Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].[NH2:2][C:3]1[N:8]=[C:7]([S:9][CH3:10])[N:6]=[C:5]([N:11]2[CH2:16][CH2:15][CH:14]([NH:17]C(=O)OC(C)(C)C)[CH2:13][CH2:12]2)[CH:4]=1>O1CCOCC1>[ClH:1].[NH2:17][CH:14]1[CH2:15][CH2:16][N:11]([C:5]2[N:6]=[C:7]([S:9][CH3:10])[N:8]=[C:3]([NH2:2])[CH:4]=2)[CH2:12][CH2:13]1
Reactant: CSc1nc(N)cc(N2CCC(NC(=O)OC(C)(C)C)CC2)n1
Agent: Cl
Solvent: C1COCCO1
Product: CSc1nc(N)cc(N2CCC(N)CC2)n1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
4 N Hydrogen chloride in dioxane (3 ml) was added to tert-butyl 1-[6-amino-2-(methylthio)pyrimidin-4-yl]piperidin-4-ylcarbamate (Intermediate 45, 0.29 mg 0.86 mmol). The mixture was stirred at room temperature for 90 minutes. The solvent was removed in vacuo to afford the title compound (238 mg).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:10][CH2:11][C:12]([CH3:15])([CH3:14])[N:13]=2)=[CH:5][CH:4]=1)[CH3:2].[CH2:16]([Li])CCC.CI>O1CCCC1>[CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([C:9]2[O:10][CH2:11][C:12]([CH3:14])([CH3:15])[N:13]=2)=[C:7]([CH3:16])[CH:8]=1)[CH3:2]
Reactant: [Li]CCCC
Reactant: CCc1ccc(C2=NC(C)(C)CO2)cc1
Solvent: CI
Solvent: C1CCOC1
Product: CCc1ccc(C2=NC(C)(C)CO2)c(C)c1
Temperature: 0 °C
Reaction time: 2.5 h

Procedure:
To a solution of the product from step (i) (43 g) in tetrahydrofuran (600 ml) at -10° C. was added n-butyllithium (2.5M solution in hexanes, 94 ml). The mixture was stirred for 2.5 hours at 0° C. then cooled to -30° C. and treated with methyl iodide (62 ml). The mixture was warmed to room temperature and partitioned between ethyl acetate and water. The organic phase was dried and evaporated and the residue purified by chromatography eluting with 5% ethyl acetate in isohexane. Yield 28.4 g.
Reaction SMILES: [C:1]([NH:3][C:4]([NH:9][CH3:10])=[N:5][CH2:6][CH2:7]S)#[N:2].C(NC(NC[CH2:18][SH:19])=N)#N>>[C:1]([NH:3][C:4]([NH:9][CH3:10])=[N:5][CH2:6][CH2:7][CH2:18][SH:19])#[N:2]
Reactant: N#CNC(=N)NCCS
Reactant: CNC(=NCCS)NC#N
Product: CNC(=NCCCS)NC#N

Procedure:
for N-cyano-N'-methyl-N"-(2-mercaptoethyl)guanidine in the procedure of Example 2(ii) leads to the production of (a)
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[CH:4][C:3]=1[CH3:16].[Cl:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[C:19]=1[N:25]=[C:26]=[O:27]>C1COCC1>[Cl:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[C:19]=1[NH:25][C:26](=[O:27])[NH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][C:12]([CH3:13])([CH3:15])[CH3:14])=[O:10])=[CH:4][C:3]=1[CH3:16]
Reactant: Cc1cc(CC(=O)OC(C)(C)C)ccc1N
Reactant: O=C=Nc1c(Cl)cccc1Cl
Solvent: C1CCOC1
Product: Cc1cc(CC(=O)OC(C)(C)C)ccc1NC(=O)Nc1c(Cl)cccc1Cl
Reaction time: 3 h
Yield: 74.1 %

