Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N([O-])=O.[Na+].[C:5]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20](=[O:22])[CH3:21])=[CH:16][C:15]=2N)[CH2:10][CH2:9]1)(=[O:7])[CH3:6].[ClH:24]>O>[C:5]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20](=[O:22])[CH3:21])=[CH:16][C:15]=2[Cl:24])[CH2:10][CH2:9]1)(=[O:7])[CH3:6]
Reactant: Cl
Reactant: CC(=O)c1ccc(C2CCN(C(C)=O)CC2)c(N)c1
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: CC(=O)c1ccc(C2CCN(C(C)=O)CC2)c(Cl)c1
Reaction time: 2 h

Procedure:
A solution of 4.5 g of sodium nitrite in 10 ml of water is added dropwise at 0°, with stirring, to a suspension of 16 g of N-acetyl-4-(2-amino-4-acetyl-phenyl)-piperidine in 75 ml of concentrated hydrochloric acid and 75 ml of water; stirring is continued at 0° for 2 hours; the reaction solution, which is now clear, is transferred to a dropping funnel precooled to 0°, and is slowly added dropwise to a solution, cooled to 0° and being stirred, of 16 g of copper-I-chloride in 150 ml of semi-concentrated hydrochloric acid. Stirring is maintained at 15° until the evolution of nitrogen has ceased (about 1 hour). An addition of 300 ml of water is made, and extraction is performed three times with 150 ml of ethyl acetate each time. The organic phases are extracted three times at 0° with 150 ml of 2 N sodium hydroxide solution each time; they are then cleared by filtration, washed neutral, dried over sodium sulphate and concentrated in vacuo. The oily N-acetyl-4-(2-chloro-4-acetyl-phenyl)-piperidine obtained in this manner can be used without purification.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[N:2]1.[H-].[Na+].Br[C:9]1[N:13]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[F:21])[N:12]=[C:11]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=2)[N:10]=1.O>CN(C=O)C>[F:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[CH2:14][N:13]1[C:9]([N:1]2[CH:5]=[CH:4][CH:3]=[N:2]2)=[N:10][C:11]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=2)=[N:12]1
Reactant: c1cn[nH]c1
Reactant: Fc1ccccc1Cn1nc(-c2ccccn2)nc1Br
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Fc1ccccc1Cn1nc(-c2ccccn2)nc1-n1cccn1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A solution of pyrazole (1.1 eq) in DMF is treated with sodium hydride (e.g., about 60% w/w in mineral oil, about 1.2 eq) and stirred for about 10 min at room temperature. 2-(5-Bromo-1-(2-fluorobenzyl)-1H-1,2,4-triazol-3-yl)pyridine (I-16, e.g., 1.0 eq) is then added. The resultant mixture is warmed to about 50° C. and stirred at that temperature for about 1 h. The reaction solution is cooled to room temperature, poured into water, and filtered to yield 2-(1-(2-fluorobenzyl)-5-(1H-pyrazol-1-yl)-1H-1,2,4-triazol-3-yl)pyridine (I-10) as a solid.
Reaction SMILES: [Li+].C[Si]([N-][Si](C)(C)C)(C)C.[NH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.F[C:19]1[C:26]([N+:27]([O-:29])=[O:28])=[CH:25][CH:24]=[C:23]([F:30])[C:20]=1[C:21]#[N:22]>C1COCC1>[F:30][C:23]1[C:20]([C:21]#[N:22])=[C:19]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:26]([N+:27]([O-:29])=[O:28])=[CH:25][CH:24]=1
Reactant: N#Cc1c(F)ccc([N+](=O)[O-])c1F
Reactant: Nc1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: N#Cc1c(F)ccc([N+](=O)[O-])c1Nc1ccccc1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 55.2 %

