Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:9]([OH:14])(=[O:13])[C:10]([CH3:12])=[O:11].[OH-].[K+]>CO>[O:11]=[C:10](/[CH:12]=[CH:1]/[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:9]([OH:14])=[O:13]
Reactant: CC(=O)C(=O)O
Reactant: O=Cc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)C(=O)/C=C/c1ccccc1
Temperature: 10 °C
Reaction time: 1 h
Yield: 92.9 %

Procedure:
In a 2 L 3-necked flask equipped with a mechanical stirrer, dropping funnel and thermometer was placed benzaldehyde (119.8 g, 1.13 mol) and pyruvic acid (99.44 g, 1.13 mol) in methanol (100 mL) under argon. The reaction mixture was cooled to 10° C. A freshly prepared solution of potassium hydroxide (95.2 g, 1.7 mol) in methanol (350 mL) was added over 30 min. During the addition, the solution turned yellow and eventually a precipitate was formed. The reaction was allowed to warm to room temperature and was placed in a refrigerator overnight. The granular solid in the flask was collected, and was suspended over a cold mixture of methanol (500 mL) and ether (500 mL). After stirring for 1 hr, the solid was collected and dried in a desiccator under high vacuum to give 185 g of a solid. This solid was dissolved in water (1500 mL) and extracted with ethyl acetate (2×200 mL). The aqueous layer was acidified with 3M HCl to pH 2 and extracted with dichloromethane (5×250 mL). The combined organic layers were washed with brine (2×250 mL), dried over magnesium sulfate (30 g) and concentrated under reduced pressure to give 84 g of intermediate 1 as an oil which solidified (32%).
Reaction SMILES: [I:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([N+:11]([O-])=O)[CH:3]=1.Cl.[CH3:15][O:16][C:17](=[O:29])[CH:18]([NH2:28])[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=1.O>O=S(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:15][O:16][C:17](=[O:29])[C@@H:18]([NH:28][C:6](=[O:8])[C:5]1[CH:9]=[CH:10][C:2]([I:1])=[CH:3][C:4]=1[NH2:11])[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=1
Reactant: O=C(O)c1ccc(I)cc1[N+](=O)[O-]
Reactant: COC(=O)C(N)Cc1ccc(Cl)c(Cl)c1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: O
Solvent: O=S(Cl)Cl
Product: COC(=O)[C@H](Cc1ccc(Cl)c(Cl)c1)NC(=O)c1ccc(I)cc1N
Temperature: 25 °C
Reaction time: 8 h
Yield: 52.9 %

Procedure:
A solution of 4-iodo-2-nitrobenzoic acid (0.35 g, 1.20 mmol) dissolved in SOCl2 (5 mL) was heated at reflux for 2 h. The mixture was concentrated and the resulting liquid was dissolved in DMF (5 mL). DMAP (161 mg, 1.32 mmol) and 2-amino-3-(3,4-dichloro-phenyl)-propionic acid methyl ester hydrochloride (0.37 g, 1.32 mmol) were added and the solution was stirred overnight at rt. The mixture was poured into water and extracted with EtOAc (3×). The organic layers were combined, dried (MgSO4), and concentrated to provide the crude product as a yellow oil. The oil was purified by flash chromatography (hexanes/EtOAc) to provide the product as a colorless oil (50%, 313 mg). 1H NMR (400 MHz, CDCl3): 7.59 (d, J=8.1, 2H), 7.37 (d, J=8.2, 1H), 7.28 (d, J=2.0, 1H), 7.18 (d, J=8.0, 1H), 7.04 (dd, J=8.2, 2.0, 1H), 6.49 (d, J=7.4, 1H), 5.10-5.04 (m, 1H), 3.81 (s, 3H), 3.33-3.17 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[CH3:9].[C:10]1([CH3:22])[CH:15]=[CH:14][C:13]([S:16]([N:19]=[C:20]=[O:21])(=[O:18])=[O:17])=[CH:12][CH:11]=1>C1(C)C=CC=CC=1.C(Cl)Cl>[Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:20]([NH:19][S:16]([C:13]2[CH:14]=[CH:15][C:10]([CH3:22])=[CH:11][CH:12]=2)(=[O:18])=[O:17])=[O:21])=[CH:4][C:3]=1[CH3:9]
Reactant: Cc1cc(N)ccc1Br
Reactant: Cc1ccc(S(=O)(=O)N=C=O)cc1
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)NC(=O)Nc2ccc(Br)c(C)c2)cc1
Reaction time: 8 h
Yield: 80 %

Procedure:
A solution of 5.58 g of 4-bromo-3-methyl-aniline in 20 ml of toluene and 5 ml of methylene chloride was added to a solution of 5.91 g of p-toluene-sulfonyl isocyanate in 50 ml of toluene and 10 ml of methylene chloride under a nitrogen atmosphere. The mixture was stirred overnight and filtered, providing 9.19 g of the title product, m.p. 178°-180° C.
