Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O.[OH-].[Na+].[S:4](Cl)([C:7]1[CH:13]=[CH:12][C:10]([CH3:11])=[CH:9][CH:8]=1)(=[O:6])=[O:5].C(O)(=[O:17])C>O1CCCC1>[CH3:11][C:10]1[CH:9]=[CH:8][C:7]([S:4]([OH:17])(=[O:6])=[O:5])=[CH:13][CH:12]=1
Reactant: CC(=O)O
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(S(=O)(=O)O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 84731.5 %

Procedure:
To water (288 mL), sodium hydroxide (180 g, 4.5 mol, 5.0 eq) was added. At 0° C., methanol-d3 (32.4 g, 900 mmol, 1.0 eq) was added, and the solution of tosyl chloride (206 g, 1.1 mmol, 1.2 eq) in tetrahydrofuran (288 mL) was dropwise added slowly. The mixture was warmed to room temperature and stirred overnight. The mixture was neutralized to neutral by dropwise adding acetic acid (206 g) at 25° C., filtered and partitioned. The aqueous phase was extracted with ethyl acetate (100 mL). The filter cake was dissolved in water (300 mL) and extracted with ethyl acetate (200 mL). The organic phases were combined and washed with saturated sodium carbonate (100 mL) and saturated brine (100 mL), dried over anhydrous sodium sulfate and filtered. The solvent in the filtrate was removed under reduced pressure to afford the title compound (160.5 g, purity 99%, yield 94%) as a pale yellow liquid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([N+:20]([O-:22])=[O:21])[C:9]=1[O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=1)[CH:5]=O.[CH3:23]/[C:24](/[NH2:28])=[CH:25]\[C:26]#[N:27].[CH2:29]([CH:32]1[CH2:37][C:36](=[O:38])[CH2:35][C:34](=O)[CH2:33]1)[CH2:30][CH3:31]>C(O)C>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]2[C:35]3[C:36](=[O:38])[CH2:37][CH:32]([CH2:29][CH2:30][CH3:31])[CH2:33][C:34]=3[NH:28][C:24]([CH3:23])=[C:25]2[C:26]#[N:27])[CH:7]=[C:8]([N+:20]([O-:22])=[O:21])[C:9]=1[O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=1
Reactant: C/C(N)=C\C#N
Reactant: COc1cccc(COc2c(Br)cc(C=O)cc2[N+](=O)[O-])c1
Reactant: CCCC1CC(=O)CC(=O)C1
Solvent: CCO
Product: CCCC1CC(=O)C2=C(C1)NC(C)=C(C#N)C2c1cc(Br)c(OCc2cccc(OC)c2)c([N+](=O)[O-])c1
Temperature: 80 °C
Reaction time: 17 h

Procedure:
A mixture of 3-bromo-4-(3-methoxy-benzyloxy)-5-nitro-benzaldehyde (50 mg), 3-aminocrotonitrile (13 mg) and 5-propylcyclohexane-1,3-dione (25 mg) in 10 ml of ethanol was stirred at 80° C. for 17 h. The mixture was concentrated in vacuo. The residue was purified by chromatography on silicagel in heptane/ethyl acetate 8/2→1/1 (v/v) as eluent.
Reaction SMILES: C([O:8][C@H:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C@@H:10]1[N:15]1[CH2:20][CH2:19][C:18]2[N:21]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=3[Cl:39])[C:22]([C:25]3[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=3)=[C:23]([CH3:24])[C:17]=2[C:16]1=[O:40])C1C=CC=CC=1.C(O[C@H]1CCCC[C@@H]1N)C1C=CC=CC=1.ClC1C=CC=CC=1N1C2CCNCC=2C=C1C1C=CC(OC)=CC=1.C[Si](I)(C)C>C(Cl)Cl>[Cl:39][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=1[N:21]1[C:18]2[CH2:19][CH2:20][N:15]([C@H:10]3[CH2:11][CH2:12][CH2:13][CH2:14][C@@H:9]3[OH:8])[C:16](=[O:40])[C:17]=2[C:23]([CH3:24])=[C:22]1[C:25]1[CH:26]=[CH:27][C:28]([O:31][CH3:32])=[CH:29][CH:30]=1
Reactant: COc1ccc(-c2c(C)c3c(n2-c2ccccc2Cl)CCN([C@H]2CCCC[C@@H]2OCc2ccccc2)C3=O)cc1
Agent: COc1ccc(-c2cc3c(n2-c2ccccc2Cl)CCNC3)cc1
Agent: C[Si](C)(C)I
Agent: N[C@H]1CCCC[C@@H]1OCc1ccccc1
Solvent: ClCCl
Product: COc1ccc(-c2c(C)c3c(n2-c2ccccc2Cl)CCN([C@H]2CCCC[C@@H]2O)C3=O)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 24 %

