Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][N:2]=[C:3]([NH2:10])[C:4]1[CH:9]=[CH:8][CH:7]=[N:6][CH:5]=1.[F:11][C:12]1[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=1[C:14](O)=O.N>>[F:11][C:12]1[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=1[C:14]1[O:1][N:2]=[C:3]([C:4]2[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=2)[N:10]=1
Reactant: O=C(O)c1ccccc1F
Reactant: NC(=NO)c1cccnc1
Agent: N
Product: Fc1ccccc1-c1nc(-c2cccnc2)no1

Procedure:
The title compound was prepared according to the procedure of Example 8 using N′-hydroxynicotinimidamide (Aldrich) and 2-fluorobenzoic acid (Aldrich). 1H NMR (300 MHz, CD3OD) δ 7.38-7.49 (m, 2H), 7.64 (ddd, J=8.0, 4.9, 1.0 Hz, 1H), 7.70-7.79 (m, 1H), 8.28 (td, J=7.5, 1.9 Hz, 1H), 8.57 (dt, J=8.1, 1.9 Hz, 1H), 8.74 (dd, J=4.7, 1.7 Hz, 1H), 9.31 (dd, J=2.2, 0.8 Hz, 1H) ppm; MS (DCI/NH3) m/z 242 (M+H)+.
Reaction SMILES: C([O:3][C:4](=[O:25])[CH2:5][CH:6]1[O:10][B:9]([OH:11])[C:8]2[CH:12]=[C:13]([O:18][C:19]3[N:24]=[CH:23][CH:22]=[CH:21][N:20]=3)[CH:14]=[C:15]([CH2:16][CH3:17])[C:7]1=2)C.[Li+].[OH-].Cl>C1COCC1.O>[CH2:16]([C:15]1[C:7]2[CH:6]([CH2:5][C:4]([OH:25])=[O:3])[O:10][B:9]([OH:11])[C:8]=2[CH:12]=[C:13]([O:18][C:19]2[N:20]=[CH:21][CH:22]=[CH:23][N:24]=2)[CH:14]=1)[CH3:17]
Reactant: CCOC(=O)CC1OB(O)c2cc(Oc3ncccn3)cc(CC)c21
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCc1cc(Oc2ncccn2)cc2c1C(CC(=O)O)OB2O
Temperature: 25 °C
Reaction time: 2 h
Yield: 25.1 %

Procedure:
To a solution of [4-ethyl-1-hydroxy-6-(pyrimidin-2-yloxy)-1,3-dihydro-benzo[c][1,2]oxaborol-3-yl]-acetic acid ethyl ester (0.13 g, 0.38 mmol) in THF (8 mL) and H2O (2 mL) was added LiOH (0.091 g) at 0° C. The resulting mixture was stirred at room temperature for 2 hours then cooled to 0° C. and acidified to pH 3 with 6N HCl. The mixture was concentrated in vacuo and the residue purified by preparative HPLC to give [4-ethyl-1-hydroxy-6-(pyrimidin-2-yloxy)-1,3-dihydro-benzo[c][1,2]oxaborol-3-yl]-acetic acid (0.030 g, 25%). 1H NMR (400 MHz, DMSO-d6δ9.00 (br s, 1H), 8.63 (s, 1H), 8.62 (s, 1H), 7.25 (s, 1H), 7.24 (s, 1H), 7.23 (s, 1H), 7.10 (s, 1H), 5.51 (m, 1H), 3.01 (m, 1H), 2.61 (m, 2H), 2.14 (m, 1H), 1.17 (m, 3H). MS (ES) m/z: 313 (M−1)−. HPLC purity: 99.12% (220 nm), 98.58% (Maxplot).
Reaction SMILES: [CH2:1]([CH:5]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH:2]([CH3:4])[CH3:3].[H-].[Na+].Cl[C:19]1[CH:20]=[CH:21][C:22]([N+:29]([O-:31])=[O:30])=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:24]=1>CN(C=O)C>[CH2:1]([C:5]([C:19]1[CH:20]=[CH:21][C:22]([N+:29]([O-:31])=[O:30])=[C:23]([C:25]([F:26])([F:28])[F:27])[CH:24]=1)([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH:2]([CH3:4])[CH3:3]
Reactant: CCOC(=O)C(CC(C)C)C(=O)OCC
Reactant: O=[N+]([O-])c1ccc(Cl)cc1C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(CC(C)C)(C(=O)OCC)c1ccc([N+](=O)[O-])c(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 87.4 %

