Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:15]([O:17][CH2:18][CH2:19][CH2:20][O:21][C:22]4[CH:23]=[C:24]([CH:26]=[CH:27][CH:28]=4)[NH2:25])=[N:14][CH:13]=[N:12][C:11]=3[S:10][CH:9]=2)=[CH:4][CH:3]=1.[CH3:29][S:30](Cl)(=[O:32])=[O:31].C(N(C(C)C)CC)(C)C>ClCCl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:15]([O:17][CH2:18][CH2:19][CH2:20][O:21][C:22]4[CH:23]=[C:24]([NH:25][S:30]([CH3:29])(=[O:32])=[O:31])[CH:26]=[CH:27][CH:28]=4)=[N:14][CH:13]=[N:12][C:11]=3[S:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: Nc1cccc(OCCCOc2ncnc3scc(-c4ccc(F)cc4)c23)c1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)Nc1cccc(OCCCOc2ncnc3scc(-c4ccc(F)cc4)c23)c1
Reaction time: 12 h
Yield: 38.5 %

Procedure:
A solution of 3-(3-{[5-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}propoxy)aniline (50 mg, 0.126 mmol) in dichloromethane (1.5 mL) was added to methanesulfonyl chloride (58 mg, 0.51 mmol) while stirring, followed by the addition of a solution of diisopropylethylamine (18 mg, 0.14 mmol) in dichloromethane (0.5 mL). Stirring was continued for 12 hours at room temperature and then the solvent was evaporated in vacuo. The residue was dissolved in ethyl acetate (30 mL), washed with sodium bicarbonate (2×25 mL) and the organic layer was isolated and concentrated. The product was purified by silica gel chromatography using 40% ethyl acetate in hexanes to give 23 mg (40%) of N-[3-(3-{[5-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}propoxy)phenyl]methanesulfonamide as a yellow solid. MS [M+H] 474.7. 1H NMR (400 MHz, CDCl3) δ (ppm) 8.65 (s, 1H), 7.42 (m, 2H), 7.23 (t, J=68.0 Hz, 1H), 7.22 (s, 1H), 7.06-7.01 (m, 2H), 6.76 (dd, J=8.0, 2.0 Hz, 1H), 6.68 (t, J=2.4 Hz, 1H), 6.58 (dd, J=8.0, 2.4 Hz, 1H), 6.32 (b, 1H), 4.58 (t, J=6.0 Hz, 2H), 3.01 (s, 3H), 2.07 (m, 2H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[C:9]1[C:10]2[C:11]3[C:12](=[N:24][N:25]([CH2:27][C:28]4[C:33]([CH3:34])=[C:32]([O:35][CH3:36])[C:31]([CH3:37])=[CH:30][N:29]=4)[N:26]=2)[CH:13]=[C:14]([CH2:19]C(OC)=O)[C:15]=3[CH2:16][S:17][N:18]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1(P([N:59]=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.C(N(CC)CC)C>C1C=CC=CC=1>[NH2:59][CH2:19][C:14]1[C:15]2[CH2:16][S:17][N:18]=[C:9]([N:8]([C:38]([O:40][C:41]([CH3:44])([CH3:42])[CH3:43])=[O:39])[C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[C:10]3=[N:26][N:25]([CH2:27][C:28]4[C:33]([CH3:34])=[C:32]([O:35][CH3:36])[C:31]([CH3:37])=[CH:30][N:29]=4)[N:24]=[C:12]([C:11]=23)[CH:13]=1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: COC(=O)Cc1cc2nn(Cc3ncc(C)c(OC)c3C)nc3c-2c1CSN=C3N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: COc1c(C)cnc(Cn2nc3cc(CN)c4c-3c(n2)C(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)=NSC4)c1C
Temperature: 55 °C
Reaction time: 2 h

