Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[K+].[Br:3][C:4]1[C:5]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:6]([C:11]([O:13]CC)=[O:12])[N:7]([CH3:10])[C:8]=1[CH3:9]>O.C(O)C>[Br:3][C:4]1[C:5]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:6]([C:11]([OH:13])=[O:12])[N:7]([CH3:10])[C:8]=1[CH3:9]
Reactant: CCOC(=O)c1c(-c2ccccc2)c(Br)c(C)n1C
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1c(Br)c(-c2ccccc2)c(C(=O)O)n1C
Yield: 68.4 %

Procedure:
A solution of potassium hydroxide (1.40 g, 25.0 mmol) in water (3 mL) was added to a solution of ethyl 4-bromo-1,5-dimethyl-3-phenyl-pyrrole-2-carboxylate (1.60 g, 4.97 mmol) in ethanol (5 mL) and the reaction mixture was refluxed overnight. The solvent was evaporated and the residue was washed with diethyl ether. The resultant filter cake was acidified with diluted HCl and extracted with ether. The organic layer was washed with water, brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 4-bromo-1,5-dimethyl-3-phenyl-pyrrole-2-carboxylic acid (1.0 g, 69%) as a solid.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:30][CH2:29][C:10]3([CH2:13][CH:12]([NH:14][C:15]([O:17][CH2:18][C:19]4[O:23][N:22]=[C:21]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH:20]=4)=[O:16])[CH2:11]3)[CH2:9]2)=[N:6][CH:7]=1.[F:31][C:32]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C(Cl)Cl>[F:31][C:32]1[CH:37]=[CH:36][C:35]([C:2]2[CH:3]=[CH:4][C:5]([N:8]3[CH2:30][CH2:29][C:10]4([CH2:11][CH:12]([NH:14][C:15]([O:17][CH2:18][C:19]5[O:23][N:22]=[C:21]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH:20]=5)=[O:16])[CH2:13]4)[CH2:9]3)=[N:6][CH:7]=2)=[CH:34][CH:33]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: CCOC(=O)c1cc(COC(=O)NC2CC3(CCN(c4ccc(Br)cn4)C3)C2)on1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClCCl
Product: CCOC(=O)c1cc(COC(=O)NC2CC3(CCN(c4ccc(-c5ccc(F)cc5)cn4)C3)C2)on1
Yield: 48.4 %

Procedure:
The process is performed according to the procedure described in Example 2 (step 2.7.). Starting with 1.00 g (2.09 mmol) of ethyl 5-[6-(5-bromopyridin-2-yl)-6-azaspiro[3.4]oct-2-ylcarbamoyloxymethyl]isoxazole-3-carboxylate (isomer 6) and 0.29 g (2.09 mmol) of 4-fluorophenylboronic acid, 2.03 g (6.26 mmol) of caesium carbonate and 0.17 g (0.21 mmol) of PdCl2dppf.CH2Cl2, 0.50 g of a gum is obtained after chromatography on silica gel, eluting with a 90/10 mixture of cyclohexane and ethyl acetate.
