Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:30]=[CH:29][CH:28]=[CH:27][C:3]=1[C:4]([NH:6][C:7]1[CH:19]=[C:18]([O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:17]=[CH:16][C:8]=1[C:9]([O:11]C(C)(C)C)=[O:10])=[O:5]>FC(F)(F)C(O)=O>[F:1][C:2]1[CH:30]=[CH:29][CH:28]=[CH:27][C:3]=1[C:4]([NH:6][C:7]1[CH:19]=[C:18]([O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:17]=[CH:16][C:8]=1[C:9]([OH:11])=[O:10])=[O:5]
Reactant: CC(C)(C)OC(=O)c1ccc(Oc2ccccc2)cc1NC(=O)c1ccccc1F
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1cc(Oc2ccccc2)ccc1C(=O)O)c1ccccc1F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
10 mL of trifluoroacetic acid was added to the obtained tert-butyl 2-(2-fluorobenzamido)-4-phenoxybenzoate and stirred at room temperature for 2 hours. The solvent was evaporated under reduced pressure and diisopropyl ether was added to the obtained residue and a solid substance was separated by filtration to obtain 30 mg of 2-(2-fluorobenzamido)-4-phenoxybenzoic acid as white solid.
Reaction SMILES: C1O[CH:4]([C:5]2[CH:10]=[CH:9][C:8]([CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=3)=[CH:7][CH:6]=2)[O:3]C1.Cl>O1CCCC1>[Cl:18][C:14]1[CH:13]=[C:12]([CH2:11][C:8]2[CH:7]=[CH:6][C:5]([CH:4]=[O:3])=[CH:10][CH:9]=2)[CH:17]=[CH:16][CH:15]=1
Reactant: Clc1cccc(Cc2ccc(C3OCCO3)cc2)c1
Agent: Cl
Solvent: C1CCOC1
Product: O=Cc1ccc(Cc2cccc(Cl)c2)cc1
Reaction time: 0.25 h
Yield: 100.1 %

Procedure:
To a solution of 4-(3-chlorophenylmethyl)benzaldehyde ethylene acetal (19.9 g) in tetrahydrofuran (80 ml) was added dropwise 10% hydrochloric acid (25.0 ml). After stirring for 15 minutes under ice-cooling, tetrahydrofuran was removed by using a reduced pressure distillation, and the residue was extracted with ethyl acetate. The organic layer was washed with water, saturated aqueous sodium hydrogencarbonate solution and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled away to give the title compound (16.72 g) at a quantitative yield.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](F)[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]=1[CH3:12].C([O-])([O-])=O.[Cs+].[Cs+].[CH3:19][CH:20]([OH:22])[CH3:21]>>[Cl:1][C:2]1[CH:7]=[C:6]([O:22][CH:20]([CH3:21])[CH3:19])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]=1[CH3:12]
Reactant: Cc1cc([N+](=O)[O-])c(F)cc1Cl
Reactant: CC(C)O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: Cc1cc([N+](=O)[O-])c(OC(C)C)cc1Cl

Procedure:
To a solution of 25 g (0.131 mol) of 2-chloro-4-fluoro-5-nitrotoluene in 250 ml of 2-propanol is added 208 g (0.659 mol, 5 eq.) of Cs2CO3. The mixture is stirred at 60° C. overnight and most of the 2-propanol is evaporated under reduced pressure. Water is added and the solution is extracted with EtOAc. The organic layers are combined, dried over MgSO4, concentrated and the crude product filtrated over a silica plug (eluent: 95/5 hexanes/EtOAc) to afford 2-chloro-4-isopropoxy-5-nitrotoluene as a pale yellow fluffy solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH3:14])[C:5]([N+:11]([O-])=O)=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].Cl[Sn]Cl.C([O-])(O)=O.[Na+]>CCOC(C)=O>[NH2:11][C:5]1[C:4]([CH3:14])=[CH:3][C:2]([F:1])=[CH:10][C:6]=1[C:7]([OH:9])=[O:8]
Reactant: Cc1cc(F)cc(C(=O)O)c1[N+](=O)[O-]
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: Cc1cc(F)cc(C(=O)O)c1N
Temperature: 70 °C

