Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[CH:13]2[CH2:14][CH2:15][CH:9]1[CH2:10][C:11](=O)[CH2:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:18][OH:19].N1C=CC=CC=1>C(O)C>[CH2:1]([N:8]1[CH:13]2[CH2:14][CH2:15][CH:9]1[CH2:10][C:11](=[N:18][OH:19])[CH2:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CC2CCC(C1)N2Cc1ccccc1
Reactant: NO
Agent: Cl
Solvent: CCO
Solvent: c1ccncc1
Product: ON=C1CC2CCC(C1)N2Cc1ccccc1

Procedure:
2,5-dimethoxytetrahydrofuran (95) is combined with acetone dicarboxylic acid (96) and benzyl amine HCl salt (97) in sodium acetate to give 8-benzyl-8-azabicyclo[3.2.1]octan-3-one 98. The ketone 98 in ethanol is added to hydroxylamine hydrochloride and pyridine, and heated under reflux conditions to afford 8-benzyl-8-azabicyclo[3.2.1]octan-3-one oxime 99. The oxime 99 in 1-pentanol is combined with sodium metal and heated under reflux to produce 8-benzyl-8-azabicyclo[3.2.1]octan-3-amine 100. The amine 100 in CH2Cl2 (13 mL) is treated with 1M Na2CO3 and isobutyryl chloride to yield amide 101. The amide 101 is dissolved in CHCl3 and pyridine followed by the addition of POCl3. To this was then added diisopropylethylamine and appropriately deuterated acetylhydrazine 110 to produce triazol 102. The triazole 102 in EtOH was treated with Pd(OH)2/C (140 mg) under an H2 atmosphere to yield amine 103. Amine 103 was combined with appropriately deuterated aldehyde 111 in CH2Cl2 (5 mL), Na2SO4 and NaCNBD3 to afford 107. A solution of 107 in HCl/MeOH was heated to reflux to afford the free amine 108. The amine 108 in CH2Cl2 was combined with saturated Na2CO3 and H2O followed by appropriately deuterated cyclohexanecarbonyl chloride 109 to produce a compound of Formula II.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH:7][C:8](=[O:15])OCC(Cl)(Cl)Cl)[CH:2]=1.[N:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:22]1[N:26]=[C:25]([N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)[S:24][N:23]=1.C(N(C(C)C)CC)(C)C.O>CS(C)=O>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH:7][C:8]([N:30]2[CH2:29][CH2:28][N:27]([C:25]3[S:24][N:23]=[C:22]([C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][N:16]=4)[N:26]=3)[CH2:32][CH2:31]2)=[O:15])[CH:2]=1
Reactant: O=C(Nc1cccnc1)OCC(Cl)(Cl)Cl
Reactant: c1ccc(-c2nsc(N3CCNCC3)n2)nc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Solvent: O
Product: O=C(Nc1cccnc1)N1CCN(c2nc(-c3ccccn3)ns2)CC1
Yield: 38.6 %

Procedure:
A mixed solution of 2,2,2-trichloroethyl pyridin-3-ylcarbamate (297 mg, 1.10 mmol), 1-(3-pyridin-2-yl-1,2,4-thiadiazol-5-yl)piperazine (300 mg, 1.21 mmol) and diisopropylethylamine (0.211 ml, 1.21 mmol) in dimethyl sulfoxide (2.5 ml) was stirred at 80° C. for 3 hours. Water was poured to the reaction mixture, and the resulting solution was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:1, followed by ethyl acetate:methanol=9:1) and recrystallized from a mixed solvent of hexane and tetrahydrofuran to give 156 mg (38.5%) of the desired product as a solid.
Reaction SMILES: FC1C=CC(CN)=CC=1.[F:10][C:11]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:12]=1[CH2:13][NH2:14].[CH2:20]([N:27]1[CH2:31][CH2:30][N:29]([C:32]2[S:33][C:34]([C:38](O)=[O:39])=[C:35]([CH3:37])[N:36]=2)[C:28]1=[O:41])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[CH2:20]([N:27]1[CH2:31][CH2:30][N:29]([C:32]2[S:33][C:34]([C:38]([NH:14][CH2:13][C:12]3[CH:15]=[CH:16][C:17]([F:19])=[CH:18][C:11]=3[F:10])=[O:39])=[C:35]([CH3:37])[N:36]=2)[C:28]1=[O:41])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: NCc1ccc(F)cc1F
Reactant: Cc1nc(N2CCN(Cc3ccccc3)C2=O)sc1C(=O)O
Agent: NCc1ccc(F)cc1
Product: Cc1nc(N2CCN(Cc3ccccc3)C2=O)sc1C(=O)NCc1ccc(F)cc1F
Yield: 45 %

