Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([OH:12])[CH:3]=1.[C:13]([CH:17]1[CH2:22][CH2:21][CH:20](OS(C)(=O)=O)[CH2:19][CH2:18]1)([CH3:16])([CH3:15])[CH3:14].C(=O)([O-])[O-].[Cs+].[Cs+]>C(O)(C)(C)C.CC(=O)CC>[C:13]([CH:17]1[CH2:22][CH2:21][CH:20]([O:12][C:4]2[CH:3]=[C:2]([I:1])[C:11]3[C:6]([CH:5]=2)=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH2:19][CH2:18]1)([CH3:16])([CH3:15])[CH3:14]
Reactant: Oc1cc(I)c2ccccc2c1
Reactant: CC(C)(C)C1CCC(OS(C)(=O)=O)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)(C)O
Solvent: CCC(C)=O
Product: CC(C)(C)C1CCC(Oc2cc(I)c3ccccc3c2)CC1
Temperature: 100 °C
Yield: 72.8 %

Procedure:
A mixture of 4-iodo-naphthalen-2-ol (1.0 g, 3.7 mmol) (See, for example. Australian Journal of Chemistry (1963), 16 401-10. b. Journal of the Chemical Society (1943), 468-9, which is incorporated by reference in its entirety), methanesulfonic acid 4-tert-butyl-cyclohexyl ester 1.8 g, 7.4 mmol) and cesium carbonate (3.6 g, 11 mmol) in tert-butyl alcohol (10 mL) and 2-butanone (7 mL) was heated in a sealed vial at 100° C. for 4 hrs. The mixture was partitioned between water and dichloromethane. The organic phase was washed with brine, dried over MgSO4, filtered and concentrated. The residue was purified via a silica gel column eluted with EtOAc in hexanes from 0 to 30% to give light yellow precipitate (1.10 g, yield: 73%). ESI-MS: 409.10 (M+H)+.
Reaction SMILES: O.[NH2:2][NH2:3].[CH:4]([C:6]1[C:10]([CH3:11])=[C:9]([CH3:12])[NH:8][C:7]=1[C:13]([O:15]C)=O)=O>C(O)(=O)C>[CH3:12][C:9]1[N:8]=[C:7]2[C:13](=[O:15])[NH:2][NH:3][CH:4]=[C:6]2[C:10]=1[CH3:11]
Reactant: COC(=O)c1[nH]c(C)c(C)c1C=O
Reactant: NN
Solvent: CC(=O)O
Solvent: O
Product: Cc1nc2c(=O)[nH][nH]cc-2c1C
Temperature: 110 °C
Reaction time: 2 h
Yield: 94.7 %

Procedure:
1.50 g (0.030 mole) of hydrazine monohydrate were dropwised added slowly to a solution of 4.00 g (0.022 mole) of methyl 3-formyl-4,5-dimethylpyrrole-2-carboxylate in 80 ml of acetic acid at room temperature and the resulting mixture was stirred at 110° C. for 2 hours. After completion of the reaction, the reaction mixture was poured into ice-water. The resulting precipitates were collected by filtration and washed well with water. The precipitates were dissolved in dichloromethane and the solution was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to give 3.40 g of 2,3-dimethyl-6,7-dihydropyrrolo[2,3-d]pyridazin-7-one as a grayish-white powder.
Reaction SMILES: [OH-].[Na+].[OH:3][C:4]1[C:9]([OH:10])=[CH:8][CH:7]=[CH:6][N:5]=1.[CH3:11]OS(OC)(=O)=O.[N+:18]([O-:21])(O)=[O:19]>S(=O)(=O)(O)O>[CH3:11][O:10][C:9]1[C:4](=[O:3])[NH:5][CH:6]=[C:7]([N+:18]([O-:21])=[O:19])[CH:8]=1
Reactant: O=[N+]([O-])O
Reactant: Oc1cccnc1O
Reactant: COS(=O)(=O)OC
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: COc1cc([N+](=O)[O-])c[nH]c1=O
Temperature: 5 °C
Reaction time: 20 h

