Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][NH:8][CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[F:11][C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][C:19]=1F)[CH:15]=[O:16]>>[O:1]1[C:5]2([CH2:10][CH2:9][N:8]([C:19]3[CH:18]=[CH:17][C:14]([CH:15]=[O:16])=[CH:13][C:12]=3[F:11])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1
Reactant: C1CC2(CCN1)OCCO2
Reactant: O=Cc1ccc(F)c(F)c1
Product: O=Cc1ccc(N2CCC3(CC2)OCCO3)c(F)c1

Procedure:
The title compound was prepared from 1,4 dioxa-8-azaspiro[4.5]decane and 3,4-difluorobenzaldehyde according to the procedure of Example 56 as an orange oil; 1H NMR (300 MHz, CDCl3) δ 1.88 (t, J=5.7 Hz, 4H), 3.35 (t, J=5.8 Hz, 4H), 4.01 (s, 4H), 6.96 (t, J=7.8 Hz, 1H), 7.47-7.49 (m, 1H), 7.53-7.58 (m, 1H), 9.81 (s, 1H); MS (ES) m/z: 265.8 (MH+).
Reaction SMILES: [C:1]([NH:9][C@@H:10]1[CH2:19][CH2:18][C:13]2(OCC[O:14]2)[CH2:12][C@@H:11]1[C:20]([OH:22])=[O:21])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl>C(#N)C>[C:1]([NH:9][C@@H:10]1[CH2:19][CH2:18][C:13](=[O:14])[CH2:12][C@@H:11]1[C:20]([OH:22])=[O:21])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(N[C@@H]1CCC2(C[C@@H]1C(=O)O)OCCO2)c1ccccc1
Agent: Cl
Solvent: CC#N
Product: O=C1CC[C@@H](NC(=O)c2ccccc2)[C@@H](C(=O)O)C1
Yield: 67 %

Procedure:
(7S,8R)-8-Benzamido-1,4-dioxaspiro[4.5]decane-7-carboxylic acid (750 mg, 2.456 mmol) was dissolved in acetonitrile (10 mL) at 25° C. with stirring. 1N HCl (12.28 mL, 12.28 mmol) was then added thereto and the reaction stirred at 25° C. for about 16 hours. The reaction was concentrated to remove the acetonitrile. White solids precipitated and ethyl acetate and THF were added to dissolve the solids. The resulting mixture was rinsed (3×) with water. The organic layer was dried over sodium sulfate and concentrated to give (1S,2R)-2-benzamido-5-oxocyclohexanecarboxylic acid (430 mg, 1.646 mmol, 67.0% yield) as a white solid. MS (ESI+)=262.11 (M+H)+.
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([C@H:14]2[C:19]3=[N:20][S:21](=[O:25])(=[O:24])[CH2:22][CH2:23][N:18]3[CH2:17][CH2:16][NH:15]2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:33](Cl)(=[O:35])[CH3:34].O>C1COCC1>[C:33]([N:15]1[CH2:16][CH2:17][N:18]2[C:19](=[N:20][S:21](=[O:25])(=[O:24])[CH2:22][CH2:23]2)[C@@H:14]1[C:11]1[CH:12]=[CH:13][C:8]([O:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:9][CH:10]=1)(=[O:35])[CH3:34]
Reactant: CC(=O)Cl
Reactant: O=S1(=O)CCN2CCN[C@@H](c3ccc(Oc4ccccc4)cc3)C2=N1
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)N1CCN2CCS(=O)(=O)N=C2[C@@H]1c1ccc(Oc2ccccc2)cc1
Reaction time: 20 h

