Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[C:12]2=[C:13]([Cl:25])[N:14]=[CH:15][C:16]([C:17]([N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)=[O:18])=[C:11]2[C:10]([CH3:26])=[CH:9]1)=O)(C)(C)C.[CH:27]1([NH2:33])[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1.CS(O)(=O)=O>O1CCOCC1>[ClH:25].[CH:27]1([NH:33][C:13]2[N:14]=[CH:15][C:16]([C:17]([N:19]3[CH2:20][CH2:21][O:22][CH2:23][CH2:24]3)=[O:18])=[C:11]3[C:10]([CH3:26])=[CH:9][NH:8][C:12]=23)[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1
Reactant: Cc1cn(C(=O)OC(C)(C)C)c2c(Cl)ncc(C(=O)N3CCOCC3)c12
Reactant: NC1CCCCC1
Agent: CS(=O)(=O)O
Solvent: C1COCCO1
Product: Cc1c[nH]c2c(NC3CCCCC3)ncc(C(=O)N3CCOCC3)c12
Product: Cl
Temperature: 180 °C

Procedure:
A mixture of 7-chloro-3-methyl-4-(1-morpholin-4-yl-methanoyl)-pyrrolo[2,3-c]pyridine-1-carboxylic acid tert-butyl ester (66 mg), cyclohexylamine (80 ul), and methanesulfonic acid (45 ul) in 1,4-dioxane (1 ml) was heated under microwave conditions at 180° C. for 30 minutes. Cyclohexylamine (600 ul in total) was added and the mixture heated under microwave conditions at 180° C. for 2.5 h. The solid mass obtained was purified as described in Example 11(c) to afford the title compound (31 mg).
Reaction SMILES: F[C:2]1[C:7]([C:8]2[N:13]=[C:12]([CH3:14])[N:11]=[C:10]([NH2:15])[N:9]=2)=[CH:6][C:5]([O:16][CH2:17][CH2:18][O:19][CH3:20])=[CH:4][N:3]=1.[NH2:21][C:22]1[CH:23]=[C:24]([NH:29][S:30]([CH3:33])(=[O:32])=[O:31])[C:25]([CH3:28])=[N:26][CH:27]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].C1COCC1>CN(C=O)C>[NH2:15][C:10]1[N:11]=[C:12]([CH3:14])[N:13]=[C:8]([C:7]2[C:2]([NH:21][C:22]3[CH:23]=[C:24]([NH:29][S:30]([CH3:33])(=[O:32])=[O:31])[C:25]([CH3:28])=[N:26][CH:27]=3)=[N:3][CH:4]=[C:5]([O:16][CH2:17][CH2:18][O:19][CH3:20])[CH:6]=2)[N:9]=1
Reactant: COCCOc1cnc(F)c(-c2nc(C)nc(N)n2)c1
Reactant: Cc1ncc(N)cc1NS(C)(=O)=O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COCCOc1cnc(Nc2cnc(C)c(NS(C)(=O)=O)c2)c(-c2nc(C)nc(N)n2)c1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 30.3 %

Procedure:
To a 15 mL round-bottom flask was added 4-(2-fluoro-5-(2-methoxyethoxy)pyridin-3-yl)-6-methyl-1,3,5-triazin-2-amine (Example 335 Step 3) (0.050 g, 0.179 mmol), N-(5-amino-2-methylpyridin-3-yl)methanesulfonamide (0.043 g, 0.215 mmol), and DMF (2.0 mL). The mixture was cooled to 0° C. under N2. Sodium bis(trimethylsilyl)amide, 1.0 m in THF (Aldrich) (0.145 mL, 0.716 mmol) was then added to the solution in one portion. The now dark burgundy color mixture was stirred at 0° C. for 10 min then warmed up to rt and stirred for 1 h. The reaction mixture was partitioned between sat. NH4Cl and CHCl3. The aqueous layer was extracted with more CHCl3 (2×10 mL). The combined organic layers were dried over MgSO4 and concentrated. The crude product was purified by column chromatography (16 g, 5% to 10% MeOH in DCM) to afford the desired product as a yellow solid (25 mg). MS (ESI pos. ion) m/z: 461.0. 