Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]([CH2:8][C:9]1[NH:10][CH:11]=[C:12]([C:14]2[CH:27]=[CH:26][C:17]([O:18][C:19]3[CH:25]=[CH:24][C:22]([NH2:23])=[CH:21][CH:20]=3)=[CH:16][CH:15]=2)[N:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.CI.[CH2:37]([OH:39])[CH3:38]>>[O:1]([CH2:8][C:9]1[NH:10][CH:11]=[C:12]([C:14]2[CH:27]=[CH:26][C:17]([O:18][C:19]3[CH:20]=[CH:21][C:22]([NH:23][C:37](=[O:39])[CH3:38])=[CH:24][CH:25]=3)=[CH:16][CH:15]=2)[N:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCO
Reactant: Nc1ccc(Oc2ccc(-c3c[nH]c(COc4ccccc4)n3)cc2)cc1
Solvent: CCN(CC)CC
Solvent: CI
Product: CC(=O)Nc1ccc(Oc2ccc(-c3c[nH]c(COc4ccccc4)n3)cc2)cc1
Reaction time: 20 h

Procedure:
4-{4-[2-(phenoxymethyl)-1H-imidazol-4-yl]phenoxy}aniline (600 mg, 0.00168 mol), (prepared according to a method analogous to that described in Example 28) is suspended in ethanol (30 ml) at 0° C. Triethylamine (0.235 ml, 0.00168 mol) and methyl iodide (0.136 ml, 0.0022 mol) are added. The mixture is stirred for 20 hours then evaporated to dryness. The residue obtained is adsorbed on silica then purified by chromatography on a Biotage-type silica column (eluent: ethyl acetate-heptane: 4-6 to 5-5). After washing with diethyl ether and isopentane, a beige-coloured powder is obtained.
Reaction SMILES: [CH3:1][N:2]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][OH:17])=[CH:12][CH:11]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[N-:18]=[C:19]=[O:20].C[O:22][C:23](=[O:33])[C@H:24]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)N>>[CH3:1][N:2]([CH2:9][C:10]1[CH:11]=[CH:12][C:13]([CH2:16][O:17][C:19]([NH:18][CH:24]([CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:23]([OH:33])=[O:22])=[O:20])=[CH:14][CH:15]=1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: [N-]=C=O
Reactant: CN(Cc1ccc(CO)cc1)c1ccccc1
Reactant: COC(=O)[C@@H](N)Cc1ccccc1
Product: CN(Cc1ccc(COC(=O)NC(Cc2ccccc2)C(=O)O)cc1)c1ccccc1

Procedure:
Following the procedure in J.Org. Chem. 1996, 61 (11), 3849-3862, methyl-4-formylbenzoate (0.821 g, 5.00 mmol) was dissolved in 1,2-dichloroethane (75 ml) at room temperature. N-methylaniline (0.542 ml, 5.00 mmol) was added followed by sodium triacetoxyborohydride (1.484 g, 7.00 mmol). The mixture was allowed to stir at room temperature overnight. The mixture was quenched with saturated sodium bicarbonate solution and extracted with diethyl ether. The organic extracts were dried over anhydrous sodium sulfate and concentrated en vacuo. The residue was purified by-flash chromatography on silica eluted with 4:1 hexane/acetone to give 1.097 g (85.9%) of a slightly yellow oil of 4-[(methyl-phenyl-amino)-methyl]-benzoic acid methyl ester. Reduction to {4-[(methyl-phenyl-amino)-methyl]-phenyl}-methanol, condensation with(R)-2-isocyanato-3-phenyl-propionate of formula 5 and hydrolysis as described for example in Example 1 Steps 2-4, yielded about 1.5 g of 2-{4-[(methyl-phenyl-amino)-methyl]-benzyloxycarbonylamino}-3-phenyl-propionic 169, mp. 69.6-70.1° C.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.Cl.[CH3:11][N:12]([CH2:14][CH2:15]Cl)[CH3:13].CN(C)C=O.C(=O)([O-])[O-].[K+].[K+]>C(OC(C)C)(C)C.O>[CH3:11][N:12]([CH3:13])[CH2:14][CH2:15][O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(O)cc1
Reactant: CN(C)CCCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC(C)OC(C)C
Solvent: O
Product: CN(C)CCOc1ccc(C=O)cc1
Temperature: 60 °C
Reaction time: 8 h
Yield: 21.3 %

