Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][P:2](=[O:7])([O:5][CH3:6])[O:3][CH3:4].C([Li])CCC.CCCCCC.[O:19]([CH2:26][C:27](OC)=[O:28])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C1COCC1.C(O)(=O)C>[O:28]=[C:27]([CH2:26][O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:1][P:2](=[O:7])([O:5][CH3:6])[O:3][CH3:4]
Reactant: COC(=O)COc1ccccc1
Reactant: COP(C)(=O)OC
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CC(=O)O
Product: COP(=O)(CC(=O)COc1ccccc1)OC
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 82608.7 %

Procedure:
Dimethyl methylphosphonate (18 ml, 0.166 mol) was addded to anhydrous THF (150 ml) under argon atmosphere and cooled to -78° C. After 20 min. a solution of n-butyl lithium in hexane (1.59N, 108.8 ml, 0.173 mmol) was added to the mixture. After being stirred for 30 min. a solution of methyl phenoxyacetate (10 ml, 0.069 mmol) in 10 ml of anhydrous THF was added, and the reaction mixture was stirred successively for 30 min. at -78° C. and for 30 min. at room temperature, and acidified with acetic acid. After confirming a weakly acidic pH of the solution thus obtained, THF was distilled out. Water (50 ml) was added to the residue, and the resulting mixture was extracted with ethyl acetate (150 ml×3). The combined organic layers were washed with 100 ml of water and with 100 ml of brine, dried over anhydrous sodium sulfate, and concentrated. The oily product was distilled under reduced pressure to afford dimethyl 2-oxo-3-phenoxypropylphosphonate (14.65 g, 0.057 mol, yield: 82.3%). B.p.: 145°-147° C./0.1 mmHg. The product was identified by the following data.
Reaction SMILES: [CH3:1][NH:2][CH3:3].Cl.[CH2:5]([O:7][CH:8]([O:10][CH:11]([CH:20]1[CH2:25][CH2:24][C:23](=O)[CH2:22][CH2:21]1)[CH2:12][O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH3:9])[CH3:6].[C-:27]#[N:28].[K+]>O.O1CCCC1.CO>[CH3:1][N:2]([CH3:3])[C:23]1([C:27]#[N:28])[CH2:24][CH2:25][CH:20]([CH:11]([O:10][CH:8]([O:7][CH2:5][CH3:6])[CH3:9])[CH2:12][O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:21][CH2:22]1
Reactant: CNC
Reactant: [C-]#N
Reactant: CCOC(C)OC(COc1ccccc1)C1CCC(=O)CC1
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CCOC(C)OC(COc1ccccc1)C1CCC(C#N)(N(C)C)CC1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
40% aqueous dimethylamine solution (1.73 ml, 13.7 mmol) was added to a mixture of 4 M hydrochloric acid (747 μl) and methanol (448 μl), while cooling with ice, and the mixture was added to 4-[1-(1-ethoxy-ethoxy)-2-phenoxyethyl]cyclohexanone (880 mg, 2.87 mmol), before potassium cyanide (448 mg, 6.88 mg) was added. Tetrahydrofuran (3 ml) was also added for solubilization. The reaction mixture was stirred at room temperature for 6 h, water (50 ml) was then added and the mixture was extracted with diethyl ether (4×30 ml). The combined organic phases were concentrated in vacuo, the residue was taken up in methylene chloride (30 ml) and the mixture was washed with water (30 ml). The organic phase was dried with sodium sulfate and concentrated in vacuo.