Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:31]=[CH:30][CH:29]=[CH:28][C:3]=1[CH2:4][NH:5][C:6]1[C:11]([C:12]([NH2:14])=[O:13])=[CH:10][N:9]=[C:8]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([CH:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)=[CH:18][CH:17]=2)[CH:7]=1.Cl.CCN(C(C)C)C(C)C.[CH3:42][S:43]([Cl:46])(=[O:45])=[O:44]>CN1C(=O)CCC1>[F:1][C:2]1[CH:31]=[CH:30][CH:29]=[CH:28][C:3]=1[CH2:4][NH:5][C:6]1[C:11]([C:12]([NH2:14])=[O:13])=[CH:10][N:9]=[C:8]([NH:15][C:16]2[CH:17]=[CH:18][C:19]([CH:22]3[CH2:27][CH2:26][N:25]([S:43]([CH3:42])(=[O:45])=[O:44])[CH2:24][CH2:23]3)=[CH:20][CH:21]=2)[CH:7]=1.[ClH:46]
Reactant: NC(=O)c1cnc(Nc2ccc(C3CCNCC3)cc2)cc1NCc1ccccc1F
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)N1CCC(c2ccc(Nc3cc(NCc4ccccc4F)c(C(N)=O)cn3)cc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Compound 4-(2-fluorobenzylamino)-6-(4-(piperidin-4-yl)phenylamino)nicotinamide (Example 106) HCl salt (100 mg, 0.2 mmol) was stirred in 5 mL NMP. To the solution were added DIEA (0.18 mL, 1.0 mmol) and MsCl (0.047 mL, 0.6 mmol). The mixture was stirred at RT for 30 min and quenched with Me2NH. The mixture was concentrated in vacuo and subjected to reverse phase prep HPLC to isolate the title compound as HCl salt. UV=259 nm. M+H found for C25H28FN5O3S: 498.5. NMR (CD3OD): 8.13 (1H, s), 7.39-7.34 (3H, m), 7.29 (1H, td, J=8.0; 2.0 Hz), 7.19-7.10 (4H, m), 5.88 (1H, s), 4.51 (2H, s), 3.86 (2H, m), 2.88 (2H, m), 2.85 (3H, s), 2.75 (1H, m), 1.97 (2H, m), 1.79 (2H, m) ppm.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[N:8]([CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)[C:7](=[O:21])[C:6](=[O:22])[NH:5]2.[CH3:23][O:24][C:25]([C:27]1(OC)[CH2:31][CH2:30][CH:29](OC)O1)=[O:26].C1(C)C=CC(S(O)(=O)=O)=CC=1>CN(C)C=O.C1(C)C=CC=CC=1>[CH:15]1([N:8]2[C:9]3[C:4](=[CH:3][C:2]([N:1]4[CH:29]=[CH:30][CH:31]=[C:27]4[C:25]([O:24][CH3:23])=[O:26])=[C:11]([N+:12]([O-:14])=[O:13])[CH:10]=3)[NH:5][C:6](=[O:22])[C:7]2=[O:21])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: COC(=O)C1(OC)CCC(OC)O1
Reactant: Nc1cc2[nH]c(=O)c(=O)n(C3CCCCC3)c2cc1[N+](=O)[O-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: COC(=O)c1cccn1-c1cc2[nH]c(=O)c(=O)n(C3CCCCC3)c2cc1[N+](=O)[O-]
Yield: 80.8 %

