Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[N:10]([CH2:21][CH2:22][C:23]1[C:31]2[C:26](=[CH:27][CH:28]=[C:29]([C:32]([C:35](=[O:45])[N:36]([CH2:41][CH2:42][CH2:43][CH3:44])[CH2:37][CH2:38][CH2:39][CH3:40])([CH3:34])[CH3:33])[CH:30]=2)[NH:25][C:24]=1[C:46]1[CH:51]=[C:50]([CH3:52])[CH:49]=[C:48]([CH3:53])[CH:47]=1)[CH2:11][CH2:12][CH2:13][CH2:14][C:15]1[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=1)C1C=CC=CC=1.CCO>[Pd].CCOC(C)=O>[CH3:53][C:48]1[CH:47]=[C:46]([C:24]2[NH:25][C:26]3[C:31]([C:23]=2[CH2:22][CH2:21][NH:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)=[CH:30][C:29]([C:32]([CH3:33])([CH3:34])[C:35]([N:36]([CH2:37][CH2:38][CH2:39][CH3:40])[CH2:41][CH2:42][CH2:43][CH3:44])=[O:45])=[CH:28][CH:27]=3)[CH:51]=[C:50]([CH3:52])[CH:49]=1
Reactant: CCCCN(CCCC)C(=O)C(C)(C)c1ccc2[nH]c(-c3cc(C)cc(C)c3)c(CCN(CCCCc3cccnc3)C(=O)OCc3ccccc3)c2c1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCCCN(CCCC)C(=O)C(C)(C)c1ccc2[nH]c(-c3cc(C)cc(C)c3)c(CCNCCCCc3cccnc3)c2c1
Reaction time: 6 h

Procedure:
A mixture of 76.5 mg (0.105 mmol) of [2-[5-(1-dibutylcarbamoyl-1-methylethyl)-2-(3,5-dimethylphenyl)-1H-indol-3-yl]ethyl]-[4-(pyridin-3-yl)butyl]carbamic acid benzyl ester, 40 mg of 10% palladium on carbon, 4 ml of absolute EtOH, and 4 ml of EtOAc was shaken with H2 (approx. 47 psig) in a pressure vessel for 6 hours. The catalyst was removed by filtration through Celite under N2, and the filtrate was concentrated in vacuo at room temperature. The residue was purified by preparative TLC on 4 Analtech tapered silica gel plates (20×20 cm), which were developed in 92.5:7.5:0.75 CH2Cl2 -MeOH-concentrated NH4OH. The product band from each plate was isolated, combined, and extracted with 92.5:7.5:0.75 CH2Cl2 -MeOH-concentrated NH4OH. Concentration of the extracts in vacuo yielded 51.4 mg (82%) of a pale yellow, stiff gum; homogeneous by TLC in 92.5:7.5:0.75 CH2Cl2 -MeOH-concentrated NH40H. 500 MHz 1H NMR (CDCl3) was consistent with the assigned structure. Mass spectrum (ESI): m/e 595.6 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[CH:4][N:3]=1.[CH:9]1([N:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)[CH2:13][CH2:12][CH2:11][CH2:10]1>CN(C=O)C>[CH:9]1([N:14]2[CH2:15][CH2:16][N:17]([C:2]3[N:7]=[C:6]([NH2:8])[CH:5]=[CH:4][N:3]=3)[CH2:18][CH2:19]2)[CH2:10][CH2:11][CH2:12][CH2:13]1
Reactant: Nc1ccnc(Cl)n1
Reactant: C1CCC(N2CCNCC2)C1
Solvent: CN(C)C=O
Product: Nc1ccnc(N2CCN(C3CCCC3)CC2)n1
Temperature: 70 °C
Yield: 51 %

