Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(O[C:8](=[O:27])[NH:9][C:10]2[S:11][C:12]3[C:18]([CH:19]4[CH2:24][O:23][CH2:22][CH2:21][O:20]4)=[CH:17][CH:16]=[C:15]([O:25][CH3:26])[C:13]=3[N:14]=2)C=CC=CC=1.FC(F)(F)C(O)=O.[O:35]1[C:39]2([CH2:44][CH2:43][NH:42][CH2:41][CH2:40]2)[CH2:38][CH2:37][CH2:36]1.C(N(C(C)C)C(C)C)C>C(Cl)(Cl)Cl>[O:20]1[CH2:21][CH2:22][O:23][CH2:24][CH:19]1[C:18]1[C:12]2[S:11][C:10]([NH:9][C:8]([N:42]3[CH2:43][CH2:44][C:39]4([O:35][CH2:36][CH2:37][CH2:38]4)[CH2:40][CH2:41]3)=[O:27])=[N:14][C:13]=2[C:15]([O:25][CH3:26])=[CH:16][CH:17]=1
Reactant: COc1ccc(C2COCCO2)c2sc(NC(=O)Oc3ccccc3)nc12
Reactant: C1COC2(C1)CCNCC2
Solvent: ClC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(C2COCCO2)c2sc(NC(=O)N3CCC4(CCCO4)CC3)nc12

Procedure:
From (+)-(7-[1,4]dioxan-2-yl-4-methoxy-benzothiazol-2-yl)-carbamic acid phenyl ester with 1-oxa-8-aza-spiro[4.5]decane trifluoroacetate and N-ethyldiisopropylamine in chloroform. [α]D20=+25.8° (c=1.01, CHCl3), ES-MS m/e (%): 434 (M+H+, 100).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]([Cl:11])[C:8]([CH3:12])=[C:7]([CH3:13])[C:3]=1[C:4]([OH:6])=[O:5].Cl(O)(=O)(=O)=O>C(OC(C)(C)C)(=O)C.CCOC(C)=O>[Cl:1][C:2]1[N:10]=[C:9]([Cl:11])[C:8]([CH3:12])=[C:7]([CH3:13])[C:3]=1[C:4]([O:6][C:3]([CH3:7])([CH3:4])[CH3:2])=[O:5]
Reactant: Cc1c(Cl)nc(Cl)c(C(=O)O)c1C
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: CCOC(C)=O
Solvent: CC(=O)OC(C)(C)C
Product: Cc1c(Cl)nc(Cl)c(C(=O)OC(C)(C)C)c1C
Reaction time: 1 h
Yield: 144.8 %

Procedure:
To a solution of 2,6-dichloro-4,5-dimethylnicotinic acid (2.75 g, 12.5 mmol, 1 equiv) in tertbutyl acetate (83 mL) was added concentrated perchloric acid (3.2 mL, 37.5 mmol, 3 equiv). The reaction was stirred 1 h and then diluted with EtOAc. The organic solution was then washed with 10% potassium carbonate, dried (Na2SO4), and concentrated in vacuo. The crude product was purified by silica gel flash column chromatography (0-100% DCM/hexane) to provide the product (2.50 g, 72%) as a waxy white solid. 1H NMR (400 MHz, CDCl3) δ 2.35 (s, 3H), 2.32 (s, 3H), 1.62 (s, 9H); LCMS (ESI, M+1): 276.00.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](B(O)O)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].Cl[C:17]1[N:27]=[CH:26][CH:25]=[CH:24][C:18]=1[C:19]([O:21][CH2:22][CH3:23])=[O:20]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:17]2[N:27]=[CH:26][CH:25]=[CH:24][C:18]=2[C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10]
Reactant: COc1cc(B(O)O)cc(OC)c1OC
Reactant: CCOC(=O)c1cccnc1Cl
Product: CCOC(=O)c1cccnc1-c1cc(OC)c(OC)c(OC)c1