Procedure:
To a suspension of 4-hydroxybenzaldehyde (2.0 g), dimethylaminoethyl chloride hydrochloride (2.83 g), dimethylformamide (8 mL) in diisopropylether (1 mL) is added potassium carbonate (5.53 g) and the mixture was stirred at 60° C. overnight. To the reaction mixture was added water and the mixture was extracted with ethyl acetate (×2). The organic layer is concentrated in vacuo and the resultant crude product was purified by a column chromatography on silica gel (solvent; chloroform/methanol=100:0→90:10) to give 4-[2-(dimethylamino)ethoxy]benzaldehyde (674 mg, yield: 21%) as an oil.
Reaction SMILES: [CH2:1]([N:7]1[CH2:12][CH2:11][C:10]([CH3:27])([C:13]2[CH:18]=[CH:17][CH:16]=[C:15](OS(C(F)(F)F)(=O)=O)[CH:14]=2)[CH:9]([CH3:28])[CH2:8]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[C-:29]#[N:30].[K+]>CN1CCCC1=O>[NH3:7].[CH2:1]([N:7]1[CH2:12][CH2:11][C:10]([CH3:27])([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:29]#[N:30])[CH:14]=2)[CH:9]([CH3:28])[CH2:8]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: [C-]#N
Reactant: CCCCCCN1CCC(C)(c2cccc(OS(=O)(=O)C(F)(F)F)c2)C(C)C1
Agent: [K+]
Solvent: CN1CCCC1=O
Product: CCCCCCN1CCC(C)(c2cccc(C#N)c2)C(C)C1
Product: N
Temperature: 60 °C
Reaction time: 3 h
Yield: 194.8 %

Procedure:
A solution of 1-hexyl-3,4-dimethyl-4-(3-trifluoromethanesulfonyloxyphenyl)piperidine (Preparation 1, 500 mg, 1.19 mmol) in 1-methyl-2-pyrrolidinone (2.5 mL) was added to a flask containing potassium cyanide (155 mg, 2.38 mmol). The solution was de-oxygenated by evacuating and flushing with nitrogen three times. Catalytic quantities of palladium(II) acetate and 1,1 ′-bis(diphenylphosphino)ferrocene were added and the reaction mixture was warmed to 60° C., at which temperature it was stirred for 3 hours. The reaction mixture was cooled to room temperature and poured into saturated aqueous sodium hydrogencarbonate solution (50 mL). The product was extracted into ethyl acetate (3×30 mL). The combined organics were dried (Na2SO4) and concentrated in vacuo. The residue was purified by column chromatography on silica gel (15 g) eluted with a gradient of ethyl acetate:hexane:0.880 ammonia (20:79:1 to 50:49:1) to give the title compound as an oil (346 mg).
Reaction SMILES: C([O:3][C:4]([C:6]1([NH:9][C:10]([C:12]2[C:13]([OH:36])=[C:14]3[C:19](=[CH:20][N:21]=2)[N:18]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:17](=[O:29])[C:16]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[CH:15]3)=[O:11])[CH2:8][CH2:7]1)=[O:5])C.[OH-].[Na+].CO.C1COCC1>C([O-])(O)=O.[Na+]>[CH2:22]([N:18]1[C:19]2[C:14](=[C:13]([OH:36])[C:12]([C:10]([NH:9][C:6]3([C:4]([OH:5])=[O:3])[CH2:8][CH2:7]3)=[O:11])=[N:21][CH:20]=2)[CH:15]=[C:16]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:17]1=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CCOC(=O)C1(NC(=O)c2ncc3c(cc(-c4ccccc4)c(=O)n3Cc3ccccc3)c2O)CC1
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(NC1(C(=O)O)CC1)c1ncc2c(cc(-c3ccccc3)c(=O)n2Cc2ccccc2)c1O
Temperature: 25 °C
Reaction time: 16 h
Yield: 39.7 %

