Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12](Br)=[C:13]([CH:16]=1)[CH:14]=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:18]([C:21]1[CH:22]=[CH:23][C:24]([O:30][CH3:31])=[C:25](B(O)O)[CH:26]=1)([CH3:20])[CH3:19].C(=O)([O-])[O-].[Cs+].[Cs+].C(OCC)(=O)C>O1CCOCC1>[CH2:1]([O:8][C:9]1[CH:16]=[C:13]([CH:14]=[O:15])[C:12]([C:25]2[CH:26]=[C:21]([CH:18]([CH3:20])[CH3:19])[CH:22]=[CH:23][C:24]=2[O:30][CH3:31])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(C(C)C)cc1B(O)O
Reactant: O=Cc1cc(OCc2ccccc2)ccc1Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: COc1ccc(C(C)C)cc1-c1ccc(OCc2ccccc2)cc1C=O
Temperature: 80 °C
Reaction time: 6 h
Yield: 96.1 %

Procedure:
5-Benzyloxy-2-bromo-benzaldehyde (1.0 g) is dissolved in 1,4-dioxane (30 ml) and thereto are added [1,1′-bis(diphenylphosphino)ferrocene]-dichloropalladium dichloromethane complex (280 mg), (5-isopropyl-2-methoxyphenyl)boronic acid (800 mg) and cesium carbonate (1.68 g) and the mixture is stirred under nitrogen atmosphere at 80° C. for 6 hours. The reaction mixture is cooled to room temperature, and thereto are added ethyl acetate and a saturated aqueous sodium bicarbonate solution, and the mixture is separated, and the organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane:ethyl acetate=9:1→4:1) to give 4-benzyloxy-5′-isopropyl-2′-methoxy-biphenyl-2-carbaldehyde (1.19 g). MS (m/z): 361 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:23]3[C:18](=[CH:19][C:20](F)=[CH:21][CH:22]=3)[N:17]=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N:25]1[N:26]=[CH:27][N:28]([CH2:30][CH2:31][CH2:32][OH:33])[CH:29]=1.CC([O-])(C)C.[K+]>COCCOC.CS(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:23]3[C:18](=[CH:19][C:20]([O:33][CH2:32][CH2:31][CH2:30][N:28]4[CH:27]=[N:26][N:25]=[CH:29]4)=[CH:21][CH:22]=3)[N:17]=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: OCCCn1cnnc1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ncnc3cc(F)ccc23)CC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CCC(c2ncnc3cc(OCCCn4cnnc4)ccc23)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 4-(7-fluoro-quinazolin-4-yl)-piperidin-1-carboxylic acid tert-butyl ester (31.6 mg, 95.5 μmol), as prepared in Example 12b, 3-[1,2,4]-triazol-4-yl-propan-1-ol (ChemPacific) (12.0 mg, 94.5 μmol), and KOtBu (11.7 mg, 104 μmol) in DME (100 μL) and DMSO (50 μL) was stirred at rt for 1 hr. The resulting homogeneous amber solution was partitioned with DCM (2 mL) and 0.5M sodium phosphate/pH 7 (2 mL). The organic layer was concentrated to provide the crude title compound. LC/MS (ESI): calcd mass 438.2, found 439.1 (MH)+.
Reaction SMILES: [CH:1]1[CH:5]=[C:4]([C:6]([CH2:8][CH2:9][CH2:10]Cl)=[O:7])[S:3][CH:2]=1.[N-:12]=[N+:13]=[N-:14].[Na+]>CN(C=O)C>[N:12]([CH2:10][CH2:9][CH2:8][C:6]([C:4]1[S:3][CH:2]=[CH:1][CH:5]=1)=[O:7])=[N+:13]=[N-:14]
Reactant: [N-]=[N+]=[N-]
Reactant: O=C(CCCCl)c1cccs1
Agent: [Na+]
Solvent: CN(C)C=O
Product: [N-]=[N+]=NCCCC(=O)c1cccs1
Temperature: 70 °C
Reaction time: 1.5 h
Yield: 83.1 %

