Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][N:6]=[C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14](Br)[CH:15]=2)[O:10][C:9]([C:18]2[N:19]=[CH:20][C:21]3[C:26]([CH:27]=2)=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:8]1)([CH3:4])([CH3:3])[CH3:2].CC(C)([O-])C.[K+].[NH:34]1[CH2:38][CH2:37][CH2:36][CH2:35]1.COCCOC>C(OCC)(=O)C>[C:1]([O:5][N:6]=[C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([N:34]3[CH2:38][CH2:37][CH2:36][CH2:35]3)[CH:15]=2)[O:10][C:9]([C:18]2[N:19]=[CH:20][C:21]3[C:26]([CH:27]=2)=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:8]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: C1CCNC1
Reactant: CC(C)(C)ON=c1cc(-c2cc3ccccc3cn2)oc2ccc(Br)cc12
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: CC(C)(C)ON=c1cc(-c2cc3ccccc3cn2)oc2ccc(N3CCCC3)cc12
Temperature: 80 °C
Yield: 65.6 %

Procedure:
A vial was charged with 6-bromo-2-isoquinolin-3-yl-chromen-4-one O-tert-butyl oxime (100 mg, 0.236 mmol), Pd-PEPPSI® (3 mg, 0.005 mmol), potassium tert-butoxide (40 mg, 0.354 mmol) and purged with argon for 15 min. Pyrrolidine (24 μl, 0.283 mmol) and dry 1,2-dimethoxyethane (1 ml) were added and the solution was heated at 80° C. for 18 hours. The mixture was diluted with ethyl acetate washed with a saturated aqueous solution of ammonium chloride, water and brine, dried over sodium sulfate and purified by flash chromatography over silica gel (cyclohexane/dichloromethane: 0-80%) to yield 2-isoquinolin-3-yl-6-(pyrrolidin-1-yl)-chromen-4-one O-tert-butyl oxime (64 mg, 65%).
Reaction SMILES: CO.C([O:10][C:11]([C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:16]=[C:15]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[O:29][C:30](=[O:32])[CH3:31])[CH:14]=1)=[O:12])C1C=CC=CC=1.[H][H]>O.[C].[Pd]>[C:30]([O:29][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=1[C:15]1[CH:14]=[C:13]([C:11]([OH:12])=[O:10])[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:16]=1)(=[O:32])[CH3:31]
Reactant: CC(=O)Oc1ccccc1-c1cc(C(=O)OCc2ccccc2)c2ccccc2n1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: O
Product: CC(=O)Oc1ccccc1-c1cc(C(=O)O)c2ccccc2n1
Yield: 85 %

Procedure:
A suspension of 50% hydrated 10% palladium-carbon (180 mg) in water (1 mL) was added to a methanol (10 mL) solution of 2-(2-acetoxyphenyl)-4-quinolinecarboxylic acid benzyl ester (940 mg, 2.34 mmol) obtained above, and the mixture was stirred for 7 hours in a hydrogen atmosphere. The catalyst was filtered off through celite, and then, the solvent was distilled off to obtain the title compound (610 mg, 1.99 mmol).
Reaction SMILES: Br[CH2:2][C:3]1[C:8]2[S:9][CH:10]=[CH:11][C:7]=2[C:6]([O:12][CH2:13][CH2:14][C:15]2[N:16]=[C:17]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[O:18][C:19]=2[CH3:20])=[CH:5][CH:4]=1.[S:27]1[CH2:31][C:30](=[O:32])[NH:29][C:28]1=[O:33]>>[CH3:20][C:19]1[O:18][C:17]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)=[N:16][C:15]=1[CH2:14][CH2:13][O:12][C:6]1[C:7]2[CH:11]=[CH:10][S:9][C:8]=2[C:3]([CH2:2][CH:31]2[S:27][C:28](=[O:33])[NH:29][C:30]2=[O:32])=[CH:4][CH:5]=1
Reactant: O=C1CSC(=O)N1
Reactant: Cc1oc(-c2ccccc2)nc1CCOc1ccc(CBr)c2sccc12
Product: Cc1oc(-c2ccccc2)nc1CCOc1ccc(CC2SC(=O)NC2=O)c2sccc12