Procedure:
A mixture of 1-[(1-benzyl-5-hydroxy-2-oxo-3-phenyl-1,2-dihydro-[1,7]naphthyridine-6-carbonyl)-amino]-cyclopropanecarboxylic acid ethyl ester (40 mg, 0.083 mmol), 2 M NaOH (3 mL), MeOH (3 mL) and THF (3 mL) was stirred at r.t. for 16 h, then concentrated to approximately one-third of its original volume. 1 M HCl was added to acidify the mixture, and the resulting suspension was extracted with EtOAc. The organic layer was dried over MgSO4 and concentrated. The residue was dissolved in saturated NaHCO3 and washes several times with ether. The aqueous layer was acidified to pH about 3, and the resulting precipitate was isolated by filtration. The crude solid was purified by silica gel chromatography (5-60% EtOAc/hexanes+1% AcOH). The product isolated was dissolved in saturated NaHCO3 and washed several times with ether. The aqueous layer was acidified to pH about 3, and the resulting precipitate was isolated by filtration to give 15 mg of the title compound. MS: (+) m/z 456.35 (M+1).
Reaction SMILES: [N:1]#[C:2][NH2:3].[H-].[Na+].[N:6]1[CH:11]=[CH:10][CH:9]=[C:8]([N:12]=[C:13]=[S:14])[CH:7]=1>C1COCC1>[C:2]([NH:3][C:13]([NH:12][C:8]1[CH:7]=[N:6][CH:11]=[CH:10][CH:9]=1)=[S:14])#[N:1]
Reactant: N#CN
Reactant: S=C=Nc1cccnc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: N#CNC(=S)Nc1cccnc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 72.5 %

Procedure:
A solution of cyanamide (352 mg, 8.40 mmol) in THF (20 mL) at 0° C. was treated with sodium hydride (211 mg of 95% reagent, 8.80 mmol). The slurry was stirred for 30 minutes at 0° C. and treated with a solution of 3-pyridyl isothiocyanate (1.12 g, 8.20 mmol) in THF (8 mL). The cooling bath was removed, and the reaction mixture was stirred for 30 minutes. The reaction was quenched with water (15 mL), poured into ethyl acetate (40 mL), and partitioned. The organic phase was washed with brine (10 mL), dried (Na2SO4), filtered, and concentrated. The residue was dissolved in diethyl ether, treated with HCl (2M solution in diethyl ether), and the resulting precipitate was collected providing 1.06 g of the desired product as an off-white solid.
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[O:15])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[F:23][C:24]([F:35])([F:34])[C:25]1[CH:26]=[C:27](B(O)O)[CH:28]=[CH:29][CH:30]=1.C(OCC)(=O)C>C1CCCCC1>[F:23][C:24]([F:35])([F:34])[C:25]1[CH:30]=[C:29]([C:2]2[N:7]=[N:6][C:5]([N:8]3[CH2:13][CH2:12][N:11]([C:14]([O:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[O:15])[CH2:10][CH2:9]3)=[CH:4][CH:3]=2)[CH:28]=[CH:27][CH:26]=1
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Reactant: CCOC(=O)COC(=O)N1CCN(c2ccc(Cl)nn2)CC1
Solvent: CCOC(C)=O
Solvent: C1CCCCC1
Product: CCOC(=O)COC(=O)N1CCN(c2ccc(-c3cccc(C(F)(F)F)c3)nn2)CC1
Yield: 43.7 %

