Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([NH:8][C@H:9]([C:22]([NH:24][C@H:25]([C:27]([O:29][CH2:30][CH2:31][O:32][C:33]1[CH:38]=[CH:37][C:36]([C:39]2[C:44]([C:45]#[N:46])=[C:43]([N:47]3[CH2:51][CH2:50][CH2:49][CH2:48]3)[N:42]=[C:41]([S:52][CH2:53][C:54]3[N:55]=[C:56]([C:59]4[CH:64]=[CH:63][C:62]([Cl:65])=[CH:61][CH:60]=4)[S:57][CH:58]=3)[C:40]=2[C:66]#[N:67])=[CH:35][CH:34]=1)=[O:28])[CH3:26])=[O:23])[CH2:10][CH2:11][CH2:12][CH2:13][NH:14]C(OC(C)(C)C)=O)=O)(C)(C)C.[ClH:68]>ClCCl.C(OCC)C>[ClH:65].[ClH:68].[NH2:8][C@H:9]([C:22]([NH:24][C@H:25]([C:27]([O:29][CH2:30][CH2:31][O:32][C:33]1[CH:34]=[CH:35][C:36]([C:39]2[C:44]([C:45]#[N:46])=[C:43]([N:47]3[CH2:48][CH2:49][CH2:50][CH2:51]3)[N:42]=[C:41]([S:52][CH2:53][C:54]3[N:55]=[C:56]([C:59]4[CH:64]=[CH:63][C:62]([Cl:65])=[CH:61][CH:60]=4)[S:57][CH:58]=3)[C:40]=2[C:66]#[N:67])=[CH:37][CH:38]=1)=[O:28])[CH3:26])=[O:23])[CH2:10][CH2:11][CH2:12][CH2:13][NH2:14]
Reactant: C[C@H](NC(=O)[C@H](CCCCNC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)C(=O)OCCOc1ccc(-c2c(C#N)c(SCc3csc(-c4ccc(Cl)cc4)n3)nc(N3CCCC3)c2C#N)cc1
Agent: Cl
Solvent: CCOCC
Solvent: ClCCl
Product: C[C@H](NC(=O)[C@@H](N)CCCCN)C(=O)OCCOc1ccc(-c2c(C#N)c(SCc3csc(-c4ccc(Cl)cc4)n3)nc(N3CCCC3)c2C#N)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
300 mg (0.308 mmol) of 2-{4-(2-({(2-(4-chlorophenyl)-1,3-thiazol-4-yl)methyl}sulfanyl)-3,5-dicyano-6-(pyrrolidin-1-yl)pyridin-4-yl)phenoxy}ethyl N2,N6-bis(tert-butoxycarbonyl)-L-lysyl-L-alaninate (Example 26A) were initially charged in 5.4 ml of dichloromethane. 3.08 ml (6.163 mmol) of a 1N solution of hydrogen chloride in diethyl ether were added, and the reaction solution was then stirred at RT overnight. The solid formed was filtered off, triturated with 2.5 ml of cold dichloromethane and filtered off again. This gave 250 mg (96% of theory) of the target compound.
Reaction SMILES: Cl[S:2]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:14])[CH2:8]2)(=[O:4])=[O:3].[CH3:15][NH:16][CH3:17]>CO>[CH3:15][N:16]([CH3:17])[S:2]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:14])[CH2:8]2)(=[O:4])=[O:3]
Reactant: CNC
Reactant: O=C1Cc2cc(S(=O)(=O)Cl)ccc2N1
Solvent: CO
Product: CN(C)S(=O)(=O)c1ccc2c(c1)CC(=O)N2
Temperature: 25 °C
Reaction time: 4 h
Yield: 79 %

