Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:21])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH2:12][C@@H:13]2[CH2:17][O:16][C:15]([CH3:19])([CH3:18])[O:14]2)[C:6]=1[CH3:20].[OH-].[Li+]>CO>[CH3:18][C:15]1([CH3:19])[O:14][C@H:13]([CH2:12][O:11][C:7]2[C:6]([CH3:20])=[C:5]([CH2:4][C:3]([OH:21])=[O:2])[CH:10]=[CH:9][CH:8]=2)[CH2:17][O:16]1
Reactant: COC(=O)Cc1cccc(OC[C@@H]2COC(C)(C)O2)c1C
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: Cc1c(CC(=O)O)cccc1OC[C@@H]1COC(C)(C)O1

Procedure:
To a solution of 2-diazo-1-[3-(2,2-dimethyl-[1,3]-dioxolan-4-ylmethoxy)-2-methylphenyl]ethanone (0.5 g, 1.73 mmol) in 20 mL of methanol at room temperature was added dropwise a solution of silver benzoate (52 mg, 13%) in 2.6 mL of triethylamine. The solution turned greenish and then brown, black precipitate formed. After stirring for 1.5 h, it was filtered through celite and the filtrate was concentrated. The residue was then purified on a silica gel column with 20% ethyl acetate in hexane to afford 0.43 g of [3-((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-2-methylphenyl] acetic acid methyl ester. The above ester was then hydrolyzed by stirring with lithium hydroxide (0.25 g) in 5 mL of methanol at room temperature to give 0.4 g of [3-((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-2-methylphenyl] acetic acid.
Reaction SMILES: [CH2:1]([NH:7][C:8]1[S:9][CH:10]=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:12]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[H-].[Na+].Cl[CH2:22][C:23]1[CH:42]=[CH:41][C:26]([CH2:27][O:28][C:29]2[CH:34]=[CH:33][C:32]([CH2:35][CH2:36][C:37]([O:39][CH3:40])=[O:38])=[CH:31][CH:30]=2)=[CH:25][CH:24]=1.Cl>CN(C)C=O>[CH2:1]([N:7]([CH2:22][C:23]1[CH:42]=[CH:41][C:26]([CH2:27][O:28][C:29]2[CH:34]=[CH:33][C:32]([CH2:35][CH2:36][C:37]([O:39][CH3:40])=[O:38])=[CH:31][CH:30]=2)=[CH:25][CH:24]=1)[C:8]1[S:9][CH:10]=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:12]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCNc1nc(-c2ccccc2)cs1
Reactant: COC(=O)CCc1ccc(OCc2ccc(CCl)cc2)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCCCN(Cc1ccc(COc2ccc(CCC(=O)OC)cc2)cc1)c1nc(-c2ccccc2)cs1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 48 %

Procedure:
To a solution of N-hexyl-4-phenyl-1,3-thiazol-2-amine (390 mg) in N,N-dimethylformamide (1.0 mL) was added sodium hydride (60%, oil, 50 mg) at room temperature and the mixture was stirred at room temperature for 30 min. Methyl 3-(4-{[4-(chloromethyl)benzyl]oxy}phenyl)propanoate (318 mg) was added to the reaction mixture and the mixture was stirred at room temperature for 1 hr. The reaction mixture was poured into 1N aqueous hydrochloric acid, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was concentrated, and the residue was purified by silica gel column chromatography with ethyl acetate-hexane (gradient of 1:19 to 1:1 by volume ratio) to give the title compound (260 mg, yield 48%) as a pale-yellow oil.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][N:9]([CH2:21][CH2:22][CH3:23])[CH:10]2[CH2:19][CH2:18][C:17]3[C:16]([OH:20])=[CH:15][CH:14]=[CH:13][C:12]=3[CH2:11]2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[S:24]1[C:28]([C:29](O)=[O:30])=[CH:27][C:26]2[CH:32]=[CH:33][CH:34]=[CH:35][C:25]1=2>>[S:24]1[C:28]([C:29]([N:4]2[CH2:5][CH2:6][N:1]([CH2:7][CH2:8][N:9]([CH:10]3[CH2:19][CH2:18][C:17]4[C:12](=[CH:13][CH:14]=[CH:15][C:16]=4[OH:20])[CH2:11]3)[CH2:21][CH2:22][CH3:23])[CH2:2][CH2:3]2)=[O:30])=[CH:27][C:26]2[CH:32]=[CH:33][CH:34]=[CH:35][C:25]1=2
Reactant: O=C(O)c1cc2ccccc2s1
Reactant: CCCN(CCN1CCNCC1)C1CCc2c(O)cccc2C1
Product: CCCN(CCN1CCN(C(=O)c2cc3ccccc3s2)CC1)C1CCc2c(O)cccc2C1
Yield: 99.9 %

