Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:49])[CH2:5][NH:6][C:7](=[O:48])[NH:8][CH2:9][C@:10]12[CH2:44][CH2:43][C@@H:42]([C:45]([CH3:47])=[CH2:46])[C@@H:11]1[C@@H:12]1[C@@:25]([CH3:28])([CH2:26][CH2:27]2)[C@@:24]2([CH3:29])[C@@H:15]([C@:16]3([CH3:41])[C@@H:21]([CH2:22][CH2:23]2)[C:20]([CH3:31])([CH3:30])[C:19]([C:32]2[CH:40]=[CH:39][C:35]([C:36]([OH:38])=[O:37])=[CH:34][CH:33]=2)=[CH:18][CH2:17]3)[CH2:14][CH2:13]1)C.[OH-].[Na+]>O1CCOCC1.CO>[CH3:1][O:3][C:4](=[O:49])[CH2:5][NH:6][C:7](=[O:48])[NH:8][CH2:9][C@:10]12[CH2:44][CH2:43][C@@H:42]([C:45]([CH3:47])=[CH2:46])[C@@H:11]1[C@@H:12]1[C@@:25]([CH3:28])([CH2:26][CH2:27]2)[C@@:24]2([CH3:29])[C@@H:15]([C@:16]3([CH3:41])[C@@H:21]([CH2:22][CH2:23]2)[C:20]([CH3:31])([CH3:30])[C:19]([C:32]2[CH:33]=[CH:34][C:35]([C:36]([OH:38])=[O:37])=[CH:39][CH:40]=2)=[CH:18][CH2:17]3)[CH2:14][CH2:13]1
Reactant: C=C(C)[C@@H]1CC[C@]2(CNC(=O)NCC(=O)OCC)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1COCCO1
Product: C=C(C)[C@@H]1CC[C@]2(CNC(=O)NCC(=O)OC)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 70 °C
Reaction time: 2 h
Yield: 0 %

Procedure:
4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((3-(2-ethoxy-2-oxoethyl)ureido)methyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoic acid (7 mg, 10.40 mmol) was dissolved in dioxane (2 ml) and methanol (1 ml). A solution of sodium hydroxide (1N, 0.021 ml, 0.021 mmol) was added. The mixture was stirred at 70° C. for 2 h. The solvent was removed under reduced pressure and the residue was purified by prep. HPLC to afford the title compound as a white solid (2 mg, 29.2%). LCMS: m/e 659.4 (MH+), 2.84 min (method 3). 1H NMR (500 MHz, MeOD) δ ppm 7.86 (d, J=8.2 Hz, 2H), 7.14 (d, J=7.9 Hz, 2H), 5.23-5.38 (m, 1H), 4.74 (s, 1H), 4.62 (s, 1H), 3.91 (s, 2H), 3.71-3.78 (m, 3H), 2.95-3.10 (m, 1H), 2.46-2.62 (m, 1H), 2.12-2.25 (m, 1H), 2.05 (s, 1H), 1.99-2.03 (m, 1H), 1.91-1.99 (m, 6H), 1.89 (br. s., 2H), 1.76-1.83 (m, 2H), 1.71-1.76 (m, 4H), 1.69 (br. s., 1H), 1.48 (br. s., 4H), 1.31 (br. s., 4H), 1.19 (s, 3H), 1.07 (br. s., 3H), 1.05 (s, 3H), 0.97 (s, 3H), 0.96 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[C:23]([Cl:24])=[CH:22][C:5]([C:6]([NH:8][CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)[CH2:11][CH2:10]2)=[O:7])=[C:4]([O:25][CH3:26])[CH:3]=1.C(N(CC)CC)C.[CH3:34][N:35]([CH3:39])[C:36](Cl)=[O:37]>C(Cl)Cl>[NH2:1][C:2]1[C:23]([Cl:24])=[CH:22][C:5]([C:6]([NH:8][CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH:16]3[CH2:17][CH2:18][N:19]([C:36](=[O:37])[N:35]([CH3:39])[CH3:34])[CH2:20][CH2:21]3)[CH2:11][CH2:10]2)=[O:7])=[C:4]([O:25][CH3:26])[CH:3]=1
Reactant: COc1cc(N)c(Cl)cc1C(=O)NC1CCN(CC2CCNCC2)CC1
Reactant: CN(C)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc(N)c(Cl)cc1C(=O)NC1CCN(CC2CCN(C(=O)N(C)C)CC2)CC1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of 4-amino-5-chloro-2-methoxy-N-[1-(4-piperidinylmethyl)-4-piperidinyl]benzamide (610 mg) in methylene chloride (30 ml) is added triethylamine (0.22 ml), and further thereto is added dimethylcarbamoyl chloride (0.15 ml) under ice-cooling. The mixture is stirred at room temperature for 5 hours. The reaction mixture is washed with water and a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent is evaporated under reduced pressure. The residue is purified by basic silica gel column chromatography (eluent; chloroform) to give the desired compound (720 mg) as white amorphous.
Reaction SMILES: [OH:1]/[N:2]=[C:3](\[C:10]#[N:11])/[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:12][C:13]1[CH:18]=[CH:17][C:16]([S:19](Cl)(=[O:21])=[O:20])=[CH:15][CH:14]=1>C1(C)C=CC=CC=1.C(OCC)(=O)C>[S:19]([O:1]/[N:2]=[C:3](\[C:10]#[N:11])/[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)([C:16]1[CH:17]=[CH:18][C:13]([CH3:12])=[CH:14][CH:15]=1)(=[O:21])=[O:20]
Reactant: N#C/C(=N\O)c1ccccc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: Cc1ccc(S(=O)(=O)O/N=C(\C#N)c2ccccc2)cc1
Reaction time: 2 h
Yield: 60.4 %

