Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:3]2[CH2:11][CH2:10][N:9]([C:12]3[C:17]([C:18]([F:21])([F:20])[F:19])=[CH:16][CH:15]=[CH:14][N:13]=3)[CH2:8][C:4]=2[N:5]=[CH:6][N:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.[F:70][C:71]([F:83])([F:82])[S:72]([C:75]1[CH:80]=[CH:79][C:78]([NH2:81])=[CH:77][CH:76]=1)(=[O:74])=[O:73]>O1CCOCC1.C(OCC)(=O)C>[F:19][C:18]([F:21])([F:20])[C:17]1[C:12]([N:9]2[CH2:10][CH2:11][C:3]3[C:2]([NH:81][C:78]4[CH:79]=[CH:80][C:75]([S:72]([C:71]([F:83])([F:70])[F:82])(=[O:74])=[O:73])=[CH:76][CH:77]=4)=[N:7][CH:6]=[N:5][C:4]=3[CH2:8]2)=[N:13][CH:14]=[CH:15][CH:16]=1
Reactant: FC(F)(F)c1cccnc1N1CCc2c(Cl)ncnc2C1
Reactant: Nc1ccc(S(=O)(=O)C(F)(F)F)cc1
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: O=S(=O)(c1ccc(Nc2ncnc3c2CCN(c2ncccc2C(F)(F)F)C3)cc1)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 55 %

Procedure:
A mixture of 4-chloro-7-(3-(trifluoromethyl)pyridin-2-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine (0.100 g, 0.000314 mol) tris(dibenzylideneacetone)dipalladium(0) (0.058 g, 0.000063 mol), Cesium Carbonate (0.311 g, 0.000944 mol) and Xantphos (0.018 g, 0.000031 mol) in 1,4-Dioxane (3 mL, 0.04 mol) was stirred at room temperature for 10 minutes in a 5 mL microwave vial. 4-(trifluoromethylsulfonyl)benzenamine (0.15 g, 0.00063 mol) was then added as a solution in dioxane (0.5 mL) and the mixture was stirred for an additional 5 minutes. The mixture was heated via microwave in a sealed tube at 140° C. for 30 minutes, allowed to cool, and reduced in vacuo. The resulting black solid was taken up in ethyl acetate (50 mL) and washed with brine and water (2×50 mL), dried over magnesium sulfate, and reduced in vacuo. The mixture was purified by flash chromatography using an ethyl acetate:hexanes (0-100%) gradient. The combined pure fractions were reduced in vacuo to yield the desired product as a tan solid (0.087 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[N:16]([CH2:20][C:21]([OH:24])([CH3:23])[CH3:22])[N:15]=[CH:14]3)=[C:6]([CH:9]=1)[C:7]#[N:8].N1C(C)=CC=CC=1C.[Si:33](OS(C(F)(F)F)(=O)=O)([C:36]([CH3:39])([CH3:38])[CH3:37])([CH3:35])[CH3:34]>ClCCl.CCOCC>[Si:33]([O:24][C:21]([CH3:22])([CH3:23])[CH2:20][N:16]1[C:17]2[C:13](=[CH:12][C:11]([O:10][C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:9][C:6]=3[C:7]#[N:8])=[CH:19][CH:18]=2)[CH:14]=[N:15]1)([C:36]([CH3:39])([CH3:38])[CH3:37])([CH3:35])[CH3:34]
Reactant: CC(C)(O)Cn1ncc2cc(Oc3ccc(F)cc3C#N)ccc21
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: CCOCC
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: CC(C)(Cn1ncc2cc(Oc3ccc(F)cc3C#N)ccc21)O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 75.1 %

