Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[N:12]3[CH:13]=[CH:14][C:15]([C:17]([CH3:27])([O:19][Si:20]([CH2:25][CH3:26])([CH2:23][CH3:24])[CH2:21][CH3:22])[CH3:18])=[N:16][C:11]3=[N:10][CH:9]=2)[CH:5]=[CH:4][N:3]=1.C([Sn](CCCC)(CCCC)[C:33]1[S:34][CH:35]=[CH:36][N:37]=1)CCC.N#N>C1COCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:18][C:17]([C:15]1[CH:14]=[CH:13][N:12]2[C:8]([C:6]3[CH:5]=[CH:4][N:3]=[C:2]([C:33]4[S:34][CH:35]=[CH:36][N:37]=4)[N:7]=3)=[CH:9][N:10]=[C:11]2[N:16]=1)([O:19][Si:20]([CH2:25][CH3:26])([CH2:23][CH3:24])[CH2:21][CH3:22])[CH3:27]
Reactant: CC[Si](CC)(CC)OC(C)(C)c1ccn2c(-c3ccnc(Cl)n3)cnc2n1
Reactant: CCCC[Sn](CCCC)(CCCC)c1nccs1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: N#N
Solvent: C1CCOC1
Product: CC[Si](CC)(CC)OC(C)(C)c1ccn2c(-c3ccnc(-c4nccs4)n3)cnc2n1
Yield: 56.6 %

Procedure:
A solution of 3-(2-chloropyrimidin-4-yl)-7-(1-methyl-1-triethylsilanyloxyethyl)imidazo[1,2-α]pyrimidine (prepared as in Example 34) (200 mg, 0.50 mmol) and 2-tributylstannylthiazole (370 mg, 1.0 mmol) in THF (10 ml) was degassed with a stream of N2 for 10 min, then tetrakis(triphenylphosphine)palladium(0) (29 mg, 5 mol %) was added and the reaction heated at reflux for 5 h. The mixture was concentrated under reduced pressure while dry loading onto silica and then purified by column chromatography on silica using 100% EtOAc as the eluent to afford 7-(1-methyl-1-triethylsilanyloxyethyl)-3-[2-(thiazol-2-yl)pyrimidin-4-yl]imidazo[1,2-α]pyrimidine (128 mg, 57%); m/z (ES+) 453 (M+H+).
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][C@@H:10]([NH:13][C:14]2[N:19]=[CH:18][C:17](/[CH:20]=[CH:21]/[C:22]([OH:24])=O)=[CH:16][C:15]=2[CH3:25])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH:27]1[O:32][NH2:33].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>CN(C=O)C.O>[CH2:1]([N:8]1[CH2:12][CH2:11][C@@H:10]([NH:13][C:14]2[N:19]=[CH:18][C:17](/[CH:20]=[CH:21]/[C:22]([NH:33][O:32][CH:27]3[CH2:28][CH2:29][CH2:30][CH2:31][O:26]3)=[O:24])=[CH:16][C:15]=2[CH3:25])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cc(/C=C/C(=O)O)cnc1N[C@@H]1CCN(Cc2ccccc2)C1
Reactant: NOC1CCCCO1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(/C=C/C(=O)NOC2CCCCO2)cnc1N[C@@H]1CCN(Cc2ccccc2)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 70 %

Procedure:
To a solution of (2E)-3-(6-{[(3R)-1-benzyl-3-pyrrolidinyl]amino}-5-methyl-3-pyridyl)acrylic acid (338 mg, crude) in DMF (4 mL) was added O-(tetrahydro-2H-pyran-2-yl)hydroxylamine (153 mg), HOBt (203 mg), and EDCI (233 mg) and the resulting mixture was stirred at ambient temperature for 3 hours. The reaction mixture was diluted with water and extracted with AcOEt. The organic phase was washed with sat NH4Cl aq solution, sat NaHCO3 aq solution, and brine, and dried over Na2SO4. The solvent was removed in vacuo and the residue was purified by preparative thin layer chromatography (chloroform:methanol=90:10) to give (2E)-3-(6-{[(3R)-1-benzyl-3-pyrrolidinyl]amino}-5-methyl-3-pyridyl)-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide (306 mg) as pale yellow form.
Reaction SMILES: [CH2:1]([C:8]1[C:9]([NH:20][CH:21]([CH2:25][CH3:26])[C:22]([OH:24])=O)=[N:10][CH:11]=[C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl>[CH2:1]([C:8]1[NH:13][C:12]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[CH:11][N:10]2[C:22](=[O:24])[C:21]([CH2:25][CH3:26])=[N:20][C:9]=12)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCC(Nc1ncc(-c2ccccc2)nc1Cc1ccccc1)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCc1nc2c(Cc3ccccc3)[nH]c(-c3ccccc3)cn-2c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 89 %

