Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:10](OS(C(F)(F)F)(=O)=O)=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][O:5][C:6]2=[O:19].[CH:20]([O:22][CH2:23][CH2:24][CH2:25][CH3:26])=[CH2:21].CCN(CC)CC.C1C=CC(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>CC([O-])=O.CC([O-])=O.[Pd+2].CN(C=O)C>[CH2:23]([O:22][C:20]([C:10]1[C:2]([CH3:1])=[C:3]2[C:7](=[CH:8][CH:9]=1)[C:6](=[O:19])[O:5][CH2:4]2)=[CH2:21])[CH2:24][CH2:25][CH3:26]
Reactant: Cc1c(OS(=O)(=O)C(F)(F)F)ccc2c1COC2=O
Reactant: C=COCCCC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(CCCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C=C(OCCCC)c1ccc2c(c1C)COC2=O
Temperature: 80 °C
Reaction time: 1 h

Procedure:
To a 1 L 3-neck was charged trifluoromethanesulfonic acid 4-methyl-1-oxo-1,3-dihydro-isobenzofuran-5-yl ester (63.0 g, 213 mmol), DMF (315 mL), butyl vinyl ether (138 mL, 1063 mmol)) then Et3N (35.6 mL, 255 mmol). The solution was sparged with N2 for 20 min. To the solution was added Pd(OAc)2 (1.19 g., 5.32 mmol) and DPPP (2.41 g., 5.85 mmol) and sparged for an additional 10 min then heated to 80° C. After a 1 hr age, the solution was cooled to <10° C. then quenched with 630 mL EtOAc and washed with 5% NH4Cl (2×315 mL), 10% brine (2×315 mL), dried over MgSO4, filtered, concentrated by rotary evaporation and flushed with EtOAc (3×100 mL) to remove excess butyl vinyl ether, providing crude 5-(1-butoxy-vinyl)-4-methyl-3H-isobenzofuran-1-one. 1H NMR (400 MHz, DMSO-d6): δ 7.67 (d, J=7.7 Hz, 1H), 7.48 (d, J=7.7 Hz, 1H), 5.42 (s, 2H), 4.54 (d, J=2.3 Hz, 1H), 4.27 (d, J=2.3 Hz, 1H), 3.85 (t, J=6.4 Hz, 2H), 2.27 (s, 3H), 1.71-1.64 (m, 2H), 1.46-1.37 (m, 2H), 0.92 (t, J=7.4 Hz, 3H)
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]([NH2:12])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].N1C=CC=CC=1.[CH3:19][C:20]1([CH3:37])[CH2:29][CH2:28][C:27]([CH3:31])([CH3:30])[C:26]2[CH:25]=[C:24]([C:32](=[O:36])[C:33](Cl)=[O:34])[CH:23]=[CH:22][C:21]1=2.O>C1COCC1>[OH:1][C:2]1[CH:11]=[C:10]([NH:12][C:33]([C:32]([C:24]2[CH:23]=[CH:22][C:21]3[C:20]([CH3:37])([CH3:19])[CH2:29][CH2:28][C:27]([CH3:31])([CH3:30])[C:26]=3[CH:25]=2)=[O:36])=[O:34])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: CC1(C)CCC(C)(C)c2cc(C(=O)C(=O)Cl)ccc21
Reactant: COC(=O)c1ccc(N)cc1O
Solvent: C1CCOC1
Solvent: c1ccncc1
Solvent: O
Product: COC(=O)c1ccc(NC(=O)C(=O)c2ccc3c(c2)C(C)(C)CCC3(C)C)cc1O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
6.7 g (40 mmol) of methyl 2-hydroxy-4-aminobenzoate, 10 ml (0.12 mol) of pyridine and 50 ml of THF are introduced into a round-bottomed flask. A solution of 10.5 g (40 mmol) of 5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthylglyoxyloyl chloride, prepared in 1(c), in 100 ml of THF is added dropwise and the mixture is stirred at room temperature for 4 h. The reaction medium is poured into water, the mixture is extracted with ethyl ether and the organic phase is separated after settling has taken place, dried over magnesium sulphate and evaporated. The residue obtained is purified by chromatography on a silica column and eluted with a mixture of dichloromethane and hexane (30:70). After evaporation of the solvents, 7.3 g (45%) of methyl ester, melting point 146°-7° C., are collected.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7](=[O:29])[C:8]2[CH:9]=[C:10]3[CH:20]=[C:19]([F:21])[C:18]([N:22]4[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]4)=[C:17]([F:28])[C:11]3=[N:12][C:13]=2[N:14]([CH3:16])[CH:15]=1)=[O:5])C.[OH-].[K+].C(O)(=O)C>C(O)C>[F:21][C:19]1[C:18]([N:22]2[CH2:23][CH2:24][NH:25][CH2:26][CH2:27]2)=[C:17]([F:28])[C:11]2=[N:12][C:13]3[N:14]([CH3:16])[CH:15]=[C:6]([C:4]([OH:5])=[O:3])[C:7](=[O:29])[C:8]=3[CH:9]=[C:10]2[CH:20]=1
Reactant: CCOC(=O)c1cn(C)c2nc3c(F)c(N4CCNCC4)c(F)cc3cc2c1=O
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: CC(=O)O
Product: Cn1cc(C(=O)O)c(=O)c2cc3cc(F)c(N4CCNCC4)c(F)c3nc21
Yield: 67.2 %