Procedure:
LiHMDS (1.0M in THF, 38 mL, 38.0 mmol) was added dropwise to a stirred solution of aniline (1.86 g, 19.9 mmol) in anhydrous THF (30 mL) under a nitrogen atmosphere at −78° C. After 10 min stirring at −78° C., a solution of 2,6-difluoro-3-nitrobenzonitrile (3.5 g, 19.0 mmol) in THF (15 mL) was added and stirring at −78° C. continued for 30 min. The crude mixture was quenched with water and diluted with EtOAc. The resulting emulsion was filtered through a pad of Celite® and the organic fraction separated, washed with brine, dried (MgSO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, gradient 0-100% EtOAc in cyclohexane) to afford the title compound (2.7 g, 55%). 1H NMR (CDCl3, 400 MHz): δ 9.94 (1H, br s), 8.51 (1H, dd, J=9.50, 5.88 Hz), 7.51-7.21 (5H, m), 6.68 (1H, dd, J=9.50, 7.46 Hz).
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[CH2:13][NH:14][C:15]1[CH:24]=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][CH:16]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[CH2:13][NH:14][C:15]1[CH:24]=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][CH:16]=1
Reactant: COC(=O)c1ccc(NCC2CCCN2C(=O)OC(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)c1ccc(NCC2CCCN2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.1 %

Procedure:
To a stirred solution of methyl 4-[1-(tert-butoxycarbonyl)-2-pyrrolidinylmethylamino]benzoate (2.17 g, 6.490 mmol) in CH2Cl2 (44 mL) was added TFA (8.7 mL) at 0° C., and the resulting mixture was stirred overnight at room temp. The solvent was removed under a reduced pressure and the residue was treated with 1 N NaOH. The mixture was extracted with CH2Cl2. The extract was washed with brine, dried over Na2SO4, and the solvent was concentrated under a reduced pressure to afford 1.34 g (88%) methyl 4-(2-pyrrolidinylmethylamino)benzoate as a brown oil, which is used to the subsequent reaction without further purification.
Reaction SMILES: [O:1]=[S:2]1(=[O:19])[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[CH:12]=[CH:11][C:10]([CH:13]([CH3:17])[C:14]([OH:16])=O)=[CH:9][C:8]=1[F:18].ON1C2C=CC=CC=2N=N1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(C(C)C)C(C)C)C.[Cl:61][C:62]1[CH:63]=[C:64]([N:68]2[C:72]([CH2:73][NH2:74])=[CH:71][C:70]([C:75]([F:78])([F:77])[F:76])=[N:69]2)[CH:65]=[CH:66][CH:67]=1>C1COCC1>[Cl:61][C:62]1[CH:63]=[C:64]([N:68]2[C:72]([CH2:73][NH:74][C:14](=[O:16])[CH:13]([C:10]3[CH:11]=[CH:12][C:7]([N:3]4[CH2:4][CH2:5][CH2:6][S:2]4(=[O:1])=[O:19])=[C:8]([F:18])[CH:9]=3)[CH3:17])=[CH:71][C:70]([C:75]([F:76])([F:77])[F:78])=[N:69]2)[CH:65]=[CH:66][CH:67]=1
Reactant: NCc1cc(C(F)(F)F)nn1-c1cccc(Cl)c1
Reactant: CC(C(=O)O)c1ccc(N2CCCS2(=O)=O)c(F)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(C(=O)NCc1cc(C(F)(F)F)nn1-c1cccc(Cl)c1)c1ccc(N2CCCS2(=O)=O)c(F)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 71.7 %

