Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([F:13])[CH:5]=[C:6]2[C:11]=1[N:10]=[C:9](O)[N:8]=[CH:7]2.P(Cl)(Cl)([Cl:16])=O>>[Br:1][C:2]1[CH:3]=[C:4]([F:13])[CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([Cl:16])[N:8]=[CH:7]2
Reactant: O=P(Cl)(Cl)Cl
Reactant: Oc1ncc2cc(F)cc(Br)c2n1
Product: Fc1cc(Br)c2nc(Cl)ncc2c1
Reaction time: 0.33 h
Yield: 89 %

Procedure:
A 0.5M suspension of 8-bromo-6-fluoroquinazolin-2-ol in phosphorus oxychloride was heated to 110° C. in an oil bath. The suspension was turned to a brown color solution in 20 min. LCMS data showed that the reaction was complete after 1 h. The phosphorus oxychloride was removed by concentration. The residue was mixed with ice water, and adjusted pH to 7 by adding sodium bicarbonate. Reaction mixture was extracted with ethyl acetate. Combined organic phase was washed with water, brine, dried over sodium sulfate and concentrated to give desired product in 89% yield. ES/MS m/z 261/263 (MH+).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:22])[CH2:10][C@H:11]([NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:12][OH:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CN=C1.[C:28]([Si:32](Cl)([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)([CH3:31])([CH3:30])[CH3:29]>CN(C)C=O.O>[CH2:1]([O:8][C:9](=[O:22])[CH2:10][C@H:11]([NH:14][C:15]([O:17][C:18]([CH3:19])([CH3:21])[CH3:20])=[O:16])[CH2:12][O:13][Si:32]([C:28]([CH3:31])([CH3:30])[CH3:29])([C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@H](CO)CC(=O)OCc1ccccc1
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@H](CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)CC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of (S)-3-tert-butoxycarbonylamino-4-hydroxy-butyric acid benzyl ester (1.34 g, 4.37 mmol) (prepared using the method of Rodriguez, Marc; Linares, Muriel; Doulut, Sylvie; Heitz, Annie; Martinez, Jean; Tetrahedron Lett. (1991), 32(7), 923-6) and imidazole (0.88 g, 13.01 mmol in dimethylformamide (7 ml) is treated with tertbutyldiphenylsilyl chloride (1.69 ml, 6.5 mmol). The reaction mixture is stirred together at room temperature for 1 hour, then diluted with water and extracted into ethylacetate. The ethylacetate phase is dried over MgSO4 and evaporated. The crude product is purified by flash silica chromatography (elution with 1:1 ethylacetate/hexane) to afford (S)-3-tert-butoxycarbonylamino-4-(tert-butyl-diphenyl-silanyloxy)-butyric acid benzyl ester. [M-BOC] 448.0.
Reaction SMILES: C([O:3][C:4](=[O:23])[C:5]([CH2:15][C:16]1[CH:21]=[CH:20][C:19](O)=[CH:18][CH:17]=1)([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH2:6][CH3:7])C.[C:24]1([C:30]2[O:31][C:32]([CH3:48])=[C:33]([CH2:35][CH2:36][O:37]S(C3C=CC(C)=CC=3)(=O)=O)[N:34]=2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[CH3:48][C:32]1[O:31][C:30]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)=[N:34][C:33]=1[CH2:35][CH2:36][O:37][C:19]1[CH:20]=[CH:21][C:16]([CH2:15][C:5]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)([CH2:6][CH3:7])[C:4]([OH:23])=[O:3])=[CH:17][CH:18]=1
Reactant: Cc1ccc(S(=O)(=O)OCCc2nc(-c3ccccc3)oc2C)cc1
Reactant: CCOC(=O)C(CC)(Cc1ccc(O)cc1)Oc1ccccc1
Product: CCC(Cc1ccc(OCCc2nc(-c3ccccc3)oc2C)cc1)(Oc1ccccc1)C(=O)O

