Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([Cl:9])=[CH:4][C:3]=1Cl.[OH-:11].[Na+]>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([Cl:9])=[CH:4][C:3]=1[OH:11]
Reactant: Clc1cc(Cl)c(Cl)cc1Cl
Reactant: [OH-]
Agent: [Na+]
Product: Oc1cc(Cl)c(Cl)cc1Cl

Procedure:
The presently employed technology to produce 2,4,5-trichlorophenoxyacetic acid (2,4,5-T) and 2,4,5-trichlorophenol (2,4,5-TCP) commercially involves the dechlorination of 1,2,4,5-tetrachlorobenzene with aqueous sodium hydroxide or anhydrous sodium hydroxide in the presence of alcohols under elevated temperatures and pressures to form 2,4,5-TCP according to the reaction: ##STR2## Under the conditions of alkalinity, temperature and pressure, this process produces between 1 to 100 parts per million of the highly toxic teratogen 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) according to the reaction: ##STR3##
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]1[CH2:17][C:18]([O:20]C)=[O:19])=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>CO>[C:1]([O:5][C:6]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]1[CH2:17][C:18]([OH:20])=[O:19])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)CC1c2ccccc2CN1C(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)N1Cc2ccccc2C1CC(=O)O
Temperature: 25 °C
Reaction time: 48 h
Yield: 99.5 %

Procedure:
To 1-methoxycarbonylmethyl-1,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester (52.6 g, 180.5 mmol) in MeOH (500 mL) was added 1 N NaOH (199 mL, 199.0 mmol). The mixture is stirred at r.t. for about 48 hours and then concentrated to dryness. The resulting residue was dissolved in water (300 mL) and extracted with diethyl ether (2×). The aqueous portion was acidified to pH 2 with 10% aqueous sodium bisulfate and extracted with EtOAc. The combined organic extracts were dried (MgSO4) and concentrated to dryness to afford about 49.8 g of the final compound (99%). EIS-MS 276 [M−1].
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([C:26]2[CH:27]=[CH:28][C:29]([O:40]S(C(F)(F)F)(=O)=O)=[C:30]([C:32]3[CH:37]=[CH:36][CH:35]=[C:34]([O:38][CH3:39])[CH:33]=3)[CH:31]=2)([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)[N:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].P([O-])([O-])([O-])=O.[K+].[K+].[K+].COC1C=C(B(O)O)C=CC=1.COCCOC.O.C(O)C>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(OCC)(=O)C>[C:1]([O:5][C:6](=[O:7])[NH:8][C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([C:26]2[CH:31]=[C:30]([C:32]3[CH:37]=[CH:36][CH:35]=[C:34]([O:38][CH3:39])[CH:33]=3)[C:29]([OH:40])=[CH:28][CH:27]=2)([C:18]2[CH:19]=[CH:20][C:21]([O:24][CH3:25])=[CH:22][CH:23]=2)[N:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccc(C2(c3ccc(OS(=O)(=O)C(F)(F)F)c(-c4cccc(OC)c4)c3)N=C(NC(=O)OC(C)(C)C)c3ccccc32)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: COc1cccc(B(O)O)c1
Agent: O=P([O-])([O-])[O-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: COCCOC
Product: COc1ccc(C2(c3ccc(O)c(-c4cccc(OC)c4)c3)N=C(NC(=O)OC(C)(C)C)c3ccccc32)cc1

