Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N[C:2]1[C:7]([O:8][C:9]2[CH:10]=[C:11]([CH:14]=[C:15]([Cl:17])[CH:16]=2)[C:12]#[N:13])=[C:6]([Cl:18])[CH:5]=[CH:4][N:3]=1.N([O-])=[O:20].[Na+]>OS(O)(=O)=O>[Cl:17][C:15]1[CH:14]=[C:11]([CH:10]=[C:9]([O:8][C:7]2[C:2]([OH:20])=[N:3][CH:4]=[CH:5][C:6]=2[Cl:18])[CH:16]=1)[C:12]#[N:13]
Reactant: N#Cc1cc(Cl)cc(Oc2c(Cl)ccnc2N)c1
Reactant: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: N#Cc1cc(Cl)cc(Oc2c(Cl)ccnc2O)c1
Temperature: 100 °C
Reaction time: 0.08 h

Procedure:
To a suspension of 3-[(2-amino-4-chloropyridin-3-yl)oxy]-5-chlorobenzonitrile (590 mg, 2.106 mmol) in 5% aqueous H2SO4 (20 mL) cooled over an ice bath for 5 minutes was added sodium nitrite (247 mg, 3.58 mmol) and stirred 5 minutes. This mixture was then heated to 100° C. for 5 minutes. The mixture was re-cooled over an ice bath and treated with additional sodium nitrite (124 mg, 1.79 mmol), stirred cold for another 5 minutes and then heated to 100° C. for 5 minutes. The reaction mixture was again cooled over an ice bath and the resulting white solid was filtered and washed with water (4×5 mL). This solid was dried under high vacuum to provide the title compound. LRMS (M+1): 280.7.
Reaction SMILES: [NH:1]([C:8]1[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=1[NH2:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][C:22](O)=O)[CH:16]=1.P(Cl)(Cl)(Cl)=O>C(Cl)(Cl)Cl>[N:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][C:22]2[N:1]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=3[N:10]=2)[CH:16]=1
Reactant: Nc1ccccc1Nc1ccccc1
Reactant: O=C(O)Cc1cccnc1
Solvent: ClC(Cl)Cl
Solvent: O=P(Cl)(Cl)Cl
Product: c1ccc(-n2c(Cc3cccnc3)nc3ccccc32)cc1
Yield: 35.1 %

Procedure:
To a solution of 2-anilinoaniline (1.84 g) and 3-pyridineacetic acid (1.37 g) in chloroform (20 ml) was dropwise added phosphorus oxychloride (1.53 g) and the mixture was refluxed for 6 hours. After removal of the solvent under reduced pressure, the resultant residue was poured into a saturated aqueous solution of sodium bicarbonate. The mixture was extracted twice with ethyl acetate. The combined extract was washed with water and a saturated aqueous solution of sodium chloride successively, and dried over magnesium sulfate. The solvent was removed under reduced pressure to give a crystalline product, which was recrystallized from a mixture of isopropyl alcohol and n-hexane (1:2) to give 2-(pyridin-3-yl)methyl-1-phenyl-1H-benzimidazole (1.0 g).
Reaction SMILES: [C:1]1([C:7]#[C:8][CH2:9][CH2:10][CH:11]=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:13]([CH:15]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:14]>C(Cl)Cl>[C:1]1([C:7]#[C:8][CH2:9][CH2:10]/[CH:11]=[CH:15]/[CH:13]=[O:14])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=CC=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=CCCC#Cc1ccccc1
Solvent: ClCCl
Product: O=C/C=C/CCC#Cc1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 42.9 %

Procedure:
5-Phenylpent-4-ynal (0.5 g) in CH2Cl2 (5 ml) was added to a solution of formylmethylenetriphenyl phosphorane (1.8 g) in CH2Cl2 (10 ml) and the mixture was stirred at room temperature under a dry nitrogen atmosphere for 24 hours. The solvent was removed under reduced pressure and the residue was slurried with ether (50 ml), filtered, and the residue washed with ether. The ethereal solutions were combined and the product was purified by chromatography on silica eluting with ether:hexane (1:9) to yield 7-phenylhept-2E-en-6-ynal (0.25 g) as a yellow oil.
