Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: BrCCBr.C=C.C[Si](C)(C)Cl.[CH3:12][N:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[C:15](I)[C:14]1=[O:21].CN1C=C(I)C(C)=CC1=O.O1C=CC=C1P(C1OC=CC=1)C1OC=CC=1.[CH3:48][O:49][C:50](=[O:68])[C@H:51]([CH2:60][C:61]1[CH:66]=[CH:65][C:64](I)=[CH:63][CH:62]=1)[NH:52][C:53]([O:55][C:56]([CH3:59])([CH3:58])[CH3:57])=[O:54].[Cl-].[NH4+]>C1COCC1.CC(N(C)C)=O.[Zn].C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd]>[CH3:48][O:49][C:50](=[O:68])[C@H:51]([CH2:60][C:61]1[CH:62]=[CH:63][C:64]([C:15]2[C:14](=[O:21])[N:13]([CH3:12])[CH:18]=[CH:17][C:16]=2[CH3:19])=[CH:65][CH:66]=1)[NH:52][C:53]([O:55][C:56]([CH3:59])([CH3:57])[CH3:58])=[O:54]
Reactant: Cc1ccn(C)c(=O)c1I
Reactant: COC(=O)[C@H](Cc1ccc(I)cc1)NC(=O)OC(C)(C)C
Agent: [Pd]
Agent: C=C
Agent: C[Si](C)(C)Cl
Solvent: C1CCOC1
Solvent: BrCCBr
Solvent: CC(=O)N(C)C
Product: COC(=O)[C@H](Cc1ccc(-c2c(C)ccn(C)c2=O)cc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 14 %

Procedure:
To a suspension of zinc dust (0.66 g, 10 mmol) in THF (1.0 mL) was added 1,2-dibromoethane (86 μL, 1 mmol)) at room temperature. This suspension was heated to 60-65° C. with a heat gun until evolution of ethylene gas ceased. Then, the suspension was cooled to room temperature and trimethylchlorosilane (0.126 mL, 1 mmol)) was added and the mixture was stirred for 15 min. A mixture of 1,4-dimethyl-3-iodo-2(1H)-pyridone and 1,4-dimethyl-5-iodo-2(1H)-pyridone (0.92 g, 3.69 mmol) in DMA (3 mL) was warmed to effect dissolution and was added in one portion to the reaction mixture. After addition, the mixture was heated to 70° C. and was stirred for 15 h, at which time the TLC analysis of an aliquot, which had been quenched with saturated ammonium chloride solution, indicated the absence of starting material. The reaction mixture was diluted with THF (4 mL) and was cooled to room temperature. The excess zinc dust was allowed to settle until a clear supernatant liquid formed (˜3 h). The above prepared solution containing the zinc compound (3.69 mmol) was added to a solution of Pd(dba)2 (54 mg, 0.1 mmol), trifurylphosphine (102 mg, 0.4 mmol) and N-[(1,1-dimethylethoxy)carbonyl]-4-iodo-L-phenylalanine methyl ester (1.01 g, 2.5 mmol) in THF (4 mL) at room temperature and the light yellow mixture was stirred for 15 h at 50° C. Then, the mixture was poured into a saturated ammonium chloride solution and was extracted with ethyl acetate (3×50 mL). The combined extracts were washed with brine solution (150 mL) and were dried over anhydrous magnesium sulfate. Filtration of the drying agent and concentration gave the crude product which was purified by silica gel chromatography on a Biotage (40 m) column to obtain 0.141 g (14% yield) of N-[(1,1-dimethylethoxyl)carbonyl]-4-(1,4-dimethyl-2-oxo-3-pyridinyl)-L-phenylalanine methyl ester as an amorphous white solid. ES-HRMS m/e calcd for C22H28N2O5 (M+Na) 423.1890, found 423.1894 and 0.350 g (35% yield) of N-[(1,1-dimethylethoxyl)carbonyl]-4-(1,4-dimethyl-2-oxo-5-pyridinyl)-L-phenylalanine methyl ester as an amorphous white solid. ES-HRMS m/e calcd for C22H28N2O5 (M+Na) 423.1890, found 423.1897
Reaction SMILES: C[O:2][C:3](=[O:32])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([NH:16][C:17]([C:19]3[C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=4[O:21][C:20]=3[CH2:28][CH2:29][CH2:30][CH3:31])=[O:18])[CH:12]=2)[CH:7]=1.[OH-].[Na+:34]>C1COCC1.O>[Na+:34].[CH2:28]([C:20]1[O:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[C:19]=1[C:17]([NH:16][C:11]1[CH:12]=[C:13]2[C:8](=[CH:9][CH:10]=1)[CH:7]=[C:6]([O:5][CH2:4][C:3]([O-:32])=[O:2])[CH:15]=[CH:14]2)=[O:18])[CH2:29][CH2:30][CH3:31]
Reactant: CCCCc1oc2ccccc2c1C(=O)Nc1ccc2cc(OCC(=O)OC)ccc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCCCc1oc2ccccc2c1C(=O)Nc1ccc2cc(OCC(=O)[O-])ccc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.5 %

