Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][CH2:8]/[CH:9]=[CH:10]/B1OC(C)(C)C(C)(C)O1)([CH3:4])([CH3:3])[CH3:2].Br[C:22]1[C:31]2[C:26](=[CH:27][C:28]3[CH:35]=[CH:34][CH:33]=[CH:32][C:29]=3[CH:30]=2)[C:25]2=[N:36][NH:37][C:38](=[O:39])[N:24]2[CH:23]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1COCC1.O>[C:1]([O:5][C:6](=[O:20])[NH:7][CH2:8]/[CH:9]=[CH:10]/[C:22]1[C:31]2[C:26](=[CH:27][C:28]3[CH:35]=[CH:34][CH:33]=[CH:32][C:29]=3[CH:30]=2)[C:25]2=[N:36][NH:37][C:38](=[O:39])[N:24]2[CH:23]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)NC/C=C/B1OC(C)(C)C(C)(C)O1
Reactant: O=c1[nH]nc2c3cc4ccccc4cc3c(Br)cn12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)NC/C=C/c1cn2c(=O)[nH]nc2c2cc3ccccc3cc12
Temperature: 150 °C

Procedure:
To a solution of tert-butyl[(2E)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)prop-2-en-1-yl]carbamate (3-3) (32.5 mg, 0.115 mmol, 4 eq) and 6-bromobenzo[g][1,2,4]triazolo[3,4-a]isoquinolin-3(2H)-one (7-6) (9.0 mg, 0.029 mmol, 1 eq) in THF (0.5 ml) was added a solution of cesium carbonate (18.7 mg, 0.058 mmol, 2 eq) in water (0.2 ml), and the resulting mixture was deoxygenated with nitrogen and treated with Pd(dppf) (1.0 mg, 0.0014 mmol, 0.05 eq). The reaction mixture was deoxygenated again, and heated in a sealed tube under microwave irradiation for 8 min at 150° C. The resulting suspension was filtered through a pad of Celite washing with DMF, and the filtrate was purified on RP HPLC (MeCN/Water with TFA) to afford the desired coupling product 7-7. LRMS m/z: found 391.2, calcd. (M+H) 391.2.
Reaction SMILES: C[O:2][C:3]([C:5]1[N:6]=[CH:7][C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH:9]=2)=O.OC(C(F)(F)F)=O.[NH2:29][CH2:30][C:31]([CH3:36])([CH3:35])[C:32]([OH:34])=[O:33].C[O-].[Na+]>CCO>[OH:15][C:14]1[C:13]2[C:8](=[CH:9][C:10]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:11][CH:12]=2)[CH:7]=[N:6][C:5]=1[C:3]([NH:29][CH2:30][C:31]([CH3:36])([CH3:35])[C:32]([OH:34])=[O:33])=[O:2]
Reactant: CC(C)(CN)C(=O)O
Reactant: COC(=O)c1ncc2cc(-c3ccccc3)ccc2c1O
Agent: C[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(CNC(=O)c1ncc2cc(-c3ccccc3)ccc2c1O)C(=O)O
Temperature: 150 °C
Yield: 47.4 %

Procedure:
A mixture of 4-hydroxy-7-phenyl-isoquinoline-3-carboxylic acid methyl ester (60 mg, 0.22 mmol), 3-amino-2,2-dimethyl-propionic acid TFA salt (200 mg, 0.86 mmol) and NaOMe (93 mg, 1.72 mmol) in EtOH (2.2 mL) was heated at 150° C. in a microwave reactor for 6 h. The solvent was evaporated, and the residue was partitioned between water and EtOAc. 1 M HCl was added with vigorous stirring until pH was ˜2. The organic layer was dried over MgSO4 and concentrated. The crude product was purified by column chromatography (0-30% EtOAc/hexanes+2% AcOH) to give 38 mg of the title compound. MS: (+) m/z 365.11 (M+1).
Reaction SMILES: [F:1][CH:2]([F:12])[O:3][CH:4]1[CH2:9][CH2:8][N:7](C=O)[CH2:6][CH2:5]1.[OH-].[K+]>O>[F:1][CH:2]([F:12])[O:3][CH:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1
Reactant: O=CN1CCC(OC(F)F)CC1
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: FC(F)OC1CCNCC1
Reaction time: 3 h
Yield: 48.3 %

