Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([Cl:4])(Cl)=[O:2].[CH3:5][C:6]1([CH3:18])[CH2:11][CH:10]([N:12]2[CH2:16][CH2:15][NH:14][C:13]2=[O:17])[CH2:9][CH2:8][O:7]1.N1C=CC=CC=1>C(Cl)Cl>[CH3:5][C:6]1([CH3:18])[CH2:11][CH:10]([N:12]2[CH2:16][CH2:15][N:14]([C:1]([Cl:4])=[O:2])[C:13]2=[O:17])[CH2:9][CH2:8][O:7]1
Reactant: CC1(C)CC(N2CCNC2=O)CCO1
Reactant: O=C(Cl)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC1(C)CC(N2CCN(C(=O)Cl)C2=O)CCO1
Temperature: 25 °C
Yield: 100 %

Procedure:
A 0° C. solution of phosgene (20% in toluene, 0.361 mL, 0.676 mmol) in DCM (2 mL), under Ar, was treated slowly drop-wise with a solution of 1-(2,2-dimethyltetrahydro-2H-pyran-4-yl)imidazolidin-2-one (0.067 g, 0.338 mmol) and pyridine (0.055 mL, 0.676 mmol) in DCM (1 mL). The mixture was warmed to RT and concentrated to dryness to afford 3-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-oxoimidazolidine-1-carbonyl chloride as a yellow solid which was carried on to the next step assuming 100% yield (88 mg).
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]2[C:11]([C:12]3[CH:17]=[CH:16][N:15]=[C:14]([S:18][CH3:19])[N:13]=3)=[CH:10][NH:9][N:8]=2)=[CH:4][CH:3]=1.I[CH:21]([CH3:23])[CH3:22].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[Cl:1][C:2]1[S:6][C:5]([C:7]2[C:11]([C:12]3[CH:17]=[CH:16][N:15]=[C:14]([S:18][CH3:19])[N:13]=3)=[CH:10][N:9]([CH:21]([CH3:23])[CH3:22])[N:8]=2)=[CH:4][CH:3]=1
Reactant: CC(C)I
Reactant: CSc1nccc(-c2c[nH]nc2-c2ccc(Cl)s2)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CSc1nccc(-c2cn(C(C)C)nc2-c2ccc(Cl)s2)n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 73.9 %

Procedure:
To a solution of 4-[3-(5-chloro-2-thienyl)-1H-pyrazol-4-yl]-2-(methylsulfanyl)pyrimidin (1 eq, 16.2 mmol) in 120 mL N,N-dimethylformamide were added 2-iodopropane (1.5 eq, 24.3 mmol) and cesium carbonate (1.1 eq, 17.8 mmol). The reaction mixture was stirred at room temperature for 4 h and the solvent was then evaporated. The residue was diluted with water and dichloromethane. The layers were separated and the aqueous layer was extracted three times with dichloromethane. The combined organic extracts were dried over MgSO4 filtered and concentrated. The residue was purified by chromatography on silica gel (dichloromethane) to afford 4.2 g of 4-[3-(5-chloro-2-thienyl)-1-isopropyl-1H-pyrazol-4-yl]-2-(methylsulfanyl)pyrimidin (70% yield).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][C:3]=1[N+:11]([O-])=O.O.[CH:15]([C:18]1[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=1)([CH3:17])[CH3:16]>C1COCC1>[NH2:11][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:2]=1[CH3:1])[C:6]([NH:24][C:20]1[CH:21]=[CH:22][CH:23]=[C:18]([CH:15]([CH3:17])[CH3:16])[CH:19]=1)=[O:7]
Reactant: Cc1ccc(C(=O)Cl)cc1[N+](=O)[O-]
Reactant: CC(C)c1cccc(N)c1
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(C(=O)Nc2cccc(C(C)C)c2)cc1N
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 4-methyl-3-nitro-benzoyl chloride (2.00 g, 0.010 mol) in THF (30 mL), in a water bath-cooled 100 mL round bottom flask, was added 3-isopropyl-phenylamine (1.35 g, 0.010 mol) dropwise. The reaction was allowed to stir at room temperature for 1 hour before being concentrated. The mixture was taken up in EtOAc and washed with NaHCO3 (aq., conc.) and then brine. The solution was dried over MgSO4, filtered, and concentrated to yield the title compound as an orange oil that solidifies upon standing. MS m/z 299=[M+H]+. Calc'd for C17H18N2O3: 298.34.
Reaction SMILES: [Na].[C:2]([O:10][CH2:11][CH3:12])(=[O:9])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].Cl.Cl[CH2:15][C:16]1[C:21]([CH2:22]Cl)=[CH:20][CH:19]=[CH:18][N:17]=1>C(O)C>[CH2:11]([O:10][C:2]([C:3]1([C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH2:15][C:16]2[N:17]=[CH:18][CH:19]=[CH:20][C:21]=2[CH2:22]1)=[O:9])[CH3:12]
Reactant: ClCc1cccnc1CCl
Reactant: CCOC(=O)CC(=O)OCC
Agent: Cl
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)C1(C(=O)OCC)Cc2cccnc2C1
Temperature: 25 °C

