Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][CH2:9][OH:10].[H-].[Na+].F[C:14]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][N:15]=1>C1COCC1>[F:20][C:18]1[CH:17]=[CH:16][N:15]=[C:14]([O:10][CH2:9][CH2:8][O:7][CH:2]2[CH2:3][CH2:4][CH2:5][CH2:6][O:1]2)[CH:19]=1
Reactant: Fc1ccnc(F)c1
Reactant: OCCOC1CCCCO1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Fc1ccnc(OCCOC2CCCCO2)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 52.5 %

Procedure:
2-(Tetrahydro-2H-pyran-2yl-oxy)ethanol (731 mg, 679 μL, 5.00 mmol) was suspended in anhydrous THF and NaH (60% dispersion in mineral oil, 240 mg, 6.0 mmol) was added portionwise, resulting in evolution of gas and the reaction stirred at room temp. After 15 min, a solution of 2,4-difluoropyridine (690 mg, 6.00 mmol) in anhydrous THF (2 mL) was slowly added. After stirring for 2 h, the reaction was partitioned between H2O and EtOAc. The organic layer was separated, and the aqueous extracted again with EtOAc. The combined organics were dried over MgSO4, concentrated in vacuo and subjected to FCC, eluting with 0-30% EtOAc/cyclohexane, to afford the title compound as a colourless oil (633 mg, 43%). LCMS (Method 3) Rt 3.57 min, m/z 264.2 [M+Na].
Reaction SMILES: [CH2:1]([NH:15][CH2:16][CH2:17][NH:18][CH2:19][CH2:20][NH2:21])[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:22](OC)(=[O:27])[CH2:23][C:24]([CH3:26])=O>>[CH2:1]([NH:15][CH2:16][CH2:17][N:18]1[C:22](=[O:27])[CH2:23][C:24]([CH3:26])=[N:21][CH2:20][CH2:19]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: CCCCCCCCCCCCCCNCCNCCN
Reactant: COC(=O)CC(C)=O
Product: CCCCCCCCCCCCCCNCCN1CCN=C(C)CC1=O

Procedure:
Into an apparatus similar to that in Example 1, were charged 299.5 g (1 mole) of N-tetradecyldiethylenetriamine and 116.1 g (1 mole) of methyl acetoacetate. At 150° to 160° C., 18 g of water and 32 g of methanol were distilled off to obtain 4-tetradecylaminoethyl-7-methyl-3,6-dihydro-2H-1,4-diazepin-5-one.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[SH:9].F[C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1.C(=O)([O-])[O-].[K+].[K+]>O>[N:13]1[CH:14]=[CH:15][CH:16]=[CH:11][C:12]=1[S:9][C:3]1[CH:4]=[C:5]([Cl:8])[CH:6]=[CH:7][C:2]=1[Cl:1]
Reactant: Sc1cc(Cl)ccc1Cl
Reactant: Fc1cccnc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: Clc1ccc(Cl)c(Sc2ccccn2)c1
Temperature: 100 °C

Procedure:
89.5 g (0.500 mol) of 2,5-dichlorobenzenethiol, 53.4 g (0.55 mol) of 3-fluoropyridine, 82.9 g (0.60 mol) of potassium carbonate, and 550 mL of anhydrous N,N′-dimethyl acetamide were weighed in a 2 L three-necked flask equipped with a stirrer, thermometer, cooling pipe, and nitrogen inlet tube. The reaction solution was heated to 100° C. for 3 hours under a nitrogen atmosphere using an oil bath. After confirming the disappearance of raw materials by way of thin-layer chromatography, the reaction liquid was allowed to cool to room temperature. Thereafter, the reaction liquid was gradually added to 3 L of water, and the product was solidified and filtered. The product obtained by filtering was dissolved in 2.5 L of toluene, and then washed with a sodium chloride solution using a separating funnel till the aqueous layer became neutral. The organic layer was dried using magnesium sulfate, and then the solvent was removed by an evaporator to obtain 2,5-dichlorophenyl pyridyl sulfide of an intermediate in an approximate yield amount of 129 g.
Reaction SMILES: N1C=CC=CC=1.[CH3:7][O:8][C:9]1[CH:10]=[C:11]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17]1[CH:16]([CH3:22])[N:15]([C:23](=[O:25])[CH3:24])[CH2:14][CH2:13][C:12]2=1.[C:26](OC(=O)C)(=[O:28])[CH3:27]>C1(C)C=CC=CC=1>[C:23]([N:15]1[CH2:14][CH2:13][C:12]2[C:11]3[C:19](=[CH:20][CH:21]=[C:9]([O:8][CH3:7])[CH:10]=3)[N:18]([C:26](=[O:28])[CH3:27])[C:17]=2[CH:16]1[CH3:22])(=[O:25])[CH3:24]
Reactant: COc1ccc2[nH]c3c(c2c1)CCN(C(C)=O)C3C
Reactant: CC(=O)OC(C)=O
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: COc1ccc2c(c1)c1c(n2C(C)=O)C(C)N(C(C)=O)CC1
Yield: 22 %

