Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:3]([CH3:24])[C:4](=[O:23])[C:5]2([C:15]3[C:10](=[CH:11][CH:12]=[C:13](Br)[CH:14]=3)[O:9][CH:8]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:7]2)[N:6]=1.[S:25]1[CH:29]=[CH:28][CH:27]=[C:26]1B(O)O.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH2:1][C:2]1[N:3]([CH3:24])[C:4](=[O:23])[C:5]2([C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:26]4[S:25][CH:29]=[CH:28][CH:27]=4)[CH:14]=3)[O:9][CH:8]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:7]2)[N:6]=1
Reactant: OB(O)c1cccs1
Reactant: CN1C(=O)C2(CC(c3ccccc3)Oc3ccc(Br)cc32)N=C1N
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: CN1C(=O)C2(CC(c3ccccc3)Oc3ccc(-c4cccs4)cc32)N=C1N
Temperature: 120 °C
Reaction time: 0.58 h
Yield: 4.5 %

Procedure:
A mixture of 2′-amino-6-bromo-1′-methyl-2-phenylspiro[chroman-4,4′-imidazol]-5′(1′H)-one (21 mg, 0.05 mmol), thiophen-2-ylboronic acid (14 mg, 0.1 mmol), Cs2CO3 solution (2 M, 0.5 mL) and Pd(PPh3)2Cl2 (10 mg) in 1,4-dioxane (1 mL) was stirred in a microwave test tube under Ar at 120° C. for 35 minutes. The reaction mixture was concentrated in vacuo to give the residue, which was purified by preparative TLC to give 2′-amino-1′-methyl-2-phenyl-6-(thiophen-2-yl)spiro[chroman-4,4′-imidazol]-5′-(1′H)-one (0.87 mg, 4%). 1H-NMR (MeOD): 2.45-2.54 (M, 1H), 2.60-2.63 (m, 1H), 3.32 (s, 3H), 5.88 (d, 1H), 7.06-7.14 (m, 2H), 7.33-7.39 (m, 2H), 7.41-7.50 (m, 3H), 7.51-7.64 (m, 4H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13]#[CH:14])[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].Br[C:16]1[S:17][CH:18]=[C:19]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[N:20]=1>CN(C=O)C.C(N(CC)CC)C.C(OCC)(=O)C.[Cu](I)I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:12][O:11][C:7]1[CH:6]=[C:5]([C:13]#[C:14][C:16]2[S:17][CH:18]=[C:19]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[N:20]=2)[CH:4]=[C:3]([O:2][CH3:1])[C:8]=1[O:9][CH3:10]
Reactant: C#Cc1cc(OC)c(OC)c(OC)c1
Reactant: CCOC(=O)c1csc(Br)n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1csc(C#Cc2cc(OC)c(OC)c(OC)c2)n1
Temperature: 45 °C
Reaction time: 4 h

Procedure:
3,4,5-Trimethoxyphenylacetylene (1.34 g), ethyl 2-bromothiazole-4-carboxylate (1.98 g) and copper iodide (53 mg) were dissolved in a mixed solvent of DMF (3 mL) and triethylamine (6 mL), and to the solution dichlorobis-(triphenylphosphine)palladium (II) (99 mg) was added, and the mixture was stirred at 45° C. for 4 hours under an argon atmosphere. The reaction mixture was diluted with ethyl acetate, washed with 2 M hydrochloric acid, water and saturated brine, dried over anhydrous sodium sulfate. After concentrating the reaction mixture under reduced pressure, the residue was purified by column chromatography on silica gel (hexane:ethyl acetate=4:1 to 3:1) to obtain the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:18](Cl)=[N:17][S:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N:20]1[CH:25]=[CH:24][C:23]([CH2:26][OH:27])=[CH:22][CH:21]=1.C(C(CCC)[O-])(C)(C)C.[K+].C(O)(C)(C)C>CCOC(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:18]([O:27][CH2:26][C:23]3[CH:24]=[CH:25][N:20]=[CH:21][CH:22]=3)=[N:17][S:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCN(c2nsnc2Cl)CC1
Reactant: OCc1ccncc1
Agent: CCCC([O-])C(C)(C)C
Agent: [K+]
Solvent: CC(C)(C)O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCN(c2nsnc2OCc2ccncc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 57 %

