Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][C:7]2[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=2[CH2:9]Cl)=[CH:4][CH:3]=1.[C-:17]#[N:18].[Na+]>CS(C)=O>[F:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][C:7]2[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=2[CH2:9][C:17]#[N:18])=[CH:4][CH:3]=1
Reactant: [C-]#N
Reactant: Fc1ccc(Oc2ccccc2CCl)cc1
Agent: [Na+]
Solvent: CS(C)=O
Product: N#CCc1ccccc1Oc1ccc(F)cc1
Temperature: 0 °C
Reaction time: 26 h

Procedure:
12.0 g of 2-(4-fluorophenoxy)benzyl chloride are added portionwise over a 30 minute span to a mixture of 2.9 g of sodium cyanide in 120 ml of dimethylsulfoxide. After total addition, the reaction mixture is stirred for 26 hours before being poured onto 150-200 ml of crushed ice. The mixture is extracted four times with 70 ml portions of ether and the combined ether extracts are successively washed four times with 50 ml portions of water, washed once with 25 ml of saturated sodium chloride solution and dried, providing a clear oil. The oil is distilled at 128.5° C. and 0.1 mm to provide 2-(4-fluorophenoxy)benzyl cyanide.
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5].C(N(CC)CC)C.[Cl:27][C:28]([Cl:33])([Cl:32])[C:29](Cl)=[O:30].O>C(Cl)(Cl)Cl>[C:4]([C:3]1[CH:12]=[C:13]([C:16]([F:17])([F:18])[F:19])[CH:14]=[CH:15][C:2]=1[NH:1][C:29](=[O:30])[C:28]([Cl:33])([Cl:32])[Cl:27])(=[O:5])[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Reactant: Nc1ccc(C(F)(F)F)cc1C(=O)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Solvent: O
Product: O=C(c1ccccc1)c1cc(C(F)(F)F)ccc1NC(=O)C(Cl)(Cl)Cl
Reaction time: 0.5 h
Yield: 91.6 %

Procedure:
To a solution of 762 mg of 2-amino-5-trifluoromethylbenzophenone in 10 ml of chloroform was added dropwise 349 mg of triethylamine, and then 627 mg of trichloroacetyl chloride was added dropwise under ice cooling. After stirring at the same temperature for 30 minutes, 50 ml of water was added, thereby separating layers. The organic layer was collected and concentrated. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=5:1) to obtain 1.08 g of 2′-benzoyl-2,2,2-trichloro-4′-trifluoromethylacetanilide. 1H NMR (CDCl3): 7.53-7.58 (2H, m), 7.66-7.75 (3H, m), 7.90-7.95 (2H, m), 8.81 (1H, d, J=8.6 Hz), 12.38 (1H, br. s).
Reaction SMILES: Cl[C:2]1[N:3]([CH2:10][C:11]2([CH3:14])[CH2:13][O:12]2)[CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1.[F:15][C:16]([F:32])([F:31])[C:17]1[CH:30]=[CH:29][C:20]([C:21]([CH:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)=[O:22])=[CH:19][CH:18]=1.C([O-])(=O)C.[Na+].CN(C=O)C>O>[CH3:14][C:11]1([CH2:13][N:26]2[CH2:25][CH2:24][CH:23]([C:21](=[O:22])[C:20]3[CH:29]=[CH:30][C:17]([C:16]([F:31])([F:32])[F:15])=[CH:18][CH:19]=3)[CH2:28][CH2:27]2)[O:12][C:2]2=[N:6][C:5]([N+:7]([O-:9])=[O:8])=[CH:4][N:3]2[CH2:10]1
Reactant: O=C(c1ccc(C(F)(F)F)cc1)C1CCNCC1
Reactant: CC1(Cn2cc([N+](=O)[O-])nc2Cl)CO1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC1(CN2CCC(C(=O)c3ccc(C(F)(F)F)cc3)CC2)Cn2cc([N+](=O)[O-])nc2O1
Temperature: 80 °C
Reaction time: 8 h
Yield: 28.4 %

