Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Li+].C([N:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([NH:20][S:21]([C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=3/[CH:31]=[CH:32]\[CH2:33][N:34]([CH2:37][CH3:38])[CH2:35][CH3:36])(=[O:23])=[O:22])[C:14]=2[C:16]([O:18]C)=[O:17])[C@H:9]2[CH2:39][CH2:40][O:41][C@H:8]2[CH2:7]1)(=O)C>O1CCOCC1.O>[CH2:37]([N:34]([CH2:35][CH3:36])[CH2:33]/[CH:32]=[CH:31]\[C:25]1[CH:26]=[C:27]([F:30])[CH:28]=[CH:29][C:24]=1[S:21]([NH:20][C:13]1[C:14]([C:16]([OH:18])=[O:17])=[C:15]2[C:10]([C@H:9]3[CH2:39][CH2:40][O:41][C@H:8]3[CH2:7][NH:6]2)=[CH:11][CH:12]=1)(=[O:23])=[O:22])[CH3:38]
Reactant: CCN(CC)C/C=C\c1cc(F)ccc1S(=O)(=O)Nc1ccc2c(c1C(=O)OC)N(C(C)=O)C[C@@H]1OCC[C@H]21
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CCN(CC)C/C=C\c1cc(F)ccc1S(=O)(=O)Nc1ccc2c(c1C(=O)O)NC[C@@H]1OCC[C@H]21
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 9.3 %

Procedure:
Lithium hydroxide (0.09 g) was added to a solution of methyl cis-(3aRS,9bRS)-5-acetyl-7-[2-((Z)-3-diethylaminoprop-1-enyl)-4-fluorobenzenesulfonylamino]-1,2,3a,4,5,9b-hexahydrofuro[2,3-c]quinoline-6-carboxylate (Intermediate 27, 0.06 g) in a mixture of dioxane (5 mL) and water (1 mL) and the mixture was stirred and heated at 80° C. overnight. The mixture was then irradiated in the microwave at 150° C. for 30 minutes and then at 180° C. for 30 minutes. After cooling, the mixture was filtered and the filtrate was acidified by addition of formic acid (1 mL) and then evaporated to dryness. The residue was purified by preparative HPLC (C18) eluting with a mixture of acetonitrile and water, containing 0.1% formic acid, with a gradient of 10-98%. The isolated product was dissolved in DCM and evaporated to dryness then dissolved in ether and evaporated to dryness to give cis-(3aRS,9bRS)-7-[2-((Z)-3-diethylaminoprop-1-enyl)-4-fluorobenzenesulfonylamino]-1,2,3a,4,5,9b-hexahydrofuro[2,3-c]quinoline-6-carboxylic acid (0.005 g) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([CH2:12][CH:13]=[CH2:14])[CH2:9][NH:10][CH3:11])=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[Cl:24][C:25]1[CH:26]=[C:27]([CH:31]=[C:32]([Cl:34])[CH:33]=1)[C:28](Cl)=[O:29]>C(Cl)Cl>[Cl:24][C:25]1[CH:26]=[C:27]([CH:31]=[C:32]([Cl:34])[CH:33]=1)[C:28]([N:10]([CH2:9][C@H:8]([C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=1)[CH2:12][CH:13]=[CH2:14])[CH3:11])=[O:29]
Reactant: O=C(Cl)c1cc(Cl)cc(Cl)c1
Reactant: C=CC[C@H](CNC)c1ccc(F)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C=CC[C@H](CN(C)C(=O)c1cc(Cl)cc(Cl)c1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 74.9 %

