Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[S:3][C:4]2[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:5]=2[N:6]=1.[CH:13]1([CH2:19][NH2:20])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1.CCN(C(C)C)C(C)C>CN1C(=O)CCC1.CCOC(C)=O>[CH:13]1([CH2:19][NH:20][C:2]2[S:3][C:4]3[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:5]=3[N:6]=2)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: NCC1CCCCC1
Reactant: COc1ccc2nc(Cl)sc2c1
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc2nc(NCC3CCCCC3)sc2c1
Temperature: 107.5 °C
Reaction time: 66 h
Yield: 94.9 %

Procedure:
To a solution of 2-chloro-6-methoxybenzo[d]thiazole (900 mg, 4.5 mmol) in 4.5 mL of NMP was added cyclohexylmethanamine (865 mg, 7.65 mmol) and DIPEA (1.57 mL, 9.0 mmol). The reaction solution was stirred at 105-110° C. for 66 hours. The reaction was diluted with EtOAc (250 mL) and washed with saturated NaHCO3 (2×60 mL), water (3×60 mL), saturated NaCl (60 mL), dried with sodium sulfate, filtered and concentrated in vacuo to give N-(cyclohexylmethyl)-6-methoxybenzo[d]thiazol-2-amine as a solid (1.18 grams). ES/MS m/z 277.1 (MH+).
Reaction SMILES: Br[CH:2]([CH3:16])[C:3]([C:5]1[CH:6]=[CH:7][C:8]2[S:12][C:11](=[O:13])[N:10]([CH3:14])[C:9]=2[CH:15]=1)=O.[NH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1>>[CH3:16][C:2]1[N:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]2=[N:17][C:3]=1[C:5]1[CH:6]=[CH:7][C:8]2[S:12][C:11](=[O:13])[N:10]([CH3:14])[C:9]=2[CH:15]=1
Reactant: CC(Br)C(=O)c1ccc2sc(=O)n(C)c2c1
Reactant: Nc1ccccn1
Product: Cc1c(-c2ccc3sc(=O)n(C)c3c2)nc2ccccn12
Yield: 50.8 %

Procedure:
5-(3-Methylimidazo[1,2-a]pyridin-2-yl)-3-methyl-2-benzothiazolinone (1.5 g) was prepared in the substantially same manner as that of Example 4 from 5-(2-bromopropionyl)-3-methyl-2-benzothiazolinone (3.0 g) and 2-aminopyridine (2.3 g).
Reaction SMILES: [Cl:1][C:2]1[C:7]([OH:8])=[CH:6][C:5]([N:9]2[C:13](=[O:14])[N:12]([CH2:15][CH2:16][CH2:17][F:18])[C:11]([CH3:19])=[N:10]2)=[C:4]([F:20])[CH:3]=1.[CH2:21](Br)[C:22]#[CH:23].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Cl:1][C:2]1[C:7]([O:8][CH2:23][C:22]#[CH:21])=[CH:6][C:5]([N:9]2[C:13](=[O:14])[N:12]([CH2:15][CH2:16][CH2:17][F:18])[C:11]([CH3:19])=[N:10]2)=[C:4]([F:20])[CH:3]=1
Reactant: Cc1nn(-c2cc(O)c(Cl)cc2F)c(=O)n1CCCF
Reactant: C#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C#CCOc1cc(-n2nc(C)n(CCCF)c2=O)c(F)cc1Cl
Temperature: 25 °C
Yield: 61.5 %

Procedure:
A stirred solution of 0.5 g (0.002 mole) of 1-(4-chloro-2-fluoro-5-hydroxyphenyl)-4-(3-fluoropropyl)-4,5-dihydro-3-methyl-1,2,4-triazol-5(1H)-one, 0.43 g (0.004 mole) of propargyl bromide and 0.33 g (0.002 mole) of potassium carbonate in 20 mL of acetone was heated under reflux for 5 hours. The reaction mixture was cooled to ambient temperature and filtered. The filtrate was concentrated under reduced pressure to a residual oil. The residual oil was subjected to column chromatography on silica gel using 4:1 methylene chloride:heptane as an eluant. The appropriate fractions were combined and concentrated under reduced pressure to give 0.42 g of 1-(4-chloro-2-fluoro-5-propargyloxyphenyl)-4-(3-fluoropropyl)-4,5-dihydro-3-methyl-1,2,4-triazol-5(1H)-one as an oil.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[CH2:11][NH:10][CH2:9][CH2:8]2.[OH-].[Na+].C([O-])(O)=O.[Na+].[C:20](OC(=O)C)(=[O:22])[CH3:21]>ClCCl>[C:20]([N:10]1[CH2:9][CH2:8][C:7]2[C:12](=[C:3]([Cl:2])[CH:4]=[CH:5][CH:6]=2)[CH2:11]1)(=[O:22])[CH3:21]
