Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:8]1([OH:26])[CH2:13][CH2:12][N:11]([C:14]([C:16]2[C:24]3[O:23][CH2:22][O:21][C:20]=3[CH:19]=[CH:18][C:17]=2Br)=[O:15])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:27]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][CH:28]=1.C(=O)([O-])[O-].[Na+].[Na+].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>[CH2:1]([C:8]1([OH:26])[CH2:13][CH2:12][N:11]([C:14]([C:16]2[C:24]3[O:23][CH2:22][O:21][C:20]=3[CH:19]=[CH:18][C:17]=2[C:30]2[CH:31]=[CH:32][N:27]=[CH:28][CH:29]=2)=[O:15])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(c1c(Br)ccc2c1OCO2)N1CCC(O)(Cc2ccccc2)CC1
Reactant: OB(O)c1ccncc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: O=C(c1c(-c2ccncc2)ccc2c1OCO2)N1CCC(O)(Cc2ccccc2)CC1
Temperature: 150 °C
Reaction time: 1 h
Yield: 170.7 %

Procedure:
A mixture of (4-benzyl-4-hydroxypiperidin-1-yl) (5-bromo-1,3-benzodioxol-4-yl)methanone (0.50 g), pyridine-4-boronic acid (0.22 g), sodium carbonate (0.38 g), tetrakis(triphenylphosphine)palladium(0) (0.069 g), water (0.50 mL) and DME (2.5 mL) was stirred at 150° C. for 1 hr under microwave irradiation. The reaction mixture was diluted with water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane) to give the title compound (0.85 g).
Reaction SMILES: [C:1]([C:3]1[CH:12]=[CH:11][C:6]2[NH:7][C:8]([SH:10])=[N:9][C:5]=2[CH:4]=1)#[N:2].[CH3:13][O:14][C:15](=[O:24])[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22]Br)[CH:17]=1.C([O-])([O-])=O.[K+].[K+]>CC(C)=O.CN(C=O)C>[C:1]([C:3]1[CH:12]=[CH:11][C:6]2[N:7]=[C:8]([S:10][CH2:22][C:18]3[CH:19]=[CH:20][CH:21]=[C:16]([C:15]([O:14][CH3:13])=[O:24])[CH:17]=3)[NH:9][C:5]=2[CH:4]=1)#[N:2]
Reactant: COC(=O)c1cccc(CBr)c1
Reactant: N#Cc1ccc2[nH]c(S)nc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC(C)=O
Product: COC(=O)c1cccc(CSc2nc3ccc(C#N)cc3[nH]2)c1
Yield: 58.8 %

Procedure:
A suspension of 5-cyano-1H-benzoimidazole-2-thiol (35 mg, 0.2 mmol), 3-bromomethyl-benzoic acid methyl ester (46 mg, 0.2 mmol) and K2CO3 (55 mg, 0.4 mmol) in acetone (0.6 ml) and 3 drops of DMF is refluxed for 2 h. It is cooled down and filtered over a short plug of silica gel and rinsed with AcOEt. The solvent is removed under a stream of air. The crude residue is purified by flash chromatography on silica-gel (AcOEt/heptane, 1:2), yielding the title compound (38 mg) in 59% as a yellowish gum: tR=6.14 min (LC-1), ESI-MS (pos.): m/z 324.14 [M+H]+, ESI-MS (neg.): m/z 322.22 [M−H]+; 1H-NMR (CDCl3): δ (ppm) 3.92 (s, 3H, Me), 4.67 (s, 2H, SCH2), 5.29 (s, 1H, NH), 7.36-7.56 (m, 4Harom), 7.65 (d, 1Harom), 7.94 (d, 1Harom), 8.10 (s, 1Harom)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:39]([F:42])([F:41])[F:40])[O:13][N:12]=[C:11]([C:14]3[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[C:17]([C:24]([NH:26][CH2:27][CH2:28][S:29]([CH3:38])(=[N:31]C(=O)C(F)(F)F)=[O:30])=[O:25])=[CH:16][CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.C(=O)([O-])[O-].[K+].[K+]>CO>[Cl:8][C:6]1[CH:5]=[C:4]([C:9]2([C:39]([F:40])([F:42])[F:41])[O:13][N:12]=[C:11]([C:14]3[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[C:17]([C:24]([NH:26][CH2:27][CH2:28][S:29]([CH3:38])(=[NH:31])=[O:30])=[O:25])=[CH:16][CH:15]=3)[CH2:10]2)[CH:3]=[C:2]([Cl:1])[CH:7]=1
Reactant: CS(=O)(CCNC(=O)c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)c2ccccc12)=NC(=O)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CS(=N)(=O)CCNC(=O)c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)c2ccccc12

