Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][NH:2]1.[N:10]1([C:16]2[N:17]=[C:18]([CH2:23][C:24](OCC)=[O:25])[NH:19][C:20](=[O:22])[CH:21]=2)[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1.C[Al](C)C>C1(C)C=CC=CC=1.O1CCCC1>[CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][N:2]1[C:24](=[O:25])[CH2:23][C:18]1[NH:19][C:20](=[O:22])[CH:21]=[C:16]([N:10]2[CH2:11][CH2:12][O:13][CH2:14][CH2:15]2)[N:17]=1
Reactant: c1ccc2c(c1)CNC2
Reactant: CCOC(=O)Cc1nc(N2CCOCC2)cc(=O)[nH]1
Agent: C[Al](C)C
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: O=C(Cc1nc(N2CCOCC2)cc(=O)[nH]1)N1Cc2ccccc2C1
Yield: 23.5 %

Procedure:
The product is prepared according to the procedure described in example 70, using 250 mg of isoindoline, 267 mg of ethyl [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate prepared in stage 1 of example 1 and 1.15 ml of a 2M solution of trimethylaluminium, in a mixture of 20 ml of toluene and 10 ml of tetrahydrofuran. 80 mg of 2-[2-(1,3-dihydro-2H-isoindol-2-yl)-2-oxoethyl]-6-(morpholin-4-yl)pyrimidin-4(3H)-one are thus obtained in the form of a white powder, the characteristics of which are the following:
Reaction SMILES: Br[C:2]1[C:7]([C:8]2[C:9](=[O:29])[N:10]([CH:26]([CH3:28])[CH3:27])[C:11](=[O:25])[N:12]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=3)[C:13]=2[CH3:14])=[CH:6][CH:5]=[CH:4][N:3]=1.[C:30]([C:32]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=1)#[N:31].O.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:26]([N:10]1[C:9](=[O:29])[C:8]([C:7]2[C:2]([C:35]3[CH:36]=[CH:37][C:32]([C:30]#[N:31])=[CH:33][CH:34]=3)=[N:3][CH:4]=[CH:5][CH:6]=2)=[C:13]([CH3:14])[N:12]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=2)[C:11]1=[O:25])([CH3:28])[CH3:27]
Reactant: Cc1c(-c2cccnc2Br)c(=O)n(C(C)C)c(=O)n1-c1cccc(C(F)(F)F)c1
Reactant: N#Cc1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: Cc1c(-c2cccnc2-c2ccc(C#N)cc2)c(=O)n(C(C)C)c(=O)n1-c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Yield: 85.3 %

Procedure:
5-(2-Bromopyridin-3-yl)-3-isopropyl-6-methyl-1-(3-(trifluoromethyl)phenyl)pyrimidin-2,4(1H,3H)-dione (prepared in Reference Example 189) (132 mg) and 4-cyanophenylboronic acid (166 mg) were dissolved in 1,4-dioxane (10 ml). Thereto were added under nitrogen atmosphere water (1 ml), sodium carbonate (239 mg) and tetrakis(triphenylphosphine)palladium (33 mg) and the resulting mixture was stirred with heating under reflux for one and a half hours. The reaction mixture was cooled to room temperature, and thereto was then water and the resulting mixture was extracted with ethyl acetate (50 ml). The organic layer was washed with saturated saline (50 ml), dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: firstly hexane/ethyl acetate, secondly chloroform/methanol) to afford 4-(3-(3-isopropyl-6-methyl-2,4-dioxo-1-(3-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydropyrimidin-5-yl)pyridin-2-yl)benzonitrile (118 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([N:9]2[CH2:14][CH2:13][CH:12]([N:15]3[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]3)[CH2:11][CH2:10]2)[CH:6]=[CH:5][C:4]=1[NH2:22].CS([C:26]1[N:31]=[CH:30][C:29]2=[CH:32][CH:33]=[C:34]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=3[O:41][CH3:42])[N:28]2[N:27]=1)=O.C(N(CC)C(C)C)(C)C.COCCO>>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([N:9]2[CH2:14][CH2:13][CH:12]([N:15]3[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]3)[CH2:11][CH2:10]2)[CH:6]=[CH:5][C:4]=1[NH:22][C:26]1[N:31]=[CH:30][C:29]2=[CH:32][CH:33]=[C:34]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=3[O:41][CH3:42])[N:28]2[N:27]=1
Reactant: COc1ccccc1-c1ccc2cnc(S(C)=O)nn12
Reactant: COc1cc(N2CCC(N3CCN(C)CC3)CC2)ccc1N
Solvent: COCCO
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(N2CCC(N3CCN(C)CC3)CC2)ccc1Nc1ncc2ccc(-c3ccccc3OC)n2n1

