Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)CCC)C.CC(C)=O.[CH3:13][C:14](=O)[CH2:15][C:16](=O)[CH2:17][CH2:18][CH3:19].[C:22]([CH2:24][C:25]([NH2:27])=[O:26])#[N:23].N1CCCCC1>CCOCC.CCO>[CH3:13][C:14]1[CH:15]=[C:16]([CH2:17][CH2:18][CH3:19])[NH:27][C:25](=[O:26])[C:24]=1[C:22]#[N:23]
Reactant: N#CCC(N)=O
Reactant: CCCC(=O)CC(C)=O
Solvent: C1CCNCC1
Solvent: CCCC(=O)OCC
Solvent: CCO
Product: CCCc1cc(C)c(C#N)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 4 h
Yield: 40 %

Procedure:
To a solution of NaNH2 (32.5 g, 862 mmol) in anhydrous ether (500 mL) at 30° C. was added dropwise a mixture of butyric acid ethyl ester (50 g, 431 mmol) and acetone (37.5 g, 646.5 mol). After addition, the reaction mixture was stirred for 4 h. The reaction mixture was poured onto ice water with stirring. Additional ether was added, and the layers were separated. The aqueous layer was acidified to pH 5.0 with 2 N HCl and then to pH 7.5 with Na2CO3. The aqueous layer was then extracted with ether. The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. The crude product, 2,4-heptanedione (20 g, 156 mmol), and 2-cyanoacetamide (13.12 g, 156 mmol) were suspended in EtOH (160 mL) at 75° C., followed by addition of piperidine (13.2 g, 156 mmol). The contents were stirred and heated at reflux for 1 h. The mixture was cooled to room temperature and filtered. The collected solid was suspended in water and stirred for 1 h. The mixture was filtered and dried to give 4-methyl-2-oxo-6-propyl-1,2-dihydro-3-pyridinecarbonitrile (11 g, 40%). LCMS E-S(M+H)=181.1. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.3-12.4 (br s, 1H), 6.25 (s, 1H), 3.64 (s, 3H), 2.50 (t, 2H), 1.63 (m, 2H), 0.94 (t, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[CH:14]=[C:13]([NH2:15])[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1.[Cl:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:18]=1[N:24]=[C:25]=[O:26]>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[N:10]=[CH:11][N:12]=[C:13]([NH:15][C:25]([NH:24][C:18]3[C:19]([Cl:23])=[CH:20][CH:21]=[CH:22][C:17]=3[Cl:16])=[O:26])[CH:14]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C=Nc1c(Cl)cccc1Cl
Reactant: Nc1cc(Nc2cccc(Cl)c2)ncn1
Product: O=C(Nc1cc(Nc2cccc(Cl)c2)ncn1)Nc1c(Cl)cccc1Cl

Procedure:
The title compound is prepared analogously as described in Example 127 from N-(3-chloro-phenyl)-pyrimidine-4,6-diamine and 2,6-dichlorophenyl isocyanate.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:33])[CH2:4][NH:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH:16]=[C:15]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=3[Cl:24])[N:14]=[C:13]2[CH2:25][C:26]2[CH:31]=[CH:30][C:29](Br)=[CH:28][CH:27]=2)=[CH:8][CH:7]=1.C(OB([C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)O)CCC>>[CH3:1][O:2][C:3](=[O:33])[CH2:4][NH:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH:16]=[C:15]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=3[Cl:24])[N:14]=[C:13]2[CH2:25][C:26]2[CH:31]=[CH:30][C:29]([C:44]3[CH:43]=[CH:42][C:41]([CH:6]([CH2:7][CH3:8])[CH3:11])=[CH:46][CH:45]=3)=[CH:28][CH:27]=2)=[CH:8][CH:7]=1
Reactant: COC(=O)CNc1ccc(-n2cc(-c3ccc(Cl)cc3Cl)nc2Cc2ccc(Br)cc2)cc1
Reactant: CCCCOB(O)c1ccccc1
Product: CCC(C)c1ccc(-c2ccc(Cc3nc(-c4ccc(Cl)cc4Cl)cn3-c3ccc(NCC(=O)OC)cc3)cc2)cc1

