Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([S:4]([NH2:7])(=[O:6])=[O:5])[CH2:3][CH2:2]1.C(N(CC)CC)C.Cl[C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH2:19]([O:18][C:16](=[O:17])[NH:7][S:4]([CH:1]1[CH2:3][CH2:2]1)(=[O:6])=[O:5])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: NS(=O)(=O)C1CC1
Reactant: O=C(Cl)OCc1ccccc1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NS(=O)(=O)C1CC1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of cyclopropanesulfonamide (6.51 g, triethylamine (40 mL) and DMAP (0.656 g) in DCM (150 mL) was slowly added benzyl chloroformate (12 mL). The mixture was stirred at room temperature for 18 hours. The mixture was washed with 1 N HCl. The aqueous layer (pH 1) was extracted with EtOAc (×2). The combined organics were washed with brine, dried over anhydrous MgSO4 and concentrated. The resulting residue was purified by flash chromatography (ISCO, 0-10% methanol in dichloromethane) to afford the desired product (7.8 g). 1H NMR (400 MHz, CDCl3): δ (ppm) 7.56-7.44 (m, 1H), 7.38 (s, 5H), 5.22 (s, 2H), 2.92-2.84 (m, 1H), 1.40-1.35 (m, 2H), 1.12-1.06 (m, 2H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][NH:12][C:11](=[O:15])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:22][O:23][C:24]([C:26]1[S:27][C:28]([CH2:31][CH2:32]OS(C)(=O)=O)=[CH:29][CH:30]=1)=[O:25]>CN(C=O)C>[CH3:22][O:23][C:24]([C:26]1[S:27][C:28]([CH2:31][CH2:32][N:12]2[CH:13]=[CH:14][C:9]([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[CH:10][C:11]2=[O:15])=[CH:29][CH:30]=1)=[O:25]
Reactant: COC(=O)c1ccc(CCOS(C)(=O)=O)s1
Reactant: O=c1cc(OCc2ccccc2)cc[nH]1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(CCn2ccc(OCc3ccccc3)cc2=O)s1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 1.20 g (5.96 mmol) 4-benzyloxy-1H-pyridin-2-one in DMF is added subsequently 3.89 g (11.9 mmol) cesium carbonate and 1.58 g (5.96 mmol) 5-(2-methanesulfonyloxy-ethyl)thiophene-2-carboxylic acid methyl ester (preparation 11a). The reaction mixture is stirred overnight at RT. After filtration, the residue is purified via reverse HPLC chromatography (Zorbax stable bond, C18; water (0.1% formic acid)/acetonitrile (0.1% formic acid) 95:5 to 10:90).
Reaction SMILES: [CH3:1][C:2]1[CH:31]=[CH:30][CH:29]=[C:28]([CH3:32])[C:3]=1[CH2:4][NH:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][C:15]=1[F:16])[N:12]=[C:11]([N:17]1[CH:21]=[C:20]([C:22]([O:24]CC)=[O:23])[CH:19]=[N:18]1)[NH:10][C:9]2=O.[CH3:33][NH:34][CH3:35]>>[CH3:33][N:34]([CH3:35])[C:9]1[C:8]2[C:13](=[CH:14][C:15]([F:16])=[C:6]([NH:5][CH2:4][C:3]3[C:28]([CH3:32])=[CH:29][CH:30]=[CH:31][C:2]=3[CH3:1])[CH:7]=2)[N:12]=[C:11]([N:17]2[CH:21]=[C:20]([C:22]([OH:24])=[O:23])[CH:19]=[N:18]2)[N:10]=1
Reactant: CNC
Reactant: CCOC(=O)c1cnn(-c2nc3cc(F)c(NCc4c(C)cccc4C)cc3c(=O)[nH]2)c1
Product: Cc1cccc(C)c1CNc1cc2c(N(C)C)nc(-n3cc(C(=O)O)cn3)nc2cc1F

