Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][C:9]1[N:24]=[C:23]([C:25]2[CH:33]=[CH:32][C:31]3[N:30]4[CH2:34][CH:35]([NH:37][CH3:38])[CH2:36][C:29]4=[CH:28][C:27]=3[CH:26]=2)[C:22]([CH3:39])=[C:21]([O:40]CC2C=CC=CC=2)[C:10]=1[C:11]([O:13]CC1C=CC=CC=1)=[O:12])C1C=CC=CC=1.[ClH:48]>CO.[Pd]>[ClH:48].[OH:40][C:21]1[C:22]([CH3:39])=[C:23]([C:25]2[CH:33]=[CH:32][C:31]3[N:30]4[CH2:34][CH:35]([NH:37][CH3:38])[CH2:36][C:29]4=[CH:28][C:27]=3[CH:26]=2)[NH:24][C:9](=[O:8])[C:10]=1[C:11]([OH:13])=[O:12]
Reactant: CNC1Cc2cc3cc(-c4nc(OCc5ccccc5)c(C(=O)OCc5ccccc5)c(OCc5ccccc5)c4C)ccc3n2C1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CNC1Cc2cc3cc(-c4[nH]c(=O)c(C(=O)O)c(O)c4C)ccc3n2C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 49 %

Procedure:
The intermediate from Step 2 (70 mg, 0.11 mmol) was dissolved in MeOH (2 mL). To the solution was added 10% Pd/C (20 mg) and 3 N HCl in MeOH (0.1 mL). The mixture was stirred under H2 (1 atm) at room temperature for 16 h. The mixture was filtered through a 5 μm cartridge. The filtrate was concentrated, leaving the product (21 mg, 49%) as an off white powder.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[NH:9][CH:10]=[CH:11][N:12]=2)[CH:5]=[CH:6][CH:7]=1.Cl[CH2:14][C:15]1[N:16]=[C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][N:18]2[C:24]=1[CH2:25][CH2:26][CH3:27].CO.C(Cl)Cl>CC(N(C)C)=O.CCOC(C)=O>[Cl:23][C:20]1[CH:21]=[CH:22][C:17]2[N:18]([C:24]([CH2:25][CH2:26][CH3:27])=[C:15]([CH2:14][N:12]3[CH:11]=[CH:10][N:9]=[C:8]3[C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=3)[N:16]=2)[CH:19]=1
Reactant: Fc1cccc(-c2ncc[nH]2)c1
Reactant: CCCc1c(CCl)nc2ccc(Cl)cn12
Solvent: ClCCl
Solvent: CO
Solvent: CCOC(C)=O
Product: CCCc1c(Cn2ccnc2-c2cccc(F)c2)nc2ccc(Cl)cn12
Temperature: 60 °C
Reaction time: 0.25 h

