Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC1C(F)=C(F)C(F)=C(C=1)C(Cl)=O.[F:14][C:15]1[C:16]([F:29])=[C:17]([F:28])[C:18]([F:27])=[C:19]([C:24]([OH:26])=[O:25])[C:20]=1C(O)=O.[N:30]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH:33]=[CH:32][CH:31]=1>>[N:30]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH:33]=[CH:32][CH:31]=1.[F:14][C:15]1[C:16]([F:29])=[C:17]([F:28])[C:18]([F:27])=[C:19]([CH:20]=1)[C:24]([OH:26])=[O:25]
Reactant: O=C(O)c1c(F)c(F)c(F)c(F)c1C(=O)O
Agent: O=C(Cl)c1cc(F)c(F)c(F)c1F
Solvent: c1ccc2ncccc2c1
Product: O=C(O)c1cc(F)c(F)c(F)c1F

Procedure:
DE-A 38 10 093 describes the preparation of tetrafluorobenzoyl chloride by decarboxylation of tetrafluorophthalic acid which is dissolved in an excess of quinoline. After the reaction is completed, a quinoline salt of tetrafluorobenzoic acid is obtained, which is then suspended in thionyl chloride and reacted with heating. The 2,3,4,5-tetrafluorobenzoyl chloride is then obtained by fractional distillation (cf. also Example 4).
Reaction SMILES: O.[NH:2]1[CH2:7][CH2:6][CH:5]([CH2:8][N:9]2[CH2:13][CH2:12][CH2:11][C:10]2=[O:14])[CH2:4][CH2:3]1.[CH2:15]([O:22][C:23]1[C:24](Cl)=[N:25][C:26]([C:29]([F:32])([F:31])[F:30])=[N:27][CH:28]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C>[C:16]1([CH2:15][O:22][C:23]2[C:24]([N:2]3[CH2:3][CH2:4][CH:5]([CH2:8][N:9]4[CH2:13][CH2:12][CH2:11][C:10]4=[O:14])[CH2:6][CH2:7]3)=[N:25][C:26]([C:29]([F:31])([F:32])[F:30])=[N:27][CH:28]=2)[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: FC(F)(F)c1ncc(OCc2ccccc2)c(Cl)n1
Reactant: O=C1CCCN1CC1CCNCC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: O=C1CCCN1CC1CCN(c2nc(C(F)(F)F)ncc2OCc2ccccc2)CC1
Yield: 79.8 %

Procedure:
A mixture of 1-[(4-piperidinyl)methyl]-2-pyrrolidinone hydrate (XXV 0.63 g, 3.46 mmol), compound XXIV (1.0 g, 3.46 mmol), and sodium carbonate (0.8 g, 6.92 mmol) in acetonitrile (20 mL) was refluxed for 18 hr. The mixture was cooled, filtered, and concentrated in vacuo. The residue was chromatographed on silica gel using ethyl acetate as the eluent to give the desired product (1.2 g, 79.8%, mp: 155°-157°).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]2[CH:19]=[C:18]3[C:13]([C:14]([OH:26])=[C:15]([C:21](OCC)=[O:22])[C:16](=[O:20])[NH:17]3)=[N:12][CH:11]=2)[CH:5]=[CH:6][C:7]=1[F:8].[NH2:27][CH2:28][C:29]([CH3:33])([CH3:32])[CH2:30][OH:31]>>[F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]2[CH:19]=[C:18]3[C:13]([C:14]([OH:26])=[C:15]([C:21]([NH:27][CH2:28][C:29]([CH3:33])([CH3:32])[CH2:30][OH:31])=[O:22])[C:16](=[O:20])[NH:17]3)=[N:12][CH:11]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)c(F)c3)cc2[nH]c1=O
Reactant: CC(C)(CN)CO
Product: CC(C)(CO)CNC(=O)c1c(O)c2ncc(Cc3ccc(F)c(F)c3)cc2[nH]c1=O

