Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:12]=[C:11]([NH:13][CH2:14][CH2:15][CH3:16])[C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][N:3]=1.[F:17][C:18]1[CH:19]=[C:20]([CH:22]=[CH:23][CH:24]=1)[NH2:21].C(=O)([O-])[O-].[Cs+].[Cs+].C(=O)([O-])O.[Na+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C(OCC)(=O)C>[F:17][C:18]1[CH:19]=[C:20]([NH:21][C:2]2[CH:12]=[C:11]([NH:13][CH2:14][CH2:15][CH3:16])[C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][N:3]=2)[CH:22]=[CH:23][CH:24]=1
Reactant: CCCNc1cc(Cl)ncc1C(=O)OCC
Reactant: Nc1cccc(F)c1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CCCNc1cc(Nc2cccc(F)c2)ncc1C(=O)OCC
Temperature: 85 °C
Reaction time: 5 h
Yield: 90 %

Procedure:
To a solution of tris(dibenzylideneacetone)dipalladium(0) (80 mg) and 4,5′-bis(diphenylphosphino)-9,9′-dimethylxanthene (100 mg) in 1,4-dioxane (5 mL), ethyl 6-chloro-4-(propylamino)nicotinate (S14, 210 mg), 3-fluoroaniline (193 mg) and cesium carbonate (565 mg) were added at room temperature, and the mixture was stirred at 80 to 90° C. for 5 hours. The reaction mixture was cooled to room temperature, and then saturated aqueous sodium hydrogencarbonate and ethyl acetate were added to the reaction mixture. The insoluble matter was removed by filtration through Florisil. The organic layer was separated, washed with saturated aqueous sodium chloride, and then dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent, 90 to 60% hexane in ethyl acetate) to obtain ethyl 6-((3-fluorophenyl)amino)-4-(propylamino)nicotinate (S15, 247 mg).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]O.[S:18](Cl)([C:21]1[CH:27]=[CH:26][C:24]([CH3:25])=[CH:23][CH:22]=1)(=[O:20])=[O:19].N1C=CC=CC=1>O>[CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][S:18]([C:21]1[CH:27]=[CH:26][C:24]([CH3:25])=[CH:23][CH:22]=1)(=[O:20])=[O:19]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COCCOCCOCCCCCCCCO
Solvent: c1ccncc1
Solvent: O
Product: COCCOCCOCCCCCCCCS(=O)(=O)c1ccc(C)cc1

Procedure:
A mixture of 40 g of 8-[2-(2-methoxyethoxy)ethoxy]-1-octanol, 35.31 g of tosyl chloride and 200 ml of pyridine was stored in a chill room overnight, then poured into water and extracted with ether. The ether extract was washed successively with water, dilute hydrochloric acid and saturated aqueous sodium bisulfite, dried and the solvent removed, giving the desired compound as an oil which was used without further purification in Example 8.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]2[CH:10]=[C:11]([C:20]([NH:22][C@H:23]3[CH2:28][CH2:27][CH2:26][CH2:25][C@@H:24]3[OH:29])=[O:21])[C:12](=[O:19])[N:13]3[C:18]=2[CH:17]=[CH:16][CH:15]=[CH:14]3)=[N:6][CH:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:36][N:37]1[CH:41]=[C:40](B2OC(C)(C)C(C)(C)O2)[CH:39]=[N:38]1>C1COCC1.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[OH:29][C@H:24]1[CH2:25][CH2:26][CH2:27][CH2:28][C@@H:23]1[NH:22][C:20]([C:11]1[C:12](=[O:19])[N:13]2[C:18]([CH:17]=[CH:16][CH:15]=[CH:14]2)=[C:9]([CH2:8][C:5]2[CH:4]=[CH:3][C:2]([C:40]3[CH:39]=[N:38][N:37]([CH3:36])[CH:41]=3)=[CH:7][N:6]=2)[CH:10]=1)=[O:21]
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: O=C(N[C@H]1CCCC[C@@H]1O)c1cc(Cc2ccc(Br)cn2)c2ccccn2c1=O
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Product: Cn1cc(-c2ccc(Cc3cc(C(=O)N[C@H]4CCCC[C@@H]4O)c(=O)n4ccccc34)nc2)cn1
Temperature: 100 °C

