Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+].[F:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH:10]1[C:14](=[O:15])[C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([O:24][CH3:25])=[O:23])[CH:17]=2)=[C:12]([NH:26][CH3:27])[O:11]1.[CH2:28](Br)[CH:29]=C>O.C(Cl)Cl.[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1>[F:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH:10]1[C:14](=[O:15])[C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([O:24][CH3:25])=[O:23])[CH:17]=2)=[C:12]([NH:26][CH2:27][CH:28]=[CH2:29])[O:11]1
Reactant: C=CCBr
Reactant: CNC1=C(c2cccc(C(=O)OC)c2)C(=O)C(c2ccccc2F)O1
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: C=CCNC1=C(c2cccc(C(=O)OC)c2)C(=O)C(c2ccccc2F)O1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
One gram of sodium hydroxide in 4.0 ml of water is added to a mixture of 4.0 g of 2-(2-fluorophenyl)-3-oxo-4-(3-methoxycarbonylphenyl)-5-methylamino-2,3-dihydrofuran in 80 ml of methylene chloride at room temperature followed by the addition of 1.48 g of allyl bromide and 0.27 g of benzyltriethylammonium chloride. This will result in a two-phase mixture. This mixture is stirred at room temperature for about 18 hours and this is washed with water, dried over magnesium sulfate and concentrated in vacuo. The residue is purified by chromatography over silica gel eluting with chloroform to yield the title compound.
Reaction SMILES: [Mg].Br[C:3]1[CH:11]=[CH:10][C:6]2[O:7][CH2:8][O:9][C:5]=2[CH:4]=1.[CH2:12]1[O:15][C@H:13]1[CH3:14]>O1CCCC1.CCOCC.[Cu]I>[CH3:12][C@H:13]([OH:15])[CH2:14][C:3]1[CH:11]=[CH:10][C:6]2[O:7][CH2:8][O:9][C:5]=2[CH:4]=1
Reactant: C[C@H]1CO1
Reactant: Brc1ccc2c(c1)OCO2
Agent: [Cu]I
Agent: [Mg]
Solvent: C1CCOC1
Solvent: CCOCC
Product: C[C@H](O)Cc1ccc2c(c1)OCO2
Temperature: -50 °C
Reaction time: 8 h
Yield: 91 %

Procedure:
To a suspension of magnesium turnings (17 g) in 50 mL tetrahydrofuran was added dropwise a solution of 5-bromo-1,3-benzodioxole (93.6 g). After complete addition, the mixture was diluted with 250 mL tetrahydrofuran and the resulting mixture was stirred overnight. 13 mL of the solution (0.78 M) was transferred to a round bottom flask containing copper(I) iodide (0.12 g). The resulting mixture was cooled to -50° C. and a solution of (S)-(-)-propylene oxide in 3 mL tetrahydrofuran was slowly added then stirred 10 min. The mixture was diluted with ether. The isolated organic phase was washed with water and brine. The aqueous wash was extracted with ether (2×) and the combined organic solutions were dried over magnesium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (50% ether in pentane) to give 1.66 g of the desired product (91%). Chiral HPLC analysis indicated that the optical purity of the material was 98.3%.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH2:10].CN(C)C=O.[H-].[Na+].Cl[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=1>O.CC1C=CC=CC=1>[F:26][C:22]1[CH:21]=[C:20]([CH2:19][N:1]2[C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[N:3]=[C:2]2[NH2:10])[CH:25]=[CH:24][CH:23]=1
Reactant: Fc1cccc(CCl)c1
Reactant: Nc1nc2ccccc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: Nc1nc2ccccc2n1Cc1cccc(F)c1
Temperature: 40 °C
Reaction time: 0.5 h

Procedure:
To a stirred and heated (60° C.) solution of 41.3 parts of 1H-benzimidazol-2-amine in 162 parts of N,N-dimethylformamide (DMF) were added portionwise during a 40 minutes period 12 parts of sodium hydride dispersion 60%. Upon completion, stirring at 60° C. was continued for 30 minutes. After cooling to 40° C., there was added dropwise during 25 minutes a solution of 50 parts of 1-(chloromethyl)-3-fluorobenzene in 9 parts of DMF and 36 parts of methylbenzene. After the addition was complete, the whole was stirred for 1.50 hours at 50°-65° C. The reaction mixture was cooled and water was added. The solid product was filtered off and crystallized from a mixture of 2,2'-oxybispropane, tetrahydrofuran and methanol. The product was filtered off and recrystallized from methylbenzene, yielding 34.8 parts of 1-[(3-fluorophenyl)methyl]-1H-benzimidazol-2-amine; mp. 188.1° C. (1).
