Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[N+:15]([O-:17])=[O:16])[C:5]([Cl:18])=[CH:4][N:3]=1.[NH2:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]2[CH2:31][CH2:30][N:29]([C:32](=[O:34])[CH3:33])[CH2:28][CH2:27]2)=[CH:22][C:21]=1[O:35][CH3:36].CO>C(Cl)(Cl)Cl>[Cl:18][C:5]1[C:6]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[N+:15]([O-:17])=[O:16])=[N:7][C:2]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([N:26]3[CH2:31][CH2:30][N:29]([C:32](=[O:34])[CH3:33])[CH2:28][CH2:27]3)=[CH:22][C:21]=2[O:35][CH3:36])=[N:3][CH:4]=1
Reactant: O=[N+]([O-])c1ccccc1Oc1nc(Cl)ncc1Cl
Reactant: COc1cc(N2CCN(C(C)=O)CC2)ccc1N
Solvent: ClC(Cl)Cl
Solvent: CO
Product: COc1cc(N2CCN(C(C)=O)CC2)ccc1Nc1ncc(Cl)c(Oc2ccccc2[N+](=O)[O-])n1
Temperature: 100 °C

Procedure:
To a stirred solution of 2,5-dichloro-4-(2-nitrophenoxy)pyrimidine (300 mg, 1.052 mmol) in 0.08M p-PTSA/1,4-dioxane (10 mL) was added 1-(4-(4-amino-3-methoxy phenyl)piperazin-1-yl)ethanone (262 mg, 1.052 mmol), and the mixture was heated to 100° C. for 16 h. TLC showed completion of starting material (TLC system: 5% methanol in chloroform (Rf): 0.4). 1,4-dioxane was evaporated under reduced pressure, and the remainder was diluted with ethyl acetate (35 mL) and the remainder was washed with water (10 mL) followed by saturated NaHCO3 solution (10 mL). The organic layer was separated, dried over sodium sulphate, and concentrated. Crude compound was purified by column chromatography using silica gel (100-200 mesh) with 3% methanol in chloroform to obtain 1-(4-(4-(5-chloro-4-(2-nitrophenoxy)pyrimidin-2-ylamino)-3-methoxyphenyl) piperazin-1-yl)ethanone as a grey solid. (Yield: 140 mg, 26.6%). MS: m/z 308.4 (ES+, M+H).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]([C:11]([Cl:13])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4]([Cl:6])=[O:5].[C:14](OCCC)(=O)[C:15]1C=CC(C([O-])=O)=CC=1.[K+].S(Cl)(Cl)=O>C1(C)C=CC=CC=1>[CH2:1]([C:2]1[CH:10]=[C:9]([C:11]([Cl:13])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4]([Cl:6])=[O:5])[CH2:14][CH3:15]
Reactant: CCCOC(=O)c1ccc(C(=O)[O-])cc1
Reactant: Cc1cc(C(=O)Cl)ccc1C(=O)Cl
Agent: [K+]
Solvent: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: CCCc1cc(C(=O)Cl)ccc1C(=O)Cl

Procedure:
This compound was prepared by the procedure described for monomethyl terephthaloyl chloride. Typical reagent levels were as follows: potassium monopropyl terephthalate (49.0g, 0.20 mole), thionyl chloride (29.8g, 0.25 mole) and 100 ml of toluene. The product was used without further purification.
Reaction SMILES: [CH:1]1([N:6]2[CH2:11][CH2:10][N:9]([C:12]([C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][CH:22]=3)[NH:19][C:18]([C:23]([N:25]3[CH2:30][CH2:29][C:28]([F:32])([F:31])[CH2:27][CH2:26]3)=[O:24])=[CH:17]4)=[O:13])[CH2:8][CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:33]([O:35][C:36]([C:38]1[CH:39]=[C:40](B(O)O)[CH:41]=[CH:42][CH:43]=1)=[O:37])[CH3:34].N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH2:33]([O:35][C:36](=[O:37])[C:38]1[CH:39]=[CH:40][CH:41]=[C:42]([N:19]2[C:20]3[C:16](=[CH:15][C:14]([C:12]([N:9]4[CH2:8][CH2:7][N:6]([CH:1]5[CH2:5][CH2:4][CH2:3][CH2:2]5)[CH2:11][CH2:10]4)=[O:13])=[CH:22][CH:21]=3)[CH:17]=[C:18]2[C:23]([N:25]2[CH2:26][CH2:27][C:28]([F:31])([F:32])[CH2:29][CH2:30]2)=[O:24])[CH:43]=1)[CH3:34]
Reactant: CCOC(=O)c1cccc(B(O)O)c1
Reactant: O=C(c1ccc2[nH]c(C(=O)N3CCC(F)(F)CC3)cc2c1)N1CCN(C2CCCC2)CC1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)c1cccc(-n2c(C(=O)N3CCC(F)(F)CC3)cc3cc(C(=O)N4CCN(C5CCCC5)CC4)ccc32)c1
Yield: 69 %