Procedure:
To a solution of 1-[(5-bromopyridin-2-yl)methyl]-N-[(1S,2S)-2-hydroxycyclohexyl]-4-oxo-4H-quinolizine-3-carboxamide (Example 2, 0.045 g, 0.099 mmol) in 2 mL of THF under an atmosphere of nitrogen was added aqueous cesium carbonate (1 N, 0.20 mL, 0.20 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.062 g, 0.30 mmol), and bis(tri-tert-butylphosphine)palladium(0) (5.0 mg, 0.010 mmol). The reaction was heated at 100° C. for 15 h, cooled to rt, and concentrated in vacuo. The resultant residue was subjected to purification via reverse phase HPLC to provide the title compound that gave a proton NMR spectra consistent with theory and a high resolution mass spectrum (ES+) m/z of 472.2330 calculated for M+H+ [C27H30N5O3: 472.2343]: 1H NMR (400 MHz, CD3OD) δ 9.50 (d, J=7.0 Hz, 1H), 8.83 (s, 1H), 8.53-8.50 (m, 1H), 8.35-8.30 (m, 1H), 8.16 (s, 1H), 8.06-7.97 (m, 2H), 7.88 (d, J=8.0 Hz, 1H), 7.56 (d, J=8.2 Hz, 1H), 7.52-7.48 (m, 1H), 4.62 (s, 2H), 3.95 (s, 3H), 3.86-3.81 (m, 1H), 3.55-3.48 (m, 1H), 3.21-3.12 (m, 1H), 2.13-2.10 (m, 1H), 2.03-1.87 (m, 1H), 1.79-1.73 (m, 2H), 1.40-1.24 (m, 3H).
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[CH:6][C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=1.[Cl:13][C:14]1[CH:15]=[C:16]([CH:22]=[CH:23][C:24]=1[S:25](=[O:39])(=[O:38])[NH:26][CH2:27][C:28]1[CH:29]=[C:30]2[CH:36]=[CH:35][N:34]([CH3:37])[C:31]2=[N:32][CH:33]=1)[C:17]([O:19][CH2:20][CH3:21])=[O:18]>>[Cl:13][C:14]1[CH:15]=[C:16]([CH:22]=[CH:23][C:24]=1[S:25](=[O:38])(=[O:39])[N:26]([C:2]1[C:7]([Cl:8])=[CH:6][C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=1)[CH2:27][C:28]1[CH:29]=[C:30]2[CH:36]=[CH:35][N:34]([CH3:37])[C:31]2=[N:32][CH:33]=1)[C:17]([O:19][CH2:20][CH3:21])=[O:18]
Reactant: CCOC(=O)c1ccc(S(=O)(=O)NCc2cnc3c(ccn3C)c2)c(Cl)c1
Reactant: FC(F)(F)c1cnc(Cl)c(Cl)c1
Product: CCOC(=O)c1ccc(S(=O)(=O)N(Cc2cnc3c(ccn3C)c2)c2ncc(C(F)(F)F)cc2Cl)c(Cl)c1

Procedure:
The titled compound was prepared according to the procedure described in step-2 of Example 1 from 2,3-dichloro-5-(trifluoromethyl)pyridine and ethyl 3-chloro-4-(N-((1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)methyl)sulfamoyl)benzoate (step-2 of Example 35).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:12][N:11]=[CH:10][C:9]=1[C:13]([OH:15])=O.C(O)(=O)C(O)=O.[F:22][C:23]1[CH:28]=[CH:27][C:26]([CH:29]2[CH2:33][CH2:32][NH:31][CH2:30]2)=[CH:25][CH:24]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:12][N:11]=[CH:10][C:9]=1[C:13]([N:31]1[CH2:32][CH2:33][CH:29]([C:26]2[CH:27]=[CH:28][C:23]([F:22])=[CH:24][CH:25]=2)[CH2:30]1)=[O:15]
Reactant: Fc1ccc(C2CCNC2)cc1
Reactant: O=C(O)c1cnoc1-c1ccccc1Cl
Agent: O=C(O)C(=O)O
Product: O=C(c1cnoc1-c1ccccc1Cl)N1CCC(c2ccc(F)cc2)C1

