Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([C:8]([OH:13])=[N:9][NH:10]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[Na].Br[CH2:16][C:17]1[CH:26]=[CH:25][C:20]([C:21]([O:23][CH3:24])=[O:22])=[CH:19][C:18]=1[O:27][CH3:28]>CO.CN(C)C=O.C(OCC)(=O)C>[OH:13][C:8]1[C:7]2[C:11](=[CH:12][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)[N:10]([CH2:16][C:17]2[CH:26]=[CH:25][C:20]([C:21]([O:23][CH3:24])=[O:22])=[CH:19][C:18]=2[O:27][CH3:28])[N:9]=1
Reactant: O=[N+]([O-])c1ccc2c(O)n[nH]c2c1
Reactant: COC(=O)c1ccc(CBr)c(OC)c1
Agent: [Na]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(Cn2nc(O)c3ccc([N+](=O)[O-])cc32)c(OC)c1
Temperature: 50 °C
Yield: 38.5 %

Procedure:
6-Nitroindazolol (0.206 g.) was added to a solution of sodium (0.026 g.) in methanol (1.5 ml.), and the mixture heated at 50° C. for 10 minutes. A solution of methyl 4-bromomethyl-3-methoxybenzoate (B) (0. 327 g.) in methanol (3.75 ml.) and N,N-dimethylformamide (DMF) (1.25 ml.) was added, and the mixture was refluxed for 18 hours. The cooled mixture was diluted with ethyl acetate and DMF, and washed with water and brine, then dried (MgSO4) and evaporated. The residue was triturated with 1:1 v/v ethyl acetate: ether to give methyl 4-[3-hydroxy-6-nitroindazol-1-ylmethyl]-3-methoxybenzoate (T) (0.158 g., 38%) as a yellow solid, m.p. 231°-235° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([S:13][CH3:14])=[C:11]([C:15]([O:17]C(C)(C)C)=[O:16])[N:10]=[C:9]2[C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=2[Cl:29])=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([S:13][CH3:14])=[C:11]([C:15]([OH:17])=[O:16])[N:10]=[C:9]2[C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=2[Cl:29])=[CH:4][CH:3]=1
Reactant: CSc1c(C(=O)OC(C)(C)C)nc(-c2ccc(Cl)cc2Cl)n1-c1ccc(Cl)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CSc1c(C(=O)O)nc(-c2ccc(Cl)cc2Cl)n1-c1ccc(Cl)cc1
Yield: 98 %

Procedure:
To a magnetically stirred solution of tert-butyl 1-(4-chlorophenyl)-2-(2,4-dichlorophenyl)-5-methylsulfanyl-1H-imidazole-4-carboxylate (4.00 g, 8.53 mmol) in CH2Cl2 (60 ml) was added excess TFA (8.40 ml, 0.111 mol). The solution was reacted at room temperature for 16 hours and subsequently concentrated in vacuo. Water was added and the formed precipitate was collected by filtration and subsequently dried to give 1-(4-chlorophenyl)-2-(2,4-dichlorophenyl)-5-methylsulfanyl-1H-imidazole-4-carboxylic acid in 98% yield, mp˜100° C. (decomposition); 1H-NMR (400 MHz, CDCl3) δ 2.41 (s, 3H), 3.60 (br s, 1H), 7.08 (br d, J˜8 Hz, 2H), 7.26 (dd, J=8 and 2 Hz, 1H), 7.30 (d, J=8 Hz, 1H), 7.35 (d, J=2 Hz, 1H), 7.37 (br d, J˜8 Hz, 2H).
Reaction SMILES: Cl.[Br:2][C:3]1[C:11]([CH3:12])=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[C:5]([NH:13]N)[CH:4]=1.O=[C:16]1[CH2:21][CH2:20][CH2:19][CH:18]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:17]1.C(O)(=O)C>C1(C)C=CC=CC=1>[Br:2][C:3]1[C:11]([CH3:12])=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[C:5]2[C:4]=1[C:21]1[CH2:20][CH2:19][CH:18]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:17][C:16]=1[NH:13]2
Reactant: CCOC(=O)C1CCCC(=O)C1
Reactant: Cc1cc(C(=O)O)c(NN)cc1Br
Agent: Cl
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: CCOC(=O)C1CCc2c([nH]c3c(C(=O)O)cc(C)c(Br)c23)C1
Temperature: 117 °C
Yield: 54.6 %