Procedure:
The Standard Procedure (B) was utilized to prepare the title compound from 2-(4-hydroxybenzyl)-2-phenoxybutyric acid ethyl ester and toluene-4-sulfonic acid 2-(2-phenyl-5-methyl-oxazol-4-yl)-ethyl ester. 1H NMR (400 MHz, CDCl3) δ 7.99-7.94 (m, 2H), 7.44-7.40 (m, 3H), 7.32-7.28 (m, 2H), 7.07 (t, 1H, J=7.4 Hz), 7.02-6.97 (m, 4H), 6.79-6.74 (m, 2H), 4.18 (t, 2H, J=6.6 Hz), 3.29 (s, 2H), 2.98 (t, 2H, J=6.6 Hz), 2.37 (s, 3H), 2.14 (qd, 1H, J=14.8, 7.6 Hz), 2.07 (qd, 1H, J=14.8, 7.6 Hz), 0.91 (t, 3H, J=7.6 Hz).
Reaction SMILES: I[C:2]1[C:10]2[CH2:9][CH2:8][O:7][C:6](=[O:11])[C:5]=2[S:4][CH:3]=1.[CH3:12]B(O)O.C([O-])([O-])=O.[Na+].[Na+].[OH-].[Na+].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C([O-])(O)=O.[Na+]>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.CCO.O.C(COC)OC>[CH3:12][C:2]1[C:10]2[CH2:9][CH2:8][O:7][C:6](=[O:11])[C:5]=2[S:4][CH:3]=1
Reactant: CB(O)O
Reactant: O=C1OCCc2c(I)csc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Solvent: CCO
Solvent: COCCOC
Solvent: O
Product: Cc1csc2c1CCOC2=O
Temperature: 25 °C
Yield: 22.1 %

Procedure:
Mix 3-iodo-4,5-dihydro-thieno[2,3-c]pyran-7-one (1.0, 3.57 mmol) and methyl boronic acid (428 mg, 7.14 mmol) in 7:3:1 dimethoxyethane:water:EtOH (10 mL) and add 2.0 M Na2CO3 (3.5 mL). Bubble dry argon gas through the reaction mixture for 10-15 min to remove oxygen. Add Pd(PPh3)4 (210 mg, 0.18 mmol) and heat using microwave irradiation to 130° C. for 45 min. Pour into 1 N NaOH (50 mL) and wash with hexanes (50 mL). Acidify the aqueous layer with 5N HCl until pH=1 and extract with EtOAc (3×50 mL). Wash the combined organic extracts with brine (50 mL). Concentrate, then add toluene (35 mL) to the crude intermediate. Add p-toluenesulfonic acid monohydrate (339 mg, 1.8 mmol) and heat to 80° C. overnight. Cool to RT, pour into aqueous NaHCO3 (100 mL) and extract with EtOAc (3×100 mL). Wash the combined extracts with brine (100 mL). Dry the organic portion, filter and concentrate. Purify using silica gel chromatography (0-50% EtOAc/hexanes) to provide 133 mg (22%) of the desired product. ES/MS m/z 169.3 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[O:13][N:12]=[CH:11][C:10]=1[CH2:14][CH2:15][C:16]([OH:18])=[O:17].S(=O)(=O)(O)O.[CH3:24]O>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[O:13][N:12]=[CH:11][C:10]=1[CH2:14][CH2:15][C:16]([O:18][CH3:24])=[O:17]
Reactant: O=C(O)CCc1cnoc1-c1ccc(Cl)cc1Cl
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)CCc1cnoc1-c1ccc(Cl)cc1Cl
Yield: 94 %

Procedure:
A mixture of 3-[5-(2,4-dichlorophenyl)-4-isoxazolyl]propionic acid (3.00 g), conc. sulfuric acid (0.1 ml) and methanol (50 ml) was refluxed for 4 hr. The reaction mixture was concentrated, water was added to the residue and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and methyl 3-[5-(2,4-dichlorophenyl)-4-isoxazolyl]propionate (2.96 g, yield 94%) was obtained as a colorless oil from a fraction eluted with ethyl acetate-hexane (1:4, volume ratio). NMR (CDCl3) δ: 2.46–2.58 (2H, m), 2.71–2.81 (2H, m), 3.66 (3H, s), 7.35–7.42 (2H, m), 7.54–7.58 (1H, m), 8.28 (1H, s).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([SH:8])[N:5]=[C:4]([OH:9])[CH:3]=1.CC(O)=O.N[C@@H:15]([CH2:17][OH:18])[CH3:16]>O>[OH:18][CH2:17][C@H:15]([NH:1][C:2]1[N:7]=[C:6]([SH:8])[N:5]=[C:4]([OH:9])[CH:3]=1)[CH3:16]
Reactant: C[C@@H](N)CO
Reactant: Nc1cc(O)nc(S)n1
Solvent: CC(=O)O
Solvent: O
Product: C[C@H](CO)Nc1cc(O)nc(S)n1
Temperature: 50 °C

