Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:3]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)=[CH:4][C:5]([NH:8][C:9]2[N:10]=[CH:11][C:12]([C:15]#[N:16])=[N:13][CH:14]=2)=[N:6][CH:7]=1.[C:23]1(B(O)O)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C.O>[O:20]1[CH2:21][CH2:22][N:17]([C:3]2[C:2]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:7][N:6]=[C:5]([NH:8][C:9]3[N:10]=[CH:11][C:12]([C:15]#[N:16])=[N:13][CH:14]=3)[CH:4]=2)[CH2:18][CH2:19]1
Reactant: OB(O)c1ccccc1
Reactant: N#Cc1cnc(Nc2cc(N3CCOCC3)c(Cl)cn2)cn1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: N#Cc1cnc(Nc2cc(N3CCOCC3)c(-c3ccccc3)cn2)cn1
Temperature: 150 °C
Yield: 27.9 %

Procedure:
A mixture of 5-(5-chloro-4-morpholinopyridin-2-ylamino)pyrazine-2-carbonitrile (50 mg, 0.16 mmol), phenylboronic acid (38 mg, 0.31 mmol), sodium carbonate (41 mg, 0.39 mmol) and Bedford catalyst (1 mg, 0.01 mmol) in a mixture of acetonitrile-water (4:1, 2.5 mL) was heated at 150° C. by microwave irradiation for 30 minutes. The crude reaction mixture was purified by ion exchange chromatography on SCX-II acidic resin (500 mg) eluting with methanol, then 2M ammonia-methanol. The basic fractions were combined and solvent was evaporated. Preparative TLC, eluting with ethyl acetate-hexane (2:3) gave 5-(4-morpholino-5-phenylpyridin-2-ylamino)pyrazine-2-carbonitrile as a yellow solid (16 mg, 28%).
Reaction SMILES: [OH-].[K+].[Cl:3][C:4]1[C:5]([N:10]2[C:14]([C:15]([O:17]CC)=[O:16])=[CH:13][C:12]([C:20]([F:23])([F:22])[F:21])=[N:11]2)=[N:6][CH:7]=[CH:8][CH:9]=1>O.C(O)C>[Cl:3][C:4]1[C:5]([N:10]2[C:14]([C:15]([OH:17])=[O:16])=[CH:13][C:12]([C:20]([F:23])([F:21])[F:22])=[N:11]2)=[N:6][CH:7]=[CH:8][CH:9]=1
Reactant: CCOC(=O)c1cc(C(F)(F)F)nn1-c1ncccc1Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)c1cc(C(F)(F)F)nn1-c1ncccc1Cl
Reaction time: 0.5 h
Yield: 93 %

Procedure:
Potassium hydroxide (0.5 g, 85%, 2.28 mmol) in water (1 mL) was added to ethyl 1-(3-chloro-2-pyridinyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylate (i.e. the product of Example 4) (0.66 g, 2.07 mmol) in ethanol (3 mL). After about 30 minutes, the-solvent was removed under reduced pressure, and the mixture was dissolved in water (40 mL). The solution was washed with ethyl acetate (20 mL). The aqueous layer was acidified with. concentrated hydrochloric acid and was extracted with ethyl acetate (3×20 mL). The combined extracts were dried and evaporated to give the product as a solid (0.53 g, 93% yield), m.p. 178-179° C. (after crystallization from hexanes-ethyl acetate).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:13])=[N:11][N:12]=2)=[CH:4][C:3]=1[C:14]1[CH:19]=[CH:18][C:17]([C:20]([OH:22])=O)=[CH:16][CH:15]=1.[CH3:23][NH:24][C:25](=[O:33])[C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([NH2:32])[CH:27]=1>>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:13])=[N:11][N:12]=2)=[CH:4][C:3]=1[C:14]1[CH:15]=[CH:16][C:17]([C:20]([NH:32][C:28]2[CH:29]=[CH:30][CH:31]=[C:26]([C:25]([NH:24][CH3:23])=[O:33])[CH:27]=2)=[O:22])=[CH:18][CH:19]=1
Reactant: Cc1nnc(-c2ccc(C)c(-c3ccc(C(=O)O)cc3)c2)o1
Reactant: CNC(=O)c1cccc(N)c1
Product: CNC(=O)c1cccc(NC(=O)c2ccc(-c3cc(-c4nnc(C)o4)ccc3C)cc2)c1

Procedure:
2′-Methyl-N-{3-[(methylamino)carbonyl]phenyl}-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxamide was prepared from 2′-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxylic acid and N-methyl-3-aminobenzamide using method I. LCMS; retention time 3.04 min, MH+ 427.
