Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[Li].[O:3]1[CH2:7][CH2:6][CH2:5][CH2:4]1>>[CH3:4][C:5]1[CH2:7][CH2:6][CH2:5][CH2:4][C:6]=1[CH:7]=[O:3]
Reactant: C1CCOC1
Agent: [Li]C
Product: CC1=C(C=O)CCCC1

Procedure:
To 118 ml. (190 mmole) of 1.6M methyllithium in tetrahydrofuran, cooled under N2 to -78° C., was added over 30 minutes title product of the preceding Preparation (16 g., 95 mmole) in 100 ml. ether. After 30 minutes at -78° C., the reaction mixture was warmed slowly to room temperature, stirred for 1 hour, quenched by slowly adding 50 ml. 1N HCl, stirred 15 minutes, poured into 500 ml. water and extracted 3×150 ml. ether. The combined ether extracts were washed 1×50 ml. H2O, 1×50 ml. saturated NaHCO3, dried over Na2SO4, concentrated to an oil, taken up in 300 ml. acetone, cooled to 0° C. and treated dropwise with Jones reagent until a faint orange color persisted (about 10 ml.). The solution was warmed to room temperature, stirred 15 minutes, diluted with 200 ml. of water, and concentrated in vacuo to remove acetone. The concentrate was extracted 3×100 ml. ether. The ether extracts were combined, washed 1×50 ml. water and 1×50 ml. saturated NaHCO3, dried over Na2SO4 ; concentrated to an oil and title product recovered by distillation, 6.4 g., b.p. 58°-62°/0.2 mm., pnmr (CCl4) includes aldehyde proton peak at delta 9.9-10 ppm.
Reaction SMILES: [CH2:1]([C:6]1[CH:14]=[CH:13][C:9]([C:10](O)=[O:11])=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH2:4][CH3:5].C(Cl)(=O)C(Cl)=O.Cl.[CH3:22][NH:23][O:24][CH3:25].N1C=CC=CC=1>C(Cl)Cl.CN(C=O)C>[CH3:25][O:24][N:23]([CH3:22])[C:10](=[O:11])[C:9]1[CH:13]=[CH:14][C:6]([CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])=[CH:7][CH:8]=1
Reactant: CCCCCc1ccc(C(=O)O)cc1
Reactant: CNOC
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: c1ccncc1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCCCCc1ccc(C(=O)N(C)OC)cc1
Temperature: 0 °C
Reaction time: 4.5 h
Yield: 96.4 %

Procedure:
To a solution of 4-pentylbenzoic acid (5 g, 0.026 mol) in 260 ml of CH2Cl2 containing molecular sieves (4 Å), two drops of DMF was added, and then oxalyl chloride (5.45 g, 0.043 mol) was added dropwise. After stirring for 4.5 h the mixture was filtered, concentrated on the rotatory evaporator and pumped for 15 min. The residue was redissolved in 130 ml of CH2Cl2 and N,O-dimethylhydroxylamine HCl (3.04 g, 0.031 mol) was added at room temperature. After cooling the solution to 0° C., 5.3 ml of pyridine (0.065 mol) was added and the solution was stirred at 23° C. for 18 h. The solution was concentrated on the rotatory evaporator and the residue was partitioned between brine and a mixture of ether and CH2Cl2 (1:1). The organic layer was separated, dried and concentrated to yield 5.9 g (98%) of 2, which was used without further purification in the subsequent step. 1H NMR (100 MHz, CDCl3) δ 0.9 (t, 3H), 1.45 (m, 6H), 2.6 (t, J=6.4 Hz, 2H), 3.3 (s, 3H), 3.5 (s, 3H), 7.2 (d, J=8.0 Hz, 2H), 7.6 (d, J=8.2 Hz, 2H).
Reaction SMILES: [BH4-].[Na+].[CH3:3][C:4]([C:6]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][C:9]2[O:15][CH2:16][O:17][C:8]=2[CH:7]=1)=[O:5].C(Cl)Cl.[Cl-].[NH4+]>CO>[CH2:16]1[O:17][C:8]2[C:9](=[CH:10][C:11]([N+:12]([O-:14])=[O:13])=[C:6]([CH:4]([OH:5])[CH3:3])[CH:7]=2)[O:15]1
Reactant: CC(=O)c1cc2c(cc1[N+](=O)[O-])OCO2
Agent: [BH4-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Solvent: ClCCl
Product: CC(O)c1cc2c(cc1[N+](=O)[O-])OCO2
Temperature: 0 °C

