Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:7]([CH:8]([OH:28])[C:9]2[C:17]3[C:12](=[N:13][CH:14]=[CH:15][CH:16]=3)[N:11]([Si](C(C)C)(C(C)C)C(C)C)[CH:10]=2)=[C:6]([F:29])[CH:5]=[CH:4][C:3]=1[NH:30][S:31]([C:34]1[CH:39]=[CH:38][CH:37]=[C:36]([O:40][CH3:41])[CH:35]=1)(=[O:33])=[O:32].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O>O1CCCC1>[F:1][C:2]1[C:7]([CH:8]([OH:28])[C:9]2[C:17]3[C:12](=[N:13][CH:14]=[CH:15][CH:16]=3)[NH:11][CH:10]=2)=[C:6]([F:29])[CH:5]=[CH:4][C:3]=1[NH:30][S:31]([C:34]1[CH:39]=[CH:38][CH:37]=[C:36]([O:40][CH3:41])[CH:35]=1)(=[O:33])=[O:32]
Reactant: COc1cccc(S(=O)(=O)Nc2ccc(F)c(C(O)c3cn([Si](C(C)C)(C(C)C)C(C)C)c4ncccc34)c2F)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: COc1cccc(S(=O)(=O)Nc2ccc(F)c(C(O)c3c[nH]c4ncccc34)c2F)c1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To N-{2,4-difluoro-3-[hydroxy-(1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methyl]-phenyl}-3-methoxy-benzenesulfonamide (92, 0.075 g, 0.12 mmol) in tetrahydrofuran (3.0 mL), was added tetra-n-butylammonium fluoride (0.039 g, 0.15 mmol). The reaction was stirred at room temperature for 20 minutes. The reaction was poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 3% methanol in dichloromethane to give light yellow solid (93, 0.030 g, 55%). MS (ESI) [M+H+]+=446.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13](=[O:14])[NH:12][C:11](=[O:15])[O:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].[CH2:16]=[O:17].O>CO.C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13](=[O:14])[N:12]([CH2:16][OH:17])[C:11](=[O:15])[O:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=c1[nH]c(=O)n(-c2ccc(Cl)c(Cl)c2)o1
Reactant: C=O
Solvent: ClCCl
Solvent: CO
Solvent: O
Product: O=c1on(-c2ccc(Cl)c(Cl)c2)c(=O)n1CO
Reaction time: 2 h

Procedure:
2-(3,4-Dichlorophenyl)-1,2,4-oxadiazolidin-3,5-dione (0.05 mole) dissolved in methanol (100 ml) and aqueous formaldehyde (37% conc.; 0.06 mole) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. The reaction mixture is heated at reflux, with stirring for a period of about 2 hours. After this time the reaction mixture is stripped of methanol and water, leaving a residue. This residue is dissolved in methylene chloride, and the resulting solution is washed with water. The washed solution is dried over anhydrous magnesium sulfate, filtered and stripped of solvent to yield the desired product 2-(3,4-dichlorophenyl)-4-hydroxymethyl-1,2,4-oxadiazolidin-3,5-dione.
Reaction SMILES: [C:1]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][N+:9]1[C:17]2[C:12](=[C:13]([F:19])[CH:14]=[C:15]([F:18])[CH:16]=2)[C:11]([CH3:21])([CH3:20])[C:10]=1[CH3:22])([OH:3])=[O:2].Cl.[C:24]1([N:30]=[CH:31][CH2:32][CH:33]=NC2C=CC=CC=2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(OC(=O)C)(=O)C>C(O)(=O)C>[F:19][C:13]1[CH:14]=[C:15]([F:18])[CH:16]=[C:17]2[C:12]=1[C:11]([CH3:21])([CH3:20])/[C:10](=[CH:22]\[CH:33]=[CH:32]\[CH:31]=[N:30]\[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)/[N:9]2[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][C:1]([OH:3])=[O:2]
Reactant: CC1=[N+](CCCCCC(=O)O)c2cc(F)cc(F)c2C1(C)C
Reactant: C(CC=Nc1ccccc1)=Nc1ccccc1
Agent: Cl
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: CC1(C)/C(=C\C=C\C=N\c2ccccc2)N(CCCCCC(=O)O)c2cc(F)cc(F)c21
Temperature: 120 °C

