Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C@@H:10]2[CH2:12][C@H:11]2[C:13]([OH:15])=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].O1CCCC1.ClC(OCC)=O.[CH3:27][CH:28]([NH2:38])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37]>C(Cl)(Cl)Cl.C(N(CC)CC)C>[CH3:27][CH:28]([NH:38][C:13]([C@@H:11]1[CH2:12][C@H:10]1[C:7]1[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=1)=[O:15])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37]
Reactant: O=C(O)[C@@H]1C[C@H]1c1ccc([N+](=O)[O-])cc1
Reactant: CCCCCCCCCC(C)N
Agent: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Product: CCCCCCCCCC(C)NC(=O)[C@@H]1C[C@H]1c1ccc([N+](=O)[O-])cc1
Temperature: 5 °C
Reaction time: 0.25 h

Procedure:
To a stirred slurry of 2.1 g. of trans-2-(4-nitrophenyl)cyclopropanecarboxylic acid in 30 ml. of tetrahydrofuran was added 1.1 g. of triethylamine. The clear solution thus obtained was cooled to ca. 5° C., and a solution of 1.2 g. of ethyl chloroformate in 5 ml. of chloroform was added dropwise, with stirring, during 15 minutes. Stirring was continued for 20 minutes, and then a solution of 1.9 g. of 1-methyldecylamine in 5 ml. of chloroform was added dropwise during 15 minutes. The cooling bath was removed, and stirring was continued for 1 hour. At this point the solvent was removed in vacuo and the residue was triturated with ether. The solid which remained out of solution was removed by filtration and discarded. The ether was evaporated in vacuo, and the residue was recrystallized from a 1:1 mixture of isopropanol and petroleum ether. This afforded 2.9 g. of the title compound as a waxy solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].C([Li])CCC.[CH3:14][O:15][CH2:16][C:17](=[O:19])[CH3:18]>>[OH:19][C:17]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8])([CH3:18])[CH2:16][O:15][CH3:14]
Reactant: Oc1ccccc1Br
Reactant: COCC(C)=O
Agent: [Li]CCCC
Product: COCC(C)(O)c1ccccc1O

Procedure:
2-(2-hydroxy-1-methoxypropan-2-yl)phenol was prepared according to the procedure described for 417a using 2-bromophenol (400 μL, 3.4 mmol), n-butyllithium in hexanes (1.6 M, 5.0 mL, 7.9 mmol) and methoxyacetone (412 uL, 4.48 mmol). 1H NMR (400 MHz, CDCl3) ppm 1.64 (s, 3H), 3.45 (d, J=9.3 Hz, 1H), 3.47 (s, 3H), 3.77 (d, J=9.3 Hz, 1H), 6.85 (m, 1H), 6.90 (m, 1H), 7.04 (m, 1H), 7.20 (m, 1H), 9.22 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([C:10]#[N:11])=[CH:6][C:5]=1[O:12][CH3:13]>CO.O.[Ni]>[CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][NH2:11])=[CH:6][C:5]=1[O:12][CH3:13]
Reactant: COC(=O)c1ccc(C#N)cc1OC
Agent: [Ni]
Solvent: CO
Solvent: O
Product: COC(=O)c1ccc(CN)cc1OC
Reaction time: 16 h
Yield: 37.4 %

