Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[C:5]([O:9][C:10](=[O:31])[NH:11][CH2:12][C@H:13]([OH:30])[CH2:14][NH:15][C:16]1[CH:17]=[C:18]2[C:22](=[C:23]([F:25])[CH:24]=1)[N:21]([CH:26]1[CH2:28][CH2:27]1)[C:20](=[O:29])[CH2:19]2)([CH3:8])([CH3:7])[CH3:6].C(N(CC)CC)C>ClCCl>[C:5]([O:9][C:10](=[O:31])[NH:11][CH2:12][C@@H:13]1[O:30][C:1](=[O:2])[N:15]([C:16]2[CH:17]=[C:18]3[C:22](=[C:23]([F:25])[CH:24]=2)[N:21]([CH:26]2[CH2:27][CH2:28]2)[C:20](=[O:29])[CH2:19]3)[CH2:14]1)([CH3:8])([CH3:6])[CH3:7]
Reactant: O=C(Cl)Cl
Reactant: CC(C)(C)OC(=O)NC[C@H](O)CNc1cc(F)c2c(c1)CC(=O)N2C1CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC[C@H]1CN(c2cc(F)c3c(c2)CC(=O)N3C2CC2)C(=O)O1
Reaction time: 0.5 h

Procedure:
Phosgene (20% solution in toluene, 0.754 ml, 7.71 mmol) is added to (R)-[3-(1-cyclopropyl-7-fluoro-2-oxo-2,3-dihydro-1H-indol-5-ylamino)-2-hydroxy-propyl]-carbamic acid tert-butyl ester (0.390 g, 1.03 mmol) and triethylamine (0.711 ml, 5.13 mmol) in dichloromethane (5 ml) at 0° C. and stirred for 30 minutes. The mixture is diluted with dichloromethane, washed with water and brine, dried (Na2SO4) and evaporated to give the title compound as a yellow solid. HPLC r.t. 4.96 min; MS for C20H24FN3O5 m/z 406 (M+H)+.
Reaction SMILES: C([O:3][C:4]([C@@H:6]1[C@@H:11]2[C@H:7]1[CH2:8][C@@H:9]([O:23][CH2:24][CH:25]=[CH2:26])[C@@:10]2([NH2:22])[C:12]([O:14]CC1C=CC=CC=1)=[O:13])=[O:5])C.O[Li].O.Cl>C1COCC1.O.CO>[CH2:24]([O:23][C@@H:9]1[CH2:8][C@@H:7]2[C@@H:11]([C@H:6]2[C:4]([OH:5])=[O:3])[C@:10]1([NH2:22])[C:12]([OH:14])=[O:13])[CH:25]=[CH2:26]
Reactant: C=CCO[C@@H]1C[C@H]2[C@H](C(=O)OCC)[C@H]2[C@]1(N)C(=O)OCc1ccccc1
Agent: Cl
Agent: [Li]O
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: C=CCO[C@@H]1C[C@H]2[C@H](C(=O)O)[C@H]2[C@]1(N)C(=O)O
Temperature: 23 °C

Procedure:
A solution of (1S,2R,3R,5R,6S)-3-allyloxy-2-amino-bicyclo [3.1.0]hexane-2,6-dicarboxylic acid 2-benzyl ester 6-ethyl ester (XXIV-2) (47 mg, 0.131 mmol) and LiOH.H2O (15 mg, 0.357 mmol) in THF (4 mL), H2O (2 mL) and MeOH (0.4 mL) was stirred at 23° C. for 36 h. The solution was acidified with conc. HCl and evaporated to dryness. The remaining pale yellow solid was suspended in EtOH, filtered, washed with more EtOH and the filtrate was evaporated to dryness. The residue was dissolved in EtOH (1 mL) and propylene oxide (1 mL) and refluxed for 3 min, whereupon the amino acid precipiated. After cooling to 23° C., the product was filtered off, washed with ether and dried to give (1S,2R,3R,5R,6S)-3-allyloxy-2-amino-bicyclo[3.1.0]hexane-2,6-dicarboxylic acid (I-9) (19 mg, 59%) as a white solid. 1H-NMR (250 MHz, D2O) □1.48 (1H, t, J=3.5 Hz), 1.78 (2H, m), 1.98 (1H, ddd, J=12.5, 8,3.5 Hz), 2.27 (1H, dd, J=12.5, 7 Hz), 3.44 (1H, bt, J=7.5 Hz), 3.97 (2H, m), 5.13-5.26 (2H, m), 5.82 (1H, ddt, J=18, 11, 6 Hz); MS[ISN] 240 [(M-H)- ]; mp>250° C.; ΞD20 -10.62° (c=0.40, H2O).
