Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][CH:4]=1)#[CH:2].Br[C:11]1[CH:12]=[C:13]([CH:23]=[CH:24][CH:25]=1)[C:14]([C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=1)=[O:15].C1(C)C=CC=CC=1>C(N(CC)CC)C>[F:9][C:6]1[CH:7]=[CH:8][C:3]([C:1]#[C:2][C:24]2[CH:25]=[CH:11][CH:12]=[C:13]([C:14](=[O:15])[C:16]3[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=3)[CH:23]=2)=[CH:4][CH:5]=1
Reactant: C#Cc1ccc(F)cc1
Reactant: O=C(c1ccc(F)cc1)c1cccc(Br)c1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: O=C(c1ccc(F)cc1)c1cccc(C#Cc2ccc(F)cc2)c1
Temperature: 80 °C
Reaction time: 3 h

Procedure:
Thus a reaction mixture is formed by dissolving appropriate amounts of 1-ethynyl-4-fluorobenzene, 3-bromo-4′-fluorobenzophenone, and tetrakis(triphenylphosphine)palladium[0] in a de-aerated aprotic solvent, for example, triethylamine. Alternatively, toluene can be used as a first solvent and triethylamine added as a cosolvent in a stoichiometric equivalent to 3-bromo-4′-fluorobenzophenone. The reaction mixture is heated to 80° C. with stirring under an inert atmosphere, e.g. argon, for approximately three hours. The reaction mixture is then allowed to cool to ambient while stirring is continued for approximately 16 hours. A white precipitate of triethylamine hydrobromide is removed by filtration and the aprotic solvents employed are removed by evaporation. The resulting solids are dissolved in a solvent, e.g. dichloromethane, or preferably toluene due to its relatively higher environmental friendliness, and then washed with water, an aqueous 2% HCl solution, brine, and then dried. After solvent evaporation, a good yield of white crystalline 4-fluoro-3′-(4-fluorobenzoyl)tolane, melting at approximately 127-128° C. is obtained. Purification by recrystallization from acetone results in a material with a melting point of 130-131° C. Alternatively, recrystallization from toluene provide a crystalline material in the form of rhombic fine needles with a melting point of 135-136° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[C:5]([CH3:10])[CH:4]=1.[Cl:11][C:12]1[CH:20]=[CH:19][C:15]([C:16](Cl)=[O:17])=[CH:14][N:13]=1.ClC1C=CC(C(NC2C=CC(I)=C(C)C=2)=O)=CN=1>>[Cl:11][C:12]1[CH:20]=[CH:19][C:15]([C:16]([NH:7][C:6]2[CH:8]=[CH:9][C:3]([O:2][CH3:1])=[CH:4][C:5]=2[CH3:10])=[O:17])=[CH:14][N:13]=1
Reactant: COc1ccc(N)c(C)c1
Reactant: O=C(Cl)c1ccc(Cl)nc1
Agent: Cc1cc(NC(=O)c2ccc(Cl)nc2)ccc1I
Product: COc1ccc(NC(=O)c2ccc(Cl)nc2)c(C)c1

Procedure:
6-Chloro-N-(4-methoxy-2-methyl-phenyl)-nicotinamide was prepared from 4-methoxy-2-methyl aniline and 6-chloronicotinoyl chloride following a procedure similar to the one described in the synthesis of 6-chloro-N-(4-iodo-3-methyl-phenyl)-nicotinamide, above. The product was isolated after precipitation out of a small volume of CH2Cl2 with hexanes. HRMS m/z calcd for C14H13N2O2Cl [M+H]+: 277.0739. Found: 277.0738.
Reaction SMILES: [N:1]1([C:7]2[C:18]3=[C:19]4[N:14]([CH2:15][CH2:16][CH2:17]3)[CH:13]=[C:12]([C:20]([OH:22])=[O:21])[C:11](=[O:23])[C:10]4=[CH:9][CH:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].[OH-].[Na+].[CH2:32](Cl)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.Cl>CO.O>[CH2:32]([N:4]1[CH2:5][CH2:6][N:1]([C:7]2[C:18]3=[C:19]4[N:14]([CH2:15][CH2:16][CH2:17]3)[CH:13]=[C:12]([C:20]([OH:22])=[O:21])[C:11](=[O:23])[C:10]4=[CH:9][CH:8]=2)[CH2:2][CH2:3]1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: ClCc1ccccc1
Reactant: O=C(O)c1cn2c3c(c(N4CCNCC4)ccc3c1=O)CCC2
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: O=C(O)c1cn2c3c(c(N4CCN(Cc5ccccc5)CC4)ccc3c1=O)CCC2
Yield: 9.7 %