Procedure:
To a solution of 2-[4-(1,1-Dioxo-[1,2]thiazolidin-2-yl)-3-fluoro-phenyl]-propionic acid (50 mg, 0.174 mmol) in THF (1.3 mL) was added 1-hydroxybenzotriazole (23 mg, 0.174 mmol), O-(1H-benzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumtetrafluoroborate (56 mg, 0.174 mmol), n-ethyldiisopropylamine (0.059 mL, 0.348 mmol) and (1-(3-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methanamine (47 mg, 0.174 mmol). The reaction mixture was stirred for 48 h at room temperature. The reaction mixture was concentrated in vacuo and purified by column chromatography (eluent: ethyl acetate/cyclohexan (2:1)) to give pure N-[[2-(3-chlorophenyl)-5-(trifluoromethyl)-2H-pyrazol-3-yl]-methyl]-2-[4-(1,1-dioxo-[1,2]thiazolidin-2-yl)-3-fluoro-phenyl]-propionamide (example compound C1) (68 mg, 72%).
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[NH:15])[CH2:6][C:7]1[C:12]([F:13])=[CH:11][CH:10]=[CH:9][C:8]=1[F:14])[CH3:3].[C:16](N)(=O)C(NN)=O.CN>CN(C)C=O>[CH2:2]([O:4][C:5](=[N:15][CH3:16])[CH2:6][C:7]1[C:12]([F:13])=[CH:11][CH:10]=[CH:9][C:8]=1[F:14])[CH3:3]
Reactant: NNC(=O)C(N)=O
Reactant: CCOC(=N)Cc1c(F)cccc1F
Agent: CN
Agent: Cl
Solvent: CN(C)C=O
Product: CCOC(Cc1c(F)cccc1F)=NC
Reaction time: 1 h

Procedure:
70.7 g (300 mmol) of 1-ethoxy-2-(2,6-difluorophenyl)-1-imino-ethane hydrochloride are added, while stirring, to a suspension of 30.9 g (300 mmol) of oxalic acid monoamide monohydrazide in 900 ml of N,N-dimethylformamide. The reaction mixture is heated to 80° and stirred at this temperature for 1 hour. During a period of 20 minutes 10.6 g of methylamine are passed into the resulting white suspension, which leads to the formation of a clear yellow solution. During a period of 1 hour a further 15.9 g of methylamine are passed into the solution. The solution is then stirred for another hour at 80°. The solvent is evaporated in vacuo. 400 ml of water are added to the residue. The aqueous mixture is stirred and the crystals are filtered off. 300 ml of water are added to the crystals. The mixture is again stirred and the crystals are filtered off. The crystals are dissolved in hot ethanol (ca. 500 ml). After the addition of activated charcoal the mixture is filtered over Hyflo. The filtrate is evaporated until crystallisation starts (ca. 230 ml of ethanol have to be distilled off). The mixture is then cooled in an ice bath. The crystals are filtered off and dried overnight in vacuo, yielding the product of example 1.
Reaction SMILES: [OH:1][N:2]=[C:3]([NH2:10])[C:4]1[CH:9]=[CH:8][CH:7]=[N:6][CH:5]=1.[C:11]([O:15][C:16]([NH:18][CH2:19][C:20]1[CH:21]=[C:22]([CH:26]=[CH:27][CH:28]=1)[C:23](O)=O)=[O:17])([CH3:14])([CH3:13])[CH3:12].N>>[N:6]1[CH:7]=[CH:8][CH:9]=[C:4]([C:3]2[N:10]=[C:23]([C:22]3[CH:21]=[C:20]([CH:28]=[CH:27][CH:26]=3)[CH2:19][NH:18][C:16](=[O:17])[O:15][C:11]([CH3:14])([CH3:12])[CH3:13])[O:1][N:2]=2)[CH:5]=1
Reactant: CC(C)(C)OC(=O)NCc1cccc(C(=O)O)c1
Reactant: NC(=NO)c1cccnc1
Agent: N
Product: CC(C)(C)OC(=O)NCc1cccc(-c2nc(-c3cccnc3)no2)c1

