Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][NH:7][C:8]=1[C:9]#[N:10])([O-])=O.C(O)(=O)C.[CH:15](N)=[NH:16]>C(O)C.[Pd]>[NH:7]1[C:8]2[C:9]([NH2:10])=[N:16][CH:15]=[N:1][C:4]=2[CH:5]=[N:6]1
Reactant: N#Cc1[nH]ncc1[N+](=O)[O-]
Reactant: N=CN
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CCO
Product: Nc1ncnc2cn[nH]c12
Yield: 62.9 %

Procedure:
4-Nitro-1H-5-pyrazolecarbonitrile (6.25 g, 45.3 mmol) in ethanol (100 mL) was treated with 10% Palladium on carbon (0.50 g) and hydrogenated in a Parr shaker at 50 psi for 18 hours. The catalyst was removed by filtration through a pad of diatomaceous earth. The filtrate was then treated with formamidine acetate (37.7 g, 0.363 mol) then the mixture was heated at reflux for one hour. The mixture was cooled and then approximately 50 mL of the solvent was removed under reduced pressure. The precipitate which formed was isolated by filtration and washed with ethyl acetate (3×25 mL) then discarded. The filtrate was concentrated under reduced pressure to a volume of approximately 40 mL. The mixture was heated to dissolve all of the material then applied to a silica gel column which was eluted with ethyl acetate/methanol (8:2). The appropriate fractions were concentrated to give the title compound (3.85 g, 61%) which contained 18% formamidine acetate by weight as determined by 1H NMR: 1H NMR (DMSO-d6, 400 MHz) δ 13.3 bs, 1H), 8.15 (s, 1H) 8.07 (s, 1H), 7.47 (bs, 2H); 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 4.95 min; MS: MH+ 136.1, M−H+ 134.1
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:20][CH2:19][C:11]3([CH2:15][NH:14][C@H:13]([C:16]([OH:18])=[O:17])[CH2:12]3)[CH2:10][CH2:9]2)[CH:5]=[C:4]([O:21][C@H:22]([C:27]2[CH:32]=[CH:31][C:30]([C:33]3[CH:38]=[CH:37][C:36]([CH3:39])=[C:35]([CH3:40])[CH:34]=3)=[CH:29][C:28]=2[N:41]2[CH:45]=[CH:44][C:43]([CH3:46])=[N:42]2)[C:23]([F:26])([F:25])[F:24])[N:3]=1.[CH3:47][CH:48](O)[CH3:49]>S(Cl)(Cl)=O>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:20][CH2:19][C:11]3([CH2:15][NH:14][C@H:13]([C:16]([O:18][CH:48]([CH3:49])[CH3:47])=[O:17])[CH2:12]3)[CH2:10][CH2:9]2)[CH:5]=[C:4]([O:21][C@H:22]([C:27]2[CH:32]=[CH:31][C:30]([C:33]3[CH:38]=[CH:37][C:36]([CH3:39])=[C:35]([CH3:40])[CH:34]=3)=[CH:29][C:28]=2[N:41]2[CH:45]=[CH:44][C:43]([CH3:46])=[N:42]2)[C:23]([F:26])([F:25])[F:24])[N:3]=1
Reactant: CC(C)O
Reactant: Cc1ccn(-c2cc(-c3ccc(C)c(C)c3)ccc2[C@@H](Oc2cc(N3CCC4(CC3)CN[C@H](C(=O)O)C4)nc(N)n2)C(F)(F)F)n1
Solvent: O=S(Cl)Cl
Product: Cc1ccn(-c2cc(-c3ccc(C)c(C)c3)ccc2[C@@H](Oc2cc(N3CCC4(CC3)CN[C@H](C(=O)OC(C)C)C4)nc(N)n2)C(F)(F)F)n1
Temperature: 25 °C

Procedure:
To a solution of the compound of Example 1m (400 mg, 0.53 mmol) in propan-2-ol (5 mL) was added thionyl chloride (2 drops) at 0° C. The mixture was warmed to RT and then heated to reflux for 2 h. Then the reaction mixture was cooled to RT, concentrated and neutralized with saturated aqueous NaHCO3 solution to pH 7-8. The aqueous layer was extracted with CH2Cl2. The combined organic layers were washed with brine, dried over Na2SO4, filtered, concentrated in vacuo and purified by flash column (0˜10% MeOH in DCM) on silica gel to afford the title compound as a white solid.
