Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[O:12][C:11]2[CH:10]=[CH:9][C:5]([CH2:6][CH2:7][NH2:8])=[CH:4][C:3]=2[O:2]1.Cl[C:14]1[C:15]2[C:28]([CH3:29])=[CH:27][S:26][C:16]=2[N:17]=[C:18]([C:20]2[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=2)[N:19]=1>>[N:23]1[CH:22]=[CH:21][C:20]([C:18]2[N:19]=[C:14]([NH:8][CH2:7][CH2:6][C:5]3[CH:9]=[CH:10][C:11]4[O:12][CH2:1][O:2][C:3]=4[CH:4]=3)[C:15]3[C:28]([CH3:29])=[CH:27][S:26][C:16]=3[N:17]=2)=[CH:25][CH:24]=1
Reactant: Cc1csc2nc(-c3ccncc3)nc(Cl)c12
Reactant: NCCc1ccc2c(c1)OCO2
Product: Cc1csc2nc(-c3ccncc3)nc(NCCc3ccc4c(c3)OCO4)c12

Procedure:
With the procedure of Example 1, the reaction of 3,4-methylenedioxyphenethylamine with 4-chloro-2-(pyridin-4-yl)-5-methyl-thieno-[2,3-d]-pyrimidine yields 2-(pyridin-4-yl)-4-(3,4-methylenedioxyphenethylamino)-5-methyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)[CH2:9][NH2:10])=[CH:4][CH:3]=1.[C:18]([O:26][C@@H:27]1[C@H:31]([O:32][C:33](=[O:40])[C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C@@H:30]([C:41]([NH:43][CH2:44][CH3:45])=[O:42])[O:29][C@H:28]1[N:46]1[CH:54]=[N:53][C:52]2[C:47]1=[N:48][C:49]([I:56])=[N:50][C:51]=2Cl)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(O)(C)C>[C:18]([O:26][C@@H:27]1[C@H:31]([O:32][C:33](=[O:40])[C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[C@@H:30]([C:41]([NH:43][CH2:44][CH3:45])=[O:42])[O:29][C@H:28]1[N:46]1[CH:54]=[N:53][C:52]2[C:47]1=[N:48][C:49]([I:56])=[N:50][C:51]=2[NH:10][CH2:9][CH:8]([C:11]1[CH:12]=[CH:13][C:14]([Cl:17])=[CH:15][CH:16]=1)[C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: NCC(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Reactant: CCNC(=O)[C@H]1O[C@@H](n2cnc3c(Cl)nc(I)nc32)[C@H](OC(=O)c2ccccc2)[C@@H]1OC(=O)c1ccccc1
Solvent: CC(C)O
Product: CCNC(=O)[C@H]1O[C@@H](n2cnc3c(NCC(c4ccc(Cl)cc4)c4ccc(Cl)cc4)nc(I)nc32)[C@H](OC(=O)c2ccccc2)[C@@H]1OC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 48.9 %

Procedure:
2,2-Bis(4-chlorophenyl)ethanamine (426 mg, 1.51 mmol) (J. Am. Chem. Soc., 1983, 105(10), 3138) was added to a stirred solution of (2R,3R,4S,5S)-4-(benzoyloxy)-2-(6-chloro-2-iodo-9H-purin-9-yl)-5-[(ethylamino)carbonyl]tetrahydro-3-furanyl benzoate (500 mg, 0.755 mmol) (Preparation 47) in isopropyl alcohol (20 ml) at room temperature. The reaction mixture was stirred at room temperature for 48 hours. The solvent was removed under reduced pressure to give a residue that was purified by column chromatography on silica gel eluting with dichloromethane:methanol:(99:1 by volume). The solvent was removed under reduced pressure to give the title compound (329 mg) as a foam.
Reaction SMILES: Br[C:2]1[CH:15]=[CH:14][C:13]2[O:12][C:11]3[C:6](=[CH:7][C:8]([O:16][CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:9][CH:10]=3)[C@:5]3([CH2:25][O:24][C:23]([NH2:26])=[N:22]3)[C:4]=2[CH:3]=1.C([Sn](CCCC)(CCCC)[C:32]1[CH:37]=[N:36][CH:35]=[CH:34][N:33]=1)CCC.O1CCOCC1>CO.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>[CH2:17]([O:16][C:8]1[CH:9]=[CH:10][C:11]2[O:12][C:13]3[C:4](=[CH:3][C:2]([C:32]4[CH:37]=[N:36][CH:35]=[CH:34][N:33]=4)=[CH:15][CH:14]=3)[C@@:5]3([CH2:25][O:24][C:23]([NH2:26])=[N:22]3)[C:6]=2[CH:7]=1)[C:18]([CH3:19])([CH3:21])[CH3:20]
Reactant: CC(C)(C)COc1ccc2c(c1)[C@]1(COC(N)=N1)c1cc(Br)ccc1O2
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnccn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Solvent: CO
Product: CC(C)(C)COc1ccc2c(c1)[C@]1(COC(N)=N1)c1cc(-c3cnccn3)ccc1O2