Procedure:
A mixture of 4-chloro-2′-butyrothienone (3.0 g, 15.9 mmol) and sodium azide (2.07 g, 31.8 mmol) in DMF (50 mL) was stirred at 70° C. for 1.5 h. The reaction mixture was then partitioned between ethyl acetate (200 mL) and water (200 mL). The organic layer was washed with water (100 mL), saturated aqueous sodium bicarbonate (100 mL) and brine (100 mL) and dried over sodium sulfate. Removal of the solvent in vacuum provided the title compound (2.58 g, 83% yield). MS m/e 218; HPLC retention time 0.85 min (Method B).
Reaction SMILES: [CH2:1]1[O:11][C:10]2[CH:9]=[C:8]([N+:12]([O-:14])=[O:13])[C:5]([CH:6]=[O:7])=[CH:4][C:3]=2[O:2]1.[Mn]([O-])(=O)(=O)=[O:16].[K+]>O.CC(C)=O>[N+:12]([C:8]1[C:5]([C:6]([OH:16])=[O:7])=[CH:4][C:3]2[O:2][CH2:1][O:11][C:10]=2[CH:9]=1)([O-:14])=[O:13]
Reactant: O=Cc1cc2c(cc1[N+](=O)[O-])OCO2
Reactant: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: O=C(O)c1cc2c(cc1[N+](=O)[O-])OCO2
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.6 %

Procedure:
A mixture of 3,4-(methylenedioxy)-6-nitrobenzaldehyde (25 g, 128 mmol) and potassium permanganate (40 g, 253 mmol) in a mixture of 300 mL water and 200 mL acetone was stirred overnight at ambient temperature and then heated to 100° C. for 1 hour. The reaction mixture was filtered through Celite®, acetone was removed in vacuo, and the product precipitated from the water solution by acidification to pH 1.2 with concentrated hydrochloric acid to give 6-nitro-benzo[1,3]dioxole-5-carboxylic acid [19.88 g (73%)].
Reaction SMILES: [NH2:1][C:2]1[CH:13]=[CH:12][C:5]2[O:6][C:7]3([C:10](=[O:11])[C:4]=2[CH:3]=1)[CH2:9][CH2:8]3.C(=O)([O-])[O-].[Ca+2].[Br:19]Br>C(Cl)(Cl)(Cl)Cl.C(Cl)Cl>[NH2:1][C:2]1[CH:13]=[CH:12][C:5]2[O:6][C:7]3([C:10](=[O:11])[C:4]=2[C:3]=1[Br:19])[CH2:9][CH2:8]3
Reactant: Nc1ccc2c(c1)C(=O)C1(CC1)O2
Reactant: BrBr
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: ClCCl
Solvent: ClC(Cl)(Cl)Cl
Product: Nc1ccc2c(c1Br)C(=O)C1(CC1)O2
Temperature: -17 °C
Reaction time: 0.75 h