Procedure:
3,4,5-Trimethoxyphenylboronic acid (694 mg) and ethyl 2-chloronicotinate (608 mg) were reacted in the same manner as in Preparation Example 1 to obtain the title compound.
Reaction SMILES: O=C1C(C(O)=O)=CC=C(C(F)(F)F)N1.C(Br)C#C.C(=O)([O-])[O-].[K+].[K+].C1OCCOCCOCCOCCOCCOC1.[CH2:43]([O:46][C:47]1[N:57]=[C:56]([C:58]([F:61])([F:60])[F:59])[CH:55]=[CH:54][C:48]=1[C:49]([O:51]CC)=[O:50])[C:44]#[CH:45].[OH-].[K+]>CN(C)C=O.C(#N)C.O.O1CCOCC1>[CH2:43]([O:46][C:47]1[N:57]=[C:56]([C:58]([F:61])([F:59])[F:60])[CH:55]=[CH:54][C:48]=1[C:49]([OH:51])=[O:50])[C:44]#[CH:45]
Reactant: C#CCOc1nc(C(F)(F)F)ccc1C(=O)OCC
Agent: C#CCBr
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C(O)c1ccc(C(F)(F)F)[nH]c1=O
Solvent: O
Solvent: CN(C)C=O
Solvent: CC#N
Product: C#CCOc1nc(C(F)(F)F)ccc1C(=O)O
Reaction time: 5 h

Procedure:
47 g (0.2 mol) of 2-oxo-6-trifluoromethyl-1,2-dihydropyridine-3-carboxylic acid, 20 ml (0.25 mol) of propargyl bromide and 43 g (0.31 mol) of potassium carbonate are heated to a temperature of 75° C. in a mixture of 40 ml of dimethylformamide and 80 ml of acetonitrile in the presence of a catalytic amount of 18-crown-6 ether. After 5 hours, the mixture is partitioned between ethyl acetate and saturated sodium chloride solution. The crude product is filtered through a silica gel column using 15% ethyl acetate in hexane. The main component, which is obtained in the form of an oil, is the pure ethyl 2-prop-2-ynyloxy-6-trifluoromethylnicotinate; 1H-NMR (CDCl3): 8.31, d, CH, 7.38, d, CH, 5.13, d, CH2, 4.41, q, CH2, 2.48, t, CCH, 1.41 ppm, t, CH3. 36.3 g (0.13 mol) of this product is stirred over a period of 16 hours with a solution of 11.5 g (0.17 mol) of potassium hydroxide in 50 ml of water and 50 ml of dioxane. After acidification and extraction with ethyl acetate, crystalline 2-prop-2-ynyloxy-6-trifluoromethylnicotinic acid is obtained; 1H-NMR (CDCl3): 10.0, b, OH, 8.53, d, CH, 7.44, d, CH, 5.22, d, CH2, 2.54 ppm, t, CCH.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][C@H:9]([O:13][C:14]1[NH:15][C:16]([NH2:25])=[C:17]2[C:21]([N:22]=1)=[N:20][C:19]([O:23][CH3:24])=[N:18]2)[CH2:10][CH2:11][CH3:12].Br[CH2:27][CH2:28][CH2:29][CH2:30][CH:31]1[CH2:35][CH2:34][O:33][CH2:32]1>>[CH3:8][C@H:9]([O:13][C:14]1[N:22]=[C:21]2[C:17]([N:18]=[C:19]([O:23][CH3:24])[N:20]2[CH2:27][CH2:28][CH2:29][CH2:30][CH:31]2[CH2:35][CH2:34][O:33][CH2:32]2)=[C:16]([NH2:25])[N:15]=1)[CH2:10][CH2:11][CH3:12]
Reactant: BrCCCCC1CCOC1
Reactant: CCC[C@H](C)Oc1nc2nc(OC)nc-2c(N)[nH]1
Solvent: O=C(O)C(F)(F)F
Product: CCC[C@H](C)Oc1nc(N)c2nc(OC)n(CCCCC3CCOC3)c2n1

Procedure:
Prepared similarly to Intermediate 220 from 2-{[(1S)-1-methylbutyl]oxy}-8-(methyloxy)-1H-purin-6-amine trifluoroacetate and 3-(4-bromobutyl)tetrahydrofuran.
Reaction SMILES: [C:1]([OH:6])(=[O:5])[C:2]([CH3:4])=[CH2:3].[OH-:7].[Na+]>O>[C:1]([O:6][C:3](=[O:7])[C:2]([CH3:4])=[CH2:1])(=[O:5])[C:2]([CH3:4])=[CH2:3]
Reactant: C=C(C)C(=O)O
Reactant: [OH-]
Agent: [Na+]
Solvent: O
Product: C=C(C)C(=O)OC(=O)C(=C)C