Procedure:
A vial was charged with (R)-2′-bromo-7′-(neopentyloxy)-5H-spiro[oxazole-4,9′-xanthen]-2-amine (55.6 mg, 0.133 mmol), tetrakis(triphenylphosphine)palladium (0) (15.40 mg, 0.013 mmol), 2-(tributylstannyl)pyrazine (148 mg, 0.400 mmol), and dioxane (0.7 mL). The vial was sealed under a blanket of Ar gas and placed in a 100° C. oil for 16 h. The mixture was then cooled and filtered through celite. The filtrate was evaporated, and the residue was purified by chromatography on a 12-g Redi-Sep column, eluting with 0-10% MeOH/DCM to give a brown oil. This oil was dissolved in MeOH and filtered through a 2 micron filter, then purified further by reverse-phase HPLC (10-90% CH3CN/H2O with 0.1% TFA). The product containing fractions were combined in saturated aqueous sodium bicarbonate solution with the aid of MeOH. The mixture was extracted with DCM (2×), and the combined organic extracts were dried over sodium sulfate, filtered, and evaporated to give (S)-2′-(neopentyloxy)-7′-(pyrazin-2-yl)-5H-spiro[oxazole-4,9′-xanthen]-2-amine as a white solid. MS m/z=417.2 [M+H]+. Calc'd for C24H25N4O3: 417.19.
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([Cl:8])[N:3]=1.[OH:9][C:10]1[CH:11]=[CH:12][CH:13]=[C:14]2[C:18]=1[C:17](=[O:19])[CH2:16][CH2:15]2>CCOC(C)=O>[Cl:8][C:4]1[CH:5]=[N:6][CH:7]=[C:2]([O:9][C:10]2[CH:11]=[CH:12][CH:13]=[C:14]3[C:18]=2[C:17](=[O:19])[CH2:16][CH2:15]3)[N:3]=1
Reactant: Clc1cncc(Cl)n1
Reactant: O=C1CCc2cccc(O)c21
Solvent: CCOC(C)=O
Product: O=C1CCc2cccc(Oc3cncc(Cl)n3)c21
Yield: 100 %

Procedure:
Using Method DD with 2,6-dichloropyrazine (200 mg, 1.34 mmol) and 7-hydroxyindanone (219 mg, 1.49 mmol), and crystallisation in AcOEt, the title compound was obtained (348 mg). Yield: 100%. 1H NMR (250 MHz, DMSO-d6) δ 2.56-2.61 (m, 2H, H3), 3.16 (t, 2H, H3, J=5.6 Hz), 7.25 (d, 1H, Harom 4, J=7.9 Hz), 7.54 (d, 1H, Harom 6, J=7.6 Hz), 7.78 (t, 1H, Harom 5, J=8.3 Hz), 8.49 (s, 1H, HPz 5), 8.62 (s, 1H, HPz 3). m/z: 261.0 [(M+H)+, calcd for C13H9ClN2O2 260.0].
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@H:9]([NH:16]C(=O)OC(C)(C)C)[CH2:10][CH2:11][S:12]([CH3:15])(=[O:14])=[O:13])[CH:5]=[CH:6][C:7]=1[Cl:8].Cl.O1CCOCC1>C(Cl)Cl.CCOCC>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([C@H:9]([NH2:16])[CH2:10][CH2:11][S:12]([CH3:15])(=[O:14])=[O:13])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CC(C)(C)OC(=O)N[C@H](CCS(C)(=O)=O)c1ccc(Cl)c(Cl)c1
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Solvent: ClCCl
Product: CS(=O)(=O)CC[C@@H](N)c1ccc(Cl)c(Cl)c1
Reaction time: 8 h
Yield: 151.1 %

