Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)S(O[Si](C)(C)C)(=O)=O.[CH2:13]([C@@H:20]1[CH2:24][O:23][C:22](=[O:25])[N:21]1[C:26]([C@@H:28]1[CH2:33][CH2:32][C:31](=[O:34])[CH2:30][C@H:29]1[CH2:35][O:36][CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)=[O:27])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C[Si](C)(C)[O:46][CH2:47][CH2:48]O[Si](C)(C)C.C(N(CC)CC)C>C(Cl)Cl>[CH2:13]([C@@H:20]1[CH2:24][O:23][C:22](=[O:25])[N:21]1[C:26]([C@@H:28]1[CH2:33][CH2:32][C:31]2([O:46][CH2:47][CH2:48][O:34]2)[CH2:30][C@H:29]1[CH2:35][O:36][CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)=[O:27])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: C[Si](C)(C)OCCO[Si](C)(C)C
Reactant: O=C1CC[C@@H](C(=O)N2C(=O)OC[C@H]2Cc2ccccc2)[C@H](COCc2ccccc2)C1
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C1OC[C@@H](Cc2ccccc2)N1C(=O)[C@@H]1CCC2(C[C@H]1COCc1ccccc1)OCCO2
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Trimethylsilyl trifluoromethanesulfonate (2.5 mL) was added dropwise to a 0° C. solution of (4R)-4-benzyl-3-({(1R,2R)-2-[(benzyloxy)methyl]-4-oxocyclohexyl}carbonyl)-1,3-oxazolidin-2-one (57.89 g, 138 mmol) and 1,2-bis-(trimethylsilyloxy)ethane (35.4 g, 172 mmol) in CH2Cl2 (400 mL) followed by stirring at rt for 4 h. Triethylamine (3 mL) was then added at 0° C. and the mixture was washed with saturated aqueous NaHCO3 solution and dried over Na2SO4. Concentration in vacuo gave (4R)-4-benzyl-3-({(7R,8R)-7-[(benzyloxy)methyl]-1,4-dioxaspiro[4.5]dec-8-yl}carbonyl)-1,3-oxazolidin-2-one as a thick, tan colored syrup. 1H NMR (500 MHz, d6-acetone) δ 7.36-7.22 (10H, m), 4.48 (1H, m), 4.42 (2H, s), 4.11 (1H, dd, J= 3.1, 8.9 Hz), 3.97 (4H, m), 3.94-3.90 (1H, t, J= 9.0 Hz), 3.67 (1H, m), 3.44-3.38 (2H, m), 3.09 (1H, dd, J= 3.3, 13.5 Hz), 2.92 (1H, dd, J= 8.3, 13.5 Hz), 2.52 (1H, m), 1.97 (1H, m), 1.86-1.76 (3H, m), 1.57-1.50 (1H, m), 1.44 (1H, t, J= 12.8 Hz).
Reaction SMILES: [CH:1]1([Mg]Br)[CH2:3][CH2:2]1.[NH2:6][C:7]1[C:12]2=[C:13]([C:25]3[CH:30]=[CH:29][C:28]([NH:31][C:32]([NH:34][C:35]4[CH:40]=[C:39]([C:41]([F:44])([F:43])[F:42])[CH:38]=[CH:37][N:36]=4)=[O:33])=[CH:27][CH:26]=3)[C:14]([CH:23]=[O:24])=[C:15]([CH2:16][N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)[N:11]2[N:10]=[CH:9][N:8]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C1COCC1.CCOC(C)=O>[NH2:6][C:7]1[C:12]2=[C:13]([C:25]3[CH:26]=[CH:27][C:28]([NH:31][C:32]([NH:34][C:35]4[CH:40]=[C:39]([C:41]([F:43])([F:44])[F:42])[CH:38]=[CH:37][N:36]=4)=[O:33])=[CH:29][CH:30]=3)[C:14]([C:23]([CH:1]3[CH2:3][CH2:2]3)=[O:24])=[C:15]([CH2:16][N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)[N:11]2[N:10]=[CH:9][N:8]=1
Reactant: Nc1ncnn2c(CN3CCOCC3)c(C=O)c(-c3ccc(NC(=O)Nc4cc(C(F)(F)F)ccn4)cc3)c12
Reactant: Br[Mg]C1CC1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Nc1ncnn2c(CN3CCOCC3)c(C(=O)C3CC3)c(-c3ccc(NC(=O)Nc4cc(C(F)(F)F)ccn4)cc3)c12
Yield: 10.8 %