Procedure:
To a stirred solution of 4-[5-(3,5-dichlorophenyl)-4,5-dihydro-5-(trifluoromethyl)-3-isoxazolyl]-N-[2-[S-methyl-N-(2,2,2-trifluoroacetyl)sulfonimidoyl]ethyl]-1-naphthalene-carboxamide (i.e. the title compound of Example 3) (60 mg) in methanol (4 mL) was added potassium carbonate (230 mg) at room temperature. After stirring for 30 minutes at room temperature, the reaction mixture was filtered through a short pad of silical gel and rinsed with ethyl acetate. After concentration, the residue was purified by column chromatography on silica gel using dichloromethane/methanol (98:2 to 92:8) as eluent to provide the title product, a compound of the present invention, as a white solid (39 mg, 76% yield).
Reaction SMILES: [C:1]([O-:10])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].[Na+].[CH:12]1[C:17](=[O:18])[C:16]([OH:19])=[CH:15][O:14][C:13]=1[CH2:20]Cl.CN(C)C=O>C(OCC)(=O)C>[OH:4][C:3]1[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=1[C:1]([O:10][CH2:20][C:13]1[O:14][CH:15]=[C:16]([OH:19])[C:17](=[O:18])[CH:12]=1)=[O:9]
Reactant: O=c1cc(CCl)occ1O
Reactant: O=C([O-])c1ccccc1O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(OCc1cc(=O)c(O)co1)c1ccccc1O
Temperature: 110 °C
Reaction time: 2 h
Yield: 52.3 %

Procedure:
1 g(6.2 mmole) of sodium salicylate and 0.9 g(15.6 mmole) of chlorokojic acid were dissolved into 70 ml of N,N-dimethylformamide. The resulting solution was heated with stirring for 2 hours in an oil bath of 110° C. After distillating solvent, the residue was dissolved in 300 ml of ethyl acetate. The ethyl acetate solution was washed with 5% chloric acid and distilled water, dried over magnesium sulfate, decolored with active charcoal and filtered. The filtrate was concentrated to give 0.85 g(58%) of 2-(2-hydroxybenzoyl) oxymethyl-5-hydroxy-4H-pyran-4-one as a solid.
Reaction SMILES: [N+:1]([C:3]1[CH:14]=[CH:13][CH:12]=[CH:11][C:4]=1[CH2:5][NH:6][C:7]([NH:9][CH3:10])=[O:8])#[C-:2].[C:15]([OH:21])(=O)[CH2:16][C:17]([OH:19])=O.C(OC(=O)C)(=O)C>C(O)(=O)C>[N+:1]([C:3]1[CH:14]=[CH:13][CH:12]=[CH:11][C:4]=1[CH2:5][N:6]1[C:15](=[O:21])[CH2:16][C:17](=[O:19])[N:9]([CH3:10])[C:7]1=[O:8])#[C-:2]
Reactant: O=C(O)CC(=O)O
Reactant: [C-]#[N+]c1ccccc1CNC(=O)NC
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: [C-]#[N+]c1ccccc1CN1C(=O)CC(=O)N(C)C1=O
Temperature: 60 °C
Reaction time: 2 h
Yield: 60 %

Procedure:
In an alternate embodiment, 1-(2-isocyanobenzyl)-3-methylurea (30 g), acetic acid (105 ml) and malonic acid (18 g) were mixed and heated to 60° C. Acetic anhydride (60 ml) was added at 60° C. and heating was continued for two hours at 80° C. The reaction mixture was poured over ice water (300 ml) and the obtained solid was filtered, washed with water (1×500 ml) and methyl-tert-butylether (100 ml). The yield is 60% with 93.4% purity.
Reaction SMILES: Cl.Cl[C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1.[CH3:9][NH:10][CH2:11][CH2:12][NH:13][CH3:14].C(=O)(O)[O-].[Na+]>C(O)CC(C)C>[CH3:9][N:10]([C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1)[CH2:11][CH2:12][NH:13][CH3:14]
Reactant: Clc1ccncc1
Reactant: CNCCNC
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)CCO
Product: CNCCN(C)c1ccncc1
Yield: 50.2 %

