Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([NH:12][C:13](=[O:17])OCC)[C:6]([O:18][CH3:19])=[N:5]2.[C:20]([C:23]1[CH:28]=[CH:27][C:26]([N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)=[CH:25][CH:24]=1)(=[O:22])[CH3:21]>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([NH:12][C:13]([N:32]1[CH2:31][CH2:30][N:29]([C:26]3[CH:25]=[CH:24][C:23]([C:20](=[O:22])[CH3:21])=[CH:28][CH:27]=3)[CH2:34][CH2:33]1)=[O:17])[C:6]([O:18][CH3:19])=[N:5]2
Reactant: CC(=O)c1ccc(N2CCNCC2)cc1
Reactant: CCOC(=O)Nc1nc2ccc(Cl)cc2nc1OC
Product: COc1nc2cc(Cl)ccc2nc1NC(=O)N1CCN(c2ccc(C(C)=O)cc2)CC1
Yield: 81 %

Procedure:
Ethyl N-(6-chloro-3-methoxyquinoxalin-2-yl)carbamate and 1-(4-acetylphenyl)piperazine were reacted by the same way with the example 106 to obtain the titled compound (yield, 81%). 1H NMR (300 MHz, CDCl3): δ 2.54 (s, 3H), 3.50 (s, 4H), 3.79 (s, 4H), 4.15 (s, 3H), 6.89 (d, J=9.0 Hz, 2H), 7.31-7.50 (m, 2H), 7.65-7.75 (m, 2H), 7.90 (d, J=8.7 Hz, 2H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C@@H:4]1[CH2:8][C@@H:7]([OH:9])[CH2:6][N:5]1[CH:10]=[O:11].[C:13]([Si:17](Cl)([CH3:19])[CH3:18])([CH3:16])([CH3:15])[CH3:14].N1C=CN=C1>CN(C)C=O.C(Cl)Cl>[CH3:1][O:2][C:3](=[O:12])[C@@H:4]1[CH2:8][C@@H:7]([O:9][Si:17]([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:19])[CH3:18])[CH2:6][N:5]1[CH:10]=[O:11]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: COC(=O)[C@@H]1C[C@@H](O)CN1C=O
Agent: c1c[nH]cn1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COC(=O)[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CN1C=O
Yield: 96.4 %

Procedure:
To a solution of (2S,4R)-1-formyl-4-hydroxyproline methyl ester (3.46 g, 20.0 mmol) in N,N-dimethylformamide (10 ml) and methylene chloride (20 ml) were successively added tert-butylchlorodimethylsilane (3.20 g, 21.2 mmol) and imidazole (1.47 g, 21.6 mmol) under a nitrogen atmosphere under cooling with ice under stirring. The mixture was stirred at room temperature for 4 h. Then, the reaction solution was washed with water, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was subjected to silica gel column chromatography (Wakogel™ C-300, heptane-ethyl acetate=1:1) to give the title compound (5.54 g, yield: 96.3%).
Reaction SMILES: B(Cl)(Cl)Cl.[C:5]([C:7]1[CH:8]=[C:9]([C:17]2[S:21][CH2:20][N:19]([C:22]3[CH:27]=[CH:26][C:25]([CH2:28][CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])=[CH:24][C:23]=3[CH3:35])[N:18]=2)[CH:10]=[CH:11][C:12]=1[O:13]C(C)C)#[N:6]>C(Cl)Cl>[C:5]([C:7]1[CH:8]=[C:9]([C:17]2[S:21][CH2:20][N:19]([C:22]3[CH:27]=[CH:26][C:25]([CH2:28][CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])=[CH:24][C:23]=3[CH3:35])[N:18]=2)[CH:10]=[CH:11][C:12]=1[OH:13])#[N:6]
Reactant: CCOC(=O)CCc1ccc(N2CSC(c3ccc(OC(C)C)c(C#N)c3)=N2)c(C)c1
Agent: ClB(Cl)Cl
Solvent: ClCCl
Product: CCOC(=O)CCc1ccc(N2CSC(c3ccc(O)c(C#N)c3)=N2)c(C)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 50.6 %

