Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH:3]([C:14]1[C:15]([CH3:31])=[C:16]([NH:20][C:21](=[O:30])[O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:17]=[CH:18][CH:19]=1)[C:4]1[C:12]2[C:7](=[CH:8][C:9]([Br:13])=[CH:10][CH:11]=2)[NH:6][CH:5]=1.O=[CH:33][C:34]([O:36][CH2:37][CH3:38])=[O:35].C1(C)C=CC=CC=1.Cl.O1CCOCC1>O1CCCC1>[CH2:23]([O:22][C:21]([NH:20][C:16]1[C:15]([CH3:31])=[C:14]([C:3]2[C:4]3[C:12]4[C:7](=[CH:8][C:9]([Br:13])=[CH:10][CH:11]=4)[NH:6][C:5]=3[C:33]([C:34]([O:36][CH2:37][CH3:38])=[O:35])=[N:1][CH:2]=2)[CH:19]=[CH:18][CH:17]=1)=[O:30])[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: CCOC(=O)C=O
Reactant: Cc1c(NC(=O)OCc2ccccc2)cccc1C(CN)c1c[nH]c2cc(Br)ccc12
Agent: Cl
Solvent: C1COCCO1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CCOC(=O)c1ncc(-c2cccc(NC(=O)OCc3ccccc3)c2C)c2c1[nH]c1cc(Br)ccc12
Temperature: 25 °C
Reaction time: 24 h
Yield: 36 %

Procedure:
To a mixture of benzyl 3-(2-amino-1-(6-bromo-1H-indol-3-yl)ethyl)-2-methylphenylcarbamate (2.320 g, 4.85 mmol) and 4 angstrom molecular sieves (powder, activated, <5 mesh, 1.80 g) in tetrahydrofuran (100 mL) at room temperature was added ethyl 2-oxoacetate in toluene (1.923 mL, 9.70 mmol), followed by hydrogen chloride in 1,4-dioxane (1.334 mL, 5.33 mmol). The mixture was stirred at room temperature for 24 h. The solid phase was removed by suction filtration through CELITE®, and the filtrate was concentrated under vacuum. The residue was diluted with water (60 mL), basified with saturated NaHCO3 solution, and extracted with ethyl acetate (3×80 mL). The combined extract was washed with brine (60 mL) and dried over anhydrous MgSO4. The solvent was removed under vacuum. To the residue was added p-xylene (200 mL) and 10% Pd/C (1.5 g), and the mixture was heated under atmosphere at 125° C. for 16 hr. The solid phase was removed by suction filtration through CELITE®. The filtrate was concentrated under vacuum, and the residue was purified by ISCO (220 g silica gel, solid loading, 20-50% ethyl acetate/hexane) to provide the desired product (0.977 g, 36% yield) as a beige solid.
Reaction SMILES: [CH:1]([C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=1)=[O:2].[CH3:13][C:14](=[N:18]O)[C:15](=O)[CH3:16].[ClH:20].C(OCC)(=O)C>>[Cl:20][CH2:13][C:14]1[N:18]=[C:1]([C:3]2[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=2)[O:2][C:15]=1[CH3:16]
Reactant: CC(=O)C(C)=NO
Reactant: Cl
Reactant: COC(=O)c1ccc(C=O)cc1
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(-c2nc(CCl)c(C)o2)cc1
Temperature: 25 °C
Reaction time: 96 h
Yield: 42 %

