Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([Br:8])[N:3]=1.[N:9]1([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:15][CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.CCN(C(C)C)C(C)C>CCO>[Br:8][C:4]1[N:3]=[C:2]([N:12]2[CH2:13][CH2:14][CH2:15][N:9]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:10][CH2:11]2)[CH:7]=[N:6][CH:5]=1
Reactant: Brc1cncc(Br)n1
Reactant: CC(C)(C)OC(=O)N1CCCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCCN(c2cncc(Br)n2)CC1
Temperature: 100 °C
Yield: 70 %

Procedure:
A mixture of 2,6-dibromopyrazine (0.47 g, 2 mmol), tert-butyl 1,4-diazepane-1-carboxylate (0.4 g, 2 mmol), and DIPEA (0.78 g, 6 mmol) in EtOH (10 mL) was heated at 100° C. for 15 hours. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by silica gel chromatography using petroleum ether/ethyl acetate (5% to 50%) as eluting solvents to afford tert-butyl 4-(6-bromopyrazin-2-yl)-1,4-diazepane-1-carboxylate as colorless oil (0.5 g, 70%). MS (ESI) m/z: 357 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([CH3:17])=[N:8][C:9]([Cl:16])=[C:10]([N+:13]([O-:15])=[O:14])[C:11]=1Cl)=[O:5])[CH3:2].[CH2:18]([NH2:22])[CH2:19][CH2:20][CH3:21].C(NC1C=C(Cl)NC(C)([N+]([O-])=O)C=1C(OCC)=O)CCC>CO.C(N(CC)CC)C>[CH2:1]([O:3][C:4]([C:6]1[C:7]([CH3:17])=[N:8][C:9]([Cl:16])=[C:10]([N+:13]([O-:15])=[O:14])[C:11]=1[NH:22][CH2:18][CH2:19][CH2:20][CH3:21])=[O:5])[CH3:2]
Reactant: CCCCN
Reactant: CCOC(=O)c1c(C)nc(Cl)c([N+](=O)[O-])c1Cl
Agent: CCCCNC1=C(C(=O)OCC)C(C)([N+](=O)[O-])NC(Cl)=C1
Solvent: CCN(CC)CC
Solvent: CO
Product: CCCCNc1c(C(=O)OCC)c(C)nc(Cl)c1[N+](=O)[O-]

Procedure:
139.5 g. of 4,6-dichloro-2-methyl-5-nitropyridine-3-carboxylic acid ethyl ester (0.5 Mol.) are dissolved in about 500 ml. of methanol. 60 g. of triethylamine are added and the solution is heated at reflux temperature. At this point, 36.5 g. of n-butylamine are added dropwise. The solvent is then removed in vacuo and 500 ml. of benzene are added to the residue. The triethylamine hydrochloride is filtered off and the solvent evaporated. The resulting oil is dissolved in 300 ml. of methanol and yields on cooling 110 g. of 4-butylamino-6-chloro-2-methyl-2-nitropyridine-3-carboxylic acid, ethyl ester (70%), m.p. 33°-35° (methanol).
Reaction SMILES: [Cl-].[NH4+].O.[Cl:4][C:5]1[C:10]([C:11]([F:14])([F:13])[F:12])=[CH:9][C:8]([N+:15]([O-])=O)=[CH:7][N:6]=1>CO>[Cl:4][C:5]1[N:6]=[CH:7][C:8]([NH2:15])=[CH:9][C:10]=1[C:11]([F:14])([F:12])[F:13]
Reactant: O=[N+]([O-])c1cnc(Cl)c(C(F)(F)F)c1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Solvent: O
Product: Nc1cnc(Cl)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 64 %