1H NMR (300 MHz, DMSO-d6) δ ppm 2.45 (d, J=2.63 Hz, 6H) 2.52 (s, 3H) 3.06 (s, 3H) 3.61-3.73 (m, 2H) 4.09-4.23 (m, 2H) 7.77 (br. s., 1H) 7.89 (br. s., 1H) 8.17 (d, J=2.92 Hz, 1H) 8.33 (d, J=1.75 Hz, 1H) 8.42 (d, J=3.07 Hz, 1H) 8.65 (s, 1H) 9.29 (br. s., 1H) 11.76 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]12[CH2:12][CH:7]3[CH2:8][CH:9]([CH2:11][C:5]([CH2:13][N:14]4[C:18]([CH3:19])=[CH:17][CH:16]=[N:15]4)([CH2:6]3)[CH2:4]1)[CH2:10]2.[I:20]N1C(=O)CCC1=O>CN(C=O)C.C(OCC)(=O)C>[I:20][C:17]1[CH:16]=[N:15][N:14]([CH2:13][C:5]23[CH2:6][CH:7]4[CH2:8][CH:9]([CH2:10][C:3]([O:2][CH3:1])([CH2:12]4)[CH2:4]2)[CH2:11]3)[C:18]=1[CH3:19]
Reactant: O=C1CCC(=O)N1I
Reactant: COC12CC3CC(CC(Cn4nccc4C)(C3)C1)C2
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC12CC3CC(CC(Cn4ncc(I)c4C)(C3)C1)C2

Procedure:
A mixture of EXAMPLE 16D (0.116 g) and N-iodosuccinimide (0.11 g) in 1 mL DMF was stirred overnight. The mixture was taken up in ethyl acetate, and the resulting solution was washed three times with water, and brine, then dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on silica gel with 0-50% ethyl acetate/hexanes to provide the title compound.
Reaction SMILES: Cl.[NH2:2][C:3]1[C:18]([Cl:19])=[CH:17][C:6]([C:7]([NH:9][CH2:10][CH:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)=[O:8])=[C:5]([O:20][CH3:21])[CH:4]=1.C(=O)([O-])[O-].[K+].[K+].BrCCC[C:32]1[CH:33]=[C:34]2[C:39](=[O:40])[NH:38][C:36](=[O:37])[C:35]2=[CH:41][CH:42]=1.[C:43]1(C)[CH:48]=CC=C[CH:44]=1>CN(C)C=O>[NH2:2][C:3]1[C:18]([Cl:19])=[CH:17][C:6]([C:7]([NH:9][CH2:10][CH:11]2[CH2:12][CH2:13][N:14]([CH2:44][CH2:43][CH2:48][N:38]3[C:39](=[O:40])[C:34]4[C:35](=[CH:41][CH:42]=[CH:32][CH:33]=4)[C:36]3=[O:37])[CH2:15][CH2:16]2)=[O:8])=[C:5]([O:20][CH3:21])[CH:4]=1
Reactant: Cc1ccccc1
Reactant: O=C1NC(=O)c2cc(CCCBr)ccc21
Reactant: COc1cc(N)c(Cl)cc1C(=O)NCC1CCNCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCN2C(=O)c3ccccc3C2=O)CC1
Temperature: 70 °C
Reaction time: 5 h

Procedure:
4-Amino-5-chloro-2-methoxy-N-(piperidin-4-ylmethyl)benzamide hydrochloride (8.0 g) was dissolved in dimethylformamide (100 ml) and toluene (100 ml). Potassium carbonate (9.9 g) and 4-bromopropylphthalimide (6.4 g) were added, and the mixture was stirred at 70° C. for 5 hr. The reaction mixture was concentrated under reduced pressure and the residue was extracted with ethyl acetate. The extract was dried over magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography to give 4.0 g of 4-amino-5-chloro-N-(1-(3-(2,3-dihydro-1,3-dioxo-1 H-isoindol-2-yl)propyl)piperidin-4-ylmethyl)-2-methoxybenzamide.
