Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:8]=[C:9]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:10]=[CH:11][CH:12]=2)[CH:2]=1.C[Si](C)(C)[N-][Si](C)(C)C.[Na+].Br[CH2:30][CH2:31][CH2:32][CH2:33][Cl:34].O>CN(C)C=O.O1CCCC1>[Cl:34][CH2:33][CH2:32][CH2:31][CH2:30][CH:13]([C:9]1[CH:10]=[CH:11][CH:12]=[C:7]([C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)[CH:8]=1)[C:14]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: ClCCCCBr
Reactant: CCOC(=O)Cc1cccc(-c2cccnc2)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C(CCCCCl)c1cccc(-c2cccnc2)c1
Reaction time: 0.17 h

Procedure:
To a solution of 0.363 g (1.5 mmol) of ethyl m-(3-pyridyl)phenylacetate in 5.4 mL dry dimethylformamide at 5° C. is added 1.56 mL of a 1M solution of sodium hexamethyldisilazide in tetrahydrofuran. The organic layer is evaporated to dryness and resulting orange colored solution is stirred for 10 minutes and 0.54 mL (4.7 mmol) 1-bromo-4-chlorobutane is added rapidly. The reaction is stirred at 5° C. for 2 hours and then poured into water and extracted thrice with ether. The organic layer is evaporated to dryness and the resulting oil is purified by flash chromatography using 1:1 ether and hexane to obtain ethyl 6-chloro-2-[m-(3-pyridyl)phenyl]hexanoate; IR (CH2Cl2): 1728, 1278, 1184, 1165, 1023 cm-1.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][CH2:5][CH2:6][NH2:7].[OH-:8].[Na+].Cl[C:11]1[N:16]=[C:15]([N:17]([CH2:28][CH2:29][CH2:30][CH3:31])[CH:18]2[CH2:23][C:22]([CH3:25])([CH3:24])[NH:21][C:20]([CH3:27])([CH3:26])[CH2:19]2)[N:14]=[C:13]([N:32]2[C:37]([CH3:39])([CH3:38])[CH2:36][CH:35]([O:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46])[CH2:34][C:33]2([CH3:48])[CH3:47])[N:12]=1>O.C1(C)C=CC=CC=1>[CH3:48][C:33]1([CH3:47])[CH2:34][CH:35]([O:8][CH2:46][CH2:45][CH2:44][CH2:43][CH2:42][CH3:41])[CH2:36][C:37]([CH3:38])([CH3:39])[N:32]1[C:13]1[N:14]=[C:15]([N:17]([CH2:28][CH2:29][CH2:30][CH3:31])[CH:18]2[CH2:23][C:22]([CH3:25])([CH3:24])[NH:21][C:20]([CH3:27])([CH3:26])[CH2:19]2)[N:16]=[C:11]([NH:1][CH2:2][CH2:3][N:4]([C:11]2[N:12]=[C:13]([N:32]3[C:33]([CH3:47])([CH3:48])[CH2:34][CH:35]([O:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46])[CH2:36][C:37]3([CH3:39])[CH3:38])[N:14]=[C:15]([N:17]([CH2:28][CH2:29][CH2:30][CH3:31])[CH:18]3[CH2:19][C:20]([CH3:27])([CH3:26])[NH:21][C:22]([CH3:25])([CH3:24])[CH2:23]3)[N:16]=2)[CH2:5][CH2:6][NH:7][C:11]2[N:12]=[C:13]([N:32]3[C:33]([CH3:48])([CH3:47])[CH2:34][CH:35]([O:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46])[CH2:36][C:37]3([CH3:38])[CH3:39])[N:14]=[C:15]([N:17]([CH2:28][CH2:29][CH2:30][CH3:31])[CH:18]3[CH2:23][C:22]([CH3:25])([CH3:24])[NH:21][C:20]([CH3:27])([CH3:26])[CH2:19]3)[N:16]=2)[N:12]=1
Reactant: NCCNCCN
Reactant: [OH-]
Reactant: CCCCCCOC1CC(C)(C)N(c2nc(Cl)nc(N(CCCC)C3CC(C)(C)NC(C)(C)C3)n2)C(C)(C)C1
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: CCCCCCOC1CC(C)(C)N(c2nc(NCCN(CCNc3nc(N(CCCC)C4CC(C)(C)NC(C)(C)C4)nc(N4C(C)(C)CC(OCCCCCC)CC4(C)C)n3)c3nc(N(CCCC)C4CC(C)(C)NC(C)(C)C4)nc(N4C(C)(C)CC(OCCCCCC)CC4(C)C)n3)nc(N(CCCC)C3CC(C)(C)NC(C)(C)C3)n2)C(C)(C)C1
Reaction time: 14 h

