Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:5][N:6]=[C:7]1[C:16]2[C:11](=[CH:12][C:13]([C:17]#[C:18][CH2:19][OH:20])=[CH:14][CH:15]=2)[O:10][C:9]([C:21]2[N:22]=[CH:23][C:24]3[C:29]([CH:30]=2)=[CH:28][CH:27]=[CH:26][CH:25]=3)=[CH:8]1)(C)(C)C.Br[CH2:32][CH2:33][O:34][CH3:35]>>[CH:23]1[C:24]2[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:30]=[C:21]([C:9]2[O:10][C:11]3[C:16]([C:7](=[N:6][OH:5])[CH:8]=2)=[CH:15][CH:14]=[C:13]([C:17]#[C:18][CH2:19][O:20][CH2:32][CH2:33][O:34][CH3:35])[CH:12]=3)[N:22]=1
Reactant: CC(C)(C)ON=c1cc(-c2cc3ccccc3cn2)oc2cc(C#CCO)ccc12
Reactant: COCCBr
Product: COCCOCC#Cc1ccc2c(=NO)cc(-c3cc4ccccc4cn3)oc2c1

Procedure:
2-Isoquinolin-3-yl-7-[3-(2-methoxy-ethoxy)-prop-1-ynyl]-chromen-4-one oxime was prepared in 7% overall yield using the methods described in examples 42 and 42A, starting from 7-(3-hydroxy-prop-1-ynyl)-2-Isoquinolin-3-yl-chromen-4-one O-tert-butyl oxime (example 54A) and bromoethylmethylether. The title compound was isolated as a beige solid and as a 90/10 mixture of Z/E oxime isomers after triturating in diethyl ether.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[N:20]3[N:21]=[CH:22][C:23](C(O)=O)=[CH:24][C:19]3=[C:18]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:17]=2[CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[C:37]([F:41])[C:36]=2[CH3:42])=[O:15])[CH2:10][CH2:9]1)=O)(C)(C)C.N1C2C(=CC=CC=2)C=CC=1.Cl.O1CCOCC1>[Cu]>[F:41][C:37]1[C:36]([CH3:42])=[C:35]([CH:40]=[CH:39][CH:38]=1)[CH2:34][C:17]1[C:18]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)=[C:19]2[CH:24]=[CH:23][CH:22]=[N:21][N:20]2[C:16]=1[C:14]([N:11]1[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1)=[O:15]
Reactant: Cc1c(F)cccc1Cc1c(-c2ccccc2)c2cc(C(=O)O)cnn2c1C(=O)N1CCN(C(=O)OC(C)(C)C)CC1
Agent: [Cu]
Agent: Cl
Solvent: C1COCCO1
Solvent: c1ccc2ncccc2c1
Product: Cc1c(F)cccc1Cc1c(-c2ccccc2)c2cccnn2c1C(=O)N1CCNCC1
Temperature: 170 °C
Reaction time: 8 h
Yield: 37.3 %