Procedure:
To [3-(3-bromo-4-hydroxy-phenyl)-3-(4-methoxy-phenyl)-3H-isoindol-1-yl]-carbamic acid tert-butyl ester (Scheme #2, E) (364 mg, 0.72 mmol) was added potassium phosphate (303 mg, 1.43 mmol), 3-methoxyphenylboronic acid (163 mg, 1.07 mmol), dichlorobis(triphenylphosphine)palladium(II) (50 mg, 0.072 mmol), and 1,2-dimethoxyethane: water:ethanol (7:3:2, 20 mL). The reaction was placed in a hot bath and heated to reflux. After 10 minutes additional 3-methoxyphenylboronic acid (60 mg) and dichlorobis(triphenylphosphine)palladium(II) (25 mg) were added and the reaction refluxed for 30 minutes. Ethyl acetate was added, salts filtered off, and the filtrate removed of solvent under reduced pressure. The mixture was purified three times; first using 20 g silica eluting with 5% acetone/dichloromethane, second using 20 g silica eluting with dichloromethane then 5% acetone/dichloromethane, and third using 40 g silica eluting with a gradient of hexanes to 50% ethyl acetate/hexanes. The product was removed of solvent under reduced pressure to give the title compounds as a white solid which was placed under high vacuum over night (208 mg, 54%). 1H NMR (300 MHz, DMSO-d6-/TFA-d) δ 8.62 (d, J=7.9 Hz, 1 H), 7.88 (t, J=7.6 Hz, 1 H), 7.78-7.69 (m, 2 H), 7.34-7.29 (m, 4 H), 7.10-7.02 (m, 3 H), 6.95-6.86 (m, 4 H), 3.76 (d, J=2.1 Hz, 6 H), 1.62 (s, 9 H); MS (APCI+) m/z 537 [M+1]+; tR=2.50 min.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][CH2:16][C:17]3([CH2:23][OH:24])[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)[N:10]=2)=[CH:4][C:5](F)=[N:6][CH:7]=1.[CH3:25][O:26][CH2:27][C@H:28]([NH:30][C@H:31]1[CH2:36][CH2:35][C@H:34]([NH2:37])[CH2:33][CH2:32]1)[CH3:29]>>[Cl:1][C:2]1[C:3]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][CH2:16][C:17]3([CH2:23][OH:24])[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)[N:10]=2)=[CH:4][C:5]([NH:37][C@H:34]2[CH2:33][CH2:32][C@H:31]([NH:30][C@H:28]([CH3:29])[CH2:27][O:26][CH3:25])[CH2:36][CH2:35]2)=[N:6][CH:7]=1
Reactant: OCC1(CNc2cccc(-c3cc(F)ncc3Cl)n2)CCOCC1
Reactant: COC[C@@H](C)N[C@H]1CC[C@H](N)CC1
Product: COC[C@@H](C)N[C@H]1CC[C@H](Nc2cc(-c3cccc(NCC4(CO)CCOCC4)n3)c(Cl)cn2)CC1

Procedure:
Following the same procedure as in Example 1b using (4-((5′-chloro-2′-fluoro-2,4′-bipyridin-6-ylamino)methyl)tetrahydro-2H-pyran-4-yl)methanol (from step 4) and trans-N1-((R)-1-methoxypropan-2-yl)cyclohexane-1,4-diamine, the desired product was obtained. LCMS (m/z): 518.2 (MH+), retention time=0.47 min.
Reaction SMILES: [CH3:1][N:2]([CH3:15])[C:3]1[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[CH:9]=[CH:8][C:4]=1[C:5](O)=O.Cl.Cl.[NH2:18][C:19]1[C:24]([NH2:25])=[CH:23][CH:22]=[C:21]([O:26][CH3:27])[N:20]=1>P(Cl)(Cl)(Cl)=O>[CH3:1][N:2]([CH3:15])[C:3]1[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[CH:9]=[CH:8][C:4]=1[C:5]1[NH:25][C:24]2[C:19]([N:18]=1)=[N:20][C:21]([O:26][CH3:27])=[CH:22][CH:23]=2
Reactant: CN(C)c1cc([N+](=O)[O-])ccc1C(=O)O
Reactant: COc1ccc(N)c(N)n1
Agent: Cl
Solvent: O=P(Cl)(Cl)Cl
Product: COc1ccc2[nH]c(-c3ccc([N+](=O)[O-])cc3N(C)C)nc2n1

