Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [PH3:1].[CH2:2]=[C:3]([CH3:5])[CH3:4]>>[CH2:2]([P:1]([CH2:2][CH:3]([CH3:5])[CH3:4])[CH2:2][CH:3]([CH3:5])[CH3:4])[CH:3]([CH3:5])[CH3:4]
Reactant: P
Reactant: C=C(C)C
Product: CC(C)CP(CC(C)C)CC(C)C
Yield: 13.5 %

Procedure:
By subjecting a mixture of hydrogen phosphide and isobutene in a glass vessel to irradiation with ultraviolet light at 20° C., it is also possible by the process just described to produce triisobutylphosphine, which is obtained in a yield of about 13.5%, after 150 minutes.
Reaction SMILES: [CH2:1]=[CH:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]CC.CN(C)[CH:17]=[O:18].[N+]([O-])([N+]([O-])=O)=[O:21].O=O.[O-2].[Ca+2]>C1C=CC=CC=1>[C:17]([OH:18])(=[O:21])[CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CN(C)C=O
Reactant: C=CCCCCCCCCCCCC
Reactant: O=[N+]([O-])[N+](=O)[O-]
Agent: O=O
Agent: [Ca+2]
Agent: [O-2]
Solvent: c1ccccc1
Product: CCCCCCCCCCCCC(=O)O
Reaction time: 0.5 h
Yield: 92.4 %

Procedure:
Tetradecene (19.8 grams, 0.1 mole) and dimethylformamide (20 milliliters, 0.26 mole) dissolved in 100 milliliters of benzene were treated with a 1:6 volume to volume ratio mixture of dinitrogen tetroxide (9.2 grams, 0.1 mole) and oxygen at 10° C. over a period of four hours and the mixture was swept with oxygen for an additional 15 minutes. Calcium oxide (5.6 grams, 0.1 mole) was added to the cooled stirred mixture and after 30 minutes, the solid material (37.6 grams) was separated by filtration and 300 milliliters of water were added thereto. After one hour at reflux, the solution was cooled and acidified with 6N hydrochloric acid to precipitate 19.8 grams (92 percent yield) of tridecanoic acid.
Reaction SMILES: [CH3:1][I:2].[CH:3]1([CH2:6][O:7][C:8]2[C:12]([C:13]3[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=3)=[N:11][S:10][N:9]=2)[CH2:5][CH2:4]1>CC(C)=O>[I-:2].[CH:3]1([CH2:6][O:7][C:8]2[C:12]([C:13]3[CH:14]=[N+:15]([CH3:1])[CH:16]=[CH:17][CH:18]=3)=[N:11][S:10][N:9]=2)[CH2:4][CH2:5]1
Reactant: c1cncc(-c2nsnc2OCC2CC2)c1
Reactant: CI
Solvent: CC(C)=O
Product: C[n+]1cccc(-c2nsnc2OCC2CC2)c1
Product: [I-]
Temperature: 25 °C
Reaction time: 36 h

Procedure:
A mixture of methyl iodide (0.25 ml, 4 mmol) and 3-(3-cyclopropylmethoxy-1,2,5-thiadiazol-4-yl)pyridine (400 mg, 1.7 mmol) in acetone (5 ml) was stirred at room temperature for 36 h. The title compound precipitated from the solution and was collected by filtration to yield 0.41 g (65%).
Reaction SMILES: Cl.C([C:4]1[C:9]([OH:10])=[C:8]([CH2:11][OH:12])C(CO)=CN=1)=O.C(N(CC)CC)C.C([O:25][C:26](=[O:28])[CH3:27])(=O)C>O1CCCC1>[CH3:4][C:9]([CH2:8][C:11]([CH2:27][C:26]([OH:25])=[O:28])=[O:12])=[O:10]
Reactant: O=Cc1ncc(CO)c(CO)c1O
Reactant: CC(=O)OC(C)=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)CC(=O)CC(=O)O
Reaction time: 1 h

Procedure:
A solution of one equivalent of 2-formyl-3-hydroxy-4,5-dihydroxymethylpyridine hydrochloride in 400 ml. anhydrous tetrahydrofuran is treated with four equivalents of triethylamine and aged for one hour at room temperature. Then three equivalents of acetic anhydride are introduced, and the reaction mixture is aged 4 hours at room temperature. The reaction mixture is concentrated under reduced pressure to a gum. This is treated with a mixture of 300 ml. of diethyl ether and 300 ml. of distilled water. After shaking well, the layers are separated and the ether layer is dried over magnesium sulfate. After evaporation to dryness, the desired triacetate is obtained as a viscous oil.
