Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][CH2:2][CH:3]([N:21]1[CH:25]=[C:24]([C:26]2[C:27]3[CH:34]=[CH:33][N:32]([CH2:35][O:36][CH2:37][CH2:38][Si:39]([CH3:42])([CH3:41])[CH3:40])[C:28]=3[N:29]=[CH:30][N:31]=2)[CH:23]=[N:22]1)[CH2:4][N:5]1[CH2:10][CH2:9][N:8](C(OCC2C=CC=CC=2)=O)[CH2:7][CH2:6]1.FCC(N1CCN(C(OCC2C=CC=CC=2)=O)CC1)CN1C=C(C2C3C=CN(COCC[Si](C)(C)C)C=3N=CN=2)C=N1.[H][H]>CO.[Pd]>[F:1][CH2:2][CH:3]([N:21]1[CH:25]=[C:24]([C:26]2[C:27]3[CH:34]=[CH:33][N:32]([CH2:35][O:36][CH2:37][CH2:38][Si:39]([CH3:42])([CH3:41])[CH3:40])[C:28]=3[N:29]=[CH:30][N:31]=2)[CH:23]=[N:22]1)[CH2:4][N:5]1[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C(CF)CN4CCN(C(=O)OCc5ccccc5)CC4)c3)ncnc21
Reactant: [H][H]
Agent: [Pd]
Agent: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(CC(CF)N4CCN(C(=O)OCc5ccccc5)CC4)c3)ncnc21
Solvent: CO
Product: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C(CF)CN4CCNCC4)c3)ncnc21

Procedure:
A mixture of (±)-benzyl 4-{3-fluoro-2-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propyl}piperazine-1-carboxylate (0.064 g, 0.11 mmol) and (±)-benzyl 4-(2-fluoro-1-{[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]methyl}ethyl)piperazine-1-carboxylate (0.064 g, 0.11 mmol) in 5 mL of methanol was hydrogenated in the presence of 5% Pd/C, under balloon pressure of hydrogen, for 2 h. After filtering off the catalyst, the filtrate was concentrated and used directly in next step. LCMS calculated for C22H35FN7OSi(M+H)+: m/z=460.3; Found: 460.4.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([CH:16]([OH:22])[CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[C:12]([Cl:23])[CH:11]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>O1CCOCC1.[O-2].[O-2].[Mn+4]>[C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16](=[O:22])[CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[C:12]([Cl:23])[CH:11]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)CC(O)c1ccc(CNC(=O)OC(C)(C)C)cc1Cl
Agent: [Mn+4]
Agent: [O-2]
Solvent: C1COCCO1
Product: CC(C)(C)CC(=O)c1ccc(CNC(=O)OC(C)(C)C)cc1Cl
Temperature: 70 °C
Yield: 64.4 %

Procedure:
Add manganese dioxide (1.096 g, 12.6 mmol) to a solution of N-(tert-butoxycarbonyl)-3-chloro-4-(1-hydroxy-3,3-dimethyl-butyl)-benzylamine (274 mg, 0.8 mmol) in anhydrous 1,4-dioxane (11.5 mL) at room temperature. Heat the mixture at 70° C. overnight. Filter the reaction mixture over Celite® and concentrate in vacuo. Purify by chromatography on silica gel eluting with hexane/EtOAc (4:1) to obtain the desired intermediate as a yellow oil (175 mg, 64%).
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([CH2:18][CH2:19][CH3:20])[C:10]([C:11]3[CH:16]=[CH:15][N:14]=[C:13](F)[CH:12]=3)=[C:6]2[CH:5]=[CH:4][CH:3]=1.[CH:21]1([NH2:26])[CH2:25][CH2:24][CH2:23][CH2:22]1>>[CH:21]1([NH:26][C:2]2[N:7]3[N:8]=[C:9]([CH2:18][CH2:19][CH3:20])[C:10]([C:11]4[CH:16]=[CH:15][N:14]=[C:13]([NH:26][CH:21]5[CH2:25][CH2:24][CH2:23][CH2:22]5)[CH:12]=4)=[C:6]3[CH:5]=[CH:4][CH:3]=2)[CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: NC1CCCC1
Reactant: CCCc1nn2c(Cl)cccc2c1-c1ccnc(F)c1
Product: CCCc1nn2c(NC3CCCC3)cccc2c1-c1ccnc(NC2CCCC2)c1
Temperature: 25 °C
Yield: 77 %

