Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([Si:5]([CH3:19])([CH3:18])[O:6][CH2:7][C:8]1[CH:13]=[C:12]([O:14][CH3:15])[CH:11]=[CH:10][C:9]=1[CH2:16][CH3:17])([CH3:4])([CH3:3])[CH3:2].C1C(=O)N([Br:27])C(=O)C1>C(Cl)(Cl)(Cl)Cl>[C:1]([Si:5]([CH3:19])([CH3:18])[O:6][CH2:7][C:8]1[CH:13]=[C:12]([O:14][CH3:15])[C:11]([Br:27])=[CH:10][C:9]=1[CH2:16][CH3:17])([CH3:3])([CH3:4])[CH3:2]
Reactant: CCc1ccc(OC)cc1CO[Si](C)(C)C(C)(C)C
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: CCc1cc(Br)c(OC)cc1CO[Si](C)(C)C(C)(C)C
Reaction time: 16 h
Yield: 62 %

Procedure:
Under a nitrogen atmosphere, 24.85 9 (0.0885 mol) of tert-butyl-dimethyl-(2-ethyl-5-methoxy-benzyloxy)-silane (16) and 15.77 g (0.0885 mmol) of NBS were combined in 500 mL of carbon tetrachloride, followed by the addition of 100 g of silica gel 60 (EM Science). The reaction was allowed to stir for 16 hours in the absence of light. The reaction mixture was filtered and the silica gel was washed with dichloromethane. The filtrate was washed with dichloromethane (1×300 mL). The combined organic extracts were washed with 1M NaOH (2×300 mL), dilute NaHSO3 (1×200 mL) and brine (1×200 mL), dried over magnesium sulfate, filtered and concentrated in vacuo to yield crude tert-butyl-dimethyl-(4-bromo-2-ethyl-5-methoxy-benzyloxy)-silane (17). Crude tert-butyl-dimethyl-(4-bromo-2-ethyl-5-methoxy-benzyloxy)-silane (17) was chromatographed on a silica gel column with 20% CHCl3 in hexane to afford 19.70 g (62%) of tert-butyl-dimethyl-(4-bromo-2-ethyl-5-methoxy-benzyloxy)-silane (17).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][O:4][C:3]2=[C:7]([C:10]3[CH:15]=[CH:14][C:13]([C:16]#[C:17][Si](C)(C)C)=[CH:12][CH:11]=3)[S:8][CH:9]=[C:2]12.C(=O)([O-])[O-].[Ca+2]>CO>[C:16]([C:13]1[CH:12]=[CH:11][C:10]([C:7]2[S:8][CH:9]=[C:2]3[C:3]=2[O:4][CH2:5][CH2:6][O:1]3)=[CH:15][CH:14]=1)#[CH:17]
Reactant: C[Si](C)(C)C#Cc1ccc(-c2scc3c2OCCO3)cc1
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: CO
Product: C#Cc1ccc(-c2scc3c2OCCO3)cc1
Reaction time: 12 h
Yield: 91.7 %

Procedure:
As shown in the following Reaction 4, 200 mg (0.63 mmol) of [4-(2,3-Dihydro-thieno[3,4-b][1,4]dioxin-5-yl)-phenylethynyl]-trimethyl-silane obtained in C of Example 1-1 was melted in 5 mL of methyl alcohol, and 170 mg (1.27 mmol, 2 eq) of calcium carbonate was added thereto, and then the reaction product was stirred for 12 hours. Next, the reaction solution was extracted with 10 mL of methylene chloride 1 time. The organic solvent layer was dehydrated with magnesium sulfate, filtered, and then distilled under reduced pressure. The compound distilled under reduced pressure was purified with a column chromatography (mobile phase volume ratio: methylene chloride:n-hexane=2:3) to obtain 140 mg of 5-(4-Ethynyl-phenyl)-2,3-dihydro-thieno[3,4-b][1,4]dioxine with the yield of 93%. NMR data of the obtained compound is as follows. [1H NMR (400 MHz, CDCl3): δ 3.10 (s, 1H), 4.23-4.26 (m, 2H), 4.29-4.32 (m, 2H), 6.33 (s, 1H), 7.46 (d, 2H), 7.67 (d, 2H)].
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([C:17]([OH:19])=[O:18])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)(Cl)=O.[CH3:24]O>>[N:11]1([C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:10])[CH2:12][CH2:13][CH:14]([C:17]([O:19][CH3:24])=[O:18])[CH2:15][CH2:16]1
Reactant: CO
Reactant: O=C(O)C1CCN(C(=O)OCc2ccccc2)CC1
Solvent: O=S(Cl)Cl
Product: COC(=O)C1CCN(C(=O)OCc2ccccc2)CC1