Procedure:
Following the procedure as describe in Example 9, making variations as required to replace 4-fluorobenzylamine with 2,4-difluorobenzylamine to react with 2-(3-benzyl-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid, the title compound was obtained as a white powder in 45% yield: mp 157-158° C.; 1H NMR (300 MHz, DMSO-d6) δ 7.39-7.23 (m, 6H), 6.84-6.74 (m, 2H), 6.06 (t, J=5.7 Hz, 1H), 4.53 (d, J=5.7 Hz, 2H), 4.49 (s, 2H), 4.03 (t, J=8.4 Hz, 2H), 3.43 (t, J=8.4 Hz, 2H), 2.57 (s, 3H); 13C NMR (75 MHz, DMSO-d6) δ 164.1, 162.7, 160.8, 157.4, 155.3, 153.3, 135.5, 131.2, 128.9, 128.3, 128.0, 121.2, 117.0, 111.5, 103.9, 47.9, 42.0, 41.6, 37.4, 17.2; MS (ES+) m/z 443.2 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][C:8]2=O)=[CH:4][C:3]=1[N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1.[Cl-].[OH:19][NH3+:20].C([O-])(=O)C.[Na+].O>C(O)C.C(OCC)(=O)C>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][C:8]2=[N:20][OH:19])=[CH:4][C:3]=1[N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1
Reactant: O=C1CCc2cc(N3CCOCC3)c(F)cc21
Reactant: [NH3+]O
Agent: CC(=O)[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCO
Product: ON=C1CCc2cc(N3CCOCC3)c(F)cc21
Yield: 102.5 %

Procedure:
A solution of 6-fluoro-5-morpholin-4-ylindan-1-one (200 mg), hydroxylammonium chloride (102 mg) and sodium acetate (241 mg) in ethanol (5.0 mL) was heated to reflux for 1 hour. After confirming that the raw materials disappeared, water and ethyl acetate were added to the reaction solution and the organic layer was partitioned. The resulting organic layer was washed with brine, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure to obtain 218 mg of 6-fluoro-5-morpholin-4-ylindan-1-one oxime. Next, 10% palladium-carbon (water content: 48%, 200 mg) was added to a solution of the resulting 6-fluoro-5-morpholin-4-ylindan-1-one oxime (218 mg) in ethanol (5.0 mL), and the reaction solution was stirred in a hydrogen atmosphere (0.4 MPa) at room temperature for 9 hours. The reaction solution was filtered on a celite, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (Carrier: Chromatorex™ NH, elution solvent:heptane-ethyl acetate system→ethyl acetate-methanol system) to obtain 56.0 mg of the title compound. The physical properties of the compound are as follows.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:40])[CH:12]([C:22]2[CH:27]=[CH:26][C:25]([CH2:28][O:29][Si](C(C)C)(C(C)C)C(C)C)=[CH:24][CH:23]=2)[CH2:13][NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[CH:6][C:5]=1[F:41])(=[O:3])[NH2:2].CCCC[N+](CCCC)(CCCC)CCCC.[F-].CCOC(C)=O>C1COCC1>[C:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:40])[CH:12]([C:22]2[CH:23]=[CH:24][C:25]([CH2:28][OH:29])=[CH:26][CH:27]=2)[CH2:13][NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[CH:6][C:5]=1[F:41])(=[O:3])[NH2:2]
Reactant: CC(C)[Si](OCc1ccc(C(CNC(=O)OC(C)(C)C)C(=O)Nc2ccc(C(N)=O)c(F)c2)cc1)(C(C)C)C(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCC(C(=O)Nc1ccc(C(N)=O)c(F)c1)c1ccc(CO)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To tert-butyl 3-(4-carbamoyl-3-fluorophenylamino)-3-oxo-2-(4-((thisopropylsilyloxy)methyl)phenyl)propylcarbamate (E337) in THF under N2 at 0° C. was added TBAF, and the solution was stirred for 30 min at 0° C. The reaction was warmed to room temperature and stirred another 3.5 h. The compound was poured into EtOAc and washed with NH4Cl(sat), dried (MgSO4), filtered, and evaporated. Column chromatography (SiO2, 0-20% MeOH/CH2Cl2 gradient) gave pure tert-butyl 3-(4-carbamoyl-3-fluorophenylamino)-2-(4-(hydroxymethyl)phenyl)-3-oxopropylcarbamate (E337-1)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:5]=[CH:4][N:3]=1.[CH3:14][Si]([N-][Si](C)(C)C)(C)C.[K+].CI.[NH4+].[Cl-]>C1COCC1.CCOCC>[Cl:1][C:2]1[CH:7]=[C:6]([CH:8]([CH3:14])[C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:5]=[CH:4][N:3]=1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: CCOC(=O)Cc1ccnc(Cl)c1
Agent: [Cl-]
Agent: [K+]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: CI
Product: CCOC(=O)C(C)c1ccnc(Cl)c1
Temperature: 25 °C
Yield: 58.7 %

