Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][C:12]([C:15]1[N:19]([CH3:20])[C:18]([C:21]2[CH:26]=[CH:25][C:24](F)=[CH:23][C:22]=2[C:28]([F:31])([F:30])[F:29])=[N:17][N:16]=1)([CH3:14])[CH3:13])[C:5]([NH2:7])=[O:6].[CH3:32][S-:33].[Na+].O>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][C:12]([CH3:14])([C:15]1[N:19]([CH3:20])[C:18]([C:21]2[CH:26]=[CH:25][C:24]([S:33][CH3:32])=[CH:23][C:22]=2[C:28]([F:31])([F:30])[F:29])=[N:17][N:16]=1)[CH3:13])[C:5]([NH2:7])=[O:6]
Reactant: C[S-]
Reactant: Cn1c(-c2ccc(F)cc2C(F)(F)F)nnc1C(C)(C)Oc1ccc(C(N)=O)cc1Br
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CSc1ccc(-c2nnc(C(C)(C)Oc3ccc(C(N)=O)cc3Br)n2C)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 51.4 %

Procedure:
3-bromo-4-(1-{5-[4-fluoro-2-(trifluoromethyl)phenyl]-4-methyl-4H-1,2,4-triazol-3-yl}-1-methylethoxy}benzamide (300 mg) was dissolved in DMF (6 ml), and sodium thiomethoxide (210 mg) was added thereto, followed by stirring at room temperature for 30 minutes. Water was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting solid was washed with ethyl acetate to obtain, as a white solid, 3-bromo-4-(1-methyl-1-{4-methyl-5-[4-(methylsulfanyl)-2-(trifluoromethyl)phenyl)-4H-1,2,4-triazol-3-yl}ethoxy]benzamide (163 mg).
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C:8]1[N:9]=[N:10][S:11][CH:12]=1)[C:5]([OH:7])=O.[NH2:13][CH:14]1[C:32](=[O:33])[N:16]2[C:17]([C:29]([OH:31])=[O:30])=[C:18]([CH2:21][S:22][C:23]3[N:27]([CH3:28])[N:26]=[N:25][N:24]=3)[CH2:19][S:20][C@H:15]12>>[CH3:1][O:2][N:3]=[C:4]([C:8]1[N:9]=[N:10][S:11][CH:12]=1)[C:5]([NH:13][CH:14]1[C:32](=[O:33])[N:16]2[C:17]([C:29]([OH:31])=[O:30])=[C:18]([CH2:21][S:22][C:23]3[N:27]([CH3:28])[N:26]=[N:25][N:24]=3)[CH2:19][S:20][C@H:15]12)=[O:7]
Reactant: Cn1nnnc1SCC1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Reactant: CON=C(C(=O)O)c1csnn1
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(CSc3nnnn3C)CS[C@H]12)c1csnn1
Yield: 56.4 %

Procedure:
2-Methoxyimino-2-(1,2,3-thiadiazol-4-yl)acetic acid (anti isomer) (1 g.) and 7-amino-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (1.9 g.) were reacted according to similar manners to those of Examples 1(b) and 8 to give pale yellow powder of 7-[2-methoxyimino-2-(1,2,3-thiadiazol-4-yl)acetamido]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (anti isomer) (1.5 g.).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:10])[CH:5]=[C:6]([CH3:9])[C:7]=1[CH3:8].[CH3:11][C:12](=[CH2:15])[CH2:13]O.C(O)=O>C(OC(C)C)(C)C>[CH3:11][C:12]1([CH3:15])[CH2:13][C:3]2[C:2]([CH3:1])=[C:7]([CH3:8])[C:6]([CH3:9])=[CH:5][C:4]=2[O:10]1
Reactant: C=C(C)CO
Reactant: Cc1cc(O)cc(C)c1C
Solvent: O=CO
Solvent: CC(C)OC(C)C
Product: Cc1cc2c(c(C)c1C)CC(C)(C)O2
Yield: 41.5 %

