Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]1[C:15](=O)O[C:12](=O)[C@@H:4]([NH:5]C(=O)C(F)(F)F)[CH2:3]1.[O:17]1[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[CH2:19][CH2:18]1.CC(C(O)=O)C[C@@H](C(O)=O)N>>[NH2:5][CH:4]1[CH2:12][C:23]2=[CH:22][C:21]3[O:17][CH2:18][CH2:19][C:20]=3[CH:25]=[C:24]2[CH2:15][CH:2]([CH3:1])[CH2:3]1
Reactant: c1ccc2c(c1)CCO2
Reactant: CC1C[C@H](NC(=O)C(F)(F)F)C(=O)OC1=O
Agent: CC(C[C@H](N)C(=O)O)C(=O)O
Product: CC1Cc2cc3c(cc2CC(N)C1)OCC3

Procedure:
This compound may be prepared by condensing 4-methyl-N-trifluoroacetylglutamic anhydride with 2,3-dihydrobenzofuran according to the process described in Example 2. The synthesis of 4-methylglutamic acid is known (J. Pharm. Scien., (1975), 64, No. 11, p. 1855-1858).
Reaction SMILES: [S:1]([C:19]1[CH2:20][CH:21]2[C:26](=[O:27])[N:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:23](=[O:24])[CH:22]2[CH2:34][CH:35]=1)[C:2]1[CH2:3][CH:4]2[C:9](=[O:10])[N:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:6](=[O:7])[CH:5]2[CH2:17][CH:18]=1.[S]>>[S:1]([C:2]1[CH:3]=[C:4]2[C:9](=[O:10])[N:8]([C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:6](=[O:7])[C:5]2=[CH:17][CH:18]=1)[C:19]1[CH:20]=[C:21]2[C:26](=[O:27])[N:25]([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)[C:23](=[O:24])[C:22]2=[CH:34][CH:35]=1
Reactant: O=C1C2CC=C(SC3=CCC4C(=O)N(c5ccccc5)C(=O)C4C3)CC2C(=O)N1c1ccccc1
Agent: [S]
Product: O=C1c2ccc(Sc3ccc4c(c3)C(=O)N(c3ccccc3)C4=O)cc2C(=O)N1c1ccccc1
Temperature: 25 °C
Yield: 31.2 %

Procedure:
A mixture of 200 mg (0.41 mmol) of 4,4'-thiobis(N-phenyl-1,2,3,6-tetrahydrophthalimide) and 53 mg (1.7 mmol) of elemental sulfur was heated to 240°-260° C. (sand bath) for 20 minutes and cooled to room temperature. The resulting brown residue was purified by preparative TLC on silica gel (eluent: 1% methanol in dichloromethane) to give 61 mg (31% yield) of 4,4'-thiobis(N-phenylphthalimide) as a yellow solid. Trituration with dichloromethane afforded a white solid: mp 275°-280° C.; (lit 293°-295° C.--see U.S. Pat. No. 3,989,712); IR (KBr) 3065, 1710, 1375 cm-1 ; 1H NMR (slurry in DMSO-d6) 7.52 (m, 5H), 7.97 (m, 3H).
Reaction SMILES: C([O-])([O-])=O.[Na+].[Na+].CO.[CH:9]1([NH:15][CH2:16][C:17]2[CH:26]=[CH:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:18]=2B2OC(C)(C)C(C)(C)O2)[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1.Br[C:37]1[N:42]=[C:41]([CH:43]=[O:44])[CH:40]=[CH:39][CH:38]=1>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.C1(C)C=CC=CC=1>[CH:9]1([NH:15][CH2:16][C:17]2[CH:26]=[CH:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:18]=2[C:37]2[N:42]=[C:41]([CH:43]=[O:44])[CH:40]=[CH:39][CH:38]=2)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]1
Reactant: O=Cc1cccc(Br)n1
Reactant: CC1(C)OB(c2c(CNC3CCCCC3)ccc3ccccc23)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CO
Solvent: O
Product: O=Cc1cccc(-c2c(CNC3CCCCC3)ccc3ccccc23)n1
Temperature: 25 °C

Procedure:
A solution of 21.2 g (74.1 mmol) of Na2CO3×10H2O in 660 ml of water and 190 ml of methanol was purged with argon for 30 min. The obtained solution was added to a mixture of 29.9 g (80.0 mmol) of cyclohexyl{[1-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-naphthyl]methyl}amine, 14.0 g (80.0 mmol) of 6-bromopyridine-2-carbaldehyde, 4.62 g (4.00 mmol) of Pd(PPh3)4, and 780 ml of toluene in argon atmosphere. This mixture was refluxed for 10 h using a mechanical stirrer, then cooled to room temperature. The organic layer was separated, dried over Na2SO4, evaporated to 300 ml in volume, and then extracted with 3×300 ml of 2M HCl. The combined aqueous layer was alkalified to pH 10 by the saturated aqueous K2CO3, and then extracted with 3×200 ml of dichloromethane. The combined organic extract was dried over Na2SO4 and evaporated to dryness. Yield 23.1 g (84%) of a brown oil. Anal. Calc for C23H24N2O: C 80.20; H 7.02; N 8.13. Found: C 80.78; H 7.11; N 8.01.1H NMR (CDCl3): δ 10.08 (s, 1H, CHO), 7.96-8.03 (m, 2H, 3-H, 4-H in Py), 7.83-7.89 (m, 2H, 8,5-H in Py), 7.59-7.64 (m, 2H, 5-H in Py and 4-H in naphthyl), 7.39-7.43 (m, 1H, 6-H in naphthyl), 7.30-7.34 (m, 1H, 7-H in naphthyl), 7.20-7.23 (m, 1H, 3-H in naphthyl), 3.56 (m, 2H, CH2), 2.21 (m, 1H, 1-H in Cy), 1.57-1.66 (m, 4H, Cy), 1.02-1.11 (m, 4H, Cy), 0.88-0.96 (m, 2H, Cy).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[CH2:9][O:10][C:11]1[CH:18]=[CH:17][C:14]([CH:15]=O)=[CH:13][CH:12]=1.C([O-])(=O)C.[Na+].[S:24]1[CH2:30][C:28](=[O:29])[NH:27][C:25]1=[S:26]>C(O)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[CH2:9][O:10][C:11]1[CH:18]=[CH:17][C:14]([CH:15]=[C:30]2[S:24][C:25](=[S:26])[NH:27][C:28]2=[O:29])=[CH:13][CH:12]=1
Reactant: O=Cc1ccc(OCc2c(F)cccc2Cl)cc1
Reactant: O=C1CSC(=S)N1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: O=C1NC(=S)SC1=Cc1ccc(OCc2c(F)cccc2Cl)cc1

Procedure:
Under a nitrogen atmosphere in a round bottom flask 4-[(2-chloro-6-fluorophenyl)methoxy]benzaldehyde (1.00 g, 3.78 mmol) was dissolved in acetic acid (19 ml). To this solution was added sodium acetate (1.08 g, 13.2 mmol) and then rhodanine (0.50 g, 3.75 mmol). The reaction mixture was then heated to reflux and maintained at this temeprature. The progress of the reaction was monitored by thin layer chromatography.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:9]=[N:10][CH:11]=[N:12][CH:13]=1.[CH3:14][O:15][C:16]1[CH:41]=[CH:40][C:19]([CH2:20][N:21]([C:35]2[S:36][CH:37]=[CH:38][N:39]=2)[S:22]([C:25]2[CH:26]=[CH:27][C:28]3[NH:33][CH2:32][CH2:31][O:30][C:29]=3[CH:34]=2)(=[O:24])=[O:23])=[CH:18][CH:17]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.CC(C)([O-])C.[Na+]>C1(C)C=CC=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:14][O:15][C:16]1[CH:17]=[CH:18][C:19]([CH2:20][N:21]([C:35]2[S:36][CH:37]=[CH:38][N:39]=2)[S:22]([C:25]2[CH:26]=[CH:27][C:28]3[N:33]([C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=4[C:8]4[CH:9]=[N:10][CH:11]=[N:12][CH:13]=4)[CH2:32][CH2:31][O:30][C:29]=3[CH:34]=2)(=[O:24])=[O:23])=[CH:40][CH:41]=1
Reactant: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(c2)OCCN3)cc1
Reactant: Brc1ccccc1-c1cncnc1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: Cc1ccccc1
Product: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(c2)OCCN3c2ccccc2-c2cncnc2)cc1
Temperature: 100 °C
Yield: 40.9 %

Procedure:
A mixture of 5-(2-bromophenyl)pyrimidine (251 mg, 1.07 mmol), INTERMEDIate M (300 mg, 7.17 mmol), Pd2(dba)3 (65 mg, 0.0717 mmol), Xantphos (82 mg, 0.143 mmol) and sodium-tert-butoxide (137 mg, 1.43 mmol) in toluene (8 mL) was degassed for 10 min. The reaction mixture was subjected to microwave heating for 1 h at 100° C. After completion, the reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (3×15 mL). The organic layer was dried over sodium sulfate and concentrated under reduced pressure to obtain the crude material which was purified by combiflash column chromatography (column size: 12 g; elution: 35% ethyl acetate in hexane) to get N-(4-methoxybenzyl)-4-(2-(pyrimidin-5-yl)phenyl)-N-(thiazol-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide as yellow solid (250 mg, 41.0%); MS (ESI, positive ion) m/z: 572.0 (M+1).
Reaction SMILES: [CH2:1]([NH:4][C:5]1[CH:10]=[CH:9][N:8]2[CH:11]=[C:12]([CH3:14])[N:13]=[C:7]2[C:6]=1I)[CH:2]=[CH2:3].CCN(CC)CC>[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC.CC([O-])=O.CC([O-])=O.[Pd+2].CN(C=O)C>[CH3:14][C:12]1[CH2:11][N:8]2[CH:9]=[CH:10][C:5]3[C:6]([C:2]([CH3:3])=[CH:1][N:4]=3)=[C:7]2[N:13]=1
Reactant: C=CCNc1ccn2cc(C)nc2c1I
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC1=Nc2c3c(C)cnc-3ccn2C1
Temperature: 25 °C
Reaction time: 72 h
Yield: 37.9 %

Procedure:
A mixture of 30 (117 mg, 0.37 mmol), anhydrous DMF (5 mL), Et3N (130 μL, 0.94 mmol), tetrabutylammonium chloride (104 mg, 0.37 mmol), Pd(OAc)2 (9 mg, 40.1 μmol) was stirred for 3 days at room temperature. After removal of the solvent, the residue was diluted with H2O (10 mL), basified with Na2CO3 to pH=10-12 and extracted with CH2Cl2 (3×20 mL). The CH2Cl2 extracts were dried (Na2SO4), filtered and evaporated. The residue was purified by chromatography using CH2Cl2/EtOAc (4/1, v/v) as eluent to afford compound 31 (26 mg, yield: 38%); mp 211° C.; IR (KBr) 3099, 3068, 3006, 2913, 2858, 1633, 1517 cm−1; 1H NMR (400 MHz, CDCl3) δ 2.45 (s, 3H), 2.61 (s, 3H), 6.78 (d, 1H, J=7.2 Hz), 6.90 (s, 1H), 7.22 (s, 1H), 7.66 (d, 1H, J=7.2 Hz), 9.55 (brs, 1H); 13C NMR (100 MHz, CDCl3) δ 11.9, 14.3, 101.5, 109.0, 113.3, 113.7, 119.8, 120.6, 131.1, 140.0, 142.6. Anal. Calcd for C11H11N3: C, 71.33; H, 5.99; N, 22.69. Found: C, 70.94; H, 5.89; N, 23.01.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:10]=[CH:11][C:12]3[N:16]=[N:15][N:14]([CH:17]([CH3:20])[CH:18]=O)[C:13]=3[CH:21]=2)[CH:5]=[C:4]([F:22])[C:3]=1[C:23]([F:26])([F:25])[F:24].Cl.[NH2:28][NH:29][C:30]([NH2:32])=[O:31].C([O-])(=O)C.[Na+]>C(O)C>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:10]=[CH:11][C:12]3[N:16]=[N:15][N:14]([CH:17]([CH3:18])[CH:20]=[N:28][NH:29][C:30]([NH2:32])=[O:31])[C:13]=3[CH:21]=2)[CH:5]=[C:4]([F:22])[C:3]=1[C:23]([F:26])([F:25])[F:24]
Reactant: NNC(N)=O
Reactant: CC(C=O)n1nnc2ccc(Oc3cc(F)c(C(F)(F)F)c(Cl)c3)cc21
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CC(C=NNC(N)=O)n1nnc2ccc(Oc3cc(F)c(C(F)(F)F)c(Cl)c3)cc21

Procedure:
A mixture of 6-[(2-chloro-α,α,α,6-tetrafluoro-p-tolyl)oxy]-α-methyl-1H-benzotriazole-1-acetaldehyde (0.0295 mole), semicarbazide hydrochloride (4.0 g, 0.035 mole), and sodium acetate (5.8 g, 0.071 mole) in aqueous ethanol is heated to reflux temperature, cooled and filtered. The solid filter cake is recrystallized from ethanol to give the title compound as a solid, mp 170°-171° C., identified by elemental and NMR analyses.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.OS(O)(=O)=O.[CH3:24][CH2:25]O>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([C:12]2[CH:13]=[CH:14][C:15]([Cl:18])=[CH:16][CH:17]=2)[C:9]([O:11][CH2:24][CH3:25])=[O:10])=[CH:6][CH:7]=1
Reactant: O=C(O)C(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)C(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Temperature: 100 °C
Reaction time: 18 h

Procedure:
To a solution of bis(4-chlorophenyl)acetic acid (5.00 g, 17.8 mmol) in EtOH (100 mL) in a 500 mL round bottom flask, was added H2SO4, 36N (0.0988 mL, 1.78 mmol). The mixture was stirred at 100° C. for 18 hours. The mixture was then concentrated in vacuo, diluted with EtOAc (200 mL), and washed with deionized water (3×100 mL) and then with brine (100 mL). The organic layer was dried over MgSO4, concentrated, and dried in vacuo to give the crude product ethyl 2,2-bis(4-chlorophenyl)acetate (5.473 g). MS m/e=309 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N:8]2[C:12](=[O:13])[C@H:11]3[C@@H:14]([Si](C)(C)C)[S:15][CH2:16][C@H:10]3[C:9]2=[O:21])[CH:5]=[CH:6][CH:7]=1.[F-].[Cs+].O.C1C=CC=CC=1>CN(P(N(C)C)(N(C)C)=O)C.O>[Br:1][C:2]1[CH:3]=[C:4]([N:8]2[C:9](=[O:21])[C@@H:10]3[CH2:16][S:15][CH2:14][C@@H:11]3[C:12]2=[O:13])[CH:5]=[CH:6][CH:7]=1
Reactant: C[Si](C)(C)[C@H]1SC[C@H]2C(=O)N(c3cccc(Br)c3)C(=O)[C@H]21
Agent: [Cs+]
Agent: [F-]
Solvent: O
Solvent: c1ccccc1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: O=C1[C@H]2CSC[C@H]2C(=O)N1c1cccc(Br)c1
Temperature: 80 °C
Yield: 56 %

Procedure:
To a solution of (3S,3aS,6aR)-5-(3-bromo-phenyl)-3-trimethylsilanyl-tetrahydro-thieno[3,4-c]pyrrole-4,6-dione (637 mg, 1.66 mmol) in HMPA (5 ml) and water (2 drops) was added powdered cesium fluoride (254 mg, 1.66 mmol). The mixture was heated (80° C., oil bath) for 8 hours and then stirred over night at ambient. Water (50 ml) and benzene (60 ml) were added and the material was shaken. The organic phase was collected and washed with brine (50 ml). The benzene phase was collected and the aqueous phase was back-extracted (2×40 ml) with benzene. The organics were combined, dried (MgSO4), filtered and stripped. The remainder was purified by silica gel chromatography eluting with 4% to 45% ethyl acetate in hexanes to afford 290 mg of (3aR,6aS)-5-(3-bromo-phenyl)-tetrahydro-thieno[3,4-c]pyrrole-4,6-dione, as a brown-yellow solid.
Reaction SMILES: [C:1]([S:4][C:5]1[S:12]S[CH:10]2[N:7]([C:8](=[O:13])[CH2:9]2)[C:6]=1[C:14]([O:16][CH2:17][O:18][C:19](=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21])=[O:15])(=[O:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[2H]C(Cl)(Cl)Cl>[C:1]([S:4][C:5]1[S:12][CH:10]2[N:7]([C:8](=[O:13])[CH2:9]2)[C:6]=1[C:14]([O:16][CH2:17][O:18][C:19](=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21])=[O:15])(=[O:3])[CH3:2]
Reactant: CC(=O)SC1=C(C(=O)OCOC(=O)C(C)(C)C)N2C(=O)CC2SS1
Agent: [2H]C(Cl)(Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CC(=O)SC1=C(C(=O)OCOC(=O)C(C)(C)C)N2C(=O)CC2S1

Procedure:
To a solution of 22 mg of pivaloyloxymethyl 3-acetylthio-8-oxo-4,5-dithia-1-azabicyclo[4,2,0]oct-2-ene-2-carboxylate in deuterochloroform were added 14.7 mg of triphenylphosphine. TLC analysis indicated complete conversion of the starting material and the product was shown by IR and NMR analysis to be the title compound. This product was isolated by chromatography on silica gel using ethyl acetate/hexane mixtures as solvent. The yield of product was 13 mg (65%).
Reaction SMILES: BrC1C=CC(C2NC=C(C3N(C(C)C)N=C(C)N=3)N=2)=C(F)C=1.Cl.[Br:24][C:25]1[CH:33]=[CH:32][C:28]([C:29](=[NH:31])[NH2:30])=[C:27]([F:34])[CH:26]=1.Cl[CH2:36][C:37](=O)[C:38]([OH:40])=[O:39]>>[Br:24][C:25]1[CH:33]=[CH:32][C:28]([C:29]2[NH:30][CH:36]=[C:37]([C:38]([OH:40])=[O:39])[N:31]=2)=[C:27]([F:34])[CH:26]=1
Reactant: N=C(N)c1ccc(Br)cc1F
Reactant: O=C(O)C(=O)CCl
Agent: Cc1nc(-c2c[nH]c(-c3ccc(Br)cc3F)n2)n(C(C)C)n1
Agent: Cl
Product: O=C(O)c1c[nH]c(-c2ccc(Br)cc2F)n1

Procedure:
Scheme 11 shows the synthesis of 5-(2-(4-bromo-2-fluorophenyl)-1H-imidazol-4-yl)-1-isopropyl-3-methyl-1H-1,2,4-triazole V from 4-bromo-2-fluorobenzimidamide hydrochloride 12. 3-Chloro-2-oxopropanoic acid and 12 are reacted with base to give 2-(4-bromo-2-fluorophenyl)-1H-imidazole-4-carboxylic acid 30. Alternatively, 3-bromo-2-oxopropanoic acid can be reacted with 12 to give 30. Reaction of 30 with N′-isopropylacetohydrazonamide 6 and coupling reagent HBTU (N,N,N′,N′-tetramethyl-O-(1H-benzotriazol-1-yl)uronium hexafluorophosphate, 0-(Benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate, CAS Ref No. 94790-37-1) in DMF gives intermediate, 2-(4-bromo-2-fluorophenyl)-N-(1-(2-isopropylhydrazinyl)ethylidene)-1H-imidazole-4-carboxamide 31 which need not be isolated and cyclizes upon heating to give V. Alternatively, 5-(2-(4-chloro-2-fluorophenyl)-1H-imidazol-4-yl)-1-isopropyl-3-methyl-1H-1,2,4-triazole 44, the chloro version of V, can be prepared from 4-chloro-2-fluorobenzonitrile 38 (Scheme 15)
Reaction SMILES: [Cl:1][C:2]1[C:7]2[S:8][C:9](C(O)=O)=[CH:10][C:6]=2[CH:5]=[CH:4][CH:3]=1>N1C2C(=CC=CC=2)C=CC=1.Cl.[Cu]>[Cl:1][C:2]1[C:7]2[S:8][CH:9]=[CH:10][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1cc2cccc(Cl)c2s1
Agent: [Cu]
Agent: Cl
Solvent: c1ccc2ncccc2c1
Product: Clc1cccc2ccsc12
Temperature: 190 °C
Reaction time: 1.5 h

Procedure:
7-Chlorobenzo[b]thiophene-2-carboxylic acid (2.5 g, 11.8 mmol) was suspended in quinoline (20 mL) and treated with copper (0.779 g, 13 mmol). The mixture was heated to 190° C. After 1.5 h, the mixture was allowed to cool down to room temperature and diluted with 200 mL of 2 N HCl. The mixture was extracted three times with ethyl acetate. All the organic layers were combined and washed with 1 N HCl, water and brine, then dried with sodium sulfate. Purification was achieved by flash chromatography using 10 to 20% ethyl acetate in hexanes. Yield=1.8 g.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[CH:10]=[C:9]([C:11]([NH:13][C@@H:14]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)[C:15](O)=[O:16])=[O:12])[NH:8][C:5]2=[N:6][CH:7]=1.[OH:26][C@@H:27]1[CH2:31][CH2:30][NH:29][CH2:28]1.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C>CN(C=O)C>[F:25][C:22]1[CH:21]=[CH:20][C:19]([CH2:18][C@H:14]([NH:13][C:11]([C:9]2[NH:8][C:5]3=[N:6][CH:7]=[C:2]([Cl:1])[CH:3]=[C:4]3[CH:10]=2)=[O:12])[C:15]([N:29]2[CH2:30][CH2:31][CH:27]([OH:26])[CH2:28]2)=[O:16])=[CH:24][CH:23]=1
Reactant: O=C(N[C@@H](Cc1ccc(F)cc1)C(=O)O)c1cc2cc(Cl)cnc2[nH]1
Reactant: O[C@@H]1CCNC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(N[C@@H](Cc1ccc(F)cc1)C(=O)N1CCC(O)C1)c1cc2cc(Cl)cnc2[nH]1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of 2-(S)-[(5-chloro-1H-pyrrolo[2,3-b]pyridine-2-carbonyl)amino]-3-(4-fluorophenyl)propionic acid (EXAMPLE 286, 30 mg, 0.08 mmol) in DMF (3 mL) was added (R)-(+)-3-hydroxypyrrolidine (7.2 mg, 0.08 mmol), HOBt (11.2 mg, 0.08 mmol) and DIPEA (30.3 μL, 0.17 mmol). After 5 min, EDCI (20.7 mg, 0.11 mmol) was added and the reaction was stirred at rt for 16 h. The solvent was removed in vacuo and the residue partitioned between water (20 mL) and ethyl acetate (3×20 mL). The combined organic fractions were washed with 2N sodium hydroxide solution (20 mL), brine (20 mL), dried (MgSO4) and concentrated in vacuo. The crude product was triturated from methanol to give the title compound. m/z (ES+)=431 [M+H]+; RT=3.44 min.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:10]2[C:15]([F:16])=[CH:14][C:13]([C:17]([OH:20])([CH3:19])[CH3:18])=[CH:12][C:11]=2[F:21])=[CH:5][C:6]=1[C:7]([NH2:9])=[O:8].Cl[C:23]1[N:28]=[C:27]([F:29])[C:26]([C:30]([OH:33])([CH3:32])[CH3:31])=[CH:25][CH:24]=1>>[F:16][C:15]1[CH:14]=[C:13]([C:17]([OH:20])([CH3:18])[CH3:19])[CH:12]=[C:11]([F:21])[C:10]=1[C:4]1[S:3][C:2]([NH:1][C:23]2[CH:24]=[CH:25][C:26]([C:30]([OH:33])([CH3:32])[CH3:31])=[C:27]([F:29])[N:28]=2)=[C:6]([C:7]([NH2:9])=[O:8])[CH:5]=1
Reactant: CC(C)(O)c1ccc(Cl)nc1F
Reactant: CC(C)(O)c1cc(F)c(-c2cc(C(N)=O)c(N)s2)c(F)c1
Product: CC(C)(O)c1cc(F)c(-c2cc(C(N)=O)c(Nc3ccc(C(C)(C)O)c(F)n3)s2)c(F)c1

Procedure:
The title compound was prepared as described in Example 1 using, 2-amino-5-[2,6-difluoro-4-(1-hydroxy-1-methylethyl)phenyl]thiophene-3-carboxamide (52 mg, 0.17 mmol) and 2-(6-chloro-2-fluoropyridin-3-yl)propan-2-ol (32 mg, 0.17 mmol) as starting materials.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:10]2[C:15]([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([F:24])[CH:17]=3)=[N:14][NH:13][C:12](=[O:25])[CH:11]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[CH2:26](I)[CH:27]([CH3:29])[CH3:28]>>[F:1][C:2]1[CH:3]=[C:4]([C:10]2[C:15]([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([F:24])[CH:17]=3)=[N:14][N:13]([CH2:26][CH:27]([CH3:29])[CH3:28])[C:12](=[O:25])[CH:11]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: CC(C)CI
Reactant: COc1ccc(-c2cc(=O)[nH]nc2-c2ccc(OC)c(F)c2)cc1F
Product: COc1ccc(-c2cc(=O)n(CC(C)C)nc2-c2ccc(OC)c(F)c2)cc1F

Procedure:
Using 5,6-bis(3-fluoro-4-methoxyphenyl)-2H-pyridazin-3-one and isobutyl iodide as starting materials, the procedures of Example 146 were repeated likewise, whereby the title compound was obtained quantitatively.
Reaction SMILES: BrCCC/C=C\C/C=C\CC.O1CCCCC1OCCC/C=C\C/C=C\CC.[C:29]([O:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39]/[CH:40]=[CH:41]\[CH2:42]/[CH:43]=[CH:44]\[CH2:45][CH3:46])(=[O:31])[CH3:30]>>[C:29]([O:32][CH2:33][CH2:34]/[CH:35]=[CH:36]/[CH2:37][CH2:38][CH2:39]/[CH:40]=[CH:41]\[CH2:42][CH2:43][CH2:44][CH2:45][CH3:46])(=[O:31])[CH3:30]
Reactant: CC/C=C\C/C=C\CCCCCCCOC(C)=O
Agent: CC/C=C\C/C=C\CCCBr
Agent: CC/C=C\C/C=C\CCCOC1CCCCO1
Product: CCCCC/C=C\CCC/C=C/CCOC(C)=O

