Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[C:5]1[CH:10]=[C:9]([CH3:11])[N:8]=[C:7]([CH:12]=[CH:13][CH3:14])[CH:6]=1)[CH3:2]>C1COCC1.[Pd]>[CH2:1]([O:3][C:4](=[O:15])[C:5]1[CH:10]=[C:9]([CH3:11])[N:8]=[C:7]([CH2:12][CH2:13][CH3:14])[CH:6]=1)[CH3:2]
Reactant: CC=Cc1cc(C(=O)OCC)cc(C)n1
Agent: [Pd]
Solvent: C1CCOC1
Product: CCCc1cc(C(=O)OCC)cc(C)n1
Temperature: 25 °C
Reaction time: 15 h
Yield: 101.8 %

Procedure:
2-propenyl-6-methylisonicotinic acid ethyl ester (2.25 g, 10.9 mmol) is dissolved in THF (100 mL), Pd/C (300 mg, 10% Pd) is added and the mixture is stirred under 1 atm H2 at rt for 15 h. The catalyst is filtered off and the filtrate is evaporated to give 2-propyl-6-methylisonicotinic acid ethyl ester (2.30 g) as a colourless oil; LC-MS: tR=0.65 min, [M+1]+=208.12.
Reaction SMILES: [H-].[K+].[CH:3]1([C@@:6]23[CH2:13][CH2:12][C:11](=[O:14])[N:10]2[C@@H:9]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:8][O:7]3)[CH2:5][CH2:4]1.C1(S(OC)=O)C=CC=CC=1.C([O-])([O-])=O.[Na+].[Na+]>C1COCC1.C1(C)C=CC=CC=1>[CH:3]1([C@@:6]23[CH:13]=[CH:12][C:11](=[O:14])[N:10]2[C@@H:9]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:8][O:7]3)[CH2:5][CH2:4]1
Reactant: O=C1CC[C@@]2(C3CC3)OC[C@H](c3ccccc3)N12
Agent: COS(=O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: O=C1C=C[C@@]2(C3CC3)OC[C@H](c3ccccc3)N12
Temperature: 25 °C
Reaction time: 16 h
Yield: 72.1 %

Procedure:
To potassium hydride (35 weight % in oil, washed with heptane (×3), 3.01 g, 26.3 mmol), in THF (20 mL) was added a solution of (3S,7aS)-7a-cyclopropyl-3-phenyltetrahydropyrrolo[2,1-b]oxazol-5(6H)-one (preparation #23) (2.56 g, 10.5 mmol) in THF (20 mL) dropwise via an addition funnel. A solution of methyl benzenesulfinate (1.97 g, 12.6 mmol) in THF (20 mL) was then added dropwise via an addition funnel. The reaction mixture was stirred at ambient temperature for about 16 hours. The reaction was quenched by the addition of water (4.2 mL). The mixture was concentrated and the residue was partitioned between 0.5 M H3PO4 (100 mL) and DCM (200 mL). The layers were separated and the aqueous layer was extracted with DCM (3×100 mL). The combined organic extracts were washed with brine, dried over MgSO4, filtered and concentrated to yield a light brown solid. Toluene (83 mL) was added followed by solid Na2CO3 (10.35 g). The reaction mixture was refluxed for about 16 hours and then filtered and concentrated in vacuo. The residue was purified on a Biotage silica gel column eluting with heptane/EtOAc (4:1). A second purification on silica gel eluting DCM/EtOAc (1:0 to 4:1) afforded (3S,7aR)-7a-cyclopropyl-3-phenyl-2,3-dihydropyrrolo[2,1-b]oxazol-5(7aH)-one (1.82 g, 7.57 mmol). 1H NMR (CDCl3-d) δ 7.34 (m, 4H), 7.28 (m, 1H), 7.11 (d, 1H), 6.08 (d, 1H), 5.06 (t, 1H), 4.69 (t, 1H), 4.43 (dd, 1H), 1.14 (m, 1H), 0.45 (m, 2H), 0.32 (m, 1H), 0.21 (m, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH:9]=[C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13](=[O:20])[NH:12][C:11]2=[O:21])=[CH:4][CH:3]=1.Cl.[Cl:23][CH2:24][CH2:25][NH:26][CH2:27][CH2:28]Cl>>[ClH:23].[N:1]1([C:2]2[CH:7]=[CH:6][C:5]([NH:8][CH:9]=[C:10]3[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[C:13](=[O:20])[NH:12][C:11]3=[O:21])=[CH:4][CH:3]=2)[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1
Reactant: Nc1ccc(NC=C2C(=O)NC(=O)c3ccccc32)cc1
Reactant: ClCCNCCCl
Agent: Cl
Product: O=C1NC(=O)c2ccccc2C1=CNc1ccc(N2CCNCC2)cc1
Reaction time: 0.17 h
Yield: 99.8 %

