Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[CH:16]=[CH:15][C:14]([CH2:17][N:18]2[C:22]([CH:23]=[O:24])=[C:21]([Cl:25])[N:20]=[C:19]2[CH:26](Br)[CH2:27][CH2:28][CH3:29])=[CH:13][CH:12]=1)([O:3][CH3:4])=[O:2].N12CCCN=CC1CCCC2>O1CCCC1.C(OCC)C>[C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[CH:16]=[CH:15][C:14]([CH2:17][N:18]2[C:22]([CH:23]=[O:24])=[C:21]([Cl:25])[N:20]=[C:19]2/[CH:26]=[CH:27]/[CH2:28][CH3:29])=[CH:13][CH:12]=1)([O:3][CH3:4])=[O:2]
Reactant: CCCC(Br)c1nc(Cl)c(C=O)n1Cc1ccc(-c2ccccc2C(=O)OC)cc1
Agent: C1=NCCCN2CCCCC12
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC/C=C/c1nc(Cl)c(C=O)n1Cc1ccc(-c2ccccc2C(=O)OC)cc1
Yield: 57.7 %

Procedure:
A solution of 0.54 g of 1-[(2'-carbomethoxybiphenyl-4-yl)methyl]-2-(1-bromobutyl)-4-chloroimidazole-5-carboxaldehyde and 0.33 mL of 1,8-diazabicyclo[4.5.0]undec-7-ene in 10 mL of tetrahydrofuran was stirred at 25° C. for 18 hours. The reaction mixture was diluted with diethyl ether, washed with dilute hydrochloric acid, water, and brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. Column chromatography (elution: ethyl acetate/benzene) furnished 0.26 g of 1-[(2'-carbomethoxybiphenyl-4-yl)methyl]-2-(1-trans-butenyl)-4-chloroimidazole-5-carboxaldehyde. NMR (200 MHz, CDCl3) δ9.75 (s, 1H); 7.82 (d, 1H); 7.51 (t, 1H); 7.40 (t, 1H); 7.33-7.07 (m, 6H); 6.27 (d, 1H); 5.62 (s, 2H); 3.62 (s, 3H); 2.30 (quint., 2H); 1.09 (t, 3H).
Reaction SMILES: [CH2:1]([C:3]1[C:8](=[O:9])[NH:7][C:6]([CH3:10])=[C:5]([C:11]2[S:15][C:14]([S:16]([Cl:19])(=[O:18])=[O:17])=[CH:13][CH:12]=2)[CH:4]=1)[CH3:2].[N:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1>>[ClH:19].[CH2:1]([C:3]1[C:8](=[O:9])[NH:7][C:6]([CH3:10])=[C:5]([C:11]2[S:15][C:14]([S:16]([N:29]3[CH2:30][CH2:31][N:26]([C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][N:20]=4)[CH2:27][CH2:28]3)(=[O:18])=[O:17])=[CH:13][CH:12]=2)[CH:4]=1)[CH3:2]
Reactant: CCc1cc(-c2ccc(S(=O)(=O)Cl)s2)c(C)[nH]c1=O
Reactant: c1ccc(N2CCNCC2)nc1
Product: CCc1cc(-c2ccc(S(=O)(=O)N3CCN(c4ccccn4)CC3)s2)c(C)[nH]c1=O
Product: Cl
Yield: 37 %

Procedure:
5-(5-Ethyl-2-methyl-6-oxo-1,6-dihydropyridin-3-yl)thiophene-2-sulfonyl chloride is reacted with 1-(pyridin-2-yl)piperazine as described in Step 5, Example 24 to give the title compound as a yellow solid (37% yield). LC/MS: RT 2.32 min; m/e 445 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][O:7][C:8]2[CH:13]=[CH:12][C:11]([N:14]([CH2:21][CH2:22][CH:23]([CH3:25])[CH3:24])[CH:15]3[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[CH3:28][C:29]([CH3:34])([CH3:33])[CH2:30][CH:31]=O>>[CH3:28][C:29]([CH3:34])([CH3:33])[CH2:30][CH2:31][N:18]1[CH2:17][CH2:16][CH:15]([N:14]([C:11]2[CH:10]=[CH:9][C:8]([O:7][CH2:6][C:5]3[CH:26]=[CH:27][C:2]([F:1])=[CH:3][CH:4]=3)=[CH:13][CH:12]=2)[CH2:21][CH2:22][CH:23]([CH3:24])[CH3:25])[CH2:20][CH2:19]1
Reactant: CC(C)(C)CC=O
Reactant: CC(C)CCN(c1ccc(OCc2ccc(F)cc2)cc1)C1CCNCC1
Product: CC(C)CCN(c1ccc(OCc2ccc(F)cc2)cc1)C1CCN(CCC(C)(C)C)CC1

