Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[CH:14][CH:15]=3)[N:10]([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[F:24])[N:9]=2)=[N:4][C:3]=1[NH2:25].[CH3:26][C:27]1[C:32](B(O)O)=[CH:31][CH:30]=[CH:29][N:28]=1.C(=O)([O-])[O-].[K+].[K+].C1(P(C2CCCCC2)C2CCCCC2)CCCCC1>O1CCOCC1.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]>[F:24][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[CH2:17][N:10]1[C:11]2=[N:12][CH:13]=[CH:14][CH:15]=[C:16]2[C:8]([C:5]2[N:6]=[N:7][C:2]([C:32]3[C:27]([CH3:26])=[N:28][CH:29]=[CH:30][CH:31]=3)=[C:3]([NH2:25])[N:4]=2)=[N:9]1
Reactant: Nc1nc(-c2nn(Cc3ccccc3F)c3ncccc23)nnc1Cl
Reactant: Cc1ncccc1B(O)O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Solvent: C1COCCO1
Product: Cc1ncccc1-c1nnc(-c2nn(Cc3ccccc3F)c3ncccc23)nc1N
Yield: 24.6 %

Procedure:
Under an argon atmosphere, 140 mg (purity 65%, 0.256 mmol) of 6-chloro-3-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-1,2,4-triazine-5-amine were suspended in 5 ml of absolute dioxane. 105 mg (0.767 mmol) of (2-methylpyridin-3-yl)boronic acid, 1.023 ml (1.023 mmol) of 1N aqueous potassium carbonate solution, and 14 mg (0.051 mmol) of tricyclohexylphosphine were added and argon was passed through the suspension with stirring. Then, 28 mg (0.038 mmol) of 1,1′-bis(diphenylphosphino)ferrocenepalladium(II) chloride were added and the reaction mixture was stirred for 30 min in the microwave at 140° C. Again, 19 mg (0.026 mmol) of 1,1′-bis(diphenylphosphino)ferrocenepalladium(II) chloride were added and the reaction mixture was stirred for 40 min in the microwave at 150° C. After cooling, the mixture was filtered over an Extrelut cartridge and after-washed with a mixture of dichloromethane/methanol (v/v=20:1). The filtrate was concentrated and the residue was purified by preparative HPLC (mobile phase: acetonitrile/water, gradient 20:80→100:0). 26 mg of the target compound were obtained (18% of theory).
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][CH2:4][NH:3]1.[Cl:7][CH2:8][CH2:9][CH2:10][N:11]=[C:12]=[O:13]>C1(C)C=CC=CC=1.C(OCC)(=O)C>[Cl:7][CH2:8][CH2:9][CH2:10][NH:11][C:12]([N:3]1[CH2:4][CH2:5][CH2:6][C:2]1=[O:1])=[O:13]
Reactant: O=C1CCCN1
Reactant: O=C=NCCCCl
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: O=C1CCCN1C(=O)NCCCCl
Reaction time: 8 h
Yield: 81.5 %

Procedure:
A mixture of 17.1 g (201 mmol) of 2-oxopyrrolidine and 20 g (167 mmol) of chloropropyl isocyanate was heated with stirring at 95°-105° C. overnight. After cooling, the reaction solution was refined by silica gel chromatography. The resulting product obtained from the eluate with toluene-ethyl acetate (20/1-10/1 v/v) was washed with ether-n-hexane and then collected by filtration, whereby 27.87 g of the objective compound 1-(3-chloropropylcarbamoyl)-2-oxopyrrolidine (III-2) melting at 57.0°-58.0° C. was obtained as crystals. Yield: 81.0%.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[C:5]([CH:7]1[CH2:12][CH2:11][N:10]([CH3:13])[CH2:9][CH2:8]1)=[O:6].[F:17][C:18]([F:30])([F:29])[O:19][C:20]1[CH:21]=[C:22]([CH:26]=[CH:27][CH:28]=1)[C:23](Cl)=[O:24]>>[F:17][C:18]([F:29])([F:30])[O:19][C:20]1[CH:21]=[C:22]([CH:26]=[CH:27][CH:28]=1)[C:23]([NH:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[C:5]([CH:7]1[CH2:8][CH2:9][N:10]([CH3:13])[CH2:11][CH2:12]1)=[O:6])=[O:24]
Reactant: CN1CCC(C(=O)c2cccc(N)c2)CC1
Reactant: O=C(Cl)c1cccc(OC(F)(F)F)c1
Product: CN1CCC(C(=O)c2cccc(NC(=O)c3cccc(OC(F)(F)F)c3)c2)CC1

