Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Sn](Cl)Cl.[C:4]([C:6]1[CH:11]=[CH:10][C:9]([N:12]2C=C[C:15]([NH2:18])=[C:14]([N+:19]([O-])=O)[CH2:13]2)=[CH:8][CH:7]=1)#[N:5].[CH2:22](O)[CH3:23]>O>[NH2:19][C:14]1[CH:15]=[N:18][CH:22]=[CH:23][C:13]=1[NH:12][C:9]1[CH:8]=[CH:7][C:6]([C:4]#[N:5])=[CH:11][CH:10]=1
Reactant: N#Cc1ccc(N2C=CC(N)=C([N+](=O)[O-])C2)cc1
Reactant: CCO
Agent: Cl[Sn]Cl
Solvent: O
Product: N#Cc1ccc(Nc2ccncc2N)cc1
Temperature: 0 °C

Procedure:
According to a modification of the method of Pharm. Helv. Acta, 1975, 50, 188., tin dichloride dibydrate (56.4 g, 250 mmol) was added to a suspension of N-(4-cyanophenyl)-4-amino-3-nitropyridine (12.0 g, 50 mmol) in 2N aqueous bydrochloric acid (35 ml), water (150 ml) and ethanol (75 ml) and the resulting mixture was heated to reflux for 10 minutes under nitrogen. The mixture was cooled in ice, poured into ice-cold 2N aqueous sodium bydroxide (400 ml) and filtered. The creamy-coloured solid was washed with 2N aqueous sodium hydroxide and water, and then dried in a vacuum desiccator. The product, 3-amino-4-(4'-cyanophenyl)aminopyridine, 9.31 g, gradually turns reddish brown on exposure to light and air.
Reaction SMILES: [C:1]1([C:7]2[C:8]3[C:13]([CH:14]=[C:15]4[C:20]=2[CH:19]=[CH:18][CH:17]=[CH:16]4)=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:21]Br.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)(Cl)(Cl)Cl.C1(C)C=CC=CC=1>[Br:21][C:14]1[C:15]2[C:20]([C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[C:8]3[C:13]=1[CH:12]=[CH:11][CH:10]=[CH:9]3)=[CH:19][CH:18]=[CH:17][CH:16]=2
Reactant: BrBr
Reactant: c1ccc(-c2c3ccccc3cc3ccccc23)cc1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: Brc1c2ccccc2c(-c2ccccc2)c2ccccc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
25.0 g (98.3 mmol) of 9-phenylanthracene was put into a 1-L three-neck flask, and 300 mL of carbon tetrachloride was added thereto. A solution in which 15.6 g (98.3 mmol) of bromine was dissolved in 40 mL of carbon tetrachloride was dropped in the reaction solution at the room temperature. After the dropping, the reaction solution was stirred at the room temperature for 1 hour. Thereafter, the reaction is completed by adding a sodium thiosulfate aqueous solution, and the solution was further stirred for 1 hour. An organic layer of the reaction mixture was washed with aqueous sodium hydroxide (2.0 mol/L) and saturated saline and dried with magnesium sulfate. This mixture was filtrated naturally, and the filtrate was condensed to obtain a solid. The solid was dissolved in toluene, and the solution was subjected to suction filtration through Florisil, celite, and then alumina. The filtrate was concentrated to obtain a solid, and the solid was recrystallized with a mixture solution of dichloromethane and hexane, whereby 27.8 g of a light yellow powdery solid that was a target matter was obtained with the yield of 85%.
Reaction SMILES: C[O:2][CH2:3][C:4]([O:6][CH3:7])=O.[CH2:8]([O:15][C:16]1[CH:17]=[C:18]([Mg]Br)[CH:19]=[CH:20][CH:21]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>CCOCC>[CH2:8]([O:15][C:16]1[CH:21]=[C:20]([C:3](=[O:2])[CH2:4][O:6][CH3:7])[CH:19]=[CH:18][CH:17]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: COCC(=O)OC
Reactant: Br[Mg]c1cccc(OCc2ccccc2)c1
Solvent: CCOCC
Product: COCC(=O)c1cccc(OCc2ccccc2)c1
Temperature: 25 °C
Yield: 13.8 %

