Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1.[Cl:18][C:19]1[CH:20]=[C:21]([CH:25]=[CH:26][CH:27]=1)[C:22](Cl)=[O:23]>>[Cl:18][C:19]1[CH:20]=[C:21]([CH:25]=[CH:26][CH:27]=1)[C:22]([NH:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1)=[O:23]
Reactant: O=C(Cl)c1cccc(Cl)c1
Reactant: CN1CCC(c2c[nH]c3ccc(N)nc23)CC1
Product: CN1CCC(c2c[nH]c3ccc(NC(=O)c4cccc(Cl)c4)nc23)CC1
Yield: 80.1 %

Procedure:
Beginning with 0.085 gm (0.369 mMol) 5-amino-3-(1-methylpiperidin-4-yl)pyrrolo[3,2-b]pyridine and 0.099 mL (0.776 mMol) 3-chlorobenzoyl chloride, 0.109 gm (80.1%) of the title compound was recovered as a crystalline solid by the procedure described in Example 16.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][CH:10]=[C:9]([Si:13]([CH3:16])([CH3:15])[CH3:14])[C:3]=1[C:4]([NH:6][CH2:7][CH3:8])=[O:5].[Li]C(C)(C)C.CCCCC.C(Br)C[Br:29]>C1COCC1>[Br:29][CH2:16][Si:13]([CH3:15])([CH3:14])[C:9]1[CH:10]=[CH:11][CH:12]=[C:2]([Cl:1])[C:3]=1[C:4]([NH:6][CH2:7][CH3:8])=[O:5]
Reactant: CCNC(=O)c1c(Cl)cccc1[Si](C)(C)C
Reactant: BrCCBr
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: CCCCC
Product: CCNC(=O)c1c(Cl)cccc1[Si](C)(C)CBr
Temperature: -78 °C
Reaction time: 1.5 h
Yield: 17.9 %

Procedure:
To a solution of the compound of example 45 (1.28 g, 5 mmol) in THF (30 mL) at -78° C. was added a 1.7M solution of t-BuLi in pentane (6.5 mL, 11 mmol, 2.2 eq) such that the temperature was less than -70° C. The reaction was stirred at -78° C. for 1.5 h and ethylene dibromide (0.52 mL, 6.0 mmol, 1.2 eq) was added. The reaction was stirred for 15 min at -78° C. and worked up in the usual manner. The crude product was purified by RC and recrystallized from aq methanol to afford the title compound as white needles (0.30 g, 18%). m.p. 98°-99° C.
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([NH:7][C:8]2[CH:13]=[CH:12][C:11]([N:14]([CH3:16])[CH3:15])=[CH:10][CH:9]=2)[C:3]=1[C:17]([NH2:19])=[O:18].[OH:20][C:21]1[CH:28]=[CH:27][C:24]([CH:25]=O)=[CH:23][CH:22]=1.N1CCCCC1>C(O)C>[CH3:16][N:14]([CH3:15])[C:11]1[CH:10]=[CH:9][C:8]([NH:7][C:4]2[C:3]([C:17]([NH2:19])=[O:18])=[C:2]([N:1]=[CH:25][C:24]3[CH:27]=[CH:28][C:21]([OH:20])=[CH:22][CH:23]=3)[NH:6][N:5]=2)=[CH:13][CH:12]=1
Reactant: CN(C)c1ccc(Nc2n[nH]c(N)c2C(N)=O)cc1
Reactant: O=Cc1ccc(O)cc1
Solvent: C1CCNCC1
Solvent: CCO
Product: CN(C)c1ccc(Nc2n[nH]c(N=Cc3ccc(O)cc3)c2C(N)=O)cc1
Yield: 90 %