Procedure:
A solution of 2-Methoxy-4-[4-(4-methyl-piperazin-1-yl)-piperidin-1-yl]-phenylamine (0.18 g, 0.00059 mol) with 2-methanesulfinyl-7-(2-methoxy-phenyl)-pyrrolo[2,1-f][1,2,4]triazine (85 mg, 0.30 mol) and N,N-diisopropylethylamine (0.057 g, 0.44 mmol) in 2-methoxyethanol (1.0 mL, 0.013 mol) in a microwave vessel was microwaved on 300 watts, 180° C. for 30 minutes. Repeated microwave for 30 minutes more to get to completion. Filtered through 0.45μ filter and purified by reverse phase HPLC. Concentrated and dissolved in DCM/MeOH and free-based with solid MP-carbonate. Filtered and concentrated {2-methoxy-4-[4-(4-methyl-piperazin-1-yl)-piperidin-1-yl]-phenyl}-[7-(2-methoxy-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-2-yl]-amineisolated as a brownish film (12 mg, 8%). 1H-NMR (CDCl3) δ 8.69 (s, 1H), 8.24 (d, J=8.8 Hz, 1H), 8.03 (d, J=7.6 Hz, 1H), 7.44 (t, J=8.0, 1H), 7.31 (s, 1H), 7.14 (t, J=7.5, 1H), 7.08 (d, J=8.0, 1H), 7.03 (d, J=4.7 Hz, 1H), 6.83 (d, J=4.6 Hz, 1H), 6.57-6.45 (m, 1H), 6.46-6.43 (m, 1H), 3.89 (s, 3H), 3.62 (s, 3H), 3.64 (broad d, J=12.3 Hz, 2H), 2.72-2.66 (m, 4H), 2.55-2.51 (broad m, 3H), 1.97 (broad d, J=12.4 Hz, 2H), 1.78-1.72 (m, 2H), 1.32-1.20 (m, 2H), 0.94-0.85 (m, 2H); LC/MS (ESI+): 528 (M+H).
Reaction SMILES: [CH2:1]([OH:6])[CH:2](O)[CH2:3][CH3:4].C(O[CH:11](O)[CH2:12][CH2:13][CH3:14])(=[O:9])C.C(OC(C)C(OC(=O)C)C)(=O)C>C(O)(=O)C>[CH2:1]([OH:6])[CH2:2][CH2:3][CH2:4][OH:9].[CH2:11]=[CH:12][CH:13]=[CH2:14]
Reactant: CCCC(O)OC(C)=O
Reactant: CCC(O)CO
Agent: CC(=O)OC(C)C(C)OC(C)=O
Solvent: CC(=O)O
Product: C=CC=C
Product: OCCCCO

Procedure:
Further, in a process for preparing a polyester according to the present invention, crude 1,2-butanediol (hereinafter referred to as crude 1,2-BG) containing acetoxyhydroxybutane and/or diacetoxybutane may be used as 1,2-butanediol. Crude 1,2-BG is usually formed as a by-product during the preparation of 1,4-butanediol by the reaction of butadiene with acetic acid, such crude 1,2-BG contains various acetoxy compounds. For instance, from a gas chromatography analysis, a typical sample of such crude 1,2-BG has been found to have a composition comprising 54% by weight of 1,2-BG, 23% by weight of 1-acetoxy-2-hydroxybutane, 8% by weight of 1-hydroxy-2-acetoxybutane, 10% by weight of 1,2-diacetoxybutane and 5% by weight of other substances such as 1,3-butanediol and 1,4-butanediol, and thus it has been found that the major components of the impurities are acetoxy derivatives of 1,2-BG.
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:4][CH:3]=1.CO.[C:18]1(B(O)O)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C([O-])([O-])=O.[K+].[K+]>C1COCC1.O>[C:18]1([C:2]2[N:7]=[CH:6][C:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:4][CH:3]=2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(Br)nc1
Reactant: OB(O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)Nc1ccc(-c2ccccc2)nc1
Temperature: 70 °C
Yield: 68.4 %

