Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([CH3:18])=[N:10][O:11][C:12]=2[CH2:13][C:14]([O:16][CH3:17])=[O:15])=[CH:4][CH:3]=1.[CH3:19][O:20]/[N:21]=[C:22](/[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)\[CH2:23][O:24][C:25]1[CH:30]=[CH:29][C:28]([CH2:31]O)=[CH:27][CH:26]=1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>O.C1(C)C=CC=CC=1>[CH3:19][O:20]/[N:21]=[C:22](/[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)\[CH2:23][O:24][C:25]1[CH:30]=[CH:29][C:28]([CH2:31][O:1][C:2]2[CH:3]=[CH:4][C:5]([C:8]3[C:9]([CH3:18])=[N:10][O:11][C:12]=3[CH2:13][C:14]([O:16][CH3:17])=[O:15])=[CH:6][CH:7]=2)=[CH:27][CH:26]=1
Reactant: CO/N=C(\COc1ccc(CO)cc1)c1ccccc1
Reactant: COC(=O)Cc1onc(C)c1-c1ccc(O)cc1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: O
Solvent: Cc1ccccc1
Product: CO/N=C(\COc1ccc(COc2ccc(-c3c(C)noc3CC(=O)OC)cc2)cc1)c1ccccc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 77.6 %

Procedure:
To a 50 mL two neck RB flask fitted with magnetic stirrer was charged with 15 mL of toluene. To the stirred solvent were added methyl [4-(4-hydroxyphenyl)-3-methyl-1,2-oxazol-5-yl]acetate (0.3 g, 1.21 mmol), (1Z)-2-[4-(hydroxymethyl)phenoxy]-1-phenylethanone O-methyloxime (0.33 g, 1.21 mmol) and tri-(n-butyl)phosphine (0.39 g, 1.94 mmol) under nitrogen atmosphere. The reaction mixture was cooled to 0° C. and 1,1′-(azodicarbonyl)-dipiperidine (0.49 g, 1.94 mmol) was added portion wise and stirred at room temperature for 2 h. After completion of the reaction, the reaction mixture was poured into water (20 mL) and extracted with ethyl acetate (25 mL). The organic layer was dried over anhydrous Na2SO4 and the solvent was removed under reduced pressure. The crude material was purified by silica gel column chromatography using ethyl acetate and petroleum ether as eluents. The product was obtained as colorless oil (0.47 g, yield: 77%). 1H NMR (300 MHz, CDCl3): δ 7.57-7.61 (m, 2H), 7.26-7.30 (m, 5H), 7.11-7.14 (d, 2H), 6.94-6.97 (d, 2H), 6.85-6.88 (d, 2H), 5.14 (s, 2H), 4.93 (s, 2H), 3.99 (s, 3H), 3.68 (s, 2H), 3.65 (s, 3H), 2.20 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][C:5]([CH2:6][CH2:7][N:8]=[C:9]=[O:10])=[CH:4][CH:3]=1.[CH3:13][NH:14][C:15]1[CH:16]=[C:17]([C:21]2[CH:26]=[CH:25][C:24]([CH2:27][CH2:28][C:29]([O:31][CH3:32])=[O:30])=[CH:23][CH:22]=2)[CH:18]=[CH:19][CH:20]=1.[Cl-].[NH4+]>O1CCCC1.C(N(CC)CC)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH2:7][NH:8][C:9](=[O:10])[N:14]([C:15]2[CH:16]=[C:17]([C:21]3[CH:26]=[CH:25][C:24]([CH2:27][CH2:28][C:29]([O:31][CH3:32])=[O:30])=[CH:23][CH:22]=3)[CH:18]=[CH:19][CH:20]=2)[CH3:13])=[CH:11][CH:12]=1
Reactant: O=C=NCCc1ccc(F)cc1
Reactant: CNc1cccc(-c2ccc(CCC(=O)OC)cc2)c1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)CCc1ccc(-c2cccc(N(C)C(=O)NCCc3ccc(F)cc3)c2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 55.3 %

