Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C:3]1[O:4][C:5](=[O:9])[O:6][C:7]=1[CH3:8].[Na+].[I-].O=C(C1C=CC=CC=1)C[O:15][C:16](=[O:44])[C@H:17]([OH:43])[CH2:18][N:19]([CH2:29][C:30]1[CH:35]=[CH:34][C:33]([C:36]2[CH:41]=[CH:40][CH:39]=[C:38]([Cl:42])[CH:37]=2)=[CH:32][CH:31]=1)[NH:20][C:21]([C:23]1[O:27][N:26]=[C:25]([OH:28])[CH:24]=1)=[O:22].C(=O)([O-])[O-].[Cs+].[Cs+].CC(O)=O>CC(C)=O.[Zn]>[Cl:42][C:38]1[CH:37]=[C:36]([C:33]2[CH:32]=[CH:31][C:30]([CH2:29][N:19]([CH2:18][C@@H:17]([OH:43])[C:16]([OH:44])=[O:15])[NH:20][C:21]([C:23]3[O:27][N:26]=[C:25]([O:28][CH2:2][C:3]4[O:4][C:5](=[O:9])[O:6][C:7]=4[CH3:8])[CH:24]=3)=[O:22])=[CH:35][CH:34]=2)[CH:41]=[CH:40][CH:39]=1
Reactant: Cc1oc(=O)oc1CCl
Reactant: O=C(COC(=O)[C@H](O)CN(Cc1ccc(-c2cccc(Cl)c2)cc1)NC(=O)c1cc(O)no1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Solvent: CC(C)=O
Solvent: CC(=O)O
Product: Cc1oc(=O)oc1COc1cc(C(=O)NN(Cc2ccc(-c3cccc(Cl)c3)cc2)C[C@@H](O)C(=O)O)on1
Temperature: 60 °C
Reaction time: 1 h
Yield: 14.1 %

Procedure:
A mixture of 4-chloromethyl-5-methyl-1,3-dioxol-2-one (11.9 μL, 109 μmol) and NaI (16.4 mg, 109 μmol) in acetone (2.0 mL, 27 mmol) was stirred at 60° C. for 1 hour, then cooled to room temperature and added to a mixture of (R)-3-[N-(3′-chlorobiphenyl-4-ylmethyl)-N′-(3-hydroxyisoxazole-5-carbonyl)hydrazino]-2-hydroxypropionic acid 2-oxo-2-phenylethyl ester (20.0 mg, 36.4 μmol) and cesium carbonate (14.2 mg, 43.6 μmol) in acetone (1 mL). The resulting mixture was stirred at 60° C. for 2 hours, concentrated, purified by flash chromatography (EtOAc/hexanes=0-100%). The desired fractions were combined and concentrated. Zinc (178 mg, 2.7 mmol) and AcOH (1.0 mL, 18 mmol) were added and the resulting mixture was stirred at room temperature for 2 hours. The solids were washed with AcOH (0.5 mL) then filtered. The filtrates were combined and purified by reverse phase preparative HPLC to yield the title compound (2.8 mg). MS m/z [M+H]+ calc'd for C25H22ClN3O9, 544.10. found 544.5.
Reaction SMILES: C1(C2C=CC(CNCCC3C=CC(F)=C(C(F)(F)F)C=3)=CC=2)CC1.[Cl:25][C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][C:33]=1[C:34]1([CH3:37])[CH2:36][CH2:35]1)[CH:29]=O.[Cl:38][C:39]1[CH:40]=[C:41]([CH2:46][CH2:47][NH2:48])[CH:42]=[CH:43][C:44]=1[Cl:45].[BH4-].[Na+]>>[Cl:25][C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][C:33]=1[C:34]1([CH3:37])[CH2:36][CH2:35]1)[CH2:29][NH:48][CH2:47][CH2:46][C:41]1[CH:42]=[CH:43][C:44]([Cl:45])=[C:39]([Cl:38])[CH:40]=1
Reactant: NCCc1ccc(Cl)c(Cl)c1
Reactant: CC1(c2ccc(C=O)cc2Cl)CC1
Agent: Fc1ccc(CCNCc2ccc(C3CC3)cc2)cc1C(F)(F)F
Agent: [BH4-]
Agent: [Na+]
Product: CC1(c2ccc(CNCCc3ccc(Cl)c(Cl)c3)cc2Cl)CC1
Yield: 99 %

Procedure:
The title compound was synthesized in analogy to (4-cyclopropylbenzyl)-[2-(4-fluoro-3-trifluoromethylphenyl)-ethyl]-amine (described in example S53) using 3-chloro-4-(1-methylcyclopropyl)-benzaldehyde (prepared as described in example S105) (90 mg, 0.46 mmol), 2-(3,4-dichlorophenyl)-ethylamine (88 mg, 0.46 mmol) and sodium borohydride (26 mg, 0.70 mmol). The desired product (168 mg, 99%) was isolated without further purification as a colorless oil. MS (ISP) 370.1 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[C:3]=1[C:4]([OH:6])=O.[CH3:12][C:13]1[N:18]=[CH:17][C:16]([CH:19]([N:22]2[CH2:28][CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[CH2:20][NH2:21])=[CH:15][N:14]=1>>[Cl:11][C:7]1[CH:8]=[CH:9][CH:10]=[C:2]([Cl:1])[C:3]=1[C:4]([NH:21][CH2:20][CH:19]([C:16]1[CH:17]=[N:18][C:13]([CH3:12])=[N:14][CH:15]=1)[N:22]1[CH2:28][CH2:27][CH2:26][O:25][CH2:24][CH2:23]1)=[O:6]
Reactant: Cc1ncc(C(CN)N2CCCOCC2)cn1
Reactant: O=C(O)c1c(Cl)cccc1Cl
Product: Cc1ncc(C(CNC(=O)c2c(Cl)cccc2Cl)N2CCCOCC2)cn1

Procedure:
From 2,6-dichlorobenzoic acid and 2-(2-methylpyrimidin-5-yl)-2-(1,4-oxazepan-4-yl)ethanamine.
Reaction SMILES: [CH:1]1([Mg]Br)[CH2:4][CH2:3][CH2:2]1.[C:7]([C:9]1[S:10][C:11](SC)=[C:12]2[C:17](=[O:18])[CH2:16][C:15]([CH3:20])([CH3:19])[CH2:14][C:13]=12)#[N:8]>>[C:7]([C:9]1[S:10][C:11]([CH:1]2[CH2:4][CH2:3][CH2:2]2)=[C:12]2[C:17](=[O:18])[CH2:16][C:15]([CH3:20])([CH3:19])[CH2:14][C:13]=12)#[N:8]
Reactant: Br[Mg]C1CCC1
Reactant: CSc1sc(C#N)c2c1C(=O)CC(C)(C)C2
Product: CC1(C)CC(=O)c2c(C3CCC3)sc(C#N)c2C1
Yield: 18 %

Procedure:
In the same way as described in Example 6, Step 1, using cyclobutylmagnesium bromide and 1-cyano-6,6-dimethyl-3-methylthio-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one, the title compound (0.37 g, 18%) was isolated as a pale yellow solid. mp 65-68° C. 1HNMR (360 MHz, CDCl3) δ 1.06 (6H, s), 1.90-1.98 (1H, m), 2.00-2.12 (3H, m), 2.40 (2H, s), 2.50-2.62 (2H, m), 2.83 (2H, s), 4.45-4.56 (1H, m).
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.[CH3:6][O:7][C:8]1[CH:15]=[CH:14][C:11]([CH2:12]Cl)=[CH:10][CH:9]=1.C1CCN2C(=NCCC2)CC1>C1COCC1>[CH3:6][O:7][C:8]1[CH:15]=[CH:14][C:11]([CH2:12][N:1]2[CH:5]=[N:4][CH:3]=[N:2]2)=[CH:10][CH:9]=1
Reactant: c1nc[nH]n1
Reactant: COc1ccc(CCl)cc1
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: COc1ccc(Cn2cncn2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 56.9 %

Procedure:
To 1,2,4-triazole (2.0 g, 29 mmol) in THF (80 mL) at 0° C. was added 4-methoxybenzyl chloride (4.0 mL, 29 mmol) and DBU (5.20 mL, 34.7 mmol). The reaction mixture was warmed to room temperature and allowed to stir overnight. The solution was filtered and the filtrate was concentrated. The resulting residue was purified by column chromatography (EtOAc/MeOH, 1:9) to give 3.12 g (57%) of 1-(4-methoxybenzyl)-1H-1,2,4-triazole as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[C:10]([N+:11]([O-:13])=[O:12])=[C:9]([O:14][C:15]3[CH:16]=[C:17]([NH:21][C:22](=[O:34])[C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([C:32]#[N:33])([CH3:31])[CH3:30])[CH:24]=4)[CH:18]=[CH:19][CH:20]=3)[CH:8]=[CH:7][C:5]=2[N:6]=1.[C:35](Cl)(=[O:37])[CH3:36]>N1C=CC=CC=1>[C:35]([NH:1][C:2]1[S:3][C:4]2[C:10]([N+:11]([O-:13])=[O:12])=[C:9]([O:14][C:15]3[CH:16]=[C:17]([NH:21][C:22](=[O:34])[C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([C:32]#[N:33])([CH3:30])[CH3:31])[CH:24]=4)[CH:18]=[CH:19][CH:20]=3)[CH:8]=[CH:7][C:5]=2[N:6]=1)(=[O:37])[CH3:36]
Reactant: CC(C)(C#N)c1cccc(C(=O)Nc2cccc(Oc3ccc4nc(N)sc4c3[N+](=O)[O-])c2)c1
Reactant: CC(=O)Cl
Solvent: c1ccncc1
Product: CC(=O)Nc1nc2ccc(Oc3cccc(NC(=O)c4cccc(C(C)(C)C#N)c4)c3)c([N+](=O)[O-])c2s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 51.7 %

Procedure:
To a solution of N-{3-[(2-amino-7-nitro-1,3-benzothiazol-6-yl)oxy]phenyl}-3-(1-cyano-1-methylethyl)benzamide (200 mg, 0.42 mmol) produced in Example 37(ii) in pyridine (2 mL) was added acetyl chloride (39 μL, 0.548 mmol), and the mixture was stirred at room temperature for 2 hr. The reaction mixture was concentrated under reduced pressure, and the residue was suspended in ethyl acetate (20 mL), washed successively with 5% aqueous sodium hydrogen carbonate solution (20 mL) and saturated brine (20 mL), and dried over anhydrous sodium sulfate. Insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate/n-hexane=50/50→100/0), and the obtained solution was concentrated under reduced pressure. The residue was crystallized from ethyl acetate/n-hexane/diethyl ether to give the title compound (112 mg, 52%) as a yellow powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([O:13][CH2:14][C:15]([N:18]3[C:23](=[O:24])[CH:22]=[CH:21][C:20]([NH:25]C(=O)OC(C)(C)C)=[CH:19]3)([CH3:17])[CH3:16])=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:25][C:20]1[CH:21]=[CH:22][C:23](=[O:24])[N:18]([C:15]([CH3:16])([CH3:17])[CH2:14][O:13][C:7]2[C:6]3[C:11](=[CH:12][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)[N:10]=[CH:9][CH:8]=2)[CH:19]=1
Reactant: COc1ccc2c(OCC(C)(C)n3cc(NC(=O)OC(C)(C)C)ccc3=O)ccnc2c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc2c(OCC(C)(C)n3cc(N)ccc3=O)ccnc2c1
Reaction time: 1.5 h

Procedure:
To a stirred solution of tert-butyl 1-(1-(7-methoxyquinolin-4-yloxy)-2-methylpropan-2-yl)-6-oxo-1,6-dihydropyridin-3-ylcarbamate (55 mg, 125 μmol) in CH2Cl2 (1 mL) was added TFA (3 mL). After 90 min at 23° C., the solvents were removed under reduced pressure. The residue was partitioned between CH2Cl2 and NaOH (1 M). The organic was dried over MgSO4, reduced to a brown solid under reduced pressure. MS (ESI pos. ion) m/z (MH+): 340. Calc'd exact mass for C19H21N3O3: 339. 1H NMR (400 MHz, Chloroform-d) 8 ppm 1.65 (s, 6 H) 2.35 (s, 2 H) 3.94 (s, 3 H) 3.99 (s, 2 H) 6.30 (d, J=5.52 Hz, 1 H) 6.64 (d, J=9.03 Hz, 1 H) 7.09-7.20 (m, 4 H) 7.29-7.36 (m, 2 H) 7.64 (s, 1 H) 7.82 (d, J=9.03 Hz, 1 H) 8.31-8.39 (m, 1 H).
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[NH:5]1[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1.C(OC([N:18]1[C:23](=[O:24])[CH:22]2[CH:20]([CH:21]2[C:25]([O-:27])=[O:26])[CH:19]1[C:28]([O-:30])=[O:29])=O)(C)(C)C.O>C(Cl)Cl>[C:25]([CH:21]1[CH:22]([C:23]([N:5]2[CH2:10][CH2:9][O:8][CH2:7][CH2:6]2)=[O:24])[CH:20]1[CH:19]([C:28]([OH:30])=[O:29])[NH2:18])([OH:27])=[O:26]
Reactant: C1COCCN1
Reactant: CC(C)(C)OC(=O)N1C(=O)C2C(C(=O)[O-])C2C1C(=O)[O-]
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: O
Product: NC(C(=O)O)C1C(C(=O)O)C1C(=O)N1CCOCC1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 112.9 %

Procedure:
To a solution of AlCl3 (73 mg, 0.54 mmol) in dry CH2Cl2 (3 mL) at 0° C., morpholine (90 μl, 1.04 mmol) in dry CH2Cl2 (3 mL) was added dropwise. The mixture was stirred at room temperature for 20 min, and then ethyl (1SR, 2SR, 5RS, 6RS) 3-tert-butoxycarbonyl-4-oxo-3-azabicyclo[3.1.0]hexane-2,6-dicarboxylate (143 mg, 0.41 mmol) in dry CH2Cl2 (1 mL) was added. After stirring at room temperature for 1 h, a mixture of ice and water was added. The layers were separated and the aqueous phase was extracted with CH2Cl2. The combined organic layers were dried over MgSO4 and the solvent removed under reduced pressure. The residue was purified by flash chromatography (hexane/ethyl acetate 1/1) to give 126 mg of the desired compound (70% yield).
Reaction SMILES: [Cl:1]CCC(C1C=CC=CC=1)=O.BrCC(C1C=CC(Cl)=CC=1)=O.[CH3:23][N:24]1[C:29]([N:30]2[CH2:35][CH2:34][N:33]([CH2:36][C:37](=[O:45])[C:38]3[CH:43]=[CH:42][C:41]([Cl:44])=[CH:40][CH:39]=3)[CH2:32][CH2:31]2)=[CH:28][C:27](=[O:46])[N:26]([CH3:47])[C:25]1=[O:48]>>[ClH:1].[CH3:23][N:24]1[C:29]([N:30]2[CH2:31][CH2:32][N:33]([CH2:36][C:37](=[O:45])[C:38]3[CH:43]=[CH:42][C:41]([Cl:44])=[CH:40][CH:39]=3)[CH2:34][CH2:35]2)=[CH:28][C:27](=[O:46])[N:26]([CH3:47])[C:25]1=[O:48]
Reactant: O=C(CCCl)c1ccccc1
Agent: Cn1c(N2CCN(CC(=O)c3ccc(Cl)cc3)CC2)cc(=O)n(C)c1=O
Agent: O=C(CBr)c1ccc(Cl)cc1
Product: Cl

Procedure:
The same treatment as in Example 32 was effected except that 3-chloropropiophenone was replaced with 2.4 g of 2-bromo-4'-chloroacetophenone, thereby obtaining 2.5 g of the crystals of 1,3-dimethyl-6-[4-(2-oxo-2-[4-chlorophenyl]ethyl)piperazin-1-yl]-2,4(1H,3H)-pyrimidinedione.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([O:11][CH3:12])[N:3]=1.[CH3:13][O:14][C:15](=[O:20])[CH:16]([CH3:19])[CH2:17][NH2:18].C(=O)([O-])[O-].[K+].[K+]>O1CCCC1>[CH3:13][O:14][C:15](=[O:20])[CH:16]([CH3:19])[CH2:17][NH:18][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([O:11][CH3:12])[N:3]=1
Reactant: COc1ccc([N+](=O)[O-])c(Cl)n1
Reactant: COC(=O)C(C)CN
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COC(=O)C(C)CNc1nc(OC)ccc1[N+](=O)[O-]
Temperature: 50 °C
Reaction time: 12 h
Yield: 98 %

Procedure:
To a solution of 2-chloro-6-methoxy-3-nitropyridine (3 g, 15.91 mmol) in tetrahydrofuran (20 mL) was added methyl-3-amino-2-methylpropanoate (2.05 g, 17.50 mmol) and potassium carbonate (4.40 g, 31.82 mmol). The mixture was stirred at 50° C. for 12 hours. The reaction mixture was concentrated in vacuo and washed with water (20 mL), extracted with acetic ester (20 mL×3). The combined organic phase was dried by anhydrous sodium sulphate, and then filtered. The filtrate was concentrated and purified by column chromatograph silica gel (elute: dichloromethane/Methanol: 100:1→80:1) to give methyl-3-((6-methoxy-3-nitropyridin-2-yl)amino)-2-methylpropanoate (4.2 g, 97%) as a yellow oil.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([O:7][C:8]2[CH:17]=[CH:16][C:11]([C:12](OC)=[O:13])=[CH:10][CH:9]=2)[CH:2]=1.[NH2:18][NH2:19]>CCO>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([O:7][C:8]2[CH:17]=[CH:16][C:11]([C:12]([NH:18][NH2:19])=[O:13])=[CH:10][CH:9]=2)[CH:2]=1
Reactant: NN
Reactant: COC(=O)c1ccc(Oc2cccnc2)cc1
Solvent: CCO
Product: NNC(=O)c1ccc(Oc2cccnc2)cc1
Yield: 100 %

Procedure:
Methyl 4-(pyridine-3-yloxy)benzoate (4.8 g, 20.94 mmol) was dissolved in ca. 150 mL of EtOH and anhydrous hydrazine (4.08 g , 4.0 mL) was added via a syringe. The resulting yellow solution was refluxed for 24 hrs. Then solvent was removed in vacuo to give the title product (4.8 g, 100% yield) as yellow viscous oil, which upon standing slowly solidified.
Reaction SMILES: [NH2:1][C:2]1[N:3]([CH3:22])[C:4](=[O:21])[C:5]2[C:10]([C:11]3[C:16]([CH3:17])=[CH:15][C:14]([CH3:18])=[CH:13][C:12]=3[CH3:19])=[CH:9][N:8]([CH3:20])[C:6]=2[N:7]=1.[H-].[Na+].Br[CH:26]([CH2:29][CH3:30])[CH2:27][CH3:28]>CN(C)C=O>[CH2:27]([CH:26]([NH:1][C:2]1[N:3]([CH3:22])[C:4](=[O:21])[C:5]2[C:10]([C:11]3[C:16]([CH3:17])=[CH:15][C:14]([CH3:18])=[CH:13][C:12]=3[CH3:19])=[CH:9][N:8]([CH3:20])[C:6]=2[N:7]=1)[CH2:29][CH3:30])[CH3:28]
Reactant: Cc1cc(C)c(-c2cn(C)c3nc(N)n(C)c(=O)c23)c(C)c1
Reactant: CCC(Br)CC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCC(CC)Nc1nc2c(c(-c3c(C)cc(C)cc3C)cn2C)c(=O)n1C
Temperature: 25 °C
Reaction time: 0.42 h
Yield: 24.8 %

Procedure:
To a solution of 2-amino-5-mesityl-3,7-dimethyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one (0.062 g, 0.209 mmol) in N,N-dimethylformamide (0.5 mL) was added sodium hydride (66% in oil, 0.016 g, 0.439 mmol), and the mixture was allowed to stir at room temperature for 25 minutes. 3-Bromopentane (0.055 mL, 0.439 mmol) twice at room temperature and sodium hydride (66% in oil, 0.016 g, 0.439 mmol) at 0° C. was added during the reaction, stirring at room temperature for 15 hours and at 60° C. for 52 hours. After cooling, the reaction mixture was diluted with ice-cold water and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with hexane/ethyl acetate (4:1-2:1). The desired fractions were concentrated in vacuo. The residual crystals were washed with diisopropyl ether-hexane to give 0.019 g (25%) of the title compound.
Reaction SMILES: [CH3:1][CH:2]([CH3:38])[C@H:3]([NH:33][C:34](=[O:37])[O:35][CH3:36])[C:4](=[O:32])[N:5]1[CH2:9][CH2:8][CH2:7][C@H:6]1[C:10]1[NH:14][C:13]2[C:15]3[C:20]([CH:21]=[CH:22][C:12]=2[N:11]=1)=[CH:19][C:18](B1OC(C)(C)C(C)(C)O1)=[CH:17][CH:16]=3.Br[C:40]1[CH:41]=[C:42]2[C:64](=[CH:65][CH:66]=1)[C:46]1[NH:47][C:48]([C@@H:50]3[C@@H:55]4[CH2:56][C@@H:52]([CH2:53][CH2:54]4)[N:51]3[C:57]([O:59][C:60]([CH3:63])([CH3:62])[CH3:61])=[O:58])=[N:49][C:45]=1[CH:44]=[CH:43]2.C([O-])([O-])=O.[K+].[K+]>COCCOC.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>[CH3:36][O:35][C:34]([NH:33][C@@H:3]([CH:2]([CH3:38])[CH3:1])[C:4]([N:5]1[CH2:9][CH2:8][CH2:7][C@H:6]1[C:10]1[NH:14][C:13]2[C:15]3[C:20]([CH:21]=[CH:22][C:12]=2[N:11]=1)=[CH:19][C:18]([C:40]1[CH:41]=[C:42]2[C:64](=[CH:65][CH:66]=1)[C:46]1[NH:47][C:48]([C@@H:50]4[C@@H:55]5[CH2:56][C@@H:52]([CH2:53][CH2:54]5)[N:51]4[C:57]([O:59][C:60]([CH3:62])([CH3:63])[CH3:61])=[O:58])=[N:49][C:45]=1[CH:44]=[CH:43]2)=[CH:17][CH:16]=3)=[O:32])=[O:37]
Reactant: CC(C)(C)OC(=O)N1[C@@H]2CC[C@@H](C2)[C@H]1c1nc2ccc3cc(Br)ccc3c2[nH]1
Reactant: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1nc2ccc3cc(B4OC(C)(C)C(C)(C)O4)ccc3c2[nH]1)C(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Product: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1nc2ccc3cc(-c4ccc5c(ccc6nc([C@@H]7[C@H]8CC[C@H](C8)N7C(=O)OC(C)(C)C)[nH]c65)c4)ccc3c2[nH]1)C(C)C
Temperature: 25 °C
Reaction time: 18 h
Yield: 36.3 %

Procedure:
Methyl (S)-3-methyl-1-oxo-1-((S)-2-(7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-naphtho[1,2-d]imidazol-2-yl)pyrrolidin-1-yl)butan-2-ylcarbamate (372 mg, 0.715 mmol), (1R,3S,4S)-tert-butyl 3-(7-bromo-1H-naphtho[1,2-d]imidazol-2-yl)-2-azabicyclo[2.2.1]heptane-2-carboxylate (317 mg, 0.715 mmol), Pd(PPh3)4 (83 mg, 0.0715 mmol) and K2CO3 (2M in H2O, 0.7 mL, 1.4 mmol) were suspended in DME (3.6 mL). The mixture was degassed for 13 min with bubbling N2, then heated to reflux. After 18 h, the reaction mixture was cooled to RT and 5 mL MeOH was added. EtOAc was added and the organics were washed with saturated aqueous NaHCO3 and brine, dried over MgSO4, filtered and concentrated. The crude residue was purified by silica column chromatography (0% to 33% MeOH/EtOAc) to afford the title compound (196 mg, 36%).
Reaction SMILES: C([O:3][C:4]([C:6]12[CH2:11][CH:10]1[CH2:9][N:8]([CH3:12])[CH2:7]2)=[O:5])C.S(=O)(=O)(O)O>C(O)C.O>[CH3:12][N:8]1[CH2:9][CH:10]2[C:6]([C:4]([OH:5])=[O:3])([CH2:11]2)[CH2:7]1
Reactant: CCOC(=O)C12CC1CN(C)C2
Agent: O=S(=O)(O)O
Solvent: CCO
Solvent: O
Product: CN1CC2CC2(C(=O)O)C1

Procedure:
A solution of 10 g of 3-methyl-3-azabicyclo[3.1.0]-hexane-1-carboxylic acid ethyl ester in 20 ml of ethanol is treated with a solution of 18.8 g of Ba(OH)2 ·8H2O in 500 ml of water. The resultant mixture is boiled under reflux for 15 hours. After cooling, the mixture is neutralized with 10% sulphuric acid. The resultant barium sulphate is filtered off. The filtrate is evaporated and taken up in methanol. After filtration through talc, the filtrate is concentrated to yield the title compound as crystals of M.Pt. 193°-195°.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:5]([F:21])=[C:6]([CH:19]=[O:20])[C:7]([C:10]2[C:11]([CH:17]=[O:18])=[C:12]([F:16])[CH:13]=[CH:14][CH:15]=2)=[CH:8][CH:9]=1)[CH3:2].C(N(CC)CC)C>[Br-].C([N+]1C(C)=C(CCO)SC=1)C.CN(C=O)C>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]2[C:10]3[C:11](=[C:12]([F:16])[CH:13]=[CH:14][CH:15]=3)[C:17](=[O:18])[C:19](=[O:20])[C:6]=2[C:5]=1[F:21])[CH3:2]
Reactant: CCOc1ccc(-c2cccc(F)c2C=O)c(C=O)c1F
Agent: CC[n+]1csc(CCO)c1C
Agent: [Br-]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOc1ccc2c(c1F)C(=O)C(=O)c1c(F)cccc1-2
Yield: 703.9 %

Procedure:
Under a nitrogen atmosphere, a DMF (50 mL) solution of compound (85) (10.0 g, 3.45 mmol), 3-ethyl-5-(2-hydroxyethyl)-4-methylthiazole-3-iumbromide (1.74 g, 6.89 mmol) and triethylamine (1.05 g, 10.34 mmol) was agitated at 60° C. for 6 hours. The reaction mixture was quenched with 150 mL of water, and extracted with 50 mL of dichloromethane three times. Combined organic layers were washed with a 1N hydrochloric acid aqueous solution, water and saturated brine, and then dried over magnesium sulfate, and a solvent was distilled off by an evaporator. The residue was washed with toluene, and thus 2-ethoxy-1,8-difluorophenanthrene-9,10-dione (86) (7.0 g, yield 70.5%) was obtained.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:14])[CH2:8][CH2:7]2)([OH:3])=O.N1C=CC=CC=1.S(Cl)(Cl)=O.[CH2:25]([N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C(Cl)Cl.CO.C(Cl)(Cl)Cl>[CH2:25]([N:32]1[CH2:37][CH2:36][N:35]([C:1]([C:4]2[CH:5]=[C:6]3[C:11](=[CH:12][CH:13]=2)[NH:10][C:9](=[O:14])[CH2:8][CH2:7]3)=[O:3])[CH2:34][CH2:33]1)[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: c1ccc(CN2CCNCC2)cc1
Reactant: O=C1CCc2cc(C(=O)O)ccc2N1
Solvent: O=S(Cl)Cl
Solvent: CO
Solvent: ClCCl
Product: O=C1CCc2cc(C(=O)N3CCN(Cc4ccccc4)CC3)ccc2N1
Reaction time: 1 h

Procedure:
1.9 Grams of 6-carboxy-3,4-dihydrocarbostyril was suspended in 200 ml of methylene chloride, then 2 ml of pyridine was added to the suspension and under stirring 1.4 g of thionyl chloride was added dropwise in keeping the inside temperature at 0°-20° C. After the addition of thionyl chloride, the reaction mixture was kept at the same temperature and stirred for 1 hour, then 1.74 g of benzylpiperazine in 10 ml of methylene chloride solution was added to the mixture. Then the reaction mixture was further stirred at a room temperature for 4 hours. The reaction mixture was washed thoroughly with an aqueous solution of potassium carbonate, then washed with water and a diluted hydrochloric acid, dried with anhydrous sodium sulfate and the solvent was removed by distillation. The residue thus obtained was treated by a silica gel column chromatography (Silica gel: Wako C-200, eluate:chloroform:methanol (volume/volume)=20:1). The objective product was recrystallized from ethanol to obtain 325 mg of 6-(4-benzyl-1-piperazinylcarbonyl)-3,4-dihydrocarbostyril. Colorless needle-like crystals. Melting point: 198°-200° C.
Reaction SMILES: [C:1]([NH:8][OH:9])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[OH-].[K+].[CH2:12]([O:14][C:15](=[O:20])[C:16](Br)([CH3:18])[CH3:17])[CH3:13]>C(O)C>[CH2:12]([O:14][C:15](=[O:20])[C:16]([O:9][NH:8][C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])([CH3:18])[CH3:17])[CH3:13]
Reactant: CCOC(=O)C(C)(C)Br
Reactant: CC(C)(C)OC(=O)NO
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCOC(=O)C(C)(C)ONC(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 98.4 %

Procedure:
To a solution of N-Boc-hydroxylamine (5.2 g, 39.05 mmol) in ethanol (100 mL) was added potassium hydroxide (2.63 g, 46.86 mmol), the mixture stirred at room temperature until a solution was formed. 2-Bromoisobutyric acid ethyl ester (6.87 mL, 46.9 mmol) was added and the reaction mixture heated at reflux for 18 hours. The reaction mixture was cooled to room temperature then filtered, and the filtrate was concentrated in vacuo. The resultant oily residue was partitioned between water (75 mL) and diethyl ether and the aqueous fraction was extracted with diethyl ether (2×100 mL). The combined organic extracts were dried (Na2SO4), filtered and concentrated in vacuo to give the title compound as a clear oil (9.5 g, 99%). LCMS (method C): RT=2.55 min, [M+H]+=248. 1H NMR (CDCl3, 400 MHz) 4.20 (q, 2H), 1.50 (s, 6H), 1.49 (s, 9H), 1.30 (t, 3H).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.ClCCl.[CH3:10][C@@H:11]1[CH2:13][C@H:12]1[C:14]([OH:16])=O.[NH2:17][C:18]1[S:22][N:21]=[C:20]([C:23]2[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=2)[C:19]=1[CH3:30].N1C=CC=CC=1>CN(C=O)C.C1(C)C=CC=CC=1.C1COCC1.CCOC(C)=O>[OH:29][C:26]1[CH:25]=[CH:24][C:23]([C:20]2[C:19]([CH3:30])=[C:18]([NH:17][C:14]([C@@H:12]3[CH2:13][C@H:11]3[CH3:10])=[O:16])[S:22][N:21]=2)=[CH:28][CH:27]=1
Reactant: C[C@@H]1C[C@H]1C(=O)O
Reactant: Cc1c(-c2ccc(O)cc2)nsc1N
Agent: O=C(Cl)C(=O)Cl
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Solvent: ClCCl
Product: Cc1c(-c2ccc(O)cc2)nsc1NC(=O)[C@@H]1C[C@H]1C
Reaction time: 3 h
Yield: 64.6 %

Procedure:
Add oxalyl chloride (2 M in dichloromethane, (0.291 mL, 0.583 mmol) to a stirred solution of (R,R)-2-methylcyclopropanecarboxylic acid (0.06 g, 0.58 mmol) and DMF (1 drop-catalytic) in toluene (1 mL). Stir 3 h and add the now formed acid chloride to a stirred solution of 4-(5-amino-4-methylisothiazol-3-yl)phenol (0.060 g, 0.291 mmol) and pyridine (0.07 g, 0.87 mmol) in THF (1 mL). Stir 1 h and dilute with EtOAc (300 mL), and wash with 1 N NaOH (2 times 100 mL) then water (100 mL), dry (MgSO4) and evaporate. Crystallize from chloroform and hexane. Yield: 64.6%. ES-MS: m/e 289.0 (m+1).
Reaction SMILES: [Cl:1][CH2:2][C:3](=[O:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].C(O)(=O)C.[CH2:15](N)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C(OCC)(=O)C>[Cl:1][CH2:2][C:3](=[O:10])[C:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])=[CH:15][CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: CCOC(=O)CC(=O)CCl
Reactant: NCc1ccccc1
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CCOC(=O)C(=CC1CCCCC1)C(=O)CCl
Reaction time: 24 h

Procedure:
A mixture of ethyl 4-chloro-3-oxo-butanoate (57.3 ml), cyclohexylaldehyde (53.65 ml), acetic acid (2.75 ml) and benzylamine (4.38 ml) is kept for 24 hrs at room temperature. It is then diluted with 150 ml of ethyl acetate and washed with 100 ml of water, then with 100 ml of saturated sodium carbonate solution and finally with 100 ml of a saturated solution of NaH2PO4. The solvent is evaporated to give 108.43 g of 4-chloro3-oxo-2-ethoxycarbonyl-1-cyclohexyl-but-1-ene.