Procedure:
A mixture of (Z)—N-hydroxybenzimidoyl cyanide (8 g, 55.1 mmol) and 4-methylbenzene-1-sulfonyl chloride (10.51 g, 55.1 mmol) in toluene (70 mL) was heated at reflux. After 2 h, the reaction was allowed to cool, diluted with ethyl acetate (100 mL) and washed with water (50 mL) and brine (50 mL). The organic layer was dried over anhydrous Na2SO4 and concentrated to yield (Z)—N-(tosyloxy)benzimidoyl cyanide (10 g, 33.3 mmol, 60.4% yield) as a light yellow solid.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:17][CH:16]2[CH:18]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21](OS(C(F)(F)F)(=O)=O)[CH:20]=3)[CH:13]([CH2:14][CH2:15]2)[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=[NH:46])(C1C=CC=CC=1)C1C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.Cl.C([O-])(O)=O.[Na+]>C1COCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:1]([O:8][C:9]([N:11]1[CH2:17][CH:16]2[CH:18]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([NH2:46])[CH:20]=3)[CH:13]([CH2:14][CH2:15]2)[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N=C(c1ccccc1)c1ccccc1
Reactant: O=C(OCc1ccccc1)N1CC2CCC(C1)C2c1cccc(OS(=O)(=O)C(F)(F)F)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cl
Solvent: C1CCOC1
Product: Nc1cccc(C2C3CCC2CN(C(=O)OCc2ccccc2)C3)c1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 56.6 %

