Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.C(N(CC)CC)C.[Br:20]Br.O>C(O)(=O)C>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:11][C:12]=1[Br:20]
Reactant: BrBr
Reactant: CCOC(=O)c1ccc(N)cc1
Solvent: CC(=O)O
Solvent: O
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccc(N)c(Br)c1
Temperature: 25 °C
Yield: 103.6 %

Procedure:
To a solution of ethyl 4-aminobenzoate (10.0 g, 59.3 mmol) and triethylamine (18.4 mL, 130 mmol) in acetic acid (30 mL) was slowly added dropwise bromine (3.04 mL, 59.3 mmol) under stirring at room temperature. The reaction mixture was stirred at room temperature for 2 hr and cold water (400 mL) was added. The precipitated solid was collected by filtration, washed with cold water and vacuum dried to give crude ethyl 4-amino-3-bromobenzoate (15.0 g) as red-pink crystals. The obtained crystals were dissolved in ethyl acetate (60 mL), and 4 M hydrogen chloride/ethyl acetate solution was added. The precipitated solid was collected by filtration, washed with a mixed solvent (1:1) of ethyl acetate-diethyl ether, and vacuum dried to give a mixture (8.99 g) of ethyl 4-aminobenzoate hydrochloride and ethyl 4-amino-3-bromobenzoate hydrochloride as colorless crystals. Successively, to a solution of the obtained mixture (1.00 g) in pyridine (12 mL) were added acetic anhydride (0.69 mL, 7.13 mmol) and 4-dimethylaminopyridine (catalytic amount) with stirring at room temperature, and the mixture was stirred overnight at the same temperature. The reaction solution was concentrated under reduced pressure, brine was added to the residue, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (hexane/ethyl acetate=9/1-hexane/ethyl acetate=1/1) to give the title compound (758 mg, yield 40%, 3 steps) as colorless crystals.
Reaction SMILES: CCOCC.[OH:6][CH2:7][CH:8]1[CH2:13][CH2:12][N:11]([C:14]#[N:15])[CH2:10][CH2:9]1.[OH:16][NH:17][C:18](=N)[CH:19]([CH3:21])[CH3:20].Cl>CCOC(C)=O.[Cl-].[Cl-].[Zn+2].C(O)C>[CH3:20][CH:19]([C:18]1[N:15]=[C:14]([N:11]2[CH2:12][CH2:13][CH:8]([CH2:7][OH:6])[CH2:9][CH2:10]2)[O:16][N:17]=1)[CH3:21]
Reactant: CC(C)C(=N)NO
Reactant: N#CN1CCC(CO)CC1
Agent: Cl
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CCOCC
Solvent: CCO
Solvent: CCOC(C)=O
Product: CC(C)c1noc(N2CCC(CO)CC2)n1
Reaction time: 0.25 h
Yield: 38.9 %

Procedure:
A solution of 1N ZnCl2 in Et2O (60.7 mL, 60.7 mmol) was added dropwise over 15 min to a solution of 4-(hydroxymethyl)-1-piperidinecarbonitrile (7.09 g, 50.6 mmol) and N-hydroxy-2-methylpropanimidamide (6.2 g, 60.7 mmol) in EtOAc (150 mL) at ambient temperature. The reaction mixture was left at ambient temperature for 15 min, decanted, and triturated with Et2O to give a white solid. The solid was heated in a solution of concentrated HCl (15 mL) and ethanol (30 mL) for 1 h. Ethanol was removed in vacuo, and the resulting residue was charged with water (150 mL). The mixture was neutralized with Na2CO3, and extracted with CH2Cl2. The organic extracts were dried over MgSO4, filtered, and the filtrate was concentrated. The crude product was purified by chromatography on a silica gel column using 0 to 100% EtOAc/hexane to give 4.44 g (39%) of {1-[3-(1-methylethyl)-1,2,4-oxadiazol-5-yl]-4-piperidinyl}methanol as a clear oil. 1H NMR (400 MHz, CDCl3): δ 4.20-4.10 (m, 2H), 3.51 (d, 2H, J=6.4 Hz), 3.07-2.97 (m, 2H), 2.90-2.75 (m, 1H), 1.85-1.75 (m, 2H), 1.76-1.62 (m, 1H), 1.36-1.19 (m, 8H); LRMS (ESI), m/z 226 (M+H).
Reaction SMILES: [CH2:1]([NH:5][C:6](=[O:12])[C:7]([O:9][CH2:10][CH3:11])=[O:8])[C:2]([CH3:4])=O.O=P(Cl)(Cl)Cl.O>C1(C)C=CC=CC=1>[CH3:4][C:2]1[O:12][C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[N:5][CH:1]=1
Reactant: CCOC(=O)C(=O)NCC(C)=O
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: CCOC(=O)c1ncc(C)o1
Yield: 61.9 %

