Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(NC(C)C)(C)C.[CH2:8]([Li])[CH2:9][CH2:10][CH3:11].CN(C)P(N(C)C)(N(C)C)=O.[C:24]([OH:28])(=[O:27])[CH2:25][CH3:26].BrCC#CC.Cl>O1CCCC1>[CH3:26][CH:25]([CH2:8][C:9]#[C:10][CH3:11])[C:24]([OH:28])=[O:27]
Reactant: [Li]CCCC
Reactant: CCC(=O)O
Agent: CC#CCBr
Agent: Cl
Solvent: CC(C)NC(C)C
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: C1CCOC1
Product: CC#CCC(C)C(=O)O
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 106 %

Procedure:
Diisopropylamine (26.0 g, 0.257 mmol, 3.1 eq) in 130 ml of tetrahydrofuran initially at -50° C. is treated dropwise with n-butyllithium (98.8 ml, 1.6 M, 0.158 mol, 1.9 eq) over an 8 minute period while allowing the temperature to rise to -25° C. After 5 minutes longer at -20° C., the reaction mixture is treated dropwise with a mixture of hexamethylphosphoramide (17.8 g, 0.099 mol, 1,2 eq) and propionic acid (6.14 g, 0.083 mol, 1.0 eq) over a 7 minute period while the temperature rises to 0° C. Following addition the reaction mixture is warmed to room temperature and maintained there for 35 minutes. The contents are then cooled to 0° C. in an ice bath, treated dropwise over a 12 minute period with 1-bromo-2-butyne (11.0 g, 0.083 mol, 1.0 eq) in 8 ml of tetrahydrofuran. The temperature, which rises to 16° C. during addition, is allowed to warm to room temperature thereafter where it is maintained for 2 hours. The contents are carefully poured into 300 ml of 10% HCl with stirring (exothermic) followed by 500 ml of ether-pentane (1:1). The organic layer is separated and the aqueous phase extracted 2 more times with etherpentane (1:1) giving 1800 ml of total extract volume. The combined extracts are washed with water 2×60 ml) and the combined organic extracts are dried over anhydrous sodium sulfate, magnesium sulfate and concentrated at reduced pressure to provide 11.1 g (over theory) of 2-methyl-4-hexynoic acid which is converted to the methyl ester by treatment with methyl iodide.
Reaction SMILES: [C:1]([O:4][C@H:5]1[C@@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@H:10]([O:16][C:17](=[O:19])[CH3:18])[C@@H:9]([CH2:20][O:21][C:22](=[O:24])[CH3:23])[O:8][CH:6]1[OH:7])(=[O:3])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].C([O:38][C:39](=[O:49])[CH:40]([C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[CH2:41]Br)C1C=CC=CC=1.COC(C)(C)C>[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC.O1CCOCC1>[C:1]([O:4][C@H:5]1[C@@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@H:10]([O:16][C:17](=[O:19])[CH3:18])[C@@H:9]([CH2:20][O:21][C:22](=[O:24])[CH3:23])[O:8][CH:6]1[O:7][CH2:41][CH:40]([C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[C:39]([OH:49])=[O:38])(=[O:3])[CH3:2]
Reactant: O=C(OCc1ccccc1)C(CBr)c1ccccc1
Reactant: CC(=O)OC[C@H]1OC(O)[C@@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: C1COCCO1
Solvent: COC(C)(C)C
Product: CC(=O)OC[C@H]1OC(OCC(C(=O)O)c2ccccc2)[C@@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 0 °C