Procedure:
This compound was prepared from ethyl 7-[(3,4-difluorophenyl)methyl]-4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate and 3-amino-2,2-dimethylpropanol employing methods similar to those described in Example 9 and was obtained as an off-white solid: 1H NMR (d6-DMSO) δ 8.40 (1H, br s), 7.41-7.36 (3H, m), 7.12 (1H, br s), 4.70 (1H, br s), 4.07 (2H, s), 3.20-3.15 (4H, m), 0.83 (3H, s), 0.77 (3H, s); HRMS calcd for C21H21F2N3O4+H+: 418.1578. Found 418.1573.
Reaction SMILES: [CH3:1][C:2]1[CH:15]=[CH:14][C:13]2[S:12](=[O:17])(=[O:16])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5](=[O:18])[C:4]=2[CH:3]=1.S(=O)(=O)(O)[OH:20].[OH2:24]>C(O)(=O)C.[O-2].[O-2].[O-2].[Cr+6]>[C:1]([C:2]1[CH:15]=[CH:14][C:13]2[S:12](=[O:17])(=[O:16])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5](=[O:18])[C:4]=2[CH:3]=1)([OH:20])=[O:24]
Reactant: Cc1ccc2c(c1)C(=O)c1ccccc1S2(=O)=O
Reactant: O
Reactant: O=S(=O)(O)O
Agent: [Cr+6]
Agent: [O-2]
Solvent: CC(=O)O
Product: O=C(O)c1ccc2c(c1)C(=O)c1ccccc1S2(=O)=O

Procedure:
A solution of chromium trioxide (1.50 g) in water (4.0 ml) was added to 2-methylthioxanthone-10,10-dioxide (1.29 g) in acetic acid (25 ml). Sulphuric acid (2.0 ml) was added and the mixture was boiled under reflux for 15 min. The mixture was cooled, and the crystallised product was filtered off, washed with water, and dried at 110° C, m.p. 276° C.
Reaction SMILES: Cl.[C:2]1([CH:8]2[CH:13]=[CH:12][NH:11][CH2:10][CH2:9]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(C(C)C)C(C)C)C.[C:23]1([C:29]2([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)[O:33][C:32]3[CH:34]=[CH:35][C:36]([S:38](Cl)(=[O:40])=[O:39])=[CH:37][C:31]=3[O:30]2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.Cl>C(Cl)Cl>[C:42]1([C:29]2([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[O:33][C:32]3[CH:34]=[CH:35][C:36]([S:38]([N:11]4[CH2:10][CH:9]=[C:8]([C:2]5[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=5)[CH2:13][CH2:12]4)(=[O:39])=[O:40])=[CH:37][C:31]=3[O:30]2)[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1
Reactant: O=S(=O)(Cl)c1ccc2c(c1)OC(c1ccccc1)(c1ccccc1)O2
Reactant: C1=CC(c2ccccc2)CCN1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=S(=O)(c1ccc2c(c1)OC(c1ccccc1)(c1ccccc1)O2)N1CC=C(c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 47.6 %

Procedure:
4-Phenyl-1,2,3,4-tetrahydropyridine hydrochloride (15.92 mg, 0.10 mmol) was suspended in methylene chloride (2 ml). Ethyldiisopropylamine (0.035 ml, 0.20 mmol) was added and the solution was shaken for 10 minutes at room temperature. 2,2-Diphenyl-benzo[1,3]dioxole-5-sulfonyl chloride (37.28 mg, 0.10 mmol) was added and the reaction was shaken at room temperature for 12 hours. Aqueous HCl (0.1 N, 1.0 ml) was added and the mixture shaken for 30 minutes, the aqueous layer removed and the organic phase concentrated and purified by preparative reverse phase HPLC (YMC, ODS-AQ packing; 20%→95% CH3CN/H2O) to yield the sulfonamide (23.6 mg, 48%).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][N:8]=[CH:7][CH:6]=1.[C-:11]#[N:12].[K+]>C(#N)C.C1OCCOC2C(=CC=CC=2)OCCOCCOC2C(=CC=CC=2)OC1>[N:8]1[CH:9]=[CH:10][C:5]([CH2:4][CH2:3][CH2:2][C:11]#[N:12])=[CH:6][CH:7]=1
Reactant: ClCCCc1ccncc1
Reactant: [C-]#N
Agent: [K+]
Agent: c1ccc2c(c1)OCCOCCOc1ccccc1OCCOCCO2
Solvent: CC#N
Product: N#CCCCc1ccncc1
Temperature: 25 °C
Yield: 84.5 %

