Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH:7]=[CH:6][C:5](=[O:8])[N:4]([CH3:9])[C:3]1=[O:10].[N+:11]([CH2:13]S(C1C=CC(C)=CC=1)(=O)=O)#[C-:12].CC([O-])(C)C.[K+]>CC1OCCC1.CO>[CH3:1][N:2]1[C:7]2=[CH:12][NH:11][CH:13]=[C:6]2[C:5](=[O:8])[N:4]([CH3:9])[C:3]1=[O:10]
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Reactant: Cn1ccc(=O)n(C)c1=O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CO
Solvent: CC1CCCO1
Product: Cn1c(=O)c2c[nH]cc2n(C)c1=O
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
1,3-Dimethylpyrimidine-2,4(1H,3H)-dione (commercial (40 g, 285 mmol) and 1-(isocyano methylsulfonyl)-4-methylbenzene (commercial) (84 g, 428 mmol) were dissolved in 2-MeTHF (1000 mL) under nitrogen at 30° C. and held for 5 mins. The vessel was then cooled to 0° C. (internal). A solution of KOtBu (commercial) (64.1 g, 571 mmol) in 2-MeTHF (500 mL was added to the solution via a dropping funnel over 0.5 h, such that the internal temperature remained below 5° C. On addition of the KOtBu solution, an orange precipitate formed. An additional portion of 2-MeTHF (455 mL) was charged via dropping funnel over 5 mins. After 40 mins, the dark orange suspension was quenched with sat NH4Cl solution (2×400 mL) charged via dropping funnel over 15 mins. The suspension was then diluted with EtOAc (1 L), the layers were separated and the aqueous extracted with EtOAc (3×1 L). The combined organics were dried (MgSO4) and filtered under reduced pressure. The solvent was removed under reduced pressure to afford a brown semi-solid. The solids were suspended in MeOH (300 mL), sonicated and stirred at room temperature for 15 mins, filtered by reduced pressure filtration and washed with MeOH (100 mL). The solid was dried under vacuum at 50° C. for 24 h. The title compound was obtained as a pale brown amorphous solid (26.34 g, 52%)
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[C:12]2[CH2:13][C:14]([O:16][CH2:17][CH3:18])=[CH:15][C:11]=2[NH:10][N:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].N1C=CC=CC=1.[C:25]1([CH3:35])[CH:30]=[CH:29][C:28]([S:31](Cl)(=[O:33])=[O:32])=[CH:27][CH:26]=1>C(Cl)Cl>[C:1]([O:5][C:6]([C:8]1[C:12]2[CH2:13][C:14]([O:16][CH2:17][CH3:18])=[CH:15][C:11]=2[N:10]([S:31]([C:28]2[CH:29]=[CH:30][C:25]([CH3:35])=[CH:26][CH:27]=2)(=[O:33])=[O:32])[N:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC1=Cc2[nH]nc(C(=O)OC(C)(C)C)c2C1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC1=Cc2c(c(C(=O)OC(C)(C)C)nn2S(=O)(=O)c2ccc(C)cc2)C1

Procedure:
To a solution of the pyrazole intermediate from step A (275 mg, 1.1 mmol) above in CH2Cl2 (5 mL) was added pyridine (178 μL, 2.2 mmol) and p-toluene sulfonyl chloride (230 mg, 1.21 mmol). After stirring the resulting reaction mixture at room temperature for 3 hours it was diluted with CH2Cl2, washed with 1N HCl, saturated NaHCO3, dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography (SiO2) using 10% ethyl acetate-hexanes.
Reaction SMILES: [NH2:1][C@H:2]([C:11]1[CH:12]=[N:13][CH:14]=[C:15]([Br:17])[CH:16]=1)[CH2:3][C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5].O=C1CCC(=O)N1[O:25][C:26]([C@@H:28]1[CH2:33][CH2:32][CH2:31][N:30]([C:34](=[O:50])[CH2:35][CH2:36][CH:37]2[CH2:42][CH2:41][N:40]([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[CH2:39][CH2:38]2)[CH2:29]1)=O.C(N(CC)CC)C>CN(C=O)C.ClCCl>[Br:17][C:15]1[CH:16]=[C:11]([C@@H:2]([NH:1][C:26]([C@@H:28]2[CH2:33][CH2:32][CH2:31][N:30]([C:34](=[O:50])[CH2:35][CH2:36][CH:37]3[CH2:42][CH2:41][N:40]([C:43]([O:45][C:46]([CH3:48])([CH3:47])[CH3:49])=[O:44])[CH2:39][CH2:38]3)[CH2:29]2)=[O:25])[CH2:3][C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5])[CH:12]=[N:13][CH:14]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CCC(=O)N2CCC[C@@H](C(=O)ON3C(=O)CCC3=O)C2)CC1
Reactant: CC(C)(C)OC(=O)C[C@H](N)c1cncc(Br)c1
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)C[C@H](NC(=O)[C@@H]1CCCN(C(=O)CCC2CCN(C(=O)OC(C)(C)C)CC2)C1)c1cncc(Br)c1
Yield: 72.9 %