Procedure:
Sodium metal (0.345 g, 15.0 mmol) is dissolved in ethanol (20 ml) and diethyl malonate (0.713 g, 4.70 mmol) is added, followed by a suspension of 2,3-bis(chloromethyl)pyridine hydrochloride (Org. Process Res. Dev., 2002, 6, 938; 1.0 g, 4.70 mmol) in ethanol (15 ml) over 5 minutes. The reaction is heated to reflux for 5 hours, cooled to ambient temperature and filtered. The filtrate is evaporated, taken into water and extracted with ethyl acetate. The combined organic phases are washed with brine, dried (MgSO4) and evaporated. The crude product is purified by flash column chromatography (3:1-2:1 isohexanes-EtOAc gradient) to afford 5,7-dihydro-[1]pyrindine-6,6-dicarboxylic acid diethyl ester, MH+264.
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([C:7]([O:9][CH3:10])=[O:8])=[C:4]([NH:11][C:12](=O)[C:13](F)(F)F)[CH:3]=1.Br.Br[CH2:20][C:21]1[CH:22]=[N:23][CH:24]=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+].CC(N(C)C)=O>O>[Br:1][C:2]1[S:6][C:5]([C:7]([O:9][CH3:10])=[O:8])=[C:4]([NH:11][CH2:12][C:13]2[CH:24]=[N:23][CH:22]=[CH:21][CH:20]=2)[CH:3]=1
Reactant: BrCc1cccnc1
Reactant: COC(=O)c1sc(Br)cc1NC(=O)C(F)(F)F
Agent: Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: COC(=O)c1sc(Br)cc1NCc1cccnc1
Temperature: 80 °C
Reaction time: 2 h
Yield: 52.6 %

Procedure:
A mixture of methyl 5-bromo-3-[(trifluoroacetyl)amino]thiophene-2-carboxylate (100 mg, 1.51 mmol), 3-(bromomethyl)pyridine hydrobromide (457 mg, 1.81 mmol), cesium carbonate (1.72 g, 5.29 mmol) and DMA (15 mL) was stirred at 80° C. for 2 h. Then, water was added to quench the reaction. The organic materials were extracted with EtOAc. The combined extracts were washed with water and brine, dried over Na2SO4 and filtered. After removal of the solvent at reduced pressure, the residue was dissolved in MeOH (5 mL). To the solution were added potassium carbonate (500 mg) and water (2.5 mL). The mixture was stirred at room temperature for 2 h. After removal of the solvent at reduced pressure, the organic materials were extracted with EtOAc. The combined extracts were washed with brine, dried over Na2SO4 and filtered. After removal of the solvent at reduced pressure, the residue was purified by column chromatography (Purif, silica gel, hexane to 50:50 hexane/EtOAc) to give the title compound (260 mg, 53%) as a yellow solid:
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([OH:24])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:27])[F:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:29][C:30]([F:41])([F:40])[O:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[CH2:38]O>>[CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH2:38][C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=3[O:31][C:30]([F:29])([F:40])[F:41])[CH:19]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:26])[F:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OCc1ccccc1OC(F)(F)F
Reactant: Oc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Product: FC(F)(F)Oc1ccccc1COc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1