Procedure:
4-(4-Chloro-[1,2,5]thiadiazol-3-yl)-piperazine-1-carboxylic acid tert-butyl ester (10.0 g, 33 mmol), pyridin-4-yl-methanol (6.9 g, 63 mmol) and a solution of 1M potassium tert-butyl butoxide in tert-butyl alcohol (60.0 mL, 60 mmol) were combined and stirred at room temperature overnight. The reaction mixture is diluted with EtOAc and washed with H2O (3×), sat'd NaCl (1×), dried (Na2SO4), and concentrated in vacuo. The crude product is purified by column chromatography (4:1 hexanes:EtOAc, followed by 1:1 hexanes:EtOAc) to give 7.1 g (57%) of 4-[4-(pyridin-4-ylmethoxy)-[1,2,5]thiadiazol-3-yl]-piperazine-1-carboxylic acid tert-butyl ester. 1H NMR (CDCl3) 8.65 (d, 2H), 7.32 (d, 2H), 5.49 (s, 2H), 3.55 (m, 8H) 1.48 (s, 9H) ppm. LC-MS (MH+)=378.
Reaction SMILES: [OH:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[C:4]([CH2:6][CH2:7][C:8]([O:10][CH3:11])=[O:9])=[O:5].C(=O)([O-])[O-].[K+].[K+].[CH2:22]([CH:24]1[O:26][CH2:25]1)Br>CC(CC)=O>[O:26]1[CH2:25][CH:24]1[CH2:22][O:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[C:4]([CH2:6][CH2:7][C:8]([O:10][CH3:11])=[O:9])=[O:5]
Reactant: COC(=O)CCC(=O)c1ccccc1O
Reactant: BrCC1CO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: COC(=O)CCC(=O)c1ccccc1OCC1CO1
Yield: 104.7 %