Procedure:
A mixture of {6-[(2-butyl-benzofuran-3-carbonyl)-amino]-naphthalen-2-yloxy}-acetic acid methyl ester (103 mg, 0.239 mmol), prepared in the previous step, and 1 N NaOH (239 μL, 0.239 mmol) in 10 mL of THF plus 5 mL of water was stirred at room temperature for 21 h (overnight). The solvent was removed under reduced pressure to give the title compound (95 mg, 87%) as a yellow solid, MS m/z: 416 [M−H]−.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C@@H:3]([OH:32])[CH2:4][C@H:5]([NH:19][C:20]([C@@H:22]([NH:27][C:28](=[O:31])[O:29][CH3:30])[C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:9][CH:8]=1.[CH3:40][O:41][C:42]1[CH:62]=[CH:61][CH:60]=[CH:59][C:43]=1[CH2:44][N:45]1[CH2:49][CH2:48][N:47]([C@@H:50]([C:54]([CH3:57])([CH3:56])[CH3:55])[C:51](O)=[O:52])[C:46]1=[O:58].CCOP(ON1N=NC2C=CC=CC=2C1=O)(OCC)=O.C(N(CC)C(C)C)(C)C>C1COCC1>[OH:32][C@H:3]([C@@H:2]([NH:1][C:51](=[O:52])[C@@H:50]([N:47]1[CH2:48][CH2:49][N:45]([CH2:44][C:43]2[CH:59]=[CH:60][CH:61]=[CH:62][C:42]=2[O:41][CH3:40])[C:46]1=[O:58])[C:54]([CH3:57])([CH3:56])[CH3:55])[CH2:33][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)[CH2:4][C@H:5]([NH:19][C:20]([C@@H:22]([NH:27][C:28](=[O:31])[O:29][CH3:30])[C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:9][CH:8]=1
Reactant: COC(=O)N[C@H](C(=O)N[C@H](Cc1ccc(-c2ccccn2)cc1)C[C@H](O)[C@@H](N)Cc1ccccc1)C(C)(C)C
Reactant: COc1ccccc1CN1CCN([C@H](C(=O)O)C(C)(C)C)C1=O
Agent: CCOP(=O)(OCC)On1nnc2ccccc2c1=O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)N[C@H](C(=O)N[C@H](Cc1ccc(-c2ccccn2)cc1)C[C@H](O)[C@H](Cc1ccccc1)NC(=O)[C@@H](N1CCN(Cc2ccccc2OC)C1=O)C(C)(C)C)C(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 50.4 %