Procedure:
To a solution of 3A (8.3 g, 30.3 mmol) in THF (50 mL)-MeOH (50 mL) at RT was added phenylboronic acid (7.44 g, 61 mmol), PXPd (489 mg, 0.91 mmol), followed by K2CO3 (16.75 g, 121 mmol). The reaction mixture was stirred at 70° C. in a preheated oil bath for lh. After this time, the reaction mixture was cooled to RT. The reaction mixture was poured into water (100 mL), and the resultant mixture was extracted with EtOAc (3×100 mL). The combined organics were washed with saturated NaCl, dried (Na2SO4), filtered and concentrated. The resulting residue was triturated with 30% EtOAc in hexane. The solid was collected by filtration to give the title compound as an off-white solid (5.6 g, 68%). LC/MS (method A): retention time=2.83 min, (M+H)+=271.
Reaction SMILES: [S:1]1[C:5]([C:6]2[CH:11]=[CH:10][C:9]([CH2:12][N:13]([NH:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:14][C@H:15]([OH:31])[C@@H:16]([NH:24]C(=O)C(F)(F)F)[CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:8][CH:7]=2)=[CH:4][N:3]=[CH:2]1.C(Cl)Cl.O>CO>[S:1]1[C:5]([C:6]2[CH:11]=[CH:10][C:9]([CH2:12][N:13]([NH:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:14][C@H:15]([OH:31])[C@@H:16]([NH2:24])[CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:8][CH:7]=2)=[CH:4][N:3]=[CH:2]1
Reactant: CC(C)(C)OC(=O)NN(Cc1ccc(-c2cncs2)cc1)C[C@H](O)[C@H](Cc1ccccc1)NC(=O)C(F)(F)F
Solvent: O
Solvent: CO
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NN(Cc1ccc(-c2cncs2)cc1)C[C@H](O)[C@@H](N)Cc1ccccc1
Temperature: 70 °C
Reaction time: 15 h

Procedure:
100 ml of a 1N KDCO3 solution are added dropwise to a solution of 5.646 g (10.0 mmol) of 1-[4-(thiazol-5-yl)-phenyl]-4(S)-hydroxy-2-(tert-butoxycarbonyl)amino-5(S)-(trifluoroacetyl)amino-6-phenyl-2-azahexane in 100 ml of methanol and the mixture is stirred at 70° C. for 15 hours. Methylene chloride and water are added; the aqueous phase is separated off and extracted 2× with methylene chloride. The organic phases are washed 2× with water, dried (Na2SO4) and concentrated by evaporation, yielding the title compound: Anal. (C25H32N4O3S (0.53 H2O)) calc. C 62.80, H 6.97, N 11.72, S 6.71, H2O 2.00: found C 63.2, H 7.01, N 11.57, S 6.49, H2O 1.98; HPLC20-100 : tRet =11.5.
Reaction SMILES: Br[C:2]1[C:3]2[C:8]([C:9]([C:16]3[CH:21]=[C:20]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH:19]=[C:18]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[CH:17]=3)=[C:10]3[C:15]=1[CH:14]=[CH:13][CH:12]=[CH:11]3)=[CH:7][CH:6]=[CH:5][CH:4]=2.[C:34]1([C:40]([C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=2)=[CH:41][C:42]2[CH:47]=[CH:46][C:45](OB(O)O)=[CH:44][CH:43]=2)[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:34]1([C:40]([C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=2)=[CH:41][C:42]2[CH:47]=[CH:46][C:45]([C:2]3[C:3]4[C:8]([C:9]([C:16]5[CH:21]=[C:20]([C:22]6[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=6)[CH:19]=[C:18]([C:28]6[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=6)[CH:17]=5)=[C:10]5[C:15]=3[CH:14]=[CH:13][CH:12]=[CH:11]5)=[CH:7][CH:6]=[CH:5][CH:4]=4)=[CH:44][CH:43]=2)[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: OB(O)Oc1ccc(C=C(c2ccccc2)c2ccccc2)cc1
Reactant: Brc1c2ccccc2c(-c2cc(-c3ccccc3)cc(-c3ccccc3)c2)c2ccccc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: C(=C(c1ccccc1)c1ccccc1)c1ccc(-c2c3ccccc3c(-c3cc(-c4ccccc4)cc(-c4ccccc4)c3)c3ccccc23)cc1
Yield: 81 %

