Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:30]=[CH:29][C:5]2[N:6]([CH3:28])[C:7](=[O:27])[CH2:8][N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]4[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=4)=[CH:13][CH:12]=3)[C:4]=2[CH:3]=1.CC(C)([O-])C.[K+].[F:37][C:38]([F:48])([F:47])[C:39]1[CH:46]=[CH:45][C:42]([CH2:43]Br)=[CH:41][CH:40]=1>O1CCCC1>[Cl:1][C:2]1[CH:30]=[CH:29][C:5]2[N:6]([CH3:28])[C:7](=[O:27])[CH:8]([CH2:43][C:42]3[CH:41]=[CH:40][C:39]([C:38]([F:37])([F:47])[F:48])=[CH:46][CH:45]=3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]4[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=4)=[CH:13][CH:12]=3)[C:4]=2[CH:3]=1
Reactant: COc1ccc(COc2ccc(C3=NCC(=O)N(C)c4ccc(Cl)cc43)cc2)cc1
Reactant: FC(F)(F)c1ccc(CBr)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COc1ccc(COc2ccc(C3=NC(Cc4ccc(C(F)(F)F)cc4)C(=O)N(C)c4ccc(Cl)cc43)cc2)cc1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 48 %

Procedure:
(Z)-7-Chloro-5-(4-(4-methoxybenzyloxy)phenyl)-1-methyl-1H-benzo[e][1,4]diazepin-2(3H)-one (75 mg, 0.18 mmol) was dissolved in tetrahydrofuran (4 mL), and the solution was cooled to −78° C. under a nitrogen atmosphere. A 1 M solution of potassium tert-butoxide in tetrahydrofuran (267 μL, 0.267 mmol) was added dropwise, and the solution was stirred for 10 minutes. 4-(trifluoromethyl)benzyl bromide (64 mg, 0.267 mmol, solution in 1 mL tetrahydrofuran) was then added dropwise, and the cooling bath was then removed. The reaction was stirred at room temperature for 2 hours, and it was then quenched with water, and the mixture was portioned between water and ethyl acetate. The aqueous portion was extracted into ethyl acetate again, and the combined organic extracts were dried over sodium sulfate, and then concentrated, and purified by chromatography (gradient; 9:1 hexanes:ethyl acetate to 6:4 hexanes:ethyl acetate, then isocratic) yielding the product as a clear residue (50 mg, 49%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=[O:34])[NH:20][CH:21]3[CH2:26][CH2:25][CH:24]([C:27]4[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=4)[CH2:23][CH2:22]3)=[CH:15][CH:14]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:35]([O:37]CC)=[O:36].[OH-].[Na+]>C1COCC1.C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:14]=[CH:15][C:16]([C:19](=[O:34])[NH:20][CH:21]3[CH2:22][CH2:23][CH:24]([C:27]4[CH:28]=[CH:29][C:30]([Cl:33])=[CH:31][CH:32]=4)[CH2:25][CH2:26]3)=[CH:17][CH:18]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:35]([OH:37])=[O:36]
Reactant: CCOC(=O)C1CCOc2cc(Oc3ccc(C(=O)NC4CCC(c5ccc(Cl)cc5)CC4)cc3)c(Cl)cc21
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: O=C(NC1CCC(c2ccc(Cl)cc2)CC1)c1ccc(Oc2cc3c(cc2Cl)C(C(=O)O)CCO3)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 75.7 %

Procedure:
To a suspension of ethyl 6-chloro-7-(4-(4-(4-chlorophenyl)cyclohexylcarbamoyl)phenoxy)chroman-4-carboxylate (0.065 g, 0.11 mmol) in 3:1 THF/ethanol (1 ml) was added 1M sodium hydroxide (0.24 ml, 0.24 mmol), and the reaction was stirred for 16 hours at ambient temperature. The reaction was concentrated, taken up in water, acidified with 1M hydrochloric acid, and extracted twice with EtOAc. The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated to yield 45 mg of the title compound (73% yield).
Reaction SMILES: [C:1]([O:5][C:6](=[O:35])[N:7]([C@@H:22]([C:24]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:27]([F:34])=[CH:26][CH:25]=1)[CH3:23])[CH2:8][CH2:9][CH2:10][C@H:11]1[CH2:20][CH:19]([OH:21])[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:12]1)([CH3:4])([CH3:3])[CH3:2].C1C=C[NH+]=CC=1.[O-][Cr](Cl)(=O)=O>>[C:1]([O:5][C:6](=[O:35])[N:7]([C@@H:22]([C:24]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:27]([F:34])=[CH:26][CH:25]=1)[CH3:23])[CH2:8][CH2:9][CH2:10][C@H:11]1[CH2:20][C:19](=[O:21])[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:12]1)([CH3:2])([CH3:3])[CH3:4]
Reactant: C[C@H](c1ccc(F)c2ccccc12)N(CCC[C@@H]1Cc2ccccc2C(O)C1)C(=O)OC(C)(C)C
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Product: C[C@H](c1ccc(F)c2ccccc12)N(CCC[C@H]1CC(=O)c2ccccc2C1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 56.7 %