Procedure:
To a solution of methyl methoxyacetate (available from Aldrich) (0.48 mL, 4.8 mmol) in ether (20 mL) was added 3-benzyloxyphenylmagnesium bromide (1.0 M in THF) (available from Aldrich) (5.0 mL, 5.0 mmol) dropwise at −78° C. The mixture was warmed to room temperature overnight, quenched with 1 N HCl, and diluted with EtOAc. The organic layers were washed with water and brine, dried (MgSO4), and concentrated. The crude product was purified by silica gel flash chromatography (0-20% EtOAc/hexane) to afford 102.A (0.17 g, 14% yield) as a pale yellow oil.
Reaction SMILES: [NH2:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][N:3]=1.Cl[CH2:10][C:11](=O)[CH3:12]>CO>[OH:8][C:7]1[C:2]2[N:3]([CH:10]=[C:11]([CH3:12])[N:1]=2)[CH:4]=[CH:5][CH:6]=1
Reactant: CC(=O)CCl
Reactant: Nc1ncccc1O
Solvent: CO
Product: Cc1cn2cccc(O)c2n1
Temperature: 25 °C
Yield: 52 %

Procedure:
A 1L two-necked round bottom flask containing molecular sieves (30 g, Type 4 Å) was vacuum flame-dried and cooled to room temperature. The flask was then charged with 2-amino-3-hydroxypyridine (11.2 g, 0.1 mol), chloroacetone (33.5 mL, 0.4 mol) and anhydrous methanol (400 mL) under argon. The resultant mixture was refluxed for 16 h, the molecular sieves were filtered off and the filtrate was concentrated in vacuo. The dark brown residue was dissolved in water (150 mL) and the resultant solution was extracted with diethyl ether (150 mL) and dichloromethane (2×50 mL). The dichloromethane extracts were combined and back-washed with water (20 mL). The aqueous layers were combined and adjusted to pH 10 with 40% aq NaOH, triggering precipitation of a solid. The precipitate was collected, washed successively with water (2×100 mL) and dichloromethane (100 mL), and dried over P2O5 in vacuo, giving 7.7 g (52% yield) of 8-hydroxy-2-methylimidazo[1,2-α]pyridine as a pale brown powder.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:8])=[N:6][CH:7]=1.[H-].[Na+].I[CH2:12][CH3:13]>CN(C=O)C.C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5](=[O:8])[N:6]([CH2:12][CH3:13])[CH:7]=1
Reactant: CCI
Reactant: Oc1ccc(Br)cn1
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCn1cc(Br)ccc1=O
Reaction time: 0.5 h

Procedure:
A solution of 5-bromopyridin-2-ol (1.74 g, 10.00 mmol) in DMF (20 ml) was treated with NaH at room temperature and then stirred for 30 min. Iodoethane (0.823 ml, 12.00 mmol) was added to the mixture and the reaction was stirred overnight at room temperature. The reaction was diluted with DCM, washed with water, dried over Na2SO4, and concentrated to dryness via rotary evaporation to provide the title compound as a crude product which was used without further purification.
Reaction SMILES: CO.[OH-].[K+].[C:5]1([C:12]([O:14]C)=[O:13])([C:8]([O:10]C)=[O:9])[CH2:7][CH2:6]1.S(=O)(=O)(O)O>O>[C:5]1([C:12]([OH:14])=[O:13])([C:8]([OH:10])=[O:9])[CH2:7][CH2:6]1
Reactant: COC(=O)C1(C(=O)OC)CC1
Agent: O=S(=O)(O)O
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)C1(C(=O)O)CC1
Reaction time: 1.5 h