Procedure:
5-amino-3-((4-(dimethylamino)phenyl)amino)-1H-pyrazole-4-carboxamide (900 mg) was suspended in 10 mL of ethanol and 4-hydroxybenzaldehyde (634 mg, 1.5 eq.) and piperidine (0.25 eq., 89 mL) was added. The reaction was stirred at reflux until the starting material was absent and confirmed by HPLC. After the reaction was complete (18 hrs) it was brought to room temperature and filtered to obtain 3-((4-(dimethylamino)phenyl)amino)-5-((4-hydroxybenzylidene)amino)-1H-pyrazole-4-carboxamide t as a yellow to orange powder. The product was washed with ethanol to remove any excess 4-hydroxybenzaldehyde. Product was allowed to dry under vacuum for 1 hr (1.130 g, 90% yield).
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[CH:7]2.[C:13]([C:17]1[CH:24]=[CH:23][C:20]([CH2:21]Br)=[CH:19][CH:18]=1)([CH3:16])([CH3:15])[CH3:14]>CN(C=O)C>[Br:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH2:21][C:20]1[CH:23]=[CH:24][C:17]([C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:18][CH:19]=1)[CH:8]=[CH:7]2
Reactant: Brc1ccc2[nH]ccc2c1
Reactant: CC(C)(C)c1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)c1ccc(Cn2ccc3cc(Br)ccc32)cc1
Temperature: 0 °C
Reaction time: 2.5 h
Yield: 97.8 %

Procedure:
NaH (60%, 36.8 g, 921 mmol) was added portionwise to a stirring solution of 5-bromoindole (152.0 g, 768 mmol) in DMF (1.4 L) at 0° C. under a nitrogen atmosphere over a period of one hour. The mixture was stirred at 0° C. for one hour and at room temperature for 2.5 hours. 4-(tert-Butyl)benzyl bromide (180.0 g, 768 mmol) was added over a period of one hour. The mixture was stirred at room temperature for 3 hours. The reaction was quenched with aqueous ammonium chloride (5%, 1.4 L). The precipitated solid was isolated by filtration, washed with water (5×0.5 L), then with petroleum ether (0.3 L). The solid was dried in the air and then under vacuum at 60° C. for 18 hours to afford the title compound as a white solid (257 g, 97%), m.p. 108–109° C. Mass spectrum (ESI, [M+H]+) m/z 342. 1HNMR (400 MHz, DMSO-d6) δ 7.73 (s, 1H), δ 7.55 (s, 1H), δ 7.44 (d, 1H, J=8.71 Hz), 7.30 (d, 2H, J=7.96 Hz), 7.19 (d, 1H, J=8.71 Hz), 7.10 (d, 2H, J=7.63 Hz), 6.46 (s, 1H), 5.36 (s, 2H), and 1.21 ppm (s, 9H).
Reaction SMILES: C(N(CC)CC)C.[CH3:8][S:9](Cl)(=[O:11])=[O:10].[NH:13]1[CH2:18][CH2:17][C:16]([C:19]2[CH:24]=[CH:23][C:22]([N:25]3[CH2:29][C@H:28]([CH2:30][NH:31][C:32](=[O:34])[CH3:33])[O:27][C:26]3=[O:35])=[CH:21][CH:20]=2)=[CH:15][CH2:14]1>ClCCl>[CH3:8][S:9]([N:13]1[CH2:18][CH2:17][C:16]([C:19]2[CH:24]=[CH:23][C:22]([N:25]3[CH2:29][C@H:28]([CH2:30][NH:31][C:32](=[O:34])[CH3:33])[O:27][C:26]3=[O:35])=[CH:21][CH:20]=2)=[CH:15][CH2:14]1)(=[O:11])=[O:10]
Reactant: CS(=O)(=O)Cl
Reactant: CC(=O)NC[C@H]1CN(c2ccc(C3=CCNCC3)cc2)C(=O)O1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)NC[C@H]1CN(c2ccc(C3=CCN(S(C)(=O)=O)CC3)cc2)C(=O)O1