Procedure:
A mixture of the compound of example 8, step 11 (0.057 g, 0.10 mmol), copper powder (0.007 g, 0.10 mmol) and quinoline (0.40 ml) was plunged into an oil bath pre-heated at 170° C. for 1.25 h. After cooling to room temperature and evaporation of the volatiles under reduced pressure, the residue was dissolved in EA (10 ml) and the solution washed with water and brine, dried over magnesium sulfate, filtered and concentrated to dryness. The obtained orange oil was purified by chromatography on silica gel (DCM/MOH, 100:0, then 90:10). The product was dissolved in 2 ml of DCM and a 4 N solution of hydrogen chloride in dioxane (0.25 ml, 0.98 mmol) was added. After stirring at room temperature overnight, the solution was evaporated to dryness. The obtained solid was triturated several times with diethyl ether and dried in vacuo at 50° C. to give 0.016 g of the title compound in the form of [6-(3-fluoro-2-methyl-benzyl)-5-phenyl-pyrrolo[1,2-b]pyridazin-7-yl]-piperazin-1-yl-methanone hydrochloride as an orange solid with the following characteristics:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[NH:13][C:12](=[O:14])[N:11]([C:15]2[CH:24]=[CH:23][C:18]([C:19](OC)=[O:20])=[C:17]([O:25][CH3:26])[CH:16]=2)[N:10]=1.[F:27][C:28]1[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:31][C:29]=1[NH2:30].C[Al](C)C>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[NH:13][C:12](=[O:14])[N:11]([C:15]2[CH:24]=[CH:23][C:18]([C:19]([NH:30][C:29]3[CH:31]=[C:32]([C:35]([F:36])([F:37])[F:38])[CH:33]=[CH:34][C:28]=3[F:27])=[O:20])=[C:17]([O:25][CH3:26])[CH:16]=2)[N:10]=1
Reactant: Nc1cc(C(F)(F)F)ccc1F
Reactant: COC(=O)c1ccc(-n2nc(-c3c(F)cccc3Cl)[nH]c2=O)cc1OC
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: COc1cc(-n2nc(-c3c(F)cccc3Cl)[nH]c2=O)ccc1C(=O)Nc1cc(C(F)(F)F)ccc1F
Yield: 35.9 %

Procedure:
The title compound was prepared according to the procedure described in Example-31, by using methyl 4-(3-(2-chloro-6-fluorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-2-methoxybenzoate (step-2 of Intermediate-15, 0.100 g, 0.26 mmol), 2-fluoro-5-trifluoromethyl aniline (0.070 g, 0.39 mmol) and trimethyl aluminium (2M solution in toluene (0.5 mL) to afford 0.049 g of desired product. 1H NMR (DMSO-d6): δ 4.05 (s, 3H), 7.50 (t, J=8.4 Hz, 1H), 7.57-7.70 (m, 3H), 7.72-7.77 (m, 2H), 7.85 (s, 1H), 8.08 (d, J=8.4 Hz, 1H), 8.67 (d, J=6.3 Hz, 1H), 10.38 (br s, 1H), 12.82 (br s, 1H); MS (m/z): 525.15 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:18]=[CH:17][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([S:13](Cl)(=[O:15])=[O:14])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.[C:28]([O:32][C:33](=[O:39])[C@@H:34]([CH:36]([CH3:38])[CH3:37])[NH2:35])([CH3:31])([CH3:30])[CH3:29]>ClCCl>[C:28]([O:32][C:33](=[O:39])[C@@H:34]([CH:36]([CH3:37])[CH3:38])[NH:35][S:13]([C:10]1[CH:11]=[CH:12][C:7]([O:6][C:5]2[CH:17]=[CH:18][C:2]([Br:1])=[CH:3][CH:4]=2)=[CH:8][CH:9]=1)(=[O:15])=[O:14])([CH3:31])([CH3:30])[CH3:29]
Reactant: O=S(=O)(Cl)c1ccc(Oc2ccc(Br)cc2)cc1
Reactant: CC(C)[C@@H](N)C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)[C@@H](NS(=O)(=O)c1ccc(Oc2ccc(Br)cc2)cc1)C(=O)OC(C)(C)C
Reaction time: 3 h
Yield: 64 %