Procedure:
The above compound may be made analogous to Example 1 using ethyl 1-(6-((2,6-dimethylbenzyl)amino)-7-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylate in step D and dimethylamine in step E. MS (ESI): predicted mass calcd. for C23H23FN6O2, 434.2
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][CH:11]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]3[CH:30]=[CH:29][C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[N:22]=3)=[CH:15][CH:14]=2)O)=[CH:4][CH:3]=1.[C:31]([O:35][CH2:36][CH3:37])(=[O:34])[CH2:32][SH:33].B(F)(F)F.CCOCC>C(Cl)Cl>[CH2:36]([O:35][C:31](=[O:34])[CH2:32][S:33][CH:11]([C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]2[CH:30]=[CH:29][C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[N:22]=2)=[CH:15][CH:14]=1)[CH2:10][CH2:9][CH2:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)[CH3:37]
Reactant: OC(CCCc1ccc(Cl)cc1)c1ccc(OCc2ccc3ccccc3n2)cc1
Reactant: CCOC(=O)CS
Agent: FB(F)F
Solvent: CCOCC
Solvent: ClCCl
Product: CCOC(=O)CSC(CCCc1ccc(Cl)cc1)c1ccc(OCc2ccc3ccccc3n2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 78.8 %

Procedure:
To a mixture of 4-(4-chlorophenyl)-1 -[4-(2-quinolylmethoxy)phenyl]butan-1-ol from Example 2 (830 mg; 2 mmol) and ethyl thioglycolate (0.283 ml; 2.5 mmol) in methylene chloride (20 ml) at 0° C. was added boron trifluoride etherate (0.62 ml; 5 mmol) dropwise. The resulting mixture was stirred at 0° C. for 1 h and at room temperature for 1 h. After the mixture was concentrated in vacuo and the residue was purified by chromatography (silica gel; hexane-ethyl acetate 3:1) to afford 820 mg of {[4-(4-chlorophenyl)-1-(4-[2-quinolinylmethoxy]phenyl)butyl]thio}acetic acid ethyl ester.
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[CH2:7][O:6][CH:5]([C:8]([OH:10])=[O:9])[CH2:4][O:3]1.C(Cl)(=O)C(Cl)=O.[CH2:18](O)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CN(C)C=O.ClCCl>[CH2:18]([O:9][C:8]([CH:5]1[CH2:4][O:3][C:2]([CH3:11])([CH3:1])[CH2:7][O:6]1)=[O:10])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CC1(C)COC(C(=O)O)CO1
Reactant: OCc1ccccc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC1(C)COC(C(=O)OCc2ccccc2)CO1
Temperature: 25 °C
Reaction time: 20 h
Yield: 74 %