Procedure:
A mixture composed of methyl {4-[bis(tert-butoxycarbonyl)amino]-2-[(4-methoxy-3,5-dimethylpyridin-2-yl)methyl]-2,7-dihydro-6-thia-1,2,3,5-tetraazabenzo[cd]azulen-8-yl}acetate of Example 111 (121 mg), diphenylphosphoryl azide (64 μl), triethylamine (69 μl) and benzene (2 ml) was heated with stirring at a bath temperature of 55° C. for two hours. The reaction mixture was concentrated under reduced pressure. Tetrahydrofuran (8 ml) and a 1 N sodium hydroxide solution (4 ml) were added to the resulting residue, and the mixture was heated with stirring at a bath temperature of 55° C. for one hour. A 0.2 N sodium hydroxide solution was added, followed by extraction with ethyl acetate. The organic layer was dried over sodium sulfate and filtered. Then, the filtrate was concentrated under reduced pressure. The concentrated residue was purified by silica gel column chromatography (chloroform-methanol) to obtain the title compound (41 mg) as a brown oil. Although the product contained impurities, it was directly used for the next reaction without further purification.
Reaction SMILES: [CH2:1]([O:3][C:4](OCC)=[CH:5][C:6](=[O:11])[C:7]([F:10])([F:9])[F:8])[CH3:2].[NH4+:15].[OH-]>CC#N.O>[NH2:15]/[C:4](/[O:3][CH2:1][CH3:2])=[CH:5]\[C:6](=[O:11])[C:7]([F:10])([F:9])[F:8]
Reactant: CCOC(=CC(=O)C(F)(F)F)OCC
Reactant: [NH4+]
Agent: [OH-]
Solvent: CC#N
Solvent: O
Product: CCO/C(N)=C/C(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 93 %

Procedure:
To a solution of 4,4-diethoxy-1,1,1-trifluorobut-3-en-2-one (7.94 g, 37.4 mmol) in MeCN (30 mL) at room temperature was dropped 28% solution of NH4OH in water (7 mL). It was stirred at room temperature overnight. After solvent was removed under reduced pressure, to it was added CH2Cl2 and washed with water. The organic layer was dried over MgSO4 and concentrated under reduced pressure to afford (E)-4-amino-4-ethoxy-1,1,1-trifluorobut-3-en-2-one as solid (6.371 g, 93%). 1H NMR (300 MHz, CDCl3) δ 9.79 (br, 1H), 5.66 br, 1H), 5.13 (s, 1H), 4.15 (q, 2H), 1.38 (t, 3H); LC-MS (ESI) m/z 184 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:24]=[CH:23][C:5]2[C:6]3[N:7]=[C:8]([N:14]4[C:18]([C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:17][N:16]=[N:15]4)[S:9][C:10]=3[CH2:11][CH2:12][O:13][C:4]=2[CH:3]=1>CO.[Pd]>[C:19]([C:18]1[N:14]([C:8]2[S:9][C:10]3[CH2:11][CH2:12][O:13][C:4]4[CH:3]=[CH:2][CH:24]=[CH:23][C:5]=4[C:6]=3[N:7]=2)[N:15]=[N:16][CH:17]=1)([CH3:22])([CH3:20])[CH3:21]
Reactant: CC(C)(C)c1cnnn1-c1nc2c(s1)CCOc1cc(Br)ccc1-2
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)c1cnnn1-c1nc2c(s1)CCOc1ccccc1-2
Temperature: 25 °C
Reaction time: 16 h
Yield: 66.2 %