Reaction SMILES: [OH:1][C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.Br[CH2:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14].[H-].[Na+]>CN(C=O)C>[O:1]=[C:2]1[N:6]([CH2:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[NH:3]1
Reactant: Oc1nc2ccccc2[nH]1
Reactant: CC(C)(C)OC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Cn1c(=O)[nH]c2ccccc21
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a stirred mixture of 2-hydroxybenzimidazole (4.00 g, 29.8 mmol) and tert-butyl bromoacetate (5.53 g, 28.3 mmol) in DMF (50 mL) at 0° C. was added sodium hydride (1.31 g of a 60% dispersion in mineral oil, 32.8 mmol). The mixture was stirred at 0° C. for 1 h, then quenched with saturated aqueous NaHCO3 and concentrated in vacuo. The residue was partitioned between EtOAc (500 mL) and H2O (300 mL) and the organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel chromatography, eluting with a gradient of CH2Cl2:EtOAc-100:0 to 0:100, to give the title compound. MS: m/z=249 (M+1).
Reaction SMILES: [CH2:1]([N:3]([C:29](=O)[C:30]1[CH:35]=[CH:34][C:33]([OH:36])=[CH:32][CH:31]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[CH:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([O:22]C(=O)C(C)(C)C)[CH:16]=[CH:15][C:14]=2[CH2:13]1)[CH3:2].Cl[CH2:39][C:40]([NH:42][CH2:43][CH2:44][F:45])=O>>[CH2:1]([N:3]([CH2:29][C:30]1[CH:31]=[CH:32][C:33]([O:36][CH2:39][CH2:40][NH:42][CH2:43][CH2:44][F:45])=[CH:34][CH:35]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[CH:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([OH:22])[CH:16]=[CH:15][C:14]=2[CH2:13]1)[CH3:2]
Reactant: O=C(CCl)NCCF
Reactant: CCN(C(=O)c1ccc(O)cc1)c1cc(OC)ccc1C1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Product: CCN(Cc1ccc(OCCNCCF)cc1)c1cc(OC)ccc1C1CCc2cc(O)ccc2C1
Yield: 40.7 %

Procedure:
Synthesized from pivalic acid 6-{2-[ethyl(4-hydroxybenzoyl)amino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (25 mg) and 2-chloro-N-(2-fluoroethyl)acetamide (13 mg) according to an analogous synthetic method to Example 567 and purified by LC-MS, the title compound (10 mg) was obtained.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[CH2:10][N:9](CC1C=CC(OC)=CC=1OC)[CH2:8]2)=[O:4].[C:25]1(OC)C=CC=CC=1.O.C(Cl)Cl.[C:37]([OH:43])([C:39]([F:42])([F:41])[F:40])=[O:38]>>[F:40][C:39]([F:42])([F:41])[C:37]([OH:43])=[O:38].[CH2:1]([O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[CH2:10][NH:9][CH2:8]2)=[O:4])[CH3:25]
Reactant: COC(=O)c1ccc2c(c1)CN(Cc1ccc(OC)cc1OC)C2
Reactant: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)c1ccc2c(c1)CNC2

Procedure:
A solution of 2-(2,4-dimethoxy-benzyl)-2,3-dihydro-1H-isoindole-5-carboxylic acid methyl ester (215 mg) and anisole (200 μl) in 1 ml of TFA was heated at 140° C. for 30 minutes in a CEM discover microwave synthesiser. The reaction was partititioned between water and DCM, the water layer was separated, washed with DCM then evaporated and re-evaporated with toluene/MeOH (×2) to give 105 mg of the title compound. 1H NMR (DMSO-d6) 9.70 (2H, br s), 8.02 (1H, s), 8.98 (1H, d), 7.57 (1H, d), 4.60 (2H, s), 4.56 (2H, s), 3.89 (3H, s).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH:12]=[C:11]([C:14](=[O:22])[CH2:15][C:16]2[CH:20]=[CH:19][S:18][C:17]=2[F:21])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(O)C.[OH-].[Pd+2].[OH-].[C]>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([C:14](=[O:22])[CH2:15][C:16]2[CH:20]=[CH:19][S:18][C:17]=2[F:21])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cc1ccsc1F)C1=CCN(Cc2ccccc2)CC1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: O=C(Cc1ccsc1F)C1CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 81.3 %

Procedure:
After dissolving 292 mg of 1-benzyl-4-[2-(2-fluoro-3-thienyl)acetyl]-1,2,3,6-tetrahydropyridine in 10 ml of ethanol, 0.1 g of 20% palladium hydroxide-carbon (hydrous) was added and the mixture was stirred for 1 hour at room temperature under a hydrogen atmosphere (1 atm). The reaction mixture was filtered and the filtrate was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (solvent: n-hexane/ethyl acetate) to obtain the title compound (239 mg, 81% yield).
