Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)CC)C.[CH2:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10][C:9]1=[O:17].[CH3:18][Si:19]([CH3:22])([CH3:21])Cl>O1CCCC1>[CH3:18][Si:19]([CH3:22])([CH3:21])[O:17][C:9]1[CH2:10][C:11]2[C:16]([CH:8]=1)=[CH:15][CH:14]=[CH:13][CH:12]=2
Reactant: C[Si](C)(C)Cl
Reactant: O=C1Cc2ccccc2C1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C[Si](C)(C)OC1=Cc2ccccc2C1
Reaction time: 3 h
Yield: 71 %

Procedure:
30.3 g (0.30 mole) of triethylamine are added to a solution of 36.5 g (0.28 mole) of 2-indanone and 32.4 g (0.30 mole) of trimethylchlorosilane in 300 ml of tetrahydrofuran at room temperature while stirring. Stirring is continued for a further 3 hours at room temperature (20° C.), the precipitate which has separated out is filtered off under suction and the filtrate is evaporated down. The residue is purified by distillation (53° C., 0.3 mbar). 40.6 g (72%) of 2-trimethylsilyloxy-1H-indene are obtained as a colorless liquid in this manner.
Reaction SMILES: [OH:1][NH:2][C:3](=[NH:12])[O:4][C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][CH:6]=1.CCN(C(C)C)C(C)C.[O:22]1[CH:26]=[CH:25][CH:24]=[C:23]1[C:27](Cl)=O>O1CCOCC1>[Cl:11][C:8]1[CH:9]=[CH:10][C:5]([O:4][C:3]2[N:12]=[C:27]([C:23]3[O:22][CH:26]=[CH:25][CH:24]=3)[O:1][N:2]=2)=[CH:6][CH:7]=1
Reactant: O=C(Cl)c1ccco1
Reactant: N=C(NO)Oc1ccc(Cl)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: Clc1ccc(Oc2noc(-c3ccco3)n2)cc1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 50 %

Procedure:
To the mixture of 4-chlorophenyl hydroxycarbamimidate (0.5 mmol. 1 eq) and DIEA (1.25 mmol, 2.5 eq) in dioxane was added dropwise furan-2-carbonyl chloride (0.53 mmol, 1.05 eq) at 0-5° C. The mixture was allowed to warm to room temperature and then stirred for 0.5-1 h or until complete as determined by LC-MS analysis of the reaction mixture. The cyclodehydration reaction was run at reflux (115-120° C.) overnight. The mixture was cooled down and solvent was removed in vacuo. The resulting residue was purified by HPLC purification to provide desired 3-(4-Chloro-phenoxy)-5-furan-2-yl-[1,2,4]oxadiazole in a yield of 50% and purity of 99.9%. LC-MS [M+H] 263.3 (C12H7ClN2O3+H, requires 263.65). 1H NMR (DMSO-d6) δ 8.17 (d, 1H, J=1.75), 7.63 (d, 1H, J=3.5), 7.55 (d, 2H, J=8.8), 7.46 (d, 2H, J=8.8), 6.87 (m, 1H).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([OH:7])[CH2:3][CH2:2]1.[NH2:8][C:9]1[CH:16]=[CH:15][CH:14]=[C:13](F)[C:10]=1[C:11]#[N:12]>>[NH2:8][C:9]1[CH:16]=[CH:15][CH:14]=[C:13]([O:7][CH:4]2[CH2:5][CH2:6][O:1][CH2:2][CH2:3]2)[C:10]=1[C:11]#[N:12]
Reactant: OC1CCOCC1
Reactant: N#Cc1c(N)cccc1F
Product: N#Cc1c(N)cccc1OC1CCOCC1