Procedure:
A mixture of 4-chloropyridine hydrochloride (15.0 g), N,N'-dimethyl-1,2-ethanediamine (22.0 g) and sodium bicarbonate (25.20 g) in isoamyl alcohol (100 ml) was heated under reflux for 48 hours and then evaporated. The residue was extracted several times with hot dichloromethane and the combined extracts were filtered and evaporated. The residue was distilled to give the product (8.30 g), b.p. 168°-172° @ 15 mm.
Reaction SMILES: N[C:2]1[CH:10]=[CH:9][CH:5]([C:6]([OH:8])=[O:7])[C:4]([OH:12])(O)[CH:3]=1.S(=O)(=O)(O)O.N([O-])=O.[Na+].[I-:22].[K+]>O>[OH:12][C:4]1[CH:3]=[C:2]([I:22])[CH:10]=[CH:9][C:5]=1[C:6]([OH:8])=[O:7]
Reactant: NC1=CC(O)(O)C(C(=O)O)C=C1
Reactant: [I-]
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: O
Product: O=C(O)c1ccc(I)cc1O
Temperature: 70 °C
Reaction time: 0.33 h

Procedure:
A sample of 4-amino-2-hydroxysalicylic acid (10 g, 65.3 mmol) is charged to a 2 liter Erlenmeyer flask equipped with a large stir bar, cooled in an ice/water bath and treated with concentrated sulfuric acid (20 mL) and enough water to make a free flowing suspension (˜50 mL). After stirring for 20 minutes, the reaction is treated with a solution of sodium nitrite (4.55 g, 66.0 mmol) in water (20 mL) over the course of 10 minutes. After stirring an additional 3 minutes, the reaction is treated with a solution of potassium iodide (16.9 g, 101 mmol) in water (30 mL) over the course of 15 minutes. The cooling bath is removed and the reaction is carefully monitored and stirred as it generates a significant amount of nitrogen gas. After the reaction subsides, it is briefly heated to 70° C. after which it is allowed to cool to room temperature and sit overnight. The resulting solid is collected by filtration, washed with water and dried to give crude 2-hydroxy-4-iodo-benzoic acid that is used in the next reaction without further purification: ESMS m/z 265.0 (M+H+).
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[I:7][C:8]1[CH:13]=[CH:12][C:11]([S:14](Cl)(=[O:16])=[O:15])=[CH:10][CH:9]=1.[OH-].[Na+].OS(O)(=O)=O>O.O1CCOCC1>[I:7][C:8]1[CH:13]=[CH:12][C:11]([S:14]([OH:16])=[O:15])=[CH:10][CH:9]=1
Reactant: O=S(=O)(Cl)c1ccc(I)cc1
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: O=S(O)c1ccc(I)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 94 %

Procedure:
A solution of sodium carbonate (9.4 g, 74.375 mmol) in water (30 mL, 10 v/w) was dropwise added to a solution of 4-iodo-benzenesulfonyl chloride (3 g, 9.917 mmol) in 1,4-dioxane (15 mL, 5 v/w) at room temperature, followed by stirring at room temperature for 30 min. Then, 1N aqueous sodium hydroxide was dropwise added thereto so as to adjust the pH of the reaction mixture to 14, followed by stirring at room temperature for 12 hours. The reaction mixture was cooled to 0° C., and conc. H2SO4 solution was dropwise to adjust the pH of the reaction mixture to 1. The reaction mixture was extracted three times with ethyl acetate, and the organic layer thus obtained was washed with water. The washed layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the title compound (2.5 g).
Reaction SMILES: S([O-])([O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]C)(=O)=O.[Na+].S(OOS([O-])(=O)=O)([O-])(=O)=[O:20].[K+].[K+].C(N)(=O)C=C.C(OC)(=O)C(C)=C.C(OCCCC)(=O)C=C.C(O)(=O)C(C)=C.C(OCCOCCOCCOC(=O)C=C)(=O)C=C.[OH-].[Na+]>O>[CH:8]([CH:7]=[CH:6][C:5]([OH:4])=[O:20])=[CH:9][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: CCCCCCCCCCCCOS(=O)(=O)[O-]
Reactant: O=S(=O)([O-])OOS(=O)(=O)[O-]
Agent: C=C(C)C(=O)O
Agent: C=C(C)C(=O)OC
Agent: C=CC(=O)OCCCC
Solvent: O
Product: O=C(O)C=CC=Cc1ccccc1
Temperature: 75 °C
Reaction time: 3 h