Procedure:
[(2S)-2-(4-Fluorophenyl)pent-4-en-1-yl]methylamine (see Bioorg. Med. Chem. Lett; 2001; 265-270; 150 mg, 0.78 mmol) was dissolved in CH2Cl2 (5 mL) and to the resultant solution were added DIPEA (221 mg, 1.71 mmol) and 3,5-dichlorobenzoyl chloride (178 mg, 0.85 mmol) in the given order. The mixture was stirred for 4 h at room temperature, diluted with CH2Cl2 (20 mL), and then washed with water (10 mL), aqueous KHSO4 (1M, 10 mL) and brine (10 mL). The organic solution was dried over Na2SO4. The solvent was removed by evaporation and there was obtained 214 mg (75%) of 3,5-dichloro-N-[(2S)-2-(4fluorophenyl)pent-4-en-1-yl]-N-methylbenzamide as an oil. 1H NMR (500 MHz, CDCl3): 2.2-2.4 (cm, 2H), 2.6 (s, 2H), 2.9-3.9 (cm, 4H), 4.9-5.1 (m, 2H), 5.5-5.8 (m, 1H), 6.7 (s, 1H), 6.9-7.4 (cm, 6H); LCMS: m/z 367 (M+1)+.
Reaction SMILES: [CH2:1]([CH:6]1[CH2:11][CH2:10][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[C:13]=2[F:19])=[CH:8][CH2:7]1)[CH2:2][CH2:3][CH2:4][CH3:5].[H][H]>C1(C)C=CC=CC=1.[Pd]>[CH2:1]([CH:6]1[CH2:11][CH2:10][CH:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[C:13]=2[F:19])[CH2:8][CH2:7]1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: [H][H]
Reactant: CCCCCC1CC=C(c2cccc(F)c2F)CC1
Agent: [Pd]
Solvent: Cc1ccccc1
Product: CCCCCC1CCC(c2cccc(F)c2F)CC1
Yield: 93.3 %

Procedure:
The compound (9) (50.0 g) was dissolved in a mixed solvent of toluene (150 ml) and Solmix A-11 (150 ml), Pd/C (0.5 g) was added thereto, and the mixture was stirred at room temperature under a hydrogen atmosphere until hydrogen absorption had ceased. After the reaction had been completed, Pd/C was removed and then the solvent was distilled off. The residue obtained was purified with a fractional operation by means of column chromatography using heptane as the eluent and silica gel as the stationary phase powder, and further purified by means of recrystallization from Solmix A-11 and dried, giving 47.0 g of 4-pentyl-(2,3-difluorophenyl)cyclohexane (10). The yield based on the compound (9) was 94.0%.
Reaction SMILES: [C:1]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([OH:19])=O)(=[O:10])[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.[NH2:20][OH:21].Cl>C(N(CC)CC)C>[OH:21][NH:20][C:17](=[O:19])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][C:1](=[O:10])[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1
Reactant: NO
Reactant: COc1ccc(C(=O)CCCCCCC(=O)O)cc1
Agent: Cl
Solvent: CCN(CC)CC
Product: COc1ccc(C(=O)CCCCCCC(=O)NO)cc1
Yield: 48 %