Procedure:
2.0 g of 8-(1-piperazinyl)-6,7-dihydro-1-oxo-1H,5H-benzo[ij]quinolizine-2-carboxylic acid was added to 20 ml of water having dissolved therein 2.0 g of potassium carbonate and the mixture was stirred at room temperature for 30 minutes. After dissolving insoluble materials completely with the addition of 3 ml of 1 N aqueous sodium hydroxide solution, 10 ml of methanol having dissolved therein 0.9 g of benzyl chloride was added dropwise to the mixture while ice-cooling. After completion of the addition, the resulitng mixture was heat-refluxed for 3 hours to form a uniform solution. The solution obtained was treated with activated carbon while hot and rendered neutral with a 10% aqueous hydrochloric acid to precipitate crystals, which were separated by filtration and washed with water. Recrystallization of the crystals thus treated from dimethylformamide gave 0.25 g of 8-(4-benzyl-1-piperazinyl)-6,7-dihydro-1-oxo-1H,5H-benzo[ij]-quinolizine-2-carboxylic acid having a melting point of 274° to 278° C.
Reaction SMILES: O1CCCC1.[NH2:6][C:7]1[C:16]2[C:11](=[CH:12][C:13]([O:19][CH3:20])=[C:14]([O:17][CH3:18])[CH:15]=2)[N:10]=[C:9]([N:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)[N:8]=1.[C:27](Cl)(=[O:33])[CH:28]=[CH:29][CH:30]=[CH:31][CH3:32]>C(N(CC)CC)C>[NH2:6][C:7]1[C:16]2[C:11](=[CH:12][C:13]([O:19][CH3:20])=[C:14]([O:17][CH3:18])[CH:15]=2)[N:10]=[C:9]([N:21]2[CH2:26][CH2:25][N:24]([C:27](=[O:33])[CH:28]=[CH:29][CH:30]=[CH:31][CH3:32])[CH2:23][CH2:22]2)[N:8]=1
Reactant: COc1cc2nc(N3CCNCC3)nc(N)c2cc1OC
Reactant: CC=CC=CC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC=CC=CC(=O)N1CCN(c2nc(N)c3cc(OC)c(OC)cc3n2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 85.1 %