Procedure:
Cyclopropyl magnesium bromide (7.40 mL, 3.70 mmol, 0.5 M in diethyl ether) was added dropwise to a stirring solution of Example 85 (200 mg, 0.37 mmol) in THF (10 mL). This was allowed to stir until the reaction was complete by HPLC (1 hour). Additional amounts of the grinard reagent were added as needed. The reaction was quenched with methanol and was worked up by adding 1 volume of saturated NH4Cl solution and 5 volumes of EtOAc. The organic layer was washed 2× with NH4Cl and 1× with sodium carbonate soln. The organic layer was dried over Na2SO4 and concentrated. The crude intermediate was dissolved in DMSO (3 nth) and treated with Dess-Martin periodinane (174.7 mg, 0.412 mmol). The reaction was allowed to stir until the reaction was complete by HPLC (2 hours). The reaction was diluted with EtOAc (200 mL) and washed 2× with both saturated NaHCO3 and 2M sodium thiosulfate solution. The organic layer was dried over Na2SO4 and concentrated to give a crude solid which was purified by HPLC (10-70% ACN/H2O) to give 26.3 mg of the above compound (0.04 mmol, 12.3% yield). 1H-NMR (DMSO-d6). δ 9.98 (s, 1H), 9.82 (s, 1H), 8.60 (d, J=5.4 Hz, 1H), 8.11 (s, 1H), 8.03 (s, 1H), 7.69 (d, J=8.4 Hz, 2H), 7.45-7.41 (m, 3H), 4.08 (s, 2H), 3.55-3.52 (m, 4H), 2.46-2.43 (m, 4 H), 2.07-1.97 (m, 1H), 0.95-0.91 (m, 2H), 0.74-0.69 (m, 2H). MS [M+H]+=581; LCMS RT=2.68 min.
Reaction SMILES: Cl.[N:2]1([CH:7]2[CH2:22][C:11]3[C:12]4[NH:13][C:14](=[O:21])[C:15](=[O:20])[NH:16][C:17]=4[CH:18]=[CH:19][C:10]=3[CH2:9][CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3]1.[N+:23]([O-])([OH:25])=[O:24]>FC(F)(F)C(O)=O>[N+:23]([C:19]1[C:10]2[CH2:9][CH2:8][CH:7]([N:2]3[CH2:6][CH2:5][CH2:4][CH2:3]3)[CH2:22][C:11]=2[C:12]2[NH:13][C:14](=[O:21])[C:15](=[O:20])[NH:16][C:17]=2[CH:18]=1)([O-:25])=[O:24]
Reactant: O=c1[nH]c2ccc3c(c2[nH]c1=O)CC(N1CCCC1)CC3
Reactant: O=[N+]([O-])O
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Product: O=c1[nH]c2cc([N+](=O)[O-])c3c(c2[nH]c1=O)CC(N1CCCC1)CC3
Reaction time: 2 h

Procedure:
A mixture of 9-pyrrolidin-1-yl-1,4,7,8,9,10-hexahydrobenzo[f]quinoxaline-2,3-dione hydrochloride (35 mg) in trifluoroacetic acid (2 mL) was cooled in an ice bath and treated with 0.5 mL fuming nitric acid. After 2 h at room temperature, the solvent was evaporated and the residue suspended in acetone:water, and the resulting solid collected by filtration (35 mg). Calc'd for C16H18N4O4.HCl: C, 52.39; H, 5.22; H, 15.27; found: C, 42.95; H, 4.69; N, 16.28. MS M+1 (331).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[CH:14][CH:15]=3)[NH:10][CH:9]=2)[CH:5]=[C:4]([Cl:17])[N:3]=1.[C@@H:18]1([NH2:25])[CH2:23][CH2:22][CH2:21][CH2:20][C@H:19]1[NH2:24]>C(#N)C>[Cl:17][C:4]1[N:3]=[C:2]([NH:24][C@@H:19]2[CH2:20][CH2:21][CH2:22][CH2:23][C@H:18]2[NH2:25])[CH:7]=[C:6]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[CH:14][CH:15]=3)[NH:10][CH:9]=2)[CH:5]=1
Reactant: N[C@@H]1CCCC[C@H]1N
Reactant: Clc1cc(-c2c[nH]c3ncccc23)cc(Cl)n1
Solvent: CC#N
Product: N[C@@H]1CCCC[C@H]1Nc1cc(-c2c[nH]c3ncccc23)cc(Cl)n1