Procedure:
0.71 ml of diethylenetriamine and 0.9 g of NaOH, dissolved in 3 ml of water, are added to 10.6 g of the monochloro derivative from Example 70, dissolved in 50 ml of toluene. After warming to 100°, the solvent begins to distill off. A further 50 ml of toluene and 1 g of polyethylene glycol 1000 and 0.9 g of NaOH are added and the mixture is heated with stirring for 14 h under reflux. After cooling, the reaction mixture is diluted using 100 ml of ethyl acetate and the solution is washed four times with water. The organic solution is dried over Na2SO4 and evaporated. The residue is dissolved in 50 ml of methanol, filtered through 200 g of silica gel and washed with 500 ml of methanol. The methanol solution is evaporated, the residue being a nearly colorless resin.
Reaction SMILES: [C:1]([O:5][CH2:6][CH:7]([CH3:15])[C:8](OC(C)(C)C)=[O:9])([CH3:4])([CH3:3])[CH3:2].[H-].[Al+3].[Li+].[H-].[H-].[H-]>>[C:1]([O:5][CH2:6][CH:7]([CH3:15])[CH2:8][OH:9])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(COC(C)(C)C)C(=O)OC(C)(C)C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: CC(CO)COC(C)(C)C
Yield: 88 %

Procedure:
Reduction of rac.-tert. butyl 3-tert.butoxy-2-methylpropionate was carried out with lithium aluminum hydride using the procedure described in Example 2. The resulting rac.-3-tert. butoxy-2-methyl-1-propanol was obtained in 88% yield as a colorless liquid, b.p. 70°-72° C. (10 mm Hg.).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[O:9][C:10]1[C:19]2[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=2)[N:13]=[CH:12][CH:11]=1)[NH2:5].C(O)C.[CH3:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[C:34]([N:36]=[C:37]=[S:38])=[O:35]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([NH:5][C:37]([NH:36][C:34](=[O:35])[C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=2[CH3:27])=[S:38])[CH:6]=[CH:7][C:8]=1[O:9][C:10]1[C:19]2[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=2)[N:13]=[CH:12][CH:11]=1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3Cl)c2cc1OC
Reactant: Cc1ccccc1C(=O)N=C=S
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)c4ccccc4C)cc3Cl)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 90 %

Procedure:
3-Chloro-4-[(6,7-dimethoxy-4-quinolyl)oxy]aniline (50 mg) was dissolved in toluene (5 ml) and ethanol (1 ml) to prepare a solution. Commercially available 2-methyl-1-benzenecarbonyl isothiocyanate (50 μl) was then added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (69 mg, yield 90%).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][C:5](=O)[CH2:4][CH2:3]1.Cl.[CH3:10][O:11][C:12]1[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][C:13]=1[CH2:14][NH2:15].[SH:22][CH2:23][C:24](O)=[O:25].O>C1C=CC=CC=1>[CH3:10][O:11][C:12]1[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][C:13]=1[CH2:14][N:15]1[C:5]2([CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]2)[S:22][CH2:23][C:24]1=[O:25]
Reactant: O=C(O)CS
Reactant: CN1CCC(=O)CC1
Reactant: COc1ccc(CN)c(OC)c1
Agent: Cl
Solvent: c1ccccc1
Solvent: O
Product: COc1ccc(CN2C(=O)CSC23CCN(C)CC3)c(OC)c1
Temperature: 25 °C
Yield: 15 %

