Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:3]([F:16])=[C:4]2[C:9](=[O:10])[N:8]([CH3:11])[C:6](=[O:7])[C:5]2=[C:12]([F:15])[C:13]=1[F:14].[C:17](=O)([O-])[O-].[K+].[K+].S(OC)(OC)(=O)=O.Cl>O.CC(C)=O>[CH3:17][O:1][C:2]1[C:3]([F:16])=[C:4]2[C:9](=[O:10])[N:8]([CH3:11])[C:6](=[O:7])[C:5]2=[C:12]([F:15])[C:13]=1[F:14]
Reactant: O=C([O-])[O-]
Reactant: CN1C(=O)c2c(F)c(O)c(F)c(F)c2C1=O
Agent: Cl
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Solvent: COS(=O)(=O)OC
Product: COc1c(F)c(F)c2c(c1F)C(=O)N(C)C2=O

Procedure:
The solids from Example 1 were combined with 375 mL of acetone, and 61.08 g of potassium carbonate. With stirring, 55.77 g of dimethyl sulfate was added, and the entire mixture was heated to reflux for 1.5 h. After cooling, 500 mL of water was added and the reaction was acidified with HCl to a pH of 1.0. The mixture was extracted with ethyl acetate and washed with water. After drying with magnesium sulfate and removal of the solvent, 45.08 g of a yellow solid was collected. The solid was assayed as 72% 4-methoxy-3,5,6-trifluoro-N-methylphthalimide. 19F NMR (ppm acetone d6): -133.0 (m), -140.8 (m), -142.6 (m), 1H NMR (ppm acetone d6) 3.05 (s), 4.19 (s).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH:4](OS(C)(=O)=O)[CH2:5][O:6][CH3:7].[N-:13]=[N+:14]=[N-:15].[Na+]>CC(N(C)C)=O.O>[CH3:1][O:2][CH2:3][CH:4]([N:13]=[N+:14]=[N-:15])[CH2:5][O:6][CH3:7]
Reactant: COCC(COC)OS(C)(=O)=O
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: COCC(COC)N=[N+]=[N-]
Reaction time: 24 h
Yield: 72.5 %

Procedure:
1,3-Dimethoxy-2-methanesulphonyloxypropane (Method 49; 3.74 g, 19 mmol) and sodium azide (2.03 g, 31 mmol) in DMA (55 ml) was heated at 100° C. for 8 hours then left to stand at ambient temperature for 24 hours. The mixture was diluted with water, extracted with ethyl acetate, the extracts combined and washed with water, dried (MgSO4) and the volatiles removed by evaporation to give the title compound (2.0 g, 74%) as a clear oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[N:10][N:11]([CH3:13])[CH:12]=2)=[CH:4][C:3]=1[N:14]1[CH:19]=[C:18]([O:20][CH3:21])[C:17](=[O:22])[C:16]([C:23](N(OC)C)=[O:24])=[N:15]1.[CH3:29][Mg+].[Br-]>C1COCC1>[C:23]([C:16]1[C:17](=[O:22])[C:18]([O:20][CH3:21])=[CH:19][N:14]([C:3]2[CH:4]=[C:5]([C:8]3[CH:9]=[N:10][N:11]([CH3:13])[CH:12]=3)[CH:6]=[CH:7][C:2]=2[F:1])[N:15]=1)(=[O:24])[CH3:29]
Reactant: C[Mg+]
Reactant: COc1cn(-c2cc(-c3cnn(C)c3)ccc2F)nc(C(=O)N(C)OC)c1=O
Agent: [Br-]
Solvent: C1CCOC1
Product: COc1cn(-c2cc(-c3cnn(C)c3)ccc2F)nc(C(C)=O)c1=O
Temperature: -78 °C
Reaction time: 2 h
Yield: 85.5 %