Procedure:
A mixture of methyl 4-formylbenzoate (1.63 g), 2,3-butanedione-2-oxime (1.0 g) and 4N hydrogenchloride-ethyl acetate solution (10 mL) was stirred at room temperature for 4 days. After concentration of the reaction mixture, the obtained crystals were washed with diethyl ether. Tetrahydrofuran (30 mL) was added to the crystals, and thionyl chloride (1.90 g) was further added. The mixture was heated under reflux for 3 hrs. After concentration of the reaction mixture, saturated aqueous sodium hydrogen carbonate was added to the residue, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to give methyl 4-(4-chloromethyl-5-methyl-1,3-oxazol-2-yl)benzoate as colorless crystals (1.10 g, 42%) from a fraction eluted with ethyl acetate-hexane (1:3, v/v). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 130-131° C.
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]([N+:10]([O-:12])=[O:11])=[C:6]([CH:9]=1)[CH:7]=[O:8].[C:13]1([OH:19])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CCOC(C)=O.CCCCCC>[N+:10]([C:5]1[CH:4]=[CH:3][C:2]([O:19][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:9][C:6]=1[CH:7]=[O:8])([O-:12])=[O:11]
Reactant: O=Cc1cc(F)ccc1[N+](=O)[O-]
Reactant: Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: O=Cc1cc(Oc2ccccc2)ccc1[N+](=O)[O-]
Temperature: 120 °C

Procedure:
A mixture of 5-fluoro-2-nitrobenzaldehyde (15.00 g, 0.089 mol), phenol (9.12 g, 0.098 mol), and K2CO3 (13.5 g, 0.089 mol) in 200 mL of DMF was heated at 120° C. for 50 min. The reaction mixture was cooled and concentrated in vacuo. To the residue was added EtOAc (500 mL) and H2O (500 mL). The layers were separated, and the EtOAc extract was concentrated. The residue was purified on silica gel using 20% EtOAc-hexane as eluent. The product containing fractions were combined and concentrated to yield a yellow oil which solidified on standing. This material was dissolved in a minimal quantity of EtOAc and hexane, and the resulting solution was cooled in a dry ice acetone bath. Filtration yielded 2-nitro-5-phenoxy-benzaldehyde as a light yellow solid. The filtrate was concentrated in vacuo to yield additional 2-nitro-5-phenoxy-benzaldehyde.
Reaction SMILES: C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C.[CH:30]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=1)=[CH2:31].Br[C:39]1[CH:40]=[CH:41][C:42]2[C:43]3[N:52]([CH2:53][CH2:54][CH2:55][O:56][CH3:57])[C:51]([CH2:58][O:59][CH2:60][CH3:61])=[N:50][C:44]=3[C:45]([NH2:49])=[N:46][C:47]=2[CH:48]=1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(C)C=CC=CC=1>[CH2:60]([O:59][CH2:58][C:51]1[N:52]([CH2:53][CH2:54][CH2:55][O:56][CH3:57])[C:43]2[C:42]3[CH:41]=[CH:40][C:39](/[CH:31]=[CH:30]/[C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=4)=[CH:48][C:47]=3[N:46]=[C:45]([NH2:49])[C:44]=2[N:50]=1)[CH3:61]
Reactant: C=Cc1ccccn1
Reactant: CCOCc1nc2c(N)nc3cc(Br)ccc3c2n1CCCOC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCOCc1nc2c(N)nc3cc(/C=C/c4ccccn4)ccc3c2n1CCCOC
Temperature: 120 °C