Procedure:
Kt-BuO (0.69 mL of 1 M in THF, 0.69 mmol) is added to a solution of 3-fluoro-(1H-imidazol-2-yl)benzene (88 mg, 0.58 mmol) in anhydrous DMA (1 mL). After 15 minutes, 2-chloromethyl-6-chloro-3-(1-propyl)-imidazolo[1,2-a]pyridine (140 mg, 0.58 mmol) is added and the reaction mixture is stirred and heated at 60° C. for 15 minutes. The reaction mixture is diluted with EtOAc (10 mL), washed with water (3 mL), brine (3 mL), dried over Na2SO4, filtered and evaporated at reduced pressure to obtain a yellow solid. Sequential chromatography on silica gel eluting with EtOAc and then 5%MeOH/CH2Cl2 provides 6-chloro-2-{[2-(3-fluoropheny)-1H-imidazol-1-yl]methyl}-3-propylimidazo[1,2-a]pyridine as a cream-colored yellow solid. TLC (10% MeOH/CH2Cl2) Rf=0.35.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:29]2[C:38]3[C:33](=[C:34](Br)[CH:35]=[C:36]([CH3:39])[CH:37]=3)[CH:32]=[CH:31][CH:30]=2)[C@@H:9]([C:13]2[CH:28]=[CH:27][C:16]([C:17]([NH:19][CH2:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[O:18])=[CH:15][CH:14]=2)[CH2:10][CH2:11][CH3:12])=[CH:4][CH:3]=1.[CH3:41][N:42](C=O)C>[C-]#N.[Zn+2].[C-]#N.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>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:29]2[C:38]3[C:33](=[C:34]([C:41]#[N:42])[CH:35]=[C:36]([CH3:39])[CH:37]=3)[CH:32]=[CH:31][CH:30]=2)[C@@H:9]([C:13]2[CH:28]=[CH:27][C:16]([C:17]([NH:19][CH2:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[O:18])=[CH:15][CH:14]=2)[CH2:10][CH2:11][CH3:12])=[CH:4][CH:3]=1
Reactant: CCC[C@H](c1ccc(C(=O)NCCC(=O)OCC)cc1)C(c1ccc(Cl)cc1)c1cccc2c(Br)cc(C)cc12
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: CCC[C@H](c1ccc(C(=O)NCCC(=O)OCC)cc1)C(c1ccc(Cl)cc1)c1cccc2c(C#N)cc(C)cc12
Temperature: 110 °C
Reaction time: 24 h

Procedure:
To a solution of ethyl N-(4-{(1S)-1-[(4-chlorophenyl)(5-bromo-7-methyl-1-naphthyl)methyl]butyl}benzoyl)-β-alaninate (40 mg, 0.064 mmol) in DMF (3 mL) was added zinc cyanide (8.3 mg, 0.071 mmol) and Pd(Ph3P)4 (22.3 mg, 0.019 mmol). The resulting reaction mixture was stirred at 110° C. for 24 hours, then concentrated. The resulting residue was purified by preparative TLC eluting with 40% EtOAc/hexanes afforded a 9:1 mixture of naphthyl regioisomers. The residue was purified by preparative HPLC (Chiralcel OD column) eluting with 5% EtOH/heptane to afford the major diastereomer of the title compound. 1H NMR (500 MHz, CDCl3): δ 8.14 (s, 1H); 7.90 (d, J=8.5 Hz, 1H); 7.65 (d, J=7.5 Hz, 1H); 7.63 (s, 1H); 7.48 (d, J=8.5 Hz, 2H); 7.42 (m, 1H); 7.36 (d, J=8.5 Hz, 2H); 7.26 (d, J=8.0 Hz, 2H); 7.20 (d, J=8.5 Hz, 2H); 6.66 (m, 1H); 5.00 (d, J=11.5 Hz, 1H); 4.13 (q, J=7.2 Hz, 2H); 3.62 (q, J=11.8 Hz, 2H); 3.56 (m, 1H); 2.54 (q, 14.5 Hz, 2H); 2.54 (s, 3H); 1.62-1.51 (m, 2H); 1.25 (t, J=7.3 Hz, 3H), 1.06-1.00 (m, 2H); 0.74 (t, J=7.2 Hz, 3H). LC3 4.06 min. [M+H]+ 567.
Reaction SMILES: [OH:1][CH:2]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=1)[C:3]1[CH:4]=[C:5]([C:16]([OH:18])=O)[CH:6]=[C:7]([C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=2)[CH:8]=1.[CH3:25][C:26]1[N:31]=[CH:30][C:29]([CH2:32][NH2:33])=[CH:28][CH:27]=1.F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[OH:1][CH:2]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=1)[C:3]1[CH:4]=[C:5]([C:16]([NH:33][CH2:32][C:29]2[CH:30]=[N:31][C:26]([CH3:25])=[CH:27][CH:28]=2)=[O:18])[CH:6]=[C:7]([C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=2)[CH:8]=1
Reactant: Cc1ccc(-c2cc(C(=O)O)cc(C(O)c3ccccn3)c2)cc1
Reactant: Cc1ccc(CN)cn1
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: Cc1ccc(-c2cc(C(=O)NCc3ccc(C)nc3)cc(C(O)c3ccccn3)c2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 5-(hydroxy-pyridin-2-yl-methyl)-4′-methyl-biphenyl-3-carboxylic acid (35 mg, 0.11 mmol) in N,N-dimethylformamide (1 mL) were added (6-methylpyridin-3-yl)methanamine (40 mg, 0.33 mmol), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (100 mg, 0.26 mmol), and N,N-diisopropylethylamine (100 μL, 0.57 mmol). The reaction mixture was stirred for 16 hours at 25° C. The reaction mixture was purified by preparative HPLC (100×21.2 mm C18 column, CH3CN/water[10 mM Et2NH]) to afford a light color solid.
Reaction SMILES: [CH3:1][CH:2]([CH3:15])[CH2:3][C:4]([C:6]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=[O:11])=[CH:8][CH:7]=1)=[O:5]>ClCCl.COC(C)(C)C>[CH3:1][CH:2]([CH3:15])[CH2:3][C:4]([C:6]1[CH:14]=[CH:13][C:9]([C:10]([O:12][C:2]([CH3:15])([CH3:3])[CH3:1])=[O:11])=[CH:8][CH:7]=1)=[O:5]
Reactant: CC(C)CC(=O)c1ccc(C(=O)O)cc1
Solvent: COC(C)(C)C
Solvent: ClCCl
Product: CC(C)CC(=O)c1ccc(C(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 50 h