Procedure:
To a mixture of 1-[2-fluoro-5-(1-methyl-1H-pyrazol-4-yl)phenyl]-N,5-dimethoxy-N-methyl-4-oxo-1,4-dihydropyridazine-3-carboxamide (267 mg, 0.687 mmol) in THF (80 mL) was added MeMgBr (1.0 M in THF, 2.06 mL, 2.06 mmol) at −78° C. under N2. The mixture was stirred at −78° C. for 2 h. To the mixture was added MeMgBr (1.0 M in THF, 0.687 mL, 0.687 mmol) at −78° C. The mixture was stirred at −78° C. for 1 h. To the mixture was added MeMgBr (1.0 M in THF, 1.37 mL, 1.37 mmol) at −78° C. The mixture was stirred at −78° C. for 3 h. The reaction was quenched with saturated NH4Cl aqueous solution at −78° C. The mixture was diluted with saturated NaHCO3 aqueous solution, extracted with EtOAc, dried over Na2SO4, filtered, concentrated in vacuo and purified by column chromatography on silica gel (EtOAc/MeOH=100/0 to 70/30) to yield the title compound (201 mg, 85% yield) as a yellow solid: 1H NMR (DMSO-d6, 300 MHz): δ ppm 2.52 (3H, s), 3.82 (3H, s), 3.87 (3H, s), 7.53 (1H, dd, J=10.6, 8.7 Hz), 7.78 (1H, ddd, J=8.7, 4.5, 2.3 Hz), 7.92-8.00 (2H, m), 8.23 (1H, s), 8.56 (1H, d, J=1.5 Hz).
Reaction SMILES: C(N(CC)CC)C.[CH3:8][S:9](Cl)(=[O:11])=[O:10].[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][C:23]([CH2:26][CH2:27][C@H:28]3[O:37][C@@H:31]4[O:32][C:33]([CH3:36])([CH3:35])[O:34][C@@H:30]4[C@@H:29]3[CH2:38][CH2:39][OH:40])=[CH:22][CH:21]=2)=[CH:16][CH:15]=1.O>ClCCl>[CH3:8][S:9]([O:40][CH2:39][CH2:38][C@H:29]1[C@@H:30]2[C@@H:31]([O:32][C:33]([CH3:36])([CH3:35])[O:34]2)[O:37][C@@H:28]1[CH2:27][CH2:26][C:23]1[CH:22]=[CH:21][C:20]([C:17]2[CH:18]=[CH:19][C:14]([Cl:13])=[CH:15][CH:16]=2)=[CH:25][CH:24]=1)(=[O:11])=[O:10]
Reactant: CC1(C)O[C@H]2O[C@H](CCc3ccc(-c4ccc(Cl)cc4)cc3)[C@@H](CCO)[C@H]2O1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CC1(C)O[C@H]2O[C@H](CCc3ccc(-c4ccc(Cl)cc4)cc3)[C@@H](CCOS(C)(=O)=O)[C@H]2O1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Triethylamine (0.43 ml) and methanesulfonyl chloride (0.21 mL) were added to a solution of the compound obtained from step i above (0.6 g) in dichloromethane (15 mL) at 0° C. The reaction mixture was stirred at room temperature for 2 hours. Dichloromethane and water were added to reaction mixture. The organic layer was separated, washed with water, dried, and concentrated under reduced pressure to furnish the title compound (0.6 g).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[C:13]([C:15]2[CH:16]=[N:17][NH:18][CH:19]=2)[CH:12]=[C:11]([F:20])[C:10]=1[C:21]1[S:25][C:24]([N:26]2[CH2:29][C:28]3([CH2:34][CH2:33][N:32]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:31][CH2:30]3)[CH2:27]2)=[N:23][N:22]=1)C1C=CC=CC=1>CO.C(Cl)Cl.[Pd]>[F:20][C:11]1[CH:12]=[C:13]([C:15]2[CH:16]=[N:17][NH:18][CH:19]=2)[CH:14]=[C:9]([OH:8])[C:10]=1[C:21]1[S:25][C:24]([N:26]2[CH2:27][C:28]3([CH2:34][CH2:33][N:32]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:31][CH2:30]3)[CH2:29]2)=[N:23][N:22]=1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CN(c1nnc(-c3c(F)cc(-c4cn[nH]c4)cc3OCc3ccccc3)s1)C2
Agent: [Pd]
Solvent: CO
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC2(CC1)CN(c1nnc(-c3c(O)cc(-c4cn[nH]c4)cc3F)s1)C2
Temperature: 25 °C
Reaction time: 18 h
Yield: 74.5 %

