Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][C:9]1[C:10]([C:22](O)=O)=[N:11][CH:12]=[N:13][C:14]=1[C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=1)C1C=CC=CC=1.[NH2:25][C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][C:33]=1[NH2:34])[C:29]#[N:30].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>CN(C=O)C>[OH:8][C:9]1[C:10]([C:22]2[NH:34][C:33]3[CH:32]=[CH:31][C:28]([C:29]#[N:30])=[CH:27][C:26]=3[N:25]=2)=[N:11][CH:12]=[N:13][C:14]=1[C:15]1[CH:16]=[CH:17][C:18]([CH3:21])=[CH:19][CH:20]=1
Reactant: Cc1ccc(-c2ncnc(C(=O)O)c2OCc2ccccc2)cc1
Reactant: N#Cc1ccc(N)c(N)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccc(-c2ncnc(-c3nc4cc(C#N)ccc4[nH]3)c2O)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 5-(benzyloxy)-6-p-tolylpyrimidine-4-carboxylic acid P72 (80 mg, 0.25 mmol) in DMF (3 mL) was added 3,4-diaminobenzonitrile (40 mg, 0.30 mmol), HATU (124 mg, 0.33 mmol) and diisopropylethylamine (48 mg, 0.37 mmol). The reaction mixture was stirred at room temperature for 18 hours. The organic solvent was evaporated under reduced pressure. Ethyl acetate and 1 N hydrochloric acid were added. The organic layer was washed with water and saturated brine. The organic layer was dried over anhydrous sodium sulfate. The organic solvent was evaporated under reduced pressure. The intermediate was purified by flash column chromatography. The intermediate was dissolved in acetic acid (5 mL) and heated in a microwave reactor at 160° C. for 1 hour. The organic solvent was evaporated under reduced pressure. Trifluoroacetic acid (5 mL) was added and the solution was heated in a microwave reactor at 120° C. for 30 minutes. The organic solvent was evaporated under reduced pressure. The crude product was purified by RP-HPLC to afford the desired 2-(5-hydroxy-6-p-tolylpyrimidin-4-yl)-1H-benzo[d]imidazole-5-carbonitrile P73 (16 mg, 0.049 mmol).
Reaction SMILES: C(O[CH:5]1[CH2:11][CH2:10][CH2:9][CH2:8][C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH3:18])=[CH:6]1)(=O)C.C[Si]([N:23]=[N+:24]=[N-:25])(C)C.Cl([O-])(=O)(=O)=O.[Mg+2].Cl([O-])(=O)(=O)=O.O>ClCCCl>[N:23]([CH:5]1[CH2:11][CH2:10][CH2:9][CH2:8][C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH3:18])=[CH:6]1)=[N+:24]=[N-:25]
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: CC(=O)OC1C=C(c2ccccc2C)CCCC1
Agent: [Mg+2]
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: ClCCCl
Solvent: O
Product: Cc1ccccc1C1=CC(N=[N+]=[N-])CCCC1

Procedure:
To a solution of the compound obtained in Step C (3.52 g/14.65 mmol) in 50 ml of 1,2-dichloroethane there are added dropwise trimethylsilyl azide (TMSN3), and then 0.326 g (1.46 mmol) of magnesium perchlorate (Mg(ClO4)2), and the whole is stirred at room temperature overnight. Hydrolysis is then carried out using H2O, followed by extraction with AcOEt; the organic phases are then combined, washed with a saturated NaCl solution, dried over MgSO4 and concentrated to dryness. The yellow oil so obtained is chromatographed over a column of silica gel (cyclohexane, 2% AcOEt) to yield the title product in the form of a translucent oil.
Reaction SMILES: CS[C:3]([C:25]1[C:30]([Cl:31])=[CH:29][CH:28]=[CH:27][C:26]=1[F:32])=[N:4][C:5]([C:7]1[S:8][C:9]([C:14]2[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=2)=[C:10]([Br:13])[C:11]=1[CH3:12])=O.C(O)(=O)C(O)=O.[CH2:39]([NH:41][NH2:42])[CH3:40]>C1(C)C=CC=CC=1.CCOCC>[Cl:31][C:30]1[CH:29]=[CH:28][CH:27]=[C:26]([F:32])[C:25]=1[C:3]1[N:4]=[C:5]([C:7]2[S:8][C:9]([C:14]3[CH:15]=[CH:16][C:17]([O:20][C:21]([F:23])([F:24])[F:22])=[CH:18][CH:19]=3)=[C:10]([Br:13])[C:11]=2[CH3:12])[N:41]([CH2:39][CH3:40])[N:42]=1
Reactant: CSC(=NC(=O)c1sc(-c2ccc(OC(F)(F)F)cc2)c(Br)c1C)c1c(F)cccc1Cl
Reactant: CCNN
Agent: O=C(O)C(=O)O
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: CCn1nc(-c2c(F)cccc2Cl)nc1-c1sc(-c2ccc(OC(F)(F)F)cc2)c(Br)c1C
Temperature: 25 °C
Reaction time: 64 h
Yield: 0 %