Procedure:
4-(difluoromethoxy)piperidine-1-carbaldehyde (17) (2.7 g, 15.07 mmol) and potassium hydroxide (2.96 g, 52.74 mmol) were dissolved in water (40 mL) and stirred vigorously for 3 hours. The reaction was extracted with diethyl ether (3×75 mL), the organic layer was dried over MgSO4, filtered and evaporated to afford an orange liquid. The crude product was purified by distillation at 0.70 mBar, collecting fractions that distilled at 25° C. to afford the desired material as a colourless oil (1.100 g, 48.3%); 1H NMR (400.132 MHz, CDCl3) δ 1.50 (1H, s), 1.66-1.57 (2H, m), 1.95-1.89 (2H, m), 2.70-2.64 (2H, m), 3.09 (2H, dt), 4.25-4.19 (1H, m), 6.24 (1H, t).
Reaction SMILES: N1(O[C:11]2[N:16]=[C:15]([NH:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:14]([C:25]([NH2:27])=[O:26])=[CH:13][N:12]=2)C2C=CC=CC=2N=N1.[NH2:28][C:29]1[CH:30]=[C:31]([NH:35][C:36]([C@@H:38]2[CH2:42][CH2:41][CH2:40][N:39]2[CH3:43])=[O:37])[CH:32]=[CH:33][CH:34]=1.CC1C=CC(S(O)(=O)=O)=CC=1>CN1C(=O)CCC1>[CH2:18]([NH:17][C:15]1[C:14]([C:25]([NH2:27])=[O:26])=[CH:13][N:12]=[C:11]([NH:28][C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([NH:35][C:36]([C@@H:38]3[CH2:42][CH2:41][CH2:40][N:39]3[CH3:43])=[O:37])[CH:30]=2)[N:16]=1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: CN1CCC[C@H]1C(=O)Nc1cccc(N)c1
Reactant: NC(=O)c1cnc(On2nnc3ccccc32)nc1NCc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CN1CCCC1=O
Product: CN1CCC[C@H]1C(=O)Nc1cccc(Nc2ncc(C(N)=O)c(NCc3ccccc3)n2)c1
Temperature: 100 °C
Yield: 77 %

