H:2]([C:4]1[N:5]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:6](=[O:15])[C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[CH:9][C:8]=2[NH:31][CH2:30][C:27]1[CH:28]=[CH:29][C:24]([O:23][CH3:22])=[CH:25][CH:26]=1)[CH3:3]
Reactant: C[C@H](N)c1cc2cccc(Cl)c2c(=O)n1-c1ccccc1
Reactant: COc1ccc(CN)cc1
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(CNc2cccc3cc([C@H](C)N)n(-c4ccccc4)c(=O)c23)cc1
Temperature: 180 °C
Reaction time: 6 h

Procedure:
In a MW compatible vial, (S)-3-(1-aminoethyl)-8-chloro-2-phenylisoquinolin-1(2H)-one (700 mg, 2.343 mmol), (4-methoxyphenyl)methanamine (3.2 g, 23.4 mmol, 20 eq.) and diisopropylethylamine (1.6 mL, 9.4 mmol, 4 eq.) were dissolved in NMP (12 mL). The vial was sealed and heated to 180° C. in a under MW irradiation and stirred for 6 hr. The reaction mixture was cooled to RT, partitioned between Ethyl acetate and water. The organic phase was separated, washed with saturated aqueous sodium chloride solution, dried with sodium sulfate and concentrated. The residue was purified with silica gel chromatography using a gradient of DCM and MeOH to afford (S)-3-(1-aminoethyl)-8-((4-methoxybenzyl)amino)-2-phenylisoquinolin-1(2H)-one. ESI-MS m/z: 400.1 [M+H]+. (S)-3-(1-aminoethyl)-8-((4-methoxybenzyl)amino)-2-phenylisoquinolin-1(2H)-one (720 mg, 1.8 mmol), 2-((tert-butoxycarbonyl)amino)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (1.2 g, 4.31 mmol, 2.4 eq.), HOBt (700 mg, 4.57 mmol, 2.5 eq.) and EDC (800 mg, 4.17 mmol, 2.3 eq.) were suspended in DMF (30 mL). The reaction mixture was charged with diisopropylethylamine (2 mL, 11.45 mmol, 6.4 eq.) and stirred at RT for 1 hr. The reaction mixture was partitioned between Ethyl acetate and water. The organic phase was separated, washed with saturated aqueous sodium chloride solution, dried with sodium sulfate and concentrated. The residue was purified with silica gel chromatography using a gradient of Ethyl acetate and hexanes and triturated with MeOH to afford (S)-tert-butyl (3-((1-(8-((4-methoxybenzyl)amino)-1-oxo-2-phenyl-1,2-dihydroisoquinolin-3-yl)ethyl)carbamoyl)pyrazolo[1,5-a]pyrimidin-2-yl)carbamate. ESI-MS m/z: 660.3 [M+H]+. (S)-tert-butyl (3-((1-(8-((4-methoxybenzyl)amino)-1-oxo-2-phenyl-1,2-dihydroisoquinolin-3-yl)ethyl)carbamoyl)pyrazolo[1,5-a]pyrimidin-2-yl)carbamate (360 mg, 0.546 mmol) and anisole (238 μL, 2.183 mmol, 4 eq.) was dissolved TFA (2 mL) and stirred at 60° C. for 1 hr. The reaction mixture was poured in a saturated aqueous bicarbonate solution. The organic phase was dried with sodium sulfate and concentrated. The residue was purified with silica gel chromatography using a gradient of DCM. The residue was purified on semi-prep HPLC (C-18) using a gradient of ACN/Water/Formic acid to afford (S)-2-amino-N-(1-(8-amino-1-oxo-2-phenyl-1,2-dihydroisoquinolin-3-yl)ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide. ESI-MS m/z: 440.2 [M+H]+.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[CH:42]=[C:41]([CH3:43])[C:19]3[N:20]=[C:21]([C:23]4[C:24](=[O:40])[NH:25][CH:26]=[CH:27][C:28]=4[NH:29][CH2:30][CH:31]([C:33]4[CH:38]=[CH:37][CH:36]=[C:35]([Cl:39])[CH:34]=4)[OH:32])[NH:22][C:18]=3[CH:17]=2)=[O:15])[CH2:10][CH2:9]1)=O)(C)(C)C.O1CCOCC1.Cl>CO>[Cl:39][C:35]1[CH:34]=[C:33]([CH:31]([OH:32])[CH2:30][NH:29][C:28]2[CH:27]=[CH:26][NH:25][C:24](=[O:40])[C:23]=2[C:21]2[NH:22][C:18]3[CH:17]=[C:16]([C:14]([N:11]4[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]4)=[O:15])[CH:42]=[C:41]([CH3:43])[C:19]=3[N:20]=2)[CH:38]=[CH:37][CH:36]=1
Reactant: Cc1cc(C(=O)N2CCN(C(=O)OC(C)(C)C)CC2)cc2[nH]c(-c3c(NCC(O)c4cccc(Cl)c4)cc[nH]c3=O)nc12
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: Cc1cc(C(=O)N2CCNCC2)cc2[nH]c(-c3c(NCC(O)c4cccc(Cl)c4)cc[nH]c3=O)nc12
Temperature: 25 °C
Reaction time: 14 h
Yield: 52.6 %