Procedure:
To a solution of diethyl isobutylmalonate (50.0 g, 231 mmol) in anhydrous DMF (200 mL) cooled in an ice bath was added NaH (60%, 11.1 g, 277 mmol) in small portions. After the addition, the reaction mixture was stirred at 0° C. for 10 min and then at room temperature for 30 min. 5-Chloro-2-nitrobenzotrifluoride (47.3 g, 210 mmol) in anhydrous DMF (50 mL) was added dropwise and the mixture was stirred at room temperature for two days. The DMF was removed under high vacuum and the residue was diluted with ethyl acetate (400 mL). Water (400 mL) was added dropwise; ammonium chloride (25 g) was added and the layers were separated. The organic layer was washed with brine (400 mL), dried over sodium sulfate, and concentrated under reduced pressure to give a red-brown oil, which was purified by silica-gel flash chromatography eluting with heptane/ethyl acetate (12:1) to give the desired product diethyl 2-isobutyl-2-(4-nitro-3-(trifluoromethyl)phenyl)malonate (74.4 g, 87%) as a yellow oil: 1H NMR (300 MHz, CDCl3): δ 8.07 (s, 1H), 7.94 (d, 2H, J=8.7 Hz), 7.88 (d, 2H, J=8.7 Hz), 4.25 (m, 4H), 2.33 (d, 2H, J=6.6 Hz), 1.51 (m, 1H), 1.26 (t, 6H, J=7.2 Hz), 0.84 (d, 6H, J=6.6 Hz); 13C NMR (75 MHz, CDCl3): δ 169.23, 146.71, 142.86, 132.94, 127.94 (q, J=5 Hz), 124.55, 123.12 (q, J=33 Hz), 121.79 (q, J=272 Hz), 62.19, 61.59, 44.16, 24.66, 23.66, 13.89.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]1[CH2:10][C:11]([CH:13]1[S:17][CH2:16][NH:15][C@@H:14]1[C:18]([OH:20])=O)=[O:12].[NH:21]1[CH2:27][CH2:26][CH2:25][C@H:22]1[CH2:23][OH:24].CCN=C=NCCCN(C)C.Cl>C(Cl)Cl>[CH2:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH2:1][CH:2]1[CH2:10][C:11]([CH:13]1[S:17][CH2:16][NH:15][C@@H:14]1[C:18]([N:21]1[CH2:27][CH2:26][CH2:25][C@H:22]1[CH2:23][OH:24])=[O:20])=[O:12]
Reactant: OC[C@@H]1CCCN1
Reactant: O=C(CC1Cc2ccccc2C1)C1SCN[C@@H]1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: O=C(CC1Cc2ccccc2C1)C1SCN[C@@H]1C(=O)N1CCC[C@H]1CO
Reaction time: 0.5 h
Yield: 42.4 %