Procedure:
The 81A product (11.51 gm) was allowed to react under the conditions of Example 1 with 5.28 gm XSA, 9.99 gm methacrylic acid, 2.78 gm AMPS, and 44.50 gm water. After reaction, 6.94 grams of water was added along with NaOH to adjust pH to 4.4 (referred to below as 81B). The solution contained 29% solids.
Reaction SMILES: C([O:5][C:6]([CH2:8][O:9][C:10]1[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:11]=1[CH:18]1[C:26]2[C:21](=[CH:22][CH:23]=[C:24]([O:27][CH2:28][CH2:29][CH3:30])[CH:25]=2)[CH:20]([C:31]2[CH:36]=[CH:35][C:34]3[O:37][CH2:38][O:39][C:33]=3[CH:32]=2)[CH:19]1C(O)=O)=[O:7])(C)(C)C.C([N:45](CC)CC)C>C1C=CC=CC=1.Cl.O1CCOCC1>[NH2:45][CH:19]1[CH:18]([C:11]2[CH:12]=[CH:13][C:14]([O:16][CH3:17])=[CH:15][C:10]=2[O:9][CH2:8][C:6]([OH:5])=[O:7])[C:26]2[C:21](=[CH:22][CH:23]=[C:24]([O:27][CH2:28][CH2:29][CH3:30])[CH:25]=2)[CH:20]1[C:31]1[CH:36]=[CH:35][C:34]2[O:37][CH2:38][O:39][C:33]=2[CH:32]=1
Reactant: CCCOc1ccc2c(c1)C(c1ccc(OC)cc1OCC(=O)OC(C)(C)C)C(C(=O)O)C2c1ccc2c(c1)OCO2
Reactant: CCN(CC)CC
Agent: Cl
Solvent: c1ccccc1
Solvent: C1COCCO1
Product: CCCOc1ccc2c(c1)C(c1ccc(OC)cc1OCC(=O)O)C(N)C2c1ccc2c(c1)OCO2
Temperature: 75 °C
Yield: 45.2 %

Procedure:
(1RS, 2SR, 3RS)-3-(2-tert--butoxycarbonylmethoxy-4-methoxyphenyl)-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylic acid (100 mg, 0.18 mmol), triphenylphosphonyl azide (0.03 ml, 0.18 mmol), and triethylamine (73 mg, 0.72 mmol) were dissolved in dry benzene (4 ml) and heated at 40° C. for 2 h and at 75° C. for 2 h. The reaction mixture was then partitioned between 1N HCl and ethyl acetate. The organic layer was washed with water and brine, dried (MgSO4 anhyd.), filtered and evaporated to give the corresponding isocianate as a colorless oil. After purification by column chromatography (silica gel, ethyl acetate/hexane 30:70), the isocianate (100 mg) thus obtained was dissolved in 1M HCl in dioxane (3 mL) and the mixture was heated at 80° C. overnight. The solvent was removed in vacuo, the residue was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried (MgSO4) and concentrated to give a colorless oil that was purified by HPLC (1:1 CNCH3:H2O(containing 0.1% TFA)) to produce the desired product (40 mg, 42%) as an off-white solid, m.p. 181-182° C. (dec).
Reaction SMILES: C([O:4][CH:5]([CH2:14][O:15]C(=O)C)[CH:6]=[CH:7][C:8]1[CH:13]=[N:12][CH:11]=[CH:10][N:9]=1)(=O)C.[Na]>CO>[OH:4][CH:5]([CH2:14][OH:15])[CH:6]=[CH:7][C:8]1[CH:13]=[N:12][CH:11]=[CH:10][N:9]=1
Reactant: CC(=O)OCC(C=Cc1cnccn1)OC(C)=O
Agent: [Na]
Solvent: CO
Product: OCC(O)C=Cc1cnccn1
Reaction time: 8 h
Yield: 99 %