Procedure:
In a three-necked flask equipped with a magnetic stirrer and Dean-Stark a solution of 1-methyl-4-piperidone (0.27 ml, 2.4 mmol), 2,4-dimethoxybenzylamine hydrochloride (0.72 gr, 3.5 mmol) and mercaptoacetic acid (0.24 ml, 3.5 mmol) in benzene (5 ml) was refluxed for 3 h. The reaction mixture was cooled to room temperature, water (10 ml) was added and the organic phase was separated. The pH of the aqueous phase was adjusted to pH 10 with 2.5N aqueous sodium hydroxide solution and then the aqueous cooled to room temperature, water (10 ml) was added and the organic phase was separated. The pH of the evaporated. Flash chromatography (silica, 10% methanol in chloroform) of the residue gave AF286 (140 mg, 15% yield). 1H-NMR (CDCl3) δ 1.66 (m, 2H), 2.21 (m, 4H), 2.27 (s, 3H, NCH3), 2.77 (m, 2H), 3.64 (s, 2H, SCH2), 3.78 (s, 3H, OCH3), 3.80 (s, 3H, OCH3), 4.52 (s, 2H, NCH2),
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[C:11]3[S:12][C:13]([C:15]([N:17]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[Cl:27])[CH2:18][CH2:19][OH:20])=[O:16])=[CH:14][C:10]=3[CH2:9][CH2:8][O:7][C:6]=2[CH:28]=1.C[OH:30].CN.C1CCN2[C:36](=[N:37][CH2:38]CC2)CC1>C1COCC1.C(OCC)(=O)C.[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[Mo]>[Cl:27][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[N:17]([CH2:18][CH2:19][OH:20])[C:15]([C:13]1[S:12][C:11]2[C:5]3[CH:4]=[CH:3][C:2]([C:38]([NH:37][CH3:36])=[O:30])=[CH:28][C:6]=3[O:7][CH2:8][CH2:9][C:10]=2[CH:14]=1)=[O:16]
Reactant: O=C(c1cc2c(s1)-c1ccc(Br)cc1OCC2)N(CCO)c1ccccc1Cl
Reactant: CO
Reactant: C1CCC2=NCCCN2CC1
Agent: [Mo]
Agent: CN
Agent: [C-]#[O+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CNC(=O)c1ccc2c(c1)OCCc1cc(C(=O)N(CCO)c3ccccc3Cl)sc1-2
Reaction time: 0.33 h
Yield: 4.2 %

Procedure:
Under ambient conditions a sealable reaction vessel was charged with 8-bromo-N-(2-chlorophenyl)-N-(2-hydroxyethyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carboxamide (0.08 g, 0.17 mmol), molybdenum hexacarbonyl (0.044 g, 0.167 mmol) in methanol (0.5 ml, 10 mmol)/THF 1 ml, 10 mmol), followed by the addition of 2M methylamine in THF (0.251 ml), /trans-D(mu-acetato)bis[di-o-tolylphosphino)benzyl]dipalladium(II) (32.3 mg, 0.0334 mmol). Finally, DBU (0.025 ml, 0.167 mmol) was added and the reaction vial was quickly sealed. The charged reaction vial was flash heated on a Biotage Emrys Optimizer microwave at 150° C. for 20 minutes. The cooled reaction mixture was diluted with ethyl acetate and filtered through a bed of Celite. The filtrate was concentrated to a solid and purified by MPLC on silica to give 3.2 mg 154 (yield=4.3% of theoretical). MS: (ESI+) 458.2
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:30]([O:32]CC)=O)=[N:4][C:5]([NH:17][C@@H:18]2[CH2:22][CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19]2)=[N:6][C:7]=1[NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[O:15][CH3:16].C(OC([N:42]1CC[C@@H](NC2N=C(C(OCC)=O)C([N+]([O-])=O)=C(NC3C=CC=CC=3OC)N=2)C1)=O)(C)(C)C.[CH2:71]([OH:73])C>[Pd]>[CH3:16][O:15][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[N:8]1[C:71](=[O:73])[NH:1][C:2]2[C:7]1=[N:6][C:5]([NH:17][C@@H:18]1[CH2:22][CH2:21][NH:20][CH2:19]1)=[N:4][C:3]=2[C:30]([NH2:42])=[O:32]
Reactant: CCOC(=O)c1nc(N[C@@H]2CCN(C(=O)OC(C)(C)C)C2)nc(Nc2ccccc2OC)c1N
Reactant: CCO
Reactant: CCOC(=O)c1nc(N[C@@H]2CCN(C(=O)OC(C)(C)C)C2)nc(Nc2ccccc2OC)c1[N+](=O)[O-]
Agent: [Pd]
Product: COc1ccccc1-n1c(=O)[nH]c2c(C(N)=O)nc(N[C@@H]3CCNC3)nc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 89 %