Reaction SMILES: [F:1][CH2:2][CH:3]([N:6]1[CH2:12][CH2:11][C:10]2[CH:13]=[C:14]([NH2:19])[C:15]([O:17][CH3:18])=[CH:16][C:9]=2[CH2:8][CH2:7]1)[CH2:4][F:5].Cl[C:21]1[N:26]=[C:25]([NH:27][C:28]2[CH:33]=[CH:32][C:31]([N:34]3[CH2:39][CH2:38][O:37][CH2:36][CH2:35]3)=[CH:30][C:29]=2[O:40][CH3:41])[C:24]([Cl:42])=[CH:23][N:22]=1>>[Cl:42][C:24]1[C:25]([NH:27][C:28]2[CH:33]=[CH:32][C:31]([N:34]3[CH2:35][CH2:36][O:37][CH2:38][CH2:39]3)=[CH:30][C:29]=2[O:40][CH3:41])=[N:26][C:21]([NH:19][C:14]2[C:15]([O:17][CH3:18])=[CH:16][C:9]3[CH2:8][CH2:7][N:6]([CH:3]([CH2:2][F:1])[CH2:4][F:5])[CH2:12][CH2:11][C:10]=3[CH:13]=2)=[N:22][CH:23]=1
Reactant: COc1cc2c(cc1N)CCN(C(CF)CF)CC2
Reactant: COc1cc(N2CCOCC2)ccc1Nc1nc(Cl)ncc1Cl
Product: COc1cc2c(cc1Nc1ncc(Cl)c(Nc3ccc(N4CCOCC4)cc3OC)n1)CCN(C(CF)CF)CC2

Procedure:
5-Chloro-N(2)-[3-(2-fluoro-1-fluoromethyl-ethyl)-8-methoxy-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yl]-N(4)-(2-methoxy-4-morpholin-4-yl-phenyl)-pyrimidine-2,4-diamine was prepared from 3-(2-fluoro-1-fluoromethyl-ethyl)-8-methoxy-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamine and (2,5-dichloro-pyrimidin-4-yl)-(2-methoxy-4-morpholin-4-yl-phenyl)-amine in an analogous manner to Example 308c. Product isolated as a white foam (60 mg, 30%). LCMS (m/e) 589 (M+H); 1H-NMR (CDCl3, 400 MHz) δ 8.29 (d, 1H, J=8.7 Hz), 8.14 (s, 1H), 8.04 (s, 1H), 7.57 (s, 1H), 7.45 (s, 1H), 6.66 (s, 1H), 6.57 (s, 1H), 5.52 (d, 1H, J=8.7 Hz), 4.75-4.67 (m, 2H), 4.63-4.56 (m, 2H), 3.94 (s, 3H), 3.93-3.89 (m, 4H), 3.88 (s, 3H), 3.2-3.10 (m, 5H), 2.93-2.79 (m, 8H).
