Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH:5]=[CH:4][N:3]=[CH:2]1.[CH3:15][O:16][CH:17]([O:21][CH3:22])N(C)C>>[CH3:15][O:16][CH:17]([O:21][CH3:22])[N:12]1[CH2:13][CH2:14][CH:9]([CH2:8][CH2:7][CH2:6][N:1]2[CH:5]=[CH:4][N:3]=[CH:2]2)[CH2:10][CH2:11]1
Reactant: c1cn(CCCC2CCNCC2)cn1
Reactant: COC(OC)N(C)C
Product: COC(OC)N1CCC(CCCn2ccnc2)CC1
Temperature: 100 °C

Procedure:
A mixture of 4-[3-(1H-imidazol-1-yl)propyl]-piperidine (1.5 g, 0.0078M) and dimethylformamide dimethylacetal (10 ml) was heated at 100° C. for 16 hrs. The excess of dimethylformamide dimethylacetal was removed to give 4-[3-(1H-imidazol-1-yl)propyl]-1-piperidinecarboxaldehyde dimethylacetal. To the mixture of 6-aminopenicillanic acid (1.16 g, 0.0053M) and diisopropylethylamine (1.03 ml) in dry CHCl3 (9 ml) was added the above piperidinecarboxaldehyde in CHCl3 (5 ml) at 0° C. and stirred at that temperature for 1 hr, then at room temperature for 3 hrs. After the reaction, the solvent was removed and the residue dissolved in water (40 ml). The aqueous solution, washed with diethyl ether, was adjusted to pH 3 with dilute aqueous HCl and purified on Sephadex LH 20 column to give [2S-(2alpha,5alpha,6beta)]-6-[[4-[3-(1 H-imidazol-1-yl)propyl]-1-piperidinyl]methylene]amino]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid 1.2 mole hydrochloride monohydrate (0.87 g, 39% yield).
Reaction SMILES: [CH3:1][C:2]([CH3:45])([CH3:44])[CH:3]([NH:16][C:17]1[C:22]([F:23])=[CH:21][N:20]=[C:19]([C:24]2[C:32]3[C:27](=[N:28][CH:29]=[C:30]([F:33])[CH:31]=3)[N:26]([S:34]([C:37]3[CH:43]=[CH:42][C:40]([CH3:41])=[CH:39][CH:38]=3)(=[O:36])=[O:35])[CH:25]=2)[N:18]=1)[CH2:4][CH2:5][Se]C1C=CC=CC=1[N+]([O-])=O.C1C=C(Cl)C=C(C(OO)=O)C=1>C(Cl)(Cl)Cl.ClCCl>[CH3:1][C:2]([CH3:45])([CH3:44])[CH:3]([NH:16][C:17]1[C:22]([F:23])=[CH:21][N:20]=[C:19]([C:24]2[C:32]3[C:27](=[N:28][CH:29]=[C:30]([F:33])[CH:31]=3)[N:26]([S:34]([C:37]3[CH:38]=[CH:39][C:40]([CH3:41])=[CH:42][CH:43]=3)(=[O:36])=[O:35])[CH:25]=2)[N:18]=1)[CH:4]=[CH2:5]
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3ncc(F)c(NC(CC[Se]c4ccccc4[N+](=O)[O-])C(C)(C)C)n3)c3cc(F)cnc32)cc1
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: C=CC(Nc1nc(-c2cn(S(=O)(=O)c3ccc(C)cc3)c3ncc(F)cc23)ncc1F)C(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.4 %

