Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@@H:13]2[O:22][C:21]3[C:16](=[CH:17][CH:18]=[C:19]4[NH:25][C:24]([C:26]([F:29])([F:28])[F:27])=[N:23][C:20]4=3)[O:15][CH2:14]2)(=O)=O)=CC=1.[NH:30]1[CH2:35][CH:34]=[C:33]([C:36]2[C:44]3[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=3)[NH:38][CH:37]=2)[CH2:32][CH2:31]1>CS(C)=O.C(OCC)(=O)C>[NH:38]1[C:39]2[C:44](=[CH:43][CH:42]=[CH:41][CH:40]=2)[C:36]([C:33]2[CH2:34][CH2:35][N:30]([CH2:12][CH:13]3[O:22][C:21]4[C:16](=[CH:17][CH:18]=[C:19]5[NH:25][C:24]([C:26]([F:27])([F:29])[F:28])=[N:23][C:20]5=4)[O:15][CH2:14]3)[CH2:31][CH:32]=2)=[CH:37]1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2COc3ccc4[nH]c(C(F)(F)F)nc4c3O2)cc1
Reactant: C1=C(c2c[nH]c3ccccc23)CCNC1
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: FC(F)(F)c1nc2c3c(ccc2[nH]1)OCC(CN1CC=C(c2c[nH]c4ccccc24)CC1)O3
Temperature: 85 °C
Yield: 73.3 %

Procedure:
A mixture of 0.50 g (1.2 mmole) of [(8R)-2-trifluoromethyl-7,8-dihydro-3H-6,9-dioxa-1,3-diaza-cyclopenta[a]naphthalen-8-yl]methyl 4-methylbenzenesulfonate and 1.0 g (5.0 mmole) of 3-(1,2,3,6-tetrahydro-4-pyridinyl)-1H-indole in 8.0 mL of DMSO was heated at 85° C. under nitrogen for 6 hours. The reaction was allowed to come to room temperature, diluted to 400 mL with ethyl acetate, washed with 400 mL portions of saturated aqueous sodium bicarbonate, water and saturated brine, dried over sodium sulfate, filtered and evaporated in vacuum. The residue was column chromatographed on silica gel with 1% methanol in chloroform as eluant and the product fractions concentrated in vacuum to give 0.40 g of the desired compound as the free base. Recrystallization from ethanol with the addition of 0.12 g of fumaric acid gave 0.24 g of the (S)-enantiomer of the title compound as a pale yellow solid fumarate, m.p. 231-233° C.
Reaction SMILES: [Mg].FC1C=C2C(=CC=1)N(C1C=CC(F)=CC=1)CC(N1CCNCC1C1C=CSC=1)(C(O)=O)C2=O.[C:35]([O:43][CH2:44][CH3:45])(=[O:42])[CH2:36][C:37]([O:39][CH2:40][CH3:41])=[O:38].C(=O)=O.CC(C)=O.[F:53][C:54]1[C:59]([C:60](Cl)=[O:61])=[C:58]([F:63])[C:57]([F:64])=[C:56]([F:65])[C:55]=1[F:66]>C(O)C.CCOCC.C(Cl)(Cl)(Cl)Cl>[F:53][C:54]1[C:59]([C:60]([CH:36]([C:37]([O:39][CH2:40][CH3:41])=[O:38])[C:35]([O:43][CH2:44][CH3:45])=[O:42])=[O:61])=[C:58]([F:63])[C:57]([F:64])=[C:56]([F:65])[C:55]=1[F:66]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: O=C(Cl)c1c(F)c(F)c(F)c(F)c1F
Agent: O=C(O)C1(N2CCNCC2c2ccsc2)CN(c2ccc(F)cc2)c2ccc(F)cc2C1=O
Agent: O=C=O
Agent: [Mg]
Solvent: CCO
Solvent: CC(C)=O
Solvent: CCOCC
Product: CCOC(=O)C(C(=O)OCC)C(=O)c1c(F)c(F)c(F)c(F)c1F
Yield: 99.6 %