Procedure:
A dry mixture of 4-[(4-Amino-phenylamino)-methylene]-4H-isoquinoline-1,3-dione (140 mg, 0.5 mmol) and bis(chloroethyl)amine hydrochloride (90 mg, 0.5 mmol) is placed in a microwave at 900 W for 10 minutes. The crude product, 4-[(4-piperazin-1-yl-phenylamino)-methylene]-4H-isoquinoline-1,3-dione hydrochloride (192 mg), thus obtained is used as such for the next reaction.
Reaction SMILES: N1C(C)=CC=CC=1C.[C:9]([O:17][C@@H:18]([CH3:39])[C:19](=[O:38])[C@H:20]([CH3:37])[C@H:21]([OH:36])/[C:22](/[CH3:35])=[CH:23]/[CH2:24][O:25][CH2:26][C:27]1[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=1)(=[O:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[Si:40](OS(C(F)(F)F)(=O)=O)([C:43]([CH3:46])([CH3:45])[CH3:44])([CH3:42])[CH3:41].C(=O)([O-])O.[Na+]>ClCCl>[C:9]([O:17][C@@H:18]([CH3:39])[C:19](=[O:38])[C@H:20]([CH3:37])[C@H:21]([O:36][Si:40]([C:43]([CH3:46])([CH3:45])[CH3:44])([CH3:42])[CH3:41])/[C:22](/[CH3:35])=[CH:23]/[CH2:24][O:25][CH2:26][C:27]1[CH:28]=[CH:29][C:30]([O:33][CH3:34])=[CH:31][CH:32]=1)(=[O:16])[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Reactant: COc1ccc(COC/C=C(\C)[C@@H](O)[C@@H](C)C(=O)[C@H](C)OC(=O)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: COc1ccc(COC/C=C(\C)[C@@H](O[Si](C)(C)C(C)(C)C)[C@@H](C)C(=O)[C@H](C)OC(=O)c2ccccc2)cc1
Temperature: -78 °C
Yield: 100.4 %