Procedure:
A mixture of 5-fluoro-3-methyl-2-nitrobenzoic acid (4.86 g, 24.42 mmol) and SnCl2 (16.5 g, 72.36 mmol) in EtOAc was heated at 70° C. overnight. After cooling at rt, the pH was adjusted to 7-8 with satd. aq. NaHCO3. The mixture was extracted with EtOAc, and the organic layer was washed with brine, filtered through diatomaceous earth, and dried over Na2SO4 to provide the title compound, which was used without further purification. ESI-MS (m/z): 170 [M+1]+.
Reaction SMILES: C[O-].[Na+].[F:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C@@:11]1([CH2:15][N:16]2[CH:20]=[N:19][CH:18]=[N:17]2)[C@H:13]([CH3:14])[O:12]1.C([S:24][C@@H:25]1[CH2:30][O:29][C@@H:28]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[O:27][CH2:26]1)(=O)C>C(O)C>[F:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C@:11]([OH:12])([C@H:13]([S:24][C@@H:25]1[CH2:26][O:27][C@@H:28]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[O:29][CH2:30]1)[CH3:14])[CH2:15][N:16]1[CH:20]=[N:19][CH:18]=[N:17]1
Reactant: CC(=O)S[C@H]1CO[C@H](c2ccccc2)OC1
Reactant: C[C@@H]1O[C@@]1(Cn1cncn1)c1ccccc1F
Agent: C[O-]
Agent: [Na+]
Solvent: CCO
Product: C[C@@H](S[C@H]1CO[C@H](c2ccccc2)OC1)[C@](O)(Cn1cncn1)c1ccccc1F
Temperature: 87 °C
Reaction time: 13 h

Procedure:
0.12 ml (0.59 mmol) of a 4.9 M methanolic solution of sodium methoxide were added to a solution of 0.93 g (4.0 mmol) of (2R,3S)-2-(2-fluorophenyl)-3-methyl-2-[(1H-1,2,4-triazol-1-yl)methyl]oxirane [prepared as described in Chem. Pharm. Bull., 43, 441-449 (1995)] and 1.14 g (4.8 mmol) of trans-5-(acetylthio)-2-phenyl-1,3-dioxane [prepared as described in Japanese Patent Application (Kokai) Hei 8-333350] in 15 ml of ethanol. The resulting mixture was stirred at 87° C. for 13 hours. After cooling, the reaction mixture was partitioned between ethyl acetate and an aqueous ammonium chloride solution. The organic solution was washed with saturated aqueous sodium chloride solution and then concentrated under reduced pressure. The resulting oily residue was purified by chromatography on a silica gel (75 g) column using a 3:2 mixture of ethyl acetate and hexane as the eluant to afford 0.68 g (yield 40%) of the title compound as a non-crystalline solid.
Reaction SMILES: C([O:8][C@H:9]1[C@H:15]([O:16]CC2C=CC=CC=2)[C@@H:14]([O:24]CC2C=CC=CC=2)[C@:13]2([C:33]3[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([CH2:40][C:41]4[CH:42]=[CH:43][C:44]5[O:48][CH2:47][CH2:46][C:45]=5[CH:49]=4)[CH:34]=3)[O:32][C@@:10]1([CH2:50][OH:51])[CH2:11][O:12]2)C1C=CC=CC=1.ClC1C=CC=CC=1Cl>[Pd]>[Cl:39][C:36]1[CH:37]=[CH:38][C:33]([C@@:13]23[O:32][C@@:10]([CH2:50][OH:51])([CH2:11][O:12]2)[C@@H:9]([OH:8])[C@H:15]([OH:16])[C@H:14]3[OH:24])=[CH:34][C:35]=1[CH2:40][C:41]1[CH:42]=[CH:43][C:44]2[O:48][CH2:47][CH2:46][C:45]=2[CH:49]=1
Reactant: OC[C@@]12CO[C@@](c3ccc(Cl)c(Cc4ccc5c(c4)CCO5)c3)(O1)[C@H](OCc1ccccc1)[C@@H](OCc1ccccc1)[C@@H]2OCc1ccccc1
Agent: [Pd]
Solvent: Clc1ccccc1Cl
Product: OC[C@@]12CO[C@@](c3ccc(Cl)c(Cc4ccc5c(c4)CCO5)c3)(O1)[C@H](O)[C@@H](O)[C@@H]2O
Reaction time: 1.5 h
Yield: 95.3 %

