Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]12[NH:8][CH:5]([CH2:6][CH2:7]1)[CH2:4][C:3]([C:9]1[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[NH:11][CH:10]=1)=[CH:2]2.Cl[CH2:19][CH2:20][O:21][C:22]1[CH:30]=[CH:29][CH:28]=[C:27]2[C:23]=1[CH:24]=[CH:25][NH:26]2.C([O-])([O-])=O.[K+].[K+]>CC#N>[NH:26]1[C:27]2[C:23](=[C:22]([O:21][CH2:20][CH2:19][N:8]3[CH:5]4[CH2:6][CH2:7][CH:1]3[CH:2]=[C:3]([C:9]3[C:17]5[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=5)[NH:11][CH:10]=3)[CH2:4]4)[CH:30]=[CH:29][CH:28]=2)[CH:24]=[CH:25]1
Reactant: ClCCOc1cccc2[nH]ccc12
Reactant: C1=C(c2c[nH]c3ccccc23)CC2CCC1N2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C1=C(c2c[nH]c3ccccc23)CC2CCC1N2CCOc1cccc2[nH]ccc12
Temperature: 80 °C
Yield: 61 %

Procedure:
To 200 mg (0.89 mmol) 3-(8-aza-bicyclo[3.2.1]oct-2-en-3-yl)-1H-indole, 174 mg (0.89 mmol) 4-(2-chloroethoxy)-1H-indole and 10 mL MeCN is added 246 mg (1.78 mmol) K2CO3. After heating at 80° C. for 12 h, the reaction mixture is cooled to 23° C., filtered through celite and evaporated to a light yellow oil. Flash chromatography on SiO2 gel, eluting with CHCl3/MeOH (20/1 to 10/1), gives 208 mg (0.54 mmol, a 61% yield) of the title compound as an off-white solid. The corresponding oxalate salt is prepared by combining the title compound with 1 equivalent of oxalic acid in EtOH/Et2O. The oxalate salt of the title compound precipitates as an off-white solid. Recrystallization from EtOH/Et2O gives the oxalate salt of the title compound as an off-white solid. mp: 135-138° C.; MS (ES) m/z 384 (MH)+.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[C:16]([CH3:23])=[N:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=4)[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:24]([O:27][CH:28]=[CH2:29])[CH2:25][CH3:26])=[CH:4][CH:3]=1.[CH2:30]([Zn]CC)C.ICI>ClCCl>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[C:16]([CH3:23])=[N:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=4)[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:24]([O:27][CH:28]2[CH2:30][CH2:29]2)[CH2:25][CH3:26])=[CH:4][CH:3]=1
Reactant: CC[Zn]CC
Reactant: C=COC(CC)c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(OC)nc1C
Solvent: ICI
Solvent: ClCCl
Product: CCC(OC1CC1)c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(OC)nc1C
Temperature: 0 °C
Reaction time: 5 h

Procedure:
To a solution of 9-chloro-6-[1-(ethenyloxy)propyl]-1-(6-methoxy-2-methylpyridin-3-yl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazole (65.0 mg, 0.157 mmol) in dichloromethane (1.5 mL) were added diethyl zinc (1.0 M solution in n-hexane, 0.787 mL, 0.787 mmol) and diiodomethane (0.13 mL, 1.57 mmol) at 0° C. The reaction mixture was stirred at 0° C. for 5 hrs. The mixture was quenched with aqueous saturated ammonium chloride and extracted with ethyl acetate (×3). The combined organic layer was washed with water (×2) and brine (×1), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo, the residue was purified by silica gel column chromatography eluting with a 0-40% ethyl acetate/n-hexane gradient mixture to give the mixture contained title compound. To the solution of residue in ethyl acetate/MeOH (1.0 mL/0.5 mL) was added 4N hydrochloric acid/ethyl acetate (25 μL). The reaction mixture was stirred at room temperature for 3 hrs. After the mixture was concentrated. The residue was purified by silica gel column chromatography eluting with a 0-40% ethyl acetate/n-hexane gradient mixture to give the title compound as a colorless amorphous (7.0 mg, 0.0184 mmol, 10%).
Reaction SMILES: [Br:1][C:2](=O)[CH:3]([Br:5])C.C(O[CH:10]([O:14][CH2:15][CH3:16])[O:11][CH2:12][CH3:13])C>C(O)C>[CH2:15]([O:14][CH:10]([O:11][CH2:12][CH3:13])[CH:3]([Br:5])[CH2:2][Br:1])[CH3:16]
Reactant: CCOC(OCC)OCC
Reactant: CC(Br)C(=O)Br
Solvent: CCO
Product: CCOC(OCC)C(Br)CBr

