Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([S:11][CH3:12])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[Li]CCCC.B(F)(F)F.CCOCC.[O:27]1[CH:33]2[CH:28]1[CH2:29][O:30][CH2:31][CH2:32]2.Cl>C1COCC1.CCCCCC.CCOC(C)=O>[CH3:12][S:11][C:8]1[CH:9]=[CH:10][C:5]([S:2]([CH2:1][C@@H:33]2[CH2:32][CH2:31][O:30][CH2:29][C@H:28]2[OH:27])(=[O:4])=[O:3])=[CH:6][CH:7]=1
Reactant: C1CC2OC2CO1
Reactant: CSc1ccc(S(C)(=O)=O)cc1
Agent: Cl
Agent: FB(F)F
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CSc1ccc(S(=O)(=O)C[C@@H]2CCOC[C@H]2O)cc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 20.2 %

Procedure:
1-Methanesulfonyl-4-methylsulfanyl-benzene (4.3 g) was dissolved in THF (40 ml) and cooled to −78° C. prior to the slow addition of 1.6 M n-BuLi in hexane (13.4 ml). After 0.5 h, BF3.Et2O (2.7 ml) was added followed by 3,4-epoxytetrahydropyran (2.2 g) (Berti et al. Tetrahedron 1974, 30, 4013) (2.3 g) in THF (20 ml). After an addition 1 h at −78° C., the solution was warmed to 0° C. After 2 h, the solution was cooled to −78° C. and 1N HCl solution (aq) was added. The solution was warmed to rt and EtOAc was added. The organic layer was washed with brine, dried, filtered, and concentrated. Flash chromatography of the resulting residue gave (3S*,4R*)-4-(4-methylsulfanyl-benzenesulfonylmethyl)-tetrahydro-pyran-3-ol (1.3 g) as the major product. MS found: (M+H)+=303.0. (23b) The above derivative (23a) (1.3 g) was dissolved in CH2Cl2 (15 ml) and cooled to 0° C. prior to the addition of Et3N (1.7 ml) and methanesulfonyl chloride (0.5 ml). After 1.5 h, the CH2Cl2 was removed and EtOAc was added. This was washed with 1N HCl, saturated NaHCO3, and brine. The organic layer was dried, filtered, and concentrated. This solid was dissolved in DMSO (10 ml) prior to the addition of NaN3 (1.3 g). This was heated at 85° C. for 18 h. After cooling to 0° C., water was added and it was extracted with EtOAc. The organic layer was washed with brine, dried, filtered, and concentrated. Flash chromatography of the resulting residue gave (3R*,4R*)-3-azido-4-(4-methylsulfanyl-benzenesulfonylmethyl)-tetrahydro-pyran (0.93 g). MS found: (M+H)+=328.0. (23c) The above derivative (23d)(0.9 g) was dissolved in MeOH (10 ml) prior to the addition of 5% Pd/BaSO4 (800 mg). A hydrogen balloon was added and the solution was stirred for 1.5 h. The palladium was filtered off and the solution was concentrated to (3R*,4R*)-4-(4-methylsulfanyl-benzenesulfonylmethyl)-tetrahydro-pyran-3-ylamine (750 mg) as a major product. MS found: (M−H)−=300.5 (23d) A portion (66 mg) of the above derivative (23c) was dissolved in DMF (1.1 ml) prior to the addition of DIEA (0.14 ml) and example (1d)(50 mg). After cooling to 0° C., BOP reagent (97 mg) was added. The resulting mixture was warmed to rt and stirred overnight before being concentrated. 1N HCl was added. This was exacted with EtOAc. The organic layer was washed with NaHCO3(aq), dried, filtered and concentrated. Reverse phase HPLC purification (gradient elution, water/acetonitrile/TFA) of the resulting residue provided the title compound (53 mg). MS found: (M+H)+=528.1.