Procedure:
N,N-Diethylaminopyridine (530 mg) and pyridine (1.1 mL) are added to a solution of 1-(6-methoxy-1 -methyl-2,3,4,9-tetrahydro- 1H-β-carbolin-2-yl)-1-ethanone (933 mg) in toluene (100 mL) and acetic anhydride (6 mL). The mixture is refluxed for 48 h. After evaporation of the toluene, the crude product is taken up in water and then extracted with dichloromethane and, after separation on silica gel (chloroform/methanol eluent), the 1-(2-acetyl-6-methoxy-1-methyl-2,3,4,9-tetrahydro-1 H-β-carbolin-9-yl) 1 -ethanone is obtained (22% yield).
Reaction SMILES: [C:1]([OH:5])(=[O:4])[CH:2]=[CH2:3].O[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][CH:23]=1)[CH:20]=[C:19]([C:24]([OH:26])=[O:25])[CH:18]=[CH:17]2.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C=CC(O)=CC=1)O>ClCCCl>[C:1]([O:5][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][CH:23]=1)[CH:20]=[C:19]([C:24]([OH:26])=[O:25])[CH:18]=[CH:17]2)(=[O:4])[CH:2]=[CH2:3]
Reactant: C=CC(=O)O
Reactant: O=C(O)c1ccc2cc(OCCCCCCO)ccc2c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Oc1ccc(O)cc1
Solvent: O
Solvent: ClCCCl
Product: C=CC(=O)OCCCCCCOc1ccc2cc(C(=O)O)ccc2c1

Procedure:
In 270 g of 1,2-dichloroethane were added 108.11 g (1.5 mmol) of acrylic acid, 21.63 g (75 mmol) of 6-(6-hydroxy-hexa-1-yloxy)-2-naphthoic acid obtained in Step 1, 4.28 g (23 mol) of p-toluenesulfonic acid monohydrate, and 0.83 g (7.5 mmol) of hydroquinone, and the solution was refluxed for 4 hours. After evaporation of the solvent, 270 g of water was added to the residue, and the precipitate was collected by filtration and dried in an oven at 40° C. overnight. The dried product was recrystallized from acetone to yield the desired product, 6-(6-acryloyloxy-hexa-1-yloxy)-2-naphthoic acid, as light-yellow powder (16.97 g, Yield: 65%).
Reaction SMILES: [F:1][CH2:2][CH2:3][O:4][CH2:5][C:6]1[CH:7]=[CH:8][C:9]([NH:13]C(=O)C(C)(C)C)=[N:10][C:11]=1[CH3:12].[OH-].[Na+]>>[F:1][CH2:2][CH2:3][O:4][CH2:5][C:6]1[CH:7]=[CH:8][C:9]([NH2:13])=[N:10][C:11]=1[CH3:12]
Reactant: Cc1nc(NC(=O)C(C)(C)C)ccc1COCCF
Agent: [Na+]
Agent: [OH-]
Product: Cc1nc(N)ccc1COCCF

