Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH2:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.I[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[N+:17]([O-:19])=[O:18]>>[N+:17]([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[NH:9][C:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)([O-:19])=[O:18]
Reactant: NC(=O)c1ccccc1
Reactant: O=[N+]([O-])c1ccccc1I
Product: O=C(Nc1ccccc1[N+](=O)[O-])c1ccccc1
Yield: 70.3 %

Procedure:
Using general procedure A, benzamide (150 mg, 1.24 mmol) was coupled with 1-iodo-2-nitrobenzene (260 mg, 1.04 mmol). The crude product was purified by flash chromatography on silica gel (2×15 cm; hexane-ethyl acetate 8:1; 15 mL fractions). Fractions 8-14 provided 177 mg (70% yield) of the product as bright yellow needles. The 1H NMR spectrum was in accord with that reported by Murphy et al. Murphy, J. A.; Rasheed, F.; Gastaldi, S.; Ravishanker, T.; Lewis, N. J. Chem. Soc., Perkin Trans 1 1997, 1549.
Reaction SMILES: [H-].[Na+].[CH3:3][CH:4]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:5]([O:7][CH2:8][CH3:9])=[O:6].[Cl:15][C:16]1[N:17]=[N:18][C:19](Cl)=[CH:20][CH:21]=1>O1CCOCC1>[Cl:15][C:16]1[N:17]=[N:18][C:19]([C:4]([CH3:3])([C:5]([O:7][CH2:8][CH3:9])=[O:6])[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:20][CH:21]=1
Reactant: CCOC(=O)C(C)C(=O)OCC
Reactant: Clc1ccc(Cl)nn1
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CCOC(=O)C(C)(C(=O)OCC)c1ccc(Cl)nn1
Temperature: 0 °C
Reaction time: 1 h
Yield: 24.9 %

Procedure:
To a mixture of NaH (13.42 g, 336 mmol) in dioxane (800 mL) was added diethyl 2-methylmalonate (42.9 ml, 252 mmol) drop-wise at 0° C. The reaction was stirred at 0° C. for 1 hr and allowed to warm to ambient temperature. 3,6-dichloropyridazine (25 g, 168 mmol) was then added portion-wise at 25° C. The reaction was then stirred at reflux for 1 hr. Solvent was removed via rotary evaporation and the resulting residue was dissolved in EtOAc. The organic solution was washed with saturated NaHCO3 (100 mL) followed by 5% citric acid. The organic layer was then dried with MgSO4, filtered, and concentrated to dryness. The resulting residue was purified via MPLC (Hex:EtOAc, 3:1) to provide the title compound, diethyl 2-(6-chloropyridazin-3-yl)-2-methylmalonate 48A (12 g, 25% yield) as a yellow oil. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.18 (s, 6 H) 1.81 (s, 3H) 4.21 (dd, J=7.07, 2.27 Hz, 4 H) 8.00 (s, 2 H). ESI-MS:m/z 287.1 (M+H)+.
Reaction SMILES: [CH:1]([C:3]1[C:12]([CH3:13])=[C:11]([CH3:14])[C:10]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:26]=[CH:25][N:24]([CH3:27])[N:23]=3)=[CH:18][CH:17]=2)=[CH:9][C:4]=1[C:5](OC)=[O:6])=O.Cl.[NH2:29][C@H:30]1[CH2:34][CH2:33][CH2:32][C@@H:31]1[OH:35].C(N(CC)CC)C.S([O-])([O-])(=O)=O.[Mg+2]>C1COCC1>[OH:35][C@H:31]1[CH2:32][CH2:33][CH2:34][C@@H:30]1[N:29]1[CH2:1][C:3]2[C:4](=[CH:9][C:10]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]4[CH:26]=[CH:25][N:24]([CH3:27])[N:23]=4)=[CH:18][CH:17]=3)=[C:11]([CH3:14])[C:12]=2[CH3:13])[C:5]1=[O:6]
Reactant: COC(=O)c1cc(Cc2ccc(-c3ccn(C)n3)cc2)c(C)c(C)c1C=O
Reactant: N[C@H]1CCC[C@@H]1O
Agent: Cl
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1c(Cc2ccc(-c3ccn(C)n3)cc2)cc2c(c1C)CN([C@H]1CCC[C@@H]1O)C2=O
Temperature: 25 °C
Reaction time: 7.5 h
Yield: 44.2 %

Procedure:
A solution of methyl 2-formyl-3,4-dimethyl-5-(4-(1-methyl-1H-pyrazol-3-yl)benzyl)benzoate (0.09 g), (1S,2S)-2-aminocyclopentanol hydrochloride (0.03 g), triethylamine (0.03 mL) and anhydrous magnesium sulfate (0.06 g) in THF (1.80 mL) was stirred at room temperature for 46 hr under nitrogen atmosphere. The insoluble substance was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was diluted with methanol (1.80 mL) and THF (1.80 mL), sodium triacetoxyborohydride (0.10 g) was added thereto, and the mixture was stirred at room temperature for 7.5 hr. The reaction mixture was diluted with ethyl acetate, and the mixture was washed with water and saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (0.04 g).
Reaction SMILES: [C:1]([C:3]1[C:4]2[S:12][C:11]([C:13]3[CH:18]=[CH:17][C:16]([C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:15][CH:14]=3)=[CH:10][C:5]=2[C:6](=O)[NH:7][CH:8]=1)#[N:2].P(Cl)(Cl)([Cl:25])=O>>[Cl:25][C:6]1[C:5]2[CH:10]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:15][CH:14]=3)[S:12][C:4]=2[C:3]([C:1]#[N:2])=[CH:8][N:7]=1
Reactant: CC(C)(C)c1ccc(-c2cc3c(=O)[nH]cc(C#N)c3s2)cc1
Reactant: O=P(Cl)(Cl)Cl
Product: CC(C)(C)c1ccc(-c2cc3c(Cl)ncc(C#N)c3s2)cc1
Reaction time: 1 h

Procedure:
7-Cyano-2-(4′-t-butylphenyl)-4-oxo-4,5-dihydrothieno[3,2-c]-pyridine was dissolved in phosphorus oxychloride (25 mL) and the resulting solution heated at reflux for 2 h. After this time the mixture was poured into ice and stirred for 1 h. The precipitated solid was filtered and washed with water, drying by suction in air at room temperature affording 1.05 g of 101.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14](=[O:23])[CH2:15][C:16]([CH3:22])([CH3:21])[C:17]([O:19]C)=[O:18])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[CH3:24][C:25]1[C:30]2[N:31]=[C:32](S(C)(=O)=O)[O:33][C:29]=2[CH:28]=[CH:27][CH:26]=1.[OH-].[Na+].Cl>ClC(Cl)C.CO>[CH3:21][C:16]([CH3:22])([CH2:15][C:14]([C:11]1[CH:12]=[CH:13][C:8]([C:5]2[CH:4]=[CH:3][C:2]([NH:1][C:32]3[O:33][C:29]4[CH:28]=[CH:27][CH:26]=[C:25]([CH3:24])[C:30]=4[N:31]=3)=[CH:7][CH:6]=2)=[CH:9][CH:10]=1)=[O:23])[C:17]([OH:19])=[O:18]
Reactant: Cc1cccc2oc(S(C)(=O)=O)nc12
Reactant: COC(=O)C(C)(C)CC(=O)c1ccc(-c2ccc(N)cc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(Cl)Cl
Solvent: CO
Product: Cc1cccc2oc(Nc3ccc(-c4ccc(C(=O)CC(C)(C)C(=O)O)cc4)cc3)nc12
Temperature: 85 °C
Yield: 31.7 %

Procedure:
To a solution of methyl 4-(4′-amino-1,1′-biphenyl-4-yl)-2,2-dimethyl-4-oxobutanoate (74 mg, 0.24 mmol) in dichloroethane (3 mL), 4-methyl-2-(methylsulfonyl)-1,3-benzoxazole (50 mg, 0.24 mmol) was added, and the mixture was heated at 85° C. overnight. The solvent was removed by rotary evaporation and the residue was redissolved in DMF (5 mL). A solution of 1 N aqueous NaOH (0.72 mL, 0.72 mmol) was added, and the mixture was heated at 65° C. overnight. A solution of 1 N aqueous HCl (0.24 mL, 0.24 mmol) and methanol (5 mL) was added to the reaction mixture and the crude product was purified by preparative reverse-phase HPLC (water/acetonitrile gradient, containing 0.1% TFA) to afford 2,2-dimethyl-4-{4′-[(4-methyl-1,3-benzoxazol-2-yl)amino]-1,1′-biphenyl-4-yl}-4-oxobutanoic acid as a white solid (32.6 mg, 32.1%). 1H NMR (300 MHz, DMSO-d6) δ 8.00-7.80 (m, 8 H), 7.30 (d, 1 H), 7.05 (d, 2 H), 3.30 (s, 2 H), 2.50 (s, 3 H), 1.10 (s, 6 H); LC-MS ret. time 3.77 min (method 2), m/z 429.2 (MH+).
Reaction SMILES: [CH:1](=[O:3])[CH3:2].[F:4][CH:5]([N+:9]([O-:11])=[O:10])[N+:6]([O-:8])=[O:7].S(=O)(=O)(O)O>C(=O)(O)[O-].[Na+].O>[F:4][C:5]([N+:9]([O-:11])=[O:10])([N+:6]([O-:8])=[O:7])[CH:1]([OH:3])[CH3:2]
Reactant: CC=O
Reactant: O=[N+]([O-])C(F)[N+](=O)[O-]
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: CC(O)C(F)([N+](=O)[O-])[N+](=O)[O-]

Procedure:
"1-fluoro-1,1-dinitropropanol-2. A 38% aqueous solution of acetaldehyde, 5.2 g, was added to a well-stirred and cooled mixture of 3.7 g of fluorodinitromethane and 5 ml of water. A few drops of saturated sodium bicarbonate solution was added and the mixture stirred with continued cooling for 1 hr. It was then acidified with dilute sulfuric acid, the product extracted into methylene chloride, and the extract dried and distilled. Obtained was 4 g (79%), bp 40°-42° (0.5 mm)."
Reaction SMILES: ClC1C=CC(C2C=CN3C(=O)[NH:15][N:16]=[C:10]3[C:9]=2[C:18]2C=CN=CC=2)=CC=1.[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]2[CH:36]=[CH:35][N:34]3[C:37](=[O:51])[N:38]([CH2:40][C:41]4[CH:46]=[CH:45][C:44](S(C)(=O)=O)=[CH:43][CH:42]=4)[N:39]=[C:33]3[C:32]=2[C:52]2[CH:57]=[CH:56][N:55]=[CH:54][CH:53]=2)=[CH:27][CH:26]=1>>[N:16]1([C:44]2[CH:45]=[CH:46][C:41]([CH2:40][N:38]3[C:37](=[O:51])[N:34]4[CH:35]=[CH:36][C:31]([C:28]5[CH:29]=[CH:30][C:25]([Cl:24])=[CH:26][CH:27]=5)=[C:32]([C:52]5[CH:57]=[CH:56][N:55]=[CH:54][CH:53]=5)[C:33]4=[N:39]3)=[CH:42][CH:43]=2)[CH:10]=[CH:9][CH:18]=[N:15]1
Reactant: CS(=O)(=O)c1ccc(Cn2nc3c(-c4ccncc4)c(-c4ccc(Cl)cc4)ccn3c2=O)cc1
Reactant: O=c1[nH]nc2c(-c3ccncc3)c(-c3ccc(Cl)cc3)ccn12
Product: O=c1n(Cc2ccc(-n3cccn3)cc2)nc2c(-c3ccncc3)c(-c3ccc(Cl)cc3)ccn12

Procedure:
The title compound was prepared by coupling 7-(4-chlorophenyl)-8-(pyridin-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one with the requisite benzyl halide in a manner analogous to that in which 7-(4-chlorophenyl)-2-(4-(methylsufonyl)benzyl)-8-(pyridin-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one was prepared. HPLC/MS: retention time=2.72 min, [M+H]+=479.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]([CH3:11])([CH3:10])[CH3:9])[C:5]([OH:12])=[CH:4][C:3]=1[CH2:13][C:14](Cl)=[O:15].C1(C)C=CC=CC=1.[CH2:24]([OH:36])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35].Cl>N1C=CC=CC=1>[CH3:1][C:2]1[CH:7]=[C:6]([C:8]([CH3:11])([CH3:9])[CH3:10])[C:5]([OH:12])=[CH:4][C:3]=1[CH2:13][C:14]([O:36][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])=[O:15]
Reactant: CCCCCCCCCCCCO
Reactant: Cc1cc(C(C)(C)C)c(O)cc1CC(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCCOC(=O)Cc1cc(O)c(C(C)(C)C)cc1C
Reaction time: 8 h
Yield: 84.9 %

Procedure:
Into a 500-ml four-necked flask, were charged 24.1 g of 2-methyl-4-t-butyl-5-hydroxyphenylacetyl chloride, 300 ml of toluene and 50 ml of pyridine. After replacing air in the reactor by nitrogen, 18.7 g of dodecyl alcohol was added to the mixture at 30° to 40° C., and then the reaction was continued at 30° to 40° C. for about 8 hours. After completion of the reaction, pyridine was neutralized with diluted hydrochloric acid, and the reaction mixture was washed with water, dried over anhydrons sodium sulfate and then freed from the solvent under reduced pressure to obtain 33.2 g (85% yield) of viscous dodecyl 2-methyl-4-t-butyl-5-hydroxyphenylacetate.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[NH2:1][C:2]1[C:3]([CH2:4][OH:5])=[CH:7][CH:8]=[CH:9][N:10]=1
Reactant: Nc1ncccc1C(=O)O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Nc1ncccc1CO
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 82.9 %

Procedure:
To a solution of 2-aminonicotinic acid (20.5 g, 148.1 mmole) in THF was added lithium aluminum hydride (300 mL, 1.0 M in THF) over 30 minutes. The reaction solution was heated to reflux for 18 hrs and then was cooled to room temperature. The reaction was quenched by the sequential dropwise addition of H2O (11.5 mL), 15% NaOH (11.5 mL), and H2O (34.5 mL). The mixture was stirred for 15 min, then was filtered through celite®, and the filter pad was washed thoroughly with THF followed by 5% CH3OH/CHCl3. The filtrate was concentrated to give the title compound (15.24 g, 83%) as a waxy light yellow solid: MS (ES) m/e 125 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([CH3:8])[C:4]([CH3:12])([CH2:9][CH2:10][NH2:11])[CH:3]1[CH3:13].Br[CH2:15][CH2:16][CH2:17][CH2:18]Br.C(=O)([O-])[O-].[K+].[K+]>C(#N)C.CCOCC>[CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([CH3:8])[C:4]([CH3:12])([CH2:9][CH2:10][N:11]2[CH2:18][CH2:17][CH2:16][CH2:15]2)[CH:3]1[CH3:13]
Reactant: CC1CCN(C)C(C)C1(C)CCN
Reactant: BrCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CC#N
Product: CC1CCN(C)C(C)C1(C)CCN1CCCC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 45.9 %

Procedure:
A solution of 1,2,3,4-tetramethyl-3-piperidineethanamine (9.8 g, 53 mmol) in acetonitrile (50 mL) was added dropwise over about 2 hours to a suspension of 1,4-dibromobutane (6.6 mL, 55.7 mmol) and potassium carbonate (26 g, 200 mmol) in acetonitrile (250 mL). The reaction mixture was stirred at room temperature for 24 hours, diluted with ether and the inorganic salts were removed by filtration. The solvent was removed in vacuo and the oily residue was purified by column chromatography on silica gel eluting with 2% isopropylamine/hexanes to afford 5.8 g (46%) of 1,2,3,4-tetramethyl-3-[2-(1-pyrrolidinyl)ethyl]piperidine. The product was dissolved in ether (25 mL) and treated with 6.5N ethereal HCl (10 mL) at 0° C. The mixture was warmed to room temperature, diluted with ether (10 mL) and cooled back to 0° C. to precipitate the dihydrochloride salt. The salt (4.3 g) was isolated as a white solid and had a melting point of 225°-227° C. (dec.) when recrystallized from ether (35 mL).
Reaction SMILES: [CH3:1][C:2]1([CH3:24])[C:11]2[C:6](=[C:7]([CH3:22])[CH:8]=[C:9]([NH:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[N+:19]([O-])=O)[CH:10]=2)[NH:5][C:4](=[O:23])[CH2:3]1.[H][H].C>>[CH3:1][C:2]1([CH3:24])[C:11]2[C:6](=[C:7]([CH3:22])[CH:8]=[C:9]([NH:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[NH2:19])[CH:10]=2)[NH:5][C:4](=[O:23])[CH2:3]1
Reactant: Cc1cc(Nc2ccccc2[N+](=O)[O-])cc2c1NC(=O)CC2(C)C
Reactant: [H][H]
Product: Cc1cc(Nc2ccccc2N)cc2c1NC(=O)CC2(C)C

Procedure:
This compound, m.p. 90°, was prepared similarly to Preparation 17 using 3,4-dihydro-4,4,8-trimethyl-6-[(N-2-nitrophenyl)-amino]-2-(1H)-quinolone hydrogen and palladised charcoal as starting materials. The product was characterised spectroscopically and used directly in Example 14.
Reaction SMILES: Cl[C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1.[F:16][C:17]1[CH:31]=[C:30]2[C:20]([NH:21][CH:22]=[C:23]2[CH2:24][CH:25]([C:27]([OH:29])=[O:28])[NH2:26])=[CH:19][CH:18]=1>>[C:27]([CH:25]([NH:26][C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1)[CH2:24][C:23]1[C:30]2[C:20](=[CH:19][CH:18]=[C:17]([F:16])[CH:31]=2)[NH:21][CH:22]=1)([OH:29])=[O:28]
Reactant: O=C(O)c1cc2cc(Cl)ccc2nc1Cl
Reactant: NC(Cc1c[nH]c2ccc(F)cc12)C(=O)O
Product: O=C(O)c1cc2cc(Cl)ccc2nc1NC(Cc1c[nH]c2ccc(F)cc12)C(=O)O
Yield: 90 %

Procedure:
In close analogy to the procedure described in Example 1, 2,6-dichloroquinoline-3-carboxylic acid is reacted with 5-fluoro-DL-tryptophan to provide the title compound in 90% yield as yellow needles (recrystallization from DMF/water).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[N:6][C:7]([CH2:11][OH:12])=[CH:8][CH:9]=2)[N:4]=[C:3]1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]#[N:22])=[CH:17][CH:16]=1>ClCCl.[O-2].[O-2].[Mn+4]>[CH3:1][N:2]1[C:10]2[C:5](=[N:6][C:7]([CH:11]=[O:12])=[CH:8][CH:9]=2)[N:4]=[C:3]1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]#[N:22])=[CH:17][CH:16]=1
Reactant: Cn1c(COc2ccc(C#N)cc2)nc2nc(CO)ccc21
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: Cn1c(COc2ccc(C#N)cc2)nc2nc(C=O)ccc21
Reaction time: 96 h

Procedure:
3.65 g (12.5 mmol) of 1-methyl-2-[(4-cyanophenyl)oxymethyl]-5-hydroxymethylimidazo[4,5-b]pyridine were dissolved in 500 mL of dichloromethane and mixed with 15.0 g of manganese dioxide. After 96 hours at room temperature, the mixture was filtered through kieselguhr and the solvent was distilled off. The filtrate obtained was evaporated down, the crystalline precipitate was triturated with ether, suction filtered, and dried. Yield: 3.05 g white powder (84% of theory), C16H12N4O2 (292.30); melting point: 231° C.-234° C.
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([CH2:11][CH2:12][C:13]3[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[C:15]([O:21][CH3:22])[CH:14]=3)[N:9]=2)[NH:4][C:3]=1[C:23]1[CH:28]=[CH:27][C:26]([N:29]2[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]2)=[CH:25][CH:24]=1.[CH3:36][Zn]C>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:22][O:21][C:15]1[CH:14]=[C:13]([CH2:12][CH2:11][C:8]2[N:9]=[C:10]3[C:2]([CH3:36])=[C:3]([C:23]4[CH:28]=[CH:27][C:26]([N:29]5[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]5)=[CH:25][CH:24]=4)[NH:4][C:5]3=[N:6][CH:7]=2)[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=1
Reactant: COc1cc(CCc2cnc3[nH]c(-c4ccc(N5CCN(C)CC5)cc4)c(Br)c3n2)cc(OC)c1
Reactant: C[Zn]C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: C1COCCO1
Product: COc1cc(CCc2cnc3[nH]c(-c4ccc(N5CCN(C)CC5)cc4)c(C)c3n2)cc(OC)c1
Temperature: 90 °C
Reaction time: 4 h
Yield: 23.9 %

Procedure:
To a stirred solution of 7-bromo-2-[2-(3,5-dimethoxyphenyl)ethyl]-6-[4-(4-methylpiperazin-1-yl)phenyl]-5H-pyrrolo[2,3-b]pyrazine (from Example 46, 20.0 mg, 37.3 μmol) and Pd(dppf)Cl2 (2.7 mg, 3.7 μmol) in 1,4-dioxane (0.8 mL), dimethylzinc (2.0 M in toluene, 47 μL, 94.0 μmol) was added at ambient temperature. The reaction mixture was then warmed up to 90° C. After 4 hours, the volatiles were removed and the residue was purified on RP-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.05% TFA, at flow rate of 30 mL/min) to give the desired product (4.2 mg) as its TFA salt. LCMS calculated for C28H34N5O2 (M+H)+: m/z=472.2. Found: 472.2.
Reaction SMILES: [Br:1][C:2]1[CH:20]=[CH:19][C:5]([CH2:6][NH:7][CH2:8][C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])=[CH:4][CH:3]=1.[C:21](OC(=O)C)(=[O:23])[CH3:22]>C(Cl)Cl>[Br:1][C:2]1[CH:20]=[CH:19][C:5]([CH2:6][N:7]([CH2:8][C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[C:21](=[O:23])[CH3:22])=[CH:4][CH:3]=1
Reactant: O=C(CNCc1ccc(Br)cc1)OCc1ccccc1
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Product: CC(=O)N(CC(=O)OCc1ccccc1)Cc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.2 %

Procedure:
To a solution of 80A (500 mg, 1.50 mmol) in 5 mL CH2Cl2, were added TEA (0.229 mL, 1.65 mmol) and acetic anhydride (0.156 mL, 1.65 mmol). The mixture was stirred at rt for 2 h, then concentrated. The crude product was purified via flash chromatography (0 to 100% EtOAc in hexanes) to afford 80B (560 mg, 99%). MS (ESI) m/z 376.0 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][CH:6]2[N:11]1[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([NH:19][C:20]2[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=2)=[O:18])[C:12]1=[O:26].[N:27]1[CH:32]=[CH:31][CH:30]=[C:29](B(O)O)[CH:28]=1.C(=O)([O-])[O-].[K+].[K+]>O.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>[O:26]=[C:12]1[C:13]([C:17]([NH:19][C:20]2[CH:21]=[CH:22][N:23]=[CH:24][CH:25]=2)=[O:18])=[CH:14][CH:15]=[CH:16][N:11]1[CH:6]1[C:7]2[C:3](=[C:2]([C:29]3[CH:28]=[N:27][CH:32]=[CH:31][CH:30]=3)[CH:10]=[CH:9][CH:8]=2)[CH2:4][CH2:5]1
Reactant: O=C(Nc1ccncc1)c1cccn(C2CCc3c(Br)cccc32)c1=O
Reactant: OB(O)c1cccnc1
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: O
Product: O=C(Nc1ccncc1)c1cccn(C2CCc3c(-c4cccnc4)cccc32)c1=O

Procedure:
2-oxo-1-(4-(pyridin-3-yl)-2,3-dihydro-1H-inden-1-yl)-N-(pyridin-4-yl)-1,2-dihydropyridine-3-carboxamide was prepared by heating a mixture of 1-(4-bromo-2,3-dihydro-1H-inden-1-yl)-2-oxo-N-(pyridin-4-yl)-1,2-dihydropyridine-3-carboxamide (35.1 mg, 0.0855 mmol, 1.0 eq.), pyridin-3-ylboronic acid (12.8 mg, 0.104 mmol, 1.2 eq.), Pd(PPh3)4 (5.6 mg, 0.0048 mmol, 0.056 eq.), and potassium carbonate (15.1 mg, 0.109 mmol, 1.3 eq.) in 0.80 mL of dioxanes and 0.20 mL of H2O in a microwave at 140° C. for 5 min. The crude material was filtered through celite and the filtrate was purified by reverse phase HPLC using the method of 5-35% ACN/H2O in 40 min The purified material was concentrated and dried under vacuum to give 2-oxo-1-(4-(pyridin-3-yl)-2,3-dihydro-1H-inden-1-yl)-N-(pyridin-4-yl)-1,2-dihydropyridine-3-carboxamide as a clear colorless oil. Retention time (min)=8.051, method [8], MS (ESI) 409.2 (M+H); 1H NMR (300 MHz, CDCl3) δ 9.19 (m, 1H), 8.90 (m, 1H), 8.67 (m, 2H), 8.53 (m, 2H), 8.24 (d, J=7.1 Hz, 2H), 8.06 (m, 1H), 7.53 (m, 2H), 7.32 (m, 1H), 6.71 (t, J=7.7 Hz, 1H), 6.62 (t, J=7.1 Hz, 1H), 3.20 (m, 3H), 2.95 (m 1H), 2.19 (m, 1H).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([C:7]([OH:9])=O)[CH2:3][CH2:2]1.O.ON1C2C=CC=CC=2N=N1.[CH:21]1([N:25]2[CH2:31][CH2:30][C:29]3[CH:32]=[CH:33][C:34]([O:36][C:37]4[N:42]=[CH:41][C:40]([NH2:43])=[CH:39][CH:38]=4)=[CH:35][C:28]=3[CH2:27][CH2:26]2)[CH2:24][CH2:23][CH2:22]1>ClCCl>[CH:21]1([N:25]2[CH2:26][CH2:27][C:28]3[CH:35]=[C:34]([O:36][C:37]4[N:42]=[CH:41][C:40]([NH:43][C:7]([CH:4]5[CH2:3][CH2:2][O:1][CH2:6][CH2:5]5)=[O:9])=[CH:39][CH:38]=4)[CH:33]=[CH:32][C:29]=3[CH2:30][CH2:31]2)[CH2:22][CH2:23][CH2:24]1
Reactant: O=C(O)C1CCOCC1
Reactant: Nc1ccc(Oc2ccc3c(c2)CCN(C2CCC2)CC3)nc1
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCl
Product: O=C(Nc1ccc(Oc2ccc3c(c2)CCN(C2CCC2)CC3)nc1)C1CCOCC1
Reaction time: 16 h

Procedure:
Tetrahydro-pyran-4-carboxylic acid (252 mg, 1.94 mmol), 1-hydroxy benzotriazole hydrate (262 mg, 1.94 mmol) and N-cyclohexylcarbodiimide N′-methyl polystyrene (1.7 mmol/g, 2.3 g, 3.88 mmol) were stirred at room temperature in dichloromethane (10 ml) for 15 minutes. 6-[(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-3-pyridinamine (E236) (300 mg, 0.97 mmol) was added and stirring continued for 16 hours. The reaction mixture was applied to a SCX ion exchange cartridge (Varian bond-elute, 5 g) and washed with methanol and then a mixture of 0.880 ammonia/methanol. The combined basic fractions were concentrated in vacuo and the resulting residue was purified by column chromatography eluting with a mixture of 0.880 ammonia:methanol:dichloromethane (0.5:4.5:95) to afford the title product (E241); MS (ES+) m/e 422 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[O:9][C:10]1[C:18]2[O:17][C:16]([CH3:20])([CH3:19])[CH2:15][C:14]=2[CH:13]=[CH:12][CH:11]=1)[NH2:5].[F:21][C:22]1[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[C:23]=1[C:24]([N:26]=[C:27]=[O:28])=[O:25]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([NH:5][C:27]([NH:26][C:24](=[O:25])[C:23]2[C:29]([F:33])=[CH:30][CH:31]=[CH:32][C:22]=2[F:21])=[O:28])[CH:6]=[CH:7][C:8]=1[O:9][C:10]1[C:18]2[O:17][C:16]([CH3:20])([CH3:19])[CH2:15][C:14]=2[CH:13]=[CH:12][CH:11]=1
Reactant: CC1(C)Cc2cccc(Oc3ccc(N)cc3Cl)c2O1
Reactant: O=C=NC(=O)c1c(F)cccc1F
Solvent: Cc1ccccc1
Product: CC1(C)Cc2cccc(Oc3ccc(NC(=O)NC(=O)c4c(F)cccc4F)cc3Cl)c2O1
Temperature: 70 °C
Yield: 83.2 %

Procedure:
Solution containing 4.0 g (13.8 m moles) of 3-chloro-4-(2,3-dihydro-2,2-dimethyl-7-benzofuranyloxy)aniline in 45 ml of toluene was placed under an atmosphere of nitrogen and heated to 70° C. To this was added 3.79 g (20 m moles) of 2,6-difluorobenzoyl isocyanate in 5 ml of toluene via an addition funnel. The resulting mixture was heated for 45 min. and then cooled to room temperature. The mixture was further cooled below 0° C. in a freezer and then filtered. The collected solid was washed with cold toluene. This was dried under vacuum to afford 5.43 g of the desired product as a white solid, mp 171° C. NMR (DMSO-d6): δ1.40 (s, 6H), 3.05 (s, 2H), 6.3-8.0 (m, 10H), 10.20 (broad s, 1H), 11.47 (broad s, 1H).