Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH:4]1[CH2:6][CH:5]1[CH:7]1[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH2:8]1.[F:20][C:21]1[CH:22]=[C:23](O)[CH:24]=[CH:25][C:26]=1[C:27]1[O:28][C:29]([CH3:32])=[N:30][N:31]=1>>[F:20][C:21]1[CH:22]=[C:23]([CH:24]=[CH:25][C:26]=1[C:27]1[O:28][C:29]([CH3:32])=[N:30][N:31]=1)[O:1][CH2:2][CH2:3][C@H:4]1[CH2:6][C@H:5]1[CH:7]1[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH2:8]1
Reactant: CC(C)(C)OC(=O)N1CCC(C2CC2CCO)CC1
Reactant: Cc1nnc(-c2ccc(O)cc2F)o1
Product: Cc1nnc(-c2ccc(OCC[C@H]3C[C@H]3C3CCN(C(=O)OC(C)(C)C)CC3)cc2F)o1

Procedure:
The title compound was synthesized using rac-tert-butyl 4-[2-(2-hydroxyethyl)cyclopropyl]piperidine-1-carboxylate from Example 1 and 3-fluoro-4-(5-methyl-1,3,4-oxadiazol-2-yl)phenol through a Mitsunobu reaction by a procedure analogous to that procedure reported for Example 6, step 3.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=O)[CH2:6][CH2:5]2.Cl.[CH2:13]([O:20][NH2:21])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.N1C=CC=CC=1>C(O)C>[CH2:13]([O:20]/[N:21]=[C:7]1\[CH2:6][CH2:5][C:4]2[C:8]\1=[CH:9][CH:10]=[C:2]([Br:1])[CH:3]=2)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C1CCc2cc(Br)ccc21
Reactant: NOCc1ccccc1
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Product: Brc1ccc2c(c1)CC/C2=N\OCc1ccccc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 84 %

Procedure:
To 5-bromoindanone (5.66 g) in 60 mL ethanol was added 5.57 g O-benzylhydroxylamine hydrochloride and 3.2 mL pyridine. The mixture was stirred at ambient temperature for 5 hours. The volatiles were removed under vacuum and the solid residue partitioned between saturated aqueous sodium bicarbonate and ethyl acetate. The ethyl acetate was washed with brine, dried over magnesium sulfate, filtered, and evaporated under vacuum to afford crude product as an amber oil. The crude material was crystallized from hexane to afford 5.43 g (84% yield) light tan solid. 1H NMR (CDCl3) was consistent with the desired product. LC/MS indicated a single peak with a M+1 molecular ion of m/z 318.1 by positive ESI.
Reaction SMILES: [CH2:1]([NH:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][CH:6]=1)[CH3:2].[CH2:13]([OH:16])[C:14]#[CH:15].[CH2:17]=O>>[CH2:1]([N:3]([CH2:4][C:5]1[CH:6]=[CH:7][C:8]([O:11][CH3:12])=[CH:9][CH:10]=1)[CH2:17][C:15]#[C:14][CH2:13][OH:16])[CH3:2]
Reactant: C=O
Reactant: C#CCO
Reactant: CCNCc1ccc(OC)cc1
Product: CCN(CC#CCO)Cc1ccc(OC)cc1

Procedure:
reacting N-ethyl-4-methoxybenzenemethanamine with 2-propyn-1-ol and paraformaldehyde in an inert solvent in the presence of cuprous chloride to produce 4-[N-ethyl-(4-methoxyphenyl)methylamino]-2-butyn-1-ol (V);
Reaction SMILES: [C:1]1([C@@H:7]([NH:9][C:10]2[N:15]=[C:14](Cl)[CH:13]=[C:12]([CH3:17])[N:11]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Na].[N:19]1[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[NH:21][CH:20]=1>CN(C=O)C>[C:1]1([C@@H:7]([NH:9][C:10]2[N:15]=[C:14]([N:19]3[C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=4[N:21]=[CH:20]3)[CH:13]=[C:12]([CH3:17])[N:11]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: c1ccc2[nH]cnc2c1
Reactant: Cc1cc(Cl)nc(N[C@@H](C)c2ccccc2)n1
Agent: [Na]
Solvent: CN(C)C=O
Product: Cc1cc(-n2cnc3ccccc32)nc(N[C@@H](C)c2ccccc2)n1
Temperature: 100 °C