Procedure:
To a cooled (0° C.) solution of 5-Fluoro-2-[1-(2-hydroxy-2-methylpropyl)-1H-indazol-5-yloxy]-benzonitrile (0.070 g, 0.215 mmol) and 2,6-lutidine (0.030 g, 0.284 mmol) in dichloromethane (2 mL) was added TBSOTf (0.063 g, 0.240 mmol). The reaction mixture was warmed to room temperature and stirred for 1 hour. The mixture was diluted with ether (50 mL) and washed with 0.2N HCl, NaHCO3, and brine, dried over MgSO4, and concentrated under reduced pressure. The residue was chromatographed eluting with ether/hexanes (1:3) to afford 0.071 g of pale yellow oil (94% yield).
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]([CH3:12])[C:5]2[C:6](=[O:9])[O:7][CH2:8][C:4]=2[C:3]=1[CH3:13].[CH:14]([B-](F)(F)F)=[CH2:15].[K+]>CCO.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:13][C:3]1[C:4]2[CH2:8][O:7][C:6](=[O:9])[C:5]=2[C:10]([CH3:12])=[CH:11][C:2]=1[CH:14]=[CH2:15]
Reactant: Cc1cc(Br)c(C)c2c1C(=O)OC2
Reactant: C=C[B-](F)(F)F
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [K+]
Solvent: CCO
Product: C=Cc1cc(C)c2c(c1C)COC2=O

Procedure:
A mixture of 5-bromo-4,7-dimethyl-2-benzofuran-1(3H)-one (0.7 g, 2.9 mmol), potassium vinyltrifluoroborate (0.544 g, 4 mmol) and Pd(dppf)2Cl2 (0.07 g) in 20 mL of EtOH and 20 mL of TEA was refluxed under N2 for 4 hours. The mixture was concentrated and the residue was purified by column chromatography to afford 4,7-Dimethyl-5-vinyl-2-benzofuran-1(3H)-one.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[C:6](=[O:22])[N:7]([CH:14]1[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]1=[O:21])[C:8]2=[O:13].N12CCCN=C1CCCCC2.ON1C2C=CC=CC=2N=N1.[CH3:44][O:45][C:46]1[CH:47]=[C:48]([CH2:54][C:55](O)=[O:56])[CH:49]=[C:50]([O:52][CH3:53])[CH:51]=1.Cl.CN(C)CCCN=C=NCC>C(#N)C>[CH3:53][O:52][C:50]1[CH:49]=[C:48]([CH2:54][C:55]([NH:2][CH2:3][C:4]2[CH:12]=[CH:11][CH:10]=[C:9]3[C:5]=2[C:6](=[O:22])[N:7]([CH:14]2[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]2=[O:21])[C:8]3=[O:13])=[O:56])[CH:47]=[C:46]([O:45][CH3:44])[CH:51]=1
Reactant: NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Reactant: COc1cc(CC(=O)O)cc(OC)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: COc1cc(CC(=O)NCc2cccc3c2C(=O)N(C2CCC(=O)NC2=O)C3=O)cc(OC)c1
Reaction time: 0.17 h
Yield: 78.1 %