Procedure:
Prepared as in Example 22b from tetrahydro-2H-pyran-4-ol and 2-amino-6-fluorobenzonitrile as a colorless oil (48%). 1H NMR (400 MHz, CDCl3) δ 1.87 (m, 2H), 2.00 (m, 2H), 3.63 (m, 2H), 4.00 (m, 2H), 4.42 (s, 2H), 4.58 (m, 1H), 6.23 (d, J=8.4 Hz, 1H), 6.30 (d, J=8.4 Hz, 1H), 7.20 (t, J=8.4 Hz, 1H). MS 219 (MH+).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([NH:17][S:18]([C:21]2[CH:26]=[CH:25][C:24]([NH2:27])=[CH:23][CH:22]=2)(=[O:20])=[O:19])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.[C:37](Cl)(=[O:40])[CH:38]=[CH2:39]>C1COCC1>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([NH:17][S:18]([C:21]2[CH:26]=[CH:25][C:24]([NH:27][C:37](=[O:40])[CH:38]=[CH2:39])=[CH:23][CH:22]=2)(=[O:20])=[O:19])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=CC(=O)Cl
Reactant: Nc1ccc(S(=O)(=O)NC2CCN(C(=O)OCc3ccccc3)CC2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: C=CC(=O)Nc1ccc(S(=O)(=O)NC2CCN(C(=O)OCc3ccccc3)CC2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 8.4 %

Procedure:
4-(4-Amino-benzenesulfonylamino)-piperidine-1-carboxylic acid benzyl ester (1 g, 2.4 mmol) was dissolved in THF (10 ml). To this was added diisopropylethylamine (1.27 ml, 7.2 mmol) in one portion followed by the drop wise addition of acryloyl chloride (0.2 ml, 2.6 mmol) and the mixture was stirred at room temperature under a nitrogen atmosphere for 3 hours. The THF was removed under vacuum and the resulting crude material was purified by column chromatography (elution: 40% heptane, 60% ethyl acetate) to give the title compound (89 mg, 8% yield) as a white powder.
Reaction SMILES: [CH3:1][C@H:2]([NH:7][C:8]([C:10]1[C:18]2[C:13](=[N:14][CH:15]=[C:16]([C:19]3[C:27]4[C:22](=[CH:23][CH:24]=[C:25]([Cl:28])[CH:26]=4)[N:21]([CH3:29])[N:20]=3)[N:17]=2)[N:12](COCC[Si](C)(C)C)[CH:11]=1)=[O:9])[C:3]([CH3:6])([CH3:5])[CH3:4].FC(F)(F)C(O)=O.C(N)CN>ClCCl>[CH3:1][C@H:2]([NH:7][C:8]([C:10]1[C:18]2[C:13](=[N:14][CH:15]=[C:16]([C:19]3[C:27]4[C:22](=[CH:23][CH:24]=[C:25]([Cl:28])[CH:26]=4)[N:21]([CH3:29])[N:20]=3)[N:17]=2)[NH:12][CH:11]=1)=[O:9])[C:3]([CH3:6])([CH3:5])[CH3:4]
Reactant: C[C@H](NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C)c4ccc(Cl)cc34)nc12)C(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: NCCN
Solvent: ClCCl
Product: C[C@H](NC(=O)c1c[nH]c2ncc(-c3nn(C)c4ccc(Cl)cc34)nc12)C(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 85.9 %

Procedure:
In a round-bottomed flask, 2-(5-chloro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanylethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ((S)-1,2,2-trimethyl-propyl)-amide (90 mg, 0.17 mmol) was dissolved in dichloromethane (0.8 ml) and trifluoroacetic acid (0.5 ml, 6.6 mmol) was added. The reaction mixture was stirred at room temperature for 2 h then concentrated. The residue was redissolved in dichloromethane (0.8 ml) and ethylenediamine (0.7 ml, 9.9 mmol) was added. The solution was stirred at room temperature for 1.5 h then quenched with water and diluted with ethyl acetate. The resultant suspension was filtered, rinsed with hot water and ethyl acetate then dried under high vacuum to provide 60 mg (83%) of 2-(5-chloro-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ((S)-1,2,2-trimethyl-propyl)-amide as a light yellow powder. MS: (M+H)+=411; 1H NMR (DMSO-d6, 300 MHz): δ (ppm) 12.43 (br. s., 1H), 9.08 (s, 1H), 8.45 (s, 1H), 8.33 (s, 1H), 8.00 (d, J=10.2 Hz, 1H), 7.85 (d, J=8.9 Hz, 1H), 7.55 (dd, J=8.9, 1.5 Hz, 1H), 4.20 (s, 3H), 4.06-4.28 (m, 1H), 1.33 (d, J=6.8 Hz, 3H), 0.92 (s, 9H).
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[C:6]=1[F:17])=[O:4].C(=O)([O-])[O-].[K+].[K+].Br[CH2:27][CH2:28][O:29][CH3:30]>C(#N)C>[F:19][C:2]([F:1])([F:18])[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH:11]2[CH2:16][CH2:15][N:14]([CH2:27][CH2:28][O:29][CH3:30])[CH2:13][CH2:12]2)[C:6]=1[F:17])=[O:4]
Reactant: O=C(c1cccc(C2CCNCC2)c1F)C(F)(F)F
Reactant: COCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COCCN1CCC(c2cccc(C(=O)C(F)(F)F)c2F)CC1