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])C.C(O)=O.[NH2:11][C:12]1[N:17]=[C:16]([CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:15]=[CH:14][CH:13]=1.O>C(OCC)(=O)C>[CH:1]([NH:11][C:12]1[N:17]=[C:16]([CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:15]=[CH:14][CH:13]=1)=[O:3]
Reactant: CCOC(=O)Cc1cccc(N)n1
Reactant: CC(=O)OC(C)=O
Solvent: O
Solvent: O=CO
Solvent: CCOC(C)=O
Product: CCOC(=O)Cc1cccc(NC=O)n1
Reaction time: 0.5 h

Procedure:
Acetic anhydride (16.6 ml.) and 98% formic acid (7.32 ml.) were mixed at room temperature and stirred at 50° to 66° C. for 30 minutes. The solution was dropwise added to a solution of ethyl 2-(6-aminopyridin-2-yl)acetate (26.5 g.) in ethyl acetate (250 ml.) at 20° to 23° C. over 30 minutes, and stirred at the same temperature for one hour. Cool water was added to the resultant solution and shaked sufficiently. The ethyl acetate layer was separated, washed with water, an aqueous solution of sodium bicarbonate and water in turn, dried and concentrated under reduced pressure to give ethyl 2-(6-formamidopyridin-2-yl)acetate (28 g.), mp 35° to 38° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:18]([N+:19]([O-])=O)=[C:17]([OH:22])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:23]([O:30][C:31]1[C:40]([N+:41]([O-])=O)=[C:39]([OH:44])[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][N:37]=2)[N:32]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[NH2:19][C:18]1[C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[N:10][C:11]2[C:16]([C:17]=1[OH:22])=[CH:15][CH:14]=[CH:13][CH:12]=2.[NH2:41][C:40]1[C:31]([O:30][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[N:32][C:33]2[C:38]([C:39]=1[OH:44])=[N:37][CH:36]=[CH:35][CH:34]=2
Reactant: O=[N+]([O-])c1c(OCc2ccccc2)nc2cccnc2c1O
Reactant: O=[N+]([O-])c1c(OCc2ccccc2)nc2ccccc2c1O
Product: Nc1c(OCc2ccccc2)nc2ccccc2c1O
Product: Nc1c(OCc2ccccc2)nc2cccnc2c1O

Procedure:
In step (4) of Reaction Scheme V, a benzyloxy-3-nitroquinolin-4-ol or benzyloxy-3-nitro[1,5]naphthyridin-4-ol of Formula XLVI is reduced to provide a 3-amino-benzyloxyquinolin-4-ol or 3-aminobenzyloxy[1,5]naphthyridin-4-ol of Formula XLVII. The reaction can be carried out by hydrogenation using a heterogeneous hydrogenation catalyst such as platinum on carbon. The hydrogenation is conveniently carried out in a Parr apparatus in a suitable solvent such as dimethylformamide (DMF). The reaction can be carried out at ambient temperature, and the product or the hydrochloride salt thereof can be isolated using conventional methods.