Procedure:
Compound 40i was prepared following Procedure G using 39b (175 mg, 0.551 mmol) and benzo[b]thiophene-2-carboxylic acid (118 mg, 0.661 mmol) to give 40i (263 mg, 64%) after column chromatography. 1H NMR (400 MHz, CD3OD) 0.91-0.97 (t, 3H, J=7.2 Hz), 1.53-1.68 (m, 3H), 2.50-2.63 (m, 7H), 2.78-3.02 (m, 7H), 3.77-3.79 (bs, 4H), 6.55-6.59 (t, 2H, J=8 Hz), 6.89-6.93 (t, 1H, J=8.4 Hz), 7.40-7.46 (m, 2H), 7.61 (s, 1H), 7.85-7.91 (m, 2H). The free base of 40i was converted into its HCl salt. m.p. 131-134° C. Anal. [C28H35N3O2S.2HCl.1.5H2O] C, H, N.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH:11]([C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][C:21]=3[F:22])[N:18]([CH3:23])[N:17]=[CH:16]4)[CH3:12])=[CH:9][N:10]=2)[N:7]=1.[F-].[K+].[NH:26]1[CH2:31][CH2:30][NH:29][CH2:28][C:27]1=[O:32]>CN1C(=O)CCC1.CCOC(C)=O>[F:22][C:21]1[CH:20]=[C:19]2[C:15]([CH:16]=[N:17][N:18]2[CH3:23])=[CH:14][C:13]=1[CH:11]([C:8]1[N:6]2[N:7]=[C:2]([N:29]3[CH2:30][CH2:31][NH:26][C:27](=[O:32])[CH2:28]3)[CH:3]=[CH:4][C:5]2=[N:10][CH:9]=1)[CH3:12]
Reactant: O=C1CNCCN1
Reactant: CC(c1cc2cnn(C)c2cc1F)c1cnc2ccc(Cl)nn12
Agent: [F-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: CC(c1cc2cnn(C)c2cc1F)c1cnc2ccc(N3CCNC(=O)C3)nn12
Temperature: 180 °C
Reaction time: 2 h