Procedure:
2-((3-benzyl-5-phenylpyrazin-2-yl)amino)butanoic acid was dissolved in DCM (10 mL). Pyridine (0.5 mL) was added followed by N,N′-Dicyclohexylcarbodiimide (137 mg, 0.67 mmol). The reaction mixture was slowly stirred at room temperature for 1 hr. The solvent was evaporated, and the residue purified by flash chromatography (eluting solvent: EtOAc to DCM to 10% methanol in DCM) to give the product as a yellow powder (110 mg, 89%). 1H NMR (300 MHz, CD3OD, δ): 7.26 (m, 3H), 6.84-7:07 (m, 8H), 4.03 (s, 2H), 2.47 (q, J=9.0 Hz, 2H), 0.96 (t, J=9.0 Hz, 3H); MS (ESI): m/z 330.2 (M+1).
Reaction SMILES: [NH2:1][S:2][O:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:19]3[C:18]4[CH:20]=[C:21]([N+:24]([O-])=O)[CH:22]=[CH:23][C:17]=4[CH2:16][CH2:15][C:14]=3[C:13]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[N:12]2)=[CH:7][CH:6]=1.[H][H]>CN(C=O)C.[Pd]>[NH2:24][C:21]1[CH:22]=[CH:23][C:17]2[CH2:16][CH2:15][C:14]3[C:13]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[N:12][N:11]([C:8]4[CH:7]=[CH:6][C:5]([O:4][O:3][S:2][NH2:1])=[CH:10][CH:9]=4)[C:19]=3[C:18]=2[CH:20]=1
Reactant: CCOC(=O)c1nn(-c2ccc(OOSN)cc2)c2c1CCc1ccc([N+](=O)[O-])cc1-2
Reactant: [H][H]
Agent: [Pd]
Solvent: CN(C)C=O
Product: CCOC(=O)c1nn(-c2ccc(OOSN)cc2)c2c1CCc1ccc(N)cc1-2
Yield: 85.8 %

Procedure:
The product of Example 2 (2.0 g) and 10% Pd/C (350 mg) in DMF (20 mL) were shaken at 55 psi hydrogen for 3 hours. The catalyst was removed by filtration and the filtrate was concentrated under vacuum to yield a yellow wax. The wax was triturated with methanol and the resulting amber solid was collected by filtration to afford the title compound (1.6 g).
Reaction SMILES: [CH3:1][N:2]([CH3:36])[CH2:3][CH2:4][O:5][C:6]1[N:11]=[CH:10][C:9]([NH:12][C:13](=[O:31])[CH2:14][C:15]2[CH:20]=[CH:19][C:18](B3OC(C)(C)C(C)(C)O3)=[CH:17][C:16]=2[F:30])=[CH:8][C:7]=1[C:32]([F:35])([F:34])[F:33].[CH2:37]([O:44][C:45]1[CH:50]=[C:49]([O:51][CH2:52][CH3:53])[C:48](I)=[CH:47][N:46]=1)[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1.C([O-])([O-])=O.[Cs+].[Cs+]>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]>[CH2:37]([O:44][C:45]1[N:46]=[CH:47][C:48]([C:18]2[CH:19]=[CH:20][C:15]([CH2:14][C:13]([NH:12][C:9]3[CH:10]=[N:11][C:6]([O:5][CH2:4][CH2:3][N:2]([CH3:1])[CH3:36])=[C:7]([C:32]([F:33])([F:34])[F:35])[CH:8]=3)=[O:31])=[C:16]([F:30])[CH:17]=2)=[C:49]([O:51][CH2:52][CH3:53])[CH:50]=1)[C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1
Reactant: CN(C)CCOc1ncc(NC(=O)Cc2ccc(B3OC(C)(C)C(C)(C)O3)cc2F)cc1C(F)(F)F
Reactant: CCOc1cc(OCc2ccccc2)ncc1I
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: CCOc1cc(OCc2ccccc2)ncc1-c1ccc(CC(=O)Nc2cnc(OCCN(C)C)c(C(F)(F)F)c2)c(F)c1
Yield: 11.8 %

