Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13]4=[C:14]([O:22][CH2:23][CH2:24][N:12]4[CH:11]=2)[CH:15]=[C:16](I)[CH:17]=3)=[O:9])=[CH:4][CH:3]=1.[CH2:27]([OH:30])[C:28]#[CH:29].O>C(NCC)C.CO.[Cu+].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>[Cl:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13]4=[C:14]([O:22][CH2:23][CH2:24][N:12]4[CH:11]=2)[CH:15]=[C:16]([C:29]#[C:28][CH2:27][OH:30])[CH:17]=3)=[O:9])=[CH:4][CH:3]=1
Reactant: C#CCO
Reactant: O=C(NCc1ccc(Cl)cc1)c1cn2c3c(cc(I)cc3c1=O)OCC2
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu+]
Solvent: CCNCC
Solvent: CO
Solvent: O
Product: O=C(NCc1ccc(Cl)cc1)c1cn2c3c(cc(C#CCO)cc3c1=O)OCC2
Reaction time: 18 h

Procedure:
To a mixture of 539 mg of N-(4-chlorobenzyl)-9-iodo-7-oxo-2,3-dihydro-7H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxamide of Preparation 10, 78 mg of copper (I) odide, and 30 mg of bis(triphenylphosphine)palladium dichloride in 11 mL of diethylamine, stirred vigorously under argon, is added 82 μL of propargyl alcohol. The mixture is stirred for 18 hours, then diluted with a little methanol and added to 120 mL of stirred water. The precipitated solid is filtered, washed well with water, and dried in vacuo. The solid is then dissolved in chloroform-methanol, and the solution is filtered to remove copper salts and then absorbed onto silica gel. Flash chromatography eluting with 2-6% methanol in dichloromethane provides 217 mg of the title compound.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([N:7]2[CH2:12][CH2:11][O:10][CH2:9][CH2:8]2)[CH2:3][CH2:2]1.[Br:13][C:14]1[CH:19]=[CH:18][C:17](B(O)O)=[CH:16][CH:15]=1.N1C=CC=CC=1.ClCCl>O>[Br:13][C:14]1[CH:19]=[CH:18][C:17]([N:1]2[CH2:6][CH2:5][CH:4]([N:7]3[CH2:12][CH2:11][O:10][CH2:9][CH2:8]3)[CH2:3][CH2:2]2)=[CH:16][CH:15]=1
Reactant: OB(O)c1ccc(Br)cc1
Reactant: C1CC(N2CCOCC2)CCN1
Solvent: c1ccncc1
Solvent: O
Solvent: ClCCl
Product: Brc1ccc(N2CCC(N3CCOCC3)CC2)cc1
Temperature: 25 °C
Reaction time: 144 h