Procedure:
The starting material for this example, namely 5-[(1S,2S)-2-(benzyloxy)cyclohexyl]-1-(2-chlorophenyl)-2-(4-methoxyphenyl)-3-methyl-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one, was prepared by following the methods described in Scheme 2 and Examples 12–19, using (1S,2S)-2-(benzyloxy)cyclohexylamine as R4NH2 (Scheme 2). Then, a sample of 5-[(1S,2S)-2-(benzyloxy)cyclohexyl]-1-(2-chlorophenyl)-2-(4-methoxyphenyl)-3-methyl-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one (200 mg, 0.36 mmol) was dissolved in methylene chloride (5 mL). Trimethylsilyl iodide (0.054 mL, 0.396 mmol) was added dropwise and the solution was stirred at rt for 18 h. The solvent was removed and the crude material was purified by silica gel column, eluting with methylene chloride followed by methanol. The product was isolated as a white solid (40.0 mg, 24%). LC-MS m/z (MH+) 465.3, retention time 3.23 min (method 1).
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:12]2[CH:11]=[CH:10][N:9]=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[CH2:6][CH2:5]1.[CH3:28][C:29]([CH3:34])([CH3:33])[C:30](O)=[O:31]>>[O:4]1[C:12]2[CH:11]=[CH:10][N:9]=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:30](=[O:31])[C:29]([CH3:34])([CH3:33])[CH3:28])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[CH2:6][CH2:5]1
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3CCO4)CC2)CC1
Reactant: CC(C)(C)C(=O)O
Agent: Cl
Product: CC(C)(C)C(=O)N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3CCO4)CC2)CC1

Procedure:
The title compound, white solid (70 mg, 68%), MS (ISP) m/z=415.4 [(M+H)+], mp 185° C., was prepared in accordance with the general method of example 32 from trans-4-{2-[4-(2,3-dihydrofuro[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexanamine trihydrochloride (intermediate C) (110 mg, 0.25 mmol) and 2,2-dimethyl-propionic acid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([N:11]2[CH2:18][CH:17]3[CH:13]([CH2:14][NH:15][CH2:16]3)[CH2:12]2)[N:4]=1.[N:19]1([C:24]2[CH:32]=[CH:31][CH:30]=[CH:29][C:25]=2[C:26](O)=[O:27])[CH:23]=[CH:22][CH:21]=[N:20]1>>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([N:11]2[CH2:18][CH:17]3[CH:13]([CH2:14][N:15]([C:26]([C:25]4[CH:29]=[CH:30][CH:31]=[CH:32][C:24]=4[N:19]4[CH:23]=[CH:22][CH:21]=[N:20]4)=[O:27])[CH2:16]3)[CH2:12]2)[N:4]=1
Reactant: O=C(O)c1ccccc1-n1cccn1
Reactant: COc1cc(OC)nc(N2CC3CNCC3C2)n1
Product: COc1cc(OC)nc(N2CC3CN(C(=O)c4ccccc4-n4cccn4)CC3C2)n1