Procedure:
Sodium borohydride (log; 0.27 mol) was added slowly to a cold, stirring suspension of 53 g (0.25 mol) of 4,5-methylenedioxy-2-nitroacetophenone in 400 mL methanol. The temperature was kept below 10° C. by slow addition of the NaBH4 and external cooling with an ice bath. Stirring was continued at ambient temperature for another two hours, at which time TLC (CH2Cl2) indicated complete conversion of the ketone. The mixture was poured into one liter of ice-water and the resulting suspension was neutralized with ammonium chloride and then extracted three times with 400 mL CH2Cl2 or EtOAc (the product can be collected by filtration and washed at this point, but it is somewhat soluble in water and this results in a yield of only ˜60%). The combined organic extracts were washed with brine, then dried with MgSO4 and evaporated. The crude product was purified from the main byproduct by dissolving it in a minimum volume of CH2Cl2 or THF(˜175 ml) and then precipitating it by slowly adding hexane (1000 ml) while stirring (yield 51 g; 80% overall). It can also be recrystallized (e.g., toluene-hexane), but this reduces the yield.
Reaction SMILES: [CH3:1][NH:2][C:3]([NH:5][C:6]1([CH3:16])[C:14]2[CH:13]=[CH:12][S:11][C:10]=2[CH2:9][CH2:8][CH:7]1I)=[O:4].[O-2].[Mg+2].[H][H]>[Pd].CO>[CH3:1][NH:2][C:3]([NH:5][C:6]1([CH3:16])[C:14]2[CH:13]=[CH:12][S:11][C:10]=2[CH2:9][CH2:8][CH2:7]1)=[O:4]
Reactant: CNC(=O)NC1(C)c2ccsc2CCC1I
Reactant: [H][H]
Agent: [Pd]
Agent: [Mg+2]
Agent: [O-2]
Solvent: CO
Product: CNC(=O)NC1(C)CCCc2sccc21

Procedure:
Deiodination of 1-methyl-3-(5-iodo-4-methyl-4,5,6,7-tetrahydrobenzo[b]thien-4-yl)urea is accomplished by treating a methanol mixture of this compound with palladium on carbon and magnesium oxide in a Paar hydrogenator at 50 psig. After uptake of the hydrogen is completed, the mixture is filtered through diatomaceous earth and filtrate is evaporated to dryness to afford 1-methyl-3-(4-methyl-4,5,6,7-tetrahydrobenzo[b]thien-4-yl)urea, melting point 135° C. to 145° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[C:9]3[CH:10]=[CH:11][C:12]([NH2:14])=[CH:13][C:8]=3[S:7](=[O:16])(=[O:15])[C:6]=2[CH:17]=1.[Cl:18][CH2:19][C:20](Cl)=[O:21]>CC(C)=O>[Cl:18][CH2:19][C:20]([NH:1][C:2]1[CH:3]=[CH:4][C:5]2[C:9]3[CH:10]=[CH:11][C:12]([NH:14][C:20](=[O:21])[CH2:19][Cl:18])=[CH:13][C:8]=3[S:7](=[O:16])(=[O:15])[C:6]=2[CH:17]=1)=[O:21]
Reactant: O=C(Cl)CCl
Reactant: Nc1ccc2c(c1)S(=O)(=O)c1cc(N)ccc1-2
Solvent: CC(C)=O
Product: O=C(CCl)Nc1ccc2c(c1)S(=O)(=O)c1cc(NC(=O)CCl)ccc1-2
Temperature: 100 °C