Procedure:
This compound was prepared according to the procedure of example 69, substituting 3-(3-benzyl-8-trifluoromethyl-quinolin-4-yl)-phenol and (2-trifluoromethoxy-phenyl)-methanol. MS (ESI) m/z 554.
Reaction SMILES: [CH:1]([C:3]1[C:11]2[C:10]([C:12]([O:14][CH3:15])=[O:13])=[CH:9][CH:8]=[N:7][C:6]=2[N:5]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH:4]=1)=O.[NH2:23][C:24]1([CH3:37])[CH2:29][CH2:28][N:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:26][CH2:25]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[C:33]([O:32][C:30]([N:27]1[CH2:26][CH2:25][C:24]([NH:23][CH2:1][C:3]2[C:11]3[C:10]([C:12]([O:14][CH3:15])=[O:13])=[CH:9][CH:8]=[N:7][C:6]=3[N:5]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH:4]=2)([CH3:37])[CH2:29][CH2:28]1)=[O:31])([CH3:36])([CH3:35])[CH3:34]
Reactant: COC(=O)c1ccnc2c1c(C=O)cn2C(=O)OC(C)(C)C
Reactant: CC1(N)CCN(C(=O)OC(C)(C)C)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)c1ccnc2c1c(CNC1(C)CCN(C(=O)OC(C)(C)C)CC1)cn2C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 76.9 %

Procedure:
1-tert-Butyl 4-methyl 3-formyl-1H-pyrrolo[2,3-b]pyridine-1,4-dicarboxylate (71 mg, 0.233 mmol) was dissolved in DCM (5 mL) and tert-butyl 4-amino-4-methylpiperidine-1-carboxylate (50 mg, 0.233 mmol) was added to the solution and allowed to stir for 2 h at room temperature. Then sodium triacetoxyborohydride (148 mg, 0.700 mmol) was added and the mixture was allowed to stir for 2 h at room temperature. The solution was quenched with water and extracted with DCM. The organics were dried over MgSO4 and concentrated in vacuo. Purification by silica gel chromatography (70% EtOAc/Hexanes) gave 90 mg of 1-tert-butyl 4-methyl 3-((1-(tert-butoxycarbonyl)-4-methylpiperidin-4-ylamino)methyl)-1H-pyrrolo[2,3-b]pyridine-1,4-dicarboxylate. [M+H] found 403.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]([CH3:16])([CH3:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:5][CH:4]=1)#[N:2].[ClH:17]>C(O)C.[C].[Pd]>[ClH:17].[NH2:2][CH2:1][C:3]1[CH:4]=[CH:5][C:6]([C:9]([CH3:15])([CH3:16])[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:7][CH:8]=1
Reactant: CCOC(=O)C(C)(C)c1ccc(C#N)cc1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: CCOC(=O)C(C)(C)c1ccc(CN)cc1
Reaction time: 3 h

Procedure:
To a solution of 280 mg of ethyl 2-(4-cyanophenyl)-2-methylpropanoate in 10 ml of ethanol were added 2 mL of 1 M hydrochloric acid and 120 mg of 10% palladium-carbon in this order, followed by stirring for 3 hours under a hydrogen atmosphere at 3 atm. The catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure and dried to obtain 345 mg of, ethyl 2-[4-(aminomethyl)phenyl]-2-methylpropanoate hydrochloride.
Reaction SMILES: C([O:3][C:4](=O)[CH:5]([CH:11](OCC)[CH:12]([N:19]1[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7])C>C1(C)C(C)=CC=CC=1>[CH2:9]([O:8][C:6]([C:5]1[C:4](=[O:3])[N:14]2[CH:13]([CH:18]=[CH:17][CH:16]=[CH:15]2)[CH:12]([N:19]2[CH2:20][CH2:21][N:22]([C:25]([O:27][C:28]([CH3:30])([CH3:29])[CH3:31])=[O:26])[CH2:23][CH2:24]2)[CH:11]=1)=[O:7])[CH3:10]
Reactant: CCOC(=O)C(C(=O)OCC)C(OCC)C(c1ccccn1)N1CCN(C(=O)OC(C)(C)C)CC1
Solvent: Cc1ccccc1C
Product: CCOC(=O)C1=CC(N2CCN(C(=O)OC(C)(C)C)CC2)C2C=CC=CN2C1=O
Temperature: 140 °C
Yield: 70.9 %