Procedure:
To a stirred solution of 374 (395 mg, 1.03 mmol) in DCM (5 mL) was added a 4M HCl in dioxane (1.03 mL, 4.13 mmol) and stirring was continued overnight. The mixture was diluted with ether, filtered, dried and concentrated to afford 248 mg (75%) of (R)-1-(3,4-dichlorophenyl)-3-(methylsulfonyl)propan-1-amine hydrochloride (376) as white solid.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH:4]1[CH:10]=[CH:9][N:8]([C:11](=[O:33])[C:12]2[CH:17]=[CH:16][C:15]([NH:18][C:19](=[O:32])[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[CH:14][CH:13]=2)[C:7]2[CH:34]=[CH:35][CH:36]=[CH:37][C:6]=2[S:5]1.C(OC([NH:45][C:46]([CH3:51])([CH3:50])[C:47](O)=[O:48])=O)(C)(C)C.ON1C2C=CC=CC=2N=N1.[ClH:62].CN(C)CCCN=C=NCC.C(=O)([O-])[O-].[K+].[K+]>C(Cl)Cl.O>[ClH:62].[NH2:45][C:46]([CH3:51])([CH3:50])[C:47]([NH:1][CH2:2][CH2:3][CH:4]1[CH:10]=[CH:9][N:8]([C:11](=[O:33])[C:12]2[CH:13]=[CH:14][C:15]([NH:18][C:19](=[O:32])[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)=[CH:16][CH:17]=2)[C:7]2[CH:34]=[CH:35][CH:36]=[CH:37][C:6]=2[S:5]1)=[O:48]
Reactant: CC(C)(C)OC(=O)NC(C)(C)C(=O)O
Reactant: NCCC1C=CN(C(=O)c2ccc(NC(=O)c3ccccc3-c3ccccc3)cc2)c2ccccc2S1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: O
Solvent: ClCCl
Product: CC(C)(N)C(=O)NCCC1C=CN(C(=O)c2ccc(NC(=O)c3ccccc3-c3ccccc3)cc2)c2ccccc2S1

Procedure:
A mixture of Compound 28 as prepared in Example 14 (0.180 g, 0.36 mM), 2-(tert-butoxycarbonylaminoisobutyric acid (0.072 g, 0.36 mM), 1-hydroxybenzotriazole (0.05 g, 0.36 mM) and 1-[3-(dimethyamino)propyl]-3-ethylcarbodiimide hydrochloride (0.169 g, 0.9 mM) in methylene chloride (30 ml) was stirred at room temperature for 6 hours and a saturated potassium carbonate solution was added. Water was added and the layers were separated. The methylene chloride layer was dried (MgSO4), evaporated in vacuo and the resulting semi-solid purified by chromatography. The BOC group was removed with trifluoroacetic acid to give the desired amine. The HCl salt was prepared and recrystallized from methanol/diethyl ether to give the desired product as a white crystalline solid. m/z (MH+)593.
Reaction SMILES: [CH:1]1([N:5]2[C:13]3[C:8](=[CH:9][CH:10]=[C:11]([O:14][CH:15]([F:17])[F:16])[CH:12]=3)[C:7]([C:18]#[N:19])=[CH:6]2)[CH2:4][CH2:3][CH2:2]1.[CH2:20]([Sn:24](I)([CH2:29][CH2:30][CH2:31][CH3:32])[CH2:25][CH2:26][CH2:27][CH3:28])[CH2:21][CH2:22][CH3:23].[Li+].CC([N-]C(C)C)C>C1COCC1>[CH:1]1([N:5]2[C:13]3[C:8](=[CH:9][CH:10]=[C:11]([O:14][CH:15]([F:16])[F:17])[CH:12]=3)[C:7]([C:18]#[N:19])=[C:6]2[Sn:24]([CH2:25][CH2:26][CH2:27][CH3:28])([CH2:29][CH2:30][CH2:31][CH3:32])[CH2:20][CH2:21][CH2:22][CH3:23])[CH2:2][CH2:3][CH2:4]1
Reactant: CCCC[Sn](I)(CCCC)CCCC
Reactant: N#Cc1cn(C2CCC2)c2cc(OC(F)F)ccc12
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1c(C#N)c2ccc(OC(F)F)cc2n1C1CCC1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To 1-cyclobutyl-6-difluoromethoxy-1H-indole-3-carbonitrile (830 mg, 3.17 mmol) in THF (10 mL) was added tributyltin iodide (1.13 mL, 4.04 mmol) and the solution cooled to −78° C. A solution of LDA (1.5M in cyclohexane, 3.4 mL, 5.1 mmol) was added dropwise. After complete addition the bath was removed and the mixture stirred at room temperature for 1 hour. THF was then removed under vacuum and the residue filtered through silica gel using CH2Cl2 as an eluant and the mixture concentrated. The residue was purified by flash chromatography using 30-50% CH2Cl2/hexanes to provide 1-cyclobutyl-6-difluoromethoxy-2-tributylstannanyl-1H-indole-3-carbonitrile as a clear, colorless oil (1.23 g, 70%).
Reaction SMILES: [C:1]1([C:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:21][C:22]([O:24][CH:25]([CH3:27])[CH3:26])=[O:23].C([O-])([O-])=O.[K+].[K+]>C(#N)C>[C:1]1([C:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:8]2[CH2:9][CH2:10][N:11]([CH2:21][C:22]([O:24][CH:25]([CH3:27])[CH3:26])=[O:23])[CH2:12][CH2:13]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1ccc(C(=C2CCNCC2)c2ccccc2)cc1
Reactant: CC(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)OC(=O)CN1CCC(=C(c2ccccc2)c2ccccc2)CC1
Yield: 71.5 %

