Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:39])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]([F:16])=[C:12]2[C:7]=1[C:8]([O:35][CH:36]([F:38])[F:37])=[C:9]([CH2:19][C:20]1[CH:25]=[CH:24][C:23](B3OC(C)(C)C(C)(C)O3)=[CH:22][CH:21]=1)[C:10]([CH2:17][CH3:18])=[N:11]2.Br[C:41]1[N:46]=[CH:45][CH:44]=[CH:43][N:42]=1.O1CCOCC1.C(=O)([O-])[O-].[Cs+].[Cs+]>C(OCC)(=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[F:38][CH:36]([F:37])[O:35][C:8]1[C:7]2[C:12](=[C:13]([F:16])[CH:14]=[CH:15][C:6]=2[O:5][CH2:4][C:3]([OH:2])=[O:39])[N:11]=[C:10]([CH2:17][CH3:18])[C:9]=1[CH2:19][C:20]1[CH:21]=[CH:22][C:23]([C:41]2[N:46]=[CH:45][CH:44]=[CH:43][N:42]=2)=[CH:24][CH:25]=1
Reactant: Brc1ncccn1
Reactant: CCc1nc2c(F)ccc(OCC(=O)OC)c2c(OC(F)F)c1Cc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CCc1nc2c(F)ccc(OCC(=O)O)c2c(OC(F)F)c1Cc1ccc(-c2ncccn2)cc1
Temperature: 110 °C
Reaction time: 1 h
Yield: 23.7 %

Procedure:
A mixture of {4-difluoromethoxy-2-ethyl-8-fluoro-3-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)benzyl]quinolin-5-yloxy}acetic acid methyl ester (0.10 g), 2-bromopyrimidine (0.076 g), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (0.016 g), 1,4-dioxane (2.0 mL) and 2.0 M aqueous cesium carbonate solution (0.38 mL) was heated by microwave irradiation at 90 to 130° C. for 1 hour. The mixture was cooled to room temperature, diluted with ethyl acetate and then filtered. The filtrate was concentrated under reduced pressure and the residue dissolved in tetrahydrofuran (5.0 mL) and 1.0 M aqueous lithium hydroxide solution (0.38 mL), and the resulting mixture was stirred at room temperature for 1 hour. The mixture was acidified by the addition of 0.1 M aqueous hydrochloric acid solution and then concentrated under reduced pressure. Purification of the residue by preparative reverse-phase HPLC gave title compound (0.021 g).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]2[NH:9][C:10](=[O:17])[C:11]3[S:16][CH:15]=[CH:14][C:12]=3[N:13]=2)[CH:5]=[CH:6][CH:7]=1.[C:18]([O-])(=[O:20])[CH3:19].[Na+]>C(OC(=O)C)(=O)C>[O:17]=[C:10]1[NH:9][C:8]([C:4]2[CH:3]=[C:2]([O:1][C:18](=[O:20])[CH3:19])[CH:7]=[CH:6][CH:5]=2)=[N:13][C:12]2[CH:14]=[CH:15][S:16][C:11]1=2
Reactant: O=c1[nH]c(-c2cccc(O)c2)nc2ccsc12
Reactant: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Product: CC(=O)Oc1cccc(-c2nc3ccsc3c(=O)[nH]2)c1
Temperature: 0 °C
Yield: 80.6 %

Procedure:
A mixture of 2-(3-hydroxy-phenyl)-3H-thieno[3,2-d]pyrimidin-4-one (28.58 g, 0.12 mol) and sodium acetate (1.1 eq., 0.13 mol, 10.56 g) in acetic anhydride (280 mL) was heated under reflux for 1.5 hours. The mixture was then cooled in ice-water and the grey solid collected by filtration, washed with water and dried to yield compound 4 (27.69 g, 82%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:11]=[C:12]([C:17]([O:19][CH3:20])=[O:18])[C:13](=[O:16])[NH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[F:21][C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][C:29]=1[F:30])[CH2:25]Br>>[F:21][C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][C:29]=1[F:30])[CH2:25][N:14]1[C:13](=[O:16])[C:12]([C:17]([O:19][CH3:20])=[O:18])=[CH:11][C:10]([C:4]2[CH:5]=[CH:6][C:7]([O:8][CH3:9])=[C:2]([F:1])[CH:3]=2)=[N:15]1
Reactant: Fc1ccc(CBr)cc1F
Reactant: COC(=O)c1cc(-c2ccc(OC)c(F)c2)n[nH]c1=O
Product: COC(=O)c1cc(-c2ccc(OC)c(F)c2)nn(Cc2ccc(F)c(F)c2)c1=O
Yield: 92.1 %