Procedure:
A solution containing the product from Example 1H (0.020 g, 0.038 mmol) in THF (0.4 mL) was treated with the product from Example 75A (0.018 g, 0.056 mmol), DEPBT (0.017 g, 0.057 mmol), and N,N-diisopropylethylamine (0.033 mL, 0.189 mmol), stirred at 25° C. for 2 hours, and partitioned between ethyl acetate and 10% Na2CO3 solution. The organic phase was washed with additional 10% Na2CO3 solution and brine, dried over MgSO4, filtered and concentrated. The residue was purified by reversed phase chromatography on a C18 column eluting with 5-100% acetonitrile in water (0.1% TFA). The product was partitioned between ethyl acetate and saturated NaHCO3 solution. The organic phase was washed brine, dried over MgSO4, filtered and concentrated to give the title compound (0.016 g, 47% yield). 1H NMR (300 MHz, DMSO-d6), δ ppm 0.80 (s, 9 H), 0.89 (m, 9 H), 1.26 (m, 1 H), 1.39 (m, 1 H), 1.54 (m, 1 H), 2.41 (m, 1 H), 2.65 (m, 2 H), 2.89 (m, 3 H), 3.20 (m, 1 H), 3.54 (m, 4 H), 3.81 (m, 4 H), 3.93 (m, 1 H), 4.02 (m, 1 H), 4.28 (m, 3 H), 4.44 (d, J=7.35 Hz, 1 H), 6.91 (m, 2 H), 7.04 (m, 6 H), 7.14 (d, J=7.35 Hz, 1 H), 7.28 (m, 4 H), 7.51 (d, J=9.93 Hz, 1 H), 7.90 (m, 5 H), 8.65 (d, J=4.04 Hz, 1 H).
Reaction SMILES: [NH2:1][C:2]([CH2:5][OH:6])([CH3:4])[CH3:3].[C:7](Cl)(=[O:10])[CH:8]=[CH2:9]>C(Cl)(Cl)Cl>[CH2:9]=[CH:8][C:7]([NH:1][C:2]([CH2:5][OH:6])([CH3:4])[CH3:3])=[O:10]
Reactant: C=CC(=O)Cl
Reactant: CC(C)(N)CO
Solvent: ClC(Cl)Cl
Product: C=CC(=O)NC(C)(C)CO
Temperature: 2.5 °C
Reaction time: 2 h
Yield: 100.3 %

Procedure:
To a stirred solution of H2NC(CH3)2CH2OH (16.8 g, 188 mmol) in CHCl3 (150 mL),under nitrogen at 0° C., acryloyl chloride (8.5 g, 94 mmol) (filtered over basic alumna) was added drop-wise via an addition funnel in such a way that the temperature did not exceed 5° C. (˜1.5 h). After complete addition, the reaction mixture was stirred for ˜2 h at 0-5° C., brought to room temperature, filtered and the filtrate concentrated by rotary evaporation. The residue was treated with 75 ml CHCl3 and ˜20 g basic alumina. This mixture was stirred for 0.5 h at room temperature (20-25° C.) and filtered. The alumina was washed with 2×10 mL CHCl3 and the combined filtrate was concentrated at reduced pressure to afford CH2═CHC(O)NHC(CH3)2CH2OH (13.5 g ) as a semisolid material. This material was used in the next step without further purification. 1H NMR (CDCl3) spectral data is consistent with the structure; δ 6.27 (br s, overlaps, 1H), 6.24 (dd, 1H), 6.14 (dd, 1H), 5.63 (dd, 1H), 4.88 (brs, 1H), 3.59 (s, 2H), 1.3 1 (s, 6H) ppm.
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH3:13].C1C(=O)N([Br:21])C(=O)C1.CC(N=NC(C#N)(C)C)(C#N)C>C(Cl)(Cl)(Cl)Cl>[Br:1][C:2]1[S:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][Br:21]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1nc(-c2ccccc2)sc1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: BrCc1nc(-c2ccccc2)sc1Br