Procedure:
A solution of 7-chloro-3-(2-fluoropyridin-4-yl)-2-propylpyrazolo[1,5-a]pyridine (41 mg, 0.14 mmol) in cyclopentylamine (5 mL) was heated in a sealed vessel at 150° C. for 18 h. The mixture was cooled to room temperature and concentrated in vacuo and the residue was purified by flash chromatography on silica gel (2:1 hexane-ethyl acetate) to give N-cyclopentyl-3-[2-(cyclopentylamino)pyridin-4-yl]-2-propylpyrazolo[1,5-a]pyridin-7-amine (44 mg, 77%) as a yellow solid. 1H NMR (CDCl3) δ 8.10 (d, 1H), 7.18 (t, 1H), 7.00 (d, 1H), 6.73 (d, 1H), 6.52 (s, 1H), 5.97–5.91 (m, 2H), 5.07 (m, 1H), 4.00 (m, 2H), 2.95 (t, 2H), 2.18–2.05 (m, 4H), 1.87–1.57 (m, 14H), 1.02 (t, 3H); MS m/z 404 (M+1).
Reaction SMILES: [CH2:1]([C:4]1[CH:15]=[CH:14][C:7]2[O:8][CH:9]([C:11](=[O:13])[CH3:12])[O:10][C:6]=2[CH:5]=1)CC.[CH2:16]([Li])C>>[CH3:1][C:4]1[CH:15]=[CH:14][C:7]2[O:8][CH:9]([C:11](=[O:13])[CH2:12][CH3:16])[O:10][C:6]=2[CH:5]=1
Reactant: CCCc1ccc2c(c1)OC(C(C)=O)O2
Reactant: [Li]CC
Product: CCC(=O)C1Oc2ccc(C)cc2O1

Procedure:
Obtained in 30% (1st step) and 33% (2nd step) yields from 4-methylcatechol according to the typical procedure described for 1-(5-propyl-1,3-benzodioxol-2-yl)-1-ethanone, except the use of ethyl lithium instead of methyl lithium.
Reaction SMILES: Cl[C:2]1[NH:6][C:5]2[CH:7]=[C:8]([C:20]([F:23])([F:22])[F:21])[CH:9]=[C:10]([C:11]3[CH:16]=[C:15]([F:17])[C:14]([F:18])=[C:13]([F:19])[CH:12]=3)[C:4]=2[N:3]=1.[Br:24][C:25]1[C:26]([N:31]2[CH2:36][CH2:35][NH:34][C@H:33]([CH3:37])[CH2:32]2)=[N:27][CH:28]=[CH:29][CH:30]=1>>[Br:24][C:25]1[C:26]([N:31]2[CH2:36][CH2:35][N:34]([C:2]3[NH:3][C:4]4[C:10]([C:11]5[CH:16]=[C:15]([F:17])[C:14]([F:18])=[C:13]([F:19])[CH:12]=5)=[CH:9][C:8]([C:20]([F:23])([F:22])[F:21])=[CH:7][C:5]=4[N:6]=3)[C@H:33]([CH3:37])[CH2:32]2)=[N:27][CH:28]=[CH:29][CH:30]=1
Reactant: C[C@@H]1CN(c2ncccc2Br)CCN1
Reactant: Fc1cc(-c2cc(C(F)(F)F)cc3[nH]c(Cl)nc23)cc(F)c1F
Product: C[C@@H]1CN(c2ncccc2Br)CCN1c1nc2cc(C(F)(F)F)cc(-c3cc(F)c(F)c(F)c3)c2[nH]1