Procedure:
6-Amino-2-mercapto-4-pyrimidinol (16.1 g), AcOH (14.3 ml) and (R)-Alaninol (39 ml) were heated at 170° C. for 5 h. The mixture was cooled to approximately 50° C., diluted with water (500 ml) and cooled at 0° C. for 20 h. The resulting solid was filtered, washed with water and dried in vacuo to yield a mixture of subtitle product and starting material (2:1) as a cream coloured solid. Yield 7.2 g.
Reaction SMILES: [N+:1]([C:4]1[CH:31]=[CH:30][C:7]([NH:8][C:9]2[CH:10]=[C:11]3[C:16](=[O:17])[NH:15][C:13](=[O:14])[C:12]3=[CH:18][C:19]=2[NH:20][C:21]2[CH:26]=[CH:25][C:24]([N+:27]([O-])=O)=[CH:23][CH:22]=2)=[CH:6][CH:5]=1)([O-])=O>C1COCC1.[Ni]>[NH2:27][C:24]1[CH:25]=[CH:26][C:21]([NH:20][C:19]2[CH:18]=[C:12]3[C:13](=[O:14])[NH:15][C:16](=[O:17])[C:11]3=[CH:10][C:9]=2[NH:8][C:7]2[CH:30]=[CH:31][C:4]([NH2:1])=[CH:5][CH:6]=2)=[CH:22][CH:23]=1
Reactant: O=C1NC(=O)c2cc(Nc3ccc([N+](=O)[O-])cc3)c(Nc3ccc([N+](=O)[O-])cc3)cc21
Agent: [Ni]
Solvent: C1CCOC1
Product: Nc1ccc(Nc2cc3c(cc2Nc2ccc(N)cc2)C(=O)NC3=O)cc1

Procedure:
A solution of 38 mg (0.09 mmol) of 4,5-bis(4-nitroanilino)phthalimide in 15 ml of THF is hydrogenated with 10% Raney nickel as catalyst for three hours at normal pressure and room temperature. The catalyst is filtered off and the reaction mixture is concentrated by evaporation, yielding the title compound in the form of a slightly yellowish powder: m.p. 154°-157° C., FAB-MS: 360 (M+ +H).
Reaction SMILES: CO[NH:3][C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH3:12])[N:7]=1)=[NH:5].[Cl-].[NH4+]>CCO.O>[CH3:12][C:8]1[N:7]=[C:6]([C:4]([NH2:5])=[NH:3])[CH:11]=[CH:10][CH:9]=1
Reactant: CONC(=N)c1cccc(C)n1
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: Cc1cccc(C(=N)N)n1
Temperature: 80 °C

Procedure:
To a solution of N-methoxy-6-methyl-pyridine-2-carboxamidine (1 eq, 32.9 mmol, 4.94 g) in EtOH (40 ml) and water (10 ml) at room temperature is added ammonium chloride (1 eq, 32.9 mmol, 1.76 g). The resulting mixture is heated to 80° C. for 4 hours and then allowed to cool to room temperature overnight. The solvent is removed in vacuo to afford the title compound which is used in subsequent steps without further purification [2M+H]+=271
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]([CH3:30])([CH2:17][NH:18][S:19]([C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=1[Cl:29])(=[O:21])=[O:20])[C:13]([O:15]C)=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].C([O-])(O)=O.[Na+].Cl>CO.O>[CH2:1]([O:8][C:9]([NH:11][C:12]([CH3:30])([CH2:17][NH:18][S:19]([C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=1[Cl:29])(=[O:20])=[O:21])[C:13]([OH:15])=[O:14])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)C(C)(CNS(=O)(=O)c1ccc(Cl)cc1Cl)NC(=O)OCc1ccccc1
Agent: Cl
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CO
Product: CC(CNS(=O)(=O)c1ccc(Cl)cc1Cl)(NC(=O)OCc1ccccc1)C(=O)O
Temperature: 60 °C
Reaction time: 2 h
Yield: 87.7 %