Procedure:
A solution of (5,5-dimethyl-[1,4]dioxan-2-yl)-methanol (657 mg, 4.5 mmol) in 1 M potassium hydroxide solution (6.7 mL, 6.7 mmol) was stirred at 5° C. A solution of potassium permanganate (1.42 g, 9 mmol) in water (10 mL) was added dropwise maintaining the internal temperature below 10° C. The reaction mixture was stirred at 5° C. for 1 h and then at room temperature for 18 h. The reaction mixture was filtered through Celite and the filter pad was washed with water and methanol and the filtrate was evaporated. The residue was acidified to pH 2 with hydrochloric acid (2 M) and the mixture was extracted with ethyl acetate and chloroform. The organic extracts were combined and washed with a small volume of brine. The organic solution was filtered through a hydrophobic frit and the filtrate was evaporated to afford crude 5,5-dimethyl-[1,4]dioxane-2-carboxylic acid (694 mg, 4.5 mmol) as a waxy solid. LCMS (m/z) 159.1 [M−H], Tr=0.88 min. A solution of 5,5-dimethyl-[1,4]dioxane-2-carboxylic acid (750 mg, 4.7 mmol), oxalyl chloride (600 mg, 0.4 mL, 4.7 mmol) and N,N-dimethylformamide (2 drops) in dichloromethane (15 mL) was stirred at room temperature under nitrogen for 2 h. A solution of benzyl alcohol (508 mg, 0.5 mL, 4.7 mmol) in dichloromethane (2 mL) was added and the reaction mixture was stirred at room temperature for 20 h. Additional benzyl alcohol (0.5 mL, 4.7 mmol) was added and the reaction mixture was stirred at room temperature for 18 h. The solvent was evaporated and the residue was purified by silica gel chromatography using a gradient of iso-hexanes/ethyl acetate 9:1 to 1:1 to afford the title compound (870 mg, 74%) as an oil. 1H NMR (300 MHz, CDCl3) δ 1.19 (s, 3H), 1.32 (s, 3H), 3.43 (d, J=11.4 Hz, 1H), 3.72 (d, J=11.4 Hz, 1H), 3.88-3.92 (m, 2H), 4.21 (dd, J=8.2, 4.7 Hz, 1H), 5.24 (s, 2H), 7.34-7.39 (m, 5H). LCMS (m/z) 273.1 [M+Na], Tr=2.41 min.
Reaction SMILES: [OH:1][CH:2]([C:7]([O:20][CH3:21])([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:3]([O:5][CH3:6])=[O:4].C(=O)([O-])[O-].[K+].[K+].[CH3:28][O:29][C:30]1[N:35]=[C:34](Cl)[CH:33]=[C:32]([O:37][CH3:38])[N:31]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C)C=O.O>[CH3:28][O:29][C:30]1[N:35]=[C:34]([O:1][CH:2]([C:7]([O:20][CH3:21])([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:3]([O:5][CH3:6])=[O:4])[CH:33]=[C:32]([O:37][CH3:38])[N:31]=1
Reactant: COC(=O)C(O)C(OC)(c1ccccc1)c1ccccc1
Reactant: COc1cc(Cl)nc(OC)n1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)C(Oc1cc(OC)nc(OC)n1)C(OC)(c1ccccc1)c1ccccc1
Temperature: 100 °C
Reaction time: 6 h

Procedure:
1.15 g (4 mmol) of methyl 2-hydroxy-3-methoxy-3,3-diphenyl-propionate were dissolved in 10 ml of dimethylformamide, and 276 mg (2 mmol) of potassium carbonate were added. Then 524 mg (3 mmol) of 2,6-dimethoxy-4-chloropyrimidine were added, and the mixture was stirred at 100° C. for 6 hours. It was then cautiously hydrolyzed with 10 ml of water, the pH was adjusted to 5 with citric acid and, after extraction with ethyl acetate, the organic phase was washed with water then dried over magnesium sulfate, and the solvent was removed by distillation. The oily residue (1.9 g) was chromatographed on silica gel, resulting in 617 mg of a slightly impure oil.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][O:12]1)[N:6]=[C:5]2[C:17]1[N:22]=[C:21]([O:23][C@H:24]2[CH2:31][N:30]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:29][CH2:28][C:25]32[CH2:27][CH2:26]3)[CH:20]=[N:19][CH:18]=1.[Cl-].[C:40]([O:44][C:45](=[O:48])[CH2:46][Zn+])([CH3:43])([CH3:42])[CH3:41].CCOCC.N#N>O1CCOCC1>[C:40]([O:44][C:45](=[O:48])[CH2:46][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][O:12]1)[N:6]=[C:5]2[C:17]1[N:22]=[C:21]([O:23][C@H:24]2[CH2:31][N:30]([C:32]([O:34][C:35]([CH3:37])([CH3:36])[CH3:38])=[O:33])[CH2:29][CH2:28][C:25]32[CH2:27][CH2:26]3)[CH:20]=[N:19][CH:18]=1)([CH3:43])([CH3:42])[CH3:41]
Reactant: CC(C)(C)OC(=O)C[Zn+]
Reactant: CC(C)(C)OC(=O)N1CCC2(CC2)[C@@H](Oc2cncc(-c3nn(C4CCCCO4)c4ccc(Br)cc34)n2)C1
Agent: N#N
Agent: [Cl-]
Solvent: CCOCC
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)Cc1ccc2c(c1)c(-c1cncc(O[C@H]3CN(C(=O)OC(C)(C)C)CCC34CC4)n1)nn2C1CCCCO1
Temperature: 80 °C
Reaction time: 16 h
Yield: 61.8 %

