Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@@H:2]([CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH2:3][C@H:4]([OH:26])[C@@H:5]([NH:13][C:14]([C@@H:16]([NH:21][C:22](=[O:25])[O:23][CH3:24])[C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH3:34][C@@H:35]([CH2:54][CH3:55])[C@H:36]([N:40]1[CH2:44][CH2:43][N:42]([CH2:45][C:46]2[C:47]([CH3:52])=[N:48][CH:49]=[CH:50][CH:51]=2)[C:41]1=[O:53])[C:37](O)=[O:38].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1>CN(C=O)C>[CH2:6]([C@H:5]([NH:13][C:14]([C@@H:16]([NH:21][C:22](=[O:25])[O:23][CH3:24])[C:17]([CH3:19])([CH3:20])[CH3:18])=[O:15])[C@@H:4]([OH:26])[CH2:3][C@@H:2]([NH:1][C:37](=[O:38])[C@@H:36]([N:40]1[CH2:44][CH2:43][N:42]([CH2:45][C:46]2[C:47]([CH3:52])=[N:48][CH:49]=[CH:50][CH:51]=2)[C:41]1=[O:53])[CH:35]([CH3:34])[CH2:54][CH3:55])[CH2:27][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccccc1)[C@@H](O)C[C@@H](N)Cc1ccccc1)C(C)(C)C
Reactant: CC[C@H](C)[C@@H](C(=O)O)N1CCN(Cc2cccnc2C)C1=O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CCC(C)[C@@H](C(=O)N[C@@H](Cc1ccccc1)C[C@H](O)[C@H](Cc1ccccc1)NC(=O)[C@@H](NC(=O)OC)C(C)(C)C)N1CCN(Cc2cccnc2C)C1=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 54 %

Procedure:
A solution containing the product from Example 8B (2.0 g, 4.40 mmol) in DMF (10 mL) was treated with the product from Example 15C (1.34 g, 4.39 mmol), EDAC (1.01 g, 5.27 mmol), HOBT (0.7 g, 5.19 mmol), and NMM (0.96 mL, 8.72 mmol), stirred at 25° C. for 16 hours, treated with Example 15C (0.13 g), EDAC (0.5 g), HOBT (0.35 g), NMM (1 mL), and DMF (5 mL), stirred for 64 hours at 25° C. and concentrated. The concentrate was partitioned between ethyl acetate and saturated NaHCO3. The organic phase was washed with brine, dried over Na2SO4, filtered and concentrated. The residue was chromatographed on silica gel eluting with 0-4% methanol/dichloromethane to give the title compound (1.76 g, 54% yield). 1H NMR (300 MHz, DMSO-d6), δ ppm 0.68 (d, J=6.62 Hz, 3 H), 0.81 (m, 15 H), 1.26 (m, 1 H), 1.49 (m, 2 H), 1.78 (m, 1 H), 2.45 (m, 5 H), 2.70 (m, 3 H), 2.90 (m, 2 H), 3.04 (m, 2 H), 3.59 (m, 4 H), 3.87 (m, 2 H), 4.13 (m, 2 H), 4.31 (s, 2 H), 4.79 (d, J=5.52 Hz, 1 H), 6.80 (d, J=9.19 Hz, 1 H), 7.05 (s, 3 H), 7.19 (m, 5 H), 7.51 (m, 2 H), 7.86 (d, J=8.82 Hz, 1 H), 8.36 (d, J=3.68 Hz, 1 H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[N:13]([CH3:14])[C:12]([C:15]3[CH:19]=[CH:18][N:17]([CH2:20][CH3:21])[N:16]=3)=[N:11][C:10]=2[C:22]2[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[CH:24][CH:23]=2)=[CH:4][CH:3]=1.[NH2:30][OH:31].CC(N(C)C)=O>CCO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8][C:9]2[N:13]([CH3:14])[C:12]([C:15]3[CH:19]=[CH:18][N:17]([CH2:20][CH3:21])[N:16]=3)=[N:11][C:10]=2[C:22]2[CH:23]=[CH:24][C:25]([C:26](=[N:30][OH:31])[NH2:27])=[CH:28][CH:29]=2)=[CH:6][CH:7]=1
Reactant: NO
Reactant: CCn1ccc(-c2nc(-c3ccc(C#N)cc3)c(Sc3ccc(Cl)cc3)n2C)n1
Solvent: CCO
Solvent: CC(=O)N(C)C
Product: CCn1ccc(-c2nc(-c3ccc(C(N)=NO)cc3)c(Sc3ccc(Cl)cc3)n2C)n1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a suspension of step 3 product C-5 (240 mg, 0.572 mmol) in EtOH (5 ml) was added hydroxylamine (199 mg, 2.86 mmol) and DMA (0.498 ml, 2.86 mmol). After stirred at rt for 10 min, the reaction mixture was heated at 80° C. for 2 hrs. and then concentrated. To the residue was added EtOAc and washed with Na2CO3 (aq), organic layer was dried, and concentrated to give 4-{5-[(4-chlorophenyl)sulfanyl]-2-(1-ethyl-1H-pyrazol-3-yl)-1-methyl-1H-imidazol-4-yl}-N′-hydroxybenzenecarboximidamide (230 mg), which was used for further reaction without purification. LCMS: [M+1]+=453.2.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:9]([OH:11])=[O:10])=[N:6][C:7]=1Cl.[CH3:12][C:13]1([CH2:17][OH:18])[CH2:16][O:15][CH2:14]1.[H-].[Na+].Cl>CN(C=O)C.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:9]([OH:11])=[O:10])=[N:6][C:7]=1[O:18][CH2:17][C:13]1([CH3:12])[CH2:16][O:15][CH2:14]1
Reactant: CC1(CO)COC1
Reactant: O=C(O)c1ccc(Br)c(Cl)n1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC1(COc2nc(C(=O)O)ccc2Br)COC1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 27.1 %