Procedure:
An amount of 0.45 gm of 2-dimethylamino-4-nitro-benzoic acid is suspended in 15 ml of phosphorus oxychloride, and 0.45 gm of 2,3-diamino-6-methoxy-pyridine dihydrochloride are added. The mixture is refluxed for two hours and after cooling poured onto water. The aqueous solution is made ammoniacal with cooling, and the product precipitated is treated as in Example 4(b).
Reaction SMILES: [CH3:1][C:2]([CH3:26])([CH3:25])[C:3]([O:5][C:6]1[CH:7]=[CH:8][C:9]2[N:10]=[C:11]3[C:16]([O:17][C:18]=2[CH:19]=1)=[CH:15][C:14](=[O:20])[C:13]([CH2:21][CH2:22][CH2:23][OH:24])=[CH:12]3)=[O:4].C(N(CC)CC)C.[CH:34]([N:37]([CH:45]([CH3:47])[CH3:46])[P:38](Cl)[O:39][CH2:40][CH2:41][C:42]#[N:43])([CH3:36])[CH3:35].CO>C(Cl)Cl.CCOCC.CCCCCC>[CH3:1][C:2]([CH3:26])([CH3:25])[C:3]([O:5][C:6]1[CH:7]=[CH:8][C:9]2[N:10]=[C:11]3[C:16]([O:17][C:18]=2[CH:19]=1)=[CH:15][C:14](=[O:20])[C:13]([CH2:21][CH2:22][CH2:23][O:24][P:38]([N:37]([CH:45]([CH3:47])[CH3:46])[CH:34]([CH3:35])[CH3:36])[O:39][CH2:40][CH2:41][C:42]#[N:43])=[CH:12]3)=[O:4]
Reactant: CC(C)(C)C(=O)Oc1ccc2nc3cc(CCCO)c(=O)cc-3oc2c1
Reactant: CC(C)N(C(C)C)P(Cl)OCCC#N
Solvent: CO
Solvent: CCN(CC)CC
Solvent: CCCCCC
Product: CC(C)N(C(C)C)P(OCCC#N)OCCCc1cc2nc3ccc(OC(=O)C(C)(C)C)cc3oc-2cc1=O
Reaction time: 0.5 h

Procedure:
36b (0.38 g, 1.1 mmol) was dissolved in 6 mL of anhydrous CH2Cl2. Triethylamine (1.5 mL) was added followed by 2-cyanoethyl diisopropylchlorophosphoramidite (0.29 mL, 1.3 mmol). The solution was kept at room temperature for 30 min, MeOH (0.1 mL) was added and the reaction was concentrated under vacuum. The residue obtained was partitioned between ethyl acetate and NaHCO3. The organic phase was washed with saturated NaCl, dried over Na2SO4 and concentrated to afford the crude amidite. It was dissolved in 2 mL of ether and added dropwise to ˜50 mL of hexane. The resultant orange solid was collected by filtration, washed with hexane and dried. The yield was 0.4 g.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][N:3]=1.[F:9][C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][C:11]=1B1OC(C)(C)C(C)(C)O1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].O>O1CCOCC1.C1C=CC([PH+]([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C1C=CC([PH+]([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C(Cl)Cl.Cl[Pd]Cl.[Fe]>[F:8][C:5]1[CH:6]=[CH:7][C:2]([C:11]2[CH:12]=[C:13]([N+:16]([O-:18])=[O:17])[CH:14]=[CH:15][C:10]=2[F:9])=[N:3][CH:4]=1
Reactant: Fc1ccc(Br)nc1
Reactant: CC1(C)OB(c2cc([N+](=O)[O-])ccc2F)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe]
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: O
Product: O=[N+]([O-])c1ccc(F)c(-c2ccc(F)cn2)c1
Temperature: 90 °C
Reaction time: 24 h
Yield: 48.7 %

