Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC)(=O)C1C=CC(C([O-])=O)=CC=1.[K+:14].[C:15]([O:29]CCC)(=[O:28])[C:16]1[CH:27]=[CH:26][C:19]([C:20]([O:22][CH2:23][CH2:24][CH3:25])=[O:21])=[CH:18][CH:17]=1.[OH-].[K+].C1(C)C=CC=CC=1>C(O)CC>[C:20]([O:22][CH2:23][CH2:24][CH3:25])(=[O:21])[C:19]1[CH:26]=[CH:27][C:16]([C:15]([O-:29])=[O:28])=[CH:17][CH:18]=1.[K+:14]
Reactant: CCCOC(=O)c1ccc(C(=O)OCCC)cc1
Agent: COC(=O)c1ccc(C(=O)[O-])cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCCO
Solvent: Cc1ccccc1
Product: CCCOC(=O)c1ccc(C(=O)[O-])cc1
Yield: 95 %

Procedure:
This compound was prepared by the procedure described for potassium monomethyl terephthalate. Typical reagent levels were as follows: dipropyl terephthalate (97.3 g, 0.39 mole), potassium hydroxide (22.0g, 0.39 mole), 100 ml of toluene and 200 ml of 1-propanol. After workup 92.0 g of product was recovered which represented a 95% yield.
Reaction SMILES: Cl[C:2]1[C:7]([CH3:8])=[C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[CH3:15])[N:5]=[CH:4][N:3]=1.[C:16]1(B(O)O)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)[Pd][P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O.C(#N)C>[CH3:8][C:7]1[C:2]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:3][CH:4]=[N:5][C:6]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH3:15]
Reactant: OB(O)c1ccccc1
Reactant: Cc1ccccc1-c1ncnc(Cl)c1C
Agent: c1ccc([P]([Pd][P](c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: Cc1ccccc1-c1ncnc(-c2ccccc2)c1C
Yield: 87 %

Procedure:
Next, into a recovery flask equipped with a reflux pipe were put 1.9 g of 4-chloro-5-methyl-6-(2-methylphenyl)pyrimidine obtained in Step 1, 1.7 g of phenylboronic acid, 1.1 g of sodium carbonate, 0.105 g of bis(triphenylphosphine)palladium (II) dichloride (abbreviation: Pd(PPh3)2Cl2), 20 mL of water, and 20 mL of acetonitrile, and the air in the flask was replaced with argon. This reaction container was heated by irradiation with microwaves (2.45 GHz, 100 W) for 1 hour. After that, water was added to this solution and an organic layer was extracted with dichloromethane. The obtained organic layer was washed with saturated aqueous solution of sodium hydrogen carbonate, water, and saturated saline, and was dried with magnesium sulfate. The solution after drying was filtered. The solvent of this solution was distilled off, and then the obtained residue was purified by silica gel column chromatography using hexane and ethyl acetate as a developing solvent in a ratio of 9:1 and the obtained fraction was concentrated, so that 5-methyl-6-(2-methylphenyl)-4-phenylpyrimidine was obtained (a white solid, yield of 87%). A synthesis scheme (q-2) of Step 2 is shown below.