Procedure:
(rac)-6-Chloro-3-[1-(6-fluoro-1-methyl-1H-indazol-5-yl)-ethyl]-imidazo[1,2-b]pyridazine (Intermediate G, 100 mg, 0.303 mmol), KF (88 mg, 1.5 mmol), piperazin-2-one (91 mg, 0.91 mmol) were suspended in NMP (1 mL). The RM was stirred at 180° C. for 2 h. The mixture was diluted with EtOAc and washed with 1M Na2CO3 (1×) and water (2×). The aqueous was further extracted with EtOAc (2×). The combined organic layers were dried over Na2SO4, filtered and concentrated. The residue was purified by preparative UPLC with acetonitrile and water (+0.1% TFA). The fractions were joined and were lyophilized. The residue was dissolved in MeOH and it was passed through an SPE cartridge of HCO3 to remove the TFA salt. The filtrate was evaporated and the residue was triturated with pentane. The precipitate was filtered off and dried to afford the title compound as a white solid (tR 0.88 min (conditions 4), MH+=394, 1H-NMR in DMSO-d6: 8.10 (br. s, 1H); 7.95-7.87 (m, 2H); 7.65 (s, 1H); 7.51 (s, 1H); 7.54 (d, 1H); 7.49 (s, 1H); 7.22 (d, 1H); 4.79 (q, 1H); 3.95 (s, 4H); 3.87-3.78 (m, 1H); 3.67-3.55 (m, 2H); 3.22 (dd, 1H); 3.29-3.14 (m, 1H); 1.71 (d, 3H)).
Reaction SMILES: [CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[NH:6][C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.[F:16][C:17]([F:31])([F:30])[C:18]1[N:23]=[CH:22][C:21]([C:24](=[CH2:29])[C:25]([O:27][CH3:28])=[O:26])=[CH:20][CH:19]=1.[OH-].[K+]>CN1C(=O)CCC1>[F:30][C:17]([F:16])([F:31])[C:18]1[N:23]=[CH:22][C:21]([CH:24]([CH2:29][N:6]2[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]3[CH2:3][N:2]([CH3:1])[CH2:15][CH2:14][C:5]2=3)[C:25]([O:27][CH3:28])=[O:26])=[CH:20][CH:19]=1
Reactant: Cc1ccc2[nH]c3c(c2c1)CN(C)CC3
Reactant: C=C(C(=O)OC)c1ccc(C(F)(F)F)nc1
Agent: [K+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Product: COC(=O)C(Cn1c2c(c3cc(C)ccc31)CN(C)CC2)c1ccc(C(F)(F)F)nc1

Procedure:
The title compound is prepared from a mixture of 2,3,4,5-tetrahydro-2,8-dimethyl-1H-pyrido[4,3-b]indole, methyl 2-(6-(trifluoromethyl)pyridin-3-yl)acrylate and KOH (5-7 equiv) in NMP at a temperature ranging between 25 deg C. to 100 deg C. The product obtained is isolated by preparative HPLC.
Reaction SMILES: [Cl:1][C:2]1[CH:6]=[C:5]([C:7]([O:9]C)=[O:8])[N:4]([C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)[N:3]=1.O.[OH-].[Li+].O1CCOCC1>O>[Cl:1][C:2]1[CH:6]=[C:5]([C:7]([OH:9])=[O:8])[N:4]([C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)[N:3]=1
Reactant: COC(=O)c1cc(Cl)nn1-c1cccnc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)c1cc(Cl)nn1-c1cccnc1

Procedure:
In step c of Scheme 2, methyl 3-chloro-1-(pyridin-3-yl)-1H-pyrazole-5-carboxylate (6d) is saponified in the presence of an inorganic base, preferably metal hydroxides or their hydrates such as lithium hydroxide hydrate (LiOH.H2O) in water and a polar solvent such as dioxane at temperatures from about 0° C. to about 30° C. to yield 3-chloro-1-(pyridin-3-yl)-1H-pyrazole-5-carboxylic acid (6e). Alternatively, this process can also be accomplished by hydrolysis by exposing methyl 3-chloro-1-(pyridin-3-yl)-1H-pyrazole-5-carboxylate (6d) to a concentrated acid such as hydrochloric acid in water at temperatures from about 30° C. to about 100° C.
Reaction SMILES: Br[CH2:2][C:3]1[C:8](=[O:9])[N:7]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([O:18][CH3:19])=[O:17])[CH:11]=2)[C:6]2[N:20]=[CH:21][CH:22]=[CH:23][C:5]=2[N:4]=1.[CH3:24][C:25]1[NH:26][CH:27]=[CH:28][N:29]=1.C(=O)(O)[O-].[Na+]>CN(C)C=O>[CH3:19][O:18][C:16]([C:12]1[CH:11]=[C:10]([N:7]2[C:8](=[O:9])[C:3]([CH2:2][N:26]3[CH:27]=[CH:28][N:29]=[C:25]3[CH3:24])=[N:4][C:5]3[CH:23]=[CH:22][CH:21]=[N:20][C:6]2=3)[CH:15]=[CH:14][CH:13]=1)=[O:17]
Reactant: COC(=O)c1cccc(-n2c(=O)c(CBr)nc3cccnc32)c1
Reactant: Cc1ncc[nH]1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(-n2c(=O)c(Cn3ccnc3C)nc3cccnc32)c1
Temperature: 80 °C
Reaction time: 1 h
Yield: 0.3 %