Procedure:
{4-[2-(4-Bromo-benzyl)-4-(2,4-dichloro-phenyl)-imidazol-1-yl]-phenylamino}-acetic acid methyl ester (1.8 g, 3.3 mmol) was coupled with 4-sec butyl-phenyl boronic acid (750 mg, 4.0 mmol) according to general procedure G to give {4-[2-(4′-sec-butyl-biphenyl-4-ylmethyl)-4-(2,4-dichloro-phenyl)-imidazol-1-yl]-phenylamino}-acetic acid methyl ester.
Reaction SMILES: C([O:3][C:4]([C@H:6]1[CH2:11][CH2:10][C@H:9]([O:12][C:13]2[N:14]=[N:15][CH:16]=[CH:17][CH:18]=2)[CH2:8][CH2:7]1)=[O:5])C.[OH-].[Na+]>O1CCOCC1>[N:15]1[CH:16]=[CH:17][CH:18]=[C:13]([O:12][C@H:9]2[CH2:8][CH2:7][C@H:6]([C:4]([OH:5])=[O:3])[CH2:11][CH2:10]2)[N:14]=1
Reactant: CCOC(=O)[C@H]1CC[C@H](Oc2cccnn2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: O=C(O)[C@H]1CC[C@H](Oc2cccnn2)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of cis/trans-4-(pyridazin-3-yloxy)-cyclohexanecarboxylic acid ethyl ester (1:1) (1.05 g, 4.19 mmol) in 1,4-dioxane (21 ml) was added 2 M aqueous sodium hydroxide solution (21 ml, 42 mmol). Stirring at room temperature for 16 h was followed by acidification to pH 2-3 with 1 M aqueous hydrogen chloride solution (44 ml) and extraction with three 100-ml portions of ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo to give the title compound (0.80 g, 86%) as off-white solid.
Reaction SMILES: C(OC([NH:8][C:9]([C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:23]([Cl:24])=[CH:22][N:21]=[C:20]([NH:25][C:26]3[CH:31]=[CH:30][C:29]([CH2:32][CH2:33]O)=[CH:28][CH:27]=3)[N:19]=2)=[CH:14][CH:13]=1)([CH3:11])[CH3:10])=O)(C)(C)C.C(N(C(C)C)CC)C.[CH3:43][C:44]1[NH:45][CH:46]=[CH:47][N:48]=1.C([NH+](CC)CC)C>C(#N)C.O1CCCC1>[NH2:8][C:9]([C:12]1[CH:13]=[CH:14][C:15]([C:18]2[C:23]([Cl:24])=[CH:22][N:21]=[C:20]([NH:25][C:26]3[CH:27]=[CH:28][C:29]([CH2:32][CH2:33][N:45]4[CH:46]=[CH:47][N:48]=[C:44]4[CH3:43])=[CH:30][CH:31]=3)[N:19]=2)=[CH:16][CH:17]=1)([CH3:11])[CH3:10]
Reactant: CC(C)(C)OC(=O)NC(C)(C)c1ccc(-c2nc(Nc3ccc(CCO)cc3)ncc2Cl)cc1
Reactant: Cc1ncc[nH]1
Agent: CCN(CC)C(C)C
Agent: CC[NH+](CC)CC
Solvent: C1CCOC1
Solvent: CC#N
Product: Cc1nccn1CCc1ccc(Nc2ncc(Cl)c(-c3ccc(C(C)(C)N)cc3)n2)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 43.4 %

