Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:11]=[CH:12][C:13]2[NH:17][C:16](=O)[N:15]([C:19]3[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=3)[C:14]=2[CH:26]=1.C(=O)(O)[O-].[Na+].P(Cl)(Cl)([Cl:35])=O>>[CH3:1][O:2][C:3](=[O:27])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:11]=[CH:12][C:13]2[N:17]=[C:16]([Cl:35])[N:15]([C:19]3[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=3)[C:14]=2[CH:26]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COC(=O)CCCCCOc1ccc2[nH]c(=O)n(-c3ccc(C)cc3)c2c1
Agent: O=C([O-])O
Agent: [Na+]
Product: COC(=O)CCCCCOc1ccc2nc(Cl)n(-c3ccc(C)cc3)c2c1

Procedure:
2.5 g of 6-[[1-(4-methylphenyl)-2-oxo-2,3-dihydro-1H-benzoimidazol-6-yl]oxy]hexanoic acid methyl ester was mixed with 10 ml of phosphorus oxychloride, and the mixture was refluxed for 2 hours. After cooling, it was stirred into saturated sodium bicarbonate solution, extracted three times with ethyl acetate, the combined organic phases were dried on sodium sulfate and concentrated by evaporation in a vacuum. The residue was purified by column chromatography on silica gel. 1.28 g was obtained.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[NH2:14][C@@H:15]([CH2:19][C:20]1[CH:25]=[C:24]([O:26][CH3:27])[C:23]([O:28][CH3:29])=[C:22]([O:30][CH3:31])[CH:21]=1)[C:16]([OH:18])=[O:17].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.[Cu]I>[C:4]1([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=[C:2]([NH:14][C@@H:15]([CH2:19][C:20]2[CH:21]=[C:22]([O:30][CH3:31])[C:23]([O:28][CH3:29])=[C:24]([O:26][CH3:27])[CH:25]=2)[C:16]([OH:18])=[O:17])[CH:3]=1
Reactant: COc1cc(C[C@H](N)C(=O)O)cc(OC)c1OC
Reactant: Brc1cccc(-c2ccccc2)c1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc(C[C@H](Nc2cccc(-c3ccccc3)c2)C(=O)O)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 24 h

Procedure:
The title compound is prepared by heating a suspension of 3-bromo-biphenyl (1.47 mL, 8.54 mMol, Aldrich 25,538-6), (S)-2-amino-3-(3,4,5-trimethoxy-phenyl)-propionic acid (3,4,5-OCH3-phe-OH) (3.27 g, 12.81 mMol), K2CO3 (1.18 g, 8.54 mMol) and CuI (163 mg, 0.854 mMol) in DMF abs. (10.6 mL) for 24 h at 90° C., under an argon atmosphere. The resulting mixture is allowed to cool to rt, then concentrated in vacuo and purified by MPLC (CH3CN/H2O/TFA) to afford the title compound.
Reaction SMILES: [Cl-].[Cl:2][C:3]1[N:9]([CH2:10][CH2:11][CH2:12][CH:13]=[N+:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=3)=[CH:16][CH2:15]2)[C:8](=[O:26])[C:7]2[CH:27]=[CH:28][CH:29]=[CH:30][C:6]=2[O:5][CH:4]=1.[BH4-].[Na+].O>C(O)C>[Cl:2][C:3]1[N:9]([CH2:10][CH2:11][CH2:12][CH2:13][N:14]2[CH2:19][CH2:18][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=3)=[CH:16][CH2:15]2)[C:8](=[O:26])[C:7]2[CH:27]=[CH:28][CH:29]=[CH:30][C:6]=2[O:5][CH:4]=1
Reactant: O=C1c2ccccc2OC=C(Cl)N1CCCC=[N+]1C=CC(c2ccccn2)=CC1
Agent: [BH4-]
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: O=C1c2ccccc2OC=C(Cl)N1CCCCN1CC=C(c2ccccn2)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 81 %