Procedure:
A solution of N-(6-(2-(dimethylamino)ethoxy)-5-(trifluoromethyl)pyridin-3-yl)-2-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetamide (30 mg, 0.059 mmol), 2-(benzyloxy)-4-ethoxy-5-iodopyridine (20.84 mg, 0.059 mmol), PdCl2(dppf) (42.9 mg, 0.059 mmol) and Cs2CO3 (19.12 mg, 0.059 mmol) in 1,4-dioxane (3 mL) and H2O (1 mL) was stirred at 110° C. for 15 min. After LCMS analysis showed the starting material had disappeared, the solvent was removed in vacuo. The residue was dissolved in EA (30 mL) and washed with H2O (10 mL) and brine (10 mL). The organic layer was dried over Na2SO4, filtered and concentrated. The crude product was purified by preparative TLC (DCM/MeOH=10/1) to yield 2-(4-(6-(benzyloxy)-4-ethoxypyridin-3-yl)-2-fluorophenyl)-N-(6-(2-(dimethylamino)ethoxy)-5-(trifluoromethyl)pyridin-3-yl)acetamide (5 mg, 6.97 μmol, 11.9% yield): 1H NMR (400 MHz, CD3OD) δ 8.56 (s, 1H), 8.33 (d, J=2.0 Hz, 1H), 7.99 (s, 1H), 7.48-7.30 (m, 8H), 6.51 (s, 1H), 5.38 (s, 2H), 4.64 (t, J=5.2 Hz, 2H), 4.16 (m, 2H), 3.84 (s, 2H), 3.03 (t, J=5.2 Hz, 2H), 2.53 (s, 6H), 1.40 (t, J=7.0 Hz, 3H); ES-LCMS m/z 613.1 (M+H).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[OH:6][C:7]([CH3:37])([CH3:36])[CH2:8][C@@:9]1([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[O:14][C:13](=[O:15])[N:12]([C@H:16]([C:18]2[CH:23]=[CH:22][C:21]([CH:24]3[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]3)=[CH:20][CH:19]=2)[CH3:17])[CH2:11][CH2:10]1.C(N(CC)CC)C>ClCCl>[OH:6][C:7]([CH3:36])([CH3:37])[CH2:8][C@@:9]1([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[O:14][C:13](=[O:15])[N:12]([C@H:16]([C:18]2[CH:23]=[CH:22][C:21]([CH:24]3[CH2:29][CH2:28][N:27]([S:2]([CH3:1])(=[O:4])=[O:3])[CH2:26][CH2:25]3)=[CH:20][CH:19]=2)[CH3:17])[CH2:11][CH2:10]1
Reactant: CS(=O)(=O)Cl
Reactant: C[C@@H](c1ccc(C2CCNCC2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@@H](c1ccc(C2CCN(S(C)(=O)=O)CC2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O