Reactant: CC(=O)OC(C)=O
Reactant: Clc1cccc2c1CNCC2
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(=O)N1CCc2cccc(Cl)c2C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of 28.6 g of 8-chloro-1,2,3,4-tetrahydoisoquinoline hydrochloride in 140 ml of dichloromethane was added 140 ml of 1N aqueous NaOH solution and 17.6 g of NaHCO3. To the solution was added dropwise 14.5 ml of acetic anhydride at 5° C. The mixture was stirred at room temperature for 1 hour. The organic layer was separated and the aqueous layer was extracted with dichloromethane. The combined organic extracts were washed with water, dried over anhydrous sodium sulfate. The solvent was distilled off to give 29.1 g of the title compound as a pale red oil.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[N:4][N:5]([CH2:7][C:8]#[N:9])[N:6]=1.[C:10]1([CH:16]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:17](Cl)=[O:18])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[C:8]([CH2:7][N:5]1[N:4]=[N:3][C:2]([NH:1][C:17](=[O:18])[CH:16]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[N:6]1)#[N:9]
Reactant: O=C(Cl)C(c1ccccc1)c1ccccc1
Reactant: N#CCn1nnc(N)n1
Product: N#CCn1nnc(NC(=O)C(c2ccccc2)c2ccccc2)n1

Procedure:
The title compound, white solid, m.p. 173-174° and MS: m/e=319.3 (M++H) was prepared in accordance with the general method of example 1 from (5-amino-tetrazol-2-yl)-acetonitrile and diphenylacetyl chloride.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([S:11]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)(=[O:13])=[O:12])[CH:6]=[CH:5]2.[C:20]([O:25][CH3:26])(=[O:24])/[CH:21]=[CH:22]/[CH3:23].C(N(CC)CC)C.[I-]>CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(OCC)(=O)C.CCCCCC>[CH3:26][O:25][C:20](=[O:24])[CH:21]=[C:22]([C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([S:11]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)(=[O:13])=[O:12])[CH:6]=[CH:5]2)[CH3:23]
Reactant: C/C=C/C(=O)OC
Reactant: O=S(=O)(c1ccccc1)n1ccc2cc(I)ccc21
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [I-]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: COC(=O)C=C(C)c1ccc2c(ccn2S(=O)(=O)c2ccccc2)c1
Temperature: 100 °C
Reaction time: 13 h
Yield: 109.6 %

Procedure:
5-Iodo-N-benzenesulfonylindole (18.09 g, 47 mmol), methyl crotonate (40 mL, 378 mmol), triethylamine (145 mL), and palladium acetate (2.65 g, 11.8 mmol) were combined in DMF (600 mL). The reaction was heated at 100° C. for 4 h. TLC (3:1) hexane:ethyl acetate showed iodide still present. Methyl crotonate (25 mL) and dichlorobis(triphenylphosphine) palladium(II) (3.31 g, 4.7 mmol) was added. The reaction was heated for an additional 4 h and then at room temperature for 13 h at which time starting material was virtually gone. The solids were allowed to settle and most of the liquid decanted off. The remaining portion was filtered through a pad of celite to remove the solids and the volume reduced somewhat in vacuo. The solution was diluted with water (1 L) and washed with diethyl ether (3×500 mL). The organic portion was washed with 1N HCl (2×500 mL), brine (2×500 mL), dried (MgSO4), filtered and evaporated in vacuo to provide 18.3 g of a dark brown oil. The material was purified preparatively in two runs on a Waters 2000LC using a gradient elution of (98:2) ethyl acetate:hexane to 66:34 ethyl acetate:hexane to give 6.79 g (40%). Mp: 80-85° C.