Procedure:
800 mg of the compound of Example 23 was dissolved in 20 ml of ethanol, 140 mg (2 equivalents) of sodium borohydride was added under ice cooling, then the result was agitated at room temperature for 10 minutes. Water was added and extraction was performed with ethyl acetate. The organic layer was washed with water and saturated saline, then was dried with anhydrous magnesium sulfate. The solvent was distilled off and the resultant crude product was refined with silica gel column chromatography (methylene chloride:methanol=30:1), to obtain the above-referenced compound in an amount of 600 mg (yield of 81%).
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][CH2:8][C:9]1[O:10][C:11]2[CH:17]=[CH:16][C:15]([C:18]3[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[CH:20][CH:19]=3)=[CH:14][C:12]=2[CH:13]=1.[I:26]N1C(=O)CCC1=O>>[I:26][C:13]1[C:12]2[CH:14]=[C:15]([C:18]3[CH:19]=[CH:20][C:21]([C:22]#[N:23])=[CH:24][CH:25]=3)[CH:16]=[CH:17][C:11]=2[O:10][C:9]=1[CH2:8][CH2:7][N:3]1[CH2:4][CH2:5][CH2:6][C@H:2]1[CH3:1]
Reactant: C[C@@H]1CCCN1CCc1cc2cc(-c3ccc(C#N)cc3)ccc2o1
Reactant: O=C1CCC(=O)N1I
Product: C[C@@H]1CCCN1CCc1oc2ccc(-c3ccc(C#N)cc3)cc2c1I
Yield: 18 %

Procedure:
The mono-(L)-tartaric acid salt of the product of Example 1D and N-iodosuccinimide were processed as in Example 156, except that a large excess of N-iodosuccinimide (2.4 molar equivalents) was utilized, to provide the title compound as a tan gum (18% yield). MS (ESI) m/z 457 (M+H)+; 1HNMR (300 MHz, CD3OD) δ 1.49 (d, 3 H), 1.67-1.84 (m, 1 H), 2.00-2.25 (m, 2 H), 2.29-2.44 (m, 1 H), 3.22-3.63 (m, 5 H), 3.72-3.91 (m, 2 H), 7.59-7.64 (m, 2 H), 7.72 (dd, 1 H), 7.80-7.89 (m, 4 H).
Reaction SMILES: [NH2:1][C:2]([N:4]1[CH2:8][CH2:7][N:6]([C:9]2[CH:14]=[CH:13][C:12]([O:15]C)=[C:11]([O:17]C)[CH:10]=2)[C:5]1=[O:19])=[O:3].B(Br)(Br)Br>ClCCl>[NH2:1][C:2]([N:4]1[CH2:8][CH2:7][N:6]([C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[C:11]([OH:17])[CH:10]=2)[C:5]1=[O:19])=[O:3]
Reactant: COc1ccc(N2CCN(C(N)=O)C2=O)cc1OC
Agent: BrB(Br)Br
Solvent: ClCCl
Product: NC(=O)N1CCN(c2ccc(O)c(O)c2)C1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 14 g (52.8 mmol) of 1-(aminocarbonyl)-3-(3,4-dimethoxyphenyl)-2-imidazolidinone in 700 ml of dichloromethane was cooled to -78° C., and 39.7 g (158 mmol) of boron tribromide was added dropwise. The dry-ice bath was removed and the reaction mixture was stirred overnight at ambient temperature. The mixture was cooled to 0° C., and 20 ml of water was added dropwise. The precipitate was filtered off by suction and stirred with water for one hour. The product was filtered off and dried in vacuo; yield: 8.51 g; melting point >250° C.
Reaction SMILES: C[Al](C)C.[CH2:5]([NH2:7])[CH3:6].[Si:8]([O:25][CH2:26][C:27]1[C:28]([N:42]2[CH2:47][C@H:46]([CH3:48])[O:45][C@H:44]([CH3:49])[CH2:43]2)=[C:29]([F:41])[C:30]2[O:34][N:33]=[C:32]([C:35](OCC)=[O:36])[C:31]=2[CH:40]=1)([C:21]([CH3:24])([CH3:23])[CH3:22])([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C1(C)C=CC=CC=1>[Si:8]([O:25][CH2:26][C:27]1[C:28]([N:42]2[CH2:43][C@H:44]([CH3:49])[O:45][C@H:46]([CH3:48])[CH2:47]2)=[C:29]([F:41])[C:30]2[O:34][N:33]=[C:32]([C:35]([NH:7][CH2:5][CH3:6])=[O:36])[C:31]=2[CH:40]=1)([C:21]([CH3:22])([CH3:24])[CH3:23])([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: CCN
Reactant: CCOC(=O)c1noc2c(F)c(N3C[C@@H](C)O[C@@H](C)C3)c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)cc12
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: CCNC(=O)c1noc2c(F)c(N3C[C@@H](C)O[C@@H](C)C3)c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)cc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Under a nitrogen atmosphere, trimethylaluminum (2M in toluene, 1206 μl, 2.41 mmol) was slowly added (gas evolution) to an ice cooled solution of ethylamine (2M in THF) (1206 μl, 2.41 mmol) in 7 ml of toluene. The reaction was allowed to warm to room temperature and stirred for 2 hours. Ethyl 5-((tert-butyldiphenylsilyloxy)methyl)-6-((2R,6S)-2,6-dimethylmorpholino)-7-fluorobenzo[d]isoxazole-3-carboxylate, (Intermediate 204, 190 mg, 0.32 mmol) was added as a solution in toluene (3 ml). The reaction was stirred at 45° C. for 18 hours. The reaction was quenched drop wise (vigorous gas evolution) with 2 ml of 1N HCl. The crude reaction was filtered to remove solids, diluted with water and extracted twice with ethyl acetate. The organic layers were combined, washed twice with brine, dried over MgSO4 and concentrated to give an oil. The oil was purified by silica gel column chromatorgraphy using a gradient of hexanes to ethyl acetate. Fractions were combined and concentrated to give the title compound. (170 mg, 0.288 mmol, 90%).
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][C:5]([NH2:7])=[NH:6].[C:8]1(=O)[CH2:12][CH2:11][CH2:10][C:9]1=O.[NH4+].[OH-]>O.C(O)C.Cl>[NH2:6][C:5]1[NH:7][C:9]2=[CH:10][CH:11]=[CH:12][C:8]2=[N:3][CH:4]=1
Reactant: O=C1CCCC1=O
Reactant: N=C(N)CN
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Nc1cnc2cccc-2[nH]1