Procedure:
To the product of Example 21(6.7 g, 42.9 mmol) in 300 mL of acetonitrile (CH3CN), was added potassium cyanide (KCN, 11.2 g, 171.7 mmol) and dibenzo-18-crown-6 (1.0 g, 2.8 mmol). After the reaction had been refluxed for 18 hours, it was cooled to room temperature, and stripped of all solvent under reduced pressure. The residue was partitioned between 100 mL each of water and CH2Cl2 and the aqueous phase was washed with 3×100 mL of CH2Cl2. The combined organic phase was dried (Na2SO4), filtered, and stripped of solvent to yield 6.7 g of crude product. This material was purified by HPLC on silica gel to yield 5.3 g of the title material as a yellow oil.
Reaction SMILES: [C:1]([O:10][CH3:11])(=[O:9])[C:2]([CH2:4][C:5](OC)=[O:6])=[CH2:3].[CH2:12]([NH2:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CO>[CH2:12]([N:19]1[CH2:3][CH:2]([C:1]([O:10][CH3:11])=[O:9])[CH2:4][C:5]1=[O:6])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: C=C(CC(=O)OC)C(=O)OC
Reactant: NCc1ccccc1
Solvent: CO
Product: COC(=O)C1CC(=O)N(Cc2ccccc2)C1

Procedure:
A solution of dimethyl itaconate (50 g, 0.32 mole) in methanol (40 ml) was treated with benzylamine (34.6 ml, 0.32 mole) and the mixture heated under reflux for 2.5h. The solution was then concentrated in vacuo and the residue purified by distillation (b.p. 162°-170° C.0.2 mm) to give a pale yellow oil. This solidified on standing to give the title compound (D10) as a beige solid (66.2 g, 89%), m.p. 62°-63° C.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[CH3:7][C:8](C)(C1C=CC=C(C(C)(C)O)C=1)O.C(OC=C)(=O)C.[OH:27][C:28]([C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([C:37]([CH3:42])([O:39][CH:40]=[CH2:41])[CH3:38])[CH:32]=1)([CH3:30])[CH3:29]>C1(C)C=CC=CC=1>[CH3:38][C:37]([C:33]1[CH:34]=[CH:35][CH:36]=[C:31]([C:28]([O:27][CH:7]=[CH2:8])([CH3:30])[CH3:29])[CH:32]=1)([O:39][CH:40]=[CH2:41])[CH3:42]
Reactant: C=COC(C)(C)c1cccc(C(C)(C)O)c1
Reactant: CC(C)(O)c1cccc(C(C)(C)O)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: C=COC(C)=O
Product: C=COC(C)(C)c1cccc(C(C)(C)OC=C)c1
Temperature: 100 °C
Reaction time: 6 h

