Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(Cl)Cl.[C:4]([C:8]1[C:9]([CH3:31])([CH3:30])[CH2:10][O:11][C:12]=1[C:13]1[O:14][C:15]2[CH:21]=[CH:20][C:19]([O:22][Si:23]([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24])=[CH:18][C:16]=2[CH:17]=1)([CH3:7])([CH3:6])[CH3:5].[Na].[O:33]=[O:34]>>[C:4]([C:8]12[O:34][O:33][C:12]1([C:13]1[O:14][C:15]3[CH:21]=[CH:20][C:19]([O:22][Si:23]([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:24])[CH3:25])=[CH:18][C:16]=3[CH:17]=1)[O:11][CH2:10][C:9]2([CH3:31])[CH3:30])([CH3:7])([CH3:5])[CH3:6]
Reactant: O=O
Reactant: CC(C)(C)C1=C(c2cc3cc(O[Si](C)(C)C(C)(C)C)ccc3o2)OCC1(C)C
Agent: [Na]
Solvent: ClCCl
Product: CC(C)(C)C12OOC1(c1cc3cc(O[Si](C)(C)C(C)(C)C)ccc3o1)OCC2(C)C
Yield: 85 %

Procedure:
Adding 1 mg of TPP to 4 ml of methylene chloride dissolving 132 mg (0.286 mmol) of 4-t-butyl-5-(5-(t-butyldimethylsiloxy)benzofuran-2-yl)-3,3-dimethyl-2,3-dihydrofuran (Compound [18]), the mixture was stirred in oxygen atmosphere, at the temperature of −78° C. This solution was externally irritated with a 940 W sodium lamp for 4 hours. The reaction mixture was concentrated and fractionated with aliquot thin layer chromatography using the mixture of hexane and ethyl acetate (hexane:ethyl acetate=7:1) to obtain 114 mg of 5-t-butyl-1-(5-(t-butyldimethylsiloxy)benzofuran-2-yl)-4,4-dimethyl-2,6,7-trioxabicyclo[3.2.0]heptane (Compound [19]) as a white solid. Yield 85.0%.
Reaction SMILES: [CH:1]1[C:6]([NH2:7])=[CH:5][C:4]2[C:8]([O:10][C:11]3([C:21]4[CH:22]=[CH:23][C:24]([OH:26])=[CH:25][C:20]=4[O:19][C:13]4[CH:14]=[C:15]([OH:18])[CH:16]=[CH:17][C:12]3=4)[C:3]=2[CH:2]=1)=[O:9].[C:27]1(=[O:37])[O:32][C:30](=[O:31])[C:29]2=[CH:33][CH:34]=[CH:35][CH:36]=[C:28]12>C(O)(=O)C>[CH:1]1[CH:6]=[CH:5][C:4]([C:8]([OH:10])=[O:9])=[C:3]([C:11]2[C:12]3[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][C:13]=3[O:19][C:20]3[C:21]=2[CH:22]=[CH:23][C:24]([CH:25]=3)=[O:26])[CH:2]=1.[C:27]([OH:32])(=[O:37])[C:28]1[C:29](=[CH:33][CH:34]=[CH:35][CH:36]=1)[C:30]([NH2:7])=[O:31]
Reactant: Nc1ccc2c(c1)C(=O)OC21c2ccc(O)cc2Oc2cc(O)ccc21
Reactant: O=C1OC(=O)c2ccccc21
Solvent: CC(=O)O
Product: NC(=O)c1ccccc1C(=O)O
Product: O=C(O)c1ccccc1-c1c2ccc(=O)cc-2oc2cc(O)ccc12