Procedure:
A mixture of 4-bromo-2-hydrazinyl-5-methylbenzoic acid hydrochloride (2.17 g, 7.71 mmol), ethyl 3-oxocyclohexanecarboxylate (1.44 g, 8.48 mmol) and acetic acid (1.32 mL, 23.1 mmol) in toluene (40 mL) was heated in an oil bath at 117° C. for 5 h. The mixture was concentrated and dried under vacuum, and the residue was diluted with toluene (18 mL) and TFA (4.5 mL). The mixture was heated at 90° C. overnight. The cooled mixture was diluted with EtOAc, sonicated, and the precipitate was collected by filtration and washed with EtOAc to give a yellow solid. The filtrate was concentrated and the residue was suspended in EtOAc with sonication. The precipitate was collected by filtration and combined with the first precipitate. The solid was triturated with MeOH to give 5-bromo-2-(ethoxycarbonyl)-6-methyl-2,3,4,9-tetrahydro-1H-carbazole-8-carboxylic acid as a pale yellow solid (1.60 g, 55% yield). Mass spectrum m/z 380, 382 (M+H)+.
Reaction SMILES: [CH2:1]([Zn]CC)C.ICI.[CH2:9]([O:16][C:17]([N:19]1[CH2:24][CH:23]=[C:22]([CH2:25][CH2:26][OH:27])[CH2:21][CH2:20]1)=[O:18])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[Cl-].[NH4+].Cl>ClC(Cl)C>[CH2:9]([O:16][C:17]([N:19]1[CH2:20][CH2:21][C:22]2([CH2:25][CH2:26][OH:27])[CH:23]([CH2:1]2)[CH2:24]1)=[O:18])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=C(OCc1ccccc1)N1CC=C(CCO)CC1
Reactant: CC[Zn]CC
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: ICI
Solvent: CC(Cl)Cl
Product: O=C(OCc1ccccc1)N1CCC2(CCO)CC2C1
Temperature: 25 °C
Reaction time: 144 h

Procedure:
Under ice-cooling, 75 ml of diethylzinc and 33.5 g of diiodomethane were added to 500 ml of dichloroethane. After further adding a solution of 6.53 g of 2-[1-(benzyloxycarbonyl)-1,2,3,6-tetrahydropyridin-4-yl]ethanol in dichloroethane (20 ml), the resulting mixture was stirred at room temperature for 6 days. Then the reaction mixture was poured into a mixture of saturated ammonium chloride with 1 N hydrochloric acid, washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate followed by filtration. After distilling off the solvent under reduced pressure, the obtained residue was purified by silica gel column chromatography (eluted with n-hexane/ethyl acetate) to thereby give 1.22 g of the title compound as an oily substance.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl.[CH3:54][O:55][C:56](=[O:65])[CH2:57][CH2:58][CH:59]1[CH2:64][CH2:63][NH:62][CH2:61][CH2:60]1.Br[C:67]1[CH:72]=[CH:71][C:70]([C:73]([F:76])([F:75])[F:74])=[CH:69][CH:68]=1>O1CCOCC1.C(OCC)(=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:54][O:55][C:56](=[O:65])[CH2:57][CH2:58][CH:59]1[CH2:64][CH2:63][N:62]([C:67]2[CH:72]=[CH:71][C:70]([C:73]([F:76])([F:75])[F:74])=[CH:69][CH:68]=2)[CH2:61][CH2:60]1
Reactant: COC(=O)CCC1CCNCC1
Reactant: FC(F)(F)c1ccc(Br)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: COC(=O)CCC1CCN(c2ccc(C(F)(F)F)cc2)CC1
Reaction time: 0.42 h
Yield: 76 %