Procedure:
To a mixture of tert-butyl 4-amino-3-methylphenylacetate (1.88 g, 8.51 mmol), 2,6-dichlorophenyl isocyanate (1.60 g, 8.51 mmol) in THF (40 ml) was added Et3 N (0.24 ml, 1.70 mmol) at room temperature. After 3 h stirring, the reaction mixture was concentrated in vacuo. The residue was triturated by the addition of n-hexane, to give tert-butyl 4-[N′-(2,6-dichlorophenyl)ureido]-3-methylphenylacetate (2.58 g, 74%) as a colorless powder. mp 243–244° C. (dec.); 1H-NMR (CDCl3) δ 1.45 (s, 9H), 2.30 (s, 3H), 3.49 (s, 2H), 6.24 (s, 2H), 7.12–7.16 (m, 3H), 7.35 (d, J=8.3 Hz, 2H), 7.51 (d, J=7.8 Hz, 1H).
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([O:10][C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[NH:16][C:15]([C:20]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)=[O:21])=[CH:14]3)[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[Cl:28][C:29]1[CH:30]=[C:31](B(O)O)[CH:32]=[CH:33][C:34]=1[Cl:35]>>[Cl:28][C:29]1[CH:30]=[C:31]([N:16]2[C:17]3[C:13](=[CH:12][C:11]([O:10][CH:7]4[CH2:6][CH2:5][N:4]([CH:1]([CH3:3])[CH3:2])[CH2:9][CH2:8]4)=[CH:19][CH:18]=3)[CH:14]=[C:15]2[C:20]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)=[O:21])[CH:32]=[CH:33][C:34]=1[Cl:35]
Reactant: CC(C)N1CCC(Oc2ccc3[nH]c(C(=O)N4CCOCC4)cc3c2)CC1
Reactant: OB(O)c1ccc(Cl)c(Cl)c1
Product: CC(C)N1CCC(Oc2ccc3c(c2)cc(C(=O)N2CCOCC2)n3-c2ccc(Cl)c(Cl)c2)CC1

Procedure:
In analogy to the procedure described for the synthesis of example 6, the title compound was synthesized from [5-(1-isopropyl-piperidin-4-yloxy)-1H-indol-2-yl]-morpholin-4-yl-methanone (intermediate 2) and 3,4-dichlorobenzeneboronic acid. The title compound was obtained in 90% yield as yellow foam. MS (m/e): 516.2 (MH+, 100%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13]2[CH:22]=[C:21]3[C:16]([CH:17]=[CH:18][CH:19]=[N:20]3)=[CH:15][N:14]=2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].C(N(CC)C1C=CC=CC=1)C.P(Cl)(Cl)([Cl:36])=O>COC(C)(C)C>[Cl:36][C:15]1[N:14]=[C:13]([C:5]2[CH:6]=[C:7]([O:11][CH3:12])[C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=2)[CH:22]=[C:21]2[C:16]=1[CH:17]=[CH:18][CH:19]=[N:20]2
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1cc(-c2cc3ncccc3cn2)cc(OC)c1OC
Solvent: COC(C)(C)C
Solvent: CCN(CC)c1ccccc1
Product: COc1cc(-c2cc3ncccc3c(Cl)n2)cc(OC)c1OC

Procedure:
565 mg 7-(3,4,5-Trimethoxy-phenyl)-[1,6]-naphthyridine (5.2) and 15 μL N,N-diethylaniline were stirred into 4 mL phosphorus oxychloride overnight at 100° C. and at ambient temperature over 2 days. The reaction mixture was evaporated down, and a small amount of ethyl acetate was added. Upon scratching a precipitate were formed. Methyl-tert-butylether was added and the precipitate was isolated and dried overnight at 50° C. under vacuo.
Reaction SMILES: [OH:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[CH:12]=[C:11]4[CH:17]=[CH:18][CH:19]=[CH:20][C:10]4=[CH:9][C:8]=3[O:7][C:6]=2[CH:5]=[C:4]([OH:21])[CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH2:28]1[S:30][CH:29]1[CH2:31]Cl>CC(C)=O>[OH:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[CH:12]=[C:11]4[CH:17]=[CH:18][CH:19]=[CH:20][C:10]4=[CH:9][C:8]=3[O:7][C:6]=2[CH:5]=[C:4]([O:21][CH2:31][CH:29]2[CH2:28][S:30]2)[CH:3]=1
Reactant: ClCC1CS1
Reactant: O=c1c2cc3ccccc3cc2oc2cc(O)cc(O)c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=c1c2cc3ccccc3cc2oc2cc(OCC3CS3)cc(O)c12
Temperature: 57.5 °C
Yield: 20.8 %