Procedure:
A mixture of derivatised resin (1) (55 mg), N,N-diethylisopropylamine (38 mg, 0.30 mmol), and 2-methylimidazole (8 mg, 0.10 mmol) in anhydrous acetonitrile (2 ml) was heated at 70° for 18 h, with agitation. The mixture was allowed to cool to room temperature then diluted with anhydrous tetrahydrofuran (2 ml) and treated with polystyrene methylisocyanate (Argonaut Technologies, 120 mg, 1.65 mmol/g, 0.2 mmol equivalent) and macroporous triethylammonium methylpolystyrene carbonate (Argonaut Technologies, 38 mg, 2.64 mmol/g, 0.1 mmol equivalent). The resulting mixture was agitated at room temperature for 6 h, then filtered and washed once with dichloromethane. The combined filtrate and washings were evaporated to dryness under a stream of nitrogen, then resuspended in dichloromethane (1 mL) and treated with trifluoroacetic acid (1 mL) for 1 h at room temperature. The mixture was evaporated to give the title compound (19.4 mg).
Reaction SMILES: [CH2:1]([C:3]1[O:7][C:6]([CH2:8][C:9]2[CH:10]=[C:11]([NH:29]C(=O)C(F)(F)F)[CH:12]=[CH:13][C:14]=2[S:15](=[O:28])(=[O:27])[NH:16][C:17]2[CH:18]=[CH:19][C:20]3[CH2:24][O:23][B:22]([OH:25])[C:21]=3[CH:26]=2)=[N:5][N:4]=1)[CH3:2]>[NH4+].CO>[NH2:29][C:11]1[CH:12]=[CH:13][C:14]([S:15]([NH:16][C:17]2[CH:18]=[CH:19][C:20]3[CH2:24][O:23][B:22]([OH:25])[C:21]=3[CH:26]=2)(=[O:27])=[O:28])=[C:9]([CH2:8][C:6]2[O:7][C:3]([CH2:1][CH3:2])=[N:4][N:5]=2)[CH:10]=1
Reactant: CCc1nnc(Cc2cc(NC(=O)C(F)(F)F)ccc2S(=O)(=O)Nc2ccc3c(c2)B(O)OC3)o1
Agent: [NH4+]
Solvent: CO
Product: CCc1nnc(Cc2cc(N)ccc2S(=O)(=O)Nc2ccc3c(c2)B(O)OC3)o1
Yield: 64.8 %

Procedure:
A solution of N-(3-((5-ethyl-1,3,4-oxadiazol-2-yl)methyl)-4-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)sulfamoyl)phenyl)-2,2,2-trifluoroacetamide (390 mg, 0.76 mmol) in 7M ammonium in MeOH (10 mL) was stirred in a sealed tube at 50° C. for 16 hours. After concentrated, the crude mixture was purified by prep HPLC (SunFire Prep C18 OBD 5 uM 30×50 mm column) to give the title compound as a yellow solid (204 mg, yield 64%). MS calcd for (C18H19BN4O5S): 414.2, MS found (ESI negative): (M−H)−=413.1. 1H NMR (DMSO-d6) δ (ppm): 10.0 (s, 1H), 9.16 (bs, 1H), 7.56 (d, J=8.8 Hz, 1H), 7.42 (s, 1H), 7.22 (d, J=8.0 Hz, 1H), 7.11 (d, J=8.4 Hz, 1H), 6.42 (d, J=8.8 Hz, 1H), 6.26 (s, 1H), 4.85 (s, 2H), 4.42 (s, 2H), 2.75 (q, 2H), 1.19 (t, 3H).
Reaction SMILES: [H-].[Na+].[F:3][CH:4]([F:17])[O:5][C:6]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[C:7]=1[C:8](=[N:10][OH:11])[NH2:9].Br[CH2:19][CH:20]1[CH2:22][CH2:21]1.O>CN(C)C=O>[CH:20]1([CH2:19][O:11][N:10]=[C:8]([NH2:9])[C:7]2[C:12]([F:16])=[CH:13][CH:14]=[CH:15][C:6]=2[O:5][CH:4]([F:3])[F:17])[CH2:22][CH2:21]1
Reactant: BrCC1CC1
Reactant: NC(=NO)c1c(F)cccc1OC(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: NC(=NOCC1CC1)c1c(F)cccc1OC(F)F
Reaction time: 3 h
Yield: 52 %

