Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:15]#[N:16])=[C:4]2[CH:13]=[CH:12][CH:11]=[C:10]3[C:5]2=[C:6]([CH:14]=1)[CH2:7][O:8][CH2:9]3.[CH3:17][Al](C)C.C1(C)C=CC=CC=1.O.O.O.O.C([O-])(=O)C(C(C([O-])=O)O)O.[Na+].[K+].[OH-].[Na+]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:3]([C:15](=[NH:16])[CH3:17])=[C:4]2[CH:13]=[CH:12][CH:11]=[C:10]3[C:5]2=[C:6]([CH:14]=1)[CH2:7][O:8][CH2:9]3
Reactant: N#Cc1c(Cl)cc2c3c(cccc13)COC2
Reactant: C[Al](C)C
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: CC(=N)c1c(Cl)cc2c3c(cccc13)COC2
Temperature: 105 °C
Yield: 102.8 %

Procedure:
5-Chloro-1H,3H-benzo[de]isochromen-6-carbonitrile (20 g, 87.08 mmol) obtained in Step 5 of Example 71 was suspended in anhydrous toluene (100 mL) under nitrogen atmosphere, and 2 M trimethyl aluminum-toluene solution (218 mL, 435 mmol) was added at room temperature. The obtained solution was stirred while heating in a 105° C. oil bath for 12 hours. The reaction solution was cooled to room temperature, and then slowly poured into an aqueous solution of potassium sodium (+)-tartarate tetrahydrate (184 g). 2 N aqueous sodium hydroxide solution (250 mL) was additionally added, and after stirring for 30 minutes, this was extracted with ethyl acetate (500 mL). The separated organic layer was washed with water (300 mL) and brine, then dried over anhydrous sodium sulfate, filtered, concentrated, and thus, 1-(5-chloro-1H,3H-benzo[de]isochromen-6-yl)-ethylidene-amine (22 g) was obtained as an orange-colored oil like substance.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9](=[O:28])[C:10]3[CH:11]=[CH:12][C:13]4[N:25](C=O)[CH2:24][CH2:23][CH2:22][O:21][C:14]=4[C:15]=3[O:16][C:17]=2[CH:18]([CH3:20])[CH3:19])=[CH:4][CH:3]=1>Cl.CO.C(OCC)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9](=[O:28])[C:10]3[CH:11]=[CH:12][C:13]4[NH:25][CH2:24][CH2:23][CH2:22][O:21][C:14]=4[C:15]=3[O:16][C:17]=2[CH:18]([CH3:20])[CH3:19])=[CH:4][CH:3]=1
Reactant: CC(C)c1oc2c3c(ccc2c(=O)c1-c1ccc(Cl)cc1)N(C=O)CCCO3
Agent: Cl
Solvent: CCOCC
Solvent: CO
Product: CC(C)c1oc2c3c(ccc2c(=O)c1-c1ccc(Cl)cc1)NCCCO3
Temperature: 25 °C

Procedure:
A stirred mixture of 3-(4-chlorophenyl)-2-isopropyl-4-oxo-9,10-dihydro-4H,8H-1,11-dioxa-7-aza-cyclohepta[a]naphthalene-7-carbaldehyde (0.063 g, 0.158 mmol) in 1M HCl solution (4 ml) and methanol (6 ml) is heated under reflux for 1 h under a nitrogen atmosphere. The mixture is allowed to cool to room temperature, and the methanol solvent is removed by evaporation in vacuo. The concentrated mixture is diluted with water (5 ml) and treated with solid sodium hydrogen carbonate, until a pH of 7-8 is attained. The mixture is washed successively with ethyl acetate and methylene chloride. The combined organic phases are dried (magnesium sulfate) and filtered, and the solvent is removed by evaporation in vacuo to afford a crude orange solid. This is stirred overnight in a solution of 2M HCl in diethyl ether (3 ml), filtered and dried at room temperature under high vacuum to give the title compound as a cream-coloured solid.
Reaction SMILES: [NH:1]1[C:6]2[CH:7]=[CH:8][S:9][C:5]=2[C:4](=[O:10])[O:3][C:2]1=[O:11].[CH2:12](Br)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[CH2:12]([N:1]1[C:6]2[CH:7]=[CH:8][S:9][C:5]=2[C:4](=[O:10])[O:3][C:2]1=[O:11])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=c1[nH]c2ccsc2c(=O)o1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=c1oc(=O)n(Cc2ccccc2)c2ccsc12
Yield: 78.6 %