Procedure:
340 μL (1.84 mmol, 2 eq) of 4-fluorophenethyl isocyanate are added to a solution of 250 mg (0.92 mmol, 1 eq) of methyl 3-(3′-methylaminobiphenyl-4-yl)propanoate in 8 mL of a 4/1 tetrahydrofuran/triethylamine mixture. The reaction mixture is stirred for 24 hours at room temperature. The reaction is stopped by addition of 10 mL of saturated ammonium chloride solution and then extracted with ethyl acetate. The organic phases are combined and dried over sodium sulfate. The solvents are evaporated off and the residue is then chromatographed on silica gel (70/30 heptane/ethyl acetate). 221 mg of methyl 3-(3′-{3-[2-(4-fluorophenyl)ethyl]-1-methylureido}biphenyl-4-yl)propanoate are obtained. Yield=55%
Reaction SMILES: [Cl-].[CH3:2][O:3]C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C([Li])CCC.[S:29]1[C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=2[C:33](=O)[CH2:32][CH2:31][CH2:30]1.Cl(O)(=O)(=O)=O>O1CCCC1.CCCCCC>[S:29]1[C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=2[CH:33]([CH:2]=[O:3])[CH2:32][CH2:31][CH2:30]1
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C1CCCSc2ccccc21
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: O=CC1CCCSc2ccccc21
Reaction time: 0.08 h
Yield: 58.3 %

Procedure:
A solution of 20.0 g of methoxymethyltriphenylphosphonium chloride in 60 ml of absolute tetrahydrofuran was treated dropwise at 20° C. under argon with 43 ml of 1.4N n-butyllithium in hexane. The mixture was stirred for 1/4 hour. Thereafter, the mixture was treated with 8.02 g of 3,4-dihydro-1-benzothiepin-5(2H)-one in a small amount of tetrahydrofuran. After 5 minutes, the cooling bath was removed and the reaction mixture was stirred at room temperature for an additional 11/2 hours. Thereafter, the reaction mixture was partitioned between petroleum ether and ethanol/water (8:2). The lighter phase was washed with water, dried over sodium sulfate and evaporated. There were obtained 11.8 g of crude product which were dissolved in 80 ml of tetrahydrofuran and treated under argon with 100 ml of 35% perchloric acid. The reaction mixture was stirred overnight, poured on to ice, extracted with ether, washed with 5% sodium carbonate solution, dried and evaporated. Chromatorgraphy on silica gel (petroleum ether/ethyl acetate 92:8) yielded 5.04 g of 2,3,4,5-tetrahydro-1-benzothiepine-5-carboxaldehyde as a colorless oil.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[O:10][C:9]([C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1)=[CH:8][C:7]2=O.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:30])=CC=1>C1(C)C=CC=CC=1>[CH3:19][O:18][C:15]1[CH:16]=[CH:17][C:12]([C:9]2[O:10][C:11]3[C:6]([C:7](=[S:30])[CH:8]=2)=[CH:5][CH:4]=[CH:3][C:2]=3[CH3:1])=[CH:13][CH:14]=1
Reactant: COc1ccc(-c2cc(=O)c3cccc(C)c3o2)cc1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: COc1ccc(-c2cc(=S)c3cccc(C)c3o2)cc1
Yield: 125.9 %

Procedure:
Compound I-23 was prepared according to the general method described above in Scheme 1. A stirred mixture of 8-methyl-4′-methoxyflavone (200.0 mg, 0.75 mmol), Lawesson's reagent (182.3 mg, 0.45 mmol) and anhydrous toluene (4.0 mL) was refluxed under N2 for 1.5 hr. The solvent was removed under vacuum and the residue was purified by silica gel chromatography (20% ethyl acetate/hexane) to give 2-(4-Methoxy-phenyl)-8-methyl-chromene-4-thione (160.0 mg, 75.5% yield) as a red solid. Thione was used in next step without further purification. LC/MS: (M+H) 283.1. LC/Method A/8.967 min, 90.0% purity by area %.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[O:3][C:4]1[CH:10]=[CH:9][C:7](N)=[CH:6][CH:5]=1.N([O-])=[O:14].[Na+]>OS(O)(=O)=O>[F:1][C:2]([F:12])([F:11])[O:3][C:4]1[CH:10]=[CH:9][C:7]([OH:14])=[CH:6][CH:5]=1
Reactant: O=N[O-]
Reactant: Nc1ccc(OC(F)(F)F)cc1
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: Oc1ccc(OC(F)(F)F)cc1
Temperature: 0 °C
Reaction time: 2.5 h
Yield: 70.2 %

