Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[C:3]([CH3:22])=[N:4][C:5]2[C:10]([N:11]=1)=[C:9]([C:12]1[NH:20][C:19]3[CH2:18][CH2:17][NH:16][C:15](=[O:21])[C:14]=3[CH:13]=1)[CH:8]=[CH:7][CH:6]=2.[CH3:23][C:24]1([NH2:28])[CH2:27][O:26][CH2:25]1.CCN(C(C)C)C(C)C>>[CH3:22][C:3]1[C:2]([NH:28][C:24]2([CH3:23])[CH2:27][O:26][CH2:25]2)=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[C:12]2[NH:20][C:19]3[CH2:18][CH2:17][NH:16][C:15](=[O:21])[C:14]=3[CH:13]=2)[N:4]=1
Reactant: Cc1nc2cccc(-c3cc4c([nH]3)CCNC4=O)c2nc1F
Reactant: CC1(N)COC1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc2cccc(-c3cc4c([nH]3)CCNC4=O)c2nc1NC1(C)COC1
Temperature: 100 °C
Yield: 38 %

Procedure:
Prepared similarly to that described in Example 131 using 2-(3-fluoro-2-methylquinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (Example 126; 47 mg, 0.159 mmol), 3-methyloxetan-3-amine (27.6 mg, 0.317 mmol; Synthonix, Wake Forest, N.C.), and DIPEA (83 μl, 0.476 mmol), heating at 100° C. for 2.5 h. Purification by silica gel (100% DCM to 6% MeOH/DCM) provided 2-(2-methyl-3-((3-methyloxetan-3-yl)amino)quinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (38% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.80 (s, 3H) 2.57 (s, 3H) 2.89 (t, J=6.85 Hz, 2H) 3.45 (td, J=6.85, 2.35 Hz, 2H) 4.60 (d, J=6.26 Hz, 2H) 4.87 (d, J=6.26 Hz, 2H) 6.95 (br. s., 1H) 7.06 (d, J=2.35 Hz, 1H) 7.34-7.41 (m, 2H) 7.61 (dd, J=8.02, 1.37 Hz, 1H) 7.82 (dd, J=7.63, 1.37 Hz, 1H) 11.66 (br. s., 1H). MS (ESI, pos. ion) m/z: 364.2 (M+1).
Reaction SMILES: [N+:1]([CH:4]([N+:8]([O-:10])=[O:9])[N+:5]([O-:7])=[O:6])([O-:3])=[O:2].[CH:11]([CH:13]=[CH2:14])=[O:12]>O>[N+:1]([C:4]([N+:8]([O-:10])=[O:9])([N+:5]([O-:7])=[O:6])[CH2:14][CH2:13][CH:11]=[O:12])([O-:3])=[O:2]
Reactant: O=[N+]([O-])C([N+](=O)[O-])[N+](=O)[O-]
Reactant: C=CC=O
Solvent: O
Product: O=CCCC([N+](=O)[O-])([N+](=O)[O-])[N+](=O)[O-]
Temperature: 9 °C
Yield: 90.7 %