Reaction SMILES: C([O:8][C:9]1[C:18]2[O:17][CH2:16][C@H:15]([CH2:19][N:20]3[CH2:25][CH2:24][CH2:23][C@H:22]([C:26]4[CH:27]=[C:28]([OH:32])[CH:29]=[CH:30][CH:31]=4)[CH2:21]3)[O:14][C:13]=2[CH:12]=[CH:11][CH:10]=1)C1C=CC=CC=1>C(OCC)(=O)C.[Pd]>[OH:32][C:28]1[CH:27]=[C:26]([C@H:22]2[CH2:23][CH2:24][CH2:25][N:20]([CH2:19][C@@H:15]3[O:14][C:13]4[CH:12]=[CH:11][CH:10]=[C:9]([OH:8])[C:18]=4[O:17][CH2:16]3)[CH2:21]2)[CH:31]=[CH:30][CH:29]=1
Reactant: Oc1cccc([C@H]2CCCN(C[C@H]3COc4c(OCc5ccccc5)cccc4O3)C2)c1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Oc1cccc([C@H]2CCCN(C[C@H]3COc4c(O)cccc4O3)C2)c1
Reaction time: 6 h
Yield: 100.2 %

Procedure:
A mixture of 3-[(R*)-1-((S)-5-benzyloxy-2,3-dihydro-benzo[1,4]dioxin-2-ylmethyl)-piperidin-3-yl]-phenol (84 mg, 0.19 mmol) and palladium-on-carbon (60 mg) in ethyl acetate (10 ml) were stirred and hydrogenated for 6 h. The reaction mixture was filtered and washed with ethyl acetate (10 ml), and evaporated to dryness. The crude product was purified with flash chromatography using dichloromethane and methanol as eluents to give 65 mg of the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:10]([F:11])=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[F:12].[C:13]([NH:17][C:18](=[O:32])[C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH2:25][N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[CH:20]=1)([CH3:16])([CH3:15])[CH3:14].C(N(CC)CC)C.CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O>ClCCl.C(OCC)(=O)C>[NH2:1][C:2]1[C:3]([F:12])=[CH:4][C:5]([C:6]([N:29]2[CH2:28][CH2:27][N:26]([CH2:25][C:21]3[CH:20]=[C:19]([CH:24]=[CH:23][CH:22]=3)[C:18]([NH:17][C:13]([CH3:15])([CH3:16])[CH3:14])=[O:32])[CH2:31][CH2:30]2)=[O:8])=[CH:9][C:10]=1[F:11]
Reactant: CC(C)(C)NC(=O)c1cccc(CN2CCNCC2)c1
Reactant: Nc1c(F)cc(C(=O)O)cc1F
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)(C)NC(=O)c1cccc(CN2CCN(C(=O)c3cc(F)c(N)c(F)c3)CC2)c1
Reaction time: 2 h
Yield: 90 %

Procedure:
To a stirred solution of 4-ammo-3,5-difluorobenzoic acid (1 g, 5.78 mmoles), N-tert-butyl-3-(piperazin-1-ylmethyl)benzamide (1.59 g, 5.78 mmoles) and triethylamine (4 mL) in dichloromethane (30 mL) was added 1-propanephosphonic acid cyclic anhydride (8 mL, 50% solution in ethyl acetate). After 2 hours stirring, the reaction mixture was diluted with ethyl acetate and washed with sodium carbonate (aqueous) (3×), dried (magnesium sulfate) and concentrated under reduced pressure to give the title compound (2.24 g) as an off-white foam.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([SH:11])[S:9][CH:10]=1)=[O:5])[CH3:2].[H-].[Na+].Br[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].O>CN(C=O)C>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([S:11][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[S:9][CH:10]=1)=[O:5])[CH3:2]
Reactant: CCCCCCCCBr
Reactant: CCOC(=O)c1csc(S)n1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCCCCCSc1nc(C(=O)OCC)cs1
Reaction time: 0.17 h
Yield: 78 %

Procedure:
To a solution of 2-mercaptothiazole-4-carboxylic acid ethyl ester (Zhelyazkov, L.; Todorova, N.; Manolova, P. Tr. Nauchnoizsled. Khim.-Farm. Inst., 9, 59-67 (1974); Chem. Abstr., 83, 58706 q) (3.0 g) in DMF (20 ml) is added sodium hydride (0.70 g of 60% dispersion). After 10 min, 1-bromooctane (3.0 ml) is added, and the mixture is stirred at 60° for 30 min. The mixture is poured into water and extracted with ether, and the extracts are dried, filtered, and concentrated. The residue is recrystallized from hexane to provide 2-(octylthio)thiazole-4-carboxylic acid ethyl ester as a colorless solid (3.7 g, 78%). This material is reduced in the usual fashion with lithium aluminum hydride in THF, providing 2-(octylthio)thiazole-4-methanol (2.12 g, 67%) as a colorless oil after chromatography. This is combined with DDQ (1.8 g) in 1,4-dioxane (25 ml) and stirred for 48 hr at room temperature. The reaction mixture is filtered, and the filtrate is concentrated and chromatographed with dichloromethane to provide 2-(octylthio)thiazole-4-carboxaldehyde as a tan solid (1.67 g, 81%).
