Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:8]1[S:12][C:11]2[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=2[C:9]=1[C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:28]=[CH:27][C:26]([OH:29])=[C:25]([C:30]3[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=3)[CH:24]=2)=[CH:19][CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[O:39][C:40](=[O:50])[C@H:41]([CH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)O>>[CH2:1]([C:8]1[S:12][C:11]2[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=2[C:9]=1[C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:28]=[CH:27][C:26]([O:29][C@H:41]([CH2:43][C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)[C:40]([OH:50])=[O:39])=[C:25]([C:30]3[CH:31]=[CH:32][C:33]([O:36][CH3:37])=[CH:34][CH:35]=3)[CH:24]=2)=[CH:19][CH:18]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)[C@@H](O)Cc1ccccc1
Reactant: COc1ccc(-c2cc(-c3ccc(-c4c(Cc5ccccc5)sc5ccccc45)cc3)ccc2O)cc1
Product: COc1ccc(-c2cc(-c3ccc(-c4c(Cc5ccccc5)sc5ccccc45)cc3)ccc2O[C@H](Cc2ccccc2)C(=O)O)cc1

Procedure:
The title compound was prepared from 4-(2-benzyl-benzo[b]thiophene-3-yl)-4″-methoxy-[1,1′;3′,1″]terphenyl-4′-ol, and (S)-(−)-3-phenyllactic acid methyl ester, in substantially the same manner, as described in Example 1, steps g-h , and was obtained as a white solid, mp 82-84° C.; MS m/e 645 (M−H)+;
Reaction SMILES: C(O)C.[Br:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([CH:15]=O)=[CH:7][CH:6]=1.Cl.[NH2:18][OH:19].C([O-])(=O)C.[Na+]>O>[Br:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8](/[CH:15]=[N:18]/[OH:19])=[CH:7][CH:6]=1
Reactant: O=Cc1ccc(Br)c2ccccc12
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: O/N=C/c1ccc(Br)c2ccccc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Into a 250-mL round-bottom flask, was placed ethanol (100 mL), water (40 mL), 4-bromonaphthalene-1-carbaldehyde (4.3 g, 18.29 mmol, 1.00 equiv), hydroxylamine hydrochloride (1.52 g, 21.87 mmol, 1.20 equiv), sodium acetate (2.25 g, 27.43 mmol, 1.50 equiv). The resulting solution was stirred for 2 h at room temperature. The resulting mixture was concentrated under vacuum. The solids were collected by filtration and washed with enough water. The solid was dried in an oven under reduced pressure. This resulted in 4.5 g (98%) of (E)-N-[(4-bromonaphthalen-1-yl)methylidene]hydroxylamine as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[CH:6][C:3]=1[CH2:4][OH:5].Br[CH2:15][C:16]1[CH:17]=[C:18]([CH2:24][CH:25]([O:29][CH:30]([CH3:32])[CH3:31])[C:26]([O-:28])=[O:27])[CH:19]=[CH:20][C:21]=1[O:22][CH3:23]>>[F:1][C:2]1[CH:9]=[C:8]([C:10]([F:11])([F:12])[F:13])[CH:7]=[CH:6][C:3]=1[CH2:4][O:5][CH2:15][C:16]1[CH:17]=[C:18]([CH2:24][CH:25]([O:29][CH:30]([CH3:32])[CH3:31])[C:26]([OH:28])=[O:27])[CH:19]=[CH:20][C:21]=1[O:22][CH3:23]
Reactant: COc1ccc(CC(OC(C)C)C(=O)[O-])cc1CBr
Reactant: OCc1ccc(C(F)(F)F)cc1F
Product: COc1ccc(CC(OC(C)C)C(=O)O)cc1COCc1ccc(C(F)(F)F)cc1F