Procedure:
10 g (33 mmol) of 6-amino-1-cyclohexyl-7-nitro-2,3(1H,4H)-quinoxalinedione (Example 28e), 6.9 g (36 mmol) of 2-methoxycarbonyl-2,5-dimethoxytetrahydrofuran and a spatula tip of p-toluenesulfonic acid were refluxed in a mixture of 50 ml of dimethylformamide and 50 ml of toluene with a water trap. After reaction was complete, the mixture was concentrated under reduced pressure, and the residue was treated with water. The precipitate was filtered off with suction to yield 11 g (79%) of the product. Melting point 211°-212° C.
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:25])([F:24])[C:5]([NH:7][CH2:8][CH2:9][C:10]1[CH:14]=[CH:13][N:12]([S:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)(=[O:17])=[O:16])[CH:11]=1)=[O:6].[CH3:26]I.O>CN(C)C=O>[CH3:26][N:7]([CH2:8][CH2:9][C:10]1[CH:14]=[CH:13][N:12]([S:15]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)(=[O:16])=[O:17])[CH:11]=1)[C:5](=[O:6])[C:4]([F:24])([F:3])[F:25]
Reactant: CI
Reactant: O=C(NCCc1ccn(S(=O)(=O)c2ccccc2)c1)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CN(CCc1ccn(S(=O)(=O)c2ccccc2)c1)C(=O)C(F)(F)F
Temperature: 70 °C

Procedure:
50% Sodium hydride oil dispersion (0.62 g) was added to an ice-cooled solution of N-trifluoroacetyl-2-(1-phenylsulphonyl-3-pyrrolyl)ethylamine (3.59 g) in dimethylformamide (20 ml) after 20 minutes, methyl iodide (1.76 g) was added and the mixture was heated at 70° C. overnight. After cooling, water was added and the mixture was extracted with ether 3 times. The ether was washed with water, dried and evaporated to give N-methyl-N-trifluoroacetyl-2-(1-phenylsulphonyl-3-pyrrolyl)ethylamine as an oil. The oil was dissolved in methanol (40 ml), 0.880 ammonia added and the solution was stirred for 6 hours. After evaporation, the residue was dissolved in 5M hydrochloric acid and extracted with ether. The aqueous part was basified with 0.880 ammonia and the product was extracted into dichloromethane. The extracts were washed with water, dried and evaporated to give the title product as a pure oil.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]1[CH2:10][C:11]([CH:13]1[S:17][CH2:16][NH:15][C@@H:14]1[C:18]([N:20]1[CH2:26][CH2:25][CH2:24][C@H:21]1[CH:22]=O)=[O:19])=[O:12].Cl.[NH2:28][OH:29].N1C=CC=CC=1>CN(C)C=O>[CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]1[CH2:10][C:11]([CH:13]1[S:17][CH2:16][NH:15][C@@H:14]1[C:18]([N:20]1[CH2:26][CH2:25][CH2:24][C@H:21]1[CH:22]=[N:28][OH:29])=[O:19])=[O:12]
Reactant: NO
Reactant: O=C[C@@H]1CCCN1C(=O)[C@H]1NCSC1C(=O)CC1Cc2ccccc2C1
Agent: Cl
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: O=C(CC1Cc2ccccc2C1)C1SCN[C@@H]1C(=O)N1CCC[C@H]1C=NO
Temperature: 70 °C
Reaction time: 1.5 h
Yield: 31 %

Procedure:
1-[3-(Indan-2-ylacetyl)-L-thioprolyl]-L-prolinal (372 mg), hydroxylamine hydrochloride salt (76 mg) and pyridine (89 μl) were dissolved in 5 ml of dimethylformamide, and stirred at 70° C. for 1.5 hours. After concentrating the reaction solution under reduced pressure, the resulting residue was dissolved in 30 ml of methylene chloride, washed by saturated aqueous sodium chloride solution, and dried over magnesium sulfate, followed by distillation of the solvent under reduced pressure. The resulting residue was purified by column chromatography to obtain 120 mg of (2S)-1-[3-(indan-2-ylacetyl)-L-thioprolyl]-2-pyrrolidine aldoxime. Yield; 31%.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][N:3]=1.[C:9]1(=O)[O:14][C:12](=[O:13])[C:11]2=[CH:15][CH:16]=[CH:17][CH:18]=[C:10]12.C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH3:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([N:1]2[C:12](=[O:13])[C:11]3[C:10](=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:9]2=[O:14])[CH:7]=1
Reactant: O=C1OC(=O)c2ccccc21
Reactant: Cc1ccnc(N)c1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: Cc1ccnc(N2C(=O)c3ccccc3C2=O)c1
Temperature: 25 °C
Yield: 55.8 %