Procedure:
A suspension of 0.8 g of 3-ethoxycarbonyl-7,9-difluoro-1-methyl-4-oxo-8-(1-piperazinyl)-1,4-dihydrobenzo[b][1,8]naphthyridine in 20 cm3 of ethanol and 20 cm3 of N aqueous potassium hydroxide solution is heated at a temperature close to 75° C. for 1 hour and a half. 12 g of a 10% aqueous acetic acid solution are added to the solution obtained, at this temperature. The insoluble matter obtained is drained at about 75° C. and washed 3 times with 30 cm3 of water at about 20° C. After recrystallizing once from 90 cm3 of dimethylformamide, 0.5 g of 7,9-difluoro-1-methyl-4-oxo-8-(1-piperazinyl)-1,4-dihydro-benzo[b][1,8]naphthyridine-3-carboxylic acid is obtained in the form of a yellow solid melting at 345°-347° C.
Reaction SMILES: Br[CH2:2][C:3]1[C:13]([Cl:14])=[N:12][CH:11]=[CH:10][C:4]=1[C:5]([O:7]CC)=O.Cl.[CH3:16][C:17]1[CH:18]=[C:19]([CH:29]([NH2:31])[CH3:30])[N:20]=[N:21][C:22]=1[O:23][CH2:24][C:25]([F:28])([F:27])[F:26]>>[Cl:14][C:13]1[C:3]2[CH2:2][N:31]([CH:29]([C:19]3[N:20]=[N:21][C:22]([O:23][CH2:24][C:25]([F:27])([F:28])[F:26])=[C:17]([CH3:16])[CH:18]=3)[CH3:30])[C:5](=[O:7])[C:4]=2[CH:10]=[CH:11][N:12]=1
Reactant: CCOC(=O)c1ccnc(Cl)c1CBr
Reactant: Cc1cc(C(C)N)nnc1OCC(F)(F)F
Agent: Cl
Product: Cc1cc(C(C)N2Cc3c(ccnc3Cl)C2=O)nnc1OCC(F)(F)F
Yield: 75 %

Procedure:
The title compound is prepared in 75% yield (210 mg, brown oil) from ethyl 3-(bromomethyl)-2-chloroisonicotinate (200 mg, 0.72 mmol, Step-1 of Intermediate-1) and 1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridazin-3-yl)ethanamine hydrochloride (230 mg, 0.86 mmol, Amine-48, single enantiomer) in a similar manner to Intermediate-2.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[CH3:14][CH:15]1[C:28]2[C:19](=[C:20]3[C:25](=[CH:26][CH:27]=2)[N:24]=[CH:23][CH:22]=[CH:21]3)[CH2:18][CH2:17][NH:16]1>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:16]3[CH:15]([CH3:14])[C:28]4[C:19](=[C:20]5[C:25](=[CH:26][CH:27]=4)[N:24]=[CH:23][CH:22]=[CH:21]5)[CH2:18][CH2:17]3)=[O:13])[CH:10]=2)[CH:7]=1
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Reactant: CC1NCCc2c1ccc1ncccc21
Product: CC1c2ccc3ncccc3c2CCN1C(=O)c1cc2ncc(Br)cn2n1