Reaction SMILES: FC(F)(F)C([O-])=O.[Br:8][C:9]1[C:21]2[C:20]3[CH2:19][CH2:18][NH2+:17][CH2:16][C:15]=3[CH:14]=[N:13][C:12]=2[NH:11][N:10]=1.[N:22]([C:25]1[CH:26]=[C:27]([CH:36]=[CH:37][CH:38]=1)[O:28][C:29]1[CH:34]=[N:33][CH:32]=[C:31]([CH3:35])[N:30]=1)=[C:23]=[O:24]>>[Br:8][C:9]1[C:21]2[C:20]3[CH2:19][CH2:18][N:17]([C:23]([NH:22][C:25]4[CH:38]=[CH:37][CH:36]=[C:27]([O:28][C:29]5[CH:34]=[N:33][CH:32]=[C:31]([CH3:35])[N:30]=5)[CH:26]=4)=[O:24])[CH2:16][C:15]=3[CH:14]=[N:13][C:12]=2[NH:11][N:10]=1
Reactant: Cc1cncc(Oc2cccc(N=C=O)c2)n1
Reactant: Brc1n[nH]c2ncc3c(c12)CC[NH2+]C3
Agent: O=C([O-])C(F)(F)F
Product: Cc1cncc(Oc2cccc(NC(=O)N3CCc4c(cnc5[nH]nc(Br)c45)C3)c2)n1

Procedure:
The compound, 1-bromo-N-{3-[(6-methylpyrazin-2-yl)oxy]phenyl}-3,6,8,9-tetrahydro-7H-pyrazolo[3,4-c][2,7]naphthyridine-7-carboxamide was prepared using 1-bromo-6,7,8,9-tetrahydro-3H-pyrazolo[3,4-c][2,7]naphthyridin-7-ium 2,2,2-trifluoroacetate and 2-(3-isocyanatophenoxy)-6-methylpyrazine as described in general procedure M. Yellow solid; M.p.=221-223° C.; 400 MHz 1H NMR (DMSO-d6) δ: 13.96 (s, 1H), 8.87 (s, 1H), 8.40 (s, 1H), 8.28 (s, 1H), 8.27 (s, 1H), 7.4-7.26 (m, 3H), 6.79-6.74 (m, 1H), 4.76 (s, 2H), 3.82 (t, J=6 Hz, 2H), 3.37 (t, J=6 Hz, 2H), 2.35 (s, 3H); LCMS [M+H]: 479.9.
Reaction SMILES: Br[C:2]1[NH:3][C:4]2[C:9]([C:10]=1[CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)=[CH:8][CH:7]=[C:6]([C:17]([O:19][CH3:20])=[O:18])[CH:5]=2.CC1(C)C(C)(C)OB([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[NH2:35])O1.C(=O)([O-])O.[Na+]>COCCOC.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>[NH2:35][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=1[C:2]1[NH:3][C:4]2[C:9]([C:10]=1[CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)=[CH:8][CH:7]=[C:6]([C:17]([O:19][CH3:20])=[O:18])[CH:5]=2
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c(Br)[nH]c2c1
Reactant: CC1(C)OB(c2ccccc2N)OC1(C)C
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: COCCOC
Solvent: O
Product: COC(=O)c1ccc2c(C3CCCCC3)c(-c3ccccc3N)[nH]c2c1
Temperature: 25 °C
Yield: 96.4 %

Procedure:
To a suspension of methyl 2-bromo-3-cyclohexyl-1H-indole-6-carboxylate (6.50 g, 19.3 mmol) obtained in the same manner as in the method described in WO03/010140 and 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenylamine (5.08 g, 23.2 mmol) in 1,2-dimethoxyethane (90 ml) and water (45 ml) were added sodium hydrogen carbonate (4.81 g, 57.9 mmol) and tetrakis(triphenylphosphine)palladium (1.12 mg, 0.965 mmol), and the mixture was heated under reflux for 9 hr. The mixture was allowed to cool to room temperature, and water was added to the reaction mixture. The mixture was extracted with ethyl acetate and the organic layer was washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated brine and dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (hexane:ethyl acetate=4:1-3:1) to give methyl 2-(2-aminophenyl)-3-cyclohexyl-1H-indole-6-carboxylate (6.48 g, yield 96%).