Procedure:
The process is performed according to the procedure described in Example 1 (step 1.3.). Starting with 1.15 g (3.50 mmol) of 2-(ethyloxy)-2-oxoethyl 4-(6-chloro-3-pyridazinyl)-1-piperazinecarboxylate, obtained in step 10.1., 1.99 g (10.49 mmol) of 3-(trifluoromethyl)phenyl-boronic acid, 2.97 g (13.99 mmol) of hydrated potassium phosphate and 0.40 g (0.35 mmol) of tetrakis(triphenyl-phosphine)palladium, and after chromatography on silica gel, eluting with a 35/65 and then 45/55 mixture of ethyl acetate and cyclohexane, 0.67 g of pure product is obtained in the form of a solid.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[C:6]([O:11][CH2:12][C@@H:13]3[CH2:15][O:14]3)[CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3]1.[CH:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18][C:17]=1[N:26]1[CH2:33][C@H:32]2[NH:34][CH2:35][C@@H:27]1[CH2:28][CH:29]=[CH:30][CH2:31]2.CCN(C(C)C)C(C)C>C(O)C>[CH3:1][N:2]1[C:10]2[C:5](=[C:6]([O:11][CH2:12][C@@H:13]([OH:14])[CH2:15][N:34]3[CH2:35][CH:27]4[N:26]([C:17]5[CH:18]=[CH:19][C:20]6[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=6)[CH:16]=5)[CH2:33][CH:32]3[CH2:31][CH:30]=[CH:29][CH2:28]4)[CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3]1
Reactant: C1=CC[C@H]2CN[C@@H](C1)CN2c1ccc2ccccc2c1
Reactant: Cn1ccc2c(OC[C@@H]3CO3)cccc21
Agent: C1=C\C[C@H]2CN[C@@H](C/1)CN2c1ccc2ccccc2c1
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: Cn1ccc2c(OC[C@@H](O)CN3CC4CC=CCC3CN4c3ccc4ccccc4c3)cccc21
Temperature: 120 °C

Procedure:
(S)-1-Methyl-4-oxiranylmethoxy-1H-indole (50 mg, 0.25 mmol) and Z-(1S,6S)-7-naphthalen-2-yl-7,9-diaza-bicyclo[4.2.2]dec-3-ene (50 mg, 0.189 mmol) were placed in a μW tube with ethanol (2 ml), DIPEA (100 μL, 0.576 mmol) and heated to 120° C. for 900 sec. The solvent was evaporated from the reaction mixture and the residue was purified via flash chromatography (gradient 30% to 100% ethyl acetate/heptane) to yield the title compound as a residue.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[C:5]([OH:8])=[N:6][CH:7]=1.C([O-])([O-])=O.[K+].[K+].[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.O>CN(C=O)C>[CH2:18]([N:6]1[CH:7]=[C:2]([Br:1])[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[C:5]1=[O:8])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=[N+]([O-])c1cc(Br)cnc1O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=c1c([N+](=O)[O-])cc(Br)cn1Cc1ccccc1
Temperature: 50 °C
Reaction time: 8 h
Yield: 78.9 %

Procedure:
A solution of 5-bromo-3-nitro-pyridin-2-ol (5.0 g, 22.8 mmol) and K2CO3 (9.5 g, 3 equiv., 69 mmol) in DMF (25 mL) was treated with benzyl bromide (4.3 g, 1.1 equiv., 25 mmol) and heated to 50° C. After stirring overnight, the solution was poured into water (150 mL) and extracted with ethyl acetate (2×150 mL). The combined organic layers were washed with sat'd aq NaCl, dried over anhydrous MgSO4, filtered and concentrated in vacuo. Purification by flash column chromatography (30-40% ethyl acetate in heptane) afforded 1-benzyl-5-bromo-3-nitro-1H-pyridin-2-one as a yellow solid (5.56 g, 79%).
Reaction SMILES: B(F)(F)F.[CH3:5][CH2:6][O:7]CC.[CH3:10][O:11][C:12]1[CH:21]=[C:20]2[C:15]([CH2:16][CH2:17][CH2:18][C:19]2=[O:22])=[CH:14][CH:13]=1>C(OC(=O)C)(=O)C>[C:6]([CH:18]1[CH2:17][CH2:16][C:15]2[C:20](=[CH:21][C:12]([O:11][CH3:10])=[CH:13][CH:14]=2)[C:19]1=[O:22])(=[O:7])[CH3:5]
Reactant: COc1ccc2c(c1)C(=O)CCC2
Reactant: CCOCC
Agent: FB(F)F
Solvent: CC(=O)OC(C)=O
Product: COc1ccc2c(c1)C(=O)C(C(C)=O)CC2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Boron trifluoride etherate (0.53 mL) was added dropwise to a stirred mixture of 7-methoxytetralone (176 mg, 1 mmol) in acetic anhydride (1.8 mL). The reaction was stirred at room temperature for 2 hours, then poured into ice-water and stirred for 1 hour. The mixture was extracted with ether, and the ether extracts were evaporated. The residue was diluted with methanol (12 mL) and saturated sodium acetate (8 mL) and stirred at reflux for 4 hours. After cooling to room temperature, the solution was extracted with dichloromethane. The organic extracts were washed with brine, dried over MgSO4, and concentrated. SiO2 chromatography with 5-20% ethyl acetate/hexanes gave 72.5 mg of the desired product. LC-MS (C13H14O3 calculated 218) m/z 217 (M−H).
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6](F)[N:5]=[CH:4][N:3]=1.[CH2:10]([OH:14])[C:11]#[C:12][CH3:13].C(N(CC)C(C)C)(C)C>O1CCCC1>[CH2:10]([O:14][C:6]1[C:7]([F:8])=[C:2]([F:1])[N:3]=[CH:4][N:5]=1)[C:11]#[C:12][CH3:13]
Reactant: Fc1ncnc(F)c1F
Reactant: CC#CCO
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC#CCOc1ncnc(F)c1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 75.7 %