Procedure:
A mixture that consists of 34.83 g (100 mmol) of 2,3,4,6-tetra-O-acetyl-mannopyranose, 1.39 g (5 mmol) of tetrabutylammonium chloride and 35.8 g (110 mmol) of fine-powder cesium carbonate in 400 ml of dioxane is cooled to 0° C. At 0° C., 47.88 g (150 mmol) of 2-phenyl-3-bromopropionic acid-benzyl ester, dissolved in 30 ml of dioxane, is added in drops over 10 minutes while being stirred vigorously. It is stirred for one hour at 0° C. 250 ml of MTB (methyl-tert-butyl ether) is added, solid is filtered out, and the filtrate is evaporated to the dry state in a vacuum. The residue is taken up in 500 ml of tetrahydrofuran. 5 g of palladium (10%) on activated carbon is added thereto and hydrogenated until hydrogen absorption is completed. Then, catalyst is filtered out, it is rewashed with a little tetrahydrofuran, the organic solutions are combined, and it is evaporated to the dry state in a vacuum. The residue is chromatographed on silica gel (mobile solvent: dichloromethane/n=hexane/ethanol/acetic acid=20:5:3:0.5). The product-containing fractions are concentrated by evaporation, dissolved in 400 ml of ethyl acetate and shaken out three times with 200 ml of water. Then, the organic phase is separated and evaporated to the dry state in a vacuum.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][CH:12]([O:14][CH2:15][CH3:16])[CH3:13])[C:6]#[N:7].[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:6][NH2:7])[CH:8]=[CH:9][C:10]=1[O:11][CH:12]([O:14][CH2:15][CH3:16])[CH3:13]
Reactant: CCOC(C)Oc1ccc(C#N)cc1OC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(C)Oc1ccc(CN)cc1OC
Temperature: 0 °C
Yield: 71.3 %

Procedure:
A solution of 5.0 g of 3-methoxy-4-(2-ethoxy-1-oxapropyl)benzonitrile in 25 ml anhydrous THF was added dropwise to 119.5 ml 1 M lithium aluminum hydride in THF. The mixture was refluxed for four hours, cooled to 0° C., and the excess reagent was quenched with 5 N NaOH. The precipitated aluminum salts were removed by filtration and the THF evaporated. The residue was partitioned between 200 ml ether and 75 ml H2O. The remaining ether layer was washed with 75 ml of brine, dried (K2CO3), filtered, and evaporated to yield 3.63 g of 2-methoxy-4-aminomethyl-(2-ethoxy-1-oxapropyl)benzene.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][OH:8])[N:2]=1.S(Cl)(Cl)=O.[CH:13]1([NH:16][C:17](=[O:35])[C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[C:20]([NH:25][C:26](=[O:34])[C:27]3[CH:32]=[CH:31][C:30](O)=[CH:29][CH:28]=3)[CH:19]=2)[CH2:15][CH2:14]1.C(=O)([O-])[O-].[Cs+].[Cs+]>C(Cl)Cl.CS(C)=O.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH:13]1([NH:16][C:17](=[O:35])[C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[C:20]([NH:25][C:26](=[O:34])[C:27]3[CH:28]=[CH:29][C:30]([O:8][CH2:7][C:3]4[N:2]=[N:1][CH:6]=[CH:5][CH:4]=4)=[CH:31][CH:32]=3)[CH:19]=2)[CH2:15][CH2:14]1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1NC(=O)c1ccc(O)cc1
Reactant: OCc1cccnn1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Solvent: CS(C)=O
Product: Cc1ccc(C(=O)NC2CC2)cc1NC(=O)c1ccc(OCc2cccnn2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 5.9 %

Procedure:
To a solution of 3-pyridazinylmethanol (140 mg, 1.27 mmol) in DCM (5 mL) was added thionyl chloride (103 μl, 1.42 mmol) and the resulting mixture stirred at room temperature for 4 h. The solvent was evaporated under reduced pressure and then to the residue in DMSO (4 mL) was added N-cyclopropyl-3-[(4-hydroxybenzoyl)amino]-4-methylbenzamide (197 mg, 0.636 mmol), cesium carbonate (621 mg, 1.91 mmol) and tetrabutylammonium iodide (235 mg, 0.636 mmol) and the resulting mixture stirred at 60° C. for 16 h. The reaction mixture was added to a 20 g SCX column and product eluted with methanol. Concentration under reduced pressure gave impure product which was further purified on silica column chromatography eluting with 0-20% methanol/1% ammonium hydroxide SG 0.88 in ethyl acetate. Evaporation and trituration with DCM and diethyl ether and filtration gave the title compound as a solid (15 mg, 5.9%); NMR Spectrum: (DMSOd6) 0.57 (m, 2H), 0.68 (m, 2H), 2.26 (s, 3H), 2.86 (m, 1H), 5.54 (s, 2H), 7.21 (d, 2H), 7.34 (d, 1H), 7.64 (m, 1H), 7.79 (m, 2H), 7.86 (m, 1H), 7.99 (m, 2H), 8.37 (m, 1H), 9.24 (m, 1H), 9.86 (s, 1H); Mass Spectrum: M−H− 401.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([S:8]([NH:11][C:12]2[C:21]([NH:22][C:23]3[CH:28]=[C:27]([O:29][CH3:30])[CH:26]=[C:25]([O:31][CH3:32])[CH:24]=3)=[N:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]=2)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.C(OC([N:40]1[CH2:43][CH:42]([C:44](O)=[O:45])[CH2:41]1)=O)(C)(C)C.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.O1CCOCC1>CC(N(C)C)=O>[CH3:30][O:29][C:27]1[CH:28]=[C:23]([NH:22][C:21]2[C:12]([NH:11][S:8]([C:4]3[CH:3]=[C:2]([NH:1][C:44]([CH:42]4[CH2:43][NH:40][CH2:41]4)=[O:45])[CH:7]=[CH:6][CH:5]=3)(=[O:9])=[O:10])=[N:13][C:14]3[C:19]([N:20]=2)=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:24]=[C:25]([O:31][CH3:32])[CH:26]=1
Reactant: CC(C)(C)OC(=O)N1CC(C(=O)O)C1
Reactant: COc1cc(Nc2nc3ccccc3nc2NS(=O)(=O)c2cccc(N)c2)cc(OC)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC(=O)N(C)C
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(Nc2nc3ccccc3nc2NS(=O)(=O)c2cccc(NC(=O)C3CNC3)c2)cc(OC)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Into a 20 mL vial was added 3-amino-N-(3-(3,5-dimethoxy-phenylamino)quinoxalin-2-yl)benzenesulfonamide (0.24 mmol, 1 equiv), prepared using procedures similar to those described in Example 15, DMA (5 mL) and 1-(tert-butoxycarbonyl)azetidine-3-carboxylic acid (0.336 mmol, 1.4 equiv). Hunig's Base (0.792 mmol, 3.3 equiv) and HATU (0.288 mmol, 1.2 equiv) were added to the vial and the reaction mixture was then stirred at room temperature overnight. Completion of the reaction was indicated by LCMS. The solvent was removed by rotary evaporation. The crude mixture was carried forward