Reaction SMILES: [CH:1]1([C:4]2[N:9]=[C:8]([C:10]3[NH:28][C:13]4=[N:14][C:15]([N:18]5[CH2:23][CH2:22][CH2:21][C@@H:20]([C:24]([O:26]C)=[O:25])[CH2:19]5)=[CH:16][CH:17]=[C:12]4[N:11]=3)[CH:7]=[CH:6][N:5]=2)[CH2:3][CH2:2]1.[OH-].[Na+]>C(O)C>[CH:1]1([C:4]2[N:9]=[C:8]([C:10]3[NH:28][C:13]4=[N:14][C:15]([N:18]5[CH2:23][CH2:22][CH2:21][C@@H:20]([C:24]([OH:26])=[O:25])[CH2:19]5)=[CH:16][CH:17]=[C:12]4[N:11]=3)[CH:7]=[CH:6][N:5]=2)[CH2:3][CH2:2]1
Reactant: COC(=O)[C@@H]1CCCN(c2ccc3nc(-c4ccnc(C5CC5)n4)[nH]c3n2)C1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)[C@@H]1CCCN(c2ccc3nc(-c4ccnc(C5CC5)n4)[nH]c3n2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 83.2 %

Procedure:
To a solution of (R)-methyl 1-(2-(2-cyclopropylpyrimidin-4-yl)-3H-imidazo[4,5-b]pyridin-5-yl)piperidine-3-carboxylate (250 mg, 0.66 mmol) in ethanol (10 mL), was added an aqueous solution of sodium hydroxide (1N, 5 mL). The reaction mixture was stirred at room temperature for 2 h. The solvent was distilled off and the residue was partitioned between water and ethyl acetate. The aqueous layer was acidified with aqueous hydrochloric acid (10%) to pH˜2. The resulting precipitate was collected by filtration and dried under vacuum to afford (R)-1-(2-(2-cyclopropylpyrimidin-4-yl)-3H-imidazo[4,5-b]pyridin-5-yl)piperidine-3-carboxylic acid (200 mg). MS (ES+APCI) (M+H) 365.2
Reaction SMILES: [N+]([C:4]1[CH:9]=[CH:8][N+:7]([O-:10])=[C:6]([CH2:11][CH2:12][CH3:13])[CH:5]=1)([O-])=O.[CH3:14][O-:15].[Na+]>CO>[CH3:14][O:15][C:4]1[CH:9]=[CH:8][N+:7]([O-:10])=[C:6]([CH2:11][CH2:12][CH3:13])[CH:5]=1
Reactant: C[O-]
Reactant: CCCc1cc([N+](=O)[O-])cc[n+]1[O-]
Agent: [Na+]
Solvent: CO
Product: CCCc1cc(OC)cc[n+]1[O-]
Reaction time: 3 h
Yield: 97 %

Procedure:
A solution of 4-nitro-2-n-propylpyridine-N-oxide (146.0 g, 0.8 mol) in 500 ml of anhydrous methanol was stirred and 190 ml of a 4.6 M methanolic sodium methoxide solution was added dropwise. When the addition was complete, the mixture was stirred for three hours. The precipitated sodium nitrite was filtered off and washed with methanol. The filtrate was evaporated and the residue was stirred with 300 ml of dichloromethane. The mixture was filtered and evaporated to afford 129 g (97%) of 4-methoxy-2-n-propylpyridine-N-oxide as an oil. 1H-NMR (CDCl3, 200 MHz) δ: 1.07 (t, 3H), 1.80 (sext, 2H), 2.80 (t, 2H), 3.87 (s, 3H), 6.66-6.78 (m, 2H), 8.17 (d, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]([NH:14][CH2:15][C@@H:16]3[CH2:20][CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17]3)[N:11]3[C:28](=[O:32])[N:29]([CH3:31])[N:30]=[C:10]3[C:9]=2[C:33]2[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][CH:34]=2)=[CH:4][CH:3]=1>C(O)(C(F)(F)F)=O.C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:13]=[C:12]([NH:14][CH2:15][C@@H:16]3[CH2:20][CH2:19][NH:18][CH2:17]3)[N:11]3[C:28](=[O:32])[N:29]([CH3:31])[N:30]=[C:10]3[C:9]=2[C:33]2[CH:34]=[CH:35][C:36]([Cl:39])=[CH:37][CH:38]=2)=[CH:6][CH:7]=1