Procedure:
The preparation of Example 43: [1-(3,3-Dimethyl-butyl)-piperidin-4-yl]-[4-(4-fluoro-benzyloxy)-phenyl]-(3-methyl-butyl)-amine was prepared in accordance with the methods of Step 7 in Example 40, except that [4-(4-Fluoro-benzyloxy)-phenyl]-(3-methyl-butyl)-piperidin-4-yl-amine (43c) was used instead of (4-Cyclohexylmethoxy-phenyl)-(3-methyl-butyl)-piperidin-4-yl-amine (40f) and 3,3-dimethylbutyraldehyde was used instead of isovaleraldehyde.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH2:9])=[CH:4][C:3]=1[O:10][CH3:11].CCN(C(C)C)C(C)C.[CH2:21]([O:23][CH:24]([O:29][CH2:30][CH3:31])[C:25](=[NH:28])OC)[CH3:22]>CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][C:25](=[NH:28])[CH:24]([O:29][CH2:30][CH3:31])[O:23][CH2:21][CH3:22])=[CH:4][C:3]=1[O:10][CH3:11]
Reactant: COc1cc(CN)ccc1Cl
Reactant: CCOC(OCC)C(=N)OC
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: CCOC(OCC)C(=N)NCc1ccc(Cl)c(OC)c1
Temperature: 70 °C
Reaction time: 2 h

Procedure:
To a mixture of (4-chloro-3-methoxyphenyl)methanamine (392 mg, 2.284 mmol) (as the hydrochloride salt), Hunig's Base (0.5 mL, 2.86 mmol), and MeOH (2 mL) was added a solution of methyl 2,2-diethoxyacetimidate (295 mg, 1.83 mmol) in MeOH (1 mL) and the resulting mixture was heated with stirring in an oil bath at 70° C. for 2 hrs and allowed to cool to room temperature over 3 days. The solvent was removed in vacuo and the residue was used without further purification.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH2:8][C@H:7]([CH:9]([CH3:11])[CH3:10])[N:6]([C:12]2[CH:17]=[CH:16][N:15]3[N:18]=[CH:19][C:20]([C:21]4[CH:26]=[CH:25][C:24]([C:27]5[N:31]=[CH:30][N:29](COCC[Si](C)(C)C)[N:28]=5)=[CH:23][CH:22]=4)=[C:14]3[N:13]=2)[C:5]1=[O:40].FC(F)(F)C(O)=O.[OH-].[Na+].CO>>[NH:29]1[CH:30]=[N:31][C:27]([C:24]2[CH:23]=[CH:22][C:21]([C:20]3[CH:19]=[N:18][N:15]4[CH:16]=[CH:17][C:12]([N:6]5[C@@H:7]([CH:9]([CH3:11])[CH3:10])[CH2:8][N:4]([CH2:3][CH2:2][OH:1])[C:5]5=[O:40])=[N:13][C:14]=34)=[CH:26][CH:25]=2)=[N:28]1
Reactant: CC(C)[C@H]1CN(CCO)C(=O)N1c1ccn2ncc(-c3ccc(-c4ncn(COCC[Si](C)(C)C)n4)cc3)c2n1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: CC(C)[C@H]1CN(CCO)C(=O)N1c1ccn2ncc(-c3ccc(-c4nc[nH]n4)cc3)c2n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 4.4 %