Procedure:
To a degassed mixture of 2-bromo-5-fluoropyridine (1.88 g, 10.7 mmol), 2-(2-fluoro-5-nitrophenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (3.13 g, 11.6 mmol) and potassium phosphate (8.2 g, 38.6 mmol) in 1,4-dioxane (40 ml) was added dichloro[1,1′-bis(diphenylphosphino)ferrocene]-palladium(II) dichloromethane adduct (189 mg) and the mixture stirred for 24 h at 90° C. The reaction was cooled to ambient temperature, poured into water (100 ml) and extracted with ethyl acetate (4×50 ml). The combined organic phases were dried over anhydrous sodium sulfate, filtered and evaporated to dryness. Purification by chromatography (silica gel, CH2Cl2) and then crystallisation from isohexane gave 5-fluoro-2-(2-fluoro-5-nitrophenyl)pyridine (1.23 g, 44%): MS (ES+) m/z 237.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][C:3]=1[NH2:4].[C:10]([C:16]([O:18][CH3:19])=[O:17])#[C:11][C:12]([O:14][CH3:15])=[O:13]>CO>[F:1][C:2]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][C:3]=1[NH:4]/[C:11](=[CH:10]/[C:16]([O:18][CH3:19])=[O:17])/[C:12]([O:14][CH3:15])=[O:13]
Reactant: Nc1cc(F)ccc1F
Reactant: COC(=O)C#CC(=O)OC
Solvent: CO
Product: COC(=O)/C=C(/Nc1cc(F)ccc1F)C(=O)OC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution 2,5-difluoroaniline (X1) (3.00 mL, 29.9 mmol) in MeOH (30 mL) was added dimethyl acetylenedicarboxylate (P2) (DMAD, 4.44 mL, 35.9 mmol). The reaction was stirred at room temperature for 2 h. The mixture was concentrated and the residue was purified by silica gel flash chromatography (gradient 0-30% EtOAc in Hex) to give dimethyl (2E)-2-[(2,5-difluorophenyl)amino]but-2-enedioate (X2). ES-MS [M+1]+=272.2.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:15])=[C:4]([NH:8][CH2:9][C:10]2[NH:11][CH:12]=[N:13][CH:14]=2)[CH:5]=[CH:6][CH:7]=1.[CH:16](=O)[CH3:17].C([BH3-])#N.[Na+]>CO.[Cl-].[Zn+2].[Cl-]>[Cl:1][C:2]1[C:3]([F:15])=[C:4]([N:8]([CH2:16][CH3:17])[CH2:9][C:10]2[NH:11][CH:12]=[N:13][CH:14]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC=O
Reactant: Fc1c(Cl)cccc1NCc1cnc[nH]1
Agent: [BH3-]C#N
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Product: CCN(Cc1cnc[nH]1)c1cccc(Cl)c1F
Temperature: 40 °C
Reaction time: 8 h
Yield: 63.1 %

Procedure:
(3-Chloro-2-fluoro-phenyl)-(3H-imidazol-4-ylmethyl)-amine (0.24 g, 1 mmol) was dissolved in methanol (15 ml). Then acetaldehyde (0.28 ml, 5 mmol), zinc chloride (0.55 g, 4 mmol) and sodium cyanoborohydride (0.19 g, 3 mmol) were added and the reaction mixture was allowed to stir at 40° C. overnight. After cooling, the reaction mixture was poured onto ammoniumchloride/ice and extracted with ethyl acetate (2 times 50 ml). The organic layer was dried over magnesium sulfate and evaporated. The residue was purified using flash chromatography (SiO2; eluent: heptane/ethyl acetate=90:10) to yield a light yellow oil (0.16 g, 63%); MS (ISP): 254.1 ((M+H)+.).
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:15]([CH2:30][CH3:31])[C:16](=[O:29])[CH:17]=[C:18]([C:20]3[CH:25]=[CH:24][C:23]([C:26]#[N:27])=[C:22]([F:28])[CH:21]=3)[N:19]=2)[CH2:10][CH2:9]1)(C)(C)C.Cl>CC(=O)OCC>[NH2:7][CH:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:15]([CH2:30][CH3:31])[C:16](=[O:29])[CH:17]=[C:18]([C:20]3[CH:25]=[CH:24][C:23]([C:26]#[N:27])=[C:22]([F:28])[CH:21]=3)[N:19]=2)[CH2:10][CH2:9]1
Reactant: CCn1c(N2CCC(NC(=O)OC(C)(C)C)CC2)nc(-c2ccc(C#N)c(F)c2)cc1=O
Agent: Cl
Solvent: CCOC(C)=O
Product: CCn1c(N2CCC(N)CC2)nc(-c2ccc(C#N)c(F)c2)cc1=O
Reaction time: 0.5 h
Yield: 107.2 %

