Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]=[C:2]1[O:6][C:4](=[O:5])[CH2:3]1.[CH:7]1([NH2:14])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1>O1CCCC1>[CH:7]1([NH:14][C:4](=[O:5])[CH2:3][C:2](=[O:6])[CH3:1])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: NC1CCCCCC1
Reactant: C=C1CC(=O)O1
Solvent: C1CCOC1
Product: CC(=O)CC(=O)NC1CCCCCC1
Temperature: 6 °C
Reaction time: 4 h
Yield: 68.9 %

Procedure:
37.1 g of diketene were added with stirring over 15 minutes to a mixture of 50 g of cycloheptylamine and 600 ml of tetrahydrofuran cooled to 6° C. and the mixture was stirred for 4 hours at room temperature. The mixture was distilled to dryness under reduced pressure and the residue was chromatographed over silica gel with elution with an 8-2 methylene chloride-acetone mixture to obtain 60 g of N-cycloheptyl-acetylacetamide melting at 52° C. 40 g of the said product and 1 g of p-toluene sulfonic acid were added to a mixture of 32 g of methyl orthoformate and 100 ml of methanol and after stirring the mixture for 8 hours at room temperature, 2 ml of quinoline were added thereto. The mixture was distilled to dryness under reduced pressure and the residue was added to toluene. The mixture was heated at 145° C. for 4 hours while distilling a toluene-methanol azeotrope. The toluene was evaporated by distillation under reduced pressure and the residue was chromatographed over silica gel. An 8-2 methylene chloride-methanol mixture was the eluant and the product was empasted with isopropyl ether to obtain 22 g of N-cycloheptyl-3-methoxy-crotonamide melting at 120° C. The RMN spectra showed the product to be the E isomer.
Reaction SMILES: [C:1]([CH:3]1[CH2:5][CH2:4]1)#[CH:2].C([Li])CCC.[C:11]([O:15][C:16](=[O:37])[NH:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][O:26][CH2:27][CH2:28][O:29][CH3:30])=[CH:20][C:19]=1[C:31](=[O:36])[C:32]([F:35])([F:34])[F:33])([CH3:14])([CH3:13])[CH3:12].[Cl-].[NH4+]>ClCCl.C(O)(C)C.C1COCC1>[C:11]([O:15][C:16](=[O:37])[NH:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][O:26][CH2:27][CH2:28][O:29][CH3:30])=[CH:20][C:19]=1[C:31]([OH:36])([C:32]([F:35])([F:34])[F:33])[C:2]#[C:1][CH:3]1[CH2:5][CH2:4]1)([CH3:14])([CH3:12])[CH3:13]
Reactant: COCCOCOc1ccc(NC(=O)OC(C)(C)C)c(C(=O)C(F)(F)F)c1
Reactant: C#CC1CC1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CC(C)O
Solvent: C1CCOC1
Solvent: ClCCl
Product: COCCOCOc1ccc(NC(=O)OC(C)(C)C)c(C(O)(C#CC2CC2)C(F)(F)F)c1
Temperature: -40 °C
Reaction time: 0.17 h
Yield: 61 %