Procedure:
A solution of aminoacetamidine dihydrochloride (Mengelberg, M. Chem. Ber. 89, 1185 (1956)) (2.4 g, 0.01 mol, 1 equiv.) in H2O (~10 mL) was added dropwise to a cold (0° C.) stirring solution of 1,2-cyclopentanedione (1.0 g, 0.01 mol) in ethanol (8-10 mL). After allowing the reaction mixture to come to room temperature, concentrated NH4OH (aq.) was added slowly until the pH was 8-9. Small amounts of concentrated NH4OH were added as needed in order to maintain a pH of 8-9. When the 1,2-cycopentanedione was no longer visible on TLC (30% EtOAc/hexanes) the reaction mixture was diluted with 5% HCl, washed (3×) with CH2Cl2 and the organic portions discarded. The aqueous portion was made basic with 6N NaOH (aq.), extracted (4×) with CH2Cl2 and the combined extracts dried over sodium sulfate. Concentration of the solution under reduced pressure gave 2-amino-cyclopent[b]pyrazine as a greenish-yellow solid.
Reaction SMILES: [CH3:1][C:2]([CH3:14])([S:4]([NH:6][C:7]([CH3:13])([CH3:12])/[C:8](=[N:10]/[OH:11])/[NH2:9])=[O:5])[CH3:3].[CH3:15]C(O)=O>>[CH3:3][C:2]([S:4]([NH:6][C:7]([CH:8]1[N:9]=[CH:15][O:11][NH:10]1)([CH3:13])[CH3:12])=[O:5])([CH3:14])[CH3:1]
Reactant: CC(=O)O
Reactant: CC(C)(NS(=O)C(C)(C)C)/C(N)=N/O
Product: CC(C)(NS(=O)C(C)(C)C)C1N=CON1
Temperature: 25 °C
Reaction time: 16 h
Yield: 18 %