Procedure:
To a solution of 5-bromo-6-chloropicolinic acid (Example 280a) (0.75 g, 3.17 mmol) in dry DMF (18 ml) under argon was added (3-methyloxetan-3-yl)-methanol (389 mg, 3.81 mmol) and NaH (279 mg, 6.98 mmol) was added by portions. The reaction mixture was stirred at room temperature for 20 min until gas release ceased. The reaction mixture was then stirred at 110° C. for 16 h. The reaction mixture was diluted with ethyl acetate, and the solution was poured into a separatory funnel with 10 ml aq. solution 1.0M HCl. After extraction, the organic phase was collected and the aqueous phase was back extracted with ethylacetate. The organic phases were combined, dried over Na2SO4 and evaporated down in vacuo. The residue was purified by preparative HPLC to give the title compound (260 mg, 27%), MS (EI): m/e=302.0 [M+H]+.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:4]=1[N+:11]([O-])=O>C(O)C.[Pd]>[NH2:11][C:4]1[CH:5]=[C:6]([O:9][CH3:10])[CH:7]=[CH:8][C:3]=1[NH:2][CH3:1]
Reactant: CNc1ccc(OC)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Product: CNc1ccc(OC)cc1N

Procedure:
A solution of 0.75 g (4.1mmol) N-methyl-4-methoxy-2-nitroaniline in 150 ml ethanol was hydrogenated at atm. pressure by using 5% Pd-C (0,1 g) as a catalyst. The reaction mixture was filtered, added 2 ml 1N hydrochloric acid and then evaporated in vacuo to give 2-amino-4-methoxy-N-methylaniline as crystals.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[C:5]([NH2:11])=[C:4]([CH3:12])[CH:3]=1.O.O.[Sn](Cl)(Cl)(Cl)Cl>C(O)C>[Br:1][C:2]1[CH:7]=[C:6]([NH2:8])[C:5]([NH2:11])=[C:4]([CH3:12])[CH:3]=1
Reactant: Cc1cc(Br)cc([N+](=O)[O-])c1N
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: CCO
Solvent: O
Product: Cc1cc(Br)cc(N)c1N
Temperature: 25 °C
Yield: 59.3 %

