Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[O:7][C:6](=[O:8])[N:5]([C:9]2[CH:18]=[C:17]3[C:12]([CH:13]=[C:14]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[C:26]([F:29])([F:28])[F:27])[NH:15][C:16]3=[O:19])=[CH:11][CH:10]=2)[CH2:4]1.N1C=CC=CC=1.[CH3:36][S:37](Cl)(=[O:39])=[O:38].O>C(Cl)Cl>[O:8]=[C:6]1[N:5]([C:9]2[CH:18]=[C:17]3[C:12]([CH:13]=[C:14]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[C:26]([F:28])([F:27])[F:29])[NH:15][C:16]3=[O:19])=[CH:11][CH:10]=2)[CH2:4][C@H:3]([CH2:2][NH:1][S:37]([CH3:36])(=[O:39])=[O:38])[O:7]1
Reactant: NC[C@H]1CN(c2ccc3cc(-c4ccccc4C(F)(F)F)[nH]c(=O)c3c2)C(=O)O1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: O
Solvent: c1ccncc1
Product: CS(=O)(=O)NC[C@H]1CN(c2ccc3cc(-c4ccccc4C(F)(F)F)[nH]c(=O)c3c2)C(=O)O1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 37.4 %

Procedure:
The 7-((S)-5-aminomethyl-2-oxooxazolidin-3-yl)-3-(2-trifluoromethylphenyl)-2H-isoquinolin-1-one (30 mg, 0.07 mmol) obtained in step B was dissolved in methylene chloride (0.3 ml). Thereafter, pyridine (30 μl, 0.37 mmol) and methanesulfonyl chloride (5.8 μl, 0.07 mmol) were added to the solution, and the obtained mixture was stirred at 0° C. for 30 minutes. Thereafter, water was added to the reaction solution, and the mixture was then extracted with methylene chloride. The extract was washed with water and a saturated saline solution, and was then dried over magnesium sulfate. Thereafter, the solvent was distilled away under reduced pressure. The obtained residue was purified by silica gel column chromatography (methylene chloride:methanol=20:1), so as to obtain N-{(R)-2-oxo-3-[1-oxo-3-(2-trifluoromethylphenyl)-1,2-dihydroisoquinolin-7-yl]oxazolidin-5-ylmethyl}methanesulfonamide (12.6 mg, 36%) in the form of a colorless solid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[CH3:11])[C:7](=[O:12])[N:6]([C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=1)[CH:5]2O.[C:21]([CH:26]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:23][CH2:24][CH3:25])=[O:22]>C1(C)C=CC=CC=1>[CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[CH3:11])[C:7](=[O:12])[N:6]([C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=1)[CH:5]2[CH2:26][C:21]([O:23][CH2:24][CH3:25])=[O:22]
Reactant: Cc1cc2c(cc1C)C(O)N(c1ccc(F)cc1)C2=O
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Product: CCOC(=O)CC1c2cc(C)c(C)cc2C(=O)N1c1ccc(F)cc1
Yield: 32.8 %

Procedure:
The product of above-mentioned (1-b) (0.90 g, 3.3 mmol) and (carboethoxymethylene)triphenylphosphorane (1.4 g, 3.9 mmol) was heated under reflux in toluene (15 ml) under an argon atmosphere for 3.5 hrs. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (chloroform methanol=50:1) to give 0.37 g of 5,6-dimethyl-2-(4-fluorophenyl)-3-ethoxycarbonylmethylisoindolin-1-one [IUPAC name: ethyl 2-[2-(4-fluorophenyl)-5,6-dimethyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl]acetate].
Reaction SMILES: [OH:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]=[C:15]([C:17]3[O:21][N:20]=[C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:18]=3[C:28]([F:31])([F:30])[F:29])[O:14][N:13]=2)=[CH:8][CH:7]=1)[C:3](O)=[O:4].C[N:33]1CCO[CH2:35][CH2:34]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH2:34]([NH:33][C:3](=[O:4])[CH:2]([OH:1])[C:6]1[CH:7]=[CH:8][C:9]([C:12]2[N:16]=[C:15]([C:17]3[O:21][N:20]=[C:19]([C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=4)[C:18]=3[C:28]([F:31])([F:29])[F:30])[O:14][N:13]=2)=[CH:10][CH:11]=1)[CH3:35]
Reactant: O=C(O)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Reactant: CN1CCOCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: CCNC(=O)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Reaction time: 8 h
Yield: 56.5 %