Procedure:
To 20 ml of tetrahydrofuran were added 1.16 g of 4-amino-6,7-dimethoxy-2-(1-piperazinyl)quinazoline and 1.5 g of triethylamine. There was then added 0.52 g of 2,4-hexadienoyl chloride, after which the mixture was stirred at room temperature for 3 hours. The reaction mixture was then concentrated by evaporation under reduced pressure, and the resulting residue was washed with water and recrystallized from ethanol, to give 1.3 g of the desired Compound No. 10 in the form of pale yellow powdery crystals melting at 231°-233° C.
Reaction SMILES: CC(OC(/N=N/C(OC(C)(C)C)=O)=O)(C)C.[Cl:17][C:18]1[CH:19]=[C:20]([CH:35]=[CH:36][C:37]=1[F:38])[NH:21][C:22]1[C:31]2[C:30]([OH:32])=[CH:29][C:28]([O:33][CH3:34])=[CH:27][C:26]=2[N:25]=[CH:24][N:23]=1.[Si:39]([O:46][C@H:47]1[CH2:51][N:50]([C:52]([O:54][C:55]([CH3:58])([CH3:57])[CH3:56])=[O:53])[C@@H:49]([CH2:59]O)[CH2:48]1)([C:42]([CH3:45])([CH3:44])[CH3:43])([CH3:41])[CH3:40].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[Si:39]([O:46][C@H:47]1[CH2:51][N:50]([C:52]([O:54][C:55]([CH3:58])([CH3:57])[CH3:56])=[O:53])[C@@H:49]([CH2:59][O:32][C:30]2[CH:29]=[C:28]([O:33][CH3:34])[CH:27]=[C:26]3[C:31]=2[C:22]([NH:21][C:20]2[CH:35]=[CH:36][C:37]([F:38])=[C:18]([Cl:17])[CH:19]=2)=[N:23][CH:24]=[N:25]3)[CH2:48]1)([C:42]([CH3:45])([CH3:44])[CH3:43])([CH3:41])[CH3:40]
Reactant: COc1cc(O)c2c(Nc3ccc(F)c(Cl)c3)ncnc2c1
Reactant: CC(C)(C)OC(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@@H]1CO
Agent: CC(C)(C)OC(=O)/N=N/C(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1cc(OC[C@H]2C[C@@H](O[Si](C)(C)C(C)(C)C)CN2C(=O)OC(C)(C)C)c2c(Nc3ccc(F)c(Cl)c3)ncnc2c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 50 %

Procedure:
Di-tert-butylazodicarboxylate (DTAD, 914 mg) was added in one portion to a mixture of 4-[3-chloro-4-fluoroanilino]-7-methoxyquinazolin-5-ol (848 mg), tert-butyl (2R,4R)-4-{[tert-butyl(dimethyl)silyl]oxy}-2-(hydroxymethyl)-pyrrolidine-1-carboxylate (1.10 g), and triphenylphosphine (1.04 g) in DCM (100 ml) at room temperature, under an atmosphere of nitrogen. The reaction mixture was stirred at room temperature for 24 hours and then concentrated in vacuo to leave a brown oil. Purification by column chromatography, using 0-50% ethyl acetate in hexane as eluent, gave tert-butyl (2R,4R)-4-{[tert-butyl(dimethyl)silyl]-oxy}-2-[({4-[3-chloro-4-fluoroanilino]-7-methoxy-quinazolin-5-yl}oxy)methyl]-pyrrolidine-1-carboxylate as a white solid (839 mg, 50%); Mass spectrum MH+ 633.
Reaction SMILES: O[CH2:2][C@@]12[C@@H]3[C@H]([C@H]4[C@@](CC3)(C)C(=O)CC4)C[C@H](C)C1=CC(=O)CC2.C[O-].[C:26]1([Si:32]([C:61]2[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=2)([C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=2)[O:33][CH2:34][C@@:35]23[C@@H:52]4[C@H:43]([C@H:44]5[C@@:48]([CH2:50][CH2:51]4)([CH3:49])[C:47](=[O:53])[CH2:46][CH2:45]5)[CH2:42][CH2:41][C:40]2=[CH:39][C:38](=[O:54])[CH2:37][CH2:36]3)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[CH3:2][C@H:36]1[C@@:35]2([CH2:34][O:33][Si:32]([C:61]3[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=3)([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[C:55]3[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=3)[C:40]([CH2:41][CH2:42][C@@H:43]3[C@@H:52]2[CH2:51][CH2:50][C@@:48]2([CH3:49])[C@H:44]3[CH2:45][CH2:46][C:47]2=[O:53])=[CH:39][C:38](=[O:54])[CH2:37]1
Reactant: C[C@H]1C[C@@H]2[C@H](CC[C@]3(C)C(=O)CC[C@@H]23)[C@@]2(CO)CCC(=O)C=C12
Reactant: C[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@]43CO[Si](c3ccccc3)(c3ccccc3)c3ccccc3)[C@@H]1CCC2=O
Agent: C[O-]
Product: C[C@@H]1CC(=O)C=C2CC[C@@H]3[C@H](CC[C@]4(C)C(=O)CC[C@@H]34)[C@]21CO[Si](c1ccccc1)(c1ccccc1)c1ccccc1