Reaction SMILES: [Si]([O:8][C@H:9]([C@@H:11]1[C@@H:14]([S:15][C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)[NH:13][C:12]1=[O:23])[CH3:10])(C(C)(C)C)(C)C>O1CCCC1.CO>[Cl:22][C:19]1[CH:18]=[CH:17][C:16]([S:15][CH:14]2[NH:13][C:12](=[O:23])[CH:11]2[CH:9]([OH:8])[CH3:10])=[CH:21][CH:20]=1
Reactant: C[C@H](O[Si](C)(C)C(C)(C)C)[C@H]1C(=O)N[C@@H]1Sc1ccc(Cl)cc1
Solvent: C1CCOC1
Solvent: CO
Product: CC(O)C1C(=O)NC1Sc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
1.65 g (4.44 mmol) of ra -(αS*,3S*,4R*)-3-[1-(t-butyldimethylsilyloxy)ethyl]4-[(p-chlorophenyl)thio]-azetidinone are dissolved in 70 ml of tetrahydrofuran/methanol 12 percent hydrochloric acid (4:2:1). The solution is stirred at room temperature for 4 hours and then evaporated. The residue is taken up in 50 ml of ethyl acetate, washed with 20 ml of saturated sodium chloride solution and evaporated. The residue obtained is washed with ether/hexane (1:1) and dried. There is obtained pure rac-(αS*,3S*,4R*)-4-[(p-chlorophenyl)thio]-3-(1-hydroxyethyl)-2-azetidinone; IR: 1760 cm-1.
Reaction SMILES: [CH3:1][C:2]1[C:7](=[O:8])[N:6]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([N:15]3[C:19](=[O:20])[CH2:18][CH2:17][C:16]3=[O:21])[CH:10]=2)[C:5]2[N:22]=[CH:23][CH:24]=[CH:25][C:4]=2[N:3]=1.[Br:26]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>>[Br:26][CH2:1][C:2]1[C:7](=[O:8])[N:6]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([N:15]3[C:16](=[O:21])[CH2:17][CH2:18][C:19]3=[O:20])[CH:10]=2)[C:5]2[N:22]=[CH:23][CH:24]=[CH:25][C:4]=2[N:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1nc2cccnc2n(-c2cccc(N3C(=O)CCC3=O)c2)c1=O
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Product: O=C1CCC(=O)N1c1cccc(-n2c(=O)c(CBr)nc3cccnc32)c1
Yield: 68.6 %

Procedure:
The solution of 2-methyl-4-(3-succinimidophenyl)-3-oxo-3,4-dihydropyrido[2,3-b]pyrazine (18.4 g), N-bromosuccinimide (12.7 g) and benzoylperoxide (1.6 g) were refluxed for 4 hours. The mixture was evaporated and purified by chromatography (chloroform) to obtain 2-bromomethyl-4-(3-succinimidophenyl)-3-oxo-3,4-dihydropyrido[2,3-b]pyrazine (15.6 g) as yellow crystals.
Reaction SMILES: Br[C:2]1[C:3]2[N:4]([CH:17]=[N:18][N:19]=2)[CH:5]=[C:6]([C:8]2[S:12][C:11]([NH:13][CH:14]([CH3:16])[CH3:15])=[N:10][CH:9]=2)[CH:7]=1.[F:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1B(O)O.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C1(C)C=CC=CC=1.CCO.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:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[C:2]1[C:3]2[N:4]([CH:17]=[N:18][N:19]=2)[CH:5]=[C:6]([C:8]2[S:12][C:11]([NH:13][CH:14]([CH3:16])[CH3:15])=[N:10][CH:9]=2)[CH:7]=1
Reactant: OB(O)c1ccccc1F
Reactant: CC(C)Nc1ncc(-c2cc(Br)c3nncn3c2)s1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CC(C)Nc1ncc(-c2cc(-c3ccccc3F)c3nncn3c2)s1
Temperature: 100 °C
Yield: 47 %

Procedure:
A mixture of 5-(8-bromo-[1,2,4]triazolo[4,3-a]pyridin-6-yl)-N-isopropylthiazol-2-amine (19.6 mg, 0.0579 mmol) and 2-fluorophenylboronic acid (12.7 mg, 0.081 mmol) in toluene (0.58 mL) was degassed via nitrogen bubble, then was added Pd(PPh3)4 (3.3 mg, 0.003 mmol), aqueous K3PO4 (2 M, 58 μL, 0.116 mmol) and ethanol (84 μL). The reaction mixture was heated to 100° C. overnight, cooled to rt, diluted with EtOH (1 mL), filtered and concentrated. The residues were purified directly by reverse phase preparative HPLC and the product containing fractions were concentrated and neutralized with aqueous NaHCO3 to precipitate the product. The solids were filtered, washed and dried to give (9.7 mg, 47% yield). LCMS 354.23, Tr 3.50 min (Conditions A).