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH3:6])=[O:4].C([O-])([O-])=O.[K+].[K+].[CH:13]1([N:16]2[C:24]3[C:19](=[C:20]([OH:49])[CH:21]=[C:22]([C:25]([N:27]4[CH2:32][CH2:31][C:30]5([CH2:41][C:40](=[O:42])[C:39]6[C:34](=[CH:35][CH:36]=[C:37]([C:43]7[CH:44]=[N:45][N:46]([CH3:48])[CH:47]=7)[CH:38]=6)[O:33]5)[CH2:29][CH2:28]4)=[O:26])[CH:23]=3)[CH:18]=[CH:17]2)[CH2:15][CH2:14]1>CN(C=O)C.CCOC(C)=O>[CH:13]1([N:16]2[C:24]3[C:19](=[C:20]([O:49][CH2:2][C:3]([O:5][CH3:6])=[O:4])[CH:21]=[C:22]([C:25]([N:27]4[CH2:28][CH2:29][C:30]5([CH2:41][C:40](=[O:42])[C:39]6[C:34](=[CH:35][CH:36]=[C:37]([C:43]7[CH:44]=[N:45][N:46]([CH3:48])[CH:47]=7)[CH:38]=6)[O:33]5)[CH2:31][CH2:32]4)=[O:26])[CH:23]=3)[CH:18]=[CH:17]2)[CH2:14][CH2:15]1
Reactant: COC(=O)CBr
Reactant: Cn1cc(-c2ccc3c(c2)C(=O)CC2(CCN(C(=O)c4cc(O)c5ccn(C6CC6)c5c4)CC2)O3)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)COc1cc(C(=O)N2CCC3(CC2)CC(=O)c2cc(-c4cnn(C)c4)ccc2O3)cc2c1ccn2C1CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Methyl bromoacetate (0.059 ml, 0.604 mmol) was added to a stirred mixture of K2CO3 (111 mg, 0.806 mmol), 1′-[(1-cyclopropyl-4-hydroxy-1H-indol-6-yl)carbonyl]-6-(1-methyl-1H-pyrazol-4-yl)spiro[chroman-2,4′-piperidin]-4-one (200 mg, 0.403 mmol) in DMF (2 ml) and the mixture was stirred at room temperature overnight. The mixture was diluted with EtOAc, washed with water, brine, and dried over MgSO4. After filteration and evaporation, the residue was purified by silicagel column chromatography (CHCl3/MeOH) to give intended compound as yellow oil.
Reaction SMILES: [C:1]([Si:5]([O:8][C:9]1[CH:14]=[C:13]([F:15])[CH:12]=[C:11]([F:16])[CH:10]=1)([CH3:7])[CH3:6])([CH3:4])([CH3:3])[CH3:2].C([Li])CCC.C(O[B:26]1[O:30][C:29]([CH3:32])([CH3:31])[C:28]([CH3:34])([CH3:33])[O:27]1)(C)C>C1COCC1>[C:1]([Si:5]([O:8][C:9]1[CH:10]=[C:11]([F:16])[C:12]([B:26]2[O:30][C:29]([CH3:32])([CH3:31])[C:28]([CH3:34])([CH3:33])[O:27]2)=[C:13]([F:15])[CH:14]=1)([CH3:7])[CH3:6])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)OB1OC(C)(C)C(C)(C)O1
Reactant: CC(C)(C)[Si](C)(C)Oc1cc(F)cc(F)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC1(C)OB(c2c(F)cc(O[Si](C)(C)C(C)(C)C)cc2F)OC1(C)C
Temperature: -78 °C
Reaction time: 1 h
Yield: 91 %

Procedure:
To a solution of tert-butyl(3,5-difluorophenoxy)dimethylsilane (1.0 eq) in dry THF (0.2 M) under an atmosphere of N2 at −78° C. was added n-butyllithium (1 eq, 1.6 M in hexanes) slowly keeping the internal temperature below −65° C. The reaction was stirred for 1 hr at −78° C., followed by the addition of 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (2.1 eq). The reaction was allowed to warm to room temperature. Upon completion, the reaction was quenched with NaHCO3 (sat.) and extracted with EtOAc. The organics were washed with brine, dried over Na2SO4, filtered and concentrated to yield tert-butyl(3,5-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)dimethylsilane in 91% yield. 1H NMR (400 MHz, <cdcl3>) δ ppm 0.21 (s, 6H) 0.97 (s, 9H) 1.37 (s, 12H) 6.33 (d, J=9.39 Hz, 2H).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([O:10][CH3:11])[C:5]([NH2:9])=[N:6][C:7]=1[Cl:8].[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([S:19](Cl)(=[O:21])=[O:20])=[CH:15][CH:14]=1>>[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([S:19]([NH:9][C:5]2[C:4]([O:10][CH3:11])=[N:3][C:2]([Cl:1])=[C:7]([Cl:8])[N:6]=2)(=[O:21])=[O:20])=[CH:15][CH:14]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: COc1nc(Cl)c(Cl)nc1N
Product: COc1nc(Cl)c(Cl)nc1NS(=O)(=O)c1ccc(Cl)cc1

Procedure:
Prepared by the method of Example 1 (reaction performed at room temperature) using 5,6-dichloro-3-methoxy-2-pyrazinamine (0.1 g) and 4-chlorobenzenesulphonyl chloride (0.13 g). Yield 0.09 g.