Procedure:
A mixture of 0.5 g (3.86 mmol) 2-chloro-4-pyrimidinylamine (commercially available) and 1-cyclopentyl-piperazine (commercially available) in 1 mL DMF was heated to 70° C. for 16 h. The residue after filtration washed with diethyl ether and dried to yield 0.49 g (51%) of the title compound (intermediate 1) as white solid. MS (m/e): 284.3 (MH+).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH:11]([C:13]3[CH:14]=[CH:15][C:16]4[N:17]([CH:19]=[C:20]([NH:22][C:23]([CH:25]5[CH2:27][CH2:26]5)=[O:24])[N:21]=4)[N:18]=3)[CH3:12])=[N:9][N:10]=2)[CH:7]=1.N(C1C=CC=CN=1)N>>[N:10]1[N:9]=[C:8]([CH:11]([C:13]2[CH:14]=[CH:15][C:16]3[N:17]([CH:19]=[C:20]([NH:22][C:23]([CH:25]4[CH2:27][CH2:26]4)=[O:24])[N:21]=3)[N:18]=2)[CH3:12])[N:6]2[CH:7]=[CH:2][CH:3]=[CH:4][C:5]=12
Reactant: CC(c1ccc2nc(NC(=O)C3CC3)cn2n1)c1nnc2ccc(Br)cn12
Agent: NNc1ccccn1
Product: CC(c1ccc2nc(NC(=O)C3CC3)cn2n1)c1nnc2ccccn12

Procedure:
The title compound was synthesized using an analogous procedure to that described in the preparation of Compound 48 (Method A) using 2-hydrazinylpyridine. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.73-0.87 (m, 4 H) 1.83-1.99 (m, 4 H) 5.04-5.15 (m, 1 H) 6.94-7.04 (m, 1 H) 7.19 (d, J=9.35 Hz, 1 H) 7.38-7.47 (m, 1 H) 7.80 (d, J=9.35 Hz, 1 H) 7.94 (d, J=9.85 Hz, 1 H) 8.10 (s, 1 H) 8.35 (d, J=7.07 Hz, 1 H) 11.14 (s, 1 H). MS:m/z 348.2 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]3[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=3)=[CH:7][C:6]=2[CH:17]=1.[C:18]([OH:28])(=[O:27])[C:19]1[CH:26]=[CH:25][C:22]([CH:23]=O)=[CH:21][CH:20]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]3[CH:15]=[CH:14][C:13]([CH:16]=[CH:23][C:22]4[CH:25]=[CH:26][C:19]([C:18]([OH:28])=[O:27])=[CH:20][CH:21]=4)=[CH:12][CH:11]=3)=[CH:7][C:6]=2[CH:17]=1
Reactant: O=Cc1ccc(C(=O)O)cc1
Reactant: Cc1ccc(-c2cc3cc(Cl)ccc3o2)cc1
Product: O=C(O)c1ccc(C=Cc2ccc(-c3cc4cc(Cl)ccc4o3)cc2)cc1

Procedure:
When 5-chloro-2-(p-tolyl)benzofuran was condensed with the anil derivative of terephthalaldehydic acid according to the procedure described in Example 1, there was obtained 5-chloro-2-[4-(4-carboxystyryl)phenyl]benzofuran which melted at 347°-348°C following recrystallization from trichlorobenzene. The wavelength of maximum excitation of this compound was 372 nm and the wavelength of maximum emission was 424 nm.
Reaction SMILES: [CH3:1][C:2]([CH2:9][CH2:10][CH2:11][CH:12]([CH3:19])[CH2:13][CH2:14][CH2:15][CH:16]([CH3:18])[CH3:17])=[CH:3][CH2:4][C:5]([O:7][CH3:8])=[O:6].[OH:20][CH2:21][CH:22](CO)[OH:23].C(=O)([O-])[O-].[K+].[K+].Cl>CN(C)C=O>[CH3:1][C:2]([CH2:9][CH2:10][CH2:11][CH:12]([CH3:19])[CH2:13][CH2:14][CH2:15][CH:16]([CH3:18])[CH3:17])=[CH:3][CH2:4][C:5]([O:7][CH2:8][CH:21]([CH2:22][OH:23])[OH:20])=[O:6]
Reactant: COC(=O)CC=C(C)CCCC(C)CCCC(C)C
Reactant: OCC(O)CO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=CCC(=O)OCC(O)CO)CCCC(C)CCCC(C)C
Temperature: 100 °C
Reaction time: 18 h
Yield: 23.6 %