Procedure:
0.5 g of 4,5,6-trifluoropyrimidine, 0.31 g of 2-butyn-1-ol and 0.62 ml of N,N-diisopropylethylamine were added to 1 ml of tetrahydrofuran, then the mixture was stirred at room temperature for 1 hour. Then the reaction mixture was subjected to silica gel column chromatography to obtain 0.52 g of 4-(2-butynyloxy)-5,6-difluoropyrimidine.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[CH2:4][C:5]1[C:9]2[CH:10]=[C:11](Br)[C:12]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=3[Cl:23])=[CH:13][C:8]=2[O:7][CH:6]=1.[C:26]([O-])([O-])=O.[Na+].[Na+].CB(O)O>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:1][O:2][C:3](=[O:25])[CH2:4][C:5]1[C:9]2[CH:10]=[C:11]([CH3:26])[C:12]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=3[Cl:23])=[CH:13][C:8]=2[O:7][CH:6]=1
Reactant: COC(=O)Cc1coc2cc(OCc3ccc(Cl)cc3Cl)c(Br)cc12
Reactant: O=C([O-])[O-]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CB(O)O
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: COC(=O)Cc1coc2cc(OCc3ccc(Cl)cc3Cl)c(C)cc12
Temperature: 80 °C
Reaction time: 7 h

Procedure:
To the mixture of methyl(5-bromo-6-((2,4-dichlorobenzyl)oxy)-1-benzofuran-3-yl)acetate (166 mg), aqueous 2M Na2CO3 (0.561 mL) and methylboronic acid (44.7 mg) in DME (3.7 mL) was added Pd(Ph3P)4 (43.2 mg). The mixture was stirred at 80° C. for 7 h. To the mixture was added methylboronic acid (44.8 mg) again. The mixture was stirred at 80° C. under nitrogen atmosphere over weekend. The mixture was diluted with water and extracted with EtOAc. The organic layer was washed with brine, dried over MgSO4, and concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc/hexane) to give the title compound (45.0 mg).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][O:9][CH:10]2[CH:15]3[O:16][C:17]4[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH3:25])[C:18]=4[O:19][CH:14]3[CH2:13][CH2:12][CH2:11]2)[CH2:3][CH2:2]1.[CH3:26][Br:27]>>[Br-:27].[CH3:25][O:24][C:20]1[C:18]2[O:19][CH:14]3[CH2:13][CH2:12][CH2:11][CH:10]([O:9][CH2:8][CH2:7][N+:4]4([CH3:26])[CH2:5][CH2:6][O:1][CH2:2][CH2:3]4)[CH:15]3[O:16][C:17]=2[CH:23]=[CH:22][CH:21]=1
Reactant: COc1cccc2c1OC1CCCC(OCCN3CCOCC3)C1O2
Reactant: CBr
Product: COc1cccc2c1OC1CCCC(OCC[N+]3(C)CCOCC3)C1O2
Product: [Br-]