Procedure:
A 7.35 g portion of magnesium chips, 1 5 ml of carbon tetrachloride and 15 ml of absolute ethanol were added to a dry flask. A solution of 48.1 g of diethyl malonate in 30 ml of absolute ethanol and 120 ml of anhydrous ether was added dropwise over a one hour period. When addition was complete, the mixture was stirred at reflux for 3 hours then cooled to -10° C. with dry ice/acetone. A solution of 70 g of pentafluorobenzoyl chloride in 120 ml of ether was added over 2 hours, maintaining the temperature at not more than -5° C. The mixture was then stirred overnight at room temperature, partially evaporated, cooled in crushed ice and an ice cold solution of 7.5 ml of concentrated sulfuric acid in 300 ml of Water was added at a rate such that the internal temperature did not go above 5° C. The mixture was extracted several times with ether, the extracts combined, washed with saturated sodium chloride, dried and concentrated, giving 106 g of (pentafluorobenzoyl)propanedioic acid, diethyl ester as a yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3](Cl)=[O:4].[N+:6]([CH:9]=[C:10]1[NH:15][CH2:14][CH2:13][CH2:12][S:11]1)([O-:8])=[O:7].C(N(CC)CC)C>ClCCl>[CH3:1][O:2][C:3]([N:15]1[CH2:14][CH2:13][CH2:12][S:11][C:10]1=[CH:9][N+:6]([O-:8])=[O:7])=[O:4]
Reactant: COC(=O)Cl
Reactant: O=[N+]([O-])C=C1NCCCS1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)N1CCCSC1=C[N+](=O)[O-]
Temperature: 25 °C

Procedure:
Methoxycarbonyl chloride (5.7 g) in dichloromethane (60 ml) was added dropwise over a period of 30 minutes to a solution of 2-nitromethylene-tetrahydro-2H-1,3-thiazine (6.4 g) and triethylamine (10.4 ml) in dichloromethane (60 ml) at -20° C. under nitrogen. The reaction mixture was allowed to warm to ambient temperature over a period of 60 minutes and was then washed with 2% hydrochloric acid. The organic phase was dried (MgSO4) and the solvent was removed under reduced pressure. The residue was triturated with ethyl acetate to yield the required product as a crystalline solid m.p. 93°-95° C.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][NH2:14].[OH:15][CH2:16][C@@H:17]([NH:25][C:26](=[O:30])[C:27](O)=[O:28])[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C>[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][NH:14][C:27](=[O:28])[C:26]([NH:25][C@@H:17]([CH2:18][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[CH2:16][OH:15])=[O:30]
Reactant: O=C(O)C(=O)N[C@H](CO)Cc1ccccc1
Reactant: NCCc1c[nH]c2ccc(Cl)cc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(NCCc1c[nH]c2ccc(Cl)cc12)C(=O)N[C@H](CO)Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 57.6 %

Procedure:
The mixture of 2-(5-chloro-1H-indol-3-yl)ethanamine hydrochloride (0.256 g; 1.09 mmol), (S)-2-(1-hydroxy-3-phenylpropan-2-ylamino)-2-oxoacetic acid (0.267 g; 1.19 mmol), HATU (0.413 g: 1.09 mmol) and N,N-diisopropylethylamine (0.474 mL; 2.71 mmol) in DMF (5 mL) was stirred at room temperature overnight and concentrated under reduced pressure. The residue was dissolved in dichloromethane, the organic layer was washed with water, and was concentrated under reduced pressure. The crude material was purified by flash chromatography on silica gel (eluent 1 to 10% methanol in dichloromethane) to yield 0.251 g (58%) of (S)—N1-(2-(5-chloro-1H-indol-3-yl)ethyl)-N2-(1-hydroxy-3-phenylpropan-2-yl)oxalamide as a white solid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH2:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:19]([C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=1[F:28])#[CH:20].C1(C)C=CC=CC=1>C(#N)C.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[F:28][C:22]1[CH:23]=[C:24]([F:27])[CH:25]=[CH:26][C:21]=1[C:19]#[C:20][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][CH:3]=1
Reactant: Nc1nc(Cl)ccc1[N+](=O)[O-]
Reactant: C#Cc1ccc(F)cc1F
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Solvent: CC#N
Product: Nc1nc(C#Cc2ccc(F)cc2F)ccc1[N+](=O)[O-]
Temperature: 32.5 °C
Yield: 84.5 %