Procedure:
A mixture of amine 20 (779 mg, 3.12 mmol), isopropyl bromoacetate (575 mg, 3.18 mmol), K2CO3 (1.34 g, 3 eq), and acetonitrile (28 mL) was stirred at reflux overnight. The reaction mixture was filtered, evaporated to dryness, and then chromatographed over silica gel using 5:1 heptane/EtOAc to give 0.78 g of 15d as an oil that crystallized on standing. The structure was confirmed by 1H NMR. (Acetate esters 15b and 15c were similarly prepared.)
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[C:6]([C:7]([N:9]([C:11]2[CH:12]=[N:13][CH:14]=[CH:15][C:16]=2[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[Cl:23])[CH3:10])=[O:8])[CH:5]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3].C(C(C(C([O-])=O)O)O)([O-])=O.[Na+].[K+].CCOC(C)=O>C1COCC1>[Cl:23][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[C:16]1[CH:15]=[CH:14][N:13]=[CH:12][C:11]=1[N:9]([CH3:10])[C:7](=[O:8])[C:6]1[CH:24]=[C:25]([C:27]([F:29])([F:30])[F:28])[CH:26]=[C:4]([CH2:3][OH:2])[CH:5]=1
Reactant: COC(=O)c1cc(C(=O)N(C)c2cnccc2-c2ccccc2Cl)cc(C(F)(F)F)c1
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CN(C(=O)c1cc(CO)cc(C(F)(F)F)c1)c1cnccc1-c1ccccc1Cl
Reaction time: 1 h

Procedure:
To a solution of N-[4-(2-chloro-phenyl)-pyridin-3-yl]-N-methyl-5-trifluoromethyl-isophthalamic acid methyl ester (300 mg, 668 μmol, example 75) in THF (5 mL) was added LiAlH4 (26.6 mg, 702 μmol) at 0° C. The reaction mixture was stirred at this temperature for 1 hour. The reaction mixture was poured on 30 mL aqueous 10% potassium-sodium-tartrate solution and 30 mL EtOAc and the layers were separated. The aqueous layer was extracted a second time with 30 mL EtOAc. The combined organic layers were washed with 30 mL brine, dried over MgSO4, filtered and concentrated under vacuum. The compound was purified by silica gel chromatography using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of n-heptane:EtOAc (100:0 to 0:100). Colorless solid (102 mg, 36%). MS (ESI): m/z=421.092 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[NH:9][C:10]1[N:14]2[CH:15]=[CH:16][CH:17]=[N:18][C:13]2=[N:12][C:11]=1[C:19]1[C:35]([O:36][CH3:37])=[CH:34][C:33]([O:38][CH3:39])=[CH:32][C:20]=1[C:21]([NH:23][NH:24]C(OC(C)(C)C)=O)=[O:22]>Cl.O1CCOCC1>[Cl:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[NH:9][C:10]1[N:14]2[CH:15]=[CH:16][CH:17]=[N:18][C:13]2=[N:12][C:11]=1[C:19]1[C:35]([O:36][CH3:37])=[CH:34][C:33]([O:38][CH3:39])=[CH:32][C:20]=1[C:21]([NH:23][NH2:24])=[O:22]
Reactant: COc1cc(OC)c(-c2nc3ncccn3c2Nc2c(Cl)cccc2Cl)c(C(=O)NNC(=O)OC(C)(C)C)c1
Agent: Cl
Solvent: C1COCCO1
Product: COc1cc(OC)c(-c2nc3ncccn3c2Nc2c(Cl)cccc2Cl)c(C(=O)NN)c1
Yield: 84 %