Procedure:
A suspension of 8-bromo-2-(5-tert-butyl-[1,2,3]triazol-1-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene (101 mg, 0.25 mmol) and 10% Pd/C (250 mg) in MeOH (5 mL) was stirred at RT under a hydrogen atmosphere for 16 h. The reaction mixture was flushed with nitrogen, filtered through Celite, washed with ethyl acetate and concentrated in vacuo. The resulting residue was purified by flash chromatography (SiO2, 20% ethyl acetate in cyclohexane) to give 434 as a white solid (54 mg, 66%). LCMS (Method C): RT=13.19 min, [M+H]+=327.
Reaction SMILES: [N:1]1[NH:2][N:3]=[N:4][C:5]=1[NH2:6].Cl[CH2:8][C:9]1[C:10]([CH3:15])=[N:11][O:12][C:13]=1[CH3:14].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.ClCCl>[CH3:15][C:10]1[C:9]([CH2:8][N:2]2[N:3]=[N:4][C:5]([NH2:6])=[N:1]2)=[C:13]([CH3:14])[O:12][N:11]=1
Reactant: Nc1nn[nH]n1
Reactant: Cc1noc(C)c1CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1noc(C)c1Cn1nnc(N)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 40 %

Procedure:
2H-tetrazol-5-amine (1.29 g, 12.5 mmol), 4-(chloromethyl)-3,5-dimethylisoxazole (1.56 mL, 12.5 mmol) and potassium carbonate (1.73 g, 15.5 mmol) in DMF (20 mL) were heated to 80° C. with stirring for 16 hours. The reaction was cooled to room temperature, diluted with dichloromethane (100 mL) and washed consecutively with brine and water. The organics were dried over sodium sulfate and concentrated with rotary evaporation. The crude product was purified by silica gel chromatography (0-10% gradient ethyl acetate/dichloromethane) affording 2-((3,5-dimethylisoxazol-4-yl)methyl)-2H-tetrazol-5-amine as a white crystalline solid (970 mg, 40% yield) MS M+H calculated 195.1, found 195.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1/[CH:10]=[CH:11]/[CH:12]=[C:13](\[O:17][CH3:18])/[C:14]([OH:16])=O.[NH2:19][CH:20]1[CH2:25][C:24]([CH3:27])([CH3:26])[N:23]([CH3:28])[C:22]([CH3:30])([CH3:29])[CH2:21]1.O.ON1C2N=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>CN(C=O)C>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1/[CH:10]=[CH:11]/[CH:12]=[C:13](\[O:17][CH3:18])/[C:14]([NH:19][CH:20]1[CH2:21][C:22]([CH3:29])([CH3:30])[N:23]([CH3:28])[C:24]([CH3:27])([CH3:26])[CH2:25]1)=[O:16]
Reactant: CN1C(C)(C)CC(N)CC1(C)C
Reactant: CO/C(=C\C=C\c1cc2ccccc2s1)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: O
Product: CO/C(=C\C=C\c1cc2ccccc2s1)C(=O)NC1CC(C)(C)N(C)C(C)(C)C1
Yield: 26.6 %

Procedure:
A solution of (2Z,4E)-5-(benzothiophen-2-yl)-2-methoxy-2,4-pentadienoic acid (53 mg, 0.20 mmol), 4-amino-1,2,2,6,6-pentamethylpiperidine (34 mg, 0.20 mmol), 1-hydroxy-7-azabenzotriazole hydrate (27 mg, 0.20 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (38 mg, 0.20 mmol) in DMF (1 ml) was stirred at RT for 6 hours. After the same work up as seen in example 3 pure title compound was obtained (22 mg, 0.054 mmol, yield 26.6%) as white crystals, m.p.=240°.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([O:10][C:11]2[CH:16]=[CH:15][C:14](Cl)=[C:13]([N+:18]([O-:20])=[O:19])[CH:12]=2)[CH3:9])=[CH:4][CH:3]=1.[SH:21][C:22]1[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([O:10][C:11]2[CH:16]=[CH:15][C:14]([S:21][C:22]3[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=3)=[C:13]([N+:18]([O-:20])=[O:19])[CH:12]=2)[CH3:9])=[CH:4][CH:3]=1
Reactant: Oc1ccc(S)cc1
Reactant: CC(Oc1ccc(Cl)c([N+](=O)[O-])c1)c1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(Oc1ccc(Sc2ccc(O)cc2)c([N+](=O)[O-])c1)c1ccc(Br)cc1
Temperature: 25 °C
Yield: 68.2 %