Procedure:
To (S)-1-(2-hydroxyethyl)-4-isopropyl-3-(3-(4-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-3-yl)phenyl)pyrazolo[1,5-a]pyrimidin-5-yl)imidazolidin-2-one (0.18 g, 0.32 mmol) was added trifluoroacetic acid (5 mL) and the reaction was stirred at ambient temperature for 3 hours. The reaction was concentrated in vacuo and the material purified by reverse preparative HPLC to yield the crude product and the corresponding trifluoroacetate ester. To this material was added 1N NaOH/MeOH and the mixture stirred at ambient temperature for 2 hours. The mixture was concentrated in vacuo. The combined crude product was purified by reverse preparative HPLC to give (S)-3-(3-(4-(1H-1,2,4-triazol-3-yl)phenyl)pyrazolo[1,5-a]pyrimidin-5-yl)-1-(2-hydroxyethyl)-4-isopropylimidazolidin-2-one (0.0061 g, 0.014 mmol, 4.4% yield) as the mono TFA salt. LCMS (APCI+) m/z 433 [M+H]+.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([NH:10][C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([CH2:20][C:21]4[CH:26]=[C:25]([F:27])[CH:24]=[C:23]([F:28])[CH:22]=4)[CH:18]=3)[NH:13][N:12]=2)=[O:9])=[CH:6][CH:5]=[C:4]([Cl:29])[N:3]=1.CCN(C(C)C)C(C)C.[O:39]1[CH2:44][CH2:43][CH:42]([NH2:45])[CH2:41][CH2:40]1>O1CCOCC1.CCOC(C)=O>[Cl:29][C:4]1[N:3]=[C:2]([NH:45][CH:42]2[CH2:43][CH2:44][O:39][CH2:40][CH2:41]2)[C:7]([C:8]([NH:10][C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([CH2:20][C:21]4[CH:22]=[C:23]([F:28])[CH:24]=[C:25]([F:27])[CH:26]=4)[CH:18]=3)[NH:13][N:12]=2)=[O:9])=[CH:6][CH:5]=1
Reactant: NC1CCOCC1
Reactant: O=C(Nc1n[nH]c2ccc(Cc3cc(F)cc(F)c3)cc12)c1ccc(Cl)nc1Cl
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1n[nH]c2ccc(Cc3cc(F)cc(F)c3)cc12)c1ccc(Cl)nc1NC1CCOCC1

Procedure:
A solution of 2,6-dichloro-N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]pyridine-3-carboxamide (80 mg, 0.18 mmol) in dioxane (1 mL) was heated at 100° C. for 24 hours in the presence of DIPEA (0.1 mL, 0.55 mmol) and tetrahydro-2H-pyran-4-amine. (28 mg, 0.28 mmol) Reaction mixture was diluted with EtOAc and washed with water. The organic layer was dried over sodium sulfate, filtered and evaporated. The crude was purified by flash chromatography on silica gel using DCM/EtOH 95:5 as the eluant, affording 57 mg of the title compound.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([C:11]([OH:13])=O)[N:2]=1.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[NH2:36][CH2:37][CH2:38][CH2:39][N:40]1[C:52]2[C:51]3[CH:50]=[CH:49][CH:48]=[CH:47][C:46]=3[N:45]=[C:44]([NH2:53])[C:43]=2[N:42]=[C:41]1[CH2:54][CH2:55][CH2:56][CH3:57]>CN1CCCC1=O>[NH2:53][C:44]1[C:43]2[N:42]=[C:41]([CH2:54][CH2:55][CH2:56][CH3:57])[N:40]([CH2:39][CH2:38][CH2:37][NH:36][C:11]([C:3]3[N:2]=[CH:1][C:10]4[C:5]([CH:4]=3)=[CH:6][CH:7]=[CH:8][CH:9]=4)=[O:13])[C:52]=2[C:51]2[CH:50]=[CH:49][CH:48]=[CH:47][C:46]=2[N:45]=1
Reactant: O=C(O)c1cc2ccccc2cn1
Reactant: CCCCc1nc2c(N)nc3ccccc3c2n1CCCN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCCC1=O
Product: CCCCc1nc2c(N)nc3ccccc3c2n1CCCNC(=O)c1cc2ccccc2cn1
Reaction time: 0.29 h
Yield: 75.4 %