Procedure:
Following the procedure described in Example 14, step 3, but substituting carboxylic acid 50b for 37 and using 1.1 equivalent of NH2OH.HCl and triethylamine each, the title compound was obtained as light yellow solid in 48% yield: 1H NMR (300 MHz, CD3OD/CDCl3=5/1) δ 7.94 (d, J=9.0 Hz, 2H), 6.95 (d, J=9.0 Hz, 2H), 3.88 (s, 3H), 2.93 (t, J=7.2 Hz, 2H), 2.11 (t, J=7.5 Hz, 2H), 1.59-1.79(m, 4H), 1.37 (m, 4H); 13C NMR (75.4 MHz, CD3OD/CDCl3=5/1) δ 24.15, 25.04, 28.59(2), 32.51, 37.88, 55.21, 113.54, 129.58, 130.20, 163.39, 171.10, 200.06.
Reaction SMILES: [Br:1][C:2]1[C:3](O[C:6](=[O:8])[CH:7]=1)=[O:4].[CH2:9]([NH2:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C(O)(=O)C.C(Cl)Cl>[CH2:9]([N:16]1[C:6](=[O:8])[CH:7]=[C:2]([Br:1])[C:3]1=[O:4])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: NCc1ccccc1
Reactant: O=C1C=C(Br)C(=O)O1
Solvent: ClCCl
Solvent: CC(=O)O
Product: O=C1C=C(Br)C(=O)N1Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of bromomaleic anhydride (1 g, 5.7 mmol) and benzyl amine (0.7 mL, 6.8 mmol) in acetic acid (15 mL) was warmed to 50° C. and stirred overnight. The reaction was then cooled to room temperature, diluted with CH2Cl2 (50 mL) and washed with NaHCO3 (3×25 mL) and brine (25 mL). The organic layer was then dried (MgSO4), filtered and the solvent removed under reduced pressure. The residue was purified using gradient flash chromatography (0-100% ethyl acetate in pet ether) to provide 1-benzyl-3-bromo-1H-pyrrole-2,5-dione (18). 1H NMR (400 MHz, CDCl3) δ 4.71 (s, 2H), 6.87 (s, 2H), 7.26-7.37 (m, 5H). A stirred solution of 1-benzyl-3-bromo-1H-pyrrole-2,5-dione (0.26 g, 1.0 mmol) and p-tolylboronic acid (0.16 g, 1.2 mmol) in dioxane (10 mL) was degassed with a stream of nitrogen for 10 minutes before being treated with CsF (0.39 g, 2.6 mmol) and C12Pd(dppf).CH2Cl2 (0.05 g, 0.06 mmol). The reaction was stirred at room temperature for 1 h then warmed to 40° C. for 1 h. The mixture was then cooled, diluted with CH2Cl2 (30 mL) and filtered through a pad of celite. The filtrate was concentrated under reduced pressure and purified using gradient flash chromatography (0-10% ethyl acetate in pet ether) to provide the title compound 15.
Reaction SMILES: Cl[C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH2:18]([CH:20]([NH2:23])[CH2:21][CH3:22])[CH3:19].C([O-])(=O)C.[K+]>[Cu].O>[CH2:18]([CH:20]([NH:23][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1)[CH2:21][CH3:22])[CH3:19]
Reactant: CCC(N)CC
Reactant: O=C1c2ccccc2C(=O)c2c(Cl)cccc21
Agent: [Cu]
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: O
Product: CCC(CC)Nc1cccc2c1C(=O)c1ccccc1C2=O
Temperature: 180 °C

Procedure:
A Parr stainless steel high pressure reactor was charged with 1-chloroanthraquinone (24.3 g), 1-ethylpropylamine (17.5 g), potassium acetate (14.0 g), activated copper metal (0.7 g), and water (0.05 g). The reaction vessel was sealed and heated to a temperature of 180° C. in an oil bath for 12 hours. The oil bath was removed and the vessel was allowed to return to ambient conditions. The solid was extracted with methylene chloride and the insoluble materials removed by filtration. The solvent was removed and the solid recrystallized from hot methanol. The material was chromatographed on a silica gel column using toluene as the eluent.
Reaction SMILES: FC(F)(F)C(OC(=O)C(F)(F)F)=O.[Cl:14][C:15]1[CH:45]=[CH:44][C:18]([CH2:19][O:20][C:21]2[CH:26]=[CH:25][N:24]([C:27]3[CH:28]=[CH:29][C:30]4[N:34]=[C:33]([CH:35]5[CH2:37][CH:36]5[C:38]([NH2:40])=O)[N:32]([CH3:41])[C:31]=4[CH:42]=3)[C:23](=[O:43])[CH:22]=2)=[CH:17][CH:16]=1.N1C=CC=CC=1>C1COCC1>[Cl:14][C:15]1[CH:45]=[CH:44][C:18]([CH2:19][O:20][C:21]2[CH:26]=[CH:25][N:24]([C:27]3[CH:28]=[CH:29][C:30]4[N:34]=[C:33]([CH:35]5[CH2:37][CH:36]5[C:38]#[N:40])[N:32]([CH3:41])[C:31]=4[CH:42]=3)[C:23](=[O:43])[CH:22]=2)=[CH:17][CH:16]=1
Reactant: Cn1c(C2CC2C(N)=O)nc2ccc(-n3ccc(OCc4ccc(Cl)cc4)cc3=O)cc21
Solvent: C1CCOC1
Solvent: c1ccncc1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: Cn1c(C2CC2C#N)nc2ccc(-n3ccc(OCc4ccc(Cl)cc4)cc3=O)cc21
Temperature: 0 °C
Reaction time: 2 h
Yield: 18.7 %

