Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[S:6][N:5]=[C:4]([S:7][CH3:8])[C:3]=1[C:9]#[N:10].[CH3:11][N:12]=[C:13]=[O:14]>C([O-])(=O)C.C([O-])(=O)C.C([Sn+2]CCCC)CCC.O1CCCC1>[CH3:11][NH:12][C:13]([NH:1][C:2]1[S:6][N:5]=[C:4]([S:7][CH3:8])[C:3]=1[C:9]#[N:10])=[O:14]
Reactant: CN=C=O
Reactant: CSc1nsc(N)c1C#N
Agent: CC(=O)[O-]
Agent: CCCC[Sn+2]CCCC
Solvent: C1CCOC1
Product: CNC(=O)Nc1snc(SC)c1C#N
Reaction time: 8 h

Procedure:
A solution of 27.4 g of 5-amino-4-cyano-3-(methylthio)isothiazole, 9.7 g of methyl isocyanate, and 50 drops of dibutyltin diacetate in 150 ml of tetrahydrofuran was heated under reflux during 16 hours. Comparative thin-layer chromatography indicated the reaction to be 50% complete. An additional 10 ml of methyl isocyanate and 20 drops of dibutyltin diacetate were added and the heating continued for eight hours. Comparative thinlayer chromatography indicated that the reaction was still only 50% complete. An additional 10 g of methyl isocyanate were added to the reaction mixture, and the heating was continued overnight. The solid was isolated from the slurry by filtration to give a first crop of 1-methyl-3-(4-cyano-3-(methylthio)-5-isothiazolyl)urea, m.p. 250° (resolidified and m.p. 290°-292°). The filtrate was evaporated to give a tan solid. This solid was recrystallized from ethanol to give a second crop of product. The mother liquor was concentrated to give a third crop. The total yield was 33.4 g of 1-methyl-3-(4-cyano-3-(methylthio)-5-isothiazollyl)urea. Recrystallization from ethanol gave a solid, m.p. 248°-250°, resolidified, m.p. 286°. The nmr spectrum was consistent with the assigned structure.
Reaction SMILES: [OH:1][N:2]=[C:3](Cl)[C:4]1[C:8]([NH:9][CH2:10][CH2:11][O:12][CH3:13])=[N:7][O:6][N:5]=1.FC(F)(F)C(O)=O.[Cl:22][C:23]1[CH:24]=[C:25]([CH2:28][NH2:29])[O:26][CH:27]=1>>[Cl:22][C:23]1[CH:24]=[C:25]([CH2:28][NH:29][C:3]([C:4]2[C:8]([NH:9][CH2:10][CH2:11][O:12][CH3:13])=[N:7][O:6][N:5]=2)=[N:2][OH:1])[O:26][CH:27]=1
Reactant: NCc1cc(Cl)co1
Reactant: COCCNc1nonc1C(Cl)=NO
Solvent: O=C(O)C(F)(F)F
Product: COCCNc1nonc1C(=NO)NCc1cc(Cl)co1

Procedure:
The desired compound was prepared according to the procedure of Example 20, step C, using N-hydroxy-4-(2-methoxyethylamino)-1,2,5-oxadiazole-3-carbimidoyl chloride and 1-(4-chloro-2-furyl)methanamine trifluoroacetate as the starting material in quantitative yield. LCMS calculated for C11H15ClN5O4 (M+H)+: m/z=316.0.
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[CH2:7][N:8]1[CH:12]=[C:11](Br)[CH:10]=[N:9]1)([CH3:4])([CH3:3])[CH3:2].[CH:15]1(B(O)O)[CH2:17][CH2:16]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C1(P(C2CCCCC2)C2CCCCC2)CCCCC1>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O>[CH:15]1([C:11]2[CH:10]=[N:9][N:8]([CH2:7][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:14])[CH:12]=2)[CH2:17][CH2:16]1
Reactant: CC(C)(C)OC(=O)Cn1cc(Br)cn1
Reactant: OB(O)C1CC1
Agent: [Pd+2]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)(C)OC(=O)Cn1cc(C2CC2)cn1
Yield: 21 %