Procedure:
A mixture of 2-bromomethyl-4-(3-methoxycarbonylphenyl)-3-oxo-3,4-dihydropyrido[2,3-b]pyrazine (1.22 g) and 2-methylimidazole (1.35 g) in N,N-dimethylformamide (10 ml) was stirred at 80° C. for 1 hour. Then the mixture was poured into aqueous sodium bicarbonate and extracted with ethyl acetate twice. The combined organic solution was washed with aqueous sodium bicarbonate and brine, dried over magnesium sulfate and concentrated. The residue was chromatographed on silica gel column (5% methanol in chloroform) to give 4-(3-methoxycarbonylphenyl)-2-[(2-methylimidazol-1-yl)methyl]-3-oxo-3,4-dihydropyrido[2,3-b]pyrazine (15 4 mg).
Reaction SMILES: [CH2:1]([S:5][C:6]1[CH:11]=[CH:10][N+:9]([O-])=[CH:8][CH:7]=1)[CH:2]([CH3:4])[CH3:3].C(OC(=O)C)(=[O:15])C.[OH-].[Na+]>CO>[CH2:1]([S:5][C:6]1[CH:11]=[CH:10][NH:9][C:8](=[O:15])[CH:7]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)CSc1cc[n+]([O-])cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)CSc1cc[nH]c(=O)c1

Procedure:
A mixture of 500 mg of 4-(isobutylthio)pyridine-N-oxide, 5 ml of acetic anhydride was heated at reflux for 10 hours. The mixture was cooled, then added MeOH and 3N NaOH was added dropwise at pH 9˜11 and stirred. After 1 hour solution was evaporated and 3N HCl was added dropwise at pH6.5˜7.5, extracted with ethyl acetate and subjected to silica gel column chromatography (hexane/ethyl acetate) to obtain the compound (90 mg).
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:4]=[C:5]([C:9]2[N:13]([CH2:14][C:15]([OH:17])=[O:16])[N:12]=[N:11][N:10]=2)[CH:6]=[CH:7][CH:8]=1.S(=O)(=O)(O)O.[CH2:25](O)[CH2:26][OH:27]>>[OH:27][CH2:26][CH2:25][O:16][C:15](=[O:17])[CH2:14][N:13]1[C:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:1])([F:18])[F:19])[CH:4]=2)=[N:10][N:11]=[N:12]1
Reactant: O=C(O)Cn1nnnc1-c1cccc(C(F)(F)F)c1
Reactant: OCCO
Agent: O=S(=O)(O)O
Product: O=C(Cn1nnnc1-c1cccc(C(F)(F)F)c1)OCCO
Temperature: 90 °C
Reaction time: 2.5 h
Yield: 88.9 %

Procedure:
To a solution of 300 mg (1.10 mM) of [5-(3-trifluoromethylphenyl)tetrazol-1-yl] acetic acid in 2 ml of ethylene glycol was added 0.2 ml of sulfuric acid. After the addition, the mixture was stirred at 90° C. for 2.5 hrs. The mixture was then poured into ice-water and extracted with ethyl acetate. The organic phase was washed with water, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The resultant residue was subjected to silica gel column chromatography (eluent: chloroform/methyl alcohol=20/1) for separation and purification, to give 310 mg (yield 88.9%) of [5-(3-trifluoromethylphenyl)tetrazol-1-yl] acetic acid 2-hydroxyethyl ester.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]=[C:8]([C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][C:27]=2[Cl:33])[N:9]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:14][CH:13]=2)[C:10]=1[CH3:11])=[O:5])C.[OH-].[K+].Cl>CO.O>[CH2:19]([O:18][C:15]1[CH:14]=[CH:13][C:12]([N:9]2[C:10]([CH3:11])=[C:6]([C:4]([OH:5])=[O:3])[N:7]=[C:8]2[C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][C:27]=2[Cl:33])=[CH:17][CH:16]=1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: CCOC(=O)c1nc(-c2ccc(Cl)cc2Cl)n(-c2ccc(OCc3ccccc3)cc2)c1C
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1c(C(=O)O)nc(-c2ccc(Cl)cc2Cl)n1-c1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Yield: 99 %