Procedure:
To a stirred solution of ethyl 2-(2-chloropyridin-4-yl)acetate (44) (2.5 g, 12.52 mmol) in THF (25 mL), under nitrogen at −78° C. was added a solution of KHMDS (0.5M in toluene, 26.3 mL, 13.2 mmol). The mixture was warmed to RT for 10 min, then re-cooled to −78° C. and methyl iodide (0.820 mL, 13.15 mmol) added in a single portion and the mixture allowed to warm to RT. Saturated aqueous NH4Cl solution was added and the mixture was diluted with ether. The organic layer was washed with water and brine and then dried (MgSO4) and evaporated in vacuo. The residue was purified by flash column chromatography (SiO2, 100 g, 5-10% EtOAc in isohexane, gradient elution) to afford the title compound (51) (1.57 g, 56%): m/z 214 (M+H)+ (ES+).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([CH:8]1[C:16]2[C:11](=[CH:12][C:13]([F:17])=[CH:14][CH:15]=2)[NH:10][C:9]1=[O:18])=[O:7].ClS([N:23]=[C:24]=[O:25])(=O)=O.C(#N)C>O>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([CH:8]1[C:16]2[C:11](=[CH:12][C:13]([F:17])=[CH:14][CH:15]=2)[N:10]([C:24]([NH2:23])=[O:25])[C:9]1=[O:18])=[O:7]
Reactant: O=C1Nc2cc(F)ccc2C1C(=O)c1ccco1
Reactant: O=C=NS(=O)(=O)Cl
Solvent: CC#N
Solvent: O
Product: NC(=O)N1C(=O)C(C(=O)c2ccco2)c2ccc(F)cc21
Yield: 17 %

Procedure:
Following substantially the procedure of Example 24, the title compound was prepared in 17% yield from 3-(2-furoyl)-6-fluoro-2-oxindole (0.30 g, 1.2 mmole), chlorosulfonyl isocyanate (0.20 g, 1.4 mmole), acetonitrile (15 ml) and water (10 ml). Yield=60 mg, m.p. 231°-235° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[H-].[Na+].C1(C)C=CC(S(O[CH2:21][C@H:22]([O:31][Si](C(C)(C)C)(C)C)[CH2:23][CH2:24][C:25]2[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=2)(=O)=O)=CC=1.F.C(=O)([O-])O.[Na+]>CN(C)C=O.C(#N)C.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:21][C@H:22]([OH:31])[CH2:23][CH2:24][C:25]2[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=2)=[CH:4][CH:3]=1
Reactant: Oc1ccc(Br)cc1
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H](CCc2cccnc2)O[Si](C)(C)C(C)(C)C)cc1
Agent: F
Agent: O=C([O-])O
Agent: [H-]
Solvent: CN(C)C=O
Solvent: O
Solvent: CC#N
Product: O[C@H](CCc1cccnc1)COc1ccc(Br)cc1
Reaction time: 0.5 h
Yield: 82.4 %