Procedure:
0.4 g of 80% pure sodium hydride was added to a solution of 3.0 g of 2-difluoromethoxy-6-fluorobenzamidoxime in 30 ml of dimethylformamide (DMF) at 0 to 5° C. and the mixture was stirred at this temperature for 3 hours. 1.8 g of bromocyclopropylmethane were subsequently added at the same temperature, and stirring was subsequently continued for 2 hours at 5° C. and overnight at room temperature. The batch was stirred into 300 ml of water and extracted three times with in each case 70 ml of cyclohexane. After the cyclohexane had been evaporated, 1.9 g of the desired product were obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[Cl:10])[CH2:5][NH2:6].F[C:12]1[CH:20]=[N:19][CH:18]=[CH:17][C:13]=1[C:14]([OH:16])=[O:15]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[Cl:10])[CH2:5][NH:6][C:17]1[CH:18]=[N:19][CH:20]=[CH:12][C:13]=1[C:14]([OH:16])=[O:15]
Reactant: NCc1ccc(Cl)c(Cl)c1
Reactant: O=C(O)c1ccncc1F
Product: O=C(O)c1ccncc1NCc1ccc(Cl)c(Cl)c1
Yield: 37 %

Procedure:
The title compound was prepared in 37% yield from 3,4-dichlorobenzylamine and 3-fluoroisonicotinic acid according to the procedure for the preparation of Example 3. 1H NMR (400 MHz, DMSO-d6): δ 13.48 (br s, 1H), 8.10 (s, 1H), 7.84 (d, 1H, J=5.0 Hz), 7.57-7.65 (m, 3H), 7.35 (dd, 1H, J=8.3, 1.9 Hz), 4.59 (s, 2H). [M+H] calc'd for C13H10Cl2N2O2, 297, 299; found 297, 299.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:17])([CH3:16])[C:9]([O:11][CH2:12][CH2:13][CH2:14][CH3:15])=[O:10])=[CH:4][CH:3]=1.[Br:18]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:18][CH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([CH3:16])([CH3:17])[C:9]([O:11][CH2:12][CH2:13][CH2:14][CH3:15])=[O:10])=[CH:6][CH:7]=1
Reactant: CCCCOC(=O)C(C)(C)c1ccc(C)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CCCCOC(=O)C(C)(C)c1ccc(CBr)cc1
Temperature: 25 °C
Yield: 101.5 %

Procedure:
To a solution of t butyl 2-(4-methylphenyl)-2,2-dimethylacetate (19.4 g, 83 mmol) in carbon tetrachloride (350 mL) was added N-bromosuccinimide (16.2 g, 92 mmol) and benzoyl peroxide (0.5 g). The mixture was heated under reflux for 1 hour. The mixture was cooled to rt, and the precipitate was removed by filtration. The filtrate was washed with 10% NaHCO3 and brine, dried (Na2SO4), and evaporated to give t butyl 2-(4-bromomethylphenyl)-2,2-dimethylacetate as a light yellow oil (26.4 g, 100%).
Reaction SMILES: CC(C)([O-])C.[K+].Br.[Cl:8][C:9]1[CH:15]=[CH:14][CH:13]=[C:12]([OH:16])[C:10]=1[NH2:11].[CH3:17][O:18][C:19]1[CH:24]=[C:23]([O:25][CH3:26])[N:22]=[C:21](S(C)(=O)=O)[N:20]=1>CN(C)C=O>[Cl:8][C:9]1[CH:15]=[CH:14][CH:13]=[C:12]([O:16][C:21]2[N:22]=[C:23]([O:25][CH3:26])[CH:24]=[C:19]([O:18][CH3:17])[N:20]=2)[C:10]=1[NH2:11]
Reactant: COc1cc(OC)nc(S(C)(=O)=O)n1
Reactant: Nc1c(O)cccc1Cl
Agent: Br
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc(OC)nc(Oc2cccc(Cl)c2N)n1
Temperature: 80 °C
Reaction time: 0.17 h
Yield: 3 %