Procedure:
p-Trifluoromethoxy aniline (49.60 g) was added rapidly dropwise to vigorously stirred 9N aqueous H2SO4 (500 mL) at 40° C. The mixture was heated to dissolve the solid, then cooled to 0° C. To the fine white suspension, a solution of sodium nitrite (19.46 g in 50 mL of H2O) was added portionwise until an immediate positive KI/starch test result was obtained. This cold solution of diazonium salt was added rapidly dropwise to 9N aqueous H2SO4 (500 mL) at 110° C. Stirring and heating was continued for 2.5 hours. The mixture was cooled to 10° C. and extracted with diethyl ether (3×500 mL). The combined organic layers were dried (MgSO4), filtered and evaporated in vacuo, then flash chromatographed on SiO2 using diethyl ether as eluant to give 35.0 g of the desired phenol as a light brown oil. The oil was distilled (b.p.=75°-80° C. at 20 torr.) to afford a yellow liquid.
Reaction SMILES: Br[C:2]1[C:3]([O:9][CH2:10][CH2:11][CH2:12][CH3:13])=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1.[F:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][C:16]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1>[CH2:10]([O:9][C:3]1[C:2]([C:16]2[CH:17]=[C:18]([C:21]([F:23])([F:24])[F:22])[CH:19]=[CH:20][C:15]=2[F:14])=[CH:7][C:6]([CH3:8])=[CH:5][N:4]=1)[CH2:11][CH2:12][CH3:13]
Reactant: OB(O)c1cc(C(F)(F)F)ccc1F
Reactant: CCCCOc1ncc(C)cc1Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCCCOc1ncc(C)cc1-c1cc(C(F)(F)F)ccc1F
Temperature: 90 °C
Reaction time: 18 h
Yield: 77.6 %

Procedure:
3-Bromo-2-butoxy-5-methyl-pyridine (0.96 g, 3.9 mmol) was dissolved in toluene (6 mL). To this solution was added [2-fluoro-5-(trifluoromethyl)phenyl]-boronic acid (1.2 g, 5.9 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloro-methane complex (161 mg), and 2 N sodium carbonate solution (5.9 mL). The whole mixture was heated with stirring at 90° C. for 18 h, cooled to room temperature and eluted with ethyl acetate over 10 g ChemElut (Varian). The solvent was evaporated and the residue was purified by column chromatography on silica (n-heptane/ethyl acetate gradient) to yield 0.99 g of the title compound as a yellow oil, MS (ISP) 328.3 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[N:10]([CH2:19][CH2:20][O:21][CH3:22])[C:11](=[O:18])[C:12]([C:15]([OH:17])=O)=[CH:13][N:14]=2)[CH:5]=[C:6]([F:8])[CH:7]=1.C(Cl)(=O)C(Cl)=O.[CH:29]12[CH2:36][CH:33]([CH2:34][CH2:35]1)[C:32](=[O:37])[CH2:31][C:30]2=[O:38].C(N(CC)CC)C.OC(C)(C)C#N>ClCCl.CN(C)C=O>[F:8][C:6]1[CH:5]=[C:4]([C:9]2[N:10]([CH2:19][CH2:20][O:21][CH3:22])[C:11](=[O:18])[C:12]([C:15]([C:31]3[C:32](=[O:37])[CH:33]4[CH2:36][CH:29]([CH2:35][CH2:34]4)[C:30]=3[OH:38])=[O:17])=[CH:13][N:14]=2)[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: COCCn1c(-c2cc(F)cc(F)c2)ncc(C(=O)O)c1=O
Reactant: O=C1CC(=O)C2CCC1C2
Agent: CC(C)(O)C#N
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COCCn1c(-c2cc(F)cc(F)c2)ncc(C(=O)C2=C(O)C3CCC(C3)C2=O)c1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 2-(3,5-difluorophenyl)-1,6-dihydro-1-(2-methoxyethyl)-6-oxo-5-pyrimidinecarboxylic acid (i.e. the product from Example 9, Step D) (0.25 g, 0.81 mmol) in 10 mL of dichloromethane was added oxalyl chloride (0.21 g, 1.6 mmol) and one drop of N,N-dimethylformamide. The reaction mixture was stirred at room temperature for 2 h and then concentrated under reduced pressure. The remaining crude oil was re-dissolved in dichloromethane (10 mL) and then treated with bicyclo[3.2.1]octane-2,4-dione (0.12 g, 0.88 mmol) (prepared according to U.S. Pat. No. 6,815,563) and triethylamine (0.16 g, 1.6 mmol). After 30 min at room temperature, a catalytic amount of 2-hydroxy-2-methyl-propanenitrile (0.0075 g, 0.088 mmol) and triethylamine (0.16 g, 1.6 mmol) were added and the reaction mixture was stirred at ambient temperature over night. The reaction mixture was then concentrated under reduced pressure and purified by medium pressure liquid chromatography on silica gel eluting with 0 to 10% methanol in chloroform to provide 0.180 g of the title compound (also known as 3-[[2-(3,5-difluorophenyl)-1,6-dihydro-1-(2-methoxyethyl)-6-oxo-5-pyrimidinyl]carbonyl]biciclo[3.2.1]octane-2,4-dione), a compound of the present invention, as a solid.
Reaction SMILES: CS(O[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:38])[C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[C:17]([NH:22][C:23]([C:25]3[C:29]4[N:30]=[CH:31][N:32]=[C:33]([NH:34][CH:35]5[CH2:37][CH2:36]5)[C:28]=4[S:27][CH:26]=3)=[O:24])[CH:16]=2)=[CH:9][C:8]=1[C:39]([F:42])([F:41])[F:40])(=O)=O.C([O-])([O-])=O.[K+].[K+].[CH3:49][C:50]1[N:51]=[CH:52][NH:53][CH:54]=1>CN(C=O)C.C(OCC)(=O)C>[CH:35]1([NH:34][C:33]2[C:28]3[S:27][CH:26]=[C:25]([C:23]([NH:22][C:17]4[CH:16]=[C:15]([C:14](=[O:38])[NH:13][C:10]5[CH:11]=[CH:12][C:7]([CH2:6][N:53]6[CH:54]=[C:50]([CH3:49])[N:51]=[CH:52]6)=[C:8]([C:39]([F:42])([F:40])[F:41])[CH:9]=5)[CH:20]=[CH:19][C:18]=4[CH3:21])=[O:24])[C:29]=3[N:30]=[CH:31][N:32]=2)[CH2:36][CH2:37]1
Reactant: Cc1ccc(C(=O)Nc2ccc(COS(C)(=O)=O)c(C(F)(F)F)c2)cc1NC(=O)c1csc2c(NC3CC3)ncnc12
Reactant: Cc1c[nH]cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1cn(Cc2ccc(NC(=O)c3ccc(C)c(NC(=O)c4csc5c(NC6CC6)ncnc45)c3)cc2C(F)(F)F)cn1
Temperature: 25 °C
Reaction time: 18 h
Yield: 79.1 %