Procedure:
2.60 g of 2-(3,4-diacetoxy-1-butenyl)pyrazine (4104) was added to a solution of 78 mg of sodium in 50 ml of methanol. This was stirred at 25° overnight and then concentrated in vacuo. The product was purified by gel permeation chromatography (Biogel P-2/water) and gave 1.71 g of 2-(3,4-dihydroxy-1-butenyl)pyrazine (4105) as a pale yellow oil. UV H2O max: 234 (4.08), 292 (3.86).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[Cl:7][C:8]1[C:9]([CH3:18])=[C:10]([CH:15]=[CH:16][CH:17]=1)[C:11](OC)=[O:12].O.[OH-].[Na+]>O1CCCC1>[Cl:7][C:8]1[C:9]([CH3:18])=[C:10]([CH2:11][OH:12])[CH:15]=[CH:16][CH:17]=1
Reactant: COC(=O)c1cccc(Cl)c1C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1c(Cl)cccc1CO
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 94.3 %

Procedure:
A solution of lithium aluminium hydride (29.8 mL, 29.8 mmol) in THF was cooled to 0° C., and a solution of methyl 3-chloro-2-methylbenzoate (2.5 g, 13.54 mmol) in Tetrahydrofuran (THF) (20 mL) was added dropwise. The mixture was stirred at 0° C. for half hour, warmed up to RT gradually, and stirred at RT for 2 hours. Water and 6N NaOH (4 ml) were added to quench the reaction. The mixture was filtered and the filtrate was concentrated to afford the crude product as a white solid (2.0 g, 94%). 1H NMR (400 MHz, CDCl3) δppm 7.30˜7.35 (m, 2H), 7.16 (m, 1H), 4.74 (s, 2H), 2.40 (s, 3H).
Reaction SMILES: C(OP(OCC)([N:6]1[CH2:10][C:9]2([C:23]([O:25][CH3:26])=[O:24])[CH2:11][O:12][C:13]3[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[CH:15][C:14]=3[C:8]2=[N:7]1)=O)C.[ClH:30]>CO>[ClH:30].[F:21][C:19]([F:20])([F:22])[C:17]1[CH:16]=[CH:15][C:14]2[C:8]3[C:9]([C:23]([O:25][CH3:26])=[O:24])([CH2:11][O:12][C:13]=2[CH:18]=1)[CH2:10][NH:6][N:7]=3
Reactant: CCOP(=O)(OCC)N1CC2(C(=O)OC)COc3cc(C(F)(F)F)ccc3C2=N1
Agent: Cl
Solvent: CO
Product: COC(=O)C12CNN=C1c1ccc(C(F)(F)F)cc1OC2
Temperature: 66 °C
Yield: 88.8 %

Procedure:
A mixture of the product of Step G (38 g, 0.087 mol) 200 mL of methanol, and 18 g (0.50 mol) hydrogen chloride was heated at reflux (66° C.) for 21/2 hours. The solution was concentrated, toluene (50 mL) was added to the residue and, the mixture concentrated again. Another 50 mL toluene was added and evaporated a second time. After adding 100 mL of toluene, the slurry was chilled, and then filtered. The solid was washed with toluene, then hexanes to yield 26 g of a pale yellow product, m.p. 175°-176° C., dec. Recrystallization from a mixture of tetrahydrofuran and methanol gave a colorless solid, m.p. 185°-186° C., dec.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].[CH:9]([C:11]([CH3:13])=O)=[CH2:10]>C(O)(=O)C.[Cl-].[Zn+2].[Cl-]>[Cl:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:3]=1[N:4]=[CH:10][CH:9]=[C:11]2[CH3:13]
Reactant: Nc1ccccc1Cl
Reactant: C=CC(C)=O
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CC(=O)O
Product: Cc1ccnc2c(Cl)cccc12
Temperature: 70 °C
Reaction time: 0.08 h
Yield: 62 %