Procedure:
A solution of 200 μL (2.3 mmol) of ethynyl-cyclopropane in 2 mL of freshly distilled THF was cooled to −40° C. and 1 mL (2.5 mmol) of n-butyl lithium (2.5M in hexane) was added under argon atmosphere. The reaction mixture was allowed to stir at −40° C. for 10 minutes. To the reaction mixture a solution of 400 mg (1.0 mmol) of 6 in 4 mL of freshly distilled THF was added, and the reaction was allowed to stir at −40° C. for 15 minutes. To the reaction mixture 2 mL of isopropanol were added followed by 20 mL of saturated ammonium chloride solution at −40° C. The reaction mixture was warmed up to room temperature, and 30 mL of dichloromethane was added. The organic layer was separated, and the aqueous layer was extracted with 3×30 mL of dichloromethane. The organic layers were combined, dried (anhydrous Na2SO4), and concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography using 20% ethyl acetate in hexane to give 280 mg (0.61 mmol, 60%) of 7 [LC-MS; M+Na 482.2].
Reaction SMILES: [CH:1]([C:4]1([CH3:17])[NH:8][C:7]([C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][N:10]=2)=[N:6][C:5]1=[O:16])([CH3:3])[CH3:2].C([Li])CCC.C[O:24][C:25](=O)[C:26]([N:28]([CH3:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:27].O>O1CCCC1>[CH:1]([C:4]1([CH3:17])[C:5](=[O:16])[NH:6][C:7]([C:9]2[C:14]([C:25](=[O:24])[C:26]([N:28]([CH3:35])[C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)=[O:27])=[CH:13][C:12]([CH3:15])=[CH:11][N:10]=2)=[N:8]1)([CH3:3])[CH3:2]
Reactant: COC(=O)C(=O)N(C)c1ccccc1
Reactant: Cc1ccc(C2=NC(=O)C(C)(C(C)C)N2)nc1
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: Cc1cnc(C2=NC(C)(C(C)C)C(=O)N2)c(C(=O)C(=O)N(C)c2ccccc2)c1
Temperature: -70 °C
Reaction time: 3 h
Yield: 40.8 %

Procedure:
To a stirred solution of 2.5 g(0.011 mole) of 2-(5-isopropyl-5-methyl-4-oxo-2-imidazolin-2 -yl)-5-methyl pyridine in 100ml of anhydrous tetrahydrofuran cooled to -70° C. under the presence of nitrogen was added dropwise a 9.68 ml of 2.5 molar n-butyllithium, thus maintaining temperature below -65° C. The solution was stirred at -70° C. for 3 hr and a solution 1.96 g of N-methyl-N-phenyl oxamic acid methyl ester(3.4 g, 0.016 mole) in 10 ml of anhydrous tetrahydrofuran was added dropwise while maintaining temperature below -65° C. After stirring another hour at -70° C., the solution was poured into water and extracted with methylene chloride. The combined organic phases were dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to give crude product. The crude product was purified by column chromatography to produce 1.76 g of pale yellow solid(m.p.=153°~156° C.).
Reaction SMILES: [CH2:1]([S:4][C:5]1[N:9]=[CH:8][NH:7][N:6]=1)[CH2:2][CH3:3].[CH2:10]([N:13]([CH2:17][CH:18]=[CH2:19])[C:14](Cl)=[O:15])[CH:11]=[CH2:12].O1CCCC1>C(N(CC)CC)C>[CH2:10]([N:13]([CH2:17][CH:18]=[CH2:19])[C:14]([N:7]1[CH:8]=[N:9][C:5]([S:4][CH2:1][CH2:2][CH3:3])=[N:6]1)=[O:15])[CH:11]=[CH2:12]
Reactant: CCCSc1nc[nH]n1
Reactant: C=CCN(CC=C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C=CCN(CC=C)C(=O)n1cnc(SCCC)n1