Procedure:
(Z)-2-(1,1-dimethylethylsulfinamido)-N′-hydroxy-2-methylpropanimidamide (140 mg, 0.633 mmol) in AcOH (4 ml) was treated with [diethoxy(2H)methoxy]ethane (0.106 ml, 0.633 mmol) at rt. The reaction was allowed to stir at rt for 16 h. LCMS showed a major peak with the expected M+H. The reaction was concentrated to dryness azeotroping with toluene 3×. The resulting oil was purified on silica gel (Biotage, EtOAc/hexanes gradient (Rf ˜0.2 in 70% EtOAc/Hex, visualized with permanganate stain), to give the expected product (27 mg, 0.12 mmol, 18% yield) consistent by LCMS. LC-MS retention time: 1.47 min; m/z (MH+): 233. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Phenomenex-Luna 3u C18 2.0×30 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 1 mL/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where solvent A was 5% MeOH/95% H2O/10 mM ammonium acetate and solvent B was 5% H2O/95% MeOH/10 mM ammonium acetate. MS data was determined using a Micromass Platform for LC in electrospray mode. Step 2: Preparation of the titled compound: 2-[(2H)-1,2,4-oxadiazol-3-yl]propan-2-amine hydrochloride HCl (1.0 mL, 1.9 mmol) (2 M in Et2O) was added to a stirring solution of 2-methyl-N-{2-[(2H)-1,2,4-oxadiazol-3-yl]propan-2-yl}propane-2-sulfinamide (27 mg, 0.12 mmol) in MeOH (1 mL) at rt. The reaction was allowed to stir for 2 h and then concentrated azeotroping with toluene to give the expected product (15 mg, 0.091 mmol, 78% yield) consistent by NMR. 1H NMR (400 MHz, METHANOL-d4) δ 1.77 (s, 6H).
Reaction SMILES: [C:1]([NH:5][C:6]1[O:7][C:8]([C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[N:16]([S:20]([C:23]2[CH:29]=[CH:28][C:26]([CH3:27])=[CH:25][CH:24]=2)(=[O:22])=[O:21])[CH:15]=[C:14]3B2OC(C)(C)C(C)(C)O2)=[N:9][N:10]=1)([CH3:4])([CH3:3])[CH3:2].P([O-])([O-])([O-])=O.[K+].[K+].[K+].Cl[C:48]1[N:53]=[C:52]([O:54][CH3:55])[C:51]([F:56])=[CH:50][N:49]=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1>[C:1]([NH:5][C:6]1[O:7][C:8]([C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[N:16]([S:20]([C:23]2[CH:24]=[CH:25][C:26]([CH3:27])=[CH:28][CH:29]=2)(=[O:21])=[O:22])[CH:15]=[C:14]3[C:48]2[N:53]=[C:52]([O:54][CH3:55])[C:51]([F:56])=[CH:50][N:49]=2)=[N:9][N:10]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: COc1nc(Cl)ncc1F
Reactant: Cc1ccc(S(=O)(=O)n2cc(B3OC(C)(C)C(C)(C)O3)c3cc(-c4nnc(NC(C)(C)C)o4)ccc32)cc1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: COc1nc(-c2cn(S(=O)(=O)c3ccc(C)cc3)c3ccc(-c4nnc(NC(C)(C)C)o4)cc23)ncc1F
Temperature: 130 °C
Yield: 60.8 %

Procedure:
N-tert-Butyl-5-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1H-indol-5-yl)-1,3,4-oxadiazol-2-amine (166 mg, 0.309 mmol), dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine (6.63 mg, 0.014 mmol) (Strem), Pd2(dba)3 (6.37 mg, 6.96 μmol) (Strem), potassium phosphate (148 mg, 0.696 mmol) (Sigma-Aldrich) and 2-chloro-5-fluoro-4-methoxypyrimidine (37.7 mg, 0.232 mmol) were weighed into a 5 mL glass microwave tube. The tube was purged with argon and the solids were treated with dioxane (2 mL) and water (0.200 mL). The tube was sealed, and the contents were heated an Initiator microwave reactor (Personal Chemistry, Biotage AB, Inc., Upssala, Sweden) at 130° C. for 20 min. The mixture was treated with H2O and extracted with EtOAc. The organic layer was washed with brine, dried over MgSO4, filtered and concentrated. The crude material was purified by flash chromatography (eluting with 5-60% EtOAc in Hex) to give N-tert-butyl-5-(3-(5-fluoro-4-methoxypyrimidin-2-yl)-1-tosyl-1H-indol-5-yl)-1,3,4-oxadiazol-2-amine (75.5 mg, 0.141 mmol, 60.7%) as an off white solid. MS (ESI, pos. ion) m/z: 537.0 (M+1). 1H NMR (400 MHz, DMSO-d6) δ ppm 8.98-9.03 (m, 1H), 8.72 (d, J=3.1 Hz, 1H), 8.56 (s, 1H), 8.16 (d, J=8.8 Hz, 1H), 8.02-8.07 (m, 2H), 7.86-7.92 (m, 1H), 7.64 (s, 1H), 7.40-7.48 (m, 2H), 4.22 (s, 3H), 2.33 (s, 3H), 1.35-1.41 (m, 9H).
Reaction SMILES: [CH3:1][C:2]([CH:13]=[CH:14][C:15]1[C:20]([CH3:22])([CH3:21])[CH2:19][CH2:18][C:17](=[O:23])[C:16]=1[CH3:24])=[C:3]=[CH:4][P:5](=[O:12])([O:9][CH2:10][CH3:11])[O:6][CH2:7][CH3:8].C([O-])=O.[NH4+]>>[CH3:1][C:2]([CH:13]=[CH:14][C:15]1[C:20]([CH3:22])([CH3:21])[CH2:19][CH2:18][C:17](=[O:23])[C:16]=1[CH3:24])=[CH:3][CH2:4][P:5](=[O:12])([O:6][CH2:7][CH3:8])[O:9][CH2:10][CH3:11]
Reactant: CCOP(=O)(C=C=C(C)C=CC1=C(C)C(=O)CCC1(C)C)OCC
Agent: O=C[O-]
Agent: [NH4+]
Product: CCOP(=O)(CC=C(C)C=CC1=C(C)C(=O)CCC1(C)C)OCC