Procedure:
MeSO2Cl (29 μL) was added to a solution of (S)-6-(2-hydroxy-2-methyl-propyl)-6-phenyl-3-[(S)-1-(4-piperidin-4-yl-phenyl)-ethyl]-[1,3]oxazinan-2-one (150 mg) and triethylamine (100 μL) in dichloromethane (3 mL) at room temperature. After stirring the solution at room temperature overnight, more dichloromethane was added and the resulting solution was washed with aqueous NaHCO3 solution, water, and brine. The organic solution was then dried (MgSO4) and concentrated. The residue was purified by HPLC on reversed phase (MeCN/H2O/NH3) to afford the title compound.
Reaction SMILES: [CH:1]1([C:6]2([CH2:14][O:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]([CH3:26])([CH3:25])[C:23]#[N:24])=[C:18]([F:27])[CH:17]=3)[CH2:11][C:10](=[O:12])[CH2:9][C:8](=[O:13])[O:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:28][C:29]1[CH:30]=[N:31][C:32]2[N:33]([N:35]=[C:36]([CH:38]=O)[N:37]=2)[CH:34]=1>CO>[CH:1]1([C:6]2([CH2:14][O:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]([CH3:25])([CH3:26])[C:23]#[N:24])=[C:18]([F:27])[CH:17]=3)[CH2:11][C:10]([OH:12])=[C:9]([CH2:38][C:36]3[N:37]=[C:32]4[N:31]=[CH:30][C:29]([CH3:28])=[CH:34][N:33]4[N:35]=3)[C:8](=[O:13])[O:7]2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: Cc1cnc2nc(C=O)nn2c1
Reactant: CC(C)(C#N)c1ccc(OCC2(C3CCCC3)CC(=O)CC(=O)O2)cc1F
Solvent: CO
Product: Cc1cnc2nc(CC3=C(O)CC(COc4ccc(C(C)(C)C#N)c(F)c4)(C4CCCC4)OC3=O)nn2c1
Reaction time: 5 h
Yield: 32.4 %

Procedure:
A solution of 2-[4-(2-Cyclopentyl-4,6-dioxo-tetra hydro-pyran-2-ylmethoxy)-2-fluoro-phenyl]-2-methyl-propionitrile (200 mg, 0.54 mmol) in anhydrous MeOH (4.0 mL) was treated with 6-Methyl-[1,2,4]triazolo[1,5-a]pyrimidine-2-carbaldehyde (140 mg, 0.86 mmol), followed by borane-dimethylamine complex (47 mg, 0.8 mmol) at room temperature. The reaction was stirred for 5 hours before it was quenched by the addition of 0.5N HCl (25 mL). The mixture was extracted with 10% MeOH in CH2Cl2 (3×10 mL) and the combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by crystallization from EtOAc/Hexanes to give the product as a white solid (91 mg, 32% yield). 1H NMR (300 MHz, DMSO-d6) δ: 1.67 (m, 8H), 1.70 (s, 6H), 2.38 (s, 3H), 2.55 (m, 1H), 2.77 (m, 2H), 3.77 (m, 2H), 4.12 (m, 1H), 4.44 (m, 1H), 6.97 (m 2H), 7.35 (m, 1H), 8.69 (s, 1H), 9.03 (s, 1H), 10.98 (brs, 1H).
Reaction SMILES: [NH:1]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C@H:2]([C:7]([OH:9])=O)[CH2:3][CH:4]([CH3:6])[CH3:5].F[B-](F)(F)F.[N:22]1([O:31][C:32](N(C)C)=[N+](C)C)[C:26]2C=CC=CC=2N=N1.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.CNOC>C(Cl)Cl>[NH:1]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C@H:2]([C:7]([N:22]([CH3:26])[O:31][CH3:32])=[O:9])[CH2:3][CH:4]([CH3:5])[CH3:6]
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: CNOC
Agent: F[B-](F)(F)F
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CON(C)C(=O)[C@H](CC(C)C)NC(=O)OC(C)(C)C
Reaction time: 0.08 h