Procedure:
A solution of (4R)-tert-butyl 4-(6-(5-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)pyrazin-2-yloxy)-6-azaspiro[2.5]octane-6-carboxylate (209 mg, 0.358 mmol), PdCl2(Amphos) (12.66 mg, 0.018 mmol), and (2-tert-butoxy-2-oxoethyl)zinc(II) chloride in Et2O (1073 μL, 0.536 mmol) in dioxane (3576 μL) was heated to 80° C. under a purged stream of N2; the reaction was stirred for 16 h at 80° C. The crude was adsorbed onto silica and was purified via automated flash chromatography (silica gel) with 100% hexanes to 50% EtOAc/hexanes to give (4R)-tert-butyl 4-(6-(5-(2-tert-butoxy-2-oxo ethyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)pyrazin-2-yloxy)-6-azaspiro[2.5]octane-6-carboxylate (137 mg, 0.221 mmol, 61.8% yield) as a yellow oil. MS (ESI, pos. ion) m/z: 620.3 (M+1).
Reaction SMILES: [C:1]([C:3]1[N:4]=[CH:5][S:6][CH:7]=1)#[N:2].Cl.[C:9]1(N)[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[NH2:15]>>[CH:13]1[CH:14]=[CH:9][C:10]2[N:15]=[C:1]([C:3]3[N:4]=[CH:5][S:6][CH:7]=3)[NH:2][C:11]=2[CH:12]=1
Reactant: Nc1ccccc1N
Reactant: N#Cc1cscn1
Agent: Cl
Product: c1ccc2[nH]c(-c3cscn3)nc2c1
Temperature: 201 °C
Reaction time: 5 h
Yield: 75.5 %

Procedure:
The mixture was heated and when the pot temperature reached 164° C., distillation commenced. The temperature gradually increased to 201° C. and a total of 44 ml of water plus ethylene glycol distillate were removed. The mixture was allowed to cool to 100° C. before 27.5 g (0.25 moles) of 4-cyanothiazole were added to the solution containing o-phenylenediamine monohydrochloride. The reaction mixture was heated to 125° C. and held within a temperature range of 125°-130° C. for a period of 5 hours. Thiabendazole formed as a precipitte during the 5 hours of heating. The reaction was monitored by gas chromatography and determined to be complete when the peaks corresponding to o-phenylenediamine and 4-cyanothiazole were negligible. Next, the reaction mass was cooled to 50° C. and filtered to collect the precipitate using a Buchner funnel and #4 Whatman filter paper. The wet cake was washed with 1.5 L of deionized water. The washed precipitate was dried overnight in a vacuum oven under 15-20" Hg and at a temperature of 90° C. The weight of dry thiabendazole crystals was 38.0 g, which corresponds to a yield of 75.5%. The purity was determined to be 99.67% (based on area %) using HPLC analysis.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:52]=[CH:51][C:6]([C:7]([O:22][CH2:23][C@H:24]2[O:28][C@@H:27]([N:29]3[CH:37]=[C:35]([CH3:36])[C:33](=[O:34])[NH:32][C:30]3=[O:31])[CH2:26][C@:25]2([CH2:39]OS(C2C=CC(C)=CC=2)(=O)=O)[OH:38])([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2)=[CH:5][CH:4]=1.[N-:53]=[N+:54]=[N-:55].[Na+]>CN(C=O)C.CCOC(C)=O>[CH3:15][O:14][C:11]1[CH:10]=[CH:9][C:8]([C:7]([O:22][CH2:23][C@H:24]2[O:28][C@@H:27]([N:29]3[CH:37]=[C:35]([CH3:36])[C:33](=[O:34])[NH:32][C:30]3=[O:31])[CH2:26][C@:25]2([CH2:39][N:53]=[N+:54]=[N-:55])[OH:38])([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:52][CH:51]=2)=[CH:13][CH:12]=1
Reactant: COc1ccc(C(OC[C@H]2O[C@@H](n3cc(C)c(=O)[nH]c3=O)C[C@@]2(O)COS(=O)(=O)c2ccc(C)cc2)(c2ccccc2)c2ccc(OC)cc2)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ccc(C(OC[C@H]2O[C@@H](n3cc(C)c(=O)[nH]c3=O)C[C@@]2(O)CN=[N+]=[N-])(c2ccccc2)c2ccc(OC)cc2)cc1
Temperature: 25 °C
Yield: 91 %