Reaction SMILES: [N:1]1[C:9]2[CH2:8][CH2:7][NH:6][CH2:5][C:4]=2[S:3][C:2]=1[NH:10][C:11](=[O:13])[CH3:12].Cl[C:15]1[CH:20]=[N:19][CH:18]=[CH:17][N:16]=1.O>CN1C(=O)CCC1>[N:16]1[CH:17]=[CH:18][N:19]=[CH:20][C:15]=1[N:6]1[CH2:7][CH2:8][C:9]2[N:1]=[C:2]([NH:10][C:11](=[O:13])[CH3:12])[S:3][C:4]=2[CH2:5]1
Reactant: CC(=O)Nc1nc2c(s1)CNCC2
Reactant: Clc1cnccn1
Solvent: CN1CCCC1=O
Solvent: O
Product: CC(=O)Nc1nc2c(s1)CN(c1cnccn1)CC2
Temperature: 250 °C
Yield: 9.7 %

Procedure:
As shown in step 10-iv of Scheme 10, to a solution of 50 mg of Compound 1035 in 3 mL of NMP was added 100 mg of 2-chloro pyrazine. The reaction mixture was warmed to 250° C. for 10 minutes under microwave irradiation. The reaction was poured into water (10 mL) and the crude product collected by filtration. The crude solid was purified by silica gel chromatography (CH2Cl2 to EtOH) to provide N-(5-(pyrazin-2-yl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)acetamide (Compound 1, 6.8 mg): ESMS (M+H) 276.16.
Reaction SMILES: [CH2:1]([O:8][C@:9]1([CH:33]=[CH2:34])[C@@H:13]([CH2:14][O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[O:12][C@@H:11]([N:23]2[CH:31]=[C:29]([CH3:30])[C:27](=[O:28])[NH:26][C:24]2=[O:25])[C@@H:10]1[OH:32])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:35][S:36](Cl)(=[O:38])=[O:37]>N1C=CC=CC=1>[CH2:1]([O:8][C@:9]1([CH:33]=[CH2:34])[C@@H:13]([CH2:14][O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[O:12][C@@H:11]([N:23]2[CH:31]=[C:29]([CH3:30])[C:27](=[O:28])[NH:26][C:24]2=[O:25])[C@@H:10]1[O:32][S:36]([CH3:35])(=[O:38])=[O:37])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=C[C@@]1(OCc2ccccc2)[C@@H](COCc2ccccc2)O[C@@H](n2cc(C)c(=O)[nH]c2=O)[C@@H]1O
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: C=C[C@@]1(OCc2ccccc2)[C@@H](COCc2ccccc2)O[C@@H](n2cc(C)c(=O)[nH]c2=O)[C@@H]1OS(C)(=O)=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 84.3 %

Procedure:
Nucleoside 24 (2.57 g, 5.53 mmol) was dissolved in anhydrous pyridine (18 cm3) and cooled to 0° C. Methanesulfonyl chloride (1.28 cm3, 16.6 mmol) was added dropwise and the mixture was stirred at room temperature for 30 min. The reaction was quenched with water (5 cm3) and the resulting mixture was extracted with dichloromethane (3×80 cm3). The combined extract was washed with saturated aqueous sodium hydrogencarbonate (3×120 cm3) and dried (Na2SO4). The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography using dichloromethane/methanol (99:1, v/v) as eluent to give nucleoside 25 as a yellow foam (2.53 g, 84%). δH (CDCl3) 8.92 (1H, br s, NH), 7.71 (1H, d, J 1.4, 6-H), 7.41-7.28 (10H, m, Bn), 6.57 (1H, d, J 7.8, 1′-H), 5.99-5.61 (4H, m, 2′-H, 1″-H and 2″-Ha, 2″-Hb), 4.86-4.50 (4H, m, Bn), 4.37 (1H, dd, J 1.5, 2.4, 4′-H), 8.82 (1H, dd, J 2.6, 11.0, 5′-Ha), 3.55 (1H, dd, J 1.2, 11.0, 5′-Hb), 3.02 (3H, s, CH3), 1.47 (3H, d, J 1.1, CH3). δC (CDCl3) 163.7 (C-4), 151.5 (C-2), 138.7, 136.7 (Bn), 135.7 (C-6), 130.9 (C-1″), 128.8, 128.5, 128.4, 127.6, 127.0 (Bn), 121.8 (C-2″), 111.9 (C-5), 85.1 (C-1′), 84.5 (C-3′), 84.0 (C-4′), 80.7 (C-2′), 73.7 (C-5′), 69.2, 67.7 (Bn), 38.9 (CH3), 11.8 (CH3).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[O:5][C:4](=[O:9])[CH:3]=1.[C:10](Cl)(=[O:12])[CH3:11]>FC(F)(F)C(O)=O>[C:10]([C:3]1[C:4](=[O:9])[O:5][C:6]([CH3:8])=[CH:7][C:2]=1[OH:1])(=[O:12])[CH3:11]