Procedure:
To a stirred solution of 2-chloroaniline (1 g. 7.8 mmol.) in acetic acid (10 ml), activated silferc (1.25 g. ferric chloride 7.8 mmol) was added under nitrogen atmosphere. The reaction mixture was stirred for 5 minutes and methyl vinyl ketone (MVK) (0.6 g, 8.5 mmol) was added slowly over a period of 15 minutes. The reaction mixture was heated to 70° C. and maintained between 70-75° C. for one hour. Anhydrous zinc chloride (1.0 g. 7.8 mmol) was added and the reaction was further refluxed for two hours. The reaction mixture was cooled, filtered, basified with 10% NaOH solution, extracted with ethyl acetate (3×20 ml), dried over Na2SO4 and evaporated to give the product; Yield 62%.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[CH:8][N:7]([CH:11]3[CH2:16][CH2:15][CH2:14][CH2:13][O:12]3)[C:6]=2[CH:5]=[CH:4][C:3]=1[CH2:17][N:18](C)[C:19](=O)OC(C)(C)C.Cl.O1CCOCC1>CO>[Cl:1][C:2]1[C:10]2[N:9]=[CH:8][N:7]([CH:11]3[CH2:16][CH2:15][CH2:14][CH2:13][O:12]3)[C:6]=2[CH:5]=[CH:4][C:3]=1[CH2:17][NH:18][CH3:19]
Reactant: CN(Cc1ccc2c(ncn2C2CCCCO2)c1Cl)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: CNCc1ccc2c(ncn2C2CCCCO2)c1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 146700.41 %

Procedure:
To a solution of 218 (363 mg, 0.96 mmol) in MeOH (6 mL) was added 4N HCl/dioxane (2.87 ml, 11.5 mmol) and the reaction was stirred at RT for 2 h then concentrated in vacuo to afford 394 g (100%) of 1-(4-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-benzo[d]imidazol-5-yl)-N-methylmethanamine (220) as its bis-HCl salt: MS (ESI) m/z=280.1 [M+1]+.
Reaction SMILES: [CH3:1][S:2]([C:5]1[S:9][C:8]([C:10]2[N:14]3[CH:15]=[C:16]([C:19]4[C:20]([C:43](O)=[O:44])=[N:21][N:22]([C:24]([C:37]5[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=5)([C:31]5[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=5)[C:25]5[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=5)[CH:23]=4)[CH:17]=[CH:18][C:13]3=[N:12][CH:11]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].Cl.C([N:49]=C=NCCCN(C)C)C.[Cl-].[NH4+].C(N(CC)CC)C>CN(C)C=O>[CH3:1][S:2]([C:5]1[S:9][C:8]([C:10]2[N:14]3[CH:15]=[C:16]([C:19]4[C:20]([C:43]([NH2:49])=[O:44])=[N:21][N:22]([C:24]([C:31]5[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=5)([C:25]5[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=5)[C:37]5[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=5)[CH:23]=4)[CH:17]=[CH:18][C:13]3=[N:12][CH:11]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3]
Reactant: CCN=C=NCCCN(C)C
Reactant: CS(=O)(=O)c1ccc(-c2cnc3ccc(-c4cn(C(c5ccccc5)(c5ccccc5)c5ccccc5)nc4C(=O)O)cn23)s1
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1ccc(-c2cnc3ccc(-c4cn(C(c5ccccc5)(c5ccccc5)c5ccccc5)nc4C(N)=O)cn23)s1
Reaction time: 8 h
Yield: 55.1 %