Reaction SMILES: CO[C:3](=[O:15])[C@H:4]([CH2:13][OH:14])[NH:5][C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7].[CH2:16]([Mg]Br)[CH3:17].[Cl-].[NH4+].[CH2:22](OCC)[CH3:23]>>[CH2:22]([C:3]([OH:15])([CH2:16][CH3:17])[CH:4]([NH:5][C:6](=[O:7])[O:8][C:9]([CH3:10])([CH3:11])[CH3:12])[CH2:13][OH:14])[CH3:23]
Reactant: COC(=O)[C@H](CO)NC(=O)OC(C)(C)C
Reactant: CCOCC
Reactant: CC[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Product: CCC(O)(CC)C(CO)NC(=O)OC(C)(C)C
Temperature: -78 °C
Yield: 79 %

Procedure:
Boc-serine methyl ester (6.30 g) was dissolved in diethyl ether (150 ml), and a solution of ethyl magnesium bromide (in 3 M diethyl ether, 57 ml) was added dropwise thereto while the mixture was cooled to −78° C. After addition by dropping, the temperature of the reaction mixture was elevated to room temperature, and mixed at room temperature for 2 hours. The reaction mixture was again cooled to 0° C., and a saturated aqueous ammonium chloride solution was added dropwise thereto. The organic layer was collected by separation, and the aqueous layer was extracted three times with ethyl acetate. The extracts were all mixed, washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound as a colorless oil (1.10 g, 79%).
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH:8]2[CH2:13][C:12]([CH3:15])([OH:14])[CH2:11][CH:10]([C:16]3[C:21]([CH3:22])=[CH:20][CH:19]=[CH:18][N:17]=3)[NH:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.Br[CH2:24][CH2:25][CH2:26][CH2:27][N:28]1[C:36](=[O:37])[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:29]1=[O:38].CCN(C(C)C)C(C)C>CN(C=O)C>[OH:14][C:12]1([CH3:15])[CH2:13][CH:8]([C:3]2[C:2]([CH3:1])=[CH:7][CH:6]=[CH:5][N:4]=2)[N:9]([CH2:24][CH2:25][CH2:26][CH2:27][N:28]2[C:36](=[O:37])[C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[C:29]2=[O:38])[CH:10]([C:16]2[C:21]([CH3:22])=[CH:20][CH:19]=[CH:18][N:17]=2)[CH2:11]1
Reactant: O=C1c2ccccc2C(=O)N1CCCCBr
Reactant: Cc1cccnc1C1CC(C)(O)CC(c2ncccc2C)N1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cccnc1C1CC(C)(O)CC(c2ncccc2C)N1CCCCN1C(=O)c2ccccc2C1=O
Temperature: 60 °C
Reaction time: 24 h

Procedure:
To a solution of meso-2′β,6′β-[3,4′,3″-trimethyl-1′,2′,3′,4′,5′,6′-hexahydro-[2,2′;6′,2″]terpyridin-4′-ol (0.2499 g, 0.84 mmol) in DMF (9 mL) was added 2-(4-bromo-butyl)-isoindole-1,3-dione (0.2605 g, 0.92 mmol), KI (0.0142 g, 0.08 mmol), and DIPEA (0.29 mL, 1.68 mmol), and stirred at 60° C. for 24 hours. The mixture was concentrated, and saturated NaHCO3 (30 mL) was added and extracted with CH2Cl2 (3×35 mL). The combined organic extracts were washed with brine (2×20 mL), dried (Na2SO4), filtered, and concentrated. Purification of the crude material by column chromatography on silica gel (50:1:1 CH2Cl2—MeOH—NH4OH) provided 0.3144 g (75%) of meso-2′β,6′β-[2-[4-(4′-hydroxy-3,4′,3″-trimethyl-3′,4′,5′,6′-tetrahydro-2′H-[2,2′;6′,2″]terpyridin-1′yl)-butyl]-isoindole-1,3-dione as a white solid. 1H NMR (CDCl3) δ 0.48 (s, 1H), 0.86 (s, 2H), 1.42 (s, 3H), 1.68-1.72 (m, 2H), 2.18-2.38 (m, 6H), 2.45 (s, 6H), 3.15 (t, 2H, J=6.0 Hz), 4.13 (d, 2H, J=12.0 Hz), 6.94-7.03 (m, 2H), 7.25-7.34 (m, 2H), 7.67-7.70 (m, 2H), 7.75-7.78 (m, 2H), 8.32-8.34 (m, 2H).