Reactant: Cn1nc2c(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3)nc(NC[C@@H]3CCN(C(=O)OC(C)(C)C)C3)n2c1=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cn1nc2c(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3)nc(NC[C@@H]3CCNC3)n2c1=O
Temperature: 25 °C

Procedure:
A solution of (S)-tert-butyl 3-((7,8-bis(4-chlorophenyl)-2-methyl-3-oxo-2,3-dihydro-[1,2,4]triazolo[4,3-c]pyrimidin-5-ylamino)methyl)pyrrolidine-1-carboxylate (85 mg, 0.15 mmol) in a mixture of TFA (0.1 mL) and CH2Cl2 (0.5 mL) was stirred at room temperature until HPLC/MS indicated complete conversion to the title compound. The reaction mixture was then partitioned between EtOAc and saturated aqueous sodium bicarbonate solution. The organic phase was separated, dried, and evaporated. The residue was purified by preparative reverse phase HPLC (without TFA) to obtain the title compound as a pale yellow solid. HPLC/MS: retention time 3.475 min, [M+H]30 =469.
Reaction SMILES: [OH:1][C:2]1[C:3]([C:12]([O:14][CH2:15][CH2:16][CH3:17])=[O:13])=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[CH2:18]([O:25][C:26]1[CH:35]=[C:34]2[C:29]([C:30](Cl)=[CH:31][CH:32]=[N:33]2)=[CH:28][C:27]=1[O:37][CH3:38])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.O>CN(C)C1C=CN=CC=1.ClC1C=CC=CC=1Cl>[CH2:18]([O:25][C:26]1[CH:35]=[C:34]2[C:29]([C:30]([O:1][C:2]3[C:3]([C:12]([O:14][CH2:15][CH2:16][CH3:17])=[O:13])=[CH:4][C:5]4[C:10]([CH:11]=3)=[CH:9][CH:8]=[CH:7][CH:6]=4)=[CH:31][CH:32]=[N:33]2)=[CH:28][C:27]=1[O:37][CH3:38])[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: COc1cc2c(Cl)ccnc2cc1OCc1ccccc1
Reactant: CCCOC(=O)c1cc2ccccc2cc1O
Agent: CN(C)c1ccncc1
Solvent: Clc1ccccc1Cl
Solvent: O
Product: CCCOC(=O)c1cc2ccccc2cc1Oc1ccnc2cc(OCc3ccccc3)c(OC)cc12
Temperature: 120 °C
Reaction time: 5 h
Yield: 50.1 %

Procedure:
Propyl 3-hydroxy-naphthalene-2-carboxylate (460 mg), 7-benzyloxy-4-chloro-6-methoxyquinoline (200 mg), and 4-dimethylaminopyridine (244 mg) were suspended in o-dichlorobenzene (4 ml), and the mixture was stirred at 120° C. for 5 hr. The reaction solution was cooled to room temperature, water was then added to the reaction solution, and the mixture was extracted with chloroform. The chloroform layer was washed with saturated brine and was dried over anhydrous sodium sulfate, the solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using chloroform-acetone to give propyl 3-(7-benzyloxy-6-methoxy-quinolin-4-yloxy)-naphthalene-2-carboxylate (165 mg, yield 50%).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3](=[O:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[H-].[Na+].F[C:16]1[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][C:17]=1[C:18](Cl)=[O:19]>C1(C)C=CC=CC=1.C(OCC)C>[F:1][C:2]([F:11])([F:12])[C:3]1[O:10][C:16]2[CH:24]=[CH:23][C:22]([C:25]([F:26])([F:28])[F:27])=[CH:21][C:17]=2[C:18](=[O:19])[C:4]=1[C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: O=C(Cl)c1cc(C(F)(F)F)ccc1F
Reactant: CCOC(=O)CC(=O)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: CCOC(=O)c1c(C(F)(F)F)oc2ccc(C(F)(F)F)cc2c1=O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a stirred solution of ethyl 4,4,4-trifluoroacetoacetate (3.22 mL, 4.06 g, 22.07 mmol) in toluene (100 mL) was added portion-wise sodium hydride (0.971 g, of 60% oil dispersion reagent, 22.07 mmol) causing gas evolution. After gas evolution has subsided, 2-fluoro-5-(trifluoromethyl)benzoyl chloride (5.00 g, 22.07 mmol) was added. The reaction was stirred at room temperature for 24 hours, then heated to 105° C. for 24 hours. After cooling to room temperature, the reaction was diluted with diethyl ether and the resulting solution was washed with H2O and brine, dried over MgSO4, filtered and concentrated in vacuo yielding a slightly sticky white solid. This solid was triturated with hexanes yielding the desired ester(3.05 g, 39%) as a white powder: mp 116–120.1° C. 1H NMR (CDCl3/300 MHz) 8.52 (d, 2H, J=1.6 Hz), 8.03 (dd, 1H, J=8.9, 2.2 Hz), 7.71 (d, 1H, J=8.9 Hz), 4.48 (q, 2H, J=7.3 Hz), 1.39 (t, 3H, J=7.3 Hz). FABLRMS m/z 355 (M+H). Anal. Calc'd for C14H8F6O4: C, 47.45; H, 2.28. Found: C, 47.59; H, 2.43.
Reaction SMILES: [O:1]1CCO[CH:2]1[CH2:6][N:7]1[C:16]2[C:11](=[CH:12][C:13]([Br:17])=[CH:14][CH:15]=2)[CH:10]=[CH:9][C:8]1=[O:18].C(=O)([O-])O.[Na+]>FC(F)(F)C(O)=O>[Br:17][C:13]1[CH:12]=[C:11]2[C:16](=[CH:15][CH:14]=1)[N:7]([CH2:6][CH:2]=[O:1])[C:8](=[O:18])[CH:9]=[CH:10]2
Reactant: O=c1ccc2cc(Br)ccc2n1CC1OCCO1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: O=CCn1c(=O)ccc2cc(Br)ccc21
Temperature: 40 °C
Reaction time: 15 h

Procedure:
0.56 g of 1-(1,3-dioxolan-2-ylmethyl)-6-bromoquinolin-2(1H)-one was dissolved in 4.5 mL of 67% aqueous trifluoroacetic acid solution, and stirred at room temperature for 18.5 hours, at 40° C. for 7.5 hours, further at room temperature for 15 hours. After the reaction mixture was alkalized by adding aqueous saturated sodium hydrogen carbonate solution, it was extracted with ethyl acetate. The organic layer was washed with aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure to give (6-bromo-2-oxoquinolin-1(2H)-yl)acetaldehyde as a pale yellow solid.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([CH:9]([C:11]2[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[C:13]([F:19])[C:12]=2[F:20])[OH:10])=[CH:4][N:3]=1.C(=O)(O)[O-].[Na+].CC1(C)N([O])C(C)(C)CCC1.Cl[O-].[Na+]>ClCCl.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.O>[Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([C:9]([C:11]2[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[C:13]([F:19])[C:12]=2[F:20])=[O:10])=[CH:4][N:3]=1