Procedure:
3.2 120 mg of tert-butyl N′-{2-[3-(2,6-dichlorophenylamino)imidazo[1,2-a]-pyrimidin-2-yl]-3,5-dimethoxybenzoyl}hydrazinecarboxylate are stirred at RT for 1 hour in 3 ml of 4 N HCl in dioxane. The reaction mixture is evaporated, the residue is triturated with a little ethyl acetate and filtered off with suction, giving 90 mg (84%) of 2-[3-(2,6-dichlorophenylamino)imidazo-[1,2-a]pyrimidin-2-yl]-3,5-dimethoxybenzohydrazide as hydrochloride; MS-FAB (M+H+)=474.3; Rf (polar method): 1.33 min.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:10]=[CH:11][C:12]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[N:13][CH:14]=2)[CH:5]=[CH:4][N:3]=1.[C:23]([Si](C)(C)C)#[CH:24]>CN(C=O)C.CCOC(C)=O.[Cu]I>[C:23]([C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:10]=[CH:11][C:12]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[N:13][CH:14]=2)[CH:5]=[CH:4][N:3]=1)#[CH:24]
Reactant: C#C[Si](C)(C)C
Reactant: CC(C)(C)OC(=O)Nc1ccc(Oc2ccnc(Cl)c2)cn1
Agent: [Cu]I
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C#Cc1cc(Oc2ccc(NC(=O)OC(C)(C)C)nc2)ccn1
Temperature: 75 °C
Reaction time: 2 h
Yield: 42.7 %

Procedure:
A solution of tert-butyl (5-((2-chloropyridin-4-yl)oxy)pyridin-2-yl)carbamate (0.70 g, 2.18 mmol) in DMF (5 mL) was sparged with Ar, treated with ethynyltrimethylsilane (0.64 g, 6.55 mmol), TEA (1 mL), copper(I)iodide (0.042 g, 0.22 mmol) and trans dichlorobis(triphenylphosphine)palladium(0) (0.15 g, 0.22 mmol) and heated at 75° C., under Ar, overnight. The mixture was cooled to RT, diluted with EtOAc, the solids removed via filtration through diatomaceous earth and washed with EtOAc and water. The layers of the filtrate were separated, the aqueous layer extracted with EtOAc (2×) and the combined organics were washed with brine, dried over Na2SO4 and concentrated to dryness. The material was dissolved in MeOH (20 mL), treated with K2CO3 (0.7 g), stirred at RT for 2 h, then concentrated to dryness. The residue was treated with EtOAc, sonicated, the solids removed via filtration through diatomaceous earth, washed with EtOAc and the filtrate concentrated to dryness and purified via silica gel chromatography (EtOAc/Hex) to afford tert-butyl (5-((2-ethynylpyridin-4-yl)oxy)pyridin-2-yl)carbamate (0.29 g, 43%). 1H NMR (400 MHz, DMSO-d6): δ 9.96 (s, 1 H), 8.41 (d, J=5.6 Hz, 1 H), 8.18 (d, J=2.8 Hz, 1 H), 7.88 (d, J=9.2 Hz, 1 H), 7.66 (m, 1 H), 7.07 (d, J=2.4 Hz, 1 H), 6.95 (m, 1 H), 4.34 (s, 1 H), 1.46 (s, 9 H); MS (ESI) m/z: 312.1 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]=1[CH:13]=O.C([O-])(=O)C.[NH4+].[N+:20]([CH3:23])([O-:22])=[O:21]>O>[N+:20]([CH:23]=[CH:13][C:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:11]=[CH:12][C:3]=1[O:2][CH3:1])([O-:22])=[O:21]
Reactant: COc1ccc2ccccc2c1C=O
Reactant: C[N+](=O)[O-]
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: O
Product: COc1ccc2ccccc2c1C=C[N+](=O)[O-]
Yield: 95 %