Reaction SMILES: [C:1](#[N:3])[CH3:2].[OH2:4].C(N(CC)CC)C.[N:12]1[CH:17]=[CH:16][CH:15]=C[C:13]=1C>C(O)(=O)C>[CH2:16]([C:17]1[N:12]=[CH:13][N:3]=[C:1]([OH:4])[CH:2]=1)[CH3:15]
Reactant: CC#N
Reactant: O
Reactant: Cc1ccccn1
Solvent: CCN(CC)CC
Solvent: CC(=O)O
Product: CCc1cc(O)ncn1

Procedure:
12.9 g of methyl 3-amino-2-pentenoate, 45.1 g of formamide and 48.2 g of a 28 % methanolic solution of sodium methoxide are mixed and stirred under heating, and the methanol was distilled off until the internal temperature rose to 110° C. Subsequently, the reaction was carried out for 3 hours at 110° C. and after cooling, a quantitative analysis was carried out by high performance liquid (HPL) chromatography to reveal that 11.4 g of 6-ethyl-4-hydroxypyrimidine were formed (Yield: 91.9 mol %). After the reaction solution was neutralized with conc. sulfuric acid, the formed inorganic salt was removed off and the resulting filtrate was concentrated under a reduced pressure (5 mm Hg, 130° C., for 2 hours) and the residue obtained was subjected to recrystallization from acetone to give 10.1 g of a crystal of 6-ethyl-4-hydroxypyrimidine. m.p.: 131° to 134° C.; the conditions for HLP chromatography: column: ODS-80Tm; 4.6φ ×150 mm: detector: U.V. 254 nm; eluent: acetonitrile: water: triethylamine=500:500:1 adjusted to pH 6.5 with acetic acid; flow rate: 1 ml/min.; internal standard: α-picoline
Reaction SMILES: C(OC(Cl)=O)C.[Cl:7][C:8]1[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][CH:9]=1.C(N(CC)CC)C.[NH2:24][CH2:25][CH2:26][N:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1>CC(C)=O>[Cl:7][C:8]1[CH:9]=[CH:10][C:11]([C:12]([NH:24][CH2:25][CH2:26][N:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)=[O:14])=[CH:15][CH:16]=1
Reactant: NCCN1CCOCC1
Reactant: O=C(O)c1ccc(Cl)cc1
Agent: CCOC(=O)Cl
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: O=C(NCCN1CCOCC1)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
5.3 Ml. of chloroformic acid ethyl ester are added dropwise to a solution of 8.6 g. of p-chlorobenzoic acid and 7.6 ml. of triethylamine in 150 ml. of acetone, with stirring and cooling with ice-water. After one hour at 0° C., a solution of 6.5 g. of N-(2-aminoethyl)-morpholine in 50 ml. of acetone is added dropwise to the mixture and the mixture is then stirred overnight at room temperature. Thereafter it is concentrated, allowed to stand for 2 hours in the refrigerator and filtered. The filtrate is evaporated to dryness and the residue is taken up in 250 ml. of water and 250 ml. of methylene chloride. The phases are separated and the methylene chloride extract is dried over sodium sulfate and evaporated. The residue is recrystallized from isopropanol and 7.8 g. of p-chloro-N-(2-morpholinoethyl)-benzamide are obtained, which is identical to the product obtained in Example 1.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:24][NH2:25])=[N:4][CH:5]=[C:6](/[CH:8]=[CH:9]/[CH:10]([C:15]2[CH:20]=[C:19]([Cl:21])[C:18]([Cl:22])=[C:17]([Cl:23])[CH:16]=2)[C:11]([F:14])([F:13])[F:12])[CH:7]=1.[F:26][C:27]([F:33])([F:32])[CH2:28][C:29](O)=[O:30].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.O.CCN(C(C)C)C(C)C>C(Cl)Cl>[Cl:1][C:2]1[C:3]([CH2:24][NH:25][C:29](=[O:30])[CH2:28][C:27]([F:33])([F:32])[F:26])=[N:4][CH:5]=[C:6](/[CH:8]=[CH:9]/[CH:10]([C:15]2[CH:20]=[C:19]([Cl:21])[C:18]([Cl:22])=[C:17]([Cl:23])[CH:16]=2)[C:11]([F:14])([F:12])[F:13])[CH:7]=1
