Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[C:5]([Br:7])[CH:6]=1.[C:8]([Si:12]([CH3:33])([CH3:32])[O:13][CH:14]1[C:22]2[C:17](=[C:18](B3OC(C)(C)C(C)(C)O3)[CH:19]=[CH:20][CH:21]=2)[CH2:16][CH2:15]1)([CH3:11])([CH3:10])[CH3:9].C(=O)([O-])[O-].[K+].[K+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.COCCOC.O>[Br:7][C:5]1[CH:6]=[C:2]([C:18]2[CH:19]=[CH:20][CH:21]=[C:22]3[C:17]=2[CH2:16][CH2:15][CH:14]3[O:13][Si:12]([C:8]([CH3:11])([CH3:10])[CH3:9])([CH3:32])[CH3:33])[S:3][CH:4]=1
Reactant: CC1(C)OB(c2cccc3c2CCC3O[Si](C)(C)C(C)(C)C)OC1(C)C
Reactant: Brc1csc(Br)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: CC(C)(C)[Si](C)(C)OC1CCc2c(-c3cc(Br)cs3)cccc21

Procedure:
Prepared using General Procedure 1. A 2 mL microwave vial was charged with 2,4-dibromothiophene (15 mg, 0.06 mmol), tert-butyldimethyl((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden-1-yl)oxy)silane IND INT-8 (23 mg, 0.06 mmol), potassium carbonate (26 mg, 0.18 mmol) and 3:1 mixture of DME/H2O (2 mL). The reaction mixture was degassed by bubbling N2 through the stirred solution for 10 min. Pd(PPh3)4 (5 mg, 0.004 mmol) was added and the solution degassed for an additional 2 min. The vial was subjected to microwave irradiation at 70° C. for 30 min or until starting material consumed. The resulting ((4-(4-bromothiophen-2-yl)-2,3-dihydro-1H-inden-1-yl)oxy)(tert-butyl)dimethylsilane THIO INT-4 was carried onto the next experiment without workup and purification. LCMS-ESI (m/z) calculated for C19H25BrOSSi: 408.1; no M+ found, tR=6.50 min (Method 1).
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH:13]=[C:12]([C:14]([NH2:16])=O)[N:11]=[CH:10]1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:28])=CC=1>C1C=CC=CC=1>[F:1][C:2]([F:18])([F:17])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH:13]=[C:12]([C:14](=[S:28])[NH2:16])[N:11]=[CH:10]1
Reactant: NC(=O)c1cn(-c2ccccc2C(F)(F)F)cn1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: c1ccccc1
Product: NC(=S)c1cn(-c2ccccc2C(F)(F)F)cn1
Yield: 184.3 %

Procedure:
A mixture of 1-(3′-methylsulfonyl)biphenyl-4-yl)-2-(2-(trifluoromethyl)phenyl-1H-imidazole-4-carboxamide (243 mg, 0.5 mmol), Lawesson's reagent (243 mg, 0.6 mmol), and dry benzene (15 mL) was stirred at reflux for 2 h. The solvent was removed in vacuo, and the crude product was purified by flash chromatography (SiO2, 90% EtOAc/hexanes) to give 1-(3′-methylsulfonyl)biphenyl-4-yl)-2-(2-(trifluoromethyl)phenyl-1H-imidazole-4-carbothioamide as a yellow solid (250 mg, 100%). MS (ESI) 502 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10]1[C:11]([O:24][CH3:25])=[N:12][CH:13]=[CH:14][C:15]=1[C:16]1([CH2:22][CH3:23])OCCC[O:17]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.CCCCCCC>C(O)C.O>[CH2:1]([O:8][CH2:9][C:10]1[C:11]([O:24][CH3:25])=[N:12][CH:13]=[CH:14][C:15]=1[C:16](=[O:17])[CH2:22][CH3:23])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCC1(c2ccnc(OC)c2COCc2ccccc2)OCCCO1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Solvent: CCCCCCC
Solvent: O
Product: CCC(=O)c1ccnc(OC)c1COCc1ccccc1
Temperature: 80 °C
Reaction time: 6.25 h
Yield: 96.5 %

Procedure:
To stirred solution of 4.120 g 3-benzyloxymethyl-4-(2-ethyl-[1,3]dioxan-2-yl)-2-methoxy-pyridine as obtained from Example 6 (12.00 mmol) in 96 mL ethanol and 24 mL water were added at room temperature 461 mg para-toluenesulfonic acid monohydrate (2.40 mmol, 0.2 eq). The mixture was subsequently heated to 80° C. and the reaction was monitored by HPLC and after 6.25 h at 80° C. (<0.2% area starting material as obtained from Example 6), the solution was cooled down to room temperature and poured into 600 mL heptane. The organic phase was washed with 600 mL water, subsequently with 600 mL aqueous NaHCO3 solution (0.1 M) and again with 600 mL water. The organic phase was dried over 20 g Na2SO4 (30 min) and filtered. The solid was washed with 40 mL heptane. After evaporation of solvent in a rotary evaporator (40° C./10 mbar), the title compound (3.302 g, 96% by weight) was obtained as a light yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([C:8]([CH3:11])([CH3:10])[CH3:9])[CH:5]=[CH:4][C:3]=1[OH:12].C(N(CC)CC)C.[CH3:20][O:21][CH2:22][CH2:23][O:24][CH2:25]Cl.O>ClCCl>[Br:1][C:2]1[CH:7]=[C:6]([C:8]([CH3:9])([CH3:11])[CH3:10])[CH:5]=[CH:4][C:3]=1[O:12][CH2:20][O:21][CH2:22][CH2:23][O:24][CH3:25]
Reactant: COCCOCCl
Reactant: CC(C)(C)c1ccc(O)c(Br)c1
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: COCCOCOc1ccc(C(C)(C)C)cc1Br
Reaction time: 8 h
Yield: 72.3 %

Procedure:
To a solution of 2-bromo-4-(tert-butyl)phenol [Intermediate 1, Step 1] (5.0 g, 21.8 mmol) and triethylamine (4.4 g, 43.5 mmol) in anhydrous dichloromethane (20 mL) at room temperature under nitrogen was added dropwise 2-methoxyethoxymethyl chloride (2.5 mL, 21.9 mmol) and the reaction mixture stirred overnight. The reaction mixture was poured into water (100 mL), the organic phase separated, dried (MgSO4), filtered and concentrated under reduced pressure to give 2-bromo-4-(tert-butyl)-1-((2-methoxyethoxy)methoxy)benzene (5.0 g, 72% yield).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3](/[CH:11]=[CH:12]/[C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19]C)=[O:18])=[CH:15][CH:14]=2)[CH:2]=1.O.[OH-].[Na+].Cl>CO>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3](/[CH:11]=[CH:12]/[C:13]2[CH:22]=[CH:21][C:16]([C:17]([OH:19])=[O:18])=[CH:15][CH:14]=2)[CH:2]=1
Reactant: COC(=O)c1ccc(/C=C/c2cnc3ccccc3c2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1ccc(/C=C/c2cnc3ccccc3c2)cc1

Procedure:
Methyl 4-[(E)-2-(3-quinolinyl)ethenyl]benzoate (0.840 mg, 3.36 mmol; see step (i) above) was suspended in methanol (10 mL) and water (20 mL) to which sodium hydroxide solution (NaOH 0.580 g, 14.5 mmol in water 10 mL) was added with stirring. The reaction mixture was heated under reflux for 2 h. At the beginning the starting material dissolved then white precipitate appeared. The reaction mixture was cooled in an ice bath then (dilute HCl was added dropwise with vigorous stirring until pH 2 was attained. The title compound formed as a yellow solid material, which was filtered off, washed with water and dried in vacuo at 60° C. (0.640 g, 69%), m.p.=287-290° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[NH:12][CH2:13][CH3:14])[N:8]=[CH:7][N:6]=[C:5]2[N:15]1[CH2:20][CH2:19][N:18]([C:21](=[S:30])[NH:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:17][CH2:16]1.C(N(CC)CC)C.[C:38](Cl)(=[O:45])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1.O>ClCCl>[C:38]([NH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[NH:12][CH2:13][CH3:14])[N:8]=[CH:7][N:6]=[C:5]2[N:15]1[CH2:20][CH2:19][N:18]([C:21](=[S:30])[NH:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:17][CH2:16]1)(=[O:45])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1
Reactant: CCNc1cc2ncnc(N3CCN(C(=S)NCc4ccccc4)CC3)c2cc1N
Reactant: O=C(Cl)c1ccccc1
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CCNc1cc2ncnc(N3CCN(C(=S)NCc4ccccc4)CC3)c2cc1NC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 38 %

Procedure:
To a solution of 504.9 mg (1.20 mmol) of 4-(6-amino-7-ethylamino-4-quinazolinyl)-N-benzyl-1-piperazinethiocarboxamide obtained in Example 461 in 15 ml of dichloromethane were added 0.50 ml (3.6 mmol) of triethylamine and 0.17 ml (1.44 mmol) of benzoyl chloride, followed by overnight stirring at room temperature in an atmosphere of argon. After addition of water, the reaction mixture was extracted with dichloromethane, and the organic layer was washed with water and dried over sodium sulfate. After the solvent was evaporated, the residue was purified by silica gel chromatography to give the desired compound as colorless crystals.
Reaction SMILES: [N:1]1[N:2]([C:10]2[CH:15]=[C:14]([CH3:16])[CH:13]=[CH:12][C:11]=2[OH:17])[N:3]=[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12.N(C(C)(C)C#N)=NC(C)(C)C#N.[Br:30]Br>C(Cl)(Cl)(Cl)Cl>[N:1]1[N:2]([C:10]2[CH:15]=[C:14]([CH2:16][Br:30])[CH:13]=[CH:12][C:11]=2[OH:17])[N:3]=[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12
Reactant: BrBr
Reactant: Cc1ccc(O)c(-n2nc3ccccc3n2)c1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: Oc1ccc(CBr)cc1-n1nc2ccccc2n1
Temperature: 25 °C

Procedure:
2-(2H-Benzotriazole-2-yl)-4-bromomethylphenol was prepared from the bromination of 2-(2H-Benzotriazole-2-yl)-4-methylphenol using azobis isobutyronitrile (AIBN) as an initiator. In a 500 ml three-necked round bottomed flask, 5 g (0.0223 mol) of 2-(2H-Benzotriazole-2-yl)-4-methylphenol and 100 mg of AIBN were taken and dissolved in 150 ml of dry carbon tetrachloride. In a separate conical flask 4.18 g (1.5 ml, 0.03 mol) of bromine was dissolved in 75 ml of dry carbon tetrachloride and solution was transferred to a cylindrical funnel with pressure equalizing tube. Three-necked round-bottomed flask containing solution of 2-(2H-Benzotriazole-2-yl)-4-methylphenol was kept in oil-bath with temperature 47° C. Nitrogen was bubbled through the solution for creating inert atmosphere. Cylindrical funnel containing bromine solution was mounted on the three-necked round-bottomed flask. Solution in the flask was continuously stirred with the help of magnetic stirrer. Bromine solution was added, drop-by-drop, from funnel to the flask for a span of 4-5 hours till all the solution was poured out. After that heating was stopped and the final reaction mixture was allowed to cool at room temperature. Product was separated by solvent evaporation. Finally the product was purified by recrystallization from acetone. The yield of 2-(2H-Benzotriazole-2-yl)-4-bromomethylphenol was 5.5 g (80%).
Reaction SMILES: [NH:1]([C:3]1[N:8]([CH2:9][CH:10]([CH3:12])[CH3:11])[C:7](=[O:13])[N:6]([CH3:14])[C:5](=[O:15])[CH:4]=1)[NH2:2].[F:16][C:17]([F:31])([F:30])[C:18]1[CH:19]=[C:20]2[C:25](=[CH:26][CH:27]=1)[N:24]=[CH:23][CH:22]=[C:21]2[CH:28]=O.[CH3:32][N:33]1[CH:37]=[C:36]([C:38](=[O:40])[CH3:39])[CH:35]=[C:34]1[CH:41]=O>>[C:38]([C:36]1[CH:35]=[C:34]([C:41]2[N:2]([CH2:28][C:21]3[C:20]4[C:25](=[CH:26][CH:27]=[C:18]([C:17]([F:31])([F:30])[F:16])[CH:19]=4)[N:24]=[CH:23][CH:22]=3)[N:1]=[C:3]3[C:4]=2[C:5](=[O:15])[N:6]([CH3:14])[C:7](=[O:13])[N:8]3[CH2:9][CH:10]([CH3:11])[CH3:12])[N:33]([CH3:32])[CH:37]=1)(=[O:40])[CH3:39]
Reactant: CC(=O)c1cc(C=O)n(C)c1
Reactant: O=Cc1ccnc2ccc(C(F)(F)F)cc12
Reactant: CC(C)Cn1c(NN)cc(=O)n(C)c1=O
Product: CC(=O)c1cc(-c2c3c(=O)n(C)c(=O)n(CC(C)C)c3nn2Cc2ccnc3ccc(C(F)(F)F)cc23)n(C)c1

Procedure:
This compound was made following the procedure described above, starting with 6-hydrazino-1-isobutyl-3-methylpyrimidine-2,4(1H,3H)-dione, and condensing first with 6-trifluoromethylquinoline-4-carbaldehyde, followed by 1-methyl-4-acetyl-1H-pyrrole-2-carbaldehyde. 553(M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[O:8][C:7]([C:9]3[S:10][CH:11]=[CH:12][CH:13]=3)=[N:6][C:5]2=[C:14]([C:16]([OH:18])=O)[CH:15]=1.Cl.Cl.[NH2:21][C@H:22]1[CH:27]2[CH2:28][CH2:29][N:24]([CH2:25][CH2:26]2)[CH2:23]1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>CN(C=O)C.ClCCl>[N:24]12[CH2:29][CH2:28][CH:27]([CH2:26][CH2:25]1)[C@H:22]([NH:21][C:16]([C:14]1[CH:15]=[C:2]([Cl:1])[CH:3]=[C:4]3[O:8][C:7]([C:9]4[S:10][CH:11]=[CH:12][CH:13]=4)=[N:6][C:5]=13)=[O:18])[CH2:23]2
Reactant: O=C(O)c1cc(Cl)cc2oc(-c3cccs3)nc12
Reactant: N[C@@H]1CN2CCC1CC2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(N[C@@H]1CN2CCC1CC2)c1cc(Cl)cc2oc(-c3cccs3)nc12
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 30.9 %

Procedure:
A mixture of 6-chloro-2-(thiophen-2-yl)benzo[d]oxazole-4-carboxylic acid (70 mg, 0.25 mmol), (S)-(−)-3-aminoquinuclidine dihydrochloride (50 mg, 0.25 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (96 mg, 0.50 mmol) and 1-hydroxybenzotriazole (68 mg, 0.50 mmol) in DMF (2 mL) was stirred at room temperature for 5 min, then triethylamine (0.13 mL, 1.00 mmol) was added. The resulting reaction mixture was stirred at room temperature for 12 h. The mixture was diluted with dichloromethane (20 mL), then washed with a saturated solution of sodium bicarbonate (10 mL). The aqueous layer was further extracted with dichloromethane (3×15 mL). The combined organics were dried (Na2SO4), filtered and concentrated. The crude material was purified by column chromatography (silica gel, 89:10:1 dichloromethane/methanol/concentrated ammonium hydroxide) to afford (s) —N-(1-azabicyclo[2.2.2]oct-3-yl)-6-chloro-2-thiophen-2-ylbenzoxazole-4-carboxamide (30 mg, 31%) as a white solid: 1H NMR (500 MHz, CDCl3) δ 9.40 (d, J=7.5 Hz, 1H), 8.16 (d, J=2.0 Hz, 1H), 7.94 (dd, J=4.0, 1.5 Hz, 1H), 7.67-7.65 (m, 2H), 7.26-7.23 (m, 1H), 4.30-4.26 (m, 1H), 3.49 (ddd, J=11.5, 9.5, 2.0 Hz, 1H), 3.15-2.85 (m, 4H), 2.77 (dd, J=14.5, 3.5 Hz, 1H), 2.15-2.05 (m, 2H), 1.78-1.70 (m, 2H), 1.65-1.53 (m, 1H); MS (ESI+) m/z 388 (M+H); HPLC>99% (AUC), tR=13.84 min.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([CH2:8][CH2:9][O:10][C:11]2[CH:18]=[CH:17][C:14]([CH:15]=O)=[CH:13][CH:12]=2)[CH:5]=[CH:4][CH:3]=1.[S:19]1[CH2:23][C:22](=[O:24])[NH:21][C:20]1=[O:25].C(O)C.N1CCCCC1>C(O)(=O)C>[CH3:1][C:2]1[N:7]=[C:6]([CH2:8][CH2:9][O:10][C:11]2[CH:18]=[CH:17][C:14]([CH:15]=[C:23]3[S:19][C:20](=[O:25])[NH:21][C:22]3=[O:24])=[CH:13][CH:12]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CSC(=O)N1
Reactant: Cc1cccc(CCOc2ccc(C=O)cc2)n1
Solvent: CCO
Solvent: C1CCNCC1
Solvent: CC(=O)O
Product: Cc1cccc(CCOc2ccc(C=C3SC(=O)NC3=O)cc2)n1
Temperature: 0 °C

Procedure:
A mixture of 4-[2-(6-methyl-2-pyridyl)ethoxy]benzaldehyde (1.21 g), 2,4-thiazolidinedione (0.59 g), ethanol (50 ml) and piperidine (0.33 g) was heated under reflux for 16 hours. The reaction mixture was poured into ice-water and acidified with acetic acid. The resulting crystals were collected by filtration to give 5-{4-[2-(6-methyl-2-pyridyl)ethoxy]benzylidene}-2,4-thiazolidinedione. Yield: 1.34 g (78.5%). Recrystallization from methanol gave pale yellow prisms. m.p.: 180.5°-182° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@H:8]([N:10]=[N+]=[N-])[CH2:7][N:6]1[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[O:4]>CO.[Pd]>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@H:8]([NH2:10])[CH2:7][N:6]1[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[O:4]
Reactant: COC(=O)[C@@H]1C[C@H](N=[N+]=[N-])CN1C(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CO
Product: COC(=O)[C@@H]1C[C@H](N)CN1C(=O)OC(C)(C)C
Yield: 96.8 %

Procedure:
(2S,4S)-4-azidopyrrolidine-1,2-dicarboxylic acid 1-t-butyl ester 2-methyl ester (8.5 g, 31 mmol) and Pd/C (10% w/w, 2.0 g) were stirred in MeOH (150 mL) at room temperature under an atmosphere of hydrogen for 48 hours. The mixture was filtered and the filtrate evaporated to afford the title compound (7.34 g, 30 mmol), which was used without further purification. MS m/z: [M+1-1]+ calcd for C11H20N2O4, 244.3. found 245.3.
Reaction SMILES: [C:1]([O-:6])(=O)[C:2]([NH2:4])=[O:3].[NH2:7][C:8]1[CH:13]=[CH:12][C:11](C(C2C=CC(O)=CC=2)(C)C)=[CH:10][CH:9]=1>ClC1C=CC=CC=1Cl>[CH:11]1[CH:12]=[CH:13][C:8]([NH:7][C:1]([C:2]([NH:4][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:3])=[O:6])=[CH:9][CH:10]=1
Reactant: CC(C)(c1ccc(N)cc1)c1ccc(O)cc1
Reactant: NC(=O)C(=O)[O-]
Solvent: Clc1ccccc1Cl
Product: O=C(Nc1ccccc1)C(=O)Nc1ccccc1

Procedure:
Ar=2,2-(4,4′-phenylene)propyl (also known as compound (VIII)): A mixture of oxamate, compound (XII), (2.415 g, 10.18 mmol) and 2-(4-aminophenyl)-2-(4′-hydroxyphenyl)propane (2.545 g, 11.2 mmol) were suspended in o-dichlorobenzene (10 ml), degassed, and heated to reflux for 20 hrs. TLC indicated complete conversion of the oxamate. The crude reaction mixture was concentrated under reduced pressure, taken up in dichloromethane, and filtered through a plug of silica gel. The product was recrystallized from hexanes/dichloromethane and again filtered through silica gel, yielding the desired oxanilide as white fine crystals.
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[F:13][C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][CH:22]=1)[NH:19][C:18]([C:23]([OH:25])=O)=[CH:17]2.[CH2:26]([NH:29][C:30]1[C:31]([N:36]2[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]2)=[N:32][CH:33]=[CH:34][CH:35]=1)[CH2:27][CH3:28]>C1COCC1.ClCCl>[CH3:28][CH2:27][CH2:26][NH:29][C:30]1[CH:35]=[CH:34][CH:33]=[N:32][C:31]=1[N:36]1[CH2:41][CH2:40][N:39]([C:23]([C:18]2[NH:19][C:20]3[CH:21]=[CH:22][C:14]([F:13])=[CH:15][C:16]=3[CH:17]=2)=[O:25])[CH2:38][CH2:37]1
Reactant: O=C(O)c1cc2cc(F)ccc2[nH]1
Reactant: CCCNc1cccnc1N1CCNCC1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCCNc1cccnc1N1CCN(C(=O)c2cc3cc(F)ccc3[nH]2)CC1
Reaction time: 1 h

Procedure:
1,1'-carbonyldiimidazole (0.48) is added to a 20°-25° solution of 5-fluoroindole-2-carboxylic acid (I, 0.53 g) in THF (6 ml). After 1 hour of stirring the above reaction is added dropwise via cannula to a solution of [3-(propylamino)-2-pyridinyl]piperazine (II, PREPARATION 7, 0.72 g) in THF (6 ml) at -10° (ice/acetone bath). The reaction is stirred for 30 minutes at -10°, slowly warming to 20°-25°, and stirred for 4 hours. The reaction is diluted with dichloromethane (50 ml), washed with saturated aqueous sodium bicarbonate (40 ml), saline (40 ml), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The concentrate is purified by flash column chromatography (40 g silica gel) eluting with ethyl acetate/hexane (1/1). The appropriate fractions are pooled and concentrated to give the title compound, mp 196°-198°; IR (mineral oil) 3200, 2920-3000, 1630 and 1424 cm-1 ; NMR (300 MHz, CDCl3) 9.82, 7.72, 7.35, 7.27, 7.03, 6.95, 6.86, 6.78, 4.32, 4.09, 3.21, 3.08, 1.71 and 1.05 δ; CMR (300 MHz, CDCl3) 162.3, 159.5, 149.7, 137.4, 135.1, 132.3, 130.7, 127.5, 127.4, 120.4, 116.3, 113.4, 112.9, 112.7, 112.5, 106.1, 105.8, 105.8, 105.1, 105.0, 49.0, 45.2, 22.5 and 11.6 δ; MS (m/e) 382, 381, 190, 176, 164, 162, 134 and 120.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]([OH:9])=O)[N:4]=[CH:3]1.C1C=CC2N(O)N=NC=2C=1.Cl.CN(C)CCCN=C=NCC.Cl.[CH3:33][C@@H:34]1[CH2:38][CH2:37][CH2:36][N:35]1[C:39]1[N:44]=[C:43]([NH:45][C:46]2[CH:51]=[C:50]([C:52]([F:55])([F:54])[F:53])[CH:49]=[CH:48][N:47]=2)[CH:42]=[C:41]([CH:56]2[CH2:60][CH2:59][NH:58][CH2:57]2)[CH:40]=1.CCN(C(C)C)C(C)C>C(Cl)(Cl)Cl.C(Cl)Cl>[CH3:1][N:2]1[CH:6]=[C:5]([C:7]([N:58]2[CH2:59][CH2:60][CH:56]([C:41]3[CH:42]=[C:43]([NH:45][C:46]4[CH:51]=[C:50]([C:52]([F:53])([F:54])[F:55])[CH:49]=[CH:48][N:47]=4)[N:44]=[C:39]([N:35]4[CH2:36][CH2:37][CH2:38][CH:34]4[CH3:33])[CH:40]=3)[CH2:57]2)=[O:9])[N:4]=[CH:3]1
Reactant: C[C@@H]1CCCN1c1cc(C2CCNC2)cc(Nc2cc(C(F)(F)F)ccn2)n1
Reactant: Cn1cnc(C(=O)O)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: CC1CCCN1c1cc(C2CCN(C(=O)c3cn(C)cn3)C2)cc(Nc2cc(C(F)(F)F)ccn2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 15.3 %

Procedure:
To a mixture of 1-methylimidazole-4-carboxylic acid (39.79 mg, 0.315 mmol, 1.5 equiv.), HOBT (57.42 mg, 0.420 mmol, 2.0 equiv.), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (81.46 mg; 0.420 mmol, 2.0 equiv.) in chloroform (3.0 mL) was added 6-[(2R)-2-methylpyrrolidin-1-yl]-4-pyrrolidin-3-yl-N-[4-(trifluoromethyl)-2-pyridyl]pyridin-2-amine hydrochloride (90 mg, 0.210 mmol) followed by DIPEA (0.148 mL, 0.841 mmol, 4.0 equiv.). The resulting mixture was stirred at rt for 2 h. It was diluted with DCM (10 mL), washed with 10% citric acid and 1 N NaHCO3, dried over Na2SO4, filtered, concentrated in vacuo, and purified by HPLC to afford 16.1 mg (15.3%) of product as yellow solid. 1H NMR (400 MHz, DMSO) δ 9.74 (s, 1H), 8.80 (s, 1H), 8.41 (d, J=5.1 Hz, 1H), 7.68-7.60 (m, 2H), 7.10 (d, J=5.1 Hz, 1H), 6.39 (s, 1H), 5.90 (s, 1H), 4.48-4.09 (m, 3H), 3.94-3.73 (m, 2H), 3.69 (d, J=5.2 Hz, 3H), 3.56-3.43 (m, 2H), 3.25-3.18 (m, 1H), 2.31-2.13 (m, 1H), 2.12-1.86 (m, 4H), 1.73-1.63 (m, 1H), 1.17 (d, J=6.0 Hz, 3H). LC-MS: m/z=500 (M+H+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C@H:9]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH2:10][OH:11])[CH:5]=[C:6]([F:8])[CH:7]=1.C(N(CC)CC)C.[CH3:27][S:28](Cl)(=[O:30])=[O:29].C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH3:27][S:28]([O:11][CH2:10][C@@H:9]([NH:12][C:13]([O:14][C:15]([CH3:16])([CH3:18])[CH3:17])=[O:19])[C:4]1[CH:5]=[C:6]([F:8])[CH:7]=[C:2]([Br:1])[CH:3]=1)(=[O:30])=[O:29]
Reactant: CC(C)(C)OC(=O)N[C@H](CO)c1cc(F)cc(Br)c1
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@H](COS(C)(=O)=O)c1cc(F)cc(Br)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
To a stirred solution of (S)-tert-butyl (1-(3-bromo-5-fluorophenyl)-2-hydroxyethyl)carbamate (4.8 g, 14.36 mmol) in anhydrous DCM (100 mL) at 0° C. was added triethylamine (4.00 mL, 28.7 mmol) followed by methanesulfonyl chloride (1.343 mL, 17.24 mmol). The reaction was stirred at 0° C. for 1 hr, by which time the LCMS indicated the reaction had gone to completion. The reaction mixture was poured into saturated NaHCO3 solution (100 mL). The mixture was shaken, the layers separated and the aqueous layer was extracted with DCM (2×50 mL). The combined organics were washed with NaHCO3 solution (50 mL) and brine (50 mL), dried (MgSO4), filtered and concentrated, giving (S)-2-((tert-butoxycarbonyl)amino)-2-(3-bromo-5-fluorophenyl)ethyl methanesulfonate (5.92 g, 14.36 mmol, 100% yield) as a very pale orange solid. 1H NMR (500 MHz, DMSO-d6) δ ppm 7.75 (d, J=8.83 Hz, 1H), 7.43-7.55 (m, 2H), 7.31 (d, J=9.46 Hz, 1H), 4.86-5.00 (m, 1H), 4.30 (dd, J=10.09, 5.04 Hz, 1H), 4.24 (t, J=9.30 Hz, 1H), 3.16-3.23 (m, 3H), 1.36-1.44 (m, 9H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[CH2:6][CH2:5]2.[BH4-].[Na+]>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH:7]([OH:11])[CH2:6][CH2:5]2
Reactant: O=C1CCc2cc(Br)ccc21
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: OC1CCc2cc(Br)ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.8 %

Procedure:
To a solution of 5-bromo-1-indanone (2.0 g, 9.5 mmol) in THF (20 mL) was added NaBH4 (0.5 g, 12.8 mmol). After stirring at room temperature overnight, the solution was quenched by addition of water. The resulting solution was extracted with EtOAc twice. The combined EtOAc layers were dried over Na2SO4 and concentrated under vacuum to give 2.0 g of the title compound as a solid. MS calculated for C9H9BrO: (M+H)+ 212.9. found 194.9 (M+H—H2O)+, 197.0 (M+H—H2O)+.
Reaction SMILES: C1CCC(N=C=NC2CCCCC2)CC1.[OH:16][N:17]1[C:21](=[O:22])[CH2:20][CH2:19][C:18]1=[O:23].[CH3:24][C:25]1[CH:30]=[CH:29][N:28]=[C:27]([C:31]2[CH:36]=[C:35]([CH2:37][CH2:38][CH2:39][C:40](O)=[O:41])[CH:34]=[CH:33][N:32]=2)[CH:26]=1>ClCCl>[C:21]1(=[O:22])[N:17]([O:16][C:40](=[O:41])[CH2:39][CH2:38][CH2:37][C:35]2[CH:34]=[CH:33][N:32]=[C:31]([C:27]3[CH:26]=[C:25]([CH3:24])[CH:30]=[CH:29][N:28]=3)[CH:36]=2)[C:18](=[O:23])[CH2:19][CH2:20]1
Reactant: O=C1CCC(=O)N1O
Reactant: Cc1ccnc(-c2cc(CCCC(=O)O)ccn2)c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: Cc1ccnc(-c2cc(CCCC(=O)ON3C(=O)CCC3=O)ccn2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
More specifically, with reference to the reaction scheme I ,4-(4′-methyl-[2,2′]bipyridinyl-4-yl)-butyric acid succinimidyl ester was obtained according to step (5) as follows. 27 mg of DCC (0.129 mmol) and 14 mg N-hydroxysuccinimide (0.129 mmol) were added to 30 mg (0.117 mmol) of 4-(4′-methyl-[2,2′]bipyridinyl-4-yl)-butyric acid (prepared as schematically illustrated by steps (1)-(4) of the reaction scheme I, according to the published procedure in Della Ciana et al., JOC 1989, 54, 1731-1725) in dichloromethane and stirred at room temperature for 2 hours. After 2 hours, the reaction mixture was filtered and concentrated in vacuo. The pure final 4-(4′-methyl-[2,2′]bipyridinyl-4-yl)-butyric acid succinimidyl ester was obtained as a clear oil after column chromatography (SiO2, EtOAc, Hex). 1H NMR: 8.55 (dd, 4H), 8.26 (d, 2H), 7.21 (d, 2H), 2.86 (m, 6H), 2.68 (t, 2H), 2.46 (s, 3H), 2.171 (t, 2H). ESI-MS: m/z=354.