Procedure:
2,6-Lutidine (38.2 ml, 328 mmol) was added to an anhydrous dichloromethane (1.00 l) solution of (1S,3R,4S,5E)-4-hydroxy-7-[(4-methoxybenzyl)oxy]-1,3,5-trimethyl-2-oxohept-5-en-1-yl benzoate (70.0 g, 164 mmol) at −78° C. under nitrogen atmosphere. Trifluoromethanesulfonic acid tert-butyldimethylsilyl ester (56.5 ml, 246 mmol) was added dropwise to the reaction solution over 10 minutes. After the reaction solution was stirred at −78° C. for one and a half hour, a saturated sodium hydrogen carbonate aqueous solution was added at −78° C. The reaction solution was warmed to room temperature, which was then extracted with dichloromethane. After the organic layer was washed with water and brine sequentially, it was dried over anhydrous magnesium sulfate. After the drying agent was filtered off, the organic layer was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (Kanto Chemical, commercial name Silica gel 60N, granular, neutral, 0.040 mm-0.100 mm; n-heptane:ethyl acetate=8:1) to obtain the title compound (89.0 g) as a colorless oil.
Reaction SMILES: C([O:3][C:4](=[O:27])[CH:5]([CH:11]([C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=2[F:26])=[CH:15][CH:14]=1)[CH3:12])C(OCC)=O)C.[OH-].[K+].Cl.C(=O)=O>C(O)(=O)C>[F:26][C:20]1[CH:21]=[C:22]([F:25])[CH:23]=[CH:24][C:19]=1[C:16]1[CH:17]=[CH:18][C:13]([CH:11]([CH3:12])[CH2:5][C:4]([OH:27])=[O:3])=[CH:14][CH:15]=1
Reactant: CCOC(=O)C(C(=O)OCC)C(C)c1ccc(-c2ccc(F)cc2F)cc1
Agent: Cl
Agent: O=C=O
Agent: [K+]
Solvent: CC(=O)O
Product: CC(CC(=O)O)c1ccc(-c2ccc(F)cc2F)cc1

Procedure:
A solution of crude 1-(2',4'-difluoro-4-biphenylyl)-ethylmalonic acid, obtained by saponifying 2 g. of 1-(2',4'-difluoro-4-biphenylyl)ethylmalonic acid diethyl ester with ethanolic KOH under N2, in 20 ml. of acetic acid and 20 ml. of 15% HCl is heated under reflux under N2 until evolution of CO2 has ceased. After cooling, the customary work up gives 3-(2',4'-difluoro-4-biphenylyl)butyric acid, m.p. 109°-110°.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:14][C:15]2[CH:19]=[C:18]([CH3:20])[NH:17][N:16]=2)[N:3]=1.[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([NH2:28])=[CH:24][CH:23]=1>>[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([NH:28][C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=3)[CH:5]=[C:4]([NH:14][C:15]3[CH:19]=[C:18]([CH3:20])[NH:17][N:16]=3)[N:3]=2)=[CH:24][CH:23]=1
Reactant: COc1ccc2c(Cl)nc(Nc3cc(C)[nH]n3)cc2c1
Reactant: Nc1ccc(Cl)cc1
Product: COc1ccc2c(Nc3ccc(Cl)cc3)nc(Nc3cc(C)[nH]n3)cc2c1

Procedure:
Similar procedure as described in example 273 was used, starting from (1-chloro-6-methoxy-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine and 4-chloro-phenylamine to give N1-(4-chloro-phenyl)-6-methoxy-N3-(5-methyl-1H-pyrazol-3-yl)-isoquinoline-1,3-diamine. LC-MS m/e 381(MH+).
Reaction SMILES: [C:1]([O:9][C:10]1[CH:18]=[CH:17][C:13]([C:14](O)=[O:15])=[CH:12][CH:11]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:21])=O>CN(C)C=O>[C:1]([O:9][C:10]1[CH:18]=[CH:17][C:13]([C:14]([Cl:21])=[O:15])=[CH:12][CH:11]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccc(OC(=O)c2ccccc2)cc1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: O=C(Cl)c1ccc(OC(=O)c2ccccc2)cc1

Procedure:
10.00 g (41.3 mmol) of 4-(benzoyloxy)benzoic acid and one drop of N,N-dimethylformamide are refluxed in 40 ml of thionyl chloride with stirring until gas is no longer evolved. The excess thionyl chloride is very substantially removed by distillation under reduced pressure and co-distilled twice with petroleum ether (50/70) under reduced pressure from the remaining residue for complete removal. Purification is carried out by recrystallization from 150 ml of petroleum ether (50/70)/ethyl acetate 2:1, and the crystals are washed with 4 ml of petroleum ether (50/70)
Reaction SMILES: O[CH2:2][C:3]1[O:4][C:5]2[C:10]([C:11](=[O:13])[CH:12]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.S(Cl)([Cl:16])=O>C(Cl)(Cl)Cl>[Cl:16][CH2:2][C:3]1[O:4][C:5]2[C:10]([C:11](=[O:13])[CH:12]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2
Reactant: O=c1cc(CO)oc2ccccc12
Reactant: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Product: O=c1cc(CCl)oc2ccccc12
Temperature: 25 °C
Reaction time: 24 h