Procedure:
Using 2-fluoro-4-(trifluoromethyl)benzyl alcohol and 3-[3-(bromomethyl)-4-methoxyphenyl]-2-isopropoxypropanoate, 3-[3-([2-fluoro-4-(trifluoromethyl)benzyl]oxymethyl)-4-methoxyphenyl]-2-isopropoxypropanoic acid was obtained in the same method as in Example 247).
Reaction SMILES: [OH-:1].[Na+].[CH3:3][N:4]1[C:13]2[N:12]=[CH:11][N:10]=[C:9]([N:14]3[CH2:19][CH2:18][CH:17]([N:20]4[C:24]5[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=5[NH:22][C:21]4=[O:29])[CH2:16][CH2:15]3)[C:8]=2[N:7]=[C:6](OC)[C:5]1=[O:32].Cl>CO>[CH3:3][N:4]1[C:6]([C:5]([OH:32])=[O:1])=[N:7][C:8]2[C:13]1=[N:12][CH:11]=[N:10][C:9]=2[N:14]1[CH2:15][CH2:16][CH:17]([N:20]2[C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=3[NH:22][C:21]2=[O:29])[CH2:18][CH2:19]1
Reactant: COc1nc2c(N3CCC(n4c(=O)[nH]c5ccccc54)CC3)ncnc2n(C)c1=O
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: Cn1c(C(=O)O)nc2c(N3CCC(n4c(=O)[nH]c5ccccc54)CC3)ncnc21
Temperature: 80 °C
Reaction time: 12 h
Yield: 589.5 %

Procedure:
Methanol (25 mL) and aqueous 2M sodium hydroxide solution (25.4 mmol, 12.7 mL, 10 equiv) were added to 8-methyl-6-(methyloxy)-4-[4-(2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)piperidin-1-yl]pteridin-7(8H)-one (1.00 g, 2.54 mmol, 1 equiv) in a 100 mL single-necked round bottomed flask fitted with a Teflon stirrer. The resulting stirred slurry was then heated to 80° C. and the reaction was monitored by LC/MS. The reaction mixture gradually became clear and homogenous. LC/MS indicated that the reaction was complete after 12 hours. The new product peak was characterized by a 394 (MH+) molecular ion and a 350 (MH+−44 (—CO2) decarboxylation fragmentation peak. The reaction mixture was then allowed to cool to room temperature. The stirred reaction mixture was then acidified to pH 2 by the gradual addition of aqueous 3M hydrochloric acid, resulting in the precipitation of a white solid. The resulting slurry was then stirred for 30 minutes and then filtered off. The solid was washed with cold water (2×10 mL) and dried at reduced pressure to give 5.89 g (82% yield) of the title compound as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 10.89 (broad s, 1H), 8.33 (s, 1H), 7.17 (dd, 1H), 6.91 (m, 3H), 5.40 (v broad s, 2H), 4.56 (t, 1H), 3.22 (broad s, 2H), 2.33 (d, 2H), 1.85 (d, 2H). MS (EI) for C18H17N7O3: 394 (MH+), 350 (MH+−44 (—CO2).
Reaction SMILES: [O-:1][CH2:2][CH3:3].[Na+].[Cl:5][C:6]1[CH:7]=[C:8]2[C:16](=[C:17]([N+:20]([O-:22])=[O:21])[C:18]=1F)[NH:15][C:14]1[CH:13]=[N:12][CH:11]=[CH:10][C:9]2=1.Cl>CS(C)=O.O>[Cl:5][C:6]1[CH:7]=[C:8]2[C:16](=[C:17]([N+:20]([O-:22])=[O:21])[C:18]=1[O:1][CH2:2][CH3:3])[NH:15][C:14]1[CH:13]=[N:12][CH:11]=[CH:10][C:9]2=1
Reactant: CC[O-]
Reactant: O=[N+]([O-])c1c(F)c(Cl)cc2c1[nH]c1cnccc12
Agent: Cl
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CCOc1c(Cl)cc2c([nH]c3cnccc32)c1[N+](=O)[O-]
Reaction time: 8 h
Yield: 40 %