Procedure:
In a 4 liter multinecked flask, 800 ml of aqueous saturated K2 SO4 solution (from previous batches, neutralized), 500 ml of methanol and 330 g of KOH (85%, 5.0 mol) are heated and then, at 68° C., over a period of 90 minutes, a 316.2 g amount of dimethyl cyclopropane-1,1-dicarboxylate (2.0 mol) is added gradually. During the postreaction time of 4 hours, some of the methanol distills. After the reaction solution has cooled it is acidified, with cooling, with a 281 g amount of sulfuric acid (96% strength, 2.75 mol) which has previously been diluted with 100 ml of water. The K2SO4 which crystallizes is filtered via a sintered disk, washed with methanol and dried: 380 g (87.2% of the theoretical yield).
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[C:14]([N+:16]([O-])=O)[CH:13]=[CH:12][C:3]=1[O:4][CH2:5][CH2:6][N:7]([CH2:10][CH3:11])[CH2:8][CH3:9].ClCCl.CO>CO>[Cl:1][C:2]1[CH:15]=[C:14]([NH2:16])[CH:13]=[CH:12][C:3]=1[O:4][CH2:5][CH2:6][N:7]([CH2:8][CH3:9])[CH2:10][CH3:11]
Reactant: CCN(CC)CCOc1ccc([N+](=O)[O-])cc1Cl
Solvent: CO
Solvent: ClCCl
Product: CCN(CC)CCOc1ccc(N)cc1Cl

Procedure:
Prepared analogously to Example 3.1.b. from [2-(2-chloro-4-nitrophenoxy)ethyl]diethylamine in methanol in a reaction time of 4.5 hours. Yield: 36.12 g (81.8% of theory); C12H19ClN2O (M=242.75); calc.: molecular ion peak (M+H)+: 243/245; found: molecular ion peak (M+H)+: 243/245; Rf value: 0.36 (silica gel, dichloromethane/methanol (90:10)).
Reaction SMILES: [O:1]([CH:8]1[CH2:17][CH2:16][C:11]2(OCC[O:12]2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C1COCC1.Cl>[O:1]([CH:8]1[CH2:9][CH2:10][C:11](=[O:12])[CH2:16][CH2:17]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccc(OC2CCC3(CC2)OCCO3)cc1
Agent: Cl
Solvent: C1CCOC1
Product: O=C1CCC(Oc2ccccc2)CC1
Temperature: 50 °C
Reaction time: 3 h
Yield: 55.3 %

Procedure:
To a solution of compound 8-phenoxy-1,4-dioxa-spiro[4.5]decane (2.0 g, 8.55 mmol) in THF (12 mL), 3N HCl (aqueous, 12 mL) was added and the reaction mixture was stirred at 50° C. for 3 h. Excess THF was removed in rotary evaporator and the crude reaction mixture was partitioned between water and ethyl acetate. The organic layer was separated, dried (Na2SO4) and concentrated. The residue was purified by silica gel column chromatography using ethyl acetate and hexane (1:4) to obtain 4-phenoxy-cyclohexanone (900 mg, 56%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:13])[C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=1.S([O-])(O)(=O)=O.Cl[O-].[Na+].O>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:13])[C:9]([F:11])([F:12])[F:10])=[CH:4][N:3]=1
Reactant: OC(c1ccc(Cl)nc1)C(F)(F)F
Agent: O=S(=O)([O-])O
Agent: [Na+]
Agent: [O-]Cl
Solvent: Cc1ccccc1
Solvent: O
Product: O=C(c1ccc(Cl)nc1)C(F)(F)F

Procedure:
2.11 g (0.01 mol) of 2-chloro-5-(2,2,2-trifluoro-1-hydroxyethyl)pyridine and 0.18 g (0.0005 mol) of tetrabutylammnonium hydrogen sulfate are dissolved in 25 ml of toluene at room temperature. 6.1 ml (0.012 mol) of an approximately 12% strength sodium hypochlorite solution are metered in within 5 minutes with vigorous stirring and the mixture is stirred for a further 2.5 hours during which the reaction temperature rises to 27° C. The reaction mixture is added to 50 ml of water, the phases are separated, the aqueous phase is extracted several times with toluene and the combined organic phases are washed with saturated aqueous sodium chloride solution. After drying the organic phases with sodium sulfate, the volatiles are distilled off. Following distillation of the crude product in a kugelrohr (0.4 mbar, 100°-115° C. bath temperature), 1.78 g (85% of theory) of 2-chloro-5-trifluoroacetylpyridine are obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:13])[C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=1.Cl[O-].[Na+].O>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C(C)=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:13])[C:9]([F:11])([F:12])[F:10])=[CH:4][N:3]=1
Reactant: OC(c1ccc(Cl)nc1)C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1C
Product: O=C(c1ccc(Cl)nc1)C(F)(F)F

