Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH:4]([CH:9]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH:20]2[CH2:24][CH2:23][CH2:22][CH2:21]2)[CH:12]=1)[CH3:10])[C:5](OC)=[O:6])(=O)[CH3:2].O.[NH2:26][NH2:27]>C(O)C>[CH:20]1([O:19][C:13]2[CH:12]=[C:11]([CH:9]([C:4]3[C:5](=[O:6])[N:26]=[N:27][C:1]=3[CH3:2])[CH3:10])[CH:16]=[CH:15][C:14]=2[O:17][CH3:18])[CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: NN
Reactant: COC(=O)C(C(C)=O)C(C)c1ccc(OC)c(OC2CCCC2)c1
Solvent: O
Solvent: CCO
Product: COc1ccc(C(C)C2=C(C)N=NC2=O)cc1OC1CCCC1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 22.4 %

Procedure:
To a stirred solution of methyl 2-acetyl-3-(3-cyclopentyloxy-4-methoxyphenyl)-butanoate (362 mg, 1.08 mmol) in absolute ethanol (10 ml) at 0° C. was added hydrazine monohydrate (54 mg, 1.08 mmol) in one portion. The resulting solution was stirred at 0° C. for 45 minutes and then refluxed at 80° C. for 3 hours. Further hydrazine monohydrate (15.6 mg, 3.1×10-4 mol) was added and refluxing continued for a further 3 hours. After cooling to room temperature, the reaction mixture was concentrated in vacuo and purified by flash chromatography (SiO2 ; methylene chloride/ethanol/ammonia (97.5:2.5:0.25)) to afford the title compound as a white solid (76 mg).
Reaction SMILES: Br[C:2]1[CH2:6][CH2:5][CH2:4][C:3]=1[C:7]1[CH:12]=[CH:11][C:10]([S:13][CH3:14])=[CH:9][CH:8]=1.[F:15][C:16]1[CH:21]=[CH:20][C:19](B(O)O)=[C:18]([CH3:25])[CH:17]=1>>[F:15][C:16]1[CH:21]=[CH:20][C:19]([C:2]2[CH2:6][CH2:5][CH2:4][C:3]=2[C:7]2[CH:12]=[CH:11][C:10]([S:13][CH3:14])=[CH:9][CH:8]=2)=[C:18]([CH3:25])[CH:17]=1
Reactant: Cc1cc(F)ccc1B(O)O
Reactant: CSc1ccc(C2=C(Br)CCC2)cc1
Product: CSc1ccc(C2=C(c3ccc(F)cc3C)CCC2)cc1
Yield: 88.2 %

Procedure:
Following the synthetic procedure outlined in Step 3 of Example 1, 500 mg (1.9 mmol) of 1-(2-bromocyclopenten-1-yl)-4-(methylthio)benzene (Example 1, Step 2) was reacted with 590 mg (3.8 mmol) of 4-fluoro-2-methylphenylboronic acid (Step 1). Purification by silica gel chromatography (MPLC) with hexane gave 500 mg (95% ) of 1-[2-(4-fluoro-2-methylphenyl)cyclopenten-1-yl]-4-(methylthio)benzene as a colorless solid: mp 67°-68° C.; NMR (CDCl3) δ 2.00-2.11 (m, 2H), 2.05 (s, 3H), 2.41 (s, 3H), 2.69-2.77 (m, 2H), 2.86-2.95 (m, 2H), 6.80-7.07 (m, 7H) .