Procedure:
[(1S,2S,3S,4R,5S)-2,3,4-tribenzyloxy-5-[4-chloro-3-(2,3-dihydrobenzofuran-5-ylmethyl)phenyl]-6,8-dioxabicyclo[3.2.1]octan-1-yl]methanol 5m (100 mg, 0.14 mmol) was dissolved in 5 mL of mixed solution (THF and MeOH, v:v=1:1), followed by addition of o-dichlorobenzene (208 mg, 1.42 mmol) and Palladium/carbon (10 mg, 10%). The mixture was exchanged with H2 three times and stirred for 1.5 hours, filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by thin layer chromatography with developing solvent system A to obtain the title compound (1S,2S,3S,4R,5S)-5-[4-chloro-3-(2,3-dihydrobenzofuran-5-ylmethyl)phenyl]-1-(hydroxymethyl)-6,8-dioxabicyclo[3.2.1]octane-2,3,4-triol 5 (58 mg, white solid), yield: 93.5%. MS m/z (ESI): 435.1 [M+1]; 1H NMR (400 MHz, CD3OD): δ 7.47 (d, 1H), 7.39-7.35 (m, 2H), 7.04 (s, 1H), 6.93 (d, 1H), 6.62 (d, 1H), 4.50 (t, 2H), 4.17 (d, 1H), 4.03 (s, 2H), 3.88-3.79 (m, 2H), 3.71-3.65 (m, 2H), 3.62-3.56 (m, 2H), 3.15 (t, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:23]#[N:24])[N:5]([CH2:8][CH2:9][CH:10]([N:12]2C(=O)C3C(=CC=CC=3)C2=O)[CH3:11])[C:6]=1[CH3:7].NN>C(O)C>[NH2:12][CH:10]([CH3:11])[CH2:9][CH2:8][N:5]1[C:6]([CH3:7])=[C:2]([Cl:1])[CH:3]=[C:4]1[C:23]#[N:24]
Reactant: Cc1c(Cl)cc(C#N)n1CCC(C)N1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: CCO
Product: Cc1c(Cl)cc(C#N)n1CCC(C)N
Temperature: 25 °C

Procedure:
A solution of 3.2 g (9.4 mmol) of 4-chloro-1-[3-(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)butyl]-5-methyl-1H-pyrrole-2-carbonitrile and 4.8 mL (94 mmol) of hydrazine in ethanol was heated at reflux for 60 min and cooled to room temperature. Precipitated solids were filtered and rinsed with ethyl acetate and the filtrate was concentrated to afford 1-(3-aminobutyl)-4-chloro-5-methyl-1H-pyrrole-2-carbonitrile as an oil.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.[H-].[Na+].[C:14]1([CH2:20][CH2:21][CH2:22]Br)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C1(C)C=CC=CC=1.CN(C=O)C.CCOC(C)=O.O>[C:14]1([CH2:20][CH2:21][CH2:22][O:1][C:2]2[CH:3]=[CH:4][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:10][CH:11]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: COC(=O)c1ccc(O)cc1
Reactant: BrCCCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OCCCc2ccccc2)cc1

Procedure:
To a solution of p-hydroxybenzoic acid, methyl ester (2.0 g, 13.2 mmol) in toluene/DMF (2:1) under argon was added NaH (630 mg, 2.0 eq.). After stirring for 15 minutes 3-phenylpropyl bromide (3.0 ml, 1.5 eq.) was added and the mixture refluxed for 4 hours. The solution was diluted with EtOAc and water. The organic layer was washed with H2O, 5% KHSO4 and brine, then dried over anhydrous MgSO4. Concentration in vacuo gave a yellow oil which solidified upon standing. Recrystallization from hexane/EtOAc gave title compound, a cream colored solid, 1.35 g (38%).
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[C:7]1([CH2:17][CH2:18][C:19](OCC)=[O:20])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9][CH:8]=1.O>CCOCC>[C:7]1([CH2:17][CH2:18][CH2:19][OH:20])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9][CH:8]=1
Reactant: CCOC(=O)CCc1cccc2ccccc12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CCOCC
Product: OCCCc1cccc2ccccc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of LiAlH4 (1.91 g, 50.4 mmol) in anhydrous ether (50 mL) was added dropwise a solution of 8 (11.5 g, 50.4 mmol) in ether (50 mL) over 30 minutes at 0° C. under argon and then the mixture was stirred at room temperature (overnight). The reaction mixture was cooled to 0° C. and quenched by slow (30 minutes addition of H2O (7.2 mL, 0.4 mol), then the mixture was stirred at 0° C. (1 h). Solid was removed by filtration washed with ether, then the combined ether solution was dried (Na2SO4) and taken to dryness, yielding 9 as an oil70 (9.36 g, 100%). 1H NMR (CDCl3) δ 8.08 (1H, dd, J=2.4, 7.4 Hz), 7.88 (1H, m), 7.74 (1H, d, J=7.6 Hz), 7.34˜7.57 (4H, m), 3.76 (2H, t, J=6.4 Hz), 3.20 (2H, t, J=7.5 Hz), 2.05 (2H, m), 1.75 (1H, brs).
Reaction SMILES: [CH3:1]CCCCC.C([Li])CCC.[CH3:12][O:13][C:14]1[CH:15]=[CH:16][C:17]2[O:23][CH2:22][C:21]3[N:24]=[CH:25][CH:26]=[CH:27][C:20]=3[C:19](=O)[C:18]=2[CH:29]=1.[Cl-].[NH4+].C(OCC)(=O)C>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[CH3:12][O:13][C:14]1[CH:15]=[CH:16][C:17]2[O:23][CH2:22][C:21]3[N:24]=[CH:25][CH:26]=[CH:27][C:20]=3[C:19](=[CH2:1])[C:18]=2[CH:29]=1
Reactant: CCCCCC
Reactant: COc1ccc2c(c1)C(=O)c1cccnc1CO2
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C=C1c2cc(OC)ccc2OCc2ncccc21
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To a solution of methyltriphenylphosphonium bromide (2.2 g) in THF (20 ml) was added 1.6M n-butyl lithium hexane solution (2.9 ml) at 0° C. for 30 minutes. To the reaction mixture cooled to 0° C. was added 5,11-dihydro-7-methoxypyrido[2,3-c][1]benzoxepin-5-one (1.0 g) dropwise as THF solution (5 ml), and the mixture was warmed to room temperature, and stirred for 3 hours. Aqueous ammonium chloride and ethyl acetate were added to the reaction mixture, the organic layer was separated and washed with saturated aqueous sodium chloride, and dried with magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography eluting with ethyl acetate-hexane (1:4) to give 5,11-dihydro-7-methoxy-5-methylenepyrido[2,3-c][1]benzoxepine (0.14 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([NH:9][C:10](=[O:14])[O:11][CH2:12][CH3:13])=[C:5]([CH3:15])[CH:4]=1.CC(C)([O-])C.[K+].[CH3:22][C@:23]1([CH2:31][N:32]2[C:36]3[CH:37]=[C:38]([C:41]#[N:42])[CH:39]=[CH:40][C:35]=3[N:34]=[CH:33]2)[CH2:30]CC[C@:25]2(O[CH2:26]2)[CH2:24]1.C([O-])(O)=O.[Na+]>CN1C(=O)CCC1>[CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([N:9]2[CH2:13][C@@:12]3([CH2:26][CH2:25][CH2:24][C@@:23]([CH2:31][N:32]4[C:36]5[CH:37]=[C:38]([C:41]#[N:42])[CH:39]=[CH:40][C:35]=5[N:34]=[CH:33]4)([CH3:22])[CH2:30]3)[O:11][C:10]2=[O:14])=[C:5]([CH3:15])[CH:4]=1
Reactant: CCOC(=O)Nc1cnc(OC)cc1C
Reactant: C[C@]1(Cn2cnc3ccc(C#N)cc32)CCC[C@@]2(CO2)C1
Agent: CC(C)(C)[O-]
Agent: O=C([O-])O
Agent: [K+]
Solvent: CN1CCCC1=O
Product: COc1cc(C)c(N2C[C@@]3(CCC[C@](C)(Cn4cnc5ccc(C#N)cc54)C3)OC2=O)cn1
Temperature: 55 °C
Reaction time: 16 h