Procedure:
1-(Benzyloxycarbonyl)piperidine-4-carboxylic acid (48.5 g) in methanol (485 ml) was cooled to 0° C., and thionyl chloride (13.34 ml) was added dropwise. The mixture was then refluxed for 20 min. (TLC monitoring). When the conversion was complete, the methanol was distilled off and the residue was taken up in water (15 ml) and extracted with ethyl acetate (2×150 ml). The combined organic phases were extracted with water and sat. sodium chloride solution, dried (Na2SO4) and concentrated in vacuo. Yield: 38 g (67%)
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][CH2:9][C:10]1[N:15]=[C:14]([C:16]2[S:17][C:18]3[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=3[C:20](=[O:22])[N:21]=2)[CH:13]=[CH:12][CH:11]=1.[P:27](Cl)([O:32][CH2:33][CH3:34])([O:29][CH2:30][CH3:31])=[S:28].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[O:22]=[C:20]1[C:19]2[CH:23]=[CH:24][CH:25]=[CH:26][C:18]=2[S:17][C:16]([C:14]2[N:15]=[C:10]([CH2:9][NH:8][P:27]([O:32][CH2:33][CH3:34])([O:29][CH2:30][CH3:31])=[S:28])[CH:11]=[CH:12][CH:13]=2)=[N:21]1
Reactant: NCc1cccc(-c2nc(=O)c3ccccc3s2)n1
Reactant: CCOP(=S)(Cl)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Product: CCOP(=S)(NCc1cccc(-c2nc(=O)c3ccccc3s2)n1)OCC
Temperature: 25 °C
Reaction time: 2 h
Yield: 85.9 %

Procedure:
2-[6-(Aminomethyl)-2-pyridyl]-4H-1,3-benzothiazine-4-one trifluoroacetic acid salt (400 mg, 1.0 mmol) and diethyl chlorothiophosphate (410 mg, 2.2 mmol) were dissolved in acetonitrile (15 ml), and potassium carbonate (430 mg, 3.1 mmol) was added thereto. The mixture was stirred at room temperature for 2 hrs. The solvent was evaporated, and the residue was subjected to a silica gel column chromatography. The fractions eluted with ethyl acetate-hexane (1:2, v/v) were collected, concentrated and recrystallized from ethyl acetate-hexane to give the titled compound (362 mg, 82%) as white crystals.
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([NH:10][CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][C:18]4[CH:23]=[CH:22][N:21]=[C:20]([C:24]5[CH:29]=[C:28]([O:30][CH3:31])[C:27]([O:32][CH3:33])=[C:26]([O:34][CH3:35])[CH:25]=5)[CH:19]=4)[CH2:13][CH2:12]3)=[CH:4][C:3]=2[O:2]1.[CH3:36][O:37][C:38]1[CH:39]=[C:40]([C:48]2[CH:49]=[C:50]([CH:53]=[CH:54][CH:55]=2)[CH2:51][Cl:52])[CH:41]=[C:42]([O:46][CH3:47])[C:43]=1[O:44][CH3:45].C1(N)C(F)=C(F)C(F)=C(N)C=1F.[ClH:68].Cl>>[ClH:52].[ClH:68].[CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([N:10]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][C:18]4[CH:23]=[CH:22][N:21]=[C:20]([C:24]5[CH:25]=[C:26]([O:34][CH3:35])[C:27]([O:32][CH3:33])=[C:28]([O:30][CH3:31])[CH:29]=5)[CH:19]=4)[CH2:13][CH2:12]3)[CH2:51][C:50]3[CH:53]=[CH:54][CH:55]=[C:48]([C:40]4[CH:41]=[C:42]([O:46][CH3:47])[C:43]([O:44][CH3:45])=[C:38]([O:37][CH3:36])[CH:39]=4)[CH:49]=3)=[CH:4][C:3]=2[O:2]1
Reactant: COc1cc(-c2cccc(CCl)c2)cc(OC)c1OC
Reactant: COc1cc(-c2cc(CN3CCC(Nc4ccc5c(c4)OCO5)CC3)ccn2)cc(OC)c1OC
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Product: COc1cc(-c2cccc(CN(c3ccc4c(c3)OCO4)C3CCN(Cc4ccnc(-c5cc(OC)c(OC)c(OC)c5)c4)CC3)c2)cc(OC)c1OC

Procedure:
4-(3,4-Methylenedioxyphenylamino)-1-[[2-(3,4,5-trimethoxyphenyl)pyridin-4-yl]methyl]piperidine (119 mg) and 3-(3,4,5-trimethoxyphenyl)benzyl chloride (114 mg) were condensed by the same manner as described in Example 9. Yellow oil of a free base was converted to a dihydrochloride which gave the title compound as yellow powder.
Reaction SMILES: Cl.[NH2:2][OH:3].C([O-])(=O)C.[Na+].[CH3:9][C:10]1([CH3:17])[CH2:15][CH2:14][CH2:13][C:12](=O)[CH2:11]1>O.CO>[CH3:9][C:10]1([CH3:17])[CH2:15][CH2:14][CH2:13][C:12](=[N:2][OH:3])[CH2:11]1
Reactant: CC1(C)CCCC(=O)C1
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC1(C)CCCC(=NO)C1

Procedure:
Hydroxylamine hydrochloride (8.76 g) was dissolved in water (100 mL). To the solution, a solution of sodium acetate (17.8 g) and 3,3-dimethylcyclohexanone (4.55 g) in methanol (20 mL) was added at room temperature, and the mixture was heated to reflux for 1.5 hours. Organic matter was extracted with ethyl acetate and dried over anhydrous sodium sulfate, and the solvent was then distilled off under reduced pressure to obtain a crude product of 3,3-dimethylcyclohexanone oxime.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.Cl[C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20][N:19]=1.CCN(C(C)C)C(C)C>O1CCOCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([CH:11]2[CH2:16][CH2:15][N:14]([C:18]3[C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[CH:21]=[CH:20][N:19]=3)[CH2:13][CH2:12]2)(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: O=S(=O)(c1ccc(Cl)cc1)C1CCNCC1
Reactant: Clc1nccc2ccccc12
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: O=S(=O)(c1ccc(Cl)cc1)C1CCN(c2nccc3ccccc23)CC1
Yield: 10.2 %

Procedure:
Using the procedure from Example 7A, 4-[(4-chlorophenyl)sulfonyl]piperidine (100 mg, 0.38 mmol) was reacted with 1-chloroisoquinoline (131 mg, 0.76 mmol), DIEA (0.27 ml, 1.52) and 1,4-dioxane (0.3 ml) at 190° C. to afford the title compound (15 mg), an off-white solid, in 10% yield.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[N+:17]([O-:19])=[O:18])[C:5]([NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:6].[C:20]([O:24][C:25](=[O:34])[NH:26][CH2:27][CH:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1)([CH3:23])([CH3:22])[CH3:21].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:20]([O:24][C:25](=[O:34])[NH:26][CH2:27][CH:28]1[CH2:29][CH2:30][N:31]([C:2]2[CH:3]=[C:4]([C:5](=[O:6])[NH:7][C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH:14]=[CH:15][C:16]=2[N+:17]([O-:19])=[O:18])[CH2:32][CH2:33]1)([CH3:23])([CH3:21])[CH3:22]
Reactant: CC(C)(C)OC(=O)NCC1CCNCC1
Reactant: O=C(Nc1ccccc1)c1ccc([N+](=O)[O-])c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCC1CCN(c2cc(C(=O)Nc3ccccc3)ccc2[N+](=O)[O-])CC1
Temperature: 50 °C
Yield: 61 %