Reaction SMILES: [O:1]=[C:2]1[N:7]2[CH:8]=[N:9][C:10]3[CH:11]=[C:12]([NH:16][C:17](=[O:22])[C:18]([CH3:21])([CH3:20])[CH3:19])[CH:13]=[CH:14][C:15]=3[C:6]2=[N:5][CH:4]=[C:3]1[C:23]([O:25]C)=[O:24].[I-].[Li+].Cl>N1C=CC=CC=1.O>[O:1]=[C:2]1[N:7]2[CH:8]=[N:9][C:10]3[CH:11]=[C:12]([NH:16][C:17](=[O:22])[C:18]([CH3:20])([CH3:21])[CH3:19])[CH:13]=[CH:14][C:15]=3[C:6]2=[N:5][CH:4]=[C:3]1[C:23]([OH:25])=[O:24]
Reactant: COC(=O)c1cnc2c3ccc(NC(=O)C(C)(C)C)cc3ncn2c1=O
Agent: Cl
Agent: [I-]
Agent: [Li+]
Solvent: O
Solvent: c1ccncc1
Product: CC(C)(C)C(=O)Nc1ccc2c(c1)ncn1c(=O)c(C(=O)O)cnc21
Temperature: 120 °C
Reaction time: 0.5 h
Yield: 46.5 %

Procedure:
A mixture of methyl 4-oxo-9-pivalamido-4H-pyrimido[1,2-C]quinazoline-3-carboxylate (6.5 g) and anhydrous lithium iodide (16.25 g) in dry pyridine (65 ml) was stirred at 100° C. for 1 hour and 30 minutes and at 120° C. for additional 30 minutes. The reaction mixture was concentrated under reduced pressure to give an oily residue, which was dissolved in water. The resulting solution was adjusted to pH 1 with conc. hydrochloric acid to give yellow crystals, which were separated by filtration, washed with water, and dried. The crude crystals were dissolved in a mixture of chloroform and methanol under heating. The solution was filtered to remove insoluble materials. The solution was concentrated under reduced pressure until crystallization began and cooled. The resulting crystals were collected by filtration and dried. There was obtained 4-oxo-9-pivalamido-4H-pyrimido-[1,2-C]quinazoline-3-carboxylic acid (2.9 g).
Reaction SMILES: [CH3:1][C@@:2]1([C:8](O)=[O:9])[CH2:6][CH2:5][C:4](=[O:7])[O:3]1.O1CCCC1>O>[OH:9][CH2:8][C@@:2]1([CH3:1])[O:3][C:4](=[O:7])[CH2:5][CH2:6]1
Reactant: C[C@@]1(C(=O)O)CCC(=O)O1
Solvent: C1CCOC1
Solvent: O
Product: C[C@@]1(CO)CCC(=O)O1
Reaction time: 0.5 h

Procedure:
To a solution of 14.8 g. (102.7 mmol) of (S)-(-)-2-methyl-5-oxotetrahydro-2-furoic acid mp 84°-87° C.; [α]25D -16.56° in 70 ml. of dry tetrahydrofuran (THF) was added 10.1 ml. (8.1 g.; 106.7 mmol) of borane-methyl sulphide complex, dropwise, with stirring over a 0.5 hr. period. Occasional ice-bath cooling was employed to maintain the internal temperature below 30°. After stirring at room temperature for 1.5 hr., the reaction mixture was cautiously decomposed by the dropwise addition of 6.2 ml. of H2O. The mixture was then concentrated under water aspirator pressure and the residue was taken up in ethyl acetate and filtered. The solids were washed thoroughly with ethyl acetate and filtered. The solids were washed thoroughly with ethyl acetate and the filtrate and washes were combined and concentrated in vacuo giving (S)-(+)-5-(hydroxymethyl)-5-methyldihydro-2(3H)-furanone as a colorless oil (13.6 g.) which was used without further purification.