Procedure:
To a suspension of 1-(4-benzyloxyphenyl)-2-(2,4-dichlorophenyl)-5-methyl-1H-imidazole-4-carboxylic acid ethyl ester, from Ex. 1, Step 2 (3.62 g, 7.5 mmol) in 60 ml methanol was added potassium hydroxide (4.05 g, 72 mmol) in water (20 ml), and the reaction mixture was refluxed for 2 hours. The mixture was cooled to room temperature, acidified to pH˜2 with 1 M HCl and extracted with ethyl acetate (2×200 ml). The combined organic phases were dried (Na2SO4), filtered and concentrated to give 3.38 g (99%) of the title compound.
Reaction SMILES: [CH:1]1([C:5]2[O:9][N:8]=[C:7]([C:10]3[C:15]([Cl:16])=[CH:14][CH:13]=[CH:12][C:11]=3[Cl:17])[C:6]=2[C:18](OCC)=[O:19])[CH2:4][CH2:3][CH2:2]1.[H-].C([Al+]CC(C)C)C(C)C.C1(C)C=CC=CC=1>C1COCC1>[CH:1]1([C:5]2[O:9][N:8]=[C:7]([C:10]3[C:11]([Cl:17])=[CH:12][CH:13]=[CH:14][C:15]=3[Cl:16])[C:6]=2[CH2:18][OH:19])[CH2:2][CH2:3][CH2:4]1
Reactant: CCOC(=O)c1c(-c2c(Cl)cccc2Cl)noc1C1CCC1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: OCc1c(-c2c(Cl)cccc2Cl)noc1C1CCC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 97.5 %

Procedure:
To a solution of ethyl 5-cyclobutyl-3-(2,6-dichlorophenyl)-4-isoxazolecarboxylate (1.52 g, 4.47 mmol) in THF (20 mL) at 0° C. was slowly added a 1.5 M solution of diisobutylaluminum hydride in toluene (6.26 mL, 9.39 mmol). The solution was allowed to warm slowly to ambient temperature. After approximately 4 hr of stirring, the solution was re-cooled to 0° C. and an additional 6 mL of diisobutylaluminum hydride was added. After approximately 1.5 hr of stirring the mixture was re-cooled to 0° C., quenched with aqueous Rochelle's salt and allowed to stir overnight while warming to ambient temperature. The mixture was extracted twice with ethyl acetate. The combined organic layers were washed with Rochelle's salt followed by with brine and then dried over magnesium sulfate and concentrated to afford [5-cyclobutyl-3-(2,6-dichlorophenyl)-4-isoxazolyl]methanol (1.30 g, 98%). 1H-NMR (400 MHz, DMSO-d6) δ 7.61-7.51 (m, 3H), 4.87 (t, J=5 Hz, 1H), 4.10 (d, J=5 Hz, 2H), 3.91-3.83 (m, 1H), 2.42-2.28 (m, 4H), 2.08-1.98 (m, 1H), 1.94-1.84 (m, 1H).
Reaction SMILES: [CH2:1]([C@H:3]1[CH2:8][C@H:7]2[C@H:9]3[C@H:18]([CH2:19][CH2:20][C@:5]2([CH3:6])[C@H:4]1[O:22][C:23](=[O:26])[CH2:24]Br)[C@@H:17]1[C:12](=[CH:13][C:14](=[O:21])[CH2:15][CH2:16]1)[CH2:11][CH2:10]3)[CH3:2].CN(C=O)C.[CH:32]1([CH2:38][CH2:39][C:40]([OH:42])=[O:41])[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1>CC(C)=O.[OH-].[Na+]>[CH2:1]([C@H:3]1[CH2:8][C@H:7]2[C@H:9]3[C@H:18]([CH2:19][CH2:20][C@:5]2([CH3:6])[C@H:4]1[O:22][C:23](=[O:26])[CH2:24][O:42][C:40](=[O:41])[CH2:39][CH2:38][CH:32]1[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1)[C@@H:17]1[C:12](=[CH:13][C:14](=[O:21])[CH2:15][CH2:16]1)[CH2:11][CH2:10]3)[CH3:2]
Reactant: O=C(O)CCC1CCCCC1
Reactant: CC[C@H]1C[C@H]2[C@@H]3CCC4=CC(=O)CC[C@@H]4[C@H]3CC[C@]2(C)[C@H]1OC(=O)CBr
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: CN(C)C=O
Product: CC[C@H]1C[C@H]2[C@@H]3CCC4=CC(=O)CC[C@@H]4[C@H]3CC[C@]2(C)[C@H]1OC(=O)COC(=O)CCC1CCCCC1