Procedure:
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 4-Methyl-1,2,3,4-tetrahydro-[3,7]phenanthroline to provide the title compound in moderate yield.
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([NH:14][C:15]([C:17]3[CH:18]=[C:19]4[C:24](=[CH:25][CH:26]=3)[C:23](Cl)=[N:22][N:21]=[C:20]4[Cl:28])=[O:16])[CH:11]=[CH:12][CH:13]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+].[O:31]1CCOCC1.Cl>O>[N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([NH:14][C:15]([C:17]3[CH:18]=[C:19]4[C:24](=[CH:25][CH:26]=3)[C:23](=[O:31])[NH:22][N:21]=[C:20]4[Cl:28])=[O:16])[CH:11]=[CH:12][CH:13]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(Nc1cccc(CN2CCCCC2)c1)c1ccc2c(Cl)nnc(Cl)c2c1
Reactant: C1COCCO1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(Nc1cccc(CN2CCCCC2)c1)c1ccc2c(=O)[nH]nc(Cl)c2c1
Temperature: 50 °C

Procedure:
A mixture of 1,4-dichloro-phthalazine-6-carboxylic acid (3-piperidin-1-ylmethyl-phenyl)-amide (257 mg, 0.619 mmol), 2N NaOH (3.1 mL, 6.19 mmol) and dioxane (5 mL) was heated to 50° C. for 1 h. The reaction was diluted with water, acidified with conc. HCl to ˜pH 6. The reaction mixture was concentrated to low volume and filtered through celite. Preparatory HPLC afforded the desired regioisomer 4-chloro-1-oxo-1,2-dihydro-phthalazine-6-carboxylic acid (3-piperidin-1-ylmethyl-phenyl)-amide hydroformate (16 mg) as a pale yellow solid, 1H NMR (400 MHz, d6-DMSO) δ: 1.54 (m, 2H), 1.44 (m, 4H), 2.28 (m, 4H), 3.37 (s, 2H), 7.00 (m, 1H), 7.25 (m, 1H), 7.67 (m, 2H), 8.06 (d, 1H), 8.10 (s, 1H), 8.47 (dd, 1H), 8.82 (d, 1H), 10.63 (1H), 12.95 (s, 1H) ppm; m/z (M+1) 396.95.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[Cl:12].C(=O)([O-])[O-].[K+].[K+].[CH2:19](I)[CH2:20][CH3:21]>CN(C=O)C>[Cl:12][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:2]=1[O:1][CH2:19][CH2:20][CH3:21])[C:6]([O:8][CH3:9])=[O:7]
Reactant: CCCI
Reactant: COC(=O)c1ccc(O)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCOc1ccc(C(=O)OC)cc1Cl
Temperature: 70 °C
Yield: 100.9 %

Procedure:
Methyl 4-hydroxy-3-chlorobenzoate (10 g, 53.6 mmol) was dissolved in DMF (110 ml) and then potassium carbonate (14.8 g, 107.2 mmol) was added followed by n-propyliodide (10.4 ml, 107.2 mmol). The reaction was heated to 70° C. overnight, filtered and then the fitrate was partitioned between EtOAc and water. The organic layer was separated, dried and evaporated to give the title compound as a yellow oil (12.37 g). MS (ES) C11H1335ClO3 requires 228; found 229 (MH+).
Reaction SMILES: [Br:1][C:2]1[C:3]([C:8]([OH:10])=[O:9])=[N:4][CH:5]=[N:6][CH:7]=1.[C:11](Cl)(=O)C(Cl)=O>C(Cl)Cl.CN(C=O)C>[CH3:11][O:9][C:8]([C:3]1[C:2]([Br:1])=[CH:7][N:6]=[CH:5][N:4]=1)=[O:10]
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1ncncc1Br
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COC(=O)c1ncncc1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 39 %