Procedure:
A mixture of palladium (II) acetate (63 mg; 0.28 mmol), (±)-2,2′-bis-diphenylphosphanyl-[1,1′]binaphthalenyl (258 mg; 0.41 mmol) and cesium carbonate (1.30 g; 4.00 mmol) in dioxane (3 mL) is placed in an ultrasonic bath for 25 minutes. 3-Piperidin-4-yl-propionic acid methyl ester hydrochloride (415 mg; 2.0 mmol, prepared in accordance with Example 138) and 1-bromo-4-trifluoromethyl-benzene (443 mg; 2.00 mmol) are then added and the reaction mixture is stirred for 2 hours under reflux. New catalyst solution [prepared as above from palladium (II) acetate (63 mg; 0.28 mmol), (±)-2,2′-bis-diphenylphosphanyl-[1,1′]binaphthalenyl (258 mg; 0.41 mmol), cesium carbonate (1.30 g; 4.00 mmol) and dioxane (3 mL)] is prepared with the aid of an ultrasonic bath and added to the reaction mixture. After stiffing under reflux for 3 hours, the mixture is diluted with ethyl acetate and is filtered. The filtrate is concentrated under high vacuum and the obtained residue is purified by column chromatography on silica gel (hexanes/dichloromethane 50:50 v/v to 100) to afford the desired compound (480 mg; 1.52 mmol).
Reaction SMILES: C([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([Br:9])[N:4]=1)=O.[CH:10]([C:13]1[CH:19]=[CH:18][CH:17]=[C:16]([CH:20]([CH3:22])[CH3:21])[C:14]=1[NH2:15])([CH3:12])[CH3:11].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[Br:9][C:5]1[NH:4][C:3](=[N:15][C:14]2[C:16]([CH:20]([CH3:21])[CH3:22])=[CH:17][CH:18]=[CH:19][C:13]=2[CH:10]([CH3:12])[CH3:11])[CH:8]=[CH:7][CH:6]=1
Reactant: O=Cc1cccc(Br)n1
Reactant: CC(C)c1cccc(C(C)C)c1N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CC(C)c1cccc(C(C)C)c1N=c1cccc(Br)[nH]1
Temperature: 70 °C

Procedure:
A dry, 500 mL 3-neck round bottom flask is charged with a solution of 2-formyl-6-bromopyridine (72.1 g, 383 mmol) and 2,6-diisopropylaniline (72.5 g, 383 mmol) in 500 mL of anhydrous toluene containing 0.3 nm molecular sieves (6 g) and 80 mg of p-toluene sulfonic acid. The reactor is equipped with a condenser, an overhead mechanical stirrer and a thermocouple well. The mixture is heated to 70° C. under N2 for 12 h. After filtration and removal of the volatiles under reduced pressure, a brown oil is isolated. Yield is 109 g, 81.9 percent.
Reaction SMILES: [C:1]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[O-]CC.[Na+].[C:16]([O:20][C:21]([N:23]1[CH2:28][CH2:27][CH:26]([CH2:29]OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:25][CH2:24]1)=[O:22])([CH3:19])([CH3:18])[CH3:17]>C(O)C>[C:16]([O:20][C:21]([N:23]1[CH2:28][CH2:27][CH:26]([CH2:29][CH:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[C:1]([O:9][CH2:10][CH3:11])=[O:8])[CH2:25][CH2:24]1)=[O:22])([CH3:19])([CH3:17])[CH3:18]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: Cc1ccc(S(=O)(=O)OCC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C(CC1CCN(C(=O)OC(C)(C)C)CC1)C(=O)OCC
Yield: 69.2 %

Procedure:
Diethyl malonate (10.4 g, 65 mmol) was added to a solution of sodium ethoxide (4.42 g, 65 mmol) in ethanol (75 mL). 1-(tert-Butoxycarbonyl)-4-[(p-toluenesulfonyloxy)methyl]piperidine (25 g, 68 mmol), prepared as in Example 1, Step (a), was added and the mixture was heated at reflux for 4 hours. The mixture was cooled and partitioned between ethyl acetate and water. The ethyl acetate layer was separated, washed with water and then brine, dried over sodium sulfate, and evaporated. Purification of the residue by silica gel chromatography (25% ethyl acetate-hexane) gave 1-(tert-butoxycarbonyl)-4-[2,2-di(ethoxycarbonyl)ethyl]piperidine (16 g, 45 mmol) as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]([CH2:13][OH:14])([CH2:11]O)[CH2:9][OH:10])[CH:5]=[CH:6][CH:7]=1.C(=O)(OCC)OCC.[OH-].[K+]>CCO>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2([CH2:9][OH:10])[CH2:11][O:14][CH2:13]2)[CH:5]=[CH:6][CH:7]=1
Reactant: OCC(CO)(CO)c1cccc(Cl)c1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: CCOC(=O)OCC
Product: OCC1(c2cccc(Cl)c2)COC1
Temperature: 190 °C