Procedure:
A mixture of Example 61a (3.4 g) in acetonitrile (30 mL) and trans-cyclohexane-1,2-diamine was heated at 170° C. for 40 minutes in a Biotage microwave reactor. The reaction mixture was extracted with ethyl acetate (2×), washed with brine and sodium bicarbonate. The combined organic layers were treated with 1M HCl. The aqueous layer was treated with NaOH (1M) and the material crashed out of the solution to give 0.797 mg of the title compound.
Reaction SMILES: C(N(CC)CC)C.[C:8]([O:15]C([O-])=O)([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=O.CN(C1C=CC=CN=1)C.[CH2:28]([CH:31]1[CH2:35][NH:34][C:33](=[O:36])[CH2:32]1)[CH2:29][CH3:30]>C(Cl)Cl>[O:36]=[C:33]1[CH2:32][CH:31]([CH2:28][CH2:29][CH3:30])[CH2:35][N:34]1[C:8]([O:10][C:11]([CH3:12])([CH3:13])[CH3:14])=[O:15]
Reactant: CCCC1CNC(=O)C1
Reactant: CC(C)(C)OC(=O)OC(=O)[O-]
Agent: CN(C)c1ccccn1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCC1CC(=O)N(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 12 h
Yield: 61.9 %

Procedure:
Triethylamine (81.4 ml, 10 mmol), tert-butyl dicarbonate (4.2 g, 19.2 mmol) and dimethylaminopyridine (1.18 g, 9.58 mmol) were added to a solution of 4-propyl-2-pyrrolidinone (1.22 g, 9.59 mmol) in methylene chloride (20 ml) and the mixture was stirred at room temperature for 12 hours. After distilling off the solvent under reduced pressure, the residue was purified by silica gel column chromatography (solvent: n-hexane-ethyl acetate) to yield the title compound (1.35 g) as a colorless oil. 1H-NMR (CDCl3) δ(ppm) 0.93 (3H, t, J=7.2 Hz), 1.28-1.50 (4H, m), 1.52 (9H, s), 2.14-2.32 (2H, m), 2.61 (1H, dd, J=15.0 Hz, 7.0 Hz), 3.30 (1H, dd, J=10.8 Hz, 7.2 Hz), 3.87 (1H, dd, J=10.8 Hz, 8.0 Hz)
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:30])[C:10](=[C:27]([CH3:29])[CH3:28])[N:11]1[C:14](=[O:15])[C:13]([Br:17])([Br:16])[CH:12]1S(C1C=C(C)ON=1)(N)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:31]N1C(=O)CCC1=O>C(Cl)(Cl)Cl>[CH2:1]([O:8][C:9](=[O:30])[C:10](=[C:27]([CH3:29])[CH3:28])[N:11]1[C:14](=[O:15])[C:13]([Br:17])([Br:16])[CH:12]1[Br:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)=C(C(=O)OCc1ccccc1)N1C(=O)C(Br)(Br)C1[SH](N)(=O)c1cc(C)on1
Solvent: ClC(Cl)Cl
Product: CC(C)=C(C(=O)OCc1ccccc1)N1C(=O)C(Br)(Br)C1Br
Temperature: 25 °C
Reaction time: 2 h
Yield: 61.5 %