Reaction SMILES: [Na].[CH3:2][CH:3]([SH:5])[CH3:4].[N+:6]([C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=1)[CH2:12]Cl)([O-:8])=[O:7]>CO>[N+:6]([C:9]1[CH:16]=[CH:15][CH:14]=[C:11]([CH2:12][S:5][CH:3]([CH3:4])[CH3:2])[CH:10]=1)([O-:8])=[O:7]
Reactant: O=[N+]([O-])c1cccc(CCl)c1
Reactant: CC(C)S
Agent: [Na]
Solvent: CO
Product: CC(C)SCc1cccc([N+](=O)[O-])c1
Temperature: -15 °C
Reaction time: 2 h

Procedure:
A solution of sodium methoxyde (15.5 mL, 25 wt % in methanol) was diluted with methanol (85 mL) and treated with 2-propanethiol (6.3 mL) at room temperature for 60 minutes, cooled to −15° C., treated with 3-nitrobenzylchloride (10 g) in 3 portions, kept for 2 hours at −15° C., then the temperature was increased to room temperature. The reaction mixture was concentrated in vacuo, treated with diethyl ether (300 mL), washed with water (2×100 mL) and brine (100 mL), dried with sodium sulfate and evaporated to dryness. The title compound (12.3 g) was thus obtained and used without further purification.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([I:15])[CH:10]=2)[CH:5]=[CH:4][N:3]=1.[C:16](=O)([O-])[O-].[K+].[K+].CI.O>CN(C)C=O>[Cl:1][C:2]1[N:7]=[C:6]([N:8]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([I:15])[CH:10]=2)[CH3:16])[CH:5]=[CH:4][N:3]=1
Reactant: Clc1nccc(Nc2cccc(I)c2)n1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CI
Solvent: CN(C)C=O
Product: CN(c1cccc(I)c1)c1ccnc(Cl)n1
Temperature: 20 °C
Reaction time: 5 h
Yield: 76.3 %

Procedure:
A solution of 2-chloro-N-(3-iodophenyl)pyrimidin-4-amine (1.1 g, 3.3 mmol) and potassium carbonate (0.92 g, 6.6 mmol) in N,N-dimethylformamide (6.6 mL) was treated with methyl iodide (0.52 mL, 8.3 mmol) and stirred at 20° C. for 5 h. The reaction mixture was poured into water (50 mL) and extracted with ethyl acetate (200 mL). The organic layer was separated and washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to a crude solid. This material was purified by flash column chromatography to give the desired product (0.87 g, 75%) as a tan oil. LCMS for C11H10ClIN3 (M+H)+: m/z=346.0.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:16]=[C:15]([Br:17])[CH:14]=[CH:13][C:4]=1[O:5][CH2:6][CH2:7][N:8]1[CH2:12][CH2:11][CH2:10][CH2:9]1.[H-].[Na+].[CH2:20](Br)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CN(C=O)C.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH2:20]([O:1][CH2:2][C:3]1[CH:16]=[C:15]([Br:17])[CH:14]=[CH:13][C:4]=1[O:5][CH2:6][CH2:7][N:8]1[CH2:9][CH2:10][CH2:11][CH2:12]1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: BrCc1ccccc1