Reactant: COc1ccc(F)c(F)c1C(O)c1cnc(Cl)nc1Cl
Agent: CC1(C)CCCC(C)(C)N1[O]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])O
Solvent: ClCCl
Solvent: O
Product: COc1ccc(F)c(F)c1C(=O)c1cnc(Cl)nc1Cl
Temperature: 0 °C
Yield: 85.5 %

Procedure:
A mixture of rac-(2,4-dichloro-pyrimidin-5-yl)-(2,3-difluoro-6-methoxy-phenyl)-methanol (20.5 g, 63.8 mmol, Example 287) in dichloromethane (180 mL) was chilled with stirring to 0° C. and added water (20 mL), sodium bicarbonate powder (2.42 g, 28.73 mmol, Aldrich), tetrabutylammonium bromide (0.617 g, 1.915 mmol, Aldrich), and 2,2,6,6-tetramethyl-1-piperidinyloxy, free radical (0.1 g, 0.638 mmol, TEMPO, Aldrich). Sodium hypochlorite solution (6.15%, Aldrich) was added portionwise until all starting material was oxidized (TLC ethyl acetate/hexanes 3:1). The cold reaction mixture was then washed with water (2×), dried (MgSO4) and concentrated adding hexanes. Filtration of the cold mixture gave 17.4 g of (2,4-dichloro-pyrimidin-5-yl)-(2,3-difluoro-6-methoxy-phenyl)-methanone, MP 137–139° C.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([N+:9]([O-])=O)=[CH:4][C:3]=1[C@:12]1([CH2:23][F:24])[CH2:17][C@@H:16]([C:18]([F:21])([F:20])[F:19])[O:15][C:14]([NH2:22])=[N:13]1>CCO.[Pd]>[NH2:9][C:5]1[CH:6]=[C:7]([F:8])[C:2]([F:1])=[C:3]([C@:12]2([CH2:23][F:24])[CH2:17][C@@H:16]([C:18]([F:21])([F:19])[F:20])[O:15][C:14]([NH2:22])=[N:13]2)[CH:4]=1
Reactant: NC1=N[C@](CF)(c2cc([N+](=O)[O-])cc(F)c2F)C[C@@H](C(F)(F)F)O1
Agent: [Pd]
Solvent: CCO
Product: NC1=N[C@](CF)(c2cc(N)cc(F)c2F)C[C@@H](C(F)(F)F)O1

Procedure:
A mixture of (4S,6S)-4-(2,3-difluoro-5-nitrophenyl)-4-(fluoromethyl)-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-amine (1.85 g, 5.18 mmol) and palladium 10 wt. % (dry basis) on activated carbon, wet (1.000 mL, 0.940 mmol) in EtOH (20 mL) was hydrogenated under a hydrogen balloon for 4 days until full conversion to the desired product. The reaction mixture was filtered through celite and the filter cake was rinsed with EtOAc followed by MeOH/DCM (10%). The filtrate was concentrated to dryness. The residue was triturated with DCM and the resulted suspension was filtered through filter paper. The filter cake was washed with DCM and dried in air to afford (4S,6S)-4-(5-amino-2,3-difluorophenyl)-4-(fluoromethyl)-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-amine (1.2 g, 3.67 mmol, 70.8% yield) as off-white solid. MS m/z=328.1 [M+H]+. Calculated for C12H11F6N30: 327.2