Procedure:
The title compound was prepared according to the procedure of Example 8 using N′-hydroxynicotinimidamide (Aldrich) and 3-((tert-butoxycarbonylamino)methyl)benzoic acid (Fluka). 1H NMR (300 MHz, DMSO-d6) δ 1.42 (s, 9H), 4.27 (d, J=6.1 Hz, 2H), 7.51-7.72 (m, 4H), 8.01-8.17 (m, 2H), 8.45 (dt, J=8.1, 1.9 Hz, 1H), 8.82 (dd, J=5.1, 1.7 Hz, 1H), 9.26 (dd, J=2.2, 0.8 Hz, 1H) ppm; MS (DCI/NH3) m/z 353 (M+H)+.
Reaction SMILES: Cl.C[O:3][C:4](=[O:16])[C@H:5]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([F:14])=[C:10]([Br:15])[CH:9]=1)[NH2:6].[N:17]1[S:21][N:20]=[C:19]2[C:22]([S:26]([NH:29][C:30]3[CH:38]=[C:37]([Cl:39])[C:36]([Cl:40])=[CH:35][C:31]=3[C:32](O)=[O:33])(=[O:28])=[O:27])=[CH:23][CH:24]=[CH:25][C:18]=12>>[N:17]1[S:21][N:20]=[C:19]2[C:22]([S:26]([NH:29][C:30]3[CH:38]=[C:37]([Cl:39])[C:36]([Cl:40])=[CH:35][C:31]=3[C:32]([NH:6][C@@H:5]([CH2:7][C:8]3[CH:13]=[CH:12][C:11]([F:14])=[C:10]([Br:15])[CH:9]=3)[C:4]([OH:3])=[O:16])=[O:33])(=[O:28])=[O:27])=[CH:23][CH:24]=[CH:25][C:18]=12
Reactant: O=C(O)c1cc(Cl)c(Cl)cc1NS(=O)(=O)c1cccc2nsnc12
Reactant: COC(=O)[C@@H](N)Cc1ccc(F)c(Br)c1
Agent: Cl
Product: O=C(N[C@@H](Cc1ccc(F)c(Br)c1)C(=O)O)c1cc(Cl)c(Cl)cc1NS(=O)(=O)c1cccc2nsnc12

Procedure:
The title compound was prepared from 3-bromo-4-fluoro-L-phenylalanine methyl ester hydrochloride and 2-(benzo[1,2,5]thiadiazole-4-sulfonylamino)-4,5-dichloro-benzoic acid as in Example 1, Part C, followed by hydrolysis of the resulting methyl ester as in EXAMPLE 2, Part E. HPLC: RT=10.10 min. MS (ESI−): mass calcd. for C22H14BrCl2FN4O5S2, 648.31; m/z found, 645/647/649 [M−H]−. 1H NMR (400 MHz, acetone-d6): 11.58 (s, 1H), 8.47-8.42 (m, 1H), 8.34-8.20 (m, 2H), 7.92-7.85 (m, 1H), 7.85-7.80 (m, 1H), 7.75-7.70 (m, 1H), 7.67-7.60 (m, 1H), 7.42-7.35 (m, 1H), 7.25-7.18 (m, 1H), 4.96-4.87 (m, 1H), 3.40-3.32 (m, 1H), 3.20-3.10 (m, 1H).
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].C[O:8][C:9](=[O:21])[CH2:10][C:11]1[C:12]2[CH:19]=[CH:18][CH:17]=[C:16]([OH:20])[C:13]=2[S:14][CH:15]=1.Cl[CH2:23][C:24]1[CH:28]=[C:27]([C:29]2[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=2)[O:26][N:25]=1>C(#N)C.ClCCl>[Cl:35][C:32]1[CH:31]=[CH:30][C:29]([C:27]2[O:26][N:25]=[C:24]([CH2:23][O:20][C:16]3[C:13]4[S:14][CH:15]=[C:11]([CH2:10][C:9]([OH:8])=[O:21])[C:12]=4[CH:19]=[CH:18][CH:17]=3)[CH:28]=2)=[CH:34][CH:33]=1
Reactant: COC(=O)Cc1csc2c(O)cccc12
Reactant: ClCc1cc(-c2ccc(Cl)cc2)on1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClCCl
Solvent: CC#N
Product: O=C(O)Cc1csc2c(OCc3cc(-c4ccc(Cl)cc4)on3)cccc12
Reaction time: 20 h
Yield: 38 %

Procedure:
Cesium carbonate (0.31 g, 90 mmol) was added to a stirred solution of compound 77B from the preceding step (0.14 g, 0.63 mmol) and commercially available 3-chloromethyl-5-(4-chloro-phenyl)-isoxazole (0.14 g, 0.63 mmol) in 15-20 mL of acetonitrile at room temp. After 20 hours the mixture was stripped of solvent in vacuo. The residue was dissolved in dichloromethane and filtered through a short column of Celite® over silica gel, eluting with several column volumes of solvent. The filtrate was stripped of solvent in vacuo, and the residue recrystallized from DMF to afford 0.1 g (38% yield) of the title compound as a snow-white solid; mp 155-156° C. Calc for C21H16ClNO4S: C, 60.94; H, 3.90; N, 3.38. found: C, 60.67; H, 3.72; N, 3.41. Step 4. Preparation of {7-[5-(4-Chloro-phenyl)-isoxazol-3-ylmethoxy]-benzo[b]thiophen-3-yl}-acetic acid (Compound 77D)
Reaction SMILES: [C:1]1([CH2:7][OH:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.CS(C)=O.[H-].[Na+].S(C1C=CC(C)=CC=1)(O[CH2:19][CH:20]([CH2:25][CH3:26])[CH2:21][CH2:22][CH2:23][CH3:24])(=O)=O>O>[CH2:25]([CH:20]([CH2:21][CH2:22][CH2:23][CH3:24])[CH2:19][O:8][CH2:7][CH:1]1[CH2:6][CH2:5][CH2:4][CH:3]=[CH:2]1)[CH3:26]
Reactant: CCCCC(CC)COS(=O)(=O)c1ccc(C)cc1
Reactant: OCC1=CCCCC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CCCCC(CC)COCC1C=CCCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A 500 mL round bottom flask equipped with a mechanical stirrer was charged with 33.6g (0.30 mol) cyclohexene-1-methanol, and 260 mL of DMSO. Sodium hydride (8.43 g, 95% in purity; 0.334 mol) was slowly added to above mixture in ice bath over 40 min. After the above mixture was reacted at room temperature for 2 hrs, the reaction mixture was warmed to room temperature. 2-Ethylhexyl tosylate (85.2 g, 0.30 mol) was slowly added to the above mixture over 15 min. The reaction was carried out for another 1 hr at room temperature, then 60° C. for 2 hrs. The reaction mixture was added to water (200 mL), and then extracted with chloroform (3×180 mL), washed with water (2×100 mL). The organic layer was evaporated and the residue distilled to give pure product.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][O:15][C:16]2[CH:25]=[C:24]3[C:19]([C:20]([NH:26][C:27]4[C:32]([Cl:33])=[CH:31][CH:30]=[C:29]5[O:34][CH2:35][O:36][C:28]=45)=[N:21][CH:22]=[N:23]3)=[C:18]([O:37][CH:38]3[CH2:43][CH2:42][O:41][CH2:40][CH2:39]3)[CH:17]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[Cl:33][C:32]1[C:27]([NH:26][C:20]2[C:19]3[C:24](=[CH:25][C:16]([O:15][CH2:14][CH:11]4[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]4)=[CH:17][C:18]=3[O:37][CH:38]3[CH2:39][CH2:40][O:41][CH2:42][CH2:43]3)[N:23]=[CH:22][N:21]=2)=[C:28]2[O:36][CH2:35][O:34][C:29]2=[CH:30][CH:31]=1
Reactant: CC(C)(C)OC(=O)N1CCC(COc2cc(OC3CCOCC3)c3c(Nc4c(Cl)ccc5c4OCO5)ncnc3c2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Clc1ccc2c(c1Nc1ncnc3cc(OCC4CCNCC4)cc(OC4CCOCC4)c13)OCO2
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 33.5 %

Procedure:
A mixture of 7-[N-(tert-butoxycarbonyl)piperidin-4-ylmethoxy]-4-(6-chloro-2,3-methylenedioxyanilino)-5-tetrahydropyran-4-yloxyquinazoline (0.25 g), trifluoroacetic acid (1 ml) and methylene chloride (1 ml) was stirred at ambient temperature for 1.5 hours. The mixture was evaporated and the residue was purified by column chromatography on silica using a 93:7 mixture of methylene chloride and a saturated methanolic ammonia solution as eluent. The material so obtained was partitioned between ethyl acetate and an aqueous ammonium hydroxide solution. The organic layer was dried over magnesium sulphate and evaporated. There was thus obtained the title compound (0.07 g); NMR Spectrum: (CDCl3 and D2O) 1.5-1.7 (m, 2H), 1.9-2.1 (m, 4H), 2.2-2.3 (m, 2H), 2.8 (m, 2H), 3.32 (d, 2H), 3.65 (m, 2H), 3.9-4.1 (m, 3H), 4.8 (m, 1H), 6.08 (s, 2H), 6.52 (br s, 1H), 6.72 (d, 1H), 6.8 (s, 1H), 6.98 (d, 1H), 8.5 (s, 1H); Mass Spectrum: M+H+ 513 and 515.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[CH:9][CH:10]=[C:6]2[N:5]=[C:4]([C:11]2[CH:12]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:14]=[CH:15][CH:16]=2)[CH:3]=1.C([O-])(=O)C.[Na+].[H][H]>[Pd]>[F:19][C:17]([F:18])([F:20])[C:13]1[CH:14]=[CH:15][CH:16]=[C:11]([C:4]2[CH:3]=[CH:2][N:7]3[N:8]=[CH:9][CH:10]=[C:6]3[N:5]=2)[CH:12]=1
Reactant: FC(F)(F)c1cccc(-c2cc(Cl)n3nccc3n2)c1
Reactant: [H][H]
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Na+]
Product: FC(F)(F)c1cccc(-c2ccn3nccc3n2)c1

Procedure:
The mixture of 1.65 g. 7-chloro-5-(α,α,α-trifluoro-m-tolyl)pyrazolo[1,5-a]pyrimidine, 0.46 g. of anhydrous sodium acetate, 0.20 g. of 10% palladium on charcoal catayst and 100 ml. of absolute alcohol is hydrogenated in a Parr apparatus beginning at 10 lbs. pressure until one equivalent of hydrogen is absorbed in about 40 minutes. The catalyst is removed by filtration and the solvent is evaporated to dryness and water is added. The solid is collected by filtration and is recrystallized from methylene chloride-hexane to yield the desired material, m.p. 117°-118° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=O)[CH:5]=[C:6]([F:8])[CH:7]=1.[NH2:13][C@H:14]([C:19]([NH:21][CH:22]1[N:28]=[C:27]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:26]2[CH:35]=[CH:36][CH:37]=[CH:38][C:25]=2[N:24]([CH3:39])[C:23]1=[O:40])=[O:20])[C:15]([CH3:18])([CH3:17])[CH3:16]>>[F:8][C:6]1[CH:5]=[C:4]([CH2:9][C:10]([NH:13][C@H:14]([C:19]([NH:21][CH:22]2[N:28]=[C:27]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:26]3[CH:35]=[CH:36][CH:37]=[CH:38][C:25]=3[N:24]([CH3:39])[C:23]2=[O:40])=[O:20])[C:15]([CH3:18])([CH3:17])[CH3:16])=[O:12])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: CN1C(=O)C(NC(=O)[C@@H](N)C(C)(C)C)N=C(c2ccccc2)c2ccccc21
Reactant: O=C(O)Cc1cc(F)cc(F)c1
Product: CN1C(=O)C(NC(=O)[C@@H](NC(=O)Cc2cc(F)cc(F)c2)C(C)(C)C)N=C(c2ccccc2)c2ccccc21