Procedure:
To a 0° C. suspension of 4-(4-bromophenoxy)benzene sulfonyl chloride (1.10 g, 3.16 mmol) in 20 mL of dichloromethane was added a solution of diisoproylethylamine (1.10 mL, 6.3 mmol) and D-valine tert-butyl ester (660 mg, 3.8 mol) in 11 mL of dichloromethane. The ice bath was removed, and the reaction was stirred for 3 h, diluted with 30 mL dichloromethane, and 30 ml of 1 M HCl was added. The layers were separated, and the aqueous layer was washed with 30 mL of dichloromethane. The combined dichloromethane fractions were washed with brine, dried over MgSO4, and concentrated. The residue was chromatographed on silica, eluting with 25% ethyl acetate in hexane, to give 980 mg (64%) of N-[4-(4-bromophenoxy)benzenesulfonyl]-D-valine t-butyl ester as a white foam.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=3[N:12]=2)=[CH:4][C:3]=1[N+:17]([O-:19])=[O:18].C(N(CC)CC)C.Cl.[C:28]([C:32]1[CH:33]=[C:34]([CH:37]=[CH:38][CH:39]=1)[CH2:35][NH2:36])([O:30][CH3:31])=[O:29].O>C(#N)C>[CH3:31][O:30][C:28]([C:32]1[CH:33]=[C:34]([CH2:35][NH:36][C:2]2[CH:7]=[CH:6][C:5]([C:8]3[O:9][C:10]4[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=4[N:12]=3)=[CH:4][C:3]=2[N+:17]([O-:19])=[O:18])[CH:37]=[CH:38][CH:39]=1)=[O:29]
Reactant: O=[N+]([O-])c1cc(-c2nc3ccccc3o2)ccc1F
Reactant: COC(=O)c1cccc(CN)c1
Agent: Cl
Solvent: CC#N
Solvent: O
Solvent: CCN(CC)CC
Product: COC(=O)c1cccc(CNc2ccc(-c3nc4ccccc4o3)cc2[N+](=O)[O-])c1
Temperature: 25 °C
Yield: 93.5 %

Procedure:
To a suspension of 2-(4-fluoro-3-nitrophenyl)benzoxazole (see Working Example 15-2) (250 mg, 0.968 mmol) in acetonitrile (5 mL) was added triethylamine (245 mg, 2.42 mmol) and 3-carbomethoxybenzylamine hydrochloride (215 mg, 1.07 mmol), and this was heated to reflux for 2 hours. After the reaction was complete, this was cooled to room temperature, water was added, and after the precipitated crystals were filtered and washed with water, they were dried to yield the title compound (365 mg, 94% yield).
Reaction SMILES: C(N(CC)CC)C.[CH3:8][O:9][C:10]1[C:11]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:12][N:13]2[C:18]=1[CH:17]=[CH:16][CH:15]=[CH:14]2.[O:25]=[C:26]1[C:31]2[CH:32]=[C:33]([C:36](O)=[O:37])[CH:34]=[CH:35][C:30]=2[N:29]=[C:28]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[O:27]1>ClC(Cl)C>[CH3:8][O:9][C:10]1[C:11]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[C:12]([C:36]([C:33]2[CH:34]=[CH:35][C:30]3[N:29]=[C:28]([C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)[O:27][C:26](=[O:25])[C:31]=3[CH:32]=2)=[O:37])[N:13]2[C:18]=1[CH:17]=[CH:16][CH:15]=[CH:14]2
Reactant: COc1c(-c2ccccc2)cn2ccccc12
Reactant: O=C(O)c1ccc2nc(-c3ccccc3)oc(=O)c2c1
Solvent: CC(Cl)Cl
Solvent: CCN(CC)CC
Product: COc1c(-c2ccccc2)c(C(=O)c2ccc3nc(-c4ccccc4)oc(=O)c3c2)n2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.3 %