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of 350 mg (0.001 mol) of 5-aminofluorescein and 200 mg of phthalic anhydride in 5 milliliters of glacial acetic acid was stirred at ambient temperature for 48 hours. The yellow reddish product was filtered and washed once with acetic acid and twice with diethyl ether. 460 Mg of fluorescein-phthalamic acid was obtained. I.R (KBR) showed bands at 3060; 3000; 1685; 1590; 1540; 1480; 1430; 1350; 1310; 1270; 1230; 1195; 1150; and 1115 cm-1.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][NH:5][N:6]1[C:18]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]=[C:10]([NH2:19])[C:9]=2[N:8]=[C:7]1[CH2:20][O:21][CH2:22][CH3:23].[CH2:24]([N:26]=[C:27]=[O:28])[CH3:25]>C(Cl)Cl>[NH2:19][C:10]1[C:9]2[N:8]=[C:7]([CH2:20][O:21][CH2:22][CH3:23])[N:6]([NH:5][CH2:4][CH2:3][CH2:2][NH:1][C:27]([NH:26][CH2:24][CH3:25])=[O:28])[C:18]=2[C:17]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N:11]=1
Reactant: CCN=C=O
Reactant: CCOCc1nc2c(N)nc3ccccc3c2n1NCCCN
Solvent: ClCCl
Product: CCNC(=O)NCCCNn1c(COCC)nc2c(N)nc3ccccc3c21
Temperature: 25 °C
Reaction time: 17 h
Yield: 66.6 %

Procedure:
A solution of N1-(3-aminopropyl)-2-ethoxymethyl-1H-imidazo[4,5-c]quinoline-1,4-diamine (1.42 g, 4.52 mmol) in 25 mL of CH2Cl2 was placed under an atmosphere of nitrogen and chilled in an ice water bath. The solution was slowly treated with ethyl isocyanate (0.375 mL, 4.74 mmol). Upon addition the reaction mixture became thick and additional CH2Cl2 had to be added to keep the mixture stirring. The reaction was allowed to slowly warm to ambient temperature. After 17 h, the reaction was concentrated under reduced pressure to yield an off-white solid. The solid was purified by chromatography (SiO2, 15–50% (80:18:2 CHCl3:MeOH:NH4OH) in CHCl3) to yield an off-white solid. The solid was recrystallized from MeCN to give 1-(3-{[4-amino-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]amino}propyl)-3-ethylurea (1.16 g) as a white solid. mp 138–141° C.; 1H NMR (300 MHz, DMSO-d6) δ 8.45 (dd, J=8.1, 1.0 Hz, 1H), 7.58 (dd, J=8.3, 0.9 Hz, 1H), 7.46–7.41 (m, 1H), 7.27–7.21 (m, 1H), 6.96 (t, J=5.6 Hz, 1H), 6.60 (s, 2H), 5.83 (t, J=5.7 Hz, 1H), 5.73 (t, J=5.5 Hz, 1H), 4.75 (s, 2H), 3.61 (q, J=7.0 Hz, 2H), 3.20–3.08 (m, 4H), 3.03–2.94 (m, 2H), 1.68 (p, J=6.9 Hz, 2H), 1.17 (t, J=7.0 Hz, 3H), 0.96 (t, J=7.1 Hz, 3H); 13C NMR (125 MHz, DMSO-d6) δ 158.4, 152.3, 149.5, 145.3, 132.4, 127.4, 126.1, 124.2, 121.3, 121.2, 114.8, 65.9, 63.1, 50.2, 37.6, 34.4, 28.9, 16.0, 15.4; MS (ESI) m/z 386 (M+H)+; Anal. Calcd for C19H27N7O2•0.5H2O: C, 57.85; H, 7.15; N, 24.85; Found: C, 57.84; H, 7.31; N, 25.04.