Procedure:
(R/S)-2-Hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetic acid (Int-V, 20 mg, 0.046 mmol) was dissolved in DMF (1 mL) prior to the addition of 4-methylmorpholine (0.041 mL, 0.371 mmol), ethanamine, HCl (4.92 mg, 0.060 mmol), and HATU (31.7 mg, 0.083 mmol). This was stirred overnight and was then purified by preparative HPLC (PHENOMENEX® Luna 5u C18 21.2×100 mm, gradient elution with Method 1—MeOH/water containing 0.1% trifluoroacetic acid as defined above, 0% B to 100% B over 10 min, 20 mL/min, 220 nM, product retention time=12.0 min) to give (R/S)-N-ethyl-2-hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetamide (14.5 mg, 0.026 mmol, 56.5% yield): LCMS=459.1 [M+H]+; 1H NMR (400 MHz, methanol-d4) δ ppm 8.17 (2 H, d, J=8.35 Hz), 7.66-7.74 (4 H, m), 7.53-7.64 (3 H, m), 5.10 (1 H, s), 3.21-3.30 (2 H, m), 1.14 (3 H, t, J=7.25 Hz). HPLC Peak RT=10.60 min (Analytical Method C).
Reaction SMILES: [Cl:1][C:2]1[CH:29]=[CH:28][CH:27]=[CH:26][C:3]=1[C:4]([NH:6][C:7]1[C:8]([N:13]([CH2:20][CH2:21][CH2:22][N:23]([CH3:25])[CH3:24])[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[N:9][CH:10]=[CH:11][CH:12]=1)=O.P(Cl)(Cl)(Cl)=O.Cl>ClC(Cl)C(Cl)Cl>[Cl:1][C:2]1[CH:29]=[CH:28][CH:27]=[CH:26][C:3]=1[C:4]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[N:13]([CH2:20][CH2:21][CH2:22][N:23]([CH3:25])[CH3:24])[C:8]2[N:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]=1
Reactant: CN(C)CCCN(c1ccccc1)c1ncccc1NC(=O)c1ccccc1Cl
Agent: Cl
Solvent: ClC(Cl)C(Cl)Cl
Solvent: O=P(Cl)(Cl)Cl
Product: CN(C)CCCN1c2ccccc2C(c2ccccc2Cl)=Nc2cccnc21

Procedure:
A solution of 7.0 g (0.017 mole) of 2-chloro-N-[2-[[3-(dimethylamino)propyl]phenylamino]-3-pyridinyl]benzamide and 10.5 g (0.069 mole) of phosphorus oxychloride in 5 ml of 1,1,2,2-tetrachlorethane was heated under nitrogen atmosphere at 110°-115° C. for 16 hr. The cooled reaction mixture was poured into ice and 10 ml of dilute hydrochloric acid added. The mixture was extracted twice with petroleum ether. The acidic portion was made basic with sodium hydroxide pellets and thereafter extracted twice with methylene chloride. The combined methylene chloride extracts were washed with water, dried over sodium sulfate and concentrated in vacuo. The residue was crystallized from isopropyl ether yielding 6.0 g (90%) of material. Recrystallization from isopropyl alcohol-isopropyl ether gave a yellow solid, m.p. 104°-105.6° C.
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:9]CO)(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2].N1C(C)=CC=CC=1C.[F:20][C:21]([F:34])([F:33])[S:22]([O:25]S(C(F)(F)F)(=O)=O)(=[O:24])=[O:23]>ClCCl.C(OCC)C>[F:20][C:21]([F:34])([F:33])[S:22]([O:25][CH2:9][P:4]([O:3][CH2:1][CH3:2])([O:5][CH2:6][CH3:7])=[O:8])(=[O:24])=[O:23]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: CCOP(=O)(CCO)OCC
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Solvent: CCOCC
Product: CCOP(=O)(COS(=O)(=O)C(F)(F)F)OCC
Temperature: -50 °C
Reaction time: 1.5 h