Procedure:
A suspension of 2.3 g of 5-chlorosulfonyl-2-oxindole (prepared as described in Compound IN-02) in 10 mL of 2 M dimethylamine in methanol was stirred at room temperature for 4 hours at which time a white solid was present. The precipitate was collected by vacuum filtration, washed with 5 mL of 1 N sodium hydroxide and 5 mL of 1 N hydrochloric acid and dried under vacuum at 40° C. overnight to give 1.9 g (79% yield) of 5-dimethylaminosulfonyl-2-oxindole.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:39])[C@H:10]([CH:36]([CH3:38])[CH3:37])[NH:11][C:12](=[O:35])[C@@H:13]([CH2:31][CH:32]([CH3:34])[CH3:33])[NH:14]C(=O)C(O)C1CCCN1C(OC(C)(C)C)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:40].O1CCOCC1>ClCCl>[ClH:40].[CH2:1]([O:8][C:9](=[O:39])[C@H:10]([CH:36]([CH3:38])[CH3:37])[NH:11][C:12](=[O:35])[C@H:13]([CH2:31][CH:32]([CH3:33])[CH3:34])[NH2:14])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)C[C@@H](NC(=O)C(O)C1CCCN1C(=O)OC(C)(C)C)C(=O)N[C@H](C(=O)OCc1ccccc1)C(C)C
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: CC(C)C[C@H](N)C(=O)N[C@H](C(=O)OCc1ccccc1)C(C)C

Procedure:
[2-Hydroxy-2-(N-t-butyloxycarbonylpyrrolidin-2-yl)acetyl]-D-leucylvaline benzyl ester (200 mg) was added to dry dichloromethane (1 ml) and 4N hydrochloric acid/dioxane (1 ml) was added to the solution under cooling with ice to conduct a reaction at room temperature for 1.5 h. The reaction liquid was concentrated under reduced pressure and the residue was washed with n-hexane and dried to give 2-hydroxy-2-(pyrrolidin-2-yl)acetyl]-D-leucylvaline benzyl ester hydrochloride.
Reaction SMILES: Br[C:2]1[N:3]([CH2:21][CH2:22][C:23]#[N:24])[C:4]2[C:9]([C:10]=1[CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)=[CH:8][CH:7]=[C:6]([C:17]([O:19][CH3:20])=[O:18])[CH:5]=2.[CH:25]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1B(O)O)=O.[Li+].[Cl-].C(=O)([O-])[O-].[Na+].[Na+]>C(O)C.C1(C)C=CC=CC=1.C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:23]([C:22]1[CH2:21][N:3]2[C:4]3[CH:5]=[C:6]([C:17]([O:19][CH3:20])=[O:18])[CH:7]=[CH:8][C:9]=3[C:10]([CH:11]3[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]3)=[C:2]2[C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=2[CH:25]=1)#[N:24]
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c(Br)n(CCC#N)c2c1
Reactant: O=Cc1ccccc1B(O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: CCO
Product: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CC(C#N)=Cc1ccccc1-3