Procedure:
A well stirred mixture of methyl 3-(2-hydroxybenzoyl)propionate (63.3 g, 0.3 mole), potassium carbonate (48.4 g, 0.35 mole), epibromohydrin (117 ml, 1.4 mole), and dry ethyl methyl ketone (2000 ml) was heated under reflux for 28 hours. Evaporation of the filtered solution under reduced pressure gave methyl 3-[2-(2,3-epoxypropoxy)benzoyl]propionate (83 g, 100%).
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([N:8]1[CH2:14][CH2:13][C:12]2=[CH:15][N:16]([C:18]3[CH:26]=[CH:25][C:21]([C:22]([OH:24])=O)=[CH:20][CH:19]=3)[N:17]=[C:11]2[CH2:10][CH2:9]1)=[O:7])([CH3:4])[CH3:3].O=C(N1C=CN=C1)N1C=CN=C1.C1(C)C=CC=CC=1.O[NH:47]/[C:48](=[N:50]\[H])/[CH3:49]>ClCCl>[CH3:49][C:48]1[N:50]=[C:22]([C:21]2[CH:20]=[CH:19][C:18]([N:16]3[CH:15]=[C:12]4[C:11]([CH2:10][CH2:9][N:8]([C:6]([O:5][C:2]([CH3:3])([CH3:4])[CH3:1])=[O:7])[CH2:14][CH2:13]4)=[N:17]3)=[CH:26][CH:25]=2)[O:24][N:47]=1
Reactant: CC(C)(C)OC(=O)N1CCc2cn(-c3ccc(C(=O)O)cc3)nc2CC1
Reactant: [H]/N=C(/C)NO
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: Cc1noc(-c2ccc(-n3cc4c(n3)CCN(C(=O)OC(C)(C)C)CC4)cc2)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of 4-[6-{[(1,1-dimethylethyl)oxy]carbonyl}-5,6,7,8-tetrahydropyrazolo[3,4-d]azepin-2(4H)-yl]benzoic acid (may be prepared as described in Description 23) (185 mg, 0.52 mmol) in dichloromethane (10 ml) was added 1,1′-(oxomethanediyl)bis-1H-imidazole (168 mg, 1.04 mmol) and the reaction stirred at room temperature, under argon, overnight. The solvent was evaporated in vacuo. Toluene (5 ml) and then (1Z)-N-hydroxyethanimidamide (may be prepared as described in Description 30) (116 mg, 1.56 mmol) were added and the reaction mixture heated, under argon, at reflux overnight. A further 2 eq. of 1,1′-(oxomethanediyl)bis-1H-imidazole was added and stirring continued for a further 40 minutes. A further 3 eq. of (1Z)-N-hydroxyethanimidamide was added and stirring continued for a further 3 hours. The reaction was cooled to room temperature and the solvent evaporated in vacuo. The resulting crude mixture was diluted with dichloromethane and water, and extracted into dichloromethane (×2). The combined organic fractions were washed with water (×1), dried over magnesium sulphate and solvent evaporated in vacuo to afford the title compound (D34). MS (ES+) m/e 340 [M-tBu]+.
Reaction SMILES: [CH3:1][O:2]/[N:3]=[C:4](/[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)\[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][OH:14])=[CH:9][CH:8]=1.[C:21]([CH2:23][C:24]1[CH:29]=[C:28](O)[CH:27]=[CH:26][C:25]=1[CH2:31][CH2:32][C:33]([O:35]C)=[O:34])#[N:22]>>[C:21]([CH2:23][C:24]1[CH:29]=[C:28]([O:14][CH2:13][C:10]2[CH:11]=[CH:12][C:7]([O:6][CH2:5]/[C:4](=[N:3]\[O:2][CH3:1])/[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:8][CH:9]=2)[CH:27]=[CH:26][C:25]=1[CH2:31][CH2:32][C:33]([OH:35])=[O:34])#[N:22]
Reactant: CO/N=C(\COc1ccc(CO)cc1)c1ccccc1
Reactant: COC(=O)CCc1ccc(O)cc1CC#N
Product: CO/N=C(\COc1ccc(COc2ccc(CCC(=O)O)c(CC#N)c2)cc1)c1ccccc1
Yield: 71 %

Procedure:
Compound 44 was synthesized from (1Z)-2-[4-(hydroxymethyl)-phenoxy]-1-phenylethanone O-methyloxime (0.3 g, 1.28 mmol) and methyl 3-[2-(cyanomethyl)-4-hydroxyphenyl]propanoate (0.348 g, 1.28 mmol) by following the procedure described in scheme 18 (0.1 g, yield: 71.00%); Purity: 92.72%.
Reaction SMILES: [CH:1]1([C:4]([O:6]CC)=O)[CH2:3][CH2:2]1.[C:9]([O:12][CH2:13][CH3:14])(=[O:11])[CH3:10]>>[CH:1]1([C:4](=[O:6])[CH2:10][C:9]([O:12][CH2:13][CH3:14])=[O:11])[CH2:2][CH2:3]1
Reactant: CCOC(=O)C1CC1
Reactant: CCOC(C)=O
Product: CCOC(=O)CC(=O)C1CC1