Procedure:
Preparation according to Example 1: 2,2,2-trifluoro-1-(2-fluoro-3-piperidin-4-ylphenyl)ethanone (0.01 g), acetonitrile (2 ml), potassium carbonate (0.01 g) and 1-bromo-2-methoxyethane (0.01 g). MS m/z (rel. intensity, 70 eV) 333 (M+, 1), 289 (15), 288 (bp), 264 (4), 148 (6).
Reaction SMILES: [H-].[Na+].[CH:3]1[C:14]2=[C:15]3[CH:10]([CH2:11][CH2:12][CH2:13]2)[CH2:9][CH2:8][CH2:7][C:6]3=[CH:5][C:4]=1[NH:16][C:17]1[N:22]=[CH:21][C:20]([C:23]([O:25]CC)=[O:24])=[CH:19][N:18]=1.Br[CH2:29][CH3:30].[Cl-].[NH4+]>CN(C)C=O>[CH2:29]([N:16]([C:4]1[CH:5]=[C:6]2[C:15]3[CH:10]([CH2:9][CH2:8][CH2:7]2)[CH2:11][CH2:12][CH2:13][C:14]=3[CH:3]=1)[C:17]1[N:22]=[CH:21][C:20]([C:23]([OH:25])=[O:24])=[CH:19][N:18]=1)[CH3:30]
Reactant: CCBr
Reactant: CCOC(=O)c1cnc(Nc2cc3c4c(c2)CCCC4CCC3)nc1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: CCN(c1cc2c3c(c1)CCCC3CCC2)c1ncc(C(=O)O)cn1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 77 %