Procedure:
Reduced iron (1.3 g) and ammonium chloride (2.1 g) were added to water (40 mL), and the mixture was stirred at room temperature for 5 min. A solution of 2-chloro-5-nitro-3-(trifluoromethyl)pyridine (1.8 g) in methanol (40 mL) was added, and the mixture was stirred at room temperature for 1 hr. Reduced iron (2.3 g) was added, and the mixture was further stirred at the same temperature for 3 hr. The reaction mixture was filtered through celite, and celite was washed with ethyl acetate. The filtrate was extracted with ethyl acetate, and the extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent:hexane-ethyl acetate=19:1→1:1) to give the title compound as a solid (yield 1.0 g, 65%).
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].S(=O)(=O)(O)O.[C:10]1([CH:16]([CH2:20][CH3:21])[C:17]([OH:19])=[O:18])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[N+:1]([C:13]1[CH:14]=[CH:15][C:10]([CH:16]([CH2:20][CH3:21])[C:17]([OH:19])=[O:18])=[CH:11][CH:12]=1)([O-:4])=[O:2]
Reactant: CCC(C(=O)O)c1ccccc1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: CCC(C(=O)O)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 69 %

Procedure:
A mixture of concentrated nitric acid (32 mL) and concentrated sulfuric acid (32 mL) were cooled in an ice salt bath. Solid 2-phenylbutyric acid (16.42 g, 100 mmol) was added in small portions maintaining the solution temperature below 10° C. The reaction was warmed to room temperature and allowed to stir for 1 hour. The product was isolated by pouring the reaction mixture onto 150 mL of crushed ice, filtering the white solid and recrystallizing from EtOH to give 14.5 g (69%) of the product as white crystals.
Reaction SMILES: [CH:1]1([CH2:7][OH:8])[CH2:6][CH2:5][CH:4]=[CH:3][CH2:2]1.C(N(CC)C(C)C)(C)C.[C:18]([Si:22]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)Cl)([CH3:21])([CH3:20])[CH3:19]>C(Cl)Cl>[Si:22]([O:8][CH:7]=[C:1]1[CH2:6][CH2:5][CH2:4][CH:3]=[CH:2]1)([C:18]([CH3:21])([CH3:20])[CH3:19])([C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: OCC1CC=CCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)[Si](OC=C1C=CCCC1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a mixture of 3-cyclohexene-1-methanol (Aldrich, 13.0 mL, 0.11 mol), N,N-diisopropylethylamine (43 mL, 0.244 mol) and 4-dimeehylaminopyridine (2.70 g., 0.022 mol) in 375 mL of dry CH2Cl2 under N2 at 25° C. was added tert- butyldiphenylchlorosilane (32 mL, 0.123 mol). The mixture was stirred at 25° C. for 48 hours. The reaction mixture was washed sequentially with 150 mL portions of 1N HCl, water, brine and dried over anhydrous MgSO4. The solvent was evaporated. The residue was loaded onto a 4"×4" column of silica and slowly eluted using hexanes as eluant. 3-(tert-butyldiphenylsilyloxymethylene)-1-cyclohexene, 33.6 g (86%), was obtained as a colorless oil which was homogenous by TLC (Rf=0.4, hexanes).
Reaction SMILES: [C:1]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[CH:12]1([CH2:18]Br)[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1>[O-]CC.[Na+]>[CH2:10]([O:9][C:1](=[O:8])[CH:2]([CH2:18][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)[C:3]([O:5][CH2:6][CH3:7])=[O:4])[CH3:11]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: BrCC1CCCCC1
Agent: CC[O-]
Agent: [Na+]
Product: CCOC(=O)C(CC1CCCCC1)C(=O)OCC
Yield: 66.4 %

Procedure:
Diethyl malonate (16.0 g) was added to a freshly prepared solution of sodium ethoxide (from 2.3 g of sodium in 150 ml of absolute ethanol), followed by 17.7 g of cyclohexylmethyl bromide. The mixture was heated under reflux for four hours and evaporated to dryness. The resulting mixture was treated with water, extracted with ethyl acetate and the extracts washed with water, brine and dried (MgSO4). Evaporation gave an oil which was distilled in vacuo to give 17 g of diethyl(cyclohexylmethyl)malonate (b.p. 104°-107° C. at 0.2 mm Hg).
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][N:4]=[C:3]1SC.[N+:9]([CH2:12][C:13]([O:15]C)=[O:14])([O-:11])=[O:10]>[Cl-].[Zn+2].[Cl-]>[CH3:1][N:2]1[CH2:6][CH2:5][NH:4][C:3]1=[C:12]([N+:9]([O-:11])=[O:10])[C:13]([OH:15])=[O:14]
Reactant: COC(=O)C[N+](=O)[O-]
Reactant: CSC1=NCCN1C
Agent: [Cl-]
Agent: [Zn+2]
Product: CN1CCNC1=C(C(=O)O)[N+](=O)[O-]
Reaction time: 0.5 h