Procedure:
0.08 g (0.168 mmol) of methyl 2-benzyloxycarbonylamino-3-(2,4-dichlorobenzenesulfonylamino)-2-methylpropionate and 0.093 g (0.674 mmol) of potassium carbonate are stirred in a mixture of 4.5 ml of MeOH and 0.5 ml of water for 90 min. Then 3 ml of saturated NaHCO3 solution are added, and the mixture is stirred at 60° C. for 2 h. 0.5 ml of water is added, followed by 4N HCl (aq) until a pH of 2 is reached. The solution is extracted 3 times with 10 ml of EtOAc each time, the combined organic phases are dried over MgSO4, and the solvent is removed in vacuo. 68 mg of the desired product are obtained. MW=460 (calculated, monoisotopic), measured value: (M+H)+461.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[O:3][C:4]1[CH:12]=[CH:11][C:7]([C:8](Cl)=[O:9])=[CH:6][CH:5]=1.[NH2:15][C@:16]([CH3:30])([CH2:19][N:20]1[CH:29]=[C:23]2[N:24]=[CH:25][C:26]([Br:28])=[CH:27][C:22]2=[N:21]1)[C:17]#[N:18]>C1COCC1>[Br:28][C:26]1[CH:25]=[N:24][C:23]2=[CH:29][N:20]([CH2:19][C@@:16]([NH:15][C:8](=[O:9])[C:7]3[CH:11]=[CH:12][C:4]([O:3][C:2]([F:14])([F:13])[F:1])=[CH:5][CH:6]=3)([C:17]#[N:18])[CH3:30])[N:21]=[C:22]2[CH:27]=1
Reactant: C[C@](N)(C#N)Cn1cc2ncc(Br)cc2n1
Reactant: O=C(Cl)c1ccc(OC(F)(F)F)cc1
Solvent: C1CCOC1
Product: C[C@](C#N)(Cn1cc2ncc(Br)cc2n1)NC(=O)c1ccc(OC(F)(F)F)cc1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
4-Trifluoromethoxybenzoyl chloride (14.5 mL) was added at around 0° C. to a cold solution of (R)-2-amino-3-(6-bromo-pyrazolo[4,3-b]pyridin-2-yl)-2-methyl-propionitrile (23.4 g, 95% ee) in dry THF (600 mL) mixed with TEA (13.4 mL). The reaction mixture was stirred for around 4 hours at around 0° C. The cold reaction mixture was then filtered through a short plug of Celite® and basic alumina and solvent evaporated under reduced pressure. The resulting residue was triturated with DCM to afford a solid that was isolated by filtration to give the title compound as a white solid (28.6 g, 73.1%, 99.6% analytical purity, 99% ee). The filtrate was collected and solvent evaporated under reduced pressure. The residue was loaded on silica gel and purified by chromatography (SiO2, heptane/EA) to afford a second crop of title compound as a white solid (4.1 g, 10.5%). MS (ES): M/Z [M+H]=468. 1H NMR: (400 MHz, CHLOROFORM-d): 1.94 (s, 3H), 4.86 (d, J=14.0 Hz, 1H), 5.02 (d, J=14.0 Hz, 1H), 7.33 (d, J=8.1 Hz, 2H), 7.83-7.92 (m, 2H), 8.02 (s, 1H), 8.21 (dd, J=2.0, 0.7 Hz, 1H), 8.40 (d, J=0.7 Hz, 1H) and 8.62 (d, J=2.0 Hz, 1H). 19F NMR (376 MHz, CHLOROFORM-d): −58.1 (s, 3F).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:10]=[C:9]([C:11]([OH:13])=O)[CH:8]=[CH:7][CH:6]=1)=[O:4].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.[NH2:39][CH2:40][C:41]1[C:46]([CH2:47][CH3:48])=[N:45][C:44]2[N:49]([CH2:52][CH3:53])[N:50]=[CH:51][C:43]=2[C:42]=1[NH:54][CH:55]1[CH2:60][CH2:59][O:58][CH2:57][CH2:56]1>ClCCl>[CH2:52]([N:49]1[C:44]2=[N:45][C:46]([CH2:47][CH3:48])=[C:41]([CH2:40][NH:39][C:11]([C:9]3[N:10]=[C:5]([C:3]([O:2][CH3:1])=[O:4])[CH:6]=[CH:7][CH:8]=3)=[O:13])[C:42]([NH:54][CH:55]3[CH2:56][CH2:57][O:58][CH2:59][CH2:60]3)=[C:43]2[CH:51]=[N:50]1)[CH3:53]
Reactant: COC(=O)c1cccc(C(=O)O)n1
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CN
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)OC)n1
Temperature: 25 °C
Yield: 87 %