Procedure:
4-(3-(4-(Cyclopropylamino)thieno[3,2-d]pyrimidine-7-carboxamido)-4-methylbenzamido)-2-(trifluoromethyl)benzyl methanesulfonate (30 mg, 0.048 mmol) was dissolved in DMF (1 mL), K2CO3 (20 mg, 0.145 mmol) and 4-methyl-1H-imidazole (20 mg, 0.242 mmol) were added thereto and stirred at room temperature for 18 hours. The reaction mixture was diluted with ethyl acetate (10 mL) and washed with brine. The organic layer was dried with MgSO4, filtered and concentrated under reduced pressure. The resulting mixture was purified by silica gel chromatography (MeOH/DCM=5/95) to obtain the title compound (23 mg, 78% yield).
Reaction SMILES: F[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:8]([C:12]([F:15])([F:14])[F:13])[O:9]2)=[CH:4][CH:3]=1.[CH3:21][C:22]([CH3:27])([CH3:26])[CH2:23]CN.C([O-])([O-])=O.[K+].[K+].C[N:35](C=O)C>>[CH2:23]([NH:35][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:8]([C:12]([F:15])([F:14])[F:13])[O:9]2)=[CH:4][CH:3]=1)[C:22]([CH3:26])([CH3:21])[CH3:27]
Reactant: CC(C)(C)CCN
Reactant: CN(C)C=O
Reactant: CCOC(=O)C1=Cc2ccc(F)cc2OC1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCOC(=O)C1=Cc2ccc(NCC(C)(C)C)cc2OC1C(F)(F)F
Temperature: 90 °C