Procedure:
A mixture of 4-cyano-2-methoxy-benzoic acid methyl ester (1.01 g, 5.28 mmol) in methanol (50 mL) was added to Raney-nickel 2800 slurry in water (a few grams washed with methanol to remove the water, Aldrich) and it was put under a 50 psi hydrogen atmosphere for 16 hrs. The mixture was filtered through Celite under an argon atmosphere and concentrated and then purified by flash chromatography to give 4-aminomethyl-2-methoxy-benzoic acid methyl ester (385.7 mg, 34.7%).
Reaction SMILES: [Br:1][C:2]1[C:3](F)=[C:4]2[C:10]([NH:11][C:12](=[O:16])[CH:13]([CH3:15])[CH3:14])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[F:18][C@@H:19]1[CH2:24][CH2:23][NH:22][CH2:21][C@H:20]1[NH:25]C(=O)OC(C)(C)C.CCN(C(C)C)C(C)C.C(O)(C(F)(F)F)=O.C(Cl)[Cl:50]>CCCCO>[ClH:50].[NH2:25][C@H:20]1[C@H:19]([F:18])[CH2:24][CH2:23][N:22]([C:3]2[C:2]([Br:1])=[CH:7][N:6]=[C:5]3[NH:8][CH:9]=[C:10]([NH:11][C:12](=[O:16])[CH:13]([CH3:15])[CH3:14])[C:4]=23)[CH2:21]1
Reactant: ClCCl
Reactant: CC(C)C(=O)Nc1c[nH]c2ncc(Br)c(F)c12
Reactant: CC(C)(C)OC(=O)N[C@@H]1CNCC[C@H]1F
Solvent: CCCCO
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)C(=O)Nc1c[nH]c2ncc(Br)c(N3CC[C@@H](F)[C@H](N)C3)c12
Product: Cl
Temperature: 146 °C
Reaction time: 40 h
Yield: 11 %

Procedure:
A mixture of N-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)isobutyramide (0.10 g, 0.33 mmol; Example 15, Step A), tert-butyl trans-4-fluoropiperidin-3-ylcarbamate (0.22 g, 1.00 mmol, Example J) and DIEA (0.17 mL, 1.00 mmol) in n-BuOH (3 mL) was stirred at 146° C. (bath) for 40 hours. The solvent was removed, and the residue was dissolved in ethyl acetate (20 mL), washed with water (10 mL), brine (10 mL), dried (sodium sulfate) and concentrated in vacuo. The residue was purified by reverse phase chromatography (Biotage SP4, C-18 25M+, 10-80% CH3CN/water, 20 CV). The product isolated was dissolved in DCM (2 mL), and TFA (0.5 mL) was added. The mixture was stirred at room temperature for 1 hour. The solvent was removed. The residue was dissolved in MeOH (1 mL), and 2N HCl in ether (3 mL) was added. The solid formed was collected to give N-(4-(trans-3-amino-4-fluoropiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)isobutyramide hydrochloride (0.017 g, 11%) as a solid. 1H NMR (400 MHz, D2O) δ 8.24 (s, 1H), 7.27 (s, 1H), 3.83 (m 1H), 3.70 (m, 1H), 3.45 (m, 1H), 3.25 (m, 2H), 2.64 (m, 1H), 2.21 (m, 2H), 1.88 (m, 1H), 1.10 (m, 6H). LCMS (APCI+) m/z 398(M+H)+.
Reaction SMILES: [CH:1]1[C:6]([C:7]2[CH:8]=[CH:9][C:10]([F:14])=[CH:11][C:12]=2[F:13])=[CH:5][C:4]([C:15]([OH:17])=[O:16])=[C:3]([OH:18])[CH:2]=1.Cl.CN(C)[CH2:22][CH2:23][CH2:24]N=C=N.O.ON1C2C=CC=CC=2N=N1.C(O)CC>CN(C)C=O.O>[F:13][C:12]1[CH:11]=[C:10]([F:14])[CH:9]=[CH:8][C:7]=1[C:6]1[CH:5]=[C:4]([C:15]([O:17][CH2:22][CH2:23][CH3:24])=[O:16])[C:3]([OH:18])=[CH:2][CH:1]=1
Reactant: O=C(O)c1cc(-c2ccc(F)cc2F)ccc1O
Reactant: CN(C)CCCN=C=N
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CCCO
Product: CCCOC(=O)c1cc(-c2ccc(F)cc2F)ccc1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 30.6 %

