Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]=[C:2]1[NH:6][C:5]([C:11]([F:14])([F:13])[F:12])([C:7]([F:10])([F:9])[F:8])[C:4](=[C:15]([F:20])[C:16]([F:19])([F:18])[F:17])[S:3]1.C(N(CC)CC)C.[F:28][C:29]([F:40])([F:39])[C:30]1[CH:38]=[CH:37][C:33]([C:34](Cl)=[O:35])=[CH:32][CH:31]=1>C1(C)C=CC=CC=1>[F:28][C:29]([F:39])([F:40])[C:30]1[CH:38]=[CH:37][C:33]([C:34]([NH:1][C:2]2[S:3][C:4](=[C:15]([F:20])[C:16]([F:17])([F:18])[F:19])[C:5]([C:7]([F:10])([F:9])[F:8])([C:11]([F:12])([F:13])[F:14])[N:6]=2)=[O:35])=[CH:32][CH:31]=1
Reactant: N=C1NC(C(F)(F)F)(C(F)(F)F)C(=C(F)C(F)(F)F)S1
Reactant: O=C(Cl)c1ccc(C(F)(F)F)cc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: O=C(NC1=NC(C(F)(F)F)(C(F)(F)F)C(=C(F)C(F)(F)F)S1)c1ccc(C(F)(F)F)cc1
Temperature: 103 °C
Reaction time: 3 h

Procedure:
In toluene (40 ml) were dissolved 2-imino-4,4-bis(trifluoromethyl)-5-(tetrafluoroethylidene)-1,3-thiazolidine (2.0 g) and triethylamine (1.0 ml), and a solution of 4-trifluoromethylbenzoyl chloride (1.5 g) dissolved in toluene (10 ml) was gradually added thereto under cooling and the mixture was stirred at 103° C. for 3 hours.
Reaction SMILES: Br[CH2:2][CH:3]1[O:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[O:5][CH2:4]1.[CH3:13][C:14]1[CH:19]=[CH:18][C:17]([CH:20]2[CH2:25][CH2:24][CH2:23][NH:22][CH2:21]2)=[CH:16][CH:15]=1.Cl.C(N(CC)CC)C>C(#N)C>[O:8]1[C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[O:5][CH2:4][CH:3]1[CH2:2][N:22]1[CH2:23][CH2:24][CH2:25][CH:20]([C:17]2[CH:16]=[CH:15][C:14]([CH3:13])=[CH:19][CH:18]=2)[CH2:21]1
Reactant: BrCC1COc2ccccc2O1
Reactant: Cc1ccc(C2CCCNC2)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1ccc(C2CCCN(CC3COc4ccccc4O3)C2)cc1

Procedure:
A mixture of 2-bromomethyl-2,3-dihydrobenzo[1,4]dioxine (36 mg, 0.16 mmol), 3-(4-methylphenyl)piperidine.HCl (35 mg, 0.16 mmol) and triethylamine (38 mg, 0.38 mmol) in acetonitrile (2 mL) was heated in a microwave reactor at 140-150° C. for 9 h. The mixture was absorbed on silica and purified by flash chromatography using a gradient of heptane and EtOAc as eluent to give 20 mg of the title compound.
Reaction SMILES: [CH2:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][C:10]2[C:13]([C:17](=[O:19])[NH2:18])=[C:14]([NH2:16])[S:15][C:9]=2[CH2:8]1)=[O:6])[CH:2]=[CH2:3].[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([N:27]=[C:28]=[O:29])=[CH:23][CH:22]=1>N1C=CC=CC=1>[CH2:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][C:10]2[C:13]([C:17](=[O:19])[NH2:18])=[C:14]([NH:16][C:28]([NH:27][C:24]3[CH:25]=[CH:26][C:21]([Cl:20])=[CH:22][CH:23]=3)=[O:29])[S:15][C:9]=2[CH2:8]1)=[O:6])[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)N1CCc2c(sc(N)c2C(N)=O)C1
Reactant: O=C=Nc1ccc(Cl)cc1
Solvent: c1ccncc1
Product: C=CCOC(=O)N1CCc2c(sc(NC(=O)Nc3ccc(Cl)cc3)c2C(N)=O)C1
Yield: 46 %