Procedure:
Tetrakis(triphenylphosphine)palladium(0) (207 mg, 0.18 mmol) was added to a stirred and degassed mixture of methyl 2-bromo-1-(2-cyanoethyl)-3-cyclohexyl-1H-indole-6-carboxylate (695 mg, 1.8 mmol), 2-formylphenyl boronic acid (233 mg, 1.56 mmol), LiCl (151 mg, 3.57 mmol) in ethanol (5.8 mL) and toluene (5.8 mL) containing 1M aqueous sodium carbonate (5 mL, 5 mmol). The mixture was stirred under reflux for 2 hr. The mixture was cooled and diluted with ethyl acetate. The organic layer was washed with water (2×), followed by brine, and dried over sodium sulfate. The extract was concentrated and partially purified by chromatography on SiO2 (35 g) using the flash technique and eluting with methylene chloride with between 10–20% ethyl acetate. A solution of the residue when stood in methanol deposited yellow needles of the titled compound. MS m/z 397 (MH+); (500 MHz, CHLOROFORM-D) δ ppm 1.31–2.16 (m, 10 H) 2.73–2.89 (m, 1 H) 3.97 (s, 3 H) 4.46 (s, 1 H) 5.00–5.17 (m, 1 H) 7.41–7.47 (m, 1 H) 7.49–7.53 (m, 1 H) 7.55 (s, 1 H) 7.57–7.61 (m, 1 H) 7.79 (d, J=8.55 Hz, 1 H) 7.91 (d, J=8.55 Hz, 1 H) 8.18 (s, 1 H).
Reaction SMILES: [CH3:1][C:2]1([CH3:27])[CH2:7][CH:6]([NH:8][C:9]2[N:14]=[C:13]([C:15]3[S:19][C:18]4[CH:20]=[C:21]([OH:24])[CH:22]=[CH:23][C:17]=4[CH:16]=3)[CH:12]=[CH:11][N:10]=2)[CH2:5][C:4]([CH3:26])([CH3:25])[NH:3]1.[C:28]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C[CH:29]=1.CCO.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[CH2:28]([O:24][C:21]1[CH:22]=[CH:23][C:17]2[CH:16]=[C:15]([C:13]3[CH:12]=[CH:11][N:10]=[C:9]([NH:8][CH:6]4[CH2:7][C:2]([CH3:27])([CH3:1])[NH:3][C:4]([CH3:26])([CH3:25])[CH2:5]4)[N:14]=3)[S:19][C:18]=2[CH:20]=1)[CH3:29]
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: CC1(C)CC(Nc2nccc(-c3cc4ccc(O)cc4s3)n2)CC(C)(C)N1
Agent: CCOC(=O)/N=N/C(=O)OCC
Solvent: CCO
Solvent: C1CCOC1
Product: CCOc1ccc2cc(-c3ccnc(NC4CC(C)(C)NC(C)(C)C4)n3)sc2c1
Temperature: 25 °C

Procedure:
Compound of Example 153 (76 mg, 0.2 mmol), triphenylphosphine (80 mg, 0.3 mmol) and EtOH (30 mg, 0.65 mmol) were suspended in 8 ml of THF, then diethylazodicarboxylate (52 mg, 0.3 mmol) dissolved in 4 ml THF was added dropwise. This mixture was stirred at room temperature over night and afterwards evaporated. The crude was purified by chromatography on silicagel (DCM/MeOH/ammonia:9/1/0.1). Yield: 33 mg (40%).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([OH:12])=[CH:4][C:3]=1[C:13]([NH:15][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][CH3:31])=[O:14].[CH3:32][S:33]([CH:36](O)[CH3:37])(=[O:35])=[O:34].C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC=CC=1>O>[OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([O:12][CH2:37][CH2:36][S:33]([CH3:32])(=[O:35])=[O:34])=[CH:4][C:3]=1[C:13]([NH:15][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][CH3:31])=[O:14]
Reactant: CCCCCCCCCCCCCCCCNC(=O)c1cc(O)c2ccccc2c1O
Reactant: CC(O)S(C)(=O)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CCCCCCCCCCCCCCCCNC(=O)c1cc(OCCS(C)(=O)=O)c2ccccc2c1O