Procedure:
The process of obtaining the resin emulsion (styrene-acrylic acid) was as follows. A reactor having a stirrer, a reflux condenser, a dripping device, and a thermometer was loaded with 800 g of ion-exchanged water and 1 g of sodium lauryl sulfate, and the reactor was heated to 75° C. under stirring while nitrogen was introduced. Six (6) grams of potassium persulfate, a polymerization initiator, was added and dissolved with the internal temperature maintained at 75° C. An emulsion was prepared beforehand by combining 450 g of ion-exchanged water and 2 g of sodium lauryl sulfate with 20 g of acrylamide, 600 g of methyl methacrylate, 215 g of butyl acrylate, 30 g of methacrylic acid, and 5 g of triethylene glycol diacrylate under stirring, and this emulsion was continuously added dropwise to the reaction solution over 5 hours. The obtained mixture was incubated for 3 hours. After the resulting aqueous emulsion had cooled to room temperature, ion-exchanged water and sodium hydroxide solution were added until the solid content was 30% by mass and the pH was 8. The resin emulsion (styrene-acrylic acid) was obtained in this way.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[CH2:13][CH:12]([NH:17][S:18]([CH:21]([CH3:23])[CH3:22])(=[O:20])=[O:19])[CH2:11]3)[CH:5]=[CH:6][CH:7]=1.C(N(C(C)C)CC)(C)C.[CH2:33]([N:35]=[C:36]=[O:37])[CH3:34]>ClCCl>[CH2:33]([NH:35][C:36]([NH:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[CH2:13][CH:12]([NH:17][S:18]([CH:21]([CH3:23])[CH3:22])(=[O:20])=[O:19])[CH2:11]3)[CH:5]=[CH:6][CH:7]=1)=[O:37])[CH3:34]
Reactant: CC(C)S(=O)(=O)NC1Cc2ccc(-c3cccc(N)c3)cc2C1
Reactant: CCN=C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCNC(=O)Nc1cccc(-c2ccc3c(c2)CC(NS(=O)(=O)C(C)C)C3)c1
Yield: 23.1 %

Procedure:
A solution of Intermediate 4 (45 mg, 0.14 mmol), and diisopropylethylamine (36 mg, 0.28 mmol) in dry dichloromethane (3 ml) was cooled to 0° C. using an ice/methanol bath. Ethyl isocyanate (10 mg, 0.14 mmol) was added with stirring under argon and the whole mixture stirred at room temperature for 1 h. The reaction mixture was partitioned between dichloromethane (5 ml) and 1N hydrochloric acid (5 ml). The organic layer was removed and reduced to minimum volume under reduced pressure. The crude mixture was purified by flash column chromatography eluting from 0-50% ethyl acetate in 40-60° C. petroleum ether to give the title compound as a colourless oil (13 mg, 24%); mass spectrum (ES): Found 400 (ES−), C21H27N3O3S requires 401; 1H-NMR (400 MHz, CDCl3) δ 1.16 (3H, m), 1.38 (6H, m), 2.93 (2H, m), 3.19 (1H, m), 3.32 (4H, m), 4.32 (1H, m), 4.44 (1H, m), 4.82 (1H, m), 6.48 (1H, s), 7.23 (3H, m), 7.36 (3H, m), 7.54 (1H, m).
Reaction SMILES: Cl.[C:2]([NH:10][NH2:11])(=[O:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[O-:12][C:13]#[N:14].[K+]>O>[C:2]([NH:10][NH:11][C:13]([NH2:14])=[O:12])(=[O:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: N#C[O-]
Reactant: NNC(=O)c1ccccc1
Agent: Cl
Agent: [K+]
Solvent: O
Product: NC(=O)NNC(=O)c1ccccc1
Reaction time: 1 h