Procedure:
A mixture of 5-Bromo-4-methyl-2-phenyl-1,3-thiazole (1.00 g, 3.93 mmol), NBS (0.84 g, 4.72 mmol) and catalytic amount of AIBN in CCl4 (20 mL) was heated at reflux for 24 h. No starting material was seen by 1H NMR. The solvent was removed. The title compound was obtained as a colorless solid after flash chromatography using EtOAc/hexane (3:97) as the eluant. 1H NMR (500 MHz, CDCl3): δ 7.90 (m, 3H), 7.48 (m, 2H), 4.61 (s, 2H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:15]=[C:14]([O:16][C:17]3[C:22]([CH3:23])=[CH:21][C:20]([N+:24]([O-])=O)=[CH:19][C:18]=3[CH3:27])[CH:13]=[CH:12][C:11]=2[OH:28])=[O:9])=[CH:4][CH:3]=1>C(OCC)(=O)C.[Pt]>[NH2:24][C:20]1[CH:21]=[C:22]([CH3:23])[C:17]([O:16][C:14]2[CH:13]=[CH:12][C:11]([OH:28])=[C:10]([C:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)=[O:9])[CH:15]=2)=[C:18]([CH3:27])[CH:19]=1
Reactant: Cc1cc([N+](=O)[O-])cc(C)c1Oc1ccc(O)c(C(=O)c2ccc(F)cc2)c1
Agent: [Pt]
Solvent: CCOC(C)=O
Product: Cc1cc(N)cc(C)c1Oc1ccc(O)c(C(=O)c2ccc(F)cc2)c1

Procedure:
(4-Fluorophenyl)[2-hydroxy-5-(2,6-dimethyl-4-nitrophenoxy)phenyl]methanone (62.8 g, 0.16 mol) is dissolved in ethyl acetate (4 L) and hydrogenated at atmospheric pressure over 5% platinum on carbon (13.2 g). When the theoretical amount of hydrogen is consumed, the hydrogenation is stopped, the catalyst is filtered off, and the ethyl acetate solution is concentrated to dryness at 50°/3 mm Hg. The residue is triturated hot with isopropanol (1 L) and collected to yield [5-(4-amino-2,6-dimethylphenoxy)-2-hydroxyphenyl](4-fluorophenyl)methanone, m.p. 198°-202°.
Reaction SMILES: CS(O[CH2:6][C:7]1[CH:12]=[C:11]([O:13][C@H:14]2[CH2:19][CH2:18][C@@H:17]([N:20]3[CH2:23][C:22]([CH2:46][C:47]#[N:48])([N:24]4[CH:28]=[C:27]([C:29]5[C:30]6[CH:37]=[CH:36][N:35]([CH2:38][O:39][CH2:40][CH2:41][Si:42]([CH3:45])([CH3:44])[CH3:43])[C:31]=6[N:32]=[CH:33][N:34]=5)[CH:26]=[N:25]4)[CH2:21]3)[CH2:16][CH2:15]2)[N:10]=[C:9]([C:49]([F:52])([F:51])[F:50])[N:8]=1)(=O)=O.[C:53]([NH2:57])([CH3:56])([CH3:55])[CH3:54].S([O-])(=O)(=O)C>C1COCC1>[C:53]([NH:57][CH2:6][C:7]1[N:8]=[C:9]([C:49]([F:52])([F:51])[F:50])[N:10]=[C:11]([O:13][C@@H:14]2[CH2:19][CH2:18][C@H:17]([N:20]3[CH2:23][C:22]([CH2:46][C:47]#[N:48])([N:24]4[CH:28]=[C:27]([C:29]5[C:30]6[CH:37]=[CH:36][N:35]([CH2:38][O:39][CH2:40][CH2:41][Si:42]([CH3:43])([CH3:45])[CH3:44])[C:31]=6[N:32]=[CH:33][N:34]=5)[CH:26]=[N:25]4)[CH2:21]3)[CH2:16][CH2:15]2)[CH:12]=1)([CH3:56])([CH3:55])[CH3:54]
Reactant: CC(C)(C)N
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C4(CC#N)CN([C@H]5CC[C@@H](Oc6cc(COS(C)(=O)=O)nc(C(F)(F)F)n6)CC5)C4)c3)ncnc21
Agent: CS(=O)(=O)[O-]
Solvent: C1CCOC1
Product: CC(C)(C)NCc1cc(O[C@H]2CC[C@@H](N3CC(CC#N)(n4cc(-c5ncnc6c5ccn6COCC[Si](C)(C)C)cn4)C3)CC2)nc(C(F)(F)F)n1
Temperature: 50 °C