Procedure:
A solution of 2.59 g of 1-amino-3-cyclopropyl-3-p-trifluoromethylphenoxy-propane (obtainable by a condensation reaction of ethyl cyclopropanecarboxylate with ethyl acetate to give ethyl 3-cyclopropyl-propan-3-on-1-oate; reduction of the latter to ethyl 3-cyclopropyl-propan-3-ol-1-oate; reaction of the latter with p-trifluoromethylphenol analogously to Example 3, to give ethyl 3-cyclopropyl-3-p-trifluoromethylphenoxy-propanoate; reaction with NH3 to give the amide; and reduction of the latter with LiAlH4) and 1.5 g of benzaldehyde in 25 ml of toluene is boiled for one hour under a water separator. The solution of the resulting 1-benzylideneamino-3-cyclopropyl-3-p-trifluoromethylphenoxy-propane is heated with 5 g of methyl iodide for 12 hours at 150° in a tube and then evaporated. The resulting quaternary salt is boiled for 10 minutes in 90% ethanol. The mixture is again evaporated, the residue is taken up in dilute hydrochloric acid and the benzaldehyde which has been split off is removed by extraction with ether. The acid, aqueous solution is rendered alkaline with sodium hydroxide solution and worked up in the customary manner. 1-Methylamino-3-cyclopropyl-3-p-trifluoromethylphenoxypropane is obtained. Rf 0.22 (A).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][C:17]([NH2:20])=[C:16]([C:21]3[CH2:22][CH2:23][S:24][CH2:25][CH:26]=3)[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[K+].[C:28]([C:30]1[N:31]=[C:32]([C:43]([O-])=[O:44])[N:33]([CH2:35][O:36][CH2:37][CH2:38][Si:39]([CH3:42])([CH3:41])[CH3:40])[CH:34]=1)#[N:29].C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.CCOC(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:43]([C:32]3[N:33]([CH2:35][O:36][CH2:37][CH2:38][Si:39]([CH3:42])([CH3:41])[CH3:40])[CH:34]=[C:30]([C:28]#[N:29])[N:31]=3)=[O:44])=[C:16]([C:21]3[CH2:26][CH2:25][S:24][CH2:23][CH:22]=3)[CH:15]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C[Si](C)(C)CCOCn1cc(C#N)nc1C(=O)[O-]
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(N)c(C3=CCSCC3)c2)CC1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(NC(=O)c3nc(C#N)cn3COCC[Si](C)(C)C)c(C3=CCSCC3)c2)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 85 %

Procedure:
To a mixture of 4-[4-amino-3-(3,6-dihydro-2H-thiopyran-4-yl)-phenyl]-piperidine-1-carboxylic acid tert-butyl ester (as prepared in the previous step, 45 mg, 0.12 mmol), potassium 4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylate (as prepared in Example 3, step (d), 44 mg, 0.144 mmol) and PyBroP (67 mg, 0.144 mmol) in 2 mL of DMF was added DIEA (42 μL, 0.24 mmol). The resulting mixture was stirred at RT for 4 h under Ar. Treated with 30 mL of EtOAc, the mixture was washed with H2O (3×10 mL), brine (10 mL) and dried (Na2SO4). Removal of the solvent under reduced pressure followed by flash chromatography of the residue on silica gel (1-2% EtOAc/DCM) gave 64 mg (85%) of the title compound as a light yellow oil. 1H-NMR (CDCl3; 400 MHz): δ 9.51 (s, 1H), 8.21 (d, 1H, J=8.5 Hz), 7.78 (s, 1H), 7.16 (dd, 1H, J=8.5, 2.1 Hz), 7.02 (d, 1H, J=2.1 Hz), 6.00 (m, 1H), 5.92 (s, 2H), 4.25 (br s, 2H), 3.66 (t, 2H, J=8.2), 3.42 (m, 2H), 2.93 (dd, 2H, J=5.7, 5.7 Hz), 2.79 (m, 2H), 2.63 (dddd, 1H, J=12.3, 12.3, 3.3, 3.3 Hz), 2.49-2.56 (m, 2H), 1.82(d, 2H, J=12.8 Hz), 1.56-1.66 (m, 2H), 1.49 (s, 9H), 0.97 (t, 2H, J=8.2 Hz), 0.00 (s, 9H).
Reaction SMILES: [OH:1][CH2:2][C:3]1[C:4]([I:20])=[C:5]([C:7]([I:19])=[C:8]([C:11]([NH:13][CH2:14][CH:15]([OH:18])[CH2:16][OH:17])=[O:12])[C:9]=1[I:10])[NH2:6].C(Cl)Cl>C(OC(=O)C)(=O)C.N1C=CC=CC=1>[C:2]([O:1][CH2:2][C:3]1[C:4]([I:20])=[C:5]([C:7]([I:19])=[C:8]([C:11]([NH:13][CH2:14][CH:15]([O:18][C:16](=[O:17])[CH3:15])[CH2:16][O:17][C:11](=[O:12])[CH3:8])=[O:12])[C:9]=1[I:10])[NH2:6])(=[O:1])[CH3:3]
Reactant: Nc1c(I)c(CO)c(I)c(C(=O)NCC(O)CO)c1I
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: CC(=O)OC(C)=O
Product: CC(=O)OCc1c(I)c(N)c(I)c(C(=O)NCC(COC(C)=O)OC(C)=O)c1I
Temperature: 25 °C
Reaction time: 24 h