Procedure:
The title compound was prepared from 5-(2-chlorophenyl)isoxazole-4-carboxylic acid (11.2 mg, 0.050 mmol) and 3-(4-fluorophenyl)pyrrolidine oxalate (15.3 mg, 0.060 mmol) as described in synthetic method C and thereafter purified by preparative HPLC method B to give a solid (5.2 mg). Calcd for C20H16ClFN2O2: 370.0884, found 370.0890.
Reaction SMILES: [C:1]([O:10]C)(=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[SH:4].[C:12]([C:14]1[CH:15]=[CH:16][C:17]([O:20][CH2:21][CH2:22][O:23][CH2:24][CH3:25])=[N:18][CH:19]=1)#[N:13].C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH2:24]([O:23][CH2:22][CH2:21][O:20][C:17]1[N:18]=[CH:19][C:14]([C:12]2[S:4][C:3]3[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=3[C:1](=[O:10])[N:13]=2)=[CH:15][CH:16]=1)[CH3:25]
Reactant: COC(=O)c1ccccc1S
Reactant: CCOCCOc1ccc(C#N)cn1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCOCCOc1ccc(-c2nc(=O)c3ccccc3s2)cn1
Yield: 57.3 %

Procedure:
A mixture of methyl thiosalicylate (2.96 g, 17.6 mmol), 5-cyano-2-(2-ethoxy)ethoxypyridine (3.07 g, 16.0 mmol), triethylamine (2.37 ml, 17.0 mmol) and toluene (15 ml) was refluxed under nitrogen atmosphere for 40 hrs. The reaction mixture was concentrated. The residue was subjected to a silica gel column chromatography, eluted with ethyl acetate-hexane (1:1, v/v) and recrystallized from acetone-ethyl acetate-isopropylether to give the titled compound (3.01 g, 57%).
Reaction SMILES: C(N(CC)CC)C.Cl[C:9]1[S:10][C:11](Cl)=[CH:12][C:13]=1[S:14]([N:17]1[CH2:22][C@H:21]2[CH2:23][CH2:24][C@@H:18]1[C@H:19]([C:25]([NH:27][C:28]1[CH:33]=[CH:32][C:31]([O:34][CH:35]([CH3:37])[CH3:36])=[CH:30][CH:29]=1)=[O:26])[CH2:20]2)(=[O:16])=[O:15].[H][H]>[OH-].[Pd+2].[OH-].[C].CO>[CH:35]([O:34][C:31]1[CH:32]=[CH:33][C:28]([NH:27][C:25]([C@H:19]2[C@H:18]3[CH2:24][CH2:23][C@H:21]([CH2:22][N:17]3[S:14]([C:13]3[CH:12]=[CH:11][S:10][CH:9]=3)(=[O:15])=[O:16])[CH2:20]2)=[O:26])=[CH:29][CH:30]=1)([CH3:37])[CH3:36]
Reactant: [H][H]
Reactant: CC(C)Oc1ccc(NC(=O)[C@@H]2C[C@@H]3CC[C@H]2N(S(=O)(=O)c2cc(Cl)sc2Cl)C3)cc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: CO
Product: CC(C)Oc1ccc(NC(=O)[C@@H]2C[C@@H]3CC[C@H]2N(S(=O)(=O)c2ccsc2)C3)cc1

Procedure:
Triethylamine (0.065 mL, 0.42 mmol) and 20% palladium hydroxide-carbon catalyst (8 mg) were added to a methanol (2 mL) solution of the compound (35 mg, 0.0695 mmol) synthesized in Example 25, and the mixture was stirred for 5 hours in a hydrogen (4 atm) atmosphere. The reaction mixture was then celite filtered, and the filtrate was concentrated. The resulting residue was then purified using silica gel column chromatography to obtain the target (9.9 mg, 33%).
Reaction SMILES: C(=O)CC.C(=O)CCC.[CH2:10]([CH:12]([CH2:15][CH2:16][CH2:17][CH3:18])[CH2:13][OH:14])[CH3:11]>>[CH2:10]([C:12](=[CH:15][CH2:16][CH2:17][CH3:18])[CH:13]=[O:14])[CH3:11]
Reactant: CCCCC(CC)CO
Solvent: CCC=O
Solvent: CCCC=O
Product: CCCC=C(C=O)CC

