Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: NC(C)(C)C[O:4]C1C=CC(C#N)=CC=1F.[C:16]([O:20][C:21](=[O:37])[NH:22][C:23]([CH3:36])([CH3:35])[CH2:24][O:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]#N)=[CH:28][C:27]=1[F:34])([CH3:19])([CH3:18])[CH3:17]>>[C:16]([O:20][C:21](=[O:37])[NH:22][C:23]([CH3:36])([CH3:35])[CH2:24][O:25][C:26]1[CH:31]=[CH:30][C:29]([CH:32]=[O:4])=[CH:28][C:27]=1[F:34])([CH3:19])([CH3:18])[CH3:17]
Reactant: CC(C)(COc1ccc(C#N)cc1F)NC(=O)OC(C)(C)C
Reactant: CC(C)(N)COc1ccc(C#N)cc1F
Product: CC(C)(COc1ccc(C=O)cc1F)NC(=O)OC(C)(C)C

Procedure:
Synthesized from 4-(2-amino-2-methylpropoxy)-3-fluorobenzonitrile according to an analogous synthetic method to Preparation Example 19, tert-butyl[2-(4-cyano-2-fluorophenoxy)-1,1-dimethylethyl]carbamate (1.0 g) was used according to an analogous synthetic method to Preparation Example 20 to provide the title compound (715 mg).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:14]([N:15]=1)=[C:13]1[C:8]([CH:9]=[CH:10][C:11](=O)[N:12]1C)=[CH:7][CH:6]=2.P(Br)(Br)([Br:20])=O.P(Cl)(Cl)(Cl)(Cl)Cl>>[Br:20][C:11]1[CH:10]=[CH:9][C:8]2[C:13](=[C:14]3[C:5](=[CH:6][CH:7]=2)[CH:4]=[CH:3][C:2]([Br:1])=[N:15]3)[N:12]=1
Reactant: Cn1c(=O)ccc2ccc3ccc(Br)nc3c21
Reactant: O=P(Br)(Br)Br
Agent: ClP(Cl)(Cl)(Cl)Cl
Product: Brc1ccc2ccc3ccc(Br)nc3c2n1
Temperature: 70 °C
Reaction time: 5.5 h
Yield: 81.3 %

Procedure:
Under a stream of argon, to compound (9) (8.4 g; 29.1 mmol), phosphorus oxybromide (3.25 g; 174 mmol) and phosphorus pentachloride (15.4 g; 35.8 mmol) were added in an ice bath. The reaction temperature was raised to 65 to 75° C., and the resulting reaction mixture was stirred for 5.5 hours. The reaction mixture was cooled in an ice bath and evaporated under reduced pressure. Excess phosphorus oxybromide was removed and the resulting reaction concentrate was poured into ice water, and was made alkaline with concentrated aqueous ammonia. While solids which precipitated out were separated by filtration, they were washed with water to give crude title compound (10). The crude compound (10) was dried, and separated and purified by silica gel column chromatography (SiO2 300 g) (CHCl3/methanol=50/1 to 40/1 to 30/1) to give 8 g (yield: 81%) of the title compound (10).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]([CH2:13][CH2:14][C:15]3[S:16][C:17]([C:21]([OH:23])=O)=[C:18]([CH3:20])[N:19]=3)=[C:11]([CH3:24])[O:10][N:9]=2)=[N:6][CH:7]=1.[CH2:25]([NH2:27])[CH3:26]>>[CH2:25]([NH:27][C:21]([C:17]1[S:16][C:15]([CH2:14][CH2:13][C:12]2[C:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][N:6]=3)=[N:9][O:10][C:11]=2[CH3:24])=[N:19][C:18]=1[CH3:20])=[O:23])[CH3:26]
Reactant: Cc1nc(CCc2c(-c3ccc(F)cn3)noc2C)sc1C(=O)O
Reactant: CCN
Product: CCNC(=O)c1sc(CCc2c(-c3ccc(F)cn3)noc2C)nc1C
Yield: 64 %