Procedure:
3-Hydroxymethyl-5-(2,3-dihydroxypropylaminocarbonyl)-2,4,6-triiodoaniline (1.89 g, 3.06 mmol) prepared according to Example 3d, was dissolved in a mixture of acetic anhydride (5 ml) and pyridine (5 ml). The mixture was stirred at room temperature for 24 h, CH2Cl2 (100 ml) was added and the solution was washed with water (3×25 ml), with a saturated aqueous solution of NaHCO3, dried (Na2SO4) and evaporated. The product was purified by flash chromatography on silica-gel using a mixture of CH2Cl2 and methanol (98:2) as the eluent.
Reaction SMILES: [CH3:1][S:2]([NH2:5])(=[O:4])=[O:3].Cl[C:7]1(Cl)[O:11][C:10]2[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=2[O:8]1.C(OCC)(=O)C>C1C=CC=CC=1>[CH3:1][S:2]([N:5]=[C:7]1[O:11][C:10]2[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=2[O:8]1)(=[O:4])=[O:3]
Reactant: ClC1(Cl)Oc2ccccc2O1
Reactant: CS(N)(=O)=O
Solvent: c1ccccc1
Solvent: CCOC(C)=O
Product: CS(=O)(=O)N=c1oc2ccccc2o1
Temperature: 25 °C
Yield: 83.2 %

Procedure:
53.4 g of methanesulfonamide and 89.4 g of 2,2-dichloro-1,3-benzodioxole were heated under reflux with 400 ml of anhydrous ethyl acetate for 7 hours. After cooling, the solvent was removed by distillation under reduced pressure. To the residue thus obtained was added 200 ml of benzene, and the mixture was refluxed for 10 minutes and then cooled slowly to room temperature with stirring. The crystals deposited were collected by filtration and washed with benzene, water and 2-propanol in this order to obtain 83 g (yield: 83%) of 2-methanesulfonylimino-1,3-benzodioxole.
Reaction SMILES: C(N(CC)CC)C.C(Cl)Cl.[CH:11]1([CH2:14][N:15]2[C:23]([N:24]3[CH2:29][CH2:28][NH:27][C@@H:26]([CH3:30])[CH2:25]3)=[N:22][C:21]3[C:16]2=[N:17][C:18]([C:37]2[CH:38]=[N:39][C:40]([NH2:43])=[N:41][CH:42]=2)=[N:19][C:20]=3[N:31]2[CH2:36][CH2:35][O:34][CH2:33][CH2:32]2)[CH2:13][CH2:12]1.[C:44](OC(=O)C)(=[O:46])[CH3:45]>C(Cl)Cl.CO>[C:44]([N:27]1[CH2:28][CH2:29][N:24]([C:23]2[N:15]([CH2:14][CH:11]3[CH2:13][CH2:12]3)[C:16]3[C:21]([N:22]=2)=[C:20]([N:31]2[CH2:36][CH2:35][O:34][CH2:33][CH2:32]2)[N:19]=[C:18]([C:37]2[CH:42]=[N:41][C:40]([NH2:43])=[N:39][CH:38]=2)[N:17]=3)[CH2:25][C@@H:26]1[CH3:30])(=[O:46])[CH3:45]
Reactant: C[C@H]1CN(c2nc3c(N4CCOCC4)nc(-c4cnc(N)nc4)nc3n2CC2CC2)CCN1
Reactant: CC(=O)OC(C)=O
Solvent: CO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)N1CCN(c2nc3c(N4CCOCC4)nc(-c4cnc(N)nc4)nc3n2CC2CC2)C[C@@H]1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 98 %

