Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]#[N:15])[CH:9]=2)=[CH:4][C:3]=1[C:16]1[C:17]([N+:27]([O-:29])=[O:28])=[N:18][N:19]([CH:21]2[CH2:26][CH2:25][CH2:24][CH2:23][O:22]2)[CH:20]=1.C(=O)([O-])[O-].[K+].[K+].[Cl:36][C:37]1[C:38](F)=[CH:39][C:40]([F:63])=[C:41]([S:43]([N:46]([CH2:52][C:53]2[CH:58]=[CH:57][C:56]([O:59][CH3:60])=[CH:55][C:54]=2[O:61][CH3:62])[C:47]2[S:48][CH:49]=[N:50][N:51]=2)(=[O:45])=[O:44])[CH:42]=1>CS(C)=O>[Cl:36][C:37]1[C:38]([O:1][C:2]2[CH:7]=[CH:6][C:5]([C:8]3[CH:13]=[CH:12][CH:11]=[C:10]([C:14]#[N:15])[CH:9]=3)=[CH:4][C:3]=2[C:16]2[C:17]([N+:27]([O-:29])=[O:28])=[N:18][N:19]([CH:21]3[CH2:26][CH2:25][CH2:24][CH2:23][O:22]3)[CH:20]=2)=[CH:39][C:40]([F:63])=[C:41]([S:43]([N:46]([CH2:52][C:53]2[CH:58]=[CH:57][C:56]([O:59][CH3:60])=[CH:55][C:54]=2[O:61][CH3:62])[C:47]2[S:48][CH:49]=[N:50][N:51]=2)(=[O:44])=[O:45])[CH:42]=1
Reactant: N#Cc1cccc(-c2ccc(O)c(-c3cn(C4CCCCO4)nc3[N+](=O)[O-])c2)c1
Reactant: COc1ccc(CN(c2nncs2)S(=O)(=O)c2cc(Cl)c(F)cc2F)c(OC)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: COc1ccc(CN(c2nncs2)S(=O)(=O)c2cc(Cl)c(Oc3ccc(-c4cccc(C#N)c4)cc3-c3cn(C4CCCCO4)nc3[N+](=O)[O-])cc2F)c(OC)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.7 %

Procedure:
4′-Hydroxy-3′-(3-nitro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)biphenyl-3-carbonitrile (Preparation 64, 250 mg, 0.64 mmol) was dissolved in DMSO (3.5 mL) and potassium carbonate (177 mg, 1.28 mmol) was added followed by 5-chloro-N-(2,4-dimethoxybenzyl)-2,4-difluoro-N-(1,3,4-thiadiazol-2-yl)benzenesulfonamide (Preparation 16, 310 mg, 0.67 mmol). The reaction was stirred at room temperature for 1 hour and then partitioned between ethyl acetate and water. The aqueous phase was separated and extracted with EtOAc (3×5 mL) and the combined organic layers were washed with brine, dried over anhydrous MgSO4, filtered and concentrated in vacuo. The residue was purified on silica gel by Biotage™ (10% to 80% EtOAc in heptane over 12 CV) to give the title compound (451 mg, 85%) as a light yellow foam.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:5]([O:6][C:7]2[C:16]3[C:11](=[CH:12][C:13]([OH:19])=[C:14]([O:17][CH3:18])[CH:15]=3)[N:10]=[CH:9][N:8]=2)=[C:4]([F:22])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl.Cl[CH2:31][C:32]1[CH:37]=[CH:36][N:35]=[CH:34][CH:33]=1>CN(C=O)C>[Cl:1][C:2]1[CH:21]=[CH:20][C:5]([O:6][C:7]2[C:16]3[C:11](=[CH:12][C:13]([O:19][CH2:31][C:32]4[CH:37]=[CH:36][N:35]=[CH:34][CH:33]=4)=[C:14]([O:17][CH3:18])[CH:15]=3)[N:10]=[CH:9][N:8]=2)=[C:4]([F:22])[CH:3]=1
Reactant: COc1cc2c(Oc3ccc(Cl)cc3F)ncnc2cc1O
Reactant: ClCc1ccncc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3ccc(Cl)cc3F)ncnc2cc1OCc1ccncc1
Temperature: 80 °C
Yield: 79.8 %