Procedure:
To a mixture of {1-[4-(4-cyano-3-fluoro-phenyl)-1-ethyl-6-oxo-1,6-dihydro-pyrimidin-2-yl]-piperidin-4-yl}-carbamic acid tert-butyl ester (180 mg, 0.41 mmol) in EA (5 mL) was added a 4 M solution of HCl in EA (3 mL). The reaction mixture was stirred for 30 min. The solvent was evaporated in vacuo to give 150 mg of the titled compound (97%) as a yellow solid (HCl salt). 1H NMR (400 MHz, CD3OD): δ 1.28 (t, J=7.2 Hz, 1H), 1.48-1.52 (m, 2H), 1.99-2.02 (m, 2H), 2.94-3.01 (m, 2H), 3.33-3.38 (m, 1H), 6.81 (q, J=6.8 Hz, 2H), 4.85-4.88 (m, 2H), 6.95 (s, 1H), 7.73 (t, J=8.0 Hz, 1H), 7.90-7.95 (m, 2H). [M+H] Calc'd for C18H20FN5O, 342. Found, 342.
Reaction SMILES: [CH3:1][C:2]([CH3:22])=[CH:3][CH2:4][CH2:5]/[C:6](/[CH3:21])=[CH:7]/[CH2:8][CH2:9]/[C:10](/[CH3:20])=[CH:11]/[CH2:12][S:13][CH2:14][C@H:15]([NH2:19])[C:16]([OH:18])=[O:17].C(N(CC)C(C)C)(C)C.[CH2:32]([O:34][C:35](=[O:41])[CH2:36][CH2:37][N:38]=[C:39]=[O:40])[CH3:33]>C(Cl)Cl>[CH3:20]/[C:10](/[CH2:9][CH2:8]/[CH:7]=[C:6](\[CH3:21])/[CH2:5][CH2:4][CH:3]=[C:2]([CH3:22])[CH3:1])=[CH:11]\[CH2:12][S:13][CH2:14][C@@H:15]([C:16]([OH:18])=[O:17])[NH:19][C:39](=[O:40])[NH:38][CH2:37][CH2:36][C:35](=[O:41])[O:34][CH2:32][CH3:33]
Reactant: CCOC(=O)CCN=C=O
Reactant: CC(C)=CCC/C(C)=C/CC/C(C)=C/CSC[C@H](N)C(=O)O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)CCNC(=O)N[C@@H](CSC/C=C(\C)CC/C=C(\C)CCC=C(C)C)C(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
S-trans, trans-Farnesyl-L-cysteine (325 mg, 1 mmol) and N,N-diisopropyl-ethyl-amine (650 mg, 5 mmol) were mixed in CH2Cl2 (10 mL). Ethyl-3-isocyanato-propionate (143, 1 mmol) was added to the reaction mixture. The reaction solution was stirred at room temperature overnight and the solvent was removed by rotary evaporation. The remaining residue was dissolved in ethyl acetate (100 mL) and washed with 1 N HCl solution (50 mL×2). The ethyl acetate solution was dried over Na2SO4 and concentrated to a crude reaction mixture. The resulting mixture was purified by HPLC (200 mg, 43%) to yield Compound D. 1H-NMR (500 MHz, MeOH-d4): δ 1.28 (t, J=7.5 Hz, 3H), 1.62 (s, 3H), 1.63 (s, 3H), 1.69 (s, 3H), 1.70 (s, 3H), 1.98 (m, 2H), 2.06 (m, 6H), 2.52 (t, J=6.5, 2H), 2.79 (dd, J=7.0, 14.0 Hz, 1H), 2.93 (dd, J=4.5, 13.5 Hz, 1H), 3.17 (dd, J=7.5, 13.5 Hz, 1H), 3.28 (dd, J=8.5, 13.5 Hz, 1H), 3.41 (t, J=6.5 Hz, 3H), 4.16 (q, J=7.5 Hz, 2H), 4.50 (dd, J=4.5, 6.5 Hz, 1H), 5.11 (m, 2H), 5.23 (t, J=7.5, 1H). 13C-NMR (125 MHz, MeOH-d4): δ 14.6, 16.1, 16.2, 17.8, 26.0, 27.4, 27.8, 30.5, 34.4, 35.9, 36.7, 40.8, 40.9, 54.0, 61.7, 121.7, 125.1, 125.5, 132.1, 136.3, 140.5, 160.2, 173.8, 175.0; ES-MS: mass calcd for Chemical Formula: C24H40N2O5S 468.7. Found (M+Na) m/z 491.3.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([S:10](Cl)(=[O:12])=[O:11])=[CH:6][C:5]=1[C:14]1[NH:19][C:18](=[O:20])[C:17]2=[C:21]([CH3:29])[N:22]=[C:23]([CH:24]([CH2:27][CH3:28])[CH2:25][CH3:26])[N:16]2[N:15]=1)[CH3:2].[OH:30][CH2:31][CH:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1.C(OC1C=CC(S(N2CCC(O)CC2C)(=O)=O)=CC=1C1NC(=O)C2=C(C)N=C(C(CC)CC)N2N=1)C>>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([S:10]([N:35]2[CH2:36][CH2:37][CH:32]([CH2:31][OH:30])[CH2:33][CH2:34]2)(=[O:12])=[O:11])=[CH:6][C:5]=1[C:14]1[NH:19][C:18](=[O:20])[C:17]2=[C:21]([CH3:29])[N:22]=[C:23]([CH:24]([CH2:27][CH3:28])[CH2:25][CH3:26])[N:16]2[N:15]=1)[CH3:2]
Reactant: CCOc1ccc(S(=O)(=O)Cl)cc1-c1nn2c(C(CC)CC)nc(C)c2c(=O)[nH]1
Reactant: OCC1CCNCC1
Agent: CCOc1ccc(S(=O)(=O)N2CCC(O)CC2C)cc1-c1nn2c(C(CC)CC)nc(C)c2c(=O)[nH]1
Product: CCOc1ccc(S(=O)(=O)N2CCC(CO)CC2)cc1-c1nn2c(C(CC)CC)nc(C)c2c(=O)[nH]1

Procedure:
Analogously, using 400 mg (0.911 mmol) of 4-ethoxy-3-(5-methyl-4-oxo-7-(1-ethylpropyl)-3,4-dihydroimidazo[5,1-f][1,2,4]triazin-2-yl)-benzenesulphonyl chloride and; 10 mg (2.734 mmol) of 4-hydroxymethylpiperidine, 270 mg (57.3% of theory) of 2-[2-ethoxy-5-(4-hydroxy-methylpiperidine-1-sulphonyl)-phenyl]-7-(1-ethylpropyl)-5-methyl-3H-imidazo[5,1-f][1,2,4]triazin-4-one.
Reaction SMILES: [CH:1]1[C:6]([C:7]([NH2:10])=[N:8][NH2:9])=[CH:5][CH:4]=[N:3][CH:2]=1.O=[C:12]([C:18](OCC)=[O:19])[C:13]([O:15][CH2:16][CH3:17])=[O:14]>C(O)C>[O:19]=[C:18]1[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[N:9][NH:8][C:7]([C:6]2[CH:5]=[CH:4][N:3]=[CH:2][CH:1]=2)=[N:10]1
Reactant: NN=C(N)c1ccncc1
Reactant: CCOC(=O)C(=O)C(=O)OCC
Solvent: CCO
Product: CCOC(=O)c1n[nH]c(-c2ccncc2)nc1=O
Reaction time: 13 h
Yield: 56 %

Procedure:
In ethanol (20 ml), 4-pyridinecarboxyamidrazone (1.48 g) was dissolved. To the resulting solution, diethyl ketomalonate (1.65 ml) was added dropwise at room temperature, followed by stirring for 13 hours. After heating under reflux for 4 hours, the reaction mixture was cooled. Yellow crystals thus precipitated were collected by filtration and dried, whereby the title compound (1.50 g, 56%) was obtained.
Reaction SMILES: [CH3:1][N:2]1[C:7]2[C:8](C)=[CH:9][NH:10][C:6]=2[C:5](=[O:12])[N:4]([CH3:13])[C:3]1=[O:14].Br[CH2:16][C:17]([NH:19][C:20]1[S:21][CH:22]=[C:23]([C:25]2[CH:30]=[CH:29][C:28]([F:31])=[C:27]([C:32]([F:35])([F:34])[F:33])[CH:26]=2)[N:24]=1)=[O:18].[H-].[Na+]>CN(C=O)C>[CH3:1][N:2]1[C:7]2[CH:8]=[CH:9][N:10]([CH2:16][C:17]([NH:19][C:20]3[S:21][CH:22]=[C:23]([C:25]4[CH:30]=[CH:29][C:28]([F:31])=[C:27]([C:32]([F:35])([F:33])[F:34])[CH:26]=4)[N:24]=3)=[O:18])[C:6]=2[C:5](=[O:12])[N:4]([CH3:13])[C:3]1=[O:14]
Reactant: O=C(CBr)Nc1nc(-c2ccc(F)c(C(F)(F)F)c2)cs1
Reactant: Cc1c[nH]c2c(=O)n(C)c(=O)n(C)c12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1c(=O)c2c(ccn2CC(=O)Nc2nc(-c3ccc(F)c(C(F)(F)F)c3)cs2)n(C)c1=O