Procedure:
Under an atmosphere of argon, 9-bromo-10-(3,5-diphenylphenyl)anthracene (3.9 g, 8.0 mmole), 4-(2,2-diphenylvinyl)phenylboric acid (2.7 g, 9.0 mmole, 1.1 eq) and tetrakis(triphenylphosphine)palladium(0) (0.18 g, 0.16 mmole, 2% Pd) were suspended in toluene (30 ml). To the obtained suspension, a 2M aqueous solution of sodium carbonate (2.9 g, 27 mmole, 3 eq/15 ml) was added, and the resultant mixture was refluxed for 10 hours. An organic layer was separated from the reaction mixture, washed with a saturated aqueous solution of sodium chloride (30 ml) and dried with magnesium sulfate. After the solvent was removed by distillation, a brown solid substance was obtained. The obtained solid substance was purified in accordance with the column chromatography (silica gel/hexane+10% dichloromethane, hexane+20% dichloromethane), and a white solid substance (4.3 g, the yield: 81%) was obtained. The result of examination of the obtained product in accordance with 1H-NMR was as follows:
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:11][CH2:12][CH2:13][OH:14])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([O-:7])=[O:6].[Cl:15][C:16]1[CH:21]=[C:20]([Cl:22])[CH:19]=[C:18]([CH3:23])[C:17]=1[N:24]=[C:25]=[S:26].O1CCC[CH2:28]1>>[Cl:15][C:16]1[CH:21]=[C:20]([Cl:22])[CH:19]=[C:18]([CH3:23])[C:17]=1[NH:24][C:25]([NH:1][C:2]1[C:3]([NH:11][CH2:12][CH2:13][OH:14])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([O:7][CH3:28])=[O:6])=[S:26]
Reactant: Nc1cccc(C(=O)[O-])c1NCCO
Reactant: Cc1cc(Cl)cc(Cl)c1N=C=S
Reactant: C1CCOC1
Product: COC(=O)c1cccc(NC(=S)Nc2c(C)cc(Cl)cc2Cl)c1NCCO
Temperature: 50 °C
Reaction time: 24 h

Procedure:
A solution of 3-amino-2-[(2-hydroxyethyl)amino]benzoate (521 mg, 2.48 mmol) and 2,4-dichloro-6-methylphenylisothiocyanate (595 mg, 2.73 mmol) in tetrahydrofuran (25 mL) was stirred at room temperature for 18 hr. The mixture was warmed to 50° C. and it was stirred at 50° C. for 24 hr. The reaction mixture was concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with a 20-80% ethyl acetate/n-hexane gradient mixture to give the title compound (959.9 mg) as a colorless amorphous.
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[C:11]([OH:13])=O)[CH2:4][CH2:3][CH2:2]1.[CH2:14]([O:16][C:17]([C:19]1([NH2:28])[CH2:27][C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:20]1)=[O:18])[CH3:15].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH2:14]([O:16][C:17]([C:19]1([NH:28][C:11]([C:9]2[CH:8]=[CH:7][CH:6]=[C:5]3[C:10]=2[NH:1][CH2:2][CH2:3][CH2:4]3)=[O:13])[CH2:27][C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:20]1)=[O:18])[CH3:15]
Reactant: CCOC(=O)C1(N)Cc2ccccc2C1
Reactant: O=C(O)c1cccc2c1NCCC2
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)C1(NC(=O)c2cccc3c2NCCC3)Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.9 %