Reactant: NCc1ncc(/C=C/C(c2cc(Cl)c(Cl)c(Cl)c2)C(F)(F)F)cc1Cl
Reactant: O=C(O)CC(F)(F)F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: ClCCl
Product: O=C(CC(F)(F)F)NCc1ncc(/C=C/C(c2cc(Cl)c(Cl)c(Cl)c2)C(F)(F)F)cc1Cl
Yield: 27.8 %

Procedure:
To a stirred solution of (E)-(3-chloro-5-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)pyridin-2-yl)methanamine (0.1 g, 0.2 mmol) in CH2Cl2 (5 mL) were added 3,3,3-trifluoropropanoic acid (45 mg, 0.350 mmol), EDC.HCl (67 mg, 0.350 mmol), HOBt.H2O (71 mg, 0.467 mmol) and DIPEA (60.2 mg, 0.467 mmol), and the reaction mixture was stirred at ambient temperature for 18 h. The reaction mixture was diluted with CH2Cl2 and washed with water. The combined CH2Cl2 layer was washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. Purification by flash column chromatography (SiO2, 100-200 mesh; 15% EtOAc in petroleum ether) afforded the title compound as a pale yellow liquid (30 mg, 35%): 1H NMR (400 MHz, CDCl3) δ 8.41 (s, 1H), 7.77 (s, 1H), 7.47 (br s, 1H), 7.40 (s, 2H), 6.58 (d, J=16.0 Hz, 1H), 6.45 (dd, J=16.0, 8.0 Hz, 1H), 4.68 (d, J=4.0 Hz, 2H), 4.14 (m, 1H), 3.24 (q, J=10.8 Hz, 2H); ESIMS m/z 536.88 ([M−H]−); IR (thin film) 3320, 1674, 1114, 808.
Reaction SMILES: C(N)CCC.C(OC1C2N=NN(CC)C=2[C:12](C(O)=O)=[C:11]([CH3:23])[N:10]=1)C.[CH2:24]([O:26][C:27]([C:29]1[C:30]2[N:41]([CH2:42][CH3:43])[N:40]=[N:39][C:31]=2[C:32](OCC)=[N:33][C:34]=1[CH3:35])=[O:28])[CH3:25]>>[CH2:24]([O:26][C:27]([C:29]1[C:30]2[N:41]([CH2:42][CH3:43])[N:40]=[N:39][C:31]=2[C:32]([NH:10][CH:11]([CH3:23])[CH3:12])=[N:33][C:34]=1[CH3:35])=[O:28])[CH3:25]
Reactant: CCOC(=O)c1c(C)nc(OCC)c2nnn(CC)c12
Reactant: CCOc1nc(C)c(C(=O)O)c2c1nnn2CC
Solvent: CCCCN
Product: CCOC(=O)c1c(C)nc(NC(C)C)c2nnn(CC)c12

Procedure:
The following additional compounds are obtained by the procedure of Example 2 by substituting the appropriate amine for the butylamine and another product of Example 1 for the 4-ethoxy-1-ethyl-6-methyl-1H-1,2,3-triazolo[4,5-c]pyridine-7-carboxylic acid ethyl ester:
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12](O)([C:18]([F:21])([F:20])[F:19])[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC(C(F)(F)F)=O)(C(F)(F)F)=O.N1C=CC=CC=1>C(OCC)C>[CH2:1]([O:8][C:9]([N:11]=[C:12]([C:18]([F:19])([F:21])[F:20])[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(O)(NC(=O)OCc1ccccc1)C(F)(F)F
Solvent: c1ccncc1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: CCOCC
Product: CCOC(=O)C(=NC(=O)OCc1ccccc1)C(F)(F)F
Temperature: 25 °C
Reaction time: 6 h
Yield: 97 %

Procedure:
To a solution of ethyl 2-(benzyloxycarbonylamino)-3,3,3-trifluoro-2-hydroxypropanoate (49.0 g, 153 mmol) in diethyl ether (350 mL) was added dropwise TFAA (35.3 g, 168 mmol) at 0° C. followed by addition of pyridine dropwise (26.5 g, 336 mmol) at 0° C. The reaction mixture was allowed to warm to ambient temperature and stirred for 6 h. The mixture was filtered and the filtrate was concentrated to afford ethyl 2-(benzyloxycarbonylimino)-3,3,3-trifluoropropanoate (45.0 g, 97% yield), which was used directly without further purification.
