Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][NH2:10].[Br:11][C:12]1[S:16][C:15]2=[N:17][C:18]([C:20](O)=[O:21])=[CH:19][N:14]2[CH:13]=1>>[Br:11][C:12]1[S:16][C:15]2=[N:17][C:18]([C:20]([NH:10][CH2:9][C:3]3[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][C:4]=3[Cl:8])=[O:21])=[CH:19][N:14]2[CH:13]=1
Reactant: O=C(O)c1cn2cc(Br)sc2n1
Reactant: NCc1c(Cl)cccc1Cl
Product: O=C(NCc1c(Cl)cccc1Cl)c1cn2cc(Br)sc2n1

Procedure:
The title compound was prepared by essentially following the same procedures described for Intermediate XLIV, using (2,6-dichlorophenyl)methanamine and 2-bromoimidazo[2,1-b]thiazole-6-carboxylic acid as starting materials.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([S:10]([CH2:13][C:14]#[N:15])(=[O:12])=[O:11])=[CH:6][CH:5]=1.Br[CH2:17][C:18]#[N:19]>O1CCCC1>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([S:10]([CH:13]([CH2:17][C:18]#[N:19])[C:14]#[N:15])(=[O:11])=[O:12])=[CH:8][CH:9]=1
Reactant: N#CCBr
Reactant: N#CCS(=O)(=O)c1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: N#CCC(C#N)S(=O)(=O)c1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 11.8 %

Procedure:
To a 500 mL reaction flask was added 2.0 g (51.0 mmole) sodium hydride (60% dispersion in oil) and 20 mL hexanes. The hexanes were removed by pipette and replaced by 90 mL dry tetrahydrofuran (THF). The suspension was cooled to 0° C. and a solution of 10.0 g (46.4 mmole) 4-chlorophenylsulfonyl acetonitrile in 90 mL THF was added via addition funnel over 10 minutes maintaining the reaction temperature below 12° C. The resulting solution was removed from the cold bath and stirred at room temperature for 40 min. The solution was recooled to 0°C. and 3.4 mL (48.7 mmole) bromoacetonitrile in 5 mL THF was added dropwise via addition funnel. After 5 minutes, the reaction was removed from the cold bath and stirred at room temperature for two hours. The reaction was quenched with 1 mL of saturated ammonium chloride and concentrated to an oil which was transferred with 150 mL of dichloromethane to a separatory funnel containing 120 mL water. The organic layer was separated and washed once more with 120 mL water and once with 120 mL brine. The organic layer was then dried (Na2SO4), filtered, concentrated, and chromatographed through a bed of silica gel using 85:15 hexane:ethyl acetate. Isolation gave 1.4 g (12% yield) of the title compound as a yellow powder that was 96% pure by HPLC, m.p. 130-137° C.
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[NH:11][C:12]([C:14]1[CH:15]=[N:16][N:17]([C:23]3[CH:28]=[CH:27][C:26](Cl)=[C:25]([C:30]([F:33])([F:32])[F:31])[CH:24]=3)[C:18]=1[C:19]([CH3:22])([CH3:21])[CH3:20])=[O:13])[CH2:8]2.C12CC3CC(CC(C3)C1NC(C1C=NN(C3C=CC([C:60]([O:62][CH2:63][CH3:64])=[O:61])=CC=3C)C=1C(C)(C)C)=O)C2>>[CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[NH:11][C:12]([C:14]1[CH:15]=[N:16][N:17]([C:23]3[CH:28]=[CH:27][C:26]([C:60]([O:62][CH2:63][CH3:64])=[O:61])=[C:25]([C:30]([F:33])([F:32])[F:31])[CH:24]=3)[C:18]=1[C:19]([CH3:22])([CH3:21])[CH3:20])=[O:13])[CH2:8]2
Reactant: CCOC(=O)c1ccc(-n2ncc(C(=O)NC3C4CC5CC(C4)CC3C5)c2C(C)(C)C)c(C)c1
Reactant: CC(C)(C)c1c(C(=O)NC2C3CC4CC(C3)CC2C4)cnn1-c1ccc(Cl)c(C(F)(F)F)c1
Product: CCOC(=O)c1ccc(-n2ncc(C(=O)NC3C4CC5CC(C4)CC3C5)c2C(C)(C)C)cc1C(F)(F)F