Procedure:
1.0 g (3.7 mmol) of methyl 4,8,12-trimethyltridec-3-enoate was slowly added dropwise to a solution of 0.86 g (9.3 mmol) of glycerol and 0.62 g (4.4 mmol) of potassium carbonate in dry N,N-dimethylformamide (4 mL) at 100° C. After the reaction mixture was stirred at 100° C. for 18 hours, 1M hydrochloric acid was added. The resulting solution was extracted with ether, and the extract was washed with saturated sodium bicarbonate aqueous solution and saturated brine, successively, and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated, and the resulting residue was purified by silica gel column chromatography (ethyl acetate/hexane mixture) to obtain 287 mg of the title compound (24% yield) as a colorless viscous liquid.
Reaction SMILES: CC1NC(C2C=CC=CC=2)=CC=1C(OCC)=O.C1(S(Cl)(=O)=O)C=CC=CC=1.[CH3:28][C:29]1[N:30]([S:45]([C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)(=[O:47])=[O:46])[C:31]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)=[CH:32][C:33]=1[C:34](OCC)=[O:35]>>[CH3:28][C:29]1[N:30]([S:45]([C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)(=[O:47])=[O:46])[C:31]([C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=2)=[CH:32][C:33]=1[CH:34]=[O:35]
Reactant: CCOC(=O)c1cc(-c2ccccc2)n(S(=O)(=O)c2ccccc2)c1C
Agent: CCOC(=O)c1cc(-c2ccccc2)[nH]c1C
Agent: O=S(=O)(Cl)c1ccccc1
Product: Cc1c(C=O)cc(-c2ccccc2)n1S(=O)(=O)c1ccccc1

Procedure:
Using ethyl 2-methyl-5-phenyl-1H-pyrrole-3-carboxylate and benzenesulfonyl chloride, a procedure as in Reference Example 4 was performed to synthesize ethyl 2-methyl-5-phenyl-1-(phenylsulfonyl)-1H-pyrrole-3-carboxylate, and procedures as in Reference Examples 5 and 6 were sequentially performed to give the title compound as a colorless oil.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[CH2:12]([C:16]1[CH2:23][S:22][CH:21]2[N:18]([C:19](=[O:56])[CH:20]2[NH:24][C:25](=[O:55])[C:26](=[N:52][O:53][CH3:54])[C:27]2[N:28]=[C:29]([NH:32][C:33]([C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=3)([C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[S:30][CH:31]=2)[C:17]=1[C:57]([O:59][CH:60]([C:67]1[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=1)[C:61]1[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=1)=[O:58])[C:13]([CH3:15])=[O:14].CCC=CCCCC.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[CH2:12]([C:16]1[CH2:23][S:22](=[O:9])[CH:21]2[N:18]([C:19](=[O:56])[CH:20]2[NH:24][C:25](=[O:55])[C:26](=[N:52][O:53][CH3:54])[C:27]2[N:28]=[C:29]([NH:32][C:33]([C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)([C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=3)[C:46]3[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=3)[S:30][CH:31]=2)[C:17]=1[C:57]([O:59][CH:60]([C:67]1[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=1)[C:61]1[CH:62]=[CH:63][CH:64]=[CH:65][CH:66]=1)=[O:58])[C:13]([CH3:15])=[O:14]
Reactant: CON=C(C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CC(C)=O)CSC12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: CCC=CCCCC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CC(C)=O)CS(=O)C12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A solution of 85% pure m-chloroperbenzoic acid (1.6 g) in methylene chloride (50 cc) is added, in the course of 20 minutes, to a solution, cooled to 0° C., of a mixture of the 3-acetonyl-2-benzhydryloxycarbonyl-7-[2-methoxyimino-2-(2-tritylaminothiazol-4-yl)-acetamido]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene and -oct-3-ene isomers (6.7 g) in methylene chloride (100 cc). The mixture is stirred for 11/2 hours at 0° C. and a saturated solution of sodium bicarbonate (50 cc) is then added. The organic phase is decanted, dried over sodium sulphate and concentrated to dryness under reduced pressure (20 mm Hg; 2.7 kPa) at 20° C. The residue is chromatographed on a column of Merck silica gel (0.06-0.20) (75 g) (diameter of the column: 3 cm; height: 21 cm). Elution is carried out with a 70/30 (by volumne) ethyl acetate/cyclohexane mixture (1.5 liters), 100 cc fractions being collected. Fractions 7 to 10 are concentrated to dryness under reduced pressure (20 mm Hg; 2.7 kPa) at 20° C. This yields the syn isomer of 3-acetonyl-2-benzhydryloxycarbonyl-7-[2-methoxyimino-2-(2-tritylaminothiazol-4-yl)-acetamido]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-5-oxide (5 g) in the form of a hard yellow foam.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[CH:5]([NH:12][CH:13]=[O:14])[CH:6](O)[C:7]([CH2:9][CH3:10])=[CH2:8])[CH3:2].S(Br)(Br)=O.[P:20]([O:25]C)([O:23][CH3:24])[O:21][CH3:22]>>[CH2:1]([O:3][C:4](=[O:15])[CH:5]([NH:12][CH:13]=[O:14])/[CH:6]=[C:7](\[CH2:9][CH3:10])/[CH2:8][P:20]([O:23][CH3:24])([O:21][CH3:22])=[O:25])[CH3:2]
Reactant: COP(OC)OC
Reactant: C=C(CC)C(O)C(NC=O)C(=O)OCC
Agent: O=S(Br)Br
Product: CCOC(=O)C(/C=C(\CC)CP(=O)(OC)OC)NC=O