Procedure:
2-[2-(4-tert-Butoxycarbonyl-piperazin-1-yl)-1-ethoxy-2-pyridin-2-yl-ethyl]-malonic acid diethyl ester (2.40 g, 4.86 mmol) was dissolved in xylene (20 mL) and heated at 140° C. for 12 hours. After cooling, the volatiles were evaporated and the residue was purified by column chromatography (EtOAc) to give 1-(4-tert-Butoxycarbonyl-piperazin-1-yl)-4-oxo-1,9a-dihydro-4H-quinolizine-3-carboxylic acid ethyl ester (1.39 g, 71%) as an orange solid. 1H NMR (CDCl3, 400 MHz) δ 9.48 (d, J=7.2 Hz, 1H), 8.34 (s, 1H), 7.69 (td, J=7.2 Hz, J=1.2 Hz, 1H), 7.23 (m, 1H), 4.44 (q, J=7.2 Hz, 2H), 4.14 (m, 2H), 3.10 (m, 2H), 2.88 (m, 4H), 1.51 (s, 9H), 1.43 (t, J=7.2 Hz, 3H). LCMS (APCI+) m/z 402 [M+H]+; Rt=2.85 min.
Reaction SMILES: [C:1]([C:5]1[C:19]([OH:20])=[C:18]([CH2:21][C:22]([CH3:24])=[CH2:23])[C:8]2[CH2:9][C:10]3([O:17][C:7]=2[CH:6]=1)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]3)([CH3:4])([CH3:3])[CH3:2]>C(O)C.[Pd]>[C:1]([C:5]1[C:19]([OH:20])=[C:18]([CH2:21][CH:22]([CH3:24])[CH3:23])[C:8]2[CH2:9][C:10]3([O:17][C:7]=2[CH:6]=1)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]3)([CH3:4])([CH3:3])[CH3:2]
Reactant: C=C(C)Cc1c(O)c(C(C)(C)C)cc2c1CC1(CCCCCC1)O2
Agent: [Pd]
Solvent: CCO
Product: CC(C)Cc1c(O)c(C(C)(C)C)cc2c1CC1(CCCCCC1)O2
Yield: 69.6 %

Procedure:
0.80 g of 6-t-butyl-5-hydroxy-4-(2-methyl-2-propenyl)-2,3-dihydrobenzofuran-2-spiro-1′-cycloheptane synthesized in Example 10 was dissolved in 5 ml of ethanol and the solution was treated with 0.05 g of 10% palladium on carbon in the same manner as in Example 9 to give 0.56 g of 6-t-butyl-5-hydroxy-4-(2-methylpropyl)-2,3-dihydrobenzofuran-2-spiro-1′-cycloheptane as a pale yellow oil (yield 70%).
Reaction SMILES: C(O[C:5](=[O:7])C)(=O)C.[OH:8][NH:9][CH:10]([CH2:35][CH2:36][CH2:37][C:38]1[N:43]=[CH:42][CH:41]=[CH:40][N:39]=1)[CH2:11][S:12]([N:15]1[CH2:20][CH2:19][N:18]([C:21]2[N:26]=[CH:25][C:24]([C:27]#[C:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=3)=[CH:23][N:22]=2)[CH2:17][CH2:16]1)(=[O:14])=[O:13]>O1CCCC1.C(O)=O>[OH:8][N:9]([CH:10]([CH2:11][S:12]([N:15]1[CH2:16][CH2:17][N:18]([C:21]2[N:22]=[CH:23][C:24]([C:27]#[C:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=3)=[CH:25][N:26]=2)[CH2:19][CH2:20]1)(=[O:14])=[O:13])[CH2:35][CH2:36][CH2:37][C:38]1[N:39]=[CH:40][CH:41]=[CH:42][N:43]=1)[CH:5]=[O:7]
Reactant: CC(=O)OC(C)=O
Reactant: O=S(=O)(CC(CCCc1ncccn1)NO)N1CCN(c2ncc(C#Cc3ccccn3)cn2)CC1
Solvent: C1CCOC1
Solvent: O=CO
Product: O=CN(O)C(CCCc1ncccn1)CS(=O)(=O)N1CCN(c2ncc(C#Cc3ccccn3)cn2)CC1
Temperature: 45 °C
Reaction time: 0.75 h