Procedure:
To 1-(5-carboxypentyl)-4,6-difluoro-2,3,3-trimethyl-3H-indolium (50 mg) was added malonaldehyde bis(phenylimine) monohydrochloride (37.6 mg), acetic anhydride (2 ml) and acetic acid (1 ml). This mixture was heated to 120° C. for 1 hour after which time it was cooled to room temperature. This crude reaction mixture (ca. 32 mg/ml product) was used without purification as further described.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:8]=[C:9]([CH:13]=[CH:14][CH:15]=2)[C:10]([OH:12])=O)[CH:2]=1.[N:16]1([CH2:22][CH2:23][O:24][C:25]2[C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[C:28]([NH2:35])=[CH:27][CH:26]=2)[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1>>[N:16]1([CH2:22][CH2:23][O:24][C:25]2[C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[C:28]([NH:35][C:10](=[O:12])[C:9]3[CH:13]=[CH:14][CH:15]=[C:7]([C:3]4[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=4)[CH:8]=3)=[CH:27][CH:26]=2)[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1
Reactant: O=C(O)c1cccc(-c2cccnc2)c1
Reactant: Nc1ccc(OCCN2CCOCC2)c2ccccc12
Product: O=C(Nc1ccc(OCCN2CCOCC2)c2ccccc12)c1cccc(-c2cccnc2)c1

Procedure:
Compound is prepared from 3-pyridin-3-yl-benzoic acid and 4-(2-morpholin-4-yl-ethoxy)-naphthalen-1-ylamine according to conditions described in general procedure G. (0.218 g) (63%). Mp: 77-78° C. 1H NMR (300 MHz, DMSOd6) 10.42 (s, 1H), 9.06 (s, 1H), 8.63 (d, J=3.9 Hz, 1H), 8.48 (s, 1H), 8.22 (d, J=8.1 Hz, 2H), 8.10 (d, J=7.5 Hz, 1H), 7.98 (m, 2H), 7.69 (t, J=7.5 Hz, 1H), 7.56-7.47 (m, 4H), 7.04 (d, J=8.4 Hz, 1H), 4.33 (brt, 2H), 3.60 (brs, 4H), 2.88 (brs, 2H), 2.57 (brs, 4H). MS: 454 (M+1).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[N+:6]([O-])[C:5]([C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:14])=O>>[Cl:14][C:7]1[N:6]=[C:5]([C:9]([OH:11])=[O:10])[CH:4]=[CH:3][C:2]=1[CH3:1]
Reactant: Cc1ccc(C(=O)O)[n+]([O-])c1
Reactant: O=P(Cl)(Cl)Cl
Product: Cc1ccc(C(=O)O)nc1Cl
Temperature: 105 °C
Reaction time: 3 h
Yield: 84.3 %

Procedure:
5-Methyl-2-pyridinecarboxylic acid 1-oxide (0.9 g, 5.88 mmol) was added to phosphoryl trichloride (30 mL). The mixture was stirred at 105° C. for 3 h. After that the mixture was cooled to room temperature, added to ice water slowly and extracted with methylene chloride (4×30 mL). The organic layer was washed with brine (50 mL), dried over anhydrous sodium sulfate, and concentrated to give the crude product (0.85 g, 84.3%); MS (EI): m/e=172.0 [M+H]+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:13]=[CH:12][C:10]([NH2:11])=[CH:9][CH:8]=2)=[CH:3][CH:2]=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.ON1C2N=CC=CC=2N=N1.[N+:48]([C:51]1[CH:61]=[CH:60][CH:59]=[CH:58][C:52]=1[O:53][CH2:54][C:55](O)=[O:56])([O-])=O.C(N(CC)C(C)C)(C)C>CN(C)C=O.O>[NH2:48][C:51]1[CH:61]=[CH:60][CH:59]=[CH:58][C:52]=1[O:53][CH2:54][C:55]([NH:11][C:10]1[CH:12]=[CH:13][C:7]([C:4]2[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=2)=[CH:8][CH:9]=1)=[O:56]
Reactant: Nc1ccc(-c2ccncc2)cc1
Reactant: O=C(O)COc1ccccc1[N+](=O)[O-]
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2cccnc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: Nc1ccccc1OCC(=O)Nc1ccc(-c2ccncc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 4 %