Procedure:
A slurry of 5′-O-(4,4′-dimethoxytrityl)-3′-p-toluen-sulfonyloxymethylthymidine (0.40 g; 0.55 mmol) and NaN3 (0.11 g; 1.65 mmol) in anhydrous DMF (3 ml) was heated at 50° C. for 3 days. The reaction mixture was cooled to room temperature, diluted with EtOAc (30 ml), and washed with water (3×40 ml) , then with 10% NaHCO3 (3×40 ml). The organic layer was dried over Na2SO4, concentrated and purified by chromatography on silica (EtOAc-Hexanes, 1:1) to yield 0.30 g (92%) of 5′-O-(4,4′-dimethoxytrityl)-3′- C-azidomethylthymidine as a colorless powder.
Reaction SMILES: [C:1](OCC)(=[O:7])[C:2](OCC)=[O:3].[CH3:11][N:12]([CH3:31])[C:13](=[O:30])[CH2:14][N:15]([C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=1)[CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18].CC[O-].[Na+].C(O)(=O)C>O>[CH3:31][N:12]([CH3:11])[C:13]([C:14]1[N:15]([C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=2)[C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[C:2]([OH:3])[C:1]=1[OH:7])=[O:30]
Reactant: CCOC(=O)C(=O)OCC
Reactant: CCOC(=O)CN(CC(=O)N(C)C)c1ccc(OC)cc1
Agent: CC[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CCOC(=O)c1c(O)c(O)c(C(=O)N(C)C)n1-c1ccc(OC)cc1
Temperature: 85 °C
Reaction time: 1.5 h
Yield: 59 %

Procedure:
Diethyl oxalate (2.54 ml, 18.6 mmol) was added dropwise to a stirred solution of ethyl 2-((2-(dimethylamino)-2-oxoethyl)(4-methoxyphenyl)amino)acetate (20) (5.21 g, 17.7 mmol) in NaOEt (21% by wt in EtOH) (27.8 ml, 74.3 mol), the mixture was stirred at 85° C. for 1.5 h. The reaction was quenched with acetic acid (10.1 ml, 177 mmol) and the resulting suspension was poured into iced water (200 mL), and extracted with EtOAc (3×100 mL), combined organics were washed with brine (200 mL), dried (MgSO4), filtered and solvents removed in vacuo to afford a brown oil. The residue was purified by silica gel chromatography (80 g, 0-10% MeOH (+1% NH3) in DCM) to afford ethyl 5-(dimethylcarbamoyl)-3,4-dihydroxy-1-(4-methoxyphenyl)-1H-pyrrole-2-carboxylate (UL1-012) (3.64 g, 53%) as a white solid: m/z 349 (M+H)+ (ES+), 347 (M−H)− (ES−). 1H NMR (400 MHz, DMSO-d6) δ: 8.60 (s, 1H), 8.46 (s, 1H), 7.08-7.01 (m, 2H), 6.90-6.82 (m, 2H), 4.00 (q, J=7.0 Hz, 2H), 3.76 (s, 3H), 2.83 (br s, 6H), 0.99 (t, J=7.1 Hz, 6H).
Reaction SMILES: [CH2:1]([N:5]([CH3:12])[CH2:6][CH2:7][C:8]([CH3:11])([NH2:10])[CH3:9])[CH2:2][CH2:3][CH3:4].[C:13](ON1C(=O)CCC1=O)([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14]>C1COCC1>[CH2:1]([N:5]([CH3:12])[CH2:6][CH2:7][C:8]([NH:10][C:13](=[O:14])[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)([CH3:11])[CH3:9])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN(C)CCC(C)(C)N
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Solvent: C1CCOC1
Product: CCCCN(C)CCC(C)(C)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 39.9 %