Procedure:
1.52 g of 2-methoxynaphthaldehyde (8.16 mmol), 0.4 g of ammonium acetate (5.19 mmol) and 20 cm3 of nitromethane (96%) are introduced into a 50-cm3 two-necked round-bottomed flask equipped with a condenser. The reaction mixture is heated to reflux for 1 h 30 min while stirring. It becomes yellow. The nitromethane is evaporated off in a rotary evaporator and the residue is then taken up with dichloromethane. Hydrolysis of the ammonium acetate is carried out by pouring the above mixture into water. The aqueous phase is washed twice with CH2Cl2, the organic phase once with water. The latter phase is dried with MgSO4 and the solvent is removed in a rotary evaporator. 1.77 g of yellow crystals (equivalent to 7.73 mmol of the expected product) are then obtained, corresponding to a 95% yield.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([CH2:5][C:6]2[N:7]([CH3:33])[C:8]3[C:13]([N:14]=2)=[C:12]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[N:11]=[C:10]([N:21]2[C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=4[N:23]=[C:22]2[C@H:30]([OH:32])[CH3:31])[N:9]=3)[CH2:2]1.CCN(C(C)C)C(C)C.[C:43](Cl)(=[O:47])[CH:44]([CH3:46])[CH3:45]>C(Cl)Cl>[OH:32][C@@H:30]([C:22]1[N:21]([C:10]2[N:9]=[C:8]3[C:13]([N:14]=[C:6]([CH2:5][CH:3]4[CH2:4][N:1]([C:43](=[O:47])[CH:44]([CH3:46])[CH3:45])[CH2:2]4)[N:7]3[CH3:33])=[C:12]([N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)[N:11]=2)[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[N:23]=1)[CH3:31]
Reactant: C[C@@H](O)c1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CC3CNC3)n(C)c2n1
Reactant: CC(C)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)C(=O)N1CC(Cc2nc3c(N4CCOCC4)nc(-n4c([C@@H](C)O)nc5ccccc54)nc3n2C)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 23.7 %

Procedure:
To a solution of (R)-1-[1-(8-azetidin-3-ylmethyl-9-methyl-6-morpholin-4-yl-9H-purin-2-yl)-1H-benzoimidazol-2-yl]ethanol (57 mg, 0.13 mmol) in DCM (2 mL) was added DIPEA (24 μL, 0.14 mmol) and isobutyryl chloride (14 μL, 0.13 mmol) and the resulting mixture stirred at r.t. for 1 h. The reaction mixture was partitioned between DCM and H2O, the organic phase dried (phase separator) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, MeOH:DCM, 0-8%) affording 860 (16 mg, 24%). LCMS (method I): RT 3.46 min, [M+H]+ 519.3. 1H NMR (DMSO, 400 MHz): δ 7.96-7.95 (1 H, m), 7.70-7.69 (1 H, m), 7.30-7.25 (2 H, m), 5.58-5.57 (1 H, m), 5.39 (1 H, d, J=6.34 Hz), 4.36-4.09 (4 H, brd s), 4.35 (1 H, t, J=8.22 Hz), 4.02 (1 H, t, J=8.79 Hz), 3.95-3.94 (1 H, m), 3.80-3.75 (4 H, m), 3.72 (3 H, s), 3.67 (1 H, dd, J=9.77, 5.28 Hz), 3.24-3.23 (3 H, m), 2.45-2.44 (1 H, m), 1.60 (3 H, d, J=6.49 Hz), 0.98 (3 H, d, J=1.77 Hz), 0.97 (3 H, d, J=1.79 Hz)
Reaction SMILES: [OH-].[Na+].[C:3]1([S:9][CH:10]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH2:24][O:25][N:26]=[C:27]([C:29]3[CH:34]=[CH:33][C:32]([C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][N:36]=4)=[CH:31][CH:30]=3)[CH3:28])=[CH:18][CH:17]=2)[C:11]([O:13]C)=[O:12])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.CO>O1CCOCC1>[C:3]1([S:9][CH:10]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH2:24][O:25][N:26]=[C:27]([C:29]3[CH:30]=[CH:31][C:32]([C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][N:36]=4)=[CH:33][CH:34]=3)[CH3:28])=[CH:18][CH:17]=2)[C:11]([OH:13])=[O:12])[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: COC(=O)C(Cc1ccc(OCCON=C(C)c2ccc(-c3ccccn3)cc2)cc1)Sc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1COCCO1
Product: CC(=NOCCOc1ccc(CC(Sc2ccccc2)C(=O)O)cc1)c1ccc(-c2ccccn2)cc1
Temperature: 50 °C
Reaction time: 4 h
Yield: 95.1 %