Procedure:
3-(Indan-2-ylacetyl)-L-thioproline (4.40 g) and L-prolinol (1.53 g) were dissolved in 150 ml of methylene chloride, followed by addition of 2.90 g of WSC-HCl under agitation while cooling in ice and subsequent agitation for-another 30 minutes at room temperature. The reaction solution was washed sequentially in 5 HCl, saturated aqueous solution of sodium bicarbonate, saturated aqueous sodium chloride solution, followed by drying over anhydrous magnesium sulfate. After distilling off the solvent under reduced pressure, the residue was purified by column chromatography to obtain 2.40 g of 1-[3-(indan-2-yl-acetyl)-L-thioprolyl]-L-prolinol. Yield; 42%.
Reaction SMILES: C[O:2][C:3](=[O:36])[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:16]3=[CH:17][C:18]4[C:19]([CH3:28])([CH3:27])[CH2:20][CH2:21][C:22]([CH3:26])([CH3:25])[C:23]=4[CH:24]=[C:15]3[N:14]([CH3:29])[C:13]3[CH:30]=[CH:31][C:32]([C:34]#[N:35])=[CH:33][C:12]=3[N:11]=2)=[CH:6][CH:5]=1.[OH-].[Na+].Cl>CN(C=O)C.C1COCC1.O>[C:34]([C:32]1[CH:31]=[CH:30][C:13]2[N:14]([CH3:29])[C:15]3[C:16]([C:10]([C:7]4[CH:6]=[CH:5][C:4]([C:3]([OH:36])=[O:2])=[CH:9][CH:8]=4)=[N:11][C:12]=2[CH:33]=1)=[CH:17][C:18]1[C:19]([CH3:28])([CH3:27])[CH2:20][CH2:21][C:22]([CH3:25])([CH3:26])[C:23]=1[CH:24]=3)#[N:35]
Reactant: COC(=O)c1ccc(C2=Nc3cc(C#N)ccc3N(C)c3cc4c(cc32)C(C)(C)CCC4(C)C)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CN(C)C=O
Product: CN1c2ccc(C#N)cc2N=C(c2ccc(C(=O)O)cc2)c2cc3c(cc21)C(C)(C)CCC3(C)C
Reaction time: 24 h

Procedure:
To a solution of 4-(2-cyano-5,7,7,10,10-pentamethyl-7,8,9,10-tetrahydro-5H-5,13-diazabenzo[4,5]cyclohepta[1,2-b]naphthalen-12-yl)benzoic acid methyl ester (33) (R4=CH3, Z=H, 12.3 mmol) in DMF (15 mL) and THF (45 mL) is added 2 N NaOH (18.5 mmol) at room temperature. The reaction mixture is stirred at the same temperature for 1 day. The mixture is acidified by 1 N HCl (30 mL), diluted with H2O, and extracted with EtOAc. The organic layer is dried over MgSO4 and evaporated in vacuo. The resulting solid is washed with hexane and Et2O to give (34) (R4=CH3, Z=H): 1H-NMR (CDCl3) δ: 1.08 (3H, s), 1.15 (3H, s), 1.28 (3H, s), 1.32 (3H, s), 1.61-1.72 (4H, m), 3.28 (3H, s), 6.90 (1H, s), 6.63 (1H, s), 6.99 (1H, d), 7.41 (1H, dd), 7.57 (1H, d), 7.90 (2H, d), 8.17 (2H, d).
Reaction SMILES: [C:1]([CH2:3][CH2:4][P:5]([CH:10]([F:12])[F:11])(=[O:9])[O:6][CH2:7][CH3:8])#[N:2].N>C(O)C.[Ni]>[NH2:2][CH2:1][CH2:3][CH2:4][P:5]([CH:10]([F:12])[F:11])(=[O:9])[O:6][CH2:7][CH3:8]
Reactant: CCOP(=O)(CCC#N)C(F)F
Agent: [Ni]
Agent: N
Solvent: CCO
Product: CCOP(=O)(CCCN)C(F)F
Reaction time: 9 h

Procedure:
A solution of 1.0 g (5.1 mmol) of ethyl P-(2-cyanoethyl)-P-difluoromethyl-phosphinate in 10 ml of dry ethanol is treated with 4 g of liquid ammonia and 0.3 g of Raney nickel. The reaction mixture is hydrogenated at 50° for 9 hours at 100 mbar. The reaction mixture is cooled, filtrated and evaporated to dryness. Chromatographic purification yields ethyl P-(3-aminopropyl)-P-difluoromethyl-phosphinate as a colourless oil of Rf =0.22 (dichloromethane/methanol/aqueous ammonia; 80:19:1).
Reaction SMILES: Cl[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2([C:14]([O:16][CH3:17])=[O:15])[CH2:13][CH2:12]2)=[CH:7][CH:6]=1)=O.[NH2:18][C:19]([NH2:21])=[S:20]>C(O)C.C(OCC)(=O)C>[NH2:21][C:19]1[S:20][CH:2]=[C:3]([C:5]2[CH:10]=[CH:9][C:8]([C:11]3([C:14]([O:16][CH3:17])=[O:15])[CH2:13][CH2:12]3)=[CH:7][CH:6]=2)[N:18]=1
Reactant: NC(N)=S
Reactant: COC(=O)C1(c2ccc(C(=O)CCl)cc2)CC1
Solvent: CCOC(C)=O
Solvent: CCO
Product: COC(=O)C1(c2ccc(-c3csc(N)n3)cc2)CC1