Reaction SMILES: CC1(C)[O:6][C@@H:5]([CH2:7][O:8][NH:9][C:10]([C:12]2[CH:20]=[CH:19][C:15]3[CH:16]=[N:17][S:18][C:14]=3[C:13]=2[NH:21][C:22]2[CH:27]=[CH:26][C:25]([I:28])=[CH:24][C:23]=2[F:29])=[O:11])[CH2:4][O:3]1.Cl>CO>[OH:6][C@H:5]([CH2:4][OH:3])[CH2:7][O:8][NH:9][C:10]([C:12]1[CH:20]=[CH:19][C:15]2[CH:16]=[N:17][S:18][C:14]=2[C:13]=1[NH:21][C:22]1[CH:27]=[CH:26][C:25]([I:28])=[CH:24][C:23]=1[F:29])=[O:11]
Reactant: CC1(C)OC[C@H](CONC(=O)c2ccc3cnsc3c2Nc2ccc(I)cc2F)O1
Agent: Cl
Solvent: CO
Product: O=C(NOC[C@H](O)CO)c1ccc2cnsc2c1Nc1ccc(I)cc1F
Temperature: 25 °C
Reaction time: 18 h
Yield: 52.6 %

Procedure:
To a solution of 7-(2-fluoro-4-iodo-phenylamino)-benzo[d]isothiazole-6-carboxylic acid ((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-amide (263 mg, 0.48 mmol) in MeOH (10 mL) was added a 1.0M aqueous solution of hydrochloric acid (0.97 mL). The reaction mixture was stirred at room temperature for 18 hours before being concentrated in vacuo. The resultant residue was taken up in ethyl acetate, washed with a saturated aqueous solution of sodium hydrogen carbonate then brine, dried (Na2SO4), filtered and evaporated in vacuo. The resultant residue was subjected to flash chromatography (Si—PPC, gradient 0% to 100%, ethyl acetate in DCM) to afford the title compound as a yellow solid (127 mg, 53%). LCMS (method A): RT=9.05 min, [M+H]+=504. 1H NMR (CD3OD, 400 MHz) 8.88 (1 H, s), 7.74 (1 H, d, J=8.36 Hz), 7.61 (1 H, d, J=8.35 Hz), 7.53 (1 H, dd, J=10.01, 1.93 Hz), 7.44 (1 H, ddd, J=8.36, 1.93, 1.06 Hz), 6.76 (1 H, t, J=8.53 Hz), 4.05 (1 H, dd, J=10.03, 3.50 Hz), 3.96-3.83 (2 H, m), 3.63-3.52 (2 H, m).
Reaction SMILES: S(Cl)([Cl:3])=O.[Cl:5][C:6]1[CH:7]=[CH:8][C:9]([O:16][CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[C:10]([CH2:12][CH2:13][CH2:14]O)[CH:11]=1.CN(C)P(=O)(N(C)C)N(C)C.O>O1CCCC1>[Cl:5][C:6]1[CH:7]=[CH:8][C:9]([O:16][CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[C:10]([CH2:12][CH2:13][CH2:14][Cl:3])[CH:11]=1
Reactant: O=S(Cl)Cl
Reactant: OCCCc1cc(Cl)ccc1OCCc1ccccc1
Solvent: C1CCOC1
Solvent: O
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: ClCCCc1cc(Cl)ccc1OCCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1.22 ml of thionyl chloride was added to a solution of 3.24 g of 3-[5-chloro-2-(2-phenylethoxy)phenyl]propanol and 5 ml of hexamethylphosphoric triamide in 25 ml of tetrahydrofuran under ice-cooling and stirred at room temperature for 2 hours. The reaction mixture was poured into water (100 ml), extracted with ethyl acetate, successively washed with water twice and a saturated aqueous solution of sodium hydrogencarbonate 4 times and dried over anhydrous magnesium sulfate. After evaporation of the solvent under reduced pressure, 3.21 g of crude 4-chloro-2-(3-chloropropyl)-1-(2-phenylethoxy)benzene was obtained. This compound was not purified any more but used in the subsequent reaction.
