Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4]([C:6]1([S:20]([C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=2)(=[O:22])=[O:21])[CH2:11][CH2:10][N:9]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])C>C1COCC1.CO.[OH-].[Na+]>[F:19][C:16]1[CH:15]=[CH:14][C:13]([CH2:12][N:9]2[CH2:10][CH2:11][C:6]([S:20]([C:23]3[CH:24]=[CH:25][C:26]([O:29][CH3:30])=[CH:27][CH:28]=3)(=[O:22])=[O:21])([C:4]([OH:5])=[O:3])[CH2:7][CH2:8]2)=[CH:18][CH:17]=1
Reactant: CCOC(=O)C1(S(=O)(=O)c2ccc(OC)cc2)CCN(Cc2ccc(F)cc2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc(S(=O)(=O)C2(C(=O)O)CCN(Cc3ccc(F)cc3)CC2)cc1

Procedure:
1-(4-Fluoro-benzyl)-4-(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylic acid was prepared starting from 1-(4-fluoro-benzyl)-4-(4-methoxy-benzenesulfonyl)-piperidine-4- carboxylic acid ethyl ester (17.4 g, 40 nmnol) dissolved in THF:methanol 3:1 and 10N NaOH (40 ml). The resulting reaction mixture was worked up as outlined in example 83. Yield 10.8 g (66%); colorlesssolid; mp 154° C.; MS: 408 (M+H)+.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([CH:20]([OH:26])[CH:21](OCC)O)[C:12]2[O:17][CH2:16][C:15](=[O:18])[NH:14][C:13]=2[CH:19]=1)C1C=CC=CC=1.[NH2:27][C:28]([CH3:43])([CH3:42])[CH2:29][CH2:30][N:31]1[C:35]2[CH:36]=[C:37]([CH3:40])[CH:38]=[CH:39][C:34]=2[NH:33][C:32]1=[O:41].FC(F)(F)C([O-])=O>>[CH3:43][C:28]([NH:27][CH2:21][CH:20]([C:11]1[C:12]2[O:17][CH2:16][C:15](=[O:18])[NH:14][C:13]=2[CH:19]=[C:9]([OH:8])[CH:10]=1)[OH:26])([CH3:42])[CH2:29][CH2:30][N:31]1[C:35]2[CH:36]=[C:37]([CH3:40])[CH:38]=[CH:39][C:34]=2[NH:33][C:32]1=[O:41]
Reactant: CCOC(O)C(O)c1cc(OCc2ccccc2)cc2c1OCC(=O)N2
Reactant: Cc1ccc2[nH]c(=O)n(CCC(C)(C)N)c2c1
Agent: O=C([O-])C(F)(F)F
Product: Cc1ccc2[nH]c(=O)n(CCC(C)(C)NCC(O)c3cc(O)cc4c3OCC(=O)N4)c2c1

Procedure:
The compound is prepared according to general method 1 from 357 mg (1 mmol) 6-benzyloxy-8-(2-ethoxy-1,2-dihydroxy-ethyl)-4H-benzo[1,4]oxazin-3-one and 233 mg (1 mmol) 1-(3-amino-3-methyl-butyl)-6-methyl-1,3-dihydro-benzimidazol-2-one. Yield: 170 mg (31%, trifluoroacetate); mass spectroscopy: [M+H]+=441.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2-:13].[Na+]>>[NH2:13][C:8]1[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[CH:12][CH:11]=[CH:10][N:9]=1
Reactant: [NH2-]
Reactant: c1ccc(-c2cccnc2)cc1
Agent: [Na+]
Product: Nc1ncccc1-c1ccccc1

