Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N+:12]([O-])=O)[CH:5]=[C:6]2[C:10]=1[NH:9][C:8](=[O:11])[CH2:7]2.CCO>[Pd].CCOC(C)=O>[NH2:12][C:4]1[CH:5]=[C:6]2[C:10](=[C:2]([F:1])[CH:3]=1)[NH:9][C:8](=[O:11])[CH2:7]2
Reactant: O=C1Cc2cc([N+](=O)[O-])cc(F)c2N1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: Nc1cc(F)c2c(c1)CC(=O)N2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
7-fluoro-5-nitro-1,3-dihydro-2H-indol-2-one (8.5 g, 43.3 mmol) from Step 1 of this example was dissolved with stirring in 1:1 EtOH and EtOAc (433 ml). Palladium on carbon (10%, 2.55 g) was added and the slurry degassed and placed under an atmosphere of hydrogen (3×) and stirred at RT for 3 hours. The mixture was filtered through CELITE, the filter cake washed with EtOAc (3×100 ml), the filtrates combined and the volatiles removed in vacuum to give the titled compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:30])=[C:6]([CH:29]=1)[C:7]([NH:9][C:10]1[S:11][C:12]([C:26](O)=[O:27])=[C:13]([C:15]2[C:20]([F:21])=[C:19]([F:22])[C:18]([F:23])=[C:17]([F:24])[C:16]=2[F:25])[N:14]=1)=[O:8].CN.O.O[N:35]1[C:39]2C=CC=CC=2N=N1.CCN=C=NCCCN(C)C.Cl.Cl>O1CCCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:30])=[C:6]([CH:29]=1)[C:7]([NH:9][C:10]1[S:11][C:12]([C:26]([NH:35][CH3:39])=[O:27])=[C:13]([C:15]2[C:16]([F:25])=[C:17]([F:24])[C:18]([F:23])=[C:19]([F:22])[C:20]=2[F:21])[N:14]=1)=[O:8]
Reactant: On1nnc2ccccc21
Reactant: O=C(Nc1nc(-c2c(F)c(F)c(F)c(F)c2F)c(C(=O)O)s1)c1cc(Br)ccc1O
Agent: CCN=C=NCCCN(C)C
Agent: CN
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: CNC(=O)c1sc(NC(=O)c2cc(Br)ccc2O)nc1-c1c(F)c(F)c(F)c(F)c1F
Temperature: 25 °C
Reaction time: 18 h
Yield: 35.1 %

Procedure:
A mixture of 2-(5-bromo-2-hydroxybenzoyl)amino-4-(pentafluorophenyl)-thiazole-5-carboxylic acid (0.20 g, 0.48 mmol), methylamine 40% methanol solution (0.2 ml), 1-hydroxybenzotriazole hydrate (96.7 mg, 0.72 mmol), WSC-HCl (137.2 mg, 0.72 mmol) and tetrahydrofuran (15 mL) was stirred at room temperature for 18 hours. The reaction mixture was poured into 2 N hydrochloric acid and extracted with ethyl acetate. After the organic layer was washed with water and brine, dried over anhydrous sodium sulfate, the residue obtained by evaporation under reduced pressure was purified by chromatography on silica gel (n-hexane:ethyl acetate=1:2), and crystallized (dichloromethane/n-hexane) to give the title compound (87.9 mg, 42.6%) as a white powder.
Reaction SMILES: C([O:5][C:6](=[O:51])[C:7]([O:10]/[N:11]=[C:12](/[C:38]1[N:39]=[C:40]([NH:43]C(OC(C)(C)C)=O)[S:41][CH:42]=1)\[C:13]([NH:15][C@@H:16]1[C:19](=[O:20])[N:18]([S:21]([O-:24])(=[O:23])=[O:22])[C@@H:17]1[CH2:25][N:26]1[CH:30]=[C:29]([C:31]2[CH:36]=[CH:35][N+:34]([CH3:37])=[CH:33][CH:32]=2)[N:28]=[N:27]1)=[O:14])([CH3:9])[CH3:8])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:43][C:40]1[S:41][CH:42]=[C:38](/[C:12](=[N:11]/[O:10][C:7]([C:6]([OH:51])=[O:5])([CH3:8])[CH3:9])/[C:13]([NH:15][C@@H:16]2[C:19](=[O:20])[N:18]([S:21]([O-:24])(=[O:22])=[O:23])[C@@H:17]2[CH2:25][N:26]2[CH:30]=[C:29]([C:31]3[CH:32]=[CH:33][N+:34]([CH3:37])=[CH:35][CH:36]=3)[N:28]=[N:27]2)=[O:14])[N:39]=1
Reactant: C[n+]1ccc(-c2cn(C[C@@H]3[C@H](NC(=O)/C(=N\OC(C)(C)C(=O)OC(C)(C)C)c4csc(NC(=O)OC(C)(C)C)n4)C(=O)N3S(=O)(=O)[O-])nn2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[n+]1ccc(-c2cn(C[C@@H]3[C@H](NC(=O)/C(=N\OC(C)(C)C(=O)O)c4csc(N)n4)C(=O)N3S(=O)(=O)[O-])nn2)cc1
Yield: 41.6 %