Procedure:
To a stirred solution of tert-Butyl((R)-1-(4-fluoronaphthalen-1-yl)ethyl)(3-((2R)-4-hydroxy-1,2,3,4-tetrahydronaphthalen-2-yl)propyl)carbamate (886 mg, 1.855 mmol) DCM (8 mL), PCC (304 mg, 2.226 mmol) was added at 0° C. and stirred for 1 h at 25° C. The reaction mixture was filtered through celite bed and the filtrate concentrated to get the crude compound. This crude compound was purified by column chromatography (Biotage) using eluent (1:9, ethyl acetate:n-hexane) to get the title compound (500 mg). m/z 476.42.
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[CH2:7][C:6]([CH3:9])([CH3:8])[CH2:5][CH:4]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:16]2[CH2:17][CH2:18][NH:19][CH2:20][CH:21]=2)[CH2:3]1.[CH:23](=O)[CH2:24][CH2:25][CH3:26].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C.C(=O)([O-])O.[Na+]>O1CCCC1.C(OCC)(=O)C>[CH2:23]([N:19]1[CH2:18][CH:17]=[C:16]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[CH:4]2[CH2:3][C:2]([CH3:22])([CH3:1])[CH2:7][C:6]([CH3:8])([CH3:9])[CH2:5]2)[CH2:21][CH2:20]1)[CH2:24][CH2:25][CH3:26]
Reactant: CCCC=O
Reactant: CC1(C)CC(c2ccccc2C2=CCNCC2)CC(C)(C)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CCCCN1CC=C(c2ccccc2C2CC(C)(C)CC(C)(C)C2)CC1
Temperature: 25 °C
Reaction time: 13 h
Yield: 45 %

Procedure:
To a solution of 4-[2-(3,3,5,5-tetramethylcyclohexyl)phenyl]-1,2,3,6-tetrahydropyridine (130 mg, 0.44 mmol) produced in Example (102e) in tetrahydrofuran (2 mL) were added butyraldehyde (37.8 mg, 0.52 mmol), sodium triacetoxyborohydride (139 mg, 0.66 mmol) and acetic acid (52.5 mg, 0.87 mmol), followed by stirring for 13 hours at room temperature. Saturated aqueous solution of sodium hydrogencarbonate was added to the reaction mixture and extraction was performed with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and then the filtrate was concentrated under reduced pressure. The resultant residue was purified by NH silica gel column chromatography (ethyl acetate/heptane) to give 70 mg of 1-butyl-4-[2-(3,3,5,5-tetramethylcyclohexyl)phenyl]-1,2,3,6-tetrahydropyridine as a light yellow oil.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][C:16]=1[O:17][CH3:18])C=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC1C=CC=C(C(OO)=[O:27])C=1>CO>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([OH:27])[CH:14]=[CH:15][C:16]=1[O:17][CH3:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(C=O)cc1OCc1ccccc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: CO
Product: COc1ccc(O)cc1OCc1ccccc1

Procedure:
FIGS. 17 and 18 disclose a procedure for synthesizing futoenone and futoenone derivative compounds. Benzyl bromide (BnBr) is used to protect isovanillin (201) by reaction using phase transfer conditions to yield 3-benzyloxy-4-methoxybenzaldehyde (202). Oxidation of 3-benzyloxy-4-methoxybenzaldehyde (202) with m-chloroperbenzoic acid followed by hydrolysis in refluxing methanol yields 3-benzyloxy-4-methoxyphenol (203). The phenol is placed in toluene and the suspension is treated with n-butyl-lithium to form a precipitate. 1,4-dibromobutene is then added to the reaction and the contents are heated to reflux overnight to form vinylbenzofuran (206). An ester (207) is formed using a Horner-Emmons modified Wittig reaction and is subsequently reduced to the allylic alcohol (208) using diisobutylaluminum hydride. The allylic alcohol can then be epoxidized in a Sharpless epoxidation to form 2-(2,3'-epoxybutanol)-7-benzyloxy-6-methoxydihydrobenzofuran (209).
Reaction SMILES: [BH4-].[Na+].[CH3:3][C:4]1([CH3:15])[CH2:9][C:8](=[O:10])[CH2:7][CH2:6][CH:5]1[C:11]([O:13][CH3:14])=[O:12]>CO.O>[OH:10][CH:8]1[CH2:7][CH2:6][CH:5]([C:11]([O:13][CH3:14])=[O:12])[C:4]([CH3:15])([CH3:3])[CH2:9]1
Reactant: COC(=O)C1CCC(=O)CC1(C)C
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COC(=O)C1CCC(O)CC1(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Sodium borohydride (6.19 g, 163 mmol) was added in portions at 0° C. to a solution of methyl 2,2-dimethyl-4-oxocyclohexanecarboxylate (10.0 g, 54.3 mmol) in methanol (200 mL). The mixture was stirred at room temperature for 30 minutes. Then the mixture was diluted with water and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure to give methyl 4-hydroxy-2,2-dimethylcyclohexanecarboxylate. 1H NMR (400 MHz, CDCl3): δ 3.89-3.84 (m, 1H), 3.65 (s, 3H), 2.21 (s, 1H), 1.79-1.73 (m, 1H), 1.70-1.68 (m, 3H), 1.49-1.35 (m, 2H), 1.06 (s, 6H).
Reaction SMILES: [CH3:1][N:2]([CH3:24])[C:3]1[O:7][N:6]=[C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([OH:22])=O)=[CH:16][CH:15]=3)=[C:10]([CH3:23])[CH:9]=2)[N:4]=1.[CH3:25][N:26]1[CH2:31][CH2:30][C:29]2([C:43]3[C:34](=[CH:35][C:36]4[CH2:37][CH2:38][CH2:39][NH:40][C:41]=4[CH:42]=3)[O:33][CH2:32]2)[CH2:28][CH2:27]1>>[CH3:25][N:26]1[CH2:31][CH2:30][C:29]2([C:43]3[C:34](=[CH:35][C:36]4[CH2:37][CH2:38][CH2:39][N:40]([C:20]([C:17]5[CH:16]=[CH:15][C:14]([C:11]6[CH:12]=[CH:13][C:8]([C:5]7[N:4]=[C:3]([N:2]([CH3:24])[CH3:1])[O:7][N:6]=7)=[CH:9][C:10]=6[CH3:23])=[CH:19][CH:18]=5)=[O:22])[C:41]=4[CH:42]=3)[O:33][CH2:32]2)[CH2:28][CH2:27]1
Reactant: CN1CCC2(CC1)COc1cc3c(cc12)NCCC3
Reactant: Cc1cc(-c2noc(N(C)C)n2)ccc1-c1ccc(C(=O)O)cc1
Product: Cc1cc(-c2noc(N(C)C)n2)ccc1-c1ccc(C(=O)N2CCCc3cc4c(cc32)C2(CCN(C)CC2)CO4)cc1

Procedure:
The title compound was prepared from 4'-(5-dimethylamino-1,2,4-oxadiazol-3-yl)-2'-methylbiphenyl-4-carboxylic acid D(14) and 2,3,5,6,7,8-hexahydro-1'-methylspiro[furo[2,3-g]quinoline-3,4'-piperidine] (D10) using a procedure similar to that of Example 1 (26%). This was converted to hydrochloride salt. M.p. 118-120° C.
Reaction SMILES: [NH2:1][N:2]1[C:7](=[O:8])[C:6]([CH:9]([CH2:12][CH3:13])[CH2:10][CH3:11])=[N:5][N:4]=[C:3]1[S:14][CH3:15].[OH-].[Na+].[CH3:18]I>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1>[CH3:18][NH:1][N:2]1[C:7](=[O:8])[C:6]([CH:9]([CH2:10][CH3:11])[CH2:12][CH3:13])=[N:5][N:4]=[C:3]1[S:14][CH3:15]
Reactant: CCC(CC)c1nnc(SC)n(N)c1=O
Reactant: CI
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCC(CC)c1nnc(SC)n(NC)c1=O
Reaction time: 1 h
Yield: 87.1 %

Procedure:
4.2 g (0.018 mol) of 4-amino-3-methylthio-6-(pent-3-yl)-1,2,4-triazin-5(4H)-one are introduced at room temperature into a mixture of 7.5 ml of 45% strength sodium hydroxide solution and 7.5 ml of toluene. 7.1 g (0.05 mol) of methyl iodide and 0.6 g of tetrabutylammonium bromide are then added all at once at room temperature. The mixture is stirred vigorously, and the temperature rises from 21° C. to 31° C. Stirring of the reaction mixture is continued for 1 hour, and the organic top phase is then removed in a separation funnel and stirred in 100 ml of water. The mixture is extracted with methylene chloride (three times, using 70 ml each time) and then filtered over silica gel, which, after concentrating, gives 3.8 g (87% of theory) of 4-methylamino-3-methylthio-6-(pent-3-yl)-1,2,4-triazin-5-(4H}-one as a colorless oil of refractive index nD20 =1.553.
Reaction SMILES: Cl.[F:2][C:3]([F:29])([F:28])[C:4]1[CH:5]=[C:6]([CH:21]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:23]=1)[CH2:7][O:8][C@H:9]1[CH2:14][CH2:13][NH:12][CH2:11][C@H:10]1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.Br[CH2:31][C:32]([NH2:34])=[O:33]>>[F:29][C:3]([F:2])([F:28])[C:4]1[CH:5]=[C:6]([CH:21]=[C:22]([C:24]([F:27])([F:25])[F:26])[CH:23]=1)[CH2:7][O:8][C@H:9]1[CH2:14][CH2:13][N:12]([CH2:31][C:32]([NH2:34])=[O:33])[CH2:11][C@H:10]1[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: FC(F)(F)c1cc(CO[C@H]2CCNC[C@H]2c2ccccc2)cc(C(F)(F)F)c1
Reactant: NC(=O)CBr
Agent: Cl
Product: NC(=O)CN1CC[C@H](OCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@H](c2ccccc2)C1
Yield: 52.9 %

Procedure:
The compound (0.15 g) obtained in Example 1 and bromoacetamide (0.094 g) were reacted and treated in the same manner as in the method described in Example 7 to obtain the title compound as colorless crystals (0.083 g, 52%).
Reaction SMILES: O.[OH-].[Li+].[N:4]1([CH2:9][C:10]([O:12]CC)=O)[CH:8]=[CH:7][CH:6]=[N:5]1.Cl.Cl.[CH3:17][N:18]1[CH2:23][CH2:22][N:21]([C:24]2[CH:29]=[C:28]([C:30]3[CH:39]=[C:38]4[C:33]([CH2:34][CH2:35][NH:36][CH2:37]4)=[CH:32][CH:31]=3)[N:27]=[C:26]([NH2:40])[N:25]=2)[CH2:20][CH2:19]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C>CO.O>[CH3:17][N:18]1[CH2:19][CH2:20][N:21]([C:24]2[CH:29]=[C:28]([C:30]3[CH:39]=[C:38]4[C:33]([CH2:34][CH2:35][N:36]([C:10](=[O:12])[CH2:9][N:4]5[CH:8]=[CH:7][CH:6]=[N:5]5)[CH2:37]4)=[CH:32][CH:31]=3)[N:27]=[C:26]([NH2:40])[N:25]=2)[CH2:22][CH2:23]1
Reactant: CN1CCN(c2cc(-c3ccc4c(c3)CNCC4)nc(N)n2)CC1
Reactant: CCOC(=O)Cn1cccn1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CO
Solvent: CCN(CC)CC
Solvent: O
Product: CN1CCN(c2cc(-c3ccc4c(c3)CN(C(=O)Cn3cccn3)CC4)nc(N)n2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Lithium hydroxide monohydrate (4.4 mg, 0.10 mmol) was added to a solution of ethyl 1H-pyrazol-1-ylacetate (8.0 mg, 0.052 mmol) (Key Organics/Bionet, Cat. #4Y-0601) in methanol (1.0 mL) and water (0.3 mL). The reaction mixture was stirred at r.t. overnight. The mixture was adjusted to pH=4 with aqueous HCl, and concentrated. The residue was dissolved in N,N-dimethylformamide (0.5 mL). To the solution was added 4-(4-methylpiperazin-1-yl)-6-(1,2,3,4-tetrahydroisoquinolin-7-yl)pyrimidin-2-amine HCl salt (15 mg, 0.034 mmol), followed by benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (18 mg, 0.041 mmol) and triethylamine (19 uL, 0.14 mmol). The reaction mixture was stirred at r.t. for 2 h. The mixture was purified by RP-LCMS (pH=10) to afford the desired product. Analytic LCMS (M+H)+: m/z=433.1.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][NH2:9].[C:10](Cl)([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11]>C(Cl)Cl.CO.C(Cl)Cl>[CH2:13]([O:12][C:10](=[O:11])[NH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][NH2:9])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: NCCCCCCCN
Solvent: ClCCl
Solvent: CO
Product: NCCCCCCCNC(=O)OCc1ccccc1
Yield: 32.4 %

Procedure:
On an ice-water bath, to the solution of 1,7-diaminoheptane (1.433 g, 11 mmol) in CH2Cl2/MeOH (125 mL/125 mL) was added the solution of CbzCl (1.71 g, 10 mmol) in CH2Cl2 (250 mL) dropwise within 12 h while keeping the temperature below 5° C. The mixture was allowed to stir at the same temperature for another half of an hour before concentrated under reduced pressure to remove most of the MeOH. Water (150 mL) was then added, and the aqueous layer was adjusted to pH=2 using 6 N HCl. The layers were separated. The aqueous layer was washed with DCM (50 mL×3), then adjusted to pH=12 with 10 N NaOH and extracted with DCM (50 mL×3). The combined organic layers were dried over Na2SO4, concentrated and purified by flash column using DCM/MeOH (9/1) to give 856 mg white solid in 32% yield. 1H NMR (400 MHz, CDCl3): δ7.35-7.29 (m, 5H), 5.09 (s, 2H), 4.73 (brs, 1H), 3.18 (q, J=6.64 Hz, 2H), 2.67 (t, J=6.94 Hz, 2H), 1.55-1.44 (m, 2H), 1.44-1.40 (m, 2H), 1.32 (m, 6H). 13C NMR (100 MHz, CDCl3): δ 156.40, 136.70, 128.50, 128.09, 128.06, 66.55, 42.18, 41.06, 33.71, 29.91, 29.09, 26.76, 26.68. mp 78-80° C. IR v (Diamond, cm−1): 3327, 1686, 1532, 1263, 1144. MS (ESI) m/z found 264.8 (M+H)+.
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][C:2]=1[S:10][CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:21]=1[N:20]([CH3:22])[CH2:19][CH2:18][C:17]2=[O:23].[CH3:24][Li]>O1CCCC1>[N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][C:2]=1[S:10][CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:21]=1[N:20]([CH3:22])[CH2:19][CH2:18][C:17]2([OH:23])[CH3:24]
Reactant: CN1CCC(=O)c2cccc(CSc3nc4ccccc4[nH]3)c21
Reactant: [Li]C
Solvent: C1CCOC1
Product: CN1CCC(C)(O)c2cccc(CSc3nc4ccccc4[nH]3)c21
Temperature: -10 °C

Procedure:
To a solution of 8-(2-benzimidazolyl)thiomethyl-1-methyl-4-oxo-1,2,3,4-tetrahydroquinoline (300 mg) in tetrahydrofuran (10 ml) was added dropwise methyl lithium (1.5M solution in tetrahydrofuran) (1.33 ml) with stirring at -10° C. Then the mixture was stirred for 30 minutes at the same temperature. After distilling off the solvent, the residue was extracted with dichloromethane, washed with water, and dried, then the solvent was distilled off. The resulting residue was purified by silica gel column chromatography [eluent:n-hexane-ethyl acetate-dichloromethane (10:5:2)], and recrystallized from dichloromethane-diethyl ether to give 8-(2-benzimidazolyl)thiomethyl-4-hydroxy-1,4-dimethyl-1,2,3,4-tetrahydroquinoline (96 mg).
Reaction SMILES: [CH2:1]([O:15][C:16]1[O:20][C:19]([C:21]([OH:23])=[O:22])=[CH:18][CH:17]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].C[O-].[Na+:26]>CO>[Na+:26].[CH2:1]([O:15][C:16]1[O:20][C:19]([C:21]([O-:23])=[O:22])=[CH:18][CH:17]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CCCCCCCCCCCCCCOc1ccc(C(=O)O)o1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CCCCCCCCCCCCCCOc1ccc(C(=O)[O-])o1

Procedure:
To 19.5 g (0.06 mols) of 5-tetradecyloxy-2-furoic acid in 500 ml of methanol is added 6 g (0.111 mole) of sodium methoxide. The mixture is refluxed, and the methanol is distilled off being replaced by water. The aqueous solution is cooled, the precipitate collected and dried to give 5-tetradecyloxy-2-furoic acid sodium salt, M.P. 240°-245° C (dec.).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]=[C:13]([CH2:22][C:23]#[N:24])[N:14]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=4[Cl:21])[C:5]=3[C:4]=2[CH:3]=1.Cl.[NH2:26][OH:27].C(=O)([O-])[O-].[Na+].[Na+]>O.CN(C=O)C>[Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]=[C:13]([CH2:22][C:23]([NH:26][OH:27])=[NH:24])[N:14]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=4[Cl:21])[C:5]=3[C:4]=2[CH:3]=1
Reactant: NO
Reactant: N#CCc1nc2cnc3ccc(Cl)cc3c2n1-c1ccccc1Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: N=C(Cc1nc2cnc3ccc(Cl)cc3c2n1-c1ccccc1Cl)NO

Procedure:
The title compound is prepared in analogy to Example 86, starting from 500 mg (1.415 mmol) of [8-chloro-1-(2-chloro-phenyl)-1H-imidazo[4,5-]quinolin-2-yl]-acetonitrile (Example 85), 590 mg (8.5 mmol) hydroxylamin hydrochloride, 495 mg (4.67 mmol) sodium carbonate in 2.8 ml water and 11.5 ml DMF. mp: 114° C.; MS: 386 (M++1); HPLC: tret=70.40 min (Grad 1).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[C:5]([O:11][CH3:12])=[CH:4][C:3]=1[C:13]1[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=1>CCOC(C)=O.CO>[CH3:1][C:2]1[C:3]([C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[CH:4][C:5]([O:11][CH3:12])=[C:6]([CH:7]=1)[NH2:8]
Reactant: COc1cc(-c2ccncc2)c(C)cc1[N+](=O)[O-]
Solvent: CO
Solvent: CCOC(C)=O
Product: COc1cc(-c2ccncc2)c(C)cc1N
Reaction time: 72 h
Yield: 106.1 %

Procedure:
4-[2-methyl-5-(methyloxy)-4-nitrophenyl]pyridine (Example 157, step A) (2.44 g, 9.99 mmol) was placed in a 250 mL high pressure vessel and dissolved in 60 mL of 1 to 1 EtOAc/MeOH. 5 wt % Platinum(sulfided)/carbon (1.17 g, 0.3 mmol) was added followed quickly by a rubber septum. The flask was evacuated and filled with N2 six times to remove any oxygen. The vessel was then pressurized with H2 (60 psi). The solution stirred for 72 h. The vessel was evacuated and filled with N2 six times to remove any H2. The solution was filtered through celite and evaporated to give the title compound of step A (2.28 g, 10.6 mmol, 100%). 1H NMR (400 MHz, DMSO-d6) δ ppm 8.50-8.53 (m, 2H), 7.30-7.33 (m, 2H), 6.68 (s, 1H), 6.54 (s, 1H), 4.88 (bs, 2H), 3.75 (s, 3H), 2.12 (s, 3H).
Reaction SMILES: [F:1][C:2]1[N:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[C:9](=O)([O-])[O-].[K+].[K+].CI.CN(C=O)C>O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][CH3:9])=[CH:6][N:7]=1
Reactant: O=C([O-])[O-]
Reactant: Oc1ccc(F)nc1
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(F)nc1
Temperature: 45 °C
Reaction time: 2.5 h
Yield: 92.6 %