Procedure:
A 12 L three-necked, round-bottom flask with a thermometer, mechanical stirrer, and 1000 ml addition funnel was charged with 6377 g of an 11% aqueous trinitromethane solution (701.5 g; 4.675 mol) and cooled in a dry-ice bath at 9° C. A solution of acrolein (274.1 g, 4.90 mol) in 2000 ml of water was added at a rate that maintained the temperature at 0° C. The dry-ice bath was removed and the stirred solution allowed to warm to room temperature overnight. The two phases were separated and the aqueous layer was extracted with CH2Cl2 (2×2000 ml). The combined organic layers were washed with water (2×2000 ml). The product was dried (MgSO4) and concentrated to give 878 g (91%) of the aldehyde as a yellow oil; nD =1.4731 (26C). The infrared spectrum showed bands at 1725 cm-1 (C=O), 1590, 1300, and 800 cm-1 (NO2).
Reaction SMILES: [OH:1][C:2]([C:13]1[CH:18]=[CH:17][C:16]([N:19]([CH2:29][CH:30]([CH3:32])[CH3:31])[S:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)(=[O:22])=[O:21])=[CH:15][CH:14]=1)([C:9]([F:12])([F:11])[F:10])[C:3]#[C:4][Si](C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C(Cl)Cl.C1COCC1>[OH:1][C:2]([C:13]1[CH:18]=[CH:17][C:16]([N:19]([CH2:29][CH:30]([CH3:32])[CH3:31])[S:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)(=[O:22])=[O:21])=[CH:15][CH:14]=1)([C:9]([F:12])([F:11])[F:10])[C:3]#[CH:4]
Reactant: CC(C)CN(c1ccc(C(O)(C#C[Si](C)(C)C)C(F)(F)F)cc1)S(=O)(=O)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: ClCCl
Product: C#CC(O)(c1ccc(N(CC(C)C)S(=O)(=O)c2ccccc2)cc1)C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 0.25 g (0.51 mmol) of N-[4-(1-hydroxy-1-trifluoromethyl-3-trimethylsilanyl-prop-2-ynyl)-phenyl]-N-isobutyl-benzenesulfonamide (Example 74) in 6 mL of CH2Cl2 was added 0.4 mL of a 1 M solution of tetrabutylammonium fluoride in THF. The mixture was stirred at room temperature for 1 hour. CH2Cl2 (60 mL) was added and the solution was washed with saturated aqueous NH4Cl-solution (20 mL) and brine (15 mL). The organic layer was dried over Na2SO4, filtered and the filtrate was concentrated. The residue was purified by chromatography on silica gel, (hexane:EtOAc, 7:3) to give the title compound.
Reaction SMILES: N1C=CC=[CH:3][C:2]1=O.[N+:8]([C:11]1[C:12]([OH:18])=[N:13][CH:14]=[CH:15][C:16]=1[OH:17])([O-:10])=[O:9].[H-].[Na+].C(I)C>CN(C=O)C>[CH2:2]([N:13]1[CH:14]=[CH:15][C:16]([OH:17])=[C:11]([N+:8]([O-:10])=[O:9])[C:12]1=[O:18])[CH3:3]
Reactant: O=c1cccc[nH]1
Reactant: O=[N+]([O-])c1c(O)ccnc1O
Agent: [H-]
Agent: [Na+]
Solvent: CCI
Solvent: CN(C)C=O
Product: CCn1ccc(O)c([N+](=O)[O-])c1=O
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 53 %

Procedure:
1-Ethyl-4-hydroxy-3-nitro-1H-)pyridin-2-one: To a solution of 3-nitro-pyridine-2,4-diol (1.0 g, 6.41 mmol) in DMF (10 mL) at 0° C., was added NaH (0.51 g, 12.82 mmol 60% in mineral oil). After stirring at 0° C. for 15 min, ethyl iodide (1.10 g, 7.05 mmol) was added and the reaction was stirred at 55° C. for 17 h. After cooling to room temperature, the mixture was poured into ice water, and then filtered to remove insoluble material. The filtrate was acidified with 1 N HCl, extracted with CH2Cl2, dried with MgSO4, and concentrated. The product was rinsed with EtOH to give 1-ethyl-4-hydroxy-3-nitro-1H-pyridin-2-one (0.63 g, 53% yield). 1H-NMR (DMSO): 8, 7.79 (d, 1H, J=7.6 Hz), 6.09 (d, 1H, J=7.6 Hz), 3.90 (q, 2H, J=7.2 Hz), 1.19 (t, 3H, J=7.2 Hz).
Reaction SMILES: [C:1](=O)([O-])[O-].[K+].[K+].[OH:7][CH2:8][CH:9]([O:12][C:13]1[CH:18]=CC=C[CH:14]=1)[CH:10]=[CH2:11]>CO>[OH:7][CH2:8][CH:9]([O:12][C:13]([CH3:14])([CH3:18])[CH3:1])[CH:10]=[CH2:11]
Reactant: C=CC(CO)Oc1ccccc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C=CC(CO)OC(C)(C)C
Reaction time: 8 h