Procedure:
To a stirred solution of ethyl 2-(acetonylamino)-2-oxo-acetate (9.2 g, 53.12 mmol) in toluene (100.0 mL), is added POCl3 (4.95 mL, 53.12 mmol) and the reaction mixture is refluxed for 16 hours. The reaction mixture is cooled, added portionwise to water (100.0 mL) and stirred vigorously. The organic layer is washed with saturated NaHCO3 solution (2×50 mL), water (2×50 mL), dried over Na2SO4, and evaporated under reduced pressure. The crude material is purified by silica gel chromatography eluting with hexane:ethyl acetate (8.0:2.0) to give the title compound (5.1 g, 61.9%) as a yellow oil. ESI/MS m/z 156.2.1 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].C([O-])([O-])=O.[Cs+].[Cs+].Br[CH:16]([CH3:22])[C:17]([O:19][CH2:20][CH3:21])=[O:18]>CN(C=O)C>[CH2:20]([O:19][C:17](=[O:18])[CH:16]([O:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[F:1])[CH3:22])[CH3:21]
Reactant: Oc1ccccc1F
Reactant: CCOC(=O)C(C)Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)Oc1ccccc1F
Temperature: 90 °C
Reaction time: 16 h

Procedure:
2-Fluorophenol (0.30 mol), Cs2CO3 (197.0 g, 0.61 mol), and ethyl 2-bromopropionate (54.3 g, 0.30 mol) were combined in anhydrous DMF (1000 mL) and stirred at 90° C. under an atmosphere of nitrogen. After 16 h, the DMF was removed in vacuo. The residue was dissolved in ethyl acetate (300 mL) and washed twice with water and once with brine. The organic layer was dried over Na2SO4 and concentrated in vacuo to produce an oil.
Reaction SMILES: [F:1][C:2]([F:11])([C:7]([F:10])([F:9])[F:8])[CH2:3][CH2:4][CH2:5][OH:6].[S:12](Cl)([C:15]1[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=1)(=[O:14])=[O:13].S(=O)(=O)(O)O>N1C=CC=CC=1>[F:1][C:2]([F:11])([C:7]([F:8])([F:9])[F:10])[CH2:3][CH2:4][CH2:5][O:6][S:12]([C:15]1[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=1)(=[O:14])=[O:13]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OCCCC(F)(F)C(F)(F)F
Agent: O=S(=O)(O)O
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCCCC(F)(F)C(F)(F)F)cc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 101.3 %