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]2[O:13][CH2:12][CH2:11][N:10]([S:14]([C:17]3[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:18]=3[O:24][CH3:25])(=[O:16])=[O:15])[C:9]=2[CH:26]=1)=[O:4].[OH-].[Na+]>O1CCCC1.CO>[Cl:23][C:21]1[CH:20]=[CH:19][C:18]([O:24][CH3:25])=[C:17]([S:14]([N:10]2[C:9]3[CH:26]=[C:5]([C:3]([OH:4])=[O:2])[CH:6]=[CH:7][C:8]=3[O:13][CH2:12][CH2:11]2)(=[O:15])=[O:16])[CH:22]=1
Reactant: COC(=O)c1ccc2c(c1)N(S(=O)(=O)c1cc(Cl)ccc1OC)CCO2
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(Cl)cc1S(=O)(=O)N1CCOc2ccc(C(=O)O)cc21
Temperature: 45 °C
Reaction time: 1.5 h

Procedure:
A solution of 4-(5-chloro-2-methoxy-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carboxylic acid methyl ester (7.1 g, 17.8 mmol) in tetrahydrofuran (100 mL) and methanol (50 mL) was treated with 3N NaOH (25 mL, 75 mmol, 4.2 equiv.). The mixture was stirred at 45° C. for 1.5 hours. The organic solvents were then removed and the residue acidified with HCl 3N (25 mL). The white precipitate which formed was filtered, washing with water, and dried under high vacuum. 4-(5-Chloro-2-methoxy-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carboxylic acid was obtained as a white solid, 6.79 g (99%), MS (ISP): m/e=382.0 (M−H), which was used crude in the following reaction.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:37])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH2:11][N:12]([CH2:18][CH2:19][CH2:20][N:21]2[C:29](=[O:30])[NH:28][C:27]3[C:22]2=[N:23][C:24]([O:32][CH2:33][CH2:34][CH2:35][CH3:36])=[N:25][C:26]=3[NH2:31])[C:13](=[O:17])[CH2:14][S:15][CH3:16])[CH:6]=1.CO.C1C=C(Cl)C=C(C(OO)=[O:48])C=1>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:37])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH2:11][N:12]([CH2:18][CH2:19][CH2:20][N:21]2[C:29](=[O:30])[NH:28][C:27]3[C:22]2=[N:23][C:24]([O:32][CH2:33][CH2:34][CH2:35][CH3:36])=[N:25][C:26]=3[NH2:31])[C:13](=[O:17])[CH2:14][S:15]([CH3:16])=[O:48])[CH:6]=1
Reactant: CCCCOc1nc(N)c2[nH]c(=O)n(CCCN(Cc3cccc(CC(=O)OC)c3)C(=O)CSC)c2n1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Solvent: CO
Product: CCCCOc1nc(N)c2[nH]c(=O)n(CCCN(Cc3cccc(CC(=O)OC)c3)C(=O)CS(C)=O)c2n1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
The product from example 12 (150 mg) was dissolved in DCM (10 ml) and methanol (2 ml) and mCPBA (0.1 g) added. The mixture was stirred at rt for 3 h then purified by RPHPLC, which afforded the title compound. Yield 50 mg.
Reaction SMILES: [F:1][C:2]1([F:17])[O:6][C:5]2[CH:7]=[CH:8][C:9]([C:11]3([C:14](Cl)=[O:15])[CH2:13][CH2:12]3)=[CH:10][C:4]=2[O:3]1.[NH2:18][C:19]1[CH:27]=[CH:26][C:25]2[NH:24][C:23]([C:28]([CH3:31])([CH3:30])[CH3:29])=[CH:22][C:21]=2[C:20]=1[C:32]#[N:33].C(N(CC)CC)C>CN(C=O)C>[C:28]([C:23]1[NH:24][C:25]2[C:21]([CH:22]=1)=[C:20]([C:32]#[N:33])[C:19]([NH:18][C:14]([C:11]1([C:9]3[CH:8]=[CH:7][C:5]4[O:6][C:2]([F:17])([F:1])[O:3][C:4]=4[CH:10]=3)[CH2:13][CH2:12]1)=[O:15])=[CH:27][CH:26]=2)([CH3:31])([CH3:29])[CH3:30]
