Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.N1C2C(=CC=CC=2)C=CC=1.[N+:16]([C:19]1[C:20](O)=[N:21][CH:22]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:24]=1)([O-:18])=[O:17].C([O-])([O-])=O.[Na+].[Na+]>O>[Cl:3][C:20]1[C:19]([N+:16]([O-:18])=[O:17])=[CH:24][C:23]([C:25]([F:28])([F:27])[F:26])=[CH:22][N:21]=1
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)cnc1O
Reactant: O=P(Cl)(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: c1ccc2ncccc2c1
Product: O=[N+]([O-])c1cc(C(F)(F)F)cnc1Cl
Temperature: 100 °C
Yield: 55 %

Procedure:
To a solution of phosphoryl chloride (2.0 mL, 21.2 mmol) and quinoline (1.30 mL, 10.8 mmol) was added solid powder 3-nitro-5-(trifluoromethyl)pyridin-2-ol (4.00 g, 18.3 mmol) (95% purity). The resulting dark brown thick suspension was heated to reflux for 4 h and gradually turned into a very cloudy dark brown solution. After cooling to 100° C., water (11 mL) was slowly added to the mixture which was further cooled to room temperature and neutralized carefully with Na2CO3. The resulting solution was extracted with EtOAc three times. The extracts were combined, dried over MgSO4, filtered, and evaporated in vacuo. The residue was purified by flash chromatography on silica gel (EtOAc/hexanes 30:70) to afford 2.28 g of desired product.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH:14]=[CH:15][C:16]=1[O:17][CH2:18][CH2:19][O:20][CH3:21])[C:9]([O:11][CH2:12][CH3:13])=[O:10].S(=O)(=O)(O)O.[N+:27]([O-])([OH:29])=[O:28].[Cl-].[Na+]>C1(C)C=CC=CC=1.C(O)(=O)C>[CH3:21][O:20][CH2:19][CH2:18][O:17][C:16]1[C:6]([O:5][CH2:4][CH2:3][O:2][CH3:1])=[CH:7][C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:14]([N+:27]([O-:29])=[O:28])[CH:15]=1
Reactant: O=[N+]([O-])O
Reactant: CCOC(=O)c1ccc(OCCOC)c(OCCOC)c1
Agent: O=S(=O)(O)O
Agent: [Cl-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cc(OCCOC)c(OCCOC)cc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 100 %

Procedure:
In a 20 L-volume glass reaction vessel equipped with a stirrer, a thermometer and a reflux condenser, the acetic acid solution containing 2,023 g (6.78 moles) of ethyl 3,4-bis(2-methoxyethoxy)benzoate prepared in the Synthesis Example 1 was placed. To the solution, 318 g (3.18 moles) of concentrated sulfuric acid was gently added while stirring the solution at room temperature. The mixture was heated to 60 to 70° C. To the mixture, 1,857 g (20.34 moles) of 69 wt. % nitric acid was gently added while stirring the mixture. The resulting mixture was allowed to react for 2 hours while maintaining the temperature. After the reaction was complete, the reaction solution was cooled to room temperature. To the reaction solution, 5,200 mL of a 20 wt. % aqueous sodium chloride solution and 5,200 mL of toluene were added. The separated organic layer (toluene layer) was washed twice with 7,800 mL of a 1 mole per L aqueous sodium hydroxide solution, and further washed twice with 7,800 mL of a 20 wt. % aqueous sodium chloride solution. The organic layer was concentrated under reduced pressure to obtain 2,328 g of ethyl 4,5-bis(2-methoxyethoxy)-2-nitrobenzoate as an orange liquid (isolation yield: 100%).
Reaction SMILES: [C:1]([N:8]1[CH2:14][CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH3:15][S:16](Cl)(=[O:18])=[O:17]>C(N(CC)CC)C>[C:4]([O:3][C:1]([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([S:16]([CH3:15])(=[O:18])=[O:17])[CH2:10][CH2:9]1)=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCCNCC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCCN(S(C)(=O)=O)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To 1-BOC-homopiperazine (0.8 ml) was added methane sulphonyl chloride (0.34 ml) and triethylamine (0.68 ml). The reaction mixture was stirred at room temperature for 4 hours. The reaction mixture was then partitioned between dichloromethane and water. The combined organic extracts were then washed with brine and dried (MgSO4). The solvent was removed in vacuo to yield 1.23 g crude 4-methanesulfonyl-[1,4]diazepane-1-carboxylic acid tert-butyl ester.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4](=[O:8])[O:5][C:6]=1[CH3:7].C1C(=O)N([Br:16])C(=O)C1>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:16][CH2:1][C:2]1[O:3][C:4](=[O:8])[O:5][C:6]=1[CH3:7]
Reactant: Cc1oc(=O)oc1C
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: Cc1oc(=O)oc1CBr
Temperature: 80 °C
Yield: 98 %