Procedure:
A mixture of 5.75 g. 3-propylthio-1,2,4-triazole, 6.8 g. diallylcarbamoyl chloride, 25 ml. dry tetrahydrofuran and 8 ml. dry triethylamine was refluxed under anhydrous conditions for 3 hours. The reaction mixture was worked up as described in Example 1 to produce an oil which was distilled under reduced pressure to give 1-diallylcarbamoyl-3-propylthio-1,2,4-triazole, b.p. 134° - 135°C./0.1 mm. Gas-liquid chromatographic (GLC) assay indicated a content of 1-isomer of 94.2%. Elemental analysis satisfactory.
Reaction SMILES: [CH2:1]([O:3][C:4]1[N:12]=[CH:11][C:10]([S:13]([N:16]2[CH2:21][CH2:20][N:19]([CH2:22][CH3:23])[CH2:18][CH2:17]2)(=[O:15])=[O:14])=[CH:9][C:5]=1[C:6]([OH:8])=O)[CH3:2].[NH2:24][C:25]1[C:26]([C:36]([NH2:38])=[O:37])=[N:27][N:28]([CH2:32][CH2:33][O:34][CH3:35])[C:29]=1[CH2:30][CH3:31]>C(OCC)(=O)C>[C:36]([C:26]1[C:25]([NH:24][C:6](=[O:8])[C:5]2[CH:9]=[C:10]([S:13]([N:16]3[CH2:17][CH2:18][N:19]([CH2:22][CH3:23])[CH2:20][CH2:21]3)(=[O:14])=[O:15])[CH:11]=[N:12][C:4]=2[O:3][CH2:1][CH3:2])=[C:29]([CH2:30][CH3:31])[N:28]([CH2:32][CH2:33][O:34][CH3:35])[N:27]=1)(=[O:37])[NH2:38]
Reactant: CCc1c(N)c(C(N)=O)nn1CCOC
Reactant: CCOc1ncc(S(=O)(=O)N2CCN(CC)CC2)cc1C(=O)O
Solvent: CCOC(C)=O
Product: CCOc1ncc(S(=O)(=O)N2CCN(CC)CC2)cc1C(=O)Nc1c(C(N)=O)nn(CCOC)c1CC
Temperature: 45 °C
Reaction time: 0.67 h
Yield: 14.5 %

Procedure:
2-ethoxy-5-(4-ethyl-1-piperazinylsulfonyl)nicotinic acid (2.31 kg, 6.73 Mol) was suspended in ethyl acetate (16.2 L) and 1,1-carbonyldimidazole (1.09 kg, 6.73 Mol) was added at room temperature. The reaction mixture was heated at 45° C. for 40 minutes and then the reaction was stirred for a further 40 minutes at reflux. After cooling to ambient temperature 4-amino-5-ethyl-1-(2-methoxyethyl)-1H-pyrazole-3-carboxamide (1.5 kg, 7.06 Mol) was added to the cooled mixture, and the reaction stirred for a further 15 hours under reflux. The mixture was cooled filtered and the filter cake was washed with 90% water/10% ethyl acetate, (2 mL/g) to afford N-[3-carbamoyl-5-ethyl-1-(2-methoxyethyl)-1H-pyrazol-4-yl}-2-ethoxy-5-(4-ethyl-1-piperazinyl sulfonyl) nicotinamide as an off white crystalline solid, 3.16 kg, 88%. m.p.=156° C. Found: C, 51.33; H, 6.56; N, 18.36. C23H35N7O6S requires C, 51.40; H, 6.53; N, 18.25%.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][Si:6]([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7].[CH3:13][NH2:14].CO>CO>[Si:6]([O:5][CH2:4][CH2:3][CH2:2][NH:14][CH3:13])([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7]
Reactant: CC(C)(C)[Si](C)(C)OCCCBr
Reactant: CN
Solvent: CO
Product: CNCCCO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.2 %

Procedure:
(3-Bromopropoxy)(tert-butyl)dimethylsilane (1.65 g, 6.52 mmol) was dissolved in methanol (13 mL), and the mixture was added to a 40% methyl amine-methanol solution (13.3 mL, 130.0 mmol) under ice cooling, and the mixture was stirred overnight at room temperature. The solvent was evaporated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (ethyl acetate:methanol=10:1→methylene chloride:methanol=10:1, v/v) to give the title compound (864 mg; yield, 65%) as a yellow oily substance.
Reaction SMILES: C(OC(=O)[N:7]([C:28]1[CH:33]=[CH:32][C:31]([CH:34]=[CH:35][CH2:36][CH2:37][N:38]2[CH:42]=[CH:41][N:40]=[N:39]2)=[CH:30][CH:29]=1)[CH2:8][C:9]1[N:10]=[C:11]([CH:14]=[CH:15][C:16]2[CH:21]=[CH:20][C:19]([S:22]([C:24]([F:27])([F:26])[F:25])=[O:23])=[CH:18][CH:17]=2)[O:12][CH:13]=1)(C)(C)C.O.C(=O)([O-])[O-].[Na+].[Na+]>FC(F)(F)C(O)=O.ClCCl>[N:38]1([CH2:37][CH2:36][CH:35]=[CH:34][C:31]2[CH:32]=[CH:33][C:28]([NH:7][CH2:8][C:9]3[N:10]=[C:11]([CH:14]=[CH:15][C:16]4[CH:17]=[CH:18][C:19]([S:22]([C:24]([F:26])([F:27])[F:25])=[O:23])=[CH:20][CH:21]=4)[O:12][CH:13]=3)=[CH:29][CH:30]=2)[CH:42]=[CH:41][N:40]=[N:39]1
Reactant: CC(C)(C)OC(=O)N(Cc1coc(C=Cc2ccc(S(=O)C(F)(F)F)cc2)n1)c1ccc(C=CCCn2ccnn2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: O=S(c1ccc(C=Cc2nc(CNc3ccc(C=CCCn4ccnn4)cc3)co2)cc1)C(F)(F)F
Yield: 10 %