Reaction SMILES: [H-].[Na+].[C:3]([O:9][CH3:10])(=[O:8])[CH2:4][C:5]([CH3:7])=[O:6].C([Li])CCC.[F:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]([CH:32]([CH3:34])[CH3:33])[C:24]=2[CH:35]=[O:36])=[CH:19][CH:18]=1>C1COCC1>[CH3:10][O:9][C:3](=[O:8])[CH:4]=[C:5]([OH:6])[CH2:7][CH:35]([C:24]1[N:25]([CH:32]([CH3:34])[CH3:33])[C:26]2[C:31]([C:23]=1[C:20]1[CH:21]=[CH:22][C:17]([F:16])=[CH:18][CH:19]=1)=[CH:30][CH:29]=[CH:28][CH:27]=2)[OH:36]
Reactant: COC(=O)CC(C)=O
Reactant: CC(C)n1c(C=O)c(-c2ccc(F)cc2)c2ccccc21
Agent: [H-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)C=C(O)CC(O)c1c(-c2ccc(F)cc2)c2ccccc2n1C(C)C
Temperature: 3 °C
Reaction time: 4 h

Procedure:
0.256 g (5.87 mmol) of sodium hydride (55%) is introduced into a thoroughly heated 100 ml three-necked round-bottomed flask, equipped with a magnetic stirrer, thermometer, dropping funnel and nitrogen delivery line, and washed twice with 5 ml of pentane. The pentane is removed using a pipette and the sodium hydride is blown dry with nitrogen. 20 ml of THF, rendered absolute using sodium, are then added, and the suspension is cooled to 3° C. by means of an ice bath with stirring. 0.68 g (5.87 mmol) of methyl acetoacetate dissolved in 5 ml of absolute THF is then slowly added dropwise so that the internal temperature does not exceed 5° C. The suspension is stirred for 15 min. while cooling with ice. 3.75 ml (6.0 mmol) of butyllithium (1.6M in hexane) are slowly added dropwise to the almost clear solution so that the internal temperature does not exceed 5° C. The clear yellow solution is stirred for 20 min. while cooling with ice. 1.0 g (3.55 mmol) of 3-(4-fluorophenyl)-1-isopropyl-1H-indole-2-carbaldehyde dissolved in 5 ml of absolute THF are added dropwise over a period of 2 min., in the course of which the internal temperature rises to 10° C. After 4 hours, the reaction mixture is poured into 100 ml of ice-water, stirred for 10 min. and extracted 3 times with 100 ml of ethyl acetate. The combined organic phases are washed twice with 100 ml of saturated sodium chloride solution in order to render neutral, dried over magnesium sulfate, filtered and concentrated by evaporation at 80° C.