Procedure:
A mixture of 2-chloro-1-(2-methyloxiran-2-ylmethyl)-4-nitroimidazole prepared in Example 6 (80 mg, 0.37 mmol), 4-(4-trifluoromethylbenzoyl)piperidine (95 mg, 0.37 mmol), sodium acetate (150 mg, 1.83 mmol) and DMF (2 ml) was stirred at 80° C. overnight. The reaction mixture was poured into water, and extracted with ethyl acetate twice. The organic phases were combined, washed with water three times, washed with a saturated saline solution, dried over sodium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/n-hexane=1/1) to afford 2-methyl-6-nitro-2-[4-(4-trifluoromethylbenzoyl)piperidin-1-yl]methyl-2,3-dihydroimidazo[2,1-b]oxazole (46 mg, yield 29%) as a white powder.
Reaction SMILES: [OH-].[Na+].[CH3:3][O:4][C:5]1[CH:19]=[CH:18][C:8]([CH2:9][NH:10][C:11](=[O:17])[C@@H:12](Br)[C@H:13]([OH:15])[CH3:14])=[CH:7][CH:6]=1>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.C(Cl)Cl>[CH3:3][O:4][C:5]1[CH:19]=[CH:18][C:8]([CH2:9][NH:10][C:11](=[O:17])[C@@H:12]2[O:15][C@@H:13]2[CH3:14])=[CH:7][CH:6]=1
Reactant: COc1ccc(CNC(=O)[C@@H](Br)[C@@H](C)O)cc1
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Product: COc1ccc(CNC(=O)[C@@H]2O[C@@H]2C)cc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
50 ml of 50% NaOH solution and 456 mg (2 mmol) of benzyltriethylammonium chloride are added to a solution of 6.04 g (20 mmol) of (2S,3R)-2-bromo-3-hydroxybutyric acid p-methoxybenzylamide in 150 ml of methylene chloride. The two-phase mixture is stirred vigorously for 20 hours at room temperature. The organic layer is separated off and the aqueous phase is then extracted with methylene chloride. The combined methylene chloride solutions are dried and concentrated by evaporation. The resulting crude product is chromatographed over 40 times its weight of silica gel in the system methylene chloride/methanol (99:1). After crystallisation of the pure fractions from methylene chloride/diethyl ether/petroleum ether, the title compound, melting point 75°-76°, is obtained.
Reaction SMILES: [C:1]([N:4]([CH3:20])[C:5]1[N:10]=[CH:9][C:8]([NH:11][C:12](=[O:19])OCC(Cl)(Cl)Cl)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[C:21]1([C:27]2[N:31]=[C:30]([N:32]3[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]3)[S:29][N:28]=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(N(C(C)C)CC)(C)C.CS(C)=O>O>[C:1]([N:4]([CH3:20])[C:5]1[N:10]=[CH:9][C:8]([NH:11][C:12]([N:35]2[CH2:36][CH2:37][N:32]([C:30]3[S:29][N:28]=[C:27]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[N:31]=3)[CH2:33][CH2:34]2)=[O:19])=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: c1ccc(-c2nsc(N3CCNCC3)n2)cc1
Reactant: CC(=O)N(C)c1ccc(NC(=O)OCC(Cl)(Cl)Cl)cn1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CS(C)=O
Product: CC(=O)N(C)c1ccc(NC(=O)N2CCN(c3nc(-c4ccccc4)ns3)CC2)cn1
Yield: 39.3 %