Procedure:
To a stirred suspension of 4-aminomethyl-2-(2,6-dioxo-piperidin-3-yl)-isoindole-1,3-dione hydrochloride (0.7 g, 2.2 mmol) in acetonitrile (60 mL), was added 1,8-diazabicyclo[5,4,0]undec-7-ene (0.8 g, 5.4 mmol). After stirring for 10 minutes, 1-hydroxybenzotriazole (0.4 g, 2.6 mmol) and 3,5-dimethoxyphenylacetic acid (0.5 g, 2.4 mmol) were added, followed by 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.6 g, 3.2 mmol). The mixture was stirred at room temperature overnight and was then concentrated in vacuo. The residue was dissolved in CH2Cl2 (80 mL) and washed with water (40 mL), 1NHCl (2×30 mL), water (40 mL), and brine (40 mL), and dried over MgSO4. Solvent was removed in vacuo, and the residue was purified by ISCO silica gel flash chromatography (Eluent: EtOAc: CH2Cl2 3:7) to afford 2-(3,5-dimethoxy-phenyl)-N-[2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-acetamide (0.8 g, 79%) as a white solid: mp 294-296° C.; HPLC: Waters Symmetry C-18, 3.9×150 mm, 5 micro, 1 mL/min, 240 nm, 40/60 (CH3CN/H2O): tR=2.88 min. (98%); 1H NMR (DMSO-d6) δ 2.03-2.07 (m, 1H), 2.52-2.63 (m, 2H), 2.84-2.94 (m, 1H), 3.45 (s, 2H), 3.71 (s, 6H), 4.70 (d, J=5.9 Hz, 2H), 5.12-5.18 (dd, J=5.3 and 12.8 Hz, 1H), 6.37 (t, J=2.2 Hz, 1H), 6.46 (d, J=2.2 Hz, 2H), 7.51-7.67 (m, 1H), 7.72-7.81 (m, 2H), 8.61 (t, J=5.9 Hz, 1H), 11.13 (s, 1H); 13C NMR (DMSO-d6) δ 21.94, 30.90, 37.83, 42.51, 48.82, 55.05, 98.34, 107.08, 121.88, 127.12, 131.51, 133.17, 134.61, 138.20, 139.18, 160.28, 166.90, 167.42, 169.77, 170.34, 172.73; Anal. Calcd. for C24H23N3O7: C, 61.93; H, 4.98; N, 9.03. Found: C, 61.62; H, 4.61; N, 8.91.
Reaction SMILES: [C:1]([C:3]1[CH:26]=[CH:25][C:6]([CH2:7][NH:8][C:9](=[O:24])[C:10]2[CH:15]=[CH:14][CH:13]=[N:12][C:11]=2[O:16][C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)=[CH:5][CH:4]=1)#[N:2].[N-:27]=[N+:28]=[N-:29].C([Sn](=O)CCCC)CCC>C1(C)C=CC=CC=1>[F:23][C:20]1[CH:21]=[CH:22][C:17]([O:16][C:11]2[N:12]=[CH:13][CH:14]=[CH:15][C:10]=2[C:9]([NH:8][CH2:7][C:6]2[CH:5]=[CH:4][C:3]([C:1]3[NH:29][N:28]=[N:27][N:2]=3)=[CH:26][CH:25]=2)=[O:24])=[CH:18][CH:19]=1
Reactant: N#Cc1ccc(CNC(=O)c2cccnc2Oc2ccc(F)cc2)cc1
Reactant: [N-]=[N+]=[N-]
Agent: CCCC[Sn](=O)CCCC
Solvent: Cc1ccccc1
Product: O=C(NCc1ccc(-c2nnn[nH]2)cc1)c1cccnc1Oc1ccc(F)cc1
Temperature: 110 °C

Procedure:
N-(4-Cyano-benzyl)-2-(4-fluoro-phenoxy)-nicotinamide (0.090 g) was placed in a sealable tube with anhydrous toluene (2 mL). Timethylsilyl azide (0.10 mL) was added, followed dibutyltin oxide (0.010 g) and the reaction mixture heated to 110° C. for 20 h. The reaction mixture was allowed to cool to ambient temperature, and quenched with 30% sodium bicarbonate (10 mL). Ethyl acetate (10 mL) was added and the aqueous layer collected. The organic layer was subsequently extracted with 30% sodium bicarbonate (2×10 mL). The combined aqueous portions were brought to pH 2 with 3N hydrochloric acid, and extracted with ethyl acetate (5×25 mL). The combined organics were dried over magnesium sulfate, filtered, and concentrated to dryness in vacuo to yield the title compound (0.040 g).
Reaction SMILES: [NH2:1][C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][C:4]([OH:6])=[O:5].[OH-].[Na+:11].CC(C)=O.[C:16](Cl)(=[O:33])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]>O>[C:16]([NH:1][C@H:2]([C:7]([O-:9])=[O:8])[CH2:3][C:4]([O-:6])=[O:5])(=[O:33])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32].[Na+:11].[Na+:11]
Reactant: CCCCCCCCCCCCCCCCC(=O)Cl
Reactant: N[C@@H](CC(=O)O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: O
Product: CCCCCCCCCCCCCCCCC(=O)N[C@@H](CC(=O)[O-])C(=O)[O-]
Temperature: 0 °C
Reaction time: 2 h