Reaction SMILES: [NH2:1][C@H:2]1[C:15](=[O:16])[N:14]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=2)[CH2:13][C:5]2[C:6]3[CH:7]=[N:8][NH:9][C:10]=3[CH:11]=[CH:12][C:4]=2[CH2:3]1.[O:28]=[C:29]1[NH:37][C:32]2=[N:33][CH:34]=[CH:35][CH:36]=[C:31]2[C:30]21[CH2:48][C:40]1[CH:41]=[N:42][C:43]([C:45](O)=[O:46])=[CH:44][C:39]=1[CH2:38]2.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C=O)C>[O:28]=[C:29]1[NH:37][C:32]2=[N:33][CH:34]=[CH:35][CH:36]=[C:31]2[C:30]21[CH2:48][C:40]1[CH:41]=[N:42][C:43]([C:45]([NH:1][C@H:2]3[C:15](=[O:16])[N:14]([CH2:17][C:18]4[CH:23]=[CH:22][C:21]([C:24]([F:26])([F:25])[F:27])=[CH:20][CH:19]=4)[CH2:13][C:5]4[C:6]5[CH:7]=[N:8][NH:9][C:10]=5[CH:11]=[CH:12][C:4]=4[CH2:3]3)=[O:46])=[CH:44][C:39]=1[CH2:38]2
Reactant: O=C(O)c1cc2c(cn1)CC1(C2)C(=O)Nc2ncccc21
Reactant: N[C@@H]1Cc2ccc3[nH]ncc3c2CN(Cc2ccc(C(F)(F)F)cc2)C1=O
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: O=C(N[C@@H]1Cc2ccc3[nH]ncc3c2CN(Cc2ccc(C(F)(F)F)cc2)C1=O)c1cc2c(cn1)CC1(C2)C(=O)Nc2ncccc21
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 7-(R)-amino-9-(4-trifluoromethylbenzyl)-6,7,9,10-tetrahydro-3H-2,3,9-triazacyclohepta[e]inden-8-one (86 mg, 0.23 mmol) [Chaturvedula et al. WO 2006/052378], (±)-2′-oxo-1′,2′,5,7-tetrahydrospiro[cyclopenta[c]pyridine-6,3′-pyrrolo[2,3-b]pyridine]-3-carboxylic acid (79 mg, 0.28 mmol, described in Intermediate 5), HOBT (43 mg, 0.28 mmol), and EDC (54 mg, 0.28 mmol) in DMF (2 mL) is stirred at ambient temperature for 18 h. The reaction mixture is purified directly by HPLC using a reversed phase C18 column and eluting with a gradient of H2O:CH3CN:CF3CO2H-90:10:0.1 to 5:95:0.1. The pure, product-containing fractions are combined and made basic with saturated aqueous NaHCO3. The resulting mixture is extracted with EtOAc (2×20 mL), and the combined organic extracts are washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo to provide the title compound.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][CH2:6][C@H:7]([OH:12])[C:8]([O:10][CH3:11])=[O:9])[CH3:4].Cl[C:14]1[N:19]=[CH:18][N:17]=[C:16]2[N:20]([C:23]3[C:28]([Cl:29])=[CH:27][CH:26]=[CH:25][N:24]=3)[N:21]=[CH:22][C:15]=12.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCCC1>[Cl:29][C:28]1[C:23]([N:20]2[C:16]3[N:17]=[CH:18][N:19]=[C:14]([O:12][C@@H:7]([CH2:6][O:5][CH2:3][CH3:4])[C:8]([O:10][CH3:11])=[O:9])[C:15]=3[CH:22]=[N:21]2)=[N:24][CH:25]=[CH:26][CH:27]=1
Reactant: Clc1cccnc1-n1ncc2c(Cl)ncnc21
Reactant: CCOC[C@H](O)C(=O)OC
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC[C@H](Oc1ncnc2c1cnn2-c1ncccc1Cl)C(=O)OC
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 75.1 %

Procedure:
60% sodium hydride in mineral oil (0.96 g, 24.1 mmol) was added portionwise to (S)-methyl 3-ethoxy-2-hydroxypropanoate (Intermediate G4) (2.97 g, 20.1 mmol) in tetrahydrofuran (50 mL) cooled to 0° C. over a period of 1 minute under nitrogen. The resulting solution was stirred at 0° C. for 10 minutes. A solution of 4-chloro-1-(3-chloropyridin-2-yl)-1H-pyrazolo[3,4-d]pyrimidine (Intermediate B15) (5.87 g, 22.1 mmol) in tetrahydrofuran (50 mL) was added dropwise over a period of 2 minutes. The resulting mixture was allowed to warm to ambient temperature and stirred for 2 hour. The reaction was cooled to ˜10° C., 1M citric acid (20 mL) added and the mixture was extracted with EtOAc (2×50 mL). The organic extracts were washed with water (25 mL) and saturated brine (25 mL), dried over MgSO4, filtered and evaporated. The residue was purified by flash silica chromatography, elution gradient 50 to 100% EtOAc in isohexane to give the methyl (2S)-2-[1-(3-chloropyridin-2-yl)pyrazolo[4,5-e]pyrimidin-4-yl]oxy-3-ethoxypropanoate (5.7 g, 70% ee). This was further purified by chiral HPLC on Chiralcel OJ eluting with isohexane/isopropanol/triethylamine (70:30:0.1) at 60 mL/min. to give the enantiomerically pure product (3.8 g, 50%) as a colourless gum. 1H NMR (400 MHz, CDCl3) δ 1.25 (3H, t), 3.60-3.73 (2H, m), 3.79 (3H, s), 4.00-4.11 (2H, m), 5.85 (1H, dd), 7.45 (1H, dd), 8.00 (1H, dd), 8.42 (1H, s), 8.58 (1H, s), 8.61 (1H, dd), m/z (ESI+) (M+H)+=378; HPLC tR=1.84 min.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:13]2[S:12][C:11]([NH2:14])=[N:10][C:9]=2[C:8]([O:15][CH3:16])=[CH:7][CH:6]=1)=[O:4].[F:17][C:18]1[CH:26]=[CH:25][C:21]([C:22](Cl)=[O:23])=[CH:20][CH:19]=1>>[CH3:1][O:2][C:3]([C:5]1[C:13]2[S:12][C:11]([NH:14][C:22](=[O:23])[C:21]3[CH:25]=[CH:26][C:18]([F:17])=[CH:19][CH:20]=3)=[N:10][C:9]=2[C:8]([O:15][CH3:16])=[CH:7][CH:6]=1)=[O:4]
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: COC(=O)c1ccc(OC)c2nc(N)sc12
Product: COC(=O)c1ccc(OC)c2nc(NC(=O)c3ccc(F)cc3)sc12

Procedure:
Using 2-amino-4-methoxy-benzothiazole-7-carboxylic acid methyl ester and 4-fluoro-benzoyl chloride the title compound was obtained as a white solid (91% yield), MS: m/e=361.1 (M+H+).
Reaction SMILES: [Na].[C:2]([OH:5])(=[S:4])[CH3:3].[CH2:6]([O:8][C:9]([CH:11]1[CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]1[C:20](=[O:24])[CH:21](Br)[CH3:22])=[O:10])[CH3:7]>C(O)C>[CH2:6]([O:8][C:9]([CH:11]1[CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]1[C:20](=[O:24])[CH:21]([S:4][C:2](=[O:5])[CH3:3])[CH3:22])=[O:10])[CH3:7]
Reactant: CC(O)=S
Reactant: CCOC(=O)C1Cc2ccccc2N1C(=O)C(C)Br
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)C1Cc2ccccc2N1C(=O)C(C)SC(C)=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To the solution of 0.35 g of sodium in 50 ml of ethanol, 1.2 g of thioacetic acid are added and the mixture stirred for 0.5 hours at room temperature. Then 4.5 g 1-(2-bromopropanoyl)-indoline-2-carboxylic acid ethyl ester are added and the mixture is refluxed for 8 hours. It is cooled to room temperature, evaporated, and the residue partitioned between 30 ml of methylene chloride, 70 ml of diethyl ether and 50 ml of water. The organic layer is dried and evaporated, to yield the 1-(2-acetylthiopropanoyl)-indoline-2-carboxylic acid ethyl ester as an oil.