Procedure:
As described for example 31b, 2-{2-[3-(5-fluoro-pyridin-2-yl)-5-methyl-isoxazol-4-yl]-ethyl}-4-methyl-thiazole-5-carboxylic acid (69 mg, 0.20 mmol) was converted, using ethylamine (2M solution in THF) instead of 4-aminotetrahydropyran, to the title compound (48 mg, 64%) which was obtained as an off white solid. MS: m/e=375.2 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([CH:14]([OH:18])[CH2:15][CH:16]=C)=[C:12]([CH:19]([CH3:21])[CH3:20])[N:11]=[C:10]([N:22]([CH3:27])[S:23]([CH3:26])(=[O:25])=[O:24])[N:9]=2)=[CH:4][CH:3]=1.I([O-])(=O)(=O)=[O:29].[Na+]>CO.[Os](=O)(=O)(=O)=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:13]([CH:14]([OH:18])[CH2:15][CH:16]=[O:29])=[C:12]([CH:19]([CH3:20])[CH3:21])[N:11]=[C:10]([N:22]([CH3:27])[S:23]([CH3:26])(=[O:24])=[O:25])[N:9]=2)=[CH:6][CH:7]=1
Reactant: C=CCC(O)c1c(-c2ccc(F)cc2)nc(N(C)S(C)(=O)=O)nc1C(C)C
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: CO
Product: CC(C)c1nc(N(C)S(C)(=O)=O)nc(-c2ccc(F)cc2)c1C(O)CC=O
Yield: 3 %

Procedure:
To a solution of N-[4-(4-fluorophenyl)-5-(1-hydroxybut-3-enyl)-6-isopropyl-pyrimidin-2-yl]-N-methylmethanesulfonamide (2 g, 5.08 mmol) in a mixture of 30 mL methanol and 4 mL buffer solution (pH=7), sodium periodate (3.2 g, 15.2 mmol) and osmium tetroxide (0.3 mL, 4% wt. in water, 13 mg) are added at room temperature. The reaction mass is stirred and the progress of the reaction is monitored by TLC. Upon completion of the reaction, the reaction mixture is filtered through celite bed (1 g) and washed with ethyl acetate (2×10 mL). The filtrate is distilled under reduced pressure until solvents are removed. To the residue, ethyl acetate (200 mL) is added and washed with DM water (50 mL) and brine (50 mL), subsequently. The solvent is distilled off under reduced pressure to afford 2.1 g crude product. Part of the residue (200 mg) is purified through silica gel column chromatography eluting with (20%-30%) ethylacetate:cyclohexane to obtain 60 mg pure N-(4-(4-fluorophenyl)-5-(1-hydroxy-3-oxopropyl)-6-isopropylpyrimidin-2-yl)-N-methylmethanesulfonamide.
Reaction SMILES: [H-].[Na+].[I-].[CH:4]([C:6]1[CH:7]=[C:8]([C:19]([NH:21][CH2:22][C:23]2[CH:24]=[N:25][C:26]([CH3:29])=[CH:27][CH:28]=2)=[O:20])[CH:9]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)[CH:11]=1)=[O:5].[CH3:30]S(C)=O>>[CH3:18][C:15]1[CH:14]=[CH:13][C:12]([C:10]2[CH:11]=[C:6]([CH:4]3[CH2:30][O:5]3)[CH:7]=[C:8]([C:19]([NH:21][CH2:22][C:23]3[CH:24]=[N:25][C:26]([CH3:29])=[CH:27][CH:28]=3)=[O:20])[CH:9]=2)=[CH:17][CH:16]=1
Reactant: Cc1ccc(-c2cc(C=O)cc(C(=O)NCc3ccc(C)nc3)c2)cc1
Reactant: CS(C)=O
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Product: Cc1ccc(-c2cc(C(=O)NCc3ccc(C)nc3)cc(C3CO3)c2)cc1
Temperature: -10 °C