Procedure:
Beginning with 4-[3-aminobenzoyl]-1-methylpiperidine (25 mg, 0.115 mmol) and 3-(trifluoromethoxy)benzoyl chloride (37 μL, 0.229 mmol) and mixing for 24 h, 50.4 mg (>100%) of the title compound were recovered.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([O:14][C@@H:15]([CH3:20])[C:16]([F:19])([F:18])[F:17])=[CH:12][N:11]=[C:10]([C:21](O)=[O:22])[N:9]=2)=[CH:4][CH:3]=1.[F:24][C:25]([F:34])([F:33])[C:26]1[CH:30]=[C:29]([CH2:31][NH2:32])[O:28][N:27]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([O:14][C@@H:15]([CH3:20])[C:16]([F:17])([F:19])[F:18])=[CH:12][N:11]=[C:10]([C:21]([NH:32][CH2:31][C:29]3[O:28][N:27]=[C:26]([C:25]([F:24])([F:33])[F:34])[CH:30]=3)=[O:22])[N:9]=2)=[CH:4][CH:3]=1
Reactant: C[C@H](Oc1cnc(C(=O)O)nc1-c1ccc(Cl)cc1)C(F)(F)F
Reactant: NCc1cc(C(F)(F)F)no1
Product: C[C@H](Oc1cnc(C(=O)NCc2cc(C(F)(F)F)no2)nc1-c1ccc(Cl)cc1)C(F)(F)F

Procedure:
The title compound was synthesized in analogy to Example 1 using (S)-4-(4-chlorophenyl)-5-(1,1,1-trifluoropropan-2-yloxy)pyrimidine-2-carboxylic acid (example AQ) and 3-trifluoromethyl-isoxazol-5-methanamine (example BA) as starting materials; LC-MS (UV peak area/ESI) 100%, 495.0965 (M+H)+.
Reaction SMILES: [C:1]1([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:6]=[CH:5][C:4]([CH2:7][CH:8]([CH2:19][C:20]([O:22]C(C)(C)C)=[O:21])[C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])=[CH:3][CH:2]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:12]([O:11][C:9](=[O:10])[CH:8]([CH2:7][C:4]1[CH:3]=[CH:2][C:1]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)=[CH:6][CH:5]=1)[CH2:19][C:20]([OH:22])=[O:21])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CC(C)(C)OC(=O)CC(Cc1ccc(-c2ccccc2)cc1)C(=O)OCc1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)CC(Cc1ccc(-c2ccccc2)cc1)C(=O)OCc1ccccc1
Reaction time: 1 h
Yield: 99.7 %

Procedure:
To a solution of 1-benzyl 4-tert-butyl 2-(biphenyl-4-ylmethyl)succinate (90 mg, 0.209 mmol) in DCM (1 ml), TFA (0.322 ml, 4.18 mmol) was added. The reaction mixture was allowed to stir for 1 hour, and then concentrated under reduced pressure to give 4-(benzyloxy)-3-(biphenyl-4-ylmethyl)-4-oxobutanoic acid (78 mg); Retention time=1.48 minutes (condition B); MS (m−1)=373.2.
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[CH:6][N:5]=[CH:4]1.[Cl:8][C:9]1[CH:34]=[CH:33][CH:32]=[C:31]([Cl:35])[C:10]=1[CH2:11][O:12][C@@H:13]1[O:18][C@@H:17]([CH2:19]OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:16][CH2:15][CH2:14]1.[I-].[Na+]>CN(C)C=O>[Cl:8][C:9]1[CH:34]=[CH:33][CH:32]=[C:31]([Cl:35])[C:10]=1[CH2:11][O:12][C@@H:13]1[O:18][C@@H:17]([CH2:19][N:3]2[CH:7]=[CH:6][N:5]=[CH:4]2)[CH2:16][CH2:15][CH2:14]1
Reactant: c1c[nH]cn1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2CCC[C@H](OCc3c(Cl)cccc3Cl)O2)cc1
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Clc1cccc(Cl)c1CO[C@H]1CCC[C@H](Cn2ccnc2)O1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 94.3 %