Procedure:
To a suspension of 4-bromo-2-methyl-6-nitro-phenylamine (20 g, 0.086 mol) in ethanol (200 mL) was added tin chloride dihydrate (49.2 g, 0.258 mol). The reaction mixture was heated to reflux for 14 h, cooled to room temperature, and concentrated in vacuo. The residue was diluted with ethyl acetate (150 mL) and treated with triethylamine (40 mL). The resulting slurry was filtered through a pad of celite, and the filtercake was rinsed with three portions ethyl acetate (50 mL). The filtrate was washed with saturated NaHCO3, water, and brine, then dried over Na2SO4 and filtered. After removal of the solvent, the residue was purified by flash chromatography on silica gel (30% EtOAc/hexane, then 5% MeOH/CH2Cl2) to yield the title compound (10.26 g, 59%) as a yellow oil. 1H NMR (300 MHz, CDCl3) δ 6.77 (1H, d, J=2.0 Hz), 6.74 (1H, d, J=2.0 Hz), 2.16 (3H, s). LCMS (M+H)+ m/z 201. (t=0.83 min.).
Reaction SMILES: C(OC([NH:8][CH:9]1[CH2:18][C:17]2[C:12](=[CH:13][C:14]([C:19]3[CH:20]=[CH:21][N:22]4[C:27]([C:28]=3[CH3:29])=[C:26]([CH:30]3[CH2:32][CH2:31]3)[CH:25]=[C:24]([C:33]([OH:35])=[O:34])[C:23]4=[O:36])=[CH:15][CH:16]=2)[NH:11][C:10]1=[O:37])=O)(C)(C)C.[ClH:38].O1CCOCC1>C(#N)C>[ClH:38].[NH2:8][CH:9]1[CH2:18][C:17]2[C:12](=[CH:13][C:14]([C:19]3[CH:20]=[CH:21][N:22]4[C:27]([C:28]=3[CH3:29])=[C:26]([CH:30]3[CH2:31][CH2:32]3)[CH:25]=[C:24]([C:33]([OH:35])=[O:34])[C:23]4=[O:36])=[CH:15][CH:16]=2)[NH:11][C:10]1=[O:37]
Reactant: Cc1c(-c2ccc3c(c2)NC(=O)C(NC(=O)OC(C)(C)C)C3)ccn2c(=O)c(C(=O)O)cc(C3CC3)c12
Agent: Cl
Solvent: C1COCCO1
Solvent: CC#N
Product: Cc1c(-c2ccc3c(c2)NC(=O)C(N)C3)ccn2c(=O)c(C(=O)O)cc(C3CC3)c12
Reaction time: 4 h

Procedure:
8-(3-(tert-Butoxycarbonylamino)-2-oxo-1,2,3,4-tetrahydroquinolin-7-yl)-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid (29 mg, 0.046 mmol) was dissolved in acetonitrile (4 mL). HCl 4M in dioxane (1 mL, 4 mmol) was added. The mixture was stirred for 4 h and a suspension was formed. The solvents were evaporated and the crude was triturated with diethyl ether (4 mL) to afford the title compound EXAMPLE 50 as a yellow solid (20 mg, 98%). ESI-MS m/z: 404 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([OH:16])=O)[C:9]2=[O:17])=[CH:4][CH:3]=1.[F:18][C:19]1[CH:20]=[C:21]([CH:23]=[CH:24][C:25]=1[O:26][C:27]1[CH:32]=[CH:31][N:30]=[C:29]2[CH:33]=[C:34]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[O:35][C:28]=12)[NH2:22]>>[F:18][C:19]1[CH:20]=[C:21]([NH:22][C:14]([C:10]2[C:9](=[O:17])[N:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[CH:13]=[CH:12][CH:11]=2)=[O:16])[CH:23]=[CH:24][C:25]=1[O:26][C:27]1[CH:32]=[CH:31][N:30]=[C:29]2[CH:33]=[C:34]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[O:35][C:28]=12
Reactant: Nc1ccc(Oc2ccnc3cc(-c4ccccc4)oc23)c(F)c1
Reactant: O=C(O)c1cccn(-c2ccc(F)cc2)c1=O
Product: O=C(Nc1ccc(Oc2ccnc3cc(-c4ccccc4)oc23)c(F)c1)c1cccn(-c2ccc(F)cc2)c1=O