Procedure:
A mixture of sodium hydride (60% in mineral oil, 0.85 g, 21.2 mmol) in dimethyl sulfoxide (75 mL) was cooled to −10° C. Trimethylsufoxonium iodide (4.66 g, 21.2 mmol) in DMSO (25 mL) was added dropwise over a 10 mM period. The mixture was warmed to room temperature and stirred for an additional hour. The mixture was cooled to 0° C. and 5-formyl-4′-methyl-N-((6-methylpyridin-3-yl)methyl)biphenyl-3-carboxamide (3.65 g, 10.6 mmol) in DMSO (25 mL) was added dropwise over a 10 minute period. The mixture was warmed to room temperature and stirred for 1 hour. The mixture was poured onto ice and extracted with ethyl acetate (3×150 mL). The combined extracts were dried over sodium sulfate and concentrated in vacuo. The mixture was purified by column chromatography using methylene chloride:methanol gradient (2-10%) to afford the title compound as a yellow oil. LC-MS: 358.8 [M+1]+.
Reaction SMILES: [O:1]([CH2:8][C:9]1[S:10][CH:11]2[CH:14]([N:15]=1)[C:13](=[O:16])[NH:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:17]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)(=[O:20])[CH:18]=[O:19]>C1C=CC=CC=1>[CH2:22]([O:21][C:17]([CH:18]([N:12]1[CH:11]2[CH:14]([N:15]=[C:9]([CH2:8][O:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[S:10]2)[C:13]1=[O:16])[OH:19])=[O:20])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=C1NC2SC(COc3ccccc3)=NC12
Reactant: O=CC(=O)OCc1ccccc1
Solvent: c1ccccc1
Product: O=C(OCc1ccccc1)C(O)N1C(=O)C2N=C(COc3ccccc3)SC21
Temperature: 25 °C
Yield: 514.1 %

Procedure:
Into a 500 ml. flask equipped with a Dean-Stark condenser filled with Molecular Sieves 3A (™, manufactured by Nakarai Chemicals Ltd.) were charged with 3-phenoxymethyl-6-oxo-2-thia-4,7-diazabicyclo[3,2,0]hept-3-ene (995 mg.), benzyl glyoxylate (6.2 g.) and benzene (80 ml.). The mixture was heated under reflux for 3.5 hours. After benzene (40 ml.) was distilled off, the resultant solution was cooled to room temperature, and 25% aqueous solution of sodium bisulfite (150 ml.) was added thereto. The mixture was stirred for half an hour, and the precipitate was filtered off and washed with benzene. The organic layer was separated and washed twice with water (50 ml.) and twice with an aqueous solution of sodium chloride (150 ml.). Drying over magnesium sulfate and removal of the solvent gave an oil (8.7 g.) of 7-(1-benzyloxycarbonyl-1-hydroxymethyl)-3-phenoxymethyl-6-oxo-2-thia-4,7-diazabicyclo[3,2,0]hept-3-ene.
Reaction SMILES: [CH2:1]([N:8]1[CH2:18][CH2:17][C:11]2[N:12]=[CH:13][N:14]=[C:15](Cl)[C:10]=2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:19][C:20]([F:32])([F:31])[S:21]([C:24]1[CH:30]=[CH:29][C:27]([NH2:28])=[CH:26][CH:25]=1)(=[O:23])=[O:22]>>[CH2:1]([N:8]1[CH2:18][CH2:17][C:11]2[N:12]=[CH:13][N:14]=[C:15]([NH:28][C:27]3[CH:29]=[CH:30][C:24]([S:21]([C:20]([F:32])([F:19])[F:31])(=[O:23])=[O:22])=[CH:25][CH:26]=3)[C:10]=2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccc(S(=O)(=O)C(F)(F)F)cc1
Reactant: Clc1ncnc2c1CN(Cc1ccccc1)CC2
Product: O=S(=O)(c1ccc(Nc2ncnc3c2CN(Cc2ccccc2)CC3)cc1)C(F)(F)F