Procedure:
The title compound was prepared in a manner analogous to Example 15 utilizing Intermediate 39 and 2-pyrazol-1-yl-benzoic acid. MS (ESI) mass calcd. for C22H24N6O3, 420.46; m/z found, 421.1 [M+H]+. 1H NMR (CDCl3): 7.74 (d, J=2.0 Hz, 1H), 7.59-7.29 (m, 5H), 6.31 (br s, 1H), 5.32 (s, 1H), 3.90-3.64 (m, 7.8H), 3.61-3.41 (m, 2.2H), 3.40-3.05 (m, 3H), 2.95-2.65 (m, 3H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=O)[CH:5]=[C:6]([F:8])[CH:7]=1.[NH2:13][C@H:14]([C:16]([C:18]1([NH2:38])[N:24]=[C:23]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[F:31])[C:22]2[CH:32]=[CH:33][CH:34]=[CH:35][C:21]=2[N:20]([CH3:36])[C:19]1=[O:37])=[O:17])[CH3:15]>>[F:8][C:6]1[CH:5]=[C:4]([CH2:9][C:10]([NH:13][C@H:14]([C:16]([C:18]2([NH2:38])[N:24]=[C:23]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[F:31])[C:22]3[CH:32]=[CH:33][CH:34]=[CH:35][C:21]=3[N:20]([CH3:36])[C:19]2=[O:37])=[O:17])[CH3:15])=[O:12])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: O=C(O)Cc1cc(F)cc(F)c1
Reactant: C[C@H](N)C(=O)C1(N)N=C(c2ccccc2F)c2ccccc2N(C)C1=O
Product: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)C1(N)N=C(c2ccccc2F)c2ccccc2N(C)C1=O

Procedure:
Following General Procedure D above using 3,5-difluorophenylacetic acid (Oakwood Products, Inc.) and 3-(L-alaninyl)-amino-2,3-dihydro-1-methyl-5-(2-fluorophenyl)-1H-1,4-benzodiazepin-2-one (Example 8-I), the title compound was prepared as a white solid having a melting point of 185-188° C.
Reaction SMILES: [BH4-].[Na+].[C:3]([O:7][C:8]([NH:10][C:11]1[S:12][CH:13]=[C:14](/[CH:16]=[C:17]2\[CH2:18][N:19]([C:24]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH2:20][CH2:21][C:22]\2=[O:23])[N:15]=1)=[O:9])([CH3:6])([CH3:5])[CH3:4].ClCCl>C(O)C>[C:3]([O:7][C:8]([NH:10][C:11]1[S:12][CH:13]=[C:14](/[CH:16]=[C:17]2\[CH2:18][N:19]([C:24]([C:37]3[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=3)([C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)[C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH2:20][CH2:21][CH:22]\2[OH:23])[N:15]=1)=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: CC(C)(C)OC(=O)Nc1nc(/C=C2\CN(C(c3ccccc3)(c3ccccc3)c3ccccc3)CCC2=O)cs1
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCO
Product: CC(C)(C)OC(=O)Nc1nc(/C=C2\CN(C(c3ccccc3)(c3ccccc3)c3ccccc3)CCC2O)cs1
Temperature: 0 °C

Procedure:
Sodium borohydride (0.27 g) was added to a solution of (E)-3-{[2-(t-butoxycarbonylamino)-1,3-thiazol-4-yl]methylidene}-1-(triphenylmethyl)piperidin-4-one (3.1 g) in a mixed solvent of dichloromethane (15 ml) and ethanol (15 ml), while stirring at 0° C. After being stirred at room temperature for 1.5 hours, the mixture was partitioned between water and ethyl acetate. The organic layer was separated, washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The extract was concentrated under reduced pressure to afford the title compound as a yellow amorphous solid in a quantitative yield.
Reaction SMILES: [Si:1](Cl)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[OH:9][C:10]1[CH:33]=[CH:32][C:13]2[CH:14]([C:24]3[C:25](=[O:31])[NH:26][C:27](=[O:30])[NH:28][CH:29]=3)[C:15]3[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][C:16]=3[CH:17]=[CH:18][C:12]=2[CH:11]=1.N1C=CN=C1>CN(C)C=O>[CH3:5][C:4]([Si:1]([CH3:3])([CH3:2])[O:9][C:10]1[CH:33]=[CH:32][C:13]2[CH:14]([C:24]3[C:25](=[O:31])[NH:26][C:27](=[O:30])[NH:28][CH:29]=3)[C:15]3[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][C:16]=3[CH:17]=[CH:18][C:12]=2[CH:11]=1)([CH3:7])[CH3:6]
Reactant: Cc1ccc2c(c1)C=Cc1cc(O)ccc1C2c1c[nH]c(=O)[nH]c1=O
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: Cc1ccc2c(c1)C=Cc1cc(O[Si](C)(C)C(C)(C)C)ccc1C2c1c[nH]c(=O)[nH]c1=O
Reaction time: 3 h