Procedure:
Crude N1-butyl-N1,3-dimethylbutane-1,3-diamine (5.00 g, 29.0 mmol) was dissolved into THF (100 mL). To this solution was added CbzOSu (7.23 g, 1 equiv, 29.0 mmol) in one portion. The reaction was left to stir at room temperature for 3 d. The solvent was removed and the residue was taken up in a mixture of diethyl ether (150 mL) and water (50 mL). The layers were separated and the organic layer washed with 1 M sodium carbonate (2×50 mL), 1M HCl (50 mL), and brine (100 mL). The organic layer was dried over anhydrous MgSO4, filtered and concentrated to a pale yellow oil. The crude oil was purified on an ISCO purification system with gradient elution from 10-80% ethyl acetate in hexanes. The desired fractions were collected and concentrated to give a white solid (3.55 g, yield: 40.0%). 1H NMR (CDCl3, 400 MHz): δ 0.83-0.87 (t, J=7.2, 3H), 1.25-1.35 (m, 2H), 1.40 (s, 6H), 1.41-1.45 (m, 2H), 1.59-1.62 (t, J=6.4, 2H), 2.18 (s, 3H), 2.28-2.32 (t, J=6.4, 2H), 2.43-2.47 (t, J=6.4, 2H), 5.04 (s, 2H), 7.27-7.37 (m, 5H). LRMS (ESI+) for C18H30N2O2 (306.2); Found: 307 (MH+).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]([OH:14])C1C=CC=CC=1.[H-].[Na+].Cl[C:18]1[CH:23]=[CH:22][N+:21]([O-:24])=[CH:20][CH:19]=1>O1CCOCC1>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][O:14][C:18]1[CH:23]=[CH:22][N+:21]([O-:24])=[CH:20][CH:19]=1
Reactant: [O-][n+]1ccc(Cl)cc1
Reactant: OC(c1ccccc1)c1ccccn1
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: [O-][n+]1ccc(OCc2ccccn2)cc1
Temperature: 120 °C
Reaction time: 0.5 h
Yield: 19.4 %