Procedure:
Sodium hydroxide (8.6 g, 0.215 mole) and 2,3-dihydroxypyridine (22.0 g, 0.20 mole) were added to distilled water (75 ml). After cooling to 5° C., dimethylsulfate (25.0 g, 0.21 mole) was added dropwise; the reaction mixture was stirred for 20 hours while slowly warming to room temperature. The water was removed in vacuo (approximately 65° C.) to obtain a syrup which was dissolved in concentrated sulfuric acid (50 to 60 ml) at 5° C. A cold mixture of concentrated nitric acid (20 ml) in concentrated sulfuric acid (20 ml) was added at a rate to maintain the reaction mixture between 10° to 15° C. After the addition was complete, the mixture was stirred for 30 minutes at 5° C. and then poured onto ice (approximately 400 ml). The resulting red precipitate was collected by filtration and recrystallized from water; yield, 5.8 g (17 percent).
Reaction SMILES: [P:1]([O-:8])([O:5][CH2:6][CH3:7])[O:2][CH2:3][CH3:4].[H-].[Na+].[Br:11][C:12]1[CH:19]=[CH:18][CH:17]=[CH:16][C:13]=1[CH2:14]Br.O>C1COCC1>[Br:11][C:12]1[CH:19]=[CH:18][CH:17]=[CH:16][C:13]=1[CH2:14][P:1](=[O:8])([O:5][CH2:6][CH3:7])[O:2][CH2:3][CH3:4]
Reactant: CCOP([O-])OCC
Reactant: BrCc1ccccc1Br
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCOP(=O)(Cc1ccccc1Br)OCC
Reaction time: 0.08 h

Procedure:
Diethyl phosphite (0.77 mL, 6.0 mmol) was dissolved in dry THF (10 mL) in a dry schlenk tube under an argon atmosphere. The solution was cooled on an ice bath and NaH (0.24 g, 60% in oil, 6.0 mmol) was added and stirred for 5 min. 2-bromo-benzylbromide (1.0 g, 4.0 mmol) dissolved in 2 mL dry THF was added and the reaction mixture was refluxed overnight. H2O (20 mL) was added and the water phase was extracted with EtOAc (3×10 mL). The combined organic phases were washed with brine, dried (MgSO4), filtered and evaporated in vacuo. The crude product was purified by flash chromatography using EtOAc as the eluent to afford the title compound as a colourless oil.
Reaction SMILES: Cl.Cl.C([CH:5]1[C@@H:14]2[N:9]([CH2:10][CH2:11][C:12]3[C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=4[O:15][C:13]=32)[CH2:8][CH2:7][C@H:6]1NCCCS(N)(=O)=O)#N.[C:30](N1C=CN=C1)([N:32]1C=CN=C1)=O.Cl>>[CH:5]1[CH:6]([C:30]#[N:32])[CH:7]=[CH:8][N:9]2[C:14]=1[C:13]1[O:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:12]=1[CH:11]=[CH:10]2
Reactant: N#CC1[C@H]2c3oc4ccccc4c3CCN2CC[C@H]1NCCCS(N)(=O)=O
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: Cl
Product: N#CC1C=CN2C=Cc3c(oc4ccccc34)C2=C1