Procedure:
To a mixture of di-μ-chlorobis(1,5-cyclooctadiene) diiridium(I) [Ir(cod)Cl]2 (67 mg, 0.1 mmol) and sodium carbonate (640 mg, 6 mmol) in toluene (5 ml) were added α,α,α′,α′-tetramethyl-1,3-benzenedimethanol (5 mmol) and vinyl acetate (2.15 g, 25 mmol), followed by stirring at 100° C. in an atmosphere of argon gas for 6 hours. The reaction mixture was analyzed by gas chromatography to find that 1-(1-hydroxy-1-methylethyl)-3-(1-methyl-1-vinyloxyethyl)benzene and 1,3-bis(1-methyl-1-vinyloxyethyl)benzene were formed in yields of 8% and 70%, respectively, with a conversion from α,α,α′,α′-tetramethyl-1,3-benzenedimethanol of 98%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH:9]([O:18][C:19]([O:21]C2C=CC=CC=2)=O)[CH2:10][CH2:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:4][CH:3]=1.C([O-])(=O)C.[NH4+:33].C(O)(=O)C>O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:33][C:19](=[O:21])[O:18][C:9]=2[CH2:10][CH2:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:4][CH:3]=1
Reactant: CCOC(=O)CCCC(OC(=O)Oc1ccccc1)C(=O)c1ccc(F)cc1
Reactant: [NH4+]
Agent: CC(=O)[O-]
Solvent: CC(=O)O
Solvent: O
Product: CCOC(=O)CCCc1oc(=O)[nH]c1-c1ccc(F)cc1

Procedure:
A mixture of ethyl 6-(4-fluorophenyl)-6-oxo-5-phenoxycarbonyloxyhexanoate (18.0 g), ammonium acetate (17.8 g) and acetic acid (100 ml) was stirred with heating under reflux for 2 hours. The reaction mixture was poured into water (500 ml) and extracted with ethyl acetate (200 ml×2), and the extract was washed with water (200 ml). The organic layer was dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography, and ethyl 4-[4-(4-fluorophenyl)-2-oxo-4-oxazolin-5-yl]butanoate was obtained as an oil (7.67 g, 56%) from an ethyl acetate-hexane (1:1, v/v)-eluted fraction.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9]([CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)(=[O:11])=[O:10])[CH:5]=[CH:6][C:7]=1[Cl:8].Cl[C:19]1[C:24]([N+:25]([O-:27])=[O:26])=[CH:23][CH:22]=[CH:21][N:20]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([S:9]([CH:12]2[CH2:17][CH2:16][N:15]([C:19]3[C:24]([N+:25]([O-:27])=[O:26])=[CH:23][CH:22]=[CH:21][N:20]=3)[CH2:14][CH2:13]2)(=[O:11])=[O:10])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=S(=O)(c1ccc(Cl)c(Cl)c1)C1CCNCC1
Reactant: O=[N+]([O-])c1cccnc1Cl
Product: O=[N+]([O-])c1cccnc1N1CCC(S(=O)(=O)c2ccc(Cl)c(Cl)c2)CC1
Yield: 99.9 %

Procedure:
Using the procedure from Example 7A, Step 7E, 4-[(3,4-dichlorophenyl)sulfonyl]piperidine (150 mg, 0.51 mmol) was reacted with 2-chloro-3-nitropyridine (97 mg, 0.61 mmol) to afford the title compound (212 mg), a yellow solid, in 74% yield.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[H-].[Na+].[N:13]1[C:20]([Cl:21])=[N:19][C:17](Cl)=[N:16][C:14]=1[Cl:15]>O1CCCC1>[Cl:15][C:14]1[N:13]=[C:20]([Cl:21])[N:19]=[C:17]([N:3]2[C:4]3[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=3[N:6]=[C:2]2[CH3:1])[N:16]=1
Reactant: Clc1nc(Cl)nc(Cl)n1
Reactant: Cc1nc2ccccc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1nc2ccccc2n1-c1nc(Cl)nc(Cl)n1
Temperature: 0 °C
Reaction time: 1 h
Yield: 24.5 %