Procedure:
2-Chloro-6-(trifluoromethyl)-4-(3,4,5-trifluorophenyl)-1H-benzoimidazole (52 mg, 0.15 mmol, Example 51b) reacted with (3R)-1-(3-bromopyridin-2-yl)-3-methylpiperazine (48 mg, 0.2 mmol, Example 43a) under the conditions of Example 3c to give the title compound as a white amorphous solid. MS (ESI, pos. ion) m/z: 570 (M+1).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][OH:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[C:21]1([CH3:31])[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[CH:23][CH:22]=1>C(Cl)Cl>[C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][S:27]([C:24]2[CH:25]=[CH:26][C:21]([CH3:31])=[CH:22][CH:23]=2)(=[O:29])=[O:28])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OCCCCCCc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCCCCCCc2ccccc2)cc1
Temperature: 25 °C
Yield: 99.8 %

Procedure:
A solution of 6-phenyl-1-hexanol (2.9 g, 16.27 mmoles), CH2Cl2 (30 ml), triethylamine (4.76 ml, 34.16 mmoles) and p-toluensulphonyl chloride (3.26 g, 17.08 mmoles) was kept under stirring at room temperature for 1 night, washed with water, 5% HCl and NaHCO3 and evaporated to give 5.4 g of the title compound (yield: 100%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6](Cl)[C:5]([F:9])=[CH:4][N:3]=1.[NH2:10][C:11]1[CH:12]=[C:13]([CH:18]=[CH:19][CH:20]=1)[O:14][CH2:15][CH2:16][OH:17]>>[OH:17][CH2:16][CH2:15][O:14][C:13]1[CH:12]=[C:11]([NH:10][C:2]2[N:7]=[C:6]([NH:10][C:11]3[CH:20]=[CH:19][CH:18]=[C:13]([O:14][CH2:15][CH2:16][OH:17])[CH:12]=3)[C:5]([F:9])=[CH:4][N:3]=2)[CH:20]=[CH:19][CH:18]=1
Reactant: Fc1cnc(Cl)nc1Cl
Reactant: Nc1cccc(OCCO)c1
Product: OCCOc1cccc(Nc2ncc(F)c(Nc3cccc(OCCO)c3)n2)c1

Procedure:
In like manner to the preparation of N2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine, 2,4-dichloro-5-fluoropyrimidine and 2-(3-aminophenoxy)ethanol were reacted to produce N2,N4-bis[3-(2-hydroxyethoxy)phenyl]-5-fluoro-2,4-pyrimidinediamine. 1H NMR (DMSO-d6): δ 9.50 (br s, 1H), 9.35 (br s, 1H), 8.13 (d, 1H, J=4.1 Hz), 7.44 (d, 1H, J=7.6 Hz), 7.26-7.19 (m, 4H), 7.10 (t, 1H, J=7.6 Hz), 6.65 (dd, 1H, J=2.3 and 8.2 Hz), 6.50 (dd, 1H, J=2.3 and 8.2 Hz), 5.0 (br s, 2H), 3.91 (t, 2H, J=5.2 Hz), 3.85 (t, 2H, J=5.2 Hz), 3.68 (qt, 2H, J=5.2 Hz), 3.66 (qt, 2H, J=5.2 Hz); LCMS: ret. time: 15.76 min.; purity: 97%; MS (m/e): 401 (MH+).
Reaction SMILES: [F:1][C:2]1[C:11]([CH3:12])=[C:10]2[C:5]([N:6]=[CH:7][C:8]([O:13][CH3:14])=[N:9]2)=[CH:4][CH:3]=1.[Br:15]N1C(=O)CCC1=O>C(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:15][CH2:12][C:11]1[C:2]([F:1])=[CH:3][CH:4]=[C:5]2[C:10]=1[N:9]=[C:8]([O:13][CH3:14])[CH:7]=[N:6]2
Reactant: COc1cnc2ccc(F)c(C)c2n1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)Cl
Product: COc1cnc2ccc(F)c(CBr)c2n1
Yield: 102.3 %