Procedure:
To a solution of 1,2,3,4-tetrahydro-quinoline-8-carboxylic acid (173 mg, 0.97 mmol), 2-amino-indan-2-carboxylic acid ethyl ester (200 mg, 0.97 mmol), HATU (553 mg, 1.46 mmol) in anhydrous DMF (20 mL) is added DIPEA (241 μL, 1.46 mmol). The resulting solution is stirred at RT overnight. After the removal of DMF in vacuo, the residue is dissolved in EtOAc (40 mL) and washed with water (1×10 mL) and brine (2×10 mL). The organic layer is dried over anhydrous Na2SO4 and concentrated in vacuo. The residue is purified by HPLC to give a pure product (63) as white solid (300 mg, 85%).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[C:10](=[O:11])[C:9]([CH3:12])=[CH:8][NH:7][C:6]1=[O:13].[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([N:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)=[C:17]([O:27][CH3:28])[CH:16]=1>>[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([N:21]2[CH2:22][CH2:23][N:24]([CH2:2][CH2:3][CH2:4][N:5]3[C:10](=[O:11])[C:9]([CH3:12])=[CH:8][NH:7][C:6]3=[O:13])[CH2:25][CH2:26]2)=[C:17]([O:27][CH3:28])[CH:16]=1
Reactant: COc1cc(Cl)ccc1N1CCNCC1
Reactant: Cc1c[nH]c(=O)n(CCCCl)c1=O
Product: COc1cc(Cl)ccc1N1CCN(CCCn2c(=O)[nH]cc(C)c2=O)CC1
Temperature: 25 °C

Procedure:
A mixture of 3-(3-chloropropyl)-5-methyl-2,4(1H,3H)-pyrimidinedione (223 mg, 0.98 mmol), prepared as in Example 19, and 1-(4-chloro-2-methoxyphenyl)piperazine (200 mg, 0.98 mmol), prepared as in Example 12, was heated 2 hours with stirring at 180° to 190° C., allowed to cool to 25° C. and then purified by preparative thin layer chromatography on silica gel eluting with methylene chloride/(methylene chloride/methanol/ammonium hydroxide-60:10:1) (7:3) to give 3-{3-[4-(4-chloro-2-methoxyphenyl)piperazin-1-yl]propyl}-5-methyl-2,4(1H,3H)-pyrimidinedione. The free base was recrystallized from a solution of hydrogen chloride in methanol to give 3-{3-[4-(4-chloro-2-methoxyphenyl)piperazin-1-yl]propyl}-5-methyl-2,4(1H,3H)-pyrimidinedione hydrochloride, m.p. 182°-184° C. Anal.: Calcd. for C19H25ClN4O3.(HCl)2 : C, 48.25; H, 5.92; N, 11.84%; Found: C, 48.55; H, 5.81; N, 11.85%.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][C@H:6]1[O:24][C:25]1[C:29]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([CH2:37][CH2:38][CH2:39][C:40](=[O:48])[NH:41][C:42]([C:45](O)=[O:46])([CH3:44])[CH3:43])=[CH:33][CH:32]=2)=[C:28]([CH:49]([CH3:51])[CH3:50])[NH:27][N:26]=1)(=[O:3])[CH3:2].[CH2:52]([O:59][C:60]([N:62]1[CH2:67][CH2:66][NH:65][CH2:64][CH2:63]1)=[O:61])[C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O.O>[C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][C@H:6]1[O:24][C:25]1[C:29]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([CH2:37][CH2:38][CH2:39][C:40](=[O:48])[NH:41][C:42]([C:45]([N:65]3[CH2:66][CH2:67][N:62]([C:60]([O:59][CH2:52][C:53]4[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=4)=[O:61])[CH2:63][CH2:64]3)=[O:46])([CH3:44])[CH3:43])=[CH:33][CH:32]=2)=[C:28]([CH:49]([CH3:51])[CH3:50])[NH:27][N:26]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C(C)C)c2Cc2ccc(CCCC(=O)NC(C)(C)C(=O)O)cc2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Reactant: O=C(OCc1ccccc1)N1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C(C)C)c2Cc2ccc(CCCC(=O)NC(C)(C)C(=O)N3CCN(C(=O)OCc4ccccc4)CC3)cc2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.4 %