Procedure:
To a mixture of 2-Amino-4-methylpyridine (21.6 g, 0.2 mol) and phthalic anhydride (29.6 g, 0.2 mol) in toluene (160 ml), was added triethylamine (2.8 ml, 0.02 mol). The mixture was refluxed for 5 hr. After cooling to room temperature, the mixture was evaporated in vacuo and the residue was suspended in acetic anhydride (250 ml). The mixture was then heated to reflux for 4 hr until the solid dissolves completely. After cooling to room temperature, white precipitate was collected by filtration and washed with acetic anhydride and hexane, and dried in high vacuo to give 26.6 g (56%) of 2-(4-methyl-pyridin-2-yl)-isoindole-1,3-dione as a white solid. 1H NMR (200 MHz, CDCl3) δ 2.45 (3H, s), 7.18 (1H, d, J=5.0 Hz), 7.25 (1H, s), 7.76-7.99 (4H, m), 8.53 (1H, d, J=5.0 Hz). m/z (EI) 238 (M+).
Reaction SMILES: [F:1][CH:2]([F:26])[O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]1[CH:15]=[C:14]([O:16][CH3:17])[C:13](=[O:18])[C:12]([C:19](=O)[CH:20]=[CH:21][N:22](C)C)=[N:11]1.[C:27]1([NH:33]N)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>CC(O)=O>[F:1][CH:2]([F:26])[O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]1[CH:15]=[C:14]([O:16][CH3:17])[C:13](=[O:18])[C:12]([C:19]2[N:33]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[N:22]=[CH:21][CH:20]=2)=[N:11]1
Reactant: NNc1ccccc1
Reactant: COc1cn(-c2ccccc2OC(F)F)nc(C(=O)C=CN(C)C)c1=O
Solvent: CC(=O)O
Product: COc1cn(-c2ccccc2OC(F)F)nc(-c2ccnn2-c2ccccc2)c1=O
Temperature: 25 °C
Yield: 67.6 %

Procedure:
A solution of 1-[2-(difluoromethoxy)phenyl]-3-[3-(dimethylamino)prop-2-enoyl]-5-methoxypyridazin-4(1H)-one (0.50 g, 1.369 mmol) and phenylhydrazine (0.269 mL, 2.74 mmol) in AcOH (5 mL) was refluxed for 2 h. After cooling to room temperature, the mixture was concentrated under reduced pressure. The residue was diluted with AcOEt, washed successively with 1 M HCl aqueous solution, saturated NaHCO3 aqueous solution, and brine, dried over MgSO4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with hexane/AcOEt (7/3-0/10) to give the title compound (0.38 g, 68% yield) as an off-white amorphous solid: 1H NMR (300 MHz, CDCl3): δ ppm 3.88 (3H, s), 6.37 (1H, t, J=72.3 Hz), 6.57 (1H, dd, J=8.1, 1.7 Hz), 7.09-7.16 (1H, m), 7.22-7.25 (2H, m), 7.34-7.42 (6H, m), 7.76-7.78 (2H, m). LC-MS (ESI) m/z 411 [M+H]+. Anal. Calcd. for C21H16F2N4O3: C, 61.15; H, 4.07; N, 13.79. Found: C, 61.23; H, 4.11; N, 13.71.
Reaction SMILES: [C:1]([NH:8][CH:9]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:10]([O:12][CH3:13])=[O:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C(O)(=O)C.[H][H]>CO.[Rh]>[C:1]([NH:8][CH:9]([CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)[C:10]([O:12][CH3:13])=[O:11])([O:3][C:4]([CH3:6])([CH3:7])[CH3:5])=[O:2]
Reactant: [H][H]
Reactant: COC(=O)C(NC(=O)OC(C)(C)C)c1ccccc1
Agent: [Rh]
Solvent: CC(=O)O
Solvent: CO
Product: COC(=O)C(NC(=O)OC(C)(C)C)C1CCCCC1