Procedure:
A mixture of (9S)-9-(4-phenoxyphenyl)-3,4,6,7,8,9-hexahydropyrazino[2,1-c][1,2,4]thiadiazine 2,2-dioxide (129 mg), triethylamine (0.100 mL) and acetyl chloride (0.026 mL) in THF (4 mL) was stirred at 0° C. to room temperature for 20 hr. The reaction mixture was added with water, and the precipitate was filtered. The collected solid was purified by recrystallization from MeOH-EtOAc then preparative HPLC (C18, MeCN in H2O with 10 mM NH4HCO3). The combined collected fractions were concentrated in vacuo. The resulting solid was recrystallized from EtOAc—IPE to give the title compound (60 mg) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[C:7]2[CH:11]1[CH2:16][CH2:15][N:14]([C:17](=[O:29])[CH2:18][C:19]2[CH:24]=[C:23]([N+:25]([O-])=O)[CH:22]=[CH:21][C:20]=2[CH3:28])[CH2:13][CH2:12]1.Cl>[Fe].C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[C:7]2[CH:11]1[CH2:16][CH2:15][N:14]([C:17](=[O:29])[CH2:18][C:19]2[CH:24]=[C:23]([NH2:25])[CH:22]=[CH:21][C:20]=2[CH3:28])[CH2:13][CH2:12]1
Reactant: Cc1ccc([N+](=O)[O-])cc1CC(=O)N1CCC(c2c[nH]c3c(Cl)cccc23)CC1
Agent: [Fe]
Agent: Cl
Solvent: CCO
Product: Cc1ccc(N)cc1CC(=O)N1CCC(c2c[nH]c3c(Cl)cccc23)CC1
Yield: 92.9 %

Procedure:
A mixture of (2-methyl-5-nitrophenyl)acetic acid (2.5 g) and 1,1′-carbonyldiimidazole (2.1 g) in dimethyl formamide (50 mL) was stirred at room temperature for 15 min and subsequently added a solution of 7-chloro-3-(piperidin-4-yl)-1H-indole (3.0 g) in dimethyl formamide (50 mL). The resulting mixture was stirred at room temperature for 1 h and poured onto an ice/water mixture. The compound was isolated by filtration and dissolved in tetrahydrofuran. The organic phase was washed with brine, dried (MgSO4), filtered and concentrated in vacuo to give 7-chloro-3-{1-[2-(2-methyl-5-nitrophenyl)-1-oxoethyl]-piperidin-4-yl}-1H-indole (4.7 g). A mixture of 7-chloro-3-{1-[2-(2-methyl-5-nitrophenyl)-1-oxoethyl]-piperidin-4-yl}-1H-indole (16.6 g) and ethanol (500 mL) was heated to reflux temperature and subsequently added concentrated HCl (22 mL) and iron powder (11.3 g) over a period of 30 min. The resulting mixture was boiled under reflux for an additional 90 min, filtered hot and concentrated in vacuo. The residue was dissolved in tetrahydrofuran, and the organic phase was washed with brine, dried (MgSO4), filtered and concentrated in vacuo to give give 7-chloro-3-{1-[2-(5-amino-2-methylphenyl)-1-oxoethyl]-piperidin-4-yl}-1H-indole (14.3 g). A suspension of lithium aluminium hydride (6.4 g) in tetrahydrofuran (250 mL) was cooled (5° C.) and subsequently added a mixture of 7-chloro-3-{1-[2-(5-amino-2-methylphenyl)-1-oxoethyl]-piperidin-4-yl}-1H-indole (16.0 g) in tetrahydrofuran (250 mL). The resulting mixture was boiled under reflux for 90 min, cooled to 5° C. and quenched by the addition of water. The mixture was dried (MgSO4), stirred for 10 min, filtered and concentrated in vacuo to give 7-chloro-3-{1-[2-(5-amino-2-methylphenyl)ethyl]piperidin-4-yl}-1H-indole (12.4 g). A solution of 7-chloro-3-{1-[2-(5-amino-2-methylphenyl)ethyl]piperidin-4-yl}-1H-indole (1.0 g) and N-ethyldiisopropylamine (0.7 g) in tetrahydrofuran (25 mL) was cooled (5° C.) and subsequently added a solution of (4-fluorophenyl)acetyl chloride in tetrahydrofuran (25 mL). The resulting mixture was stirred at room temperature for 1 h and subsequently poured onto brine. The aqueous phase was extracted with tetrahydrofuran, and the combined organic phases were dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by flash chromatography on silicagel (eluent:ethyl acetate/heptane/triethylamine 70:30:5) to give the product (0.81 g). LC/MS (m/z) 504 (MH+), RT=2.45, purity: 62%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13](=[O:14])[O:12][N:11]=[C:10]2[C:15]2[C:19]([CH2:20][OH:21])=[N:18][O:17][N:16]=2)[CH:5]=[CH:6][C:7]=1[F:8].[C:22]1(O)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13](=[O:14])[O:12][N:11]=[C:10]2[C:15]2[C:19]([CH2:20][O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[N:18][O:17][N:16]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: Oc1ccccc1
Reactant: O=c1onc(-c2nonc2CO)n1-c1ccc(F)c(Cl)c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=c1onc(-c2nonc2COc2ccccc2)n1-c1ccc(F)c(Cl)c1
Temperature: 0 °C
Reaction time: 4 h
Yield: 48.2 %