Procedure:
The process of the invention for the manufacture of N-(2-((2R,12bS)-2′-oxo-1,3,4,6,7,12b-hexahydrospiro[benzofuro[2,3-a]quinolizine-2,4′-imidazolidine]-3′-yl)ethyl)-methanesulfon-amide having the formula I comprises the steps, where in the first step (S)-1,3,4,6,7,12b-hexahydro-2H-benzo[b]furo[2,3-a]quinolizin-2-one of formula II and N-(2-aminoethyl)methanesulfonamide of formula III are contacted with trimethylsilyl cyanide in the presence of an agent capable of capturing water molecules, in an organic solvent, followed by adding hydrogen chloride to obtain (2R,12bS)-[2-[(cyano-1,3,4,6,7,12b-hexahydrobenzofuro-[2,3-a]quinolizine-2-yl)-amino]ethyl]methanesulfon-amide dihydrochloride, in the second step (2R,12bS)-[2-[(cyano-1,3,4,6,7,12b-hexahydrobenzofuro-[2,3-a]quinolizine-2-yl)-amino]-ethyl]methanesulfonamide dihydrochloride is contacted with 1,1′-carbonyldiimidazole in the presence of a hydrogen chloride acceptor in an organic solvent to obtain (2R,12bS)-1,3,4,6,7,12b-hexahydro-[2,3-methylsulfonyl)-2-oxo-1-imidazolidinyl]-2H-benzo-furo[2,3-a]quinolizine-2-carbonitrile, and in the third step (2R,12bS)-1,3,4,6,7,12b-hexahydro-[2,3-methylsulfonyl)-2-oxo-1-imidazolidinyl]-2H-benzofuro[2,3-a]quinolizine-2-carbonitrile is contacted with hydrogen in the presence of Raney nickel catalyst and sodium methoxide or potassium tert-butoxide in methanol solvent to yield N-(2-((2R,12bS)-2′-oxo-1,3,4,6,7,12b-hexa-hydrospiro-[benzofuro[2,3-a]quinolizine-2,4′-imidazolidine]-3′-yl)ethyl)-methanesulfonamide.
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].ClC1C=CC=C(C(OO)=[O:25])C=1>C(Cl)Cl>[Si:1]([O:8][CH2:9][CH2:10][C:11]1[CH:12]=[CH:13][N+:14]([O-:25])=[CH:15][CH:16]=1)([C:4]([CH3:6])([CH3:7])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OCCc1ccncc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCCc1cc[n+]([O-])cc1

Procedure:
To a stirred solution of 28.8 g of 4-(tert-butyldimethylsilyloxyethyl)-pyridine in 300 ml of methylene chloride is added 24 g of m-chloroperbenzoic acid. After 4 hours the solution is washed with aqueous sodium carbonate solution and water. The solution is dried over sodium sulfate, filtered and concentrated in vacuo to yield 4-(tert-butyl-dimethylsilyloxyethyl)-pyridine-N-oxide.
Reaction SMILES: [CH3:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[C:4]([CH3:9])[N:3]=1.N1C=CC=CC=1.[Cl:16][CH2:17][C:18](Cl)=[O:19]>CCOCC>[CH3:1][C:2]1[C:7]([NH:8][C:18](=[O:19])[CH2:17][Cl:16])=[CH:6][CH:5]=[C:4]([CH3:9])[N:3]=1
Reactant: Cc1ccc(N)c(C)n1
Reactant: O=C(Cl)CCl
Solvent: c1ccncc1
Solvent: CCOCC
Product: Cc1ccc(NC(=O)CCl)c(C)n1
Reaction time: 1 h

Procedure:
A solution of 2,6-dimethyl-3-aminopyridine (24.9 grams) in ether (200 ml), and pyridine (21 grams) are charged into a glass reaction vessel equipped with mechanical stirrer, thermometer and addition funnel. The reaction mixture is cooled to a temperature below about 10° C and chloroacetyl chloride (11.3 grams) is slowly added over a period of about 15 minutes. Stirring and cooling is continued for an additional period of about 1 hour to ensure the completion of the reaction. The resulting precipitate is then recovered by filtration, is washed with aqueous potassium carbonate and with water, and is dried to yield the desired product N-(2,6-dimethyl-3-pyridyl)-α-chloroacetamide.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][S:9](Cl)(=[O:11])=[O:10].[OH:13][CH2:14][C:15]1[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][C:16]=1[O:17][C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][CH:25]=1)[C:21]#[N:22]>C(Cl)Cl>[CH3:8][S:9]([O:13][CH2:14][C:15]1[CH:29]=[CH:28][C:27]([C:30]([F:31])([F:32])[F:33])=[CH:26][C:16]=1[O:17][C:18]1[CH:25]=[CH:24][CH:23]=[C:20]([C:21]#[N:22])[CH:19]=1)(=[O:11])=[O:10]
Reactant: N#Cc1cccc(Oc2cc(C(F)(F)F)ccc2CO)c1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCc1ccc(C(F)(F)F)cc1Oc1cccc(C#N)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Triethylamine (0.33 ml) followed by methanesulphonyl chloride (0.185 ml) were added to a solution of the product from step (ii) (0.7 g) in DCM (20 ml) at −20° C. The mixture was stirred at 0° C. for 1 h, then diluted with dichloromethane, washed with water, dried and evaporated under reduced pressure, yield 0.97 g.
Reaction SMILES: [CH2:1]([CH:3]([C:6](=O)[CH3:7])[CH:4]=O)[CH3:2].[Na].[C:10]([CH2:12][C:13]([NH2:15])=[O:14])#[N:11].C([O-])(=O)C.[NH2+]1CCCCC1>O.C(O)(=O)C>[C:10]([C:12]1[C:13](=[O:14])[NH:15][C:1]([CH3:2])=[C:3]([CH2:6][CH3:7])[CH:4]=1)#[N:11]
Reactant: CCC(C=O)C(C)=O
Reactant: N#CCC(N)=O
Agent: C1CC[NH2+]CC1
Agent: CC(=O)[O-]
Agent: [Na]
Solvent: CC(=O)O
Solvent: O
Product: CCc1cc(C#N)c(=O)[nH]c1C
Temperature: 25 °C