Procedure:
To a solution of 2-[(S)-1-phenylethylamino]-4-chloro-6-methylpyrimidine (11 mg, 0.044 mmol, 1 eq) in DMF (0.2 mL) was added a solution of benzimidazole sodium salt (0.088 mL of a 1M solution, 0.088 mmol, 2 eq). The mixture was warmed to 100° C. for 2 h. The mixture was cooled and the DMF was removed under reduced pressure. The residue was purified by preparative thin layer chromatography (eluted with 2:1 hexanes/acetone to give 9.9 mg of the title compound. 1H NMR (500 MHz, CDCl3): δ 1.23 (3H, d, J=7 Hz), 2.45 (3H, s), 5.2 (1H br s), 5.62 (1H, br s), 6.6 (1H, s), 7.2-7.5 (7H, m), 7.8 (2H, d, J=8 Hz), 8.46 (1H, br s). Mass spectrum (NH3/CI): 330.1 (M+1).
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[C:11]([CH:12]([CH3:14])[CH3:13])=[CH:10][CH:9]=[CH:8][C:7]=1[CH:15]([CH3:17])[CH3:16])=[O:4].[CH2:18]([NH:23][CH2:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[C:37]2[N:41]([C:42]([C:55]3[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=3)([C:49]3[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=3)[C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)[N:40]=[N:39][N:38]=2)=[CH:27][CH:26]=1)[CH2:19][CH2:20][CH2:21][CH3:22].[I-].[K+].C(N(CC)CC)C>CN(C)C=O.C(OCC)(=O)C>[CH:15]([C:7]1[CH:8]=[CH:9][CH:10]=[C:11]([CH:12]([CH3:14])[CH3:13])[C:6]=1[NH:5][C:3]([CH2:2][N:23]([CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH2:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[C:37]2[N:41]([C:42]([C:55]3[CH:56]=[CH:57][CH:58]=[CH:59][CH:60]=3)([C:49]3[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=3)[C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)[N:40]=[N:39][N:38]=2)=[CH:27][CH:26]=1)=[O:4])([CH3:17])[CH3:16]
Reactant: CCCCCNCc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: CC(C)c1cccc(C(C)C)c1NC(=O)CCl
Agent: [I-]
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCCCN(CC(=O)Nc1c(C(C)C)cccc1C(C)C)Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Temperature: 80 °C
Yield: 33 %

Procedure:
N-(Chloroacetyl)-2,6-diisopropylaniline (196.3 mg), N-pentyl-N-[[2′-[N-(triphenylmethyl)tetrazol-5-yl]-1,1′-biphenyl-4-yl]methyl]amine (430.0 mg), potassium iodide (70 mg) and triethylamine (0.6 g) were suspended in dimethylformamide (3 mL). The resulting mixture was heated to about 80° C., and then stirred at that temperature. Three hours later, the reaction mixture was cooled, ethyl acetate (30 mL) was added, and the mixture was washed four times with brine (50 mL, each). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was subjected to chromatography on a silica gel column (hexane/ethyl acetate) to afford N-[[[(2,6-diisopropylphenyl)amino]carbonyl]methyl]-N-pentyl-N-[[2′-[N-(triphenylmethyl)tetrazol-5-yl]-1,1′-biphenyl-4-yl]methyl]amine (196.4 mg). Yield: 33%.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[C:6]([CH3:11])[CH:7]=[CH:8][CH:9]=2)[C:4]([CH2:12][N:13]2[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=3[N:15]([C@@H:22]([CH2:27][CH2:28][CH3:29])[CH2:23][C:24]([OH:26])=O)[C:14]2=[O:30])=[CH:3]1.C1N=CN(C(N2C=NC=C2)=O)C=1.[C:43]1([S:49]([NH2:52])(=[O:51])=[O:50])[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1.C1CCN2C(=NCCC2)CC1.Cl>O.C1COCC1>[CH3:1][N:2]1[C:10]2[C:5](=[C:6]([CH3:11])[CH:7]=[CH:8][CH:9]=2)[C:4]([CH2:12][N:13]2[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=3[N:15]([C@@H:22]([CH2:27][CH2:28][CH3:29])[CH2:23][C:24]([NH:52][S:49]([C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)(=[O:51])=[O:50])=[O:26])[C:14]2=[O:30])=[CH:3]1
Reactant: CCC[C@@H](CC(=O)O)n1c(=O)n(Cc2cn(C)c3cccc(C)c23)c2ccccc21
Reactant: NS(=O)(=O)c1ccccc1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: O
Solvent: C1CCOC1
Product: CCC[C@@H](CC(=O)NS(=O)(=O)c1ccccc1)n1c(=O)n(Cc2cn(C)c3cccc(C)c23)c2ccccc21
Temperature: 55 °C
Reaction time: 0.5 h
Yield: 47.4 %