Procedure:
Ethyl 4-[4-(2-adamantylcarbamoyl)-5-tert-butyl-pyrazol-1-yl]-2-(trifluoromethyl)benzoate was prepared from N-(2-adamantyl)-1-[4-chloro-3-(trifluoromethyl)phenyl]-5-tert-butyl-pyrazole-4-carboxamide (Intermediate #118) by the same process used for Intermediate #113.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH:11]([CH2:14][CH3:15])[CH2:12][CH3:13])=[C:6]([NH:16][C:17](=O)[CH2:18][C:19]2[S:20][CH:21]=[CH:22][CH:23]=2)[CH:5]=1.Cl>O1CCOCC1>[CH3:1][O:2][C:3]([C:4]1[CH:9]=[CH:8][C:7]2[N:10]([CH:11]([CH2:14][CH3:15])[CH2:12][CH3:13])[C:17]([CH2:18][C:19]3[S:20][CH:21]=[CH:22][CH:23]=3)=[N:16][C:6]=2[CH:5]=1)=[O:25]
Reactant: CCC(CC)Nc1ccc(C(=O)OC)cc1NC(=O)Cc1cccs1
Agent: Cl
Solvent: C1COCCO1
Product: CCC(CC)n1c(Cc2cccs2)nc2cc(C(=O)OC)ccc21
Temperature: 120 °C
Yield: 100.9 %

Procedure:
0.72 g of 4-(1-ethyl-propylamino)-3-(2-thiophen-2-yl-acetylamino)-benzoic acid methyl ester were dissolved in 5 ml of dry dioxane and 10 ml of 4M hydrochloric acid in dioxane were added. The reaction was heated in a microwave reactor to 120° C. for 10 min and concentrated to yield 0.69 g (100%) of 1-(1-ethyl-propyl)-2-thiophen-2-ylmethyl-1H-benzoimidazole-5-carboxylic acid methyl ester as a brown solid which was used in the next step without further purification.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:24])[C@@H:9]1[CH2:13][CH2:12][N:11](C(OCC2C=CC=CC=2)=O)[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.[OH-].[OH-].[Pd+2]>[CH3:24][N:8]([C@@H:9]1[CH2:13][CH2:12][NH:11][CH2:10]1)[C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(C(=O)OC(C)(C)C)[C@@H]1CCN(C(=O)OCc2ccccc2)C1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CN(C(=O)OC(C)(C)C)[C@@H]1CCNC1

Procedure:
To a stirred solution of benzyl (3R)-3-[(tert-butoxycarbonyl)(methyl)amino]pyrrolidine-1-carboxylate 34a (1.5 g, 5.17 mmole) in MeOH (10 ml) was added Pd(OH)2 on carbon (150 mg). The reaction mixture was under 1 atmosphere of H2 overnight, filtered through celite and concentrated, in vacuo. The residue obtained was used directly in the subsequent reaction without any further purification, vide infra. 1H NMR (300 MHz, CD3OD) δ 4.47 (1H, m), 3.20 (1H, m), 2.91 (2H, m), 2.76 (1H, m), 2.69 (3H, s), 1.89 (1H, m), 1.68 (1H, m), 1.35 (9H, s).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:5]=[C:4]([NH2:14])[N:3]=1.[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=1>>[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:2]2[CH:7]=[C:6]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[N:5]=[C:4]([NH2:14])[N:3]=2)=[CH:18][CH:17]=1
Reactant: Nc1nc(Cl)cc(-c2ccccc2)n1
Reactant: Nc1ccc(Cl)cc1
Product: Nc1nc(Nc2ccc(Cl)cc2)cc(-c2ccccc2)n1