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[CH:14][C:5]2[NH:6][C:7](=[O:13])[CH2:8][CH2:9][C:10]([CH3:12])([CH3:11])[C:4]=2[CH:3]=1.[C:16]([NH:19][C:20]1[CH:29]=[CH:28][C:23]([C:24]([NH:26][CH3:27])=[O:25])=[C:22]([NH:30][C:31]2[C:36]([Cl:37])=[CH:35][N:34]=[C:33](Cl)[N:32]=2)[CH:21]=1)(=[O:18])[CH3:17]>>[C:16]([NH:19][C:20]1[CH:29]=[CH:28][C:23]([C:24]([NH:26][CH3:27])=[O:25])=[C:22]([NH:30][C:31]2[C:36]([Cl:37])=[CH:35][N:34]=[C:33]([NH:1][C:2]3[CH:15]=[CH:14][C:5]4[NH:6][C:7](=[O:13])[CH2:8][CH2:9][C:10]([CH3:12])([CH3:11])[C:4]=4[CH:3]=3)[N:32]=2)[CH:21]=1)(=[O:18])[CH3:17]
Reactant: CNC(=O)c1ccc(NC(C)=O)cc1Nc1nc(Cl)ncc1Cl
Reactant: CC1(C)CCC(=O)Nc2ccc(N)cc21
Product: CNC(=O)c1ccc(NC(C)=O)cc1Nc1nc(Nc2ccc3c(c2)C(C)(C)CCC(=O)N3)ncc1Cl

Procedure:
4-Acetylamino-2-[5-chloro-2-(5,5-dimethyl-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-7-ylamino)-pyrimidin-4-ylamino]-N-methyl-benzamide was prepared from 7-Amino-5,5-dimethyl-1,3,4,5-tetrahydro-benzo[b]azepin-2-one and 4-Acetylamino-2-(2,5-dichloro-pyrimidin-4-ylamino)-N-methyl-benzamide in an analogous manner to Example 1221d. Title compound was isolated as a white powder, 27 mg, 35%. MP >300, LCMS: 522.21 (M+H), HPLC purity 100%, 1H-NMR (DMSO-d6, 400 MHz) δ 11.60 (s, 1H), 9.99 (s, 1H), 9.39 (s, 1H), 9.27 (s, 1H), 8.61 (d, J=4.5 Hz, 1H), 8.53 (s, 1H), 8.23 (s, 1H), 7.72-7.68 (m, 2H), 7.57 (d, J=8.8 Hz, 1H), 7.50 (s, 1H), 6.78 (d, J=8.6 Hz, 1H), 2.78 (d, J=3.9 Hz, 3H), 2.15-2.13 (m, 2H), 2.03 (s, 3H), 1.98-1.96 (m, 2H).
Reaction SMILES: C([Si]([O:8]/[C:9](/[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=1)=[CH:10]\[CH3:11])(C)C)(C)(C)C.CC[C@@H]1[C@@H]2C[C@H]([C@@H](OC3C4C(=CC=CC=4)C(O[C@@H](C4C=CN=C5C=4C=C(OC)C=C5)[C@@H]4N5C[C@H](CC)[C@@H](CC5)C4)=NN=3)C3C=CN=C4C=3C=C([O:40]C)C=C4)N(CC2)C1.CS(N)(=O)=O>C(O)(C)(C)C.O>[F:18][C:14]1[CH:13]=[C:12]([C:9](=[O:8])[C@H:10]([OH:40])[CH3:11])[CH:17]=[CH:16][CH:15]=1
Reactant: CC[C@H]1CN2CC[C@H]1C[C@@H]2[C@@H](Oc1nnc(O[C@@H](c2ccnc3ccc(OC)cc23)[C@H]2C[C@@H]3CCN2C[C@@H]3CC)c2ccccc12)c1ccnc2ccc(OC)cc12
Reactant: C/C=C(\O[Si](C)(C)C(C)(C)C)c1cccc(F)c1
Agent: CS(N)(=O)=O
Solvent: CC(C)(C)O
Solvent: O
Product: C[C@@H](O)C(=O)c1cccc(F)c1
Yield: 87.2 %

Procedure:
Compound 10c was synthesized by a procedure similar to that described for (R)-10a using (Z)-tert-butyl(1-(3-fluorophenyl)prop-1-enyloxy)dimethylsilane, (9c, 8.0 g, 0.030 mol), AD-mix-β (42.1 g), and CH3SO2NH2 (2.90 g, 0.0301 mol) in tert-butyl alcohol-water (120 mL:120 mL). The reaction was quenched with sodium sulfite (30.1 g). After purification, 4.4 g (87%) of the desired product 10c was isolated: [α]20D +58.1° (c 3.2, CHCl3); 1H NMR (CDCl3) δ 7.74-7.59 (m, 2H), 7.54-7.45 (m, 1H), 7.37-7.28 (m, 1H), 5.19-5.07 (m, 1H), 1.76 (d, 1H, J=6.3 Hz), 1.46 (d, 3H, J=6.9 Hz); 13C NMR (CDCl3) δ 201.6, 164.9, 131.0, (d), 124.7, 121.3 (d), 115.8 (d), 69.9, 22.4. C9H9FO2.