Procedure:
1,3-dihydroxy-12H-benzo[b]xanthen-12-one (0.05 g, 0.18 mmol) synthesized in Step 1 of Example 18, K2CO3 (0.07 g, 0.54 mmol), and anhydrous acetone (18 mL) were charged to a dry round-bottom flask. Under stirring, epithiochlorohydrin (0.07 g, 0.72 mmol) dissolved in anhydrous acetone (2 mL) was added thereto. The reaction liquid was stirred with reflux at a temperature of 55 to 60° C. under a nitrogen atmosphere (overnight). Solid of the reaction mixture was filtered and removed, and the filtrate was concentrated under reduced pressure. The resulting residue was separated and purified by silica gel column chromatography (developing solvent: ethyl acetate:n-hexane=1:3 (v/v)) to give the title compound (13.1 mg, 20.8%) as a yellow solid.
Reaction SMILES: N#N.C1(NC2CCCCC2)CCCCC1.[Li]CCCC.[C:21]([O:25][C:26](=[O:28])[CH3:27])([CH3:24])([CH3:23])[CH3:22].Br[C:30]1[CH:31]=[C:32]([C:36]2([CH3:41])[O:40][CH2:39][CH2:38][O:37]2)[CH:33]=[CH:34][CH:35]=1>C1(C)C=CC=CC=1.CCCCCC>[C:21]([O:25][C:26](=[O:28])[CH2:27][C:34]1[CH:35]=[CH:30][CH:31]=[C:32]([C:36]2([CH3:41])[O:37][CH2:38][CH2:39][O:40]2)[CH:33]=1)([CH3:24])([CH3:23])[CH3:22]
Reactant: CC(=O)OC(C)(C)C
Reactant: CC1(c2cccc(Br)c2)OCCO1
Agent: C1CCC(NC2CCCCC2)CC1
Agent: N#N
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)Cc1cccc(C2(C)OCCO2)c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a degassed solution of dicyclohexylamine (1.03 mL, 5.18 mmol) in toluene (30 mL) was treated 0° C. with n-BuLi (2.07 mL of a 2.5M solution in hexane, 5.18 mmol) and the reaction was stirred at 0° C. for 30 min. Acetic acid tert-butyl ester (0.59 mL, 4.40 mmol) was added dropwise and the reaction mixture was stirred at 0° C. for 50 min. To this solution was added a degassed suspension of 2-(3-bromo-phenyl)-2-methyl-[1,3]dioxolane (972 mg, 4.00 mmol) and {[P(t-Bu)3]PdBr}2 (25 mg, 0.03 mmol) and the reaction mixture was stirred at rt for 5 h. The reaction volume was reduced to half by rotary evaporation. The concentrated solution was washed with sat. aq. NH4Cl (30 mL). A large amount of precipitate formed between the aq. and org. layers. The org. layer was separated, and the aq. layer was washed with ether (5×20 mL). The combined org. layers were dried over MgSO4, filtered, and the solvent was removed under reduced. Purification of the residue by FC (9:1 hept-EA) gave the title compound as a yellow oil. TLC: rf (9:1 hept-EA)=0.26. LC-MS-conditions 02: tR=1.05 min.
Reaction SMILES: [Br:1][C:2]1[C:11]([CH2:12][CH2:13][CH3:14])=[CH:10][C:9]2[C:4](=[CH:5][C:6]([F:17])=[C:7]([O:15][CH3:16])[CH:8]=2)[C:3]=1[OH:18].[CH3:19][O:20][CH2:21]Cl.C(N(C(C)C)CC)(C)C>C1COCC1>[Br:1][C:2]1[C:11]([CH2:12][CH2:13][CH3:14])=[CH:10][C:9]2[C:4](=[CH:5][C:6]([F:17])=[C:7]([O:15][CH3:16])[CH:8]=2)[C:3]=1[O:18][CH2:19][O:20][CH3:21]
Reactant: COCCl
Reactant: CCCc1cc2cc(OC)c(F)cc2c(O)c1Br
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCCc1cc2cc(OC)c(F)cc2c(OCOC)c1Br
Yield: 83 %