Procedure:
4-(3-Chloro-4-fluorophenyl)-3-[4-(hydroxymethyl)-1,2,5-oxadiazol-3-yl]-1,2,4-oxadiazol-5(4H)-one (15 mg, 0.0480 mmol), phenol (14 mg, 0.14 mmol) and triphenylphosphine (16 mg, 0.062 mmol) were dissolved in anhydrous THF (500 μL) then cooled to 0° C., followed by a dropwise addition of diethyl azodicarboxylate (9.8 μL, 0.062 mmol) in a solution of THF. Reaction was allowed to warm to rt then stirred 4 hrs. After concentration in vacuo, the sample was purified by reverse phase HPLC to yield a white powder (9 mg, 48%). MF=C17H10ClFN4O4; LCMS calculated for C17H11ClFN4O4(M+H)+: m/z=389.045
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[N:12]([S:13]([C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=3)(=[O:15])=[O:14])[CH:11]([C:23](O)=[O:24])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.O[NH:27][C:28](=[NH:30])[CH3:29]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[N:12]([S:13]([C:16]3[CH:17]=[CH:18][C:19]([CH3:22])=[CH:20][CH:21]=3)(=[O:15])=[O:14])[CH:11]([C:23]3[O:24][N:30]=[C:28]([CH3:29])[N:27]=3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: CC(=N)NO
Reactant: Cc1ccc(S(=O)(=O)N2C(C(=O)O)CCC2c2ccc(F)cc2)cc1
Product: Cc1ccc(S(=O)(=O)N2C(c3ccc(F)cc3)CCC2c2nc(C)no2)cc1

Procedure:
The title compound, off-white solid, m.p. 128° C. and MS: m/e=401.2 (M+) was prepared in accordance with the general method of example 13 from (2RS,5SR)-5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidine-2-carboxylic acid and N-hydroxy-acetamidine.
Reaction SMILES: [S:1]1[CH:5]=[C:4]([C:6]([CH:8]2[CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][CH2:9]2)=[O:7])[C:3]2[CH:21]=[CH:22][CH:23]=[CH:24][C:2]1=2>FC(F)(F)C(O)=O.C(OCC)C>[S:1]1[CH:5]=[C:4]([C:6]([CH:8]2[CH2:9][CH2:10][NH:11][CH2:12][CH2:13]2)=[O:7])[C:3]2[CH:21]=[CH:22][CH:23]=[CH:24][C:2]1=2
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)c2csc3ccccc23)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: CCOCC
Product: O=C(c1csc2ccccc12)C1CCNCC1
Temperature: 25 °C
Reaction time: 0.58 h