Procedure:
(S)-3-[3-(1,4-Dimethyl-1H-indol-3-ylmethyl)-2-oxo-2,3-dihydro-benzimidazol-1-yl]-hexanoic acid (25 mg, 0.062 mmol) is dissolved THF (0.5 mL) and CDI (22 mg, 0.14 mmol) is added into it at room temperature. The mixture is stirred for 30 min and then it is heated at 55° C. for 1 hr. After the mixture is cooled down to room temperature, Benzenesulfonamide (19 mg, 0.12 mmol) is added and after 10 min, DBU (0.018 mL, 0.12 mmol) is added. The mixture is then stirred for 16 hr at room temperature. 1 mL of 1.0 M HCl is added followed by 10 mL of water. The mixture is extracted with EtOAc (3×20 mL) and the organic layers are combined, dried and concentrated to give crude product. Purification by Preparative TLC affords 16 mg (47%) of N-{(S)-3-[3-(1,4-Dimethyl-1H-indol-3-ylmethyl)-2-oxo-2,3-dihydro-benzimidazol-1-yl]-hexanoyl}-benzenesulfonamide. LCMS (ESMS): m/z 545.32 (M+H+).
Reaction SMILES: [C:1]1([N:7]2C(=O)C3=CNC4C=CC=CC=4C3=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:22]1[C:31]2[C:26](=[CH:27][C:28]([F:33])=[C:29]([F:32])[CH:30]=2)[N:25]=[CH:24][C:23]=1[C:34]([O:36]CC)=O.C1(NN)C=CC=CC=1>>[F:33][C:28]1[C:29]([F:32])=[CH:30][C:31]2[C:22]3[C:23]([C:34](=[O:36])[N:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[N:8]=3)=[CH:24][NH:25][C:26]=2[CH:27]=1
Reactant: CCOC(=O)c1cnc2cc(F)c(F)cc2c1Cl
Reactant: O=c1c2c[nH]c3ccccc3c-2nn1-c1ccccc1
Solvent: NNc1ccccc1
Product: O=c1c2c[nH]c3cc(F)c(F)cc3c-2nn1-c1ccccc1

Procedure:
The title compound was prepared following the procedure described in Step 3 for the synthesis of 4a, using 3c and phenyl hydrazine. 1H NMR (DMSO-d6) δ (ppm): 7.18 (1H, t, J=7.82 Hz), 7.43 (2H, dd, J=8.30, 7.33 Hz), 7.75 (1H, dd, J=11.22, 7.32 Hz), 8.18, 3H, m), 8.90 (1H, s). m/z 298.2 (MH+).
Reaction SMILES: [CH3:1][O:2][CH:3]([CH2:8][C:9]1[N:10]=[CH:11][N:12]([C:14]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:13]=1)[C:4]([O:6]C)=[O:5].[OH-].[Na+]>O1CCCC1.CO.O>[CH3:1][O:2][CH:3]([CH2:8][C:9]1[N:10]=[CH:11][N:12]([C:14]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:13]=1)[C:4]([OH:6])=[O:5]
Reactant: COC(=O)C(Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1)OC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: COC(Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1)C(=O)O
Reaction time: 1.75 h
Yield: 96.3 %