Procedure:
196 mg of 55% sodium hydride were added to a solution of 306 mg of imidazole in 14 ml of dimethylformamide and the mixture was stirred at 80° C. for 30 minutes. The mixture was then cooled to room temperature, after which 1.335 g of trans-6-(2,6-dichlorobenzyloxy)-2-tosyloxymethyltetrahydropyran and 450 mg of sodium iodide were added thereto; the mixture was then stirred at 80°-85° C. for 2 hours. At the end of this time, the mixture was treated and purified essentially as described in Example 1(b), to give 965 mg of the title compound in the form of a colourless oil.
Reaction SMILES: COC1C=[C:5]([CH:9](C)[CH2:10][CH2:11][C:12](=[O:15])C=C)[CH:6]=[CH:7]C=1.CCC(=[O:24])CCCC>[OH-].[K+]>[CH2:6]([CH:5]1[C:9](=[O:24])[CH2:10][CH2:11][C:12]1=[O:15])[CH3:7]
Reactant: C=CC(=O)CCC(C)c1cccc(OC)c1
Reactant: CCCCC(=O)CC
Agent: [K+]
Agent: [OH-]
Product: CCC1C(=O)CCC1=O

Procedure:
Reflux a mixture of 6-(m-methoxyphenyl)hept-1-en-3-one and 1-diethylamino-6-)m-methoxypheyl)heptan-3-one (10 g, obtained by slow distillation of the latter substance) with 2-ethylcyclopentane-1,3-dione (7g) in 0.12% methanolic potassium hydroxide solution (40 cc) for 15 hours. Remove most of the methanol under reduced pressure and add a mixture of equal volumes or ether and benzene (50 cc). Wash the solution with 5% aqueous sodium hydroxide, water, 10% hydrochloric acid, and brine, and dry. Evaporate the solvent to leave as residue the triketone adduct 2-(6-m-methoxyphenyl-3-oxoheptyl)-2-ethylcyclopentane-1,3-dione (14 g); infrared absorption peak at 5.80 μ.
Reaction SMILES: [CH:1]1([N:5]2[CH2:11][CH2:10][C:9]3[CH:12]=[CH:13][C:14]([O:16][C:17]4[CH:22]=[CH:21][C:20](I)=[CH:19][N:18]=4)=[CH:15][C:8]=3[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.N1C2C(=CC=C3C=2N=CC=C3)C=CC=1.[CH3:38][CH:39]1[NH:43][C:42](=[O:44])[CH2:41][CH2:40]1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.[Cu]I>[CH:1]1([N:5]2[CH2:11][CH2:10][C:9]3[CH:12]=[CH:13][C:14]([O:16][C:17]4[N:18]=[CH:19][C:20]([N:43]5[CH:39]([CH3:38])[CH2:40][CH2:41][C:42]5=[O:44])=[CH:21][CH:22]=4)=[CH:15][C:8]=3[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1
Reactant: CC1CCC(=O)N1
Reactant: Ic1ccc(Oc2ccc3c(c2)CCN(C2CCC2)CC3)nc1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: CC1CCC(=O)N1c1ccc(Oc2ccc3c(c2)CCN(C2CCC2)CC3)nc1
Temperature: 175 °C
Yield: 50 %