Procedure:
2-Methylbenzimidazole (5.0 g) was dissolved in tetrahydrofuran (50 ml), and sodium hydride (60% purity, oily) (1.6 g) was added thereto at room temperature. After stirring for 1 hour, cyanuric chloride (7.0 g) was added at room temperature, followed by stirring for 3 hours. Ice water was added, followed by extraction with ethyl acetate, washing with a saturated sodium chloride aqueous solution and drying over anhydrous magnesium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography to obtain 2.6 g of the desired product as a white powder (m.p. at least 300° C.)
Reaction SMILES: [H-].[Na+].[NH:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[NH:5][C:4]1=[O:12].[CH3:13][O:14][C:15](=[O:24])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]Br>CN(C=O)C>[CH3:13][O:14][C:15](=[O:24])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][N:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[NH:5][C:4]1=[O:12]
Reactant: O=c1[nH]c2ccccc2[nH]1
Reactant: COC(=O)CCCCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)CCCCCCCn1c(=O)[nH]c2ccccc21

Procedure:
The product is produced as described in example 1 from 2.8 g. of NaH (80% suspension in mineral oil), 25 g. of benzimidazolin-2-one, 180 cc. of DMF, 22.1 g. of 8-bromocaprylic acid methyl ester and 2.8 g. of NaJ. Eluant in chromatographic purification: chloroform/methanol.
Reaction SMILES: C(C1C=CC([C:11]2[N:16]=[C:15]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([CH3:26])([CH3:25])[CH3:24])=[CH:19][CH:18]=3)[N:14]=[C:13]([C:27]3[CH:32]=[C:31]([CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])[C:30]([OH:39])=[CH:29][C:28]=3[OH:40])[N:12]=2)=CC=1)(C)(C)C.C(=O)([O-])[O-].[K+].[K+].[I-].[K+].Cl[CH2:50][C:51]([O:53][CH2:54][CH3:55])=[O:52]>CC(C)=O>[C:23]([C:20]1[CH:19]=[CH:18][C:17]([C:15]2[NH:14][C:13]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([CH3:26])([CH3:25])[CH3:24])=[CH:19][CH:18]=3)([C:27]3[CH:32]=[C:31]([CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])[C:30]([O:39][CH2:50][C:51]([O:53][CH2:54][CH3:55])=[O:52])=[CH:29][C:28]=3[OH:40])[N:12]=[CH:11][N:16]=2)=[CH:22][CH:21]=1)([CH3:24])([CH3:25])[CH3:26]
Reactant: CCOC(=O)CCl
Reactant: CCCCCCc1cc(-c2nc(-c3ccc(C(C)(C)C)cc3)nc(-c3ccc(C(C)(C)C)cc3)n2)c(O)cc1O
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCCCCc1cc(C2(c3ccc(C(C)(C)C)cc3)N=CN=C(c3ccc(C(C)(C)C)cc3)N2)c(O)cc1OCC(=O)OCC
Temperature: 25 °C
Yield: 171.8 %

Procedure:
To a stirred mixture of 10 g of 2,4-bis(4-tert-butylphenyl)-6-(2,4-dihydroxy-5-hexylphenyl)-1,3,5-triazine, 7.4 g of anhydrous potassium carbonate, 0.5 g of potassium iodide, and 80 mL of acetone was added 2.2 mL (2.5 g) of ethyl chloroacetate. The mixture was stirred at reflux for 2.5 h and then allowed to cool to room temperature. The solids were removed by filtration and washed with methylene chloride. The combined filtrates were concentrated under reduced pressure to a volume of 75 mL and diluted with 50 mL of methanol. The resulting solid was collected by filtration and washed with methanol. After drying in vacuo, 10 g of 2,6-bis(4-tert-butylphenyl)-6-(2-hydroxy-4-ethoxycarbonylmethoxy-5-hexylphenyl)-1,3,5-triazine was obtained. The structure was verified by 1HNMR spectroscopy.
Reaction SMILES: COC1C=CC(C[S:8][C@@H:9]2[CH2:13][N:12]([C:14]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=3)=[O:15])[C@H:11]([C:27]([OH:29])=O)[CH2:10]2)=CC=1.C(Cl)(=O)C(C)(C)C.FC(F)(F)C(O)=O.[CH3:46][N:47]([C@H:61]1[CH2:65][CH2:64][NH:63][CH2:62]1)[C:48]([O:50][CH2:51][C:52]1[CH:57]=[CH:56][C:55]([N+:58]([O-:60])=[O:59])=[CH:54][CH:53]=1)=[O:49]>>[SH:8][C@@H:9]1[CH2:13][N:12]([C:14]([O:16][CH2:17][C:18]2[CH:19]=[CH:20][C:21]([N+:24]([O-:26])=[O:25])=[CH:22][CH:23]=2)=[O:15])[C@H:11]([C:27]([N:63]2[CH2:64][CH2:65][C@H:61]([N:47]([CH3:46])[C:48]([O:50][CH2:51][C:52]3[CH:57]=[CH:56][C:55]([N+:58]([O-:60])=[O:59])=[CH:54][CH:53]=3)=[O:49])[CH2:62]2)=[O:29])[CH2:10]1
Reactant: CN(C(=O)OCc1ccc([N+](=O)[O-])cc1)[C@H]1CCNC1
Reactant: COc1ccc(CS[C@H]2C[C@@H](C(=O)O)N(C(=O)OCc3ccc([N+](=O)[O-])cc3)C2)cc1
Agent: CC(C)(C)C(=O)Cl
Solvent: O=C(O)C(F)(F)F
Product: CN(C(=O)OCc1ccc([N+](=O)[O-])cc1)[C@H]1CCN(C(=O)[C@@H]2C[C@H](S)CN2C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Yield: 76 %