Reactant: CC(=O)Cl
Reactant: Cc1cc(O)cc(=O)o1
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)c1c(O)cc(C)oc1=O
Yield: 34.7 %

Procedure:
Dissolve 4-hydroxy-6-methyl-pyran-2-one (12.6 g, 100 mmol) in trifluoroacetic acid (50 ml). and add 7.8 g (100 mml) of acetyl chloride dropwise. Heat this mixture at reflux for 5 hours. Evaporate the reaction mixture under reduced pressure. Add 50 ml of water, extract with ethyl acetate (50 ml×3) and combine the organic layers. Wash with brine and dry (sodium sulfate). Chromatograph on silica gel, eluting with chloroform to provide 5.8 g (34.5 mmol) of 3-acetyl-4-hydroxy-6-methyl-pyran-2-one.
Reaction SMILES: C(OC(=O)[N:5]([N:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10]1)[CH2:6][CH2:7][CH3:8])C.[OH-].[Na+]>C(O)CO.O>[N:9]1([NH:5][CH2:6][CH2:7][CH3:8])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10]1
Reactant: CCCN(C(=O)OCC)n1ccc2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: OCCO
Product: CCCNn1ccc2ccccc21
Temperature: 120 °C
Reaction time: 4 h

Procedure:
To a suspension of NaHCO3 (50 g, 0.7 mole) in 100 ml dichloromethane (DCM) was added a solution of 1H-indol-1-amine (36 g, 0.27 mole) in 200 ml DCM. After cooling to 0° C. with an ice bath, a solution of ethyl chloroformate (29 ml, 0.30 mole) in 50 ml DCM was added over a period of thirty minutes. After stirring at ambient temperature for three hours, the mixture was filtered, and the filtrate washed with water, then dried (saturated NaCl, anhydrous MgSO4). After filtering, the solvent was evaporated to an oil which was eluted on a silica gel column with DCM, via high performance liquid chromatography (HPLC) to give N-(1H-indol-1-yl) carbamic acid ethyl ester, 33.6 g (61%) as an oil. To a cold solution of N-(1H-indol-1-yl) carbamic acid ethyl ester (15 g, 0.07 mole) in 100 ml tetrahydrofuran, was added potassium t-butoxide (9 g, 0.08 mole), and the mixture stirred at 5° C. for one hour. To this was added 1-bromopropane (7.3 ml, 0.08 mole), and the mixture stirred at ambient temperature for five hours. The mixture was poured into 300 ml iced-water, stirred for five minutes, then extracted with ethyl acetate. The organic layer was washed with water, then dried (saturated, NaCl, anhydrous MgSO4). After filtering, the solvent was evaporated to give N-(1H-indol-1-yl)-N-propylcarbamic acid ethyl ester as an oil, 16.5 g (91%). To a solution of N-(1H-indol-1-yl)-N-propylcarbamic acid ethyl ester (16.5 g, 0.067 mole) in 35 ml ethylene glycol, was added a solution of NaOH (10 g, 0.25 mole) in 30 ml water. After stirring at 120° C. for four hours, the mixture was poured into 300 ml ice water, stirred for five minutes, then extracted with ethyl acetate. The organic layer was washed with water, then dried (saturated NaCl, anhydrous MgSO4). After filtering, the solvent was evaporated to give N-(1H-indol-1-yl)-N-propylamine, 9.0 g (78%) as an oil.