Reaction SMILES: [CH2:1]([C:3]1[C:4]([F:17])=[CH:5][N:6]=[C:7]2[C:12]=1[N:11]([CH2:13][CH:14]=C)[C:10](=[O:16])[CH:9]=[CH:8]2)[CH3:2].O.I([O-])(=O)(=O)=[O:20].[Na+]>O1CCOCC1.[Cl-].[Na+].O.CCOC(C)=O.[Os](=O)(=O)(=O)=O>[CH2:1]([C:3]1[C:4]([F:17])=[CH:5][N:6]=[C:7]2[C:12]=1[N:11]([CH2:13][CH:14]=[O:20])[C:10](=[O:16])[CH:9]=[CH:8]2)[CH3:2]
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: C=CCn1c(=O)ccc2ncc(F)c(CC)c21
Agent: O=[Os](=O)(=O)=O
Agent: [Cl-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Solvent: CCOC(C)=O
Product: CCc1c(F)cnc2ccc(=O)n(CC=O)c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.8 %

Procedure:
8-ethyl-7-fluoro-1-(2-propen-1-yl)-1,5-naphthyridin-2(1H)-one (0.181 g, 0.781 mmol) was dissolved in 1,4-dioxane (4.0 mL) and water (3.5 ml) at rt under argon. Then sodium periodate (0.418 g, 1.95 mmol) was added followed by osmium tetroxide (0.175 mL of 4% aqueous solution). After 10 mins a white precipitate came out of solution, further addition of water (2 ml) was required to re-dissolve everything. After the reaction had been left stirring at rt overnight, it was then diluted with brine (20 ml) and EtOAc (20 ml). The aqueous was then separated and washed a further with EtOAc (3×20 ml). The organic layers were then combined, dried using sodium sulphate, filtered and solvent removed to give the crude product as a yellow solid (0.168 g).
Reaction SMILES: C[O:2][C:3]([CH:5]([N:9]1[CH:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:11]([NH2:19])[C:10]1=[O:20])[CH:6]([CH3:8])[CH3:7])=[O:4]>C(O)C.[Pd]>[NH2:19][C@H:11]([C:10]([NH:9][C@H:5]([C:3]([OH:4])=[O:2])[CH:6]([CH3:8])[CH3:7])=[O:20])[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: COC(=O)C(C(C)C)N1C(=O)C(N)C1c1ccccc1
Agent: [Pd]
Solvent: CCO
Product: CC(C)[C@H](NC(=O)[C@@H](N)Cc1ccccc1)C(=O)O
Reaction time: 12 h
Yield: 85.8 %

Procedure:
According to the same procedure as in Example 1, 1-(methoxycarbonyl-2-methylpropyl)-3-amino-4-phenylazetidin-2-one (458 mg.) was subjected to hydrogenolysis at 50° C. in ethanol (30 ml.) under a hydrogen pressure of one atmosphere in the presence of a 10% Pd-C (175 mg.). The reaction was completed in 12 hours. The same after-treatment as in Example 1 was followed to give methyl ester of phenylalanylvaline (376 mg., yield: 81.5%) which was an oil. The NMR and IR spectra were completely identical with those of the authentic sample obtained in Example 5.