Procedure:
4,5-dimethyl-2-oxo-1,3-dioxole (5 g, 43.82 mmol), NBS (8.19 g, 46.01 mmol), and benzoyl peroxide (20 mg) were dissolved in CCl4 (30 mL) and heated to 80° C. for 1.5 h. The reaction mixture was cooled to r.t and the solid was filtered off. The filtrate was concentrated. The residue was purified by silica gel column to give 8.29 g of 4-bromomethyl-5-methyl-2-oxo-1,3-dioxole as a yellow oil. TEA (12 mL, 86.1 mmol) was added dropwise to a solution of 4-bromomethyl-5-methyl-2-oxo-1,3-dioxole (6 g, 310.09 mmol) and formic acid (3.36 mL) in CH3CN (96 mL) while keeping the temperature under 20° C. The mixture was stirred at r.t. for 2 h and concentrated. The product was partitioned between H2O and EtOAc (3×). The organic layer was dried with Na2SO4, concentrated and dried in vacuo to give crude formate. The resulting formate was dissolved in MeOH (40 mL) and 0.5 mL of concentrated HCl was added. The mixture was stirred at r.t. for 5 h, concentrated, and co-evaporated with toluene. The crude product was purified by silica gel column to give 2.8 g of 4-hydroxymethyl-5-methyl-2-oxo-1,3-dioxole in 69% yield. 1H NMR (300 MHz, CDCl3): δ 4.40 (s, 2H), 2.60 (broad, s, 1H), 2.20 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.[C:21]1([CH2:27][C:28]2[CH:36]=[CH:35][CH:34]=[CH:33][C:29]=2[C:30](Cl)=[O:31])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(Cl)Cl>[C:21]1([CH2:27][C:28]2[CH:36]=[CH:35][CH:34]=[CH:33][C:29]=2[C:30]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:10][CH:11]=2)=[O:31])[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: COC(=O)c1ccc(N)cc1
Reactant: O=C(Cl)c1ccccc1Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)c1ccc(NC(=O)c2ccccc2Cc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 72.8 %

Procedure:
To 3.03 g of methyl 4-aminobenzoate and 3.12 g of N,N-diisopropylethylamine in 75 ml of methylene chloride is added 5.54 g of 2-(phenylmethyl)benzoyl chloride and the reactants stirred at room temperature for 18 hours. The reaction mixture is washed with water, saturated aqueous NaHCO3 and the organic layer dried (Na2SO4). The organic layer is passed through hydrous magnesium silicate two times and hexane added to the filtrate at the boil to give 5.04 g of the desired product as a crystalline solid, m.p. 138°-139° C.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)([O-:3])=[O:2].[Cl:10][S:11](O)(=[O:13])=[O:12]>S(=O)(=O)(O)N>[N+:1]([C:4]1[CH:9]=[C:8]([S:11]([Cl:10])(=[O:13])=[O:12])[CH:7]=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccccc1
Reactant: O=S(=O)(O)Cl
Agent: NS(=O)(=O)O
Product: O=[N+]([O-])c1cccc(S(=O)(=O)Cl)c1
Temperature: 105 °C
Reaction time: 6 h
Yield: 87.8 %

Procedure:
123.1 g (1.0 mol) of nitrobenzene are allowed to run rapidly into 582.5 g (5.0 mol) of chlorosulfonic acid and 1 g of sulfamic acid at room temperature. The mixture is then heated to 105° C. and stirred at this temperature for 6 hours. For working up, the reaction mixture is dripped into ice water. The precipitated crystals are filtered off with suction and washed with water. 194.6 g of dry 3-nitrobenzenesulfonyl chloride having a melting point of 59°-61° C., corresponding to a yield of 87.8% of theory, are obtained.
Reaction SMILES: [CH2:1]([OH:6])[CH2:2][CH2:3][CH2:4][OH:5].[Si:7](Cl)([C:20]([CH3:23])([CH3:22])[CH3:21])([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.N1C=CN=C1.O>CN(C)C=O>[O:5]([CH2:4][CH2:3][CH2:2][CH2:1][OH:6])[Si:7]([C:20]([CH3:23])([CH3:22])[CH3:21])([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: OCCCCO
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)[Si](OCCCCO)(c1ccccc1)c1ccccc1
Yield: 64.9 %