Procedure:
5.01 ml diethyl-(hydroxyethyl)-phosphonate are dissolved in 50 ml dichloromethane, combined with 4.42 ml of 2,6-lutidine and cooled to −50° C. Then a solution of 6 ml trifluoromethanesulphonic acid anhydride in 10 ml dichloromethane is slowly added dropwise. Within 1.5 hours the mixture is allowed to come up to 0° C. and then diluted with 300 ml cold diethyl ether. Any solids precipitated are filtered off and the filtrate is washed twice with ice water, once with 1 N hydrochloric acid and once with saturated sodium chloride solution. After drying with sodium sulphate the solvents are eliminated in vacuo.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([CH:19]=[O:20])[C:11]=1[O:12][CH2:13][O:14][CH2:15][CH2:16][O:17][CH3:18])[C:5]([O:7][CH3:8])=[O:6].[C:21]([NH:25][S:26]([C:29]1[CH:34]=[CH:33][CH:32]=[C:31](B2OC(C)(C)C(C)(C)O2)[CH:30]=1)(=[O:28])=[O:27])([CH3:24])([CH3:23])[CH3:22]>>[C:21]([NH:25][S:26]([C:29]1[CH:30]=[C:31]([C:2]2[C:11]([O:12][CH2:13][O:14][CH2:15][CH2:16][O:17][CH3:18])=[C:10]([CH:19]=[O:20])[CH:9]=[C:4]([C:5]([O:7][CH3:8])=[O:6])[CH:3]=2)[CH:32]=[CH:33][CH:34]=1)(=[O:28])=[O:27])([CH3:24])([CH3:22])[CH3:23]
Reactant: COCCOCOc1c(Br)cc(C(=O)OC)cc1C=O
Reactant: CC(C)(C)NS(=O)(=O)c1cccc(B2OC(C)(C)C(C)(C)O2)c1
Product: COCCOCOc1c(C=O)cc(C(=O)OC)cc1-c1cccc(S(=O)(=O)NC(C)(C)C)c1
Yield: 78.2 %

Procedure:
Proceeding as in Reference 19, but substituting 3-bromo-2-hydroxy-5-methylbenzaldehyde (0.60 g, 2.5 mmol) and N-tert-butyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzenesulfonamide (0.846 g, 2.5 mmol), gave N-tert-butyl-3′-formyl-2′-(2-methoxyethoxymethoxy)-5′-methyl-biphenyl-3-sulfonamide (0.87 g) Proceeding as in Reference 19, but substituting methyl 3-bromo-5-formyl-4-(2-methoxyethoxymethoxy)-benzoate (2.00 g, 5.76 mmol, 1.0 eq.) and N-tert-butyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)benzenesulfonamide (1.95 g, 5.76 mmol, 1.0 eq.), gave methyl 3′-tert-butylsulfamoyl-5-formyl-6-(2-methoxyethoxymethoxy)-biphenyl-3-carboxylate (2.16 g) as a yellow gum.
Reaction SMILES: [C:1]([C:5]1[CH:30]=[CH:29][C:8]([CH2:9][NH:10][C:11](=[O:28])[NH:12][CH2:13][C:14]2[CH:19]=[C:18]([CH:20]=[CH2:21])[C:17]([NH:22][S:23]([CH3:26])(=[O:25])=[O:24])=[C:16]([F:27])[CH:15]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[H][H]>CO.[Pd]>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([CH2:9][NH:10][C:11](=[O:28])[NH:12][CH2:13][C:14]2[CH:15]=[C:16]([F:27])[C:17]([NH:22][S:23]([CH3:26])(=[O:24])=[O:25])=[C:18]([CH2:20][CH3:21])[CH:19]=2)=[CH:29][CH:30]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: [H][H]
Reactant: C=Cc1cc(CNC(=O)NCc2ccc(C(C)(C)C)cc2)cc(F)c1NS(C)(=O)=O
Agent: [Pd]
Solvent: CO
Product: CCc1cc(CNC(=O)NCc2ccc(C(C)(C)C)cc2)cc(F)c1NS(C)(=O)=O
Reaction time: 1 h
Yield: 90.7 %