Procedure:
To a 20 mL microwave vial, 6-fluoropyridin-3-ol (Alfa Aesar, 1.04 g, 9.18 mmol), potassium carbonate (1.90 g, 13.8 mmol) and methyl iodide (Aldrich, 0.689 mL, 11.0 mmol) were mixed into DMF (6 mL). The brown mixture was stirred at 45° C. for 2.5 h. The mixture was diluted with water and the aqueous phase was extracted with EtOAc (3×20 mL). The combined organic phases were washed with saturated aqueous sodium chloride (30 mL). The organic phase was dried over sodium sulfate, filtered and concentrated in vacuo to afford 2-fluoro-5-methoxypyridine (1.08 g, 92% yield) as a light brown oil. This material was used in the next reaction without further purification. 1H NMR (400 MHz, CDCl3) δ ppm 7.79-7.85 (m, 1H) 7.33 (td, J=6.02, 3.23 Hz, 1H) 6.86 (dd, J=8.90, 3.42 Hz, 1H) 3.85 (s, 3H). m/z (ESI, positive ion): 128.1 (M+H)+.
Reaction SMILES: [C:1]([N:3]=[C:4]1[NH:9][CH2:8][CH2:7][CH2:6][N:5]1[C@@H:10]1[C:15]2[CH:16]=[C:17]([C:20]#[N:21])[CH:18]=[CH:19][C:14]=2[O:13][C:12]([CH3:23])([CH3:22])[C@H:11]1[OH:24])#[N:2].[C:25](OC(=O)C)(=[O:27])[CH3:26]>N1C=CC=CC=1>[C:25]([O:24][C@H:11]1[C@H:10]([N:5]2[CH2:6][CH2:7][CH2:8][NH:9][C:4]2=[N:3][C:1]#[N:2])[C:15]2[CH:16]=[C:17]([C:20]#[N:21])[CH:18]=[CH:19][C:14]=2[O:13][C:12]1([CH3:22])[CH3:23])(=[O:27])[CH3:26]
Reactant: CC(=O)OC(C)=O
Reactant: CC1(C)Oc2ccc(C#N)cc2[C@@H](N2CCCNC2=NC#N)[C@@H]1O
Solvent: c1ccncc1
Product: CC(=O)O[C@H]1[C@H](N2CCCNC2=NC#N)c2cc(C#N)ccc2OC1(C)C
Temperature: 25 °C
Reaction time: 168 h

Procedure:
A mixture of trans-4-(2-cyanoiminohexahydropyrimidin-1-yl)-3,4-dihydro-3-hydroxy-2,2-dimethyl-2H-1-benzopyran-6-carbonitrile (651 mg) and acetic anhydride (0.76 ml) in pyridine (2 ml) was stirred for 7 days at room temperature. The mixture was concentrated under reduced pressure, and the residue was dissolved in ethyl acetate, washed twice with water and dried over anhydrous magnesium sulfate. The solvent was evaporated in vacuo and the residue was pulverized with diisopropyl ether to give trans-3-acetoxy-4-(2-cyanoiminohexahydropyrimidin-1-yl)-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-6carbonitrile (0.76 g).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([Br:12])=[CH:4][N:3]=1.[Br-].[CH2:14]([Zn+])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[NH4+].[Cl-]>C1COCC1.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>[CH2:14]([C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([Br:12])=[CH:4][N:3]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: Clc1ncc(Br)c2ccccc12
Reactant: [Zn+]Cc1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Agent: [Cl-]
Solvent: C1CCOC1
Product: Brc1cnc(Cc2ccccc2)c2ccccc12
Temperature: 25 °C
Reaction time: 12 h
Yield: 25 %

Procedure:
In a 40 mL vial 490 mg (2.00 mmol) 1-chloro-4-bromo-isoquinoline and 40 mg (0.034 mmol) tetrakis(triphenylphosphine)palladium(0) is added to 4 mL THF. After all solids are dissolved, 8 mL of 0.5 M (4.0 mmol) benzyl zinc bromide in THF is slowly added by syringe and the resulting reaction mixture is stirred at 25° C. After 12 hrs, the mixture is poured into cold solution of saturated NH4Cl and extracted with EtOAc. The organic extracts are concentrated in vacuo and the resulting residue is purified by silica chromatography using a heptane/EtOAc gradient. Pure fractions are pooled and evaporated to give 150 mg (0.50 mmol) of the title compound.