Procedure:
Following the procedure of Example 1(6), 6-(3-fluoro-4-methoxyphenyl)-4-methoxycarbonyl-2H-pyridazin-3-one and 3,4-difluorobenzyl bromide were reacted to yield the title compound as a yellow crystalline powder (yield: 92.1%).
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[F:13][C:14]1[CH:19]=[C:18]([F:20])[C:17]([F:21])=[CH:16][C:15]=1[Br:22].[C:23](=[O:25])=[O:24]>C1COCC1.CCOCC>[Br:22][C:15]1[C:14]([F:13])=[C:19]([C:18]([F:20])=[C:17]([F:21])[CH:16]=1)[C:23]([OH:25])=[O:24]
Reactant: O=C=O
Reactant: Fc1cc(F)c(Br)cc1F
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: O=C(O)c1c(F)c(F)cc(Br)c1F
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 84.5 %

Procedure:
n-Butyl lithium (2.6M in hexanes, 32 mL, 84 mmol) was added over 10 minutes to a solution of diisopropylamine (8.89 g, 88 mmol) in THF (80 mL) stirred under N2 at 0° C. After a further 10 minutes at 0°, the solution was transferred by catheter over 40 minutes to a solution of 2,4,5-trifluorobromobenzene (16.88 g, 80 mmol) in THF (200 mL) stirred under N2 at -78° C. After a further 15 minutes the solution was blown through a catheter over -2 minutes onto a slurry of CO2 (-200 mL) in ether (400 mL) with vigorous stirring. When the CO2 evaporated the slurry was washed with dilute HCl (1M, 200 mL) and water (100 mL). The organic phase was extracted with dilute NaOH (0.5M, 2×100 mL). The aqueous phase was extracted with ether (2×100 mL), and the combined organic phases were washed with water (100 mL), saturated brine (100 mL), and dried (MgSO4). The solvent was removed under reduced pressure to give 3-bromo-2,5,6-trifluorobenzoic acid (17.25 g, 84.5%) as white microcrystalline needles; mp 114°-6° C. (sublimation).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10](=[O:12])[CH3:11])=[CH:5][CH:4]=1.[Cl:13][S:14](O)(=[O:16])=[O:15]>O>[Cl:13][S:14]([C:4]1[CH:5]=[C:6]([CH2:9][C:10](=[O:12])[CH3:11])[CH:7]=[CH:8][C:3]=1[O:2][CH3:1])(=[O:16])=[O:15]
Reactant: O=S(=O)(O)Cl
Reactant: COc1ccc(CC(C)=O)cc1
Solvent: O
Product: COc1ccc(CC(C)=O)cc1S(=O)(=O)Cl

Procedure:
The (3-aminosulfonyl-4-methoxy)phenylacetone (4) is a novel compound and it may be prepared in analogy to a process described in U.S. Pat. No. 544,958 for related compounds. The starting compound is 4-methoxyphenyl acetone which is chlorosulfonated by chlorosulfonic acid at 0-5° C. After treating the reaction mixture with water, the resulting 3-chlorosulfonyl-4-methoxyphenylacetone (9) is formed in solid state and is isolated by filtration. The compound (9) is then treated in ethyl acetate solution with aqueous ammonia at 5° C. The formed crystals of crude (4) are recovered by filtration. The crude (4) may be purified by crystallization, e.g. from ethanol.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([CH3:9])[CH:8]=1)N.CS(O)(=O)=O.N([O-])=O.[Na+].N.[ClH:20]>C(O)(=O)C>[Cl:20][C:4]1[CH:6]=[C:7]([CH3:9])[CH:8]=[C:2]([CH3:1])[CH:3]=1
Reactant: Cc1cc(C)cc(N)c1
Reactant: Cl
Agent: CS(=O)(=O)O
Agent: N
Agent: O=N[O-]
Solvent: CC(=O)O
Product: Cc1cc(C)cc(Cl)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 3,5-dimethylaniline (36.3 g; 0.3 mole) in glacial acetic acid (200 ml) is treated with methanesulfonic acid (60 g) and the stirred mixture cooled to 0°-5° C. in an ice-salt bath. An ice cold solution of sodium nitrite (21 g in 80 ml H2O) is slowly added over a half hour period and this diazonium solution then added quickly to an ice cold solution of cuprous chloride [from cooper sulphate 5 H2O (125 g), sodium chloride (32.5 g) and sodium sulphate (71 g)] in concentrated hydrochloric acid (160 ml). The mixture becomes very thick and is allowed to warm to room temperature. The stirring is continued overnight and the solution heated to 60° C. for 1/2 hour. Concentrated ammonia is added with cooling until the solution is alkaline and the oil extracted with ether. Distillation of the dried ether extract gives 5-chloro-m-xylene, b.p. 70°-73°/12 mm (25.6 g).
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:3][CH2:2]1.[NH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1>C(#N)C>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11]([N:21]4[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]4)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:3][CH2:2]1
Reactant: C1CNCCN1
Reactant: O=C(O)c1cn(C2CC2)c2c(F)c(F)c(F)cc2c1=O
Solvent: CC#N
Product: O=C(O)c1cn(C2CC2)c2c(F)c(N3CCNCC3)c(F)cc2c1=O
Reaction time: 8 h
Yield: 54.3 %