Procedure:
Tert-butyl dimethylsilylchloride (0.98 g) was added to a mixture of the product from step (i) and imidazole (0.74 g) in dimethylformamide (20 ml). The reaction mixture was stirred for 3 hours and partitioned between water and ethyl acetate. The organic layer was washed with water, dried (MgSO4) and evaporated under reduced pressure. Purification was by chromatography eluting with 50-70% ethyl acetate in isohexane. Yield 0.71 g.
Reaction SMILES: C([O:5][C:6](=[O:49])[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH2:13][CH:14]([NH:28][C:29](=[O:46])[CH:30]=[C:31]2[CH2:36][CH2:35][CH:34]([CH2:37][NH:38]C(OC(C)(C)C)=O)[CH2:33][CH2:32]2)[B:15]2[O:23]C3C(C)(C4CC(C3)C4(C)C)[O:16]2)[C:8]=1OC)(C)(C)C.B(Cl)(Cl)Cl>>[NH2:38][CH2:37][CH:34]1[CH2:35][CH2:36][C:31](=[CH:30][C:29]([NH:28][C@H:14]2[CH2:13][C:9]3[CH:10]=[CH:11][CH:12]=[C:7]([C:6]([OH:5])=[O:49])[C:8]=3[O:23][B:15]2[OH:16])=[O:46])[CH2:32][CH2:33]1
Reactant: COc1c(CC(NC(=O)C=C2CCC(CNC(=O)OC(C)(C)C)CC2)B2OC3CC4CC(C4(C)C)C3(C)O2)cccc1C(=O)OC(C)(C)C
Agent: ClB(Cl)Cl
Product: NCC1CCC(=CC(=O)N[C@H]2Cc3cccc(C(=O)O)c3OB2O)CC1

Procedure:
Prepared from 3-[2-{2-[4-(tert-Butoxycarbonylamino-methyl)-cyclohexylidene]-acetylamino}-2-(2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.02,6]dec-4-yl)-ethyl]-2-methoxy-benzoic acid tert-butyl ester and BCl3 following the procedure described in Step 2 of Example 1. The crude product was purified by reverse phase preparative HPLC and dried using lyophilization. ESI-MS m/z 359 (MH)+.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([N:13]2[CH2:18][CH2:17][N:16]([CH:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)[CH2:15][CH2:14]2)[CH:7]=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11])[CH3:2].I[CH2:26][CH2:27][F:28].C([O-])([O-])=O.[Na+].[Na+]>C(#N)C>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([N:13]2[CH2:14][CH2:15][N:16]([CH:19]3[CH2:24][CH2:23][N:22]([CH2:26][CH2:27][F:28])[CH2:21][CH2:20]3)[CH2:17][CH2:18]2)[CH:7]=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11])[CH3:2]
Reactant: FCCI
Reactant: CCOc1cc(N2CCN(C3CCNCC3)CC2)ccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: CCOc1cc(N2CCN(C3CCN(CCF)CC3)CC2)ccc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 65.1 %