Procedure:
The 2-(hydroxymethyl)-4H-chromen-4-one was dissolved in 30 ml of anhydrous chloroform at room temperature, 1 ml of thionyl chloride was added to the solution, and reaction mixture was stirred at room temperature for 24 hours. The solvent was thereafter evaporated, and the obtained liquid was dissolved in anhydrous hexane, which was also evaporated again to give 2-(chloromethyl)-4H-chromen-4-one which was further reacted without purification.
Reaction SMILES: BrCC1C=C(C=C(F)C=1)C#N.N[C:13](=[N:32]O)[C:14]1[CH:15]=[C:16]([CH:28]=[C:29]([F:31])[CH:30]=1)[CH2:17][N:18]([CH3:27])[CH2:19][C:20](OC(C)(C)C)=O.CNCC[C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39]>>[C:13]([C:14]1[CH:15]=[C:16]([CH:28]=[C:29]([F:31])[CH:30]=1)[CH2:17][N:18]([CH3:27])[CH2:19][CH2:20][C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])#[N:32]
Reactant: CN(CC(=O)OC(C)(C)C)Cc1cc(F)cc(C(N)=NO)c1
Reactant: CNCCC(=O)OC(C)(C)C
Agent: N#Cc1cc(F)cc(CBr)c1
Product: CN(CCC(=O)OC(C)(C)C)Cc1cc(F)cc(C#N)c1

Procedure:
The title compound was prepared according the general procedure 10, starting from 3-(bromomethyl)-5-fluorobenzonitrile (Intermediate 24 Step 1, 750 mg, 3.5 mmol) and tert-butyl N-methyl-beta-alaninate (670 mg, 4.2 mmol, prepared as described in Biorg. Med. Chem. (11) 2003, 3083-3099). It was isolated as a pale yellow oil. 1H NMR (DMSO-d6, 300 MHz) δ 7.73 (ddd, J=8.6, 2.6, 1.4 Hz, 1H), 7.61 (s, 1H), 7.56-7.45 (m, 1H), 3.53 (s, 2H), 2.60 (t, J=6.7 Hz, 2H), 2.38 (t, J=6.7 Hz, 2H), 2.12 (s, 3H), 1.40 (s, 9H). LC/MS (Method B): 293.3 (M+H)+. HPLC (Method A) Rt 2.61 min (Purity: 96.2%).
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][N:4]([CH3:7])[C:3]1=O.[NH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.P(Cl)(Cl)(Cl)=O>C1C=CC=CC=1>[CH3:1][N:2]1[CH2:6][CH2:5][N:4]([CH3:7])[C:3]1=[N:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: CN1CCN(C)C1=O
Reactant: Nc1ccccc1-c1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Solvent: c1ccccc1
Product: CN1CCN(C)C1=Nc1ccccc1-c1ccccc1

Procedure:
A mixture of 1,3-dimethyl-2-imidazolidinone (5.5 g) in benzene (30 ml), 2-aminobiphenyl (5.1 g) in benzene (20 ml) and phosphorus oxychloride (4.4 ml) was heated at 80°-85° C. for 20 hours to yield 2-(1,3-dimethyl-2-imidazolidinylideneamino)biphenyl (m.p. 90°-91° C.) which was recrystallised from hexane.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:15][CH3:16])=[C:6]([NH:8][C:9](=[O:14])[C:10]([F:13])([F:12])[F:11])[CH:7]=1.[CH3:17][Si:18]([C:21]#[CH:22])([CH3:20])[CH3:19].C(N(CC)CC)C>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.C1COCC1>[F:11][C:10]([F:13])([F:12])[C:9]([NH:8][C:6]1[CH:7]=[C:2]([C:22]#[C:21][Si:18]([CH3:20])([CH3:19])[CH3:17])[CH:3]=[CH:4][C:5]=1[O:15][CH3:16])=[O:14]
Reactant: C#C[Si](C)(C)C
Reactant: COc1ccc(Br)cc1NC(=O)C(F)(F)F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1ccc(C#C[Si](C)(C)C)cc1NC(=O)C(F)(F)F
Temperature: 60 °C
Yield: 43.1 %

