Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O.[NH2:2][NH2:3].[F:4][C:5]([F:19])([F:18])[C:6]([F:17])([F:16])[C:7](=O)[CH2:8][C:9](=O)[C:10]([CH3:13])([CH3:12])[CH3:11]>C(O)C>[C:10]([C:9]1[CH:8]=[C:7]([C:6]([F:17])([F:16])[C:5]([F:19])([F:18])[F:4])[NH:3][N:2]=1)([CH3:13])([CH3:12])[CH3:11]
Reactant: CC(C)(C)C(=O)CC(=O)C(F)(F)C(F)(F)F
Reactant: NN
Solvent: O
Solvent: CCO
Product: CC(C)(C)c1cc(C(F)(F)C(F)(F)F)[nH]n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.5 %

Procedure:
At room temperature, hydrazine hydrate (2.06 g) is added to a solution of 1,1,1,2,2-pentafluoro-6,6-dimethylheptane-3,5-dione (10.1 g) in ethanol (100 ml). The reaction mixture is stirred at room temperature overnight. After removal of the solvents under reduced pressure, 3-tert-butyl-5-(pentafluoroethyl)-1H-pyrazole (7.9 g, 79%) is obtained.
Reaction SMILES: C(O)C.[N:4]1[C:12]([C:13](=[O:15])[CH3:14])=[C:11]2[C:7]([N:8]=[CH:9][NH:10]2)=[N:6][CH:5]=1.[BH4-].[Na+].Cl>O>[N:4]1[C:12]([CH:13]([OH:15])[CH3:14])=[C:11]2[C:7]([N:8]=[CH:9][NH:10]2)=[N:6][CH:5]=1
Reactant: CC(=O)c1ncnc2nc[nH]c12
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CC(O)c1ncnc2nc[nH]c12
Temperature: 25 °C
Reaction time: 4 h
Yield: 80.4 %

Procedure:
To an ethanol solution (80 ml) of 0.70 g of (purin-6-yl)ethanone was added 0.70 g of sodium borohydride and the resulting mixture was stirred at room temperature for 4 hours. The excessive reagent was decomposed by adding water and 4 N hydrochloric acid and distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluted by dichloromethane/methanol) to thereby give 0.57 g of the title compound as a white solid.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]([NH:13][CH2:14][C:15](O)=[O:16])=[O:12])=[CH:10][C:5]=2[N:4]=[C:3]1[NH:18][C:19]1[S:20][C:21]2[CH:27]=[C:26]([O:28][C:29]([F:32])([F:31])[F:30])[CH:25]=[CH:24][C:22]=2[N:23]=1.[CH3:33][N:34]([CH3:40])[C@H:35]1[CH2:39][CH2:38][NH:37][CH2:36]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:33][N:34]([CH3:40])[C@H:35]1[CH2:39][CH2:38][N:37]([C:15](=[O:16])[CH2:14][NH:13][C:11]([C:9]2[CH:8]=[CH:7][C:6]3[N:2]([CH3:1])[C:3]([NH:18][C:19]4[S:20][C:21]5[CH:27]=[C:26]([O:28][C:29]([F:32])([F:30])[F:31])[CH:25]=[CH:24][C:22]=5[N:23]=4)=[N:4][C:5]=3[CH:10]=2)=[O:12])[CH2:36]1
Reactant: Cn1c(Nc2nc3ccc(OC(F)(F)F)cc3s2)nc2cc(C(=O)NCC(=O)O)ccc21
Reactant: CN(C)[C@H]1CCNC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN(C)[C@H]1CCN(C(=O)CNC(=O)c2ccc3c(c2)nc(Nc2nc4ccc(OC(F)(F)F)cc4s2)n3C)C1
Yield: 35.6 %