Procedure:
2-Amino-3-phenylpyridine is prepared by reacting 46.5 g. 3-phenylpyridine with 11.7 g. of sodium amide at a temperature of 250° in the presence of mineral oil. The 2-amino-3-phenylpyridine that is formed is purifed by distillation and is substituted for the 2-amino-4-phenylpyridine in Example 8 to obtain the named compound.
Reaction SMILES: OC(C(F)(F)F)=O.[NH2:8][C@@H:9]([CH2:26][C:27]1[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=1)[C:10]([NH:12][C:13]1[N:17]([CH3:18])[N:16]=[C:15]([C:19]2[CH:24]=[CH:23][N:22]=[C:21]([CH3:25])[CH:20]=2)[CH:14]=1)=[O:11].CCN(C(C)C)C(C)C.S1C=C(C=O)N=C1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[Cl:64]CCCl>CC(O)=O>[ClH:64].[NH2:8][C@@H:9]([CH2:26][C:27]1[CH:28]=[CH:29][C:30]([F:33])=[CH:31][CH:32]=1)[C:10]([NH:12][C:13]1[N:17]([CH3:18])[N:16]=[C:15]([C:19]2[CH:24]=[CH:23][N:22]=[C:21]([CH3:25])[CH:20]=2)[CH:14]=1)=[O:11]
Reactant: ClCCCl
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cc1cc(-c2cc(NC(=O)[C@@H](N)Cc3ccc(F)cc3)n(C)n2)ccn1
Agent: O=Cc1cscn1
Solvent: O=C(O)C(F)(F)F
Solvent: CC(=O)O
Solvent: CCN(C(C)C)C(C)C
Product: Cl
Temperature: 65 °C
Reaction time: 0.5 h

Procedure:
To a 100 ml flask was added (2S)-2-amino-3-(4-fluorophenyl)-N-(1-methyl-3-(2-methylpyridin-4-yl)-1H-pyrazol-5-yl)propanamide TFA (85 mg, 0.182 mmoles), 5 ml of DCE, DIEA (48 μl, 0.27 mmole, Make sure pH=7), 50 ul of AcOH and thiazole-4-carbaldehyde (16 mg, 0.15 mmole). The reaction was stirred at 65° C. for 5 minutes at which time sodium triacetoxyborohydride (116 mg, 0.55 mmoles) was added and stirred at 65° C. for an additional 30 minutes. The solvent was then removed and the crude purified by reverse phase preparative HPLC to give (2S)-2-amino-3-(4-fluorophenyl)-N-(1-methyl-3-(2-methylpyridin-4-yl)-1H-pyrazol-5-yl)propanamide HCl (27.8 mg, 34% yield) after salt exchange using 1 M HCl in ether (546 ul, 0.55 mmole). LCMS ESI (pos.) m/e: 451.1 (M+1): 1H NMR (500 MHz, MeOH-d) δ ppm 9.04 (d, J=1.22 Hz, 1H) 8.50 (d, J=6.11 Hz, 1H) 8.16 (s, 1H) 8.11 (d, J=6.11 Hz, 1H) 7.78 (s, 1H) 7.25 (dd, J=8.19, 5.26 Hz, 2H) 6.95-7.10 (m, 3H) 4.44 (s, 2H) 4.41 (dd, J=8.93, 5.99 Hz, 1H) 3.56 (s, 3H) 3.40 (dd, J=13.33, 5.50 Hz, 1H) 3.15 (dd, J=13.57, 9.41 Hz, 1H) 2.70 (s, 3H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C@H:10]([C@H:14]([OH:16])[CH3:15])[C:11]([OH:13])=O)=[CH:5][C:4]=1[C:17]([F:20])([F:19])[F:18])#[N:2].[C:21]([C:23]1[CH:32]=[CH:31][C:26]([C:27]([NH:29][NH2:30])=[O:28])=[CH:25][CH:24]=1)#[N:22].O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.C(N(CC)CC)C>C1COCC1>[C:21]([C:23]1[CH:24]=[CH:25][C:26]([C:27]([NH:29][NH:30][C:11](=[O:13])[C@H:10]([NH:9][C:6]2[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[C:4]([C:17]([F:20])([F:19])[F:18])[CH:5]=2)[C@H:14]([OH:16])[CH3:15])=[O:28])=[CH:31][CH:32]=1)#[N:22]
Reactant: C[C@@H](O)[C@@H](Nc1ccc(C#N)c(C(F)(F)F)c1)C(=O)O
Reactant: N#Cc1ccc(C(=O)NN)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: C[C@@H](O)[C@@H](Nc1ccc(C#N)c(C(F)(F)F)c1)C(=O)NNC(=O)c1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
To a pre-cooled (−30° C.) solution of (2R,3R)-2-(4-cyano-3-(trifluoromethyl)-phenylamino)-3-hydroxybutanoic acid (1.05 g, 3.64 mmol) and 4-cyanobenzohydrazide (587 mg, 3.64 mmol) in anhydrous THF (60 mL) was added 1-Hydroxybenzotriazole monohydrate (563 mg, 3.64 mmol) and N-(3-Dimethylaminopropyl)-N′-ethylcarbodimide-HCl (1.40 g, 7.29 mmol) at −30° C. followed by triethylamine (1.02 mL, 7.29 mmol). The reaction mixture warmed to room temperature and stirred for 17 h, then quenched with 5% aq. citric acid (150 mL). The solution was extracted with EtOAc (150 mL). The organic extract was washed with 5% aq. citric acid (2×80 mL), sat. aq. NaHCO3 (3×80 mL), H2O (2×100 mL), dried (Na2SO4), filtered and concentrated under reduced pressure to provide the title compound as an off white solid (1.57 g, 100%): 1H NMR (400 MHz, acetone-d6, δ in ppm) 8.10 (dm, J=8.8 Hz, 2H), 7.94 (dm, J=8.8 Hz, 2H), 7.73 (d, J=8.6 Hz, 1H), 7.31 (d, J=2.3 Hz, 1H), 7.07 (dd, J=2.3, 8.6 Hz, 1H), 6.66 (d, J=7.2 Hz, 1H), 4.26-4.18 (m, 2H), 1.35 (d, J=6.3 Hz, 3H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:11])[CH2:9][CH3:10])=[CH:4][CH:3]=1.[C:12](=O)([O-])[O-].[K+].[K+].S(OC)(OC)(=O)=O>C(#N)C>[CH3:12][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8](=[O:11])[CH2:9][CH3:10])=[CH:6][CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: CCC(=O)c1ccc(O)cc1
Agent: [K+]
Solvent: COS(=O)(=O)OC
Solvent: CC#N
Product: CCC(=O)c1ccc(OC)cc1
Temperature: 25 °C