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][CH:3]=1.C([Li])CCC.[CH2:14]([N:21]1[CH:26]2[CH2:27][CH2:28][CH:22]1[CH2:23][C:24](=[O:29])[CH2:25]2)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[OH-].[Na+]>C(OCC)C>[CH2:14]([N:21]1[CH:22]2[CH2:28][CH2:27][CH:26]1[CH2:25][C:24]([C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][CH:3]=1)([OH:29])[CH2:23]2)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: O=C1CC2CCC(C1)N2Cc1ccccc1
Reactant: Fc1ccc(Br)cc1
Agent: [Li]CCCC
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Product: OC1(c2ccc(F)cc2)CC2CCC(C1)N2Cc1ccccc1
Temperature: -35 °C

Procedure:
1-Bromo-4-fluoro-benzene (22.7 g) dissolved in diethylether (100 mL) is added to a solution of n-butyllithium (1.7 mol/L in pentane, 86.8 mL) in diethylether (200 mL) cooled to −35° C. The combined solutions are stirred at −35 to −40° C. for 1 h, before 8-benzyl-8-aza-bicyclo[3.2.1]octan-3-one (22.5 g) dissolved in diethylether (150 mL) is added quickly. The solution is warmed to −10° C. within 1 h and then the reaction is quenched by the addition of aqueous NH4Cl solution. The resulting mixture is extracted with ethyl acetate, the combined extracts are washed with brine, and 4 M hydrochloric acid is added to the organic phase. The organic phase is separated from the aqueous phase and an oily precipitation formed after the addition. The oily and aqueous phase are combined and basified with 4 M aqueous NaOH solution and the resulting mixture is extracted with ethyl acetate. The organic extracts are dried (Na2SO4) and the solvent is evaporated to give the title compound.
Reaction SMILES: C([NH:8][C:9]1[C:17]2[O:16][C:15]([CH3:19])([CH3:18])[C:14](=[O:20])[C:13]=2[C:12]([CH3:21])=[C:11]([CH3:22])[C:10]=1[CH3:23])C1C=CC=CC=1>C(OCC)(=O)C.CCCCCC>[NH2:8][C:9]1[C:17]2[O:16][C:15]([CH3:18])([CH3:19])[C:14](=[O:20])[C:13]=2[C:12]([CH3:21])=[C:11]([CH3:22])[C:10]=1[CH3:23]
Reactant: Cc1c(C)c(NCc2ccccc2)c2c(c1C)C(=O)C(C)(C)O2
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: Cc1c(C)c(N)c2c(c1C)C(=O)C(C)(C)O2

Procedure:
Using 7-(benzylamino)-2,2,4,5,6-pentamethyl-1-benzofuran-3(2H)-one obtained in Reference Example 53, the title compound was synthesized in the same manner as in Reference Example 30. Yield: quantitative. Melting point: 141-142° C. (ethyl acetate-hexane).