Procedure:
Dissolve 4-[(benzo[b]thiophene-3-yl)carbonyl]-1-piperidinecarboxylic acid, 1,1-dimethylethyl ester (3.75 g, 10.8 mmol) in trifluoroacetic acid (30 mL). Stir at room temperature for 30-40 minutes. Cool in an ice bath and dilute with ethyl ether (200 mL). Keep at 0° C. for 1-2 hours, collect the solid by filtration and recrystallize (methanol/ethyl ether) to give the title compound as small colorless plates; mp 195°-197° C.
Reaction SMILES: [F:1][C:2]1[C:3]2[CH:4]=[C:5]3[C:14]4[N:15]=[C:16]([C:19]5[C:20]([N:38]([CH3:43])[S:39]([CH3:42])(=[O:41])=[O:40])=[CH:21][C:22]6[O:26][C:25]([C:27]7[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=7)=[C:24]([C:34]([NH2:36])=[O:35])[C:23]=6[CH:37]=5)[CH:17]=[CH:18][C:13]=4[O:12][CH2:11][N:6]3[C:7]=2[CH:8]=[CH:9][CH:10]=1>CN(C(OC)OC)C>[CH3:5][N:6](/[CH:11]=[N:36]\[C:34]([C:24]1[C:23]2[CH:37]=[C:19]([C:16]3[CH:17]=[CH:18][C:13]4[O:12][CH2:11][N:6]5[C:7]6[CH:8]=[CH:9][CH:10]=[C:2]([F:1])[C:3]=6[CH:4]=[C:5]5[C:14]=4[N:15]=3)[C:20]([N:38]([CH3:43])[S:39]([CH3:42])(=[O:41])=[O:40])=[CH:21][C:22]=2[O:26][C:25]=1[C:27]1[CH:28]=[CH:29][C:30]([F:33])=[CH:31][CH:32]=1)=[O:35])[CH3:7]
Reactant: CN(c1cc2oc(-c3ccc(F)cc3)c(C(N)=O)c2cc1-c1ccc2c(n1)-c1cc3c(F)cccc3n1CO2)S(C)(=O)=O
Agent: COC(OC)N(C)C
Product: CN(C)/C=N\C(=O)c1c(-c2ccc(F)cc2)oc2cc(N(C)S(C)(=O)=O)c(-c3ccc4c(n3)-c3cc5c(F)cccc5n3CO4)cc12

Procedure:
To a solution of 5-(11-fluoro-6H-pyrido[2′,3′:5,6][1,3]oxazino[3,4-a]indol-2-yl)-2-(4-fluorophenyl)-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide (80 mg, 0.13 mmol) in DMF-DMA (2 mL) was stirred at 120° C. for 2 hour. The reaction mixture was concentrated in vacuo and the resulting residue was used to the next step without further purification. 1H-NMR (CDCl3, 400 MHz) δ 8.66 (s, 2H), 8.10˜8.15 (m, 2H), 7.63 (s, 1H), 7.58 (d, J=8.4 Hz, 1H), 7.48 (d, J=8.4 Hz, 1H), 7.10˜7.24 (m, 5H), 6.82˜6.87 (m, 1H), 6.00 (s, 2H), 3.38 (s, 3H), 3.16 (s, 3H), 3.08 (s, 3H), 2.78 (s, 3H). MS (M+H)+: 656.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([CH3:11])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].[Br:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17][NH2:18])=[CH:15][CH:14]=1>CCO>[Br:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17][NH:18][C:2]2[CH:3]=[C:4]([CH3:11])[CH:5]=[CH:6][C:7]=2[N+:8]([O-:10])=[O:9])=[CH:15][CH:14]=1
Reactant: Cc1ccc([N+](=O)[O-])c(F)c1
Reactant: NCc1ccc(Br)cc1
Solvent: CCO
Product: Cc1ccc([N+](=O)[O-])c(NCc2ccc(Br)cc2)c1
Temperature: 25 °C
Yield: 72.6 %