Procedure:
Solid 4-bromophenol (2.08 g) was added to a stirred suspension of sodium hydride (60%, 0.48 g) in dimethylformamide (30 ml) and the resulting solution stirred for 30 minutes. (2R)-2-(tert-butyldimethylsilyloxy)-4-(pyridin-3-yl)-1-butyl para-toluenesulfonate (4.35 g, Example 5d)) was added and the mixture stirred at 60° C. for 2 hours. After cooling the mixture was poured into water (50 ml) and extracted with ethyl acetate. The combined organic extracts were dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue obtained was dissolved in acetonitrile (20 ml) and hydrofluoric acid (40% in water; 5 ml, CAUTION) was added. The mixture was stirred for 1 hour and then poured into a solution of saturated aqueous sodium hydrogencarbonate. The mixture was extracted with ethyl acetate and the combined organic extracts were dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue obtained was purified by column chromatography over silica eluting with acetone:hexane (1:1) to give the sub-title compound as a solid (2.65 g).
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:9][C:10]1[S:11][CH:12]=[C:13]([C:15](O)=[O:16])[N:14]=1.O=C1N(P(Cl)(N2CCOC2=O)=O)CCO1.C(N(C(C)C)CC)(C)C>CN(C=O)C>[CH2:1]([NH:8][C:15]([C:13]1[N:14]=[C:10]([Br:9])[S:11][CH:12]=1)=[O:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCc1ccccc1
Reactant: O=C(O)c1csc(Br)n1
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(NCc1ccccc1)c1csc(Br)n1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Benzyl amine was loaded to 4-formyl-3,5-dimethoxyphenoxymethyl functionalized polystyrene resin (PAL) via reductive amination to give PAL-benzyl amine resin. See, Ding. S.; Grey, N. S. Wu, X.; Ding, Q.; Schultz, P. G. J. Am. Chem. Soc. 2002, 124, 1594-1596. A reaction flask containing PAL-benzyl amine resin (200 mg, 0.2 mmol), 2-bromothiazole-4-carboxylic acid (83 mg, 0.4 mmol), bis(2-oxo-3-oxazolidinyl)phosphinic chloride (BOP-Cl) (153 mg, 0.6 mmol) and diisopropylethylamine (0.17 mL, 1 mmol) in DMF (3 mL) was shaken for 24 hr at room temperature. The resin was washed with methanol, dichloromethane and dried in vacuo to give PAL resin-N-benzyl-2-bromothiazole-4-carboxamide, which was then added to a flame-dried reaction vial, followed by 4-aminopyrimidine (95 mg, 1 mmol), Pd2(dba)3 (46 mg, 0.05 mmol), Xantphos (87 mg, 0.15 mmol) and NaOtBu (192 mg, 2 mmol). The vial was sure safe capped and degassed, then charged with argon and anhydrous dioxane (1.5 mL). The reaction was shaken for 24 hours at 90° C. The resin was washed with sodium diethyldithiocarbamate solution (0.05 M in DMF), methanol and dichloromethane and dried in vacuo. The resin was subsequently cleaved with cleavage cocktail TFA:CH2Cl2:H2O (45:55:5) (2 mL) for 2 hr. The resin was filtered, the filtrate was collected and evaporated in vacuo to give the crude which was then purified by HPLC to give the title compound (30 mg, 48%).
Reaction SMILES: [CH:1]1([CH:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:8]O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.CS(Cl)(=O)=O.[N-:28]=[N+:29]=[N-:30].[Na+]>ClCCl.CCCCCC.O>[N:28]([CH2:8][CH:7]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)=[N+:29]=[N-:30]
Reactant: [N-]=[N+]=[N-]
Reactant: OCC(c1ccccc1)C1CCCCC1
Agent: CS(=O)(=O)Cl
Agent: [Na+]
Solvent: CCCCCC
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: [N-]=[N+]=NCC(c1ccccc1)C1CCCCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 78.1 %