Procedure:
5-Aminospiro[benzo[b]furan-2(3H),1'-cyclopropane]-3-one (0.747 g.) and calcium carbonate (0.47 g.) were suspended in a mixture of carbon tetrachloride (20 ml.) and methylene chloride (5 ml.). The suspension was cooled to -17° C., then bromine (0.22 ml.) was added thereto dropwise, followed by stirring for 45 minutes. The reaction mixture was poured into ice-water, then extracted with ethyl acetate. The extract was washed with water and dried. The solvent was evaporated off, and the residue was recrystallized from ethanol-water. By the above procedure there was obtained 5-amino-4-bromospiro[benzo[b]furan-2(3H),1'-cyclopropane]-3-one as yellow needles melting at 167°-170° C. Yield 0.6 g.
Reaction SMILES: [C:1]1([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:6]=[CH:5][C:4]([CH:7]=O)=[CH:3][CH:2]=1.FC(F)(F)C([O-])=O.[C:22]([C:25]1[C:26]([NH:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)=[N:27][N:28]([C:30]2([CH2:36][C:37]#[N:38])[CH2:35][CH2:34][NH2+:33][CH2:32][CH2:31]2)[CH:29]=1)(=[O:24])[NH2:23].C(O)(C(F)(F)F)=O>CN(C=O)C>[C:1]1([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:6]=[CH:5][C:4]([CH2:7][N:33]2[CH2:34][CH2:35][C:30]([N:28]3[CH:29]=[C:25]([C:22]([NH2:23])=[O:24])[C:26]([NH:39][C:40]4[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=4)=[N:27]3)([CH2:36][C:37]#[N:38])[CH2:31][CH2:32]2)=[CH:3][CH:2]=1
Reactant: O=Cc1ccc(-c2ccccc2)cc1
Reactant: N#CCC1(n2cc(C(N)=O)c(Nc3ccccc3)n2)CC[NH2+]CC1
Agent: O=C([O-])C(F)(F)F
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: N#CCC1(n2cc(C(N)=O)c(Nc3ccccc3)n2)CCN(Cc2ccc(-c3ccccc3)cc2)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Biphenyl-4-carbaldehyde (12 mg, 0.070 mmol) was treated with a solution of 4-[4-carbamoyl-3-(phenylamino)-1H-pyrazol-1-yl]-4-(cyanomethyl)piperidinium trifluoroacetate (Intermediate #38-2) (20 mg, 0.050 mmol) and TFA (0.020 mL, 0.23 mmol) in DMF (0.65 mL). The resulting solution was then treated with MP-(OAc)3BH (80 mg, 0.16 mmol). The resulting mixture was shaken at ambient temperature for 16 hours on an orbital shaker. The mixture was then filtered through a 0.45 micron fit and the fit was washed with DMSO (1.0 mL). The filtrate was then purified directly by reverse-phase preparative HPLC (using a gradient elution of 5-95% MeCN/water, with 0.1% v/v NH4OH modifier). Desired fractions were identified, combined, and concentrated in vacuo to afford the title compound, Example #21-1.
Reaction SMILES: [CH2:1]([C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][C:16]([O:18]CC)=[O:17])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>C1COCC1.CO>[CH2:1]([C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][C:16]([OH:18])=[O:17])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)CCc1ccc(Cc2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)CCc1ccc(Cc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of ethyl 3-(4-benzylphenyl)propanoate (S39, 320 mg, 1.19 mmol) in THF/MeOH (1/1, 10 mL) was treated with aqueous 4 N NaOH (1 mL) and stirred for 3 h at 25° C. The reaction mixture was concentrated, diluted with aqueous 1 N HCl and extracted with CH2Cl2. The organic layer was dried over Na2SO4, filtered and concentrated to afford S40 (260 mg, 1.08 mmol, 91%) as a white solid: 1H NMR (CDCl3, 500 MHz) 7.27-7.06 (m, 9H), 3.91 (s, 2H), 2.86 (br s, 2H), 2.59 (br s, 2H); 13C NMR (CDCl3, 100 MHz) 179.9, 141.1, 138.8, 138.4, 128.9, 128.8, 128.4, 128.2, 126.0, 41.4, 36.9, 30.7.
Reaction SMILES: [CH2:1]([O:4][C@@H:5]1[C@@H:9]([CH2:10][O:11][Si](C(C)(C)C)(C)C)[O:8][C@@H:7]([N:19]2[CH:26]=[C:25]([I:27])[C:23]([NH2:24])=[N:22][C:20]2=[O:21])[CH2:6]1)[CH:2]=[CH2:3].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[CH2:1]([O:4][C@@H:5]1[C@@H:9]([CH2:10][OH:11])[O:8][C@@H:7]([N:19]2[CH:26]=[C:25]([I:27])[C:23]([NH2:24])=[N:22][C:20]2=[O:21])[CH2:6]1)[CH:2]=[CH2:3]
Reactant: C=CCO[C@H]1C[C@H](n2cc(I)c(N)nc2=O)O[C@@H]1CO[Si](C)(C)C(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: C=CCO[C@H]1C[C@H](n2cc(I)c(N)nc2=O)O[C@@H]1CO
Reaction time: 1 h