Procedure:
Triethylamine (253 mg), followed by a solution of methanesulfonyl chloride (69 mg) in dichloromethane (1 ml) was added, with ice-bath cooling, to a stirred suspension of N-((5S)-3-(4-(1,2,5,6-tetrahydropyrid-4-yl)phenyl)-2-oxooxazolidin-5-ylmethyl)acetamide (215 mg, Example 2) in dichloromethane (10 ml). TLC showed complete reaction after 2 hours. The reaction mixture was washed with 2N. HCl, water, saturated sodium hydrogen carbonate and brine. The organic phase was dried over anhydrous sodium sulfate and evaporated to give the title compound as a crystalline solid which was recrystallised from acetonitrile (yield=117 mg, 60%).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].C1(O)C=CC=CC=1.[CH3:20][O:21][C:22](=[O:27])[CH:23](Br)[CH2:24][CH3:25]>>[CH:6]([C:5]1[CH:8]=[CH:9][C:2]([O:1][CH:23]([CH2:24][CH3:25])[C:22]([O:21][CH3:20])=[O:27])=[C:3]([N+:10]([O-:12])=[O:11])[CH:4]=1)=[O:7]
Reactant: CCC(Br)C(=O)OC
Reactant: O=Cc1ccc(O)c([N+](=O)[O-])c1
Solvent: Oc1ccccc1
Product: CCC(Oc1ccc(C=O)cc1[N+](=O)[O-])C(=O)OC

Procedure:
Using 4-hydroxy-3-nitrobenzaldehyde as the phenol and methyl-2-bromobutanoate as the alkylating agent in the general procedure of alkylation of substituted 2-nitrophenols gives a clear yellow oil: 1H NMR (DMSO-d6, 400 MHz): δ=9.94 (s, 1H), 8.44 (d, J=2.3 Hz, 1H), 8.13 (dd, J=8.8, 2.0 Hz, 1H), 7.42 (d, J=8.8 Hz, 1H), 5.36 (dd, J=6.6, 4.5 Hz, 1H), 3.70 (s, 3H), 1.88-2.05 (m, 2H), 0.98 ppm (t, J=7.5 Hz, 3H). ESI-MS: m/z 268.2 (M+H)+.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][NH:15][C:16]([CH:18]2[S:28][C:27]3[N:29]4[C:20](=[CH:21][N:22]=[C:23]4[CH:24]=[CH:25][CH:26]=3)[CH2:19]2)=[O:17])[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:30]>CC(O)C>[ClH:30].[ClH:30].[NH:8]1[CH2:13][CH2:12][CH:11]([CH2:14][NH:15][C:16]([CH:18]2[S:28][C:27]3[N:29]4[C:20](=[CH:21][N:22]=[C:23]4[CH:24]=[CH:25][CH:26]=3)[CH2:19]2)=[O:17])[CH2:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCC(CNC(=O)C2Cc3cnc4cccc(n34)S2)CC1
Agent: Cl
Solvent: CC(C)O
Product: O=C(NCC1CCNCC1)C1Cc2cnc3cccc(n23)S1
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.2 %

Procedure:
To a solution of 480 g (1.15 mM) of N-[(1-tert-butoxycarbonyl-4-piperidyl)methyl]-3,4-dihydro-5-thia-1,8b-diazaacenaphthylene-4-carboxamide in 20 ml of 2-propanol was added 0.47 ml (5.76 mM) of 12N-hydrochloric acid and the mixture was stirred at room temperature for 1 hours. This reaction mixture was concentrated under reduced pressure and the resulting crystals were collected by filtration and rinsed with a small amount of ether to provide 404 mg (90.2%) of the title compound as white crystals.
Reaction SMILES: [C:1]1([Se:7][C:8]2[CH:21]=[CH:20][C:11]3[N:12]=[C:13]([NH:15][C:16]([O:18][CH3:19])=[O:17])[NH:14][C:10]=3[CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.ClC1C=CC=C(C(OO)=[O:30])C=1>C(O)(=O)C>[C:1]1([Se:7]([C:8]2[CH:21]=[CH:20][C:11]3[N:12]=[C:13]([NH:15][C:16]([O:18][CH3:19])=[O:17])[NH:14][C:10]=3[CH:9]=2)=[O:30])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COC(=O)Nc1nc2ccc([Se]c3ccccc3)cc2[nH]1
Solvent: CC(=O)O
Product: COC(=O)Nc1nc2ccc([Se](=O)c3ccccc3)cc2[nH]1
Temperature: 25 °C