Procedure:
Following essentially the same procedure but substituting 19-hydroxhy-1β-methyl-4-androstene-3,17-dione and 19-hydroxy-6α-methyl-4-androstene-3,17-dione for the 19-hydroxy-4-androstene-3,17-dione above results in the preparation of 1β-methyl-19-triphenylsiloxy-4-androstene-3,17-dione and 6α-methyl-19-triphenylsilioxy-4-androstene-3,17-dione.
Reaction SMILES: [C:1]([S@@:5]([NH:7][C@H:8]([C:13]1([C:18]([O:20]CC)=O)[S:17][CH2:16][CH2:15][S:14]1)[CH2:9][CH:10]1[CH2:12][CH2:11]1)=[O:6])([CH3:4])([CH3:3])[CH3:2].[CH3:23][NH2:24].C(O)C>>[C:1]([S@@:5]([NH:7][C@H:8]([C:13]1([C:18]([NH:24][CH3:23])=[O:20])[S:17][CH2:16][CH2:15][S:14]1)[CH2:9][CH:10]1[CH2:12][CH2:11]1)=[O:6])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)C1([C@H](CC2CC2)N[S@@](=O)C(C)(C)C)SCCS1
Reactant: CN
Solvent: CCO
Product: CNC(=O)C1([C@H](CC2CC2)N[S@@](=O)C(C)(C)C)SCCS1
Temperature: 25 °C
Reaction time: 2 h
Yield: 93 %

Procedure:
A heavy-walled glass tube was charged with ethyl (S,SS)-2-[1-(tert-butylsulfinylamino)-2-cyclopropylethyl]-1,3-dithiolane-2-carboxylate (2.00 g, 5.47 mmol) and a chilled 8.0 M solution of methylamine in ethanol (5 mL, 40 mmol). The mixture was allowed to warm to room temperature and was stirred for 2 hours at which time reaction was complete by HPLC analysis. Distillation of the solvent at reduced pressure afforded the title compound (1.79 g, 93%) as an amber glass.
Reaction SMILES: Br[CH2:2][C:3]1[N:4]([CH3:28])[C:5]2[C:10]([N:11]=1)=[C:9]([N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)[N:8]=[C:7]([N:18]1[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[N:20]=[C:19]1[CH3:27])[N:6]=2.[NH:29]1[CH2:34][CH2:33][CH2:32][CH:31]([C:35]([OH:38])([CH3:37])[CH3:36])[CH2:30]1>>[CH3:28][N:4]1[C:3]([CH2:2][N:29]2[CH2:34][CH2:33][CH2:32][CH:31]([C:35]([OH:38])([CH3:37])[CH3:36])[CH2:30]2)=[N:11][C:10]2[C:5]1=[N:6][C:7]([N:18]1[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[N:20]=[C:19]1[CH3:27])=[N:8][C:9]=2[N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1
Reactant: CC(C)(O)C1CCCNC1
Reactant: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CBr)n(C)c2n1
Product: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CCCC(C(C)(C)O)C3)n(C)c2n1

Procedure:
Following General Procedure E of amine alkylation, 4-(8-(bromomethyl)-9-methyl-2-(2-methyl-1H-benzo[d]imidazol-1-yl)-9H-purin-6-yl)morpholine and 2-(piperidin-3-yl)propan-2-ol were reacted to give 265. M+H=505.3
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][C:11]([CH:13]3[CH2:18][CH2:17][N:16]([C:19](=[O:21])[CH3:20])[CH2:15][CH2:14]3)=[N:10][C:9]=2[CH2:22][OH:23])=[CH:4][CH:3]=1.[H-].[Na+].[CH3:26]I>O1CCCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][C:11]([CH:13]3[CH2:18][CH2:17][N:16]([C:19](=[O:21])[CH3:20])[CH2:15][CH2:14]3)=[N:10][C:9]=2[CH2:22][O:23][CH3:26])=[CH:4][CH:3]=1
Reactant: CC(=O)N1CCC(c2nc(CO)c(-c3ccc(F)cc3)o2)CC1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCc1nc(C2CCN(C(C)=O)CC2)oc1-c1ccc(F)cc1
Reaction time: 0.08 h
Yield: 75.7 %