Procedure:
5-bromopyrimidine-4-carboxylic acid (prepared according to the procedure described in U.S. Pat. No. 4,110,450) (1.0 eq, 6.14 g, 30.2 mmol) was suspended in CH2Cl2 (100 ml). Oxalylchloride (1.1 eq, 2.9 ml, 33.0 mmol) was added followed by 2 drops of DMF. The mixture was stirred at room temperature overnight and the volatiles were removed in vacuo. The residue was taken in MeOH (50 ml) and heated. After evaporation of MeOH in vacuo the compound was dissolved in CH2Cl2 and poured on a prepacked silica gel column. The material was eluted using 20% Ethyl acetate in hexanes. Evaporation of the solvent provided methyl-5-bromopyrimidine-4-carboxylate as a light orange crystalline solid (2.54 g, 39% yield). LCMS (ES): 95% pure, m/z 217 [M]+; 219 [M+2]+; 1H NMR (CDCl3, 400 MHz) δ 4.04 (s, 3H), 9.02 (s, 1H), 9.21 (s, 1H) ppm.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:10]2[O:11][C:12]3[CH:18]=[CH:17][C:16]([C:19]4[CH:24]=[CH:23][C:22]5[O:25][CH2:26][O:27][C:21]=5[CH:20]=4)=[CH:15][C:13]=3[N:14]=2)[C:5]([O:8][CH3:9])=[CH:6][CH:7]=1.[CH:28]1[C:33]([C:34]([OH:36])=[O:35])=[CH:32][C:31]2[C:37]([O:39][C:40](=O)[C:30]=2[CH:29]=1)=[O:38]>>[CH3:9][O:8][C:5]1[C:4]([C:10]2[O:11][C:12]3[CH:18]=[CH:17][C:16]([C:19]4[CH:24]=[CH:23][C:22]5[O:25][CH2:26][O:27][C:21]=5[CH:20]=4)=[CH:15][C:13]=3[N:14]=2)=[CH:3][C:2]([N:1]2[C:37](=[O:38])[C:31]3[C:30](=[CH:29][CH:28]=[C:33]([C:34]([OH:36])=[O:35])[CH:32]=3)[C:40]2=[O:39])=[CH:7][CH:6]=1
Reactant: O=C(O)c1ccc2c(c1)C(=O)OC2=O
Reactant: COc1ccc(N)cc1-c1nc2cc(-c3ccc4c(c3)OCO4)ccc2o1
Product: COc1ccc(N2C(=O)c3ccc(C(=O)O)cc3C2=O)cc1-c1nc2cc(-c3ccc4c(c3)OCO4)ccc2o1

Procedure:
Prepared by the method of Example 15f), from 2-(3-amino-6-methoxyphenyl)-5-(3,4-methylenedioxyphenyl)benzoxazole (50 mg, 0.14 mmol) and 1,2,4-benzenetricarboxylic anhydride (27 mg, 0.14 mmol) the title compound was obtained (72 mg, 92%). 1H NMR (DMSO) δ 13.85(s, 1H), 8.44(dd, 1H), 8.33(s, 1H), 8.21(d, 1H), 8.11(d, 1H), 8.02(d, 1H), 7.83(d, 1H), 7.71(dd, 1H), 7.66(dd, 1H), 7.47(d, 1H), 7.35(d, 1H), 7.22(dd, 1H), 7.03(d, 1H), 6.08(s, 2H), 4.03(s, 3H). MS 535.1 m/z (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][O:7][C:8]2=[C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[NH:13][C:12]2=[O:20])=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.[CH:30]1([C:33](Cl)=[O:34])[CH2:32][CH2:31]1>C1COCC1>[O:20]=[C:12]1[C:11](=[C:8]2[C:9]3[C:5](=[CH:4][CH:3]=[C:2]([NH:1][C:33]([CH:30]4[CH2:32][CH2:31]4)=[O:34])[CH:10]=3)[CH2:6][O:7]2)[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[NH:13]1
Reactant: O=C(Cl)C1CC1
Reactant: Nc1ccc2c(c1)C(=C1C(=O)Nc3ccccc31)OC2
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: O=C1Nc2ccccc2C1=C1OCc2ccc(NC(=O)C3CC3)cc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 71.2 %