Procedure:
A solution of 17.3 g of 4,4,5,5,5-pentafluoropentanol in 40 ml of pyridine is mixed at 0° C. with 21 g of tosyl chloride and stirred for 3 hours at 0° C. For working up, the reaction mixture is added to 2 n sulfuric acid, extracted with diethyl ether, washed neutral with water, dried on sodium sulfate and concentrated by evaporation in a vacuum. 32.7 g of crude toluene-4-sulfonic acid-4,4,5,5,5-pentafluoropentyl ester is obtained as oil. The latter is dissolved in 300 ml of acetone and refluxed with 23 g of potassium thioacetate for 18 hours at 100° C. bath temperature. Then, it is mixed with water, extracted with diethyl ether, washed with water, dried on sodium sulfate, concentrated by evaporation in a vacuum and distilled. At 173°-177° C., 15 g of thioacetic acid-S-(4,4,5,5,5-pentafluoropentyl)-ester is obtained.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[C@H:12]1[O:16][C:15](=[O:17])[NH:14][C@@H:13]1[CH3:18].[H-].[Na+].Br[CH2:22][C:23]1[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[C:25]([C:33]([F:36])([F:35])[F:34])[CH:24]=1>C1COCC1>[F:30][C:29]([F:31])([F:32])[C:27]1[CH:28]=[C:23]([CH:24]=[C:25]([C:33]([F:36])([F:34])[F:35])[CH:26]=1)[CH2:22][N:14]1[C@H:13]([CH3:18])[C@@H:12]([C:3]2[CH:4]=[C:5]([C:8]([F:9])([F:10])[F:11])[CH:6]=[CH:7][C:2]=2[I:1])[O:16][C:15]1=[O:17]
Reactant: FC(F)(F)c1cc(CBr)cc(C(F)(F)F)c1
Reactant: C[C@H]1NC(=O)O[C@@H]1c1cc(C(F)(F)F)ccc1I
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C[C@@H]1[C@@H](c2cc(C(F)(F)F)ccc2I)OC(=O)N1Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reaction time: 0.5 h

Procedure:
(4R,5R)-5-[2-iodo-5-(trifluoromethyl)phenyl]-4-methyl-1,3-oxazolidin-2-one (INTERMEDIATE 12, 1.451 g, 3.910 mmol) was dissolved in anhydrous THF (30 mL) and cooled in an ice bath. Sodium hydride (60% w/w in mineral oil, 172 mg, 4.301 mmol) was added into the reaction mixture all in once. The reaction was stirred cold (ice bath) for 30 min followed by addition of 1-(bromomethyl)-3,5-bis(trifluoromethyl)benzene (1.078 mL, 1.80 mg, 5.865 mmol). The crude mixture was cooled (ice bath) and quenched adding by NH4Cl (aq, sat.) when reaction time was 5 hours. Reaction crude was extracted with ethyl acetate. The combined organic extracts were dried over Na2SO4, filtered, and concentrated to an oil. The oil was purified by flash chromatography (SiO2, Biotage 40+M cartridge, EtOAc/hexanes) to afford (4R,5R)-3-[3,5-bis(trifluoromethyl)benzyl]-5-[2-iodo-5-(trifluoromethyl)phenyl]-4-methyl-1,3-oxazolidin-2-one. LCMS calc.=596.98; found=598.05 (M+1)+. 132.6 mg of unreacted starting material was also recovered.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11](=[O:19])[CH:12]=[CH:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[N-:20]=[N+:21]=[N-:22].[Na+].O>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:6]=[CH:7][C:8]=1[O:9][CH3:10])[C:11]([C:12]1[NH:22][N:21]=[N:20][C:13]=1[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[O:19]
Reactant: [N-]=[N+]=[N-]
Reactant: CCOC(=O)C=CC(=O)c1ccc(OC)c(OC)c1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1nn[nH]c1C(=O)c1ccc(OC)c(OC)c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 52.9 %