Procedure:
3,3-dibromo-alpha-(1-methylethylidene)-2-[(5-methyl-isoxazole-3-yl)-aminosulfinyl]-4-oxo-1-azetidine acetic acid benzyl ester (5.61 g; 0.01 mole) was dissolved in chloroform (120 mL), N-bromosuccinimide (7.12 g; 0.04 mole) was added to the reaction mixture and it was stirred for two hours at room temperature. The reaction mixture was evaporated, methylene chloride and n-hexane were added to the dry residue, the precipitate was sucked off and the filtrate was evaporated to a dry residue. The obtained product was purified by flash chromatography with the solvent system petroleum ether-methylene chloride (1:1). There was obtained 2,3,3-tribromo-alpha-(1-methylethylidene)-4-oxo-1-azetidine acetic acid benzyl ester (3.05 g, 61.5%), which was subjected to a reaction with silver tetrafluoroborate in methanol analogously to the reaction described under 1a. After isolation 3,3-dibromo-2-methoxy-alpha-(1-methylethylidene)-4-oxo-1-azetidine acetic acid benzyl ester with spectroscopic data identical to those disclosed under 1a was obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][N:9]=[CH:10]2)=[CH:5][C:4]=1F.C(OC(=O)[NH:20][C@H:21]1[CH2:26][CH2:25][C@@H:24]([OH:27])[CH2:23][CH2:22]1)(C)(C)C>>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][N:9]=[CH:10]2)=[CH:5][C:4]=1[O:27][C@@H:24]1[CH2:25][CH2:26][C@H:21]([NH2:20])[CH2:22][CH2:23]1
Reactant: COc1cc2cnccc2cc1F
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](O)CC1
Product: COc1cc2cnccc2cc1O[C@H]1CC[C@@H](N)CC1

Procedure:
Starting from 7-methoxy-6-fluoro-isoquinoline (7) and cis-(4-hydroxy-cyclohexyl)-carbamic acid tert-butyl ester the title compound was prepared as trifluoroacetate by the method described for trans-[4-(5-chloro-isoquinolin-6-yloxy)-cyclohexyl]-carbamic acid tert-butyl ester (10) followed by deprotection using 4M hydrochloric acid in isopropanol and purification via preparative HPLC. Rt=0.62 min (Method #2). Detected mass: 273.19 (M+H+).
Reaction SMILES: [F:1][C:2]1[C:7]([CH:8]([CH3:10])[CH3:9])=[CH:6][C:5]([C:11]2[CH:19]=[C:18]3[C:14]([C:15](O)([CH3:20])[CH2:16][CH2:17]3)=[CH:13][C:12]=2[C:22]([O:24][CH3:25])=[O:23])=[C:4]([O:26][CH3:27])[CH:3]=1.CC1C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1.CCOC(C)=O>[F:1][C:2]1[C:7]([CH:8]([CH3:10])[CH3:9])=[CH:6][C:5]([C:11]2[CH:19]=[C:18]3[C:14]([C:15]([CH3:20])=[CH:16][CH2:17]3)=[CH:13][C:12]=2[C:22]([O:24][CH3:25])=[O:23])=[C:4]([O:26][CH3:27])[CH:3]=1
Reactant: COC(=O)c1cc2c(cc1-c1cc(C(C)C)c(F)cc1OC)CCC2(C)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: COC(=O)c1cc2c(cc1-c1cc(C(C)C)c(F)cc1OC)CC=C2C
Temperature: 80 °C

Procedure:
To a solution of methyl 6-(4-fluoro-5-isopropyl-2-methoxyphenyl)-3-hydroxy-3-methylindane-5-carboxylate (22.6 mg, 0.061 mmol) in toluene (1 mL) at room temperature was added TsOH (5.8 mg, 0.030 mmol). The reaction mixture was heated at 80° C. for 1.5 h. The reaction mixture was diluted with EtOAc. The organic layer was washed consecutively with sat. aq. NaHCO3 (1×) and brine (1×), dried (Na2SO4), filtered and concentrated in vacuo to give methyl 6-(4-fluoro-5-isopropyl-2-methoxyphenyl)-3-methyl-1H-indene-5-carboxylate. LCMS calc.=377.2; found=376.9 (M+Na)+. 1H NMR (500 MHz, CDCl3): δ 7.85 (s, 1H); 7.41 (s, 1H); 7.14 (d, J=8.7 Hz, 1H); 6.63 (d, J=12.1 Hz, 1H); 6.30 (t, J=1.5 Hz, 1H); 3.72 (s, 3H); 3.72 (s, 3H); 3.42 (d, J=1.5 Hz, 2H); 3.29-3.21 (m, 1H); 2.25 (s, 3H); 1.31 (d, J=6.9 Hz, 6H).
Reaction SMILES: [N:1]1([CH2:7][CH2:8][NH2:9])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Cl[C:11]1[N:16]=[CH:15][C:14]2[C:17](=[C:22]3[C:30]4[C:25](=[CH:26][CH:27]=[C:28]([F:31])[CH:29]=4)[NH:24][C:23]3=[O:32])[O:18][CH:19]([CH2:20][CH3:21])[C:13]=2[C:12]=1[Cl:33].O>O1CCOCC1>[Cl:33][C:12]1[C:13]2[CH:19]([CH2:20][CH3:21])[O:18][C:17](=[C:22]3[C:30]4[C:25](=[CH:26][CH:27]=[C:28]([F:31])[CH:29]=4)[NH:24][C:23]3=[O:32])[C:14]=2[CH:15]=[N:16][C:11]=1[NH:9][CH2:8][CH2:7][N:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: NCCN1CCOCC1
Reactant: CCC1OC(=C2C(=O)Nc3ccc(F)cc32)c2cnc(Cl)c(Cl)c21
Solvent: O
Solvent: C1COCCO1
Product: CCC1OC(=C2C(=O)Nc3ccc(F)cc32)c2cnc(NCCN3CCOCC3)c(Cl)c21
Temperature: 100 °C
Yield: 17.8 %