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([O:8][CH:9]([F:11])[F:10])=[CH:4][N:3]=1.ClC1N=CC(OC2CCN(C)CC2)=CN=1.[F:27][C:28]1([F:74])[CH2:33][CH2:32][CH:31]([C:34]2[C:43]3[CH:42]([O:44]CC4C=CC(OC)=CC=4)[CH2:41][C:40]([CH3:55])([CH3:54])[CH2:39][C:38]=3[N:37]=[C:36]([CH:56]3[CH2:61][CH2:60][NH:59][CH2:58][CH2:57]3)[C:35]=2[CH:62]([F:73])[C:63]2[CH:68]=[CH:67][C:66]([C:69]([F:72])([F:71])[F:70])=[CH:65][CH:64]=2)[CH2:30][CH2:29]1>>[F:74][C:28]1([F:27])[CH2:33][CH2:32][CH:31]([C:34]2[C:43]3[CH:42]([OH:44])[CH2:41][C:40]([CH3:54])([CH3:55])[CH2:39][C:38]=3[N:37]=[C:36]([CH:56]3[CH2:61][CH2:60][N:59]([C:2]4[N:7]=[CH:6][C:5]([O:8][CH:9]([F:11])[F:10])=[CH:4][N:3]=4)[CH2:58][CH2:57]3)[C:35]=2[CH:62]([F:73])[C:63]2[CH:68]=[CH:67][C:66]([C:69]([F:71])([F:72])[F:70])=[CH:65][CH:64]=2)[CH2:30][CH2:29]1
Reactant: COc1ccc(COC2CC(C)(C)Cc3nc(C4CCNCC4)c(C(F)c4ccc(C(F)(F)F)cc4)c(C4CCC(F)(F)CC4)c32)cc1
Reactant: FC(F)Oc1cnc(Cl)nc1
Agent: CN1CCC(Oc2cnc(Cl)nc2)CC1
Product: CC1(C)Cc2nc(C3CCN(c4ncc(OC(F)F)cn4)CC3)c(C(F)c3ccc(C(F)(F)F)cc3)c(C3CCC(F)(F)CC3)c2C(O)C1

Procedure:
Reactions similar to those of Reference Example 29 and Example 38 were performed except for using 2-chloro-5-(difluoromethoxy)pyrimidine, which was prepared by a method similar to that of Reference Example 32, instead of 2-chloro-5-[(1-methylpiperidin-4-yl)oxy]pyrimidine, and from 102 mg (151 μmol) of (−)-4-(4,4-Difluorocyclohexyl)-3-{fluoro[4-(trifluoromethyl)phenyl]methyl}-5-[(4-methoxybenzyl)oxy]-7,7-dimethyl-2-(piperidin-4-yl)-5,6,7,8-tetrahydroquinoline, which was prepared by a method similar to that of Reference Example 10, 52 mg of the title compound was obtained as a white solid (yield: 49%).
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])[C:16]([CH3:20])([CH3:19])[NH:15][C:14]3=[O:21])[CH:10]=[N:9]2)=[C:5]([CH3:22])[O:4][N:3]=1.Br[CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([O:31][CH3:32])[CH:26]=1>>[CH3:1][C:2]1[C:6]([CH2:7][N:8]2[CH:12]=[C:11]([N:13]3[C:17](=[O:18])[C:16]([CH3:19])([CH3:20])[N:15]([CH2:24][C:25]4[CH:30]=[CH:29][CH:28]=[C:27]([O:31][CH3:32])[CH:26]=4)[C:14]3=[O:21])[CH:10]=[N:9]2)=[C:5]([CH3:22])[O:4][N:3]=1
Reactant: COc1cccc(CBr)c1
Reactant: Cc1noc(C)c1Cn1cc(N2C(=O)NC(C)(C)C2=O)cn1
Product: COc1cccc(CN2C(=O)N(c3cnn(Cc4c(C)noc4C)c3)C(=O)C2(C)C)c1
Yield: 30 %

Procedure:
Prepared as in Example 12-16 from 3-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)-5,5-dimethylimidazolidine-2,4-dione (Example 12-16a) and 1-(bromomethyl)-3-methoxybenzene. Yield 30%, white solid. 1H NMR (DMSO-d6, 400 MHz): s, 6H), 2.16 (s, 3H), 2.42 (s, 3H), 3.74 (s, 3H), 4.53 (s, 2H), 5.20 (s, 2H), 6.83 (m, 1H) 6.96 (m, 2H), 7.25 (t, J=8.0 Hz, 1H), 7.83 (d, J=0.8 Hz, 1H), 8.21 (d, J=0.8 Hz, 1H). mp 107-108° C. MS 424 (MH+). The title compound was shown to inhibit hT2R08 bitter receptor and had an IC50 of 0.08 μM.