Procedure:
A mixture of 4-(4-chloro-2-fluorophenoxy)-7-hydroxy-6-methoxyquinazoline (112 mg, 0.35 mmol), potassium carbonate (138 mg, 1 mmol) and 4-(chloromethyl)pyridine hydrochloride (59 mg, 0.36 mmol) in DMF (2 ml) was heated at 80° C. for 1 hour. The mixture was allowed to cool and partitioned between ethyl acetate and water. The organic layer was separated, washed with water and brine, dried (MgSO4) and the solvent removed by evaporation. The residue was purified by column chromatography eluting with methylene chloride/methanol (95/5) to give 4-(4-chloro-2-fluorophenoxy)-6-methoxy-7-((4-pyridyl)methoxy)quinazoline (115 mg, 80%). m.p. 197-198° C. 1H NMR Spectrum: (DMSOd6) 4.03(s, 3H); 5.46(s, 2H); 7.45(d, 1H); 7.49(s, 1H); 7.5(d, 2H); 7.58(t, 1H); 7.62(s, 1H); 7.72(dd, 1H); 8.58(s, 1H); 8.65(d, 2H) MS-ESI: 412 [MH]+
Reaction SMILES: Br[C:2]1[C:3]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=2)=[N:4][N:5]2[C:10]=1[CH:9]=[CH:8][C:7]([O:11][CH:12]([F:14])[F:13])=[N:6]2.C(=O)([O-])[O-].[Na+].[Na+].[CH3:28][S:29]([C:32]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=1)(=[O:31])=[O:30]>CN(C=O)C.C(OCC)(=O)C>[F:13][CH:12]([F:14])[O:11][C:7]1[CH:8]=[CH:9][C:10]2[N:5]([N:4]=[C:3]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=3)[C:2]=2[C:35]2[CH:36]=[CH:37][C:32]([S:29]([CH3:28])(=[O:31])=[O:30])=[CH:33][CH:34]=2)[N:6]=1
Reactant: Fc1cccc(-c2nn3nc(OC(F)F)ccc3c2Br)c1
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1ccc(-c2c(-c3cccc(F)c3)nn3nc(OC(F)F)ccc23)cc1
Yield: 38.1 %

Procedure:
To a stirred solution of 3-bromo-6-difluoromethoxy-2-(3-fluoro-phenyl)-pyrazolo[1,5-b]pyridazine (286 mg) in DMF(20 ml) was added 2N aq sodium carbonate (10 ml). To this mixture was added 4-methanesulfonyl-phenylboronic acid (180 mg) and tetrakis triphenylphosphine palladium(0) (34 mg). The resulting mixture was stirred and heated to reflux for 18 hours. The cooled reaction mixture was diluted with ethyl acetate (300 ml) and the organic solution washed with water (10×30 ml) and brine (30 ml), dried (Na2SO4) and evaporated to give a gum which was purified by flash column chromatography with chloroform:ethyl acetate (50:1 to 5:1) as eluant. Combination of appropriate fractions and concentration gave the title compound as an off-white solid (132 mg, 37%).
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[N:6][C:7]([S:11][CH3:12])=[N:8][CH:9]=2)[N:4]([CH2:13][C@H:14]2[CH2:19][CH2:18][C@H:17]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH2:16][CH2:15]2)[N:3]=1.[C:28]1(B(O)O)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.P(=O)([O-])[O-].[K+].[K+].O1CCOCC1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[C:23]([O:22][C:21](=[O:27])[NH:20][CH:17]1[CH2:18][CH2:19][CH:14]([CH2:13][N:4]2[C:5]3=[N:6][C:7]([S:11][CH3:12])=[N:8][CH:9]=[C:10]3[C:2]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[N:3]2)[CH2:15][CH2:16]1)([CH3:26])([CH3:25])[CH3:24]
Reactant: OB(O)c1ccccc1
Reactant: CSc1ncc2c(Br)nn(C[C@H]3CC[C@H](NC(=O)OC(C)(C)C)CC3)c2n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=[PH]([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CSc1ncc2c(-c3ccccc3)nn(CC3CCC(NC(=O)OC(C)(C)C)CC3)c2n1
Temperature: 150 °C
Yield: 88.2 %