Reaction SMILES: [C:1]([C:9]1[N:14]=[C:13]([CH2:15][OH:16])[CH:12]=[CH:11][CH:10]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([CH:24]=[CH:25][CH:26]([CH:30]([CH3:32])[CH3:31])[C:27](O)=[O:28])=[CH:20][CH:19]=1.[F:33][C:34]1[CH:39]=[CH:38][C:37]([CH:40]=[CH:41][CH:42]([CH:46]([CH3:48])[CH3:47])[C:43]([OH:45])=[O:44])=[CH:36][CH:35]=1>>[Cl:17][C:18]1[CH:19]=[CH:20][C:21]([CH:24]=[CH:25][CH:26]([CH:30]([CH3:32])[CH3:31])[C:27]([O:16][CH2:15][C:13]2[CH:12]=[CH:11][CH:10]=[C:9]([C:1](=[O:8])[C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[N:14]=2)=[O:28])=[CH:22][CH:23]=1.[F:33][C:34]1[CH:35]=[CH:36][C:37]([CH:40]=[CH:41][CH:42]([CH:46]([CH3:48])[CH3:47])[C:43]([O:45][CH2:15][C:13]2[CH:12]=[CH:11][CH:10]=[C:9]([C:1](=[O:8])[C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[N:14]=2)=[O:44])=[CH:38][CH:39]=1
Reactant: O=C(c1ccccc1)c1cccc(CO)n1
Reactant: CC(C)C(C=Cc1ccc(F)cc1)C(=O)O
Reactant: CC(C)C(C=Cc1ccc(Cl)cc1)C(=O)O
Product: CC(C)C(C=Cc1ccc(Cl)cc1)C(=O)OCc1cccc(C(=O)c2ccccc2)n1
Product: CC(C)C(C=Cc1ccc(F)cc1)C(=O)OCc1cccc(C(=O)c2ccccc2)n1

Procedure:
The compounds (6-benzoyl-2-pyridyl)methanol is reacted with 4-(4-chlorophenyl)-2-isopropyl-3-butenoic acid or 4-(4-fluorophenyl)-2-isopropyl-3-butenoic acid, following the procedure of Example 3, to give (6-benzoyl-2-pyridyl)methyl 4-(4-chlorophenyl)-2-isopropyl-3-butenoate or (6-benzoyl-2-pyridyl)methyl 4-(4-fluorophenyl)-2-isopropyl-3-butenoate. (6-Benzoyl-2-pyridyl)methanol is prepared as described in my application Ser. No. 069,446, filed on or about Aug. 24, 1979.
Reaction SMILES: [C:1]1(=[O:15])[C:10]2[C:5]3[C:6](=[CH:11][CH:12]=[CH:13][C:4]=3[C:3](=[O:14])[NH:2]1)[CH:7]=[CH:8][CH:9]=2.[Br:16][CH2:17][CH:18](Br)[CH3:19]>>[Br:16][CH2:17][CH2:18][CH2:19][N:2]1[C:3](=[O:14])[C:4]2[CH:13]=[CH:12][CH:11]=[C:6]3[C:5]=2[C:10](=[CH:9][CH:8]=[CH:7]3)[C:1]1=[O:15]
Reactant: CC(Br)CBr
Reactant: O=C1NC(=O)c2cccc3cccc1c23
Product: O=C1c2cccc3cccc(c23)C(=O)N1CCCBr

Procedure:
This compound was prepared according to GP-1 using benzo[de]isoquinoline-1,3-dione (1) and 1,2 dibromopropane (2a) The crude product was purified by flash column chromatography using EtOAc-hexane to provide 3a. 1H NMR (500 MHz, CDCl3) δ 8.62 (d, J=7.0 Hz 2H), 8.23 (d, J=8.0 Hz, 2H), 7.77 (t, J=7.5 Hz, 2H), 4.34 (t, J=7.5, 2H), 3.51 (t, J=7.0 Hz, 2H), 2.37-2.32 (m, 2H). MS (ES+) m/z 340 (M+Na)+.
Reaction SMILES: N[C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.N([O-])=O.[Na+].[F:16][B-](F)(F)F.[H+]>O>[F:16][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2
Reactant: F[B-](F)(F)F
Reactant: Nc1cnc2ccccc2c1
Agent: O=N[O-]
Agent: [H+]
Agent: [Na+]
Solvent: O
Product: Fc1cnc2ccccc2c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
23.5 g of 3-aminoquinoline and 12.1 g of sodium nitrite in 20 cm3 of distilled water were added cautiously to 100 cm3 of tetrafluoroboric acid cooled to about 0° C., with vigorous stirring, and the reaction mixture was thus stirred for 30 minutes. The suspension was filtered, spin-filtered, washed with 3 times 30 cm3 of ice-cold tetrafluoroboric acid, 50 cm3 of ice-cold ethanol and 4 times 30 cm3 of diethyl ether. The solid was dried in a desiccator (2 kPa) in the region of 20° C. and then taken up in 200 cm3 of toluene and heated at a temperature in the region of 90° C. for 1 hour with stirring. After cooling to about 20° C., the phases of the reaction mass were separated by settling and the insoluble oil was washed with 3 times 100 cm3 of toluene and taken up in 110 cm3 of water, which was basified by slow addition of sodium hydrogen carbonate so that the pH was at about 8. The aqueous phase was extracted with 5 times 100 cm3 of diethyl ether and the organic phases were combined, washed with twice 50 cm3 of water, dried over magnesium sulfate and taken up with vegetable charcoal (3S), filtered and concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 45° C. The oil was taken up in 50 cm3 of a 40-60° C. petroleum ether/ethyl acetate mixture (90/10 by volume) and the insoluble material was filtered off, rinsed with twice 25 cm3 of a 40-60° C. petroleum ether/ethyl acetate mixture (90/10 by volume) and dried in a desiccator under reduced pressure (2 kPa) at a temperature in the region of 20° C. The filtrate was concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40° C. The residue obtained was purified by chromatography under atmospheric pressure, on a column of silica gel (particle size 20-45μ; diameter 5 cm; height 45 cm), eluting with a 40-60° C. petroleum ether/ethyl acetate mixture (90/10 by volume) and collecting 100-cm3 fractions. Fractions 20 to 31 were combined and then concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40° C. 13 g of 3-fluoroquinoline were obtained in the form of a colorless liquid.
Reaction SMILES: [C:1]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][C:8]1[NH:9][C:10](=[O:19])[C:11]([OH:18])=[C:12]([C:14](OC)=[O:15])[N:13]=1.[CH2:26]([NH2:34])[CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[CH2:26]([NH:34][C:14]([C:12]1[N:13]=[C:8]([CH2:7][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=2[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[NH:9][C:10](=[O:19])[C:11]=1[OH:18])=[O:15])[CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: COC(=O)c1nc(Cc2ccccc2-c2ccccc2)[nH]c(=O)c1O
Reactant: NCCc1ccccc1
Product: O=C(NCCc1ccccc1)c1nc(Cc2ccccc2-c2ccccc2)[nH]c(=O)c1O
Yield: 42.6 %

Procedure:
The synthesis was performed as in Example 21 using methyl 2-(biphenyl-2-ylmethyl)-5-hydroxy-6-oxo-1,6-dihydropyrimidine-4-carboxylate (0.10 g, 298 μmol) and phenethylamine (0.5 ml; 3.98 mmol) to provide the title compound as an off-white solid (0.054 g; 42%). LCMS: m/z=425 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][NH:21][CH2:22][C:23]([O:25]CC)=[O:24])=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:35].[OH-].[Li+].Cl>CN(C=O)C>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:28]([O:30][C:31]([CH3:33])([CH3:32])[CH3:34])=[O:29])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][NH:21][CH2:22][C:23]([OH:25])=[O:24])=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:35]
Reactant: CCOC(=O)CNCc1ccc2c(c1)cc(-c1ccc(Cl)c3c1C(=O)NC3)n2C(=O)OC(C)(C)C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)n1c(-c2ccc(Cl)c3c2C(=O)NC3)cc2cc(CNCC(=O)O)ccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 61 %

Procedure:
4-Chloro-7-[1-(tert-butoxycarbonyl)-5-(ethoxycarbonylmethylaminomethyl)indol-2-yl]isoindolinone (43.4 mg) was dissolved in DMF (2 mL), and the solution was added with 4 mol/L aqueous lithium hydroxide solution (1 mL), followed by stirring at room temperature for 1 hour. The reaction mixture was added with 1 mol/L hydrochloric acid, extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to obtain 4-chloro-7-[1-(tert-butoxycarbonyl)-5-(carboxymethylaminomethyl)indol-2-yl]isoindolinone (25.0 mg).
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[NH:6][C:5](=[O:7])[NH:4][C:3]1=[O:8].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19]>CN(C=O)C>[CH3:1][C:2]1([CH3:9])[C:3](=[O:8])[N:4]([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:5](=[O:7])[NH:6]1
Reactant: CCOC(=O)CBr
Reactant: CC1(C)NC(=O)NC1=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)CN1C(=O)NC(C)(C)C1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 32.7 %

Procedure:
A solution of 5,5-dimethylhydantoin (10 g, 78 mmol) in DMF (400 mL) was treated with cesium carbonate (25 g, 78 mmol) stirred at r.t. for 30 min then treated with ethyl bromoacetate (11.3 mL, 102 mmol) and allowed to stir overnight. The reaction mixture was partitioned between ethyl acetate and a 1 to 1 mixture of brine and water. The organics were washed with brine, dried (Na2SO4), filtered, concentrated and purified via silica gel column chromatography eluting with 30 to 50% ethyl acetate/hexane to give 5.47 g of the title compound as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[NH:8][C:7](=[O:9])[C@H:6]1[CH2:10][CH2:11][CH2:12][NH:13][C:14]([NH:26][C:27]([O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:28])=[N:15][C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17])=[O:4].C(N(CC)CC)C.[CH3:44][S:45](Cl)(=[O:47])=[O:46]>C(Cl)Cl>[CH3:1][O:2][C:3]([C@@H:5]1[N:8]([S:45]([CH3:44])(=[O:47])=[O:46])[C:7](=[O:9])[C@H:6]1[CH2:10][CH2:11][CH2:12][NH:13][C:14]([NH:26][C:27]([O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:28])=[N:15][C:16]([O:18][CH2:19][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)=[O:17])=[O:4]
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)[C@@H]1NC(=O)[C@H]1CCCNC(=NC(=O)OCc1ccccc1)NC(=O)OCc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)[C@H]1[C@H](CCCNC(=NC(=O)OCc2ccccc2)NC(=O)OCc2ccccc2)C(=O)N1S(C)(=O)=O
Yield: 37 %

Procedure:
To a vigorously stirred methylene chloride (10 mL) solution of compound 7 (0.8 g, 1.6 mmol) and triethylamine (4.86 g, 48 mmol ) was added methanesulfonyl chloride (5.52 g, 48 mmol) dropwise. The reaction mixture was diluted with additional CH2Cl2 and washed with pH 7.0 aqueous buffer. The organic phase was dried (Na2SO4) and concentrated. The residue was purified by silica gel chromatography (CH2Cl2 : MeOH/99:1) to afford 340 mg (37%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:20])=[C:6]([C:8]2[CH:9]=[N:10][N:11](C(OC(C)(C)C)=O)[CH:12]=2)[CH:7]=1.[C:21]([C:23]1[CH:24]=[C:25]([S:30]([NH:33][C:34]2[S:35][CH:36]=[CH:37][N:38]=2)(=[O:32])=[O:31])[CH:26]=[CH:27][C:28]=1F)#[N:22].C(=O)([O-])[O-].[K+].[K+].Cl>CS(C)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:20][C:28]2[CH:27]=[CH:26][C:25]([S:30]([NH:33][C:34]3[S:35][CH:36]=[CH:37][N:38]=3)(=[O:31])=[O:32])=[CH:24][C:23]=2[C:21]#[N:22])=[C:6]([C:8]2[CH:12]=[N:11][NH:10][CH:9]=2)[CH:7]=1
Reactant: N#Cc1cc(S(=O)(=O)Nc2nccs2)ccc1F
Reactant: CC(C)(C)OC(=O)n1cc(-c2cc(Cl)ccc2O)cn1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: N#Cc1cc(S(=O)(=O)Nc2nccs2)ccc1Oc1ccc(Cl)cc1-c1cn[nH]c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
tert-Butyl 4-(5-chloro-2-hydroxyphenyl)-1H-pyrazole-1-carboxylate (Preparation 205, 624 mg, 2.12 mmol), 3-cyano-4-fluoro-N-1,3-thiazol-2-ylbenzenesulfonamide (Preparation 46, 500 mg, 1.76 mmol) and potassium carbonate (732 mg, 5.30 mmol) were stirred in dimethyl sulphoxide (10 ml) at 50° C. for 2 hours. The reaction was cooled to room temperature and the mixture poured dropwise into hydrochloric acid (2M aqueous, 100 ml). The mixture was stirred at room temperature for 18 hours. The precipitate was filtered and suspended in methanol (10 ml). The mixture was treated with hydrogen chloride (4M in dioxane, 2 ml). The mixture was then stirred at room temperature over for 60 hours. The mixture was evaporated in vacuo. The residue was dissolved in methanol (5 ml). The black solution was passed through an ISOLUTE™ SCX cartridge. The cartridge was eluted with methanol (100 ml) followed by ammonia (2M in methanol). The dark ammonia solution was evaporated in vacuo. The residue was dissolved in dichloromethane/methanol (95/5, 5 ml) and passed through a pad of silica. The solution was evaporated in vacuo. The residue was purified using a silica gel column chromatography eluting with dichloromethane:ethyl acetate (gradient 1:0 to 1:9, by volume). Concentration in vacuo afforded the title compound as a white solid. Yield 427 mg, 53%
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[C:3]1[CH:4]=[C:5]([C:13]([CH3:27])([CH3:26])[C:14]([N:16]([C:18]2[CH:19]=[N:20][C:21]([Cl:25])=[CH:22][C:23]=2I)[CH3:17])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[CH3:30][C:31]1[CH:36]=[CH:35][N:34]=[CH:33][C:32]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:1][C:2]([F:29])([F:28])[C:3]1[CH:4]=[C:5]([C:13]([CH3:27])([CH3:26])[C:14]([N:16]([C:18]2[CH:19]=[N:20][C:21]([Cl:25])=[CH:22][C:23]=2[C:32]2[CH:33]=[N:34][CH:35]=[CH:36][C:31]=2[CH3:30])[CH3:17])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: Cc1ccncc1B(O)O
Reactant: CN(C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cnc(Cl)cc1I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: Cc1ccncc1-c1cc(Cl)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 110 °C
Yield: 83 %

Procedure:
2-[3,5-bis(trifluoromethyl)phenyl]-N-(6-chloro-4-iodo-3-pyridinyl)-N,2-dimethylpropanamide (400 mg, 0.726 mmol), 4-methylpyridine-3 boronic acid (130 mg, 0.944 mmol), sodium carbonate (0.8 mL, 2M), tetrakistriphenylphosphine palladium (7.8 mg, 0.00726 mmol) was added in dioxane (4 mL) and stirred under argon before heating in the microwave at 110° C. for 30 minutes., added more 4-methylpyridine-3 boronic acid (67.5 mg, 0.49 mmol) and tetrakistriphenylphosphinepalladium (7.8 mg, 0.00726 mmol) and heated at 110° C. for 30 minutes. therefore added more 4-methylpyridine-3 boronic acid (51 mg, 037 mmol), tetrakistriphenylphosphinepalladium (7.8 mg, 0.00726 mmol) and heated under microwave conditions at 110° C. for 30 minutes., therefore added 4-methylpyridine-3 boronic acid (47 mg, 0.34 mmol), tetrakistriphenylphosphinepalladium (7.8 mg, 0.00726 mmol) and heated at 110° C. for 30 minutes. Residue partitioned between EtOAc and Brine. Aqueous layer was extracted with EtOAc ×3. Combined extracts were dried and solvent evaporated. Residue purified on a 12+M horizon column eluting with Pet Ether to 1:1 EtOAc: Pet Ether. Unable to isolate clean fractions. Sample sent to be purified by Mass Directed Auto-Prep (MDAP) chromatography, white solid didn't dissolve was found to be desired material. This was combined with product isolated from the MDAP to afford the title compound as a white solid in an 83% yield.
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([CH:8]2[CH2:10][CH2:9]2)[NH:5][C:6]=1[Br:7].[H-].[Na+].[CH3:13][Si:14]([CH3:21])([CH3:20])[CH2:15][CH2:16][O:17][CH2:18]Cl>C1COCC1>[Br:1][C:2]1[N:3]=[C:4]([CH:8]2[CH2:10][CH2:9]2)[N:5]([CH2:18][O:17][CH2:16][CH2:15][Si:14]([CH3:21])([CH3:20])[CH3:13])[C:6]=1[Br:7]
Reactant: C[Si](C)(C)CCOCCl
Reactant: Brc1nc(C2CC2)[nH]c1Br
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCn1c(C2CC2)nc(Br)c1Br
Reaction time: 0.5 h
Yield: 88.1 %

Procedure:
A solution of 4,5-dibromo-2-cyclopropyl-1H-imidazole (60 g, 226 mmol) in THF (150 mL) was added dropwise over 50 minutes under nitrogen to a stirring mixture of sodium hydride (95%, 6.3 g, 250 mmol) in dry THF (150 mL) at 0° C. The reaction mixture was stirred 30 minutes and 2-(trimethylsilyl)ethoxymethylchloride (SEMCl, 40 mL, 38 g, 226 mmol) was added dropwise over 50 minutes at 0° C. After stirring for 1 hour, the reaction was slowly quenched with water (20 mL) and added EtOAc (500 mL). The mixture was washed with water (2×750 mL) and the combined aqueous portions were back extracted with EtOAc (200 mL). The combined organic portions were washed with brine (1 L), dried (Na2SO4), and concentrated. The resulting residue was dissolved in heptane (200 mL) and the resulting solution was passed through a pad of silica gel, eluting with heptane (4×500 mL) and EtOAc-heptane (1:4, 2×250 mL) to give 4,5-dibromo-2-cyclopropyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole (79 g, 199 mmol, 88%) as a pale yellow solid after concentration: LCMS(m/z) 394.9 (MH+), tR=1.20 minutes, 1H NMR (400 MHz, CDCl3) δ ppm-0.04-0.05 (m, 9H), 0.87-1.12 (m, 6H), 1.88-2.04 (m, 1H), 3.55-3.66 (m, 2H), 5.37 (s, 2H).