Procedure:
Potassium t-butoxide (22.4 g) was added portionwise to stirred, cooled 2-chloro-6-hydroxyaniline hydrobromide (22.5 g) in dimethylformamide (100 ml) under nitrogen. After 10 minutes, 4,6-dimethoxy-2-methylsulphonyl pyrimidine (21.8 g) was added, and the mixture was heated at 80° C. with stirring for 22 hours. After addition to ice/water, the precipitated solid was separated by filtration, washed thoroughly with water, dried and recrystallised from isopropanol yielding 17.5 g of the desired product, mp 84°-86° C. Reduction in volume of the mother liquors gave a further 0.85 g of product, mp 86°-87° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]=[CH:8][CH2:9][CH2:10][O:11]C2CCCCO2)[CH:2]=1.Cl>CO.O.[Pd]>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][CH2:8][CH2:9][CH2:10][OH:11])[CH:2]=1
Reactant: C(=Cc1cccnc1)CCOC1CCCCO1
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: O
Product: OCCCCc1cccnc1
Yield: 241.5 %

Procedure:
10 g (43 mmol) of 2-[4-(3-pyridyl)but-3-enoxy]tetrahydropyran in 200 ml of methanol/water 1:1 (v/v) is acidified by 2N hydrochloric acid and hydrogenated for 16 hours over 2 g 10% palladium on carbon. After filtration, the solvent is removed, the remaining residue is neutralized by saturated aqueous bicarbonate, and the product is extraced with several portions of ether. Purification of the crude product by column chromatography on silica gel yields 15.7 g (87%) of 4-(3-pyridyl)but-Anol as colourless viscous oil. (C9H13NO; F.W. 151.2).
Reaction SMILES: [CH:1]([O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]Br)([CH3:3])[CH3:2].[NH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1>>[CH:1]([O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][N:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)([CH3:3])[CH3:2]
Reactant: C1CCNCC1
Reactant: CC(C)OCCCCCCCCCBr
Product: CC(C)OCCCCCCCCCN1CCCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 68.8 %

Procedure:
Mix 9-bromononanyl isopropyl ether (730 mg, 2.75 mmol) and piperidine (1 mL, 10 mmol) and stir at room temperature overnight. Add additional piperidine (5 mL) and heat at 100° C. for 4 hours. Partition between ethyl ether and 5N sodium hydroxide. Separate the organic phase and extract the aqueous phase with ethyl ether (2×30 mL). Combine the organic phases and dry (MgSO4). Evaporate the solvent in vacuo to yield 510 mg yellow oil. Purify by silica gel chromatography (ethyl acetate followed by 10% MeOH/ethyl acetate) to yield 380 mg (51%) of the title compound as a pale yellow oil.
Reaction SMILES: O.[Br:2][C:3]1[N:7]([CH2:8][CH:9]=[C:10]([CH3:12])[CH3:11])[C:6]([C:13](OC)=[O:14])=[C:5]([CH:17]([OH:22])[CH2:18][N+:19]([O-])=O)[N:4]=1.C(O)(=O)C>C(O)C.[Fe]>[Br:2][C:3]1[N:7]([CH2:8][CH:9]=[C:10]([CH3:12])[CH3:11])[C:6]2[C:13](=[O:14])[NH:19][CH2:18][CH:17]([OH:22])[C:5]=2[N:4]=1
Reactant: COC(=O)c1c(C(O)C[N+](=O)[O-])nc(Br)n1CC=C(C)C
Agent: [Fe]
Solvent: O
Solvent: CCO
Solvent: CC(=O)O
Product: CC(C)=CCn1c(Br)nc2c1C(=O)NCC2O