Procedure:
The title compound was prepared substantially according to the procedure given for Compound 4A, using 6-benzyl-4-chloro-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine (0.2 g, 0.77 mmol), and 4-(trifluoromethylsulphonyl)aniline (0.27 g, 1.2 mmol) to give the desired N-benzyl intermediate as a brown solid (278 mg. 82%).
Reaction SMILES: [O:1]=[C:2]1[NH:6][C:5]2[CH:7]=[CH:8][C:9]([C:11]([OH:13])=O)=[CH:10][C:4]=2[S:3]1.[CH2:14]1[C@H:23]2[C@H:18]([CH2:19][CH2:20][C:21]3[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=32)[NH:17][CH2:16][CH2:15]1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>>[CH2:14]1[C@H:23]2[C@H:18]([CH2:19][CH2:20][C:21]3[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=32)[N:17]([C:11]([C:9]2[CH:8]=[CH:7][C:5]3[NH:6][C:2](=[O:1])[S:3][C:4]=3[CH:10]=2)=[O:13])[CH2:16][CH2:15]1
Reactant: O=C(O)c1ccc2[nH]c(=O)sc2c1
Reactant: c1ccc2c(c1)CC[C@@H]1NCCC[C@H]21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: O=C(c1ccc2[nH]c(=O)sc2c1)N1CCC[C@@H]2c3ccccc3CC[C@@H]21
Yield: 56 %

Procedure:
The title compound is prepared from 2-oxo-2,3-dihydro-benzothiazole-6-carboxylic acid and cis-1,2,3,4,4a,5,6,10b-octahydro-benzo[f]quinoline following a procedure analogous to that described in Example 1 [2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate is used]. Yield: 56% of theory; LC (method 3): tR=2.32 min; Mass spectrum (ESI+): m/z=365 [M+H]+.
Reaction SMILES: C([O:5][C:6]([C@H:8]1[CH2:12][CH2:11][CH2:10][N:9]1[C:13](=[O:48])[CH2:14][N:15]([CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)[C:16]([N:18]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[CH2:19][C:20]([N:22]1[CH2:26][CH2:25][CH2:24][C@@H:23]1[C:27]([O:29]C(C)(C)C)=[O:28])=[O:21])=[O:17])=[O:7])(C)(C)C>Cl.O1CCOCC1>[CH2:41]([N:15]([CH2:14][C:13]([N:9]1[CH2:10][CH2:11][CH2:12][C@@H:8]1[C:6]([OH:7])=[O:5])=[O:48])[C:16]([N:18]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[CH2:19][C:20]([N:22]1[CH2:26][CH2:25][CH2:24][C@@H:23]1[C:27]([OH:29])=[O:28])=[O:21])=[O:17])[C:42]1[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=1
Reactant: CC(C)(C)OC(=O)[C@H]1CCCN1C(=O)CN(Cc1ccccc1)C(=O)N(CC(=O)N1CCC[C@@H]1C(=O)OC(C)(C)C)Cc1ccccc1
Agent: Cl
Solvent: C1COCCO1
Product: O=C(O)[C@H]1CCCN1C(=O)CN(Cc1ccccc1)C(=O)N(CC(=O)N1CCC[C@@H]1C(=O)O)Cc1ccccc1
Yield: 40.7 %

Procedure:
A solution of 220 mg (0.33 mmol) (R)-1-[[1,3-Dibenzyl-3-[2-[(R)-2-tert-butoxycarbonyl-pyrrolidin-1-yl]-2-oxo-ethyl]-ureido]-acetyl]-pyrrolidine-2-carboxylic acid tert-butyl ester in 5 ml 4 N hydrochloric acid solution in dioxane was stirred for 5 h at room temperature. The product was extracted with 1 N sodium hydroxide solution, the basic extract was acidified with 1 N hydrochloric acid solution to pH 4 and the product extracted with ethyl acetate. The organic phase was dried (magnesium sulfate) and evaporated to give 74 mg (41%) of the title compound as a brown oil.
Reaction SMILES: [CH:1]([S:4]([NH2:7])(=[O:6])=[O:5])([CH3:3])[CH3:2].[CH2:8]([O:10][C:11]([C:13]1[O:14][C:15]2[CH:22]=[CH:21][CH:20]=[C:19](OS(C(F)(F)F)(=O)=O)[C:16]=2[C:17]=1[CH3:18])=[O:12])[CH3:9]>>[CH2:8]([O:10][C:11]([C:13]1[O:14][C:15]2[CH:22]=[CH:21][CH:20]=[C:19]([NH:7][S:4]([CH:1]([CH3:3])[CH3:2])(=[O:6])=[O:5])[C:16]=2[C:17]=1[CH3:18])=[O:12])[CH3:9]
Reactant: CC(C)S(N)(=O)=O
Reactant: CCOC(=O)c1oc2cccc(OS(=O)(=O)C(F)(F)F)c2c1C
Product: CCOC(=O)c1oc2cccc(NS(=O)(=O)C(C)C)c2c1C
Yield: 23 %