Procedure:
To a solution of 1.00 g (10.2 mmol) of 1,4-butanediol in 20 ml of dry dimethylformamide were added 2.80 g (10.2 mmol) of tert-butyldiphenylsilyl chloride and 3.47 g (51.0 mmol) of imidazole in an atmosphere of argon. The mixture was allowed to react at 0° C. for 24 hours. To the solution was added water followed by extraction with dichloromethane. The organic layer was washed with water and concentrated under reduced pressure. The residue thus obtained was subjected to silica gel column chromatography for separation and purification. Elution with dichloromethane-methanol (100:1) yielded 2.17 g (6.62 mmol) of 4-(tert-butyldiphenylsiloxy)-1-butanol.
Reaction SMILES: [CH2:1]([OH:6])[CH2:2][CH2:3][CH2:4][OH:5].C(N(C(C)C)CC)(C)C.[C:16]([Si:20](Cl)([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([CH3:19])([CH3:18])[CH3:17].N#N>ClCCl>[C:16]([Si:20]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[O:5][CH2:4][CH2:3][CH2:2][CH2:1][OH:6])([CH3:19])([CH3:17])[CH3:18]
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: OCCCCO
Agent: N#N
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)[Si](OCCCCO)(c1ccccc1)c1ccccc1
Yield: 172.5 %

Procedure:
To a solution of 1,4-butanediol (5 g, 55 mol) in dichlormethane (10 mL) containing diisopropylethylamine (10 mL) was added tert-butylchlorodiphenylsilane (5 mL, 18 mmol) dropwise under N2 atmosphere at 18° C. over 2 h. The resultant solution was stirred at room temperature for 4 hours and concentrated under reduced pressure. Purification by column chromatography with hexane/ethyl acetate (1/1) gave 4-(tert-butyl-diphenyl-silanyloxy)-butan-1-ol (10.2 g, 85% yield) as colorless oil: 1H NMR (400 MHz, CDCl3) δ 7.62-7.71 (4H, m); 7.32-7.43 (6H, m), 3.63-3.69 (4H, m), 1.83 (1H, br s), 1.59-1.71 (4H, m), 1.03 (9H, s).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([O:11][CH3:12])[CH:10]=1)[CH:6]=O.[N+:13]([CH3:16])([O-:15])=[O:14].[OH-].[Na+]>O.CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5](/[CH:6]=[CH:16]/[N+:13]([O-:15])=[O:14])[CH:8]=[C:9]([O:11][CH3:12])[CH:10]=1
Reactant: C[N+](=O)[O-]
Reactant: COc1cc(C=O)cc(OC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1cc(/C=C/[N+](=O)[O-])cc(OC)c1
Temperature: 0 °C

Procedure:
A solution of 3,5-dimethoxybenzaldehyde (34.5 g., 0.208 mole) and nitromethane (12.69 g., 0.208 mole) in 40 ml. of MeOH was cooled to 0° under N2 . A solution was prepared by dissolving NaOH (8.43 g., 0.211 mole) in 10 ml. of H2O then diluting to 20 ml. with ice-water. This solution was then added dropwise to the methanol mixture. After 15 minutes the reaction was diluted with ice-H2O and added slowly to a solution of 40 ml. concentrated HC1in 60 ml. H2O. The resulting precipitate (44 g.) was filtered and recrystallized from methanol to give 28.6 g. of product, m.p. 132°; reported, J. Org. Chem. 27, p. 376 (1962), m.p. 133.5-134.5.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:6].[C:13]([NH:21][CH:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1)(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C([O-])([O-])=O.[K+].[K+].O>C(Cl)(Cl)Cl>[C:5]([CH2:4][CH2:3][CH2:2][N:25]1[CH2:26][CH2:27][CH:22]([NH:21][C:13](=[O:20])[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:23][CH2:24]1)(=[O:6])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=C(NC1CCNCC1)c1ccccc1
Reactant: O=C(CCCCl)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClC(Cl)Cl
Product: O=C(CCCN1CCC(NC(=O)c2ccccc2)CC1)c1ccccc1
Yield: 9.1 %