Procedure:
3-(2,3,4,6-Tetra-O-acetyl-β-D-galactopyranosyloxy)-4-[(4-{3-[1-carboxy-1-(methyl)ethylcarbamoyl]propyl}phenyl)-methyl]-5-isopropyl-1H-pyrazole (37 g) was dissolved in N,N-dimethylformamide (180 mL). To the solution were added 1-(benzyloxycarbonyl)piperazine (28.4 g), 1-hydroxybenzo-triazole (10.5 g) and 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride (14.8 g), and the mixture was stirred at room temperature overnight. The reaction mixture was poured into water, and the resulting mixture was extracted with ethyl acetate twice. The extracts were washed with water and brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=1/2-ethyl acetate) to give the title compound (40.5 g).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]2[C:10]3([CH2:14][CH2:13][N:12]([CH2:15]/[CH:16]=[CH:17]/[C:18]4[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=4)[CH2:11]3)[CH2:9][NH:8][C:5]2=[CH:6][CH:7]=1.C(N(CC)CC)C.[Cl:32][C:33]1[CH:34]=[C:35]([CH:39]=[CH:40][N:41]=1)[C:36](Cl)=[O:37].C(=O)(O)[O-].[Na+]>ClCCl>[Cl:32][C:33]1[CH:34]=[C:35]([C:36]([N:8]2[C:5]3[C:4](=[CH:3][CH:2]=[CH:7][CH:6]=3)[C:10]3([CH2:14][CH2:13][N:12]([CH2:15]/[CH:16]=[CH:17]/[C:18]4[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=4)[CH2:11]3)[CH2:9]2)=[O:37])[CH:39]=[CH:40][N:41]=1
Reactant: O=C(Cl)c1ccnc(Cl)c1
Reactant: Clc1ccc(/C=C/CN2CCC3(CNc4ccc(Cl)cc43)C2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(c1ccnc(Cl)c1)N1CC2(CCN(C/C=C/c3ccc(Cl)cc3)C2)c2ccccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 49 %

Procedure:
A solution of 5-chloro-1′-[trans-3-(4-chlorophenyl)allyl]spiro[indoline-3,3′-pyrrolidine] (150 mg) and triethylamine (0.24 ml) in dichloromethane (5 ml) at 0° C. under argon was treated with 2-chloro-isonicotinoyl chloride (147 mg). The resulting solution was stirred at room temperature for 1 hour, poured into saturated aqueous sodium bicarbonate, extracted with ethyl acetate, dried (Na2SO4) and concentrated in vacuo. Silica gel chromatography of the residue (eluent cyclohexane:ethyl acetate 6:4) afforded the title compound, 1-(2-chloropyridin-4-yl)carbonyl-1′-[trans-3-(4-chlorophenyl)allyl]spiro[indoline-3,3′-pyrrolidine] (95 mg), which was characterised by its mass and NMR spectra. MS (ES+) 498/500 (M+H+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:15]=[O:16])[N:5]([C:8]2[C:13]([Cl:14])=[CH:12][CH:11]=[CH:10][N:9]=2)[C:6]=1[Br:7].CC(C)=[O:19].[Mn]([O-])(=O)(=O)=O.[K+]>O>[Br:1][C:2]1[CH:3]=[C:4]([C:15]([OH:19])=[O:16])[N:5]([C:8]2[C:13]([Cl:14])=[CH:12][CH:11]=[CH:10][N:9]=2)[C:6]=1[Br:7]
Reactant: O=Cc1cc(Br)c(Br)n1-c1ncccc1Cl
Reactant: CC(C)=O
Agent: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Solvent: O
Product: O=C(O)c1cc(Br)c(Br)n1-c1ncccc1Cl
Temperature: 60 °C
Reaction time: 2 h