Procedure:
This half-ester R-3k (104 mg; 0.4 mmol) was dissolved in methanol (5 mL) and treated with potassium carbonate (110 mg; 0.8 mmol; 2 equiv.) and stirred overnight to completely consume 3k (tlc analysis). The reaction mixture was diluted with water (25 mL) and ether (25 mL) and the layers were separated. The aqueous layer was extracted with ether (2×15 mL). The combined organic solution was dried (MgSO4) and concentrated to afford 62 mg (94%) of R-1k. All achiral properties of 1k are as reported above. [α]D20 -14.2° (C. 1.01, CH3OH). The absolute configuration of 1k was inferred to be R-(-) by analogy with the absolute configuration results of the enzymatic reaction of 1j. 1H nmr analysis of the MTPA ester using an analogous procedure to that of Dale et al., J. Org. Chem., 1969, 34, 2543, indicated 54% ee for R-1k.
Reaction SMILES: [C:1]([C:3]1[CH:27]=[CH:26][C:6]([O:7][C:8]2[N:16]=[C:15]([O:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]#[N:25])=[CH:20][CH:19]=3)[CH:14]=[CH:13][C:9]=2[C:10](O)=[O:11])=[CH:5][CH:4]=1)#[N:2].[C:28]([O:32][C:33]([N:35]1[CH2:40][CH2:39][CH:38]([NH2:41])[CH2:37][CH2:36]1)=[O:34])([CH3:31])([CH3:30])[CH3:29]>>[C:28]([O:32][C:33]([N:35]1[CH2:40][CH2:39][CH:38]([NH:41][C:10]([C:9]2[C:8]([O:7][C:6]3[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:27][CH:26]=3)=[N:16][C:15]([O:17][C:18]3[CH:19]=[CH:20][C:21]([C:24]#[N:25])=[CH:22][CH:23]=3)=[CH:14][CH:13]=2)=[O:11])[CH2:37][CH2:36]1)=[O:34])([CH3:31])([CH3:29])[CH3:30]
Reactant: N#Cc1ccc(Oc2ccc(C(=O)O)c(Oc3ccc(C#N)cc3)n2)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Product: CC(C)(C)OC(=O)N1CCC(NC(=O)c2ccc(Oc3ccc(C#N)cc3)nc2Oc2ccc(C#N)cc2)CC1
Yield: 75 %

Procedure:
Following the procedure of Example 5(c) 2,6-bis(4-cyano phenoxy)-nicotinic acid 1.5 g (4.20 mmol) and 4-amino-piperidine-1-carboxylic acid tert-butyl ester (0.84 g, 4.20 mmol) were used to afford 1.7 g of the required product. Percentage purity (LCMS): 74.6%, (M+1)=539.2 (with BOC).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7](=[O:11])[CH2:8][C:9]#[N:10].[F:12][C:13]1[CH:18]=[CH:17][C:16]([N:19]=[C:20]=[O:21])=[CH:15][CH:14]=1>C1(C)C=CC=CC=1.C(N(CC)CC)C>[CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7](=[O:11])[CH:8]([C:20](=[O:21])[NH:19][C:16]1[CH:17]=[CH:18][C:13]([F:12])=[CH:14][CH:15]=1)[C:9]#[N:10]
Reactant: O=C=Nc1ccc(F)cc1
Reactant: Cn1cccc1C(=O)CC#N
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: Cn1cccc1C(=O)C(C#N)C(=O)Nc1ccc(F)cc1
Reaction time: 8 h

Procedure:
To the suspension of 4.0 g of 1-methyl-β-oxo-2-pyrrolpropionitrile in 70 ml of toluene and 3.2 g of triethylamine, 3.7 g of p-fluorophenylisocyanate are added while stirring. The mixture is warmed on the steam cone until dissolution and the red-brown solution is allowed to stand overnight at room temperature. It is evaporated on the steam cone, the residue taken up in methanol and the solution poured into the mixture of 8 ml of 5 N hydrochloric acid and 300 ml of water. The precipitated crystals are collected, washed with water, dried, triturated with methanol and recrystalllized from ethyl acetate, to yield the 1-methyl-β-oxo-α-(p-fluorophenylcarbamoyl)-2-pyrrolpropionitrile melting at 198°-199°.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[CH:5]=[C:6]1[CH2:9][N:8](C(C2C=CC=CC=2)C2C=CC=CC=2)[CH2:7]1)[CH3:2].[H][H]>C(O)C.[OH-].[OH-].[Pd+2]>[CH2:1]([O:3][C:4](=[O:23])[CH2:5][CH:6]1[CH2:9][NH:8][CH2:7]1)[CH3:2]
Reactant: CCOC(=O)C=C1CN(C(c2ccccc2)c2ccccc2)C1
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: CCOC(=O)CC1CNC1

Procedure:
To a solution of (1-benzhydrylazetidin-3-ylidene)-acetic acid ethyl ester (5.0 g, 16 mmol) in ethanol (200 mL) was added palladium hydroxide on carbon (1.5 g). This mixture was vigorously shaken under a 50 psi hydrogen atmosphere for 24 hrs, then filtered and concentrated to give an oil, used without additional purification.
Reaction SMILES: [CH3:1][C:2]1[N:6]([C:7]2[CH:17]=[CH:16][CH:15]=[CH:14][C:8]=2[C:9](OCC)=[O:10])[N:5]=[N:4][N:3]=1.[O-]CC.[K+]>CN(C)C=O.O>[N:5]1[N:6]2[C:7]3[C:8]([C:9]([OH:10])=[CH:1][C:2]2=[N:3][N:4]=1)=[CH:14][CH:15]=[CH:16][CH:17]=3
Reactant: CCOC(=O)c1ccccc1-n1nnnc1C
Agent: CC[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Oc1cc2nnnn2c2ccccc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 99.9 %

Procedure:
Under a nitrogen atmosphere, ethyl 2-(5-methyl-1H-tetrazol-1-yl)benzoate (92.7 g, 0.34 mol) was dissolved in N,N-dimethylformamide (600 ml) and the solution was chilled in an ice water bath. Potassium ethoxide (67.2 g, 0.80 mol) was added slowly to the solution. After a few minutes, the ice water bath was removed and the reaction was stirred at room temperature for 3 hours. The reaction was treated with 100 ml of water and approximately 300-400 ml of solvent was removed in vacuo. The remainder of the reaction was poured over a solution of glacial acetic acid (125 ml) in ice water (2 L). A precipitate formed and the mixture was diluted with additional water (3 L). The solid was collected by vacuum filtration to yield 63.25 g of tetrazolo[1,5-a]quinolin-5-ol as a yellow solid.
Reaction SMILES: C1(C[O:8][C:9](=[O:49])[CH2:10][N:11]([C:23]2[CH:28]=[C:27]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])[CH:26]=[C:25]([CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH3:48])[CH:24]=2)[CH2:12][C:13]([O:15]CC2C=CC=CC=2)=[O:14])C=CC=CC=1>[Pd].C1COCC1>[C:9]([CH2:10][N:11]([C:23]1[CH:24]=[C:25]([CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH3:48])[CH:26]=[C:27]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])[CH:28]=1)[CH2:12][C:13]([OH:15])=[O:14])([OH:49])=[O:8]
Reactant: CCCCCCCCCCc1cc(CCCCCCCCCC)cc(N(CC(=O)OCc2ccccc2)CC(=O)OCc2ccccc2)c1
Agent: [Pd]
Solvent: C1CCOC1
Product: CCCCCCCCCCc1cc(CCCCCCCCCC)cc(N(CC(=O)O)CC(=O)O)c1
Reaction time: 5 h
Yield: 81.3 %