Reaction SMILES: [CH3:1][NH:2][C:3]([C@@H:5]1[CH2:10][CH2:9][CH2:8][CH2:7][C@@H:6]1[NH:11][C:12]1[C:17]([Cl:18])=[CH:16][N:15]=[C:14](Cl)[N:13]=1)=[O:4].[CH2:20]([N:22]1[CH2:28][CH2:27][C:26]2[CH:29]=[C:30]([NH2:33])[CH:31]=[CH:32][C:25]=2[CH2:24][CH2:23]1)[CH3:21].C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O.C(=O)(O)[O-].[Na+]>C(O)(C)C>[CH3:1][NH:2][C:3]([C@@H:5]1[CH2:10][CH2:9][CH2:8][CH2:7][C@@H:6]1[NH:11][C:12]1[C:17]([Cl:18])=[CH:16][N:15]=[C:14]([NH:33][C:30]2[CH:31]=[CH:32][C:25]3[CH2:24][CH2:23][N:22]([CH2:20][CH3:21])[CH2:28][CH2:27][C:26]=3[CH:29]=2)[N:13]=1)=[O:4]
Reactant: CNC(=O)[C@@H]1CCCC[C@@H]1Nc1nc(Cl)ncc1Cl
Reactant: CCN1CCc2ccc(N)cc2CC1
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Product: CCN1CCc2ccc(Nc3ncc(Cl)c(N[C@H]4CCCC[C@H]4C(=O)NC)n3)cc2CC1
Reaction time: 8 h
Yield: 46.7 %

Procedure:
cis-2-(2,5-dichloro-pyrimidin-4-ylamino)-cyclohexanecarboxylic acid methylamide (45 mg, 0.15 mmol) and 3-ethyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamine (30 mg, 0.16 mmol) were combined with camphorsulfonic acid (60 mg, 0.25 mmol) in 3 mL isopropyl alcohol and subjected to microwave irradiation at 120° C. for 2 hours. Solid sodium bicarbonate (a pinch) was added and the mixture was stored in a freezer overnight. The mixture was subsequently concentrated and the organics were partitioned between dichloromethane and saturated sodium bicarbonate solution (100 mL each). The organic layer was separated and was dried (sodium sulfate) to afford a solid which was purified on amine functionalized silica (10% to 100% ethyl acetate:hexane gradient elution) to afford 32 mg (47%) of a white solid. Mp: 143° C.; MS: 458.59 (M+H); 1H NMR (chloroform-d): δ 7.90 (s, 1H), δ 7.35-7.24 (m, 2H), δ 7.04 (d, J=8 Hz, 1H), δ 6.82 (s, 1H), δ 6.51 (d, J=7 Hz, 1H), δ 5.64 (br s, 1H), δ 4.34 (m, 1H), δ 2.97-2.54 (m, 6H), δ 2.79 (d, J=4 Hz, 3H), δ 2.36-0.78 (m, 13H), δ 1.12 (t, J=7 Hz, 3H).
Reaction SMILES: [F:1][C:2]([F:17])([S:13][CH2:14][CH2:15][OH:16])[C:3]([F:12])([F:11])[C:4]([F:10])([F:9])[C:5]([F:8])([F:7])[F:6].[Cl:18][CH:19]([CH2:23][Cl:24])[C:20](O)=[O:21]>C1CCCCC1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[Cl:18][CH:19]([CH2:23][Cl:24])[C:20]([O:16][CH2:15][CH2:14][S:13][C:2]([F:1])([F:17])[C:3]([F:12])([F:11])[C:4]([F:10])([F:9])[C:5]([F:8])([F:7])[F:6])=[O:21]
Reactant: OCCSC(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reactant: O=C(O)C(Cl)CCl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: C1CCCCC1
Product: O=C(OCCSC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)C(Cl)CCl
Yield: 96.5 %

Procedure:
1,1,1,2,2,3,3,4,4-nonafluoro-4-iodobutane (138.4 g (400 mmol)) was dissolved in a mixture liquid of DMF (400 ml) and water (80 ml), and mercaptoethanol (32.2 g (400 mmol)) was added. Further, sodium formate (27.2 g (400 mol)), sodium sulfite heptahydrate (100.9 g (400 mmol)) were added, and stirred at room temperature (23° C.) for one night. Water (1 L) and isopropyl ether (1 L) were added to the reaction liquid, which was separated. A water layer was further extracted with isopropyl ether (500 ml×2). The organic