Procedure:
A suspension of sodium hydride (60%, 0.008 g) in N,N-dimethylformamide (2 ml) was added with ethyl 2-[(5,6,6a,7,8,9-hexahydro-4H-2-phenalenyl)amino]pyrimidine-5-carboxylate (0.032 g) dissolved in N,N-dimethylformamide (1 ml), and the mixture was stirred at room temperature for 10 minutes. The reaction mixture was added with bromoethane (0.017 ml), and the mixture was stirred overnight. The reaction mixture was added with saturated aqueous ammonium chloride, and the mixture was extracted with diethyl ether. The organic layer was washed successively with water and saturated brine, and dried over anhydrous sodium sulfate. The organic layer was concentrated under reduced pressure, the resulting residue was suspended in ethanol (5 ml), the suspension was added with 20% aqueous sodium hydroxide (1 ml), and the mixture was stirred at 50° C. for 3 hours. The reaction mixture was left to cool and then made acidic with 2 N aqueous hydrochloric acid, and the mixture was extracted with chloroform. The organic layer was washed successively with water and saturated brine, and dried over anhydrous sodium sulfate. The organic layer was concentrated under reduced pressure, and the resulting residue was recrystallized from chloroform-n-hexane to obtain the title compound (0.023 g, yield: 77%) as colorless needles (melting point: 252-253° C.).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[N:16]=[CH:15][C:14]([CH:17]3[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]3)=[CH:13][CH:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[N:7]=1.C([O:33][CH2:34][C:35]1[C:40](B2OC(C)(C)C(C)(C)O2)=[CH:39][CH:38]=[CH:37][C:36]=1[N:50]1[N:59]=[CH:58][C:57]2[C:52](=[C:53]([F:64])[CH:54]=[C:55]([C:60]([CH3:63])([CH3:62])[CH3:61])[CH:56]=2)[C:51]1=[O:65])(=O)C.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd]>[C:60]([C:55]1[CH:56]=[C:57]2[C:52](=[C:53]([F:64])[CH:54]=1)[C:51](=[O:65])[N:50]([C:36]1[C:35]([CH2:34][OH:33])=[C:40]([C:2]3[CH:3]=[C:4]([NH:10][C:11]4[N:16]=[CH:15][C:14]([CH:17]5[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]5)=[CH:13][CH:12]=4)[C:5](=[O:9])[N:6]([CH3:8])[N:7]=3)[CH:39]=[CH:38][CH:37]=1)[N:59]=[CH:58]2)([CH3:63])([CH3:61])[CH3:62]
Reactant: Cn1nc(Cl)cc(Nc2ccc(C3CCN(C(=O)OC(C)(C)C)CC3)cn2)c1=O
Reactant: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)cccc1-n1ncc2cc(C(C)(C)C)cc(F)c2c1=O
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: C1COCCO1
Product: Cn1nc(-c2cccc(-n3ncc4cc(C(C)(C)C)cc(F)c4c3=O)c2CO)cc(Nc2ccc(C3CCN(C(=O)OC(C)(C)C)CC3)cn2)c1=O

Procedure:
This reaction was carried out under similar conditions to those described above in step 7 of the preparation of Example 6. A solution of tert-butyl 4-(6-(6-chloro-2-methyl-3-oxo-2,3-dihydropyridazin-4-ylamino)pyridin-3-yl)piperidine-1-carboxylate (150 mg, 357 mmol), 2-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl acetate (177 mg, 357 μmol), xPhos (17 mg, 35.7 mmol) and potassium phosphate (190 mg, 893 mmol) in 10 ml of dioxane/water (9:1) was degassed with nitrogen for 10 minutes and bis(dibenzylideneacetone)palladium (0) (10.3, 17.9 mmol) was added.
Reaction SMILES: [N:1]1(C(=O)C)[C:5]2=[CH:6][N:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[N:2]1.[OH-].[Na+]>O1CCCC1.CO.O>[NH:1]1[C:5]2=[CH:6][N:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[N:2]1
Reactant: CC(=O)n1ncc2ccncc21
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: c1cc2cn[nH]c2cn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 1-pyrazolo[3,4-c]pyridin-1-yl-ethanone (20.2 mg, 0.17 mmol, 1 equiv) in tetrahydrofuran (2 mL) and methanol (0.5 mL) was added sodium hydroxide aqueous solution (2M, 0.25 mL). The reaction solution was stirred at room temperature for 1 hr and then concentrated in vacuo to provide a crude residue. The crude residue was diluted with water (20 mL) and extracted with dichloromethane (2×100 mL). The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated in vacuo to provide 1H-pyrazolo[3,4-c]pyridine as white powder, which used without further purification: LCMS (ES) M+H 120.3, Rf 0.22 min (Agilent Zorbax SB-C18, 2.1×50 mm, 5μ, 35° C., 1 ml/min flow rate, a 2.5 min gradient of 20% to 100% B with a 1.1 min wash at 100% B; A=0.1% formic acid /5% acetonitrile /94.9% water, B=0.1% formic acid /5% water/94.9% acetonitrile).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[C:13]([N+:14]([O-])=O)=[C:12]([NH:17][C:18]([C:20]3[N:21]([CH3:30])[N:22]=[C:23]([C:26]([CH3:29])([CH3:28])[CH3:27])[C:24]=3[Cl:25])=O)[CH:11]=[C:10]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[C:37]([F:40])([F:39])[F:38])[N:9]=2)[CH2:4][CH2:3]1>CC(O)=O.[Fe]>[C:26]([C:23]1[C:24]([Cl:25])=[C:20]([C:18]2[NH:14][C:13]3[C:8]([N:5]4[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]4)=[N:9][C:10]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=4[C:37]([F:39])([F:40])[F:38])=[CH:11][C:12]=3[N:17]=2)[N:21]([CH3:30])[N:22]=1)([CH3:28])([CH3:27])[CH3:29]
Reactant: CN1CCN(c2nc(-c3ccccc3C(F)(F)F)cc(NC(=O)c3c(Cl)c(C(C)(C)C)nn3C)c2[N+](=O)[O-])CC1
Agent: [Fe]
Solvent: CC(=O)O
Product: CN1CCN(c2nc(-c3ccccc3C(F)(F)F)cc3nc(-c4c(Cl)c(C(C)(C)C)nn4C)[nH]c23)CC1
Temperature: 100 °C
Reaction time: 0.08 h