Procedure:
Dry THF (3 ml) was treated with trimethylsilyl iodide (260 mg, 185 μl, 1.30 mmol) at room temperature and stirred for 15 min to form 4-trimethylsiloxybutyl iodide (11). A solution of CuCN. (LiCl)2 in THF (1M, 100 μl) was added, and the mixture was cooled to -40° C. The above prepared solution of Grignard reagent 10, was then added over a period of 30 min, and a white precipitate formed. The mixture was stirred at -40° to -20° C. for 1 hr followed by an additional 1 hr at room temperature. The reaction was quenched with ammonium chloride solution and ammonia mixture (2:1, v/v), and the product was extracted with hexane/ether (1:1) mixture (Rf =0.60, 19:1 hexane/ethyl acetate, v/v). The crude (8Z,11Z)-trimethylsiloxy-8,11-tetradecadiene (12) was dissolved in THF (6 ml) and deprotected with tetrabutylammonium fluoride solution in THF (1M, 2 ml) to form the alcohol 13. Acetylation of the alcohol 13 with acetic anhydride/pyridine mixture (0.1 ml/1 ml) and purification by flash chromatography afforded (8Z,11Z)-8,11-tetradecadien-1-yl acetate (14) (80 mg) in 34% yield based on the starting bromide (5). 1H NMR (400 MHz) δ: 5.36 (m, 4H, CH=CH-8, 9, 11, 12), 4.05 (t, J=6.7, 7.0 Hz, 2H, CH2 -1), 2.77 (dd, J=6.4, 6.4 Hz, 2H, =CH--CH2 --CH=), 2.06 (m, 4H, CH2 -7, 13), 2.04 (s, 3H, --COCH3), 1.60 (tt, J=7.3, 7.3, 7.6, 7.6 Hz, 2H, CH2 -6), 1.4-1.2 (m, 8H, CH2 -2, 3, 4, 5), 0.97 (t, J=7.3, 7.6 Hz, 3H, CH3 -14). 13C NMR (100.6 MHz) δ: 171.2 (C=O), 131.7 (=CH-12), 130.0 (=CH-11), 128.0 (=CH-9), 127.3 (=CH-8), 64.6 (CH2 -1), 29.5 (CH2 -2), 29.1 (CH2 -3, 4), 28.6 (CH2 -5), 27.2 (CH2 -6), 25.9 (CH2 -7), 25.5 (CH2 -10), 21.0 (CH3C=O), 20.5 (CH2 -13), 14.3 (CH3). MS [EI, m/z(%)] 252 (M+,2), 209 (M+ -43, 1), 192 (M+ -60, 23), 163 (4); 149 (8), 135 (14), 121 (38), 110 (19), 107 (19), 95 (39), 93 (40), 82 (26), 81 (57), 79 (66), 67 (100), 55 (38), 43 (93), 41 (50). IR (gas phase, cm-1) 3017 (cis=C--H str), 2936 (CH2), 1761 (C=O), 1233, 1040 (--O--). (3E,8Z)-3,8-tetradecadienyl acetate was synthesized as described in detail below with reference to the following reaction sequence. ##STR17##
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([C:11]2[N:15]=[C:14]([C:16]3[CH:21]=[CH:20][C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[CH3:28])=[C:18]([CH2:29][O:30][CH3:31])[CH:17]=3)[O:13][N:12]=2)[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].C(Cl)(=O)C([Cl:35])=O.CN(C=O)C>C(Cl)Cl>[F:1][C:2]1[CH:10]=[C:9]([C:11]2[N:15]=[C:14]([C:16]3[CH:21]=[CH:20][C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[CH3:28])=[C:18]([CH2:29][O:30][CH3:31])[CH:17]=3)[O:13][N:12]=2)[CH:8]=[CH:7][C:3]=1[C:4]([Cl:35])=[O:5]
Reactant: O=C(Cl)C(=O)Cl
Reactant: COCc1cc(-c2nc(-c3ccc(C(=O)O)c(F)c3)no2)ccc1-c1ccccc1C
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COCc1cc(-c2nc(-c3ccc(C(=O)Cl)c(F)c3)no2)ccc1-c1ccccc1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 101.2 %

Procedure:
To a solution of example 35 (2 170 mg; 5.2 mmol) in dry DCM (40 mL), oxalyl chloride (1 316 μl; 15.6 mmol) was added followed by dry DMF (40 μl). The reaction mixture was stirred at RT for 2 h and concentrated to afford 2-fluoro-4-{5-[2-(methoxymethyl)-2′-methylbiphenyl-4-yl]-1,2,4-oxadiazol-3-yl}benzoyl chloride as a white powder (2300 mg, 100%). In dry THF (1 mL) with a catalytic amount of DMF was swelled morpholinomethyl polystyrene high loading resin (NovaBiochem; 35.77 mg; 0.14 mmol), 3.9 mmol/g). 2-Fluoro-4-{5-[2-(methoxymethyl)-2′-methylbiphenyl-4-yl]-1,2,4-oxadiazol-3-yl}benzoyl chloride (25 mg; 0.06 mmol) was added followed by sarcosine methyl ester hydrochloride (15.98 mg; 0.11 mmol). The mixture was stirred overnight at rt. Isocyanate resin Si—NCO (Argonaut, 97 mg; 1.5 eq; 1.7 mmol/g) was added and the mixture stirred for 2 h. It was filtered through a SAX column (2 g) to obtain the title compound as a colorless oil. LC/MS (Method B): 504.2 (M+H)+ HPLC (Method A) Rt: 5.39 min (purity: 97%).