Procedure:
6-Chloro-3-nitro-pyridin-2-ylamine (16.2 kg, 93.3 mol), acetonitrile (130.8 L), cuprous iodide (0.18 kg, 1.0 mol), and bis(triphenylphosphine)palladium (II) chloride (0.66 kg, 0.9 mol) are combined under a nitrogen atmosphere at 20-25° C. with stirring. Triethylamine (19.7 L, 141.3 mol) is added and the mixture is heated to 30-35° C. A solution of 1-ethynyl-2,4-difluoro-benzene (18.0 kg, 130.3 mol) in acetonitrile (32.6 L) is added under a nitrogen atmosphere at 30-35° C. The mixture is stirred at 15-25° C. for 2-4 h. Toluene (80.0 L) is added and the mixture is stirred for 0.5-1 h, then cooled to 0-5° C. and stirred for 2-4 h. The reaction mixture is centrifuged and the filter cake is rinsed with toluene (2×64 L) and water (2×32.4 L). The solids are dried under reduced pressure below 50° C. to furnish the title compound as a yellow solid (21.7 kg, 83%).
Reaction SMILES: [Cl:1][C:2]1[C:7](=[O:8])[N:6]([C:9]2[CH:10]=[C:11]([CH:19]=[CH:20][C:21]=2[CH3:22])[C:12]([NH:14][CH2:15][C:16]([NH2:18])=[O:17])=[O:13])[CH:5]=[N:4][C:3]=1[O:23][CH2:24][C:25]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=1[F:32].Cl.N[CH2:35][C:36](N)=O>>[NH2:18][C:16]([C@@H:15]([NH:14][C:12](=[O:13])[C:11]1[CH:19]=[CH:20][C:21]([CH3:22])=[C:9]([N:6]2[C:7](=[O:8])[C:2]([Cl:1])=[C:3]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=3[F:32])[N:4]=[CH:5]2)[CH:10]=1)[CH2:35][CH3:36])=[O:17]
Reactant: NCC(N)=O
Reactant: Cc1ccc(C(=O)NCC(N)=O)cc1-n1cnc(OCc2ccc(F)cc2F)c(Cl)c1=O
Agent: Cl
Product: CC[C@H](NC(=O)c1ccc(C)c(-n2cnc(OCc3ccc(F)cc3F)c(Cl)c2=O)c1)C(N)=O

Procedure:
The title compound was prepared using a procedure similar to that used in Step 4 of the synthesis of 3-[5-chloro-4-[(2,4-difluorobenzyl)oxy]-6-oxopyrimidin-1(6H)-yl]-N-[1-(aminocarbonyl)methyl]-4-methylbenzamide by substituting L-alpha-aminobutyric acid amide for glycineamide HCl. 1H NMR (CD3OD/400 MHz) δ8.32 (s, 1H), 7.95 (m, 1H), 7.83 (m, 1H), 7.61 (q, 1H, J=8.0 Hz), 7.54 (d, 1H, J=8.0 Hz), 7.01 (m, 2H), 5.60 (m, 2H), 4.45 (m, 1H), 2.20 (s, 3H), 1.93 (m, 1H), 1.79 (m, 1H), 1.01 (t, 3H, J=7.6 Hz). ESHRMS m/z 491.1303 (M+H calculated for C23H22ClF2N4O4 requires 491.1292).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[C:11]2\[O:12][C:13]3[C:20]([CH2:21][CH2:22][CH:23]4[CH2:28][CH2:27][N:26](C(OC(C)(C)C)=O)[CH2:25][CH2:24]4)=[C:19]([O:36][CH3:37])[C:18]([F:38])=[CH:17][C:14]=3[C:15]\2=[O:16])=[N:2]1.Cl>C(Cl)Cl.O1CCOCC1>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[C:11]2\[O:12][C:13]3[C:20]([CH2:21][CH2:22][CH:23]4[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]4)=[C:19]([O:36][CH3:37])[C:18]([F:38])=[CH:17][C:14]=3[C:15]\2=[O:16])=[N:2]1
Reactant: COc1c(F)cc2c(c1CCC1CCN(C(=O)OC(C)(C)C)CC1)O/C(=C\c1n[nH]c3ccccc13)C2=O
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: COc1c(F)cc2c(c1CCC1CCNCC1)O/C(=C\c1n[nH]c3ccccc13)C2=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 81.4 %