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH:3]=1.C=O.[C:13]1([CH3:23])[CH:18]=[CH:17][C:16](S(O)(=O)=O)=[CH:15][CH:14]=1>C1(C)C=CC=CC=1>[CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][C:3]=1[CH2:1][C:2]1[CH2:23][C:13]2[C:18]([C:3]=1[CH3:4])=[CH:17][CH:16]=[CH:15][CH:14]=2
Reactant: CC1=CCc2ccccc21
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: C=O
Solvent: Cc1ccccc1
Product: CC1=C(CC2=C(C)c3ccccc3C2)Cc2ccccc21
Temperature: 80 °C
Reaction time: 1 h
Yield: 247.4 %

Procedure:
In a 500 mL flask equipped with magnetic stirring bar were introduced 14.8 g (0.114 moles) of 3-methyl-indene, 2.3 g (0.077 moles) of para-formaldehyde and 4.37 g (0.023 moles) of para-toluenesulphonic acid in 200 ml of toluene; the mixture was heated to 80° C. and was maintained under stirring for 1 hour at 80° C. Then the reaction was quenched with water/NaHCO3; the conversion, measured by gas chromatographic analysis, was 85.9%. The organic layer was separated, washed with water and brought to dryness under reduced pressure. The crude product was crystallized upon standing at room temperature, and then was further purified by washing with pentane or MeOH, thus isolating 15.5 g of bis(3-methyl-2-indenyl)methane (purity of 89.8% by G.C.; yield=89.8%). The results of the 1H-NMR analysis correspond to the ones reported above.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[C:18](Cl)[N:17]=[C:16]([S:21]([CH3:24])(=[O:23])=[O:22])[N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(O)C.[F:28][C:29]([F:40])([F:39])[C:30]1[CH:31]=[C:32](B(O)O)[CH:33]=[CH:34][CH:35]=1.C(=O)([O-])[O-].[Na+].[Na+]>O.C1(C)C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[C:18]([C:34]3[CH:33]=[CH:32][CH:31]=[C:30]([C:29]([F:40])([F:39])[F:28])[CH:35]=3)[N:17]=[C:16]([S:21]([CH3:24])(=[O:23])=[O:22])[N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCN(c2cc(Cl)nc(S(C)(=O)=O)n2)CC1
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCN(c2cc(-c3cccc(C(F)(F)F)c3)nc(S(C)(=O)=O)n2)CC1
Yield: 111.5 %

Procedure:
To a stirring solution of 4-(6-chloro-2-methanesulfonyl-pyrimidin-4-yl)-piperazine-1-carboxylic acid tert-butyl ester (500 mg) in a 1:1 mixture of ethanol and toluene (10 ml) was added 3-(trifluoromethyl)phenylboronic acid (277 mg), sodium carbonate (422 mg), water (500 μl) and CombiPhos-Pd6 (30.5 mg) catalyst mixture. The resulting suspension was heated at reflux for 3 hrs before being filtered through celite and concentrated in vacuo to give 4-[2-methanesulfonyl-6-(3-trifluoromethyl-phenyl)-pyrimidin-4-yl]-piperazine-1-carboxylic acid tert-butyl ester as a yellow oil (720 mg).
Reaction SMILES: C([O:5]O)(C)(C)C.C(CC(C)(C)C)(C)C.[CH2:15]([OH:25])/[CH:16]=[CH:17]/[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(Cl)Cl.O.CC(O[Ti](OC(C)C)(OC(C)C)OC(C)C)C>[CH2:18]([C@@H:17]1[O:5][C@H:16]1[CH2:15][OH:25])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: CCCCCCC/C=C/CO
Reactant: CC(C)(C)OO
Agent: CC(C)O[Ti](OC(C)C)(OC(C)C)OC(C)C
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: ClCCl
Solvent: O
Solvent: CC(C)CC(C)(C)C
Product: CCCCCCC[C@@H]1O[C@H]1CO
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A suspension of 2.00 g of 4A powdered molecular sieves in 50 ml of dry CH2Cl2 was cooled to 0° C. under argon. To the cooled suspension was added 273 mg (1.00 mmole) of Ti(OiPr)4 and 314 mg (1.34 mmole) of L(+)diisopropyl tartrate via syringe. The mixture was stirred for 15 min and cooled to -20° C. A solution of tert-butylhydroperoxide in isooctane (3.8 M, 7.57 ml, 28.8 mmole) was added slowly to the mixture and the catalyst was allowed to "age" for 30 min at -20° C. A solution of 3.00 g (19.2 mmole) of E-2-decen-1-ol in 10 ml of CH2Cl2 was