Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]([C:18](OC)=[O:19])=[C:7]([CH3:17])[N:8]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[CH2:10][C:9]=12)=O.[H-].[H-].[H-].[H-].[Li+].[Al+3].O.[OH-].[Na+]>ClCCl.CCOCC>[OH:19][CH2:18][C:6]1[C:5]([CH2:3][OH:2])=[C:9]2[CH2:10][C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:16]=3[N:8]2[C:7]=1[CH3:17]
Reactant: COC(=O)c1c(C(=O)OC)c2n(c1C)-c1ccccc1C2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CCOCC
Solvent: ClCCl
Product: Cc1c(CO)c(CO)c2n1-c1ccccc1C2
Reaction time: 0.25 h
Yield: 77.3 %

Procedure:
A solution of 3-methyl-8H-3a-azacyclopenta[a]indene-1,2-dicarboxylic acid dimethyl ester (3.14 g, 11 mmol) in anhydrous dichloromethane (30 mL) was added dropwise to a stirred suspension of LiAlH4 (1.04 g, 27.5 mmol) in anhydrous ether (45 mL) at 0° C. The mixture was stirred for 15 min after the addition was complete. The excess LiAlH4 was carefully decomposed by the slow, sequential addition of water (1.3 mL), 15% NaOH aqueous solution (1.3 mL), and water (3.6 mL). The solid inorganic salt was removed by filtration and washed with dichloromethane. The combined filtrate and washings was concentrated in vacuo to dryness. The residue was triturated with ether, the solid product was collected by filtration, and dried to give (2-hydroxymethyl-3-methyl-8H-3a-aza-cyclopenta-[a]inden-1-yl)methanol (DA-1090) 1.95 g (77%): mp 123-125° C.; 1H NMR (DMSO-d6) δ 2.53 (3H, s, Me), 3.80 (2H, s, CH2), 4.35 (2H, d, J=5.2 Hz, CH2O), 4.44 (2H, d, J=5.2 Hz, CH2O), 4.47 (1H, t, J=5.2 Hz, exchangeable, OH), 4.61 (1H, t, J=5.2 Hz, exchangeable, OH), 7.07-7.10 (1H, m, Hz, ArH), 7.29-7.33 (1H, m, ArH), 7.46-7.48 (2H, m, 2×ArH). Anal. Calcd. for C14H15NO2: C, 73.34; H, 6.59; N, 6.11. Found: C, 73.08; H, 6.59; N, 6.04.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=3)[N:8]=2)=[CH:3][CH:2]=1.[CH3:21][CH2:22][O:23][C:24]([CH2:26]Br)=[O:25]>>[N:1]1[CH:2]=[CH:3][C:4]([C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([O:20][CH2:26][C:24]([O:23][CH2:22][CH3:21])=[O:25])=[CH:16][CH:15]=3)[N:8]=2)=[CH:5][CH:6]=1
Reactant: Oc1ccc(Nc2nccc(-c3ccncc3)n2)cc1
Reactant: CCOC(=O)CBr
Product: CCOC(=O)COc1ccc(Nc2nccc(-c3ccncc3)n2)cc1