Procedure:
To a stirring solution of 2-cyclohexyl-2-phenyl-ethanol (0.9 g, 0.00441 mole) and triethylamine (0.536 g, 0.0053 mole) in dichloromethane (10 mL) at 0° C. was added methanesulfonyl chloride (0.606 g, 0.0053 mole). The reaction was stirred at RT for 2 h. The reaction mixture was next poured into water, and extracted three times with dichloromethane. The solvent was removed and DMF (10 mL) was added to the residue. NaN3 (0.57 g, 0.0088 mole) was added to the solution and the mixture was then stirred overnight at RT. The reaction mixture was washed with water and extracted three times with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography over silica gel (silica gel 60, EM Science) using 20% ethyl acetate:hexane as eluent to afford 0.79 g (78% yield) of the title compound as an oil. 1H-NMR (400 MHz, CDCl3) δ 7.26-7.08 (m, 5H), 3.58 (dd, 1H, J=5.2 Hz), 3.48 (dd, 1H, J=8.8 Hz), 2.53 (q, 1H. J=5.2 Hz), 1.87-0.7 (m, 11H).
Reaction SMILES: [CH:1]([C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].Cl[C:12]([O:14][C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=1)=[O:13]>C(Cl)Cl.N1C=CC=CC=1>[N+:21]([C:18]1[CH:17]=[CH:16][C:15]([O:14][C:12](=[O:13])[NH:8][C:7]2[CH:9]=[CH:10][C:4]([CH:1]([CH3:3])[CH3:2])=[CH:5][CH:6]=2)=[CH:20][CH:19]=1)([O-:23])=[O:22]
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: CC(C)c1ccc(N)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)c1ccc(NC(=O)Oc2ccc([N+](=O)[O-])cc2)cc1
Reaction time: 0.01 h
Yield: 95.1 %

Procedure:
To a solution of 4-isopropylaniline (3.02 g, 22.3 mmol) in DCM (40 mL) and pyridine (10 mL) was added 4-nitrophenyl chloroformate (4.09 g, 20.3 mmol) portionwise with stirring over ˜30 sec with brief ice-bath cooling. After stirring at rt for 1 h, the homogeneous solution was diluted with DCM (100 mL) and washed with 0.6 M HCl (1×250 mL), 0.025 M HCl (1×400 mL), water (1×100 mL), and 1 M NaHCO3 (1×100 mL). The organic layer was dried (Na2SO4) and concentrated to give the title compound as a light peach-colored solid (5.80 g, 95%). 1H-NMR (300 MHz, CDCl3) δ 8.28 (m, 2H), 7.42-7.32 (m, 4H), 7.22 (m, 2H), 6.93 (br s, 1H), 2.90 (h, J=6.9 Hz, 1H), 1.24 (d, J=6.9 Hz, 6H). LC/MS (ESI): calcd mass 300.1, 601.3 (2MH)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:12]=[C:13]([C:15]2([O:21][CH3:22])[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[CH:14]=1)[O:5][CH2:6][C:7]([O:9]CC)=[O:8]>[Li+].[OH-].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>[F:1][C:2]1[CH:3]=[C:4]([CH:12]=[C:13]([C:15]2([O:21][CH3:22])[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[CH:14]=1)[O:5][CH2:6][C:7]([OH:9])=[O:8]
Reactant: CCOC(=O)COc1cc(F)cc(C2(OC)CCOCC2)c1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Li+]
Agent: [OH-]
Product: COC1(c2cc(F)cc(OCC(=O)O)c2)CCOCC1
Yield: 91.5 %

Procedure:
A solution of ethyl 3-fluoro-5-(4-methoxy-3,4,5,6-tetrahydro-2H-pyran-4-yl)phenoxyacetate (Step 1) (0.3 g, 1 mmol) in ethanolic LiOH (1M, 1.5 ml) was stirred at room temperature for 2 h. The reaction mixture was diluted with 5% citric acid (10 mL) and extracted with ether (2×15 mL). The ether extracts were combined and washed with water (2×20 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure to give 0.26 g (95%) of 3-fluoro-5-(4-methoxy-3,4,5,6-tetrahydro-2H-pyran-4-yl)phenoxyacetic acid as a colorless viscous liquid: 1H NMR (CDCl3/300 MHz) δ 6.78 (d, 2H, J=10.5 Hz), 6.50 (d, 1H, J=10.5 Hz), 4.68 (s, 2H), 3.82 (m, 4H), 2.99 (s, 3H), 1.92 (m, 4H); FABMS m/z=284 (M+H), HRMS calcd for for C14H17FO5 283.0982, found 283.09923.
Reaction SMILES: [CH2:1]([O:19][CH2:20][CH:21]([CH2:30]O)[O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].C1(C)C=CC=CC=1.C(Br)(Br)(Br)[Br:40].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)(Cl)Cl>[CH2:1]([O:19][CH2:20][CH:21]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH2:30][Br:40])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: BrC(Br)(Br)Br
Reactant: CCCCCCCCCCCCCCCCCCOCC(CO)OCc1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: ClC(Cl)Cl
Product: CCCCCCCCCCCCCCCCCCOCC(CBr)OCc1ccccc1