Procedure:
reacting the 3-methyl-5-(2,6,6-trimethyl-3-oxocyclohex-1-enyl)-1,2,4-pentatrienylphosphonic acid, diethyl ester with ammonium formate or a trialkylammonium formate to form 3-methyl-5-(2,6,6-trimethyl-3-oxocyclohex-1-enyl)-2,4-pentadienylphosphonic acid, diethyl ester; and
Reaction SMILES: [C:1]([C:5]1[N:10]=[C:9]([O:11][CH3:12])[N:8]=[C:7]([O:13][CH:14]2[CH2:31][CH:30]3[CH:16]([C:17](=[O:37])[N:18]([CH3:36])[CH2:19][CH2:20][CH2:21][CH2:22][CH:23]=[CH:24][CH:25]4[C:27]([C:33]([OH:35])=O)([NH:28][C:29]3=[O:32])[CH2:26]4)[CH2:15]2)[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].CCN=C=NCCCN(C)C.[CH:49]1([S:52]([NH2:55])(=[O:54])=[O:53])[CH2:51][CH2:50]1.C1CCN2C(=NCCC2)CC1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(Cl)Cl>[C:1]([C:5]1[N:10]=[C:9]([O:11][CH3:12])[N:8]=[C:7]([O:13][CH:14]2[CH2:31][CH:30]3[CH:16]([C:17](=[O:37])[N:18]([CH3:36])[CH2:19][CH2:20][CH2:21][CH2:22][CH:23]=[CH:24][CH:25]4[C:27]([C:33]([NH:55][S:52]([CH:49]5[CH2:51][CH2:50]5)(=[O:54])=[O:53])=[O:35])([NH:28][C:29]3=[O:32])[CH2:26]4)[CH2:15]2)[CH:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: NS(=O)(=O)C1CC1
Reactant: COc1nc(OC2CC3C(=O)NC4(C(=O)O)CC4C=CCCCCN(C)C(=O)C3C2)cc(C(C)(C)C)n1
Agent: CCN=C=NCCCN(C)C
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Product: COc1nc(OC2CC3C(=O)NC4(C(=O)NS(=O)(=O)C5CC5)CC4C=CCCCCN(C)C(=O)C3C2)cc(C(C)(C)C)n1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
Compound 3j (120 mg, 0.233 mmol) was dissolved in DCM (10 ml). EDAC (54 mg, 0.28 mmol) was added and the reaction mixture was stirred at RT for 2.5 h. Cyclo-propanesulfonic acid amide (31 mg, 0.256 mmol) and DBU (73 μl, 0.489 mmol) were added and the reaction mixture was stirred at RT over night. 5% Citric acid was added and the organic layer was washed with brine, dried, filtered and evaporated. Purifica-tion by preparative HPLC yielded the pure title compound of (65 mg, 45%), MS (M+H)+618.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[NH:9][CH:10]1[CH2:15][CH2:14][N:13]([C:16]([O:18][CH3:19])=[O:17])[CH2:12][CH:11]1[CH3:20].N[C:22](N)=[O:23]>>[Cl:8][C:6]1[CH:5]=[CH:4][C:3]2[N:9]([CH:10]3[CH2:15][CH2:14][N:13]([C:16]([O:18][CH3:19])=[O:17])[CH2:12][CH:11]3[CH3:20])[C:22](=[O:23])[NH:1][C:2]=2[CH:7]=1
Reactant: COC(=O)N1CCC(Nc2ccc(Cl)cc2N)C(C)C1
Reactant: NC(N)=O
Product: COC(=O)N1CCC(n2c(=O)[nH]c3cc(Cl)ccc32)C(C)C1