Reaction SMILES: [F:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([F:12])[C:3]=1[N:13]1[CH2:22][C:21]2[C:16](=[N:17][C:18](S(C)=O)=[N:19][CH:20]=2)[N:15]([CH2:26][CH3:27])[C:14]1=[O:28].[NH2:29][C@H:30]1[CH2:35][CH2:34][C@H:33]([OH:36])[CH2:32][CH2:31]1>>[F:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([F:12])[C:3]=1[N:13]1[CH2:22][C:21]2[C:16](=[N:17][C:18]([NH:29][CH:30]3[CH2:35][CH2:34][CH:33]([OH:36])[CH2:32][CH2:31]3)=[N:19][CH:20]=2)[N:15]([CH2:26][CH3:27])[C:14]1=[O:28]
Reactant: CCN1C(=O)N(c2c(F)c(OC)cc(OC)c2F)Cc2cnc(S(C)=O)nc21
Reactant: N[C@H]1CC[C@H](O)CC1
Product: CCN1C(=O)N(c2c(F)c(OC)cc(OC)c2F)Cc2cnc(NC3CCC(O)CC3)nc21
Yield: 89.2 %

Procedure:
3-(2,6-Difluoro-3,5-dimethoxy-phenyl)-1-ethyl-7-(4-hydroxy-cyclohexylamino)-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one was prepared as described in Example 5 using 0.5 g (1.21 mmol) of 3-(2,6-difluoro-3,5-dimethoxy-phenyl)-1-ethyl-7-methylsulfinyl-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one and 0.42 g (3.64 mmol) of trans-4-aminocyclohexanol. The crude product was purified using medium-pressure chromatography eluting with 20:1 dichloromethane/methanol to give 0.50 g (89%) of the title compound: mp 198° C.–202° C. MS (APCI) (m+1)/z 464.1.
Reaction SMILES: [Si](OC[C@@H]1C=C(C(=O)N)[C@H](O)CN1C(OC(C)(C)C)=O)(C(C)(C)C)(C)C.[CH2:27]([O:30][N:31]([C@H:47]1[CH2:52][N:51]([C:53]([O:55][C:56]([CH3:59])([CH3:58])[CH3:57])=[O:54])[C@H:50]([CH2:60][O:61][Si:62]([C:65]([CH3:68])([CH3:67])[CH3:66])([CH3:64])[CH3:63])[CH:49]=[C:48]1[C:69](=[O:71])[NH2:70])[S:32]([C:35]1[CH:40]=[CH:39][C:38]([N+]([O-])=O)=[CH:37][C:36]=1[N+:44]([O-:46])=[O:45])(=[O:34])=[O:33])[CH:28]=[CH2:29].C(ONS(C1C=CC=CC=1[N+]([O-])=O)(=O)=O)C=C.C(ONS(C1C=CC([N+]([O-])=O)=CC=1[N+]([O-])=O)(=O)=O)C=C>>[CH2:27]([O:30][N:31]([C@H:47]1[CH2:52][N:51]([C:53]([O:55][C:56]([CH3:59])([CH3:58])[CH3:57])=[O:54])[C@H:50]([CH2:60][O:61][Si:62]([C:65]([CH3:68])([CH3:67])[CH3:66])([CH3:63])[CH3:64])[CH:49]=[C:48]1[C:69](=[O:71])[NH2:70])[S:32]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[N+:44]([O-:46])=[O:45])(=[O:34])=[O:33])[CH:28]=[CH2:29]
Reactant: C=CCON([C@H]1CN(C(=O)OC(C)(C)C)[C@H](CO[Si](C)(C)C(C)(C)C)C=C1C(N)=O)S(=O)(=O)c1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Agent: C=CCONS(=O)(=O)c1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Agent: C=CCONS(=O)(=O)c1ccccc1[N+](=O)[O-]
Agent: CC(C)(C)OC(=O)N1C[C@@H](O)C(C(N)=O)=C[C@H]1CO[Si](C)(C)C(C)(C)C