Procedure:
A mixture of 5.58 g of 4-[[4-(4-pyridinyl)-2-pyrimidinyl]amino]phenol was reacted with ethyl bromo acetate as described in Example 255, giving 1.8 g of the desired product as yellow crystals, mp 109°-111° C.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2/[CH:10]=[CH:11]/[C:12]([NH:14][S:15]([C:18]2[S:19][CH:20]=[CH:21][CH:22]=2)(=[O:17])=[O:16])=[O:13])[CH:3]=[CH:2]1.S1C=CC=C1S(N)(=O)=O.Cl.CN(C)CCCN=C=NCC.N1C2C(=CC=CC=2C=CC(O)=O)C=C1.Cl>CN(C)C1C=CN=CC=1.C(Cl)Cl>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[CH:10]=[CH:11][C:12]([NH:14][S:15]([C:18]2[S:19][CH:20]=[CH:21][CH:22]=2)(=[O:16])=[O:17])=[O:13])[CH:3]=[CH:2]1
Reactant: O=C(/C=C/c1cccc2cc[nH]c12)NS(=O)(=O)c1cccs1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: O=C(C=Cc1cccc2cc[nH]c12)NS(=O)(=O)c1cccs1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
Thiophene-2-sulfonic acid ((E)-3-1H-indol-7-yl-acryloyl)-amide (I-4) To a round bottom flask (500 mL) which contained a solution of thiophenesulfonamide (1.05 g, 6 mmol), 4-dimethyaminopyridine (DMAP, 1.56 g, 13 mmol) and 1-[3-(dimethyamino)propyl]-3-ethylcarbodiimide hydrochloride (EDCI, 2.4 g, 13 mmol) in CH2Cl2 (150 mL) was added 3-(1H-indol-7-yl)-acrylic acid I-3 (1.2 g, 6 mmol) at rt. The mixture which resulted was allowed to stir at rt for 72 h, then was cooled to 5° C. and was acidified with addition of aq HCl (10%) until pH=1, which was followed by extraction of CH2Cl2/MeOH (9/1, 3×100 mL). The combined organic layers were dried over anhyd. Na2SO4 and the solvent was removed under reduced pressure to provide the crude product which was purified by flash chromatography (silica gel, CH2Cl2; CH2Cl2/EtOAc/hexane=1:10:20-1:20:10) to afford desired thiophene-2-sulfonic acid (3-1H-indol-7-yl-acryloyl)-amide I-4 (1.2 g, 56%) as a white solid. MS(ESI−)m/z(331.1, 100%). LCMS(ESI−)>95%.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:19][CH3:20])=[C:6]([C:8]([CH3:18])([CH3:17])[CH2:9][C:10]2([C:13]([F:16])([F:15])[F:14])[CH2:12][O:11]2)[CH:7]=1.[S:21]1[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[NH:24][CH2:23][CH2:22]1>CN(C)C=O.C(OCC)C>[S:21]1[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[N:24]([CH2:12][C:10]([OH:11])([CH2:9][C:8]([C:6]2[CH:7]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=2[O:19][CH3:20])([CH3:18])[CH3:17])[C:13]([F:16])([F:15])[F:14])[CH2:23][CH2:22]1
Reactant: COc1ccc(F)cc1C(C)(C)CC1(C(F)(F)F)CO1
Reactant: c1ccc2c(c1)NCCS2
Solvent: CN(C)C=O
Solvent: CCOCC
Product: COc1ccc(F)cc1C(C)(C)CC(O)(CN1CCSc2ccccc21)C(F)(F)F

Procedure:
A solution of 2-[2-(5-fluoro-2-methoxyphenyl)-2-methylpropyl]-2-trifluoromethyloxirane (118 mg) and 3,4-dihydro-2H-1,4-benzothiazine (H. I. El-Subbagh et al., Arch. Pharm. Med. Chem., 1999, 332, pp. 19-24) (122 mg) in dimethylformamide (1 mL) was heated at 140° C. for 73 hours. The resulting mixture was diluted with diethyl ether, washed with saturated aqueous sodium bicarbonate, water and brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified by radial chromatography with a chromatotron (eluted with 0% to 1% ethyl acetate-hexanes) to give the title compound as a white solid (53.5 mg), m.p. 103° C.-104° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=O)[CH2:8][CH2:7][CH2:6]2.[CH:14]#[N:15].[Cl-].[Al+3].[Cl-].[Cl-]>[N+](C1C=CC=CC=1)([O-])=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([C:14]#[N:15])=[CH:8][CH2:7][CH2:6]2
Reactant: C#N
Reactant: COc1ccc2c(c1)CCCC2=O
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=[N+]([O-])c1ccccc1
Product: COc1ccc2c(c1)CCC=C2C#N