Procedure:
[6-[(cis-4-{3-(Cyanomethyl)-3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}cyclohexyl)oxy]-2-(trifluoromethyl)pyrimidin-4-yl]methyl methanesulfonate (240 mg, 0.32 mmol) was dissolved in THF (2 mL), followed by addition of tert-butylamine (530 μL, 5.0 mmol). The flask was capped and heated in a 50° C. bath for 1 hour. LCMS and HPLC showed 92% conversion of the mesylate to product. HPLC showed the product to have UVmax 224, 250 and 308 nm. After another hour, the solvent was removed by rotary evaporation.
Reaction SMILES: [C:1](O)(=[O:5])[C:2]([CH3:4])=[CH2:3].[F:7][C:8]1[C:13]([O:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH:21]([CH3:23])[CH3:22])=[C:12]([F:24])[C:11]([F:25])=[C:10]([F:26])[C:9]=1[F:27].CS(O)(=O)=O.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>>[CH:21]([C:16]1[CH:17]=[C:18]2[C:19]([CH2:3][CH:2]([CH3:4])[C:1]2=[O:5])=[CH:20][C:15]=1[O:14][C:13]1[C:8]([F:7])=[C:9]([F:27])[C:10]([F:26])=[C:11]([F:25])[C:12]=1[F:24])([CH3:23])[CH3:22]
Reactant: CC(C)c1ccccc1Oc1c(F)c(F)c(F)c(F)c1F
Reactant: C=C(C)C(=O)O
Agent: CS(=O)(=O)O
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Product: CC1Cc2cc(Oc3c(F)c(F)c(F)c(F)c3F)c(C(C)C)cc2C1=O
Temperature: 70 °C
Reaction time: 1 h
Yield: 21.4 %

Procedure:
A mixture of 39.3 g (0.46 mol) of methacrylic acid and 115 g (0.38 mol) of 1-(pentafluorophenoxy)-2-isopropylbenzene was added dropwise to Eaton's reagent (prepared from 99 g of P4O10 and 500 ml of MeSO3H) for 1 h at 70° C. The resulting mixture was stirred at 70° C. for 1 h, then cooled to room temperature, and poured on 1000 cm3 of ice. The crude product was extracted with 3×200 ml of dichloromethane. The organic extract was washed with aqueous K2CO3, dried over Na2SO4, and then evaporated to dryness. The product was purified by flash chromatography on silica gel 60 (40-63 um; eluent: n-hexane-dichloromethane=5:1, vol., then n-hexane-dichloromethane-ether=50:25:1, vol.) to give 30.1 g (20%) of the title indanone. Additionally, 39.4 g of the starting 1-(pentafluorophenoxy)-2-isopropylbenzene was isolated also.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19]#[N:20])[C:3]=1[S:21]([C:23]([F:26])([F:25])[F:24])=[O:22].[OH:27]O.O>C(O)(=O)C.[O-][W]([O-])(=O)=O.[Na+].[Na+]>[NH2:1][C:2]1[N:6]([C:7]2[C:8]([Cl:18])=[CH:9][C:10]([C:14]([F:15])([F:16])[F:17])=[CH:11][C:12]=2[Cl:13])[N:5]=[C:4]([C:19]#[N:20])[C:3]=1[S:21]([C:23]([F:25])([F:24])[F:26])(=[O:27])=[O:22]
Reactant: OO
Reactant: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(N)c1S(=O)C(F)(F)F
Agent: O=[W](=O)([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(N)c1S(=O)(=O)C(F)(F)F
Yield: 110.3 %

