Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][O:7][C:8]1[C:12]([I:13])=[C:11]([NH:14][S:15]([C:18]2[CH:23]=[CH:22][C:21]([C:24]([CH3:27])([CH3:26])[CH3:25])=[CH:20][CH:19]=2)(=[O:17])=[O:16])[O:10][N:9]=1)(=[O:3])[CH3:2].N1[CH:33]=[CH:32][CH:31]=CC=1>ClCCl>[C:1]([O:4][CH2:5][CH2:6][O:7][C:8]1[C:12]([I:13])=[C:11]([N:14]([S:15]([C:18]2[CH:19]=[CH:20][C:21]([C:24]([CH3:27])([CH3:26])[CH3:25])=[CH:22][CH:23]=2)(=[O:17])=[O:16])[C:1]([O:4][CH2:5][CH:32]([CH3:31])[CH3:33])=[O:3])[O:10][N:9]=1)(=[O:3])[CH3:2]
Reactant: c1ccncc1
Reactant: CC(=O)OCCOc1noc(NS(=O)(=O)c2ccc(C(C)(C)C)cc2)c1I
Solvent: ClCCl
Product: CC(=O)OCCOc1noc(N(C(=O)OCC(C)C)S(=O)(=O)c2ccc(C(C)(C)C)cc2)c1I
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirring solution of 2-{[5-({[4-(tert-butyl)phenyl]sulfonyl}amino)-4-iodo-3-isoxazolyl]oxy}ethyl acetate (Preparation 4) (9.44 g) in dichloromethane was added pyridine (1.65 mL) followed by the slow addition of isobutylchloroforomate (2.41 mL) over 10 minutes. The reaction mixture was stirred at room temperature for one hour. The solvent was removed in vacuo to yield the crude material. This was purified using column chromatography (300 g silica, compound loaded with dichloromethane (15 mL) using a gradient elution of hexane (100% to 75%) and ethyl acetate (0% to 25%) to yield the desired compound as a yellow oil (7.70 g).
Reaction SMILES: [O-]CC.[K+].[C:5]([O:12][CH2:13][CH3:14])(=[O:11])[C:6]([O:8]CC)=O.[CH3:15][C:16]1[CH:21]=[CH:20][N:19]=[CH:18][C:17]=1[N+:22]([O-:24])=[O:23]>C(OCC)C.C(O)C>[CH2:13]([O:12][C:5](=[O:11])[C:6](=[O:8])[CH2:15][C:16]1[CH:21]=[CH:20][N:19]=[CH:18][C:17]=1[N+:22]([O-:24])=[O:23])[CH3:14]
Reactant: Cc1ccncc1[N+](=O)[O-]
Reactant: CCOC(=O)C(=O)OCC
Agent: CC[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CCO
Product: CCOC(=O)C(=O)Cc1ccncc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of potassium ethoxide (3.1 g, 36.2 mmol) in diethyl ether (70 mL) and ethanol (10 mL) under an argon atmosphere was added diethyl oxalate (4.9 mL, 36.2 mmol) and the reaction stirred at rt for 30 min. A solution of 4-methyl-3-nitropyridine (5.0 g, 36.2 mmol) in diethyl ether (20 mL) was added resulting in the immediate formation of a dark red precipitate. The reaction mixture was stirred at rt for 72 h, then cooled to 0° C. and filtered. The solid was dissolved in water (500 mL) acidified to pH 4 with acetic acid and the precipitate collected and dried to give the title compound as a red solid. δH (d6 DMSO): 1.27 (3H, t), 4.25 (2H, q), 6.74 (1H, s), 8.34 (1H, d), 8.43 (1H, d), 8.98 (1H, s); m/z (ES+)=239 [M+H]+.