Procedure:
N-{4-[3-(4-t-butyl-benzyl)-ureidomethyl]-2-fluoro-6-vinyl-phenyl}methanesulfonamide (15.6 mg, 0.04 mmol) was dissolved in methanol. To the solution was added Pd/C (10 wt. %) and air in the flask was displaced with hydrogen gas. The reaction solution was stirred for 1 hour. After confirming the completion of the reaction with TLC, Pd/C was filtered off through celite. The methanol was removed under reduced pressure and column-chromatographed (n-hexane/ethyl acetate ˜1/1) to yield a white solid (15.8 mg, 100.0%).
Reaction SMILES: C([O:5][C:6](=[O:52])[CH:7]([CH:28]([C:30](=[O:51])[C@H:31]([CH2:36][CH2:37][CH2:38][CH2:39][NH:40][C:41]([O:43][CH2:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)=[O:42])[NH:32][C:33](=[O:35])[CH3:34])[NH2:29])[CH2:8][C:9]1([C:14](=[O:27])[NH:15][C@H:16]2[CH2:21][CH2:20][C@@H:19]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:18][CH2:17]2)[CH2:13][CH2:12][CH2:11][CH2:10]1)(C)(C)C>FC(F)(F)C(O)=O.ClCCl>[C:33]([NH:32][C@H:31]([C:30]([CH:28]([NH2:29])[CH:7]([CH2:8][C:9]1([C:14](=[O:27])[NH:15][C@H:16]2[CH2:21][CH2:20][C@@H:19]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:18][CH2:17]2)[CH2:13][CH2:12][CH2:11][CH2:10]1)[C:6]([OH:52])=[O:5])=[O:51])[CH2:36][CH2:37][CH2:38][CH2:39][NH:40][C:41]([O:43][CH2:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)=[O:42])(=[O:35])[CH3:34]
Reactant: CCOC(=O)[C@H]1CC[C@@H](NC(=O)C2(CC(C(=O)OC(C)(C)C)C(N)C(=O)[C@H](CCCCNC(=O)OCc3ccccc3)NC(C)=O)CCCC2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)[C@H]1CC[C@@H](NC(=O)C2(CC(C(=O)O)C(N)C(=O)[C@H](CCCCNC(=O)OCc3ccccc3)NC(C)=O)CCCC2)CC1
Reaction time: 8 h

Procedure:
The t-butyl ester from Example 1 (571 mg, 0.783 mmol) was dissolved in a mixture of trifluoroacetic acid (2 ml) and dichloromethane (1 ml). The solution was kept at 4° C. overnight, then concentrated to dryness under vacuum, and the residue was azeotroped six times with dichloromethane. The resulting crude product was then taken up in ethyl acetate and washed with water until the washings were neutral. The organic phase was dried (MgSO4) and evaporated under vacuum to afford the title compound (442 mg, 84%) as a white foam. Found: C,61.89; H,7.76; N,7.93. C35H52N4O9 (0.5 H2O) requires C,61.65; H,7.69; N,8.22%.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1.[Br:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:19]Br)=[CH:17][CH:16]=1>>[Br:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:19][O:13][C:10]2[CH:11]=[CH:12][C:7]([CH2:6][C:2]3[NH:1][CH:5]=[CH:4][N:3]=3)=[CH:8][CH:9]=2)=[CH:17][CH:16]=1
Reactant: Oc1ccc(Cc2ncc[nH]2)cc1
Reactant: BrCc1ccc(Br)cc1
Product: Brc1ccc(COc2ccc(Cc3ncc[nH]3)cc2)cc1