Procedure:
To an oven-dried flask under N2 was added N-[5-bromo-2-(methyloxy)phenyl]-2,2,2-trifluoroacetamide (1.53 g, 0.005 mol), anhydrous degassed THF (100 mL), dichlorobis(triphenylphosphine)palladium(II) (0.45 g, 0.6 mmol), copper(I) iodide (73 mg, 0.38 mmol), and trimethylsilylacetylene (1.26 g, 13 mmol). Next, triethylamine (5.19 g, 50 mmol) was added dropwise and the resulting mixture was heated at 60° C. overnight. The crude reaction mixture was adsorbed to silica gel and purified by column chromatography (0-10% EtOAc in hexanes) to afford the desired product (0.68 g, 42%) as an off white solid. ESIMS (M−H)−=314.
Reaction SMILES: [CH3:1][C:2](=[O:7])[CH2:3][C:4](=[O:6])[CH3:5].[C:8]1([CH2:14][CH2:15][CH2:16]I)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[C:8]1([CH2:14][CH2:15][CH2:16][CH:3]([C:2](=[O:7])[CH3:1])[C:4](=[O:6])[CH3:5])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CC(=O)CC(C)=O
Reactant: ICCCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(=O)C(CCCc1ccccc1)C(C)=O
Yield: 40.1 %

Procedure:
A mixture of pentane-2,4-dione (3.87 g, 38.6 mmol), 3-phenyl-1-iodopropane (3.18 g, 12.9 mmol) and anhydrous potassium carbonate (1.7 g, 12.3 mmol) in acetone (7.5 mL) was heated to reflux for 24 hours. The room temperature reaction mixture was filtered, and the filter cake washed with acetone (25 mL×3). The combined filtrates were concentrated, and the residue was partitioned between ethyl acetate and water. The organic layer was washed with water and brine, dried (magnesium sulfate), and concentrated to an oil. Flash chromatography over silica (ethyl acetate/hexanes) afforded 1.13 g (42%) of a colorless oil. The proton spectrum in deuterochloroform showed the product exists as a mixture of keto and enol tautomers.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[CH2:5][NH:6][S:7]([C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=1)(=[O:9])=[O:8])[CH3:2].[C:18](=O)([O-])[O-].[K+].[K+].IC>CN(C=O)C.O>[CH2:1]([O:3][C:4](=[O:17])[CH2:5][N:6]([S:7]([C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=1)(=[O:9])=[O:8])[CH3:18])[CH3:2]
Reactant: CCOC(=O)CNS(=O)(=O)c1ccc(F)cc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Solvent: O
Product: CCOC(=O)CN(C)S(=O)(=O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 99.1 %

Procedure:
To a solution of 3.00 g (0.011 mol) of the product of Example 13 in 30 mL of DMF was added 4.76 g (0.034 mol) of potassium carbonate followed by 1.43 mL (0.023 mol) of iodomethane. The reaction was stirred at room temperature for 5 h and then diluted with water and extracted with ether. The combined organics were washed water, dried over MgSO4, filtered and concentrated in vacuo. The residue was chromatographed on silica gel eluting with ethyl acetate/hexanes (1:3) to provide 3.0 g (95%) of the N-methyl sulfonamide as a colorless oil. Electrospray Mass Spec 275.9 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6](Br)[CH:7]=1.[F:9][C:10]1[CH:11]=[C:12](B(O)O)[CH:13]=[CH:14][CH:15]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].O>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CN(C=O)C>[F:9][C:10]1[CH:15]=[C:14]([C:6]2[CH:7]=[C:2]([NH2:1])[CH:3]=[N:4][CH:5]=2)[CH:13]=[CH:12][CH:11]=1
Reactant: Nc1cncc(Br)c1
Reactant: OB(O)c1cccc(F)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Nc1cncc(-c2cccc(F)c2)c1
Temperature: 180 °C
Yield: 83.1 %