Procedure:
A solution of 2,2,2-trichloroethyl {6-[acetyl(methyl)amino]pyridin-3-yl}carbamate (200 mg, 0.587 mmol), 1-(3-phenyl-1,2,4-thiadiazol-5-yl)piperazine (145 mg, 0.587 mmol), diisopropylethylamine (0.102 ml, 0.587 mmol) and dimethylsulfoxide (4 ml) was stirred at 70° C. for 12 hours, the reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was recrystallized from a mixed solvent of ethyl acetate and hexane to obtain the desired product (101 mg, 39.3%) as a solid.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[N:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)[CH:6]=1.O.[OH-].[Na+]>C(O)(=O)C>[N+:1]([C:13]1[CH:12]=[C:11]([C:7]2[CH:6]=[N:5][CH:10]=[CH:9][CH:8]=2)[CH:16]=[CH:15][C:14]=1[OH:17])([O-:4])=[O:2]
Reactant: O=[N+]([O-])O
Reactant: Oc1ccc(-c2cccnc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: O=[N+]([O-])c1cc(-c2cccnc2)ccc1O
Temperature: 60 °C
Yield: 43.4 %

Procedure:
Nitric acid (60 μL, 1.0 mmol) was added to a solution of 4-pyridin-3-yl-phenol (164 mg, 0.96 mmol) in acetic acid (2.8 mL). The mixture was heated at 60° C. for 30 min and the solution turned orange/brown in color. Upon cooling, water was added (3 mL) and 6 N NaOH (aq) was added until the solution was basic. The solution was extracted with ethyl acetate (3×) and then the aqueous phase was concentrated. The crude residue was washed with boiling methanol to afford 90 mg (43%) of 2-nitro4-pyridin-3yl-phenol as an orange solid: mp>300° C., MS (Cl) m/z 217.1 (M+1).
Reaction SMILES: Cl[CH2:2][C:3]1[N:12]2[CH:13]=[N:14][N:15]=[C:11]2[C:10]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[N:4]=1.[O:16]1CCOCC1.[OH-].[Na+].Cl>CC(C)=O>[N:12]1[CH:13]=[N:14][N:15]2[C:11]=1[C:10]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:4][C:3](=[O:16])[CH2:2]2
Reactant: C1COCCO1
Reactant: ClCc1nc2ccccc2c2nncn12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Product: O=C1Cn2ncnc2-c2ccccc2N1
Temperature: 5 °C
Reaction time: 17 h

Procedure:
4.1. 77 g of 5-(chloromethyl)-1,2,4-triazolo[4,3-c]quinazoline are suspended in 2.0 l of acetone (or dioxan) and cooled to 5° C. 410 ml of 1N sodium hydroxide solution are added in such a manner that the temperature rises to about 13° C. The mixture is stirred at room temperature for 17 h. The reaction mixture is then made slightly acidic (pH 6) with 3N hydrochloric acid and concentrated in a vacuum. The crystalline precipitate is filtered off, washed and dried. There are obtained 65 g of crude 5H-[1,2,4]triazolo[1,5-d][1,4]benzodiazepin-6(7H)-one. The filtrate is saturated with sodium chloride and extracted 3 times with 0.51 of dichloromethane each time. The organic phases are evaporated in a vacuum. 12 g of crude 5H-[1,2,4]triazolo[1,5-d][1,4]benzodiazepin-6(7H)-one are obtained. Both crude crystallizates (77 g) are dissolved together in 5 l of dichloromethane and 250 ml of ethanol at reflux temperature. A small insoluble constituent is separated by filtration, the filtrate is cooled to room temperature and filtered through a column of 1500 g of silica gel. The column is rinsed with a mixture of 5.7 l of dichloromethane and 0.3 l of ethanol. After concentrating all eluates, there are obtained 62 g of yellow crystals. These are stirred at reflux temperature as a suspension in 600 ml of ethyl acetate and then cooled to 0° C. The crystals are filtered off, washed with diethyl ether and dried. There are obtained 51 g of 5H-[1,2,4]triazolo[1,5-d][1,4]benzodiazepin-6(7H)-one of m.p. 223°-223° C.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][NH2:11])=[CH:6][CH:5]=1.O.O.O.C([O-])(=O)C.[Na+].[C:20](OCC)(=[O:25])[CH2:21][C:22]([CH3:24])=O>C(O)C>[CH3:24][C:22]1[CH2:21][C:20](=[O:25])[N:10]([C:7]2[CH:8]=[CH:9][C:4]([O:3][CH3:2])=[CH:5][CH:6]=2)[N:11]=1
Reactant: COc1ccc(NN)cc1
Reactant: CCOC(=O)CC(C)=O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: COc1ccc(N2N=C(C)CC2=O)cc1
Yield: 42.8 %