Procedure:
2-Pyridylbenzylalcohol (1.67 g, 15.3 mmol) was dissolved in 1,4-dioxane (25 mL) and NaH (60% weight dispersion in mineral oil, 0.92 g, 23 mmol) was added. After stirring for 30 minutes, 4-chloropyridine-N-oxide (2.27 g, 17.5 mmol) was added and the reaction mixture was heated for 1 h at 120° C. Upon cooling, the mixture was purified by flash column chromatography (40 g ISCO column eluting with methylene chloride and a methanol/ammonia mixture (10:1); gradient 100% methylene chloride to 90% methylene chloride over 30 min at 40 mL/min) to provide the title compound (600 mg, 38%) as a brown solid: 1H NMR (500 MHz, CDCl3) δ 8.62-8.61 (m, 1H), 8.13-8.10 (m, 2H), 7.74 (overlapping ddd, J=7.8, 1.4 Hz, 1H), 7.44 (d, J=7.8 Hz, 1H), 7.30 (d, J=4.8 Hz, 1H), 6.92-6.89 (m, 2H), 5.23 (s, 2H).
Reaction SMILES: [CH2:1]([C:10]([C:21]#[N:22])([CH2:16][CH2:17][C:18]([OH:20])=[O:19])[CH2:11][CH2:12][C:13]([OH:15])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH3:9])[CH:3]=1.Cl[C:24]1C=CC(C(C#N)(CCC(O)=O)CCC(O)=O)=CC=1.O1CCCC1.CC(C)([O-])C.[K+]>C(O)(=O)C>[CH2:1]([C:10]1([C:21]#[N:22])[CH2:11][CH2:12][C:13](=[O:15])[CH:17]([C:18]([O:20][CH3:24])=[O:19])[CH2:16]1)[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH3:9])[CH:3]=1
Reactant: N#CC(CCC(=O)O)(CCC(=O)O)c1ccc(Cl)cc1
Reactant: COc1cccc(CC(C#N)(CCC(=O)O)CCC(=O)O)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: COC(=O)C1CC(C#N)(Cc2cccc(OC)c2)CCC1=O
Yield: 99 %

Procedure:
Following the procedure of Example 1, Part B, but substituting 30.34 gm. (0.0951 mole) of the dimethyl ester of 4-(m-anisyl)-4-cyanopimelic acid (prepared in Part A, above) for the 34.97 gm. of the dimethyl ester of 4-(p-chlorophenyl)-4-cyanopimelic acid and using 620 ml. of the tetrahydrofuran, 21.3 gm. (0.19 mole) of the potassium tert-butoxide, and 150 ml. of the 2.5 N glacial acetic acid instead of the 700 ml., the 24.4 gm. (0.218 mole), and the 175 ml., respectively, there is prepared 29.1 gm. (99% yield) of 4-(m-anisyl)-2-carbomethoxy-4-cyanocyclohexanone as a gum.
Reaction SMILES: C(OC(C=N[C:8]1[CH:9]=[C:10]([NH:14][C:15]2[N:20]=[C:19]([NH:21][C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([OH:28])[CH:23]=3)[C:18]([F:29])=[CH:17][N:16]=2)[CH:11]=[CH:12][CH:13]=1)=O)C.[NH2:30][CH2:31][CH2:32][OH:33]>>[F:29][C:18]1[C:19]([NH:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([OH:28])[CH:23]=2)=[N:20][C:15]([NH:14][C:10]2[CH:11]=[CH:12][CH:13]=[C:8]([N:30]=[CH:31][C:32]([NH:30][CH2:31][CH2:32][OH:33])=[O:33])[CH:9]=2)=[N:16][CH:17]=1
Reactant: CCOC(=O)C=Nc1cccc(Nc2ncc(F)c(Nc3cccc(O)c3)n2)c1
Reactant: NCCO
Product: O=C(C=Nc1cccc(Nc2ncc(F)c(Nc3cccc(O)c3)n2)c1)NCCO

Procedure:
In like manner to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-morpholinoethyleneamino)carbonylmethyleneaminophenyl]-2,4-pyrimidinediamine, N2-(3-ethoxycarbonylmethyleneaminophenyl)-5-fluoro-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine and 2-aminoethanol were reacted to prepare 5-fluoro-N4-(3-hydroxyphenyl)-N2-[3-(N2-hydroxyethylamino)carbonylmethyleneaminophenyl]-2,4-pyrimidinediamine. LCMS: ret. time: 13.28 min.; purity: 97.3%; MS (m/e): 413.04 (MH+).
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5]Br.[CH3:7][C:8](=[CH:10][CH2:11][CH2:12]/[C:13](=[CH:15]/[CH2:16][OH:17])/[CH3:14])[CH3:9].C([N+](CCCC)(CCCC)CCCC)CCC>CCCCCC.O>[CH2:16]([O:17][CH2:5][CH2:4][CH2:3][CH2:2][Br:1])/[CH:15]=[C:13](/[CH2:12][CH2:11][CH:10]=[C:8]([CH3:9])[CH3:7])\[CH3:14]
Reactant: CC(C)=CCC/C(C)=C/CO
Reactant: BrCCCCBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: O
Solvent: CCCCCC
Product: CC(C)=CCC/C(C)=C/COCCCCBr
Temperature: 25 °C
Reaction time: 20 h
Yield: 352.4 %