Procedure:
A microwave tube was charged with tert-butyl trans-4-((3-bromo-6-(methylthio)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)cyclohexylcarbamate (0.046 g, 0.1 mmol), phenylboronic acid (0.037 g, 0.3 mmol), potassium phosphonate (0.063 g, 0.3 mmol), tetrakis(triphenylphosphine)palladium (0.012 g, 0.01 mmol), dioxane (2 mL) and water (0.5 mL). The mixture was heated in microwave at 150° C. for 10 min. The reaction mixture was poured into water. The aqueous layer was extracted with Et2O (3×). The combined organic layers were dried (Na2SO4), concentrated, and purified by Isco to give tert-Butyl-4-((6-(methylthio)-3-phenyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)cyclohexylcarbamate (0.040 g, 88%) as a white solid. MS m/z 454.3 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH3:8][O:9][C:10]1[CH:11]=[C:12]([CH:18]([NH:26][CH2:27][CH:28]([C:30]2[CH:31]=[CH:32][C:33]([O:41]CC3C=CC=CC=3)=[C:34]([NH:36][S:37]([CH3:40])(=[O:39])=[O:38])[CH:35]=2)[OH:29])[CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:13]=[CH:14][C:15]=1[O:16][CH3:17].[H][H]>[Pd].CO>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH3:8][O:9][C:10]1[CH:11]=[C:12]([CH:18]([NH:26][CH2:27][CH:28]([C:30]2[CH:31]=[CH:32][C:33]([OH:41])=[C:34]([NH:36][S:37]([CH3:40])(=[O:38])=[O:39])[CH:35]=2)[OH:29])[CH2:19][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:13]=[CH:14][C:15]=1[O:16][CH3:17]
Reactant: [H][H]
Reactant: COc1ccc(C(Cc2ccccc2)NCC(O)c2ccc(OCc3ccccc3)c(NS(C)(=O)=O)c2)cc1OC
Agent: [Pd]
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: COc1ccc(C(Cc2ccccc2)NCC(O)c2ccc(O)c(NS(C)(=O)=O)c2)cc1OC
Yield: 97.4 %

Procedure:
N-[5-[2-[[1-(3,4-Dimethoxyphenyl)-2-phenylethyl]amino]-1-hydroxyethyl]-2-(phenylmethoxy)phenyl]methanesulfonamide, trifluoroacetate salt (220 mg, 0.38 mmol) was hydrogenated using 10% Pd/C (120 mg) and MeOH (25 mL, AR grade) at 40 psi of hydrogen in a Parr apparatus for one hour at room temperature. The catalyst was filtered through Celite and washed with MeOH. The filtrate and MeOH washings were combined and concentrated to afford 178 mg (0.37 mmol, 96% yield) of the title compound as a pale yellow crystalline powder. The title compound is a racemic mixture of diastereomers.
Reaction SMILES: [CH3:1][C:2]([CH3:7])=[CH:3][C:4]([OH:6])=[O:5].[Li+].[CH3:9][CH:10]([N-]C(C)C)C.C(I)C.Cl>C1COCC1.C1COCC1.CCCCCC>[CH2:9]([CH:3]([C:2]([CH3:7])=[CH2:1])[C:4]([OH:6])=[O:5])[CH3:10]
Reactant: CC(C)=CC(=O)O
Reactant: CC(C)[N-]C(C)C
Agent: Cl
Agent: [Li+]
Solvent: CCCCCC
Solvent: CCI
Solvent: C1CCOC1
Product: C=C(C)C(CC)C(=O)O
Temperature: -10 °C
Reaction time: 0.33 h
Yield: 120.2 %