Procedure:
3-Cyclobutyl-7-[(5-iodo-2-pyridinyl)oxy]-2,3,4,5-tetrahydro-1H-3-benzazepine (E207) (294 mg, 0.7 mmol) 1,10 phenanthroline (38 mg, 0.2 mmol), 5-methyl-2-pyrrolidinone (139 mg 1.4 mmol) were dissolved in dioxane (2 ml). Copper(I) Iodide (39 mg, 0.2 mmol) and caesium carbonate (479 mg, 1.5 mmol) were added and the mixture heated in a microwave reactor at 175° C. for 15 minutes. The mixture was cooled and filtered through celite, washing through with dichloromethane. The filtrate was concentrated in vacuo and the crude material purified by column chromatography, eluting with dichloromethane through to a mixture of 0.880 ammonia:methanol:dichloromethane (1:9:90) to afford the title compound (137 mg); MS (ES+) m/e 392 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])SCCCS1.O.C(=O)(O)[O-:17].[Na+]>CC(C)=O>[O:17]=[C:2]([CH3:1])[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9]
Reactant: O=C([O-])O
Reactant: CC(C)(C)OC(=O)C1(C)SCCCS1
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: CC(=O)C(=O)OC(C)(C)C
Temperature: -20 °C
Reaction time: 0.5 h
Yield: 40 %

Procedure:
tert-Butyl 2-methyl-1,3-dithiane-2-carboxylate (2 g, 8.547 mmol) was dissolved in acetone (85.5 mL), and water (0.5 mL) was added. The flask was then cooled in a cold bath at −20° C. Small aliquots of N-bromosuceinimide (15.4 g, 85.47 mmol) were added over 20 minutes. The reaction mixture was stirred at the same temperature for further 30 minutes, and then quenched by adding an aqueous solution of sodium bicarbonate (7.18 g, 85.47 mmol in 90 mL of water). Insoluble material was removed by filtration. The filtrate was diluted in water (200 mL) and extracted with tert-butyl methyl ether (150 mL). The separated organic layer was washed with water and a saturated brine in order, then dried over anhydrous sodium sulfate, and then filtered. The filtrate was concentrated. The residue was purified by silica gel column chromatography (n-hexane/ethyl acetate) to obtain the target compound as pale yellow oil at a yield of 40%.
Reaction SMILES: [C:1](=[O:5])([O:3][CH3:4])[NH2:2].O=[C:7]([CH2:11][CH2:12][PH:13]([CH2:15][OH:16])=[O:14])[C:8]([OH:10])=[O:9].C(O)(=O)C>C1(C)C=CC=CC=1>[CH3:4][O:3][C:1]([NH:2]/[C:7](=[CH:11]\[CH2:12][PH:13]([CH2:15][OH:16])=[O:14])/[C:8]([OH:10])=[O:9])=[O:5]
Reactant: O=C(O)C(=O)CC[PH](=O)CO
Reactant: COC(N)=O
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: COC(=O)N/C(=C\C[PH](=O)CO)C(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 75.4 %

Procedure:
5.835 g of methyl carbamate and 10.000 g of 2-oxo-4-(hydroxymethylphosphinyl)-butanoic acid were added to 17 mL of acetic acid to be suspended. After being dissolved by heating, 68 mL of toluene was added thereto and then the solution was refluxed with vigorous stirring. The internal temperature of the reaction solution was from 106 to 108 deg. C. Four hours later, dissipation of almost all the raw materials was confirmed by HPLC measurement. At this point, the area ratio of Z form to E form was 94:6. After removing about 42 mL of the solvent under a reduced pressure, followed by adding 23 mL of acetic acid, and then the resultant was stirred for 1 hour at 80 deg. C. The precipitate which was obtained by cooling the solution gradually to room temperature and stirring over-night, was filtered and then the filtrate was washed with acetic acid. After being washed with acetone, dried for 5 hours from 40 to 50 deg. C. under a reduced pressure, 9.931 g of the objective compound was obtained (75.4% yield, Z:E=99.6:0.4).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][C:12]([OH:14])=[O:13])[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.S(=O)(=O)(O)O.[CH3:20]O>>[CH3:20][O:13][C:12](=[O:14])[CH2:11][C:5]1[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=[C:3]([O:2][CH3:1])[CH:4]=1
Reactant: CO
Reactant: COc1cc(CC(=O)O)cc(OC)c1
Agent: O=S(=O)(O)O
Product: COC(=O)Cc1cc(OC)cc(OC)c1