Procedure:
7 g of 1,2-dibromo-propionaldehyde are added to a mixture of 5 g of ortho-formic acid triethyl-ester and 10 ml of ethanol. The solution is refluxed for 2 hours, remains standing for a night, then it is vacuum-distilled.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[CH:8][C:4]=1[C:5]([OH:7])=O.[NH2:14][CH2:15][C:16]1[CH:17]=[C:18]([CH2:24][CH:25]([O:31][CH:32]([CH3:34])[CH3:33])[C:26]([O:28]CC)=[O:27])[CH:19]=[CH:20][C:21]=1[O:22][CH3:23]>>[CH3:1][O:2][C:3]1[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[CH:8][C:4]=1[C:5]([NH:14][CH2:15][C:16]1[CH:17]=[C:18]([CH2:24][CH:25]([O:31][CH:32]([CH3:34])[CH3:33])[C:26]([OH:28])=[O:27])[CH:19]=[CH:20][C:21]=1[O:22][CH3:23])=[O:7]
Reactant: COc1ccc(C(=O)O)c(OC)c1
Reactant: CCOC(=O)C(Cc1ccc(OC)c(CN)c1)OC(C)C
Product: COc1ccc(C(=O)NCc2cc(CC(OC(C)C)C(=O)O)ccc2OC)c(OC)c1

Procedure:
Using 2,4-dimethoxybenzoic acid and ethyl 3-[3-(aminomethyl)-4-methoxyphenyl]-2-isopropoxypropanoate, 3-(3-[(2,4-dimethoxybenzoyl)amino]methyl-4-methoxyphenyl)-2-isopropoxypropanoic acid was obtained in the same method as in Example 19d) and then in Example 19e).
Reaction SMILES: [CH3:1][C:2]([CH:6]1[O:10][O:9][C:7]1=[O:8])([CH2:4]O)[CH3:3].[H-].[Na+].[CH2:13](Br)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.O>C1COCC1.ClCCl>[CH2:13]([O:10][C@@H:6]1[C:2]([CH3:1])([CH3:3])[CH2:4][O:9][C:7]1=[O:8])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CC(C)(CO)C1OOC1=O
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC1(C)COC(=O)[C@@H]1OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of D(−)-pantolactone (20.0 g, 153.7 mmol) and sodium hydride (4.4 g, 184.4 mmol) in anhydrous THF was stirred under an atmosphere of nitrogen at room temperature for 1 hour. The resultant mixture was treated with benzyl bromide (31.5 g, 184.4 mmol) and stirred at room temperature overnight. The product mixture was treated with water and diluted with dichloromethane. The organic extract was washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under vacuum. The residue was subjected to purification on silica gel eluting with 0-5% methanol in dichloromethane gradient. Collection and concentration of appropriate fractions provided the title compound.
Reaction SMILES: Cl.F[C:3]1[C:8]([C:9]2[N:14]=[C:13]([CH3:15])[N:12]=[C:11]([NH2:16])[N:10]=2)=[CH:7][CH:6]=[CH:5][N:4]=1.[NH:17]1[C:25]2[CH:24]=[CH:23][CH:22]=[C:21]([NH2:26])[C:20]=2[CH:19]=[CH:18]1.O1CCOCC1>>[NH2:16][C:11]1[N:12]=[C:13]([CH3:15])[N:14]=[C:9]([C:8]2[C:3]([NH:26][C:21]3[C:20]4[CH:19]=[CH:18][NH:17][C:25]=4[CH:24]=[CH:23][CH:22]=3)=[N:4][CH:5]=[CH:6][CH:7]=2)[N:10]=1
Reactant: Nc1cccc2[nH]ccc12
Reactant: Cc1nc(N)nc(-c2cccnc2F)n1
Agent: Cl
Solvent: C1COCCO1
Product: Cc1nc(N)nc(-c2cccnc2Nc2cccc3[nH]ccc23)n1
Temperature: 100 °C
Yield: 21.9 %