Procedure:
The title compound was prepared by procedure G using 1-(4-fluoro-phenyl)-2-oxo-1,2-dihydro-pyridine-3-carboxylic acid (26.21 mg; 0.11 mmol; 1.20 eq.) instead of 1-(2-hydroxy-2-methyl-propyl)-5-methyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxylic acid and using 3-fluoro-4-[(2-phenylfuro[3,2-b]pyridin-7-yl)oxy]aniline (30.00 mg; 0.09 mmol; 1.00 eq.) instead of 4-[(2-phenylfuro[3,2-b]pyridin-7-yl)oxy]aniline, and was obtained as a beige solid (36 mg, 72%). (HPLC (method F): 89%, RT: 4.63 min); MS (m/z) 536 [M+H]+, RT: 4.2 min.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]([CH3:30])=[C:8]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[NH:9][C:10]=1[CH2:11][CH2:12][CH2:13][NH:14][CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1)=O)C.C[Al](C)C>C1(C)C=CC=CC=1>[C:26]([O:25][C:23]([C:8]1[NH:9][C:10]2[CH2:11][CH2:12][CH2:13][N:14]([CH2:15][CH2:16][N:17]3[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)[C:4](=[O:3])[C:6]=2[C:7]=1[CH3:30])=[O:24])([CH3:29])([CH3:28])[CH3:27]
Reactant: CCOC(=O)c1c(CCCNCCN2CCCCC2)[nH]c(C(=O)OC(C)(C)C)c1C
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: Cc1c(C(=O)OC(C)(C)C)[nH]c2c1C(=O)N(CCN1CCCCC1)CCC2
Yield: 52.4 %

Procedure:
3-Methyl-5-[3-(2-piperidin-1-yl-ethylamino)-propyl]-1H-pyrrole-2,4-dicarboxylic acid 2-tert-butyl ester 4-ethyl ester 32a (225 mg, 0.534 mmol) was dissolved in 5 ml of dry toluene under stirring, the reaction system was cooled in an ice-water bath, and added with a solution of trimethyl aluminum in toluene (0.534 ml, 2 mol/L, 1.07 mmol) under an argon atmosphere. Upon completion of the addition, the reaction system was stirred for 20 minutes at room temperature until no white smoke was released, refluxed for another 3 hours in an oil bath. After thin lay chromatography showed the disappearance of starting materials, the oil bath was removed, the reaction mixture was added with saturated brine (10 ml) and ethyl acetate (20 ml), stirred for 15 minutes at room temperature and filtered. The filter cake was washed with ethyl acetate (10 ml×3). The filtrate was extracted with ethyl acetate (10 ml×2). The combined organic extracts were washed with saturated brine (10 ml×2), dried over anhydrous magnesium sulfate, filtered to remove the drying agent and concentrated under reduced pressure to obtain the title compound 3-methyl-4-oxo-5-(2-piperidin-1-yl-ethyl)-1,4,5,6,7,8-hexahydro-pyrrolo[3,2-c]azepine-2-carboxylic acid tert-butyl ester 32b (105 mg) as a colorless oil to be used directly in the next step.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[NH2:20][C:21]1[C:22]([C:26]2[N:27]([C:46]3[CH:51]=[CH:50][C:49]([OH:52])=[CH:48][CH:47]=3)[C:28]3[CH:33]=[C:32]([O:34][C:35]4[CH:36]=[C:37]([NH:41][C:42](=[O:44])[CH3:43])[CH:38]=[CH:39][CH:40]=4)[N:31]=[CH:30][C:29]=3[N:45]=2)=[N:23][O:24][N:25]=1.C([NH:60][CH2:61][CH2:62]O)(OC(C)(C)C)=O.O>O1CCOCC1>[NH2:60][CH2:61][CH2:62][O:52][C:49]1[CH:50]=[CH:51][C:46]([N:27]2[C:28]3[CH:33]=[C:32]([O:34][C:35]4[CH:36]=[C:37]([NH:41][C:42](=[O:44])[CH3:43])[CH:38]=[CH:39][CH:40]=4)[N:31]=[CH:30][C:29]=3[N:45]=[C:26]2[C:22]2[C:21]([NH2:20])=[N:25][O:24][N:23]=2)=[CH:47][CH:48]=1
Reactant: CC(C)(C)OC(=O)NCCO
Reactant: CC(=O)Nc1cccc(Oc2cc3c(cn2)nc(-c2nonc2N)n3-c2ccc(O)cc2)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1COCCO1
Product: CC(=O)Nc1cccc(Oc2cc3c(cn2)nc(-c2nonc2N)n3-c2ccc(OCCN)cc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 15.6 %