Procedure:
A mixture of ethyl 7-fluoro-2-(trifluoromethyl)-2H-chromene-3-carboxylate (Example 612a, Step 2) (0.45 g, 1.54 mmole) and 3,3-dimethylbutylamine (0.13 g, 1.54 mmole) was dissolved in anhydrous DMF (5 mL), warmed to 90° C. and treated with K2CO3 (0.25 g, 1.84 mmole). The mixture was maintained at 90° C. for 24 hrs, cooled to room temperature, filtered through celite and condensed to a viscous oil (0.55g, 98%). No further purification was performed. LCMS m/z 358.00 (M+H).
Reaction SMILES: OC(C)CC(OCC)=O.[N:10]([CH2:13][CH:14]([OH:21])[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[N+:11]=[N-:12]>>[N:10]([CH2:13][C@@H:14]([OH:21])[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[N+:11]=[N-:12]
Reactant: CCOC(=O)CC(O)CN=[N+]=[N-]
Agent: CCOC(=O)CC(C)O
Product: CCOC(=O)C[C@H](O)CN=[N+]=[N-]
Reaction time: 1 h
Yield: 80.2 %

Procedure:
Instead of ethyl 3-hydroxybutyrate used in Example 1, ethyl 4-azido-3-hydroxybutyrate was used. The reaction was carried out for 1 hour and ethyl (S)-4-azido-3-hydroxybutyrate (80.2% e.e) was obtained at 83.5% conversion.
Reaction SMILES: [C:1]1([N:7]([CH2:14][CH:15]2[C:24]3[C:19](=[CH:20][C:21]([O:27]C)=[C:22]([O:25]C)[CH:23]=3)[CH2:18][CH2:17][NH:16]2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.B(Br)(Br)[Br:30]>ClCCl>[BrH:30].[C:1]1([N:7]([CH2:14][CH:15]2[C:24]3[C:19](=[CH:20][C:21]([OH:27])=[C:22]([OH:25])[CH:23]=3)[CH2:18][CH2:17][NH:16]2)[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COc1cc2c(cc1OC)C(CN(c1ccccc1)c1ccccc1)NCC2
Reactant: BrB(Br)Br
Solvent: ClCCl
Product: Br
Product: Oc1cc2c(cc1O)C(CN(c1ccccc1)c1ccccc1)NCC2
Reaction time: 19 h
Yield: 76.1 %

Procedure:
To a solution of 1-(N,N-diphenylaminomethyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline (0.38 g) in anhydrous dichloromethane (15 ml) was dropwise added a solution of boron tribromide (0.75 g) in anhydrous dichloromethane (5 ml) at -60° C. with stirring. The mixture was stirred for 2.5 hours at the same temperature and the reaction temperature was elevated to ambient temperature over 19 hours. Dichloromethane was removed and to the residue were added methanol and a small amount of water. The mixture was warmed and concentrated to dryness. The residue was crystallized with a mixture of acetone and ether and the crystals were collected by filtration to give 1-(N,N-diphenylaminomethyl)-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline hydrobromide (0.33 g).
Reaction SMILES: N(C(OC(C)C)=O)=NC(OC(C)C)=O.[CH:15]1([C@@:20]([OH:30])([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:21]([OH:23])=[O:22])[CH2:19][CH2:18][CH2:17][CH2:16]1.[C:31]([O:35][C:36]([N:38]1[CH2:42][CH2:41][C@@H:40](O)[CH2:39]1)=[O:37])([CH3:34])([CH3:33])[CH3:32].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[C:31]([O:35][C:36]([N:38]1[CH2:42][CH2:41][CH:40]([O:22][C:21](=[O:23])[C@:20]([CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)([OH:30])[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH2:39]1)=[O:37])([CH3:34])([CH3:32])[CH3:33]
Reactant: O=C(O)[C@](O)(c1ccccc1)C1CCCC1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](O)C1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(OC(=O)[C@](O)(c2ccccc2)C2CCCC2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
At room temperature, diisopropyl azodicarboxylate (980 μl, 5 mmol) was slowly added to a mixture of (R)-cyclopentylhydroxyphenylacetic acid (1.1 g, 5 mmol), (R)-3-hydroxypyrrolidine-1-carboxylic acid t-butyl ester (1.0 g, 5.5 mmol), and triphenyl-phosphine (1.3 g, 5 mmol) in 10 ml of THF. The reaction mixture was then stirred at room temperature overnight.
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[C:4]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[CH:3]=1.[OH:24][C:25]1[CH:34]=[C:33]2[C:28]([CH:29]=[CH:30][CH:31]=[N:32]2)=[CH:27][CH:26]=1.[H-].[Na+]>CN(C=O)C>[C:8]1([C:5]2[N:6]=[N:7][C:2]([O:24][C:25]3[CH:34]=[C:33]4[C:28]([CH:29]=[CH:30][CH:31]=[N:32]4)=[CH:27][CH:26]=3)=[CH:3][C:4]=2[C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: FC(F)(F)c1ccc(-c2cc(Cl)nnc2-c2ccccc2)cc1
Reactant: Oc1ccc2cccnc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: FC(F)(F)c1ccc(-c2cc(Oc3ccc4cccnc4c3)nnc2-c2ccccc2)cc1
Temperature: 50 °C
Reaction time: 15 h