Procedure:
2-Bromo-7-fluoro-6-(methyloxy)-3-propyl-1-naphthalenol (134) (0.52 g, 1.66 mmol) was treated with chloromethyl methyl ether in the presence of diisopropylethylamine in THF to give 0.49 g (83%) of the title compound (135) as a light yellow oil. 1H NMR (400 MHz, CDCl3): δ 1.01 (t, J=7.3 Hz, 3H), 1.65-1.75 (m, 2H), 2.83 (t, J=7.8 Hz, 2H), 3.72 (s, 3H), 3.98 (s, 3H), 5.21 (s, 2H), 7.10 (d, J=8.3 Hz, 1H), 7.37 (s, 1H), 7.76 (d, J=12.4 Hz, 1H). LCMS (ESI): m/z 379 (M+Na)+.
Reaction SMILES: [Si:1]([O:8][C@H:9]1[CH2:18][C:17]([CH3:20])([CH3:19])[CH2:16][C:15]2[N:14]=[C:13]([CH:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)[C:12]([C@@H:27]([C:29]3[CH:34]=[CH:33][C:32]([C:35]([CH3:38])([CH3:37])[CH3:36])=[CH:31][CH:30]=3)[OH:28])=[C:11](I)[C:10]1=2)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[O:40]1[CH2:45][CH:44]=[C:43](B2OC(C)(C)C(C)(C)O2)[CH2:42][CH2:41]1.C(=O)([O-])[O-].[Cs+].[Cs+].[F-].[Cs+]>O.O1CCCC1.C1(C)C=CC=CC=1>[Si:1]([O:8][C@H:9]1[CH2:18][C:17]([CH3:20])([CH3:19])[CH2:16][C:15]2[N:14]=[C:13]([CH:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)[C:12]([C@@H:27]([C:29]3[CH:34]=[CH:33][C:32]([C:35]([CH3:38])([CH3:37])[CH3:36])=[CH:31][CH:30]=3)[OH:28])=[C:11]([C:43]3[CH2:44][CH2:45][O:40][CH2:41][CH:42]=3)[C:10]1=2)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC1(C)OB(C2=CCOCC2)OC1(C)C
Reactant: CC1(C)Cc2nc(C3CCOCC3)c([C@H](O)c3ccc(C(C)(C)C)cc3)c(I)c2[C@@H](O[Si](C)(C)C(C)(C)C)C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CC1(C)Cc2nc(C3CCOCC3)c([C@H](O)c3ccc(C(C)(C)C)cc3)c(C3=CCOCC3)c2[C@@H](O[Si](C)(C)C(C)(C)C)C1

Procedure:
Obtained by starting from (R)—((S)-5-(tert-butyldimethylsilyloxy)-4-iodo-7,7-dimethyl-2-(tetrahydro-2H-pyran-4-yl)-5,6,7,8-tetrahydroquinolin-3-yl)(4-tert-butylphenyl)methanol and 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane. A 2 M solution of caesium carbonate in water is used instead caesium fluoride. The reaction is run in tetrahydrofurane/toluene 4:1.
Reaction SMILES: [CH:1]1([N:4]2[C:8]([NH2:9])=[C:7]([I:10])[CH:6]=[N:5]2)[CH2:3][CH2:2]1.C(NC(C)C)(C)C.[C:18](Cl)(=[O:20])[CH3:19]>ClCCl>[CH:1]1([N:4]2[C:8]([NH:9][C:18](=[O:20])[CH3:19])=[C:7]([I:10])[CH:6]=[N:5]2)[CH2:3][CH2:2]1
Reactant: CC(=O)Cl
Reactant: Nc1c(I)cnn1C1CC1
Solvent: CC(C)NC(C)C
Solvent: ClCCl
Product: CC(=O)Nc1c(I)cnn1C1CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 103.1 %