Reaction SMILES: Br[C:2]1[C:6](Br)=[C:5]([CH:8]([OH:19])[C:9]([F:18])([F:17])[C:10]([F:16])([F:15])[C:11]([F:14])([F:13])[F:12])[NH:4][C:3]=1C(O)C(F)(F)C(F)(F)C(F)(F)F.[H-].[Na+].[H][H].[CH3:36][Si:37](Cl)([CH3:39])[CH3:38]>C1COCC1>[F:17][C:9]([F:18])([C:10]([F:15])([F:16])[C:11]([F:12])([F:13])[F:14])[CH:8]([C:6]1[CH:2]=[CH:3][NH:4][C:5]=1[CH:8]([O:19][Si:37]([CH3:39])([CH3:38])[CH3:36])[C:9]([F:17])([F:18])[C:10]([F:15])([F:16])[C:11]([F:12])([F:13])[F:14])[O:19][Si:37]([CH3:39])([CH3:38])[CH3:36]
Reactant: OC(c1[nH]c(C(O)C(F)(F)C(F)(F)C(F)(F)F)c(Br)c1Br)C(F)(F)C(F)(F)C(F)(F)F
Reactant: [H][H]
Reactant: C[Si](C)(C)Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C[Si](C)(C)OC(c1cc[nH]c1C(O[Si](C)(C)C)C(F)(F)C(F)(F)C(F)(F)F)C(F)(F)C(F)(F)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 50 %

Procedure:
3,4-Dibromo-2,5-bis(2',2',3',3',4',4',4'-heptafluoro-1'-hydroxybutyl)pyrrole (1 mmol, 0.62 g) was dissolved in 25 ml of dry THF and transferred to a cooled (0° C.) suspension of sodium hydride (2.0 mmol, 0.048 g) in 100 mL of THF. When hydrogen evolution ceased (after 2 hours) trimethylsilyl chloride (2 mmol, 0.218 g) was added by syringe. The mixture was stirred at room temperature overnight before the solvent was removed in vacuo. The remaining residue was partitioned between 10% sodium bicarbonate solution and ether and the organic layer was dried over magnesium sulfate, filtered and evaporated to leave a brown oil. The product was purified by chromatography on silica gel using hexane as eluant. The product was the first material off the column (rf =0.5) The fractions containing this spot were evaporated to leave a colorless oil which solidified upon cooling under vacuum to leave 3,4-dibromo-2,5-(bis(2',2',3',3',4',4',4'-heptafluoro-1'-trimethylsilyloxybutyl)pyrrole as white needles. (380 mg, 50% yield) 1H NMR (360 MHz, CDCl3) 8.84 (broad s, 1 H); 5.30 (dd, 2 H, J1=19.5, J2=1.0); 0.06 (s, 18 H).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([NH2:27])[C:5]2[CH:11]=[C:10]([CH:12]=[CH:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]([O:22]C(C)(C)C)=[O:21])=[CH:16][CH:15]=3)[CH:9]=[N:8][C:6]=2[N:7]=1.Cl.CCOCC>[N+](C)([O-])=O>[NH2:1][C:2]1[N:3]=[C:4]([NH2:27])[C:5]2[CH:11]=[C:10]([CH:12]=[CH:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]([OH:22])=[O:21])=[CH:16][CH:15]=3)[CH:9]=[N:8][C:6]=2[N:7]=1
Reactant: CC(C)(C)OC(=O)c1ccc(C=Cc2cnc3nc(N)nc(N)c3c2)cc1
Agent: Cl
Solvent: C[N+](=O)[O-]
Solvent: CCOCC
Product: Nc1nc(N)c2cc(C=Cc3ccc(C(=O)O)cc3)cnc2n1

Procedure:
Alternatively, 0.48 g of 2,4-diamino-6-[2-(4-tert-butoxycarbonylphenyl)ethenyl]pyrido[2,3-d]pyrimidine was added to a saturated solution of hydrogen chloride in 20 mL of nitromethane at 0°. The reaction mixture quickly became viscous and turned a deep yellow color and after a few minutes of stirring, a granular solid formed. After 1 hour of stirring, 50 mL of ether were added and the precipitate was collected by filtration. The collected solid was dissolved in 50 mL of 10% aqueous sodium carbonate. Acidification with acetic acid then resulted in the separation of a yellow solid which was collected by filtration and dried under reduced pressure; yield 0.31 g (92%) of 2,4-diamino-6-[2-(4-carboxyphenyl)ethenyl]pyrido[2,3-d]pyrimidine; NMR (Me2SO-d6) delta 6.75(s, 2H), 7.35, 7.85(AB q, 4H, J=9 Hz), 8.38(s, 2H); IR (Nujol) 3400-2300, 3380, 3150, 1700, 1650, 1630, 1590 cm-1 .