Procedure:
A mixture of Example 86C (1.1 g, 5.10 mmol), diethyl carbonate (722 mg, 6.10 mmol), and KOH (15 mg) was heated at 80° C., allowing the mixture to become homogeneous. The mixture was then heated at 95° C. for 4 hours during which time EtOH distilled off from the mixture. Distillation was continued until the pot temperature was 190° C., and then the pressure was reduced to 50 mm, maintaining the pot temperature at 190° C. for 1 hour. The residue was purified by Prep-TLC (eluted with petroleum ether:ethyl acetate=1:1).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.[Cl-].[F:13][C:14]([F:24])([F:23])[C:15]1[CH:22]=[CH:21][C:18]([CH2:19][Zn+])=[CH:17][CH:16]=1.C(Cl)Cl>C1COCC1>[F:13][C:14]([F:23])([F:24])[C:15]1[CH:22]=[CH:21][C:18]([CH2:19][C:2]2[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=2)=[CH:17][CH:16]=1
Reactant: COC(=O)c1ccc(Br)cc1
Reactant: FC(F)(F)c1ccc(C[Zn+])cc1
Agent: [Cl-]
Solvent: ClCCl
Solvent: C1CCOC1
Product: COC(=O)c1ccc(Cc2ccc(C(F)(F)F)cc2)cc1
Temperature: 70 °C
Yield: 54.8 %

Procedure:
Argon was bubbled through a mixture of methyl 4-bromobenzoate 42a (9.3 mmol, 2.0 g), 2 mL of THF, and 4-trifluoromethylbenzylzinc chloride (0.5 M in THF, 46.5 mmol, 93 mL) for 5 min. Pd(dffp)Cl2.CH2Cl2 (0.5 mol, 409 mg) was added and the reaction tube was capped and heated at 70° C. for 16 h. The mixture was cooled and filtered through Celite. Water was added to the filtrate and the resulting solid was filtered off. The organic solution was dried over MgSO4 and concentrated. The crude product was purified by flash chromatography (silica gel, 0-10% EtOAc in heptane) to give 1.5 g (55%) of methyl 4-(4-(trifluoromethyl)benzyl)benzoate, 42b.
Reaction SMILES: C([Li])CCC.[CH2:6]([OH:9])[CH2:7][OH:8].Br[CH2:11][CH:12]=[C:13]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[CH3:27])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH3:20]>O>[CH3:27][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[C:13]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH3:20])=[CH:12][CH2:11][O:8][CH2:7][CH2:6][OH:9]
Reactant: Cc1ccccc1C(=CCBr)c1ccccc1C
Reactant: OCCO
Agent: [Li]CCCC
Solvent: O
Product: Cc1ccccc1C(=CCOCCO)c1ccccc1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 30 %

Procedure:
A solution of n-butyllithium in hexanes (14 ml, 2.5 M) was added dropwise under a nitrogen atmosphere to ethylene glycol (28 ml) at 0° C. When addition was complete the mixture was stirred 0.5 h at room temperature. 3-Bromo-1,1-bis(2-methylphenyl)-1-propene (10.5 g, 35 mmol, prepared in a similar way to the method described in Example 23) was added and the reaction mixture was stirred at room temperature for 12 h and at 70° C. for 24 h. Water (100 ml) was added and the mixture was extracted with ethyl acetate (3×100 ml). The combined organic extracts were dried over magnesium sulphate and the solvent evaporated in vacuo. Flash chromatography of the residue on silica gel (250 g) using a mixture of n-heptane and ethyl acetate (10:1) as eluent provided 3.0 g (30%) of 2-(3,3-bis(2-methylphenyl)-2-propen-1-yloxy)ethanol.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[Cl:11].[N:12]1([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.C(=O)([O-])[O-].[K+].[K+]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.CS(C)=O.O>[Cl:11][C:3]1[CH:4]=[C:5]([N+:8]([O-:10])=[O:9])[CH:6]=[CH:7][C:2]=1[N:15]1[CH2:14][CH2:13][N:12]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:17][CH2:16]1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=[N+]([O-])c1ccc(Br)c(Cl)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [Br-]
Solvent: CS(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(c2ccc([N+](=O)[O-])cc2Cl)CC1
Temperature: 125 °C

Procedure:
A mixture of 1-bromo-2-chloro-4-nitrobenzene (1 g, 4.2 mmol), tert-butyl piperazine-1-carboxylate (0.86 g, 4.6 mmol), potassium carbonate (878 mg, 6.4 mmol) and tetrabutyl ammonium bromide (137 mg, 0.42 mmol) in dimethylsulfoxide (20 mL) was heated at 125° C. for 3 hours. After cooling to ambient temperature, the mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by flash chromatography on silica gel eluting with 5/1 petroleum ether/ethyl acetate to give the title compound. MS: 342 (M+H+)
Reaction SMILES: [OH:1][C:2]1[CH:15]=[C:14]([OH:16])[CH:13]=[CH:12][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5].[CH2:17]([N:21]([CH:26]1[CH2:31][C:30]([CH3:33])([CH3:32])[N:29]([O:34][CH3:35])[C:28]([CH3:37])([CH3:36])[CH2:27]1)[C:22](=[O:25])[CH2:23]Cl)[CH2:18][CH2:19][CH3:20].C(=O)([O-])[O-].[K+].[K+].[I-].[K+].Cl>C(OCC)(=O)C.CN(C)C=O>[OH:1][C:2]1[CH:15]=[C:14]([O:16][CH2:23][C:22]([N:21]([CH:26]2[CH2:31][C:30]([CH3:33])([CH3:32])[N:29]([O:34][CH3:35])[C:28]([CH3:36])([CH3:37])[CH2:27]2)[CH2:17][CH2:18][CH2:19][CH3:20])=[O:25])[CH:13]=[CH:12][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5]
Reactant: O=C(c1ccccc1)c1ccc(O)cc1O
Reactant: CCCCN(C(=O)CCl)C1CC(C)(C)N(OC)C(C)(C)C1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCCN(C(=O)COc1ccc(C(=O)c2ccccc2)c(O)c1)C1CC(C)(C)N(OC)C(C)(C)C1
Temperature: 80 °C
Yield: 23.1 %

Procedure:
A mixture of 10.1 g (47.0 mmol) of 2,4-dihydroxybenzophenone, 15.0 g (47.0 mmol) of N-butyl-N-(1-methoxy-2,2,6,6-tetramethylpiperidin-4-yl)chloroacetamide, 19.5 g (0.141 mol) of potassium carbonate, 0.8 g (4.7 mmol) of potassium iodide, and 100 ml of N,N-dimethylformamide is heated at 80° C. for 20 hours. The reaction mixture is treated with 1N hydrochloric acid (600 ml). The brown precipitate is dissolved in ethyl acetate (400 ml), and this solution is washed with water (200 ml) and saturated sodium chloride solution (200 ml), then dried over magnesium sulfate and concentrated to a glass. Purification by flash chromatography on silica gel (3:1 heptane: ethyl acetate) affords 5.4 g (23% yield) of the title compound, a yellow glass.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]([N:10]=[S:11]([CH2:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])([CH3:13])=[O:12])=[O:9])=[CH:4][C:3]=1[C:22]#[C:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([NH2:30])[CH:25]=1.[F:31][C:32]([F:43])([F:42])[C:33]1[CH:34]=[C:35]([CH:39]=[CH:40][CH:41]=1)[C:36](O)=[O:37]>>[NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]([N:10]=[S:11]([CH2:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])([CH3:13])=[O:12])=[O:9])=[CH:4][C:3]=1[C:22]#[C:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([NH:30][C:36](=[O:37])[C:35]2[CH:39]=[CH:40][CH:41]=[C:33]([C:32]([F:31])([F:42])[F:43])[CH:34]=2)[CH:25]=1
Reactant: COC(=O)CCCCS(C)(=O)=NC(=O)c1cnc(N)c(C#Cc2cccc(N)c2)c1
Reactant: O=C(O)c1cccc(C(F)(F)F)c1
Product: COC(=O)CCCCS(C)(=O)=NC(=O)c1cnc(N)c(C#Cc2cccc(NC(=O)c3cccc(C(F)(F)F)c3)c2)c1

Procedure:
In a manner similar to that described in Example 25, methyl 5-[N-({6-amino-5-[(3-aminophenyl)ethynyl]pyridin-3-yl}carbonyl)-S-methylsulfonimidoyl]pentanoate and 3-(trifluoromethyl)benzoic acid were coupled to give the title compound as a white foam (78 mg).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([OH:13])=[O:12])[CH:10]=1)[NH:7][CH:6]=[CH:5]2.[C:14](=O)([O-])[O-].[K+].[K+].CI.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C=O)C>[CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([O:13][CH3:14])=[O:12])[CH:10]=1)[NH:7][CH:6]=[CH:5]2
Reactant: Cc1cc(C(=O)O)c2[nH]ccc2c1
Reactant: O=C([O-])[O-]
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)c1cc(C)cc2cc[nH]c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 101 %

Procedure:
To 5-methyl-1H-indole-7-carboxylic acid (1.1 g), potassium carbonate (1.3 g) was added DMF (22 mL), and then methyl iodide (1.3 mL) was added thereto under ice-cooling. After stirring at room temperature overnight, the reaction mixture was adjusted to pH 3 by adding a 10% aqueous citric acid solution. The mixture was extracted with ethyl acetate, and the obtained organic layer was washed with water, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate: 95/5-85/15) to obtain methyl 5-methyl-1H-indole-7-carboxylate (1.2 g).
Reaction SMILES: [CH2:1]([N:5]1[CH2:10][CH2:9][N:8]([CH:11]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:12]([O:14]C)=[O:13])[C:7](=[O:23])[C:6]1=[O:24])[CH2:2][CH2:3][CH3:4].O.[OH-].[Li+].Cl>C1COCC1.O>[CH2:1]([N:5]1[CH2:10][CH2:9][N:8]([CH:11]([CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:12]([OH:14])=[O:13])[C:7](=[O:23])[C:6]1=[O:24])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN1CCN(C(Cc2ccccc2)C(=O)OC)C(=O)C1=O
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCCCN1CCN(C(Cc2ccccc2)C(=O)O)C(=O)C1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of methyl 2-(4-butyl-2,3-dioxopiperazin-1-yl)-3-phenylpropanoate from Step A (130 mg, 0.39 mmol) in 10 mL THF and 3.9 mL water was added lithium hydroxide monohydrate (50 mg, 1.2 mmol). The reaction was stirred at rt for 2 h and HCl (1M, 1.2 mL) was added. Solvent evaporation gave 2-(4-butyl-2,3-dioxopiperazin-1-yl)-3-phenylpropanoic acid. 1H NMR (CD3OD) δ 7.26 (m, 5H), 5.18 (X of ABX, 1H, J=11.6 Hz, J=5 Hz), 3.55-3.17 (m, 8H), 1.50 (m, 2H), 1.27 (m, 2H), 0.92 (t, 3H, J=7.3 Hz).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.CCCCCC.[Br:19][C:20]1[CH:21]=[CH:22][C:23]([F:26])=[N:24][CH:25]=1.[CH3:27][O:28][C:29]1[CH:40]=[CH:39][CH:38]=[CH:37][C:30]=1[C:31](N(OC)C)=[O:32]>C1COCC1>[Br:19][C:20]1[CH:21]=[C:22]([C:31]([C:30]2[CH:37]=[CH:38][CH:39]=[CH:40][C:29]=2[O:28][CH3:27])=[O:32])[C:23]([F:26])=[N:24][CH:25]=1
Reactant: Fc1ccc(Br)cn1
Reactant: COc1ccccc1C(=O)N(C)OC
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: COc1ccccc1C(=O)c1cc(Br)cnc1F
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 21.9 %

Procedure:
To a round bottom flask were added di-iso-propylamine (5 ml, 35 mmol), and anhydrous THF (40 ml). The solution was stirred at −78° C. for 5 minutes under nitrogen. Then a 2.5 M solution of n-butyl lithium in hexane (12 ml, 30 mmol) was added slowly and the resulting solution was allowed to stir at −78° C. for another 30 minutes. At this time 5-bromo-2-fluoro-pyridine (5 g, 28 mmol) was added dropwise and the solution was allowed to sir at −40° C. for 2 hours. Then 2, N-dimethoxy-N-methyl-benzamide (7.2 g, 37 mmol) in THF (10 ml) was added and the resulting mixture was stirred at −40° C. for another 2 hours. The reaction was then quenched with 10% citric acid (40 ml) and worked up with ethyl acetate, brine, dried with Na2SO4. Silica chromatography of the crude using a gradient of ethyl acetate and hexane afforded (5-bromo-2-fluoro-pyridin-3-yl)-(2-methoxy-phenyl)-methanone (1.9 g, 21% yield). 1H NMR (500 MHz, DMSO-d6) δ 3.64 (s, 3H), 7.14 (m, 1H), 7.18 (d, 1H), 7.65 (m, 2H), 8.38 (d, 1H), 8.58 (s, 1H).). MS: m/z 310+312 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][CH2:10][C:11]([N:13]2[CH2:18][CH2:17][CH2:16][C@@H:15]([N:19]([CH3:39])[C:20]3[C:21]4[CH:28]=[CH:27][N:26](S(C5C=CC(C)=CC=5)(=O)=O)[C:22]=4[N:23]=[CH:24][N:25]=3)[CH2:14]2)=[O:12])[CH:5]=[C:6]([Cl:8])[CH:7]=1.O.C([O-])([O-])=O.[K+].[K+]>CO.CCOC(C)=O>[Cl:8][C:6]1[CH:5]=[C:4]([NH:9][CH2:10][C:11]([N:13]2[CH2:18][CH2:17][CH2:16][C@@H:15]([N:19]([CH3:39])[C:20]3[C:21]4[CH:28]=[CH:27][NH:26][C:22]=4[N:23]=[CH:24][N:25]=3)[CH2:14]2)=[O:12])[CH:3]=[C:2]([Cl:1])[CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(N(C)[C@@H]4CCCN(C(=O)CNc5cc(Cl)cc(Cl)c5)C4)ncnc32)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: O
Product: CN(c1ncnc2[nH]ccc12)[C@@H]1CCCN(C(=O)CNc2cc(Cl)cc(Cl)c2)C1
Temperature: 60 °C
Yield: 101.5 %

Procedure:
To a solution of (R)-2-(3,5-dichlorophenylamino)-1-(3-(methyl(7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidin-1-yl)ethanone (150 mg, 0.25 mmol) in MeOH:H2O (4:1 mL) was added K2CO3 (141 mg, 1.0 mmol) and the reaction mixture was heated to 60° C. for 1 h. The reaction mixture was concentrated in vacuo and the residue obtained was diluted in EtOAc (50 mL). The EtOAc suspension was filtered through celite and the filtrate was then dried over Na2SO4, and concentrated in vacuo to give a residue that was subjected to purification by column chromatography (silica gel, gradient MeOH in DCM) to afford the titled intermediate (110 mg, 50%). 1H NMR (400 MHz, DMSO-d6): δ 11.65 (d, J=11.2 Hz, 1H), 8.10 (d, J=6.4 Hz, 1H), 7.14 (d, J=13.6 Hz, 1H), 6.75 (s, 1H), 6.69 (s, 1H), 6.62 (s, 1H), 6.55 (s, 1H), 6.35 (m, 1H), 4.69 (m, 1H), 4.41 (m, 1H), 3.99 (m, 2H), 3.00 (m, 1H), 2.88 (m, 1H), 2.60 (m, 1H), 2.49 (s, 3H), 1.94-1.80 (m, 2H), 1.65 (m, 1H), 1.49 (m, 1H). LC-MS: m/z [M+1]=455.