Procedure:
Followed the general procedure for the acid mediated deprotection using (2R,3S)-3-((Z)-2-(((1-(tert-butoxy)-2-methyl-1-oxopropan-2-yl)oxy)imino)-2-(2-((tert-butoxycarbonyl)amino)thiazol-4-yl)acetamido)-2-((4-(1-methylpyridin-1-ium-4-yl)-1H-1,2,3-triazol-1-yl)methyl)-4-oxoazetidine-1-sulfonate (24 mg, 0.032 mmol), DCM (1.2 mL) and TFA (0.3 mL, 3.9 mmol). The crude residue was purified by reverse phase prep HPLC (XBridge, 30×100 mm, 5 μm, C18 column; ACN-water with 0.1% formic acid modifier, 1 mL/min), affording the title compound (7.9 mg, 41%) as a white solid. LCMS: m/z=592.0 (M−1); 1H NMR (400 MHz, D2O): δ 8.76 (s, 1H), 8.62 (d, J=6.8 Hz, 2H), 8.19 (d, J=6.4 Hz, 2H), 6.76 (s, 1H), 5.42 (d, J=5.2 Hz, 1H), 4.98-4.81 (m, 2H; partially obscured by residual solvent peak), 4.66-4.54 (m, 1H assumed: obscured by residual solvent peak), 4.22 (s, 3H), 1.30 (s, 3H), 1.27 (s, 3H).
Reaction SMILES: CN(C)C=O.[CH3:6][N:7]([CH3:22])[CH:8]([CH3:21])[CH2:9][CH2:10][N:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]([NH2:20])=[N:12]1.Br.Br[CH2:25][CH2:26][CH2:27][N:28]([CH2:31][CH3:32])[CH2:29][CH3:30].C(=O)([O-])[O-].[K+].[K+]>C(Cl)(Cl)Cl.O>[CH3:22][N:7]([CH3:6])[CH:8]([CH3:21])[CH2:9][CH2:10][N:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]([NH:20][CH2:25][CH2:26][CH2:27][N:28]([CH2:31][CH3:32])[CH2:29][CH3:30])=[N:12]1
Reactant: CC(CCn1nc(N)c2ccccc21)N(C)C
Reactant: CCN(CC)CCCBr
Agent: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: CCN(CC)CCCNc1nn(CCC(C)N(C)C)c2ccccc12
Temperature: 80 °C
Reaction time: 12 h
Yield: 55.4 %