Procedure:
Reaction of the 2-formylamino-3-hydroxy-4-ethyl-4-pentenoic acid ethyl ester with thionyl bromide and subsequent treatment with trimethyl phosphite in a manner analogous to that described in Example 1 yields E-2-formylamino-4-ethyl-5-dimethylphosphono-3-pentenoic acid ethyl ester.
Reaction SMILES: [C:1]([N:4]1[CH2:8][CH2:7][N:6]([C:9]2[CH:14]=[C:13](Cl)[CH:12]=[CH:11][C:10]=2[C:16]([N:18]2[CH2:23][CH2:22][N:21]([C:24]3[C:29]([CH3:30])=[CH:28][C:27]([CH:31]4[CH2:33][CH2:32]4)=[CH:26][N:25]=3)[CH2:20][CH2:19]2)=[O:17])[C:5]1=[O:34])(=[O:3])[CH3:2].[O:35]1[CH2:39][CH2:38][NH:37][C:36]1=[O:40]>>[C:1]([N:4]1[CH2:8][CH2:7][N:6]([C:9]2[CH:14]=[C:13]([N:37]3[CH2:38][CH2:39][O:35][C:36]3=[O:40])[CH:12]=[CH:11][C:10]=2[C:16]([N:18]2[CH2:23][CH2:22][N:21]([C:24]3[C:29]([CH3:30])=[CH:28][C:27]([CH:31]4[CH2:33][CH2:32]4)=[CH:26][N:25]=3)[CH2:20][CH2:19]2)=[O:17])[C:5]1=[O:34])(=[O:3])[CH3:2]
Reactant: O=C1NCCO1
Reactant: CC(=O)N1CCN(c2cc(Cl)ccc2C(=O)N2CCN(c3ncc(C4CC4)cc3C)CC2)C1=O
Product: CC(=O)N1CCN(c2cc(N3CCOC3=O)ccc2C(=O)N2CCN(c3ncc(C4CC4)cc3C)CC2)C1=O
Yield: 3.6 %