Procedure:
Following the method described in Example 53, 4-chloro-6-phenyl-pyrimidin-2-ylamine and 4-chloro-phenylamine provided the title compound as the hydrochloride salt (63% yield). 1H NMR (DMSO-d6) δ 6.70 (s, 1H, Ar), 7.47 (d, 2H, J=8.7 Hz, Ar), 7.66 (d, 3H, J=6.9 Hz, Ar), 7.88 (d, 4H, J=7.2 Hz, Ar), 9.42 (s, 1H, NH), 12.91 (s, 1H, NH).
Reaction SMILES: [F:1][C:2]1[CH:31]=[CH:30][C:5]([C:6]([C:8]2[C:17](OS(C(F)(F)F)(=O)=O)=[CH:16][CH:15]=[C:14]3[C:9]=2[CH:10]=[CH:11][C:12]([S:26]([CH3:29])(=[O:28])=[O:27])=[CH:13]3)=[O:7])=[CH:4][CH:3]=1.[C-:32]#[N:33].[K+]>O1CCOCC1.[Cl-].[Na+].O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([C:8]2[C:17]([C:32]#[N:33])=[CH:16][CH:15]=[C:14]3[C:9]=2[CH:10]=[CH:11][C:12]([S:26]([CH3:29])(=[O:28])=[O:27])=[CH:13]3)=[O:7])=[CH:30][CH:31]=1
Reactant: CS(=O)(=O)c1ccc2c(C(=O)c3ccc(F)cc3)c(OS(=O)(=O)C(F)(F)F)ccc2c1
Reactant: [C-]#N
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CS(=O)(=O)c1ccc2c(C(=O)c3ccc(F)cc3)c(C#N)ccc2c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 63.1 %

Procedure:
A mixture of 5-(4-fluorobenzoyl)-6-trifluoromethylsulfonyloxy-2-methylsulfonylnaphthalene (2.5 g, 5.2 mmol) [prepared as described in step 1 above], potassium cyanide (0.41 g, 6.3 mmol), and tetrakis(triphenylphosphine)palladium(0) (0.30 g, 0.26 mmol) in dioxane (50 ml) was heated at reflux under argon. After 16 h, the reaction mixture was cooled to RT, poured into brine, and the product wias extracted into ethyl acetate. The organic layer was dried with sodium sulfate and concentrated in vacuo. The crude product was purified by flash chromatography (gradient elution, 10-60% ethyl acetate/hexane) and then recrystallized from ethyl acetate-hexane to give 1.16 g of 5-(4-fluorobenzoyl)-6-cyano-2-methylsulfonylnaphthalene as a solid (63% yield).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([C:9]2[N:10]([CH3:14])[CH:11]=[CH:12][N:13]=2)[CH:6]=[CH:7][CH:8]=1.B(Br)(Br)Br.C(=O)(O)[O-].[Na+]>ClCCl>[CH3:14][N:10]1[CH:11]=[CH:12][N:13]=[C:9]1[C:5]1[CH:4]=[C:3]([OH:2])[CH:8]=[CH:7][CH:6]=1
Reactant: COc1cccc(-c2nccn2C)c1
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Cn1ccnc1-c1cccc(O)c1
Temperature: 0 °C
Reaction time: 40 h
Yield: 31 %