Procedure:
Diflunisal (500 mg), 1-ethyl-3-(3-dimethylaminopropylcarbodiimide hydrochloride (458 mg), 1-hydroxybenzotriazole hydrate (36.7 mg), and propanol (2 ml) were dissolved in N,N-dimethylformamide to prepare a solution which was then stirred at room temperature overnight. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by column chromatography using acetone-hexane to give propyl 5-(2,4-difluorophenyl)salicylate (179 mg, yield 30%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][C:6]=2[Br:12].FC(F)(F)C([N:17]1[CH2:26][CH2:25][C:24]2[C:19](=[CH:20][C:21]([S:27](Cl)(=[O:29])=[O:28])=[CH:22][CH:23]=2)[CH2:18]1)=O.[OH-].[Na+].Cl.[CH2:36]([OH:38])[CH3:37]>>[Br:12][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:5]=1[N:4]=[CH:3][C:2]([N:1]([C:36](=[O:38])[CH3:37])[S:27]([C:21]1[CH:20]=[C:19]3[C:24]([CH2:25][CH2:26][NH:17][CH2:18]3)=[CH:23][CH:22]=1)(=[O:28])=[O:29])=[CH:11]2
Reactant: CCO
Reactant: Nc1cnc2c(Br)cccc2c1
Reactant: O=C(N1CCc2ccc(S(=O)(=O)Cl)cc2C1)C(F)(F)F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CC(=O)N(c1cnc2c(Br)cccc2c1)S(=O)(=O)c1ccc2c(c1)CNCC2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
White crystals (180 mg) were obtained in the same manner as in Example 1, except using 145 mg (0.65 mmol) of 3-amino-8-bromoquinoline (Preparation Example 5) and 277 mg (0.85 mmol) of 1,2,3,4-tetrahydro-2-(trifluoroacetyl)isoquinoline-7-sulfonyl chloride. To the crystals were added ethanol (20 ml) and 1 N sodium hydroxide aqueous solution (0.5 ml), followed by stirring at room temperature for 30 minutes. To the reaction mixture was added 1 N hydrochloric acid (0.4 ml), followed by extracting with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate and concentrated. To the resulting residue were added pyridine (0.5 ml) and acetic anhydride (0.014 ml), followed by stirring at room temperature for 1 hour. Brine was added thereto, and the mixture was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and concentrated. The residue was purified by silica gel chromatography, to give 113 mg of the title compound.
Reaction SMILES: [N:1]1([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:33][CH2:32][CH2:31][C@H:2]1[C:3]([NH:5][C@@H:6]([C:17]([NH:19][C@H:20]([C:28](O)=[O:29])[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:18])[CH2:7][C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[NH:10][CH:9]=1)=[O:4].[NH2:41][C@@H:42]([C:53]([NH:55][C@H:56]([C:61]([N:63]([CH3:72])[C@H:64]([C:69]([NH2:71])=[O:70])[CH2:65][CH2:66][CH2:67][CH3:68])=[O:62])[CH2:57][CH:58]([CH3:60])[CH3:59])=[O:54])[CH2:43][C:44]1[C:52]2[C:47](=[CH:48][CH:49]=[CH:50][CH:51]=2)[NH:46][CH:45]=1.C1(N=C=NC2CCCCC2)CCCCC1.ON1C2C=CC=CC=2N=N1>>[N:1]1([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:33][CH2:32][CH2:31][C@H:2]1[C:3]([NH:5][C@@H:6]([C:17]([NH:19][C@H:20]([C:28]([NH:41][C@@H:42]([C:53]([NH:55][C@H:56]([C:61]([N:63]([CH3:72])[C@H:64]([C:69]([NH2:71])=[O:70])[CH2:65][CH2:66][CH2:67][CH3:68])=[O:62])[CH2:57][CH:58]([CH3:59])[CH3:60])=[O:54])[CH2:43][C:44]1[C:52]2[C:47](=[CH:48][CH:49]=[CH:50][CH:51]=2)[NH:46][CH:45]=1)=[O:29])[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:18])[CH2:7][C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[NH:10][CH:9]=1)=[O:4]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)N[C@H](Cc1c[nH]c2ccccc12)C(=O)N[C@@H](Cc1ccccc1)C(=O)O
Reactant: CCCC[C@@H](C(N)=O)N(C)C(=O)[C@H](CC(C)C)NC(=O)[C@H](N)Cc1c[nH]c2ccccc12
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Product: CCCC[C@@H](C(N)=O)N(C)C(=O)[C@H](CC(C)C)NC(=O)[C@@H](Cc1c[nH]c2ccccc12)NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H](Cc1c[nH]c2ccccc12)NC(=O)[C@@H]1CCCN1C(=O)OC(C)(C)C
Yield: 64 %