Procedure:
8-[3-(Trifluoro-methanesulfonyloxy)-phenyl]-3-aza-bicyclo[3.2.1]octane-3-carboxylic acid benzyl ester (800 mg, theoretical amount 1.24 mmol) was azeotroped with THF (2×20 mL) then dissolved in anhydrous THF (10 mL) with benzophenone imine (0.260 mL, 1.55 mmol), cesium carbonate (606 mg, 1.86 mmol) and BINAP (racemic, 77 mg, 0.12 mmol). The reaction vessel was degassed (evac./N2 purge 3×) before charging with palladium (II) acetate (28 mg, 0.12 mmol). The reaction was warmed to 80° C. 18 h, at which point it was judged complete by APCI MS. To this was added fresh THF (10 mL) followed by 2N HCl (5 mL) and this solution was allowed to stir at room temperature 30 min. The reaction mixture was neutralized with saturated aqueous NaHCO3 solution. The product was extracted with EtOAc (3×30 mL), washed with saturated aqueous NaCl solution (1×30 mL), dried over Na2SO4 and concentrated to give the crude product. Flash chromatography provided the title compound as a thick yellow oil (236 mg, 57%). (TLC 30% EtOAc/hexanes Rf 0.15). 1H NMR (400 MHz, CDCl3) δ 7.35 (m, 2H), 7.30 (m, 3H), 7.10 (m, 1H), 6.65 (m, 1H), 6.55 (m, 2H), 5.15 (s, 2H), 4.07 (dd, J=12.5, 2.5 Hz, 1H), 3.99 (dd, J=12.5, 2.5 Hz, 1H), 3.13 (d, J=12.5 Hz, 1H), 3.08 (d, J=12.5 Hz, 1H), 2.86 (s, 1H), 2.55 (brs, 1H), 2.48 (br s, 1H), 1.69 (m, 2H), 1.52 (m, 2H). APCI MS m/z 338.1 (M+1)+; 378.3 (M+CH3CN)+.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1)#[N:2].[CH3:10][C:11]([C:13]1[CH:18]=[CH:17][C:16](F)=[CH:15][C:14]=1[Cl:20])=[O:12].C([O-])([O-])=O.[K+].[K+].CCCCCCC.CCOC(C)=O>CC(N(C)C)=O.O>[C:11]([C:13]1[CH:18]=[CH:17][C:16]([O:9][C:6]2[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=2)=[CH:15][C:14]=1[Cl:20])(=[O:12])[CH3:10]
Reactant: CC(=O)c1ccc(F)cc1Cl
Reactant: N#Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCCC
Solvent: O
Solvent: CCOC(C)=O
Product: CC(=O)c1ccc(Oc2ccc(C#N)cc2)cc1Cl

Procedure:
To a solution 4-cyanophenol (CAS Reg. No. 767-00-0, 1.2 g), 2-chloro-4-fluoroacetophenone (CAS Reg. No. 700-35-6, 1.7 g) in DMA (10 ml) was added K2CO3 (1.66 g). The mixture is refluxed for 5 h. TLC (heptane/EtOAc 2:1) showed complete conversion. Water was added and the mixture was extracted with DCM. The combined organic layers were dried over Na2SO4 and then concentrated to an oil. The residue was purified by flash chromatography (SiO2, EtOAc/heptane 1:2) to give the title compound (1.8 g) as yellow oil. MS (m/e)=272.2 [M+H+].
Reaction SMILES: [OH-:1].[K+].Br[C:4]1[CH:23]=[CH:22][C:7]([CH2:8][C:9]2[C:10]([CH2:20][CH3:21])=[N:11][N:12]3[C:17]([CH3:18])=[CH:16][C:15]([CH3:19])=[N:14][C:13]=23)=[CH:6][CH:5]=1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:20]([C:10]1[C:9]([CH2:8][C:7]2[CH:22]=[CH:23][C:4]([OH:1])=[CH:5][CH:6]=2)=[C:13]2[N:14]=[C:15]([CH3:19])[CH:16]=[C:17]([CH3:18])[N:12]2[N:11]=1)[CH3:21]
Reactant: [OH-]
Reactant: CCc1nn2c(C)cc(C)nc2c1Cc1ccc(Br)cc1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: [K+]
Product: CCc1nn2c(C)cc(C)nc2c1Cc1ccc(O)cc1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
Potassiumhydroxide (1.96 g, 34.9 mmol) was dissolved in 30 ml of a 1:1 mixture of argon-flushed dioxane and water. After addition of 3-(4-bromo-benzyl)-2-ethyl-5,7-dimethyl-pyrazolo[1,5-a]pyrimidine (3) (4 g, 11.62 mmol), Pd2(dba)3 (426 mg, 0.465 mmol) and tetramethyl Xphos (894 mg, 1.859 mmol), the mixture was flushed with argon and stirred for 1 h at 100° C. Then the mixture was treated with 1N HCl and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over Na2 SO4 and evaporated. Purification by chromatography (silica gel, ethylaceta/n-heptane) gave a yellow solid.
Reaction SMILES: [CH3:1][N:2]([CH3:19])[C:3]([C:5]1[N:14]([C:15]([CH3:18])([CH3:17])[CH3:16])[C:8]2[N:9]=[C:10](Cl)[N:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4].[C:20]([O:24][C:25]([N:27]1[CH:32]2[CH2:33][CH2:34][CH:28]1[CH2:29][N:30]([C:35]([C:37]1[CH:38]=[N:39][C:40]([NH2:43])=[CH:41][CH:42]=1)=[O:36])[CH2:31]2)=[O:26])([CH3:23])([CH3:22])[CH3:21]>>[C:20]([O:24][C:25]([N:27]1[CH:28]2[CH2:34][CH2:33][CH:32]1[CH2:31][N:30]([C:35]([C:37]1[CH:38]=[N:39][C:40]([NH:43][C:10]3[N:11]=[CH:12][C:7]4[CH:6]=[C:5]([C:3](=[O:4])[N:2]([CH3:19])[CH3:1])[N:14]([C:15]([CH3:18])([CH3:17])[CH3:16])[C:8]=4[N:9]=3)=[CH:41][CH:42]=1)=[O:36])[CH2:29]2)=[O:26])([CH3:23])([CH3:21])[CH3:22]
Reactant: CC(C)(C)OC(=O)N1C2CCC1CN(C(=O)c1ccc(N)nc1)C2
Reactant: CN(C)C(=O)c1cc2cnc(Cl)nc2n1C(C)(C)C
Product: CN(C)C(=O)c1cc2cnc(Nc3ccc(C(=O)N4CC5CCC(C4)N5C(=O)OC(C)(C)C)cn3)nc2n1C(C)(C)C
Yield: 61.4 %