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[C:3]1[CH:4]=[C:5]([C:9]2[C:10]3[N:11]([N:15]=[C:16]([NH:18][C:19]4[CH:28]=[CH:27][C:22]([C:23]([O:25]C)=[O:24])=[CH:21][CH:20]=4)[N:17]=3)[CH:12]=[CH:13][CH:14]=2)[CH:6]=[CH:7][CH:8]=1.Cl>[OH-].[Na+].O1CCOCC1>[F:29][C:2]([F:1])([F:30])[C:3]1[CH:4]=[C:5]([C:9]2[C:10]3[N:11]([N:15]=[C:16]([NH:18][C:19]4[CH:28]=[CH:27][C:22]([C:23]([OH:25])=[O:24])=[CH:21][CH:20]=4)[N:17]=3)[CH:12]=[CH:13][CH:14]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: COC(=O)c1ccc(Nc2nc3c(-c4cccc(C(F)(F)F)c4)cccn3n2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: O=C(O)c1ccc(Nc2nc3c(-c4cccc(C(F)(F)F)c4)cccn3n2)cc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 100.4 %

Procedure:
A solution of methyl 4-(8-(3-(trifluoromethyl)phenyl)-[1,2,4]triazolo[1,5-a]pyridine-2-ylamino)benzoate (1.03 g, 2.50 mmol, 1 equiv) in 2M aqueous sodium hydroxide (10 mL) and 1,4-dioxane (5 mL) was heated at 80-90° C. After 3 h, the solution was cooled to 0° C. and neutralized by the addition of 6M HCl until pH=4-5. The resulting solid was collected by filtration and rinsed sequentially with water, isopropanol, and hexanes to afford crude 4-(8-(3-(trifluoromethyl)phenyl)-[1,2,4] triazolo[1,5-a]pyridin-2-ylamino)benzoic acid (1.0 g, HPLC purity: 89%). LCMS (ESI) m/z: 398.9; 1H NMR (400 MHz, DMSO-d6) δ: 12.45 (br s, 1H), 10.22 (s, 1H), 8.89 (d, J=6.8 Hz, 1H), 8.65 (s, 1H), 8.42 (d, J=6.9 Hz, 1H), 8.03 (m, 1H), 7.77-7.84 (m, 6H), 7.21 (t, J=7.0 Hz, 1H).
Reaction SMILES: C([O:8][C:9]1[C:14]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)=[CH:13][C:12]([C:22]([C:27]2[N:28]=[CH:29][N:30](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[CH:31]=2)([OH:26])[CH:23]([CH3:25])[CH3:24])=[CH:11][CH:10]=1)C1C=CC=CC=1>CO.[C].[Pd]>[F:21][C:18]1[CH:19]=[CH:20][C:15]([C:14]2[C:9]([OH:8])=[CH:10][CH:11]=[C:12]([C:22]([OH:26])([C:27]3[N:28]=[CH:29][NH:30][CH:31]=3)[CH:23]([CH3:25])[CH3:24])[CH:13]=2)=[CH:16][CH:17]=1
Reactant: CC(C)C(O)(c1ccc(OCc2ccccc2)c(-c2ccc(F)cc2)c1)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: [Pd]
Solvent: CO
Product: CC(C)C(O)(c1ccc(O)c(-c2ccc(F)cc2)c1)c1c[nH]cn1
Temperature: 25 °C
Reaction time: 4 h
Yield: 123.5 %

Procedure:
A suspension of 1-[6-benzyloxy-4′-fluoro[1,1′-biphenyl]-3-yl]-2-methyl-1-(1-trityl-1H-imidazol-4-yl)-1-propanol (647 mg) and 10% palladium carbon (647 mg) in methanol (15 ml) was stirred under a hydrogen atmosphere at room temperature for 4 h. The reaction mixture was filtered through Celite and the filtrate was concentrated. The residue was purified by silica gel chomatography (eluent; ethyl acetate→ethyl acetate:methanol=20:1). Recrystallization from ethyl acetate-hexane gave the title compound (396 mg) as colorless powder crystals.