Procedure:
Condensation of BocPro-DTrp-PheOH (part B of Example 17, 0.700 g.) and HDTrp-Leu-MeNleNH2 (0.520 g.) using dicyclohexylcarbodiimide and 1-hydroxybenzotriazole gave BocPro-DTrp-Phe-DTrp-Leu-MeNleNH2 in 64% yield. De-t-butoxycarbonylation of BocPro-DTrp-Phe-DTrp-Leu-MeNleNH2 (0.750 g.) using trifluoroacetic acid in dimethyl sulfide and ethanedithiol gave HPro-DTrp-Phe-DTrp-Leu-MeNleNH2, which was isolated as the amorphous white solid phosphate (1:1) salt tetrahydrate in 30% yield.
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:14]=[C:13]([C:15]([O:17][CH3:18])=[O:16])[CH:12]=[C:11]2[C:7]=1[CH:8]=[CH:9][NH:10]2)(=[O:4])=[O:3].[C:19](=O)([O-])[O-].[K+].[K+].IC>C1COCC1>[CH3:19][N:5]([S:2]([CH3:1])(=[O:3])=[O:4])[C:6]1[CH:14]=[C:13]([C:15]([O:17][CH3:18])=[O:16])[CH:12]=[C:11]2[C:7]=1[CH:8]=[CH:9][NH:10]2
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1cc(NS(C)(=O)=O)c2cc[nH]c2c1
Agent: [K+]
Solvent: CI
Solvent: C1CCOC1
Product: COC(=O)c1cc(N(C)S(C)(=O)=O)c2cc[nH]c2c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 69.2 %

Procedure:
To a mixture of Methyl 4-[(methylsulfonyl)amino]-1H -indole-6-carboxylate (0.6 g) in THF (10 mL) was added potassium carbonate (0.309 g) and iodomethane (0.63 mL). The mixture was stirred at room temperature for 4 h then heated to 40° C. overnight. Iodomethane (0.3 mL) was added and the mixture heated an additional 3 h. The mixture was cooled to room temperature, partitioned between water and diethyl ether, dried over anhydrous sodium sulfate and concentrated. The residue was dissolved in ether and decolorizing carbon (2 g) was added and the mixture refluxed for 5 minutes then filtered through celite while hot. The ether was removed under reduced pressure to give 0.437 g of the title compound: MS (ESI+) for C12 H14 N2 O4 Si m/z 321.1 (M+K).
Reaction SMILES: [F:1][CH:2]([F:11])[C:3]([CH:8]([F:10])[F:9])([OH:7])[C:4](O)=[O:5].C(C1NC=CN=1)(C1NC=CN=1)=O.[NH2:24][C:25]1[CH:38]=[CH:37][C:28]([C:29]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[O:30])=[CH:27][CH:26]=1>O1CCCC1>[C:31]1([C:29]([C:28]2[CH:27]=[CH:26][C:25]([NH:24][C:4](=[O:5])[C:3]([OH:7])([CH:8]([F:10])[F:9])[CH:2]([F:11])[F:1])=[CH:38][CH:37]=2)=[O:30])[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: Nc1ccc(C(=O)c2ccccc2)cc1
Reactant: O=C(O)C(O)(C(F)F)C(F)F
Agent: O=C(c1ncc[nH]1)c1ncc[nH]1
Solvent: C1CCOC1
Product: O=C(c1ccccc1)c1ccc(NC(=O)C(O)(C(F)F)C(F)F)cc1
Yield: 25 %

Procedure:
To a solution of 2,2,-bis-difluoromethyl-2-hydroxy-acetic acid (1.76 g, 10 mmole) in tetrahydrofuran (40ml) was added carbonyl diimidazole (0.81 g, 5 mmole). The flask was placed in a sonic bath and the reaction sonicated for 20 minutes followed by addition of 4-aminobenzophenone. The reaction was sonicated for 18 hours. The reaction mixture was filtered and the filtrate evaporated to dryness. The recovered pasty solid was washed with ether and the combined ether washings evaporated. The recovered solid was crystallized from ethyl acetate/hexane to give the title compound (0.89g, 25%) as yellow crystals; mp 139°-142° C. 1H--NMR (300 MHz, d6 --DMSO) : 6.48(t, J=53.7Hz, 2H, HCF2); 7.53-7.77 7H, ArH, OH); 7.95-7.98(m, 3H, ArH); 10.43 (s, 1H, NH). MS(CI,CH4) 356(M+1, 100%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[F:8].C1(=O)[O:14][C:12](=[O:13])[CH2:11][CH2:10]1.[Cl-].[Al+3].[Cl-].[Cl-].N1CC[O:23][CH2:22]C1>>[F:1][C:2]1[CH:7]=[C:6]([CH:5]=[CH:4][C:3]=1[F:8])[C:22]([CH:11]([CH3:10])[C:12]([OH:14])=[O:13])=[O:23]
Reactant: O=C1CCC(=O)O1
Reactant: Fc1ccccc1F
Reactant: C1COCCN1
Agent: [Al+3]
Agent: [Cl-]
Product: CC(C(=O)O)C(=O)c1ccc(F)c(F)c1

Procedure:
33 g of 3,4-difluoro-benzoylpropionic acid (obtained by Friedel-Crafts acylation of 1,2-difluorobenzene with succinic anhydride in the presence of aluminium chloride) together with 60 ml of morpholine are heated at 150° C. for 20 hours with stirring. The reaction mixture is cooled, dissolved in ethylacetate, and this solution is washed with 2 N hydrochloric acid and extracted with 5 N hydrochloric acid. The pH-value of the 5 N hydrochloric acid extracts is brought to 6 with concentrated sodium hydroxide solution, and the suspension formed is extracted with ethyl acetate. The organic phases are washed with water, dried over sodium sulfate and concentrated by evaporation. The crystalline residue (31.7 g) together with 18 g of potassium hydroxide, 180 ml of water and 180 ml of ethanol is refluxed for 10 hours; it is then cooled, concentrated by evaporation and distributed between water and ethyl acetate. The pH-value of the aqueous phases is adjusted to 5, and the 3-fluoro-4-morpholino-benzoylpropionic acid which has precipitated is filtered off under suction and dried (m.p. 164°-168° C.).
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[O:6][C@@H:5]([CH2:7][C:8]([OH:10])=[O:9])[C:4](=[O:11])[O:3]1.C(O)(=O)[C@H](CC(O)=O)O.N1C=CN=C1.[Si:27](Cl)([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28]>CN(C)C=O.C1(C)C=CC=CC=1>[CH3:1][C:2]1([CH3:12])[O:6][CH:5]([CH2:7][C:8]([O:10][Si:27]([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28])=[O:9])[C:4](=[O:11])[O:3]1
Reactant: CC1(C)OC(=O)[C@H](CC(=O)O)O1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: O=C(O)C[C@H](O)C(=O)O
Agent: c1c[nH]cn1
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: CC1(C)OC(=O)C(CC(=O)O[Si](C)(C)C(C)(C)C)O1
Temperature: 22 °C
Reaction time: 18 h
Yield: 95.6 %

Procedure:
A solution of (S)-(+)-2,2-dimethyl-5-oxo-1,3-dioxolane-4-acetic acid (13.20 g, 75.8 mmol), which was derived from L-malic acid by means known in the art, in N,N-dimethylformamide (25 ml) was treated at 22° C. with imidazole (10.56 g, 0.155 mmol) followed by tert-butyldimethylsilyl chloride (12.0 g, 79.6 mmol) and the resulting mixture was stirred at 22° C. for 18 h. The reaction mixture was then diluted with toluene (500 ml), washed with water (×3), saturated sodium bicarbonate and brine. After drying (magnesium sulfate), the solvent was evaporated under reduced pressure to give an oil. Distillation under vacuum gave 20.9 g (96%) of the title material as a clear oil: Bp 80-90° C./0.1 torr (bulb to bulb distillation, air bath temperature). 1H NMR (400 MHz, CDCl3) δ: 0.33 (s, 3), 0.36 (s, 3), 1.00 (s, 9), 1.11 (s, 3), 1.37 (s, 3), 2.72 (m, 2), 4.35 (dd, 1, J=4, 6).
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH:7]([N:10]2[C:21]3=[C:22]4[C:16](=[C:17]5[N:26]([CH3:27])[CH:25]=[CH:24][C:23]([NH2:28])=[C:18]5[CH:19]=[CH:20]3)[C:15](=[O:29])[NH:14][C:13]4=[CH:12][CH2:11]2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[CH3:30][C:31]1[S:32][C:33]([CH2:36][C:37](O)=[O:38])=[CH:34][N:35]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)C(C)C)C>CN(C)C(=O)C>[C:1]([N:4]1[CH2:9][CH2:8][CH:7]([N:10]2[C:21]3=[C:22]4[C:16](=[C:17]5[N:26]([CH3:27])[CH:25]=[CH:24][C:23]([NH:28][C:37](=[O:38])[CH2:36][C:33]6[S:32][C:31]([CH3:30])=[N:35][CH:34]=6)=[C:18]5[CH:19]=[CH:20]3)[C:15](=[O:29])[NH:14][C:13]4=[CH:12][CH2:11]2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: Cc1ncc(CC(=O)O)s1
Reactant: CC(=O)N1CCC(N2CC=c3[nH]c(=O)c4c5c(ccc2c3-4)=C(N)C=CN5C)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: CC(=O)N1CCC(N2CC=c3[nH]c(=O)c4c5c(ccc2c3-4)=C(NC(=O)Cc2cnc(C)s2)C=CN5C)CC1
Temperature: 25 °C
Reaction time: 22 h
Yield: 95.3 %

Procedure:
A mixture of Example 73d (0.02 g, 0.051 mmol), 2-(2-methylthiazol-5-yl)acetic acid (0.012 g, 0.077 mmol), and 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate(V) (0.029 g, 0.077 mmol) in N,N-dimethyl acetamide (0.5 mL) was treated with N-ethyl-N-isopropylpropan-2-amine (0.027 mL, 0.153 mmol) and stirred at ambient temperature for 22 hours. The reaction mixture was partitioned between ethyl acetate and water and washed with saturated aqueous sodium chloride. The aqueous layers were combined, saturated with solid sodium chloride and extracted with ethyl acetate (4×100 mL). The organic layers were combined, dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by flash chromatography (silica gel, 0-15% methanol in dichloromethane). The material was further purified by reverse phase HPLC(C18, acetonitrile/water (0.1% TFA), 10-100%) to provide 0.0258 g (78%) of the title compound as the TFA salt. 1H NMR (400 MHz, PYRIDINE-d5) δ 11.24 (s, 1H), 10.34 (s, 1H), 8.34 (d, J=2.44 Hz, 1H), 7.62 (s, 1H), 7.54 (d, J=2.75 Hz, 1H), 7.35 (s, 1H), 7.21 (d, J=8.54 Hz, 1H), 6.89 (s, 1H), 4.20 (s, 2H), 4.13 (s, 3H), 4.07 (s, 2H), 3.64 (m, 1H), 3.25 (m, 1H), 2.63 (m, 2H), 2.55 (s, 3H), 2.59 (m, 1H), 1.93 (s, 3H), 1.69 (m, 2H), 1.50 (m, 2H). MS (ESI+) m/z 531.1 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10]2[CH:25]=[CH:24][C:13]3[C@:14]4([CH3:23])[C@@H:19]([CH2:20][CH2:21][C:12]=3[CH:11]=2)[NH:18][C:17](=[O:22])[CH:16]=[CH:15]4)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[C:26](O)(C)(C)C.CC(C)([O-])C.[K+].CI>C(OCC)(=O)C>[CH3:26][N:18]1[C@H:19]2[C@@:14]([CH3:23])([C:13]3[CH:24]=[CH:25][C:10]([C:6]4[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=4)=[CH:11][C:12]=3[CH2:21][CH2:20]2)[CH:15]=[CH:16][C:17]1=[O:22]
Reactant: CC(C)(C)O
Reactant: C[C@]12C=CC(=O)N[C@@H]1CCc1cc(-c3cccc([N+](=O)[O-])c3)ccc12
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CI
Product: CN1C(=O)C=C[C@]2(C)c3ccc(-c4cccc([N+](=O)[O-])c4)cc3CC[C@@H]12
Temperature: 25 °C
Reaction time: 4 h
Yield: 75 %