layer was washed with 10% hydrochloric acid (500 ml), water (500 ml) and a saturated saline solution (500 ml), dried over anhydrous magnesium sulfate and filtered. The solvent was distilled off to give 2-(perfluorobutylthio)ethanol. Then, p-toluene sulfonic acid monohydrate (2.5 g (13.1 mmol)) was added to a solution of 2-(perfluorobutylthio)ethanol (50 g (equivalent to 158 mmol)) and 2,3-dichloropropionic acid (22.5 g (157 mmol)) in cyclohexane (500 ml), and was subjected to dehydration condensation reaction (bath temperature: 90° C.) for one night by using a Dean-Stark method. The reaction liquid was filtered with celite. An organic layer was washed with water three times and with saturated saline solution, and dried over anhydrous magnesium sulfate. The filtration and concentration under reduced pressure gave crude 2-(perfluorobutylthio)ethyl 2,3-dichloropropionate (63.8 g). Yield: 96.5%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][O:10][C:11]2[N:12]=[C:13]([NH2:50])[C:14]3[N:15]=[CH:16][N:17]([C:48]=3[N:49]=2)[C@@H:18]2[O:47][C@H:37]([CH2:38][O:39][Si](C(C)(C)C)(C)C)[C@@H:28]([O:29][Si](C(C)(C)C)(C)C)[C@H:19]2[O:20][Si](C(C)(C)C)(C)C)=[CH:4][CH:3]=1.N1C=CC=CC=1.F>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][O:10][C:11]2[N:12]=[C:13]([NH2:50])[C:14]3[N:15]=[CH:16][N:17]([C:48]=3[N:49]=2)[C@@H:18]2[O:47][C@H:37]([CH2:38][OH:39])[C@@H:28]([OH:29])[C@H:19]2[OH:20])=[CH:6][CH:7]=1
Reactant: CC(C)(C)[Si](C)(C)OC[C@H]1O[C@@H](n2cnc3c(N)nc(OCCc4ccc(Cl)cc4)nc32)[C@H](O[Si](C)(C)C(C)(C)C)[C@@H]1O[Si](C)(C)C(C)(C)C
Agent: F
Solvent: CO
Solvent: c1ccncc1
Product: Nc1nc(OCCc2ccc(Cl)cc2)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Temperature: 50 °C
Yield: 50 %

Procedure:
To a solution of 2-[2-(4-chlorophenyl)ethoxy]-2′,3′,5′-tri-O-(TERT-butyldimethylsilyl)-adenosine (Example 1, 500 mg, 0.654 mmol) in 7 mL of anhydrous methanol flushed with nitrogen was added 323 mg (5 equiv.) of hydrogen fluoride-pyridine. The reaction was heated to 50° C. for 18 hours. Upon disappearance of the starting material as indicated by LC analysis, the reaction was allowed to cool to room temperature, which resulted in precipitation of a white solid. This was collected by filtration, rinsed with 3 mL of methanol and dried to obtain 138 mg (50%) of the desired product as a white solid.
Reaction SMILES: N1([O:10][C:11]2[C:12]3[N:13]=[CH:14][N:15]([C:38]=3[N:39]=[CH:40][N:41]=2)[C@@H:16]2[O:37][C@H:27]([CH2:28][O:29][Si:30]([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31])[C@@H:18]([O:19][Si:20]([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21])[CH2:17]2)C2C=CC=CC=2N=N1.[CH2:42](O)[CH:43]=[CH2:44].C([O-])([O-])=O.[Cs+].[Cs+]>>[CH2:44]([O:10][C:11]1[C:12]2[N:13]=[CH:14][N:15]([C:38]=2[N:39]=[CH:40][N:41]=1)[C@@H:16]1[O:37][C@H:27]([CH2:28][O:29][Si:30]([C:33]([CH3:35])([CH3:34])[CH3:36])([CH3:32])[CH3:31])[C@@H:18]([O:19][Si:20]([C:23]([CH3:25])([CH3:26])[CH3:24])([CH3:21])[CH3:22])[CH2:17]1)[CH:43]=[CH2:42]
Reactant: CC(C)(C)[Si](C)(C)OC[C@H]1O[C@@H](n2cnc3c(On4nnc5ccccc54)ncnc32)C[C@@H]1O[Si](C)(C)C(C)(C)C
Reactant: C=CCO