Procedure:
To 7-fluoro-8-methyl-2-(methyloxy)quinoxaline (50 g, 260 mmol) in dry chloroform (1 L) were added N-bromosuccinimide (52 g, 292 mmol) and benzoyl peroxide (70%, 0.42 g) and the mixture was heated under reflux, illuminated with a 120 W lamp, for 2 h. After cooling, the mixture was washed with water. The aqueous phase was re-extracted twice with dichloromethane and the combined organic fractions were washed with water, dried and evaporated to give product (72.1 g, 100%).
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:18].[CH3:19][O:20][C:21]1[CH:22]=[C:23]([CH2:29][C:30](O)=[O:31])[CH:24]=[C:25]([O:27][CH3:28])[CH:26]=1>>[CH3:28][O:27][C:25]1[CH:24]=[C:23]([CH2:29][C:30]([NH:1][N:2]2[N:11]=[C:10]([N:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]2=[O:18])=[O:31])[CH:22]=[C:21]([O:20][CH3:19])[CH:26]=1
Reactant: Nn1nc(N2CCOCC2)c2ccccc2c1=O
Reactant: COc1cc(CC(=O)O)cc(OC)c1
Product: COc1cc(CC(=O)Nn2nc(N3CCOCC3)c3ccccc3c2=O)cc(OC)c1

Procedure:
The product of Example 1B and 2-(3,5-dimethoxyphenyl)acetic acid were treated using a method similar to that described in Example 111 to give the title compound. 1H NMR (500 MHz, DMSO-d6/Deuterium Oxide) δ ppm 8.31 (dd, J=7.9, 1.3 Hz, 1H), 8.03 (d, J=1.3 Hz, 1H), 7.97-8.01 (m, 1H), 7.91 (td, J=7.5, 1.3 Hz, 1H), 6.58 (d, J=2.3 Hz, 2H), 6.41 (t, J=2.3 Hz, 1H), 3.80-3.84 (m, 4H), 3.76 (s, 6H), 3.59 (s, 2H), 3.08-3.11 (m, 4H); MS (ESI−) M/Z 423 (M−H)−.
Reaction SMILES: O[C:2]1([CH2:5][CH2:6][C@@H:7]([CH2:23][O:24]S(C2C=CC(C)=CC=2)(=O)=O)[CH2:8][C@H:9]2[CH2:13][O:12][C:11]([CH3:15])([CH3:14])[N:10]2[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:4][CH2:3]1.C[Mg+].[Br-]>C1COCC1>[CH2:4]1[C:2]2([CH2:5][CH2:6][C@H:7]([CH2:8][C@H:9]3[CH2:13][O:12][C:11]([CH3:15])([CH3:14])[N:10]3[C:16]([O:18][C:19]([CH3:22])([CH3:20])[CH3:21])=[O:17])[CH2:23][O:24]2)[CH2:3]1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H](CCC2(O)CC2)C[C@H]2COC(C)(C)N2C(=O)OC(C)(C)C)cc1
Agent: C[Mg+]
Agent: [Br-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1[C@@H](C[C@H]2CCC3(CC3)OC2)COC1(C)C
Yield: 91 %

Procedure:
The (S)-tert-butyl 4-((R)-4-(1-hydroxycyclopropyl)-2-(tosyloxymethyl)butyl)-2,2-dimethyloxazolidine-3-carboxylate was dissolved in 30 mL of THF and MeMgBr (7.0 mL of a 3.0 M solution, 2.0 equiv) was added and the mixture heated to reflux for 56 hr. After cooling to ambient the mixture was quenched by addition of water and the mixture transferred to a separatory funnel. The layers were separated and the organic layer were washed with brine, dried over Na2SO4, filtered and evaporated. The pyran derivative was purified by flash chromatography on silica (40 g) eluting with 0-29% EtOAc in hexanes. This afforded 1.05 g (91% yield) of (S)-tert-butyl 4-(((R)-4-oxaspiro[2.5]oct-6-yl)methyl)-2,2-dimethyloxazolidine-3-carboxylate. MS ESI +ve m/z 348 (M+Na).
Reaction SMILES: [H-].[Na+:2].CN(C=O)C.[C:8]([O:16][CH2:17][CH3:18])(=[O:15])[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11]>CCCCCCC>[Na:2][CH:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:8]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: [Na+]
Reactant: CCOC(=O)CC(=O)OCC
Agent: [H-]
Solvent: CCCCCCC
Solvent: CN(C)C=O
Product: CCOC(=O)C([Na])C(=O)OCC
Reaction time: 0.5 h