Procedure:
4-Methoxy-phenylhydrazine hydrochloride (5.6 g, 32 mmol; product of Aldrich Chem. Co.), sodium acetate trihydrate (5.45 g, 40 mmol; product of Kishida Chemicals) and ethyl acetoacetate (4.16 g, 32 mmol; product of Kishida Chemicals) were dissolved in 40 ml ethanol, and the solution was heated under reflux for two hours to complete the reaction. After cooling, the solvent was distilled off from the reaction mixture under reduced pressure, 40 ml ethanol was added to the residue, and the insoluble matters were removed by filtration. The filtrate was concentrated to dryness under reduced pressure, the residue was dissolved in a small volume of a solvent mixture of benzene and ethyl acetate (4:1), and the solution was subjected to silica gel chromatography (150 g of Silica Gel 60; product of Merck) Elution was performed by using a solvent mixture of benzene and ethyl acetate (4:1), the eluate was concentrated to dryness under reduced pressure, and the residue was recrystallized with methanol, giving 2.80 g (yield: 42.9%) of PMPMP. Its structure was confirmed by 1H NMR and 13C NMR. The spectra thus obtained are shown in Table 1 below.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([N:9]2[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]2)=[C:6]([F:8])[CH:7]=1.N1C=CC=CC=1.Cl[C:22]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23].C(=O)(O)[O-].[Na+]>ClCCl>[CH2:25]([O:24][C:22]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([N:9]2[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]2)=[C:6]([F:8])[CH:7]=1)=[O:23])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: Cc1cn(-c2ccc(N)cc2F)cn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1cn(-c2ccc(NC(=O)OCc3ccccc3)cc2F)cn1
Reaction time: 16 h
Yield: 92.9 %

Procedure:
5-Amino-2-(4-methylimidazol-1-yl)fluorobenzene (50.6 g, 0.265 M) was dissolved in dry dichloromethane (800 ml) under nitrogen, and cooled to −5°. Pyridine (26.1 g, 0.33 M) was added, followed by benzyl chloroformate (49.9 g, 0.292 M) over 30 minutes. The mixture was stirred and the temperature allowed to rise to ambient over 16 hours. Aqueous sodium bicarbonate (5%, 350 ml) was added, the organic layer separated, and the aqueous layer re-extracted with dichloromethane (2×200 ml), and combined organics dried (magnesium sulfate). After filtration and evaporation, the residue was recrystallised from toluene (300 ml) to give title product (80 g). NMR (DMSO-d6) δ: 2.15 (s, 3H); 5.16 (s, 2H); 7.13 (s, 1H); 7.31 (dd, 1H); 7.41 (m, 5H); 7.48 (t, 1H); 7.57 (dd, 1H); 7.78 (s, 1H); 10.15 (br s, 1H). MS (ESP): 326 (MH+) for C18H16FN3O2
Reaction SMILES: Br[CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([N+:10]([O-:12])=[O:11])[CH:5]=1.[CH2:13]([N:15](CC)[CH2:16]C)C.CNC>C(#N)C>[CH3:13][N:15]([CH3:16])[CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([N+:10]([O-:12])=[O:11])[CH:5]=1
Reactant: CCN(CC)CC
Reactant: O=[N+]([O-])c1cccc(CCBr)c1
Agent: CNC
Solvent: CC#N
Product: CN(C)CCc1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
In a 250 mL round bottom flask was charged 1-(2-bromoethyl)-3-nitrobenzene (10 g, 43.5 mmol) and acetonitrile (36 mL). The suspension was treated with triethylamine (18.1 mL, 130 mmol) and dimethylamine (2 M in tetrahydrofuran, 65.2 mL, 130 mmol). The resulting mixture was stirred at ambient temperature for 48 hours. The mixture was concentrated. The residual solid was partitioned between ethyl acetate (130 mL) and 60 ml saturated aqueous sodium bicarbonate. The aqueous layer was washed with ethyl acetate (75 mL). The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated. The concentrate was purified by flash chromatography on an 80 g silica gel column using an AnaLogix IntelliFlash 280 system eluting with a gradient of from 0% to 7% methanol in CH2Cl2 to provide the title compound. MS (DCI(+)) m/e 195.1 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7](I)[C:8]2[C:9](=[O:23])[N:10]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:11]=[CH:12][C:13]=2[C:14]=1[OH:15])=[O:4].[F:25][C:26]1[CH:27]=[C:28](B(O)O)[CH:29]=[N:30][CH:31]=1.C([O-])([O-])=O.[Cs+].[Cs+].Cl>CN(C=O)C.[Cl-].[Na+].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.CCOC(C)=O>[CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7]([C:28]2[CH:29]=[N:30][CH:31]=[C:26]([F:25])[CH:27]=2)[C:8]2[C:9](=[O:23])[N:10]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:11]=[CH:12][C:13]=2[C:14]=1[OH:15])=[O:4]
Reactant: COC(=O)c1nc(I)c2c(=O)n(Cc3ccccc3)ccc2c1O
Reactant: OB(O)c1cncc(F)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)c1nc(-c2cncc(F)c2)c2c(=O)n(Cc3ccccc3)ccc2c1O
Temperature: 100 °C
Yield: 55.7 %