Procedure:
Starting material 8 (1 g, 3.6 mmol) was dissolved in 12 ml of pyridine and p-chlorphenyl isocyanate (546 mg, 3.6 mmol) was added. The red solution was stirred over the weekend. The solvent was reduced in a vacuum centrifuge. The crude product was used without further purification (green-brown solid, 1.13 g, 65% content 9, 46% yield).
Reaction SMILES: [CH:1]1[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][C:2]=1[NH:11][NH2:12].[C:13](OCC)(=[O:18])[CH2:14][C:15]([CH3:17])=O>C(O)(=O)C>[CH3:17][C:15]1[CH2:14][C:13](=[O:18])[N:11]([C:2]2[CH:3]=[CH:4][C:5]3[CH2:6][CH2:7][CH2:8][CH2:9][C:10]=3[CH:1]=2)[N:12]=1
Reactant: CCOC(=O)CC(C)=O
Reactant: NNc1ccc2c(c1)CCCC2
Solvent: CC(=O)O
Product: CC1=NN(c2ccc3c(c2)CCCC3)C(=O)C1
Temperature: 100 °C
Yield: 56.3 %

Procedure:
(5,6,7,8-Tetrahydro-naphthalen-2-yl)-hydrazine 7b (2.0 g, 12.3 mmol) was dissolved in 50 mL of acetic acid followed by addition of ethyl acetoacetate (1.57 mL, 12.3 mmol). The reaction mixture was heated to 100° C. overnight. The mixture was concentrated under reduced pressure and the resulting residue was purified by silica gel column chromatography to obtain the title compound 5-methyl-2-(5,6,7,8-tetrahydro-naphthalen-2-yl)-2,4-dihydro-pyrazol-3-one 7c (1.58 g, yield 56.2%) as a colourless oil.
Reaction SMILES: [CH3:1][NH:2][S:3](Cl)(=[O:5])=[O:4].[Cl:7][C:8]1[CH:17]=[CH:16][C:11]([O:12][CH2:13][CH2:14][OH:15])=[CH:10][CH:9]=1.N1C=CC=CC=1>C(Cl)Cl>[Cl:7][C:8]1[CH:17]=[CH:16][C:11]([O:12][CH2:13][CH2:14][O:15][S:3](=[O:5])(=[O:4])[NH:2][CH3:1])=[CH:10][CH:9]=1
Reactant: CNS(=O)(=O)Cl
Reactant: OCCOc1ccc(Cl)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CNS(=O)(=O)OCCOc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 33.5 %

Procedure:
To a stirred solution of 45.0 g (0.347 mole) of methylsulfamoyl chloride prepared above in 100 ml of methylene chloride was added in a thin stream a solution of 25.0 g (0.145 mole) of 2-(4-chlorophenoxy)ethanol (Lancaster Synthesis, Inc., Windham, N.H. 03087) in 30 ml (0.369 mole) of pyridine and 100 ml of methylene chloride and the reaction mixture was stirred at ambient temperature for 3 days. The solids were removed by filtration and the filtrate was evaporated under reduced pressure to yield a brown viscous residue. The residue was partitioned between water and ethyl ether (400 ml each). The organic layer was washed twice with 300 ml portions of water, dried over magnesium sulfate and the solvent evaporated under reduced pressure to yield a solid residue. The solid was triturated with 100 ml of isopropyl ether and the solid was recollected by filtration. The solid was recrystallized from isopropyl ether to give 12.9 g (34%) of title compound as a white solid, m.p. 101° -104° C.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([NH:8][C@@H:9]([C:13]([OH:15])=O)[CH:10]1[CH2:12][CH2:11]1)=[O:7])([CH3:4])[CH3:3].Cl.[NH:17]1[CH2:20][CH:19]([C:21]#[N:22])[CH2:18]1.C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[C:2]([O:5][C:6](=[O:7])[NH:8][C@H:9]([CH:10]1[CH2:11][CH2:12]1)[C:13]([N:17]1[CH2:20][CH:19]([C:21]#[N:22])[CH2:18]1)=[O:15])([CH3:1])([CH3:3])[CH3:4]
Reactant: N#CC1CNC1
Reactant: CC(C)(C)OC(=O)N[C@@H](C(=O)O)C1CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N[C@@H](C(=O)N1CC(C#N)C1)C1CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 59.3 %