Procedure:
To a solution of 4′-hydroxypropiophenone (1.0 g, 6.67 mmol) in acetonitrile (50.0 mL) was added potassium carbonate (7.17 g, 66.7 mmol) and the mixture heated to reflux for 90 min. After this time the reaction mixture was allowed to cool to room temperature and dimethyl sulphate (1.05 mL, 11.1 mmol) was added and the reaction mixture was heated to reflux for a further 19 h. After cooling the acetonitrile was evaporated under reduced pressure and the residue taken up in water and extracted with dichloromethane. The dichloromethane extract was dried (MgSO4) and evaporated under reduced pressure to give 4′-methoxypropiophenone as a yellow oil, (970 mg, 89%) 1H nmr (d6-DMSO, 300 MHz) 1.06, t (7.2 Hz), CH3; 2.95, q (7.2 Hz), CH2; 3.83, s, OMe; 7.02, d (6.9 Hz), H3′,5′; 7.93, d (6.9 Hz), H2′,6′. ESI (+ve) MS m/z 165 (M+H, 100%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9](Cl)(=[O:11])=[O:10])=[C:5]([N+:13]([O-:15])=[O:14])[CH:4]=1.C(N(CC)CC)C.[CH2:23]([CH2:25][NH2:26])[OH:24].C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl.O>[OH:24][CH2:23][CH2:25][NH:26][S:9]([C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][C:5]=1[N+:13]([O-:15])=[O:14])(=[O:11])=[O:10]
Reactant: COc1ccc(S(=O)(=O)Cl)c([N+](=O)[O-])c1
Reactant: NCCO
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: COc1ccc(S(=O)(=O)NCCO)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 85.3 %