Reactant: O=C(Cl)C1(c2ccc3c(c2)OC(F)(F)O3)CC1
Reactant: CC(C)(C)c1cc2c(C#N)c(N)ccc2[nH]1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)c1cc2c(C#N)c(NC(=O)C3(c4ccc5c(c4)OC(F)(F)O5)CC3)ccc2[nH]1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarbonyl chloride (26 mg, 0.1 mmol) was added to a solution of 5-amino-2-tert-butyl-1H-indole-4-carbonitrile (21 mg, 0.1 mmol) and triethylamine (41.7 μL, 0.3 mmol) in DMF (1 mL). The reaction was stirred at room temperature overnight, then filtered and purified by reverse-phase HPLC to yield the product, N-(2-tert-butyl-4-cyano-1H-indol-5-yl)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide. ESI-MS m/z calc. 437.2, found 438.7 (M+1)+, Retention time 2.10 minutes. 1H NMR (400 MHz, DMSO-d6) δ 11.48 (s, 1H), 8.88 (s, 1H), 7.52 (d, J=8.5 Hz, 2H), 7.41 (d, J=8.3 Hz, 1H), 7.32 (dd, J=1.5, 8.3 Hz, 1H), 7.03 (d, J=8.6 Hz, 1H), 6.21 (d, J=1.8 Hz, 1H), 1.51-1.49 (m, 2H), 1.36 (s, 9H), 1.18-1.16 (m, 2H).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH:11]([O:13][C:14]1[CH:22]=[CH:21][CH:20]=[C:16]([C:17](O)=[O:18])[C:15]=1[C:23](O)=[O:24])[CH3:12].Cl.[NH2:27][CH:28]1[CH2:34][CH2:33][C:32](=[O:35])[NH:31][C:29]1=[O:30]>N1C=CC=CC=1>[O:30]=[C:29]1[CH:28]([N:27]2[C:23](=[O:24])[C:15]3[C:16](=[CH:20][CH:21]=[CH:22][C:14]=3[O:13][CH:11]([C:2]3[CH:3]=[CH:4][C:5]4[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=4)[CH:1]=3)[CH3:12])[C:17]2=[O:18])[CH2:34][CH2:33][C:32](=[O:35])[NH:31]1
Reactant: CC(Oc1cccc(C(=O)O)c1C(=O)O)c1ccc2ccccc2c1
Reactant: NC1CCC(=O)NC1=O
Agent: Cl
Solvent: c1ccncc1
Product: CC(Oc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O)c1ccc2ccccc2c1
Yield: 64 %

Procedure:
A mixture of 3-(1-naphthalen-2-yl-ethoxy)-phthalic acid (0.36 g, 1.0 mmol) and rac-α-aminoglutarimide hydrochloride (0.16 g, 1.0 mmol) in pyridine (10 mL) was heated to reflux for 16 h. The mixture was cooled and evaporated under vacuum. The residue was dissolved in ethyl acetate (100 mL) and washed with dilute aqueous HCl (2×100 mL) and water (100 mL), and was evaporated. The residue was chromatographed using a CH2Cl2-methanol gradient, eluting the product at 95:5 CH2Cl2-methanol, 0.27 g, in 64% yield; mp 174-176° C.; HPLC, Waters Symmetry C-18, 3.9×150 mm, 5 μm, 1 mL/min, 240 nm, 60/40 CH3CN/0.1% H3PO4, 3.69 (99.65%); 1H NMR (DMSO-d6) δ 1.71 (d, J=6.0 Hz, 3H), 1.99-2.09 (m, 1H), 2.51-2.65 (m, 2H), 2.84-2.97 (m, 1H), 5.13 (dd, J=12.5 Hz, J=5.3 Hz, 1H), 6.00 (q, J=6.0 Hz, 1H), 7.39 (d, J=7.2 Hz, 1H), 7.44-7.53 (m, 3H), 7.62 (d, J=8.5 Hz, 1H), 7.69 (t, J=7.9 Hz, 1H), 7.87-7.96 (m, 3H), 8.00 (s, 1H), 11.15 (s, 1H): 13C NMR (DMSO-d6) δ 22.0, 23.7, 31.0, 48.8, 76.5, 115.5, 117.2, 121.5, 123.6, 124.5, 126.2, 126.4, 127.6, 127.8, 128.5, 132.5, 132.7, 133.4, 136.7, 139.4, 154.8, 165.3, 166.7, 170.0, 172.8; Anal. Calcd for C25H20N2O5: C, 70.08; H, 4.71; N, 6.54. Found: C, 69.71; H, 4.51; N, 6.28.