Procedure:
0.17 g (0.4 mmol) of 5-amino-1-(2,6-dichloro-4-(trifluoromethyl) phenyl)-4-((trifluoromethyl) sulfinyl)-1H-pyrazol-3-carbonitrile, 0.01 g (0.03 mmol) of sodium tungstate.2H2O, and 0.07 g (0.6 mmol) of 30% aqueous hydrogen peroxide were dissolved in 1 mL acetic acid and reacted at 55° C. for 6 hours. The reaction solution was cooled, 10 mL water was added, and the reaction mixture was extracted twice with 10 mL ethyl acetate. The ethyl acetate layer was washed with water, then dehydrated over anhydrous magnesium sulfate, filtered and concentrated to give 0.2 g pale yellow crystal of 5-amino-1-(2,6-dichloro-4-(trifluoromethyl) phenyl)-4-((trifluoromethyl) sulfonyl)-1H-pyrazol-3-carbonitrile.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]([N:12]=[N+]=[N-])[CH3:11])[CH:5]=1)([O-:3])=[O:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[OH-].[Na+]>O1CCCC1.C(OCC)(=O)C>[N+:1]([C:4]1[CH:5]=[C:6]([CH:7]=[CH:8][CH:9]=1)[CH:10]([NH2:12])[CH3:11])([O-:3])=[O:2]
Reactant: CC(N=[N+]=[N-])c1cccc([N+](=O)[O-])c1
Agent: [Na+]
Agent: [OH-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(N)c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 97.9 %

Procedure:
1-Nitro-3-(1-azidoethyl)benzene (1.3 g, 6.76 mmol) was dissolved in tetrahydrofuran and triphenylphosphine (1.9 g, 7.4 mmol) was added. The resulting solution was stirred at ambient temperature for 18 hours. 1M aqueous sodium hydroxide (1 ml) was then added and the stirring continued for 48 hours. The reaction was diluted with ethyl acetate, washed with brine several times, dried over magnesium sulfate, filtered, and evaporated. The residue was chromatographed (silica gel, 2:1 hexane:ethyl acetate) to provide 1.1 g of the title compound. (99%). 1H NMR(CDCl3)
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[CH:12][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1.Br[CH:21]([CH3:30])[C:22]([O:28][CH3:29])=[CH:23][C:24]([O:26]C)=[O:25].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Cl:1][C:2]1[CH:15]=[C:14]([C:16]([F:18])([F:17])[F:19])[CH:13]=[CH:12][C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([O:11][CH:21]([CH3:30])[C:22]([O:28][CH3:29])=[CH:23][C:24]([OH:26])=[O:25])=[CH:9][CH:10]=1
Reactant: Oc1ccc(Oc2ccc(C(F)(F)F)cc2Cl)cc1
Reactant: COC(=O)C=C(OC)C(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=CC(=O)O)C(C)Oc1ccc(Oc2ccc(C(F)(F)F)cc2Cl)cc1

Procedure:
A mixture of 4-(2-chloro-4-trifluoromethylphenoxy)phenol (6.9 mmol.), methyl 4-bromo-3-methoxy-2-pentenoate (8.9 mmol.) and potassium carbonate (1.5 equis.) in acetone (15 ml.) is refluxed for 48 hours. After filtration, the filtrate was concentrated and the residue chromatographed on silia gel using 20% ethylacetate/hexane to give the methyl ester of 4-[4-(2-chloro-4-trifluoromethylphenoxy)phenoxy]-3-methoxy-2-pentenoic acid.
Reaction SMILES: Br[CH:2]1[S:6][C:5](=[O:7])[NH:4][C:3]1=[O:8].[Cl:9][C:10]1[CH:11]=[CH:12][C:13]2[S:17][C:16]([SH:18])=[N:15][C:14]=2[CH:19]=1>>[Cl:9][C:10]1[CH:11]=[CH:12][C:13]2[S:17][C:16]([S:18][CH:2]3[S:6][C:5](=[O:7])[NH:4][C:3]3=[O:8])=[N:15][C:14]=2[CH:19]=1
Reactant: Sc1nc2cc(Cl)ccc2s1
Reactant: O=C1NC(=O)C(Br)S1
Product: O=C1NC(=O)C(Sc2nc3cc(Cl)ccc3s2)S1