Procedure:
2.25 ml (16.12 mmol) of triethylamine and 3 g (13.44 mmol) of 1-methoxy-2-phenylindolizine (according to the method described in WO 03/084956) diluted in 20 ml of dichloroethane are added, under an inert atmosphere at ambient temperature, to 4.22 g (14.78 mmol) of 4-oxo-2-phenyl-4H-3,1-benzoxazine-6-carboxylic acid (described in WO 06/097625) in 100 ml of dichloroethane. After stirring overnight at ambient temperature, the reaction medium is filtered, and rinsed with dichloroethane. The filtrate is washed with water, dried over sodium sulphate, filtered, and concentrated under reduced pressure. The residue is filtered through a silica pâté, elution being carried out with dichloromethane. 4.4 g of a yellow solid are obtained.
Reaction SMILES: [F-].C([N+:6](CCCC)(CCCC)CCCC)CCC.[Cl:19][C:20]1[CH:21]=[C:22]([C:27]2([CH2:38][CH2:39][O:40][Si](C(C)(C)C)(C3C=CC=CC=3)C3C=CC=CC=3)[CH2:29][C:28]2([C:34]([O:36][CH3:37])=[O:35])[C:30](OC)=[O:31])[CH:23]=[CH:24][C:25]=1[Cl:26].[NH4+].[OH-]>C1COCC1.CO>[NH2:6][C:30]([C:28]1([C:34]([O:36][CH3:37])=[O:35])[CH2:29][C:27]1([C:22]1[CH:23]=[CH:24][C:25]([Cl:26])=[C:20]([Cl:19])[CH:21]=1)[CH2:38][CH2:39][OH:40])=[O:31]
Reactant: CCCC[N+](CCCC)(CCCC)CCCC
Reactant: COC(=O)C1(C(=O)OC)CC1(CCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)c1ccc(Cl)c(Cl)c1
Agent: [F-]
Agent: [NH4+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)C1(C(N)=O)CC1(CCO)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Tetrabutylammonium fluoride (TBAF) (5.6 mL, 1.1M/TFH) was added dropwise to a stirred solution of dimethyl 2-(3,4-dichlorophenyl)-2-(2-{[(1,1-dimethylethyl)(diphenyl)silyl]oxy}ethyl)-1,1-cyclopropanedicarboxylate (P14, 2.38 g) in THF (27 mL), at 0° C. After 4 h the ice-bath was removed and the reaction mixture was stirred for 3 h at RT. The solvent was removed under reduced pressure, the residue was treated with ether and water, the organic phase washed with brine, dried over Na2SO4 and the solvent evaporated under vacuum to give the crude lactone intermediate (2.08 g). This product was dissolved in a mixture of THF (15 mL) and methanol (10 mL), at RT, aqueous NH4OH (28%, 16 mL) was added dropwise and the reaction mixture was stirred for 4 h. The mixture was concentrated under reduced pressure, the residue was taken up with DCM and water, the organic phase was washed with brine, dried over Na2SO4 and the solvent evaporated under vacuum. The crude product was purified by FC (eluting with DCM/methanol from 1/0 to 9/1) to give the title compound (0.89 g) as a white foam.
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)[CH2:4]1.CCN(CC)CC.[C:23]([O:27][C:28]([NH:30][CH2:31][C:32](O)=[O:33])=[O:29])([CH3:26])([CH3:25])[CH3:24].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>ClCCl>[C:23]([O:27][C:28]([NH:30][CH2:31][C:32]([NH:1][CH2:2][CH:3]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:10]=[CH:11][C:12]([Cl:15])=[CH:13][CH:14]=2)[CH2:4]1)=[O:33])=[O:29])([CH3:26])([CH3:25])[CH3:24]
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: NCC1CCN(Cc2ccc(Cl)cc2)C1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NCC(=O)NCC1CCN(Cc2ccc(Cl)cc2)C1
Temperature: 25 °C
Reaction time: 15 h
Yield: 90.3 %