Procedure:
To a solution of 4-(4-pyridinyl)aniline (400 mg), O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (1.34 g), 1-hydroxy-7-azabenzotriazole (480 mg) and (2-nitrophenoxy)acetic acid (695 mg) in N,N-dimethylformamide (10 ml) was added N,N-diisopropylethylamine (1.3 ml), which was stirred overnight at ambient temperature. The reaction mixture was poured into water (30 ml) and stirred for 30 minutes. Insoluble material was collected, washed with water, dried and purified by column chromatography on silica gel (gradient, CHCl3, 10% MeOH in CHCl3). The aliquots of obtained product (100 mg) and 10% palladium on carbon (50% wet, 30 mg) in N,N-dimethylformamide (10 ml) was stirred at ambient temperature for 3 hours under an atmospheric pressure of hydrogen. The catalyst was removed and evaporated under reduced pressure. The resultant was purified by column chromatography on silica gel (gradient, CHCl3, 10% MeOH in CHCl3), which was recrystallized from EtOH to give 2-(2-aminophenoxy)-N-[4-(4-pyridinyl)phenyl]acetamide (30 mg) as an off-white powder.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N:8]2[CH:12]=[C:11]([CH3:13])[N:10]=[C:9]2S)[CH:5]=[CH:6][CH:7]=1.OO>C(O)(=O)C.O>[Br:1][C:2]1[CH:3]=[C:4]([N:8]2[CH:12]=[C:11]([CH3:13])[N:10]=[CH:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cn(-c2cccc(Br)c2)c(S)n1
Agent: OO
Solvent: O
Solvent: CC(=O)O
Product: Cc1cn(-c2cccc(Br)c2)cn1
Temperature: 23 °C
Reaction time: 0.5 h
Yield: 72.9 %

Procedure:
Step 1) A mixture of commercially available 3-bromophenylisothiocyanate (10.06 g, 47.0 mmol) and 2-aminopropionaldehyde dimethylacetal (5.96 mL, 47.0 mmol) in EtOH (50 mL) was refluxed for 1 h. Evaporated to dryness to give 1-(3-bromo-phenyl)-3-(2,2-dimethoxy-1-methyl-ethyl)-thiourea as an off-white solid (15.69 g, 100%). Step 2) A mixture of the above prepared 1-(3-bromo-phenyl)-3-(2,2-dimethoxy-1-methyl-ethyl)-thiourea (15.69 g, 47 mmol) in H2O (85 mL) and 37% HCl (8.5 mL) was refluxed for 4.5 h. Removed from oil bath, added ice and ice water (total volume: 250 mL), the precipitate was filtered off, washed several times with ice water and dried in vacuum at 60° C. to give the 1-(3-bromo-phenyl)-4-methyl-1H-imidazole-2-thiol as a light orange solid (8.71 g, 69%). Step 3) To a suspension of the above prepared 1-(3-bromo-phenyl)-4-methyl-1H-imidazole-2-thiol (6.00 g, 22 mmol) in acetic acid (20 mL) and water (5 mL) was added dropwise 35% H2O2 (13.4 mL, 156 mmol) within 15 min keeping the internal temperature below 60° C. Stirred at 23° C. for 30 min, poured onto ice, destroyed excess H2O2 by addition of sat. Na2SO3-sol., adjusted pH with 32% NaOH-sol. until pH 9 is reached, extracted with EtOAc (3×100 mL), the combined organic layers were washed with brine and dried over Na2SO4. Removal of the solvent in vacuum left a red oil, which was purified by silica gel column chromatography with EtOAc to give the 1-(3-bromo-phenyl)-4-methyl-1H-imidazole as a brown oil (3.80 g, 72%). Step 4) A mixture of the above prepared 1-(3-bromo-phenyl)-4-methyl-1H-imidazole (0.313 g, 1.31 mmol), bis(pinacolato)diboron (0.364 g, 1.438 mmol), potassium acetate (0.389 g, 3.96 mmol) and PdCl2(PPh3)2 (0.023 g, 3 mol %) in DMF at 100° C. for 2 h; then addition of Pd(OAc)2 (0.007 g, 3 mol %) and dppf (0.018 g, 3 mol %) and stirred at 100° C. overnight. This solution obtained was used directly.] according to the general procedure VI. Obtained as an off-white solid (0.140 g, 32%). MS (ISP) 394.0 [(M+H)+]; mp 126-132° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=O.[CH3:10][O:11][C:12]([CH:14]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:13]>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[CH:14][C:12]([O:11][CH3:10])=[O:13]
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1cccc(Br)c1
Solvent: Cc1ccccc1
Product: COC(=O)C=Cc1cccc(Br)c1
Yield: 82.1 %