Reaction SMILES: [C:1]1([CH2:7][C:8](=[O:10])[CH3:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:11][C:12]1[CH:19]=[CH:18][C:15]([CH:16]=O)=[CH:14][CH:13]=1.N1CCCCC1>C1C=CC=CC=1>[Br:11][C:12]1[CH:19]=[CH:18][C:15]([CH:16]=[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:8](=[O:10])[CH3:9])=[CH:14][CH:13]=1
Reactant: CC(=O)Cc1ccccc1
Reactant: O=Cc1ccc(Br)cc1
Solvent: c1ccccc1
Solvent: C1CCNCC1
Product: CC(=O)C(=Cc1ccc(Br)cc1)c1ccccc1
Yield: 38.2 %

Procedure:
A mixture of phenylacetone (4.92 g, 36.7 mmol) and 4-bromobenzaldehyde (6.78 g, 36.7 mmol) in benzene (40 ml) in the presence of piperidine (0.11 ml, 1.47 mmol) was refluxed for 48 hours. After evaporation, the obtained residue was chromatographed on a column of silica gel (300 g) as eluting with ethyl acetate/hexane (1:20 to 1:2) to afford a yellow solid, which was washed with ethyl acetate/hexane to give 4.22 g (38%) of the title compound as a pale yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][C:17]=1[Cl:18])[O:5][C:6]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][C:7]=1[CH:8]=[O:9].CC(C)=[O:21].OS(O)(=O)=O.O=[Cr](=O)=O>CC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][C:17]=1[Cl:18])[O:5][C:6]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][C:7]=1[C:8]([OH:21])=[O:9]
Reactant: O=Cc1cc(F)ccc1Oc1ccc(Cl)c(Cl)c1
Reactant: CC(C)=O
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Product: O=C(O)c1cc(F)ccc1Oc1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Alternatively, a solution of 4.28 g (15 mmol) of 2-(3,4-dichloro-phenoxy)-5-fluorobenzaldehyde (Preparation no. 5) in 25 mL of acetone was cooled to 5-10° C. and treated via syringe with 5.8 mL (15.6 mmol) of 2.67 M Jones reagent*. After 1 hr at this temperature, the reaction was quenched with 8 mL of isopropanol, allowed to warm to 25° C., and filtered through a pad of d.e. The filtrate was concentrated in vacuo to approximately ¼ volume, diluted with water and extracted several times with CHCl3. The organic layers were washed with water, then with saturated NaCl and finally dried over MgSO4 and concentrated to provide 2-(3,4-dichlorophenoxy)-5-fluoro-benzoic acid as a tan solid, 4.19 g. 1H-nmr (CDCl3, 400 MHz, δ): 7.78 (dd, 1H), 7.38 (d, 1H), 7.27 (m, 1H), 6.98 (m, 2H), 6.81 (dd, 1H).
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:6]=[C:7]([CH:32]=[CH:33][C:34]=1[N+:35]([O-:37])=[O:36])[C:8]([C:10]1[N:18]2[C:13]([CH:14]=[C:15]([NH:19][CH3:20])[CH:16]=[CH:17]2)=[C:12]([C:21]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:22])[C:11]=1[CH3:31])=[O:9].[CH3:38]I.Cl>CN(C)C=O.ClCCl>[CH3:20][N:19]([CH3:38])[C:15]1[CH:16]=[CH:17][N:18]2[C:13]([CH:14]=1)=[C:12]([C:21]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22])[C:11]([CH3:31])=[C:10]2[C:8](=[O:9])[C:7]1[CH:32]=[CH:33][C:34]([N+:35]([O-:37])=[O:36])=[C:5]([O:4][CH3:3])[CH:6]=1
Reactant: CNc1ccn2c(C(=O)c3ccc([N+](=O)[O-])c(OC)c3)c(C)c(C(=O)OCc3ccccc3)c2c1
Reactant: CI
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1cc(C(=O)c2c(C)c(C(=O)OCc3ccccc3)c3cc(N(C)C)ccn23)ccc1[N+](=O)[O-]
Temperature: 40 °C
Reaction time: 0.17 h
Yield: 81.1 %

Procedure:
80 mg (1.67 mmol) of sodium hydride (60% as a dispersion in oil) at room temperature are added in portions to 525 mg (1.11 mmol) of benzyl [3-(3-methoxy-4-nitrobenzoyl)-2-methyl-7-methylaminoindolizin-1-yl]carboxylate in solution in 10 mL of dimethylformamide. After 10 minutes, 138 μL (2.22 mmol) of methyl iodide are added to the reaction mixture. The medium is stirred at 40° C. for 2 hours, poured into a molar solution of hydrochloric acid and then extracted with ethyl acetate. The organic phase is washed with a saturated aqueous sodium chloride solution, dried over sodium sulfate and concentrated under reduced pressure. The solid obtained is taken up in dichloromethane and filtered. 439 mg of a light orange-coloured solid are obtained.