Procedure:
A solution of methyl 5-phenylseleno-2-benzimidazolecarbamate (5.0 g, 14.5 mmole) in acetic acid (50 ml.) was cooled to 10°-15° C. while 85% 3-chloroperbenzoic acid (3.0 g, 14.7 mmole) was added in portions. The solution was then allowed to warm to room temperature, and the solvent was evaporated under reduced pressure. The residue was stirred with sodium carbonate solution and filtered, and the solid product was crystallised from a mixture of equal parts of acetic acid and methanol, to give methyl 5-phenylseleninyl-2-benzimidazolecarbamate, m.p. 222° C. with decomposition. All other 5-phenylseleninylbenzimidazole carbamates of the invention may be manufactured in exactly the same manner, by using the appropriate 1-6C alkyl 5-(optionally substituted phenyl)seleno-2-benzimidazolecarbamate in place of methyl 5-phenylseleno-2-benzimidazolecarbamate.
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][C:7]2[CH:15]=[CH:14][C:10]([C:11](Cl)=[O:12])=[CH:9][CH:8]=2)=[C:4]([N+:18]([O-:20])=[O:19])[CH:3]=1.[CH3:21][O:22][NH:23][CH3:24]>>[Cl:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][C:7]2[CH:15]=[CH:14][C:10]([C:11]([N:23]([O:22][CH3:21])[CH3:24])=[O:12])=[CH:9][CH:8]=2)=[C:4]([N+:18]([O-:20])=[O:19])[CH:3]=1
Reactant: O=C(Cl)c1ccc(Oc2ccc(Cl)cc2[N+](=O)[O-])cc1
Reactant: CNOC
Product: CON(C)C(=O)c1ccc(Oc2ccc(Cl)cc2[N+](=O)[O-])cc1
Yield: 95.6 %

Procedure:
The product from Example 126c (1.0 g, 3.20 mmol) was reacted with N-methoxymethanamine (391 mg, 6.41 mmol) for 12 h following the procedure from Example 126d giving the title compound (1.03 g, 100%).
Reaction SMILES: Br[C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[NH:9][C:10](=[O:14])[CH2:11][CH2:12][CH3:13].[CH3:15][C:16]([CH3:21])([CH3:20])[C:17]#[C:18]C>CCN(CC)CC.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:15][C:16]([CH3:21])([CH3:20])[C:17]#[C:18][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[NH:9][C:10](=[O:14])[CH2:11][CH2:12][CH3:13]
Reactant: CC#CC(C)(C)C
Reactant: CCCC(=O)Nc1cccc(F)c1Br
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: CCCC(=O)Nc1cccc(F)c1C#CC(C)(C)C
Temperature: 80 °C
Yield: 60.1 %