Procedure:
In a round-bottomed flask Boc-D-cyclopropylglycine (500 mg, 2.32 mmol) and azetidine-3-carbonitrile hydrochloride (441 mg, 3.72 mmol) were dissolved in DMF (10 ml). N,N-Diisopropylethylamine (1.2 ml, 6.87 mmol) was added followed by HATU (972 mg, 2.56 mmol). The reaction mixture was stirred at room temperature overnight then quenched with water and extracted with diethyl ether (2×). The combined organic layers were washed twice with water and once with brine then dried over sodium sulfate, filtered and concentrated. The residue was triturated with petroleum ether to afford 384 mg (59%) of [(R)-2-(3-cyano-azetidin-1-yl)-1-cyclopropyl-2-oxo-ethyl]-carbamic acid tert-butyl ester as an off-white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[CH2:10][CH2:11][CH2:12][C:13]#[C:14][S:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)(=[O:17])=[O:16])=[CH:4][CH:3]=1>ClCCCl>[Cl:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:6][CH:7]=1)[CH:8]=[C:9]1[CH2:10][CH2:11][CH2:12][C:13]1=[C:14]2[S:15]([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)(=[O:16])=[O:17]
Reactant: O=S(=O)(C#CCCC/C=C/c1ccc(Cl)cc1)c1ccccc1
Solvent: ClCCCl
Product: O=S(=O)(c1ccccc1)c1c2c(cc3ccc(Cl)cc13)CCC2
Temperature: 180 °C
Reaction time: 0.25 h
Yield: 89.7 %

Procedure:
To a 2-5 mL microwave irradiation vial equipped with a stir bar was added enyne 5g (0.045 g, 0.13 mmol) in DCE (2.2 mL). The reaction was irradiated with stirring at 180° C. for 15 min until complete by TLC. The reaction turned light yellow in color. The reaction was then transferred to a vial, concentrated under reduced pressure, and dried under vacuum to yield naphthalene 6g as a white solid (0.040 g, 89%).
Reaction SMILES: [CH2:1]([OH:3])[CH3:2].[H-].[Na+].Br[C:7]1[CH:8]=[C:9]([CH:30]=[CH:31][N:32]=1)[C:10]([NH:12][C:13]1[S:14][C:15]2[C:21]([N:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)=[CH:20][CH:19]=[C:18]([O:28][CH3:29])[C:16]=2[N:17]=1)=[O:11]>O1CCOCC1>[CH2:1]([O:3][C:7]1[CH:8]=[C:9]([CH:30]=[CH:31][N:32]=1)[C:10]([NH:12][C:13]1[S:14][C:15]2[C:21]([N:22]3[CH2:23][CH2:24][O:25][CH2:26][CH2:27]3)=[CH:20][CH:19]=[C:18]([O:28][CH3:29])[C:16]=2[N:17]=1)=[O:11])[CH3:2]
Reactant: COc1ccc(N2CCOCC2)c2sc(NC(=O)c3ccnc(Br)c3)nc12
Reactant: CCO
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CCOc1cc(C(=O)Nc2nc3c(OC)ccc(N4CCOCC4)c3s2)ccn1
Temperature: 50 °C
Yield: 44.4 %