Procedure:
The product from Example 44B (1.15 g, 3.22 mmol) was reacted with 4-mercapto-phenol (403 mg, 3.22 mmol) and K2CO3 (890 mg, 6.44 mmol) in 25 mL of DMF at 80° C. for 18 h. Cooled to room temperature and poured into water. Extracted with CH2Cl2 and washed several times with water. Dried over Na2SO4, filtered and concentrated under vacuum giving the title compound (980 mg, 68%).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5](B(O)O)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10])=[O:2].Cl[C:15]1[CH:20]=[CH:19][N:18]=[C:17]([CH3:21])[CH:16]=1.C(=O)([O-])[O-].[K+].[K+]>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:10][O:9][C:8]1[CH:7]=[CH:6][C:5]([C:15]2[CH:20]=[CH:19][N:18]=[C:17]([CH3:21])[CH:16]=2)=[CH:4][C:3]=1[CH:1]=[O:2]
Reactant: Cc1cc(Cl)ccn1
Reactant: COc1ccc(B(O)O)cc1C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: COc1ccc(-c2ccnc(C)c2)cc1C=O
Temperature: 85 °C

Procedure:
A stirred suspension of 3-formyl-4-methoxybenzeneboronic acid (700 mg, 3.89 mmol), 4-chloro-2-picoline (494 mg, 3.89 mmol), potassium carbonate (1.45 g, 10.5 mmol) and tetrakis(triphenylphosphine)palladium(0) (225 mg, 0.19 mmol) in 1,2-dimethoxyethane (14 mL) and water (5 mL) is degassed at RT with N2 for 15 minutes then warmed for 16 h at 85° C. The reaction mixture is then cooled to RT and 2 M HCl (15 mL) added. The aqueous layer is washed with TBME (15 mL) then basified to pH 10 with aqueous K2CO3 and extracted into EtOAc (3×50 mL); The combined organic phases are dried over Na2SO4 and the solvents removed in vacuo to give the title compound.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:12]2[S:13][C:14]([CH3:25])=[C:15]([CH2:17][O:18][CH:19]3[CH2:24][CH2:23][CH2:22][CH2:21][O:20]3)[N:16]=2)[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.C([Li])CCC.CN(C)[CH:33]=[O:34].O>O1CCCC1>[CH3:25][C:14]1[S:13][C:12]([C:4]2[CH:3]=[C:2]([CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=2)[CH:33]=[O:34])=[N:16][C:15]=1[CH2:17][O:18][CH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][O:20]1
Reactant: Cc1sc(-c2cc(Br)cc(C(F)(F)F)c2)nc1COC1CCCCO1
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: Cc1sc(-c2cc(C=O)cc(C(F)(F)F)c2)nc1COC1CCCCO1
Temperature: -78 °C
Reaction time: 1 h
Yield: 24.4 %