Procedure:
By reaction and treatment in the same manner as in Example 201 and using 1-acetyl-3-{5-chloro-2-[4-(5-cyclopropyl-3-methylpyridin-2-yl)piperazine-1-carbonyl]phenyl}imidazolidin-2-one (342 mg) described in Preparation Example 196 and oxazolidin-2-one (61.8 mg), the title compound (13.6 mg) was obtained.
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[NH:8][C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4].N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.C(P(CCCC)CCCC)CCC.[S:59]1[C:63]2[CH:64]=[CH:65][CH:66]=[CH:67][C:62]=2[N:61]=[C:60]1[CH2:68]O>C(OCC)(=O)C.O1CCCC1>[S:59]1[C:63]2[CH:64]=[CH:65][CH:66]=[CH:67][C:62]=2[N:61]=[C:60]1[CH2:68][N:8]1[C:9](=[O:26])[C:10]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=3)=[CH:14][CH:13]=2)=[C:5]([CH2:1][CH2:2][CH2:3][CH3:4])[N:6]=[C:7]1[CH3:27]
Reactant: OCc1nc2ccccc2s1
Reactant: CCCCc1nc(C)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCCc1nc(C)n(Cc2nc3ccccc3s2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 44.6 %

Procedure:
A mixture of 4′-[(4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile (1 g), 1,1′-(azodicarbonyl)dipiperidine (1.41 g), tributylphosphine (1.56 mL), 1,3-benzothiazol-2-ylmethanol (0.69 g) and tetrahydrofuran (50 mL) was stirred at room temperature for 4 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.63 g, 45%).
Reaction SMILES: [Na].CC(O[CH2:6][C:7]1[CH2:24][S:23][C@@H:10]2[C@H:11]([NH:14][C:15]([CH2:17][C:18]3[S:22][CH:21]=[CH:20][CH:19]=3)=[O:16])[C:12](=[O:13])[N:9]2[C:8]=1[C:25]([OH:27])=[O:26])=O.[SH:28][C:29]1[N:30]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[C:31]([CH2:34][CH2:35][C:36]([OH:38])=[O:37])=[N:32][N:33]=1.C(=O)(O)[O-].[Na+].Cl>O>[S:22]1[CH:21]=[CH:20][CH:19]=[C:18]1[CH2:17][C:15]([NH:14][CH:11]1[C:12](=[O:13])[N:9]2[C:8]([C:25]([OH:27])=[O:26])=[C:7]([CH2:6][S:28][C:29]3[N:30]([C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)[C:31]([CH2:34][CH2:35][C:36]([OH:38])=[O:37])=[N:32][N:33]=3)[CH2:24][S:23][C@H:10]12)=[O:16]
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](NC(=O)Cc3cccs3)[C@H]2SC1
Reactant: O=C(O)CCc1nnc(S)n1-c1ccccc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: O=C(O)CCc1nnc(SCC2=C(C(=O)O)N3C(=O)C(NC(=O)Cc4cccs4)[C@H]3SC2)n1-c1ccccc1
Temperature: 0 °C
Yield: 87.5 %