dried over 3A molecular sieves for 15 min before being added to the mixture slowly, with stirring, at -20° C. The solution was then placed in the freezer (-30° C.) and allowed to stand for 24 H. The mixture was-warmed to 0° C. and poured into a solution of 1.00 g of citric acid and 5.00 g of FeSO4 in 15 ml H2O. The organic layer was separated and the aqueous layer washed twice with 20 ml of CH2Cl2. The CH2Cl2 layers are combined, dried over MgSO4, filtered and evaporated to yield a sticky white solid. Recrystallization from Et2O:petroleum ether afforded 2.43 g of white solid, mp 50-1° C. 1H NMR δ 3.92 (ddd, 1, J=2, 6, 12 Hz), 3.63 (ddd, 1, J=4, 8, 12 Hz), 2.94 (m, 2), 1.73 (dd, 1, J=6, 7 Hz), 1.6-1.2 (m, 12), 0.88 (t, 3, J=7 Hz). Mass Spectra: M-31(--CH2OH)(0.5)148.1, M(100)69.1.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([CH:12]=[CH:13][C:14]3[CH:15]=[C:16]([C@@H:20]([OH:39])[CH2:21][CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[C:29]([O:32][CH:33]4[CH2:38][CH2:37][CH2:36][CH2:35][O:34]4)([CH3:31])[CH3:30])[CH:17]=[CH:18][CH:19]=3)=[N:9]2)=[CH:4][CH:3]=1.[CH3:40][S:41](Cl)(=[O:43])=[O:42].CCN(CC)CC.C([O-])(O)=O.[Na+]>C(Cl)Cl>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([CH:12]=[CH:13][C:14]3[CH:15]=[C:16]([C@@H:20]([O:39][S:41]([CH3:40])(=[O:43])=[O:42])[CH2:21][CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[C:29]([O:32][CH:33]4[CH2:38][CH2:37][CH2:36][CH2:35][O:34]4)([CH3:31])[CH3:30])[CH:17]=[CH:18][CH:19]=3)=[N:9]2)=[CH:4][CH:3]=1
Reactant: CC(C)(OC1CCCCO1)c1ccccc1CC[C@H](O)c1cccc(C=Cc2ccc3ccc(Cl)cc3n2)c1
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(OC1CCCCO1)c1ccccc1CC[C@H](OS(C)(=O)=O)c1cccc(C=Cc2ccc3ccc(Cl)cc3n2)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a 0.1M solution of the alcohol of Step 6 in CH2Cl2 at -40° C. was added 1.3 equiv. of methanesulfonyl chloride and 1.5 equiv. of Et3N and the mixture was stirred 30 min at -40° C. and 1 h at 0° C. Saturated NaHCO3 was then added and the title mesylate was extracted in CH2Cl2, dried over Na2SO4, concentrated and stripped twice with toluene. The residual title compound was used for subsequent reactions without further purification.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[N:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[Cl:19])[N:11]=[C:10]([C:20]([F:26])([F:25])[C:21]([F:24])([F:23])[F:22])[CH2:9]2)=[CH:4][CH:3]=1.[CH3:27][S:28][C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O.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>[Cl:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[N:12]1[CH:8]([C:5]2[CH:6]=[CH:7][C:2]([C:32]3[CH:33]=[CH:34][C:29]([S:28][CH3:27])=[CH:30][CH:31]=3)=[CH:3][CH:4]=2)[CH2:9][C:10]([C:20]([F:25])([F:26])[C:21]([F:22])([F:24])[F:23])=[N:11]1
Reactant: FC(F)(F)C(F)(F)C1=NN(c2ccccc2Cl)C(c2ccc(Br)cc2)C1
Reactant: CSc1ccc(B(O)O)cc1
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: CN(C)C=O
Product: CSc1ccc(-c2ccc(C3CC(C(F)(F)C(F)(F)F)=NN3c3ccccc3Cl)cc2)cc1
Yield: 58.8 %

Procedure:
A solution of 5-(4-bromo-phenyl)-1-(2-chloro-phenyl)-3-pentafluoroethyl-4,5-dihydro-1H-pyrazole (100.0 mg, 0.19 mmol) prepared in Step 3 of Preparation 1, 4-(methylthio)phenylboronic acid (80.0 mg, 0.28 mmol), Pd(PPh3)4 (26 mg, cat.), and a 2N sodium carbonate solution 0.6 mL in N,N-dimethylformamide (5 mL) were stirred at 80° C. for 6 hours. The reaction mixture was concentrated under reduced pressure and then extracted with ethyl acetate. The extract was washed with distilled water, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure to give a yellow liquid residue. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/20) to give 55.5 mg of the titled compound as a pale yellow liquid.