Procedure:
6-[(Methyloxy)carbonyl]-2-pyridinecarboxylic acid (272 mg, 1.500 mmol) was dissolved in dichloromethane (50 mL) and stirred under argon at room temperature. Then HBTU (569 mg, 1.500 mmol) was added followed by 5-(aminomethyl)-1,6-diethyl-N-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-b]pyridin-4-amine hydrochloride (510 mg, 1.5 mmol) and then the TEA (0.418 mL, 3.00 mmol). The mixture was stirred under argon overnight. The solvent was evaporated, and the residue partitioned between EtOAc (75 mL) and water (25 ml). The organic phase was washed with water (3×25 mL), brine, dried over anhydrous sodium sulfate, filtered and evaporated to give the crude residue. It was purified by CombiFlash on a 12 gram silica column eluted with 60-100% EtOAc in hexane. Product fractions were combined and concentrated to give methyl 6-[({[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}amino)carbonyl]-2-pyridinecarboxylate (609 mg, 1.305 mmol, 87% yield) as a white solid. LC-MS m/z 467 (M+H)+, 0.74 min (ret time).
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13]([C:18]([N:20]1[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]1)=[O:19])=[CH:12]2)C1C=CC=CC=1>C(O)C.C(OC(=O)C)C.[Pd]>[OH:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13]([C:18]([N:20]1[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]1)=[O:19])=[CH:12]2
Reactant: CN1CCN(C(=O)c2cc3cc(OCc4ccccc4)ccc3[nH]2)CC1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CN1CCN(C(=O)c2cc3cc(O)ccc3[nH]2)CC1
Yield: 22.9 %

Procedure:
A mixture of the product of Example 5, (5-Benzyloxy-1H-indol-2-yl)-(4-methyl-piperazin-1-yl)-methanone (0.2 g) in a mixture of ethanol (3 mL) and ethylacetate (5 mL) was treated with 10% palladium on carbon (approximately 0.025 g) and hydrogenated at atmospheric pressure for 2 h. The reaction mixture was filtered through a pad of Celite and the residue washed with methanol. The solvent in the combined filtrates was removed under reduced pressure, and the residue was purified via silica gel chromatography (3-10% 2 M ammonia in methanol/dichloromethane) to afford the title compound (0.034 g, 23%). 1H NMR (400 MHz, CD3OD): δ 7.20 (d, J=8.0 Hz, 1H), 6.90 (m, 1H), 6.75 (dd, J=4, 8 Hz, 1H), 6.54 (m,1H), 3.80 (br.m, 4H), 2.44 (m, 4H), 2.27 (s, 3H). MS (electrospray): exact mass calculated for C14H17N3O2, 259.13; m/z found, 260.0 [M+H]+.
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][C:8]([NH2:10])=[CH:9][C:4]=2[NH:3][CH:2]=1.[Cl:11][C:12]1[CH:22]=[CH:21][C:15]2[S:16][CH:17]=[C:18]([CH2:19]Br)[C:14]=2[CH:13]=1.C([O-])([O-])=O.[K+].[K+]>>[Cl:11][C:12]1[CH:22]=[CH:21][C:15]2[S:16][CH:17]=[C:18]([CH2:19][N:10]([CH2:19][C:18]3[C:14]4[CH:13]=[C:12]([Cl:11])[CH:22]=[CH:21][C:15]=4[S:16][CH:17]=3)[C:8]3[CH:7]=[CH:6][C:5]4[NH:1][CH:2]=[N:3][C:4]=4[CH:9]=3)[C:14]=2[CH:13]=1
Reactant: Nc1ccc2nc[nH]c2c1
Reactant: Clc1ccc2scc(CBr)c2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Clc1ccc2scc(CN(Cc3csc4ccc(Cl)cc34)c3ccc4[nH]cnc4c3)c2c1