Procedure:
10 g (0.023 mol) of 1,4-dihydroxy-N-n-hexadecyl-2-naphthamide, 5.7 g (0.046 mol) of methylsulfonylethanol and 4.4 g (0.023 mol) of p-toluenesulfonic acid were added to 50 ml of dehydrated toluene. The mixture was refluxed with heating for 5 hours and the water produced was removed. Toluene was removed under reduced pressure. 100 ml of methanol was added to the mixture. The crystals thus deposited were collected by filtration to obtain 10.8 g (88%) of Coupler (2). Melting Point: 107° to 109° C. (recrystallized from methanol).
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:9]1[C:10]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=2)=[C:11]2[C:16](=[CH:17][C:18]=1[CH3:19])[N:15]=[C:14]([CH2:20][O:21][CH3:22])[CH:13]=[CH:12]2)[CH2:7][OH:8])([CH3:4])([CH3:3])[CH3:2].[O-][CH2:31]C.[Na+]>C(O)C.CO>[C:1]([O:5][C@@H:6]([C:9]1[C:10]([C:23]2[CH:24]=[CH:25][C:26]([Cl:29])=[CH:27][CH:28]=2)=[C:11]2[C:16](=[CH:17][C:18]=1[CH3:19])[N:15]=[C:14]([CH2:20][O:21][CH2:22][CH3:31])[CH:13]=[CH:12]2)[CH2:7][OH:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC[O-]
Reactant: COCc1ccc2c(-c3ccc(Cl)cc3)c([C@@H](CO)OC(C)(C)C)c(C)cc2n1
Agent: [Na+]
Solvent: CCO
Solvent: CO
Product: CCOCc1ccc2c(-c3ccc(Cl)cc3)c([C@@H](CO)OC(C)(C)C)c(C)cc2n1

Procedure:
(S)-2-tert-Butoxy-2-(5-(4-chlorophenyl)-2-(ethoxymethyl)-7-methylquinolin-6-yl)ethanol was prepared following the procedure used to prepare compound (S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-2-(methoxymethyl)-7-methylquinolin-6-yl)ethanol of Example 12, except that sodium ethoxide in ethanol solution was used instead of sodium methoxide in methanol solution. LCMS-ESI+ (m/z): 428.2, 430.2 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[C:10]2[C:5](=[CH:6][C:7]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)=[CH:8][CH:9]=2)[NH:4][CH2:3]1.Cl[C:19]1[C:28]2[C:23](=[CH:24][CH:25]=[C:26]([Cl:29])[CH:27]=2)[N:22]=[C:21]([CH3:30])[C:20]=1[CH2:31][CH3:32].C(=O)([O-])[O-].[Cs+].[Cs+].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:29][C:26]1[CH:27]=[C:28]2[C:23](=[CH:24][CH:25]=1)[N:22]=[C:21]([CH3:30])[C:20]([CH2:31][CH3:32])=[C:19]2[N:4]1[C:5]2[C:10](=[CH:9][CH:8]=[C:7]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)[CH:6]=2)[C:2]([CH3:17])([CH3:1])[CH2:3]1
Reactant: CC1(C)CNc2cc(N3CCOCC3)ccc21
Reactant: CCc1c(C)nc2ccc(Cl)cc2c1Cl
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: CCc1c(C)nc2ccc(Cl)cc2c1N1CC(C)(C)c2ccc(N3CCOCC3)cc21

Procedure:
Prepared according to procedure T using 4-(3,3-dimethylindolin-6-yl)morpholine (0.033 g, 0.139 mmol), 4,6-dichloro-3-ethyl-2-methylquinoline (0.04 g, 0.167 mmol), cesium carbonate (0.091 g, 0.278 mmol), Pd2(dba)3 (0.013 g, 0.014 mmol) and (±) BINAP (0.013 g, 0.021 mmol) in 1,4-dioxane (1 mL). After purification by HPLC 6-chloro-4-(3,3-dimethyl-6-(4-morpholinyl)-2,3-dihydro-1H-indol-1-yl)-3-ethyl-2-methylquinoline was obtained: 1H NMR (500 MHz, chloroform-d) δ ppm 8.40 (1H, d, J=9.0 Hz), 7.72 (1H, d, J=9.0 Hz), 7.68 (1H, s), 7.13 (1H, s), 6.57 (1H, d, J=8.1 Hz), 5.73 (1H, br. s.), 3.75 (4H, m), 2.97 (6H, br. s.), 1.44 (5H, d, J=16.4 Hz), 1.19 (6H, m), 0.80 (3H, d, J=15.4 Hz). Mass Spectrum (ESI) m/e=436 (M+1).
Reaction SMILES: I(O)(=O)(=O)=O.[I:6]I.S(=O)(=O)(O)O.[Cl:13][C:14]1[C:19]([F:20])=[CH:18][CH:17]=[C:16]([Cl:21])[C:15]=1[C@H:22]([O:24][C:25]1[C:26]([NH2:31])=[N:27][CH:28]=[CH:29][CH:30]=1)[CH3:23]>C(O)(=O)C.O>[I:6][C:29]1[CH:30]=[C:25]([O:24][C@@H:22]([C:15]2[C:16]([Cl:21])=[CH:17][CH:18]=[C:19]([F:20])[C:14]=2[Cl:13])[CH3:23])[C:26]([NH2:31])=[N:27][CH:28]=1
Reactant: C[C@@H](Oc1cccnc1N)c1c(Cl)ccc(F)c1Cl
Reactant: II
Agent: O=S(=O)(O)O
Agent: [O-][I+3]([O-])([O-])O
Solvent: CC(=O)O
Solvent: O
Product: C[C@@H](Oc1cc(I)cnc1N)c1c(Cl)ccc(F)c1Cl
Temperature: 80 °C
Yield: 120 %