Procedure:
A mixture of 40 mg 4-{3-[5-(methylsulfonyl)-2-thienyl]imidazo[1,2-a]pyridin-6-yl}-1-trityl-1H-3-pyrazole carboxylic acid, 37 mg 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride, 26 mg 1-oxybenzotriazole, 17 mg ammonium chloride, 0.077 mL triethylamine and 3 mL N,N-dimethylformamide was left overnight at room temperature. The solvent was evaporated, and the residue was purified by NH silica gel column chromatography (ethyl acetate/methanol) to give 22 mg 4-{3-[5-(methylsulfonyl)-2-thienyl]imidazo[1,2-a]-pyridin-6-yl}-1-trityl-1H-3-pyrazole carboxamide as colorless crystals. This product was subjected to deprotection of the trityl group in the same manner as in Example 79, to give 14 mg of the title compound as colorless crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([N+:9]([O-:11])=[O:10])=[C:7]([NH2:12])[CH:6]=[C:5]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]([F:22])([F:21])[F:20])[N:4]=1.[H-].[Na+].[C:25]([C:29]1[CH:33]=[C:32]([C:34](O)=[O:35])[O:31][N:30]=1)([CH3:28])([CH3:27])[CH3:26].C(Cl)(=O)C(Cl)=O>C1COCC1.C(Cl)Cl.CN(C=O)C>[CH3:1][O:2][C:3]1[C:8]([N+:9]([O-:11])=[O:10])=[C:7]([NH:12][C:34]([C:32]2[O:31][N:30]=[C:29]([C:25]([CH3:28])([CH3:27])[CH3:26])[CH:33]=2)=[O:35])[CH:6]=[C:5]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]([F:22])([F:20])[F:21])[N:4]=1
Reactant: COc1nc(-c2ccccc2C(F)(F)F)cc(N)c1[N+](=O)[O-]
Reactant: CC(C)(C)c1cc(C(=O)O)on1
Agent: O=C(Cl)C(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COc1nc(-c2ccccc2C(F)(F)F)cc(NC(=O)c2cc(C(C)(C)C)no2)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 2-methoxy-3-nitro-6-(2-trifluoromethyl-phenyl)-pyridin-4-ylamine (163 mg, 0.519 mmol, prepared as described in STEP B above) in THF (10 mL) was treated with NaH (62.2 mg, 1.56 mmol, 60% dispersion in oil), and the mixture was allowed to stir at room temperature for 1 h. Simultaneously, a solution of 3-tert-butyl-isoxazole-5-carboxylic acid (114 mg, 0.674 mmol, prepared as described in Example I above) in anhydrous DCM (10 mL) was treated with oxalyl chloride (58.8 μL, 0.674 mmol) and DMF (2 drops), and the mixture was stirred at room temperature for 1 h. Volatile components were removed in vacuo, and the residue was taken up in anhydrous THF (6 mL). The above-prepared acid chloride solution was added to the sodium anilide solution above, and the mixture was stirred at room temperature for 1 h. The mixture was quenched with saturated aqueous NH4Cl (20 mL) and extracted twice with EtOAc (25 mL). The residue was purified on a 12-g SEPRA Si 50 SPE column (Flow rate=15 mL/min; Eluent=EtOAc-hexanes, 1:99 for 10 min, then 1:99 to 1:4 over 40 min) to yield 3-tert-butyl-isoxazole-5-carboxylic acid [2-methoxy-3-nitro-6-(2-trifluoromethyl-phenyl)-pyridin-4-yl]-amide as a white solid. 1H-NMR (400 MHz, CDCl3) δ: 10.62 (s, 1H), 8.39 (s, 1H), 7.82 (d, J=7.3 Hz, 1H), 7.63-7.69 (m, 1H), 7.58-7.63 (m, 1H), 7.56 (d, J=7.6 Hz, 1H), 6.98 (s, 1H), 4.09 (s, 3H), 1.38 (s, 9H). Mass Spectrum (LCMS, APCI pos.): Calculated for C21H19N4O5F3: 465.1 (M+H). Measured: 465.1.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[N:7]([CH3:8])[N:6]=[C:5]([OH:9])[C:4]=1[Cl:10].F[C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[C:16]([O:23][CH3:24])[CH:15]=1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[F:12][C:2]([F:1])([F:11])[C:3]1[N:7]([CH3:8])[N:6]=[C:5]([O:9][C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[C:16]([O:23][CH3:24])[CH:15]=2)[C:4]=1[Cl:10]
Reactant: COc1cc(F)ccc1[N+](=O)[O-]
Reactant: Cn1nc(O)c(Cl)c1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: COc1cc(Oc2nn(C)c(C(F)(F)F)c2Cl)ccc1[N+](=O)[O-]
Yield: 93.1 %