Procedure:
To a cold (0° C.) solution of racemic N-(4,4-dimethyl-1-((2-nitrophenyl)selanyl)pentan-3-yl)-5-fluoro-2-(5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]yridin-3-yl)pyrimidin-4-amine, 88a, (1.01 g, 1.45 mmol) in chloroform (15 mL) was added mCPBA (0.40 g of 77%, 1.79 mmol). After stirring for 1 hour at room temperature, the mixture was diluted with dichloromethane (100 mL) and the resulting solution was washed with aqueous sodium bicarbonate solution. The organic phase was dried (MgSO4), filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography (0 to 100% EtOAc/Hexanes) to afford 623 mg of the desired product: LCMS Gradient 10-90%, 0.1% formic acid, 5 minutes, C18/ACN, (M+H) 496.76.
Reaction SMILES: [CH3:1][C:2]1[C:31]([CH3:32])=[CH:30][CH:29]=[CH:28][C:3]=1[O:4][CH2:5][CH2:6][CH2:7][C:8]([N:10]1[C:19]2[C:14](=[C:15](C3C=CC(CO)=CC=3)[CH:16]=[CH:17][CH:18]=2)[CH2:13][CH2:12][CH2:11]1)=[O:9].OCC1C=CC(B(O)O)=CC=1.CC1(C)C(C)(C)OB([C:52]2[CH:53]=[C:54]([CH:64]=[CH:65][CH:66]=2)[CH2:55][NH:56][C:57](=[O:63])[O:58][C:59]([CH3:62])([CH3:61])[CH3:60])O1>>[CH3:1][C:2]1[C:31]([CH3:32])=[CH:30][CH:29]=[CH:28][C:3]=1[O:4][CH2:5][CH2:6][CH2:7][C:8]([N:10]1[C:19]2[C:14](=[C:15]([C:52]3[CH:53]=[C:54]([CH:64]=[CH:65][CH:66]=3)[CH2:55][NH:56][C:57](=[O:63])[O:58][C:59]([CH3:60])([CH3:61])[CH3:62])[CH:16]=[CH:17][CH:18]=2)[CH2:13][CH2:12][CH2:11]1)=[O:9]
Reactant: Cc1cccc(OCCCC(=O)N2CCCc3c(-c4ccc(CO)cc4)cccc32)c1C
Reactant: CC(C)(C)OC(=O)NCc1cccc(B2OC(C)(C)C(C)(C)O2)c1
Agent: OCc1ccc(B(O)O)cc1
Product: Cc1cccc(OCCCC(=O)N2CCCc3c(-c4cccc(CNC(=O)OC(C)(C)C)c4)cccc32)c1C

Procedure:
The title compound was prepared using a procedure analogous to 4-(2,3-dimethylphenoxy)-1-(5-(4-(hydroxymethyl)phenyl)-3,4-dihydroquinolin-1(2H)-yl)butan-1-one except that 4-(hydroxymethyl)phenylboronic acid was replaced with tert-butyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzylcarbamate. LCMS, [M+Na]+=551.4.
Reaction SMILES: [S:1]1[CH2:6][CH:5]=[C:4]([C:7]2[CH:12]=[CH:11][C:10]([N:13]3[CH2:17][C@H:16]([CH2:18][OH:19])[O:15][C:14]3=[O:20])=[CH:9][C:8]=2[F:21])[CH2:3][CH2:2]1.C(N(CC)CC)C.[CH3:29][S:30](Cl)(=[O:32])=[O:31]>ClCCl>[S:1]1[CH2:2][CH:3]=[C:4]([C:7]2[CH:12]=[CH:11][C:10]([N:13]3[CH2:17][C@H:16]([CH2:18][O:19][S:30]([CH3:29])(=[O:32])=[O:31])[O:15][C:14]3=[O:20])=[CH:9][C:8]=2[F:21])[CH2:5][CH2:6]1
Reactant: O=C1O[C@@H](CO)CN1c1ccc(C2=CCSCC2)c(F)c1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OC[C@H]1CN(c2ccc(C3=CCSCC3)c(F)c2)C(=O)O1
Temperature: -20 °C

Procedure:
(5R)-3-[4-(3,6-dihydro-2H-thiopyran-4-yl)-3-fluorophenyl]-5-hydroxymethyloxazolidin-2-one (14 g, 45.3 mmol) was dissolved in dichloromethane (300 ml) and triethylamine (8.8 ml, 63.3 mmol) was added. It was cooled to −20° C. and methanesulfonyl chloride (4.22 ml, 54.4 mmol), dissolved in dichloromethane (50 ml), was added dropwise. The reaction mixture was allowed to warm to room temperature and was quenched with potassium phosphate buffer (pH 7). Dichloromethane was removed under vacuum and it was extracted with ethyl acetate, washed with water and dried over magnesium sulfate. The title compound (16.9 g) was precipitated from dichloromethane by addition of hexane.
Reaction SMILES: [NH:1]([C:3]1[CH:8]=[CH:7][N:6]=[C:5]([O:9][CH3:10])[N:4]=1)[NH2:2].[CH3:11][CH2:12][CH2:13]CCC.[CH3:17][CH2:18][O:19][C:20]([CH3:22])=[O:21]>>[CH3:10][O:9][C:5]1[N:4]=[C:3]([N:1]2[C:22]([C:20]([O:19][CH2:18][CH3:17])=[O:21])=[CH:11][C:12]([CH3:13])=[N:2]2)[CH:8]=[CH:7][N:6]=1
Reactant: CCCCCC
Reactant: CCOC(C)=O
Reactant: COc1nccc(NN)n1
Product: CCOC(=O)c1cc(C)nn1-c1ccnc(OC)n1