Procedure:
A mixture of 7-benzyl-4-hydroxy-1-iodo-8-oxo-7,8-dihydro-[2,7]naphthyridine-3-carboxylic acid methyl ester (117 mg, 0.27 mmol), 5-fluoropyridine-3-boronic acid (45 mg, 0.32 mmol), Cs2CO3 (175 mg, 0.54 mmol) and Pd(PPh3)4 (31 mg, 0.027 mmol) in 5 mL of DMF was heated at 100° C. for 16 h under N2 atmosphere. After the mixture was cooled to r.t., EtOAc (50 mL) and brine (10 mL) were added. 1 M HCl was added with stirring until pH was about 4. The aqueous layer was extracted with additional EtOAc, and the combined organic layer was dried over MgSO4 and concentrated. The crude product was purified by silica gel chromatography (5-70% EtOAc/hexanes) to give 61 mg of the title compound. MS: (+) m/z 405.97 (M+1).
Reaction SMILES: [C:1]([CH:6]1[CH2:11][S:10][CH2:9][CH2:8][NH:7]1)([O:3][CH2:4][CH3:5])=[O:2].[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([N:19]=[C:20]=[O:21])=[CH:15][CH:14]=1>C(N(CC)CC)C>[C:1]([CH:6]1[CH2:11][S:10][CH2:9][CH2:8][N:7]1[C:20]([NH:19][C:16]1[CH:17]=[CH:18][C:13]([Cl:12])=[CH:14][CH:15]=1)=[O:21])([O:3][CH2:4][CH3:5])=[O:2]
Reactant: O=C=Nc1ccc(Cl)cc1
Reactant: CCOC(=O)C1CSCCN1
Solvent: CCN(CC)CC
Product: CCOC(=O)C1CSCCN1C(=O)Nc1ccc(Cl)cc1
Temperature: 25 °C
Yield: 30.5 %

Procedure:
Seven grams of 3-carbethoxythiomorpholine and 6.5 g of 4-chlorophenyl isocyanate were added to 60 ml of hexanes containing 10 drops of triethylamine as a catalyst. A mild exothermic reaction took place as the reactants mixed. After the mixture cooled to room temperature, the precipitate was collected by filtration and recrystallized from a mixture of methylene chloride and ether to give 4 g of 3-carbethoxy-4-(4-chlorophenylaminocarbonyl)thiomorpholine, mp 152.5°-154.5° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[CH:4][C:3]=1[Cl:13].[Br:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[N:21]=[C:22]=[O:23]>C1COCC1>[Br:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[NH:21][C:22](=[O:23])[NH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[CH:4][C:3]=1[Cl:13]
Reactant: O=C=Nc1ccccc1Br
Reactant: COC(=O)Cc1ccc(N)c(Cl)c1
Solvent: C1CCOC1
Product: COC(=O)Cc1ccc(NC(=O)Nc2ccccc2Br)c(Cl)c1
Reaction time: 24 h
Yield: 67.3 %