Procedure:
Periodic acid (60 mg, 0.24 mmol), iodine (130 mg, 0.5 mmol), and sulfuric acid (0.03 mL) were added sequentially to a stirred solution of 3-[(1R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy]pyridin-2-amine (0.97 mmol) in a mixture of acetic acid (3 mL) and H2O (0.5 mL). The resulting solution was heated to 80° C. for 5 h. The cooled reaction mixture was quenched with Na2SO3 (80 mg) and basicified with saturated Na2CO3 (2×100 mL) to pH 7. CH2Cl2 (2×50 mL) was added to extract the aqueous solution. The combined organic layers were dried over Na2SO4 then filtered and concentrated under vacuum. The residue was purified by flash chromatography (eluting with 35→40% EtOAc in hexanes) to give the title compound as a yellow oil (254 mg; 0.6 mmol; 61.6% yield); MS (APCI) (M+H)+ 426. 1H NMR (400 MHz, chloroform-D) δ ppm 1.81 (d, J=6.8 Hz, 3H) 4.86 (s, 2H) 5.98 (q, J=6.57 Hz, 1H) 6.96 (d, J=1.5 Hz, 1H) 7.08 (dd, J=9.0, 8.0 Hz, 1H) 7.31 (dd, J=8.8, 4.8 Hz, 1H) 7.78 (d, J=1.8 Hz, 1H).
Reaction SMILES: [C:1]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].Br[CH2:13][CH2:14]Br.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:3]([C:2]1([C:1]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6])[CH2:14][CH2:13]1)(=[O:4])[CH3:5]
Reactant: BrCCBr
Reactant: CC(=O)CC(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)C1(C(=O)OC(C)(C)C)CC1
Temperature: 60 °C
Reaction time: 3.5 h
Yield: 56111.1 %

Procedure:
A mixture of tert-butyl acetoacetate (497 mL, 3.00 mol), 1,2-dibromoethane (310 mL, 3.60 mmol), potassium carbonate (1.106 k g, 8.00 mmol), and dimethylformamide (2.0 L) was stirred in a water bath at 30° C. for 1.5 hours, in a water bath at 60° C. for 3.5 hours, and in a water bath at 30° C. for 4 days. The reaction mixture was separated by filtration through celite, and the residue on the celite was washed with diethylether (3.5 L). The filtrate and the diethylether used for the washing were combined and added to water (2 L), and the organic layer was separated. The aqueous layer was extracted with diethylether (2 L), and water (1 L) was added to the resulting aqueous layer, and further extraction was conducted by adding diethylether (2 L). All organic layers were combined, and washed with 10% aqueous solution of citric acid (2 L), water (2 L×3), and saturated aqueous solution of sodium chloride (2 L×3), and dried by adding anhydrous sodium sulfate. After removing the dessicating agent by filtration, the solvent was removed by distillation under reduced pressure, and the residue was distilled under reduced pressure to obtain 371.8 g of the target compound (10 mmHg, distillation fraction of 72 to 78° C., 2.02 mol, 67%) as a colorless transparent oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13]3[N:14]([CH2:25][C@H:26]4[CH2:31][CH2:30][C@H:29]([CH3:32])[CH2:28][CH2:27]4)[C:15]([NH:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[F:24])=[N:16][C:12]=3[CH:11]=[C:10]([C:33](=[NH:36])[NH:34][OH:35])[N:9]=2)[CH:5]=[N:6][CH:7]=1.[O:37]1[C:41](=O)NC=N1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13]3[N:14]([CH2:25][C@H:26]4[CH2:27][CH2:28][C@H:29]([CH3:32])[CH2:30][CH2:31]4)[C:15]([NH:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[F:24])=[N:16][C:12]=3[CH:11]=[C:10]([C:33]3[NH:36][C:41](=[O:37])[O:35][N:34]=3)[N:9]=2)[CH:5]=[N:6][CH:7]=1
Reactant: O=c1[nH]cno1
Reactant: C[C@H]1CC[C@H](Cn2c(Nc3ccccc3F)nc3cc(C(=N)NO)nc(-c4cncc(Cl)c4)c32)CC1
Product: C[C@H]1CC[C@H](Cn2c(Nc3ccccc3F)nc3cc(-c4noc(=O)[nH]4)nc(-c4cncc(Cl)c4)c32)CC1

Procedure:
Using a procedure analogous to that described in Example 3.94 (Step 3), and starting with 4-(5-chloropyridin-3-yl)-2-((2-fluorophenyl)amino)-N-hydroxy-3-((trans-4-methylcyclohexyl)methyl)-3H-imidazo[4,5-c]pyridine-6-carboximidamide, 3-(4-(5-chloropyridin-3-yl)-2-(2-fluorophenyl)amino)-3-((trans-4-methylcyclohexyl)methyl)-3H-imidazo[4,5-c]pyridin-6-yl)-1,2,4-oxadiazol-5(4H)-one (TFA salt) was prepared. MS ESI calc'd. for C27H25ClFNγO2 [M+H]+ 534. found 534. 1H NMR (500 MHz, DMSO-d6) δ 12.83 (s, 1H), 9.27 (s, 1H), 8.83 (m, J=20.7, 2H), 8.39 (s, 1H), 7.81 (s, 1H), 7.65 (m, 1H), 7.26 (m, 3H), 3.85 (s, 2H), 1.44 (d, 2H), 1.07 (m, 2H), 0.71 (m, J=6.5, 7H), 0.54 (m, 2H)
Reaction SMILES: C(O[C:6](=[O:15])[C:7]1[CH:12]=[C:11]([CH3:13])[N:10]=[C:9]([CH3:14])[CH:8]=1)CCC.Cl.[CH3:17][NH:18][O:19][CH3:20].C([Mg]Cl)(C)C>C1COCC1>[CH3:20][O:19][N:18]([CH3:17])[C:6](=[O:15])[C:7]1[CH:8]=[C:9]([CH3:14])[N:10]=[C:11]([CH3:13])[CH:12]=1
Reactant: CCCCOC(=O)c1cc(C)nc(C)c1
Reactant: CNOC
Agent: CC(C)[Mg]Cl
Agent: Cl
Solvent: C1CCOC1
Product: CON(C)C(=O)c1cc(C)nc(C)c1
Temperature: -20 °C
Reaction time: 2.5 h
Yield: 90.3 %