Reaction SMILES: [NH2:1][C:2]1[C:11]([F:12])=[C:10](F)[C:9]([O:14][CH3:15])=[C:8]2[C:3]=1[C:4](=[O:28])[C:5]([C:25]([OH:27])=[O:26])=[C:6]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[N:7]2[CH:16]1[CH2:18][CH2:17]1.[N:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[NH:35][CH2:36][CH2:37][NH2:38].C(N(CC)CC)C.[NH4+].[Cl-]>CS(C)=O.O>[NH2:1][C:2]1[C:11]([F:12])=[C:10]([NH:38][CH2:37][CH2:36][NH:35][C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][N:29]=2)[C:9]([O:14][CH3:15])=[C:8]2[C:3]=1[C:4](=[O:28])[C:5]([C:25]([OH:27])=[O:26])=[C:6]([C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[N:7]2[CH:16]1[CH2:18][CH2:17]1
Reactant: COc1c(F)c(F)c(N)c2c(=O)c(C(=O)O)c(-c3ccccc3)n(C3CC3)c12
Reactant: NCCNc1ccccn1
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: COc1c(NCCNc2ccccn2)c(F)c(N)c2c(=O)c(C(=O)O)c(-c3ccccc3)n(C3CC3)c12
Reaction time: 0.5 h
Yield: 49.8 %

Procedure:
A solution of 5-amino-1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methoxy-4-oxo-2-phenylquinoline-3-carboxylic acid (550 mg, 1.42 mmol), N-2-pyridyl-1,2-ethanediamine (292 mg, 2.13 mmol) and triethylamine (0.297 mL, 2.13 mmol) in DMSO (7 mL) was stirred at 120° C. for 6 h. To the reaction mixture, water and NH4Cl was added to neutralize and the suspension was stirred for 30 min. The crude product was extracted with EtOAc, washed with brine, dried over MgSO4 and the solvent was removed in vacuo. The crude product was purified by column chromatography (Hexane:EtOAc 1:1→1:5) to yield 5-amino-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-4-oxo-2-phenyl-7-[2-(2-pyridylamino)ethylamino]quinoline-3-carboxylic acid (356 mg, 50%) as a yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=O.[NH2:11][C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[N:15][C:16]([C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)=[CH:17][CH:18]=2)[N:13]=1.C(O)CC>O>[F:28][C:25]1[CH:24]=[CH:23][C:22]([C:16]2[N:15]=[C:14]3[C:19]([CH:20]=[CH:21][C:12]([NH:11][C:5](=[O:7])[C:4]4[CH:8]=[CH:9][CH:10]=[C:2]([Br:1])[CH:3]=4)=[N:13]3)=[CH:18][CH:17]=2)=[CH:27][CH:26]=1
Reactant: Nc1ccc2ccc(-c3ccc(F)cc3)nc2n1
Reactant: O=C(O)c1cccc(Br)c1
Solvent: CCCO
Solvent: O
Product: O=C(Nc1ccc2ccc(-c3ccc(F)cc3)nc2n1)c1cccc(Br)c1
Temperature: 4 °C
Yield: 46.7 %

Procedure:
The procedure is analogous to that described in Example 11, but starting with 3-bromobenzoic acid (2.1 g), N,N'-carbonyldiimidazole (1.6 g) and 2-amino-7-(4-fluorophenyl)-1,8-naphthyridine (1.7 g). The product obtained by precipitation in water (2 g) is dissolved in boiling propanol (200 cc). After cooling for 4 hours at 4° C., the crystallized solid is separated by filtration, washed with propanol (3×10 cc) and dried at 40° C. under reduced pressure (0.07 kPa). N-[7-(4-Fluorophenyl)-1,8-naphthyridin-2-yl]-3-bromobenzamide (1.4 g), m.p. 210° C., is obtained.