Reaction SMILES: [Cl-].[CH3:2][C:3]1[N:7]2[C:8](=[O:32])[CH:9]=[C:10]([CH2:12][P+](C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[N:11]=[C:6]2[S:5][CH:4]=1.[H-].[Na+].[CH:35]1([CH2:38][O:39][C:40]2[C:47]([O:48][CH3:49])=[CH:46][CH:45]=[CH:44][C:41]=2[CH:42]=O)[CH2:37][CH2:36]1>CS(C)=O>[CH:35]1([CH2:38][O:39][C:40]2[C:47]([O:48][CH3:49])=[CH:46][CH:45]=[CH:44][C:41]=2/[CH:42]=[CH:12]/[C:10]2[N:11]=[C:6]3[S:5][CH:4]=[C:3]([CH3:2])[N:7]3[C:8](=[O:32])[CH:9]=2)[CH2:36][CH2:37]1
Reactant: Cc1csc2nc(C[P+](c3ccccc3)(c3ccccc3)c3ccccc3)cc(=O)n12
Reactant: COc1cccc(C=O)c1OCC1CC1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: COc1cccc(/C=C/c2cc(=O)n3c(C)csc3n2)c1OCC1CC1

Procedure:
A stirred suspension of Step 2 intermediate (1.0 g, 2.096 mmol) in dry DMSO (12 ml) was treated with NaH (92 mg, 2.306 mmol) and 2-(cyclopropylmethoxy)-3-methoxybenzaldehyde (475 mg, 2.306 mmol) according to the procedure described in Step 3, Intermediate 2 to yield a crude solid which was purified by column chromatography using 2% ethyl acetate in DCM to afford 260 mg of the desired compound as an off-white solid; 1H NMR (300 MHz, DMSO-d6) δ 0.31-0.32 (m, 2H), 0.53-0.55 (m, 2H), 1.18-1.22 (m, 1H), 2.66 (s, 3H), 3.73-3.76 (m, 2H), 3.79 (s, 3H), 6.15 (s, 1H), 6.97-7.13 (m, 4H), 7.30-7.33 (m, 1H), 8.07 (d, J=16.2 Hz 1H); ESI-MS (m/z) 369.26 (M+H)+.
Reaction SMILES: [Br-].[C:2]1([C:8]([PH3+])([C:15]2C=CC=[CH:17][CH:16]=2)[C:9]2[CH:14]=CC=C[CH:10]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:22]([Li])[CH2:23]CC.C1C2CC3C(=CC=CC=3)C=2C=CC=1C=O>C1COCC1.CCCCCC>[CH:22]([C:17]1[CH:16]=[CH:15][C:8]2[C:2]3[C:3](=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH2:14][C:9]=2[CH:10]=1)=[CH2:23]
Reactant: [PH3+]C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: [Li]CCCC
Agent: O=Cc1ccc2c(c1)Cc1ccccc1-2
Agent: [Br-]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: C=Cc1ccc2c(c1)Cc1ccccc1-2
Reaction time: 2 h

Procedure:
Triphenylmethyl phosphonium bromide (36 gms/0.1 mole) in 500 milliliters of dry THF is treated under nitrogen with 90 milliliters of a 1.1 molar solution of n-butyl lithium in hexane and stirred for 2 hours. A solution of 19.4 gms. (0.1 mole) of fluorene-2-carboxaldehyde in 100 milliliters of THF is added dropwise and the final mixture refluxed for 11/2 hours. One liter of hexane is added to the cold solution and the precipitate filtered off. The filtrate is evaporated and the residue chromatographed on alumina (Woehlm neutral) using hexane to give 15 gms. (75% theory) of product. Recrystallization from hexane yields 2-vinylfluorene as colorless plates. The structure of the product is confirmed by nuclear magnetic resonance and elemental analysis.
