Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C@H:9]([C:11]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15](=[O:23])[C:14]3=[C:24](C)[CH:25]=[CH:26][N:13]3[N:12]=2)[CH3:10])[C:3]=1I.CC1(C)C(C)(C)OB([C:37]2[CH:38]=[N:39][NH:40][CH:41]=2)O1>[Pd].C(=O)([O-])[O-].[Na+].[Na+]>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C@H:9]([C:11]2[N:16]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:15](=[O:23])[C:14]3=[CH:24][CH:25]=[CH:26][N:13]3[N:12]=2)[CH3:10])[C:3]=1[C:37]1[CH:38]=[N:39][NH:40][CH:41]=1
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc(N)c3I)n(-c3ccccc3)c(=O)c12
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: C[C@H](Nc1ncnc(N)c1-c1cn[nH]c1)c1nn2cccc2c(=O)n1-c1ccccc1
Temperature: 80 °C
Reaction time: 18 h
Yield: 28.8 %

Procedure:
The title compound was prepared following the experimental procedure described in Example 3 from 100 mg (0.21 mmol) of (S)-2-(1-((6-amino-5-iodopyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one and 62 mg (0.32 mmol) of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole. The mixture was stirred at 80° C. for 18 hours and then an excess of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (62 mg), palladium catalyst (19 mg) and aqueous sodium carbonate solution (320 μl) were added and the reaction mixture was stirred at 80° C. for 24 hours more. The product was purified by flash chromatography (0% to 15%, dichloromethane-methanol) to obtain 25 mg (29% yield) of the title compound.
Reaction SMILES: C(OC[O:10][CH2:11][C@@H:12]([CH3:27])[CH2:13][CH2:14][CH2:15][C:16]([CH3:26])([CH3:25])[O:17][Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19])C1C=CC=CC=1.[H][H]>C(OCC)(=O)C.[Pd]>[Si:18]([O:17][C:16]([CH3:25])([CH3:26])[CH2:15][CH2:14][CH2:13][C@H:12]([CH3:27])[CH2:11][OH:10])([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19]
Reactant: [H][H]
Reactant: C[C@@H](CCCC(C)(C)O[Si](C)(C)C(C)(C)C)COCOCc1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: C[C@H](CO)CCCC(C)(C)O[Si](C)(C)C(C)(C)C
Yield: 78 %

Procedure:
2nd procedure. To a solution of compound 3 (0.5 g, 1.27 mmol) in ethyl acetate (25 mL) was added Pd/C (10%, 380 mg) at room temperature. The reaction mixture was hydrogenated for 3 h under the hydrogen pressure of 10 Pa. Then, the mixture was filtered and the solvent was evaporated under reduced pressure. The oily residue was applied on a silica Sep-Pak cartridge (5 g) and washed with hexane/AcOEt (9:1) producing an oily alcohol 4 (272 mg, 78%).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[NH:7]1[CH2:12][CH2:11][O:10][CH2:9][CH2:8]1.Cl[CH2:14][C:15]([C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[NH:22][C:21](=[O:26])[CH2:20]2)=[O:16]>CN(C=O)C.[I-].[K+]>[O:10]1[CH2:11][CH2:12][N:7]([CH2:14][C:15]([C:17]2[CH:18]=[C:19]3[C:23](=[CH:24][CH:25]=2)[NH:22][C:21](=[O:26])[CH2:20]3)=[O:16])[CH2:8][CH2:9]1
Reactant: O=C1Cc2cc(C(=O)CCl)ccc2N1
Reactant: C1COCCN1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C1Cc2cc(C(=O)CN3CCOCC3)ccc2N1
Temperature: 25 °C
Reaction time: 1 h
Yield: 51.7 %