Procedure:
Methyl-N-{[3-methyl-4-bromo-5-(4-trifluoromethoxyphenyl)-2-thienyl]-carbonyl}-2-fluoro-6-chlorobenzenecarbimidothioate (0.85 g, 1.5 mmol) and ethylhydrazine oxalate (0.90 g, 6 mmol) were combined in toluene (5 mL) and stirred 64 h at 25° C. and heated to reflux for 18 h. The reaction mixture was diluted with ether and washed with 0.1 M hydrochloric acid and brine, dried over anhydrous magnesium sulfate and concentrated to a crude pale yellow oil. Chromatography (silica gel, 10% ethylacetate/hexane) afforded the product as a clear oil (0.250 mg, 30%): 1H NMR (CDCl3) δ 7.73 (2H, d), 7.0–7.5 (5H, m), 4.3 (2H, q), 2.40 (3H, s), 1.55 (3H, t); EI/MS 546 m/e (M+).
Reaction SMILES: [CH3:1][C:2]1[C:7]([C:8]2[N:9]([C:18]3[CH:23]=[CH:22][C:21]([S:24]([CH3:27])(=[O:26])=[O:25])=[CH:20][CH:19]=3)[CH2:10][C:11](O)([C:13]([F:16])([F:15])[F:14])[N:12]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH3:1][C:2]1[C:7]([C:8]2[N:9]([C:18]3[CH:23]=[CH:22][C:21]([S:24]([CH3:27])(=[O:26])=[O:25])=[CH:20][CH:19]=3)[CH:10]=[C:11]([C:13]([F:15])([F:16])[F:14])[N:12]=2)=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: Cc1ncccc1C1=NC(O)(C(F)(F)F)CN1c1ccc(S(C)(=O)=O)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1ncccc1-c1nc(C(F)(F)F)cn1-c1ccc(S(C)(=O)=O)cc1
Yield: 73.4 %

Procedure:
A mixture of 2-methyl-3-[4-hydroxy-1-[4-(methylsulfonyl)phenyl]-4-(trifluoromethyl)-4,5-dihydro-1H-imidazol-2-yl]pyridine from step 3 (3.97 g, 0.01 mol) and p-toluenesulfonic acid monohydrate (0.60 g, 0.0032 mol) in 250 mL of toluene was heated to reflux for 24 hours. The reaction mixture was cooled and the solvent was removed under reduced pressure. The residue was partitioned between water and methylene chloride. The organic layer was washed with water, saturated sodium bicarbonate solution and brine, dried over magnesium sulfate and filtered. The filtrate was evaporated in vacuo and the crude product was purified by recrystallization from ethyl acetate/hexane to give 2.8 g of 2-methyl-3-[1-[4-(methylsulfonyl)phenyl]-4-(trifluoromethyl)-1H-imidazol-2-yl]pyridine (73%): mp 160–161° C. Anal. Calc'd. for C17H14F3N3O2S: C, 53.54, H, 3.70, N, 11.02, S, 8.41. Found: C, 53.58, Ho 3.88, N, 11.02, S, 8.51.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11]3[CH2:18][C:17](=[O:19])[NH:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[F:8].[CH2:20]([N:22]1[CH2:27][CH2:26][N:25]([C:28]([C:30]2[NH:34][C:33]([CH:35]=O)=[C:32]([CH3:37])[CH:31]=2)=[O:29])[CH2:24][CH2:23]1)[CH3:21]>N1CCCCC1.C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11]3[C:18](=[CH:35][C:33]4[NH:34][C:30]([C:28]([N:25]5[CH2:24][CH2:23][N:22]([CH2:20][CH3:21])[CH2:27][CH2:26]5)=[O:29])=[CH:31][C:32]=4[CH3:37])[C:17](=[O:19])[NH:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: O=C1Cc2c(ncnc2Nc2ccc(F)c(Cl)c2)N1
Reactant: CCN1CCN(C(=O)c2cc(C)c(C=O)[nH]2)CC1
Solvent: CCO
Solvent: C1CCNCC1
Product: CCN1CCN(C(=O)c2cc(C)c(C=C3C(=O)Nc4ncnc(Nc5ccc(F)c(Cl)c5)c43)[nH]2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.9 %