Procedure:
To a stirred solution of 1-[3-(ethyloxy)-4-nitrophenyl]-4-(4-piperidinyl)piperazine (0.28 g, 0.83 mmol) and 1-iodo-2-fluoroethane (0.29 g, 1.67 mmol) in acetonitrile (17 mL) was added Na2CO3 (0.106 g, 1.0 mmol). The reaction was stirred under N2 and heated to reflux for 4 h. The temperature was lowered to 75° C. and the reaction was stirred overnight (approximately 16 h). The reaction was cooled to rt and then concentrated under vacuum. The residue was purified by silica gel chromatography to give the title compound of step B (206 mg, 0.54 mmol, 65%) as a yellow solid. MS (ESI): 381 [M+H]+.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:10].[NH:11]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:14](=O)[C:12]1=[O:13].Cl>C(O)(=O)C>[CH:18]1[CH:19]=[CH:20][C:21]2[NH:11][C:12](=[O:13])/[C:14](=[C:3]3\[C:4]4[CH:5]=[CH:6][CH:7]=[CH:8][C:9]=4[NH:1][C:2]\3=[O:10])/[C:16]=2[CH:17]=1
Reactant: O=C1Cc2ccccc2N1
Reactant: O=C1Nc2ccccc2C1=O
Agent: Cl
Solvent: CC(=O)O
Product: O=C1Nc2ccccc2/C1=C1\C(=O)Nc2ccccc21
Yield: 84 %

Procedure:
Isoindigo was synthesized by reaction of oxindole with isatin in acetic acid with addition of hydrochloric acid (Wahl A., Bayard P., Comptes Rendues Hebdomadaires des Seances de L'Academie des Sciences, 148, (1909), 716-719).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[N:3]=1.[NH2:18][N:19]1[CH:23]=[N:22][N:21]=[CH:20]1>>[N:19]1([NH:18][C:2]2[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]3[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=3)[N:3]=2)[CH:23]=[N:22][N:21]=[CH:20]1
Reactant: Nn1cnnc1
Reactant: FC(F)(F)c1cc(Cl)nc(-c2cccnc2)n1
Product: FC(F)(F)c1cc(Nn2cnnc2)nc(-c2cccnc2)n1

Procedure:
The title compound was prepared from 4-chloro-2-(3-pyridinyl)-6-trifluoromethylpyrimidine (50 mg, 0.192 mmol) and 1-amino-1,3,4-triazole (24 mg, 0.288 mmol) similar to Example 190 and was isolated as a solid. 1H NMR (CDCl3): 9.61 (brs, 1H), 8.71–8.66 (m, 4H), 7.41 (m, 2H), 6.69 (s, 1H), 5.18 (s, 2H).
Reaction SMILES: [C:1]1([C:7]2([C:10]([Cl:12])=[O:11])[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:13]12[CH2:20][CH2:19][CH:16]([CH2:17][CH2:18]1)[CH:15]([OH:21])[CH2:14]2>>[ClH:12].[C:1]1([C:7]2([C:10]([O:21][CH:15]3[CH:16]4[CH2:19][CH2:20][N:13]([CH2:18][CH2:17]4)[CH2:14]3)=[O:11])[CH2:8][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cl)C1(c2ccccc2)CC1
Reactant: OC1CN2CCC1CC2
Product: Cl
Product: O=C(OC1CN2CCC1CC2)C1(c2ccccc2)CC1