Procedure:
To a solution of 3-(6-Amino-3H-isobenzofuran-1-ylidene)-1,3-dihydro-indol-2-one (50.0 mg, 0.189 mmol) and N,N-diisopropylethylamine (98.8 μL, 0.567 mmol) in 2.0 mL THF was added cyclopropane carbonyl chloride (17.2 μL, 0.189 mmol). After stirring at room temperature for 1 h, the slurry was warmed briefly, stirred 10 min at room temperature, filtered and rinsed with MeOH and EtOAc/hexanes (1:1) to afford the title compound (44.7 mg, 71%) as a yellow solid.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([N:8]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[CH2:9][O:10][CH2:11][CH2:12][Si:13]([CH3:16])([CH3:15])[CH3:14])[N:5]2[N:25]=[CH:26][CH:27]=[C:4]2[N:3]=1.CC1(C)C(C)(C)OB([C:36]2[CH2:41][CH2:40][N:39]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:38][CH:37]=2)O1.C(Cl)Cl.C([O-])([O-])=O.[Na+].[Na+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].COCCOC>[CH3:14][Si:13]([CH3:16])([CH3:15])[CH2:12][CH2:11][O:10][CH2:9][N:8]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[C:6]1[N:5]2[N:25]=[CH:26][CH:27]=[C:4]2[N:3]=[C:2]([C:36]2[CH2:41][CH2:40][N:39]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:38][CH:37]=2)[CH:7]=1
Reactant: C[Si](C)(C)CCOCN(COCC[Si](C)(C)C)c1cc(Cl)nc2ccnn12
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: COCCOC
Product: CC(C)(C)OC(=O)N1CC=C(c2cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n3nccc3n2)CC1
Temperature: 100 °C
Reaction time: 8 h
Yield: 80 %

Procedure:
To a pressure tube were charged 5-chloro-N,N-bis((2-(trimethylsilyl)ethoxy)methyl)pyrazolo[1,5-a]pyrimidin-7-amine (5.36 g, 12.5 mmols), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate (4.26 g, 13.8 mmols), PdCl2(dppf).CH2Cl2 ([1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (1:1)) (510 mg, 0.62 mmol), 2M Na2CO3 (30 mL) and DME (60 mL). The tube was degassed with Ar briefly, capped and heated at 100° C. with stirring overnight. After cooling, the reaction mixture was diluted with EtOAc and water, organic layer was isolated, washed with brine and dried (MgSO4). After solvent was removed under reduced pressure, the residue was purified on silica. Elution with EtOAc in hexanes (0-25%) gave tert-butyl 4-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)pyrazolo[1,5-a]pyrimidin-5-yl)-5,6-dihydropyridine-1(2H)-carboxylate (5.76 g, 80%).
Reaction SMILES: [CH3:1]O.S(Cl)(Cl)(=O)=O.[NH:8]1[C:12](=[O:13])[CH2:11][CH2:10][C@H:9]1[C:14]([OH:16])=[O:15]>CN(C=O)C>[CH3:1][O:15][C:14](=[O:16])[C@@H:9]1[CH2:10][CH2:11][C:12](=[O:13])[NH:8]1
Reactant: O=C1CC[C@@H](C(=O)O)N1
Reactant: CO
Solvent: CN(C)C=O
Solvent: O=S(=O)(Cl)Cl
Product: COC(=O)[C@@H]1CCC(=O)N1
Temperature: 25 °C
Reaction time: 36 h
Yield: 91 %