Procedure:
A mixture of 4-(3-chloro-4-fluoro-phenylamino)-5,7-dihydro-pyrrolo[2,3-d]pyrimidin-6-one (70 mg, 0.25 mmol), 5-(4-ethyl-piperazine-1-carbonyl)-3-methyl-1H-pyrrole-2-carbaldehyde (74.8 mg, 0.3 mmol) and piperidine (3 drops) in ethanol (2 mL) was stirred at room temperature for overnight. The precipitate was collected by vacuum filtration, washed with ethanol and dried to give 93 mg (73%) of the title compound. 1H NMR (300 MHz, DMSN d6) δ 3.40 (br s, 1H, NH), 11.81 (br s, 1H, NH), 9.28 (br s, 1H), 8.33 (s, 1H), 7.72 (m, 1H), 7.33-7.45 (m, 3H), 6.58 (m, 1H), 3.68 (m, 4H, 2×CH2), 2.31-2.42 (m, 6H), 2.22 (s, 3H, CH3), 1.01 (t, J=7.2 Hz, 3H, CH2CH3). MS 510 [M++1].
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([Cl:11])=[CH:4][N:3]=1.[OH:12][C:13]1[CH:25]=[CH:24][C:16]([O:17][CH:18]([CH3:23])[C:19]([O:21][CH3:22])=[O:20])=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>[I-].[K+].C(#N)C>[Cl:11][C:5]1[CH:6]=[C:7]([N+:8]([O-:10])=[O:9])[C:2]([O:12][C:13]2[CH:14]=[CH:15][C:16]([O:17][CH:18]([CH3:23])[C:19]([O:21][CH3:22])=[O:20])=[CH:24][CH:25]=2)=[N:3][CH:4]=1
Reactant: COC(=O)C(C)Oc1ccc(O)cc1
Reactant: O=[N+]([O-])c1cc(Cl)cnc1Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)C(C)Oc1ccc(Oc2ncc(Cl)cc2[N+](=O)[O-])cc1
Yield: 93.1 %

Procedure:
38.6 g (0.20 mole) of 2.5-dichloro-3-nitropyridine, 41.2 g (0.21 mole) of methyl 2-(4-hydroxyphenoxy)propionate, 400 ml of acetonitrile, 35.9 g (0.26 mole) of potassium carbonate and 0.33 g (0.002 mole) of potassium iodide are heated for 13 hours to 80° C. The reaction mixture is filtered and the filter cake is washed with acetonitrile. The filtrate is concentrated by evaporation and the residue is taken up in 500 ml of methylene chloride. After treating the solution with 15 g of activated carbon, it is filtered through a layer of silica gel and the filtrate is concentrated by evaporation. The residue is crystallised from a mixture of hexane and ethyl acetate, affording 65.7 g (93.1% of theory) of methyl 2-[4-(5-chloro-3-nitropyridin-2-yloxy)phenoxy]propionate with a melting point of 91°-92° C.
Reaction SMILES: N[C:2]1C=CC(C)=CC=1.O=P(Cl)(Cl)Cl.[CH3:14][NH:15][C:16]1[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=1>CO>[CH3:14][N:15]([CH3:2])[C:16]1[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=1
Reactant: Cc1ccc(N)cc1
Reactant: CNc1ccc(C)cc1
Solvent: CO
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1ccc(N(C)C)cc1
Temperature: 280 °C
Reaction time: 3 h
Yield: 94 %