Procedure:
2N HCl(aq) (0.42 mL, 833 μmol) was added to a stirred mixture of 4-(2-fluoropyridin-3-yl)-6-methyl-1,3,5-triazin-2-amine (171 mg, 833 μmol) and 1H-indol-4-amine (132 mg, 1000 μmol) in 1,4-dioxane (4.00 mL, 46762 μmol) and the brown mixture was heated at 100° C. overnight. After cooling, the reaction mixture was concentrated and the crude residue was dissolved in DCM/MeOH and mixed with SiO2. The solvent was evaporated and the residue was purified by flash column chromatography (pure DCM to 5% MeOH in DCM) followed by washing the eluent concentrates with EtOAc to give N-(3-(4-amino-6-methyl-1,3,5-triazin-2-yl)pyridin-2-yl)-1H-indol-4-amine (58 mg, 22%) as a yellow solid. LCMS (API-ES) m/z 318 (M+H)+; 1H NMR (400 MHz, d6-DMSO) δ ppm 12.00 (s, 1H) 11.15 (br. s., 1H) 8.77 (dd, J=7.78, 1.76 Hz, 1H) 8.38 (dd, J=4.52, 1.51 Hz, 1H) 8.09 (d, J=6.02 Hz, 1H) 7.53-7.81 (m, 2H) 7.35 (t, J=2.76 Hz, 1H) 6.99-7.19 (m, 2H) 6.90 (dd, J=7.78, 4.77 Hz, 1H) 6.66 (br. s., 1H) 2.55 (s, 3H).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:10]=[C:9]([NH:11][CH2:12][C:13](=[O:18])[C:14]([CH3:17])([CH3:16])[CH3:15])[N:8]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:7]=1)=[O:5])C.[OH-].[Na+]>C(O)C>[CH3:15][C:14]([CH3:17])([CH3:16])[C:13](=[O:18])[CH2:12][NH:11][C:9]1[N:8]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[N:7]=[C:6]([C:4]([OH:5])=[O:3])[CH:10]=1
Reactant: CCOC(=O)c1cc(NCC(=O)C(C)(C)C)n(-c2ccccc2)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)(C)C(=O)CNc1cc(C(=O)O)nn1-c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 82 %