Procedure:
To a solution of the starting nucleoside (40) (323 mg, 0.64 mmol) in THF (15 ml) under N2 protected atmosphere was added at room temperature tetrabutylammonium fluoride (TBAF) 1M in THF (0.7 ml, 0.7 mmol). Mixture stirred for one hour and then quenched by addition of H2O (5 ml). THF was evaporated and aqueous residue extracted into EtOAc (3×25 ml). Combined organic extracts were dried (MgSO4), filtered and the volatiles evaporated under reduced pressure giving a crude material which was purified by flash chromatography on a pre-packed silica column eluted with EtOAc. The product (41) was obtained as a white solid (233 mg, 93%). 1H NMR (d6 DMSO) δ 1.96-2.05 (m, 1H, H-2′) 2.24 (ddd, J=13.5, 5.8 and 2.8 Hz, 1H, H-2′), 3.50-3.62 (m, 2H, H5′), 3.91-3.97 (m, 2H, H3′,H4′), 4.03-4.07 (m, 2H, HHC—CH═), 5.11-5.16 (m, 2H, OH, CH═CHH), 5.24 (dd, J=17.2, 1.6 Hz, 1H, CH═CHH), 5.82-5.91 (m, 1H, CH═CHH), 6.02 (dd, J=7.6, 6.0 Hz, 1H, H-1′), 6.60 (s, 1H, NHH), 7.79 (s, 1H, NHH), 8.21 (s, 1H, H-6). MS (ES): m/z (%) (M−H) 392 (100%).
Reaction SMILES: I.[NH2:2][C:3]1[C:4]([C:11]([NH:13][C:14](=[NH:17])SC)=[O:12])=[N:5][C:6]([Cl:10])=[C:7]([NH2:9])[N:8]=1.C(N(CC)CC)C.[CH2:25]([O:27][C:28](=[O:42])[CH2:29][O:30][C:31]1[CH:36]=[CH:35][C:34]([CH2:37][CH2:38][CH2:39][CH2:40][NH2:41])=[CH:33][CH:32]=1)[CH3:26]>C1COCC1>[CH2:25]([O:27][C:28](=[O:42])[CH2:29][O:30][C:31]1[CH:36]=[CH:35][C:34]([CH2:37][CH2:38][CH2:39][CH2:40][NH:41][C:14]([NH2:17])=[N:13][C:11]([C:4]2[C:3]([NH2:2])=[N:8][C:7]([NH2:9])=[C:6]([Cl:10])[N:5]=2)=[O:12])=[CH:33][CH:32]=1)[CH3:26]
Reactant: CCOC(=O)COc1ccc(CCCCN)cc1
Reactant: CSC(=N)NC(=O)c1nc(Cl)c(N)nc1N
Agent: I
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)COc1ccc(CCCCNC(N)=NC(=O)c2nc(Cl)c(N)nc2N)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 56.7 %

Procedure:
1-(3,5-Diamino-6-chloropyrazinoyl)-2-methylisothiourea hydriodide (0.74 g, 1.9 mmol) and triethylamine (0.5 mL) were sequentially added into a solution of 48 (0.62 g, 2.47 mmol) in THF (10 mL). The reaction mixture was stirred in the boiling solvent for 4 h and at room temperature overnight. The solvent was evaporated and the residue was purified by column chromatography (silica gel, 6:1:0.1 chloroform/ethanol/concentrated ammonium hydroxide) to provide 49 (0.5 g, 57%) as a yellow solid. The purity of the product was confirmed by HPLC. m/z (APCI)=464 [C20H26ClN7O4+H]+.
Reaction SMILES: [C:1]1([C@H:7]([NH:9][C:10]([NH:12][C:13]2[CH:22]=[C:21]3[NH:23][N:24]=[C:19]4[C:20]3=[C:15]([CH2:16][CH2:17][NH:18]4)[N:14]=2)=[O:11])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[C:32](Cl)(=[O:34])[CH3:33]>C(Cl)Cl>[C:32]([N:18]1[CH2:17][CH2:16][C:15]2[N:14]=[C:13]([NH:12][C:10]([NH:9][C@@H:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH3:8])=[O:11])[CH:22]=[C:21]3[NH:23][N:24]=[C:19]1[C:20]=23)(=[O:34])[CH3:33]
Reactant: CC(=O)Cl
Reactant: C[C@@H](NC(=O)Nc1cc2[nH]nc3c2c(n1)CCN3)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)N1CCc2nc(NC(=O)N[C@H](C)c3ccccc3)cc3[nH]nc1c23
Reaction time: 1 h