Reaction SMILES: [OH:1][N:2]=[C:3](Cl)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[C:11]([C:13]1[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=1)#[CH:12].C(N(CC)CC)C.O>O1CCCC1>[C:4]1([C:3]2[CH:12]=[C:11]([C:13]3[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=3)[O:1][N:2]=2)[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: ON=C(Cl)c1ccccc1
Reactant: C#Cc1ccc(C(=O)OC)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1ccc(-c2cc(-c3ccccc3)no2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 87 %

Procedure:
To a solution (100 ml) of N-hydroxybenzenimidoyl chloride (2.25 g) and methyl 4-ethynylbenzoate (2.30 g) in tetrahydrofuran was added dropwise a solution (10 ml) of triethylamine (2.30 ml) in tetrahydrofuran under an argon atmosphere at 0° C. This mixture was stirred overnight at room temperature and poured into water. The mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was recrystallized from hexane-tetrahydrofuran to give methyl 4-(3-phenyl-5-isoxazolyl)benzoate (3.49 g, yield 87%) as colorless crystals. melting point: 205–206° C.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:14]=[CH:13][C:12]([N:15]3[C:19]4=[N:20][CH:21]=[N:22][CH:23]=[C:18]4[CH:17]=[N:16]3)=[CH:11][CH:10]=2)O1.[OH-:25].[Na+].OO>C1COCC1>[N:15]1([C:12]2[CH:13]=[CH:14][C:9]([OH:25])=[CH:10][CH:11]=2)[C:19]2=[N:20][CH:21]=[N:22][CH:23]=[C:18]2[CH:17]=[N:16]1
Reactant: CC1(C)OB(c2ccc(-n3ncc4cncnc43)cc2)OC1(C)C
Reactant: [OH-]
Agent: OO
Agent: [Na+]
Solvent: C1CCOC1
Product: Oc1ccc(-n2ncc3cncnc32)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
The title compound 4-(1H-pyrazolo[3,4-d]pyrimidin-1-yl)phenol (22) was prepared by the following procedure: To a solution of 1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-pyrazolo[3,4-d]pyrimidine (22C) (100 mg, 0.31 mmol) in THF (5 mL) was added NaOH (0.248 mL, 0.621 mmol) and hydrogen peroxide (0.048 mL, 0.466 mmol). The mixture was stirred at 0° C. for 30 minutes The reaction mixture was concentrated and the residue was dissolved water (8 mL). The aqueous solution was acidified with diluted HCl. The white precipitate was collected, washed with water and dried to provide the title compound 4-(1H-pyrazolo[3,4-d]pyrimidin-1-yl)phenol (22): 1H NMR (400 MHz, DMSO-D6) δ ppm 9.75 (1H, s), 9.44 (1H, s), 9.09 (1H, s), 8.59 (1H, s), 7.82-7.99 (2H, m), 6.83-7.05 (2H, m).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[C@H:5]([OH:23])[CH2:6][C@H:7]([NH2:22])[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[CH:16]=2)=[CH:11][CH:10]=1)[CH3:2].C(O)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28]C=1.Cl.O1CCOCC1.[OH:40][C:41]1[N:45]([CH3:46])[N:44]=[C:43]([C:47](O)=[O:48])[CH:42]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN(C=O)C.CCN(C(C)C)C(C)C>>[CH2:1]([O:3][C:4](=[O:24])[C@H:5]([OH:23])[CH2:6][C@H:7]([NH:22][C:47]([C:43]1[CH:42]=[C:41]([OH:40])[N:45]([CH3:46])[N:44]=1)=[O:48])[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[CH:16]=2)=[CH:11][CH:10]=1)[C:2]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:26]=1