Reaction SMILES: [N:1]1([CH2:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[S:13]([NH2:16])(=[O:15])=[O:14])[CH:5]=[N:4][CH:3]=[N:2]1.C1([O:23][C:24](=O)[NH:25][C:26]2[N:31]=[C:30]([O:32][CH3:33])[CH:29]=[C:28]([O:34][CH3:35])[N:27]=2)C=CC=CC=1.C1CCN2C(=NCCC2)CC1>O1CCOCC1.O>[CH3:33][O:32][C:30]1[CH:29]=[C:28]([O:34][CH3:35])[N:27]=[C:26]([NH:25][C:24]([NH:16][S:13]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][N:1]2[CH2:5][N:4]=[CH:3][NH:2]2)(=[O:15])=[O:14])=[O:23])[N:31]=1
Reactant: NS(=O)(=O)c1ccccc1Cn1cncn1
Reactant: COc1cc(OC)nc(NC(=O)Oc2ccccc2)n1
Solvent: C1CCC2=NCCCN2CC1
Solvent: O
Solvent: C1COCCO1
Product: COc1cc(OC)nc(NC(=O)NS(=O)(=O)c2ccccc2CN2CN=CN2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 70.7 %

Procedure:
By the procedure of Example 4, 0.4 g of the product of Example 7 was reacted with 0.52 g of phenyl(4,6-dimethoxypyrimidin-2-yl)carbamate and 0.26 g of "DBU" in 10 ml of p-dioxane. After stirring at 25° C. for two hours, the resulting suspension was diluted with about 50 ml of water, and filtered; the resulting filtrate was acidified with concentrated hydrochloric acid to pH 4, then filtered. The residue was washed 2×10 ml water, suction-dried 16 hours, then triturated with about 10 ml of warm ethyl acetate to yield 0.5 g of the subject compound; m.p. 219°-220° C. IR(nujol): 1690 cm-1 (c=o); NMR(CDCl3): ppm 3.9(S, 6H, OCH3); 5.8(S, 1H, py H); 6.0(S, 2H, CH2); 7.9 and 8.2(2S, 2H, tri 2H); 7.1-7.6(m, 4H, Ar+NH); 8.15(m, 1H, Ar).