Procedure:
(R)-1-(1-phenylethyl)-3-(1,3,4,5-tetrahydropyrazolo[3,4,5-de][1,6]naphthyridin-7-yl)urea (Example 136; 13 mg, 0.040 mmol) and triethylamine (50 mg, 0.494 mmol) were taken in DCM (0.15 mL) and added acetyl chloride (20 mg, 0.255 mmol) and stirred for 1 hour. The reaction mixture was diluted with DCM, washed with aqueous sodium bicarbonate, brine, dried with sodium sulfate and concentrated. Purification of the residue by flash column (0-15% MeOH-DCM) gave (R)-1-(3 acetyl-1,3,4,5-tetrahydropyrazolo[3,4,5-de][1,6]naphthyridin-7-yl)-3-(1-phenylethyl)urea. MS ESI calc'd. for C19H20N6O2 [M+H]+ 365. found 365. 1H NMR (ppm, 500 MHz, DMSO-d6) δ 12.35 (s, 1H), 9.13-9.05 (m, 1H), 8.05-7.86 (m, 1H), 7.39-7.28 (m, 6H), 7.27-7.18 (m, 1H), 3.06-2.96 (m, 2H), 1.38 (t, J=9.1, 3H), 1.25-1.18 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:13]2=[N:14][CH:15]=[CH:16][C:17](I)=[C:12]2[CH:11]=[N:10]1.CC1(C)C(C)(C)[O:23][B:22](B2OC(C)(C)C(C)(C)O2)[O:21]1.C([O-])(=O)C.[K+].C(Cl)Cl>CS(C)=O>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:13]2=[N:14][CH:15]=[CH:16][C:17]([B:22]([OH:23])[OH:21])=[C:12]2[CH:11]=[N:10]1
Reactant: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Reactant: Fc1ccc(-n2ncc3c(I)ccnc32)c(Cl)c1
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CS(C)=O
Product: OB(O)c1ccnc2c1cnn2-c1ccc(F)cc1Cl
Temperature: 85 °C