Procedure:
In 20 ml of acetone is dissolved 1.0 ml of cyclohexanepropionic acid, and 3.0 ml of 2N-NaOH is added, followed by addition of 1.2 g of 16β-ethyl-17β-bromoacetoxy-4-estren-3-one and 20 ml of DMF. The mixture is refluxed for 8 hours, and thereafter treated in the same manner as Example 26. The reaction mixture is chromatographed on a silica gel column. Following passage of 200 ml of n-hexane-diisopropyl ether (3:7), elution is carried out with 800 ml of a 1:1 mixture of the same solvents. The eluate is evaporated under reduced pressure to remove the solvent, giving 1.21 g of the above-identified compound as a light-yellow viscous oil.
Reaction SMILES: Cl.C([O:6][C:7]([C@@H:9]1[CH2:13][CH2:12][CH2:11][N:10]1[C:14]1[N:19]=[CH:18][C:17]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:16][N:15]=1)=[O:8])(C)(C)C>O1CCOCC1>[CH2:23]([O:22][C:20]([C:17]1[CH:16]=[N:15][C:14]([N:10]2[CH2:11][CH2:12][CH2:13][C@H:9]2[C:7]([OH:8])=[O:6])=[N:19][CH:18]=1)=[O:21])[CH3:24]
Reactant: CCOC(=O)c1cnc(N2CCC[C@H]2C(=O)OC(C)(C)C)nc1
Agent: Cl
Solvent: C1COCCO1
Product: CCOC(=O)c1cnc(N2CCC[C@H]2C(=O)O)nc1
Reaction time: 8 h

Procedure:
HCl in dioxane (3 mL) was added to compound 498 (278 mg, 0.865 mmol) and the reaction mixture was stirred overnight. The reaction was then concentrated to afford compound 499 which was used without further purification. MS (m/z): 266.2 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([N+:14]([O-:16])=[O:15])[C:11]=1[O:12][CH3:13])[C:6](Cl)=[O:7].[CH3:17][N:18]1[CH:22]=[CH:21][N:20]=[CH:19]1.C(N(CC)CC)C.[OH-].[Na+]>N1C=CC=CC=1>[CH3:17][N:18]1[CH:22]=[CH:21][N:20]=[C:19]1[C:6]([C:5]1[CH:9]=[C:10]([N+:14]([O-:16])=[O:15])[C:11]([O:12][CH3:13])=[C:3]([O:2][CH3:1])[CH:4]=1)=[O:7]
Reactant: Cn1ccnc1
Reactant: COc1cc(C(=O)Cl)cc([N+](=O)[O-])c1OC
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: COc1cc(C(=O)c2nccn2C)cc([N+](=O)[O-])c1OC
Temperature: 0 °C
Reaction time: 3 h