Procedure:
To a solution of (±)-4-[1-(2-{4-[2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-2-oxo-1,2-dihydro-pyridin-3-yl}-7-methyl-3H-benzimidazol-5-yl)-methanoyl]-piperazine-1-carboxylic acid tert-butyl ester (40 mg, 0.06 mmol) in methanol (5 mL) was added 4.0 M HCl dioxane solution (0.1 mL, excess). The reaction mixture was stirred at room temperature for 14 h. After concentration, the residue was purified by prep. HPLC to give the title compound (16 mg, 63%) as a white foam. 1H NMR (300 MHz, CD3OD) δ 7.56 (1H, s), 7.53 (1H, s), 7.23–7.41 (4H, m), 7.17 (1H, m), 6.26 (1H, d, J=7.6 Hz), 4.99 (1H, dd, J=4.7, 6.4 Hz), 3.91 (4H, broad s), 3.74 (1H, dd, J=4.7, 13.5 Hz), 3.65 (1H, dd, J=6.4, 13.5 Hz), 3.31 (4H, broad s), 2.63 (3H, s). LCMS (M+H)+ m/z 507 (t=1.38 min.).
Reaction SMILES: [CH3:1][C:2]1[CH:16]=[CH:15][CH:14]=[C:13]([CH3:17])[C:3]=1[N:4]([C:8](=[O:12])[CH2:9][O:10][CH3:11])[CH2:5][C:6]#[CH:7].S([O-])([O-])(=O)=[O:19].[NH4+].[NH4+]>S([O-])([O-])(=O)=O.[Hg+2].C(O)=O>[CH3:1][C:2]1[CH:16]=[CH:15][CH:14]=[C:13]([CH3:17])[C:3]=1[N:4]([CH2:5][C:6]([CH3:7])=[O:19])[C:8](=[O:12])[CH2:9][O:10][CH3:11]
Reactant: C#CCN(C(=O)COC)c1c(C)cccc1C
Reactant: O=S(=O)([O-])[O-]
Agent: [Hg+2]
Agent: [NH4+]
Solvent: O=CO
Product: COCC(=O)N(CC(C)=O)c1c(C)cccc1C
Temperature: 80 °C
Reaction time: 6 h
Yield: 77 %

Procedure:
23.1 g (0.1 mol) of 2,6-dimethyl-N-methoxyacetyl-N-propargyl-aniline in 150 ml of 85% strength formic acid were heated to 80° C., and 0.5 g of mercury sulphate was then added to the reaction mixture. The mixture was stirred for a further 6 hours at 80° C. and, after cooling, saturated ammonium sulphate solution was added to the solution and the mixture was extracted with methylene chloride. After naturalizing the methylene chloride phase with sodium bicarbonate solution, the organic phase was dried with sodium sulphate and concentrated. 20.5 g (77% of theory) of 2,6-dimethyl-N-acetonyl-N-methoxyacetyl-aniline of melting point 56°-57° C. were obtained. ##STR179## Process variant (c)
Reaction SMILES: Br[CH2:2][CH2:3][CH:4]([S:9]([OH:12])(=[O:11])=[O:10])[C:5]([O:7][CH3:8])=[O:6].[C:13]([OH:16])(=[S:15])[CH3:14].CCN(C(C)C)C(C)C>C1COCC1>[C:13]([S:15][CH2:2][CH2:3][CH:4]([S:9]([OH:12])(=[O:11])=[O:10])[C:5]([O:7][CH3:8])=[O:6])(=[O:16])[CH3:14]
Reactant: CC(O)=S
Reactant: COC(=O)C(CCBr)S(=O)(=O)O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COC(=O)C(CCSC(C)=O)S(=O)(=O)O
Temperature: 70 °C
Reaction time: 8 h
Yield: 90 %