Procedure:
To a solution of 2-(1H-benzo[d][1,2,3]triazol-1-yloxy)-4-(benzylamino)pyrimidine-5-carboxamide (50 mg, 0.14 mmol) in NMP (1 mL) was added (S)—N-(3-aminophenyl)-1-methylpyrrolidine-2-carboxamide (33 mg, 0.152 mmol) and pTsOH*H2O (60 mg, 0.28 mmol). The mixture was heated at 100° C. for 2 h, cooled to room temperature, and purified by preparative HPLC to give of (S)-4-(benzylamino)-2-(3-(1-methylpyrrolidine-2-carboxamido)phenylamino)pyrimidine-5-carboxamide (48 mg). MS found for C24H27N7O2 as (M+H)+ 446.5. λ=247.5.
Reaction SMILES: [C:1]([O:5][C:6](=[O:9])[NH:7][CH3:8])([CH3:4])([CH3:3])[CH3:2].[CH2:10]([O:17][C:18]1[CH:23]=[CH:22][N:21]([CH2:24][CH2:25][C:26]2[CH:31]=[CH:30][C:29]([CH2:32]Br)=[CH:28][CH:27]=2)[C:20](=[O:34])[CH:19]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C1COCC1.CCOC(C)=O.O>[C:1]([O:5][C:6](=[O:9])[N:7]([CH2:32][C:29]1[CH:30]=[CH:31][C:26]([CH2:25][CH2:24][N:21]2[CH:22]=[CH:23][C:18]([O:17][CH2:10][C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=3)=[CH:19][C:20]2=[O:34])=[CH:27][CH:28]=1)[CH3:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=c1cc(OCc2ccccc2)ccn1CCc1ccc(CBr)cc1
Reactant: CNC(=O)OC(C)(C)C
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: CN(Cc1ccc(CCn2ccc(OCc3ccccc3)cc2=O)cc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To 49 mg (0.38 mmol) methyl-carbamic acid tert-butyl ester in 4.0 mL THF is added at RT 48 mg (0.43 mmol) potassium-tert-butylate. The reaction mixture is stirred 20 min at RT and then 100 mg (0.25 mmol) 4-benzyloxy-1-[2-(4-bromomethyl-phenyl)-ethyl]-1H-pyridin-2-one (example 1.1a) is added. The mixture is stirred additional 1 h at RT and is diluted with EtOAc and water. The layers are separated and the organic phase is washed with water, dried over MgSO4, filtered and the solvent is evaporated to afford the product.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([N:10]([CH2:27][CH2:28][CH3:29])[CH:11]([CH2:17][C:18]1[C:26]2[N:25]=[CH:24][NH:23][C:22]=2[CH:21]=[CH:20][CH:19]=1)[C:12](OCC)=[O:13])[CH2:8][CH3:9].C(Cl)(Cl)Cl.C(O)C>C1COCC1.CO>[CH2:27]([N:10]([CH2:7][CH2:8][CH3:9])[CH:11]([CH2:17][C:18]1[C:26]2[N:25]=[CH:24][NH:23][C:22]=2[CH:21]=[CH:20][CH:19]=1)[CH2:12][OH:13])[CH2:28][CH3:29]
Reactant: CCCN(CCC)C(Cc1cccc2[nH]cnc12)C(=O)OCC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCO
Solvent: CO
Solvent: C1CCOC1
Product: CCCN(CCC)C(CO)Cc1cccc2[nH]cnc12
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 100.4 %

Procedure:
Lithium aluminum hydride (250 mg, 6.6 mmol) was added at 0° C. to a stirred solution of ethyl α-(dipropylamino)-1H-benzimidazole-4-propanoate (1.5 g, 4.7 mmol) in dry THF (50 mL), and the solution was allowed to warm to room temperature. TLC in 10% methanol:chloroform showed that the reaction was complete in 15 minutes. Ethanol (5 mL) was added and the solvents were removed under reduced pressure. The residue was partitioned between ethyl acetate and water. Evaporation of the ethyl acetate gave 1.3 g of β-(dipropylamino)-1H-benzimidazole-4-propanol which was used without further purification.
Reaction SMILES: Br[CH:2]1[CH2:8][CH2:7][S:6][C:5]2[CH:9]=[CH:10][CH:11]=[CH:12][C:4]=2[C:3]1=[O:13].C(=O)([O-])[O-].[Li+].[Li+]>CN(C)C=O.S(C1C=CC(C)=CC=1)([O-])(=O)=O.[Ag+]>[O:13]=[C:3]1[C:7]2([CH2:8][CH2:2]2)[S:6][C:5]2[CH:9]=[CH:10][CH:11]=[CH:12][C:4]1=2
Reactant: O=C1c2ccccc2SCCC1Br
Agent: [Ag+]
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: O=C1c2ccccc2SC12CC2
Temperature: 0 °C