Procedure:
This substance is prepared analogously to Example 1 from 4-(1-imidazolylmethyl)-phenol and 4-bromobenzyl bromide.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7](O)=[O:8])=[CH:5][C:4]=1/[CH:12]=[CH:13]/[C:14]1[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=1.[C:25]([O:29][CH2:30][C@@H:31]([C:33]([OH:35])=[O:34])[NH2:32])([CH3:28])([CH3:27])[CH3:26]>>[C:25]([O:29][CH2:30][C@H:31]([NH:32][C:7](=[O:8])[C:6]1[CH:10]=[CH:11][C:3]([O:2][CH3:1])=[C:4](/[CH:12]=[CH:13]/[C:14]2[CH:19]=[CH:18][C:17]([O:20][C:21]([F:22])([F:24])[F:23])=[CH:16][CH:15]=2)[CH:5]=1)[C:33]([OH:35])=[O:34])([CH3:28])([CH3:26])[CH3:27]
Reactant: COc1ccc(C(=O)O)cc1/C=C/c1ccc(OC(F)(F)F)cc1
Reactant: CC(C)(C)OC[C@H](N)C(=O)O
Product: COc1ccc(C(=O)N[C@@H](COC(C)(C)C)C(=O)O)cc1/C=C/c1ccc(OC(F)(F)F)cc1

Procedure:
The (S)-3-t-butoxy-2-{4-methoxy-3-[(E)-2-(4-trifluoromethoxyphenyl)vinyl]benzoylamino}propionic acid was synthesized from 4-methoxy-3-[(E)-2-(4-trifluoromethoxyphenyl)vinyl]benzoic acid obtained in step B of Example 2-2-1 and O-t-butyl-L-serine in accordance with the same procedure as in the methods described in step C of Example 1-2-3.
Reaction SMILES: [OH:1][C:2]([C:30]1[CH:35]=[CH:34][C:33]([C:36]2[CH:41]=[CH:40][CH:39]=[C:38]([CH2:42][NH:43][C:44](=[O:46])[CH3:45])[CH:37]=2)=[CH:32][CH:31]=1)([C:6]1[N:7]=[CH:8][N:9](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:10]=1)[CH:3]([CH3:5])[CH3:4].Cl.N1C=CC=CC=1>>[OH:1][C:2]([C:30]1[CH:31]=[CH:32][C:33]([C:36]2[CH:41]=[CH:40][CH:39]=[C:38]([CH2:42][NH:43][C:44](=[O:46])[CH3:45])[CH:37]=2)=[CH:34][CH:35]=1)([C:6]1[N:7]=[CH:8][NH:9][CH:10]=1)[CH:3]([CH3:5])[CH3:4]
Reactant: CC(=O)NCc1cccc(-c2ccc(C(O)(c3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)cn3)C(C)C)cc2)c1
Agent: Cl
Solvent: c1ccncc1
Product: CC(=O)NCc1cccc(-c2ccc(C(O)(c3c[nH]cn3)C(C)C)cc2)c1
Yield: 77.8 %

Procedure:
By the reaction in the same manner as in Example 4-(iii) using N-({4′-[1-hydroxy-2-methyl-1-(1-trityl-1H-imidazol-4-yl)propyl][1,1′-biphenyl]-3-yl}methyl)acetamide (1.05 g) and pyridine hydrochloride (278 mg), the title compound (490 mg) was obtained as a colorless amorphous powder.
Reaction SMILES: [C:1]1([C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]([NH:17][C:18]3[CH:37]=[CH:36][C:21]([O:22][C:23]4[C:28]([C:29]5[C:30]([C:34]#[N:35])=[N:31][NH:32][CH:33]=5)=[CH:27][CH:26]=[CH:25][N:24]=4)=[CH:20][CH:19]=3)=[N:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-:39].[K+].[K+].OO>CS(C)=O>[C:1]1([C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]([NH:17][C:18]3[CH:19]=[CH:20][C:21]([O:22][C:23]4[C:28]([C:29]5[C:30]([C:34]([NH2:35])=[O:39])=[N:31][NH:32][CH:33]=5)=[CH:27][CH:26]=[CH:25][N:24]=4)=[CH:36][CH:37]=3)=[N:9][N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C([O-])[O-]
Reactant: N#Cc1n[nH]cc1-c1cccnc1Oc1ccc(Nc2nnc(-c3ccccc3)c3ccccc23)cc1
Agent: OO
Agent: [K+]
Solvent: CS(C)=O
Product: NC(=O)c1n[nH]cc1-c1cccnc1Oc1ccc(Nc2nnc(-c3ccccc3)c3ccccc23)cc1
Temperature: 20 °C
Reaction time: 72 h