Procedure:
reacting 4-[2-(7-Bromomethyl-benzo[b]thiophen-4-yloxy)-ethyl]-5-methyl-2-phenyl-oxazole with 2,4-thiazolidinedione to give 5-{4-[2-(5-Methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzo[b]thiophen-7-ylmethyl}2,4-thiazolidinedione,
Reaction SMILES: CC[O-].[Na+].[Na].[C:6]1([CH2:12][O:13][C:14]([NH:16][CH:17]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[C:18]([O:20][CH2:21][CH3:22])=[O:19])=[O:15])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[CH2:28](Br)[C:29]#[CH:30]>C(O)C.C1(C)C=CC=CC=1>[C:6]1([CH2:12][O:13][C:14]([NH:16][C:17]([C:28]#[C:29][CH3:30])([C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:23]([O:25][CH2:26][CH3:27])=[O:24])=[O:15])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: C#CCBr
Reactant: CCOC(=O)C(NC(=O)OCc1ccccc1)C(=O)OCC
Agent: CC[O-]
Agent: [Na+]
Agent: [Na]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CC#CC(NC(=O)OCc1ccccc1)(C(=O)OCC)C(=O)OCC
Yield: 41.9 %

Procedure:
A solution of sodium ethylate previously prepared from 500 mg of sodium in 20 ml of ethanol is added to 6 g of diethyl 2-[[(phenylmethoxy)carbonyl]amino]-propanedioate (prepared according to Bladon. C. M. J.Chem. Soc. Perkin. Trans I 9, 1151-1158 (1990) in 30 ml of ethanol then, after 30 minutes, 3 g of propargyl bromide at 80% in toluene is added and the reaction mixture is heated under reflux for 1 hour. The reaction mixture is then brought back to ambient temperature followed by evaporation under reduced pressure, taking up in dichloromethane, washing and drying. After evaporation under reduced pressure 6 g of the expected product is obtained which is purified by chromatography, eluting with a Cyclohexane/Ethyl acetate mixture 85/15. 2.82 g of purified product is obtained.
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]1[C:8]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=2)=[C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:6]=[C:5]1[CH2:21][OH:22].Cl[CH2:24][P:25](=[O:32])([O:29][CH2:30][CH3:31])[O:26][CH2:27][CH3:28]>CN(C=O)C.CN(P(N(C)C)(N(C)C)=O)C>[CH3:3][N:4]1[C:8]([C:9]2[CH:10]=[CH:11][N:12]=[CH:13][CH:14]=2)=[C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:6]=[C:5]1[CH2:21][O:22][CH2:24][P:25](=[O:32])([O:29][CH2:30][CH3:31])[O:26][CH2:27][CH3:28]
Reactant: CCOP(=O)(CCl)OCC
Reactant: Cn1c(CO)nc(-c2ccccc2)c1-c1ccncc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: CN(C)C=O
Product: CCOP(=O)(COCc1nc(-c2ccccc2)c(-c2ccncc2)n1C)OCC
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a suspension of 80% NaH in mineral oil (0.013 g, 0.452 mmol) in DMF at 0° C. was added 1-methyl-2-hydroxymethyl-4-phenyl-5-[4-pyridinyl]imidazole (0.100 g, 0.377 mmol) in DMF. The resulting bright yellow solution was stirred at 0° C. for 0.5 h when diethyl chloromethylphosphonate (0.070 mL, 0.452 mmol) dissolved in 0.079 mL, of HMPA was added. The resulting mixture was stirred at 0° C. for 15 min and then warmed to rt. After 5 h, the solution was partitioned between CH2Cl2 and H2O. The organic extract was washed with aqueous NaCl and dried (MgSO4). The solvent was removed in vacuo, and the residue was purified by flash chromatography, eluting with 50:1 CH2Cl2 /MeOH. The title compound was obtained as a light amber oil (0.088 g, 56%): ESMS (m/z): 416 (M+ +H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:9]([OH:11])=O)=[C:6]([CH:8]=1)[NH2:7].BrC1C=CC=C2C=1C(O)=[N:16]N2>>[Br:1][C:2]1[CH:8]=[C:6]2[C:5]([C:9]([OH:11])=[N:16][NH:7]2)=[CH:4][CH:3]=1
Reactant: Oc1n[nH]c2cccc(Br)c12
Reactant: Nc1cc(Br)ccc1C(=O)O
Product: Oc1n[nH]c2cc(Br)ccc12