Procedure:
A mixture of ethyl (6-methoxy-4-methylpyridin-3-yl)carbamate (0.593 g, 2.82 mmol) and potassium tert-butoxide (0.275 g, 2.452 mmol) in NMP (4.90 mL) was stirred at RT for 5 min before 1-(((3S,5S)-5-methyl-1-oxaspiro[2.5]octan-5-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile (0.69 g, 2.452 mmol) was added. The reaction mixture was stirred at 55° C. for 16 h, then at 70° C. for 2.5 h and then at 85° C. for 16 h. Saturated aq NaHCO3 was added and the mixture was extracted with EtOAc. The organic layer was concentrated and purified via HPLC (Waters, Sunfire C-18 column, OBD, 20-60% MeCN in water (0.1% TFA), 16 min, with at-column dilution, flow rate 45 mL/min). Fractions contained desired products were free based with NaHCO3, extracted with DCM, dried over Na2SO4 and concentrated. The resulted foam was crystallized by stirring with a solution of 1/3 DCM/isopropanol (4 mL total) in an uncapped vial overnight. The resulted cloudy mix was concentrated to ˜2 mL volume and then stirred for 1 h. The resulted light pink solids were collected by filtration and dried on high vacuum for 2 h to yield 1-(((5S,7S)-3-(6-methoxy-4-methylpyridin-3-yl)-7-methyl-2-oxo-1-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile. 1H NMR (400 MHz, CDCl3) δ 8.07 (s, 1H), 8.01 (s, 1H), 7.92 (d, J=8.53 Hz, 1H), 7.78 (s, 1H), 7.59 (dd, J=1.25, 8.28 Hz, 1H), 6.66 (s, 1H), 4.04 (s, 2H), 3.93 (s, 3H), 3.52-3.58 (m, 2H), 2.25 (s, 4H), 2.01 (d, J=13.80 Hz, 2H), 1.63-1.77 (m, 2H), 1.60 (s, 1H), 1.50 (d, J=13.80 Hz, 1H), 1.37-1.42 (m, 4H). MS (m/z) 446.2 (M+H+).
Reaction SMILES: Br[C:2]1[C:7]([Cl:8])=[CH:6][C:5](O)=[C:4]([Cl:10])[CH:3]=1.[Cl:11]C1C=CC(Cl)=CC=1O.ClC1C=C(Cl)C=CC=1O>>[Cl:10][C:4]1[CH:3]=[CH:2][C:7]([Cl:8])=[CH:6][C:5]=1[Cl:11]
Reactant: Oc1cc(Cl)c(Br)cc1Cl
Reactant: Oc1cc(Cl)ccc1Cl
Agent: Oc1ccc(Cl)cc1Cl
Product: Clc1ccc(Cl)c(Cl)c1

Procedure:
A process for the preparation of 4-bromo-2,5-dichlorophenol which comprises reacting a mixture of 2,5-dichlorophenol and 2,4-dichlorophenol obtained by saponifying 1,2,4-trichlorobenzene and distilling 3,4-dichlorophenol from the resulting mixture, with an equimolar amount of bromine in a glacial acetic acid reaction medium at a temperature of about 30° C. and thereafter recovering the 4-bromo-2,5-dichlorophenol.
Reaction SMILES: C(N1C=[C:15]2[C:10]([CH:11]=[C:12]([B:17]3[O:21][C:20]([CH3:23])([CH3:22])[C:19]([CH3:25])([CH3:24])[O:18]3)[CH:13]=[CH:14]2)=N1)C1C=CC=CC=1.BrC1C=C([CH:33]2[CH2:38][CH2:37][N:36]([C:39]([OH:41])=[O:40])[CH2:35][CH2:34]2)C=CC=1>>[C:19]([O:41][C:39]([N:36]1[CH2:35][CH2:34][CH:33]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([B:17]3[O:18][C:19]([CH3:24])([CH3:25])[C:20]([CH3:22])([CH3:23])[O:21]3)[CH:11]=2)[CH2:38][CH2:37]1)=[O:40])([CH3:25])([CH3:24])[CH3:20]
Reactant: O=C(O)N1CCC(c2cccc(Br)c2)CC1
Reactant: CC1(C)OB(c2ccc3cn(Cc4ccccc4)nc3c2)OC1(C)C
Product: CC(C)(C)OC(=O)N1CCC(c2cccc(B3OC(C)(C)C(C)(C)O3)c2)CC1