Procedure:
A mixture of 3-(aminomethyl)-1-(4-chlorobenzyl)pyrrolidine (860 mg, 3.8 mmol), Et3N (5.7 mmol), N-tert-butoxycarbonylglycine (704 mg), EDCI (594 mg), HOBt (673 mg), and dichloromethane (20 mL) was stirred at room temperature for 15 h. Dichloromethane (50 mL) was added and the solution was washed with 2 N NaOH solution (50 mL×2), dried over anhydrous sodium sulfate, filtered, and concentrated to afford 3-[{N-(tert-butoxycarbonyl)glycyl}aminomethyl]-1-(4-chlorobenzyl)pyrrolidine (1.31 g, 90%).
Reaction SMILES: [Cl-].[Cl-].[Cl-].[Al+3].[Cl:5][C:6]1[CH:14]=[CH:13][C:9]([C:10](Cl)=[O:11])=[CH:8][CH:7]=1.[F:15][C:16]1[CH:17]=[C:18]([O:22][CH3:23])[CH:19]=[CH:20][CH:21]=1>[N+](C1C=CC=CC=1)([O-])=O>[Cl:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([C:21]2[CH:20]=[CH:19][C:18]([O:22][CH3:23])=[CH:17][C:16]=2[F:15])=[O:11])=[CH:8][CH:7]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: COc1cccc(F)c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=[N+]([O-])c1ccccc1
Product: COc1ccc(C(=O)c2ccc(Cl)cc2)c(F)c1
Temperature: 20 °C
Reaction time: 8 h
Yield: 41.6 %

Procedure:
Aluminium trichloride (144 g, 1.08 mol) was added to a cooled (0° C.) solution of nitrobenzene (450 mL). A solution of 4-chlorobenzoyl chloride (128.5 mL, 1 mol) in nitrobenzene (200 mL) was slowly added. 3-Fluoroanisole (108.5 mL, 0.95 mol) was slowly added. The reaction mixture was stirred overnight at 20° C., partitioned between ice water and ethyl acetate. The aqueous layer was extracted with ethyl acetate and the combined organic phase was washed with water, dried over sodium sulfate, filtered and concentrated in vacuo. The warm solution was poured onto cyclohexane. The solid was filtered, washed with cyclohexane and dried in vacuo, affording the title compound (104.5 g, 41%) as an off-white solid.
Reaction SMILES: [N:1]1([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4][CH:3]2[CH2:6][NH:7][CH2:8][CH:2]12.I[C:17]1[CH:18]=[CH:19][CH:20]=[C:21]2[C:26]=1[N:25]=[CH:24][C:23]([S:27]([C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]([F:39])([F:38])[F:37])[CH:31]=1)(=[O:29])=[O:28])=[CH:22]2>>[F:39][C:36]([F:37])([F:38])[C:32]1[CH:31]=[C:30]([S:27]([C:23]2[CH:24]=[N:25][C:26]3[C:21]([CH:22]=2)=[CH:20][CH:19]=[CH:18][C:17]=3[N:7]2[CH2:6][CH:3]3[CH:2]([N:1]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]3)[CH2:8]2)(=[O:29])=[O:28])[CH:35]=[CH:34][CH:33]=1
Reactant: O=S(=O)(c1cccc(C(F)(F)F)c1)c1cnc2c(I)cccc2c1
Reactant: CC(C)(C)OC(=O)N1CCC2CNCC21
Product: CC(C)(C)OC(=O)N1CCC2CN(c3cccc4cc(S(=O)(=O)c5cccc(C(F)(F)F)c5)cnc34)CC21
Yield: 56 %

Procedure:
The title compound was prepared by analogy to the procedure of Example 1.3, except using tert-butyl hexahydropyrrolo[3,4-b]pyrrole-1(2H)-carboxylate and 8-iodo-3-(3-(trifluoromethyl)phenylsulfonyl)quinoline. 133 mg (56%) of the title compound were obtained as a pale yellow solid.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:12]3[C:17]([CH:18]=[C:19]4[C:24]=2[CH:23]=[CH:22][CH:21]=[CH:20]4)=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[Br:25]Br.C(Cl)(Cl)(Cl)Cl>O>[Br:25][C:18]1[C:19]2[C:24]([C:11]([C:8]3[CH:7]=[CH:6][C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])=[CH:10][CH:9]=3)=[C:12]3[C:17]=1[CH:16]=[CH:15][CH:14]=[CH:13]3)=[CH:23][CH:22]=[CH:21][CH:20]=2
Reactant: BrBr
Reactant: CC(C)(C)c1ccc(-c2c3ccccc3cc3ccccc23)cc1
Solvent: ClC(Cl)(Cl)Cl
Solvent: O
Product: CC(C)(C)c1ccc(-c2c3ccccc3c(Br)c3ccccc23)cc1
Temperature: 25 °C
Yield: 96.5 %