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][C:14]1[CH:19]=[C:18]([F:20])[CH:17]=[C:16]([F:21])[CH:15]=1)[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:22](=O)([O-])[O-].[K+].[K+].S(OC)(OC)(=O)=O.[OH-].[NH4+]>CN(C=O)C>[CH3:22][O:11][C:10](=[O:12])[C@@H:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:13][C:14]1[CH:15]=[C:16]([F:21])[CH:17]=[C:18]([F:20])[CH:19]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1cc(F)cc(F)c1)C(=O)O
Reactant: O=C([O-])[O-]
Agent: [K+]
Agent: [NH4+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: COS(=O)(=O)OC
Product: COC(=O)[C@H](Cc1cc(F)cc(F)c1)NC(=O)OC(C)(C)C
Reaction time: 1 h

Procedure:
(2S)-2-[(tert-butoxycarbonyl)amino]-3-(3,5-difluorophenyl)propanoic acid (I, 5.0 g, 0.017 moles, 1.0 equivalent) and potassium carbonate (2.5 g, 0.018 moles, 1.1 equivalent) and DMF (100 mL) are mixed. To this heterogeneous mixture is then added dimethyl sulfate (1.6 mL, 2.1 g, 0.017 moles, 1.0 equivalent) and the contents are then stirred at 20-25° overnight. Once the reaction is complete as measured by HPLC, ammonium hydroxide (10%, 20 mL) is added and allowed to stir for 1 hr. The contents are stirred for 30 min then cooled to 0° and filtered. The solids are washed with cold water (20 mL) and dried under reduced pressure to give the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:5]([OH:32])=[C:6]([CH:10]=[C:11]([CH:13]2[C:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[C:17]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[NH:16][C:15](=[O:31])[NH:14]2)[CH:12]=1)[C:7]([OH:9])=O)[CH3:2].[NH4+].[Cl-].CC[N:37]=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1>CN(C=O)C>[CH2:1]([O:3][C:4]1[C:5]([OH:32])=[C:6]([CH:10]=[C:11]([CH:13]2[C:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[C:17]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[NH:16][C:15](=[O:31])[NH:14]2)[CH:12]=1)[C:7]([NH2:37])=[O:9])[CH3:2]
Reactant: CCOc1cc(C2NC(=O)NC(c3ccccc3)=C2c2ccccc2)cc(C(=O)O)c1O
Reactant: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CCOc1cc(C2NC(=O)NC(c3ccccc3)=C2c2ccccc2)cc(C(N)=O)c1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 16.4 %

Procedure:
A mixture of Compound 77 (described previously) (280 mg, 0.65 mmol), NH4Cl (41 mg, 0.78 mmol), EDCI (149 mg, 0.78 mmol), HOBT (105 mg, 0.78 mmol), and NMM (0.29 mL, 2.6 mmol) in DMF (5 mL) was stirred at room temperature for two hours. LCMS showed most of the starting material was consumed. 100 mL of a mixture of EtOAc and MeOH (v/v=10:1) was added to dilute the mixture. The organic layer was washed with brine (20 mL×2), dried over Na2SO4, filtered, concentrated, and purified by preparative HPLC to afford Compound 82 as a yellow solid (46 mg, yield: 16.4%). 1H NMR (DMSO-d6 400 MHz): δ 12.94 (s, 1H), 8.58 (s, 1H), 8.30 (s, 1H), 7.86 (s, 1H), 7.37 (s, 1H), 7.33 (s, 1H), 7.20-7.25 (m, 5H), 7.11 (s, 1H), 6.97-7.02 (m, 3H), 6.80 (d, J=6.8 Hz, 2H), 5.10 (d, J=2.4 Hz, 1H), 4.00 (q, J=7.2 Hz, 2H), 1.32 (t, J=6.8 Hz, 3H); MS (ESI): m/z 430.1 [M+1]+.