Procedure:
A 100-mL round-bottom flask was charged with 1-cyclopropyl-4-iodo-1H-pyrazol-5-amine (0.250 g, 1.00 mmol), N,N-diisopropylamine (0.52 mL, 2.99 mmol) and dichloromethane (8 mL), and the solution was cooled to 0° C. A solution of acetyl chloride (0.085 mL, 1.19 mmol) in dichloromethane (2 mL) was added dropwise, and the resulting solution stirred for 1 h at 0° C. The reaction mixture was concentrated under vacuum, and the residue was purified via column chromatography on silica gel (gradient elution with 0.5-50% ethyl acetate/petroleum ether) to afford N-(1-cyclopropyl-4-iodo-1H-pyrazol-5-yl)acetamide (0.300 g, 92%) as yellow oil. MS (ESI, pos. ion) m/z 292 [M+H]+.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.[Br:6][C:7]1[CH:12]=[C:11]([CH:13]([CH3:15])[CH3:14])[CH:10]=[CH:9][C:8]=1[N:16]([C:19]1[N:24]=[C:23]([N:25]2[CH2:30][CH2:29][C:28](=[O:31])[CH2:27][CH2:26]2)[CH:22]=[C:21]([CH3:32])[N:20]=1)[CH2:17][CH3:18]>>[Br:6][C:7]1[CH:12]=[C:11]([CH:13]([CH3:14])[CH3:15])[CH:10]=[CH:9][C:8]=1[N:16]([C:19]1[N:24]=[C:23]([N:25]2[CH2:30][CH2:29][C:28]([C:2]3[S:1][CH:5]=[CH:4][CH:3]=3)([OH:31])[CH2:27][CH2:26]2)[CH:22]=[C:21]([CH3:32])[N:20]=1)[CH2:17][CH3:18]
Reactant: CCN(c1nc(C)cc(N2CCC(=O)CC2)n1)c1ccc(C(C)C)cc1Br
Reactant: c1ccsc1
Product: CCN(c1nc(C)cc(N2CCC(O)(c3cccs3)CC2)n1)c1ccc(C(C)C)cc1Br
Yield: 44.2 %

Procedure:
The operation of Example 4-(1) was followed using 168 mg of thiophene and 432 mg of 2-[N-(2-bromo-4-isopropylphenyl)-N-ethylamino]-6-methyl-4-(4-oxopiperidin-1-yl)pyrimidine to give 228 mg of 2-(N-(2-bromo-4-isopropylphenyl)-N-ethylamino]-4-[4-(thiophen-2-yl)-4-hydroxypiperidin-l-yl]-6-methylpyrimidine.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N:8]1[CH2:12][CH2:11][NH:10][C:9]1=[O:13].Br[C:15]1[S:19][C:18]2[CH:20]=[CH:21][C:22]([F:24])=[CH:23][C:17]=2[C:16]=1[CH3:25].N[C@@H]1CCCC[C@H]1N.C(=O)([O-])[O-].[K+].[K+]>[Cu](I)I.O1CCOCC1>[F:24][C:22]1[CH:21]=[CH:20][C:18]2[S:19][C:15]([N:10]3[CH2:11][CH2:12][N:8]([C:3]4[CH:4]=[N:5][CH:6]=[CH:7][C:2]=4[CH3:1])[C:9]3=[O:13])=[C:16]([CH3:25])[C:17]=2[CH:23]=1
Reactant: Cc1ccncc1N1CCNC1=O
Reactant: Cc1c(Br)sc2ccc(F)cc12
Agent: I[Cu]I
Agent: N[C@@H]1CCCC[C@H]1N
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: Cc1ccncc1N1CCN(c2sc3ccc(F)cc3c2C)C1=O
Yield: 54.6 %