Procedure:
To a mixture of methyl 4-amino-3-chlorophenylacetate (1.00 g, 5.01 mmol) and 2-bromophenyl isocyanate (0.62 ml, 5.01 mmol) in THF (20 ml) was added Et3 N (0.14 ml, 1.00 mmol) at room temperature. After 1 day stirring, 2-bromophenyl isocyanate (0.60 ml, 5.01 mmol) was added to the reaction mixture and stirred 24 h. The reaction mixture was concentrated in vacuo. The residue was triturated by the addition of n-hexane to give methyl 4-[N′-(2-bromophenyl)ureido]-3-chlorophenylacetate (1.34 g, 67%) as a colorless powder. 1H-NMR (CDCl3) δ 3.58 (s, 3H), 3.70 (s, 2H), 6.98 (m, 3H), 7.19 (dd, J=8.3, 1.9 Hz, 1H), 7.32 (m, 1H), 7.51 (m, 2H), 8:05 (m, 1H); MS (ESI) m/z 398 (M++1), 400 (M++3), 402 (M++5).
Reaction SMILES: N1C=CC=CC=1.[O:7]([Si:15]([CH3:18])([CH3:17])[CH3:16])S(C(F)(F)F)(=O)=O.[CH2:19]([C:21](O)([CH2:52][CH3:53])[C:22]#[C:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]([CH2:49][CH3:50])([C:33]2[CH:38]=[CH:37][C:36]([B:39]3[O:43][C:42]([CH3:45])([CH3:44])[C:41]([CH3:47])([CH3:46])[O:40]3)=[C:35]([CH3:48])[CH:34]=2)[CH2:31][CH3:32])=[CH:26][C:25]=1[CH3:51])[CH3:20].C(=O)(O)[O-].[Na+]>ClCCl>[CH2:31]([C:30]([C:33]1[CH:38]=[CH:37][C:36]([B:39]2[O:40][C:41]([CH3:46])([CH3:47])[C:42]([CH3:45])([CH3:44])[O:43]2)=[C:35]([CH3:48])[CH:34]=1)([C:27]1[CH:28]=[CH:29][C:24]([C:23]#[C:22][C:21]([CH2:19][CH3:20])([O:7][Si:15]([CH3:18])([CH3:17])[CH3:16])[CH2:52][CH3:53])=[C:25]([CH3:51])[CH:26]=1)[CH2:49][CH3:50])[CH3:32]
Reactant: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Reactant: CCC(O)(C#Cc1ccc(C(CC)(CC)c2ccc(B3OC(C)(C)C(C)(C)O3)c(C)c2)cc1C)CC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCC(C#Cc1ccc(C(CC)(CC)c2ccc(B3OC(C)(C)C(C)(C)O3)c(C)c2)cc1C)(CC)O[Si](C)(C)C
Reaction time: 1 h
Yield: 78.7 %