Procedure:
In dry dimethylformamide, 0.5 g of 4-bromo-2,3-dihydrobenzo[b]thiepin-5(4H)-one, 0.6 g of silver tosylate and 0.2 g of lithium carbonate are heated under reflux for 12 hours, at the end of which time the reaction mixture is poured in ice-water. The resultant crystals are recovered by filtration and dried. This crude product is purified by thin-layer chromatography on silica gel (solvent system: benzene-n-hexane=1:3). The crude crystals thus obtained are recrystallized from methylene chloride-n-hexane. By the above procedure there is obtained 3-oxo-2,3-dihydro[1]-benzothiophene-2-spirocyclopropane as colorless prisms melting at 70° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]([CH:13]([NH2:20])[CH2:14][CH2:15][CH2:16][CH:17]([CH3:19])[CH3:18])[NH:11][CH:12]=2)[CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.[C:28]1(=O)[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO.O>[Br:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]([CH:13]([NH:20][CH:28]3[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]3)[CH2:14][CH2:15][CH2:16][CH:17]([CH3:18])[CH3:19])[NH:11][CH:12]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CCCCC1
Reactant: CC(C)CCCC(N)c1nc(-c2cccc(Br)c2)c[nH]1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O
Solvent: CCN(CC)CC
Solvent: CO
Product: CC(C)CCCC(NC1CCCCC1)c1nc(-c2cccc(Br)c2)c[nH]1
Temperature: 23 °C
Reaction time: 0.5 h
Yield: 38 %

Procedure:
A mixture containing 1-(4-(3-bromophenyl)-1H-imidazol-2-yl)-5-methyl-1-hexanamine (obtained at stage 13777.3; 0.8 g; 0.0019 mol), triethylamine (0.4 ml; 0.003 mol) and cyclohexanone (0.32 ml; 0.0023 mol) in 10 ml methanol was agitated for about 30 minutes at about 23° C. Sodium triacetoxyborohydride (630 mg; 0.003 mol) was then added. The reaction mixture was agitated for about 16 hours and then poured into water. After extraction with ethyl acetate, the organic phase was washed with a saturated sodium chloride solution and then dried over magnesium sulfate. The solvent was evaporated and the residue purified over a silica column (eluent mixture CH2Cl2-MeOH/95-05). A white-colored powder was obtained with a yield of 38%. Melting point: 236-238° C. MH+=418.2.
Reaction SMILES: [C:1]([NH:9][CH:10]([CH2:26][CH2:27][CH2:28][CH3:29])[C:11](=[O:25])[CH2:12][N:13]([CH3:24])[C:14]([N:16]1[CH2:23][CH2:22][CH2:21][C@H:17]1[C:18]([OH:20])=[O:19])=[O:15])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+]>>[C:1]([NH:9][CH:10]([CH2:26][CH2:27][CH2:28][CH3:29])[CH:11]([OH:25])[CH2:12][N:13]([CH3:24])[C:14]([N:16]1[CH2:23][CH2:22][CH2:21][C@H:17]1[C:18]([OH:20])=[O:19])=[O:15])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCCC(NC(=O)c1ccccc1)C(=O)CN(C)C(=O)N1CCC[C@H]1C(=O)O
Agent: [BH4-]
Agent: [Na+]
Product: CCCCC(NC(=O)c1ccccc1)C(O)CN(C)C(=O)N1CCC[C@H]1C(=O)O

Procedure:
The product from part (h) is treated with sodium borohydride according to the procedure of Example 1(f) to yield (±)-1-[[[3-(benzoylamino)-2-hydroxyheptyl]methylamino]carbonyl]-L-proline.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH:7]=[O:8])=[CH:3][CH:2]=1.[CH2:9]([Li])[CH:10]=[CH2:11].O>C1COCC1>[N:1]1[CH:6]=[CH:5][C:4]([CH:7]([OH:8])[CH2:11][CH:10]=[CH2:9])=[CH:3][CH:2]=1
Reactant: [Li]CC=C
Reactant: O=Cc1ccncc1
Solvent: O
Solvent: C1CCOC1
Product: C=CCC(O)c1ccncc1
Temperature: 0 °C
Yield: 63 %