Procedure:
358 mg of the sodium salt of 7-(2-thienylacetamido)-cephalosporanic acid and 256 mg of 3-(2-mercapto-1-phenyl-1,3,4-triazol-5-yl)propionic acid were dissolved in 5 ml of water and 4.12 ml of a 0.5N aqueous solution of sodium bicarbonate. The resulting solution was heated on a water bath at 63° to 65° C. in a nitrogen atmosphere for 4.5 hours. After completion of the reaction, 5 ml of ice-water and 3 ml of 1N HCl were added to the reaction mixture while ice-cooling and stirring to precipitate white crystals, which were then filtered and washed with water. Immediately thereafter, the white crystals were throughly washed with diethyl ether to obtain 440 mg of 7-(2-thienylacetamido)-3-[5-(2-carboxyethyl)-1-phenyl-1,3,4-triazol-2-yl]thiomethyl-3-cephem-4-carboxylic acid (yield, 87.5%).
Reaction SMILES: [F:1][C:2]1[C:3](F)=[C:4]([F:13])[C:5]([F:12])=[C:6]([C:10]#[N:11])[C:7]=1[C:8]#[N:9].[F:15][C:16]1[C:21]([OH:22])=[C:20]([F:23])[C:19]([F:24])=[C:18]([OH:25])[C:17]=1[F:26].[Na].[Na]>CN(C=O)C>[C:8]([C:7]1[C:2]([F:1])=[C:3]([C:4]([F:13])=[C:5]([F:12])[C:6]=1[C:10]#[N:11])[O:22][C:21]1[C:16]([F:15])=[C:17]([F:26])[C:18]([O:25][C:3]2[C:4]([F:13])=[C:5]([F:12])[C:6]([C:10]#[N:11])=[C:7]([C:8]#[N:9])[C:2]=2[F:1])=[C:19]([F:24])[C:20]=1[F:23])#[N:9]
Reactant: N#Cc1c(F)c(F)c(F)c(F)c1C#N
Reactant: Oc1c(F)c(F)c(O)c(F)c1F
Agent: [Na]
Solvent: CN(C)C=O
Product: N#Cc1c(F)c(F)c(Oc2c(F)c(F)c(Oc3c(F)c(F)c(C#N)c(C#N)c3F)c(F)c2F)c(F)c1C#N
Reaction time: 0.33 h
Yield: 53.9 %

Procedure:
In an Erlenmeyer flask were charged 40.0 g (0.2 mol) of tetrafluorophthalonitrile and 0.1 liter of DMF. The flask containing the mixture was immersed in an ice-water bath to keep the mixture at 0° to 5° C. To the mixture was added portionwise in 10 minutes 11.3 g (0.05 mol) of disodium tetrafluorohydroquinone. The resulting mixture was stirred at that temperature for 20 minutes and then at room temperature for 30 minutes. Thereafter, the reaction mixture was treated in the same manner as in Example 16 and the product was identified in the same manner as in Example 16. Thus 14.6 g of 1,4-bis(3,4-dicyanotrifluorophenoxy)tetrafluorobenzene was obtained in a yield of 54%.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[N:10]([C:14]1[N:19]=[CH:18][C:17]([O:20][CH:21]3[CH2:26][CH2:25][N:24]([C:27]#[N:28])[CH2:23][CH2:22]3)=[CH:16][CH:15]=1)[CH:9]=[CH:8]2)(=[O:4])=[O:3].[OH:29][NH:30][C:31](=N)[CH:32]([CH3:34])[CH3:33]>C1COCC1.[Cl-].[Zn+2].[Cl-]>[CH:32]([C:31]1[N:28]=[C:27]([N:24]2[CH2:25][CH2:26][CH:21]([O:20][C:17]3[CH:18]=[N:19][C:14]([N:10]4[C:11]5[C:7](=[CH:6][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[CH:13][CH:12]=5)[CH:8]=[CH:9]4)=[CH:15][CH:16]=3)[CH2:22][CH2:23]2)[O:29][N:30]=1)([CH3:34])[CH3:33]
Reactant: CS(=O)(=O)c1ccc2c(ccn2-c2ccc(OC3CCN(C#N)CC3)cn2)c1
Reactant: CC(C)C(=N)NO
Agent: [Cl-]
Agent: [Zn+2]
Solvent: C1CCOC1
Product: CC(C)c1noc(N2CCC(Oc3ccc(-n4ccc5cc(S(C)(=O)=O)ccc54)nc3)CC2)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 31.5 %