Procedure:
5.0 g (19.2 mmol) of 4-bromo-1-methoxy-1-oxobutane-2-sulfonic acid in 100 ml of THF was added 3.0 ml of thioacetic acid and 9.0 ml of DIPEA in 100 ml of THF. The mixture was stirred overnight then refluxed at 70° C. for 1 hr, evaporated and co-evaporated with 3×100 ml of water after being neutralized to pH 7 with NaHCO3. The mixture was redissolved in methanol, filtered through celite, concentrated and purified with SiO2 chromatography eluted with CH3OH/CH2Cl2/HCOOH 37.5:250:1 to 50:250:1) to afford 4.4 g (90% yield) of the title compound. 1H NMR (D2O) 3.95 (dd, 1H, J=4.1, 10.3 Hz), 3.83 (s, 3H), 3.74 (m, 2H), 3.22 (dd, 2H, J=7.4, 14.9 Hz), 2.39 (s, 3H); 13C NMR 203.88, 172.91, 67.32, 56.17, 29.04, 20.61; MS m/z−254.8 (M−H)
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][N:5]([CH3:17])[C:6]=1[C:7]1[CH:8]=[C:9]([C:13]([O:15][CH3:16])=[O:14])[S:10][C:11]=1[CH3:12].C(=O)([O-])[O-].[K+].[K+].[CH3:24][C:25]1(C)[C:29](C)(C)OB(C(C)=C)O1>O1CCOCC1.O.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[CH3:12][C:11]1[S:10][C:9]([C:13]([O:15][CH3:16])=[O:14])=[CH:8][C:7]=1[C:6]1[N:5]([CH3:17])[N:4]=[CH:3][C:2]=1[C:25]([CH3:29])=[CH2:24]
Reactant: C=C(C)B1OC(C)(C)C(C)(C)O1
Reactant: COC(=O)c1cc(-c2c(Br)cnn2C)c(C)s1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: C=C(C)c1cnn(C)c1-c1cc(C(=O)OC)sc1C
Yield: 61.1 %

Procedure:
A solution of methyl 4-(4-bromo-1-methyl-1H-pyrazol-5-yl)-5-methyl-2-thiophenecarboxylate (300 mg, 0.95 mmol), potassium carbonate (658 mg, 4.76 mmol), bis(tri-t-butylphosphine)palladium(0) (24.32 mg, 0.05 mmol) and 4,4,5,5-tetramethyl-2-(1-methylethenyl)-1,3,2-dioxaborolane (0.18 ml, 0.95 mmol) in 1,4-dioxane (5.3 ml) and H2O (1.0 ml) was stirred at 80° C. in a sealed tube for 12 h. The reaction contents were partitioned between H2O-DCM and the aqueous phase was washed several times with DCM. The combined organic fractions were dried over Na2SO4, concentrated and purified via column chromatography (10-50% EtOAc in hexanes) affording methyl 5-methyl-4-[1-methyl-4-(1-methylethenyl)-1H-pyrazol-5-yl]-2-thiophenecarboxylate (171 mg, 0.58 mmol, 61% yield) as a yellow oil: LCMS (ES) m/z=276 (M+H)+.
Reaction SMILES: [F:1][C:2]1[C:9]([F:10])=[C:8](F)[C:7]([F:12])=[C:4]([C:5]#[N:6])[C:3]=1[C:13]#[N:14].[CH3:15][CH:16]([CH:18]([O:22][C:23]([C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:26]=1[OH:37])=[O:24])[CH:19]([CH3:21])[CH3:20])[CH3:17].[F-].[K+]>C(#N)C>[F:12][C:7]1[C:8]([O:37][C:26]2[C:27]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[CH:28][CH:29]=[CH:30][C:25]=2[C:23]([O:22][CH:18]([CH:19]([CH3:21])[CH3:20])[CH:16]([CH3:15])[CH3:17])=[O:24])=[C:9]([F:10])[C:2]([F:1])=[C:3]([C:13]#[N:14])[C:4]=1[C:5]#[N:6]
Reactant: N#Cc1c(F)c(F)c(F)c(F)c1C#N
Reactant: CC(C)C(OC(=O)c1cccc(-c2ccccc2)c1O)C(C)C
Agent: [F-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)C(OC(=O)c1cccc(-c2ccccc2)c1Oc1c(F)c(F)c(C#N)c(C#N)c1F)C(C)C
Yield: 93.4 %