Procedure:
A thick walled glass tube, equipped with magnetic stir-bar, was charged with toluene (20 mL/g), palladium (II) acetate (0.1 equivalents), tri-ortho-tolylphosphine (0.3 equivalents), triethylamine (3.0 equivalents), 2-vinylpyridine (1.0 equivalent), and 7-bromo-2-ethoxymethyl-1-(3-methoxypropyl)-1H-imidazo[4,5-c]quinolin-4-amine (1.0 eq.). The tube was purged with nitrogen and sealed. The reaction mixture was heated at 120° C. for 24–48 hours. The reaction mixture was allowed to cool and then concentrated under reduced pressure. The solid residue was partitioned between dichloromethane and water, and the mixture was adjusted to pH 12 with the addition of 10% aqueous sodium hydroxide. The organic layer was separated and purified by flash chromatography on silica gel (eluting with chloroform:methanol in a gradient from 100:0 to 90:10) followed by recrystallization from acetonitrile to provide (E)-2-ethoxymethyl-1-(3-methoxypropyl)-7-(2-pyridin-2-ylvinyl)-1H-imidazo[4,5-c]quinolin-4-amine as an off-white solid.
Reaction SMILES: C(OC([NH:11][C@H:12]1[CH2:17][CH2:16][C@@H:15]([NH:18][C:19](=O)OC(C)(C)C)[CH2:14][C@H:13]1[C:26]1[O:30][N:29]=[C:28]([CH3:31])[N:27]=1)=O)C1C=CC=CC=1.Br.[CH3:33][C:34](O)=O.[CH3:37]COCC>>[CH:34]([N:18]([CH3:19])[C@@H:15]1[CH2:16][CH2:17][C@H:12]([NH2:11])[C@H:13]([C:26]2[O:30][N:29]=[C:28]([CH3:31])[N:27]=2)[CH2:14]1)([CH3:33])[CH3:37]
Reactant: CCOCC
Reactant: CC(=O)O
Reactant: Cc1noc([C@@H]2C[C@H](NC(=O)OC(C)(C)C)CC[C@@H]2NC(=O)OCc2ccccc2)n1
Agent: Br
Product: Cc1noc([C@@H]2C[C@H](N(C)C(C)C)CC[C@@H]2N)n1
Temperature: 25 °C
Reaction time: 0.42 h

Procedure:
The entirety of benzyl (1S,2R,4R)-4-(isopropyl(methyl)amino)-2-(3-methyl-1,2,4-oxadiazol-5-yl)cyclohexylcarbamate prepared in Step 2 (270 mg, 0.7 mmol) was charged with 30% HBr/AcOH (5 mL). The reaction vessel warms and a vigorous gas evolution occurs. The mixture was stirred for 25 min at RT and then the flask was placed in a cool water bath before the addition of 20 mL of Et2O. The resulting solid was collected, washed with Et2O twice, and concentrated in vacuo to give (1R,3R,4S)-N1-isopropyl-N1-methyl-3-(3-methyl-1,2,4-oxadiazol-5-yl)cyclohexane-1,4-diamine (250 mg). MS found: (M+H)+=253.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][C:12]=2[C:14]([N:16]2[CH2:20][C@@H:19]([CH:21]3[CH2:23][CH2:22]3)[C@H:18]([CH2:24][N:25]3[CH2:30][CH2:29][CH:28]([C:31]4[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=4)[CH2:27][CH2:26]3)[CH2:17]2)=[O:15])[CH:7]=[CH:6]1.C(N(CC)CC)C.[CH3:45][C:46](OCC1C2C(=CC=CC=2)C(COC(C)=O)=C2C=1C=CC=C2)=[O:47]>C(Cl)Cl>[C:46]([NH:1][CH2:2][CH2:3][CH2:4][N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][C:12]=2[C:14]([N:16]2[CH2:20][C@@H:19]([CH:21]3[CH2:23][CH2:22]3)[C@H:18]([CH2:24][N:25]3[CH2:30][CH2:29][CH:28]([C:31]4[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=4)[CH2:27][CH2:26]3)[CH2:17]2)=[O:15])[CH:7]=[CH:6]1)(=[O:47])[CH3:45]
Reactant: NCCCn1ccc2cccc(C(=O)N3C[C@@H](CN4CCC(c5ccc(F)cc5)CC4)[C@H](C4CC4)C3)c21
Reactant: CC(=O)OCc1c2ccccc2c(COC(C)=O)c2ccccc12
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)NCCCn1ccc2cccc(C(=O)N3C[C@@H](CN4CCC(c5ccc(F)cc5)CC4)[C@H](C4CC4)C3)c21
Yield: 78 %