Procedure:
To methanol (30.0 mL), cooled to -10 to -15° C., was slowly added sulfuryl chloride (11.0 mL, 178 mmol), DMF (0.133 mL) and L-pyroglutamic acid (L=(S) configuration, 10.0 g, 77.5 mmol, Sigma Chemical Co.). The stirred mixture was allowed to warm slowly and then stirred at room temperature for 36 hours. The methanol was removed under vacuum, and the residue was dissolved in ethyl acetate (400 mL). Water (~10 mL) was added, followed by the addition of sodium carbonate until basic. The organic layer was decanted, the slurry was washed with ethyl acetate (4×15 mL), and the organics were then combined and dried over magnesium sulfate. Removal of the solvent gave crude pyroglutamic methyl ester (10.04 g, 91%). NMR and MS analysis indicated >95% purity.
Reaction SMILES: [Na].C([O:5][CH2:6][CH2:7][O:8][C:9]1[C:13]([C:14]2[CH:22]=[CH:21][C:17]3[O:18][CH2:19][O:20][C:16]=3[CH:15]=2)=[C:12]([N:23](S(C2C=CC(C(C)(C)C)=CC=2)(=O)=O)[S:24]([C:27]2[CH:32]=[CH:31][C:30]([C:33]([CH3:36])([CH3:35])[CH3:34])=[CH:29][CH:28]=2)(=[O:26])=[O:25])[N:11]([CH2:50][C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)[N:10]=1)(=O)C.Cl>C(O)C.O>[O:18]1[C:17]2[CH:21]=[CH:22][C:14]([C:13]3[C:9]([O:8][CH2:7][CH2:6][OH:5])=[N:10][N:11]([CH2:50][C:51]4[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=4)[C:12]=3[NH:23][S:24]([C:27]3[CH:28]=[CH:29][C:30]([C:33]([CH3:36])([CH3:34])[CH3:35])=[CH:31][CH:32]=3)(=[O:26])=[O:25])=[CH:15][C:16]=2[O:20][CH2:19]1
Reactant: CC(=O)OCCOc1nn(Cc2ccccc2)c(N(S(=O)(=O)c2ccc(C(C)(C)C)cc2)S(=O)(=O)c2ccc(C(C)(C)C)cc2)c1-c1ccc2c(c1)OCO2
Agent: Cl
Agent: [Na]
Solvent: O
Solvent: CCO
Product: CC(C)(C)c1ccc(S(=O)(=O)Nc2c(-c3ccc4c(c3)OCO4)c(OCCO)nn2Cc2ccccc2)cc1
Reaction time: 8 h
Yield: 95.6 %

Procedure:
An aqueous solution of sodium hydroxyde (2N, 75 ml) was added at room temperature to a solution of 2-{[4-(1,3-benzodioxol-5-yl)-1-benzyl-5-(bis{[4-(tert-butyl)phenyl]sulfonyl)amino)-1H-pyrazol-3-yl]oxy}ethyl acetate (Preparation 52) (24 g) in ethanol (300 ml) and left overnight. The reaction mixture was then diluted with water (1000 ml), acidified with an aqueous solution of HCl (1N) and extracted with ethyl acetate (3×500 ml). The combined organic phases were washed with brine (500 ml) and concentrated under reduced pressure. The yellow oil was purified by column chromatography (silica, 500 g) eluted with hexane:ethyl acetate (1:1) yielding the title compound as a pale beige solid (16 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[N:10]=[C:9]2[NH:19][NH2:20])=[CH:4][CH:3]=1.[CH:21](OCC)(OCC)OCC>C(O)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[CH:12]=[C:11]([C:15]([F:18])([F:16])[F:17])[N:10]3[CH:21]=[N:20][N:19]=[C:9]23)=[CH:4][CH:3]=1
Reactant: CCOC(OCC)OCC
Reactant: NNc1nc(C(F)(F)F)cc(=O)n1-c1ccc(Cl)cc1
Solvent: CC(=O)O
Product: O=c1cc(C(F)(F)F)n2cnnc2n1-c1ccc(Cl)cc1
Temperature: 120 °C