Procedure:
Boron trichloride (1 M in CH2Cl2, 3 mL was added to a solution of ethyl 3-(4-(5-(3-cyano-4-isopropyloxyphenyl)-1,3,4-thiadiazol-3-yl)-3-methylphenyl)propanoate (0.6 mmol, from Step C) in methylene chloride (40 mL) at 0° C. The reaction mixture was allowed to warm to rt over 4 h and then was stirred at rt for 16 h. The reaction mixture was diluted with methylene chloride (50 mL) and washed with water (50 mL). The organics were dried over magnesium sulfate, filtered and concentrated in vacuo. Silica gel chromatography eluting with EtOAc yielded 0.12 g of the title compound. 1H NMR (500 MHZ, CDCl3) δ 1H NMR (500 MHZ, CDCl3) δ 8.17 (s, 1H), 8.13 (s, 1H), 7.68 (s, 1H), 7.24 (s, 1H), 7.20-7.24 (m, 2H), 4.14-4.23 (m, 2H), 2.98-3.08 (m, 2H), 2.68-2.78 (m, 2H), 2.64 (s, 3H), 1.30 (t, J=7.1, 3H); ESI-MS (m/z) 394.2; HPLC A: 2.71 min.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:33][CH:34]2[CH2:38][CH2:37][CH2:36][CH2:35]2)[C:13]([NH:15][C:16]2[CH:21]=[N:20][C:19]([NH:22][CH2:23][CH2:24][O:25][Si](CC)(CC)CC)=[CH:18][N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].C(O)(=O)C>O1CCCC1.O>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:33][CH:34]2[CH2:35][CH2:36][CH2:37][CH2:38]2)[C:13]([NH:15][C:16]2[CH:21]=[N:20][C:19]([NH:22][CH2:23][CH2:24][OH:25])=[CH:18][N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9]
Reactant: CC[Si](CC)(CC)OCCNc1cnc(NC(=O)[C@H](CC2CCCC2)c2ccc(S(C)(=O)=O)c(Cl)c2)cn1
Solvent: O
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)Nc2cnc(NCCO)cn2)cc1Cl
Yield: 86.9 %

Procedure:
A solution of 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-[5-(2-triethylsilanyloxy-ethylamino)-pyrazin-2-yl]-propionamide (100 mg, 0.17 mmol) in tetrahydrofuran (2 mL), water (0.5 mL), and acetic acid (2 mL) was stirred at 25° C. for 6 h. The reaction mixture was then diluted with water (10 mL) and extracted with ethyl acetate (3×20 mL). The combined organic layers were washed with a saturated aqueous sodium bicarbonate solution (10 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 12M, Silica, 2/3 hexanes/ethyl acetate to 100% ethyl acetate) afforded 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-[5-(2-hydroxy-ethylamino)-pyrazin-2-yl]-propionamide (69 mg, 86%) as a white foam: (ES)+-HRMS m/e calcd for C21H27ClN4O4S (M+H)+ 467.1515, found 467.1517.
Reaction SMILES: [Mn]([O-])(=O)(=O)=O.[K+].[Cl:7][C:8]1[NH:9][C:10]2[C:15]([CH2:16][C:17]=1[CH:18]=[O:19])=[CH:14][C:13]([F:20])=[C:12]([F:21])[CH:11]=2.[OH-].[K+].S(S([O-])=O)([O-])=[O:25].[Na+].[Na+]>O>[Cl:7][C:8]1[C:17]([C:18]([OH:25])=[O:19])=[CH:16][C:15]2[C:10](=[CH:11][C:12]([F:21])=[C:13]([F:20])[CH:14]=2)[N:9]=1
Reactant: O=CC1=C(Cl)Nc2cc(F)c(F)cc2C1
Reactant: O=S([O-])S(=O)[O-]
Agent: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Product: O=C(O)c1cc2cc(F)c(F)cc2nc1Cl
Reaction time: 0.5 h
Yield: 91.3 %