Procedure:
3,4,5-Trimethylphenol (5.0 g, 36.7 mmol) and 2-methyl-2-propenol (3.2 g, 44.0 mmol) were added to formic acid (50 ml). The mixture was heated under reflux for 3 hours. The reaction mixture was diluted with isopropyl ether, washed with water and saturated sodium bicarbonate solution, dried and concentrated. The residue was purified by column chromatography on silica gel (hexane-isopropyl ether, 97:3) to obtain the desired compound (2.9 g, yield: 41.5%) as oil.
Reaction SMILES: [CH2:1]([NH:4][C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8])[CH:2]=[CH2:3].[CH2:12]=[CH:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]CC>>[CH2:1]([NH:4][C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8])/[CH:2]=[CH:3]\[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH3:12]
Reactant: C=CCCCCCCCCCCCCCC
Reactant: C=CCNC(=O)OC(C)(C)C
Product: CCCCCCCCCCCCCC/C=C\CNC(=O)OC(C)(C)C
Reaction time: 1 h
Yield: 82.1 %

Procedure:
Following the allylic amide CM general procedure, tert-butyl allylcarbamate (4.40 mg, 0.0280 mmol) was treated with 1-hexadecene (64.5 mg, 0.290 mmol), 5.0 mol % of in situ-generated complex 2 (75.0 μL, 0.02 M, 1.50 μmol), and allowed to stir under vacuum for 1 h. Z-selectivity could not be determined from 400 MHz 1H NMR spectrum of unpurified product. The resulting brown oil was purified by silica gel chromatography (96:2:2 hexanes:EtOAc:CH2Cl2) to afford 19f (8.30 mg, 0.0230 mmol, 84.0% yield, 81% Z isomer) as a white, crystalline solid. M.P. 42-46° C.; IR (neat): 3353 (br), 2922 (s), 2853 (s), 1700 (s), 1501 (m), 1457 (m), 1390 (m), 1365 (m), 1247 (m), 1170 (s), 1046 (w), 1023 (w); 1H NMR (400 MHz, CDCI3): 5.60-5.34 (overlapping Z/E 2H, m), 4.45 (overlapping Z/E, 1H, br d, J=15.6 Hz), 3.74 (E, 1H, br s), 3.66 (Z, 1H, br s), 2.06-1.96 (overlapping Z/E, 2H, m), 1.43 (overlapping Z/E, 9H, s), 1.41-1.24 (overlapping Z/E, 24H, m), 0.86 (overlapping Z/E, 3H, t, J=7.8 Hz); 13C NMR (100 MHz, CDCl3): 156.0, 155.9, 133.4, 126.3, 125.9, 79.4, 77.4, 32.4, 32.1, 29.9, 29.8 29.8, 29.8, 29.7, 29.7, 29.5, 29.4, 29.3, 28.6, 27.5, 22.8, 19.2, 14.3; HRMS (ESI+) [M+Na]+ calcd for C22H43NO2Na: 376.3191, found: 376.3184.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].[F:11][C:12]([F:16])([F:15])[CH2:13]O.S(=O)(=O)(O)O>>[OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([O:7][CH2:13][C:12]([F:16])([F:15])[F:11])=[O:6]
Reactant: OCC(F)(F)F
Reactant: O=C(O)c1cccc(O)c1
Agent: O=S(=O)(O)O
Product: O=C(OCC(F)(F)F)c1cccc(O)c1
Temperature: 95 °C

Procedure:
Into a 250 mL round bottom flask equipped with magnetic stirrer and heating mantle was added 10 parts of 3-hydroxy benzoic acid, 100 parts of 2,2,2-trifluoroethanol and 0.5 parts of concentrated sulfuric acid. The reaction mixture was heated at 95° C. for 48 hours. The solvent was evaporated under reduced pressure and the solid material was dissolved in 250 mL of ethyl acetate. The organic layer was washed with 250 mL of water, 250 mL 5% solution of sodium bicarbonate in 100 mL of water and finally with 250 mL of water. The ethyl acetate layer was dried over anhydrous sodium sulfate and the solvent was evaporated under reduced pressure, yield 4.1 parts. TLC on silica gel plate showed a single spot. The structure was confirmed on the basis of 1H NMR. The reaction proceeded as follows:
Reaction SMILES: [C:1]([C:4]12[CH2:13][CH:8]([C:9]([CH3:12])=[CH:10][CH2:11]1)[C:7](=[O:14])[CH2:6][CH:5]2[CH3:15])([CH3:3])=[CH2:2].[CH2:16](O)[CH2:17][OH:18].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C([O-])(O)=O.[Na+]>C1CCCCC1>[CH3:15][CH:5]1[C:4]2([C:1]([CH3:3])=[CH2:2])[CH2:13][CH:8]([CH:9]([CH3:12])[CH2:10][CH2:11]2)[C:7]2([O:18][CH2:17][CH2:16][O:14]2)[CH2:6]1
Reactant: C=C(C)C12CC=C(C)C(C1)C(=O)CC2C
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCCCC1
Solvent: O
Product: C=C(C)C12CCC(C)C(C1)C1(CC2C)OCCO1
Yield: 104.7 %