Procedure:
To tert-butyl (3S)-3-amino-3-(5-bromopyridin-3-yl)propanoate (1.33 g, 4.42 mmol) in DMF (17 mL) was added tert-butyl 4-{3-[(3R)-3-{[(2,5-dioxopyrrolidin-1-yl)oxy]carbonyl}piperidin-1-yl]-3-oxopropyl}piperidine-1-carboxylate (example 25c 2.54 g, 4.91 mmol) and triethylamine (1.85 mL, 13.2 mmol) in dichloromethane (17 mL) at 0° C. After 3 hours the mixture was quenched by addition of saturated aqueous ammonium chloride solution, phases were separated and the aqueous phase was extracted with diethyl ether. Combined organic extracts were dried over sodium sulphate, concentrated under reduced pressure and the residue was purified by chromatography on silica gel (ethyl acetate in hexane, 12 to 100% followed by methanol in ethyl acetate 0 to 15%) to yield 2.1 g of tert-butyl 4-[3-((3R)-3-{[(1S)-1-(5-bromopyridin-3-yl)-3-tert-butoxy-3-oxopropyl]carbamoyl}piperidin-1-yl)-3-oxopropyl]piperidine-1-carboxylate.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([O:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]3[O:20][C:21]([CH3:24])=[N:22][N:23]=3)=[CH:15][CH:14]=2)[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].O[C@@H:26]1[CH2:30][CH2:29][NH:28][C:27]1=[O:31].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[CH3:24][C:21]1[O:20][C:19]([C:16]2[CH:15]=[CH:14][C:13]([O:12][C:10]3[CH:9]=[C:4]([CH:3]=[C:2]([O:1][C@H:26]4[CH2:30][CH2:29][NH:28][C:27]4=[O:31])[CH:11]=3)[C:5]([O:7][CH3:8])=[O:6])=[CH:18][CH:17]=2)=[N:23][N:22]=1
Reactant: O=C1NCC[C@H]1O
Reactant: COC(=O)c1cc(O)cc(Oc2ccc(-c3nnc(C)o3)cc2)c1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1cc(Oc2ccc(-c3nnc(C)o3)cc2)cc(O[C@H]2CCNC2=O)c1
Temperature: 25 °C
Yield: 68.3 %

Procedure:
To a stirring mixture of Methyl 3-hydroxy-5-[4-(5-methyl-1,3,4-oxadiazol-2-yl)phenoxy]benzoate (7 g) (Intermediate 7) and (R)-(+)-3-hydroxy-2-pyrrolidinone (Intermediate 16) (2.4 g) in dry THF (200 mL) taken in round bottomed flask fitted with anhydrous CaCl2 guard tube, triphenyl phosphine (11.3 g) was added. Diisopropyl azodicarboxylate (DIAD) (6.2 mL) in dry THF (10 mL) was added drop wise to the above reaction mixture. The reaction was stirred at room temperature. Reaction was monitored by TLC for completion. After completion, reaction mixture was concentrated under vacuum to remove the solvents. Diluted with DCM and coated over silica gel and chromatographed to furnish the product as white solid (6 g).
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]([F:22])([F:21])[F:20])(=[O:12])=[O:11])[CH2:7][NH:6]1)=[O:4].[C:23]1(B(O)O)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(N(CC)CC)C>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]([F:22])([F:20])[F:21])(=[O:11])=[O:12])[CH2:7][N:6]1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:4]
Reactant: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2C(F)(F)F)CN1
Reactant: OB(O)c1ccccc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2C(F)(F)F)CN1c1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 18.2 %