Procedure:
2 g (6.07 mmol) of 5-(3,3-Dimethyl-2-oxo-butylamino)-1-phenyl-1H-pyrazole-3-carboxylic acid ethyl ester are dissolved in 15 ml ethanol, 12.1 ml (12.1 mmol, 2 eq) 1N NaOH are added and the resulting mixture is stirred overnight at RT. After evaporation of the solvent the residue is taken up in a mixture of 10 ml CH2Cl2 and 10 ml 0.1N HCl, the organic phase is separated, dried over Na2SO4 and the solvent removed in vacuo to obtain 5-(3,3-Dimethyl-2-oxo-butylamino)-1-phenyl-1H-pyrazole-3-carboxylic acid in a yield of 82% (1.5 g)
Reaction SMILES: OCCN1CCN(CC(NC2C(SC)=NC(C)=CC=2SC)=O)CC1.O[CH2:26][CH2:27][N:28]1[CH2:33][CH2:32][N:31]([CH2:34][C:35]([NH:37][C:38]2[C:39]([O:49][CH:50]([CH3:52])[CH3:51])=[N:40][C:41]([CH3:48])=[CH:42][C:43]=2[O:44][CH:45]([CH3:47])[CH3:46])=[O:36])[CH2:30][CH2:29]1.SC1NC2C=CC=CC=2N=1.[SH:63][C:64]1[O:65][C:66]2[CH:72]=[CH:71][CH:70]=[CH:69][C:67]=2[N:68]=1>>[O:65]1[C:66]2[CH:72]=[CH:71][CH:70]=[CH:69][C:67]=2[N:68]=[C:64]1[S:63][CH2:26][CH2:27][N:28]1[CH2:33][CH2:32][N:31]([CH2:34][C:35]([NH:37][C:38]2[C:39]([O:49][CH:50]([CH3:51])[CH3:52])=[N:40][C:41]([CH3:48])=[CH:42][C:43]=2[O:44][CH:45]([CH3:46])[CH3:47])=[O:36])[CH2:30][CH2:29]1
Reactant: Cc1cc(OC(C)C)c(NC(=O)CN2CCN(CCO)CC2)c(OC(C)C)n1
Reactant: Sc1nc2ccccc2o1
Agent: CSc1cc(C)nc(SC)c1NC(=O)CN1CCN(CCO)CC1
Agent: Sc1nc2ccccc2[nH]1
Product: Cc1cc(OC(C)C)c(NC(=O)CN2CCN(CCSc3nc4ccccc4o3)CC2)c(OC(C)C)n1

Procedure:
The reaction and treatments of Example 12 were repeated, except that 2-[4-(2-hydroxyethyl)piperazin-1-yl]-N-[2,4-bis(methylthio)-6-methylpyridin-3-yl]acetamide was replaced by 2-[4-(2-hydroxyethyl)piperazin-1-yl]-N-[2,4-bis(1-methylethoxy)-6-methylpyridin-3-yl]acetamide and 2-mercaptobenzimidazole was replaced by 2-mercaptobenzoxazole, to thereby yield the title compound as a pale yellow viscous oil.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[C:5]([C:14](=[O:16])[CH3:15])=[CH:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)[CH3:2].[H][H]>[Ni]>[CH2:1]([O:3][C:4](=[O:17])[CH:5]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)[C:14](=[O:16])[CH3:15])[CH3:2]
Reactant: CCOC(=O)C(=Cc1ccc(O)cc1)C(C)=O
Reactant: [H][H]
Agent: [Ni]
Product: CCOC(=O)C(Cc1ccc(O)cc1)C(C)=O

Procedure:
According to the procedure of Liebigs Ann. Chem. (1980), 9, 1392, 2-(4-hydroxy-benzyl)-3-oxo-butyric acid ethyl ester was prepared from 2-acetyl-3-(4-hydroxy-phenyl)-acrylic acid ethyl ester, Raney-nickel, hydrogen.
Reaction SMILES: O[O:2][S:3]([O-:5])=O.[K+].[CH:7]1([CH2:10][N:11]2[C:17](=[O:18])[C@H:16]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[CH2:15]S[C@@H:13]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH2:12]2)[CH2:9][CH2:8]1>CO.O>[CH:7]1([CH2:10][N:11]2[C:17](=[O:18])[C@H:16]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:24])([CH3:25])[CH3:23])[CH2:15][S:3](=[O:5])(=[O:2])[C@@H:13]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH2:12]2)[CH2:8][CH2:9]1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CS[C@@H](c2ccccc2)CN(CC2CC2)C1=O
Reactant: O=S([O-])OO
Agent: [K+]
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@@H]1CS(=O)(=O)[C@@H](c2ccccc2)CN(CC2CC2)C1=O
Reaction time: 18 h
Yield: 96.4 %