Procedure:
Formic acid (1.8 mL, 50 mmol) and acetic anhydride (0.5 mL, 5 mmol) were mixed together at 0° C. for 30 minutes, before being added to a solution 2-(4-{[2-(hydroxyamino)-5-pyrimidin-2-ylpentyl]sulfonyl}piperazin-1-yl)-5-(pyridin-2-ylethynyl)pyrimidine (190 mg, 0.37 mmol) in tetrahydrofuran (5 mL) and formic acid (1.8 mL) at 0° C. The reaction was allowed to reach room temperature and was stirred for 45 minutes. The reaction was then evaporated in vacuo, and azeotroped with toluene (2×5 mL). The residue was then dissolved in MeOH and heated to 45° C. for one hour. The solution was evaporated in vacuo, and the residue triturated with Et2O to give a white solid which was collected by filtration, washed with Et2O and dried in vacuo to give hydroxy {1-[({4-[5-(pyridin-2-ylethynyl)pyrimidin-2-yl]piperazin 1-yl}sulfonyl)methyl]-4-pyrimidin-2-ylbutyl}formamide as a white solid. (64 mg, 32%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][NH:11][C:12](=[O:17])[C:13]([F:16])([F:15])[F:14])=[CH:6][CH:5]=1)([O-])=O.C(OCC)(=O)C.[H][H]>C(O)C.[Pt]=O>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([NH:10][NH:11][C:12](=[O:17])[C:13]([F:14])([F:15])[F:16])=[CH:8][CH:9]=1
Reactant: O=C(NNc1ccc([N+](=O)[O-])cc1)C(F)(F)F
Reactant: [H][H]
Agent: O=[Pt]
Solvent: CCOC(C)=O
Solvent: CCO
Product: Nc1ccc(NNC(=O)C(F)(F)F)cc1

Procedure:
2-(4-Nitrophenyl)-1-trifluoroacetylhydrazine (2.5 g, 0.01 mole) and platinum oxide (84%, catalytic amount) were mixed in ethanol (100 ml) and ethyl acetate (100 ml) in a Parr shaker bottle. The reaction mixture was hydrogenated at room temperature until hydrogen uptake ceased. The reaction mixture was filtered and the solvent was evaporated from the filtrate leaving a brown semisolid. Yield 2.0 g (91%), no m.p. was taken on this material. Spectral data verified its structure.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][N:10]=[CH:9][N:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=1.[CH2:24]([CH2:26][NH2:27])[OH:25]>>[OH:25][CH2:24][CH2:26][NH:27][C:19](=[O:21])[C:18]1[CH:22]=[CH:23][C:15]([O:14][CH2:13][C:3]2[C:4]([C:7]3[CH:12]=[CH:11][N:10]=[CH:9][N:8]=3)=[N:5][O:6][C:2]=2[CH3:1])=[N:16][CH:17]=1
Reactant: NCCO
Reactant: Cc1onc(-c2ccncn2)c1COc1ccc(C(=O)O)cn1
Product: Cc1onc(-c2ccncn2)c1COc1ccc(C(=O)NCCO)cn1
Yield: 73 %