Procedure:
To a mixture of 3-bromobenzaldehyde (10 g) and methoxy-carbonylmethylenetriphenylphosphine (20 g) was added toluene (150 ml), and the mixture was refluxed under nitrogen atmosphere for 2 hours. The solvent was evaporated, and the organic layer was washed with water and saturated sodium chloride solution, and dried with anhydrous magnesium sulfate. Under reduced pressure, the solvent was evaporated, and the residue was purified with silica gel column (ethyl acetate/hexane) to give methyl 3-bromocinnamate (10.7 g) as colorless crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][CH:15]=1)[O:5][C:6]1[S:10][C:9]([CH2:11][NH2:12])=[CH:8][CH:7]=1.[N:16]1[CH:17]=[CH:18][N:19]2[CH:24]=[C:23]([C:25](O)=[O:26])[CH:22]=[CH:21][C:20]=12.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C>CN(C)C=O.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][CH:15]=1)[O:5][C:6]1[S:10][C:9]([CH2:11][NH:12][C:25]([C:23]2[CH:22]=[CH:21][C:20]3[N:19]([CH:18]=[CH:17][N:16]=3)[CH:24]=2)=[O:26])=[CH:8][CH:7]=1
Reactant: O=C(O)c1ccc2nccn2c1
Reactant: NCc1ccc(Oc2cccc(Cl)c2)s1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(NCc1ccc(Oc2cccc(Cl)c2)s1)c1ccc2nccn2c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 89 %

Procedure:
To a solution of C-(5-(3-chloro-phenoxy)-thiophen-2-yl)-methylamine described in Preparation Example 167 (104 mg, 0.434 mmol) and imidazo[1,2-a]pyridine-6-carboxylic acid (77 mg, 0.477 mmol) in N,N-dimethylformamide (3 mL) were added benzotriazol-1-yloxy tris(dimethylamino)phosphonium hexafluorophosphate (250 mg, 0.564 mmol) and triethylamine (181 μL) at room temperature, and the solution was stirred at room temperature for 4 hours. Water was added to the reaction solution, which was then extracted with ethyl acetate, and the organic layer was washed with water and brine. Anhydrous magnesium sulfate was added to the organic layer for drying, filtration was carried out, then, the solvent was evaporated in vacuo, the residue was purified by NH silica gel column chromatography (ethyl acetate/methanol=40/1), and the title compound (149 mg, 89%) was obtained as a white solid.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[C:16]([O:20][C:21]([N:23]1[CH2:28][CH2:27][CH:26](OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:25][CH2:24]1)=[O:22])([CH3:19])([CH3:18])[CH3:17]>CN(C)C=O>[C:16]([O:20][C:21]([N:23]1[CH2:28][CH2:27][CH:26]([O:1][C:2]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=2)[CH2:25][CH2:24]1)=[O:22])([CH3:19])([CH3:17])[CH3:18]
Reactant: Cc1ccc(S(=O)(=O)OC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Reactant: N#Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc(C#N)cc2)CC1
Yield: 55.8 %

Procedure:
A solution of 4-hydroxy benzonitrile (15 g, 0.126 moles), potassium carbonate (28.89 g, 0.208 moles) and 4-(Toluene-4-sulfonyloxy)piperidine-1-carboxylic acid tert-butyl ester (57.62 g, 0.162 moles) in dimethylformamide (150 mL) was stirred at 100° C. while monitoring the progress of the reaction by thin layer chromatography. After completion of reaction, the reaction mass was quenched on to water (400 mL) and extracted with ethyl acetate (3×300 mL). The resulting ethyl acetate layer was washed with brine solution, dried over sodium sulfate and concentrated under reduced pressure to obtain the crude residue, which was further purified by flash chromatography using (ethyl acetate:hexane, 1:9) to afford the title compound 21.25 g
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].F[C:12]1[CH:21]=[C:20]2[C:15]([C:16](=[O:22])[NH:17][CH:18]=[N:19]2)=[CH:14][CH:13]=1>CN(C)C=O>[CH2:1]([O:8][C:12]1[CH:21]=[C:20]2[C:15]([C:16](=[O:22])[NH:17][CH:18]=[N:19]2)=[CH:14][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=c1[nH]cnc2cc(F)ccc12
Reactant: OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=c1[nH]cnc2cc(OCc3ccccc3)ccc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 93.2 %