Procedure:
19.5 g of 1A, 17.8 g of methyl nitroacetate and a small amount of zinc chloride were mixed and the mixture heated to 100°-105°. After 30 minutes, the solid reaction mixture was washed with ether, then with hot methanol. The mixture then was filtered to give the methyl ester of (1-methyl-2-imidazolidinylidene)nitroacetic acid (1B) as a tan solid, m.p.: 209°-210°.
Reaction SMILES: [CH2:1]([OH:15])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].[C:16](O)(=[O:30])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]>>[C:1]([O:30][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])(=[O:15])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CCCCCCCCCCCCCC(=O)O
Reactant: CCCCCCCCCCCCCCO
Product: CCCCCCCCCCCCCCOC(=O)CCCCCCCCCCCCC
Temperature: 60 °C
Reaction time: 25 h

Procedure:
329 g of myristyl alcohol and 351 g of myristic acid were heated to 60° C. in a 1 l reservoir vessel and mixed by means of a magnetic stirrer (viscosity of the mixture at 60° C. approx. 6 mPas). The lower region of the reaction vessel was initially charged with 2.7 g of NOVOZYM 435 and the entire reaction vessel was heated to 60° C. The compressed air introduction was regulated to 0.4 l/min and then the peristaltic pump was set to ˜20 ml/min and switched on. The reflux was heated to 60° C. The course of the reaction was monitored for ˜25 h, and a conversion of 99.3% based on the fatty acid was achieved.
Reaction SMILES: [I:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([NH2:11])[N:10]=2)[N:7]=1.C(N(CC)C(C)C)(C)C.[CH:21]1([C:24](Cl)=[O:25])[CH2:23][CH2:22]1>ClCCl>[I:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([NH:11][C:24]([CH:21]3[CH2:23][CH2:22]3)=[O:25])[N:10]=2)[N:7]=1
Reactant: Nc1cn2nc(I)ccc2n1
Reactant: O=C(Cl)C1CC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1cn2nc(I)ccc2n1)C1CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To the mixture of 6-iodo-imidazo[1,2-b]pyridazin-2-ylamine (130 mg, 0.5 mmol, 1 eq) and N,N-diisopropylethylamine (0.26 mL, 3 eq) in anhydrous dichloromethane (10 mL) at room temperature was added dropwise cyclopropane carbonyl chloride (0.26 mL, 3 eq). After the reaction mixture was stirred at ambient temperature for two hours, it was partitioned between saturated aqueous sodium bicarbonate and ethyl acetate (with 10% THF added). The organic layer was isolated, washed with brine, and dried with anhydrous sodium sulfate. The upper clear solution was decanted, concentrated, and the residue was subject to a gradient column chromatography (from DCM to MeOH-DCM 1:30) to give N-(6-iodoimidazo[1,2-b]pyridazin-2-yl)cyclopropanecarboxamide as a white powder in amount of 51 mg.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:9]([C:12](=[O:14])[CH3:13])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[C:15](=O)([O-])[O-].[Cs+].[Cs+].CI>CN(C=O)C>[CH3:15][O:1][C:2]1[CH:11]=[CH:10][C:9]([C:12](=[O:14])[CH3:13])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1cc(C(C)=O)ccc1O
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)c1cc(C(C)=O)ccc1OC

Procedure:
To a stirred solution of Methyl 2-hydroxy-5-acetylbenzoate (12 g, 61.7 mmol) in DMF (200 ml) was added cesium carbonate (24.15 g, 74.1 mmol) and MeI (9.64 g, 68 mmol).
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[O:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]#[N:12])=[CH:6][CH:5]=1.N.[H][H]>[Ni].CO>[F:1][C:2]([F:13])([F:14])[O:3][C:4]1[CH:5]=[CH:6][C:7]([CH2:10][CH2:11][NH2:12])=[CH:8][CH:9]=1
Reactant: N#CCc1ccc(OC(F)(F)F)cc1
Reactant: [H][H]
Agent: [Ni]
Agent: N
Solvent: CO
Product: NCCc1ccc(OC(F)(F)F)cc1