Procedure:
A round bottom flask equipped with a drying tube was charged with 4-piperidin-4-yl-morpholine (0.21 g, 1.2 mmol), cupric acetate (0.34 g, 1.9 mmol), 4-bromobenzeneboronic acid (0.50 g, 2.5 mmol), pyridine (0.20 mL, 2.5 mmol) and dichloromethane (5 mL, 80 mmol). The blue suspension was stirred open to the air for 6 days at room temperature. Water (25 mL) was added to the green-brown suspension and stirred for 10 minutes. The mixture was extracted with ethyl acetate (3×25 mL). The combined organic layer was washed with saturated aqueous sodium chloride (25 mL), dried over magnesium sulfate, filtered and evaporated. The residue was purified via chromatography using silica gel column (40 g) and 0%→8% methanol: dichloromethane solvent gradient. 4-[1-(4-Bromo-phenyl)-piperidin-4-yl]-morpholine was isolated as a tan solid (0.168 g, 41%). MP=146-149° C. 1H NMR (400 MHz, CDCl3, δ, ppm): 7.32 (d, J=7.5 Hz, 2H), 6.79 (d, J=7.8 Hz, 2H), 3.76-3.71 (m, 4H), 3.68 (d, J=12.8 Hz, 2H), 2.71 (t, J=12.3 Hz, 2H), 2.60-2.54 (m, 4H), 2.37-2.27 (m, 1H), 1.93 (d, J=11.3 Hz, 2H), 1.69-1.58 (m, 2H). MS=325, 327 (MH)+. 49b) [8-(4-Methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[4-(4-morpholin-4-yl-piperidin-1-yl)-phenyl]-amine was prepared from 8-(4-methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine (50.0 mg, 0.173 mmol) and 4-[1-(4-bromo-phenyl)-piperidin-4-yl]-morpholine (65.0 mg, 0.200 mmol) with 2,2′-bis-dicyclohexylphosphanyl-biphenyl (20.0 mg, 0.0366 mmol) as the ligand in a manner analogous to Step 2d. The title compound was isolated as a yellow solid (0.044 g, 48%). MP=253-254° C. 1H NMR (400 MHz, CDCl3, δ, ppm): 8.47 (d, J=6.3 Hz, 1H), 8.23 (d, J=7.5 Hz, 2H), 8.08 (d, J=8.2 Hz, 2H), 7.63 (d, J=7.3 Hz, 1H), 7.47 (d, J=7.1 Hz, 2H), 7.01-6.95 (m, 3H), 6.68 (s, 1H), 3.77-3.72 (m, 4H), 3.69-3.62 (m, 2H), 3.10 (s, 3H), 2.74-2.65 (m, 2H), 2.62-2.57 (m, 4H), 2.36-2.28 (m, 1H), 1.98-1.92 (m, 2H), 1.75-1.63 (m, 2H). MS=533 (MH)+.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.[NH2:10][C:11]1[CH:15]=[CH:14][NH:13][N:12]=1.[CH3:16][O:17][CH:18]([O:27][CH3:28])[C:19](=O)[CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22]>>[Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]1[C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[C:19]([CH:18]([O:17][CH3:16])[O:27][CH3:28])[NH:10][C:11]2=[N:12][NH:13][CH:14]=[C:15]12
Reactant: CCOC(=O)CC(=O)C(OC)OC
Reactant: O=Cc1ccccc1Cl
Reactant: Nc1cc[nH]n1
Product: CCOC(=O)C1=C(C(OC)OC)Nc2n[nH]cc2C1c1ccccc1Cl

Procedure:
The title compound was prepared from 2-chlorobenzaldehyde, 3-aminopyrazole and ethyl 4,4-dimethoxy-3-oxobutanoate in the same manner as in Example 1.
Reaction SMILES: [CH:1]1([CH:7]([N:20]2[C:24]3[CH:25]=[C:26]([F:30])[C:27]([F:29])=[CH:28][C:23]=3[N:22]=[C:21]2[C:31]2[C:32]([O:39][CH3:40])=[N:33][C:34]([O:37][CH3:38])=[CH:35][CH:36]=2)[CH2:8][O:9][C:10]2[C:17]([CH3:18])=[CH:16][C:13]([C:14]#[N:15])=[CH:12][C:11]=2[CH3:19])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.C(N(CC)CC)C.[N-:49]=[N+:50]=[N-:51].[Na+].Cl>CC1C=CC=CC=1C>[CH:1]1([CH:7]([N:20]2[C:24]3[CH:25]=[C:26]([F:30])[C:27]([F:29])=[CH:28][C:23]=3[N:22]=[C:21]2[C:31]2[C:32]([O:39][CH3:40])=[N:33][C:34]([O:37][CH3:38])=[CH:35][CH:36]=2)[CH2:8][O:9][C:10]2[C:11]([CH3:19])=[CH:12][C:13]([C:14]3[NH:51][N:50]=[N:49][N:15]=3)=[CH:16][C:17]=2[CH3:18])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: [N-]=[N+]=[N-]
Reactant: COc1ccc(-c2nc3cc(F)c(F)cc3n2C(COc2c(C)cc(C#N)cc2C)C2CCCCC2)c(OC)n1
Agent: Cl
Agent: [Na+]
Solvent: Cc1ccccc1C
Solvent: CCN(CC)CC
Product: COc1ccc(-c2nc3cc(F)c(F)cc3n2C(COc2c(C)cc(-c3nnn[nH]3)cc2C)C2CCCCC2)c(OC)n1
Temperature: 145 °C
Reaction time: 8 h

