Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:6]2[CH:11]=[CH:10][C:9]([C:12]3[N:17]=[C:16]4[N:18]([CH2:22]C5CCOCC5)[C:19](=[O:21])[NH:20][C:15]4=[N:14][CH:13]=3)=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1.C[Sn](C)(C)C1C=CC(N2C=CC=N2)=CC=1.BrC1N=C2N([CH2:55][CH:56]3[CH2:61][CH2:60][O:59][CH2:58][CH2:57]3)C(=O)NC2=NC=1>CN(C=O)C>[N:1]1([C:6]2[CH:7]=[CH:8][C:9]([C:12]3[N:17]=[C:16]4[N:18]([CH2:22][CH2:55][CH:56]5[CH2:61][CH2:60][O:59][CH2:58][CH2:57]5)[C:19](=[O:21])[NH:20][C:15]4=[N:14][CH:13]=3)=[CH:10][CH:11]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: O=c1[nH]c2ncc(-c3ccc(-n4cccn4)cc3)nc2n1CC1CCOCC1
Reactant: O=c1[nH]c2ncc(Br)nc2n1CC1CCOCC1
Agent: C[Sn](C)(C)c1ccc(-n2cccn2)cc1
Solvent: CN(C)C=O
Product: O=c1[nH]c2ncc(-c3ccc(-n4cccn4)cc3)nc2n1CCC1CCOCC1
Yield: 4 %

Procedure:
6-(4-(1H-Pyrazol-1-yl)phenyl)-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one. 1-(4-(Trimethylstannyl)phenyl)-1H-pyrazole (300 mg, 0.97 mmol), 6-bromo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one (See Example 101.B) (304 mg, 0.97 mmol), dichlorobis(triphenylphosphine) palladium(II) (68 mg, 0.097 mmol) in DMF (15 mL) were reacted for 1.5 h at 90° C. The product was purified by reverse-phase semi-preparatory HPLC (10-60% acetonitrile+0.1% TFA in H2O+0.1% TFA, over 30 min). The desired fractions were concentrated and treated with aqueous 6N ammonium hydroxide (few drops). The volatiles were removed under reduced pressure, and the residue was taken up in water (2 mL), and the solid was filtered and rinsed with water to provide the title compound (14.5 mg, 4% yield). 1H NMR (400 MHz, DMSO-d6) δ 8.57(s, 1H), 8.32 (d, J=8.8, 2H), 8.01 (d, J=8.8, 2H), 7.68 (s, 2H), 2.27-2.33 (m, 2H), 1.66-1.63 (m, 2H), 1.51-1.49 (m, 2H), 1.27 (m, 2H), 0.88-0.84 (m, 2H); MS (ESI) m/z 377.3 [M+1]+; mp 294-296° C.
Reaction SMILES: [CH:1]([NH:4][C:5]1[O:6][C:7]([C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[N:15]([S:19]([C:22]2[CH:28]=[CH:27][C:25]([CH3:26])=[CH:24][CH:23]=2)(=[O:21])=[O:20])[CH:14]=[C:13]3B2OC(C)(C)C(C)(C)O2)=[N:8][N:9]=1)([CH3:3])[CH3:2].Br[C:39]1[CH:47]=[CH:46][C:42]([C:43]([OH:45])=[O:44])=[CH:41][C:40]=1[F:48].O.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.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>[F:48][C:40]1[CH:41]=[C:42]([CH:46]=[CH:47][C:39]=1[C:13]1[C:12]2[C:16](=[CH:17][CH:18]=[C:10]([C:7]3[O:6][C:5]([NH:4][CH:1]([CH3:2])[CH3:3])=[N:9][N:8]=3)[CH:11]=2)[N:15]([S:19]([C:22]2[CH:28]=[CH:27][C:25]([CH3:26])=[CH:24][CH:23]=2)(=[O:21])=[O:20])[CH:14]=1)[C:43]([OH:45])=[O:44]
Reactant: O=C(O)c1ccc(Br)c(F)c1
Reactant: Cc1ccc(S(=O)(=O)n2cc(B3OC(C)(C)C(C)(C)O3)c3cc(-c4nnc(NC(C)C)o4)ccc32)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: O
Solvent: COCCOC
Product: Cc1ccc(S(=O)(=O)n2cc(-c3ccc(C(=O)O)cc3F)c3cc(-c4nnc(NC(C)C)o4)ccc32)cc1
Temperature: 90 °C
Yield: 48.8 %

Procedure:
To a solution of N-isopropyl-5-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1H-indol-5-yl)-1,3,4-oxadiazol-2-amine (2.0 g, 3.831 mmol) and 4-bromo-3-fluorobenzoic acid (1.2 g, 5.74 mmol, Sigma-Aldrich) in DME (38 mL)/water (9 mL) was added Na2CO3 (1.35 g, 11.5 mmol) and Pd(PPh3)4 (439 mg, 0.38 mmol) and Ar gas was bubbled for 5 min. The reaction mixture was heated at 90° C. for 4 h. The reaction was quenched with water (200 mL) to get a brown precipitate. The precipitate was filtered, washed with water (2×100 mL) and dried to give crude product (1.0 g), which was used in the next step without further purification. MS (ESI, pos. ion) m/z: 535.1 (M+1).
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[O:12][C:13]3[CH:19]=[C:18]([OH:20])[CH:17]=[CH:16][C:14]=3[CH:15]=2)=[CH:7][CH:6]=1)[CH2:2][CH3:3].[H-].[Na+].CC1C=CC(S(O[CH2:34][C@@H:35]([NH:37][C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH3:36])(=O)=O)=CC=1.O>CN(C=O)C>[CH2:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[O:12][C:13]3[CH:19]=[C:18]([O:20][CH2:36][C@@H:35]([NH:37][C:38](=[O:39])[O:40][C:41]([CH3:42])([CH3:44])[CH3:43])[CH3:34])[CH:17]=[CH:16][C:14]=3[CH:15]=2)=[CH:7][CH:6]=1)[CH2:2][CH3:3]
Reactant: Cc1ccc(S(=O)(=O)OC[C@H](C)NC(=O)OC(C)(C)C)cc1
Reactant: CCCOc1ccc(-c2cc3ccc(O)cc3o2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCOc1ccc(-c2cc3ccc(OC[C@H](C)NC(=O)OC(C)(C)C)cc3o2)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 31.6 %

Procedure:
To a solution of 2-(4-propoxyphenyl)-1-benzofuran-6-ol (918 mg) in DMF (10 mL) was added sodium hydride (60% oil, 137 mg), and the mixture was stirred at room temperature for 10 min. To the reaction mixture was added (2S)-2-[(tert-butoxycarbonyl)amino]propyl 4-methylbenzenesulfonate (1.13 g), and the mixture was stirred at 60° C. for 1 hr. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (460 mg).
Reaction SMILES: [OH:1][C@H:2]([C@@H:4]1[CH2:8][O:7][C:6]([C:9]2[NH:13][C:12]([C:14]3[CH:15]=[C:16]([OH:26])[CH:17]=[C:18]([O:20][C@@H:21]([CH3:25])[CH2:22][O:23][CH3:24])[CH:19]=3)=[CH:11][CH:10]=2)=[N:5]1)[CH3:3].Cl[C:28]1[CH:33]=[N:32][C:31]([S:34]([CH3:37])(=[O:36])=[O:35])=[CH:30][N:29]=1.C(=O)([O-])[O-].[K+].[K+].O>C(#N)C>[CH3:24][O:23][CH2:22][C@@H:21]([O:20][C:18]1[CH:19]=[C:14]([C:12]2[NH:13][C:9]([C:6]3[O:7][CH2:8][C@@H:4]([C@@H:2]([OH:1])[CH3:3])[N:5]=3)=[CH:10][CH:11]=2)[CH:15]=[C:16]([O:26][C:28]2[CH:33]=[N:32][C:31]([S:34]([CH3:37])(=[O:36])=[O:35])=[CH:30][N:29]=2)[CH:17]=1)[CH3:25]
Reactant: COC[C@H](C)Oc1cc(O)cc(-c2ccc(C3=N[C@H]([C@H](C)O)CO3)[nH]2)c1
Reactant: CS(=O)(=O)c1cnc(Cl)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: COC[C@H](C)Oc1cc(Oc2cnc(S(C)(=O)=O)cn2)cc(-c2ccc(C3=N[C@H]([C@H](C)O)CO3)[nH]2)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 79.3 %

Procedure:
3-(5-{(4S)-4-[(1S)-1-Hydroxyethyl]-4,5-dihydro-1,3-oxazol-2-yl}-1H-pyrrol-2-yl)-5-{[(2S)-1-methoxypropan-2-yl]oxy}phenol (880 mg, 2.44 mmol) synthesized in Example (112c) was dissolved in acetonitrile (20 mL), and 2-chloro-5-(methylsulfonyl)pyrazine (630 mg, 3.27 mmol) synthesized in Example (97c) and potassium carbonate (1.20 g, 8.68 mmol) were added, followed by stirring at room temperature for 4 hours under nitrogen atmosphere. Water (50 mL) was added, and extraction was carried out with methylene chloride (50 mL). The organic layer was washed with saturated brine, and subsequently dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: methanol/methylene chloride=1%-3%) to afford the desired compound (1.00 g, yield 79%) as a white solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[CH3:11][N:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1>ClCCl>[CH3:11][N:12]1[CH2:17][CH2:16][N:15]([C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=2)[CH2:14][CH2:13]1
Reactant: O=[N+]([O-])c1ccc(Br)nc1
Reactant: CN1CCNCC1
Solvent: ClCCl
Product: CN1CCN(c2ccc([N+](=O)[O-])cn2)CC1
Yield: 91.4 %

Procedure:
An amount of 2 g (9.85 mmol) of 2-bromo-5-nitro-pyridin is stirred in dichloromethane (50 mL), followed by addition of 1-methylpiperazine (10.9 mL, 98.5 mmol). The reaction mixture is refluxed for 1 h. After cooling, the mixture is extracted 3× with sodium bicarbonate, followed by additional washing with brine, dried over sodium sulfate, evaporated, to afford 2 g (91% yield) of yellow crystals; mp 75-76° C.
Reaction SMILES: [CH:1]([C:4]1[CH:23]=[C:22]([C:24](=[O:30])[CH:25]=[CH:26][C:27]([OH:29])=O)[CH:21]=[CH:20][C:5]=1[O:6][CH2:7][C:8]([NH:10][C:11]1[S:12][C:13]2[CH:19]=[CH:18][CH:17]=[CH:16][C:14]=2[N:15]=1)=[O:9])([CH3:3])[CH3:2].C(N(CC)CC)C.ClC(OCC(C)C)=O.[CH3:46][N:47]1[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1>ClCCl>[CH:1]([C:4]1[CH:23]=[C:22]([C:24](=[O:30])[CH:25]=[CH:26][C:27]([N:50]2[CH2:51][CH2:52][N:47]([CH3:46])[CH2:48][CH2:49]2)=[O:29])[CH:21]=[CH:20][C:5]=1[O:6][CH2:7][C:8]([NH:10][C:11]1[S:12][C:13]2[CH:19]=[CH:18][CH:17]=[CH:16][C:14]=2[N:15]=1)=[O:9])([CH3:3])[CH3:2]
Reactant: CN1CCNCC1
Reactant: CC(C)c1cc(C(=O)C=CC(=O)O)ccc1OCC(=O)Nc1nc2ccccc2s1
Agent: CC(C)COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)c1cc(C(=O)C=CC(=O)N2CCN(C)CC2)ccc1OCC(=O)Nc1nc2ccccc2s1
Reaction time: 2.5 h

Procedure:
To a solution of 2-[2-isopropyl-4-(3-carboxyacryloyl)phenoxymethylcarbonylamino]benzothiazole (1.0 g) and triethylamine (0.4 ml) in dichloromethane (20 ml) is added dropwise isobutyl chloroformate (0.32 ml) under ice-cooling. To the mixture is added N-methylpiperazine (0.27 ml) at the same temperature, and the mixture is stirred for 2.5 hours. The reaction solution is washed with water, dried and concentrated under reduced pressure. The residue is purified by silica gel column chromatography (solvent; dichloromethane→dichloromethane:methanol=30:1), and recrystallized from ethanol to give 2-{2-isopropyl-4-[3-(4-methyl-1-piperazinylcarbonyl)acryloyl]phenoxymethylcarbonylamino}benzothiazole (0.80 g).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]([CH:6]([OH:14])[C:7]1[CH:8]=[N:9][C:10]([CH3:13])=[N:11][CH:12]=1)=[CH2:5].[C:16](OC(=O)C)(=[O:18])[CH3:17].C([O-])(O)=O.[Na+]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH3:1][O:2][C:3](=[O:15])[C:4]([CH:6]([O:14][C:16](=[O:18])[CH3:17])[C:7]1[CH:12]=[N:11][C:10]([CH3:13])=[N:9][CH:8]=1)=[CH2:5]
Reactant: C=C(C(=O)OC)C(O)c1cnc(C)nc1
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: C=C(C(=O)OC)C(OC(C)=O)c1cnc(C)nc1
Temperature: 0 °C
Reaction time: 0.03 h
Yield: 61.1 %

Procedure:
2-[Hydroxy-(2-methyl-pyrimidin-5-yl)-methyl]acrylic acid methyl ester (1.58 g, 7.58 mmol, 1 eq) and 4-DMAP (0.4 eq, 370 mg) were dissolved in 30 ml of dry DCM under argon atmosphere. To the mixture, cooled at 0° C., was added acetic anhydride (1.5 eq, 1.07 ml) dropwise, during 2 minutes. The mixture was warmed-up to room temperature and was stirred overnight (16 hours). The mixture was then poured into 150 ml of NaHCO3 saturated water solution and organic substances were extracted with DCM (3 times, 150 ml of DCM was used in total). The gathered DCM layers were dried, the solvent was evaporated and obtained was 2-[acetoxy-(2-methyl-pyrimidin-5-yl)-methyl]acrylic acid methyl ester (1.16 g, yield=61.1%, purity=90%) in form of orange transparent oil. MS: [M+H]+=251.25 1H NMR (300 MHz; CDCl3) δ/ppm 2.73 (s, 3H), 3.72 (s, 2H), 6.05 (s, 1H), 6.49 (s, 1H), 6.61 (s, 1H) 8.65 (s, 2H)
Reaction SMILES: [C:1]([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[CH:11]=[C:10]([C:15]([OH:17])=O)[CH:9]=[CH:8]2)(=[O:3])[CH3:2].S(Cl)([Cl:20])=O>CN(C)C=O.C1COCC1>[C:1]([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[CH:11]=[C:10]([C:15]([Cl:20])=[O:17])[CH:9]=[CH:8]2)(=[O:3])[CH3:2]
Reactant: O=S(Cl)Cl
Reactant: CC(=O)Oc1ccc2cc(C(=O)O)ccc2c1
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CC(=O)Oc1ccc2cc(C(=O)Cl)ccc2c1
Temperature: 25 °C

Procedure:
Into a 0.25 L, 3-necked roundbottom flask, fitted with a magnetic stirbar, addition funnel, and reflux condenser were added 6-acetoxy-2-naphthoic acid (30.0 g, 130 mmol), THF (135 mL) and dimethylformamide (approx. 20 drops). Thionyl chloride (18.6 g, 156 mmol) was added slowly dropwise to the reaction mixture over 15 minutes. The reaction mixture was heated to reflux for 2.5 hours under nitrogen and allowed to cool to room temperature overnight.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][CH2:5][CH2:6][OH:7].[O:8]=[C:9]1[NH:17][CH:16]=[N:15][C:14]2[N:13]([CH2:18][CH2:19][C:20](OCC)=[O:21])[CH:12]=[N:11][C:10]1=2.CCOCC>CO>[O:8]=[C:9]1[NH:17][CH:16]=[N:15][C:14]2[N:13]([CH2:18][CH2:19][C:20]([NH:1][CH2:2][CH2:3][NH:4][CH2:5][CH2:6][OH:7])=[O:21])[CH:12]=[N:11][C:10]1=2
Reactant: NCCNCCO
Reactant: CCOC(=O)CCn1cnc2c(=O)[nH]cnc21
Solvent: CCOCC
Solvent: CO
Product: O=C(CCn1cnc2c(=O)[nH]cnc21)NCCNCCO
Reaction time: 1 h
Yield: 38 %

Procedure:
0.500 (4,80 mmol) 2-(2-aminoethylamino)ethanol and 0.250 g (1.06 mmol) of 3-(1,6-dihydro-6-oxo-9H-purin-9-yl)propionic acid, ethyl ester (AIT-0027) were heated at 120° C. with stirring in a 10 ml round bottom flask for one hour. The reaction mixture was chromatographed on a 15 g silica-gel column using an eluant of 60% methanol/40% ethyl acetate. After 200 ml of solvent had passed through column, the eluant was changed to 80% methanol/20% ethyl acetate and finally to 100% methanol. The fractions containing the product were combined and evaporated to yield a colorless oil. The oil was treated with 50 ml ether and 5 ml methanol and was agitated with a spatula. The oil was allowed to stand overnight and the resulting white solid was obtained by filtration (120 mg). The solid was washed with ether and was found to be somewhat hygroscopic. Yield: 38%.
Reaction SMILES: [CH3:1][NH:2][C:3]1[C:8]([NH2:9])=[CH:7][C:6]([C:10]([F:13])([F:12])[F:11])=[CH:5][N:4]=1.[CH2:14]([S:17][C:18]1[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=1[C:20](O)=O)[CH:15]=[CH2:16].CCN=C=NCCCN(C)C>C1(C)C(C)=CC=CC=1>[CH2:14]([S:17][C:18]1[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=1[C:20]1[N:2]([CH3:1])[C:3]2=[N:4][CH:5]=[C:6]([C:10]([F:11])([F:12])[F:13])[CH:7]=[C:8]2[N:9]=1)[CH:15]=[CH2:16]
Reactant: C=CCSc1ccccc1C(=O)O
Reactant: CNc1ncc(C(F)(F)F)cc1N
Agent: CCN=C=NCCCN(C)C
Solvent: Cc1ccccc1C
Product: C=CCSc1ccccc1-c1nc2cc(C(F)(F)F)cnc2n1C
Temperature: 145 °C
Yield: 47.3 %

Procedure:
A mixture of N2-methyl-5-trifluoromethylpyridin-2,3-diamine (0.96 g), 2-allylsulfanylbenzoic acid (1.46 g), WSC (1.06 g), and xylene (10 ml) was stirred with heating at 145° C. for 3 hours. After the mixture was evaporated to remove xylene, acetic acid (10 ml) was added thereto, and stirred with heating at 120° C. for further 1 hour. To the reaction mixture cooled to room temperature, 5 mol/l of aqueous sodium hydroxide solution was added to neutralize, and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography to give 0.83 g of 2-(2-allylsulfanylphenyl)-3-methyl-6-trifluoromethyl-3H-imidazo[4,5-b]pyridine (hereinafter referred to as Present Compound 10).
Reaction SMILES: [CH3:1][C:2]([CH3:15])=[CH:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[C:6](=O)[C:7](=[O:13])[NH:8]2.IC1C=CC=C2C=1C(=O)C(=O)N2.CC(=C)C.[CH:32]1[C:37]([NH:38][NH2:39])=[CH:36][CH:35]=[C:34]([S:40]([NH2:43])(=[O:42])=[O:41])[CH:33]=1.Cl>>[CH3:1][C:2]([CH3:15])=[CH:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[C:6](=[N:39][NH:38][C:37]1[CH:36]=[CH:35][C:34]([S:40]([NH2:43])(=[O:41])=[O:42])=[CH:33][CH:32]=1)[C:7](=[O:13])[NH:8]2
Reactant: NNc1ccc(S(N)(=O)=O)cc1
Reactant: CC(C)=Cc1cccc2c1C(=O)C(=O)N2
Agent: C=C(C)C
Agent: Cl
Agent: O=C1Nc2cccc(I)c2C1=O
Product: CC(C)=Cc1cccc2c1C(=NNc1ccc(S(N)(=O)=O)cc1)C(=O)N2
Yield: 51 %

Procedure:
By methods described in Procedure L, 4-(2-methyl-propenyl)-1H-indole-2,3-dione was prepared from 4-iodo-1H-indole-2,3-dione and isobutylene in 34% yield: 1H NMR (DMSO-d6): δ 1.82 (s, 3H), 1.90 (s, 3H), 6.79 (d, J=7.9 Hz, 1H), 6.94 (d, J=7.9 Hz, 1H), 7.47 (t, J=7.9 Hz, 1H), 10.97 (s, 1H); APCI−MS m/z 200 (M−1)−. Condensation of 4-(2-methyl-propenyly1H-indole-2,3-dione and 4-sulfonamidophenylhydrazine hydrochloride according to Procedure G gave the title compound as a yellow solid (51% yield): 1H NMR (DMSO-d6): δ 1.84 (s, 3H), 2.04 (s, 3H), 6.78 (s, 1H), 6.79 (d, J=7.8 Hz, 1H), 6.96 (d, J=7.8 Hz, 1H), 7.24 (t, J=7.8 Hz, 1H), 7.24 (s, 2H), 7.48 (d, J=8.8 Hz, 2H), 7.80 (d, J=8.8 Hz, 2H), 11.11 (s, 1H), 12.91 (s, 1H); APCI−MS m/z 369 (M−1)−. Anal. Calcd for C18H18N4O3S: C, 58.36, H. 4.90; N, 15.12; S, 8.66. Found C, 58.41, H. 4.87; N, 15.18; S, 8.56.
Reaction SMILES: [CH:1]1[C:6]([CH:7]=O)=[CH:5][C:4]2[O:9][CH2:10][O:11][C:3]=2[CH:2]=1.C([O-])(=O)C.[NH4+].[N+:17]([CH2:20][CH3:21])([O-:19])=[O:18]>>[N+:17]([C:20]([CH3:21])=[CH:7][C:6]1[CH:1]=[CH:2][C:3]2[O:11][CH2:10][O:9][C:4]=2[CH:5]=1)([O-:19])=[O:18]
Reactant: CC[N+](=O)[O-]
Reactant: O=Cc1ccc2c(c1)OCO2
Agent: CC(=O)[O-]
Agent: [NH4+]
Product: CC(=Cc1ccc2c(c1)OCO2)[N+](=O)[O-]
Temperature: 105 °C
Yield: 40 %

Procedure:
5.00 g (33.3 mmol) piperonal (Aldrich, Milwaukee, Wis.), 12.8 g (167 mmol) ammonium acetate (Fluka), and 50 g (670 Mmol) nitroethane, 98% (Aldrich) were combined in a 100 ml round bottom flask equipped with magnetic stirrer and nitrogen inlet. The reaction mixture was heated to 105° C. for 90 minutes and the solvent was removed under vacuum to give a dark yellow liquid which was recrystallized from cold methyl alcohol three times to give a yellow crystalline solid in 40% yield. 1H NMR spectra is shown in FIG. 1.
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])[N:15]([CH2:21][C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([CH2:28][OH:29])[CH:23]=4)[C:14]3=[O:30])[CH:10]=[N:9]2)=[C:5]([CH3:31])[O:4][N:3]=1.[H-].[Na+].I[CH3:35]>CN(C)C=O.C(OCC)(=O)C>[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])[N:15]([CH2:21][C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([CH2:28][O:29][CH3:35])[CH:23]=4)[C:14]3=[O:30])[CH:10]=[N:9]2)=[C:5]([CH3:31])[O:4][N:3]=1
Reactant: Cc1noc(C)c1Cn1cc(N2C(=O)N(Cc3cccc(CO)c3)C(C)(C)C2=O)cn1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COCc1cccc(CN2C(=O)N(c3cnn(Cc4c(C)noc4C)c3)C(=O)C2(C)C)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 36 %

Procedure:
To a solution of 3-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)-1-(3-(hydroxymethyl)benzyl)-5,5-dimethylimidazolidine-2,4-dione (Example 12-34) (559 mg, 1.32 mmol) in anhydrous dimethylformamide (10 mL) at 0° C., was added sodium hydride (53 mg, 1.32 mmol), followed by iodomethane (99 ul, 1.58 mmol). The reaction was allowed to warm to room temperature and stirred for about 4 hours. The resulting mixture was diluted with ethyl acetate (40 mL) and ice water (10 mL), The organic phase was collected, dried over anhydrous MgSO4, filtered and then concentrated on the rotovap. The residue was purified by reverse phase HPLC (gradient 10% to 100% methanol/water) and further purified by column chromatography (60% EtOAc in hexane). Yield 36%, colorless gel. 1H NMR (DMSO-d6, 400 MHz): δ1.29 (s, 6H), 2.14 (s, 3H), 2.40 (s, 3H), 3.25 (s, 3H), 4.37 (s, 2H), 4.55 (s, 2H), 5.18 (s, 2H), 7.19 (t, 1H) 7.30 (d, 2H), 7.32 (s, 1H), 7.82 (s, 1H) 8.20 (s, 1H). MS 438 (MH+). The title compound was shown to inhibit hT2R08 bitter receptor and had an IC50 of 0.13 μM.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:7]([F:10])=[CH:8][N:9]=1)[CH:5]=[O:6].[CH2:11](O)[CH2:12][OH:13].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]2[O:13][CH2:12][CH2:11][O:6]2)[C:7]([F:10])=[CH:8][N:9]=1
Reactant: O=Cc1cc(Br)ncc1F
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: Fc1cnc(Br)cc1C1OCCO1

Procedure:
A mixture of 2-bromo-5-fluoroisonicotinaldehyde (495 mg, 2.43 mmol), ethylene glycol (0.27 mL, 4.85 mmol) and p-toluenesulfonic acid monohydrate (508 mg, 2.67 mmol) in toluene (13.5 mL) was refluxed for 4 hours. The mixture was concentrated and taken up in CH2Cl2, washed with 1 M NaOH, dried over sodium sulfate, filtered and concentrated. The crude product was purified by flash chromatography on silica gel (cyclohexane/EtOAc) to give INT 44.
Reaction SMILES: [CH:1]1([C:7]2[C:15]3[C:10](=[CH:11][C:12]([C:16]([O:18][CH3:19])=[O:17])=[CH:13][CH:14]=3)[NH:9][C:8]=2[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[OH:26])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:27][C:28]([O-])([CH3:30])[CH3:29].[K+].ClCC(CCl)=C>CN(C=O)C>[CH:1]1([C:7]2[C:15]3[CH:14]=[CH:13][C:12]([C:16]([O:18][CH3:19])=[O:17])=[CH:11][C:10]=3[N:9]3[C:8]=2[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[O:26][CH2:30][C:28](=[CH2:27])[CH2:29]3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c(-c3ccccc3O)[nH]c2c1
Reactant: CC(C)(C)[O-]
Agent: C=C(CCl)CCl
Agent: [K+]
Solvent: CN(C)C=O
Product: C=C1COc2ccccc2-c2c(C3CCCCC3)c3ccc(C(=O)OC)cc3n2C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 97 %

Procedure:
A solution of methyl 3-cyclohexyl-2-(2-hydroxyphenyl)-1H-indole-6-carboxylate (prepared as described in International patent application WO2006/046030) (0.12 M) in DMF was treated with KOtBu (2.1 eq) in one portion; the resulting mixture was stirred for 30 min at RT then treated dropwise with 3-chloro-2-(chloromethyl)prop-1-ene (1.1 eq). The resulting solution was stirred at RT overnight before being quenched by addition of HCl (1N) and extracted into EtOAc. The combined organic layers were washed with sat. aq. NaHCO3 and brine, before being dried (Na2SO4), filtered and concentrated in vacuo. The crude material was purified by FC (PE/EtOAc 85:15) affording the product as a yellow oil (97%). (ES+) m/z 402 (M+H)+.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[C:11]([CH3:12])=[CH:10][C:9]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:8][C:7]=1[CH3:21])=[O:4].[CH3:22][C:23]1([CH3:33])[N:27]2[CH2:28][CH2:29][NH:30][CH2:31][CH:26]2[C:25](=[O:32])[NH:24]1.C(N(CC)CC)C>CN(C)C=O>[CH3:21][C:7]1[CH:8]=[C:9]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:10]=[C:11]([CH3:12])[C:6]=1[NH:5][C:3](=[O:4])[CH2:2][N:30]1[CH2:29][CH2:28][N:27]2[C:23]([CH3:33])([CH3:22])[NH:24][C:25](=[O:32])[CH:26]2[CH2:31]1
Reactant: Cc1cc(OCc2ccccc2)cc(C)c1NC(=O)CCl
Reactant: CC1(C)NC(=O)C2CNCCN21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1cc(OCc2ccccc2)cc(C)c1NC(=O)CN1CCN2C(C1)C(=O)NC2(C)C
Temperature: 70 °C
Reaction time: 20 h
Yield: 66.8 %

Procedure:
A mixture of 13.36 parts of 2-chloro-N-[2,6-dimethyl-4-(phenylmethoxy)phenyl]acetamide, 6.76 parts of hexahydro-3,3-dimethylimidazo[1,5-a]pyrazin-1(5H)-one, 7.8 parts of N,N-diethylethanamine and 180 parts of N,N-dimethylformamide was stirred for 20 hours at 70° C. The reaction mixture was evaporated. The residue was taken up in water and the product was extracted twice with dichloromethane. The combined extracts were washed with water, dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (95:5 by volume) as eluent. The desired fraction was collected and the eluent was evaporated. The residue was crystallized from acetonitrile. The product was filtered off and dried, yielding 11.66 parts (66.8%) of N-[2,6-dimethyl-4-(phenylmethoxy)phenyl]hexahydro-3,3-dimethyl-1-oxoimidazo-[1,5-a]pyrazine-7(8H)-acetamide; mp. 223.8° C. (int. 1).
Reaction SMILES: [NH2:1][C:2]1[C:11]([F:12])=[C:10](F)[C:9]2[O:14][CH2:15][C:16]3([CH2:20][CH2:19][CH2:18][CH2:17]3)[N:7]3[C:8]=2[C:3]=1[C:4](=[O:24])[C:5]([C:21]([OH:23])=[O:22])=[CH:6]3.[N:25]1([CH2:30][CH2:31][CH2:32][NH2:33])[CH:29]=[N:28][CH:27]=[N:26]1.C(N(CC)CC)C>CS(C)=O>[N:25]1([CH2:30][CH2:31][CH2:32][NH:33][C:10]2[C:9]3[O:14][CH2:15][C:16]4([CH2:17][CH2:18][CH2:19][CH2:20]4)[N:7]4[C:8]=3[C:3]([C:4](=[O:24])[C:5]([C:21]([OH:23])=[O:22])=[CH:6]4)=[C:2]([NH2:1])[C:11]=2[F:12])[CH:29]=[N:28][CH:27]=[N:26]1
Reactant: NCCCn1cncn1
Reactant: Nc1c(F)c(F)c2c3c1c(=O)c(C(=O)O)cn3C1(CCCC1)CO2
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: Nc1c(F)c(NCCCn2cncn2)c2c3c1c(=O)c(C(=O)O)cn3C1(CCCC1)CO2
Yield: 18.1 %

Procedure:
A solution of 8-amino-9,10-difluoro-7-oxo-2,7-dihydrospiro[[1,4]oxazino[2,3,4-ij]-quinoline-3,1′-cyclopentane]-6-carboxylic acid (13 mg, 0.04 mmol) and 3-(1H-1,2,4-triazol-1-yl)propan-1-amine (5 mg, 0.04 mmol) and 5.5 μL triethylamine in DMSO (0.3 mL) was stirred at 90° C. for 24 h. The reaction mixture was cooled and freeze-dried overnight. The crude product was taken up in ACN and purified by prep HPLC to yield 10-(3-(1H-1,2,4-triazol-1-yl)propylamino)-8-amino-9-fluoro-7-oxo-2,7-dihydrospiro[[1,4]oxazino[2,3,4-ij]quinoline-3,1′-cyclopentane]-6-carboxylic acid (3.2 mg, 18%) as a yellow solid. MS (EP) m/z: 443 (M++1). (Calcd. For C21H23FN6O4, 442.18).