Procedure:
Boc-Leu-OH (1 g, 4.3 mmol) was dissolved in DCM (30 mL) and 2-(1H-Benzotriazole-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (TBTU)(1.380 g, 4.3 mmol), HOBt (0.581 g, 4.3 mmol) and DIPEA (743 μL, 4.3 mmol) were added at 0° C. After 5 min of stirring, 0,N-dimethylhydroxylamine hydrochloride (0.461 g, 4.73 mmol) and DIPEA (817 μL, 4.73 mmol) were added. All solid material dissolved within 10 min and the mixture was stirred overnight at RT. The solvent was evaporated, the reaction mixture redissolved in AcOEt and washed with H2O, 5% citric acid, H2O, 5% aqueous NaHCO3 solution, saturated NaCl solution several times. The solution was dried over MgSO4 and the solvent removed in vacuo. The desired compound was purified by silica gel column chromatography. ESI-MS: calcd. 269. found 292 [M+Na]+.
Reaction SMILES: C([C@H]1COC(C)(C)N1C(=O)C(C1C=CN(C2C=CC(C3C=CC=CC=3)=CC=2)C=1)=O)C1C=CC=CC=1.[C:36]1([C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)[CH:41]=[CH:40][C:39]([C:42]2[O:43][CH:44]=[CH:45][CH:46]=2)=[CH:38][CH:37]=1.[C:53](OCC)(=[O:59])[C:54]([O:56][CH2:57][CH3:58])=[O:55]>>[CH2:57]([O:56][C:54](=[O:55])[C:53]([C:44]1[O:43][C:42]([C:39]2[CH:40]=[CH:41][C:36]([C:47]3[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=3)=[CH:37][CH:38]=2)=[CH:46][CH:45]=1)=[O:59])[CH3:58]
Reactant: CCOC(=O)C(=O)OCC
Reactant: c1ccc(-c2ccc(-c3ccco3)cc2)cc1
Agent: CC1(C)OC[C@H](Cc2ccccc2)N1C(=O)C(=O)c1ccn(-c2ccc(-c3ccccc3)cc2)c1
Product: CCOC(=O)C(=O)c1ccc(-c2ccc(-c3ccccc3)cc2)o1
Yield: 74 %

Procedure:
According to the procedure described in Example 13 for the preparation of 1-(4(S)-benzyl-2,2-dimethyl-oxazolidin-3-yl)-2-(biphenyl-4-yl-1H-pyrrol-3-yl)ethane-1,2-dione, 2-biphenyl-4-yl-furan was deprotonated and alkylated with diethyl oxalate to give in 74% yield 2-(2-biphenyl-4-yl-furan-5-yl)-2-oxoacetic acid ethyl ester as a yellow solid, mp 91-94° C. 1H NMR: δ 7.94 (d, 2H, J=8.5 Hz), 7.83 (d, 1H, J=4.1 Hz), 7.69 (d, 2H, J=8.1 Hz), 7.64 (d, 2H, J=7.7 Hz), 7.47 (t, 2H, J=7.4 Hz), 7.39 (t, 1H, J=7.2 Hz), 6.90 (d, 1H, J=4.2 Hz), 4.44 (q, 2H, J=7.0 Hz), 1.45 (t, 3H, J=7.2 Hz). Anal. Calculated for C20H16O4 : C, 74.99; H, 5.03. Found: C, 75.11; H, 5.07.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[C:6](=[O:23])[N:7]([CH:15]1[CH2:20][CH2:19][C:18](=[O:21])[NH:17][C:16]1=[O:22])[C:8]([CH3:14])=[N:9]2.[C:24](Cl)(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(N(CC)C(C)C)(C)C>C(#N)C>[O:22]=[C:16]1[CH:15]([N:7]2[C:6](=[O:23])[C:5]3[C:10](=[CH:11][CH:12]=[CH:13][C:4]=3[CH2:3][NH:2][C:24](=[O:31])[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[N:9]=[C:8]2[CH3:14])[CH2:20][CH2:19][C:18](=[O:21])[NH:17]1
Reactant: Cc1nc2cccc(CN)c2c(=O)n1C1CCC(=O)NC1=O
Reactant: O=C(Cl)c1ccccc1
Agent: Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc2cccc(CNC(=O)c3ccccc3)c2c(=O)n1C1CCC(=O)NC1=O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 35.7 %