Procedure:
The crude carbamic ester was stirred in a mixture of trifluoroacetic acid/dichloro methane (1:1, 28 ml) for 2 h. Water (50 ml) was added and the solution was neutralized by careful addition of sodium carbonate. The organic layer is separated, washed with water and concentrated. Purification was achieved by flash column chromatography (ethyl acetate/heptane 4:1) and washing with methanol yielding [4-(4-[1,2,3]triazol-1-yl-but-1-enyl)-phenyl]-{2-[2-(4-trifluoromethanesulfinyl-phenyl)-vinyl]-oxazol-4-ylmethyl}-amine 38 (25 mg, 10%) as a yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]#[C:9][C@@H:10]2[CH2:15][CH2:14][C@@H:13]([CH3:16])[NH:12][CH2:11]2)=[N:6][CH:7]=1.C(Cl)CCl.C1C=NC2N(O)N=NC=2C=1.[CH3:31][C:32]1[CH:33]=[CH:34][C:35]([N:41]2[N:45]=[CH:44][CH:43]=[N:42]2)=[C:36]([CH:40]=1)[C:37](O)=[O:38].C(N(CC)CC)C>CN(C=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]#[C:9][C@H:10]2[CH2:11][N:12]([C:37]([C:36]3[CH:40]=[C:32]([CH3:31])[CH:33]=[CH:34][C:35]=3[N:41]3[N:45]=[CH:44][CH:43]=[N:42]3)=[O:38])[C@H:13]([CH3:16])[CH2:14][CH2:15]2)=[N:6][CH:7]=1
Reactant: Cc1ccc(-n2nccn2)c(C(=O)O)c1
Reactant: C[C@@H]1CC[C@@H](C#Cc2ccc(F)cn2)CN1
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: Cc1ccc(-n2nccn2)c(C(=O)N2C[C@H](C#Cc3ccc(F)cn3)CC[C@H]2C)c1
Temperature: 50 °C
Reaction time: 48 h

Procedure:
A solution of 5-fluoro-2-{[(3S,6R)-6-methylpiperidin-3-yl]ethynyl}pyridine (193 mg, 0.884 mmol), EDC (339 mg, 1.77 mmol), HOAT (241 mg, 1.77 mmol), and 5-methyl-2-(2H-1,2,3-triazol-2-yl)benzoic acid (216 mg, 1.06 mmol) in DMF (6 mL) was treated with triethylamine (0.37 mL, 2.7 mmol) and the reaction stirred at 50° C. for 2 d. The reaction was diluted with sat'd, aqu. NaHCO3 and extracted twice with EtOAc. The organics were washed with brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. The crude material was purified by silica gel flash chromatography eluting with 0-65% EtOAc in hexanes to provide the pure title compound as an off-white foam. The pure material gave a high resolution mass spectrum (ES+) m/z of 404.1883, calculated for M+H+ [C23H22FN5O: 404.1881] and a proton NMR spectra consistent with theory.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[CH:4][C:3]=1[NH:10][C:11](=[O:15])[CH:12]=NO.B(F)(F)F.CC[O:22]CC>>[Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[C:4]2[C:3]=1[NH:10][C:11](=[O:15])[C:12]2=[O:22]
Reactant: CCOCC
Reactant: COc1cccc(NC(=O)C=NO)c1Cl
Agent: FB(F)F
Product: COc1ccc2c(c1Cl)NC(=O)C2=O
Temperature: 90 °C
Yield: 63 %