Procedure:
A solution of 16.0 g of 3,4-dimethoxy-5-nitrobenzoyl chloride in 80 ml of pyridine is added dropwise to a solution of 2.68 g of 1-methylimidazole and 6.6 g of triethylamine in 80 ml of pyridine, whereupon the mixture is stirred at 60° for 3 hours. After treatment with 1.70 ml of 3N sodium hydroxide solution the mixture is stirred for an additional 1 hour and subsequently poured into ice-water. The separated grey crystals are filtered under suction and taken up in ethyl acetate, whereupon the organic phase is dried over magnesium sulfate and the solvent is distilled. After recrystallization from ethyl acetate/hexane there is obtained 3,4-dimethoxy-5-nitrophenyl (1-methylimidazol-2-yl) ketone in the form of colorless crystals of m.p. 144°-145°.
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[C:12]1([CH:18]([C:21]2[CH:26]=[CH:25][N:24]=[N:23][CH:22]=2)[CH2:19][NH2:20])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:20][CH2:19][CH:18]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:21]1[CH:26]=[CH:25][N:24]=[N:23][CH:22]=1)=[O:6]
Reactant: O=C(O)c1cccc(Cl)c1Cl
Reactant: NCC(c1ccccc1)c1ccnnc1
Product: O=C(NCC(c1ccccc1)c1ccnnc1)c1cccc(Cl)c1Cl

Procedure:
From 2,3-dichlorobenzoic acid and 2-phenyl-2-(pyridazin-4-yl)ethanamine. LCMS (MH+): m/z=372.1, tR (minutes, Method G)=2.05
Reaction SMILES: [CH3:1][O-:2].[Na+].Cl[C:5]1[C:10]([C:11]([OH:13])=[O:12])=[CH:9][CH:8]=[CH:7][N:6]=1>CO>[CH3:1][O:2][C:5]1[C:10]([C:11]([OH:13])=[O:12])=[CH:9][CH:8]=[CH:7][N:6]=1
Reactant: O=C(O)c1cccnc1Cl
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1ncccc1C(=O)O
Temperature: 110 °C
Reaction time: 0.5 h

Procedure:
A stainless steel stirred autoclave was charged sequentially with methanol (2.8 1.), sodium methoxide (259 g.) (in portions, keeping the temperature less than 35° C.), and 2-chloro-3-pyridinecarboxylic acid (190 g.). The autoclave was sealed and the reaction mixture heated at 110° C. (50 psig) for 48 hours. The reaction mixture was cooled to 25° C. and discharged from the autoclave. Solids were recovered by filtration. Concentration of the filtrate gave a second crop. These process steps were repeated until virtually all of the methanol had been removed. The several crops of solids were combined, taken up in 2.5 liters of water and midified with conc. hydrochloric acid to pH 2.7 keeping the temperature below 20° C. The precipitated product was granulated for 30 minutes at 15° C. and recovered by filtration (141 g.). Purified title product was obtained by recrystallization from ethyl acetate-hexane (120.5 g., m.p. 148°-150° C.).
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)[N:6]([C:8]2[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][CH:9]=2)[CH:7]=1.[CH3:25][C:26]1[C:31]([SH:32])=[CH:30][CH:29]=[CH:28][CH:27]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:24][C:21]1[CH:22]=[CH:23][C:18]([C:5]2[N:6]([C:8]3[CH:9]=[CH:10][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:12][CH:13]=3)[CH:7]=[C:3]([CH2:2][S:32][C:31]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[CH3:25])[N:4]=2)=[CH:19][CH:20]=1
Reactant: CS(=O)(=O)c1ccc(-n2cc(CCl)nc2-c2ccc(Cl)cc2)cc1
Reactant: Cc1ccccc1S
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccccc1SCc1cn(-c2ccc(S(C)(=O)=O)cc2)c(-c2ccc(Cl)cc2)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-chloromethyl-2-(4-chlorophenyl)-1-[4-(methylsulfonyl)phenyl]-1H-imidazole (Example 159, Step 1) (250 mg, 0.656 mmol) and o-thiocresol (163 mg, 1.31 mmol) in 5 ml of dry dimethylformamide was added anhydrous potassium carbonate (226 mg, 1.64 mmol). The mixture was stirred rapidly overnight at room temperature. The mixture was then partitioned between ethyl acetate and water. The aqueous layer was further extracted with ethyl acetate, the combined organic extracts washed with brine, and dried over sodium sulfate. The solution was filtered and concentrated. Chromatography of the residue over silica gel using 40% ethyl acetate in hexane gave the title compound as a very pale yellow solid (210 mg): mp (DSC) 51° C. Anal. Calc'd. for C24H21ClN2O2S2 (MW 469.03): C, 61.46; H, 4.51; N, 5.97. Found: C, 61.16; H, 4.50; N, 5.86.
Reaction SMILES: [F:1][C:2]1[C:11]([F:12])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH:8]=2)[C:3]=1[C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=1.[CH2:28](Br)[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35]>CCOCC>[F:1][C:2]1[C:11]([F:12])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH:8]=2)[C:3]=1[C:21]1[CH:22]=[CH:23][C:24]([O:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])=[CH:25][CH:26]=1
Reactant: CCCCCCCCc1ccc2c(-c3ccc(O)cc3)c(F)c(F)cc2c1
Reactant: CCCCCCCCBr
Solvent: CCOCC
Product: CCCCCCCCOc1ccc(-c2c(F)c(F)cc3cc(CCCCCCCC)ccc23)cc1