Procedure:
To a solution of (2S,4R)-4-(2-trifluoromethyl-benzenesulfonyl)-pyrrolidine-2-carboxylic acid methyl ester (see example xx) (1.03 g, 1.0 eq) in dry dichloromethane (25 mL) were added freshly powdered molecular sieves (2.88 g). Phenyl boronic acid (0.74 g, 2.0 eq) was added, followed by triethylamine (0.62 g, 2.0 eq) and copper(II)acetate (0.61 g, 1.1 eq). Oxygen gas was bubbled through the reaction mixture for 5 min. The flask was sealed with a rubber septum and left under an atmosphere of oxygen by means of a balloon. After stirring at room temperature for 24 h, the mixture was filtered and the filtrate was treated with water and filtered again. The phases were separated and the organic phase dried over sodium sulfate, filtered and evaporated. Purification by flash chromatography on silica gel with an heptane/ethyl acetate gradient yielded the title compound as a light yellow solid (0.23 g, 18%). MS (ESI): m/z=414.2 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:17]([CH2:18][C:19]([OH:21])=O)[C:12]3=[N:13][CH:14]=[CH:15][CH:16]=[C:11]3[N:10]=2)=[CH:5][CH:4]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[NH:34]1[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[N:17]([CH2:18][C:19](=[O:21])[N:34]3[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]3)[C:12]3=[N:13][CH:14]=[CH:15][CH:16]=[C:11]3[N:10]=2)=[CH:7][CH:8]=1
Reactant: COc1ccc(-c2nc3cccnc3n2CC(=O)O)cc1
Reactant: C1CCNCC1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: COc1ccc(-c2nc3cccnc3n2CC(=O)N2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 61.1 %

Procedure:
Under nitrogen bubbling, a mixture of 2-(4-methoxyphenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid (4.2 g, 0.015 mol) and 1,1'-carbonyldiimidazole (2.43 g, 0.015 mole) in 120 ml of tetrahydrofuran was stirred at room temperature for 3 hrs. Then, under nitrogen atmosphere, piperidine (1.92 g, 0.022 mole) was added and the reaction mixture was allowed to stir at room temperature overnight. The reaction mixture was filtered and the filtrate was evaporated to dryness, then placed under high vacuum for 3-4 hrs. The residue was treated with water and the solid was collected by filtration, washed with water, and dried under high vacuum at 50°-60° C. overnight. The solid was recrystallized from isopropyl alcohol with refrigeration overnight. The solid was collected by filtration, washed with cold isopropyl alcohol and water, and dried under high vacuum at 50°-60° C. overnight to give 3.21 g (62%) of title compound, mp 153°-55° C.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH:12]([CH2:14][C:15]#[CH:16])[C:11](=[O:17])[CH:10]([CH3:18])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B(F)(F)F.ClC(Cl)(Cl)C(O)=[O:26]>CO>[CH2:14]([CH:12]1[C:11](=[O:17])[CH:10]([CH3:18])[CH2:9][N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:13]1)[C:15]([CH3:16])=[O:26]
Reactant: O=C(O)C(Cl)(Cl)Cl
Reactant: C#CCC1CN(Cc2ccccc2)CC(C)C1=O
Agent: FB(F)F
Solvent: CO
Product: CC(=O)CC1CN(Cc2ccccc2)CC(C)C1=O
Reaction time: 3 h
Yield: 63630.3 %

Procedure:
A solution of the crude 1-benzyl-3-methyl-5-prop-2-ynyl-4-piperidone (10 g)from Example 5 in methanol (15 ml) was added dropwise to a stirred mixture of red mercuric oxide (1.5 g), boron trifluoride diethyletherate (1.1 ml),trichloroacetic acid (10 mg) and methanol (5 ml). The resulting mixture wasstirred for 3 hours at room temperature and then filtered and the filtrate evaporated. The residue was treated at 50° C for 1 hour with 10% sulphuric acid (100 ml), the mixture filtered and the filtrate basified with sodium carbonate. Extraction with ether, drying of the extract with magnesium sulphate and evaporation gave 10.1 g of the crude title compound(about 75% by g.l.c.) as a brown oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][C:9]([NH:11][NH2:12])=O)[CH:5]=[CH:4][N:3]=1.Cl[C:14]1[N:15]=[N:16][C:17]([C:20]2[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=2)=[CH:18][CH:19]=1>>[Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][C:9]2[N:15]3[N:16]=[C:17]([C:20]4[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=4)[CH:18]=[CH:19][C:14]3=[N:12][N:11]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Clc1ccc(-c2cccnc2)nn1
Reactant: NNC(=O)Cc1ccnc(Cl)c1
Product: Clc1cc(Cc2nnc3ccc(-c4cccnc4)nn23)ccn1