Procedure:
A soln. of 2.0 g of 5-isopropenyl-4,8-dimethylbicyclo[3.3.1]non-7-en-2-one (9.8 mmol) in 100 ml cyclohexane was treated with 1.8 g ethyleneglycol (2.9 mmol, 3.0 eq.) and 0.2 g para-toluenesulfonic acid mono hydrate (1.0 mmol 0.1 eq.). The soln. obtained was heated at reflux for 3 h (Dean-Stark apparatus), cooled and poured into aq. sat. NaHCO3 soln. (100 ml). Extraction with MTBE (2×80 ml) followed by washing of the aq. phases with H2O (100 ml) and aq. sat. NaCl soln. (150 ml), drying of org. phases over MgSO4 led to 2.6 g of crude product. FC (SiO2, hexane/MTBE 19:1) gave 0.76 g (31%) of compound 6 as colorless liquid. The boiling point of the end product is 130° C. at 0.09 mbar. Rf (hexane/MTBE 19:1) 0.47.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]#[N:9])[CH:5]=[CH:4][N:3]=1.C([O-])([O-])=O.[Na+].[Na+].[NH2:16][C:17]1[N:22]=[CH:21][C:20]([C:23]2[CH:28]=[CH:27][C:26]([N:29]3[C@@H:33]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)[C:32]([CH3:41])([CH3:40])[O:31][C:30]3=[O:42])=[CH:25][CH:24]=2)=[CH:19][C:18]=1B1OC(C)(C)C(C)(C)O1>O1CCOCC1>[NH2:16][C:17]1[C:18]([C:2]2[N:7]=[C:6]([C:8]#[N:9])[CH:5]=[CH:4][N:3]=2)=[CH:19][C:20]([C:23]2[CH:24]=[CH:25][C:26]([N:29]3[C@@H:33]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)[C:32]([CH3:40])([CH3:41])[O:31][C:30]3=[O:42])=[CH:27][CH:28]=2)=[CH:21][N:22]=1
Reactant: N#Cc1ccnc(Cl)n1
Reactant: CC1(C)OC(=O)N(c2ccc(-c3cnc(N)c(B4OC(C)(C)C(C)(C)O4)c3)cc2)[C@H]1c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CC1(C)OC(=O)N(c2ccc(-c3cnc(N)c(-c4nccc(C#N)n4)c3)cc2)[C@H]1c1ccccc1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
2-Chloropyrimidine-4-carbonitrile (22.42 mg, 0.161 mmol), Na2CO3 (134 μL, 0.268 mmol), (S)-3-(4-(6-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)phenyl)-5,5-dimethyl-4-phenyloxazolidin-2-one (65 mg, 0.134 mmol), and dichloro(1,1-bis(diphenylphosphinoferrocene))palladium(II) (10.94 mg, 0.013 mmol) were combined in dioxane (268 μL) and stirred at 100° C. in a microwave oven for 1 hour. LC-MS indicated good conversion to desired product. After cooling to room temperature, the reaction mixture was absorbed onto a plug of silica gel and purified by chromatography through a Redi-Sep pre-packed silica gel column (12 g), eluting with a gradient of 0% to 10% MeOH in DCM, to provide (S)-2-(2-amino-5-(4-(5,5-dimethyl-2-oxo-4-phenyloxazolidin-3-yl)phenyl)pyridin-3-yl)pyrimidine-4-carbonitrile as yellow solid. 1H NMR (500 MHz, DMSO-d6) δ 10.56 (s, 1H), 8.83 (d, J=4.70 Hz, 1H), 8.59 (d, J=2.67 Hz, 1H), 8.13 (d, J=8.44 Hz, 1H), 8.06 (dd, J=2.14, 6.30 Hz, 1H), 7.66 (d, J=8.66 Hz, 2H), 7.58 (d, J=8.87 Hz, 2H), 7.49 (d, J=4.49 Hz, 1H), 7.35-7.42 (m, 2H), 7.23-7.35 (m, 3H), 5.49 (s, 1H), 1.66 (s, 3H), 0.92 (s, 3H). m/z (ESI) 463.8 (M+H)+.
Reaction SMILES: [C@@H:1]1([N:10]2[CH:17]=[CH:16][C:14]([NH2:15])=[N:13][C:11]2=[O:12])[O:9][C@H:6]([CH2:7][OH:8])[C@@H:4]([OH:5])[C@H:2]1[OH:3].[H-].[Na+].I[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]>CN(C=O)C>[CH2:21]([O:3][C@@H:2]1[C@H:4]([OH:5])[C@@H:6]([CH2:7][OH:8])[O:9][C@H:1]1[N:10]1[CH:17]=[CH:16][C:14]([NH2:15])=[N:13][C:11]1=[O:12])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]
Reactant: CCCCCCCCCI
Reactant: Nc1ccn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c(=O)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCCCCCCO[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1n1ccc(N)nc1=O

Procedure:
Cytidine (10.1 g, 0.0415 mol), sodium hydride (2.0 g, 1.2 eq), iodononane (9.8 ml, 1.2 eq.) in DMF (100 ml) were reacted as per the procedure of Example 71, Step 1 to yield the 2' and 3' isomers as a sticky foam (11.6 g).
Reaction SMILES: [Na].Cl.[Br:3][C:4]1[CH:12]=[CH:11][C:7]([C:8]([NH2:10])=[NH:9])=[CH:6][CH:5]=1.C([O:15][C:16](=O)[CH:17]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:18](O)=[O:19])C>CO>[Br:3][C:4]1[CH:12]=[CH:11][C:7]([C:8]2[N:10]=[C:18]([OH:19])[C:17]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[C:16]([OH:15])[N:9]=2)=[CH:6][CH:5]=1
Reactant: CCOC(=O)C(C(=O)O)c1ccccc1
Reactant: N=C(N)c1ccc(Br)cc1
Agent: Cl
Agent: [Na]
Solvent: CO
Product: Oc1nc(-c2ccc(Br)cc2)nc(O)c1-c1ccccc1
Temperature: 80 °C

Procedure:
Into a solution of 3.45 g (150 mmol) of sodium in 100 ml methanol, here were sequentially added 10.98 g (47 mmol) 4-bromobenzamidine hydrochloride and 11.15 g (47 mmol) of phenyl malonic acid ethyl ester. The mixture was heated for 12 hours at 80° C. The deep yellow reaction solution was filtered to remove the precipitated sodium chloride and thereafter the pyrimidine was precipitated with 10 ml of 2 molar hydrochloric acid as an intensive yellow solid. The solid was sequentially washed with water, ethanol and diethyl ether. Yield: 12.70 g (37 mmol, 79% theory) of yellow solid. The pyrimidine is insoluble in all tested organic solvents as well as in water. m.p. greater >230° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:16]([C@@H:17]([CH3:21])[C:18]([OH:20])=O)[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.[C:22](N1C=CN=C1)([N:24]1C=CN=C1)=O.CN>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:16]([C@@H:17]([CH3:21])[C:18]([NH:24][CH3:22])=[O:20])[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:6][CH:7]=1
Reactant: C[C@@H](C(=O)O)n1c(-c2ccc(Cl)cc2)nc2cccnc21
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: CN
Solvent: C1CCOC1
Product: CNC(=O)[C@H](C)n1c(-c2ccc(Cl)cc2)nc2cccnc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 27.5 %

Procedure:
A solution of (S)-2-(4-chlorophenyl)-α-methyl-3H-imidazo [4,5-b]pyridine-3-acetic acid (3.0 g, 0.00995 mole), 1,1'-carbonyldiimidazole (1.61 g, 0.00995 mole) and dry tetrahydrofuran (60 ml) was stirred at room temperature for 1.75 hours with a stream of nitrogen bubbling through it. A solution of methylamine in tetrahydrofuran (20 ml of a 3.03M solution, 0.060 mole) was added and the reaction mixture was stirred at room temperature overnight under nitrogen. The solvents were removed under reduced pressure and the resulting solid was triturated in water, collected by filtration, rinsed twice with water, twice with 5% potassium hydroxide solution, and twice again with water. The solid was dissolved in hot isopropyl alcohol and filtered hot. Upon cooling to room temperature, solid precipitated which was collected by filtration and dried under high vacuum at 50° C. overnight to give 0.86 g (28%) of title compound, mp 218°-220° C.
Reaction SMILES: [CH2:1]([NH:13][CH2:14][CH2:15][NH2:16])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[CH:17]([CH:19]([CH3:25])[C:20](OCC)=O)=[O:18]>>[CH2:1]([N:13]1[C:17](=[O:18])[CH:19]([CH3:25])[CH:20]=[N:16][CH2:15][CH2:14]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCOC(=O)C(C)C=O
Reactant: CCCCCCCCCCCCNCCN
Product: CCCCCCCCCCCCN1CCN=CC(C)C1=O

Procedure:
Into an apparatus similar to that in Example 1, were charged 228.1 g (1 mole) of N-dodecylethylenediamine and 130.1 g (1 mole) of ethyl 2-formylpropionate. At 140° to 145° C., 18 g of water and 46 g of ethanol were distilled off to obtain 4-dodecyl-6-methyl-3,6-dihydro-2H-1,4-diazepin-5-one.
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7]([CH3:9])[CH:6]=[CH:5][C:3]=1[NH2:4].C([O:12][CH:13]=[C:14]([C:20](OCC)=O)[C:15]([O:17][CH2:18][CH3:19])=[O:16])C.C1(OC2C=CC=CC=2)C=CC=CC=1>C(O)C>[F:1][C:2]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]2[C:3]=1[N:4]=[CH:20][C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]2[OH:12]
Reactant: Cc1ccc(N)c(F)c1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: CCO
Product: CCOC(=O)c1cnc2c(F)cc(C)cc2c1O
Temperature: 75 °C
Yield: 55.9 %

Procedure:
A mixture of 2-fluoro-4-methylaniline (5.0 g) and diethyl ethoxymethylene-malonate (8.64 g) is heated to 130° C. for 2 h with removal of ethanol by a Dean-Stark trap. The mixture is cooled to 75° C. and diphenyl ether (50 mL) is added. The solution is heated to 250° C. for 2 h with removal of ethanol by a Dean-Stark trap, then cooled to room temperature. The resulting solid is collected, washed with hexanes and dried to yield 5.564 g of ethyl 8-fluoro-4-hydroxy-6-methylquinoline-3-carboxylate. A mixture of this ester (0.50 g) and 4-chlorobenzylamine (3.0 mL) are heated at 180° C. for 1 hour. The reaction is cooled and poured into 50 mL of diethyl ether. The resulting solid is filtered, dried, and purified by trituration in acetone to give the desired product (0.54 g).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[C:4]([CH3:12])[N:3]=1.[C:13]([NH2:17])(=[O:16])[CH2:14][CH3:15]>>[CH3:12][C:4]1[N:3]=[C:2]([NH:17][C:13](=[O:16])[CH2:14][CH3:15])[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=1
Reactant: COC(=O)c1cc(C)nc(Cl)n1
Reactant: CCC(N)=O
Product: CCC(=O)Nc1nc(C)cc(C(=O)OC)n1
Yield: 61 %

Procedure:
The title compound is prepared in 61% yield (0.73 g, a yellow solid) from methyl 2-chloro-6-methylpyrimidine-4-carboxylate (1.0 g, 5.4 mmol) and propionamide by the similar manner in Step-1 of Carboxylic acid-4.
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])[N:16]([CH3:19])[NH:15][C:14]3=[O:20])[CH:10]=[N:9]2)=[C:5]([CH3:21])[O:4][N:3]=1.C(N(CC)CC)C.[CH2:29](Br)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>C(#N)C>[CH2:29]([N:15]1[C:14](=[O:20])[N:13]([C:11]2[CH:10]=[N:9][N:8]([CH2:7][C:6]3[C:2]([CH3:1])=[N:3][O:4][C:5]=3[CH3:21])[CH:12]=2)[C:17](=[O:18])[N:16]1[CH3:19])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: Cc1noc(C)c1Cn1cc(-n2c(=O)[nH]n(C)c2=O)cn1
Reactant: BrCc1ccccc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cc1noc(C)c1Cn1cc(-n2c(=O)n(C)n(Cc3ccccc3)c2=O)cn1
Temperature: 25 °C
Reaction time: 12 h
Yield: 20.4 %

Procedure:
4-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)-1-methyl-1,2,4-triazolidine-3,5-dione (example 10-64) (785 mg, 2.7 mmol) was dissolved in acetonitrile (50 mL). Triethylamine (1 g, 10 mmol) and benzyl bromide (510 mg, 3 mmol) were added and the reaction was stirred at ambient temperature for 12 hours. The mixture was then concentrated on the rotovap, dissolved in methanol (5 mL) and purified by reversed phase HPLC (5-95% acetonitrile in H2O:25 minute gradient). The pure fractions were pooled and concentrated and the product was recrystallized form ethanol to afford 1-benzyl-4-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)-2-methyl-1,2,4-triazolidine-3,5-dione (210 mg, 20%) as a white solid. 1H NMR (DMSO-d6, 400 MHz): δ2.13 (s, 3H), 2.39 (s, 3H), 3.09 (s, 3H), 4.81 (s, 2H), 5.18 (s, 2H), 7.30-7.35 (m, 5H), 7.76 (s, 1H), 8.18 (s, 1H). MS M+H calculated 381.1. found 381.1. Melting point: 124-126° C. The title compound was shown to inhibit hT2R08 bitter receptor and had an IC50 of 0.02 μM.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]([C:18](=[O:22])[C@@H:19]([OH:21])[CH3:20])[CH2:14][CH2:13]3)=[CH:8][C:6]=2[N:7]=1.CC1(C)C(C)(C)OB([C:37]2[CH:38]=[CH:39][C:40]([NH2:43])=[N:41][CH:42]=2)O1>>[NH2:43][C:40]1[N:41]=[CH:42][C:37]([C:2]2[N:3]=[C:4]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[C:5]3[S:10][C:9]([CH2:11][N:12]4[CH2:17][CH2:16][N:15]([C:18](=[O:22])[C@@H:19]([OH:21])[CH3:20])[CH2:14][CH2:13]4)=[CH:8][C:6]=3[N:7]=2)=[CH:38][CH:39]=1
Reactant: C[C@H](O)C(=O)N1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Product: C[C@H](O)C(=O)N1CCN(Cc2cc3nc(-c4ccc(N)nc4)nc(N4CCOCC4)c3s2)CC1
Yield: 91.5 %

Procedure:
(S)-1-(4-((2-Chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperazin-1-yl)-2-hydroxypropan-1-one (61 mg) was reacted with 50 mg of 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine via General Procedure A to give 63.4 mg of 208. MS (Q1) 484.3 (M)+.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[S:8][C:7]([NH:9][C:10]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[N:6][C:5]=1/[C:29](=[N:35]/[OH:36])/[C:30]([O:32][CH2:33][CH3:34])=[O:31].[C:37](Cl)([C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1)([C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>C(OCC)(=O)C>[CH3:3][C:4]1[S:8][C:7]([NH:9][C:10]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)=[N:6][C:5]=1/[C:29](=[N:35]/[O:36][C:37]([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)([C:50]1[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=1)[C:44]1[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=1)/[C:30]([O:32][CH2:33][CH3:34])=[O:31]
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCOC(=O)/C(=N\O)c1nc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)sc1C
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CCOC(=O)/C(=N\OC(c1ccccc1)(c1ccccc1)c1ccccc1)c1nc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)sc1C
Reaction time: 20 h
Yield: 40.1 %

Procedure:
To a suspension of sodium hydride (1.37 g) in 110 ml of ethyl acetate, ethyl 2-(5-methyl-2-tritylaminothiazol-4-yl)-2-(Z)-(hydroxyimino)acetate (16.15 g) was added at room temperature. The mixture was treated with a solution of trityl chloride (9.55 g) in ethyl acetate (66 ml). After 20 hours, the reaction was quenched by ice-water. The aqueous phase was extracted with ethyl acetate, and the combined extracts were washed with brine and dried with magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel with 5%-17% ethyl acetate/hexane to give 9.8 g of ethyl 2-(5-methyl-2-tritylaminothiazol-4-yl)-2-(Z)-(trityloxyimino)acetate.
Reaction SMILES: [CH3:1][C:2]1([C:7]2[N:12]=[C:11]([CH2:13][N:14]3[CH:18]=[C:17]([NH2:19])[CH:16]=[N:15]3)[CH:10]=[CH:9][CH:8]=2)[O:6]CCO1.[F:20][C:21]([F:34])([F:33])[C:22]1[CH:27]=[CH:26][C:25](/[CH:28]=[CH:29]/[C:30](O)=[O:31])=[CH:24][CH:23]=1>>[C:2]([C:7]1[N:12]=[C:11]([CH2:13][N:14]2[CH:18]=[C:17]([NH:19][C:30](=[O:31])/[CH:29]=[CH:28]/[C:25]3[CH:24]=[CH:23][C:22]([C:21]([F:33])([F:34])[F:20])=[CH:27][CH:26]=3)[CH:16]=[N:15]2)[CH:10]=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: O=C(O)/C=C/c1ccc(C(F)(F)F)cc1
Reactant: CC1(c2cccc(Cn3cc(N)cn3)n2)OCCO1
Product: CC(=O)c1cccc(Cn2cc(NC(=O)/C=C/c3ccc(C(F)(F)F)cc3)cn2)n1