Procedure:
To a solution of 0.18 g (0.33 mmol) 4-{2-cyclohexyl-2-[2-(2,6-dimethoxy-pyridin-3-yl)-5,6-difluoro-benzoimidazol-1-yl]-ethoxy}-3,5-dimethyl-benzonitrile in 3 ml o-xylene were added 0.227 g (1.65 mmol) triethylamine hydrochloride and 0.107 g (2.65 mMol) sodium azide and the solution was heated for 7 h at 145° C. (oil bath temperature). The reaction was allowed to cool down to room temperature overnight and then was poured onto 1M aqueous hydrochloric acid solution and extracted three times with ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulfate, filtered and evaporated. The remaining oil was dissolved in acetonitrile, the solution was completely evaporated and the residue dissolved in 20 ml tert-butyl methyl ether under warming to 45° C. The solution was partially evaporated, then stored at 4° C. overnight. The resulting suspension was filtered, washed with tert-butyl methyl ether and dried under high vacuum. Light brown solid (75%). MS (Turbo Spray): m/z=590.44 [M+H].
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[Br:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Br:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][C:2]2[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=2[C:4]#[N:5])=[CH:13][CH:12]=1
Reactant: Oc1ccc(Br)cc1
Reactant: N#Cc1ccccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#Cc1ccccc1Oc1ccc(Br)cc1
Temperature: 120 °C
Reaction time: 5 h

Procedure:
A mixture of 2-fluorobenzonitrile (28.8 g), 4-bromophenol (36.9 g), potassium carbonate (58.9 g) and dimethylformamide (30 ml) was heated with stirring under nitrogen at 120° C. for 5 hours. The mixture was allowed to stand overnight at ambient temperature and then partitioned between ethyl acetate and water. The organic layer was separated, washed, dried and evaporated to give an oil which solidified on standing. The solid was triturated with petroleum ether b.p. 40-60° C. and filtered to give 2-(4-bromophenoxy)benzonitrile.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([CH3:13])=[CH:11][NH:10][C:9]=2[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:4][CH:3]=1.[H-].[Na+].[CH2:21](Br)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.CCOC(C)=O>CN(C=O)C.[Cl-].[Na+].O>[CH2:21]([N:10]1[CH:11]=[C:12]([CH3:13])[C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)=[C:9]1[C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: BrCc1ccccc1
Reactant: CCOC(=O)c1[nH]cc(C)c1-c1ccc(Cl)cc1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1c(-c2ccc(Cl)cc2)c(C)cn1Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 69.6 %

Procedure:
Ethyl 3-(4-chlorophenyl)-4-methyl-1H-pyrrole-2-carboxylate (9 g, 34.1 mmol) was dissolved in dry DMF (20 mL). At 0° C., 60% NaH in mineral oil (1.365 g, 34.1 mmol) was added. After 20 min gas evolution had ceased and benzyl bromide (4.08 mL, 34.1 mmol) was added. The reaction mixture was stirred at room temperature overnight. Brine (400 mL) was added, followed by EtOAc (400 mL). The organic layer was washed with H2O (2×400 mL), brine (400 mL), dried (Na2SO4) and evaporated under reduced pressure. The product was purified by column chromatography (silica, heptane/EtOAc, 9:1), to yield 8.40 g (70%) of the desired product.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([I:8])[CH:3]=1.C(B(CC)[C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1)C.CN(C=O)C>O>[I:8][C:4]1[CH:3]=[C:2]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[CH:7]=[CH:6][CH:5]=1
Reactant: CCB(CC)c1cccnc1
Reactant: Ic1cccc(I)c1
Solvent: CN(C)C=O
Solvent: O
Product: Ic1cccc(-c2cccnc2)c1