Procedure:
In a 250 ml round bottom flask equipped with a magnetic stir bar, 2.00 g (4.6 mmoles) of 1-O-octadecyl-2-O- benzyl-glycerol (Bachem, Switzerland) was dissolved into 120 ml of toluene. To this solution were added 4.58 g. (13.8 mmoles) of carbon tetrabromide and 3.62 g. (13.8 mmoles) of triphenylphosphine and the reaction mixture stirred for 4 hours at room temperature. The yellow suspension was filtered and the filtrate concentrated on a rotary evaporator to afford a white solid. This residue was dissolved into 50 ml chloroform, washed twice with 30 ml saturated sodium bicarbonate, dried over anhydrous magnesium sulfate and concentrated under vacuum on a rotary evaporator to afford 2.5 g of the crude product as a white powder. This crude product was purified by flash column chromatography on a silica gel 60 (E. Merck, Germany) column by sequential elution with 100 ml each of hexane, 1% ethyl acetate in hexane, 2% ethyl acetate in hexane and finally with 3% ethyl acetate in hexane. Fractions collected were screened by TLC and those fractions that contained pure product (silica gel, 5% ethyl acetate in hexane, Rf=0.56) were pooled. The pooled fractions were concentrated under vacuum on a rotary evaporator to afford a quantitative yield of the 1-O-octadecyl-2-O-benzyl-3-bromo-1,2-propanediol as a white powder.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]([C:8]([F:11])([F:10])[F:9])([OH:7])[C:4](O)=[O:5].C(N1C=CN=C1)(N1C=CN=C1)=O.C(=O)=O.[N:29]1[CH:34]=[CH:33][C:32]([S:35]([C:38]2[CH:43]=[CH:42][C:41]([NH2:44])=[CH:40][CH:39]=2)(=[O:37])=[O:36])=[CH:31][CH:30]=1>CN(C)C=O.O.O1CCCC1>[N:29]1[CH:30]=[CH:31][C:32]([S:35]([C:38]2[CH:43]=[CH:42][C:41]([NH:44][C:4](=[O:5])[C:3]([OH:7])([C:8]([F:11])([F:10])[F:9])[C:2]([F:13])([F:12])[F:1])=[CH:40][CH:39]=2)(=[O:37])=[O:36])=[CH:33][CH:34]=1
Reactant: Nc1ccc(S(=O)(=O)c2ccncc2)cc1
Reactant: O=C(O)C(O)(C(F)(F)F)C(F)(F)F
Agent: O=C(n1ccnc1)n1ccnc1
Agent: O=C=O
Solvent: O
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: O=C(Nc1ccc(S(=O)(=O)c2ccncc2)cc1)C(O)(C(F)(F)F)C(F)(F)F
Temperature: 35 °C
Yield: 4.4 %