Procedure:
To a solution of methyl 2-methoxy-3-(1-trityl-1H-imidazol-4-yl)propanoate (0.0592 g, 0.139 mmol) in tetrahydrofuran (1 mL), methanol (1 mL) and water (0.5 mL) was added 2N NaOH (0.278 mL) and the reaction mixture was stirred for 1.75 hrs. The organic solvents were removed and 1 N KHSO4 (5 mL) and ethyl acetate (10 mL) were added. The organic phase was washed with water (2×5 mL), then saturated sodium chloride (1×5 mL) and dried over MgSO4. The combined aqueous layers were re-extracted with DCM (2×10 mL), and dried over MgSO4—Solvent removal and drying in vacuo yielded 0.0552 g (96%) of 92.6% pure 2-methoxy-3-(1-trityl-1H-imidazol-4-yl)propanoic acid; retention time, 6.80 min.; column: Phenomenex Luna C18(2) (5 μm, 50×4.6 mm); gradient: 10% to 100% B in A over 10 min. at 1.25 mL/min. Solvent A: 0.1% TFA in water, Solvent B: 0.1% TFA in AcCN. LC/MS: ESI (M+H)+=413.1. 1H-NMR (CDCl3, 500 MHz): δ 3.10-3.18 (m, 1H), 3.31-3.38 (m, 1H), 3.45 (s, 3H), 4.26-4.31 (m (1H), 6.86 (s, 1H), 7.04-7.11 (m, 6H), 7.37-7.47 (m, 9H), 8.16 (s, 1H).
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH2:7][N:8]2[CH:12]=[C:11]([N:13]3[C:17](=[O:18])[CH2:16][N:15]([CH2:19]COC4C=CC=CC=4)[C:14]3=[O:28])[CH:10]=[N:9]2)=[C:5]([CH3:29])[O:4][N:3]=1.BrC[C:32]1[CH:33]=[C:34]([CH:39]=[CH:40][CH:41]=1)[C:35]([O:37]C)=[O:36].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.Cl>[CH3:1][C:2]1[C:6]([CH2:7][N:8]2[CH:12]=[C:11]([N:13]3[C:17](=[O:18])[CH2:16][N:15]([CH2:19][C:32]4[CH:33]=[C:34]([CH:39]=[CH:40][CH:41]=4)[C:35]([OH:37])=[O:36])[C:14]3=[O:28])[CH:10]=[N:9]2)=[C:5]([CH3:29])[O:4][N:3]=1
Reactant: Cc1noc(C)c1Cn1cc(N2C(=O)CN(CCOc3ccccc3)C2=O)cn1
Reactant: COC(=O)c1cccc(CBr)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Cc1noc(C)c1Cn1cc(N2C(=O)CN(Cc3cccc(C(=O)O)c3)C2=O)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 82.8 %

Procedure:
3-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)imidazolidine-2,4-dione (500 mg, 1.8 mmol) (example 10-5), methyl 3-(bromomethyl)benzoate (456 mg, 2 mmol), and cesium carbonate (650 mg, 2 mmol) were stirred in DMF (4 mL) in the microwave reactor at 85° C. for 20 minutes. The reaction was cooled, diluted with 1N aqueous HCl (100 mL) and extracted with ethyl acetate (3×, 75 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated. The crude ester was dissolved in methanol (5 mL) and aqueous NaOH (50 mL, 10% by wt) was added and the mixture was stirred at ambient temperature for 2 hours. The reaction was acidified with 1N HCl (150 mL) and extracted with ethyl acetate (3×, 75 mL). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated on the rotovap. The free acid was triturated with ethyl acetate/hexanes (1/9) and dried under vacuum to afford 3-((3-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)-2,4-dioxoimidazolidin-1-yl)methyl)benzoic acid (610 mg, 83%) as a white solid. 1H NMR (DMSO-d6, 400 2.13 (s, 3H), 2.29 (s, 3H), 4.00 (s, 2H), 4.59 (s, 2H), 5.18 (s, 2H), MHz): δ 7.46-7.59 (m, 2H), 7.78 (s, 1H), 7.85-7.88 (m, 2H), 8.18 (s, 1H). The title compound was shown to inhibit hT2R08 bitter receptor and had an IC50 of 1.8 μM.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][C:5]1[CH:6]=[N:7][N:8]([CH3:10])[CH:9]=1.C([Li])CCC.CCCCCC.C(O[B:26]1[O:30][C:29]([CH3:32])([CH3:31])[C:28]([CH3:34])([CH3:33])[O:27]1)(C)C>O1CCCC1>[CH3:1][O:2][CH2:3][CH2:4][C:5]1[CH:6]=[N:7][N:8]([CH3:10])[C:9]=1[B:26]1[O:30][C:29]([CH3:32])([CH3:31])[C:28]([CH3:34])([CH3:33])[O:27]1
Reactant: CC(C)OB1OC(C)(C)C(C)(C)O1
Reactant: COCCc1cnn(C)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COCCc1cnn(C)c1B1OC(C)(C)C(C)(C)O1
Temperature: 25 °C
Reaction time: 1 h
Yield: 43.5 %