Procedure:
A solution of 5-tert-butyl-4-chloro-2-methyl-2H-pyrazole-3-carboxylic acid [2-(4-methyl-piperazin-1-yl)-3-nitro-6-(2-trifluoromethyl-phenyl)-pyridin-4-yl]-amide (300 mg, 0.517 mmol, prepared as described in the previous step) in AcOH (10 mL) was treated with iron powder (86.7 mg, 1.55 mmol) and heated to 100° C. for 5 h. The mixture was concentrated in vacuo, treated with saturated aqueous NaHCO3 (25 mL), and extracted three times with EtOAc (30 mL). The combined extracts were dried over MgSO4 and concentrated in vacuo. The residue was purified on a 12-g SEPRA Si 50 SPE column (Isco system: Flow rate=10 mL/min; Eluent=EtOAc-hexanes, 1:99 v/v for 5 min, then 1:99 to 3:17 v/v over 40 min) to yield 2-(5-tert-butyl-4-chloro-2-methyl-2H-pyrazol-3-yl)-4-(4-methyl-piperazin-1-yl)-6-(2-trifluoromethyl-phenyl)-3H-imidazo[4,5-c]pyridine as a tan solid. 1H-NMR (400 MHz, CDCl3) δ: 9.99 (s, 1H), 7.76 (d, J=7.6 Hz, 1H), 7.56-7.61 (m, 2H), 7.45-7.52 (m, 1H), 6.95 (s, 1H), 4.30 (s, 7H), 2.59 (t, J=4.9 Hz, 4H), 2.36 (s, 3H), 1.45 (s, 9H). Mass Spectrum (LCMS, APCI pos.): Calculated for C26H29ClF3N7: 532.2 (M+H). Measured: 532.2.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.CS(O[CH2:11][CH2:12][CH:13]1[CH2:18][CH2:17][CH:16]([N:19]2[C:23]3[N:24]=[CH:25][N:26]=[C:27]([NH2:28])[C:22]=3[C:21]([C:29]3[CH:34]=[CH:33][C:32]([O:35][C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)=[CH:31][CH:30]=3)=[CH:20]2)[CH2:15][CH2:14]1)(=O)=O.[H-].[Na+]>CN(C)C=O>[N:1]1([CH2:11][CH2:12][CH:13]2[CH2:18][CH2:17][CH:16]([N:19]3[C:23]4[N:24]=[CH:25][N:26]=[C:27]([NH2:28])[C:22]=4[C:21]([C:29]4[CH:30]=[CH:31][C:32]([O:35][C:36]5[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=5)=[CH:33][CH:34]=4)=[CH:20]3)[CH2:15][CH2:14]2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: c1c[nH]cn1
Reactant: CS(=O)(=O)OCCC1CCC(n2cc(-c3ccc(Oc4ccccc4)cc3)c3c(N)ncnc32)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Nc1ncnc2c1c(-c1ccc(Oc3ccccc3)cc1)cn2C1CCC(CCn2ccnc2)CC1
Temperature: 40 °C
Reaction time: 5 h
Yield: 63 %