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[C:17]3[C:12](=[CH:13][C:14]([O:18][CH2:19][CH2:20][CH2:21][N:22]4[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]4)=[CH:15][CH:16]=3)[C:11](=[O:28])[C:10]=2[C:29]2[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][CH:30]=2)[CH:5]=[C:6]([F:8])[CH:7]=1.C(N(CC)CC)C.[CH3:43][S:44](Cl)(=[O:46])=[O:45]>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([C:9]2[C:17]3[C:12](=[CH:13][C:14]([O:18][CH2:19][CH2:20][CH2:21][N:22]4[CH2:23][CH2:24][N:25]([S:44]([CH3:43])(=[O:46])=[O:45])[CH2:26][CH2:27]4)=[CH:15][CH:16]=3)[C:11](=[O:28])[C:10]=2[C:29]2[CH:30]=[CH:31][C:32]([CH3:35])=[CH:33][CH:34]=2)[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: Cc1ccc(C2=C(c3cc(F)cc(F)c3)c3ccc(OCCCN4CCNCC4)cc3C2=O)cc1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(C2=C(c3cc(F)cc(F)c3)c3ccc(OCCCN4CCN(S(C)(=O)=O)CC4)cc3C2=O)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 74 %

Procedure:
To a solution of 3-(3,5-difluorophenyl)-6-(3-(piperazin-1-yl)propoxy)-2-p-tolyl-1H-inden-1-one (30 mg, 1.2 eq, 0.063 mmol) obtained in Step 2 in CH2Cl2 at 0° C. was added triethylamine (11 mL, 1.5 eq) and methylsulfonyl chloride (4.0 mL, 1.0 eq). The mixture was stirred for 1 h at room temperature and diluted with CH2Cl2. The mixture was washed with H2O and brine, dried over MgSO4, and concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc/hexanes=1:1) to obtain the title compound (17 mg, 74% for 2 steps).
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]([F:13])([F:12])[F:11])[CH:5]=1.C([Li])CCC.CN(C)[CH:21]=[O:22].O>C(OCC)C>[CH3:1][O:2][CH2:3][C:4]1([CH:9]=[CH:8][CH:7]=[C:6]([C:10]([F:11])([F:12])[F:13])[CH2:5]1)[CH:21]=[O:22]
Reactant: CN(C)C=O
Reactant: COCc1cccc(C(F)(F)F)c1
Agent: [Li]CCCC
Solvent: O
Solvent: CCOCC
Product: COCC1(C=O)C=CC=C(C(F)(F)F)C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
7.0 g of 1-(methoxymethyl)-3-(trifluoromethyl)benzene was dissolved in 300 ml anhydrous diethyl ether, and 19 ml n-butyl lithium (2.5 M solution in hexane) was added dropwise at −78° C. The reaction mixture was stirred at room temperature for 3 hours and cooled again at −78° C., and 10 ml N,N-dimethylformamide was added. The reaction solution was returned to room temperature, poured into water, extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and the solvent was evapoarated. The residue was subjected to silica gel column chromatography, and from fractions eluted with hexane-ethyl acetate (9:1), 5.0 g of 1-(methoxymethyl)-3-(trifluoromethyl)benzaldehyde was obtained as a reddish orange oil.
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[O:11][C:12]([NH:14][C:15]([CH3:29])([C:26](O)=[O:27])[CH2:16][C:17]1[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[NH:19][CH:18]=1)=[O:13])[CH2:8]2.O.ON1C2C=CC=CC=2N=N1.C1(N=C=NC2CCCCC2)CCCCC1.[NH2:56][CH2:57][CH2:58][C:59]1[C:67]2[C:62](=[CH:63][CH:64]=[CH:65][CH:66]=2)[NH:61][CH:60]=1>CCOC(C)=O>[NH:61]1[C:62]2[C:67](=[CH:66][CH:65]=[CH:64][CH:63]=2)[C:59]([CH2:58][CH2:57][NH:56][C:26](=[O:27])[C:15]([NH:14][C:12](=[O:13])[O:11][CH:2]2[CH:1]3[CH2:10][CH:5]4[CH2:6][CH:7]([CH2:9][CH:3]2[CH2:4]4)[CH2:8]3)([CH2:16][C:17]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[NH:19][CH:18]=2)[CH3:29])=[CH:60]1
Reactant: NCCc1c[nH]c2ccccc12
Reactant: CC(Cc1c[nH]c2ccccc12)(NC(=O)OC1C2CC3CC(C2)CC1C3)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCOC(C)=O
Product: CC(Cc1c[nH]c2ccccc12)(NC(=O)OC1C2CC3CC(C2)CC1C3)C(=O)NCCc1c[nH]c2ccccc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 0.50 g (1.26 mmol) of 2-adamantyloxycarbonyl-α-methyl-DL-tryptophan and 0.19 g (1.41 mmol) of 1-hydroxybenzotriazole hydrate in 20 mL of anhydrous EtOAc (under a N2 atmosphere) was treated in one portion with 0.34 g (1.65 mmol) of 1,3-dicyclohexylcarbodiimide. The mixture was stirred at room temperature for 2 hours, treated with 0.26 g (1.62 mmol) of tryptamine, and stirred for an additional 18 hours. The precipitated solid was filtered, washed with a small amount of fresh EtOAc, and discarded. The filtrate was diluted to 150 mL with EtOAc and washed with 5% aqueous citric acid (3×150 mL), brine (1×150 mL), 5% aqueous NaHCO3 (3×150 mL), and brine again. The organic layer was dried (Na2SO4) and evaporated (vacuum) to a tan solid. The residue was chromatographed (E. Merck prepacked Lobar column, 37×440 mm, eluted with 2% MeOH in CH2Cl2) to yield the purified product as a white foam, 0.32 g (47%); 1H NMR (CDCl3) δ1.46-1.92 (17H, m), 2.83 (2H, t, J 7 Hz), 3.23 (1H, d, J 15 Hz), 3.40 (1H, d, J 15 Hz), 3.52 (2H, m), 4.78 (1H, br s), 5.23 (1H, br s), 6.12 (1H, m), 6.77 (1H, m), 6.82 (1H, m), 7.06-7.58 (8H, m), 7.96 (2H, br s).
Reaction SMILES: [CH3:1][C@H:2]1[CH2:6][CH2:5][NH:4][C@@H:3]1[C:7](O)=[O:8].[ClH:10].O[C@H]1CCN[C@@H]1C(OCC)=O>>[ClH:10].[CH3:1][C@H:2]1[CH2:6][CH2:5][NH:4][C@@H:3]1[CH2:7][OH:8]
Reactant: C[C@H]1CCN[C@@H]1C(=O)O
Agent: CCOC(=O)[C@H]1NCC[C@@H]1O
Agent: Cl
Product: C[C@H]1CCN[C@@H]1CO

Procedure:
The title compound was prepared from (3S)-3-methyl-L-proline, using the methods used to prepare ethyl(3S)-3-hydroxy-L-prolinate hydrochloride. 1H NMR (400 MHz, DMSO-D6) δ ppm 1.1 (d, J=6.8 Hz, 3 H) 1.2 (t, J=6.8 Hz, 3 H) 1.6 (m, 1 H) 2.1 (m, 1 H) 2.3 (m, 1 H) 3.2 (m, 2 H) 3.8 (m, 1 H) 4.2 (m, 2 H) 4.7 (m, 1 H) 9.0 (s, 1 H) 10.4 (s, 1 H).