Procedure:
To a solution of N-(2-bromo-3-fluorophenyl)butyramide (2.0 g, 7.0 mmol) in Et3N (100 mL) was added 4,4-dimethylpent-2-yne (6.0 g, 60 mmol), CuI (70 mg, 3.8 mmol), and Pd(PPh3)2Cl2 (500 mg) successively at room temperature under N2. The mixture was heated at 80° C. overnight. The cooled mixture was filtered and the filtrate was extracted with EtOAc (40 mL×3). The organic layers were washed with sat. NaCl, dried over anhydrous Na2SO4, and evaporated under vacuum. The crude compound was purified by column chromatography on silica gel (10% EtOAc in petroleum ether) to give N-(2-(3,3-dimethylbut-1-ynyl)-3-fluorophenyl)butyramide (1.1 g, 55%). 1H NMR (400 MHz, CDCl3) δ 8.20 (d, J=7.6, 1H), 7.95 (s, 1H), 7.21 (m, 1H), 6.77 (t, J=7.6 Hz, 1H), 2.39 (t, J=7.6 Hz, 2H), 1.82-1.75 (m, 2H), 1.40 (s, 9H), 1.12 (t, J=7.2 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:10][F:11])[C:5]([CH:8]=[O:9])=[N:6][CH:7]=1.[OH-:12].[Na+]>C1COCC1.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:10][F:11])[C:5]([C:8]([OH:12])=[O:9])=[N:6][CH:7]=1
Reactant: O=Cc1ncc(Cl)cc1CF
Reactant: [OH-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1ncc(Cl)cc1CF
Reaction time: 0.17 h

Procedure:
To a solution of 5-chloro-3-(fluoromethyl)picolinaldehyde (55 mg, 0.32 mmol) in THF (2 mL) and water (4 mL) was added solid NaOH (13 mg) at 0° C. After 10 min, KMNO4 (100 mg) was added in one portion. After additional 10 min, the reaction mixture was filtered through a pad of celite. The celite was washed with 1 M HCl (10 mL), water and EtOAc. The phases were separated and the aqueous phase was extracted with EtOAc. The combined organic layers were dried over MgSO4 and the filtrate was concentrated under reduced pressure. The title compound was obtained as a yellow residue and taken onto the next step without further purification. LC/MS m/z=172.1 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[C:9]2[C:4]=1[CH2:5][CH2:6][CH:7]([C:16]([O:18]C)=[O:17])[CH2:8]2>CO.[OH-].[Na+]>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[C:9]2[C:4]=1[CH2:5][CH2:6][CH:7]([C:16]([OH:18])=[O:17])[CH2:8]2
Reactant: COC(=O)C1CCc2c(OC)ccc([N+](=O)[O-])c2C1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc([N+](=O)[O-])c2c1CCC(C(=O)O)C2
Yield: 95.3 %

Procedure:
A mixture of methyl 5-methoxy-8-nitro-1,2,3,4-tetrahydronaphthalene-2-carboxylate (1.9 g, 7.1 mmol) in methanol (20 mL) and 2 M NaOH (10 mL) was refluxed for 1.5 h and the solvent was evaporated in vacuo. The residue was taken up in ethyl acetate and acidified. The organic phase was separated and dried and evaporated in vacuo to afford 1.7 g (95% yield) of crystals: mp (after recrystallization in diisopropyl ether/ethanol) 189-190° C.; EIMS (70 eV) rm/z (relative intensity) 251 (30, M+).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][O:7][C:8](=[O:20])[NH:9][CH2:10][CH2:11][CH2:12][CH:13]([O:17][CH2:18][CH3:19])[O:14][CH2:15][CH3:16].[H-].[Na+]>CN(C)C=O.O.[Cl-].[Na+]>[CH2:15]([O:14][CH:13]([O:17][CH2:18][CH3:19])[CH2:12][CH2:11][CH2:10][N:9]1[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][O:7][C:8]1=[O:20])[CH3:16]
Reactant: CCOC(CCCNC(=O)OCCCCCCl)OCC
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(CCCN1CCCCCOC1=O)OCC
Temperature: 25 °C
Reaction time: 15 h
Yield: 16.9 %