Procedure:
The title compound was synthesized in analogy to example 66, from [5-(4-cyclopentyl-piperazine-1-carbonyl)-1H-indol-2-yl]-(4,4-difluoro-piperidin-1-yl)-methanone (example 8), 3-ethoxycarbonylphenylboronic acid, copper(II) acetate and pyridine in dichloromethane, to give the desired product as a white foam (69%).
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][CH2:13][OH:14])=[CH:7][C:6]=1[I:15].CC(C)([O-])C.[K+].Cl>C1COCC1>[I:15][C:6]1[CH:7]=[C:8]([CH2:11][CH2:12][CH2:13][OH:14])[CH:9]=[CH:10][C:5]=1[O:4][CH:3]=[CH2:2]
Reactant: OCCCc1ccc(OCCCl)c(I)c1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: C1CCOC1
Product: C=COc1ccc(CCCO)cc1I
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a 0° C. solution of 3-[4-(2-chloroethoxy)-3-iodophenyl]propan-1-ol (Step B) (1.00 g, 2.94 mmol) in THF (10 ml) was added potassium tert-butoxide (1M in THF) (6.61 ml, 6.61 mmol). The resulting solution was warmed to RT (turned cloudy) and stirred under nitrogen for 3 hours. Dilute HCl was added to the mixture and extracted 2 times with ethyl acetate. The combined organics were washed with brine and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with EtOAc in hexanes to afford the title compound. 1H NMR (500 MHz, CD3OD): δ 7.66 (s, 1H); 7.23-7.13 (m, 1H); 6.96-6.88 (m, 1H); 6.66 (ddd, J=28.0, 13.7, 6.2 Hz, 1H); 4.64-4.60 (m, 1H); 4.43 (dd, J=6.1, 1.6 Hz, 1H); 3.54 (t, J=6.4 2H); 2.62 (t, J=7.6 Hz, 3H); 1.81-1.74 (m, 3H).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=2)=[C:13]2[C:17]=1[C:16](=[O:18])[CH:15]([C:19]([O:21][CH3:22])=[O:20])[CH2:14]2.Br[CH2:34][C:35]1[CH:44]=[CH:43][C:38]([C:39]([O:41][CH3:42])=[O:40])=[CH:37][CH:36]=1>CC(C)=O.O>[CH3:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:31])([F:30])[F:32])[CH:24]=2)=[C:13]2[C:17]=1[C:16](=[O:18])[C:15]([CH2:34][C:35]1[CH:36]=[CH:37][C:38]([C:39]([O:41][CH3:42])=[O:40])=[CH:43][CH:44]=1)([C:19]([O:21][CH3:22])=[O:20])[CH2:14]2
Reactant: COC(=O)c1ccc(CBr)cc1
Reactant: COC(=O)C1Cc2c(-c3cccc(C(F)(F)F)c3)ccc(OC)c2C1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: COC(=O)c1ccc(CC2(C(=O)OC)Cc3c(-c4cccc(C(F)(F)F)c4)ccc(OC)c3C2=O)cc1
Temperature: 25 °C
Reaction time: 96 h
Yield: 100.4 %