Procedure:
Sodium ethoxide (232 mg, 3.4 mmol) was added to a solution of 6-chloro-7-fluoro-8-nitro-9H-β-carboline (200 mg, 0.76 mmol) in DMSO (4 ml) and the reaction mixture allowed to stir overnight. The reaction mixture was diluted with water and the pH of the solution was adjusted to about 4 by adding 1N HCl. The aqueous solution was extracted (3×) with EtOAc. The combined EtOAc layers were dried and evaporated. The crude product was purified by flash chromatography to give the desired product in 40-60% yield. 1H-NMR (300 MHz, DMSO-d6): δ 1.44 (t, 3H), 4.24 (q, 2H), 8.21 (d, 1H), 8.46 (d, 1H), 8.91 (s, 1H), 9.02 (s, 1H). Retention Time (LC, method: ammonium acetate standard): 2.37 min. MS (M+H+): 291.9.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([SH:8])[N:3]=1.IC.[C:11]([O-])([O-])=O.[K+].[K+]>C1COCC1>[CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([S:8][CH3:11])[N:3]=1
Reactant: O=C([O-])[O-]
Reactant: Cc1ccnc(S)n1
Agent: [K+]
Solvent: CI
Solvent: C1CCOC1
Product: CSc1nccc(C)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 88.9 %

Procedure:
A mixture of compound 4-methylpyrimidine-2-thiol (500 g, 3.05 mol), iodomethane (611 g, 4.27 mol) and K2CO3 (915 g, 6.71 mol) in THF (4 L) was stirred at room temperature for 18 h. The suspension was filtered and the solid was washed with ether (500 mL×2). The filtrate was concentrated and dried in vacuum to give compound 2 (380 g, 89.2%) as a yellow oil.
Reaction SMILES: [CH2:1]([O:3][C:4]([C@@H:6]1[CH2:10][C:9](=[O:11])[CH2:8][C@H:7]1[C:12]([OH:14])=O)=[O:5])[CH3:2].[NH:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1.O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>O1CCCC1>[CH2:1]([O:3][C:4]([C@@H:6]1[CH2:10][C:9](=[O:11])[CH2:8][C@H:7]1[C:12]([N:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1)=[O:14])=[O:5])[CH3:2]
Reactant: CCOC(=O)[C@@H]1CC(=O)C[C@H]1C(=O)O
Reactant: C1COCCN1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)[C@@H]1CC(=O)C[C@H]1C(=O)N1CCOCC1
Reaction time: 4 h

Procedure:
To a mixture of (1R,2R)-4-oxo-cyclopentane-1,2-dicarboxylic acid monoethyl ester (10.0 mmol) in tetrahydrofuran (25 ml) was subsequently added morpholine (11 mmol) triethylamine (70 mmol), 1-hydroxybenzotriazole hydrate (20 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC, 20 mmol) and stirring was continued at 22° C. for 4 h. The mixture was partitioned between ethyl acetate and 1N aqueous HCl, the organic layer was washed with saturated aqueous Na2CO3, dried and evaporated to give the title compound as pale brown oil. MS: 270.3 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][NH:8]2)=[C:4]([N:11]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([C:20]([F:23])([F:22])[F:21])[CH:18]=3)[CH2:13][CH2:12]2)[N:3]=1.[NH2:24][C@H:25]1[CH2:30][CH2:29][C@H:28]([NH2:31])[CH2:27][CH2:26]1>>[F:21][C:20]([F:23])([F:22])[C:17]1[CH:18]=[C:19]2[C:14]([CH2:13][CH2:12][N:11]2[C:4]2[N:3]=[C:2]([NH:24][C@H:25]3[CH2:30][CH2:29][C@H:28]([NH2:31])[CH2:27][CH2:26]3)[N:10]=[C:9]3[C:5]=2[N:6]=[CH:7][NH:8]3)=[CH:15][CH:16]=1
Reactant: N[C@H]1CC[C@H](N)CC1
Reactant: FC(F)(F)c1ccc2c(c1)N(c1nc(Cl)nc3[nH]cnc13)CC2
Product: N[C@H]1CC[C@H](Nc2nc(N3CCc4ccc(C(F)(F)F)cc43)c3nc[nH]c3n2)CC1
Temperature: 140 °C