Procedure:
To a solution of 4-(2-methoxyethyl)-1-methyl-1H-pyrazole (0.400 g, 2.85 mmol) in tetrahydrofuran (10 mL) at 0° C. was added 1.6 M n-butyllithium in hexane (6.24 mL, 9.99 mmol). The solution was stirred at room temperature for 1 h and then cooled down to −78° C. To the solution was added 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.70 mL, 3.4 mmol). The reaction was continued at −78° C. for 0.5 h, then warmed up to 0° C. (taking 0.5 h). The reaction mixture was quenched with brine, adjusted to pH=6-7 with 1 N HCl aqueous solution, and extracted with EtOAc (2×). The combined organic phases were washed with brine, dried over Na2SO4, and concentrated to give a brown oil which was further purified to provide 0.33 g (43% yield) of the desired product. LC-MS found: 267.1 (M+H)+.
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[O:15]=[C:16]1[N:20]([C:21]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:19]2[CH:40]=[CH:41][C:42]([C:44]3[CH:45]=[C:46]([CH:49]=O)[O:47][CH:48]=3)=[CH:43][C:18]=2[O:17]1.[CH3:51][N:52]1[CH2:57][CH2:56][CH:55]([NH2:58])[CH2:54][CH2:53]1.C(O)(=O)C>ClCCCl.ClCCl>[CH3:51][N:52]1[CH2:57][CH2:56][CH:55]([NH:58][CH2:49][C:46]2[O:47][CH:48]=[C:44]([C:42]3[CH:41]=[CH:40][C:19]4[N:20]([C:21]([C:34]5[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=5)([C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=5)[C:22]5[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=5)[C:16](=[O:15])[O:17][C:18]=4[CH:43]=3)[CH:45]=2)[CH2:54][CH2:53]1
Reactant: CN1CCC(N)CC1
Reactant: O=Cc1cc(-c2ccc3c(c2)oc(=O)n3C(c2ccccc2)(c2ccccc2)c2ccccc2)co1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CN1CCC(NCc2cc(-c3ccc4c(c3)oc(=O)n4C(c3ccccc3)(c3ccccc3)c3ccccc3)co2)CC1
Temperature: 25 °C
Reaction time: 21 h
Yield: 41.5 %

Procedure:
Sodium triacetoxyborohydride (339 mg, 1.6 mmol) was added to a solution of 4-(2-oxo-3-trityl-2,3-dihydro-benzooxazol-6-yl)-furan-2-carbaldehyde (377 mg, 0.8 mmol) and 1-methyl-piperidin-4-ylamine (219 mg, 1.92 mmol) and acetic acid (192 mg, 3.2 mmol) in 10 mL of 1,2-dichloroethane. The mixture was stirred at ambient temperature for 21 h, and then it was diluted with dichloromethane and washed with saturated sodium carbonate solution. The aqueous phase was extracted with dichloromethane, and the combined organic phases were washed with water and brine, dried over magnesium sulfate, filtered and concentrated to leave the crude product. Chromatography (elution with dichloromethane/methanol/acetic acid/water) gave 189 mg of product. LC/MS: Retention time, 2.38 min; (M+H)=570.
Reaction SMILES: [Br:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][C:7]23[C:15](=[O:16])[N:14]([C:17]4[CH:22]=[C:21]([Cl:23])[CH:20]=[C:19]([Cl:24])[CH:18]=4)[C:13](=[O:25])[N:12]2[CH2:11][CH2:10][NH:9][CH2:8]3)=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.Br[CH2:38][C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40]>C1COCC1>[C:42]([O:41][C:39]([CH2:38][N:9]1[CH2:8][C:7]2([CH2:6][C:5]3[CH:26]=[CH:27][C:2]([Br:1])=[CH:3][CH:4]=3)[N:12]([C:13](=[O:25])[N:14]([C:17]3[CH:22]=[C:21]([Cl:23])[CH:20]=[C:19]([Cl:24])[CH:18]=3)[C:15]2=[O:16])[CH2:11][CH2:10]1)=[O:40])([CH3:45])([CH3:44])[CH3:43]
Reactant: O=C1N(c2cc(Cl)cc(Cl)c2)C(=O)C2(Cc3ccc(Br)cc3)CNCCN12
Reactant: CC(C)(C)OC(=O)CBr
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CN1CCN2C(=O)N(c3cc(Cl)cc(Cl)c3)C(=O)C2(Cc2ccc(Br)cc2)C1
Reaction time: 40 h