Procedure:
(R)-Ethyl 5-amino-2-(1-(tert-butoxycarbonyl)pyrrolidin-3-ylamino)-6-(2-methoxy-phenylamino)pyrimidine-4-carboxylate. (R)-Ethyl 2-(1-(tert-butoxycarbonyl)pyrrolidin-3-ylamino)-6-(2-methoxyphenylamino)-5-nitropyrimidine-4-carboxylate (0.403 g, 0.802 mmol) was dissolved in ethanol (20 mL) and 10% palladium on carbon (0.080 g) were added to the flask and flushed with fresh hydrogen gas and allowed to stir at room temperature. After 16 hours, the reaction was filtered through celite and the filtrate condensed under reduced pressure. The crude oil was purified using biotage chromatography (0-100% ethyl acetate in hexanes) to afford the title compound (0.340 g, 89%). MS (ESI) m/z 473.5 [M+1]+.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].Br[C:8]1[CH:9]=[C:10]([CH:29]=[CH:30][CH:31]=1)[C:11]([NH:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][N:21]([CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)[CH3:22])=[CH:16][CH:15]=1)=[O:12].B(O)(O)[C:33]1[CH:34]=[CH:35][C:36]([CH3:39])=[CH:37][CH:38]=1>C1(C)C=CC=CC=1.C(O)C.O>[CH:23]1([N:21]([CH2:20][C:17]2[CH:18]=[CH:19][C:14]([NH:13][C:11]([C:10]3[CH:9]=[C:8]([C:33]4[CH:38]=[CH:37][C:36]([CH3:39])=[CH:35][CH:34]=4)[CH:31]=[CH:30][CH:29]=3)=[O:12])=[CH:15][CH:16]=2)[CH3:22])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: CN(Cc1ccc(NC(=O)c2cccc(Br)c2)cc1)C1CCCCC1
Reactant: Cc1ccc(B(O)O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCO
Product: Cc1ccc(-c2cccc(C(=O)Nc3ccc(CN(C)C4CCCCC4)cc3)c2)cc1

Procedure:
K2CO3 (0.2 mmol, 0.03 g) and a Pd(dppf)2 catalyst:DCM complex (1:1) (0.03 mmol, 0.02 g) was added to a mixture of 3-bromo-N-{4-[(cyclohexyl-methyl-amino)-methyl]-phenyl}-benzamide Compound 10f (0.1 mmol, 0.04 g) and p-tolylboronic acid Compound 11a (0.12 mmol, 0.02 g) in a mixed solution of toluene/ethanol/water (7 mL/1 mL/1 mL). The resulting suspension was heated to reflux for 5 hrs, concentrated and purified with preparative TLC (10% MeOH/2% Et3N/88% EtOAc) to yield 4′-methyl-biphenyl-3-carboxylic acid {4-[(cyclohexyl-methyl-amino)-methyl]-phenyl}amide Compound 11b (0.02 g, 48%). MS m/e 413 (M+1).
Reaction SMILES: C(O)(=O)C.[N+:5]([C:8]1[CH:9]=[N:10][C:11]([N:14]2[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[N:15]2)=[N:12][CH:13]=1)([O-])=O>CO.C(OCC)(=O)C.[Fe]>[F:22][C:19]([F:20])([F:21])[C:17]1[CH:16]=[N:15][N:14]([C:11]2[N:12]=[CH:13][C:8]([NH2:5])=[CH:9][N:10]=2)[CH:18]=1
Reactant: O=[N+]([O-])c1cnc(-n2cc(C(F)(F)F)cn2)nc1
Agent: [Fe]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: Nc1cnc(-n2cc(C(F)(F)F)cn2)nc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 64 %