Procedure:
Using the procedure described for the preparation of Intermediate C, 4-(3-bromo-phenyl)-piperidine-1-carboxylic acid Pert-butyl ester was converted to the title compound. 1H NMR (CD3OD) δ 7.63 (bs, 1H), 7.60 (m, 1H), 7.32 (m, 1H), 7.31 (m, 1H), 4.23 (m, 2H), 2.83-2.62 (m, 3H), 1.80 (m, 2H), 1.62 (ddd, 2H), 1.47 (s, 6H), 1.33 (s, 3H), 1.24 (s, 9H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([NH:8][C:9](OCC2C=CC=CC=2)=O)[CH:5]=[CH:4][C:3]=1[N:19]1[CH2:23][CH2:22][S:21][CH2:20]1.C([Li])CCC.[CH2:29]([O:33][C:34](=[O:38])CCC)[C@@H:30]1[O:32]C1>>[F:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:9][C@H:29]([CH2:30][OH:32])[O:33][C:34]2=[O:38])[CH:5]=[CH:4][C:3]=1[N:19]1[CH2:23][CH2:22][S:21][CH2:20]1
Reactant: CCCC(=O)OC[C@H]1CO1
Reactant: O=C(Nc1ccc(N2CCSC2)c(F)c1)OCc1ccccc1
Agent: [Li]CCCC
Product: O=C1O[C@@H](CO)CN1c1ccc(N2CCSC2)c(F)c1
Yield: 74.8 %

Procedure:
Using the same general procedure as step 3 of example 1, 3-[2-fluoro-4-(benzyloxycarbonyl) aminophenyl]thiazolidine (692 mg, 2.24 mmol) was treated sequentially with n-butyllitium (1.5 mL, 2.40 mmol) and (R)-(-)-glycidylbutyrate (0.33 mL, 2.33 mmol) to provide 500 mg (78%) of the title compound. Recystallization from methylene chloride/hexane provided an analytical sample with a melting point of 96°97° C.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7][C:6]1=[O:15].C([O-])([O-])=O.[K+].[K+].[CH2:22]([CH:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)[CH2:23][CH2:24][CH3:25].CC#N>CCOC(C)=O>[CH2:22]([CH:26]1[CH2:31][CH2:30][N:29]([CH2:2][CH2:3][CH2:4][N:5]2[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH:8]=[CH:7][C:6]2=[O:15])[CH2:28][CH2:27]1)[CH2:23][CH2:24][CH3:25]
Reactant: O=c1ccc2ccccc2n1CCCCl
Reactant: CCCCC1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CCCCC1CCN(CCCn2c(=O)ccc3ccccc32)CC1
Temperature: 50 °C
Reaction time: 60 h
Yield: 49 %