Procedure:
A mixture of 1.65 g of N-(3,5-didecylphenyl)-N-[2-(phenylmethoxy)-2-oxoethyl]glycine phenylmethylester and 0.5 g of 10% palladium on carbon in 100 ml of THF was shaken under an initial hydrogen pressure of 53 psi for 5 hours. The catalyst wasremoved by filtration and the filtrate was concentrated at reduced pressureto a solid which was recrystallized from methanol-water to give 0.98 g (81%yield, mp 78°-81°) of N-(carboxymethyl)-N-(3,5-didecylphenyl)glycine.
Reaction SMILES: [CH:1]([C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1)=[CH2:2].[Br:13][C:14]1[C:15]2[N:16]([C:20](=[O:23])[NH:21][N:22]=2)[CH:17]=[CH:18][CH:19]=1.[OH-].[K+]>CN1C(=O)CCC1.C(Cl)Cl>[Br:13][C:14]1[C:15]2[N:16]([C:20](=[O:23])[N:21]([CH2:2][CH2:1][C:3]3[CH:12]=[CH:11][C:10]4[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=4)[N:4]=3)[N:22]=2)[CH:17]=[CH:18][CH:19]=1
Reactant: C=Cc1ccc2ccccc2n1
Reactant: O=c1[nH]nc2c(Br)cccn12
Agent: [K+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CN1CCCC1=O
Product: O=c1n(CCc2ccc3ccccc3n2)nc2c(Br)cccn12
Temperature: 160 °C
Yield: 55.6 %

Procedure:
2-Vinylquinoline (1-2) (218 mg, 1.40 mmol) and triazolopyridinone 1-5 (250 mg, 1.17 mmol) were placed in a microwave vial and dissolved in NMP (3 mL). To the mixture was added catalytic powdered KOH (13 mg, 0.234 mmol), and the vial was capped and heated at 160° C. under microwave irradiation for 20 min. After cooling, the mixture was diluted with CH2Cl2 (100 mL) and washed with water (25 mL) and brine (25 mL). The organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The crude material was purified by silica gel flash column chromatography (40 g cartridge), eluting with 20-100% EtOAc/hexanes. The fractions containing the desired product (1-6) were pooled, and after solvent removal in vacuo, 240 mg (52%) of a fluffy yellow solid were obtained. 1H NMR (300 MHz, CHCl3-d) δ 8.07 (d, J=8.4 Hz, 1H), 8.02 (d, J=8.5 Hz, 1H), 7.77 (app t, J=8.0 Hz, 2H), 7.68 (t, J=7.7 Hz, 1H), 7.50 (t, J=7.5 Hz, 1H), 7.38-7.30 (m, 2H), 6.39 (dd, J=7.2, 6.7 Hz, 1H), 4.61 (t, J=7.6 Hz, 2H), 3.57 (t, J=7.6 Hz, 2H); HRMS (ES) 369.0345 (M+H) found, 369.0349 required.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([CH:13]([CH3:15])[CH3:14])=[N:10][C:9]=2[C:16]2[CH:17]=[C:18]([NH:22][S:23]([C:26]3[C:31]([F:32])=[CH:30][CH:29]=[CH:28][C:27]=3[F:33])(=[O:25])=[O:24])[CH:19]=[CH:20][CH:21]=2)[CH:5]=[CH:4][N:3]=1.[NH2:34][CH2:35][CH2:36][S:37]([CH3:40])(=[O:39])=[O:38]>Cl>[F:33][C:27]1[CH:28]=[CH:29][CH:30]=[C:31]([F:32])[C:26]=1[S:23]([NH:22][C:18]1[CH:19]=[CH:20][CH:21]=[C:16]([C:9]2[N:10]=[C:11]([CH:13]([CH3:15])[CH3:14])[S:12][C:8]=2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:34][CH2:35][CH2:36][S:37]([CH3:40])(=[O:39])=[O:38])[N:7]=2)[CH:17]=1)(=[O:25])=[O:24]
Reactant: CC(C)c1nc(-c2cccc(NS(=O)(=O)c3c(F)cccc3F)c2)c(-c2ccnc(Cl)n2)s1
Reactant: CS(=O)(=O)CCN
Agent: Cl
Product: CC(C)c1nc(-c2cccc(NS(=O)(=O)c3c(F)cccc3F)c2)c(-c2ccnc(NCCS(C)(=O)=O)n2)s1
Temperature: 60 °C
Yield: 41.5 %

Procedure:
A neat mixture of N-{3-[5-(2-chloro-4-pyrimidinyl)-2-(1-methylethyl)-1,3-thiazol-4-yl]phenyl}-2,6-difluorobenzenesulfonamide (0.15 g, 0.30 mmol) and 2-aminoethyl-methyl-sulfone (0.20 g, 1.62 mmol) was heated at 60° C. overnight. The reaction mixture was diluted with 1M HCl and extracted with DCM twice. The organic layer was dried over MgSO4 and evaporated onto silica gel. Purification by ISCO chromatography (0 to 40% 1:9 MeOH:EtOAC in DCM) afforded the title compound (74 mg, 40.0% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.04 (s, 1H), 8.06 (d, J=5.1 Hz, 1H), 7.65-7.75 (m, 1H), 7.46 (t, J=5.7 Hz, 1H), 7.35 (t, J=7.9 Hz, 1H), 7.16-7.30 (m, 5H), 6.09 (br. s., 1H), 3.60-3.73 (m, 2H), 3.34-3.38 (m, 2H), 3.25-3.30 (m, 1H), 3.02 (s, 3H), 1.36 (d, J=6.9 Hz, 6H). MS (ESI): 594.2 [M+H]+.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH3:9][O:10][C:11]1[S:15][C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:13][CH:12]=1>C(Cl)(Cl)Cl>[Br:1][C:12]1[N:13]=[C:14]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[S:15][C:11]=1[O:10][CH3:9]
Reactant: COc1cnc(-c2ccccc2)s1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)Cl
Product: COc1sc(-c2ccccc2)nc1Br
Temperature: 25 °C
Reaction time: 4 h

Procedure:
400 mg (2.1 mmol) of N-bromosuccinimide was added into 10 ml of anhydrous chloroform with 400 mg (2.1 mmol) of 5-methoxy-2-phenylthiazole under 0° C. condition and was stirred for 4 hours at a room temperature. After completion of reaction, the organic phase was extracted with ethyl acetate, and was dried with addition of magnesium sulfate. After removing the solvent, the product was developed with ethyl acetate:hexane=1:3 solvent on silica column to give 4-bromo-5-methoxy-2-phenylthiazole (Rf=0.50). The yield was 550 mg in weight and 97% in percentage.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[C:4]([Cl:12])[N:3]=1.S(=O)(=O)(O)O.[Cl:18]Cl.[OH-].[K+]>C(Cl)Cl.C(Cl)(Cl)(Cl)Cl>[NH2:1][C:2]1[C:7]([Cl:18])=[CH:6][C:5]([C:8]([F:9])([F:10])[F:11])=[C:4]([Cl:12])[N:3]=1
Reactant: ClCl
Reactant: Nc1ccc(C(F)(F)F)c(Cl)n1
Agent: O=S(=O)(O)O
Agent: [K+]
Agent: [OH-]
Solvent: ClCCl
Solvent: ClC(Cl)(Cl)Cl
Product: Nc1nc(Cl)c(C(F)(F)F)cc1Cl
Temperature: 0 °C
Reaction time: 4 h