Procedure:
A solution of 115 g of potassium permanganate in 1.215 liters of water is added in the course of 1 hour, while keeping the temperature between 10° and 14° C., to a stirred suspension, cooled to 10° C., of 70.18 g of 2-chloro-6,7-difluoro-3-formyl-1,4-dihydroquinoline in 970 cm3 of N aqueous potassium hydroxide solution. The temperature is allowed to rise to about 20° C. and the mixture is stirred for a further 30 minutes at this temperature. 38.5 g of sodium dithionite are added, the mixture is stirred for 10 minutes at a temperature close to 20° C. and filtered through diatomaceous silica and the filter cake is washed with 3 times 200 cm3 of water. The filtrate and the aqueous washing phases are combined and 140 cm3 of 35% aqueous hydrochloric acid solution are added. The precipitate formed is extracted with 4 times 800 cm3 of ethyl acetate. The combined organic extracts are washed with twice 500 cm3 of water, dried over magnesium sulphate, filtered and concentrated under reduced pressure (20 kPa) at 50° C. The residue is taken up in 400 cm3 of diethyl ether, drained and washed with twice 200 cm3 of the same solvent. 49.2 g of 2-chloro-6,7-difluoroquinoline-3-carboxylic acid are obtained in the form of a beige solid melting at 232° C., which is used for the subsequent steps without further purification.
Reaction SMILES: [O:1]1CCO[CH:2]1[C:6]1[CH:7]=[C:8]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)[CH:9]=[CH:10][CH:11]=1.Cl.O>C1COCC1>[N:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[NH:12][C:8]1[CH:7]=[C:6]([CH:11]=[CH:10][CH:9]=1)[CH:2]=[O:1]
Reactant: c1ccc(Nc2cccc(C3OCCO3)c2)nc1
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: O=Cc1cccc(Nc2ccccn2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Dissolve (3-[1,3]dioxolan-2-yl-phenyl)-pyridin-2-yl-amine (10.32 g, 42.6 mmol) in THF (150 mL). Add concentrated HCl solution (37.5 mL) and stir the solution at room temperature overnight. Concentrate the reaction, treat with water, and extract with CH2Cl2. Wash the organic extract with water, dry (Na2SO4) and concentrate to give the crude product. Purification by flash chromatography (hexanes/EtOAc (7:3)) provides the title compound as a yellow solid.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH:11]2[O:13][CH:10]2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:14]1([OH:20])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>O.C(OCC)C>[O:20]([C@@H:11]1[CH2:12][N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:9][C@H:10]1[OH:13])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: Oc1ccccc1
Reactant: c1ccc(CN2CC3OC3C2)cc1
Solvent: O
Solvent: CCOCC
Product: O[C@@H]1CN(Cc2ccccc2)C[C@H]1Oc1ccccc1
Yield: 24 %

Procedure:
A mixture of 12.3 g. of 1-benzyl-3,4-epoxypyrrolidine, 13.2 g. of phenol and 3 drops of water was heated at 120° C. under nitrogen gas for 20 hr. The mixture was cooled and dissolved in 100 ml. ethyl ether. The ethereal solution was extracted with 2×50 ml. of 5% sodium hydroxide and then washed with water. After being dried with anhydrous sodium sulfate, the solvent was evaporated and the residue weighed 14.3 g. Two crystallizations from cyclohexane gave analytically pure product melting at 101°-104° C. The yield was 24% of theory.
Reaction SMILES: [ClH:1].NC(=O)[C@@H](N[C:12](=[O:32])[CH2:13][C:14]([NH:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][C:24]2[CH:29]=[CH:28][N:27]=[C:26]([NH2:30])[CH:25]=2)=[C:19]([F:31])[CH:18]=1)=[O:15])C1C=CC=CC=1.Cl.[NH2:35][C@@H:36]([C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[C:37]([O:39][CH3:40])=[O:38]>>[ClH:1].[NH2:30][C:26]1[CH:25]=[C:24]([O:23][C:20]2[CH:21]=[CH:22][C:17]([NH:16][C:14](=[O:15])[CH2:13][C:12]([NH:35][C@@H:36]([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[C:37]([O:39][CH3:40])=[O:38])=[O:32])=[CH:18][C:19]=2[F:31])[CH:29]=[CH:28][N:27]=1
Reactant: COC(=O)[C@@H](N)c1ccccc1
Reactant: NC(=O)[C@@H](NC(=O)CC(=O)Nc1ccc(Oc2ccnc(N)c2)c(F)c1)c1ccccc1
Agent: Cl
Product: COC(=O)[C@@H](NC(=O)CC(=O)Nc1ccc(Oc2ccnc(N)c2)c(F)c1)c1ccccc1
Yield: 43 %