Procedure:
To a solution of 3-chloro-4-nitro-N-phenyl-benzamide (0.13 g, 0.47 mmol) in N,N-dimethylformamide (10 mL) were added piperidin-4-ylmethyl-carbamic acid tert-butyl ester (0.12 g, 0.56 mmol) and potassium carbonate (0.1 g, 0.72 mmol) and the resulting mixture was heated at 50° C. overnight. The reaction mixture was then heated at 80° C. for 8 hours; then more piperidin-4-ylmethyl-carbamic acid tert-butyl ester (0.33 mmol) and potassium carbonate (0.14 g, 1 mmol) were added and the resulting mixture was heated at 85° C. overnight. The reaction mixture was partitioned between water and ethyl acetate, the organic layer was separated and the aqueous layer was extracted twice with ethyl acetate. The combined organic extracts were washed with water and brine, dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The crude residue was purified on a silica gel plug (hexane/EtOAc, 20/80 to 40/60) to give 0.13 g, (61% yield) of [1-(2-nitro-5-phenylcarbamoyl-phenyl)-piperidin-4-ylmethyl]-carbamic acid tert-butyl ester as on orange colored solid.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]1([C:24]3[C:15](=[CH:16][C:17]4[O:22][CH2:21][CH2:20][O:19][C:18]=4[CH:23]=3)[O:14][CH2:13]1)[C:5](=[O:12])[N:6]2[CH3:11].[CH:25]1([C:29](Cl)=[O:30])[CH2:28][CH2:27][CH2:26]1>ClCCl.N1C=CC=CC=1>[CH3:11][N:6]1[C:7]2[C:3](=[C:2]([NH:1][C:29]([CH:25]3[CH2:28][CH2:27][CH2:26]3)=[O:30])[CH:10]=[CH:9][CH:8]=2)[C:4]2([C:24]3[C:15](=[CH:16][C:17]4[O:22][CH2:21][CH2:20][O:19][C:18]=4[CH:23]=3)[O:14][CH2:13]2)[C:5]1=[O:12]
Reactant: CN1C(=O)C2(COc3cc4c(cc32)OCCO4)c2c(N)cccc21
Reactant: O=C(Cl)C1CCC1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CN1C(=O)C2(COc3cc4c(cc32)OCCO4)c2c(NC(=O)C3CCC3)cccc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 83.1 %

Procedure:
To a solution of 4′-amino-1′-methyl-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one (700 mg, 1.72 mmol) in dichloromethane (50 mL) and pyridine (5 mL) was added cyclobutanecarbonyl chloride (0.17 mL, 1.48 mmol) at 0° C. The reaction mixture was stirred at ambient temperature for 18 h, diluted with dichloromethane (150 mL), washed sequentially with water, 10% w/v hydrochloric acid, water and brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo. The residue was subjected to column chromatography and eluted with ethyl acetate/hexanes (1/3) to afford N-(1′-methyl-2′-oxo-1′,2,2′,3-tetrahydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-4′-yl)cyclobutanecarboxamide (0.50 g, 71%): mp 234-236° C. (ethyl acetate/hexanes); 1H NMR (300 MHz, DMSO-d6) δ 8.15 (s, 1H), 7.32-7.26 (m, 1H), 7.11-7.08 (m, 1H), 6.94-6.91 (m, 1H), 6.43 (s, 1H), 6.17 (s, 1H), 4.68 (ABq, 2H), 4.13-4.05 (m, 4H), 3.15 (s, 3H), 2.96-2.90 (m, 1H), 2.05-1.64 (m, 6H); 13C NMR (75 MHz, DMSO-d6) δ 176.6, 173.5, 155.1, 144.6, 144.3, 138.3, 134.6, 129.5, 125.3, 120.8, 119.4, 112.0, 106.8, 98.8, 78.2, 64.6, 64.0, 57.1, 27.1, 25.0, 24.9, 17.9; MS (ES+) m/z 406.9 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]([O:13][CH3:14])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1.[Li]CCCC.Cl[C:21]([O:23][CH2:24][CH3:25])=[O:22].O>C1COCC1>[CH3:1][O:2][C:3]1[C:12]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[C:11]([O:13][CH3:14])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1
Reactant: CCOC(=O)Cl
Reactant: COc1cc(OC)c2ccccc2n1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)c1c(OC)nc2ccccc2c1OC
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 60 %