Reaction SMILES: [N:1]([O-])=O.[Na+].[NH2:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=[O:11])=[C:8]([CH3:15])[C:7]=1[CH3:16].O.O.[Cl:19][Sn]Cl>O.Cl>[ClH:19].[CH3:15][C:8]1[C:7]([CH3:16])=[C:6]([NH:5][NH2:1])[CH:14]=[CH:13][C:9]=1[C:10]([OH:12])=[O:11]
Reactant: Cl[Sn]Cl
Reactant: Cc1c(N)ccc(C(=O)O)c1C
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: Cc1c(NN)ccc(C(=O)O)c1C
Temperature: -5 °C
Reaction time: 2 h
Yield: 93.7 %

Procedure:
A solution of 1.87 g of NaNO2 in 7 ml of water is added slowly to a solution, cooled to -5° C., of 4.5 g of 4-amino-2,3-dimethylbenzoic acid in 135 ml of concentrated HCl. After 2 hours of stirring at -5° C., a solution of 25 g of SnCl2.2H2O in 250 ml of concentrated HCl is added at -10° C., and the mixture is stirred for 30 minutes at -5° C. and then 2 hours at RT. The mixture is filtered, and the precipitate is washed with 5 ml of concentrated HCl and dried under a stream of dry nitrogen and then under vacuum to obtain 5.5 g of expected product.
Reaction SMILES: [OH:1][C:2]1[C:6]([CH2:7][CH2:8][C:9]([O:11]CC)=[O:10])=[CH:5][N:4]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]3[N:24]=[C:25]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[O:26][C:27]=3[CH3:28])=[CH:17][CH:16]=2)[N:3]=1.[H-].[Na+].I[CH2:38][CH2:39][CH3:40].O>CN(C)C=O>[CH3:28][C:27]1[O:26][C:25]([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)=[N:24][C:23]=1[CH2:22][O:21][C:18]1[CH:17]=[CH:16][C:15]([CH2:14][N:4]2[CH:5]=[C:6]([CH2:7][CH2:8][C:9]([OH:11])=[O:10])[C:2]([O:1][CH2:38][CH2:39][CH3:40])=[N:3]2)=[CH:20][CH:19]=1
Reactant: CCOC(=O)CCc1cn(Cc2ccc(OCc3nc(-c4ccccc4)oc3C)cc2)nc1O
Reactant: CCCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCOc1nn(Cc2ccc(OCc3nc(-c4ccccc4)oc3C)cc2)cc1CCC(=O)O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of ethyl 3-[3-hydroxy-1-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyl]-1H-pyrazol-4-yl]propionate (710 mg) in N,N-dimethylformamide (10 ml), sodium hydride (60%, oily, 72.0 mg) was added at 0° C., and the solution was stirred at room temperature for 30 minutes. Iodopropane (0.33 g) was added to the reaction mixture, which was stirred at room temperature for two hours. The reaction mixture was poured into water, which was extracted with ethyl acetate. The ethyl acetate layer was washed with water, then, with saturated aqueous sodium chloride solution, and dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and a colorless oily substance was obtained from the fraction eluted with ethyl acetate-hexane (1:2, volume ratio). A mixture of the obtained oily substance, 1 N aqueous sodium hydroxide solution (3 ml), tetrahydrofuran (5 ml), and ethanol (5 ml) was stirred at room temperature for two hours, diluted with 1 N hydrochloric acid (3 ml), and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), and concentrated. The obtained colorless crystals were collected by filtration, and 3-[1-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyl]-3-propyloxy-1H-pyrazol-4-yl]propionic acid was obtained (0.59 g, yield. 81%). This was recrystallized from acetone-hexane. Melting point: 108–109° C.