Procedure:
To a slurry of 4-(3-methylbutanoyl)benzoic acid (499 mg, 2.42 mmol) in dichloromethane (6 mL) was added O-tert-butyl-NN-diisopropylisourea (1.82 g, 9.07 mmol). The mixture was stirred at room temperature for 50 hours then diluted with tert-butyl methyl ether (75 mL). The mixture was washed with sat. aq sodium bicarbonate (50 mL), dried over anhydrous Na2SO4, and filtered, and the filtrate was concentrated. Purification by silica gel flash chromatography (ethyl acetate/heptane) gave tert-butyl 4-(3-methylbutanoyl)benzoate as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 8.09-8.04 (m, 2H), 8.00-7.94 (m, 2H), 2.86 (d, J=6.8 Hz, 2H), 2.37-2.23 (m, 1H), 1.62 (s, 9H), 1.01 (d, J=6.7 Hz, 6H).
Reaction SMILES: C([N:20]1[C:24]2[CH:25]=[CH:26][C:27]([NH:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[CH:28][C:23]=2[N:22]=[CH:21]1)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH2:46](Br)[C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1>C1COCC1.O>[CH2:46]([N:29]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:27]1[CH:26]=[CH:25][C:24]2[NH:20][CH:21]=[N:22][C:23]=2[CH:28]=1)[C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1
Reactant: c1ccc(Nc2ccc3c(c2)ncn3C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: BrCc1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: c1ccc(CN(c2ccccc2)c2ccc3[nH]cnc3c2)cc1
Temperature: 0 °C
Reaction time: 24 h