Procedure:
To a solution of 6-(4-bromobenzyl)-8-(3,5-dichlorophenyl)-1,4,8-triazabicyclo[4.3.0]nonane-7,9-dione (0.11 g) in THF (5 mL) was added DIEA (0.1 mL) and tert-butyl bromoacetate (0.06 mL). Additional tert-butyl bromoacetate (0.040 mL) was added after 16 hours. After 40 hours, the reaction mixture was concentrated and the residue was diluted with EtOAc and washed with water, NaHCO3, and brine, dried (Na2SO4), filtered, and concentrated. Purification by chromatography (Silica gel: EtOAc/hexane: 1/5, Chromatotron) afforded the titled compound (0.124 g). MS (m/z) 582 (MH+). mp 74.7° C.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH3:13][NH2:14].[N:15]1([CH2:20][CH2:21][CH2:22][O:23][C:24]2[CH:31]=[CH:30][C:27]([CH:28]=O)=[CH:26][CH:25]=2)[CH2:19][CH2:18][CH2:17][CH2:16]1>>[CH3:12][O:11][C:9]1[CH:10]=[C:2]2[C:3]([C:4](=[O:6])[N:14]([CH3:13])[C:28]([C:27]3[CH:30]=[CH:31][C:24]([O:23][CH2:22][CH2:21][CH2:20][N:15]4[CH2:19][CH2:18][CH2:17][CH2:16]4)=[CH:25][CH:26]=3)=[N:1]2)=[CH:7][CH:8]=1
Reactant: CN
Reactant: COc1ccc(C(=O)O)c(N)c1
Reactant: O=Cc1ccc(OCCCN2CCCC2)cc1
Product: COc1ccc2c(=O)n(C)c(-c3ccc(OCCCN4CCCC4)cc3)nc2c1

Procedure:
The entitled compound was obtained according to the method of Example 15 but starting from 2-amino-4-methoxybenzoic acid, methylamine and 4-(3-pyrrolidin-1-ylpropoxy)benzaldehyde.
Reaction SMILES: C(N(CC)CC)C.[Cl:8][C:9]1[C:10]([C:14]2[C:22]3[O:21][C:20]([F:24])([F:23])[O:19][C:18]=3[CH:17]=[CH:16][CH:15]=2)=[N:11][NH:12][CH:13]=1.[C:25](Cl)(=[O:27])[CH3:26].O>CN(C)C1C=CN=CC=1.C1COCC1>[C:25]([N:12]1[CH:13]=[C:9]([Cl:8])[C:10]([C:14]2[C:22]3[O:21][C:20]([F:24])([F:23])[O:19][C:18]=3[CH:17]=[CH:16][CH:15]=2)=[N:11]1)(=[O:27])[CH3:26]
Reactant: FC1(F)Oc2cccc(-c3n[nH]cc3Cl)c2O1
Reactant: CC(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: CC(=O)n1cc(Cl)c(-c2cccc3c2OC(F)(F)O3)n1
Reaction time: 3 h
Yield: 92.6 %