Procedure:
1,4-Dibromobutane (42.7 g, 198 mmol), geraniol (8.78 g, 56.9 mmol) and tetrabutylammonium w/v, 70 mL) was added with stirring. The reaction mixture was heated at reflux for 3 h under N2. then left stirring under N2 for a further two days. Heating at reflux was resumed for a further 20 h and then the reaction mixture was cooled to room temperature and diluted with hexane (80 mL) and water (80 ml). The product was partitioned into the hexane layer and then the water layer was extracted with ether (2×20 mL). The combined organic layers were dried (Na2SO4) and the solvent was removed under reduced pressure to give a pale yellow oil. The oil was distilled under high vacuum (Kugelrohr) to remove the remaining dibromobutane thereby leaving the product as a yellow/orange oil (58 g).
Reaction SMILES: FC(F)(F)C(O)=O.[Br:8][C:9]1[CH:27]=[CH:26][C:25]([O:28][Si:29]([C:42]([CH3:45])([CH3:44])[CH3:43])([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[CH:24][C:10]=1[CH2:11][NH:12][C:13](=[O:23])[CH2:14][NH:15]C(OC(C)(C)C)=O>C(Cl)Cl>[Br:8][C:9]1[CH:27]=[CH:26][C:25]([O:28][Si:29]([C:42]([CH3:45])([CH3:44])[CH3:43])([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[CH:24][C:10]=1[CH2:11][NH:12][C:13](=[O:23])[CH2:14][NH2:15]
Reactant: CC(C)(C)OC(=O)NCC(=O)NCc1cc(O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)ccc1Br
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)[Si](Oc1ccc(Br)c(CNC(=O)CN)c1)(c1ccccc1)c1ccccc1
Reaction time: 1 h

Procedure:
Trifluoroacetic acid is added to a solution of product from Step C in methylene chloride. After one hour at room temperature, the solution is evaporated, and the residue is partitioned between ethyl acetate and saturated aqueous sodium bicarbonate solution. The organic phase is washed with saturated NaCl, dried over magnesium sulfate, filtered and evaporated to provide the title compound.
Reaction SMILES: [CH3:1][N:2]1[CH:12]=[CH:11][C:5]2[O:6][CH2:7][C:8](=[O:10])[NH:9][C:4]=2[C:3]1=[O:13].C1C(=O)N([Br:21])C(=O)C1.CC(=O)OCC>CC#N>[Br:21][C:11]1[C:5]2[O:6][CH2:7][C:8](=[O:10])[NH:9][C:4]=2[C:3](=[O:13])[N:2]([CH3:1])[CH:12]=1
Reactant: Cn1ccc2c(c1=O)NC(=O)CO2
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Solvent: CCOC(C)=O
Product: Cn1cc(Br)c2c(c1=O)NC(=O)CO2
Reaction time: 2 h
Yield: 78 %

Procedure:
At room temperature, to the title compound of step 1 (90 mg, 0.5 mmol) in anhydrous CH3CN (1 mL) was added NBS (89 mg, 0.5 mmol). After stirring about 2 h, additional NBS (75 mg, 0.4 mmol) was added and the reaction was complete within 20 min. EA extractive work up and silica gel chromatography gave the title compound (51 mg, 0.39 mmol) in 39% yield.