Procedure:
3-(4-(2-Aminopyridin-4-yloxy)-3-fluorophenylamino)-3-oxopropanoic acid (Compound C of Example 102, 30 mg, 0.10 mmol) was coupled with (S)-methyl 2-amino-2-phenylacetate hydrochloride (Aldrich, 30 mg, 0.10 mmol) in a manner similar to that which is described in Step C of Example 1 to give (S)-methyl 2-(3-(4-(2-aminopyridin-4-yloxy)-3-fluorophenylamino)-3-oxopropanamido)-2-phenylacetate, hydrochloride salt (21 mg, 43% yield). 1H NMR (DMSO-d6) δ 10.58 (s, 1H), 9.04 (d, 1H, J=7.0 Hz), 7.97 (d, 1H, J=7.0 Hz), 7.75-7.88 (m, 3H), 7.42 (m, 7H), 6.72 (d, 1H, J=7.0 Hz), 6.12 (s, 1H), 5.45 (d, 1H, J=7.0 Hz), 3.63 (s, 3H), 3.43-3.38 (m, 2H); MS(ESI+) m/z 453.26 (M+H)+.
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16](=[O:28])[NH:17][CH:18]3[CH2:23][CH2:22][CH:21]([C:24](=O)[CH2:25]Br)[CH2:20][CH2:19]3)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[C:29]([NH2:32])(=[S:31])[CH3:30]>C(#N)C>[CH:3]1[C:4]2[CH:12]([CH2:14][O:15][C:16](=[O:28])[NH:17][CH:18]3[CH2:19][CH2:20][CH:21]([C:24]4[N:32]=[C:29]([CH3:30])[S:31][CH:25]=4)[CH2:22][CH2:23]3)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:13]=[CH:1][CH:2]=1
Reactant: O=C(NC1CCC(C(=O)CBr)CC1)OCC1c2ccccc2-c2ccccc21
Reactant: CC(N)=S
Solvent: CC#N
Product: Cc1nc(C2CCC(NC(=O)OCC3c4ccccc4-c4ccccc43)CC2)cs1

Procedure:
4.00 g (7 mmol) of 9H-fluoren-9-ylmethyl[4-(2-bromoacetyl)cyclohexyl]carbamate (cis compound) and 0.700 g (9 mmol) of thioacetamide are refluxed in 50 mL of acetonitrile for 72 hours with stirring. Then the reaction mixture is concentrated by evaporation, the residue is purified by chromatography. Corresponding fractions are combined and evaporated to dryness. The crystalline residue is extracted with diisopropyl ether and suction filtered. Yield: 1.10 g (39%) of cis compound; NMR: LH201648; m.p.: 140° C.-141° C.
Reaction SMILES: [Cl:1][C:2]1[N:3]([CH3:40])[C:4]([C:34]2[N:38]([CH3:39])[N:37]=[CH:36][CH:35]=2)=[CH:5][C:6]=1[C:7]([NH:9][C@@H:10]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[C:30]([F:33])([F:32])[F:31])[CH2:11][N:12]1C(=O)C2C(=CC=CC=2)C1=O)=[O:8].NN>O1CCCC1.CO>[NH2:12][CH2:11][C@@H:10]([NH:9][C:7]([C:6]1[CH:5]=[C:4]([C:34]2[N:38]([CH3:39])[N:37]=[CH:36][CH:35]=2)[N:3]([CH3:40])[C:2]=1[Cl:1])=[O:8])[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[C:30]([F:33])([F:32])[F:31]
Reactant: Cn1nccc1-c1cc(C(=O)N[C@@H](Cc2ccccc2C(F)(F)F)CN2C(=O)c3ccccc3C2=O)c(Cl)n1C
Agent: NN
Solvent: C1CCOC1
Solvent: CO
Product: Cn1nccc1-c1cc(C(=O)N[C@H](CN)Cc2ccccc2C(F)(F)F)c(Cl)n1C
Yield: 59.1 %

Procedure:
To a solution of 2-chloro-N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-1-methyl-5-(1-methyl-1H-pyrazol-5-yl)-1H-pyrrole-3-carboxamide (125 mg, 0.22 mmol) in tetrahydrofuran (1.1 ml) and methanol (1.1 ml) at 25° C. was added hydrazine (0.06 ml, 1.76 mmol) dropwise. After 12 h the solution was concentrated, dry loaded onto silica and purified by column chromatography (2% MeOH in DCM (1% NH4OH)). The free base was transferred to the HCl salt by addition of excess 2M HCl in Ether (20 ml) to the residue in DCM (40 ml) affording the HCl salt of N-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-2-chloro-1-methyl-5-(1-methyl-1H-pyrazol-5-yl)-1H-pyrrole-3-carboxamide (70 mg, 0.13 mmol, 57% yield) as a white solid: LCMS (ES) m/z=440, 442 (M, M+2)+, 1H NMR (400 MHz, DMSO-d6) δ ppm 8.17 (d, J=9.09 Hz, 1 H) 8.08 (br. s., 2 H) 7.69 (d, J=8.08 Hz, 1 H) 7.58 (br. s., 1 H) 7.57 (d, J=2.02 Hz, 1 H) 7.40-7.43 (m, 1 H) 7.02 (s, 1 H) 6.48 (d, J=2.02 Hz, 1 H) 4.50-4.57 (m, 1 H) 3.78 (s, 3 H) 3.44 (s, 3 H) 2.98-3.07 (m, 4 H).
Reaction SMILES: [NH2:1][CH2:2][CH:3]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([Cl:19])[CH:13]=2)[CH2:8][CH2:7]1)=[O:5].[Cl:27][C:28]1[CH:36]=[CH:35][C:31]([C:32](Cl)=[O:33])=[CH:30][CH:29]=1>C1COCC1>[CH2:20]([CH:3]([C:4]([N:6]1[CH2:7][CH2:8][N:9]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([Cl:19])[CH:13]=2)[CH2:10][CH2:11]1)=[O:5])[CH2:2][NH:1][C:32](=[O:33])[C:31]1[CH:35]=[CH:36][C:28]([Cl:27])=[CH:29][CH:30]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: NCC(Cc1ccccc1)C(=O)N1CCN(c2ccc(Cl)c(Cl)c2)CC1
Solvent: C1CCOC1
Product: O=C(NCC(Cc1ccccc1)C(=O)N1CCN(c2ccc(Cl)c(Cl)c2)CC1)c1ccc(Cl)cc1

Procedure:
2-(Aminomethyl)-1-(4-(3,4-dichlorophenyl)piperazin-1-yl)-3-phenylpropan-1-one (40 mg, 0.1 mmol) was dissolved in THF and then TEA (10.3 mg, 0.1 mmol) followed by 4-chlorobenzoyl chloride (0.1 mmol) were added. Upon completion of addition, the reaction mixture was allowed to stir for several hours and then concentrated. The resulting concentrate was subjected to silica gel chromatography (100% EtOAc) to provide Example 7. MS Found 532.1 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([C:12]#[N:13])[CH:9]=[CH:8][C:3]=1[NH:4]C(=O)C.Cl>C(O)C>[NH2:4][C:3]1[CH:8]=[CH:9][C:10]([C:12]#[N:13])=[CH:11][C:2]=1[Cl:1]
Reactant: CC(=O)Nc1ccc(C#N)cc1Cl
Agent: Cl
Solvent: CCO
Product: N#Cc1ccc(N)c(Cl)c1
Yield: 58.2 %

Procedure:
A mixture of 2'-chloro-4'-cyanoacetanilide (12.5 g) and concentrated hydrochloric acid (10 ml) in ethanol (50 ml) was refluxed for 30 minutes, and concentrated under reduced pressure. The residue was dissolved in water, adjusted to pH 9 with 4N-sodium hydroxide aqueous solution, and extracted with chloroform. The extract was concentrated and the residue was subjected to column chromatography on silica gel (150 g) eluting with chloroform. The fractions containing the desired compound were combined and concentrated to give a powder of 4-amino-3-chlorobenzonitrile (5.7 g).
Reaction SMILES: Cl[C:2]1[C:3]([C:12]([NH:14][C:15]2[CH:20]=[CH:19][N:18]=[C:17]([C:21]([O:23]C)=[O:22])[CH:16]=2)=[O:13])=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[F:25][C:26]([F:36])([F:35])[O:27][C:28]1[CH:33]=[CH:32][C:31]([OH:34])=[CH:30][CH:29]=1.C([O-])([O-])=O.[K+].[K+].Cl>CN1C(=O)CCC1.O>[F:25][C:26]([F:35])([F:36])[O:27][C:28]1[CH:29]=[CH:30][C:31]([O:34][C:2]2[C:3]([C:12]([NH:14][C:15]3[CH:20]=[CH:19][N:18]=[C:17]([C:21]([OH:23])=[O:22])[CH:16]=3)=[O:13])=[N:4][C:5]3[C:10]([N:11]=2)=[CH:9][CH:8]=[CH:7][CH:6]=3)=[CH:32][CH:33]=1
Reactant: COC(=O)c1cc(NC(=O)c2nc3ccccc3nc2Cl)ccn1
Reactant: Oc1ccc(OC(F)(F)F)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN1CCCC1=O
Product: O=C(O)c1cc(NC(=O)c2nc3ccccc3nc2Oc2ccc(OC(F)(F)F)cc2)ccn1
Temperature: 80 °C
Reaction time: 0.17 h
Yield: 61.6 %