Procedure:
Oxone (488 mg, 0.80 mmol) was added to a solution of tert-butyl (2S,6S)-4-(cyclopropylmethyl)-5-oxo-2-phenyl-1,4-thiazepan-6-ylcarbamate (60 mg, 0.16 mmol) in methanol (7.5 mL) and water (7.5 mL). After 18 h, water was added. The mixture was extracted with ethyl acetate, and the organic layer was washed with saturated brine, dried over magnesium sulfate, filtered and concentrated to give the title compound (63 mg).
Reaction SMILES: Br[C:2]1[CH:6]=[CH:5][S:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[F:13][C:14]1[CH:35]=[CH:34][C:17]([NH:18][C:19]2[CH:31]=[C:30]([CH:32]=[CH2:33])[CH:29]=[CH:28][C:20]=2[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[CH:16][CH:15]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(OCC)(=O)C.CN(C)C(=O)C>[F:13][C:14]1[CH:35]=[CH:34][C:17]([NH:18][C:19]2[CH:31]=[C:30](/[CH:32]=[CH:33]/[C:2]3[CH:6]=[CH:5][S:4][CH:3]=3)[CH:29]=[CH:28][C:20]=2[C:21]([O:23][C:24]([CH3:27])([CH3:25])[CH3:26])=[O:22])=[CH:16][CH:15]=1
Reactant: C=Cc1ccc(C(=O)OC(C)(C)C)c(Nc2ccc(F)cc2)c1
Reactant: Brc1ccsc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: CC(C)(C)OC(=O)c1ccc(/C=C/c2ccsc2)cc1Nc1ccc(F)cc1
Temperature: 120 °C
Reaction time: 24 h

Procedure:
3-Bromothiophene 90 μL, cesium carbonate 0.31 g and palladium acetate 11 mg were added to N,N-dimethylacetamide 3.0 mL solution of tert-butyl 2-(4-fluoroanilino)-4-vinylbenzoate 0.15 g at room temperature, and it was stirred at 120° C. for 24 hours. After the reaction mixture was cooled to room temperature, ethyl acetate and 10% citric acid aqueous solution were added to it. The organic layer was separated and collected,dried over anhydrous magnesium sulfate after sequential washing with 10% citric acid aqueous solution, saturated sodium thiosulfate aqueous solution and saturated sodium chloride aqueous solution, and the solvent was removed under reduced pressure. The obtained residue was refined by silica gel column chromatography [Trikonex company, Flash Tube 2008, eluent; hexane:ethyl acetate=10:1] to give tert-butyl 2-(4-fluoroanilino)-4-((E)-2-(thiophen-3-yl)vinyl)benzoate.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([C:14]=1[CH2:15][CH2:16][CH2:17][NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[CH:12][C:11]([NH2:26])=[CH:10][CH:9]=2)=[O:5])[CH3:2].C[Si]([N:31]=[C:32]=[O:33])(C)C>C(Cl)Cl.C(N(CC)CC)C>[CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([C:14]=1[CH2:15][CH2:16][CH2:17][NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[CH:12][C:11]([NH:26][C:32]([NH2:31])=[O:33])=[CH:10][CH:9]=2)=[O:5])[CH3:2]
Reactant: C[Si](C)(C)N=C=O
Reactant: CCOC(=O)c1[nH]c2ccc(N)cc2c1CCCNC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)c1[nH]c2ccc(NC(N)=O)cc2c1CCCNC(=O)OC(C)(C)C
Reaction time: 8 h