Procedure:
340 mg of product obtained in stage 1 above are mixed with 800 mg of trans-1,4-diaminocyclohexane, and the mixture is then heated at 140° C. for approximately 8 hours. The mixture is allowed. to return to ambient temperature. Purification is carried out by chromatography on silica with a CH2Cl2-MeOH—NH4OH: 85-15-1.5 mixture for eluent. 275 mg of product are obtained and a paste is formed in HCl/ethanol: 50-50. Partial drying and drying under vacuum at 50° C. are carried out. 244 mg of expected product are obtained.
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([CH2:21][CH3:22])[C:5]([NH:10][C@@H:11]2[C:19]3C(=CC=C[CH:18]=3)C[C@@H:12]2[OH:20])=[N:6][C:7]=1[CH2:8][CH3:9].C(C1C(N[C@@H]2C[O:37]C[C@H]2O)=NC(CC)=CN=1)C>>[Br:1][C:2]1[N:3]=[C:4]([CH2:21][CH3:22])[C:5]([NH:10][C@H:11]2[CH2:12][O:20][CH2:18][C@H:19]2[OH:37])=[N:6][C:7]=1[CH2:8][CH3:9]
Reactant: CCc1cnc(CC)c(N[C@@H]2COC[C@H]2O)n1
Reactant: CCc1nc(N[C@@H]2c3ccccc3C[C@@H]2O)c(CC)nc1Br
Product: CCc1nc(N[C@H]2COC[C@H]2O)c(CC)nc1Br

Procedure:
Following the procedure for the preparation of (1R,2S)-1-[(5-bromo-3,6-diethylpyrazin-2-yl)amino]-2,3-dihydro-1H-inden-2-ol but substituting trans-(+/−)-4-[(3,6-diethylpyrazin-2-yl)amino]tetrahydrofuran-3-ol and making non-critical variations provided the title compound as a light yellow solid. IR (diffuse reflectance) 3398, 2971, 2938, 1569, 1539, 1490, 1466, 1447, 1413, 1397, 1251, 1232, 1054, 969, 891 cm−1; OAMS supporting ions at: ESI+ 315.9 & ESI− 313.9; MS (EI) m/z 315 (M+); HRMS (FAB) calcd for C12H18BRN3O2+H1 316.0661, found 316.0656; Anal. Calcd for C12H18BrN3O2: C, 45.58; H, 5.74; N, 13.29. Found: C, 45.49; H, 5.84; N, 13.14.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([CH2:14][CH3:15])[C:11]([C:16]([F:19])([F:18])[F:17])=[CH:10][C:9]=1[NH:20][C:21](=[O:39])[CH2:22][C:23]([C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([C:31]2[CH:36]=[CH:35][N:34]=[C:33]([C:37]#[N:38])[CH:32]=2)[CH:26]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:14]([C:12]1[C:11]([C:16]([F:18])([F:17])[F:19])=[CH:10][C:9]2[NH:20][C:21](=[O:39])[CH2:22][C:23]([C:25]3[CH:26]=[C:27]([C:31]4[CH:36]=[CH:35][N:34]=[C:33]([C:37]#[N:38])[CH:32]=4)[CH:28]=[CH:29][CH:30]=3)=[N:7][C:8]=2[CH:13]=1)[CH3:15]
Reactant: CCc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3ccnc(C#N)c3)c2)cc1C(F)(F)F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCc1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(-c3ccnc(C#N)c3)c1)=N2