Procedure:
Triphenylphosphine (260 mg, 1.0 mmol) was added to a solution of the product from Step 5 (220 mg, 0.5 mmol) and N—BOC-ethanolamine (161 mg, 1.0 mmol) in dioxane (4 mL) followed by addition of di-isopropylazodicarboxylate (197 uL, 1.0 mmol) and the resulting solution was allowed to stir at rt overnight. The reaction mixture was poured into water and extracted with EtOAc. The organic phases were combined, washed with brine, dried (MgSO4), filtered and the filtrate concentrated. The crude material was dissolved in dichloromethane (2 mL) and treated with TFA (1 mL) for 30 min, then concentrated and the residue was purified by reverse phase HPLC to give the title compound (38 mg, 16%). MS (ES+) m/e 487 [M+H]+.
Reaction SMILES: [CH3:1][C:2]([Si:5]([CH3:24])([CH3:23])[O:6][CH2:7][CH2:8][CH:9]1[CH:12]([CH2:13][O:14][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16])[CH2:11][CH:10]1[OH:22])([CH3:4])[CH3:3].C(N(CC)CC)C.[CH3:32][S:33](Cl)(=[O:35])=[O:34]>C(Cl)Cl>[CH3:4][C:2]([Si:5]([CH3:23])([CH3:24])[O:6][CH2:7][CH2:8][CH:9]1[CH:12]([CH2:13][O:14][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16])[CH2:11][CH:10]1[O:22][S:33]([CH3:32])(=[O:35])=[O:34])([CH3:1])[CH3:3]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)[Si](C)(C)OCCC1C(O)CC1CO[Si](C)(C)C(C)(C)C
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCCC1C(CO[Si](C)(C)C(C)(C)C)CC1OS(C)(=O)=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 89 %

Procedure:
2-(2-((1,1-Dimethylethyl)dimethylsilyl)oxy)ethyl)-3-(((1,1-dimethylethyl)dimethyl-silyl)oxymethyl)cyclobutanol (160 mg, 0.43 mmol) from Step B was dissolved in 2 mL of methylene chloride and the resultant solution was cooled to 0° C. Triethylamine (120μL) was added, followed by 36 μL of methanesulfonyl chloride. After stirring the reaction mixture for 30 min at 0° C., it was concentrated in vacuo and the residue was purified on a silica gel column eluted with 10% ethyl acetate in hexane to give 180 mg (89% yield) of the title compound.; MS DCI-NH3M/Z: 447 (M+H)+, 464 (M+NH4)+.
Reaction SMILES: [Na].[NH:2]1[CH:6]=[CH:5][CH:4]=[N:3]1.[CH2:7]([C:15]1[CH:25]=[CH:24][C:18]([O:19][CH2:20][CH:21]2[CH2:23][O:22]2)=[CH:17][CH:16]=1)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].[Na+].[Cl-]>C1COCC1>[CH2:7]([C:15]1[CH:16]=[CH:17][C:18]([O:19][CH2:20][CH:21]([OH:22])[CH2:23][N:2]2[CH:6]=[CH:5][CH:4]=[N:3]2)=[CH:24][CH:25]=1)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CCCCCCCCc1ccc(OCC2CO2)cc1
Reactant: c1cn[nH]c1
Agent: [Cl-]
Agent: [Na+]
Agent: [Na]
Solvent: C1CCOC1
Product: CCCCCCCCc1ccc(OCC(O)Cn2cccn2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
0.091 g (3.96 mmol) sodium is mixed with 5 ml absolute THF and with a solution of 0.268 g (3.94 mmol) pyrazole in 15 absolute THF. Having stirred at room temperature for 2 hours, a solution of 0.690 g (2.63 mmol) 2-(4-octylphenoxymethyl)oxirane in 10 ml THF is added drop-wise and boiled under reflux for 8 hours. The cooled reaction mixture is poured into semi-saturated NaCl solution and extracted four times using diethyl ether. The combined organic phases are concentrated to half the volume on the rotary evaporator. Washing using a semi-saturated NaCl solution, drying on sodium sulfate, filtration and reconcentration on the rotary evaporator leave as a crude product a yellow solid which is purified on silica gel by means of column chromatography (flow agent: petroleum ether/ethyl acetate 85:15) and recrystallized from petroleum ether and yields the product as a white solid.
Reaction SMILES: [NH:1]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[C@H:2]([C:6]([OH:8])=O)[C@@H:3]([CH3:5])[OH:4].Cl.[NH2:17][C@@H:18]([C:31]([NH:33][C@H:34]([C:42]([N:44]([CH2:46][C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)[CH3:45])=[O:43])[CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)=[O:32])[CH2:19][C:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[N:22]([CH:29]=[O:30])[CH:21]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>CN(C=O)C>[NH:1]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[C@H:2]([C:6]([NH:17][C@@H:18]([C:31]([NH:33][C@H:34]([C:42]([N:44]([CH2:46][C:47]1[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=1)[CH3:45])=[O:43])[CH2:35][C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1)=[O:32])[CH2:19][C:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[N:22]([CH:29]=[O:30])[CH:21]=1)=[O:8])[C@@H:3]([CH3:5])[OH:4]
Reactant: CN(Cc1ccccc1)C(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](N)Cc1cn(C=O)c2ccccc12
Reactant: C[C@@H](O)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: C[C@@H](O)[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@H](Cc1cn(C=O)c2ccccc12)C(=O)N[C@@H](Cc1ccccc1)C(=O)N(C)Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.9 %