Procedure:
Using the same reaction conditions as in Example 14, 1-(4-methyl-pyridin-3-yl)-imidazolidin-2-one (I-14b: 79.79 mg, 0.4508 mmol) was reacted with 2-bromo-5-fluoro-3-methyl-benzo[b]thiophene (110 mg, 0.4508 mmol), 1,4-dioxane (5 mL), copper iodide (8.58 mg, 0.04508 mmol), trans-1,2-diamino cyclohexane (15.48 mg, 0.1352 mmol) and potassium carbonate (124.6 mg, 0.9016 mmol) to afford the crude product. Purification by column chromatography on silica gel (1% MeOH in chloroform) afforded 84 mg of the product (60.45% yield).
Reaction SMILES: Cl.[NH2:2][C:3]1[C:7]([C:8]([O:10]CC)=O)=[C:6]([CH3:13])[NH:5][C:4]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[CH:20]([NH2:22])=O>>[CH3:13][C:6]1[NH:5][C:4]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[C:3]2[C:7]=1[C:8](=[O:10])[NH:22][CH:20]=[N:2]2
Reactant: CCOC(=O)c1c(C)[nH]c(-c2ccccc2)c1N
Reactant: NC=O
Agent: Cl
Product: Cc1[nH]c(-c2ccccc2)c2nc[nH]c(=O)c12

Procedure:
A mixture of 3 g. (0.0107 mole) of 3-amino-4-carbethoxy-5-methyl-2-phenyl-pyrrole hydrochloride and 20 ml. (0.242 mole) of formamide are cautiously heated at 160° C for 16 hours. Upon cooling to room temperature the title compound precipitates as a solid substance, which is recovered by filtration and washed with water.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C@@H:3]([NH:24][C:25]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26])[CH2:4][C:5]([NH:7][C@@H:8]([C@@H:20]([CH3:23])[CH2:21][CH3:22])[C:9]([NH:11][C@@H:12]([CH:17]([CH3:19])[CH3:18])[C:13]([O:15][CH3:16])=[O:14])=[O:10])=[O:6].[CH3:42][C:43]([CH3:64])([CH3:63])[C@H:44]([NH:48][C:49](=[O:62])[C@@H:50]([NH:55][C:56](=[O:61])[CH2:57][CH:58]([CH3:60])[CH3:59])[CH2:51][CH:52]([CH3:54])[CH3:53])[C:45](O)=[O:46].C(N(C(C)C)C(C)C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(=O)([O-])O.[Na+]>CN(C=O)C>[CH2:28]([O:27][C:25]([NH:24][C@H:3]([C@@H:2]([NH:1][C:45](=[O:46])[C@@H:44]([NH:48][C:49](=[O:62])[C@@H:50]([NH:55][C:56](=[O:61])[CH2:57][CH:58]([CH3:59])[CH3:60])[CH2:51][CH:52]([CH3:54])[CH3:53])[C:43]([CH3:63])([CH3:42])[CH3:64])[CH2:35][C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1)[CH2:4][C:5]([NH:7][C@@H:8]([C@@H:20]([CH3:23])[CH2:21][CH3:22])[C:9]([NH:11][C@@H:12]([CH:17]([CH3:19])[CH3:18])[C:13]([O:15][CH3:16])=[O:14])=[O:10])=[O:6])=[O:26])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: CC(C)CC(=O)N[C@@H](CC(C)C)C(=O)N[C@H](C(=O)O)C(C)(C)C
Reactant: CC[C@H](C)[C@H](NC(=O)C[C@H](NC(=O)OCc1ccccc1)[C@@H](N)Cc1ccccc1)C(=O)N[C@H](C(=O)OC)C(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC[C@H](C)[C@H](NC(=O)C[C@H](NC(=O)OCc1ccccc1)[C@H](Cc1ccccc1)NC(=O)[C@@H](NC(=O)[C@H](CC(C)C)NC(=O)CC(C)C)C(C)(C)C)C(=O)N[C@H](C(=O)OC)C(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.7 %