Reactant: OCc1cc(Br)ccc1OCCN1CCCC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [H-]
Agent: [I-]
Solvent: CN(C)C=O
Product: Brc1ccc(OCCN2CCCC2)c(COCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 50.8 %

Procedure:
To a solution containing (1.00 g, 3.33 mmol) 1-[2-(2-hydroxymethyl-4-bromophenoxy)ethyl]pyrrolidine (Example 205, Part A) in 65 mL of anhydrous DMF was added 173 mg of NaH (60% dispersion in mineral spirits). The dropwise of addition of (0.40 mL, 3.33 mmol) benzyl bromide and (12.0 mg, 0.0333 mmol) of tetrabutylammonium iodide followed. The reaction was stirred at room temperature, for 1.5 h. The reaction was quenched by the addition of 100 mL of water. The mixture was extracted with EtOAc (3×500 mL). The combined organic layers were washed with brine (1×300 mL) and dried over MgSO4 and concentrated under reduced pressure and azeotroped with xylenes to remove residual DMF. Purification by flash chromatography (silica gel, 3.5% to 5.5% [10% conc NH4OH in MeOH]/CH2Cl2) afforded 660 mg (1.69 mmol, 51%) of a yellow oil.
Reaction SMILES: CC(C)([O-])C.[K+].Cl.[F:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[CH2:15][NH:14][CH2:13][CH2:12]2.Br[C:20]1[CH:25]=[C:24]([CH3:26])[C:23]([NH:27][C:28](=[O:34])[CH2:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[C:22]([CH3:35])[CH:21]=1>C1(C)C=CC=CC=1>[F:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[CH2:15][N:14]([C:20]1[CH:25]=[C:24]([CH3:26])[C:23]([NH:27][C:28](=[O:34])[CH2:29][C:30]([CH3:31])([CH3:32])[CH3:33])=[C:22]([CH3:35])[CH:21]=1)[CH2:13][CH2:12]2
Reactant: Fc1ccc2c(c1)CCNC2
Reactant: Cc1cc(Br)cc(C)c1NC(=O)CC(C)(C)C
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: Cc1ccccc1
Product: Cc1cc(N2CCc3cc(F)ccc3C2)cc(C)c1NC(=O)CC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Bis(dibenzylidineacetone)palladium (390 mg, 0.68 mmol) and (2′-dicyclohexyl phosphanyl-biphenyl-2-yl)-dimethylamine (800 mg, 2.0 mmol) were added to dry toluene (150 mL purged with argon for 30 minutes) and stirred for 30 minutes under argon. Potassium tert-butoxide (4.75 mg, 42.3 mmol), 6-fluoro-1,2,3,4-tetrahydro-isoquinoline hydrochloride salt (3.2 g, 17.0 mmol), and N-(4-bromo-2,6-dimethyl-phenyl)-3,3-dimethyl-butanamide (5 g, 16.8 mmol) were then added, and the reaction mixture was stirred at 80° C. overnight. The reaction mixture was then cooled to room temperature and recrystallized from toluene to afford the title compound as a solid. (5.11 g, 83%).