Procedure:
Palladium acetate (215 mg, 0.957 mmol) was added to tert-butyl[4-bromo-1H-pyrazol-1-yl]acetate (5 g, 19.14 mmol) (see Preparation 86), cyclopropyl boronic acid (8.22 g, 95.74 mmol), potassium phosphate (8.12 g, 38.29 mmol) and tricyclohexylphosphine (537 mg, 1.91 mmol) in toluene: water (60 mL:15 mL). The mixture was degassed for 20 minutes then refluxed for 18 hours. The reaction mixture was filtered through Celite™, the filtrate was evaporated in vacuo and the residue was purified by column chromatography on silica gel (gradient of EtOAc:hexane 15:85) to afford the title compound as an off white solid in 21% yield, 1.3 g.
Reaction SMILES: Br[C:2]1[C:3]([NH:9][C:10](=[O:13])[CH2:11]I)=[N:4][CH:5]=[C:6]([Br:8])[N:7]=1.C(N(C(C)C)CC)(C)C.Cl.[CH3:24][O:25][C@@H:26]1[CH2:31][CH2:30][C@H:29]([NH2:32])[CH2:28][CH2:27]1>C(#N)C>[Br:8][C:6]1[N:7]=[C:2]2[N:32]([C@H:29]3[CH2:30][CH2:31][C@@H:26]([O:25][CH3:24])[CH2:27][CH2:28]3)[CH2:11][C:10](=[O:13])[NH:9][C:3]2=[N:4][CH:5]=1
Reactant: CO[C@H]1CC[C@@H](N)CC1
Reactant: O=C(CI)Nc1ncc(Br)nc1Br
Agent: Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CO[C@H]1CC[C@@H](N2CC(=O)Nc3ncc(Br)nc32)CC1
Temperature: 55 °C
Reaction time: 3 h
Yield: 54.3 %

Procedure:
To a solution of N-(3,5-dibromopyrazin-2-yl)-2-iodoacetamide (See Example 5.B) (1.0 g, 2.376 mmol) and diisopropylethylamine (1.038 mL, 5.94 mmol) in acetonitrile (10 mL) was added (cis)-4-methoxycyclohexanamine hydrochloride (0.413 g, 2.495 mmol). The solution was stirred at 55° C. for 3 h. The resulting precipitate was filtered and washed with acetonitrile and dried under reduced pressure to afford the title compound (0.442 g, 1.29 mmol, 55% yield). MS (ESI) m/z 341.3 [M]+, 343.3 [M+2]+.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([CH3:11])=[C:4]([Cl:12])[N:3]=1.[NH2:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][OH:22])=[CH:16][CH:15]=1>>[Cl:12][C:4]1[N:3]=[C:2]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][OH:22])=[CH:16][CH:15]=2)[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]=1[CH3:11]
Reactant: Cc1cc([N+](=O)[O-])c(Cl)nc1Cl
Reactant: Nc1ccc(CCO)cc1
Product: Cc1cc([N+](=O)[O-])c(Nc2ccc(CCO)cc2)nc1Cl

Procedure:
The title compound was prepared according to the procedure described in step 1 of Example 34 from 2,6-dichloro-5-methyl-3-nitropyridine (Horn, U.; Mutterer, F.; Weis, C. D. Helv. Chim. Acta., 1976, 59,190.) and 4-aminophenylethyl alcohol.
Reaction SMILES: [I:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[NH:12][C:11](=[O:13])O[C:8](=[O:9])[C:7]=12.[NH:14]([CH2:16]C(O)=O)[CH3:15]>CC(N(C)C)=O>[I:1][C:2]1[C:7]2[C:8](=[O:9])[N:14]([CH3:16])[CH2:15][C:11](=[O:13])[NH:12][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: O=c1[nH]c2cccc(I)c2c(=O)o1
Reactant: CNCC(=O)O
Solvent: CC(=O)N(C)C
Product: CN1CC(=O)Nc2cccc(I)c2C1=O