Procedure:
The compound was synthesized starting from benzimidazol-5-amine (133 mg; 1 mmol; 1 eq.), (5-chlorobenzo[b]thiophen-3-yl)methylbromide (576 mg; 2.2 mmol; 2.2 eq.) and K2CO3 (304 mg; 2.2 mmol; 2.2 eq.) according to method 5; Yield: 0.187 g (37.9%); MS m/z: 494.4/496.5 [M+H]+; 1H-NMR (500 MHz, DMSO d6): δ 4.84 (s, 4H); 6.90-6.92 (m, 2H); 7.37-7.39 (m, 3H); 7.51 (s, 2H); 7.88 (d, 2H); 7.94-7.96 (m, 2H); 7.98 (s, 1H); 12.00 (br s, 1H); HPLC (METHOD [A]): rt 19.77 min (100%)
Reaction SMILES: [CH3:1][N:2]([CH3:20])[C:3](=[O:19])[NH:4][C:5]1[CH:6]=[CH:7][C:8]2[N:9]([CH:11]=[C:12]([C:14]([O:16]CC)=[O:15])[N:13]=2)[CH:10]=1.[OH-].[Na+]>C(O)C>[CH3:1][N:2]([CH3:20])[C:3](=[O:19])[NH:4][C:5]1[CH:6]=[CH:7][C:8]2[N:9]([CH:11]=[C:12]([C:14]([OH:16])=[O:15])[N:13]=2)[CH:10]=1
Reactant: CCOC(=O)c1cn2cc(NC(=O)N(C)C)ccc2n1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CN(C)C(=O)Nc1ccc2nc(C(=O)O)cn2c1
Temperature: 0 °C
Yield: 112.9 %

Procedure:
Ethyl 6-(3,3-dimethylureido)imidazo[1,2-a]pyridine-2-carboxylate (0.239 mmol, 0.066 g) was dissolved in ethanol (5 ml). The solution was cooled to 0° C. and NaOH 2 M solution (0.478 mmol, 0.239 ml) was added. The resulting mixture was stirred at 0° C. Ethanol was evaporated and water was added. The pH of the water phase was adjusted to ˜4 with HCl. The mixture was extracted with EtOAc and the organic phase was dried, filtered and evaporated. The residue was triturated with MeOH/DCM 1/9. The filtered precipitate was dried under vacuum. 0.067 g of the title compound was obtained. LC-MS: [M−1]=247.24.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:12])=[C:4]([CH:8]=[CH:9][C:10]=1[F:11])[C:5]([OH:7])=[O:6].[N+:13]([O-])([OH:15])=[O:14]>>[N+:13]([C:9]1[C:10]([F:11])=[C:2]([Cl:1])[C:3]([F:12])=[C:4]([CH:8]=1)[C:5]([OH:7])=[O:6])([O-:15])=[O:14]
Reactant: O=C(O)c1ccc(F)c(Cl)c1F
Reactant: O=[N+]([O-])O
Product: O=C(O)c1cc([N+](=O)[O-])c(F)c(Cl)c1F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
An amount of 1 g of 3-chloro-2,4-difluorobenzoic acid is added to a mixture of 1 ml of fuming nitric acid and 1.3 ml of sulfuiric acid at 0° C. The suspension is then stirred at room temperature for 30 minutes and poured on ice. Filtration affords the desired product.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][C:9]([N+:13]([O-:15])=[O:14])=[CH:10][CH:11]=2)[C:6](=[C:16](Cl)[C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=2)[C:5]1=[O:25])(=O)C.[CH3:26][N:27]([CH2:29][C:30]1[CH:36]=[CH:35][C:33]([NH2:34])=[CH:32][CH:31]=1)[CH3:28].[OH-].[Na+]>CN(C=O)C.CO>[CH3:28][N:27]([CH2:29][C:30]1[CH:31]=[CH:32][C:33]([NH:34]/[C:16](=[C:6]2\[C:5](=[O:25])[NH:4][C:12]3[C:7]\2=[CH:8][C:9]([N+:13]([O-:15])=[O:14])=[CH:10][CH:11]=3)/[C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=2)=[CH:35][CH:36]=1)[CH3:26]
Reactant: CN(C)Cc1ccc(N)cc1
Reactant: CC(=O)N1C(=O)C(=C(Cl)c2ccc(C)cc2)c2cc([N+](=O)[O-])ccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CN(C)C=O
Product: Cc1ccc(/C(Nc2ccc(CN(C)C)cc2)=C2/C(=O)Nc3ccc([N+](=O)[O-])cc32)cc1