Procedure:
6-Bromo-1H-indazol-3-ol CCVII was prepared from 5-bromo-2-carboxyaniline (JOC, 1997, 62, 1240) using the procedure described for preparation of 4-Bromo-1H-indazol-3-ol CLXXXIII (Example 37).
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([Br:17])=[CH:14][CH:15]=2)[CH:10]=[C:9]1[CH2:18][OH:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:20](Cl)(=[O:22])[CH3:21]>>[C:20]([O:19][CH2:18][C:9]1[N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:16]2[C:11]([CH:10]=1)=[CH:12][C:13]([Br:17])=[CH:14][CH:15]=2)(=[O:22])[CH3:21]
Reactant: CC(=O)Cl
Reactant: OCc1cc2cc(Br)ccc2n1Cc1ccccc1
Product: CC(=O)OCc1cc2cc(Br)ccc2n1Cc1ccccc1

Procedure:
The title compound was prepared from (1-benzyl-5-bromo-1H-indol-2-yl)methanol and acetyl chloride in substantially the same manner, as described in step 4 of Example 1. The product was obtained as a semi-solid. Mass spectrum (ESI, [M−H]−) m/z 356. 1H NMR (400 MHz, DMSO-d6) δ 7.78 (d, 1H, J=2.13 Hz), 7.38 (d, 1H, J=8.86 Hz), 7.29–7.20 (m, 4H), 6.94 (d, 2H, J=7.17 Hz), 6.64 (s, 1H), 5.47 (s, 2H), 5.21 (s, 2H), and 1.79 ppm (s, 3H).
Reaction SMILES: S(=O)(=O)(O)[OH:2].I[C:7]([F:19])([F:18])[C:8]([F:17])([F:16])[C:9]([F:15])([F:14])[C:10]([F:13])([F:12])I>>[F:12][C:10]1([F:13])[C:9]([F:15])([F:14])[C:8]([F:17])([F:16])[C:7]([F:19])([F:18])[O:2]1
Reactant: FC(F)(I)C(F)(F)C(F)(F)C(F)(F)I
Reactant: O=S(=O)(O)O
Product: FC1(F)OC(F)(F)C(F)(F)C1(F)F
Temperature: 85 °C
Yield: 62 %

Procedure:
Into a four necked flask equipped with a thermometer, a reflux condenser, a dropping funnel and a stirrer, 190 g (0.7 mole as SO3) of fuming sulfuric acid containing 30% of SO3 were charged and were heated at 85° C. and then 100 g (0.22 mole) of 1,4-diiodoperfluorobutane having the formula I(CF2)4I were added dropwise to the flask. The reaction was conducted while maintaining the temperature in the reactor at 80° to 90° C. The collection and the separation of the product were conducted in accordance with the process of Example 4. As a result, the conversion was 52% and perfluorotetrahydrofuran (62% yield) and perfluoro- γ-butyrolactone (7% yield) were obtained based on the starting material.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[C:7]([Cl:12])[CH:6]=1)=O.[NH2:13][C:14](=[S:20])[C:15]([O:17][CH2:18][CH3:19])=[O:16]>C(O)C>[Cl:12][C:7]1[CH:6]=[C:5]([C:3]2[N:13]=[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[S:20][CH:2]=2)[CH:10]=[CH:9][C:8]=1[F:11]
Reactant: O=C(CBr)c1ccc(F)c(Cl)c1
Reactant: CCOC(=O)C(N)=S
Solvent: CCO
Product: CCOC(=O)c1nc(-c2ccc(F)c(Cl)c2)cs1