Procedure:
To a stirred mixture of 3-(5-aminomethyl-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione hydrogen chloride (0.59 g, 1.8 mmol) in acetonitrile (10 mL), was added benzoyl chloride (0.31 mL, 2.7 mmol) and N,N-diisopropyl ethylamine (0.77 mL, 4.4 mmol). The mixture was stirred at room temp for 15 minutes. The solvent was evaporated, and the residue was purified by flash column chromatography (Silica gel, methanol/methylene chloride 4%/96%) to give N-[3-(2,6-dioxo-piperidin-3-yl)-2-methyl-4-oxo-3,4-dihydro-quinazolin-5-ylmethyl]-benzamide as a white solid (260 mg, 36% yield); HPLC, Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 10/90 CH3CN/0.1% H3PO4, gradient to 95/5 in 5 min, kept for 5 min, 5.70 min (99.6%); mp, 247-249° C.; 1HNMR (DMSO-d6)2.17-2.23 (m, 1H, CHH), 2.59-2.90 (m, 6H, CHCH2, CH3), 4.92-5.09 (m, 2H, CH2NH), 5.26 (dd, J=6, 12 Hz, 1H, CH), 7.47-7.94 (m, 8H, Ar), 8.93 (t, J=5 Hz, 1H, CH2NH), 11.05 (s, 1H, NH); 13C NMR (DMSO-d6) δ 20.82, 23.29, 30.60, 42.12, 56.53, 117.65, 124.01, 125.43, 127.20, 128.37, 131.30, 133.95, 134.21, 140.99, 148.50, 154.81, 161.11, 166.26, 169.54, 172.62. LCMS MH=405; Anal Calcd For C22H20N4O4+0.5H2O: C, 63.91; H, 5.12; N, 13.55. Found: C, 63.78; H, 4.82; N, 13.45.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([CH:20]=[C:21]([O:25]C)[C:22]=1[O:23]C)[C:6]1[O:7][C:8]2[C:13]([C:14](=[O:19])[C:15]=1[C:16]([OH:18])=[O:17])=[CH:12][CH:11]=[CH:10][CH:9]=2.B(Br)(Br)Br.O>ClCCl>[OH:25][C:21]1[CH:20]=[C:5]([CH:4]=[C:3]([OH:2])[C:22]=1[OH:23])[C:6]1[O:7][C:8]2[C:13]([C:14](=[O:19])[C:15]=1[C:16]([OH:18])=[O:17])=[CH:12][CH:11]=[CH:10][CH:9]=2
Reactant: COc1cc(-c2oc3ccccc3c(=O)c2C(=O)O)cc(OC)c1OC
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Product: O=C(O)c1c(-c2cc(O)c(O)c(O)c2)oc2ccccc2c1=O
Temperature: 25 °C
Yield: 85 %

Procedure:
4.0 g of 3',4',5'-trimethoxyflavone-3-carboxylic acid were added to 200 ml of absolute dichloromethane and reacted with 82 ml of a 1 molar boron tribromide solution in absolute dichloromethane under a nitrogen atmosphere at 0° C. The reaction mixture was stirred for twelve hours during which it was allowed to warm to room temperature. Then, for working up, water was carefully added under ice cooling, then made up to twice the volume with water and intensively stirred. The resulting 3',4',5'-trihydroxyflavone-3-carboxylic acid precipitated and was filtered out. The filter cake was washed with water several times and recrystallized from methanol. 3 g of pure 3',4',5'-trihydroxyflavone-3-carboxylic acid were obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:24])[C:5]([CH3:23])=[C:6]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][C:20]([OH:22])=O)=[CH:15][CH:14]=2)[C:7](=[O:11])[C:8]=1[O:9][CH3:10].[NH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1>>[CH3:1][O:2][C:3]1[C:4](=[O:24])[C:5]([CH3:23])=[C:6]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][C:20]([N:25]3[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)=[O:22])=[CH:15][CH:14]=2)[C:7](=[O:11])[C:8]=1[O:9][CH3:10]
Reactant: COC1=C(OC)C(=O)C(Cc2ccc(CC(=O)O)cc2)=C(C)C1=O
Reactant: C1CCNCC1
Product: COC1=C(OC)C(=O)C(Cc2ccc(CC(=O)N3CCCCC3)cc2)=C(C)C1=O
Yield: 31.7 %