Procedure:
2.11 g (0.01 mol) of 2-chloro-5-(2,2,2-trifluoro-1-hydroxyethyl)pyridine and 0.18 g (0.0005 mol) of tetrabutylammonium hydrogen sulfate are dissolved in 30 ml of xylene at room temperature. 7.3 ml (0.012 mol) of an approximately 10% strength sodium hypochlorite solution are metered in within 5 minutes with vigorous stirring and the mixture is stirred for a further 2 hours during which the reaction temperature rises to 28° C. The reaction mixture is added to 50 ml of water, the phases are separated, the aqueous phase is extracted several times with xylene and the combined organic phases are washed with saturated aqueous sodium chloride solution. After drying the organic phase with sodium sulfate, the volatiles are distilled off. Following distillation of the crude product in a kugelrohr (0.4 mbar, 100°-110° C. bath temperature), 1.89 g (90% of theory) of 2-chloro-5-trifluoroacetylpyridine are obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:3]=1[C:4](O)=[O:5].C(=O)([O-])[O-].[K+].[K+].CI.[H-].[H-].[H-].[H-].[Li+].[Al+3].Cl>CN(C)C=O.C(OCC)(=O)C.O.C1(C)C=CC=CC=1>[CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:3]=1[CH2:4][OH:5]
Reactant: Cc1cccc(C)c1C(=O)O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Al+3]
Solvent: CI
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: Cc1cccc(C)c1CO
Reaction time: 16 h

Procedure:
To a solution of 2,6-dimethylbenzoic acid (10 g, 66.5 mmol) and potassium carbonate (9.18 g, 66.5 mmol) in dimethylformamide (67 ml), was added methyl iodide (8.28 ml, 133.16 mmol) in an ice bath, and the mixture was stirred for 16 hours. To the reaction mixture was added toluene and water, and the organic layer was washed with 3% K2CO3, 1N HCl, and brine. The organic layer was dried over Na2SO4, filtered and concentrated. The oily residue was redissolved in dry THF (135 ml), added to LiAlH4 (3.79 g, 99.8 mmol), and stirred for 4 hours in an ice bath. To the reaction mixture was added 1N HCl slowly followed by ethyl acetate, and the organic layer was washed with brine, dried over Na2SO4, filtered and concentrated. The oily residue was used without further purification.
Reaction SMILES: C[O:2][C:3](=[O:18])[CH2:4][C:5]1[C:6]2[CH:13]=[C:12]([S:14](Cl)(=[O:16])=[O:15])[CH:11]=[CH:10][C:7]=2[S:8][CH:9]=1.[CH3:19][C@H:20]1[NH:25][C@@H:24]([CH3:26])[CH2:23][N:22]([CH2:27][C:28]2[CH:33]=[CH:32][C:31]([O:34][C:35]([F:38])([F:37])[F:36])=[CH:30][CH:29]=2)[CH2:21]1>C(O)(=O)C>[CH3:26][C@H:24]1[CH2:23][N:22]([CH2:27][C:28]2[CH:29]=[CH:30][C:31]([O:34][C:35]([F:38])([F:36])[F:37])=[CH:32][CH:33]=2)[CH2:21][C@@H:20]([CH3:19])[N:25]1[S:14]([C:12]1[CH:11]=[CH:10][C:7]2[S:8][CH:9]=[C:5]([CH2:4][C:3]([OH:2])=[O:18])[C:6]=2[CH:13]=1)(=[O:16])=[O:15]
Reactant: C[C@@H]1CN(Cc2ccc(OC(F)(F)F)cc2)C[C@H](C)N1
Reactant: COC(=O)Cc1csc2ccc(S(=O)(=O)Cl)cc12
Solvent: CC(=O)O
Product: C[C@@H]1CN(Cc2ccc(OC(F)(F)F)cc2)C[C@H](C)N1S(=O)(=O)c1ccc2scc(CC(=O)O)c2c1