Procedure:
To a solution of (4,4-diethoxybutyl)carbamic acid 5-chloro-pentyl ester (11.4 g, 44 mmole) dissolved in N,N-dimethylformamide (100 mL) was added de-oiled sodium hydride (1.01 g, 42.3 mmole). The reaction mixture was stirred for 15 hours at room temperature, and then at 70° C. for 3 hours. The mixture was diluted with water, saturated aqueous sodium chloride was added, and extracted with diethyl ether. The organic phase was washed with water, dried (magnesium sulfate), and concentrated. Purification by silica gel chromatography, gave 3-(4,4-diethoxybutyl)-[1,3]oxazocan-2-one (2.03 g) as a viscous oil.
Reaction SMILES: [ClH:1].[CH3:2][S:3]([NH:6][C:7]1[CH:20]=[CH:19][C:10]([C:11]([CH:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)=[O:12])=[CH:9][CH:8]=1)(=[O:5])=[O:4].[CH3:21][C:22]1[N:27]=[C:26]([CH:28]=[CH2:29])[CH:25]=[CH:24][CH:23]=1.C([O-])(=O)C.[Na+].CO>O>[ClH:1].[ClH:1].[CH3:21][C:22]1[N:27]=[C:26]([CH2:28][CH2:29][N:16]2[CH2:17][CH2:18][CH:13]([C:11](=[O:12])[C:10]3[CH:9]=[CH:8][C:7]([NH:6][S:3]([CH3:2])(=[O:4])=[O:5])=[CH:20][CH:19]=3)[CH2:14][CH2:15]2)[CH:25]=[CH:24][CH:23]=1
Reactant: C=Cc1cccc(C)n1
Reactant: CS(=O)(=O)Nc1ccc(C(=O)C2CCNCC2)cc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: Cc1cccc(CCN2CCC(C(=O)c3ccc(NS(C)(=O)=O)cc3)CC2)n1
Yield: 150.7 %

Procedure:
0.254 g (0.797 mmol) of 4-(4-methylsulfonylaminobenzoyl)piperidine hydrochloride, 0.22 g (1.88 mmol) of 6-methyl-2-vinylpyridine and 0.15 g of sodium acetate were suspended in 3 ml of a mixture of methanol and water (1:1) and the suspension was refluxed for 2 h. The liquid reaction mixture was filtered and the filtrate was concentrated. The obtained residue was purified according to silica gel column chromatography (chloroform:methanol:aqueous ammonia=96:4:0.4). The purified product was converted into its hydrochloride with ethanolic hydrogen chloride and recrystallized from ethanol to obtain 0.285 g (yield: 81%) of the intended compound.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[F:13].[CH3:14][N:15]1[CH2:20][CH2:19][C:18](=[O:21])[CH2:17][CH2:16]1.O>O1CCCC1>[F:13][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=1[C:18]1([OH:21])[CH2:19][CH2:20][N:15]([CH3:14])[CH2:16][CH2:17]1
Reactant: CN1CCC(=O)CC1
Reactant: Fc1ccccc1Br
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: CN1CCC(O)(c2ccccc2F)CC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
46 ml of 2.4 M n-butyllithium are added over a 15 minute span to a mixture cooled to -70° C. of 17.5 g of 2-bromofluorobenzene and 50 ml of tetrahydrofuran. After total addition, the reaction mixture is stirred at between -60° to -70° C. for 15 minutes to enable complete lithiation, which results in a tan colored solution. A mixture of 11.3 g of 1-methyl-4-piperidone in 20 ml of tetrahydrofuran is added to the solution at a rate to maintain the reaction medium's temperature below -60° C. After total addition, the reaction mixture is stirred at the same low temperature for one hour before being permitted to warm to ambient temperature. Water is added and the biphasic mixture is permitted to separate into its organic and aqueous phases. The organic phase is collected and the aqueous phase is extracted thrice with ether and the ether extracts are combined with the organic phase. The combined organic solution is extracted with an excess of 2 N hydrochloric acid and then discarded. The acidic solution is basified with ammonium hydroxide, producing a heavy oil which is dissolved in a 1:1 ethyl acetate ether mixture. This solution is dried and then concentrated to dryness, leaving a viscous oil which crystallizes with cooling. The solid product is recrystallized from a benzene-hexane mixture to give prisms, mp 127°-129° C. of 4-(2-fluorophenyl)-4-hydroxy-1-methylpiperidine.
Reaction SMILES: [CH:1]1[C:6]([CH:7]=O)=[CH:5][C:4]2[O:9][CH2:10][O:11][C:3]=2[CH:2]=1.[CH:12]([C:15]1[CH:21]=[CH:20][C:18]([NH2:19])=[CH:17][CH:16]=1)([CH3:14])[CH3:13]>>[O:11]1[C:3]2[CH:2]=[CH:1][C:6]([CH2:7][NH:19][C:18]3[CH:20]=[CH:21][C:15]([CH:12]([CH3:14])[CH3:13])=[CH:16][CH:17]=3)=[CH:5][C:4]=2[O:9][CH2:10]1
Reactant: O=Cc1ccc2c(c1)OCO2
Reactant: CC(C)c1ccc(N)cc1
Product: CC(C)c1ccc(NCc2ccc3c(c2)OCO3)cc1
Yield: 76.6 %