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[C:9]1([C@H:15]2[O:22][CH2:21][C@H:20]3[N:16]2[C:17](=[O:23])[CH2:18][CH2:19]3)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[CH3:24][O:25][CH2:26]Cl.[Cl-].[NH4+]>C1COCC1>[CH3:24][O:25][CH2:26][C@H:18]1[C:17](=[O:23])[N:16]2[C@H:20]([CH2:21][O:22][C@@H:15]2[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:19]1
Reactant: O=C1CC[C@H]2CO[C@H](c3ccccc3)N12
Reactant: COCCl
Agent: CC(C)[N-]C(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COC[C@@H]1C[C@H]2CO[C@H](c3ccccc3)N2C1=O
Temperature: -78 °C
Reaction time: 1.5 h
Yield: 8.6 %

Procedure:
To a solution of lithium diisopropylamide (110 mmol, 100 ml of THF, prepared from diisopropylamine (15.6 ml, 110 mmol) and n-butyl lithium (70.1 ml, 1.57M, 110 mmol)) was added (2R,5S)-2-phenyl-3-oxa-1-azabicyclo(3.3.0)octan-8-one (10.2 g, 50 mmol) under stirring at −78° C. After stirring at the same temperature for 1 hour, a solution of chloromethyl methyl ether (5.7 ml, 75 mmol) in THF (50 ml) was added to the reaction mixture and stirring was conducted further at −78° C. for 90 minutes. The reaction mixture was poured in a saturated aqueous solution of ammonium chloride, followed by extraction with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and distilled under reduced pressure to remove the solvent. The residue was purified by silica gel column chromatography (middle pressure Yamazen, linear gradient of n-hexane/ethyl acetate from 9:1 to 7:3, 30 ml/min, φ 80 mm×300 mm, range 0.08) to give (2R,5S,7S)-7-methoxymethyl-2-phenyl-3-oxa-1-azabicyclo(3.3.0)octan-8-one (1.06 g, 9%) as a colorless oil.
Reaction SMILES: S(Cl)(Cl)(=O)=O.Br.C[O:8][C:9](=[O:33])[CH:10]([NH:16][S:17]([C:20]1[CH:32]=[CH:31][C:23]2[O:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[C:22]=2[CH:21]=1)(=[O:19])=[O:18])[CH2:11][CH2:12][CH2:13][CH2:14][NH2:15]>ClCCl.C(N(CC)CC)C>[CH:21]1[C:22]2[C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=3[O:24][C:23]=2[CH:31]=[CH:32][C:20]=1[S:17]([NH:16][CH:10]([CH2:11][CH2:12][CH2:13][CH2:14][NH:15][C:23](=[O:24])[CH:22]([C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:25]=1)[CH2:21][CH3:20])[C:9]([OH:8])=[O:33])(=[O:18])=[O:19]
Reactant: COC(=O)C(CCCCN)NS(=O)(=O)c1ccc2oc3ccccc3c2c1
Agent: Br
Solvent: O=S(=O)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCC(C(=O)NCCCCC(NS(=O)(=O)c1ccc2oc3ccccc3c2c1)C(=O)O)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
The appropriate sulfonyl chloride (1.5 equivalents, 0.18 mmol) and 70 mg of a morpholino-resin (prepared according to Booth and Hodges, Supra., 1997) were mixed in 1 mL dichloromethane in each of 10 different vials. One milliliter of a 0.12 M stock solution of 6-amino-2-(dibenzofuran-2-sulfonylamino)-hexanoic acid methyl ester hydrobromide in triethylamine was added to each of the vials. The vials were sealed and shaken for 16 hours at room temperature. An excess of an amino-resin and an isocyanato-resin (also both prepared according to Booth and Hodges, Supra, 1997) was added to each vial and shaken for 16 hours to quench unreacted starting materials. Each reaction was filtered through a plug of glass wool, and the resins were washed with 2 mL tetrahydrofuran. The filtrate was evaporated under a stream of nitrogen, and the residue in each vial was redissolved in 1 mL dioxane. One milliliter of a 0.6 M aqueous solution of lithium hydroxide was added, and the resulting mixtures were shaken for 16 hours. Each reaction was washed with diethyl ether, and the aqueous layer was then acidified with 1 molar hydrochloric acid. The reactions were extracted with ethyl acetate and evaporated under a stream of nitrogen to leave the expected products. The compounds were analyzed by LC/MS to determine purity and presence of expected molecular ion.