Procedure:
A solution of 1-{4-[5-(4-fluoro-phenyl)-4-hydroxymethyl-oxazol-2-yl]-piperidin-1-yl}-ethanone (1.0 g; 3.14 mmol) in dry tetrahydrofuran (12 ml) is treated with sodium hydride (0.16 g; 4.09 mmol) in small portions. After 5 minutes, it is added methyl iodide (0.31 ml; 5.02 mmol) and the mixture is stirred for 45 minutes. The reaction is partitioned between ethyl acetate (40 ml) and water (15 ml). The aqueous phase is washed with ethyl acetate (15 ml). The combined organic phases are washed with saturated brine (10 ml), dried over sodium sulfate and concentrated to dryness. Purification by radial chromatography on silica gel using a methanol/ethyl acetate gradient (5%-20%) afforded the product as a light yellow oil (0.79 g; 75%). HNMR (CDCl3): 7.53 (m, 2H), 7.04 (t, 2H, J=8.7 Hz), 4.43 (m, 1H), 4.37 (s, 2H), 3.80 (m, 1H), 3.37 (s, 3H), 3.15 (m, 1H), 3.0 (ttt, 1H, J=10.8; 4.1 Hz), 2.79 (m, 1H), 2.04 (m, 2H), 2.02 (s, 3H), 1.77 (m, 2H). Mass spectrum: m/e calculated (MNa+)=355; observed (MNA+)=355.
Reaction SMILES: [F:1][C:2]1[CH:18]=[CH:17][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([S:13](O)(=[O:15])=[O:14])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[Na].S(Cl)([Cl:22])=O.CN(C)C=O>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:18]=[CH:17][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([S:13]([Cl:22])(=[O:15])=[O:14])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: O=S(=O)(O)c1ccc(Oc2ccc(F)cc2)cc1
Agent: [Na]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: O=S(=O)(Cl)c1ccc(Oc2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a slurry of 15.0 g (0.052 mol) of 4-(4-fluorophenoxy)benzenesulfonic acid□, sodium salt, in 150 mL of dry toluene was added 11.3 mL (0.155 mol, 3 equivalents) of thionyl chloride and 0.04 mL (0.5 mmol, 0.01 equivalents) of dimethylformamide. The resulting mixture was stirred at room temperature for 48 hours, filtered through diatomaceous earth, and concentrated under reduced pressure to 40 mL. This solution was used without further purification to prepare 1-[4-(4-fluorophenoxy)benzenesulfonylamino] cyclopentanecarboxylic acid benzyl ester.
Reaction SMILES: [C:1]([C:3]1([C:6]2[CH:7]=[C:8]([CH:13]=[CH:14][CH:15]=2)[C:9]([O:11]C)=[O:10])[CH2:5][CH2:4]1)#[N:2].CO.O>O1CCCC1>[C:1]([C:3]1([C:6]2[CH:7]=[C:8]([CH:13]=[CH:14][CH:15]=2)[C:9]([OH:11])=[O:10])[CH2:4][CH2:5]1)#[N:2]
Reactant: COC(=O)c1cccc(C2(C#N)CC2)c1
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: N#CC1(c2cccc(C(=O)O)c2)CC1
Temperature: 25 °C
Reaction time: 14 h
Yield: 60.9 %

Procedure:
To a solution of methyl 3-(1-cyanocyclopropyl)benzoate (1.3 g, 6.4 mmol) in tetrahydrofuran (12 ml) were added lithium hydroxide•monohydrate (0.44 g, 11 mmol), methanol (4.0 mL) and water (6.0 mL), and the mixture was stirred at room temperature for 14 hr. The solvent was evaporated under reduced pressure, and the residue was diluted with water (5.0 mL). 1N Hydrochloric acid was slowly added to the mixture to adjust the pH to 5. The precipitated white precipitate was collected by filtration, washed with water, and dried to give the title compound (0.73 g, 61%) as a white powder.
Reaction SMILES: C(OCC1C(OC(=O)C)C(OC(=O)C)C(OC(=O)C)C([O:24][C:25]2[CH:29]=[CH:28][S:27][C:26]=2[C:30](=[O:39])NCC2C=CC=CC=2)O1)(=O)C.C[O-:41].[Na+].Cl>CO>[OH:24][C:25]1[CH:29]=[CH:28][S:27][C:26]=1[C:30]([OH:39])=[O:41]
Reactant: CC(=O)OCC1OC(Oc2ccsc2C(=O)NCc2ccccc2)C(OC(C)=O)C(OC(C)=O)C1OC(C)=O
Reactant: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: O=C(O)c1sccc1O
Temperature: 22 °C
Reaction time: 2 h

Procedure:
600 mg of 3,4,5-triacetoxy-6-(2-benzylcarbamoyl-thiophen-3-yloxy)-tetrahydro-pyran-2-ylmethyl acetate were dissolved in 40 ml of methanol, and 1.40 ml of a 30% strength methanolic sodium methanolate solution were added. The reaction mixture was stirred at 22° C. for 2 h, neutralized with 0.5 molar methanolic HCl solution and concentrated. The crude product was purified by column chromatography (SiO2, ethyl acetate/methanol=10:1).
Reaction SMILES: Cl.[F:2][C:3]([F:13])([F:12])[C:4]1[CH:5]=[C:6]([NH:10][NH2:11])[CH:7]=[CH:8][CH:9]=1.[CH3:14][C:15]([CH3:22])([CH3:21])[C:16](=O)[CH2:17][C:18]#[N:19]>>[C:15]([C:16]1[CH:17]=[C:18]([NH2:19])[N:10]([C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([C:3]([F:12])([F:13])[F:2])[CH:5]=2)[N:11]=1)([CH3:22])([CH3:21])[CH3:14]
Reactant: NNc1cccc(C(F)(F)F)c1
Reactant: CC(C)(C)C(=O)CC#N
Agent: Cl
Product: CC(C)(C)c1cc(N)n(-c2cccc(C(F)(F)F)c2)n1
Yield: 30.3 %

Procedure:
Following the procedure in Example 161A Step 3, 3-trifluoromethylphenylhydrazine hydrochloride (781 mg, 4.44 mmol) and 4,4-Dimethyl-3-oxopentanenitrile (500 mg, 4.0 mmol) were reacted to give 3-tert-butyl-1-(3-(trifluoromethyl)phenyl)-1H-pyrazol-5-amine (344 mg, 1.21 mmol, 30%). No NMR taken. LC-MS (ESI) m/z 284 (M+H)+.
Reaction SMILES: [N:1]1([CH2:6][CH:7]([CH2:19][O:20]CC2C=CC(OC)=CC=2)[O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:5]=[CH:4][N:3]=[CH:2]1.[H][H]>C(O)C.FC(F)(F)C(O)=O.[Pd]>[OH:20][CH2:19][CH:7]([CH2:6][N:1]1[CH:5]=[CH:4][N:3]=[CH:2]1)[O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: CCOC(=O)CCCCCOC(COCc1ccc(OC)cc1)Cn1ccnc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)CCCCCOC(CO)Cn1ccnc1
Temperature: 25 °C