Procedure:
This material was prepared in analogy to example 86 step B] from N-[5-(2-Fluoro-ethoxymethyl)-6-methyl-pyridin-2-yl]-2,2-dimethyl-propionamide (0.165 g) and 3M aqueous NaOH (1.23 mL) as an gum (0.174 g) that was used directly in the next step.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[CH:5]=[C:6]([OH:19])[CH:7]=[CH:8][C:9]=1[CH2:10][CH2:11][CH2:12][CH2:13][N:14]1[CH:18]=[CH:17][N:16]=[N:15]1.Cl[CH2:21][C:22]1[CH:23]=[CH:24][C:25]([C:28]2[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][CH:29]=2)=[N:26][CH:27]=1.O>CN(C)C=O>[CH3:3][C:4]1[CH:5]=[C:6]([CH:7]=[CH:8][C:9]=1[CH2:10][CH2:11][CH2:12][CH2:13][N:14]1[CH:18]=[CH:17][N:16]=[N:15]1)[O:19][CH2:21][C:22]1[CH:23]=[CH:24][C:25]([C:28]2[CH:29]=[CH:30][C:31]([C:34]([F:37])([F:35])[F:36])=[CH:32][CH:33]=2)=[N:26][CH:27]=1
Reactant: FC(F)(F)c1ccc(-c2ccc(CCl)cn2)cc1
Reactant: Cc1cc(O)ccc1CCCCn1ccnn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(OCc2ccc(-c3ccc(C(F)(F)F)cc3)nc2)ccc1CCCCn1ccnn1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 70.7 %

Procedure:
15 mg (0.60 mmol) of 95% sodium hydride were added at 0° C. to a solution of 116 mg (0.50 mmol) 3-methyl-4-(4-[1,2,3]triazol-1-yl-butyl)-phenol in 4.0 ml N,N-dimethylformamide and stirred for 30 min. at 0° C. 136 mg (0.50 mmol) 5-chloromethyl-2-(4-trifluoromethyl-phenyl)-pyridine were given to the reaction mixture and stirring continued at r.t overnight. After addition of 8 ml water the mixture was stirred for 1 h, the formed precipitate isolated by filtration, washed with water, methanol/water 1:1, and a small amount of ether to give 165 mg (71%) of the title compound as white powder.
Reaction SMILES: [C:1]([N:5]1[C:9](=[O:10])[C:8](Cl)=[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[S:6]1(=[O:19])=[O:18])([CH3:4])([CH3:3])[CH3:2].Cl.Cl.[F:22][C:23]1[CH:24]=[CH:25][C:26]([N:29]2[CH2:34][CH2:33][CH:32]([NH2:35])[CH2:31][CH2:30]2)=[N:27][CH:28]=1>CN(C=O)C>[C:1]([N:5]1[C:9](=[O:10])[C:8]([NH:35][CH:32]2[CH2:33][CH2:34][N:29]([C:26]3[CH:25]=[CH:24][C:23]([F:22])=[CH:28][N:27]=3)[CH2:30][CH2:31]2)=[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[S:6]1(=[O:19])=[O:18])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)N1C(=O)C(Cl)=C(c2ccccc2)S1(=O)=O
Reactant: NC1CCN(c2ccc(F)cn2)CC1
Agent: Cl
Solvent: CN(C)C=O
Product: CC(C)(C)N1C(=O)C(NC2CCN(c3ccc(F)cn3)CC2)=C(c2ccccc2)S1(=O)=O
Temperature: 130 °C
Yield: 57.5 %