Procedure:
By the reaction and treatment in the same manner as in Preparation Example 1 using piperonal (4.5 g) and 4-isopropylaniline (4.0 g) as starting materials, (benzo[d]1,3-dioxolen-5-ylmethyl)(4-isopropylphenyl)amine (6.1 g) was obtained.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=O)=[C:4]([O:18][CH3:19])[CH:3]=1.FC(F)(F)C(O)=O.C([SiH](CC)CC)C>C(Cl)Cl>[CH2:10]([C:5]1[C:4]([O:18][CH3:19])=[CH:3][C:2]([Br:1])=[CH:7][C:6]=1[O:8][CH3:9])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: COc1cc(Br)cc(OC)c1C(=O)c1ccccc1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(Br)cc(OC)c1Cc1ccccc1
Temperature: 80 °C
Yield: 98 %

Procedure:
(4-bromo-2,6-dimethoxyphenyl)(phenyl)methanone (87 mg, 0.271 mmol) was solubilized and stirred into a mixture of trifluoroacetic acid (250 μL, 12 eq) and triethylsilane (260 μL, 6 eq) heated at 80° C. for 15 h. After cooling to r.t., 20 mL of DCM were added to the reaction mixture. The organic layer was washed with a saturated NaHCO3 solution (2×20 mL), with brine, dried over MgSO4, filtered and concentrated in vacuo. The crude residue was purified by silica gel flash chromatography (cyclohexane/AcOEt 95:5) to afford the reduced compound in 98% yield (81.4 mg) as a white solid. 1H NMR (300 MHz, CDCl3) δ 7.28-7.21 (m, 4H), 7.20-7.12 (m, 1H), 6.73 (s, 2H), 3.98 (s, 2H), 3.81 (s, 6H); 13C NMR (75 MHz, CDCl3) δ 158.77 (2C), 141.23 (C), 128.57 (2CH), 128.14 (2CH), 125.63 (CH), 120.45 (C), 116.86 (C), 107.71 (2CH), 56.04 (2OCH3), 28.58 (CH2); MS (ESI) m/z: 307.4, 309.0 [M+H, 79Br, 81Br]+; 324.1, 326.1 [M+NH4, 79Br, 81Br]+.
Reaction SMILES: [C:1]([C:3]1([C:6]2[CH:7]=[C:8]([CH:12]=[CH:13][CH:14]=2)[C:9](Cl)=[O:10])[CH2:5][CH2:4]1)#[N:2].Cl.Cl.[NH2:17][C:18]1[CH:19]=[C:20]([CH:29]=[CH:30][CH:31]=1)[O:21][C:22]1[CH:23]=[CH:24][C:25]([NH2:28])=[N:26][CH:27]=1.C(=O)([O-])O.[Na+]>CN(C)C(=O)C>[NH2:28][C:25]1[N:26]=[CH:27][C:22]([O:21][C:20]2[CH:19]=[C:18]([NH:17][C:9](=[O:10])[C:8]3[CH:12]=[CH:13][CH:14]=[C:6]([C:3]4([C:1]#[N:2])[CH2:5][CH2:4]4)[CH:7]=3)[CH:31]=[CH:30][CH:29]=2)=[CH:23][CH:24]=1
Reactant: Nc1cccc(Oc2ccc(N)nc2)c1
Reactant: N#CC1(c2cccc(C(=O)Cl)c2)CC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: N#CC1(c2cccc(C(=O)Nc3cccc(Oc4ccc(N)nc4)c3)c2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 75 %