Procedure:
A solution of 2-morpholin-4-yl-ethylamine (178 mg, 1.37 mmol) in 3 mL of dioxane is treated with 3-(6,7-dichloro-1-ethyl-1H-furo[3,4-c]pyridin-3-ylidene)-5-fluoro-1,3-dihydro-indol-2-one (100 mg, 0.27 mmol) in one portion and the reaction mixture is heated to 100° C. for 12 hr. The reaction mixture is treated with 12 mL of water and then heated at reflux for 1 hr. The reaction mixture is cooled to room temperature and the precipitate which formed is collected by filtration and dried under vacuum to give the title compound as a yellow solid (22 mg, 18%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][NH:10][CH2:11][CH2:12][OH:13])[CH:6]=[CH:7][CH:8]=1.[C:14](Cl)(=[O:19])[C:15]([CH3:18])([CH3:17])[CH3:16].N1C=CC=CC=1>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][NH:10][CH2:11][CH2:12][O:13][C:14](=[O:19])[C:15]([CH3:18])([CH3:17])[CH3:16])[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(CNCCO)c1
Reactant: CC(C)(C)C(=O)Cl
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: COc1cccc(CNCCOC(=O)C(C)(C)C)c1
Temperature: 85 °C
Reaction time: 2 h

Procedure:
Next, in toluene (100 ml) were added 2-[(3-methoxyphenyl)methylamino]ethanol (8.1 g), pivaloyl chloride (10.8 g, 89.4 mmol), and pyridine (8.5 g, 107 mmol). The mixture was stirred at room temperature for 1 hour and further at 85° C. for 2 hours. After pyridine hydrochloride was removed by filtration, the filtrate was concentrated. The product was purified by silica gel chromatography to give 2,2-dimethylpropionic acid 2-[(3-methoxyphenyl)methylamino]ethyl ester as a colorless oily matter (yield: 10.4 g (78.4%)).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[N:10]=[C:11]([NH2:14])[NH:12][CH:13]=1.CC([O-])=O.[Na+].[Cl:20][C:21]1[CH:34]=[CH:33][C:24]([CH:25]=[C:26]([C:30](=O)[CH3:31])[C:27]([NH2:29])=[O:28])=[CH:23][C:22]=1[F:35]>C1COCC1.CO>[Cl:20][C:21]1[CH:34]=[CH:33][C:24]([CH:25]2[N:12]3[CH:13]=[C:9]([C:4]4[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=4[O:2][CH3:1])[N:10]=[C:11]3[NH:14][C:30]([CH3:31])=[C:26]2[C:27]([NH2:29])=[O:28])=[CH:23][C:22]=1[F:35]
Reactant: COc1ccccc1-c1c[nH]c(N)n1
Reactant: CC(=O)C(=Cc1ccc(Cl)c(F)c1)C(N)=O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccccc1-c1cn2c(n1)NC(C)=C(C(N)=O)C2c1ccc(Cl)c(F)c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 54.4 %