Procedure:
A solution of benzyl alcohol (5.27 g, 48.7 mmol) in N,N-dimethylformamide (12 mL) was cooled to 0° C. prior to the portion-wise addition of sodium hydride (60% dispersion in mineral oil, 1.95 g, 48.7 mmol). This mixture was warmed to room temperature and stirred for 30 minutes before being cooled to 0° C. followed by the addition of a solution of the product from Step 1 (2.0 g, 12 mmol) in N,N-dimethylformamide (12 mL). After the addition, the reaction was warmed to 95° C. for 16 hours. After cooling to room temperature, the reaction was partitioned between EtOAc and H2O. The layers were separated and the precipitated solids in the organic layer were collected by filtration, washed with EtOAc and air dried. A second crop of solids was collected and the filtrate washed with saturated sodium chloride solution, dried over sodium sulfate and concentrated to provide a third crop of solids. Combination of the solids and drying to constant weight afforded 2.82 g (93%) of 7-(benzyloxy)quinazolin-4(3H)-one as a tan solid. MS 253.3 (ES+).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:11]=1[O:12][CH2:13][CH:14]1[CH2:16][O:15]1)[C:7]#[N:8])([O-:3])=[O:2].[CH:17]12[CH2:25][CH:21]([CH2:22][NH:23][CH2:24]1)[CH2:20][N:19]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:18]2.O>CC(O)C>[C:7]([C:6]1[CH:9]=[CH:10][C:11]([O:12][CH2:13][CH:14]([OH:15])[CH2:16][N:23]2[CH2:24][CH:17]3[CH2:25][CH:21]([CH2:20][N:19]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:18]3)[CH2:22]2)=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1)#[N:8]
Reactant: CC(C)(C)OC(=O)N1CC2CNCC(C2)C1
Reactant: N#Cc1ccc(OCC2CO2)c([N+](=O)[O-])c1
Solvent: O
Solvent: CC(C)O
Product: CC(C)(C)OC(=O)N1CC2CC(CN(CC(O)COc3ccc(C#N)cc3[N+](=O)[O-])C2)C1
Yield: 54 %

Procedure:
3-Nitro-4-(2-oxiranylmethoxy)benzonitrile (2.9 g; 13.2 mmol; from step (a) above) was added to a stirred solution of tert-butyl 3,7-diazabicyclo[3.3.1]nonane-3-carboxylate (3 g; 13.2 mmol; see Example F above) in IPA:H2O (12.5 mL; 9:1), and the reaction mixture was refluxed for 3 h. Concentration of the reaction mixture and purification by column chromatography (DCM:MeOH; 15:1) gave the title compound in a 54% yield.
Reaction SMILES: [NH2:1][CH2:2][C:3]([NH:5][C@H:6]([C:14]([NH:16][C:17]1[CH:25]=[CH:24][C:20]([N+:21]([O-:23])=[O:22])=[CH:19][CH:18]=1)=[O:15])[CH2:7][CH2:8][CH2:9][NH:10][C:11](=[NH:13])[NH2:12])=[O:4].[NH:26](C(OC(C)(C)C)=O)[C@@H:27]([C:32](O)=[O:33])[CH2:28][CH:29]([CH3:31])[CH3:30].CCN(C(C)C)C(C)C>CN(C=O)C>[NH2:26][C@@H:27]([C:32]([NH:1][CH2:2][C:3]([NH:5][C@H:6]([C:14]([NH:16][C:17]1[CH:18]=[CH:19][C:20]([N+:21]([O-:23])=[O:22])=[CH:24][CH:25]=1)=[O:15])[CH2:7][CH2:8][CH2:9][NH:10][C:11](=[NH:12])[NH2:13])=[O:4])=[O:33])[CH2:28][CH:29]([CH3:31])[CH3:30]
Reactant: CC(C)C[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: N=C(N)NCCC[C@H](NC(=O)CN)C(=O)Nc1ccc([N+](=O)[O-])cc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)C[C@@H](N)C(=O)NCC(=O)N[C@@H](CCCNC(=N)N)C(=O)Nc1ccc([N+](=O)[O-])cc1
Reaction time: 2 h
Yield: 107.6 %

Procedure:
Following the procedures of Preparation Ic, a reaction mixture comprising (i) 910 mg (1.57 mmol) of H-Gly-L-Arg-pNA.2H-TFA, (ii) 363 mg (1.57 mmol) of Boc-D-Leu-OH, (iii) 1.2 ml of DIEA and (iv) 695 mg (1.57 mmol) of Bop is reacted in DMF and the reaction mixture is kept at RT for 2 h, with stirring. After evaporation to dryness under vacuum, the evaporation residue is chromatographed on silica gel using a CHCl3 /MeOH/AcOH gradient (20/3/1 to 10/3/1 v/v) as the eluent. The homogeneous fractions collected are pooled and the eluent is evaporated off. Lyophilization gives 785 mg (yield: 80%) of the expected product in pure form.
Reaction SMILES: [B-](F)(F)(F)F.[B-](F)(F)(F)F.C1[N+]2(CCl)CC[N+]([F:21])(CC2)C1.[Br:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[N:30]=[C:31]([N:34]3[C@@H:38]([CH2:39][CH3:40])[CH2:37][O:36][C:35]3=[O:41])[S:32][CH:33]=2)=[CH:25][CH:24]=1>C(#N)C>[Br:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[N:30]=[C:31]([N:34]3[C@@H:38]([CH2:39][CH3:40])[CH2:37][O:36][C:35]3=[O:41])[S:32][C:33]=2[F:21])=[CH:25][CH:24]=1
Reactant: CC[C@H]1COC(=O)N1c1nc(-c2ccc(Br)cc2)cs1
Reactant: F[N+]12CC[N+](CCl)(CC1)CC2
Agent: F[B-](F)(F)F
Solvent: CC#N
Product: CC[C@H]1COC(=O)N1c1nc(-c2ccc(Br)cc2)c(F)s1
Temperature: 25 °C
Reaction time: 21.5 h

Procedure:
The Selectfluor® reagent (2.2125 g, 6.25 mmol) in 250 mL of acetonitrile was added under nitrogen dropwise over 1.5 h to a solution of (4S)-3-[4-(4-bromophenyl)-1,3-thiazol-2-yl]-4-ethyl-1,3-oxazolidin-2-one (2.0015 g, 5.67 mmol), prepared in step 2 of Example 7, in 250 mL of acetonitrile at room temperature. After the addition, the reaction was stirred at room temperature for 21.5 h. The reaction was concentrated under reduced pressure to remove the acetonitrile. The residue was partitioned between methylene chloride and 2 N HCl. The organic layer was separated and the aqueous layer extracted three times with methylene chloride. The combined extracts were dried (anhydrous MgSO4), filtered and the solvent removed under reduced pressure to give 2.11 g of a tan foam. Purification of the foam on 800 g of silica gel (230-400 mesh) using 50% methylene chloride-hexane to 100% methylene chloride as the eluents gave the title compound (914.8 mg, 44%) as a white solid, mp 105-107° C.; MS (ES) m/z 370.9 [M+H]+; Anal. Calcd for C14H12BrFN2O2S: C, 45.30; H, 3.26; N, 7.55. Found: C, 45.53; H, 3.09; N, 7.37.
Reaction SMILES: [F:1]C1N=CC=CC=1C(NC(C1C=CC=CC=1)CN1CCOCC1)=O.[ClH:25].Cl.[NH:27]1[C:31]2=[N:32][CH:33]=[CH:34][C:35]([O:36][C:37]3[CH:42]=[CH:41][C:40]([NH:43][C:44]4[N:59]=[CH:58][CH:57]=[CH:56][C:45]=4[C:46]([NH:48][C:49]4[CH:54]=[CH:53][CH:52]=[CH:51][C:50]=4[CH3:55])=[O:47])=[CH:39][C:38]=3[F:60])=[C:30]2[CH:29]=[CH:28]1>>[ClH:25].[NH:27]1[C:31]2=[N:32][CH:33]=[CH:34][C:35]([O:36][C:37]3[CH:42]=[CH:41][C:40]([NH:43][C:44]4[N:59]=[CH:58][CH:57]=[CH:56][C:45]=4[C:46]([NH:48][CH2:49][C:54]4[CH:53]=[CH:52][C:51]([F:1])=[CH:50][CH:55]=4)=[O:47])=[CH:39][C:38]=3[F:60])=[C:30]2[CH:29]=[CH:28]1
Reactant: O=C(NC(CN1CCOCC1)c1ccccc1)c1cccnc1F
Reactant: Cc1ccccc1NC(=O)c1cccnc1Nc1ccc(Oc2ccnc3[nH]ccc23)c(F)c1
Agent: Cl
Product: O=C(NCc1ccc(F)cc1)c1cccnc1Nc1ccc(Oc2ccnc3[nH]ccc23)c(F)c1
Yield: 13 %