Procedure:
Glacial acetic acid (2.78 g, 46.3 mmol) was slowly added to a solution of 5-nitro-2-(4-(trifluoromethyl)-1H-pyrazol-1-yl)pyrimidine (1.5 g, 5.8 mmol) and iron powder (1.94 g, 34.7 mmol) in methanol (30 mL). The reaction was stirred at room temperature for 3 hours. The reaction was then diluted with ethyl acetate (50 mL) and filtered through Celite. The filtrate was neutralized with saturated aqueous potassium carbonate. The organic layer was separated and washed with water and brine, dried over sodium sulfate, filtered, and concentrated to give 2-(4-(trifluoromethyl)-1H-pyrazol-1-yl)pyrimidin-5-amine (850 mg, 64%) as a yellow solid. 1H NMR (400 MHz, CDCl3, δ): 8.68 (s, 1H), 8.16 (s, 2H), 7.87 (s, 1H), 3.82 (s, 2H).
Reaction SMILES: [CH:1]1[C:6]2[C:7]([O:9][C:10](=[O:11])[C:5]=2[CH:4]=[C:3]2[C:12]([O:14][C:15](=[O:16])[C:2]=12)=[O:13])=[O:8].C([N:20](C(C)C)CC)(C)C.[O:26]([C:33]1[CH:34]=[C:35]([CH:48]=[CH:49][CH:50]=1)[CH2:36][NH:37][C@@H:38]1[C:47]2[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=2)[CH2:41][CH2:40][CH2:39]1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.[OH-].[NH4+]>>[NH2:20][C:7]([C:6]1[CH:1]=[C:2]([C:15]([N:37]([CH2:36][C:35]2[CH:48]=[CH:49][CH:50]=[C:33]([O:26][C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH:34]=2)[C@@H:38]2[C:47]3[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=3)[CH2:41][CH2:40][CH2:39]2)=[O:16])[C:3]([C:12]([OH:14])=[O:13])=[CH:4][C:5]=1[C:10]([OH:9])=[O:11])=[O:8]
Reactant: CCN(C(C)C)C(C)C
Reactant: c1ccc(Oc2cccc(CN[C@H]3CCCc4ccccc43)c2)cc1
Reactant: O=c1oc(=O)c2cc3c(=O)oc(=O)c3cc12
Agent: [NH4+]
Agent: [OH-]
Product: NC(=O)c1cc(C(=O)N(Cc2cccc(Oc3ccccc3)c2)[C@H]2CCCc3ccccc32)c(C(=O)O)cc1C(=O)O
Yield: 21 %

Procedure:
1,2,4,5-Benzenetetracarboxylic dianhydride (1 mmol), diisopropylethyl amine, N-(3-phenoxybenzyl)-N-[(1S)-1,2,3,4-tetrahydro-1-naphthalenyl]amine and ammonium hydroxide were processed as described in Example 100 to provide the title compounds as a white solid (120 mg, 21% yield).
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[C:3]1[N:4]=[CH:5][NH:6][CH:7]=1.Cl[C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-])=O)=[CH:13][N:12]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C.O>[F:1][C:2]([F:9])([F:8])[C:3]1[N:4]=[CH:5][N:6]([C:11]2[N:12]=[CH:13][C:14]([NH2:17])=[CH:15][CH:16]=2)[CH:7]=1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: FC(F)(F)c1c[nH]cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: Nc1ccc(-n2cnc(C(F)(F)F)c2)nc1
Temperature: 85 °C
Reaction time: 5 h

Procedure:
A mixture of 4-(trifluoromethyl)-1H-imidazole (2000 mg, 14.70 mmol), 2-chloro-5-nitropyridine (2330 mg, 14.70 mmol), and potassium carbonate (4060 mg, 29.4 mmol) in acetonitrile (14.7 mL) was heated at 85° C. overnight. The reaction was diluted with water and extracted three times with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated. The crude residue was dissolved in ethanol (20 mL) and ethyl acetate (15 mL). 10 wt % Palladium on carbon (500 mg) was added to the solution. The mixture was pressurized to 50 psi hydrogen and was shaken for 5 hours. The reaction was filtered through celite, rinsing with methanol. The filtrate was concentrated to give 6-(4-(trifluoromethyl)-1H-imidazol-1-yl)pyridin-3-amine. 1H NMR (400 MHz, CDCl3, δ): 8.15 (s, 1H), 7.93 (d, J=2.73 Hz, 1H), 7.85 (s, 1H), 7.20-7.15 (m, 1H), 7.14-7.09 (m, 1H), 3.13-2.30 (m, 2H). MS (M+HCO2−): 273.0.
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[S:18][C:17]3[C:16](=[O:19])[N:15]([CH2:20][CH2:21][C:22]4[CH:27]=[CH:26][C:25]([CH2:28][NH:29][CH3:30])=[CH:24][CH:23]=4)[CH:14]=[N:13][C:12]=3[CH:11]=2)=[CH:6][CH:5]=1.BrC[C:33]([NH2:35])=[O:34].[CH2:36](N(CC)CC)C.CN(C)C=O>C(OCC)(=O)C>[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[S:18][C:17]3[C:16](=[O:19])[N:15]([CH2:20][CH2:21][C:22]4[CH:23]=[CH:24][C:25]([CH2:28][N:29]([CH3:36])[CH2:30][C:33]([NH2:35])=[O:34])=[CH:26][CH:27]=4)[CH:14]=[N:13][C:12]=3[CH:11]=2)=[CH:6][CH:5]=1
Reactant: CNCc1ccc(CCn2cnc3cc(-c4ccc(Cl)cc4)sc3c2=O)cc1
Reactant: CCN(CC)CC
Reactant: NC(=O)CBr
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CN(CC(N)=O)Cc1ccc(CCn2cnc3cc(-c4ccc(Cl)cc4)sc3c2=O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 29 %