Procedure:
Prepared analogously to Example 2 from 1-acetyl-3-[1-chloro-1-(p-tolyl)-methylidene)-5-nitro-2-indolinone and 4-dimethylaminomethyl-aniline in DMF and subsequent treatment with sodium hydroxide solution in methanol.
Reaction SMILES: C(C1C=CC(C2C=C(C)SC=2CO)=CC=1)C.OC1C=CC(CCC(OCC)=O)=C(F)C=1F.[CH2:33]([C:35]1[CH:40]=[CH:39][C:38]([C:41]2[CH:45]=[C:44]([CH3:46])[S:43][C:42]=2[CH2:47][O:48][C:49]2[CH:54]=[CH:53][C:52]([CH2:55][CH2:56][C:57]([O:59]CC)=[O:58])=[C:51]([F:62])[C:50]=2[F:63])=[CH:37][CH:36]=1)[CH3:34]>>[CH2:33]([C:35]1[CH:36]=[CH:37][C:38]([C:41]2[CH:45]=[C:44]([CH3:46])[S:43][C:42]=2[CH2:47][O:48][C:49]2[CH:54]=[CH:53][C:52]([CH2:55][CH2:56][C:57]([OH:59])=[O:58])=[C:51]([F:62])[C:50]=2[F:63])=[CH:39][CH:40]=1)[CH3:34]
Reactant: CCOC(=O)CCc1ccc(OCc2sc(C)cc2-c2ccc(CC)cc2)c(F)c1F
Agent: CCOC(=O)CCc1ccc(O)c(F)c1F
Agent: CCc1ccc(-c2cc(C)sc2CO)cc1
Product: CCc1ccc(-c2cc(C)sc2COc2ccc(CCC(=O)O)c(F)c2F)cc1

Procedure:
The title compound was prepared according to the procedure described in Example 208 by coupling of (3-(4-ethylphenyl)-5-methylthiophen-2-yl)methanol and ethyl 3-(4-hydroxy-2,3-difluoro phenyl)propanoate followed by hydrolysis of ethyl 3-(4-((3-(4-ethylphenyl)-5-methylthiophen-2-yl)methoxy)-2,3-difluorophenyl)propanoate to afford the desired product as an off-white solid. 1H NMR (400 MHz, CDCl3) δ 7.55 (d, J=7.9 Hz, 2H), 7.30 (s, 1H), 7.25 (d, J=7.5 Hz, 2H), 7.02 (d, J=7.8 Hz, 1H), 6.68 (d, J=7.5 Hz, 1H), 5.10 (s, 2H), 2.98 (t, J=7.5 Hz, 2H), 2.71 (m, J=7.8 Hz, 2H), 2.68 (t, J=6.5 Hz, 2H), 2.55 (s, 3H), 1.36 (t, J=8.5 Hz, 3H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:36]=[CH:37][CH:38]=1)[CH2:6][N:7]([C:29]1[CH:34]=[CH:33][C:32]([OH:35])=[CH:31][CH:30]=1)[CH:8]1[CH2:13][CH2:12][N:11]([CH:14]([CH3:28])[CH2:15][CH2:16][NH:17][C:18](=[O:27])[C:19]2[C:24]([CH3:25])=[CH:23][CH:22]=[CH:21][C:20]=2[CH3:26])[CH2:10][CH2:9]1)#[N:2].C([O-])([O-])=O.[K+].[K+].Br[CH2:46][C:47]([O:49][CH3:50])=[O:48]>CN(C=O)C>[CH3:50][O:49][C:47](=[O:48])[CH2:46][O:35][C:32]1[CH:33]=[CH:34][C:29]([N:7]([CH2:6][C:5]2[CH:36]=[CH:37][CH:38]=[C:3]([C:1]#[N:2])[CH:4]=2)[CH:8]2[CH2:13][CH2:12][N:11]([CH:14]([CH3:28])[CH2:15][CH2:16][NH:17][C:18](=[O:27])[C:19]3[C:24]([CH3:25])=[CH:23][CH:22]=[CH:21][C:20]=3[CH3:26])[CH2:10][CH2:9]2)=[CH:30][CH:31]=1
Reactant: Cc1cccc(C)c1C(=O)NCCC(C)N1CCC(N(Cc2cccc(C#N)c2)c2ccc(O)cc2)CC1
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)COc1ccc(N(Cc2cccc(C#N)c2)C2CCN(C(C)CCNC(=O)c3c(C)cccc3C)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.2 %