Procedure:
A 7 mL vial was charged with 1-(3-chloropropyl)-1H-quinolin-2-one (0.450 g, 2.0 mmol), K2CO3 (0.34 g, 2.5 mmol), KI (0.42 g, 2.5 mmol), 4-butylpiperidine (0.30 g, 2.1 mmol) and dry CH3CN (3 mL). The mixture was shaken at 50° C. for 60 h and thereafter diluted with EtOAc (50 mL) and washed with water (50 mL). The water phase was extracted with EtOAc (2×50 mL). The combined organic phase was dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash CC (SiO2; EtOAc/MeOH 4:1) followed by prep RP-HPLC to give the title compound (0.32 g, 49%). 1H NMR (CD3OD) δ 7.88 (d, J=9.6 Hz), 7.68 (brd, J=8.0 Hz), 7.65-7.61 (m, 2H), 7.33-7.25 (m, 1H), 6.64 (d, 9.6 Hz), 4.39-4.32 (m, 2H), 2.95-2.86 (m, 2H), 2.50-2.43 (m, 2H), 2.01-1.86 (m, 4H), 1.71-1.62 (m, 2H), 1.35-1.12 (m, 9H), 0.89 (t, J=6.6 Hz); 13C NMR (CD3OD) δ 163.1, 140.4, 139.0, 131.1, 129.2, 122.6, 121.4, 120.3, 114.7, 55.8, 53.9, 40.6, 36.2, 35.7, 32.0, 28.9, 24.7, 22.8, 13.2.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:15]=[C:14]2[C:9]([CH:10]=[CH:11][C:12](=[O:16])[NH:13]2)=[CH:8][CH:7]=1.[Na+].[I-].[Cl:19][C:20]1[C:25]([Cl:26])=[CH:24][CH:23]=[CH:22][C:21]=1[N:27]1[CH2:33][CH2:32][CH2:31][N:30](CCCCOC2C=C3C(CCC(=O)N3)=CC=2)[CH2:29][CH2:28]1.C([O-])([O-])=O.[K+].[K+]>CC#N.O>[Cl:19][C:20]1[C:25]([Cl:26])=[CH:24][CH:23]=[CH:22][C:21]=1[N:27]1[CH2:33][CH2:32][CH2:31][N:30]([CH2:2][CH2:3][CH2:4][O:5][C:6]2[CH:15]=[C:14]3[C:9]([CH:10]=[CH:11][C:12](=[O:16])[NH:13]3)=[CH:8][CH:7]=2)[CH2:29][CH2:28]1
Reactant: O=c1ccc2ccc(OCCCBr)cc2[nH]1
Reactant: O=C1CCc2ccc(OCCCCN3CCCN(c4cccc(Cl)c4Cl)CC3)cc2N1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: O=c1ccc2ccc(OCCCN3CCCN(c4cccc(Cl)c4Cl)CC3)cc2[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 39.3 %

Procedure:
A mixture of intermediate 32 (217 mg, 0.77 mmol) and NaI (231 mg, 1.54 mmol) in CH3CN was heated to reflux for 30 min and then cooled to rt. Intermediate 2 (217 mg, 0.77 mmol) and anhydrous K2CO3 (425 mg, 3.08 mmol) were added to the mixture. The resulting mixture was heated to reflux and stirred overnight. The reaction solution was diluted with water and extracted with EtOAc. The combined EtOAc layers were washed with brine, dried over anhydrous Na2SO4, concentrated in vacuo and purified by flash chromatography on silica gel column (elution with DCM/MeOH=30:1) to give 7-(3-(4-(2,3-dichlorophenyl)-1,4-diazepan-1-yl)propoxy)quinolin-2(1H)-one (compound 15) (135 mg, 39%). 1H NMR (300 MHz, CDCl3) δ 11.96 (bs., 1H), 7.72 (d, J=9.3 Hz, 1H) 7.45 (d, J=8.7 Hz, 1H), 7.09-7.07 (m, 2H), 7.01-6.99 (m, 1H), 6.83-6.81 (m, 2H), 6.54 (d, J=9.0 Hz, 1H), 4.15 (t, J=5.7 Hz, 2H), 3.31 (d, J=5.1 Hz, 4H), 2.92-2.96 (m, 4H), 2.76 (t, J=6.6 Hz, 2H), 2.03-1.01 (m, 4H). HPLC: 99%, RT 2.348 min. MS (ESI) m/z 446.1 [M+H]+. mp: 117-118° C.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11](=[O:14])[C:10]([CH2:19][CH3:20])(C(OC)=O)[CH2:9]1)=O)(C)(C)C.[ClH:21]>>[ClH:21].[CH2:19]([CH:10]1[C:11](=[O:14])[CH2:12][CH2:13][NH:8][CH2:9]1)[CH3:20]
Reactant: CCC1(C(=O)OC)CN(C(=O)OC(C)(C)C)CCC1=O
Agent: Cl
Product: CCC1CNCCC1=O
Yield: 55 %