Procedure:
Wash 29 g (2 equiv.) of NaH (60% dispersion in oil) with heptane (2×80 mL). Combine the washed Nail with 60 mL of DMF, then slowly add 11.0 g (68.8 mmol) of diethyl malonate while keeping the reaction temperature below 30° C. Stir the resulting mixture for 30 min to form a solution of diethyl sodiomalonate.
Reaction SMILES: [BH4-].[Na+].[CH3:3][C:4]1[C:8]([CH2:9][O:10][C:11]2[CH:18]=[CH:17][C:14]([CH:15]=[O:16])=[CH:13][CH:12]=2)=[CH:7][N:6]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)[N:5]=1.CO>O1CCCC1>[CH3:3][C:4]1[C:8]([CH2:9][O:10][C:11]2[CH:12]=[CH:13][C:14]([CH2:15][OH:16])=[CH:17][CH:18]=2)=[CH:7][N:6]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)[N:5]=1
Reactant: Cc1nn(-c2ccccn2)cc1COc1ccc(C=O)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1nn(-c2ccccn2)cc1COc1ccc(CO)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 96.8 %

Procedure:
Sodium borohydride (0.25 g) was added to a mixture of 4-[3-methyl-1-(2-pyridyl)-1H-pyrazol-4-ylmethoxy]benzaldehyde (3.50 g), methanol (5 ml), and tetrahydrofuran (25 ml) at 0° C., and the mixture was stirred at room temperature for 30 minutes. After the reaction mixture was concentrated under reduced pressure, diluted hydrochloric acid was added to the residue, which was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), and then concentrated. The residue was subjected to silica gel column chromatography, and 4-[3-methyl-1-(2-pyridyl)-1H-pyrazol-4-ylmethoxy]benzyl alcohol (3.41 g, yield: 97%) was obtained as colorless crystals from the fraction eluted with ethyl acetate-hexane (1:2, volume ratio). This was recrystallized from ethyl acetate-hexane. Melting point: 83–84° C.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([OH:11])[CH:8]=[CH:9][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:12][O:13]C(Cl)Cl.Cl.O>C(Cl)Cl>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH:12]=[O:13])=[C:7]([OH:11])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cccc(O)c1
Reactant: COC(Cl)Cl
Agent: Cl
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)c1ccc(C=O)c(O)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 52.1 %