Procedure:
To a solution of 6-chloro-3-phenyl-4-(4-trifluoromethyl-phenyl)-pyridazine, (Example 13 (e)), (106 mg, 0.3 mmol) and 7-hydroxyquinoline (55 mg, 0.4 mmol, Acros) in DMF (2.5 mL) was added NaH (22 mg, 0.6 mmol, 60% suspension in mineral oil, Aldrich) and the mixture was stired at room temperature for 15 h. The reaction mixture was then heated at 50° C. for another 28 h, allowed to cool to room temperature and the solvent removed in vacuum. The residue was partitioned between EtOAc/H2O and the aqueous layer was extracted with EtOAc. The combined organic layers were evaporated onto SiO2 and purified by flash silica gel chromatography with EtOAc/hexanes (0:1→3:7) as eluant to give the title compound as an off-white amorphous solid. Mp: 178–183° C. MS (ESI, pos ion.) m/z: 444 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:56])[NH:4][CH:5]([C:9]([N:11]1[CH:17]([C:18]2[NH:19][C:20]([C:23]3[CH:28]=[CH:27][C:26]([C:29]4[CH:34]=[CH:33][C:32]([C:35]5[NH:36][C:37]([CH:40]6[CH2:44][CH2:43][CH2:42][N:41]6[C:45](=[O:55])[CH:46]([NH:50][C:51]([O:53][CH3:54])=[O:52])[CH:47]([CH3:49])[CH3:48])=[N:38][CH:39]=5)=[CH:31][CH:30]=4)=[CH:25][CH:24]=3)=[CH:21][N:22]=2)C[C:13]2(CC2)[CH2:12]1)=[O:10])[CH:6]([CH3:8])[CH3:7].[S:57]1CCNC1>>[CH3:1][O:2][C:3](=[O:56])[NH:4][CH:5]([C:9]([N:11]1[CH2:12][CH2:13][S:57][CH:17]1[C:18]1[NH:19][C:20]([C:23]2[CH:28]=[CH:27][C:26]([C:29]3[CH:34]=[CH:33][C:32]([C:35]4[NH:36][C:37]([CH:40]5[CH2:44][CH2:43][CH2:42][N:41]5[C:45](=[O:55])[CH:46]([NH:50][C:51]([O:53][CH3:54])=[O:52])[CH:47]([CH3:49])[CH3:48])=[N:38][CH:39]=4)=[CH:31][CH:30]=3)=[CH:25][CH:24]=2)=[CH:21][N:22]=1)=[O:10])[CH:6]([CH3:8])[CH3:7]
Reactant: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc(-c3ccc(-c4cnc(C5CC6(CC6)CN5C(=O)C(NC(=O)OC)C(C)C)[nH]4)cc3)cc2)[nH]1)C(C)C
Reactant: C1CSCN1
Product: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc(-c3ccc(-c4cnc(C5SCCN5C(=O)C(NC(=O)OC)C(C)C)[nH]4)cc3)cc2)[nH]1)C(C)C

Procedure:
(Example DX) was prepared in a similar fashion to (1-{6-[5-(4′-{2-[1-(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-biphenyl-4-yl)-1H-imidazol-2-yl]-5-aza-spiro[2.4]heptane-5-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (Example DW), replacing the cyclopropyl proline carboxylic acid with the corresponding thiazolidine derivative.
Reaction SMILES: Br.C1(C)C=C(C)C=C(C)C=1S([N:13]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][NH2:25])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][NH2:19])(=O)=O.C1(O)C=CC=CC=1.C(Cl)(Cl)[Cl:35]>>[ClH:35].[ClH:35].[ClH:35].[NH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][NH:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][NH2:19]
Reactant: Cc1cc(C)c(S(=O)(=O)N(CCCCCN)CCCCCN)c(C)c1
Reactant: ClC(Cl)Cl
Agent: Br
Solvent: Oc1ccccc1
Product: Cl
Product: NCCCCCNCCCCCN