Procedure:
A mixture of 4-chlorobutyrophenone (447 mg, 2.45 mmol), 4-benzamidopiperidine (500 mg, 2.45 mmol) and K2CO3 (338 mg, 2.45 mmol) was heated up in boiling water bath for 1 hour. The reaction mixture was portioned between water and CHCl3. The organic layer was separated and dried over Na2SO4. After filtration and removal of solvent, the residue was purified by chromatography (SiO2, MeOH:CHCl3, 5:95). Recrystallization from AcOEt/hexane gave a white powder (78 mg, 8.2%). mp 143-144° C.; 1H NMR (CD3OD, 400 MHz) δ 1.65 (dq, J1 =3.16 Hz, J2 =11.9 Hz, 2H), 1.90-2.00 (m, 4H), 2.18 (t, J=11.9 Hz, 2H), 2.48 (m, 2H), 3.00-3.10 (m, 4H), 3.88 (m, 1H), 7.40-8.00 (m, 10H); Mass spectrum (M+1)+ at m/z 351.
Reaction SMILES: [O:1]1[CH:6]=[CH:5][CH2:4][CH2:3][CH2:2]1.[I:7][CH2:8][CH2:9][OH:10].C1(C)C=CC(S(O)(=O)=O)=CC=1.C([O-])([O-])=O.[K+].[K+]>CCOCC>[I:7][CH2:8][CH2:9][O:10][CH:6]1[CH2:5][CH2:4][CH2:3][CH2:2][O:1]1
Reactant: C1=COCCC1
Reactant: OCCI
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Product: ICCOC1CCCCO1
Reaction time: 1 h

Procedure:
Freshly distilled dihydropyran (Aldrich, 59.0 g, 0.7 mol) was added dropwise to a cooled solution of 2-iodoethanol (Aldrich, 98 g, 0.57 mol) in Et2O (1 L) containing 0.1 g of p-toluenesulfonic acid (Eastman). The solution was then stirred for 1 h at 5°. Solid K2CO3 (Mallinckrodt, 5 g) was then added to the reaction mixture and the resulting suspension stirred an additional 1 h at RT. The reaction was then filtered and the remaining solid washed with Et2O (1 L). The organic solutions were combined and concentrated rotary evaporation (in a flask washed with 1% NEt3 in H2O). The crude 2-(2-iodoethoxy)tetrahydro-2-H-pyran (~100 g, 68.9%) was used without further purification.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][O:9][C:10]([C:12]1[N:13]=[CH:14][NH:15][CH:16]=1)=[O:11].[C:17]1([C:23](Cl)([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C(#N)C>[CH3:8][O:9][C:10]([C:12]1[N:13]=[CH:14][N:15]([C:23]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:16]=1)=[O:11]
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COC(=O)c1c[nH]cn1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COC(=O)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reaction time: 8 h
Yield: 95.8 %

Procedure:
Add triethylamine (1.88 mL, 13.48 mmol) to a mixture of methyl-4-imidazolecarboxylate (1.0 g, 7.93 mmol) and triphenylmethyl chloride (2.43 g, 8.72 mmol) in anhydrous acetonitrile (25 mL) over 10 min at room temperature and stir overnight. Quench with water and extract with ethyl acetate (3×). Combine the organic layers, wash with 1N hydrochloride solution, water, saturated aqueous sodium bicarbonate solution and brine sequentially, dry over sodium sulfate, and concentrate to provide the title compound 1-trityl-1H-imidazole-4-carboxylic acid methyl ester (2.8 g, 7.60 mmol).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5](Cl)(=[O:7])[CH3:6].[Br:9][C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1>C(Cl)Cl>[C:5]([O:16][C:13]1[CH:14]=[CH:15][C:10]([Br:9])=[CH:11][CH:12]=1)(=[O:7])[CH3:6]
Reactant: CC(=O)Cl
Reactant: Oc1ccc(Br)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CC(=O)Oc1ccc(Br)cc1
Temperature: 0 °C
Yield: 84.8 %