Procedure:
Triethylamine (80.3 μl, 0.58 mmol) was added to a methylene chloride solution (3.0 ml) of 5-{9-(cyclopropylmethyl)-8-[(3S)-3-methylpiperazin-1-yl]-6-morpholin-4-yl-9H-purin-2-yl}pyrimidin-2-amine (108.1 mg, 0.24 mmol) at room temperature followed by the addition of acetic anhydride (27.2 μl, 0.29 mmol) with ice cooling. The resulting mixture was stirred at room temperature for 2 hours and then the reaction mixture was poured into methylene chloride-methanol (10:1), washed with water, and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure and the resulting residue was purified by medium pressure silica gel column chromatography (methylene chloride:methanol=49:1 to 19:1) to give the title compound (115.8 mg, 98%) as a pale yellow solid.
Reaction SMILES: F[P-](F)(F)(F)(F)F.[N:8]1(O[P+](N(C)C)(N(C)C)[N:19]([CH3:21])[CH3:20])[C:12]2[CH:13]=CC=C[C:11]=2N=N1.C[CH2:29][N:30](C(C)C)[CH:31]([CH3:33])[CH3:32].N[C@H](C(O)=O)[C@@H](C)O.[NH2:45][C@H:46](C(O)=O)[CH2:47][C:48]1C=CC(O)=[CH:50][CH:49]=1>>[CH3:13][CH:12]([CH3:11])[N:8]=[C:29]=[N:30][CH:31]([CH3:33])[CH3:32].[CH3:20][N:19]([C:48]1[CH:49]=[CH:50][N:45]=[CH:46][CH:47]=1)[CH3:21]
Reactant: N[C@@H](Cc1ccc(O)cc1)C(=O)O
Reactant: CCN(C(C)C)C(C)C
Reactant: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: C[C@@H](O)[C@H](N)C(=O)O
Agent: F[P-](F)(F)(F)(F)F
Product: CC(C)N=C=NC(C)C
Product: CN(C)c1ccncc1

Procedure:
Ester bond between the pipecolic handle and side chain of amino acids was formed by using BOP/DIEA coupling for 90 minutes. Loading was determined by Fmoc titration on aliquots of resins 12, 14 and 18 for Thr, Ser and Tyr-functionalized resins, respectively (Table 3). Surprisingly, use of DIC/DMAP activation didn't give better result than BOP/DIEA mediated esterification. In a general manner, alcohol immobilization was less efficient than amine loading, according to Fmoc titration results, even when a negative malachite green test was observed. In particular with resins 12 and 14, obtained by the esterification of Fmoc-Thr-OMe and Fmoc-Ser-OMe side chains, experimental loadings were only 0.30 mmol/g and 0.32 mmol/g (i.e. 43% and 44% yield compared to maximum theoretical loading of 0.70 mmol/g). This result has to be put in perspective with the difficulty of loading primary alcohols on trityl-based resins giving experimental loading yields lower than 20% when compared to theoretical maximum loading (Barlos et al., 1988).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][C:10]1[N:14]2[CH:15]=[C:16]([F:19])[CH:17]=[CH:18][C:13]2=[N:12][C:11]=1[C:20]1[CH:28]=[CH:27][CH:26]=[CH:25][C:21]=1[C:22](O)=[O:23].[C:29]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])(=[O:32])[NH:30][NH2:31].CCN=C=NCCCN(C)C.Cl.O>CN(C=O)C>[CH3:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[C:3]=1[NH:9][C:10]1[N:14]2[CH:15]=[C:16]([F:19])[CH:17]=[CH:18][C:13]2=[N:12][C:11]=1[C:20]1[CH:28]=[CH:27][CH:26]=[CH:25][C:21]=1[C:22]([NH:31][NH:30][C:29]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])=[O:23]
Reactant: Cc1cccc(C)c1Nc1c(-c2ccccc2C(=O)O)nc2ccc(F)cn12
Reactant: CC(C)(C)OC(=O)NN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cccc(C)c1Nc1c(-c2ccccc2C(=O)NNC(=O)OC(C)(C)C)nc2ccc(F)cn12
Temperature: 25 °C
Reaction time: 5 h
Yield: 57 %