Procedure:
A solution (3.0 mL) of ethyl 4-(3,4-dimethoxyphenyl)-4-oxo-2-butenoate (104 mg, 0.39 mmol) in N,N-dimethylformamide was added to a solution (5.0 mL) of sodium azide (40 mg, 0.62 mmol) in N,N-dimethylformamide at 5° C. The temperature of the reaction solution was raised to room temperature before the reaction solution was stirred for 6 hr. After the completion of the reaction, iced water (10 mL) was added to the reaction solution, and the mixture was washed with ethyl acetate. The aqueous layer was then adjusted to pH 1.5 by the addition of 2 N hydrochloric acid, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and the solvent was then removed by evaporation under the reduced pressure. The oil thus obtained was dried in vacuo to give ethyl 5-(3,4-dimethoxybenzoyl)-1H-1,2,3-triazole-4-carboxylate (63 mg, yield 52%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15]O)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br-].[Li+].P(Br)(Br)[Br:20]>CN(C)C=O>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][Br:20])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrP(Br)Br
Reactant: OCc1ccc(OCc2ccccc2)cc1
Agent: [Br-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: BrCc1ccc(OCc2ccccc2)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A mixture of (4-(benzyloxy)phenyl)methanol (2.14 g) and lithium bromide (1.0 g) in N,N-dimethylformamide (20 mL) was cooled to 0° C. To this solution was added PBr3 (1.0 mL). The solution was stirred at room temperature for 2 hours. The reaction mixture was partitioned between water and ethyl acetate. The aqueous layer was extracted with additional ethyl acetate, twice. The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated. The residue was purified by flash column chromatography on silica gel eluting with 5% ethyl acetate in hexanes to provide the title compound.
Reaction SMILES: Cl.[F:2][C:3]([F:17])([F:16])[C:4]1[CH:5]=[C:6]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[CH:7]=[CH:8][CH:9]=1.ClCCl.Br[CH2:22][CH2:23][CH2:24][Cl:25].C(N(CC)CC)C>CCCCCC>[Cl:25][CH2:24][CH2:23][CH2:22][N:13]1[CH2:14][CH2:15][N:10]([C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([C:3]([F:2])([F:16])[F:17])[CH:5]=2)[CH2:11][CH2:12]1
Reactant: FC(F)(F)c1cccc(N2CCNCC2)c1
Reactant: ClCCCBr
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCCCCC
Solvent: ClCCl
Product: FC(F)(F)c1cccc(N2CCN(CCCCl)CC2)c1
Temperature: 25 °C

Procedure:
To a 100 mL flask was added 1-(3-trifluoromethylphenyl)piperazine HCl (5035 mg, 18.88 mmol) and 60 mL dichloromethane. 1-Bromo-3-chloropropane (1730 ul, 20.78 mmol, 1.10 eq) was added, then triethylamine (5.25 mL, 37.7 mmol, 2.00 eq). The solution was refluxed for 9 hours, then cooled to 25° C. 100 mL of hexane was then added, and the resulting suspension was vacuum filtered. The filtrate was concentrated in vacuum and purified by column chromatography using dichloromethane as eluant resulting in an oil of 1-(3-Chloropropyl)-4-(3-trifluoromethylphenyl)piperazine.
Reaction SMILES: [CH3:1][C:2]1[CH:12]=[CH:11][C:5]([CH:6]=[CH:7][C:8](O)=[O:9])=[CH:4][CH:3]=1.S(Cl)([Cl:15])=O>C1C=CC=CC=1>[CH3:1][C:2]1[CH:12]=[CH:11][C:5]([CH:6]=[CH:7][C:8]([Cl:15])=[O:9])=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: Cc1ccc(C=CC(=O)O)cc1
Solvent: c1ccccc1
Product: Cc1ccc(C=CC(=O)Cl)cc1

Procedure:
100 ml of benzene was added to 16.2 grams of p-methylcinnamic acid. 12 ml of thionyl chloride was added dropwise slowly thereto at ambient temperature. The temperature was elevated to 70° C. and the heating was continued until foaming ceased. Benzene and thionyl chloride were distilled off and the residue was dried thoroughly under reduced pressure.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[CH:18][CH:19]=3)[NH:14][CH:13]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].Br[CH2:22][C:23]1[CH:27]=[CH:26][O:25][CH:24]=1>>[CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[CH:18][CH:19]=3)[N:14]([CH2:22][C:23]3[CH:27]=[CH:26][O:25][CH:24]=3)[CH:13]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCC(c2c[nH]c3ncccc23)CC1
Reactant: BrCc1ccoc1
Product: CCOC(=O)N1CCC(c2cn(Cc3ccoc3)c3ncccc23)CC1