Reaction SMILES: Cl.[CH:2]([N:5]1[CH:9]=[C:8]([C:10]2[N:15]=[C:14]([C:16]3[CH:17]=[N:18][N:19]([C:21]4([CH2:25][C:26]#[N:27])[CH2:24][NH:23][CH2:22]4)[CH:20]=3)[N:13]3[CH:28]=[CH:29][N:30]=[C:12]3[CH:11]=2)[CH:7]=[N:6]1)([CH3:4])[CH3:3].C(#N)C.C(=O)([O-])[O-].[K+].[K+].FC(F)(F)S(O[CH2:46][C:47]([F:50])([F:49])[F:48])(=O)=O>C(Cl)Cl>[CH:2]([N:5]1[CH:9]=[C:8]([C:10]2[N:15]=[C:14]([C:16]3[CH:17]=[N:18][N:19]([C:21]4([CH2:25][C:26]#[N:27])[CH2:22][N:23]([CH2:46][C:47]([F:50])([F:49])[F:48])[CH2:24]4)[CH:20]=3)[N:13]3[CH:28]=[CH:29][N:30]=[C:12]3[CH:11]=2)[CH:7]=[N:6]1)([CH3:4])[CH3:3]
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Reactant: CC(C)n1cc(-c2cc3nccn3c(-c3cnn(C4(CC#N)CNC4)c3)n2)cn1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CC#N
Product: CC(C)n1cc(-c2cc3nccn3c(-c3cnn(C4(CC#N)CN(CC(F)(F)F)C4)c3)n2)cn1
Yield: 47 %

Procedure:
To a flask charged with 2-(3-(4-(7-(1-isopropyl-1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidin-5-yl)-1H-pyrazol-1-yl)azetidin-3-yl)acetonitrile hydrochloride (0.050 g, 0.10 mmol) was added 1 mL of acetonitrile, potassium carbonate (0.10 g, 0.75 mmol), and 2,2,2-trifluoroethyl trifluoromethanesulfonate (0.040 g, 0.17 mmol) at ambient temperature with stirring. The reaction flask was then sealed and allowed to proceed at ambient temperature over the weekend. The reaction was diluted with DCM and the suspension was loaded directly onto a silica gel column pre-wetted and eluted with 75% ethyl acetate in Hexanes with 1% ammonium hydroxide to afford the title compound (0.022 g, 0.047 mmol, 47% yield). MS (apci) m/z=470.2 (M+H).
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([S:20][C:21]3[C:30]4[C:25](=[CH:26][C:27]([O:41][CH3:42])=[C:28]([O:31][CH2:32][CH2:33][CH2:34][N:35]5[CH2:40][CH2:39]C[CH2:37][CH2:36]5)[CH:29]=4)[N:24]=[CH:23][N:22]=3)[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].N1CC[S:46](=[O:50])(=[O:49])CC1>>[C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([S:20][C:21]3[C:30]4[C:25](=[CH:26][C:27]([O:41][CH3:42])=[C:28]([O:31][CH2:32][CH2:33][CH2:34][N:35]5[CH2:40][CH2:39][S:46](=[O:50])(=[O:49])[CH2:37][CH2:36]5)[CH:29]=4)[N:24]=[CH:23][N:22]=3)[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1cc2ncnc(Sc3cccc(NC(=O)Nc4cc(C(C)(C)C)on4)c3)c2cc1OCCCN1CCCCC1
Reactant: O=S1(=O)CCNCC1
Product: COc1cc2ncnc(Sc3cccc(NC(=O)Nc4cc(C(C)(C)C)on4)c3)c2cc1OCCCN1CCS(=O)(=O)CC1
Yield: 23 %

Procedure:
The title compound was prepared as described in Example 57B by using 1-(5-tert-butylisoxazol-3-yl)-3-(3-(6-(3-chloropropoxy)-7-methoxyquinazolin-4-ylthio)phenyl)urea from Example 57B (200 mg, 0.37 mmol) and thiomorpholine 1,1-dioxide (150 mg, 1.11 mmol) to afford 1-(5-tert-butyl-isoxazol-3-yl)-3-(3-{6-[3-(1,1-dioxo-thiomorpholin-4-yl)-propoxy]-7-methoxy-quinazolin-4-ylsulfanyl}-phenyl)-urea (54.51 mg, 23%) as a solid. 1H NMR (300 MHz, DMSO-d6) δ 9.59 (s, 1H), 9.01 (s, 1H), 8.69 (s, 1H), 7.85 (s, 1H), 7.52-7.27 (m, 5H), 6.49 (s, 1H), 4.25-4.21 (m, 2H), 3.99 (s, 3H), 3.11 (bs, 4H), 2.95 (bs, 4H), 2.70-2.65 (m, 2H), 2.01-1.97 (m, 2H), 1.27 (s, 9H); LC-MS (ESI) m/z 641 (M+H)+.