Procedure:
According to the method described in J. Heterocyclic Chem., 24, 351 (1987), a mixture of 2-ethyl-3-oxobutanal, sodium salt (37.5 g, 0.275 mmol), cyanoacetamide (25.2 g, 0.30 mol), aqueous piperidinium acetate (22 mL) [prepared from glacial acetic acid (4.2 mL), water (10 mL) and piperidine (7.2 mL)] in water (775 ml) was refluxed for four hours. Glacial acetic acid (30 ml) was added cautiously (much foaming) as the product precipitated. Upon cooling to room temperature, the product was collected by filtration, washed with cold water and air dried. The product had m.p. of 237°-240° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.O.C(=O)([O-])[O-].[Ca+2].[C:15](Cl)(Cl)=[S:16]>C(Cl)(Cl)Cl>[N:1]([C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1)=[C:15]=[S:16]
Reactant: S=C(Cl)Cl
Reactant: Nc1ccc(S)cc1
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: ClC(Cl)Cl
Solvent: O
Product: S=C=Nc1ccc(S)cc1
Temperature: 35 °C

Procedure:
A solution of 4-aminothiophenol (7.00 g, 0.056 mol) in chloroform (75 ml) was added to a stirred, cooled (0° C.) solution of water (40 ml), chloroform (20 ml), calcium carbonate (6.60 g, 0.066 mol), and thiophosgene (6.95 g, 0.060 mol) at 0°-5° C. The mixture was heated at 35° C. for 1 hour and poured into water (50 ml) before separating the two layers. The organic layer was washed with hydrochloric acid (1%, 100 ml) and dried (MgSO4). The solvent was removed in vacuo to afford an orange semi-solid which was used in the next step without purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]=[C:10]=[O:11])[CH:5]=[CH:6][C:7]=1[CH3:8].[Br:12]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:12][CH2:8][C:7]1[CH:6]=[CH:5][C:4]([N:9]=[C:10]=[O:11])=[CH:3][C:2]=1[Cl:1]
Reactant: Cc1ccc(N=C=O)cc1Cl
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: O=C=Nc1ccc(CBr)c(Cl)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 100 %

Procedure:
To a stirred solution of 100.0 grams (0.597 mole) of 3-chloro-4-methylphenylisocyanate in 1000 ml of carbon tetrachloride, under an argon atmosphere were added 116.8 grams (0.656 mole) of N-bromosuccinimide and 5.0 grams (0.021 mole) of benzoyl peroxide. The reaction mixture was warmed to reflux where it stirred for 4 hours; then it was allowed to cool to ambient temperature as it stood for 16 hours. The mixture was filtered and the filtrate concentrated under reduced pressure to give 147.1 grams of 4-bromomethyl-3-chlorophenylisocyanate as a residual oil. The oil was used without further purification.
Reaction SMILES: [CH2:1]([S:3]([C:6]1[N:10]=[CH:9][NH:8][N:7]=1)(=[O:5])=[O:4])[CH3:2].[CH2:11]([N:14]([CH2:18][CH2:19][CH3:20])[C:15](Cl)=[O:16])[CH2:12][CH3:13]>>[CH2:11]([N:14]([CH2:18][CH2:19][CH3:20])[C:15]([N:8]1[CH:9]=[N:10][C:6]([S:3]([CH2:1][CH3:2])(=[O:5])=[O:4])=[N:7]1)=[O:16])[CH2:12][CH3:13]
Reactant: CCS(=O)(=O)c1nc[nH]n1
Reactant: CCCN(CCC)C(=O)Cl
Product: CCCN(CCC)C(=O)n1cnc(S(=O)(=O)CC)n1