Procedure:
Trifluoroacetic anhydride (0.181 ml) was added to a solution of (1RS,2SR)-2-(6-(4-((4-chlorobenzyl)oxy)-2-oxopyridin-1(2H)-yl)-1-methyl-1H-benzimidazol-2-yl)cyclopropanecarboxamide (195 mg) and pyridine (0.105 ml) in THF (5 ml) at 0° C. The mixture was stirred at 0° C. for 2 h. The mixture was quenched with saturated NaHCO3 solution at 0° C. and extracted with EtOAc. The organic layer was separated, washed with water and brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (MeOH/EtOAc). The residue was recrystallized from EtOH/hexane to give the title compound (35 mg) as a white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:10])=[O:9])=[CH:4][CH:3]=1.C([O:14][C:15](=O)[C:16]([F:19])([F:18])[F:17])(C)C.C[O-].[Na+].Cl>O.C1(C)C=CC=CC=1>[F:17][C:16]([F:19])([F:18])[C:15](=[O:14])[CH2:10][C:8]([C:5]1[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=1)=[O:9]
Reactant: CC(C)OC(=O)C(F)(F)F
Reactant: CC(=O)c1ccc(C)cc1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1ccc(C(=O)CC(=O)C(F)(F)F)cc1
Temperature: 75 °C
Reaction time: 4 h
Yield: 68.6 %

Procedure:
A mixture of 4-methylacetophenone (0.85 g), isopropyltrifluoroacetate (1.0 g) and toluene (2 ml) was added to a mixture of sodium methoxide (0.4 g) and toluene (2 ml) at 35-40° C. The reaction mixture was stirred at 75° C. for 4 hours. The reaction mixture was cooled to 25-30° C. Water (2 ml) and aqueous HCl (3 ml, 20%) were added and the reaction mixture was stirred at 25-30° C. for 30 minutes. The layers were separated. Aqueous layer was extracted with toluene (2×2 ml). The organic layers were combined and the solvent was removed by distillation at 55° C. under vacuum to obtain the title compound (Yield: 1.0 g).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[C:7]([F:12])[CH:6]=1.Br[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:1][O:2][C:3](=[O:13])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH3:15])=[C:7]([F:12])[CH:6]=1
Reactant: CCCCCCCCCCCCCCBr
Reactant: COC(=O)Cc1ccc(O)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCCCCCCCCCCCCOc1ccc(CC(=O)OC)cc1F
Yield: 97.5 %

Procedure:
A mixture of 23.0 g of product from Example 60, 34.6 g of 1-bromotetradecane, 54.6 g of potassium carbonate and 250 ml of acetone is heated at reflux temperature for 48 hours. The cooled reaction is filtered and concentrated in vacuo. The residue is purified by column chromatography (silica gel:0-4.5% ethyl acetate/hexane) to give 46.3 g of the desired product as colorless prisms.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.[NH2:12][C:13]1[CH:31]=[C:30]([Cl:32])[CH:29]=[CH:28][C:14]=1[O:15][C:16]1[CH:27]=[CH:26][C:19]([C:20]([N:22]([CH2:24][CH3:25])[CH3:23])=[O:21])=[CH:18][CH:17]=1>>[N:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][N:7]=2)[C:2]([NH:12][C:13]2[CH:31]=[C:30]([Cl:32])[CH:29]=[CH:28][C:14]=2[O:15][C:16]2[CH:27]=[CH:26][C:19]([C:20]([N:22]([CH2:24][CH3:25])[CH3:23])=[O:21])=[CH:18][CH:17]=2)=[CH:3][CH:4]=1
Reactant: CCN(C)C(=O)c1ccc(Oc2ccc(Cl)cc2N)cc1
Reactant: Clc1ccnc2ncccc12
Product: CCN(C)C(=O)c1ccc(Oc2ccc(Cl)cc2Nc2ccnc3ncccc23)cc1