Procedure:
To 1.00 g (3.53 mmol) of 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid in 10.0 ml of acetonitrile and 0.54 g (3.53 mmol) of 1,8-diazobicyclo[5.4.0]undec-7-ene, was added 1.70 g (19.7 mmol) of piperazine. The mixture was refluxed for one hour and then stirred overnight. It was concentrated, dissolved in ammonium hydroxide and filtered. The filtrate was then concentrated to one-half volume and filtered to give 0.67 g of the title compound, mp >270° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:12][CH:11]([NH:19][CH3:20])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].[CH2:21]=O.[OH-].[K+]>C(O)=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:12][CH:11]([N:19]([CH3:21])[CH3:20])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: C=O
Reactant: CNC1Cc2ccccc2C(c2ccc(Cl)c(Cl)c2)C1
Agent: [K+]
Agent: [OH-]
Solvent: O=CO
Product: CN(C)C1Cc2ccccc2C(c2ccc(Cl)c(Cl)c2)C1
Yield: 93 %

Procedure:
The respective methylamine 7 (e.g., 28.4 mg, 0.0927 mmol) was dissolved in 96% formic acid (0.5 mL) and 37% aqueous formaldehyde (0.5 mL) and heated at 100° C. for two hours. After cooling, the solution was basicified (aq KOH) and extracted with MTBE. The organic phase was dried with sodium sulfate, filtered, and evaporated to give the dimethylamine (e.g., 27.1 mg, 93%) as a clear oil.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH2:6][CH2:5]2.[CH:13]1([N:19]2[C:23]([CH2:24][CH2:25][CH2:26][CH2:27]Cl)=[N:22][N:21]=[N:20]2)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1.C(=O)([O-])[O-].[K+].[K+]>[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC.S([O-])([O-])=O.[Na+].[Na+].O>[CH:13]1([N:19]2[C:23]([CH2:24][CH2:25][CH2:26][CH2:27][O:1][C:2]3[CH:3]=[C:4]4[C:9](=[CH:10][CH:11]=3)[NH:8][C:7](=[O:12])[CH2:6][CH2:5]4)=[N:22][N:21]=[N:20]2)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]1
Reactant: O=C1CCc2cc(O)ccc2N1
Reactant: ClCCCCc1nnnn1C1CCCCC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: O=S([O-])[O-]
Solvent: O
Product: O=C1CCc2cc(OCCCCc3nnnn3C3CCCCC3)ccc2N1
Temperature: 25 °C
Yield: 87.7 %