Procedure:
90 ml of water and 5.40 g iron powder are added to 4.15 g methyl 2-bromo-5-(1-hydroxy-2-nitro-ethyl)-3-(3-methyl-2-buten-1-yl)-3H-imidazole-4-carboxylate in 270 ml of ethanol. The mixture is refluxed, combined with 36 ml glacial acetic acid and stirred for one and a half hours at reflux temperature. The cooled reaction solution is filtered through Celite. The filtrate is evaporated down, combined with ethanol and made basic with solid potassium carbonate. The mixture is stirred for three hours at 60° C. Then the ethanol is distilled off, the flask residue is combined with water and extracted with ethyl acetate. The combined extracts are dried over magnesium sulphate and evaporated down. The crude product is purified by chromatography over a silica gel column with methylene chloride/methanol (1:1 to 7:1) as eluant.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH:4]([C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:16][CH3:17])[CH:14]=2)[CH:9]=[CH:8][CH:7]=1)[OH:5].C(=O)([O-])[O-].[K+].[K+].[C:24](Cl)(=[O:26])[CH3:25]>O.C(OCC)(=O)C>[OH:5][CH:4]([C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:16][CH3:17])[CH:14]=2)[CH:9]=[CH:8][CH:7]=1)[CH2:3][NH:2][C:24](=[O:26])[CH3:25]
Reactant: CC(=O)Cl
Reactant: COc1ccc2cccc(C(O)CN)c2c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Product: COc1ccc2cccc(C(O)CNC(C)=O)c2c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
The compound obtained in Step E (20 mmol) is dissolved in a mixture of water/ethyl acetate (25 ml/75 ml) cooled to 0° C. Potassium carbonate (60 mmol) is added, and then acetyl chloride (26 mmol) is added dropwise to the reaction mixture. The mixture is stirred vigorously for 30 minutes at ambient temperature. The two phases are separated and the organic phase is washed with 0.1M aqueous hydrochloric acid solution and then with water. After drying over magnesium sulphate, the organic phase is evaporated under reduced pressure. The residue obtained is recrystallised from acetonitrile to yield the title product in the form of a white solid.
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[C:5](Cl)(=[O:9])[CH:6]([CH3:8])[CH3:7].[CH3:11][O:12][C:13]([CH2:15][O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14].Cl>CCCCCC.C(OCC)(=O)C>[C:5]([C:20]1[CH:21]=[CH:22][C:17]([O:16][CH2:15][C:13]([O:12][CH3:11])=[O:14])=[CH:18][CH:19]=1)(=[O:9])[CH:6]([CH3:8])[CH3:7]
Reactant: COC(=O)COc1ccccc1
Reactant: CC(C)C(=O)Cl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: COC(=O)COc1ccc(C(=O)C(C)C)cc1
Temperature: 0 °C

Procedure:
To an oven-dried round bottom flask was added anhydrous AlCl3 (24.1 g, 0.18 mol), which was subsequently purged with Ar. Methylene chloride (10 mL) was added via syringe and the resulting slurry was cooled to 0° C. in an ice bath. The isobutryl chloride (6.9 mL, 6.6×10−2 mol) was added dropwise via syringe. The methyl phenoxy acetate (8.7 mL, 6.0×10−2 mol) was added dropwise via syringe. The reaction was stirred until deemed complete by thin layer chromatography (TLC) (25% ethyl acetate in hexane) (approximately 2 h). The reaction mixture was poured slowly into a mixture of ice (100 g) and concentrated HCl (40 mL). The organic layer was separated and the organic layer extracted with methylene chloride (3×100 mL). The combined organic layers were washed with water (3×100 mL) and dried over MgSO4. The solvent was removed in vacuo to reveal 14 g of a white, crystalline solid (quantitative yield). 1H NMR (300 NMR, CDCl3) δ7.97 (2H, d, J=8.9 Hz), 6.96 (2H, J=8.9 Hz), 4.71 (2H, s), 3.82 (3H, s), 3.51 (1H, septet, J=6.8 Hz), 1.22 (6H, d, J=6.8 Hz).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[P:7](Cl)([O:11][CH3:12])([O:9][CH3:10])=[S:8].[C:14]([C:16]1[S:17][C:18]([O:22][CH2:23][CH2:24][CH2:25][CH3:26])=[CH:19][C:20]=1[OH:21])#[N:15]>C(#N)C>[C:14]([C:16]1[S:17][C:18]([O:22][CH2:23][CH2:24][CH2:25][CH3:26])=[CH:19][C:20]=1[O:21][P:7]([O:11][CH3:12])([O:9][CH3:10])=[S:8])#[N:15]
Reactant: CCCCOc1cc(O)c(C#N)s1
Reactant: COP(=S)(Cl)OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCCCOc1cc(OP(=S)(OC)OC)c(C#N)s1
Temperature: 20 °C
Reaction time: 24 h
Yield: 68.9 %

Procedure:
7 g of potassium carbonate and 8 g of O,O-dimethyl chlorothiophosphate were added to a solution of 9.8 g of 2-cyano-3-hydroxy-5-n-butoxy-thiophene in 150 ml of acetonitrile and the mixture was stirred for 24 hours at 20° C. and was then filtered. The filtrate was evaporated to dryness and the residue was chromatographed over silica gel. Elution with benzene yielded 11 g of 2-cyano-3-(dimethoxythiophosphoryloxy)-5-n-butoxy-thiophene with a refractive index of nD20 = 1.5375.
Reaction SMILES: [N:1]([CH2:4][C:5]1[N:6]=[C:7]([N:10]2[CH2:13][CH:12]([O:14][Si:15]([C:28]([CH3:31])([CH3:30])[CH3:29])([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:11]2)[S:8][CH:9]=1)=[N+]=[N-].Cl[C:33]([O:35][CH2:36][C:37]1[CH:42]=[CH:41][C:40]([N+:43]([O-:45])=[O:44])=[CH:39][CH:38]=1)=[O:34].C(N(CC)CC)C>CO.[OH-].[OH-].[Pd+2]>[Si:15]([O:14][CH:12]1[CH2:13][N:10]([C:7]2[S:8][CH:9]=[C:5]([CH2:4][NH:1][C:33]([O:35][CH2:36][C:37]3[CH:38]=[CH:39][C:40]([N+:43]([O-:45])=[O:44])=[CH:41][CH:42]=3)=[O:34])[N:6]=2)[CH2:11]1)([C:28]([CH3:31])([CH3:30])[CH3:29])([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CC(C)(C)[Si](OC1CN(c2nc(CN=[N+]=[N-])cs2)C1)(c1ccccc1)c1ccccc1
Reactant: O=C(Cl)OCc1ccc([N+](=O)[O-])cc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: CO
Product: CC(C)(C)[Si](OC1CN(c2nc(CNC(=O)OCc3ccc([N+](=O)[O-])cc3)cs2)C1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 60.7 %