Reaction SMILES: [C:1]1([NH:7][CH:8]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:9][CH2:10][NH2:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:18](O)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.O>C1(C)C(C)=CC=CC=1>[C:12]1([CH:8]([NH:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:9][CH2:10][NH:11][C:18](=[O:25])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C(O)c1ccccc1
Reactant: NCCC(Nc1ccccc1)c1ccccc1
Solvent: O
Solvent: Cc1ccccc1C
Product: O=C(NCCC(Nc1ccccc1)c1ccccc1)c1ccccc1
Yield: 27.5 %

Procedure:
A solution of N,1-diphenyl-1,3-propanediamine (5.0 g, 22 mmoles, described in Example 2) and benzoic acid (12.5 g, 105 mmoles) in dry xylene (300 ml) is refluxed for 20 hr using a Dean-Stark water separator. The mixture is cooled and washed with several portions of 2 N hydrochloric acid. The aqueous extracts are combined, basified with dilute sodium hydroxide and extracted with chloroform. The organic extract is washed with brine, dried over magnesium sulfate and evaporated. The residue is chromatographed an silica gel using chloroform and the eluates are evaporated. The residue is crystallized from benzene-hexane to obtain the title compound (2.0 g), mp 120°-121° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:9]([O:11][CH3:12])=[O:10])[O:5][C:6]=1[CH2:7][CH3:8].C(=O)([O-])[O-].[K+].[K+].[CH3:19][N:20]1[C:24](B2OC(C)(C)C(C)(C)O2)=[CH:23][CH:22]=[N:21]1>CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[CH2:7]([C:6]1[O:5][C:4]([C:9]([O:11][CH3:12])=[O:10])=[CH:3][C:2]=1[C:24]1[N:20]([CH3:19])[N:21]=[CH:22][CH:23]=1)[CH3:8]
Reactant: CCc1oc(C(=O)OC)cc1Br
Reactant: Cn1nccc1B1OC(C)(C)C(C)(C)O1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCc1oc(C(=O)OC)cc1-c1ccnn1C
Temperature: 80 °C
Reaction time: 1 h
Yield: 71.4 %

Procedure:
A solution of methyl 4-bromo-5-ethyl-2-furancarboxylate (1.1 g, 4.72 mmol), potassium carbonate (3.26 g, 23.60 mmol), 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1.178 g, 5.66 mmol)[prepared according to Preparation 7] and bis(tri-t-butylphosphine)palladium(0) (0.121 g, 0.24 mmol) were combined in a sealed tube and stirred at 80° C. for 1 h. LCMS showed 4:1 pdt/sm. Additional 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1.178 g, 5.66 mmol) and bis(tri-t-butylphosphine)palladium(0) (0.121 g, 0.24 mmol) were added and the solution stirred an additional 2 h where crude LCMS showed nearly complete conversion to product. The reaction contents were then partitioned between H2O-DCM and the aqueous phase was washed several times with DCM. The combined organic fractions were dried over Na2SO4, concentrated and purified via column chromatography (10-50% EtOAc in hexanes) affording methyl 5-ethyl-4-(1-methyl-1H-pyrazol-5-yl)-2-furancarboxylate (950 mg, 3.37 mmol, 71.3% yield) as a yellow oil: LCMS (ES) m/e 235 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9]CC2C=CC=CC=2)[CH:6]=[CH:5][C:4]=1[C:17]1[NH:25][C:24]2[C:19](=[N:20][C:21]([O:26]CC3C=CC=CC=3)=[N:22][CH:23]=2)[N:18]=1.[H][H].[OH-].[Na+].O>C(O)C.[Pd]>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([OH:9])[CH:6]=[CH:5][C:4]=1[C:17]1[NH:25][C:24]2[CH:23]=[N:22][C:21](=[O:26])[NH:20][C:19]=2[N:18]=1
Reactant: COc1cc(OCc2ccccc2)ccc1-c1nc2nc(OCc3ccccc3)ncc2[nH]1
Reactant: [H][H]
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COc1cc(O)ccc1-c1nc2[nH]c(=O)ncc2[nH]1

Procedure:
Three grams of 8-(2-methoxy-4-benzyloxy-phenyl)-2-benzyloxypurine are dissolved in 100 ml of ethanol and hydrogenated in the presence of 1 gm of 20% palladium/charcoal for two hours at 50° C. with hydrogen at 5 bar. The catalyst is filtered off and washed with hot ethanol. The filtrates are evaporated, and the residue is triturated with methylene chloride. The solid product obtained is stirred with 30 ml of 2N sodium hydroxide solution. The solution is filtered, and the filtrate is acidified with glacial acetic acid. The precipitate formed is separated from the solution by centrifuging and purified by triturating with acetone. The product contains 1 mol of water of crystallization.
Reaction SMILES: [SH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.[H-].[Na+].Cl[CH:15]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH2:16][N:17]1[CH:21]=[CH:20][N:19]=[CH:18]1.[Cl-].[Na+]>CN(C)C=O>[C:22]1([CH:15]([S:1][C:2]2[CH:3]=[CH:4][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:10][CH:11]=2)[CH2:16][N:17]2[CH:21]=[CH:20][N:19]=[CH:18]2)[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: ClC(Cn1ccnc1)c1ccccc1
Reactant: COC(=O)c1ccc(S)cc1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(SC(Cn2ccnc2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 30.4 %

Procedure:
1.5 g of methyl 4-mercaptobenzoate was dissolved in 8 ml of dry dimethylformamide, and the resulting solution was added to 388 mg of a 55% w/w suspension of sodium hydride in mineral oil, whilst ice-cooling, and then the mixture was stirred at room temperature for 30 minutes. A solution of 1.5 g of 1-(2-chloro-2-phenylethyl)imidazole dissolved in 8 ml of dry dimethylformamide was added to the thus obtained solution, and the mixture was then heated at 65° to 70° C. for 6 hours. At the end of this time, the reaction mixture was poured into a saturated aqueous solution of sodium chloride, and the resulting solution was extracted with diethyl ether. The extract was washed with water and dried over anhydrous potassium carbonate, and then the solvent was removed by distillation. The residue was purified by column chromatography through silica gel (eluent: ethyl acetate:triethylamine=40:1 by volume) to obtain 747 mg of the title compound as a colorless powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:4]=1[C:11](=[O:29])[CH2:12][N:13]1[C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:16][C:15](C2C=NC=CC=2)=[N:14]1.[CH3:30][Si:31](C)([CH3:42])[C:32]1C=C(C(OCC)=O)NN=1.BrCC(C1C=C(OC)C=CC=1OC)=O>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:4]=1[C:11](=[O:29])[CH2:12][N:13]1[C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:16][C:15]([Si:31]([CH3:42])([CH3:32])[CH3:30])=[N:14]1
Reactant: CCOC(=O)c1cc([Si](C)(C)C)n[nH]1
Reactant: CCOC(=O)c1cc(-c2cccnc2)nn1CC(=O)c1cc(OC)ccc1OC
Agent: COc1ccc(OC)c(C(=O)CBr)c1
Product: CCOC(=O)c1cc([Si](C)(C)C)nn1CC(=O)c1cc(OC)ccc1OC

Procedure:
This compound was prepared in a similar method to ethyl 1-(2-(2,5-dimethoxyphenyl)-2-oxoethyl)-3-(pyridin-3-yl)-1H-pyrazole-5-carboxylate using ethyl 3-(trimethylsilyl)-1H-pyrazole-5-carboxylate and 2-bromo-1-(2,5-dimethoxyphenyl)ethanone (Purchased from Aldrich). 1H-NMR δ 7.40 (d, 1H), 7.12 (dd, 1H), 7.02 (dd, 1H), 6.96 (d, 1H), 5.72 (s, 2H), 4.40 (q, 2H), 3.96 (s, 3H), 3.78 (s, 3H), 1.39 (t, 3H), 0.28 (s, 9H).
Reaction SMILES: [CH:1]1([NH:4][C:5]2[O:6][CH2:7][C:8](=[O:14])[C:9]=2[C:10]([O:12][CH3:13])=[O:11])[CH2:3][CH2:2]1.C(OC)(=O)CC(OC)=O.ClCC(Cl)=O.C1(N)CC1.[NH:33]1[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][N:40]=2)[C:35]([CH:42]=O)=[CH:34]1.N1CCC[C@H]1C(O)=O>C(O)C>[NH:33]1[C:41]2=[N:40][CH:39]=[CH:38][CH:37]=[C:36]2[C:35]([CH:42]=[C:7]2[O:6][C:5]([NH:4][CH:1]3[CH2:2][CH2:3]3)=[C:9]([C:10]([O:12][CH3:13])=[O:11])[C:8]2=[O:14])=[CH:34]1
Reactant: COC(=O)C1=C(NC2CC2)OCC1=O
Reactant: O=Cc1c[nH]c2ncccc12
Agent: NC1CC1
Agent: O=C(Cl)CCl
Agent: O=C(O)[C@@H]1CCCN1
Solvent: COC(=O)CC(=O)OC
Solvent: CCO
Product: COC(=O)C1=C(NC2CC2)OC(=Cc2c[nH]c3ncccc23)C1=O
Temperature: 25 °C
Yield: 1.5 %

Procedure:
To a solution of methyl 2-(cyclopropylamino)-4-oxo-4,5-dihydrofuran-3-carboxylate (0.50 g, 2.5 mmol) which similarly prepared according to the procedure described in the Example 4, First step using dimethyl malonate, chloroacetyl chloride and cyclopropylamine, and 7-azaindole-3-carboxaldehyde (0.37 g, 2.5 mmol) in ethanol (6.0 mL), L-proline (0.029 g, 0.25 mmol) was added at ambient temperature. The mixture was refluxed for 16 h. Cooled to ambient temperature, the precipitate was collected by filtration, washed with methanol then dried to afford the titled compound as solid (0.012 g, y. 30%).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][C:9](Cl)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:12][O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[Al+3].[Cl-].[Cl-].[Cl-].Cl>ClCCl.O>[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([C:9](=[O:10])[CH2:8][CH2:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[CH:16][CH:15]=1
Reactant: O=C(Cl)CCc1ccccc1
Reactant: COc1ccccc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: ClCCl
Product: COc1ccc(C(=O)CCc2ccccc2)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a 500 ml three-necked flask provided with a mechanical agitator and a thermometer were added a solution of 22.4 g (133.2 mmol) in theoretical amount of 3-phenylpropionyl chloride which was prepared in the step 1, dissolved in 100 ml dichloromethane, 14.4 g (205.9 mmol) methylphenyl ether and 150 ml dichloromethane, the mixture was cooled in an ice salt bath to lower than −5° C., while maintaining the inside temperature at −5° C. to −10° C., 17.8 g (133.2 mmol) anhydrous AlCl3 was added portionwise, upon the completion of addition. The mixture was stirred at this temperature for 1 hour and then at room temperature for 1 hour, the resultant was poured under stirring into a mixture of 100 g ice, 100 g water and 40 ml concentrated hydrochloric acid, the organic layer was separated, and the aqueous layer was extracted with dichloromethane twice ×20 ml, the organic layers were combined and washed with saturated brine, then with saturated aqueous sodium bicarbonate solution, and then with saturated brine until neutrality, dried over anhydrous magnesium sulfate, filtrated and concentrated under a reduced pressure to obtain a crude product, which was recrystallized with petroleum ether and ethyl acetate (2:1) to obtain a 23.5 g product, the mother liquid was concentrated and recrystallized to obtain a 3.3 g product in a yield of 83.7% in total, mp: 96-97□. 1H-NMR (CDCl3, 400 MHz) δ: 3.05 (2H, t, J=8.16 Hz), 3.25 (2H, t, J=8.16 Hz), 3.86 (3H, s, OCH3), 6.92 (2H, d, J=9.00 Hz, ArH), 7.18˜7.32 (5H, m, ArH), 7.94 (2H, d, J=9.00 Hz, ArH); EI-MS m/e (%): 240.1 (M+, 37), 135 (100).
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[O:7][CH2:6][CH:5]([CH2:8][OH:9])[CH2:4][O:3]1.CCN(CC)CC.[S:18](Cl)([C:21]1[CH:27]=[CH:26][C:24]([CH3:25])=[CH:23][CH:22]=1)(=[O:20])=[O:19]>C(Cl)Cl>[CH3:25][C:24]1[CH:26]=[CH:27][C:21]([S:18]([O:9][CH2:8][CH:5]2[CH2:6][O:7][C:2]([CH3:10])([CH3:1])[O:3][CH2:4]2)(=[O:20])=[O:19])=[CH:22][CH:23]=1
Reactant: CC1(C)OCC(CO)CO1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)OCC2COC(C)(C)OC2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.3 %

Procedure:
To a solution of 1.5 g (10.26 mmol) of (2,2-dimethyl-1,3-dioxan-5-yl)methanol and 1.71 mL of Et3N in 15 mL of DCM, cooled to 0° C., are added 2.15 g (11.3 mmol) of tosyl chloride. The medium is allowed to warm to room temperature, and stirring is continued for 1 hour. The medium is taken up in 100 mL of DCM, washed successively with 0.1N HCl (2×20 mL) and brine (20 mL), dried over Na2SO4, concentrated under reduced pressure and then purified by chromatography on a column of silica gel, eluting with a 99/1 DCM/MeOH mixture. 3 g of (2,2-dimethyl-1,3-dioxan-5-yl)methyl 4-methylbenzenesulfonate are obtained in the form of a colourless oil.