Procedure:
The title product was prepared in analogy to the procedure described in Example 57 using 4-hydrazinyl-2-methoxypyrimidine (Step 59.1). tR: 4.28 min (HPLC 1); tR: 0.93 min (LC-MS 2); ESI-MS: 263 [M+H]+ (LC-MS 2); Rf=0.58 (hexane/EtOAc 1:1).
Reaction SMILES: [C:1]([C:4]1[C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:8][N:7]([CH2:16][CH3:17])[C:6](=[O:18])[C:5]=1[N+:19]([O-])=O)(=[O:3])[CH3:2].N[C:23]1[CH:32]=[CH:31][CH:30]=[C:29]2[C:24]=1[CH:25]=[CH:26][C:27]([CH3:33])=[N:28]2>C(O)C>[C:1]([C:4]1[C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:8][N:7]([CH2:16][CH3:17])[C:6](=[O:18])[C:5]=1[NH:19][C:23]1[CH:32]=[CH:31][CH:30]=[C:29]2[C:24]=1[CH:25]=[CH:26][C:27]([CH3:33])=[N:28]2)(=[O:3])[CH3:2]
Reactant: Cc1ccc2c(N)cccc2n1
Reactant: CCn1nc(-c2ccccc2)c(C(C)=O)c([N+](=O)[O-])c1=O
Solvent: CCO
Product: CCn1nc(-c2ccccc2)c(C(C)=O)c(Nc2cccc3nc(C)ccc23)c1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 57.7 %

Procedure:
To a stirred solution of 100 mg (0.348 mmol) of 5-acetyl-2-ethyl-4-nitro-6-phenylpyridazin-3(2H)-one (Dal Piaz, V et al, J. Med. Chem. 1997, 40, 1417) in ethanol (5 mL), 5-amino-2-methylquinoline (83 mg, 0.522 mmol) was added. The resulting mixture was stirred at room temperature during three hours and the final product was collected by filtration and washed with diethylether to yield the title compound (80 mg, 57.6% yield).
Reaction SMILES: [O:1]([C:8]1[C:21](C(C)(C)C)=[CH:20][C:19]([CH3:26])=[CH:18][C:9]=1/[N:10]=[CH:11]/[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O(CCCC)CCCC.[C:36]1([Li])[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>C1COCC1>[O:1]([C:8]1[CH:21]=[CH:20][C:19]([CH3:26])=[CH:18][C:9]=1[NH:10][CH:11]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cc(/N=C/c2ccccn2)c(Oc2ccccc2)c(C(C)(C)C)c1
Reactant: [Li]c1ccccc1
Solvent: CCCCOCCCC
Solvent: C1CCOC1
Product: Cc1ccc(Oc2ccccc2)c(NC(c2ccccc2)c2ccccn2)c1
Reaction time: 0.25 h
Yield: 62 %