Procedure:
A solution of 3,3-dimethylacrylic acid (2.00 g, 20 mmol) in THF (30 mL) was added dropwise to a solution of LDA (44 mmol) in THF/hexane (60 mL) at −78 ° C. After warming to −10 ° C. and stirring for 20 min, the reaction was recooled to −78 ° C. and a solution of ethyl iodide (6.86 g, 44 mmol)) in THF (30 mL) was added. The reaction was allowed to warm to room temperature overnight. To the resulting dark orange solution was added 1 M HCl until acidic. The organic layer was separated, washed with H2O and brine, dried (MgSO4), filtered and concentrated to yield a brown oil of 2-ethyl-3-methylbut-3-enoic acid (3.08g), which was used crude in the next reaction. To reduce the acid group the crude product was dissolved in THF (70 mL) and cooled to 0° C. To this was added LiAlH4 (2280 mg, 60 mmol). Workup gave 2.7 g of a pale yellow oil, which was purified by flash chromatography (silica gel, 10% EtOAC in pet. ether) to give 1.70 g of 2-ethyl-3-methylbut-3-en-1-ol as an oil. The alcohol (560 mg, 4.91 mmol) was converted into a mesylate by dissolving in DCM (25 mL) at 0 ° C., then adding MsCl (675 mg, 5.9 mmol) followed by Et3N (595 mg, 5.9 mmol). After 30 min the reaction was partitioned between DCM and 0.1 N HCl, the aqueous layer extracted with DCM (2×), and the organic fractions combined and washed with brine, filtered and concentrated to give 200 mg of a pale yellow oil. The crude mesylate (4.91 mmol) was dissolved in acetonitrile (20 mL) and NaN3 (957 mg, 14.7 mmol) was added. After 1 h DMF (6.5 mL) was added and the reaction heated to reflux for 3 h, then cooled. EtOAc (40 mL) and NaHCO3 solution were added and the organic layer was washed with H2O (2×), brine (1×) and dried, then filtered to give a pale yellow solution of 3-(azidomethyl)-2-methylpent-1-ene that was used crude in the next reaction. A suspension of the azide (4.91 mmol) in 50 mL EtOAC was hydrogenated at 40 psi over Lindlar catalyst (460 mg) for 16 h, then filtered through Celite to leave a colourless solution. Flash chromatography (silica gel, 1-5% MeOH in DCM) produced 120 mg of pure amine 57, with a further 95 mg of impure material
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH:12]([CH3:14])[CH3:13])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[Br:15][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][CH:23]=1)[CH:19]=O.[CH2:24]=[C:25]([CH3:27])[CH3:26].FC(F)(F)S([O-])(=O)=O.[Yb+3].FC(F)(F)S([O-])(=O)=O.FC(F)(F)S([O-])(=O)=O>C(#N)C.C(OCC)(=O)C>[CH:12]([NH:11][S:8]([C:5]1[CH:6]=[C:7]2[C:2](=[CH:3][CH:4]=1)[NH:1][CH:19]([C:18]1[CH:21]=[CH:22][CH:23]=[C:16]([Br:15])[CH:17]=1)[CH2:24][C:25]2([CH3:27])[CH3:26])(=[O:10])=[O:9])([CH3:14])[CH3:13]
Reactant: O=Cc1cccc(Br)c1
Reactant: CC(C)NS(=O)(=O)c1ccc(N)cc1
Reactant: C=C(C)C
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CC(C)NS(=O)(=O)c1ccc2c(c1)C(C)(C)CC(c1cccc(Br)c1)N2
Temperature: 80 °C
Reaction time: 18 h
Yield: 47.4 %