Procedure:
In a four-neck flask having an inner volume of 100 ml, 3.00 g (15 m.mols) of 3,4,5,6-tetrafluorophthalonitrile, 4.69 g (15 m.mols) of 2-(2,4-dimethyl-3-pentyloxy)carbonyl-6-phenylphenol, 2.62 g (45 m.mols) of potassium fluoride, and 50 ml of acetonitrile were placed and left reacting under reflux for six hours. After the reaction, the reaction mass was filtered and then distilled to expel the solvent by evaporation and obtain 6.90 g (14 m.mols) of 3,5,6-trifluoro-4-(2-(2,4-dimethyl-3-pentyloxy)carbonyl-6-phenylphenoxy)phthalonitrile as the product aimed at.
Reaction SMILES: Br[C:2]1[CH:10]=[C:9](Br)[CH:8]=[C:7]2[C:3]=1[C:4]([CH2:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])=[C:5]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[NH:6]2.[C:24]1(B(O)O)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.O.O.O.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCOCC1>[C:24]1([C:2]2[CH:10]=[C:9]([C:2]3[CH:10]=[CH:9][CH:8]=[CH:7][CH:3]=3)[CH:8]=[C:7]3[C:3]=2[C:4]([CH2:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])=[C:5]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[NH:6]3)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: OB(O)c1ccccc1
Reactant: CCOC(=O)CCc1c(C(=O)OCC)[nH]c2cc(Br)cc(Br)c12
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CCOC(=O)CCc1c(C(=O)OCC)[nH]c2cc(-c3ccccc3)cc(-c3ccccc3)c12
Temperature: 25 °C