Procedure:
A solution of tert-butyl 2-(5-(2-(benzyloxy)-6-fluoro-4-(1H-pyrazol-4-yl)phenyl)-1,3,4-thiadiazol-2-yl)-2,7-diazaspiro[3.5]nonane-7-carboxylate (86 mg, 0.149 mmol) in a 1:1: mixture MeOH:DCM (3 mL) was added to a nitrogen flushed flask containing 10% Pd/C (8.6 mg). The reaction mixture was placed under a hydrogen atmosphere (balloon) and stirred at room temperature for 18 hours. The reaction mixture was flushed with nitrogen and an additional 8.6 mg of 10% Pd/C was added. The reaction was diluted with 1:1 MeOH:DCM (3 mL), and again placed under a hydrogen atmosphere (balloon) and stirred at room temperature for an additional 5 days. The reaction mixture was flushed with nitrogen, diluted with 10% MeOH in DCM (50 mL) and filtered through celite. The filtrate was concentrated in vacuo to afford a pale brown/off-white solid. The solid was re-dissolved in 25% MeOH in DCM (10 mL) and added to a nitrogen flushed flash containing 10% Pd/C (8.6 mg). The reaction mixture was placed under a hydrogen atmosphere (balloon) and left to stir at room temperature for 18 hours. The reaction mixture was diluted with 10% MeOH in DCM (50 mL) and filtered through celite. The filtrate was concentrated in vacuo to afford the crude product as a brown solid. The crude material was purified by flash chromatography using a 10 g silica cartridge running a MeOH/DCM gradient and collecting by mass to afford an the title compound as a pale brown solid (54 mg, 74% yield). LC-MS: Rt 1.33 min; MS m/z 487.3 [M+H]+ [Method A]. 1H NMR (400 MHz, DMSO-d6) δ 13.09 (s, 1H), 11.92 (s, 1H), 8.36 (d, J=1.7 Hz, 1H), 8.04 (d, J=1.9 Hz, 1H), 7.22 (dd, J=12.6, 1.6 Hz, 1H), 7.14-7.19 (m, 1H), 3.92 (s, 4H), 3.28-3.31 (m, 4H), 1.69-1.79 (m, 4H), 1.40 (s, 9H).
Reaction SMILES: [F:1][C:2]1[CH:24]=[C:23]([N+:25]([O-])=O)[CH:22]=[CH:21][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12]([C:14]([N:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)=[O:15])[S:13][C:6]=12.[BH4-].[Na+]>CO.C1COCC1>[NH2:25][C:23]1[CH:22]=[CH:21][C:3]([O:4][C:5]2[CH:10]=[CH:9][N:8]=[C:7]3[CH:11]=[C:12]([C:14]([N:16]4[CH2:17][CH2:18][CH2:19][CH2:20]4)=[O:15])[S:13][C:6]=23)=[C:2]([F:1])[CH:24]=1
Reactant: O=C(c1cc2nccc(Oc3ccc([N+](=O)[O-])cc3F)c2s1)N1CCCC1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: Nc1ccc(Oc2ccnc3cc(C(=O)N4CCCC4)sc23)c(F)c1
Reaction time: 1 h
Yield: 91.4 %

Procedure:
To a solution of 22 (3.23 g, 8.33 mmol) and NiCl2.6H2O (3.96 g, 16.66 mmol) in MeOH/THF (100/100 mL) was added NaBH4 (1.24 g, 33.32 mmol). The reaction mixture was stirred for 1 hr, concentrated to dryness and the resultant solid was dissolved in 10% HCl. The aqueous solution was then made basic with concentrated NH4OH solution and extracted with EtOAc. The organic phase was collected, dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford 23 as a black solid (2.72 g, 91% yield). MS (m/z): 358.2 (M+H).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH:10]([NH:12][C:13]2[N:18]=[C:17]([N:19]3[CH2:24][CH2:23][C:22](=[O:25])[N:21]4[CH2:26][CH:27]=[C:28]([C:30]5[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=5)[N:29]=[C:20]34)[CH:16]=[CH:15][N:14]=2)[CH3:11])=[CH:5][CH:4]=1>ClCCl.[O-2].[O-2].[Mn+4]>[O:25]=[C:22]1[N:21]2[CH2:26][CH:27]=[C:28]([C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)[N:29]=[C:20]2[N:19]([C:17]2[CH:16]=[CH:15][N:14]=[C:13]([NH:12][CH:10]([CH3:11])[CH2:9][C:6]3[CH:7]=[CH:8][C:3]([CH:2]=[O:1])=[CH:4][CH:5]=3)[N:18]=2)[CH2:24][CH2:23]1
Reactant: CC(Cc1ccc(CO)cc1)Nc1nccc(N2CCC(=O)N3CC=C(c4ccccc4)N=C32)n1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: CC(Cc1ccc(C=O)cc1)Nc1nccc(N2CCC(=O)N3CC=C(c4ccccc4)N=C32)n1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
The mixture of 1-{2-[2-(4-hydroxymethyl-phenyl)-1-methyl-ethylamino]-pyrimidin-4-yl}-8-phenyl-1,2,3,6-tetrahydro -pyrimido[1,2-a]pyrimidin-4-one (0.38 g, 0.81 mmol) and manganese dioxide (3.5 g, 40.5 mmol) in dichloromethane was stirred at room temperature for 3 h. The mixture was filtered off and concentrated to afford a white solid. M+1=467.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([C:8]2[NH:9][CH:10]=[CH:11][C:12](=O)[N:13]=2)[CH:5]=[CH:6][CH:7]=1.P(Cl)(Cl)([Cl:17])=O>>[Cl:17][C:12]1[CH:11]=[CH:10][N:9]=[C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([I:1])[CH:3]=2)[N:13]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1cc[nH]c(-c2cccc(I)c2)n1
Product: Clc1ccnc(-c2cccc(I)c2)n1