Procedure:
N-BOC-a-phenylglycine, methyl ester (1.2 g) is dissolved in methanol (50 ml) containing acetic acid (1 ml). 5% rhodium on aluminum powder (0.60 g) is added and the mixture shaken under 50 psi hydrogen for about 18 hours. The mixture is filtered, evaporated in vacuo , and the residue taken up into ethyl acetate. The organic solution is washed with water, saturated sodium bicarbonate solution, water, brine, dried over magnesium sulfate, filtered, evaporated in vacuo to give N-BOC-a-cyclohexylglycine, methyl ester.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][C:6]=1[C:7]([OH:9])=O)([CH3:3])[CH3:2].[N:18]1([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)C(C)C)C>>[C:27]([O:26][C:24]([N:18]1[CH2:23][CH2:22][N:21]([C:7](=[O:9])[C:6]2[CH:10]=[C:11]([S:14]([CH3:17])(=[O:16])=[O:15])[CH:12]=[CH:13][C:5]=2[O:4][CH:1]([CH3:2])[CH3:3])[CH2:20][CH2:19]1)=[O:25])([CH3:30])([CH3:28])[CH3:29]
Reactant: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)O
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)N1CCN(C(=O)OC(C)(C)C)CC1
Yield: 96.9 %

Procedure:
A solution of 2-isopropoxy-5-methanesulfonyl-benzoic acid (compound 1.2, 1.0 g), tert-butyl 1-piperazinecarboxylate (0.78 g), TBTU (1.4 g) and N-ethyldiisopropylamine (4 mL) was stirred at room temperature for 2 hours. After such time, the reaction mixture was concentrated in vacuo and purified by column chromatography (SiO2) to give 4-(2-Isopropoxy-5-methanesulfonyl-benzoyl)-piperazine-1-carboxylic acid tert-butyl ester as a colorless foam (1.6 g). The latter was dissolved in dichloromethane (11 mL) and treated with trifluroacetic acid (4.2 mL) for 30 minutes. After such time the reaction mixture was concentrated in vacuo to yield the title compound (1.6 g) as light yellow oil. MS (m/e): 327.1 (M+H+, 100%).
Reaction SMILES: [Br:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([N:9]2[C:18]3[C:13](=[CH:14][C:15]([S:19](OC4C(F)=C(F)C(F)=C(F)C=4F)(=[O:21])=[O:20])=[CH:16][CH:17]=3)[CH:12]=[CH:11][C:10]2=[O:34])=[C:4]([CH3:35])[CH:3]=1.[O:36]1[CH:40]=[CH:39][C:38]([NH2:41])=[N:37]1.C1COCC1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>Cl.CCOC(C)=O>[Br:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([N:9]2[C:18]3[C:13](=[CH:14][C:15]([S:19]([NH:41][C:38]4[CH:39]=[CH:40][O:36][N:37]=4)(=[O:21])=[O:20])=[CH:16][CH:17]=3)[CH:12]=[CH:11][C:10]2=[O:34])=[C:4]([CH3:35])[CH:3]=1
Reactant: Nc1ccon1
Reactant: Cc1cc(Br)c(F)cc1-n1c(=O)ccc2cc(S(=O)(=O)Oc3c(F)c(F)c(F)c(F)c3F)ccc21
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1cc(Br)c(F)cc1-n1c(=O)ccc2cc(S(=O)(=O)Nc3ccon3)ccc21
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 70.5 %