Procedure:
Compound 245d (10.46 g, 45.74 mmol) was added portionwise to BF3.Et2O at 40° C. The mixture was then heated at 90° C. for 3 hrs. After cooling down to room temperature, the reaction mixture was poured into crushed ice and extracted with EtOAc. Organics were dried over Na2SO4, filtered, concentrated under reduced pressure, and purified by chromatography on silica gel (petroleum ether/EtOAc). The compound obtained was recrystallised from EtOH to yield compound 246d as a brown solid in 63% yield. 1H NMR (DMSO-d6, 400 MHz) δ (ppm) 3.96 (s, 3H), 6.79 (d, J=9.10 Hz, 1H), 7.52 (d, J=9.10 Hz, 1H), 11.40 (s, 1H).
Reaction SMILES: Cl.[C:2]([O:18][CH3:19])(=[O:17])/[CH:3]=[CH:4]/[C:5]([O:7][CH2:8][C:9](=[O:16])[N:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1)=[O:6].[C:20](Cl)(=[O:22])[CH3:21].C(N(C(C)C)CC)(C)C>ClCCl>[C:5]([O:7][CH2:8][C:9]([N:10]1[CH2:15][CH2:14][N:13]([C:20](=[O:22])[CH3:21])[CH2:12][CH2:11]1)=[O:16])(=[O:6])/[CH:4]=[CH:3]/[C:2]([O:18][CH3:19])=[O:17]
Reactant: COC(=O)/C=C/C(=O)OCC(=O)N1CCNCC1
Reactant: CC(=O)Cl
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)/C=C/C(=O)OCC(=O)N1CCN(C(C)=O)CC1
Yield: 59.2 %

Procedure:
Methyl 2-oxo-2-piperazinylethyl(2E)but-2-ene-1,4-dioate hydrochloride (14) (0.20 g, 0.68 mmol) was reacted with acetyl chloride (AcCl) (0.60 mL, 0.66 g, 0.84 mmol) and diisopropylethylamine (0.70 mL, 0.52 g, 4.0 mmol) in dichloromethane (DCM). Following aqueous work-up, the crude product was purified by silica gel flash chromatography to afford 0.12 g (54% yield) of the title compound (16) as a white solid. 1H NMR (CDCl3, 400 MHz): δ 6.98-6.93 (m, 2H), 4.86 (s, 2H), 3.83 (s, 3H), 3.66 3.63 (m, 4H), 3.50-3.40 (m, 4H), 2.14 (s, 3H). MS (ESI): m/z 299.12 (M+H)+.
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:3].[CH3:11][C@H:12]1[CH2:17][O:16][CH2:15][CH2:14][N:13]1[C:18]1[CH:23]=[C:22]([C:24]([S:27]([C:30]([CH3:33])([CH3:32])[CH3:31])(=[O:29])=[O:28])([CH3:26])[CH3:25])[N:21]=[C:20]([C:34]2[CH:40]=[CH:39][C:37]([NH2:38])=[CH:36][CH:35]=2)[N:19]=1.C(=O)([O-])O.[Na+]>O1CCOCC1>[CH3:11][C@H:12]1[CH2:17][O:16][CH2:15][CH2:14][N:13]1[C:18]1[CH:23]=[C:22]([C:24]([S:27]([C:30]([CH3:33])([CH3:32])[CH3:31])(=[O:29])=[O:28])([CH3:25])[CH3:26])[N:21]=[C:20]([C:34]2[CH:40]=[CH:39][C:37]([NH:38][C:2](=[O:3])[O:4][C:5]3[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=3)=[CH:36][CH:35]=2)[N:19]=1
Reactant: C[C@H]1COCCN1c1cc(C(C)(C)S(=O)(=O)C(C)(C)C)nc(-c2ccc(N)cc2)n1
Reactant: O=C(Cl)Oc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: C[C@H]1COCCN1c1cc(C(C)(C)S(=O)(=O)C(C)(C)C)nc(-c2ccc(NC(=O)Oc3ccccc3)cc2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.2 %