Procedure:
Into a flask having a capacity of 200 ml were introduced 12.00 g of 6-hydroxy-3,4-dihydrocarbostyril, 19.60 g of 1-cyclohexyl-5-(4-chlorobutyl)-1,2,3,4-tetrazole, 8.20 g of 50% aqueous solution of tetrabutylammonium chloride, 12.20 g of potassium carbonate, 0.60 g of sodium sulfite and 60 ml of water. The content of the flask was heated under reflux for 8 hours with stirring. After the reaction, the reaction mixture was cooled to ambient temperature, and the deposited crude crystal was once collected by filtration. After washing the crystal firstly with 36 ml of methanol and then with 60 ml of water, the crystal was again introduced into a flask having a capacity of 200 ml and heated under reflux together with 84 ml of methanol for 2 hours. The solution thus obtained was cooled to 10° C. The crystal was collected by filtration, washed firstly with 24 ml of methanol and then with 24 ml of water, and dried at 80° C. Thus, 23.84 g (yield 87.7%) of 6-[4-(1-cyclohexyl-1,2,3,4-tetrazol-5-yl)butoxy]-3,4-dihydrocarbostyril was obtained as a colorless needle-like crystalline product.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH2:6][CH2:5]2.[CH:13]1([N:19]2[C:23]([CH2:24][CH2:25][CH2:26][CH2:27]Cl)=[N:22][N:21]=[N:20]2)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1.C(=O)([O-])[O-].[K+].[K+]>S([O-])([O-])=O.[Na+].[Na+].CO>[CH:11]1[C:2]([O:1][CH2:27][CH2:26][CH2:25][CH2:24][C:23]2[N:19]([CH:13]3[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]3)[N:20]=[N:21][N:22]=2)=[CH:3][C:4]2[CH2:5][CH2:6][C:7]([NH:8][C:9]=2[CH:10]=1)=[O:12]
Reactant: ClCCCCc1nnnn1C1CCCCC1
Reactant: O=C1CCc2cc(O)ccc2N1
Agent: O=C([O-])[O-]
Agent: O=S([O-])[O-]
Agent: [K+]
Solvent: CO
Product: O=C1CCc2cc(OCCCCc3nnnn3C3CCCCC3)ccc2N1
Temperature: 85 °C
Reaction time: 0.25 h
Yield: 94.4 %

Procedure:
Into a reaction vessel having a capacity of 500 mL were introduced 6-hydroxy-3,4-dihydrocarbostyril (30 g, 0.18 mol), 1-cyclohexyl-5-(4-chlorobutyl)-1,2,3,4-tetrazole (49.1 g, 0.20 mol, 1.1 M), potassium carbonate (83.84 g, 0.61 mol, 3.3 M), sodium sulfite (1.5 g, 0.01 mol) and purified water (150 mL). The mixture of the reactants was heated at about 85° C. for about 6 hours with circulating by continuous disperser (pipeline homomixer T.K.ROBO MIX manufactured by TOKUSHUKIKA KOGYO CO. LTD.). After the completion of the reaction, the reaction mixture was cooled to around 50° C. and the deposited crude crystals were once collected by filtration. The crystals obtained were introduced into a flask having a capacity of 1 L and purified water (300 mL) was added thereto, then the crystals were washed with stirring at about 85° C. for about 15 minutes. After washing the crystals, the reaction mixture was cooled to around 50° C. and the precipitated crystals were collected by filtration. The crystals obtained were introduced into a flask again and methanol (210 mL) was added thereto, then the crystals were washed with stirring at about 25° C. for about 15 minutes. The reaction mixture was cooled to 10° C. or less, the precipitated crystalline product was collected by filtration and washed with methanol (60 mL), then dried at about 80° C. Thus, 62.79 g of cilostazol was obtained. Yield: 92.44%, Purity: 99.61%, m.p.: 158–159° C.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8].[CH3:10]O>>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([O:9][CH3:10])=[O:8]
Reactant: CO
Reactant: O=C(O)CCCCCBr
Product: COC(=O)CCCCCBr
Temperature: 25 °C
Reaction time: 4 h
Yield: 99 %

Procedure:
To a 1 L round bottom flask, charged with 20 g (102.5 mmol) of 6-bromohexanoic acid and 500 mL of methanol, was bubbled hydrogen chloride gas for 2–3 minutes. The mixture was stirred at room temperature for 4 hours and concentrated to afford 21.0 g of the product as a yellow oil (99%): 1H-NMR (200 MHz, d6-DMSO); 3.57 (s, 3H), 3.51 (t, 2H), 2.30 (t, 2H), 1.78 (pentet, 2H), and 1.62–1.27 (m, 4H) ppm.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]#[N:10])[CH:5]=[N:6][CH:7]=1.Br[CH2:12][CH2:13]Cl.CCOC(C)=O>[OH-].[Na+].[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([C:8]2([C:9]#[N:10])[CH2:13][CH2:12]2)[CH:5]=[N:6][CH:7]=1
Reactant: N#CCc1cncc(Br)c1
Reactant: ClCCBr
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: N#CC1(c2cncc(Br)c2)CC1
Temperature: 25 °C
Yield: 55 %