Procedure:
1.35 g of the compound from Example 1A having a purity of 68% (5.37 mmol) are heated under reflux in 25 ml of ethanol, a solution of 0.72 g (5.37 mmol) of ethyl amino(thioxo)acetate and 10 ml of ethanol is added dropwise and the mixture is heated under reflux for 18 hours. The reaction mixture is concentrated and the residue is purified by flash chromatography (mobile phase: cyclohexane/ethyl acetate 10:1), and 1.94 g of the title compound having a purity of 57% (100% of theory) are obtained.
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:8]2=[C:9]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[N:10]=[CH:11][CH:12]=[C:7]2[CH2:6][CH2:5]1.[O:28]1[CH2:32][CH2:31][CH2:30][CH:29]1[C:33](O)=[O:34]>>[O:4]1[C:8]2=[C:9]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:33]([CH:29]5[CH2:30][CH2:31][CH2:32][O:28]5)=[O:34])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[N:10]=[CH:11][CH:12]=[C:7]2[CH2:6][CH2:5]1
Reactant: O=C(O)C1CCCO1
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3OCC4)CC2)CC1
Agent: Cl
Product: O=C(N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3OCC4)CC2)CC1)C1CCCO1

Procedure:
The title compound, white solid (62 mg, 58%), MS (ISP) m/z=429.3 [(M+H)+], mp 145° C., was prepared in accordance with the general method of example 6 from trans-4-{2-[4-(2,3-dihydro-furo[2,3-c]pyridin-7-yl)-piperazin-1-yl]-ethyl}-cyclohexylamine trihydrochloride (intermediate B) (110 mg, 0.25 mmol) and (RS)-tetrahydro-furan-2-carboxylic acid.
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:9][C:10]1[N:11]=[C:12](Cl)[C:13]2[CH:18]=[C:17]([CH3:19])[S:16][C:14]=2[N:15]=1>>[Cl:9][C:10]1[N:11]=[C:12]([NH:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:13]2[CH:18]=[C:17]([CH3:19])[S:16][C:14]=2[N:15]=1
Reactant: NCc1ccccc1
Reactant: Cc1cc2c(Cl)nc(Cl)nc2s1
Product: Cc1cc2c(NCc3ccccc3)nc(Cl)nc2s1

Procedure:
Following the procedure of Example 1, the reaction of benzylamine with 2,4-dichloro-6-methyl-thieno-[2,3-d]-pyrimidine yields 2-chloro-6-methyl-4-benzylamino-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [CH2:1]([C:8]1[S:12][C:11]([NH2:13])=[N:10][C:9]=1[C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:22][O:23][C:24]1[CH:25]=[C:26]([CH:30]=[CH:31][C:32]=1[O:33][CH3:34])[C:27](Cl)=[O:28]>>[CH2:1]([C:8]1[S:12][C:11]([NH:13][C:27](=[O:28])[C:26]2[CH:30]=[CH:31][C:32]([O:33][CH3:34])=[C:24]([O:23][CH3:22])[CH:25]=2)=[N:10][C:9]=1[C:14]1[CH:15]=[CH:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(-c2nc(N)sc2Cc2ccccc2)cc1
Reactant: COc1ccc(C(=O)Cl)cc1OC
Product: COc1ccc(-c2nc(NC(=O)c3ccc(OC)c(OC)c3)sc2Cc2ccccc2)cc1
Yield: 46.5 %

Procedure:
A procedure similar to that in Example 4 was used. 5-benzyl-4-(4-methoxy-phenyl)-thiazol-2-ylamine prepared in Example 1 and 3,4-dimethoxy-benzoyl chloride prepared in the step 1 were used as starting materials, allowed to react at room temperature overnight, followed by post-treatment to obtain a crude product, which was purified by a silica gel column chromatography eluted with petroleum ether and ethyl acetate (10:1) to obtain a product as a white solid in a yield of 46.5%, mp: 179-180└. 1H-NMR (CDCl3, 400 MHz) δ: 3.79 (3H, s, OCH3), 3.83 (3H, s, OCH3), 3.89 (3H, s, OCH3), 4.22 (2H, s, CH2), 6.73 (1H, d, J=8.40 Hz, ArH), 6.78 (2H, d, J=8.40 Hz, ArH), 7.26˜7.35 (9H, m, ArH), 11.03 (1H, br, CONH); EI-MS m/e (%): 460.1 (M+, 99), 164.9 (100); HREI-MS Calcd. for C26H24N2O4S: 460.1457. found: 460.1463. Anal. Calcd. for C26H24N2O4S: C, 67.81; H, 5.25; N, 6.08. found: C, 67.62; H, 5.20; N, 6.50.
Reaction SMILES: [C:1]([N:4]1[CH2:13][CH2:12][C:7]([C:14]#[N:15])([C:8]([O:10][CH3:11])=[O:9])[CH2:6][CH2:5]1)(=[O:3])[CH3:2].N>[Ni].CO>[C:1]([N:4]1[CH2:13][CH2:12][C:7]([CH2:14][NH2:15])([C:8]([O:10][CH3:11])=[O:9])[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: COC(=O)C1(C#N)CCN(C(C)=O)CC1
Agent: [Ni]
Agent: N
Solvent: CO
Product: COC(=O)C1(CN)CCN(C(C)=O)CC1
Reaction time: 2 h

Procedure:
A mixture of methyl 1-acetyl-4-cyanoisonipecotate (3.95 g), Raney nickel (3 g), concentrated ammonia solution (15 ml) and methanol (100 ml) was stirred at 5 atms under hydrogen atmosphere for 2 hours, and the catalyst was filtered off. The reaction solution was concentrated to give light blue oil of methyl 1-acetyl-4-aminomethylisonipecotate. To a solution of the obtained methyl 1-acetyl-4-aminomethylisonipecotate and N-(2,2-diethoxyethyl)-Z-glycine (6.12 g) in acetonitrile (100 ml) was added WSC (6.12 g), and the mixture was stirred at room temperature for 15 hours. The reaction solution was concentrated, and to the residue were added ethyl acetate and water. The separated organic layer was washed with water, sodium bicarbonate solution, citric acid solution and brine, dried and concentrated, and the residue was dissolved in toluene (100 ml). To the solution was added p-toluene sulfonic acid hydrate (164 mg), and the mixture was stirred at 100° C. for 30 minutes. The reaction solution was washed with saturated sodium bicarbonate solution and brine, dried and concentrated, and the residue was purified with silica gel column chromatography (ethyl acetate:methanol=50:1) to give colorless oil of 1-(1-acetyl-4-methoxycarbonylpiperidin-4-ylmethyl)-4-benzyloxycarbonyl-2-oxo-1,2,3,4-tetrahydropyrazine (2.4 g).
Reaction SMILES: [Br:1][C:2]1[C:3]([C:9]([OH:11])=[O:10])=[N:4][CH:5]=[CH:6][C:7]=1[Cl:8].Cl.[CH3:13]O>>[Br:1][C:2]1[C:3]([C:9]([O:11][CH3:13])=[O:10])=[N:4][CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C(O)c1nccc(Cl)c1Br
Reactant: CO
Agent: Cl
Product: COC(=O)c1nccc(Cl)c1Br
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 3-bromo-4-chloropyridine-2-carboxylic acid (1.75 g, 7.4 mmol) in MeOH was added anhydrous HCl. The resulting mixture was stirred at room temperature for 18 hr. The reaction mixture was concentrated to give a solid, which was partitioned between Et2O and saturated NaHCO3. Organic layer was dried over MgSO4, filtered and concentrated to give a brown residue. This material was purified via flash column chromatography to yield 1.35 g of product as a pale yellow oil.
Reaction SMILES: [C:1]([C:3]1[CH:27]=[CH:26][C:6]([O:7][C:8]2[N:16]=[C:15]([O:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]#[N:25])=[CH:20][CH:19]=3)[CH:14]=[CH:13][C:9]=2[C:10](O)=[O:11])=[CH:5][CH:4]=1)#[N:2].[CH2:28]([O:30][C:31](=[O:35])[CH2:32][CH2:33][NH2:34])[CH3:29]>>[CH2:28]([O:30][C:31](=[O:35])[CH2:32][CH2:33][NH:34][C:10]([C:9]1[C:8]([O:7][C:6]2[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:27][CH:26]=2)=[N:16][C:15]([O:17][C:18]2[CH:19]=[CH:20][C:21]([C:24]#[N:25])=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)=[O:11])[CH3:29]
Reactant: CCOC(=O)CCN
Reactant: N#Cc1ccc(Oc2ccc(C(=O)O)c(Oc3ccc(C#N)cc3)n2)cc1
Product: CCOC(=O)CCNC(=O)c1ccc(Oc2ccc(C#N)cc2)nc1Oc1ccc(C#N)cc1
Yield: 77.1 %