Procedure:
8.02 g (0.04 mol) of 5-trifluoromethyl-4- chloro-3-hydroxy-1-methylpyrazole and 6.85 g (0.04 mol) of 4-fluoro-2-methoxynitrobenzene were mixed together with 6.22 g (0.045 mol) of potassium carbonate in 50 ml of DMSO for 4 hours at a temperature of 72° C. and overnight at a temperature of 85° C. The product was isolated in accordance with Example 2(c) to give 13.1 g (93% yield) of a yellow solid, m.p. 71°-73.5° C.
Reaction SMILES: [C:1]([C:5]1[CH:42]=[CH:41][C:8]([C:9]([N:11]2[C@@H:15]([C:16]3[N:17]=[C:18]([N:21]([CH3:23])[CH3:22])[S:19][CH:20]=3)[C@@H:14]([C:24]3[CH:29]=[N:28][CH:27]=[CH:26][N:25]=3)[CH2:13][C@@:12]2([CH2:37][CH:38]([CH3:40])[CH3:39])[C:30]([O:32]C(C)(C)C)=[O:31])=[O:10])=[CH:7][C:6]=1[O:43][CH3:44])([CH3:4])([CH3:3])[CH3:2].C(O)(C(F)(F)F)=O>>[C:1]([C:5]1[CH:42]=[CH:41][C:8]([C:9]([N:11]2[C@@H:15]([C:16]3[N:17]=[C:18]([N:21]([CH3:23])[CH3:22])[S:19][CH:20]=3)[C@@H:14]([C:24]3[CH:29]=[N:28][CH:27]=[CH:26][N:25]=3)[CH2:13][C@@:12]2([CH2:37][CH:38]([CH3:39])[CH3:40])[C:30]([OH:32])=[O:31])=[O:10])=[CH:7][C:6]=1[O:43][CH3:44])([CH3:3])([CH3:4])[CH3:2]
Reactant: COc1cc(C(=O)N2[C@@H](c3csc(N(C)C)n3)[C@@H](c3cnccn3)C[C@@]2(CC(C)C)C(=O)OC(C)(C)C)ccc1C(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(C(=O)N2[C@@H](c3csc(N(C)C)n3)[C@@H](c3cnccn3)C[C@@]2(CC(C)C)C(=O)O)ccc1C(C)(C)C

Procedure:
The tert-butyl ester from stage A was deprotected with TFA in a similar manner to that described in Example 1, to afford the title compound as a solid.
Reaction SMILES: O[C:2]1[N:7]2[N:8]=[C:9]([CH2:11][C:12]([O:14][CH3:15])=[O:13])[N:10]=[C:6]2[N:5]=[C:4]([CH3:16])[CH:3]=1.P(Cl)(Cl)([Cl:19])=O>>[Cl:19][C:2]1[N:7]2[N:8]=[C:9]([CH2:11][C:12]([O:14][CH3:15])=[O:13])[N:10]=[C:6]2[N:5]=[C:4]([CH3:16])[CH:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COC(=O)Cc1nc2nc(C)cc(O)n2n1
Product: COC(=O)Cc1nc2nc(C)cc(Cl)n2n1

Procedure:
A solution of the product obtained in Step 3 (1.5 g) in 15 ml of phosphorus oxychloride was refluxed for two hours, excess phosphorus oxychloride was distilled off, the residue was dissolved in chloroform, and the solution was washed with ice water. After removing the solvent from the organic layer under reduced pressure, the residue was purified by silica gel chromatography, affording 1 g of the objective compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[SH:8].C([O-])([O-])=O.[K+].[K+].[CH2:15](I)[CH:16]([CH3:18])[CH3:17]>CN(C=O)C.CCOC(C)=O>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][CH2:15][CH:16]([CH3:18])[CH3:17]
Reactant: CC(C)CI
Reactant: Sc1ccccc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)CSc1ccccc1Br
Temperature: 40 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
To a solution of 2-bromobenzene thiol (10.0 g, 52.8 mmol, 1.0 eq.) in DMF (250 mL) was added K2CO3 (17.5 g, 126.7 mmol, 2.4 eq.) and isobutyl iodide (7.3 mL, 63.36 mmol, 1.2 eq). The reaction was warmed to about 40° C. and stirred overnight. The mixture was diluted with EtOAc (300 mL) and washed with water (100 mL) and brine (100 mL). The organic layer was extracted with EtOAc(2×). The combined organic extracts were dried (Na2SO4), filtered and concentrated to afford 1-bromo-2-isobutylsulfanyl-benzene (12.94 g, 52.8 mmol, 100%), which is then taken to the next step without any further purification. GCMS (EI): 244.0
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[C:5](=[O:13])[C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1)[CH3:2].[H-].[Na+].Br[CH2:18][C:19]([N:21]1[CH2:26][CH2:25][N:24]([CH2:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[C:35]([F:38])([F:37])[F:36])[CH2:23][CH2:22]1)=[O:20]>CN(C)C=O>[CH2:1]([O:3][C:4](=[O:14])[C:5](=[O:13])[C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:18][C:19](=[O:20])[N:21]2[CH2:22][CH2:23][N:24]([CH2:27][CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[C:35]([F:38])([F:36])[F:37])[CH2:25][CH2:26]2)=[CH:8][CH:7]=1)[CH3:2]
Reactant: O=C(CBr)N1CCN(CCc2ccccc2C(F)(F)F)CC1
Reactant: CCOC(=O)C(=O)c1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(=O)c1ccc(OCC(=O)N2CCN(CCc3ccccc3C(F)(F)F)CC2)cc1
Reaction time: 0.25 h
Yield: 32.3 %