Procedure:
Following general N—C coupling procedure 1, 7-tert-Butyl-2-chloro-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (150 mg, 0.534 mmol, 1.0 eq) was combined with 3-(6-Amino-pyridine-3-carbonyl)-3,8-diaza-bicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (178 mg, 0.534 mmol, 1.0 eq) which gave 3-[6-(7-tert-Butyl-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-pyridine-3-carbonyl]-3,8-diaza-bicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (189 mg) in 61% yield. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.43 (s, 10H) 1.59 (br. s., 2H) 1.74-1.84 (m, 12 H) 3.00 (d, J=2.53 Hz, 7H) 4.14 (br. s., 2H) 6.48 (s, 1H) 7.85 (dd, J=8.84, 2.27 Hz, 1H) 8.28-8.39 (m, 2H) 8.80 (s, 1H) 9.89 (s, 1H). MS m/z 577.6 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)[CH3:2].[H][H]>[Pd]>[C:4]([CH:5]1[CH2:10][CH2:9][C:8](=[O:11])[CH2:7][CH2:6]1)([O:3][CH2:1][CH3:2])=[O:12]
Reactant: CCOC(=O)c1ccc(O)cc1
Reactant: [H][H]
Agent: [Pd]
Product: CCOC(=O)C1CCC(=O)CC1

Procedure:
Into a 1-liter magnetically stirred autoclave is placed 489 grams of ethyl-p-hydroxybenzoate having the structure: ##STR139## and 5% palladium on carbon catalyst (4 grams). The autoclave is sealed and hydrogenated at 125°-140° C. and 50 psig hydrogen pressure until the uptake of hydrogen is approximately 70% of theory. GLC analysis indicates that the reaction product at this point contains 71% ketone having the structure: ##STR140## 7.6% alcohol having the structure: ##STR141## and 20% starting material having the structure: ##STR142##
Reaction SMILES: S(Cl)([Cl:3])=O.[CH2:5]([O:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22]O)=[CH:20][CH:19]=1)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].CN(C=O)C>C(Cl)Cl>[CH2:5]([O:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22][Cl:3])=[CH:20][CH:19]=1)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCCCCCOc1ccc(CO)cc1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCCCCCCCCCCCOc1ccc(CCl)cc1
Reaction time: 0.12 h