Procedure:
Tetrahydrofuran (5 ml, dry) was added to a mixture of 2,2-bis-trifluoromethyl-2-hydroxyacetic acid (1.29 g, 6.1 mmol) and 1,1'-carbonyldiimidazole (0.99 g, 6.1 mmol), while under a nitrogen atmosphere. There was an immediate evolution of carbon dioxide. The reaction was heated at 35° C. for 15 min. The reaction was treated with a solution of 4-(4-pyridylsulfonyl)benzeneamine (1.43 g, 6.1 mmol) in dimethylformamide (15 ml, dry), and heated to 69° C. in an ultrasonic bath for 19.5 hrs. The reaction was poured into water (300 ml), and extracted with ethyl ether (3×300 ml). The combined organic portions were evaporated and preabsorbed onto silica gel (10 gm). Chromatography of this material on silica gel, eluting with methylene chloride/ethyl acetate (first 100:0 and then 70:30) provided a white solid. Recrystallization from acetone gave starting 4-(4-pyridylsulfonyl)benzeneamine. The filtrate was evaporated and chromatographed on silca gel eluting with chloroform/methanol (first 100:0 and then 98:2) provided the title compound (0.115 g, 6%) as a white solid; mp 235°-237° C. 1H-NMR (250 MHz, d6 -DHSO): 7.90 (d, J=4.6, 2H, ArH), 8.04 (d, 4H, ArH), 8.89 (d, J=4.68 Hz, 2H, ArH), 9.90 (s, 1H, OH), 10.97 (s, 1H, NH). MS(CI,CH4): 429 (M+1)
Reaction SMILES: Br[C:2]1[C:3]2[NH:7][C:6]([C:8]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)=[C:9]3[N:31]=[C:12]([CH:13]=[C:14]4[NH:30][C:17](=[C:18]([C:24]5[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=5)[C:19]5[CH:20]=[CH:21][C:22]=1[N:23]=5)[CH:16]=[CH:15]4)[CH:11]=[CH:10]3)=[CH:5][CH:4]=2.[NH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1.C1C=CC(P(C2C(OC3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=CC=3)=CC=CC=2)C2C=CC=CC=2)=CC=1.P.C(=O)([O-])[O-].[Cs+].[Cs+]>C1COCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(OCC)(=O)C>[C:39]1([NH:38][C:2]2[C:3]3[NH:7][C:6]([C:8]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)=[C:9]4[N:31]=[C:12]([CH:13]=[C:14]5[NH:30][C:17](=[C:18]([C:24]6[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=6)[C:19]6[CH:20]=[CH:21][C:22]=2[N:23]=6)[CH:16]=[CH:15]5)[CH:11]=[CH:10]4)=[CH:5][CH:4]=3)[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1
Reactant: Nc1ccccc1
Reactant: Brc1c2nc(c(-c3ccccc3)c3ccc(cc4nc(c(-c5ccccc5)c5ccc1[nH]5)C=C4)[nH]3)C=C2
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C1=Cc2nc1cc1ccc([nH]1)c(-c1ccccc1)c1nc(c(Nc3ccccc3)c3ccc([nH]3)c2-c2ccccc2)C=C1

Procedure:
The general procedure was used to couple 5-bromo-10,20-diphenylporphyrin (27 mg, 0.05 mmol) with aniline (17 μL, 0,18 mmol), using palladium acetate (0.55 mg, 0.0025 mmol) as the palledium precursor, DPEphos (2.0 mg, 0.0038 mmol) as the phosphine ligand and cesium carbonate (22.8 mg, 0.070 mmol) as the base. The reaction was conducted in THF (5 mL) at 68° C. for 19 h. The title compound was isolated by flash chromatography (silica gel, ethyl acetate:hexanes (v)=1:4) as red solids (27 mg, 98%). 1H NMR (300 MHz, THF-d8): δ 10.14 (s, 1H), 9.44 (d, J=4.8 Hz, 2H), 9.42 (s, 1H), 9.30 (d, J=4.8 Hz, 2H), 8.90 (d, J=4.8 Hz, 2H), 8.77 (d, J=4.8 Hz, 2H), 8.21 (m, 4H), 7.78 (m, 6H), 7.06 (t, J=7.4, 2H), 6.86 (d, J=7.4 Hz, 2H), 6.69 (J=7.4 Hz, 1H), −2.54 (s, 2H). 13C NMR (75 MHz, THF-d8): δ 154.8, 147.7, 142.7, 135.5, 132.1, 131.9, 131.1, 129.7, 128.5, 127.7, 120.6, 120.1, 119.0, 115.5, 105.1. IR (film, cm−1): 3302, 3043, 1599, 1495, 1476, 1338, 1309, 1255, 1064, 973, 958, 797, 748. UV-vis(THF, λmax, nm): 412, 512, 582, 660. HRMS-EI ([M]+): calcd for C38H27N5, 553.2266; found: 553.2274 with an isotope distribution pattern that is same as the calculated one.