without further purification. The residue was suspended in 5 mL ethyl acetate and chilled in an ice bath. A solution of 4 N HCl in dioxane (3 mL, 5 equiv) was added with stirring. The reaction mixture was then stirred at room temperature overnight. The solid materials were collected by filtration, washed with ethylacetate then purified further by preparative reverse-phase HPLC (ammonium acetate/ACN). A Waters Fractionlynx preparative reverse-phase HPLC; equipped with a Waters SunFire Prep C18, OCD 5 μM, 30×70 mm column and running a 5-100% gradient with a binary solvent system of 25 mM ammonium acetate in water/acetonitrile; was used to carry out the purification. N-(3-(N-(3-(3,5-dimethoxy-phenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)azetidine-3-carboxamide was obtained (26 mg, 20%). 1H-NMR (400 MHz, d6-DMSO): 10.26 (s, 1H), 8.81 (s, 1H), 8.25 (t, 8.14 (s, 1H), 7.74 (d, 1H), 7.69 (d, 1H), 7.41-7.39 (m, 1H), 7.36 (d, 1H), 7.32 (d, 2H), 7.30-7.28 (dd, 1H), 7.14-7.11 (m, 2H), 6.14 (t, 1H), 4.09 (d, 4H), 3.78 (s, 6H); MS (EI) m/z C26H26N6O5S: 535.6 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([CH:17]([OH:22])[CH2:18][CH:19]([CH3:21])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[OH-].[Na+]>C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([C:17](=[O:22])[CH2:18][CH:19]([CH3:20])[CH3:21])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: CC(C)CC(O)c1ccc2c(cnn2-c2ccc(F)cc2)c1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CC(C)CC(=O)c1ccc2c(cnn2-c2ccc(F)cc2)c1
Reaction time: 12 h
Yield: 93.3 %

Procedure:
1-(1-(4-Fluorophenyl)-1H-indazol-5-yl)-3-methylbutan-1-ol (650 mg, 2.17 mmol) was dissolved in 50 mL dry DCM and Dess-Martin periodinane (1.0 g, 2.36 mmol) was added. The reaction mixture was stirred for 12 h. The reaction was poured into 1N NaOH and extracted with DCM×3. The organic layers were dried over MgSO4, filtered, and concentrated to give 600 mg (92% yield) of 1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-3-methylbutan-1-one. MS found: (M+H)+=297.
Reaction SMILES: [S-:1][C:2]#[N:3].[NH4+].[CH:5]([C:7]1[CH:14]=[CH:13][C:10]([CH2:11]Cl)=[CH:9][CH:8]=1)=[CH2:6]>CC(C)=O>[CH:5]([C:7]1[CH:14]=[CH:13][C:10]([CH2:11][S:1][C:2]#[N:3])=[CH:9][CH:8]=1)=[CH2:6]
Reactant: C=Cc1ccc(CCl)cc1
Reactant: N#C[S-]
Agent: [NH4+]
Solvent: CC(C)=O
Product: C=Cc1ccc(CSC#N)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 59.3 %

Procedure:
Ammonium thiocyanate (2 equiv., 43 g, 0.50 mol) was dissolved in acetone (200 ml) and 4-vinylbenzyl chloride (43 g, 0.25 mol) was added to the reaction flask. The mixture was stirred at room temperature overnight. The reaction mixture was filtered and acetone removed under reduced pressure. The resulting product was dissolved in hexane, filtered, and the solvent removed under reduced pressure. The monomer was isolated as a red-orange, slightly viscous liquid (26 g, yield 52%). 1H NMR (CDCl3) δ (ppm) 4.13 (s, 2H), 5.29 (d, 1H), 5.76 (d, 1H), 6.67 (dd, 1H), 7.31 (m, 4H).
Reaction SMILES: C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.[CH3:35][CH:36]1[N:41]([C:42]2[CH:43]=[C:44]([NH2:54])[C:45]([N:48]3[CH2:53][CH2:52][O:51][CH2:50][CH2:49]3)=[N:46][CH:47]=2)[CH2:40][CH2:39][O:38][CH2:37]1.Cl[C:56]1[C:65]2[C:60](=[CH:61][C:62]([F:67])=[CH:63][C:64]=2[F:66])[N:59]=[C:58]([C:68]2[CH:69]=[N:70][CH:71]=[CH:72][CH:73]=2)[C:57]=1[CH3:74].CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:66][C:64]1[CH:63]=[C:62]([F:67])[CH:61]=[C:60]2[C:65]=1[C:56]([NH:54][C:44]1[C:45]([N:48]3[CH2:49][CH2:50][O:51][CH2:52][CH2:53]3)=[N:46][CH:47]=[C:42]([N:41]3[CH2:40][CH2:39][O:38][CH2:37][CH:36]3[CH3:35])[CH:43]=1)=[C:57]([CH3:74])[C:58]([C:68]1[CH:69]=[N:70][CH:71]=[CH:72][CH:73]=1)=[N:59]2
Reactant: Cc1c(-c2cccnc2)nc2cc(F)cc(F)c2c1Cl
Reactant: CC1COCCN1c1cnc(N2CCOCC2)c(N)c1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: Cc1ccccc1
Product: Cc1c(-c2cccnc2)nc2cc(F)cc(F)c2c1Nc1cc(N2CCOCC2C)cnc1N1CCOCC1

Procedure:
The Buchwald coupled products were prepared according to Procedure H using a solution of dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine (0.021 g, 0.044 mmol), 5-(3-methylmorpholino)-2-morpholinopyridin-3-amine (0.092 g, 0.33 mmol), 4-chloro-5,7-difluoro-3-methyl-2-(pyridin-3-yl)quinoline (0.08 g, 0.28 mmol), Pd2dba3 (0.010 g, 0.011 mmol) and sodium tert-butoxide (0.066 g, 0.69 mmol) in toluene (2.8 mL) at 100° C. for 27 h. The crude product was purified by column chromatography on silica gel (0 to 100% DCM/MeOH/ammonium hydroxide (90/9/1)) to give the desired product 5,7-difluoro-3-methyl-N-(5-(3-methylmorpholino)-2-morpholinopyridin-3-yl)-2-(pyridin-3-yl)quinolin-4-amine. The mixture of enantiomers was separated on chiral IC (3×8×15 cm) using 30% isopropanol (0.1% DEA)/CO2, at a flow rate of 100 bar 70 mL/min, (230 nM, injection vol.: 1.5 mL, 4 mg/mL) to give both enantiomers with an ee of 99%; The initial peak (R)-5,7-difluoro-3-methyl-N-(5-(3-methylmorpholino)-2-morpholinopyridin-3-yl)-2-(pyridin-3-yl)quinolin-4-amine or (S)-5,7-difluoro-3-methyl-N-(5-(3-methylmorpholino)-2-morpholinopyridin-3-yl)-2-(pyridin-3-yl)-quinolin-4-amine. 1H NMR (400 MHz, DMSO-d6) δ ppm 6.89 (1H, m), 8.01 (1H, td, J=7.8, 1.8 Hz), 7.90 (1H, m), 7.77 (1H, br. s), 7.66 (1H, m), 7.53-7.46 (3H, m), 6.33 (1H, m), 3.82-3.47 (10H, m), 3.02-2.88 (5H, m), 2.12 (3H, s), 0.92 (3H, br. s.). Mass Spectrum (ESI) m/e=533.2 (M+1). Further elution gave (S)-5,7-difluoro-3-methyl-N-(5-(3-methylmorpholino)-2-morpholinopyridin-3-yl)-2-(pyridin-3-yl)quinolin-4-amine or (R)-5,7-difluoro-3-methyl-N-(5-(3-methylmorpholino)-2-morpholinopyridin-3-yl)-2-(pyridin-3-yl)quinolin-4-amine. 1H NMR (400 MHz, DMSO-d6) δ ppm 6.89 (1H, m), 8.01 (1H, td, J=7.8, 1.8 Hz), 7.90 (1H, m), 7.77 (1H, br. s), 7.66 (1H, m), 7.53-7.46 (3H, m), 6.33 (1H, m), 3.82-3.47 (10H, m), 3.02-2.88 (5H, m), 2.12 (3H, s), 0.92 (3H, br. s.). Mass Spectrum (ESI) m/e=533.2 (M+1). These compounds were arbitrarily assigned as R and S.