Procedure:
N1-Trityl-N-phenyl-benzimidazol-5-amine (1.13 g; 2.5 mmol; 1 eq.) was dissolved in THF (5 ml), cooled to 0° C. and treated with lithiumbis(trimethylsilyl)amide 1M in THF (3 ml; 3 mmol; 1.2 eq.). Benzylbromide (3 mmol; 1.2 eq.) was added and stirred at room temperature for 24 h. The mixture was diluted with water and extracted with ethyl acetate (3×25 ml). The combined organic layers were dried over Na2SO4 and evaporated. The residue was dissolved in MeOH (5 ml) and treated with TFA (1 ml). After heating to reflux overnight the mixture was poured into saturated NaHCO3-solution and extracted with ethyl acetate (3×25 ml). The combined organic layers were dried over Na2SO4 and evaporated. The residue was purified by flash chromatography on silica using a CHCl3/MeOH gradient. Yield: 0.046 g (6.2%); MS m/z: 300.1 [M+H]+; 1H-NMR, 500 MHz, 1H-NMR (500 MHz, DMSO d6): δ 5.00 (s, 2H); 6.70-6.73 (m, 1H); 6.78-6.79 (m, 2H); 7.06-7.08 (m, 1H); 7.10-7.13 (m, 2H); 7.18-7.21 (m, 1H); 7.29-7.31 (m, 2H); 7.36-7.37 (m, 3H); 7.54 (d, 1H, 3J=8.5 Hz); 8.30 (s, 1H); 12.32 (br s, 1H); HPLC (METHOD [A]): rt 15.47 min (95.1%)
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([NH:8][C:9](=[O:19])[C:10]2[C:15]([Cl:16])=[CH:14][C:13]([Cl:17])=[CH:12][C:11]=2[Cl:18])[CH:5]=[CH:4][N:3]=1.[CH:20]1([C:23](Cl)=[O:24])[CH2:22][CH2:21]1>N1C=CC=CC=1>[Cl:16][C:15]1[CH:14]=[C:13]([Cl:17])[CH:12]=[C:11]([Cl:18])[C:10]=1[C:9]([NH:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([NH:1][C:23]([CH:20]2[CH2:22][CH2:21]2)=[O:24])[CH:7]=1)=[O:19]
Reactant: Nc1cc(NC(=O)c2c(Cl)cc(Cl)cc2Cl)ccn1
Reactant: O=C(Cl)C1CC1
Solvent: c1ccncc1
Product: O=C(Nc1ccnc(NC(=O)C2CC2)c1)c1c(Cl)cc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 10 %

Procedure:
To a cooled (0° C.) solution of N-(2-aminopyridin-4-yl)-2,4,6-trichlorobenzamide (82 mg, 0.26 mmol) in pyridine (5 mL) under nitrogen atmosphere was added cyclopropanecarbonyl chloride (41 mg, 0.39 mmol) dropwise. The mixture was allowed to warm to room temperature, stirred overnight, and then quenched with water (15 mL). The reaction was extracted with ethyl acetate (3×10 ml). The combined organic extracts were washed with water (20 mL), dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by prep-HPLC (Gilson GX 281, Shim-pack PRC-ODS 250 mm×20 mm×2, gradient: CH3CN/10 mm/L NH4HCO3, 17 min) to afford the desired product (10 mg, 17% yield). 1H NMR (500 MHz, CDCl3): δ 8.19 (d, J=1.5 Hz, 1H), 8.13 (d, J=6.0 Hz, 1H), 7.52 (s, 2H), 7.49-7.47 (m, 2H) 1.78 (s, 1H), 0.88-0.86 (m, 2H), 0.81-0.78 (m, J=9.5 Hz, 2H). LCMS (ESI) m/z: 367.1 [M+H+].
Reaction SMILES: N.Cl[C:3]1[NH:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]2[C:13](=[O:26])[N:14]([C:17]3[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH3:25])=[CH:19][CH:18]=3)[C:15](=[O:16])[C:4]=12>C1COCC1>[CH2:24]([O:23][C:20]1[CH:19]=[CH:18][C:17]([N:14]2[C:15](=[O:16])[C:4]3=[CH:3][NH:12][C:11]4[C:6]([N:5]3[C:13]2=[O:26])=[CH:7][CH:8]=[CH:9][CH:10]=4)=[CH:22][CH:21]=1)[CH3:25]
Reactant: CCOc1ccc(-n2c(=O)c3c(Cl)[nH]c4ccccc4n-3c2=O)cc1
Agent: N
Solvent: C1CCOC1
Product: CCOc1ccc(-n2c(=O)c3c[nH]c4ccccc4n-3c2=O)cc1
Temperature: 25 °C