Reactant: Cn1nc(C(=O)O)cc1O
Reactant: OCc1ccccc1
Reactant: CCOC(=O)[C@H](O)C[C@H](N)Cc1ccc(-c2cccc(Cl)c2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cn1nc(C(=O)N[C@H](Cc2ccc(-c3cccc(Cl)c3)cc2)C[C@@H](O)C(=O)OCc2ccccc2)cc1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.6 %

Procedure:
A mixture of (2R,4R)-4-amino-5-(3′-chlorobiphenyl-4-yl)-2-hydroxypentanoic acid ethyl ester (150.0 mg, 431 μmol), benzyl alcohol (446.2 μL, 4.3 mmol), and 4.0 M HCl in 1,4-dioxane (431 μL, 1.7 mmol) was stirred at room temperature overnight, then at 50° C. for 1 hour. The mixture was then concentrated under reduced pressure. 5-Hydroxy-1-methyl-1H-pyrazole-3-carboxylic acid (30.6 mg, 216 μmol) and HATU (98.4 mg, 259 mol) were stirred in DMF (0.5 mL, 5 mmol) for 10 minutes, then added to the concentrated mixture, along with DIPEA (113 μL, 647 μmol). The resulting mixture was stirred at room temperature for 2 hours and concentrated under reduced pressure. The residue was dissolved in 50% AcOH-water (5 mL), filtered, and purified by reverse phase preparative HPLC to yield the title compound (81.4 mg).
Reaction SMILES: [OH:1][C@@H:2]1[C@H:6]([CH2:7][CH:8]([CH3:10])[CH3:9])[NH:5][C:4](=[O:11])[CH2:3]1.O1CCCC1.[O:17]1[CH:22]=[CH:21][CH2:20][CH2:19][CH2:18]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>ClCCl>[CH3:10][CH:8]([CH3:9])[CH2:7][CH:6]1[NH:5][C:4](=[O:11])[CH2:3][CH:2]1[O:1][CH:18]1[CH2:19][CH2:20][CH2:21][CH2:22][O:17]1
Reactant: C1=COCCC1
Reactant: CC(C)C[C@@H]1NC(=O)C[C@@H]1O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: O
Product: CC(C)CC1NC(=O)CC1OC1CCCCO1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 2.8 g (17.8 mmol) of (4S-cis)-4-hydroxy-5-(2-methylpropyl)-2-pyrrolidinone, 20 ml of tetrahydrofuran and 20 ml of dichloromethane is treated with 1.8 ml (19.7 mmol) of 3,4-dihydro-2H-pyran and 150 mg (0.79 mmol) of para-toluenesulfonic acid hydrate. The resulting solution is stirred at room temperature overnight and then partitioned between ethyl acetate and a 5% aqueous solution of sodium bicarbonate. The organic layer is separated, dried over magnesium sulfate, evaporated, and the residue filtered through a 175 ml bed of silica gel. Elution with hexane-ethyl acetate (1:1 then 1:2 and finally 0:1) affords 5-(2-methylpropyl)-4-[(tetrahydro-2H-pyran-2-yl)oxy]-2-pyrrolidinone, (pyranyl center R, S; other centers S) after evaporation from diethyl ether; mp 67°-69° C.