Procedure:
Phenyl chloroformate (0.368 mL, 2.93 mmol) was added to 4-[4-[(3S)-3-methylmorpholin-4-yl]-6-(2-tert-butylsulfonylpropan-2-yl)pyrimidin-2-yl]aniline (1.153 g, 2.67 mmol) and sodium hydrogen carbonate (0.336 g, 4.00 mmol) in dioxane (20 mL) at RT. The resulting slurry was stirred at RT for 2 hours. The reaction mixture was partitioned between ethyl acetate and water. The organic solution was dried (MgSO4), filtered and concentrated under reduced pressure. The residue was chromatographed on silica, eluting with 20%-70% ethyl acetate in isohexane, to give the desired material as a near colourless solid (1.42 g).
Reaction SMILES: [CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[C:13]2[CH:18]=[CH:17][C:16](B3OC(C)(C)C(C)(C)O3)=[C:15]([F:28])[CH:14]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1.[NH2:29][C:30]1[N:35]=[C:34]([C:36]#[N:37])[C:33](Br)=[CH:32][CH:31]=1>>[NH2:29][C:30]1[N:35]=[C:34]([C:36]#[N:37])[C:33]([C:16]2[CH:17]=[CH:18][C:13]([C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=3[S:4]([CH:1]3[CH2:3][CH2:2]3)(=[O:6])=[O:5])=[CH:14][C:15]=2[F:28])=[CH:32][CH:31]=1
Reactant: N#Cc1nc(N)ccc1Br
Reactant: CC1(C)OB(c2ccc(-c3ccccc3S(=O)(=O)C3CC3)cc2F)OC1(C)C
Product: N#Cc1nc(N)ccc1-c1ccc(-c2ccccc2S(=O)(=O)C2CC2)cc1F

Procedure:
The title compound was prepared using analogous conditions to those described in Example 6 2-(2′-(cyclopropylsulfonyl)-3-fluoro-[1,1′-biphenyl]-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane and 6-amino-3-bromo-2-cyanopyridine. MS (ESI): mass calcd. for C21H16FN3O2S, 393.09; m/z found, 393.9 [M+H]+. 1H NMR (500 MHz, DMSO-d6) δ 8.07 (d, J=7.9, 1H), 7.71-7.64 (m, 1H), 7.64-7.58 (m, 2H), 7.54-7.48 (m, 1H), 7.40 (dd, J=19.2, 9.2, 2H), 7.33 (dd, J=7.9, 1.6, 1H), 6.86 (d, J=8.7, 1H), 6.79 (d, J=10.0, 3H), 1.03 (s, 9H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[N:11]=[C:12]1[NH:16][C@@H:15]([CH:17]([CH3:19])[CH3:18])[CH2:14][S:13]1.[CH:20]1(Br)[CH2:24][CH2:23][CH2:22][CH2:21]1>>[CH3:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[N:11]=[C:12]1[N:16]([CH:20]2[CH2:24][CH2:23][CH2:22][CH2:21]2)[C@@H:15]([CH:17]([CH3:19])[CH3:18])[CH2:14][S:13]1
Reactant: Cc1cc([N+](=O)[O-])ccc1N=C1N[C@@H](C(C)C)CS1
Reactant: BrC1CCCC1
Product: Cc1cc([N+](=O)[O-])ccc1N=C1SC[C@H](C(C)C)N1C1CCCC1