Procedure:
Under a nitrogen atmosphere at −78° C., to a solution (80 mL) of the compound (7.3 g, 17 mmol) obtained in Example 95a in tetrahydrofuran was added n-butyllithium (1.6M hexane solution, 16 mL, 25 mmol), and the mixture was stirred at the same temperature for 1 hr. Anhydrous N,N-dimethylformamide (2.6 mL, 33 mmol) was added to the reaction mixture, and the mixture was stirred overnight while allowing to spontaneously warm to room temperature from −78° C. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The resulting crude title compound was purified by column chromatography (hexane-hexane/ethyl acetate=80/20) to give the title compound (1.6 g, 24%) as an orange oil.
Reaction SMILES: [CH3:1][C:2]([SH:5])([CH3:4])[CH3:3].[H-].[Na+].[Br:8][C:9]1[N:10]=[C:11](Br)[N:12]2[CH:17]=[CH:16][N:15]=[C:14]([NH2:18])[C:13]=12>CN(C=O)C>[Br:8][C:9]1[N:10]=[C:11]([S:5][C:2]([CH3:4])([CH3:3])[CH3:1])[N:12]2[CH:17]=[CH:16][N:15]=[C:14]([NH2:18])[C:13]=12
Reactant: CC(C)(C)S
Reactant: Nc1nccn2c(Br)nc(Br)c12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)Sc1nc(Br)c2c(N)nccn12
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A bohdan block vessel was charged with 2-methyl-2-propanethiol (20 uL, 0.0002 mol) in DMF (2 mL) and the reaction mixture was degassed 3×. Sodium hydride (0.01 g, 0.0004 mol) was then added and the reaction mixture was stirred at rt for 10 min. 1,3-Dibromo-imidazo[1,5-a]pyrazin-8-ylamine (30 mg, 0.0001 mol) was added to the reaction mixture and the reaction mixture was heated at 70° C. overnight. The reaction mixture turned red in color as the reaction progressed. The reaction mixture was concentrated and purified by prep TLC using a mixture of 7 N5% NH3 in MeOH/DCM to afford the title compound as a white solid. 1H NMR (400 MHz, CD3OD-d4): δ=1.37 (s, 9H), 7.13 (d, J=5.05 Hz, 1H), 7.84 (d, J=5.05 Hz, 1H). MS(ES+): m/z 303.02 (100)[MH+]. HPLC: tR=2.30 min (Open Lynx polar—5 min).
Reaction SMILES: [C:1]([O:9][CH:10]1[CH2:15][C:14]([CH3:17])([CH3:16])[N:13]([OH:18])[C:12]([CH3:20])([CH3:19])[CH2:11]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:21]([O:25][CH:26]1[CH2:31][C:30]([CH3:33])([CH3:32])[N:29]([O:34][CH3:35])[C:28]([CH3:37])([CH3:36])[CH2:27]1)(=[O:24])[CH:22]=[CH2:23]>>[C:1]([O:9][CH:10]1[CH2:11][C:12]([CH3:20])([CH3:19])[N:13]([O:18][CH2:23][CH2:22][C:21]([O:25][CH:26]2[CH2:27][C:28]([CH3:36])([CH3:37])[N:29]([O:34][CH3:35])[C:30]([CH3:32])([CH3:33])[CH2:31]2)=[O:24])[C:14]([CH3:16])([CH3:17])[CH2:15]1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=CC(=O)OC1CC(C)(C)N(OC)C(C)(C)C1
Reactant: CC1(C)CC(OC(=O)c2ccccc2)CC(C)(C)N1O
Product: CON1C(C)(C)CC(OC(=O)CCON2C(C)(C)CC(OC(=O)c3ccccc3)CC2(C)C)CC1(C)C
Yield: 50 %

Procedure:
The title compound is prepared in 50% yield as a colorless syrup from 4-benzoyloxy-1-oxyl-2,2,6,6-tetramethylpiperidine and 1-methoxy-2,2,6,6-tetramethylpiperidin-4-yl acrylate following the general procedure of Example 12.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)([OH:8])[CH2:4][CH2:3]1.[H-].[Na+].Cl[C:18]1[CH:23]=[N:22][CH:21]=[CH:20][N:19]=1.O>CS(C)=O>[CH3:1][N:2]1[CH2:7][CH2:6][C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)([O:8][C:18]2[CH:23]=[N:22][CH:21]=[CH:20][N:19]=2)[CH2:4][CH2:3]1
Reactant: CN1CCC(O)(c2ccccc2)CC1
Reactant: Clc1cnccn1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CN1CCC(Oc2cnccn2)(c2ccccc2)CC1
Yield: 11.1 %