Procedure:
To a solution of 3-fluoro-4-nitrotoluene (0.30 g, 1.93 mmol) in EtOH (18 ml) at rt under nitrogen was added 4-bromobenzylamine (0.36 g, 1.93 mmol) slowly. The reaction was warmed to reflux where it was maintained for 2 d. After this time, the mixture was cooled to rt and concentrated under reduced pressure. The crude product was partitioned between H2O and EtOAc and the organic phase was separated, washed with 5N HCl, dried (Na2SO4) and concentrated under reduced pressure to provide (4-bromo-benzyl)-(5-methyl-2-nitro-phenyl)-amine (0.45 g, 72%) as a yellow solid.
Reaction SMILES: [CH2:1]=[C:2]1[CH2:11][CH2:10][C:5]2(OCC[O:6]2)[CH2:4][CH2:3]1.[N+](=[CH:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[N-]>C(Cl)Cl.C(O[Rh]OC(=O)C)(=O)C>[O:6]=[C:5]1[CH2:10][CH2:11][C:2]2([C@@H:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:1]2)[CH2:3][CH2:4]1
Reactant: CCOC(=O)C=[N+]=[N-]
Reactant: C=C1CCC2(CC1)OCCO2
Agent: CC(=O)O[Rh]OC(C)=O
Solvent: ClCCl
Product: CCOC(=O)[C@H]1CC12CCC(=O)CC2
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.5 %

Procedure:
A solution of diacetoxyrhodium (0.14 g, 0.317 mmol) and 8-methylene-1,4-dioxaspiro[4.5]decane (1.5 g, 9.73 mmol) in DCM (20 mL) was heated to reflux, and a solution of ethyl 2-diazoacetate (2.018 mL, 19.45 mmol) in DCM (6 mL) was added to it via syringe pump at 3.0 mL/h. The reaction mixture was stirred for 2 h after the completion of the addition, cooled to rt and concentrated. The residue was purified by silica gel chromatography (EtOAc/hexane) to afford ethyl (1S)-6-oxospiro[2.5]octane-1-carboxylate (1.9 g). 1H NMR (400 MHz, CDCl3) δ ppm 4.08-4.18 (2H, m), 3.94-3.99 (4H, m), 1.83 (4H, m), 1.59-1.67 (2H, m), 1.49-1.58 (2H, m), 1.35-1.46 (1H, m), 1.23-1.30 (3H, m), 1.15 (1H, t, J=4.89 Hz), 0.90 (1H, dd, J=7.91, 4.39 Hz).
Reaction SMILES: [OH-].[Na+].[F:3][C:4]1[CH:5]=[C:6]([C:27]2[C:28]([CH3:44])=[CH:29][C:30]([O:33][CH2:34][C:35]3([C:39]([O:41]CC)=[O:40])[CH2:38][CH2:37][CH2:36]3)=[N:31][CH:32]=2)[CH:7]=[CH:8][C:9]=1[C:10]1[N:11]([CH2:19][O:20][CH2:21][CH2:22][Si:23]([CH3:26])([CH3:25])[CH3:24])[CH:12]=[C:13]([C:15]([F:18])([F:17])[F:16])[N:14]=1>CO>[F:3][C:4]1[CH:5]=[C:6]([C:27]2[C:28]([CH3:44])=[CH:29][C:30]([O:33][CH2:34][C:35]3([C:39]([OH:41])=[O:40])[CH2:36][CH2:37][CH2:38]3)=[N:31][CH:32]=2)[CH:7]=[CH:8][C:9]=1[C:10]1[N:11]([CH2:19][O:20][CH2:21][CH2:22][Si:23]([CH3:26])([CH3:25])[CH3:24])[CH:12]=[C:13]([C:15]([F:18])([F:16])[F:17])[N:14]=1
Reactant: CCOC(=O)C1(COc2cc(C)c(-c3ccc(-c4nc(C(F)(F)F)cn4COCC[Si](C)(C)C)c(F)c3)cn2)CCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1cc(OCC2(C(=O)O)CCC2)ncc1-c1ccc(-c2nc(C(F)(F)F)cn2COCC[Si](C)(C)C)c(F)c1
Yield: 102.5 %