Reaction SMILES: [H-].[Na+].[C:3]1([OH:9])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[H][H].[Cl:12][C:13]1[CH:22]=[C:21]2[C:16]([CH2:17][O:18][C:19]2=[O:20])=[CH:15][CH:14]=1>CN(C)C=O>[O:9]([CH2:17][C:16]1[CH:15]=[CH:14][C:13]([Cl:12])=[CH:22][C:21]=1[C:19]([OH:20])=[O:18])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: O=C1OCc2ccc(Cl)cc21
Reactant: Oc1ccccc1
Reactant: [H][H]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(O)c1cc(Cl)ccc1COc1ccccc1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
Sodium hydride (1.0 mol) is suspended in about 300 ml. of dimethylformamide and phenol (1.0 mol) in about 200 ml. of dimethylformamide is added dropwise, keeping the reaction temperature around 25° C. The mixture is stirred until hydrogen evolution is completed. 6-Chlorophthalide (1.0 mol) in about 250 ml. of dimethylformamide is then added slowly. The resulting mixture is refluxed for 2 hours and allowed to stand at room temperature overnight. The reaction mixture is diluted with ice/water and extracted several times with ether. The aqueous fraction is acidified with dilute hydrochloric acid and extracted with ether. The ether is dried and concentrated to a gummy solid which is recrystallized from a minimum volume of alcohol to give 2-phenoxymethyl-5-chlorobenzoic acid, m.p. 149°-155° C.
Reaction SMILES: [C:1]1([CH:7]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:8][N:9]2[CH2:14][CH2:13][CH2:12][C@H:11]([CH2:15][OH:16])[CH2:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CCN(CC)CC.N1C=CC=CC=1>CS(C)=O>[C:1]1([CH:7]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:8][N:9]2[CH2:14][CH2:13][CH2:12][C@H:11]([CH:15]=[O:16])[CH2:10]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: OC[C@H]1CCCN(CC(c2ccccc2)c2ccccc2)C1
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Solvent: CS(C)=O
Product: O=C[C@H]1CCCN(CC(c2ccccc2)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1-(2,2-Diphenylethyl)-3(S)-hydroxymethyl-piperidine (Example 18, Step B)-(2.10 g, 7.10 mmol) and Et3N (2.97 mL, 21.3 mmol) were dissolved in dry DMSO (40 mL) and cooled in an ice bath. Pyridine SO3 complex (3.39 g, 21.3 mmol) was added slowly, and the solution was stirred for 1 hr while allowing to warm to room temperature. The solution was poured into ice water, extracted with CH2CL2 (2×), the combined organics washed with satd NaHCO3 solution, H2O, brine, and dried (MgSO4). Filtration and concentration gave the title compound without further purification. Step B: Preparation of 1-(2,2-Diphenylethyl)-3(S)-[N-(1-(cyanobenzyl)-1H-imidazol-5-ylethyl)aminomethyl]-piperidine
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH:9][C:10]([NH:12][C:13]1[CH:33]=[CH:32][C:16]([O:17][C:18]2[CH:23]=[CH:22][N:21]=[C:20]([C:24]3[NH:28][CH:27]=[C:26]([C:29]([OH:31])=O)[CH:25]=3)[CH:19]=2)=[CH:15][CH:14]=1)=[O:11].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.Cl.[NH:68]1[C:72]([CH2:73][CH2:74][CH2:75][NH2:76])=[N:71][N:70]=[N:69]1.Cl>CN(C=O)C.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH:9][C:10]([NH:12][C:13]1[CH:14]=[CH:15][C:16]([O:17][C:18]2[CH:23]=[CH:22][N:21]=[C:20]([C:24]3[NH:28][CH:27]=[C:26]([C:29]([NH:76][CH2:75][CH2:74][CH2:73][C:72]4[N:68]=[N:69][NH:70][N:71]=4)=[O:31])[CH:25]=3)[CH:19]=2)=[CH:32][CH:33]=1)=[O:11]
Reactant: NCCCc1nnn[nH]1
Reactant: Cc1ccc(F)c(NC(=O)Nc2ccc(Oc3ccnc(-c4cc(C(=O)O)c[nH]4)c3)cc2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: Cc1ccc(F)c(NC(=O)Nc2ccc(Oc3ccnc(-c4cc(C(=O)NCCCc5nn[nH]n5)c[nH]4)c3)cc2)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a stirred solution of 5-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrole-3-carboxylic acid (100 mg, 0.22 mmol) in 10 ml of anhydrous DMF were added HATU (91 mg, 0.24 mmol) and N,N-diisopropylethylamine (85 mg, 0.66 mmol). The mixture was stirred at room temperature for 10 minutes, followed by addition of 3-(1H-tetrazol-5-yl)propan-1-amine hydrochloride (54 mg, 0.33 mmol). The mixture was stirred at room temperature for another 60 minutes and poured into 100 ml of water with vigorous stirring. 1M HCl was added dropwise until pH=5. The precipitates were filtered, washed with water and dried in vacuo to give 5-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-N-[3-(2H-tetrazol-5-yl)propyl]-1H-pyrrole-3-carboxamide as light brown solid. Yield: 105 mg, 85%.
Reaction SMILES: [H-].[Na+].CS(C)=O.[Br-].[C:8]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([OH:10])=[O:9].[C:35]([C:43]1[S:44][CH:45]=[CH:46][CH:47]=1)(=O)[C:36]1[CH:41]=[CH:40][CH:39]=[N:38][CH:37]=1>O1CCCC1.O>[N:38]1[CH:39]=[CH:40][CH:41]=[C:36](/[C:35](/[C:43]2[S:44][CH:45]=[CH:46][CH:47]=2)=[CH:15]/[CH2:14][CH2:13][CH2:12][CH2:11][C:8]([OH:10])=[O:9])[CH:37]=1
Reactant: O=C(O)CCCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C(c1cccnc1)c1cccs1
Agent: [Br-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CS(C)=O
Product: O=C(O)CCCC/C=C(/c1cccnc1)c1cccs1
Temperature: 85 °C
Reaction time: 8 h
Yield: 28.5 %

Procedure:
Sodium hydride (60% in oil, 10 g, 0.25 mole) was added to dimethyl sulfoxide (250 ml) under argon and the mixture was stirred at 85° C. for an hour. The mixture was then cooled to room temperature and 5-carboxypentyltriphenylphosphonium bromide (52 g, 0.11 mole) was added gradually with the temperature being maintained at 40° C. The resulting mixture was stirred for 10 minutes, and a solution of 2-nicotinoylthiophene (20 g, 0.11 mole) in tetrahydrofuran (60 ml) was added dropwise. After the addition, the mixture was stirred at room temperature for 30 minutes, and water (300 ml) was added. The aqueous solution was extracted twice with toluene (300 ml) to remove the neutral substance. The aqueous layer was adjusted to pH 5.5 with 2N hydrochloric acid and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried (magnesium sulfate) and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography using ethyl acetate as eluant and the eluate was concentrated. The resulting oily product was dissolved in ethyl acetate and the solution was allowed to stand overnight to give (Z)-7-(3-pyridyl)-7-(2-thienyl)-6-heptenoic acid (9 g, 29%). Mp 93°-94° C.
Reaction SMILES: [N:1]1([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=O.CN([P+](O[N:27]1N=N[C:29]2C=CC=[CH:33][C:28]1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F.C[N:44]([CH:46]=[O:47])C>C(N(CC)CC)C>[N:1]1([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([NH:27][C:28]([C:46]([NH2:44])=[O:47])([CH3:33])[CH3:29])=[O:5]
Reactant: CN(C)C=O
Reactant: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)NC(C)(C)C(N)=O

Procedure:
Deprotection of 100 mg of the compound obtained by the process 1 was performed similarly to that in Example 28 (Process 3), and the obtained product was dissolved in 3 ml of DMF and neutralized with 68 μl of triethylamine under ice cooling. To the neutralized solution, 107 mg of Boc-Pro-OH, 237 mg of Bop reagent and 137 μl of triethylamine were added and the resultant mixture was stirred for 2 hr. The reaction mixture was treated similarly to that in Example 86 (Process 3) to give 35 mg of the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH2:14])[CH:10]([CH3:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.Cl[CH2:24][CH2:25][CH2:26][C:27](Cl)=[O:28].[H-].[Na+]>C(Cl)Cl.CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([N:14]2[CH2:24][CH2:25][CH2:26][C:27]2=[O:28])[C@H:10]([CH3:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3].[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@@H:11]([N:14]2[CH2:24][CH2:25][CH2:26][C:27]2=[O:28])[C@H:10]([CH3:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC1CN(C(=O)OC(C)(C)C)CCC1N
Reactant: O=C(Cl)CCCCl
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: C[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@@H]1N1CCCC1=O
Product: C[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@H]1N1CCCC1=O
Temperature: 0 °C
Yield: 39 %
Yield: 18 %

Procedure:
To an ice-cold solution of 4-amino-3-methyl-piperidine-1-carboxylic acid tert-butyl ester (2.5 g 12 mmol) and triethylamine (31 ml, 23 mmol) in CH2Cl2 (100 ml) was added 4-chlorobutyric acid chloride (11 ml, 14 mmol) and the reaction allowed to come to room temperature. The reaction was then washed with water, was dried (Na2SO4) and concentrated. The crude amide (1.9 g, 6 mmol) was redissolved in DMF (50 ml), cooled to 0° C. and sodium hydride (0.3 g, 12 mmol) was added portionwise. The mixture was allowed to reach room temperature, the reaction concentrated and the residue redissolved in CH2Cl2 and washed with saturated sodium hydrogen carbonate, dried (Na2SO4) and concentrated. Flash column chromatography (EtOAc:n-heptane 9:1-95:5) separated the title compounds affording (cis)-3-Methyl-4-(2-oxo-pyrrolidin-1-yl)-piperidine-1-carboxylic acid tert-butyl ester (0.3 g, 18%) and (trans)-3-methyl-4-(2-oxo-pyrrolidin-1-yl)-piperidine-1-carboxylic acid tert-butyl ester (0.63 g, 39%) as yellow oils. MS: 283.4 (MH+).
Reaction SMILES: Cl[C:2]1[S:6][N:5]=[C:4]([S:7][CH3:8])[N:3]=1.Cl[C:10]1[CH:15]=[CH:14][N:13]=[CH:12][C:11]=1[CH2:16][OH:17].[H-].[Na+].[Cl-:20].[NH4+]>CN(C)C=O>[Cl:20][C:14]1[N:13]=[CH:12][C:11]([CH2:16][O:17][C:2]2[S:6][N:5]=[C:4]([S:7][CH3:8])[N:3]=2)=[CH:10][CH:15]=1
Reactant: CSc1nsc(Cl)n1
Reactant: OCc1cnccc1Cl
Reactant: [Cl-]
Agent: [H-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CSc1nsc(OCc2ccc(Cl)nc2)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Into 2.5 ml of N,N-dimethylformamide were dissolved 200 mg of 5-chloro-3-methylthio-1,2,4-thiadiazole and 207 mg of 4-chloro-3-pyridylmethyl alcohol, 59 mg of sodium hydride (60% in oil) was added thereto under ice-cooling, and the reaction mixture was stirred for 0.5 hour under ice-cooling and for 1 hour at room temperature. The reaction mixture was added to saturated ammonium chloride aqueous solution, and extracted with t-butyl methyl ether. The organic layer was concentrated, and the residue obtained was subjected to silica gel column chromatography to give 170 mg of 5-(6-chloro-3-pyridyl)methyloxy-3-methylthio-1,2,4-thiadiazole (hereinafter, referred to as the present compound (21)).
Reaction SMILES: [Cl:1][C:2]1[CH:39]=[CH:38][C:5]2[NH:6][C:7]([C@@H:9]([NH:11][C:12](=[O:37])[C:13]3[CH:18]=[CH:17][C:16]([C:19]([N:21]4[CH2:25][CH2:24][CH2:23][C@H:22]4[CH2:26][CH2:27][NH:28]C(OC(C)(C)C)=O)=[O:20])=[C:15]([Cl:36])[CH:14]=3)[CH3:10])=[N:8][C:4]=2[CH:3]=1.FC(F)(F)C(O)=O.ClCCl.CO.N.ClCl>>[Cl:1][C:2]1[CH:39]=[CH:38][C:5]2[NH:6][C:7]([C@@H:9]([NH:11][C:12](=[O:37])[C:13]3[CH:18]=[CH:17][C:16]([C:19]([N:21]4[CH2:25][CH2:24][CH2:23][C@H:22]4[CH2:26][CH2:27][NH2:28])=[O:20])=[C:15]([Cl:36])[CH:14]=3)[CH3:10])=[N:8][C:4]=2[CH:3]=1
Reactant: C[C@H](NC(=O)c1ccc(C(=O)N2CCC[C@H]2CCNC(=O)OC(C)(C)C)c(Cl)c1)c1nc2cc(Cl)ccc2[nH]1
Agent: ClCl
Agent: N
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@H](NC(=O)c1ccc(C(=O)N2CCC[C@H]2CCN)c(Cl)c1)c1nc2cc(Cl)ccc2[nH]1

Procedure:
Prepared analogously to Example 17 from N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)ethyl]-3-chloro-4-{(2S)-2-[2-(N-tert-butoxycarbonylamino)ethyl]pyrrolidin-1-ylcarbonyl}benzamide and trifluoroacetic acid. Yield: quantitative; Rf value: 0.10 (silica gel; dichloromethane/methanol/ammonia=9:1:0.1); C23H25Cl2N5O2 (474.39); mass spectrum: (M+H)+=474/476/478 (chlorine isotope).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([N:9]2[CH2:16][CH:15]3[CH:11]([CH2:12][NH:13][CH2:14]3)[CH2:10]2)[N:3]=1.[C:17]1([C:23]2[CH:27]=[CH:26][O:25][C:24]=2[C:28](O)=[O:29])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(OCC)(=O)C.CN(C=O)C>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([N:9]2[CH2:16][CH:15]3[CH:11]([CH2:12][N:13]([C:28]([C:24]4[O:25][CH:26]=[CH:27][C:23]=4[C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=4)=[O:29])[CH2:14]3)[CH2:10]2)[N:3]=1
Reactant: O=C(O)c1occc1-c1ccccc1
Reactant: Cc1cc(C)nc(N2CC3CNCC3C2)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cc(C)nc(N2CC3CN(C(=O)c4occc4-c4ccccc4)CC3C2)n1
Yield: 27.6 %

Procedure:
A mixture of 2-(4,6-dimethyl-pyrimidin-2-yl)-octahydro-pyrrolo[3,4-c]pyrrole (60.0 mg, 0.28 mmol), 3-phenyl-furan-2-carboxylic acid (61.8 mg, 0.30 mmol), HATU (156.8 mg, 0.41 mmol) and DIPEA (107.0 mg, 0.83 mmol) was stirred into DMF (5.0 mL) at room temperature for 30 minutes. The reaction mixture was diluted with ethyl acetate (60.0 mL) and washed with water (2×100 mL). The organic phase was dried (Na2SO4), filtered and concentrated to dryness. The crude product was purified using Dionex HPLC to yield pure title compound (30.0 mg, 28.0%). MS (ESI) mass calcd. for C23H24N4O2, 388.47; m/z found 389.2 [M+H]+. 1H NMR (CDCl3): 7.56-7.50 (m, 2H), 7.46 (d, J=1.8, 1H), 7.37-7.30 (m, 2H), 7.25-7.19 (m, 1H), 6.61 (d, J=1.8, 1H), 6.29 (s, 1H), 3.95-3.80 (m, 2H), 3.75-3.60 (m, 3H), 3.51 (dd, J=11.6, 5.0 1H), 3.42 (dd, J=11.6, 4.1, 1H), 3.33 (dd, J=11.6, 5.4, 1H), 3.02-2.81 (m, 2H), 2.35-2.22 (m, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:13]([CH2:14][O:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:31]=[C:30]4[C:25]([CH:26]=[C:27]([C:32]([O:34]C)=[O:33])[CH:28]=[N:29]4)=[CH:24][CH:23]=3)=[CH:18][CH:17]=2)=[C:12]([CH:36]([CH3:38])[CH3:37])[O:11][N:10]=1.C1COCC1.O.[OH-].[Na+]>CCO>[Cl:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[C:9]1[C:13]([CH2:14][O:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:31]=[C:30]4[C:25]([CH:26]=[C:27]([C:32]([OH:34])=[O:33])[CH:28]=[N:29]4)=[CH:24][CH:23]=3)=[CH:18][CH:17]=2)=[C:12]([CH:36]([CH3:38])[CH3:37])[O:11][N:10]=1
Reactant: COC(=O)c1cnc2cc(-c3ccc(OCc4c(-c5c(Cl)cccc5Cl)noc4C(C)C)cc3)ccc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Solvent: O
Product: CC(C)c1onc(-c2c(Cl)cccc2Cl)c1COc1ccc(-c2ccc3cc(C(=O)O)cnc3c2)cc1
Temperature: 50 °C
Reaction time: 16 h
Yield: 66.7 %

Procedure:
To 47 mg (0.09 mmol) of methyl 7-[4-({[3-(2,6-dichlorophenyl)-5-(1-methylethyl)-4-isoxazolyl]methyl}oxy)phenyl]-3-quinolinecarboxylate in a mixture of 3 mL of EtOH, 1 mL THF and 1 mL H2O was added 35 mg (0.86 mmol) of NaOH and the mixture stirred at 50° C. for 16 hr. The mixture was concentrated to ⅓ volume then added dropwise to a a stirred solution of 10 mL of 0.5 M HCl (aq.). The resulting solids were collected by suction filtration, washed with water then dried to yield 32 mg (70%) of 7-[4-({[3-(2,6-dichlorophenyl)-5-(1-methylethyl)-4-isoxazolyl]methyl}oxy)phenyl]-3-quinolinecarboxylic acid as a yellow solid. 1H NMR (400 MHz, DMSO-d6): δ 9.30 (s, 1H), 8.97 (s, 1H), 8.24-8.21 (m, 2H), 7.99 (d, J=8 Hz, 1H), 7.76 (d, J=8 Hz, 2H), 7.63-7.61 (m, 2H), 7.55-7.52 (m, 1H), 6.93 (d, J=9 Hz, 2H), 4.88 (s, 2H), 3.50-3.44 (septet, J =7 Hz, 1H), 1.33 (d, J=7 Hz, 6H). ESI-LCMS m/z 534 (M+H)+.
Reaction SMILES: [CH3:1][C@H:2]([CH2:7][CH2:8][CH2:9][C@H:10]([CH3:17])[CH2:11][CH2:12][CH2:13][CH:14]([CH3:16])[CH3:15])[CH2:3][CH2:4][CH2:5]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:37]Br.O>CN(C)C=O.CCCCCC>[Br:37][CH2:5][CH2:4][CH2:3][C@H:2]([CH3:1])[CH2:7][CH2:8][CH2:9][C@H:10]([CH3:17])[CH2:11][CH2:12][CH2:13][CH:14]([CH3:16])[CH3:15]
Reactant: CC(C)CCC[C@@H](C)CCC[C@@H](C)CCCO
Reactant: BrBr
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCCCCC
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)CCC[C@@H](C)CCC[C@@H](C)CCCBr
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 9.6 g (39.6 mmol) of (4R,8R)-4,8,12-trimethyltridecanol in 30 mL of anhydrous N,N-dimethylformamide was added 10.7 g (40.84 mmol) of triphenylphosphine. The solution was stirred in an acetone-ice bath (-10° C.) while 2.1 mL (41 mmol) of bromine was added dropwise. The temperature rose to 5° C. The reaction mixture was stirred at room temperature for 1 hr then poured into 100 mL of water and 150 mL of hexane. After filtration, the layers were separated and the aqueous phase was extracted with 2×150 mL of hexane. The hexane layers were washed with saturated NaHCO3 solution, dried (MgSO4), filtered through a plug of silica gel, and concentrated in vacuo. Kugelrohr distillation (150°-160° C. bath temperature, 1 mm Hg) of the residue gave 2 fractions: 5.15 g of 95.8% GC purity and 3.55 g of 97.9% GC purity (72.2% yield). Redistillation of the larger fraction gave (4R,8R)-1-bromo-4,8,12-trimethyltridecane as a colorless liquid bp 120° C. (0.15 mm) having a GC purity of 97.9%; [a]25D-3.01° (c 2.09, hexane).