Procedure:
650 ml of methanol, 260 g of (4-trifluoromethoxyphenyl)acetonitrile, and moist Raney nickel in an amount corresponding to 0.39 mol were initially charged in an autoclave, and 260 ml of ammonia were condensed in. The mixture was hydrogenated at 130° C. and a hydrogen pressure of 140 bar for 2 hours. The reaction mixture was then vented at room temperature, and the catalyst was filtered off. The filtrate was distilled at 10 hPa. This gave 224.5 g of 2-(4-trifluoromethoxyphenyl)ethylamine as a colorless liquid (86.7% of theory) of b.p. 84-86° C.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[CH:7]=O)[CH3:2].[CH:14]1([NH:20][OH:21])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1>>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:7]=[N+:20]([CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[O-:21])[CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[CH3:2]
Reactant: CCOc1cc(C=O)ccc1OC
Reactant: ONC1CCCCC1
Product: CCOc1cc(C=[N+]([O-])C2CCCCC2)ccc1OC

Procedure:
The title compound was prepared according to the procedure described in Example 11 using 3-ethoxy-4-methoxybenzaldehyde and N-cyclohexylhydroxylamine. The title compound was isolated in 57% yield as a solid, m.p. 113.5° C.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[OH:11].C[O-].[Na+].[I-].[Na+].Cl[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][OH:24]>O.CC(N(C)C)=O>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[O:11][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][OH:24]
Reactant: OCCCCCCCl
Reactant: Oc1ccc2ccccc2c1
Agent: C[O-]
Agent: [I-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: OCCCCCCOc1ccc2ccccc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 15.6 %

Procedure:
A mixture of 50.0 g (0.348 mole) of 2-naphthol, 18.8 g (0.348 mole) of sodium methoxide, 2.0 g of sodium iodide and 800 ml of dimethylacetamide was stirred at room temperature for 1 hour, 47.5 g (0.348 mole) of 6-chlorohexanol was added. The mixture was heated to reflux with stirring for two hours, allowed to cool and poured into 3 liters of water and extracted with diethylether. The ether layer was evaporated to dryness to give a solid residue which was recrystallized from methanol to give 13.3 g of 6-(2-naphthalenyloxy)hexanol, mp=64°-65° C.
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[OH:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][OH:21].C(=O)([O-])[O-].[Na+].[Na+]>C(C(C)=O)C.C(Cl)Cl>[C:1]1([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[O:13][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][OH:21])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Oc1ccccc1-c1ccccc1
Reactant: OCCCCCCBr
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCC(C)=O
Solvent: ClCCl
Product: OCCCCCCOc1ccccc1-c1ccccc1
Yield: 165.7 %

Procedure:
40.0 g (235 mmol) of 2-phenylphenol from Tokyo Chemical Industry Co., Ltd. and 51.06 g (282 mmol) of 6-bromo-1-hexanol from Tokyo Chemical Industry Co., Ltd. were dissolved in 600 mL of methyl ethyl ketone from Kanto Chemical Co., Inc. to prepare a solution. 97.4 g of sodium carbonate were added to the solution, and refluxed for 8 hrs. After the solution was cooled to have room temperature, it was filtered and condensed. The resultant light brown liquid was dissolved in methylene chloride and washed with water. The isolated organic layer was dried with magnesium sulfide and a solvent was removed therefrom. The residue was refined by silica gel column chromatography using methylene chloride as an eluent to obtain 105.3 g of 6-(2-phenyl-phenoxy)hexane-1-ol.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[C:5]1([CH3:15])[CH:10]=[CH:9][C:8]([S:11](Cl)(=[O:13])=[O:12])=[CH:7][CH:6]=1>O.C(O)C>[C:5]1([CH3:15])[CH:10]=[CH:9][C:8]([S:11]([N:1]=[N+:2]=[N-:3])(=[O:13])=[O:12])=[CH:7][CH:6]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Cc1ccc(S(=O)(=O)N=[N+]=[N-])cc1
Yield: 80.3 %