Procedure:
To a solution of 2,4-dimethoxyquinoline (11.5 g, 60.8 mmol) in anhydrous THF was added dropwise n-BuLi (2.5 M in hexane, 48.6 mL, 122 mmol) at 0° C. After stirring for 1.5 h at 0° C., the mixture was added to a solution of ethyl chloroformate in anhydrous THF and stirred at 0° C. for additional 30 min and then at room temperature overnight. The reaction mixture was poured into water and extracted with CH2Cl2. The organic layer was dried over Na2SO4 and concentrated under vacuum. The resulting residue was purified by column chromatography (petroleum ether/EtOAc=50/1) to give ethyl 2,4-dimethoxyquinoline-3-carboxylate (9.6 g, 60%).
Reaction SMILES: [H-].[Na+].[C:3]1([CH2:9][CH2:10][CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[OH:19])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl.[CH3:21][N:22]([CH3:27])[CH2:23][CH2:24][CH2:25]Cl>CC(N(C)C)=O>[CH3:21][N:22]([CH2:23][CH2:24][CH2:25][O:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[CH2:12][CH2:11][CH2:10][CH2:9][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1)[CH3:27]
Reactant: Oc1ccccc1CCCCc1ccccc1
Reactant: CN(C)CCCCl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: CN(C)CCCOc1ccccc1CCCCc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 67.5 %

Procedure:
96 mg of sodium hydride (as a 55% w/w dispersion in mineral oil) were added, whilst ice-cooling and stirring, to a solution of 226 mg of 2-(4-phenylbutyl)phenol (prepared as described in Preparation 3) in 10 ml of dimethylacetamide, and the resulting mixture was stirred at the same temperature for 30 minutes. At the end of this time, 174 mg of 3-dimethylaminopropyl chloride hydrochloride were added, and the reaction mixture was stirred at 70° C. for 14 hours. It was then poured into ice-water, and the aqueous mixture was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate and concentrated by evaporation under reduced pressure. The oily residue was purified by column chromatography through silica gel, using a 10:1 by volume mixture of methylene chloride and methanol as the eluent, to give 210 mg (yield 67%) of the title compound as a pale yellow oil.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[NH:12][CH2:13][C:14]1([OH:27])[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]1)=[CH:9][CH:8]=[CH:7][CH:6]=2.C(N(CC)CC)C.[CH2:35]([O:37][CH2:38][C:39](Cl)=O)[CH3:36]>ClCCl>[CH2:35]([O:37][CH2:38][C:39]1[N:12]([CH2:13][C:14]2([OH:27])[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:24])([CH3:26])[CH3:25])=[O:21])[CH2:16][CH2:15]2)[C:11]2[C:10]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[N:4]=[CH:3][C:2]=2[N:1]=1)[CH3:36]
Reactant: CC(C)(C)OC(=O)N1CCC(O)(CNc2c(N)cnc3ccccc23)CC1
Reactant: CCOCC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOCc1nc2cnc3ccccc3c2n1CC1(O)CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 3 h

Procedure:
To a solution of tert-butyl 4-{[(3-aminoquinolin-4-yl)amino]methyl}-4-hydroxypiperidine-1-carboxylate (50.3 mmol, prepared as described above) in dichloromethane (330 mL) at 0° C. was added triethylamine (8 mL, 57.4 mmol) followed by dropwise addition of ethoxyacetyl chloride (88%, 6.59 g, 50.3 mmol). After 3 h at rt, more triethylamine (4 mL) and acid chloride (1.70 g) were added. The solution was stirred 1 h, then concentrated in vacuo to a foam and ethanol (400 mL) and triethylamine (24 mL) were added. The resulting solution was heated at reflux for 20 h and then concentrated in vacuo. The residue was dissolved in dichloromethane (600 mL) and washed with water (2×200 mL) and brine (2×250 mL). The organic layer was dried twice over MgSO4, filtered, and concentrated to an oil. The oil was purified twice by flash chromatography (silica gel, gradient elution with 3-5% methanol/dichloromethane) to provide tert-butyl 4-{[2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]methyl}-4-hydroxypiperidine-1-carboxylate as a yellow foam containing dichloromethane (13.13 g). Based on 1H NMR integration, the calculated amount of product was 12.59 g (57%).
Reaction SMILES: [CH2:1]([C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[C:5]([O:23]COC)=[C:6]([O:21][CH3:22])[CH:7]=[C:8]2/[CH:13]=[C:14](/[CH3:20])\[C:15]([O:17]CC)=[O:16])[CH3:2].[OH-].[K+].Cl>C(O)C>[CH2:1]([C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[C:5]([OH:23])=[C:6]([O:21][CH3:22])[CH:7]=[C:8]2/[CH:13]=[C:14](/[CH3:20])\[C:15]([OH:17])=[O:16])[CH3:2]
Reactant: CCOC(=O)/C(C)=C\c1cc(OC)c(OCOC)c2c(CC)cccc12
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCc1cccc2c(/C=C(/C)C(=O)O)cc(OC)c(O)c12
Yield: 116 %