Procedure:
A slurry of 21.8 g of 3,7-diaminodibenzothiophene S,S-dioxide in 400 ml of acetone was cooled in an ice bath while 30.2 ml of chloroacetyl chloride was carefully added. The bath was removed and the mixture heated at 100° C. with stirring, then cooled and poured into ice water. The precipitate was collected, washed with water and dried giving 34.9 g of the desired product as a solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[N:11][C:12]([O:16][CH3:17])=[CH:13][CH:14]=2)[C@@H:9]([NH:18][C:19]2[N:24]=[C:23]([CH2:25][C:26]3[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[C:28]([C:36]([F:39])([F:38])[F:37])[CH:27]=3)[C:22]([C:40](O)=[O:41])=[CH:21][N:20]=2)[CH2:8][C@H:7]1[CH2:43][CH3:44])=[O:5])[CH3:2].Cl.C([O:50][C:51](=[O:56])[CH2:52][CH2:53][NH:54][CH3:55])(C)(C)C.O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>CN(C)C=O.C(N(CC)CC)C>[CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[N:11][C:12]([O:16][CH3:17])=[CH:13][CH:14]=2)[C@@H:9]([NH:18][C:19]2[N:24]=[C:23]([CH2:25][C:26]3[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[C:28]([C:36]([F:37])([F:39])[F:38])[CH:27]=3)[C:22]([C:40](=[O:41])[N:54]([CH2:53][CH2:52][C:51]([OH:56])=[O:50])[CH3:55])=[CH:21][N:20]=2)[CH2:8][C@H:7]1[CH2:43][CH3:44])=[O:5])[CH3:2]
Reactant: CNCCC(=O)OC(C)(C)C
Reactant: CCOC(=O)N1c2ccc(OC)nc2[C@@H](Nc2ncc(C(=O)O)c(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)n2)C[C@H]1CC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)N1c2ccc(OC)nc2[C@@H](Nc2ncc(C(=O)N(C)CCC(=O)O)c(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)n2)C[C@H]1CC
Temperature: 25 °C
Reaction time: 21 h
Yield: 98.2 %

Procedure:
(2R,4S)-4-{[3,5-Bis(trifluoromethyl)benzyl]-(5-carboxypyrimidin-2-yl)}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthyridine-1-carboxylic acid ethyl ester (200 mg) is dissolved in N,N-dimethylformamide (2 ml), and thereto are added triethylamine (53 μl), 3-methylaminopropionic acid tert-butyl ester hydrochloride (101.14 mg), 1-hydroxybenzotriazole hydrate (65 mg) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (92 mg) under ice-cooling. The mixture is stirred at room temperature for 21 hours. The reaction solution is concentrated under reduced pressure, then the residue is partitioned by adding a saturated aqueous sodium bicarbonate solution and ethyl acetate, and the organic layer is concentrated under reduced pressure. The resulting residue is dissolved in a solution (2 ml) of 4N hydrochloric acid in 1,4-dioxane and stirred at room temperature for 1 hour. To the reaction solution is added excessive saturated aqueous sodium bicarbonate solution, and the mixture is neutralized with 1N HCl, then extracted with ethyl acetate and concentrated under reduced pressure. The resulting residue is purified by column chromatography (silica gel; chloroform:methanol=1:0→19:1) to give (2R,4S)-4-([3,5-bis-(trifluoromethyl)benzyl]-{5-[(2-carboxyethyl)methylcarbamoyl]pyrimidin-2-yl})amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthyridine-1-carboxylic acid ethyl ester (223 mg). MS (m/z): 713 [M+H]+.
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4](/[CH:6]=[CH:7]/[CH2:8]P(OCC)(OCC)=O)=[O:5].[H-].[Na+].[CH3:19][O:20][C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=1)[CH:24]=O.CN(C)C=O>O1CCCC1>[CH3:19][O:20][C:21]1[CH:22]=[C:23](/[CH:24]=[CH:8]/[CH:7]=[CH:6]/[C:4]([O:3][CH2:2][CH3:1])=[O:5])[CH:26]=[CH:27][CH:28]=1
Reactant: COc1cccc(C=O)c1
Reactant: CCOC(=O)/C=C/CP(=O)(OCC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CCOC(=O)/C=C/C=C/c1cccc(OC)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 36.8 %