Procedure:
300 mg of methyl (S)-2-[(2S,3S)-2-((3S,4S)-4-amino-3-benzyloxycarbonylamino-5-phenylpentanoylamino)-3-methylpentanoylamino]-3-methylbutyrate (hydrochloride), 170.1 mg of (S)-3,3-dimethyl-2-[(S)-4-methyl-2-(3-methylbutyrylamino)pentanoylamino]butyric acid and 163.4 l of ethyldiisopropylamine were dissolved in about 10 ml of DMF in a flask with ice cooling, 197.0 mg of HATU (C10H15N6O*PF6) were added, and the mixture was stirred at RT overnight. The yellow reaction mixture was poured into saturated sodium hydrogencarbonate solution and stirred for 15 min. The precipitate formed was filtered off with suction, triturated with dilute formic acid, filtered off with suction again, washed with water and dried, giving 340 mg of methyl (S)-2-[(2S,3S)-2-((3S,4S)-3-benzyloxycarbonylamino-4-{(S)-3,3-dimethyl-2-[(S)-4-methyl-2-(3-methylbutyrylamino)pentanoylamino]butyrylamino}-5-phenylpentanoylamino)-3-methylpentanoylamino]-3-methylbutyrate as a white solid. (Yield 82%). MS-FAB (M+H+)=880.1 Rf (polar method): 2.91 min.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:9][C:8]([C:10]2[CH:15]=[C:14]([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH:23]([CH3:25])[CH3:24])=[C:18]([Cl:26])[CH:17]=3)[N:13]=[CH:12][N:11]=2)=[CH:7][N:6]1[C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])=[O:4]>[Pd].CCOC(C)=O>[CH3:1][O:2][C:3]([CH:5]1[CH2:9][CH:8]([C:10]2[CH:15]=[C:14]([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH:23]([CH3:25])[CH3:24])=[C:18]([Cl:26])[CH:17]=3)[N:13]=[CH:12][N:11]=2)[CH2:7][N:6]1[C:27]([O:29][C:30]([CH3:32])([CH3:31])[CH3:33])=[O:28])=[O:4]
Reactant: COC(=O)C1CC(c2cc(-c3ccc(OC(C)C)c(Cl)c3)ncn2)=CN1C(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COC(=O)C1CC(c2cc(-c3ccc(OC(C)C)c(Cl)c3)ncn2)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 24 h
Yield: 105 %

Procedure:
10% Palladium on carbon (0.22 g, 0.21 mmol) was added in one portion to a stirred solution of 4-[6-(3-chloro-4-isopropoxy-phenyl)-pyrimidin-4-yl]-2,3-dihydro-pyrrole-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (0.03 g, 0.06 mmol) in EtOAc (15 ml) and the mixture was stirred at room temperature under a hydrogen atmosphere for 24 hours. After this time, the mixture was filtered through celite and the resulting filtrate concentrated to give the title compound (0.03 g, 22% yield) as a colourless oil. Tr=2.61 min m/z (ES+) (M+H+) 476.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1[CH:17]=[CH:16][NH:15][C:14](=[O:18])[N:13]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:26][C:27]([O:29]C)=[O:28]>CN(C)C=O>[CH2:1]([O:8][C:9]([N:11]([CH2:26][C:27]([OH:29])=[O:28])[C:12]1[CH:17]=[CH:16][NH:15][C:14](=[O:18])[N:13]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)CBr
Reactant: O=C(Nc1cc[nH]c(=O)n1)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(O)CN(C(=O)OCc1ccccc1)c1cc[nH]c(=O)n1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To a suspension of N-benzyloxycarbonyl cytosine (0.317 mol) and potassium carbonate (0.317 mol) in dimethylformamide (900 ml) is added methyl bromoacetate (0.317 mol) and the mixture is stirred vigorously overnight under nitrogen. The mixture is filtered, washed with ether and evaporated to dryness, in vacuo. The solid residue is treated with water (300 ml) and 4N hydrochloric acid (12 ml), stirred for 20 minutes at 0° C., filtered and washed with water (2×100 ml). The precipitate is treated with water and 2N sodium hydroxide (60 ml), and is boiled for 10 minutes. The mixture is cooled to 0° C., filtered, and precipitated by the addition of 4N hydrochloric acid (70 ml) to afford the pure title compound.
Reaction SMILES: [N:1](OCCC(C)C)=[O:2].[Cl:9][C:10]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:11]=1[CH:12]=[CH:13][N:14]1[CH:22]=[C:21]([CH3:23])[N:20]=[C:15]12>O1CCOCC1>[Cl:9][C:10]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:11]=1[CH:12]=[CH:13][N:14]1[C:22]([N:1]=[O:2])=[C:21]([CH3:23])[N:20]=[C:15]12
Reactant: CC(C)CCON=O
Reactant: Cc1cn2ccc3c(Cl)cccc3c2n1
Solvent: C1COCCO1
Product: Cc1nc2c3cccc(Cl)c3ccn2c1N=O
Yield: 39.7 %