Procedure:
Methanol (6.3 mL) and 1N aqueous sodium hydroxide solution (2.6 mL) were added to ethyl 1-{[(5-{3-fluoro-4-[4-(trifluoromethyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl]phenyl}-4-methylpyridin-2-yl)oxy]methyl}cyclobutanecarboxylate (315 mg) and the mixture was refluxed for 1 hour. Methanol was distilled off under reduced pressure, and the residue was neutralized by 1N hydrochloric acid. The mixture was extracted with ethyl acetate, the organic layer was washed with a saturated brine, and dried over anhydrous magnesium sulfate. After concentrating the mixture under reduced pressure, the obtained residue was purified by silica gel column chromatography (chloroform:methanol=100:0 to 95:5) to obtain 1-{[(5-{3-fluoro-4-[4-(trifluoromethyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl]phenyl}-4-methylpyridin-2-yl)oxy]methyl}cyclobutanecarboxylic acid (308 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[CH:5][CH:4]=1.Cl[C:17]1[CH:18]=[CH:19][C:20]2[N:21]([C:23]([C:26]([F:29])([F:28])[F:27])=[N:24][N:25]=2)[N:22]=1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][N:10]2[CH2:15][CH2:14][N:13]([C:17]3[CH:18]=[CH:19][C:20]4[N:21]([C:23]([C:26]([F:27])([F:29])[F:28])=[N:24][N:25]=4)[N:22]=3)[CH2:12][CH2:11]2)=[CH:5][CH:4]=1
Reactant: FC(F)(F)c1nnc2ccc(Cl)nn12
Reactant: COc1ccc(CN2CCNCC2)cc1
Product: COc1ccc(CN2CCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)cc1

Procedure:
A mixture of 1-[(4-methoxyphenyl)methyl]piperazine and 6-chloro-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine was allowed to react by General Synthetic Method 3. The crude product was purified by hplc using a Waters XTerra C18 column (5μ silica, 19 mm diameter, 100 mm length) eluted with decreasingly polar mixtures of water (containing 0.1% aqueous ammonia) and acetonitrile as eluents to give 6-[4-[(4-methoxyphenyl)methyl]piperazin-1-yl]-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9]([CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)(=[O:11])=[O:10])[CH:5]=[CH:6][C:7]=1[Cl:8].Cl[C:19]1[C:24]([C:25]#[N:26])=[CH:23][CH:22]=[CH:21][N:20]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([S:9]([CH:12]2[CH2:17][CH2:16][N:15]([C:19]3[N:20]=[CH:21][CH:22]=[CH:23][C:24]=3[C:25]#[N:26])[CH2:14][CH2:13]2)(=[O:11])=[O:10])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: N#Cc1cccnc1Cl
Reactant: O=S(=O)(c1ccc(Cl)c(Cl)c1)C1CCNCC1
Product: N#Cc1cccnc1N1CCC(S(=O)(=O)c2ccc(Cl)c(Cl)c2)CC1
Yield: 99.9 %

Procedure:
Using the procedure from Example 7A, Step 7E, 4-[(3,4-dichlorophenyl)sulfonyl]piperidine (150 mg, 0.51 mmol) was reacted with 2-chloro-3-cyanopyridine (85 mg, 0.61 mmol) to afford the title compound (202 mg), a white solid, in 77% yield.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:44]=[CH:43][C:12]([C:13]([O:15][C:16]2[CH:21]=[CH:20][C:19]([CH2:22][N:23]([CH2:35][C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[C:24](=[O:34])[C:25]3[CH:30]=[CH:29][C:28]([N+:31]([O-])=O)=[CH:27][CH:26]=3)=[CH:18][CH:17]=2)=[O:14])=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]>C1COCC1.[Pd]>[CH2:1]([O:8][C:9]1[CH:44]=[CH:43][C:12]([C:13]([O:15][C:16]2[CH:21]=[CH:20][C:19]([CH2:22][N:23]([CH2:35][C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[C:24](=[O:34])[C:25]3[CH:26]=[CH:27][C:28]([NH2:31])=[CH:29][CH:30]=3)=[CH:18][CH:17]=2)=[O:14])=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCCCCOc1ccc(C(=O)Oc2ccc(CN(CC(=O)OC(C)(C)C)C(=O)c3ccc([N+](=O)[O-])cc3)cc2)cc1
Agent: [Pd]
Solvent: C1CCOC1
Product: CCCCCCCOc1ccc(C(=O)Oc2ccc(CN(CC(=O)OC(C)(C)C)C(=O)c3ccc(N)cc3)cc2)cc1