Procedure:
Under argon a suspension of 2,6-dimethyl-isonicotinic acid butyl ester (16.67 g) and N,O-dimethylhydroxylamine hydrochloride (12.2 g) in THF (150 mL) was cooled down to −20° C. A solution of isopropylmagnesium chloride (2M in THF, 120.6 mL) was added over 20 min maintaining the temperature below −5° C. The mixture was stirred for 2.5 hours at −10° C. and quenched with a saturated aqueous solution of NH4Cl (200 mL). The phases were separated and the inorganic one was extracted with EtOAc (2×). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. Column chromatography on silica gel (EtOAc/n-heptane 2:1 to EtOAc) yielded the title compound (14.1 g, 90%) as a yellow liquid, MS (ESI+): m/z=195.0 [M+H]+.
Reaction SMILES: C(O)=O.C=O.NC1[CH:8]=[N:9][C:10]2[C:15]([CH:16]=1)=[CH:14][C:13]([O:17][CH3:18])=[C:12]([O:19][CH3:20])[CH:11]=2.[OH-].[Na+].[CH3:23][N:24]([CH3:27])[CH:25]=O>O>[CH3:23][N:24]([CH3:27])[C:25]1[CH:8]=[N:9][C:10]2[C:15]([CH:16]=1)=[CH:14][C:13]([O:17][CH3:18])=[C:12]([O:19][CH3:20])[CH:11]=2
Reactant: CN(C)C=O
Reactant: COc1cc2cc(N)cnc2cc1OC
Agent: C=O
Agent: [Na+]
Agent: [OH-]
Solvent: O=CO
Solvent: O
Product: COc1cc2cc(N(C)C)cnc2cc1OC

Procedure:
A mixture of 113.5 g (2.45 mole) of 99% formic acid and 200 ml of formaldehyde (36.5% w/v) is added, under stirring and by cooling at 15°-20° C., to a solution of 100 g (0.49 mole) of 3-amino-6,7-dimethoxyquinoline (prepared according to J. Med. Chem., 22, 1005, 1979) in 400 ml of N,N-dimethylformamide. The thus obtained mixture is refluxed for 6 hours, then water is added, the pH is adjusted to 10 with 40% NaOH and the mixture is extracted with ethyl acetate.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1[F:8].[C:12]1(OB(O)O)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:8][C:7]1[CH:6]=[CH:5][C:4]([N+:9]([O-:11])=[O:10])=[CH:3][C:2]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=[N+]([O-])c1ccc(F)c(Cl)c1
Reactant: OB(O)Oc1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: O=[N+]([O-])c1ccc(F)c(-c2ccccc2)c1
Temperature: 80 °C

Procedure:
1.75 g (0.01 mole) of 3-chloro-4-fluoronitrobenzene and 0.013 mole of phenylboric acid were dissolved in 70 mL of 1,2-dimethoxyethane under argon. Then, 0.5 g (0.0005 mole) of tetrakis(triphenylphosphine)palladium and 13 mL of 2N potassium carbonate solution were added, and the reaction mixture was heated to 80° C. At the end of the reaction, the reaction mixture was poured into 100 mL of ethyl acetate. The organic phase was extracted with dilute sodium hydroxide solution and then dried over magnesium sulfate. The solvent was distilled off from a rotary evaporator, and the residue was purified [by column chromatography] on silica gel using hexane/toluene (10:1) [as the eluent].
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[C:5]1([C@H:11]2[CH2:16][CH2:15][C@H:14]([NH2:17])[CH2:13][CH2:12]2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>C1(C)C=CC=CC=1.CCOCC>[C:5]1([C@H:11]2[CH2:12][CH2:13][C@H:14]([N:17]=[C:1]=[O:2])[CH2:15][CH2:16]2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: O=C(Cl)Cl
Reactant: N[C@H]1CC[C@H](c2ccccc2)CC1
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: O=C=N[C@H]1CC[C@H](c2ccccc2)CC1
Temperature: 80 °C