Procedure:
Boc-Thr-OH (1.23 g), HCl.H-D-Trp(CHO)-Phe-NMeBzl (3.0 g) and HOBT (0.757 g) were dissolved in DMF (40 ml). To this solution was added WSC (887 mg) under ice cooling and the mixture was stirred for 1.5 hours at the same temperature and overnight at room temperature. After evaporation and extraction with ethyl acetate, the organic layer was washed successively with water, diluted sodium hydrogencarbonate solution, water, 0.5N hydrochloric acid, and sodium chloride solution and dried over magnesium sulfate. The evaporated residue was crystallized from a mixed solvent of ethyl acetate and diisopropyl ether (1:1) (10 ml) with seeding and the crystals were washed out by addition of diisopropyl ether (30 ml) and dried to give Boc-Thr-D-Trp(CHO)-Phe-NMeBzl (3.64 g).
Reaction SMILES: [N:1]([CH2:4][CH2:5][CH2:6][CH:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1)=[N+:2]=[N-:3].[CH:13](OC)=[O:14]>>[CH:13]([N:10]1[CH2:9][CH2:8][CH:7]([CH2:6][CH2:5][CH2:4][N:1]=[N+:2]=[N-:3])[CH2:12][CH2:11]1)=[O:14]
Reactant: [N-]=[N+]=NCCCC1CCNCC1
Reactant: COC=O
Product: [N-]=[N+]=NCCCC1CCN(C=O)CC1

Procedure:
A solution of 4-(3'-azidopropyl)-piperidine (1.5 g) in methyl formate (5 ml) was refluxed for 1 hour. Evaporation to dryness gave the desired compound as an oil. The IR-spectrum (CHCl3) showed strong bands at 2100, 1660, 1440 and 1270 cm-1.
Reaction SMILES: [OH:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]=[C:15]([C:17]3[O:21][N:20]=[C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:18]=3[C:28]([F:31])([F:30])[F:29])[O:14][N:13]=2)=[CH:8][CH:7]=1)[C:3](O)=[O:4].CN1CCOCC1.[CH3:39][S:40]([CH2:43][CH2:44][NH2:45])(=[O:42])=[O:41].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C=O)C>[OH:1][CH:2]([C:6]1[CH:7]=[CH:8][C:9]([C:12]2[N:16]=[C:15]([C:17]3[O:21][N:20]=[C:19]([C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=4)[C:18]=3[C:28]([F:31])([F:29])[F:30])[O:14][N:13]=2)=[CH:10][CH:11]=1)[C:3]([NH:45][CH2:44][CH2:43][S:40]([CH3:39])(=[O:42])=[O:41])=[O:4]
Reactant: O=C(O)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Reactant: CS(=O)(=O)CCN
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CS(=O)(=O)CCNC(=O)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Reaction time: 8 h
Yield: 37 %