Procedure:
The title compound was prepared in analogous manner to that in Example 4. The 1-phenylcyclopropanecarbonyl chloride obtained after the chlorination step was reacted with 3-quinuclidinol at 80° C. for 21 h. The reaction mixture was filtered and chromatographed on silica gel using toluene-Et3N 95:5 as eluent. The yield was 0.76 g (40%); mp 229-233° C.; 1H NMR (D2O) δ 1.42-1.48 (m, 2H), 1.72-1.78 (m, 2H), 1.81-1.98 (m, 3H), 2.10 (m, 1H), 2.40 (m, 1H), 3.14 (m, 1H), 3.25-3.41 (m, 4H), 3.71 (m, 1H), 5.17 (m, 1H), 7.44 (m, 1H), 7.49 (m, 2H), 7.55 (m, 2H) Anal. (C17H21NO2.HCl) C, H, N.
Reaction SMILES: C([O:5][C:6]([CH2:8][CH2:9][C:10]([NH:12][C@H:13]([C:22]([NH:24][C@H:25]([C:35]([NH:37][C@H:38]([C:47]([NH:49][C@H:50]([C:55]([NH:57][C@H:58]([C:63]([NH:65][C@H:66]([CH:71](OC)[O:72]C)[CH2:67][C:68]#[C:69][CH3:70])=[O:64])[CH2:59][CH:60]([CH3:62])[CH3:61])=[O:56])[C:51]([CH3:54])([CH3:53])[CH3:52])=[O:48])[CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=1[CH3:46])=[O:36])[CH2:26][CH2:27][C:28](=[O:34])[O:29]C(C)(C)C)=[O:23])[CH2:14][C:15](=[O:21])[O:16]C(C)(C)C)=[O:11])=[O:7])(C)(C)C>FC(F)(F)C(O)=O.ClCCl.O>[C:6]([CH2:8][CH2:9][C:10]([NH:12][C@H:13]([C:22]([NH:24][C@H:25]([C:35]([NH:37][C@H:38]([C:47]([NH:49][C@H:50]([C:55]([NH:57][C@H:58]([C:63]([NH:65][C@@H:66]([CH2:67][C:68]#[C:69][CH3:70])[CH:71]=[O:72])=[O:64])[CH2:59][CH:60]([CH3:62])[CH3:61])=[O:56])[C:51]([CH3:52])([CH3:54])[CH3:53])=[O:48])[CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=1[CH3:46])=[O:36])[CH2:26][CH2:27][C:28](=[O:29])[OH:34])=[O:23])[CH2:14][C:15](=[O:16])[OH:21])=[O:11])([OH:7])=[O:5]
Reactant: CC#CC[C@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](NC(=O)[C@H](Cc1ccccc1C)NC(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)[C@H](CC(=O)OC(C)(C)C)NC(=O)CCC(=O)OC(C)(C)C)C(C)(C)C)C(OC)OC
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC#CC[C@@H](C=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](NC(=O)[C@H](Cc1ccccc1C)NC(=O)[C@H](CCC(=O)O)NC(=O)[C@H](CC(=O)O)NC(=O)CCC(=O)O)C(C)(C)C
Reaction time: 1 h
Yield: 77.4 %

Procedure:
49 mg (0.046 mmol) of N2-[N-[N-[N-[N-[3-(tert-butoxycarbonyl)propionyl]-O-tert-butyl-L-α-aspartyl]-O-tert-butyl-L-α-glutamyl]-2-methyl-L-phenylalanyl]-3-methyl-L-valyl]-N1-[1(S)-(dimethoxymethyl)-3-pentynyl]-L-leucinamide were dissolved in 4 ml of trifluoroacetic acid/dichloromethane (1:1) containing3 drops of water and the solution was stirred for 1 hour under a nitrogen atmosphere. The solution was evaporated to dryness under a vacuum and the residue was re-evaporated twice with toluene. The solid was triturated with 10 ml of diethyl ether to give 30 mg of 2(S)-[[N-[N-[N-[N-[N-(3-carboxypropionyl)-L-α-aspartyl]-L-α-glutamyl]-2-methyl-L-phenylalanyl]-3-methyl-L-valyl]-L-leucyl]amino]-4-hexynal as a white solid; MS: m/e 843.6 [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.[Cl:21][C:22]1[CH:30]=[CH:29][CH:28]=[CH:27][C:23]=1[CH2:24][CH2:25]Br>>[Cl:21][C:22]1[CH:30]=[CH:29][CH:28]=[CH:27][C:23]=1[CH2:24][CH2:25][N:15]1[CH2:16][C:17](=[O:18])[N:13]([C:11]2[CH:10]=[N:9][N:8]([CH2:7][C:6]3[C:2]([CH3:1])=[N:3][O:4][C:5]=3[CH3:20])[CH:12]=2)[C:14]1=[O:19]
Reactant: Cc1noc(C)c1Cn1cc(N2C(=O)CNC2=O)cn1
Reactant: Clc1ccccc1CCBr
Product: Cc1noc(C)c1Cn1cc(N2C(=O)CN(CCc3ccccc3Cl)C2=O)cn1
Yield: 25 %