Reaction SMILES: [CH2:1]([C:6]1[CH:7]=[N:8][C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]#N)=[CH:14][CH:13]=2)=[N:10][CH:11]=1)[CH2:2][CH2:3][CH2:4]C.[CH2:20](C1C=NC(C2C=CC(C#N)=CC=2)=NC=1)CCCCC.C(C1C=CC(C2N=CC(C3C=CC(CCCC)=CC=3)=CN=2)=CC=1)#N.C(C1C=CC(C2C=CC(CCCCC)=CC=2)=CC=1)C>>[CH2:1]([C:6]1[CH:11]=[N:10][C:9]([C:12]2[CH:13]=[CH:14][C:15]([CH2:18][CH3:20])=[CH:16][CH:17]=2)=[N:8][CH:7]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCCCc1cnc(-c2ccc(C#N)cc2)nc1
Reactant: CCCCCc1cnc(-c2ccc(C#N)cc2)nc1
Agent: CCCCCc1ccc(-c2ccc(CC)cc2)cc1
Agent: CCCCc1ccc(-c2cnc(-c3ccc(C#N)cc3)nc2)cc1
Product: CCCCc1cnc(-c2ccc(CC)cc2)nc1

Procedure:
A liquid crystal mixture, in accordance with claim 20, 10.3% p-n-butylbenzoic acid p'-cyanophenyl ester, 11.1% p-n-pentylbenzoic acid p'-cyanophenyl ester, 14.3% p-n-hexylbenzoic acid p'-cyanophenyl ester, 15.4% p-n-heptylbenzoic acid p'-cyanophenyl ester, 11.0% 5-n-pentyl-2-(4-cyanophenyl)pyrimidine, 21.2% 5-n-hexyl-2-(4-cyanophenyl)pyrimidine, 15.6% 2-(4-cyanophenyl)-5-(4-n-butylphenyl)pyrimidine and 15% 4-ethyl-4'-n-pentylbiphenyl.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[C:9]([O:14][CH2:15][CH3:16])[CH:8]=1)[CH3:2].Cl[CH2:19][C:20]1[C:21]([CH3:36])=[N:22][C:23]([C:26]2[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][CH:27]=2)=[CH:24][CH:25]=1>>[CH2:1]([O:3][C:4](=[O:17])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:19][C:20]2[C:21]([CH3:36])=[N:22][C:23]([C:26]3[CH:27]=[CH:28][C:29]([C:32]([F:35])([F:33])[F:34])=[CH:30][CH:31]=3)=[CH:24][CH:25]=2)=[C:9]([O:14][CH2:15][CH3:16])[CH:8]=1)[CH3:2]
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)ccc1CCl
Reactant: CCOC(=O)CCc1ccc(O)c(OCC)c1
Product: CCOC(=O)CCc1ccc(OCc2ccc(-c3ccc(C(F)(F)F)cc3)nc2C)c(OCC)c1

Procedure:
In analogy to the procedures described in examples 8A] and 31B], 3-(3-ethoxy-4-hydroxy-phenyl)-propionic acid ethyl ester [Eur. Pat. Appl. (1996), EP 710659/A1] was reacted with 3-chloromethyl-2-methyl-6-(4-trifluoromethyl-phenyl)-pyridine (example 1N]) to give 3-{3-ethoxy-4-[2-methyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-ylmethoxy]-phenyl}-propionic acid ethyl ester, which was subsequently saponified to yield the title compound as colorless solid.