Procedure:
Under a nitrogen atmosphere, a solution of perfluorophenyl 1-(4-bromo-5-fluoro-2-methylphenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonate (1.50 g, 2.59 mmol), isoxazol-3-amine (0.268 ml, 3.63 mmol) and THF (25.9 ml) was cooled in an ice-bath for 15 min, then lithium bis(trimethylsilyl)amide (1M in THF) (6.48 ml, 6.48 mmol) was added dropwise. After 10 min, the whole was warmed to rt and stirred for 30 min. 6.48 mL of additional LHMDS was added and the reaction was stirred for 1 h. The mixture was diluted with 1N aq. HCl and EtOAc. The layers were separated, and the organic layer was washed with 1N aq. HCl. The aq. layers were combined and extracted with EtOAc (2×). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated. The crude material was absorbed onto a plug of silica gel and purified by chromatography through a Redi-Sep pre-packed silica gel column (40 g), eluting with a gradient of 0% to 70% EtOAc in heptane, to provide 1-(4-bromo-5-fluoro-2-methylphenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (873 mg, 70.4% yield) as brown solid. m/z (ESI) [M+H]+=477.9. NMR (400 MHz, DMSO-d6) δ ppm 1.17 (t, J=7.15 Hz, 1 H) 1.86 (s, 2 H) 1.99 (s, 1 H) 5.55 (br. s., 1 H) 5.88 (d, J=1.76 Hz, 1 H) 6.44 (d, J=1.87 Hz, 1 H) 6.78 (d, J=9.02 Hz, 1H) 6.83 (d, J=9.64 Hz, 1 H) 7.55 (d, J=9.12 Hz, 1 H) 7.84 (dd, J=8.91, 2.28 Hz, 1 H) 7.92 (dd, J=7.57, 0.52 Hz, 1 H) 8.27 (d, J=9.54 Hz, 1 H) 8.32 (d, J=1.76 Hz, 1 H) 8.40 (d, J=2.28 Hz, 1 H) 8.72 (d, J=1.76 Hz, 1 H) 11.67 (s, 1 H).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:20]=[CH:19][C:6]([CH2:7][N:8]([C:10]2[CH:15]=[CH:14][C:13]([CH:16]([CH3:18])[CH3:17])=[CH:12][CH:11]=2)N)=[CH:5][CH:4]=1.CC[O:23][C:24]([CH2:26][CH:27]1[C:32](=O)[CH2:31][CH2:30][CH2:29][CH2:28]1)=[O:25]>>[Cl:2][C:3]1[CH:20]=[CH:19][C:6]([CH2:7][N:8]2[C:28]3[CH:27]([CH2:26][C:24]([OH:25])=[O:23])[CH2:32][CH2:31][CH2:30][C:29]=3[C:15]3[C:10]2=[CH:11][CH:12]=[C:13]([CH:16]([CH3:18])[CH3:17])[CH:14]=3)=[CH:5][CH:4]=1
Reactant: CC(C)c1ccc(N(N)Cc2ccc(Cl)cc2)cc1
Reactant: CCOC(=O)CC1CCCCC1=O
Agent: Cl
Product: CC(C)c1ccc2c(c1)c1c(n2Cc2ccc(Cl)cc2)C(CC(=O)O)CCC1

Procedure:
Following the procedure of Example 1, but using 1(4-chlorobenzyl)-1-(4-isopropylphenyl)hydrazine hydrochloride and ethyl 2-cyclohexanone acetate as starting material, the title compound was prepared.
Reaction SMILES: [CH2:1]([C:3]1([CH2:16][CH3:17])[C:8]2[CH:9]=[C:10]([OH:13])[CH:11]=[CH:12][C:7]=2[N:6]([CH3:14])[C:5](=[O:15])[O:4]1)[CH3:2].[Cl:18][C:19]1[CH:20]=[C:21](B(O)O)[CH:22]=[CH:23][C:24]=1[F:25].C(N(CC)CC)C>C(Cl)Cl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[Cl:18][C:19]1[CH:20]=[C:21]([CH:22]=[CH:23][C:24]=1[F:25])[O:13][C:10]1[CH:11]=[CH:12][C:7]2[N:6]([CH3:14])[C:5](=[O:15])[O:4][C:3]([CH2:1][CH3:2])([CH2:16][CH3:17])[C:8]=2[CH:9]=1
Reactant: CCC1(CC)OC(=O)N(C)c2ccc(O)cc21
Reactant: OB(O)c1ccc(F)c(Cl)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCC1(CC)OC(=O)N(C)c2ccc(Oc3ccc(F)c(Cl)c3)cc21
Temperature: 25 °C
Reaction time: 144 h
Yield: 8.6 %