Procedure:
To a suspension of (5-bromo-pyridin-3-yl)-acetonitrile (1.0 g, 5.1 mmol) in 50% NaOH (20 mL) is added 1-bromo-2-chloro-ethane (764 mg, 5.33 mmol) and benzyl triethylammonium chloride (15 mg, 0.11 mmol). The resultant mixture is heated to 60° C. for 2 h. After cooling down to room temperature, EtOAc is added and extracted. The organic layers are combined and washed with brine, dried over Na2SO4, filtered and concentrated. The product is purified by column to afford 626 mg 1-(5-bromo-pyridin-3-yl)-cyclopropanecarbonitrile (55% yield).
Reaction SMILES: [NH2:1][C:2]1[S:6][N:5]=[C:4](/[C:7](=[N:11]/[O:12][CH3:13])/[C:8](O)=[O:9])[N:3]=1.P(Cl)(Cl)([Cl:16])=O>CN(C)C=O>[NH2:1][C:2]1[S:6][N:5]=[C:4](/[C:7](=[N:11]/[O:12][CH3:13])/[C:8]([Cl:16])=[O:9])[N:3]=1
Reactant: CO/N=C(\C(=O)O)c1nsc(N)n1
Reactant: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Product: CO/N=C(\C(=O)Cl)c1nsc(N)n1

Procedure:
In a manner similar to Example 1, a reaction was conducted using 2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(Z)-methoxyiminoacetic acid whose average particle size was 2.4 μ. Subsequent to dropwise addition of a chlorinating reagent which had been prepared from phosphorus oxychloride and N,N-dimethylformamide, they were reacted for 1 minute. The reaction product was post-treated, and its purity was analyzed by HPLC by the method described above.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=[O:22])[CH2:10][N:11]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]2=[O:21])=[CH:5][CH:4]=1.[CH2:23](O)[CH2:24][OH:25].CC1C=CC(S(O)(=O)=O)=CC=1.C(O)CCC>CC1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2([CH2:10][N:11]3[C:19](=[O:20])[C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[C:12]3=[O:21])[O:25][CH2:24][CH2:23][O:22]2)=[CH:7][CH:8]=1
Reactant: OCCO
Reactant: COc1ccc(C(=O)CN2C(=O)c3ccccc3C2=O)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCCCO
Solvent: Cc1ccccc1
Product: COc1ccc(C2(CN3C(=O)c4ccccc4C3=O)OCCO2)cc1

Procedure:
A mixture of 94 parts of 2-[2-(4-methoxyphenyl)-2-oxoethyl]-1H-isoindole-1,3(2H)-dione, 21 parts of 1,2-ethanediol, 3 parts of 4-methylbenzenesulfonic acid, 40 parts of 1-butanol and 450 parts of methylbenzene is stirred and refluxed for 15 hours using a waterseparator. The reaction mixture is cooled and washed with a diluted sodium hydroxide solution. The organic phase is dried, filtered and evaporated. The solid residue is triturated in 2,2'-oxybispropane. The product is filtered off and dried, yielding 102 parts of 2-[2-(4-methoxyphenyl)-1,3-dioxolan-2-ylmethyl]-1H-isoindole-1,3(2H)-dione
Reaction SMILES: Cl.[CH3:2][CH:3]([C:5]1[NH:9][C:8]2[CH2:10][CH2:11][CH2:12][C:13](=[O:14])[C:7]=2[N:6]=1)[CH3:4].[Cl:15][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][C:23]=1[Cl:24])[CH2:19]Br.[OH-].[Na+].Cl.CC(O)C>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1>[ClH:15].[Cl:15][C:16]1[CH:17]=[C:18]([CH2:19][N:6]2[C:7]3[C:13](=[O:14])[CH2:12][CH2:11][CH2:10][C:8]=3[N:9]=[C:5]2[CH:3]([CH3:2])[CH3:4])[CH:21]=[CH:22][C:23]=1[Cl:24]
Reactant: CC(C)c1nc2c([nH]1)CCCC2=O
Reactant: Clc1ccc(CBr)cc1Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [Br-]
Solvent: CC(C)O
Solvent: Cc1ccccc1
Product: CC(C)c1nc2c(n1Cc1ccc(Cl)c(Cl)c1)C(=O)CCC2
Temperature: 20 °C
Reaction time: 0.5 h