Procedure:
1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid [2-((S)-3-dimethylamino-pyrrolidin-1-yl)-2-oxo-ethyl]amide (35 mg) was prepared by following General Procedure F starting from {[1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carbonyl]-amino}-acetic acid (95 mg), dimethyl-(S)-pyrrolidin-3-yl-amine (20 mg), HBTU (85 mg), and DIEA (70 uL) in DMF (1 mL). LC/MS: m/z 561.6. 1H NMR (DMSO-d6, 400 MHz): δ 8.67-8.66 (m, 1H), 8.12 (s, 1H), 7.96 (s, 1H), 7.84-7.82 (d, 1H), 7.66-7.64 (d, 1H), 7.55-7.53 (d, 1H), 7.40-7.37 (d, 1H), 4.09-4.07 (m, 3H), 3.86-3.80 (m, 2H), 3.69 (s, 3H), 3.57 (s, 2H), 2.82-2.78 (m, 6H), 2.30-2.27 (m, 2H), —NH proton signal was not observed.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6](Cl)=[O:7].[N:9]1[C:14]2[NH:15][C:16]3[CH:24]=[CH:23][CH:22]=[CH:21][C:17]=3[C:18](=[O:20])[NH:19][C:13]=2[CH:12]=[CH:11][CH:10]=1>C1(C)C(C)=CC=CC=1>[Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]([N:15]1[C:16]2[CH:24]=[CH:23][CH:22]=[CH:21][C:17]=2[C:18](=[O:20])[NH:19][C:13]2[CH:12]=[CH:11][CH:10]=[N:9][C:14]1=2)=[O:7]
Reactant: O=C(Cl)CCCCCl
Reactant: O=C1Nc2cccnc2Nc2ccccc21
Solvent: Cc1ccccc1C
Product: O=C1Nc2cccnc2N(C(=O)CCCCCl)c2ccccc21

Procedure:
A solution of 5-chlorovaleryl chloride and 5,11-dihydro-6H-pyrido-[2,3-b][1,4]-benzodiazepine-6-one in xylene was reacted to obtain 11-(5-chlorovaleryl)-5,11-dihydro-6H-pyrido-[2,3-b][1,4]-benzodiazepine-6-one which after crystallization from n-propanol melted at 170°-172° C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4]2([O:11][C:10]3[C:12]4[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=3[S:8][CH2:7]2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:3][CH2:2]1.[Cl:22][C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=1)[C:26](Cl)=[O:27]>>[Cl:22][C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=1)[C:26]([N:1]1[CH2:2][CH2:3][C:4]2([O:11][C:10]3[C:12]4[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=3[S:8][CH2:7]2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:5][CH2:6]1)=[O:27]
Reactant: O=C(Cl)c1cccc(Cl)c1
Reactant: O=C1C(=O)c2ccccc2C2=C1SCC1(CCNCC1)O2
Product: O=C1C(=O)c2ccccc2C2=C1SCC1(CCN(C(=O)c3cccc(Cl)c3)CC1)O2

Procedure:
Compound 55 was synthesized using spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione, 3-chlorobenzoyl chloride and conditions outlined in procedure N. M.p.=155-158° C.; 300 MHz 1H NMR (DMSO-d6) δ 7.89 (m, 2H), 7.69 (t, 1H), 7.52 (m, 4H), 7.40 (m, 1H), 4.40 (m, 1H), 3.50 (brm, 2H), 3.24 (m, 1H), 3.11 (s, 2H), 2.08 (m, 1H), 1.90 (m, 3H); LCMS: 440 [M+H].
Reaction SMILES: [OH:1][C@H:2]1[CH2:23][CH2:22][C@@:21]2([CH3:24])[CH:4]([CH2:5][CH2:6][C:7]3[C:8]4[C@:17]([CH3:25])([CH2:18][CH2:19][C:20]=32)[C@@H:11]([C@@H:12]([CH3:16])[CH2:13][CH:14]=O)[CH2:10][CH:9]=4)[C:3]1([CH3:27])[CH3:26].[CH3:28][N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[CH3:28][N:29]1[CH2:34][CH2:33][N:32]([CH2:14][CH2:13][C@@H:12]([C@@H:11]2[C@:17]3([CH3:25])[C:8]([C:7]4[CH2:6][CH2:5][C@@H:4]5[C@:21]([C:20]=4[CH2:19][CH2:18]3)([CH3:24])[CH2:22][CH2:23][C@H:2]([OH:1])[C:3]5([CH3:27])[CH3:26])=[CH:9][CH2:10]2)[CH3:16])[CH2:31][CH2:30]1
Reactant: CN1CCNCC1
Reactant: C[C@@H](CC=O)[C@H]1CC=C2C3=C(CC[C@@]21C)[C@@]1(C)CC[C@H](O)C(C)(C)C1CC3
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: C[C@@H](CCN1CCN(C)CC1)[C@H]1CC=C2C3=C(CC[C@@]21C)[C@@]1(C)CC[C@H](O)C(C)(C)[C@@H]1CC3