Procedure:
To 60 ml of anhydrous N, N-dimethylformamide were added 7.50 g of the 1-(3-dimethylaminobutyl)-3-aminoindazole, 8.98 g of 3-bromopropyldiethylamine hydrobromide and 7.89 g of anhydrous potassium carbonate, and the mixture was stirred for 12 hours at 80° C. After cooling, the mixture was added with 80 ml of water and extracted with diethyl ether. The diethyl ether layer was extracted three times with 2N hydrochloric acid, and the hydrochloric acid layer was washed with diethyl ether. The pH of the layer was adjusted to at least 11 with potassium carbonate, and the alkali layer was extracted three times with chloroform. The chloroform layer was dried over anhydrous sodium sulfate, and chloroform was removed under reduced pressure. The residue thus obtained was subjected to an alumina-column chromatography (alumina: 200 g) using chloroform as the developing solvent to give 6.18 g of 1-(3-dimethylaminobutyl)-3-(3-diethylaminopropylamino)indazole having the following analytical values in a yield of 52%.
Reaction SMILES: C[O:2][C:3](=[O:38])[CH:4]([O:35][CH2:36][CH3:37])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][N:14]([CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[C:15]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][C:19]=2[O:26][CH3:27])=[O:16])=[CH:8][CH:7]=1.[Li+].[OH-]>O1CCCC1>[CH3:27][O:26][C:19]1[CH:20]=[C:21]([O:24][CH3:25])[CH:22]=[CH:23][C:18]=1[NH:17][C:15](=[O:16])[N:14]([CH2:13][CH2:12][C:9]1[CH:10]=[CH:11][C:6]([CH2:5][CH:4]([O:35][CH2:36][CH3:37])[C:3]([OH:38])=[O:2])=[CH:7][CH:8]=1)[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34]
Reactant: CCCCCCCN(CCc1ccc(CC(OCC)C(=O)OC)cc1)C(=O)Nc1ccc(OC)cc1OC
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCCCCCCN(CCc1ccc(CC(OCC)C(=O)O)cc1)C(=O)Nc1ccc(OC)cc1OC
Temperature: 25 °C
Reaction time: 16 h
Yield: 94.7 %

Procedure:
A solution of 3-(4-{2-[3-(2,4-dimethoxy-phenyl)-1-heptyl-ureido]-ethyl}-phenyl)-2-ethoxy-propionic acid methyl ester (249 mg, 0.47 mmol) and 1 M LiOH (1.41 mmol, 1.41 mL) in tetrahydrofuran (2 mL) was allowed to stir at room temperature for 16 hours. The solution was quenched by the addition of 2 N HCl until the solution had a pH<2. After dilution with twice its volume in water, the aqueous layer was extracted with diethyl ether (2×). The organic layers were combined, washed with 2 M HCl (2×), dried over anhydrous sodium sulfate, and concentrated to give 3-(4-{2-[3-(2,4-dimethoxy-phenyl)-1-heptyl-ureido]-ethyl}-phenyl)-2-ethoxy-propionic acid as a clear oil (229 mg, 95%).
Reaction SMILES: [NH2:1][C:2]1[C:11]([I:12])=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([Cl:13])[CH:3]=1.C([O-])([O-])=O.[Ca+2].I[Cl:20]>CO.C(Cl)Cl>[NH2:1][C:2]1[C:11]([I:12])=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([Cl:13])[CH:3]=1.[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:10]([Cl:20])[C:11]=1[I:12]
Reactant: ClI
Agent: COC(=O)c1cc(I)c(N)cc1Cl
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: CO
Solvent: ClCCl
Product: COC(=O)c1ccc(N)c(I)c1Cl
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Methyl 4-amino-2-chloro-5-iodo-benzoate, 70n. To a suspension of compound 70m (1.18 g, 6.38 mmol) and CaCO3 (12.8 mmol, 1.28 g) in MeOH (13 mL) was added a solution of iodine monochloride (6.70 mmol, 1.09 g) in CH2Cl2 (6 mL) dropwise at room temperature. The resulting reaction mixture was stirred at room temperature for 1.5 h. The reaction mixture was concentrated and then partitioned between EtOAc and water. The organic layer was concentrated and purified by flash column chromatography (silica gel, 20-25% EtOAc/hexanes) to provide methyl 4-amino-2-chloro-5-iodo-benzoate 70n as major the product and methyl 4-amino-2-chloro-3-iodo-benzoate 70o as the minor product.
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][NH2:10])=[CH:5][CH:4]=1.Cl[C:12]1[C:17]([N+:18]([O-:20])=[O:19])=[CH:16][CH:15]=[CH:14][N:13]=1.C(=O)([O-])[O-].[Na+].[Na+].[I-].[K+]>CN(C)C=O>[F:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][NH:10][C:12]2[C:17]([N+:18]([O-:20])=[O:19])=[CH:16][CH:15]=[CH:14][N:13]=2)=[CH:5][CH:4]=1
Reactant: NCc1ccc(F)cc1
Reactant: O=[N+]([O-])c1cccnc1Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cccnc1NCc1ccc(F)cc1
Temperature: 90 °C
Reaction time: 1 h
Yield: 71 %