Procedure:
The title compound was prepared as described in Example 1 as a pale orange solid from (2-Chloro-pyridin-4-yl)-acetic acid hydrazide (0.61 mmol) and 3-chloro-6-pyridin-3-yl-pyridazine (0.33 mmol). 1H NMR (CDCl3/CD3OD) δ 9.17 (1H, d, J=2.6 Hz), 8.79 (1H, dd, J=4.9 Hz, 1.6 Hz), 8.32 (1H, d, J=4.6 Hz), 8.30 (1H, d, J=9.5 Hz), 8.28 (1H, ddd, J=8.0 Hz, 2.4 Hz, 1.6 Hz), 7.70 (1H, d, J=9.6 Hz), 7.58 (1H, m), 7.47 (1H, s), 7.34 (1H, m), 4.67 (2H, s). ESI-MS (m/z): Calcd for C1-6H11N6Cl: 322.1; found 323.3 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[O:13][CH2:14][C:15]1[N:16]=[C:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[O:18][CH:19]=1)[CH:6]=[CH:7][CH:8]=O.[O:26]1[CH2:30][C:29](=[O:31])[NH:28][C:27]1=[O:32].N1CCCCC1>C(O)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[O:13][CH2:14][C:15]1[N:16]=[C:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[O:18][CH:19]=1)[CH:6]=[CH:7][CH:8]=[C:30]1[O:26][C:27](=[O:32])[NH:28][C:29]1=[O:31]
Reactant: COc1cc(C=CC=O)ccc1OCc1coc(-c2ccccc2)n1
Reactant: O=C1COC(=O)N1
Solvent: C1CCNCC1
Solvent: CC(=O)O
Product: COc1cc(C=CC=C2OC(=O)NC2=O)ccc1OCc1coc(-c2ccccc2)n1
Reaction time: 72 h
Yield: 42.3 %

Procedure:
A mixture of 3-methoxy-4-(2-phenyl-4-oxazolylmethoxy)cinnamaldehyde (5.5 g), 2,4-oxazolidinedione (6.7 g), piperidine (1.4 g) and acetic acid (120 ml) was stirred for three days under reflux. The reaction mixture was cooled, and resulting crystalline precipitate was collected by filtration, which was washed with water, ethanol and isopropyl ether, successively to give 5-[3-methoxy-4-(2-phenyl-4-oxazolylmethoxy)cinnamylidene]-2,4-oxazolidinedione (2.9 g, 43%), which was recrystallized from chloroform-methanol to afford yellow needles, m.p.227-228° C.
Reaction SMILES: [C:1]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[CH:6][CH:5]=1)([OH:3])=O.O=S(Cl)Cl.[CH2:16]([NH:18][CH2:19][CH3:20])[CH3:17]>C1(C)C=CC=CC=1.C(Cl)Cl>[CH2:16]([N:18]([CH2:19][CH3:20])[C:1](=[O:3])[C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[CH:6][CH:5]=1)[CH3:17]
Reactant: O=Cc1ccc(C(=O)O)cc1
Reactant: CCNCC
Solvent: O=S(Cl)Cl
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CCN(CC)C(=O)c1ccc(C=O)cc1
Reaction time: 1 h