Procedure:
(20S)-3β-hydroxy-4,4,20-trimethyl-pregna-8,14-dien-21-carbaldehyde was treated with 1-methylpiperazin and sodium tris(acetoxy)borohydride as described in Example 9d). (20S)-20-[(4-methylpiperazin-1-yl)ethyl]-4,4-dimethyl-5α-pregna-8,14-dien-3β-ol was isolated as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:16]=[C:17]([CH:21]=[CH:22][CH:23]=2)[C:18](O)=[O:19])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:24][C:25]1[CH:26]=[C:27]([NH:32][C:33](=[O:47])[C:34]2[CH:39]=[C:38]([N:40]3[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]3)[CH:37]=[C:36]([F:46])[CH:35]=2)[CH:28]=[CH:29][C:30]=1[CH3:31]>>[F:46][C:36]1[CH:35]=[C:34]([CH:39]=[C:38]([N:40]2[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]2)[CH:37]=1)[C:33]([NH:32][C:27]1[CH:28]=[CH:29][C:30]([CH3:31])=[C:25]([NH:24][C:18](=[O:19])[C:17]2[CH:21]=[CH:22][CH:23]=[C:15]([O:14][CH:11]3[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:13][CH2:12]3)[CH:16]=2)[CH:26]=1)=[O:47]
Reactant: Cc1ccc(NC(=O)c2cc(F)cc(N3CCCCC3)c2)cc1N
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2cccc(C(=O)O)c2)CC1
Product: Cc1ccc(NC(=O)c2cc(F)cc(N3CCCCC3)c2)cc1NC(=O)c1cccc(OC2CCN(C(=O)OC(C)(C)C)CC2)c1
Yield: 59 %

Procedure:
Using an analogous procedure to that described in the first paragraph of Example 50, 3-(1-tert-butoxycarbonylpiperidin-4-yloxy)benzoic acid was reacted with N-(3-amino-4-methylphenyl)-3-fluoro-5-piperidinobenzamide to give N-[5-(3-fluoro-5-piperidinobenzamido)-2-methylphenyl]-3-(1-tert-butoxycarbonylpiperidin-4-yloxy)benzamide in 59% yield; NMR Spectrum: (DMSOd6) 1.38 (s, 9H), 1.59 (m, 8H), 1.95 (m, 1H), 2.19 (s, 3H), 3.20 (m, 6H), 3.64 (m, 2H), 4.63 (m, 1H), 6.90 (d, 1H), 7.02 (d, 1H), 7.22 (m, 3H), 7.41 (t, 1H), 7.57 (m, 3H), 7.78 (s, 1H), 9.83 (s, 1H), 10.13 (s, 1H); Mass Spectrum: M+H+ 631.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][C:18]([O:20]C)=[O:19])[CH:13]=[CH:14][CH:15]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[Na+].[Na+].O>CO>[C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][C:18]([OH:20])=[O:19])[CH:13]=[CH:14][CH:15]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)C=Cc1cccc(CNC(=O)OC(C)(C)C)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)NCc1cccc(C=CC(=O)O)c1
Temperature: 0 °C
Yield: 90.7 %

Procedure:
After a stirred mixture of 4.06 g (14 mmol) of methyl 3-[3-(tert-butoxycarbonyl aminomethyl)phenyl]-2-propenoate, 3.0 g (28.3 mmol) of sodium carbonate, 75 ml of water and 75 ml of methanol was heated at reflux for 5 hours, the produced methanol was distilled off and the solution was cooled to 0° C. and acidified with 1N hydrochloric acid. The resulting mixture was extrated with ethyl acetate. The extracts were washed with brine, dried (Na2SO4) and concentrated. Recrystallization of the residual solid from 1:3 ethyl acetate-hexane gave 3.52 g (91%) of the product as crystals, mp 121°-123° C.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[O:9][CH:8]=[CH:7][C:6]=2[CH:5]=[CH:4][C:3]=1[C:11]([O:13]C)=[O:12]>[OH-].[K+].CO>[CH3:1][C:2]1[C:10]2[O:9][CH:8]=[CH:7][C:6]=2[CH:5]=[CH:4][C:3]=1[C:11]([OH:13])=[O:12]
Reactant: COC(=O)c1ccc2ccoc2c1C
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: Cc1c(C(=O)O)ccc2ccoc12
Yield: 75.1 %