Procedure:
Coupling of isopropylsulfonamide with 3-methyl-4-trifluoromethanesulfonyloxy-benzofuran-2-carboxylic acid ethyl ester was carried out according to Example 36, Step 1 to give 3-methyl-4-(propane-2-sulfonylamino)-benzofuran-2-carboxylic acid ethyl ester in 23% yield. 1H NMR (400 MHz, CDCl3) δ ppm 1.4 (t, J=6.4 Hz, 9 H) 2.9 (t, 3 H) 3.5 (m, 1 H) 4.5 (q, J=7.1 Hz, 2 H) 6.6 (s, 1 H) 7.4 (m, 3 H).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]3[CH:15]=[C:16]([S:20](Cl)(=[O:22])=[O:21])[CH:17]=[CH:18][CH:19]=3)[N:9]=2)[CH:5]=[C:4]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=2)[CH:3]=1.[CH2:34]([NH2:41])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>C1COCC1.CCOC(C)=O>[CH2:34]([NH:41][S:20]([C:16]1[CH:17]=[CH:18][CH:19]=[C:14]([C:10]2[N:9]=[C:8]([C:6]3[CH:5]=[C:4]([C:24]4[CH:25]=[CH:26][C:27]([C:30]([F:32])([F:33])[F:31])=[CH:28][CH:29]=4)[CH:3]=[C:2]([CH3:1])[N:7]=3)[CH:13]=[CH:12][CH:11]=2)[CH:15]=1)(=[O:22])=[O:21])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: NCc1ccccc1
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2cccc(-c3cccc(S(=O)(=O)Cl)c3)n2)n1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2cccc(-c3cccc(S(=O)(=O)NCc4ccccc4)c3)n2)n1
Yield: 43.7 %

Procedure:
The title compound was prepared from 3-[6′-methyl-4′-(4-trifluoromethyl-phenyl)-[2,2′]bipyridinyl-6-yl]-benzenesulfonyl chloride (example I.2) (0.200 g, 0.409 mmol) by treatment with commercially available benzylamine (0.22 ml, 2.05 mmol) in THF (5 mL) at 23° C. for 16 h. Diluted with EtOAc, washed with 5% citric acid, sat. NaHCO3-sol. and brine, dried organic layer over Na2SO4. Removal of the solvent in vacuum left a crude product, which was purified by silica gel column chromatography with EtOAc followed by trituration with diethyl ether/heptane to give the title compound (0.100 g, 49%) as a white solid. MS (ISP) 560.2 [(M+H)+]; mp 168° C.
Reaction SMILES: Br[CH:2]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4].[NH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1>C1COCC1.[Cl-].[Na+].O>[C:8]1([CH:2]([N:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[C:3]([O:5][CH2:6][CH3:7])=[O:4])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: C1CCNCC1
Reactant: CCOC(=O)C(Br)c1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)C(c1ccccc1)N1CCCCC1
Reaction time: 3 h
Yield: 34.1 %