Procedure:
A mixture of 8.7 g (0.03 mol) of 6-iodoisatoic acid anhydride, 3.2 g (0.036 mol) of sarcosine and 25 ml of dimethylacetamide is heated to boiling under reflux for 1 hour. After cooling and dilution with water, the mixture is extracted with chloroform. The chloroform extracts are dried and evaporated. After recrystallization of the crude product from methylene chloride/ether, there is obtained 3,4-dihydro-6-iodo-4-methyl-2H-1,4-benzodiazepine-2,5(1H)-dione of melting point 214°-217°.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:24][CH2:23][C@@:22]2([CH3:25])[C@@H:4]([C@@H:5]([OH:27])[CH2:6][C@@H:7]3[C@@H:21]2[CH2:20][CH2:19][C@@:18]2([CH3:26])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C@H:12]([CH3:17])[CH2:13][CH2:14][CH:15]=[O:16])[CH2:3]1.[C:28](Cl)(=[O:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>N1C=CC=CC=1>[C:28]([O:1][C@@H:2]1[CH2:24][CH2:23][C@@:22]2([CH3:25])[C@@H:4]([C@@H:5]([O:27][C:5](=[O:27])[C:4]3[CH:22]=[CH:23][CH:24]=[CH:2][CH:3]=3)[CH2:6][C@@H:7]3[C@@H:21]2[CH2:20][CH2:19][C@@:18]2([CH3:26])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C@H:12]([CH3:17])[CH2:13][CH2:14][CH:15]=[O:16])[CH2:3]1)(=[O:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: C[C@H](CCC=O)[C@H]1CC[C@H]2[C@@H]3C[C@H](O)[C@H]4C[C@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Reactant: O=C(Cl)c1ccccc1
Solvent: c1ccncc1
Product: C[C@H](CCC=O)[C@H]1CC[C@H]2[C@@H]3C[C@H](OC(=O)c4ccccc4)[C@H]4C[C@H](OC(=O)c5ccccc5)CC[C@]4(C)[C@H]3CC[C@]12C
Temperature: 0 °C
Reaction time: 5 h

Procedure:
One gram of 3α,6α-bis(hydroxy)-5α-cholane-24-al is dissolved in 5 ml of pyridine. With external cooling, 1 ml of benzoyl chloride is added dropwise with stirring. The mixture is kept at room temperature for five hours, then stirred with ice water. By extraction with methylene chloride, the reaction product is removed. The methylene chloride solution is repeatedly washed with dilute hydrochloric acid, then with water. After drying, the solvent is evaporated. The residue is 3α,6α-bis(benzoyloxy)-5α-cholane-24-al.
Reaction SMILES: [Na].C[O-].[CH3:4][C:5]1[N:10]=[CH:9][C:8]([CH2:11][C:12]#[N:13])=[CH:7][CH:6]=1.[CH3:14][C:15]1[CH:16]=[CH:17][C:18]([N+:23]([O-:25])=[O:24])=[C:19]([CH:22]=1)[CH:20]=O>CO.O>[CH3:14][C:15]1[CH:16]=[CH:17][C:18]([N+:23]([O-:25])=[O:24])=[C:19](/[CH:20]=[C:11](\[C:8]2[CH:9]=[N:10][C:5]([CH3:4])=[CH:6][CH:7]=2)/[C:12]#[N:13])[CH:22]=1
Reactant: Cc1ccc(CC#N)cn1
Reactant: Cc1ccc([N+](=O)[O-])c(C=O)c1
Agent: C[O-]
Agent: [Na]
Solvent: O
Solvent: CO
Product: Cc1ccc([N+](=O)[O-])c(/C=C(/C#N)c2ccc(C)nc2)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 54.9 %

Procedure:
Sodium metal (1.9 g, 0.0848 mol) was dissolved in MeOH (180 mL), and the resulting methoxide solution was cooled to 0° C. To this was added 2-(6-methylpyridin-3-yl)acetonitrile (11.19 g, 0.0848 mol), and the reaction mixture was stirred for 30 min. at 0° C. 5-Methyl-2-nitrobenzaldehyde (7.0 g, 0.0424 mol) was added at 0° C., and the mixture was further stirred for 1 h at 0° C. After completion of reaction (monitored by TLC), the mixture was diluted with water (100 mL), and extracted with EtOAc (3×150 mL). The organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure and purified by column chromatography (20% EtOAc:hexane in silica 100-200 mesh, diameter of column—5.0 cm, height of silica—approx. 5 inch) to give the desired compound as a yellow colored solid (6.5 g, 59% yield).
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[C:11]2[C:6](=[CH:7][C:8]([Br:12])=[CH:9][CH:10]=2)[NH:5][CH2:4][CH2:3]1.I[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+]>[Cu]I.O>[CH3:1][C:2]1([CH3:13])[C:11]2[C:6](=[CH:7][C:8]([Br:12])=[CH:9][CH:10]=2)[N:5]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:4][CH2:3]1
Reactant: CC1(C)CCNc2cc(Br)ccc21
Reactant: Ic1ccccc1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CC1(C)CCN(c2ccccc2)c2cc(Br)ccc21
Temperature: 185 °C