Reaction SMILES: [CH3:1][O:2][CH:3]=[CH:4][C:5]([O:7][Si](C)(C)C)=[CH2:6].[C:12]([O:16][CH2:17][CH3:18])(=[O:15])C=O.O.FC(F)(F)C(O)=O>C1COCC1>[CH2:17]([O:16][C:12]([CH:1]1[CH2:6][C:5](=[O:7])[CH:4]=[CH:3][O:2]1)=[O:15])[CH3:18]
Reactant: CCOC(=O)C=O
Reactant: C=C(C=COC)O[Si](C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)C1CC(=O)C=CO1
Reaction time: 0.5 h
Yield: 102.2 %

Procedure:
ZnCl (0.63 g, 4.6 mmol) was dissolved in anhydrous THF (15 mL) and added to a solution of 1-methoxy-3-(trimethylsilyloxy)-1,3-butadiene (7.94 g, 46.0 mmol) and ethyl glyoxalate (7.05 g, 69.0 mmol) in totuene (30 mL) at room temperature. After stirring for 30 minutes, water (30 mL) and TFA (trifluoracetic acid) (2 mL) were added and the mixture was stirred vigorously for 20 min. After concentration, the residue was partitioned between EtOAc (200 mL) and water (100 mL). The separated organic layer was washed with brine, dried over sodium sulfate, and concentrated to give 8.0 g (100%) of brown oil which was carried to the next step without further purification. 1H NMR (CDCl3) δ 1.30 (t, 3H), 2.85 (d, 2H), 4.26 (q 2H), 5.00 (t, 1H), 5.48 (d, 1H), 7.39 (d, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[C:10]([Cl:30])=[C:11]([N:17]2[CH2:22][CH2:21][N:20]([CH:23]3[CH2:26][O:25][CH2:24]3)[CH:19]([C:27]([O-:29])=O)[CH2:18]2)[CH:12]=[C:13]([C:15]#[N:16])[CH:14]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Li].CCN(C(C)C)C(C)C.[NH:41]1[CH2:46][CH2:45][O:44][CH2:43][CH2:42]1.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC>C1COCC1.C1(C)C=CC=CC=1>[Cl:30][C:10]1[C:11]([N:17]2[CH2:22][CH2:21][N:20]([CH:23]3[CH2:26][O:25][CH2:24]3)[CH:19]([C:27]([N:41]3[CH2:46][CH2:45][O:44][CH2:43][CH2:42]3)=[O:29])[CH2:18]2)=[CH:12][C:13]([C:15]#[N:16])=[CH:14][C:9]=1[NH:8][C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2]
Reactant: C1COCCN1
Reactant: CC(C)(C)OC(=O)Nc1cc(C#N)cc(N2CCN(C3COC3)C(C(=O)[O-])C2)c1Cl
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: [Li]
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)Nc1cc(C#N)cc(N2CCN(C3COC3)C(C(=O)N3CCOCC3)C2)c1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4-(3-((tert-butoxycarbonyl)amino)-2-chloro-5-cyanophenyl)-1-(oxetan-3-yl)piperazine-2-carboxylate, lithium salt (200 mg, 0.452 mmol) was azeotroped 3× with toluene and 4 Å molecular sieves were added. THF (3 mL) was added, followed by DIPEA (0.118 mL, 0.677 mmol), morpholine (0.117 mL, 1.355 mmol), and T3P (0.538 mL, 0.903 mmol). The reaction was stirred at room temperature for 1 h. The reaction mixture was filtered through a small pad of celite, rinsing with EtOAc. The solvent was removed in vacuo and the material was purified by flash column chromatography (0-4% MeOH/DCM). Tert-butyl (2-chloro-5-cyano-3-(3-(morpholine-4-carbonyl)-4-(oxetan-3-yl)piperazin-1-yl)phenyl)carbamate (112 mg) was obtained as an off-white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([NH2:8])=[N:6][CH:7]=1.Br[C:10]1[N:11]=[C:12]2[C:18]([C:19]([NH:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[CH:17][N:16]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:33])([CH3:32])[CH3:31])[C:13]2=[N:14][CH:15]=1.CC(C)([O-])C.