Procedure:
A process which comprises (1) cyanating 6-methoxy-tetralone by reacting it with hydrogen cyanide and aluminum chloride in nitrobenzene at about 60°-120° C. so as to form 6-methoxy-1-cyano-3,4-dihydronaphthalene, (2) intimately mixing the resultant solution with an aqueous solution of sodium hydroxide or potassium hydroxide in the presence of a phase transfer agent at about 15°-100° C. as as to aromatize the 6-methoxy-1-cyano-3,4-dihydronaphthalene, and (3) brominating the resultant 6-methoxy-1-cyanonaphthalene while still in nitrobenzene so as to form 6-methoxy-5-bromo-1-cyanonaphthalene.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[S:8][C@@H:9]([CH2:12][C:13]3[NH:14][CH:15]=[CH:16][N:17]=3)[C@@H:10]([OH:11])[C:6]=2[CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH3:20][S:21][CH2:22]Cl.CCOCC>CN(C)C=O>[Cl:1][C:2]1[C:7]2[S:8][C@@H:9]([CH2:12][C:13]3[NH:17][CH:16]=[CH:15][N:14]=3)[C@@H:10]([O:11][CH2:20][S:21][CH3:22])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: O[C@H]1c2cccc(Cl)c2S[C@H]1Cc1ncc[nH]1
Reactant: CSCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CSCO[C@H]1c2cccc(Cl)c2S[C@H]1Cc1ncc[nH]1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of cis-7-chloro-3-hydroxy-2,3-dihydro-2-(1'-imidazolylmethyl)benzo(b)thiophene (2.67 gms., 10 mmols) in dry dimethylformamide (30 ml.) at 0°-5° C., add sodium hydride (50% oil dispersion) (0.53 gms., 11 mmols) and stir for one hour at room temperature. Add chloromethyl methyl sulfide (1.06 gms., 11 mmols) and stir again for one hour at room temperature. Pour the reaction mixture into ether (500 ml.) and extract with three portions (500 ml. each) of water. Dry the ether solution over anhydrous magnesium sulfate and evaporate in vacuo. Chromatograph the resultant residue by high pressure liquid chromatography using two silica gel cartridges and eluting with ethyl acetate. Combine the like eluates as determined by thin layer chromatography and evaporate the combined residues to give cis-7-chloro-3-(methylthiomethoxy)-2,3-dihydro-2-(1'-imidazolylmethyl)benzo(b)-thiophene.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[NH:10][C:11]1[CH:20]=[CH:19][CH:18]=[CH:17][C:12]=1[C:13]([NH:15][NH2:16])=[O:14].[CH:21](OCC)(OCC)OCC.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(O)C>[Cl:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[NH:10][C:11]1[CH:20]=[CH:19][CH:18]=[CH:17][C:12]=1[C:13]1[O:14][CH:21]=[N:16][N:15]=1
Reactant: CCOC(OCC)OCC
Reactant: Cc1ccc(Cl)c(Nc2ccccc2C(=O)NN)c1Cl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Product: Cc1ccc(Cl)c(Nc2ccccc2-c2nnco2)c1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 67 %

Procedure:
To a room temperature suspension of 2-[(2,6-dichloro-3-methylphenyl)amino]-benzoic acid hydrazide (355.1 mg, 1.15 mmoles) in 6 ml of ethanol is added 2 ml of triethyl orthoformate followed by p-toluenesulfonic acid (20 mg, 0.11 mmoles). After stirring at room temperature overnight, the clear yellow solution is concentrated in vacuo. The residue is subjected to flash chromatography eluting with hexane:ethyl acetate (3:1). Subsequent recrystallization from ethanol yields 244.1 mg (67%) of 2,6-dichloro-3-methyl-N-[2-(1,3,4-oxadiazol-2-yl)phenyl]benzenamine, mp 180°-181° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([O:8]COC)[CH:5]=[CH:4][C:3]=1[CH2:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15].[CH2:19](I)[CH3:20].C(=O)([O-])[O-].[K+].[K+].S(=O)(=O)(O)O>C(O)C.O.CN(C)C=O>[CH2:19]([O:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[CH2:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH3:20]
Reactant: CCOC(=O)CCc1ccc(OCOC)cc1O
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCO
Product: CCOC(=O)CCc1ccc(O)cc1OCC
Temperature: 25 °C
Reaction time: 13 h
Yield: 63.7 %