Procedure:
A solution of THF (10 mL), ammonia (10 mL) and 4-Chloro-2-(4-ethoxyphenyl)-imidazo[1,5,a]quinoxaline-1,3(2H,5H)-dione (100 mg) was heated to 100° C. in a sealed tube for 4 hours. After cooling to room temperature the solvent was removed in vacuo. The solid was slurried in 50% EtOH-H2O and filtered to yield 4-Amino-2-(4-ethoxyphenyl-imidazo[1,5,a]quinoxaline-1,3(2H,5H)-dione (Compound 37).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[O:10][C:11]([O:23][CH2:24][CH3:25])=[C:12]([C:14]([NH:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:15])[N:13]=1>FC(F)(F)C1C=CC=CC=1>[F:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[C:3]=1[C:9]1[O:15][C:14]([NH:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[C:12]([C:11]([O:23][CH2:24][CH3:25])=[O:10])[N:13]=1
Reactant: CCOc1oc(-c2c(F)cccc2F)nc1C(=O)Nc1ccccc1
Solvent: FC(F)(F)c1ccccc1
Product: CCOC(=O)c1nc(-c2c(F)cccc2F)oc1Nc1ccccc1
Yield: 99.4 %

Procedure:
A solution of 2-(2,6-difluorophenyl)-5-ethoxy-N-phenyloxazole-4-carboxamide (0.13 g, 0.38 mmol) in trifluorotoluene was heated at 180° C. for 5 minutes in the microwave. The solvent was removed in vacuo to give ethyl 2-(2,6-difluorophenyl)-5-(phenylamino)oxazole-4-carboxylate (0.13 g) as a brown solid which was used without further purification. LCMS (1) Rt: 2.40 min; m/z (ES+) 345.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([NH:7][C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][C:18]([F:21])([F:20])[F:19])=[CH:13][CH:12]=2)=[O:9])[N:4]=[C:3]1[C:22](O)=[O:23].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.[Cl:50][CH2:51][CH2:52][CH2:53][NH2:54].C(N(CC)CC)C>CN(C=O)C.CN(C1C=CN=CC=1)C>[Cl:50][CH2:51][CH2:52][CH2:53][NH:54][C:22]([C:3]1[N:2]([CH3:1])[CH:6]=[C:5]([NH:7][C:8]([NH:10][C:11]2[CH:12]=[CH:13][C:14]([O:17][C:18]([F:21])([F:20])[F:19])=[CH:15][CH:16]=2)=[O:9])[N:4]=1)=[O:23]
Reactant: NCCCCl
Reactant: Cn1cc(NC(=O)Nc2ccc(OC(F)(F)F)cc2)nc1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cn1cc(NC(=O)Nc2ccc(OC(F)(F)F)cc2)nc1C(=O)NCCCCl
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
140 mg (0.36 mmol) of 1-methyl-4-[({[4-(trifluoromethoxy)phenyl]amino}carbonyl)amino]-1H-imidazole-2-carboxylic acid (Example 29A) are dissolved in 8 ml of DMF and, after addition of 204 mg (0.54 mmol) of HATU and 66 mg (0.54 mmol) of DMAP, stirred at room temperature for 15 minutes. Then a solution of 93 mg (0.72 mmol) of 3-chloropropan-1-amine hydrochloride and 80 mg (0.79 mmol) of triethylamine in 1 ml of DMF is added dropwise, and the reaction mixture is stirred overnight. The reaction mixture is purified by preparative HPLC. The product-containing fractions are evaporated in vacuo.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([O:11][CH2:12][C:13]1[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][CH:14]=1)[CH2:8][CH2:9][CH3:10].N>O1CCCC1>[CH2:7]([O:11][CH2:12][C:13]1[CH:14]=[CH:15][C:16]([CH2:17][NH2:18])=[CH:19][CH:20]=1)[CH2:8][CH2:9][CH3:10]
Reactant: CCCCOCc1ccc(C#N)cc1
Agent: N
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: CCCCOCc1ccc(CN)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 100.2 %