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:13]2[S:14][CH:15]=[C:16]([C:18]3[CH:23]=[C:22]([CH2:24][C:25]([CH3:27])=C)[C:21]([O:28][CH2:29][O:30][CH3:31])=[C:20]([C:32]([O:34][CH2:35][O:36][CH2:37]OC)=[O:33])[CH:19]=3)[N:17]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH3:12])[CH3:2].[O:40]=[O+][O-].CSC>CO>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:13]2[S:14][CH:15]=[C:16]([C:18]3[CH:23]=[C:22]([CH2:24][C:25](=[O:40])[CH3:27])[C:21]([O:28][CH2:29][O:30][CH3:31])=[C:20]([C:32]([O:34][CH2:35][O:36][CH3:37])=[O:33])[CH:19]=3)[N:17]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH3:12])[CH3:2]
Reactant: C=C(C)Cc1cc(-c2csc(-c3ccc(OCC)c(OCC)c3)n2)cc(C(=O)OCOCOC)c1OCOC
Reactant: O=[O+][O-]
Solvent: CO
Solvent: CSC
Product: CCOc1ccc(-c2nc(-c3cc(CC(C)=O)c(OCOC)c(C(=O)OCOC)c3)cs2)cc1OCC
Reaction time: 1 h

Procedure:
In 20 ml of methanol was dissolved 1 g of 2-(3,4-diethoxyphenyl)-4-[3-methoxymethoxymethoxycarbonyl-4-methoxymethoxy-5-(2-methyl-2-propenyl)phenyl]thiazole. Into the solution being stirred under ice-cooling was blown ozone. After 1 hour, 0.5 ml of methyl sulfide was added. The mixture was stirred at the same temperature for 30 minutes. The solvent was removed from the reaction mixture by distillation. To the residue were added 50 ml of dichloromethane and 25 ml of water. The organic layer was separated, washed with 15 ml of a saturated aqueous sodium chloride solution, dried and subjected to distillation to remove the solvent. The residue was purified by silica gel column chromatography (eluent: dichloromethane/n-hexane=2/3 by v/v) to obtain 500 mg of 2-(3,4-diethoxyphenyl)-4-(3-methoxymethoxycarbonyl-4-methoxymethoxy-5-acetylmethylphenyl)thiazole as a colorless oily substance.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:13]=[C:12]2[C:8]([CH:9]=[CH:10][NH:11]2)=[C:7]([CH2:14][N:15]2[CH2:20][CH2:19][N:18](C([O:23][C:24]([CH3:27])(C)C)=O)[CH2:17][CH2:16]2)[CH:6]=1.[F:28][C:29]1[CH:34]=[CH:33][C:32]([S:35](Cl)(=[O:37])=[O:36])=[CH:31][CH:30]=1>C1COCC1>[C:24]([OH:36])(=[O:23])[CH3:27].[F:28][C:29]1[CH:34]=[CH:33][C:32]([S:35]([N:11]2[C:12]3[C:8](=[C:7]([CH2:14][N:15]4[CH2:16][CH2:17][NH:18][CH2:19][CH2:20]4)[CH:6]=[C:5]([O:4][CH3:3])[CH:13]=3)[CH:9]=[CH:10]2)(=[O:37])=[O:36])=[CH:31][CH:30]=1
Reactant: COc1cc(CN2CCN(C(=O)OC(C)(C)C)CC2)c2cc[nH]c2c1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(=O)O
Product: COc1cc(CN2CCNCC2)c2ccn(S(=O)(=O)c3ccc(F)cc3)c2c1
Reaction time: 0.08 h
Yield: 49 %

Procedure:
NaH (6 mg, 0.14 mmol, 60% in mineral oil) was added to tert-butyl 4-[(6-methoxy-1H-indol-4-yl)methyl]piperazine-1-carboxylate (10 mg, 0.029 mmol; Intermediate 40) in dry THF (1 mL). The reaction mixture was stirred for 5 min, 4-fluorobenzenesulfonyl chloride (8 mg, 0.044 mmol) in dry THF (0.5 mL) was added and the mixture was stirred over night. The reaction mixture was cooled on ice and quenched with ice and THF was evaporated. The residue was dissolved in MeOH (3 mL) and conc. HCl (0.5 mL) was added. The mixture was irradiated by microwaves at 100° C. for 300 s, the volume