Procedure:
To a stirred solution of 0.52 ml (8.90 mmol) ethanol in 30 ml dioxane at room temperature was added 486 mg (11.1 mmol) sodium hydride (55% dispersion in mineral oil) and the mixture heated at 50° C. for 30 minutes. 1.00 g (2.23 mmol) 2-bromo-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-isonicotinamide was then added and the mixture heated at 115° C. for 72 h. The reaction mixture was then cooled to room temperature and concentrated in vacuo. The residue was resuspended in dichloromethane, and washed sequentially with water and saturated brine. The organic phase was then dried over sodium sulfate and concentrated in vacuo. The residue was resuspended in methanol and concentrated in vacuo to 2 ml, 20 ml ether added, and the resulting crystals were collected by filtration and dried in vacuo to afford 410 mg (44%) 2-ethoxy-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-isonicotinamide as a light yellow crystalline solid.
Reaction SMILES: CS(OCCCCO[C:11]1[CH:12]=[CH:13][C:14]2[NH:19][C:18](=[O:20])[O:17][C:16]([CH3:22])([CH3:21])[C:15]=2[CH:23]=1)(=O)=O.[CH3:24][C:25]1[CH:26]=[C:27]([SH:32])[CH:28]=[CH:29][C:30]=1[CH3:31]>>[CH3:24][C:25]1[CH:26]=[C:27]([S:32][CH2:13][CH2:14][CH2:15][CH2:16][O:17][C:12]2[CH:11]=[CH:23][C:15]3[C:16]([CH3:21])([CH3:22])[O:17][C:18](=[O:20])[NH:19][C:14]=3[CH:13]=2)[CH:28]=[CH:29][C:30]=1[CH3:31]
Reactant: CC1(C)OC(=O)Nc2ccc(OCCCCOS(C)(=O)=O)cc21
Reactant: Cc1ccc(S)cc1C
Product: Cc1ccc(SCCCCOc2ccc3c(c2)NC(=O)OC3(C)C)cc1C

Procedure:
Prepared analogously to Example 210 from 6-(4-methanesulfonyloxy-butoxy)-4,4-dimethyl-4H-3,1-benzoxazin-2-one and 3,4-dimethyl-thiophenol.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[C:18]1[CH:26]=[C:25]2[C:21]([C:22]([NH:35][C:36](=[O:40])[CH2:37][CH2:38][CH3:39])=[N:23][N:24]2[CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:34])([CH3:33])[CH3:32])=[CH:20][CH:19]=1>O1CCOCC1.C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:18]2[CH:26]=[C:25]3[C:21]([C:22]([NH:35][C:36](=[O:40])[CH2:37][CH2:38][CH3:39])=[N:23][N:24]3[CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:34])([CH3:32])[CH3:33])=[CH:20][CH:19]=2)=[CH:4][CH:3]=1
Reactant: CCCC(=O)Nc1nn(COCC[Si](C)(C)C)c2cc(Br)ccc12
Reactant: OB(O)c1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CCCC(=O)Nc1nn(COCC[Si](C)(C)C)c2cc(-c3ccc(Cl)cc3)ccc12
Temperature: 104 °C
Reaction time: 16 h
Yield: 61.9 %

Procedure:
512 mg of 4-chlorophenylboronic acid, 578 mg of potassium carbonate, and 167 mg of tetrakis(triphenyl)palladium are added to 900 mg of N-[6-bromo-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-indazol-3-yl]butanamide, described in Example 51, in 40 cm3 of dioxane. The mixture is then heated at about 104° C. for 2 hours and the temperature is allowed to return to about 19° C. over 16 hours. The reaction medium is diluted with 75 cm3 of ethyl acetate, filtered through a sinter funnel packed with Celite and concentrated to dryness under reduced pressure (2 kPa; 50° C.). The residue is taken up in 100 cm3 of ethyl acetate and 50 cm3 of water. The organic phase is washed again with 25 cm3 of saturated aqueous sodium chloride solution and then separated out after settling of the phases has taken place, dried over magnesium sulphate, filtered and evaporated under reduced pressure (2 kPa; 50° C.). The residue is purified by chromatography under an argon pressure of 50 kPa, on a column of silica gel (particle size 40-60 μm; diameter 2.5 cm), eluting with a cyclohexane/ethyl acetate mixture (80/20 by volume). The fractions containing the expected product are combined and evaporated under reduced pressure (2 kPa; 50° C.); 600 mg of N-[6-(4-chlorophenyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-indazol-3-yl]butanamide are obtained in the form of a yellow wax.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([Cl:8])[N:5]=[C:4](Cl)[CH:3]=1.[CH3:10][CH:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14][CH2:13][NH:12]1.C(N(CC)CC)C>CN(C)C=O>[CH3:1][C:2]1[N:7]=[C:6]([Cl:8])[N:5]=[C:4]([N:12]2[CH2:13][CH2:14][C:15]3[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:11]2[CH3:10])[CH:3]=1
Reactant: Cc1cc(Cl)nc(Cl)n1
Reactant: CC1NCCc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1cc(N2CCc3ccccc3C2C)nc(Cl)n1
Yield: 50.2 %