Reaction SMILES: [H-].[Na+].[C:3]1([OH:9])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl[C:11]1[C:16]([N+:17]([O-:19])=[O:18])=[C:15]([NH:20][CH2:21][CH2:22][CH2:23][OH:24])[C:14]([CH3:25])=[C:13]([CH3:26])[N:12]=1>O1CCCC1>[CH3:26][C:13]1[C:14]([CH3:25])=[C:15]([NH:20][CH2:21][CH2:22][CH2:23][OH:24])[C:16]([N+:17]([O-:19])=[O:18])=[C:11]([O:9][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[N:12]=1
Reactant: Cc1nc(Cl)c([N+](=O)[O-])c(NCCCO)c1C
Reactant: Oc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1nc(Oc2ccccc2)c([N+](=O)[O-])c(NCCCO)c1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 55.9 %

Procedure:
Sodium hydride (7.80 g of a 60% dispersion in mineral oil, 195 mmol) was added in portions to a chilled (0° C.) solution of phenol (18.36 g, 195 mmol) in tetrahydrofuran (200 mL). After the addition was completed the reaction mixture was allowed to stir at ambient temperature for 30 minutes. Solid 3-[(2-chloro-5,6-dimethyl-3-nitropyridin-4-yl)amino]propan-1-ol (16.89 g, 65.0 mmol) was added and the reaction mixture was heated at reflux for 5 days. The reaction mixture was concentrated under reduced pressure. The residue was partitioned between ethyl acetate (400 mL) and water (100 mL). The organic layer was separated, washed with brine, dried over sodium sulfate, filtered and then concentrated under reduced pressure. The residue was purified by flash chromatography (500 mL silica gel eluting with a gradient of 30-75% ethyl acetate in hexanes) and then heated under high vacuum until it melted. The melt solidified to provide 11.54 g of 3-[(2,3-dimethyl-5-nitro-6-phenoxypyridin-4-yl)amino]propan-1-ol.
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][C:5]2[O:6][C@H:7]([C:16]([OH:18])=[O:17])[O:8][C@H:9]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[C:4]=2[CH:3]=1.[N+](=[CH2:23])=[N-]>CCOCC>[Cl:1][C:2]1[CH:20]=[CH:19][C:5]2[O:6][C@H:7]([C:16]([O:18][CH3:23])=[O:17])[O:8][C@H:9]([C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:4]=2[CH:3]=1
Reactant: O=C(O)[C@H]1Oc2ccc(Cl)cc2[C@@H](c2ccccc2)O1
Reactant: C=[N+]=[N-]
Solvent: CCOCC
Product: COC(=O)[C@H]1Oc2ccc(Cl)cc2[C@@H](c2ccccc2)O1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To an ether solution of cis-6-chloro-4-phenyl-1,3-benzodioxan-2-carboxylic acid (2.14 g, 7.36 mmoles), chilled in an ice bath, was added an ethereal solution of diazomethane until the yellow color of the diazomethane was no longer discharged. The solution was stirred in the ice bath for 10 minutes at room temp. for 10 minutes, and finally at 35° for 15 minutes. The ether solution was washed with dil.NaHCO3 solution (2 portions), water (2 portions), and saturated brine (1 portion), and dried over anhydrous Na2SO4. The solvent was evaporated to yield a solid which was recrystallized from benzene-Skellysolve B (essentially n-hexane). The yield was 1.71 g (76%); m.p. 129.5°-131°. NMR (CDCl3), β6.6 (d, 1H, C(5)H, cis); 5.65 ppm (s, 1H, C(2)H, cis).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([N:7]2[CH:11]=[C:10]([C:12]3[N:17]=[C:16]([S:18]([NH2:21])(=[O:20])=[O:19])[CH:15]=[CH:14][CH:13]=3)[CH:9]=[N:8]2)[CH:2]=1.[H-].[Na+].[C:24](Cl)(=[O:26])[CH3:25]>C(#N)C>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([N:7]2[CH:11]=[C:10]([C:12]3[N:17]=[C:16]([S:18]([NH:21][C:24](=[O:26])[CH3:25])(=[O:19])=[O:20])[CH:15]=[CH:14][CH:13]=3)[CH:9]=[N:8]2)[CH:2]=1
Reactant: CC(=O)Cl
Reactant: NS(=O)(=O)c1cccc(-c2cnn(-c3cccnc3)c2)n1
Agent: [H-]
Agent: [Na+]
Solvent: CC#N
Product: CC(=O)NS(=O)(=O)c1cccc(-c2cnn(-c3cccnc3)c2)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
6-[1-(Pyridin-3-yl)-1H-pyrazol-4-yl]pyridin-2-sulphonamide (0.15 g, 0.44 mmol) was initially charged in acetonitrile (1.5 ml) under argon, and sodium hydride (0.026 g, 0.66 mmol, 60%) was added in portions. The reaction mixture was stirred at room temperature for 1 h, then acetyl chloride (0.052 g, 0.66 mmol) was added dropwise. The reaction mixture was stirred at 82° C. for 33 h and, after cooling, the solvent was removed under reduced pressure. The residue was taken up in saturated sodium hydrogencarbonate solution, dichloromethane was added and the precipitated solid was filtered off. The phases of the filtrate were separated; the aqueous phase was adjusted to pH 3 with hydrochloric acid and left to stand for 16 h. The precipitated crystals were filtered off with suction. Yield 0.02 g (12% of theory) of N-({6-[1-(pyridin-3-yl)-1H-pyrazol-4-yl]pyridin-2-yl}sulphonyl)acetamide.