Procedure:
4-Methoxy-2-nitrobenzenesulfonyl chloride (3.1 g; 12.3 mmol; 1 eq) is dissolved in DCM (60 mL) in the presence of triethylamine (1.7 mL; 12.3 mmol; 1 eq) at 0° C. Ethanolamine (0.6 mL; 13.6 mmol; 1.1 eq) is then added and the reaction mixture is stirred at room temperature for 16 h. Water is added to the reaction mixture then aqueous Na2CO3. The organic phase is dried over MgSO4 and the solvent is evaporated under reduced pressure to give 2.9 g (85%) of the title compound as an orange oil, 1H NMR (DMSO-d6) δ 7.92 (d, J=3.2 Hz, 1H), 7.85-7.78 (m, 1H), 7.56 (d, J=2.5 Hz, 1H), 7.37 (dd, J=8.9, 2.6 Hz, 1H), 4.79-4.71 (m, 1H), 3.90 (s, 3H), 3.42-3.46 (m, 2H), 2.92-2.87 (m, 2H). HPLC (max plot) 52.3%; Rt 220 min. UPLCIMS: (ES+) 277.2, (ES−) 275.2.
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:17]([O:18]C(=O)C)[C@@H:16]([O:22]C(=O)C)[C@@H:15]([CH2:26][O:27]C(=O)C)[O:14][C@H:6]1[S:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)(=O)C.C[O-].[Na+]>CO>[S:7]([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C@@H:6]1[O:14][C@H:15]([CH2:26][OH:27])[C@H:16]([OH:22])[C@H:17]([OH:18])[C@H:5]1[OH:4]
Reactant: CC(=O)OC[C@H]1O[C@@H](Sc2ccccc2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: OC[C@H]1O[C@@H](Sc2ccccc2)[C@H](O)[C@@H](O)[C@H]1O
Reaction time: 1 h

Procedure:
To 8 (31.7 g, 72.07 mmol, 1 eq) dissolved in dry MeOH (800 mL) under argon was added sodium methanolate (17.3 g, 302.7 mmol, 4.2 eq). After being stirred for 1 h, Amberlite IR 120 (300 g) was added and the mixture was stirred for 15 min up to pH=7. The solution was filtered through alumina. The cake was washed with MeOH (150 mL) and the organic layer was concentrated. The crude was engaged in the next step.
Reaction SMILES: C(O[C:6]([NH:8][C@@H:9]([CH2:22][CH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1)[C@@H:10]([OH:21])[CH2:11][C@@H:12]([C:17]([OH:20])([CH3:19])[CH3:18])[C:13]([NH:15][CH3:16])=[O:14])=[O:7])(C)(C)C.Cl.[C:30]([O:34][C:35]([NH:37][C@H:38](C(O)=O)[CH2:39][C:40]1[N:41]=[CH:42][S:43][CH:44]=1)=[O:36])([CH3:33])([CH3:32])[CH3:31].P(C#N)(OCC)(OCC)=O.C(N(CC)CC)C>O1CCOCC1.O1CCCC1>[C:30]([O:34][C:35]([NH:37][C@H:38]([C:6]([NH:8][C@@H:9]([CH2:22][CH:23]1[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]1)[C@@H:10]([OH:21])[CH2:11][C@@H:12]([C:17]([OH:20])([CH3:18])[CH3:19])[C:13]([NH:15][CH3:16])=[O:14])=[O:7])[CH2:39][C:40]1[N:41]=[CH:42][S:43][CH:44]=1)=[O:36])([CH3:33])([CH3:31])[CH3:32]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1cscn1)C(=O)O
Reactant: CNC(=O)[C@@H](C[C@H](O)[C@H](CC1CCCCC1)NC(=O)OC(C)(C)C)C(C)(C)O
Agent: CCOP(=O)(C#N)OCC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: C1COCCO1
Product: CNC(=O)[C@@H](C[C@H](O)[C@H](CC1CCCCC1)NC(=O)[C@H](Cc1cscn1)NC(=O)OC(C)(C)C)C(C)(C)O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 91 %