Procedure:
In accordance with the same procedure as in Step 1 of Example 1, except that 6-methyl-2,4-dichloropyrimidine (6.52 g, 40 mmol), 1-methyl-1,2,3,4-tetrahydroisoquinoline (6.6 g, 44 mmol), triethylamine(6.8 ml, 48.8 mmol) and N,N-dimethylformamide(30 ml) were used as starting materials, 5.5 g of the titled compound was prepared. (Yield: 50.2%)
Reaction SMILES: F[P-](F)(F)(F)(F)F.[F:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]2[CH:25]=[C:24]3[C:19]([C:20]([OH:38])=[C:21]([C:31]([NH:33][CH2:34][CH2:35][O:36][CH3:37])=[O:32])[C:22](=[O:30])[N:23]3[CH2:26][C:27]([OH:29])=O)=[N:18][CH:17]=2)=[CH:11][CH:10]=1.C(N(CC)CC)C.[CH:46]1([NH2:50])[CH2:49][CH2:48][CH2:47]1>CN(C=O)C>[CH:46]1([NH:50][C:27](=[O:29])[CH2:26][N:23]2[C:24]3[C:19](=[N:18][CH:17]=[C:16]([CH2:15][C:12]4[CH:13]=[CH:14][C:9]([F:8])=[CH:10][CH:11]=4)[CH:25]=3)[C:20]([OH:38])=[C:21]([C:31]([NH:33][CH2:34][CH2:35][O:36][CH3:37])=[O:32])[C:22]2=[O:30])[CH2:49][CH2:48][CH2:47]1
Reactant: COCCNC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CC(=O)O)c1=O
Reactant: NC1CCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COCCNC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CC(=O)NC2CCC2)c1=O

Procedure:
O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′,-tetramethyluroniuum hexafluorophosphate (57 mg, 0.15 mmol) was added to a mixture of [7-[(4-fluorophenyl)methyl]-4-hydroxy-3-({[2-(methyloxy)ethyl]amino}carbonyl)-2-oxo-1,5-naphthyridine-1(2H)-yl]acetic acid, the title compound in Example 171 (50 mg, 0.12 mmol), triethylamine (0.02 mL, 0.15 mmol) and cyclobutylamine (0.012 mL, 0.15 mmol) in DMF (1 mL) at rt. After 1 h, the mixture was diluted with H2O (4 mL) and the title compound was collected by filtration to give a white solid: 1H NMR (d6-DMSO) δ 10.22 (1H, m), 8.54 (1H, s), 8.42 (1H, m), 7.75 (1H, s), 7.31 (2H, m), 7.10 (2H, m), 4.81 (2H, s), 4.13 (1H, m), 4.10 (2H, s), 3.52 (4H, m), 3.27 (3H, s), 2.09 (2H, m), 1.84 (2H, m), 1.59 (2H, m); HRMS calcd for C25H27FN4O5+H+: 483.2044. Found: 483.2049.
Reaction SMILES: N1CCCCC1.[CH3:7][O:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][C:16]=1[O:17][CH3:18])[CH:12]=O.C([CH2:22][C:23]([NH:25][C:26]1[C:27]([C:36]([OH:38])=[O:37])=[CH:28][C:29]2[C:34]([CH:35]=1)=[CH:33][CH:32]=[CH:31][CH:30]=2)=[O:24])(O)=O.Cl>C1(C)C=CC=CC=1>[CH3:7][O:8][C:9]1[CH:10]=[C:11](/[CH:12]=[CH:22]/[C:23]([NH:25][C:26]2[C:27]([C:36]([OH:38])=[O:37])=[CH:28][C:29]3[C:34]([CH:35]=2)=[CH:33][CH:32]=[CH:31][CH:30]=3)=[O:24])[CH:14]=[CH:15][C:16]=1[O:17][CH3:18]
Reactant: O=C(O)CC(=O)Nc1cc2ccccc2cc1C(=O)O
Reactant: COc1ccc(C=O)cc1OC
Agent: Cl
Solvent: C1CCNCC1
Solvent: Cc1ccccc1
Product: COc1ccc(/C=C/C(=O)Nc2cc3ccccc3cc2C(=O)O)cc1OC
Yield: 67.6 %