Procedure:
A mixture of ethyl 3-(2-hydroxy-4-methoxymethoxyphenyl)propionate (6.00 g), ethyl iodide (5.52 g), anhydrous potassium carbonate (3.26 g) and N,N-dimethylformamide (50 mL) was stirred at room temperature for 13 hrs. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated to give an oil. A mixture of the obtained oil, 10% aqueous sulfuric acid solution (10 mL) and ethanol (300 mL) was stirred with heating under reflux for 6 hrs. The reaction mixture was concentrated under reduced pressure and the residue was diluted with water, and then basified with a saturated aqueous sodium hydrogencarbonate. The mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The obtained residue was subjected to silica gel column chromatography to give ethyl 3-(2-ethoxy-4-hydroxyphenyl)propionate as a colorless oil (3.58 g, 64%) from a fraction eluted with ethyl acetate-hexane (1:6, v/v).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[N+:7]([C:10]1[CH:15]=[CH:14][C:13]([C:16]2([C:22](OCC)=[O:23])[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)=[CH:12][CH:11]=1)([O-:9])=[O:8].O.O.O.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Na+].[Na+]>O1CCCC1>[N+:7]([C:10]1[CH:15]=[CH:14][C:13]([C:16]2([CH2:22][OH:23])[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)=[CH:12][CH:11]=1)([O-:9])=[O:8]
Reactant: CCOC(=O)C1(c2ccc([N+](=O)[O-])cc2)CCOCC1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Product: O=[N+]([O-])c1ccc(C2(CO)CCOCC2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 38.8 %

Procedure:
To a solution of lithium aluminium hydride (300 mg) in tetrahydrofuran (20 mL) was added dropwise a solution of ethyl 4-(4-nitrophenyl)tetrahydro-2H-pyran-4-carboxylate (1.0 g) obtained in Step A of Example 151 in tetrahydrofuran (10 mL) at −78° C., and the mixture was stirred at 0° C. for 1 hr. To the reaction mixture was added sodium sulfate decahydrate, and the mixture was stirred at room temperature for 2 hr. The insoluble substance was removed by filtration through Celite, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (330 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:4]=1[CH:13]=O.C([O-])(=O)C.[NH4+].[N+:20]([CH2:23][CH3:24])([O-])=O.[H-].[Al+3].[Li+].[H-].[H-].[H-].[ClH:31]>C(O)C.O1CCCC1.C(OCC)C>[ClH:31].[CH3:1][O:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:4]=1[CH2:13][CH:23]([NH2:20])[CH3:24]
Reactant: COc1c(C=O)ccc2ccccc12
Reactant: CC[N+](=O)[O-]
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Al+3]
Solvent: CCO
Solvent: C1CCOC1
Solvent: CCOCC
Product: COc1c(CC(C)N)ccc2ccccc12
Temperature: 70 °C
Reaction time: 3 h

Procedure:
The product from Step C (3.04 g, 18.3 mmol) was dissolved in ethanol (50 mL), ammonium acetate (1.55 g, 20.10 mmol) was added followed by nitroethane (2.75 g, 36.5 mmol). The reaction mixture was stirred at 70° C. for 3 h and then the solvent was removed. The residue was dissolved in ethyl acetate (100 mL) and washed with water (2×100 mL). The organic layer was dried (MgSO4) and concentrated to give a solid, which was dissolved in anhydrous tetrahydrofuran (100 mL) and cooled to 0° C. To this solution, a 1 M solution of lithium aluminum hydride in tetrahydrofuran (73 mL) was added and the reaction mixture allowed to warm to room temperature and stirred for 2 h followed by heating at reflux for an additional 2 h. Excess lithium aluminum hydride was consumed by adding ethyl acetate (50 mL) and then water (400 mL). The organic material was extracted with dichloromethane, dried (MgSO4), and concentrated to give an oil which was transformed to hydrochloride salt by adding 1 M solution of hydrogen chloride in diethyl ether. The white solid was collected by filtration: 1H NMR (DMSO-d) δ 1.14 (d, 3H, CH3), 2.94 (m, 2H, CH2), 3.52 (m, 1H, CH), 3.89 (s, 3H, OCH3), 7.38–8.06 (m, 6H, Ar—H), 8.19 (bs, NH3+); MS 216 (M+1). Analysis. Calcd. for C14H17NO.HCl.0.3 H2O: C, 65.39; H, 7.21; N, 5.56. Found: C, 65.16; H, 7.07; N, 5.42.
Reaction SMILES: [NH2:1][C:2]1[C:11]([F:12])=[C:10](F)[C:9]2[O:14][CH2:15][C:16]([CH3:18])([CH3:17])[N:7]3[C:8]=2[C:3]=1[C:4](=[O:21])[C:5]([C:19]#[N:20])=[CH:6]3.[N:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[CH2:28][CH2:29][CH2:30][NH2:31]>CS(C)=O>[NH2:1][C:2]1[C:11]([F:12])=[C:10]([NH:31][CH2:30][CH2:29][CH2:28][C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][N:22]=2)[C:9]2[O:14][CH2:15][C:16]([CH3:18])([CH3:17])[N:7]3[C:8]=2[C:3]=1[C:4](=[O:21])[C:5]([C:19]#[N:20])=[CH:6]3
Reactant: CC1(C)COc2c(F)c(F)c(N)c3c(=O)c(C#N)cn1c23
Reactant: NCCCc1ccccn1
Solvent: CS(C)=O
Product: CC1(C)COc2c(NCCCc3ccccn3)c(F)c(N)c3c(=O)c(C#N)cn1c23
Temperature: 120 °C
Yield: 29.1 %