Procedure:
The product from Example 16c (100 mg, 0.61 mmol) was reacted with the product from Example 133b (185 mg, 0.61 mmol) for 18 h following the procedure from Example 1g giving the crude title compound which was purified by HPLC with TFA providing the product as a trifluoroacetic acid (141 mg, 42%). 1H NMR (300 MHz, DMSO-d6) δ ppm: 0.86-1.18 (m, 3H) 2.62-2.92 (m, 5H) 6.76 (d, J=7.35 Hz, 1H) 6.94 (d, J=8.82 Hz, 2H) 7.25 (d, J=8.09 Hz, 2H) 7.34 (d, J=8.82 Hz, 1H) 7.63 (dd, J=8.82, 2.57 Hz, 1H) 7.75 (d, J=2.57 Hz, 1H) 7.85 (dd, J=8.46, 4.41 Hz, 1H) 8.61 (d, J=6.99 Hz, 1H) 8.96 (dd, J=8.64, 1.29 Hz, 1H) 9.14 (dd, J=4.23, 1.29 Hz, 1H) 11.06 (s, 1H) 14.74 (s, 1H); MS (ESI+) m/z 433 (M+H−TFA)+.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][CH:18]=[CH:19][C:20]2[N:29]=[CH:28][C:27]3[C:26]([CH3:31])([CH3:30])[O:25][C:24](=[O:32])[NH:23][C:22]=3[CH:21]=2)[CH2:11][CH2:10]1>CCO.C1COCC1.CCOC(C)=O.[Ni]>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]2[N:29]=[CH:28][C:27]3[C:26]([CH3:30])([CH3:31])[O:25][C:24](=[O:32])[NH:23][C:22]=3[CH:21]=2)[CH2:11][CH2:10]1
Reactant: CC1(C)OC(=O)Nc2cc(C=CCCCN3CCN(c4cccc(Cl)c4Cl)CC3)ncc21
Agent: [Ni]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCO
Product: CC1(C)OC(=O)Nc2cc(CCCCCN3CCN(c4cccc(Cl)c4Cl)CC3)ncc21
Yield: 44.2 %

Procedure:
7-{5-[4-(2,3-Dichloro-phenyl)-piperazin-1-yl]-pent-1-enyl}-4,4-dimethyl-1,4-dihydro-pyrido[4,3-d][1,3]oxazin-2-one (452 mg, 0.95 mmol) was hydrogentated using Ra—Ni in EtOH/THF. The reaction was filtered and concentrated. Purification by liquid chromatography (5% MeOH/CH2Cl2 with 0.5% NH4OH) gave a white foam (385 mg, 85% pure). The foam was dissolved in a minimal amount of EtOAc and, upon standing, a white precipitate formed. The precipitate was filtered and washed with Et2O to give the title compound as a white solid (200 mg, 0.42 mmol, 44%). MS: APCI: M+1: 477.1 (Exact Mass: 476.17).
Reaction SMILES: [CH3:1][C:2]([CH2:7][CH2:8][CH:9]=[C:10]([CH3:22])[CH2:11][CH2:12][CH:13]=[C:14]([CH3:21])[CH2:15][CH2:16][CH:17]=[C:18]([CH3:20])[CH3:19])=[CH:3][C:4]([OH:6])=O.[CH3:23][N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1>>[CH3:1][C:2]([CH2:7][CH2:8][CH:9]=[C:10]([CH3:22])[CH2:11][CH2:12][CH:13]=[C:14]([CH3:21])[CH2:15][CH2:16][CH:17]=[C:18]([CH3:20])[CH3:19])=[CH:3][C:4]([N:27]1[CH2:28][CH2:29][N:24]([CH3:23])[CH2:25][CH2:26]1)=[O:6]
Reactant: CC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CC(=O)O
Reactant: CN1CCNCC1
Product: CC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CC(=O)N1CCN(C)CC1
Yield: 90 %