Reaction SMILES: [N:1]1([C@H:6]2[CH2:10][CH2:9][CH2:8][C@H:7]2[NH2:11])[CH2:5][CH2:4][CH2:3][CH2:2]1.[Br:12][C:13]1[CH:21]=[CH:20][C:16]([C:17](O)=[O:18])=[C:15]([CH3:22])[CH:14]=1>>[Br:12][C:13]1[CH:21]=[CH:20][C:16]([C:17]([NH:11][C@@H:7]2[CH2:8][CH2:9][CH2:10][C@@H:6]2[N:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)=[O:18])=[C:15]([CH3:22])[CH:14]=1
Reactant: N[C@@H]1CCC[C@@H]1N1CCCC1
Reactant: Cc1cc(Br)ccc1C(=O)O
Product: Cc1cc(Br)ccc1C(=O)N[C@@H]1CCC[C@@H]1N1CCCC1

Procedure:
The title compound, white solid, MS: m/e=351.2/353.1 [(M+H)+], was prepared in accordance with the general method of example 5 from cis-2-pyrrolidin-1-yl-cyclopentylamine (intermediate Q) and 4-bromo-2-methyl-benzoic acid.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][CH:2]1[CH2:11][OH:12].[CH2:13]([O:15][C:16](=[O:20])[C:17]#[C:18][CH3:19])[CH3:14].C(P(CCCC)CCCC)CCC>O1CCCC1>[CH2:13]([O:15][C:16](=[O:20])/[CH:17]=[C:18](/[O:12][CH2:11][CH:2]1[O:1][C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3]1)\[CH3:19])[CH3:14]
Reactant: CC#CC(=O)OCC
Reactant: OCC1COc2ccccc2O1
Agent: CCCCP(CCCC)CCCC
Solvent: C1CCOC1
Product: CCOC(=O)/C=C(\C)OCC1COc2ccccc2O1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 40.2 %

Procedure:
To a stirred mixture of (2,3-dihydro-benzo[1,4]dioxin-2-yl)-methanol (1.01 g, 5.90 mmol) and ethyl-2-butynoate (820 mg, 7.08 mmol) in tetrahydrofuran (15 mL) was added tri-n-butylphosphine (0.25 g, 1.18 mmol). The mixture was stirred at room temperature for 1.5 h. Upon completion of the reaction the tetrahydrofuran was removed in vacuo. The crude product obtained was purified by ISCO flash chromatography (Teledyne Isco RediSep Flash Column 40 g; 0% to 50% ethyl acetate/hexanes) to afford (E)-3-(2,3-dihydro-benzo[1,4]dioxin-2-ylmethoxy)-but-2-enoic acid ethyl ester (660 mg, 40%) as a colorless oil: LR-ES-MS m/z calculated for C15H18O5 [M]+ 278, observed [M+H]+ 279.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12](Cl)=[C:11]([C:14]#[N:15])[N:10]([CH2:16][CH2:17][CH3:18])[C:9]2=[O:19])=[CH:4][CH:3]=1.ClC1C(OCC#C)=C[C:24]([N:31]2C(Cl)=C(C#N)N(CCC)C2=O)=C(F)C=1.[C-]#N.[K+]>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:24]#[N:31])=[C:11]([C:14]#[N:15])[N:10]([CH2:16][CH2:17][CH3:18])[C:9]2=[O:19])=[CH:4][CH:3]=1
Reactant: C#CCOc1cc(-n2c(Cl)c(C#N)n(CCC)c2=O)c(F)cc1Cl
Reactant: CCCn1c(C#N)c(Cl)n(-c2ccc(Cl)cc2)c1=O
Agent: [C-]#N
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCn1c(C#N)c(C#N)n(-c2ccc(Cl)cc2)c1=O

Procedure:
The product of Example 1, 1-(4-chlorophenyl)-5-chloro-4-cyano-3-propyl-1,3-dihydro-2H-imidazol-2-one (V) (0.75 g, 2.5 mmol), was stirred in 25 mL of dimethylformamide. To this mixture was added KCN (0.5 g, 7.5 mmol) and the resulting mixture was heated to reflux for ten minutes, cooled, poured onto water, and extracted three times with 50 mL ethyl acetate. This material was then dried, filtered, and evaporated via standard techniques to give 0.38 g of 1-(4-chlorophenyl)-4,5-dicyano-3-propyl-1,3-dihydro-2H-imidazol-2-one (VI) recrystallized from ethyl acetate/hexane (m.p. 163°-5° C.).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[CH:8]=[C:7]([CH2:9][CH2:10][NH:11]C(OC(C)(C)C)=O)[N:6]=[CH:5]1.C(N(CC)CC)C.C1C(=O)N([O:33][C:34]([CH2:36][CH2:37][C:38]2[CH:43]=[CH:42][C:41]([OH:44])=[CH:40][CH:39]=2)=O)C(=O)C1>C(Cl)Cl>[OH:44][C:41]1[CH:40]=[CH:39][C:38]([CH2:37][CH2:36][C:34]([NH:1][CH2:2][CH2:3][N:4]2[CH:8]=[C:7]([CH2:9][CH2:10][NH2:11])[N:6]=[CH:5]2)=[O:33])=[CH:43][CH:42]=1