Procedure:
A mixture of 749 g of p-toluidine, 1,008 g of methanol and 7.9 g of POCl3 is introduced into a 3 l autoclave with an up-and-down stirrer. After closing the autoclave, it is heated up to 280° C. and kept at this temperature for about 3 hours. A pressure of about 60 bar is thereby established. A crude oil composed of <1% of p-toluidine, 1% of N-methyl-p-toluidine and 94% of N,N-dimethyl-p-toluidine is obtained.
Reaction SMILES: CC(C)([O-])C.[K+].[F:7][C:8]1[CH:9]=[CH:10][C:11]2[N:16]=[C:15]([C:17]3[CH:22]=[CH:21][C:20]([N:23]4[CH2:27][CH2:26][CH2:25][CH2:24]4)=[CH:19][C:18]=3[O:28][CH:29]3[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]3)[O:14][C:13](=[O:36])[C:12]=2[CH:37]=1.[Cl:38][C:39]1[CH:40]=[C:41]([CH:43]=[CH:44][C:45]=1[Cl:46])[NH2:42]>>[Cl:38][C:39]1[CH:40]=[C:41]([NH:42][C:13](=[O:36])[C:12]2[CH:37]=[C:8]([F:7])[CH:9]=[CH:10][C:11]=2[NH:16][C:15](=[O:14])[C:17]2[CH:22]=[CH:21][C:20]([N:23]3[CH2:24][CH2:25][CH2:26][CH2:27]3)=[CH:19][C:18]=2[O:28][CH:29]2[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]2)[CH:43]=[CH:44][C:45]=1[Cl:46]
Reactant: CN1CCC(Oc2cc(N3CCCC3)ccc2-c2nc3ccc(F)cc3c(=O)o2)CC1
Reactant: Nc1ccc(Cl)c(Cl)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Product: CN1CCC(Oc2cc(N3CCCC3)ccc2C(=O)Nc2ccc(F)cc2C(=O)Nc2ccc(Cl)c(Cl)c2)CC1

Procedure:
Using methods substantially equivalent to those described in Example 91-G, except using potassium t-butoxide as the base; N-(3,4-dichlorophenyl)-5-fluoro-2-[2-(1-methylpiperidin-4-yloxy)-4-(pyrrolidin-1-yl)benzoylamino]benzamide was prepared from 6-fluoro-2-[2-(1-methylpiperidin-4-yloxy)-4-(pyrrolidin-1-yl)phenyl]-4H-3,1-benzoxazin-4-one and 3,4-dichloroaniline.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH:5]([C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=1)[C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=1.[C:20]1(=[O:30])[NH:24][C:23](=[O:25])[C:22]2=[CH:26][CH:27]=[CH:28][CH:29]=[C:21]12.[K].O>CN(C=O)C>[F:12][C:9]1[CH:10]=[CH:11][C:6]([CH:5]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[CH2:4][CH2:3][CH2:2][N:24]2[C:20](=[O:30])[C:21]3[C:22](=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:23]2=[O:25])=[CH:7][CH:8]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: Fc1ccc(C(CCCBr)c2ccc(F)cc2)cc1
Agent: [K]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1CCCC(c1ccc(F)cc1)c1ccc(F)cc1
Temperature: 50 °C
Reaction time: 16 h
Yield: 94.9 %

Procedure:
A suspension consisting of 1,1′-(4-bromobutylidene)bis[4-fluorobenzene] (25 g, 77 mmol) and potassium phthalimide (17 g, 92 mmol) in 300 mL DMF was stirred at 50° C. for 16 hours, cooled to 25° C., and poured into 900 mL of cold H2O. The mixture was extracted with ethyl acetate (3×300 mL), and the combined extracts were washed with H2O (2×1 L), followed by brine (700 mL), then dried over anhydrous sodium sulfate. Evaporation of solvent in vacuo afforded 28.6 g of a golden oil, which was triturated with 250 mL 2,2,4-trimethylpentane containing 5% 2-propanol, and the solid thus obtained was collected by filtration and dried at 50° C. in vacuo, to give 28.7 g (97%) of titled compound as a white powder; mp 69-70° C. APCI-MS m/z 391.1 (M−).
Reaction SMILES: C(OC([N:11]1[CH2:15][C@H:14]([O:16][Si](C)(C)C)[CH2:13][C@H:12]1[CH2:21][O:22][CH3:23])=O)C1C=CC=CC=1.[H][H]>CO>[CH3:23][O:22][CH2:21][C@H:12]1[NH:11][CH2:15][C@H:14]([OH:16])[CH2:13]1
Reactant: COC[C@@H]1C[C@@H](O[Si](C)(C)C)CN1C(=O)OCc1ccccc1
Reactant: [H][H]
Solvent: CO
Product: COC[C@@H]1C[C@@H](O)CN1
Reaction time: 2 h
Yield: 82.4 %