Procedure:
A solution of 1,3-diiodobenzene (1.10 g, 3.3 mmol), 3-(diethylboryl)pyridine (0.48 g, 3.3 mmol), tetrakis(triphenlyphosphine)palladium(0) (0.010 g, 0.0086 mmol) potassium carbonate (0.922 g, 6.64 mmol), in mixed solvent of 3 mL DMF and 1 mL water, was heated at 150° C. for 5 minutes under microwave irradiation. The reaction mixture was quenched with H2O (30 mL), then extracted with EtOAc (3×30 mL) and the combined organic extracts washed with brine. The organic phase was dried over Na2SO4 and concentrated in vacuo. The crude purified by liquid chromatography on silica gel using an ISCO single channel system (Hexane/EtOAc=9/1 to 1/9) to afford 3-(3-iodophenyl)pyridine as a yellow oil.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]#[N:9])=[CH:4][N:3]=1.[CH3:10][S-:11].[Na+].C1COCC1.C(OCC)(=O)C>O>[C:8]([C:5]1[CH:6]=[CH:7][C:2]([S:11][CH3:10])=[N:3][CH:4]=1)#[N:9]
Reactant: C[S-]
Reactant: N#Cc1ccc(Cl)nc1
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: CSc1ccc(C#N)cn1
Yield: 99.6 %

Procedure:
2-Chloro-5-cyanopyridine (2.10 g, 15.1 mmol) and sodium thiomethoxide (1.16 g, 16.5 mmol) were added to THF (30 ml). The reaction mixture was refluxed for 9 hrs and combined with ethyl acetate and water. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated to give the titled compound (2.26 g, 100%) as pale yellow crystals.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH:11]([C:13](O)=[O:14])[CH2:10][C:9]1=[O:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:17](N1C=CN=C1)([N:19]1C=CN=C1)=O.CN>C(Cl)Cl>[CH3:17][NH:19][C:13]([CH:11]1[CH2:12][N:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:9](=[O:16])[CH2:10]1)=[O:14]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: O=C(O)C1CC(=O)N(Cc2ccccc2)C1
Agent: CN
Solvent: ClCCl
Product: CNC(=O)C1CC(=O)N(Cc2ccccc2)C1
Reaction time: 1 h

Procedure:
0.2 mole of (1-benzyl-2-oxo-4-pyrrolidinyl)carboxylic acid (described in Journal of Organic Chemistry, 1961; 26: p 1519) is dissolved in 200 cm3 of methylene chloride. The mixture is treated with 32.4 g of carbonyldiimidazole. It is left in contact for 1 hour and then a solution consisting of 20 g of methylamine and 200 cm3 of methylene chloride is added. The mixture is left in contact for 12 hours at room temperature, washed with water and then dried over magnesium sulfate. An oil which is the expected compound is obtained.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:11][C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([Cl:19])[CH:13]=2)=[C:6]([CH:10]=1)[CH2:7][NH:8][CH3:9].[NH2:20][C:21]1[CH:25]=[CH:24][NH:23][N:22]=1.C(=O)([O-])[O-].[K+].[K+]>[Cu]>[ClH:18].[ClH:18].[Cl:19][C:14]1[CH:13]=[C:12]([CH:17]=[CH:16][C:15]=1[Cl:18])[O:11][C:5]1[CH:4]=[CH:3][C:2]([N:23]2[CH:24]=[CH:25][C:21]([NH2:20])=[N:22]2)=[CH:10][C:6]=1[CH2:7][NH:8][CH3:9]
Reactant: CNCc1cc(Br)ccc1Oc1ccc(Cl)c(Cl)c1
Reactant: Nc1cc[nH]n1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CNCc1cc(-n2ccc(N)n2)ccc1Oc1ccc(Cl)c(Cl)c1
Product: Cl