Procedure:
2-tert-Butyl-4-chloro-5-phenylisothiazol-3(2H)-one 1,1-dioxide (0.175 g, 0.58 mmol), 1-(5-fluoropyridin-2-yl)piperidin-4-amine dihydrochloride (0.155 g, 0.58 mmol) and TEA (0.23 g, 2.31 mmol) was dissolved in dry DMF (3 ml) and heated in a microwave reactor at 130° C. for 30 mins. The reaction mixture was purified by preparative HPLC to yield the title compound (0.153 g, 58%). 1H NMR (500 MHz, CDCl3): δ 8.01-7.95 (m, 1H), 7.56-7.49 (m, 2H), 7.48-7.39 (m, 3H), 7.23-7.16 (m, 1H), 6.56-6.48 (m, 1H), 5.25-5.15 (m, 1H), 3.98-3.86 (m, 2H), 3.17-3.04 (m, 1H), 2.47-2.36 (m, 2H), 1.80-1.64 (m, 2H), 1.72 (s, 9H), 1.43-1.30 (m, 2H); 13C NMR (125 MHz, CDCl3): δ 159.9, 156.1, 154.7, 152.7, 134.8, 134.6, 134.1, 131.9, 130.1, 128.9, 125.3, 108.3, 107.3, 61.8, 50.5, 45.0, 32.0, 27.8; Mass Spectrum: M−H+ 459.
Reaction SMILES: FC(F)(F)C(O)=O.[CH:8]1([CH:12]([OH:24])[C:13]2[CH:23]=[CH:22][C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:15][CH:14]=2)[CH2:11][CH2:10][CH2:9]1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>ClCCl>[CH:8]1([C:12]([C:13]2[CH:14]=[CH:15][C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:22][CH:23]=2)=[O:24])[CH2:11][CH2:10][CH2:9]1
Reactant: CCOC(=O)c1ccc(C(O)C2CCC2)cc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1ccc(C(=O)C2CCC2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 77.5 %

Procedure:
Trifluoroacetic acid (613 mg, 5.38 mmol) was added dropwise to a 0° C. solution of ethyl 4-(cyclobutyl(hydroxy)methyl)benzoate (700 mg, 3 mmol) in dichloromethane (10 mL). Then Dess-Martin periodinane (2.03 g, 4.78 mmol) was added and the reaction was warmed to room temperature and stirred for 2 hours. The reaction was quenched with 1 N aqueous sodium hydrosulfite (10 mL) and extracted with ethyl acetate (3×30 mL). The combined organics were dried over sodium sulfate, filtered, and concentrated. Purification by flash column chromatography gave ethyl 4-(cyclobutanecarbonyl)benzoate (540 mg, 78%) as an oil. 1H NMR (400 MHz, CDCl3, δ): 8.04 (d, J=8.4 Hz, 2H), 7.86 (d, J=8.4 Hz, 2 H), 4.33 (q, J=7.2 Hz, 2H), 3.90-3.99 (m, 1H), 2.20-2.40 (m, 4H), 2.00-2.09 (m, 1H), 1.81-1.90 (m, 1H), 1.34 (t, J=7.2 Hz, 3H).
Reaction SMILES: [CH3:1][CH:2]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:19]=[CH:18][C:13]([C:14]([O:16]C)=O)=[CH:12][CH:11]=2)[CH2:6][CH2:5]1)[CH3:3].[NH2:20][C:21]1[N:25](C(OC(C)(C)C)=O)[N:24]=[C:23]([CH2:33][CH2:34][C:35]2[CH:40]=[C:39]([O:41][CH3:42])[CH:38]=[C:37]([O:43][CH3:44])[CH:36]=2)[CH:22]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+]>C1COCC1>[CH3:42][O:41][C:39]1[CH:40]=[C:35]([CH2:34][CH2:33][C:23]2[NH:24][N:25]=[C:21]([NH:20][C:14](=[O:16])[C:13]3[CH:12]=[CH:11][C:10]([N:7]4[CH2:6][CH2:5][N:4]([CH:2]([CH3:1])[CH3:3])[CH2:9][CH2:8]4)=[CH:19][CH:18]=3)[CH:22]=2)[CH:36]=[C:37]([O:43][CH3:44])[CH:38]=1
Reactant: COc1cc(CCc2cc(N)n(C(=O)OC(C)(C)C)n2)cc(OC)c1
Reactant: COC(=O)c1ccc(N2CCN(C(C)C)CC2)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cc(CCc2cc(NC(=O)c3ccc(N4CCN(C(C)C)CC4)cc3)n[nH]2)cc(OC)c1
Yield: 5.4 %