Reaction SMILES: C([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]3[N:26]=[C:25]([CH3:27])[CH:24]=[C:23]([C:28]4[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][CH:29]=4)[N:22]=3)[N:16]=2)[CH:10]=1)(=[O:8])=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O>>[CH3:27][C:25]1[CH:24]=[C:23]([C:28]2[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:35])[F:36])=[CH:30][CH:29]=2)[N:22]=[C:21]([C:17]2[N:16]=[C:15]([C:11]3[CH:10]=[C:9]([S:6]([NH2:5])(=[O:8])=[O:7])[CH:14]=[CH:13][CH:12]=3)[CH:20]=[CH:19][CH:18]=2)[N:26]=1
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)nc(-c2cccc(-c3cccc(S(=O)(=O)NC(C)(C)C)c3)n2)n1
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)nc(-c2cccc(-c3cccc(S(N)(=O)=O)c3)n2)n1
Temperature: 23 °C
Reaction time: 3 h
Yield: 99.8 %

Procedure:
To N-tert-butyl-3-{6-[4-methyl-6-(4-trifluoromethyl-phenyl)-pyrimidin-2-yl]-pyridin-2-yl}-benzenesulfonamide (Example 418) (0.250 g, 0.475 mmol) was added TFA (3 mL) and the reaction mixture was stirred at 23° C. for 3 h. The mixture was partitioned between EtOAc and saturated NaHCO3 solution, the organic layer was dried over MgSO4. Removal of the solvent in vacuum left a crude product which was triturated with diethyl ether to give the title compound as a white solid (0.223 g, 100%). MS (ISP) 471.2 [(M+H)+]; mp 239° C. (dec.).
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:5]([C:6]([NH:8][C:9]2[N:10]([CH2:22][CH2:23][CH3:24])[C:11](=[O:21])[N:12]([CH:18]3[CH2:20][CH2:19]3)[C:13](=[O:17])[C:14]=2[N:15]=O)=O)=[CH:4][N:3]=1.[O-]S(S([O-])=O)=O.[Na+].[Na+]>CS(C)=O>[Cl:1][C:2]1[N:3]=[CH:4][C:5]([C:6]2[NH:15][C:14]3[C:13](=[O:17])[N:12]([CH:18]4[CH2:20][CH2:19]4)[C:11](=[O:21])[N:10]([CH2:22][CH2:23][CH3:24])[C:9]=3[N:8]=2)=[CH:25][CH:26]=1
Reactant: CCCn1c(NC(=O)c2ccc(Cl)nc2)c(N=O)c(=O)n(C2CC2)c1=O
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CCCn1c(=O)n(C2CC2)c(=O)c2[nH]c(-c3ccc(Cl)nc3)nc21
Temperature: 90 °C
Reaction time: 3 h
Yield: 77 %

Procedure:
To a solution of 6-Chloro-N-(1-cyclopropyl-5-nitroso-2,6-dioxo-3-propyl-1,2,3,6-tetrahydro-pyrimidin-4-yl)-nicotinamide (8.2 g, 21.71 mmol, 1 eq) in 60 ml of DMSO was added Na2S2O4 (15.11 g, 86.84 mmol, 4 eq). The mixture was stirred at 90° C. for 3 hours. The mixture was quenched with water (50 ml). The resulting precipitate was obtained by filtration and washed with water to give the desired product (5.78 g, 77%) after vacuum dried overnight at 40° C.: 1H NMR (400 MHz, DMSO-d6) δ 14.1 (1H), 9.08 (1H), 8.48 (1H), 7.7 (1H), 4.00 (2H), 2.62 (1H), 1.78 (2H), 1.14 (2H), 0.92 (3H), 0.75 (2H); m/z (ES+) 346.79