Procedure:
In a 20-mL sealed tube was dissolved 4-(2-(4-(4-phenylphthalazin-1-ylamino)phenoxy)pyridin-3-yl)-1H-pyrazole-3-carbonitrile (0.070 g, 0.145 mmol) in DMSO (1.0 mL). To this was added potassium carbonate (0.024 g, 0.174 mmol) and hydrogen peroxide (0.445 mL, 14.5 mmol) and the mixture was stirred at 20° C. for 3 days and quenched with water. The product was extracted into EtOAc, washed 1× saturated NaHCO3, 1×H2O, dried over Na2SO4, filtered through fritted funnel and concentrated. The title compound was purified using a Gilson reverse phase liquid chromatography system. The product fractions were extracted into CH2Cl2. The organic layers were washed organics 1× saturated NaHCO3, 1×H2O, dried with Na2SO4, filtered through fritted funnel and concentrated to yield 4-(2-(4-(4-phenylphthalazin-1-ylamino)phenoxy)pyridin-3-yl)-1H-pyrazole-3-carboxamide as light yellow solid. MS m/z=500 [M+1]+. Calc'd for C29H21N7O2: 499.52.
Reaction SMILES: [C:1]([S:4][CH2:5][CH:6]([CH:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH3:11])[C:7]([OH:9])=O)(=[O:3])[CH3:2].[CH2:18]([O:25][C:26](=[O:30])[C@H:27]([CH3:29])[NH2:28])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[CH2:18]([O:25][C:26](=[O:30])[C@H:27]([CH3:29])[NH:28][C:7](=[O:9])[CH:6]([CH2:5][S:4][C:1](=[O:3])[CH3:2])[CH:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH3:11])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CC(=O)SCC(C(=O)O)C(C)c1ccccc1
Reactant: C[C@H](N)C(=O)OCc1ccccc1
Product: CC(=O)SCC(C(=O)N[C@@H](C)C(=O)OCc1ccccc1)C(C)c1ccccc1
Yield: 68 %

Procedure:
Using the procedure described in Example 60, starting with 2-acetylthiomethyl-3-phenylbutanoic acid and alanine benzyl ester, and after purification by chromatography, eluting with a cyclohexane/ethyl acetate (75:25 by volume) mixture, N-(2-acetylthiomethyl-1-oxo-3-phenylbutyl)alanine benzyl ester is obtained in a 68% yield, the characteristics of which are as follows: Rf =0.31 [hexane/ethyl acetate (75:25 by volume)].
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:8]([CH2:9][CH2:10][C:11]([O:13]CC)=[O:12])=[CH:7][N:6]([CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]3[N:27]=[C:28]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[O:29][C:30]=3[CH3:31])=[CH:20][CH:19]=2)[N:5]=1)[CH3:2].[OH-].[Na+].O1CCCC1.C(O)C>Cl>[CH2:1]([O:3][C:4]1[C:8]([CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[CH:7][N:6]([CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]3[N:27]=[C:28]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[O:29][C:30]=3[CH3:31])=[CH:20][CH:19]=2)[N:5]=1)[CH3:2]
Reactant: CCOC(=O)CCc1cn(CCc2ccc(OCc3nc(-c4ccccc4)oc3C)cc2)nc1OCC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CCOc1nn(CCc2ccc(OCc3nc(-c4ccccc4)oc3C)cc2)cc1CCC(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 86.3 %