Procedure:
Potassium carbonate (15 mg, 0.11 mmol) was added to a solution of methyl 7-methoxy-1-oxo-4-(3-(trifluoromethyl)phenyl)-2,3-dihydro-1H-indene-2-carboxylate (26 mg, 0.07 mmol) in acetone (1.0 mL). Methyl 4-(bromomethyl)benzoate (32 mg, 0.14 mmol) was added and the mixture was stirred at room temperature. After 4 d, the reaction mixture was diluted with water (10 mL) and extracted with EtOAc (3×20 mL). The combined organic extracts were dried (Na2SO4), filtered and concentrated. The resulting crude residue was purified by combiflash (4 g column, hexanes→EtOAc, gradient) to afford 36 mg (98%) of methyl 7-methoxy-2-(4-(methoxycarbonyl)benzyl)-1-oxo-4-(3-(trifluoromethyl)phenyl)-2,3-dihydro-1H-indene-2-carboxylate.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N:8]2[CH:12]=[C:11]([C:13]([OH:15])=O)[N:10]=[CH:9]2)[CH:5]=[CH:6][CH:7]=1.[C:16]([NH:19][NH2:20])(=[O:18])[CH3:17].ON1C2N=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>CN(C=O)C>[C:16]([NH:19][NH:20][C:13]([C:11]1[N:10]=[CH:9][N:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=2)[CH:12]=1)=[O:15])(=[O:18])[CH3:17]
Reactant: CC(=O)NN
Reactant: O=C(O)c1cn(-c2cccc(Br)c2)cn1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Product: CC(=O)NNC(=O)c1cn(-c2cccc(Br)c2)cn1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 5 (0.30 g, 1.1 mmol), acethydrazide (82 mg, 1.1 mmol) diisopropylethyl amine (975 uL, 5.6 mmol), and 1-hydroxy-7-azabenzotriazole (HOAt, 177 mg, 1.3 mmol) in DMF (10 mL) was added and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide, hydrochloride (EDC HCl; 249 mg, 1.3 mmol). The mixture was stirred at room temperature for 16 h. The solvent was evaporated and the residue was extracted with hot ethyl acetate. The solvent was evaporated and crystallised from MeOH to give the title compound.
Reaction SMILES: [C:1]([O:4][CH2:5][CH:6]=[C:7]([CH3:15])[CH2:8][CH2:9][CH:10](Cl)[C:11]([CH3:13])=[CH2:12])(=[O:3])[CH3:2].[I-].[Na+].C[N+]1([O-])CC[O:22]CC1.CN(C)C=O>O>[C:1]([O:4][CH2:5][CH:6]=[C:7]([CH3:15])[CH2:8][CH2:9][CH:10]=[C:11]([CH3:13])[CH:12]=[O:22])(=[O:3])[CH3:2]
Reactant: C[N+]1([O-])CCOCC1
Reactant: C=C(C)C(Cl)CCC(C)=CCOC(C)=O
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)OCC=C(C)CCC=C(C)C=O
Temperature: 50 °C
Reaction time: 4 h
Yield: 74.7 %