Procedure:
A mixture of 1.20 g (3.00 mmoles) of (2S, 4S, 5S)-5-(t-butoxycarbonylamino)-6-cyclohexyl-4-hydroxy-2-(1-hydroxy-1-methylethyl)-N-methylhexanamide (prepared as described in Preparation 23) in 20 ml of a 4N solution of hydrogen chloride in dioxane was stirred at room temperature for 30 minutes under an atmosphere of nitrogen. At the end of this time, the reaction mixture was concentrated by evaporation under reduced pressure, and then diethyl ether was added to the residue. The solvent was then removed by distillation under reduced pressure from the resulting solution. The same operation was repeated in total three times, and the residue was then dried under reduced pressure for 8 hours. At the end of this time, 900 mg (3.30 mmoles) of N-(t-butoxycarbonyl)-3-(4-thiazolyl)-L-alanine were added to a suspension of the dried material in 20 ml of anhydrous tetrahydrofuran, and then 0.50 ml (3.30 mmoles) of diethyl cyanophosphate and 0.92 ml (6.60 mmoles) of triethylamine were added to the resulting mixture, whilst ice-cooling and under an atmosphere of nitrogen. The mixture was then stirred for 5 hours, after which the solvent was removed by distillation under reduced pressure, and the residue was purified by medium pressure silica gel column chromatography (using a 20:1 by volume mixture of methylene chloride and methanol as eluent), followed by recrystallization from diisopropyl ether, to give 1.51 g (yield 91%) or the title compound as white crystals, melting at 203°-205° C.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH2:6][C:5]1([CH2:9][N:10]([C:13]1[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:16]([O:23][CH3:24])=[CH:15][CH:14]=1)[CH:11]=O)[CH2:4][CH2:3][CH2:2]2.Cl>C1COCC1>[N:1]12[CH2:8][CH2:7][CH2:6][C:5]1([CH2:9][N:10]([C:13]1[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:16]([O:23][CH3:24])=[CH:15][CH:14]=1)[CH3:11])[CH2:4][CH2:3][CH2:2]2
Reactant: COc1ccc(N(C=O)CC23CCCN2CCC3)c2ccccc12
Agent: Cl
Solvent: C1CCOC1
Product: COc1ccc(N(C)CC23CCCN2CCC3)c2ccccc12
Yield: 95.7 %

Procedure:
To 1M borane-THF complex solution (40.0 ml, 40.0 mmol), 1-[N-(1-azabicyclo[3.3.0]octan-5-yl)methyl-N-formylamino]-4-methoxynaphthalene (2.90 g, 8.95 mmol) in absolute THF (20 ml) was added dropwise at 25° C. After refluxed for 1 hour, the reaction mixture was cooled, refluxed for 10 minutes subsequent to addition of 6N-HCl (10 ml), concentrated in vacuo, made into alkaline by addition of sodium hydroxide pellets, extracted by ethyl ether, dried over anhydrous sodium sulfate, concentrated in vacuo, and purified by chromatography to afford the desired compound (2.66 g, 96.0%), as a colorless liquid.
Reaction SMILES: [CH3:1][N:2]([CH3:15])[CH2:3][CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([NH2:14])=[CH:11][CH:12]=2)[CH:7]=[N:6]1.[O:16]([C:23]1[CH:28]=[CH:27][C:26]([N:29]=[C:30]=[O:31])=[CH:25][CH:24]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C1COCC1>[CH3:1][N:2]([CH3:15])[CH2:3][CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([NH:14][C:30]([NH:29][C:26]3[CH:27]=[CH:28][C:23]([O:16][C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=4)=[CH:24][CH:25]=3)=[O:31])=[CH:11][CH:12]=2)[CH:7]=[N:6]1
Reactant: CN(C)CCn1ncc2cc(N)ccc21
Reactant: O=C=Nc1ccc(Oc2ccccc2)cc1
Solvent: C1CCOC1
Product: CN(C)CCn1ncc2cc(NC(=O)Nc3ccc(Oc4ccccc4)cc3)ccc21
Temperature: 50 °C