Procedure:
A solution of 0.02 g (0.04 mmol) of 1-(N-(3-aminopropyl)-7-indolecarbonyl)-3-(R)-(4-(4-fluorophenyl)piperidinylmethyl)-4-(S)-(cyclopropyl)pyrrolidine, 0.025 mL (0.18 mmol) of triethylamine and 0.015 mL (0.16 mmol) of acetic anydride in 2 mL of CH2Cl2 was stirred for 12 h at rt. The reaction mixture was partitioned between EtOAc and water. The organic fractions were washed with sat'd NaCl solution, dried over MgSO4, filtered and the filtrate was concentrated. The residue was purified by chromatography (silica, acetone:hexanes, 1:1) to give 17 mg of the title compound. Mass Spectrum (EI) m/e 545 (M+1).
Reaction SMILES: C=O.[Cl:3][C:4]1[C:5]([C:50]([F:53])([F:52])[F:51])=[CH:6][C:7]2[N:11]=[C:10]([CH2:12][CH2:13][CH2:14][CH2:15][NH:16][CH2:17][C@@H:18]3[C@H:22]4[O:23][C:24]([CH3:27])([CH3:26])[O:25][C@H:21]4[C@H:20]([N:28]4[C:32]5[N:33]=[CH:34][N:35]=[C:36]([NH:37][CH:38]6[CH2:40][CH2:39]6)[C:31]=5[CH:30]=[CH:29]4)[CH2:19]3)[N:9]([CH2:41][O:42][CH2:43][CH2:44][Si:45]([CH3:48])([CH3:47])[CH3:46])[C:8]=2[CH:49]=1.[BH3-][C:55]#N.[Na+]>CO.C1COCC1>[Cl:3][C:4]1[C:5]([C:50]([F:53])([F:51])[F:52])=[CH:6][C:7]2[N:11]=[C:10]([CH2:12][CH2:13][CH2:14][CH2:15][N:16]([CH2:17][C@@H:18]3[C@H:22]4[O:23][C:24]([CH3:27])([CH3:26])[O:25][C@H:21]4[C@H:20]([N:28]4[C:32]5[N:33]=[CH:34][N:35]=[C:36]([NH:37][CH:38]6[CH2:39][CH2:40]6)[C:31]=5[CH:30]=[CH:29]4)[CH2:19]3)[CH3:55])[N:9]([CH2:41][O:42][CH2:43][CH2:44][Si:45]([CH3:48])([CH3:47])[CH3:46])[C:8]=2[CH:49]=1
Reactant: [BH3-]C#N
Reactant: CC1(C)O[C@@H]2[C@@H](CNCCCCc3nc4cc(C(F)(F)F)c(Cl)cc4n3COCC[Si](C)(C)C)C[C@@H](n3ccc4c(NC5CC5)ncnc43)[C@@H]2O1
Agent: C=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CN(CCCCc1nc2cc(C(F)(F)F)c(Cl)cc2n1COCC[Si](C)(C)C)C[C@H]1C[C@@H](n2ccc3c(NC4CC4)ncnc32)[C@@H]2OC(C)(C)O[C@H]12
Reaction time: 1 h
Yield: 62 %

Procedure:
37% aq. Formaldehyde (54.07 uL, 0.722 mmol, 2 eq) was added to a solution of 7-[(3aS,4R,6R,6aR)-6-[({4-[6-chloro-5-(trifluoromethyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-1,3-benzodiazol-2-yl]butyl}amino)methyl]-2,2-dimethyl-hexahydrocyclopenta[d][1,3]dioxol-4-yl]-N-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (270 mg, 0.361 mmol, 1 eq) in MeOH:THF (1:1, 10 ml) at RT and stirred. NaCNBH3 was then added portionwise and continued stirring for 1 h. LCMS at 1 hr showed the reaction to be complete. The solvent was then removed in vacuo. The residue was dissolved in DCM (30 ml) and washed with water (30 ml) before drying over Na2SO4, filtering and evaporated. Purification by preparative TLC, eluting three times with MeOH:DCM (6:94) gave the desired product as a colorless oil (200 mg, 62%): MS (ESI+) for C37H51ClF3N7O3Si m/z 762.30 [M+H]+; HPLC purity 86% (ret. time, 1.75 min).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:22]#[N:23])=[CH:4][C:5]2[N:9]=[C:8]([CH2:10][CH3:11])[N:7]([C:12]3[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][OH:20])=[CH:14][CH:13]=3)[C:6]=2[CH:21]=1.CS(C)=[O:26].OO>[OH-].[Na+].CO>[Cl:1][C:2]1[C:3]([C:22]([NH2:23])=[O:26])=[CH:4][C:5]2[N:9]=[C:8]([CH2:10][CH3:11])[N:7]([C:12]3[CH:13]=[CH:14][C:15]([CH2:18][CH2:19][OH:20])=[CH:16][CH:17]=3)[C:6]=2[CH:21]=1
Reactant: CS(C)=O
Reactant: CCc1nc2cc(C#N)c(Cl)cc2n1-c1ccc(CCO)cc1
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCc1nc2cc(C(N)=O)c(Cl)cc2n1-c1ccc(CCO)cc1
Temperature: 50 °C
Reaction time: 2 h
Yield: 74.7 %