Procedure:
Following General Procedure D above using 3,5-difluorophenylacetic acid (Oakwood Products, Inc.) and 3-(L-tert-leucinyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one (Example 8-Z), the title compound was prepared as a solid (mp.=221-222° C.). The product was purified by slurrying in ether.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([F:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:36][O:37][C:38]1[CH:43]=[C:42]([NH2:44])[CH:41]=[CH:40][N:39]=1.CCN(CC)CC>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([F:11])=[C:6]([CH:10]=1)[C:7]([NH:44][C:42]1[CH:41]=[CH:40][N:39]=[C:38]([O:37][CH3:36])[CH:43]=1)=[O:9]
Reactant: COc1cc(N)ccn1
Reactant: O=C(O)c1cc(Cl)ccc1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc(NC(=O)c2cc(Cl)ccc2F)ccn1
Yield: 47.3 %

Procedure:
A solution of 5-chloro-2-fluoro-benzoic acid (5.0 g, 28.64 mmol), HATU (10.89 g, 28.64 mmol), 2-methoxypyridin-4-amine (3.6 g, 28.64 mmol) and Et3N (15.98 mL, 114.60 mmol) in dichloromethane (45.0 mL) was stirred at room temperature overnight. The crude mixture was purified by column chromatography eluting with a gradient of ethyl acetate in hexanes (0-50%) to yield 5-chloro-2-fluoro-N-(2-methoxy-4-pyridyl)benzamide (3.8 g, 47%) as a white solid. ESI-MS m/z calc. 280.04. found 281.3 (M+1)+; Retention time: 1.31 minutes (3 minutes run).
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH2:7][N:8]2[CH:12]=[C:11]([N:13]3[C:17](=[O:18])[N:16]([CH3:19])[NH:15][C:14]3=[O:20])[CH:10]=[N:9]2)=[C:5]([CH3:21])[O:4][N:3]=1.BrC[CH2:24][C:25]1[CH:30]=[CH:29][C:28](F)=[CH:27][CH:26]=1>>[CH2:24]([N:15]1[C:14](=[O:20])[N:13]([C:11]2[CH:10]=[N:9][N:8]([CH2:7][C:6]3[C:2]([CH3:1])=[N:3][O:4][C:5]=3[CH3:21])[CH:12]=2)[C:17](=[O:18])[N:16]1[CH3:19])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: Cc1noc(C)c1Cn1cc(-n2c(=O)[nH]n(C)c2=O)cn1
Reactant: Fc1ccc(CCBr)cc1
Product: Cc1noc(C)c1Cn1cc(-n2c(=O)n(C)n(Cc3ccccc3)c2=O)cn1
Yield: 14 %

Procedure:
Prepared as in Example 10-65 from 4-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)-1-methyl-1,2,4-triazolidine-3,5-dione (example 10-64) and 1-(2-bromoethyl)-4-fluorobenzene. Yield: 14%. 1H NMR (CDCl3, 400 MHz): δ2.18 (s, 3H), 2.40 (s, 3H), 2.87 (t, J=6.8 Hz, 2H), 3.14 (s, 3H), 3.83 (t, J=7.2 Hz, 2H), 5.03 (s, 2H), 6.95 (t, J=8.4 Hz, 2H), 7.14 (t, J=8 Hz, 2H), 7.77 (s, 1H), 7.95 (s, 1H). The title compound was shown to inhibit hT2R08 bitter receptor and had an IC50 of 0.01 μM.
Reaction SMILES: Cl.[C:2]([NH:6][NH2:7])([CH3:5])([CH3:4])[CH3:3].C([O-])(=O)C.[Na+].Cl[C:14](=[CH2:17])[C:15]#[N:16]>C(O)C>[C:2]([N:6]1[C:15]([NH2:16])=[CH:14][CH:17]=[N:7]1)([CH3:5])([CH3:4])[CH3:3]
Reactant: CC(C)(C)NN
Reactant: C=C(Cl)C#N
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CC(C)(C)n1nccc1N
Temperature: 80 °C
Reaction time: 12 h