Reaction SMILES: [C:1]([C:4]1[CH:19]=[CH:18][C:7]([CH:8]=[CH:9][C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:11])=[CH:6][CH:5]=1)([OH:3])=[O:2].[OH:20]O.Cl>[OH-].[Na+].O>[C:1]([C:4]1[CH:19]=[CH:18][C:7]([CH:8]2[O:20][CH:9]2[C:10]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[O:11])=[CH:6][CH:5]=1)([OH:3])=[O:2]
Reactant: O=C(O)c1ccc(C=CC(=O)c2ccccc2)cc1
Reactant: OO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)c1ccc(C2OC2C(=O)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 18.9 g of 4-carboxybenzalacetophenone in 7.5 ml of 1N sodium hydroxide solution and 225 ml of water was added 15 ml of 30% hydrogen peroxide. After cooling in an ice-water bath, 50 ml of 0.5N sodium hydroxide was added dropwise over 5 min. The reaction mixture was stirred at room temperature for 31/4 hrs. and acidified to pH of 6.5 with 1N hydrochloric acid. After stirring at room temperature for 1 hr., the solid was collected on a filter, washed with water and air-dried. Recrystallization from ethanol gave 11 g of 3-(4-carboxyphenyl)-1-phenyl-2,3-epoxy-1-propanone as colorless crystals, m.p. 170°-172° C. after drying at 80° C under vacuum for 3 hrs.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[C:3]=1[C:4]([OH:6])=[O:5].C(=O)([O-])[O-].[K+].[K+].Cl[CH2:19][N:20]1[C:24](=[O:25])[C:23]([CH3:29])([CH2:26][CH2:27][CH3:28])[N:22]([CH3:30])[S:21]1(=[O:32])=[O:31]>CN(C=O)C>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[C:3]=1[C:4]([O:6][CH2:19][N:20]1[C:24](=[O:25])[C:23]([CH3:29])([CH2:26][CH2:27][CH3:28])[N:22]([CH3:30])[S:21]1(=[O:31])=[O:32])=[O:5]
Reactant: O=C(O)c1c(Cl)cccc1Cl
Reactant: CCCC1(C)C(=O)N(CCl)S(=O)(=O)N1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCC1(C)C(=O)N(COC(=O)c2c(Cl)cccc2Cl)S(=O)(=O)N1C
Temperature: 25 °C
Reaction time: 12 h
Yield: 60.2 %

Procedure:
To a stirred solution of 2,6-dichlorobenzoic acid (206 mg, 1.08 mmol) and 112 mg (0.812 mmol) of potassium carbonate in 20 ml of DMF under nitrogen was added 2-chloromethyl-4-methyl-4-propyl-5-methyl-1,2,5-thiadiazolidin-3-one 1,1-dioxide (250 mg, 0. 981 mmol) and the mixture was allowed to react at room temperature for 12 hours. After adding an additional 2,6-dichlorobenzoic acid (0.038 g) and 0.055 g of potassium carbonate, the mixture was stirred at room temperature for additional 12 hours. The mixture was diluted with ice/water, extracted with ethyl acetate, and the organic layer was washed with water, brine, and dried. The organic solution was concentrated in vacuo and the residue was purified by flash chromatography (silica gel; 10% ethyl acetate in hexane) to afford 266 mg (66%) of 2- (2,6-dichlorophenylcarbonyloxymethyl)-4-methyl-4-propyl-5-methyl-1,2,5-thiadiazolidin-3-one 1,1-dioxide (Formula I: Ar-2,6-Cl2 -phenyl; R1 =propyl; R2 =CH3 ; R3 =CH3) as a solid, m.p. 93°-95° C.