[Na+].CN(C=O)C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O.C1(C)C=CC=CC=1>[C:22]([NH:21][C:19]([C:18]1[C:12]2[C:13](=[N:14][CH:15]=[C:10]([NH:8][C:5]3[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][N:6]=3)[N:11]=2)[N:16]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:33])([CH3:32])[CH3:31])[CH:17]=1)=[O:20])([CH3:25])([CH3:24])[CH3:23]
Reactant: Cc1ccc(N)nc1
Reactant: CC(C)(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(Br)nc12
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(Nc2cnc3c(n2)c(C(=O)NC(C)(C)C)cn3COCC[Si](C)(C)C)nc1
Temperature: 140 °C
Yield: 58.1 %

Procedure:
To a mixture of 5-methylpyridin-2-amine (38.0 mg, 351 μmol), 2-bromo-N-tert-butyl-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (100 mg, 234 μmol) (R)-(+)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (7.28 mg, 11.7 μmol), palladium(II) acetate (13.1 mg, 58.5 μmol) and sodium tert-butoxide (56.2 mg, 585 μmol) was added DMF (1 mL) and toluene (500 μL) and the mixture heated in a microwave at 140° C. for 20 min. The dark mixture generated was poured into water and extracted with ethyl acetate. The organic layers were combined, washed with brine, dried (magnesium sulfate), filtered and purified by chromatography (silica, 30-70% ethyl acetate in hexanes) to give N-tert-butyl-2-(5-methylpyridin-2-ylamino)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (62 mg, 136 μmol, 58%) as an off white solid. MS (EI/CI) m/z: 455.3 [M+H].
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:18](=[O:19])[N:17]2[C:12]([C:13]([CH3:21])([CH3:20])[O:14][CH2:15][CH2:16]2)=[N:11][C:10]=1[C:22](O)=[O:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[N:33]1[CH2:36][CH2:35][C:34]1=[O:37]>>[O:37]=[C:34]1[CH2:35][CH2:36][N:33]1[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=1[CH2:26][NH:25][C:22]([C:10]1[N:11]=[C:12]2[N:17]([C:18](=[O:19])[C:9]=1[O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH2:16][CH2:15][O:14][C:13]2([CH3:21])[CH3:20])=[O:23]
Reactant: CC1(C)OCCn2c1nc(C(=O)O)c(OCc1ccccc1)c2=O
Reactant: NCc1ccccc1N1CCC1=O
Product: CC1(C)OCCn2c1nc(C(=O)NCc1ccccc1N1CCC1=O)c(OCc1ccccc1)c2=O

Procedure:
The title compound can be prepared from intermediate 27, 3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido-[2,1-c][1,4]oxazine-2-carboxylic acid and 1-(2-(aminomethyl)phenyl)azetidin-2-one, derived from reduction of intermediate 115, 2-(2-oxoazetidin-1-yl)benzonitrile. 1H NMR (400 MHz, CDCl3) δ ppm: 8.67 (1H, brt, J=6.3 Hz), 7.60 (1H, dd, J=1.3, 7.6 Hz), 7.53–7.50 (1H, dd, m), 7.34–7.24 (5H, m), 7.18 (1H, ddd(dt), J=1.2, 7.4 Hz), 7.10 (1H, dd, J=1.2, 8.0 Hz), 5.27 (2H, s), 4.60 (2H, d, J=6.3 Hz), 4.01–3.95 (4H, m), 3.71 (2H, t, J=4.5 Hz), 3.10 (2H, t, J=4.5 Hz), 1.60 (6H, s); LCMS (+ESI, M+H+) m/z 489.