Procedure:
In an analogous manner to that described in Example 20, 3-ethylsulphonyl-1,2,4-triazole was reacted with dipropylcarbamoyl chloride to give 1-dipropylcarbamoyl-3-ethylsulphonyl-1,2,4-triazole, m.p. 44° - 45° C. Elemental analysis satisfactory.
Reaction SMILES: I.[NH2:2][C:3]1[N:4]([CH3:8])[CH2:5][CH2:6][N:7]=1.[OH-].[Na+].[C:11]1([N:17]=[C:18]=[S:19])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[CH3:8][N:4]1[CH2:5][CH2:6][NH:7][C:3]1=[N:2][C:18]([NH:17][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[S:19]
Reactant: S=C=Nc1ccccc1
Reactant: CN1CCN=C1N
Agent: I
Agent: [Na+]
Agent: [OH-]
Product: CN1CCNC1=NC(=S)Nc1ccccc1
Yield: 86.1 %

Procedure:
2-Amino-1-methylimidazoline hydroiodide (26.75 g, 0.117 mole) is converted to its free base form by treatment with 50% sodium hydroxide. The base is extracted with methylene chloride and the extract dried over potassium carbonate and filtered. To this solution is added phenylisothiocyanate (15.81 g, 0.117 mole) and the reaction mixture is refluxed for three hours. The hot solution is filtered, concentrated to a small volume in vacuo, ether added, chilled, and the solid filtered off to give 23.6 g (86.1%) of N-(1-methyl-2-imidazolidinylidene)-N'-phenylthiourea; m.p. 205°-208° C.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[C:6]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[N:7][O:8][C:9]=1[CH3:10])=O.[NH2:17][C:18]1[CH:23]=[C:22]([CH2:24][CH3:25])[CH:21]=[CH:20][N:19]=1>>[CH2:24]([C:22]1[CH:21]=[CH:20][N:19]2[CH:2]=[C:3]([C:5]3[C:6]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)=[N:7][O:8][C:9]=3[CH3:10])[N:17]=[C:18]2[CH:23]=1)[CH3:25]
Reactant: CCc1ccnc(N)c1
Reactant: Cc1onc(-c2ccccc2)c1C(=O)CBr
Product: CCc1ccn2cc(-c3c(-c4ccccc4)noc3C)nc2c1
Yield: 27 %

Procedure:
As described for Example 2, 4-(bromoacetyl)-5-methyl-3-phenylisoxazole (commercially available) (140 mg, 0.5 mmol) was converted, using 2-amino-4-ethylpyridine instead of 2-amino-3-methylpyridine, to the title compound (33 mg, 27%) which was obtained as a yellow oil. MS: m/e=304.0 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([OH:17])=O)[CH3:14])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1.[NH2:18][CH:19]1[CH2:28][C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[N:21]([CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:20]1=[O:36]>>[CH2:29]([N:21]1[C:22]2[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:28][CH:19]([NH:18][C:15](=[O:17])[C@H:13]([CH3:14])[NH:12][C:10](=[O:11])[CH2:9][C:4]2[CH:5]=[C:6]([F:8])[CH:7]=[C:2]([F:1])[CH:3]=2)[C:20]1=[O:36])[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: NC1Cc2ccccc2N(Cc2ccccc2)C1=O
Reactant: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)O
Product: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)NC1Cc2ccccc2N(Cc2ccccc2)C1=O