Procedure:
0.25 g (0.005 mol) of 4-dimethylaminopyridine and 4.25 g (0.042 mol) of triethylamine are added to 11.0 g (0.046 mol) of 4-chloro,3-(2,2-difluorobenzo-1,3-dioxol-4-yl)-1H-pyrazole (prepared as described in patent PH 91-033) dissolved in 100 ml of THF. A solution of 3.6 g (0.046 mol) of acetyl chloride in 50 ml of THF is run dropwise and at 0° C. onto this solution. Stirring is continued for 3 h at room temperature. The reaction mixture is poured into 300 ml of water and extracted with ethyl acetate. After drying the organic phase and concentration under vacuum, the residue is triturated with 50 ml of heptane, filtered and dried. We obtain 12.8 g of 1-acetyl-4-chloro-3-(2,2-difluorobenzo-1,3-dioxol-4-yl)pyrazole melting at 131° C.
Reaction SMILES: [CH:1]([C:4]1([CH3:18])[N:8]2[C:9](=[O:16])[C:10]3[C:15]([C:7]2=[N:6][C:5]1=[O:17])=[CH:14][CH:13]=[CH:12][CH:11]=3)([CH3:3])[CH3:2].[CH3:19][NH:20][CH3:21]>O1CCCC1>[CH:1]([C:4]1([CH3:18])[NH:8][C:7]([C:15]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:9]([N:20]([CH3:21])[CH3:19])=[O:16])=[N:6][C:5]1=[O:17])([CH3:2])[CH3:3]
Reactant: CNC
Reactant: CC(C)C1(C)C(=O)N=C2c3ccccc3C(=O)N21
Solvent: C1CCOC1
Product: CC(C)C1(C)NC(c2ccccc2C(=O)N(C)C)=NC1=O
Temperature: 50 °C
Reaction time: 16 h
Yield: 91.3 %

Procedure:
To a cold solution of 180 g of 3-isopropyl-3-methyl-5H-imidazo[2,1-a] isoindole-2-(3H), 5-dione in 300 ml of dry tetrahydrofuran in a pressure bottle is added 68 g of dimethylamine. The bottle is sealed and the mixture heated to 50° C. with stirring for 16 hours. The mixture is cooled, and the contents of the bottle transferred to a flask. The solvent is then removed in vacuo. The crystalline residue is then suspended in ether, filtered, washed with ether, and air-dried to give 195 g of o-(5-isopropyl-5-methyl-4-oxo-2-imidazolin-2-yl)-N,N-dimethylbenzamide, melting point 144°-146° C. This product is recrystallized from acetonitrile to give an analytically pure product, melting point 147°-150° C.
Reaction SMILES: [NH2:1][C:2]1[C:6]([I:7])=[C:5]([CH3:8])[O:4][N:3]=1.[C:9]1([S:15](Cl)(=[O:17])=[O:16])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>>[I:7][C:6]1[C:2]([NH:1][S:15]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)(=[O:17])=[O:16])=[N:3][O:4][C:5]=1[CH3:8]
Reactant: Cc1onc(N)c1I
Reactant: O=S(=O)(Cl)c1ccccc1
Product: Cc1onc(NS(=O)(=O)c2ccccc2)c1I

Procedure:
N-(4-Iodo-5-methyl-3-isoxazolyl)benzenesulfonamide was prepared from 3-amino-4-iodo-5-methylisoxazole and benzenesulfonyl chloride according to the procedures described in Example 25b. The crude product was purified by recrystallization from ethyl acetate/hexanes to give a brown powder m.p. 138-141° C., yield 46%.
Reaction SMILES: [OH:1][C:2]1[CH:17]=[CH:16][CH:15]=[CH:14][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[O:12][CH3:13])=[O:5].C(=O)([O-])[O-].[K+].[K+].[CH2:24](Br)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>CS(C)=O.C(OCC)C.O>[CH2:24]([O:1][C:2]1[CH:17]=[CH:16][CH:15]=[CH:14][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[O:12][CH3:13])=[O:5])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: COc1ccccc1C(=O)c1ccccc1O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOCC
Solvent: CS(C)=O
Product: COc1ccccc1C(=O)c1ccccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 2-hydroxy-2′-methoxybenzophenone (12) (8.08 g, 0.0354 mol), potassium carbonate (24.5 g, 0.177 mol) and benzyl bromide (4.4 mL, 0.037 mol) in 90 mL of dimethylsulfoxide was stirred overnight at room temperature. The resulting reaction mixture was diluted with diethyl ether and water and the aqueous layer was extracted with fresh diethyl ether. The combined organic layers were washed with water, followed by saturated NaCI and dried over sodium sulfate. After purification by flash column chromatography (silica gel, dichloromethane/hexanes eluent), 2-benzyloxy-2′-methoxybenzophenone (13) was obtained as a colorless oil.