Procedure:
Isoquinoline-3-carboxylic acid (1.05 g, 6.05 mmol) was stirred in 1-methyl-2-pyrrolidinone (50 mL). 1-Hydroxybenzotriazole (885 mg, 6.55 mmol) was added in a single portion. This solution was stirred for 15-20 minutes and then cooled in an ice bath. 1-[3-(Dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (1.26 g, 6.55 mmol) was added in small portions over a period of 10 minutes. The solution was stirred for 1 hour and then added dropwise to a solution of 1-(3-aminopropyl)-2-butyl-1H-imidazo[4,5-c]quinolin-4-amine (1.50 g, 5.04 mmol) in 1-methyl-2-pyrrolidinone (100 mL). After 3 hours the reaction mixture was poured into distilled water (800 mL). A solid precipitated. This material was stirred for 5 hours, isolated by filtration and then air dried over the weekend. The solid was taken up in chloroform (100 mL) and then purified by column chromatography (silica gel eluting sequentially with chloroform (1 L), 1% methanol in chloroform (1 L) and 5% methanol in chloroform (1 L)). The purified material was slurried with hot acetonitrile, cooled, isolated by filtration and then dried in a vacuum oven to provide 1.72 g of N-[3-(4-amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)propyl]isoquinoline-3-carboxamide as a solid, m.p. 203.8-205.3° C. Analysis: Calculated for C27H28N6O: % C, 71.66; % H, 6.24; % N, 18.57. Found: % C, 71.63; % H, 6.17; % N, 18.57.
Reaction SMILES: [CH3:1][N:2]1[C:7]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][O:17][C:18]3[CH:23]=[CH:22][C:21]([N+:24]([O-])=O)=[CH:20][CH:19]=3)[CH2:10][CH2:9]2)=[CH:6][C:5](=[O:27])[N:4]([CH3:28])[C:3]1=[O:29]>CO.[Pd]>[NH2:24][C:21]1[CH:22]=[CH:23][C:18]([O:17][CH2:16][CH2:15][CH2:14][N:11]2[CH2:10][CH2:9][N:8]([C:7]3[N:2]([CH3:1])[C:3](=[O:29])[N:4]([CH3:28])[C:5](=[O:27])[CH:6]=3)[CH2:13][CH2:12]2)=[CH:19][CH:20]=1
Reactant: Cn1c(N2CCN(CCCOc3ccc([N+](=O)[O-])cc3)CC2)cc(=O)n(C)c1=O
Agent: [Pd]
Solvent: CO
Product: Cn1c(N2CCN(CCCOc3ccc(N)cc3)CC2)cc(=O)n(C)c1=O
Reaction time: 0.5 h
Yield: 83.2 %

Procedure:
2 g of 1,3-dimethyl-6-[4-(3-[4-nitrophenoxy)propyl)piperazin-1-yl]-2,4(1H,3H)-pyrimidinedione (Compound f) obtained in Reference Example 4 was suspended in 300 ml of methanol and 500 mg of 10% Pd/c solution was added to the suspension, and hydrogenation was then carried out at ordinary pressure for 30 minutes. The catalyst was removed by filtration, and the solvent was distilled off, thereby obtaining 1.54 g of 6-[4-(3-[4-aminophenoxy)propyl)piperazin-1-yl]-1,3-dimethyl-2,4(1H,3H)-pyrimidinedione.
Reaction SMILES: C(OC([N:8]1[CH2:11][CH:10]([N:12]2[C:16]3[CH:17]=[C:18]([F:21])[CH:19]=[CH:20][C:15]=3[N:14]=[C:13]2[C@@H:22]([NH:24][C:25]2[N:33]=[CH:32][N:31]=[C:30]3[C:26]=2[N:27]=[CH:28][NH:29]3)[CH3:23])[CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH:8]1[CH2:9][CH:10]([N:12]2[C:16]3[CH:17]=[C:18]([F:21])[CH:19]=[CH:20][C:15]=3[N:14]=[C:13]2[CH:22]([NH:24][C:25]2[N:33]=[CH:32][N:31]=[C:30]3[C:26]=2[N:27]=[CH:28][NH:29]3)[CH3:23])[CH2:11]1
Reactant: C[C@H](Nc1ncnc2[nH]cnc12)c1nc2ccc(F)cc2n1C1CN(C(=O)OC(C)(C)C)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(Nc1ncnc2[nH]cnc12)c1nc2ccc(F)cc2n1C1CNC1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 96.6 %