Procedure:
Ethyl 4,6-dibromo-3-(3-ethoxy-3-oxopropyl)-1H-indole-2-carboxylate (0.244 g, 0.5 mmol), phenylboronic acid (0.147 g, 1.2 mmol, 2.4 equiv.) and potassium phosphate trihydrate (0.400 g, 1.5 mmol, 3.0 equiv.) were mixed together in a 10 ml microwave vial. The vial was purged with Argon and trans-dichlorobis(triphenylphosphine)-palladium (II) (0.021, 0.03 mmol, 6 mol %) and 5 ml of dry dioxane were added to the mixture. The microwave vial was capped and irradiated at 100 watt, 150° C., under pressure up to 10 bars. Then it was allowed to cool down to rt, and toluene was removed under reduced pressure and the residue was dissolved in dichloromethane and washed with water. The organic layer was dried over magnesium sulfate, filtered, and evaporated to dryness. The residue was purified by silica gel column chromatography using 20% of ethyl acetate/cyclohexane as eluent to yield a light-beige-colored solid in 60-70%. 1H-NMR (DMSO-d6) δ 1.09, 1.32 (each t, 3H, 3J=7.1 Hz, CH3); 2.11 (m, 2H, 2′-H); 2.84 (m, 2H, 1′-H); 3.89, 4.33 (each q, 2H, 4J=7.1 Hz, CH2); 7.12 (d, 1H, 2J=1.6 Hz, 7-H); 7.35 (t, 1H, 3J=7.4 Hz, Ph-ring); 7.43 (m, 7H, Ph-ring); 7.67 (d, 1H, 2J=0.9 Hz, 5-H); 7.68 (d, 1H, 2J=1.6 Hz, Phenyl-ring); 11.84 (s, 1H, NH). 13C-NMR (DMSO-d6) δ 14.2, 14.3 (2CH3, each C═OOCH2CH3); 20.5 (C-2′); 34.8 (C-1′); 59.5, 60.5 (2CH2, each C═OOCH2CH3); 109.6 (C-5); 121.1 (C-7); 121.8 (C-3); 123.6 (C-2); 124.7 (C-3a); 127.0 (C-2″, C-6″); 127.4 (C-4″′); 127.5 (C-4″); 128.0 (C-3′″, C-5″′); 129.0 (C-3″, C-5″); 129.1 (C-2′″, C-6″′); 136.7 (C-7a); 137.4 (C-4), 137.6 (C-6); 140.7 (C-1″); 140.8 (C-1′″); 161.5 (2′-CO2Et); 171.7 (2-CO2Et). LC-MS (m/z): 442 [M]+, 440 [M]−. Purity (LC-MS): 96%.
Reaction SMILES: [C@@H]1(N2C3N=C(N)NC(=O)C=3N=C2)O[C@H](CO)[C@@H]([OH:4])C1.[CH2:20]1[C@H:24]([N:25]2[C:29]3[N:30]=[C:31](N)[N:32]=[C:33]([NH2:34])[C:28]=3[N:27]=[CH:26]2)[O:23][C@H:22]([CH2:36][OH:37])[C@H:21]1[OH:38]>>[C@@H:24]1([N:25]2[C:29]3[N:30]=[CH:31][N:32]=[C:33]([NH2:34])[C:28]=3[N:27]=[CH:26]2)[O:23][C@H:22]([CH2:36][OH:37])[C@@H:21]([OH:38])[C@H:20]1[OH:4]
Reactant: Nc1nc(N)c2ncn([C@H]3C[C@H](O)[C@@H](CO)O3)c2n1
Reactant: Nc1nc2c(ncn2[C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)[nH]1
Product: Nc1ncnc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O

Procedure:
It is possible to prepare 2′-deoxyguanosine by putting 2,6-diaminopurine-2′-deoxyriboside obtained above under the action of an adenosine deaminase or a material containing said enzyme in an aqueous medium. The action of the adenosine deaminase may either be effected on 2,6-diaminopurine-2′-deoxyriboside in the reaction solution described above without separation or on a product separated from the mixture after reaction. The method for collection or separation includes a method using a synthetic adsorption resin and other routine collecting or separating methods.
Reaction SMILES: [CH2:1]([C:3]1[NH:4][CH:5]=[C:6]([CH3:8])[N:7]=1)[CH3:2].C(N(CC)CC)C.[Cl:16][C:17]1[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[C:18]=1[C:19](Cl)=[O:20]>O1CCCC1>[Cl:16][C:17]1[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[C:18]=1[C:19]([N:4]1[CH:5]=[C:6]([CH3:8])[N:7]=[C:3]1[CH2:1][CH3:2])=[O:20]
Reactant: CCc1nc(C)c[nH]1
Reactant: O=C(Cl)c1c(Cl)cccc1Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCc1nc(C)cn1C(=O)c1c(Cl)cccc1Cl
Yield: 64.3 %

Procedure:
22.02 g of 2-ethyl-4-methyl-imidazole and 20.85 g of triethylamine are dissolved in 250 ml of tetrahydrofuran. There are then added dropwise, at reflux temperature within 20 minutes, 41.88 g of 2,6-dichlorobenzoyl chloride, dissolved in 100 ml of tetrahydrofuran, and the mixture is refluxed for 30 minutes, and subsequently further processed as described in Example 1. Recrystallisation of the crude product from 120 ml of acetonitrile yields 36.4 g of product (64.3% of theory), m.p. 112°-113.5° C.
Reaction SMILES: C([O:8][C:9]1[C:10]2[N:11]3[C:15](=[CH:16][CH:17]=1)[C:14]([CH2:18][CH3:19])=[C:13]([C:20]1[CH:25]=[CH:24][C:23]([O:26]CC4C=CC=CC=4)=[CH:22][CH:21]=1)[C:12]3=[C:34]([CH2:36][O:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][N:46]1[CH2:51][CH2:50][CH2:49][CH2:48][CH2:47]1)[CH:35]=2)C1C=CC=CC=1.[H][H]>[Pd].C(O)C.O1CCCC1>[CH2:18]([C:14]1[C:15]2[N:11]3[C:10](=[CH:35][C:34]([CH2:36][O:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][N:46]4[CH2:51][CH2:50][CH2:49][CH2:48][CH2:47]4)=[C:12]3[C:13]=1[C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=1)[C:9]([OH:8])=[CH:17][CH:16]=2)[CH3:19]
Reactant: [H][H]
Reactant: CCc1c(-c2ccc(OCc3ccccc3)cc2)c2c(COCCCCCCCCN3CCCCC3)cc3c(OCc4ccccc4)ccc1n32
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: CCc1c(-c2ccc(O)cc2)c2c(COCCCCCCCCN3CCCCC3)cc3c(O)ccc1n32
Yield: 85.4 %