Procedure:
A solution of methyl 4-[(3-chloroquinoxaline-2-carbonyl)amino]pyridine-2-carboxylate (2.6 g, 7.59 mmol), 4-(trifluoromethoxy)phenol (982.5 μL, 7.59 mmol) and K2CO3 (3.14 g, 22.76 mmol) in NMP (52.00 mL) was stirred at 70° C. for two hours and at room temperature for 12 hours. 120 ml of water were added and the reaction mixture was heated to 80° C. for 60 minutes. The reaction mixture was cooled to 45° C., aqueous HCl (1.0 N) was added until a precipitate formed. This mixture was stirred for 10 minutes, and then it was filtered. The filter cake was washed with an excess of water until the pH paper showed neutral and then it was washed with an excess of hexanes. The residue was dispersed in 120 ml of ethyl acetate, stirred for 15 minutes then it was filtered. The filter cake was washed with 10 ml ethyl acetate, 10 ml dichloromethane and dried overnight to give 44344-(trifluoromethoxy)phenoxy)quinoxaline-2-carboxamido)picolinic acid (33) (2.2 g, 61%) as a light tan-colored solid. ESI-MS m/z calc. 470.08, found 471.3 (M+1)+; Retention time: 1.51 minutes (3 minutes run). 1H NMR (400 MHz, DMSO-d6) δ 11.58 (s, 1H), 8.67 (d, J=5.5 Hz, 1H), 8.51 (d, J=2.1 Hz, 1H), 8.22 (dd, J=8.4, 1.6 Hz, 1H), 7.99 (dd, J=5.5, 2.2 Hz, 1H), 7.93-7.77 (m, 3H), 7.52 (s, 4H) ppm.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[K+].[C:11](=[N:24][CH:25]1[CH2:29][CH2:28][O:27][C:26]1=[O:30])([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[N:31]1[CH:36]=[CH:35][C:34]([CH2:37]Cl)=[CH:33][CH:32]=1>C1COCC1>[C:11](=[N:24][C:25]1([CH2:37][C:34]2[CH:35]=[CH:36][N:31]=[CH:32][CH:33]=2)[CH2:29][CH2:28][O:27][C:26]1=[O:30])([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C1OCCC1N=C(c1ccccc1)c1ccccc1
Reactant: ClCc1ccncc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Product: O=C1OCCC1(Cc1ccncc1)N=C(c1ccccc1)c1ccccc1
Temperature: 40 °C
Reaction time: 0.5 h

Procedure:
Potassium bis-(trimethylsilyl)amide (2.67, 13.4 mMol) was dissolved in anhydrous THF (50 mL) under an atmosphere of dry N2. The mixture was cooled to 40° C. to which was added a solution of 3-(benzhydrylidene-amino)-dihydro-furan-2-one (3.38 g, 12.7 mMol) in THF (30 mL). The mixture was warmed to ambient temperature and stirred at this temperature for 30 minutes. The solution was then cooled to 40° C. and a solution of 4-picolyl chloride (1.70 g, 13.4 mMol) in THF (20 mL) was added. The reaction mixture was warmed to ambient temperature and stirred for 18 hours. The mixture was partitioned between ethyl acetate-(EtOAc) and water.
Reaction SMILES: [CH3:1][CH:2]([N:4]1[C:12](/[CH:13]=[CH:14]/[CH:15]([OH:23])[CH2:16][CH:17]([OH:22])[CH2:18][C:19]([OH:21])=[O:20])=[C:11]([C:24]2[CH:25]=[CH:26][C:27]([F:30])=[CH:28][CH:29]=2)[C:10]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]1=2)[CH3:3].CC(N1C(/C=C/[C@@H](O)C[C@@H](O)CC([O-])=O)=C(C2C=CC(F)=CC=2)C2C=CC=CC1=2)C.[Na+:61]>>[CH3:3][CH:2]([N:4]1[C:12](/[CH:13]=[CH:14]/[CH:15]([OH:23])[CH2:16][CH:17]([OH:22])[CH2:18][C:19]([O-:21])=[O:20])=[C:11]([C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)[C:10]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]1=2)[CH3:1].[Na+:61]
Reactant: CC(C)n1c(/C=C/C(O)CC(O)CC(=O)O)c(-c2ccc(F)cc2)c2ccccc21
Agent: CC(C)n1c(/C=C/[C@@H](O)C[C@@H](O)CC(=O)[O-])c(-c2ccc(F)cc2)c2ccccc21
Agent: [Na+]
Product: CC(C)n1c(/C=C/C(O)CC(O)CC(=O)[O-])c(-c2ccc(F)cc2)c2ccccc21