Procedure:
As described for example 313b, 6-(5-methyl-3-pyrimidin-4-yl-isoxazol-4-ylmethoxy)-nicotinic acid (53 mg, 0.17 mmol) was converted, using ethanolamine instead of isopropylamine, to the title compound (44 mg, 73%) which was obtained as a white solid. MS: m/e=356.3 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9]O)=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[O:30]1[CH2:34][C:33](=[O:35])[NH:32][C:31]1=[O:36].N(C(OC(C)C)=O)=NC(OC(C)C)=O>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][N:32]2[C:33](=[O:35])[CH2:34][O:30][C:31]2=[O:36])=[CH:6][CH:7]=1
Reactant: O=C1COC(=O)N1
Reactant: OCCc1ccc(Br)cc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: O=C1COC(=O)N1CCc1ccc(Br)cc1

Procedure:
The procedure described in Example 2 (step 2.1.) is used; starting from 4 g (19.89 mmol) of 2-(4-bromophenyl)ethanol, 6.3 g (23.87 mmol) of triphenylphosphine, 2.4 g (23.87 mmol) of 1,3-oxazolidine-2,4-dione and 4.8 g (23.87 mmol) of diisopropyl azodicarboxylate, 4.6 g of pure product are obtained in the form of a white solid, after chromatography on silica gel, eluting with dichloromethane.
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:13][C@@H:12]([N:14]([CH2:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]=[CH:24][CH:23]=2)[C:15](=[O:20])[C:16]([F:19])([F:18])[F:17])[CH2:11][CH2:10][NH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[N:33]1[CH:38]=[CH:37][C:36]([CH2:39][C:40](O)=[O:41])=[CH:35][CH:34]=1.O=C1N(P(Cl)(N2CCOC2=O)=O)CCO1.C(N(CC)CC)C>>[CH2:1]([C@@H:8]1[CH2:13][C@@H:12]([N:14]([CH2:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]=[CH:24][CH:23]=2)[C:15](=[O:20])[C:16]([F:18])([F:19])[F:17])[CH2:11][CH2:10][N:9]1[C:40](=[O:41])[CH2:39][C:36]1[CH:37]=[CH:38][N:33]=[CH:34][CH:35]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(N(Cc1ccnc2ccccc12)[C@H]1CCN[C@H](Cc2ccccc2)C1)C(F)(F)F
Reactant: O=C(O)Cc1ccncc1
Agent: Cl
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: CCN(CC)CC
Product: O=C(Cc1ccncc1)N1CC[C@H](N(Cc2ccnc3ccccc23)C(=O)C(F)(F)F)C[C@H]1Cc1ccccc1

Procedure:
200 mg (0.468 mmol) of (2R*,4S*)-2-benzyl-N-(4-quinolylmethyl)-N-trifluoroacetyl-4-piperidinamine are reacted in analogy to Example 4 with 98 mg (0.561 mmol) of 4-pyridylacetic acid hydrochloride, 143 mg (0.562 mmol) of bis-(2-oxo-3-oxazolidinyl)phosphinic chloride and 209 μl (1.50 mmol) of triethylamine. The title compound is obtained as white foam. TLC: methylene chloride/methanol/conc. ammonia (700:50:1) Rf =0.56, FD-MS: M+ =546.
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([F:14])=[C:10]([O:15][C:16]2[N:21]=[C:20]3[S:22][C:23]([NH2:25])=[N:24][C:19]3=[CH:18][CH:17]=2)[CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[C:27](Cl)(=[O:29])[CH3:28].O>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[C:1]([O:5][C:6](=[O:26])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([F:14])=[C:10]([O:15][C:16]2[N:21]=[C:20]3[S:22][C:23]([NH:25][C:27](=[O:29])[CH3:28])=[N:24][C:19]3=[CH:18][CH:17]=2)[CH:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccc(F)c(Oc2ccc3nc(N)sc3n2)c1
Reactant: CC(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: c1ccncc1
Product: CC(=O)Nc1nc2ccc(Oc3cc(NC(=O)OC(C)(C)C)ccc3F)nc2s1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of tert-butyl{3-[(2-amino[1,3]thiazolo[5,4-b]pyridin-5-yl)oxy]-4-fluorophenyl}carbamate (0.94 g, 2.5 mmol) and N,N-dimethylpyridine-4-amine (0.31 g, 2.5 mmol) in pyridine (5 mL) was added dropwise acetyl chloride (0.40 g, 5 mmol) under ice-cooling, and the mixture was stirred at room temperature overnight. To the reaction mixture was added water (100 mL), and the mixture was extracted with ethyl acetate (100 mL×2). The ethyl acetate layers were combined, and dried over anhydrous magnesium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was triturated with diethyl ether to give the title compound (1.05 g, quantitatively) as a white amorphous.
Reaction SMILES: [Cl:1][C:2]1[C:10]([O:11][CH3:12])=[C:9]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH:24]=[CH:23][CH:22]=[N:21]3)=[CH:16][CH:15]=2)[CH:8]=[C:7]2[C:3]=1[CH:4](O)[N:5]([C@@H:26]1[CH2:31][CH2:30][CH2:29][CH2:28][C@H:27]1[OH:32])[C:6]2=[O:25].FC(F)(F)C(O)=O.C([SiH](CC)CC)C.C(=O)(O)[O-].[Na+]>ClCCl>[Cl:1][C:2]1[C:10]([O:11][CH3:12])=[C:9]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH:24]=[CH:23][CH:22]=[N:21]3)=[CH:16][CH:15]=2)[CH:8]=[C:7]2[C:3]=1[CH2:4][N:5]([C@@H:26]1[CH2:31][CH2:30][CH2:29][CH2:28][C@H:27]1[OH:32])[C:6]2=[O:25]
Reactant: COc1c(Cc2ccc(-n3cccn3)cc2)cc2c(c1Cl)C(O)N([C@@H]1CCCC[C@H]1O)C2=O
Agent: CC[SiH](CC)CC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1c(Cc2ccc(-n3cccn3)cc2)cc2c(c1Cl)CN([C@@H]1CCCC[C@H]1O)C2=O
Reaction time: 0.25 h
Yield: 29.6 %