Procedure:
After dissolving 22.5 g (0.35 mole) of sodium azide in a small amount of water, the resulting solution was diluted with 130 ml of 90% hydrous ethanol. An ethanol solution having 60 g (0.32 mole) of p-toluenesulfonyl chloride dissolved therein was added dropwise to the solution at 10 to 25° C. They were reacted at room temperature for 2.5 hours. An oil obtained by concentrating the reaction mixture under reduced pressure was washed with water several times and then, dried over anhydrous magnesium sulfate. The desiccant was then removed, whereby 50.7 g of p-toluenesulfonyl azide was obtained as a colorless oil.
Reaction SMILES: F[C:2]1[C:7]([I:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[S:9]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[N:11]=[C:10]1[NH:18][C:19]1[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CS(C)=O>[I:8][C:7]1[C:2]([O:25][C:22]2[CH:21]=[CH:20][C:19]([NH:18][C:10]3[S:9][C:13]4[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=4[N:11]=3)=[CH:24][CH:23]=2)=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: Oc1ccc(Nc2nc3ccccc3s2)cc1
Reactant: Fc1ncccc1I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: O
Product: Ic1cccnc1Oc1ccc(Nc2nc3ccccc3s2)cc1
Temperature: 80 °C

Procedure:
A mixture of 2-fluoro-3-iodopyridine (4.93 g, 22.11 mmol), 4-(benzo[d]thiazol-2-ylamino)phenol (6.16 g, 25.4 mmol), and cesium carbonate (10.81 g, 33.2 mmol) in DMSO (50 mL) was heated at 80° C. overnight. The reaction was cooled to rt and poured into water (200 mL). The solution was extracted with EtOAc (3×) and the combined organic layers were washed with brine, evaporated onto silica gel and purified by flash chromatography (Isco (240 gram)) eluting with EtOAc:hexanes (0:1→1:1) to give a white crystalline solid. MS (ESI, pos. ion) m/z: 445.8 (M+1).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=1.[N+:11]([O-])([OH:13])=[O:12]>S(=O)(=O)(O)O>[OH:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=1
Reactant: O=[N+]([O-])O
Reactant: O=C(O)c1ccc(O)nc1
Agent: O=S(=O)(O)O
Product: O=C(O)c1cnc(O)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 36 %

Procedure:
To a solution of 30 g (0.217 mol) 6-hydroxy-nicotinic acid in 50 ml concentrated sulfuric acid was added 60 ml of a 1:1 mixture of conc. sulfuric acid and conc. nitric acid below 20° C. and stirred for 1 h at room temperature and afterwards heated to 80° C. for 4 h. The mixture was poured onto ice and the formed precipitate was collected and dried to yield 14.2 g (36%) of the title compound as a yellow amorphous solid.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH:3]([CH2:6][OH:7])[CH2:2]1.C(N(CC)CC)C.[C:15]1([CH3:25])[CH:20]=[CH:19][C:18]([S:21](Cl)(=[O:23])=[O:22])=[CH:17][CH:16]=1>ClCCl>[CH3:25][C:15]1[CH:20]=[CH:19][C:18]([S:21]([O:7][CH2:6][CH:3]2[CH2:4][CH2:5][O:1][CH2:2]2)(=[O:23])=[O:22])=[CH:17][CH:16]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OCC1CCOC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)OCC2CCOC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.8 %

Procedure:
To a solution of (tetrahydrofuran-3-yl)methanol (5.15 g, 50.4 mmol) in dichloromethane (200 mL) were added triethylamine (21.08 mL, 151 mmol) and p-toluenesulfonyl chloride (9.61 g, 50.4 mmol) and the mixture was stirred at room temperature overnight. The reaction mixture was washed with water (100 mL) and brine (100 mL). The organic layer was dried with sodium sulfate, filtered and concentrated. The crude product was purified by column chromatography using an Analogix® Intelliflash280™ (SiO2, 0-40% ethyl acetate in hexane) to provide the title compound (12.5 g, 97%) as colorless viscous liquid. 1H NMR (300 MHz, DMSO-D6) δ ppm 1.40-1.51 (m, 1H) 1.83-1.95 (m, 1H) 2.43 (s, 3H) 3.28-3.31 (m, 1H) 3.31-3.37 (m, 1H) 3.51-3.67 (m, 3H) 3.90-4.00 (m, 2H) 7.48-7.51 (m, 2H) 7.78-7.82 (m, 2H); MS (DCI/NH3) m/z 274 (M+NH4)+.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][OH:6].N1C=CC=CC=1.[CH2:13]([O:20][C:21](Cl)=[O:22])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>ClCCl>[OH:6][CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:21](=[O:22])[O:20][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: NCCCCO
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(NCCCCO)OCc1ccccc1
Yield: 27.4 %