Procedure:
A solution of 1-methyl-4-phenyl-4-piperidinol (7.65 g, 40 mM), in DMSO (100 ml) was treated with 50% sodium hydride dispersion (2.0 g, 40 mM) and the mixture warmed to 80° until a clear solution was obtained. After cooling to room temperature a solution of 2-chloropyrazine (5.6 g, 40 mM) in DMSO (10 ml) was added. After 48 hours the reaction mixture was poured on to water (400 ml), extracted with ether (3×250 ml), the organic phase dried and the solvents removed under reduced pressure. Recrystallisation of the residue from cyclohexane gave recovered 1-methyl-4-phenyl-4-piperidinol (2 g). Chromatography of the mother liquors on Grade III silica using 3% methanol in chloroform as eluant, evaporation of the appropriate fractions and recrystallisation from pentane gave the title compound (1.2 g) m.p. 115°-6° C.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([O:11][CH2:12][CH2:13][CH2:14][CH3:15])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([O:28]C)[N:6]2[CH2:16][CH2:17][CH2:18][N:19]1[CH2:24][CH2:23][N:22]([CH2:25][CH2:26][OH:27])[CH2:21][CH2:20]1.Cl>CO.O1CCOCC1>[NH2:1][C:2]1[N:10]=[C:9]([O:11][CH2:12][CH2:13][CH2:14][CH3:15])[N:8]=[C:7]2[C:3]=1[NH:4][C:5](=[O:28])[N:6]2[CH2:16][CH2:17][CH2:18][N:19]1[CH2:24][CH2:23][N:22]([CH2:25][CH2:26][OH:27])[CH2:21][CH2:20]1
Reactant: CCCCOc1nc(N)c2nc(OC)n(CCCN3CCN(CCO)CC3)c2n1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: CCCCOc1nc(N)c2[nH]c(=O)n(CCCN3CCN(CCO)CC3)c2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.2 %

Procedure:
2-(4-{3-[6-Amino-2-(butyloxy)-8-(methyloxy)-9H-purin-9-yl]propyl}-1-piperazinyl)ethanol (for example, as prepared for Intermediate 39) (80 mg, 0.196 mmol) was dissolved in methanol (5.5 mL) and 4M HCl in 1,4-dioxane (1.2 mL) was added. The solution was stirred at room temperature overnight, then evaporated in vacuo. The solid residue was taken up in the minimum amount of methanol and put onto a 2 g aminopropyl SPE that had been pre-conditioned with 50 mL methanol. Appropriate fractions were evaporated in vacuo to give the title compound as a white solid (68 mg).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:33]([CH2:34][O:35][CH2:36][CH2:37][Si:38]([CH3:41])([CH3:40])[CH3:39])[C:18]3[N:19]=[CH:20][N:21]=[C:22]([O:23][C:24]4[CH:25]=[C:26]5[C:30](=[CH:31][CH:32]=4)[NH:29][CH:28]=[CH:27]5)[C:17]=3[CH:16]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH2:44]([NH:46][C:47](=O)[O:48]C1C=CC=CC=1)[CH3:45].O>CN(C)C=O>[CH2:44]([NH:46][C:47]([N:29]1[C:30]2[C:26](=[CH:25][C:24]([O:23][C:22]3[C:17]4[CH:16]=[C:15]([C:12]5[CH:11]=[CH:10][C:9]([O:8][CH2:1][C:2]6[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=6)=[CH:14][CH:13]=5)[N:33]([CH2:34][O:35][CH2:36][CH2:37][Si:38]([CH3:41])([CH3:40])[CH3:39])[C:18]=4[N:19]=[CH:20][N:21]=3)=[CH:32][CH:31]=2)[CH:27]=[CH:28]1)=[O:48])[CH3:45]
Reactant: C[Si](C)(C)CCOCn1c(-c2ccc(OCc3ccccc3)cc2)cc2c(Oc3ccc4[nH]ccc4c3)ncnc21
Reactant: CCNC(=O)Oc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCNC(=O)n1ccc2cc(Oc3ncnc4c3cc(-c3ccc(OCc5ccccc5)cc3)n4COCC[Si](C)(C)C)ccc21
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 68 %