Procedure:
To a stirred solution of 2-(3-methoxyphenyl)-1-methyl-1H-imidazole (step 1, 724 mg, 3.8 mmol) in dichloromethane (2 mL) was added a solution of boron tribromide (1 M in dichloromethane, 5 mL) at 0° C. The mixture was stirred at 0° C. for 3 h and at room temperature for 40 h. The mixture was poured into aqueous sodium bicarbonate solution (10 mL). The precipitated solids were collected by filtration and dried under reduced pressure to afford 205 mg (31%) of the title compound as a pale brown solid: 1H-NMR (CDCl3) δ 7.29–7.22 (2H, m), 7.09–7.07 (2H, m), 6.94 (1H, d, J=1.1 Hz), 6.83–6.78 (1H, m), 3.72 (3H, s); MS (ESI) m/z 175 (M+H)+, 173 (M−H)−.
Reaction SMILES: [Li+].CC([N-]C(C)C)C.C(=O)=O.CO.C(OP([CH2:22]/[CH:23]=[CH:24]/[C:25]([O:27][CH2:28][CH3:29])=[O:26])(OCC)=O)C.[CH:30](=O)[C:31]1[CH:36]=[CH:35][CH:34]=[N:33][CH:32]=1>C1COCC1.C(O)(=O)C>[N:33]1[CH:34]=[CH:35][CH:36]=[C:31]([CH:30]=[CH:22][CH:23]=[CH:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH:32]=1
Reactant: CCOC(=O)/C=C/CP(=O)(OCC)OCC
Reactant: O=Cc1cccnc1
Agent: CC(C)[N-]C(C)C
Agent: O=C=O
Agent: [Li+]
Solvent: CO
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CCOC(=O)C=CC=Cc1cccnc1
Yield: 89098.4 %

Procedure:
A solution of LDA (16.5 ml of 2M solution, 3.5 g, 0.03 mol) in THF (100 ml) was cooled to −70° C. or below (dry ice-methanol bath) under a nitrogen flow and treated dropwise with ethyl 4-diethylphosphonocrotonate (8.6 g, 0.037 mmol) while stirring. The mixture was further stirred for 15 minutes, treated dropwise with nicotinaldehyde (3.2 g, 0.030 mol), and then stirred at 0° C. for 1.5 hours. Next, the mixture was treated with acetic acid and evaporated. To the residue was added saturated aqueous sodium hydrogen carbonate and the mixture was extracted with ethyl acetate. The extract was treated according to conventional techniques. Evaporation of solvent yielded ethyl 5-(pyridin-3-yl)penta-2,4-dienoate as an oil (6.7 g).
Reaction SMILES: [C:1]([C:5]1[N:10]=[C:9]([N:11]2[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][CH2:19]Cl)[CH2:13][CH2:12]2)[CH:8]=[C:7]([CH:21]2[CH2:24][CH2:23][CH2:22]2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:25][N:26]1[CH:30]=[N:29][N:28]=[C:27]1[SH:31].[OH-].[Li+].[I-].[K+]>CN(C)C=O>[C:1]([C:5]1[N:10]=[C:9]([N:11]2[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][CH2:19][S:31][C:27]3[N:26]([CH3:25])[CH:30]=[N:29][N:28]=3)[CH2:13][CH2:12]2)[CH:8]=[C:7]([CH:21]2[CH2:24][CH2:23][CH2:22]2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cn1cnnc1S
Reactant: CC(C)(C)c1nc(C2CCC2)cc(N2CCN(CCCCl)CC2)n1
Agent: [I-]
Agent: [K+]
Agent: [Li+]
Solvent: CN(C)C=O
Product: Cn1cnnc1SCCCN1CCN(c2cc(C3CCC3)nc(C(C)(C)C)n2)CC1
Temperature: 25 °C
Reaction time: 14 h
Yield: 47 %

Procedure:
0.8 g of 2-tert-Butyl-4-[4-(3-chloro-propyl)-piperazin-1-yl]-6-cyclobutyl-pyrimidine (2.28 mmol), 0.29 g of 4-methyl-3-mercapto-1,2,4-triazole (2.52 mmol), 0.15 g of lithium hydroxide and a tip of a spatula of potassium iodide were dissolved in 20 ml of dimethylformamide. The mixture was stirred for 14 h at room temperature and then extracted with water and ethyl acetate. The organic layer was dried over magnesium sulfate, filtered, and evaporated to dryness. The residue was then purified by column chromatography on silica gel (dichloromethane-methanol (2-10%)) to yield an oily residue that was precipitated with acetonitrile thereby yielding 0.46 g of the title compound (47%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@H:12]([C:13]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[O:14][SiH2:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH2:11][CH2:10][C:9]1=[O:32])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.O([CH2:51][CH3:52])S(C(F)(F)F)(=O)=O>C1COCC1>[C:1]([O:5][C:6]([N:8]1[C@H:12]([C:13]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[O:14][SiH2:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH2:11][C@@H:10]([CH2:51][CH3:52])[C:9]1=[O:32])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1C(=O)CC[C@H]1C(O[SiH2]C(C)(C)C)(c1ccccc1)c1ccccc1
Reactant: CCOS(=O)(=O)C(F)(F)F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC[C@@H]1C[C@@H](C(O[SiH2]C(C)(C)C)(c2ccccc2)c2ccccc2)N(C(=O)OC(C)(C)C)C1=O
Reaction time: 0.75 h
Yield: 90 %