Procedure:
Following the procedure of Example 5(c) 2,6-bis(4-Cyano phenoxy)-nicotinic acid 0.5 g (1.42 mmol) and 3-amino-propionic acid ethyl ester (0.166 g, 1.42 mmol) were used to afford 0.5 g of the required product. Percentage purity (LCMS): 30.7%, (M+1)=456.1.
Reaction SMILES: C[Si](C)(C)[CH:3]1[S:8][CH2:7][CH2:6][CH2:5][S:4]1.C([Li])CCC.[CH3:16][O:17][CH:18]1[CH:22]([CH:23]=O)[CH2:21][CH:20]([O:25][CH3:26])[O:19]1.[NH4+].[Cl-]>C1COCC1>[CH3:16][O:17][CH:18]1[CH:22]([CH:23]=[C:3]2[S:8][CH2:7][CH2:6][CH2:5][S:4]2)[CH2:21][CH:20]([O:25][CH3:26])[O:19]1
Reactant: C[Si](C)(C)C1SCCCS1
Reactant: COC1CC(C=O)C(OC)O1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: COC1CC(C=C2SCCCS2)C(OC)O1
Reaction time: 0.25 h
Yield: 67.3 %

Procedure:
According to a procedure described in Boger, D. L.; Brotherton, C. E. J. Org. Chem. 1984, 49, 4050-4055, to a solution of 2-trimethylsilyl-1,3-dithiane (1.2 mL, 6.3 mmol) in dry THF (40 mL) at 0° C. was added n-butyllithium (4 mL of 1.6 M in hexanes). After 15 minutes at 0° C. and 20 minutes at 4 mL of 1.6 M ambient temperature, a solution of 2,5-dimethoxytetrahydrofuran-3-carboxaldehyde (1.00 g, 6.00 mmol) in dry THF (10 mL) was added dropwise. After 17 hours at ambient temperature, the resultant mixture was treated with saturated aqueous NH4Cl (10 mL) and partitioned between EtOAc and H2O. The layers were separated and the aqueousueous phase extracted with EtOAc:hex (1:1) two times. The combined organic layers were washed with brine, dried over Na2SO4, and concentrated to afford a residue which was purified via flash column chromatograpy with 10% EtOAc/hex as eluant to yield 1.06 g (70%) of a mixture of diastereomeric 2-(2,5-dimethoxy-tetrahydrofuran-3-yl-methylidene)-1,3-dithiane as a yellow oil, which was used without any further purification. 1H NMR: δ 6.00 (d, 1H, J=9.6 Hz), 5.93 (d, 1H, J=9.6 Hz), 5.77 (d, 1H, J=9.6 Hz). Anal. Calculated for C11H18O3S2: C, 50.35; H, 6.92; S, 24.44. Found: C, 50.07; H, 7.00; S, 24.33.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+].Br[C:21]1[S:22][C:23]2[C:29]([N+:30]([O-:32])=[O:31])=[C:28]([O:33][CH3:34])[CH:27]=[CH:26][C:24]=2[N:25]=1>O.COCCOC>[CH3:34][O:33][C:28]1[CH:27]=[CH:26][C:24]2[N:25]=[C:21]([C:2]3[CH:3]=[CH:4][C:5]4[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=4)[CH:1]=3)[S:22][C:23]=2[C:29]=1[N+:30]([O-:32])=[O:31]