Procedure:
(R/S)-2-Hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetic acid (Int-V, 20 mg, 0.046 mmol) was dissolved in DMF (1 mL) prior to the addition of 4-methylmorpholine (0.031 mL, 0.278 mmol), 2-(methylsulfonyl)ethanamine (10.28 mg, 0.083 mmol), and BOP (36.9 mg, 0.083 mmol). The reaction mixture was stirred overnight and was then purified via preparative LCMS 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 methanol:water with 10-mM ammonium acetate; Mobile Phase B: 95:5 methanol:water with 10-mM ammonium acetate; Gradient: 50-100% B over 25 minutes, then a 5-minute hold at 100% B; Flow rate=20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation to give (R/S)-2-hydroxy-N-(2-(methylsulfonyl)ethyl)-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetamide (9.2 mg, 0.017 mmol, 36.2% yield): LCMS=537.1 [M+H]+; 1H NMR (400 MHz, methanol-d4 and CDCl3) δ ppm 8.15 (2 H, d, J=8.28 Hz), 7.66 (4 H, t, J=7.78 Hz), 7.47-7.60 (3H, m), 5.13 (1 H, s), 3.73 (2 H, t, J=6.40 Hz), 3.23-3.31 (2 H, m), 2.94 (3 H, s); Analytical LCMS: column: Mac-mod Halo C18, 4.6×50 mm, 2.7-μm particles; Mobile Phase A: 5:95 acetonitrile:water with 0.05% TFA; Mobile Phase B: 90:10 acetonitrile:water with 0.05% TFA; Temperature: 45° C.; Gradient: 0-100% B over 4 minutes, flow rate=4 mL/min, product retention=2.4 min.
Reaction SMILES: [F:1][C:2]1[C:3]([CH3:17])=[CH:4][C:5]2[N:9]=[CH:8][N:7]([CH:10]3[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]3)[C:6]=2[CH:16]=1.[F:18][C:19]1[CH:20]=[C:21]2[C:25](=[CH:26][CH:27]=1)[CH2:24][CH:23]([CH:28]=O)[CH2:22]2.[BH3-]C#N.[Na+]>CO.C(O)(=O)C>[F:1][C:2]1[C:3]([CH3:17])=[CH:4][C:5]2[N:9]=[CH:8][N:7]([CH:10]3[CH2:11][CH2:12][N:13]([CH2:28][CH:23]4[CH2:22][C:21]5[C:25](=[CH:26][CH:27]=[C:19]([F:18])[CH:20]=5)[CH2:24]4)[CH2:14][CH2:15]3)[C:6]=2[CH:16]=1
Reactant: O=CC1Cc2ccc(F)cc2C1
Reactant: Cc1cc2ncn(C3CCNCC3)c2cc1F
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: Cc1cc2ncn(C3CCN(CC4Cc5ccc(F)cc5C4)CC3)c2cc1F
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 24.5 %

Procedure:
A mixture of 6-fluoro-5-methyl-1-piperidin-4-yl-1H-benzoimidazole (70 mg, 0.300 mmol) and 5-fluoroindane-2-carbaldehyde (49 mg, 0.300 mmol) in CH3OH (4 mL) and acetic acid (0.2 mL) was stirred at rt for 15 minutes. NaCNBH3 (40 mg, 0.635 mmol) was added and then the reaction mixture was stirred for 1 hour. The solvent was removed and the residue was diluted with CH2Cl2. The organic layers were washed with saturated NaHCO3, brine, and dried over Na2SO4. The organic extracts were removed under the reduced pressure and the residue was purified by flash chromatography (5% CH3OH in CH2Cl2) to afford 6-fluoro-1-[1-(5-fluoro-indan-2-ylmethyl)-piperidin-4-yl]-5-methyl-1H-benzoimidazole (28 mg, 24%) as a white solid.
Reaction SMILES: [CH3:1][S:2][C:3]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)[O:5][N:4]=1.[C:17]1([CH2:23][CH2:24]Br)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[CH3:1][S:2][C:3]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:24][CH2:23][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:12][CH:11]=2)[O:5][N:4]=1
Reactant: BrCCc1ccccc1
Reactant: CSc1noc(-c2ccc(O)cc2)c1C#N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CSc1noc(-c2ccc(OCCc3ccccc3)cc2)c1C#N
Yield: 80 %

Procedure:
Equimolecular amounts of (III), 2-phenyl-ethyl bromide and K2CO3 were refluxed in acetone for 48 h. The mixture was concentrated to small volume and shaken with diethyl ether and water. The ether phase was washed with 2 M NaOH, then with water, evaporated to dryness and the residue was recrystallized from ethanol. The title product was obtained in an 80% yield (abbreviation ON-6), m.p. 93-940° C. (ethanol); IR (KBr) 2227 (CN) cm1; 1H NMR (CDCl3) (δ, ppm) 2.66 (s, 3H, SCH3); 3.14 (t, 2H, CH2—Ph); 4.26 (t, 2H, O—CH2); 7.30 (m, 5H, arom.); 6.99-8.00 (m, 4H, arom.).