Procedure:
{5-|cis-2,6-dimethyl-4-(4-trifluoromethoxy-benzyl)-piperazine-1-sulfonyl|-benzo|b|thiophen-3-yl}-acetic acid: The compound {5-[cis-2,6-dimethyl-4-(4-trifluoromethoxy-benzyl)-piperazine-1-sulfonyl]-benzo[b]thiophen-3-yl}-acetic acid was synthesized according to the procedure in Example 37 using (5-chlorosulfonyl-benzo[b]thiophen-3-yl)-acetic acid methyl ester and cis-3,5-dimethyl-1-(4-trifluoromethoxy-benzyl)-piperazine from Example 95, Step 1. 1H NMR (400 MHz, CD3OD) δ 8.48 (s, 1H), 7.96 (d, 1H), 7.88-7.80 (m, 2H), 7.57 (d, 2H), 7.28 (d, 2H), 4.60-4.50 (m, 2H), 4.36 (s, 2H), 3.97 (s, 2H), 3.38-3.28 (m, 2H), 2.74-2.64 (m, 2H), 1.55 (d, 6H); LCMS 542.9 (M+1)+.
Reaction SMILES: [CH3:1][CH:2]([OH:9])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].OO>[Pt]>[CH3:1][C:2](=[O:9])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCC(C)O
Agent: [Pt]
Agent: OO
Product: CCCCCCC(C)=O
Temperature: 90 °C
Reaction time: 0.17 h
Yield: 95 %

Procedure:
Platinum black (1.50 g, 7.7 mmol) and 2-octanol (100 g, 768 mmol) were mixed and stirred at 90° C. for 10 minutes. A 30% aqueous hydrogen peroxide solution (104 g, 918 mmol) was gradually added dropwise to the mixed solution, followed by stirring at 90° C. for 20 hours, and then the reaction solution was cooled to room temperature. The organic phase was separated and washed with 100 ml of a saturated aqueous sodium thiosulfate solution, followed by distillation, and 2-octanone was obtained in yield of 95% (93.9 g, 730 mmol).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[CH2:9][OH:10]>C(Cl)Cl.O=[Mn]=O>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[CH:9]=[O:10]
Reactant: Nc1ccc(Br)cc1CO
Agent: O=[Mn]=O
Solvent: ClCCl
Product: Nc1ccc(Br)cc1C=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.8 %

Procedure:
A mixture of (2-amino-5-bromophenyl)methanol (10 g, 49.5 mmol) and MnO2 (25.8 g, 296.6 mmol) in CH2Cl2 (400 mL) was stirred at RT overnight. LCMS showed the reaction was completed. The solid was filtered off, and the filtrate was concentrated to give the title compound as a light yellow solid (8 g, 81%), which was directly used in next step without further purification. MS (ES+) C7H6BrNO requires: 199. found: 200, 202 [M+H]+.
Reaction SMILES: C(#N)C.[Br:4][C:5]1[CH:6]=[CH:7][C:8]([F:22])=[C:9]([CH:11](Cl)[C:12]2[S:13][C:14]3[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=3[CH:16]=2)[CH:10]=1.[BH4-].[Na+].[OH-].[Na+]>O>[Br:4][C:5]1[CH:6]=[CH:7][C:8]([F:22])=[C:9]([CH:10]=1)[CH2:11][C:12]1[S:13][C:14]2[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=2[CH:16]=1
Reactant: Fc1ccc(Br)cc1C(Cl)c1cc2ccccc2s1
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Solvent: O
Product: Fc1ccc(Br)cc1Cc1cc2ccccc2s1
Temperature: 40 °C
Reaction time: 17.5 h
Yield: 80.9 %