Procedure:
A solution of tert-butyl (Z)-4-(2-{2-[(1H-indazol-3-yl)methylene]-5-fluoro-6-methoxy-3-oxo-2,3-dihydrobenzofuran-7-yl}ethyl)piperidine-1-carboxylate (0.0231 g, 0.0443 mmol) in methylene chloride (3 mL) was added with a 4 M solution of hydrogen chloride in 1,4-dioxane (3 mL), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated, the resulting residue was added with saturated aqueous sodium hydrogencarbonate, and the precipitated solid was collected by filtration. The solid was washed with water, and then dried under reduced pressure to obtain (Z)-2-[(1H-indazol-3-yl)methylene]-5-fluoro-6-methoxy-7-[2-(piperidin-4-yl)ethyl]benzofuran-3(2H)-one (0.0152 g, 81%).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:20][C@@H:21]([OH:26])[CH2:22][C@H:23]([OH:25])[CH3:24].C(OC(N=NC(OC(C)C)=O)=O)(C)C.C1(C)C=CC=CC=1.[N+]([C:51]1[CH:59]=[CH:58][C:54]([C:55](O)=[O:56])=[CH:53][CH:52]=1)([O-])=O>C1COCC1.O>[C:55]([O:25][C@@H:23]([CH3:24])[CH2:22][C@H:21]([OH:26])[CH3:20])(=[O:56])[C:54]1[CH:58]=[CH:59][CH:51]=[CH:52][CH:53]=1
Reactant: C[C@@H](O)C[C@@H](C)O
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: C[C@@H](O)C[C@H](C)OC(=O)c1ccccc1
Reaction time: 1 h

Procedure:
After triphenylphosphine (566 mg, 2.16 mmol), (2R,4R)-2,4-pentanediol (225 mg, 2.16 mmol), and THF (6 ml) were added to a 50 mL flask, a 40% azodicarboxylic acid diisopropyl ester-toluene solution (1.13 mL, 2.16 mmol) dissolved in THF (6 mL) was added dropwise thereto at 20° C. Subsequently, 4-nitrobenzoic acid (300 mg, 1.80 mmol) dissolved in THF (6 mL) was added dropwise thereto at 20° C., and the reaction was allowed to proceed for one hour. Water (0.5 ml) was added, and concentration was carried out. Then, water (10 ml) was added to the solution, and extraction was carried out using diethyl ether (10 mL,×2). Then, the organic layer was washed with water (10 ml) and saturated salt water (10 ml), and dehumidified with anhydrous magnesium sulfate. Subsequently, a crude product obtained by concentration was purified by column chromatography (silica gel, 40% ethyl acetate-hexane solution) to give (4S,2R)-4-benzoyloxypentane-2-ol containing 1,2-hydrazinedicarboxylic acid diisopropyl ester as 593 mg of a pale yellow solid substance. Measurement of 1H-NMR showed that 379 mg of (4S,2R)-4-(4-nitrobenzoyloxy)pentane-2-ol (yield: 83%/4-nitrobenzoic acid), and 213 mg of 1,2-hydrazinedicarboxylic acid diisopropyl ester were contained.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:8][N:9]2[C:13](=[O:14])[CH2:12][CH2:11][CH:10]2[C:15]([OH:17])=O)[CH:5]=[CH:6][CH:7]=1.S(Cl)(Cl)=O.[Cl-].[Al+3].[Cl-].[Cl-]>ClCCl>[F:1][C:2]1[CH:7]=[CH:6][C:5]2[C:15](=[O:17])[CH:10]3[CH2:11][CH2:12][C:13](=[O:14])[N:9]3[CH2:8][C:4]=2[CH:3]=1
Reactant: O=C(O)C1CCC(=O)N1Cc1cccc(F)c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: O=C1c2ccc(F)cc2CN2C(=O)CCC12
Temperature: 5 °C
Reaction time: 8 h