Procedure:
A mixture of 1-(2-dimethylamino-ethyl)-1H-indazol-5-ylamine (42 mg, 0.17 mmol), 4-phenoxyphenyl isocyanate (36 mg, 0.17 mmol) in 2 mL of THF was heated to 50° C. for 6 hours, cool to room temperature and concentrated under reduced pressure. The residue was dissolved in 1.5 mL of a 1:1 mixture of dimethyl sulfoxide/methanol and purified by preparative reverse-phase HPLC. 1H NMR (300 MHz, DMSO-d6) ppm 2.85 (s, 6H), 3.63 (t, J=6.40, 2H), 4.77 (t, J=6.40, 2H), 7.09 (m, 2H), 6.97 (m, 4H), 7.36 (m, 2H), 7.47 (m, 1H), 7.57 (m, 2H), 7.67 (m, 1H), 7.97 (s, 1H), 8.10 (s, 1H), 8.98 (s, 1H); MS (DCI/NH3) m/z 416 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:32])[NH:4][CH:5]([C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[C:16]1[NH:17][C:18]([C:21]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:24](Br)=[CH:23][CH:22]=2)=[CH:19][N:20]=1)=[O:10])[CH:6]([CH3:8])[CH3:7].[CH3:33][O:34][C:35](=[O:68])[NH:36][CH:37]([C:41]([N:43]1[CH2:47][CH2:46][CH2:45][CH:44]1[C:48]1[NH:49][C:50]([C:53]2[CH:58]=[CH:57][C:56](B3OC(C)(C)C(C)(C)O3)=[CH:55][CH:54]=2)=[CH:51][N:52]=1)=[O:42])[CH:38]([CH3:40])[CH3:39].C([O-])(O)=O.[Na+]>COCCOC.O>[CH3:1][O:2][C:3](=[O:32])[NH:4][CH:5]([C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[C:16]1[NH:17][C:18]([C:21]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:24]([C:56]3[CH:57]=[CH:58][C:53]([C:50]4[NH:49][C:48]([CH:44]5[CH2:45][CH2:46][CH2:47][N:43]5[C:41](=[O:42])[CH:37]([NH:36][C:35]([O:34][CH3:33])=[O:68])[CH:38]([CH3:40])[CH3:39])=[N:52][CH:51]=4)=[CH:54][CH:55]=3)=[CH:23][CH:22]=2)=[CH:19][N:20]=1)=[O:10])[CH:6]([CH3:8])[CH3:7]
Reactant: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)[nH]1)C(C)C
Reactant: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc(Br)c3ccccc23)[nH]1)C(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc(-c3ccc(-c4cnc(C5CCCN5C(=O)C(NC(=O)OC)C(C)C)[nH]4)c4ccccc34)cc2)[nH]1)C(C)C
Temperature: 85 °C
Reaction time: 16 h
Yield: 21 %

Procedure:
(1-{2-[5-(4-Bromo-naphthalen-1-yl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (0.115 g), [2-Methyl-1-(2-{5-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-propyl]-carbamic acid methyl ester (0.111 g), and NaHCO3 (0.0623 g) were dissolved in a mixture of 1,2-dimethoxyethane (3 mL) and water (1 mL). The solution was degassed with nitrogen, and Pd(PPh3)4 (0.0114 g) was added. The reaction mixture was stirred at 85° C. for 16 hours and evaporated under vacuum. Solid was dissolved in ethyl acetate (10 mL) and extracted twice with water (10 mL) and once with brine (10 mL). Solution was evaporated, dissolved in DMF, purified by reverse phase HPLC (5-70% acetonitrile:water), and lyophilized, giving [1-(2-{5-[4-(4-{2-[1-(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-phenyl)-naphthalen-1-yl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-2-methyl-propyl]-carbamic acid methyl ester (0.037 g, 21%) as a white solid: 1H-NMR: 300 MHz, (CHCl3-d1) δ: 8.9 (m, 1H), 7.6 (m, 2H), 7.4 (m, 5H), 7.0 (m, 2H), 6.8 (m, 2H), 5.8 (m, 2H), 5.3 (m, 2H), 4.3 (m, 2H), 4.0 (m, 4H), 3.6 (s, 6H), 2.4 (m, 6H), 2.0 (m, 6H), 0.8 (m, 12H); MS (ESI) m/z 789 [M+H]+.
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][NH:15][C:14]3=[O:19])[CH:10]=[N:9]2)=[C:5]([CH3:20])[O:4][N:3]=1.[CH3:21][O:22][C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=1)[CH2:26]Br>>[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]([CH2:26][C:25]4[CH:28]=[CH:29][CH:30]=[C:23]([O:22][CH3:21])[CH:24]=4)[C:14]3=[O:19])[CH:10]=[N:9]2)=[C:5]([CH3:20])[O:4][N:3]=1
Reactant: COc1cccc(CBr)c1
Reactant: Cc1noc(C)c1Cn1cc(N2C(=O)CNC2=O)cn1
Product: COc1cccc(CN2CC(=O)N(c3cnn(Cc4c(C)noc4C)c3)C2=O)c1
Yield: 55 %