Procedure:
4.75 g (50 mmol) of pyridine-4-carboxaldehyde was dissolved in 50 ml THF and cooled to 0° C. Allyl lithium was then added with stirring until the mixture turned the dark color characteristic of the allyl lithium solution. After stirring for an additional 5 minutes, water was slowly added at 0° C. until two phases formed and all precipitate was dissolved. The THF layer was separated, dried over MgSO4, and evaporated in vacuo to an oil. Flash chromatography yielded 4.69 g (63%) of product as an oil. 1H NMR (CDCL3): 8.5 and 7.3 (4H, pyridyl), 5.8 and 5.15 (3H, vinyl), 4.75 (1H, CHOH), 3.6 (1H, OH), and 2.5 (2H, CH2) ppm.
Reaction SMILES: [CH2:1]([O:8][CH2:9][N:10]1[CH:14]=[CH:13][CH:12]=[N:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li]CCCC.[CH2:20]([O:27][C:28]1[CH:29]=[C:30]([CH:33]=[CH:34][C:35]=1[N+:36]([O-:38])=[O:37])[CH:31]=[O:32])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C1COCC1>[CH2:1]([O:8][CH2:9][N:10]1[C:14]([CH:31]([C:30]2[CH:33]=[CH:34][C:35]([N+:36]([O-:38])=[O:37])=[C:28]([O:27][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH:29]=2)[OH:32])=[CH:13][CH:12]=[N:11]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1ccc([N+](=O)[O-])c(OCc2ccccc2)c1
Reactant: c1ccc(COCn2cccn2)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(C(O)c2ccnn2COCc2ccccc2)cc1OCc1ccccc1
Temperature: -78 °C
Reaction time: 0.33 h

Procedure:
To a solution of 1-benzyloxymethyl-1H-pyrazole (Example 279, step A) (278 mg, 1.48 mmol) in THF (4 mL) at −78° C. is added n-BuLi (2.5 M in hexanes, 0.60 mL, 1.5 mmol) dropwise. The mixture is stirred at −78° C. for 20 min then a solution of 3-benzyloxy-4-nitrobenzaldehyde (Example 83, step A) (315 mg, 1.23 mmol) in THF (4 mL) is added dropwise. The mixture is stirred at −78° C. for 30 min and then is partitioned between EtOAc and aq. NH4Cl. The organic phase is dried over MgSO4 and concentrated. The crude material is chromatographed to afford the title compound as a light brown oil: (M+1)+=446, (M+HCO2−)=490.
Reaction SMILES: Br[C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[B:13](OC(C)C)([O:18]C(C)C)[O:14]C(C)C.[Li]CCCC>Cl>[C:7]1([C:3]2[S:4][CH:5]=[CH:6][C:2]=2[B:13]([OH:18])[OH:14])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: Brc1ccsc1-c1ccccc1
Agent: Cl
Agent: [Li]CCCC
Product: OB(O)c1ccsc1-c1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 5.1 %

Procedure:
To a mixture of 3-bromo-2-phenylthiophene (1.99 g, 8.32 mmol) and B(Oi-Pr)3 (1.81 mL, 12.5 mmol) in TI-IF (20 mL) was added n-BuLi (1.65 M in hexane, 10.1 mL, 16.6 mmol) at −78° C. The mixture was stirred at −78° C. for 30 min and at 0° C. for 30 min. The mixture was diluted with 1 M HCl aqueous solution at 0° C., extracted with EtOAc, washed with brine, dried over Na2SO4, filtered, concentrated in vacuo and purified by column chromatography on silica gel (hexane/EtOAc=90/10 to 0/100) to yield the title compound (87.4 mg, 5% yield) as a white solid: 1H NMR (DMSO-d6, 300 MHz): δ ppm 7.19 (1H, d, J=4.9 Hz), 7.27-7.44 (3H, m), 7.46-7.58 (3H, m), 8.06 (2H, s).
Reaction SMILES: FC(F)(F)C(O)=O.C1(OC)C=CC=CC=1.[Cl:16][C:17]1[CH:18]=[CH:19][C:20]([C:25]#[C:26][C@@H:27]2[N:31](CC3C=CC(OC)=CC=3OC)[C:30](=[O:43])[CH2:29][CH2:28]2)=[N:21][C:22]=1[O:23][CH3:24]>>[Cl:16][C:17]1[CH:18]=[CH:19][C:20]([C:25]#[C:26][C@@H:27]2[NH:31][C:30](=[O:43])[CH2:29][CH2:28]2)=[N:21][C:22]=1[O:23][CH3:24]
Reactant: COc1ccc(CN2C(=O)CC[C@@H]2C#Cc2ccc(Cl)c(OC)n2)c(OC)c1
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: COc1nc(C#C[C@H]2CCC(=O)N2)ccc1Cl
Temperature: 80 °C
Reaction time: 2 h
Yield: 81.9 %