Procedure:
1.15 g (3.99 mmols) of 6-chloro-3,7-dimethyl-2,7-octadienyl acetate (purity: 80%), 0.91 g (6 mmols) of sodium iodide and 1.36 g (10 mmols) of N-methylmorpholine N-oxide (monohydrate) were placed in a flask, to which was added 5 ml of N,N-dimethylformamide. The mixture was agitated at 50° C. for 4 hours. After completion of the reaction, 10 ml of water was added to the reaction mixture, followed by extraction twice each with 70 ml of diethyl ether. The resulting extract was washed with each 20 ml of 3% sulfuric acid, a saturated sodium hydrogen carbonate aqueous solution and a 10% sodium sulfite aqueous solution, and dried with magnesium sulfate. After drying, the solvent was removed by distillation from the solution and the resulting residue was purified by column chromatography using silica gel [eluent: ethyl acetate/hexane (volume by ratio)=1/9-1/3], thereby obtaining 0.627 g of 8-acetoxy-2,6-dimethyl-2,6-octadienal. Yield: 75%. The results of an instrumental analysis of the 8-acetoxy-2,6-dimethyl-2,6-octadienal are as follows.
Reaction SMILES: [CH:1]1([C:4]2[CH:9]=[CH:8][C:7]([C:10]3[N:14]([CH3:15])[CH:13]=[N:12][C:11]=3[C:16]3[CH:21]=[C:20]([C:22]([OH:24])=[O:23])[CH:19]=[CH:18][N:17]=3)=[CH:6][CH:5]=2)[CH2:3][CH2:2]1.[CH3:25]O>S(=O)(=O)(O)O>[CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:10]3[N:14]([CH3:15])[CH:13]=[N:12][C:11]=3[C:16]3[CH:21]=[C:20]([C:22]([O:24][CH3:25])=[O:23])[CH:19]=[CH:18][N:17]=3)=[CH:8][CH:9]=2)[CH2:2][CH2:3]1
Reactant: CO
Reactant: Cn1cnc(-c2cc(C(=O)O)ccn2)c1-c1ccc(C2CC2)cc1
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccnc(-c2ncn(C)c2-c2ccc(C3CC3)cc2)c1
Yield: 94 %

Procedure:
To a mixture of 2-[5-(4-cyclopropylphenyl)-1-methyl-1H-imidazol-4-yl]pyridine-4-carboxylic acid (26 mg, 0.08 mmol, Example 7) in MeOH (5 mL) was added 3 drops of concentrated sulfuric acid. The reaction mixture was heated to reflux for 1 hr. It was then concentrated, separated between water and ethyl acetate. Organic layer dried and concentrated to give the title compound as light pink solid (25 mg, 94%). 1H NMR (400 MHz, DMSO-d6): δ 0.77 (2H, m), 1.02 (2H, m), 2.02 (1H, m), 3.54 (3H, s), 3.85 (3H, s), 7.22 (2H, d&s, J=7.8 Hz), 7.36 (2H, d&s, J=8.1 Hz), 7.64 (1H, d, J=4.4 Hz), 7.98 (1H, s), 8.51 (1H, s), 8.63 (1H, s). [M+H] Calc'd for C20H19N3O2, 334. Found, 334.
Reaction SMILES: CN(C)C=O.[CH3:6][C:7]1[CH:13]=[CH:12][CH:11]=[C:10]([CH3:14])[C:8]=1[NH2:9].Cl[CH2:16][C:17]([NH2:19])=[O:18].C(=O)([O-])[O-].[K+].[K+]>O>[NH2:19][C:17]([CH2:16][NH:9][C:8]1[C:10]([CH3:14])=[CH:11][CH:12]=[CH:13][C:7]=1[CH3:6])=[O:18]
Reactant: Cc1cccc(C)c1N
Reactant: NC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cccc(C)c1NCC(N)=O

Procedure:
Add 200 ml dimethylformamide to a mixture of 2,6-dimethylaniline (36.3 g, 0.30 mol), 2-chloroacetamide (74.8 g, 0.80 mol) and potassium carbonate (41.4 g, 0.3 mol). Heat at 120° for 72 hours, allow to cool, and pour into water. Extract with 1:1 ether-ethyl acetate. Wash the organic with 1.0 N HCl. Neutralize the aqueous layer with NaHCO3 and extract it with ethyl acetate. Dry, concentrate, and distill to collect a fraction, b.p. 157°-167°/0.1 mm. Recrystallize from methylene chloride-hexane to give as a solid, m.p. 91°-92°, N-aminocarbonylmethyl-2,6-dimethylaniline.
Reaction SMILES: [O-:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Na+].[NH2:9][C:10]1[C:15]([N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)=[N:14][C:13](Br)=[CH:12][N:11]=1>>[NH2:9][C:10]1[C:15]([N:16]2[CH2:17][CH2:18][O:19][CH2:20][CH2:21]2)=[N:14][C:13]([O:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:12][N:11]=1
Reactant: [O-]c1ccccc1
Reactant: Nc1ncc(Br)nc1N1CCOCC1
Agent: [Na+]
Product: Nc1ncc(Oc2ccccc2)nc1N1CCOCC1

Procedure:
A suspension of 0.1 mole of sodium phenoxide and 0.1 mole of 2-amino-3-morpholino-5-bromopyrazine is refluxed 10-20 hours. The cooled mixture is extracted with diethyl ether, washed with cold 2 N sodium hydroxide solution, dried and evaporated to give 2-amino-3-morpholino-5-phenoxypyrazine.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([NH2:7])[N:4]=[CH:3]1.Br[C:9]1[C:10](=[O:17])[N:11]([CH3:16])[CH:12]=[C:13]([Br:15])[CH:14]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C(=O)([O-])[O-].[Cs+].[Cs+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[Br:15][C:13]1[CH:14]=[C:9]([NH:7][C:5]2[N:4]=[CH:3][N:2]([CH3:1])[CH:6]=2)[C:10](=[O:17])[N:11]([CH3:16])[CH:12]=1
Reactant: Cn1cc(Br)cc(Br)c1=O
Reactant: Cn1cnc(N)c1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: Cn1cnc(Nc2cc(Br)cn(C)c2=O)c1
Temperature: 92 °C
Yield: 75 %

Procedure:
A 100-mL single-neck round-bottomed flask equipped with a magnetic stirrer and a reflux condenser was charged with 1,4-dioxane (50 mL), 268b (1.1 g, 11.3 mmol), 3,5-dibromo-1-methylpyridin-2(1H)-one (3.0 g, 11.3 mmol), Pd2(dba)3 (1.0 g, 1.13 mmol), XantPhos (1.3 g, 2.26 mmol), and cesium carbonate (7.3 g, 22.6 mmol). After three cycles of vacuum/argon flush, the mixture was heated at 92° C. for 4.5 hrs. It was then cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure and the resulting residue was purified by silica-gel column chromatography eluting with dichloromethane/methanol (100:1 to 50:1) to afford 268c (2.4 g, 76%) as yellow solid. MS-ESI: [M+H]+ 283.1
Reaction SMILES: [CH3:1][C:2]1[N:6]([CH2:7][C:8]([N:10]2[CH2:15][CH2:14][CH:13]([N:16]3[CH:20]=[CH:19][C:18]([C:21]([OH:23])=O)=[N:17]3)[CH2:12][CH2:11]2)=[O:9])[N:5]=[C:4]([C:24]([F:27])([F:26])[F:25])[CH:3]=1.CN1CCOCC1.[CH3:35][NH:36][C@H:37]1[C:46]2[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=2)[CH2:40][CH2:39][CH2:38]1>ClCCl.O>[CH3:35][N:36]([C@H:37]1[C:46]2[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=2)[CH2:40][CH2:39][CH2:38]1)[C:21]([C:18]1[CH:19]=[CH:20][N:16]([CH:13]2[CH2:12][CH2:11][N:10]([C:8](=[O:9])[CH2:7][N:6]3[C:2]([CH3:1])=[CH:3][C:4]([C:24]([F:26])([F:25])[F:27])=[N:5]3)[CH2:15][CH2:14]2)[N:17]=1)=[O:23]
Reactant: Cc1cc(C(F)(F)F)nn1CC(=O)N1CCC(n2ccc(C(=O)O)n2)CC1
Reactant: CN[C@@H]1CCCc2ccccc21
Solvent: CN1CCOCC1
Solvent: O
Solvent: ClCCl
Product: Cc1cc(C(F)(F)F)nn1CC(=O)N1CCC(n2ccc(C(=O)N(C)[C@@H]3CCCc4ccccc43)n2)CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 14.9 %