Procedure:
A mixture of ethyl 3-[3-ethoxy-1-[2-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)phenyl]ethyl]-1H-pyrazol-4-yl]propionate (1.08 g), 1 N aqueous sodium hydroxide solution (4.2 ml), tetrahydrofuran (3 ml), and ethanol (3 ml) was stirred at room temperature for two hours, diluted with 1 N hydrochloric acid (5 ml), and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), and concentrated. The obtained crystals were collected by filtration, and 3-[3-ethoxy-1-[2-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)phenyl]ethyl]-1H-pyrazol-4-yl]propionic acid (880 mg, yield: 88%) was obtained. This was recrystallized from ethyl acetate-hexane. Melting point: 110–111° C.
Reaction SMILES: C([NH:8][CH:9]1[CH2:23][CH:12]2[CH2:13][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:15][CH:11]2[CH2:10]1)C1C=CC=CC=1.CC(O)=O>CO.[OH-].[OH-].[Pd+2]>[NH2:8][CH:9]1[CH2:23][CH:12]2[CH2:13][N:14]([C:16]([O:18][C:19]([CH3:21])([CH3:20])[CH3:22])=[O:17])[CH2:15][CH:11]2[CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CC2CC(NCc3ccccc3)CC2C1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)(C)OC(=O)N1CC2CC(N)CC2C1
Temperature: 40 °C
Reaction time: 8 h
Yield: 86.2 %

Procedure:
To a solution of tert-butyl 5-(benzylamino)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (6.50 g, 20.5 mmol) and AcOH (1.23 g, 20.5 mmol) in MeOH (150 mL) was added Pd(OH)2/C (10% wt, 1.00 g), and the suspension was stirred at 40° C. under H2 atmosphere overnight. The mixture was filtered through a pad of Celite and then concentrated in vacuo. The residue was dissolved in saturated NaHCO3 solution (70 mL) and extracted with DCM (100 mL×3). The combined organic phases were washed with brine (100 mL×3), dried over anhydrous Na2SO4, then filtered and concentrated in vacuo to give the title compound as a yellow solid (4.00 g, 86.2%).
Reaction SMILES: C([O:14][C:15]([C:17]1([O:20]/[N:21]=[C:22](/[C:62]2[N:63]=[C:64]([NH:67]C(OC(C)(C)C)=O)[S:65][CH:66]=2)\[C:23]([NH:25][C@@H:26]2[C:29](=[O:30])[N:28]([S:31]([OH:34])(=[O:33])=[O:32])[C@@H:27]2[CH2:35][N:36]2[N:40]=[C:39]([C@@H:41]([N:43](C(OC(C)(C)C)=O)[CH2:44][CH2:45][CH2:46][NH:47]C(OC(C)(C)C)=O)[CH3:42])[CH:38]=[N:37]2)=[O:24])[CH2:19][CH2:18]1)=[O:16])(C1C=CC=CC=1)C1C=CC=CC=1.C1(OC)C=CC=CC=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:47][CH2:46][CH2:45][CH2:44][NH:43][C@H:41]([C:39]1[CH:38]=[N:37][N:36]([CH2:35][C@@H:27]2[C@H:26]([NH:25][C:23](=[O:24])/[C:22](=[N:21]\[O:20][C:17]3([C:15]([OH:16])=[O:14])[CH2:19][CH2:18]3)/[C:62]3[N:63]=[C:64]([NH2:67])[S:65][CH:66]=3)[C:29](=[O:30])[N:28]2[S:31]([OH:34])(=[O:32])=[O:33])[N:40]=1)[CH3:42]
Reactant: C[C@@H](c1cnn(C[C@@H]2[C@H](NC(=O)/C(=N\OC3(C(=O)OC(c4ccccc4)c4ccccc4)CC3)c3csc(NC(=O)OC(C)(C)C)n3)C(=O)N2S(=O)(=O)O)n1)N(CCCNC(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Solvent: COc1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@H](NCCCN)c1cnn(C[C@@H]2[C@H](NC(=O)/C(=N\OC3(C(=O)O)CC3)c3csc(N)n3)C(=O)N2S(=O)(=O)O)n1
Temperature: 0 °C
Yield: 25.8 %