Procedure:
To a solution of 50.00 g of (±)-1-[(3-fluorophenyl)methyl]-5-oxo-2-pyrrolidine carboxylic acid in sieve dried dichloromethane (450 ml), 27.48 g of thionyl chloride was added, and the resultant solution was stirred and refluxed for 5 hours. An infrared spectrum of the solution indicated the presence of the acid chloride. After standing overnight at ambient temperature, the solution was chilled to 5° C. and 84 g of aluminum chloride was added in portions with vigorous stirring. The reaction was exothermic and there was a slow evolution of gas. The mixture was stirred at ambient temperature for 3 hours. The reaction was quenched by the addition of ice chips and water. The two phases of the mixture was separated and the aqueous phase was extracted with dichloromethane (4×150 ml). The combined organic phase was dried (Na2SO4) and concentrated to a solid (69.73 g).
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[CH:4]=O.[C:11]([O:15]C(=O)CC)(=[O:14])[CH2:12][CH3:13].C([O-])(=O)CC.[Na+].[OH-].[K+]>O>[F:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[CH:4]=[C:12]([CH3:13])[C:11]([OH:15])=[O:14]
Reactant: O=Cc1ccc(F)cc1F
Reactant: CCC(=O)OC(=O)CC
Agent: CCC(=O)[O-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Product: CC(=Cc1ccc(F)cc1F)C(=O)O

Procedure:
A 500 ml., three-necked flask is fitted with reflux condenser, drying tube, stirrer and N2 inlet. To a mixture of 55.4 g. (0.39 mole) of 2,4-difluorobenzaldehyde and 56 ml. of propionic anhydride is added 38 g. (0.39 mole) of sodium propionate. The reaction mixture is heated at 135-140° (oil bath temp.) for 19 hours with stirring under nitrogen. The still warm solution is poured into 1 l. of water with stirring. A solid separates, which upon adding 56 g. of potassium hydroxide, dissolves. The solution is extracted with ether, and then heated on the steam bath to remove the ether. After cooling in an ice-bath, concentrated hydrochloric acid is added with stirring. The product which separates is collected and washed with cold water. After drying at 60° over KOH, 2,4-difluoro-α-methylcinnamic acid, M.P. 126-128° is obtained.
Reaction SMILES: C(O[C:4]([C:6]1[N:14]([CH3:15])[C:13]2[CH:12]=[CH:11][N:10]=[CH:9][C:8]=2[C:7]=1[NH:16][C:17]1[CH:22]=[CH:21][C:20]([I:23])=[CH:19][C:18]=1[F:24])=[O:5])C.[OH-].[Na+].[CH3:27][C:28]1([CH3:36])[O:32][C@@H:31]([CH2:33][O:34][NH2:35])[CH2:30][O:29]1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>C1COCC1.C(O)C>[CH3:27][C:28]1([CH3:36])[O:32][C@@H:31]([CH2:33][O:34][NH:35][C:4]([C:6]2[N:14]([CH3:15])[C:13]3[CH:12]=[CH:11][N:10]=[CH:9][C:8]=3[C:7]=2[NH:16][C:17]2[CH:22]=[CH:21][C:20]([I:23])=[CH:19][C:18]=2[F:24])=[O:5])[CH2:30][O:29]1
Reactant: CC1(C)OC[C@H](CON)O1
Reactant: CCOC(=O)c1c(Nc2ccc(I)cc2F)c2cnccc2n1C
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Solvent: C1CCOC1
Product: Cn1c(C(=O)NOC[C@H]2COC(C)(C)O2)c(Nc2ccc(I)cc2F)c2cnccc21
Temperature: 65 °C
Reaction time: 19 h
Yield: 62.6 %

Procedure:
A mixture of 3-(2-fluoro-4-iodo-phenylamino)-1-methyl-1H-pyrrolo[3,2-c]pyridine-2-carboxylic acid ethyl ester (90 mg, 0.21 mmol), 1N aqueous NaOH solution (0.22 ml, 0.22 mmol) and ethanol (3 ml) were heated at 65° C. for 2.5 hours. The reaction mixture was concentrated and then azeotroped with toluene (2×5 ml) to give a solid residue. The solid residue was dissolved in anhydrous THF (5 ml) and O—((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)hydroxylamine (49 mg, 0.41 mmol), EDCI (49 mg, 0.26 mmol), HOBt (39 mg, 0.29 mmol) and DIPEA (109 μl, 0.62 mmol) were added. After stirring for 19 hours the solvent was evaporated and the residue was partitioned between ethyl acetate (30 ml) and water (20 ml). The organic layer was isolated, dried over sodium sulphate then filtered and evaporated to give a yellow oil. The oil was purified by flash chromatography (Si-PPC, pentane:ethyl acetate, gradient 50:50 to 0:100) to afford the title compound as a yellow solid (71 mg, 65%). LCMS (method B): RT=2.87 min, M+H+=542.
Reaction SMILES: C[O:2][C:3]([CH:5]1[CH2:7][CH:6]1[C:8]1[S:9][C:10]([C:13](=[O:39])[NH:14][CH2:15][C@H:16]([NH:24][C:25]([O:27][CH2:28][C:29]23[CH2:38][CH:33]4[CH2:34][CH:35]([CH2:37][CH:31]([CH2:32]4)[CH2:30]2)[CH2:36]3)=[O:26])[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[CH:11][CH:12]=1)=O.[NH2:40][C:41]1[NH:42][CH2:43][CH2:44][CH2:45][N:46]=1>CN(C)C=O>[C:20]([O:19][C:17](=[O:18])[C@@H:16]([NH:24][C:25]([O:27][CH2:28][C:29]12[CH2:38][CH:33]3[CH2:32][CH:31]([CH2:37][CH:35]([CH2:34]3)[CH2:36]1)[CH2:30]2)=[O:26])[CH2:15][NH:14][C:13]([C:10]1[S:9][C:8]([CH:6]2[CH2:7][CH:5]2[C:3](=[O:2])[NH:40][C:41]2[NH:46][CH2:45][CH2:44][CH2:43][N:42]=2)=[CH:12][CH:11]=1)=[O:39])([CH3:21])([CH3:23])[CH3:22]
Reactant: NC1=NCCCN1
Reactant: COC(=O)C1CC1c1ccc(C(=O)NC[C@H](NC(=O)OCC23CC4CC(CC(C4)C2)C3)C(=O)OC(C)(C)C)s1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)[C@H](CNC(=O)c1ccc(C2CC2C(=O)NC2=NCCCN2)s1)NC(=O)OCC12CC3CC(CC(C3)C1)C2

Procedure:
The product obtained in step b) was dissolved in 4 ml of anhydrous dimethylformamide and stirred under an argon atmosphere with 99 mg of 2-amino-1,4,5,6-tetrahydropyrimidine for 7 hours at room temperature. The solvent was removed in vacuo and the residue was chromatographed (silica gel; ethyl acetate/methanol (1/1, v/v)). The fractions containing the title compound were pooled and evaporated under reduced pressure to give 53 mg of a colourless resin.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[C:5]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:6]([C:12]1[CH:19]=[CH:18][C:15]([CH:16]=O)=[CH:14][CH:13]=1)=[N:7]2.[NH:26]1[CH2:31][CH2:30][CH:29]([C:32]2[N:36]=[C:35]([C:37]3[N:42]=[CH:41][CH:40]=[CH:39][N:38]=3)[NH:34][N:33]=2)[CH2:28][CH2:27]1.C(N(CC)CC)C.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CN1C(=O)CCC1.C(OCC)(=O)C>[Cl:1][C:2]1[N:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[C:5]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:6]([C:12]1[CH:19]=[CH:18][C:15]([CH2:16][N:26]3[CH2:27][CH2:28][CH:29]([C:32]4[NH:36][C:35]([C:37]5[N:42]=[CH:41][CH:40]=[CH:39][N:38]=5)=[N:34][N:33]=4)[CH2:30][CH2:31]3)=[CH:14][CH:13]=1)=[N:7]2
Reactant: O=Cc1ccc(-c2nc3ccnc(Cl)c3cc2-c2ccccc2)cc1
Reactant: c1cnc(-c2nc(C3CCNCC3)n[nH]2)nc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCN(CC)CC
Solvent: CN1CCCC1=O
Product: Clc1nccc2nc(-c3ccc(CN4CCC(c5nnc(-c6ncccn6)[nH]5)CC4)cc3)c(-c3ccccc3)cc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 9-1 (0.25 g, 0.73 mMol) and 11-1 (0.23 g, 0.87 mMol) in NMP (5 mL) was added triethylamine (0.3 mL, 2.2 mMol) followed by acetic acid (0.082 mL, 1.5 mMol). After stirring at ambient temperature overnight, sodium triacetoxyborohydride (0.18 g, 0.87 mMol) was added. Upon completion, the reaction was diluted with ethyl acetate and washed with saturated NaHCO3, followed by water, then brine. The organic layer was dried with Na2SO4 and MgSO4, filtered and concentrated in vacuo to yield 11-2. LC/MS calculated: 559.1; observed: 559.3
Reaction SMILES: [CH3:1][O:2][C:3](=[O:37])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][N:11]([C:17]2[CH:22]=[CH:21][N:20]=[C:19]([C:23]3[CH:28]=[CH:27][C:26]([O:29]CC4C=CC=CC=4)=[CH:25][CH:24]=3)[N:18]=2)[CH:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)[CH:5]=1>[Pd].CO.C(Cl)Cl>[CH3:1][O:2][C:3](=[O:37])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][N:11]([CH:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)[C:17]2[CH:22]=[CH:21][N:20]=[C:19]([C:23]3[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=3)[N:18]=2)[CH:5]=1
Reactant: COC(=O)c1cccc(CN(c2ccnc(-c3ccc(OCc4ccccc4)cc3)n2)C2CCCC2)c1
Agent: [Pd]
Solvent: ClCCl
Solvent: CO
Product: COC(=O)c1cccc(CN(c2ccnc(-c3ccc(O)cc3)n2)C2CCCC2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a MeOH-DCM solution (4:1, 4 mL) of 3-({[2-(4-benzyloxy-phenyl)-pyrimidin-4-yl]-cyclopentyl-amino}-methyl)-benzoic acid methyl ester (116 mg, 0.235 mmol) was added 10% Pd/C (25 mg), and the reaction mixture was stirred at room temperature for 2 h under a hydrogen atmosphere (balloon). The mixture was filtered through a pad of Celite and then concentrated. The 3-({cyclopentyl-[2-(4-hydroxy-phenyl)-pyrimidin-4-yl]-amino}-methyl)-benzoic acid methyl ester obtained was used without further purification. LCMS m/z: 405 (M+1)+.
Reaction SMILES: [Cl:1][C:2]1[C:15]([C:16]2[NH:20][C:19](=[O:21])[N:18]([C:22]3[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=3)[N:17]=2)=[CH:14][C:5]([CH2:6][NH:7]C(=O)C(F)(F)F)=[C:4]([F:32])[CH:3]=1.[OH-].[K+].O>C1COCC1>[NH2:7][CH2:6][C:5]1[C:4]([F:32])=[CH:3][C:2]([Cl:1])=[C:15]([C:16]2[NH:20][C:19](=[O:21])[N:18]([C:22]3[CH:23]=[CH:24][C:25]([C:28]([F:30])([F:31])[F:29])=[CH:26][CH:27]=3)[N:17]=2)[CH:14]=1
Reactant: O=C(NCc1cc(-c2nn(-c3ccc(C(F)(F)F)cc3)c(=O)[nH]2)c(Cl)cc1F)C(F)(F)F
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: NCc1cc(-c2nn(-c3ccc(C(F)(F)F)cc3)c(=O)[nH]2)c(Cl)cc1F
Yield: 99.9 %

Procedure:
The title compound was prepared according to the procedure described in Intermediate-66 by using N-(4-chloro-2-fluoro-5-(1-(4-(trifluoromethyl)phenyl)-4,5-dihydro-5-oxo-1H-1,2,4-triazol-3-yl)benzyl)-2,2,2-trifluoroacetamide (Example-113; 0.100 g, 0.207 mmol), KOH (0.034 g, 0.622 mol), water (5 mL) and THF (5.0 mL) to afford 0.080 g of the desired product.
Reaction SMILES: C[C:2]1([CH3:11])[N:7]([O])[C:6](C)(C)[CH2:5][CH2:4][CH2:3]1.[CH3:12][C:13]1[N:21]([C:22]([C:24]2[CH:25]=[CH:26][C:27]([Cl:30])=[CH:28][CH:29]=2)=[O:23])[C:20]2[CH:19]=[CH:18][C:17]([O:31][CH3:32])=[CH:16][C:15]=2[C:14]=1[CH2:33][C:34]([OH:36])=[O:35].[CH3:37][C:38]1([CH3:48])[N:43]([OH:44])[C:42]([CH3:46])([CH3:45])[CH2:41][CH:40]([OH:47])[CH2:39]1.C(OC1C(=CC=CC=1)C(Cl)=O)(=O)C>>[CH2:3]1[CH2:2][CH2:11][CH:6]([N:7]=[C:22]=[N:21][CH:20]2[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]2)[CH2:5][CH2:4]1.[CH3:37][C:38]1([CH3:48])[N:43]([OH:44])[C:42]([CH3:46])([CH3:45])[CH2:41][CH:40]([OH:47])[CH2:39]1.[CH3:12][C:13]1[N:21]([C:22]([C:24]2[CH:25]=[CH:26][C:27]([Cl:30])=[CH:28][CH:29]=2)=[O:23])[C:20]2[CH:19]=[CH:18][C:17]([O:31][CH3:32])=[CH:16][C:15]=2[C:14]=1[CH2:33][C:34]([OH:36])=[O:35]
Reactant: CC1(C)CCCC(C)(C)N1[O]
Agent: CC(=O)Oc1ccccc1C(=O)Cl
Agent: CC1(C)CC(O)CC(C)(C)N1O
Agent: COc1ccc2c(c1)c(CC(=O)O)c(C)n2C(=O)c1ccc(Cl)cc1
Product: C(=NC1CCCCC1)=NC1CCCCC1

Procedure:
Scheme 1 below depicts the chemical synthesis of the ASA and indomethacin-nitroxide conjugates (1) and (2). Condensation of 4-hydroxy-TEMPO with acetylsalicyloyl chloride gave (1) in 48% yield and DCC-mediated coupling of 4-hydroxy-TEMPO with indomethacin gave (2) in 84% yield. The NMR spectroscopy, mass spectrometry and elemental analysis (set forth above) supported the structure of both 1 and 2.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[NH2:10][OH:11]>CO>[OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[N:10][OH:11])=[CH:4][CH:3]=1
Reactant: NO
Reactant: O=Cc1ccc(O)cc1
Solvent: CO
Product: ON=Cc1ccc(O)cc1
Reaction time: 2 h

Procedure:
Into a 500 ml round bottom flask equipped with a magnetic stirring bar, 40.49 g (331.6 mmol) of 4-hydroxybenzaldehyde were added. The aldehyde was dissolved in 240 ml methanol. To the stirred solution, 22.99 g (348.1 mmol) of 50% aqueous solution of hydroxylamine was added over a 15 min. period. The mixture was stirred for an additional 2 hr, at which time it was judged to be complete by the disappearance of the starting aldehyde as observed by thin layer chromatography (SiO2/CH3OH: CH2CL2 5:95). The solvent was removed in vacuo to give the product 4-hydroxybenzaldehyde oxime as a dark tan oil, which was recrystallized from water.