Procedure:
71.2 g of ethyl (Z)-3-(5-ethyl-3-methoxy-4-methoxymethoxy-1-naphthyl)-2-methylpropenoate was dissolved in 600 ml of ethanol and a potassium hydroxide aqueous solution (potassium hydroxide 71 g/water 140 ml) was added, followed by refluxing for 1 hour. The reaction mixture was cooled on an ice bath, after which 700 ml of 2N hydrochloric acid was added to make it acidic, followed by extraction with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate. The solvent was evaporated to obtain 66 g of the titled compound as a yellow oil.
Reaction SMILES: C([Li])CCC.CC1(C)CCCC(C)(C)N1.[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=1.CN(C)[CH:26]=[O:27]>CCCCCC.O1CCCC1>[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([F:23])=[C:19]([CH:18]=1)[CH:26]=[O:27]
Reactant: CN(C)C=O
Reactant: Fc1ccc(Cl)cc1
Agent: CC1(C)CCCC(C)(C)N1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: O=Cc1cc(Cl)ccc1F
Temperature: 0 °C
Reaction time: 2 h
Yield: 64.6 %

Procedure:
To a solution of 1.6M butyllithium in hexane (32 ml) was added anhydrous tetrahydrofuran (100 ml), and then added dropwise 2,2,6,6-tetramethylpiperidine (8.4 ml) at −70° C. or less. To the mixture was added dropwise a solution of 1-chloro-4-fluorobenzene (6.5 g) in anhydrous tetrahydrofuran (20 ml), and the mixture was stirred at −70° C. or less for 2 hours. To the mixture was added dropwise a solution of dimethylformamide (6.5 g) in tetrahydrofuran (15 ml), and the mixture was allowed to stand to warm up to 0° C. The reaction solution was poured into ice-water and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried with magnesium sulfate. Under reduced pressure, the solvent was evaporated to give oil of 5-chloro-2-fluorobenzaldehyde (5.1 g).
Reaction SMILES: [Si]([O:8][C:9]1[C:10](=[O:23])[N:11]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18](Cl)[CH:17]=2)[CH:12]=[CH:13][CH:14]=1)(C(C)(C)C)(C)C.[ClH:24]>CCOC(C)=O>[Cl:24][C:19]1[CH:20]=[CH:21][C:16]([CH2:15][N:11]2[CH:12]=[CH:13][CH:14]=[C:9]([OH:8])[C:10]2=[O:23])=[CH:17][CH:18]=1
Reactant: CC(C)(C)[Si](C)(C)Oc1cccn(Cc2cccc(Cl)c2)c1=O
Reactant: Cl
Solvent: CCOC(C)=O
Product: O=c1c(O)cccn1Cc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 3-(tert-butyldimethylsilanyloxy)-1-(3-chlorobenzyl)-1H-pyridin-2-one, 2, (2.36 g, 10 mmol) in EtOAc (25 mL) as added 5 M HCl (25 mL) with vigorous stirring at room temperature. The reaction was monitored by TLC for the disappearance of starting material and was complete within 30 minutes. The organic layer was decanted and the aqueous phase extracted with dichloromethane (2×50 mL). The combined organic layers were dried over Na2SO4 and the solvent removed under reduced pressure. The crude product was recrystallized from dichloromethane. The yield was nearly quantitative. 1H NMR (360 MHz, DMSO-d6) δ ppm 5.12 (2H, s); 6.13 (1H, t, J=7.04); 6.71 (1H, dd, J=7.04, 1.59); 7.23-7.28 (2H, m); 7.36-7.43 (2H, m); 9.10 (1H, br. s).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([S:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:5]([NH2:8])=[N:6][CH:7]=1.[C:16]([N:24]=[C:25]=[S:26])(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C1COCC1>[C:16]([NH:24][C:25]([NH:8][C:5]1[C:4]([S:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:3][C:2]([Br:1])=[CH:7][N:6]=1)=[S:26])(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: Nc1ncc(Br)cc1Sc1ccccc1
Reactant: O=C(N=C=S)c1ccccc1
Solvent: C1CCOC1
Product: O=C(NC(=S)Nc1ncc(Br)cc1Sc1ccccc1)c1ccccc1
Yield: 95.6 %