Procedure:
The aldol condensation of propanal or butanal is an important step in the production of oxo alcohols such as 2-ethyl hexanol. For example, as described in GB 1462328, butanal is typically condensed using an aqueous caustic catalyst at a temperature of the order of 80 to 140° C. to give 2-ethyl hexenal which is then hydrogenated to 2-ethyl hexanol.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([CH2:20][CH2:21][C:22]([O:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][NH:31][C:32]([NH:34][S:35]([C:38]1[CH:44]=[CH:43][C:41]([CH3:42])=[CH:40][CH:39]=1)(=[O:37])=[O:36])=[NH:33])=[O:23])[C:10]([O:12]CC1C=CC=CC=1)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].C>CO.[Pd]>[NH:33]=[C:32]([NH:34][S:35]([C:38]1[CH:39]=[CH:40][C:41]([CH3:42])=[CH:43][CH:44]=1)(=[O:36])=[O:37])[NH:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][O:24][C:22](=[O:23])[CH2:21][CH2:20][CH:9]([C:10]([OH:12])=[O:11])[NH:8][C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc(S(=O)(=O)NC(=N)NCCCCCCOC(=O)CCC(NC(=O)OC(C)(C)C)C(=O)OCc2ccccc2)cc1
Agent: [Pd]
Solvent: CO
Product: Cc1ccc(S(=O)(=O)NC(=N)NCCCCCCOC(=O)CCC(NC(=O)OC(C)(C)C)C(=O)O)cc1
Yield: 85.7 %

Procedure:
103.6 mg (0.16 mmol) of 1-benzyl 5-(6-(3-tosylguanidino)hexyl) 2-(tert-butoxycarbonylamino)pentanedioate under nitrogen in MeOH. A few mg of 10% Palladium over activated charcoal were added. 3 vacuo hydrogen flush were done before stirring vigorously the reaction under a H2 atmosphere for 2 days. The reaction was filtered over celite and the solvent evaporated to give 74.4 mg of a colorless oil (yield=86%).
Reaction SMILES: [BH4-].[Na+].[CH3:3][O:4][C:5]([C:7]1([C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[O:16][CH2:15][CH2:14][C:13]3=O)[CH2:9][CH2:8]1)=[O:6]>FC(F)(F)C(O)=O>[CH3:3][O:4][C:5]([C:7]1([C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[O:16][CH2:15][CH2:14][CH2:13]3)[CH2:8][CH2:9]1)=[O:6]
Reactant: COC(=O)C1(c2ccc3c(c2)C(=O)CCO3)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)C1(c2ccc3c(c2)CCCO3)CC1
Yield: 92.7 %

Procedure:
To trifluoroacetic acid (20 mL) was added NaBH4 (0.70 g, 130 mmol) in portions at 0° C. under N2 atmosphere. After stirring for 5 mm, a solution of 1-(4-oxo-chroman-6-yl)-cyclopropanecarboxylic methyl ester (1.6 g, 6.5 mmol) was added at 15° C. The reaction mixture was stirred for 1 h at room temperature before being slowly quenched with water. The resulting mixture was extracted with EtOAc (50 mL×3). The combined organic extracts dried over anhydrous Na2SO4 and evaporated under vacuum to give 1-chroman-6-yl-cyclopropanecarboxylic methyl ester (1.4 g, 92%), which was used directly in the next step. 1H NMR (300 MHz, CDCl3) δ 7.07-7.00 (m, 2H), 6.73 (d, J=8.4 Hz, 1H), 4.17 (t, J=5.1 Hz, 2H), 3.62 (s, 3H), 2.79-2.75 (m, 2H), 2.05-1.96 (m, 2H), 1.57-1.54 (m, 2H), 1.16-1.13 (m, 2H).
Reaction SMILES: [OH:1][C:2]([CH3:35])([CH3:34])[CH2:3][C@@:4]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16](B3OC(C)(C)C(C)(C)O3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1.Br[C:37]1[CH:38]=[N:39][C:40]([N:43]2[CH:47]=[CH:46][N:45]=[CH:44]2)=[N:41][CH:42]=1.C([O-])([O-])=O.[Cs+].[Cs+].O>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O1CCOCC1>[N:43]1([C:40]2[N:39]=[CH:38][C:37]([C:16]3[CH:15]=[CH:14][C:13]([C@@H:11]([N:7]4[CH2:6][CH2:5][C@:4]([CH2:3][C:2]([OH:1])([CH3:34])[CH3:35])([C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=5)[O:9][C:8]4=[O:10])[CH3:12])=[CH:18][CH:17]=3)=[CH:42][N:41]=2)[CH:47]=[CH:46][N:45]=[CH:44]1
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Reactant: Brc1cnc(-n2ccnc2)nc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: C[C@@H](c1ccc(-c2cnc(-n3ccnc3)nc2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Temperature: 110 °C
Yield: 57.9 %