Reaction SMILES: Cl[S:2]([N:5]=[C:6]=[O:7])(=[O:4])=[O:3].[C:8]1([CH2:14][OH:15])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.Cl.[CH3:17][O:18][C:19](=[O:25])[CH:20]([NH2:24])[CH2:21][CH2:22][CH3:23].C(N(CC)CC)C.Cl.[Cl-].[Na+]>C(Cl)Cl>[CH3:17][O:18][C:19](=[O:25])[CH:20]([NH:24][S:2]([NH:5][C:6]([O:15][CH2:14][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:7])(=[O:4])=[O:3])[CH2:21][CH2:22][CH3:23]
Reactant: O=C=NS(=O)(=O)Cl
Reactant: CCCC(N)C(=O)OC
Reactant: OCc1ccccc1
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCC(NS(=O)(=O)NC(=O)OCc1ccccc1)C(=O)OC
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 8.1 %

Procedure:
To a stirred solution of 14.72 ml (0.17 mol) of chlorosulfonyl isocyanate in 400 ml of methylene chloride was added phenylmethanol (17.69 ml, 0.17 mol) at 0°-5° C. After stirring the above solution for 1.5 hours, a solution of 31.24 g (0.186 mol) of 2-amino-pentanoic acid methyl ester hydrochloride in 1100 ml of methylene chloride containing triethylamine (71 ml, 0.5 mol) was added at 0°-5° C., and the resulting mixture was stirred overnight allowing the mixture to warm to room temperature. The reaction mixture was poured into 10% aq. HCl solution, saturated with sodium chloride, and the organic layer was separated. The aqueous layer was extracted with methylene chloride/ethyl acetate (4:1, 2x) and the combined organic layer was washed with brine, dried over magnesium sulfate and concentrated in vacuo to yield 4.77 g (82%) of 2-(N-carbobenzyloxyaminosulfonyl)aminopentanoic acid methyl ester, (Formula XII: R=CH3 ; R1 =propyl; R2 =H; R3 =H), m.p. 76°-78° C.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[O:3][C:4]1[CH:17]=[CH:16][C:7]([O:8][C:9]2[CH:14]=[CH:13][N+:12]([O-])=[CH:11][CH:10]=2)=[CH:6][CH:5]=1.C([O-])=O.[NH4+]>C(O)C.[Pd]>[F:19][C:2]([F:1])([F:18])[O:3][C:4]1[CH:5]=[CH:6][C:7]([O:8][C:9]2[CH:10]=[CH:11][N:12]=[CH:13][CH:14]=2)=[CH:16][CH:17]=1
Reactant: [O-][n+]1ccc(Oc2ccc(OC(F)(F)F)cc2)cc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: FC(F)(F)Oc1ccc(Oc2ccncc2)cc1
Temperature: 20 °C
Reaction time: 6 h
Yield: 97.8 %

Procedure:
After 4-[4-(Trifluoromethoxy)phenoxy]pyridine-N-oxide (50 mg) was dissolved in ethanol (1.8 mL) and 10 w/w % palladium on carbon (4 mg) was added. And then Ammonium formate (120 mg) was added. The resulting mixture was stirred at 20° C. for 6 hr. The reaction mixture was filtered to remove the catalyst followed by concentration in vacuo to give a residual substance. And the a residual substance was extracted with dichloromethane. The extract was condensed under reduced pressure to give 46 mg (98% yield) of a colorless oily target compound.
Reaction SMILES: [CH2:1]([N:3]=[C:4]=[O:5])[CH3:2].[NH2:6][C:7]1[S:8][C:9]([C:13]2[CH:14]=[C:15]([NH:20][S:21]([CH3:24])(=[O:23])=[O:22])[C:16]([Cl:19])=[N:17][CH:18]=2)=[C:10]([CH3:12])[N:11]=1>C1COCC1>[Cl:19][C:16]1[C:15]([NH:20][S:21]([CH3:24])(=[O:23])=[O:22])=[CH:14][C:13]([C:9]2[S:8][C:7]([NH:6][C:4]([NH:3][CH2:1][CH3:2])=[O:5])=[N:11][C:10]=2[CH3:12])=[CH:18][N:17]=1
Reactant: Cc1nc(N)sc1-c1cnc(Cl)c(NS(C)(=O)=O)c1
Reactant: CCN=C=O
Solvent: C1CCOC1
Product: CCNC(=O)Nc1nc(C)c(-c2cnc(Cl)c(NS(C)(=O)=O)c2)s1
Temperature: 125 °C

Procedure:
Ethyl isocyanate (0.036 mL) was added to a stirred solution of N-[5-(2-amino-4-methyl-1,3-thiazol-5-yl)-2-chloropyridin-3-yl]methanesulfonamide (48 mg) in THF (0.5 mL) and the mixture was placed in a sealed glass reaction vessel and heated to 125° C. in a microwave reactor for 1 hour. The resultant mixture was evaporated and the residue was purified by column chromatography on silica using a solvent gradient of 0% to 6% methanol in dichloromethane as eluent. The material so obtained was purified further by preparative HPLC on reversed-phase silica using a solvent gradient of 10% to 100% acetonitrile in water (containing 1% acetic acid) as eluent. The material so obtained was triturated under diethyl ether. There was thus obtained the title compound as a solid (16 mg); 1H NMR Spectrum: (DMSOd6) 1.07 (t, 3H), 2.31 (s, 3H), 3.1, (s, 3H), 3.10-3.20 (m, 2H), 6.54 (br s, 11H), 7.82 (d, 1H), 8.24 (s, 1H), 9.84 (s, 1H), 10.53 (s, 1H); Mass Spectrum: M+H+ 390.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:15]2[NH:16][C:17](=[O:25])[N:18]3[CH:23]=[CH:22][N:21]=[C:20]([Cl:24])[C:19]=23)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.I[CH2:27][CH3:28]>CCO.C(=O)([O-])[O-].[Ag+2]>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:15]2[N:16]=[C:17]([O:25][CH2:27][CH3:28])[N:18]3[CH:23]=[CH:22][N:21]=[C:20]([Cl:24])[C:19]=23)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCI
Reactant: O=c1[nH]c(-c2cccc(OCc3ccccc3)c2)c2c(Cl)nccn12
Agent: [Ag+2]
Agent: O=C([O-])[O-]
Solvent: CCO
Product: CCOc1nc(-c2cccc(OCc3ccccc3)c2)c2c(Cl)nccn12
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A solution of 1-(3-benzyloxy-phenyl)-8-chloro-2H-imidazo[1,5-a]pyrazin-3-one (50.0 mg, 0.14 mmol) and silver carbonate (85 mg, 0.31 mmol) in anhydrous EtOH (1 mL) was charged with iodoethane (0.012 mL, 0.15 mmol) and stirred at rt for 48 h. The reaction mixture was partitioned between DCM and H2O and separated. The aqueous layer was washed with DCM (3×) and the combined organic layers were washed with brine (1×), dried over Na2SO4, filtered and concentrated in vacuo and the crude material was purified by chromatography on silica gel [eluting with 2% EtOAc in DCM], to yield the desired product as a yellow oil/gum; 1H NMR (CDCl3, 400 MHz) δ 1.51 (t, J=7.2 Hz, 3H), 4.68 (q, J=7.2 Hz, 2H), 5.13 (s, 2H), 7.00-7.05 (m, 1H), 7.13 (d, J=5.2 Hz, 1H), 7.27-7.48 (m, 9H); MS (ES+) m/z=380.07 (100) [MH+], HPLC: tR=4.04 min (MicromassZQ, polar—5 min).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([S:12]([N:15]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][C:23]=3[O:30][CH3:31])[C:16]3[S:17][CH:18]=[CH:19][N:20]=3)(=[O:14])=[O:13])=[CH:9][CH:10]=2)[C:5]([F:32])=[CH:4][N:3]=1.[CH3:33][O:34][C:35]1[CH:40]=[C:39]([C:41]([F:44])([F:43])[F:42])[CH:38]=[CH:37][C:36]=1B(O)O.C(=O)([O-])[O-].[K+].[K+].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.O>[CH3:31][O:30][C:23]1[CH:24]=[C:25]([O:28][CH3:29])[CH:26]=[CH:27][C:22]=1[CH2:21][N:15]([C:16]1[S:17][CH:18]=[CH:19][N:20]=1)[S:12]([C:8]1[CH:7]=[C:6]2[C:11](=[CH:10][CH:9]=1)[C:2]([C:36]1[CH:37]=[CH:38][C:39]([C:41]([F:44])([F:43])[F:42])=[CH:40][C:35]=1[O:34][CH3:33])=[N:3][CH:4]=[C:5]2[F:32])(=[O:14])=[O:13]