Procedure:
A mixture of methyl 1-[4-(chloroacetyl)phenyl]cyclopropanecarboxylate (0.30 g, 1.2 mmol) and thiourea (0.18 g, 2.4 mmol) in ethanol (5.0 ml) was refluxed overnight. The reaction mixture was diluted with ethyl acetate and washed with saturated NaHCO3 and brine successively; then dried; and then concentrated. The residue was tritrurated with ether followed by filtration to afford the product. LC-MS: 275.1 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].O[CH2:12][NH:13][C:14](=[O:19])[C:15]([F:18])([F:17])[F:16]>S(=O)(=O)(O)O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:12][NH:13][C:14](=[O:19])[C:15]([F:18])([F:17])[F:16])=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9]
Reactant: O=C(NCO)C(F)(F)F
Reactant: O=[N+]([O-])c1ccccc1Cl
Agent: O=S(=O)(O)O
Product: O=C(NCc1ccc(Cl)c([N+](=O)[O-])c1)C(F)(F)F
Temperature: 75 °C
Yield: 30891.9 %

Procedure:
To a solution of 1-chloro-2-nitrobenzene (10.0 g, 0.063 mmol) in conc. sulphuric acid (150 mL) was added N-hydroxy methyl trifluoro acetamide (9.98 g, 0.069 mmol). The reaction mixture was heated at 70-80° C. for 24 h. The reaction mass was quenched in ice cold water, neutralised with sodium hydroxide and extracted with DCM. The organic layer was concentrated and the obtained crude product was purified by column chromatography on silica gel eluting with 4% EtOAc: pet. ether to afford 5.5 g of desired product. 1H NMR (300 MHz, DMSO d6): 4.48 (d, J=3.9 Hz, 2H), 7.62-7.64 (m, 1H), 7.72-7.78 (m, 1H), 7.97-8.01 (m, 1H), 10.09 (brs, 1H).
Reaction SMILES: [N+]([O-])([N+]([O-])=O)=O.N[C:8]1[CH:9]=[CH:10][C:11]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)=[C:12]([CH:15]=1)[C:13]#[N:14].[I-:22].[Na+].O>C(#N)C>[I:22][C:8]1[CH:9]=[CH:10][C:11]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)=[C:12]([CH:15]=1)[C:13]#[N:14]
Reactant: N#Cc1cc(N)ccc1-c1ccccn1
Reactant: [I-]
Agent: O=[N+]([O-])[N+](=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: N#Cc1cc(I)ccc1-c1ccccn1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
Dinitrogen tetroxide (2.2 equiv.) was added to a suspension of 5-amino-2-pyridin-2-ylbenzonitrile (0.85 mmol) in acetonitrile (8.5 mL) at −30° C. After 5 min, sodium iodide (1.28 mmol, 1.5 equiv.), and the mixture was stirred for 10 minutes. Water (10 mL) was added and the reaction was allowed to warm to room temperature over 30 min. The product was extracted with methylene chloride and the extracts were washed with saturated sodium thiosulfate solution and brine, dried over sodium sulfate and concentrated. The resulting residue was passed through a silica gel plug, rinsing with 2% methanol in methylene chloride to provide 5-iodo-2-pyridin-2-ylbenzonitrile, which was used without further purification.
Reaction SMILES: C(OC([NH:8][C:9]1[C:14]([C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:16])=[C:13]([CH3:25])[C:12]([CH2:26][CH2:27][CH3:28])=[CH:11][CH:10]=1)=O)(C)(C)C>Cl.O1CCOCC1>[NH2:8][C:9]1[C:14]([C:15]([O:17][CH2:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[O:16])=[C:13]([CH3:25])[C:12]([CH2:26][CH2:27][CH3:28])=[CH:11][CH:10]=1
Reactant: CCCc1ccc(NC(=O)OC(C)(C)C)c(C(=O)OCc2ccccc2)c1C
Agent: Cl
Solvent: C1COCCO1
Product: CCCc1ccc(N)c(C(=O)OCc2ccccc2)c1C
Yield: 112.9 %