Procedure:
Under N2 in a flame-dried 15 mL round bottomed flask, fitted with a magnetic stirrer were placed 318 mg (0.88 mmol) of 5-bromo-2-(3,4-dichlorophenoxy)-N-methylbenzylamine (title compound of Example 15), 1.50 g (18 mmol) of 3-aminopyrazole, 56 mg (0.88 mmol) of copper powder and 122 mg (0.88 mmol) of potassium carbonate. The mixture was heated to 130° C. for a total of one hour, cooled and stirred at room temperature overnight. The tarry residue was partitioned between EtOAc and dilute aqueous EDTA (ethylenediaminetetraacetic acid), the organic layer was washed with water and saturated aqueous NaCl, then dried over Na2SO4. After filtration the solvent was removed in vacuo to give an oil, 287 mg, which was eluted on silica gel with a gradient system of NH4OH:CH3OH:CHCl3 (from 2:2:96 to 2:10:88). The product fractions were concentrated to an oil (110 mg) which was dissolved in 25 mL EtOAc and treated with 0.6 mL of 1 N HCl in Et2O. The solids which precipitated were filtered, washed with a small amount of Et2O and dried under vacuum to give 60 mg of the title product, m.p. 225-233° C.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][NH:6][S:7]([C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:12][CH:11]=1)(=[O:9])=[O:8].Br[CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]>>[OH:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]([CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[S:7]([C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:12][CH:11]=1)(=[O:9])=[O:8]
Reactant: O=S(=O)(NCCCCO)c1ccc(-c2ccccc2)cc1
Reactant: CCCCCBr
Product: CCCCCN(CCCCO)S(=O)(=O)c1ccc(-c2ccccc2)cc1

Procedure:
Using a method analogous to that described in Example 4, with biphenyl-4-sulfonic acid-(4-hydroxybutyl)-amide and bromopentane, reacted at 60° C. for 3 hours, the title compound was obtained as an amorphous white solid. δC (CDCl3, 62.9 MHz): 14.0, 22.3, 25.3, 28.4, 29.6, 48.1, 48.4, 62.2, 127.3, 127.6, 128.4, 129.0, 138.5, 139.4 and 145.2. δH (CDCl3, 250 MHz): 0.84 (3H, t, J 7.0), 1.24 (4H, m), 1.50 (6H, m), 2.06 (1H, s), 3.14 (4H, m), 3.62 (2H, t, J 5.95), 7.41 (3H, m), 7.56 (2H, d, J 7.94), 7.67 (2H, d, J 8.55) and 7.83 (2H, d, J 8.24).
Reaction SMILES: [CH3:1][C:2]1[CH:25]=[CH:24][C:5]2[N:6]=[C:7]([C:9]3[CH:23]=[CH:22][C:12]([CH2:13]P(=O)(OCC)OCC)=[CH:11][CH:10]=3)[S:8][C:4]=2[CH:3]=1.CC(C)([O-])C.[K+].[CH:32](=O)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.CCCCCC.CCOC(C)=O>C1COCC1>[CH3:1][C:2]1[CH:25]=[CH:24][C:5]2[N:6]=[C:7]([C:9]3[CH:10]=[CH:11][C:12](/[CH:13]=[CH:32]/[C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)=[CH:22][CH:23]=3)[S:8][C:4]=2[CH:3]=1
Reactant: O=Cc1ccccc1
Reactant: CCOP(=O)(Cc1ccc(-c2nc3ccc(C)cc3s2)cc1)OCC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1ccc2nc(-c3ccc(/C=C/c4ccccc4)cc3)sc2c1
Yield: 61.1 %

Procedure:
Prepared as described in the Alkene Formation section using diethyl 4-(6-methylbenzothiazol-2-yl)benzylphosphonate (0.30 g, 0.80 mmol) in dry THF (15 ml), potassium t-butoxide (0.10 g, 0.88 mmol) and benzaldehyde (0.085 g, 0.80 mmol) in dry THF (5 ml) to give the title compound (0.16 g, 60%) as a pale yellow solid after work-up and flash chromatography (2:1 Hexane/EtOAc).
Reaction SMILES: [F:1][C:2]1[N:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.Cl[C:10]1[C:19]2[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=2)[N:13]=[CH:12][CH:11]=1.O>CN(C)C1C=CN=CC=1.ClC1C=CC=CC=1Cl>[F:1][C:2]1[N:7]=[CH:6][C:5]([O:8][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][CH:11]=2)=[CH:4][CH:3]=1
Reactant: Oc1ccc(F)nc1
Reactant: COc1cc2nccc(Cl)c2cc1OC
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: Clc1ccccc1Cl
Product: COc1cc2nccc(Oc3ccc(F)nc3)c2cc1OC
Temperature: 140 °C
Reaction time: 3.5 h
Yield: 75.3 %