Procedure:
Prepared as in example 10-52 from 3-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)imidazolidine-2,4-dione (example 10-1) and 2-chlorophenethyl bromide. Yield: 25%. MS M+H calculated 414.13; found 414.2. The title compound was shown to inhibit hT2R08 bitter receptor and had an IC50 of 0.25 μM.
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][C:8]([N+:12]([O-:14])=[O:13])=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[S:15]([C:18]1[CH:23]=[CH:22][C:21]([F:24])=[C:20]([F:25])[CH:19]=1)(=[O:17])=[O:16].[F:26][C:27]1[CH:28]=[C:29](B(O)O)[CH:30]=[CH:31][CH:32]=1>>[F:25][C:20]1[CH:19]=[C:18]([S:15]([C:3]2[CH:4]=[N:5][C:6]3[C:11]([C:2]=2[C:31]2[CH:30]=[CH:29][CH:28]=[C:27]([F:26])[CH:32]=2)=[CH:10][CH:9]=[C:8]([N+:12]([O-:14])=[O:13])[CH:7]=3)(=[O:17])=[O:16])[CH:23]=[CH:22][C:21]=1[F:24]
Reactant: O=[N+]([O-])c1ccc2c(Br)c(S(=O)(=O)c3ccc(F)c(F)c3)cnc2c1
Reactant: OB(O)c1cccc(F)c1
Product: O=[N+]([O-])c1ccc2c(-c3cccc(F)c3)c(S(=O)(=O)c3ccc(F)c(F)c3)cnc2c1
Yield: 56.7 %

Procedure:
The title compound was prepared applying the procedure described in Example 7 from 4-Bromo-3-(3,4-difluoro-benzenesulfonyl)-7-nitro-quinoline (0.53 g, 1.23 mmol) and 3-fluorophenylboronic acid (0.21 g, 1.5 mmol). The crude product was purified by column chromatography on silica gel (Kieselgel 60, eluent: chloroform) and crystallized from methanol to obtain 0.31 g of the title compound in 57% yield.
Reaction SMILES: [C:1]([O:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][N:15]1[C:23]2[C:22](OC3C=CC=CC=3)=[N:21][CH:20]=[N:19][C:18]=2[CH:17]=[C:16]1[CH3:31])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:32][C:33]1[CH:34]=[C:35]([CH:37]=[CH:38][C:39]=1[O:40][CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[C:44]([F:48])[CH:43]=1)[NH2:36].Cl.N1C=CC=CC=1.C1(O)C=CC=CC=1>ClCCl>[C:1]([O:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][N:15]1[C:23]2[C:22]([NH:36][C:35]3[CH:37]=[CH:38][C:39]([O:40][CH2:41][C:42]4[CH:47]=[CH:46][CH:45]=[C:44]([F:48])[CH:43]=4)=[C:33]([Cl:32])[CH:34]=3)=[N:21][CH:20]=[N:19][C:18]=2[CH:17]=[C:16]1[CH3:31])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1ccc(OCc2cccc(F)c2)c(Cl)c1
Reactant: Cc1cc2ncnc(Oc3ccccc3)c2n1CCOCCOC(=O)c1ccccc1
Agent: Cl
Solvent: Oc1ccccc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1cc2ncnc(Nc3ccc(OCc4cccc(F)c4)c(Cl)c3)c2n1CCOCCOC(=O)c1ccccc1
Temperature: 120 °C
Reaction time: 3 h
Yield: 26.2 %