Procedure:
To a stirred solution of 4,4-diethyl-6-hydroxy-1-methyl-1,4-dihydro-2H-3,1-benzoxazin-2-one (0.30 g, 1.28 mmol) and 3-chloro-4-fluorophenylboronic acid (0.67 g, 3.83 mmol) in methylene chloride (15 mL) was added triethylamine (0.6 mL, 4.3 mmol) and copper (II) acetate (0.46 g, 2.56 mmol). The reaction mixture was stirred at room temperature for 6 days and partitioned between ammonium chloride solution (sat.) and methylene chloride. The organic layer washed with 1N sodium hydroxide solution, dried over magnesium sulfate and concentrated to give 6-(3-chloro-4-fluorophenoxy)-4,4-diethyl-1-methyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one as a yellow oil (0.04 g, 9%). 1H NMR (DMSO-d6): δ 7.45 (t, J=9.1 Hz, 1H), 7.21 (dd, J=6.2, 3.0 Hz, 1H), 7.13 (d, J=8.7 Hz, 1H), 7.08 (m, 2H), 6.99 (m, 1H), 3.29 (s, 3H), 2.01 (m, 2H), 1.88 (m, 2H), 0.79 (t, J=7.3 Hz, 6H). MS (ESI) m/z 364/366 ([M+H]+); HRMS: calcd for C19H19ClFNO3, 363.1037. found (ESI+), 364.1106.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:21]2[CH:22]=[N:23][N:24]3[CH:29]=[CH:28][C:27]([N:30]4[C@@H:34]([C:35]5[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=5[O:41][CH3:42])[CH2:33][O:32][C:31]4=[O:43])=[N:26][C:25]=23)[CH:5]=[CH:6][C:7]=1[C:8]1[N:12]=[CH:11][N:10](COCC[Si](C)(C)C)[N:9]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([C:21]2[CH:22]=[N:23][N:24]3[CH:29]=[CH:28][C:27]([N:30]4[C@@H:34]([C:35]5[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=5[O:41][CH3:42])[CH2:33][O:32][C:31]4=[O:43])=[N:26][C:25]=23)[CH:5]=[CH:6][C:7]=1[C:8]1[N:12]=[CH:11][NH:10][N:9]=1
Reactant: COc1ccccc1[C@H]1COC(=O)N1c1ccn2ncc(-c3ccc(-c4ncn(COCC[Si](C)(C)C)n4)c(F)c3)c2n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccccc1[C@H]1COC(=O)N1c1ccn2ncc(-c3ccc(-c4nc[nH]n4)c(F)c3)c2n1
Reaction time: 18 h
Yield: 32.9 %