Procedure:
The title compound was prepared from (2-{3-[3-(2-cyano-pyridin-4-yl)-phenyl]-3-oxo-propionylamino}-5-ethyl-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example M190) (300 mg, 0.54 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a white solid (158 mg, 67%).
Reaction SMILES: O.NN.[CH3:4][O:5][C:6]1[CH:7]=[C:8](/[CH:16]=[CH:17]/[CH:18]=[CH:19]/[C:20]([N:22]2[CH2:27][CH2:26][N:25]([C:28](=[O:45])/[CH:29]=[CH:30]/[CH:31]=[CH:32]/[C:33]3[CH:38]=[C:37]([O:39][CH3:40])[C:36]([O:41][CH3:42])=[C:35]([O:43][CH3:44])[CH:34]=3)[CH2:24][CH:23]2[CH2:46][N:47]2C(=O)C3=CC=CC=C3C2=O)=[O:21])[CH:9]=[C:10]([O:14][CH3:15])[C:11]=1[O:12][CH3:13]>CO>[NH2:47][CH2:46][CH:23]1[CH2:24][N:25]([C:28](=[O:45])/[CH:29]=[CH:30]/[CH:31]=[CH:32]/[C:33]2[CH:38]=[C:37]([O:39][CH3:40])[C:36]([O:41][CH3:42])=[C:35]([O:43][CH3:44])[CH:34]=2)[CH2:26][CH2:27][N:22]1[C:20](=[O:21])/[CH:19]=[CH:18]/[CH:17]=[CH:16]/[C:8]1[CH:7]=[C:6]([O:5][CH3:4])[C:11]([O:12][CH3:13])=[C:10]([O:14][CH3:15])[CH:9]=1
Reactant: COc1cc(/C=C/C=C/C(=O)N2CCN(C(=O)/C=C/C=C/c3cc(OC)c(OC)c(OC)c3)C(CN3C(=O)c4ccccc4C3=O)C2)cc(OC)c1OC
Agent: NN
Solvent: O
Solvent: CO
Product: COc1cc(/C=C/C=C/C(=O)N2CCN(C(=O)/C=C/C=C/c3cc(OC)c(OC)c(OC)c3)C(CN)C2)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 17 h
Yield: 65.8 %

Procedure:
A solution of 1.3 ml (26 mmol) of hydrazine hydrate in methanol (2 ml) was added to a suspension of 430 mg (0.58 mmol) of N-[1,4-bis[5-(3,4,5-trimethoxyphenyl)penta-(2E,4E)-dienoyl]-2-piperazinylmethyl]phthalimide synthesized by the process described in Example 48 in methanol (8 ml), and the mixture was stirred for 17 hours at room temperature. The reaction mixture was concentrated under reduced pressure, and the resultant residue was extracted with chloroform. An organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate and water, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The resultant crude oil was purified by column chromatography on silica gel to obtain 232 mg (yield: 65%) of 2-aminomethyl-1,4-bis[5-(3,4,5-trimethoxyphenyl)penta-(2E,4E)-dienoyl]piperazine as a pale yellow amorphous powder.
Reaction SMILES: [CH2:1]=[O:2].Cl.CON=C[C:8]1[CH:13]=[C:12]([N:14]2[C:22](=[O:23])[C:21]3[CH2:20][CH2:19][CH2:18][CH2:17][C:16]=3[C:15]2=[O:24])[C:11]([Cl:25])=[CH:10][C:9]=1[Cl:26]>C(O)(=O)C>[Cl:26][C:9]1[CH:10]=[C:11]([Cl:25])[C:12]([N:14]2[C:15](=[O:24])[C:16]3[CH2:17][CH2:18][CH2:19][CH2:20][C:21]=3[C:22]2=[O:23])=[CH:13][C:8]=1[CH:1]=[O:2]
Reactant: CON=Cc1cc(N2C(=O)C3=C(CCCC3)C2=O)c(Cl)cc1Cl
Reactant: C=O
Agent: Cl
Solvent: CC(=O)O
Product: O=Cc1cc(N2C(=O)C3=C(CCCC3)C2=O)c(Cl)cc1Cl
Temperature: 55 °C