Procedure:
Prepared as in example 10-5 from 3-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)imidazolidine-2,4-dione (example 6) and 3-methoxy-benzyl bromide. Yield: 55%. 1NMR (CDCl3, 400 MHz): δ2.19 (s, 3H), 2.42 (s, 3H), 3.81 (s, 3H), 3.85 (s, 2H), 4.58 (s, 2H), 5.06 (s, 2H), 6.81-6.88 (m, 3H), 7.26-7.31 (m, 1H), 7.92 (s, 1H), 8.08 (s, 1H). The title compound was shown to inhibit hT2R08 bitter receptor and had an IC50 of 0.07 μM.
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[CH:12][C:11]([CH2:14][NH:15][C@@H:16]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[CH:19]=2)[CH3:17])=[CH:10][C:3]=1[O:4][CH2:5][C:6]([O:8]C)=[O:7].C[Si](C)(C)[O-].[K+]>C1COCC1>[Cl:1][C:2]1[CH:13]=[CH:12][C:11]([CH2:14][NH:15][C@@H:16]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[CH:19]=2)[CH3:17])=[CH:10][C:3]=1[O:4][CH2:5][C:6]([OH:8])=[O:7]
Reactant: COC(=O)COc1cc(CN[C@H](C)c2cccc(Cl)c2)ccc1Cl
Agent: C[Si](C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: C[C@@H](NCc1ccc(Cl)c(OCC(=O)O)c1)c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 72.7 %

Procedure:
To a solution of (R)-methyl 2-(2-chloro-5-((1-(3-chlorophenyl)ethylamino) methyl)phenoxy)acetate 100 (50 mg, 136 μmol) in 2 mL of dry THF, was added potassium trimethylsilanolate (17 mg, 136 μmol). The solution was stirred at ambient temperature for 2 h. The reaction was concentrated and the resulting crude material was purified with reverse phase preparatory HPLC. The desired fractions were combined and lyophilized to give (R)-2-(2-chloro-5-((1-(3-chlorophenyl)ethylamino)methyl)phenoxy)acetic acid 101 (35 mg, 73% yield) as a white solid and as the TFA salt. 1H NMR (400 MHz, d4-methanol) δ ppm 1.71 (d, J=6.85 Hz, 3H) 3.98 (d, J=13.30 Hz, 1H) 4.16 (d, J=13.11 Hz, 1H) 4.44 (m, 1H) 4.81 (s, 2H) 6.97-7.01 (m, 1H) 7.05-7.07 (m, 1H) 7.41-7.52 (m, 4H) 7.54-7.57 (s, 1H). Mass spectrum: calculated for C17H17Cl2NO3 354.2. found 355.3 (M++1).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([I:11])=[N:7][NH:8]2)=[CH:4][CH:3]=1.[CH3:12][C:13]([O-])(C)C.[K+].ICC>C1COCC1>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([I:11])=[N:7][N:8]2[CH2:12][CH3:13])=[CH:4][CH:3]=1
Reactant: CC(C)(C)[O-]
Reactant: Clc1ccc2c(I)n[nH]c2c1
Agent: [K+]
Solvent: CCI
Solvent: C1CCOC1
Product: CCn1nc(I)c2ccc(Cl)cc21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 61.9 %