Procedure:
Following a procedure similar to that described in Preparation 18, but using 1.21 g of (2S,4S)-4-(4-methoxybenzylthio)-1-(4-nitrobenzyloxycarbonyl)-2-pyrrolidinecarboxylic acid, 343 mg of pivaloyl chloride and 1.27 g of (3S)-3-[N-methyl-N-(4-nitrobenzyloxycarbonyl)amino]pyrrolidine trifluoroacetate, 1.21 g of the title compound were obtained as a powder.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:4]=[CH:5][C:6]([CH2:9]O)=[N:7][CH:8]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:33]>ClCCl>[Br:33][CH2:9][C:6]1[CH:5]=[CH:4][C:3]([C:2]([F:12])([F:11])[F:1])=[CH:8][N:7]=1
Reactant: BrC(Br)(Br)Br
Reactant: OCc1ccc(C(F)(F)F)cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: FC(F)(F)c1ccc(CBr)nc1
Reaction time: 1 h
Yield: 73.8 %

Procedure:
To (5-trifluoromethyl-pyridin-2-yl)-methanol (1.65 g) in dichloromethane (20 ml) at 0° C. (ice-bath) under nitrogen was added triphenylphosphine (3.66 g, 13.98 mmol) in portions, followed by addition of carbon tetrabromide (3.23 g) in portions. The ice-bath was removed and the flask was sealed with a glass stopper. The reaction mixture was gently stirred for 1 hour. The crude reaction mixture was loaded onto a silica gel column (120 g), and eluted with methyl acetate/hexane to give 2-bromomethyl-5-trifluoromethyl-pyridine as a light orange oil (1.65 g, 73%).
Reaction SMILES: C(OC(=O)[N:7]([CH2:14][CH2:15][O:16][C:17]1[CH:22]=[C:21]([C:23](=[O:32])[N:24]([CH2:28][CH2:29][C:30]#[N:31])[CH:25]2[CH2:27][CH2:26]2)[CH:20]=[C:19]([Cl:33])[CH:18]=1)[C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1)(C)(C)C.FC(F)(F)C(O)=[O:38]>ClCCl>[ClH:33].[C:30]([CH2:29][CH2:28][N:24]([CH:25]1[CH2:26][CH2:27]1)[C:23](=[O:32])[C:21]1[CH:22]=[C:17]([O:16][CH2:15][CH2:14][NH:7][C:8]2[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=2)[CH:18]=[C:19]([Cl:33])[CH:20]=1)(=[O:38])[NH2:31]
Reactant: O=C(O)C(F)(F)F
Reactant: CC(C)(C)OC(=O)N(CCOc1cc(Cl)cc(C(=O)N(CCC#N)C2CC2)c1)c1ccncc1
Solvent: ClCCl
Product: Cl
Product: NC(=O)CCN(C(=O)c1cc(Cl)cc(OCCNc2ccncc2)c1)C1CC1
Reaction time: 18 h