Procedure:
To an ice-cooled solution of triethyl 4-phosphonocrotonate (24.0 g, 95.9 mmol) in tetrahydrofuran (100 mL) was added by small portions sodium hydride (60% in oil, 3.84 g, 96.0 mmol), and the mixture was stirred under nitrogen atmosphere for 30 min. A solution of 3-methoxybenzaldehyde (12.3 g, 90.0 mmol) in tetrahydrofuran (100 mL) was added dropwise to the reaction mixture and the mixture was stirred at room temperature for 2 hr. N,N-Dimethylformamide (50 mL) was added and the mixture was further stirred for 18 hr. The reaction mixture was concentrated under reduced pressure, and 1 M hydrochloric acid was added, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (10%-30% ethyl acetate/hexane) to give the title compound (7.70 g, yield 37%) as a yellow oil.
Reaction SMILES: C1(C[O:8][C:9](=[O:46])[C:10]2[CH:15]=[C:14]([O:16][CH2:17][CH2:18][CH2:19][O:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH:13]=[C:12]([O:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45])[CH:11]=2)C=CC=CC=1.[H][H]>[Pd]>[CH2:28]([O:27][C:12]1[CH:11]=[C:10]([CH:15]=[C:14]([O:16][CH2:17][CH2:18][CH2:19][O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:13]=1)[C:9]([OH:46])=[O:8])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45]
Reactant: CCCCCCCCCCCCCCCCCCOc1cc(OCCCOc2ccccc2)cc(C(=O)OCc2ccccc2)c1
Reactant: [H][H]
Agent: [Pd]
Product: CCCCCCCCCCCCCCCCCCOc1cc(OCCCOc2ccccc2)cc(C(=O)O)c1
Yield: 94.3 %

Procedure:
A mixture of 14.6 g of 3-(octadecyloxy)-5-(3-phenoxypropoxy) benzoic acid phenylmethyl ester and 3 g of 10% palladium on carbon was shaken in a hydrogen atmosphere at room temperature for 2 hours. The catalyst was removed by filtration and the filtrate was concentrated to a solid which was recrystallized from ether-hexane to give 11.8 g (95% yield, mp 79°-81°) of 3-(octadecyloxy)-5-(3-phenoxypropoxy)benzoic acid.
Reaction SMILES: I[C@H:2]1[C@H:8]2[CH2:9][C@H:5]([C:6](=[O:10])[O:7]2)[CH2:4][CH2:3]1.[OH-].[Na+].[CH2:13]([OH:15])[CH3:14]>>[O:15]1[C@@H:2]2[C@H:13]1[CH2:14][C@H:5]([C:6]([O:7][CH2:8][CH3:9])=[O:10])[CH2:4][CH2:3]2
Reactant: O=C1O[C@@H]2C[C@H]1CC[C@H]2I
Reactant: CCO
Agent: [Na+]
Agent: [OH-]
Product: CCOC(=O)[C@@H]1CC[C@@H]2O[C@@H]2C1
Temperature: 25 °C
Reaction time: 7 h

Procedure:
(1R*,4R*,5R*)-4-Iodo-6-oxabicyclo[3.2.1]octan-7-one (J. Org. Chem., 1996, Vol. 61, p. 8687) (14.3 g) was dissolved in ethanol (130 ml), a 2N aqueous solution (34.5 ml) of sodium hydroxide was added under ice cooling, and the mixture was then stirred at room temperature for 7 hours. After the solvent was distilled off under reduced pressure, and water was added to the residue to conduct extraction with dichloromethane, the extract was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by column chromatography on silica gel (hexane:ethyl acetate=83:17) to obtain the title compound (6.54 g) as a colorless oil.
Reaction SMILES: CS(Cl)(=O)=O.[N:6]1([CH2:19][CH:20](O)[CH3:21])[CH:10]=[CH:9][C:8]2[CH2:11][O:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[C:7]1=2.C(N(CC)CC)C.[N-:30]=[N+:31]=[N-:32].[Na+]>ClCCl.C(OCC)C.CN(C)C=O.O>[N:30]([CH:20]([CH3:21])[CH2:19][N:6]1[CH:10]=[CH:9][C:8]2[CH2:11][O:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[C:7]1=2)=[N+:31]=[N-:32]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(O)Cn1ccc2c1-c1ccccc1OC2
Agent: CS(=O)(=O)Cl
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CC(Cn1ccc2c1-c1ccccc1OC2)N=[N+]=[N-]
Yield: 71.3 %