Procedure:
To a solution of 3,5-dimethoxyphenylacetic acid (1.99 g, 10.0 mmol) (Transworld) in methanol (20 mL) was added concentrated sulfuric acid (1.0 mL) and the reaction mixture was heated at reflux for 24 hours. The reaction mixture was concentrated in vacuo. The residue was then diluted with ethyl acetate (100 mL) and successively washed with water (50 mL) and brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give the crude 3,5-dimethoxyphenylacetic acid methyl ester as a black oil which was used in the next step without further purification. (Yield 2.05 g, 97.6%).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][C:3]1=[O:11].[N+:12]([O-])([OH:14])=[O:13]>S(=O)(=O)(O)O>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([N+:12]([O-:14])=[O:13])=[CH:8][CH:9]=2)[CH2:4][C:3]1=[O:11]
Reactant: CN1C(=O)Cc2ccccc21
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: CN1C(=O)Cc2cc([N+](=O)[O-])ccc21
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
2 g 1-methyl-1,3-dihydro-indol-2-one are dissolved in 10 ml concentrated sulphuric acid and cooled to 0° C. To this is added dropwise a solution of 620 μl concentrated nitric acid in 2 ml concentrated sulphuric acid and the mixture is stirred for 30 minutes. Then it is poured onto 50 g ice, stirred for 1 hour, the solid is removed by suction filtering and dried in vacuo.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH2:10][NH:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:7]=[CH:8][CH:9]=1)([O-])=O>[C].[Pd].C(OCC)(=O)C>[NH2:1][C:4]1[CH:5]=[C:6]([CH2:10][NH:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:7]=[CH:8][CH:9]=1
Reactant: O=[N+]([O-])c1cccc(CNCCc2ccccc2)c1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Nc1cccc(CNCCc2ccccc2)c1
Yield: 61 %

Procedure:
Using the compound obtained in Example 377 as a starting material and also using 5% palladium-carbon and ethyl acetate as a catalyst and a solvent, respectively, reaction was performed as in Example 2 to give 487 mg of the titled compound (yield, 61%).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[NH2:7][C:8]1[N:20]=[C:19]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[OH:27])[CH:18]=[C:17]([C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([NH2:34])[CH:29]=2)[C:9]=1[C:10](OC(C)(C)C)=[O:11]>C1COCC1>[NH2:7][C:8]1[N:20]=[C:19]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[OH:27])[CH:18]=[C:17]([C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([NH2:34])[CH:29]=2)[C:9]=1[CH2:10][OH:11]
Reactant: CC(C)(C)OC(=O)c1c(-c2cccc(N)c2)cc(-c2ccccc2O)nc1N
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Nc1cccc(-c2cc(-c3ccccc3O)nc(N)c2CO)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 46.3 %

Procedure:
To a cold (0° C.) suspension of lithium aluminum hydride (0.077 g, 1.62 mmol) in THF (3 mL) under an argon atmosphere was added dropwise a solution of tert-butyl 2-amino-4-(3-aminophenyl)-6-(2-hydroxyphenyl)nicotinate (0.353 g, 0.935 mmol) in THF (2 mL) with stirring. After 30 minutes, the mixture was allowed to warm to room temperature, and the stirring was continued at room temperature for 2 hrs. and at 50° C. overnight. After cooled to room temperature, the reaction mixture was quenched with water and extracted with ethyl acetate. The separated organic phase was washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by recrystallization from methanol to give 2-[6-amino-4-(3-aminophenyl)-5-(hydroxymethyl)-2-pyridinyl]phenol as a pale yellow solid (0.133 g, yield 45%).
Reaction SMILES: [P:1]([O:5][CH2:6][C@H:7]1[O:11][C@@H:10]([N:12]2[C:26]3[N:25]=[CH:24][N:23]=[C:16]([NH:17]C(=O)CCC)[C:15]=3[N:14]=[CH:13]2)[C@H:9]([O:27][CH3:28])[C@@H:8]1[O:29]C(=O)C1C=CC=CC=1)([OH:4])([OH:3])=[O:2].C(N(CC)CC)C.C[Si](Cl)(C)C.II.O.C(S)C>N1C=CC=CC=1>[P:1]([O:5][CH2:6][C@H:7]1[O:11][C@@H:10]([N:12]2[C:26]3[N:25]=[CH:24][N:23]=[C:16]([NH2:17])[C:15]=3[N:14]=[CH:13]2)[C@H:9]([O:27][CH3:28])[C@@H:8]1[OH:29])([OH:3])([OH:4])=[O:2]
Reactant: CCCC(=O)Nc1ncnc2c1ncn2[C@@H]1O[C@H](COP(=O)(O)O)[C@@H](OC(=O)c2ccccc2)[C@H]1OC
Agent: C[Si](C)(C)Cl
Agent: II
Solvent: CCS
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: CO[C@@H]1[C@H](O)[C@@H](COP(=O)(O)O)O[C@H]1n1cnc2c(N)ncnc21
Reaction time: 0.08 h
Yield: 37 %

Procedure:
3′-O-Benzoyl-N6-butyryl-2′-O-methyl adenosine 5′-H-phosphonate 10 (55 mg, 0.088 mmol) was dried by evaporation of added dry pyridine (5 mL) and 30 min drying on a vacuum pump. To the compound was added pyridine (0.8 mL), triethylamine (5 eq, 0.44 mmol, 61 μL) and trimethyl silyl chloride (5 eq, 0.44 mmol, 55.7 μL). The reaction was stirred for 15 min at room temperature, whereupon a solution of I2/H2O in pyridine (1.1 eq 12, 24 mg, 50 μL H2O, 500 μL pyridine) was added. After an additional 5 min a sample was taken and analysed by 31P NMR which showed complete oxidation. A drop of ethanethiol was added to achieve a colorless solution, the solvent was removed under reduced pressure and the crude compound was dissolved in MeOH/NH3 (sat.). The mixture was left overnight at room temperature, whereupon the solvent was removed under reduced pressure and the solid was dissolved in water. The aqueous solution was washed with diethyl ether (2×). The water layer was then collected, concentrated under reduced pressure and purified by RP-HPLC using a triethyl ammonium acetate buffer pH 6.5. RT=14 min (0-20 min 12% B, B=50% CH3CN). Yield 37% of compound 11 as triethyl ammonium salt (18.4 mg). 31P NMR (D2O) δ-1.02, 13C NMR δ 7.3, 22.4, 45.7, 57.2, 63.0, 68.3, 70.7, 82.3, 84.1, 84.4, 118.2, 126.5, 140.2, 148.2, 151.8, 154.6, 180.4, 199.5, MS (ES-TOF) m/z calculated: 361.08. found: 361.10.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]2[CH:8](Br)[CH2:9][O:10][C:11]3[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][C:12]=3[C:13]=2[N:14]=1)=[O:4].[NH:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1>C1COCC1.CCCCCC>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]2[CH:8]([N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)[CH2:9][O:10][C:11]3[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][C:12]=3[C:13]=2[N:14]=1)=[O:4]
Reactant: C1COCCN1
Reactant: COC(=O)c1nc2c(s1)C(Br)COc1ccc(Br)cc1-2
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COC(=O)c1nc2c(s1)C(N1CCOCC1)COc1ccc(Br)cc1-2
Temperature: 60 °C
Reaction time: 5 h
Yield: 73.9 %

Procedure:
To a solution of 4,9-Dibromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid methyl ester (400 mg, 0.954 mmol) in THF (6 mL) was added morpholine (416 mg, 4.775 mmol). The reaction mixture was stirred at 60° C. for 5 h. Then the mixture was cooled to room temperature and partitioned between EtOAc and H2O, and the aqueous layer was extracted with EtOAc (2×20 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo to afford crude product as yellow oil. The oily product was stirred in n-Hexane (6 mL) at room temperature for 0.5 h and then filtered to afford compound 9-Bromo-4-morpholin-4-yl-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid methyl ester (300 mg, 75%) as a light yellow solid. 1H NMR (400 MHz, DMSO-d6): δ 8.39 (d, J=2.6 Hz, 1H), 7.48 (dd, J1=8.6 Hz, J2=2.6 Hz, 1H), 7.13 (d, J1=8.64 Hz, 1H), 4.55 (dd, J1=12.08 Hz, J2=3.32 Hz, 1H), 4.40 (dd, J1=6.6 Hz, J2=3.2 Hz, 1H), 4.31 (m, 1H); 3.94 (s, 31-1) 3.56 (m, 4H); 2.68 (m, 4H); LC-MS (ESI & APCI): 427.2 (M+2).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:9]([O:11]C)=[O:10])=[N:4][C:5]([Cl:8])=[CH:6][N:7]=1.[OH-].[Na+].C(OCC)(=O)C.O>CO>[Cl:1][C:2]1[C:3]([C:9]([OH:11])=[O:10])=[N:4][C:5]([Cl:8])=[CH:6][N:7]=1
Reactant: COC(=O)c1nc(Cl)cnc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CO
Product: O=C(O)c1nc(Cl)cnc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.8 %