Procedure:
9 ml of a 37% strength by weight aqueous formaldehyde solution and 9 ml of concentrated hydrochloric acid were added to a solution of 10.6 g (30 mmol) of 2,4-dichloro-5-(1,3,4,5,6,7-hexahydro-1,3-dioxo-2H-isoindol-2-yl)benzaldehyde (O-methyl)oxime in 45 ml of acetic acid. The mixture was subsequently heated for 1 hour at 50-60° C., whereupon the reaction mixture was poured into 300 ml of ice-water. The product was extracted from the resulting mixture using 200 ml of dichloromethane. The extract was dried over magnesium sulfate and then concentrated. The residue was purified by means of silica gel chromatography (eluent: hexane/ethyl acetate=4:1). Yield: 5.2 g; 1H NMR (270 MHz; in CDCl3): δ [ppm]=1.85 (s, 4H), 2.45 (s, 4H), 7.67 (s, 1H), 7.81 (s, 1H), 10.40 (s, 1H).
Reaction SMILES: [O:1]1[CH2:3][CH:2]1[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:14]=[C:13]([C:15]3[O:19][N:18]=[C:17]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:16]=3[C:26]([F:29])([F:28])[F:27])[O:12][N:11]=2)=[CH:6][CH:5]=1.[NH:30]1[CH2:35][CH2:34][O:33][CH:32]([CH2:36][C:37]([OH:39])=[O:38])[CH2:31]1>CC(O)C.CS(C)=O>[OH:1][CH:2]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:14]=[C:13]([C:15]3[O:19][N:18]=[C:17]([C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=4)[C:16]=3[C:26]([F:28])([F:27])[F:29])[O:12][N:11]=2)=[CH:6][CH:5]=1)[CH2:3][N:30]1[CH2:35][CH2:34][O:33][CH:32]([CH2:36][C:37]([OH:39])=[O:38])[CH2:31]1
Reactant: O=C(O)CC1CNCCO1
Reactant: FC(F)(F)c1c(-c2ccccc2)noc1-c1nc(-c2ccc(C3CO3)cc2)no1
Solvent: CS(C)=O
Solvent: CC(C)O
Product: O=C(O)CC1CN(CC(O)c2ccc(-c3noc(-c4onc(-c5ccccc5)c4C(F)(F)F)n3)cc2)CCO1
Reaction time: 8 h

Procedure:
To a mixture of 3-(4-(oxiran-2-yl)phenyl)-5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazole, Preparation 28C (25 mg, 0.063 mmol) in 2-propanol (2 mL) and DMSO (1 mL) was added 2-(morpholin-2-yl)acetic acid (18.18 mg, 0.125 mmol). The reaction mixture was hated at 80° C. overnight. The crude material was purified via preparative LC/MS with the following conditions: Column: Waters XBridge C18, 19×250 mm, 5-μm particles; Guard Column: Waters XBridge C18, 19×10 mm, 5-μm particles; Mobile Phase A: 5:95 acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10-mM ammonium acetate; Gradient: 15-100% B over 25 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the desired product was 12.8 mg, and its purity was 99%. 1H NMR (400 MHz, MeOD) δ ppm 8.18 (2H, d, J=8.28 Hz), 7.38-7.86 (7H, m), 5.03 (1H, ddd, J=9.03, 4.39, 4.14 Hz), 3.97-4.11 (1H, m), 3.90 (1H, t, J=9.66 Hz), 3.69-3.84 (1H, m), 2.97-3.21 (2H, m), 2.69-2.93 (2H, m), 2.18-2.63 (4H, m). MS (m+1)=545.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:16]=[C:17]([C:19]2[N:20]([CH2:29][CH:30]3[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]3)[C:21]([CH3:28])=[C:22]([S:24](=[O:27])(=[O:26])[NH2:25])[CH:23]=2)[CH:18]=1)[O:8][CH2:9][CH2:10][CH2:11][C:12]([O:14]C)=[O:13])([CH3:4])([CH3:3])[CH3:2].[Li+].[OH-]>CO.C1COCC1>[C:1]([C:5]1[CH:6]=[C:7]([CH:16]=[C:17]([C:19]2[N:20]([CH2:29][CH:30]3[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35]3)[C:21]([CH3:28])=[C:22]([S:24](=[O:26])(=[O:27])[NH2:25])[CH:23]=2)[CH:18]=1)[O:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)CCCOc1cc(-c2cc(S(N)(=O)=O)c(C)n2CC2CCCCC2)cc(C(C)(C)C)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1c(S(N)(=O)=O)cc(-c2cc(OCCCC(=O)O)cc(C(C)(C)C)c2)n1CC1CCCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.9 %