Procedure:
Thionyl chloride (38.8 g, 328 mmol) was added dropwise to a 0° C. solution of 4-Dodecyloxybenzyl alcohol (80.0 g, 274 mmol) in dry CH2Cl2 (900 mL) with a catalytic amount of DMF. Upon addition, reaction was allowed to stir for 5-10 minutes, while monitoring through TLC (CH2Cl2) for completion. Reaction mixture was concentrated under reduced pressure and the resulting residue re-crystallized from acetone to give the title benzyl chloride, decomposes upon melting. 77g (92%).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([CH:13]=[CH:14][N:15]=3)[N:12]=2)[CH:4]=[N:3]1.[Br:16]N1C(=O)CCC1=O.CCOC(C)=O>CN(C=O)C>[Br:16][C:13]1[N:11]2[N:12]=[C:7]([C:5]3[CH:4]=[N:3][N:2]([CH3:1])[CH:6]=3)[CH:8]=[CH:9][C:10]2=[N:15][CH:14]=1
Reactant: Cn1cc(-c2ccc3nccn3n2)cn1
Reactant: O=C1CCC(=O)N1Br
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cn1cc(-c2ccc3ncc(Br)n3n2)cn1
Temperature: 0 °C

Procedure:
6-(1-Methyl-1H-pyrazol-4-yl)-imidazo[1,2-b]pyridazine (Stage 8.2, 2.22 g, 11.1 mmol) was dissolved in DMF (33 mL) and cooled down to 0° C. with an ice-water bath. Then N-bromo-succinimide (2.3 g, 12.3 mmol) was added and the RM was stirred at the same temperature for 1 h45. It was then taken up with EtOAc and washed with a saturated solution of NaHCO3 and brine. The organic layer was dried over Na2SO4 and the solvent was removed. The residue was triturated with Et2O and the precipitate was filtered off to afford the title compound as a yellow solid (tR 1.3 min (conditions 2), MH+=278).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:11])=[C:6]([CH:10]=1)[C:7](O)=[O:8].[NH2:12][C:13]1[C:14]([CH3:24])=[C:15]([CH:20]=[CH:21][C:22]=1[CH3:23])[C:16]([O:18][CH3:19])=[O:17].C(N(CC)C(C)C)(C)C.CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:11])=[C:6]([CH:10]=1)[C:7]([NH:12][C:13]1[C:14]([CH3:24])=[C:15]([CH:20]=[CH:21][C:22]=1[CH3:23])[C:16]([O:18][CH3:19])=[O:17])=[O:8]
Reactant: Cc1ccc(Br)cc1C(=O)O
Reactant: COC(=O)c1ccc(C)c(N)c1C
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc(C)c(NC(=O)c2cc(Br)ccc2C)c1C
Reaction time: 0.17 h
Yield: 88.6 %

Procedure:
To a solution of 5-bromo-2-methylbenzoic acid (2.0 g, 0.0093 mol) in CH2Cl2 (20 mL) at 0° C. are added methyl 3-amino-2,4-dimethylbenzoate (1.49 g, 0.0084 mol, see preparation 10) and N,N-diisopropylethylamine (4.79 g, 0.0372 mol). After stirring the reaction mixture for 10 minutes, 1-propanephosphonic acid cyclic anhydride (50% solution in ethyl acetate, 8.87 g, 0.028 mol) is added via syringe and stirred at 50° C. After 16 hours, the solvent is removed under reduced pressure and the residue is diluted with water and extracted twice with ethyl acetate. The organic layers are combined and dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue is purified by flash chromatography (silica gel) using 10% ethyl acetate in hexane to give the title compound as a white solid (2.80 g, 80%). Mass spectrum (m/z): 376.1 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:11]=1)[C:7](Cl)=[N:8][OH:9].[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]#[CH:20])=[CH:15][CH:14]=1.N>>[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[O:9][N:8]=[C:7]([C:6]3[CH:5]=[N:4][CH:3]=[C:2]([Cl:1])[CH:11]=3)[CH:20]=2)=[CH:15][CH:14]=1
Reactant: ON=C(Cl)c1cncc(Cl)c1
Reactant: C#Cc1ccc(Cl)cc1
Agent: N
Product: Clc1ccc(-c2cc(-c3cncc(Cl)c3)no2)cc1