Procedure:
2.00 ml of a 1N aqueous sodium hydroxide solution was added to a mixture of 350 mg of methyl 2-phenylthio-3-[4-[2-[[1-[4(2-pyridyl)phenyl]ethylidene]aminoxy]ethoxy]phenyl]propionate obtained in Example 3, 3 ml of methanol and 2 ml of dioxane, and the mixture was stirred at 50° C. for 4 hours. After the reaction, the reaction mixture was concentrated and diluted with water. Then, the pH of the reaction mixture was adjusted to a value of 3 with 1N hydrochloric acid and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated to obtain 324 mg of the desired compound as a foamy solid.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([CH:7]=[O:8])[CH2:3][CH2:2]1.Br[C:10]1[C:11]([F:16])=[N:12][CH:13]=[CH:14][CH:15]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[F:16][C:11]1[C:10]([C:4]2([CH:7]=[O:8])[CH2:5][CH2:6][O:1][CH2:2][CH2:3]2)=[CH:15][CH:14]=[CH:13][N:12]=1
Reactant: Fc1ncccc1Br
Reactant: O=CC1CCOCC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: O=CC1(c2cccnc2F)CCOCC1
Temperature: 100 °C

Procedure:
Into a sealed tube was added tetrahydro-2H-pyran-4-carbaldehyde (0.25 g, 2.190 mmol), 3-bromo-2-fluoropyridine (0.321 g, 1.825 mmol), palladium(ii) acetate (0.016 g, 0.073 mmol), cesium carbonate (0.714 g, 2.190 mmol), water (1.644 μL, 0.091 mmol), BINAP (0.068 g, 0.110 mmol) in Dioxane (7.30 mL). The resulting mixture was heated to 100° C. overnight. More catalyst and ligand (palladium(ii) acetate (0.016 g, 0.073 mmol), binap (0.068 g, 0.110 mmol)) were added and the resulting mixture was heated to 113° C. until the starting material was completely consumed. Aqueous work up followed by DCM extraction. Purification by Biotage (0-100% MeOH/DCM) & prep-plate TLC (5% MeOH/DCM) produced product which was advanced to the next step.
Reaction SMILES: [C:1]([NH:8][C:9]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:10]([OH:12])=[O:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C(=O)([O-])[O-].[Cs+].[Cs+].CN(C)C=O.[CH2:38](Br)[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>CO.O>[CH2:38]([O:11][C:10](=[O:12])[C:9]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[NH:8][C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1
Reactant: CC(C)(C)OC(=O)NC(Cc1ccccc1)(Cc1ccccc1)C(=O)O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CO
Product: CC(C)(C)OC(=O)NC(Cc1ccccc1)(Cc1ccccc1)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
BOC-2,2-dibenzyl glycine (3.29 g, 9.25 mmol) is dissolved in a solution of methanol(18 ml) and water (2 ml) and the pH adjusted to 8 with 20% cesium carbonate solution (11 ml). The solution is concentrated in vacuo to dryness and the residue dissolved in dimethylformamide (DMF) (25 ml) and re-concentrated twice and dried under high vacuum. The cesium salt is taken up into DMF (25 ml), benzyl bromide (1.74 g, 10.2 mmol) is added and the mixture stirred at room temperature for 16 hours. The mixture is concentrated in vacuo and the residue diluted with ether. The organic phase is washed with water, brine, dried over magnesium sulfate, and concentrated in vacuo. The crude product is purified by flash chromatography, eluting with 10% ethyl acetate in hexane to give BOC-2,2-dibenzyl glycine benzyl ester.