concentrated to ˜1.5 mL, followed of filtering and purification by preparative HPLC/UV (System A, 25-55% MeCN, 0.1% NH4OAc). The title compound (5 mg, 39%) was obtained as a white solid. MS (ESI+) for C20H22FN3O3S m/z 404 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:18]([C:19](O)=[O:20])=[CH:17][C:12]3[C:13]([CH3:16])=[N:14][O:15][C:11]=3[C:10]=2[F:22])=[C:4]([Cl:23])[CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH3:36][S:37]([NH2:40])(=[O:39])=[O:38].C1CCN2C(=NCCC2)CC1>C1COCC1.CCOC(C)=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:18]([C:19]([NH:40][S:37]([CH3:36])(=[O:39])=[O:38])=[O:20])=[CH:17][C:12]3[C:13]([CH3:16])=[N:14][O:15][C:11]=3[C:10]=2[F:22])=[C:4]([Cl:23])[CH:3]=1
Reactant: CS(N)(=O)=O
Reactant: Cc1noc2c(F)c(Nc3ccc(Br)cc3Cl)c(C(=O)O)cc12
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1noc2c(F)c(Nc3ccc(Br)cc3Cl)c(C(=O)NS(C)(=O)=O)cc12
Temperature: 50 °C
Yield: 69.9 %

Procedure:
A mixture of 6-(4-bromo-2-chlorophenylamino)-7-fluoro-3-methylbenzo[d]isoxazole-5-carboxylic acid (9a) (41 mg, 0.102 mmol) and carbonyldiimidazole (23 mg, 0.140 mmol) in THF (1 mL) was stirred at 50° C. in a sealed tube reactor. The reaction mixture was cooled to room temperature and methanesulfonamide (17 mg, 0.179 mmol) was added followed by DBU (0.025 mL, 0.164 mmol). After stirring at 50° C. for 1 hour, the reaction mixture was cooled to room temperature, and diluted with EtOAc. The organic layer was washed with water, 1 N HCl, and brine. The organic layer was dried (MgSO4) and concentrated. Purification by flash column chromatography using the Biotage system (7% MeOH in CH2Cl2) provided 34 mg (65% yield) of the desired product (13a). MS APCI (−) m/z 474, 476 (M+, Br, Cl pattern) detected. 1H NMR (400 MHz, CD3OD) δ 8.27 (s, 1H), 7.53 (s, 1H), 7.27 (d, 1H), 6.73 (t, 1H), 3.11 (s, 3H), 2.55 (s, 3H): 19F NMR (376 MHz, CD3OD)−141.84 (s, 1F).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([S:14]([CH3:17])(=[O:16])=[O:15])[CH:11]=[C:10]([C:18](O)=[O:19])[CH:9]=2)=[CH:4][CH:3]=1.Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1.[NH2:44][C@@H:45]([CH3:48])[CH2:46][OH:47].C(N(CC)C(C)C)(C)C>C(Cl)Cl>[OH:47][CH2:46][C@@H:45]([NH:44][C:18]([C:10]1[CH:9]=[C:8]([C:5]2[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=2)[CH:13]=[C:12]([S:14]([CH3:17])(=[O:15])=[O:16])[CH:11]=1)=[O:19])[CH3:48]
Reactant: C[C@H](N)CO
Reactant: Cc1ccc(-c2cc(C(=O)O)cc(S(C)(=O)=O)c2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1ccc(-c2cc(C(=O)N[C@@H](C)CO)cc(S(C)(=O)=O)c2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 4′-methyl-5-(methylsulfonyl)biphenyl-3-carboxylic acid (50 mg, 0.17 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (36 mg, 0.19 mmol), 1-hydroxybenzotriazole hydrate (26 mg, 0.17 mmol), and CH2Cl2 (2 mL) were added (S)-2-aminopropan-1-ol (19 mg, 0.26 mmol) and N,N-diisopropylethylamine (0.045 mL, 0.26 mmol). The mixture was stirred at room temperature overnight and then concentrated in vacuo. The residue was purified by preparative HPLC (100×20.2 mm, C18 column; 30-60% MeCN-water[10 mM Et2NH]) to yield a white solid.