Procedure:
The product of Example 110A (0.137 g, 0.81 mmol) was reacted with benzyl bromide (0.10 mL, 0.85 mmol), and potassium carbonate (0.134 g, 0.97 mmol) in dimethylformamide (5 mL) at ambient temperature for 20 hours. The reaction mixture was diluted with water and the resulting precipitate was collecte by filtration, and dried to give the title compound (0.165 g, 80%). MS (DCI/NH3) m/z 277 (M+NH4)+; 1H NMR (300 MHz, DMSO-d6) δ 5.21 (s, 2 H) 7.25 (d, J=5.52 Hz, 1 H) 7.35 (m, 5 H) 8.28 (d, J=5.52 Hz, 1 H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](I)=[C:4]([O:9][C:10]([F:13])([F:12])[F:11])[CH:3]=1.CC(O)(C)[C:16]#[C:17][C:18]1[CH:27]=[CH:26][C:21]([O:22][CH2:23][CH2:24][OH:25])=[CH:20][CH:19]=1>[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.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:16]#[C:17][C:18]2[CH:27]=[CH:26][C:21]([O:22][CH2:23][CH2:24][OH:25])=[CH:20][CH:19]=2)=[C:4]([O:9][C:10]([F:13])([F:12])[F:11])[CH:3]=1
Reactant: CC(C)(O)C#Cc1ccc(OCCO)cc1
Reactant: FC(F)(F)Oc1cc(Br)ccc1I
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: OCCOc1ccc(C#Cc2ccc(Br)cc2OC(F)(F)F)cc1
Yield: 81.9 %

Procedure:
A flask equipped with a stirrer and a thermometer was charged with 3.35 g (9.13 mmol) of 4-bromo-2-(trifluoromethoxy)iodobenzene and 19 ml of triethylamine under a nitrogen atmosphere. Then 1.48 g (9.13 mmol) of 2-[4-(3-methyl-3-hydroxybutyne-1-yl)phenoxy]ethanol, 13.7 mg (0.072 mmol) of copper (I) iodide, 63.2 mg (0.24 mmol) of triphenylphosphine, and 13.7 mg (0.020 mmol) of dichlorobis(triphenylphosphine)palladium were added at room temperature, and stirred under reflux for 6 hours. After the insolubles were filtered off and the solvent was distilled off, ethyl acetate was added to the resulting distillate, and the pH was adjusted to an acidity with 1N hydrochloric acid to effect ethyl acetate extraction. The resulting extract was washed with NaCl saturated water, dried over anhydrous sodium sulfate, filtered, and concentrated to thereby obtain 3.85 g of a crude product in the form of a yellowish brown solid. The crude product was then purified by silica gel column chromatography using hexane/ethyl acetate as an eluting solvent to obtain 3.0 g of 2-(4-{2-[4-bromo-2-(trifluoromethoxy)phenyl]ethynyl}phenoxy)ethanol in the form of a light yellow solid in a 82% yield.
Reaction SMILES: [CH3:1][C:2]1[C:11]([N+]([O-])=O)=[CH:10][C:9]([CH3:15])=[C:8]2[C:3]=1[C:4]([O:16][CH3:17])=[CH:5][CH:6]=[N:7]2.C(O)C.[OH-].[NH4+:22]>O>[NH2:22][C:4]1([O:16][CH3:17])[C:3]2[C:8](=[C:9]([CH3:15])[CH:10]=[CH:11][C:2]=2[CH3:1])[N:7]=[CH:6][CH2:5]1
Reactant: [NH4+]
Reactant: COc1ccnc2c(C)cc([N+](=O)[O-])c(C)c12
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COC1(N)CC=Nc2c(C)ccc(C)c21