Procedure:
To a solution of 12 (300 mg, 1.12 mmol) in THF was added 1.24 mL of a 1.8M nBu2O solution of phenyl lithium at −40° C. After stirring for 15 min, the reaction was quenched with water (1 mL). MgSO4 was added and the mixture filtered to give a yellow solution. Removal of the solvent under vacuum gave C1 as a yellow oil (240 mg, 62% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([OH:16])=[N:6][C:7]=1[NH:8][CH:9]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1.[CH:17]1(NC2N=C(O)C=CC=2[N+]([O-])=O)CCCCC[CH2:18]1>CC(C)(C)C([O-])([O-])[O-]>[CH:9]1([N:8]2[C:7]3=[N:6][C:5]([OH:16])=[CH:4][CH:3]=[C:2]3[N:1]=[C:17]2[CH3:18])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: O=[N+]([O-])c1ccc(O)nc1NC1CCCCCC1
Reactant: Nc1ccc(O)nc1NC1CCCCCC1
Agent: CC(C)(C)C([O-])([O-])[O-]
Product: Cc1nc2ccc(O)nc2n1C1CCCCCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
5-Amino-6-(cycloheptylamino)pyridin-2-ol, prepared in a similar manner as the one described in Example 1.3 from 6-(cycloheptylamino)-5-nitropyridin-2-ol, was taken up in trimethylorthoacetate and stirred at room temperature overnight. The solvent was removed under reduced pressure and the residue was purified by preparative HPLC to give the title compound. LCMS m/z=246.1 [M+H]+; 1H NMR (400 MHz, acetonitrile-d3) δ ppm 1.55-1.80 (m, 6H), 1.85-2.05 (m, 4H), 2.50-2.60 (m, 2H), 2.80 (s, 3H), 4.50-4.60 (m, 1H), 6.84 (d, J=8.8 Hz, 1H), 8.01 (d, J=8.8 Hz, 1H).
Reaction SMILES: [I:1][CH2:2][C:3]1[N:4]=[C:5]([C:14]2[CH:19]=[CH:18][C:17](C)=[CH:16][CH:15]=2)[O:6][C:7]=1[C:8]1C=CC=CC=1.C/C(/C(C)=O)=N\O.[F:28]C1C=CC(C=O)=CC=1>>[F:28][C:17]1[CH:18]=[CH:19][C:14]([C:5]2[O:6][C:7]([CH3:8])=[C:3]([CH2:2][I:1])[N:4]=2)=[CH:15][CH:16]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: Cc1ccc(-c2nc(CI)c(-c3ccccc3)o2)cc1
Agent: CC(=O)/C(C)=N/O
Product: Cc1oc(-c2ccc(F)cc2)nc1CI

Procedure:
Analogously to the building block synthesis of 4-iodomethyl-5-phenyl-2-p-tolyloxazole, diacetylmonoxime and 4-fluorobenzaldehyde gave 2-(4-fluorophenyl)-4-iodomethyl-5-methyloxazole.
Reaction SMILES: N(OC(C)(C)C)=O.ON1C(=O)C2=CC=CC=C2C1=O.[CH3:20][C:21]1[CH:29]=[CH:28][C:24]([CH:25]=[N:26]O)=[CH:23][CH:22]=1.CC1C=CC(C=O)=CC=1>C(O)(=O)C.CC1C=CC(C)=CC=1>[CH3:20][C:21]1[CH:29]=[CH:28][C:24]([C:25]#[N:26])=[CH:23][CH:22]=1
Reactant: Cc1ccc(C=NO)cc1
Agent: CC(C)(C)ON=O
Agent: Cc1ccc(C=O)cc1
Agent: O=C1c2ccccc2C(=O)N1O
Solvent: CC(=O)O
Solvent: Cc1ccc(C)cc1
Product: Cc1ccc(C#N)cc1
Temperature: 60 °C
Reaction time: 20 h

Procedure:
In a flask p-xylene (1 ml), t-butyl nitrite (1 mmol), N-hydroxyphthalimide (0.1 mmol), and acetic acid (1 ml) were placed and were stirred at 60° C. in an atmosphere of argon gas (1 atm=0.101 MPa) for 20 hours. The resulting reaction mixture was analyzed to find that p-methylbenzaldehyde oxime, p-methylbenzaldehyde, and p-methylbenzonitrile were formed in yields of 60%, 3%, and 3%, respectively.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([NH2:8])[N:3]=1.[Cl:9][C:10]1[CH:18]=[C:17]([Cl:19])[CH:16]=[C:15]([Cl:20])[C:11]=1[C:12](Cl)=[O:13]>O1CCOCC1>[NH2:8][C:4]1[N:3]=[C:2]([NH:1][C:12](=[O:13])[C:11]2[C:15]([Cl:20])=[CH:16][C:17]([Cl:19])=[CH:18][C:10]=2[Cl:9])[CH:7]=[CH:6][CH:5]=1
Reactant: Nc1cccc(N)n1
Reactant: O=C(Cl)c1c(Cl)cc(Cl)cc1Cl
Solvent: C1COCCO1
Product: Nc1cccc(NC(=O)c2c(Cl)cc(Cl)cc2Cl)n1
Yield: 39.5 %