Procedure:
To a stirred solution of 4-amino-N-isopropyl-benzenesulfonamide (4.0 g, 18.7 mmol) and 3-bromo-benzaldehyde (3.8 g, 20.5 mmol) in acetonitrile (150 mL) were added isobutene (6.5 mL, 93.5 mmoll) and ytterbium(III) trifluoromethanesulfonate (Yb(OTf)3) (2.4 g, 3.7 mmol). The resulting mixture was stirred at 80° C. for 18 h in sealed tube. The mixture solution was diluted with ethyl acetate (300 mL) and washed with water (100 mL×2) and brine (100 mL×2) and then dried over anhydrous sodium sulfate. The solvent was removed in vacuo and the residue was purified by ISCO combi-flash chromatography (gradient elution, 10-40% ethyl acetate in petroleum ether) to afford 2-(3-bromo-phenyl)-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline-6-sulfonic acid isopropylamide (3.8 g, 47.4%) as a light yellow solid: MS (ESI) M+1=437.1.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:10]=[C:9]([CH2:11][O:12][CH2:13][CH2:14][O:15][CH2:16][CH2:17][O:18][CH3:19])[N:8]([CH2:20][C:21]2[CH:25]=[C:24]([C:26]3[S:27][C:28]([Cl:31])=[CH:29][CH:30]=3)[O:23][N:22]=2)[N:7]=1)=[O:5])C.[OH-].[Na+].Cl>C1COCC1.O>[Cl:31][C:28]1[S:27][C:26]([C:24]2[O:23][N:22]=[C:21]([CH2:20][N:8]3[C:9]([CH2:11][O:12][CH2:13][CH2:14][O:15][CH2:16][CH2:17][O:18][CH3:19])=[CH:10][C:6]([C:4]([OH:5])=[O:3])=[N:7]3)[CH:25]=2)=[CH:30][CH:29]=1
Reactant: CCOC(=O)c1cc(COCCOCCOC)n(Cc2cc(-c3ccc(Cl)s3)on2)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: COCCOCCOCc1cc(C(=O)O)nn1Cc1cc(-c2ccc(Cl)s2)on1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 130 mg 1-[5-(5-Chloro-thiophen-2-yl)-isoxazol-3-ylmethyl]-5-[2-(2-methoxy-ethoxy)-ethoxymethyl]-1H-pyrazole-3-carboxylic acid ethyl ester in 5 ml THF and 5 ml of water 3 ml of a 1M NaOH were added and the reaction mixture was stirred for 3 h at RT. Then the mixture was acidified with half concentrated hydrochloric acid to pH 3 and the precipitate collected by filtration and washed with 10 ml water. The product was obtained as a white solid which was dried under reduced pressure. Yield: 60 mg.
Reaction SMILES: [CH2:1]([O:19][CH2:20][C:21]([O:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])(O)[CH3:22])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].S(Br)([Br:45])=O.[Na].C(=O)(O)[O-]>CN(C)C=O>[Br:45][CH2:22][CH:21]([O:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])[CH2:20][O:19][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCCCCCCCCCCCCOCC(C)(O)OCCCCCCCCCCCCCCCCCC
Reactant: O=S(Br)Br
Agent: O=C([O-])O
Agent: [Na]
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCCCCCCCOCC(CBr)OCCCCCCCCCCCCCCCCCC
Temperature: 100 °C

Procedure:
To a solution of 15 g of 1,2-dioctadecyloxy-2-propanol in 450 ml of dimethylformamide 21 g of thionylbromide were added dropwise while stirring and cooling, after which the reaction mixture was heated at 100° C for 5 hours. After cooling down, the resultant mixture was slowly poured into 400 ml of 5% sodium-bicarbonate solution. The aqueous solution was extracted with 4 × 150 ml of diethylether, after which the ether extract was consecutively washed with water, 5% sodium bicarbonate solution and water. After drying on sodium sulphate the solvent was removed under vacuum. The coarse product thus obtained was purified by means of column chromatography. The yield was 14 g of 1-bromo-2,3-dioctadecyloxypropane with a melting point of 38°-38.8° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([N+:8]([O-:10])=[O:9])=[N:6][CH:7]=1.[Cl:11][C:12]1[CH:19]=[CH:18][C:15]([CH2:16]Br)=[CH:14][CH:13]=1>>[Cl:11][C:12]1[CH:19]=[CH:18][C:15]([CH2:16][O:1][C:2]2[CH:3]=[CH:4][C:5]([N+:8]([O-:10])=[O:9])=[N:6][CH:7]=2)=[CH:14][CH:13]=1
Reactant: O=[N+]([O-])c1ccc(O)cn1
Reactant: Clc1ccc(CBr)cc1
Product: O=[N+]([O-])c1ccc(OCc2ccc(Cl)cc2)cn1