Procedure:
To a solution of 0.19 g (0.78 mmol) of 4,4-dimethyl-1,2,3,4-tetrahydro-7-bromoquinoline and 5.5 g (3.0 mL, 27 mmol) of 4-iodobenzene stirring under argon, were added 0.30 g (2.2 mmol) of potassium carbonate and 0.12 g (0.63 mmol) of copper(I) iodide. The resulting mixture was heated at 185° C. for 96 hours. The reaction was cooled to room temperature, water was added, and the mixture was extracted with methylene chloride (2x). The combined organic layers were washed with brine, dried (Na2SO4), filtered, and concentrated in vacuo to give an oil. The residue was purified by flash chromatography (hexanes) to give the product as a clear oil. PNMR (300 MHz, CDCl3) d 1.33 (6 H, s), 1.84 (2 H, t, J=6.1 Hz), 3.62 (2 H, t, J=6.1 Hz), 6.77 (1 H, d, J=2.0 Hz), 6.81 (1 H, dd, J=8.2, 2.0 Hz), 7.10 (1 H, d, J=8.2 Hz), 7.16-7.23 (3 H, m), 7.39 (2 H, 2 doublets overlapping).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[Br:11][C:12]1[CH:13]=[C:14]([C:18]([CH3:22])([CH3:21])[CH2:19][OH:20])[CH:15]=[N:16][CH:17]=1.C(N(CC)CC)C>ClCCl>[Br:11][C:12]1[CH:13]=[C:14]([C:18]([CH3:22])([CH3:21])[CH:19]=[O:20])[CH:15]=[N:16][CH:17]=1
Reactant: CC(C)(CO)c1cncc(Br)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CC(C)(C=O)c1cncc(Br)c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of oxalyl chloride in dichloromethane (2.0 M, 0.869 mL, 1.74 mmol) was diluted with dichloromethane (2 mL) and then a solution of dimethylsulfoxide (0.250 mL, 3.50 mmol) in dichloromethane (1 mL) was added at −78° C. After stirring for 15 minutes, a solution of the title compound from Example 53 Step E (0.200 g, 0.869 mmol) in dichloromethane (3 mL) was added. The resulting reaction stirred for 30 minutes before triethylamine (0.600 mL, 4.35 mmol) was added. The reaction warmed to room temperature slowly and stirred overnight. It was quenched with the addition of water and then extracted with dichloromethane. The combined organics were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and concentrated under reduced pressure. Purification by flash chromatography on silica gel (25-100% ethyl acetate in hexanes) provided the title compound: LCMS m/z 229.87 [M+2H]+; 1H NMR (500 MHz, CDCl3) δ 9.53 (s, 1H), 8.61 (s, 1H), 8.47 (s, 1H), 7.73 (s, 1H), 1.51 (s, 6H).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([C:15]([N:17]2[CH2:22][CH2:21][N:20]([C:23]3[C:28]([CH3:29])=[CH:27][C:26]([CH:30]4[CH2:32][CH2:31]4)=[CH:25][N:24]=3)[CH2:19][CH2:18]2)=[O:16])=[C:6]([N:8]2[CH2:12][CH2:11][N:10]([CH3:13])[C:9]2=[O:14])[CH:7]=1.[NH:33]1[CH2:37][CH2:36][CH2:35][C:34]1=[O:38]>>[CH:30]1([C:26]2[CH:27]=[C:28]([CH3:29])[C:23]([N:20]3[CH2:21][CH2:22][N:17]([C:15]([C:5]4[CH:4]=[CH:3][C:2]([N:33]5[CH2:37][CH2:36][CH2:35][C:34]5=[O:38])=[CH:7][C:6]=4[N:8]4[CH2:12][CH2:11][N:10]([CH3:13])[C:9]4=[O:14])=[O:16])[CH2:18][CH2:19]3)=[N:24][CH:25]=2)[CH2:32][CH2:31]1
Reactant: O=C1CCCN1
Reactant: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(Cl)cc2N2CCN(C)C2=O)CC1
Product: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(N3CCCC3=O)cc2N2CCN(C)C2=O)CC1
Yield: 47.4 %