Procedure:
5-Amino-3-[3-(t-butoxycarbonylamino)-propyl]-1H-indole-2-carboxylic acid ethyl ester (40 mg, 0.11 mmol, 1.0 equiv) was dissolved in 10 mL of methylene chloride and 1 mL of triethylamine. Trimethylsilyl isocyanate was added and the solution was stirred overnight. In the morning the reaction was washed with 10 mL of water and the organic layer was concentrated. The crude residue was purified by flash chromatography on silica (10 g of SiO2) using 0% ethyl acetate in methylene chloride to 100% ethyl acetate graded over 25 min at a flow rate of 15 mL/min-then 100% ethylacetate for another 15 min. The fractions with pure product (TLC) were combined and concentrated to provide 5-ureido-3-[3-(t-butoxycarbonylamino)-propyl]-1H-indole-2-carboxylic acid ethyl ester as a white solid (41 mg). This material was used without further purification.
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[NH:7][CH:8]([CH2:14][C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=1)[C:9](=[O:13])[CH:10]=[N+]=[N-])([CH3:4])([CH3:3])[CH3:2].[BrH:25]>C1COCC1>[C:1]([O:5][C:6](=[O:24])[NH:7][CH:8]([CH2:14][C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=1)[C:9](=[O:13])[CH2:10][Br:25])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NC(Cc1ccc([N+](=O)[O-])cc1)C(=O)C=[N+]=[N-]
Reactant: Br
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC(Cc1ccc([N+](=O)[O-])cc1)C(=O)CBr
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
To a 0° C. solution of [3-diazo-1-(4-nitrobenzyl)-2-oxo-propyl]-carbamic acid tert-butyl ester, 50, (0.350 g, 1.04 mmol) in THF (5 mL) is added dropwise 48% aq. HBr (0.14 mL, 1.25 mmol). The reaction mixture is stirred at 0° C. for 1.5 hours and quenched at 0° C. with saturated aqueous Na2CO3. The mixture is extracted with EtOAc (3×25 mL) and the combined organic extracts are washed with brine, dried (Na2SO4), filtered and concentrated in vacuo to afford 0.400 g of the desired product that is used in the next step without further purification. 1H NMR (300 MHz, CDCl3) δ 8.20 (d, J=8.4 Hz, 2H), 7.39 (d, J=8.4 Hz, 2H), 5.06 (d, J=7.8 Hz, 1H), 4.80 (q, J=6.3 Hz, 1H), 4.04 (s, 2H), 1.42 (s, 9H).
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11])[C:5]#[N:6].[CH3:13][O-:14].[Na+]>C1COCC1>[CH3:13][O:14][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11])[C:5]#[N:6]
Reactant: C[O-]
Reactant: N#Cc1ccc([N+](=O)[O-])c(F)c1
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cc(C#N)ccc1[N+](=O)[O-]
Reaction time: 0.5 h