Procedure:
A solution of 5.69 g (30 mmol) of titan tetrachloride in 15 ml DCM were added dropwise at 0° C. under nitrogen to 3.76 g (25 mmol) of 3-tert-butylphenol dissolved in 75 ml DCM. After stirring for 30 min 3.16 g (27.5 mmol) of dichloromethyl methyl ether was added. The reaction mixture was stirred for 2 h at 0° C. Carefully 30 ml of 1N aqueous HCl solution and then 90 ml water were added. The reaction mixture was extracted twice with DCM. The combined organic layers were washed with saturated aqueous NaCl solution, dried over sodium sulfate, filtered and the solvent was evaporated. The residue was purified by column chromatography (250 g silica gel, DCM) to yield 2.32 g (52%) 4-tert-butyl-2-hydroxy benzaldehyde as a light yellow oil. 1H NMR (DMSO-d6, 300 MHz): δ 10.62 (br s, 1H), 10.18 (s, 1H), 7.61 (d, 1H), 7.04 (d, 1H), 6.98 (s, 1H).
Reaction SMILES: N[C@H](C(O)=O)CC1N=CNC=1.[Cl-].[K+].[Na+].[Cl-].[Mg+2].[Cl-].[Cl-].P(OC[C@H]1O[C@@H](N2C3N=CN=C(N)C=3N=C2)[C@H](O)[C@@H]1O)(OP(OP(O)(O)=O)(O)=O)(=O)O.C[C@@H]1O[C@@H]([O:57][C@@H:58]2[CH2:67][C@:66]3(O)[C@@:61](CO)([C@H:62]4[C@H:75](O)[CH2:74][C@@:73]5(C)[C@:69](O)([CH2:70][CH2:71][C@@H:72]5[C:78]5C[O:82][C:80](=[O:81])[CH:79]=5)[C@@H:63]4[CH2:64][CH2:65]3)[C@H:60](O)[CH2:59]2)[C@H](O)[C@H](O)[C@H]1O>O>[CH3:71][CH2:70][CH2:69][CH2:63][CH2:64][CH:65]=[CH:66][CH2:67][C@@H:58]([OH:57])[CH:59]=[CH:60][CH:61]=[CH:62][CH2:75][CH:74]=[CH:73][CH2:72][CH2:78][CH2:79][C:80]([OH:82])=[O:81]
Reactant: C[C@@H]1O[C@@H](O[C@H]2C[C@@H](O)[C@]3(CO)[C@H]4[C@H](O)C[C@]5(C)[C@@H](C6=CC(=O)OC6)CC[C@]5(O)[C@@H]4CC[C@]3(O)C2)[C@H](O)[C@H](O)[C@H]1O
Agent: N[C@@H](Cc1c[nH]cn1)C(=O)O
Agent: Nc1ncnc2c1ncn2[C@@H]1O[C@H](COP(=O)(O)OP(=O)(O)OP(=O)(O)O)[C@@H](O)[C@H]1O
Agent: [Cl-]
Solvent: O
Product: CCCCCC=CC[C@@H](O)C=CC=CCC=CCCCC(=O)O
Reaction time: 0.08 h

Procedure:
The activity of Na+ -K+ -ATPase was measured as the rate of release of inorganic phosphate in the presence of 30 mM histidine, 20 mM KCl, 30 mM NaCl, 3 mM MgCl2 and 3 mM ATP, pH 7.5 [Jorgenson, supra]. After equilibration for 5 min. at 37° C., 10 μl of the enzyme preparation (1-5 μg protein) was added to 0.5 ml of reaction mixture. The reaction was allowed to proceed for 30 min. at 37° C. The compounds to be tested were dissolved in PBS buffer and added to the enzyme 10 min. prior to the addition of the reaction mixture. Ouabain was dissolved in distilled water. The reaction was terminated by the addition of 0.8 ml color reagent containing ammonium molybdate malachite green and sterox as described by O. A. Candia et al., Biochim. Biophys. Acta 602, pp. 389-400 (1980). After 1 min., 100 μl of 34% sodium citrate solution was added and mixed. The final solution was then read at 660 mm in a Beckman DB spectrophotometer. Al solutions were read against references containing the same concentration of ATP as the incubation tubes. Enzyme activity was expressed as μmol Pi released/h/mg protein.
Reaction SMILES: [C@@H:1]1([N:9]2[CH:17]=[C:15]([CH3:16])[C:13](=[O:14])[NH:12][C:10]2=[O:11])[O:8][C@H:5]([CH2:6][OH:7])[C@@H:3]([OH:4])[CH2:2]1.CN1CCOCC1.[CH3:25][S:26](Cl)(=[O:28])=[O:27].Cl>O.CC(C)=O>[CH3:25][S:26]([O:4][C@@H:3]1[C@@H:5]([CH2:6][O:7][S:26]([CH3:25])(=[O:28])=[O:27])[O:8][C@@H:1]([N:9]2[CH:17]=[C:15]([CH3:16])[C:13](=[O:14])[NH:12][C:10]2=[O:11])[CH2:2]1)(=[O:28])=[O:27]
Reactant: Cc1cn([C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)[nH]c1=O
Reactant: CS(=O)(=O)Cl
Agent: *CC*
Agent: Cl
Solvent: CN1CCOCC1
Solvent: CC(C)=O
Solvent: O
Product: Cc1cn([C@H]2C[C@H](OS(C)(=O)=O)[C@@H](COS(C)(=O)=O)O2)c(=O)[nH]c1=O
Yield: 94.5 %