Procedure:
N-[5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-yl]-4-(4-propan-2-ylpiperazin-1-yl)benzamide was prepared as for Example 94, but starting from methyl 4-(4-propan-2-yl-piperizin-1-yl)benzoate (263 mg, 0.84 mmol), tert-butyl 5-amino-3-[2-(3,5-dimethoxyphenyl)ethyl]-1H-pyrazole-1-carboxylate (244 mg, 0.7 mmol) and 1M NaHMDS (1.13 ml, 1.13 mmol) in THF (5 ml). The crude product was purified by reverse phase prep. HPLC (basic) using a 38-58% gradient of acetonitrile in water containing 1% 0.880 ammonia. The clean fractions were taken and evaporated to afford the title compound as a white solid (18 mg, 5%); 1H NMR (399.9 MHz, DMSO-d6) δ 1.02 (6H, d), 2.55-2.61 (4H, m), 2.65-2.76 (1H, m), 2.89 (2H, s), 3.21-3.28 (4H, s), 3.31 (2H, s), 3.72 (6H, s), 6.33 (1H, t), 6.42 (2H, d), 6.45 (1H, s), 6.95 (2H, d), 7.90 (2H, d), 10.29 (1H, s), 12.07 (1H, s)
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:20])[N:5]([CH:12]1[CH2:17][CH2:16][C:15](=[O:18])[NH:14][C:13]1=[O:19])[C:6]2=[O:11].[Cl:21][C:22]1[CH:30]=[CH:29][C:25]([C:26](Cl)=[O:27])=[CH:24][CH:23]=1.CO>C1COCC1>[Cl:21][C:22]1[CH:30]=[CH:29][C:25]([C:26]([NH:1][C:2]2[CH:10]=[CH:9][CH:8]=[C:7]3[C:3]=2[C:4](=[O:20])[N:5]([CH:12]2[CH2:17][CH2:16][C:15](=[O:18])[NH:14][C:13]2=[O:19])[C:6]3=[O:11])=[O:27])=[CH:24][CH:23]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: Nc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Solvent: C1CCOC1
Solvent: CO
Product: O=C1CCC(N2C(=O)c3cccc(NC(=O)c4ccc(Cl)cc4)c3C2=O)C(=O)N1
Yield: 80.9 %

Procedure:
A mixture of 4-amino-2-(2,6-dioxo(3-piperidyl))isoindoline-1,3-dione (1.2 g, 4.5 mmol) and 4-chlorobenzoyl chloride (1.1 mL, 8.8 mmol) in THF (40 mL) was heated to reflux for 15 h. To the mixture was added methanol (5 mL) to give a suspension. The suspension was filtered and washed with ether (2×10 mL) then methanol (5 mL) to give 4-chloro-N-[2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]-benzamide as a white solid (1.5 g, 81% yield): mp, 261–263° C.; 1H NMR (DMSO-d6) δ 2.05–2.09 (m, 1H, CHH), 2.49–2.65 (m, 2H, CH2), 2.83–2.98 (m, 1H, CHH), 5.18 (dd, J=5.5, 12.8 Hz, 1H, NCH), 7.68–7.72 (m, 3H, Ar), 7.89–8.01 (m, 3H, Ar), 8.52 (d, J=8.2, Hz, 1H, Ar), 10.47 (s, 1H, NH), 11.16 (s, 1H, NH); 13C NMR (DMSO-d6) δ 21.99, 30.92, 48.98, 118.48, 119.06, 126.76, 129.10, 129.29, 131.46, 132.13, 136.28, 137.47, 164.08, 166.60, 167.86, 169.67, 172.72; Anal Calcd for C20H14N3O5Cl+0.2 H2O: C, 57.83; H, 3.49; N, 10.12; Cl, 8.53; H2O, 0.87. Found: C, 57.88; H, 3.33; N, 9.93; Cl, 8.53; H2O, 0.73.
Reaction SMILES: [Si:1]([O:8][C@H:9]1[C:14](=[CH2:15])[C@H:13]([CH2:16][O:17][Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19])[CH2:12]/[C:11](=[CH:25]\[C:26](OCC)=[O:27])/[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].ClCCl.[H-].C([Al+]CC(C)C)C(C)C>C1(C)C=CC=CC=1>[Si:1]([O:8][C@H:9]1[C:14](=[CH2:15])[C@H:13]([CH2:16][O:17][Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:19])[CH3:20])[CH2:12]/[C:11](=[CH:25]\[CH2:26][OH:27])/[CH2:10]1)([C:4]([CH3:6])([CH3:5])[CH3:7])([CH3:3])[CH3:2]
Reactant: C=C1[C@H](CO[Si](C)(C)C(C)(C)C)C/C(=C\C(=O)OCC)C[C@H]1O[Si](C)(C)C(C)(C)C
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: C=C1[C@H](CO[Si](C)(C)C(C)(C)C)C/C(=C\CO)C[C@H]1O[Si](C)(C)C(C)(C)C
Reaction time: 1 h
Yield: 54.8 %