Procedure:
2.2 250 mg (0.666 mmol) of 2-[3-(2,6-dimethylphenylamino)-6-fluoroimidazo[1,2-a]pyridin-2-yl]benzoic acid, 88 mg (0.666 mmol) of tert-butyl carbazate, 153 mg (0.800 mmol) of N-(3-dimethylaminopropyl)-N-ethylcarbodiimide hydrochloride (DAPECI) are dissolved in 1 ml of DMF and stirred at RT for 5 hours. The mixture is subsequently added to water, the precipitated solid is filtered off with suction and dried, giving 187 mg (57%) of tert-butyl N′-{2-[3-(2,6-dimethylphenylamino)-6-fluoroimidazo[1,2-a]-pyridin-2-yl]benzoyl}hydrazinecarboxylate as solid; MS-FAB (M+H+)=490.8; Rf (HPLC, polar method): 1.47 min. This is employed in the next step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([N+:11]([O-:13])=[O:12])=[C:8](Br)[CH:9]=1)=[O:4].CCN(CC)CC.[Br:21][C:22]1[CH:23]=[C:24]([SH:28])[CH:25]=[CH:26][CH:27]=1>C1COCC1>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([N+:11]([O-:13])=[O:12])=[C:8]([S:28][C:24]2[CH:25]=[CH:26][CH:27]=[C:22]([Br:21])[CH:23]=2)[CH:9]=1)=[O:4]
Reactant: COC(=O)c1cc(Br)c([N+](=O)[O-])s1
Reactant: Sc1cccc(Br)c1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)c1cc(Sc2cccc(Br)c2)c([N+](=O)[O-])s1
Yield: 99.8 %

Procedure:
4-Bromo-5-nitro-thiophene-2-carboxylic acid methyl ester ((Example 114, step c) 1 g, 3.75 mmol) and Et3N (523 μL, 3.75 mmol) were dissolved with THF (10 mL) into a round bottom flask with stir bar. To this 3-bromothiophenol (467 μL, 4.51 mmol) was added with stirring. The reaction became turbid therefore additional THF (12 mL) was added. The reaction was stirred at rt for 12 hours. The reaction mixture was concentrated in vacuo and then dissolved into EtOAc. The organic layer was washed several times with saturated NaHCO3 and brine. The combined organic layers were dried over sodium sulfate. Removal of the solvents in vacuo yielded the title compound (1.40 g, quantitative yield), which was used without further purification. 1H-NMR (CDCl3): δ 7.79 (t, 1H, J=1.8 Hz), 7.67–7.70 (m, 1H), 7.54–7.85 (m, 1H), 7.37–7.41 (t, 1H, J=7.9 Hz), 6.87 (s, 1H), 3.88 (s, 1H).
Reaction SMILES: [H-].[Na+].[CH:3]([C:6]1[C:7]([O:18][CH3:19])=[CH:8][C:9]([CH3:17])=[C:10]([CH2:12][C:13]([O:15][CH3:16])=[O:14])[CH:11]=1)([CH3:5])[CH3:4].[Cl:20][CH2:21][CH2:22][CH2:23]I.C(OCC)(=O)C>CN(C)C=O>[Cl:20][CH2:21][CH2:22][CH2:23][CH:12]([C:10]1[CH:11]=[C:6]([CH:3]([CH3:5])[CH3:4])[C:7]([O:18][CH3:19])=[CH:8][C:9]=1[CH3:17])[C:13]([O:15][CH3:16])=[O:14]
Reactant: COC(=O)Cc1cc(C(C)C)c(OC)cc1C
Reactant: ClCCCI
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)C(CCCCl)c1cc(C(C)C)c(OC)cc1C
Temperature: 5 °C
Reaction time: 0.08 h