Procedure:
To a microwave vial was added 3-amino-5-bromopyridine (LII) (0.400 g, 2.31 mmol), 3-fluorophenyl boronic acid (XLIX) (0.356 g, 2.54 mmol), tetrakis(triphenylphosphine)palladium(0) (0.133 g, 0.116 mmol), potassium phosphate (0.736 g, 3.47 mmol), water (1 mL), and DMF (5 mL). The reaction vial was capped, purged with argon and heated under microwave irradiation for 1 h at 180° C. The solution was filtered through a pad of Celite and concentrated under vacuum. The residue was purified by column chromatography (4:6 EtOAc:hexanes→7:3 EtOAc:hexanes) to afford the 5-(3-fluorophenyl)pyridin-3-amine (LIII) (0.360 g, 1.92 mmol, 83% yield) as a yellow-white solid. ESIMS found for C11H9FN2 m/z 189.1 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([O:9][CH3:10])[C:6]([B:11]([OH:13])[OH:12])=[CH:5][N:4]=1.O[C:15]([C:18](O)([CH3:20])[CH3:19])([CH3:17])[CH3:16]>O1CCCC1>[CH3:1][O:2][C:3]1[N:8]=[C:7]([O:9][CH3:10])[C:6]([B:11]2[O:12][C:18]([CH3:20])([CH3:19])[C:15]([CH3:17])([CH3:16])[O:13]2)=[CH:5][N:4]=1
Reactant: COc1ncc(B(O)O)c(OC)n1
Reactant: CC(C)(O)C(C)(C)O
Solvent: C1CCOC1
Product: COc1ncc(B2OC(C)(C)C(C)(C)O2)c(OC)n1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a 100 mL round-bottomed flask charged with 4 Å molecular sieves (approximately 1 g) was added the 2,4-dimethoxypyrimidine-5-boronic acid (5.34 g, 29.0 mmol) and anhydrous tetrahydrofuran (25 mL). The pinocol (2.98 g, 25.3 mmol) was added and the reaction stirred at room temperature for 1.5 hours. Additional 2,4-dimethoxypyrimidine-5-boronic acid (662.2 mg, 3.6 mmol) was added and the reaction stirred overnight. Molecular sieves and 2,4-dimethoxypyrimidine-5-boronic acid (1.53 g, 8.3 mmol) were added and the reaction stirred for 0.5 hours. Pinacol (0.613 g, 5.2 mmol) was then added. After 2 hours, the molecular sieves were removed by filtration and the filtrate was concentrated. After drying under high vacuum, the title compound was obtained as a fine yellow solid (8.61 g, 79%). 1H NMR (300.132 MHz, CDCl3) δ 8.56 (s, 1H), 4.01 (d, J=1.5 Hz, 6H), 1.34 (s, 12H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:41])[C@@H:7]([NH:20][C:21](=[O:40])[NH:22][C@@H:23]([CH2:31][CH2:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:8][CH2:9][C:10](ON1C(=O)CCC1=O)=[O:11])([CH3:4])([CH3:3])[CH3:2].[NH2:42][C@@H:43]([CH2:47][CH2:48][CH2:49][CH2:50][N:51]([CH2:66][C:67]1[N:68]([CH2:72][C:73]([O:75][C:76]([CH3:79])([CH3:78])[CH3:77])=[O:74])[CH:69]=[CH:70][N:71]=1)[CH2:52][C:53]1[N:54]([CH2:58][C:59](=[O:65])[O:60][C:61]([CH3:64])([CH3:63])[CH3:62])[CH:55]=[CH:56][N:57]=1)[C:44]([OH:46])=[O:45].CCN(C(C)C)C(C)C>CN(C=O)C>[C:61]([O:60][C:59](=[O:65])[CH2:58][N:54]1[CH:55]=[CH:56][N:57]=[C:53]1[CH2:52][N:51]([CH2:66][C:67]1[N:68]([CH2:72][C:73](=[O:74])[O:75][C:76]([CH3:79])([CH3:78])[CH3:77])[CH:69]=[CH:70][N:71]=1)[CH2:50][CH2:49][CH2:48][CH2:47][C@H:43]([NH:42][C:10](=[O:11])[CH2:9][CH2:8][C@@H:7]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:41])[NH:20][C:21](=[O:40])[NH:22][C@H:23]([C:24]([O:26][C:27]([CH3:28])([CH3:29])[CH3:30])=[O:25])[CH2:31][CH2:32][C:33](=[O:34])[O:35][C:36]([CH3:39])([CH3:38])[CH3:37])[C:44]([OH:46])=[O:45])([CH3:62])([CH3:64])[CH3:63]
Reactant: CC(C)(C)OC(=O)Cn1ccnc1CN(CCCC[C@H](N)C(=O)O)Cc1nccn1CC(=O)OC(C)(C)C
Reactant: CC(C)(C)OC(=O)CC[C@H](NC(=O)N[C@@H](CCC(=O)ON1C(=O)CCC1=O)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CC[C@H](NC(=O)N[C@@H](CCC(=O)N[C@@H](CCCCN(Cc1nccn1CC(=O)OC(C)(C)C)Cc1nccn1CC(=O)OC(C)(C)C)C(=O)O)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Yield: 85.6 %