Procedure:
To a mixture of Intermediate 84 (1000 g, 1.0 eq, 1.0 wt) and tetrabutylammonium bromide (300 g, 0.2 eq, 0.3 wt) in toluene (9.5 L, 9.5 vol) was added 3,4-dichlorobenzyl bromide (0.71 L, 1.05 eq, 0.71 vol), followed by a line rinse with toluene (0.5 L, 0.5 vol). 5M sodium hydroxide (5 L, 5.36 eq, 5 vol) was added and the biphasic mixture was stirred vigorously for 4 hours 30 minutes at 20° C. and sampled for completion by HPLC. Reaction was complete at 3 hours 30 minutes. The mixture was settled and separated. The aqueous phase was back-extracted with toluene (5 L, 5 vol). The combined organic phases were washed with water (2×2 L, 2×2 vol) and concentrated by atmospheric distillation to 3.4 L/3.4 vol. The mixture was cooled to 20° C. over 30 minutes and diluted with propan-2-ol (10 L, 10 vol). 5-6M hydrochloric acid in propan-2-ol (1.4 L, 1.5 eq, 1.40 vol) was added over 10 minutes at 55° C. The solution was stirred at 60° C. for 20 minutes and seeded with a sample of the title compound (0.4 g, 0.0004 wt). The slurry was aged at 60° C. for 30 minutes, cooled to 3° C. over 3 hours 15 minutes and stirred at this temperature for 1 hour 30 minutes. Solids were collected by vacuum filtration, washed with chilled (5° C.) propan-2-ol/toluene (6 L, 5:1 v/v, 6 vol), followed by tert-butylmethylether (2×5 L, 2×5 vol) and dried in vacuo at 40° C. for 16 hours 30 minutes. Yield of the title compound obtained was 1497 g/86% theory yield/150% w/w yield.
Reaction SMILES: [C:1]([NH:4][CH:5](C(OCC)=O)[C:6]([O:8]CC)=[O:7])(=[O:3])[CH3:2].CC(C)([O-])C.[K+].[F:22][C:23]1[CH:28]=[CH:27][C:26]([C:29](Cl)(Cl)[C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=2)=[CH:25][CH:24]=1.[I-].[K+].[OH-].[Na+]>C(N1CCCC1=O)C.C1(C)C=CC=CC=1>[C:1]([NH:4][CH:5]([CH:29]([C:30]1[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=1)[C:26]1[CH:27]=[CH:28][C:23]([F:22])=[CH:24][CH:25]=1)[C:6]([OH:8])=[O:7])(=[O:3])[CH3:2]
Reactant: CCOC(=O)C(NC(C)=O)C(=O)OCC
Reactant: Fc1ccc(C(Cl)(Cl)c2ccc(F)cc2)cc1
Agent: CC(C)(C)[O-]
Agent: [I-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCN1CCCC1=O
Product: CC(=O)NC(C(=O)O)C(c1ccc(F)cc1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution (1.1 M) of diethyl acetamidomalonate (1.15 g, 5.29 mmol) in N-ethyl-2-pyrrolidone (4.0 mL) was added potassium t-butoxide (0.58 g, 5.41 mmol), and the mixture was stirred at room temperature for 1 hr. Bis(4-fluorophenyl)methylene chloride (1.0 g, 4.21 mmol) and potassium iodide (0.70 g, 4.21 mol) were added, and the mixture was stirred at 60° C. for 6 hrs. After completion of the reaction, toluene (5 mL) and 2M aqueous sodium hydroxide solution (5 mL) were added to the reaction mixture, and the mixture was stirred at 60° C. for 5 hrs. The reaction mixture was allowed to cool to room temperature and partitioned. The aqueous layer was adjusted to 7.0 with concentrated hydrochloric acid. Ethyl acetate (8 mL) was added, and then concentrated hydrochloric acid was added. The mixture was partitioned and the aqueous layer was extracted with ethyl acetate (2 mL). The organic layers were combined, and the content of the title compound was examined by HPLC to find 1.10 g thereof contained in the organic layer (Inertsil ODS-2, 0.03 M phosphate buffer:acetonitrile=90:10-25:75 (20 min), 220 nm, 1.0 mL/min, rt).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[C:13]([NH2:23])=[N:14][CH:15]=[C:16]([C:17]4[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=4)[C:11]=3[S:10][CH:9]=2)=[CH:4][CH:3]=1.[F:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][C:26]=1[N:35]=[C:36]=[O:37]>CN(C=O)C.C1COCC1.O>[NH2:23][C:13]1[C:12]2[C:8]([C:5]3[CH:4]=[CH:3][C:2]([NH:1][C:36]([NH:35][C:26]4[CH:27]=[C:28]([C:31]([F:32])([F:34])[F:33])[CH:29]=[CH:30][C:25]=4[F:24])=[O:37])=[CH:7][CH:6]=3)=[CH:9][S:10][C:11]=2[C:16]([C:17]2[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=2)=[CH:15][N:14]=1
Reactant: Nc1ccc(-c2csc3c(-c4ccncc4)cnc(N)c23)cc1
Reactant: O=C=Nc1cc(C(F)(F)F)ccc1F
Solvent: O
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: Nc1ncc(-c2ccncc2)c2scc(-c3ccc(NC(=O)Nc4cc(C(F)(F)F)ccc4F)cc3)c12
Temperature: 25 °C
Yield: 46.2 %