Procedure:
1.23 ml of methanesulfonyl chloride were added dropwise while stirring to a solution, cooled to 0°, of 1.82 g of (RS)-1-(1,4-dihydro-[1]benzopyrano[4,3-b]pyrrol-1-yl)-propan-2-ol and 4.4 ml of triethyl-amine in 50 ml of anhydrous dichloromethane and the mixture was stirred at this temperature for an additional 1.5 hours. The reaction mixture was subsequently diluted with 280 ml of diethyl ether, washed twice with 70 ml of saturated sodium hydrogen carbonate solution each time and the combined aqueous phases were extracted once with 70 ml of diethyl ether. The combined organic phases were washed with 140 ml of saturated sodium chloride solution, dried over magnesium sulfate and evaporated in a vacuum. The brown oil obtained was dissolved in 50 ml of anhydrous dimethylformamide treated with 1.03 g of sodium azide and the reaction mixture was heated to 60° for 17 hours while stirring. After cooling, the solution was poured into 140 ml of water and extracted twice with 140 ml of diethyl ether each time. The combined organic phases were washed once with 100 ml of water and once with 100 ml of saturated sodium chloride solution, dried over magnesium sulfate and the solution was concentrated in a vacuum. The brown oil obtained was purified by column chromatography on silica gel (toluene). 1.44 g (71%) of (RS)-1-(2-azido-propyl)-1,4-dihydro-[1]benzopyrano[4,3-b]pyrrole were obtained as a colorless oil.
Reaction SMILES: [C:1]([O:10][CH3:11])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].[C:12](Cl)(=[O:14])[CH3:13].[Cl-].[Al+3].[Cl-].[Cl-]>ClC(Cl)=C(Cl)Cl>[C:12]([C:7]1[CH:8]=[C:2]([C:1]([O:10][CH3:11])=[O:9])[C:3]([OH:4])=[CH:5][CH:6]=1)(=[O:14])[CH3:13]
Reactant: COC(=O)c1ccccc1O
Reactant: CC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClC(Cl)=C(Cl)Cl
Product: COC(=O)c1cc(C(C)=O)ccc1O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of 75 g. (0.5 m.) of methyl salicylate in 200 ml. of tetrachloroethylene is cooled in an ice bath and treated with a solution of 40 g. (0.5 m.) of acetyl chloride in 200 ml. of tetrachloroethylene. To the chilled mixture is added 133 g. (1.0 m.) of aluminum chloride over a fifteen minute period, maintaining the temperature below 25° C. After the adddition is completed the mixture is stirred for 4 hours at 25° C. and then poured into ice water. The organic layer is separated, washed with water and saturated aqueous sodium bicarbonate solution, dried and evaporated. The residual oil is crystallized from hexane to give methyl 5-acetylsalicylate, m.p. 60°-62° C.
Reaction SMILES: [C:1]([O:5][CH3:6])(=[O:4])[C:2]#[CH:3].C([Li])CCC.[CH3:12][N:13]([CH3:22])[C:14]1[CH:21]=[CH:20][C:17]([CH:18]=[O:19])=[CH:16][CH:15]=1.[Cl-].[NH4+]>O1CCCC1>[CH3:12][N:13]([CH3:22])[C:14]1[CH:21]=[CH:20][C:17]([CH:18]([OH:19])[C:3]#[C:2][C:1]([O:5][CH3:6])=[O:4])=[CH:16][CH:15]=1
Reactant: CN(C)c1ccc(C=O)cc1
Reactant: C#CC(=O)OC
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: COC(=O)C#CC(O)c1ccc(N(C)C)cc1
Reaction time: 0.17 h

Procedure:
A solution of 6.7 ml (80 mmol) of methyl propiolate in 80 ml of tetrahydrofuran was treated at -78° under argon with 53.1 ml of n-butyllithium (1.6M in hexane). The mixture was stirred at -78° for 10 minutes and then a solution of 11.94 g (80 mmol) of 4-dimethylaminobenzaldehyde in 80 ml of tetrahydrofuran was added within 30 minutes. The reaction mixture was stirred at -78° for a further 20 minutes then brought to room temperature and treated with 120 ml of saturated ammonium chloride solution. The aqueous phase was extracted twice with ether, the combined organic phases were washed in sequence with saturated sodium chloride solution and with water, dried over sodium sulphate and concentrated. The residue was purified by flash chromatography on 1000 g of silica gel (elution agent methylene chloride/ethyl acetate 9:1). There was obtained methyl 4-[4-(dimethylamino)phenyl)-4-hydroxy-2-butynoate as a red oil.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][CH2:11][OH:12])([O-:3])=[O:2].N1C=CN=C1.[Si:18](Cl)([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19]>C(Cl)Cl>[C:21]([Si:18]([CH3:20])([CH3:19])[O:12][CH2:11][CH2:10][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[N+:1]([O-:3])=[O:2])([CH3:24])([CH3:23])[CH3:22]
Reactant: O=[N+]([O-])c1ccccc1CCO
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCCc1ccccc1[N+](=O)[O-]
Reaction time: 2.5 h
Yield: 96.4 %

