Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[N:14]=[C:13]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[Cl:22])[C:12]([N+:23]([O-])=O)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1N=CN([C:31](N2C=NC=C2)=[O:32])C=1>CO.[Ni]>[CH2:1]([O:8][C:9]1[N:14]=[C:13]2[N:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[Cl:22])[C:31](=[O:32])[NH:23][C:12]2=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1ccc(OCc2ccccc2)nc1Nc1ccccc1Cl
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: [Ni]
Solvent: CO
Product: O=c1[nH]c2ccc(OCc3ccccc3)nc2n1-c1ccccc1Cl
Reaction time: 8 h
Yield: 121.9 %

Procedure:
To a solution of 6-(benzyloxy)-N-(2-chlorophenyl)-3-nitropyridin-2-amine (750 mg, 2.11 mmol) in MeOH (20 mL) was added Raney nickel (300 mg). The reaction mixture was stirred overnight under H2 (1 atm), filtered through Celite® and concentrated. The residue was dissolved in DCM (40 mL) and CDI (410 mg, 2.53 mmol) was added. The mixture was stirred at room temperature for 4 h, washed with saturated NaHCO3 and water, dried over MgSO4 and concentrated to give the title compound (905 mg). LCMS m/z=352.3, [M+H]+.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10].[NH:12]1[CH:16]=[CH:15][N:14]=[N:13]1.C([O-])([O-])=O.[Cs+].[Cs+].O.CC(=O)OCC>CN(C=O)C.[Cu](I)I>[N:12]1[N:13]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[CH2:8][C:9]([OH:11])=[O:10])[N:14]=[CH:15][CH:16]=1
Reactant: c1c[nH]nn1
Reactant: O=C(O)Cc1ccccc1I
Agent: I[Cu]I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(O)Cc1ccccc1-n1nccn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-iodophenylacetic acid (500 mg) in DMF (5 mL) was added 1H-1,2,3-triazole (0.214 mL), followed by Cs2CO3 (1.21 g) upon which the temperature increased. The reaction mixture was cooled to RT and copper iodide (17.6 mg) was added. The mixture was stirred at RT overnight and at 110° C. for 1 h30. After cooling down, H2O/EA was added and the phases were separated. The aq. phase was acidified to pH=1 with 1M HCl and extracted with EA. The combined org. phases were dried (Na2SO4) and evaporated in vacuo. The residue was purified by CC (Biotage, SNAP 25 g cartridge, solvent A: Hept; solvent B: EA/AcOH 100/1; gradient in % B: 18 for 4CV, 18 to 100 over 10CV, 100 for 2CV) to afford 235 mg of white solid. LC-MS (B): tR=0.60 min; [M+H]+: 204.42.
Reaction SMILES: C[O:2][C:3]([C:5]1[S:6][C:7]([CH2:19][CH3:20])=[C:8]([B:10]2[O:14][C:13]([CH3:16])([CH3:15])[C:12]([CH3:18])([CH3:17])[O:11]2)[CH:9]=1)=[O:4].[OH-].[Na+]>CO>[CH2:19]([C:7]1[S:6][C:5]([C:3]([OH:4])=[O:2])=[CH:9][C:8]=1[B:10]1[O:14][C:13]([CH3:16])([CH3:15])[C:12]([CH3:17])([CH3:18])[O:11]1)[CH3:20]