Procedure:
To a solution of ethyl 2-bromo-2-phenylacetate 21 (1.50 g, 6.17 mmol) in THF (10 mL) at room temperature was added piperidine (0.641 mL, 6.48 mmol) and TEA (1.72 mL, 12.34 mmol) and the reaction mixture was stirred for 3 h then diluted with brine and extracted with ethyl acetate. The organic layer was dried over Na2SO4, filtered, and concentrated. The crude material was purified by silica gel column chromatography with gradient of ethyl acetate (0-50%) in hexane to afford 22 as a colorless viscous oil (520 mg, 34%). LRMS (ESI): (calc) 247.3 (found) 248.3 (MH)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH:19]([CH3:21])[CH3:20])=[C:11]([CH2:13][C:14]([O:16]CC)=[O:15])[N:12]=2)=[CH:4][CH:3]=1.CO.[OH-].[K+]>O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:9][C:10]([CH:19]([CH3:21])[CH3:20])=[C:11]([CH2:13][C:14]([OH:16])=[O:15])[N:12]=2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)Cc1nc(-c2ccc(F)cc2)oc1C(C)C
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)c1oc(-c2ccc(F)cc2)nc1CC(=O)O
Yield: 83 %

Procedure:
2.0 g of ethyl 2-[2-(4-fluorophenyl)-5-isopropyl-4-oxazolyl]acetate, 15 ml of methanol, 5 ml of water and 0.8 g of potassium hydroxide are treated in the same manner as described in Example 8. 1.5 g of 2-[2-(4-fluorophenyl)-5-isopropyl-4-oxazolyl]acetic acid are thereby obtained. Yield: 83.3%.
Reaction SMILES: CO[CH:3]=[C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7](=[O:14])[NH:6][C:5]1=[O:15].[OH:16][C:17]1[CH:18]=[C:19]([CH:21]=[CH:22][C:23]=1[OH:24])[NH2:20]>CN(C)C=O>[OH:16][C:17]1[CH:18]=[C:19]([NH:20][CH:3]=[C:4]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:14])[NH:6][C:5]2=[O:15])[CH:21]=[CH:22][C:23]=1[OH:24]
Reactant: COC=C1C(=O)NC(=O)c2ccccc21
Reactant: Nc1ccc(O)c(O)c1
Solvent: CN(C)C=O
Product: O=C1NC(=O)c2ccccc2C1=CNc1ccc(O)c(O)c1
Temperature: 115 °C
Reaction time: 1.5 h
Yield: 26.3 %

Procedure:
To a suspension of 4-Methoxymethylene-4H-isoquinoline-1,3-dione (40.6 mg, 0.2 mmol) in N,N-dimethylformamide (0.5 mL) is added 3,4-dihydroxyaniline (25 mg, 0.2 mmol). The reaction mixture is shaken at 115° C. for 1.5 hours. The reaction mixture is diluted to 2 mL with N,N-dimethylformamide and purified by C18 reverse phase HPLC. The pure fractions were combined and concentrated to yield the title compound (15.6 mg).
Reaction SMILES: [C:1]([C:5]1[C:6](=[O:16])[C:7](=O)[CH:8]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[NH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[SH:24]>CCOCC>[C:1]([C:5]1[C:6](=[O:16])[C:7]2[C:8](=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:10]=1)[S:24][C:19]1[C:18](=[CH:23][CH:22]=[CH:21][CH:20]=1)[N:17]=2)([CH3:4])([CH3:3])[CH3:2]
Reactant: Nc1ccccc1S
Reactant: CC(C)(C)C1=CC(=O)C(=O)C(C(C)(C)C)=C1
Solvent: CCOCC
Product: CC(C)(C)c1cc(C(C)(C)C)c(=O)c2nc3ccccc3sc1-2
Reaction time: 1 h

Procedure:
To a solution of 4.4 gm of 3,5-di-t-butyl-1,2-benzoquinone in 20 ml of ether was added a solution of 1.25 g of 2-aminothiophenol in 5 ml of ether. After stirring for 1 hour at 25°, the reaction mixture was evaporated. The residue was purified by flash chromatography on silica gel using 2% ethyl acetate in benzene as eluent. There was thus obtained 860 mg of the title compound as dark blue plates, m.p. 137°-141°.
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][C:3]=1[O:4][C@@H:5]([CH3:10])[C:6]([O:8][CH3:9])=[O:7].C1C(=O)N([Br:23])C(=O)C1.CC(N=NC(C#N)(C)C)(C#N)C>C(Cl)(Cl)(Cl)Cl>[Br:23][CH2:15][C:12]1[CH:13]=[CH:14][C:2]([Cl:1])=[C:3]([CH:11]=1)[O:4][C@@H:5]([CH3:10])[C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)[C@H](C)Oc1cc(C)ccc1Cl
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)[C@H](C)Oc1cc(CBr)ccc1Cl