Reaction SMILES: CO[C:3](=[O:15])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH3:11])=[C:6]([N+:12]([O-:14])=[O:13])[CH:5]=1.[CH2:16]=[O:17].C[C:19](C)([O-:21])C.[K+]>CS(C)=O>[CH3:16][O:17][C:3]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]([CH3:11])[CH2:19][OH:21])=[C:6]([N+:12]([O-:14])=[O:13])[CH:5]=1)=[O:15]
Reactant: CCc1ccc(C(=O)OC)cc1[N+](=O)[O-]
Reactant: CC(C)(C)[O-]
Reactant: C=O
Agent: [K+]
Solvent: CS(C)=O
Product: COC(=O)c1ccc(C(C)CO)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 38 %

Procedure:
To a suspension of 4-ethyl-3-nitrobenzoic acid methyl ester (11d) (10 g, 48 mmol) and paraformaldehyde (1.8 g, 60 mmol) in DMSO (10 mL) was added in portions potassium tert-butoxide (1.46 g, 12 mmol), during which the colour of the reaction mixture was changing from yellow to purple. After stirring for 2.5 hours at room temperature, the reaction mixture was directly applied to the silica gel bed of a chromatography column (100 g silica, 3.5×14 cm) and eluted with hexane/ethyl acetate (EA) (3:1, v/v). The slightly yellow product (4d) was obtained in 38% yield (4.42 g, 18 mmol). Rf=0.24 (hexanes/EtOAc 7:3). 1H NMR (250 MHz, CDCl3) δ 8.36 (d, 1H, arom. H(3)), 8.18 (dd, 1H, arom. H(5)), 7.58 (d, 1H, arom. H(6)), 3.93 (s, 3H, COOCH3), 3.78 (m, 2H, α-CH2), 3.54 (sextet, 1H, β-CH), 1.69 (d, 3H, CH3).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:15]([C:16]#[N:17])=[C:14]([CH2:18][CH3:19])[S:13][C:12]=2[C:20]([NH2:22])=[O:21])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].CO[CH:25]([N:28]([CH3:30])[CH3:29])OC>>[CH3:25][N:28]([CH:30]=[N:22][C:20]([C:12]1[S:13][C:14]([CH2:18][CH3:19])=[C:15]([C:16]#[N:17])[C:11]=1[C:8]1[CH:9]=[CH:10][C:5]([C:1]([CH3:2])([CH3:3])[CH3:4])=[CH:6][CH:7]=1)=[O:21])[CH3:29]
Reactant: CCc1sc(C(N)=O)c(-c2ccc(C(C)(C)C)cc2)c1C#N
Reactant: COC(OC)N(C)C
Product: CCc1sc(C(=O)N=CN(C)C)c(-c2ccc(C(C)(C)C)cc2)c1C#N
Temperature: 25 °C
Reaction time: 1 h
Yield: 82 %

Procedure:
Prepare a solution of 3-(4-tert-butyl-phenyl)-4-cyano-5-ethyl-thiophene-2-carboxylic acid amide (270 mg, 0.86 mmol) in 4 mL of dry dimethoxymethyl-dimethyl-amine and heat to reflux under nitrogen. After 1 hour allow 1 mL of solvent to distill out of the reaction, then cool the mixture to room temperature. Dilute the slurry with 10 mL of hexanes, filter off the resulting yellow product and wash with 5 mL hexanes. Vacuum-dry the solid overnight to give 261 mg (82%) of the title compound. MS(ES+, m/e)=368 (M++1).