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][C:16]3([CH2:22][O:23][P:24]([C:30]([CH3:33])([CH3:32])[CH3:31])([C:26]([CH3:29])([CH3:28])[CH3:27])=[O:25])[CH2:20][O:19][C:18]([CH3:21])=[N:17]3)=[CH:10][CH:9]=2)=[C:4]([F:34])[CH:3]=1.[CH3:35][C:36]1[CH:41]=[CH:40][C:39]([SH:42])=[CH:38][CH:37]=1.C(N(C(C)C)CC)(C)C.C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C(Cl)(Cl)Cl.[Pd].[Pd].O>[F:34][C:4]1[CH:3]=[C:2]([S:42][C:39]2[CH:40]=[CH:41][C:36]([CH3:35])=[CH:37][CH:38]=2)[CH:7]=[CH:6][C:5]=1[C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][C:16]2([CH2:22][O:23][P:24]([C:30]([CH3:33])([CH3:32])[CH3:31])([C:26]([CH3:29])([CH3:28])[CH3:27])=[O:25])[CH2:20][O:19][C:18]([CH3:21])=[N:17]2)=[CH:10][CH:9]=1
Reactant: CC1=NC(CCc2ccc(-c3ccc(Br)cc3F)cc2)(COP(=O)(C(C)(C)C)C(C)(C)C)CO1
Reactant: Cc1ccc(S)cc1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: CC1=NC(CCc2ccc(-c3ccc(Sc4ccc(C)cc4)cc3F)cc2)(COP(=O)(C(C)(C)C)C(C)(C)C)CO1
Yield: 53.9 %

Procedure:
A solution of 4-[2-(4′-bromo-2′-fluorobiphenyl-4-yl)ethyl]-4-di(tert-butyl)phosphoryloxymethyl-2-methyl-2-oxazoline (210 mg) of Example 23, (23-2), 4-methylbenzenethiol (49 mg), diisopropylethylamine (93 mg), tris(dibenzylideneacetone)dipalladium(0) chloroform adduct (18.6 mg) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos) (21.4 mg) in 1,4-dioxane (2 mL) was heated under reflux for 9 hr under a nitrogen atmosphere. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound (122 mg) as a pale-yellow oil.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([C:11]2[O:15][N:14]=[C:13]([C:16]3[CH:21]=[C:20]([CH3:22])[C:19]([OH:23])=[C:18]([CH2:24][CH3:25])[CH:17]=3)[N:12]=2)[CH:6]=[N:7][C:8]=1[CH2:9][CH3:10])[CH3:2].[CH2:26]([CH:28]1[O:30][CH2:29]1)Cl>C(O)(C)C.[OH-].[Na+].CC(=O)OCC>[CH2:9]([C:8]1[C:3]([CH2:1][CH3:2])=[CH:4][C:5]([C:11]2[O:15][N:14]=[C:13]([C:16]3[CH:21]=[C:20]([CH3:22])[C:19]([O:23][CH2:26][CH:28]4[CH2:29][O:30]4)=[C:18]([CH2:24][CH3:25])[CH:17]=3)[N:12]=2)=[CH:6][N:7]=1)[CH3:10]
Reactant: CCc1cc(-c2nc(-c3cc(C)c(O)c(CC)c3)no2)cnc1CC
Reactant: ClCC1CO1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: CCOC(C)=O
Product: CCc1cc(-c2nc(-c3cc(C)c(OCC4CO4)c(CC)c3)no2)cnc1CC
Temperature: 25 °C
Reaction time: 20 h
Yield: 52.5 %

Procedure:
To a solution of 4-[5-(5,6-diethyl-pyridin-3-yl)-[1,2,4]oxadiazol-3-yl]-2-ethyl-6-methyl-phenol (150 mg, 0.445 mmol) in isopropanol (10 mL) and 3 N aq. NaOH (3 mL), epichlorhydrine (164 mg, 1.78 mmol) is added. The mixture is stirred at rt for 20 h. The mixture is diluted with EA and washed with sat. aq. NaHCO3 solution. The org. extract is dried over MgSO4, filtered and evaporated. The crude product is purified by chromatography on prep. TLC plates with EA-heptane to give (RS)-2,3-diethyl-5-[3-(3-ethyl-5-methyl-4-oxiranylmethoxy-phenyl)-[1,2,4]oxadiazol-5-yl]-pyridine (92 mg) as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[S:33])[NH:10][C:11]2[S:12][CH:13]=[C:14]([C:16](=[C:22]3[S:26][C:25](=[S:27])[N:24]([CH2:28][C:29]([OH:31])=[O:30])[C:23]3=[O:32])[C:17]([O:19][CH2:20][CH3:21])=[O:18])[N:15]=2)=[CH:4][CH:3]=1.