Procedure:
Following the same procedure as in Example 8, 3.5 g (0.01 mole) of the amino ether of Example 4 were used at the start to obtain, after the action of methyl bromide, 3.3 g of the title-product of melting point 167.1° C., having the elementary analysis:
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[C:8]([CH3:10])[C:5]([C:6]#[N:7])=[C:4]([Cl:11])[N:3]=1.CN(C=O)C.[H-].[Na+].[F:19][C:20]1([F:35])[O:24][C:23]2[CH:25]=[CH:26][C:27]([C:29]3([C:32](Cl)=[O:33])[CH2:31][CH2:30]3)=[CH:28][C:22]=2[O:21]1>O1CCCC1.O>[Cl:11][C:4]1[N:3]=[C:2]([NH:1][C:32]([C:29]2([C:27]3[CH:26]=[CH:25][C:23]4[O:24][C:20]([F:35])([F:19])[O:21][C:22]=4[CH:28]=3)[CH2:31][CH2:30]2)=[O:33])[CH:9]=[C:8]([CH3:10])[C:5]=1[C:6]#[N:7]
Reactant: Cc1cc(N)nc(Cl)c1C#N
Reactant: O=C(Cl)C1(c2ccc3c(c2)OC(F)(F)O3)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(NC(=O)C2(c3ccc4c(c3)OC(F)(F)O4)CC2)nc(Cl)c1C#N
Reaction time: 0.08 h
Yield: 100.2 %

Procedure:
6-Amino-2-chloro-4-methylnicotinonitrile (252 mg, 1.50 mmol) was dissolved in a mixture of anhydrous N,N′ dimtheylformamide (DMF, 0.5 mL) and anhydrous tetrahydrofuran (THF, 4.5 mL). The reaction tube was placed in a beaker full of room temperature water to help maintain the reaction temperature. Sodium hydride (84.23 mg, 2.106 mmol, 60% by weight in mineral oil) was added and the resulting suspension was allowed to stir for 5 minutes. 1-(2,2-Difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarbonyl chloride (392.0 mg, 1.5 mmol) was added and the reaction mixture turned dark red. The crude material was evaporated to dryness, re-dissolved in a minimum of dichloromethane, and purified on 12 g of silica utilizing a gradient of 0-50% ethyl acetate in hexanes to yield the pure product as a pale yellow solid (0.589 g, 63%). ESI-MS m/z calc. 391.0. found 392.0 (M+1)+. Retention time 2.06 minutes.
Reaction SMILES: [S:1](=[O:4])([OH:3])[O-:2].[NH4+:5].[S:6]([O-])([O-:8])=[O:7]>>[S:1]([O-:7])([O-:3])(=[O:2])=[O:4].[NH4+:5].[NH4+:5].[S:6](=[O:8])=[O:7]
Reactant: O=S([O-])O
Reactant: O=S([O-])[O-]
Agent: [NH4+]
Product: O=S(=O)([O-])[O-]
Product: O=S=O

Procedure:
reacting at least a portion of the solution obtained in step (a) with ammonium bisulfite, so as to decompose the ammonium bisulfite and sulfite and to obtain ammonium sulfate as an aqueous solution and gaseous sulfur dioxide;
Reaction SMILES: CO[C:3]([C:5]1[O:9][N:8]=[C:7]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH:17]([C:34]([O:36]C(C)(C)C)=[O:35])[NH:18][C:19]([C:21]3[CH:22]=[C:23]([C:27]4[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=4)[CH:24]=[CH:25][CH:26]=3)=[O:20])=[CH:12][C:11]=2[F:41])[N:6]=1)=[O:4].C(OC(=O)[CH:48]([NH:61][C:62]([C:64]1[CH:65]=[C:66](C2C=CC(C)=CC=2)C=CC=1)=O)[CH2:49]C1C=CC(C(O)=NO)=C(F)C=1)(C)(C)C.COC(C(Cl)=O)=O.C([O-])(O)=O.[Na+]>C1(C)C=CC=CC=1.N1C=CC=CC=1>[F:41][C:11]1[CH:12]=[C:13]([CH2:16][CH:17]([NH:18][C:19]([C:21]2[CH:22]=[C:23]([C:27]3[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=3)[CH:24]=[CH:25][CH:26]=2)=[O:20])[C:34]([OH:36])=[O:35])[CH:14]=[CH:15][C:10]=1[C:7]1[N:6]=[C:5]([C:3]([N:61]2[CH2:48][CH2:49][CH:65]([CH3:66])[CH2:64][CH2:62]2)=[O:4])[O:9][N:8]=1
Reactant: Cc1ccc(-c2cccc(C(=O)NC(Cc3ccc(C(O)=NO)c(F)c3)C(=O)OC(C)(C)C)c2)cc1
Reactant: COC(=O)c1nc(-c2ccc(CC(NC(=O)c3cccc(-c4ccc(C)cc4)c3)C(=O)OC(C)(C)C)cc2F)no1
Agent: COC(=O)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: Cc1ccc(-c2cccc(C(=O)NC(Cc3ccc(-c4noc(C(=O)N5CCC(C)CC5)n4)c(F)c3)C(=O)O)c2)cc1
Yield: 64 %