Procedure:
To a solution of COMPOUND 117 (102 mg, 0.20 mmol) in DMF (1 mL) were added K2CO3 (86 mg, 0.62 mmol) followed by methyl bromoacetate (40 μL, 0.42 mmol) and the mixture was stirred at room temperature overnight to afford COMPOUND 147 as a tan solid (97 mg, 82%) following work-up and purification. 1H NMR (CDCl3) δ 0.90-1.13 (m, 2H), 0.99 (d, 3H, J=6.3 Hz), 1.49-1.54 (m, 1H), 1.69-1.81 (m, 3H), 2.12 (t, 1H, J=12.0 Hz), 2.31 (s, 6H), 2.53 (t, 1H, J=11.7 Hz), 2.73-2.88 (m, 3H), 3.24-3.31 (m, 1H), 3.41-3.49 (m, 1H), 3.71 (s, 2H), 3.78 (s, 3H), 3.86-3.90 (m, 1H), 4.52 (s, 2H), 6.51 (d, 2H, J=8.1 Hz), 6.73 (d, 2H, J=8.4 Hz), 6.94-7.00 (m, 3H), 7.42-7.50 (m, 4H), 8.42 (br s, 1H). 13C NMR (CDCl3) δ 13.79, 19.51, 29.43, 30.68, 31.28, 40.19, 44.01, 49.03, 52.51, 58.07, 60.86, 66.52, 112.73, 116.20, 116.37, 119.42, 127.62, 128.72, 129.51, 130.61, 130.78, 131.56, 134.42, 139.02, 142.79, 143.83, 150.85, 162.90, 170.14, 170.22. ES-MS m/z 583 (M+H). Anal. Calcd. for C35H422N4O4.0.3H2O: C, 71.48; H, 7.30; N, 9.53. Found. C, 71.42; H, 7.23; N, 9.40.
Reaction SMILES: [CH:1]([N-]C(C)C)(C)[CH3:2].[Li+].[CH2:9]([O:11][C:12](=[O:22])[CH2:13][CH2:14][CH2:15][C:16]1([CH3:21])[O:20][CH2:19][CH2:18][O:17]1)[CH3:10].C(I)C>O1CCCC1>[CH2:1]([CH:13]([CH2:14][CH2:15][C:16]1([CH3:21])[O:20][CH2:19][CH2:18][O:17]1)[C:12]([O:11][CH2:9][CH3:10])=[O:22])[CH3:2]
Reactant: CC(C)[N-]C(C)C
Reactant: CCOC(=O)CCCC1(C)OCCO1
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCI
Product: CCOC(=O)C(CC)CCC1(C)OCCO1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 33.9 %

Procedure:
To a freshly prepared solution of lithium diisopropylamide (40.0 mmol in tetrahydrofuran/hexane; 50 mL, 1:1) at −78° C. was added a solution of ethyl-4-(2-methyl-1,3-dioxolan-2-yl)butanoate (6.7 g, 33.3 mmol) in tetrahydrofuran (15 mL) over 15 minutes. After stirring for 15 minutes, ethyl iodide (4.0 mL, 50.0 mmol) was added rapidly via syringe. The reaction was stirred at −78° C. for 6 hours and then allowed to warm slowly to ambient temperature and stir for 16 hours. The reaction was quenched by the addition of water (50 mL) and extracted with ether (3×50 mL). The combined organics were washed with brine (50 mL), dried (magnesium sulfate), concentrated in vacuo and chromatographed (silica gel, ethyl acetate/hexane, 1:4) to afford ethyl 2-ethyl-4-(2-methyl-1,3-dioxolan-2-yl)butanoate (2.6 g, 33%) as a colorless liquid.