Reaction SMILES: NC1C=CC2C3C(C(=O)N(C4C=CC=CC=4)N=3)=CNC=2C=1.[CH3:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([N:30]2[C:45](=[O:46])[C:33]3=[CH:34][NH:35][C:36]4[CH:37]=[C:38]([N+:42]([O-])=O)[CH:39]=[CH:40][C:41]=4[C:32]3=[N:31]2)=[CH:26][CH:25]=1>>[NH2:42][C:38]1[CH:39]=[CH:40][C:41]2[C:32]3[C:33]([C:45](=[O:46])[N:30]([C:27]4[CH:28]=[CH:29][C:24]([O:23][CH3:22])=[CH:25][CH:26]=4)[N:31]=3)=[CH:34][NH:35][C:36]=2[CH:37]=1
Reactant: COc1ccc(-n2nc3c4ccc([N+](=O)[O-])cc4[nH]cc-3c2=O)cc1
Agent: Nc1ccc2c3nn(-c4ccccc4)c(=O)c-3c[nH]c2c1
Product: COc1ccc(-n2nc3c4ccc(N)cc4[nH]cc-3c2=O)cc1

Procedure:
The title compound was prepared following the procedure described for 13a using 12c. 1H-NMR (DMSO-d6) δ (ppm): 6.74 (1H, d, J=2.20 Hz) 6.79 (1H, dd, J=8.79, 2.19 Hz), 7.42 (1H, d, J=8.79 Hz), 7.43 (1H, q, J=5.22 Hz), 7.86 (1H, d, J=8.51 Hz), 8.20 (1H, d, J=9.06 Hz), 8.21 (1H, q, J=5.21 Hz), 8.47 (1H, d, J=6.32 Hz). m/z 307.3 (MH+).
Reaction SMILES: FC(F)(F)C[O:4]C1C=CC(OCC(F)(F)F)=CC=1.C[C:20]([C:22]1[CH:27]=[C:26]([O:28][CH2:29][C:30]([F:33])([F:32])[F:31])[CH:25]=[CH:24][C:23]=1[O:34][CH2:35][C:36]([F:39])([F:38])[F:37])=[O:21].C(C1C=CC=CC=1)(=O)C.Cl[O-]>>[F:37][C:36]([F:39])([F:38])[CH2:35][O:34][C:23]1[CH:24]=[CH:25][C:26]([O:28][CH2:29][C:30]([F:33])([F:32])[F:31])=[CH:27][C:22]=1[C:20]([OH:21])=[O:4]
Reactant: FC(F)(F)COc1ccc(OCC(F)(F)F)cc1
Reactant: CC(=O)c1cc(OCC(F)(F)F)ccc1OCC(F)(F)F
Agent: [O-]Cl
Solvent: CC(=O)c1ccccc1
Product: O=C(O)c1cc(OCC(F)(F)F)ccc1OCC(F)(F)F

Procedure:
In yet another aspect of the invention, a method of preparing a 2,5-bis(2,2,2-trifluoroethoxy)-N-(2-piperidylmethyl)benzamide is provided which comprises the following steps. The compound 1,4-dibromobenzene is contacted with an alkali metal 2,2,2-trifluoroethoxide in the presence of cuprous or cupric ion and in a strongly polar solvent comprising 2,2,2-trifluoroethanol to yield 1,4-bis(2,2,2-trifluoroethoxy)benzene. Then, in the presence of a Lewis acid catalyst, the 1,4-bis(2,2,2-trifluoroethoxy)benzene is treated with an acetylation agent under conditions to create 2,5-bis(2,2,2-trifluoroethoxy)acetophenone. The methyl moiety of the acetophenone function of the 2,5-bis(2,2,2-trifluoroethoxy)acetophenone is thereafter replaced using hypochlorite to yield 2,5-bis(2,2,2-trifluoroethoxy)benzoic acid. Subsequently, the 2,5-bis(2,2,2-trifluoroethoxy)benzoic acid is treated with an inorganic chloride to provide 2,5-bis(2,2,2-trifluoroethoxy)benzoic acid chloride. Finally, the resultant 2,5-bis(2,2,2-trifluoroethoxy)benzoic acid chloride is contacted with 2-aminomethylpiperidine, whereby there is formed 2,5-bis(2,2,2-trifluoroethoxy)-N-(2-piperidylmethyl)benzamide.