Procedure:
A mixture of 9.7 parts of 4-fluorobenzenemethanamine hydrochloride, 9.4 parts of 2-chloro-3-nitropyridine, 10.6 parts of sodium carbonate, 0.1 parts of potassium iodide and 90 parts of N,N-dimethylformamide is stirred for 1 hour at 90° C. The reaction mixture is cooled and poured onto water. The precipitated product is filtered off and crystallized from 2-propanol, yielding 10.5 parts (71%) of N-(4-fluorophenylmethyl)-3-nitro-2-pyridinamine; mp. 76° C.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Br:10][C:11]1[CH:12]=[C:13]([C:18]2[CH:23]=[C:22]([O:24][CH3:25])[N:21]=[CH:20][C:19]=2[NH2:26])[C:14](F)=[N:15][CH:16]=1>C1COCC1.O>[CH3:25][O:24][C:22]1[N:21]=[CH:20][C:19]2[NH:26][C:14]3[N:15]=[CH:16][C:11]([Br:10])=[CH:12][C:13]=3[C:18]=2[CH:23]=1
Reactant: COc1cc(-c2cc(Br)cnc2F)c(N)cn1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Solvent: O
Solvent: C1CCOC1
Product: COc1cc2c(cn1)[nH]c1ncc(Br)cc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 47 %

Procedure:
A 1N solution of bis(trimethylsilyl)amide in THF (6.81 mL, 6.81 mmol) was added dropwise to a solution of 5-bromo-2-fluoro-6′-methoxy-[3,4′]bipyridinyl-3′-ylamine (203 mg, 0.681 mmol) in THF (12.0 mL). The reaction mixture was stirred for 30 minutes at ambient temperature, diluted with water, and extracted into ethyl acetate. The organic phase was dried over sodium sulfate, filtered, and concentrated in vacuo. The crude residue was dissolved in ethyl acetate and methanol, absorbed onto silica gel, and purified by flash chromatography (silica, 12 g column, ISCO, 0-100% ethyl acetate in hexanes) to provide the title compound as an orange-tan solid (89.0 mg, 47%). 1H NMR (DMSO-D6, 400 MHz): 12.44-12.12 (m, 1H), 7.79 (d, J=2.6 Hz, 1H), 7.66 (d, J=3.5 Hz, 2H), 6.56 (s, 1H), 3.75 (s, 3H). LCMS (Method B): RT=1.83 min, M+H+=278/280.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:4][CH2:3]1.Cl[C:16]1[C:21]([N+:22]([O-:24])=[O:23])=[CH:20][CH:19]=[CH:18][C:17]=1[CH3:25].O>CS(C)=O>[CH2:8]([N:5]1[CH2:6][CH2:7][CH:2]([NH:1][C:16]2[C:21]([N+:22]([O-:24])=[O:23])=[CH:20][CH:19]=[CH:18][C:17]=2[CH3:25])[CH2:3][CH2:4]1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: NC1CCN(Cc2ccccc2)CC1
Reactant: Cc1cccc([N+](=O)[O-])c1Cl
Solvent: CS(C)=O
Solvent: O
Product: Cc1cccc([N+](=O)[O-])c1NC1CCN(Cc2ccccc2)CC1
Temperature: 100 °C
Reaction time: 19 h
Yield: 16 %

Procedure:
4-Amino-1-benzylpiperidine (0.20 ml) was dissolved in dimethyl sulfoxide (0.2 ml), added with 2-chloro-3-nitrotoluene (0.13 ml) and stirred at 100° C. for 19 hours. The reaction mixture was added with water (2 ml) and extracted twice with ethyl acetate (2 ml). The organic layer was dried over anhydrous magnesium sulfate, and then the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: hexane:ethyl acetate=3:1) to obtain 51.1 mg of the title compound. Yield: 16%.
Reaction SMILES: [C:1]([OH:5])(=O)[CH:2]=O.[NH2:6][NH:7][C:8]([NH:10][NH2:11])=[S:9]>O>[NH2:6][N:7]1[C:1](=[O:5])[CH:2]=[N:11][NH:10][C:8]1=[S:9]
Reactant: NNC(=S)NN
Reactant: O=CC(=O)O
Solvent: O
Product: Nn1c(=O)cn[nH]c1=S