Procedure:
A five liter, three-necked, round bottom flask was equipped with an overhead stirrer and paddle, a 500 mL dropping funnel, a Claisen adapter with thermocouple probe and a reflux condenser. Thymidine (363.3 g, 1.5 moles) and N-methylmorpholine (508.3 g, 5.02 moles) were added to the flask with acetone (2.00 L). The mixture was stirred while adding methanesulfonyl chloride (498.3 g, 4.35 moles) slowly over about one hour, with cooling to maintain 30°-35° C. during the addition. An additional 1.50 L of acetone was added to the mixture to maintain adequate stirring. After the addition was complete, the mixture was stirred for 1 hour at 30°-35° C. The reaction was then transferred in portions to water (9.66 L) being stirred in a 20 L polyethylene tank. The pH of the aqueous slurry was adjusted with 12N HCl to pH 2.5 and stirred at ambient temperature for an additional two hours. The slurry was filtered and the solid was washed with water (2.9 L) and isopropanol (1.45 L). The solid was air dried overnight to give 564.6 g (94.5%) of the title compound which assays 97.1% (by weight) purity.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:3]=1[C:4]#[N:5].O.[NH2:12][NH2:13].CC(C)=O>C(O)C>[F:10][C:6]1[CH:7]=[CH:8][CH:9]=[C:2]2[C:3]=1[C:4]([NH2:5])=[N:12][NH:13]2
Reactant: NN
Reactant: N#Cc1c(F)cccc1F
Solvent: CCO
Solvent: CC(C)=O
Solvent: O
Product: Nc1n[nH]c2cccc(F)c12
Temperature: 90 °C
Reaction time: 18 h
Yield: 140.3 %

Procedure:
To a solution of 2,6-difluorobenzonitrile (3 g, 21.6 mmol) in anhydrous ethanol (50 mL) was added hydrazine hydrate (4.18 mL, 86 mmol). The reaction was heated at 90° C. under nitrogen for 4 hours. Reaction mixture was cooled to room temperature, treated with acetone (20 mL) and left to stand for 18 hours. The mixture was evaporated in-vacuo to yield an orange/brown solid which was partitioned between saturated aqueous sodium hydrogen carbonate solution and dichloromethane. The organic layer was passed through a hydrophobic frit and evaporated in-vacuo to yield a brown solid (4.58 g), which was absorbed onto Florisil (60-100 mesh), applied to a 100 g silica SPE cartridge and purified on a Flashmaster II using a 0-10% methanol in dichloromethane gradient over 60 min. Fractions 48-57 were combined and the solvent was evaporated in-vacuo to yield the title compound as a brown solid (3.08 g, 94%). LCMS (System B) RT=1.38 min, ES+ve m/z 152 (M+H)+.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]([CH3:26])[C:11]([C:20]3[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=3)=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[N:13]=2)=[CH:5][CH:4]=1.[C:27](OC(=O)C)(=[O:29])[CH3:28]>N1C=CC=CC=1>[C:27]([NH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]([CH3:26])[C:11]([C:20]3[CH:21]=[CH:22][N:23]=[CH:24][CH:25]=3)=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[N:13]=2)=[CH:5][CH:4]=1)(=[O:29])[CH3:28]
Reactant: Cn1c(-c2ccc(CN)cc2)nc(-c2ccccc2)c1-c1ccncc1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)NCc1ccc(-c2nc(-c3ccccc3)c(-c3ccncc3)n2C)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 29.1 %