Reactant: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(Cl)ncc(F)c3c2)c(OC)c1
Reactant: COc1cc(C(F)(F)F)ccc1B(O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(-c4ccc(C(F)(F)F)cc4OC)ncc(F)c3c2)c(OC)c1
Temperature: 100 °C

Procedure:
A microwave vial was charged with 1-chloro-N-(2,4-dimethoxybenzyl)-4-fluoro-N-(thiazol-2-yl)isoquinoline-6-sulfonamide (Intermediate PPP; 0.041 g, 0.083 mmol), (2-methoxy-4-(trifluoromethyl)phenyl)boronic acid (0.027 g, 0.125 mmol), Pd(PPh3)4 (9.59 mg, 8.30 μmol), and potassium carbonate (0.057 g, 0.415 mmol). Dioxane (0.415 mL) and water (0.138 mL) were added, the vial was flushed with argon and sealed, and heated in a microwave reactor at 100° C. for 30 minutes. The reaction was diluted with ethyl acetate and washed with water. The aqueous layer was extracted with ethyl acetate, and the combined organic layers were dried with sodium sulfate, filtered, and concentrated. The material was purified via silica gel chromatography (12 g, gradient elution 0 to 100% EtOAc:Heptane) to afford N-(2,4-dimethoxybenzyl)-4-fluoro-1-(2-methoxy-4-(trifluoromethyl)phenyl)-N-(thiazol-2-yl)isoquinoline-6-sulfonamide. The material was dissolved in DCM and TFA (0.1 mL, 1.298 mmol) was added. The reaction was stirred for 30 minutes at room temperature after which time the reaction was concentrated and triturated with diethyl ether. The solids were filtered, washed with diethyl ether, and vacuum dried to afford 4-fluoro-1-(2-methoxy-4-(trifluoromethyl)phenyl)-N-(thiazol-2-yl)isoquinoline-6-sulfonamide (0.008 g, 0.017 mmol, 19.94% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm=13.00 (s, 1H), 8.74 (d, J=1.6 Hz, 1H), 8.51 (d, J=1.4 Hz, 1H), 7.99 (dd, J=1.7, 8.9 Hz, 1H), 7.79 (dd, J=1.8, 9.0 Hz, 1H), 7.61-7.55 (m, 1H), 7.55-7.46 (m, 2H), 7.31 (d, J=4.6 Hz, 1H), 6.90 (d, J=4.6 Hz, 1H), 3.75 (s, 3H). m/z (ESI) 484.2 (M+H)+.
Reaction SMILES: [Cl-].[CH3:2][C:3]1[S:7][C:6]([CH3:8])=[C:5]([CH3:9])[C:4]=1[CH2:10][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C([Li])CCC.[F:35]/[C:36](=[C:42](/[CH:44]=O)\[CH3:43])/[C:37]([O:39][CH2:40][CH3:41])=[O:38].CCOCC>O1CCCC1.O>[F:35]/[C:36](=[C:42](\[CH3:44])/[CH:43]=[CH:10]/[C:4]1[C:5]([CH3:9])=[C:6]([CH3:8])[S:7][C:3]=1[CH3:2])/[C:37]([O:39][CH2:40][CH3:41])=[O:38]
Reactant: CCOC(=O)/C(F)=C(/C)C=O
Reactant: Cc1sc(C)c(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)c1C
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Solvent: CCOCC
Product: CCOC(=O)/C(F)=C(C)\C=C\c1c(C)sc(C)c1C
Temperature: -60 °C
Yield: 58 %

Procedure:
A suspension of 21.0 g. (48 mmol) of (2,4,5-trimethyl-3-thenyl)-triphenylphosphonium chloride in tetrahydrofuran was stirred under argon while being cooled to -60° C. The ylide was formed by adding 1.1 equivalents of n-butyllithium and warming to -35° C. for 15 minutes. A solution of 7.7 g. (48 mmol) of ethyl 2E-2-fluoro-3-formyl-2-butenoate in 50 ml. of anhydrous ether was added slowly. This mixture was warmed to 0° C., poured into water, extracted with hexane, washed twice with 60% methanol/water, water, saturated sodium chloride solution, dried and evaporated. Purification by silica gel chromatography gave 8.8 g. (58% yield) of ethyl (2E,4E)-2-fluoro-3-methyl-5-(2,4,5-trimethyl-3-thienyl)-2,4-pentadienoate.