Procedure:
In a flask is placed 5,8-dimethyl-4-methoxy-6-nitroquinoline (1.16 g, 5.0 mmol) with stannous chloride dihydrate (5.64 g, 25 mmol) and ethanol (50 mL). The mixture is refluxed for 1 hour, diluted with water (100 mL) and concentrated ammonium hydroxide (30 mL), and extracted with chloroform (2×200 mL). The organic portion is dried over potassium carbonate, filtered and the solvents removed by rotary evaporation, yielding 4-amino-5,8-dimethyl-4-methoxyquinoline.
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]1[C:10]2([CH2:15][CH2:14][NH:13][CH:12]([C:16]([NH:18][C:19]3([C:22]4[CH:31]=[CH:30][C:25]([C:26]([O:28][CH3:29])=[O:27])=[CH:24][CH:23]=4)[CH2:21][CH2:20]3)=[O:17])[CH2:11]2)[CH2:9]1.[F:32][C:33]([F:43])([F:42])[C:34]1[CH:41]=[CH:40][C:37]([CH2:38]Br)=[CH:36][CH:35]=1>CC#N>[F:32][C:33]([F:42])([F:43])[C:34]1[CH:41]=[CH:40][C:37]([CH2:38][N:13]2[CH2:14][CH2:15][C:10]3([CH2:9][CH2:8]3)[CH2:11][CH:12]2[C:16]([NH:18][C:19]2([C:22]3[CH:31]=[CH:30][C:25]([C:26]([O:28][CH3:29])=[O:27])=[CH:24][CH:23]=3)[CH2:20][CH2:21]2)=[O:17])=[CH:36][CH:35]=1
Reactant: COC(=O)c1ccc(C2(NC(=O)C3CC4(CCN3)CC4)CC2)cc1
Reactant: FC(F)(F)c1ccc(CBr)cc1
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1ccc(C2(NC(=O)C3CC4(CCN3Cc3ccc(C(F)(F)F)cc3)CC4)CC2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 66.3 %

Procedure:
To a solution of methyl 4-(1-(6-azaspiro[2.5]octane-5-carboxamido)cyclopropyl)benzoate 2,2,2-trifluoroacetate (D89) (27 g, 61.03 mmol) in dry MeCN (900 ml) Cs2CO3 (39.7 g, 122.05 mmol) and a solution of 4-(trifluoromethyl)-benzylbromide (14.6 g, 61.03 mmol) in MeCN (50 ml) were added in sequence. The mixture was stirred at RT for 18 hrs. The solid was filtered off and solvents were evaporated. The residue was ri-dissolved in DCM (200 ml) and washed with H2O (3×100 ml) and NaCl sat. sol (50 ml). The organic phases were dried over Na2SO4 and evaporated to afford a white solid, which was triturated in cyclohexane to afford the title compound (D123) (19.7 g).
Reaction SMILES: [C:1](=[N:23]O)([C:8]1[CH:13]=[CH:12][C:11]([C:14](=[N:21]O)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H]>C(O)C.N.[Ni]>[NH2:21][CH:14]([C:11]1[CH:12]=[CH:13][C:8]([CH:1]([NH2:23])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:9][CH:10]=1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: [H][H]
Reactant: ON=C(c1ccccc1)c1ccc(C(=NO)c2ccccc2)cc1
Agent: [Ni]
Agent: N
Solvent: CCO
Product: NC(c1ccccc1)c1ccc(C(N)c2ccccc2)cc1