Procedure:
This compound was prepared following the procedure described in example 24, part C, starting with 3 g (11 mmol) of 4-(1H-pyrrolo[2,3-b]pyridin-3-yl)piperidine-1 carboxylic acid ethyl ester and 20 ml of a 0.6M solution of 3-bromomethylfuran freshly prepared. After standard work-up, 4.44 g of 4-(1-furan-3-ylmethyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-piperidine-1-carboxylic acid ethyl ester were obtained.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:15]([O:17][CH3:18])=[O:16])[CH2:13][NH2:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC(Cl)(Cl)C(=N)O[CH2:23][CH:24]=[CH2:25]>>[CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:15]([O:17][CH3:18])=[O:16])[CH2:13][NH:14][CH2:25][CH:24]=[CH2:23])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)[C@H](CN)NC(=O)OCc1ccccc1
Reactant: C=CCOC(=N)C(Cl)(Cl)Cl
Product: C=CCNC[C@H](NC(=O)OCc1ccccc1)C(=O)OC

Procedure:
The β-amino functionality of Nα -(benzyloxycarbonyl)-β-(amino)-L-alanine, methyl ester is then allylated with allyl trichloroacetimidate to give the corresponding Nα -(benzyloxycarbonyl)-β-(allylamino)-L-alanine, methyl ester using conditions described previously in Scheme F, step b.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[OH:10].C(N(CC)C(C)C)(C)C.[CH3:22][O:23][CH2:24]Cl>ClCCl.CC(OC)(C)C>[CH3:22][O:23][CH2:24][O:10][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[O:3][C:2]([F:11])([F:12])[F:1]
Reactant: COCCl
Reactant: Oc1ccccc1OC(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: COC(C)(C)C
Solvent: ClCCl
Product: COCOc1ccccc1OC(F)(F)F
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 92.9 %

Procedure:
A solution of 2-(trifluoromethyloxy)phenol (12.0 g, 67.4 mmol) in dichloromethane (45 mL) was cooled to 5° C., and N,N-diisopropylethylamine (23.5 mL, 135 mmol) and methoxymethyl chloride (7.68 mL, 135 mmol) were added dropwise, keeping the internal temperature≦15° C. The reaction mixture was warmed to ambient temperature, stirred for 15 min at ambient temperature, then diluted with MTBE (250 mL) and washed with 2N HCl (2×50 mL), water (50 mL), 2N NaOH (2×30 mL), water (30 mL), and brine (30 mL). The organic portion was dried (Na2SO4), filtered, and concentrated to give the title compound (13.9 g, 62.6 mmol, 93%). which was used without further purification. MS (DCI/NH3) m/z 222 (M+H)+.
Reaction SMILES: [CH:1]([CH:3]1[CH2:10][CH2:9][CH2:8][CH2:7][NH:6][C:4]1=[O:5])=C.[CH3:11][N:12](CCCC=C(C)C(N)=O)[CH3:13].[C:23]([O:28][CH2:29][CH2:30][OH:31])(=[O:27])[C:24]([CH3:26])=[CH2:25]>>[CH3:1][C:3]([C:4]([NH:6][CH2:7][CH2:8][CH2:9][N:12]([CH3:13])[CH3:11])=[O:5])=[CH2:10].[CH3:26][C:24]([C:23]([O:28][CH2:29][CH2:30][OH:31])=[O:27])=[CH2:25]
Reactant: C=CC1CCCCNC1=O
Reactant: CC(=CCCCN(C)C)C(N)=O
Agent: C=C(C)C(=O)OCCO
Product: C=C(C)C(=O)NCCCN(C)C
Temperature: 40 °C

Procedure:
The 30 g of a terpolymer of vinyl caprolactam (VCap), dimethylamino propyl methacrylamide (DMAPMA), and 2-hydroxyethyl methacrylate (HEMA) powder was added to 170 g HEMA. GMA (12 g) was added drop-wise with continuous stirring. This solution was heated at 40° C. for one hour. A representative structure for the polymeric reaction is presented below, wherein x+y+z+a=100:
Reaction SMILES: [ClH:1].O1CCOCC1.C(OC([N:15]1[CH2:20][CH2:19][N:18]([C:21]2[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][N:22]=2)[CH2:17][CH2:16]1)=O)(C)(C)C>C(Cl)Cl>[ClH:1].[N+:27]([C:24]1[CH:25]=[CH:26][C:21]([N:18]2[CH2:17][CH2:16][NH:15][CH2:20][CH2:19]2)=[N:22][CH:23]=1)([O-:29])=[O:28].[ClH:1]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc([N+](=O)[O-])cn2)CC1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: O=[N+]([O-])c1ccc(N2CCNCC2)nc1
Reaction time: 3 h