Procedure:
A microwave vial equipped with a flea stir bar was charged with (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-ethyl)-1,3-oxazinan-2-one (20 mg, 0.042 mmol), 5-bromo-2-(1H-imidazol-1-yl)pyrimidine (19 mg, 0.083 mmol), Cs2CO3 (27 mg, 0.083 mmol), water (0.1 mL) and dioxane (1 mL). The mixture was sparge with N2 for 10 min and PdCl2(dppf) (2 mg, 0.003 mmol) was added. The mixture was sparged with N2 for 10 min and heated at 110° C. for 10 min in the microwave. The mixture was diluted with MeOH (1 mL), filtered and the filtrate was purified directly by prep HPLC to afford the title compound (12.1 mg, 58%) as an oil. LC-MS Method 1 tR=1.27 min, m/z=498; 1H NMR (CD3OD) 0.96 (s, 3H), 1.27 (s, 3H), 1.58 (d, 3H), 2.17 (s, 2H), 2.26 (m, 1H), 2.50 (2H), 3.12 (m, 1H), 5.60 (q, 1H), 7.18 (d, 2H), 7.25-7.40 (5H), 7.58 (d, 2H), 7.77 (s, 1H), 8.47 (s, 1H), 9.12 (s, 2H), 9.88 (s, 1H)
Reaction SMILES: [F:1][C:2]1[N:3]([C:15]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:4]=[C:5]([CH2:7][CH2:8][CH2:9][O:10]S(C)(=O)=O)[N:6]=1.[Na].[CH3:35]O>>[F:1][C:2]1[N:3]([C:15]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:4]=[C:5]([CH2:7][CH2:8][CH2:9][O:10][CH3:35])[N:6]=1
Reactant: CO
Reactant: CS(=O)(=O)OCCCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c(F)n1
Agent: [Na]
Product: COCCCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c(F)n1

Procedure:
A solution of 2-fluoro-4-(3-methanesulphonyloxypropyl)-1-triphenylmethylimidazole in MeOH was treated with sodium metal and stirred at 65°. Work-up as for the starting material of Example 9 gave 2-fluoro-4-(3-methoxypropyl)-1-triphenylmethylimidazole, having the following n.m.r. in CDCl3 : 1.87 (m, 2H); 2.45 (t, 2H); 3.26 (s, 3H); 3.33 (t, 2H); 6.21 (s, 1H); 7.0-7.5 (m, 15H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[O:9][CH3:10].[Br:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18](Cl)=[O:19].[Cl-].[Al+3].[Cl-].[Cl-]>C(Cl)Cl>[Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([C:18](=[O:19])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][Br:11])[CH:5]=[CH:4][C:3]=1[O:9][CH3:10]
Reactant: COc1cccc(Cl)c1Cl
Reactant: O=C(Cl)CCCCCCBr
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COc1ccc(C(=O)CCCCCCBr)c(Cl)c1Cl

Procedure:
The title compound is prepared following substantially the same procedure described in Example 13, Step A, using the following substances: 2,3-dichloroanisole (89 g., 0.5 mole), 7-bromoheptanoyl chloride (127 g., 0.56 mole), aluminum chloride (74 g., 0.56 mole) and methylene chloride (500 ml.). This procedure affords 107 g. (58%) of 2,3-dichloro-4-(7-bromoheptanoyl)anisole which after recrystallization from cyclohexane melts at 57° C.
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[CH:12][C:5]([O:6][C@@H:7]([CH3:11])[C:8]([OH:10])=[O:9])=[C:4]([OH:14])[CH:3]=1.F[C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+].O>C(OCC)C>[Cl:1][C:2]1[CH:13]=[CH:12][C:5]([O:6][C@@H:7]([CH3:11])[C:8]([OH:10])=[O:9])=[C:4]([O:14][C:16]2[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=2)[CH:3]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: C[C@H](Oc1ccc(Cl)cc1O)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOCC
Product: C[C@H](Oc1ccc(Cl)cc1Oc1ccc([N+](=O)[O-])cc1)C(=O)O
Temperature: 90 °C