Procedure:
A solution of 22 parts glyoxylic acid in 22 parts water is slowly added to a hot, stirred solution of 32 parts thiocarbohydrazide in 350 parts water. The resulting mixture is refluxed until no further precipitate is formed. Upon cooling, essentially pure 4-amino-2,3-dihydro-3-thiono-as-triazin-5(4H)-one having a melting point of 211°-215° C. is obtained by filtration.
Reaction SMILES: C[O:2][C:3](=[O:23])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]#[C:19][CH2:20][OH:21])=[CH:14][CH:13]=2)=[CH:6][C:5]=1[OH:22].[Li+].[OH-]>C1COCC1.O>[OH:22][C:5]1[CH:6]=[C:7]([NH:10][CH2:11][C:12]2[CH:13]=[CH:14][C:15]([C:18]#[C:19][CH2:20][OH:21])=[CH:16][CH:17]=2)[CH:8]=[CH:9][C:4]=1[C:3]([OH:23])=[O:2]
Reactant: COC(=O)c1ccc(NCc2ccc(C#CCO)cc2)cc1O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1ccc(NCc2ccc(C#CCO)cc2)cc1O
Temperature: 90 °C
Yield: 17.3 %

Procedure:
2-Hydroxy-4-[4-(3-hydroxy-prop-1-ynyl)-benzylamino]-benzoic acid methyl ester (22 mg; 0.07 mmol) was dissolved in THF/H2O (1 mL/0.25 mL) and LiOH was added (17 mg; 0.7 mmol). The reaction mixture was heated to 90° C. for 1 hour. THF was removed by evaporation and EtOAc (3 mL) and H2O (0.5 mL) was added. The organic phase was isolated, dried (Na2SO4), filtered, evaporated to dryness and purified by flash column chromatography (SiO2-PE80-100° C./EtOAc/CH3COOH=1:1:1%) to yield 3.6 mg (17%) of pure product.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[F:12])[N:8]=[C:7]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:6]=[CH:5]2.[OH:18][C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(OCC)(=O)C.O.O1CCOCC1>[F:12][C:11]1[CH:10]=[C:9]2[C:4]([CH:5]=[CH:6][C:7]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[N:8]2)=[CH:3][C:2]=1[C:22]1[CH:23]=[CH:24][C:19]([OH:18])=[CH:20][CH:21]=1
Reactant: OB(O)c1ccc(O)cc1
Reactant: CCOC(=O)c1ccc2cc(Br)c(F)cc2n1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=P([O-])([O-])[O-]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: O
Product: CCOC(=O)c1ccc2cc(-c3ccc(O)cc3)c(F)cc2n1
Temperature: 60 °C
Yield: 61.1 %

Procedure:
Palladium(II)acetate (8.2 mg, 36.5 μmol) was added to ethyl 6-bromo-7-fluoro-2-quinolinecarboxylate (217.8 mg, 730.6 μmol), 4-hydroxy-phenyl-boronic acid (246.0 mg, 1.10 mmol), triphenylphosphine (19.2 mg, 73.1 μmol), and potassium phosphate (542.8 mg, 2.56 mmol). Then, dioxane (3.6 mL) was added to the mixture, followed by water (73 μL), and the reaction mixture was heated open to the atmosphere at 60° C. in an oil bath for 14 hours, then allowed to cool to room temperature. Water was added followed by ethyl acetate and the mixture was filtered through Celite®. The filtrate was extracted with ethyl acetate and the organic layer was dried over anhydrous magnesium sulfate, then filtered and concentrated. The residue was purified by silica gel chromatography eluting with 2:3 ethyl acetate:hexanes to give 138.9 mg (61%) of ethyl 7-fluoro-6-(4-hydroxyphenyl)-2-quinolinecarboxylate as a solid. 1H NMR (400 MHz, d6-DMSO): δ 9.82 (s, 1H), 8.61 (d, J=9 Hz, 1H), 8.23 (d, J=9 Hz, 1H), 8.11 (d, J=8 Hz, 1H), 8.01 (d, J=12 Hz, 1H), 7.53 (d, J=8 Hz, 2H), 6.92 (d, J=8 Hz, 2H), 4.42 (q, J=7 Hz, 2H), 1.38 (t, J=7 Hz, 3H). ESI-LCMS m/z 312 (M+H)+.
Reaction SMILES: CO.Cl.[C:4]([NH2:7])(=[NH:6])[CH3:5].[CH3:8][CH:9]([C:15](OCC)=[O:16])[C:10](OCC)=[O:11].O>C(O)(=O)C>[CH3:5][C:4]1[N:7]=[C:10]([OH:11])[C:9]([CH3:8])=[C:15]([OH:16])[N:6]=1
Reactant: CC(=N)N
Reactant: CCOC(=O)C(C)C(=O)OCC
Agent: Cl
Solvent: O
Solvent: CC(=O)O
Solvent: CO
Product: Cc1nc(O)c(C)c(O)n1
Temperature: 0 °C
Yield: 49 %

Procedure:
A single-necked flask containing 40 ml of methanol, placed under a nitrogen atmosphere, is cooled down to 0° C. with an ice bath, 9.72 g of sodium methylate (i.e. a solution of concentration c=3 mol.l−1) is added to the reaction mixture then 5 g (53 mmoles) of acetamidine hydrochloride is added at 0° C. and in small quantities. Stirring is maintained at ambient temperature for about twenty minutes, then 8.3 ml of diethyl methylmalonate is added dropwise. Stirring is maintained for 3 hours. Then the methanol is condensed under reduced pressure (2 kPa). The crude product obtained is taken up in a minimum amount of water, followed by cooling down to 0° C. then acidifying with pure acetic acid to a pH of between 4 and 5. The white precipitate formed is filtered and rinsed with water, ethyl ether and pentane. Then the white product is dried over P2O5 under reduced pressure (0.2 kPa). 3.3 g (Yield=49%) of expected product is obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([C:9]2[CH:10]=[C:11]([C:15](=[O:17])[CH3:16])[CH:12]=[CH:13][CH:14]=2)[CH:6]=[C:5]([NH:18][CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=2)[N:4]=1.CO[C:31](OC)([N:33]([CH3:35])[CH3:34])[CH3:32]>O>[CH3:34][N:33]([CH3:35])[C:31]([CH3:32])=[CH:16][C:15]([C:11]1[CH:12]=[CH:13][CH:14]=[C:9]([C:7]2[CH:6]=[C:5]([NH:18][CH2:19][CH2:20][C:21]3[CH:22]=[CH:23][C:24]([O:27][CH3:28])=[CH:25][CH:26]=3)[N:4]=[C:3]([O:2][CH3:1])[N:8]=2)[CH:10]=1)=[O:17]
Reactant: COC(C)(OC)N(C)C
Reactant: COc1ccc(CCNc2cc(-c3cccc(C(C)=O)c3)nc(OC)n2)cc1
Solvent: O
Product: COc1ccc(CCNc2cc(-c3cccc(C(=O)C=C(C)N(C)C)c3)nc(OC)n2)cc1
Temperature: 90 °C