Procedure:
To a solution of rac-4-chloro-3-hydroxy-2-(trans-2-hydroxycyclohexyl)-5-methoxy-6-[4-(1H-pyrazol-1-yl)benzyl]-2,3-dihydro-1H-isoindol-1-one (0.07 g) in dichloromethane (2.00 mL) was added trifluoroacetic acid (0.50 mL) under ice-cooling, and the mixture was stirred for 15 min. Then, triethylsilane (0.40 mL) was added thereto, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was poured into saturated aqueous sodium bicarbonate solution, and the mixture was extracted with ethyl acetate (×2). The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by prep-HPLC, then lyophilized to give the title compound (0.02 g).
Reaction SMILES: C([N+](CCCC)(CCCC)CCCC)CCC.[P:18]([O:22][CH2:23][C@@H:24]1[C@@H:28]([O:29][P:30]([O:33][CH2:34][C@@H:35]2[C@@H:39]([OH:40])[C@@H:38]([OH:41])[C@H:37]([N:42]3[CH:50]=[N:49][C:48]4[C:43]3=[N:44][CH:45]=[N:46][C:47]=4[NH2:51])[O:36]2)([OH:32])=[O:31])[CH2:27][C@H:26]([N:52]2[CH:57]=[CH:56][C:55]([NH2:58])=[N:54][C:53]2=[O:59])[O:25]1)([OH:21])([OH:20])=[O:19].[CH2:60]([O:67][C:68]([NH:70][CH2:71][CH2:72][CH2:73][CH2:74][C@H:75]([NH:82][C:83]([O:85][C:86]([CH3:89])([CH3:88])[CH3:87])=[O:84])[C:76](OCC#N)=[O:77])=[O:69])[C:61]1[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=1>O.O1CCCC1>[CH2:60]([O:67][C:68]([NH:70][CH2:71][CH2:72][CH2:73][CH2:74][C@@H:75]([NH:82][C:83]([O:85][C:86]([CH3:89])([CH3:88])[CH3:87])=[O:84])[C:76]([O:40][C@H:39]1[C@@H:38]([OH:41])[C@H:37]([N:42]2[CH:50]=[N:49][C:48]3[C:43]2=[N:44][CH:45]=[N:46][C:47]=3[NH2:51])[O:36][C@H:35]1[CH2:34][O:33][P:30]([O:29][C@H:28]1[CH2:27][C@H:26]([N:52]2[CH:57]=[CH:56][C:55]([NH2:58])=[N:54][C:53]2=[O:59])[O:25][C@@H:24]1[CH2:23][O:22][P:18]([OH:21])([OH:20])=[O:19])([OH:32])=[O:31])=[O:77])=[O:69])[C:61]1[CH:62]=[CH:63][CH:64]=[CH:65][CH:66]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCCNC(=O)OCc1ccccc1)C(=O)OCC#N
Reactant: Nc1ccn([C@H]2C[C@H](OP(=O)(O)OC[C@H]3O[C@@H](n4cnc5c(N)ncnc54)[C@H](O)[C@@H]3O)[C@@H](COP(=O)(O)O)O2)c(=O)n1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N[C@H](CCCCNC(=O)OCc1ccccc1)C(=O)O[C@H]1[C@@H](O)[C@H](n2cnc3c(N)ncnc32)O[C@H]1COP(=O)(O)O[C@H]1C[C@H](n2ccc(N)nc2=O)O[C@@H]1COP(=O)(O)O
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 18.1 %

Procedure:
A solution of ((2R,3S,5R)-5-(4-amino-2-oxopyrimidin-1(2H)-yl)-3-(((((2R,3S,4R,5R)-5-(6-amino-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methoxy) (hydroxy)phosphoryl)oxy)tetrahydrofuran-2-yl)methyl dihydrogenphosphate (Compound 1h) (65.6 mg, 0.103 mmol) in water (0.3 mL) and a solution of (S)-cyanomethyl 6-(((benzyloxy) carbonyl)amino)-2-((tert-butoxycarbonyl)amino)hexanoate (Compound tk45) (173 mg, 0.412 mmol) in tetrahydrofuran (0.3 mL) were added to buffer A (18 mL), and the mixture was stirred at room temperature for 0.75 hour. Following lyophilization, the resulting residue was purified by reverse-phase silica gel column chromatography (0.05% aqueous trifluoroacetic acid solution/0.05% trifluoroacetic acid-acetonitrile solution) to afford (2S)-(2R,3S,4R,5R)-2-((((((2R,3S,5R)-5-(4-amino-2-oxopyrimidin-1(2H)-yl)-2-((phosphonooxy)methyl)tetrahydrofuran-3-yl)oxy)(hydroxy)phosphoryl)oxy)methyl)-5-(6-amino-9H-purin-9-yl)-4-hydroxytetrahydrofuran-3-yl 6-(((benzyloxy)carbonyl)amino)-2-((tert-butoxycarbonyl)amino)hexanoate (Compound tk46) (18.6 mg, 18%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:29]=[CH:28][C:6]2[CH2:7][O:8][C:9](=[O:27])[N:10]([CH2:11][CH2:12][N:13]3[CH2:18][CH2:17][CH:16]([NH:19]C(=O)OC(C)(C)C)[CH2:15][CH2:14]3)[C:5]=2[CH:4]=1.FC(F)(F)C(O)=O>ClCCl>[NH2:19][CH:16]1[CH2:15][CH2:14][N:13]([CH2:12][CH2:11][N:10]2[C:5]3[CH:4]=[C:3]([O:2][CH3:1])[CH:29]=[CH:28][C:6]=3[CH2:7][O:8][C:9]2=[O:27])[CH2:18][CH2:17]1
Reactant: COc1ccc2c(c1)N(CCN1CCC(NC(=O)OC(C)(C)C)CC1)C(=O)OC2
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc2c(c1)N(CCN1CCC(N)CC1)C(=O)OC2
Reaction time: 2 h

Procedure:
A solution of tert-butyl {1-[2-(7-methoxy-2-oxo-2H-3,1-benzoxazin-1(4H)-yl)ethyl]piperidin-4-yl}carbamate (Intermediate 107) (319 mg, 0.78 mmol) in dichloromethane (8 mL) was treated at room temperature under vigorous stirring with a trifluoroacetic acid (0.75 mL, 10 mmol). After 2 hours, the reaction mixture was concentrated under reduced pressure to give 324 mg (quantitative) of product as a brown oil.