Reactant: CCc1sc(C(=O)OC)cc1B1OC(C)(C)C(C)(C)O1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCc1sc(C(=O)O)cc1B1OC(C)(C)C(C)(C)O1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Methyl-5-ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiophene-2-carboxylate (2.07 g, 5.05 mmol) was dissolved in methanol (17.7 mL) and 2N NaOH (aq) (17.7 mL, 35.3 mmol). The mixture was stirred at room temperature for 48 h. After hydrolysis was complete, the reaction mixture was concentrated to half volume (to take the methanol off) and then extracted once with diethyl ether (removes excess bis(pinacolato)diboron from previous reaction). The aqueous layer was then acidified with 1N HCl (aq) and extracted 3× with ethyl acetate. The ethyl acetate layers were combined, washed with brine 2×, dried with magnesium sulfate, filtered, and concentrated under reduced pressure. The material was left to dry to give the title compound (quantitative yield). 1H NMR (CDCl3, 500 MHz) δ 8.04 (s, 1H), 3.14 (q, J=7.5, 2H), 1.33 (t, J=7.5, 3H), 1.32 (m, 12H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH3:17])=[CH:11][CH:10]=2)[C:5]([F:18])=[CH:4][N:3]=1.C(N(C(C)C)C(C)C)C.[CH2:28]1[CH2:38][O:37][C:36]2[CH:35]=[CH:34][C:32]([NH2:33])=[CH:31][C:30]=2[O:29]1>C(O)CO>[CH2:16]([O:15][C:12]1[CH:13]=[CH:14][C:9]([NH:8][C:6]2[C:5]([F:18])=[CH:4][N:3]=[C:2]([NH:33][C:32]3[CH:34]=[CH:35][C:36]4[O:37][CH2:38][CH2:28][O:29][C:30]=4[CH:31]=3)[N:7]=2)=[CH:10][CH:11]=1)[CH3:17]
Reactant: CCOc1ccc(Nc2nc(Cl)ncc2F)cc1
Reactant: Nc1ccc2c(c1)OCCO2
Solvent: CCN(C(C)C)C(C)C
Solvent: OCCO
Product: CCOc1ccc(Nc2nc(Nc3ccc4c(c3)OCCO4)ncc2F)cc1
Temperature: 200 °C
Yield: 59.1 %

Procedure:
To a solution of 2-chloro-N4-(4-ethyloxyphenyl)-5-fluoro-4-pyrimidineamine (0.25 g, 0.93 mmol) in ethylene glycol (3 mL) under nitrogen at room temperature was added i-Pr2EtN, 0.93 mmol) followed by 3,4-ethylenedioxyaniline (0.17 g, 1.12 mmol). The reaction mixture was heated to 200° C. for 5 h and then cooled to room temperature. The mixture was partitioned between H2O (20 mL) and EtOAc (20 mL) and the aqueous layer was extracted with EtOAc (20 mL). The combined organic layers were dried (Na2SO4), filtered, and concentrated in vacuo. The crude brown solid was purified by chromatography (2:1 CHCl3/EtOAc) to afford N4-(4-ethyloxyphenyl)-N2-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine (0.21 g, 60%) as a tan solid: Rf 0.42 (4:1 CHCl3/EtOAc); mp 163.8-167.2° C. (DSC); 1H NMR (300 MHz, CDCl3) δ 7.89 (d, J=2.8 Hz, 1H), 7.50-7.45 (m, 2H), 7.17 (d, J=2.5 Hz, 1H), 6.92-6.86 (m, 3H), 6.80-6.75 (m, 2H), 6.64 (bs, 1H), 4.26-4.21 (m, 4H), 4.03 (q, J=7.0, 2H), 1.42 (t, J=6.9 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 156.1, 150.6, 143.6, 142.8, 140.3, 140.0, 139.5, 139.3, 134.0, 130.8, 123.2, 117.2, 115.1, 113.6, 109.4, 64.6, 64.0, 15.1; IR (ATR) 3403 cm−1; ESI MS m/z 383 [C20H19FN4O3+H]+; HPLC (Method A) 98.1% (AUC), tR=12.0 min. Anal. Calcd for C20H19FN4O3: C, 62.82; H, 5.01; N, 14.65. Found: C, 62.06; H, 5.01; N, 14.35.