Procedure:
Pyridine (0.116 mL, 1.432 mmol) and trimethylsilyl triflate (0.129 mL, 0.716 mmol) were added to a solution of 3-ethyl-1-(4-{1-ethyl-1-[3-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-propyl}-2-methyl-phenyl)-1-pentyn-3-ol (Example 125-(2); 175 mg, 0.358 mmol) in dichloromethane (5 mL) at 0° C., and the mixture was stirred for one hour. The reaction mixture was then poured into a saturated aqueous sodium bicarbonate solution, followed by extraction with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (hexane:ethyl acetate=100:0 to 70:30) to give the target compound as a colorless oil (158 mg, 79%).
Reaction SMILES: CS([Cl:5])(=O)=O.[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][C:16]([NH:19][C:20](=[O:31])[CH2:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([CH2:29]O)=[CH:25][CH:24]=3)=[CH:15][CH:14]=2)=[CH:9][CH:8]=1.C(N(CC)CC)C>ClCCl>[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][C:16]([NH:19][C:20](=[O:31])[CH2:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([CH2:29][Cl:5])=[CH:25][CH:24]=3)=[CH:15][CH:14]=2)=[CH:9][CH:8]=1
Reactant: CS(=O)(=O)Cl
Reactant: O=C(CCc1ccc(CO)cc1)Nc1ccc(-c2ccc(Cl)cc2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(CCc1ccc(CCl)cc1)Nc1ccc(-c2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
0.43 mL (5.6 mmol) of methanesulfonic acid chloride is slowly added dropwise at ambient temperature to a solution of 2 g (5.47 mmol) of N-(4′-chlorobiphenyl-4-yl)-3-(4-hydroxymethylphenyl)propionamide and 1.56 mL (11.2 mmol) of triethylamine in 50 mL of dichloromethane and the reaction mixture is stirred for 24 hours at ambient temperature. It is extracted with water and the organic phase is dried over sodium sulfate. The solvent is distilled off and the residue is stirred with diisopropyl ether and suction filtered. Yield: 1.45 g (69% of theory); C22H19Cl2NO (M=384.3); calc.: molecular ion peak (M+H)+: 384/86/88 (Cl2) Found: molecular ion peak (M+H)+: 384/86/88 (Cl2); Rf value: 0.45 (silica gel, dichloromethane/ethanol (50:1)).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].Br[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.C1(C)C=CC=CC=1>[CH2:14]([O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: O=Cc1ccc(O)c([N+](=O)[O-])c1
Reactant: CCCCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: CCCCCCCCOc1ccc(C=O)cc1[N+](=O)[O-]

Procedure:
A mixture of 4-hydroxy-3-nitrobenzaldehyde (10.0 g, 81.8 mmol), 1-bromooctane (15.8 mmol, 81.8 mmol), and K2CO3 (34.0 g, 0.25 mol) in DMF (150 mL) was heated to reflux for hours. After cooling the reaction back down to room temperature, the reaction mixture was diluted in toluene and the organic layer was washed with 10% HCl, brine, and water. After concentrating in vacuo, the oil was purified by short silica gel plug (10% DCM in n-hexanes). Solvent was dried in vacuo to afford the 4-octyloxy-3-nitrobenzaldehyde as a slightly colored oil.
Reaction SMILES: [CH:1]1([CH:7]([NH:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]([NH:31][CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])=[O:30])=[CH:25][CH:24]=2)[C:8]2[CH:12]=[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[O:10][C:9]=2[CH2:19][S:20][CH3:21])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH:39]OS([O-])=O.[K+]>CO.O>[CH:1]1([CH:7]([NH:22][C:23]2[CH:24]=[CH:25][C:26]([C:29]([NH:31][CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])=[O:30])=[CH:27][CH:28]=2)[C:8]2[CH:12]=[C:11]([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)[O:10][C:9]=2[CH2:19][S:20]([CH3:21])=[O:39])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)CCNC(=O)c1ccc(NC(c2cc(-c3ccccc3)oc2CSC)C2CCCCC2)cc1
Reactant: O=S([O-])OO
Agent: [K+]
Solvent: CO
Solvent: O
Product: CCOC(=O)CCNC(=O)c1ccc(NC(c2cc(-c3ccccc3)oc2CS(C)=O)C2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 71.3 %

Procedure:
Ethyl 3-[({4-[(cyclohexyl{2-[(methylsulfanyl)methyl]-5-phenylfuran-3-yl}methyl)amino]phenyl}carbonyl)amino]propanoate (267 mg) was dissolved in methanol (9 mL) and water (1 mL), OXONE (277 mg) was added, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (40% ethyl acetate/hexane to 100% ethyl acetate/hexane) to give the title compound (196 mg, 79%) as an amorphous compound.