Procedure:
(1S)-1-Isopropyl-2-hydroxyethylamine was reacted with SOCl2 followed by 2-methyl-4-nitrophenyl isothiocyanate according to Method C2a to give (4S)-2-(2-methyl-4-nitrophenylimino)-4-isopropyl-1,3-thiazolidine. The thiazolidine was reacted with cyclopentyl bromide according to Method D2a to afford (4S)-2-(2-methyl-4-nitrophenylimino)-4-isopropyl-3-cyclopentyl-1,3-thiazolidine.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8](=[N:10][C:11]2[C:16]([CH3:17])=[CH:15][C:14]([CH3:18])=[CH:13][C:12]=2[Cl:19])[CH3:9])[CH:5]=[CH:4][CH:3]=1.C([Li])CCC.CN(C)[C:27](=[O:29])[CH3:28].[Cl-].[NH4+]>C(OCC)C.CCCCCC>[Cl:19][C:12]1[CH:13]=[C:14]([CH3:18])[CH:15]=[C:16]([CH3:17])[C:11]=1[N:10]=[C:8]([C:6]1[N:7]=[C:2]([C:27](=[O:29])[CH3:28])[CH:3]=[CH:4][CH:5]=1)[CH3:9]
Reactant: CC(=Nc1c(C)cc(C)cc1Cl)c1cccc(Br)n1
Reactant: CC(=O)N(C)C
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCOCC
Solvent: CCCCCC
Product: CC(=O)c1cccc(C(C)=Nc2c(C)cc(C)cc2Cl)n1
Temperature: -70 °C
Reaction time: 0.5 h
Yield: 47 %

Procedure:
2.00 g (0.0059 mol) of [1-(6-bromopyridin-2-yl)ethylidene](2-chloro-4,6-dimethylphenyl)amine were dissolved in 25 ml of diethyl ether and cooled to −70° C. 3.70 ml (0.0059 mol) of a 1.6 M solution of butyllithium in hexane were added dropwise over a period of 15 minutes. The temperature rose to −40° C. and the mixture was stirred for another 30 minutes. The mixture was cooled to −70° C. and 0.52 g (0.0059 mol) of N,N-dimethylacetamide was added dropwise and the mixture was stirred at room temperature for another three hours. The reaction mixture was stirred with 5 ml of a saturated ammonium chloride solution. The aqueous phase was extracted twice with diethyl ether. The combined organic phases were dried over Na2SO4, filtered and the solvent was distilled off under reduced pressure. This gave 0.83 g (0.0028 mol) of the product in a yield of 47%.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][CH:3]=1.N1C=CC=CC=1.[CH2:16]([O:30][C:31]1[CH:39]=[CH:38][C:34]([C:35](Cl)=[O:36])=[CH:33][CH:32]=1)[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]>C(Cl)Cl.C(Cl)(Cl)Cl>[OH:7][CH2:6][C:5]1[CH:8]=[CH:9][C:2]([NH:1][C:35](=[O:36])[C:34]2[CH:33]=[CH:32][C:31]([O:30][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])=[CH:39][CH:38]=2)=[CH:3][CH:4]=1
Reactant: CCCCCCCCCCCCCCOc1ccc(C(=O)Cl)cc1
Reactant: Nc1ccc(CO)cc1
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCCCCCCCCCCCCOc1ccc(C(=O)Nc2ccc(CO)cc2)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 67.6 %

Procedure:
To a mixture of 9.75 g of p-aminobenzyl alcohol and 19.27 g of pyridine in 230 ml of methylene chloride cooled to 0° C. is added over 35 minutes a solution of 21.5 g of 4-tetradecyloxybenzoyl chloride in 230 ml of methylene chloride. The mixture is stirred at room temperature for 2 hours and diluted with chloroform. The mixture is heated to dissolve insolubles, washed with hot water and hot dilute hydrochloric acid then dried. The mixture is filtered hot and the solvent evaporated to a residue which is crystallized from tetrahydrofuran:hexane to give 18.1 g of the desired product as a yellow powder, m.p. 140°-145° C.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([C:8]2[O:12][CH:11]=[N:10][C:9]=2[C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[CH:5]=[CH:4][N:3]=1.[OH-].[NH4+:21].O>O1CCOCC1.[Cu-]=O>[F:19][C:16]1[CH:17]=[CH:18][C:13]([C:9]2[N:10]=[CH:11][O:12][C:8]=2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH2:21])[CH:7]=2)=[CH:14][CH:15]=1
Reactant: [NH4+]
Reactant: Fc1ccc(-c2ncoc2-c2ccnc(Br)c2)cc1
Agent: O=[Cu-]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: Nc1cc(-c2ocnc2-c2ccc(F)cc2)ccn1
Temperature: 150 °C