Procedure:
A solution of Example 148A (0.38 g, 1.0 mmol) in 4N HCl/dioxane was stirred at ambient temperature overnight and concentrated to provide the desired product (0.32 g, 100%). 1H NMR (DMSO-d6) δ 0.86 (t, 3H), 1.40-1.52 (m, 2H), 2.16 (s, 3H), 2.22 (t, 2H), 5.34 (s, 2H), 7.11 (d, 1H), 7.30-7.50 (m, 5H); MS (ESI(+) m/e 284 (M+H)+.
Reaction SMILES: C([N:8]1[CH2:16][C@H:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:14][C@@:9]1([CH3:23])[C:10]([O:12][CH3:13])=[O:11])(OC(C)(C)C)=O.Cl>CO>[CH3:13][O:12][C:10](=[O:11])[C@:9]1([CH3:23])[CH2:14][C@@H:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:16][NH:8]1
Reactant: COC(=O)[C@]1(C)C[C@@H](c2ccccc2)CN1C(=O)OC(C)(C)C
Agent: Cl
Solvent: CO
Product: COC(=O)[C@]1(C)C[C@@H](c2ccccc2)CN1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of N-BOC-2-methyl-4-(S)-phenyl-(L)-proline, methyl ester from Step B (1.85 g, 5.8 mmol) in MeOH was bubbled HCl (g) over a 10 min period. The HCl saturated solution was allowed to stir at rt for 5 h, concentrated in vacuo and azeotroped with toluene. The crude product was used in the subsequent step.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[NH:5][C:6]2[C:11]([C:12]=1[CH:13]=[O:14])=[CH:10][CH:9]=[CH:8][CH:7]=2.I[CH3:16]>CN(C=O)C>[Cl:3][C:4]1[N:5]([CH3:16])[C:6]2[C:11]([C:12]=1[CH:13]=[O:14])=[CH:10][CH:9]=[CH:8][CH:7]=2
Reactant: O=Cc1c(Cl)[nH]c2ccccc12
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1c(Cl)c(C=O)c2ccccc21
Temperature: 0 °C
Yield: 75.5 %

Procedure:
NaH (60% dispersion in mineral oil) (0.9 g, 22.5 mmole) was added portionwise over 5 min to a solution of 2-chloro-1H-indole-3-carboxaldehyde (3.8 g, 21.2 mmole) and iodomethane (1.5 mL, 24 mmole) in DMF (50 mL) with stirring at 0° C. The reaction was allowed to warm to RT and stir for 4 h, then was concentrated under vacuum. The remaining residue was taken up in EtOAc, and the solution was washed with water then brine, dried (MgSO4), and concentrated to dryness. Trituration with 1:1 Et2O/petroleum ether, filtration, and drying under vacuum gave the title compound (3.10 g, 76%) as an off-white solid: 1H NMR (400 MHz, CDCl3) δ 10.12 (s, 1H), 8.29 (m, 1H), 7.33 (m, 3H), 3.81 (s, 3H); MS (ES) m/e 194.0 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[N:6]([CH2:7][C@@H:8]2[C@H:11]([NH:12]C(=O)OCC3C=CC=CC=3)[C:10](=[O:23])[NH:9]2)[N:5]=[N:4][N:3]=1>CCO.CO.[Pd]>[NH2:12][C@H:11]1[C@@H:8]([CH2:7][N:6]2[C:2]([CH3:1])=[N:3][N:4]=[N:5]2)[NH:9][C:10]1=[O:23]
Reactant: Cc1nnnn1C[C@H]1NC(=O)[C@H]1NC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Solvent: CCO
Product: Cc1nnnn1C[C@H]1NC(=O)[C@H]1N

Procedure:
Prepared in an analogous manner to example 4, step 3 using benzyl ((2R,3S)-2-((5-methyl-1H-tetrazol-1-yl)methyl)-4-oxoazetidin-3-yl)carbamate (97 mg, 0.31 mmol) and Pd on C (10%, 50 mg) in EtOH:MeOH (5:1, 3.0 mL) for 3 h. The crude residue was used as such in following step. LCMS: Rt=0.11 min, m/z=183.2 (M+1) Method 2m_acidic.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([C@H:15]([N:22]([CH3:36])[C:23](=[O:35])[CH2:24][C:25]2[CH:30]=[CH:29][C:28]([S:31]([CH3:34])(=[O:33])=[O:32])=[CH:27][CH:26]=2)[CH2:16][N:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)[CH:12]=[CH:13][CH:14]=1)C1C=CC=CC=1>C(O)C.[OH-].[Pd+2].[OH-]>[OH:8][C:9]1[CH:10]=[C:11]([C@H:15]([N:22]([CH3:36])[C:23](=[O:35])[CH2:24][C:25]2[CH:26]=[CH:27][C:28]([S:31]([CH3:34])(=[O:33])=[O:32])=[CH:29][CH:30]=2)[CH2:16][N:17]2[CH2:18][CH2:19][CH2:20][CH2:21]2)[CH:12]=[CH:13][CH:14]=1
Reactant: CN(C(=O)Cc1ccc(S(C)(=O)=O)cc1)[C@H](CN1CCCC1)c1cccc(OCc2ccccc2)c1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: CN(C(=O)Cc1ccc(S(C)(=O)=O)cc1)[C@H](CN1CCCC1)c1cccc(O)c1
Reaction time: 6 h

Procedure:
To a solution of Example 20 (1.79 g, 3.5 mmol) in ethanol (85 mL) was added palladium hydroxide (20% on carbon) (0.15 g). This was hydrogenated at 30° C. for 6 hours, filtered through Celite, and the solvent removed in vacuo to give a white foam, 3.4 mmol, 96%.
Reaction SMILES: [C:1]([NH:5][C:6]1[C:7]([CH3:27])=[N:8][C:9]2[C:14]([N:15]=1)=[C:13]([C:16]1[NH:20][C:19]3[C@H:21]([CH2:25][OH:26])[NH:22][C:23](=[O:24])[C:18]=3[CH:17]=1)[CH:12]=[CH:11][CH:10]=2)([CH3:4])([CH3:3])[CH3:2].[C:28](NC1C(C)=NC2C(N=1)=C(C1NC3[C@@H](CO)NC(=O)C=3C=1)C=CC=2)(C)(C)C.[H-].[Na+].CI>C1COCC1.CN(C=O)C>[C:1]([NH:5][C:6]1[C:7]([CH3:27])=[N:8][C:9]2[C:14]([N:15]=1)=[C:13]([C:16]1[N:20]([CH3:28])[C:19]3[CH:21]([CH2:25][OH:26])[NH:22][C:23](=[O:24])[C:18]=3[CH:17]=1)[CH:12]=[CH:11][CH:10]=2)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1nc2cccc(-c3cc4c([nH]3)[C@H](CO)NC4=O)c2nc1NC(C)(C)C
Reactant: Cc1nc2cccc(-c3cc4c([nH]3)[C@@H](CO)NC4=O)c2nc1NC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CI
Solvent: CN(C)C=O
Product: Cc1nc2cccc(-c3cc4c(n3C)C(CO)NC4=O)c2nc1NC(C)(C)C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 75 %