Procedure:
In a one L three-necked flask were placed 16.0 g (0.12 mol) of L-aspartic acid and an aqueous solution of 9.6 g (0.24 mol) of sodium hydroxide in 150 mL of water under stirring. After the L-aspartic acid was dissolved, 120 mL of acetone was added to the mixture in the flask. Then, to the resultant reaction liquid which had been cooled to 0° C. were added dropwise over a period of 30 minutes, 29.0 g (0.1 mol) of heptadecanoyl chloride and an aqueous solution of 4 g sodium hydroxide in 30 mL of water, while maintaining the reaction temperature at 0 to 5° C. and pH at 11 to 12. Thereafter, by gradually raising the temperature of the reaction liquid to room temperature (25° C.) under stirring over a period of 2 hours, a solution of disodium heptadecanoyl-L-aspartate was obtained. To the resultant solution was added 65 mL of 5N hydrochloric acid to lower the pH of the solution to 1. The crystal thus precipitated was separated from the solution by means of vacuum filtration, washed with water and dried under reduced pressure. The resultant crystal was washed with 500 mL of hexane, dried and recrystallized from a mixed solvent of ethanol/water (8:1). As a result 21.0 g (0.054 mol) of N-heptadecanoyl-L-aspartic acid was obtained in a yield of 54.3% based on the fed heptadecanoyl chloride. The physical properties of the objective N-heptadecanoyl-L-aspartic acid were as follows.
Reaction SMILES: [OH:1][N:2]=[C:3](Cl)[C:4]1[CH:15]=[CH:14][C:7]2[B:8]([OH:13])[O:9][C:10]([CH3:12])([CH3:11])[C:6]=2[CH:5]=1.[Cl:17][C:18]1[CH:23]=[C:22]([C:24]([C:26]([F:29])([F:28])[F:27])=[CH2:25])[C:21]([Cl:30])=[C:20]([Cl:31])[C:19]=1[Cl:32]>CN(C=O)C>[CH3:11][C:10]1([CH3:12])[O:9][B:8]([OH:13])[C:7]2[CH:14]=[CH:15][C:4]([C:3]3[CH2:25][C:24]([C:22]4[CH:23]=[C:18]([Cl:17])[C:19]([Cl:32])=[C:20]([Cl:31])[C:21]=4[Cl:30])([C:26]([F:28])([F:27])[F:29])[O:1][N:2]=3)=[CH:5][C:6]1=2
Reactant: C=C(c1cc(Cl)c(Cl)c(Cl)c1Cl)C(F)(F)F
Reactant: CC1(C)OB(O)c2ccc(C(Cl)=NO)cc21
Solvent: CN(C)C=O
Product: CC1(C)OB(O)c2ccc(C3=NOC(c4cc(Cl)c(Cl)c(Cl)c4Cl)(C(F)(F)F)C3)cc21
Temperature: 25 °C
Reaction time: 12 h
Yield: 19.3 %