Procedure:
Trifluoroacetic acid (4 mL) and anisole (2 mL) were added to (5R)-5-[(5-chloro-6-methoxypyridin-2-yl)ethynyl]-1-(2,4-dimethoxybenzyl)pyrrolidin-2-one (457 mg), and the mixture was stirred at 80° C. for two hours. The reaction solution was concentrated, and the residue was diluted with chloroform, washed with saturated aqueous sodium bicarbonate and brine and dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1→0:1) to give the title compound as a colorless oil (234 mg, 82%).
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:24]([C:27]2[C:32]([F:33])=[CH:31][CH:30]=[CH:29][N:28]=2)=[CH:23][C:3]=1[C:4]([NH:6][C:7]1[N:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:10]=[C:9]([C:18](OCC)=[O:19])[CH:8]=1)=[O:5].[CH2:34]([CH2:36][NH2:37])[OH:35].C(N(CC)C(C)C)(C)C>CO>[Cl:1][C:2]1[CH:26]=[CH:25][C:24]([C:27]2[C:32]([F:33])=[CH:31][CH:30]=[CH:29][N:28]=2)=[CH:23][C:3]=1[C:4]([NH:6][C:7]1[N:11]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:10]=[C:9]([C:18]([NH:37][CH2:36][CH2:34][OH:35])=[O:19])[CH:8]=1)=[O:5]
Reactant: NCCO
Reactant: CCOC(=O)c1cc(NC(=O)c2cc(-c3ncccc3F)ccc2Cl)n(-c2ccccc2)n1
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCCO)c1cc(NC(=O)c2cc(-c3ncccc3F)ccc2Cl)n(-c2ccccc2)n1
Yield: 41.7 %

Procedure:
Ethyl 5-(2-chloro-5-(3-fluoropyridin-2-yl)benzamido)-1-phenyl-1H-pyrazole-3-carboxylate (Example 113, 40 mg, 0.09 mmol), ethanolamine (15.7 mg, 0.26 mmol) and N,N-diisopropylethylamine (33.3 mg, 0.26 mmol) in methanol (1 mL) was heated at 50° C. in a sealed vial for 17 hours. The reaction was cooled and purified using reverse phase column chromatography eluting with 3-50% MeCN in water with 0.1% ammonia to afford the title compound as a white solid (18 mg, 44%).
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[CH:28]=[CH:27][C:26]([CH3:29])=[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:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=4)[C:14]3=[O:19])[CH:10]=[N:9]2)=[C:5]([CH3:20])[O:4][N:3]=1
Reactant: Cc1ccc(CBr)cc1
Reactant: Cc1noc(C)c1Cn1cc(N2C(=O)CNC2=O)cn1
Product: Cc1ccc(CN2CC(=O)N(c3cnn(Cc4c(C)noc4C)c3)C2=O)cc1