Procedure:
The procedure of Example 9 was repeated except that 6.1 g of 3,7,11,15-tetramethyl-2,6,10,14-hexadecatetraenoic acid and 3.3 ml of 1-methylpiperazine were used as starting materials. 6.9 g (yield 90%) of the title compound was obtained as a colorless oil.
Reaction SMILES: O1C2C=CC(C(Cl)=O)=CC=2OC1.[CH3:13][O:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][C:24]=1[O:25][CH3:26])[N:21]=[CH:20][CH:19]=[C:18]2[O:27][C:28]1[CH:34]=[CH:33][C:31]([NH2:32])=[CH:30][CH:29]=1.[O:35]1[C:39]2[CH:40]=[CH:41][C:42]([C:44]([N:46]=[C:47]=[S:48])=[O:45])=[CH:43][C:38]=2[O:37][CH2:36]1>C1(C)C=CC=CC=1.C(O)C>[O:35]1[C:39]2[CH:40]=[CH:41][C:42]([C:44]([N:46]=[C:47]=[S:48])=[O:45])=[CH:43][C:38]=2[O:37][CH2:36]1.[O:35]1[C:39]2[CH:40]=[CH:41][C:42]([C:44]([NH:46][C:47]([NH:32][C:31]3[CH:33]=[CH:34][C:28]([O:27][C:18]4[C:17]5[C:22](=[CH:23][C:24]([O:25][CH3:26])=[C:15]([O:14][CH3:13])[CH:16]=5)[N:21]=[CH:20][CH:19]=4)=[CH:29][CH:30]=3)=[S:48])=[O:45])=[CH:43][C:38]=2[O:37][CH2:36]1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Agent: O=C(Cl)c1ccc2c(c1)OCO2
Agent: O=C(N=C=S)c1ccc2c(c1)OCO2
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)c4ccc5c(c4)OCO5)cc3)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 86 %

Procedure:
1,3-Benzodioxole-5-carbonyl isothiocyanate was prepared using commercially available 1,3-benzodioxole-5-carbonyl chloride (80 mg) as a starting compound according to the description of the literature. 4-[(6,7-Dimethoxy-4-quinolyl)oxy]aniline (50 mg) was dissolved in toluene (5 ml) and ethanol (1 ml) to prepare a solution. A solution of 1,3-benzodioxole-5-carbonyl isothiocyanate in ethanol (1 ml) 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 (68 mg, yield 86%).
Reaction SMILES: [C:1]1([N:7]2[C:12](=[O:13])[C:11]3[S:14][CH:15]=[C:16]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[C:10]=3[N:9]=[CH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.NC1C(C2C=CC=CC=2[F:35])=CSC=1C(OC)=O.C(O[CH2:48][CH3:49])(OCC)OCC.C(C1C=C(C=CC=1)N)=C>C(O)(=O)C>[F:35][C:22]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:16]1[C:10]2[N:9]=[CH:8][N:7]([C:1]3[CH:6]=[CH:5][CH:4]=[C:3]([CH:48]=[CH2:49])[CH:2]=3)[C:12](=[O:13])[C:11]=2[S:14][CH:15]=1
Reactant: O=c1c2scc(-c3ccccc3)c2ncn1-c1ccccc1
Reactant: COC(=O)c1scc(-c2ccccc2F)c1N
Reactant: CCOC(OCC)OCC
Agent: C=Cc1cccc(N)c1
Solvent: CC(=O)O
Product: C=Cc1cccc(-n2cnc3c(-c4ccccc4F)csc3c2=O)c1
Yield: 57.4 %