Procedure:
To a 25-mL round-bottomed flask was added (R)-2-(3-(tert-butylamino)-2-methylquinoxalin-5-yl)-6-(hydroxymethyl)-5,6-dihydropyrrolo[3,4-b]pyrrol-4(1H)-one and (S)-2-(3-(tert-butylamino)-2-methylquinoxalin-5-yl)-6-(hydroxymethyl)-5,6-dihydropyrrolo[3,4-b]pyrrol-4(1H)-one (469) (36 mg, 0.1 mmol), DMF (1 mL) and THF (1 mL). To the yellow suspension NaH (4 mg, 0.1 mmol, 60% in mineral oil) was added at RT. The reaction mixture was stirred at RT for 15 min and MeI (6 μt, 0.1 mmol) was added. The reaction mixture was stirred at RT for 1 h and the solvent was completely removed under vacuum. The crude material was absorbed onto a plug of silica gel and purified by chromatography through a Redi-Sep pre-packed silica gel column (12 g), eluting with a gradient of 3-8% MeOH in DCM to provide 2-(3-(tert-butylamino)-2-methylquinoxalin-5-yl)-6-(hydroxymethyl)-1-methyl-5,6-dihydropyrrolo[3,4-b]pyrrol-4(1H)-one (470) (28 mg, 75% yield, 50% ee) as a light yellow solid and a mixture of enantiomers. 1H NMR (400 MHz, DMSO-d6) δ 7.78 (dd, J=1.47, 8.12 Hz, 1H), 7.43-7.51 (m, 2H), 7.33-7.39 (m, 1H), 6.10 (s, 1H), 5.88 (s, 1H), 5.15 (t, J=5.38 Hz, 1H), 4.46 (t, J=6.16 Hz, 1H), 3.59 (t, J=5.97 Hz, 2H), 3.32 (s, 3H), 2.52 (s, 3H), 1.29 (s, 9H). m/z (ESI, +ve) 380.1 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]2[C:11](=[N:12][C:13]=1[CH3:14])[N:10]=[CH:9][C:8]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:7]2O)[CH3:2].N.P(Cl)(Cl)([Cl:24])=O>>[Cl:24][C:7]1[C:6]2[C:11](=[N:12][C:13]([CH3:14])=[C:4]([O:3][CH2:1][CH3:2])[CH:5]=2)[N:10]=[CH:9][C:8]=1[C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: CCOC(=O)c1cnc2nc(C)c(OCC)cc2c1O
Reactant: O=P(Cl)(Cl)Cl
Agent: N
Product: CCOC(=O)c1cnc2nc(C)c(OCC)cc2c1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Ethyl 6-ethoxy-4-hydroxy-7-methyl-1,8-naphthyridine-3-carboxylate (2.5 g) was added to phosphorus oxychloride (20 ml) with stirring at ambient temperature. The mixture was warmed to 40° C. and kept at this temperature for 1 hour then cooled to 10° C. The mixture was added to excess ice/water and the mixture basified with aqueous ammonia solution (specific gravity 0.88) while keeping the temperature below 5° C. The product was extracted into dichloromethane. The combined dichloromethane extracts were evaporated under reduced pressure at ambient temperature to give ethyl 4-chloro-6-ethoxy-7-methyl-1,8-naphthyridine-3-carboxylate, m.p. >250° C.
Reaction SMILES: N#N.[OH:3][CH:4](CO)[CH2:5][O:6][C:7]([NH:9][C@H:10]([C:14]([NH:16][CH:17]([CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)[CH:18]([OH:40])[CH2:19][NH:20][CH2:21][CH:22]([OH:39])[CH:23]([NH:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:15])[CH:11]([CH3:13])[CH3:12])=[O:8]>CO>[CH3:37][C:35]([CH3:36])([O:34][C:32]([NH:31][CH:23]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH:22]([OH:39])[CH2:21][NH:20][CH2:19][CH:18]([OH:40])[CH:17]([NH:16][C:14](=[O:15])[C@H:10]([CH:11]([CH3:13])[CH3:12])[NH:9][C:7]([O:6][CH2:5][CH2:4][OH:3])=[O:8])[CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)=[O:33])[CH3:38]
Reactant: CC(C)[C@H](NC(=O)OCC(O)CO)C(=O)NC(Cc1ccccc1)C(O)CNCC(O)C(Cc1ccccc1)NC(=O)OC(C)(C)C
Agent: N#N
Solvent: CO
Product: CC(C)[C@H](NC(=O)OCCO)C(=O)NC(Cc1ccccc1)C(O)CNCC(O)C(Cc1ccccc1)NC(=O)OC(C)(C)C