Procedure:
A mixture of 1-[1-[[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]acetyl]-4-piperidinyl]-1H-pyrazole-3-carboxylic acid (270 mg, 0.7 mmol) (i.e. the product of Example 18, Step E), N-(3-dimethylaminopropyl)-Y-ethylcarbodiimide hydrochloride (EDC) (147.61 mg, 0.77 mmol) and N-methylmorpholine (0.088 mL, 0.8 mmol) in 5 mL of dichloromethane was stirred at room temperature for 15 minutes. (1R)-1,2,3,4-tetrahydro-N-methyl-1-naphthalenamine (124.16 mg, 0.77 mmol) (i.e. the product of Example 6, Step A) was added and the reaction mixture was stirred at room temperature for 16 h. The reaction mixture was poured in water, and the organic layer was subsequently washed with water, 1 M aqueous hydrochloric acid, water, saturated aqueous solution of sodium bicarbonate, brine. The filtered reaction mixture was dried over magnesium sulfate and evaporated in vacuo. The crude product was purified by medium-pressure liquid chromatography on silica gel using 75-100 of ethyl acetate in hexanes as eluant to give 55 mg of the title compound, a compound of the present invention as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([NH:15][C@H:16]1[CH2:20][CH2:19][N:18]([C@H:21]([CH3:25])[C:22]([OH:24])=O)[C:17]1=[O:26])(=[O:14])=[O:13])[CH:6]=[CH:5]2.Cl.CN(C)CCCN=C=NCC.C1C=CC2N(O)N=NC=2C=1.[NH:49]1[CH2:54][CH2:53][O:52][CH2:51][CH2:50]1>C(Cl)Cl.C(N(CC)CC)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([NH:15][C@H:16]1[CH2:20][CH2:19][N:18]([C@H:21]([CH3:25])[C:22]([N:49]3[CH2:54][CH2:53][O:52][CH2:51][CH2:50]3)=[O:24])[C:17]1=[O:26])(=[O:13])=[O:14])[CH:6]=[CH:5]2
Reactant: C[C@H](C(=O)O)N1CC[C@H](NS(=O)(=O)c2ccc3cc(Cl)ccc3c2)C1=O
Reactant: C1COCCN1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@H](C(=O)N1CCOCC1)N1CC[C@H](NS(=O)(=O)c2ccc3cc(Cl)ccc3c2)C1=O
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of (2R)-2-((3S)-3-{[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)propanoic acid [Intermediate 28] (0.037 g) in DCM (1.0 ml) were added 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (0.036 g), HOBT (0.025 g) and triethylamine (0.026 ml) and the mixture was stirred at room temperature for 5 min. Morpholine (0.012 ml) was added and the resultant mixture stirred at room temperature for 15.5 h. The mixture was partitioned between DCM and saturated sodium bicarbonate solution and then passed through a hydrophobic frit. The organic extract was concentrated under reduced pressure and the residue was partially purified using preparative thin layer chromatography (20 cm×20 cm 1 mm thick Whatman PKF256 SiO2 plate, eluting with hexane:ethyl acetate 1:5) to give an impure sample of the title compound. This sample was repurified using preparative thin layer chromatography (20 cm×20 cm 1 mm thick Whatman PKF256 SiO2 plate, eluting with hexane:ethyl acetate 1:8) to give the title compound (0.036 g) as a white solid.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[N:5]=[C:6]([CH3:15])[C:7]2[C:8](=[N:10][C:11](=[O:14])[CH2:12][CH:13]=2)[N:9]=1.Br[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH:31]=[CH:30][CH:29]=[CH:28][C:25]=2[C:26]#[N:27])=[CH:20][CH:19]=1>CN(C=O)C>[CH3:3][C:4]1[N:5]=[C:6]([CH3:15])[C:7]2[CH:13]=[CH:12][C:11](=[O:14])[N:10]([CH2:17][C:18]3[CH:19]=[CH:20][C:21]([C:24]4[CH:31]=[CH:30][CH:29]=[CH:28][C:25]=4[C:26]#[N:27])=[CH:22][CH:23]=3)[C:8]=2[N:9]=1
Reactant: N#Cc1ccccc1-c1ccc(CBr)cc1
Reactant: Cc1nc(C)c2c(n1)=NC(=O)CC=2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1nc(C)c2ccc(=O)n(Cc3ccc(-c4ccccc4C#N)cc3)c2n1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
Using the same procedure as described in Step 1 of Example 8, to a stirred suspension of NaH (60% dispersion in mineral oil) in DMF add 2,4-dimethyl-7H-pyrido[2,3-d]pyrimidin-7-one, prepared according to T. Sakamoto, et al. Chem. Pharm. Bull., 1982, 30, 2410. After 45 min, add 2-[4-(bromomethyl)phenyl]benzonitrile in DMF and stir the mixture at room temperature for 18 h. Add water and extract the mixture with CH2Cl2. Concentrate the extracts and purify the crude product by flash chromatography (2% MeOH/CH2Cl2). Trituration with ether gives the product.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[CH2:9][O:8][C:7]([CH3:14])([CH3:13])[C:6]=2[CH:15]=1.[Cl:16][C:17]1[CH:18]=[C:19](B(O)O)[CH:20]=[C:21]([Cl:23])[CH:22]=1>>[CH3:13][C:7]1([CH3:14])[O:8][CH2:9][C:10](=[O:12])[NH:11][C:5]2[CH:4]=[CH:3][C:2]([C:19]3[CH:18]=[C:17]([Cl:16])[CH:22]=[C:21]([Cl:23])[CH:20]=3)=[CH:15][C:6]1=2
Reactant: OB(O)c1cc(Cl)cc(Cl)c1
Reactant: CC1(C)OCC(=O)Nc2ccc(Br)cc21
Product: CC1(C)OCC(=O)Nc2ccc(-c3cc(Cl)cc(Cl)c3)cc21