Procedure:
3-(4-{2-tert-Butoxycarbonyl-2-[(4′-methyl-biphenyl-3-carbonyl)-amino]-ethyl}-2-fluoro-phenyl)-[1,2,4]oxadiazole-5-carboxylic acid methyl ester. A mixture of 3-[3-fluoro-4-(hydroxy-hydroxyimino-methyl)-phenyl]-2-[(4′-methyl-biphenyl-3-carbonyl)-amino]-propionic acid tert-butyl ester (10 g, 0.02 mol) and methyl(chlorocarbonyl)formate (5 g, 0.04 mol), and pyridine (1 mL) in toluene (150 mL) was refluxed overnight. TLC showed the reaction was completed. An aqueous NaHCO3 solution (80 mL) was added to the reaction mixture, the layers were separated, and the aqueous portion was extracted with ethyl acetate (2×100 mL). The combined organic layers were washed with brine (2×30 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by chromatography and recrystallization to give the title compound (7 g, 64% yield) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([NH:11][C:12]2[CH:17]=[CH:16][C:15](C)=[CH:14][C:13]=2[N+:19]([O-])=O)[N:4]=1.[C:22](O)(=O)C>C(OCC)(=O)C.O.[Fe]>[CH3:10][O:9][C:7]1[N:8]=[C:3]([O:2][CH3:1])[N:4]=[C:5]([NH:11][C:12]2[C:13]([NH2:19])=[CH:14][CH:15]=[C:16]([CH3:22])[CH:17]=2)[N:6]=1
Reactant: COc1nc(Nc2ccc(C)cc2[N+](=O)[O-])nc(OC)n1
Reactant: CC(=O)O
Agent: [Fe]
Solvent: O
Solvent: CCOC(C)=O
Product: COc1nc(Nc2cc(C)ccc2N)nc(OC)n1

Procedure:
N-(4,6-dimethoxy-[1,3,5]triazin-2-yl)-4-methyl-2-nitroaniline (10 g) was dissolved in ethyl acetate (50 ml) and water (50 ml), and 10 g of iron power and acetic acid (2 ml) were added thereto, followed by reflux for 2 hours. Insoluble matters were removed by filtration, and the ethyl acetate layer was washed with a saturated sodium chloride aqueous solution and dried over anhydrous magnesium sulfate. The solvent was distilled off to obtain 8.8 g of the desired product as a white powder (m.p. 180-183° C.)
Reaction SMILES: Br[CH2:2][CH2:3][C:4]([OH:6])=[O:5].[SH:7][C:8]1[O:9][C:10]2[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=2[N:12]=1.[OH-].[K+]>C(O)C>[O:9]1[C:10]2[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=2[N:12]=[C:8]1[S:7][CH2:2][CH2:3][C:4]([OH:6])=[O:5]
Reactant: O=C(O)CCBr
Reactant: Sc1nc2ccccc2o1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)CCSc1nc2ccccc2o1
Yield: 58.2 %

Procedure:
Ethanol (EtOH) (35 ml), 3-bromopropanoic acid (1.53 g, 10 mmols) and 2-mercaptobenzoxazole (1.51 g, 10mmols) were added in that order to an aqueous (15 ml) solution of potassium hydroxide (KOH) (1.0 g, 17.8 mmols), and heated under reflux for 3 hours. The reaction mixture was concentrated under reduced pressure, water was added to the resulting residue, and this was made acidic (pH=1) with 1N HCl added thereto. The precipitate formed was taken out through filtration, and crystallized in acetone-ether-hexane to obtain 1.3 g (58%) of 3-(benzoxazol-2-ylthio)propanoic acid as colorless crystals.