Procedure:
A solution of methyl 7-methyl-1-benzofuran-6-carboxylate (370 mg, 1.95 mmol) in 35% aqueous potassium hydroxide/methanol (1:3, 4 mL) was stirred at reflux for 30 minutes. The methanol was removed under reduced pressure and resultant aqueous portion was brought to pH 2 using 6N aqueous hydrochloric acid. The precipitate which formed was collected by filtration and dried in vacuo to afford (258 mg, 75%) of 7-methyl-1-benzofuran-6-carboxylic acid. 1H NMR (400 MHz, DMSO-d6): 8.17 (d, 1H), 7.78 (d, 1H), 7.54 (d, 1H), 7.03 (d, 1H), 2.72 (s, 3H). MS (EI) for C10H8O3: 177 (MH+).
Reaction SMILES: C([O:4][C@H:5]([CH3:22])[CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[C:19](=[O:20])[C:18]2[NH:17][N:16]=[N:15][C:14]=2[N:13]([CH3:21])[C:11]1=[O:12])(=O)C.Cl.C(OCC)C>CO>[OH:4][C@H:5]([CH3:22])[CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[C:19](=[O:20])[C:18]2[NH:17][N:16]=[N:15][C:14]=2[N:13]([CH3:21])[C:11]1=[O:12]
Reactant: CC(=O)O[C@H](C)CCCCn1c(=O)c2[nH]nnc2n(C)c1=O
Agent: Cl
Solvent: CCOCC
Solvent: CO
Product: C[C@@H](O)CCCCn1c(=O)c2[nH]nnc2n(C)c1=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 11020.4 %

Procedure:
To a stirring solution of (R)-1-(5-acetoxyhexyl)-3-methyl-8-azaxanthine (150 mg, 0.49 mmol) in methanol (25 ml) was added an anhydrous solution of hydrogen chloride in ethyl ether (1 M, 1.0 ml, 1.0 mmol). After stirring at room temperature for 24 hours, the solvent was evaporated under reduced pressure. The crude product was purified by flash chromatography on silica gel eluting with ethyl acetate-methanol (7:1) to provide (R)-1-(5-hydroxyhexyl)-3-methyl-8-azaxanthine (CT12463) (70 mg, 54 mmol) as a white solid.
Reaction SMILES: [CH2:1]([NH:8][C:9]([C:11]1[S:15][C:14]([N:16]2[CH:20](O)[CH2:19][N:18]([CH2:22][C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)[C:17]2=[O:30])=[N:13][C:12]=1[CH3:31])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>C(Cl)(Cl)Cl>[CH2:1]([NH:8][C:9]([C:11]1[S:15][C:14]([N:16]2[CH:20]=[CH:19][N:18]([CH2:22][C:23]3[CH:24]=[CH:25][C:26]([F:29])=[CH:27][CH:28]=3)[C:17]2=[O:30])=[N:13][C:12]=1[CH3:31])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1nc(N2C(=O)N(Cc3ccc(F)cc3)CC2O)sc1C(=O)NCc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Product: Cc1nc(-n2ccn(Cc3ccc(F)cc3)c2=O)sc1C(=O)NCc1ccccc1
Yield: 64 %

Procedure:
To a solution of N-benzyl-2-(3-(4-fluorobenzyl)-5-hydroxy-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxamide (0.22 g, 0.50 mmol) in chloroform (10 mL) was added trifluoroacetic acid (10 mL) at ambient temperature. The resulting reaction mixture was heated to reflux for 8 hours. The solvent was removed in vacuo and the residue was purified by column chromatography to afford the title compound in 64% yield (0.12 g): mp 167-168° C.; 1H NMR (300 MHz, CDCl3) δ 7.34-6.96 (m, 10H), 6.30-6.29 (m, 6.12 (s, 1H), 4.76 (s, 2H), 4.55 (d, J=5.4 Hz, 2H), 2.59 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 162.6, 162.0, 153.4, 152.9, 150.5, 131.4, 129.8, 128.8, 127.8, 117.7, 120.0, 116.1, 115.8, 113.0, 107.6, 46.7, 44.1, 17.2; MS (ES+) m/z 423.2 (M+1).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][CH2:14][C:15](=[S:17])[NH2:16].[Cl:18][CH2:19][C:20](=O)[CH2:21]Cl>C(O)C>[Cl:18][CH2:19][C:20]1[N:16]=[C:15]([CH2:14][CH2:13][C:3]2[N:4]=[C:5]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)[O:6][C:2]=2[CH3:1])[S:17][CH:21]=1
Reactant: Cc1oc(-c2ccccc2)nc1CCC(N)=S
Reactant: O=C(CCl)CCl
Solvent: CCO
Product: Cc1oc(-c2ccccc2)nc1CCc1nc(CCl)cs1
Yield: 49.4 %