Procedure:
To the solution of N,1-dihydroxy-3,3-dimethyl-1,3-dihydrobenzo[c][1,2]oxaborole-5-carbimidoyl chloride (0.526 mmol) in DMF (3 mL) was added 1,2,3,4-tetrachloro-5-(3,3,3-trifluoroprop-1-en-2-yl)benzene (245 mg, 0.789 mmol) and TEA (106 mg, 1.052 mmol) at rt. The mixture was stirred at 25° C. for 12 h, quenched with water, extracted with EA (3×10 mL). The combined organic layer was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by prep-HPLC to give the final title compound 3,3-dimethyl-5-(5-(2,3,4,5-tetrachlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)benzo[c][1,2]oxaborol-1(3H)-ol (52 mg; yield 13%) as a solid. 1H NMR (400 MHz, DMSO-d6): δ 9.20 (s, 1H), 7.98 (s, 1H), 7.83 (s, 1H), 7.76-7.47 (d, J=3.2 Hz, 2H), 4.67-4.63 (d, J=18 Hz, 1H), 4.37-4.35 (d, J=18.8 Hz, 1H), 1.49 (s, 3H), 1.48 (s, 3H) ppm; MS: m/z=514 (M+1, ESI+).
Reaction SMILES: [BH4-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:11]=[C:12]3[CH:17]=[CH:16][C:15]([C:18]4[CH:27]=[C:26]5[C:21]([CH2:22][CH2:23][CH2:24][C:25]5=[O:28])=[CH:20][CH:19]=4)=[CH:14][N:13]3[CH:29]=2)=[CH:6][CH:5]=1>CO>[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:11]=[C:12]3[CH:17]=[CH:16][C:15]([C:18]4[CH:27]=[C:26]5[C:21]([CH2:22][CH2:23][CH2:24][CH:25]5[OH:28])=[CH:20][CH:19]=4)=[CH:14][N:13]3[CH:29]=2)=[CH:6][CH:5]=1
Reactant: O=C1CCCc2ccc(-c3ccc4nc(-c5ccc(Cl)cc5)cn4c3)cc21
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: OC1CCCc2ccc(-c3ccc4nc(-c5ccc(Cl)cc5)cn4c3)cc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 20.1 %

Procedure:
241 mg of sodium borohydride are added portionwise to 238 mg of 7-[2-(4-chlorophenyl)imidazo[1,2-a]pyridin-6-yl]-3,4-dihydro-2H-naphth-1-one dissolved in 25 ml of methanol. The mixture is stirred at ambient temperature for 2 hours and then the solvent is evaporated under reduced pressure. The residue is taken up between water and ethyl acetate. The organic phase is separated by settling, dried over sodium sulphate and concentrated under reduced pressure. The residue is purified by chromatography on silica gel, elution being carried out with a dichloromethane/methanol mixture. 48 mg of compound are obtained.
Reaction SMILES: [CH:1](=O)[CH3:2].[CH3:4][O:5][C:6](=[O:10])[CH2:7][C:8]#[N:9]>>[C:8]([C:7](=[CH:1][CH3:2])[C:6]([O:5][CH3:4])=[O:10])#[N:9]
Reactant: COC(=O)CC#N
Reactant: CC=O
Product: CC=C(C#N)C(=O)OC

Procedure:
Similarly to Example 1a), acetaldehyde was reacted with methyl-cyanoacetate in a Knoevenagel reaction to give methyl 2-cyanobut-2-enoate.
Reaction SMILES: [C:1]([N:18]([CH2:24][CH3:25])[C@H:19]([C:21]([OH:23])=[O:22])[CH3:20])([O:3][CH2:4][CH:5]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]2[C:6]1=[CH:7][CH:8]=[CH:9][CH:10]=2)=[O:2].C(Cl)(=O)C(Cl)=O.[CH2:32](O)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>ClCCl.CN(C)C=O.[Ag]C#N>[CH2:32]([O:22][C:21](=[O:23])[C@H:19]([CH3:20])[N:18]([C:1]([O:3][CH2:4][CH:5]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:11]=2[C:12]2[C:17]1=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:2])[CH2:24][CH3:25])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: OCc1ccccc1
Reactant: CCN(C(=O)OCC1c2ccccc2-c2ccccc21)[C@@H](C)C(=O)O
Agent: N#C[Ag]
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCN(C(=O)OCC1c2ccccc2-c2ccccc21)[C@@H](C)C(=O)OCc1ccccc1
Temperature: 80 °C
Reaction time: 1 h
Yield: 377.2 %