Procedure:
Piperidine (0.23 mL, 2.3 mmol) was added to a suspension of 3,4-dimethoxybenzaldehyde (0.38 g, 2.3 mmol) and 3-(2-carboxyacetamido)-2-naphthoic acid (0.56 g, 2.0 mmol) in toluene (5.0 mL) and treated according to Procedure 2, acidifying with 1 M HCl. (E)-3-[[3-(3,4-Dimethoxyphenyl)-1-oxo-2-propenyl]amino]-2-naphthoic acid (0.51 g, 66%) was obtained as a yellow crystalline solid; mp 212-213° C.; δH (400 MHz, DMSO-d6) 3.80 (s, 3H, OCH3), 3.84 (s, 3H, OCH3), 6.82 (d, J=15.6 Hz, 1H, CH═CHCO), 6.99 (d, =8.2 Hz, 1H, H5′), 7.25 (dd, 4,6=8.2, J2′,6′=2.0 Hz, 1H, H6′), 7.38 (d, J2′,6′=2.0 Hz, 1H, H2′), 7.49 (t, J6,7=J7,8=8.0 Hz, 1H, H7), 7.58 (d, J=15.6 Hz, 1H, CH═CHCO), 7.62 (t, J5,6=J6,7=8.0 Hz, 1H, H6), 7.89 (d, J7,8=8.0 Hz, 1H, H8), 8.03 (d, J5,6=8.0 Hz, H5), 8.71 (s, 1H, H1), 9.05 (s, 1H, H4), 11.30 (s, 1H, NH); δC (100 MHz, DMSO-d6) 55.6, 55.7, 110.4, 111.6, 117.1, 117.6, 120.1, 122.6, 125.6, 127.1, 127.3, 128.2, 129.1, 129.3, 133.1, 135.5, 136.3, 141.4, 149.0, 150.6, 164.2, 169.5; HRMS (ESI) Calculated for C22H19NO6 [M+H]+ 378.1336. found 378.1345; vmax 797, 1022, 1134, 1233, 1512, 1665, 1693, 3048 cm−1.
Reaction SMILES: [C:1]([NH:4][C@H:5]([C:14]([NH:16][C@H:17]([C:21]([N:23]1[CH2:45][CH2:44][CH2:43][CH2:42][CH:24]1[C:25]([NH:27][CH:28]1[CH:32]([O:33]CC2C=CC=CC=2)[O:31][C:30](=[O:41])[CH2:29]1)=[O:26])=[O:22])[CH:18]([CH3:20])[CH3:19])=[O:15])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)(=[O:3])[CH3:2]>CO.[OH-].[OH-].[Pd+2]>[C:1]([NH:4][C@H:5]([C:14]([NH:16][C@H:17]([C:21]([N:23]1[CH2:45][CH2:44][CH2:43][CH2:42][CH:24]1[C:25]([NH:27][CH:28]([CH:32]=[O:33])[CH2:29][C:30]([OH:41])=[O:31])=[O:26])=[O:22])[CH:18]([CH3:20])[CH3:19])=[O:15])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)N[C@H](C(=O)N1CCCCC1C(=O)NC1CC(=O)OC1OCc1ccccc1)C(C)C
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CC(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)N[C@H](C(=O)N1CCCCC1C(=O)NC(C=O)CC(=O)O)C(C)C