Procedure:
The compound of Example 16K (589 mg, 1.3 mmol) was dissolved in 20 mL of toluene and 10 mL of dichloromethane and cooled in a dry ice/acetone bath. Diisobutylaluminum hydride (1 M in hexanes, 5.8 mL, 5.8 mmol) was added dropwise. After 1 hour, the reaction was quenched by the addition of 20 mL of 20% aqueous sodium potassium tartrate. To this mixture was added 25 mL of water followed by 6 mL of 2 N HCl. The resulting mixture was extracted three times with dichloromethane. The combined extracts were washed with 10% aqueous NaCl, dried over MgSO4, filtered and concentrated in vacuo. Purification by silica gel chromatography (70 mL of SiO2, elution with dichloromethane) afforded the titled compound (294 mg, 55%), contaminated with ˜20% of an olefin isomer.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N+:5]([O-:8])=[C:4]([CH3:9])[C:3]=1[CH3:10].[OH-].[Na+].[CH2:13]([OH:22])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21].Cl>O.C1(C)C=CC=CC=1>[CH2:13]([O:22][C:2]1[CH:7]=[CH:6][N+:5]([O-:8])=[C:4]([CH3:9])[C:3]=1[CH3:10])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: Cc1c(Cl)cc[n+]([O-])c1C
Reactant: CCCCCCCCCO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O
Product: CCCCCCCCCOc1cc[n+]([O-])c(C)c1C
Temperature: 25 °C
Yield: 159.8 %

Procedure:
15.8 g (0.1 mol, 1.0 eq.) of 4-chlor-2,3-dimethylpyridine-N-oxide, 8.0 g (0.2 mol, 2.0 eq.) of caustic soda, and 28.9 g (0.2 mol, 2.0 eq.) of 1-nonanol were added to 64 mL of toluene, and the mixture was heated to reflux for 4 hours, and then cooled to room temperature. 160 mL of water was added to the reaction liquid, and then the mixture was neutralized with concentrated hydrochloric acid (8.5 g). Subsequently, the resultant was extracted with 160 mL of ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure, to obtain 42.4 g of 4-nonyloxy-2,3-dimethylpyridine-N-oxide as a black brown oily matter.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]([CH2:26][C:27]2[CH:32]=[CH:31][C:30]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])=[CH:29][CH:28]=2)[C:7](=[O:25])[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][C:11]([C:21]([O:23]C)=[O:22])=[CH:10][CH:9]=2)=[O:4].CO.[OH-].[Na+]>C1COCC1>[CH3:1][O:2][C:3]([C:5]1[N:6]([CH2:26][C:27]2[CH:28]=[CH:29][C:30]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])=[CH:31][CH:32]=2)[C:7](=[O:25])[C:8]2[C:13]([C:14]=1[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)=[CH:12][C:11]([C:21]([OH:23])=[O:22])=[CH:10][CH:9]=2)=[O:4]
Reactant: COC(=O)c1ccc2c(=O)n(Cc3ccc(C(=O)OC(C)(C)C)cc3)c(C(=O)OC)c(-c3ccccc3)c2c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)c1c(-c2ccccc2)c2cc(C(=O)O)ccc2c(=O)n1Cc1ccc(C(=O)OC(C)(C)C)cc1
Reaction time: 18 h
Yield: 73.1 %