Procedure:
Using 1-{5-chloro-2-[4-(5-cyclopropyl-3-methylpyridin-2-yl)piperazine-1-carbonyl]phenyl}-3-methylimidazolidin-2-one (82 mg) described in Preparation Example 242 and pyrrolidin-2-one (23 mg) and by the reaction and treatment in the same manner as in Example 666, the title compound (43 mg) was obtained.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[F:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]1[C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:18]([CH3:25])[NH:17][C:16](=O)[N:15]=1.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>O1CCOCC1.CCOC(C)=O>[CH2:23]([O:22][C:20]([C:19]1[C:14]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[F:7])=[N:15][C:16]([N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)=[N:17][C:18]=1[CH3:25])=[O:21])[CH3:24]
Reactant: CCOC(=O)c1c(-c2ccccc2F)nc(=O)[nH]c1C
Reactant: C1COCCN1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CCOC(=O)c1c(C)nc(N2CCOCC2)nc1-c1ccccc1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 64 %

Procedure:
Morpholine (0.5 mL) was added to a stirred solution of ethyl 4-(2-fluorophenyl)-1,2-dihydro-6-methyl-2-oxopyrimidine-5-carboxylate (0.75 g, 2.72 mmol), PyBroP (1.4 g, 3 mmol), and triethylamine (1 mL) in 1,4-dioxane (20 mL) at room temperature. The solution was stirred at room temperature for 3 h and diluted with EtOAc. The solution was washed with saturated NH4Cl and saturated aqueous NaCl solution, and dried. The solvent was removed under reduced pressure, and the residue was purified by Biotage SP1 on packed silica gel column (5%-80% EtOAC/hexanes gradient) to give 4-(2-fluorophenyl)-6-methyl-2-morpholin-4-yl-pyrimidine-5-carboxylic acid ethyl ester as an oil (0.937 g, 64%). Mass Spec. LCMS 346 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[CH2:5][CH2:6][OH:7].CCOC(/N=N/C(OCC)=O)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:42]([C:44]1[CH:49]=[CH:48][C:47](O)=[CH:46][CH:45]=1)#[N:43].[NH4+].[Cl-]>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[CH2:5][CH2:6][O:7][C:47]1[CH:48]=[CH:49][C:44]([C:42]#[N:43])=[CH:45][CH:46]=1
Reactant: N#Cc1ccc(O)cc1
Reactant: OCCc1cccc(F)c1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: N#Cc1ccc(OCCc2cccc(F)c2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 74.6 %