Procedure:
4-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-ylmethyl)phenylacetic acid (21 mg, 0.063 mmol) obtained in Example 52 and piperidine (0.0094 ml, 0.095 mmol) were used, and a method similar to that described in Example 46 was employed to obtain the title compound (7.8 mg, 0.020 mmol, yield 32%).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[N:5][C:6]([C:10]([OH:12])=O)=[CH:7][CH:8]=2)[N:3]=[CH:2]1.[CH2:13]1[C@H:22]2[C@H:17]([CH2:18][CH2:19][C:20]3[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=32)[NH:16][CH2:15][CH2:14]1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>>[CH2:13]1[C@H:22]2[C@H:17]([CH2:18][CH2:19][C:20]3[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=32)[N:16]([C:10]([C:6]2[N:5]=[C:4]3[N:3]=[CH:2][NH:1][C:9]3=[CH:8][CH:7]=2)=[O:12])[CH2:15][CH2:14]1
Reactant: c1ccc2c(c1)CC[C@@H]1NCCC[C@H]21
Reactant: O=C(O)c1ccc2[nH]cnc2n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: O=C(c1ccc2[nH]cnc2n1)N1CCC[C@@H]2c3ccccc3CC[C@@H]21
Yield: 57 %

Procedure:
The title compound is prepared from 1H-imidazo[4,5-b]pyridine-5-carboxylic acid and cis-1,2,3,4,4a,5,6,10b-octahydro-benzo[f]quinoline following a procedure analogous to that described in Example 1 [2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexa-fluorophosphate is used]. Yield: 57% of theory; LC (method 3): tR=2.10 min; Mass spectrum (ESI+): m/z=333 [M+H]+.
Reaction SMILES: [OH-].[Na+].C([O:5][C:6](=[O:38])[CH2:7][CH2:8][N:9]([C:16]([C:18]1[CH:37]=[CH:36][C:21]2[N:22]([CH3:35])[C:23]([CH2:25][NH:26][C:27]3[CH:32]=[CH:31][C:30]([C:33]#[N:34])=[CH:29][CH:28]=3)=[N:24][C:20]=2[CH:19]=1)=[O:17])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1)C>C(O)C.O>[C:33]([C:30]1[CH:31]=[CH:32][C:27]([NH:26][CH2:25][C:23]2[N:22]([CH3:35])[C:21]3[CH:36]=[CH:37][C:18]([C:16]([N:9]([C:10]4[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=4)[CH2:8][CH2:7][C:6]([OH:38])=[O:5])=[O:17])=[CH:19][C:20]=3[N:24]=2)=[CH:28][CH:29]=1)#[N:34]
Reactant: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C#N)cc1)n2C)c1ccccn1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cn1c(CNc2ccc(C#N)cc2)nc2cc(C(=O)N(CCC(=O)O)c3ccccn3)ccc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of sodium hydroxide (50.0 mmol) in 500 mL ethanol and 50 mL water was added 3-({2-[(4-Cyano-phenylamino)-methyl]-1-methyl-1H-benzoimidazole-5-carbonyl}-pyridin-2-yl-amino)-propionic acid ethyl ester (41.4 mmol). The mixture was stirred at room temperature for three hours, then ca. 350 mL ethanol were distilled off, ca. 100 mL water was added and the pH was adjusted to 6. Then diethylether (50 mL) was added and the mixture stirred over night. The product was isolated by filtration and used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][CH:16]([NH:19]C(=O)C)[CH2:15][CH2:14]2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]>Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][N:13]2[CH2:14][CH2:15][CH:16]([NH2:19])[CH2:17][CH2:18]2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(CCN2CCC(NC(C)=O)CC2)cc1OC
Agent: Cl
Product: COc1ccc(CCN2CCC(N)CC2)cc1OC