Reaction SMILES: [Br:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].S(Cl)([Cl:16])=O.C>CC1C=CC=CC=1>[Br:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([Cl:16])=[O:5]
Reactant: O=C(O)c1cccc([N+](=O)[O-])c1Br
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: O=C(Cl)c1cccc([N+](=O)[O-])c1Br
Reaction time: 8 h
Yield: 81.7 %

Procedure:
To a stirred suspension of 414 parts of 2-bromo-3-nitrobenzoic acid in 653 parts of methylbenzene there were added 440 parts of thionyl chloride. The whole was refluxed for 6 hours, cooled and left overnight. The reaction mixture was treated with activated charcoal, filtered over diatomaceous earth and evaporated. The residual oil was triturated with 396 parts of hexane (2×). The product was filtered off, washed with hexane and dried, yielding 363 parts (81.7%) of 2-bromo-3-nitrobenzoyl chloride (interm. 3).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13]2[O:21][C:20]3[C:15](=[N:16][CH:17]=[CH:18][C:19]=3[C:22]3[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=3)[C:25]([OH:27])=O)[CH:14]=2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].CN1CCOCC1.[NH2:38][CH:39]1[CH2:44][CH2:43][CH2:42][CH2:41][CH:40]1[NH2:45].O>CN(C)C=O>[NH2:38][CH:39]1[CH2:44][CH2:43][CH2:42][CH2:41][CH:40]1[NH:45][C:25](=[O:27])[C:24]1[CH:28]=[CH:29][CH:30]=[C:22]([C:19]2[CH:18]=[CH:17][N:16]=[C:15]3[CH:14]=[C:13]([C:5]4[CH:4]=[C:3]([O:2][CH3:1])[C:8]([O:9][CH3:10])=[C:7]([O:11][CH3:12])[CH:6]=4)[O:21][C:20]=23)[CH:23]=1
Reactant: NC1CCCCC1N
Reactant: COc1cc(-c2cc3nccc(-c4cccc(C(=O)O)c4)c3o2)cc(OC)c1OC
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Solvent: O
Product: COc1cc(-c2cc3nccc(-c4cccc(C(=O)NC5CCCCC5N)c4)c3o2)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 48 h
Yield: 27 %

Procedure:
3-[2-(3,4,5-Trimethoxy-phenyl)-furo[3,2-b]pyridin-7-yl]-benzoic acid (0.049 mmol) is dissolved in N,N-dimethylformamid (1.00 ml) and N-(3-dimethyl-aminopropyl)-N′-ethylcarbodiimidhydrochloride (0.110 mmol), 1-hydroxybenzotriazolhydrat (0.111 mmol), 4-Methylmorpholin (0.146 mmol) and 1,2-Diaminocyclohexane (0.049 mmol) are added. The reaction solution is stirred 2 d at RT. Water is added and the solvent removed in vacuo. The product is isolated after column reversed phase column chromatography as yellow solid in a yield of 27%. HPLC (method A): Rt 2.47 min (purity 100%); LCMS (ESI+) (method E): Rt 1.69 min, M+H+ 502.2 m/z.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([N+:11]([O-:13])=[O:12])[C:5]([NH2:10])=[N:6][C:7]=1[O:8][CH3:9].[CH3:14]B1OB(C)OB(C)O1.C(=O)([O-])[O-].[Cs+].[Cs+].CN(C)C=O>C(OCC)(=O)C.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>[CH3:9][O:8][C:7]1[N:6]=[C:5]([NH2:10])[C:4]([N+:11]([O-:13])=[O:12])=[CH:3][C:2]=1[CH3:14]
Reactant: COc1nc(N)c([N+](=O)[O-])cc1I