Procedure:
A solution of (S)-di-tert-butyl 2-(3-((S)-1-tert-butoxy-5-(2,5-dioxopyrrolidin-1-yloxy)-1,5-dioxopentan-2-yl)ureido)pentanedioate (138 mg, 0.236 mmol), (S)-2-amino-6-(bis((1-(2-tert-butoxy-2-oxoethyl)-1H-imidazol-2-yl)methyl)amino)hexanoic acid (127 mg, 0.237 mmol) and DIPEA (0.50 mL) in DMF (1.0 mL) was stirred at rt for overnight. The Solvent was removed under reduced pressure to give a residue, which was purified by biotage eluting with 1% to 50% MeOH in DCM to afford (2S,7S,11S)-2-(4-(bis((1-(2-tert-butoxy-2-oxoethyl)-1H-imidazol-2-yl)methyl)amino)butyl)-7,11-bis(tert-butoxycarbonyl)-16,16-dimethyl-4,9,14-trioxo-15-oxa-3,8,10-triazaheptadecan-1-oic acid (203 mg, 86%) as a white solid. 1H NMR (400 MHz, CDCl3) 7.40 (brs, 1 H), 6.99 (s, 2 H), 6.79 (s, 2 H), 6.12 (brs, 1 H), 5.62 (brs, 1 H), 4.67-4.28 (m, 7 H), 3.68 (d, J=14.0 Hz, 2 H), 3.62 (d, J=14.0 Hz, 2 H), 2.62-2.53 (m, 2H), 2.34-2.02 (m, 8 H), 1.83-1.42 (m, 51 H); MS (ESI), 503.5 (M/2+H)+.
Reaction SMILES: [O:1]=[C:2]1[CH:7]=[CH:6][N:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)[N:4]=[C:3]1[C:18]([OH:20])=O.C1N=CN(C(N2C=NC=C2)=O)C=1.Cl.[CH3:34][O:35][NH:36][CH3:37].CCN(C(C)C)C(C)C>C1COCC1.O>[CH3:34][O:35][N:36]([CH3:37])[C:18]([C:3]1[C:2](=[O:1])[CH:7]=[CH:6][N:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:15])([F:16])[F:17])[CH:9]=2)[N:4]=1)=[O:20]
Reactant: O=C(O)c1nn(-c2cccc(C(F)(F)F)c2)ccc1=O
Reactant: CNOC
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CON(C)C(=O)c1nn(-c2cccc(C(F)(F)F)c2)ccc1=O
Temperature: 40 °C
Reaction time: 20 h
Yield: 104.2 %