Procedure:
The acetamido compound of Example 3 (2.5 g.) in 2N hydrochloric acid (25 ml.) was treated under reflux for 3.5 hours. The cooled solution was basified and extracted with chloroform. Evaporation of the washed and dried extracts gave an oil which was treated with ethanolic hydrogen chloride to provide 1.67 g. of the title compound as its dihydrochloride, m.p. 260°-263° C. (Found: C, 53.4; H, 7.7; N, 8.3. C15H24N2O2.2HCl requires C, 53.3; H, 7.8; N, 8.3%).
Reaction SMILES: C[O:2][C:3]([CH:5]1[CH2:9][CH2:8][CH2:7][N:6]1[C:10](=[O:26])[NH:11][C:12]1[CH:17]=[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[O:24][CH3:25])[N:15]=[CH:14][N:13]=1)=[O:4].[Li+].[OH-]>C1COCC1.O>[CH3:25][O:24][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[C:16]1[N:15]=[CH:14][N:13]=[C:12]([NH:11][C:10]([N:6]2[CH2:7][CH2:8][CH2:9][CH:5]2[C:3]([OH:4])=[O:2])=[O:26])[CH:17]=1
Reactant: COC(=O)C1CCCN1C(=O)Nc1cc(-c2ccccc2OC)ncn1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccccc1-c1cc(NC(=O)N2CCCC2C(=O)O)ncn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 1-[6-(2-methoxy-phenyl)-pyrimidin-4-ylcarbamoyl]-pyrrolidine-2-carboxylic acid methyl ester (LX) (500 mg, 1.40 mmol) in a mixture of THF and water (1:1) was added a solution of LiOH (0.118 g, 2.80 mmol) in water at ice bath temperature over 10 min and then allowed to stir for two hours at room temperature. THF was evaporated and the aqueous solution was acidified with 2N HCl. This aqueous phase was then extracted with ethyl acetate (2×100 ml), the combined organic phases were washed with water and brine, dried over anhydrous sodium sulfate and concentrated in a vacuum rotavapor to afford 1-[6-(2-methoxy-phenyl)-pyrimidin-4-ylcarbamoyl]-pyrrolidine-2-carboxylic acid as a white solid. Yield: 210 mg, 43.8%.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=[O:8])[C:5]([NH2:11])=[CH:4][CH:3]=1.[C:12]([OH:21])(=[O:20])[C:13]1C(=CC=[CH:18][CH:19]=1)N>>[C:7]([C:6]1[CH:10]=[C:2]([CH3:1])[CH:3]=[CH:4][C:5]=1[NH:11][CH:13]1[CH2:19][CH2:18][O:21][C:12]1=[O:20])([OH:9])=[O:8]
Reactant: Cc1ccc(N)c(C(=O)O)c1
Reactant: Nc1ccccc1C(=O)O
Product: Cc1ccc(NC2CCOC2=O)c(C(=O)O)c1

Procedure:
In the method of the Reference Example 1, 5-methylanthranilic acid was reacted in the place of anthranilic acid to obtain α-[(2-carboxy-4-methylphenyl)amino]-γ-butyrolactone, melting point: 199°-200° C.
Reaction SMILES: C(OC([N:8]1[CH2:12][C@H:11]([O:13][Si](C(C)(C)C)(C)C)[CH2:10][C@H:9]1[C:21](=[O:27])[CH2:22][C:23](=[O:26])[NH:24][CH3:25])=O)(C)(C)C.[ClH:28]>CO>[ClH:28].[OH:13][C@H:11]1[CH2:12][NH:8][C@H:9]([C:21](=[O:27])[CH2:22][C:23](=[O:26])[NH:24][CH3:25])[CH2:10]1
Reactant: CNC(=O)CC(=O)[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CN1C(=O)OC(C)(C)C
Agent: Cl
Solvent: CO
Product: CNC(=O)CC(=O)[C@@H]1C[C@@H](O)CN1
Temperature: 25 °C
Reaction time: 6 h
Yield: 62 %

Procedure:
To a solution of (2S,4R)-N-tert-butoxycarbonyl-4-tert-butyldimethylsiloxy-2-[2-(N-methylcarbamoyl)-1-oxoethyl]pyrrolidine (2.07 g, 5.3 mmol) in methanol (10 ml) was added a 5.5N hydrogen chloride--methanol solution (6 ml, 33 mmol). The mixture was stirred at room temperature for 6 h. The reaction solution was concentrated in vacuo. Tetrahydrofuran and ethanol were added to the obtained residue, and the precipitate was collected by filtration and washed with ethanol to obtain (2S,4R)-4-hydroxy-2-[2-(N-methylcarbamoyl)-1-oxoethyl]pyrrolidine monohydrochloride (737 mg, yield: 62%).