Procedure:
To the suspension of anhydrous aluminum chloride (84.0 g, 0.49 mol) in methylene chloride (1200 mL) was add acetyl chloride (49.2 g, 0.63 mol) while stirring and cooling on ice. The mixture was stirred for 20 minutes while cooling on ice followed by addition of 4-bromophenol (98 g, 0.57 mol). The reaction mixture was stirred at room temperature for 1 h and then ice water was added. The reaction mixture was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate. After distilling off the solvent under reduced pressure, the residue was purified by silica gel column chromatography to yield 4-bromophenyl acetate (104.0 g, 85%). 1H-NMR (CDCl3): 2.28 (s, 3H), 6.98 (d, 2H), 7.48 (d, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[O:8][CH3:9].OO.C(=O)(O)[O-].[Na+].[ClH:17]>>[NH2:1][C:2]1[C:3]([Cl:17])=[N:4][CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: COc1ccncc1N
Reactant: Cl
Agent: O=C([O-])O
Agent: OO
Agent: [Na+]
Product: COc1ccnc(Cl)c1N

Procedure:
To a solution of 6.4 g (51 mmol) of 3-amino-4-methoxypyridine in 30 mL of 37 percent aqueous hydrochloric acid was slowly added 7.8 g of 30 percent aqueous hydrogen peroxide at room temperature with stirring. After 30 min this solution was slowly poured into 300 mL of saturated aqueous sodium bicarbonate and the resulting mixture was extracted with ether (3×200 mL). The ethereal extracts were combined, dried over magnesium sulfate, and filtered. The filtrate was concentrated by evaporation under reduced pressure to obtain a light brown solid. This solid was purified by column chromatography eluting with 17:83 acetone:hexane to obtain 6.54 g (81 percent of theory) of the title compound as colorless needles melting at 86°-87° C.
Reaction SMILES: P(Br)(Br)(Br)(Br)Br.[Br:7]Br.P(Br)(Br)Br.[C:13]1([CH2:19][CH2:20][CH2:21][CH:22](O)[CH3:23])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(Cl)Cl.O>[Br:7][CH:22]([CH2:21][CH2:20][CH2:19][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH3:23]
Reactant: BrBr
Reactant: CC(O)CCCc1ccccc1
Agent: BrP(Br)(Br)(Br)Br
Agent: BrP(Br)Br
Solvent: ClCCl
Solvent: O
Product: CC(Br)CCCc1ccccc1
Temperature: 0 °C
Reaction time: 2.5 h

Procedure:
To a phosphorus pentabromide, prepared by addition of bromine (9.0 g.) in methylene chloride (10 ml.) to phosphorous tribromide (15.0 g.) in methylene chloride (15 ml.) at 0° C., is added 5-phenyl-2-pentanol (8.2 g.) in methylene chloride at 0° C. The mixture is stirred for 2.5 hours at 0° C. and is then allowed to warm to room temperature. Water (50 ml.) is added, the mixture stirred for one hour and the methylene chloride layer separated. The extraction is repeated and the combined extracts washed with water, saturated sodium bicarbonate solution, brine and then dried over magnesium sulfate. Concentration of the dried extracts gives 12.4 g. of title product as a light yellow oil.
Reaction SMILES: F[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[CH3:11].[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][CH:15]=1.C(C)(C)C([O-])=O.[K+].O>CS(C)=O>[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([NH:20][C:2]2[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=2[CH3:11])=[CH:16][CH:15]=1
Reactant: COc1ccc(N)cc1
Reactant: Cc1cccc([N+](=O)[O-])c1F
Agent: CC(C)C(=O)[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: COc1ccc(Nc2c(C)cccc2[N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 42 %