Procedure:
Acetonitrile (1,260 ml) was added to 2-[(5-bromo-2-fluorophenyl)(chloro)methyl]-1-benzothiophene (265.69 g) and the mixture was heated to 40° C. The resulting solution was added to a water (1,260 ml) solution of sodium borohydride (113.0 g) and sodium hydroxide (14.9 g) at 59.0 to 67.9° C., followed by stirring at 24.1 to 67.5° C. for 17.5 hours. To the reaction mixture were added 36% hydrochloric acid (340.5 g), water (1,260 ml) and toluene (1,260 ml), and extraction was conducted. The organic layer was washed with a 5% aqueous sodium hydrogencarbonate solution (1,260 ml) and subjected to vacuum distillation to distil off the solvent. To the residue were added 2-propanol (378 ml) and methanol (756 ml), and the residue was dissolved with heating. To the solution was added, as a seed crystal, 2.7 g of the 2-(5-bromo-2-fluorobenzyl)-1-benzothiophene produced by the method of Reference Example 2, at 39.7° C., followed by stirring at 0.7 to 5.0° C. for 13 hours. The separated-out crystals were collected by filtration, washed with methanol (251 ml), and vacuum-dried to obtain, as white crystals, 2-(5-bromo-2-fluorobenzyl)-1-benzothiophene [194.05 g, yield: 80.9%, purity: 99% (HPLC)].
Reaction SMILES: [C:1]([N:4]1[C:8](=[O:9])[CH:7]=[CH:6][C:5]1=[O:10])(=[O:3])[NH2:2].[C:11]([O:15][CH2:16][CH2:17][OH:18])(=[O:14])[CH:12]=[CH2:13].O>C(#N)C.[Cl-].[Zn+2].[Cl-]>[C:5]([OH:10])(=[O:14])/[CH:6]=[CH:7]\[C:8](=[O:9])[NH:4][C:1](=[O:3])[NH2:2].[C:11]([O:15][CH2:16][CH2:17][OH:18])(=[O:14])[CH:12]=[CH2:13]
Reactant: NC(=O)N1C(=O)C=CC1=O
Agent: C=CC(=O)OCCO
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CC#N
Solvent: O
Product: NC(=O)NC(=O)/C=C\C(=O)O
Reaction time: 5 h
Yield: 167.2 %

Procedure:
A mixture of 140 g of N-carbamylmaleimide (1 mole), 121.8 g of 2-hydroxyethyl acrylate (1.05 moles) and 1.36 g of zinc chloride (0.01 moles) in 200 mL of acetonitrile was heated to reflux. After 5 hours, the mixture was poured into 500 mL of water. The solid was filtered, washed with water and dried to afford 240.7 g (94% yield) of 2-hydroxyethyl acrylate maleurate. M.P.: 88°-90° C. (dec.); 1H NMR (CDCl3): δ10.4 (br s, 1H), 8.2 (br s, 1H), 6.4 (m, 3H), 6.2 (d of d, 1H), 5.9 (m, 2H), 4.4 (A2B2, 4H); 13C NMR (CDCl3): δ165.9, 165.3, 165.2, 155.1, 133.1, 131.6, 129.5, 127.8, 63.2, 61.9; HPLC (10% CH3CN/H2O, C18): Rt=5.7 minutes.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[CH:4][CH:3]=1.[Cl:9]N1C(=O)CCC1=O>C(#N)C>[Br:1][C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[CH:4][C:3]=1[Cl:9]
Reactant: Nc1cccc(Br)n1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CC#N
Product: Nc1ccc(Cl)c(Br)n1
Temperature: 80 °C

Procedure:
To a solution of 6-bromopyridin-2-amine (1 g, 5.78 mmol) in acetonitrile (10 mL) was added N-chlorosuccinimide (0.849 g, 6.36 mmol) and the mixture was heated at 80° C. for 12 hours. The mixture was filtered through diatomaceous earth and concentrated and the residue was dissolved in ethyl acetate and washed with water and brine. Drying over anhydrous sodium sulfate, filtration, concentration and purification by column chromatography (silica gel, 30% ethyl acetate in hexane) afforded the title compound. LCMS: 209.1 (M+2)+.
Reaction SMILES: NC1N([CH2:7][C:8]2[CH:13]=[C:12]([Cl:14])[C:11]([C:15](=[O:23])[C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)=[C:10]([Cl:24])[CH:9]=2)N=NC=1C(N)=O.ClC1C=C(C)C=C(Cl)C=1C(O)=O.C(Cl)(=O)C1C=CC=CC=1.S(Cl)(Cl)=O.[Cl-].[Cl-].[Cl-].[Al+3]>CN(C)C=O.ClC1C=CC=CC=1>[Cl:22][C:19]1[CH:20]=[CH:21][C:16]([C:15]([C:11]2[C:12]([Cl:14])=[CH:13][C:8]([CH3:7])=[CH:9][C:10]=2[Cl:24])=[O:23])=[CH:17][CH:18]=1
Reactant: NC(=O)c1nnn(Cc2cc(Cl)c(C(=O)c3ccc(Cl)cc3)c(Cl)c2)c1N
Agent: Cc1cc(Cl)c(C(=O)O)c(Cl)c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=C(Cl)c1ccccc1
Solvent: CN(C)C=O
Solvent: Clc1ccccc1
Product: Cc1cc(Cl)c(C(=O)c2ccc(Cl)cc2)c(Cl)c1