Procedure:
Using a method similar to Preparation 48, using 2,6-diaminopyridine (2.6 g, 12 mmol), dioxane (80 mL), and 2,4,6-trichlorobenzoyl chloride (1.95 g, 8 mmol)(stir at 0–25° C. for 16 hr.) gives the title intermediate (1.0 g, 39% yield): mass spectrum (ion spray): m/z=316.0 (M+1).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[C:7]([C:12]([OH:14])=O)[C:8]2=[O:11])=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH:28]1([NH2:34])[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1.O>ClCCl>[CH:28]1([NH:34][C:12]([C:7]2[C:8](=[O:11])[C:9]3[C:5]([C:6]=2[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:4][CH:3]=[C:2]([OH:1])[CH:10]=3)=[O:14])[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1
Reactant: O=C(O)C1=C(c2ccccc2)c2ccc(O)cc2C1=O
Reactant: NC1CCCCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: O=C(NC1CCCCC1)C1=C(c2ccccc2)c2ccc(O)cc2C1=O
Temperature: 25 °C
Yield: 19.7 %

Procedure:
6-Hydroxy-1-oxo-3-phenyl-1H-indene-2-carboxylic acid (100 mg, 0.38 mmol) obtained in Step 2 was dissolved in dichloromethane, and triethylamine (175 μl, 1.25 mmol) and cyclohexylamine (43 μl, 0.38 mmol) were added thereto at 10° C. Then, bis(2-oxo-3-oxazoline)phosphoryl chloride (100 mg, 0.38 mmol) was further added thereto, stirred for 10˜20 minutes at RT, and then stirred for additional 1 hr in a water bath. After water was added to complete the reaction, the mixture washed with sodium bicarbonate and extracted with dichloromethane. The organic layer was separated, dried over anhydrous MgSO4, concentrated under a reduced pressure. The resulting residue was purified by flash chromatography to obtain 26 mg of the titled compound (yield: 20.0%) as a red solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[CH3:12])[N:8]=[CH:7][CH:6]=[CH:5]2.CN1CCCC1=[O:19].[C:20]([Cu])#[N:21]>O>[CH3:12][C:11]1[CH:10]=[C:9]2[C:4]([CH:5]=[CH:6][C:7](=[O:19])[NH:8]2)=[CH:3][C:2]=1[C:20]#[N:21]
Reactant: Cc1cc2ncccc2cc1Br
Reactant: CN1CCCC1=O
Reactant: N#C[Cu]
Solvent: O
Product: Cc1cc2[nH]c(=O)ccc2cc1C#N
Temperature: 20 °C
Reaction time: 8 h

Procedure:
A mixture of 6-bromo-7-methylquinolin (10 g, 42.0 mmol, prepared following J. Med. Chem. 1988, 31, 2048.), N-methyl-2-pyrrolidinone (32 mL), and CuCN (11 g, 0.13 mol) was stirred at 20° C. overnight and then at reflux temperature (202° C.) for 7 h. The mixture was poured into water (250 mL) and filtered, and the solid was washed twice with water to furnish 7-Methyl-2-oxo-1,2-dihydroquinoline-6-carbonitrile.
Reaction SMILES: [CH:1]1[C:9]2[C:8]3[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:7]=3[O:6][C:5]=2[CH:4]=[CH:3][C:2]=1[NH2:16].[C:17]([C:21]1[CH:29]=[CH:28][C:24]([C:25](Cl)=[O:26])=[CH:23][CH:22]=1)([CH3:20])([CH3:19])[CH3:18]>ClCCl>[C:17]([C:21]1[CH:22]=[CH:23][C:24]([C:25]([NH:16][C:2]2[CH:3]=[CH:4][C:5]3[O:6][C:7]4[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][C:8]=4[C:9]=3[CH:1]=2)=[O:26])=[CH:28][CH:29]=1)([CH3:20])([CH3:18])[CH3:19]
Reactant: CC(C)(C)c1ccc(C(=O)Cl)cc1
Reactant: Nc1ccc2oc3c(c2c1)CCCCCC3
Solvent: ClCCl
Product: CC(C)(C)c1ccc(C(=O)Nc2ccc3oc4c(c3c2)CCCCCC4)cc1
Yield: 60.9 %