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: C=CCOc1ncnc2c1ncn2[C@H]1C[C@H](O[Si](C)(C)C(C)(C)C)[C@@H](CO[Si](C)(C)C(C)(C)C)O1
Yield: 89 %

Procedure:
As described for the synthesis of 3′,5-bis-O-(tert-butyldimethylsilyl)-O6-methyl-2′-deoxyinosine, the allyl derivative was prepared by a reaction between O6-(benzotriazol-1-yl)-3′,5-bis-O-(tert-butyldimethylsilyl)-2′-deoxyinosine (26) (59.8 mg, 0.100 mmol) and allyl alcohol (1 mL) in the presence of Cs2CO3 (65.2 mg, 0.200 mmol) over 2 h. Chromatographic purification (SiO2, elution with 20% EtOAc in hexanes) afforded 46.4 mg (89% yield) of the title compound as a clear gum. Rf (20% EtOAc in hexanes)=0.29. 1H NMR (500 MHz, CDCl3): δ 8.51 (s, 1H, Ar—H), 8.27 (s, 1H, Ar—H), 6.50 (t, 1H, H-1′, J=6.4), 6.16 (m, 1H, —CH═), 5.45 (dd, 1H, ═CHtrans, J=17.1, 1.5), 5.29 (d, 1H, ═CHcis, J=10.7), 5.12 (d, 2H, OCH2, J=5.4), 4.61 (m, 1H, H-3′), 4.02 (q, 1H, H-4′, J=3.4), 3.87 (dd, 1H, H-5′, J=11.2, 3.9), 3.77 (dd, 1H, H-5′, J=11.2, 2.9), 2.61 (app quint, 1H, H-2′, Japp˜6.3), 2.44 (ddd, 1H, H-2′, J=12.9, 6.1, 3.9), 0.91 (s, 18H, tert-Bu), 0.09, 0.08 (2 s, 12H, SiCH3). 13C NMR (126 MHz, CDCl3): δ 160.3, 151.9, 151.6, 140.6, 132.4, 121.9, 118.5, 87.9, 84.4, 71.8, 67.5, 62.7, 41.4, 26.0, 25.7, 18.4, 18.0, −4.7, −4.8, −5.4, −5.5. FAB HRMS calcd for C25H45N4O4Si2 (M++H) 521.2979. found 521.2974.
Reaction SMILES: [CH2:1]([C@:8]([NH:38][C:39](=[O:45])[O:40][C:41]([CH3:44])([CH3:43])[CH3:42])([CH3:37])[C:9]([NH:11][NH:12][C:13](=[O:36])[C:14]1[CH:19]=[C:18]([N:20]([CH3:25])[S:21]([CH3:24])(=[O:23])=[O:22])[N:17]=[C:16]([N:26]([CH2:32][CH2:33][O:34][CH3:35])[CH2:27][CH:28]2[CH2:30][CH:29]2[CH3:31])[CH:15]=1)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1C=CN=C1.C(Br)(Br)(Br)Br>C(Cl)Cl>[CH3:35][O:34][CH2:33][CH2:32][N:26]([CH2:27][C@@H:28]1[CH2:30][C@H:29]1[CH3:31])[C:16]1[CH:15]=[C:14]([C:13]2[O:36][C:9]([C@@:8]([NH:38][C:39](=[O:45])[O:40][C:41]([CH3:42])([CH3:44])[CH3:43])([CH3:37])[CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[N:11][N:12]=2)[CH:19]=[C:18]([N:20]([CH3:25])[S:21]([CH3:24])(=[O:23])=[O:22])[N:17]=1
Reactant: COCCN(CC1CC1C)c1cc(C(=O)NNC(=O)[C@@](C)(Cc2ccccc2)NC(=O)OC(C)(C)C)cc(N(C)S(C)(=O)=O)n1
Agent: BrC(Br)(Br)Br
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COCCN(C[C@@H]1C[C@H]1C)c1cc(-c2nnc([C@@](C)(Cc3ccccc3)NC(=O)OC(C)(C)C)o2)cc(N(C)S(C)(=O)=O)n1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of tert-butyl [(1R)-1-benzyl-2-oxo-(2-{2-{(2-methoxyethyl)[(2-methylcyclopropyl)methyl]amino}-6-[methyl(methylsulfonyl)amino]isonicotinoyl}hydrazino)-1-methylethyl]carbamate (16.2 g, 25 mmol), triphenylphosphine (7.88 g, 30.1 mmol) and imidazole (2.05 g, 30.1 mmol) in DCM (150 mL) cooled to 0° C. was added carbon tetrabromide (9.97 g, 30.1 mmol) and the reaction mixture was stirred at RT for 16 h. The reaction mixture was concentrated in vacuo, and purified by flash chromatography (silica, 20% to 50% EtOAc in hexane) to give tert-butyl [(1R)-1-(5-{2-{(2-methoxyethyl)[(trans-2-methylcyclopropyl)methyl]amino}-6-[methyl(methylsulfonyl)amino]pyridin-4-yl}-1,3,4-oxadiazol-2-yl)-1-methyl-2-phenylethyl]carbamate. MS M+1=629.