Procedure:
1-(4-Azidomethyl-1,3-thiazol-2-yl)-3-t-butyldiphenylsilyloxyazetidine (1.06 g, 2.37 mmol) (obtained as described in Reference Example 62(1)) in methanol (53 ml) was subjected to catalytic hydrogenation in the presence of 20% palladium hydroxide on charcoal (1.05 g) at room temperature. After checking the completion of the reaction, the reaction mixture was filtered in order to remove the catalyst and the filtrate concentrated under reduced pressure. The residue was dissolved in methylene chloride (53.2 ml). To the mixture were added p-nitrobenzyl chloroformate (0.76 g, 3.52 mmol) and triethylamine (0.5 ml, 3.59 mmol) in an ice bath, and the mixture was stirred at room temperature overnight. After checking the completion of the reaction, the mixture was distilled under reduced pressure. The residue was partitioned between ethyl acetate and saturated aqueous sodium hydrogencarbonate solution. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using toluene:ethyl acetate (3:2) as the eluant to afford 3-t-butyldiphenylsilyloxy-1-[4-(p-nitrobenzyloxycarbonylaminomethyl)-1,3-thiazol-2-yl]azetidine (867.2 mg, yield 61%) as a yellow solid.
Reaction SMILES: C([C:3]1[N:4]([CH3:23])[CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([O:14][C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=3[F:22])=[CH:10][CH:9]=2)[N:7]=1)#N.FC1C=C(F)C=CC=1OC1C=CC(C2N=CNC=2)=CC=1.[OH-].[K+].CI>>[F:22][C:16]1[CH:17]=[C:18]([F:21])[CH:19]=[CH:20][C:15]=1[O:14][C:11]1[CH:10]=[CH:9][C:8]([C:6]2[N:7]=[CH:3][N:4]([CH3:23])[CH:5]=2)=[CH:13][CH:12]=1
Reactant: Cn1cc(-c2ccc(Oc3ccc(F)cc3F)cc2)nc1C#N
Agent: Fc1ccc(Oc2ccc(-c3c[nH]cn3)cc2)c(F)c1
Agent: [K+]
Agent: [OH-]
Solvent: CI
Product: Cn1cnc(-c2ccc(Oc3ccc(F)cc3F)cc2)c1

Procedure:
2-Cyano-4-[4-(2,4-difluorophenoxy)phenyl]-1-methyl-1H-imidazole. A mixture of crude 4-[4-(2,4-difluorophenoxy)phenyl]-1H-imidazole (prepared from 4.14 g of 2-bromo-1-[4-(2,4-difluorophenoxy)phenyl]ethanone and 35 mL of formamide as described above), solid KOH (2.57 g) and MeI (1 mL) was heated at reflux overnight. After filtration, the reaction was concentrated to dryness and the residue was purified by flash chromatography, affording 4-[4-(2,4-difluorophenoxy)phenyl]-1-methyl-1H-imidazole as a solid. A solution of 4-(dimethylamino)pyridine (1.34 g, 10.9 mmol) in 30 mL of dry DMF at −10° C. was added cyanogen bromide (5.0 M solution in MeCN; 2.1 mL, 10.5 mmol), giving a pale yellow precipitate. Solid 4-[4-(2,4-difluorophenoxy)phenyl]-1-methyl-1H-imidazole (1.39 g, 4.86 mmol) was added and the reaction was heated at 60° C. overnight. The reaction was allowed to cool to room temperature and added to water and EtOAc. The separated aqueous layer was extracted twice with EtOAc and the pooled organic layers were washed with water (3×), dried (Na2SO4), filtered and concentrated. The oily residue was purified by flash chromatography (gradient from 8.5/2.5 to 7/3 hexane/EtOAc) affording 713 mg of 2-cyano-4-[4-(2,4-difluorophenoxy)phenyl]-1-methyl-1H-imidazole as a solid, mp 109-110° C. (Rf 0.42, 7/3 hexane/EtOAc) along with 122 mg of 4-cyano-4-[4-(2,4-difluorophenoxy)phenyl]-1-methyl-1H-imidazole, mp 169-170° C. (Rf 0.32, 7/3 hexane/EtOAc). 1H NMR (2-cyano; CDCl3): δ 7.65 (d, 2H, J=9.0 Hz), 7.16 (s, 1H), 7.06 (dt, 1H, J=9.3, 5.4 Hz), 6.93 (d, 2H, J=8.7 Hz), 6.98-6.80 (m, 2H), 3.65 (s, 3H). 1H NMR (4-cyano; CDCl3): δ 7.69 (d, 2H, J=8.7 Hz), 7.27 (s, 1H), 7.09 (dt, J=8.7, 5.7 Hz), 6.96 (d, 2H, J=8.7 Hz), 7.00-6.82 (m, 2H), 3.90 (s, 3H).