Procedure:
A mixture of the compound (100 mg) obtained in Example 4, bromoacetamide (31 mg), triethylamine (73 mg) and N,N-dimethylformamide (2 ml) was stirred overnight at room temperature. The reaction mixture was diluted with ethyl acetate, washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography [developing solvent:ethyl acetate-methanol (10:1, volume ratio)] and recrystallized from ethyl acetate-hexane (1:1, volume ratio) to give the title compound (28 mg) as a colorless powder.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH2:11][CH2:12][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:14][CH2:15][C:5]=3[C:4]=2[C:3]=1[Cl:23].[H-].[Na+].Br[CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29]>CN(C=O)C>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])[C:6]3[CH2:11][CH2:12][N:13]([C:16]([O:18][C:19]([CH3:20])([CH3:22])[CH3:21])=[O:17])[CH2:14][CH2:15][C:5]=3[C:4]=2[C:3]=1[Cl:23]
Reactant: CCOC(=O)CBr
Reactant: CC(C)(C)OC(=O)N1CCc2[nH]c3ccc(Cl)c(Cl)c3c2CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)Cn1c2c(c3c(Cl)c(Cl)ccc31)CCN(C(=O)OC(C)(C)C)CC2
Reaction time: 0.25 h
Yield: 68.8 %

Procedure:
To a solution of tert-butyl 9,10-dichloro-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate (0.10 g, 0.28 mmol) in DMF (2 mL), sodium hydride (60% dispersion in mineral oil, 17 mg, 0.42 mmol) was added. After 15 min, ethyl bromoacetate(0.060 mL, 0.56 mmol) was added. The reaction was quenched with saturated aqueous NH4Cl after 2.5 h and extracted with EtOAc (3×15 mL). The combined organic extracts were washed with brine, dried over Na2SO4, decanted, and concentrated. The crude product was purified by column chromatography (Biotage, 40S) with heptane/EtOAc (3:1) to give 85 mg (70%) of a white solid: mp 136.5-138.0° C.; 1H NMR (300 MHz, CDCl3) δ 7.19 (d, J=8.7 Hz, 1H), 6.99 (d, J=8.7 Hz, 1H), 4.74 (s, 2H), 4.21 (dd, J=7.1, 7.1 Hz, 2H), 3.75 (m, 4H), 3.53 (m, 2H), 2.93 (m, 2H), 1.48 (s, 9H), 1.26 (t, J=7.1 Hz, 3H); IR (diffuse reflectance) 2985, 2976, 1737, 1685, 1466, 1450, 1414, 1367, 1344, 1249, 1213, 1169, 1156, 1115, 926 cm−1; MS (EI) m/z 440 (M+), 307, 305, 301, 299, 298, 272, 225, 189, 58, 56; Anal. Calcd for C21H26Cl2N2O4: C, 57.15; H, 5.94; N, 6.35, found: C, 57.16; H, 5.98; N, 6.27.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:10][CH:9]=2)[CH:5]=[CH:4][C:3]=1[OH:24].[CH2:25]([C@H:30]1[CH2:35][CH2:34][C@H:33]([C:36](Cl)=[O:37])[CH2:32][CH2:31]1)[CH2:26][CH2:27][CH2:28][CH3:29].O1CCOCC1.N1C=CC=CC=1>O>[CH2:25]([C@H:30]1[CH2:31][CH2:32][C@H:33]([C:36]([NH:1][C:2]2[CH:7]=[C:6]([C:8]3[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:10][CH:9]=3)[CH:5]=[CH:4][C:3]=2[OH:24])=[O:37])[CH2:34][CH2:35]1)[CH2:26][CH2:27][CH2:28][CH3:29]
Reactant: CCCCCCCCCCc1ccc(-c2ccc(O)c(N)c2)cc1
Reactant: CCCCC[C@H]1CC[C@H](C(=O)Cl)CC1
Solvent: O
Solvent: C1COCCO1
Solvent: c1ccncc1
Product: CCCCCCCCCCc1ccc(-c2ccc(O)c(NC(=O)[C@H]3CC[C@H](CCCCC)CC3)c2)cc1

Procedure:
Step i) In a 50 ml-three-necked flask, 0.70 g (2.15 mM) of 2-amino-4-(4-decylphenyl)phenol, 0.48 g (2.21 mM) of trans-4-pentylcyclohexylcarbonyl chloride and 20 ml of dioxane were placed. To the mixture, 0.77 ml of pyridine was gradually added dropwise at about 87° C. under stirring, followed by heat-stirring for 1.5 hours at about 87° C. After the reaction, the reaction mixture was poured into 150 ml of water to precipitate a crystal. The crystal was recovered by filtration, washed with methanol and recrystallized from toluene to obtain 0.61 g of 2-(trans-4-pentylcyclohexylcarbonylamino)-4-(4-decylphenyl)phenol (yield: 56.1%).
Reaction SMILES: [C:1]([CH2:3][C:4]1[C:12]2[C:7](=[N:8][CH:9]=[C:10]([F:13])[CH:11]=2)[NH:6][C:5]=1[CH3:14])#[N:2].[F:15][C:16]1[CH:25]=[CH:24][C:19]([C:20](=[O:23])[CH2:21][Cl:22])=[CH:18][CH:17]=1>C(#N)C.C(OCC)C>[ClH:22].[C:1]([CH2:3][C:4]1[C:12]2[C:7]([N:8]([CH2:21][C:20]([C:19]3[CH:24]=[CH:25][C:16]([F:15])=[CH:17][CH:18]=3)=[O:23])[CH:9]=[C:10]([F:13])[CH:11]=2)=[N:6][C:5]=1[CH3:14])#[N:2]
Reactant: O=C(CCl)c1ccc(F)cc1
Reactant: Cc1[nH]c2ncc(F)cc2c1CC#N
Solvent: CC#N
Solvent: CCOCC
Product: Cc1nc2n(CC(=O)c3ccc(F)cc3)cc(F)cc-2c1CC#N
Product: Cl
Yield: 41.7 %

Procedure:
A mixture of 3-(cyanomethyl)-5-fluoro-2-methylpyrrolo[2,3-b]pyridine (10mg, 0.053 mmol) and 4-fluorophenacyl chloride (19 mg, 0.11 mmol) in acetonitrile (0.2 ml) was refluxed under argon for 26 h, during which time the initial solution was transformed into a suspension. Then the suspension was allowed to reach room temperature, diluted with diethyl ether (2ml), and filtered. The crystalline product was washed with diethyl ether to give 8 mg (42%) of the title compound.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[C:8]1([CH2:14][CH2:15][CH2:16][NH:17][C:18](=[O:37])[C@H:19]([CH2:33][CH2:34][CH2:35][NH2:36])[N:20]([C:29](=[O:32])[CH2:30][NH2:31])[CH2:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[C:38](=[NH:43])(OCC)[CH3:39]>C(O)C>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[C:8]1([CH2:14][CH2:15][CH2:16][NH:17][C:18](=[O:37])[C@H:19]([CH2:33][CH2:34][CH2:35][NH2:36])[N:20]([C:29](=[O:32])[CH2:30][NH:31][C:38](=[NH:43])[CH3:39])[CH2:21][CH2:22][C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CCOC(C)=N
Reactant: NCCC[C@@H](C(=O)NCCCc1ccccc1)N(CCc1ccccc1)C(=O)CN
Solvent: CCO
Solvent: O=C(O)C(F)(F)F
Product: CC(=N)NCC(=O)N(CCc1ccccc1)[C@@H](CCCN)C(=O)NCCCc1ccccc1

Procedure:
Glycyl-Nα-(phenethyl)omithine 3-phenylpropylamide trifluoroacetate was treated with ethyl acetimidate in ethanol at pH9 and the product was purified by HPLC: 1H NMR (400 MHz, D2O) δ 1.6-2.0 (m, 6 H), 2.3 (s, 3 H), 2.7 (t, J=6.4 Hz, 2 H), 2.9-3.1 (m, 4 H), 3.2-3.4 (m, 2 H), 3.5-3.7 (m, 2 H), 4.1-4.3 (m, 2 H), 4.7-4.8 (m, 1 H), and 7.2-7.5 (m, 10 H); mass spectrum, m/e 453 (M+), 354, 300, 247, and 219.