Procedure:
A mixture of 3-(4-chlorophenyl)-3,4-dihydro-2-hydrazino-6-trifluoromethylpyrimidin-4-one (0.7 g), triethyl orthoformate (1.0 g) and acetic acid (10 ml) was heated for one hour at 120° C. The solvent was distilled off under reduced pressure and the residue was purified by a preparative thin-layer plate of silica gel (developing solvent: ethyl acetate/hexane=4/6) to give the compound of interest (0.45 g).
Reaction SMILES: [C:1]([NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[OH-].[Na+].[Cl-].[C:17]1([N+:23]#[N:24])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>O>[C:8]1([NH:7][C:1](=[O:6])[C:2](=[N:24][NH:23][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:3](=[O:4])[CH3:5])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CC(=O)CC(=O)Nc1ccccc1
Reactant: N#[N+]c1ccccc1
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(=O)C(=NNc1ccccc1)C(=O)Nc1ccccc1
Yield: 47.6 %

Procedure:
4.5 g (25.4 mmol) of acetoacetanilide, a solution of 3.46 g (89 mmol) of NaOH in 45 ml of water and 95 mmol of phenyldiazonium chloride were treated as described in preparation 8. The residue was crystallised from EtOH, yielding 3.4 g of the title compound. M.p.=96°-97° C.
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[CH:14][C:13]([C:16]2([CH3:21])OCC[O:17]2)=[CH:12][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5].Cl(O)(=O)(=O)=O.[OH-].[Na+]>C(O)C>[C:16]([C:13]1[CH:14]=[CH:15][C:2]([NH2:1])=[C:3]([CH:12]=1)[C:4]([C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1)=[O:5])(=[O:17])[CH3:21]
Reactant: CC1(c2ccc(N)c(C(=O)c3ccccc3)c2)OCCO1
Agent: [Na+]
Agent: [O-][Cl+3]([O-])([O-])O
Agent: [OH-]
Solvent: CCO
Product: CC(=O)c1ccc(N)c(C(=O)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 93.3 %

Procedure:
2-Amino-5-(2-methyl-1,3-dioxolan-2-yl)benzophenone (1.0 g, 3.54 mmol) was dissolved in 30 ml absolute ethanol. To this was added 1M perchloric acid (14 ml). The resulting mixture was stirred at room temperature for 18 hrs. The mixture was made basic with 3N sodium hydroxide solution and then extracted with several portions of methylene chloride. The combined methylene chloride extracts were washed with water, dried with anhydrous sodium sulfate, and evaporated to yield a yellow product (0.79 g) of mp. 158°-161° C. A portion of the product was recrystallized from a mixture of methylene chloride and hexane to yield material of mp. 158°-162° C.
Reaction SMILES: O=C1C2C(C=CC=C2)C(=O)[N:3]1[CH2:12][CH2:13][CH2:14][CH2:15][N:16]1[CH2:21][CH2:20][CH:19]([CH2:22][CH2:23][CH2:24][C:25]([NH2:27])=[O:26])[CH2:18][CH2:17]1.O.NN.C(O)(=O)C>C(O)C>[NH2:3][CH2:12][CH2:13][CH2:14][CH2:15][N:16]1[CH2:21][CH2:20][CH:19]([CH2:22][CH2:23][CH2:24][C:25]([NH2:27])=[O:26])[CH2:18][CH2:17]1
Reactant: NC(=O)CCCC1CCN(CCCCN2C(=O)C3C=CC=CC3C2=O)CC1
Agent: NN
Solvent: O
Solvent: CC(=O)O
Solvent: CCO
Product: NCCCCN1CCC(CCCC(N)=O)CC1
Temperature: 25 °C
Yield: 130.8 %