Procedure:
To a solution of 12 (250 mg, 0.86 mmol) in 4 ml of DMSO, 268 mg (1.98 mmol) of 3-(pyridin-2-yl)propan-1-amine were added. The reaction mixture was heated to 120° C. for 5 h. After cooling, the reaction mixture was freeze dried to remove DMSO and the remaining solid was purified by preparative HPLC to give the title compound as a yellow solid (102 mg, 29% yield).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([I:18])=[CH:14][C:13]=2[F:19])=[CH:9][N:10]=1)[C:5]([OH:7])=O.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH3:32][C:33]1([CH3:41])[O:37][CH:36]([CH2:38][O:39][NH2:40])[CH2:35][O:34]1.O>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([C:8]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([I:18])=[CH:14][C:13]=2[F:19])=[CH:9][N:10]=1)[C:5]([NH:40][O:39][CH2:38][C@H:36]1[CH2:35][O:34][C:33]([CH3:41])([CH3:32])[O:37]1)=[O:7]
Reactant: O=C(O)c1cc(Br)ncc1Nc1ccc(I)cc1F
Reactant: CC1(C)OCC(CON)O1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: O
Product: CC1(C)OC[C@H](CONC(=O)c2cc(Br)ncc2Nc2ccc(I)cc2F)O1
Temperature: 25 °C
Reaction time: 6 h
Yield: 55.7 %

Procedure:
2-bromo-N-{[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]methoxy}-5-[(2-fluoro-4-iodophenyl)-amino]isonicotinamide was synthesized as described in General Method 3: to a solution of 2-bromo-5-[(2-fluoro-4-iodophenyl)amino]isonicotinic acid (145.0 mg, 0.33 mmol) in DMF (1.5 ml) was added 1,1′-carbonylbis(1H-imidazole) (60 mg, 0.36 mmol). The reaction mixture was stirred at room temperature under argon for 6 hrs. Then, O-[(2,2-dimethyl-1,3-dioxolan-4-yl)methyl]hydroxylamine (125 mg, 0.83 mmol) was added, and stirred overnight. The reaction mixture was poured into water (10 ml). Extracted with EtOAc (3×15 ml), the combined organic layer was washed with brine (2×15 ml), and dried over MgSO4. The solvent was evaporated, and the residue was purified on silica gel column (Hex:EtOAc=3:1) to obtain 104 mg (55%) of 2-bromo-N-{[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]methoxy}-5-[(2-fluoro-4-iodophenyl)-amino]isonicotinamide. LC/MS:10.43 min, 566, 568.
Reaction SMILES: [CH2:1]([C@@:4]1([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]([CH3:16])([CH3:15])[CH3:14])[CH3:12])[CH2:6][CH2:5]1)[CH:2]=[CH2:3].B.C1C[O:28]CC1.[OH-].[Na+].OO.Cl>C1COCC1.O>[CH3:14][C:13]([CH3:15])([CH3:16])[CH:11]([N:7]1[CH2:6][CH2:5][C@:4]([C:17]2[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=2)([CH2:1][CH2:2][CH2:3][OH:28])[O:9][C:8]1=[O:10])[CH3:12]
Reactant: C1CCOC1
Reactant: C=CC[C@]1(c2ccc(F)cc2)CCN([C@@H](C)C(C)(C)C)C(=O)O1
Agent: B
Agent: Cl
Agent: OO
Solvent: O
Product: CC(N1CC[C@@](CCCO)(c2ccc(F)cc2)OC1=O)C(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 2.1 %