Procedure:
To (S)-methyl 2-(2-chloro-5-methylphenoxy)propanoate (2.4 g, 10.5 mmol) in CCl4 (20 mL) was added NBS (1.92 g, 11.55 mmol) and AIBN (0.35 g, 2.1 mmol). The mixture was refluxed overnight. The reaction mixture was cooled and the solvent was removed to obtain the crude. The crude was purified by flash chromatography (AcOEt/Hexane 0˜30%) to obtain the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1Cl)=[CH:13][CH:12]=[CH:11][C:10]=2[O:17][CH3:18])=[O:5])[CH3:2].[NH2:19][C:20]1[CH:27]=[CH:26][C:23]([CH:24]=[O:25])=[CH:22][CH:21]=1.Cl>CN(C=O)C>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:19][C:20]1[CH:27]=[CH:26][C:23]([CH:24]=[O:25])=[CH:22][CH:21]=1)=[CH:13][CH:12]=[CH:11][C:10]=2[O:17][CH3:18])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cnc2c(OC)cccc2c1Cl
Reactant: Nc1ccc(C=O)cc1
Agent: Cl
Solvent: CN(C)C=O
Product: CCOC(=O)c1cnc2c(OC)cccc2c1Nc1ccc(C=O)cc1
Temperature: 90 °C
Yield: 57 %

Procedure:
4-Chloro-8-methoxy-3-quinolinecarboxylic acid ethyl ester (10.62 g, 40 mmol) and 4-aminobenzaldehyde (4.85 g, 40 mmol) were suspended in dry DMF (100 mL) and treated dropwise with concentrated HCl (aq) (3.3. mL, 40 mmol). The mixture was heated at 90° C. for 40 min. After dilution with methylene chloride (800 mL) the reaction mixture was extracted with 1N NaOH (200 mL) and water (3×200 mL) and the dried (MgSO4) organic phase evaporated to a yellow oil. Crystallization from a minimum amount of ether afforded 8.0 g (22.8 mmol), 57% yield) of the product as a light yellow solid: m.p. 108°-110° C. (dec): 1H NMR (Me2SO-d6, 400 MHz) δ 9.79 (s, 1 H), 9.70 (s, 1 H), 8.99 (s, 1 H), 7.75 (d, J=8.7 Hz, 2 H), 7.64 (d, J=7.9 Hz, 1 H), 7.52 (t, J=7.9 Hz, 1 H), 7.31 (d, J=7.9 Hz, 1 H), 7.01 (d, J=8.5 Hz, 2 H), 4.02 (q, J=7.1 Hz, 2 H), 3.99 (s, 3 H), 1.08 (t,J=7.1 Hz, 3 H); MS(EI), m/z (rel. intensity)=350 (M+, 100), 321(34), 275(68), 247(58), 218(35), 205(18), 190(21); IR(KBr) 3430, 3350, 2820, 2740, 1685, 1590, 1500, 1390, 1270, 1215, 1160, 1060, 1020, 770cm-1.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[N:8]1[CH2:12][CH2:11][CH2:10][C:9]1=[O:13].Br[CH2:15][C:16]1[C:21]([Cl:22])=[CH:20][C:19]([O:23][CH3:24])=[CH:18][C:17]=1[Cl:25]>>[Cl:22][C:21]1[CH:20]=[C:19]([O:23][CH3:24])[CH:18]=[C:17]([Cl:25])[C:16]=1[CH2:15][CH:10]1[CH2:11][CH2:12][N:8]([C@@H:3]2[CH2:4][CH2:5][CH2:6][CH2:7][C@@H:2]2[CH3:1])[C:9]1=[O:13]
Reactant: COc1cc(Cl)c(CBr)c(Cl)c1
Reactant: C[C@H]1CCCC[C@H]1N1CCCC1=O
Product: COc1cc(Cl)c(CC2CCN([C@@H]3CCCC[C@@H]3C)C2=O)c(Cl)c1
Yield: 63.1 %