Procedure:
This example illustrates synthesis of a novel compound of this invention from Fluvastatin. Fluvastatin sodium (5.83 g), which was isolated from Lescol® capsules (commercially available from Novartis Pharmaceuticals, East Hanover, N.J.), was dissolved in 100 mL mixture of methanol and water (50/50, v/v). 50 mL of 10% HCl and 50 mL of methanol were added into the solution and refluxed for 2 hours. Solvent was removed by rotovaping under vacuum to obtain an orange residue. The dry residue (3.23 g) was subjected to silica gel column chromatography twice with hexane/methylene chloride/methanol gradient. The yellow crystals obtained from the fraction 1079-76-3 (Formula II) were re-crystallized with methylene chloride and methanol mixture to produce 1079-76-3C (124 mg). Mass spectrometry and 1H-NMR analysis were performed to identify the fractions as dehydrated methyl ester derivatives of Fluvastatin containing a conjugated all trans triene system in the side chain. 13C-NMR analysis confirmed the provisional structure of 1079-76-3C.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]([O:13]C)=[O:12])=[CH:7][C:6]=1[NH:15][C:16](=[O:34])[CH2:17][CH:18]([C:24]1[CH:29]=[CH:28][C:27]([CH:30]=[O:31])=[CH:26][C:25]=1[O:32][CH3:33])[CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])([CH3:4])([CH3:3])[CH3:2].[CH3:35][Mg]Br.[Cl-].[NH4+].C(OCC)(=O)C>O1CCCC1.CCCCCC>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]([OH:13])=[O:12])=[CH:7][C:6]=1[NH:15][C:16](=[O:34])[CH2:17][CH:18]([C:24]1[CH:29]=[CH:28][C:27]([C:30](=[O:31])[CH3:35])=[CH:26][C:25]=1[O:32][CH3:33])[CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])([CH3:3])([CH3:2])[CH3:4]
Reactant: CCCCCC(CC(=O)Nc1cc(C(=O)OC)ccc1C(C)(C)C)c1ccc(C=O)cc1OC
Reactant: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCCCCC(CC(=O)Nc1cc(C(=O)O)ccc1C(C)(C)C)c1ccc(C(C)=O)cc1OC
Reaction time: 0.08 h
Yield: 86 %

Procedure:
A solution of 537 mg (1.15 mmol) of N-(2-t-butyl-5-methoxycarbonylphenyl)-3-(4-formyl-2-methoxyphenyl)octanamide (prepared as described in Preparation 63A) in 10 ml of tetrahydrofuran was cooled to -78° C., and 4.1 ml (3.9 mmol) of a 0.95 M solution of methylmagnesium bromide in tetrahydrofuran were added dropwise thereto over a period of 5 minutes. The reaction mixture was stirred at the same temperature for 1 hour and then at 0° C. for 90 minutes, after which a saturated aqueous solution of ammonium chloride was added to the mixture to terminate the reaction. The mixture was then extracting with ethyl acetate. The extract was washed with water and with a saturated aqueous solution of sodium chloride, after which it was dried over anhydrous magnesium sulfate. The solvent was then removed by distillation under reduced pressure, and the resulting residue was purified by column chromatography through 25 g of silica gel, using a gradient elution method, with mixtures of ethyl acetate and hexane ranging from 1:1 to 3:2 by volume, to give 479 mg (yield 86%) of the title compound as a foam-like substance.