Procedure:
Prepared using General Procedure 5: A solution of 4-((N-(2-(tert-butoxy)-2-oxoethyl)-4-nitrobenzamido)methyl)phenyl 4-(heptyloxy)benzoate INT-3 (888 mg, 1.47 mmol) in THF (15 mL) was hydrogenated in an H-Cube (55 mmol Pd/C cartridge, 1 mL/min, 15 mL volume). The reaction mixture was concentrated to provide 896 mg of crude 4-((4-amino-N-(2-(tert-butoxy)-2-oxoethyl)benzamido)methyl)phenyl 4-(heptyloxy)benzoate INT-4. The crude material was carried forward without further purification. LCMS-ESI (m/z) calculated for C34H42N2O6: 574; found 475 [M+H-Boc]+, tR=3.48 min (Method 5). 1H NMR (400 MHz, CDCl3) δ 8.20-8.04 (m, 2H), 7.44-7.26 (m, 4H), 7.19 (d, J=8.1 Hz, 2H), 7.01-6.90 (m, 2H), 6.63 (d, J=8.3 Hz, 2H), 4.73 (s, 2H), 4.04 (t, J=6.6 Hz, 2H), 3.80-3.67 (m, 2H), 1.89-1.76 (m, 2H), 1.45 (s, 9H), 1.42-1.23 (m, 8H), 0.90 (t, J=6.9 Hz, 3H).
Reaction SMILES: C(OC([N:11]1[CH2:15][C@H:14]([CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[CH2:13][C@H:12]1[CH2:22][OH:23])=O)C1C=CC=CC=1.[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=[O:25].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.Cl>CN(C)C=O>[CH:16]1([CH:14]2[CH2:15][NH:11][C@H:12]([C:22]([OH:23])=[O:25])[CH2:13]2)[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]1
Reactant: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Reactant: O=C(OCc1ccccc1)N1C[C@H](C2CCCCC2)C[C@H]1CO
Agent: Cl
Agent: c1cc[nH+]cc1
Solvent: CN(C)C=O
Product: O=C(O)[C@@H]1CC(C2CCCCC2)CN1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of (2S-trans)-1-[(benzyloxy)-carbonyl]-4-cyclohexyl-2-pyrrolidinemethanol (0.65 g) in dimethylformamide (10 ml) was added pyridinium dichromate (2.1 g). The mixture was stirred at room temperature for 16 hours and poured onto crushed ice and hydrochloric acid (25 ml). Extraction with ethyl acetate followed by solvent evaporation yielded 0.4 g of (trans)-1-[benzyloxy)carbonyl]-4-cyclohexyl-L-proline as a thick oil. The compound can be deprotected using catalytic hydrogenation as described in Method V.
Reaction SMILES: [C:1]1(C2C=C(O)C=CC=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1.C(=O)([O-])[O-].[K+].[K+].BrC1C=C(C2N(C3C(C(C)C)=CC=CC=3C(C)C)C=CN=2)C=CC=1>[Cu]I.CN(C=O)C>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1
Reactant: Oc1cccc(-c2nccc3ccccc23)c1
Agent: [Cu]I
Agent: CC(C)c1cccc(C(C)C)c1-n1ccnc1-c1cccc(Br)c1
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: c1ccc2cnccc2c1
Temperature: 137.5 °C
Yield: 165.6 %