Reaction SMILES: CC1(C)[N:6](C(OC(C)(C)C)=O)[C@:5]([CH3:38])([C:14](=O)[CH2:15][C:16]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])=[C:20]([C:33]([F:36])([F:35])[F:34])[CH:19]=2)=O)[CH2:4][O:3]1.O.[NH2:41][NH2:42].C(O)(C(F)(F)F)=O.C(Cl)Cl>CO>[NH2:6][C@@:5]([C:14]1[CH:15]=[C:16]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])=[C:20]([C:33]([F:36])([F:35])[F:34])[CH:19]=2)[NH:42][N:41]=1)([CH3:38])[CH2:4][OH:3]
Reactant: NN
Reactant: CCCCCCCCOc1ccc(C(=O)CC(=O)[C@]2(C)COC(C)(C)N2C(=O)OC(C)(C)C)cc1C(F)(F)F
Solvent: O
Solvent: ClCCl
Solvent: CO
Product: CCCCCCCCOc1ccc(-c2cc([C@@](C)(N)CO)n[nH]2)cc1C(F)(F)F

Procedure:
The solution of (S)-tert-butyl 2,2,4-trimethyl-4-(3-(4-(octyloxy)-3-(trifluoromethyl)-phenyl)-3-oxo-propanoyl)oxazolidine-3-carboxylate (27 mg, 0.05 mmol, 1.0 equiv) and hydrazine monohydrate (2.7 μL, 0.055 mmol, 1.1 equiv) in methanol (0.2 mL) was stirred at room temperature for 2 hours. The reaction was condensed and the residue was treated with 20% TFA-DCM for 30 min. After removal of excess amount of TFA and DCM, the crude product was purified by prep. HPLC and afforded the title compound as mono-TFA salt (5.0 mg). MS (ESI, M+H+)=414.0; 1H NMR (400 MHz, CD3OD) δ 7.81 (s, 1H), 7.76 (d, 1H, J=9.2 Hz), 7.14 (d, 1H, J=9.2 Hz), 6.56 (s, 1H), 4.03 (t, 2H, J=6.0 Hz), 3.79, 3.67 (AB, 2H, J=12.0 Hz), 1.76-1.69 (m, 2H), 1.59 (s, 3H), 1.46-1.38 (m, 2H), 1.32-1.16 (m, 8H), 0.81 (t, 3H, J=7.2 Hz).
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]([C:13](=[O:15])[CH3:14])[CH:10]=[CH:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O([Si](C)(C)C)S(C(F)(F)F)(=O)=O.C(N(CC)CC)C.[CH2:35]([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=1[S:45][CH:46]([C:50](O)=[O:51])[C:47](O)=[O:48])[CH:36]([CH3:38])[CH3:37]>C(Cl)Cl>[C:7]1([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:12]=[CH:11][CH:10]=[C:9]([C:13]2[O:15][C:47](=[O:48])[C:46]([S:45][C:40]3[CH:41]=[CH:42][CH:43]=[CH:44][C:39]=3[CH2:35][CH:36]([CH3:37])[CH3:38])=[C:50]([OH:51])[CH:14]=2)[CH:8]=1
Reactant: CC(C)Cc1ccccc1SC(C(=O)O)C(=O)O
Reactant: CC(=O)c1cccc(-c2ccccc2)c1
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)Cc1ccccc1Sc1c(O)cc(-c2cccc(-c3ccccc3)c2)oc1=O

Procedure:
The title compound was prepared by Method A using 3'-phenylacetophenone (2 g, 10.20 mmol), trimethylsilyl triflate (2.27 g, 10.20 mmol), triethylamine (2.06 g, 20.40 mmol), methylene chloride (20 mL), and diethyl ester of [(2-isobutylphenyl)thio]propanedioic acid (1.14 g, 5.1 mmol). m.p. 187°-188° C. 1H NMR (400 MHz, DMSO-d6) δ 0.83 (d, 6H), 1.78 (m, 1H), 2.4 (d, 2H), 7.03 (s, 1H), 7.08 (s, 4H), 7.44 (t, 1H), 7.53 (t, 2H), 7.67 (t, 1H), 7.75 (s, 1H), 7.78 (s, 1H), 7.86 (m, 2H), 8.08 (s, 1H).