Procedure:
To a solution of 100 mg of N-(N-Acetyl-tyrosinyl-valinyl-pipecolyl)-4-amino-5-benzyloxy-2-oxotetrahydrofuran in 10 ml of methanol was added 60 mg of Pd(OH)2 on carbon and the mixture placed under an atmosphere of hydrogen via a balloon. The mixture was filtered through Celite and concentrated providing a white solid. This crude solid was dissolved in 2 ml of methanol and triturated with diethyl ether affording 26 mg of the title compound.
Reaction SMILES: [O:1]=[C:2]1[CH:7]([N:8]2[C:16](=[O:17])[C:15]3[C:14](C(O)=O)=[CH:13][C:12]([O:21][CH3:22])=[CH:11][C:10]=3[C:9]2=[O:23])[CH2:6][CH2:5][C:4](=[O:24])[NH:3]1.[N-:25]=[N+]=[N-].C1C=CC(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)=CC=1>C(N(CC)CC)C>[NH2:25][C:14]1[CH:13]=[C:12]([O:21][CH3:22])[CH:11]=[C:10]2[C:15]=1[C:16](=[O:17])[N:8]([CH:7]1[CH2:6][CH2:5][C:4](=[O:24])[NH:3][C:2]1=[O:1])[C:9]2=[O:23]
Reactant: [N-]=[N+]=[N-]
Reactant: COc1cc(C(=O)O)c2c(c1)C(=O)N(C1CCC(=O)NC1=O)C2=O
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Product: COc1cc(N)c2c(c1)C(=O)N(C1CCC(=O)NC1=O)C2=O

Procedure:
reacting 2-(2,6-dioxo-piperidin-3-yl)-6-methoxy-1,3-dioxo-2,3-dihydro-1H-isoindole-4-carboxylic acid with (a) an azide compound, in one embodiment, DPPA; in the presence of (b) a base, in one embodiment, an organic base, in another embodiment, triethylamine; to form 4-amino-2-(2,6-dioxo-piperidin-3-yl)-6-methoxy-isoindole-1,3-dione; and
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:24]([OH:26])=O)[CH2:13][C:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][CH:15]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN1CCOCC1.C(Cl)(=O)OCC.Cl.[CH2:41]([O:43][C:44](=[O:51])[C@H:45]([CH2:47][CH:48]([CH3:50])[CH3:49])[NH2:46])[CH3:42]>O1CCCC1>[CH2:41]([O:43][C:44](=[O:51])[C@H:45]([CH2:47][CH:48]([CH3:50])[CH3:49])[NH:46][C:24](=[O:26])[C@H:12]([CH2:13][C:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][CH:15]=1)[NH:11][C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10])[CH3:42]
Reactant: CCOC(=O)[C@@H](N)CC(C)C
Reactant: O=C(N[C@@H](Cc1cccc2ccccc12)C(=O)O)OCc1ccccc1
Agent: CCOC(=O)Cl
Agent: Cl
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: CCOC(=O)[C@H](CC(C)C)NC(=O)[C@H](Cc1cccc2ccccc12)NC(=O)OCc1ccccc1
Temperature: -5 °C
Reaction time: 0.25 h