Procedure:
A suspension of 848 mg (2.5 mmol) of (S)-N-Fmoc-N-ethylalanine in 10 mL Of dichloromethane was treated with 436 μL (5.0 mmol) of oxalyl chloride followed by a catalytic amount (1 drop) of dimethylformamide. The mixture was stirred for one hour, then concentrated in vacuo. The yellow, oily residue was treated with 10 mL of toluene followed by 517 mg (0.5 mmol) of benzyl alcohol and 669 mg (5.0 mmol) of silver cyanide. The mixture was heated in an 80° C. oil bath with vigorous stirring for 20 minutes, then cooled and filtered through a pad of diatomaceous earth. The liltrate was concentrated, and the residue was purified by silica gel column chromatography, using 10% acetone in hexane as eluant. Ester (142) (810 mg) was obtained as a colorless oil; TLC: Rf =0.28, 15% acetone/hexane; 1H NMR (300 MHz) consistent with structure.
Reaction SMILES: [Cl:1][C:2]1[C:18]([Cl:19])=[C:17]([CH2:20][CH2:21][C:22](=[O:38])[C:23]2[S:24][CH:25]=[C:26]([C:28]3[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][CH:29]=3)[CH:27]=2)[CH:16]=[CH:15][C:3]=1[O:4][C:5]([CH3:14])([CH3:13])[C:6]([O:8]C(C)(C)C)=[O:7].FC(F)(F)C(O)=O>>[Cl:1][C:2]1[C:18]([Cl:19])=[C:17]([CH2:20][CH2:21][C:22](=[O:38])[C:23]2[S:24][CH:25]=[C:26]([C:28]3[CH:29]=[CH:30][C:31]([C:34]([F:35])([F:36])[F:37])=[CH:32][CH:33]=3)[CH:27]=2)[CH:16]=[CH:15][C:3]=1[O:4][C:5]([CH3:13])([CH3:14])[C:6]([OH:8])=[O:7]
Reactant: CC(C)(C)OC(=O)C(C)(C)Oc1ccc(CCC(=O)c2cc(-c3ccc(C(F)(F)F)cc3)cs2)c(Cl)c1Cl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(Oc1ccc(CCC(=O)c2cc(-c3ccc(C(F)(F)F)cc3)cs2)c(Cl)c1Cl)C(=O)O

Procedure:
2-(2,3-Dichloro-4-(3-oxo-3-(4-(4-(trifluoromethyl)phenyl)thien-2-yl)propyl)-phenoxy)-2-methylpropanoic acid is prepared from tert-butyl 2-(2,3-dichloro-4-(3-oxo-3-(4-(4-(trifluoromethyl)phenyl)thien-2-yl)propyl)phenoxy)-2-methylpropanoate according to general procedure E using 17 equivalents of trifluoroacetic acid.
Reaction SMILES: [CH3:1][NH2:2].Cl[C:4]1[N:9]=[C:8]([Cl:10])[N:7]=[C:6]([NH:11][C@@H:12]2[CH2:17][CH2:16][C@H:15]([C:18]([OH:20])=[O:19])[CH2:14][CH2:13]2)[N:5]=1.[OH-].[Na+]>CC#N.O>[Cl:10][C:8]1[N:9]=[C:4]([NH:2][CH3:1])[N:5]=[C:6]([NH:11][C@@H:12]2[CH2:17][CH2:16][C@H:15]([C:18]([OH:20])=[O:19])[CH2:14][CH2:13]2)[N:7]=1
Reactant: O=C(O)[C@H]1CC[C@@H](Nc2nc(Cl)nc(Cl)n2)CC1
Reactant: CN
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Solvent: O
Product: CNc1nc(Cl)nc(N[C@H]2CC[C@@H](C(=O)O)CC2)n1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
Cold methylamine (40% (w) in water, 234 μL, 1 equivalent) was added to the crude solution of cis-4-(4,6-dichloro-1,3,5-triazin-2-ylamino)cyclohexanecarboxylic acid (2.7 mmol) in CH3CN/H2O (1/1, 20 ml), followed by 1N NaOH (5.34 ml, 1 equivalent). The reaction mixture was stirred at room temperature for 2-3 hrs. The crude product was used in the next step. MS (ES+): m/e 286.09 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[C:5](=[C:10](I)[CH:11]=[CH:12][CH:13]=1)[C:6]([O:8][CH3:9])=[O:7].[CH3:16][O:17][C:18]1[CH:19]=[C:20]([CH:22]=[CH:23][C:24]=1[O:25][CH3:26])[NH2:21].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1.C(Cl)Cl.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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:1][O:2][C:3](=[O:15])[C:4]1[C:5](=[C:10]([NH:21][C:20]2[CH:22]=[CH:23][C:24]([O:25][CH3:26])=[C:18]([O:17][CH3:16])[CH:19]=2)[CH:11]=[CH:12][CH:13]=1)[C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)c1cccc(I)c1C(=O)OC
Reactant: COc1ccc(N)cc1OC
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: COC(=O)c1cccc(Nc2ccc(OC)c(OC)c2)c1C(=O)OC
Yield: 74 %