Procedure:
Phosgene (20% in toluene, 5 ml) was added to a solution of trans-4-phenylcyclohexylamine (500 mg, 2.85 mmol) in toluene (5 ml) under nitrogen at room temperature. The resulting solution was heated at 80° C. for 24 hours. Solvents were then removed under vacuum to leave a solid residue. This residue was dispersed in ether and filtered. The eluent was collected and concentrated to give 379 mg of trans-4-phenylcyclohexylisocyanate as a light yellow oil. IR (film) 2259 cm−1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]([N:11]2[C:15](=[O:16])[CH:14]=[C:13]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:12]2[C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH3:10])=[CH:5][CH:4]=1>[Pd]>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C@@H:9]([N:11]2[C:15](=[O:16])[CH2:14][C@H:13]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[C@@H:12]2[C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH3:10])=[CH:7][CH:8]=1
Reactant: CCOC(=O)C1C(c2ccccc2)=CC(=O)N1[C@@H](C)c1ccc(OC)cc1
Agent: [Pd]
Product: CCOC(=O)[C@H]1[C@@H](c2ccccc2)CC(=O)N1[C@@H](C)c1ccc(OC)cc1
Yield: 99.3 %

Procedure:
A mixture of ethyl 1-[(1S)-1-(4-methoxyphenyl)ethyl]-5-oxo-3-phenyl-3-pyrroline-2-carboxylate (5 g, 13.7 mmol) and 10% palladium on carbon (0.5 g) was maintained under a H2 atmosphere (55 psi) overnight. The resulting mixture was filtered through a plug of Celite© and silica gel to give ethyl cis-1-[(1S)-1-(4-methoxyphenyl)ethyl]-5-oxo-3-phenylpyrrolidine-2-carboxylate (5 g, 100%). The mixture of diastereomers was triturated (Et2O) to give (4R,5R)-5-(ethoxycarbonyl)-1-(4-methoxyphenyl)ethyl]-4-phenylpyrrolidin-2-one (2.0 g, 40%): 1H NMR (CDCl3) δ 0.62 (t, J=7.1 Hz, 3H). 1.60 (d, J=6.9 Hz, 3H), 2.60 (q, J=8.1 Hz, 1H), 3.09-3.30 (m, 3H), 3.70-3.88 (m, 4H), 4.31 (d, J=8.3 Hz, 1H), 5.52 (q, J=7.3 Hz, 1H), 6.76-6.82 (m, 2H), 7.15-7.31 (m, 7H); HPLC ES-MS m/z (rel abundance) 368 (MH+, 100%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@H:12]([C:13]([OH:15])=O)[CH2:11][S:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:16][O:17][C:18](=[O:40])[C@H:19]([CH2:36][CH2:37][S:38][CH3:39])[NH:20][C:21](=[O:35])[C:22]1[CH:27]=[CH:26][C:25]([NH2:28])=[CH:24][C:23]=1[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[CH3:16][O:17][C:18](=[O:40])[C@H:19]([CH2:36][CH2:37][S:38][CH3:39])[NH:20][C:21](=[O:35])[C:22]1[CH:27]=[CH:26][C:25]([NH:28][C:13]([C@@H:12]2[CH2:11][S:10][CH2:9][N:8]2[C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])=[O:15])=[CH:24][C:23]=1[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: CC(C)(C)OC(=O)N1CSC[C@H]1C(=O)O
Reactant: COC(=O)[C@H](CCSC)NC(=O)c1ccc(N)cc1-c1ccccc1
Product: COC(=O)[C@H](CCSC)NC(=O)c1ccc(NC(=O)[C@@H]2CSCN2C(=O)OC(C)(C)C)cc1-c1ccccc1

Procedure:
The desired compound was prepared by coupling of N-tert-butoxycarbonyl-(R)-(−) thiazolidine-4-carboxylic acid, prepared as in Example 164A with [4-amino-2-phenylbenzoyl]methionine methyl ester (compound 8) according to the method of Example 163D.