Procedure:
A mixture of 4-(2-methoxyphenyl)-1H-imidazol-2-amine (0.85 g, 4.5 mmol) and NaOAc (267.3 mg, 4.95 mmol) in THF (5 mL) and MeOH (1.5 mL) was stirred at room temperature for 20 min and followed by addition of 2-(4-chloro-3-fluorobenzylidene)-3-oxobutanamide (1.09 g, 4.5 mmol). The reaction mixture was then heated to 70° C. for 2 h and evaporated under reduced pressure. The residue was suspended in THF, and the slurry mixture was filtered to give 5-(4-chloro-3-fluorophenyl)-2-(2-methoxyphenyl)-7-methyl-5,8-dihydroimidazo[1,2-a]pyrimidine-6-carboxamide (1.01 g, 54.4%) as a yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[C:11]([C:19]([OH:21])=O)=[N:12][N:13]([CH3:18])[C:14](=[O:17])[C:15]=1[CH3:16].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[CH:43]([O:45][CH2:46][CH2:47][O:48][NH2:49])=[CH2:44]>CN(C=O)C.CCOC(C)=O>[F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[C:11]([C:19]([NH:49][O:48][CH2:47][CH2:46][O:45][CH:43]=[CH2:44])=[O:21])=[N:12][N:13]([CH3:18])[C:14](=[O:17])[C:15]=1[CH3:16]
Reactant: Cc1c(Nc2ccc(I)cc2F)c(C(=O)O)nn(C)c1=O
Reactant: C=COCCON
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C=COCCONC(=O)c1nn(C)c(=O)c(C)c1Nc1ccc(I)cc1F
Reaction time: 1.5 h

Procedure:
To a suspension of 4-(2-fluoro-4-iodophenylamino)-1,5-dimethyl-6-oxo-1,6-dihydropyridazine-3-carboxylic acid (41 mg, 0.10 mmol) and HOBt (28 mg, 0.21 mmol) in DMF (1.5 mL) was added EDCI (40 mg, 0.21 mmol) at room temperature. The resulting mixture was stirred for 1.5 hours. O-(2-Vinyloxy-ethyl)-hydroxylamine (21 mg, 0.20 mmol) and TEA (0.030 mL, 0.22 mmol) was added to the activated ester at room temperature. After stirring for 1.5 hours, the reaction mixture was diluted with EtOAc and washed with saturated aqueous NH4Cl, brine, saturated aqueous NaHCO3 (2×), and brine. The organic layer was separated, dried over MgSO4, filtered, and concentrated under reduced pressure to give 4-(2-fluoro-4-iodophenylamino)-1,5-dimethyl-6-oxo-N-(2-(vinyloxy)ethoxy)-1,6-dihydropyridazine-3-carboxamide that was used directly without further purification. The title compound was prepared by the procedure previously described in Example 1 (step J) using the crude 4-(2-fluoro-4-iodophenylamino)-1,5-dimethyl-6-oxo-N-(2-(vinyloxy)ethoxy)-1,6-dihydropyridazine-3-carboxamide (40% yield over two steps). MS APCI (−) m/z 461 (M−1) detected; 1H NMR (400 MHz, CD3OD) δ 7.52 (dd, 1H), 7.44 (d, 1H), 6.63 (t, 1H), 3.98 (t, 2H), 3.80 (s, 3H), 3.74 (t, 2H), 1.78 (s, 3H).
Reaction SMILES: C(O[CH2:5][C:6]1[N:7]([CH2:27][C:28]2[CH:33]=[CH:32][C:31]([C:34]([CH3:37])([CH3:36])[CH3:35])=[CH:30][CH:29]=2)[C:8]2[C:13]([C:14]=1[C:15](=[O:19])[C:16]([OH:18])=[O:17])=[CH:12][C:11]([C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([CH3:26])[CH:21]=1)=[CH:10][CH:9]=2)(=O)C.[OH-].[K+]>C1COCC1.CO>[C:34]([C:31]1[CH:30]=[CH:29][C:28]([CH2:27][N:7]2[C:8]3[C:13](=[CH:12][C:11]([C:20]4[CH:25]=[CH:24][CH:23]=[C:22]([CH3:26])[CH:21]=4)=[CH:10][CH:9]=3)[C:14]3[C:15](=[O:19])[C:16](=[O:18])[O:17][CH2:5][C:6]2=3)=[CH:33][CH:32]=1)([CH3:37])([CH3:35])[CH3:36]
Reactant: CC(=O)OCc1c(C(=O)C(=O)O)c2cc(-c3cccc(C)c3)ccc2n1Cc1ccc(C(C)(C)C)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cccc(-c2ccc3c(c2)c2c(n3Cc3ccc(C(C)(C)C)cc3)COC(=O)C2=O)c1