Reaction SMILES: N([O-])=O.[Na+].N[C:6]1[CH:7]=[CH:8][C:9]2[CH2:10][C@H:11]3[CH2:18][S:17][C:16](=[N:19][C:20]4[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=4)[N:12]3[CH2:13][C:14]=2[CH:15]=1.[ClH:26]>O>[Cl:26][C:6]1[CH:7]=[CH:8][C:9]2[CH2:10][C@H:11]3[CH2:18][S:17][C:16](=[N:19][C:20]4[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=4)[N:12]3[CH2:13][C:14]=2[CH:15]=1
Reactant: Nc1ccc2c(c1)CN1C(=Nc3cccnc3)SC[C@@H]1C2
Reactant: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: Clc1ccc2c(c1)CN1C(=Nc3cccnc3)SC[C@@H]1C2
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A solution of sodium nitrite (3.1 g.) in distilled water (10 cc.) is added slowly to a solution, at 0° C., of (S)-7-amino-3-(pyrid-3-ylimino)-1,5,10,10a-tetrahydrothiazolo[3,4-b]isoquinoline (13 g.) in 4N hydrochloric acid (25 cc.). The mixture is stirred for 15 minutes at 0° C., and the solution obained is then added to a suspension of cuprous chloride (6 g.) in concentrated hydrochloric acid (d = 1.18; 25 cc.). The mixture is allowed to return to 20° C., and is then heated for 30 minutes at 70° C. After cooling to 20° C., distilled water (200 cc.), methylene chloride (250 cc.) and then N sodium hydroxide solution (100 cc.) are added. After filtration, the organic phase is recovered by decanting and is dried over magnesium sulphate, filtered and concentrated to dryness at 40° C., under reduced pressure (20 mm.Hg). The residue obtained is purified by chromatography on silica gel (200 g.) contained in a column of 3 cm. diameter, elution being carried out with methylene chloride containing 1% v/v of methanol (5,000 cc.), and 1 litre fractions being collected. Fractions 2 to 4 are combined and then concentrated to dryness. The residue obtained is recrystallised from a mixture of isopropanol (70 cc.) and heptane (100 cc.). (S)-7-Chloro-3-(pyrid-3-ylimino)-1,5,10,10a-tetrahydrothiazolo[3,4-b]isoquinoline (5.5 g.), melting at 125° C., is thus obtained.
Reaction SMILES: CC(C)([O-])C.[K+].[CH3:7][C:8](=[N:10][OH:11])[CH3:9].F[C:13]1[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][C:14]=1[C:21]([C:23]1[CH:28]=[C:27]([CH2:29][CH2:30][CH3:31])[C:26]([O:32][CH3:33])=[CH:25][C:24]=1[CH2:34][CH2:35][CH3:36])=[O:22]>C1COCC1>[CH3:20][O:19][C:17]1[CH:18]=[CH:13][C:14]([C:21](=[O:22])[C:23]2[CH:28]=[C:27]([CH2:29][CH2:30][CH3:31])[C:26]([O:32][CH3:33])=[CH:25][C:24]=2[CH2:34][CH2:35][CH3:36])=[C:15]([O:11][N:10]=[C:8]([CH3:9])[CH3:7])[CH:16]=1
Reactant: CC(C)=NO
Reactant: CCCc1cc(C(=O)c2ccc(OC)cc2F)c(CCC)cc1OC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCCc1cc(C(=O)c2ccc(OC)cc2ON=C(C)C)c(CCC)cc1OC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of potassium tert-butoxide (2.18 g, 19.4 mmol, heat-gunned under high vacuum) in THF (60 mL) was added acetone oxime (1.42 g, 19.4 mmol). The white slurry was stirred at room temperature for 1 h and then a solution of (2-fluoro-4-methoxyphenyl)(4-methoxy-2,5-dipropylphenyl)methanone (2.23 g, 6.47 mmol) in THF (10 mL ) was added. The mixture was stirred at 65° C. for 3 h and then quenched with a small amount of water. Most of the THF was removed in vacuo and extraction was performed in EtOAc (3×60 mL) with 50% saturated brine (50 mL). The crude product was employed in the ensuing cyclization. A portion of the crude product was subjected to preparative TLC (15% EtOAc/hexanes) to yield the title compound as a light green oil: 1H NMR (300 MHz, CDCl3) δ 0.87 (t, 3H, J=7.2 Hz), 0.92 (t, 3H, J=7.1 Hz), 1.42 (s, 3H), 1.48 (m, 2H), 1.60 (m, 2H), 1.89 (s, 3H), 2.46 (t, 2H, J=7.7 Hz), 2.77 (t, 2H, J=7.9 Hz), 3.85 (s, 3H), 3.87 (s, 3H), 6.59 (dd, 1H, J=8.6, 2.5 Hz), 6.68 (s, 1H), 7.08 (d, 1H, J=2.4 Hz), 7.13 (s, 1H), 7.55 (d, 1H, J=8.6 Hz); MS m/e 398 (M+H)+.