Reactant: CC(C)(C)OC(=O)NCCc1cn(CCN)cn1
Reactant: O=C(CCc1ccc(O)cc1)ON1C(=O)CCC1=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: NCCc1cn(CCNC(=O)CCc2ccc(O)cc2)cn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The following materials are introduced into a reaction vessel: 5 mg (0.02 mmol) of compound VII dissolved in 0.5 ml methylene chloride; 2.8 μl (0.02 mmol) of triethylamine; and last 5.3 mg (0.02 mmol) of N-succinimidyl-3-(4-hydroxyphenyl)propionate dissolved in 0.5 ml of methylene chloride. The solution is stirred for 2 hours at room temperature and then evaporated. The residue is dissolved in 0.5 ml of trifluoroacetic acid, and hydrolysis is allowed to proceed for 1 hour and 15 minutes at room temperature. The solution is evaporated, the residue then being separated on a reversed-phase column PepRPC (Pharmacia AB) with an 0.1% trifluoroacetic acid - acetonitrile gradient. At about 7% acetonitrile compound XIX is eluted. The structure has been confirmed by NMR analysis, the NMR data being the following: 2H-imidazole 8.3, 5H-imidazole 7.2, O-H-hydroxyphenyl 7.1, m-H-hydroxyphenyl 6.85, 1-CH2 -imidazole 4.15, --CH2NHCO 3.55, --CH2N + H3 3.25 t, 4-CH2 -imidazole 3.05 t, p-CH2 -hydroxyphenyl 2.75 t, --CH2CO 2.5 t.
Reaction SMILES: [NH2:1][NH2:2].O=[C:4]([CH2:8][CH2:9][C:10]([OH:12])=[O:11])[C:5](O)=[O:6]>>[O:6]=[C:5]1[NH:2][N:1]=[C:9]([C:10]([OH:12])=[O:11])[CH2:8][CH2:4]1
Reactant: O=C(O)CCC(=O)C(=O)O
Reactant: NN
Product: O=C1CCC(C(=O)O)=NN1
Yield: 99 %

Procedure:
The disclosed embodiments stem from the examination of several classes of compounds that quantitatively react with hydrazine to form stable organic products. The reaction of 2-ketoglutaric acid with hydrazine reacts to provide a greater than 99% yield of 6-oxo-1,4,5,6-tetrahydro-pyridazine-3-carboxylic acid (PCA) based on hydrazine as the limiting reagent. It has been found that this compound allows for the facile remediation of hydrazine under a variety of conditions. The focus of the disclosed embodiments concerns the use of 2-ketoglutaric acid or other dicarbonyl compounds for the remediation of hydrazine.
Reaction SMILES: Cl.[NH2:2][C@@H:3]([C:5]([NH2:7])=[O:6])[CH3:4].[C:8]([O:12][C:13](=[O:30])[C@H:14]([CH3:29])[N:15]([C:19]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:20])[CH2:16][CH:17]=O)([CH3:11])([CH3:10])[CH3:9].C(N(CC)CC)C.C([BH3-])#N.[Na+]>CO>[C:8]([O:12][C:13](=[O:30])[C@H:14]([CH3:29])[N:15]([C:19]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:20])[CH2:16][CH2:17][NH:2][C@@H:3]([C:5]([NH2:7])=[O:6])[CH3:4])([CH3:9])([CH3:10])[CH3:11]
Reactant: C[C@@H](C(=O)OC(C)(C)C)N(CC=O)C(=O)OCc1ccccc1
Reactant: C[C@@H](N)C(N)=O
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CO