Procedure:
To a solution of (2S)-2-(4-chloro-2-hydroxyphenoxy)-propanoic acid (0.216 g) and 1-fluoro-4-nitro-benzene (0.127 g) in NUT (3 ml) was added potassium carbonate (0.276 g) and the reaction heated at 90° C. for 2 h. After cooling to RT, water and diethylether were added. The aqueous layer was separated and extracted again with diethylether. The aqueous layer was isolated, acidified to pH 2 and extracted with diethylether. This later extract was dried and evaporated under reduced pressure. The residue was purified by chromatography on silica eluting with 30-50% ethylactate/isohexane+1% AcOH, yield 0.2 g
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:24][O:25][CH2:26][CH3:27])[N:14]([CH2:15][C:16]([NH:19][S:20]([CH3:23])(=[O:22])=[O:21])([CH3:18])[CH3:17])[C:10]=2[C:9]2[CH:8]=[CH:7][C:6]([O:28][CH2:29][C:30]#[CH:31])=[CH:5][C:4]=2[N:3]=1.I[C:33]1[S:34][CH:35]=[CH:36][CH:37]=1.C(N(CC)CC)C.CN(C=O)C>ClCCl.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.[Cu]I.CO.O>[NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:24][O:25][CH2:26][CH3:27])[N:14]([CH2:15][C:16]([NH:19][S:20]([CH3:23])(=[O:22])=[O:21])([CH3:17])[CH3:18])[C:10]=2[C:9]2[CH:8]=[CH:7][C:6]([O:28][CH2:29][C:30]#[C:31][C:33]3[S:34][CH:35]=[CH:36][CH:37]=3)=[CH:5][C:4]=2[N:3]=1
Reactant: Ic1cccs1
Reactant: C#CCOc1ccc2c(c1)nc(N)c1nc(COCC)n(CC(C)(C)NS(C)(=O)=O)c12
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOCc1nc2c(N)nc3cc(OCC#Cc4cccs4)ccc3c2n1CC(C)(C)NS(C)(=O)=O
Temperature: 60 °C
Reaction time: 1 h
Yield: 127.3 %

Procedure:
N-{2-[4-Amino-2-(ethoxymethyl)-7-(prop-2-ynyloxy)-1H-imidazo[4,5-c]quinolin-1-yl]-1,1-dimethylethyl}methanesulfonamide (600 mg, 1.34 mmol), 2-iodothiophene (565 mg, 2.69 mmol), triethylamine (0.50 mL, 3.5 mmol), dichlorobis(triphenylphosphine)palladium(II) (19 mg, 0.03 mmol), copper(I) iodide (10 mg, 0.05 mmol), and DMF (10 mL) were combined and heated at 60° C. overnight. After cooling to ambient temperature, the reaction was poured into water (200 mL) and a fine precipitate formed. After the mixture was stirred for 1 hour, the solid was isolated by filtration. The solid was dissolved in dichloromethane and methanol and was passed through a plug of silica gel, which was rinsed with 20% methanol in dichloromethane. The filtrate was concentrated under reduced pressure to yield approximately 900 mg of N-(2-{4-amino-2-(ethoxymethyl)-7-[(3-thien-2-ylprop-2-ynyl)oxy]-1H-imidazo[4,5-c]quinolin-1-yl}-1,1-dimethylethyl)methanesulfonamide as a dark brown semi-solid that was used without further purification in the next step.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][C:5]2=[N:6][O:7][N:8]=[C:4]2[CH:3]=1.[Cl-].[Li+].[CH2:13]([Sn](CCCC)(CCCC)CCCC)[CH:14]=[CH2:15].C1(C)C=CC=CC=1>CCOC(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>[CH2:15]([C:2]1[CH:10]=[CH:9][C:5]2=[N:6][O:7][N:8]=[C:4]2[CH:3]=1)[CH:14]=[CH2:13]
Reactant: Brc1ccc2nonc2c1
Reactant: C=CC[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: C=CCc1ccc2nonc2c1
Temperature: 110 °C