Procedure:
To a solution of 2-(4-aminomethylphenyl)-1-methyl-4-phenyl-5-(4-pyridyl)imidazole (30 mg, 0.09 mmol) [See Ex. 4 above] in pyridine (3 mL) was added acetic anhydride (0.30 mL, 3.18 mmol). The resulting solution was stirred at rt for 30 min, then concentrated under reduced pressure. The residue was purified by flash chromatography, eluting with a solvent gradient of 0-2% MeOH/CHCl3. The isolated material was triturated with Et2O to provide an off-white solid (10 mg, 28%) which was recrystallized from EtOAc to provide the title compound: mp 210-211° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][C:9](=[O:12])[CH:8]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:7]1)=[O:5])[CH3:2].[BH4-].[Na+].Cl.[H][H]>C(O)C.[Cl-].[Na+]>[CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][C@@H:9]([OH:12])[C@H:8]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCC(=O)C(c2ccccc2)C1
Reactant: [H][H]
Agent: Cl
Agent: [BH4-]
Agent: [Cl-]
Solvent: CCO
Product: CCOC(=O)N1CC[C@@H](O)[C@H](c2ccccc2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 48.4 g of 1-ethoxycarbonyl-3-phenyl-4-piperidone in 500 ml of denatured ethanol is added, dropwise at 0°-10° C. under nitrogen, a solution of 7.57 g of sodium borohydride in 325 ml of denatured ethanol, over a 30-minute period. After stirring overnight at room temperature the mixture is diluted with 1200 ml of saturated sodium chloride solution and stirred for one hour. The mixture is cautiously treated with 500 ml of 2 N hydrochloric acid and stirred until hydrogen evolution has slowed. The mixture is extracted with ether (3×600 ml) and the organic extracts concentrated in vacuo to a residue which was partitioned between ether (1200 ml) and saturated sodium chloride solution (600 ml). After drying the organic phase overnight over anhydrous sodium sulfate, removal of the solvent in vacuo affords a viscous orange gum. Purification of this crude mixture of isomers by high pressure liquid chromatography in 40% ethyl acetate/hexane affords the cis-isomer and trans-isomer as cloudy yellow gums. Trituration of the gummy trans-isomer with petroleum ether affords pure trans-isomer as a colorless solid, mp 49.5°-58° C.
Reaction SMILES: [I:1][C:2]1[C:6]2[N:7]=[CH:8][N:9]=[C:10]([NH2:11])[C:5]=2[NH:4][N:3]=1.F[C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[C:15]([O:22][CH3:23])[CH:14]=1.[H-].[Na+]>CN(C)C=O>[I:1][C:2]1[C:6]2[N:7]=[CH:8][N:9]=[C:10]([NH2:11])[C:5]=2[N:4]([C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[C:15]([O:22][CH3:23])[CH:14]=2)[N:3]=1
Reactant: Nc1ncnc2c(I)n[nH]c12
Reactant: COc1cc(F)ccc1[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc(-n2nc(I)c3ncnc(N)c32)ccc1[N+](=O)[O-]
Temperature: 85 °C
Yield: 51.2 %

Procedure:
A mixture of 3-iodo-1H-pyrazolo[4,3-d]pyrimidin-7-amine (500 mg, 1.92 mmol) and 4-fluoro-2-methoxy-1-nitrobenzene (360 mg, 2.11 mmol) in N,N-dimethylformamide (5 mL) was treated with 60% sodium hydride in oil (92 mg, 2.30 mmol) then heated in an 85° C. oil bath for 17 hours. The solvent was removed by evaporation under reduced pressure then the residue was dissolved in a minimum of hot N,N-dimethylformamide and applied to a silica gel column and eluted with ethyl acetate to provide the title compound (405 mg, 51%) as a yellow solid after concentration of the appropriate fractions: 1H NMR (DMSO-d6, 400 MHz) δ 8.38 (s, 1H), 8.10 (d, 1H), 7.47 (s, 1H), 7.30 (m, 1H), 7.15 (bs, 2H), 3.98 (s, 3H); RP-HPLC (Hypersil HS C18, 5 μm, 100 A, 250×4.6 mm; 5%-100% acetonitrile-0.05 M ammonium acetate over 25 min, 1 mL/min) tr 16.17 min; MS: MH+ 413.1, M−H+ 411.1