Reactant: CB1OB(C)OB(C)O1
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: [Cs+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1nc(N)c([N+](=O)[O-])cc1C
Temperature: 90 °C
Reaction time: 2 h
Yield: 54.7 %

Procedure:
A mixture of 5-iodo-6-methoxy-3-nitro-2-pyridineamine (1.03 g, 3.49 mmol), trimethylboroxin (456 mg, 3.63 mmol), cesium carbonate (3.56 g, 10.9 mmol), tetrakis(triphenylphosphine)palladium(0) (412 mg, 0.357 mmol) and N,N-dimethylformamide (10 ml) was stirred at 90° C. under nitrogen atmosphere. After 2 hours and 30 minutes, trimethylboroxin (500 μl, 3.58 mmol) was added, and the reaction mixture was further stirred under the same conditions for 5 hours and 30 minutes. The reaction mixture was cooled to room temperature and then diluted with ethyl acetate and water. Insoluble substance was filtered off, the organic layer of the filtrate was washed 3 times with a saturation ammonium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (silica gel: 40 g, eluting solvent: heptane, heptane/ethyl acetate=90/10) to yield the title compound (350 mg, 1.91 mmol, 54.8%) as a yellow solid.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:25]=[CH:26][C:27]=1[CH3:28])[C:6]([NH:8][C:9]1[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[C:11]([N:19]2[CH:23]=[C:22]([CH3:24])[N:21]=[CH:20]2)[CH:10]=1)=[O:7])#[CH:2].Br[C:30]1[CH:31]=[N:32][C:33]([NH:36][CH:37]2[CH2:39][CH2:38]2)=[N:34][CH:35]=1.C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.CCN(C(C)C)C(C)C>[Cu]I.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH:37]1([NH:36][C:33]2[N:34]=[CH:35][C:30]([C:2]#[C:1][C:3]3[CH:4]=[C:5]([CH:25]=[CH:26][C:27]=3[CH3:28])[C:6]([NH:8][C:9]3[CH:14]=[C:13]([C:15]([F:16])([F:17])[F:18])[CH:12]=[C:11]([N:19]4[CH:23]=[C:22]([CH3:24])[N:21]=[CH:20]4)[CH:10]=3)=[O:7])=[CH:31][N:32]=2)[CH2:39][CH2:38]1
Reactant: C#Cc1cc(C(=O)Nc2cc(-n3cnc(C)c3)cc(C(F)(F)F)c2)ccc1C
Reactant: Brc1cnc(NC2CC2)nc1
Agent: [Cu]I
Agent: [Pd+2]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cn(-c2cc(NC(=O)c3ccc(C)c(C#Cc4cnc(NC5CC5)nc4)c3)cc(C(F)(F)F)c2)cn1
Temperature: 60 °C

Procedure:
In a pressure tube with one end sealed, add 192 mg step 3 product, 3-ethynyl-4-methyl-N-(3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)benzamide (0.5 mmol), 107 mg Step 4 product, 5-bromo-N-cyclopropylpyrimidin-2-amine (0.5 mmol), 19 mg CuI (0.1 mmol), 2.2 mg Pd(OAc)2 (0.01 mmol), 2.8 mg PCy3 (0.01 mmol) 3.0 mL DMF, 193 mg DIPEA (1.5 mmol), after nitrogen replacement, the solution is heated to 60° C. for 12 h. After cooling to room temperature, the solid is filtered off by 2 cm silical gel column and washed by ethyl acetate for three times, and the solution was concentrated by vacuum evaporation for 193 mg desired product (75%).