Procedure:
A mixture of 3-(5-methyl-2-phenyl-4-oxazolyl)propanethioamide (5.47 g), 1,3-dichloro-2-propanone (3.10 g) and ethanol (100 mL) was heated under reflux for 1 hr. The reaction mixture was concentrated, and ethyl acetate was added to the residue. The organic layer was washed successively with saturated aqueous sodium hydrogencarbonate and saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The obtained residue was subjected to silica gel column chromatography to give crystals (3.50 g, 49%) of 4-[2-(4-chloromethyl-2-thiazolyl)ethyl]-5-methyl-2-phenyloxazole from a fraction eluted with ethyl acetate-hexane (1:3, v/v). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 89-90° C.
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][C:9]1[N:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[S:27]([NH:30][C@H:31]([C:33]([O:35]C(C)(C)C)=[O:34])[CH3:32])(=[O:29])=[O:28])=[CH:17][C:16]=2[F:40])=[CH:11][N:10]=1>C(Cl)Cl>[NH2:8][C:9]1[N:10]=[CH:11][C:12]([C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[S:27]([NH:30][C@H:31]([C:33]([OH:35])=[O:34])[CH3:32])(=[O:29])=[O:28])=[CH:17][C:16]=2[F:40])=[CH:13][N:14]=1
Reactant: C[C@H](NS(=O)(=O)c1ccccc1-c1ccc(-c2cnc(N)nc2)c(F)c1)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@H](NS(=O)(=O)c1ccccc1-c1ccc(-c2cnc(N)nc2)c(F)c1)C(=O)O
Reaction time: 2 h
Yield: 98.9 %

Procedure:
Trifluoroacetic acid (0.5 mL) was added to a solution of tert-butyl N-{[4′-(2-aminopyrimidin-5-yl)-3′-fluorobiphenyl-2-yl]sulfonyl}-L-alaninate (80 mg, 0.17 mmol) in DCM (1 mL) at rt. After 2 hours, the solution was concentrated to dryness and purified by HPLC to afford the title compound (70 mg, 89%). MS (ESI): mass calcd. for C19H17FN4O4S, 416.10; m/z found, 417.1 [M+H]+. 1H NMR (500 MHz, CD3OD) δ 8.72 (s, 2H), 8.10 (dd, J=8.0, 1.2, 1H), 7.66 (m, 1H), 7.61-7.53 (m, 2H), 7.37 (m, 3H), 3.73 (q, J=7.2, 1H), 1.31 (d, J=7.2, 3H).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7]([O:11][C:12]1[CH:13]=[C:14]([CH2:18][CH2:19][NH2:20])[CH:15]=[CH:16][CH:17]=1)[CH2:8][CH2:9][CH3:10].[CH:21]1([CH:27]=[CH:28][C:29](Cl)=[O:30])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1.O>C(#N)C>[CH:21]1([CH:27]=[CH:28][C:29]([NH:20][CH2:19][CH2:18][C:14]2[CH:15]=[CH:16][CH:17]=[C:12]([O:11][CH2:7][CH2:8][CH2:9][CH3:10])[CH:13]=2)=[O:30])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: O=C(Cl)C=CC1CCCCC1
Reactant: CCCCOc1cccc(CCN)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CCCCOc1cccc(CCNC(=O)C=CC2CCCCC2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 53.8 %