Procedure:
To a mixture of lithium aluminum hydride (600 mg, 13 mmol, purity: 80%) and tetrahydrofuran (10 mL) was added a mixture of 4-butoxymethyl-benzonitrile (600 mg, 3.2 mmol) described in Manufacturing Example 33-1-1 and tetrahydrofuran (10 mL) at 0° C., which was stirred for 4 hours at room temperature. 28% Aqueous ammonia solution was added dropwise to the reaction mixture at 0□. The reaction mixture was warmed to room temperature and filtered. The filtrate was concentrated under a reduced pressure to obtain the title compound (620 mg, 101%) as a crude product.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:10]3[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=3)[CH:8]=2)[CH:3]=[CH:2]1.Cl.Br[C:19]1[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=1>>[N:22]1[CH:23]=[CH:24][C:19]([N:1]2[C:9]3[C:4](=[CH:5][CH:6]=[C:7]([C:10]4[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=4)[CH:8]=3)[CH:3]=[CH:2]2)=[CH:20][CH:21]=1
Reactant: Brc1ccncc1
Reactant: Oc1ccc(-c2ccc3cc[nH]c3c2)cc1
Agent: Cl
Product: Oc1ccc(-c2ccc3ccn(-c4ccncc4)c3c2)cc1

Procedure:
The target compound was prepared as in Example 1 using 4-(1H-indol-6-yl)phenol (200 mg, 0.96 mmol) and 4-bromopyridine hydrochloride (205 mg, 1.06 mmol).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([NH2:19])[CH:14]=1)[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[O-:20][C:21]#[N:22].[K+].OP(O)(O)=O>O.C(O)(=O)C>[C:1]([O:5][C:6]([NH:8][CH:9]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([NH:19][C:21]([NH2:22])=[O:20])[CH:14]=1)[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC(C(=O)O)c1cccc(N)c1
Reactant: N#C[O-]
Agent: O=P(O)(O)O
Agent: [K+]
Solvent: O
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)NC(C(=O)O)c1cccc(NC(N)=O)c1

Procedure:
A solution of α-t-butoxycarbonylamino-m-aminophenylacetic acid (2.66 g, 0.01 mol) and potassium cyanate (0.81 g, 0.01 mol) in a mixture of water(35 ml) and acetic acid (2.5 ml) was heated at 56° for 3 hours. The solution was cooled, acidified with 40% H3PO4, and extracted with ethyl acetate. The dried extracts were evaporated to give the title product: mp 93°-95° (dec).
Reaction SMILES: C([O:3][C:4](=[O:33])[CH2:5][CH:6]([N:10]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[N:12]([CH2:19][C:20]2[CH:21]=[CH:22][CH:23]=[C:24]3[C:28]=2[N:27]([CH3:29])[C:26]([CH3:30])=[C:25]3[CH3:31])[C:11]1=[O:32])[CH2:7][CH2:8][CH3:9])C.[Li+].[OH-]>O1CCOCC1.O>[O:32]=[C:11]1[N:10]([CH:6]([CH2:7][CH2:8][CH3:9])[CH2:5][C:4]([OH:33])=[O:3])[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[N:12]1[CH2:19][C:20]1[CH:21]=[CH:22][CH:23]=[C:24]2[C:28]=1[N:27]([CH3:29])[C:26]([CH3:30])=[C:25]2[CH3:31]
Reactant: CCCC(CC(=O)OCC)n1c(=O)n(Cc2cccc3c(C)c(C)n(C)c23)c2ccccc21
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CCCC(CC(=O)O)n1c(=O)n(Cc2cccc3c(C)c(C)n(C)c23)c2ccccc21
Temperature: 25 °C
Reaction time: 5 h
Yield: 31.4 %