Reaction SMILES: NC(N)=O.S(=NC(N)=O)(=O)=O.[NH2:12][C:13]1[N:18]=[CH:17][C:16]([N:19]2[C:24](=[O:25])[C:23]3[CH:26]=[C:27]([F:32])[C:28]([NH:30][CH3:31])=[CH:29][C:22]=3[O:21][CH2:20]2)=[CH:15][C:14]=1[CH3:33].C([O:36][C:37](=O)[NH:38][S:39]([C:42]1[S:43][C:44]([Cl:47])=[CH:45][CH:46]=1)(=[O:41])=[O:40])C>>[Cl:47][C:44]1[S:43][C:42]([S:39]([NH:38][C:37]([NH:12][C:13]2[C:14]([CH3:33])=[CH:15][C:16]([N:19]3[C:24](=[O:25])[C:23]4[CH:26]=[C:27]([F:32])[C:28]([NH:30][CH3:31])=[CH:29][C:22]=4[O:21][CH2:20]3)=[CH:17][N:18]=2)=[O:36])(=[O:41])=[O:40])=[CH:46][CH:45]=1
Reactant: CNc1cc2c(cc1F)C(=O)N(c1cnc(N)c(C)c1)CO2
Reactant: CCOC(=O)NS(=O)(=O)c1ccc(Cl)s1
Agent: NC(=O)N=S(=O)=O
Agent: NC(N)=O
Product: CNc1cc2c(cc1F)C(=O)N(c1cnc(NC(=O)NS(=O)(=O)c3ccc(Cl)s3)c(C)c1)CO2
Yield: 89.5 %

Procedure:
Analogous to the sulfonylurea urea formation described in Ex 5, 3-(6-amino-5-methylpyridin-3-yl)-6-fluoro-7-(methylamino)-2,3-dihydrobenzo[e][1,3]oxazin-4-one (0.010 g, 0.034 mmol) and (5-Chloro-thiophene-2-sulfonyl)-carbamic acid ethyl ester (0.048 g, 0.166 mmol) were coupled to give 1-(5-chlorothiophen-2-ylsulfonyl)-3-(5-(6-fluoro-7-(methylamino)-4-oxo-2H-benzo[e][1,3]oxazin-3(4H)-yl)-3-methylpyridin-2-yl)urea (0.016 g, 85%). RP-HPLC: 2.7 min; ES-MS (M+H)+=526.0; 1H-NMR (DMSO-d6) δ (ppm): 2.2 (s, 3), 2.8 (s, 3), 5.6 (s, 2), 6.2 (d, 1), 6.8 (bs, 1), 7.2 (s, 1), 7.4 (d, 1), 7.6 (s, 1), 7.8 (d, 1), 8.2 (d, 1), 9.6 (bs, 1).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4](Cl)=[O:5].[CH3:12][O:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20]C)[CH:15]=1.[Cl-].[Al+3].[Cl-].[Cl-].Cl>ClCCCl>[F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4](=[O:5])[C:17]1[CH:18]=[CH:19][C:14]([O:13][CH3:12])=[CH:15][C:16]=1[OH:20]
Reactant: O=C(Cl)c1c(F)cccc1F
Reactant: COc1cccc(OC)c1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: COc1ccc(C(=O)c2c(F)cccc2F)c(O)c1
Reaction time: 1 h

Procedure:
To a mixture of 20 g of 2,6-difluorobenzoyl chloride and 15.5 g of 1,3-dimethoxybenzene in 200 ml of 1,2-dichloroethane, 15.28 g of aluminum chloride is added in portions with the internal temperature maintained at 0°-10° C. The mixture is stirred 1 hour and then refluxed 45 min. The reaction mixture is poured into concentrated hydrochloric acid and ice. The organic layer is separated, washed, dried over anhydrous sodium sulfate and evaporated. Trituration with hexane followed by recrystallization from 95% ethanol gives 2',6'-difluoro-2-hydroxy-4-methoxybenzophenone, mp 71°-72° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH2:27])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].Br[C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([O:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH:30]=1>>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH:27][C:40]4[CH:39]=[CH:38][CH:37]=[C:36]([O:35][C:31]5[CH:32]=[CH:33][CH:34]=[CH:29][CH:30]=5)[CH:41]=4)=[CH:17][CH:16]=3)=[CH:13][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4N)cc3)cc2)CC1
Reactant: Brc1cccc(Oc2ccccc2)c1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4Nc4cccc(Oc5ccccc5)c4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 68, Step 2, using 1-[4′-(4-amino-3-methyl-isoxazol-5-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester and 1-bromo-3-phenoxy-benzene.