Procedure:
A mixture of 2-[2-(6-methyl-4-phenoxy-5H-pyrrolo[3,2-d]pyrimidin-5-yl)ethoxy]ethyl benzoate (92.3 mg), 3-chloro-4-[(3-fluorobenzyl)oxy]aniline (86.3 mg), pyridine hydrochloride (81.6 mg) and phenol (156.1 mg) was stirred at 120° C. for 3 hrs, and at 140° C. for 5.5 hrs. Further, pyridine hydrochloride (77.6 mg) and phenol (188.7 mg) were added, and the mixture was stirred at 140° C. for 22.5 hrs. The reaction mixture was diluted with dichloromethane, washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was separated and purified by basic silica gel column chromatography (eluent, hexane:ethyl acetate=50:50→0:100) to give the title compound (33.3 mg) as a purple oil.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13](=[O:15])[CH3:14])=[C:9]([OH:16])[C:8]=1[CH2:17][CH2:18][CH3:19])[CH3:2].[Br:21][CH2:22][CH2:23][O:24][CH2:25][CH2:26][O:27][CH2:28][CH2:29][O:30][CH2:31][CH2:32]Br.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.CN(C)C=O>[CH2:1]([O:3][C:4](=[O:20])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13](=[O:15])[CH3:14])=[C:9]([O:16][CH2:32][CH2:31][O:30][CH2:29][CH2:28][O:27][CH2:26][CH2:25][O:24][CH2:23][CH2:22][Br:21])[C:8]=1[CH2:17][CH2:18][CH3:19])[CH3:2]
Reactant: BrCCOCCOCCOCCBr
Reactant: CCCc1c(OCC(=O)OCC)ccc(C(C)=O)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC(C)=O
Product: CCCc1c(OCC(=O)OCC)ccc(C(C)=O)c1OCCOCCOCCOCCBr
Reaction time: 24 h
Yield: 61.6 %

Procedure:
A mixture of 2.8 g (0.01 mole) of (4-acetyl-3-hydroxy-2-propylphenoxy)acetic acid ethyl ester, 11.0 g (0.034 mole) of 1,11-dibromo-3,6,9-trioxaundecane and 2.8 g (0.02 mole) of anhydrous potassium carbonate in 60 ml of anhydrous acetone and 30 ml of anhydrous dimethylformamide was stirred at reflux for 16 hours. An additional 1.4 g of potassium carbonate was added and reflux was continued for 24 hours. The solvents were removed in vacuo and the residue was chromatographed on 200 g of silica gel. Elution with 10% ethyl acetate-toluene gave 3.2 g (62% yield) of [4-acetyl-3-[2-[2-[2-(2-bromoethoxy)ethoxy]ethoxy]ethoxy]-2-propylphenoxy]acetic acid ethyl ester as an oil.
Reaction SMILES: [CH:1]1([N:6]2[C:10]3=[N:11][C:12]([C:16]4[C:25]5[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=5)[N:19]=[CH:18][CH:17]=4)=[N:13][C:14](=[O:15])[C:9]3=[C:8]([CH2:26][CH3:27])[NH:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1>[Pt]=O.C(O)(=O)C>[CH:1]1([N:6]2[C:10]3=[N:11][C:12]([CH:16]4[CH:25]5[CH:20]([CH2:21][CH2:22][CH2:23][CH2:24]5)[NH:19][CH2:18][CH2:17]4)=[N:13][C:14](=[O:15])[C:9]3=[C:8]([CH2:26][CH3:27])[NH:7]2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CCc1[nH]n(C2CCCC2)c2nc(-c3ccnc4ccccc34)nc(=O)c1-2
Agent: O=[Pt]
Solvent: CC(=O)O
Product: CCc1[nH]n(C2CCCC2)c2nc(C3CCNC4CCCCC43)nc(=O)c1-2
Temperature: 70 °C
Yield: 83.2 %

Procedure:
1-Cyclopentyl-3-ethyl-6-(4-quinolinyl)-pyrazolo[3,4-d]-pyrimidin-4-one (1.0 g, 2.7 mmol), platinum oxide (0.15 g) and acetic acid (50 ml) were combined and placed in a parr hydrogenator at 42 psi. The reaction mixture was heated at about 70° C. by an external heating jacket for 6 hours. The reaction mixture was cooled to room temperature, the catalyst was removed by filtration through a celite pad and the pad was washed with ethanol. Concentrated HCl (3 ml) was added to the filtrate and the solvents were removed in vacuo. The residue was dissolved in isopropanol (10 ml) and was heated on a steam bath for 10 minutes. A solid was collected by filtration, washed with isopropanol and dried at 90° C. in high vacuum to afford 0.83 g (84%) of 1-cyclopentyl-3-ethyl-6-(perhydro-4-quinolinyl)pyrazolo[3,4-d]pyrimidin-4-one as a white powder, m.p. >300° C.