Reaction SMILES: [C:1](Cl)(=[O:5])[CH:2]([CH3:4])[CH3:3].[C:7]([O:11][C:12](=[O:34])[CH2:13][N:14]1[C:18]2[CH:19]=[CH:20][C:21]([NH:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[CH:22][C:17]=2[N:16]=[C:15]1[CH2:31][CH2:32][CH3:33])([CH3:10])([CH3:9])[CH3:8].CCN(C(C)C)C(C)C>CN(C1C=CN=CC=1)C.C(Cl)Cl.Cl>[C:7]([O:11][C:12](=[O:34])[CH2:13][N:14]1[C:18]2[CH:19]=[CH:20][C:21]([N:23]([CH2:24][C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:1](=[O:5])[CH:2]([CH3:4])[CH3:3])=[CH:22][C:17]=2[N:16]=[C:15]1[CH2:31][CH2:32][CH3:33])([CH3:10])([CH3:9])[CH3:8]
Reactant: CCCc1nc2cc(NCc3ccccc3)ccc2n1CC(=O)OC(C)(C)C
Reactant: CC(C)C(=O)Cl
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCCc1nc2cc(N(Cc3ccccc3)C(=O)C(C)C)ccc2n1CC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Isobutyryl chloride (38 μL, 0.36 mmol) was added to a solution of (5-benzylamino-2-propyl-benzoimidazol-1-yl)-acetic acid tert-butyl ester (45 mg, 0.12 mmol), DIEA (41 μL, 0.24 mmol) and DMAP (15 mg, 0.12 mmol) in CH2Cl2 (1 mL), and stirred overnight at room temperature. The reaction solution was diluted with aqueous HCl (1.0 M) and filtered through an Extrelut column. The Extrelut column was washed with CH2Cl2, and the filtrate was concentrated to afford the subtitle compound that was used without further purification. MS calculated for C27H35N3O3+H: 450, observed: 450.
Reaction SMILES: [O:1]=[C:2]1[NH:6][CH2:5][C:4](=[O:7])[N:3]1[NH:8][C:9]([C:11]1[N:12](CC2C=CC=CC=2)[CH:13]=[C:14]([O:18]CC2C=CC=CC=2)[C:15](=[O:17])[CH:16]=1)=[O:10].FC(F)(F)C(O)=O.[H][H]>CN(C)C=O.[Pd]>[O:1]=[C:2]1[NH:6][CH2:5][C:4](=[O:7])[N:3]1[NH:8][C:9]([C:11]1[NH:12][CH:13]=[C:14]([OH:18])[C:15](=[O:17])[CH:16]=1)=[O:10]
Reactant: [H][H]
Reactant: O=C(NN1C(=O)CNC1=O)c1cc(=O)c(OCc2ccccc2)cn1Cc1ccccc1
Agent: [Pd]
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: O=C(NN1C(=O)CNC1=O)c1cc(=O)c(O)c[nH]1

Procedure:
To a solution of 10.8 g (0.025 mol) of N-(2,5-dioxo-1-imidazolidinyl)-1,4-dihydro-4-oxo-5-(phenylmethoxy)-1-(phenylmethyl)-2-pyridinecarboxamide in 200 ml of dimethylformamide was added 3.83 ml of trifluoroacetic acid (0.05 mol) and 6 g of palladium on charcoal (10%). With vigorous stirring, hydrogen was passed through the solution for 45 minutes. The catalyst was removed by filtration and the filtrate evaporated. The remaining syrup solidified on trituration with ether. Yield: 6.1 g, melting point 260°-270° C., dec.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:19]C)=[C:6]([C:8]2[N:9]=[C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][N:11]3[C:16]=2[CH:17]=[O:18])[CH:7]=1.B(Br)(Br)Br.O>ClCCl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:19])=[C:6]([C:8]2[N:9]=[C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][N:11]3[C:16]=2[CH:17]=[O:18])[CH:7]=1
Reactant: COc1ccc(Br)cc1-c1nc2ccccn2c1C=O
Agent: BrB(Br)Br
Solvent: O
Solvent: ClCCl
Product: O=Cc1c(-c2cc(Br)ccc2O)nc2ccccn12
Temperature: 25 °C
Reaction time: 2 h
Yield: 4.2 %

Procedure:
2-(5-bromo-2-methoxyphenyl)imidazo[1,2-a]pyridine-3-carbaldehyde (0.1 g, 3 mmol) was dissolved in dichloromethane (0.5 mL) at −78° C. BBr3 (1 mL) was added by dropwise stirred for 2 hours at that temperature. Then warmed to 25° C. and stirred for 10 hours. H2O (20 mL) was added by dropwise at −78° C. and extracted with EtOAc (3*50 mL), washed by aq NaHCO3 (3*50 mL) and brine (50 mL). After concentrated, the resulting residue was purified using Prep-TLC (petroleum ether:EtOAc=3:1) to provide 2-(5-bromo-2-hydroxyphenyl)imidazo[1,2-a]pyridine-3-carbaldehyde (40 mg, yield: 48%). 1H-NMR (CDCl3, 400 MHz) δ 10.29 (s, 1H), 9.76 (s, 1H), 7.78˜7.79 (m, 2H), 7.65˜7.69 (m, 1H), 7.46˜7.48 (m, 1H), 7.20˜7.22 (m, 1H), 7.00˜7.02 (m, 1H). MS (M+H)+: 317/319.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([S:28]([NH2:31])(=[O:30])=[O:29])[CH:23]=2)[C:5]2[CH:10]=[CH:9][N:8]([S:11]([C:14]3[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[C:6]=2[N:7]=1.[NH2:32][C:33]1[CH:38]=[CH:37][C:36]([N:39]2[CH2:44][CH2:43][N:42]([C:45](=[O:47])[CH3:46])[CH2:41][CH2:40]2)=[CH:35][CH:34]=1.C[Si](Cl)(C)C>C(O)CCC.O1CCOCC1>[C:45]([N:42]1[CH2:41][CH2:40][N:39]([C:36]2[CH:37]=[CH:38][C:33]([NH:32][C:2]3[N:3]=[C:4]([NH:21][C:22]4[CH:23]=[C:24]([S:28]([NH2:31])(=[O:29])=[O:30])[CH:25]=[CH:26][CH:27]=4)[C:5]4[CH:10]=[CH:9][N:8]([S:11]([C:14]5[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=5)(=[O:13])=[O:12])[C:6]=4[N:7]=3)=[CH:34][CH:35]=2)[CH2:44][CH2:43]1)(=[O:47])[CH3:46]
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(Nc4cccc(S(N)(=O)=O)c4)nc(Cl)nc32)cc1
Reactant: CC(=O)N1CCN(c2ccc(N)cc2)CC1
Agent: C[Si](C)(C)Cl
Solvent: C1COCCO1
Solvent: CCCCO
Product: CC(=O)N1CCN(c2ccc(Nc3nc(Nc4cccc(S(N)(=O)=O)c4)c4ccn(S(=O)(=O)c5ccc(C)cc5)c4n3)cc2)CC1
Temperature: 110 °C
Reaction time: 72 h
Yield: 28.8 %

Procedure:
A mixture of 2-chloro-N-(3-aminosulfonyl-phenyl)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (100 mg, 0.210 mmol), 1-(4-(4-aminophenyl)piperazin-1-yl)ethanone (92 mg, 0.42 mmol) and trimethylsilyl chloride (0.200 mL, 1.58 mmol) in nBuOH (2 mL) and dioxane (2 mL) was heated at 110° C. for 72 h. More 1-(4-(4-aminophenyl)piperazin-1-yl)ethanone (92 mg, 0.42 mmol) was added. The mixture was stirred at 110° C. for another 72 h. It was then purified by HPLC to give 3-(2-(4-(4-acetylpiperazin-1-yl)phenylamino)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)benzenesulfonamide (40 mg)
Reaction SMILES: C([O-])(=O)C.[K+].C(OC(=O)C)(=O)C.O[CH:14]([CH:19]([CH:23]([CH2:25][CH3:26])[CH3:24])[CH2:20][CH:21]=[CH2:22])[CH2:15][C:16]([OH:18])=O>>[CH:23]([C:19]1[CH2:20][C@@H:21]2[C@H:15]([CH:14]=1)[C:16](=[O:18])[CH2:22]2)([CH2:25][CH3:26])[CH3:24]
Reactant: C=CCC(C(C)CC)C(O)CC(=O)O
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CC(=O)OC(C)=O
Product: CCC(C)C1=C[C@@H]2C(=O)C[C@@H]2C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Potassium acetate (14.90 g, 151.8 mmol) was added to an acetic anhydride (71 mL) solution of 3-hydroxy-4-sec-butylhept-6-enoic acid (12.70 g, 63.5 mmol), and the mixture was stirred at room temperature for 1 hour and then stirred at 120° C. for 3.5 hours. The mixture was treated with ice water, followed by extraction with diethyl ether. The organic layer was washed with a saturated aqueous solution of sodium bicarbonate. The organic layer was dried over anhydrous magnesium sulfate. Then, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the compound of interest as a yellow oil substance (6.70 g, 64%).