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[C:3]1[CH:4]=[C:5](/[CH:13]=[CH:14]/[CH2:15][N:16]([S:26]([CH3:29])(=[O:28])=[O:27])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([OH:25])=[O:24])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1>CO.[Pd].[C]>[F:11][C:9]([F:10])([F:12])[C:7]1[CH:6]=[C:5]([CH2:13][CH2:14][CH2:15][N:16]([S:26]([CH3:29])(=[O:28])=[O:27])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([OH:25])=[O:24])[CH:4]=[C:3]([C:2]([F:1])([F:30])[F:31])[CH:8]=1
Reactant: CS(=O)(=O)N(C/C=C/c1cc(C(F)(F)F)cc(C(F)(F)F)c1)CCCCCCC(=O)O
Agent: [Pd]
Solvent: CO
Product: CS(=O)(=O)N(CCCCCCC(=O)O)CCCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reaction time: 20 h
Yield: 90.4 %

Procedure:
A solution of trans-7-{[3-(3,5-bis-trifluoromethyl-phenyl)-allyl]-methanesulfonyl-amino}-heptanoic acid (210 mg, 0.44 mmol) in MeOH (10 mL) was added to 10% Pd/carbon (200 mg). The mixture was placed on a Parr hydrogenator at 50 psi and was hydrogenated for 20 h. The reaction was filtered through Celite with the aid of MeOH and the solvent was removed in vacuo. Purification by radial chromatography (2 mm rotary plate, 20:80:0.1 v/v/v EtOAc/hexanes/AcOH) provided the title compound (190 mg). 1H NMR (CDCl3 400 MHz) 87.69 (s, 1H), 7.63 (s, 2H), 3.20 (t, 2H), 3.14 (t, 2H), 2.81 (m, 5H), 2.28 (m, 2H), 1.94 (m, 2H), 1.32 (m, 4H); MS 495 (M+18).
Reaction SMILES: N1C2C=CC=C(C=O)C=2C=[CH:2]1.[H-].[Na+].C1(S(Cl)(=O)=O)C=CC=CC=1.[C:24]1([S:30]([N:33]2[C:41]3[CH:40]=[CH:39][CH:38]=[C:37]([CH:42]=[O:43])[C:36]=3[CH:35]=[CH:34]2)(=[O:32])=[O:31])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C[Mg+].[Br-]>CN(C=O)C.C1COCC1.C1(C)C=CC=CC=1.C1COCC1.CO.C(Cl)Cl>[C:24]1([S:30]([N:33]2[C:41]3[C:36](=[C:37]([CH:42]([OH:43])[CH3:2])[CH:38]=[CH:39][CH:40]=3)[CH:35]=[CH:34]2)(=[O:31])=[O:32])[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: O=Cc1cccc2[nH]ccc12
Reactant: O=Cc1cccc2c1ccn2S(=O)(=O)c1ccccc1
Agent: C[Mg+]
Agent: O=S(=O)(Cl)c1ccccc1
Agent: [Br-]
Solvent: CN(C)C=O
Solvent: CO
Solvent: C1CCOC1
Product: CC(O)c1cccc2c1ccn2S(=O)(=O)c1ccccc1
Temperature: 0 °C
Reaction time: 0.02 h
Yield: 81 %

Procedure:
A solution of indole-4-carboxaldehyde (1.00 g, 6.89 mmol) in DMF (60 mL) under N2 was treated with NaH (95%; 20.7 mmol, 496 mg) at rt for 15 min. benzenesulfonyl chloride (972 μL, 7.58 mmol) was added and stirring continued for 1 min. it was cooled to 0° C. and quenched with H2O. The reaction mixture was extracted with EtOAc (3×), the combined org. phases washed with H2O (3×), brine and dried (Na2SO4). conc. in vacuo gave an orange glue (1.79 g), which was directly used in the Grignard addition. The solution of crude 1-(phenylsulfonyl)-1H-indole-4-carbaldehyde in THF (60 mL) was treated with MeMgBr (9.84 mL of a 1.4 M solution in Toluene/THF, 13.78 mmol) at rt for 20 min upon which another 9.84 mL (2 eq) of Grignard reagent were added and stirring continued for another 5 min. The reaction mixture was quenched with sat. NH4Cl, extracted with EtOAc (3×), the combined org. phases washed with brine, dried (Na2SO4) and the solvent removed in vacuo to give a yellow-brownish glue (2.21 g). The crude product was subjected to flash chromatography (SiO2, CH2Cl2:MeOH=100:1) to yield the title compound as a yellow/orange foam (1.687 g, 81% over 2 steps). MS (ESI+) for C16H15NO3S m/z 284 (M-OH)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][CH:4]=1.C(N(CC)CC)C.