Procedure:
To a solution of (R)-6-allyl-3-((S)-3,3-dimethylbutan-2-yl)-6-(4-fluorophenyl)-1,3-oxazinan-2-one (90 mg, 0.28 mmol) in dry THF (5 mL) was added dropwise 1 M BH3.THF (0.56 mL, 0.564 mmol) at 0° C. After stirring for 2 h at rt, the reaction mixture was cooled to 0° C. and water (1 mL), 3 M aqueous NaOH (0.5 mL) and 30% H2O2 (0.5 mL) were successively added. The mixture was stirred for 2-3 h at rt and was then diluted with water (6 mL). The pH was adjusted to 6-7 with 0.5 N HCl. The aqueous phase was extracted with EtOAc (3×5 mL). The combined organic layers were washed with saturated aqueous NaHCO3 solution (8 mL) and brine (8 mL), dried over Na2SO4, and concentrated in vacuo to give the crude product, which was purified by preparative TLC to afford (R)-3-((S)-3,3-dimethylbutan-2-yl-6-(4-fluorophenyl)-6-(3-hydroxypropyl)-1,3-oxazinan-2-one (2 mg, 2%). LC-MS Method 1 tR=1.179, min, m/z=338.1; 1H NMR (CDCl3) 0.65 (s, 9H), 0.99-1.06 (d, 3H), 1.18 (m, 1H), 1.29 (m, 1H), 1.61-1.71 (m, 1H), 1.83-2.08 (m, 3H), 2.21-2.28 (m, 1H), 2.62-2.73 (m, 1H), 3.06-3.13 (m, 1H), 3.47-3.53 (m, 2H), 4.36-4.43 (m, 1H), 6.98-7.06 (m, 2H), 7.22-7.26 (m, 2H)
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1)=[O:2].[CH3:9][O:10][C:11]1[C:12]([CH2:17][CH2:18][CH2:19][CH2:20][NH:21][C:22]2[NH:23][CH:24]=[CH:25][C:26](=[O:28])[N:27]=2)=[N:13][CH:14]=[CH:15][CH:16]=1.Cl>>[CH3:9][O:10][C:11]1[C:12]([CH2:17][CH2:18][CH2:19][CH2:20][NH:21][C:22]2[NH:23][CH:24]=[C:25]([CH:1]([C:3]3[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=3)[OH:2])[C:26](=[O:28])[N:27]=2)=[N:13][CH:14]=[CH:15][CH:16]=1
Reactant: O=Cc1ccccn1
Reactant: COc1cccnc1CCCCNc1nc(=O)cc[nH]1
Agent: Cl
Product: COc1cccnc1CCCCNc1nc(=O)c(C(O)c2ccccn2)c[nH]1

Procedure:
2-Formylpyridine is reacted with 2-(4-(3-methoxy-2-pyridyl)butylamino)-4(1H)-pyrimidinone in refluxing concentrated hydrochloric acid for 24 hours to give 2-(4-(3-methoxy-2-pyridyl)butylamino)-5-((2-pyridyl)hydroxymethyl)-4(1H)-pyrimidinone.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:8][NH:9][C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([NH:20][CH2:21][C:22]3[C:23]([NH:35][CH:36]4[CH2:41][CH2:40][O:39][CH2:38][CH2:37]4)=[C:24]4[CH:32]=[N:31][N:30]([CH2:33][CH3:34])[C:25]4=[N:26][C:27]=3[CH2:28][CH3:29])=[O:19])[N:13]=2)=[O:11])[CH:5]=[CH:6][CH:7]=1.[CH:42]([C:44]1[CH:45]=[C:46](B(O)O)[CH:47]=[CH:48][CH:49]=1)=[O:43].C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH2:33]([N:30]1[C:25]2=[N:26][C:27]([CH2:28][CH3:29])=[C:22]([CH2:21][NH:20][C:18]([C:14]3[CH:15]=[CH:16][CH:17]=[C:12]([C:10]([NH:9][CH2:8][C:4]4[CH:3]=[C:2]([C:48]5[CH:47]=[CH:46][CH:45]=[C:44]([CH:42]=[O:43])[CH:49]=5)[CH:7]=[CH:6][CH:5]=4)=[O:11])[N:13]=3)=[O:19])[C:23]([NH:35][CH:36]3[CH2:41][CH2:40][O:39][CH2:38][CH2:37]3)=[C:24]2[CH:32]=[N:31]1)[CH3:34]
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2cccc(Br)c2)n1
Reactant: O=Cc1cccc(B(O)O)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2cccc(-c3cccc(C=O)c3)c2)n1
Temperature: 100 °C
Yield: 44.5 %