Procedure:
Using the procedure to synthesize Example 1 and using reagents 1-(cis-2-methyl-cyclohexyl)-pyrrolidin-2-one (Preparation 32) (1.0 g, 5.52 mmol) and 2-(bromomethyl)-1,3-dichloro-5-methoxybenzene (1.24 g, 5.52 mmol) gives 1.29 g (63%) 3-(2,6-Dichloro-4-methoxybenzyl)-1-(cis-2-methylcyclohexyl)pyrrolidin-2-one as a white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@@H:14]([OH:15])[C:13](=[O:16])[NH:12][C:11]3[CH:17]=[CH:18][C:19]([CH3:21])=[CH:20][C:10]=3[S:9]2)=[CH:4][CH:3]=1.[CH2:22]([O:29][C:30]([N:32]([CH2:34][CH2:35]Cl)[CH3:33])=[O:31])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.[OH-].[K+]>CS(C)=O>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@@H:14]([OH:15])[C:13](=[O:16])[N:12]([CH2:35][CH2:34][N:32]([C:30]([O:29][CH2:22][C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)=[O:31])[CH3:33])[C:11]3[CH:17]=[CH:18][C:19]([CH3:21])=[CH:20][C:10]=3[S:9]2)=[CH:4][CH:3]=1
Reactant: Cc1ccc([C@@H]2Sc3cc(C)ccc3NC(=O)[C@@H]2O)cc1
Reactant: CN(CCCl)C(=O)OCc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: Cc1ccc([C@@H]2Sc3cc(C)ccc3N(CCN(C)C(=O)OCc3ccccc3)C(=O)[C@@H]2O)cc1
Yield: 80.8 %

Procedure:
A mixture of 5.96 g of (±)-cis-2-(4-methylphenyl)-3-hydroxy-8-methyl-2,3-dihydro-1,5-benzothiazepin-4(5H)-one, 5.89 g of 2-(N-benzyloxycarbonyl-N-methylamino)ethyl chloride, 1.68 g of potassium hydroxide and 85 ml of dimethylsulfoxide is treated in the same manner as described in Example 1-(1). The crude product thus obtained is purified by silica gel chromatography (solvent, benzene:ethyl acetate=9:1). 7.89 g of (±)-cis-2-(4-methylphenyl)-3-hydroxy-5-[2-(N-benzyloxycarbonyl-N-methylamino)ethyl]-8-methyl-2,3-dihydro-1,5-benzothiazepin-4(5H)-one are obtained as an oil.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[N:4][N:5]([CH3:7])[N:6]=1.[F:8][C:9]([F:23])([F:22])[C:10]1[CH:11]=[C:12]([CH:15]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:17]=1)[CH:13]=O>C1(C)C=CC=CC=1>[CH3:7][N:5]1[N:4]=[N:3][C:2]([N:1]=[CH:13][C:12]2[CH:15]=[C:16]([C:18]([F:20])([F:21])[F:19])[CH:17]=[C:10]([C:9]([F:8])([F:22])[F:23])[CH:11]=2)=[N:6]1
Reactant: Cn1nnc(N)n1
Reactant: O=Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Solvent: Cc1ccccc1
Product: Cn1nnc(N=Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)n1

Procedure:
A mixture 5-amino-2-methyltetrazole (5.00 g, 50 mmol) and 3,5-bis(trifluoromethyl)benzaldehyde (19.5 g, 81 mmol) in toluene (100 mL) is stirred and refluxed for 3 hours. The resulting mixture is concentrated to give crude 2-methyl-N-[3,5-bis(trifluoromethyl)phenylmethylene]-2H-tetrazole-5-amine.