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[N:13]([CH3:14])[C:12]([C:15]3[CH:19]=[CH:18][N:17](CC)[N:16]=3)=[N:11][C:10]=2[C:22]2[CH:27]=[CH:26][C:25]([C:28]3N=CO[N:29]=3)=[CH:24][CH:23]=2)=[CH:4][CH:3]=1.[H-].[Na+].[CH3:35][CH2:36][O:37][C:38]([CH2:40]Br)=[O:39]>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8][C:9]2[N:13]([CH3:14])[C:12]([C:15]3[CH:19]=[CH:18][N:17]([CH2:40][C:38]([O:37][CH2:36][CH3:35])=[O:39])[N:16]=3)=[N:11][C:10]=2[C:22]2[CH:27]=[CH:26][C:25]([C:28]#[N:29])=[CH:24][CH:23]=2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)CBr
Reactant: CCn1ccc(-c2nc(-c3ccc(-c4ncon4)cc3)c(Sc3ccc(Cl)cc3)n2C)n1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)Cn1ccc(-c2nc(-c3ccc(C#N)cc3)c(Sc3ccc(Cl)cc3)n2C)n1
Temperature: 0 °C
Reaction time: 1 h
Yield: 57.4 %

Procedure:
To a mixture of Step 2 product of Example 140 (100 mg, 0.255 mmol) in THF (2 ml) at 0° C. was added NaH (20.4 mg, 0.510 mmol). After stirred at 0° C. for 1 hr, ethyl bromo acetate (0.034 ml, 0.306 mmol) was added and then stirred at 0° C. for one hour. Reaction mixture was quenched with water, extracted with EtOAc, washed with brine, dried over Na2SO4, filtered, concentrated, separated by prep. TLC (Hex:EtOAc=2:1) to give ethyl (3-{5-[(4-chlorophenyl)sulfanyl]-4-(4-cyanophenyl)-1-methyl-1H-imidazol-2-yl}-1H-pyrazol-1-yl)acetate (70 mg) desired compound. LCMS: [M+1]+=478.0.
Reaction SMILES: Cl.Cl.[Br:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[C:6]([C:16]([CH3:19])([CH3:18])[CH3:17])[CH:5]=1.C(N(CC)CC)C.Cl[C:28](=[O:34])[C:29]([O:31][CH2:32][CH3:33])=[O:30].O>C1COCC1>[Br:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][N:13]([C:28](=[O:34])[C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH2:12][CH2:11]2)=[C:6]([C:16]([CH3:19])([CH3:18])[CH3:17])[CH:5]=1
Reactant: CCOC(=O)C(=O)Cl
Reactant: CC(C)(C)c1cc(Br)ccc1N1CCNCC1
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)C(=O)N1CCN(c2ccc(Br)cc2C(C)(C)C)CC1
Temperature: 0 °C
Yield: 101.9 %

Procedure:
To a stirred suspension of 1-(4-bromo-2-tert-butylphenyl)piperazine dihydrochloride (Reference Example 9, 0.300 g, 0.81 mmol) and triethylamine (564 μl, 4.05 mmol) in THF (10 mL) stirring at 0° C. was added ethyl chloro(oxo)acetate (0.144 mg, 1.05 mmol). The mixture was warmed to room temperature. After 16 h the reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated sodium hydrogen carbonate and brine, dried over MgSO4, and the solvent was evaporated under reduced pressure to give the crude product. The product was purified by flash column chromatography (silica gel, n-hexane/ethyl acetate=80:20 to 50:50) to provide ethyl [4-(4-bromo-2-tert-butylphenyl)piperazin-1-yl](oxo)acetate (0.328 g, quant) as a white solid.