Procedure:
A mixture of (S)-3-(3-(3-fluoro-4-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-3-yl)phenyl)pyrazolo[1,5-a]pyrimidin-5-yl)-4-(2-methoxyphenyl) oxazolidin-2-one (0.0424 g, 0.071 mmol) in DCM (1 mL) was treated with trifluoroacetic acid (0.5 mL) at ambient temperature. The mixture was stirred for 18 hours. The solvent was concentrated and the residue was partitioned between EtOAc and saturated aqueous NaHCO3. The aqueous layer was further extracted with EtOAc and DCM. The combined organic extracts were washed with brine, dried, and concentrated, and the crude material was purified by column chromatography (silica, 10% MeOH/dichloromethane) to afford the title compound (0.011 g, 33%) as a yellow solid. MS (APCI+) m/z 472 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][CH2:9][CH3:10])[CH:3]=1.C([Li])(CC)C.C([Li])CCC.[I:21]I>O1CCCC1>[F:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][CH3:10])[CH:5]=[CH:6][C:7]=1[I:21]
Reactant: II
Reactant: CCCc1cccc(F)c1
Agent: [Li]C(C)CC
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCc1ccc(I)c(F)c1
Temperature: -78 °C
Reaction time: 2 h
Yield: 75 %

Procedure:
1-Fluoro-3-propylbenzene (30 g, 0217 mol) and dry tetrahydrofurane (300 ml) were placed in 1 L flask equipped with mechanical stirrer, nitrogen inlet and outlet, 250 ml pressure-equilibrated dropping funnel and thermometer. The mixture was cooled down to −78° C. in a dry ice/acetone bath and 1.3 mol/L sec-butyllithium solution (170 ml, 0.221 mol) was added dropwise and the reaction temperature was kept below −70° C. After addition of all butyllithium solution the mixture was stirred for 2 hours at −78° C. and iodine (55.12 g, 0.217 mol) in dry tetrahydrofurane was added dropwise. Cooling bath was removed and heating to room temperature was allowed. The tetrahydrofurane was evaporated using rotary evaporator and the oily substance was washed off in separation funnel with sodium sulfite solution. Organic phase was separated dried over magnesium sulfate and filtered. The product was distilled under reduced pressure 0.4 mmHg, collecting the fraction of the transparent liquid boiling at 60° C. 43 g of 2-fluoro-1-iodo-4-propylbenzene was obtained, 75% of theor. yield.
Reaction SMILES: N[C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([N:11]2[CH2:15][CH2:14][CH2:13][C:12]2=[O:16])[CH:10]=1)[C:5]([OH:7])=[O:6].N([O-])=[O:18].[Na+]>O>[OH:18][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([N:11]2[CH2:15][CH2:14][CH2:13][C:12]2=[O:16])[CH:10]=1)[C:5]([OH:7])=[O:6]
Reactant: Nc1cc(C(=O)O)cc(N2CCCC2=O)c1
Reactant: O=N[O-]
Agent: [Na+]
Solvent: O
Product: O=C(O)c1cc(O)cc(N2CCCC2=O)c1
Temperature: 90 °C

Procedure:
To the solution of 1.33 g (6.0 mmol) 3-amino-5-(2-oxo-pyrrolidin-1-yl)-benzoic acid in 15 ml water and 0.75 ml (13.3 mmol, 2.2 eq) concentrated sulfuric at 0° C. are added 0.56 g (8.2 mmol, 1.35 eq) sodium nitrit. After addition of 10 ml water the reaction is heated to 90° C. After cooling to rt the reaction is extracted with EtOAc, the organic layer is dried over sodium sulfate and the solvent is evaporated at reduced pressure to give the product.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([S:14]([C:17]2[C:22]([Cl:23])=[CH:21][CH:20]=[C:19]([N+:24]([O-])=O)[C:18]=2[OH:27])(=[O:16])=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([S:14]([C:17]2[C:18]([OH:27])=[C:19]([CH:20]=[CH:21][C:22]=2[Cl:23])[NH2:24])(=[O:15])=[O:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCN(S(=O)(=O)c2c(Cl)ccc([N+](=O)[O-])c2O)CC1
Reactant: [H][H]
Agent: [Pd]
Product: CC(C)(C)OC(=O)N1CCN(S(=O)(=O)c2c(Cl)ccc(N)c2O)CC1
Yield: 92 %