Procedure:
A mixture of 1-(3-{2-methoxy-6-[2-(4-methoxy-phenyl)-ethylamino]-pyrimidin-4-yl}-phenyl)-ethanone [125 mg, 0.33 mmol, Example 35(h)] and dimethylacetamide dimethylacetal (2 mL) in a round bottom flask is heated to 90° C. for 4 hours. The reaction mixture is treated with water (20 mL) and extracted three times with EtOAc (20 mL). The combined organics are dried over magnesium sulfate, filtered and concentrated by rotary evaporator to provide 3-dimethylamino-1-(3-{2-methoxy-6-[2-(4-methoxy-phenyl)-ethylamino]-pyrimidin-4-yl}-phenyl)-but-2-en-1-one [Intermediate (47)] in quantitative yield.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:26][CH2:27][O:28][CH3:29])[N:14]([CH2:15][CH2:16][CH2:17][NH:18]C(=O)OC(C)(C)C)[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1.Cl>O1CCOCC1>[NH2:18][CH2:17][CH2:16][CH2:15][N:14]1[C:10]2[C:9]3[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=3[N:3]=[C:2]([NH2:1])[C:11]=2[N:12]=[C:13]1[CH2:26][CH2:27][O:28][CH3:29]
Reactant: COCCc1nc2c(N)nc3ccccc3c2n1CCCNC(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: COCCc1nc2c(N)nc3ccccc3c2n1CCCN
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Tert-Butyl 3-[4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]propylcarbamate (5 g, U.S. Pat. No. 6,573,273, example 148) and hydrochloric acid in dioxane (100 mL of 4 M) were combined and stirred for 4 hours at ambient temperature. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in methanol (30 mL). The pH was adjusted to pH 8 with 6 M sodium hydroxide. The solution was diluted with dichloromethane, ethyl acetate, triethylamine, and brine. The organic layer was concentrated under reduced pressure to provide an orange solid. This material was purified by prep HPLC (COMBIFLASH system eluting first with a gradient of 0 to 10% methanol in dichloromethane containing 1% ammonium hydroxide and then with a gradient of 9 to 30% methanol in dichloromethane containing 1% ammonium hydroxide) to provide 1.58 g of 1-(3-aminopropyl)-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-4-amine as a yellow solid.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].Cl[C:10]1[CH:27]=[C:14]2[C:15]3[C:20]([CH2:21][CH2:22][N:13]2[C:12](=[O:28])[N:11]=1)=[CH:19][C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=3>CC(O)C>[CH3:24][O:23][C:18]1[CH:19]=[C:20]2[C:15](=[CH:16][C:17]=1[O:25][CH3:26])[C:14]1=[CH:27][C:10](=[N:4][C:3]3[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=3[CH3:1])[NH:11][C:12](=[O:28])[N:13]1[CH2:22][CH2:21]2
Reactant: Cc1ccccc1N
Reactant: COc1cc2c(cc1OC)-c1cc(Cl)nc(=O)n1CC2
Solvent: CC(C)O
Product: COc1cc2c(cc1OC)-c1cc(=Nc3ccccc3C)[nH]c(=O)n1CC2
Temperature: 25 °C
Yield: 100.4 %

Procedure:
2-Methylaniline (5.44 ml, 51 mmol) and 2-chloro-9,10-dimethoxy-6,7-dihydro-4H-pyrimido[6,1-a]isoquinolin-4-one (5 g, 17 mmol) were suspended in propan-2-ol (400 ml) and heated at reflux, under nitrogen, for 24 h. After cooling to room temperature, the solution was concentrated in vacuo and the residue purified by flash column chromatography [dichloromethane/methanol (98:2-96:4)] to afford the title compound (6.2 g, quantitative yield) as a yellow/orange solid.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:11]3[C:16](=O)[CH2:15][C:14]([CH3:19])([CH3:18])[CH2:13][C:12]3=[O:20])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[NH2:21][C:22]1C=CC=C(F)[C:23]=1C(O)=O.C(O)(=O)C1C(=CC=CC=1)N>>[F:1][C:2]1[C:10]2[C:6]3[C:11]4[C:12](=[O:20])[CH2:13][C:14]([CH3:18])([CH3:19])[CH2:15][C:16]=4[N:21]=[C:22]([CH3:23])[C:7]=3[NH:8][C:9]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CC1(C)CC(=O)C(c2c[nH]c3cc(F)ccc23)C(=O)C1
Reactant: Nc1cccc(F)c1C(=O)O
Agent: Nc1ccccc1C(=O)O
Product: Cc1nc2c(c3c1[nH]c1cccc(F)c13)C(=O)CC(C)(C)C2