Procedure:
To a solution of 50 g of 2-fluoro-3-nitrotoluene in 1.1 L of DMSO are added at room temperature 59.5 g of para-anisidine (1.5 equivalents). After 5 minutes of stirring at room temperature, 57.9 g of potassium tert-butanoate (1.6 equivalents) are added to the reaction medium and the whole is heated to 110° C. for 1 hour. The reaction medium is directly hydrolyzed by adding 1 L of ice and water and then the aqueous phase is extracted several times with ethyl acetate. The organic phases are collected, dried on sodium sulphate, filtered and then dry concentrated. The raw product is chromatographed on silica gel (ether/cyclohexane:0/100, 5/95 and then 20/80) in order to provide 34.95 g of the expected compound as a dark red solid.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][C:5]2[CH2:6][CH2:7][O:8][C:4]=2[CH:3]=1.C([Li])CCC.CN([CH:19]=[O:20])C>C1COCC1.CCCCCC>[O:8]1[C:4]2[CH:3]=[C:2]([CH:19]=[O:20])[CH:10]=[CH:9][C:5]=2[CH2:6][CH2:7]1
Reactant: Brc1ccc2c(c1)OCC2
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: O=Cc1ccc2c(c1)OCC2
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
To an cooled solution (−78° C. internal temp) of 1 g of 6-bromo-2,3-dihydro-1-benzofuran (prepared as described by Z. J. Song, M. Zhao, L. Frey, J. Li, L. Tan, C. Y. Chen, D. M. Tschaen, R. Tillyer, E. J. J. Grabowski, R. Volante, P. J. Reider, Y. Kato, S. Okada, T. Nemoto, H. Sato, A. Akao, T. Mase, Organic Letters, 2001, Vol. 3, No. 21, 3357-3360) in 20 mL of anhydrous THF was added 4 mL of 2.5 M n-butyllithium in hexane. After stirring 10 min at −78° C., 0.5 mL of anhydrous DMF was added and the mixture allowed to warm to −20° C., quenched with 20 mL of 3N HCl and extracted into 2×50 mL of ether. Combined extracts dried over MgSO4 and concentrated under reduced pressure. Purification by flash chromatography (0-20% ethyl acetate in hexanes) gave the product as white crystalline solid. MS (m+1)=149.1; 1H NMR (400 MHz, CDCl3) 9.9 (s, 1H), 7.4 (m, 2H), 7.3 (s, 1H), 4.62 (t, 2H), 3.28 (t, 4H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:15][CH2:14][CH2:13][C@H:9]1[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.C(Cl)(=O)C(C)(C)C.Cl.[CH3:31][O:32][C:33](=[O:39])[C@@H:34]1[CH2:38][CH2:37][CH2:36][NH:35]1>C(Cl)Cl>[CH3:31][O:32][C:33](=[O:39])[C@@H:34]1[CH2:38][CH2:37][CH2:36][N:35]1[C:10](=[O:12])[C@@H:9]1[CH2:13][CH2:14][CH2:15][N:8]1[C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7]
Reactant: COC(=O)[C@@H]1CCCN1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Agent: CC(C)(C)C(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)[C@@H]1CCCN1C(=O)[C@@H]1CCCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 17 h
Yield: 85.4 %

Procedure:
METHOD 1 N-tert-butoxycarbonyl L-proline (99.69 g, 0.4631 mol) was dissolved in CH2Cl2 (800 mL). The solution was cooled to 0° C. (icebath) and triethylamine (51.50 g, 0.5089 mol) added. Pivaloyl chloride (61.45 g, 0.5096 mol) was added dropwise, resulting in the precipitation of a white solid. The reaction mixture was stirred for 1 hour at 0° C. before triethylamine (102.99 g, 1.018 mol) was added. Next, L-proline methyl ester hydrochloride (76.87 g, 0.4641 mol) was added in small portions. The icebath was removed and the reaction mixture stirred at room temperature for 17 hours. The volume was increased by addition of CH2Cl2 (2 L) and the solution washed with 30% (w/w) aqueous citric acid (3×1400 mL), saturated NaHCO3 solution (3×1400 mL) and saturated brine (2×1400 mL). The solution was dried with anhydrous MgSO4 and the solvent evaporated affording the title compound as a clear oil (129.14 g, 85%) with spectral characteristics in accordance with literature data.1
Reaction SMILES: [CH3:1][O:2][C:3](=[NH:8])[NH:4][N+:5]([O-:7])=[O:6].C(O)(=O)C.N[CH2:14][C:15]1[S:19][C:18]([Cl:20])=[N:17][CH:16]=1.[OH-].[Na+]>O>[CH3:1][O:2][C:3](=[N:4][N+:5]([O-:7])=[O:6])[NH:8][CH2:14][C:15]1[S:19][C:18]([Cl:20])=[N:17][CH:16]=1
Reactant: COC(=N)N[N+](=O)[O-]
Reactant: NCc1cnc(Cl)s1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: COC(=N[N+](=O)[O-])NCc1cnc(Cl)s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 45.9 %

Procedure:
O-methyl-N-nitroisourea (3.0 g, 0.0252 mol), acetic acid (1.5 ml, 0.0262 mol, 10.4 equivalents), and 5-(aminomethyl)-2-chlorothiazole (93% purity, 4.4 g, 0.0275 mol, 1.09 equivalents) were added to water (55 ml) in this order at 24° C. The reaction mixture was adjusted to pH 7 with 30% aqueous sodium hydroxide solution. The mixture was stirred at room temperature for 2 hours and then extracted with dichloromethane. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to provide 2.9 g (46.0% yield) of O-methyl-N-(2-chloro-5-thiazolylmethyl)-N'-nitroisourea.