Procedure:
Powdered potassium carbonate (4.5 g) was added to a solution of 2-(3-butyloxyphenyl)ethylamine (4.12 g) in acetonitrile (55 cm3). A solution of 3-cyclohexylacryloyl chloride (3.66 g) in acetonitrile (20 cm3) was added dropwise over fifteen minutes and the reaction mixture was then stirred at room temperature for 2 hours. Following treatment with distilled water (75 cm3) and SVM (3 cm3), a white precipitate was formed. This was filtered off and sucked dry to give the product (3.76 g) m.p. 67°-71° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[C:8]([NH2:13])[CH:7]=1.C[O:16][C:17](=O)[CH:18]([CH2:23][C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][C:25]=1[F:31])[C:19](=O)[CH2:20][CH3:21].O1CCOCC1>O>[CH3:1][O:2][C:3](=[O:14])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[C:8]2[C:7]=1[C:17](=[O:16])[C:18]([CH2:23][C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][C:25]=1[F:31])=[C:19]([CH2:20][CH3:21])[NH:13]2
Reactant: CCC(=O)C(Cc1ccc(Cl)cc1F)C(=O)OC
Reactant: COC(=O)COc1ccc(Cl)c(N)c1
Solvent: C1COCCO1
Solvent: O
Product: CCc1[nH]c2c(Cl)ccc(OCC(=O)OC)c2c(=O)c1Cc1ccc(Cl)cc1F
Temperature: 120 °C

Procedure:
A mixture of (3-amino-4-chlorophenoxy)acetic acid methyl ester (0.37 g), 2-(4-chloro-2-fluorobenzyl)-3-oxopentanoic acid methyl ester (0.60 g), polyphosphoric acid (3 g) and dioxane (10 mL) was heated at 120° C. for 23 hours. The reaction mixture was cooled to room temperature, diluted with water and extracted with ethyl acetate. The combined extracts were washed with water, dried over magnesium sulfate and the solvent removed under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with a mixture of ethyl acetate and cyclohexane (1:4 to 1:1 by volume) to afford title compound, 0.082 g.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5](I)=[CH:4][C:3]=1[C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][C:19]=2[C:21]2[CH:26]=[C:25](I)[C:24]([O:28][CH3:29])=[CH:23][C:22]=2[CH3:30])[CH:14]=[CH:13][CH:12]=1.[C:31]1(B(O)O)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C1(C)C=CC=CC=1.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>[CH3:29][O:28][C:24]1[C:25]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[CH:26][C:21]([C:19]2[C:20]3[C:15](=[CH:14][CH:13]=[CH:12][C:11]=3[C:3]3[CH:4]=[C:5]([C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)[C:6]([O:8][CH3:9])=[CH:7][C:2]=3[CH3:1])[CH:16]=[CH:17][CH:18]=2)=[C:22]([CH3:30])[CH:23]=1
Reactant: OB(O)c1ccccc1
Reactant: COc1cc(C)c(-c2cccc3cccc(-c4cc(I)c(OC)cc4C)c23)cc1I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: COc1cc(C)c(-c2cccc3cccc(-c4cc(-c5ccccc5)c(OC)cc4C)c23)cc1-c1ccccc1
Yield: 175 %

Procedure:
A solution of 5a (0.20 g, 0.32 mmol), phenylboronic acid (0.12 g, 0.96 mmol), Pd(PPh3)4 (0.055 g, 0.048 mmol) and K3PO4, (0.31 g, 1.44 mmol) in 5 mL of toluene was stirred at 110° C. for 18 hours. The resulting mixture was allowed to come to room temperature, quenched with water and extracted with CH2Cl2. The combined organic layers were dried over MgSO4 and concentrated in vacuo. Purification by flash chromatography on silica gel (CH2Cl2:hexanes 1:2) afforded 0.14 g (0.28 mmol, 87%) of 6 as a white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[CH3:12])[NH:8][C:7](=[O:13])[C:6](=[O:14])[NH:5]2.[N+:15]([O-])([OH:17])=[O:16]>OS(O)(=O)=O>[CH3:12][C:11]1[C:10]([N+:15]([O-:17])=[O:16])=[C:9]2[C:4](=[CH:3][C:2]=1[CH3:1])[NH:5][C:6](=[O:14])[C:7](=[O:13])[NH:8]2
Reactant: O=[N+]([O-])O
Reactant: Cc1cc2[nH]c(=O)c(=O)[nH]c2cc1C
Agent: O=S(=O)(O)O
Product: Cc1cc2[nH]c(=O)c(=O)[nH]c2c([N+](=O)[O-])c1C
Temperature: 25 °C
Reaction time: 48 h
Yield: 60 %