Procedure:
A solution of 2-(2-nitro-phenyl)ethanol (100 g, 590 mmol) in CH2Cl2 (800 mL), was treated with imidazole (117 g, 777 mmol) followed by tert-butyl-dimethylsilylchloride (562 g, 826 mmol). A white precipitate formed upon the addition and the reaction was stirred 2.5 hours. The mixture was filtered and diluted with CH2Cl2 (300 mL) and was washed with 0.1 N HCl (300 mL), H2O (400 mL), saturated aq NaHCO3 (400 mL), and brine (400 mL). The organic layer was dried over MgSO4, filtered and concentrated to give the title compound (160 g, 96%) as a transparent oil. 1H NMR (400 MHz, DMSO-d6) −0.11 (s, 6H), 0.77 (s, 9H), 3.03 (t, J=6 Hz, 2H), 3.79 (t, J=6 Hz), 7.42–7.54 (m, 2H), 7.62 (ddd, J=<1, 6, 7 Hz, 1H), 7.88 (dd, J=<1, 7 Hz, 1H). MS (electrospray, m/z) 282 (H++1).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([N+:13]([O-:15])=[O:14])[CH:12]=1)C(O)=O)([O-:3])=[O:2].ClC(Cl)C.[N-:20]=[N+]=[N-].[Na+]>OS(O)(=O)=O.O=S(=O)=O>[N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([N+:13]([O-:15])=[O:14])[CH:12]=1)[NH2:20])([O-:3])=[O:2]
Reactant: [N-]=[N+]=[N-]
Reactant: O=C(O)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Agent: O=S(=O)(O)O
Agent: O=S(=O)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: Nc1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Temperature: 25 °C
Yield: 87.9 %

Procedure:
3,5-Dinitrobenzoic acid (7, Aldrich) (106.1 grams, 0.50 mole) was dissolved in 400 milliliters of 23 to 24% oleum. Dichloroethane (480 milliliters) was added to this solution. Sodium azide (37 grams, 0.57 mole) was added in portions with stirring while maintaining the temperature below 25° C. The mixture was heated under reflux for 4 hours and allowed to cool to room temperature. The dichloroethane was removed by decantation, and the remaining mixture was poured over 9 liters of ice mixed with water. The yellow solid which separated was filtered, washed with water, and air dried to afford 80.5 grams (87.9%) of 8 with a melting point of 158° to 162° C.; literature: melting point of 162° to 163° C. (Reference 10). IR (KBr) 3335 (d, NHz), 3035, 1615 (C=O), 1575, 1525, 1440, 1325, 1090, 1050, 990, 915, 880, 810 and 730 cm -1.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][C:10](=[O:14])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:15](Br)[CH:16]=[CH2:17]>C1COCC1>[CH2:17]([N:11]1[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9][C:10]1=[O:14])[CH:16]=[CH2:15]
Reactant: C=CCBr
Reactant: CC(C)(C)OC(=O)N1CCNC(=O)C1
Solvent: C1CCOC1
Product: C=CCN1CCN(C(=O)OC(C)(C)C)CC1=O
Yield: 76 %