Procedure:
A four neck flask (1000 ml) equipped with a thermometer and a stirrer was charged with 78.2 g (0.75 mol) of 35% hydrochloric acid and 700 ml of deionized water. Added thereto was 68.0 g (0.5 mol) of benzohydrazide at room temperature (20° C.) while stirring, and then 60.7 g (0.75 mol) of potassium cyanate was gradually added in 30 minutes. Stirring was continued at 30° C. for one hour, and then crystal was filtered off and washed with 200 ml of deionized water. This was dried under reduced pressure to obtain white crystal.
Reaction SMILES: C([O:3][C:4](=[O:15])[CH2:5][S:6][C:7]1[N:12]=[C:11]([Cl:13])[CH:10]=[C:9](Cl)[N:8]=1)C.[CH3:16][C:17]1[C:23]([CH3:24])=[CH:22][CH:21]=[CH:20][C:18]=1[NH2:19].C(=O)([O-])[O-].[Na+].[Na+].Cl>C(O)C>[Cl:13][C:11]1[CH:10]=[C:9]([NH:19][C:18]2[CH:20]=[CH:21][CH:22]=[C:23]([CH3:24])[C:17]=2[CH3:16])[N:8]=[C:7]([S:6][CH2:5][C:4]([OH:3])=[O:15])[N:12]=1
Reactant: CCOC(=O)CSc1nc(Cl)cc(Cl)n1
Reactant: Cc1cccc(N)c1C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: Cc1cccc(Nc2cc(Cl)nc(SCC(=O)O)n2)c1C
Reaction time: 4 h

Procedure:
A mixture of 21.4 g of (4,6-dichloro-2-pyrimidinylthio) acetic acid ethyl ester, 9.7 g of 2,3-dimethylaniline, 8.5 g of anhydrous sodium carbonate in 200 ml. of ethanol was heated under reflux with stirring for 4 hr. The mixture was filtered and water was added to the filtrate until precipitation occurred. This material was removed by filtration and amounted to 7.0 g. This material was treated with boiling 30% sodium hydroxide solution (30 ml.) and sufficient ethanol to obtain a clear solution. After cooling in ice the material was acidified with 30% hydrochloric acid solution. The resulting product was then recrystallized from ethanol giving 4.3 g of product, mp. 146°-151°C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([N:19]2[CH:23]=[N:22][N:21]=[C:20]2[CH2:24][N:25]2[C:29](=[O:30])[C:28]3=[CH:31][CH:32]=[CH:33][CH:34]=[C:27]3[C:26]2=[O:35])=[C:8]([CH:18]=1)[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[Cl:17])=[O:10])([O-:3])=[O:2].[Br:36]N1C(=O)C2=CC=CC=C2C1=O>>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([N:19]2[C:20]([CH2:24][N:25]3[C:29](=[O:30])[C:28]4=[CH:31][CH:32]=[CH:33][CH:34]=[C:27]4[C:26]3=[O:35])=[N:21][N:22]=[C:23]2[Br:36])=[C:8]([CH:18]=1)[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[Cl:17])=[O:10])([O-:3])=[O:2]
Reactant: O=C1c2ccccc2C(=O)N1Br
Reactant: O=C(c1ccccc1Cl)c1cc([N+](=O)[O-])ccc1-n1cnnc1CN1C(=O)c2ccccc2C1=O
Product: O=C(c1ccccc1Cl)c1cc([N+](=O)[O-])ccc1-n1c(Br)nnc1CN1C(=O)c2ccccc2C1=O

Procedure:
Following the procedure of Example 1, 5-nitro-2-(3-phthalimidomethyl-4H-1,2,4-triazol-4-yl)-2'-chlorobenzophenone is reacted with N-bromophthalimide to form 5-nitro-2-(3-bromo-5-phthalimidomethyl-4H-1,2,4-triazol-4yl)-2'-chlorobenzophenone.
Reaction SMILES: C(Cl)(=O)C.[NH:5]1[CH2:10][CH:9]=[C:8]([C:11]2[CH:16]=[CH:15][C:14]([NH:17][C:18]([N:20]3[CH2:28][C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[CH2:21]3)=[O:19])=[CH:13][CH:12]=2)[CH2:7][CH2:6]1.NC1C=C2C(=CC=1)CN(C(N[C:42]1[CH:47]=[CH:46][C:45]([C:48](=[O:53])NCCC)=[CH:44][CH:43]=1)=O)C2>>[C:48]([N:5]1[CH2:6][CH:7]=[C:8]([C:11]2[CH:16]=[CH:15][C:14]([NH:17][C:18]([N:20]3[CH2:21][C:22]4[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH2:28]3)=[O:19])=[CH:13][CH:12]=2)[CH2:9][CH2:10]1)(=[O:53])[C:45]1[CH:46]=[CH:47][CH:42]=[CH:43][CH:44]=1
Reactant: CCCNC(=O)c1ccc(NC(=O)N2Cc3ccc(N)cc3C2)cc1
Reactant: O=C(Nc1ccc(C2=CCNCC2)cc1)N1Cc2ccccc2C1
Solvent: CC(=O)Cl
Product: O=C(Nc1ccc(C2=CCN(C(=O)c3ccccc3)CC2)cc1)N1Cc2ccccc2C1