Procedure:
The titled compound was prepared according to Method CB using the product of Example 69B (57 mg, 0.3 mmol) and 1-chloro-4-ethynylbenzene (Aldrich, 41 mg, 0.3 mmol). 1H NMR (300 MHz, DMSO-d6) δ7.69 (dt, J=8.9, 2.6, 2.4 Hz, 2H), 7.82 (s, 1H), 7.93 (dt, J=8.9, 2.4, 2.2 Hz, 2H), 8.44 (t, J=2.2 Hz, 1H), 8.81 (d, J=2.4 Hz, 1H), 9.08 (d, J=1.6 Hz, 1H) ppm; MS (DCI/NH3) m/z 291 (M+H)+, 293 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([O:8][CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][O:10]2)[CH:5]=[CH:4][C:3]=1[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH:21]=[O:22])[CH:16]=1.[BH4-].[Na+].[Cl-].[NH4+]>COCCOC.O1CCCC1>[CH3:1][C:2]1[CH:7]=[C:6]([O:8][CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][O:10]2)[CH:5]=[CH:4][C:3]=1[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][OH:22])[CH:16]=1
Reactant: Cc1cc(OC2CCCCO2)ccc1-c1cccc(C=O)c1
Agent: [BH4-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: COCCOC
Solvent: C1CCOC1
Product: Cc1cc(OC2CCCCO2)ccc1-c1cccc(CO)c1
Reaction time: 3 h
Yield: 89.1 %

Procedure:
2′-Methyl-4′-(tetrahydro-2H-pyran-2-yloxy)biphenyl-3-carbaldehyde (13.6 g, 45.9 mmol) was dissolved in a mixture of 1,2-dimethoxyethane (70 mL) and tetrahydrofuran (70 mL), and sodium borohydride (0.870 g, 23.0 mmol) was added under ice-cooling. The mixture was stirred at the same temperature for 3 hrs. To the reaction mixture was added aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (15%-50% ethyl acetate/hexane) to give the title compound (12.2 g, yield 89%) as a colorless oil.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]([CH2:17][C:18]([F:21])([F:20])[F:19])[C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[C:7]([C:13]([F:16])([F:15])[F:14])[CH:6]=1.O[C:23]1[N:28]=[CH:27][C:26]([NH:29][C:30](=[O:32])[CH3:31])=[CH:25][CH:24]=1>COCCOC>[C:9]([C:8]1[CH:11]=[CH:12][C:5]([N:4]([CH2:17][C:18]([F:19])([F:20])[F:21])[CH2:3][CH2:2][O:1][C:23]2[N:28]=[CH:27][C:26]([NH:29][C:30](=[O:32])[CH3:31])=[CH:25][CH:24]=2)=[CH:6][C:7]=1[C:13]([F:15])([F:16])[F:14])#[N:10]
Reactant: N#Cc1ccc(N(CCO)CC(F)(F)F)cc1C(F)(F)F
Reactant: CC(=O)Nc1ccc(O)nc1
Solvent: COCCOC
Product: CC(=O)Nc1ccc(OCCN(CC(F)(F)F)c2ccc(C#N)c(C(F)(F)F)c2)nc1

Procedure:
Synthesized as described in Example 27B from 4-[(2-hydroxyethyl)(2,2,2-trifluoroethyl)amino]-2-(trifluoromethyl)benzonitrile (Example 15B) and N-(6-hydroxy-3-pyridinyl)acetamide, using dry DME as the reaction solvent: MS (ESI) m/z 447 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N+:21]([O-])=O)=[C:6]([CH:20]=1)[C:7]([NH:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]2[O:17][CH2:18][O:19][C:13]=2[CH:12]=1)=[O:8].C(O)(=O)C.O>[Fe].C(O)C>[NH2:21][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:20][C:6]=1[C:7]([NH:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]2[O:17][CH2:18][O:19][C:13]=2[CH:12]=1)=[O:8]
Reactant: O=C(NCc1ccc2c(c1)OCO2)c1cc(Cl)ccc1[N+](=O)[O-]
Agent: [Fe]
Solvent: CCO
Solvent: O
Solvent: CC(=O)O
Product: Nc1ccc(Cl)cc1C(=O)NCc1ccc2c(c1)OCO2
Yield: 92.1 %

Procedure:
5-Chloro-N-(3,4-methylenedioxybenzyl)-2-nitrobenzamide (620 mg), acetic acid (1 ml), water (1 ml) and ethanol (20 ml) were mildly heated together under reflux, followed by the addition of 1.0 g of powdered iron in portions under stirring. The obtained mixture was refluxed for one hour and filtered under heating to remove brown insolubles. The filtrate was concentrated, followed by the addition of ethanol. The resulting mixture was dissolved by heating. Concentrated hydrochloric acid was added to the obtained solution in portions, by which the brown solution turned yellow and transparent. This yellow transparent solution was seeded to give crystals. The resulting mixture was cooled and filtered to recover the crystals. The crystals were washed with ethanol and ether and dried to give 520 mg of 2-amino-5-chloro-N-(3,4-methylenedioxybenzyl)benzamide.
Reaction SMILES: [Br:1][CH2:2][C:3]([C:5]1[CH:10]=[C:9]([S:11](=[O:16])(=[O:15])[N:12](C)C)[CH:8]=[CH:7][C:6]=1Br)=[O:4].Br[CH2:19]C(C1C=C(S(=O)(=O)N(C)C)C=C(Cl)C=1)=O.BrCC(C1C=C(S(=O)(=O)NC)C=CC=1Cl)=O.BrCC(C1C=C(S(=O)(=O)N(C)C)C=CC=1Cl)=O.BrCC(C1C=C(S(=O)(=O)N)C=CC=1Cl)=O.BrCC(C1C=C(S(=O)(=O)N(C)C)C=C(C)C=1)=O.BrCC(C1C=C(S(=O)(=O)N(C)C)C=CC=1C)=O.BrCC(C1C=C(S(=O)(=O)N)C=CC=1C)=O>>[Br:1][CH2:2][C:3]([C:5]1[CH:10]=[C:9]([S:11](=[O:16])(=[O:15])[NH2:12])[CH:8]=[C:7]([CH3:19])[CH:6]=1)=[O:4]
Reactant: CN(C)S(=O)(=O)c1ccc(Br)c(C(=O)CBr)c1
Reactant: CN(C)S(=O)(=O)c1cc(Cl)cc(C(=O)CBr)c1
Agent: CN(C)S(=O)(=O)c1ccc(Cl)c(C(=O)CBr)c1
Agent: CNS(=O)(=O)c1ccc(Cl)c(C(=O)CBr)c1
Agent: Cc1cc(C(=O)CBr)cc(S(=O)(=O)N(C)C)c1
Product: Cc1cc(C(=O)CBr)cc(S(N)(=O)=O)c1