Procedure:
A 15 mL round bottom flask was charged with (+)-(4aR)-(10bR)-8-(3-nitrophenyl)-10b-methyl-3,4,4a,5,6,10b-hexahydrobenzo[f]quinolin-3-one (12 mg, 0.034 mmol), 0.10 mL of t-butanol, and potassium t-butoxide (12 mg, 0.10 mmol). Methyl iodide (0.006 mL, 0.10 mmol) was added and the mixture was stirred at room temperature for 4 h. The mixture was diluted with ethyl acetate, and purified by silica gel chromatography (ethyl acetate eluent) to give 9 mg (75%) of the title compound as a white solid, upon trituration from diethyl ether/hexanes. mp 175°-177°. FDMS: m/e=348.
Reaction SMILES: [CH:1]1([CH:4]=O)[CH2:3][CH2:2]1.N1CCCCC1.[NH2:12][C:13]1[N:18]=[CH:17][N:16]=[C:15]2[N:19]([CH2:37][C@H:38]3[CH2:42][CH2:41][CH2:40][N:39]3[C:43](=[O:47])[CH2:44][C:45]#[N:46])[N:20]=[C:21]([C:22]3[CH:27]=[CH:26][C:25]([O:28][C:29]4[CH:34]=[C:33]([F:35])[CH:32]=[C:31]([F:36])[CH:30]=4)=[CH:24][CH:23]=3)[C:14]=12>CO>[NH2:12][C:13]1[N:18]=[CH:17][N:16]=[C:15]2[N:19]([CH2:37][C@H:38]3[CH2:42][CH2:41][CH2:40][N:39]3[C:43]([C:44](=[CH:4][CH:1]3[CH2:2][CH2:3]3)[C:45]#[N:46])=[O:47])[N:20]=[C:21]([C:22]3[CH:27]=[CH:26][C:25]([O:28][C:29]4[CH:30]=[C:31]([F:36])[CH:32]=[C:33]([F:35])[CH:34]=4)=[CH:24][CH:23]=3)[C:14]=12
Reactant: O=CC1CC1
Reactant: N#CCC(=O)N1CCC[C@@H]1Cn1nc(-c2ccc(Oc3cc(F)cc(F)c3)cc2)c2c(N)ncnc21
Solvent: CO
Solvent: C1CCNCC1
Product: N#CC(=CC1CC1)C(=O)N1CCC[C@@H]1Cn1nc(-c2ccc(Oc3cc(F)cc(F)c3)cc2)c2c(N)ncnc21
Temperature: 25 °C
Reaction time: 12 h
Yield: 49 %

Procedure:
Into a 10-mL round-bottom flask, was placed cyclopropanecarbaldehyde (28.7 mg, 0.41 mmol, 2.00 equiv), piperidine (17.4 mg, 0.20 mmol, 1.00 equiv), 3-[(2R)-2-([4-amino-3-[4-(3,5-difluorophenoxy)phenyl]-1H-pyrazolo[3,4-d]pyrimidin-1-yl]methyl)pyrrolidin-1-yl]-3-oxopropanenitrile (100 mg, 0.20 mmol, 1.00 equiv), and methanol (5 mL). The resulting solution was stirred for 12 h at 25° C. and then concentrated under vacuum. The residue was loaded onto a silica gel column and eluted with dichloromethane/methanol (50/1) to give 53.12 mg (45%) of the title compound as an off-white solid. LC-MS: (ES, m/z): MS (ESI, pos. ion) m/z: 541 (M+1). H-NMR: (CDCl3, ppm): 1HNMR (300 MHz, CD3OD, ppm), 8.28 3 (1H, s), 7.777˜7.806 (2H, t), 7.269˜7.298 (2H, t), 6.703˜6.754 (3H, t), 6.455˜6.600 (1H, d), 4.400˜4.878 (3H, m), 3.338˜3.618 (2H, m), 1.700˜2.188 (4H, m), 1.280˜1.305 (4H, m), 0.710˜0.912 (2H, m).
Reaction SMILES: O[CH2:2][C:3]([C@H:5]([C@@H:7]([C@@H:9](CO)[OH:10])O)O)=[O:4].[CH2:13]([OH:18])[CH2:14][CH:15]([CH3:17])[CH3:16]>OS(O)(=O)=O>[C:9]([O:18][CH2:13][CH2:14][CH:15]([CH3:17])[CH3:16])(=[O:10])[CH2:7][CH2:5][C:3]([CH3:2])=[O:4]
Reactant: O=C(CO)[C@@H](O)[C@H](O)[C@H](O)CO
Reactant: CC(C)CCO
Agent: O=S(=O)(O)O
Product: CC(=O)CCC(=O)OCCC(C)C
Temperature: 200 °C
Reaction time: 0.05 h
Yield: 18 %

Procedure:
In a first experiment, a mixture of crystalline fructose (10 g) in isoamyl alcohol (40 mL) and concentrated H2SO4 (0.10 mL) was placed in sealed a Teflon-lined reaction vessel inside a high-density rotor for treatment in a MicroSYNTH Microwave Labstation. The sample was heated from room temperature via microwaves to 200° C. in 3 min., and kept there for 3 min. using an irradiation power of 1000 Watts. The vessel was cooled. Analysis indicates a 59% molar yield of isoamyl HMF and 18% yield of isoamyl levulinate from fructose.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C:6](=O)[C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[C:9]([O:15][CH3:16])[CH:8]=1)C.O.[NH2:20][NH2:21]>C(O)C>[CH3:16][O:15][C:9]1[CH:8]=[C:7]([C:6]2[CH2:5][C:4](=[O:3])[NH:21][N:20]=2)[CH:12]=[CH:11][C:10]=1[O:13][CH3:14]
Reactant: NN
Reactant: CCOC(=O)CC(=O)c1ccc(OC)c(OC)c1
Solvent: CCO
Solvent: O
Product: COc1ccc(C2=NNC(=O)C2)cc1OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 59.1 %

Procedure:
To a solution of ethyl-3,4-dimethoxybenzoylacetate (1 g, 4 mmol), (Heterocycles 1979, 13, 239), in ethanol (5 ml) containing hydrazine hydrate (192 μl, 4 mmol) was stirred for 30 minutes at ambient temperature followed by 40 minutes being heated at reflux. After cooling at ambient temperature, the mixture was concentrated to half the volume and ether (10 ml) was added. After trituration, the solid was collected by filtration, washed with ether and dried under vacuum to give 3-(3,4-dimethoxyphenyl)-4,5-dihydro-1H-pyrazol-5-one (521 mg, 60%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][NH:5][C:4](=[O:8])[CH:3]=1.C(N(CC)CC)C.[N+:16]([C:19]1[CH:27]=[CH:26][C:22]([C:23](Cl)=[O:24])=[CH:21][CH:20]=1)([O-:18])=[O:17]>O1CCOCC1>[N+:16]([C:19]1[CH:20]=[CH:21][C:22]([C:23]([O:1][C:2]2[CH:7]=[CH:6][NH:5][C:4](=[O:8])[CH:3]=2)=[O:24])=[CH:26][CH:27]=1)([O-:18])=[O:17]
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Reactant: O=c1cc(O)cc[nH]1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: O=C(Oc1cc[nH]c(=O)c1)c1ccc([N+](=O)[O-])cc1
Yield: 73.4 %

Procedure:
To a suspension of 1.00 g of 4-hydroxy-2-pyridone in 50 ml of dried dioxane were added 3.78 ml of triethylamine and a solution of 2.17 g of 4-nitrobenzoyl chloride in 30 ml of dried dioxane, and the mixture was refluxed for 6 hours. After the dioxane was distilled off, the residue was washed with water and then with a 1:1 mixture of methanol-acetone to obtain the title compound in an amount of 1.72 g (yield: 73.4%)