Procedure:
4-(tert-Butyloxycarbonyl)-piperazin-2-one (1.0 g, 5.0 mmol), EXAMPLE 40, is alkylated with allyl bromide (0.48 ml, 5.5 mmol) in THF (20 ml) using the procedure described in Example 92, Part A. The title compound (0.92 g, 3.8 mmol) is obtained as a colorless liquid after chromatographed (50% ethyl acetate/hexane). EI MS m/z 240 (M+); 1H NMR (CDCl3, 300 MHz) δ5.80-5.68 (m, 1H), 5.23-5.15 (m, 2H), 4.09 (s, 2H), 4.03 (d, 2H), 3.63 (t, 2H), 3,30 (t, 2H), 1.45 (s, 9H).
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[C:6]([CH3:9])=[CH:5][C:4]([C:10]([OH:12])=O)=[CH:3]1.S(Cl)([Cl:15])=O>>[CH3:1][N:2]1[C:7](=[O:8])[C:6]([CH3:9])=[CH:5][C:4]([C:10]([Cl:15])=[O:12])=[CH:3]1
Reactant: O=S(Cl)Cl
Reactant: Cc1cc(C(=O)O)cn(C)c1=O
Product: Cc1cc(C(=O)Cl)cn(C)c1=O
Temperature: 60 °C
Yield: 100 %

Procedure:
1,5-Dimethyl-6-oxo-1,6-dihydro-pyridine-3-carboxylic acid D1 (500.000 mg; 2.991 mmol) is suspended in thionyl chloride (2.000 ml; 27.536 mmol) and heated for 2 h at 60° C. The reaction mixture is concentrated under reduced pressure. And used in the next reaction without further purification (Yield: 100%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([C:16]2[NH:20][C:19]3[CH:21]=[CH:22][CH:23]=[CH:24][C:18]=3[N:17]=2)=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:25][C:26]1[CH:33]=[CH:32][C:29]([CH2:30]O)=[CH:28][CH:27]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>O1CCCC1.C(OCC)(=O)C.CCCCCC>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([C:14]([C:16]2[N:17]([CH2:30][C:29]3[CH:32]=[CH:33][C:26]([F:25])=[CH:27][CH:28]=3)[C:18]3[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=3[N:20]=2)=[O:15])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)c2nc3ccccc3[nH]2)CC1
Reactant: OCc1ccc(F)cc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(C(=O)c2nc3ccccc3n2Cc2ccc(F)cc2)CC1
Reaction time: 23 h

Procedure:
Combine 1-(t-butoxycarbonyl)-4-(1H-benzoimidazole-2-carbonyl)-piperidine (1.50 g, 4.57 mmol), 4-fluorobenzyl alcohol (0.50 mL, 4.58 mmol) and triphenylphosphine (1.44 g, 5.50 mmol) in tetrahydrofuran (15 mL). Add diethylazodicarboxylate (0.87 mL, 5.50 mmol) dropwise at room temperature. After 23 hours, evaporate the reaction mixture in vacuo to give a residue. Chromatograph the residue on silica gel eluting with 25% ethyl acetate/hexane to give 1-(t-butoxycarbonyl)-4-(1-(4-fluoro-benzyl)-1H-benzoimidazole-2-carbonyl)-piperidine.
Reaction SMILES: I[C:2]1[C:7]([O:8][CH2:9][CH2:10][OH:11])=[CH:6][CH:5]=[C:4]([CH3:12])[N:3]=1.[H-].[Na+]>CN(C=O)C.[O-]S([O-])(=O)=O.[Cu+2]>[CH3:12][C:4]1[N:3]=[C:2]2[O:11][CH2:10][CH2:9][O:8][C:7]2=[CH:6][CH:5]=1
Reactant: Cc1ccc(OCCO)c(I)n1
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Agent: [H-]
Solvent: CN(C)C=O
Product: Cc1ccc2c(n1)OCCO2
Temperature: 100 °C
Reaction time: 8 h
Yield: 15.9 %

Procedure:
To a stirred solution of 2-(2-iodo-6-methylpyridin-3-yloxy)ethanol (350 g, 1.25 mol) in anhydrous DMF (3.5 L) was added NaH (60 g, 1.5 mol), Cu (33.7 g, 0.53 mol) and CuSO4 (100 g, 0.63 mol) at 0° C. After the addition, the mixture was stirred at 100° C. overnight. After cooling, the solvent was removed in vacuo and the residue was diluted with water (1.5 L). The aqueous solution was extracted with CH2Cl2 (3×350 mL). The combined organic layers were washed with brine (2×100 mL), dried over anhydrous Na2SO4 and concentrated. The residue was purified via column chromatography (silica gel, EtOAc/petroleum ether 1:20) to yield 6-methyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyridine (30.0 g, 16%) as a yellow oil.