Reaction SMILES: B(Br)(Br)Br.C([O:12][C:13]1[C:18]([CH3:19])=[CH:17][C:16]([C:20]2[S:21][C:22]3[C:27]([N:28]=2)=[CH:26][CH:25]=[C:24]([C:29]2([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[CH2:31][CH2:30]2)[N:23]=3)=[CH:15][C:14]=1[CH3:38])C1C=CC=CC=1>C(Cl)Cl>[CH3:38][C:14]1[CH:15]=[C:16]([C:20]2[S:21][C:22]3[C:27]([N:28]=2)=[CH:26][CH:25]=[C:24]([C:29]2([C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=4)[CH2:30][CH2:31]2)[N:23]=3)[CH:17]=[C:18]([CH3:19])[C:13]=1[OH:12]
Reactant: Cc1cc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)cc(C)c1OCc1ccccc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Cc1cc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)cc(C)c1O
Temperature: -78 °C
Reaction time: 0.08 h

Procedure:
Boron tribromide (1.0M in DCM; 963 μl, 0.963 mmol) was added to a solution of 2-(4-(benzyloxy)-3,5-dimethylphenyl)-5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridine (247.4 mg, 0.535 mmol) in DCM (24.0 mL) at −78° C., and the resulting solution was stirred at −78° C. for 5 min. Excess BBr3 was then quenched by the addition of water (50 mL), and the resulting mixture was diluted with DCM (100 mL) and allowed to warm to 25° C. The organic layer was separated, dried over sodium sulfate, filtered, and concentrated in vacuo. Chromatographic purification of the residue (silica gel, 0-100% ethyl ether/hexanes) afforded 2,6-dimethyl-4-(5-(1-phenyl-cyclopropyl)thiazolo[5,4-b]pyridin-2-yl)phenol as a white solid. MS (ESI) m/z: Calculated: 372.1; Observed: 373.2 (M++1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][C:10](=[CH:12][C:13]([O:15][CH3:16])=[O:14])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH3:17]>CCO>[C:1]([O:5][C:6]([N:8]1[CH2:9][C:10]([NH2:17])([CH2:12][C:13]([O:15][CH3:16])=[O:14])[CH2:11]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)C=C1CN(C(=O)OC(C)(C)C)C1
Reactant: N
Solvent: CCO
Product: COC(=O)CC1(N)CN(C(=O)OC(C)(C)C)C1

Procedure:
3-Methoxycarbonylmethylene-azetidine-1-carboxylic acid tert-butyl ester (1.97 g; 8.7 mmol) in EtOH (20 ml) and liquid NH3 (11 g) are heated in a steel cylinder at 800 C for 6 hours. Evaporation of the solvent delivers the title compound as yellow resin. 1H-NMR (400 MHz; DMSO-d6): 3.81 (d, 2H); 3.65 (s, 2H); 3.60 (d, 2H); 2.86 (s, 3H); 2.07 (bs, 2H); 1.43 (s, 9H). MS (m/z) ES+: 245 (100, MH+); 189 (90).
Reaction SMILES: N1C=CC=CC=1.P(Cl)(Cl)(Cl)(Cl)Cl.C1(CC([NH:22][CH:23]2[C:48](=[O:49])[N:25]3[CH:26]([C:35]([O:37][CH2:38][C:39]4[CH:44]=[CH:43][C:42]([N+:45]([O-:47])=[O:46])=[CH:41][CH:40]=4)=[O:36])[C:27](=[CH:30][O:31][C:32](=[O:34])[CH3:33])[CH2:28][S:29][C@H:24]23)=O)C=CC=CC=1.C(=O)(O)[O-].[Na+]>C(Cl)Cl.O.CO>[NH2:22][CH:23]1[C:48](=[O:49])[N:25]2[CH:26]([C:35]([O:37][CH2:38][C:39]3[CH:44]=[CH:43][C:42]([N+:45]([O-:47])=[O:46])=[CH:41][CH:40]=3)=[O:36])[C:27](=[CH:30][O:31][C:32](=[O:34])[CH3:33])[CH2:28][S:29][C@H:24]12
Reactant: CC(=O)OC=C1CS[C@@H]2C(NC(=O)Cc3ccccc3)C(=O)N2C1C(=O)OCc1ccc([N+](=O)[O-])cc1
Agent: ClP(Cl)(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Solvent: c1ccncc1
Product: CC(=O)OC=C1CS[C@@H]2C(N)C(=O)N2C1C(=O)OCc1ccc([N+](=O)[O-])cc1