Procedure:
To a solution of 2-(4-tert-butoxycarbonylbenzyl)-1-oxo-4-phenyl-1,2-dihydroisoquinoline-3,6-dicarboxylic acid dimethyl ester (1.63 g) in THF (16 ml) were added methanol (16 ml) and 8N-aqueous sodium hydroxide solution (0.8 ml) at room temperature, and the mixture was stirred for 18 hrs. The reaction mixture was concentrated under reduced pressure and water and 1N-hydrochloric acid (7 ml) were added to the residue. The aqueous layer was acidified and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Methylene chloride was added to the residue and insoluble material was removed from the mixture. The filtrate was concentrated and recrystallized (ethyl acetate-hexane) to give the title compound (1.16 g).
Reaction SMILES: C(O)(=O)C.[NH2:5][CH2:6][C:7]1[CH:18]=[CH:17][C:10]([O:11][CH2:12][C:13]([O:15][CH3:16])=[O:14])=[CH:9][CH:8]=1.[CH2:19]([C:23]1[CH:28]=[CH:27][C:26]([C:29]#[C:30][C:31]2[CH:38]=[CH:37][C:34]([CH:35]=O)=[CH:33][CH:32]=2)=[CH:25][CH:24]=1)[CH2:20][CH2:21][CH3:22]>>[CH2:19]([C:23]1[CH:28]=[CH:27][C:26]([C:29]#[C:30][C:31]2[CH:38]=[CH:37][C:34]([CH2:35][NH:5][CH2:6][C:7]3[CH:18]=[CH:17][C:10]([O:11][CH2:12][C:13]([O:15][CH3:16])=[O:14])=[CH:9][CH:8]=3)=[CH:33][CH:32]=2)=[CH:25][CH:24]=1)[CH2:20][CH2:21][CH3:22]
Reactant: COC(=O)COc1ccc(CN)cc1
Reactant: CCCCc1ccc(C#Cc2ccc(C=O)cc2)cc1
Solvent: CC(=O)O
Product: CCCCc1ccc(C#Cc2ccc(CNCc3ccc(OCC(=O)OC)cc3)cc2)cc1

Procedure:
The titled compound was prepared following the procedure A using methyl [4-(aminomethyl)phenoxy]acetate acetate and 4-[(4-butylphenyl)ethynyl]benzaldehyde as a pale yellow oil (36%). 1H NMR (CDCl3, 300 MHz) δ 7.46 (d, J=8.1 Hz, 2H), 7.42 (d, J=8.3 Hz, 2H), 7.29 (d, J=8.3 Hz, 2H), 7.25 (d, J=8.7 Hz, 2H), 7.13 (d, J=8.3 Hz, 2H), 6.86 (d, J=8.7 Hz, 2H), 4.60 (s, 2H), 3.79 (s, 3H), 3.78 (s, 2H), 3.72 (s, 2H), 2.59 (t, J=7.7 Hz, 2H), 1.58 (m, 2H), 1.34 (m, 2H), 0.91 (t, J=7.2 Hz, 3H). M+ (ESI): 442.3. HPLC, Rt: 4.17 min (Purity: 94.9%).
Reaction SMILES: [C:1]1([C:7]2[NH:8][CH:9]=[C:10]([CH:12]=[O:13])[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[CH3:16][C:17]1[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1.O>CN(C)C=O>[CH3:16][C:17]1[CH:22]=[CH:21][C:20]([S:23]([N:8]2[CH:9]=[C:10]([CH:12]=[O:13])[N:11]=[C:7]2[C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)(=[O:25])=[O:24])=[CH:19][CH:18]=1
Reactant: O=Cc1c[nH]c(-c2ccccc2)n1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)n2cc(C=O)nc2-c2ccccc2)cc1
Reaction time: 1 h
Yield: 59.5 %