Procedure:
The substituted amino-pyridine compounds of formula (I) wherein W is oxygen can be prepared by the reaction of a hydroxy-nitropyridine with a substituted phenalkyl halide to obtain the corresponding substituted nitro-pyridine which is reduced to the desired substituted amino-pyridine of formula (I). For example, the reaction of 5-hydroxy-2-nitropyridine and 4-chlorobenzyl bromide gives 5-(4-chlorobenzyloxy)-2-nitropyridine which is then reduced to 2-amino-5-(4-chlorobenzyloxy)pyridine of formula I. Alternatively, the compounds of formula I can be prepared by the reaction of a halo-nitropyridine with a substituted phenalkyl alcohol or substituted phenalkyl thiol followed by reduction of the nitro group. For example, the reaction of 2-chloro-5-nitropyridine and 4-bromobenzyl alcohol gives 2-(4-bromobenzyloxy)-5-nitropyridine which is then reduced using, for example, iron powder to give 5-amino-2-(4-bromobenzyloxy)pyridine of formula (I).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]=1[CH:12]=O.[C:14]([NH:23][NH2:24])(=[O:22])[C:15]1[C:16](=[CH:18][CH:19]=[CH:20][CH:21]=1)[OH:17]>>[OH:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]=1[CH:12]=[N:24][NH:23][C:14](=[O:22])[C:15]1[C:16](=[CH:18][CH:19]=[CH:20][CH:21]=1)[OH:17]
Reactant: O=Cc1c(O)ccc2ccccc12
Reactant: NNC(=O)c1ccccc1O
Product: O=C(NN=Cc1c(O)ccc2ccccc12)c1ccccc1O
Yield: 74 %

Procedure:
Following the general procedure of Example 1, condensation of 2-hydroxy-1-naphthaldehyde and salicylic hydrazide yielded a pale yellow solid (74%): mp 265° C.; 1H NMR d 12.32 (s, 1 H), 11.65 (br s, 1 H), 11.36 (br s, 1 H), 9.09 (s, 1 H), 7.84 (d, 1 H, J=7.5 Hz), 7.43 (m, 3 H), 7.13 (t, 1 H, J=6.0 Hz), 7.01 (t, 1 H, J=6.6 Hz), 6.83 (t, 1H, J=6.9 Hz), 6.77 (d, 1H, J=8.4 Hz), 6.57 (m, 2 H); 13C NMR d 163.72, 158.58, 157.88, 147.40, 133.75, 132.63, 131.42, 128.64, 128.49, 127.53, 127.44, 123.27, 120.65, 118.87, 118.61, 117.04, 115.35, 108.32; HRMS Calcd for C18H14N2O3 :306.1004, found 306.0985; Anal. (C18H14N2O3) C, H, N.
Reaction SMILES: [CH3:1][C:2]1([OH:8])[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.Br[C:10]1[CH:11]=[CH:12][C:13]([N+:16]([O-:18])=[O:17])=[N:14][CH:15]=1>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CS(C)=O.CCOC(C)=O>[CH3:1][C:2]1([OH:8])[CH2:7][CH2:6][N:5]([C:10]2[CH:15]=[N:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=2)[CH2:4][CH2:3]1
Reactant: CC1(O)CCNCC1
Reactant: O=[N+]([O-])c1ccc(Br)cn1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CC1(O)CCN(c2ccc([N+](=O)[O-])nc2)CC1
Temperature: 25 °C
Yield: 68 %