Reaction SMILES: C(NCCS[C:8]1[CH2:14][C@H:13]2[N:10]([C:11](=[O:17])[C@H:12]2[CH2:15][CH3:16])[C:9]=1[C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=1)=[O:19])(=O)C.N12CCC1CC=C2.C(N(C(C)C)CC)(C)C.[C:47]([NH:50][CH2:51][CH2:52]S)(=[O:49])[CH3:48]>C(#N)C>[C:47]([NH:50][CH2:51][CH2:52][C:8]1[CH2:14][CH:13]2[N:10]([C:11](=[O:17])[CH:12]2[CH2:15][CH3:16])[C:9]=1[C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=1)=[O:19])(=[O:49])[CH3:48]
Reactant: CC[C@@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(SCCNC(C)=O)C[C@H]12
Reactant: CC(=O)NCCS
Agent: C1=CN2CCC2C1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CCC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(CCNC(C)=O)CC12
Reaction time: 0.25 h

Procedure:
Preparation of trans (±)-3-[[2-(acetylamino)ethyl)thio]-6-ethyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid, (4-nitrophenyl)methyl ester (XVII, R=CH3CH2 --, R'"=CH3CONH--CH2 --CH2 --, R4 = ##STR19## A solution of the bicyclic keto ester obtained in step (c) above (XV R=CH3CH2 --) (2.49 g) in acetonitrile (15 ml) is cooled to 0° C. and diisopropylethylamine (1.42 ml) is added. Then chlorodiphenylphosphate (1.72 ml) is added drop by drop keeping the temperature at 0°/-2° C. Stirring is continued for 15 minutes at 0° C., after which thin layer chromatography confirms the complete transformation of the bicyclic keto ester XV into the enol phosphate derivative XVI (R=CH3CH2 --). An additional portion of diisopropylethylamine (1.55 ml) is added followed by the slow addition of N-acetylcysteamine (1.07 g) dissolved in acetonitrile (5 ml). The reaction mixture is then stirred at 0° C. for 30 minutes and the solid which precipitates is filtered, washed with cold acetonitrile (10 ml) and diethyl ether (20 ml), and dried in vacuo at room temperature yielding 2.03 g of trans (±)-3-[[2 -(acetylamino)ethyl]-6-ethyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid, (4-nitrophenyl)methyl ester which melts at 174°-76° C. Additional 0.46 g of equally pure product is obtained on cooling the filtrate to -20° C. for 2 hours.
Reaction SMILES: CON(C)[C:4]([C:6]1[C:7]([NH2:15])=[N:8][C:9]([S:12][CH2:13][CH3:14])=[N:10][CH:11]=1)=[O:5].[F:17][C:18]1[CH:23]=[C:22]([CH3:24])[C:21]([O:25][CH3:26])=[CH:20][C:19]=1I>>[NH2:15][C:7]1[C:6]([C:4]([C:19]2[CH:20]=[C:21]([O:25][CH3:26])[C:22]([CH3:24])=[CH:23][C:18]=2[F:17])=[O:5])=[CH:11][N:10]=[C:9]([S:12][CH2:13][CH3:14])[N:8]=1
Reactant: COc1cc(I)c(F)cc1C
Reactant: CCSc1ncc(C(=O)N(C)OC)c(N)n1
Product: CCSc1ncc(C(=O)c2cc(OC)c(C)cc2F)c(N)n1

Procedure:
The same procedure as described in Example 376 was used, starting from 4-amino-2-ethylsulfanyl-pyrimidine-5-carboxylic acid methoxy-methyl-amide (Example 1) and 1-fluoro-2-iodo-4-methoxy-5-methyl-benzene (Example 382) to give (4-amino-2-ethylsulfanyl-pyrimidin-5-yl)-(2-fluoro-5-methoxy-4-methyl-phenyl)-methanone. MS (M+H)+, 322.
Reaction SMILES: [Cl:1][C:2]1[C:10]([C:11]2([C:14]#[N:15])[CH2:13][CH2:12]2)=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].CN(C)C=O.C(Cl)(=O)C([Cl:24])=O>O1CCCC1>[Cl:1][C:2]1[C:10]([C:11]2([C:14]#[N:15])[CH2:13][CH2:12]2)=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([Cl:24])=[O:5]
Reactant: O=C(Cl)C(=O)Cl
Reactant: N#CC1(c2cccc(C(=O)O)c2Cl)CC1
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: N#CC1(c2cccc(C(=O)Cl)c2Cl)CC1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a solution of 2-chloro-3-(1-cyanocyclopropyl)benzoic acid (16.0 g, 72.2 mmol) in tetrahydrofuran (150 mL) was added N,N-dimethylformamide (0.1 mL), and oxalyl chloride (7.2 mL, 84.0 mmol) was further added dropwise at 0° C., and the mixture was stirred at room temperature for 2.5 hr. The reaction mixture was concentrated under reduced pressure to dryness to give 2-chloro-3-(1-cyanocyclopropyl)benzoyl chloride as a pale-yellow oil.