Reactant: COc1ccc2nc(Br)sc2c1[N+](=O)[O-]
Reactant: OB(O)c1ccc2ccccc2c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: COc1ccc2nc(-c3ccc4ccccc4c3)sc2c1[N+](=O)[O-]
Temperature: 85.5 °C
Reaction time: 18 h
Yield: 83.4 %

Procedure:
0.716 g (4.16 mmol; 1.1 equivalent) of 2-naphthalene boronic acid as well as a solution of 1.2 g (11.35 mmol; 3 equivalents) of sodium carbonate in 15 ml of water are added to a suspension of 1.09 g (3.78 mmol) of 2-bromo-6-methoxy-7-nitro-1,3-benzothiazole and 131 mg (0.114 mmol; 0.03 equivalent) of palladium tetrakis-triphenylphosphine in 30 ml of 1,2-dimethoxyethane. The reaction mixture is maintained under stirring at 85.5° C. for 18 hours, then after concentration under reduced pressure, 100 ml of ethyl acetate is added to the medium which is then washed with twice 75 ml of a saturated aqueous solution of sodium chloride. The organic phase is dried over sodium sulphate then the solvents are evaporated off under reduced pressure and the residue is purified by chromatography on a silica column (eluent: ethyl acetate/heptane mixture 1:2). 1.06 g (83% yield) of 6-methoxy-2-(2-naphthyl)-7-nitro-1,3-benzothiazole is obtained in the form of beige powder.
Reaction SMILES: C[O:2][C:3](=[O:24])[C:4]1[CH:9]=[C:8]([C:10]2[S:11][CH:12]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=3)[N:14]=2)[CH:7]=[CH:6][C:5]=1Br.[Cl:25][C:26]1[CH:27]=[CH:28][C:29]([C:35]#[N:36])=[C:30](B(O)O)[CH:31]=1>>[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([C:35]#[N:36])=[C:28]([C:5]2[C:4]([C:3]([OH:2])=[O:24])=[CH:9][C:8]([C:10]3[S:11][CH:12]=[C:13]([C:15]4[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=4)[N:14]=3)=[CH:7][CH:6]=2)[CH:27]=1
Reactant: N#Cc1ccc(Cl)cc1B(O)O
Reactant: COC(=O)c1cc(-c2nc(-c3ccc(Cl)c(Cl)c3)cs2)ccc1Br
Product: N#Cc1ccc(Cl)cc1-c1ccc(-c2nc(-c3ccc(Cl)c(Cl)c3)cs2)cc1C(=O)O
Yield: 12.4 %