Procedure:
4-Methylpiperidin-4-ol (2.72 g, 23.6 mmol), 5-bromo-2-nitropyridine (3.2 g, 15.8 mmol), and tetrabutylammonium iodide (72 mg, 195 umol) in DMSO (20 ml) was heated to 120° C. for 18 hr. After cooling to room temperature, the reaction mixture was then diluted with EtOAc and washed with water (3×20 mL). The organic phase was then concentrated and triturated with ether to give 4-methyl-1-(6-nitropyridin-3-yl)piperidin-4-ol as a yellow solid (2.55 g, 68.2%). (M+H)+=327.9 m/e.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:10]=[C:9]([CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[O:8][C:7]=1[CH3:17])=[O:5])C.[OH-].[Na+].Cl>C(O)C.O>[CH:11]1([C:9]2[O:8][C:7]([CH3:17])=[C:6]([C:4]([OH:5])=[O:3])[CH:10]=2)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]1
Reactant: CCOC(=O)c1cc(C2CCCCC2)oc1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1oc(C2CCCCC2)cc1C(=O)O
Yield: 76.2 %

Procedure:
A solution of 5-cyclohexyl-2-methyl-furan-3-carboxylic acid ethyl ester (143 mg, 0.605 mmol) and 2N sodium hydroxide (1.5 mL, 3.0 mmol) in 3 mL ethanol and 1.5 mL water was heated to reflux for 1 hour. The reaction mixture was cooled, pH adjusted to 1 with 1N HCl and extracted with CH2Cl2 (5×40 mL). The combined organic layers were dried over sodium sulfate, filtered and evaporated to give 5-cyclohexyl-2-methyl-furan-3-carboxylic acid (96 mg, 76%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[OH:10].[C:11]([OH:17])(=[O:16])[CH2:12][C:13]([OH:15])=O.O=P(Cl)(Cl)Cl.O>CCOCC>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[O:10][C:13](=[O:15])[CH2:12][C:11]([O:17][C:3]1[C:2]([Cl:1])=[CH:7][C:6]([Cl:8])=[CH:5][C:4]=1[Cl:9])=[O:16]
Reactant: Oc1c(Cl)cc(Cl)cc1Cl
Reactant: O=C(O)CC(=O)O
Solvent: O
Solvent: CCOCC
Solvent: O=P(Cl)(Cl)Cl
Product: O=C(CC(=O)Oc1c(Cl)cc(Cl)cc1Cl)Oc1c(Cl)cc(Cl)cc1Cl

Procedure:
A mixture of 2,4,6-trichloro-phenol (157.6 g, 0.8 mol), malonic acid (52 g, 0.5 mol), and POCl3 (98 mL, 1.05 mol) is heated at reflux for 4 hours. The reaction mixture is cooled slightly and poured into a mixture of ice, water, and ether with stirring. The solid is collected by filtration and dried in vacuo to give malonic acid bis(2,4,6-trichloro-phenyl)ester.
Reaction SMILES: [C:1]([CH2:5][CH:6]([C:13]([O:15][CH3:16])=[O:14])[CH2:7][CH2:8][C:9]([O:11]C)=O)([O:3][CH3:4])=[O:2].CO.C(C(C(OC)=O)(C(OC)=O)CCC)(OC)=O>CC1C=CC(C)=CC=1>[C:1]([C@H:5]1[C@H:6]([C:13]([O:15][CH3:16])=[O:14])[CH2:7][CH2:8][C:9]1=[O:11])([O:3][CH3:4])=[O:2]
Reactant: COC(=O)CCC(CC(=O)OC)C(=O)OC
Agent: CCCC(C(=O)OC)(C(=O)OC)C(=O)OC
Solvent: Cc1ccc(C)cc1
Solvent: CO
Product: COC(=O)[C@@H]1C(=O)CC[C@H]1C(=O)OC