[Cl-].ClC1N(C)CC[NH+]1C.[CH3:26][O:27][C:28]1[C:29](=[O:56])[C:30]([CH3:55])=[C:31]([CH2:37][C:38]2[CH:39]=[CH:40][C:41]([O:47][CH2:48][C:49]3[CH:50]=[N:51][CH:52]=[CH:53][CH:54]=3)=[C:42]([CH:46]=2)[C:43](O)=[O:44])[C:32](=[O:36])[C:33]=1[O:34][CH3:35]>C(Cl)Cl>[CH3:26][O:27][C:28]1[C:29](=[O:56])[C:30]([CH3:55])=[C:31]([CH2:37][C:38]2[CH:39]=[CH:40][C:41]([O:47][CH2:48][C:49]3[CH:50]=[N:51][CH:52]=[CH:53][CH:54]=3)=[C:42]([CH:46]=2)[C:43]([NH:7][C:6]2[CH:8]=[CH:9][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)=[O:44])[C:32](=[O:36])[C:33]=1[O:34][CH3:35]
Reactant: COc1ccc(N)cc1
Reactant: COC1=C(OC)C(=O)C(Cc2ccc(OCc3cccnc3)c(C(=O)O)c2)=C(C)C1=O
Agent: CN1CC[NH+](C)C1Cl
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC1=C(OC)C(=O)C(Cc2ccc(OCc3cccnc3)c(C(=O)Nc3ccc(OC)cc3)c2)=C(C)C1=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 23.8 %

Procedure:
p-Methoxyaniline (0.078 g, 0.639 mmol), triethylamine (0.066 g, 0.639 mmol) and 2-chloro-1,3-dimethylimidazolinium chloride (0.108 g, 0.639 mmol) were added to a methylene chloride solution (20 ml) of 5-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-(3-pyridylmethyloxy)benzoic acid (0.135 g, 0.318 mmol) and the resulting solution was stirred at room temperature for 12 hours. The reaction solution was poured into ice water and then extracted with methylene chloride. The extract was washed with water and then dried, and the solvent was removed by distillation. The obtained residue was purified by preparative thin-layer chromatography (chloroform:methanol=9:1) and then recrystallized from ether to obtain the titled compound (0.040 g, 0.0756 mmol, 24%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([OH:15])[CH:13]=2)[CH:8]=[CH:7]1)[CH3:2].Cl[CH2:18][C:19]1[C:20]([CH:35]2[CH2:37][CH2:36]2)=[N:21][C:22]([C:25]2[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=2)=[N:23][CH:24]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[I-].[K+]>CC(C)=O>[CH2:1]([O:3][C:4](=[O:16])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][CH2:18][C:19]3[C:20]([CH:35]4[CH2:37][CH2:36]4)=[N:21][C:22]([C:25]4[CH:26]=[CH:27][C:28]([C:31]([F:33])([F:34])[F:32])=[CH:29][CH:30]=4)=[N:23][CH:24]=3)[CH:13]=2)[CH:8]=[CH:7]1)[CH3:2]
Reactant: CCOC(=O)Cn1ccc2ccc(O)cc21
Reactant: FC(F)(F)c1ccc(-c2ncc(CCl)c(C3CC3)n2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Solvent: CC(C)=O
Product: CCOC(=O)Cn1ccc2ccc(OCc3cnc(-c4ccc(C(F)(F)F)cc4)nc3C3CC3)cc21
Temperature: 25 °C
Reaction time: 72 h
Yield: 63 %

Procedure:
A mixture of (6-hydroxy-indol-1-yl)-acetic acid ethyl ester (example 6 b]; 50 mg, 0.23 μmol), 5-chloromethyl-4-cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidine (example 3 d]; 78 mg, 0.25 μmol), cesium carbonate (82 mg, 0.25 μmol) and a trace of potassium iodide were suspended in acetone (5 ml). The suspension was stirred at ambient temperature for 72 h, the solvent was evaporated under reduced pressure and the residue dissolved in 1 N HCl/ice water 1/1 and ethyl acetate. The layers were separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed two times with brine/ice water 1/1 and dried over sodium sulfate. The solvent was removed under reduced pressure and the residue purified by column chromatography (silica gel, heptane/AcOEt) to give 71 mg (0.14 μmol, 63%) of the title compound as colorless crystals.