Procedure:
To (2S,4R)-2-Methoxymethyl-4-trimethylsilanyloxy-pyrrolidine-1-carboxylic acid benzyl ester 1.00 g (3.98 mmol) in 3 mL of methanol was added 10% Pd(C) 0.10 g and the mixture was stirred under 1 atmosphere of hydrogen for 24 h. The mixture was filtered through a 0.22 μM Teflon filter, concentrated and subsequently put on a high vacuum for 2 h to afford 0.43 g (86%) of (3R,5S)-5-Methoxymethyl-pyrrolidin-3-ol as clear oil. 1H NMR (CDCl3, 400 MHz) δ: 5.30 (1H, s), 4.67 (1H, t, J=5.6 Hz), 4.56 (1H, t, J=7.6 Hz), 4.26-4.21 (1H, m), 4.19 (1H, dd, J=8.1, 3.3 Hz), 3.14 (1H, d, J=12.3 Hz), 2.08 (1H, dd, J=8.2, 3.2 Hz), 1.66-1.59 (3H, m). LCMS (ACPI) (M+H+) m/z: 132.2.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[C:6]([CH2:11][S:12]([C:15]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:18]=[CH:17][CH:16]=2)(=[O:14])=[O:13])[CH:5]=1.Cl.[N:27]([O-])=O.[Na+].C(=O)(O)[O-].[Na+]>C1COCC1.O>[CH3:1][O:2][C:3]([C:4]1[CH:5]=[C:6]2[C:7](=[CH:8][CH:9]=1)[NH:10][N:27]=[C:11]2[S:12]([C:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[CH:17][CH:16]=1)(=[O:13])=[O:14])=[O:25]
Reactant: COC(=O)c1ccc(N)c(CS(=O)(=O)c2cccc3ccccc23)c1
Reactant: O=N[O-]
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1ccc2[nH]nc(S(=O)(=O)c3cccc4ccccc34)c2c1
Temperature: 3 °C

Procedure:
A mixture of 4-amino-3-(naphthalene-1-sulfonylmethyl)benzoic acid methyl ester (0.9 g, 2.5 mmoles) in THF (5 mL), and 4M HCl (10 mL) was stirred in a round bottom flask, under nitrogen, at 3° C. A solution of sodium nitrite (0.18 g, 2.62 mmoles) in H2O (1 mL) was added dropwise. The reaction mixture was poured into a cold solution of saturated sodium bicarbonate (100 mL) and extracted with EtOAc. Compound was dried over Na2SO4, and concentrated under vacuum to afford the title compound as an off white solid (0.82 g, 2.25 mmoles).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][C:24]=1[Cl:25])[CH2:5][C:6]1[NH:7][C:8](=O)[C:9]2[C:14]([CH3:15])=[C:13]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[S:12][C:10]=2[N:11]=1.P(Cl)(Cl)([Cl:28])=O.CN(C)C1C=CC=CC=1>>[Cl:28][C:8]1[C:9]2[C:14]([CH3:15])=[C:13]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[S:12][C:10]=2[N:11]=[C:6]([CH2:5][C:4]2[CH:22]=[CH:23][C:24]([Cl:25])=[C:2]([Cl:1])[CH:3]=2)[N:7]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOC(=O)c1sc2nc(Cc3ccc(Cl)c(Cl)c3)[nH]c(=O)c2c1C
Solvent: CN(C)c1ccccc1
Product: CCOC(=O)c1sc2nc(Cc3ccc(Cl)c(Cl)c3)nc(Cl)c2c1C
Reaction time: 4 h