Procedure:
Following the procedure of Example 1, 6,7,8,9,10,11-Hexahydro-benzo[b]-cycloocta[d]furan-2-ylamine (0.15 g, 0.70 mmol), 4-t-butylbenzoyl chloride (0.14 mL, 0.73 mmol), and poly(vinylpyridine) (0.5 g) in dichloromethane (17 mL) provided 4-tert-butyl-N-(6,7,8,9,10,11-hexahydrobenzo[b]cycloocta[d]furan-2-yl)benzamide (0.16 g). MS (ESI) m/z 376 ([M+H]+).
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:3].[NH2:11][C:12]1[CH:41]=[CH:40][C:15]([O:16][C:17]2[CH:22]=[CH:21][N:20]=[C:19]([NH:23][C:24](=[O:39])[CH2:25][CH:26]3[CH2:31][CH2:30][N:29]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:28][CH2:27]3)[CH:18]=2)=[CH:14][C:13]=1[Cl:42].N1C=CC=CC=1.CN(C)C=O>O>[Cl:42][C:13]1[CH:14]=[C:15]([CH:40]=[CH:41][C:12]=1[NH:11][C:2]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:3])[O:16][C:17]1[CH:22]=[CH:21][N:20]=[C:19]([NH:23][C:24](=[O:39])[CH2:25][CH:26]2[CH2:31][CH2:30][N:29]([C:32]([O:34][C:35]([CH3:38])([CH3:36])[CH3:37])=[O:33])[CH2:28][CH2:27]2)[CH:18]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CC(=O)Nc2cc(Oc3ccc(N)c(Cl)c3)ccn2)CC1
Reactant: O=C(Cl)Oc1ccccc1
Solvent: CN(C)C=O
Solvent: c1ccncc1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(CC(=O)Nc2cc(Oc3ccc(NC(=O)Oc4ccccc4)c(Cl)c3)ccn2)CC1
Temperature: 25 °C
Yield: 61.2 %

Procedure:
Phenyl chloroformate (210 mg) was added dropwise to a solution of 570 mg of tert-butyl 4-(2-{[4-(4-amino-3-chlorophenoxy)-2-pyridyl]amino}-2-oxoethyl)-1-piperidinecarboxylate, 110 mg of pyridine and 5 ml of dimethylformamide while stirring at room temperature, and the mixture was further stirred for 30 minutes. Water was added and extraction was performed with ethyl acetate. The organic layer was washed twice with water and once with brine, and then silica gel was added and the solvent was distilled off under reduced pressure. This was then charged into a dry column packed with silica gel and purification was performed by column chromatography (hexane:ethyl acetate=1:1, followed by ethyl acetate), to obtain 440 mg of tert-butyl 4-{2-[(4-{3-chloro-4-[(phenoxycarbonyl)amino]phenoxy}-2-pyridyl)amino]-2-oxoethyl}-1-piperidinecarboxylate as a light yellow oil. After adding 71 mg of aniline and 5 ml of dimethylformamide to the oil, it was stirred at 130° C. for 15 minutes. The reaction solution was returned to room temperature, NH type silica gel was added, the solvent was distilled off under reduced pressure and the reaction product was adsorbed onto the silica gel. The silica gel was charged into a dry column packed with NH type silica gel, and column purification was performed (hexane:ethyl acetate=1:1). The solvent was distilled off under reduced pressure to obtain 180 mg of the target substance.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]Br)=[CH:4][CH:3]=1.[CH3:10][CH:11]1[CH2:16][NH:15][CH2:14][CH2:13][NH:12]1.C(N(CC)CC)C.C(=O)(O)[O-].[Na+]>CN(C=O)C>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][N:15]2[CH2:14][CH2:13][NH:12][CH:11]([CH3:10])[CH2:16]2)=[CH:4][CH:3]=1
Reactant: CC1CNCCN1
Reactant: Clc1ccc(CBr)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC1CN(Cc2ccc(Cl)cc2)CCN1
Temperature: 25 °C
Reaction time: 16 h
Yield: 59.4 %