Procedure:
A suspension of 5-benzyloxy-2-(4-benzyloxyphenyl)-1-ethyl-3-((8-piperidinooctyloxy)-methyl)pyrrolo[2,1,5-cd ]indolizine (0.30 g, 0.44 mmol) and 30 mg 10% palladium on charcoal in 12 ml of ethanol and 8 ml of tetrahydrofuran was stirred in a hydrogen atmosphere for 6 hours. The reaction mixture was filtered twice and the solvent was evaporated. The resulting oil was purified by column chromatography over netural aluminium oxide activity grade I, using 10% of methanol in dichloromethane as the eluent. The product was crystallised from dichloromethane, diethyl ether and petroleum ether to afford 189 mg (85%) of 1-ethyl-5-hydroxy-2-(4-hydroxyphenyl)-3-((8-piperidinooctyloxy)methyl)pyrrolo[2,1,5-cd ]indolizine as yellow crystals. M.p. 91-95° C. (decomp.). MS(FAB): m/z 503 (M+1). 1H-NMR (DMSO-d6, 300 MHz) δ:1.17-1.71 (m, 21H); 2.61-3.09 (m, 8H); 3.38 (t, 2H); 4.68 (s, 2H); 6.92 (d, 2H); 7.12 (d, 1H); 7.22 (s, 1H); 7.48 (d, 2H); 7.83 (d, 1H); 9.58 (s, 1H); 10.59 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:18]=[CH:17][C:6]2[S:7][C:8]([C:14]([OH:16])=O)=[C:9]([O:10][CH:11]([CH3:13])[CH3:12])[C:5]=2[CH:4]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.Cl.[NH2:32][CH2:33][CH2:34][CH2:35][CH2:36][C:37]([O:39][CH3:40])=[O:38].C(N(CC)CC)C>O1CCCC1>[CH3:1][O:2][C:3]1[CH:18]=[CH:17][C:6]2[S:7][C:8]([C:14]([NH:32][CH2:33][CH2:34][CH2:35][CH2:36][C:37]([O:39][CH3:40])=[O:38])=[O:16])=[C:9]([O:10][CH:11]([CH3:12])[CH3:13])[C:5]=2[CH:4]=1
Reactant: COc1ccc2sc(C(=O)O)c(OC(C)C)c2c1
Reactant: COC(=O)CCCCN
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)CCCCNC(=O)c1sc2ccc(OC)cc2c1OC(C)C
Temperature: 0 °C
Yield: 69.8 %

Procedure:
A solution of 5-methoxy-3-(1-methylethoxy)benzo[b]thiophene-2-carboxylic acid (500 mg, 2.00 mmoles) and 1,1'-carbonyldiimidazole (421 mg, 2.60 mmoles) in 20 mL of tetrahydrofuran is heated at reflux for 1 hour. After cooling to 0° C., the HCl salt of methyl 5-aminovalerate (787 mg, 4.7 mmoles) is added followed by triethylamine (836 μL, 6.0 mmoles). The mixture is heated at reflux overnight. The mixture is partitioned between ethyl acetate and 1N HCl. The organic layer is washed with 1N HCl, saturated NaHCO3, then brine. The organic layer is next dried over magnesium sulfate, filtered, and concentrated in vacuo. The crude product is purified by flash chromatography, eluting with 1:9 ethyl acetate:hexane to provide 530 mg (70%) of product; mp 82°-84° C.