Procedure:
Following General Procedure C above using N-(3,5-difluorophenylacetyl)-L-alanine (Example B) and 3-amino-1-benzyl-1,2,3,4-tetrahydroquinolin-2-one (General Procedure 5-A), the title compound was prepared as a solid having a melting point of 196-199° C. The reaction was monitored by tlc on silica gel (Rf=0.35 in 5% methanol/dichloromethane) and purification was by flash chromatography using 5% methanol/dichloromethane as the eluant.
Reaction SMILES: [Cl-:1].[C:2]([C:5]1[CH:10]=[CH:9][N+:8]([C:11]2[CH:16]=[CH:15][C:14]([N+]([O-])=O)=[CH:13][C:12]=2[N+]([O-])=O)=[CH:7][CH:6]=1)(=[O:4])[NH2:3].[CH3:23][O:24]C1C=CC=CC=1N>CO>[Cl-:1].[C:2]([C:5]1[CH:10]=[CH:9][N+:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[O:24][CH3:23])=[CH:7][CH:6]=1)(=[O:4])[NH2:3]
Reactant: NC(=O)c1cc[n+](-c2ccc([N+](=O)[O-])cc2[N+](=O)[O-])cc1
Reactant: COc1ccccc1N
Agent: [Cl-]
Solvent: CO
Product: COc1ccccc1-[n+]1ccc(C(N)=O)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 4-carbamoyl-1-(2,4-dinitrophenyl)-pyridinium chloride (13.6 g), 2-methoxyaniline (10 ml) and methanol (500 ml) was stirred at ambient temperature for 16 hours and the solvent was removed in vacuo. Ether containing a small amount of acetone was added and the mixture heated under reflux until solidification of the product was complete. The product was collected by filtration to give 4-carbamoyl-1-(2-methoxyphenyl)-pyridinium chloride as a yellow solid (11.5 g), m.p. 229°-230° C. (dec).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[O:3][C:4]1[CH:5]=[C:6]([OH:10])[CH:7]=[CH:8][CH:9]=1.[H-].[Na+].Cl[C:16]1[CH:21]=[CH:20][CH:19]=[C:18](Cl)[N:17]=1>CN(C)C=O>[F:1][C:2]([F:11])([F:12])[O:3][C:4]1[CH:5]=[C:6]([CH:7]=[CH:8][CH:9]=1)[O:10][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([O:10][C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([O:3][C:2]([F:1])([F:11])[F:12])[CH:5]=2)[N:17]=1.[O:3]([C:2]1[CH:19]=[CH:20][CH:21]=[CH:16][N:17]=1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: Clc1cccc(Cl)n1
Reactant: Oc1cccc(OC(F)(F)F)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: FC(F)(F)Oc1cccc(Oc2cccc(Oc3cccc(OC(F)(F)F)c3)n2)c1
Product: c1ccc(Oc2ccccn2)cc1
Yield: 73 %

Procedure:
3-Trifluoromethoxyphenol (19 g; 0.106 mol) was added to oil-free sodium hydride (2.7 g) in dry dimethylformamide (120 ml). 2,6-Dichloropyridine (8 g; 0.054 mol) was then added and the reaction mixture refluxed for 4 hours. The symmetrical phenoxy pyridine 2,6-di-[3-trifluoromethoxyphenoxy]-pyridine was isolated, following conventional work up, chromatography and distillation procedures, as a colorless oil (17 g; yield 73%). Boiling point: 145° C. at 3 mm Hg.
Reaction SMILES: C([Li])CCC.CCCCCC.[C:12]1([CH2:18][CH2:19][CH2:20][CH2:21][N:22]2[CH:26]=[CH:25][N:24]=[CH:23]2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C[N:28](C)[CH:29]=[O:30].[NH4+].[Cl-]>C1COCC1>[C:12]1([CH2:18][CH2:19][CH2:20][CH2:21][N:22]2[CH:26]=[CH:25][N:24]=[C:23]2[C:29]([NH2:28])=[O:30])[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: c1ccc(CCCCn2ccnc2)cc1
Reactant: CN(C)C=O
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: NC(=O)c1nccn1CCCCc1ccccc1
Temperature: -78 °C