Procedure:
2-Bromo-4-[4-(4-fluoro-phenyl)-oxazol-5-yl]-pyridine (700 mg, 2.19 mmol), 28% aqueous ammonium hydroxide solution (14 mL) and Copper (I) oxide (314 mg, 2.19 mmol) are mixed in 1,4-dioxane (14 mL) in a microwave reaction tube. The tube is sealed and heated at 150° C. for 25 min in a microwave reactor. Then water (80 mL) is added and the mixture is extracted with EtOAc (3×50 ml). The organic layers are combined and concentrated to give the crude product. Purification by silica flash column chromatography using MeOH in DCM (gradient from 0% to 10%) affords 320 mg of desired product.
Reaction SMILES: C(C1C=C(C=CC2C=C(C)C([C:20]3[C:25](C)=[CH:24][N:23]=[CH:22][C:21]=3C)=C(C)C=2)C=C(C(C)(C)C)C=1O)(C)(C)C.[I:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42]>C(Cl)Cl>[I-:34].[CH2:35]([N+:23]1[CH:22]=[CH:21][CH:20]=[CH:25][CH:24]=1)[CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42]
Reactant: CCCCCCCCI
Reactant: Cc1cncc(C)c1-c1c(C)cc(C=Cc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)cc1C
Solvent: ClCCl
Product: CCCCCCCC[n+]1ccccc1
Product: [I-]
Temperature: 80 °C
Reaction time: 24 h

Procedure:
To a stirring solution of 13 (0.150 mg, 0.34 mmol) in dry CH2Cl2 (5 mL) was added dropwise 1-iodooctane (0.6 mL, 0.792 g, 3.3 mmol) at room temperature. The reaction mixture was then stirred at 80° C. under N2 for 1 day. After cooling to room temperature, the mixture was next concentrated in vacuo and washed with hexane (20 mL) to give the corresponding n-octyl-pyridinium iodide salt 14 as an analytically pure yellow solid (0.211 g, 95.4%). To a suspension of 12 (0.136 g, 0.2 mmol) in dry methanol (1 mL) was added dropwise a solution of sodium methoxide in methanol (0.5 mL, 0.5 M) at room temperature. A clear reddish solution was obtained from which an orange precipitate immediately formed. The precipitate was collected by filtration and washed with dry methanol to give analytically pure product (0.096 g, 86.8%) as a brown solid: mp>280° C.; 1H NMR (400 MHz, CD3OD): δ 8.816 (s, 2H), 7.395 (s, 2H), 7.317 (s, 2H), 7.160 (d, 1H, J=16.4 Hz), 6.841 (d, 1H, J=16.0 Hz), 4.547 (t, 2H, J=8.0 Hz), 2.146 (s, 6H), 2.065 (m, 2H), 1.912 (s, 6H), 1.450 (s, 18H), 1.307 (m, 10H), 0.895 (s, 3H); 13C NMR (100 MHz, CD3OD): δ 159.608, 154.285, 142.183, 139.217, 138.198, 136.351, 133.757, 131.838, 130.964, 128.398, 126.424, 124.704, 123.758, 61.530, 34.624, 32.031, 31.931, 30.493, 29.292, 26.399, 22.850, 20.057, 17.463, 14.352; HRMS (EI): m/z 553.4263 [M+]; calcd, 553.4284; Anal. Calcd. for C39H55NO.2H2O: C, 79.41; H, 10.08; N, 2.37. Found; C, 79.71; H, 9.63; N, 2.14.