Procedure:
A solution of (2-{3-chloro-5-[(2-cyano-ethyl)-cyclopropyl-carbamoyl]-phenoxy}-ethyl)-pyridin-4-yl-carbamic acid tert-butyl ester (0.075 g) in a mixture of dichloromethane (5 ml) and trifluoroacetic acid (5 ml) was stored at room temperature for 18 h and then concentrated under reduced pressure. The residue was triturated with ethereal hydrogen chloride to give the title compound (0.065 g) as a colourless gum.
Reaction SMILES: [C:1]1(=[O:11])[O:6][C:4](=O)[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.Cl.[NH2:13][C:14]1[C:15]([O:22][CH3:23])=[N:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=1.C([O-])(=O)C.[Na+]>C(O)(=O)C>[O:11]=[C:1]1[C:2]2[C:3](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4](=[O:6])[N:13]1[C:14]1[C:15]([O:22][CH3:23])=[N:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=1
Reactant: COc1ccc(N)c(OC)n1
Reactant: O=C1OC(=O)c2ccccc21
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Product: COc1ccc(N2C(=O)c3ccccc3C2=O)c(OC)n1

Procedure:
1,3-Dioxo-2-(2,6-dimethoxypyridin-3-yl)-isoindoline (5) was prepared and isolated as follows. A mixture of phthalic anhydride (0.89 g, 6 mmol), 3-amino -2,6-dimethoxypyridine monohydrochloride (95%, 1 g, 5 mmol) and sodium acetate (0.49 g, 6 mmol) in glacial acetic acid (50 ml) was refluxed for 3 h. The solvent was removed under vacuum. The residue was dissolved in dichloromethane (200 ml) and washed with water (100 ml×3), dried over Na2SO4 and concentrated to give the crude product. The crude product was recrystallized with ethyl acetate to give 5 (1.345 g, 90%) as a pale pink crystals: mp 182-183° C.; 1H NMR (CDCl3) δ 7.96-7.90 (m, 2H), 7.80-7.76 (m, 2H), 7.44 (d, J=8.1 Hz, 1H), 6.42 (d, J=8.1 Hz, 1H, 3.95 (s, 3 H), 3.91 (s, 3 H); 13C NMR (DMSO-d6) δ 166.5, 160.6, 156.1, 140.1, 132.8, 129.4, 121.4, 104.6, 99.3, 51.7, 51.5; MS (CI/CH4) 285 [M+1]+. Anal. Calcd for C15H12N2O4: C, 63.38; H, 4.25; N, 9.85. Found: C, 63.57; H, 4.18; N, 9.65.
Reaction SMILES: [CH2:1]([C:3]1[N:8]=[CH:7][C:6]([OH:9])=[CH:5][N:4]=1)[CH3:2].C(=O)([O-])[O-].[K+].[K+].[P:16]([S:22][CH2:23][CH:24]([CH3:26])[CH3:25])(=[S:21])(Cl)[O:17][CH2:18][CH3:19].[H][H]>C(#N)C>[P:16]([S:22][CH2:23][CH:24]([CH3:26])[CH3:25])(=[S:21])([O:9][C:6]1[CH:5]=[N:4][C:3]([CH2:1][CH3:2])=[N:8][CH:7]=1)[O:17][CH2:18][CH3:19]
Reactant: [H][H]
Reactant: CCOP(=S)(Cl)SCC(C)C
Reactant: CCc1ncc(O)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOP(=S)(Oc1cnc(CC)nc1)SCC(C)C