Procedure:
Added 4M HCl/dioxane (15 ml) to a solution of 4-(5-Nitro-pyridin-2-yl)-piperazine-1-carboxylic acid tert-butyl ester (2.3 g, 7.46 mmol) in MeCl2 (20 ml) at room temperature. Reaction was stirred for 3 hours and solvent was evaporated yielding the product as hydrochloride salt 1-(5-Nitro-pyridin-2-yl)-piperazine hydrochloride 8 (2.2 g)
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH3:7])=[CH:3][C:2]=1[CH3:8].[Li]CCCC.C(NCC)C.[CH3:19][N:20]([CH:22]=O)[CH3:21]>C1COCC1>[CH3:19][N:20]([CH3:22])[CH:21]=[CH:7][C:4]1[CH:5]=[CH:6][N:1]=[C:2]([CH3:8])[CH:3]=1
Reactant: Cc1ccnc(C)c1
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCNCC
Product: Cc1cc(C=CN(C)C)ccn1
Temperature: -60 °C
Reaction time: 0.5 h
Yield: 91.2 %

Procedure:
11.05 g 2,4-Lutidine (0.1 mol) were dissolved in 50 ml THF. The solution was cooled and stirred, maintaining the temperature at between −70 to −50° C. 81.25 ml nBuLi (0.13 mol) was added over 0.25 hour. The dark red solution was stirred for a further 0.5 hour, then 15.14 ml diethylamine (0.145 mol) was added in one portion producing an orange suspension. After a 0.5 hour, 15.5 ml DMF (0.2 mol) was added. The brown-red solution was stirred for 1 hour then quenched with 50 ml 50% saturated aqueous ammonium chloride solution. Upon warming to ambient temperature, the reaction mixture was extracted with tert. butyl methyl ether (TBME) (3×100 ml), and the combined organic phases were washed with 50 ml H2O, dried over Na2SO4, filtered and concentrated under reduced pressure (45° C./450-20 mbar) providing an orange-red oil (14.8 g, 91%) which was sufficiently pure (Gas Liquid Chromatography (GLC) 98 area %) to be used directly in the next step.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:9]([C:12]([F:15])([F:14])[F:13])=[CH:8][C:3]=1[CH2:4][NH:5][CH2:6][CH3:7].C(N(CC)CC)C.[CH:23]1([C:26](Cl)=[O:27])[CH2:25][CH2:24]1>C(Cl)Cl>[Br:1][C:2]1[CH:11]=[CH:10][C:9]([C:12]([F:13])([F:14])[F:15])=[CH:8][C:3]=1[CH2:4][N:5]([CH2:6][CH3:7])[C:26]([CH:23]1[CH2:25][CH2:24]1)=[O:27]
Reactant: O=C(Cl)C1CC1
Reactant: CCNCc1cc(C(F)(F)F)ccc1Br
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCN(Cc1cc(C(F)(F)F)ccc1Br)C(=O)C1CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To (2-bromo-5-trifluoromethyl-benzyl)-ethyl-amine (22.3 g, 79.1 mmol) and triethylamine (16.53 mL, 118.6 mmol) in CH2Cl2 (200 mL) was added cyclopropanecarbonyl chloride (8.68 mL, 94.9 mmol) dropwise over 15 minutes, and the reaction was stirred at room temperature for 2 hours. The mixture was partitioned between CH2Cl2 and H2O, and the aqueous layer was separated and extracted twice with CH2Cl2. The combined organic layers were dried and concentrated, and the residue was purified by silica gel chromatography (10-30% EtOAc in hexanes) to give cyclopropanecarboxylic acid (2-bromo-5-trifluoromethyl-benzyl)-ethyl-amide.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]([F:12])([F:11])[F:10])=[CH:4][CH:3]=1.C([Li])(C)(C)C.[C:18](=O)=[O:19].CN(C=O)C>C1COCC1.CCCCC>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][C:9]([F:10])([F:11])[F:12])=[CH:6][C:7]=1[CH:18]=[O:19]
Reactant: O=C=O
Reactant: Fc1ccc(OC(F)(F)F)cc1
Agent: [Li]C(C)(C)C
Solvent: CCCCC
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: O=Cc1cc(OC(F)(F)F)ccc1F
Reaction time: 0.25 h
Yield: 53 %