Procedure:
The bromoacetophenones listed below were prepared in an analogous manner: 2,2'-dibromo-5'-dimethylsulfamoyl-acetophenone, melting point 88° C., 2-bromo-3'-chloro-5'-dimethylsulfamoyl-acetophenone, melting point 77°-78° C., 2-bromo-2'-chloro-5'-methylsulfamoyl-acetophenone, melting point 99°-101° C., 2-bromo-2'-chloro-5'-dimethylsulfamoyl-acetophenone, melting point 87°-88° C., 2-bromo-2'-chloro-5'-sulfamoylacetophenone, melting point 152°-154° C., 2-bromo-3'-methyl-5'-dimethylsulfamoylacetophenone, melting point 71°-75° C., 2-bromo-2'-methyl-5'-dimethylsulfamoylacetophenone, melting point 69°-71° C. and 2-bromo-2'-methyl-5'-sulfamoylacetophenone, melting point 112°-115° C.
Reaction SMILES: [F:1][C:2]([F:53])([F:52])[C:3]1[CH:4]=[C:5]([CH:45]=[C:46]([C:48]([F:51])([F:50])[F:49])[CH:47]=1)[CH2:6][N:7]([CH:25]([C:27]1[CH:32]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:30]=[CH:29][C:28]=1[N:37]([CH2:41][CH:42]1[CH2:44][CH2:43]1)[CH2:38][CH2:39][CH3:40])[CH3:26])[C:8]1[N:13]=[CH:12][C:11]([N:14]2[CH2:19][CH2:18][CH:17]([C:20]([O:22]CC)=[O:21])[CH2:16][CH2:15]2)=[CH:10][N:9]=1.[OH-].[Na+].C(OCC)(=O)C>C(O)C>[F:53][C:2]([F:1])([F:52])[C:3]1[CH:4]=[C:5]([CH:45]=[C:46]([C:48]([F:51])([F:50])[F:49])[CH:47]=1)[CH2:6][N:7]([CH:25]([C:27]1[CH:32]=[C:31]([C:33]([F:35])([F:36])[F:34])[CH:30]=[CH:29][C:28]=1[N:37]([CH2:41][CH:42]1[CH2:43][CH2:44]1)[CH2:38][CH2:39][CH3:40])[CH3:26])[C:8]1[N:13]=[CH:12][C:11]([N:14]2[CH2:19][CH2:18][CH:17]([C:20]([OH:22])=[O:21])[CH2:16][CH2:15]2)=[CH:10][N:9]=1
Reactant: CCCN(CC1CC1)c1ccc(C(F)(F)F)cc1C(C)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ncc(N2CCC(C(=O)OCC)CC2)cn1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCCN(CC1CC1)c1ccc(C(F)(F)F)cc1C(C)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ncc(N2CCC(C(=O)O)CC2)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.8 %

Procedure:
Ethyl 1-[2-((3,5-bis-trifluoromethyl-benzyl)-{1-[2-(cyclopropylmethyl-propyl-amino)-5-trifluoromethyl-phenyl]-ethyl}-amino)-pyrimidin-5-yl]-piperidine-4-carboxylate (75 mg) is dissolved in ethanol (1 ml), and thereto is added a 2N-aqueous sodium hydroxide solution (148 μl), and the mixture is stirred at room temperature overnight. Thereto are added ethyl acetate and a dilute hydrochloric acid and the mixture is separated, and the organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (chloroform:methanol=1:0→49:1) to give 1-[2-((3,5-bis-trifluoromethyl-benzyl)-{1-[2-(cyclopropylmethyl-propyl-amino)-5-trifluoromethyl-phenyl]-ethyl}-amino)-pyrimidin-5-yl]-piperidine-4-carboxylic acid (54 mg). MS (m/z): 732 [M+H]+
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH2:7][N:8]2[CH:12]=[C:11]([N:13]3[C:17](=[O:18])[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][CH2:25][C:26]1[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=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][CH2:25][C:26]4[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=4)[C:14]3=[O:21])[CH:10]=[N:9]2)=[C:5]([CH3:22])[O:4][N:3]=1
Reactant: Cc1noc(C)c1Cn1cc(N2C(=O)NC(C)(C)C2=O)cn1
Reactant: COc1ccc(CCBr)cc1
Product: COc1ccc(CCN2C(=O)N(c3cnn(Cc4c(C)noc4C)c3)C(=O)C2(C)C)cc1

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-(2-bromoethyl)-4-methoxybenzene. MS 438 (MH+). The title compound was shown to inhibit hT2R08 bitter receptor and had an IC50 of 0.12 μM.