Procedure:
After dissolving 6-(4-benzyloxyphenyl)-4-(1H-5-indolyloxy)-7-(2-trimethylsilanylethoxymethyl)-7H-pyrrolo[2,3-d]pyrimidine (81 mg) in 1 ml of dimethylformamide, 7 mg of sodium hydride (60% dispersion) was added, the mixture was stirred at room temperature for 5 minutes, and then 31 mg of phenyl ethylcarbamate was added and the mixture was stirred for another 2 hours. Water was then added, and ethyl acetate was used for liquid separation and extraction. The organic layer was concentrated and subjected to silica gel column chromatography (hexane-ethyl acetate) to obtain 62 mg of the title compound.
Reaction SMILES: [C:1]([O:5][C:6](=[O:29])[CH2:7][N:8]1[C:17](=[O:18])[CH2:16][C:15]2[N:11]([C:12]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[N:13][N:14]=2)[C:10]2[CH:25]=[CH:26][CH:27]=[CH:28][C:9]1=2)([CH3:4])([CH3:3])[CH3:2].[NH:30]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[C:32]([CH:39]=O)=[CH:31]1.N1CCCCC1>C1(C)C=CC=CC=1>[C:1]([O:5][C:6](=[O:29])[CH2:7][N:8]1[C:17](=[O:18])[C:16](=[CH:39][C:32]2[C:33]3[C:38](=[CH:37][CH:36]=[CH:35][CH:34]=3)[NH:30][CH:31]=2)[C:15]2[N:11]([C:12]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[N:13][N:14]=2)[C:10]2[CH:25]=[CH:26][CH:27]=[CH:28][C:9]1=2)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)CN1C(=O)Cc2nnc(-c3ccccc3)n2-c2ccccc21
Reactant: O=Cc1c[nH]c2ccccc12
Solvent: Cc1ccccc1
Solvent: C1CCNCC1
Product: CC(C)(C)OC(=O)CN1C(=O)C(=Cc2c[nH]c3ccccc23)c2nnc(-c3ccccc3)n2-c2ccccc21
Temperature: 110 °C
Reaction time: 24 h
Yield: 133.4 %

Procedure:
To a solution of (5-oxo-1-phenyl-4,5-dihydro-2,3,6,10b-tetraaza-benzo[e]azulen-6-yl)-acetic acid tert-butyl ester (Preparation 13(B)) (3.66 g, 9.37 mmol) in toluene (94 mL) was added 1H-indole-3-carbaldehyde (1.63 g, 11.2 mmol) and piperidine (2.78 mL, 28.1 mmol). The reaction was heated to 110° C. in a Soxhlet for 10 hours and was stirred at room temperature for 24 hours. The precipitate was filtered and was washed with toluene to provide 6.47 g of [4-(1H-indol-3-ylmethylene)-5-oxo-1-phenyl-4,5-dihydro-2,3,6,10b-tetraaza-benzo[e]azulen-6-yl]-acetic acid tert-butyl ester. MS 518.5 (M+1).
Reaction SMILES: [O:1]([CH2:8][CH2:9][CH2:10][N:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl[C:25]1[NH:30][C:29](=[O:31])[NH:28][C:27](=[O:32])[CH:26]=1>O1CCOCC1>[O:1]([CH2:8][CH2:9][CH2:10][N:11]1[CH2:12][CH2:13][N:14]([C:25]2[NH:30][C:29](=[O:31])[NH:28][C:27](=[O:32])[CH:26]=2)[CH2:15][CH2:16]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=c1cc(Cl)[nH]c(=O)[nH]1
Reactant: c1ccc(OCCCN2CCNCC2)cc1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: O=c1cc(N2CCN(CCCOc3ccccc3)CC2)[nH]c(=O)[nH]1
Yield: 75.2 %

Procedure:
1.1 g of 1-(3-phenoxypropyl)piperazine, 0.8 ml of triethylamine and 0.59 g of 6-chloro-2,4(1H,3H)-pyrimidinedione were dissolved in 15 ml of dioxane, followed by heating under reflux for 1 hour. After cooling, the precipitated crystals were collected by filtration, and then washed with water and hot ethanol to obtain 1.0 g (yield 66% ) of 6-[4-(3-phenoxypropyl)piperazin-1-yl]-2,4(1H,3H)-pyrimidinedione.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:13]=[C:12]([O:14][CH:15]2[CH2:32][CH:31]3[CH:17]([C:18](=[O:38])[N:19]([CH3:37])[CH2:20][CH2:21][CH2:22][CH2:23][CH:24]=[CH:25][CH:26]4[C:28]([C:34](O)=[O:35])([NH:29][C:30]3=[O:33])[CH2:27]4)[CH2:16]2)[C:11]2[C:6](=[C:7]([CH3:41])[C:8]([O:39][CH3:40])=[CH:9][CH:10]=2)[N:5]=1)[CH3:2].C1N=CN(C(N2C=NC=C2)=O)C=1.[CH:54]1([S:57]([NH2:60])(=[O:59])=[O:58])[CH2:56][CH2:55]1.C1CCN2C(=NCCC2)CC1>C1COCC1>[CH2:1]([O:3][C:4]1[CH:13]=[C:12]([O:14][CH:15]2[CH2:32][CH:31]3[CH:17]([C:18](=[O:38])[N:19]([CH3:37])[CH2:20][CH2:21][CH2:22][CH2:23][CH:24]=[CH:25][CH:26]4[C:28]([C:34]([NH:60][S:57]([CH:54]5[CH2:56][CH2:55]5)(=[O:59])=[O:58])=[O:35])([NH:29][C:30]3=[O:33])[CH2:27]4)[CH2:16]2)[C:11]2[C:6](=[C:7]([CH3:41])[C:8]([O:39][CH3:40])=[CH:9][CH:10]=2)[N:5]=1)[CH3:2]
Reactant: NS(=O)(=O)C1CC1
Reactant: CCOc1cc(OC2CC3C(=O)NC4(C(=O)O)CC4C=CCCCCN(C)C(=O)C3C2)c2ccc(OC)c(C)c2n1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: CCOc1cc(OC2CC3C(=O)NC4(C(=O)NS(=O)(=O)C5CC5)CC4C=CCCCCN(C)C(=O)C3C2)c2ccc(OC)c(C)c2n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of (2) (182 mg, 0.32 mmol) and CDI (139 mg, 0.29 mmol) in dry THF (10 mL) was heated at reflux for 1.5h under nitrogen. LCMS analysis showed one peak of the intermediate (2-1) (a stable intermediate, which can be isolated by purification on silica gel). The reaction mixture was cooled to room temperature and cyclopropyl-sulfonamide (93 mg, 0.76 mmol) was added. Then, DBU (138 mg, 0.91 mmol) was added. The reaction mixture was stirred at room temperature for 1 h, then heated at 55° C. for 12 h. Next, the solvent was evaporated, and the residue partitioned between ethyl acetate and acidic water (pH=3). The organic layer was dried (Na2SO4) and evaporated. The crude material was purified by column chromatography (ethyl acetate/CH2Cl2, 1:9). The residue was sonicated in water for 1 h, filtered off and washed with isopropylether to give the title product (3) as a white powder: m/z=669 (M+H)+. 1H NMR (CDCl3): 0.90-1.30 (m, 5H), 1.31-1.52 (m, 6H), 1.61-1.72 (m, 1H), 1.73-1.99 (m, 3H), 2.09-2.20 (m, 1H), 2.30-2.42 (m, 2H), 2.48-2.62 (m, 5H), 2.70-2.83 (m, 1H), 3.01 (s, 3H), 3.30-3.41 (m, 2H), 3.94 (s, 3H), 4.50-4.73 (m, 3H), 5.05 (t, J=10.0 Hz, 2H), 5.62-5.69 (m, 1H), 5.95 (s, 1H), 6.35 (br s, 1H), 7.01 (d, J=9.1 Hz, 1H), 7.85 (d, J=9.1 Hz, 1H), 10.8 (br s, 1H).