Procedure:
A −20° C. solution of Example 121B (0.18 g, 0.57 mmol) in DMF (3 mL) and THF (3 mL) was treated dropwise with 1-fluoro-2-isocyanato-4-(trifluoromethyl)benzene (0.085 mL, 0.57 mmol) and warmed to room temperature over 1.5 hours. The resulting mixture was diluted with water and extracted twice with ethyl acetate. The combined extracts were dried (Na2SO4), filtered, concentrated and the residue was purified by flash column chromatography on silica gel with 3-5% methanol/dichloromethane to provide 138 mg of the desired product. 1H NMR (300 MHz, DMSO-d6) δ 5.74 (s, 2H), 7.44 (d, J=8.48 Hz, 3H), 7.51 (d, J=10.85 Hz, 1H), 7.55 (s, 1H), 7.64 (d, J=8.82 Hz, 2H), 7.71-7.72 (m, 1H), 7.74 (d, J=1.70 Hz, 1H), 8.10 (s, 1H), 8.64 (dd, J=7.29, 2.20 Hz, 1H), 8.67-8.69 (m, 1H), 8.70 (d, J=1.70 Hz, 1H), 8.98 (d, J=2.71 Hz, 1H), 9.40 (s, 1H); MS (ESI(+)) m/e 524 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:34])[C@@H:7]([NH:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:8][CH2:9][CH2:10][CH2:11][N:12](CC1C=CC=CC=1)[CH2:13][C@H:14]([OH:18])[CH2:15][C:16]#[N:17])([CH3:4])([CH3:3])[CH3:2].[H][H]>C(O)(=O)C.[Pd].O=[Pt]=O>[C:6]([OH:34])(=[O:5])[CH3:7].[C:6]([OH:34])(=[O:5])[CH3:7].[C:1]([O:5][C:6](=[O:34])[C@@H:7]([NH:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:8][CH2:9][CH2:10][CH2:11][NH:12][CH2:13][C@H:14]([OH:18])[CH2:15][CH2:16][NH2:17])([CH3:4])([CH3:3])[CH3:2]
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCCN(Cc1ccccc1)C[C@H](O)CC#N)C(=O)OC(C)(C)C
Agent: O=[Pt]=O
Agent: [Pd]
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N[C@@H](CCCCNC[C@H](O)CCN)C(=O)OC(C)(C)C
Reaction time: 6 h
Yield: 280.6 %

Procedure:
The Nε benzyl nitrile (6) (4.80 g, 10.7 mmol) was dissolved in glacial acetic acid (100 ml); 10% Pd—C (0.50 g) and PtO2 (1.00 g) were added; and hydrogen gas was introduced. The reaction was complete after 6 hours, and the catalyst was filtered through a bed of Celite and washed with acetic acid. The filtrate was concentrated in vacuo. Azeotropic removal of the acetic acid with toluene gave (7) as a colorless oil (5.10 g, 99%). 1H NMR (500 MHz) (CD3OD) δ 4.02-3.94 (m, 2H), 3.14-2.86 (m, 6H), 1.94 (s, 6H), 1.87-1.58 (m, 8H), 1.46 (s, 9H), 1.44 (s, 9H). 13C NMR (CD3OD) δ 169.6, 156.54, 85.3, 70.2, 62.6, 56.6, 54.2, 53.9, 34.0, 31.1, 28.2, 26.3, 23.2. HRMS m/z calcd. for C19H40N3O5 390.2968, found 390.2977. [α]25D+0.6° (c=1.00, CH3OH).