Procedure:
To a mixture of 6-chloro-2-ethyl-1-[4-(2-hydroxyethyl)phenyl]-1H-benzimidazole-5-carbonitrile (step 4, 2.4 g, 7.4 mmol), DMSO (0.7 mL, 8.8 mmol) and methanol (100 mL) was added 30% aqueous hydrogen peroxide (1.3 mL, 11 mmol) and 0.2 M aqueous NaOH (0.7 mL, 0.14 mmol). The mixture was stirred at 50° C. for 2 h. The solvent was removed and the resulting precipitates were collected by filtration. The precipitates were washed with water and dried under reduced pressure to give 1.9 g (76%) of the title compound as pale pink solids: 1H-NMR (DMSO-d6) δ 7.69 (1H, br.s), 7.61 (1H, s), 7.33-7.40 (4H, m), 6.95 (1H, s), 4.64 (1H, br.s), 3.59 (2H, t, J=6.4 Hz), 2.74 (2H, t, J=6.4 Hz), 2.62 (2H, q, J=7.4 Hz), 1.11 (3H, t, J=7.4 Hz).
Reaction SMILES: [CH2:1]([S:3][C:4]([CH3:14])([CH3:13])[C:5]([CH2:7][C:8]([O:10]CC)=O)=[O:6])[CH3:2].[CH2:15]([O:33][C:34]1[CH:40]=[CH:39][CH:38]=[CH:37][C:35]=1[NH2:36])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]>>[CH2:15]([O:33][C:34]1[CH:40]=[CH:39][CH:38]=[CH:37][C:35]=1[NH:36][C:8](=[O:10])[CH2:7][C:5](=[O:6])[C:4]([S:3][CH2:1][CH3:2])([CH3:13])[CH3:14])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]
Reactant: CCCCCCCCCCCCCCCCCCOc1ccccc1N
Reactant: CCOC(=O)CC(=O)C(C)(C)SCC
Product: CCCCCCCCCCCCCCCCCCOc1ccccc1NC(=O)CC(=O)C(C)(C)SCC
Temperature: 150 °C
Reaction time: 4 h
Yield: 85 %

Procedure:
A mixture of 21.8 g of ethyl (2-ethylthio-2-methylpropionyl)acetate obtained in Step 1 of Synthesis Example 1 and 36.1 g of 2-octadecyloxyaniline was stirred in an oil bath at 150° C for 4 hours under a reduced pressure of 50 to 100 mmHg. The reaction mixture was recrystallized from ethanol to obtain 45.3 g (yield 85%) of Coupler (10) having a melting point of 60° to 62° C.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([OH:8])=[O:7].[N+](=[CH2:11])=[N-].C(O)(=O)C>C(OCC)C>[CH3:11][O:7][C:6]([C:2]1[NH:1][CH:5]=[CH:4][CH:3]=1)=[O:8]
Reactant: O=C(O)c1ccc[nH]1
Reactant: C=[N+]=[N-]
Solvent: CCOCC
Solvent: CC(=O)O
Product: COC(=O)c1ccc[nH]1
Yield: 88.8 %