Procedure:
To a solution of 6-chloro-3-iodo-1H-indazole (913 mg, 3.28 mmol) in THF (12 ml) at 0° C. was added KOt-Bu (429 mg, 3.82 mmol). The reaction mixture was stirred at 0° C. for 30 min then added iodoethane (0.37 ml, 4.6 mmol). Stirred at 0° C. for 30 min then warmed to room temperature and stirred for 48 h. The reaction was quenched with water and extracted with EtOAc (2×). The combined organics were washed with brine then dried over MgSO4 and concentrated. The crude residue was purified by silica gel chromatography with 10% to 50% EtOAc/heptane to afford 622 mg (62%) of 6-chloro-1-ethyl-3-iodo-1H-indazole as a white powder. 1H NMR (CDCl3, 300 MHz): δ (ppm) 7.37-7.43 (m, 2H), 7.17 (dd, J=8.7, 1.1 Hz, 1H), 4.41 (q, J=7.2 Hz, 2H), 1.51 (t, J=7.2 Hz, 3H). Also isolated 174 mg (17%) of 6-chloro-2-ethyl-3-iodo-2H-indazole as a more polar, minor regioisomer. 1H NMR (CDCl3, 300 MHz): δ (ppm) 7.66-7.70 (m, 1H), 7.35 (d, J=9.1 Hz, 1H), 7.04-7.12 (m, 1H), 4.56 (q, J=7.2 Hz, 2H), 1.58 (t, J=7.2 Hz, 3H).
Reaction SMILES: Cl[CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C:3]1=O.[C:9]([NH:12][C:13]([NH2:15])=[NH:14])(=[O:11])[CH3:10]>CC#N>[NH:14]1[C:3]2[CH2:4][CH2:5][CH2:6][CH2:7][C:2]=2[N:15]=[C:13]1[NH:12][C:9](=[O:11])[CH3:10]
Reactant: CC(=O)NC(=N)N
Reactant: O=C1CCCCC1Cl
Solvent: CC#N
Product: CC(=O)Nc1nc2c([nH]1)CCCC2
Reaction time: 0.08 h
Yield: 14.7 %

Procedure:
To a solution of 5 g (38 mmol) of 2-chloro-cyclohexanone in MeCN (150 mL) was added 7 g (69 mmol) of N-acetyl-guanidine. The mixture was refluxed for 24 h. After removal of all the solvent, the residue was stirred with sat. aq. Na2CO3 (50 mL) for 5 min, filtered, and the solid was dried to provide 1 g (14%) of N-(4,5,6,7-tetrahydro-1H-benzoimidazol-2-yl)-acetamide. LCMS: 180 (M+1)+. 1H NMR (DMSO-d6, 400 MHz): δ 2.38 (m, 4H), 2.00 (s, 3H), 1.65 (m, 4H) ppm.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7](=[N:14][O:15][CH2:16][C:17]2[N:22]=[C:21]([N:23]3C(=O)C4C(=CC=CC=4)C3=O)[CH:20]=[CH:19][CH:18]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:5][N:4]=[CH:3]1.O.NN>O1CCCC1>[CH3:1][N:2]1[C:6]([C:7](=[N:14][O:15][CH2:16][C:17]2[N:22]=[C:21]([NH2:23])[CH:20]=[CH:19][CH:18]=2)[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)=[CH:5][N:4]=[CH:3]1
Reactant: Cn1cncc1C(=NOCc1cccc(N2C(=O)c3ccccc3C2=O)n1)c1ccccc1
Agent: NN
Solvent: O
Solvent: C1CCOC1
Product: Cn1cncc1C(=NOCc1cccc(N)n1)c1ccccc1
Temperature: 25 °C
Reaction time: 29 h
Yield: 81.5 %

Procedure:
To a solution of 2-{6-[({[(1-methyl-1H-imidazol-5-yl)(phenyl)methylene]amino}oxy)methyl]-pyridin-2-yl}-1H-isoindole-1,3(2H)-dione (1.87 g, 4.27 mmol) in tetrahydrofuran (20 mL) was added dropwise hydrazine hydrate (1.04 mL, 21.4 mmol). After stirring at room temperature for 29 h, the reaction mixture was filtered, the insolubles washed with ethyl acetate, and the filtrate concentrated in vacuo. Purification on silica gel afforded 6-[({[(1-methyl-1H-imidazol-5-yl)(phenyl)methylene]amino}oxy)methyl]pyridin-2-amine [1.07 g, yield 77%; HPLC/MS: m/z=308 (M+H); log P(HCOOH)=0.29].