Procedure:
To a solution of (5S)-5-(tert-Butyl-diphenyl-silanyloxymethyl)-2-oxo-pyrrolidine-1-carboxylic acid tert-butyl ester (5.0 g, 11.0 mmol) in THF (50 mL) at −78° C. was added LHMDS (1.0 M in THF, 12.6 mL, 12.6 mmol). The mixture was stirred for 30 min before ethyl triflate (1.78 mL, 1.25 equiv.) was added. The reaction was stirred between −78° C. to −40° C. for 45 min. It was quenched with 5% citric acid at −50° C., extracted with ethyl acetate. The combined organic phases were washed with 5% NaHCO3, brine, and dried over MgSO4NaHCO3, brine, and dried over MgSO4. Evaporation of the solvent and flash column chromatography (hexanes/EtOAc, 4:1) gave the desired product (90% yield) as viscous oil. 1HNMR (400 MHz, CDCl3) δ 7.63 (m, 4 H), 7.41 (m, 6 H), 4.13 (m, 2 H), 3.86 (m, 1 H), 3.74 (d, 1 H), 2.71 (m, 1 H), 2.24 (t, 1 H), 1.95 (m, 1 H), 1.78 (q, 1 H), 1.46 (s, 9 H), 0.95 (t, 3 H).
Reaction SMILES: [Cl:1][C:2]1[C:6]([N:7]([CH2:19][CH3:20])[C:8](=[O:18])[CH2:9][CH2:10][S:11][CH2:12][CH2:13][C:14]([F:17])([F:16])[F:15])=[CH:5][N:4]([C:21]2[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=2)[N:3]=1.[OH:27]O>FC(F)(F)C(O)C(F)(F)F>[Cl:1][C:2]1[C:6]([N:7]([CH2:19][CH3:20])[C:8](=[O:18])[CH2:9][CH2:10][S:11]([CH2:12][CH2:13][C:14]([F:16])([F:15])[F:17])=[O:27])=[CH:5][N:4]([C:21]2[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=2)[N:3]=1
Reactant: CCN(C(=O)CCSCCC(F)(F)F)c1cn(-c2cccnc2)nc1Cl
Reactant: OO
Solvent: OC(C(F)(F)F)C(F)(F)F
Product: CCN(C(=O)CCS(=O)CCC(F)(F)F)c1cn(-c2cccnc2)nc1Cl
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 95.2 %