Procedure:
Compounds 218b and 54 were converted to the title Compound 218c (white solid) by a two-step procedure analogous to that used for the conversion of Compound 202c to Compound 202e. m.p.=174°-179° C.; [α]D =-16.1° (c =0.23; MeOH) High resolution MS (FAB): Calculated (M+H)+ (for C33H51N4O8)=631.3707; Observed (M+H)+ =631.3709 Δ=0.3 ppm
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]([CH3:28])([CH3:27])[CH2:11][O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH:15]=2)=[CH:6][CH:5]=1.Cl[CH2:30][O:31][CH2:32][CH3:33].O>O1CCCC1>[CH2:32]([O:31][CH2:30][O:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]([CH3:28])([CH3:27])[CH2:11][O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH:15]=2)=[CH:8][CH:9]=1)[CH3:33]
Reactant: CCOCCl
Reactant: CC(C)(COCc1cccc(Oc2ccccc2)c1)c1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCOCOc1ccc(C(C)(C)COCc2cccc(Oc3ccccc3)c2)cc1
Temperature: 25 °C

Procedure:
To 50 ml dry tetrahydrofuran was added 1.0 g of sodium hydride (60% in oil) and then 5.0 g of 3-phenoxybenzyl 2-(4-hydroxyphenyl)-2-methylpropyl ether in 15 ml of dry tetrahydrofuran was added dropwise to the mixture under reflux over a period of 30 minutes. The mixture was further refluxed for 10 minutes and 5.0 ml of ethyl chloromethyl ether was added dropwise to the mixture for 30 minutes. And the resulting mixture was further refluxed for 10 minutes, cooled to room temperature, poured into water, and extracted with benzene. The benzene extract was washed with water, dried over Na2SO4, and evaporated to give the oily residue which was purified by column chromatography on 150 g silica gel (20:1 mixed solvent of benzene and ether was used as eluent) to give 5.0 g of 3-phenoxybenzyl 2-(4-ethoxymethoxyphenyl)-2-methylpropyl ether.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:10]([OH:11])=[N:9][NH:8][C:5]2=[N:6][CH:7]=1.Cl[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1.[OH-].[Na+]>CS(C)=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:10]([OH:11])=[N:9][N:8]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)[C:5]2=[N:6][CH:7]=1
Reactant: Oc1n[nH]c2ncc(Br)cc12
Reactant: COc1ccc(CCl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Product: COc1ccc(Cn2nc(O)c3cc(Br)cnc32)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 51.6 %

Procedure:
5-Bromo-1H-pyrazolo[3,4-b]pyridin-3-ol (8.68 g, 40.56 mmol) and 1-(chloromethyl)-4-methoxybenzene (16.50 mL, 121.7 mmol) were dissolved in DMSO (250 mL). Powdered NaOH (2.433 g, 60.84 mmol) was added, and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was partitioned between EtOAc and water and separated. The aqueous layer was extracted with EtOAc (3×). The combined organic layers were washed with water (3×), saturated aqueous NaHCO3 (3×), brine, and dried over Na2SO4 and concentrated giving an oily solid. This solid was triturated with EtOAc and dried to provide 5-bromo-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridin-3-ol (7.0 g, 51.7%) as a solid.
Reaction SMILES: [CH3:1][C:2]1[S:3][CH:4]=[C:5]([C:7]2[S:11][C:10]([S:12](Cl)(=[O:14])=[O:13])=[CH:9][CH:8]=2)[N:6]=1.[NH2:16][C:17]1[CH:18]=[C:19]([CH:23]=[CH:24][CH:25]=1)[C:20]([OH:22])=[O:21]>>[CH3:1][C:2]1[S:3][CH:4]=[C:5]([C:7]2[S:11][C:10]([S:12]([NH:16][C:17]3[CH:18]=[C:19]([CH:23]=[CH:24][CH:25]=3)[C:20]([OH:22])=[O:21])(=[O:14])=[O:13])=[CH:9][CH:8]=2)[N:6]=1
Reactant: Cc1nc(-c2ccc(S(=O)(=O)Cl)s2)cs1
Reactant: Nc1cccc(C(=O)O)c1
Product: Cc1nc(-c2ccc(S(=O)(=O)Nc3cccc(C(=O)O)c3)s2)cs1
Yield: 13.7 %

Procedure:
The product was prepared according to General Procedure 1, described in Example 1, starting with 5-(2-methylthiazol-4-yl)thiophene-2-sulfonyl chloride (15.4 mg, 0.055 mmol) and 3-aminobenzoic acid (6.9 mg, 0.05 mmol) affording 2.6 mg (14%) of the title compound. MS (ESI+) calcd for C15H21N2O4S3 379.995919, found 379.995859.