Procedure:
The dioxime from Step 2 (30 g) is dissolved in ethyl alcohol (300 ml), saturated with ammonia gas and Raney nickel catalyst W-6 (2 g) added. The mixture is subjected to 700 psi hydrogen pressure and heated at 70° for three hours. The catalyst is removed by filtration and 220 ml of ethanol is removed by distillation. The pale yellow precipitate is filtered and dried.
Reaction SMILES: BrC1C=CC=C2C=1CC[C@H]2O[Si](C(C)(C)C)(C)C.[C:19]([Si:23]([CH3:44])([CH3:43])[O:24][CH:25]1[C:33]2[C:28](=[C:29]([B:34]3[O:38][C:37]([CH3:40])([CH3:39])[C:36]([CH3:42])([CH3:41])[O:35]3)[CH:30]=[CH:31][CH:32]=2)[CH2:27][CH2:26]1)([CH3:22])([CH3:21])[CH3:20]>>[C:19]([Si:23]([CH3:44])([CH3:43])[O:24][C@H:25]1[C:33]2[C:28](=[C:29]([B:34]3[O:35][C:36]([CH3:42])([CH3:41])[C:37]([CH3:40])([CH3:39])[O:38]3)[CH:30]=[CH:31][CH:32]=2)[CH2:27][CH2:26]1)([CH3:22])([CH3:21])[CH3:20]
Reactant: CC1(C)OB(c2cccc3c2CCC3O[Si](C)(C)C(C)(C)C)OC1(C)C
Agent: CC(C)(C)[Si](C)(C)O[C@@H]1CCc2c(Br)cccc21
Product: CC1(C)OB(c2cccc3c2CC[C@H]3O[Si](C)(C)C(C)(C)C)OC1(C)C

Procedure:
(R)-tert-butyldimethyl((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden-1-yl)oxy)silane IND INT-7 was prepared in an analogous fashion using (R)-((4-bromo-2,3-dihydro-1H-inden-1-yl)oxy)(tert-butyl)dimethylsilane IND INT-4. Racemic (±)-tert-butyldimethyl((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden-1-yl)oxy)silane IND INT-8 was prepared in an analogous fashion from IND INT-5.
Reaction SMILES: C([N+](CCCC)(CCCC)CCCC)CCC.[P:18]([O:22][CH2:23][C@@H:24]1[C@@H:28]([O:29][P:30]([O:33][CH2:34][C@@H:35]2[C@@H:39]([OH:40])[C@@H:38]([OH:41])[C@H:37]([N:42]3[CH:50]=[N:49][C:48]4[C:43]3=[N:44][CH:45]=[N:46][C:47]=4[NH2:51])[O:36]2)([OH:32])=[O:31])[CH2:27][C@H:26]([N:52]2[CH:57]=[CH:56][C:55]([NH2:58])=[N:54][C:53]2=[O:59])[O:25]1)([OH:21])([OH:20])=[O:19].[C:60]([O:64][C:65]([NH:67][C@@H:68]([CH2:75][CH2:76][CH2:77][CH2:78][NH:79][C:80](=[O:97])[C@@H:81]([NH:89][C:90]([O:92][C:93]([CH3:96])([CH3:95])[CH3:94])=[O:91])[CH2:82][S:83][S:84][C:85]([CH3:88])([CH3:87])[CH3:86])[C:69](OCC#N)=[O:70])=[O:66])([CH3:63])([CH3:62])[CH3:61]>O.O1CCCC1>[C:60]([O:64][C:65]([NH:67][C@H:68]([CH2:75][CH2:76][CH2:77][CH2:78][NH:79][C:80](=[O:97])[C@@H:81]([NH:89][C:90]([O:92][C:93]([CH3:96])([CH3:95])[CH3:94])=[O:91])[CH2:82][S:83][S:84][C:85]([CH3:86])([CH3:87])[CH3:88])[C:69]([O:40][C@H:39]1[C@@H:38]([OH:41])[C@H:37]([N:42]2[CH:50]=[N:49][C:48]3[C:43]2=[N:44][CH:45]=[N:46][C:47]=3[NH2:51])[O:36][C@H:35]1[CH2:34][O:33][P:30]([O:29][C@H:28]1[CH2:27][C@H:26]([N:52]2[CH:57]=[CH:56][C:55]([NH2:58])=[N:54][C:53]2=[O:59])[O:25][C@@H:24]1[CH2:23][O:22][P:18]([OH:21])([OH:20])=[O:19])([OH:32])=[O:31])=[O:70])=[O:66])([CH3:61])([CH3:62])[CH3:63]
Reactant: CC(C)(C)OC(=O)N[C@@H](CSSC(C)(C)C)C(=O)NCCCC[C@H](NC(=O)OC(C)(C)C)C(=O)OCC#N
Reactant: Nc1ccn([C@H]2C[C@H](OP(=O)(O)OC[C@H]3O[C@@H](n4cnc5c(N)ncnc54)[C@H](O)[C@@H]3O)[C@@H](COP(=O)(O)O)O2)c(=O)n1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N[C@@H](CSSC(C)(C)C)C(=O)NCCCC[C@@H](NC(=O)OC(C)(C)C)C(=O)O[C@H]1[C@@H](O)[C@H](n2cnc3c(N)ncnc32)O[C@H]1COP(=O)(O)O[C@H]1C[C@H](n2ccc(N)nc2=O)O[C@@H]1COP(=O)(O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 17.3 %

Procedure:
A solution of ((2R,3S,5R)-5-(4-amino-2-oxopyrimidin-1(2H)-yl)-3-(((((2R,3S,4R,5R)-5-(6-amino-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methoxy) (hydroxy)phosphoryl)oxy)tetrahydrofuran-2-yl)methyl dihydrogenphosphate (Compound 1h) (37.9 mg, 0.060 mmol) in water (0.3 mL) and a solution of (S)-cyanomethyl 2-((tert-butoxycarbonyl)amino)-6-((R)-2-((tert-butoxycarbonyl)amino)-3-(tert-butyldisulfanyl)propanamido)hexanoate (Compound 53) (103 mg, 0.179 mmol) in tetrahydrofuran (0.3 mL) were added to buffer A (11 mL), and the mixture was stirred at room temperature for 2 hours. Following lyophilization, the resulting residue was purified by reverse-phase silica gel column chromatography (0.05% aqueous trifluoroacetic acid solution/0.05% trifluoroacetic acid-acetonitrile solution) to afford (2S)-(2R,3S,4R,5R)-2-((((((2R,3S,5R)-5-(4-amino-2-oxopyrimidin-1(2H)-yl)-2-((phosphonooxy)methyl)tetrahydrofuran-3-yl)oxy)(hydroxy)phosphoryl)oxy)methyl)-5-(6-amino-9H-purin-9-yl)-4-hydroxytetrahydrofuran-3-yl 2-((tert-butoxycarbonyl)amino)-6-((R)-2-((tert-butoxycarbonyl)amino)-3-(tert-butyldisulfanyl)propanamido)hexanoate (Compound 55) (12 mg, 17%).
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[S:5][CH2:4][CH2:3]1.[C:13](Cl)(=[O:15])[CH3:14].[Al+3].[Cl-].[Cl-].[Cl-]>C(=S)=S>[C:13]([C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[S:5][CH2:4][CH2:3][C:2]2([CH3:12])[CH3:1])(=[O:15])[CH3:14]
Reactant: CC(=O)Cl
Reactant: CC1(C)CCSc2ccccc21
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: CC(=O)c1ccc2c(c1)C(C)(C)CCS2
Temperature: 25 °C
Reaction time: 10 h
Yield: 87.8 %