Procedure:
A THF (2 mL) solution of 3-(fluoro)phenethyl alcohol (168 mg, 1.2 mmol) and DEAD (205 μL, 1.3 mmol) was very slowly added dropwise at 0° C. to a THF (4 mL) solution of triphenylphosphine (341 mg, 1.3 mmol) and 4-cyanophenol (119 mg, 1.0 mmol). The mixture was stirred at 0° C. (30 min), and then at room temperature (16 h). A saturated aqueous solution of NH4Cl (200 mL) was added dropwise at 0° C. The volatiles were evaporated under vacuum and the residue was purified by flash column chromatography on silica gel with EtOAc/hexanes (0/10 to 2/8) as the eluant to obtain 4-((3′-fluoro)phenethoxy)benzonitrile as a white solid (180 mg, 75%): Rf=0.33 (EtOAc/hexanes 1/9); mp 79-81° C.; IR (crystal) 3281, 2909, 2222, 1711, 1643, 1603, 1589, 1506, 1489, 1450, 1418, 1300, 1250, 1171, 1140, 1115, 1057, 1024, 941 cm−1; 1H NMR (400 MHz, CDCl3) δ 3.11 (t, J=7.0 Hz, CH2), 4.22 (t, J=7.0 Hz, OCH2), 6.92-7.06 (m, 5 ArH), 7.20-7.31 (m, 1 ArH), 7.57 (d, J=8.0 Hz, 2H3); 13C NMR (100 MHz, CDCl3) δ 35.2 (d, J=1.6 Hz, CH2), 68.5 (CH2O), 104.1 (C1), 113.6 (d, J=21.0 Hz, C2′ or C4′), 115.2 (C3), 115.9 (d, J=20.9 Hz, C4′ or C2′), 119.1 (CN), 124.6 (d, J=3.1 Hz, C6′), 130.0 (d, J=8.6 Hz, C5′), 134.0 (C2), 140.2 (d, J=7.0 Hz, C1′), 161.9 (C4), 162.9 (d, J=247.7 Hz, C3′); HRMS (M+H+)(ESI+) not observed [M+H+] (calcd for C13H8FNOH+ 214.0668); Anal. Calcd. for C15H12FNO: C, 74.67; H, 5.01; F, 7.87; N, 5.81. Found: C, 74.46; H, 5.11; F, 7.89; N, 5.83.
Reaction SMILES: [CH3:1][C:2]([S:21]([CH3:24])(=[O:23])=[O:22])([CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([S:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:10][CH:9]=1)[C:3](O)=[O:4].O.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C.[O:43]1[CH2:48][CH2:47][CH2:46][CH2:45][CH:44]1[O:49][NH2:50]>C(Cl)Cl.O>[CH3:1][C:2]([S:21]([CH3:24])(=[O:22])=[O:23])([CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([S:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:10][CH:9]=1)[C:3]([NH:50][O:49][CH:44]1[CH2:45][CH2:46][CH2:47][CH2:48][O:43]1)=[O:4]
Reactant: NOC1CCCCO1
Reactant: CC(CCc1ccc(Sc2ccccc2)cc1)(C(=O)O)S(C)(=O)=O
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(CCc1ccc(Sc2ccccc2)cc1)(C(=O)NOC1CCCCO1)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-methyl-2-(methylsulfonyl)-4-[4-(phenylthio)phenyl]-butanoic acid (315.7 mg, 0.866 mmol) in methylene chloride (8.66 mL) at ambient temperature was added 1,(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (230 mg, 1.2 mmol), 1-hydroxy benzotriazole monohydrate (240 mg, 1.6 mmol), triethyl amine (210 uL, 1.5 mmol) and O-tetrahydro-2H-pyran-2-yl-hydroxylamine (150 mg, 1.3 mmol). The resulting mixture was stirred at ambient temperature overnight. The mixture was diluted with methylene chloride and water. The phases were separated and the aqueous layer was extracted with methylene chloride two times. The organic extracts were combined and dried over magnesium sulfate, filtered and concentrated to a crude residue. The crude residue was purified via silica gel chromatography eluting with methylene chloride and methanol. The fractions containing the desired product were combined and concentrated to afford 2-methyl-2-(methylsulfonyl)-4-[4-(phenylthio)phenyl]-N-(tetrahydro-2H-pyran-2-yloxy)butanamide as a solid. 268.4 mg. LCMS: (M−1) 462.2.
Reaction SMILES: [H-].[Na+].CO.[C:5](/[C:8](=[C:13](\[C:15]1[C:24]([NH:25][C:26]([O:28]CC)=O)=[CH:23][C:22]2[CH2:21][CH2:20][CH2:19][CH2:18][C:17]=2[CH:16]=1)/[OH:14])/C(OC)=O)(=[O:7])[CH3:6]>C1C=CC=CC=1>[C:5]([C:8]1[C:26](=[O:28])[NH:25][C:24]2[C:15]([C:13]=1[OH:14])=[CH:16][C:17]1[CH2:18][CH2:19][CH2:20][CH2:21][C:22]=1[CH:23]=2)(=[O:7])[CH3:6]
Reactant: CCOC(=O)Nc1cc2c(cc1/C(O)=C(\C(C)=O)C(=O)OC)CCCC2
Agent: [H-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: CO
Product: CC(=O)c1c(O)c2cc3c(cc2[nH]c1=O)CCCC3
Temperature: 72 °C
Reaction time: 0.08 h