Procedure:
Following general procedure B followed by C, starting from 1-[6-(2-methyl-[1,3]dioxolan-2-yl)-pyridin-2-ylmethyl]-1H-pyrazol-4-ylamine and (E)-3-(4-trifluoromethyl-phenyl)-acrylic acid. LC-MS-conditions 02: tR=1.02 min; [M+H]+=414.95.
Reaction SMILES: [NH2:1][C:2]1[N:34]=[C:5]2[C:6]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=3)=[C:7]([CH3:23])[C:8]([C:10]3[N:14]([C:15]4[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[CH:17][CH:16]=4)[N:13]=[CH:12][CH:11]=3)=[CH:9][N:4]2[N:3]=1.CN1CCOCC1.[O:42]1[C:46](=[O:47])[CH2:45][CH2:44][C:43]1=[O:48]>C1COCC1>[C:19]([C:18]1[CH:17]=[CH:16][C:15]([N:14]2[C:10]([C:8]3[C:7]([CH3:23])=[C:6]([C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:32])([F:33])[F:31])[CH:25]=4)[C:5]4[N:4]([N:3]=[C:2]([NH:1][C:46](=[O:47])[CH2:45][CH2:44][C:43]([OH:48])=[O:42])[N:34]=4)[CH:9]=3)=[CH:11][CH:12]=[N:13]2)=[CH:22][CH:21]=1)#[N:20]
Reactant: O=C1CCC(=O)O1
Reactant: Cc1c(-c2ccnn2-c2ccc(C#N)cc2)cn2nc(N)nc2c1-c1cccc(C(F)(F)F)c1
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: Cc1c(-c2ccnn2-c2ccc(C#N)cc2)cn2nc(NC(=O)CCC(=O)O)nc2c1-c1cccc(C(F)(F)F)c1
Temperature: 120 °C
Reaction time: 96 h

Procedure:
A mixture of 4-{5-[2-amino-7-methyl-8-(3-trifluoromethyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-6-yl]-pyrazol-1-yl}-benzonitrile (Ex. 1, 230 mg, 0.50 mmol) and 4-methyl-morpholine (300 mg, 30.0 mmol) in THF (3 mL) was treated with dihydro-furan-2,5-dione (250 mg, 2.50 mmol) and heated at 120° C. under microwave irradiation for 4 hrs and then thermally at 60° C. for four days. The crude reaction mixture was purified by flash chromatography eluting with a gradient of 0-10% MeOH in DCM. The fractions containing product were concentrated in vacuo affording the title compound as a colorless glass which solidified in a white solid by standing (182 mg).
Reaction SMILES: [C:1]([N:5]([CH3:15])[C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][CH:7]=1)(=[O:4])[CH:2]=[CH2:3].[C:16]([O:20][C:21]([N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1)=[O:22])([CH3:19])([CH3:18])[CH3:17]>>[C:16]([O:20][C:21]([N:23]1[CH2:28][CH2:27][N:26]([CH2:3][CH2:2][C:1]([N:5]([CH3:15])[C:6]2[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][CH:7]=2)=[O:4])[CH2:25][CH2:24]1)=[O:22])([CH3:19])([CH3:17])[CH3:18]
Reactant: C=CC(=O)N(C)c1ccc([N+](=O)[O-])cc1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Product: CN(C(=O)CCN1CCN(C(=O)OC(C)(C)C)CC1)c1ccc([N+](=O)[O-])cc1

Procedure:
Prepared from N-acryloyl-N-methyl-4-nitro-aniline and N-tert.butoxycarbonyl-piperazine