Procedure:
A solution of 10.0 g (0.056 mol) of 4,4-dimethylthiochroman and 4.4 g (0.056 mol) of acetyl chloride in 150 mL of CS2 was added dropwise over a 45-minutes period to a stirred CS2 suspension of AlCl3 (11.22 g, 0.084 mol) in a 500-mL, round-bottom flask equipped with a condenser and nitrogen inlet. The resulting yellowish-orange mixture was allowed to stir for 10 hours at room temperature; 80 mL of ice water was added and the two layers separated. The aqueous layer was extracted with ether (3×50 mL); the ether layers were combined and dried (Na2SO4, 6 h). After evaporation, the resulting light yellow oil was vacuum distilled to give 10.83 grams (87.6%) of 6-acetyl-4,4-dimethylthiochroman as a yellowish viscous oil: bp 168°-173° C./1.0 mm; IR (neat) 1680 cm-1 ; 1H NMR (DCCl3) δ1.31 [s, 6H, (CH)3)2C], 1.89 [m, 2H, ArSCH2CH2 ], 2.52 [s, 3H, CH3C=O]3.01 [m, 2H, ArSCH2CH2 ], 7.11 [d, 1H, J=8.1 Hz, H(8)], 7.57 [dd, 1H, J=1.7 Hz, J=8.1 Hz, H(7)], 8.00 [d, 1H, J=1.7 Hz, H(5)]; 13C NMR ppm 23.1 [ArSCH2CH2 ] 26.2 [CH3C=O], 29.8 [(CH3)2C], 32.8 [(CH3)2C], 36.8 [ArSCH2CH2 ], 125.8, 126.2, 132.9, 139.4, 141.7, 196.7 [CH3C=O]. ##STR14##
Reaction SMILES: COC(=O)N[C@@H](C(C)C)C(N1[C@H](C2NC(C3C=CC(C4C=CC5C(=CC=C(C6NC([C@@H]7CCCN7[C:48](=[O:61])[C@H:49]([NH:56][C:57]([O:59][CH3:60])=[O:58])[C:50]7[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=7)=NC=6)C=5)C=4)=CC=3)=CN=2)CC2(OCCO2)C1)=O.Cl.Cl.Cl.[F:69][C:70]1([F:121])[C:82]2[CH:81]=[C:80]([C:83]3[CH:84]=[CH:85][C:86]4[N:90]=[C:89]([C@@H:91]5[CH2:95][CH2:94][CH2:93][N:92]5[C:96](=[O:109])[C@@H:97]([NH:104][C:105](=[O:108])[O:106][CH3:107])[CH:98]5[CH2:103][CH2:102][O:101][CH2:100][CH2:99]5)[NH:88][C:87]=4[CH:110]=3)[CH:79]=[CH:78][C:77]=2[C:76]2[C:71]1=[CH:72][C:73]([C:111]1[NH:115][C:114]([C@@H:116]3[CH2:120][CH2:119][CH2:118][NH:117]3)=[N:113][CH:112]=1)=[CH:74][CH:75]=2>>[CH3:107][O:106][C:105](=[O:108])[NH:104][C@@H:97]([CH:98]1[CH2:103][CH2:102][O:101][CH2:100][CH2:99]1)[C:96]([N:92]1[CH2:93][CH2:94][CH2:95][C@H:91]1[C:89]1[NH:88][C:87]2[CH:110]=[C:83]([C:80]3[CH:79]=[CH:78][C:77]4[C:76]5[C:71](=[CH:72][C:73]([C:111]6[NH:115][C:114]([C@@H:116]7[CH2:120][CH2:119][CH2:118][N:117]7[C:48](=[O:61])[C@H:49]([NH:56][C:57]([O:59][CH3:60])=[O:58])[C:50]7[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=7)=[N:113][CH:112]=6)=[CH:74][CH:75]=5)[C:70]([F:69])([F:121])[C:82]=4[CH:81]=3)[CH:84]=[CH:85][C:86]=2[N:90]=1)=[O:109]
Reactant: COC(=O)N[C@H](C(=O)N1CC2(C[C@H]1c1ncc(-c3ccc(-c4ccc5cc(-c6cnc([C@@H]7CCCN7C(=O)[C@H](NC(=O)OC)c7ccccc7)[nH]6)ccc5c4)cc3)[nH]1)OCCO2)C(C)C
Reactant: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1nc2ccc(-c3ccc4c(c3)C(F)(F)c3cc(-c5cnc([C@@H]6CCCN6)[nH]5)ccc3-4)cc2[nH]1)C1CCOCC1
Agent: Cl
Product: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1nc2ccc(-c3ccc4c(c3)C(F)(F)c3cc(-c5cnc([C@@H]6CCCN6C(=O)[C@H](NC(=O)OC)c6ccccc6)[nH]5)ccc3-4)cc2[nH]1)C1CCOCC1