Procedure:
A mixture of 3-iodophthalic acid dimethyl ester (1.0 g, 3.1 mmol), 3,4-dimethoxyaniline (0.48 g, 3.1 mmol), Pd2(dba)3 (0.13 g, 0.14 mmol), rac-BINAP (0.058 g, 0.093 mmol), and cesium carbonate (1.4 g, 4.3 mmol), in 6 mL toluene was heated to reflux under nitrogen for 24 hours. The reaction mixture was cooled, diluted with CH2Cl2 (10 mL), and then filtered through Celite, and the filter was washed with additional CH2Cl2 (30 mL). The filtrate was evaporated, and the residue was chromatographed using a hexanes-ethyl acetate gradient, eluting 0.80 g of the product at 65:35 hexanes-ethyl acetate, in 74% yield: 1H NMR (CDCl3) δ 3.84 (s, 3H), 3.87 (s, 3H), 3.89 (s, 6H), 6.71-6.77 (m, 2H), 6.85 (d, J=8.3 Hz, 1H), 6.98 (d, J=6.9 Hz, 1H), 7.14 (d, J=7.7 Hz, 1H), 7.25 (t, J=7.9 Hz, 1H), 8.08 (br, 1H).
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[C:3]1[CH:27]=[CH:26][C:6]([CH2:7][O:8][N:9]=[C:10]([C:13]2[CH:25]=[CH:24][C:16]([O:17][CH2:18][C:19]([O:21]CC)=[O:20])=[CH:15][CH:14]=2)[CH2:11][CH3:12])=[CH:5][CH:4]=1.[OH-].[Li+]>C1COCC1.O>[F:1][C:2]([F:28])([F:29])[C:3]1[CH:27]=[CH:26][C:6]([CH2:7][O:8][N:9]=[C:10]([C:13]2[CH:14]=[CH:15][C:16]([O:17][CH2:18][C:19]([OH:21])=[O:20])=[CH:24][CH:25]=2)[CH2:11][CH3:12])=[CH:5][CH:4]=1
Reactant: CCOC(=O)COc1ccc(C(CC)=NOCc2ccc(C(F)(F)F)cc2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCC(=NOCc1ccc(C(F)(F)F)cc1)c1ccc(OCC(=O)O)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 88.3 %