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[N:11]1[CH2:14][CH:13]([OH:15])[CH2:12]1.[H-].[Na+].Cl[C:19]1[N:20]=[N:21][C:22]([Cl:34])=[CH:23][C:24]=1[N:25]1[CH2:30][CH2:29][CH:28]([C:31](=[O:33])[CH3:32])[CH2:27][CH2:26]1>CN(C=O)C.O>[Cl:34][C:22]1[N:21]=[N:20][C:19]([O:15][CH:13]2[CH2:12][N:11]([C:2]3[CH:3]=[CH:4][C:5]4[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=4)[N:1]=3)[CH2:14]2)=[C:24]([N:25]2[CH2:30][CH2:29][CH:28]([C:31](=[O:33])[CH3:32])[CH2:27][CH2:26]2)[CH:23]=1
Reactant: CC(=O)C1CCN(c2cc(Cl)nnc2Cl)CC1
Reactant: OC1CN(c2ccc3ccccc3n2)C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)C1CCN(c2cc(Cl)nnc2OC2CN(c3ccc4ccccc4n3)C2)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 68.4 %

Procedure:
To a solution of 1-(quinolin-2-yl)azetidin-3-ol (see PREPARATION P1.2, step 1; 0.78 g, 3.8 mmol) in DMF (20 mL) at room temperature was added sodium hydride (60% wt in mineral oil) (0.18 g, 7.6 mmol). The mixture was stirred at room temperature for 10 min and then 1-(1-(3,6-dichloropyridazin-4-yl)piperidin-4-yl)ethanone (1.0 g, 3.8 mmol) was added. The reaction mixture was stirred at room temperature for 1 hour and then diluted with water (20 mL) and extracted with EtOAc (2×30 mL). The combined organic extracts were washed with water (10 mL) and brine (10 mL), dried over Na2SO4, and filtered. The filtrate was evaporated in vacuo and the residue was purified by flash column chromatography on silica gel (5% to 30% EtOAc in hexanes) to give the title product (1.1 g, 2.6 mmol, 70% yield) as white solid. ESI-MS (M+1): 438 calc. for C24H25ClN4O2 437.
Reaction SMILES: [CH2:1]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].[OH:18]O>C(O)(=O)C>[CH2:1]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N+:13]=1[O-:18])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: OO
Reactant: CCCCCCCCCCCc1ccccn1
Solvent: CC(=O)O
Product: CCCCCCCCCCCc1cccc[n+]1[O-]
Yield: 91 %

Procedure:
A solution of 11.0 g (47 mmol) of 2-n-undecylpyridine and 8 ml of an aqueous 35% hydrogen peroxide dissolved in 30 ml of glacial acetic acid was heated at 70° to 80° C. for 3 hours, and further 3 ml of the aqueous hydrogen peroxide was added, followed by heating at the same temperature for 9 hours. After cooling, the mixture was concentrated under a reduced pressure to about a half amount, and 50 ml of water was added and the mixture concentrated to a half amount (repeated twice). The concentrate was extracted with diethyl ether and washed with an aqueous sodium hydrogen carbonate solution. The product was dried over anhydrous sodium sulfate and concentrated under a reduced pressure. The residue was purified by separation by silica gel column chromatography (ethyl acetate→methanol:ethyl acetate=15:85) to give 10.7 g of the desired product (yield 91.0%).