Procedure:
Three (3.00) g of ethyl 2-(3,4-dichlorobenzyl)-5-methyl-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidine-6-carboxylate and 37 mL of phosphorus oxychloride were mixed, and to which 1.4 mL of N,N-dimethylaniline was added, followed by stirring at 900 for 4 hours. The reaction liquid was poured on ice and stirred for 3 hours, and the precipitated crystals were recovered by filtration and washed with water. Drying the crystals under aeration, 3.05 g of the title compound was obtained.
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([O:12][C:13]1[N:21]=[C:20]2[C:16]([N:17]=[C:18]([O:22][CH3:23])[NH:19]2)=[C:15]([NH2:24])[N:14]=1)[CH2:9][CH2:10][CH3:11].C(=O)([O-])[O-].[K+].[K+].Br[CH2:32][CH2:33][CH2:34][Cl:35]>CN(C=O)C>[CH2:8]([O:12][C:13]1[N:21]=[C:20]2[C:16]([N:17]=[C:18]([O:22][CH3:23])[N:19]2[CH2:32][CH2:33][CH2:34][Cl:35])=[C:15]([NH2:24])[N:14]=1)[CH2:9][CH2:10][CH3:11]
Reactant: ClCCCBr
Reactant: CCCCOc1nc(N)c2nc(OC)[nH]c2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: CCCCOc1nc(N)c2nc(OC)n(CCCCl)c2n1
Temperature: 50 °C
Reaction time: 5 h
Yield: 70 %

Procedure:
2-(Butyloxy)-8-(methyloxy)-9H-purin-6-amine trifluoroacetate (4.7 g, 13.38 mmol) and potassium carbonate (4.62 g, 33.4 mmol) in dry DMF (50 ml) were stirred and heated at 50° C., under nitrogen, for 75 mins. The mixture was allowed to cool to room temperature and then cooled to 0° C. and 1-bromo-3-chloropropane (2.106 g, 13.38 mmol) was added. The mixture was stirred at 0 to 10° C. for approximately 5 hours then allowed to warm to room temperature and stirred for approximately a further 40 hours when LCMS indicated approximately 70% of the desired product. The mixture was allowed to settle and the supernatant was pipetted off and the solvent evaporated on a rotary evaporator using a high vacuum pump at about 23° C. Chloroform and water was added to the combined residues which were stirred and the phases separated using a hydrophobic frit. The aqueous layer was re-extracted with further portions of chloroform and the combined chloroform extracts were evaporated under high vacuum at 23° C. to give a yellow solid (2.798 g). This crude material was combined with similar material obtained from two similar preparations (0.56 g and 0.995 g) and purified by flash column chromatography on silica using 2:1 ethyl acetate/chloroform as eluant to give the title compound as an off-white solid. (3.011 g).
Reaction SMILES: [C:1]([OH:20])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].Br[CH2:22][CH2:23][CH2:24][CH2:25][O:26][CH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][O:28]1.C(=O)([O-])[O-].[Cs+].[Cs+].O>O1CCCC1>[O:28]1[CH2:29][CH2:30][CH2:31][CH2:32][CH:27]1[O:26][CH2:25][CH2:24][CH2:23][CH2:22][O:19][C:1](=[O:20])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)O
Reactant: BrCCCCOC1CCCCO1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1CCOC1
Product: CCCCCCCC/C=C\CCCCCCCC(=O)OCCCCOC1CCCCO1
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.4 %

Procedure:
To a stirring solution of 2.0 g (7.0 mmol) of oleic acid and 1.6 g (7.0 mmol) of 2-(4-bromobutoxy)tetrahydro-2H-pyran in 20 mL of tetrahydrofuran is added 2.3 g (7.1 mmol) of cesium carbonate and the reaction mixture is stirred overnight at room temperature. The reaction mixture is poured into water and extracted with three 100 mL portions of ether. The combined organic layers are dried over MgSO4 and concentrated in vacuo affording 2.9 g (100%) of (Z)-9-octadecenoic acid 4-[(tetrahydro-2H-pyran-2-yl)oxy]butyl ester. Next, 500 mg of Dowex 50W 8X resin is added to a stirring solution of 2.9 g (7.0 mmol) of (Z)-9-octadecenoic acid 4-[(tetrahydro-2H-pyran-2-yl)oxy]butyl ester in 100 mL of 1:1 tetrahydrofuran/methanol and the reaction mixture is stirred overnight at room temperature. The reaction mixture is filtered and concentrated in vacuo affording 2.4 g (100%) of alcohol. Next, 11 mL of 2.0M Jones reagent is added at 0° C. to a stirring solution of 2.4 g (7.0 mmol) of alcohol in 75 mL of acetone and the reaction mixture is stirred for 2 hours. The reaction mixture is poured into water and extracted with three 50 mL portions of ether. The combined organic layers are dried over MgSO4 and concentrated in vacuo affording 2.1 g (81%) of title compound.
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([F:14])=[C:10]([F:15])[CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH2:19](I)[CH:20]=[CH2:21]>CN(C=O)C.CCOC(C)=O>[C:1]([O:5][C:6](=[O:16])[N:7]([CH2:21][CH:20]=[CH2:19])[C:8]1[CH:13]=[CH:12][C:11]([F:14])=[C:10]([F:15])[CH:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccc(F)c(F)c1
Reactant: C=CCI
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C=CCN(C(=O)OC(C)(C)C)c1ccc(F)c(F)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 78.8 %

Procedure:
To a solution of (3,4-difluorophenyl)-carbamic acid-tert-butyl ester (2.42 g, 10.55 mmol) in DMF (80 mL) at 0° C. under Ar was added NaH (60% dispersion in mineral oil, 0.805 g, 21 mmol, 2 eq.). The mixture was stirred at 0° C. for 30 min and then allyl iodide (6.42 mL, 53 mmol, 5 eq.) was added over 5 min. The mixture was warmed to room temperature and stirred for 2 h. The mixture was then diluted with EtOAc (100 mL) and washed with saturated aqueous NaHCO3 (100 mL). The aqueous phase was washed with EtOAc (3×60 mL) and the combined organic extracts were washed with saturated aqueous NaCl (100 mL), dried over Na2SO4, filtered and concentrated to give a brown oil which was purified by flash column chromatography by eluting with 10% EtOAc/hexanes to give allyl-(3,4-difluorophenyl)-carbamic acid-tert-butyl ester as a clear oil (2.238 g, 75%).). 1H NMR (300 MHz, CDCl3): δ 7.18 (m, 3H), 6.00 (m, 1H), 5.30 (m, 2H), 4.30 (m, 2H), 1.59 (s, 9H).
Reaction SMILES: C(O)C.O.[Cl:5][C:6]1[CH:7]=[C:8]([N+:26]([O-])=O)[CH:9]=[C:10]([Cl:25])[C:11]=1[O:12][CH:13]([CH3:24])[C:14]([F:23])([F:22])[C:15]([F:21])([F:20])[C:16]([F:19])([F:18])[F:17].Cl>C(O)C.[Fe]>[Cl:5][C:6]1[CH:7]=[C:8]([CH:9]=[C:10]([Cl:25])[C:11]=1[O:12][CH:13]([CH3:24])[C:14]([F:22])([F:23])[C:15]([F:20])([F:21])[C:16]([F:19])([F:18])[F:17])[NH2:26]
Reactant: CC(Oc1c(Cl)cc([N+](=O)[O-])cc1Cl)C(F)(F)C(F)(F)C(F)(F)F
Agent: [Fe]
Agent: Cl
Solvent: O
Solvent: CCO
Product: CC(Oc1c(Cl)cc(N)cc1Cl)C(F)(F)C(F)(F)C(F)(F)F
Yield: 62.3 %

Procedure:
5.29 g iron filings, 240 mL of a 2/1 ethanol-water mixture, and 8.3 g 3,5-dichloro-4-(1-methyl-2,2,3,3,4,4,4-heptafluorobutoxy)nitrobenzene was stirred vigorously and heated under reflux while 2.0 mL conc. HCl in 2 mL ethanol was added dropwise. After one hour 2.0 mL conc. HCl in 2.0 mL ethanol was added and reflux was maintained for 6 hrs. Then added 2.0 mL conc. HCl in 3.0 mL ethanol and maintained reflux overnight. The mixture was filtered hot through Celite. The filtrate was concentrated under vacuum before being partitioned in saturated sodium bicarbonate and diethyl ether. The layers were separated and the aqueous layer was extracted with diethyl ether. The combined organics were washed with brine, dried (MgSO4), filtered, and concentrated to give 4.79 g of 3,5-Dichloro-4-(1-methyl-2,2,3,3,4,4,4-heptafluorobutoxy)aniline as an amber oil. 1H NMR and MS confirm pure product. Anal. calcd C11H8Cl2F7NO: C, 35.32; H, 2.16; N, 3.74. Found: C, 36.40; H, 2.33; N, 3.98.