Procedure:
25 g (150.504 mmol) 3-fluoro-4-nitrobenzonitrile and 25 g (462.757 mmol) sodium methoxide are dissolved in 125 ml THF at 0° C. This reaction mixture is stirred for 30 min. The reaction mixture is extracted with ethyl acetate and 1 N hydrochloric acid. The organic phase is dried with magnesium sulphate and the solvent is eliminated in vacuo.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[CH2:4][C:5]1[C:13]2[C:8](=[N:9][CH:10]=[CH:11][CH:12]=2)[NH:7][C:6]=1[CH3:14].CCN(P1(N(C)CCCN1C)=NC(C)(C)C)CC.[N+:34]([C:37]1[CH:44]=[CH:43][C:40]([CH2:41]Br)=[CH:39][CH:38]=1)([O-:36])=[O:35]>CN(C=O)C>[CH3:1][O:2][C:3](=[O:15])[CH2:4][C:5]1[C:13]2[C:8](=[N:9][CH:10]=[CH:11][CH:12]=2)[N:7]([CH2:41][C:40]2[CH:43]=[CH:44][C:37]([N+:34]([O-:36])=[O:35])=[CH:38][CH:39]=2)[C:6]=1[CH3:14]
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Reactant: COC(=O)Cc1c(C)[nH]c2ncccc12
Agent: CCN(CC)P1(=NC(C)(C)C)N(C)CCCN1C
Solvent: CN(C)C=O
Product: COC(=O)Cc1c(C)n(Cc2ccc([N+](=O)[O-])cc2)c2ncccc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of (2-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-acetic acid methyl ester (0.78 g, 3.8 mmol) in dry DMF (10 ml) is added dropwise, BEMP (1.21 ml, 4.2 mmol) over two minutes. After stirring at room temperature for 1 hour, the resulting solution is treated with 4-nitrobenzyl bromide (1.0 g, 4.6 mmol) in one portion and stirring continues overnight. The reaction is concentrated in vacuo with toluene and the resulting oil is purified by chromatography on silica eluting with iso-hexane/ethyl acetate (3:1) to yield [2-methyl-1-(4-nitro-benzyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-acetic acid methyl ester. (MH+ 340)
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=O)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[CH:13]1([C:16](=[O:23])[CH2:17][C:18]([CH:20]2[CH2:22][CH2:21]2)=[O:19])[CH2:15][CH2:14]1.N1CCCCC1.C(O)(=O)C>C1(C)C=CC=CC=1>[C:1]([NH:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[C:17]([C:16]([CH:13]2[CH2:15][CH2:14]2)=[O:23])[C:18]([CH:20]2[CH2:22][CH2:21]2)=[O:19])=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: O=C(CC(=O)C1CC1)C1CC1
Reactant: CC(=O)Nc1ccc(C=O)cc1
Solvent: C1CCNCC1
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: CC(=O)Nc1ccc(C=C(C(=O)C2CC2)C(=O)C2CC2)cc1

Procedure:
A mixture containing 1.6 g 4-acetamidobenzaldehyde, 1.5 g 1,3-dicyclopropyl-1,3-propanedione, 0.2 ml of piperidine and 0.4 ml of acetic acid in 50 ml of toluene was refluxed for 3 h by using a Dean-Stark separator. After standing over night at room temperature the crystals were filtered and washed with toluene. The product was recrystallized from ethanol. Yield 2.0 g, mp 166°-167° C.
Reaction SMILES: [CH:1]1([O:6][C:7]2[C:12]([O:13][CH:14]([F:16])[F:15])=[CH:11][CH:10]=[CH:9][C:8]=2/[CH:17]=[CH:18]/[C:19]2[N:20]=[C:21]3[N:25]([C:26]=2[C:27]([OH:29])=O)[CH:24]=[CH:23][S:22]3)[CH2:5][CH2:4][CH2:3][CH2:2]1.[F:30][C:31]([F:39])([F:38])[C:32]1[N:33]=[C:34]([NH2:37])[S:35][CH:36]=1.CCN=C=NCCCN(C)C.Cl>CN(C1C=CN=CC=1)C.C1COCC1.CN(C=O)C>[CH:1]1([O:6][C:7]2[C:12]([O:13][CH:14]([F:16])[F:15])=[CH:11][CH:10]=[CH:9][C:8]=2/[CH:17]=[CH:18]/[C:19]2[N:20]=[C:21]3[N:25]([C:26]=2[C:27]([NH:37][C:34]2[S:35][CH:36]=[C:32]([C:31]([F:39])([F:38])[F:30])[N:33]=2)=[O:29])[CH:24]=[CH:23][S:22]3)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)c1c(/C=C/c2cccc(OC(F)F)c2OC2CCCC2)nc2sccn12
Reactant: Nc1nc(C(F)(F)F)cs1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: O=C(Nc1nc(C(F)(F)F)cs1)c1c(/C=C/c2cccc(OC(F)F)c2OC2CCCC2)nc2sccn12