Procedure:
To a solution of 3-[2-Oxo-3-(1,2,3-trimethyl-1H-indol-7-ylmethyl)-2,3-dihydro-benzoimidazol-1-yl]-hexanoic acid ethyl ester (50 mg, 0.11 mmol) in 1,4-dioxane (5 mL) and H2O (2 mL) was added LiOH (5.4 mg, 0.22 mmol). The solution was stirred at room temperature for 5 hours. The solution was concentrated and the residue was purified by CombiFlash with 10% MeOH in CH2Cl2 as the eluent to afford the desirable product 3-[2-Oxo-3-(1,2,3-trimethyl-1H-indol-7-ylmethyl)-2,3-dihydro-benzoimidazol-1-yl]-hexanoic acid (14.5 mg, 31%) as a white foam. LC-MS (M++1): 420.21.
Reaction SMILES: C(C([NH:7][C@H:8]([C:10](O)=[O:11])[CH3:9])=O)(C)(C)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.ClC(Cl)(Cl)C(Cl)(Cl)Cl.[NH2:40][C@H:41]([C:47]([OH:49])=[O:48])[CH2:42][CH2:43][C:44](=[O:46])[NH2:45].[OH-].[K+].[N+]([O-])(O)=O>ClCCCl.CCOCC.C1CCCCC1.O>[NH2:7][C@H:8]([C:10]([NH:40][C@H:41]([C:47]([OH:49])=[O:48])[CH2:42][CH2:43][C:44](=[O:46])[NH2:45])=[O:11])[CH3:9]
Reactant: C[C@H](NC(=O)C(C)(C)C)C(=O)O
Reactant: NC(=O)CC[C@H](N)C(=O)O
Agent: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1CCCCC1
Solvent: O=[N+]([O-])O
Product: C[C@H](N)C(=O)N[C@@H](CCC(N)=O)C(=O)O
Reaction time: 0.33 h
Yield: 40 %

Procedure:
In a round bottom flask, add in 10 mmol of tert-butylcarbonylalanine (Boc-Ala), 15 mmol of triphenyl phosphine and 20 mmol of hexachloroethane, and then add in 20 ml of 1,2-dichloroethane. After reacting at 10° C. for 20 min, drop it into a liquid mixture containing 30 mmol glutamine, 20 ml of water and 20 ml of cyclohexane. While reacting, regulate pH to 11 with potassium hydroxide, the reaction temperature is 20° C., the reaction time after dropping is 30 min. And then acidify it to regulate pH=1.5 with dilute nitric acid. The aqueous phase, after concentrated, reacts with trifluoroacetic acid at room temperature for 15 hours. As the reaction is finished, add in 50 ml of ether, solids deposit, the product L-Ala-L-Gln with a yield of 40% is obtained by recrystallizing the solids with tetrahydrofuran-water.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:5]([C:6]([NH:8][CH3:9])=[O:7])=[CH:4][N:3]=1.[H-].[Na+].[CH2:14]([OH:16])[CH3:15]>>[CH2:14]([O:16][C:2]1[CH:11]=[CH:10][C:5]([C:6]([NH:8][CH3:9])=[O:7])=[CH:4][N:3]=1)[CH3:15]
Reactant: CNC(=O)c1ccc(Cl)nc1
Reactant: CCO
Agent: [H-]
Agent: [Na+]
Product: CCOc1ccc(C(=O)NC)cn1
Yield: 100 %

Procedure:
To a solution of 6-chloro-N-methylnicotinamide (500 mg, 2.93 mmol) in ethanol (10 mL), sodium hydride (purity 50%) (176 mg, 7.33 mmol) was added under ice-cold conditions. The resultant mixture was heated to reflux for 8 hours. After completion of the reaction, the reaction solution was concentrated in vacuo, then filtered, washed with water and ethyl acetate, and then dried. 6-Ethoxy-N-methylnicotinamide (556 mg, yield >100%) was obtained as a white crystal.
Reaction SMILES: [C:1](#[N:3])[CH3:2].C([Li])CCC.C([O:11][C:12](=O)[C:13]1[CH:18]=[C:17]([CH3:19])[CH:16]=[C:15]([CH3:20])[CH:14]=1)C.[OH-].[Na+]>C1COCC1>[CH3:20][C:15]1[CH:14]=[C:13]([C:12](=[O:11])[CH2:2][C:1]#[N:3])[CH:18]=[C:17]([CH3:19])[CH:16]=1
Reactant: CC#N
Reactant: CCOC(=O)c1cc(C)cc(C)c1
Agent: [Li]CCCC
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1cc(C)cc(C(=O)CC#N)c1
Temperature: -78 °C
Reaction time: 8 h