Procedure:
To a mixture of sodium hydride (95%) (0.70 g, 29 mmol, 2.6 equiv) in benzene (100 mL) at 23° C. under nitrogen was added methanol (2.5 mL, 2.0 g, 62 mmol, 5.4 equiv) dropwise over 10 min. After stirring for an additional 5 min, methyl (2Z)-2-acetyl-3-{3-[(ethoxycarbonyl)amino]-5,6,7,8-tetrahydronaphthalen-2-yl}-3-hydroxyprop-2-enoate (1-4) (4.1 g, 11 mmol, 1 equiv) was added and the resulting mixture was heated at 72° C. for 20 h. The solvent was evaporated under reduced pressure and the solid residue was suspended in water (50 mL) for 30 min followed by 1 N aqueous hydrochloric acid solution (100 mL) for an additional 30 min with stirring. The solid was filtered, washed with water (100 mL) and hexanes (100 mL), and dried to yield 3-acetyl-4-hydroxy-6,7,8,9-tetrahydrobenzo[g]quinolin-2(1H)-one (1-5) as an off-white solid. LRMS m/z (M+H) 258.4 found, 258.1 required.
Reaction SMILES: [I:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][CH:3]=1.C(Cl)(=O)C([Cl:14])=O.CN(C)C=O>C(Cl)Cl>[I:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([Cl:14])=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccc(I)cc1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)c1ccc(I)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A suspension of 4-iodobenzoic acid (20.0 g, 80.6 mL) in CH2Cl2 (350 mL) at 0° C. was treated with oxalyl chloride (42.3 mL of a 2.0 M solution in CH2Cl2, 81.7 mmol). Dimethylformamide was added (0.5 mL) until a homogeneous solution was achieved and then the cooling bath was removed. The reaction mixture was stirred at ambient temperature for 3 hours and then concentrated to provide crude 4iodobenzoyl chloride as a waxy oil that was used without further purification.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([C:11]([OH:13])=O)[CH3:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.C(Cl)(=O)OCC(C)C.[NH2:29][C:30]1[CH:39]=[CH:38][C:33]([C:34]([O:36][CH3:37])=[O:35])=[CH:32][C:31]=1[S:40][CH2:41][CH2:42][C:43]([O:45][CH2:46][CH:47]([CH2:52][CH3:53])[CH2:48][CH2:49][CH2:50][CH3:51])=[O:44]>C1COCC1.C(OCC)(=O)C>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:11]([NH:29][C:30]1[CH:39]=[CH:38][C:33]([C:34]([O:36][CH3:37])=[O:35])=[CH:32][C:31]=1[S:40][CH2:41][CH2:42][C:43]([O:45][CH2:46][CH:47]([CH2:52][CH3:53])[CH2:48][CH2:49][CH2:50][CH3:51])=[O:44])=[O:13])[CH3:10])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(NC(=O)OC(C)(C)C)C(=O)O
Reactant: CCCCC(CC)COC(=O)CCSc1cc(C(=O)OC)ccc1N
Agent: CC(C)COC(=O)Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCCC(CC)COC(=O)CCSc1cc(C(=O)OC)ccc1NC(=O)[C@H](C)NC(=O)OC(C)(C)C
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 37.8 %

Procedure:
To a solution of N-(tert-butoxycarbonyl)-D,L-alanine (1.70 g, 8.98 mmol) and triethylamine (1.25 mL, 8.98 mmol) in THF (10 mL) was added 2-methylpropyl chlorocarbonate (1.16 mL, 8.98 mmol) under ice-cooling, and the mixture was stirred for 30 min. To this solution was added a solution of methyl 4-amino-3-({3-[(2-ethylhexyl)oxy]-3-oxopropyl}sulfanyl)benzoate (3.00 g, 8.16 mmol) obtained in Reference Example 82 in THF (4 mL) under a nitrogen atmosphere, and the mixture was heated under reflux at 80° C. for 16 hr. After being allowed to cool to room temperature, the reaction mixture was diluted with ethyl acetate, and the mixture was washed with 0.5N hydrochloric acid, 10% aqueous potassium carbonate solution and saturated brine, and dried over anhydrous sodium sulfate. This solution was applied to basic silica gel column chromatography (ethyl acetate). The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=19:1 to 7:3) to give methyl 4-{[N-(tert-butoxycarbonyl)alanyl]amino}-3-({3-[(2-ethylhexyl)oxy]-3-oxopropyl}sulfanyl)benzoate (1.66 g). To the obtained oil (1.66 g, 3.08 mmol) was added trifluoroacetic acid (15 mL), and the mixture was stirred for 10 min. The reaction mixture was concentrated under reduced pressure. Ethyl acetate was added to the residue, and the mixture was washed with 10% aqueous potassium carbonate solution and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give methyl 4-(alanylamino)-3-({3-[(2-ethylhexyl)oxy]-3-oxopropyl}sulfanyl)benzoate (1.32 g). To a solution of this oil (1.32 g, 3.01 mmol) in ethyl acetate (15 mL) was added acetic anhydride (0.437 mL, 4.62 mmol) at room temperature and the mixture was stirred for 30 min. The solvent was evaporated under reduced pressure, and the residue was dissolved in ethyl acetate. The solution was purified by basic silica gel column chromatography (ethyl acetate) and the obtained residue was triturated with hexane to give the title compound (1.04 g, yield 70%).