Procedure:
A mixed solution of 13.3 g of the above-mentioned 9-(4-tert-butylphenyl)anthracene, 7.52 g of bromine and 300 ml of carbon tetrachloride was heated to reflux under nitrogen atmosphere for 1 hour. After cooling the mixed solution to room temperature, 200 ml of water was injected thereto to extract 200 ml of dichloromethane therefrom. The organic layer was washed twice in 200 ml of water, dried by magnesium sulfate and thereafter concentrated by evaporation. The organic layer was washed twice in 100 ml of hexane and vacuum dried to thereafter obtain 16.09 g of 9-bromo-10-(4-tert-butylphenyl)anthracene.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH:5]=O.[NH2:13][C:14]1[CH:18]=[CH:17][NH:16][N:15]=1.[N+:19]([CH2:22][C:23](=O)[CH3:24])([O-:21])=[O:20]>>[CH3:24][C:23]1[NH:13][C:14]2=[N:15][NH:16][CH:17]=[C:18]2[CH:5]([C:4]2[CH:7]=[CH:8][CH:9]=[CH:10][C:3]=2[C:2]([F:12])([F:11])[F:1])[C:22]=1[N+:19]([O-:21])=[O:20]
Reactant: O=Cc1ccccc1C(F)(F)F
Reactant: Nc1cc[nH]n1
Reactant: CC(=O)C[N+](=O)[O-]
Product: CC1=C([N+](=O)[O-])C(c2ccccc2C(F)(F)F)c2c[nH]nc2N1

Procedure:
The title compound was prepared from 2-trifluoromethylbenzaldehyde, 3-aminopyrazole and 1-nitropropan-2-one in the same manner as in Example 1.
Reaction SMILES: [CH2:1]([C:17]1[C:22](=[O:23])[CH:21]=[C:20]([CH3:24])O[C:18]=1[CH3:25])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].Cl.[NH2:27][OH:28].C([O-])(=O)C.[Na+].O>C(O)C>[CH2:1]([C:17]1[C:22](=[O:23])[CH:21]=[C:20]([CH3:24])[N:27]([OH:28])[C:18]=1[CH3:25])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCCCCCCCCCc1c(C)oc(C)cc1=O
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCCCCCCCCCCCCCCCc1c(C)n(O)c(C)cc1=O
Temperature: 25 °C

Procedure:
A mixture of 2 (200 mg, 0.57 mmol), hydroxylamine hydrochloride (399 mg, 5.7 mmol), sodium acetate (471 mg, 5.7 mmol), water (1 mL), and ethanol (2 mL) was heated at reflux for 3 days. After the reaction mixture was cooled to room temperature, the crude product was concentrated under diminished pressure to a yellow oil. The residue was purified by chromatography on a silica gel column. Elution with 5:1 chloroform/methanol gave 3-hexadecyl-1-hydroxy-2,6-dimethylpyridin-4(1H)-one (CPD-8) as a white solid: yield 0.088 g (42%); silica gel TLC Rf 0.5 (3:1 ethyl acetate/methanol); 1H NMR (CDCl3, 400 MHz) δ 0.83-0.85 (m, 3H), 1.22-1.27 (m, 28H), 2.32 (s, 3H), 2.46 (s, 3H), 2.55 (t, 2H, J=8 Hz) and 6.7 (s, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]2[N:9]=[C:10]([S:12][CH3:13])[N:11]=[C:4]2[N:3]=1.OO.S([O-])([O-])=[O:17].[Na+].[Na+].[OH2:22]>O.O.[O-][W]([O-])(=O)=O.[Na+].[Na+].C(O)(=O)C>[CH3:13][S:12]([C:10]1[N:11]=[C:4]2[N:3]=[C:2]([CH3:1])[CH:7]=[C:6]([CH3:8])[N:5]2[N:9]=1)(=[O:17])=[O:22]
Reactant: O=S([O-])[O-]
Reactant: O
Reactant: CSc1nc2nc(C)cc(C)n2n1
Agent: O=[W](=O)([O-])[O-]
Agent: OO
Agent: [Na+]
Solvent: CC(=O)O
Product: Cc1cc(C)n2nc(S(C)(=O)=O)nc2n1
Temperature: 10 °C
Reaction time: 0.17 h
Yield: 67 %