Procedure:
Prepared as in example 10-5 from 3-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)imidazolidine-2,4-dione (example 10-1) and 1-(bromomethyl)-4-methylbenzene. Yields 25%. MS M+H calculated 380.1; found 380.1. The title compound was shown to inhibit hT2R08 bitter receptor and had an IC50 of 0.06 uM.
Reaction SMILES: O[CH:2]([C:13]1[CH:18]=[CH:17][C:16]2[O:19][CH2:20][O:21][C:15]=2[CH:14]=1)[CH2:3][CH2:4][CH:5]([CH3:12])[CH2:6][CH2:7][CH:8]=[C:9]([CH3:11])[CH3:10].OC(C1C=CC2OCOC=2C=1)CCCOCCC(C)C>>[CH3:12][CH:5]([CH2:6][CH2:7][CH:8]=[C:9]([CH3:10])[CH3:11])[CH2:4][CH:3]=[CH:2][C:13]1[CH:18]=[CH:17][C:16]2[O:19][CH2:20][O:21][C:15]=2[CH:14]=1
Reactant: CC(C)=CCCC(C)CCC(O)c1ccc2c(c1)OCO2
Agent: CC(C)CCOCCCC(O)c1ccc2c(c1)OCO2
Product: CC(C)=CCCC(C)CC=Cc1ccc2c(c1)OCO2

Procedure:
The above compound is produced in analogous manner to that described in Example 2, but using 1-(1-hydroxy-4,8-dimethyl-7-nonenyl)-3,4-methylenedioxy- benzene in the plate of 1-(1-hydroxy-4-isopentyloxybutyl)-3,4-methylenedioxybenzene. nD20 = 1.5426.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:15])=[CH:4][C:5]2[O:10][C:9]([CH3:12])([CH3:11])[CH2:8][C:7](=[O:13])[C:6]=2[CH:14]=1.[BH4-].[Na+].O>C(O)C>[Br:1][C:2]1[C:3]([CH3:15])=[CH:4][C:5]2[O:10][C:9]([CH3:12])([CH3:11])[CH2:8][CH:7]([OH:13])[C:6]=2[CH:14]=1
Reactant: Cc1cc2c(cc1Br)C(=O)CC(C)(C)O2
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Cc1cc2c(cc1Br)C(O)CC(C)(C)O2
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A stirred solution of the product of step c (26.9 g) in C2H5OH (200 ml) at 5° C. is treated with sodium borohydride (1.95 g) and stirred at room temperature for 12 h. The solvent is evaporated off under reduced pressure to give a residue which is treated with H2O (500 ml) and extracted with diethyl ether (3×200 ml). The combined extracts are dried (Na2SO4), filtered and the solvent is evaporated off under reduced pressure to yield the crude product. This is purified by chromatography (silica gel, 10% acetone in hexane) and recrystallized from diethyl ether-pentane to give the title compound, m.p. 92°-93° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11](=[C:14]([NH:17][C:18]2[CH:23]=[C:22]([Cl:24])[CH:21]=[C:20]([Cl:25])[CH:19]=2)SC)[C:12]#[N:13])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:26][CH:27]([NH2:32])[C:28]([CH3:31])([CH3:30])[CH3:29]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11](=[C:14]([NH:17][C:18]2[CH:23]=[C:22]([Cl:24])[CH:21]=[C:20]([Cl:25])[CH:19]=2)[NH:32][CH:27]([CH3:26])[C:28]([CH3:31])([CH3:30])[CH3:29])[C:12]#[N:13])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: CSC(Nc1cc(Cl)cc(Cl)c1)=C(C#N)S(=O)(=O)c1ccc(Cl)cc1
Reactant: CC(N)C(C)(C)C
Product: CC(NC(Nc1cc(Cl)cc(Cl)c1)=C(C#N)S(=O)(=O)c1ccc(Cl)cc1)C(C)(C)C
Yield: 60 %