Procedure:
A 32.9 g portion of 2-(3-iodophenyl)-4(1H)-pyrimidinone was stirred and refluxed in 123 ml. of phosphorus oxychloride for 2 hours, then cooled overnight and the solvent evaporated at 55° C. The residue was suspended in 400 ml of chloroform, then evaporated. This residue was taken up in 300 ml of chloroform, filtered and washed twice with 75 ml of chloroform. The combined filtrate and washes were evaporated giving 4-chloro-2-(3-iodophenyl)pyrimidine.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=3)=[CH:11][C:10]([C:23]([OH:25])=O)=[N:9]2)=[CH:4][CH:3]=1.S(Cl)([Cl:28])=O>O1CCCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=3)=[CH:11][C:10]([C:23]([Cl:28])=[O:25])=[N:9]2)=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)c1ccc(-c2cc(C(=O)O)nn2-c2ccc(F)cc2)cc1
Reactant: O=S(Cl)Cl
Solvent: C1CCOC1
Product: CS(=O)(=O)c1ccc(-c2cc(C(=O)Cl)nn2-c2ccc(F)cc2)cc1

Procedure:
A mixture of 1-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]pyrazole-3-carboxylic acid (6.4 g) and thionyl chloride (30 ml) in tetrahydrofuran (60 ml) was refluxed for 1 hour and concentrated under reduced pressure, giving 1-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]pyrazole-3-carbonyl chloride.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.Cl[C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=2)=[CH:4][CH:3]=1
Reactant: Fc1ccc(S)cc1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: O=[N+]([O-])c1ccc(Sc2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of 4-fluorobenzenethiol (9.86 g, 77 mmol), 1-chloro-4-nitrobenzene (12.72 g, 81 mmol) and potassium carbonate (21.25 g, 154 mmol) in acetonitrile (300 mL) is stirred at room temperature under inert atmosphere for 48 h. The mixture is diluted with water (750 mL) and the aqueous phase is extracted with dichloromethane (2×500 mL). The combined organic layers are dried over sodium sulphate, filtered and concentrated under reduced pressure. The desired product is isolated in the presence of some impurities as a yellow solid (19.4 g, 78 mmol) (HPLC-MS Method 2: retention time: 2.132 min, m/z no mass signal).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH:13]=[CH:12][C:11](=[O:14])[N:10]([C:15]3[C:20]([F:21])=[CH:19][CH:18]=[CH:17][C:16]=3[F:22])[C:4]=2[N:5]=[C:6]([S:8][CH3:9])[N:7]=1.C1C=C(Cl)C=C(C(OO)=[O:31])C=1>ClCCl>[Cl:1][C:2]1[C:3]2[CH:13]=[CH:12][C:11](=[O:14])[N:10]([C:15]3[C:16]([F:22])=[CH:17][CH:18]=[CH:19][C:20]=3[F:21])[C:4]=2[N:5]=[C:6]([S:8]([CH3:9])=[O:31])[N:7]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSc1nc(Cl)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Solvent: ClCCl
Product: CS(=O)c1nc(Cl)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Yield: 88.2 %