Procedure:
A mixture of 5 grams of 2-ethyl-5-pyrimidinol, 5 grams of finely powdered potassium carbonate, 40 ml of acetonitrile and 9.3 grams of O-ethyl S-(2-methylpropyl) phosphorochloridodithioate was stirred without external heating overnight. The solids were then removed by filtration, the filtrate concentrated under vacuum, the residue taken up in diethyl ether, the ether solution washed twice with 2% aqueous sodium hydroxide, once with saturated sodium chloride solution and dried over anhydrous sodium sulfate. The solvent was removed in a rotary evaporator leaving a pale amber colored oil having a refractive index of 25° of 1.5296. Elemental analysis showed the product contained 44.81% carbon; 6.58% hydrogen and 8.59% nitrogen. Theoretical analysis is 44.98% carbon; 6.61% hydrogen and 8.74% nitrogen.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[NH:21])[C:10]([C:13]2[C:18]([Cl:19])=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:20])([CH3:12])[CH3:11])=[C:4]([F:22])[CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:30][C:31](=[O:37])[C:32]([O:34][CH2:35][CH3:36])=[O:33].Cl>C1(C)C=CC=CC=1.C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:30][C:31]([OH:37])([C:32]([O:34][CH2:35][CH3:36])=[O:33])[N:21]=[C:9]2[C:10]([C:13]2[C:14]([Cl:20])=[CH:15][CH:16]=[CH:17][C:18]=2[Cl:19])([CH3:11])[CH3:12])=[C:4]([F:22])[CH:3]=1
Reactant: CCOC(=O)C(=O)CBr
Reactant: CC(C)(C(=N)Nc1ccc(Br)cc1F)c1c(Cl)cccc1Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCOC(=O)C1(O)CN(c2ccc(Br)cc2F)C(C(C)(C)c2c(Cl)cccc2Cl)=N1
Temperature: 5 °C
Reaction time: 1.5 h
Yield: 95.8 %

Procedure:
To a mixture of N-(4-bromo-2-fluorophenyl)-2-(2,6-dichlorophenyl)-2-methylpropanimidamide (48.0 g, 119 mmol), K2CO3 (41.0 g, 297 mmol) in toluene (180 mL) and THF (180 mL) at 55° C. was added slowly a solution of ethyl 3-bromo-2-oxopropanoate (23.3 mL, 166 mmol) in 24 mL of THF over 50 minutes. The reaction mixture was kept at 55° C. for 1.5 hours. A white slurry was observed. The reaction mixture was cooled to 5° C. HCl (0.5N, 450 mL) was added drop-wise (end point pH=9˜10). After addition, the suspension was cooled to 0° C. The solid was collected by filtration, washed with water (2×50 mL), and then dried in a vacuum oven at 60° C. overnight. Ethyl 1-(4-bromo-2-fluorophenyl)-2-(2-(2,6-dichlorophenyl)propan-2-yl)-4-hydroxy-4,5-dihydro-1H-imidazole-4-carboxylate (59 g, 114 mmol, 96% yield) was obtained as a white solid. 1H-NMR (CDCl3, 400 MHz) δ 7.11 (m, 3H), 6.96 (m, 2H), 6.72 (t, 1H, J=8.28 Hz), 4.35 (m, 2H), 4.25 (d, 1H, J=10.5 Hz), 3.80 (d, 1H, J=10.8 Hz), 1.98 (s, 3H), 1.93 (s, 3H), 1.38 (t, 3H, J=7.03 Hz); 13C-NMR (CDCl3, 126 MHz) δ 173.0, 171.5, 159.8, 157.8, 137.3, 135.7, 132.1, 131.1, 128.1, 127.4, 125.6, 122.2, 120.1, 93.5, 62.5, 45.5, 30.2, 14.0; MS m/e 517.05 (M+H+); HPLC (XBridge 5μ C18 4.6×50 mm, 4 mL/min, Solvent A: 10% MeOH/water with 0.2% H3PO4, Solvent B: 90% MeOH/water with 0.2% H3PO4, gradient with 0-100% B over 4 minutes): 2.74 minutes.