Procedure:
The title compound was prepared as described in Example 278, substituting benzoyl chloride for acetyl chloride and N-[4-(1,2,3,6-tetrahydropyridin-4-yl)phenyl]-1,3-dihydro-2H-isoindole-2-carboxamide for 5-amino-N-(4-(propylcarbamoyl)phenyl)isoindoline-2-carboxamide. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.39 (s, 1H), 7.56-7.59 (m, 2H), 7.44-7.49 (m, 5H), 7.34-7.40 (m, 4H), 7.29-7.34 (m, 2H), 5.91-6.27 (m, 1H), 4.76-4.77 (bs, 4H), 4.02-4.26 (m, 2H), 3.36-3.59 (m, 2H), 2.51-2.61 (m, 2H); MS (ESI(+)) m/e 424 (M+H)+.
Reaction SMILES: C(Cl)Cl.[OH:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[C:10](\[CH3:16])/[C:11]([O:13][CH2:14][CH3:15])=[O:12].N1C=CN=C1.[Si:22](Cl)([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23]>CN(C)C=O>[O:4]([CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[C:10](\[CH3:16])/[C:11]([O:13][CH2:14][CH3:15])=[O:12])[Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CCOC(=O)/C(C)=C/CCCCO
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCOC(=O)/C(C)=C/CCCCO[Si](C)(C)C(C)(C)C
Reaction time: 0.33 h
Yield: 98.8 %

Procedure:
To a methylene chloride solution (300 ml) of Ester 3 (13.91 g; 0.0748 mol), 43 ml of DMF (dimethylformamide) and imidazole (7.6 g; 0.112 mol) are added and the whole is stirred until imidazole is fully dissolved. Tert-butyldimethylsilyl chloride (13.5 g; 0.0897 mol) is then added thereto and the whole is stirred for 20 min. After stirring, the resultant solution is quenched using a buffer solution (100 ml) and the organic compound is extracted three times with ethyl acetate, followed by the wash of the organic layer in a saturated saline solution and drying over anhydrous magnesium sulfate. After anhydrous magnesium sulfate is filtered and the solvent is distilled off under reduced pressure, the residue is separated and purified by column chromatography (developing solution, ethyl acetate:hexane=1:1) to produce Ester 4 (22.16 g; 0.0739 mol) of 99% in yield.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:36])=[C:4]([C@@H:8]2[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:10][N:9]2[C:28]([NH:30][CH2:31][CH2:32][C:33](O)=[O:34])=[O:29])[CH:5]=[CH:6][CH:7]=1.CC[N:39](C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Cl-].[NH4+]>CN(C=O)C>[C:33]([CH2:32][CH2:31][NH:30][C:28]([N:9]1[CH2:10][CH:11]([CH2:23][C:24]([CH3:25])([CH3:26])[CH3:27])[C:12]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=2[F:22])([C:13]#[N:14])[CH:8]1[C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[F:36])=[O:29])(=[O:34])[NH2:39]
Reactant: CC(C)(C)C[C@@H]1CN(C(=O)NCCC(=O)O)[C@H](c2cccc(Cl)c2F)[C@@]1(C#N)c1ccc(Cl)cc1F
Reactant: CCN(C(C)C)C(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Solvent: CN(C)C=O
Product: CC(C)(C)CC1CN(C(=O)NCCC(N)=O)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Yield: 56.5 %