Procedure:
3.49 g (17.0 mmol) 4-Chlorobenzylbromide was added dropwise to a mixture of 2.04 g (20.4 mmol) 2-Methyl piperazine and 2.40 ml (17 mmol) triethylamine in 60 ml DMF at room temperature. The reaction mixture was stirred for 16 hours at room temperature, the poured onto aq. sodium bicarbonate solution and extracted with ethylacetate. Purification of the crude product by flash chromatography gave 2.26 g (10.1 mmol, 59%) of 1-(4-chloro-benzyl)-3-methyl-piperazine as colorless oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:12]=[C:11]([CH2:13][C@H:14]([NH:18][C:19](=[O:36])[C@@H:20]([CH2:28][S:29]([C:32]([CH3:35])([CH3:34])[CH3:33])(=[O:31])=[O:30])[CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:15]([OH:17])=O)[N:10]=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:37][C@@H:38]([CH2:46][CH:47]1[CH2:52][CH2:51][CH2:50][CH2:49][CH2:48]1)[C@@H:39]([OH:45])[C@H:40]([CH:42]1[CH2:44][CH2:43]1)[OH:41].ON1C(=O)C2C=CC=CC=2N=N1.C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C)C=O>[C:32]([S:29]([CH2:28][C@@H:20]([CH2:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[C:19]([NH:18][C@@H:14]([CH2:13][C:11]1[N:10]=[CH:9][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH:12]=1)[C:15]([NH:37][C@@H:38]([CH2:46][CH:47]1[CH2:52][CH2:51][CH2:50][CH2:49][CH2:48]1)[C@@H:39]([OH:45])[C@H:40]([CH:42]1[CH2:44][CH2:43]1)[OH:41])=[O:17])=[O:36])(=[O:31])=[O:30])([CH3:35])([CH3:33])[CH3:34]
Reactant: CC(C)(C)OC(=O)n1cnc(C[C@H](NC(=O)[C@H](Cc2ccccc2)CS(=O)(=O)C(C)(C)C)C(=O)O)c1
Reactant: N[C@@H](CC1CCCCC1)[C@@H](O)[C@@H](O)C1CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=c1c2ccccc2nnn1O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)n1cnc(C[C@H](NC(=O)[C@H](Cc2ccccc2)CS(=O)(=O)C(C)(C)C)C(=O)N[C@@H](CC2CCCCC2)[C@@H](O)[C@@H](O)C2CC2)c1
Yield: 151.3 %

Procedure:
A mixture of 1.98 g (3.06 mmol) of (S)-1-(tert-butoxycarbonyl)-α-[(S)-α-[(tert-butylsulphonyl)methyl]hydrocinnamamido]imidazole-4-propionic acid, 0.58 g (2.55 mmol) of (1S,2R,3S)-3-amino-4-cyclohexyl-1-cyclopropyl-1,2-butanediol, 0.5 g (3.06 mmol) of 3,4-dihydro-3-hydroxy-4-oxo-1,2,3-benzotriazine, 0.42 ml (3.07 mmol) of triethylamine and 1.16 g. (3.06 mmol) of HBTU in 30 ml of dimethylformamide is stirred at room temperature under argon for 2 hours. Subsequently, the dimethylformamide is evaporated in a high vacuum and the residue is taken up in 60 ml of ethyl acetate. The ethyl acetate solution is extracted with 30 ml of cold 2N sodium bicarbonate solution and the aqueous phase is back-extracted twice with 60 ml of ethyl acetate. The combined organic phases are washed in sequence with 30 ml of cold, saturated ammonium chloride solution, 30 ml of cold 2N sodium bicarbonate solution and 30 ml of saturated sodium chloride solution. The organic phase is dried over sodium sulphate and evaporated under reduced pressure. There are obtained 2.82 g of (S)-α-[(S)-α-[(tert-butylsulphonyl)methyl]hydrocinnamamido]-N-[(1S,2R,3S)-1-(cyclohexylmethyl)-3-cyclopropyl-2,3-dihydroxypropyl]-1-Boc-imidazole-4-propionamide as a pale yellow foam.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:25])[CH:10]([NH:16][C:17](=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:11](=O)[CH:12]([CH3:14])[CH3:13])[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.II.C(N(CC)CC)C>O1CCCC1>[CH2:1]([O:8][C:9]([C:10]1[N:16]=[C:17]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[O:24][C:11]=1[CH:12]([CH3:14])[CH3:13])=[O:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)C(=O)C(NC(=O)c1ccccc1)C(=O)OCc1ccccc1
Agent: II
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)c1oc(-c2ccccc2)nc1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 87.1 %