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH:23][CH2:24][CH:25]2[CH2:30][CH2:29][N:28](C(OC(C)(C)C)=O)[CH2:27][CH2:26]2)[C:5]2[C:10]([C:11]#[N:12])=[CH:9][N:8](S(C3C=CC(C)=CC=3)(=O)=O)[C:6]=2[N:7]=1.[NH2:38][C:39]1[CH:44]=[CH:43][C:42]([N:45]2[CH2:50][CH2:49][N:48]([C:51](=[O:53])[CH3:52])[CH2:47][CH2:46]2)=[CH:41][CH:40]=1.C[Si](Cl)(C)C>C(O)CCC>[C:51]([N:48]1[CH2:47][CH2:46][N:45]([C:42]2[CH:43]=[CH:44][C:39]([NH:38][C:2]3[N:3]=[C:4]([NH:23][CH2:24][CH:25]4[CH2:26][CH2:27][NH:28][CH2:29][CH2:30]4)[C:5]4[C:10]([C:11]#[N:12])=[CH:9][NH:8][C:6]=4[N:7]=3)=[CH:40][CH:41]=2)[CH2:50][CH2:49]1)(=[O:53])[CH3:52]
Reactant: CC(=O)N1CCN(c2ccc(N)cc2)CC1
Reactant: Cc1ccc(S(=O)(=O)n2cc(C#N)c3c(NCC4CCN(C(=O)OC(C)(C)C)CC4)nc(Cl)nc32)cc1
Agent: C[Si](C)(C)Cl
Solvent: CCCCO
Product: CC(=O)N1CCN(c2ccc(Nc3nc(NCC4CCNCC4)c4c(C#N)c[nH]c4n3)cc2)CC1
Temperature: 135 °C
Reaction time: 68 h
Yield: 22.7 %

Procedure:
A mixture of tert-butyl 4-((2-chloro-5-cyano-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)methyl)piperidine-1-carboxylate (127 mg, 0.233 mmol), 1-(4-(4-aminophenyl)piperazin-1-yl)ethanone (100 mg, 0.456 mmol) and TMSCl (0.200 mL, 1.58 mmol) in nBuOH (5 mL) was stirred at 135° C. for 68 h. It was then concentrated in vacuo. The residue was purified by HPLC to give the titled compound (25 mg). MS 475 (M+H); UV 204.9, 265.1, 297.2 nm.
Reaction SMILES: [Na].[CH3:2][O:3][C:4](=[O:10])[C:5](=[CH:8]O)[C:6]#[N:7].P(Cl)(Cl)(Cl)(Cl)[Cl:12].O>ClCCl>[CH3:2][O:3][C:4](=[O:10])[C:5](=[CH:8][Cl:12])[C:6]#[N:7]
Reactant: COC(=O)C(C#N)=CO
Reactant: ClP(Cl)(Cl)(Cl)Cl
Agent: [Na]
Solvent: O
Solvent: ClCCl
Product: COC(=O)C(C#N)=CCl
Temperature: 23 °C
Reaction time: 4 h

Procedure:
To a suspension of the sodium salt of methylhydroxymethylene-cyanoacetate (19.0 g, 127 mmol) in 200 mL of dichloromethane was added phosphorous pentachloride (26.5 g, 127 mmol) in one portion. The reaction mixture was allowed to exotherm to reflux temperature and then maintained at reflux with stirring for 4 hours. The resulting light yellow suspension was allowed to cool to 23° C. and then poured into 400 mL of cold water. The mixture stirred for 15 minutes and the phases were separated. The aqueous layer was extracted with 100 mL of dichloromethane and the combined organic layers were washed twice with water, dried over magnesium sulfate, and concentrated to 16.8 g of the title compound which was of sufficient purity for use in Example 1. 1H NMR (300 MHz, CDCl3) δ 3.88 (s, 3H), 7.58 (s, 0.35H), 8.04 (s, 0.65H).
Reaction SMILES: [F:1][C:2]1[CH:39]=[CH:38][C:5]([C:6](/[N:8]=[C:9]2\[NH:10][C:11]3[CH:26]=[CH:25][C:24]([CH2:27][N:28]4[CH2:33][CH2:32][CH:31]([C:34]([OH:37])([CH3:36])[CH3:35])[CH2:30][CH2:29]4)=[CH:23][C:12]=3[N:13]\2[C@@H:14]2[CH2:19][CH2:18][C@H:17]([C:20]([OH:22])=O)[CH2:16][CH2:15]2)=[O:7])=[CH:4][CH:3]=1.CN(C(ON1N=[N:55][C:50]2C=[CH:52][CH:53]=[N:54][C:49]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.N1CCNCC1>CN(C=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:6](/[N:8]=[C:9]2\[NH:10][C:11]3[CH:26]=[CH:25][C:24]([CH2:27][N:28]4[CH2:29][CH2:30][CH:31]([C:34]([OH:37])([CH3:35])[CH3:36])[CH2:32][CH2:33]4)=[CH:23][C:12]=3[N:13]\2[C@H:14]2[CH2:19][CH2:18][C@@H:17]([C:20]([N:54]3[CH2:49][CH2:50][NH:55][CH2:52][CH2:53]3)=[O:22])[CH2:16][CH2:15]2)=[O:7])=[CH:38][CH:39]=1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: CC(C)(O)C1CCN(Cc2ccc3[nH]/c(=N\C(=O)c4ccc(F)cc4)n([C@H]4CC[C@@H](C(=O)O)CC4)c3c2)CC1
Agent: C1CNCCN1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(O)C1CCN(Cc2ccc3[nH]/c(=N\C(=O)c4ccc(F)cc4)n([C@H]4CC[C@@H](C(=O)N5CCNCC5)CC4)c3c2)CC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a suspension of cis-4-((E)-2-(4-fluorobenzoylimino)-6-((4-(2-hydroxypropan-2-yl)piperidin-1-yl)methyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)cyclohexanecarboxylic acid (100 mg, 0.186 mmol) in DMF (3 mL) was added HATU (74.4 mg, 0.196 mmol) and DIPEA (0.036 mL, 0.205 mmol). The suspension was stirred for 15 minutes at RT. A solution of piperazine (161 mg, 1.863 mmol) in DMF (1 mL) was added, and the reaction was stirred at RT overnight. The reaction mixture was partitioned between water and EtOAc. The organic layer was concentrated and the residue purified by HPLC (15-90% ACN/0.1% TFA). The product fractions were combined, neutralized with saturated aqueous NaHCO3, and extracted with EtOAc (×2). The combined organic layers were washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated to provide (E)-4-fluoro-N-(6-((4-(2-hydroxypropan-2-yl)piperidin-1-yl)methyl)-1-(cis-4-(piperazine-1-carbonyl)cyclohexyl)-1H-benzo[d]imidazol-2(3H)-ylidene)benzamide as a white powder (67 mg, 59.5% yield). MS, m/z (C34H45FN6O3): calcd, 604.3. found, 605.1 [M+H].
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[F:7][C:8]1[CH:9]=[C:10]([CH:14]=[CH:15][C:16]=1[F:17])[C:11]([OH:13])=O.Cl.[NH:19]1[CH2:22][CH2:21][CH2:20]1.C(N(CC)CC)C>C(Cl)Cl.CN(C=O)C>[F:7][C:8]1[CH:9]=[C:10]([CH:14]=[CH:15][C:16]=1[F:17])[C:11]([N:19]1[CH2:22][CH2:21][CH2:20]1)=[O:13]
Reactant: O=C(O)c1ccc(F)c(F)c1
Reactant: C1CNC1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(c1ccc(F)c(F)c1)N1CCC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 50.7 %

Procedure:
Oxalyl chloride (1.05 mL, 12.0 mmol) was added to a solution of 3,4-difluorobenzoic acid (1.58 g, 10 mmol) in DCM (50 mL) containing DMF (1 drop). The reaction was stirred at ambient temperature for 16 h then evaporated to dryness. The residue was redissolved in DCM (25 mL) and azetidine hydrochloride (1.12 g, 12.0 mmol) added followed by triethylamine (4.18 mL, 30.0 mmol). The mixture was stirred at ambient temperature for 2 h then concentrated in vacuo. The residue was partitioned between ethyl acetate and 1N hydrochloric acid, the organic phase washed with a saturated aqueous solution of sodium bicarbonate followed by brine, dried (MgSO4), and concentrated in vacuo. The title compound was crystallized from an ethyl acetate/hexane mixture to give a white crystalline solid (1.0 g).
Reaction SMILES: CCCC(O[CH2:7][C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:9])C.[CH:16]([C:18]1[CH:27]=[CH:26][C:21]([C:22]([O:24][CH3:25])=[O:23])=[CH:20][CH:19]=1)=O.C(N([CH2:33][CH3:34])CC)C>ClCCl.CCCCCC.[Ti](Cl)(Cl)(Cl)Cl>[CH3:25][O:24][C:22]([C:21]1[CH:26]=[CH:27][C:18]([CH:16]=[CH:7][C:8]([C:10]2[CH:11]=[CH:12][C:13]([O:9][CH2:8][CH2:10][CH2:11][CH2:33][CH3:34])=[CH:14][CH:15]=2)=[O:9])=[CH:19][CH:20]=1)=[O:23]
Reactant: CCN(CC)CC
Reactant: CCCC(C)OCC(=O)c1ccccc1
Reactant: COC(=O)c1ccc(C=O)cc1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: CCCCCC
Solvent: ClCCl
Product: CCCCCOc1ccc(C(=O)C=Cc2ccc(C(=O)OC)cc2)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of titanium(IV) chloride (11.6 g) in dichloromethane (100 ml) was added 4-n-Pentyloxyacetophenone (10.3 g) and Methyl 4-formylbenzoate (8.21 g) in dichloromethane (50 ml) dropwise at 0° C. To the mixture was added triethylamine (11.15 ml) in dichloromethane (30 ml). The mixture was stirred at 0° C. for 30 minutes and diluted with n-hexane. The organic layer was washed with water (four times), brine and dried over magnesium sulfate. The solvents were removed under reduced pressure and the residue was triturated with iso-propyl ether. The solid was collected by filtration and dried to give 1-(4-Methoxycarbonylphenyl)-3-(4-n-pentyloxyphenyl)-1-propen-3-one (4.02 g).
Reaction SMILES: C([Li])CCC.[CH2:6]([C:8]1[CH:9]=[C:10](Br)[CH:11]=[CH:12][CH:13]=1)[CH3:7].C[O:16][B:17](OC)[O:18]C.Cl>CCCCCC.O1CCCC1>[CH2:6]([C:8]1[CH:9]=[C:10]([B:17]([OH:18])[OH:16])[CH:11]=[CH:12][CH:13]=1)[CH3:7]
Reactant: CCc1cccc(Br)c1
Reactant: COB(OC)OC
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCc1cccc(B(O)O)c1
Temperature: -70 °C
Reaction time: 1 h
Yield: 24 %

Procedure:
n-Butyllithium (11 ml of a 2.5M solution in hexane, 28 mmol) was added to a stirred solution of 3ethylbromobenzene (Chem. Pharm. Bull., 1968, 16, 2456; 4.6 g, 25 mmol) in anhydrous tetrahydrofuran (50 ml), whilst keeping the internal temperature below −60° C. The mixture was stirred at about −70° C. for 1 hour, then trimethylborate (4.4 ml, 38 mmol) added dropwise, again whilst keeping the internal temperature below −60° C. The reaction mixture was stirred at −70° C. for 30 minutes, then slowly allowed to warm to room temperature. 2M Hydrochloric acid was added, the mixture was extracted with dichloromethane (3×50 ml) and the combined extracts concentrated under reduced pressure The residue was dissolved in ether (50 ml), the solution extracted with 1M aqueous sodium hydroxide solution (2×30 ml) and the aqueous phase acidified with 2M hydrochloric acid, then extracted with ether (3×50 ml). The combined extracts were dried (MgSO4) and evaporated under reduced pressure to give the title compound as a white solid (0.9 g, 24%). δ(DMSOd6): 1.17 (t,3H), 2.57 (q,2H), 7.22 (t,2H), 7.57 (t,1H), 7.61 (s,1H), 7.93 (s,2H).
Reaction SMILES: [CH3:1][C@H:2](C(O)=O)[C:3]1[CH:4]=[CH:5][C:6]2[CH:7]=[C:8]([O:13][CH3:14])[CH:9]=[CH:10][C:11]=2[CH:12]=1.C([N:20](CC)CC)C.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.[ClH:42].C(=O)=O>C1C=CC=CC=1.O>[ClH:42].[CH3:14][O:13][C:8]1[CH:7]=[C:6]2[C:11](=[CH:10][CH:9]=1)[CH:12]=[C:3]([CH:2]([NH2:20])[CH3:1])[CH:4]=[CH:5]2
Reactant: CCN(CC)CC
Reactant: COc1ccc2cc([C@H](C)C(=O)O)ccc2c1
Agent: Cl
Agent: O=C=O
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: c1ccccc1
Solvent: O
Product: COc1ccc2cc(C(C)N)ccc2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 26.4 %

Procedure:
A further representative compound of the present invention was prepared according to Scheme 1 in the following manner. To a solution of naproxen (10.0 g, 0.04 mole) in 50 mL benzene at room temperature were added triethylamine (6.1 mL, 0.04 mole) and diphenylphosphoryl azide (9.4 mL, 0.04 mole). The solution was heated to reflux and stirred for two hours before slowly adding concentrated HCl solution (12 M; 7.2 mL, 0.08 mole) via pipet. Evolution of CO2 gas was noted. The mixture was stirred at reflux for thirty minutes, then cooled to room temperature and concentrated in vacuo. Ether was added and the solution was concentrated again. A white solid precipitate was filtered and washed with ether to give 15.4 g of crude salt. Approximately 5.0 g of the salt was then placed in water and an insoluble gum was filtered off. The aqueous layer was basified with 2N NaOH solution and extracted with ethyl acetate (3×50 mL). The organic extract was washed with brine and dried (MgSO4), filtered and concentrated in vacuo to give 2.51 g of the 1-(6-methoxynaphthalen-2-yl)ethyl amine hydrochloride salt 2.1 as a white solid.
Reaction SMILES: [OH:1][CH:2]([C:7]1[CH:8]=[C:9]([CH3:13])[CH:10]=[CH:11][CH:12]=1)[CH2:3][CH2:4][CH2:5][CH3:6].[C:14](OC(=O)C)(=[O:16])[CH3:15].N1C=CC=CC=1.CN(C1C=CC=CN=1)C>C(Cl)Cl>[C:14]([O:1][CH:2]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH3:13])[CH:8]=1)[CH2:3][CH2:4][CH2:5][CH3:6])(=[O:16])[CH3:15]
Reactant: CC(=O)OC(C)=O
Reactant: CCCCC(O)c1cccc(C)c1
Agent: CN(C)c1ccccn1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCCC(OC(C)=O)c1cccc(C)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
65.4 g of 3-(1-hydroxypentyl)toluene are dissolved in 500 ml of absolute methylene chloride at 0° C., and 104 ml of acetic anhydride, 89 ml of pyridine and 1 g of dimethylaminopyridine are added in succession. The reaction solution is stirred at 0° C. for 1 hour and at 25° C. for 2 hours and then poured onto 1 l of ice-water. After the organic phase has been separated off, it is extracted 3 times with 200 ml of methylene chloride each time. The organic phases are washed 3 times with 200 ml of 2N HCl each time, 3 times with 200 ml of saturated NaHCO3 each time and twice with 200 ml of water each time, dried over magnesium sulphate and concentrated in vacuo. The residue is distilled at 95° C./0.1 mm (bulb tube).
Reaction SMILES: [C:1]1([CH2:7][CH:8]([OH:12])[C:9]([OH:11])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:13](Cl)(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(N(CC)CC)C>CN(C)C1C=CN=CC=1.C(Cl)Cl>[C:13]([O:12][CH:8]([CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[C:9]([OH:11])=[O:10])(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: O=C(O)C(O)Cc1ccccc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(OC(Cc1ccccc1)C(=O)O)c1ccccc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 24.2 %

Procedure:
A 50 mL three-necked flask was charged with 3-phenyllactic acid (1.0 g, 6.0 mmol) and dry CH2Cl2 (12 mL). To this white slurry was added benzoyl chloride (1.04 mL, 9.0 mmol) and the mixture was cooled to 0° C. Triethylamine (0.8 mL, 6.0 mmol) was added and a light yellow solution resulted. 4-Dimethylaminopyridine (367 mg, 3.0 mmol) was added and the reaction mixture was warmed to 25° C. and stirred for 3 hours. The reaction mixture was concentrated on a rotary evaporator and ether, ethyl acetate, and water were added. The mixture was extracted with ether (3×) and ethyl acetate, dried over MgSO4, filtered and evaporated. Purification by silica gel chromatography (4:1 hexanes/ethyl acetate increased to 1:1 hexanes/ethyl acetate) yielded 392 mg (24%) of 11 as a white solid. Rf 0.15 (1:1 hexanes/ethyl acetate); mp 113° C.; IR (CDCl3) 3564-2560 (broad acid), 3028, 2924, 1720 (broad), 1452, 1268, 716 cm-1 ; 1H NMR (300 MHz, CDCl3) δ 11.25 (s, 1H), 8.08 (d, J=7.2 Hz, 2H) 7.45 (m, 8H), 5.56 (m, 1H), 3.38 (m, 2H); 13C NMR (75 MHz, CDCl3) 8 175.5, 165.9, 149.9, 135.6, 133.4, 130.1, 129.7, 129.3, 128.9, 128.5, 128.4, 127.1, 72.9, 37.2; HRMS (FAB): Calcd for (M+Li) C16H14O4Li, 277.1052; Found, 277.1065; EA Calcd for C16H14O4 : C, 71.10; H, 5.22; Found: C, 71.04; H, 5.24.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]([C:25]2[CH:30]=[CH:29][C:28]([O:31][CH:32]([CH3:34])[CH3:33])=[CH:27][CH:26]=2)[C:8]2[C:13]([C:14]=1[Cl:15])=[CH:12][C:11](B1OC(C)(C)C(C)(C)O1)=[CH:10][CH:9]=2)=[O:5])[CH3:2].Br[C:36]1[CH:41]=[CH:40][C:39]([C:42]([F:45])([F:44])[F:43])=[CH:38][N:37]=1>>[CH2:1]([O:3][C:4]([C:6]1[N:7]([C:25]2[CH:26]=[CH:27][C:28]([O:31][CH:32]([CH3:34])[CH3:33])=[CH:29][CH:30]=2)[C:8]2[C:13]([C:14]=1[Cl:15])=[CH:12][C:11]([C:36]1[CH:41]=[CH:40][C:39]([C:42]([F:45])([F:44])[F:43])=[CH:38][N:37]=1)=[CH:10][CH:9]=2)=[O:5])[CH3:2]
Reactant: FC(F)(F)c1ccc(Br)nc1
Reactant: CCOC(=O)c1c(Cl)c2cc(B3OC(C)(C)C(C)(C)O3)ccc2n1-c1ccc(OC(C)C)cc1
Product: CCOC(=O)c1c(Cl)c2cc(-c3ccc(C(F)(F)F)cn3)ccc2n1-c1ccc(OC(C)C)cc1

Procedure:
The sub-title compound was prepared in accordance with Example 8(b), from 3-chloro-1-(4-isopropoxyphenyl)-5-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)-1H-indole-2-carboxylic acid ethyl ester (see step (c)) and 2-bromo-5-(trifluoromethyl)pyridine.
Reaction SMILES: [CH2:1]([C@@H:3]([N:7]1[CH2:11][CH2:10][CH2:9][C:8]1=[O:12])[C:4](O)=[O:5])[CH3:2].C([N:15](CC)CC)C.CS(Cl)(=O)=O>C(Cl)Cl>[CH2:1]([C@@H:3]([N:7]1[CH2:11][CH2:10][CH2:9][C:8]1=[O:12])[C:4]([NH2:15])=[O:5])[CH3:2]
Reactant: CC[C@H](C(=O)O)N1CCCC1=O
Reactant: CCN(CC)CC
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Product: CC[C@H](C(N)=O)N1CCCC1=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 80.8 %

Procedure:
A suspension of (R)-alpha-ethyl-2-oxo-1-pyrrolidineacetic acid (35 g, 0.20 mol) in methylene chloride (225 ml) was cooled to 0° C. and triethylamine (41 g, 0.40 mol) and methanesulfonyl chloride (29 g, 0.26 mol) were added dropwise. The mixture was stirred at 0° C. for 30 min., then a stream of ammonia was purged in the solution at 0° C. for 2 hours. The insoluble solids were filtered and the filtrate was concentrated. The product was recrystallized from methyl isobutyl ketone to give 27.5 g (78%) of (R)-alpha-ethyl-2-oxo-1-pyrrolidineacetamide.
Reaction SMILES: [Br:1][C:2]1[C:3]([N:17]2[CH2:21][CH2:20][C@@H:19]([NH:22]C(=O)OC(C)(C)C)[CH2:18]2)=[C:4]2[C:10]([NH:11][C:12](=[O:16])[C@@H:13]([OH:15])[CH3:14])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.C(O)(C(F)(F)F)=O.C(Cl)[Cl:38]>>[ClH:38].[NH2:22][C@@H:19]1[CH2:20][CH2:21][N:17]([C:3]2[C:2]([Br:1])=[CH:7][N:6]=[C:5]3[NH:8][CH:9]=[C:10]([NH:11][C:12](=[O:16])[C@@H:13]([OH:15])[CH3:14])[C:4]=23)[CH2:18]1
Reactant: ClCCl
Reactant: C[C@H](O)C(=O)Nc1c[nH]c2ncc(Br)c(N3CC[C@@H](NC(=O)OC(C)(C)C)C3)c12
Solvent: O=C(O)C(F)(F)F
Product: C[C@H](O)C(=O)Nc1c[nH]c2ncc(Br)c(N3CC[C@@H](N)C3)c12
Product: Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 58 %

Procedure:
tert-Butyl (R)-1-(5-bromo-3-((S)-2-hydroxypropanamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)pyrrolidin-3-ylcarbamate (0.040 g, 0.085 mmol) was placed in DCM (3 mL) at room temperature. TFA (1 mL) was then added, and the reaction was stirred at room temperature for 1 hour and concentrated to dryness. The resulting residue was then purified by reverse phase chromatography (Biotage SP4, C-18 25M+, 0-50% CH3CN/water). The resulting product was next dissolved in minimal DCM (with MeOH to aid solubility) and added to a stirring solution of 1M HCl in ether. The resulting solid was filtered, washed with ether and dried to give (S)—N-(4-((R)-3-aminopyrrolidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-hydroxypropanamide hydrochloride (0.022 g, 58% yield). 1H NMR (400 MHz, D2O) δ 8.16 (s, 1H), 7.50 (s, 1H), 4.32-4.30 (q, 1H), 4.03-4.00 (m, 1H), 3.89-3.84 (m, 1H), 3.66-3.63 (m, 1H), 3.59-3.55 (m, 1H), 3.48-3.46 (m, 1H), 2.42-2.39 (m, 1H), 2.07-2.04 (m, 1H), 1.34-1.32 (d, 3H); LCMS (APCI+) m/z 368, 370 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:7]2[C:8]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]4[N:21]([CH3:29])[C:22]5[C:27]([CH:28]=4)=[CH:26][CH:25]=[CH:24][CH:23]=5)=[O:19])=[C:13]([O:30][CH3:31])[CH:12]=3)=[CH:9][S:10][C:6]=2[C:5]([C:32]([NH:34][CH2:35][CH:36]2[CH2:40][CH2:39][CH2:38][NH:37]2)=[O:33])=[CH:4][N:3]=1.Br[CH2:42][C:43]([NH2:45])=[O:44].[C:46](=[O:49])([O-])[O-:47].[K+].[K+]>CN(C)C=O>[C:32]([OH:33])(=[O:44])[CH3:5].[C:46]([OH:47])(=[O:49])[CH3:2].[C:43]([OH:44])(=[O:19])[CH3:42].[NH2:1][C:2]1[C:7]2[C:8]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]4[N:21]([CH3:29])[C:22]5[C:27]([CH:28]=4)=[CH:26][CH:25]=[CH:24][CH:23]=5)=[O:19])=[C:13]([O:30][CH3:31])[CH:12]=3)=[CH:9][S:10][C:6]=2[C:5]([C:32]([NH:34][CH2:35][CH:36]2[CH2:40][CH2:39][CH2:38][N:37]2[CH2:42][C:43]([NH2:45])=[O:44])=[O:33])=[CH:4][N:3]=1
Reactant: COc1cc(-c2csc3c(C(=O)NCC4CCCN4)cnc(N)c23)ccc1NC(=O)c1cc2ccccc2n1C
Reactant: NC(=O)CBr
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)O
Product: COc1cc(-c2csc3c(C(=O)NCC4CCCN4CC(N)=O)cnc(N)c23)ccc1NC(=O)c1cc2ccccc2n1C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 4-amino-3-(3-methoxy-4-{[(1-methyl-1H-indol-2-yl)carbonyl]amino}phenyl)-N-(pyrrolidin-2-ylmethyl)thieno[3,2-c]pyridine-7-carboxamide (0.100 g, 0.18 mmol), 2-bromoacetamide (0.03 g, 0.217 mmol) and potassium carbonate (0.05 g, 0.36 mmol) in N,N-dimethylformamide (2 mL) was stirred at ambient temperature for 18 hours. The solvent was removed in vacuo and the residue was purified by preparative RP-HPLC (Hypersil-HS C18, 8 μm, 100 Å, 25 cm; 5-100% acetonitrile-0.1M ammonium acetate over 25 min, 21 mL/min). The acetonitrile was removed in vacuo and the aqueous mixture was lyophilized to give the title compound as a white solid: 1H NMR (DMSO-d6, 400 MHz) δ 9.50 (s, 1H), 8.56 (s, 1H), 8.44 (t, 1H), 7.98 (d, 1H), 7.69 (d, 1H), 7.58 (d, 1H), 7.58 (s, 1H), 7.35 (m, 3H), 7.15 (m, 3H), 7.06 (d, 1H), 6.0 (bs, 2H), 4.04 (s, 3H), 3.91 (s, 3H), 3.42 (m, 1H), 3.38 (d, 1H), 3.24 (m, 1H), 3.04 (m, 1H), 2.86 (d, 1H), 2.79 (m, 1H), 2.27 (m, 1H), 1.86 (s, 9H), 1.85 (m, 1H), 1.68 (m, 3H); LCMS (Conditions a), Rt 2.88 min.; MS: MH+ 612.
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:13]=[C:12]([CH:14]3[O:19][CH2:18][CH2:17][NH:16][CH2:15]3)[O:11][N:10]=2)=[CH:5][CH:4]=1.C(N(CC)CC)C.[F:27][C:28]1[CH:36]=[CH:35][C:31]([C:32](Cl)=[O:33])=[CH:30][CH:29]=1.Cl>ClCCl>[F:27][C:28]1[CH:36]=[CH:35][C:31]([C:32]([N:16]2[CH2:17][CH2:18][O:19][CH:14]([C:12]3[O:11][N:10]=[C:9]([C:6]4[CH:7]=[CH:8][C:3]([F:2])=[CH:4][CH:5]=4)[N:13]=3)[CH2:15]2)=[O:33])=[CH:30][CH:29]=1
Reactant: Fc1ccc(-c2noc(C3CNCCO3)n2)cc1
Reactant: O=C(Cl)c1ccc(F)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(c1ccc(F)cc1)N1CCOC(c2nc(-c3ccc(F)cc3)no2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 61 %

Procedure:
To a suspension of 2-[3-(4-fluoro-phenyl)-[1,2,4]oxadiazol-5-yl]-morpholine hydrochloride (0.15 g, 0.53 mmol) in anhydrous dichloromethane (6 mL), under nitrogen atmosphere, triethylamine (155 mL, 1.1 mmol) and 4-fluorobenzoyl chloride (62 mL, 0.53 mmol) were subsequently added at 0° C. The reaction mixture was allowed to warm at room temperature and stirred overnight. HCl 1N (6 mL) was added and the phases were separated. The organic layer was washed sequentially with HCl 1N (6 mL), NaOH 1N (6 mL×2 times) and with water, then was dried over sodium sulphate and evaporated under reduced pressure. The crude was purified by flash chromatography (silica gel, eluent: hexane/ethyl acetate 7/3) to afford 120 mg of (4-fluoro-phenyl)-{2-[3-(4-fluoro-phenyl)-[1,2,4]oxadiazol-5-yl]-morpholin-4-yl}-methanone as a white solid.