Procedure:
A solution of 4-Chloro-2-methylsulfanyl-8-(2,6-difluoro-phenyl)-8H-pyrido[2,3-d]pyrimidin-7-one (1.0 g, 2.9 mmol) in dichloromethane (50 mL) was mixed with m-CPBA (0.69 g, 4.4 mmol). The resultant mixture was stirred at room temperature for 10 minutes and concentrated under vacou. Flash chromatography (EtOAc/Hexane, 3:1) then provided the title compound (0.91 g, 87%): MS (ES) m/z 356 (M+H)+; 1H-NMR(CDCl3) δ 2.85 (s, 3H), 7.03 (d, J=9.6 Hz, 1H), 7.15 (m, 2H) 7.53 (m, 1H), 8.18 (d, J=9.6 Hz, 1H).
Reaction SMILES: O=C1C2C(=CC=CC=2)C(=O)[N:3]1[CH2:12][C@@H:13]([CH3:41])[CH2:14][N:15]1[CH:20]=[C:19]([F:21])[CH:18]=[C:17]([C@H:22]2[CH2:26][CH2:25][CH2:24][N:23]2[C:27]2[CH:32]=[CH:31][N:30]3[N:33]=[CH:34][C:35]([C:36]([O:38][CH3:39])=[O:37])=[C:29]3[N:28]=2)[C:16]1=[O:40].NN>CO.C1COCC1>[NH2:3][CH2:12][C@@H:13]([CH3:41])[CH2:14][N:15]1[CH:20]=[C:19]([F:21])[CH:18]=[C:17]([C@H:22]2[CH2:26][CH2:25][CH2:24][N:23]2[C:27]2[CH:32]=[CH:31][N:30]3[N:33]=[CH:34][C:35]([C:36]([O:38][CH3:39])=[O:37])=[C:29]3[N:28]=2)[C:16]1=[O:40]
Reactant: COC(=O)c1cnn2ccc(N3CCC[C@@H]3c3cc(F)cn(C[C@H](C)CN4C(=O)c5ccccc5C4=O)c3=O)nc12
Agent: NN
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)c1cnn2ccc(N3CCC[C@@H]3c3cc(F)cn(C[C@H](C)CN)c3=O)nc12
Temperature: 50 °C
Reaction time: 14 h
Yield: 77 %

Procedure:
To a solution of methyl 5-((R)-2-(1-((S)-3-(1,3-dioxoisoindolin-2-yl)-2-methylpropyl)-5-fluoro-2-oxo-1,2-dihydropyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylate (110 mg, 0.197 mmol) in MeOH/THF (3 mL/3 mL) was added hydrazine (31.6 mg, 0.985 mmol). The reaction was stirred for 14 hours at 50° C. After cooling, the reaction mixture was concentrated and the resulting residue was diluted with EtOAc (20 mL) and washed with saturated aqueous NaHCO3 (5 mL), water (2×5 mL) and brine (5 mL). The organic layer was dried with Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica column chromatography, eluting with EtOAc/MeOH/NH4OH 10:1:0.1 to give the desired product (65 mg, 77% yield). MS (apci) m/z=429.2 (M+H).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[CH2:11]1[O:13][CH2:12]1>C(O)(C)C>[OH:13][CH2:12][CH2:11][O:7][C:6](=[O:8])[C:5]1[CH:9]=[CH:10][C:2]([OH:1])=[CH:3][CH:4]=1
Reactant: O=C(O)c1ccc(O)cc1
Reactant: C1CO1
Solvent: CC(C)O
Product: O=C(OCCO)c1ccc(O)cc1