Procedure:
Pyrrole-2-carboxylic acid (10.0 g, 90.0 mmol) in diethyl ether (200 mL) was treated with diazomethane (270 mmol, generated from N-nitroso-N-methyl urea), then back titrated with acetic acid until the yellow color dissipated. The solution was washed with saturated aqueous sodium bicarbonate (3×20 mL), followed by brine (3×20 mL), then was evaporated to obtain 10 g (88%) of product. 1H NMR (CDCl3) δ 3.86 (s, 3H), 6.26-6.29 (m, 1H), 6.91-6.94 (m, 1H), 6.65-6.98 (m, 1H), 9.14 (s, 1H).
Reaction SMILES: C([Li])CCC.[C:6](#[N:8])[CH3:7].[CH2:9]([O:16][C:17]([NH:19][CH:20]1[CH2:29][C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22](=[O:30])[CH2:21]1)=[O:18])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.Cl>CCCCCC.O1CCCC1.C(OCC)C>[CH2:9]([O:16][C:17]([NH:19][CH:20]1[CH2:29][C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22]([CH2:7][C:6]#[N:8])([OH:30])[CH2:21]1)=[O:18])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CC#N
Reactant: O=C(NC1CC(=O)c2ccccc2C1)OCc1ccccc1
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Solvent: C1CCOC1
Product: N#CCC1(O)CC(NC(=O)OCc2ccccc2)Cc2ccccc21
Temperature: -80 °C
Reaction time: 1 h

Procedure:
To a stirred solution of n-butyllithium in hexane (42 mL, 1.6 M) under nitrogen at −80° C., was added dry tetrahydrofuran (40 mL). To this was added over a 7 min period a solution of dry acetonitrile (2.8 g, distilled from phosphorus pentoxide) in dry tetrahydrofuran (40 mL). The resulting white suspension was stirred for 1 h at −80° C. After this time, a solution of 3-benzyloxycarbonylamino-1-oxo-1,2,3,4-tetrahydronaphthalene (9.9 g) in dry tetrahydrofuran (40 mL) was added over a 5 min period. Additional tetrahydrofuran (40 mL) was introduced to facilitate stirring. After an additional 10 min at −80° C., the reaction mixture was allowed to slowly warm to room temperature during a 15 min period. Once at room temperature, the reaction mixture was poured into a mixture of ice, concentrated aqueous hydrochloric acid solution (10 mL), and diethyl ether (100 mL). The organic layer was separated, and the aqueous layer was extracted with diethyl ether (50 mL twice). The combined organic layers were washed with water (50 mL twice), dried, and evaporated to yield a residue. The residue was chromatographed on silica gel to obtain the title compound as a mixture of diastereomers (7.5 g).
Reaction SMILES: [F:1][C:2]1[CH:16]=[C:15](F)[C:14]([F:18])=[CH:13][C:3]=1[C:4]([NH:6][C@@H:7]([CH3:12])[C:8]([F:11])([F:10])[F:9])=[O:5].Cl.[NH:20]1[CH2:23][CH:22]([OH:24])[CH2:21]1.N12CCCN=C1CCCCC2>C(#N)C.CCOC(C)=O>[F:1][C:2]1[CH:16]=[C:15]([N:20]2[CH2:23][CH:22]([OH:24])[CH2:21]2)[C:14]([F:18])=[CH:13][C:3]=1[C:4]([NH:6][C@@H:7]([CH3:12])[C:8]([F:11])([F:10])[F:9])=[O:5]
Reactant: OC1CNC1
Reactant: C[C@H](NC(=O)c1cc(F)c(F)cc1F)C(F)(F)F
Agent: Cl
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: C1CCC2=NCCCN2CC1
Product: C[C@H](NC(=O)c1cc(F)c(N2CC(O)C2)cc1F)C(F)(F)F
Temperature: 80 °C
Reaction time: 2 h
Yield: 99.2 %