Procedure:
The title compound was prepared according to the method employed to prepare (S)-1-((S)-8-(5-(4-(6-(2-((S)-1-((R)-2-(methoxycarbonylamino)-2-phenylacetyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)naphthalen-2-yl)phenyl)-1H-imidazol-2-yl)-1,4-dioxa-7-azaspiro[4.4]nonan-7-yl)-3-methyl-1-oxobutan-2-ylcarbamic acid methyl ester, except that methyl (S)-2-((S)-2-(6-(9,9-difluoro-7-(2-((S)-pyrrolidin-2-yl)-1H-imidazol-5-yl)-9H-fluoren-2-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-1-yl)-2-oxo-1-(tetrahydro-2H-pyran-4-yl)ethylcarbamate 3HCl salt was used instead of methyl (S)-3-methyl-1-oxo-1-((S)-8-(5-(4-(6-(2-((S)-pyrrolidin-2-yl)-1H-imidazol-5-yl)naphthalen-2-yl)phenyl)-1H-imidazol-2-yl)-1,4-dioxa-7-azaspiro[4.4]nonan-7-yl)butan-2-ylcarbamate 3HCl salt. MS (ESI) m/z 913.94 [M+H]+. (77.4 mg, 24%).
Reaction SMILES: [O:1]=[C:2]1[C:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH2:5][CH2:4][N:3]1[CH2:19][C:20]([OH:22])=O.CN(C)C=O.C(Cl)(=O)C([Cl:31])=O>ClCCl>[O:1]=[C:2]1[C:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH2:5][CH2:4][N:3]1[CH2:19][C:20]([Cl:31])=[O:22]
Reactant: O=C(O)CN1CCC(c2ccccc2)(c2ccccc2)C1=O
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)CN1CCC(c2ccccc2)(c2ccccc2)C1=O
Reaction time: 1 h

Procedure:
To a suspension of 2-(2-oxo-3,3-diphenylpyrrolidin-1-yl)acetic acid (1.477 g, 5.0 mmol; Example 1C) in dichloromethane (20 mL) was added catalytic amount of N,N-dimethylformamide followed by oxalyl dichloride (2.0 Min dichloromethane, 3.75 mL, 7.5 mmol). After stirring for 60 minutes, the reaction was concentrated, dried under high vacuum overnight. The resulting material was taken for further reactions without additional purification.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([NH2:13])=[N:10][O:11][N:12]=2)=[CH:4][CH:3]=1.C([N:21]1[CH2:26][CH:25]2[C:27](=O)[CH:22]1[CH2:23][CH2:24]2)C1C=CC=CC=1>>[CH:22]12[CH:27]([NH:1][C:2]3[CH:3]=[CH:4][C:5]([C:8]4[C:9]([NH2:13])=[N:10][O:11][N:12]=4)=[CH:6][CH:7]=3)[CH:25]([CH2:24][CH2:23]1)[CH2:26][NH:21]2
Reactant: Nc1ccc(-c2nonc2N)cc1
Reactant: O=C1C2CCC1N(Cc1ccccc1)C2
Product: Nc1nonc1-c1ccc(NC2C3CCC2NC3)cc1