Product: C=CCON([C@H]1CN(C(=O)OC(C)(C)C)[C@H](CO[Si](C)(C)C(C)(C)C)C=C1C(N)=O)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Yield: 74 %

Procedure:
The title compound (4.0 g, 74%) was prepared from (2S,5S)-tert-butyl 2-((tert-butyldimethylsilyloxy)methyl)-4-carbamoyl-5-hydroxy-5,6-dihydropyridine-1(2H)-carboxylate (Intermediate 104, 3.36 g, 8.69 mmol) using the same procedure to prepare Intermediate 105 from Intermediate 104, but using N-(allyloxy)-2-nitrobenzenesulfonamide (Intermediate 9, 2.24 g, 8.69 mmol) as a reagent in place of N-(allyloxy)-2,4-dinitrobenzenesulfonamide.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH2:17][CH2:16][C:15](=O)[CH2:14][CH2:13]2)=[CH:8][CH:7]=1)=[O:5])[CH3:2].[OH:19][C@@H:20]([CH2:33][NH2:34])[CH2:21][O:22][C:23]1[C:31]2[NH:30][C:29](=[O:32])[NH:28][C:27]=2[CH:26]=[CH:25][CH:24]=1.C(O)(=O)C>C(O)C.[Pd]>[CH2:1]([O:3][C:4](=[O:5])[C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH2:17][CH2:16][CH:15]([NH:34][CH2:33][C@H:20]([OH:19])[CH2:21][O:22][C:23]3[C:31]4[NH:30][C:29](=[O:32])[NH:28][C:27]=4[CH:26]=[CH:25][CH:24]=3)[CH2:14][CH2:13]2)=[CH:8][CH:7]=1)[CH3:2]
Reactant: CCOC(=O)c1ccc(N2CCC(=O)CC2)cc1
Reactant: NC[C@H](O)COc1cccc2[nH]c(=O)[nH]c12
Agent: [Pd]
Solvent: CCO
Solvent: CC(=O)O
Product: CCOC(=O)c1ccc(N2CCC(NC[C@H](O)COc3cccc4[nH]c(=O)[nH]c34)CC2)cc1
Yield: 48.4 %

Procedure:
A mixture of 1-(4-ethoxycarbonylphenyl)-4-piperidone (0.25 g, 1 mmol) (Taylor, E. C., Skotnicki, J. S. Synthesis, 1981, 606) and (S)-4-[2-hydroxy-3-aminopropoxy]-1,3-dihydro-2H-benzimidazol-2-one (0.22 g, 1 mmol) U.S. Pat. No. 5,786,356/1988) in 100 mL of ethanol and 0.5 mL of acetic acid was hydrogenated in the presence of 400 mg of 10% palladium on carbon under hydrogen (5˜20 psi) for overnight. The catalyst was then removed by filtering through a short pad of silica gel. The filtrate was concentrated and purified by thin layer chromatography (12% methanol/methylene chloride) to give the title compound as a white solid (0.22 g, 48%); mp>170° C. (decomposed); 1H NMR (300 MHz, DMSO-d6) δ 1.28 (t, J=7.0 Hz, 3 H), 1.30–1.55 (m, 2 H), 1.80–2.10 (m, 2 H), 2.80–3.10 (m, 5 H), 3.80–4.10 (m, 5 H), 4.23 (q, J=7.0 Hz, 2 H), 6.58 (d, J=7.8 Hz, 1 H), 6.62 (d, J=8.4 Hz, 1 H), 6.86 (dd, J=8.4, 7.8 Hz, 1 H), 6.98 (d, J=8.6 Hz, 2 H), 7.77 (d, J=8.6 Hz, 2 H), 10.60 (s, 1 H), 10.75 (s, 1 H); MS (ES) m/z: 455.1 (MH+); HRMS Calcd. for C24H30N4O5(MH+): 454.2216. Found: 454.2211.