Procedure:
To a mixture of 4-((6-(5-(methylsulfonyl)-1H-indol-1-yl)pyridin-3 yl)oxy)piperidine-1-carbonitrile (intermediate-36) (0.110 g, 0.27 mmol) and N-hydroxy-isobutyramidine (0.05 g, 0.5 mmol) in anhydrous THF (15 mL), 1M solution of zinc chloride in THF (0.56 mL, 0.56 mmol) was added. The suspension was stirred at room temperature for 18 h. Solvent was concentrated in vacuo, the resulting crude was dissolved in 4N HCl in ethanol, water (1:1) and stirred at 60-70° C. for 2-3 h. The reaction was quenched by saturated NaHCO3 and the organic layer was separated and concentrated. The residue was purified by flash column chromatography to give 3-isopropyl-5-(4-((6-(5-(methylsulfonyl)-1H-indol-1-yl)pyridin-3-yl)oxy)piperidin-1-yl)-1,2,4-oxadiazole (0.041 g, 30%)
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]=[C:7]=[S:8])=[O:5])[CH3:2].[CH3:9][C:10]1[CH:17]=[CH:16][C:13]([CH2:14][OH:15])=[CH:12][CH:11]=1>O1CCCC1.C(N(CC)CC)C>[C:4]([NH:6][C:7](=[S:8])[O:15][CH2:14][C:13]1[CH:16]=[CH:17][C:10]([CH3:9])=[CH:11][CH:12]=1)([O:3][CH2:1][CH3:2])=[O:5]
Reactant: CCOC(=O)N=C=S
Reactant: Cc1ccc(CO)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)NC(=S)OCc1ccc(C)cc1
Yield: 106.7 %

Procedure:
66.5 g of ethoxycarbonyl isothiocyanate were added dropwise to a solution of 61 g of p-methylbenzyl alcohol in 500 ml of tetrahydrofuran and 2 ml of triethylamine and the mixture was refluxed for 24 hours. The mixture was concentrated to dryness to obtain 135 g of raw p-methylbenzyl N-carbethoxy -thiocarbamate.
Reaction SMILES: C([O:5][C:6](=O)[NH:7][CH:8]([C:13]([N:15]1[CH2:19][CH2:18][CH2:17][CH:16]1[C:20](=[O:36])[NH:21][CH:22]1[CH2:26][C:25](=[O:27])[O:24][CH:23]1[O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:14])[C:9]([CH3:12])([CH3:11])[CH3:10])(C)(C)C.C(O)(C(F)(F)F)=O.CCN(C(C)C)C(C)C.[NH2:54][C:55]1[CH:63]=[CH:62][C:58](C(O)=O)=[CH:57][C:56]=1[Cl:64].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>C(Cl)Cl>[CH2:29]([O:28][CH:23]1[CH:22]([NH:21][C:20]([CH:16]2[CH2:17][CH2:18][CH2:19][N:15]2[C:13](=[O:14])[CH:8]([NH:7][C:6](=[O:5])[C:58]2[CH:62]=[CH:63][C:55]([NH2:54])=[C:56]([Cl:64])[CH:57]=2)[C:9]([CH3:12])([CH3:10])[CH3:11])=[O:36])[CH2:26][C:25](=[O:27])[O:24]1)[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: Nc1ccc(C(=O)O)cc1Cl
Reactant: CC(C)(C)OC(=O)NC(C(=O)N1CCCC1C(=O)NC1CC(=O)OC1OCc1ccccc1)C(C)(C)C
Agent: On1nnc2ccccc21
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: CC(C)(C)C(NC(=O)c1ccc(N)c(Cl)c1)C(=O)N1CCCC1C(=O)NC1CC(=O)OC1OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 567.1 %