Procedure:
The method of cyclizing 1,2,4-tricarbomethoxy butane, in solution in dry p-xylene containing a trace of methanol, with excess of a suspension in dry p-xylene of a dispersion of an alkali metal hydride in mineral oil, the tricarbomethoxybutane being added portionwise to the alkali metal hydride suspension with mixing at a reaction temperature of about 20° to about 40° C. for a time sufficient to form trans-2,3-dicarbomethoxycyclopentanone.
Reaction SMILES: [CH3:1][CH:2]([OH:4])[CH3:3].Cl[C:6]1[CH:11]=[CH:10][N:9]=[C:8]([C:12]2[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([C:21]4[O:25][C:24]([NH:26][CH:27]([CH3:29])[CH3:28])=[N:23][N:22]=4)[CH:19]=3)[N:14](S(C3C=CC(C)=CC=3)(=O)=O)[CH:13]=2)[N:7]=1.[H-].[Na+]>>[CH:2]([O:4][C:10]1[CH:11]=[CH:6][N:7]=[C:8]([C:12]2[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([C:21]4[O:25][C:24]([NH:26][CH:27]([CH3:29])[CH3:28])=[N:23][N:22]=4)[CH:19]=3)[NH:14][CH:13]=2)[N:9]=1)([CH3:3])[CH3:1]
Reactant: CC(C)O
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3nccc(Cl)n3)c3cc(-c4nnc(NC(C)C)o4)ccc32)cc1
Agent: [H-]
Agent: [Na+]
Product: CC(C)Nc1nnc(-c2ccc3[nH]cc(-c4nccc(OC(C)C)n4)c3c2)o1
Temperature: 100 °C
Yield: 10.2 %

Procedure:
A glass microwave reaction vessel was charged with IPA (1 mL, 13.06 mmol) and 5-(3-(4-chloropyrimidin-2-yl)-1-tosyl-1H-indol-5-yl)-N-isopropyl-1,3,4-oxadiazol-2-amine (80 mg, 0.157 mmol), followed by the addition of 60% of NaH in mineral oil (15.72 mg, 0.393 mmol, Aldrich). The reaction was stirred and heated in a Initiator microwave reactor at 100° C. for 30 min, then the solvent was removed. The residue was purified with RP-HPLC (eluent: 10-50% MeCN in water with 0.1% TFA). The fractions containing the product were combined and concentrated to remove AcCN. The remaining mixture was neutralized with NH4OH and filtered and dried to give 5-(3-(4-isopropoxypyrimidin-2-yl)-1H-indol-5-yl)-N-isopropyl-1,3,4-oxadiazol-2-amine (6.0 mg, 0.016 mmol, 10.09%) as an off-white solid. MS (ESI, pos. ion) m/z: 379.1 (M+1); 1H NMR (400 MHz, DMSO-d6) δ ppm 11.99 (1H, br. s.), 9.00 (1H, s), 8.50 (1H, d, J=5.7 Hz), 8.30 (1H, s), 7.52-7.72 (3H, m), 6.60 (1H, d, J=5.9 Hz), 5.47-5.62 (1H, m), 3.67-3.81 (1H, m), 1.42 (6H, d, J=6.1 Hz), 1.23 (6H, d, J=6.5 Hz).
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7]O[C:9]2=[O:14])([O-:3])=[O:2].[NH2:15][CH:16]([CH2:19][OH:20])[CH2:17][OH:18].CO.C(N(CC)CC)C>>[OH:18][CH2:17][CH:16]([N:15]1[CH:7]=[CH:6][C:5]2[C:10](=[CH:11][CH:12]=[CH:13][C:4]=2[N+:1]([O-:3])=[O:2])[C:9]1=[O:14])[CH2:19][OH:20]
Reactant: NC(CO)CO
Reactant: O=c1occc2c([N+](=O)[O-])cccc12
Solvent: CO
Solvent: CCN(CC)CC
Product: O=c1c2cccc([N+](=O)[O-])c2ccn1C(CO)CO

Procedure:
5-nitro-isochromen-1-one (4.2 g, 0.022 mol) and Serinol (2.0 g, 0.022 mol) were refluxed in methanol (40 mL, 1 mol) for 1 hour. TLC showed that all of the starting material was consumed. Triethylamine (5 mL, 0.04 mol) was added to the mixture and the reaction mixture was refluxed overnight. The volatiles were removed via rotovapor, and the residue was purified by flash column chromatography (40 g of silica gel, 0-50% EtOAc/Hexane), and gave a green yellow solid. MS m/z=264.7 (M+1).