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[C:3]([CH3:8])=[CH:4][C:5](=[O:7])[CH3:6].[C:11](OCC)(=O)[CH2:12]C(C)=O.[O-][CH2:21]C.[Na+].Cl>O.C1C=CC=CC=1>[CH3:11][C:12]1[CH2:8][C:3]([CH3:21])([C:2]([F:10])([F:9])[F:1])[CH2:4][C:5](=[O:7])[CH:6]=1
Reactant: CC[O-]
Reactant: CCOC(=O)CC(C)=O
Reactant: CC(=O)C=C(C)C(F)(F)F
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: c1ccccc1
Product: CC1=CC(=O)CC(C)(C(F)(F)F)C1
Temperature: 60 °C
Reaction time: 4 h
Yield: 116.6 %

Procedure:
In a dried 100 ml 3-neck flask, 15.2 g(0.1 mole) of 4-trifluoromethyl-3-penten-2-one prepared in Example 2, 13 g(0.1 mole)of ethyl acetoacetate and 3.4 g of sodium ethoxide were added to 60 ml of benzene, and stirred for 4 hrs at 60° C. The reaction mixture was cooled to room temperature and water was added. After neutralization using 10N hydrochloric acid solution, the organic layer was extracted, and dried over magnesium sulfate. The residue was distilled under the vacuum pressure of 1 mmHg, to obtain 11.2 g of the title compound as main product(yield: 58.3%) and 4.5 g of 4-ethoxycarbonyl-3,5-dimethyl-5-trifluoromethyl-2-cyclohexen-1-one(A-2) as by-product(yield: 17%).
Reaction SMILES: C1C=CC2N(O)N=[N:7][C:5]=2C=1.CCN(C(C)C)C(C)C.[O:20]=[C:21]([N:26]1[CH2:31][CH2:30][N:29]([C:32](=[O:43])[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=2[C:39]([F:42])([F:41])[F:40])[CH2:28][CH2:27]1)[CH2:22][C:23]([OH:25])=O.CCN=C=NCCCN(C)C.Cl.[CH2:56]([O:63][C:64]1N=C[C:67]([NH2:70])=[CH:66][CH:65]=1)[C:57]1[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=1>CN(C=O)C.O>[CH2:56]([O:63][C:64]1[CH:65]=[CH:66][C:67]([NH:70][C:23](=[O:25])[CH2:22][C:21](=[O:20])[N:26]2[CH2:27][CH2:28][N:29]([C:32](=[O:43])[C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=3[C:39]([F:40])([F:42])[F:41])[CH2:30][CH2:31]2)=[N:7][CH:5]=1)[C:57]1[CH:58]=[CH:59][CH:60]=[CH:61][CH:62]=1
Reactant: O=C(O)CC(=O)N1CCN(C(=O)c2ccccc2C(F)(F)F)CC1
Reactant: On1nnc2ccccc21
Reactant: Nc1ccc(OCc2ccccc2)nc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(CC(=O)N1CCN(C(=O)c2ccccc2C(F)(F)F)CC1)Nc1ccc(OCc2ccccc2)cn1
Temperature: 10 °C
Reaction time: 8 h
Yield: 39.3 %

Procedure:
HOBt (43 mg, 0.32 mmol) and DIEA (150 mg, 011 mmol) were added to a stirred solution of 3-oxo-3-[4-(2-trifluoromethyl-benzoyl)-piperazin-1-yl]-propionic acid (100 mg, 0.29 mmol) in DMF (4 mL). The reaction mixture was cooled to 10° C. and EDCI.HCl (111 mg, 0.58 mmol) followed by 6-benzyloxy-pyridin-3-ylamine (81 mg, 0.4 mmol) were added. The reaction mixture was stirred at room temperature overnight then diluted with water and the product extracted with ethyl acetate. The organics were washed with brine solution, dried over Na2SO4 and concentrated to afford a residue which was purified by column chromatography using silica gel 60-120 mesh (80% ethyl acetate in hexane) to afford 60 mg (39%) of N-(5-benzyloxy-pyridin-2-yl)-3-oxo-3-[4-(2-trifluoromethyl-benzoyl)-piperazin-1-yl]-propionamide. LCMS: 527.19 (M+1)+, 98.6%, 1H NMR: (DMSO-d6): δ 10.2 (td, 1H), 8.4 (dd, 1H), 8 (dt, 1H), 7.8 (d, 1H), 7.7 (t, 1H), 7.6 (t, 1H), 7.5 (d, 1H), 7.4 (m, 5H), 6.9 (m, 1H), 5.4 (d, 2H), 3.8 (m, 6H), 3.5 (m, 2H), 3.2 (m, 2H).