Procedure:
In a 200 ml four necked flask equipped with a thermometer, a stirrer and a reflux condenser were placed 7 g of 2-amino-5-trifluoromethyl-6-chloropyridine, 10 ml of carbon tetrachloride and 70 ml of 20% sulfuric acid to give a homogeneous solution. Chlorine gas was introduced thereinto while cooling the flask at 0° C., and the reaction was carried out for 4 hours. After confirming the completion of the reaction by thin layer chromatography, the reaction product was poured into ice water and neutralized with a potassium hydroxide solution. 50 ml of methylene chloride was added thereto, followed by washing with water. The organic phase was dried over anhydrous sodium sulfate, and the solvent was evaporated off. The solid thus obtained was washed with n-hexane to obtain 6.7 g of the desired product.
Reaction SMILES: [Li+].[OH-].[C:3]([C:5]1[CH:6]=[C:7]([C:15]2[S:19][C:18]([C:20]3[CH:25]=[CH:24][C:23]([CH2:26][CH2:27][C:28]([O:30]CC)=[O:29])=[CH:22][C:21]=3[CH3:33])=[N:17][CH:16]=2)[CH:8]=[CH:9][C:10]=1[O:11][CH:12]([CH3:14])[CH3:13])#[N:4].Cl>O.C1COCC1>[C:3]([C:5]1[CH:6]=[C:7]([C:15]2[S:19][C:18]([C:20]3[CH:25]=[CH:24][C:23]([CH2:26][CH2:27][C:28]([OH:30])=[O:29])=[CH:22][C:21]=3[CH3:33])=[N:17][CH:16]=2)[CH:8]=[CH:9][C:10]=1[O:11][CH:12]([CH3:14])[CH3:13])#[N:4]
Reactant: CCOC(=O)CCc1ccc(-c2ncc(-c3ccc(OC(C)C)c(C#N)c3)s2)c(C)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(CCC(=O)O)ccc1-c1ncc(-c2ccc(OC(C)C)c(C#N)c2)s1
Temperature: 50 °C
Yield: 64.1 %

Procedure:
A solution of 2 mg of LiOH in 1 mL water and 1 mL THF was added to ethyl 3-(4-(5-(3-cyano-4-isopropyloxyphenyl)-1,3-thiazol-2-yl)-3-methylphenyl)propanoate (0.003 g, from Step E) and the reaction was heated at 50° C. for 2 h. The reaction was acidified with 0.5 M HCl (25 mL) and the product was extracted with ethyl acetate (25 mL). The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. Silica gel chromatography eluting with 10% methanol/methylene chloride yielded 1.8 mg of the title compound: 1H NMR (500 MHZ, CDCl3) δ 7.99 (s, 1H), 7.79 (d, J=2.0 Hz, 1H), 7.75 (dd, J=6.9, 2.0 Hz, 1H), 7.72 (d, J=8.0 Hz, 1H), 7.20 (s, 1H), 7.18 (d, J=8.0 Hz, 1H), 7.05 (d, J=8.7 Hz, 1H), 4.70-4.77 (m, 1H), 3.02 (t, J=7.7 Hz, 2H), 2.76 (t, J=7.7 Hz, 2H), 2.64 (s, 3H), 1.47 (d, J=6.0 Hz, 6H).
Reaction SMILES: [I:1][C:2]1[CH:3]=[N:4][N:5]([CH2:8][C:9]2([O:16][CH2:17][CH2:18][CH:19]=O)[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[C:6]=1[CH3:7].[NH:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>ClCCl>[I:1][C:2]1[CH:3]=[N:4][N:5]([CH2:8][C:9]2([O:16][CH2:17][CH2:18][CH2:19][N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]2)[C:6]=1[CH3:7]
Reactant: Cc1c(I)cnn1CC1(OCCC=O)CCCCCC1
Reactant: C1COCCN1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: Cc1c(I)cnn1CC1(OCCCN2CCOCC2)CCCCCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of EXAMPLE 155C (393 mg) in dichloromethane (20 mL) was added morpholine (263 mg) and sodium triacetoxyborohydride (427 mg). After the reaction mixture was stirred overnight at room temperature, 2N NaOH aqueous solution (10 mL) was added and the reaction mixture was extracted with ethyl acetate, and the organic layer was washed with water and a saturated NaCl solution. After the organic layer was dried over Na2SO4, it was filtered and the solvent was evaporated under reduced pressure. The crude product was used in the next reaction without further purification.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[NH2:11][C:12]1[S:13][C:14]([CH2:22][CH3:23])=[CH:15][C:16]=1[C:17]([O:19][CH2:20][CH3:21])=[O:18].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[CH2:22]([C:14]1[S:13][C:12]([NH:11][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[N+:8]([O-:10])=[O:9])=[C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:15]=1)[CH3:23]
Reactant: O=[N+]([O-])c1ccccc1F
Reactant: CCOC(=O)c1cc(CC)sc1N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CCOC(=O)c1cc(CC)sc1Nc1ccccc1[N+](=O)[O-]
Temperature: 100 °C