Procedure:
This compound was prepared from 5-bromo-thiazolidine-2,4-dione and 5-chloro-2-mercaptobenzothiazole according to the procedure described in Example 5: mp 253-255 (dec).
Reaction SMILES: C1(=O)OCCO1.[F-:7].[K+].Cl[C:10]([O:12][CH2:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:11].ClC([O-])=O>>[F:7][C:10]([O:12][CH2:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:11]
Reactant: CC(C)(C)COC(=O)Cl
Reactant: [F-]
Agent: O=C([O-])Cl
Agent: [K+]
Solvent: O=C1OCCO1
Product: CC(C)(C)COC(=O)F
Reaction time: 1 h
Yield: 92 %

Procedure:
The preparation was carried out as in Example 2 but using 120 g of ethylene carbonate, 45 g (0.77 mol) of potassium fluoride and 75.3 g (0.5 mol) of neopentyl chloroformate. After addition of the chloroformate, stirring of the reaction mixture was continued for 1 hour at 45° C. Evaporation under vacuum was carried out as in the preceding example. By distillation under reduced pressure, 61.7 g (92% yield) of neopentyl fluoroformate were recovered with a boiling point of 60° C. at 20 mm Hg.
Reaction SMILES: [CH:1]1([CH:7]([NH:20][C:21]2[CH:29]=[CH:28][C:24]([C:25](O)=[O:26])=[CH:23][CH:22]=2)[C:8]2[CH:12]=[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[O:10][C:9]=2[CH3:19])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[NH2:31][CH2:32][CH:33]([OH:38])[C:34]([O:36]C)=[O:35].Cl.C(N=C=NCCCN(C)C)C.O.OC1C2N=NNC=2C=CC=1>CN(C)C=O.C(OCC)(=O)C.C(N(CC)CC)C>[CH:1]1([CH:7]([NH:20][C:21]2[CH:22]=[CH:23][C:24]([C:25]([NH:31][CH2:32][CH:33]([OH:38])[C:34]([OH:36])=[O:35])=[O:26])=[CH:28][CH:29]=2)[C:8]2[CH:12]=[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[O:10][C:9]=2[CH3:19])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cc1oc(-c2ccccc2)cc1C(Nc1ccc(C(=O)O)cc1)C1CCCCC1
Reactant: COC(=O)C(O)CN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1oc(-c2ccccc2)cc1C(Nc1ccc(C(=O)NCC(O)C(=O)O)cc1)C1CCCCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 88 %

Procedure:
A solution of 4-{[cyclohexyl(5-phenyl-2-methylfuran-3-yl)methyl]amino}benzoic acid (156 mg), methyl 3-amino-2-hydroxypropanoate hydrochloride (75 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (92 mg), hydroxybenzotriazole monohydrate (74 mg) and triethylamine (67 μL) in N,N-dimethylformamide (10 mL) was stirred at room temperature for 4 hr. Ethyl acetate was added, the mixture was washed with saturated aqueous sodium hydrogen carbonate solution and water, and the organic layer was dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the organic layer was dried over magnesium sulfate. The solvent was evaporated under reduced pressure. To the residue were added ethanol (2 mL), tetrahydrofuran (2 mL) and 1N lithium hydroxide (0.8 mL), and the mixture was stirred at room temperature for 1 hr. The solvent was evaporated under reduced pressure, and water (10 mL) was added. The mixture was neutralized with 1N hydrochloric acid under ice-cooling, and stirred for 1 hr. The resulting precipitate was collected by filtration and dried to give the title compound (168 mg, 88%).
Reaction SMILES: C[O:2][CH:3](OC)[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:9]2[CH2:10][O:11][B:12]([OH:13])[C:8]=2[CH:7]=1.Cl>CC(C)=O>[OH:13][B:12]1[C:8]2[CH:7]=[C:6]([O:5][CH2:4][CH:3]=[O:2])[CH:15]=[CH:14][C:9]=2[CH2:10][O:11]1
Reactant: COC(COc1ccc2c(c1)B(O)OC2)OC
Agent: Cl
Solvent: CC(C)=O
Product: O=CCOc1ccc2c(c1)B(O)OC2
Temperature: 30 °C
Reaction time: 24 h
Yield: 82.4 %