Procedure:
HBr (30% in HOAc, 26 mL), 42 (2.0 g, 5.42 mmol), and phenol (4.8 g, 51 mmol) in CHCl3 (40 mL) were reacted, and product was isolated by the method of 2 to give 0.97 (61%) of 24 as a white solid: NMR (D2O) δ 1.45 (m, 4 H), 1.70 (m, 8 H), 3.01 (m, 8 H). Anal. (C10H28Cl3N3) C, H, N.
Reaction SMILES: Cl[C:2]1[O:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[N:11]1([C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:18])[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[CH2:20]([O:19][C:17]([N:11]1[CH2:16][CH2:15][N:14]([C:2]2[O:3][C:4]3[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=3[N:6]=2)[CH2:13][CH2:12]1)=[O:18])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=C(OCc1ccccc1)N1CCNCC1
Reactant: Clc1nc2ccccc2o1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(OCc1ccccc1)N1CCN(c2nc3ccccc3o2)CC1
Temperature: 100 °C
Reaction time: 8 h
Yield: 77.4 %

Procedure:
A mixture of 2-chlorobenzoxazole (1.00 g, 6.51 mmol), benzyl 1-piperazinecarboxylate (1.43 g, 6.51 mmol), and K2CO3 (1.80 g, 13.0 mmol) in DMF (13 mL) was stirred at 100° C. overnight, cooled, diluted with water, and extracted with EtOAc. The extracts were combined, washed with water and brine, dried over Na2SO4 and concentrated in vacuo to provide the title compound (1.70 g, 77%), characterized by NMR and mass spectral analyses.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH:16]([C:17]([OH:19])=[O:18])[CH2:15][CH2:14][CH2:13][CH:12]1[C:20]([OH:22])=[O:21])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:23][O:24][C:25]1[CH:33]=[CH:32][CH:31]=[CH:30][C:26]=1[CH2:27][CH2:28][NH2:29].C(OC(=O)C)(=O)C>O1CCOCC1>[CH2:1]([O:8][C:9]([N:11]1[CH:16]2[CH2:15][CH2:14][CH2:13][CH:12]1[C:20](=[O:21])[O:18][C:17]2=[O:19])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1.[CH2:1]([O:8][C:9]([N:11]1[CH:12]2[CH2:13][CH2:14][CH2:15][CH:16]1[C:17](=[O:19])[N:29]([CH2:28][CH2:27][C:26]1[CH:30]=[CH:31][CH:32]=[CH:33][C:25]=1[O:24][CH3:23])[C:20]2=[O:22])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)C1CCCC(C(=O)O)N1C(=O)OCc1ccccc1
Reactant: COc1ccccc1CCN
Solvent: C1COCCO1
Solvent: CC(=O)OC(C)=O
Product: COc1ccccc1CCN1C(=O)C2CCCC(C1=O)N2C(=O)OCc1ccccc1
Product: O=C1OC(=O)C2CCCC1N2C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 90 %

Procedure:
2,4-Dioxo-3-oxa-9-aza-bicyclo[3.3.1]nonane-9-carboxylic acid benzyl ester (Compound 2, 1.00 g, 3.45 mmol), which was prepared from Compound 1, was dissolved in dioxane (1 mL), and 2-methoxyphenethylamine (0.50 mL, 3.45 mmol) was added from the top. The mixture was stirred at room temperature for 1 hour. After this time, acetic anhydride (0.65 mL, 6.9 mmol) was added, and the reaction was refluxed for 5 hours. Flash chromatographic purification of the residue (20% EtOAc/hexanes) gave Compound 8 (1.23 g, 90% yield) as a clear oil. Rf=0.75 (50% EtOAc/hexanes), 0.66; 1H NMR: δ 1.75-2.05 (m, 6H), 2.84-2.89 (m, 2H), 3.83 (s, 3H), 4.04-4.10 (m, 2H), 4.90 (brs, 2H), 5.16 (s, 2H), 6.78-6.83 (m, 2H), 7.05 (dd, 1H, J=7.5, 1.6), 7.13-7.20 (m, 1H), 7.33-7.41 (m, 5H).