Procedure:
A mixture of 28.2 gm (98.8 mMol) methyl 1-tert-butoxycarbonyl-4-oxo-3-ethyl-3-piperidinecarboxylate and 6N hydrochloric acid was heated at reflux for about 16 hours. The reaction mixture was concentrated under reduced pressure and the residue dissolved in ethanol. This solution was concentrated under reduced pressure to azeotropically remove water. This procedure was repeated twice to provide 7.0 gm (55%) of the desired compound.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][C:3]=1[CH2:4][NH2:5].[CH3:11][O:12][CH:13]([O:18][CH3:19])[C:14](OC)=[O:15]>CCCCCCC>[Cl:10][C:7]1[CH:8]=[CH:9][C:2]([F:1])=[C:3]([CH:6]=1)[CH2:4][NH:5][C:14](=[O:15])[CH:13]([O:18][CH3:19])[O:12][CH3:11]
Reactant: COC(=O)C(OC)OC
Reactant: NCc1cc(Cl)ccc1F
Solvent: CCCCCCC
Product: COC(OC)C(=O)NCc1cc(Cl)ccc1F
Temperature: 25 °C

Procedure:
Equimolar amounts of 2-fluoro-5-chlorobenzylamine (10.0 g, 62.5 mmol) and methyl dimethoxyacetate (8.38 g, 62.5 mmol) were heated in a sealed tube at 100° C. for 16 h. After cooling to RT, to the reaction mixture was added n-heptane (40 mL) and cooled at 4° C. overnight. The solid formed was filtered off and dried in vacuo to give the title compound as off-white solid. 1H NMR (CDCl3, 300 MHz): δ=3.40 (s, 6H), 4.52 (d, J=5.8 Hz, 2H), 4.74 (s, 1H), 6.89 (bs, 1H), 7.01 (t, J=8.4 Hz, 1H), 7.20-7.25 (m, 1H), 7.31-7.36 (m, 1H). MS (ES+): m/z 261.90/263.78 [MH+]. HPLC: tR=2.85 min (ZQ2, polar—5 min).
Reaction SMILES: [Mg].BrCCBr.Br[C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[C:9]([O:15][CH:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)[CH:8]=1.[S:21]1[CH2:25][CH2:24][C:23](=[O:26])[CH2:22]1.[Cl-].[NH4+]>O1CCCC1>[CH:16]1([O:15][C:9]2[CH:8]=[C:7]([C:23]3([OH:26])[CH2:24][CH2:25][S:21][CH2:22]3)[CH:12]=[CH:11][C:10]=2[O:13][CH3:14])[CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: O=C1CCSC1
Reactant: COc1ccc(Br)cc1OC1CCCC1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: BrCCBr
Product: COc1ccc(C2(O)CCSC2)cc1OC1CCCC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A stirring suspension of magnesium turnings (3.45 g) in dry tetrahydrofuran (60 mL) is treated with 1,2-dibromoethane (0.8 mL), and the mixture is stirred under a nitrogen atmosphere for 30 minutes. It is then treated dropwise with a solution of 4-bromo-2-cyclopentyloxyanisole (25 g); which is prepared as described in Reference Example 4 in tetrahydrofuran (20 mL), and the resulting solution is heated at reflux for 30 minutes. The solution is then cooled to room temperature and treated with a solution of tetrahydrothiophen-3-one (6.9 mL) in tetrahydrofuran (20 mL), and allowed to stand for 16 hours. It is then treated with saturated aqueous ammonium chloride solution (50 mL), and the mixture is partitioned between water (100 mL) and dichloromethane (100 mL). The aqueous phase is further extracted with dichloromethane (100 mL). The combined organic phases are dried over magnesium sulphate and evaporated. The resulting residue is subjected to flash chromatography on silica gel, using a mixture of ethyl acetate and toluene as eluent to give 3-(3-cyclopentyloxy-4-methoxyphenyl)-3-hydroxytetrahydrothiophene, in the form of a viscous oil.