Procedure:
The title compound was prepared according to the general procedure (Method B) by coupling Intermediate 5 (365 mg, 0.868 mmol) with 4-(trifluoromethyl)-1,3-thiazol-2-amine (157 mg, 0.965 mmol) in the presence of EDCI hydrochloride (333 mg, 1.737 mmol) and DMAP (98 mg, 0.868 mmol) in a mixture of THF and DMF (1:1, 6 mL) to give 34 mg of the product as an off-white solid; 1H NMR (300 MHz, DMSO-d6) δ 1.75-1.85 (m, 8H), 4.70-4.78 (m, 1H), 7.18 (t, J=74.7 Hz, 1H), 7.20-7.5 (m, 2H), 7.40-7.46 (m, 1H), 7.53 (d, J=15.9 Hz, 1H), 7.60-7.70 (m, 1H), 7.79 (d, J=15.0 Hz, 1H), 8.05-8.12 (m, 2H), 13.03 (br s, 1H); APCI-MS (m/z) 571.07 (MH)+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=2)=[CH:11][C:10]=1[NH:21][C:22](=[O:39])[C@@H:23]([NH:31]C(=O)OC(C)(C)C)[CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.O1CCOCC1>CO>[NH2:31][C@@H:23]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:22]([NH:21][C:10]1[CH:11]=[C:12]([C:15]2[CH:16]=[CH:17][N:18]=[CH:19][CH:20]=2)[CH:13]=[CH:14][C:9]=1[O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:39]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)Nc1cc(-c2ccncc2)ccc1OCc1ccccc1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: N[C@@H](Cc1ccccc1)C(=O)Nc1cc(-c2ccncc2)ccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of tert-butyl (S)-1-(3-(1H-pyrazol-4-yl)phenylamino)-1-oxo-3-phenylpropan-2-ylcarbamate 13.E (1.25 g, 2.39 mmol) in MeOH (10 mL) was added 4M HCl in dioxane solution (10 ml, 40 mmol). The resulting mixture was stirred for 2 hours at room temperature. The mixture was then concentrated to afford crude (S)-2-amino-N-(2-(benzyloxy)-5-(pyridin-4-yl)phenyl)-3-phenylpropanamide 13.F which was used in the next step without any further purification.
Reaction SMILES: OC1C=C(C=CC=1OC)C(OC)=O.ClC1C=C(CCO)C=CC=1.[CH3:24][O:25][C:26](=[O:45])[C:27]1[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[C:29]([O:35][CH2:36][CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[C:40]([Cl:44])[CH:39]=2)[CH:28]=1.[N+:46]([O-])([OH:48])=[O:47]>>[CH3:24][O:25][C:26](=[O:45])[C:27]1[CH:28]=[C:29]([O:35][CH2:36][CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[C:40]([Cl:44])[CH:39]=2)[C:30]([O:33][CH3:34])=[CH:31][C:32]=1[N+:46]([O-:48])=[O:47]
Reactant: O=[N+]([O-])O
Reactant: COC(=O)c1ccc(OC)c(OCCc2cccc(Cl)c2)c1
Agent: COC(=O)c1ccc(OC)c(O)c1
Agent: OCCc1cccc(Cl)c1
Product: COC(=O)c1cc(OCCc2cccc(Cl)c2)c(OC)cc1[N+](=O)[O-]
Reaction time: 8 h

Procedure:
Methyl 3-hydroxy-4-methoxybenzoate and 2-(3-chlorophenyl)-ethanol were reacted in analogy to step 1 of example 1. The obtained 3-[2-(3-chloro-phenyl)-ethoxy]-4-methoxy-benzoic acid methyl ester (0.750 g, 2.34 mmol) was added slowly to ice-cooled 100% nitric acid (10 ml). The ice bath was removed and stirring was continued overnight. The mixture was cautiously transferred into a stirred mixture of EA, water and an excess of sodium hydrogencarbonate and extracted with EA. The combined organic extracts were washed with a saturated sodium chloride solution, dried over sodium sulfate, filtered and evaporated to dryness. The solid residue was extracted with diethyl ether, and the ethereal solution was evaporated. The residue was stirred with HEP, and the solid was filtered and dried in vacuo to give 0.680 g of the title compound.