Procedure:
Isoamyl nitrite (140 g) was added to a suspension of 7-chloro-2-methylimidazo[2,1-a]isoquinoline (17.1 g) in dioxane (170 ml) at 50° C. and the mixture was refluxed for 15 minutes. After being cooled, the resulting precipitate was collected by filtration, washed successively with dioxane and diethyl ether and dried in a desiccator to give 7-chloro-2-methyl-3-nitrosoimidazo[2,1-a]isoquinoline (7.7 g).
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[N:7]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][C:23]([NH2:26])=[CH:22][CH:21]=2)=[C:16]([CH3:27])[CH:15]=1)[CH2:8][CH2:9][CH:10]([CH3:12])[CH3:11])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:36][S:37](Cl)(=[O:39])=[O:38]>ClCCl>[C:1]([O:5][C:6](=[O:28])[N:7]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][C:23]([NH:26][S:37]([CH3:36])(=[O:39])=[O:38])=[CH:22][CH:21]=2)=[C:16]([CH3:27])[CH:15]=1)[CH2:8][CH2:9][CH:10]([CH3:12])[CH3:11])([CH3:2])([CH3:3])[CH3:4]
Reactant: CS(=O)(=O)Cl
Reactant: Cc1cc(CN(CCC(C)C)C(=O)OC(C)(C)C)ccc1-c1ccc(N)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(CN(CCC(C)C)C(=O)OC(C)(C)C)ccc1-c1ccc(NS(C)(=O)=O)cc1
Temperature: 50 °C
Reaction time: 12 h

Procedure:
(4′-Amino-2-methyl-biphenyl-4-ylmethyl)-(3-methyl-butyl)-carbamic acid tert-butyl ester, (I-9b: 128 mg, 0.335 mmol) was dissolved in 7 ml of dichloromethane and treated with triethylamine (0.188 mL, 1.34 mmol) and methylsulfonyl chloride (0.077 mL, 1.0 mmol). After 12 hours, the volatiles were removed under reduced pressure and the residue was then dissolved in methanol (15 mL) and treated with a 2N sodium hydroxide solution (15 mL). After stirring at 50° C. for 1 hour, the reaction mixture was then concentrated under reduced pressure and residue dissolved in ethyl acetate and extracted with water. The organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified using preparative thin layer chromatography eluting with 65% ethyl acetate in heptane to afford the title compound (I-8c).
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:15](=[O:17])[N:14]([CH2:18][CH2:19][CH2:20][OH:21])[C:13](=[O:22])[NH:12][C:11]=2[N:10]=[C:9]1[Cl:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.I[CH2:25][CH3:26].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[CH2:1]([N:8]1[C:16]2[C:15](=[O:17])[N:14]([CH2:18][CH2:19][CH2:20][OH:21])[C:13](=[O:22])[N:12]([CH2:25][CH3:26])[C:11]=2[N:10]=[C:9]1[Cl:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=c1[nH]c2nc(Cl)n(Cc3ccccc3)c2c(=O)n1CCCO
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCn1c(=O)n(CCCO)c(=O)c2c1nc(Cl)n2Cc1ccccc1
Temperature: 40 °C
Reaction time: 4 h
Yield: 318 %

Procedure:
To a solution of 7-benzyl-8-chloro-1-(3-hydroxypropyl)-1H-purine-2,6(3H,7H)-dione (150 mg, 0.449 mmol) in DMF (5 mL) was added iodoethane (0.16 g, 0.13 mmol), followed by potassium carbonate (0.4 g, 2.90 mmol). The mixture was stirred at 40° C. for 4 h. The reaction was cooled and diluted with ethyl acetate. The organic phase was washed with water and brine; then it was dried over sodium sulfate, filtered and concentrated to give 7-benzyl-8-chloro-3-ethyl-1-(3-hydroxypropyl)-1H-purine-2,6(3H,7H)-dione (0.15 g, 92.3% yield) as yellow oil. LCMS retention time 1.296 min; LCMS MH+ 363.