Procedure:
6-Fluoro-3-hydroxypyridine (10 mg), 4-chloro-6,7-dimethoxyquinoline (59 mg), and 4-dimethylaminopyridine (32 mg) were suspended in o-dichlorobenzene (2 ml), and the suspension was stirred at 140° C. for 3.5 hr. The reaction solution was cooled to room temperature, water was then added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using acetone-chloroform to give the title compound (20 mg, yield 76%).
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7](Br)=[CH:6][CH:5]=1)=[O:3].C([Sn](CCCC)(CCCC)[C:16]1[S:17][CH:18]=[CH:19][N:20]=1)CCC.C(Cl)(Cl)Cl.Cl>O1CCOCC1.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>[S:17]1[CH:18]=[CH:19][N:20]=[C:16]1[C:7]1[CH:8]=[CH:9][C:4]([C:2](=[O:3])[CH3:1])=[CH:5][CH:6]=1
Reactant: CC(=O)c1ccc(Br)cc1
Reactant: CCCC[Sn](CCCC)(CCCC)c1nccs1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: C1COCCO1
Product: CC(=O)c1ccc(-c2nccs2)cc1
Temperature: 90 °C
Reaction time: 8 h
Yield: 126 %

Procedure:
4-Bromoacetophenone (500 mg, 2.51 mmol) and 2-(tributylstannyl)thiazole (0.948 ml, 3.014 mmol) were dissolved in 1,4-dioxane (8 ml), and bis(triphenylphosphine)palladium dichloride (176 mg), was added to the solution under an argon gas atmosphere. The mixture was stirred at 90° C. for 8 hours. After the reaction solution was cooled to room temperature, chloroform and 1 N—HCl were added to the solution, and the extraction/separation step was carried out. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified on silica gel column chromatography (EtOAc:hexane=1:3) to yield the title compound (643 mg) as an opaque white solid.
Reaction SMILES: [C:1]([S:4][C@@H:5]1[CH2:9][N:8]([C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=2)=[O:11])[C@H:7]([CH:23]=O)[CH2:6]1)(=[O:3])[CH3:2].[CH2:25]([SH:28])[CH2:26][SH:27].B(F)(F)F.CCOCC.C(=O)([O-])O.[Na+]>ClCCl>[C:1]([S:4][C@@H:5]1[CH2:9][N:8]([C:10]([O:12][CH2:13][C:14]2[CH:15]=[CH:16][C:17]([N+:20]([O-:22])=[O:21])=[CH:18][CH:19]=2)=[O:11])[C@H:7]([CH:23]2[S:28][CH2:25][CH2:26][S:27]2)[CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)S[C@H]1C[C@@H](C=O)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Reactant: SCCS
Agent: FB(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: ClCCl
Product: CC(=O)S[C@H]1C[C@@H](C2SCCS2)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
To a solution of (2S,4S)-4-acetylthio-2-formyl-1-(4-nitrobenzyloxycarbonyl) pyrrolidine (1.00 g) and 1,2-ethanedithiol (0.36 ml) in dichloromethane (20 ml) was added boron trifluoride etherate (0.1 ml), and the solution was stirred for 14 hours at ambient temperature. To the mixture was added saturated aqueous sodium hydrogen carbonate and the organic layer was separated, and washed with brine. The organic layer was dried over magnesium sulfate and evaporated. The residue was chromatographed on silica gel (50 ml) and eluted with a mixture of acetone and dichloromethane (2:98, V/V) to give (2S, 4S)-4-acetylthio-2-(1,3-dithiolan-2-yl) -1-(4-nitrobenzyloxycarbonyl)pyrrolidine (1.14 g).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[O:5][C:4](=[O:12])[CH:3]=1.[CH3:13][CH:14]([CH3:24])[CH2:15][CH:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)O.B(F)(F)F.CCOCC>O1CCOCC1>[OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[O:5][C:4](=[O:12])[C:3]=1[CH:16]([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[CH2:15][CH:14]([CH3:24])[CH3:13]
Reactant: CC(C)CC(O)c1ccccc1
Reactant: O=c1cc(O)c2ccccc2o1
Agent: FB(F)F
Solvent: C1COCCO1
Solvent: CCOCC
Product: CC(C)CC(c1ccccc1)c1c(O)c2ccccc2oc1=O
Temperature: 25 °C
Yield: 20.1 %