Procedure:
To a 48 mL pressure bottle containing 1-(2-chloro-4-fluorophenyl)-4-iodo-1H-pyrazolo[3,4-b]pyridine (68.5 mg, 0.183 mmol) was added 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (81.7 mg, 0.322 mmol), potassium acetate (85.1 mg, 0.867 mmol), and anhydrous DMSO (1 mL). The reaction mixture was purged with argon, then treated with PdCl2(dppf).CH2Cl2 (11.5 mg, 0.016 mmol). The reaction mixture was again purged with argon, securely capped, and heated to 85° C. for 1 h to give the desired intermediate. LC/MS (Condition B): ret. T=3.0 min, (M+H)+ 292.01.
Reaction SMILES: C(N(CC)CC)C.Cl.[NH2:9][C:10]1[N:15]=[CH:14][C:13]([C:16]2[C:17]([CH:27]=[O:28])=[N:18][N:19]([CH:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)[CH:20]=2)=[CH:12][C:11]=1[C:29]1[O:30][C:31]2[CH:37]=[CH:36][CH:35]=[CH:34][C:32]=2[N:33]=1.[C:38](Cl)(=[O:40])[CH3:39]>C(Cl)Cl>[C:38]([N:24]1[CH2:25][CH2:26][CH:21]([N:19]2[CH:20]=[C:16]([C:13]3[CH:14]=[N:15][C:10]([NH2:9])=[C:11]([C:29]4[O:30][C:31]5[CH:37]=[CH:36][CH:35]=[CH:34][C:32]=5[N:33]=4)[CH:12]=3)[C:17]([CH:27]=[O:28])=[N:18]2)[CH2:22][CH2:23]1)(=[O:40])[CH3:39]
Reactant: CC(=O)Cl
Reactant: Nc1ncc(-c2cn(C3CCNCC3)nc2C=O)cc1-c1nc2ccccc2o1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)N1CCC(n2cc(-c3cnc(N)c(-c4nc5ccccc5o4)c3)c(C=O)n2)CC1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
A solution of hydrogen chloride in 2-propanol (2047 μl, 8.19 mmol) at 25° C. was added to tert-butyl 4-[4-[6-amino-5-(1,3-benzoxazol-2-yl)-3-pyridyl]-3-formyl-pyrazol-1-yl]piperidine-1-carboxylate (200 mg). The resulting mixture was stirred at 25° C. for 2 hours. The solid was filtered and washed with isopropanol to afford 4-[6-amino-5-(1,3-benzoxazol-2-yl)-3-pyridyl]-1-(4-piperidyl)pyrazole-3-carbaldehyde hydrochloride (170 mg). A solution of triethylamine (0.171 ml) was added to 4-[6-amino-5-(1,3-benzoxazol-2-yl)-3-pyridyl]-1-(4-piperidyl)pyrazole-3-carbaldehyde hydrochloride (174 mg) dissolved in CH2Cl2 (10 ml) at 0° C. The resulting solution was stirred at 0° C. for 10 minutes. Acetyl chloride (0.032 ml) was added to the mixture at 0° C., then the mixture was stirred at 25° C. for 40 minutes. The mixture was adsorbed on silica gel. The crude product was purified by flash chromatography on silica gel eluting with 1 to 4% methanol in dichloromethane. The solvent was evaporated to dryness to afford 1-(1-acetyl-4-piperidyl)-4-[6-amino-5-(1,3-benzoxazol-2-yl)-3-pyridyl]pyrazole-3-carbaldehyde (148 mg) as a pale beige foam. NMR Spectrum: (CDCl3): 2.02-2.15 (m, 2H), 2.17 (s, 3H), 2.23-2.38 (m, 2H), 2.78-2.88 (m, 1H), 3.25-3.36 (m, 1H), 3.99-4.10 (m, 1H), 4.43-4.55 (m, 1H), 4.76-4.87 (m, 1H), 6.92 (bs, 2H), 7.34-7.41 (m, 2H), 7.59 (dd, 1H), 7.65 (s, 1H), 7.74 (dd, 1H), 8.42 (d, 1H), 8.64 (d, 1H), 10.09 (s, 1H); Mass spectrum: M+H+ 431;
Reaction SMILES: [CH2:1]([C:3]1([CH2:10][CH3:11])[CH2:8][C:7](=[O:9])[O:6][C:4]1=[O:5])[CH3:2].[CH3:12][C:13]1[CH:22]=[C:21]2[C:16]([CH:17]=[CH:18][C:19]([CH2:23][O:24][C:25]3[CH:26]=[C:27]([CH:29]=[CH:30][CH:31]=3)[NH2:28])=[N:20]2)=[CH:15][CH:14]=1>>[CH3:12][C:13]1[CH:22]=[C:21]2[C:16]([CH:17]=[CH:18][C:19]([CH2:23][O:24][C:25]3[CH:26]=[C:27]([NH:28][C:7](=[O:9])[CH2:8][C:3]([CH2:10][CH3:11])([CH2:1][CH3:2])[C:4]([OH:6])=[O:5])[CH:29]=[CH:30][CH:31]=3)=[N:20]2)=[CH:15][CH:14]=1
Reactant: CCC1(CC)CC(=O)OC1=O
Reactant: Cc1ccc2ccc(COc3cccc(N)c3)nc2c1
Product: CCC(CC)(CC(=O)Nc1cccc(OCc2ccc3ccc(C)cc3n2)c1)C(=O)O