Procedure:
A solution of 1-fluoro-4-trifluoromethoxy-benzene (21.0 g, 117 mmol) in THF (233 ml) was cooled to <−70° C. Tert.-butyllithium (86 ml of a 1.5 molar solution in pentane, 129 mmol) was added at such a rate that temperature was kept <−70° C. Stirring in the dry ice bath was continued for 15 min, then DMF (11.6 ml, 150 mmol) was added dropwise keeping temperature <−70° C. After 30 min the reaction mixture was allowed to reach rt, quenched with saturated NH4Cl solution and extracted with ether. The organic phase was washed with brine, concentrated and chromatographed (SiO2, heptane:ethyl acetate=100:0 to 80:2). The title compound (11.0 g, 53%) was obtained as a light yellow oil. 1H-NMR (300 MHz, DMSO): δ=7.60 (t, J=9.2 Hz, 1H), 7.75-7.85 (m, 2H), 10.20 (s, 1H).
Reaction SMILES: [N:1]1[C:8](Cl)=[N:7][C:5](Cl)=[N:4][C:2]=1[Cl:3].[CH:10]([NH2:13])([CH3:12])[CH3:11].[OH-].[Na+].[CH2:16]([NH2:18])[CH3:17]>CC(C)=O>[Cl:3][C:2]1[N:1]=[C:8]([NH:18][CH2:16][CH3:17])[N:7]=[C:5]([NH:13][CH:10]([CH3:12])[CH3:11])[N:4]=1
Reactant: CC(C)N
Reactant: Clc1nc(Cl)nc(Cl)n1
Reactant: CCN
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Product: CCNc1nc(Cl)nc(NC(C)C)n1

Procedure:
This test is carried out as in Example 3, feeding to the inlet end of the reactor 1317 Kg/hour of a solution containing 14% by weight of cyanuric chloride in acetone and 492 Kg/hour of an aqueous solution containing 12% by weight of isopropylamine and 8.12% by weight of sodium hydroxide. The inlet temperature of stage (a) is 18° C. and the outlet temperature is 55° C. Stage (b) is carried out under isothermal conditions with a temperature of 55° C. and for this purpose the corresponding part of the reactor is provided with heat exchange means. To the input of stage (b) there is fed 375 Kg/hour of an aqueous solution containing 12% by weight of monoethylamine and 10.64% by weight of sodium hydroxide. The reaction products are recovered at the outlet end of the reactor. The conversion of cyanuric chloride is 99% and the 2-chloro-4-ethylamino-6-isopropylamino-s-triazine thus obtained has a purity of 99%.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([Cl:11])[N:3]=1.[CH3:12][CH:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1>C(O)C>[Cl:11][C:4]1[N:3]=[C:2]([N:16]2[CH2:17][CH2:18][CH:13]([CH3:12])[CH2:14][CH2:15]2)[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1Cl
Reactant: CC1CCNCC1
Solvent: CCO
Product: CC1CCN(c2nc(Cl)ccc2[N+](=O)[O-])CC1
Temperature: 25 °C
Reaction time: 15 h
Yield: 45.1 %

Procedure:
A flask was charged with 2,6-dichloro-3-nitropyridine (1.00 g, 5.00 mmol), absolute ethanol (25 mL), and 4-methylpiperidine (0.65 mL, 5.5 mmol) and stirred 15 h at RT. The solvents were removed in vacuo and purification of the resulting residue by silica gel preparative TLC eluting with 10% ethyl acetate in hexane yielded 577 mg (45%) of the title compound as a yellow glass. LC-MS (ESI, m/z): Calcd. for C11H15ClN3O2, 256.1/258.1 (M+H); found: 256.1/258.1.