Procedure:
Under Ar(g), a solution of anhydrous acetonitrile (1.6 mL) in 35 mL anhydrous THF is cooled to −78° C. in a dry ice-acetone bath and then slowly treated with 12 mL of a 2.5 M n-butyl lithium in hexanes. The reaction mixture is maintained at −78° C. for an additional 45 min. and then slowly treated with a solution of 5 gms. of 3,5-dimethyl-benzoic acid ethyl ester in 5 mL of anhydrous THF. The resulting solution is then stirred overnight at room temperature. Subsequently, the reaction mixture is treated with 10% NaOH(aq) to dissolve solids, and then is extracted with ethyl acetate. The aqueous layer is acidified (pH 6) with HCl(aq) affording a white precipitate which subsequently is filtered The organic layer is concentrated in vacuo and the residue is triturated with isopropanol resulting in the formation of additional white precipitate. The combined precipitates provide the desired 3-(3,5-dimethyl-phenyl)-3-oxo-propionitrile in the amount of 2.0175 gms.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[C:7]([F:14])[CH:6]=1)(=[O:3])[CH3:2].S(=O)(=O)(O)O.[N+:20]([O-])([OH:22])=[O:21]>>[C:1]([NH:4][C:5]1[C:13]([N+:20]([O-:22])=[O:21])=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[C:7]([F:14])[CH:6]=1)(=[O:3])[CH3:2]
Reactant: O=[N+]([O-])O
Reactant: CC(=O)Nc1ccc(C(=O)O)c(F)c1
Agent: O=S(=O)(O)O
Product: CC(=O)Nc1cc(F)c(C(=O)O)cc1[N+](=O)[O-]

Procedure:
Prepared analogously to example 83b from 4-acetylamino-2-fluoro-benzoic acid, conc. sulphuric acid and conc. nitric acid
Reaction SMILES: [OH:1][C:2]([C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=1)=[C:3]([C:6]#[N:7])[C:4]#[N:5].[CH3:17][Si](C=[N+]=[N-])(C)C.C(O)(=O)C>C(#N)C.CO.C(OCC)C.CCOC(C)=O>[CH3:17][O:1][C:2]([C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=1)=[C:3]([C:4]#[N:5])[C:6]#[N:7]
Reactant: N#CC(C#N)=C(O)c1ccc([N+](=O)[O-])cc1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: CC#N
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: COC(=C(C#N)C#N)c1ccc([N+](=O)[O-])cc1
Reaction time: 0.33 h

Procedure:
3-Hydroxy-3-(4-nitrophenyl)-2-cyanoacrylonitrile (21.5 g, 0.10 mol) was dissolved in acetonitrile (430 mL) and of methanol (43 mL) in a flask equipped with a dropping funnel, a thermometer, a stir bar, and argon atmosphere. The flask was immersed in a −15° C. bath to the level that the internal temperature was maintained between −5° C. and 0° C. (75 mL of a 2.0 M solution in diethyl ether, 0.15 mol) was added dropwise over 20 min. HPLC analysis showed incomplete reaction, and an additional portion (25 mL, 0.05 mol) of trimethylsilyldiazomethane solution was added. This was repeated with 35 mL (0.07 mol). After 20 min, the mixture was poured into a rapidly-stirred solution of acetic acid (15 g, 0.25 mol) in EtOAc (1.8 L). The mixture was extracted with water (3×1.5 L), filtered through phase separation paper, and concentrated in vacuo. the solid residue weighed 14.4 g and was used in the next step without further purification. NMR (60 MHz) (CDCl3) δ 8.0 (AB, 4H); 4.0 (s, 3H).