Reaction SMILES: C([O:5][C:6]([NH:8][C:9]1([C:13]2[CH:18]=[CH:17][C:16]([C:19]3[C:28]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)=[CH:27][C:26]4[C:25](=O)[CH:24]([C:36](OC)=[O:37])[CH2:23][CH2:22][C:21]=4[N:20]=3)=[CH:15][CH:14]=2)[CH2:12][CH2:11][CH2:10]1)=O)(C)(C)C.[OH2:40].[NH2:41][NH2:42]>C(O)C>[C:9]([O:40][C:6](=[O:5])[NH:8][C:9]1([C:13]2[CH:18]=[CH:17][C:16]([C:19]3[C:28]([C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=4)=[CH:27][C:26]4[C:25]5=[N:41][NH:42][C:36]([OH:37])=[C:24]5[CH2:23][CH2:22][C:21]=4[N:20]=3)=[CH:15][CH:14]=2)[CH2:12][CH2:11][CH2:10]1)([CH3:13])([CH3:12])[CH3:10]
Reactant: O
Reactant: NN
Reactant: COC(=O)C1CCc2nc(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)c(-c3ccccc3)cc2C1=O
Solvent: CCO
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)-c3n[nH]c(O)c3CC4)cc2)CCC1
Temperature: 25 °C
Yield: 67.9 %

Procedure:
To a solution of methyl 2-(4-(1-((tert-butoxycarbonyl)amino)cyclobutyl)phenyl)-5-oxo-3-phenyl-5,6,7,8-tetrahydroquinoline-6-carboxylate (60 mg, 0.11 mmol) in anhydrous ethanol (1500 μL) was added hydrazine monohydrate (9 μL, 0.19 mmol). The reaction mixture was heated to reflux under a nitrogen atmosphere for 18 hours. After cooling to room temperature the reaction mixture was concentrated to dryness under reduced pressure, purified by Biotage chromatography (silica, dichloromethane:methanol, gradient elution from 99:1 to 90:10) and slurried in diethyl ether (1 mL) to give the desired product as a white solid (19 mg, 33% yield). 1H-NMR (500 MHz, CD3OD) δ 7.94 (1H, s), 7.32 (2H, d), 7.21-7.29 (5H, m), 7.14-7.21 (2H, m), 3.18 (2H, t), 2.81 (2H, t), 2.31-2.50 (4H, m), 2.00-2.12 (1, br m), 1.76-1.91 (1H, br m), 1.09-1.48 (br m). LCMS (Method A) RT=5.57 min, M+H+=509.17.
Reaction SMILES: [CH3:1][C:2]([N+:10]([O-])=[O:11])([C:4]([CH3:9])([N+:6]([O-])=[O:7])[CH3:5])[CH3:3].[NH4+].[Cl-]>C1COCC1.O.[Zn]>[OH:7][NH:6][C:4]([CH3:9])([C:2]([NH:10][OH:11])([CH3:3])[CH3:1])[CH3:5]
Reactant: CC(C)([N+](=O)[O-])C(C)(C)[N+](=O)[O-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(NO)C(C)(C)NO
Temperature: 9 °C
Reaction time: 1 h
Yield: 18376.1 %

Procedure:
2,3-Dimethyl-2,3-dinitrobutane (82.56 g, 0.47 mmol) was dissolved in a mixture of THF (1407 mL) and water (235 mL). To this solution cooled to 8-10° C., Zn powder (126.9 g, 1.95 mol) was added in one portion. A solution of NH4Cl (202.1 g, 3.77 mol) in H2O (705 mL) was added dropwise to this slurry, with continued stirring for 1 h at 10° C., and the flask was stored in cooled water for 16 h. The slurry was filtered, and the precipitate was carefully washed with THF (4×200 mL). The precipitate was then dried by three washings with diethyl ether and collected. The solution was evaporated under vacuum until THF ceased to distill off. Then the solution was protected from air, and sodium carbonate (235 g) and sodium chloride (141 g) were added with cooling. Continuous extraction with chloroform (1880 mL) was performed over 18 h. The filtrate was concentrated to give oil product, then added petroleum ether to this mixture and stirred for 30 min at room temperature, filtered, dried, to afford a white powder (12.8 g, 18.4% yield). 1HNMR (400 MHz, DMSO): δ 6.89 (s, 1H), 5.34 (s, 1H), 0.96 (s, 3H).