Procedure:
Prepared from 7-bromo-5,5-dimethyl-1,5-dihydro-4,1-benzoxazepin-2(3H)-one and 3,5-dichloro benzeneboronic acid generally according to the coupling procedure described in example 1. 1H NMR (DMSO-d6): δ 10.02 (s, 1H), 7.76 (s, 2H), 7.55-7.64 (m, 3H), 7.18 (d, J=8.45 Hz, 1H), 4.26 (s, 2H), 1.62 (s 6H); MS (ESI) m/z 336/338/340 ([M+H]+); MS (ESI) m/z 334/336/338 ([M−H]−).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][N:3]=1.[CH3:11][C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=1[N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1>>[Br:1][C:2]1[N:3]=[CH:4][C:5]([C:6]([N:22]2[CH2:23][CH2:24][N:19]([C:13]3[CH:14]=[CH:15][C:16]([CH3:18])=[CH:17][C:12]=3[CH3:11])[CH2:20][CH2:21]2)=[O:8])=[CH:9][CH:10]=1
Reactant: O=C(O)c1ccc(Br)nc1
Reactant: Cc1ccc(N2CCNCC2)c(C)c1
Product: Cc1ccc(N2CCN(C(=O)c3ccc(Br)nc3)CC2)c(C)c1
Yield: 102.5 %

Procedure:
By reaction and treatment in the same manner as in Preparation Example 1 and using 6-bromonicotinic acid (2 g) and 1-(2,4-dimethylphenyl)piperazine (1.9 g), the title compound (3.8 g) was obtained.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[CH2:3][CH2:4][C:5](=O)[CH2:6][CH2:7][CH:8]=O.[Cl-].[NH4+:14]>C(O)C.C(OCC)(=O)C>[F:1][C:2]([F:12])([F:11])[CH2:3][CH2:4][C:5]1[NH:14][CH:8]=[CH:7][CH:6]=1
Reactant: [NH4+]
Reactant: O=CCCC(=O)CCC(F)(F)F
Agent: [Cl-]
Solvent: CCO
Solvent: CCOC(C)=O
Product: FC(F)(F)CCc1ccc[nH]1
Yield: 14.5 %