Procedure:
From 4-(2,3-difluoro-6-octylnaphthalen-1-yl)phenol and 1-octyl bromide by means of the Williamson ether synthesis.
Reaction SMILES: [CH2:1]([N:4]1[CH:8]=[CH:7][N:6]=[C:5]1[C:9]1[S:13][C:12](Br)=[N:11][C:10]=1[C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=1[Cl:22])[CH:2]=[CH2:3].C[Sn](C)(C)[C:25]1[CH:30]=[CH:29][N:28]=[C:27]([NH:31][C:32](=[O:34])[CH3:33])[CH:26]=1.[Cl-].[Li+]>O1CCOCC1.[Cu]I>[CH2:1]([N:4]1[CH:8]=[CH:7][N:6]=[C:5]1[C:9]1[S:13][C:12]([C:25]2[CH:30]=[CH:29][N:28]=[C:27]([NH:31][C:32](=[O:34])[CH3:33])[CH:26]=2)=[N:11][C:10]=1[C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=1[Cl:22])[CH:2]=[CH2:3]
Reactant: C=CCn1ccnc1-c1sc(Br)nc1-c1ccc(Cl)cc1Cl
Reactant: CC(=O)Nc1cc([Sn](C)(C)C)ccn1
Agent: [Cu]I
Agent: [Cl-]
Agent: [Li+]
Solvent: C1COCCO1
Product: C=CCn1ccnc1-c1sc(-c2ccnc(NC(C)=O)c2)nc1-c1ccc(Cl)cc1Cl
Temperature: 115 °C
Yield: 43.2 %

Procedure:
To a solution of 5-(1-Allyl-1H-imidazol-2-yl)-2-bromo-4-(2,4-dichlorophenyl)-1,3-thiazole (0.133 g, 0.320 mmol) in 1,4-dioxane (8 mL) was added N-[4-(trimethylstannyl)pyridine-2-yl]acetamide (0.115 g, 0.384 mmol), lithium chloride (0.0407 g, 0.961 mmol), copper (I) iodide (0.0183 g, 0.0961 mmol) and tetrakis (triphenylphosphine)palladium(0) (0.0185 g, 0.0160 mmol). The flask was purged with argon and then the mixture was heated at 115° C. for 3 hours. The reaction was allowed to cool to room temperature, and then the solvent was evaporated in vacuo. Column chromatography was performed to yield the title compound (0.0650 g, 43%). LCMS: (FA) ES+, 472. 1H NMR (400 MHz, d4-Methanol) δ: 8.75-8.72 (m, 1H), 8.45-8.41 (m, 1H), 7.71-7.68 (m, 1H), 7.58-7.55 (m, 1H), 7.43-7.35 (m, 2H), 7.20 (d, 1H, J=1.51 Hz), 7.14 (d, J=1.51 Hz, 1H), 5.69-5.58 (m, 1H), 5.13-5.08 (m, 1H), 4.94-4.88 (m, 1H), 4.38-4.33 (m, 2H), 2.20 (s, 3H).