Procedure:
A solution of 4-amino-1-butanol (7.68 g) and pyridine (7.00 g) in dichloromethane (100 mL) was chilled in an ice bath and a solution of benzylchloroformate (14.37 g) in dichloromethane (100 mL) was slowly added with stirring over a period of thirty minutes. The ice bath was removed and the reaction was stirred for an additional 16 hours. Hydrochloric acid (1.2 M, 200 mL) was added and phases were separated. The organic phase was dried (MgSO4), filtered and concentrated under reduced pressure. The resulting residue was recrystallized from toluene and dried under vacuum to provide 5.15 g of benzyl (4-hydroxybutyl)carbamate.
Reaction SMILES: [BH4-].[Na+].[F:3][C:4]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][C:5]=1[C:11]1[CH2:12][CH2:13][CH2:14][N:15]=1>CO.O>[F:3][C:4]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][C:5]=1[CH:11]1[CH2:12][CH2:13][CH2:14][NH:15]1
Reactant: Fc1ccc(F)c(C2=NCCC2)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: Fc1ccc(F)c(C2CCCN2)c1
Reaction time: 2 h
Yield: 79.8 %

Procedure:
NaBH4 (12 g, 314.9 mmol) was added to a solution of 5-(2,5-difluorophenyl)-3,4-dihydro-2H-pyrrole (28.5 g, 157.4 mmol) in a mixture of MeOH:H2O (4:1, 250 mL) and stirring was continued at 25-35° C. for 2 h. The reaction mixture was quenched with 1N aqueous HCl solution and basified with 2N aqueous NaOH solution, extracted with DCM, dried over anhydrous sodium sulphate and concentrated under reduced pressure to afford 23 g of the title compound. MS (ESI): m/z 184 (M+H).
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([F:9])[C:3]=1[N+:10]([O-:12])=[O:11].C([O-])([O-])=O.[K+].[K+].CS(C)=O.[NH:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1>CCOC(C)=O>[F:9][C:4]1[C:3]([N+:10]([O-:12])=[O:11])=[C:2]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[CH:7]=[C:6]([F:8])[CH:5]=1
Reactant: O=[N+]([O-])c1c(F)cc(F)cc1F
Reactant: C1COCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1c(F)cc(F)cc1N1CCOCC1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
1,3,5-Trifluoro-2-nitro-benzene (5.30 g, 29.9 mmol) and K2CO3 (4.96 g, 35.9 mmol) were mixed in DMSO (40.0 mL, 564 mmol) and morpholine (2.74 mL, 31.4 mmol) was added. The reaction was stirred at rt for 48 h, diluted with EtOAc and washed twice with water. The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. Title compound isolated as a yellow oil (4.26 g, 58%). LCMS (m/e) 245 (M+H); 1H-NMR (CDCl3, 400 MHz) δ 6.67-6.58 (m, 2H), 3.80 (t, 4H, J=4.2 Hz), 3.06 (t, 4H, J=4.2 Hz), 19F-NMR (CDCl3, 400 MHz) δ −102, −118. Also obtained in this reaction, 4-(3,5-difluoro-4-nitro-phenyl)-morpholine as a yellow solid (2.85 g, 39%). m.p.=112-114° C.; LCMS (m/e) 245 (M+H); 1H-NMR (CDCl3, 400 MHz) δ 6.45-6.37 (m, 2H), 3.86 (t, 4H, J=4.5 Hz), 3.33 (t, 4H, J=4.5 Hz); 19F-NMR (CDCl3, 400 MHz) δ −115.