Procedure:
A solution of 456 mg (0.088 mmol) of 71 in CH2Cl2 (20 ml) was treated with anhydrous TFA (5 mL) then stirred at room temperature under N2 for 1 hour and evaporated to dryness. The residue was repeatedly concentrated from CH2Cl2 (3×) then dried under vacuum. The resulting residue was dissolved in CH2Cl2 (20 ml), cooled to 0° C., then treated with DIEA (1.3 ml, 8 eq, 2.46 mmol) followed by 4-amino-3-chloro-benzoic acid (202 mg, 1.17 mmol), HOBT (1833 mg, 1.35 mmol), and EDC (279 mg, 1.45 mmol). The resulting mixture was allowed to warm to room temperature and stir for 18 hours. The solvent was removed in vacuo and the residue dissolved in EtOAc then washed with distilled water (3×), 0.5N NaHSO4 (2×), saturated NaHCO3 (2×) and brine. The organic layer was dried over Na2SO4, filtered and evaporated to give a residue that was purified by flash chromatography, eluting with CH2Cl2/MeOH (99/1 to 97/3%), affording 285 mg (57% yield) of the title compound (72) as a yellow solid.
Reaction SMILES: C[O:2][C:3]1C=CC(C[C@H]2OCCNC2)=C[CH:4]=1.[C:16]([N:23]1[CH2:28][CH2:27][O:26][C@H:25]([CH2:29][C:30]2[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[C:32](I)[CH:31]=2)[CH2:24]1)([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17].C(=O)([O-])[O-].[K+].[K+].C([Sn](CCCC)(CCCC)C(OCC)=C)CCC>[Cl-].C([N+](CC)(CC)CC)C.CN(C)C=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>[C:16]([N:23]1[CH2:28][CH2:27][O:26][C@H:25]([CH2:29][C:30]2[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[C:32]([C:3](=[O:2])[CH3:4])[CH:31]=2)[CH2:24]1)([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17]
Reactant: COc1ccc(C[C@@H]2CN(C(=O)OC(C)(C)C)CCO2)cc1I
Reactant: COc1ccc(C[C@@H]2CNCCO2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Agent: CC[N+](CC)(CC)CC
Solvent: CN(C)C=O
Product: COc1ccc(C[C@@H]2CN(C(=O)OC(C)(C)C)CCO2)cc1C(C)=O
Temperature: 90 °C

Procedure:
Tetrakis(triphenylphosphine)palladium(0) (61 mg, 0.053 mmol) was added to a solution of intermediate (b), N-Boc-(R)-2-(3-Iodo-4-methoxybenzyl)morpholine (229 mg, 0.529 mmol), potassium carbonate (146 mg, 1.058 mmol), tetraethylammonium chloride (88 mg, 0.529 mmol) and tributyl(1-ethoxyvinyl)tin (0.179 mL, 0.529 mmol) in N,N-dimethyl formamide and heated to 90° C. for 18 h. The cooled reaction mixture was filtered and the liquors partitioned between ethyl acetate and water. The organic phase was separated and dried (Na2SO4) and concentrated to give the crude product which was purified by silica gel chromatography (silica: 10% ethyl acetate:dichloromethane) affording the crude material (a), N-Boc-(R)-2-(3-acetyl-4-methoxybenzyl)morpholine as a brown oil (248 mg) that was used without further purification.
Reaction SMILES: [OH:1][C:2]1[C:11]([CH:12]=O)=[C:6]2[CH2:7][CH2:8][CH2:9][O:10][C:5]2=[CH:4][CH:3]=1.[F:14][C:15]1[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:16]=1[NH2:17].[BH4-].[Na+].Cl>CO.O>[OH:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][CH2:8][CH2:7][C:6]=2[C:11]=1[CH2:12][NH:17][C:16]1[CH:18]=[CH:19][C:20]([F:22])=[CH:21][C:15]=1[F:14]
Reactant: Nc1ccc(F)cc1F
Reactant: O=Cc1c(O)ccc2c1CCCO2
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: Oc1ccc2c(c1CNc1ccc(F)cc1F)CCCO2
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 34.7 %

Procedure:
A mixture of 6-hydroxy-3,4-dihydrobenzopyran-5-carboxaldehyde (299 mg, 1.68 mmol) and 2,4 -difluoroaniline (219 mg, 1.68 mmol) in methanol (8 mL) was heated to reflux for 20 minutes during which time the intermediate Schiff's base crystallized, and, after cooling to room temperature, was collected by filtration and dried. The isolated Schiff's base (175 mg, 36%) was suspended in methanol (8 mL) and sodium borohydride (25 mg, 0.66 mmol) was added. The mixture was stirred at room temperature for 5 minutes, poured into water (50 mL) and carefully neutralized (pH=7) with 2.5 N HCl. The product was collected by filtration and dried to afford 6-hydroxy-5-(2,4-difluorophenyl)aminomethyl-3, 4-dihydrobenzopyran, (170 mg, 96.6%), m.p. 120°-121° C.