Procedure:
Mixture of 2-benzoylamino-4-methyl-3-oxo-pentanoic acid benzyl ester (1.08 g, 3 mmol), triphenylphosphine (2.01 g, 8 mmol), and iodine (1.62 g, 6.37 mmol) in tetrahydrofuran (60 mL) was cooled to −78 degrees, followed by addition of triethylamine (1.7 mL). The resulted solution was stirred at −78 degrees for about 10 min, and then was warmed up to room temperature. The reaction continued at room temperature for about 1 hr. After the reaction, the solvent was removed, and dichloromethane was added. The resulted solution was washed in sequence with saturated sodium bicarbonate, citric acid (0.5 M), and brine, dried over sodium sulfate, filtered and then concentrated in vacuo. Flash chromatography (Merck silica gel 60, 230-400 mesh, 0-40% ethyl acetate in hexane for 20 min) gave 5-isopropyl-2-phenyl-oxazole-4-carboxylic acid benzyl ester (0.84 g, 82%) as a light yellow solid. LCMS calcd for C20H19NO3 (m/e) 321, obsd 322 (M+H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([N+:17]([O-])=O)=[C:13]([CH:16]=1)[NH:14][CH3:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:20]>[C].[Pt].C1(C)C=CC=CC=1>[ClH:20].[CH2:1]([O:8][C:9]1[CH:16]=[C:13]([NH:14][CH3:15])[C:12]([NH2:17])=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CNc1cc(OCc2ccccc2)ccc1[N+](=O)[O-]
Agent: [Pt]
Agent: Cl
Solvent: Cc1ccccc1
Product: CNc1cc(OCc2ccccc2)ccc1N
Reaction time: 0.5 h
Yield: 91 %

Procedure:
5% platinum carbon (2.15 g, water content: 53.1%) was added to a toluene (300 mL) suspension of 5-benzyloxy-N-methyl-2-nitroaniline (20 g, 77.4 mmol), and catalytic hydrogenation reaction was performed at 4 atm. The reaction solution was filtered to remove a catalyst. The catalyst was washed with 2-propanol (40 mL), and the washing liquid was added to the precedent filtrate. Under ice cooling, concentrated hydrochloric acid (6.6 mL, 77.4 mmol) was added to the mixture, and the mixture was stirred under the same temperature for 30 minutes. The resulting precipitated crystals were collected by filtration, then washed with 2-propanol (60 mL), and dried at 50° C., thereby obtaining 18.6 g of a light-pink, crystal target compound (yield: 91%).
Reaction SMILES: C(N(CC)CC)C.[N:8]([C:11]1[N:19]=[C:18]([F:20])[N:17]=[C:16]2[C:12]=1[NH:13][CH:14]=[N:15]2)=[N+]=[N-].C(S)CCS>CO>[F:20][C:18]1[N:17]=[C:16]2[C:12]([NH:13][CH:14]=[N:15]2)=[C:11]([NH2:8])[N:19]=1
Reactant: [N-]=[N+]=Nc1nc(F)nc2nc[nH]c12
Agent: SCCCS
Solvent: CO
Solvent: CCN(CC)CC
Product: Nc1nc(F)nc2nc[nH]c12
Reaction time: 0.25 h
Yield: 92.8 %

Procedure:
Triethylamine (0.40 mL) was added via syringe to a solution of 6-azido-2-fluoropurine (0.256 g) and 1,3-propanedithiol (0.29 mL) in methanol (13.5 mL). After 15 minutes the reaction was complete as judged by TLC and a white precipitate had formed. The precipitate was collected by filtration and washed with two 10 mL portions of methanol and then dried to obtain 0.203 g of 2-fluoroadenine, mp>300° C. This material was identical to an authentic sample by TLC, NMR and IR.