Procedure:
The title compound was prepared according to the general procedure (Method A) by coupling Intermediate 1 (50 mg, 0.279 mmol) with 2-bromo-N-[4-(4-fluoro-3-trifluoromethylphenyl)-1,3-thiazol-2-yl]acetamide (128 mg, 0.334 mmol) in the presence of NaH (16 mg, 0.666 mmol) in dry DMF (5.0 mL) to give 75 mg of the product as an off-white solid; 1H NMR (δ ppm, DMSO-d6, 300 MHz) 3.17 (s, 3H), 3.40 (s, 3H), 5.32 (s, 2H), 6.23 (s, 1H), 7.36 (s, 1H), 7.58-7.66 (m, 1H), 7.88 (s, 1H), 8.24-8.32 (m, 2H), 12.74 (br s, 1H); APCI-MS (m/z) 480.16 (M−H).
Reaction SMILES: [C:1]1([C:7]2[O:8][C:9]([CH2:14][CH2:15][CH3:16])=[C:10]([CH2:12]O)[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(Cl)([Cl:19])=O>C1(C)C=CC=CC=1>[Cl:19][CH2:12][C:10]1[N:11]=[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[O:8][C:9]=1[CH2:14][CH2:15][CH3:16]
Reactant: O=S(Cl)Cl
Reactant: CCCc1oc(-c2ccccc2)nc1CO
Solvent: Cc1ccccc1
Product: CCCc1oc(-c2ccccc2)nc1CCl
Temperature: 25 °C
Reaction time: 1 h
Yield: 151 %

Procedure:
To a mixture of 2-phenyl-5-propyl-4-oxazolylmethanol (1.38 g) and toluene (100 mL) was added thionyl chloride (1.38 g) under ice-cooling, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was concentrated and the residue was dissolved in ethyl acetate. The mixture was washed successively with saturated aqueous sodium hydrogencarbonate and saturated brine, dried over anhydrous magnesium sulfate, and concentrated to give 4-chloromethyl-2-phenyl-5-propyloxazole as a colorless oil (2.26 g, 99%).
Reaction SMILES: C([O:3][C:4](=[O:25])[C:5]1[CH:10]=[C:9]([C:11](=[O:17])[N:12]([CH3:16])[CH2:13][CH2:14][CH3:15])[CH:8]=[C:7]([C:18](=[O:24])[N:19]([CH3:23])[CH2:20][CH2:21][CH3:22])[CH:6]=1)C.[OH-].[Li+].C1COCC1>O>[CH3:23][N:19]([CH2:20][CH2:21][CH3:22])[C:18]([C:7]1[CH:6]=[C:5]([CH:10]=[C:9]([C:11](=[O:17])[N:12]([CH3:16])[CH2:13][CH2:14][CH3:15])[CH:8]=1)[C:4]([OH:25])=[O:3])=[O:24]
Reactant: CCCN(C)C(=O)c1cc(C(=O)OCC)cc(C(=O)N(C)CCC)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCCN(C)C(=O)c1cc(C(=O)O)cc(C(=O)N(C)CCC)c1
Yield: 82.5 %

Procedure:
Stir a solution of 3,5-bis(methyl-propylcarbamoyl)-benzoic acid ethyl ester (157 mg, 0.45 mmol), 1 N lithium hydroxide (2.25 mL, 2.25 mmol) and THF (2.25 mL) for 2 h at room temperature. Dilute the reaction with water (10 mL) and extract with dichloromethane (10 mL). Acidify the aqueous with 5 N HCl, extract the aqueous with dichloromethane, dry (magnesium sulfate) and concentrate to give the title compound (119 mg, 82%).
Reaction SMILES: C([OH:4])CC.[N-:5]=[N+:6]=[N-:7].[Br:8][C:9]([CH3:14])([CH3:13])[C:10](Br)=[O:11].CN(CCN(CCN(C)C)C)C.CN(C=O)C>C1COCC1>[N-:5]=[N+:6]=[N-:7].[Br:8][C:9]([CH3:14])([CH3:13])[C:10]([O-:4])=[O:11]
Reactant: CCCO
Reactant: CC(C)(Br)C(=O)Br
Agent: CN(C)CCN(C)CCN(C)C
Agent: [N-]=[N+]=[N-]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CC(C)(Br)C(=O)[O-]
Temperature: 25 °C