Procedure:
A mixture of 30 parts of methyl 4-(2-amino-4-chlorophenylamino)-3-methyl-1-piperidinecarboxylate and 10 parts of urea is stirred and heated at 160°-180° C (oil-bath) for 3h. 30. The reaction mixture is cooled and the product is extracted with methylbenzene. The extract is washed successively with water, with a diluted hydrochloric acid solution and again with water, dried, filtered and evaporated. The oily residue is crystallized from a warm mixture of 2,2'-oxybispropane and a small amount of 2-propanol. After cooling, the product is filtered off and dried, yielding methyl 4-(5-chloro-1,3-dihydro-2-oxo-2H-benzimidazol-1-yl)-3-methyl-1-piperidinecarboxylate; mp. 196.2° C.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([OH:12])=[O:11].[CH2:13](O)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>O1CCCC1>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11]
Reactant: O=C(O)c1cc2ccccc2[nH]1
Reactant: OCc1ccccc1
Solvent: C1CCOC1
Product: O=C(OCc1ccccc1)c1cc2ccccc2[nH]1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
5 g of N,N′-carbonyldiimidazole are introduced into a solution of 5 g of indole-2-carboxylic acid in 50 ml of dry tetrahydrofuran; after stirring for 12 hours at ambient temperature, 3.7 g of benzyl alcohol are added and the reaction mixture is brought to its reflux temperature; this is maintained for 8 hours, before removing the solvent by distillation under reduced pressure. The residue is dissolved in ethyl acetate and the organic phase is washed with a N aqueous NaOH solution and then dried before evaporation of the solvent.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH3:13][N:14]1[CH2:19][CH2:18][CH2:17][CH2:16][C:15]1=[O:20].[C:21]1([Se:27]Cl)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>O1CCCC1>[CH3:13][N:14]1[CH2:19][CH2:18][CH2:17][CH:16]([Se:27][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:15]1=[O:20]
Reactant: Cl[Se]c1ccccc1
Reactant: CN1CCCCC1=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CN1CCCC([Se]c2ccccc2)C1=O
Reaction time: 0.08 h

Procedure:
A solution of diisopropylamine (3 mL, 21.2 mmol) in tetrahydrofuran (44 mL) under argon was cooled to −78° C. and added butyllithium solution, 2.5 M in hexanes (8 mL, 21.2 mmol). After 5 min, a solution of 1-methylpiperidin-2-one (2 g, 17.6 mmol) in tetrahydrofuran (2 mL) was added dropwise. After stirring for 10 min, a solution of phenylselenenyl chloride (4.0 g, 21.2 mmol) in 16 mL of tetrahydrofuran was added, and the reaction was stirred at −78° C. for 2 h. The reaction was quenched with aqueous saturated NH4Cl solution and diluted with CH2Cl2; the aqueous layer was back-extracted with CH2Cl2 (1×). The combined organic extracts were dried (MgSO4), filtered, and concentrated in vacuo to afford a crude crop of 1-methyl-3-(phenylselanyl)piperidin-2-one in dichloromethane. To the crude 1-methyl-3-(phenylselanyl)piperidin-2-one in dichloromethane (50 mL) at 0° C. under argon was added 3-chlorobenzoperoxoic acid (7.92 g, 35.3 mmol). The resulting mixture was allowed to gradually warm to room temperature overnight. The orange suspension was filtered, and the filtrate was concentrated in vacuo and partitioned between CH2Cl2 and aqueous saturated NaHCO3 solution; the aqueous layer was back-extracted with CH2Cl2 (5×). The combined organic extracts were dried (MgSO4), filtered, and concentrated in vacuo. Flash column chromatography (20% EtOAc/Hexanes to 100% EtOAc) afforded 1-methyl-5,6-dihydropyridin-2(1H)-one as a brown oil. MS (ESI, pos. ion) m/z: 112.2 (M+1).
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[C:13]2[C:8](=[C:9]([CH2:24][CH2:25][CH3:26])[C:10]3[O:17][C:16]([C:18]([O:20]CC)=[O:19])=[CH:15][C:14](=[O:23])[C:11]=3[CH:12]=2)[N:7]=[C:6]([C:27]([O:29]CC)=[O:28])[C:5]=1[CH2:32][CH2:33][CH3:34]>CO>[Cl:3][C:4]1[C:13]2[C:8](=[C:9]([CH2:24][CH2:25][CH3:26])[C:10]3[O:17][C:16]([C:18]([OH:20])=[O:19])=[CH:15][C:14](=[O:23])[C:11]=3[CH:12]=2)[N:7]=[C:6]([C:27]([OH:29])=[O:28])[C:5]=1[CH2:32][CH2:33][CH3:34]
Reactant: CCCc1c(C(=O)OCC)nc2c(CCC)c3oc(C(=O)OCC)cc(=O)c3cc2c1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCc1c(C(=O)O)nc2c(CCC)c3oc(C(=O)O)cc(=O)c3cc2c1Cl
Reaction time: 0.25 h
Yield: 70.5 %