Procedure:
To a suspension of 4-carboxybenzaldehyde (30 g, 0.2 mole) in 100 ml of toluene was added SOCl2 (97 ml, 1.3 moles) at 60° C. The reaction was heated until gas evolution ceased followed by evaporation to dryness with toluene (3×50 mL) This yielded a residue, which was dissolved in CH2Cl2 (200 mL). To this solution, cooled in an ice bath while stirring, was added diethylamine (50 mL). Stirring was continued for one hour and then the mixture heated at reflux for a further hour. After cooling, the mixture was washed successively with H2O, 2 N HCl, H2O then 2 N NaOH and finally with H2O. The solution was dried over MgSO4, filtered and concentrated to dryness yielding 41 g of oil. Distillation at 140-150° C./1.5 torr gave 36.9 g, 90% of INTERMEDIATE 1.
Reaction SMILES: [BH4-].[Na+].[CH3:3][O:4][C:5](=[O:43])[C:6]1[CH:11]=[C:10]([NH:12][CH3:13])[CH:9]=[C:8]([NH:14][C:15](=[O:42])[CH2:16][N:17]2[N:23]=[C:22]([CH:24]3[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]3)[C:21]3[CH:30]=[CH:31][CH:32]=[CH:33][C:20]=3[N:19]([CH2:34][C:35](=[O:40])[C:36]([CH3:39])([CH3:38])[CH3:37])[C:18]2=[O:41])[CH:7]=1.[NH4+].[Cl-]>CO>[CH3:3][O:4][C:5](=[O:43])[C:6]1[CH:11]=[C:10]([NH:12][CH3:13])[CH:9]=[C:8]([NH:14][C:15](=[O:42])[CH2:16][N:17]2[N:23]=[C:22]([CH:24]3[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]3)[C:21]3[CH:30]=[CH:31][CH:32]=[CH:33][C:20]=3[N:19]([CH2:34][CH:35]([OH:40])[C:36]([CH3:38])([CH3:39])[CH3:37])[C:18]2=[O:41])[CH:7]=1
Reactant: CNc1cc(NC(=O)CN2N=C(C3CCCCC3)c3ccccc3N(CC(=O)C(C)(C)C)C2=O)cc(C(=O)OC)c1
Agent: [BH4-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Product: CNc1cc(NC(=O)CN2N=C(C3CCCCC3)c3ccccc3N(CC(O)C(C)(C)C)C2=O)cc(C(=O)OC)c1
Temperature: 2.5 °C
Reaction time: 0.67 h
Yield: 96.8 %

Procedure:
Sodium borohydride (5 mg, 0.13 mmol) was added to an ice-cooled solution of 3-{2-[5-cyclohexyl-1-(3,3-dimethyl-2-oxo-butyl)-2-oxo-1,2-dihydro-3H-1,3,4-benzotriazepin-3-yl]-acetylamino}-5-methylamino-benzoic acid methyl ester (Example 74)(64 mg, 0.11 mmol) in MeOH (2 ml). The reaction mixture was stirred at 0-5° C. for 40 mins, then at room temperature for 2 h. Saturated NH4Cl solution (10 ml) was added and the product was extracted with CHCl3 (15 ml). The organic phase was dried (MgSO4), filtered and the filtrate was evaporated to afford the title compound (60 mg, 97%). 1H NMR (CDCl3) 8.10-8.79 (1H, m), 7.55 (2H, m), 7.36 (2H, m), 7.24 (1H, m), 6.95 (1H, s), 6.70 (1H, m), 4.46 (1H, m), 4.29-4.04 (2H, m), 3.89 (4H, m), 3.82-3.60 (1H, m), 3.43-3.23 (1H, m), 2.81 (4H, m), 2.15-1.66 (7H, m), 1.33-1.24 (3H, m), 0.97 and 0.93 (9H, s×2). Found C, 63.17; H, 7.59; N, 11.85%; C31H41N5O5.1.5H2O requires C, 63.03, H, 7.51, N 11.86%.
Reaction SMILES: [CH2:1]([N:5]([CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([O:35][CH3:36])[C:30]=1[O:37][CH3:38])[C:6](=[O:27])[CH2:7][CH2:8][C:9]1[CH:26]=[CH:25][C:12]([O:13][CH2:14][C:15]2[CH:24]=[CH:23][CH:22]=[CH:21][C:16]=2[C:17]([O:19]C)=[O:18])=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].[Li+].[OH-].CCOC(C)=O>C1COCC1.O>[CH2:1]([N:5]([CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([O:35][CH3:36])[C:30]=1[O:37][CH3:38])[C:6](=[O:27])[CH2:7][CH2:8][C:9]1[CH:26]=[CH:25][C:12]([O:13][CH2:14][C:15]2[CH:24]=[CH:23][CH:22]=[CH:21][C:16]=2[C:17]([OH:19])=[O:18])=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN(Cc1cccc(OC)c1OC)C(=O)CCc1ccc(OCc2ccccc2C(=O)OC)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCCN(Cc1cccc(OC)c1OC)C(=O)CCc1ccc(OCc2ccccc2C(=O)O)cc1
Yield: 88.7 %