Reaction SMILES: Br.[Br:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[CH:8][NH:9][CH:10]=[CH:11][CH:12]=1.[C:13](=O)([O-])[O-:14].[K+].[K+]>O.C(OC)=O>[CH:13]([N:9]1[CH:10]=[CH:11][CH:12]=[C:6]([O:5][CH2:4][CH2:3][Br:2])[CH:7]=[CH:8]1)=[O:14]
Reactant: O=C([O-])[O-]
Reactant: BrCCOC1=CC=CNC=C1
Agent: Br
Agent: [K+]
Solvent: O
Solvent: COC=O
Product: O=CN1C=CC=C(OCCBr)C=C1
Reaction time: 24 h

Procedure:
To a solution of (D) (10 g) in water (5 ml), methyl formate (50 ml) and potassium carbonate (10 g) were added. The mixture was stirred for 24 hours, and the organic phase was decanted. The residue was extracted twice with methyl formate. The combined organic solutions were concentrated in vacuo, and the residue was dissolved in ether, dried and chromatographed on silica gel (50 g) with ether as eluent to give (E) as a colourless oil. The IR spectrum (chloroform) showed a strong band at 1650 cm-1.
Reaction SMILES: CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH:25]1[CH:29]=[CH:28][N:27]=[C:26]1[C:30]1[C:38]2[C:33](=[N:34][CH:35]=[CH:36][CH:37]=2)[N:32]([CH2:39][C:40]([OH:42])=O)[N:31]=1.Cl.Cl.[Cl:45][C:46]1[C:51]([O:52][CH2:53][CH3:54])=[CH:50][C:49]([N:55]2[CH2:60][CH2:59][NH:58][CH2:57][CH2:56]2)=[C:48]([F:61])[CH:47]=1.CCN(C(C)C)C(C)C>>[Cl:45][C:46]1[C:51]([O:52][CH2:53][CH3:54])=[CH:50][C:49]([N:55]2[CH2:60][CH2:59][N:58]([C:40](=[O:42])[CH2:39][N:32]3[C:33]4=[N:34][CH:35]=[CH:36][CH:37]=[C:38]4[C:30]([C:26]4[NH:25][CH:29]=[CH:28][N:27]=4)=[N:31]3)[CH2:57][CH2:56]2)=[C:48]([F:61])[CH:47]=1
Reactant: O=C(O)Cn1nc(-c2ncc[nH]2)c2cccnc21
Reactant: CCOc1cc(N2CCNCC2)c(F)cc1Cl
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CCOc1cc(N2CCN(C(=O)Cn3nc(-c4ncc[nH]4)c4cccnc43)CC2)c(F)cc1Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
(Protocol A—the HBTU coupling procedure) A solution of [3-(1H-imidazol-2-yl)-pyrazolo[3,4-b]pyridin-1-yl]acetic acid (0.30 M, 0.40 mL, 0.12 mmol) was transferred to a vial. 1-(4-Chloro-5-ethoxy-2-fluorophenyl)piperazine dihydrochloride (48 mg, 0.14 mmol), O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HBTU) (55 mg, 0.14 mmol) and i-Pr2NEt (0.30 mL) were added to the vial and the mixture was stirred at ambient temperature. After 30 minutes, LC/MS analysis indicated formation of desired product and complete consumption of the carboxylic acid starting material. The mixture was diluted with EtOAc, washed with water (1×) and brine (1×), dried over Na2SO4 and evaporated. The residue was purified by silica gel chromatography (1% to 8% MeOH in CH2Cl2) to provide 1-[4-(4-chloro-5-ethoxy-2-fluorophenyl)piperazin-1-yl]-2-[3-(1H-imidazol-2-yl)pyrazolo[3,4-b]pyridin-1-yl]ethanone as a tan solid: 1H NMR (CDCl3, 400 MHz) δ 8.79 (dd, 0.6H, J=8.4, 1.6 Hz), 8.66 (dd, 0.4H, J=8.0, 1.6 Hz), 8.57-8.55 (m, 1H), 7.29-7.26 (m, 1H), 7.22-7.16 (m, 1H), 7.09-7.05 (m, 2H), 6.50-6.45 (m, 2H), 5.45 (s, 0.6H), 5.43 (s, 1.4H), 4.07-4.01 (m, 2H), 3.81-3.69 (m, 4H), 3.17-3.13 (m, 1.6H), 3.08-3.02 (m, 2.4H), 1.50-1.42 (m, 3H); LC/MS m/z (M+H)+ 484.4.