[CH2:34](O)[CH3:35].O1CCOCC1.Cl>O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[S:33])[NH:10][C:11]2[S:12][CH:13]=[C:14]([C:16](=[C:22]3[S:26][C:25](=[S:27])[N:24]([CH2:28][C:29]([O:31][CH2:34][CH3:35])=[O:30])[C:23]3=[O:32])[C:17]([O:19][CH2:20][CH3:21])=[O:18])[N:15]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(=C1SC(=S)N(CC(=O)O)C1=O)c1csc(NC(=S)Nc2ccc(Cl)cc2)n1
Reactant: CCO
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Product: CCOC(=O)CN1C(=O)C(=C(C(=O)OCC)c2csc(NC(=S)Nc3ccc(Cl)cc3)n2)SC1=S
Reaction time: 108 h

Procedure:
A mixture comprising 4.8 g of 5-{1-[2-(3-p-chloro-phenylthioureido)thiazol-4-yl]-1-ethoxycarbonylmethylene}-rhodanine-3-acetic acid, 10 g of ethanol and 50 ml of a 4N dioxane solution of hydrogen chloride was left to stand at room temperature for 4.5 days. The reaction mixture was then poured into water and extracted with ethyl acetate. The extract was washed with aqueous sodium chloride solution, and was then dried over anhydrous sodium sulfate. The solvent was evaporated off under reduced pressure, and the residue was recrystallized from a circa 1:1 by volume mixture of hexane and ethyl acetate. The resulting product was an orange powder having the following physical properties.
Reaction SMILES: [H-].[Na+].[CH:3]12[CH2:8][CH:7]1[C:6](=[O:9])[NH:5][C:4]2=[O:10].I[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]>CN(C)C=O.O>[CH2:12]([N:5]1[C:6](=[O:9])[CH:7]2[CH:3]([CH2:8]2)[C:4]1=[O:10])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: CCCCCCCCI
Reactant: O=C1NC(=O)C2CC12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCCCCCN1C(=O)C2CC2C1=O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Sodium hydride (1.48 g, 60% in oil) was added to a stirred solution of 3-azabicyclo[3.1.0]hexane-2,4-dione (4.0 g) and 1-iodooctane (8.88 g) in dry dimethylformamide (70 ml) under a nitrogen atmosphere at 0° C. The reaction mixture was stirred at 0° C. for a further 30 minutes and then at room temperature for 16 hours. The mixture was diluted with water (100 ml) and then extracted with ether (150 ml). The organic extract was washed with water (2×70 ml), dried (MgSO4) and evaporated in vacuo to leave a brown oil. The oil was purified by distillation in vacuo (boiling point 146-147° C. @ 0.1 mmHg) to give the title compound as a pale yellow oil.