Procedure:
A mixture of 2,4,5-trifluoro-N-[(1S)-2,2,2-trifluoro-1-methylethyl]benzamide (6.39 g, 23.6 mmol), azetidin-3-ol hydrochloride (3.19 g, 28.3 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (8.81 mL, 58.9 mmol) in acetonitrile (25 mL) was stirred at 80° C. for 2 h. The reaction mixture was diluted with EtOAc (75 mL) and washed with 1N HCl (50 mL), 1N NaHCO3 (60 mL), 20% brine (50 mL) and water (75 mL). The aqueous layers were extracted with EtOAc (100 mL). The organic layers were combined, dried over MgSO4, filtered and concentrated under reduced pressure to yield the desired product (7.59 g, 91.8%). 1H NMR (300 MHz, DMSO-d6) δ 8.38 (dd, J=8.9, 1.9 Hz, 1H), 7.27 (dd, J=12.8, 6.5 Hz, 1H), 6.38 (dd, J=12.3, 7.5 Hz, 1H), 5.71 (d, J=6.4 Hz, 1H), 4.74 (dp, J=15.3, 7.6 Hz, 1H), 4.62-4.46 (m, 1H), 4.30-4.15 (m, 2H), 3.71 (m, 2H), 1.29 (d, J=7.1 Hz, 3H) ppm. LCMS cacld. for C13H14F5N2O2 (M+1)+: m/z=325.1. Found: 325.1.
Reaction SMILES: C[O:2][C:3](=[O:35])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][N:11]2[C:19]3[C:14](=[CH:15][C:16]([F:20])=[CH:17][CH:18]=3)[C@:13]3([CH2:22][C@:21]3([C:26]3[CH:31]=[CH:30][C:29]([C:32]#[N:33])=[CH:28][CH:27]=3)[CH:23]([CH3:25])[CH3:24])[C:12]2=[O:34])[CH:5]=1.[OH-].[Na+].Cl>O1CCCC1.O.C(OCC)(=O)C>[C:32]([C:29]1[CH:28]=[CH:27][C:26]([C@@:21]2([CH:23]([CH3:25])[CH3:24])[C@@:13]3([C:14]4[C:19](=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=4)[N:11]([CH2:10][C:6]4[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=4)[C:3]([OH:35])=[O:2])[C:12]3=[O:34])[CH2:22]2)=[CH:31][CH:30]=1)#[N:33]
Reactant: COC(=O)c1cccc(CN2C(=O)[C@@]3(C[C@]3(c3ccc(C#N)cc3)C(C)C)c3cc(F)ccc32)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)[C@@]1(c2ccc(C#N)cc2)C[C@@]12C(=O)N(Cc1cccc(C(=O)O)c1)c1ccc(F)cc12
Reaction time: 16 h
Yield: 54 %