Procedure:
To a solution of N-(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)-N-ethyl-3-((3,3,3-trifluoropropyl)thio)propanamide (I) (500 mg, 1.229 mmol) in hexafluoroisopropanol (5 mL) stirring at room temperature was added 30% hydrogen peroxide (523 mg, 4.92 mmol). The solution was stirred at room temperature for 15 minutes. It was quenched with saturated sodium sulfite solution and extracted with CH2Cl2. Silica gel chromatography (0%-10% MeOH/CH2Cl2) gave the title compound as white semi-solid (495 mg, 95%): IR (thin film) 1660 cm−1; 1H NMR (400 MHz, CDCl3) δ 8.96 (d, J=2.4 Hz, 1H), 8.64 (dd, J=4.7, 1.4 Hz, 1H), 8.07-8.00 (m, 2H), 7.46 (ddd, J=8.3, 4.8, 0.7 Hz, 1H), 3.85-3.61 (m, 2H), 3.23-3.08 (m, 1H), 3.03-2.76 (m, 3H), 2.74-2.52 (m, 4H), 1.18 (t, J=7.2 Hz, 3H); ESIMS m/z 423 ([M+H]+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]=[C:10]([C:18](O)=[O:19])[N:9]=2)=[CH:4][CH:3]=1.[CH2:21]([N:23](CC)[CH2:24][CH3:25])[CH3:22].ClC(OCC)=O.C(NCC)C>C(Cl)(Cl)Cl>[CH2:21]([N:23]([CH2:24][CH3:25])[C:18]([C:10]1[N:9]=[C:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[C:17]2[C:12]([CH:11]=1)=[CH:13][CH:14]=[CH:15][CH:16]=2)=[O:19])[CH3:22]
Reactant: CCN(CC)CC
Reactant: O=C(O)c1cc2ccccc2c(-c2ccc(Cl)cc2)n1
Agent: CCOC(=O)Cl
Solvent: CCNCC
Solvent: ClC(Cl)Cl
Product: CCN(CC)C(=O)c1cc2ccccc2c(-c2ccc(Cl)cc2)n1
Yield: 45.9 %

Procedure:
Operations are carried out as for Example 7, starting from 2.83 g of 1-(4-chloro phenyl) isoquinoline 3-carboxylic acid, 1.15 g of triethylamine, 1.24 g of ethyl chloroformate and 0.95 of diethylamine in 100 ml of chloroform. 1.55 g of N,N-diethyl 1-(4-chloro phenyl) isoquinoline 3-carboxamide, melting at 122° C., is obtained.
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH2:7][N:8]2[CH:12]=[C:11]([N:13]3[C:17](=[O:18])[C:16]([CH3:20])([CH3:19])[NH:15][C:14]3=[O:21])[CH:10]=[N:9]2)=[C:5]([CH3:22])[O:4][N:3]=1.Br[CH2:24][C:25]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=1>>[CH3:1][C:2]1[C:6]([CH2:7][N:8]2[CH:12]=[C:11]([N:13]3[C:17](=[O:18])[C:16]([CH3:19])([CH3:20])[N:15]([CH2:24][C:25]4[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=4)[C:14]3=[O:21])[CH:10]=[N:9]2)=[C:5]([CH3:22])[O:4][N:3]=1
Reactant: Fc1ccc(CBr)cc1
Reactant: Cc1noc(C)c1Cn1cc(N2C(=O)NC(C)(C)C2=O)cn1
Product: Cc1noc(C)c1Cn1cc(N2C(=O)N(Cc3ccc(F)cc3)C(C)(C)C2=O)cn1
Yield: 40 %

Procedure:
Prepared as in Example 12-16 from 3-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)-5,5-dimethylimidazolidine-2,4-dione (Example 12-16a) and 1-(bromomethyl)-4-fluorobenzene. Yield 40%, white solid. 1H NMR (DMSO-d6, 400 MHz): s, 6H), 2.14 (s, 3H), 2.40 (s, 3H), 4.53 (s, 2H), 5.18 (s, 2H), 7.13 (m, 2H) 7.43 (m, 2H), 7.81 (s, H), 8.18 (s, 1H). MS 412 (MH+). The title compound was shown to inhibit hT2R08 bitter receptor and had an IC50 of 0.08 μM.
Reaction SMILES: C(OC([NH:6][CH:7]1[CH2:12][S:11][C:10]2[S:13][CH:14]=[CH:15][C:9]=2[CH2:8]1)=O)C.[OH-].[Na+].[ClH:18]>C(O)C(O)C>[ClH:18].[S:13]1[C:10]2[S:11][CH2:12][CH:7]([NH2:6])[CH2:8][C:9]=2[CH:15]=[CH:14]1
Reactant: CCOC(=O)NC1CSc2sccc2C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(O)CO
Product: NC1CSc2sccc2C1