Procedure:
To a solution of compound 15 (126 mg, 0.25 mmol) in methanol and THF (30 mL; 1:1) was added LiOH (25 mg, 1 mmol) and the mixture was stirred at rt overnight. The residue was concentrated and then poured into water and extracted with CH2Cl2. The organic layer was dried over MgSO4, filtered, evaporated and purified by CC to give compound 16 (98 mg, 80%). 1H-NMR (400 MHz, DMSO-d6) δ: 12.2 (br s, 1H), 6.91-6.89 (m, 4H), 6.68 (s, 1H), 6.29 (s, 1H), 4.02-3.98 (m, 2H), 3.81-3.79 (m, 2H), 2.43 (s, 3H) 2.40-2.36 (m, 5H), 1.94-1.91 (m, 2H), 1.48-1.46 (m, 3H), 1.27-1.24 (m, 12H), 0.96-0.94 (m, 3H), 0.66-0.64 (m, 2H). MS Found: 491 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]([C:13]3[CH:18]=[CH:17][C:16]([N+:19]([O-])=O)=[CH:15][CH:14]=3)[CH2:11][CH2:10][CH:9]2[C:22]2[CH:27]=[CH:26][C:25]([C:28]3[N:29]=[C:30]([C@@H:33]4[CH2:37][CH2:36][CH2:35][N:34]4[C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[NH:31][CH:32]=3)=[CH:24][CH:23]=2)=[CH:4][CH:3]=1.[H][H]>C(O)C.C1COCC1.[Pt](=O)=O>[NH2:19][C:16]1[CH:17]=[CH:18][C:13]([CH:12]2[N:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[CH:9]([C:22]3[CH:27]=[CH:26][C:25]([C:28]4[N:29]=[C:30]([C@@H:33]5[CH2:37][CH2:36][CH2:35][N:34]5[C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[NH:31][CH:32]=4)=[CH:24][CH:23]=3)[CH2:10][CH2:11]2)=[CH:14][CH:15]=1
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1c1nc(-c2ccc(C3CCC(c4ccc([N+](=O)[O-])cc4)N3c3ccc(F)cc3)cc2)c[nH]1
Agent: O=[Pt]=O
Solvent: CCO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC[C@H]1c1nc(-c2ccc(C3CCC(c4ccc(N)cc4)N3c3ccc(F)cc3)cc2)c[nH]1
Yield: 100 %

Procedure:
Dissolved the product from Example 39F (300 mg, 0.502 mmol) in ethanol (5 mL) and THF (5 mL) then added platinum(IV) oxide (22.8 mg, 0.1 mmol) and a hydrogen balloon and stirred the solution at room temperature for 2.5 h. Solution was filtered through celite and washed with methanol (10 mL), then concentrated to give the title compound (285 mg, 100%) as a colorless semi-solid and a 1/1 mixture of stereoisomers.
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH2:5][C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[NH:8][CH:7]=1)[CH3:2].[CH3:15][O:16][C:17]([CH2:19][CH2:20][CH2:21][C:22](Cl)=[O:23])=[O:18].Cl>N1C=CC=CC=1>[CH2:1]([N:3]([C:22](=[O:23])[CH2:21][CH2:20][CH2:19][C:17]([O:16][CH3:15])=[O:18])[CH2:4][CH2:5][C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[NH:8][CH:7]=1)[CH3:2]
Reactant: CCNCCc1c[nH]c2ccccc12
Reactant: COC(=O)CCCC(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Product: CCN(CCc1c[nH]c2ccccc12)C(=O)CCCC(=O)OC
Reaction time: 1 h
Yield: 74.4 %

Procedure:
10 g of N-ethyl-tryptamine (i.e., 3-(2-ethylaminoethyl)-indole) were dissolved in 80 ml of pyridine, and 9.62 g of 4-methoxycarbonylbutyryl chloride were added dropwise thereto at 10° C. The mixture was stirred for one hour. After the reaction was completed, the mixture was acidified with dilute hydrochloric acid and then extracted with ethyl acetate. The extract was washed with water, an aqueous saturated sodium bicarbonate solution and water, successively. The washed extract was dried and evaporated under reduced pressure to remove solvent. The oily residue thus obtained was recrystallized from a mixture of ethanol and petroleum ether. 12.5 g of N-ethyl-N-(4-methoxycarbonylbutyryl)-tryptamine (i.e., 3-[2-(N-ethyl-4-methoxycarbonylbutanamido)ethyl]-indole]were thereby obtained as yellow crystals. M.p. 73°-75° C. Yield: 74.4%
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[C:7]1([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[NH2:20])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.Br[CH2:22][C:23]([N:25]([CH:32]([CH3:34])[CH3:33])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:24]>CN(C=O)C>[CH:32]([N:25]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:23](=[O:24])[CH2:22][NH:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[NH:13][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1)([CH3:34])[CH3:33]
Reactant: Nc1ccccc1Nc1ccccc1
Reactant: CC(C)N(C(=O)CBr)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)N(C(=O)CNc1ccccc1Nc1ccccc1)c1ccccc1
Reaction time: 8 h
Yield: 56.1 %