Procedure:
To a time-dried flask containing a near-solution of 650 mg of 4-hydroxycoumarin and 800 mg of 3-methyl-1-phenylbutan-1-ol of Preparation 16 in 25 mL of dioxane under an argon atmosphere is added 2.5 mL of boron trifluoride etherate. The resulting yellow solution is left to stir at room temperature. After 3 days the volatiles are removed and the residue is partioned between diethyl ether and 1N sodium hydroxide. The basic aqueous phase is washed with diethyl ether and acidified to pH=1 with 6N hydrochloric acid. The resulting precipitant is repeatedly extracted with dichloromethane (methanol-chloroform Co-solvents). The combined dichloromethane extracts are washed once with dilute sodium bicarbonate to remove most of the unreacted 4-hydroxycoumarin, then brine, dried (magnesium sulfate), and finally concentrated under reduced pressure. The residue is adsorbed onto silica and flash column chromatographed with 30% to 40% ethyl acetate in hexane to yield 248 mg of the title product as a white solid.
Reaction SMILES: [CH2:1]([OH:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[Al].[CH2:11]([O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH:12]1[O:14][CH2:13]1>C1C(O)=CC=C(S(O)(=O)=O)C=1>[CH3:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH2:1][O:9][CH2:13][CH:12]([OH:14])[CH2:11][O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: CCCCCCCCOCC1CO1
Reactant: CCCCCCCCO
Agent: O=S(=O)(O)c1ccc(O)cc1
Agent: [Al]
Product: CCCCCCCCOCC(O)COCCCCCCCC
Temperature: 95 °C
Yield: 80.7 %

Procedure:
Octyl alcohol (11.7 g; 0.09 mol), aluminum triisopropxide (0.36 g; 1.77 mmol) and p-phenolsulfonic acid (0.94 g; 5.40 mmol) were placed in a 100-ml four-necked flask and heated up to 95° C. while stirring them under nitrogen. Octyl glycidyl ether (17.1 g; 0.09 mol) was then added dropwise over 10 minutes, and the resultant mixture was stirred for 3 hours as it was. After completion of the reaction, the reaction mixture was washed with a 4N aqueous solution (40 ml) of sodium hydroxide and additionally twice with water (40 ml) and then purified by vacuum distillation to obtain 23.0 g of 1,3-dioctyl glyceryl ether (9,13-dioxa-11-heneicosanol) as a colorless transparent oil (yield: 81%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH3:12])[C:4]=1[CH:5]=O.[C:13]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)(=[O:15])[CH3:14].[OH-].[Na+]>CO.O>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH3:12])[C:4]=1[CH:5]=[CH:14][C:13]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:15]
Reactant: CC(=O)c1ccccc1
Reactant: COc1cccc(OC)c1C=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1cccc(OC)c1C=CC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(39) To a solution of 2,6-dimethoxybenzaldehyde (250 mg, 1.50 mmol) and acetophenone (180 mg, 1.50 mmol) in 2.2 ml of methanol was added 1.0 ml of 40% sodium hydroxide in water at 10° C. After stirring overnight at room temperature, a solid precipitated. The precipitate was recrystallized from methanol to afford 350 mg (87.1%) of a white, flaky solid: mp 54.9-55.8° C. (lit. mp 54-55° C., Noyce and Jorgenson, J. Am. Chem. Soc., 1963, 85, 2420-2426). 1H NMR (250 MHz) δ 8.33-8.26 (d, 1H), 8.05-7.97 (m, 3H), 7.57-7.49 (m, 3H), 7.30 (m, 1H), 6.61-6.57 (d, 2H), 3.92 (s, 6H); 13C NMR 192.3, 160.6, 139.2, 136.0, 132.4, 131.7, 128.6, 125.1, 113.1, 105.8, 103.9, 56.0 ppm.