Procedure:
Using the conditions of General Procedure B for Suzuki Coupling and Hydrolysis in Parallel Mode, 2-bromo-5-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-benzoic acid methyl ester (which may be prepared as described for Intermediate 6; 89 mg, 0.2 mmol) was reacted with and 5-chloro-2-cyanophenylboronic acid (available from Combi-Blocks Inc.; 73 mg, 0.4 mmol). The resulting ester was hydrolyzed and the acid was purified to give 5′-chloro-2′-cyano-4-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-biphenyl-2-carboxylic acid (12 mg, 12%). 1H NMR (400 MHz, DMSO-d6) δ 13.38 (br s, 1H), 8.63 (d, J=2.0 Hz, 1H), 8.52 (s, 1H), 8.31-8.37 (m, 2H), 8.10 (dd, J=8.5, 2.0 Hz, 1H), 7.97 (d, J=8.3 Hz, 1H), 7.78 (d, J=8.5 Hz, 1H), 7.65-7.73 (m, 2H), 7.59 (d, J=8.0 Hz, 1H).
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH2:7][N:8]2[CH:12]=[C:11]([N:13]3[C:17](=[O:18])[CH2:16][NH:15][C:14]3=[O:19])[CH:10]=[N:9]2)=[C:5]([CH3:20])[O:4][N:3]=1.Br[CH2:22][C:23]1[N:28]=[C:27]([CH2:29][OH:30])[CH:26]=[CH:25][CH:24]=1>>[CH3:1][C:2]1[C:6]([CH2:7][N:8]2[CH:12]=[C:11]([N:13]3[C:17](=[O:18])[CH2:16][N:15]([CH2:22][C:23]4[CH:24]=[CH:25][CH:26]=[C:27]([CH2:29][OH:30])[N:28]=4)[C:14]3=[O:19])[CH:10]=[N:9]2)=[C:5]([CH3:20])[O:4][N:3]=1
Reactant: OCc1cccc(CBr)n1
Reactant: Cc1noc(C)c1Cn1cc(N2C(=O)CNC2=O)cn1
Product: Cc1noc(C)c1Cn1cc(N2C(=O)CN(Cc3cccc(CO)n3)C2=O)cn1
Yield: 35 %

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 6-bromomethyl-2-pyridinemethanol. Yield: 35%. MS M+H calculated 397.2. found 397.2. The title compound was shown to inhibit hT2R08 bitter receptor and had an IC50 of 0.72 μM.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([CH3:8])[CH:5]=[CH:4][N:3]=1.[H-].[Na+].[Br:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14](Br)[N:13]=1.O>C1COCC1>[Br:11][C:12]1[N:13]=[C:14]([NH:1][C:2]2[N:7]=[C:6]([CH3:8])[CH:5]=[CH:4][N:3]=2)[CH:15]=[CH:16][CH:17]=1
Reactant: Brc1cccc(Br)n1
Reactant: Cc1ccnc(N)n1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccnc(Nc2cccc(Br)n2)n1
Temperature: 55 °C

Procedure:
A solution of 2-amino-4-methylpyrimidine (980 mg, 8.86 mmol) in THF (10 ml) was added dropwise to a cooled suspension of NaH (60% on oil, 1 g, 25.32 mmol) in THF (15 ml) under inert atmosphere. The reaction mixture was heated at 55° C. for 2 hours. The reaction was cooled down to 0° C. and a solution of 2,6-dibromopyridine (2 g, 8.44 mmol) in THF (20 ml) was added. The reaction mixture was heated at 80° C. for 5 hours. The reaction was cooled down to 0° C. and hydrolysed carefully with water (50 ml). After extraction with EtOAc (2×100 ml), the combined extractions were dried over MgSO4. After filtration and evaporation, N-(6-bromopyridin-2-yl)-4-methylpyrimidin-2-amine was obtained and purified dry flash chromatography over SiO2 eluting with DCM/MeOH(1%)/NEt3 (0.5%) (0.846 g, 38%). 1H NMR (300 MHz, DMSO-d6) δ 10.12 (br s, 1H), 8.44 (d, J=5.0 Hz, 1H), 8.36 (d, J=8.3 Hz, 1H), 7.69 (t, J=8.0 Hz, 1H), 7.18 (dd, J=7.6, 0.6 Hz, 1H), 6.91 (d, J=5.0 Hz, 1H), 2.42 (s, 3H).