Reaction time: 0.5 h
Yield: 71.7 %

Procedure:
Pyridine (1.2 g.) was added to a solution of phosphorus pentachloride (3.1 g.) in methylene chloride (30 ml.) at 5° to 7° C. and stirred at the same temperature for 30 minutes. To the solution was added 4-nitrobenzyl 7-(2-phenylacetamido)-3-acetoxymethylenecepham-4-carboxylate (5.4 g.) at -10° C., and stirred at the same temperature for 1.5 hours. Methanol (8 ml.) was added to the solution at -30° C. and stirred at 0° C. for 40 minutes. Water (10 ml.) and methylene chloride (50 ml.) were added to the solution and adjusted to pH 5.0 with an aqueous solution of sodium bicarbonate. The organic layer was separated, washed with water (30 ml×2) and adjusted to pH 7.5 with an aqueous solution of sodium bicarbonate. The organic layer was separated, washed with a saturated aqueous solution of sodium chloride, and dried over magnesium sulfate. After treating the solution with activated charcoal, the solution was evaporated under reduced pressure. The residue was pulverized with diisopropyl ether and the precipitates were collected by filtration to give 4-nitrobenzyl 7-amino-3-acetoxymethylenecepham-4-carboxylate (3.0 g.).
Reaction SMILES: [N+:1]([C:4]([CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([CH2:7][OH:8])[CH2:5][OH:6])([O-:3])=[O:2].CO[C:19](OC)([CH3:21])[CH3:20].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CN(C=O)C.C(OCC)(=O)C>[CH3:20][C:19]1([CH3:21])[O:8][CH2:7][C:4]([N+:1]([O-:3])=[O:2])([CH2:9][CH2:10][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:5][O:6]1
Reactant: O=[N+]([O-])C(CO)(CO)CCc1ccccc1
Reactant: COC(C)(C)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC1(C)OCC(CCc2ccccc2)([N+](=O)[O-])CO1
Reaction time: 8 h

Procedure:
To a suspension of 2-nitro-2-phenethylpropane-1,3-diol (19) (40.0 mmol) in DMF (40 ml) was added 2,2-dimethoxypropane (6.0 ml, 50 mmol) and p-toluenesulfonic acid monohydrate (400 mg, 2.0 mmol) and stirring was continued overnight. The reaction mixture was diluted with ethyl acetate, washed with saturated NaHCO3 and brine, dried, and concentrated. The residue was pure enough for transformation to the next step or could be purified by silica gel column chromatography.
Reaction SMILES: O[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[CH:5]2.[H-].[Na+].C([O-])([O-])=O.[Cs+].[Cs+].BrC(C)(C)C([NH2:24])=O>O1CCOCC1.CN1C(=O)N(C)CCC1.CN1C(=O)CCC1>[NH2:24][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[CH:5]2
Reactant: Oc1ccc2ncccc2c1
Reactant: CC(C)(Br)C(N)=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [H-]
Solvent: C1COCCO1
Solvent: CN1CCCN(C)C1=O
Solvent: CN1CCCC1=O
Product: Nc1ccc2ncccc2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 39.2 %

Procedure:
To a solution of 6-hydroxyquinoline (537 mg, 3.70 mmol) in dioxane (20 mL) was added NaH (Aldrich, dry, 300 mg, 12.2 mmol) and Cs2CO3 (4.00 g, 12.2 mmol). The resulting mixture was stirred at room temperature for about 30 minutes, then 2-bromo-2-methyl-propanamide (2.03 g, 12.2 mmol) was added and the resulting mixture was stirred at reflux for 16 h. After the reflux period, NMP (20 mL), DMPU (2 mL), and NaH (Aldrich, dry, 100 mg, 4.07 mmol) were added. The resulting mixture was stirred at 150° C. for 72 h. The reaction was cooled to room temp., and partitioned between water (50 mL) and EtOAc (100 mL). The aqueous layer was extracted with EtOAc (100 mL) and the combined organics washed with water (2×50 mL), dried (Na2SO4), and concentrated to about 3 g of material. The brown oil was distilled by Kugelrohr to remove residual NMP and DMPU, then chromatographed on silica (200 mL, 4 cm diam. column), eluting with 70:30:1 EtOAc/hexane/NEt3 to obtain 6-aminoquinoline as a brown solid (210 mg, 1.45 mmol, 39.2% yield).: mp 111-113° C. (lit. 116° C., Sykes, W. O., Journal of the Chemical Society, 1956, 3087); 1H NMR (300 MHz, CDCl3) δ8.66 (dd, 1 H, J=4.27, 1.63 Hz), 7.93-7.87 (m, 2 H), 7.26 (dd, 1 H, J=8.24, 4.23 Hz), 7.16 (dd, 1 H, J=9.05, 2.69), 6.90 (d, 1 H, J=2.74), 3.97 (br s, 2 H, NH2); 13C NMR (75 MHz, CDCl3) δ146.8, 144.5, 143.5, 133.7, 130.6, 129.7, 121.5, 121.4, 107.4; MS (CI/NH3) 145.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:16]=[CH:15][C:8]([C:9]([O:11]CC#C)=[O:10])=[CH:7][C:6]=1[O:17][CH3:18])[C:2]#[CH:3].[OH-].[Na+].Cl>CO>[CH2:1]([O:4][C:5]1[CH:16]=[CH:15][C:8]([C:9]([OH:11])=[O:10])=[CH:7][C:6]=1[O:17][CH3:18])[C:2]#[CH:3]
Reactant: C#CCOC(=O)c1ccc(OCC#C)c(OC)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: C#CCOc1ccc(C(=O)O)cc1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 107.7 %

Procedure:
To 50 ml of methanol were added 13.2 g of 2-propynyl 4-(2-propynyloxy)-3-methoxybenzoate and 40 ml of a 15% aqueous sodium hydroxide solution, and the resulting mixture was stirred at room temperature for 8 hours, and then at 50° C. for 2 hours. Thereafter, the reaction mixture which had been allowed to cool to near room temperature was added to hydrochloric acid to make the mixture acidic. The precipitated crystals were collected by filtration, and dried, and 12.0 g of 4-(2-propynyloxy)-3-methoxybenzoic acid was obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4](Br)[N:3]=1.[CH:9]([Zn]C(C)C)([CH3:11])[CH3:10].CC(O)C>O1CCOCC1.C1(C)C=CC=CC=1>[CH:9]([C:4]1[N:3]=[C:2]([NH2:1])[CH:7]=[CH:6][CH:5]=1)([CH3:11])[CH3:10]
Reactant: Nc1cccc(Br)n1
Reactant: CC(C)[Zn]C(C)C
Solvent: Cc1ccccc1
Solvent: C1COCCO1
Solvent: CC(C)O
Product: CC(C)c1cccc(N)n1
Reaction time: 0.5 h

Procedure:
2-Amino-6-bromopyridine (2 g) was dissolved in dioxane (50 mL), and at 0° C. under an argon athmosphere 1,3-bis(diphenylphosphino)propane nickel (II) chloride (0.627 g) was added followed by diisopropyl zinc (23.12 mL of a 1M solution in toluene, via syringe over 30 minutes). The mixture was allowed to reflux for 15 h, poured into 2-propanol, which was then concentrated in vacuo. The residue was partitioned between AcOEt and saturated aqueous NH4Cl solution, the layers were separated and the organic layer dried over Na2SO4, filtered and evaporated. The residue was purified by flash chromatography (methylene chloride/methanol 95:5) to give 6-isopropyl-pyridin-2-ylamine as light brown oil (0.48 g). MS (EI): 136.1 (M+).