Procedure:
To a solution of 2-phenyl-1H-imidazole-4-carbaldehyde (1.73 g) in N,N-dimethylformamide (35 mL) was added sodium hydride (60% in oil, 483 mg) at room temperature, and the mixture was stirred for 1 hr. 4-Methylphenylsulfonyl chloride (1.92 g) was added, and the mixture was stirred at 50° C. for 30 min. The reaction mixture was cooled, water was added, and the mixture was extracted with ethyl acetate. The extract was washed with water, 1 mol/L hydrochloric acid and saturated aqueous sodium hydrogen carbonate solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent:hexane-ethyl acetate=9:1→7:3), and crystallized from diisopropyl ether to give the title compound as colorless crystals (yield 1.95 g, 60%).
Reaction SMILES: [CH3:1][N:2]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[C:6]([OH:12])[C:5]2[CH:13]=[CH:14][CH:15]=[CH:16][C:4]=2[S:3]1.[C:17](=O)([O-])[O-].[K+].[K+].IC>CC(C)=O>[CH3:1][N:2]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[C:6]([O:12][CH3:17])[C:5]2[CH:13]=[CH:14][CH:15]=[CH:16][C:4]=2[S:3]1
Reactant: O=C([O-])[O-]
Reactant: COC(=O)C1=C(O)c2ccccc2SN1C
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: COC(=O)C1=C(OC)c2ccccc2SN1C
Yield: 61 %

Procedure:
This compound was prepared according to Zinnes et. al., J. Med. Chem., 1973, 16, 44-48. Thus, a solution of methyl 2-methyl-4-hydroxy-2H-1,2-benzothiazine-3-carboxylate (500 mg, 1.86 mmol) (Lombardino, et. al., J. Med. Chem., 1971, 14, 1171-1177, incorporated by reference herein in its entirety) in acetone (10 ml) was treated with anhydrous potassium carbonate (2.6 g, 18.6 mmol) and iodomethane (1.32 g, 9.29 mmol) and refluxed for 40 hours. The mixture was filtered and concentrated and the residue was partitioned between ethyl acetate and water. The organic phase was washed with saturated aqueous sodium bicarbonate and brine, dried over anhydrous magnesium sulfate, filtered and concentrated to afford 285 mg (54%) of the title compound as a yellow viscous oil, used subsequently without need for further purification; NMR (CDCl3) δ 3.03 (s, 3H), 3.83 (s, 3H), 3.91 (s, 3H), 7.67-7.72 (m, 2H), 7.81-7.88 (m, 2H); MS: 284 m/z (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH:7]([NH:11][S:12]([CH:15]([CH3:17])[CH3:16])(=[O:14])=[O:13])[CH2:6][CH2:5]2.C(=O)([O-])[O-].[K+].[K+].Br[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[C:32]([F:35])([F:34])[F:33]>CN(C)C=O>[F:33][C:32]([F:34])([F:35])[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=1[CH2:25][O:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH:7]([NH:11][S:12]([CH:15]([CH3:17])[CH3:16])(=[O:14])=[O:13])[CH2:6][CH2:5]2
Reactant: CC(C)S(=O)(=O)NC1CCc2cc(O)ccc21
Reactant: FC(F)(F)c1ccccc1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)S(=O)(=O)NC1CCc2cc(OCc3ccccc3C(F)(F)F)ccc21
Temperature: 60 °C
Reaction time: 3 h
Yield: 42 %

Procedure:
N-(5-hydroxy-2,3-dihydro-1H-inden-1-yl)propane-2-sulfonamide (50 mg, 0.196 mmol) was dissolved in N,N-dimethylformamide (dry) (2 mL), potassium carbonate (54.1 mg, 0.392 mmol) and 1-(bromomethyl)-2-(trifluoromethyl)benzene (94 mg, 0.392 mmol) were added and the mixture was stirred at 60° C. for 3 hr. After this time, the reaction mixture was partitioned between EtOAc and H2O, the organic layer separated and solvent evaporated in vacuo. Purification by flash chromatography (0-100% EtOAc in heptane) afforded the title compound as a colourless oil (34 mg, 42%). MS (ESI): m/z [M−H]− 412.0