Procedure:
Methyl 2-[(4-{3-[butyl(2,3-dimethoxybenzyl)amino]-3-oxopropyl}phenoxy)methyl]-benzoate (15 mg, 0.029 mmol) was dissolved in THF/water (2/1, 2 ml) and LiOH (1.4 mg, 0.058 mmol) was added. The reaction was performed in a single node microwave oven (150° C., 7 min). Workup was done by adding EtOAc (10 ml) and washing the organic phase with two portions of HCl (2×5 ml, 1 M). The organic phase was dried (MgSO4) and the solvent was removed by evaporation to give 13 mg of 2-[(4-{3-[butyl(2,3-dimethoxybenzyl)amino]-3-oxopropyl}phenoxy)methyl]benzoic acid (yield 89%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C@@H:6]1[CH2:10][S:9][CH:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[OH:17])[N:7]1[C:18](=[O:24])[CH2:19][CH2:20][C:21](O)=[O:22])=[O:5])[CH3:2].CN1CCOCC1.[NH2:32][OH:33].Cl>O1CCCC1.ClC(OCC(C)C)=O.CO>[CH2:1]([O:3][C:4]([C@@H:6]1[CH2:10][S:9][CH:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[OH:17])[N:7]1[C:18](=[O:24])[CH2:19][CH2:20][C:21](=[O:22])[NH:32][OH:33])=[O:5])[CH3:2]
Reactant: CCOC(=O)[C@@H]1CSC(c2ccccc2O)N1C(=O)CCC(=O)O
Reactant: NO
Agent: CC(C)COC(=O)Cl
Agent: Cl
Solvent: CN1CCOCC1
Solvent: CO
Solvent: C1CCOC1
Product: CCOC(=O)[C@@H]1CSC(c2ccccc2O)N1C(=O)CCC(=O)NO
Reaction time: 2 h
Yield: 63.3 %

Procedure:
To a stirred solution of (4R)-3-(3-carboxypropanoyl)-2-(2-hydroxyphenyl)-4-thiazolidinecarboxylic acid ethyl ester (compound 8a) (1.06 g) and N-methylmorpholine (0.33 ml) in 20 ml of anhydrous tetrahydrofuran, isobutyl chloroformate (0.39 ml) was added dropwise at -15° C., and stirred for additional 2 hours at this temperature. To this solution, the methanol solution of hydroxylamine (0.3 g) was added dropwise at -50° C. The reaction mixture was stirred for 1 hour at room temperature, acidified with N hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated in vacuo. The residual oil was purified by silica gel column chlromatography to give 0.7 g (63%) of the titled compound. IR (KBr, cm-1) 3220, 1727, 1625, 1595, 1200, 1092, 753. NMR (acetone-d6, δ): 1.24 (3H, t, J=7.5 Hz, CO2CH2CH3), 2.17-3.07 (4H, m, CO--CH2)2CO), 3.30 (1H, ABq (A part), d, J=10.0, 2.0 Hz, C5 --HA), 3.47 (1H, ABq (B part), d, J=10.0, 7.0 Hz, C5 --HB), 4.14 (2H, q, J=7.5 Hz, CO2CH2), 5.18 (1H, dd, J=2.0, 7.0 Hz, C4 --H), 6.40 (1H, S, C2 --H), 6.88-7.27 (4H, m, arom. H), 8.60 (2H, br. s, NHOH), 9.77 (1H, br. s, OH )
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][OH:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O.[CH3:48][O:49][C:50](=[O:59])[C:51]1[CH:56]=[CH:55][C:54](O)=[C:53]([CH3:58])[CH:52]=1>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([CH2:14][CH2:15][O:16][C:54]2[CH:55]=[CH:56][C:51]([C:50]([O:49][CH3:48])=[O:59])=[CH:52][C:53]=2[CH3:58])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)c1ccc(O)c(C)c1
Reactant: CC(C)(C)OC(=O)N1CCN(CCO)CC1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1ccc(OCCN2CCN(C(=O)OC(C)(C)C)CC2)c(C)c1
Temperature: 0 °C
Reaction time: 20 h
Yield: 60 %