Procedure:
To a mixture of 1.0 g of 4,5-dibromo-1-(3-chloro-2-pyridinyl)-1H-pyrrole-2-carbaldehyde, 15 ml of acetone and 7 ml of water was slowly added 1.3 g of potassium permanganate at 40° C. The resulting mixture was stirred at 60° C. for 2 hours. Precipitates in the reaction mixture were removed by filtration. The resulting filtrate was washed with chloroform two times. The aqueous layer was adjusted to around pH 3 by an addition of 2N hydrochloric acid and then extracted with ethyl acetate three times. The organic layers were combined, washed with an aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure to obtain 0.69 g of 4,5-dibromo-1-(3-chloro-2-pyridinyl)-1H-pyrrole-2-carboxylic acid of the formula:
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.Br[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[F:29]>>[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]([CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[F:29])[C:14]3=[O:19])[CH:10]=[N:9]2)=[C:5]([CH3:20])[O:4][N:3]=1
Reactant: Cc1noc(C)c1Cn1cc(N2C(=O)CNC2=O)cn1
Reactant: Fc1ccccc1CBr
Product: Cc1noc(C)c1Cn1cc(N2C(=O)CN(Cc3ccccc3F)C2=O)cn1
Yield: 42 %

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 10-1) and 1-(bromomethyl)-2-fluorobenzene. Yield 42%. MS M+H calculated 384.1; found 384.1. The title compound was shown to inhibit hT2R08 bitter receptor and had an IC50 of 0.08 uM.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7]([O:9][C:10]([C:12]1([CH2:18][O:19][CH3:20])[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1)=[O:11])[CH3:8].[Cl:21][C:22]1[CH:23]=[C:24]([C:33]2[O:37][N:36]=[C:35]([C:38]3[CH:43]=[CH:42][C:41]([CH2:44]Cl)=[CH:40][CH:39]=3)[N:34]=2)[CH:25]=[CH:26][C:27]=1[CH:28]1[CH2:32][CH2:31][CH2:30][CH2:29]1>CN(C)C=O>[CH2:7]([O:9][C:10]([C:12]1([CH2:18][O:19][CH3:20])[CH2:13][CH2:14][N:15]([CH2:44][C:41]2[CH:40]=[CH:39][C:38]([C:35]3[N:34]=[C:33]([C:24]4[CH:25]=[CH:26][C:27]([CH:28]5[CH2:32][CH2:31][CH2:30][CH2:29]5)=[C:22]([Cl:21])[CH:23]=4)[O:37][N:36]=3)=[CH:43][CH:42]=2)[CH2:16][CH2:17]1)=[O:11])[CH3:8]
Reactant: CCOC(=O)C1(COC)CCNCC1
Reactant: ClCc1ccc(-c2noc(-c3ccc(C4CCCC4)c(Cl)c3)n2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)C1(COC)CCN(Cc2ccc(-c3noc(-c4ccc(C5CCCC5)c(Cl)c4)n3)cc2)CC1
Temperature: 67.5 °C

Procedure:
Potassium carbonate (0.28 g, 0.002 mol) and 4-methoxymethylpiperidine-4-carboxylic acid ethyl ester (0.4 g, 0.002 mol) are added to a solution of 5-(3-Chloro-4-cyclopentylphenyl)-3-(4-chloromethyl-phenyl)-[1,2,4]oxadiazole (0.5 g, 0.0013 mol) in N,N-dimethylformamide (15 mL). The reaction mixture is heated at 65-70° C. for 2 hours. Removal of solvent gives a crude residue which is purified by column chromatography (silica gel 230-400 mesh, toluene:ethyl acetate 4:1) to give 1-{4-[5-(3-chloro-4-cyclopentylphenyl)-[1,2,4]-oxadiazol-3-yl]benzyl}-4-methoxy methyl piperidine-4-carboxylic acid ethyl ester.