Procedure:
Potassium carbonate (800 mg, 5.8 mmol) followed by potassium iodide (30 mg, 0.2 mmol) and morpholine (500 μl, 5.7 mmol) were added to a solution of 5-(2-chloroacetyl)oxindole (1.05 g, 5 mmol), (J. Med. Chem. 1991, 1860), in DMF (20 ml) and the mixture was stirred for 1 hour at ambient temperature. The solvent was removed by evaporation and the residue was purified by reverse phase column chromatography on a Diaion (trade mark of Mitsubishi) HP20SS resin column, eluting with water/methanol (a gradient from 100/0 to 30/70). The purified product was then purified by chromatography on silica eluting with methylene chloride/methanol (95/5) to give 5-(2-morpholinoacetyl)oxindole (673 mg, 51%).
Reaction SMILES: [F:1][C:2]1[C:21]([I:22])=[CH:20][C:5]2[C:6]3[N:10]=[C:9]([C:11]([O:13]CC)=O)[NH:8][C:7]=3[CH:16]3[CH2:19][CH:18]([C:4]=2[CH:3]=1)[CH2:17]3.[NH3:23]>CO>[F:1][C:2]1[C:21]([I:22])=[CH:20][C:5]2[C:6]3[N:10]=[C:9]([C:11]([NH2:23])=[O:13])[NH:8][C:7]=3[CH:16]3[CH2:17][CH:18]([C:4]=2[CH:3]=1)[CH2:19]3
Reactant: N
Reactant: CCOC(=O)c1nc2c([nH]1)C1CC(C1)c1cc(F)c(I)cc1-2
Solvent: CO
Product: NC(=O)c1nc2c([nH]1)C1CC(C1)c1cc(F)c(I)cc1-2
Temperature: 25 °C
Yield: 78 %

Procedure:
A solution of ethyl 8-fluoro-9-iodo-3,4,5,6-tetrahydro-4,6-methanobenzo[3,4]cyclohepta[1,2-d]imidazole-2-carboxylate (302 mg at 69% purity) in methanolic ammonia (7 mL of a 7.0M solution of ammonia in methanol, 49.0 mmol) was warmed to 44° C. for 72 hr in a pressure tube. After cooling to room temperature, the precipitous solution was evaporated to dryness in vacuo. The residue was re-suspended in methanol (1 mL) and the solid collected by filtration to furnish the title compound (155 mg, 0.40 mmol, 78%) as an off-white powder: 1H NMR (500 MHz, d6-DMSO) δ 1.47-1.49 (m, 2H), 2.83-2.91 (m, 2H), 3.40-3.44 (m, 1H), 3.60-3.68 (m, 1H), 7.10 (d, J=9.2 Hz, 1H), 7.42 (br. s, 1H), 7.82 (br, s, 1H), 8.64 (d, J=6.9 Hz, 1H), 13.08 (br. s, 1H); M+H=384
Reaction SMILES: [O:1]1[CH2:20][CH:2]1[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[NH:12][CH:13]=[C:14]([C:16]([F:19])([F:18])[F:17])[N:15]=2)=[CH:7][CH:6]=1.[C:21]([NH2:25])([CH3:24])([CH3:23])[CH3:22]>>[C:21]([NH:25][CH2:20][CH:2]([OH:1])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[NH:12][CH:13]=[C:14]([C:16]([F:19])([F:18])[F:17])[N:15]=2)=[CH:7][CH:6]=1)([CH3:24])([CH3:23])[CH3:22]
Reactant: CC(C)(C)N
Reactant: FC(F)(F)c1c[nH]c(-c2ccc(OCC3CO3)cc2)n1
Product: CC(C)(C)NCC(O)COc1ccc(-c2nc(C(F)(F)F)c[nH]2)cc1

Procedure:
A solution of 2-[4-(2,3-epoxypropoxy)phenyl]trifluoromethylimidazole (2.5 g.) in tert. butylamine (20 ml.) is heated 6 hours at reflux. The excess tert.butylamine is removed by distillation at atmospheric pressure over steam. The residue is triturated with nitromethane (5 ml.) and the resulting solid removed by filtration. After recrystallization from acetonitrile, (1.2 g.) of 2-[4-(3-tert. butylamino-2-hydroxypropoxy)-phenyl]-4-trifluoromethylimidazole is obtained, m.p. 185.5°-186.5° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([NH2:17])=[N:10][N:11]3[CH:16]=[CH:15][CH:14]=[N:13][C:12]=23)=[CH:4][CH:3]=1.[OH:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[CH2:25][C:26](O)=[O:27].Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1>N1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([NH:17][C:26](=[O:27])[CH2:25][C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=3[OH:18])=[N:10][N:11]3[CH:16]=[CH:15][CH:14]=[N:13][C:12]=23)=[CH:4][CH:3]=1
Reactant: O=C(O)Cc1ccccc1O
Reactant: Nc1nn2cccnc2c1-c1ccc(Cl)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: c1ccncc1
Product: O=C(Cc1ccccc1O)Nc1nn2cccnc2c1-c1ccc(Cl)cc1
Temperature: 35 °C
Reaction time: 18 h
Yield: 19.3 %

Procedure:
The product from Example 99A (100 mg, 0.41 mmol), 2-hydroxyphenylacetic acid (124 mg, 0.82 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (157 mg, 0.82 mmol), 1-hydroxybenzotriazole hydrate (100 mg, 0.65 mmol) were combined with pyridine (8 mL) and stirred at 35° C. for 18 hours. The reaction mixture was concentrated under vacuum and purified by reverse-phase HPLC [Waters XBridge™ RP18 column, 5 μm, 30×100 mm, flow rate 40 mL/minute, 5-95% gradient of acetonitrile in buffer (0.1 M aqueous ammonium bicarbonate, adjusted to pH 10 with ammonium hydroxide)] to afford 30 mg (19%) of the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 10.28-10.56 (bs, 1H), 9.09 (dd, J=6.9, 1.7 Hz, 1H), 8.62 (dd, J=4.1, 1.7 Hz, 1H), 7.70-7.73 (m, 2H), 7.30-7.34 (m, 2H), 7.11-7.16 (m, 2H), 6.72-6.81 (m, 2H), 6.65-6.72 (m, 1H), 3.57 (s, 2H); MS (ESI) m/z 379 (M+H)+; Anal. calculated for C20H15ClN4O2.0.35H2O: C, 62.37; H, 4.11; N, 14.55. Found C, 62.16; H, 3.87; N, 14.49.
Reaction SMILES: [C:1]1([C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]([S:16]([C:19]3[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=3)(=[O:18])=[O:17])[C:8]=2[CH:26]([NH2:28])[CH3:27])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:30]1[N:38]=[CH:37][N:36]=[C:35]2[C:31]=1[N:32]=[CH:33][NH:34]2.CCN(C(C)C)C(C)C>C(O)CCC>[C:1]1([C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]([S:16]([C:19]3[CH:20]=[CH:21][C:22]([CH3:25])=[CH:23][CH:24]=3)(=[O:17])=[O:18])[C:8]=2[CH:26]([NH:28][C:30]2[N:38]=[CH:37][N:36]=[C:35]3[C:31]=2[N:32]=[CH:33][NH:34]3)[CH3:27])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Clc1ncnc2[nH]cnc12
Reactant: Cc1ccc(S(=O)(=O)n2c(C(C)N)c(-c3ccccc3)c3ccccc32)cc1
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(S(=O)(=O)n2c(C(C)Nc3ncnc4[nH]cnc34)c(-c3ccccc3)c3ccccc32)cc1
Temperature: 120 °C
Reaction time: 56 h
Yield: 91.4 %

Procedure:
A mixture of 1-[3-phenyl-1-(toluene-4-sulfonyl)-1H-indol-2-yl]ethylamine (294 mg, 0.753 mmol), 6-chloro-9H-purine (140 mg, 0.903 mmol) and DIPEA (0.20 mL, 1.13 mmol) in n-butanol (1.5 mL) was stirred in a sealed tube for 56 h at 120° C. After cooling to RT, the crude reaction mixture was loaded onto an Isolute® SCX-2 cartridge which was washed with MeOH and the product eluted with 2M NH3/MeOH. The product containing fractions were combined and concentrated under reduced pressure. The resulting residue was purified by column chromatography (Si—PCC, gradient 0-7% 2M NH3/MeOH in DCM) affording N-(1-(3-phenyl-1-tosyl-1H-indol-2-yl)ethyl)-9H-purin-6-amine as a yellow solid (350 mg, 91%). LCMS: RT 3.31 min [M+H]+ 509.1
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][N:3]=1.Cl[C:10]1[C:19](=[O:20])[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12](=[O:21])[C:11]=1O>COCCOC.O>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]2[N:3]([C:11]3[C:12](=[O:21])[C:13]4[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=4[C:19](=[O:20])[C:10]=3[N:1]=2)[CH:4]=1
Reactant: O=C1C(O)=C(Cl)C(=O)c2ccccc21
Reactant: Nc1ccc(Cl)cn1
Solvent: O
Solvent: COCCOC
Product: O=C1c2ccccc2C(=O)c2c1nc1ccc(Cl)cn21
Yield: 4 %

Procedure:
1.58 g (12.30 mmol) of 2-amino-5-chloropyridine are added to a suspension of 1.29 g (6.21 mmol) of 3-chloro-1,4-dihydro-1,4-dioxo-2-hydroxynaphthalene in solution in 10 mL of 1,2-dimethoxyethane. The reaction medium is brought to reflux for 23 h. After complete cooling, the medium is diluted in 10 mL of water. The precipitate is filtered, washed with water and heptane, and dried. The precipitate is then diluted in dichloromethane and the organic phase is washed successively with a saturated solution of sodium hydrogen carbonate and sodium chloride. The organic phase is dried on sodium sulfate, filtered, and evaporated under reduced pressure. The raw product obtained is purified on a flash column (support: silica; eluent: dichoromethane/heptane/methanol, 79.5/20.0/0.5) to produce 0.07 g of 2-chloro-6,11-dihydro-6,11-dioxo-naphtho[2',3':4,5]imidazo [1,2-a]pyridine in the form of yellow crystals after decoloration with animal black.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9](=[O:17])[C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([CH3:16])[CH:11]=2)[CH:5]=[N:4][CH:3]=1.[CH2:18]1[C@@H:22]2[CH2:23][NH:24][CH2:25][C@@H:21]2[CH2:20][N:19]1[C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27].C(N(CC)C(C)C)(C)C>CS(C)=O>[CH3:16][C:12]1[CH:11]=[C:10]([CH:15]=[CH:14][CH:13]=1)[C:9]([NH:8][C:6]1[N:7]=[C:2]([N:24]2[CH2:23][C@@H:22]3[CH2:18][N:19]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:20][C@@H:21]3[CH2:25]2)[CH:3]=[N:4][CH:5]=1)=[O:17]
Reactant: Cc1cccc(C(=O)Nc2cncc(Cl)n2)c1
Reactant: CC(C)(C)OC(=O)N1C[C@H]2CNC[C@H]2C1
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cccc(C(=O)Nc2cncc(N3C[C@H]4CN(C(=O)OC(C)(C)C)C[C@H]4C3)n2)c1
Temperature: 110 °C

Procedure:
The product from Example 24A (130.5 mg, 0.53 mmol) was reacted with the product from Example 1C (149.6 mg, 0.70 mmol) and N,N-diisopropylethylamine (110 μL) in DMSO as described in Example 19A, except that the mixture was heated to 110° C. overnight, to afford the title compound. MS (DCI/NH3) m/z 424 (M+H)+.
Reaction SMILES: [CH2:1]([C@@H:8]1[O:10][C@@H:9]1[CH2:11][OH:12])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=[O:14].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1>CN(C=O)C.O.Cl>[CH2:1]([C@H:8]1[O:10][C@H:9]1[C:11]([OH:14])=[O:12])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Reactant: CCCCCCC[C@@H]1O[C@@H]1CO
Agent: Cl
Agent: c1cc[nH+]cc1
Solvent: O
Solvent: CN(C)C=O
Product: CCCCCCC[C@H]1O[C@H]1C(=O)O
Reaction time: 8 h

Procedure:
To a solution of 300 mg (1.16 mmole) (2R-cis)-3-heptyloxiranemethanol in 50 ml of DMF was added 2.62 g (6.97 mmole) of pyridinium dichromate. The reaction was allowed to stir overnight under argon. The mixture was then diluted with 150 ml H2O and 20 ml 0.1M HCl and washed three times with 50 ml of Et2O. The combined Et2O layers are dried over MgSO4, filtered and evaporated to afford a white powder. This residue was crystallized from petroleum ether to afford 155 mg of white power, mp 53°-5° C. 1H NMR (CDCl3) δ3.60 (d, 1, J=5 Hz), 3.24 (dd, 1, J=5 12 Hz), 1.6-1.2 (m, 12), 0.88 (t, 3, J=7 Hz). Mass Spectra: M-45(--CO2H)(3.7)141.1, M(100)41.0.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:27]=[CH:28][C:29]=1[Cl:30])[C:5]([NH:7][C:8]1([CH2:23][CH2:24][C:25]#[N:26])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]([CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[C:9]1=[O:22])=[O:6].C([Sn]([N:44]=[N+:45]=[N-:46])(CCCC)CCCC)CCC.Cl>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:27]=[CH:28][C:29]=1[Cl:30])[C:5]([NH:7][C:8]1([CH2:23][CH2:24][C:25]2[NH:46][N:45]=[N:44][N:26]=2)[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]([CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[C:9]1=[O:22])=[O:6]
Reactant: CCCCCN1C(=O)C(CCC#N)(NC(=O)c2ccc(Cl)c(Cl)c2)c2ccccc21
Reactant: CCCC[Sn](CCCC)(CCCC)N=[N+]=[N-]
Agent: Cl
Solvent: Cc1ccccc1
Product: CCCCCN1C(=O)C(CCc2nnn[nH]2)(NC(=O)c2ccc(Cl)c(Cl)c2)c2ccccc21
Temperature: 110 °C
Reaction time: 3 h
Yield: 78.4 %

Procedure:
A mixture of 2.00 g of 3,4-dichloro-N-[3-(2-cyanoethyl)-2,3-dihydro-2-oxo-1-pentyl-1H-indol-3-yl]benzamide, 3.0 g of tributyltin azide (Bu3SnN3) and 1.5 ml of toluene was stirred at 110° C. for 3 hours. After cooling, a 50 ml of ethanolic 6.4% hydrochloric acid solution was added to the mixture, and the resulting mixture was stirred at room temperature for 30 minutes. After removal of solvent by evaporation, ethyl acetate and then an aqueous saturated potassium fluoride solution were added to the residue, and insolubles were removed by filtration. The ethyl acetate layer was collected by separation, washed with water and evaporated. The residue was dissolved in an aqueous 5% sodium hydroxide solution and washed with water with diethyl ether. After the aqueous layer was made acidic with 10% hydrochloric acid, it was extracted with ethyl acetate. The extract was washed with water and dried, and solvent was evaporated. The residue was recrystallized from ethyl acetate to afford 1.72 g of 3,4-dichloro-N-{2,3-dihydro-2-oxo-1-pentyl-3-[2-(1H-tetrazol-5-yl)ethyl]-1H-indol-3-yl}-benzamide as colorless needles. Melting point: 142° TO 147° C., IR (Nujol) (cm-1): 3340, 1705, 1655, 1675, 1615, FAB-MS (m/z): 489 & 487 (MH+).
Reaction SMILES: [C:1]([NH:4][C:5]1[C:13]([N+:14]([O-])=O)=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][C:6]=1O)(=[O:3])[CH3:2].O.NN.[ClH:21]>C(O)C.[Pd]>[ClH:21].[C:1]([NH:4][C:5]1[CH:6]=[CH:7][C:8]([C:9]([OH:11])=[O:10])=[CH:12][C:13]=1[NH2:14])(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1c(O)cc(C(=O)O)cc1[N+](=O)[O-]
Agent: [Pd]
Agent: Cl
Agent: NN
Solvent: O
Solvent: CCO
Product: CC(=O)Nc1ccc(C(=O)O)cc1N
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
To a stirred mixture of 107 (1.00 g, 4.46 mmol) and 10% Pd-C (1.0 g) in ethanol (10 mL) and 5% HCl (1.2 mL) was added dropwise hydrazine hydrate (55% hydrazine, 1.0 mL, 17 mmol). The mixture was stirred at room temperature for 1 hour, the catalyst was filtered, and the filtrate was concentrated under reduced pressure. Compound 108 (0.875 g, 100%) was obtained as a white solid residue: mp 220°-223° C. (methanol/hexane). A literature reference (Ellis and Jones, 1974) did not report the mp.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][P:5](=[O:12])([O:9][CH2:10][CH3:11])[O:6][CH2:7][CH3:8].[K].[CH2:14]([O:16][C:17]([O:19][NH:20][C:21](=[O:25])[O:22][CH2:23][CH3:24])=[O:18])[CH3:15]>CN(C)C=O>[CH2:23]([O:22][C:21]([N:20]([CH2:2][CH2:3][CH2:4][P:5](=[O:12])([O:9][CH2:10][CH3:11])[O:6][CH2:7][CH3:8])[O:19][C:17]([O:16][CH2:14][CH3:15])=[O:18])=[O:25])[CH3:24]
Reactant: CCOP(=O)(CCCCl)OCC
Reactant: CCOC(=O)NOC(=O)OCC
Agent: [K]
Solvent: CN(C)C=O
Product: CCOC(=O)ON(CCCP(=O)(OCC)OCC)C(=O)OCC
Reaction time: 3 h
Yield: 90.3 %

Procedure:
To a solution of diethyl 3-chloropropylphosphonate (430.6 g) in dry N,N-dimethyformamide (2.25 l) was added potassium salt of ethyl N-ethoxycarbonyloxycarbamate (429.2 g). This mixture was stirred at 64°-66° C. for three hours. After the resulting potassium chloride was removed by filtration, the filtrate was concentrated under reduced pressure. The residue was dissolved in ethyl acetate (2.0 l) and washed with water (4.0 l). The aqueous layer was extracted twice with ethyl acetate (1.2 and 0.8 l). The combined ethyl acetate layer was washed with saturated aqueous sodium chloride solution (1.5 l), dried over magnesium sulfate and concentrated under reduced pressure to give oily diethyl 3-(N-ethoxycarbonyl-N-ethoxycarbonyloxyamino)propylphosphonate (643.7 g).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([OH:13])[C:7]([F:12])=[C:8]([CH:11]=1)[CH:9]=[O:10])[CH3:2].C([O-])([O-])=O.[K+].[K+].I[CH:21]([CH3:23])[CH3:22]>CN(C=O)C>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([O:13][CH:21]([CH3:23])[CH3:22])[C:7]([F:12])=[C:8]([CH:11]=1)[CH:9]=[O:10])[CH3:2]
Reactant: CC(C)I
Reactant: CCOc1cc(O)c(F)c(C=O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOc1cc(C=O)c(F)c(OC(C)C)c1
Temperature: 50 °C
Reaction time: 16 h
Yield: 71.7 %

Procedure:
To a solution of Intermediate 7.1 (assumed 24.3 mmol) in 50 mL DMF, was added K2CO3 (4.03 g, 29.2 mmol) and 2-iodopropane (4.86 mL, 48.6 mmol). The mixture was stirred at 50° C. for 16 h, then was diluted with EtOAc/hexanes (1:1). The organic phase was washed with H2O (3×) and brine, dried (Na2SO4) and concentrated. The crude product was purified by flash chromatography (0 to 30% EtOAc/hexanes gradient) to afford 3.94 g of Intermediate 7.2 as a white solid.
Reaction SMILES: CC1C=C(C)C=C(C)C=1S(O[C:14]1[C:19]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([CH2:27][C:28]#[N:29])=[CH:23][CH:22]=2)=[C:18]([CH3:30])[N:17]=[C:16]([NH2:31])[N:15]=1)(=O)=O.[CH2:32]([NH2:36])[CH2:33][CH2:34][CH3:35]>O1CCOCC1>[NH2:31][C:16]1[N:15]=[C:14]([NH:36][CH2:32][CH2:33][CH2:34][CH3:35])[C:19]([CH2:20][C:21]2[CH:22]=[CH:23][C:24]([CH2:27][C:28]#[N:29])=[CH:25][CH:26]=2)=[C:18]([CH3:30])[N:17]=1
Reactant: Cc1cc(C)c(S(=O)(=O)Oc2nc(N)nc(C)c2Cc2ccc(CC#N)cc2)c(C)c1
Reactant: CCCCN
Solvent: C1COCCO1
Product: CCCCNc1nc(N)nc(C)c1Cc1ccc(CC#N)cc1
Reaction time: 1 h

Procedure:
A mixture of the product from step (iv) (0.3 g) and butylamine (1 ml) in 1,4-dioxane (6 ml) was sealed into a microwave tube and the reaction was performed in the CEM Microwave, at 160° C. and 100 W for 1 h. The solvent was evaporated under reduced pressure and the residue used crude in the next step.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:10][CH:9]1[CH:21]=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C-:23]#[N:24].[K+].Cl>O1CCCC1.O>[OH:22][CH:21]([CH:9]1[CH2:10][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:12][CH2:13][N:8]1[CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:23]#[N:24]
Reactant: [C-]#N
Reactant: O=CC1CN(Cc2ccccc2)CCN1Cc1ccccc1
Agent: Cl
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: N#CC(O)C1CN(Cc2ccccc2)CCN1Cc1ccccc1
Reaction time: 0.5 h
Yield: 100.4 %