Procedure:
To a solution of the product of step 3 (28 g, 0.0683 moles) in THF (140 ml), a solution of lithium hydroxide (4.3 g, 0.1024 moles) in water (140 ml) was added and the reaction mixture was stirred at 25° C. for 3 hours. The solvents were evaporated under reduced pressure. The residue was dissolved in water, acidified with 1N HCl and extracted with ethyl acetate. The combined ethyl acetate extract was washed with water & brine, dried over sodium sulphate and evapourated under reduced pressure to yield 23 gm (88%) of product as solid.
Reaction SMILES: [I:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][CH2:8]2)=[CH:4][C:3]=1[C:11]#N.[H-].C([Al+]CC(C)C)C(C)C.C1(C)C=CC=CC=1.Cl.CC[O:33]CC>C(Cl)Cl>[I:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][CH2:8]2)=[CH:4][C:3]=1[CH:11]=[O:33]
Reactant: N#Cc1cc2c(cc1I)CCC2
Reactant: CCOCC
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: O=Cc1cc2c(cc1I)CCC2
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
To a solution of 6-iodoindane-5-carbonitrile (36.5 mg, 0.136 mmol) in CH2Cl2 (1.0 mL) under N2 at −78° C. was added a solution of 1N diisobutyl aluminum hydride in toluene (272 μL, 0.272 mmol) dropwise. The reaction was stirred at −78° C. for 15 min. Keeping the temperature at −78° C., another two portions of diisobutyl aluminum hydride (100 μL each) were added until the starting material disappeared by TLC. The reaction mixture was poured into 2N HCl (45 mL) and diluted with Et2O. The mixture was stirred for 0.5 h. The Et2O layer was separated. The aqueous layer was extracted with Et2O (2×). The organic extracts were combined, dried (Na2SO4) and concentrated in vacuo. The residue was purified by flash chromatography (Si, hexanes/EtOAc) to afford 6-iodoindane-5-carbaldehyde. 1H NMR (500 MHz, CDCl3) δ 10.08 (s, 1H), 7.83 (s, 1H), 7.79 (s, 1H), 2.98 (t, J=7.5 Hz, 2H), 2.94 (t, J=7.5 Hz, 2H,), 2.19-2.13 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:9][CH3:10])=[C:6]([OH:8])[CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[CH:17](I)([CH3:19])[CH3:18]>CN(C=O)C.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:9][CH3:10])=[C:6]([O:8][CH:17]([CH3:19])[CH3:18])[CH:7]=1
Reactant: CC(C)I
Reactant: COc1ccc(Br)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ccc(Br)cc1OC(C)C
Temperature: 20 °C
Reaction time: 3 h
Yield: 81 %

Procedure:
To a solution of 5-bromo-2-methoxyphenol (0.200 g, 1 mmol) in DMF (4 mL) was added potassium carbonate (0.209 g, 1.5 mmol) and isopropyliodide (120 μL, 1.2 mmol), the reaction mixture was stirred at room temperature (20° C.) for 3 h. After this time the crude reaction mixture was diluted with ethyl acetate (100 mL) and washed with water (2×100 mL). The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo to afford a yellow oil (200 mg, 0.81 mmol, 82%). No further purification was required.
Reaction SMILES: [CH:1]12[O:12][CH:4]([CH:5]([S:7]([O:10][CH3:11])(=[O:9])=[O:8])[CH2:6]1)[CH:3]=[CH:2]2.ClC1C=CC=C(C(OO)=[O:21])C=1.S([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl>[O:21]1[C:3]2[CH:4]3[O:12][CH:1]([CH2:6][CH:5]3[S:7]([O:10][CH3:11])(=[O:8])=[O:9])[C:2]1=2
Reactant: COS(=O)(=O)C1CC2C=CC1O2
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: COS(=O)(=O)C1CC2OC1C1=C2O1
Temperature: 4 °C
Yield: 85.5 %

Procedure:
A four-neck flask having an internal capacity of 1,000 mL and fitted with a stirrer, a dropping funnel and a thermometer was charged sequentially with 22.0 g of methyl 7-oxabicyclo[2.2.1]hept-2-ene-5-sulfonate and 450 g of methylene chloride, the temperature was cooled to 4° C., and 22.9 g (0.17 mol) of m-chloroperbenzoic acid was added gradually to the flask under constant stirring so that the temperature did not exceed 10° C. Following stirring for 4 hours at 5 to 7° C., 100 g of a saturated aqueous solution of sodium sulfite was added, and the resulting mixture was stirred for 30 minutes. After standing and separating, the organic layer was washed three times with 100 g samples of saturated sodium hydrogen carbonate. The organic layer was then concentrated under reduced pressure, yielding 20.2 g of methyl 2,3-epoxy-7-oxabicyclo[2.2.1]hept-2-ene-5-sulfonate.