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][CH2:5][CH2:6][NH:7][CH2:8][CH2:9][OH:10].[C:11]1([CH3:21])[CH:16]=[CH:15][C:14]([S:17](Cl)(=[O:19])=[O:18])=[CH:13][CH:12]=1.Cl>N1C=CC=CC=1.CO>[S:17]([C:6]([S:17]([C:14]1[CH:15]=[CH:16][C:11]([CH3:21])=[CH:12][CH:13]=1)(=[O:19])=[O:18])([NH:7][CH2:8][CH2:9][OH:10])[C:5]([S:17]([C:14]1[CH:15]=[CH:16][C:11]([CH3:21])=[CH:12][CH:13]=1)(=[O:19])=[O:18])([S:17]([C:14]1[CH:15]=[CH:16][C:11]([CH3:21])=[CH:12][CH:13]=1)(=[O:19])=[O:18])[NH:4][CH2:3][CH2:2][OH:1])([C:14]1[CH:15]=[CH:16][C:11]([CH3:21])=[CH:12][CH:13]=1)(=[O:19])=[O:18]
Reactant: OCCNCCNCCO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Solvent: c1ccncc1
Solvent: CO
Product: Cc1ccc(S(=O)(=O)C(NCCO)(C(NCCO)(S(=O)(=O)c2ccc(C)cc2)S(=O)(=O)c2ccc(C)cc2)S(=O)(=O)c2ccc(C)cc2)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
N,N′-bis(2-hydroxyethyl)-ethylenediamine (Aldrich, 14.8 g, 100 mmol) and pyridine (Fluka, 200 mL) was stirred at 0° C. under nitrogen while a solution of toluene-4-sulfonyl chloride (Fluka, 77 g, 400 mmol) dissolved in pyridine (Fluka, 100 mL) was dropped into the solution over a period of 75 minutes. The temperature was slowly raised to room temperature and continued stiffed for 4 hours. Solution was poured into a mixture of ice (250 mL) and hydrochloric acid (concentrated, 250 mL) while stirring to afford a dark sticky oil. Solvents were removed by decantation, product crude washed with water, decanted and re-dissolved in methanol (250 mL). The resulting slurry was isolated by filtration and the crude product was re-dissolved in hot methanol (60° C., 600 mL) and cooled down. Solid product was filtered off and dried in vacuo. Yield 36.36 g (47.5%). Product was verified by NMR.
Reaction SMILES: ON1C2C=CC=CC=2N=N1.CN1CCOCC1.Cl.CN(C)CCCN=C=NCC.[NH2:30][CH:31]([C:33]1[C:34](=[O:47])[NH:35][C:36]([CH2:39][C:40]2[CH:45]=[CH:44][C:43]([CH3:46])=[CH:42][CH:41]=2)=[N:37][N:38]=1)[CH3:32].[C:48]([CH:51]([CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH3:60])[C:52](O)=[O:53])(=[O:50])[CH3:49]>>[C:48]([CH:51]([CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH3:60])[C:52]([NH:30][CH:31]([C:33]1[C:34](=[O:47])[NH:35][C:36]([CH2:39][C:40]2[CH:45]=[CH:44][C:43]([CH3:46])=[CH:42][CH:41]=2)=[N:37][N:38]=1)[CH3:32])=[O:53])(=[O:50])[CH3:49]
Reactant: CCCCCCC(C(C)=O)C(=O)O
Reactant: Cc1ccc(Cc2nnc(C(C)N)c(=O)[nH]2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Product: CCCCCCC(C(C)=O)C(=O)NC(C)c1nnc(Cc2ccc(C)cc2)[nH]c1=O

Procedure:
The amount of 2-acetyloctanoic acid in dichloromethane from Example 19A is reacted analogously to Example 23A with 2.14 g (15.8 mmol) of 1-hydroxy-1H-benzotriazole, 1.90 g (18.8 mmol) of 4-methylmorpholine, 3.03 g (15.8 mmol) of N′-(3-dimethylaminopropyl-N-ethylcarbodiimide hydrochloride and 3.80 mg (15.6 mmol) of 6-(1-aminoethyl)-3-(4-methylbenzyl)-1,2,4-triazin-5(4H)-one (Example 8A) to give 2-acetyl-N-{1-[3-(4-methylbenzyl)-5-oxo-4,5-dihydro-1,2,4-triazin-6-yl]ethyl}octanamide.