Procedure:
A solution of [2-[(acetyloxy)methyl]-1-(4-tert-butylbenzyl)-5-(3-methylphenyl)-1H-indol-3-yl](oxo)acetic acid (0.27 g, 0.63 mmol) and aqueous potassium hydroxide (1.0 N, 1.1 mL, 1.1 mmol) in THF:MeOH (1:1, 6.6 mL) was stirred at room temperature for 4 h. The reaction mixture was evaporated to dryness. The residue was washed with water and hexane to give an oil. This oil was partitioned between methylene chloride (80 mL) and 15% aqueous HCl (15 mL) with stirring. The organic layer was separated, washed with water and evaporated to afford the title compound as an off-white solid, mp: 196–197° C. Mass spectrum (ESI, [M+H]+) m/z 438. 1HNMR (400 MHz, DMSO-d6): δ 8.21 (s, 1H), 7.75 (d, 2H, J=8.55 Hz), 7.66 (dd, 1H, J=8.70 and 1.52 Hz), 7.50 (s, 1H), 7.47 (d, 1H, J=8.71 Hz), 7.38–7.35 (m, 3H), 7.20–7.17 (m, 3H), 5.92 (s, 2H), 5.50 (s, 2H), and 2.39 ppm (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:15][C:16]2[N:21]=[C:20](O)[CH:19]=[C:18]([CH3:23])[N:17]=2)[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]1.P(Cl)(Cl)([Cl:26])=O>>[Cl:26][C:20]1[CH:19]=[C:18]([CH3:23])[N:17]=[C:16]([NH:15][C:5]2[CH:6]=[CH:7][C:8]([N:9]3[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]3)=[C:3]([O:2][CH3:1])[CH:4]=2)[N:21]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1cc(Nc2nc(C)cc(O)n2)ccc1-n1cnc(C)c1
Product: COc1cc(Nc2nc(C)cc(Cl)n2)ccc1-n1cnc(C)c1
Yield: 100 %

Procedure:
A solution of 2-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenylamino]-6-methyl-pyrimidin-4-ol (1.45 g (46.6 mmol) in phosphorous oxychloride (4.7 mL) was heated to reflux for 2 h. The excess of phosphorous oxychloride was evaporated under reduce pressure and the residue was treated carefully with ice and then, under ice cooling, with 25% aqueous ammonia. The precipitate formed was filtered off, washed with water and then with diethyl ether and dried to give the title compound (1.53 g, 100%) as a pale-brown solid.
Reaction SMILES: Cl.Cl.[NH:3]1[CH2:8][CH2:7][CH2:6][CH:5]([NH:9][C:10]([NH:12][C:13]2[N:14]=[C:15]3[CH:21]=[CH:20][N:19]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[C:16]3=[N:17][CH:18]=2)=[O:11])[CH2:4]1.[CH3:30][CH:31]([CH3:37])[CH2:32][S:33](Cl)(=[O:35])=[O:34]>>[CH3:30][CH:31]([CH3:37])[CH2:32][S:33]([N:3]1[CH2:8][CH2:7][CH2:6][CH:5]([NH:9][C:10]([NH:12][C:13]2[N:14]=[C:15]3[CH:21]=[CH:20][N:19]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[C:16]3=[N:17][CH:18]=2)=[O:11])[CH2:4]1)(=[O:35])=[O:34]
Reactant: CC(C)CS(=O)(=O)Cl
Reactant: C[Si](C)(C)CCOCn1ccc2nc(NC(=O)NC3CCCNC3)cnc21
Agent: Cl
Product: CC(C)CS(=O)(=O)N1CCCC(NC(=O)Nc2cnc3c(ccn3COCC[Si](C)(C)C)n2)C1