Procedure:
In 10 mL of methanol was dissolved 2.0 g of methyl 3,6-dichloro-2-pyrazinecarboxylate. Then, 10.2 mL of 1 mol/L aqueous solution of sodium hydroxide was added at an ice-cooled temperature and stirred at room temperature for one hour. The reaction mixture was poured into a mixture of 200 mL of ethyl acetate and 200 mL of water, and the organic layer was separated. The organic layer was washed successively with 50 mL of water and 50 mL of saturated aqueous solution of sodium chloride and dried on anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was washed with hexane to obtain 1.6 g of 3,6-dichloro-2-pyrazinecarboxylic acid as a white-colored solid product.
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][N:3]=1.C([N-]C(C)C)(C)C.[Li+].CN([CH:20]=[O:21])C.[BH4-].[Na+]>O>[Cl:1][C:2]1[C:7]([F:8])=[C:6]([CH2:20][OH:21])[CH:5]=[CH:4][N:3]=1
Reactant: Fc1cccnc1Cl
Reactant: CN(C)C=O
Agent: CC(C)[N-]C(C)C
Agent: [BH4-]
Agent: [Li+]
Solvent: O
Product: OCc1ccnc(Cl)c1F
Temperature: 0 °C
Reaction time: 2 h
Yield: 58.2 %

Procedure:
2-Chloro-3-fluoropyridine (1.51 mL, 14.9 mmol) was added under nitrogen atmosphere at −78° C. to a mixture of 2.0 M lithium diisopropylamide (in THF) (7.44 mL, 14.9 mmol) and THY (24 mL), and the mixture was stirred at 0° C. for 2 hours. DMF (11.4 mL, 149 mmol) was added to the mixture, and the obtained mixture was stirred at 0° C. for additional 2 hours. Sodium borohydride (731 mg, 19.3 mmol) was then added thereto, and the mixture was stirred at 0° C. for 1 hour. Water was then added to the reaction solution, which was then extracted with ethyl acetate. The solution was washed with 1N HCl, sodium hydrogen carbonate solution and saturated saline. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled away under reduced pressure. The resultant residue was purified by silica gel column chromatography to yield the title compound (1.4 g, 58%).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.C([O-])(O)=O.[Na+].Cl.[CH3:16][O:17][C:18](=[O:22])[CH2:19][CH2:20][NH2:21].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO>[CH3:16][O:17][C:18](=[O:22])[CH2:19][CH2:20][NH:21][CH2:6][C:5]1[CH:8]=[CH:9][C:2]([Cl:1])=[CH:3][CH:4]=1
Reactant: O=Cc1ccc(Cl)cc1
Reactant: COC(=O)CCN
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: O=C([O-])O
Solvent: CO
Product: COC(=O)CCNCc1ccc(Cl)cc1
Temperature: 20 °C
Reaction time: 15 h

Procedure:
To a solution of 4-chlorobenzaldehyde (1 eq.) in MeOH were added NaHCO3 (1.3 eq.) and (β-alanine methyl ester hydrochloride (1.2 eq.). The reaction was stirred for 15 h at 20° C. under nitrogen, then cooled to 0° C. Sodium triacetoxyborohydride (1.5 eq.) was added portionwise. The reaction was then warmed to 20° C. and stirred for 8 h. The crude was concentrated under reduced pressure then partitioned between EtOAc and a saturated aqueous solution of NaHCO3. The aqueous layer was extracted twice with EtOAc. The organic layers were combined, dried over MgSO4, filtered and concentrated under reduced pressure. The crude was purified by chromatography on silica gel (elution with heptane/DCM/MeOH: 50/50/0, then 0/100/0, then 0/99/1) to afford 3-(4-chloro-benzylamino)-propionic acid methyl ester.