Reaction SMILES: [CH3:1][C:2]([CH3:8])([CH3:7])[CH2:3][CH2:4][CH:5]=[O:6].Br[CH2:10][C:11]([O:13][CH3:14])=[O:12].O>C1(C)C=CC=CC=1>[CH3:14][O:13][C:11](=[O:12])[CH2:10][CH:4]([CH:5]=[O:6])[CH2:3][C:2]([CH3:8])([CH3:7])[CH3:1]
Reactant: COC(=O)CBr
Reactant: CC(C)(C)CCC=O
Solvent: O
Solvent: Cc1ccccc1
Product: COC(=O)CC(C=O)CC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In a three necked flask fitted with a Dean-Stark apparatus under argon, a solution of dilsobutylamine (4.62 ml from Acros), 4,4-dimethyl pentanal 362 (2.5 g, 0.021 mol.) in toluene (20 ml) is heated at 130° C. for 2 h and water is extracted. The yellow solution is cooled down to room temperature and methyl bromoacetate (3.7 g, 0.024 mol.) is added in one time. The pink solution is stirred at room temperature overnight and 1 h at 90° C. Water (10 ml) is added at this temperature and after 1 h, the solution is cooled down to room temperature. The organic layer is washed with HCl 1N, saturated aqueous sodium bicarbonate, dried over magnesium sulfate, filtered and evaporated to afford an oil which is distilled under reduced pressure (1 mmHg) to afford 5,5-dimethyl-3-formyl-hexanoic acid methyl ester 361 as a liquid (1.1 g, 0.05 mol, Teb (1 mmHg): 69-71° C.). The aldehyde esters are then used in the reductive amination step. Alternatively, alkylation with ethyl bromoacetate can be conducted in the presence of toluene-acetonitrile 1/1 (v/v) as solvent. The final aldehyde can also be distilled under reduced pressure.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]([OH:9])=[O:8])[CH2:3][CH2:2]1.C([O-])([O-])=O.[Na+].[Na+].[C:16](=O)([O:25]N1C(=O)CCC1=O)[O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>O.CC#N>[CH2:18]([O:17][C:16]([N:1]1[CH2:6][CH2:5][CH:4]([C:7]([OH:9])=[O:8])[CH2:3][CH2:2]1)=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C(O)C1CCNCC1
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: O=C(O)C1CCN(C(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 22.4 %

Procedure:
To a solution of piperidine-4-carboxylic acid (10.0 g, 77.4 mmol) and Na2CO3 (8.21 g, 77.4 mmol) in water (100 mL) was added a solution of benzyl 2,5-dioxopyrrolidin-1-yl carbonate (19.3 g, 77.4 mmol) in MeCN (100 mL). The reaction was stirred at ambient temperature for about 16 h and then concentrated under reduced pressure. The resulting aqueous solution was quenched with aqueous NH4Cl and was then extracted with EtOAc (2×100 mL). The combined organic extracts were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give 1-(benzyloxycarbonyl)piperidine-4-carboxylic acid as a white solid (4.56 g, 22%): LC/MS (Table 2, Method a) Rt=1.93 min; MS m/z: 262 (M−H)−.