Procedure:
60% sodium hydride (928 mg) was suspended in anhydrous N,N-dimethylformamide (50 mL). A solution of methyl (5-isopropyl-4-methoxy-2-methylphenyl)acetate (5 g) in anhydrous N,N-dimethylformamide (30 mL) was added in a nitrogen atmosphere, so that the internal temperature was maintained at 4 to 6° C. After stirring at the same temperature for five minutes, 1-chloro-3-iodopropane (4.5 mL) was added so that the internal temperature was maintained at 4 to 6° C. After addition of the reagent, the mixture was brought back to room temperature and stirred for four hours. Ethyl acetate was added to the reaction solution, followed by washing with water. The resulting organic layer was washed with brine and then dried over anhydrous sodium sulfate. The drying agent was separated by filtration, and then the organic layer was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound (7.7 g). The property values of the compound are as follows.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH2:7]Br)([O-:3])=[O:2].[NH:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1>C1COCC1>[N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH2:7][N:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1cccc(CBr)c1
Reactant: C1CCNC1
Solvent: C1CCOC1
Product: O=[N+]([O-])c1cccc(CN2CCCC2)c1

Procedure:
To a solution of 3-nitrobenzylbromide (3 g, 13.9 mmol) in anhydrous THF (30 ml) was added a solution of pyrrolidine (2.3 ml, 27.8 mmol) in anhydrous THF (10 ml) dropwise with stirring. Following the addition the mixture was stirred at ambient temperature overnight. The reaction mixture was filtered, The filter cake was washed with a small volume of anhydrous THF and the filtrate was concentrated to leave the intermediate 1-(3-nitrobenzyl)pyrrolidine as an oil. This oil was dissolved in methanol (50 ml) and three equivalents of both ammonium chloride and sodium sulfide nonahydrate were added. The mixture was heated to reflux for 2 hours. After cooling the mixture was filtered. The filtercake was washed with methanol and the filtrate was concentrated under reduced pressure. The residue was dissolved in ethyl acetate and dried over sodium sulfate. Filtration and evaporation of solvent left 2i quantitatively as yellow crystals.
Reaction SMILES: [CH:1]1([OH:6])[CH2:5][CH2:4][CH2:3][CH2:2]1.[SH:7][CH2:8][CH2:9][C:10](O)=[O:11].C1(C)C=CC(S(O)(=O)=O)=CC=1>>[CH:1]1([O:6][C:10](=[O:11])[CH2:9][CH2:8][SH:7])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)CCS
Reactant: OC1CCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: O=C(CCS)OC1CCCC1
Reaction time: 8 h

Procedure:
Into a 1 liter reaction flask equipped with heating mantle, stirrer, thermometer and reflux condenser are placed 172 grams of cyclopentanol; 265 grams of 3-mercaptopropionic acid and 0.5 grams of paratoluene sulfonic acid. The reaction mass is heated to reflux and reflux is continued for a period of 8 hours. At the end of the 8 hour period, the reaction mass is fractionally distilled on a 2" splash column yielding the following fractions: