Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:17])[CH2:3][C@@H:4]([C:12]([N:14]([CH3:16])[CH3:15])=[O:13])[NH:5][C:6]1[CH2:10][S:9][C:8](=[O:11])[N:7]=1.[F:18][C:19]([F:40])([F:39])[C:20]1[CH:34]=[C:33]([C:35]([F:38])([F:37])[F:36])[CH:32]=[CH:31][C:21]=1[CH2:22][N:23]1[CH2:28][CH2:27][CH:26]([CH:29]=O)[CH2:25][CH2:24]1.C([O-])(=O)C.[NH2+]1CCCCC1>CC(O)C>[F:40][C:19]([F:18])([F:39])[C:20]1[CH:34]=[C:33]([C:35]([F:38])([F:37])[F:36])[CH:32]=[CH:31][C:21]=1[CH2:22][N:23]1[CH2:28][CH2:27][CH:26](/[CH:29]=[C:10]2/[C:6]([NH:5][C@H:4]([C:12]([N:14]([CH3:16])[CH3:15])=[O:13])[CH2:3][N:2]([CH3:17])[CH3:1])=[N:7][C:8](=[O:11])[S:9]/2)[CH2:25][CH2:24]1
Reactant: O=CC1CCN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)CC1
Reactant: CN(C)C[C@H](NC1=NC(=O)SC1)C(=O)N(C)C
Agent: C1CC[NH2+]CC1
Agent: CC(=O)[O-]
Solvent: CC(C)O
Product: CN(C)C[C@H](NC1=NC(=O)S/C1=C\C1CCN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)CC1)C(=O)N(C)C
Temperature: 60 °C
Reaction time: 8 h
Yield: 34.1 %

Procedure:
To a solution of 3-(dimethylamino)-N,N-dimethyl-N2-(2-oxo-2,5-dihydro-1,3-thiazol-4-yl)-L-alaninamide (775 mg) and 1-[2,4-bis(trifluoromethyl)benzyl]piperidine-4-carbaldehyde (1018 mg) in 2-propanol (10 mL) was added piperidinium acetate (436 mg) at room temperature. The reaction mixture was stirred at 60° C. overnight, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane) and recrystallized from ethyl acetate/heptane to give the title compound (593 mg)
Reaction SMILES: [Br:1][CH:2]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:3](O)=[O:4].S(Cl)([Cl:14])=O>>[Br:1][CH:2]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:3]([Cl:14])=[O:4]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)C(Br)c1ccccc1
Product: O=C(Cl)C(Br)c1ccccc1
Temperature: 25 °C
Reaction time: 14 h
Yield: 100 %

Procedure:
A solution of α-bromophenylacetic acid (19.3 g, 89.7 mmol) in thionylchloride (100 mL) was refluxed (2 hours), cooled (25° C.), and stirred (25° C., 14 hours). The resulting solution was concentrated in vacuo, diluted with ether, and concentrated again to yield 21.0 g (100%) of α-bromophenylacetylchloride as a slightly yellow oil which was used without further purification.
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][C:6](=[O:14])[CH2:5]1)(=[O:3])[CH3:2].[H-].[Na+].Br[CH2:18][CH:19]1[O:23][CH2:22][CH2:21][O:20]1.Cl>C(OCC)(=O)C.CN(C)C=O>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]([CH2:18][CH:19]2[O:23][CH2:22][CH2:21][O:20]2)[C:6](=[O:14])[CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CC(=O)Nc2ccccc21
Reactant: BrCC1OCCO1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(=O)N1CC(=O)N(CC2OCCO2)c2ccccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 15 mL of an N,N-dimethylformamide solution containing 957 mg of 4-acetyl-3,4-dihydro-2-oxo-1H-quinoxaline, 668 mg of sodium hydride was added, and the mixture was stirred at room temperature for 1 hour. Thereto was added 2.6 mL of 2-bromomethyl-1,3-dioxolane, and the mixture was stirred at 90° C. for 6 hours. The reaction mixture was cooled to room temperature, and then ethyl acetate and 1 mol/L hydrochloric acid were added thereto. The organic layer was separated, washed sequentially with water and an aqueous saturated sodium chloride solution and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by silica gel column chromatography [silica gel; Silica gel 60 manufactured by Kanto Chemical Co., Inc., eluent; chloroform] to obtain 1.30 g of a brown oily substance, 4-acetyl-1-(1,3-dioxolan-2-ylmethyl)-2-oxo-3,4-dihydro-1H-quinoxaline.
Reaction SMILES: C(OCC=C)C=C.[K].[CH2:9]([OH:12])[CH:10]=[CH2:11].[CH3:13][C:14]1[CH2:15][S:16][C@@H:17]2[CH:37]([NH:38][C:39](=[O:46])[CH2:40][C:41]3[S:42][CH:43]=[CH:44][CH:45]=3)[C:36](=[O:47])[N:18]2[C:19]=1[C:20]([O:22]C(C1C=CC=CC=1)C1C=CC=CC=1)=[O:21]>>[CH2:9]([O:12][C:37]1([NH:38][C:39](=[O:46])[CH2:40][C:41]2[S:42][CH:43]=[CH:44][CH:45]=2)[C:36](=[O:47])[N:18]2[C:19]([C:20]([OH:22])=[O:21])=[C:14]([CH3:13])[CH2:15][S:16][C@H:17]12)[CH:10]=[CH2:11]
Reactant: CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)Cc3cccs3)[C@H]2SC1
Reactant: C=CCO
Agent: C=CCOCC=C
Agent: [K]
Product: C=CCOC1(NC(=O)Cc2cccs2)C(=O)N2C(C(=O)O)=C(C)CS[C@@H]21

Procedure:
potassium allyloxide; allyl alcohol; benzhydryl 3-methyl-7-[2-(2-thienyl)acetamido]-3-cephem-4-carboxylate.
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([CH:14]=[CH:15][CH:16]=1)[C:11](O)=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:19])=O.Cl.S(=O)=O>>[O:1]([C:8]1[CH:9]=[C:10]([CH:14]=[CH:15][CH:16]=1)[C:11]([Cl:19])=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1cccc(Oc2ccccc2)c1
Agent: Cl
Agent: O=S=O
Product: O=C(Cl)c1cccc(Oc2ccccc2)c1

Procedure:
In a well ventilated hood, a mixture of m-phenoxy benzoic acid (200 g, 0.933 mole) (Aldrich) and thionyl chloride (105 mL, 1.44 moles) was placed in a one liter, round-bottomed flask. The flask was fitted with a magnetic stirring bar (or mechanical stirring bar for larger quantity preparation) and a reflux condenser with calcium chloride drying tube, which was attached to an exit tube, for evolved hyrogen chloride and sulfur dioxide, leading to a gas absorption trap. The mixture was heated on a heating mantle cautiously at first until a brownish-green solution was obtained (about 11/2 hours). The resulting solution was then heated gently for an additional 11/2 hours. The resulting brown solution was then cooled, and excessive thionyl chloride was distilled off at 40° C. To the resulting oil was added toluene (75 mi), and the solution was evaporated to remove a small amount of thionyl chloride. Addition and evaporation of toluene (75 mi) was repeated once more. The resulting acid chloride was then dissolved in 100 mL of tetrahydrofuran (THF dried over molecular sieves 3A), and ready to use freshly for reaction.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:5]([CH2:12][CH2:13][CH:14]([CH3:16])[CH3:15])[C:4](=[O:17])[C:3]=1[C:18]1[NH:23][C:22]2[CH:24]=[CH:25][C:26]([NH:28][S:29](=[O:42])(=[O:41])[NH:30][C:31]([O:33][CH2:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)=[O:32])=[CH:27][C:21]=2[S:20](=[O:44])(=[O:43])[N:19]=1.[CH3:45][Si](C=[N+]=[N-])(C)C>O1CCCC1.CO>[OH:1][C:2]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:5]([CH2:12][CH2:13][CH:14]([CH3:16])[CH3:15])[C:4](=[O:17])[C:3]=1[C:18]1[NH:23][C:22]2[CH:24]=[CH:25][C:26]([NH:28][S:29](=[O:42])(=[O:41])[N:30]([CH3:45])[C:31]([O:33][CH2:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)=[O:32])=[CH:27][C:21]=2[S:20](=[O:43])(=[O:44])[N:19]=1
Reactant: CC(C)CCn1c(=O)c(C2=NS(=O)(=O)c3cc(NS(=O)(=O)NC(=O)OCc4ccccc4)ccc3N2)c(O)c2cccnc21
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)CCn1c(=O)c(C2=NS(=O)(=O)c3cc(NS(=O)(=O)N(C)C(=O)OCc4ccccc4)ccc3N2)c(O)c2cccnc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 15.3 %

Procedure:
A solution of the product of Example 436 (0.032 g, 0.05 mmol) in 1:1 tetrahydrofuran/methanol (2 ml) at −10° C. was treated dropwise with trimethylsilyl diazomethane (2.0 M in hexanes, 50 μL, 0.1 mmol), then stirred at 25° C. for 16 hours and concentrated under reduced pressure. The residue was chromatographed on silica gel eluting with 3% methanol in dichloromethane to provide the title compound (5 mg, 15% yield). 1H NMR (300 MHz, DMSO-d6) δ 0.99 (d, J=6.25 Hz, 6 H) 1.58 (m, 2 H) 1.69 (m, 1 H) 3.21 (s, 3 H) 4.49 (m, 2 H) 5.19 (s, 2 H) 7.32 (m, 5 H) 7.46 (m, 1 H) 7.51 (dd, J=7.91, 4.60 Hz, 1 H) 7.58 (d, J=2.21 Hz, 1 H) 7.68 (d, J=8.82 Hz, 1 H) 8.57 (dd, J=8.09, 1.84 Hz, 1 H) 8.90 (dd, J=4.78, 1.47 Hz, 1 H) 11.29 (s, 1 H) 14.09 (s, 1 H). MS (ESI−) m/z 653 (M−H)−.
Reaction SMILES: Cl[C:2]1[C:7]([CH3:8])=[CH:6][C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1.[F-:12].[K+]>[Br-].C1([P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(#N)C.CCOCC>[F:12][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1
Reactant: Cc1cc([N+](=O)[O-])cnc1Cl
Reactant: [F-]
Agent: [Br-]
Agent: [K+]
Agent: c1ccc([P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Solvent: CC#N
Product: Cc1cc([N+](=O)[O-])cnc1F
Yield: 61.9 %

Procedure:
2-Chloro-3-methyl-5-nitropyridine (15 g, 86.9 mmol; from Maybridge Chemical Co.), KF (12 g, 258 mmol) and tetraphenylphosphonium bromide (20 g, 47.7 mmol; Aldrich) were combined in 200 mL of acetonitrile and heated at reflux for 4 days. The mixture was diluted with Et2O (500 mL) and filtered, and the filtrate was concentrated. The residue was triturated with hot hexane (4×200 mL), and the hexane solutions were combined and concentrated to afford the title compound as a solid (8.4 g, 60%): 1H NMR (DMSO-d6, 300 MHz) δ2.42 (s, 3H), 8.43 (m, 1H), 8.95 (dd, J=1.6 Hz, 1H); MS (CI/NH3) m/z: 157 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](Br)[CH:6]=[CH:7][CH:8]=1.[CH3:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[NH:16][C:15](=[O:20])[C:14]2=[O:21]>>[OH:21][C:14]1([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=2)[C:13]2[C:17](=[CH:18][CH:19]=[C:11]([CH3:10])[CH:12]=2)[NH:16][C:15]1=[O:20]
Reactant: Cc1ccc2c(c1)C(=O)C(=O)N2
Reactant: COc1cccc(Br)c1
Product: COc1cccc(C2(O)C(=O)Nc3ccc(C)cc32)c1
Yield: 94.3 %

Procedure:
With 5.61 g of 3-methoxy bromobenzene and 3.23 g of 5-methyl isatin as starting materials, 5.09 g of the title compound was obtained by a similar method to Step 21-1.
Reaction SMILES: Cl.[O:2]=[C:3]1[NH:12][C:11]2[N:10]=[CH:9][C:8](/[CH:13]=[CH:14]/[C:15]([OH:17])=O)=[CH:7][C:6]=2[CH2:5][CH2:4]1.Cl.[O:19]([CH:26]1[CH2:29][NH:28][CH2:27]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C>CN(C=O)C>[O:17]=[C:15]([N:28]1[CH2:27][CH:26]([O:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:29]1)/[CH:14]=[CH:13]/[C:8]1[CH:7]=[C:6]2[C:11](=[N:10][CH:9]=1)[NH:12][C:3](=[O:2])[CH2:4][CH2:5]2
Reactant: c1ccc(OC2CNC2)cc1
Reactant: O=C(O)/C=C/c1cnc2c(c1)CCC(=O)N2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C1CCc2cc(/C=C/C(=O)N3CC(Oc4ccccc4)C3)cnc2N1
Temperature: 25 °C
Reaction time: 8 h
Yield: 35.8 %

Procedure:
A 16 mL vial flask was successively charged with (2E)-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylic acid hydrochloride (30 mg, 0.12 mmol), DMF (3 mL), 3-phenoxyazetidine hydrochloride (26 mg, 0.14 mmol; which may be prepared as described in Step 3), DIPEA (48 μL, 0.28 mmol) and EDAC (27 mg, 0.14 mmol). The reaction mixture was stirred at room temperature overnight and concentrated to dryness. The residue was purified on preparative TLC (eluent: dichloromethane/NH3 7N in MeOH, 2.5%) to give a pale yellow solid. This solid was triturated in acetone, filtered, washed with acetone and diethyl ether then dried to give the title compound (15 mg, 36%) as a white solid.
Reaction SMILES: [C:1]([NH:4][CH2:5][CH2:6][C:7]1[N:16]=[C:15]([C:17]([OH:19])=O)[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]=1)(=[O:3])[CH3:2].Cl.[OH:21][C:22]1[C:31]([O:32][CH3:33])=[CH:30][CH:29]=[C:28]2[C:23]=1[CH2:24][CH2:25][NH:26][CH2:27]2>>[C:1]([NH:4][CH2:5][CH2:6][C:7]1[N:16]=[C:15]([C:17]([N:26]2[CH2:25][CH2:24][C:23]3[C:28](=[CH:29][CH:30]=[C:31]([O:32][CH3:33])[C:22]=3[OH:21])[CH2:27]2)=[O:19])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)NCCc1nc(C(=O)O)c2ccccc2n1
Reactant: COc1ccc2c(c1O)CCNC2
Agent: Cl
Product: COc1ccc2c(c1O)CCN(C(=O)c1nc(CCNC(C)=O)nc3ccccc13)C2
Yield: 30 %

Procedure:
Reaction of 2-(2-(acetamido)ethyl)quinazoline-4-carboxylic acid with 5-hydroxy-6-methoxy-1,2,3,4-tetrahydroisoquinoline hydrochloride gave compound 74 (30% yield) as a light yellow solid. 1H NMR (300 MHz, DMSO-d6) δ 1.74 (d, 3H), 2.60 and 2.86 (2t, 2H), 3.16 (t, 2H), 3.44 and 3.98 (2t, 2H), 3.59 (t, 2H), 3.73 and 3.79 (2s, 3H), 4.33 and 4.87 (2s, 2H), 6.32-6.91 (m, 2H), 7.65-7.75 (m, 1H), 7.82-7.92 (m, 2H), 8.01-8.05 (m, 2H), 8.66-8.70 (m, 1H); MS (ESI) m/z 421 ([M+H]+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[CH3:9].C(N(CC)CC)C.[C:17](Cl)(=[O:19])[CH3:18]>C(Cl)Cl>[C:17]([O:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[C:3]([CH3:9])[CH:4]=1)(=[O:19])[CH3:18]
Reactant: CC(=O)Cl
Reactant: Cc1cc(O)ccc1F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)Oc1ccc(F)c(C)c1
Reaction time: 1 h
Yield: 100.8 %

Procedure:
A solution of 4-fluoro-3-methylphenol (3.0 g, 23 mmol) and methylene chloride (96 mL) was cooled to 0° C. in an ice bath. Triethylamine (4.9 mL, 35 mmol) was introduced to the solution followed by dropwise addition of acetyl chloride (2.3 mL, 33 mmol). The ice bath was removed and the mixture was stirred for 1 hour. The mixture was then extracted with methylene chloride and washed with 0.5 N HCl, saturated sodium bicarbonate and brine. The extracts were dried over sodium sulfate, filtered and evaporated to give 4-fluoro-3-methylphenyl acetate (3.9 g, quantitative). 1H NMR (400 MHz, CDCl3): δ 7.00 (m, 1H), 6.87 (m, 2H), 2.29 (m, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]#[N:19])[CH:13]=2)=[C:6]([CH:10]=1)[C:7]([OH:9])=O.Cl.[NH2:21][C@H:22]([C:24]1[CH:33]=[CH:32][C:27]([C:28]([O:30][CH3:31])=[O:29])=[CH:26][CH:25]=1)[CH3:23]>>[Cl:1][C:2]1[CH:10]=[C:6]([C:7]([NH:21][C@H:22]([C:24]2[CH:33]=[CH:32][C:27]([C:28]([O:30][CH3:31])=[O:29])=[CH:26][CH:25]=2)[CH3:23])=[O:9])[C:5]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]#[N:19])[CH:13]=2)=[N:4][CH:3]=1
Reactant: COC(=O)c1ccc([C@H](C)N)cc1
Reactant: N#Cc1cccc(Cc2ncc(Cl)cc2C(=O)O)c1
Agent: Cl
Product: COC(=O)c1ccc([C@H](C)NC(=O)c2cc(Cl)cnc2Cc2cccc(C#N)c2)cc1

Procedure:
The title compound was prepared according to the procedure described in step 3 of Example 1 from 5-chloro-2-(3-cyanobenzyl)nicotinic acid (step 2) and methyl 4-[(1S)-1-aminoethyl]benzoate hydrochloride (step 3 of Example 5): 1H-NMR (CDCl3) δ 8.58 (1H, d, J=2.4 Hz), 8.05–8.02 (2H, m), 7.66 (1H, d, J=2.4 Hz), 7.50–7.27 (6H, m), 6.01 (1H, d, J=8.1 Hz), 5.32–5.23 (1H, m), 4.30 (2H, s), 3.93 (3H, s), 1.54 (3H, d, J=7.0 Hz); MS (ESI) m/z 432 (M−H)−.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH2:10])[C:6]([NH2:9])=[CH:7][CH:8]=1.[C:11]1([CH2:17][N:18]2[CH2:23][CH2:22][O:21][CH:20]([C:24](O)=O)[CH2:19]2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[OH-].[Na+]>Cl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]2[NH:9][C:24]([CH:20]3[O:21][CH2:22][CH2:23][N:18]([CH2:17][C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)[CH2:19]3)=[N:10][C:5]=2[CH:4]=1
Reactant: COc1ccc(N)c(N)c1
Reactant: O=C(O)C1CN(Cc2ccccc2)CCO1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: COc1ccc2[nH]c(C3CN(Cc4ccccc4)CCO3)nc2c1
Yield: 78.3 %

Procedure:
A solution of 4-methoxybenzene-1,2-diamine (0.5 g, 2.369 mmol) and 4-(phenylmethyl)-2-morpholinecarboxylic acid (1.221 g, 4.74 mmol) in 6N HCl (10 mL) was stirred at 105° C. overnight. The reaction mixture was neutralized with aqueous NaOH and partitioned between EtOAc (50 mL) and water (50 mL). The organic phase was washed with water (50 mL), dried (MgSO4), and evaporated in vacuo to give the crude product as a black oil. The crude product was added to a silica gel column and was eluted with 90:10 CH2Cl2/CH3OH to afford the title compound (0.6 g). LC-MS (ES) m/z=324 [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[CH2:22][C:23]1[C:24]([CH3:29])=[N:25][O:26][C:27]=1[CH3:28]>>[CH3:29][C:24]1[C:23]([CH2:22][N:15]2[CH2:16][C:17](=[O:18])[N:13]([C:11]3[CH:10]=[N:9][N:8]([CH2:7][C:6]4[C:2]([CH3:1])=[N:3][O:4][C:5]=4[CH3:20])[CH:12]=3)[C:14]2=[O:19])=[C:27]([CH3:28])[O:26][N:25]=1
Reactant: Cc1noc(C)c1Cn1cc(N2C(=O)CNC2=O)cn1
Reactant: Cc1noc(C)c1CCl
Product: Cc1noc(C)c1CN1CC(=O)N(c2cnn(Cc3c(C)noc3C)c2)C1=O
Yield: 50 %

Procedure:
Prepared as in Example 10-5 from 3-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)imidazolidine-2,4-dione and 4-(chloromethyl)-3,5-dimethylisoxazole. Yield: 50%. 1H NMR (CDCl3, 400 MHz): 2.19 (s, 3H), 2.27 (s, 3H), 2.43-2.42 (d, J=5.2 Hz, 6H), 3.82 (s, 2H), 4.40 (s, 2H), 5.05 (s, 2H), 7.92 (s, 1H), 8.05 (s, 1H). The title compound was shown to inhibit hT2R08 bitter receptor and had an IC50 of 0.04 μM.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH:10]=[N:11][NH:12]3)[N:5]=[C:4]2[N:17]([CH3:20])[N:18]=[CH:19][C:3]=12.[CH3:21][NH:22][C:23]([C:25]1[CH:26]=[C:27](B(O)O)[CH:28]=[CH:29][CH:30]=1)=[O:24].C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH:12]1[C:13]2[C:9](=[C:8]([C:6]3[N:5]=[C:4]4[N:17]([CH3:20])[N:18]=[CH:19][C:3]4=[C:2]([C:29]4[CH:30]=[C:25]([CH:26]=[CH:27][CH:28]=4)[C:23]([NH:22][CH3:21])=[O:24])[CH:7]=3)[CH:16]=[CH:15][CH:14]=2)[CH:10]=[N:11]1
Reactant: CNC(=O)c1cccc(B(O)O)c1
Reactant: Cn1ncc2c(Cl)cc(-c3cccc4[nH]ncc34)nc21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: CNC(=O)c1cccc(-c2cc(-c3cccc4[nH]ncc34)nc3c2cnn3C)c1
Temperature: 130 °C

Procedure:
4-Chloro-6-(1H-indazol-4-yl)-1-methyl-1H-pyrazolo[3,4-b]pyridine 7 (80 mg, 0.28 mmol) and 3-(N-methylaminocarbonyl)phenyl boronic acid (1.4 equiv.) were suspended in 2 ml acetonitrile. Sodium carbonate (3 equiv., 92 mg) and bis(triphenylphosphine)palladium(II) chloride (0.05 equiv.) were added as a solution in water (0.5 ml). The reaction mixture was heated in microwave at 130° C. for 20 min. Water was added to the mixture, and the precipitated product was filtered and purified by column chromatography to yield 111. NMR (CDCl3): 3.11 (3H, d), 4.34 (3H, s), 6.25 (1H, br), 7.56 (1H, m), 7.63-7.70 (2H, m), 7.84 (1H, d), 7.87 (1H, s), 7.90 (1H, d), 8.00 (1H, d), 8.21 (1H, s), 8.27 (1H, s), 8.97 (1H, s). MS: MH+ 383.09 (100%)
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:20]=[CH:19][C:7]([C:8]([NH:10][C:11]2([C:14]([O:16]CC)=[O:15])[CH2:13][CH2:12]2)=[O:9])=[CH:6][CH:5]=1)[CH3:2].[OH-].[Li+]>O1CCOCC1.O>[CH2:1]([O:3][C:4]1[CH:5]=[CH:6][C:7]([C:8]([NH:10][C:11]2([C:14]([OH:16])=[O:15])[CH2:12][CH2:13]2)=[O:9])=[CH:19][CH:20]=1)[CH3:2]
Reactant: CCOC(=O)C1(NC(=O)c2ccc(OCC)cc2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CCOc1ccc(C(=O)NC2(C(=O)O)CC2)cc1
Yield: 73.3 %

Procedure:
Dissolve ethyl 1-[(4-ethoxybenzoyl)amino]cyclopropanecarboxylate (4.25 g, 15.33 mmol) in 1,4-dioxane (60 mL) and add lithium hydroxide (LiOH) (3.22 g, 76.63 mmol) dissolved in water (30 mL). Stir the reaction for approximately 16 hours at ambient temperature. Concentrate the mixture under reduced pressure, add water, acidify with 5N HCl, and collect the precipitate by filtration to give the title compound (2.8 g, 73%) as a white solid: MS (m/z): 248 (M+1).
Reaction SMILES: Cl.[CH3:2][NH:3][O:4][CH3:5].CCN(CC)CC.[Br:13][C:14]1[CH:15]=[C:16]([CH:20]=[C:21]([C:23]([O:25][CH3:26])=[O:24])[CH:22]=1)[C:17]([OH:19])=O.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>C(Cl)Cl>[Br:13][C:14]1[CH:22]=[C:21]([CH:20]=[C:16]([C:17](=[O:19])[N:3]([O:4][CH3:5])[CH3:2])[CH:15]=1)[C:23]([O:25][CH3:26])=[O:24]
Reactant: COC(=O)c1cc(Br)cc(C(=O)O)c1
Reactant: CNOC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1cc(Br)cc(C(=O)N(C)OC)c1
Reaction time: 0.5 h
Yield: 77.4 %

Procedure:
N,O-Dimethylhydroxylamine hydrochloride (1.15 g, 11.8 mmol) was dissolved in CH2Cl2 (50 mL) and Et3N (4.8 mL, 34.4 mmol) was added. The solution was stirred for 30 min. The resultant solution was cooled to 0° C. and compound 3-bromo-5-(methoxycarbonyl)benzoic acid (2.55 g, 9.84 mmol) was added followed by EDC.HCl (3.77 g, 19.6 mmol) and HOBt (0.26 g, 1.96 mmol). The reaction mixture was allowed to come to room temperature and stirred for another 4 h. After completion, the reaction mixture was diluted with CH2Cl2. The organic layer was washed with water and brine solution and dried over anhydrous sodium sulfate. Solvent was removed under reduced pressure and the crude product was purified by column chromatography (silica 60-120 mesh, eluent 20% EtOAc in petroleum ether) to get methyl 3-bromo-5-(methoxy(methyl)carbamoyl)benzoate (2.3 g, yield 77%) as colorless liquid. 1H NMR (400 MHz, CDCl3) δ 8.29 (m, 1H), 8.27 (t, J=1.8 Hz, 1H), 8.02 (t, J=1.6 Hz, 1H), 3.95 (s, 3H), 3.57 (s, 3H), 3.39 (s, 3H). MS (ESI) m/z: Calculated for C11H12BrNO4: 300.99. found: 302.0 (M+H)+.
Reaction SMILES: [C:1]([NH2:5])(=[S:4])[CH2:2][CH3:3].Br[CH:7]([C:18]1[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=1)[C:8]([C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=1)=O.C(N(CC)CC)C>C(#N)C>[CH2:2]([C:1]1[S:4][C:7]([C:18]2[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=2)=[C:8]([C:10]2[CH:11]=[CH:12][C:13]([O:16][CH3:17])=[CH:14][CH:15]=2)[N:5]=1)[CH3:3]
Reactant: COc1ccc(C(=O)C(Br)c2cccnc2)cc1
Reactant: CCC(N)=S
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCc1nc(-c2ccc(OC)cc2)c(-c2cccnc2)s1
Yield: 84.2 %

Procedure:
In 40 ml of acetonitrile was dissolved 493 mg of thiopropionic acid amide. In the solution was suspended 2.15 g of 2-bromo-1-(4-methoxyphenyl)-2-(3-pyridyl)ethanone. To the suspension was added dropwise slowly 0.78 ml of triethylamine while stirring. The mixture was stirred for 3 hours at a refluxing temperature, then the solvent was evaporated off. To the residue was added a saturated aqueous solution of sodium hydrogen carbonate. The mixture was subjected to extraction with ethyl acetate. The extract was dried, then the solvent was evaporated off. The residue was recrystallised from ethyl acetate-isopropyl ether to yield 1.38 g (91%) of 2-ethyl-4-(4-methoxyphenyl)-5-(3-pyridyl)-1,3-thiazole, m.p. 59°-60° C.
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:9][CH2:10][CH2:11]Br)(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2].CN(C=[O:17])C>>[CH2:1]([O:3][P:4]([CH2:9][CH2:10][CH2:11][OH:17])(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2]
Reactant: CN(C)C=O
Reactant: CCOP(=O)(CCCBr)OCC
Product: CCOP(=O)(CCCO)OCC

Procedure:
Diethyl-3-hydroxypropylphosphonate (steps 1 and 2) is prepared from diethyl-3-bromopropylphosphonate. Diethyl-3-bromopropylphosphonate (12.0 g, 46 mmol), prepared by the method of Eberhard, A., et al, J Am Chem Soc (1965) 87:253-260) was stirred with 12.0 g NaOAc.3H2O in 125 ml DMF heated in a steam bath. The reaction was evaporated to dryness in vacuo after 2 hours and partitioned between H2O and EtOAc. extracting the aqueous layer five times. The ethyl acetate extract was washed once with brine, dried with Na2SO4, filtered, and evaporated to dryness in vacuo to yield 9.8 g light yellow oil (89%). 1H NMR (CDCl3) δ1.3 (tr, 6 H), 1.5-2.0 (m, 4 H), 2.03 (s, 3 H), 4.1 (dq, 6 H): thin-layer chromatography on SiGF developed with 2:1 EtOAc:CH2Cl2 gave Rf 0.30. The isolated diethyl-3-acetoxypropylphosphonate (9.8 g, 41 mmol) in 200 ml abs. EtOH was stirred with 30 ml Dowex 50 (H+) which had been rinsed three times each with H2O and EtOH. After 41/2 days at room temperature, another 10 ml of similarly prepared resin was added. Six hours later, the reaction was filtered and evaporated in vacuo. The quantitative yield of yellow oil was purified by dry column chromatography on 400 g silica packed in a 2.75-inch flat diameter nylon tube. The column was eluted with 1:9 MeOH:EtOAc and the appropriate fractions were cut and slurried with 1:1 MeOH:EtOAc. Filtration and evaporation in vacuo afforded 5.33 g (66%) pale yellow oil, which is the diethyl ester of 3-hydroxypropyl phosphonic acid. 1H NMR (CDCl3, D2O): δ1.3 (tr, 6 H), 1.6-2.08 (m, 4 H), 3.67 (tr. 2 H), 4.13 (dq. 4 H); thin-layer chromatography on SiGF developed with 1:9 MeOH:EtOAc gave an Rf of 0.57.