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[C@H:15]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C@@H:14]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C@:13]2([C:33]3[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([CH2:40][C:41]4[CH:46]=[CH:45][C:44]([O:47][CH2:48][CH3:49])=[CH:43][CH:42]=4)[CH:34]=3)[O:32][C@@:10]1([CH:50]([OH:52])[CH3:51])[CH2:11][O:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:53](OCCl)(=[O:58])[C:54]([CH3:57])([CH3:56])[CH3:55].[H-].[Na+]>O1CCCC1>[CH3:55][C:54]([CH3:57])([CH3:56])[C:53]([O:52][CH:50]([C@:10]12[O:32][C@:13]([C:33]3[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([CH2:40][C:41]4[CH:42]=[CH:43][C:44]([O:47][CH2:48][CH3:49])=[CH:45][CH:46]=4)[CH:34]=3)([O:12][CH2:11]1)[C@H:14]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C@@H:15]([O:16][CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[C@@H:9]2[O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH3:51])=[O:58]
Reactant: CC(C)(C)C(=O)OCCl
Reactant: CCOc1ccc(Cc2cc([C@]34OC[C@](C(C)O)(O3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]4OCc3ccccc3)ccc2Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOc1ccc(Cc2cc([C@]34OC[C@](C(C)OC(=O)C(C)(C)C)(O3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]4OCc3ccccc3)ccc2Cl)cc1
Temperature: 40 °C
Reaction time: 48 h
Yield: 27.8 %

Procedure:
To a solution of 1-[(1R,2S,3S,4R,5S)-2,3,4-tribenzyloxy-5-[4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl]-6,8-dioxabicyclo[3.2.1]octan-1-yl]ethanol 1m (0.4 g, 0.56 mmol, obtained from the synthetic method described in step 11 of example 1) and chloromethyl pivalate (0.36 mL, 2.5 mmol) in tetrahydrofuran (20 mL) was added sodium hydride (77.8 mg, 1.95 mmol, 60% dispersion in Mineral oil) at 0° C. The mixture was heated to 40° C. and stirred for 48 hours. The resulting mixture was quenched with saturated ammonium chloride (20 mL), and then extracted with ethyl acetate (60 mL×3). The combined organic layers were washed with water (50 mL×2) and then saturated brine (50 mL×3), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo and the residue was purified by silica gel chromatography eluted with PE/EtOAc(v/v)=10/1 to give the title compound 14a as light yellow oil (125 mg, 27.8%). The compound was characterized by the following spectroscopic data: 1H NMR (600 MHz, CDCl3) δ (ppm): 7.42-7.30 (m, 10H), 7.28-7.15 (m, 6H), 7.07 (m, 2H), 6.91 (m, 2H), 6.76 (m, 2H), 5.20 (m, 1H), 4.98 (d, 1H), 4.89-4.82 (m, 2H), 4.31 (m, 1H), 4.25 (d, 1H), 4.11-3.80 (m, 7H), 3.86 (d, 1H), 3.70 (m, 2H), 1.41 (t, 3H), 1.27 (d, 3H), 1.20 (s, 9H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([NH2:8])=[N:6][CH:7]=1.[Cl:9][CH2:10][C:11](=O)[CH2:12]Cl>CCO>[Cl:9][CH2:10][C:11]1[N:8]=[C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][N:6]2[CH:12]=1
Reactant: Nc1ccc(F)cn1
Reactant: O=C(CCl)CCl
Solvent: CCO
Product: Fc1ccc2nc(CCl)cn2c1
Temperature: 80 °C