Procedure:
A mixture of N-[(3-bromophenyl)methyl]-N′-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-2,6-pyridinedicarboxamide (600 mg, 0.967 mmol), (3-formylphenyl)boronic acid (188 mg, 1.257 mmol), Na2CO3 (307 mg, 2.90 mmol) and PdCl2(dppf) (70.7 mg, 0.097 mmol) was diluted in a mixture of 1,4-dioxane (9 mL) and water (3 mL) in a 20 mL Biotage microwave reaction tube. The mixture was degassed by bubbling argon through it for 5 minutes and it was then heated in a Biotage microwave at normal absorption for 30 min at 100° C. The crude mixture was filtered through a PL-Thiol MP SPE+ and was then washed with ethyl acetate and saturated NaHCO3. The organic layer was concentrated under vacuum to obtain the crude residue. It was purified with Gilson HPLC (with 0.1% TFA in the solvent) eluting with 15 to 80% CH3CN in water in a flow rate of 20 mL/min. The product fractions were dried under EZ2 Genevac and then combined to give N-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-N′-[(3′-formyl-3-biphenylyl)methyl]-2,6-pyridinedicarboxamide as a solid (278 mg, 44.5%). LC-MS m/z 646.1 (M+H)+, 0.91 min (ret time).
Reaction SMILES: [C:1]([S:4][C:5]([CH3:38])([CH3:37])[CH:6]([NH2:36])[C:7]([O:9][C@H:10]([C:21]1[CH:26]=[CH:25][C:24]([O:27][CH:28]([F:30])[F:29])=[C:23]([O:31][CH2:32][CH:33]2[CH2:35][CH2:34]2)[CH:22]=1)[CH2:11][C:12]1[C:17]([Cl:18])=[CH:16][N+:15]([O-:19])=[CH:14][C:13]=1[Cl:20])=[O:8])(=[O:3])[CH3:2].[C:39]1([S:45](Cl)(=[O:47])=[O:46])[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>N1C=CC=CC=1>[C:1]([S:4][C:5]([CH3:38])([CH3:37])[CH:6]([NH:36][S:45]([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)(=[O:47])=[O:46])[C:7]([O:9][C@H:10]([C:21]1[CH:26]=[CH:25][C:24]([O:27][CH:28]([F:30])[F:29])=[C:23]([O:31][CH2:32][CH:33]2[CH2:35][CH2:34]2)[CH:22]=1)[CH2:11][C:12]1[C:13]([Cl:20])=[CH:14][N+:15]([O-:19])=[CH:16][C:17]=1[Cl:18])=[O:8])(=[O:3])[CH3:2]
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CC(=O)SC(C)(C)C(N)C(=O)O[C@@H](Cc1c(Cl)c[n+]([O-])cc1Cl)c1ccc(OC(F)F)c(OCC2CC2)c1
Solvent: c1ccncc1
Product: CC(=O)SC(C)(C)C(NS(=O)(=O)c1ccccc1)C(=O)O[C@@H](Cc1c(Cl)c[n+]([O-])cc1Cl)c1ccc(OC(F)F)c(OCC2CC2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 8 %

Procedure:
4-((2S)-2-(3-(acetylthio)-2-amino-3-methylbutanoyloxy)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)ethyl)-3,5-dichloropyridine 1-oxide (101 mg, 0.170 mmol) was dissolved in pyridine (1 ml), then benzenesulfonyl chloride (60 mg, 0.340 mmol) was added at 0° C., and the mixture was stirred at RT for 2 hours. The reaction was quenched with HCl 1N, and the product was extracted with EtOAc. The organic phase was washed with HCl 1N (2×) and brine, then dried over Na2SO4. The solvent was removed and the crude product was purified by preparative reverse-phase HPLC to give 10 mg of the desired compound (Yield 8%).