Procedure:
To a solution of 5.2 g of crude 1,4-dibenzyl-2-formylpiperazine in a mixture of 30 ml of tetrahydrofuran and 10 ml of water are added 2.2 g (33.8 mmoles) of potassium cyanide and 3.4 ml of concentrated hydrochloric acid under ice-cooling, and the mixture is stirred for 30 minutes, mixed with water and extracted with chloroform. The extract is washed with water, dried over magnesium sulfate and evaporated under reduced pressure to yield 5.70 g of crude oily 2-hydroxy-2-(1,4-dibenzylpiperazin-2-yl)acetonitrile.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][C:17]=1[O:18][CH3:19])[NH:14][CH:13]=[CH:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[C:22]1([S:28](Cl)(=[O:30])=[O:29])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.CCOC(C)=O>CN(C=O)C>[C:22]1([S:28]([N:14]2[C:15]3[C:11](=[CH:10][C:9]([O:8][CH2:1][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)=[C:17]([O:18][CH3:19])[CH:16]=3)[CH:12]=[CH:13]2)(=[O:30])=[O:29])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: COc1cc2[nH]ccc2cc1OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1cc2c(ccn2S(=O)(=O)c2ccccc2)cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 89.9 %

Procedure:
A solution of 5-benzyloxy-6-methoxyindole (990 mg, 3.9 mmol) in DMF (3 mL) was added to a solution of NaH (234 mg, 5.9 mmol, 60% in oil) in DMF (1 mL) at 0° C. The ice bath was removed, and the reaction mixture allowed to stir at RT for 30 min. The reaction flask was cooled to 0° C. and PhSO2Cl (0.6 mL, 4.7 mmol) was added via syringe. The ice bath was removed and the reaction mixture stirred at RT for 24 h. Water (25 mL) was added and the aqueous layer extracted with Et2O (4×50 mL). The combined organic extracts were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo to give an oil. The residue was purified by column chromatography (25% then 40% EtOAc/hex) to furnish N-phenylsulfonyl 5-benzyloxy-6-methoxyindole as a crystalline solid (1.38 g, 90% yield).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[CH2:5][NH:6][CH2:7][CH2:8][NH:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH3:2].[N:18]1([CH2:27][CH2:28][C:29](O)=[O:30])[CH:26]=[C:24]([CH3:25])[C:22](=[O:23])[NH:21][C:19]1=[O:20].C(Cl)Cl.C1CCC(N=C=NC2CCCCC2)CC1>CN(C=O)C>[CH2:1]([O:3][C:4](=[O:17])[CH2:5][N:6]([CH2:7][CH2:8][NH:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C:29](=[O:30])[CH2:28][CH2:27][N:18]1[CH:26]=[C:24]([CH3:25])[C:22](=[O:23])[NH:21][C:19]1=[O:20])[CH3:2]
Reactant: CCOC(=O)CNCCNC(=O)OC(C)(C)C
Reactant: Cc1cn(CCC(=O)O)c(=O)[nH]c1=O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCOC(=O)CN(CCNC(=O)OC(C)(C)C)C(=O)CCn1cc(C)c(=O)[nH]c1=O
Temperature: 0 °C
Reaction time: 2 h
Yield: 58.3 %

Procedure:
N—(N′—-BOC-aminoethyl)glycine ethyl ester (1 g, 0.0041 mol) was dissolved in DMF (12 mL). DhbtOH (0.73 g, 0.0045 mol) and 3-(1-thyminyl)propanoic acid (0.89 g, 0.0045 mol) were added. Methylene chloride (12 mL) was then added and the mixture was cooled to 0° C. in an ice bath. After addition of DCC (1.01 g, 0.0049 mol), the mixture was stirred at 0° C. for 2 h, followed by 1 h at room temperature. The precipitated DCU was removed by filtration, washed with methylene chloride (25 mL), and a further amount of methylene chloride (50 mL) was added to the filtrate. The organic phase was extracted with sodium hydrogen carbonate (1 volume saturated diluted with 1 volume water, 6×100 mL), potassium sulfate (1 volume saturated diluted with 4 volumes water, 3×100 mL), and saturated aqueous sodium chloride (1×100 mL), dried over magnesium sulfate, and evaporated to dryness, in vacuo. The solid residue was suspended in methylene chloride (15 mL), and stirred for 1 h. The precipitated DCU was removed by filtration and washed with methylene chloride. The filtrate was evaporated to dryness in vacuo, and the residue purified by column chromatography on silica gel, eluting with a mixture of methanol and methylene chloride (gradient from 1 to 6% methanol in methylene chloride). This afforded the title compound as a white solid (1.02 g, 59%). Anal. for C19H30N4O7, found (calc.) C: 53.15 (53.51) H: 6.90 (7.09) N: 12.76 (13.13). The compound showed satisfactory 1H and 13C-NMR spectra.