Procedure:
A mixture of 5,7-dimethyl-2-(methylsulfanyl)-[1,2,4]triazolo[1,5-a]pyrimidine (9.9 g, 51.0 mmol), sodium tungstate dihydrate (505 mg, 1.53 mmol), and glacial acetic acid (95 mL) was added to a 200 mL RBF with a magnetic stirring bar. The flask was cooled to =10° C. using ice and water bath. A solution of 35% hydrogen peroxide in water (13.1 mL, 153.1 mmol) was slowly added via syringe. The mixture was stirred at room temperature for 10 minutes, then at 60° C. for 60 minutes. Progress of the reaction was monitored by analytical HPLC with UV detection at 215 nm. The starting material elutes with retention time of 3.8 min, and the product elutes with retention time of 1.3 min. The reaction was cooled to room temperature and a solution of sodium sulfite (3.0 g Na2SO3 in 20 mL water) (=5 mL) was added to the mixture until negative to peroxide test strip, and allowed to stir 30 minutes at room temperature. The reaction was concentrated to ˜20 mL and water was added to precipitate product. The solid was collected by filtration, rinsed with cold water (=30 mL) and dried under vacuum to afford the title compound as a white powder (7.78 g, 67% yield).
Reaction SMILES: [NH2:1][C@H:2]([C:4]([N:6]1[CH:14]2[CH:9]([CH2:10][CH2:11][CH2:12][CH2:13]2)[CH2:8][C@H:7]1[C:15]([OH:17])=[O:16])=[O:5])[CH3:3].[O:18]([CH2:25][C:26](=O)[C:27]([O:29][CH2:30][CH3:31])=[O:28])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.O(CC(=O)C(O)=O)C1C=CC=CC=1.C([BH3-])#N.[Na+]>>[C:27]([CH:26]([NH:1][C@H:2]([C:4]([N:6]1[CH:14]2[CH:9]([CH2:10][CH2:11][CH2:12][CH2:13]2)[CH2:8][C@H:7]1[C:15]([OH:17])=[O:16])=[O:5])[CH3:3])[CH2:25][O:18][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)([O:29][CH2:30][CH3:31])=[O:28]
Reactant: C[C@H](N)C(=O)N1C2CCCCC2C[C@H]1C(=O)O
Reactant: CCOC(=O)C(=O)COc1ccccc1
Agent: O=C(O)C(=O)COc1ccccc1
Agent: [BH3-]C#N
Agent: [Na+]
Product: CCOC(=O)C(COc1ccccc1)N[C@@H](C)C(=O)N1C2CCCCC2C[C@H]1C(=O)O