Procedure:
A solution of ethyl 6-[2-(1H-imidazol-1-yl)-1-[[(4-methoxyphenyl)methoxy]methyl]ethoxy]hexanoate (Example 4; 5.8 g 0.014 mol) in ethanol (20 ml) and trifluoroacetic acid (1 ml) containing a catalytic amount of 10% palladium on carbon (0.5 g) was stirred at room temperature under a hydrogen atmosphere. When hydrogen uptake had ceased the solution was filtered and the solvent was evaporated off under reduced pressure. The residue was treated with a saturated aqueous solution of sodium hydrogen carbonate and extracted with dichloromethane. The extracts were dried (Na2SO4) and the solvent was evaporated off under reduced pressure to give the crude product which was purified by column chromatography (silica gel, chloroform to 5% ethanol in chloroform) to give ethyl
Reaction SMILES: [C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24](/[C:26](=[N:53]/[O:54][C@H:55]([C:57]([O:59][CH:60]([C:67]2[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=2)[C:61]2[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=2)=[O:58])[CH3:56])/[C:27]([NH:29][CH:30]2[C:51](=[O:52])[N:32]3[C:33]([C:39]([O:41][CH2:42][C:43]4[CH:48]=[CH:47][C:46]([O:49][CH3:50])=[CH:45][CH:44]=4)=[O:40])=[C:34]([CH2:37]Cl)[CH2:35][S:36][C@H:31]23)=[O:28])[N:25]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[SH:73][C:74]1[S:75][C:76]2[CH:77]=[N:78][CH:79]=[CH:80][C:81]=2[N:82]=1.SC1SC2C=CN=CC=2N=1>>[C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24](/[C:26](=[N:53]/[O:54][C@H:55]([C:57]([O:59][CH:60]([C:67]2[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=2)[C:61]2[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=2)=[O:58])[CH3:56])/[C:27]([NH:29][CH:30]2[C:51](=[O:52])[N:32]3[C:33]([C:39]([O:41][CH2:42][C:43]4[CH:48]=[CH:47][C:46]([O:49][CH3:50])=[CH:45][CH:44]=4)=[O:40])=[C:34]([CH2:37][S:73][C:74]4[S:75][C:76]5[CH:77]=[N:78][CH:79]=[CH:80][C:81]=5[N:82]=4)[CH2:35][S:36][C@H:31]23)=[O:28])[N:25]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(COC(=O)C2=C(CCl)CS[C@@H]3C(NC(=O)/C(=N\O[C@@H](C)C(=O)OC(c4ccccc4)c4ccccc4)c4csc(NC(c5ccccc5)(c5ccccc5)c5ccccc5)n4)C(=O)N23)cc1
Reactant: Sc1nc2ccncc2s1
Agent: Sc1nc2cnccc2s1
Product: COc1ccc(COC(=O)C2=C(CSc3nc4ccncc4s3)CS[C@@H]3C(NC(=O)/C(=N\O[C@@H](C)C(=O)OC(c4ccccc4)c4ccccc4)c4csc(NC(c5ccccc5)(c5ccccc5)c5ccccc5)n4)C(=O)N23)cc1
Yield: 63.3 %

Procedure:
Using 305 mg of p-methoxybenzyl 7-[(Z)-2-(2-tritylaminothiazol-4-yl)-2-{(S)-1-diphenylmethoxycarbonylethoxyimino}acetamido]-3-chloromethyl-3-cephem-4-carboxylate and 60 mg of 2-mercaptothiazolo[5,4-c]pyridine in place of p-methoxybenzyl 7-{(Z)-2-(2-tritylaminothiazol-4-yl)-2-methoxyiminoacetamido}-3-chloromethyl-3-cephem-4-carboxylate and 2-mercaptothiazolo[4,5-c]pyridine, respectively, the reaction and purification were carried out in the same manner as in Example 1(a) to obtain 218 mg of the title compound in a yield of 63%.
Reaction SMILES: [CH2:1]([O:6][C:7]1[CH:12]=[CH:11][C:10]([Mg]Cl)=[CH:9][CH:8]=1)[CH2:2][CH2:3][CH2:4][CH3:5].C1COCC1.[CH:20]1[C:25]([Cl:26])=[CH:24][CH:23]=[C:22](Br)[CH:21]=1.S(=O)(=O)(O)O>C1COCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:26][C:25]1[CH:20]=[CH:21][C:22]([C:10]2[CH:11]=[CH:12][C:7]([O:6][CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])=[CH:8][CH:9]=2)=[CH:23][CH:24]=1
Reactant: CCCCCOc1ccc([Mg]Cl)cc1
Reactant: Clc1ccc(Br)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=S(=O)(O)O
Solvent: C1CCOC1
Product: CCCCCOc1ccc(-c2ccc(Cl)cc2)cc1