Procedure:
4-(2-Hydroxy-ethyl)-piperazine-1-carboxylic acid tert-butyl ester (500 mg, 2.2 mmol) was dissolved in THF (30 ml) and cooled down to 0° C. Polymer-supported triphenylphosphine (2.2 g, 2.2 mmol), DEAD (378 mg, 2.2 mmol) and 4-hydroxy-3-methyl-benzoic acid methyl ester from Example E29 (361 mg, 2.2 mmol) were added and the mixture was stirred for 20 h at room temperature. The resin was filtered off and the filtrate concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluant; EtOAc) to yield the title compound (495 mg, 60%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:33])[CH2:7][NH:8][C:9]([C:11]1[C:16]([O:17]CC2C=CC=CC=2)=[CH:15][C:14]([O:25]CC2C=CC=CC=2)=[CH:13][N:12]=1)=[O:10])([CH3:4])([CH3:3])[CH3:2]>CCO.[Pd]>[C:1]([O:5][C:6](=[O:33])[CH2:7][NH:8][C:9]([C:11]1[C:16]([OH:17])=[CH:15][C:14]([OH:25])=[CH:13][N:12]=1)=[O:10])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)CNC(=O)c1ncc(OCc2ccccc2)cc1OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)CNC(=O)c1ncc(O)cc1O
Reaction time: 22 h
Yield: 66 %

Procedure:
A solution of [(3,5-bis-benzyloxy-pyridine-2-carbonyl)-amino]-acetic acid tert-butyl ester, 26, (3.04 g, 6.79 mmol) in EtOH (100 mL) containing 10% Pd/C (0.300 g) is stirred under an atmosphere of H2 for 22 hours. The suspension is then filtered through Celite™, concentrated under reduced pressure, and the crude product purified over silica (2.5% MeOH/CH2Cl2) to afford 1.20 g (66% yield) of the desired compound as a colorless oil. 1H NMR (250 MHz, CDCl3) δ ppm 11.90 (1H, br s), 8.94 (1H, br s), 8.20 (1H, t, J=5.6 Hz), 7.76 (1H, d, J=2.4 Hz), 6.77 (1H, d, J=2.1 Hz), 4.13 (2H, d, J=5.5 Hz), 1.53 (9H, s). HPLC-MS: m/z 269 [M+H]+.
Reaction SMILES: [N:1]1[N:2]=[C:3]([C:19]2[CH:28]=[CH:27][C:22]([C:23]([O:25]C)=[O:24])=[CH:21][CH:20]=2)[N:4]2[C:10]=1[C:9]1[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=1[NH:7][C:6]1[N:15]=[CH:16][CH:17]=[CH:18][C:5]2=1.[OH-].[Li+].O.C(O)(=O)C>CO.C(OCC)(=O)C>[N:1]1[N:2]=[C:3]([C:19]2[CH:28]=[CH:27][C:22]([C:23]([OH:25])=[O:24])=[CH:21][CH:20]=2)[N:4]2[C:10]=1[C:9]1[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=1[NH:7][C:6]1[N:15]=[CH:16][CH:17]=[CH:18][C:5]2=1
Reactant: COC(=O)c1ccc(-c2nnc3n2-c2cccnc2Nc2ccccc2-3)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(O)c1ccc(-c2nnc3n2-c2cccnc2Nc2ccccc2-3)cc1
Temperature: 70 °C
Reaction time: 72 h

Procedure:
To a suspension of methyl 4-(9H-benzo[f]pyrido[2,3-b][1,2,4]triazolo[4,3-d][1,4]diazepin-3-yl)benzoate (0.5 g, 1.4 mmol) in methanol (20 mL) was added lithium hydroxide (0.16 g, 6.8 mmol) and water (2 mL). The reaction mixture was stirred at 70° C. for 3 days. The reaction pH was acidified by the addition of acetic acid followed by ethyl acetate. The solid was filtered off and washed with water. The solid was re-suspended in ethyl acetate, stirred, filtered off and dried under vacuum. The 4-(9H-benzo[f]pyrido[2,3-b][1,2,4]triazolo[4,3-d][1,4]diazepin-3-yl)benzoic acid was obtained as a yellow solid (0.48 g, quantitative). M.p.>300° C.; 400 MHz 1H NMR (DMSO-d6) δ: 13.20 (br.s, 1H), 8.83 (br.s, 1H), 8.23 (d, J=4.4 Hz, 1H), 8.05-7.95 (m, 3H), 7.56 (d, J=8.0 Hz, 2H), 7.45 (t, J=4.9 Hz, 1H), 7.36 (d, J=8.0 Hz, 1H), 7.2-7.1 (m, 2H), 6.92 (dd, J=7.6, 4.4 Hz, 1H); LCMS [M+H]: 356.