Procedure:
An azide functionalized ATRP initiator (azidepropyl 2-bromoisobutyrate, AzPBIB) was prepared by the esterification reaction of azide propanol with α-bromoisobutyryl bromide in anhydrous THF at 0° C. for overnight. AzPBIB was then introduced to alkyne-functionalized PEG copolymer via click chemistry. In a typical procedure, poly(OEGMA-co-PgTEGMA) (0.1 g, 0.09 mmol based on alkyne groups), AzPBIB (9.2 mg, 0.037 mmol), CuBr (5.3 mg, 0.037 mmol), PMDETA (6.4 mg, 0.037 mmol) and DMF (0.5 mL) were added to a Schlenk tube. The reaction tube was degassed by three freeze-pump-thaw cycles, sealed under vacuum, and placed in a 40° C. oil bath for 24 h. After cooling to room temperature, the flask was exposed to air. After removing most of the solvents at reduced pressure, the residues were dissolved in DCM and passed through a neutral alumina column to remove copper catalysts. The solution was then concentrated under reduced pressure and precipitated in hexane. The isolated polymer poly(OEGMA-co-PgTEGMA-co-BIBTEGMA) was dried under vacuum. The bromoisobutyrate ratio in the final copolymer is approximately 12% as determined by 1H NMR analysis.
Reaction SMILES: FC1C=CC(CNC)=CC=1.F[C:12]1[CH:21]=[CH:20][C:15]([C:16]([NH:18][CH3:19])=[O:17])=[CH:14][CH:13]=1.FC1C=CC(C(Cl)=O)=CC=1>CN>[CH3:19][NH:18][C:16](=[O:17])[C:15]1[CH:20]=[CH:21][CH:12]=[CH:13][CH:14]=1
Reactant: CNC(=O)c1ccc(F)cc1
Agent: CN
Agent: CNCc1ccc(F)cc1
Agent: O=C(Cl)c1ccc(F)cc1
Product: CNC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
This compound was prepared from 4-Fluoro-N-methylbenzylamine which in turn was prepared from 4-Fluoro-N-methylbenzamide. Practical details are as follows: 4-Fluorobenzoyl chloride (25g) was added dropwise to a stirred aqueous solution of methylamine (40% w/v; 250 ml) at 0° C. over 30 min. The mixture was stirred for 12 h at room temperature, concentrated to half volume and the resulting crystalline precipitate was collected and recrystallized from water to furnish the N-methylbenzamide as colourless needles, (24.1 g; 89.1%), m.p. 131°-132° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[O:9][CH3:10])[NH2:5].CO[CH:13]=[C:14]1[C:19](=[O:20])[O:18][C:17]([CH3:22])([CH3:21])[O:16][C:15]1=[O:23]>CC(O)C>[Br:1][C:2]1[CH:3]=[C:4]([NH:5][CH:13]=[C:14]2[C:15](=[O:23])[O:16][C:17]([CH3:21])([CH3:22])[O:18][C:19]2=[O:20])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(N)cc1Br
Reactant: COC=C1C(=O)OC(C)(C)OC1=O
Solvent: CC(C)O
Product: COc1ccc(NC=C2C(=O)OC(C)(C)OC2=O)cc1Br
Temperature: 90 °C
Yield: 84.6 %

Procedure:
To a vial charged with 3-bromo-4-methoxyaniline (1.207 g, 5.97 mmol) was added IPA (11.95 ml) and 5-(methoxymethylene)-2,2-dimethyl-1,3-dioxane-4,6-dione (1.112 g, 5.97 mmol) respectively. The mixture was heated to 90° C. for 2 hrs providing a brown solution which was cooled to room temp affording an orange precipitate which was collected by vacuum filtration affording 5-(((3-bromo-4-methoxyphenyl)amino)methylene)-2,2-dimethyl-1,3-dioxane-4,6-dione (1.8 g, 5.05 mmol, 85% yield). This solid was transferred to a 5-20 ml microwave vial and 10 ml (0.5M 1,2-dichlorobenzene) was added and the mixture irradiated at 225° C. for 15 mins affording conversion to desired product according to LC-MS. To the suspension was added diethyl ether (˜5 ml) to aid in product precipitation. To precipitate was collected via vacuum filtration and washed with ether, affording a brown solid as an isomeric mixture (˜10:1) (595 mg, 39%). m/z (ESI) 256.1 (M+H)+.