Reaction SMILES: [NH2:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:9])[NH2:8].[C:13](Cl)(=[O:25])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24].[OH-].[Na+].S(=O)(=O)(O)O>O.C(O)(C)(C)C>[C:13]([NH:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:8])[NH2:9])(=[O:25])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: N=C(N)NCCC[C@H](N)C(=O)O
Reactant: CCCCCCCCCCCC(=O)Cl
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)(C)O
Product: CCCCCCCCCCCC(=O)N[C@@H](CCCNC(=N)N)C(=O)O
Temperature: 12.5 °C
Yield: 89.9 %

Procedure:
L-Arginine (50 g) was added with t-butyl alcohol (315 g) and water (125 g). The reaction mixture was added dropwise with lauroyl chloride (69 g) and 27 wt % aqueous sodium hydroxide (50 g) over 1 hour and 20 minutes, while the system was maintained at 10 to 15° C. and pH 10 to 11. After the addition, the reaction mixture was warmed to 45° C., added with sulfuric acid (17 g) and uniformly dissolved. Then, the system was adjusted to pH 4.9 with further addition of 27 wt % aqueous sodium hydroxide. The deposited crystals were collected by filtration and washed with water to obtain white crystals (92 g, yield: 90%).
Reaction SMILES: CCN(C(C)C)C(C)C.Cl.Cl.[N:12]1([C:18]2[CH:23]=[CH:22][N:21]=[C:20]3[NH:24][N:25]=[C:26]([O:27][CH2:28][CH:29]([OH:32])[CH2:30][OH:31])[C:19]=23)[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.[C:33]([O:37][C:38]([NH:40][C@H:41]([CH2:45][C:46]1[CH:51]=[CH:50][C:49]([Cl:52])=[CH:48][CH:47]=1)[C:42](O)=[O:43])=[O:39])([CH3:36])([CH3:35])[CH3:34].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>C(Cl)Cl>[Cl:52][C:49]1[CH:50]=[CH:51][C:46]([CH2:45][C@@H:41]([NH:40][C:38](=[O:39])[O:37][C:33]([CH3:35])([CH3:34])[CH3:36])[C:42]([N:15]2[CH2:16][CH2:17][N:12]([C:18]3[CH:23]=[CH:22][N:21]=[C:20]4[NH:24][N:25]=[C:26]([O:27][CH2:28][CH:29]([OH:32])[CH2:30][OH:31])[C:19]=34)[CH2:13][CH2:14]2)=[O:43])=[CH:47][CH:48]=1
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccc(Cl)cc1)C(=O)O
Reactant: OCC(O)COc1n[nH]c2nccc(N3CCNCC3)c12
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N[C@H](Cc1ccc(Cl)cc1)C(=O)N1CCN(c2ccnc3[nH]nc(OCC(O)CO)c23)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
DIEA (0.0514 mL, 0.295 mmol) was added to 3-(4-(piperazin-1-yl)-1H-pyrazolo[3,4-b]pyridin-3-yloxy)propane-1,2-diol dihydrochloride (0.030 g, 0.0737 mmol, see Example 7), (R)-2-(tert-butoxycarbonylamino)-3-(4-chlorophenyl)propanoic acid (0.022 g, 0.074 mmol) and TBTU (0.0284 g, 0.0885 mmol) in DCM (1 mL) and stirred at room temperature for 1 hour. The reaction was concentrated to dryness. The resulting residue was dissolved in THF/MeOH (2 mL, 1:1), and a LiOH solution (1 mL, 2M) was added. The solution was stirred for 30 minutes. Ether (20 mL) was then added. The organic layer was separated, washed with brine (10 mL), and dried over sodium sulfate. After removal of solvent, the resulting residue was purified by chromatography (ethyl acetate:MeOH, 20:1) to give tert-butyl(2R)-3-(4-chlorophenyl)-1-(4-(3-(2,3-dihydroxypropoxy)-1H-pyrazolo[3,4-b]pyridin-4-yl)piperazin-1-yl)-1-oxopropan-2-ylcarbamate as a solid. The solid was dissolved in DCM (1 mL), and TFA (0.4 mL) was added. The mixture was stirred at room temperature for 1 hour and then concentrated to dryness. The resulting residue was dissolved in DCM (0.5 mL), and HCl in ether (1 mL, 2N) was added. The resulting solid was collected by filtration to give (2R)-2-amino-3-(4-chlorophenyl)-1-(4-(3-(2,3-dihydroxypropoxy)-1H-pyrazolo[3,4-b]pyridin-4-yl)piperazin-1-yl)propan-1-one (0.010 g, 25%). MS APCI (+) m/z 475.2 detected.