Procedure:
React 1-[(S)-alanyl]octahydroindole-2(S)-carboxylic acid (preparable as described in Example 1) and ethyl phenoxypyruvate, (prepared from esterification of phenoxypyruvic acid as described in Example 9) with sodium cyanoborohydride as described in Example 1 to give the title compound.
Reaction SMILES: [NH2:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1)[C:3]([OH:5])=[O:4].C(O)(=O)C.[O-:17][C:18]#[N:19].[K+].[Cl-].[Na+]>O>[NH2:19][C:18]([NH:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1)[C:3]([OH:5])=[O:4])=[O:17]
Reactant: NC(C(=O)O)c1ccc(O)cc1
Reactant: N#C[O-]
Agent: [Cl-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: NC(=O)NC(C(=O)O)c1ccc(O)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To about 0.15 mole of α-amino-4-hydroxybenzeneacetic acid dissolved in 700 ml of water and 0.2 mole of glacial acetic acid is added about 0.2 mole of potassium cyanate. The resulting mixture is stirred at room temperature for about 30 minutes. The reaction mixture is saturated with sodium chloride and then extracted with ethyl acetate. The ethyl acetate is washed with water, dried over magnesium sulfate, filtered and evaporated to give α-(aminocarbonyl)amino-4-hydroxybenzeneacetic acid.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[CH:10]=[C:9]([C:14]([C:16]1[N:17]=[CH:18][N:19](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[CH:20]=1)=[O:15])[CH:8]=[CH:7]2)[CH3:2].[CH:40]([Mg]Cl)([CH3:42])[CH3:41].[Cl-].[NH4+].O>C1COCC1>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[CH:10]=[C:9]([C:14]([C:16]1[N:17]=[CH:18][NH:19][CH:20]=1)([OH:15])[CH:40]([CH3:42])[CH3:41])[CH:8]=[CH:7]2)[CH3:2]
Reactant: CCOc1ccc2cc(C(=O)c3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)cn3)ccc2c1
Reactant: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Product: CCOc1ccc2cc(C(O)(c3c[nH]cn3)C(C)C)ccc2c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
(6-Ethoxynaphthalen-2-yl)-(1-trityl-1H-imidazol-4-yl)ketone (3.0 g) was dissolved in THF (45 ml) and a solution (2 M, 4 ml) of isopropyl magnesium chloride in THF was added dropwise under ice-cooling. The mixture was stirred at room temperature for 30 min and saturated aqueous solution (20 ml) of ammonium chloride and water (20 ml) were added. The mixture was extracted with ethyl acetate and the extract was washed with saturated brine, dried and concentrated. The residue was crystallized from ethyl acetate-diisopropyl ether to give the title compound (1.72 g) as a colorless powder. Crystallization mother liquor was purified by silica gel chromatography (eluate, hexane-ethyl acetate=1:2) to give the title compound (0.43 g).
Reaction SMILES: [N+:1]([C:4]1[CH:14]=[CH:13][CH:12]=[C:6]2[C:7]([O:9][C:10](=[O:11])[C:5]=12)=O)([O-:3])=[O:2].[NH2:15][C:16]1[CH:24]=[CH:23][C:19]([C:20]([OH:22])=[O:21])=[CH:18][CH:17]=1.C(O)C>C(O)(=O)C>[N+:1]([C:4]1[CH:14]=[CH:13][CH:12]=[C:6]2[C:7]([N:15]([C:16]3[CH:24]=[CH:23][C:19]([C:20]([OH:22])=[O:21])=[CH:18][CH:17]=3)[C:10](=[O:11])[C:5]=12)=[O:9])([O-:3])=[O:2]
Reactant: O=C1OC(=O)c2c1cccc2[N+](=O)[O-]
Reactant: Nc1ccc(C(=O)O)cc1
Solvent: CCO
Solvent: CC(=O)O
Product: O=C(O)c1ccc(N2C(=O)c3cccc([N+](=O)[O-])c3C2=O)cc1
Yield: 87.5 %

Procedure:
The starting material used in the above example can be prepared as follows: 57.9 g (0.3 mol) of 3-nitrophthalic anhydride and 41.1 g (0.3 mol) of 4-aminobenzoic acid in 600 ml of acetic acid are refluxed for 6 hours and the mixture is then stirred into 1,000 ml of 50% aqueous ethanol. The yellow product which has precipitated is filtered off with suction, washed with water and dried at 80° C./30 mm Hg for 24 hours. 82 g (88% of theory) of 4-(3-nitrophthalimidyl)-benzoic acid are obtained; melting point >300° C. IR spectrum (KBr): 1790 and 1740 cm-1 (CO--N--CO); 1550 and 1370 cm-1 (NO2).