Procedure:
The title compound is prepared analogously to the compound described in Example 20 from 2,2-diethylsuccinic acid anhydride and 3-(7-methyl-2-quinolinylmethoxy)aniline; colourless crystals of m.p. 162°-163°.
Reaction SMILES: [CH3:1][O:2][CH:3]([CH:5]1[CH2:9][CH2:8][CH2:7][N:6]1C(OC(C)(C)C)=O)[CH3:4].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:1][O:2][CH:3]([CH:5]1[CH2:9][CH2:8][CH2:7][NH:6]1)[CH3:4]
Reactant: COC(C)C1CCCN1C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(C)C1CCCN1
Reaction time: 16 h

Procedure:
To tert-butyl 2-(1-methoxyethyl)pyrrolidine-1-carboxylate (827 mg, 3.61 mmol) dissolved in DCM (15 mL) was added TFA (0.83 mL). The mixture was stirred for 16 hours. The reaction was concentrated, diluted with DCM, and washed with HCl (1 N). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure to afford 2-(1-methoxyethyl)pyrrolidine.
Reaction SMILES: [OH:1][N:2]1C(=O)C2=CC=CC=C2C1=O.Cl[CH2:14][C:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[CH:17][CH:16]=1>>[C:15]1([CH2:14][O:1][NH2:2])[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[CH:17][CH:16]=1
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: ClCc1cccc2ccccc12
Product: NOCc1cccc2ccccc12

Procedure:
Prepared by a similar procedure as described for preparation 13. Starting materials: N-Hydroxyphthalimide and 1-chloromethyl-naphthalen. 13C-NMR (DMSO-d6) δ 133.5, 133.2, 131.4, 128.2, 126.8, 126.7, 126.0, 125.6, 125.2, 124.1, 75.4.
Reaction SMILES: [CH3:1][N:2]([CH3:4])[NH2:3].[CH:5](=O)/[CH:6]=[CH:7]/[CH2:8][CH3:9]>>[CH3:1][N:2]([CH3:4])[N:3]=[CH:5]/[CH:6]=[CH:7]/[CH2:8][CH3:9]
Reactant: CC/C=C/C=O
Reactant: CN(C)N
Product: CC/C=C/C=NN(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 81.3 %

Procedure:
N,N-Dimethylhydrazine (42.0 mL 0.55 mol) was added dropwise to trans-2-pentenal (42.06 g, 0.50 mol) at such a rate that the reaction temperature could be maintained at about 0° C. The mixture was then stirred for 1 h at ambient temperature, and the organic phase separated and dried (K2CO3). Distillation (bp 84°-86° C., 25 mm Hg; lit bp 60° C., 15 mm Hg) through a 10 cm Vigreaux column gave trans-2-pentenal N,N-dimethylhydrazone (12) (51.3 g, 81%): n20 1.5104; IR (neat) 2960, 2870, 2850, 2820, 2780, 1565, 1470, 1460, 1445, 1265, 1135, 1030, 970 cm-1 ; 1H NMR (CDCl3) δ 0.98 (t, 3H, J=7.4 Hz), 2.16-2.05 (m, 2H), 2.76 (s, 6H), 5.82 (dt, 1H, J=15.6, 6.3 Hz), 6.14 (dd, 1H, J=15.6, 8.8 Hz) 6.97 (d, 1H, J=8.8 Hz).
Reaction SMILES: [OH-].[Na+].[I:3][C:4]1[CH:15]=[CH:14][C:7]([CH2:8][C@@H:9]([C:11]([OH:13])=[O:12])[NH2:10])=[CH:6][CH:5]=1.[Cl:16][C:17]1[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[C:18]=1[C:19](Cl)=[O:20].Cl>CC(C)=O.O>[Cl:16][C:17]1[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[C:18]=1[C:19]([NH:10][C@H:9]([C:11]([OH:13])=[O:12])[CH2:8][C:7]1[CH:6]=[CH:5][C:4]([I:3])=[CH:15][CH:14]=1)=[O:20]
Reactant: N[C@@H](Cc1ccc(I)cc1)C(=O)O
Reactant: O=C(Cl)c1c(Cl)cccc1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: O
Product: O=C(N[C@@H](Cc1ccc(I)cc1)C(=O)O)c1c(Cl)cccc1Cl
Temperature: 10 °C