Procedure:
Potassium carbonate (6.9 g) was added to a solution of N-phenylphenylene diamine (9.2 g) in DMF and 2-bromo-N-isopropyl-N-phenyl acetamide (12.7 g) in DMF (200 ml) and the mixture was allowed to stir overnight. The DMF was evaporated in vacuo and the residue was dissolved in ethyl acetate (400 ml) and washed exhaustively with aqueous 1N HC (4×250 ml). The organic layer was washed with water (2×200 ml), dried (Na2SO4) and evaporated to give 17.8 gm of crude alkylated product. The oil was purified by chromatography on silica gel (600 g) using first CHCl3 (8000 mL), then hexane:ethyl acetate (2:1, 8000 ml) as eluents to give the title compound (10 g), as an oil. 1H-NMR (300 MHz, CDCl3): d 7.42-6.8 (m, 14 H), 6.36 (d, 1H), 4.95 (m, 1H), 3.22 (s, 2H), 1.05 (d, 6H); MS (FAB)=360 (MH+); TLC, Rf =0.18 (CHCl3).
Reaction SMILES: O=C1C2C(=CC=CC=2)C(=O)[N:3]1[CH2:12][C@@H:13]([NH:25][C:26]([C:28]1[S:29][C:30]([CH2:39][CH3:40])=[C:31]([C:33]2[N:37]([CH3:38])[N:36]=[CH:35][CH:34]=2)[CH:32]=1)=[O:27])[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[C:21]([F:24])([F:23])[F:22].NN.Cl>O1CCCC1.CO>[NH2:3][CH2:12][C@@H:13]([NH:25][C:26]([C:28]1[S:29][C:30]([CH2:39][CH3:40])=[C:31]([C:33]2[N:37]([CH3:38])[N:36]=[CH:35][CH:34]=2)[CH:32]=1)=[O:27])[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[C:21]([F:24])([F:23])[F:22]
Reactant: CCc1sc(C(=O)N[C@@H](Cc2ccccc2C(F)(F)F)CN2C(=O)c3ccccc3C2=O)cc1-c1ccnn1C
Agent: Cl
Agent: NN
Solvent: C1CCOC1
Solvent: CO
Product: CCc1sc(C(=O)N[C@H](CN)Cc2ccccc2C(F)(F)F)cc1-c1ccnn1C
Reaction time: 12 h
Yield: 57.1 %

Procedure:
To a solution of N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-5-ethyl-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide (486 mg, 0.86 mmol) in tetrahydrofuran (2.144 ml) and methanol (2.14 ml) at 25° C. was added hydrazine (0.269 ml, 8.58 mmol) dropwise. After 12 h, the solution was concentrated, dry loaded and purified via column chromatography (silica, 5% MeOH in DCM (1% NH4OH)). The free base was then converted to the HCl salt by adding excess 4M HCl in dioxane (500 ul) to the residue in MeOH (2 ml) affording N-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-5-ethyl-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide (250 mg, 0.491 mmol, 57.2% yield)-2 HCl as a white solid: LCMS (ES) m/z=437 (M+H)+, 1H NMR (400 MHz, DMSO-d6) δ ppm 8.84 (d, J=8.84 Hz, 1H) 8.08 (br. s., 3H) 7.93 (s, 1H) 7.69 (d, J=7.83 Hz, 1H) 7.51-7.61 (m, 3H) 7.39-7.46 (m, 1H) 6.34 (d, J=2.02 Hz, 1H) 4.48 (br. s., 1H) 3.77 (s, 3H) 2.99-3.11 (m, 4H) 2.74 (q, J=7.49 Hz, 2H) 1.16 (t, J=7.45 Hz, 3H).