Procedure:
To a 250 mL flask charged with 5-Bromo-2,1,3-benzoxadiazole (5.0 g, 25 mmol), Palladium Tetrakis (0.87 g, 0.75 mmol), and lithium chloride (2.1 g, 50 mmol) was added Allyl Tri-n-butyltin (10 g, 30 mmol) and toluene (100 mL). The mixture was attached to a reflux condenser, sealed and purged with nitrogen. The reaction was heated to 110° C. for 2 hours. TLC showed good and complete reaction. The reaction was diluted with EtOAc, washed with brine, concentrated and purified by silica gel chromatography.
Reaction SMILES: [C:1]([OH:6])(=[O:5])[CH2:2][CH2:3][CH3:4].C1CCC(N=C=NC2CCCCC2)CC1.CS(O[C:27]1[CH:36]=[CH:35][C:34]2[C:29](=[CH:30][CH:31]=[C:32]([C:37](=[NH:39])[NH2:38])[CH:33]=2)[CH:28]=1)(=O)=O>N1C=CC=CC=1>[C:1]([O:6][C:27]1[CH:36]=[CH:35][C:34]2[C:29](=[CH:30][CH:31]=[C:32]([C:37](=[NH:38])[NH2:39])[CH:33]=2)[CH:28]=1)(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: CS(=O)(=O)Oc1ccc2cc(C(=N)N)ccc2c1
Reactant: CCCC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: c1ccncc1
Product: CCCC(=O)Oc1ccc2cc(C(=N)N)ccc2c1
Reaction time: 0.5 h
Yield: 38.7 %

Procedure:
To a solution of 1.6 g of n-butyric acid in 50 ml of anhydrous pyridine, while being cooled in ice, was added 4.4 g of DCC. After stirring for 30 minutes, 5.0 g of 6-amidino-2-naphthol methane-sulfonate was added to the mixture and further stirred overnight at room temperature. The precipitate was collected by filtration, washed successively with a small volume of pyridine, ethyl ether, and acetone, and dissolved in methanol at room temperature. The insolubles were collected by filtration and washed with a small volume of methanol. The filtrate and the washings were concentrated under reduced pressure and admixed with ethyl ether. The precipitated crystals were recrystallized from ethanol to obtain 1.8 g of colorless flaky crystals of 6-amidino-2-naphthyl butyrate methanesulfonate.
Reaction SMILES: C([O:4][CH2:5][CH2:6][NH:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[N:14]=[CH:13][C:12]([C:18]([O:20]CC)=O)=[C:11]2[OH:23])(=O)C.[Cl:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29][NH2:30])=[CH:27][CH:26]=1>>[Cl:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29][NH:30][C:18]([C:12]2[CH:13]=[N:14][C:15]3[C:10]([C:11]=2[OH:23])=[CH:9][C:8]([NH:7][CH2:6][CH2:5][OH:4])=[CH:17][CH:16]=3)=[O:20])=[CH:27][CH:26]=1
Reactant: NCc1ccc(Cl)cc1
Reactant: CCOC(=O)c1cnc2ccc(NCCOC(C)=O)cc2c1O
Product: O=C(NCc1ccc(Cl)cc1)c1cnc2ccc(NCCO)cc2c1O
Temperature: 160 °C

Procedure:
To a flask containing ethyl 6-{[2-(acetyloxy)ethyl]amino)-4-hydroxy-3-quinolinecarboxylate (0.04 g) is added p-chlorobenzylamine (0.5 mL). The reaction is tightly capped and heated to 160° C. overnight. The reaction is cooled to room temperature, adsorbed onto silica and chromatographed on silica eluting with 3% to 10% methanol in dichloromethane. The product-containing fractions are evaporated to give 0.02 g of the title compound as a yellow solid.
Reaction SMILES: N#N.[CH3:3][O:4][CH2:5][C:6]1[O:7][CH:8]=[C:9]([C:11](OC)=[O:12])[N:10]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3].O>C1COCC1>[CH3:3][O:4][CH2:5][C:6]1[O:7][CH:8]=[C:9]([CH2:11][OH:12])[N:10]=1
Reactant: COCc1nc(C(=O)OC)co1
Agent: N#N
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Product: COCc1nc(CO)co1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of methyl 2-(methoxymethyl)oxazole-4-carboxylate (192 mg, 1.12 mmol) in THF (11 mL) was treated dropwise at 0° C. with LiAlH4 (1.35 mL of a 1.0 M solution in THF, 1.35 mmol) and the resulting solution was stirred for 20 min at 0° C. The reaction mixture was carefully treated with water (1.0 mL) 1N NaOH (1.0 mL) followed by water (1.0 mL) and the mixture was stirred for 1 h at rt. The resulting suspension was filtered, extracted with EA and the combined org. layers were dried over MgSO4, filtered and the solvent was removed under reduced pressure to give the title compound as a brown oil. LC-MS-conditions 07: tR=0.33 min; [M+H]+=144.08.