Procedure:
A mixture of 5.3 g of 5-ethoxycarbonylamino-5,6-dihydro-4H-thieno[2,3-b]thiopyran, 20 ml of 26% aqueous sodium hydroxide and 20 ml of 1,2-propanediol is heated at 140° for 3 hours. The reaction mixture is cooled and carefully acidified with 29 ml of 6N hydrochloric acid leading to evolution of gas. The resulting mixture is basified with 50% sodium hydroxide solution and extracted with ethyl acetate. The ethyl acetate extract is evaporated to dryness, the residue is dissolved in ether, the ether solution is washed with water and evaporated to dryness. The residue is dissolved in 40 ml of ethyl acetate and 41 ml of a solution of hydrogen chloride in ethyl acetate (0.535 molar) is added. The resulting precipitate is collected and dried to yield 5,6-dihydro-4H-thieno[2,3-b]thiopyran-5-amine hydrochloride.
Reaction SMILES: [CH:1]1[C:11]2[CH:10]=[CH:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[C:6](=[O:16])[C:5]=2[CH:4]=[CH:3][C:2]=1[CH:17]([CH3:20])[CH:18]=[O:19].CC(C)=[O:23].CC(C)=O.OS(O)(=O)=O.O=[Cr](=O)=O>O>[CH:1]1[C:11]2[CH:10]=[CH:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[C:6](=[O:16])[C:5]=2[CH:4]=[CH:3][C:2]=1[CH:17]([CH3:20])[C:18]([OH:23])=[O:19]
Reactant: CC(C=O)c1ccc2c(=O)c3ccccc3ccc2c1
Reactant: CC(C)=O
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: O
Product: CC(C(=O)O)c1ccc2c(=O)c3ccccc3ccc2c1
Reaction time: 2 h
Yield: 40 %

Procedure:
0.4 Gm. of 2-(5H-dibenzo[a,d]cyclohepten-5-on-2-yl)-propionaldehyde is dissolved in 15 ml. of acetone and the solution is cooled to 0° C. under nitrogen. 0.4 ml. of 8N Jones reagent is added and the mixture is stirred for 2 hours, then diluted with water and extracted with ethyl acetate. The extract is washed with water then extracted with aqueous sodium carbonate. The aqueous solution is acidified with dilute hydrochloric acid and extracted with ethyl acetate. The ethyl acetate solution is dried and evaporated to yield 40% of 2-(5H-dibenzo[a,d]cyclohepten-5-on-2-yl)propionic acid, m.p. (chloroform-hexane) 138°-139° C.; m.p. (acetonehexane) 113°-115° C.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[C:10]([OH:12])=O)[CH:3]=[CH:2]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)C(C)C)(C)C.[C:44]([C:48]1[CH:65]=[CH:64][C:51]([CH2:52][NH:53][CH2:54][CH2:55][CH:56]([C:58]2[O:59][C:60]([CH3:63])=[CH:61][CH:62]=2)[CH3:57])=[CH:50][CH:49]=1)([CH3:47])([CH3:46])[CH3:45]>CN(C=O)C.O>[C:44]([C:48]1[CH:65]=[CH:64][C:51]([CH2:52][N:53]([CH2:54][CH2:55][CH:56]([C:58]2[O:59][C:60]([CH3:63])=[CH:61][CH:62]=2)[CH3:57])[C:10]([C:8]2[CH:7]=[CH:6][CH:5]=[C:4]3[C:9]=2[NH:1][CH:2]=[CH:3]3)=[O:12])=[CH:50][CH:49]=1)([CH3:46])([CH3:45])[CH3:47]
Reactant: Cc1ccc(C(C)CCNCc2ccc(C(C)(C)C)cc2)o1
Reactant: O=C(O)c1cccc2cc[nH]c12
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: Cc1ccc(C(C)CCN(Cc2ccc(C(C)(C)C)cc2)C(=O)c2cccc3cc[nH]c23)o1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 65.5 %