Procedure:
o-Fluoronitrobenzene (56.4 g, 0.4 mol) and ethyl 2-amino-5-ethylthiophene-3-carboxylate (100 g, 0.5 mol) were dissolved in dry dimethylsulphoxide (320 ml). The stirred solution, under nitrogen, was heated in an oil bath. When the internal temperature reached 60° C., potassium carbonate (55 g, 0.4 mol) was added and the mixture stirred at 100° C. until GLC indicated that all the o-fluoronitrobenzene had been consumed (6.5 hours). The mixture was then poured onto ice-water, acidified with concentrated hydrochloric acid and extracted with methylene chloride. The combined extracts were washed with water, dried (MgSO4) and the solvent evaporated to give a red semi-solid which was recrystallised from ethanol to give the title product as a solid (m.p. 66°-68° C.).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1OS(C(F)(F)F)(=O)=O)=[CH:13][CH:12]=[C:11]([C:24]([F:27])([F:26])[F:25])[CH:10]=2)=[O:5])[CH3:2].P([O-])([O-])([O-])=O.[K+].[K+].[K+].[C:36]([O:39][CH2:40][CH3:41])(=[O:38])[CH3:37]>O1CCOCC1.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>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[C:9]1[CH:14]=[CH:13][C:37]([C:36]([O:39][CH2:40][CH3:41])=[O:38])=[CH:11][CH:10]=1)=[CH:13][CH:12]=[C:11]([C:24]([F:27])([F:26])[F:25])[CH:10]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cnc2cc(C(F)(F)F)ccc2c1OS(=O)(=O)C(F)(F)F
Reactant: CCOC(C)=O
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: C1COCCO1
Product: CCOC(=O)c1ccc(-c2c(C(=O)OCC)cnc3cc(C(F)(F)F)ccc23)cc1

Procedure:
4-Trifluoromethanesulfonyloxy-7-trifluoromethyl-quinoline-3-carboxylic acid ethyl ester (208 mg, 0.5 mmol), 4-ethylcarboxylphenylboronic acid (107 mg, 0.55 mmol), tetrakis(triphenylphosphine)palladium(0) (29 mg) and potassium phosphate (159 mg, 0.75 mmol) were heated together in dioxane (5 mL) to 80° C. overnight. The reaction mixture was then diluted with ethyl acetate and washed with brine twice. The organic layer was dried over sodium sulfate, concentrated, and the residue purified by flash column eluted with 30% ethyl acetate in hexane to yield 4-(4-ethoxycarbonyl-phenyl)-7-trifluoromethyl-quinoline-3-carboxylic acid ethyl ester as a yellow oil.