Procedure:
2-(4-Chloro-phenylsulfonyl)-3-(3,5-dichlorophenylamino)-3-methylsulfanyl-2-propenenitrile (0.347 g, 0.8 mmol) was stirred in 1,2,2-trimethylpropylamine (1 ml) for 22 h at 100° C. under nitrogen in a sealed flask. Work up as described in Example 1, 2) gave 235 mg (60%) of the title compound. Mp 163-169° C. 1H NMR (200 MHz, CDCl3): δ=0.9 (s, 9H), 1.0 (d, 3H), 3.05 (m, 1H), 6.85 (br s, 2H), 7.2 (br s, 1H), 7.50 (d, 2H), 7.78 (d, 2H); EI SP/MS: 485 (M+), 487 (M+2), 489 (M+4), 491 (M+6).
Reaction SMILES: [CH:1]1([NH2:6])[CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:7][C:8]1[C:9](=[O:20])[C:10]2[C:15]([C:16](=[O:19])[C:17]=1Cl)=[CH:14][CH:13]=[CH:12][CH:11]=2>C(O)C>[CH:1]1([NH:6][C:17]2[C:16](=[O:19])[C:15]3[C:10]([C:9](=[O:20])[C:8]=2[Cl:7])=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NC1CCCC1
Reactant: O=C1C(Cl)=C(Cl)C(=O)c2ccccc21
Solvent: CCO
Product: O=C1C(Cl)=C(NC2CCCC2)C(=O)c2ccccc21
Temperature: 25 °C

Procedure:
18.7 G. of cyclopentylamine in 50 ml. of absolute ethanol are added dropwise while stirring at room temperature to a suspension of 22.7 g. of 2,3-dichloro-1,4-naphthoquinone in 100 ml. of absolute ethanol. After the addition, the mixture is boiled under reflux for 1 hour. The resulting dark-red mixture is then evaporated under reduced pressure. The residue is then dissolved in 600 ml. of chloroform and shaken out successively with 200 ml. of water, three times with 100 ml. of 3-N hydrochloric acid each time and three times with 100 ml. of water each time. After drying over sodium sulfate, the chloroform solution is concentrated, treated with active carbon and evaporated. After crystallization from n-hexane, 23.9 g. of 2-cyclopentylamino-3-chloro-1,4-naphthoquinone of melting point 81°-83°C. are obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@H:9]2[C@@H:15]([OH:16])[C:14](=[O:17])[N:13]([CH2:18][CH2:19][N:20]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH3:21])[C:12]3[CH:29]=[CH:30][C:31]([Cl:33])=[CH:32][C:11]=3[S:10]2)=[CH:5][CH:4]=1.[C:34](OC(=O)C)(=[O:36])[CH3:35]>N1C=CC=CC=1>[O:2]([C:3]1[CH:8]=[CH:7][C:6]([C@H:9]2[C@@H:15]([O:16][C:34](=[O:36])[CH3:35])[C:14](=[O:17])[N:13]([CH2:18][CH2:19][N:20]([C:22]([O:24][C:25]([CH3:28])([CH3:26])[CH3:27])=[O:23])[CH3:21])[C:12]3[CH:29]=[CH:30][C:31]([Cl:33])=[CH:32][C:11]=3[S:10]2)=[CH:5][CH:4]=1)[CH3:1]
Reactant: COc1ccc([C@@H]2Sc3cc(Cl)ccc3N(CCN(C)C(=O)OC(C)(C)C)C(=O)[C@@H]2O)cc1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: COc1ccc([C@@H]2Sc3cc(Cl)ccc3N(CCN(C)C(=O)OC(C)(C)C)C(=O)[C@@H]2OC(C)=O)cc1
Temperature: 110 °C
Reaction time: 4 h

Procedure:
A mixture of 1.67 g of (-)-cis-2-(4-methoxyphenyl)-3-hydroxy-5-[2-(N-tert.-butoxycarbonyl-N-methylamino)ethyl]-8-chloro-2,3-dihydro-1,5-benzothiazepin-4(5H)-one, 15 ml of acetic anhydride and 0.5 ml of pyridine is stirred at 110° C. for 4 hours. Then, the mixture is evaporated under reduced pressure to remove solvent. Benzene is added to the residue, and the mixture is evaporated under reduced pressure to remove solvent. 1.81 g of (-)-cis-2-(4-methoxylphenyl)-3-acetoxy-5-[2-(N-tert.-butoxycarbonyl-N-methylamino)ethyl]-8-chloro-2,3-dihydro-1,5-benzothiazepin-4(5H)-one are obtained as an oil.