Procedure:
2-Fluoro-N-(2-morpholino-1-phenylethyl)nicotinamide (0.096 g, 0.29 mmol) was converted to the title compound (0.022 g, 13%) in a manner similar to the preparation of 2-(4-(1H-pyrrolo[2,3-b]pyridin-4-yloxy)-3-fluorophenylamino)-N-o-tolylnicotinamide (Step B of Example 8). 1H NMR (DMSO-d6) δ 12.53 (s, 1H), 10.93-11.05 (m, 2H), 9.73 (d, 1H, J=7.8 Hz), 8.59 (dd, 1H, J=7.9, 1.3 Hz), 8.35 (dd, 1H, J=4.7, 1.4 Hz), 8.20 (d, 1H, J=6.2 Hz), 8.06-8.15 (m, 1H), 7.45-7.55 (m, 3H), 7.23-7.40 (m, 4H), 6.90-6.99 (m, 1H), 6.60 (d, 1H, J=6.2 Hz), 6.38-6.45 (m, 1H), 5.53-5.64 (m, 1H), 3.10-4.00 (m, 10H); HRMS(ESI+), 553.2363 (M+H)+ calc, 553.2368 (M+H)+ found.
Reaction SMILES: C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2)CCCCC1.[CH3:26][C:27]1[N:31]=[C:30]([C:32]2[CH:37]=[CH:36][C:35]([NH2:38])=[CH:34][CH:33]=2)[S:29][N:28]=1.Cl[C:40]1[N:45]=[C:44]([C:46]([OH:49])([CH3:48])[CH3:47])[CH:43]=[C:42]([C:50]2[CH:55]=[CH:54][C:53]([C:56]([F:59])([F:58])[F:57])=[CH:52][CH:51]=2)[N:41]=1.O>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:26][C:27]1[N:31]=[C:30]([C:32]2[CH:37]=[CH:36][C:35]([NH:38][C:40]3[N:45]=[C:44]([C:46]([OH:49])([CH3:48])[CH3:47])[CH:43]=[C:42]([C:50]4[CH:55]=[CH:54][C:53]([C:56]([F:59])([F:57])[F:58])=[CH:52][CH:51]=4)[N:41]=3)=[CH:34][CH:33]=2)[S:29][N:28]=1
Reactant: Cc1nsc(-c2ccc(N)cc2)n1
Reactant: CC(C)(O)c1cc(-c2ccc(C(F)(F)F)cc2)nc(Cl)n1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(-c2ccccc2P(C2CCCCC2)C2CCCCC2)cc1
Solvent: C1COCCO1
Solvent: O
Product: Cc1nsc(-c2ccc(Nc3nc(-c4ccc(C(F)(F)F)cc4)cc(C(C)(C)O)n3)cc2)n1
Yield: 27.6 %

Procedure:
Palladium(II) acetate (3.6 mg, 0.016 mmol) and 2-(dicyclohexylphosphino)biphenyl (11 mg, 0.032 mmol) were stirred in dioxane (1 mL) for 10 minutes at room temperature under an atmosphere of nitrogen. Sodium tert.-butylate (29 mg, 0.3 mmol), 4-(3-methyl-[1,2,4]-thiadiazol-5-yl)-phenylamine (38 mg, 0.20 mmol) and) 2-[2-chloro-6-(4-trifluoromethyl-phenyl)pyrimidine-4-yl]-propan-2-ol (70 mg, 0.22 mmol) dissolved in dioxane (1 mL) were added. The reaction was heated for 30 minutes to 130° C. in a microwave oven. Water was added and the reaction was extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel using heptane/ethyl acetate (1:1 v/v) as eluent to yield the title compound as a yellow solid (26 mg, 28%). MS ISP (m/e): 472.2 (100) [(M+H)+]. 1H NMR (CDCl3, 300 MHz): δ (ppm)=8.21 (d, 2H), 7.97 (d, 2H), 7.85 (d, 2H), 7.79 (d, 2H), 7.45 (br s, 1H, NH), 7.39 (s, 1H), 3.72 (s, 1H, OH), 2.73 (s, 3H), 1.62 (s, 6H).