Procedure:
A mixture of 4-oxo-1-[3-(trifluoromethyl)phenyl]-1,4-dihydropyridazine-3-carboxylic acid (2.00 g, 7.04 mmol) and CDI (1.26 g, 7.74 mmol) in THF (20 mL) was heated to 40° C. for 2 h. To the solution were added N-methoxymethanamine hydrochloride (1.03 g, 10.6 mmol) and i-Pr2NEt (1.84 mL, 10.6 mmol) at room temperature. The solution was stirred at room temperature for 20 h. The mixture was diluted with water, extracted with EtOAc, washed with brine, dried over Na2SO4, filtered, concentrated in vacuo and purified by column chromatography on silica gel (hexane/EtOAc=50/50 to 0/100 and EtOAc/MeOH=100/0 to 80/20) to yield the crude title compound (2.40 g) as a pale yellow solid: 1H NMR (DMSO-d6, 300 MHz): δ ppm 3.28 (3H, s), 3.61 (3H, s), 6.67 (1H, d, J=7.9 Hz), 7.77-7.90 (2H, m), 8.00-8.14 (2H, m), 8.99 (1H, d, J=7.9 Hz).
Reaction SMILES: O.NN.Cl.[CH2:5]([O:12][C:13](=[O:17])[CH2:14][O:15][NH2:16])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[CH:18]([NH:20][C:21]1[S:22][CH:23]=[C:24]([C:26](=O)[C:27]([OH:29])=[O:28])[N:25]=1)=[O:19].[OH-].[Na+]>CO.O1CCCC1.N1C=CC=CC=1>[CH2:5]([O:12][C:13]([CH2:14][O:15][N:16]=[C:26]([C:24]1[N:25]=[C:21]([NH:20][CH:18]=[O:19])[S:22][CH:23]=1)[C:27]([OH:29])=[O:28])=[O:17])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: NOCC(=O)OCc1ccccc1
Reactant: O=CNc1nc(C(=O)C(=O)O)cs1
Agent: Cl
Agent: NN
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: O=CNc1nc(C(=NOCC(=O)OCc2ccccc2)C(=O)O)cs1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of hydrazine hydrate (8.0 g) in methanol (16 ml) was added to a suspension of benzyl 2-phthalimidoxyacetate (46.0 g) in tetrahydrofuran (150 ml), and the mixture was stirred at ambient temperature for 30 minutes. To the reaction mixture was added 20% hydrochloric acid under ice-cooling, followed by stirring at the same temperature for 10 minutes. The insoluble substance was filtered off to give a solution containing benzyl2-aminooxyacetate. To this solution were added (2-formamidothiazol-4-yl)glyoxylic acid (24.7 g) and pyridine (24.8 ml), and the mixture was stirred at ambient temperature for 3 hours. The reaction mixture was adjusted to pH 7.5 with 10% aqueous sodium hydroxide and then washed with ethyl acetate. The resultant aqueous solution was acidified to pH 2.0 with 10% hydrochloric acid, followed by extraction with ethyl acetate. The extract was washed with an aqueous sodium chloride and then dried over magnesium sulfate. The solution was evaporated and the residue was pulverized with diisopropyl ether to give 2-benzyloxycarbonylmethoxyimino-2-(2-formamidothiazol-4-yl)acetic acid (syn isomer) (37 g), mp 152° C. (dec.).