Reaction time: 8 h
Yield: 57.6 %

Procedure:
According to the general protocol described in J. Heterocyclic. Chem., 1988, 25, 129-137, to solution of 5-fluoropyridin-2-amine (1.80 g, 16 mmol) in EtOH (24 mL) was added 1,3-dichloropropan-2-one (2.03 g, 16 mmol) and the resulting mixture was stirred overnight at 80° C. The solvent was evaporated, and the residue was dissolved in a minimum volume of water. The solution was neutralized (pH=8) with saturated NaHCO3. The aqueous layer was extracted with AcOEt and the organic layer was washed with saturated NaCl. The solvent was evaporated and the crude product was purified by chromatography (prepacked 25 g silicagel column, DCM as eluent) to afford 1.7 g of 2-(chloromethyl)-6-fluoro-imidazo[1,2-a]pyridine
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[CH:14]=[C:13]([NH2:15])[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[C:18]=1[N:24]=[C:25]=[O:26]>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[N:10]=[CH:11][N:12]=[C:13]([NH:15][C:25]([NH:24][C:18]3[C:17]([CH3:16])=[CH:22][CH:21]=[CH:20][C:19]=3[CH3:23])=[O:26])[CH:14]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Nc1cc(Nc2cccc(Cl)c2)ncn1
Reactant: Cc1cccc(C)c1N=C=O
Product: Cc1cccc(C)c1NC(=O)Nc1cc(Nc2cccc(Cl)c2)ncn1

Procedure:
The title compound is prepared analogously as described in Example 127 from N-(3-chloro-phenyl)-pyrimidine-4,6-diamine and 2,6-dimethylphenyl isocyanate.
Reaction SMILES: [NH:1]1[CH2:7][CH:6]([CH2:8][OH:9])[CH2:5][NH:4][CH2:3][CH2:2]1.[CH2:10]([N:17]1[C:25]2[C:24](=[O:26])[N:23]([CH3:27])[C:22](=[O:28])[N:21]([CH3:29])[C:20]=2[N:19]=[C:18]1Cl)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:10]([N:17]1[C:25]2[C:24](=[O:26])[N:23]([CH3:27])[C:22](=[O:28])[N:21]([CH3:29])[C:20]=2[N:19]=[C:18]1[N:1]1[CH2:7][CH:6]([CH2:8][OH:9])[CH2:5][NH:4][CH2:3][CH2:2]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Cn1c(=O)c2c(nc(Cl)n2Cc2ccccc2)n(C)c1=O
Reactant: OCC1CNCCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cn1c(=O)c2c(nc(N3CCNCC(CO)C3)n2Cc2ccccc2)n(C)c1=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 1 %

Procedure:
([1,4]Diazepan-6-yl)methanol (1C) including potassium carbonate salts (ca 1 mmol) was suspended in dry DMF (200 ml) and 7-benzyl-8-chloro-1,3-dimethyl-3,7-dihydro-purine-2,6-dione (199.9 mg, 0.656 mmol) and potassium carbonate (453 mg, 3.28 mmol) were added. The reaction mixture was stirred at room temperature for 24 hours, heated to 60° C. for 3 hours, heated to 95° C. for 5 hours and heated to 120° C. for 2 hours. The suspension was allowed to cool to room temperature and white salts were filtered off. The filtrate was evaporated and purified by chromatography on silica, using 5% methanol in dichloromethane as the eluent. Fractions containing the product were evaporated and purified by preparative HPLC (method A2; Rt=2.52 min.) to afford 8 mg of the title compound as an yellow oil in 1% yield.