Procedure:
Imidazole (0.070 g, 1.03 mmol) was added into a solution of 2-{4-[4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]cyclohexyl}ethyl methanesulfonate (0.052 g, 0.10 mmol) in N,N-dimethylformamide (2 mL). The mixture was stirred at 40° C. for 5 hours. 60% Sodium hydride in mineral oil (0.021 g, 052 mmol) was added and the mixture was stirred at ambient temperature overnight. The solvent was removed under reduced pressure and the residue was purified by preparative RP-HPLC to yield 7-{4-[2-(1H-1-imidazolyl)ethyl]cyclohexyl}-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (0.030 g, 0.063 mmol) as a white solid: 1H NMR (CDCl3, 400 MHz) δ 8.30(s, 1H), 7.55(br, 1H), 7.44(d, 2H), 7.42(t, 2H), 7.16(t, 1H), 7.08(m, 6H), 6.95(br, 1H), 5.49(br, 2H), 4.72(m, 1H), 4.01(t, 2H), 1.99-1.71 (m, 11H); RP-HPLC (Hypersil C18, 5 μm, 100 A, 250×4.6 mm; 25%-100% over 10 min acetonitrile-0.05M ammonium acetate, 1 mL/min) Rt 9.18 min; MS: MH+ 479.
Reaction SMILES: [ClH:1].C(OC([NH:12][C@H:13]([C:18]([NH:20][C@H:21]([C:29]([N:31]1[CH2:42][CH2:41][CH2:40][C@H:32]1[C:33]([NH:35][CH2:36][C:37]([NH2:39])=[O:38])=[O:34])=[O:30])[CH2:22][CH2:23][CH2:24][NH:25][C:26](=[NH:28])[NH2:27])=[O:19])[CH2:14][CH:15]([CH3:17])[CH3:16])=O)C1C=CC=CC=1>[Pd].CO>[ClH:1].[NH2:12][C@H:13]([C:18]([NH:20][C@H:21]([C:29]([N:31]1[CH2:42][CH2:41][CH2:40][C@H:32]1[C:33]([NH:35][CH2:36][C:37]([NH2:39])=[O:38])=[O:34])=[O:30])[CH2:22][CH2:23][CH2:24][NH:25][C:26](=[NH:27])[NH2:28])=[O:19])[CH2:14][CH:15]([CH3:16])[CH3:17]
Reactant: CC(C)C[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@@H](CCCNC(=N)N)C(=O)N1CCC[C@H]1C(=O)NCC(N)=O
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CC(C)C[C@H](N)C(=O)N[C@@H](CCCNC(=N)N)C(=O)N1CCC[C@H]1C(=O)NCC(N)=O

Procedure:
A solution of 6.43 g. of Nα -benzyloxycarbonyl-L-leucyl-L-arginyl-L-prolyl-glycinamide hydrochloride in 200 ml. of methanol with 250 mg. of 20% palladium-on-carbon is stirred under hydrogen gas for three hours, the catalyst removed by filtration, and the filtrate evaporated to dryness at 45° C. under reduced pressure. The dried residue is a foam which is suitable for use without further purification.
Reaction SMILES: [O:1]1[C:5]2=[N:6][C:7]([C:13]([OH:15])=[O:14])=[C:8]([C:10]([OH:12])=O)[CH:9]=[C:4]2[CH:3]=[CH:2]1>C(OC(=O)C)(=O)C>[O:1]1[C:5]2=[N:6][C:7]3[C:13](=[O:14])[O:15][C:10](=[O:12])[C:8]=3[CH:9]=[C:4]2[CH:3]=[CH:2]1
Reactant: O=C(O)c1cc2ccoc2nc1C(=O)O
Solvent: CC(=O)OC(C)=O
Product: O=C1OC(=O)c2nc3occc3cc21
Temperature: 25 °C
Yield: 88.4 %

Procedure:
Furo[2,3-b]pyridine-5,6-dicarboxylic acid (6.7 g, 0.032 mol) is heated at 60° C. for 30 minutes in acetic anhydride (150 mL). The reaction mixture is cooled to room temperature and concentrated in vacuo and the residue triturated with cyclohexane-ether(5:1), filtered off and dried to give 5.35 g furo[2,3-b]pyridine-5,6-dicarboxylic acid anhydride.
Reaction SMILES: N1CCCCC1.C1C2C(COC([N:24]3[CH2:29][CH2:28][CH2:27][CH2:26][C@H:25]3[C:30](=[O:49])[NH:31][CH2:32][C:33]3[CH:38]=[C:37]([Cl:39])[CH:36]=[CH:35][C:34]=3[CH2:40][NH:41][C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])=O)C3C(=CC=CC=3)C=2C=CC=1>C(Cl)Cl>[C:45]([O:44][C:42](=[O:43])[NH:41][CH2:40][C:34]1[CH:35]=[CH:36][C:37]([Cl:39])=[CH:38][C:33]=1[CH2:32][NH:31][C:30]([C@@H:25]1[CH2:26][CH2:27][CH2:28][CH2:29][NH:24]1)=[O:49])([CH3:48])([CH3:46])[CH3:47]
Reactant: CC(C)(C)OC(=O)NCc1ccc(Cl)cc1CNC(=O)[C@@H]1CCCCN1C(=O)OCC1c2ccccc2-c2ccccc21
Solvent: C1CCNCC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCc1ccc(Cl)cc1CNC(=O)[C@@H]1CCCCN1
Temperature: 25 °C
Reaction time: 1 h
Yield: 80.2 %

Procedure:
Piperidine (1.0 mL, 10.0 mmol) was added dropwise to a stirred solution of (S)-{9H-Fluoren-9-yl)methyl-2-[2-{(tert-butoxycarbonylamino)methyl}-5-chlorobenzylcarbamoyl]piperidine-1-carboxylate (0.89 g, 1.47 mmol) in CH2Cl2 (5 mL). The reaction mixture was stirred at room temperature for 1 h. Solvent was removed under reduced pressure and the crude product was purified by reverse phase combiflash column chromatography (C18; eluent: 10-100% acetonitrile:water) to afford the title compound (0.45 g) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH2:6][CH2:5][N:4]([C:7]2[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=2)[N:3]=1.CN(C)C=O.S(OOS([O-])(=O)=O)([O-])(=O)=O.[K+].[K+]>O.[OH-].[Na+]>[Cl:1][C:2]1[CH:6]=[CH:5][N:4]([C:7]2[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=2)[N:3]=1
Reactant: ClC1=NN(c2cccnc2)CC1
Agent: O=S(=O)([O-])OOS(=O)(=O)[O-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Clc1ccn(-c2cccnc2)n1
Temperature: 80 °C
Reaction time: 3 h
Yield: 53.9 %

Procedure:
A 100 mL, 3-neck round bottom flask was charged with 3-(3-chloro-4,5-dihydro-1H-pyrazol-1-yl)pyridine (3.0 g) and N,N-dimethylformamide (15 mL). potassium persulfate (6.70 g, 24.8 mmol) was added and the reaction was heated to 80° C. for 3 hours. An exotherm at about 110° C. was observed. It was allowed to cool to 80° C. and stirred at 80° C. for 3 hours, at which point a sample was diluted with water and basified with 50 wt % sodium hydroxide solution and extracted with ethyl acetate. The organic layer was analyzed by thin layer chromatography [Eluent: ethyl acetate], which showed that the desired product was formed as the major product, along with a trace of starting material and some minor impurities. The reaction mixture was cooled to 20° C. and diluted with water (50 mL). It was basified with 50% sodium hydroxide and extracted with ethyl acetate (4×30 mL). The organic layers were combined, concentrated to dryness, and purified by flash column chromatography using 30% ethyl acetate/hexanes as eluent. The pure fractions were concentrated to dryness to afford a white solid (1.60 g, 54%): mp 104-106° C.; 1H NMR (400 MHz, CDCl3) δ 8.93 (d, J=27 Hz, 1H), 8.57 (dd, J=4.8, 1.4 Hz, 1H), 8.02 (ddd, J=8.3, 2.7, 1.5 Hz, 1H), 7.91 (d, J=2.6 Hz, 1H), 7.47-7.34 (M, 1H), 6.45 (d, J=2.6 Hz, 1H); 13C NMR (101 MHz, CDCl3) δ 148.01, 142.72, 140.12, 135.99, 128.64, 126.41, 124.01, 108.08; EIMS m/z 179 ([M]+).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[CH2:9]Br.[NH:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1.C(N(CC)CC)C.C(OC(=O)C)C>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[CH2:9][N:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1
Reactant: C1COCCN1
Reactant: Clc1ccc(Br)c(CBr)c1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Clc1ccc(Br)c(CN2CCOCC2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 92 %

Procedure:
A mixture of 0.50 g (1.76 mmol) 1-Bromo-2-bromomethyl-4-chloro-benzene, 0.17 g (1.94 mmol) morpholine and 0.29 ml (210 mmol) triethylamine in 20 ml DMF was stirred overnight at room temperature. 200 ml of ethylacetate was added and the solution was extracted with sodium bicarbonate, water and brine. 0.47 g (1.62 mmol, 92%) of the title compound were obtained as a viscous oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][C:3]=1[I:12].[CH3:13]O.Cl>CO>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH3:13])=[O:10])=[CH:4][C:3]=1[I:12]
Reactant: CO
Reactant: Nc1ccc(CC(=O)O)cc1I
Agent: Cl
Product: COC(=O)Cc1ccc(N)c(I)c1
Temperature: 25 °C

Procedure:
The crude (4-amino-3-iodophenyl)acetic acid (about 40 g, about 171 mmol) in methanol (110 mL) was added 100 mL of 4 M MeOH/HCl and the solution was stirred at ambient temperature over night. Distilled the solution under reduce pressure, and the residue was purified by silica gel cloumn chromatography to give methyl (4-amino-3-iodophenyl)acetate. 1H-NMR (300 MHz, CDCl3) δ ppm 7.54 (s, 1H), 7.04 (d, J=7.9 Hz, 1H), 6.68 (d, J=7.9 Hz, 1H), 3.67 (s, 3H), 3.46 (s, 2H).
Reaction SMILES: C[O:2][C:3](=[O:31])[CH2:4][CH:5]([N:9]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[N:11]([CH2:18][C:19]2[CH:27]=[C:26]([Br:28])[CH:25]=[C:24]3[C:20]=2[CH2:21][C:22](=[O:29])[NH:23]3)[C:10]1=[O:30])[CH2:6][CH2:7][CH3:8].[OH-].[Li+].Cl>O1CCOCC1.O>[Br:28][C:26]1[CH:25]=[C:24]2[C:20]([CH2:21][C:22](=[O:29])[NH:23]2)=[C:19]([CH2:18][N:11]2[C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[N:9]([CH:5]([CH2:6][CH2:7][CH3:8])[CH2:4][C:3]([OH:31])=[O:2])[C:10]2=[O:30])[CH:27]=1
Reactant: CCCC(CC(=O)OC)n1c(=O)n(Cc2cc(Br)cc3c2CC(=O)N3)c2ccccc21
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CCCC(CC(=O)O)n1c(=O)n(Cc2cc(Br)cc3c2CC(=O)N3)c2ccccc21
Temperature: 25 °C
Yield: 93.7 %

Procedure:
3-[3-(6-Bromo-2-oxo-2,3-dihydro-1H-indol-4-ylmethyl)-2-oxo-2,3-dihydro-benzoimidazol-1-yl]-hexanoic acid methyl ester 80 mg (0.16 mmol) is dissolved in 2.5 mL of dioxane and then lithium hydroxide (10 mg, 0.43 mmol in 1.5 mL of water) is added drop wise to the reaction mixture. The reaction is stirred at room temperature and monitored by LC/MS. Upon completion the reaction is acidified by the addition of 1N HCl, and diluted with 10 mL of water. A solid precipitated that is collected and dried to give the title compound (73 mg. 0.15 mmol 96%). LCMS (ESMS): m/z 473.1 (M+H+).