Procedure:
To a solution of 1.90 g (10.0 mmol) of 6,7-dimethyl-1,4-dihydroquinoxaline-2,3-dione in 25 mL of H2SO4 (97%) kept in an ice bath was added dropwise 1.2 mL of HNO3 (69-70%) and the solution was stirred at room temperature for 48 h. It was poured into 300 mL of ice-water and stirred for 10 min. The mixture was filtered, washed with water, and dried to leave a yellow solid 1.40 g (60%). The solid was purified by DMSO/H2O precipitation followed by NaOH/HCl precipitation to leave 0.85 g of a yellow solid; mp >250° C.; 1H NMR (DMSO-d6), 2.079 (s,3), 2.246 (s,3), 7.048 (s,1), 11.770 (s,1), 12.030 (s,1). HRMS calcd. for C10H9N3O4 235.0588; found 235.0584.
Reaction SMILES: [O-]CC.[Mg+2].[O-]CC.[C:8]([O:16][CH2:17][CH3:18])(=[O:15])[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11].[Br:19][C:20]1[C:21]([Cl:31])=[C:22]([CH:26]=[C:27]([F:30])[C:28]=1[F:29])[C:23](Cl)=[O:24].S(=O)(=O)(O)O>C1(C)C=CC=CC=1>[Br:19][C:20]1[C:21]([Cl:31])=[C:22]([CH:26]=[C:27]([F:30])[C:28]=1[F:29])[C:23]([CH:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:8]([O:16][CH2:17][CH3:18])=[O:15])=[O:24]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: O=C(Cl)c1cc(F)c(F)c(Br)c1Cl
Agent: CC[O-]
Agent: O=S(=O)(O)O
Agent: [Mg+2]
Solvent: Cc1ccccc1
Product: CCOC(=O)C(C(=O)OCC)C(=O)c1cc(F)c(F)c(Br)c1Cl
Temperature: 0 °C
Reaction time: 3 h
Yield: 104.8 %

Procedure:
To the magnesium ethoxide (3.93 g) suspension was added a solution of diethyl malonate (4.65 g) in anhydrous toluene (30 ml) dropwise during 25 minutes at 20° to 25° C. The mixture was stirred at 50° to 60° C. for 3 hours, and then cooled in an acetone-dry ice bath. A solution of 3-bromo-2-chloro-4,5-difluorobenzoyl chloride (7.65 g) in anhydrous toluene (15 ml) was added dropwise to the resulting solution at -16° to 0° C. during 25 minutes. The mixture was stirred for 2.5 hours below 0° C., then further stirred at room temperature for 40 minutes, and then mixed with ice water (15 ml) containing concentrated sulfuric acid (1 ml). The resulting organic layer was collected and the water layer was extracted with toluene. The combined organic layer was washed with water, dried over anhydrous sodium sulfate and then concentrated to give the title compound (11.44 g) as pale yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][S:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])/[C:16]/2=[CH:23]\[C:24]1[NH:28][C:27]([CH3:29])=[C:26]([CH2:30][CH2:31][C:32]([OH:34])=O)[C:25]=1[CH3:35])(=[O:12])=[O:11].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH:69]1([NH:72][CH2:73][C@@H:74]2[CH2:78][CH2:77][CH2:76][NH:75]2)[CH2:71][CH2:70]1>CN(C=O)C>[CH:69]1([NH:72][CH2:73][C@@H:74]2[CH2:78][CH2:77][CH2:76][N:75]2[C:32](=[O:34])[CH2:31][CH2:30][C:26]2[C:25]([CH3:35])=[C:24](/[CH:23]=[C:16]3\[C:17](=[O:22])[NH:18][C:19]4[C:15]\3=[CH:14][C:13]([S:10]([CH2:9][C:3]3[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][C:4]=3[Cl:8])(=[O:12])=[O:11])=[CH:21][CH:20]=4)[NH:28][C:27]=2[CH3:29])[CH2:71][CH2:70]1
Reactant: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1CCC(=O)O
Reactant: C1CN[C@H](CNC2CC2)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1CCC(=O)N1CCC[C@H]1CNC1CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 3-{5-[5-(2,6-dichloro-phenylmethanesulfonyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrol-3-yl}-propionic acid (100 mg, 0.19 mmol) and DIPEA (45 mg, 1.9 eq.) in DMF (2 mL) was stirred at rt for 30 mins. To the mixture was added HATU (85 mg, 1.2 eq.). After stirring for another 3 hours, to the mixture was added cyclopropyl-(S)-1-pyrrolidin-2-ylmethyl-amine (29 mg, 1.1 eq.). After stirring for 72 hours, the reaction was concentrated and purified on a silica gel column to give the titled compound as an orange solid.