Procedure:
To a solution of (1S,2S) and (1R,2R)-methyl-3-((2-(4-cyanophenyl)-5′-fluoro-2-isopropyl-2′-oxospiro[cyclopropane-1,3′-indoline]-1′-yl)methyl)benzoate (500 mg, 1.1 mmol) in tetrahydrofuran (10 mL) was added 30% sodium hydroxide in water (3 mL) at room temperature and the mixture was stirred at that temperature for 16 hours. The mixture was neutralized with 2 N aqueous hydrochloric acid solution, diluted with ethyl acetate (50 mL), washed with water, dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification by waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% trifluoro-acetic acid in water) afforded the title compound (270 mg, 59.5%) as a white solid: LC/MS m/e calcd. for C28H23FN2O3: 454, observed (M+H)+: 455.2 1H NMR (400 MHz, MeOD-d4) δppm 7.97 (s, 1 H), 7.94 (d, J=7.83 Hz, 1 H), 7.85 (dd, J=7.96, 1.64 Hz, 1 H), 7.67 (dd, J=7.96, 1.39 Hz, 1 H), 7.61 (d, J=7.58 Hz, 1 H), 7.48 (q, I=7.83 Hz, 2 H), 6.74-6.86 (m, 3 H), 5.28 (d, I=15.92 Hz, 1 H), 5.17 (dd, J=8.72, 2.40 Hz, 1 H), 4.97 (d, J=16.17 Hz, 1 H), 3.04 (dt, J=13.64, 6.82 Hz, 1 H), 2.23-2.28 (m, 1 H), 2.20-2.23 (m, 1 H), 0.92 (d, J=7.07 Hz, 3 H), 0.81 (d, J=6.82 Hz, 3 H).
Reaction SMILES: [CH2:1]([CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][N:17]([C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[C:28]([Cl:33])[CH:27]=2)[C:18]([CH:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)=[O:19])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Si]([N:38]=[C:39]=[O:40])(C)C.C(=O)([O-])O.[Na+]>ClCCl>[CH2:1]([CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][N:17]([C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[C:28]([Cl:33])[CH:27]=2)[C:18]([CH:20]2[CH2:21][CH2:22][N:23]([C:39](=[O:40])[NH2:38])[CH2:24][CH2:25]2)=[O:19])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(C1CCNCC1)N(CCCN1CCC(Cc2ccccc2)CC1)c1ccc(Cl)c(Cl)c1
Reactant: C[Si](C)(C)N=C=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: NC(=O)N1CCC(C(=O)N(CCCN2CCC(Cc3ccccc3)CC2)c2ccc(Cl)c(Cl)c2)CC1
Temperature: 25 °C
Reaction time: 72 h
Yield: 66 %

Procedure:
To a solution of the compound obtained in Example 66 (488 mg, 1.00 mmol) in dichloromethane (10 ml) was added trimethylsilylisocyanate (2.00 ml), and the mixture was stirred at room temperature for 3 days. To the mixture was added a saturated aqueous solution of sodium hydrogen carbonate (20 ml) and the mixture was stirred for 30 minutes. The mixture was extracted with ethyl acetate (20 ml×3). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The concentrate was subjected to column chromatography (silica gel 10 g, ethyl acetate/methanol=1/0 to 9/1), and the desired fraction was concentrated under reduced pressure. To the mixture was added diethyl ether, and the resulting precipitates were collected by filtration. The precipitates were washed with diethyl ether, and dried under reduced pressure to give the titled compound (353 mg, 0.66 mmol, Yield 66%) as white crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[C:7]([O:11][CH3:12])[CH:6]=[CH:5][C:4]=1[CH:13]=[C:14]([N:19]=[N+]=[N-])[C:15]([O:17][CH3:18])=[O:16].[CH3:22]C(C)([O-])C.[K+].C1OCCOCCOCCOCCOCCOC1.IC>C1C=CC=CC=1.O>[CH3:22][N:19]1[C:5]2[C:4](=[C:3]([O:2][CH3:1])[C:8]([O:9][CH3:10])=[C:7]([O:11][CH3:12])[CH:6]=2)[CH:13]=[C:14]1[C:15]([O:17][CH3:18])=[O:16]
Reactant: COC(=O)C(=Cc1ccc(OC)c(OC)c1OC)N=[N+]=[N-]
Reactant: CC(C)(C)[O-]
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Solvent: c1ccccc1
Solvent: O
Solvent: CI
Product: COC(=O)c1cc2c(OC)c(OC)c(OC)cc2n1C
Reaction time: 0.25 h

Procedure:
Methyl 3-(2,3,4-trimethoxyphenyl)-2-azidopropenoate (799 mg), potassium tert-butoxide (438 mg) and 18-crown-6(71 mg) were dissolved in dry benzene (60 mL), and the solution was stirred for 15 minutes. Iodomethane (0.28 mL) was then added, and the mixture was stirred overnight. Water was added to the reaction mixture to conduct extraction with ethyl acetate. The resultant organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure to obtain the title compound.