Procedure:
Crude 7,7,7-trifluoro-4-oxo-heptanal (10 g, prepared above) in ethanol (100 ml) was treated with ammonium chloride (400 mmol, 21 g), then heated to reflux for 1 h. The resulting solution was diluted with ethyl acetate (300 ml) and washed with brine (2×50 ml). The organics were concentrated under reduced pressure. Purification of the residue by silica gel chromatography provided 1.3 g (21% overall from 4,4,4-trifluorobutyric acid) of 2-(3,3,3-trifluoro-propyl)-1H-pyrrole. 1H NMR (CDCl3) δ7.98 (1H, br s), 6.71 (1H, dd, J=4.1, 2.6), 6.15 (1H, dd, J=5.9, 2.8), 5.99-5.94 (1H, m), 2.92-2.85 (2H, m), 2.52-2.35 (2H, m).
Reaction SMILES: [N:1]1([CH2:7][CH2:8][O:9][C:10]2[CH:11]=[C:12]([NH2:16])[CH:13]=[CH:14][CH:15]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.CS([C:20]1[N:25]=[CH:24][C:23]2=[CH:26][CH:27]=[C:28]([C:29]3[CH:30]=[N:31][N:32]([CH3:34])[CH:33]=3)[N:22]2[N:21]=1)=O>>[CH3:34][N:32]1[CH:33]=[C:29]([C:28]2[N:22]3[C:23]([CH:24]=[N:25][C:20]([NH:16][C:12]4[CH:13]=[CH:14][CH:15]=[C:10]([O:9][CH2:8][CH2:7][N:1]5[CH2:6][CH2:5][O:4][CH2:3][CH2:2]5)[CH:11]=4)=[N:21]3)=[CH:26][CH:27]=2)[CH:30]=[N:31]1
Reactant: Nc1cccc(OCCN2CCOCC2)c1
Reactant: Cn1cc(-c2ccc3cnc(S(C)=O)nn23)cn1
Product: Cn1cc(-c2ccc3cnc(Nc4cccc(OCCN5CCOCC5)c4)nn23)cn1

Procedure:
Prepared by following a procedure analagous to Example 251c by using 3-(2-Morpholin-4-yl-ethoxy)-phenylamine and 2-Methanesulfinyl-7-(1-methyl-1H-pyrazol-4-yl)-pyrrolo[2,1-f][1,2,4]triazine. 1H-NMR (DMSO) δ 10 (brs, 1H), 9.4 (s, 1H), 8.9 (s, 1H), 8.4 (s, 1H), 8.2 (s, 1H), 7.5 (brs, 1H), 7.3 (m, 2H), 7.06 (d, J=4.6 Hz, 1H), 6.9 (d, J=4.6 Hz, 1H), 6.7 (d, J=8.0 Hz, 1H), 4.3 (m, 2H), 4-3.1 (m, 10H), 3.9 (s, 3H); LC/MS (ESI+): 420 (M+H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([Br:11])[CH:10]=1)[C:5]([NH2:7])=[O:6].[N:12]1[CH:17]=[CH:16][N:15]=[CH:14][C:13]=1[NH2:18]>>[Br:11][C:9]1[CH:8]=[C:4]([CH:3]=[C:2]([NH:18][C:13]2[CH:14]=[N:15][CH:16]=[CH:17][N:12]=2)[CH:10]=1)[C:5]([NH2:7])=[O:6]
Reactant: Nc1cnccn1
Reactant: NC(=O)c1cc(Br)cc(Br)c1
Product: NC(=O)c1cc(Br)cc(Nc2cnccn2)c1

Procedure:
3,5-Dibromo-benzamide and pyrazin-2-ylamine were coupled to give 3-bromo-5-(pyrazin-2-ylamino)-benzamide as described for Example 44. 3-Bromo-5-(pyrazin-2-ylamino)-benzamide was converted to 3-(1H-indol-4-yl)-5-(pyrazin-2-ylamino)-benzamide as described in Example 75. 1H NMR (400 MHz, CDCl3): δ 10.61 (s, 1H), 8.24 (t, J=1.8 Hz, 1H), 8.17-8.12 (m, 3H), 8.06 (s, 1H), 7.88 (s, 1H), 7.78 (t, J=1.5 Hz, 1H), 7.40 (dd, J=6.6, 2.1 Hz, 1H), 7.30 (d, J=3.1 Hz, 1H), 7.21-7.16 (m, 2H), 6.74 (d, J=2.7 Hz, 1H).