Procedure:
In a manner similar to the method described in Example 63, a mixture of rac-3-{[(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-4-(2,2-dimethyl-propyl)-pyrrolidine-1-carbonyl]-amino}-propionic acid (25 mg, 0.0464 mmole, example 73), DIPEA (42 mg, 0.324 mmol) and HATU (26.4 mg, 0.069 mmol) in DMF was reacted with ammonium chloride (6.2 mg, 0.11 mmol) to give rac-(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-4-(2,2-dimethyl-propyl)-pyrrolidine-1-carboxylic acid (2-carbamoyl-ethyl)-amide (14.1 mg, 57%). HRMS (ES+) m/z Calcd for C26H28Cl2F2N4O2+H [(M+H)+]: 537.1630; Found: 537.1630.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[N:25]=[C:24]([O:26][C@H:27]3[C@H:31]4[O:32][CH2:33][C@@H:34]([OH:35])[C@H:30]4[O:29][CH2:28]3)[N:23]([CH2:36][O:37][CH2:38][CH2:39][Si:40]([CH3:43])([CH3:42])[CH3:41])[C:5]2=[N:6][C:7]=1[C:8]1[CH:13]=[CH:12][C:11](B2OC(C)(C)C(C)(C)O2)=[CH:10][CH:9]=1.Br[C:45]1[CH:50]=[CH:49][C:48]([NH:51][S:52]([CH3:57])(=[N:54][CH2:55][CH3:56])=[O:53])=[CH:47][CH:46]=1>>[OH:35][C@H:34]1[C@H:30]2[O:29][CH2:28][C@@H:27]([O:26][C:24]3[N:23]([CH2:36][O:37][CH2:38][CH2:39][Si:40]([CH3:43])([CH3:41])[CH3:42])[C:5]4=[N:6][C:7]([C:8]5[CH:13]=[CH:12][C:11]([C:45]6[CH:46]=[CH:47][C:48]([NH:51][S:52]([CH3:57])(=[N:54][CH2:55][CH3:56])=[O:53])=[CH:49][CH:50]=6)=[CH:10][CH:9]=5)=[C:2]([Cl:1])[CH:3]=[C:4]4[N:25]=3)[C@H:31]2[O:32][CH2:33]1
Reactant: CCN=S(C)(=O)Nc1ccc(Br)cc1
Reactant: CC1(C)OB(c2ccc(-c3nc4c(cc3Cl)nc(O[C@@H]3CO[C@H]5[C@@H]3OC[C@H]5O)n4COCC[Si](C)(C)C)cc2)OC1(C)C
Product: CCN=S(C)(=O)Nc1ccc(-c2ccc(-c3nc4c(cc3Cl)nc(O[C@@H]3CO[C@H]5[C@@H]3OC[C@H]5O)n4COCC[Si](C)(C)C)cc2)cc1

Procedure:
The title compound is prepared from (3R,3aR,6R,6aR)-6-(6-chloro-5-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-3-(2-trimethylsilanyl-ethoxymethyl)-3H-imidazo[4,5-b]pyridin-2-yloxy)hexahydrofuro[3,2-b]furan-3-ol and N-(4-bromophenyl)-N′-ethyl-methanesulfonimidamide following a procedure analogous to that described for Intermediate 3 (Step 3). LC (method 1): tR=1.10 min; Mass spectrum (ESI+): m/z=700 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[N:6]=[C:5]2[CH3:19].[C-:20]#[N:21].[Na+].C(OCC)(=O)C>CN1C(=O)CCC1.[Ni](Br)Br>[C:20]([C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[N:6]=[C:5]2[CH3:19])#[N:21]
Reactant: [C-]#N
Reactant: Cc1nn(COCC[Si](C)(C)C)c2ccc(Br)cc12
Agent: Br[Ni]Br
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: Cc1nn(COCC[Si](C)(C)C)c2ccc(C#N)cc12
Temperature: 180 °C

Procedure:
To a solution of 5-bromo-3-methyl-N-(2-trimethylsilanylethoxymethyl)indazole 116 (0.5 g, 1.466 mmol) in NMP (10 mL) was added nickel bromide (0.321 g, 1.469 mmol) and sodium cyanide (0.144 g, 2.939 mmol). The reaction mixture was heated in a microwave reactor at 180° C. for 30 minutes. Ethyl acetate (100 mL) was added. The organic layer was washed with water and brine. The organic layer was dried over sodium sulfate. The organic solvent was evaporated under reduced pressure. The crude product was purified by flash column chromatography to yield the desired 5-cyano-3-methyl-N-(2-trimethylsilanylethoxymethyl)indazole 117. (0.36 g, 1.254 mmol).