Procedure:
Compound 1 can be prepared by the method described in U.S. Pat. No. 4,590,201. Briefly, 2,6-dichloro-4-methylbenzoic acid is converted to its corresponding benzoyl chloride using thionyl chloride in dimethylformamide. Reaction of this benzoyl chloride with chlorobenzene in the presence of aluminum trichloride provides 4-(4-chlorobenzoyl) 3,5-dichlorotoluene. Bromination of the methyl group is carried out using N-bromosuccinimide in the presence of catalytic amounts of dibenzoyl peroxide to provide 4-(4-chlorobenzoyl)-3,5-dichlorobenzyl bromide. The benzyl bromide is then converted to the corresponding benzyl azide using potassium azide. Treatment of the 4-(4-chlorobenzoyl)-3,5-dichlorobenzyl azide thus formed with 2-cyanoacetamide in the presence of sodium methoxide provides after workup, 5-amino-1-(4-(4-chlorobenzoyl)-3,5-dichlorobenzyl)- 1,2,3-triazole-4-carboxamide (Compound 1).
Reaction SMILES: [CH:1]1([CH2:7][O:8][C:9]([NH:11][C@H:12]([C:21](O)=[O:22])[CH2:13][C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=2)=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(Cl)(=O)OCC.C(N(CC)CC)C>O1CCCC1>[CH:1]1([CH2:7][O:8][C:9]([NH:11][C@H:12]([CH2:21][OH:22])[CH2:13][C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=2)=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(N[C@@H](Cc1ccc(O)cc1)C(=O)O)OCC1CCCCC1
Agent: CCOC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(N[C@H](CO)Cc1ccc(O)cc1)OCC1CCCCC1

Procedure:
In 30 ml of tetrahydrofuran, 3.2 g of N-(cyclohexylmethoxycarbonyl)-tyrosine was dissolved. To the solution were added 1.1 g of ethyl chlorocarbonate and 1.0 g of triethylamine while cooling with ice and stirring. After stirring the mixture for 10 minutes, the precipitate was removed by filtration. The filtrate was added to a suspension of 1.0 g of sodium borohydride and 10 ml of tetrahydrofuran cooled with ice. The mixture was stirred for 2 hours, then neutralized with hydrochloric acid and concentrated in vacuo. The residue was extracted with ethyl acetate and the extract was washed with water, dried and concentrated to dryness. The residue was crystallized from ethyl acetate-petroleum ether to give 2.3 of N-(cyclohexylmethoxycarbonyl)-tyrosinol with a melting point of 121-126° C.
Reaction SMILES: [CH:1]1([CH2:7][O:8][C:9]([NH:11][C@H:12]([C:21](O)=[O:22])[CH2:13][C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=2)=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[BH4-].[Na+].[Al].O>COCCOCCOC>[CH:1]1([CH2:7][O:8][C:9]([NH:11][C@H:12]([CH2:21][OH:22])[CH2:13][C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=2)=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(N[C@@H](Cc1ccc(O)cc1)C(=O)O)OCC1CCCCC1
Agent: [Al]
Agent: [BH4-]
Agent: [Na+]
Solvent: COCCOCCOC
Solvent: O
Product: O=C(N[C@H](CO)Cc1ccc(O)cc1)OCC1CCCCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
In 15 ml of diglyme (bis (2-methoxyethyl) ether) was dissolved 1.0 g of N-(cyclohexylmethoxycarbonyl)-tyrosine. To the solution were added 570 mg of sodium borohydride and 50 ml of diglyme solution containing 7g of anhydrous aluminium chyloride. The mixture was stirred at room temperature for two hours. After addition of 150 ml of water, the reaction mixture was concentrated in vacuo and the residue was extracted with ethyl acetate. The extract was washed with water, dried and concentrated to dryness. The residue was crystallized from ethyl acetate-petroleum ether to give N-(cyclohexylmethoxycarbonyl)-tyrosinol.