Procedure:
Water (21 mL), acetone (9.80 mL) and a 6M sodium hydroxide aqueous solution (5.20 mL) were added to 7.50 g of 4-iodo-L-phenylalanine and the resulting mixture was stirred at 10° C. to thus give a uniform solution. To this solution, there were alternatively added 4.05 mL of 2,6-dichlorobenzoyl chloride and 4.50 mL of a 6M sodium hydroxide aqueous solution while taking care to maintain the pH value of not less than 13 and the temperature of not higher than 15° C. After confirming the completion of the reaction, 6.50 mL of a 6M hydrochloric acid aqueous solution was added to the reaction system to thus precipitate the desired product. The solid thus separated was isolated through filtration under reduced pressure, washed with 15 mL of water and dried at 70° C. for 4 hours under reduced pressure to thus give 12.42 g of the intended product.
Reaction SMILES: [CH3:1][C:2]1[N:6]2[C:7]3[CH:22]=[CH:21][C:20]([N+:23]([O-])=O)=[CH:19][C:8]=3[N:9]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:10](=[O:12])[CH2:11][C:5]2=[N:4][N:3]=1.[H][H]>C(O)C.[Ni]>[CH3:1][C:2]1[N:6]2[C:7]3[CH:22]=[CH:21][C:20]([NH2:23])=[CH:19][C:8]=3[N:9]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:10](=[O:12])[CH2:11][C:5]2=[N:4][N:3]=1
Reactant: [H][H]
Reactant: Cc1nnc2n1-c1ccc([N+](=O)[O-])cc1N(c1ccccc1)C(=O)C2
Agent: [Ni]
Solvent: CCO
Product: Cc1nnc2n1-c1ccc(N)cc1N(c1ccccc1)C(=O)C2

Procedure:
33.5 g of 1-methyl-8-nitro-6-phenyl-4H-s-triazolo[4,3-a][1,5]benzodiazepin-5-one in 100 ml of ethanol containing 2.0 g of Raney nickel is hydrogenated at room temperature at an initial hydrogen pressure of 50 p.s.i. The reaction is stopped when 0.3 moles of hydrogen has been absorbed; the suspension is filtered and the filtrate evaporated to give the title compound.
Reaction SMILES: [CH2:1]([C:3]1([C:9](=O)[CH:10]=[CH:11][C:12]([OH:14])=O)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1)[CH3:2].[NH2:16][NH2:17]>C(O)C>[CH2:1]([C:3]1([C:9]2[CH:10]=[CH:11][C:12](=[O:14])[NH:16][N:17]=2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1)[CH3:2]
Reactant: NN
Reactant: CCC1(C(=O)C=CC(=O)O)CCCCC1
Solvent: CCO
Product: CCC1(c2ccc(=O)[nH]n2)CCCCC1
Reaction time: 18 h

Procedure:
To 14.0 g. of 4-(1-ethylcyclohexyl)-4-oxo-2-butenoic acid was added 100 ml. of ethanol and 4 g. of hydrazine. The mixture was stirred under reflux under a 300 watt sun-lamp in a 100 ml. Pyrex flask for 18 hours. The lamp was placed 5 cm. from the flask and emitted light of wave lengths primarily between 200 and 800 mμ. The mixture was then evaporated to dryness under vacuum, and to the residue was added 1000 ml. of diethyl ether. The ether solution was washed with 500 ml. of 0.1 N hydrochloric acid, 0.1 N sodium hydroxide and saturated sodium chloride solution, dried over magnesium sulfate and evaporated under vacuum to an oil. The oil was taken up in a little hexane and triturated to obtain a crystalline solid. The solid was recrystallized from ethyl acetate/hexane to obtain 0.15 g. of the desired product, m.p. 138°-140°. It was identified by its infrared spectrum, showing absorption bands at 1650 and 1675 cm.-1, and by its mass spectroscopy spectrum, showing its molecular ion of mass 206.