Procedure:
Into an autoclave, 138 parts by weight of p-hydroxybenzoic acid, 1 part by weight of Na2CO2 and 300 parts by weight of isopropanol were charged, and at 90° C., 66 parts by weight of ethylene oxide was added thereto, and the reaction was conducted. After the reaction, the mixture was cooled, and the precipitate was collected by filtration and recrystallized twice from water to obtain 55 parts by weight of p-hydroxylbenzoic acid-β-hydroxyethyl ester ##STR88## having a melting point of 141° C. The structure was confirmed by 1H-NMR.
Reaction SMILES: C(O)CCO.CC1C=CC(S(OCC(CC2C=CC([N+]([O-])=O)=CC=2)COS(C2C=CC(C)=CC=2)(=O)=O)(=O)=O)=CC=1.[N+:41]([C:44]1[CH:51]=[CH:50][C:47]([CH2:48]Br)=[CH:46][CH:45]=1)([O-:43])=[O:42].[C:52]([O:60][CH2:61][CH3:62])(=[O:59])[CH2:53][C:54]([O:56][CH2:57][CH3:58])=[O:55].C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[N+:41]([C:44]1[CH:51]=[CH:50][C:47]([CH2:48][CH:53]([C:54]([O:56][CH2:57][CH3:58])=[O:55])[C:52]([O:60][CH2:61][CH3:62])=[O:59])=[CH:46][CH:45]=1)([O-:43])=[O:42]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Agent: Cc1ccc(S(=O)(=O)OCC(COS(=O)(=O)c2ccc(C)cc2)Cc2ccc([N+](=O)[O-])cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: OCCCO
Solvent: CC(C)=O
Product: CCOC(=O)C(Cc1ccc([N+](=O)[O-])cc1)C(=O)OCC
Yield: 88 %

Procedure:
Although PCB-TE2A is a good chelator having an octahedral coordination site with metals like Cu, one of its two pendant arms has to be sacrificed whenever it is conjugated with biomolecules. To keep intact the octahedral coordination structure while allowing further conjugation with biomolecules, introduction of an extra functional group in the backbone is necessary. For this purpose, the inventors have synthesized a suitably tailored nitro-derivative of ditosyl ester of 1,3-propanediol, 25. The precursor was used for the construction of propylene bridge having one extra functionality. The inventors have designed the compound 25 and performed synthesis by condensation of 1 equiv. of 4-nitrobenzyl bromide with 7 equivalent of diethyl malonate in the presence of K2CO3 in acetone to give 23 in 88% yield (Scheme 6). In this reaction a mild base rather than metal alkoxide and excess of diethyl malonate were used in order to prevent the formation of dialkylate product. The diethyl-2-[(4-nitrophenyl)methyl]propanedioate 23 was reduced with sodium borohydride to afford the diol compound 24 in 85% yield. The diol 24 was tosylated by tosyl chloride in pyridine to afford the precursor 25 in 89% yield. According to Scheme 6,2-[(4-nitrophenyl)methyl]propan-1,3-diol bis(4-methylbenzene-sulfonate) (25) was prepared in high overall yield (66%).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][C:8](=O)[CH2:7][CH2:6]1.Cl.[NH2:13][OH:14]>>[OH:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][C:8](=[N:13][OH:14])[CH2:7][CH2:6]1
Reactant: NO
Reactant: O=C1CCN(CCCO)CC1
Agent: Cl
Product: OCCCN1CCC(=NO)CC1

Procedure:
1-(3-Hydroxypropyl)-4-piperidone oxime is prepared from 1-(3-hydroxypropyl)-4-piperidone and hydroxylamine hydrochloride essentially as described above in Example 38, Scheme C, step b.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH2:15])[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]1.Cl[C:17]1[N:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:20]=[CH:19][N:18]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:15][C:17]2[N:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:20]=[CH:19][N:18]=2)[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]1
Reactant: FC(F)(F)c1ccnc(Cl)n1
Reactant: COc1cc(N)ccc1-n1cnc(C)c1
Product: COc1cc(Nc2nccc(C(F)(F)F)n2)ccc1-n1cnc(C)c1

Procedure:
The title compound was prepared in analogous manner as described in example 1e) from 3-methoxy-4-(4-methyl-imidazol-1-yl)-phenylamine and 2-chloro-4-trifluoromethyl-pyrimidine. The reaction was refluxed for 16 h. The title compound was obtained as a pale-yellow solid in 43% yield.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]2[N:11]([C:15](Br)=[CH:16][N:17]=2)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:19]([Si:21]([CH3:24])([CH3:23])[CH3:22])#[CH:20].C(NC(C)C)(C)C>C(#N)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>[CH2:1]([O:8][C:9]1[C:10]2[N:11]([C:15]([C:20]#[C:19][Si:21]([CH3:24])([CH3:23])[CH3:22])=[CH:16][N:17]=2)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C#C[Si](C)(C)C
Reactant: Brc1cnc2c(OCc3ccccc3)cccn12
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CC(C)NC(C)C
Solvent: CC#N
Product: C[Si](C)(C)C#Cc1cnc2c(OCc3ccccc3)cccn12
Temperature: 25 °C
Yield: 63.7 %

Procedure:
A mixture of 8-(benzyloxy)-3-bromoimidazo[1,2-a]pyridine (10.0 g, 33.0 mmol), 9.39 mL (66.0 mmol) of ethynyltrimethylsilane, 0.580 g (0.825 mmol) of Pd(PPh3)2Cl2, 0.230 g (1.19 mmol) of CuI, and 5.09 mL (36.3 mmol) of diisopropylamine in 100 mL of acetonitrile was heated at reflux for 3 h under an atmosphere of N2. Upon cooling to ambient temperature, the reaction mixture was concentrated and the crude product was purified by silica gel flash chromatography (eluted with 20-50% EtOAc/hexanes) to provide 6.74 g of product: 321 m/z (M+H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](I)[C:5]([OH:9])=[CH:4][CH:3]=1.[C:10]([N:17]1[CH2:21][CH2:20][CH2:19][C@H:18]1[C:22]#[CH:23])([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11]>CN(C=O)C.CCOCC.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>[C:10]([N:17]1[CH2:21][CH2:20][CH2:19][C@H:18]1[C:22]1[O:9][C:5]2[C:6](=[N:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[CH:23]=1)([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11]
Reactant: C#C[C@@H]1CCCN1C(=O)OC(C)(C)C
Reactant: Oc1ccc(Cl)nc1I
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1CCC[C@H]1c1cc2nc(Cl)ccc2o1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A 3.07 g (12.0 mmol) sample of 6-chloro-2-iodo-3-pyridinol, from step 11c above, was dissolved in 10 mL of DMF, and (Ph3P)2PdCl2 (0.38 g, 0.50 mmol), CuI (0.380 g, 1.98 mmol) and triethylanue (1.7 mL, 12 mmol) were added. The mixture was stirred under N2 at room temperature for 1 hour, then 1.95 g (10.0 mmol) of 1-BOC-2-(S)-ethynylpyrrolidine, from Example 1a above, dissolved in 5 mL of DMF, was added carefully. The reaction mixture was stirred at 60° C. for 16 hours, cooled to room temperature, diluted with ether, washed with 50% brine and dried over MgSO4, then the solvent was removed. The residue was chromatographed on silica gel, eluting with 100:0 to 50:50 hexane:EtOAc to give 1.54 g of title compound: 1H NMR (DMSO, 300 MHz, 130° C.) δ 1.37 (two s, 9H), 1.89-2.07 (m, 3H), 2.37 (m, 1H), 3.40-3.54 (m, 1H), 4.98 (m, 1H), 6.72 (s, 1H), 7.26-7.29 (d, 1H, J=8.6 Hz), 7.93-7.96 (d, 1H, J=8.6 Hz); MS m/z: 323 (M+H)+.
Reaction SMILES: Cl.[C:2]1([CH2:8][CH2:9][C:10]2[N:11]=[C:12]([CH:15]3[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)[S:13][CH:14]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:21][C:22]([F:37])([F:36])[C:23]1[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][C:24]=1[C:33](Cl)=[O:34]>>[F:21][C:22]([F:36])([F:37])[C:23]1[CH:28]=[CH:27][C:26]([C:29]([F:30])([F:31])[F:32])=[CH:25][C:24]=1[C:33]([N:18]1[CH2:19][CH2:20][CH:15]([C:12]2[S:13][CH:14]=[C:10]([CH2:9][CH2:8][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[N:11]=2)[CH2:16][CH2:17]1)=[O:34]
Reactant: O=C(Cl)c1cc(C(F)(F)F)ccc1C(F)(F)F
Reactant: c1ccc(CCc2csc(C3CCNCC3)n2)cc1
Agent: Cl
Product: O=C(c1cc(C(F)(F)F)ccc1C(F)(F)F)N1CCC(c2nc(CCc3ccccc3)cs2)CC1

Procedure:
4-[4-(2-Phenylethyl)-1,3-thiazol-2-yl]piperidine hydrochloride (II-1, 309 mg) is reacted analogously to Example I-63 with 2,5-bis(trifluoromethyl)benzenecarbonyl chloride (304 mg). After chromatographic purification, this gives [2,5-bis(trifluoromethyl)phenyl]{4-[4-(2-phenylethyl)-1,3-thiazol-2-yl]piperidin-1-yl}methanone (282 mg).