Procedure:
5-Bromo-3-(phenylthio)pyridin-2-amine (17 g, 60.5 mmol), benzoyl isothiocyanate (9.79 mL, 72.6 mmol), and THF (300 mL) were stirred at 40° C. overnight. The THF was concentrated to ˜1/2 volume and 9:1 hexanes:EtOAc (500 mL) added and precipitate filtered to afford the title compound (25.7 g, 95.7% yield).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5](Cl)=[CH:6][CH:7]=1.[O:9]1[CH2:14][CH2:13][CH:12]([CH2:15][OH:16])[CH2:11][CH2:10]1>>[Cl:1][C:2]1[N:3]=[N:4][C:5]([O:16][CH2:15][CH:12]2[CH2:13][CH2:14][O:9][CH2:10][CH2:11]2)=[CH:6][CH:7]=1
Reactant: OCC1CCOCC1
Reactant: Clc1ccc(Cl)nn1
Product: Clc1ccc(OCC2CCOCC2)nn1

Procedure:
3,6-Dichloropyridazine (1.0 g, 6.712 mmol) was reacted analogously to example 4a with (tetrahydropyran-4-yl)methanol (779 mg, 6.712 mmol). Yield: 683 mg (45%), M+H+: 229.1.
Reaction SMILES: [CH2:1]([C:8]1[C:9]([CH3:15])=[C:10]([OH:14])[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Mg+2].[Cl-].[Cl-].[CH2:19]=[O:20].Cl>C(#N)C>[CH2:1]([C:8]1[CH:13]=[CH:12][C:11]([CH:19]=[O:20])=[C:10]([OH:14])[C:9]=1[CH3:15])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=O
Reactant: Cc1c(O)cccc1Cc1ccccc1
Agent: Cl
Agent: [Cl-]
Agent: [Mg+2]
Solvent: CC#N
Product: Cc1c(Cc2ccccc2)ccc(C=O)c1O
Yield: 91 %

Procedure:
To a solution of 3-benzyl-2-methylphenol prepared as in Step 3 (1.06 g, 5.36 mmole) in anhydrous acetonitrile (25 mL) were added MgCl2 (0.776 g, 8.04 mmole), TEA (2.80 mL, 20.1 mmole) and paraformaldehyde (1.09 g, 36.2 mmole), and the resulting mixture was refluxed under a dry N2 atmosphere for 3 h. The mixture was then cooled, acidified with 1 N HCl and extracted with EtOAc (2×100 ml). The combined extracts were washed with brine (100 ml), dried over MgSO4, filtered and concentrated in vacuo to give 1.10 g (91% yield) of the product as a pale yellow oil: EIHRMS m/z 226.1008 (M+, C15H14O2, Calc'd 226.0994).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([NH2:9])[CH:4]=1.[CH3:10][C:11]([O:14][C:15]([NH:17][C@@H:18]1[C:21](=[O:22])[O:20][CH2:19]1)=[O:16])([CH3:13])[CH3:12]>C1COCC1>[OH:22][CH2:21][CH:18]([NH:17][C:15](=[O:16])[O:14][C:11]([CH3:12])([CH3:10])[CH3:13])[C:19]([NH:9][C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=1)=[O:20]
Reactant: CC(C)(C)OC(=O)N[C@H]1COC1=O
Reactant: COc1cccc(N)c1
Solvent: C1CCOC1
Product: COc1cccc(NC(=O)C(CO)NC(=O)OC(C)(C)C)c1

Procedure:
To a solution of m-anisidine (171 mg, 1.38 mmol) in THF (30 ml), N-(tert-butoxycarbonyl)-L-serine β-lactone (200 mg, 1.06 mmol) was added, and the mixture was refluxed overnight under argon. The reaction mixture was concentrated on a rotary evaporator. The residue was subjected to flash column chromatography, eluting with EtOAc/hexanes of various compositions.