Procedure:
A mixture of 4-hydroxy-alpha-oxobenzeneacetic acid ethyl ester (0.256 g) in dimethylformamide (4 mL) under argon was treated with 55% sodium hydride (0.06 g), stirred for 15 minutes and then the above 1-(2-bromo-1-oxoethyl)-4-[2-[2-(trifluoromethyl)phenyl]ethyl]piperazine (0.5 g) in dimethylformamide (2 mL) was added. The mixture was stirred at room temperature for 23 hours and worked up as in Example 20. The crude product was purified by flash chromatography over silica gel (ethyl acetate-toluene; 1:1 increasing to 4:1) to afford 0.21 g of alpha-oxo-4-[2-oxo-2-[4-[2-[2-(trifiuoromethyl)phenyl]ethyl]-1-piperazinyl]ethoxy]-benzeneacetic acid ethyl ester as an oil.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3].[NH2:12][C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16]([CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])=[C:15]([N+:29]([O-:31])=[O:30])[CH:14]=1.CCN(CC)CC>C(Cl)Cl>[CH2:5]([O:4][C:2]([NH:12][C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16]([CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])=[C:15]([N+:29]([O-:31])=[O:30])[CH:14]=1)=[O:3])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CCOC(=O)Cc1c([N+](=O)[O-])cc(N)c2ccccc12
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)Cc1c([N+](=O)[O-])cc(NC(=O)OCc2ccccc2)c2ccccc12
Yield: 26.2 %

Procedure:
Benzyl chloroformate (1.56 mL, 10.94 mmol) was added to a solution of ethyl (4-amino-2-nitronaphthalen-1-yl)acetate (1.0 g, 3.65 mmoml) and Et3N (0.56 mL, 4.01 mmol) in dry CH2Cl2 (20 mL) slowly that was at 0° C. under N2 atmosphere. The mixture was heated to reflux for 3 days and concentrated. The residue was dissolved in AcOEt (50 mL), and washed with H2O (10 mL) and saturated aqueous NaCl (25 mL). The organic layer was dried (Na2SO4) and concentrated under reduced pressure. Flash chromatography (20% AcOEt-Petroleum ether to CHCl3) afforded ethyl [4-(N-benzyloxycarbonylamino)-2-nitronaphthalen-1-yl]acetate (0.39 g, 26%) as an orange solid. M.p. 160-164° C.; 1H NMR (CDCl3, 500 MHz) δ 8.09 (d, 8.5, 1H), 7.88 (d, 8.0, 1H), 7.66 (t, 8.0, 1H), 7.60 (t, 7.0, 1H), 7.46 (d, 7.5, 2H), 7.41 (t, 7.5, 2H), 7.35 (t, 7.5, 1H), 7.07 (s, 1H), 4.92 (brs, 1H), 4.52 (d, 4.0, 2H), 4.24 (s, 2H), 4.19 (q, 7.0, 2H), 1.26 (t, 7.5, 3H); IR (neat) 3397, 2927, 1723, 1594, 1537, 1515, 1439, 1333, 1200, 1124, 1027, 823, 752, 703 cm−1.