Procedure:
Reaction under N2 atmosphere. A mixture of DIPA (0.455 mol) in THF (500 ml) was stirred at −78° C. Butyllithium, 2.5M/hexane (0.390 mol) was added dropwise at −40° C. The mixture was stirred for 15 min, then re-cooled to −78° C. A solution of 1-(4-phenylbutyl)-1H-imidazole, prepared according to the procedure described in J. Chem. Soc., Perkin Trans., 1 (1975), 17, 1670–1671, (0.325 mol) in THF (350 ml) was added dropwise at −60° C. The mixture was stirred for one hour, then re-cooled to −78° C. This mixture was added dropwise to a mixture of N,N-dimethylformamide (0.390 mol, dry, p.a.) in THF (500 ml), stirred at −78° C. The reaction mixture was stirred for one hour at −78° C., then allowed to warm to room temperature while stirring overnight. A saturated aqueous NH4Cl solution (400 ml) was added and this mixture was extracted with THF. The separated organic layer was dried, filtered and the solvent evaporated, yielding 74.2 g of 1-(4-phenylbutyl)-1H-imidazole-2-carboxamide (interm. 18).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:18]=[CH:17][C:6]([CH2:7][N:8]([CH3:16])[C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:5][C:4]=1[NH:19][S:20]([CH3:23])(=[O:22])=[O:21].Cl.Cl[CH2:26][CH2:27][N:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1.[H-].[Na+].C(Cl)Cl>CN(C=O)C.C(Cl)Cl.CCOC(C)=O>[CH3:1][O:2][C:3]1[CH:18]=[CH:17][C:6]([CH2:7][N:8]([CH3:16])[C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:12])[CH3:13])=[CH:5][C:4]=1[N:19]([CH2:26][CH2:27][N:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1)[S:20]([CH3:23])(=[O:22])=[O:21]
Reactant: COc1ccc(CN(C)C(=O)OC(C)(C)C)cc1NS(C)(=O)=O
Reactant: ClCCN1CCOCC1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COc1ccc(CN(C)C(=O)OC(C)(C)C)cc1N(CCN1CCOCC1)S(C)(=O)=O
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 45.4 %

Procedure:
tert-Butyl 4-methoxy-3-(methylsulfonamido)benzyl(methyl)carbamate (189.1 mg, 0.549 mmol) was dissolved in dry DMF (10 ml) and cooled to 0° C. Nan (60% w/w dispersion in mineral oil, 48.3 mg, 1.208 mmol) was added, and the mixture was stirred 5 minutes at 0° C. and then 5 minutes at RT. 4-(2-Chloroethyl)morpholine hydrochloride (123 mg, 0.659 mmol) was added, and the mixture was stirred at RT for overnight. Additional NaH (43.93 mg, 1.098 mmol) was added over 4 days with stirring at RT. The reaction was quenched with water and brine and extracted with Et2O and twice with EtOAc. The combined organic layers were dried over Na2SO4, and the solvent was evaporated under vacuum. The crude product was purified by silica gel cartridge using as eluent:DCM to DCM/EtOAc 2:8 to give tert-butyl 4-methoxy-3-(N-(2-morpholinoethyl)methylsulfonamido)benzyl(methyl)carbamate (114 mg, 0.249 mmol, 45.4% yield).
Reaction SMILES: [O:1]=O.[CH:3]([C:6]([O:8][CH2:9][C:10]([CH3:14])(C)[CH:11]=O)=[O:7])([CH3:5])[CH3:4]>>[OH:1][C:10]([CH3:11])([CH3:14])[CH2:9][O:8][C:6]([CH:3]([CH3:4])[CH3:5])=[O:7]
Reactant: CC(C)C(=O)OCC(C)(C)C=O
Reactant: O=O
Product: CC(C)C(=O)OCC(C)(C)O
Yield: 74 %

Procedure:
80 parts of oxygen are passed into 172 parts of isopropylcarbonyloxypivalaldehyde in a stirred reactor at 100° C. in the course of 5 hours. When the reaction has ended, the reaction mixture is subjected to fractional distillation. 118 parts (74% of theory) of 2-hydroxy-1-isopropylcarbonyloxy-2-methylpropane (boiling point 48°-49° C./0.4 mbar) are obtained.