Procedure:
0.5 mol of a 25% strength by weight 4-n-pentoxyphenylmagnesium chloride/THF solution is added dropwise in the course of 30 minutes to a boiling solution of 0.5 mol of 1,4-bromochlorobenzene and 0.0025 g of Pd(dppf)Cl2 *CH2Cl2 in 100 ml of THF. After stirring under reflux for four hours, the mixture is hydrolyzed with dilute sulfuric acid (conversion 99%, selectivitity 97%). The organic phase is freed from the solvent by distillation. The 4-chloro-4'-pentoxybiphenyl thus obtained is recrystallized from ethanol.
Reaction SMILES: [CH2:1]([C:3]1[CH2:7][CH:6]=[C:5]([C:8]([CH3:11])([CH3:10])[CH3:9])[CH:4]=1)[CH3:2].C(=O)=O.CO.CCCCCC.C([Li])CCC.CN1CCN(C)C1=O.[C:36]([C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)(=O)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.Cl>C1COCC1>[C:8]([C:5]1[CH:4]=[C:3]([CH2:1][CH3:2])[C:7](=[C:36]([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH:6]=1)([CH3:11])([CH3:10])[CH3:9]
Reactant: CCC1=CC(C(C)(C)C)=CC1
Reactant: O=C(c1ccccc1)c1ccccc1
Agent: Cl
Agent: O=C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CN1CCN(C)C1=O
Solvent: CCCCCC
Product: CCC1=CC(C(C)(C)C)=CC1=C(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 55.9 %

Procedure:
Under a nitrogen atmosphere, a 300 ml three-neck flask equipped with a magnetic stirrer chip and a three-way cock was charged with 5.11 g (23.9 mmol) of 1-ethyl-3-tert-butylcyclopentadiene (75% GC purity) and 150 ml of THF. In the dry ice/methanol bath, 16 ml (25.2 mmol) of 1.56M n-butyllithium hexane solution was gradually added dropwise and the mixture was then stirred at room temperature for 20 hours. Then, 3.1 ml (28.8 mmol) of 1,3-dimethyl-2-imidazolidinone and 5.3 g (28.8 mmol) of benzophenone were sequentially added to the reaction solution obtained, and the solution was stirred for 48 hours under reflux. The reaction solution was poured into 100 ml of 2N hydrochloric acid. The organic layer was separated, and the aqueous layer was subjected to extraction with 50 ml of hexane twice. The organic layers obtained were combined with the organic layer previously obtained. The liquid was washed with a saturated aqueous solution of sodium hydrogencarbonate, water, and a saturated aqueous solution of sodium chloride, and dried over magnesium sulfate. The solvent was distilled off, and the residue was purified by column chromatography to obtain 4.2 g of an orange solid. The yield was 56%. Identification was done by 1H-NMR spectrum. The measurement results are shown as follows.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][C:15]1[O:16][C:17]2[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=2[N:19]=1)=O)(C)(C)C.FC(F)(F)C(O)=O.C(=O)([O-])[O-].[K+].[K+]>ClCCl>[NH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][C:15]1[O:16][C:17]2[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=2[N:19]=1
Reactant: CC(C)(C)OC(=O)N1CCCCC1Cc1nc2ccccc2o1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: c1ccc2oc(CC3CCCCN3)nc2c1
Yield: 29.3 %

Procedure:
(RS)-2-Benzooxazol-2-ylmethyl-piperidine-1-carboxylic acid tert butyl ester (0.50 g) in dichloromethane (8 ml) was cooled (ice-bath) and trifluoroacetic acid (2 ml) added. The mixture was stirred with ice-cooling for 4 h, poured onto saturated potassium carbonate (20 ml) and extracted with dichloromethane. The combined extracts were dried (MgSO4) and solvent removed at reduced pressure to give the title compound (0.10 g)