Procedure:
Utilizing the procedures described in Example 3 a-c except substituting 2-(4-fluoro-1H-indol-3-yl)-5,5-dimethylcyclohexane-1,3-dione for 2-(6-fluoro-1H-indol-3-yl)-5,5-dimethylcyclohexane-1,3-dione in step 3a, and 2-amino-6-fluorobenzoic acid for anthranilic acid in step 1a of Example 1, the title compound was prepared and crystallized from toluene; m.p. 246-247° C.
Reaction SMILES: [C:1]([NH:22][C@H:23]([C:36]([OH:38])=[O:37])[CH2:24][C:25]1[CH:30]=[CH:29][C:28]([O:31][P:32]([OH:35])([OH:34])=[O:33])=[CH:27][CH:26]=1)(=[O:21])[CH2:2][CH2:3][CH2:4]/[CH:5]=[CH:6]\[CH2:7][CH:8]=[CH:9][CH2:10][CH:11]=[CH:12][CH2:13][CH:14]=[CH:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].C(O)(=O)CCC/C=C\CC=CCC=CCC=CCC=CCC>>[C:1]([NH:22][C@H:23]([C:36]([OH:38])=[O:37])[CH2:24][C:25]1[CH:30]=[CH:29][C:28]([O:31][P:32]([OH:35])([OH:34])=[O:33])=[CH:27][CH:26]=1)(=[O:21])[CH2:2][CH2:3][CH2:4]/[CH:5]=[CH:6]\[CH2:7][CH:8]=[CH:9][CH2:10][CH:11]=[CH:12][CH2:13][CH:14]=[CH:15][CH2:16][CH:17]=[CH:18][CH2:19][CH3:20]
Reactant: CCCCCC=CCC=CCC=CC/C=C\CCCC(=O)N[C@@H](Cc1ccc(OP(=O)(O)O)cc1)C(=O)O
Agent: CCC=CCC=CCC=CCC=CC/C=C\CCCC(=O)O
Product: CCC=CCC=CCC=CCC=CC/C=C\CCCC(=O)N[C@@H](Cc1ccc(OP(=O)(O)O)cc1)C(=O)O

Procedure:
This compound was prepared as described above for (8), using 0.5 mmol (151 mg) of cis-5,8,11,14,17-eicosapentaenoic acid; yield 65 mg, (24%); Rf 0.05-0.10 (system B); 1H-NMR (CD3SOCD3, 200 MHz) δ0.9-1.0 (t, 3H, ω-CH3); 1.5-1.6 (t, 2H, CH2); 2.0-2.2 (m, 6H, CH2CO and 2CH2CH═CH); 2.7-3.0 (m, 10H, 4HC═CH—CH2—CH═CH and CH2Ar); 4.3-4.4 (m, 1H, NHCHCO); 5.2-5.4 (br s, 10H, 5HC═CH); 7.1 (s, 4H, Ar); 8.2-8.4 (m, 3H, NH and 2POH)
Reaction SMILES: CCN(S(F)(F)[F:7])CC.[Br:10][C:11]([Br:26])([F:25])[CH:12]([C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([N+:22]([O-:24])=[O:23])[CH:15]=1)O.CCOC(C)=O>C(Cl)Cl>[Br:10][C:11]([Br:26])([F:25])[CH:12]([F:7])[C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([N+:22]([O-:24])=[O:23])[CH:15]=1
Reactant: CCN(CC)S(F)(F)F
Reactant: COc1ccc(C(O)C(F)(Br)Br)cc1[N+](=O)[O-]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COc1ccc(C(F)C(F)(Br)Br)cc1[N+](=O)[O-]
Temperature: 0 °C

Procedure:
(DAST 730 μL (5.58 mmol; 1.8 eq) in 5 mL CH2Cl2 was added to a solution of 1.146 g (3.1 mmol) of the alcohol (7) in 7 mL CH2Cl2 at −78° C. The reaction mixture was allowed to warm up to 0° C. over a period of 2 h, quenched with 15 mL of NaHCO3 saturated solution and diluted with 20 mL of diethyl ether. The organic phase was dried over anhydrous sodium sulfate and purified by chromatography on SiO2 using Hexane/Ethyl Acetate 7:3 to give 960 mg (2.6 mmol; 84%) of a yellow oil. Rf=0.493 (Hex./AcOEt 7:3)