Reaction SMILES: [OH:1][C:2]([C:29]1[CH:43]=[CH:42][C:32]2[C:33]3[CH2:34][N:35]([CH3:41])[C:36](=[O:40])[C:37]=3[CH:38]=[CH:39][C:31]=2[CH:30]=1)([C:5]1[N:6]=[CH:7][N:8](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:9]=1)[CH2:3][CH3:4].C1COCC1>C(O)=O>[OH:1][C:2]([C:29]1[CH:43]=[CH:42][C:32]2[C:33]3[CH2:34][N:35]([CH3:41])[C:36](=[O:40])[C:37]=3[CH:38]=[CH:39][C:31]=2[CH:30]=1)([C:5]1[N:6]=[CH:7][NH:8][CH:9]=1)[CH2:3][CH3:4]
Reactant: CCC(O)(c1ccc2c3c(ccc2c1)C(=O)N(C)C3)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Solvent: C1CCOC1
Solvent: O=CO
Product: CCC(O)(c1ccc2c3c(ccc2c1)C(=O)N(C)C3)c1c[nH]cn1
Temperature: 60 °C
Yield: 84.2 %

Procedure:
7-[1-hydroxy-1-(1-trityl-1H-imidazol-4-yl)propyl]-2-methyl-1,2-dihydro-3H-benzo[e]isoindol-3-one (100 mg) was dissolved in 90% formic acid (1 mL) and THF (1 mL) and the mixture was stirred with heating at 60° C. for 30 min. The reaction mixture was concentrated, and saturated aqueous sodium hydrogen carbonate was added to the residue. The mixture was extracted with a mixed solution of ethyl acetate-THF (1:1), dried and concentrated, and the residue was purified by silica gel chromatography to give the title compound (48 mg) as a colorless powder.
Reaction SMILES: CO.[CH3:3][O:4][C:5](=[O:17])[C:6]1[CH:11]=[CH:10][C:9]([O:12][C:13](=[O:15])[CH3:14])=[CH:8][C:7]=1[OH:16].[CH:18]1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOC(/N=N/C(OCC)=O)=O>ClCCl>[CH3:3][O:4][C:5](=[O:17])[C:6]1[CH:11]=[CH:10][C:9]([O:12][C:13](=[O:15])[CH3:14])=[CH:8][C:7]=1[O:16][CH3:18]
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: COC(=O)c1ccc(OC(C)=O)cc1O
Agent: CCOC(=O)/N=N/C(=O)OCC
Solvent: ClCCl
Solvent: CO
Product: COC(=O)c1ccc(OC(C)=O)cc1OC
Temperature: 25 °C
Reaction time: 96 h
Yield: 106.7 %

Procedure:
MeOH (0.3 mL, 7.4 mmol) was added to the product from step 1 (0.962 g, 4.6 mmol), Ph3P (1.79 g, 6.8 mmol), and dichloromethane (10 mL). Then DEAD (1.32 mL, 8.4 mmol) was added to the reaction. Reaction was stirred at room temperature for 4 days. Reaction solution was concentrated by rotary evaporation and the resulting residue was purified with silica gel prep plates and 1:3 EtOAc/Hexane as eluent. Obtained 1.10 g of 4-Acetoxy-2-methoxy-benzoic acid methyl ester in quantitative yield.