Procedure:
To a solution of H197 (38 mg, 0.16 mmol) in acetone (2 mL) was added 6M HCl (0.3 mL). The reaction mixture was stirred at 30° C. for 24 hours. The residue after evaporation was purified by recrystallization to give the title compound (25.3 mg, 82.5% yield). 1H NMR (400 MHz, acetone-d6): δ 9.82 (s, 1H), 7.35 (d, J=8.0 Hz, 1H), 7.23 (d, J=2.4 Hz, 1H), 7.12 (dd, J=8.1 & 2.4 Hz, 1H), 4.96 (s, 2H) and 4.79 (s, 2H) ppm.
Reaction SMILES: [CH2:1]([C:3]1[C:8](=[O:9])[NH:7][C:6]([CH3:10])=[C:5]([C:11]2[CH:12]=[N:13][CH:14]=[C:15]([C:17]([OH:19])=O)[CH:16]=2)[CH:4]=1)[CH3:2].[OH:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[CH2:27][CH2:28][NH2:29]>>[OH:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[CH2:27][CH2:28][NH:29][C:17]([C:15]1[CH:16]=[C:11]([C:5]2[CH:4]=[C:3]([CH2:1][CH3:2])[C:8](=[O:9])[NH:7][C:6]=2[CH3:10])[CH:12]=[N:13][CH:14]=1)=[O:19]
Reactant: CCc1cc(-c2cncc(C(=O)O)c2)c(C)[nH]c1=O
Reactant: NCCc1ccccc1O
Product: CCc1cc(-c2cncc(C(=O)NCCc3ccccc3O)c2)c(C)[nH]c1=O

Procedure:
Method 1, Example 205 is substantially repeated except for utilizing 5′-ethyl-2′-methyl-6′-oxo-1′,6′-dihydro-[3,3′]bipyridinyl-5-carboxylic acid and 2-(2-hydroxy-phenyl)-ethyl-amine to afford the title compound. MS: m/e=378 (M+H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:15]=[N:16][C:17]([C:21]([F:24])([F:23])[F:22])=[C:18](I)[CH:19]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:25][C:26]1[S:30][C:29](B(O)O)=[CH:28][CH:27]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.O.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>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:15]=[N:16][C:17]([C:21]([F:24])([F:23])[F:22])=[C:18]([C:29]3[S:30][C:26]([Cl:25])=[CH:27][CH:28]=3)[CH:19]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCN(c2cc(I)c(C(F)(F)F)nn2)CC1
Reactant: OB(O)c1ccc(Cl)s1
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: [Na+]
Solvent: O
Solvent: COCCOC
Product: CC(C)(C)OC(=O)N1CCN(c2cc(-c3ccc(Cl)s3)c(C(F)(F)F)nn2)CC1
Temperature: 110 °C
Reaction time: 16 h
Yield: 77.7 %

Procedure:
A mixture of 4-(5-iodo-6-trifluoromethyl-pyridazin-3-yl)-piperazine-1-carboxylic acid tert-butyl ester (D10) (0.20 g, 0.436 mmol), 5-chlorothiophene-2-boronic acid (0.082 g, 0.51 mmol), tetrakis(triphenylphosphine)palladium (0) (0.024 g, 0.021 mmol) and sodium carbonate (0.103 g, 0.96 mmol) in dimethoxyethane (3 ml) and water (0.75 ml) was stirred in a sealed tube at 110° C. for 16 h. The mixture was then filtered through a pad of diatomaceous earth and the solvent was evaporated in vacuo. The residue was purified by column chromatography (silica gel; dichloromethane/10% ammonia in methanol (7M) in dichloromethane 97/3) to yield D15 (0.152 g, 67%) as a yellow syrup. C18H20ClF3N4O2S requires 448; Found 449 (MH+).