Procedure:
3.49 g (10 mmole) of N-benzyloxycarbonyl-3-(1-naphthyl)-L-alanine and 1.21 g (12 mmole) of N-methylmorpholine were dissolved in 30 ml of anhydrous tetrahydrofuran, and then, whilst cooling the solution at -5° C., 1.30 g (12 mmole) of ethyl chlorocarbonate was added dropwise, with stirring, over a period of 15 minutes. 2.35 g (12 mmole) of L-leucine ethyl ester hydrochloride [which had been suspended in 10 ml of methylene chloride and neutralized with 1.21 g (12 mmole) of N-methylmorpholine] were added. The mixture was stirred for 2 hours with ice cooling, and then left standing overnight at room temperature. It was then condensed by evaporation under reduced pressure. Water was added to the residue, and the precipitating oily substance was extracted with ethyl acetate. The organic extract was washed with 1N hydrochloric acid, water, a 5% w/v aqueous solution of sodium bicarbonate and a saturated aqueous solution of sodium chloride, in that order, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. The N-benzyloxycarbonyl-3-(1-naphthyl)-L-alanyl-L-leucine ethyl ester thus obtained in a syrupy form was dissolved in 30 ml of dimethylformamide, and 5.06 g (100 mmole) of hydrazine hydrate were added to the solution. The mixture was stirred for 36 hours at room temperature. The reaction product was then condensed by evaporation under reduced pressure, and water was added to the residue. The colorless crystals produced were collected by filtration, thoroughly washed with water and dried in a desiccator to yield 4.23 g of the title compound melting at 200°-204° C.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][NH2:10])=[CH:5][CH:4]=1.[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([C:18](=O)[C:19](=[N:27]O)[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=[CH:14][CH:13]=1>N1C=CC=CC=1>[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[NH:10][C:9]([C:6]3[CH:7]=[CH:8][C:3]([CH2:2][OH:1])=[CH:4][CH:5]=3)=[N:27][C:19]=2[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=[CH:14][CH:13]=1
Reactant: CC(C)(C)OC(=O)C(=NO)C(=O)c1ccc(Cl)cc1
Reactant: NCc1ccc(CO)cc1
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)c1nc(-c2ccc(CO)cc2)[nH]c1-c1ccc(Cl)cc1

Procedure:
4-(Hydroxymethyl)phenylmethylamine and tert-butyl 3-(4-chlorophenyl)-2-hydroxyimino-3-oxopropionate are dissolved in pyridine, and the mixture is treated in the same manner as in Starting Material Synthetic Example 170 to give the objective tert-butyl 5-(4-chlorophenyl)-2-(4-hydroxymethylphenyl)imidazole-4-carboxylate.
Reaction SMILES: [C:1]([O:5][C:6](=[O:31])[CH2:7][O:8][C@H:9]1[CH2:14][CH2:13][CH2:12][C@@H:11]([NH:15][C:16]2[C:17]3[CH:24]=[C:23]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[O:22][C:18]=3[N:19]=[CH:20][N:21]=2)[CH2:10]1)([CH3:4])([CH3:3])[CH3:2].C1C(=O)N([Br:39])C(=O)C1>ClC(Cl)(Cl)Cl>[C:1]([O:5][C:6](=[O:31])[CH2:7][O:8][C@H:9]1[CH2:14][CH2:13][CH2:12][C@@H:11]([NH:15][C:16]2[C:17]3[C:24]([Br:39])=[C:23]([C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=4)[O:22][C:18]=3[N:19]=[CH:20][N:21]=2)[CH2:10]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)CO[C@H]1CCC[C@@H](Nc2ncnc3oc(-c4ccccc4)cc23)C1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(C)OC(=O)CO[C@H]1CCC[C@@H](Nc2ncnc3oc(-c4ccccc4)c(Br)c23)C1

Procedure:
Suspend 132 mg (0.312 mmol) of (+/−)-cis-({3-[(6-phenylfuro[2,3-d]pyrimidin-4-yl)amino]cyclo-hexyl}oxy)acetic acid tert-butyl ester in 0.3 ml of tetrachloromethane, add 61 mg (0.343 mmol) of NBS and heat to reflux. On completion of conversion (approx. 1 h), cool the reaction mixture and isolate the product directly by preparative RP-HPLC. 104 mg (66.4% of theory) of the target compound are obtained.