Product: C[C@@H](NCCN(C(=O)OCc1ccccc1)[C@@H](C)C(=O)OC(C)(C)C)C(N)=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The D-alanine amide hydrochloride, (45) (2.5 g) (20.18 mmol) was dissolved in methanol, followed by the aldehyde (44) (3.30 g, 10.27 mmol) and triethylamine (1.40 mL, 1.0 g, 10.07 mmol). Sodium cyanoborohydride (0.86 g, 13.7 mmol) was added and the solution was kept stirring at room temperature overnight. The solution was evaporated under vacuum. The residue was taken up in chloroform:methanol (98:2) and flash chromatographed silica gel to yield the titled product (46): (2.48 g, 61%). 1H-NMR CDCl3) δ7.33 (s, 5H), 6.00 (br s, 1H), 5.20 (d, 2H), 4.67-3.00 (m, 4H), 2.77 (t, 2H), 1.83-1.23 (s/m, 13H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:7]1[CH:11]=[C:10]([NH:12][C:13](=[O:21])OC2C=CC=CC=2)[N:9]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:8]=1)([CH3:6])[CH3:5])[CH3:2].[CH3:28][O:29][C:30]1[CH:31]=[C:32]2[C:37](=[CH:38][C:39]=1[O:40][CH3:41])[N:36]=[CH:35][N:34]=[C:33]2[S:42][C:43]1[CH:44]=[C:45]([CH:47]=[CH:48][CH:49]=1)[NH2:46].C(N(CC)C(C)C)(C)C>C1COCC1>[CH3:28][O:29][C:30]1[CH:31]=[C:32]2[C:37](=[CH:38][C:39]=1[O:40][CH3:41])[N:36]=[CH:35][N:34]=[C:33]2[S:42][C:43]1[CH:44]=[C:45]([NH:46][C:13]([NH:12][C:10]2[N:9]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[N:8]=[C:7]([C:4]([O:3][CH2:1][CH3:2])([CH3:5])[CH3:6])[CH:11]=2)=[O:21])[CH:47]=[CH:48][CH:49]=1
Reactant: CCOC(C)(C)c1cc(NC(=O)Oc2ccccc2)n(-c2ccccc2)n1
Reactant: COc1cc2ncnc(Sc3cccc(N)c3)c2cc1OC
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCOC(C)(C)c1cc(NC(=O)Nc2cccc(Sc3ncnc4cc(OC)c(OC)cc34)c2)n(-c2ccccc2)n1
Yield: 64 %

Procedure:
Using the procedure described in Example 159B, using phenyl 3-(2-ethoxypropan-2-yl)-1-phenyl-1H-pyrazol-5-ylcarbamate described in Example 168B (0.115 g, 0.33 mmol), 3-(6,7-dimethoxyquinazolin-4-ylthio)aniline from Example 115B (0.103 g, 0.33 mmol), and N,N-diisopropylethylamine (0.8 mL) in THF (6 mL) at 50° C. for 5 hours, to afford 1-[3-(6,7-dimethoxyquinazolin-4-ylthio)phenyl]-3-[3-(2-ethoxypropan-2-yl)-1-phenyl-1H-pyrazol-5-yl]urea as solid (123 mg, 64%). 1H NMR (300 MHz, DMSO-d6) δ 9.26 (br, 1H), 8.69 (s, 1H), 8.54 (s, 1H), 7.80 (s, 1H), 7.54 (m, 4H), 7.23-7.45 (m, 5H), 7.24 (d, 1H), 6.42 (s, 1H), 3.99 (s, 6H), 3.25 (q, 2H), 1.46 (s, 6H), 1.04 (t, 3H); LC-MS (ESI) m/z 539 (M−OEt)+.
Reaction SMILES: [Li]CCCC.C(NC(C)C)(C)C.[Br:13][C:14]1[CH:15]=[N:16][CH:17]=[C:18]([F:20])[CH:19]=1.[CH2:21]([O:23][CH2:24][CH:25]=[O:26])[CH3:22]>C1COCC1>[Br:13][C:14]1[CH:15]=[N:16][CH:17]=[C:18]([F:20])[C:19]=1[CH:25]([OH:26])[CH2:24][O:23][CH2:21][CH3:22]
Reactant: Fc1cncc(Br)c1
Reactant: CCOCC=O
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CCOCC(O)c1c(F)cncc1Br
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
n-BuLi (2.66 mL, 4.26 mmol) was added to a solution of diisopropylamine (0.607 mL, 4.26 mmol) in THF (10 mL) at −78° C. After 30 min, 3-bromo-5-fluoropyridine (0.500 g, 2.84 mmol) in THF (10 mL) is added dropwise. The mixture was stirred at −78° C. for 1 hr, and 2-ethoxyacetaldehyde (0.464 g, 4.26 mmol) was added dropwise. The reaction mixture was stirred at −78° C. for 2 hrs. The reaction is quenched with a saturated aqueous NaHCO3 solution and the cooling bath was removed. The mixture was shaken with ethyl acetate and the organic phase is washed with brine, dried over MgSO4, and concentrated in vacuo. The residue was purified by silica gel flash chromatography employing heptane-ethyl acetate (4:1) to give 1-(3-bromo-5-fluoro-pyridin-4-yl)-2-ethoxy-ethanol. MS (ESI) m/z 266.0 (M+H)+.