Procedure:
0.1 N Sodium hydroxide (28.9 mls) was added dropwise to the diester product of step (e) (0.646 g) in refluxing methanol (100 mls) with stirring, over 15 minutes. The reaction mixture was refluxed and stirred for a further 3 hours and the solution filtered and evaporated. The residue was dissolved in water (100 mls) and acidified. The precipitated acid was collected by filtration, washed with water and dried to give 0.4 g of the desired product. A recrystallisation from ethyl acetate gave 0.24 g, mp 204° (dec).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([OH:11])=O)[CH:5]=[CH:6][CH:7]=1.[NH2:12][CH:13]([CH2:21][CH3:22])[C:14]([O:16][CH2:17][CH:18]([CH3:20])[CH3:19])=[O:15]>>[CH2:17]([O:16][C:14](=[O:15])[CH:13]([NH:12][C:9](=[O:11])[CH2:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=1)[CH2:21][CH3:22])[CH:18]([CH3:19])[CH3:20]
Reactant: O=C(O)Cc1cccc(Br)c1
Reactant: CCC(N)C(=O)OCC(C)C
Product: CCC(NC(=O)Cc1cccc(Br)c1)C(=O)OCC(C)C

Procedure:
Following General Procedure I′ above and using 3-bromophenylacetic acid (Aldrich) and iso-butyl 2-aminobutyrate (prepared following General Procedure J′ above), the title compound was prepared. The reaction was monitored by tlc on silica gel and purification was by filtration as described in the general procedure.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:16]([CH2:17][C:18]([OH:20])=O)[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:33][CH2:34][CH2:35][C:36]1[N:37]([CH3:41])[CH:38]=[CH:39][CH:40]=1>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:16]([CH2:17][C:18]([NH:33][CH2:34][CH2:35][C:36]3[N:37]([CH3:41])[CH:38]=[CH:39][CH:40]=3)=[O:20])[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:6][CH:7]=1
Reactant: Cn1cccc1CCN
Reactant: O=C(O)Cn1c(-c2ccc(Cl)cc2)nc2cccnc21
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: Cn1cccc1CCNC(=O)Cn1c(-c2ccc(Cl)cc2)nc2cccnc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 62.9 %

Procedure:
A suspension of 2-(4-chlorophenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid (5.0 g, 0.0174 mole), 1,1'-carbonyldimidazole (2.82 g, 0.0174 mole) and dry tetrahydrofuran (100 ml) was stirred at room temperature for 3 hr with a stream of nitrogen bubbling through it. A solution of 2-(2-aminoethyl)-1-methylpyrrole (5.40 g, 0.0435 mole) in tetrahydrofuran (6 ml) was added and the mixture was stirred at room temperature under nitrogen overnight. The solvent was evaporated under reduced pressure and the resulting oil was triturated in water (100 ml) which caused a solid to form. The solid was collected by filtration, rinsed twice with water, twice with 5% potassium hydroxide solution and twice again with water. The solid was dissolved in hot isopropyl alcohol and filtered hot. Water was added to the cloud point. Upon cooling, a solid precipitated which was collected by filtration, rinsed with water, and dried under high vacuum at 50° C. overnight to give 4.31 g (63%) of title compound, mp 171°-172.5° C.