Procedure:
To a solution of 3-{6-fluoro-2-[(S)-1-(9H-purin-6-ylamino)ethyl]benzoimidazol-1-yl}azetidine-1-carboxylic acid tert-butyl ester (214 mg, 0.47 mmol) in DCM (5 mL) at 0° C. was added TFA (1.7 mL) dropwise. The mixture was stirred at 0° C. for 20 min then slowly warmed to RT. Stirring was continued at RT for 1.5 h. The volatiles were removed under reduced pressure and the resulting residue was loaded onto an Isolute® SCX-2 cartridge, washed with MeOH followed by 2M NH3/MeOH. The basic fractions were combined and concentrated in vacuo to afford 378 as a white solid (160 mg, 96%). LCMS (Method K): RT 1.73 min [M+H]+ 353.0. 1H NMR (DMSO-d6, 400 MHz): δ 8.25 (1H, br s), 8.17-8.07 (2H, m), 7.95 (1H, br s), 7.64 (1H, dd, J=8.82, 5.08 Hz), 7.08 (1H, td, J=9.27, 2.42 Hz), 5.80 (1H, br s), 5.63-5.53 (1H, m), 4.14-4.06 (1H, m), 4.01 (2H, d, J=7.20 Hz), 3.93-3.74 (2H, m), 1.63 (3H, d, J=6.71 Hz)
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([NH:6][C:7](=[O:31])[N:8]2[C:11]2[CH:16]=[C:15]([O:17][CH2:18][C:19]3[C:24]([O:25][CH3:26])=[CH:23][CH:22]=[CH:21][C:20]=3[F:27])[C:14]([O:28][CH3:29])=[CH:13][C:12]=2[Cl:30])=[C:4]([O:32][CH3:33])[N:3]=1.[NH2:34][CH2:35][CH2:36][OH:37].C(O)C.[Cl-].[NH4+]>CN1CCCC1=O>[Cl:30][C:12]1[CH:13]=[C:14]([O:28][CH3:29])[C:15]([O:17][CH2:18][C:19]2[C:24]([O:25][CH3:26])=[CH:23][CH:22]=[CH:21][C:20]=2[F:27])=[CH:16][C:11]=1[N:8]1[C:7](=[O:31])[NH:6][C:5]2[C:9]1=[N:10][C:2]([NH:34][CH2:35][CH2:36][OH:37])=[N:3][C:4]=2[O:32][CH3:33]
Reactant: COc1cc(Cl)c(-n2c(=O)[nH]c3c(OC)nc(Cl)nc32)cc1OCc1c(F)cccc1OC
Reactant: NCCO
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN1CCCC1=O
Solvent: CCO
Product: COc1cc(Cl)c(-n2c(=O)[nH]c3c(OC)nc(NCCO)nc32)cc1OCc1c(F)cccc1OC
Temperature: 150 °C
Reaction time: 0.5 h
Yield: 9.5 %

Procedure:
A mixture of 2-chloro-9-[2-chloro-5-(2-fluoro-6-methoxybenzyloxy)-4-methoxyphenyl]-6-methoxy-7,9-dihydro-8H-purin-8-one (50 mg), 2-aminoethanol (19 mg), ethanol (1 mL) and 1-methyl-2-pyrrolidone (0.5 mL) was stirred at 150° C. in a sealed tube under microwave irradiation for 30 minutes. The reaction mixture was poured into a saturated aqueous ammonium chloride solution, and the resulting mixture was extracted with ethyl acetate. The extract was washed with water and brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=2/3−ethyl acetate). The obtained product was suspended in a mixed solvent (n-hexane/ethyl acetate=2/1), and collected by filtration. The collected material was dried under reduced pressure to give the title compound (5 mg).
Reaction SMILES: C[O:2][C:3](=[O:28])[C:4]1[CH:9]=[C:8]([Br:10])[CH:7]=[C:6]([CH3:11])[C:5]=1[N:12]([CH3:27])[S:13]([C:16]1[CH:21]=[CH:20][C:19]([O:22][CH:23]([CH3:26])[C:24]#[CH:25])=[CH:18][CH:17]=1)(=[O:15])=[O:14].[OH-].[Na+]>>[Br:10][C:8]1[CH:7]=[C:6]([CH3:11])[C:5]([N:12]([CH3:27])[S:13]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH:23]([CH3:26])[C:24]#[CH:25])=[CH:18][CH:17]=2)(=[O:15])=[O:14])=[C:4]([CH:9]=1)[C:3]([OH:28])=[O:2]
Reactant: C#CC(C)Oc1ccc(S(=O)(=O)N(C)c2c(C)cc(Br)cc2C(=O)OC)cc1
Agent: [Na+]
Agent: [OH-]
Product: C#CC(C)Oc1ccc(S(=O)(=O)N(C)c2c(C)cc(Br)cc2C(=O)O)cc1
Yield: 31.2 %

Procedure:
According to the procedure of Example 10, 0.241 g of the product of Example 77 was hydrolyzed with 2.6 mL of 1.0N sodium hydroxide solution to provide 0.073 g (31%) of the desired carboxylic acid as a white solid and 0.034 g (14%) of the starting ester. Electrospray Mass Spec 451.8 (M+H)+
Reaction SMILES: [Na].[OH:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:4]=1[NH:11]C(=O)C(F)(F)F.Br[CH2:19][CH:20]=[CH:21][C:22]([O:24][CH2:25][CH3:26])=[O:23]>C(O)C>[CH3:10][O:9][C:6]1[CH:7]=[CH:8][C:3]2[O:2][CH2:19][CH:20]([CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[NH:11][C:4]=2[CH:5]=1
Reactant: COc1ccc(O)c(NC(=O)C(F)(F)F)c1
Reactant: CCOC(=O)C=CCBr
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)CC1COc2ccc(OC)cc2N1
Temperature: 0 °C

Procedure:
450 ml of ethanol are introduced into a 1 l reactor, with magnetic stirring, cooled to 0° C., and 7 g (0.32 mol) of sodium are added slowly, in small portions, followed by successive dropwise addition of 37.94 g (0.16 mol) of N-(2-hydroxy-5-methoxyphenyl)trifluoroacetamide and 41.2 g (0.16 mol) of pure ethyl 4-bromo-2-butenoate, and the mixture is heated at 80° C. for 2 h.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][C:4]([NH:7][C:8]([C:10]2[C:15]([NH:16][C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)=[CH:14][CH:13]=[C:12]([CH3:23])[N:11]=2)=[O:9])=[N:3]1.BrC1C=C([CH:30]=[C:31]([F:33])C=1)C#N>>[CH3:1][N:2]1[CH:6]=[CH:5][C:4]([NH:7][C:8]([C:10]2[C:15]([NH:16][C:17]3[CH:18]=[C:31]([F:33])[CH:30]=[C:21]([C:20]#[N:19])[CH:22]=3)=[CH:14][CH:13]=[C:12]([CH3:23])[N:11]=2)=[O:9])=[N:3]1
Reactant: N#Cc1cc(F)cc(Br)c1
Reactant: Cc1ccc(Nc2cccnc2)c(C(=O)Nc2ccn(C)n2)n1
Product: Cc1ccc(Nc2cc(F)cc(C#N)c2)c(C(=O)Nc2ccn(C)n2)n1

Procedure:
The title compound, was prepared from 3-Amino-6-methyl-pyridine-2-carboxylic acid (1-methyl-1H-pyrazol-3-yl)-amide (example 16) in accordance with the general method of example 20 using 3-Bromo-5-fluorobenzonitrile instead of 3-Bromo-4-methylpyridine to yield the final compound as an off-white solid, MS (ISP): m/e=351.4 (M+H+).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1.[CH:13]1([CH2:19]C2C=CN=CC=2)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1>>[CH:13]1([CH2:19][C:4]2[CH:5]=[CH:6][N:1]=[C:2]([C:7]3[CH:12]=[C:11]([CH2:19][CH:13]4[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]4)[CH:10]=[CH:9][N:8]=3)[CH:3]=2)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: c1ccc(-c2ccccn2)nc1
Reactant: c1cc(CC2CCCCC2)ccn1
Product: c1cc(CC2CCCCC2)cc(-c2cc(CC3CCCCC3)ccn2)n1

Procedure:
The mixture was then cooled to room temperature and hydrolyzed with 50 cc of water. The oil layer was separated, and the aqueous phase was extracted with 50 cc additional xylene. The oil layer and extract were combined and distilled to give 82.4 g of unreacted 4-cyclohexylmethylpyridine (0.47 mole) and 9.0 g (0.03 mole) of 4,4'-di-(cyclohexylmethyl)-2,2'-bipyridyl boiling at 273°-276° C. at 2.5 mm Hg. The yield of 2,2'-bipyridyl product was calculated at 43.3% based on the amount of 4-cyclohexylmethylpyridine consumed. This 2,2'-bipyridyl compound (recrystallized from isopropanol) gave a melting point of 117°-119° C.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[C:15](=[O:16])[C:10]3[NH:11][CH2:12][CH:13]=[CH:14][C:9]=3[CH2:8][CH2:7][C:6]=2[CH:17]=1.[Na].[CH3:19][SH:20]>CN(C)C=O>[CH3:19][S:20][C:2]1[CH:3]=[CH:4][C:5]2[C:15](=[O:16])[C:10]3[NH:11][CH2:12][CH:13]=[CH:14][C:9]=3[CH2:8][CH2:7][C:6]=2[CH:17]=1
Reactant: CS
Reactant: O=C1C2=C(C=CCN2)CCc2cc(Cl)ccc21
Agent: [Na]
Solvent: CN(C)C=O
Product: CSc1ccc2c(c1)CCC1=C(NCC=C1)C2=O
Yield: 97 %

Procedure:
8-Chloro-5,6-dihydro-1H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-one (3.5 g) was dissolved in 60 ml of dimethylformamide, followed by the addition of 13.4 g of a 15% aqueous solution of methyl mercaptan sodium salt. The resultant mixture was refluxed for 14 hours. The reaction mixture was cooled and then concentrated under reduced pressure. Water was added to the residue, followed by extraction with methylene chloride. The resulting extract was washed with a brine, dried over anhydrous MgSO4 and then filtered. The filtrate was concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column and relevant chloroform eluate fractions were concentrated. The residue was recrystallized from toluene, whereby 3.57 g of 8-methylthio-5,6-dihydro-1H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-one were obtained (yield: 97%). 2.50(3H,s), 3.16(4H,s), 7.00-7.52(3H,m), 7.66(1H,dd), 8.12(1H,d), 8 72(1H,dd).
Reaction SMILES: [CH3:1][C:2]([CH3:21])=[CH:3][CH2:4][C@@H:5]([OH:20])[C:6]1[C:16](=[O:17])[C:15]2[C:14]([OH:18])=[CH:13][CH:12]=[C:11]([OH:19])[C:10]=2[C:8](=[O:9])[CH:7]=1.C1(N=C=NC2CCCCC2)CCCCC1.[C:37](O)(=O)[CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH3:52]>CN(C)C1C=CN=CC=1.ClCCl>[CH2:52]([O:20][CH:5]([C:6]1[C:16](=[O:17])[C:15]2[C:10]([C:8](=[O:9])[CH:7]=1)=[C:11]([OH:19])[CH:12]=[CH:13][C:14]=2[OH:18])[CH2:4][CH:3]=[C:2]([CH3:21])[CH3:1])[CH2:51][CH2:50][CH2:49][CH2:48][CH2:47][CH2:46][CH2:45][CH2:44][CH2:43][CH2:42][CH2:41][CH2:40][CH2:39][CH2:38][CH3:37]
Reactant: CCCCCCCCCCCCCCCC(=O)O
Reactant: CC(C)=CC[C@@H](O)C1=CC(=O)c2c(O)ccc(O)c2C1=O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCCCCCCCCCCCCCCCOC(CC=C(C)C)C1=CC(=O)c2c(O)ccc(O)c2C1=O
Reaction time: 0.5 h
Yield: 59.5 %

Procedure:
288 mg (1 mmole) of shikonin, 226 mg (1.1 mmole) of dicyclohexylcarbodiimide and 30 mg (0.25 mmole) of 4-dimethylaminopyridine were dissolved in 3 ml of dry dichloromethane. To the resulting solution was added 256 mg (1 mmole) of palmitic acid at 0° C. under nitrogen gas, and the mixture was stirred for 30 minutes and then at room temperature for further 3 hours. The resulting product was separated and purified according to the procedures as described in Example 1 to obtain 305 mg (Yield: 58%) of the title compound having the following structure as a red precipitate.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:6][CH2:5][N:4]([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])[CH2:3]1.C(N(CC)CC)C.[S:24](Cl)([CH3:27])(=[O:26])=[O:25]>C(OCC)(=O)C.O>[CH3:27][S:24]([O:1][C@H:2]1[CH2:6][CH2:5][N:4]([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])[CH2:3]1)(=[O:26])=[O:25]
Reactant: O=C(OCc1ccccc1)N1CC[C@@H](O)C1
Reactant: CS(=O)(=O)Cl
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CS(=O)(=O)O[C@H]1CCN(C(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 7.3 g of benzyl (R)-3-hydroxy-pyrrolidine-1-carboxylate and 5.56 ml of triethylamine in 80 ml of ethyl acetate was cooled to 0-5° C. under argon and treated within 30 minutes with a solution of 2.97 ml of mesyl chloride in 20 ml of ethyl acetate. After stirring at room temperature for 2 hours and leaving to stand for 16 hours the suspension was diluted with 40 ml of water, stirred for 10 minutes and the organic phase was separated. The organic phase was extracted in succession with 20 ml of 1N HCl, 20 ml of saturated NaHCO3 solution and 10 ml of saturated NaCl solution. The organic phase was dried over Na2SO4, filtered and the filtrate was concentrated to give 10.18 g of product as a beige oil.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=1.[CH2:13]([O:20][C:21]1[CH:22]=[CH:23][C:24]([CH2:27][CH:28]([NH:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[C:29](O)=[O:30])=[N:25][CH:26]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>ClCCl>[CH2:13]([O:20][C:21]1[CH:22]=[CH:23][C:24]([CH2:27][CH:28]([NH:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[C:29]([NH:1][CH2:2][C:3]2[CH:4]=[CH:5][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:11][CH:12]=2)=[O:30])=[N:25][CH:26]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CC(C)(C)OC(=O)NC(Cc1ccc(OCc2ccccc2)cn1)C(=O)O
Reactant: COC(=O)c1ccc(CN)cc1
Solvent: ClCCl
Product: COC(=O)c1ccc(CNC(=O)C(Cc2ccc(OCc3ccccc3)cn2)NC(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 28.9 %

Procedure:
A mixture of methyl 4-(aminomethyl)benzoate (2 g, 10 mmol), 3-(5-(benzyloxy)-pyridine-2-yl)-2-(tert-butoxycarbonylamino) propanoic acid (1.04 g, 11 mmol), and 1-ethyl-3-(3-dimethyllaminopropyl)carbodiimide hydrochloride (2 g, 10.4 mmol) in 50 mL dichloromethane was stirred at room temperature for 2 h (monitored by TLC). The mixture was extracted with water and dried over magnesium sulfate. The residue was purified by chromatography (EA:Hex=1:1) to give the title compound (1.5 g, 49%). NMR (400 MHz in CDCl3, Bruker AVANCE-400): δ 1.31 (s, 9H, Boc), 2.90 (m, 2H, CH2), 3.81 (s, 3H, OMe) 4.30 (m, 2H, CH2), 4.33 (m, 1H, CH), 5.12 (s, 2H, OBn), 6.97-7.09 (d, 1H, J=3.5 Hz, Ar—H), 7.15 (d, 1H, J=8.53 Hz, Ar—H), 7.24˜7.46 (m, 8H, Ar—H), 7.84, (d, 2H, Ar—H, J=8.24 Hz), 8.24 (br, 1H, NH), 8.43 (br, 1H, NH).