Reaction SMILES: [CH3:1][NH:2][C:3]([CH:5]1[CH2:9][CH2:8][CH2:7][N:6]1[S:10]([C:13]1[CH:18]=[CH:17][C:16]([N:19]2[CH2:28][CH2:27][C:22]3(OCCO3)[CH2:21][CH2:20]2)=[CH:15][CH:14]=1)(=[O:12])=[O:11])=[O:4].[NH2:29][CH2:30][C@H:31]([OH:44])[CH2:32][O:33][C:34]1[C:42]2[NH:41][C:40](=[O:43])[NH:39][C:38]=2[CH:37]=[CH:36][CH:35]=1>>[CH3:1][NH:2][C:3]([CH:5]1[CH2:9][CH2:8][CH2:7][N:6]1[S:10]([C:13]1[CH:18]=[CH:17][C:16]([N:19]2[CH2:28][CH2:27][CH:22]([NH:29][CH2:30][C@H:31]([OH:44])[CH2:32][O:33][C:34]3[C:42]4[NH:41][C:40](=[O:43])[NH:39][C:38]=4[CH:37]=[CH:36][CH:35]=3)[CH2:21][CH2:20]2)=[CH:15][CH:14]=1)(=[O:12])=[O:11])=[O:4]
Reactant: CNC(=O)C1CCCN1S(=O)(=O)c1ccc(N2CCC3(CC2)OCCO3)cc1
Reactant: NC[C@H](O)COc1cccc2[nH]c(=O)[nH]c12
Product: CNC(=O)C1CCCN1S(=O)(=O)c1ccc(N2CCC(NC[C@H](O)COc3cccc4[nH]c(=O)[nH]c34)CC2)cc1

Procedure:
Reference Example 20, 1-[4-(1,4-dioxa-8-aza-spiro[4.5]dec-8-yl)-benzenesulfonyl]-pyrrolidine-2-carboxylic acid methylamide, was hydrolyzed to the corresponding ketone according to the procedure of Reference Example 5, and then reacted with 4-((2S)-3-amino-2-hydroxy-propoxy)-1,3-dihydro-benzoimidazol-2-one according to the procedure of Example 1 to give the title compound as a tan solid; mp 36-39° C.; 1H NMR (300 MHz, DMSO-d6) δ 1.20-2.00 (m, 8H), 2.55 (d, 3H), 2.50-3.40 (m, 6H), 3.70-4.10 (m, 6H), 4.85-4.95 (m, 1H), 6.55 (d, 1H), 6.60 (d, 1H), 6.80 (t, 2H), 7.35 (d, 2H), 7.60 (d, 2H), 7.90 (q, 1H), 10.60 (br s, 1H), 10.70 (br s, 1H), MS (ES) m/z: 573.1 (MH+); HRMS Calcd. for C27H37N6O6S (MH+): 573.2490. Found: 573.2495.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:29])[CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][CH:14]([C:17]3[CH:18]=[C:19]([NH:23][C:24](=[O:28])[CH:25]([CH3:27])[CH3:26])[CH:20]=[CH:21][CH:22]=3)[CH2:13][CH2:12]2)=[CH:4][CH:3]=1.[Br:30][C:31]1[CH:36]=[CH:35][C:34](O)=[CH:33][CH:32]=1>>[Br:30][C:31]1[CH:36]=[CH:35][C:34]([O:29][CH:8]([C:5]2[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=2)[CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][CH:14]([C:17]3[CH:18]=[C:19]([NH:23][C:24](=[O:28])[CH:25]([CH3:26])[CH3:27])[CH:20]=[CH:21][CH:22]=3)[CH2:13][CH2:12]2)=[CH:33][CH:32]=1
Reactant: Oc1ccc(Br)cc1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCC(O)c3ccc(Br)cc3)CC2)c1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCC(Oc3ccc(Br)cc3)c3ccc(Br)cc3)CC2)c1

Procedure:
Prepared by Procedure A and Scheme AN using N-(3-{1-[3-(4-bromophenyl)-3-hydroxypropyl]-4-piperidinyl}phenyl)-2-methylpropanamide and 4-bromophenol: ESMS m/e: 612.7 (M+H)+.