Procedure:
1-[1-(2-M ethyl-propane-1-sulfonyl)-piperidin-3-yl]-3-[5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-urea was prepared in the same manner from 1-piperidin-3-yl-3-[5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-urea dihydrochloride and 2-methyl-propane-1-sulfonyl chloride.
Reaction SMILES: [N:1]#[C:2]Br.C(=O)([O-])[O-].[K+].[K+].[F:10][C:11]1[CH:19]=[C:18]2[C:14]([C:15]([N:26]3[CH2:31][CH2:30][N:29](C)[CH2:28][CH2:27]3)=[N:16][N:17]2[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:13][CH:12]=1.O>CS(C)=O>[F:10][C:11]1[CH:19]=[C:18]2[C:14]([C:15]([N:26]3[CH2:27][CH2:28][N:29]([C:2]#[N:1])[CH2:30][CH2:31]3)=[N:16][N:17]2[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)=[CH:13][CH:12]=1
Reactant: N#CBr
Reactant: CN1CCN(c2nn(-c3ccccc3)c3cc(F)ccc23)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: N#CN1CCN(c2nn(-c3ccccc3)c3cc(F)ccc23)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 47.4 %

Procedure:
To a stirred mixture of 1.6 g of cyanogen bromide, 2.1 g of potassium carbonate and 30 ml of dimethyl sulfoxide was added, dropwise, a solution of 4.8 g of 6-fluoro-3-(4-methyl-1-piperazinyl)-1-phenyl-1H-indazole in 30 ml of dimethylsulfoxide. The reaction mixture was stirred at ambient temperature for 2 hours and then poured into water. The resulting precipitate was recrystallized from ethanol to yield 2.3 g (48%) of 4-(6-fluoro-1-phenyl-1H-indazol-3-yl)-1-piperazine carbonitrile, m.p. 172°-174°.
Reaction SMILES: [CH:1]1([C:6]2([CH2:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([OH:22])=[C:18]([CH2:23][CH3:24])[CH:17]=3)[O:11][C:10](=[O:12])[CH2:9][C:8](=[O:13])[CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:25][C:26]1[CH:31]=[C:30]([CH3:32])[N:29]2[N:33]=[C:34]([CH:36]=O)[N:35]=[C:28]2[N:27]=1>>[CH:1]1([C:6]2([CH2:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([OH:22])=[C:18]([CH2:23][CH3:24])[CH:17]=3)[O:11][C:10](=[O:12])[C:9]([CH2:36][C:34]3[N:35]=[C:28]4[N:27]=[C:26]([CH3:25])[CH:31]=[C:30]([CH3:32])[N:29]4[N:33]=3)=[C:8]([OH:13])[CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCc1cc(CCC2(C3CCCC3)CC(=O)CC(=O)O2)ccc1O
Reactant: Cc1cc(C)n2nc(C=O)nc2n1
Product: CCc1cc(CCC2(C3CCCC3)CC(O)=C(Cc3nc4nc(C)cc(C)n4n3)C(=O)O2)ccc1O

Procedure:
The title compound was prepared by coupling 6-Cyclopentyl-6-[2-(3-ethyl-4-hydroxy-phenyl)-ethyl]-dihydro-pyran-2,4-dione (from Example A(22)) to 5,7-Dimethyl-[1,2,4]triazolo[1,5-α]pyrimidine-2-carbaldehyde using the Me2NHBH3 method described in the synthesis of Example B(31).
Reaction SMILES: C[N:2](C)[CH:3]=[CH:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][C:8]=1[N+:17]([O-:19])=[O:18])=[O:6].Cl.N[OH:23]>C(O)C>[OH:6][C:5]1([C:7]2[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][C:8]=2[N+:17]([O-:19])=[O:18])[O:23][N:2]=[CH:3][CH2:4]1
Reactant: NO
Reactant: CN(C)C=CC(=O)c1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Agent: Cl
Solvent: CCO
Product: O=[N+]([O-])c1cc(C(F)(F)F)ccc1C1(O)CC=NO1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.3 %

Procedure:
A mixture of 3-dimethylamino-1-(2-nitro-4-trifluoromethylphenyl)-prop-2-en-1-one (41.0 g) and hydroxylamine hydrochloride (11.9 g) in dry ethanol (280 ml) was stirred at room temperature overnight. It was evaporated to dryness and the residue was dissolved in a mixture of ether (150 ml) and water (100 ml). The layers were separated and the organic layer was washed with water (100 ml), dried (anhydrous sodium sulphate) and filtered. The filtrate was evaporated to dryness and the residue was triturated with petroleum spirit (bp 60°-80° C.) (20 ml) and filtered to give 5-hydroxy-5-(2-nitro-4-trifluoromethylphenyl)-isoxazoline (33.9 g) as a pale yellow solid mp 122°-123° C.