Procedure:
To a solution of 3-(1-cyanocyclopropyl)benzoyl chloride synthesized above in N,N-dimethylacetamide (50 mL) was added 5-(3-aminophenoxy)pyridin-2-amine dihydrochloride (3.5 g, 12.7 mmol), and the mixture was stirred at room temperature for 18 hr. 5% Aqueous sodium hydrogen carbonate solution (200 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (300 mL). The organic layer was washed with saturated brine (100 mL) and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=50/50→0/100), and triturated with ethyl acetate and hexane to give the title compound (3.84 g, 75%) as a colorless solid.
Reaction SMILES: [CH2:1]([O:4][C:5]([N:7]1[C@:11]2([C@@H:16]([F:17])[CH2:15][C@@H:14]3[C@H:12]2[C@H:13]3[C:18]([OH:20])=[O:19])[C:10](=[O:21])[O:9][CH2:8]1)=[O:6])[CH:2]=[CH2:3].C(=O)([O-])[O-].[Cs+].[Cs+].S(C1C=CC(C)=CC=1)(O[CH2:32][CH3:33])(=O)=O.O>CN(C)C=O>[F:17][C@@H:16]1[C@@:11]2([C:10](=[O:21])[O:9][CH2:8][N:7]2[C:5]([O:4][CH2:1][CH:2]=[CH2:3])=[O:6])[C@H:12]2[C@H:14]([C@@H:13]2[C:18]([O:20][CH2:32][CH3:33])=[O:19])[CH2:15]1
Reactant: CCOS(=O)(=O)c1ccc(C)cc1
Reactant: C=CCOC(=O)N1COC(=O)[C@]12[C@H]1[C@@H](C[C@@H]2F)[C@@H]1C(=O)O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: C=CCOC(=O)N1COC(=O)[C@]12[C@H]1[C@@H](C[C@@H]2F)[C@@H]1C(=O)OCC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of (1S,2S,3S,5R,6S)-3′-((allyloxy)carbonyl)-3-fluoro-5′-oxospiro[bicyclo[3.1.0]hexan-2,4′-oxazolidine]-6-carboxylic acid obtained below in Example A-1 (A-1-2, 200 mg) in N,N-dimethylformamide (6 mL), cesium carbonate (261 mg) was added, and the mixture was stirred at room temperature for 30 minutes. Ethyl tosylate (201 mg) was added and the mixture was stirred at room temperature for 1 hour. To the reaction mixture, water was added, and the mixture was extracted twice with ethyl acetate. The combined organic layer was washed once with water and once with brine, sequentially, and then the ethyl acetate layer was dried over anhydrous sodium sulfate. The insoluble was filtered off, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (silica gel cartridge, hexane:ethyl acetate=100:0-50:50) to give (1S,2S,3S,5R,6S)-3′-allyl 6-ethyl 3-fluoro-5′-oxospiro[bicyclo[3.1.0]hexan-2,4′-oxazolidine]-3′,6-dicarboxylate (Reference Example 1-1, 68 mg) as a colorless amorphous.