Procedure:
Following the general hydrogenation procedure outlined in example 15, 1-[4-(tert-butoxycarbonyl)piperazin-1-yl]sulfonyl-6-chloro-2-hydroxy-3-nitrobenzene (256 mg, 0.61 mmol) was reduced with hydrogen and 10% Pd/C (120 mg) to form the desired product (220 mg, 93%). 1H NMR (MeOD-d4): δ 6.84 (m, 2H), 3.45 (m, 4H), 3.27 (m, 4H), 1.43 (s, 9H).
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH:15]=[CH:16][C:17](O)=[O:18].[CH:20]([NH:23][NH:24][C:25](=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)([CH3:22])[CH3:21].C(N(CC)CC)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>CN(C=O)C>[CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH:15]=[CH:16][C:17]([N:23]([CH:20]([CH3:22])[CH3:21])[NH:24][C:25](=[O:32])[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)=[O:18]
Reactant: CC(C)NNC(=O)c1ccccc1
Reactant: Cc1cccc(-c2ccccc2C=CC(=O)O)c1C
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1cccc(-c2ccccc2C=CC(=O)N(NC(=O)c2ccccc2)C(C)C)c1C
Yield: 18.2 %

Procedure:
A solution of 3-(2′,3′-dimethyl-biphenyl-2-yl)-acrylic acid (120 mg, 0.40 mmoles) and benzoic acid N′-isopropyl-hydrazide (71 mg, 0.40 mmoles) in DMF (4 mL) was treated with triethylamine (0.16 mL, 1.19 mmoles), HOBT (64 mg, 0.48 mmoles) and EDCI (91 mg, 0.48 mmol) at room temperature for 48 h. The reaction mixture was partitioned between 1N HCl and ethyl acetate. The organic layer was washed successively with water, 1N NaOH and brine, then dried over sodium sulfate, filtered and concentrated. The crude was absorbed on silica and purified on a silica gel column with a 20-50% ethyl acetate/hexanes gradient to afford the product as a solid (30 mg, 18%). LC-MS m/e 403.49(M+H+)
Reaction SMILES: [CH3:1][C:2]1[N:6]=[C:5]([CH3:7])[N:4]([C:8]2[CH:13]=[C:12]([CH:14]=[CH2:15])[N:11]=[C:10]([CH2:16][CH3:17])[N:9]=2)[N:3]=1.[N+](=[CH:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])=[N-]>C1(C)C=CC=CC=1>[CH2:24]([O:23][C:21]([C@@H:20]1[CH2:15][C@H:14]1[C:12]1[CH:13]=[C:8]([N:4]2[C:5]([CH3:7])=[N:6][C:2]([CH3:1])=[N:3]2)[N:9]=[C:10]([CH2:16][CH3:17])[N:11]=1)=[O:22])[CH3:25]
Reactant: C=Cc1cc(-n2nc(C)nc2C)nc(CC)n1
Reactant: CCOC(=O)C=[N+]=[N-]
Solvent: Cc1ccccc1
Product: CCOC(=O)[C@@H]1C[C@H]1c1cc(-n2nc(C)nc2C)nc(CC)n1

Procedure:
To a solution of 4-(3,5-dimethyl-1H-1,2,4-triazol-1-yl)-2-ethyl-6-vinylpyrimidine (19-3, 860 mg, 3.75 mmol, 1.0 eq.) in toluene (20 mL) at 120° C. was added ethyl diazoacetate (0.79 mL, 7.50 mmol, 2.0 eq.) dropwise and the resulting mixture was refluxed for 4 hours. Toluene was removed by roto-evaporation and the resulting residue was purified by silica gel column chromatography (0-50% ethyl acetate in hexanes) to afford ethyl-trans-2-(6-(3,5-dimethyl-1H-1,2,4-triazol-1-yl)-2-ethylpyrimidin-4-yl)cyclopropanecarboxylate (19-4) as a light yellow solid which was carried forward for next step without further purification. LRMS m/z (M+H) 316 found, 316 required.