Procedure:
3-(isoquinolin-1-yl)phenol (1.5 g, 6.78 mmol), potassium carbonate (2.5 g, 18.12 mmol), 2-(3-bromophenyl)-1-(2,6-diisopropylphenyl)-1H-imidazole (2.60 g, 6.78 mmol), copper(I) iodide (0.039 g, 0.203 mmol) and ferric acetylacetonate (0.144 g, 0.407 mmol) were charged into the reaction flask with 45 mL of DMF. This heterogeneous mixture was degassed with nitrogen then was heated at 135-140° C. for 2½ days. The reaction mixtures were filtered through a pad of Celite® and the pad was rinsed with ethyl acetate. The filtrate was diluted with 300 mL of water. This mixture was then extracted 2×200 mL ethyl acetate. These extracts were dried over magnesium sulfate then were filtered and stripped under vacuum. The crude residue was passed through a silica gel column using 7-15% acetone/DCM. The cleaniest fractions were combined and stripped under vacuum yielding 1-(3-(3-(2,6-diisopropylphenyl)-1H-imidazol-2-yl)phenoxy)phenyl)isoquinoline (1.45 g, 40.8% yield) as a light tan solid.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH2:10][C:11]([OH:13])=O)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[CH2:14]([CH2:16][NH2:17])[OH:15].C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2C=CC=CC=2N=N1>CN(C=O)C>[OH:15][CH2:14][CH2:16][NH:17][C:11](=[O:13])[CH2:10][C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1
Reactant: NCCO
Reactant: O=C(O)Cc1cccc([N+](=O)[O-])c1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(Cc1cccc([N+](=O)[O-])c1)NCCO
Temperature: 25 °C
Reaction time: 16 h
Yield: 25.7 %

Procedure:
To a solution of 3-nitrophenylacetic acid (3.21 g, 17.7 mmol), ethanolamine (2.8 g, 46 mmol), and triethylamine (3.0 mL, 22 mmol) in anhydrous DMF (110 mL) was added a solution of benzotriazole-1-yl-oxy-tris-pyrrolidino-phosphonium hexafluorophosphate (PyBOP, 9.37 g, 18.0 mmol) in anhydrous DMF (80 mL). After stirring 16 hours at ambient temperature (under nitrogen), the reaction mixture was concentrated in vacuo, dissolved in DCM and filtered. The filtrate was washed with 10% aqueous citric acid, saturated aqueous NaHCO3, pH 7 buffer, and brine, dried over Na2SO4 and filtered. The evaporated filtrate was then purified by flash chromatography (10% methanol in DCM) giving the title compound (1.02 g, 26%) as a light yellow solid. 1H NMR (300 MHz, CDCl3/CD3OD) δ 8.18 (m, 1H), 8.11 (ddd, 1H, J=8.1 Hz, 2.4 Hz, 1.1 Hz), 7.72 (m, 1H), 7.60 (t, 1H, J=7.8 Hz), 3.62 (s, 2H), 3.44 (t, 2H, J=5.9 Hz), 3.16 (t, 2H, J=5.9 Hz).
Reaction SMILES: Cl.[SH:2][CH2:3][CH2:4][NH2:5].C(=O)([O-])[O-].[K+].[K+].[C:12](Cl)(=[O:17])[CH2:13][CH2:14][CH2:15][CH3:16].ClCCl>O>[SH:2][CH2:3][CH2:4][NH:5][C:12](=[O:17])[CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: NCCS
Reactant: CCCCC(=O)Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Product: CCCCC(=O)NCCS
Temperature: 40 °C
Reaction time: 3 h

Procedure:
Under a nitrogen atmosphere, 22.7 g of 2-mercaptoethylamine hydrochloride (0.2 mol) and 44.3 g of potassium carbonate (0.32 mol) were introduced at room temperature in solution in 130 ml of water. The solution was warmed to 40° C. and 12.0 g of valeryl chloride (0.1 mol) were added dropwise over the course of 15 minutes. The batch was stirred at 40° C. for 3 hours and then cooled to room temperature. 70 ml of dichloromethane were added and a phase separation was carried out. The organic phase was washed with 50 ml of 20% strength ammonium chloride solution, dried over sodium sulfate and freed of its solvent under reduced pressure.