Procedure:
Followed the general procedure for the acid mediated deprotection using (2R,3S)-3-((Z)-2-((1-((benzhydryloxy)carbonyl)cyclopropoxy)imino)-2-(2-((tert-butoxycarbonyl)amino)thiazol-4-yl)acetamido)-2-((4-((S)-1-((tert-butoxycarbonyl)(3-((tert-butoxycarbonyl)amino)propyl)amino)ethyl)-2H-1,2,3-triazol-2-yl)methyl)-4-oxoazetidine-1-sulfonic acid (0.709 mmol), anisole (153 mg, 1.42 mmol), TFA (273 μl, 35.5 mmol) and DCM (7.1 mL). The reaction mixture was cooled to 0° C. and diluted with DCM and ice water. After vigorous stirring the two layers were separated and aqueous layer was purified by reverse phase prepatory HPLC (XSELECT, C18, 5 um 30×100 mm ACN-water with 0.1 formic acid), affording title compound (110 mg, 25%) as a white solid. LCMS: Rt=0.50 min, m/z=601.3 (M+1) Method 2m_acidic_polar; 1H NMR (400 MHz, D2O) δ 7.87 (s, 1H) 7.04 (s, 1H) 5.61 (d, J=5.6 Hz, 1H) 5.04-4.97 (m, 1H) 4.89 (d, J=5.4 Hz, 2H) 4.69-4.62 (m, 1H) 3.13-3.00 (m, 4H) 2.04 (t, J=4.0 Hz, 2H) 1.68 (d, J=6.9 Hz, 3H) 1.23 (t, J=3.9 Hz, 2H) 1.11-1.02 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:8])=[N:6][CH:7]=1.C([Li])CCC.Cl[C:15]1[N:20]=[C:19]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[N:18]=[C:17]([N:27]2[C:31]3[CH:32]=[CH:33][CH:34]=[C:35]([O:36][CH3:37])[C:30]=3[N:29]=[C:28]2[CH:38]([F:40])[F:39])[N:16]=1>C1COCC1.C(O)(=O)C.O>[Cl:8][C:5]1[N:6]=[CH:7][C:2]([NH:1][C:15]2[N:16]=[C:17]([N:27]3[C:31]4[CH:32]=[CH:33][CH:34]=[C:35]([O:36][CH3:37])[C:30]=4[N:29]=[C:28]3[CH:38]([F:40])[F:39])[N:18]=[C:19]([N:21]3[CH2:22][CH2:23][O:24][CH2:25][CH2:26]3)[N:20]=2)=[CH:3][CH:4]=1
Reactant: COc1cccc2c1nc(C(F)F)n2-c1nc(Cl)nc(N2CCOCC2)n1
Reactant: Nc1ccc(Cl)nc1
Agent: [Li]CCCC
Solvent: O
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: COc1cccc2c1nc(C(F)F)n2-c1nc(Nc2ccc(Cl)nc2)nc(N2CCOCC2)n1
Reaction time: 0.17 h
Yield: 5 %

Procedure:
To 0.246 g (1.92 mmol) of 5-amino-2-chloropyridine in THF (4 mL) was added 0.85 mL of n-butyllithium (2.5 M solution in hexanes), and the mixture was stirred for 10 min. A solution of 0.260 g (0.66 mmol) of 1-[4-chloro-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-2-(difluoromethyl)-4-methoxy-1H-benzimidazole (Example 2) in THF (5 mL) was added. The resulting mixture was stirred at room temperature for 1 hr. After neutralization with acetic acid, the mixture was diluted with water and extracted with EtOAc. The organic layer was washed successively with water and aqueous NH3, and dried. Removal of the solvent and chromatography of the residue on alumina eluting first with hexanes/EtOAc (1:1) and then with CH2Cl2-EtOAc (1:5) gave a brown powder. Recrystallization from ethanol/CH2Cl2 gave 0.016 g (5% yield) of N-(6-chloro-3-pyridinyl)-4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-amine: mp 260-262° C.; 1H NMR (CDCl3) δ8.69 (s, 1H), 7.95-7.90 (m, 2H), 7.48 (t, J=53.5 Hz, 1H), 7.37-7.33 (m, 2H), 7.11 (s, 1H), 6.83 (d, J=8.0 Hz, 1H), 4.05 (s, 3H), 3.94-3.87 (m, 4H), 3.81 (m, 4H); Anal. Calcd. for C21H19ClF2N8O2: C, 51.6; H, 3.9; N, 22.9; Cl, 7.25. Found: C, 52.1; H, 3.9; N, 22.5; Cl, 7.1%.