Procedure:
Reaction of 4-(4-aminophenyl)-1,2,5-oxadiazol-3-amine with 2-benzyl-2-azabicyclo[2.2.1]heptan-7-one (J. R. Malpass, S. Handa, and R. White, Org. Lett., 2005, 7, 2759-2762) affords the title compound as the benzyl-protected amine. Purification by chromatography followed by removal of the benzyl group by hydrogenolysis affords the title amine.
Reaction SMILES: C[Si](Cl)(C)C.[CH2:6]([O:8][C:9]([N:11]1[C:20]2[C:15](=[N:16][C:17]([O:21]C)=[CH:18][CH:19]=2)[C@@H:14]([NH:23][C:24]2[N:29]=[C:28]([CH2:30][C:31]3[CH:36]=[C:35]([C:37]([F:40])([F:39])[F:38])[CH:34]=[C:33]([C:41]([F:44])([F:43])[F:42])[CH:32]=3)[C:27]([N:45]3[CH2:50][CH2:49][O:48][CH2:47][CH2:46]3)=[CH:26][N:25]=2)[CH2:13][C@H:12]1[CH2:51][CH3:52])=[O:10])[CH3:7].[I-].[Na+].S([O-])([O-])(=O)=S.[Na+].[Na+]>C(OCC)(=O)C.C(#N)C>[CH2:6]([O:8][C:9]([N:11]1[C:20]2[C:15](=[N:16][C:17]([OH:21])=[CH:18][CH:19]=2)[C@@H:14]([NH:23][C:24]2[N:29]=[C:28]([CH2:30][C:31]3[CH:36]=[C:35]([C:37]([F:40])([F:39])[F:38])[CH:34]=[C:33]([C:41]([F:44])([F:42])[F:43])[CH:32]=3)[C:27]([N:45]3[CH2:46][CH2:47][O:48][CH2:49][CH2:50]3)=[CH:26][N:25]=2)[CH2:13][C@H:12]1[CH2:51][CH3:52])=[O:10])[CH3:7]
Reactant: CCOC(=O)N1c2ccc(OC)nc2[C@@H](Nc2ncc(N3CCOCC3)c(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)n2)C[C@H]1CC
Agent: C[Si](C)(C)Cl
Agent: O=S([O-])([O-])=S
Agent: [I-]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CCOC(=O)N1c2ccc(O)nc2[C@@H](Nc2ncc(N3CCOCC3)c(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)n2)C[C@H]1CC
Temperature: 25 °C
Yield: 42 %

Procedure:
Trimethylsilyl chloride (4.6 ml) is added dropwise to a suspension of (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(morpholin-4-yl)pyrimidin-2-yl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthyridine-1-carboxylic acid ethyl ester (2.4 g), sodium iodide (5.4 g) and acetonitrile (50 ml) at 80° C. After addition, the reaction solution is cooled to room temperature, and a saturated aqueous sodium thiosulfate solution and ethyl acetate are added thereto. The organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by column chromatography (silica gel; hexane: ethyl acetate=2:1→0:1) to give (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(morpholin-4-yl)pyrimidin-2-yl]}amino-2-ethyl-6-hydroxy-3,4-dihydro-2H-[1,5]naphthyridine-1-carboxylic acid ethyl ester (988 mg). MS (m/z): 655 [M+H]+
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:10][C:11]1([C:14]([O:16]C)=[O:15])[CH2:13][CH2:12]1)[CH3:9])=[O:7])([CH3:4])([CH3:3])[CH3:2].O.[OH-].[Na+]>CO>[C:1]([O:5][C:6]([N:8]([CH2:10][C:11]1([C:14]([OH:16])=[O:15])[CH2:12][CH2:13]1)[CH3:9])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)C1(CN(C)C(=O)OC(C)(C)C)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CN(CC1(C(=O)O)CC1)C(=O)OC(C)(C)C
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 94 %

Procedure:
Methyl 1-{[(tert-butoxycarbonyl)(methyl)amino]methyl}cyclopropanecarboxylate was dissolved in methanol (6.8 mL) and water (5.8 mL) and treated with 10M sodium hydroxide (0.98 mL, 9.82 mmol). The solution was heated at 50° C. After 30 minutes, the reaction was cooled with an ice bath and quenched into a cold (ice bath temperature) mixture of 1N hydrogen chloride (19.6 mL) and saturated sodium chloride (19.6 mL). The product was extracted with ethyl acetate (3 times). The organic solution was dried over anhydrous sodium sulfate and filtered. Concentration of the organic solution gave the title compound (680 mg, 94% yield) which was used crude in the next step.