Procedure:
To 600 ml of ethanol were successively added 59.94 g of tert-butylhydrazine hydrochloride, 79.3 g of sodium acetate and 50 ml of 2-chloroacrylonitrile at room temperature, followed by stirring the reaction mixture at 80° C. for 12 hours. After removing the solvent in vacuo, water was added to the residue. The mixture was neutralized with sodium hydrogen carbonate, and extracted with ethyl acetate. The obtained ethyl acetate solution was washed with brine, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated in vacuo. The obtained residue was purified by a silica gel column chromatography (eluent: hexane/ethyl acetate=2/1-1/2) to give the title compound as a pale yellow oil.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[C:3]=1[C:4]#[N:5].Cl.Cl[C:13]([NH2:15])=[NH:14]>COCCOCCOC>[NH2:15][C:13]1[N:14]=[C:4]([NH2:5])[C:3]2[C:2](=[CH:9][CH:8]=[CH:7][C:6]=2[CH3:10])[N:1]=1
Reactant: N=C(N)Cl
Reactant: Cc1cccc(N)c1C#N
Agent: Cl
Solvent: COCCOCCOC
Product: Cc1cccc2nc(N)nc(N)c12

Procedure:
This compound was prepared in a manner analogous to that of Step E of Example 1, using 1 0.0 grams (0.076 mole) of 2-amino-6-methylbenzonitrile (prepared as in Example 1, Step B), and 10.0 grams (0.087 mole) of chloroformamidine hydrochloride in 40 mL of 2-methoxyethyl ether, yielding 11.5 grams of 2,4-diamino-5-methylquinazoline. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [C:1]([CH:4]1[C:13]2([CH2:18][CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15][CH2:14]2)[O:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]1=O)(=O)[CH3:2].[NH2:27][N:28](C)[C:29](=O)OC(C)(C)C.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[ClH:49]>C(O)C>[ClH:49].[ClH:49].[CH3:29][N:28]1[C:5]2[C:6]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[O:12][C:13]3([CH2:14][CH2:15][NH:16][CH2:17][CH2:18]3)[C:4]=2[C:1]([CH3:2])=[N:27]1
Reactant: CN(N)C(=O)OC(C)(C)C
Reactant: CC(=O)C1C(=O)c2ccccc2OC12CCN(C(=O)OC(C)(C)C)CC2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: CCO
Solvent: O
Product: Cc1nn(C)c2c1C1(CCNCC1)Oc1ccccc1-2
Temperature: 80 °C
Reaction time: 1 h

Procedure:
A mixture of tert-butyl 3-acetyl-4-oxospiro[chroman-2,4′-piperidine]-1′-carboxylate (250 mg, 0.70 mmol), tert-butyl N-amino-N-methyl-carbamate (120 μL, 0.84 mmol) and p-toluene sulfonic acid monohydrate (27 mg, 0.14 mmol) in ethanol (8 mL) was heated at 80° C. overnight. Additional tert-butyl N-amino-N-methyl-carbamate (120 μL, 0.84 mmol) was added and the mixture was heated at 80° C. for 6.5 h, then another portion of tert-butyl N-amino-N-methyl-carbamate (120 μL, 0.84 mmol) was added and the mixture was heated at 80° C. for 2 h. HCl (0.87 mL of 4.0 M in dioxane, 3.5 mmol) was added and the mixture was stirred at 80° C. for 1 h. After cooling, the precipitate was collected via filtration and washed with cold EtOH to provide 1,3-dimethyl-1H-spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine] dihydrochloride (295 mg, >100%, may contain some methyl hydrazine HCl salt) as a solid. ESI-MS m/z calc. 269.2, found 270.5 (M+1)+; Retention time: 1.11 minutes (3 min run). 1H NMR (400 MHz, DMSO) δ 7.71 (dd, J=7.8, 1.3 Hz, 1H), 7.33-7.27 (m, 1H), 7.17-7.14 (m, 1H), 7.11-7.05 (m, 1H), 4.02 (s, 3H), 3.28-3.15 (m, 4H), 2.40-2.30 (m, 2H), 2.23 (s, 3H), 2.07-1.97 (m 2H).