Procedure:
In the same manner as the synthesis of Compound 1, methyl 3-amino-4-(2-fluorophenyl)thiophene-2-carboxylate (80 mg, 0.3 mmol), triethyl orthoformate (0.79 ml), 3-vinylaniline (70.6 mg, 0.59 mmol), and acetic acid (0.09 ml) were used to give 64 mg (0.18 mmol, 57.4% yield) of the title compound.
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH3:13][C:14]1[N:15]=[C:16]([CH2:42][CH2:43][CH3:44])[N:17]([CH2:27][C:28]2[CH:33]=[CH:32][C:31]([C:34]3[C:35]([C:40]#[N:41])=[CH:36][CH:37]=[CH:38][CH:39]=3)=[CH:30][CH:29]=2)[C:18](=[O:26])[C:19]=1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>O.C(OCC)(=O)C>[CH3:13][C:14]1[N:15]=[C:16]([CH2:42][CH2:43][CH3:44])[N:17]([CH2:27][C:28]2[CH:33]=[CH:32][C:31]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=3[C:40]3[NH:3][C:4](=[O:7])[O:5][N:41]=3)=[CH:30][CH:29]=2)[C:18](=[O:26])[C:19]=1[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: O=C([O-])O
Reactant: CCCc1nc(C)c(-c2ccccc2)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: [NH3+]O
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CCCc1nc(C)c(-c2ccccc2)c(=O)n1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 55.5 %

Procedure:
A mixture of hydroxylammonium chloride (0.39 g), sodium hydrogen carbonate (0.59 g) and dimethyl sulfoxide (4 mL) was stirred at 40° C. for 30 min, 4′-[(4-methyl-6-oxo-5-phenyl-2-propylpyrimidin-1(6H)-yl)methyl]biphenyl-2-carbonitrile (0.30 g) was added, and the mixture was stirred at 90° C. for 18 hr. The reaction mixture was allowed to cool to room temperature, ethyl acetate and water were added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was dissolved in tetrahydrofuran (5 mL). N,N′-carbonyldiimidazole (0.14 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.13 mL) were added, and the mixture was stirred at room temperature for 3 hr. The reaction mixture was diluted with ethyl acetate, washed with 1 M hydrochloric acid and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.19 g, 55%).
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[N:8]([C:9]([C:11]2[N:12]=[C:13]([CH3:23])[S:14][C:15]=2[C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)=[O:10])[CH2:7][C@H:6]2[C@@H:4]1[CH2:5]2.[CH3:24][C:25]1[CH:26]=[C:27]([CH:31]=[C:32]([CH3:34])[CH:33]=1)[C:28](O)=[O:29]>>[CH3:24][C:25]1[CH:26]=[C:27]([CH:31]=[C:32]([CH3:34])[CH:33]=1)[C:28]([NH:1][CH2:2][C@H:3]1[N:8]([C:9]([C:11]2[N:12]=[C:13]([CH3:23])[S:14][C:15]=2[C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)=[O:10])[CH2:7][C@H:6]2[C@@H:4]1[CH2:5]2)=[O:29]
Reactant: Cc1cc(C)cc(C(=O)O)c1
Reactant: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CN)c1
Product: Cc1cc(C)cc(C(=O)NC[C@@H]2[C@H]3C[C@H]3CN2C(=O)c2nc(C)sc2-c2cccc(C)c2)c1

Procedure:
prepared by reaction of ((1S,2S,5R)-2-Aminomethyl-3-aza-bicyclo[3.1.0]hex-3-yl)-(2-methyl-5-m-tolyl-thiazol-4-yl)-methanone with 3,5-Dimethyl-benzoic acid. LC-MS (basic): tR=0.96 min; [M+H]+=460.0.
Reaction SMILES: C([NH:7][C:8]1[N:9]=[C:10]([OH:42])[C:11]2[CH2:17][CH:16]([CH2:18][CH2:19][C:20]3[CH:41]=[CH:40][C:23]([C:24]([NH:26][C@H:27]([C:35]([O:37]CC)=[O:36])[CH2:28][CH2:29][C:30]([O:32]CC)=[O:31])=[O:25])=[CH:22][CH:21]=3)[CH2:15][NH:14][C:12]=2[N:13]=1)(=O)C(C)(C)C.[OH-].[Na+].CO>C(O)(=O)C>[NH2:7][C:8]1[N:9]=[C:10]([OH:42])[C:11]2[CH2:17][CH:16]([CH2:18][CH2:19][C:20]3[CH:21]=[CH:22][C:23]([C:24]([NH:26][C@H:27]([C:35]([OH:37])=[O:36])[CH2:28][CH2:29][C:30]([OH:32])=[O:31])=[O:25])=[CH:40][CH:41]=3)[CH2:15][NH:14][C:12]=2[N:13]=1
Reactant: CCOC(=O)CC[C@H](NC(=O)c1ccc(CCC2CNc3nc(NC(=O)C(C)(C)C)nc(O)c3C2)cc1)C(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CO
Product: Nc1nc(O)c2c(n1)NCC(CCc1ccc(C(=O)N[C@@H](CCC(=O)O)C(=O)O)cc1)C2
Temperature: 25 °C
Reaction time: 70 h

Procedure:
A mixture of 0.53 g of diethyl N-(4-[2-(2-pivaloylamino-4-hydroxy-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-6-yl)ethyl]benzoyl)-L-glutamate, 3 mL of 1N sodium hydroxide, and 50 mL of methanol is stirred at room temperature for 70 hours and then acidified with glacial acetic acid and filtered. The solid thus collected is washed with methanol and dried to yield N-(4-[2-(2-amino-4-hydroxy-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-6-yl)ethyl]benzoyl)-L-glutamic acid, m.p. >250° C.; 1H NMR (dTFA) delta 7.85 (d, J=7.9 Hz, 2H, Ar), 7.45 (d, J=9 Hz, 2H, Ar), 5.00-5.25 (m, 1H, CH2COOH), 1.7-3.9 (m, 13H, CH, 2° aliphatic).
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH2:8][N:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][C:18]3[S:19][CH:20]=[CH:21][CH:22]=3)=[CH:11][C:10]2=[O:23])=[CH:6][CH:5]=[CH:4][C:3]=1[NH:24][CH2:25][C:26](O)=[O:27].CN(C(O[N:37]1N=NC2C=[CH:41][CH:42]=[CH:43][C:38]1=2)=[N+](C)C)C.[B-](F)(F)(F)F.N1CCCC1.C(N(CC)CC)C>CN(C)C=O>[CH3:1][C:2]1[C:3]([NH:24][CH2:25][C:26](=[O:27])[N:37]2[CH2:38][CH2:43][CH2:42][CH2:41]2)=[CH:4][CH:5]=[CH:6][C:7]=1[CH2:8][N:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][C:18]2[S:19][CH:20]=[CH:21][CH:22]=2)=[CH:11][C:10]1=[O:23]
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: Cc1c(Cn2ccc(OCCc3cccs3)cc2=O)cccc1NCC(=O)O
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: C1CCNC1
Product: Cc1c(Cn2ccc(OCCc3cccs3)cc2=O)cccc1NCC(=O)N1CCCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 69.8 %

Procedure:
A mixture of {2-Methyl-3-[2-oxo-4-(2-thiophen-2-yl-ethoxy)-2H-pyridin-1-ylmethyl]-phenylamino}-acetic acid (50 mg, 0.13 mmol), TBTU (60 mg, 0.19 mmol), pyrrolidine (0.02 ml, 0.25 mmol) and triethylamine (0.09 ml, 0.63 mmol) was dissolved in N,N-dimethylformamide (0.5 ml) and stirred at room temperature. After 1 hour, the resulting solution was evaporated, extracted with dichloromethane (20 ml) and subjected to silica gel column chromatography (ethyl acetate/MeOH, 20:1) to obtain the titled compound (41 mg, 71%).