Reaction SMILES: [CH3:1][CH:2]([CH3:57])[C@H:3]([NH:52][C:53](=[O:56])[O:54][CH3:55])[C:4]([N:6]1[CH2:10][CH2:9][CH2:8][C@H:7]1[C:11]1[NH:12][CH:13]=[C:14]([C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:27]=[CH:26][C:25]([C:28]4[N:29]=[C:30]([CH:33]5[CH2:40][C:36]6([CH2:39][NH:38][CH2:37]6)[CH2:35][N:34]5[C:41](=[O:51])[C@@H:42]([NH:46][C:47]([O:49][CH3:50])=[O:48])[CH:43]([CH3:45])[CH3:44])[NH:31][CH:32]=4)=[CH:24][CH:23]=3)=[CH:18][CH:17]=2)[N:15]=1)=[O:5].[CH3:58][N:59]=[C:60]=[O:61].C(=O)([O-])[O-].[K+].[K+]>C(Cl)Cl>[CH3:1][CH:2]([CH3:57])[C@H:3]([NH:52][C:53](=[O:56])[O:54][CH3:55])[C:4]([N:6]1[CH2:10][CH2:9][CH2:8][C@H:7]1[C:11]1[NH:12][CH:13]=[C:14]([C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:23]=[CH:24][C:25]([C:28]4[N:29]=[C:30]([CH:33]5[CH2:40][C:36]6([CH2:37][N:38]([C:60]([NH:59][CH3:58])=[O:61])[CH2:39]6)[CH2:35][N:34]5[C:41](=[O:51])[C@@H:42]([NH:46][C:47]([O:49][CH3:50])=[O:48])[CH:43]([CH3:44])[CH3:45])[NH:31][CH:32]=4)=[CH:26][CH:27]=3)=[CH:18][CH:17]=2)[N:15]=1)=[O:5]
Reactant: COC(=O)N[C@H](C(=O)N1CC2(CNC2)CC1c1nc(-c2ccc(-c3ccc(-c4c[nH]c([C@@H]5CCCN5C(=O)[C@@H](NC(=O)OC)C(C)C)n4)cc3)cc2)c[nH]1)C(C)C
Reactant: CN=C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: CNC(=O)N1CC2(CC(c3nc(-c4ccc(-c5ccc(-c6c[nH]c([C@@H]7CCCN7C(=O)[C@@H](NC(=O)OC)C(C)C)n6)cc5)cc4)c[nH]3)N(C(=O)[C@@H](NC(=O)OC)C(C)C)C2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 67.7 %

Procedure:
To a solution of methyl [(1S)-2-methyl-1-({(2S)-2-[4-(4′-{2-[6-((2S)-3-methyl-2-{[(methyloxy)carbonyl]amino}butanoyl)-2,6-diazaspiro[3.4]oct-7-yl]-1H-imidazol-4-yl}-4-biphenylyl)-1H-imidazol-2-yl]-1-pyrrolidinyl}carbonyl)propyl]carbamate (Example 24) (45 mg, 0.06 mmol) in anhydrous CH2Cl2 (0.6 mL) was added methyl isocyanate (0.01 mL, 0.17 mmol) and the reaction stirred at room temperature for 2 h. The solvent was removed in vacuo and the residue dissolved in methanol (1 mL) and potassium carbonate (40 mg, 0.29 mmol) was added and the reaction stirred at room temperature for 18 h. The reaction was partitioned between CH2Cl2 (10 mL) and water (5 mL), the aqueous layer was extracted with CH2Cl2 (5 mL), the organic layers were combined and dried (MgSO4) and concentrated in vacuo to afford the title compound as a yellow solid (34 mg, 70% yield). 1H NMR (400 MHz, METHANOL-d4) δ ppm 7.64 (br. s., 10H) 7.33 (br. s., 2H) 5.06-5.22 (m, 1H) 4.03-4.46 (m, 3H) 3.73-4.04 (m, 8H) 3.54-3.73 (m, 6H) 3.46 (q, J=7.0 Hz, 2H) 2.52-2.76 (m, 5H) 2.10-2.53 (m, 4H) 2.02 (br. s., 3H) 0.70-1.09 (m, 12H). HRMS for C44H57N10O7 (M+H)+ calc: 837.4412, found: 838.4416. Purity (LC-MS): 91%.