Procedure:
Compound 4 (0.30 g, 0.76 mmol) was dissolved in ethanol (5 mL). To the solution was added hydrazine monohydrate (0.11 mL, 2.28 mmol) followed by a catalytic amount of acetic acid (0.1 mL). The mixture was heated to reflux for two hours, cooled to room temperature, and concentrated under vacuum. The resulting residue was subjected to column chromatography eluting with 0-20% (20:80 ammonium hydroxide/methanol) in dichloromethane to afford the desired product 5 (0.24 g, 80%) as a colorless, viscous oil: 1H NMR (500 MHz, CD3OD) δ 1.25 (m, 4H), 1.55 (m, 6H), 1.72 (m, 2H), 2.00 (m, 2H), 2.18 (m, 3H), 2.36 (t, 2H), 2.74 (t, 2H), 2.96 (d, 2H), 3.28 (br, 4H).
Reaction SMILES: [S:1]1[CH2:7][C:5](=[O:6])[NH:4][C:2]1=S.Cl.[F:9][C:10]1[CH:15]=[CH:14][C:13]([CH:16]2[CH2:18][CH:17]2[NH2:19])=[CH:12][CH:11]=1.C(N(C(C)C)CC)(C)C>[Hg](Cl)Cl.C(#N)C>[F:9][C:10]1[CH:11]=[CH:12][C:13]([CH:16]2[CH2:18][CH:17]2[NH:19][C:2]2[S:1][CH2:7][C:5](=[O:6])[N:4]=2)=[CH:14][CH:15]=1
Reactant: NC1CC1c1ccc(F)cc1
Reactant: O=C1CSC(=S)N1
Agent: Cl
Agent: Cl[Hg]Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: O=C1CSC(NC2CC2c2ccc(F)cc2)=N1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 49.4 %

Procedure:
In a three-neck flask equipped with argon inlet was charged with rhodanine (200 mg, 1.5 mmol, 1.4 eq), anhydrous Acetonitrile (5 mL), 2-(4-fluoro-phenyl)-cyclopropylamine HCl salt (200 mg, 1.1 mmol, 1 eq) and diisopropylehtylamine (0.58 mL, 3 eq). The mixture was cooled to 0° C. and mercury (II) chloride (376 mg, 1.3 eq) was added. The reaction mixture was stirred at 0° C. for 30 minutes and room temperature for another 1.5 hours. The reaction mixture was filtered through a celite cake and washed with dichloromethane (3×20 mL), methanol (3×20 mL) and diethyl ether (3×20 mL). The filtrate and washing solutions were combined and concentrated by rotavaping to afford crude product. The crude was purified by flash chromatography (40 gram prepacked column by Isco, Inc., 230400 mesh, eluant: 0-10% methanol in dichloromethane) to obtain 136 mg of pure product. The structure was confirmed with
Reaction SMILES: [OH:1][CH:2]([CH2:39][CH2:40][CH2:41]O)[CH2:3][O:4][C@H:5]1[CH2:10][CH2:9][C@H:8]([N:11]2[C:16](=[O:17])[C:15]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]4[C:26]([C:31]#[N:32])=[CH:27][CH:28]=[CH:29][CH:30]=4)=[CH:21][CH:20]=3)=[C:14]([CH2:33][CH2:34][CH3:35])[N:13]3[N:36]=[CH:37][N:38]=[C:12]23)[CH2:7][CH2:6]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.O>O1CCCC1>[O:17]=[C:16]1[C:15]([CH2:18][C:19]2[CH:20]=[CH:21][C:22]([C:25]3[C:26]([C:31]#[N:32])=[CH:27][CH:28]=[CH:29][CH:30]=3)=[CH:23][CH:24]=2)=[C:14]([CH2:33][CH2:34][CH3:35])[N:13]2[N:36]=[CH:37][N:38]=[C:12]2[N:11]1[C@H:8]1[CH2:9][CH2:10][C@H:5]([O:4][CH2:3][CH:2]2[CH2:39][CH2:40][CH2:41][O:1]2)[CH2:6][CH2:7]1
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](OCC(O)CCCO)CC2)c2ncnn12
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](OCC3CCCO3)CC2)c2ncnn12
Temperature: 25 °C
Reaction time: 18 h

Procedure:
4′-[(4-{trans-4-[(2,5-Dihydroxypentyl)oxy]cyclohexyl}-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl]biphenyl-2-carbonitrile (0.17 g) was dissolved in tetrahydrofuran (3 mL), triphenylphosphine (0.24 g) and then diethyl azodicarboxylate (0.40 g, 40% toluene solution) were added, and the mixture was stirred at room temperature for 18 hr. The reaction mixture was added to water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.12 g, 74%).