Reaction SMILES: [C:1]([O:4][C:5]1[C:10]([Cl:11])=[CH:9][NH:8][C:7](=[O:12])[CH:6]=1)(=[O:3])[CH3:2].[C:13](Cl)(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[C:1]([O:4][C:5]1[C:10]([Cl:11])=[CH:9][N:8]=[C:7]([O:12][C:13](=[O:20])[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1cc(=O)[nH]cc1Cl
Reactant: O=C(Cl)c1ccccc1
Product: CC(=O)Oc1cc(OC(=O)c2ccccc2)ncc1Cl
Yield: 93 %

Procedure:
The general procedure of Example 20 was repeated using 500 mg of 4-acetoxy-5-chloro-2-pyridone and 0.37 ml of benzoyl chloride to produce 720 mg of the title compound in a yield of 93%.
Reaction SMILES: C1(=O)N([CH:6]([CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([N:18]3[C:22](=[O:23])[CH:21]=[CH:20][C:19]3=[O:24])=[CH:14][CH:13]=2)[C:7]([O-:9])=[O:8])C(=O)CC1.[CH3:27][OH:28]>C(N(CC)CC)C>[CH2:21]1[C:22](=[O:23])[N:18]([O:9][C:7]([CH2:6][CH2:10][CH2:11][C:12]2[CH:13]=[CH:14][C:15]([N:18]3[C:19](=[O:24])[CH:20]=[CH:21][C:22]3=[O:23])=[CH:16][CH:17]=2)=[O:8])[C:27](=[O:28])[CH2:20]1
Reactant: CO
Reactant: O=C([O-])C(CCc1ccc(N2C(=O)C=CC2=O)cc1)N1C(=O)CCC1=O
Solvent: CCN(CC)CC
Product: O=C(CCCc1ccc(N2C(=O)C=CC2=O)cc1)ON1C(=O)CCC1=O

Procedure:
The following protocol is used to conjugate PE via an SMPB intermediate: 100 micromoles of phosphatidyl ethanolamine (PE) is dissolved in 5 mL of argon-purged, anhydrous methanol containing 100 micromoles of triethylamine (TEA). The solution is maintained over an argon or nitrogen atmosphere. The reaction may also be done in dry chloroform50 mg of succinimidyl-4-(p-maleimidophenyl)butyrate (SMPB, Pierce) is the added to the PE solution, and the solution is mixed well to dissolve. The solution is allowed to react for 2 hours at room temperature, while maintaining it under an argon or nitrogen atmosphere. Methanol is removed from the reaction solution by rotary evaporation and the solids are redissolved in 5 mLchloroform. The water-soluble reaction by-products are extracted from the chloroform with an equal volume of 1% NaCl. Extraction is repeated once more. The MPB-PE derivative is purified by chromatography on a column of silicic acid (Martin F J et al., Immunospecific targeting of liposomes to cells: A novel and efficient method for covalent attachment of Fab′ fragments via disulfide bonds. Biochemistry, 1981; 20:4229-38). Chloroform is removed from the MBP-PE by rotary evaporation. The derivative is stored at −20° C. under a nitrogen atmosphere until use.