Procedure:
To a solution of 48 mg (0.3 mmol) of 1H-indole-7-carboxylic acid and 96 mg of TBTU (0.3 mmol) in 4 ml DMF, were added 0.26 ml (1.5 mmol) of N,N-diisopropylethyl amine. After stirring for 5 min at rt, 90 mg (0.3 mmol) of [rac]-(4-tert-butyl-benzyl)-[3-(5-methyl-furan-2-yl)-butyl]-amine in 1 ml DMF were added. After stirring for 2 h at rt, the reaction mixture was diluted with 50 ml water and extracted with 2×50 ml EtOAc. The combined organic phases were washed with water and brine, dried with magnesium sulfate, filtered and concentrated in vacuo. The orange residue was purified by column chromatography (8 g silica gel; heptane/EtOAc 6:1) to give 87 mg (63%) of a colorless viscous oil. MS (ISP) 443.5 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH:8]([CH2:14][C:15]3[NH:16][CH:17]=[CH:18][N:19]=3)[C:9]2(O)[CH3:12])=[CH:4][CH:3]=1.C1(C(C2C=CC=CC=2)(C2C=CC=CC=2)O)C=CC=CC=1>FC(F)(F)C(O)=O>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([CH2:14][C:15]3[NH:19][CH:18]=[CH:17][N:16]=3)=[C:9]2[CH3:12])=[CH:4][CH:3]=1
Reactant: CC1(O)c2cc(Br)ccc2CCC1Cc1ncc[nH]1
Agent: OC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: Cc1c(Cc2ncc[nH]2)ccc2ccc(Br)cc12
Yield: 75.5 %

Procedure:
A solution of 7-bromo-1-hydroxy-1-methyl-2-(1-imidazolylmethyl)-1,2,3,4-tetrahydronaphthalene (1.95 g) and triphenylmethanol (2.37 g) in trifluoroacetic acid (30 ml) was heated under reflux for 4 days. An additional 2.37 g of triphenylmethanol was added and the solution was heated under reflux for a further 5 days. The solution was evaporated and the residue was basified with diluted sodium hydroxide solution. The mixture was extracted several times with ethyl acetate and the combined extracts were washed with water and dried (Na2SO4). Evaporation of the solvent gave an oil which was chromatographed on silica gel. Elution with chloroform first gave triphenylmethane and some triphenylmethanol followed by pure product. The product-containing fractions were evaporated to give 7-bromo-2-(1-imidazolylmethyl)-1-methylnaphthalene (1.38 g). A sample crystallised from ethyl acetate/petrol (b.p. 60°-80°) had m.p. 112°-113°.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]2[N:13]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:12](=[O:20])[CH2:11][CH:10]2[CH2:21]OS(C2C=CC(C)=CC=2)(=O)=O)[CH:6]=[CH:7][CH:8]=1.[CH3:33][NH:34][CH3:35]>CN(C)C=O>[CH3:33][N:34]([CH2:21][CH:10]1[CH:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=2)[N:13]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:12](=[O:20])[CH2:11]1)[CH3:35]
Reactant: CNC
Reactant: COc1cccc(C2C(COS(=O)(=O)c3ccc(C)cc3)CC(=O)N2c2ccccc2)c1
Solvent: CN(C)C=O
Product: COc1cccc(C2C(CN(C)C)CC(=O)N2c2ccccc2)c1
Reaction time: 3 h

Procedure:
To. 22.0 gm of 5-(3-methoxyphenyl)-1-phenyl-4-(p-toluenesulfonyloxymethyl)pyrrolidin-2-one in 150 ml. of dimethylformamide was added 21 ml. of 40% aqueous dimethylamine, the solution refluxed for 3 hours and then 21 ml. more of 40% aqueous dimethylamine added and reflux continued for an additional 3 hours. After cooling the reaction was decanted into ice water and acidified. Extraction with ether following by basification of the aqueous phase with potassium carbonate yielded a semi-solid which was extracted with chloroform, dried (Na2SO4), filtered and concentrated in vacuo to a solid. Recrystallization from acetonitrile provided 7.0 gm. of beige crystals, m.p. 88°-92°.