Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([CH2:4][C:5]([CH3:9])=[CH:6][CH2:7][OH:8])([O-:3])=[O:2].[Cl:10][C:11]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:12]=1[C:13](Cl)=[O:14]>C1C=CC=CC=1>[N+:1]([CH2:4][C:5]([CH3:9])=[CH:6][CH2:7][O:8][C:13](=[O:14])[C:12]1[CH:16]=[CH:17][C:18]([Cl:20])=[CH:19][C:11]=1[Cl:10])([O-:3])=[O:2]
Reactant: O=C(Cl)c1ccc(Cl)cc1Cl
Reactant: CC(=CCO)C[N+](=O)[O-]
Solvent: c1ccccc1
Product: CC(=CCOC(=O)c1ccc(Cl)cc1Cl)C[N+](=O)[O-]
Reaction time: 8 h

Procedure:
To 0.1 Mol of 4-nitro-3-methyl-2-butenol in benzene was added 0.1 Mol of 2,4-dichlorobenzoylchloride and stirred overnight. The benzene was removed, the residue taken up in sat. sodiumbicarbonate solution and extracted with ether. The crude product was purified by column chromatography over silica gel using methylenechloride as eluting solvent. A yellowish oil was obtained.
Reaction SMILES: [CH3:1][S:2]([O:5][CH2:6][C:7]([NH:11][CH2:12][C:13]1[CH:14]=[C:15]2[C:24](=[C:25]3[C:30]=1[CH:29]=[CH:28][CH:27]=[CH:26]3)[CH:23]=[CH:22][C:21]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]2=1)([CH3:10])[CH2:8][OH:9])(=[O:4])=[O:3].[CH2:31](C1C2C=CC=CC=2C2C(=C3C(=C(C=O)C=2)C=CC=C3)C=1)[CH3:32].NC(C)(CO)CO>>[CH3:1][S:2]([O:5][CH2:6][C:7]([NH:11][CH2:12][C:13]1[CH:14]=[C:15]2[C:24](=[C:25]3[C:30]=1[CH:29]=[CH:28][CH:27]=[CH:26]3)[CH:23]=[C:22]([CH2:31][CH3:32])[C:21]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]2=1)([CH3:10])[CH2:8][OH:9])(=[O:4])=[O:3]
Reactant: CC(CO)(COS(C)(=O)=O)NCc1cc2c3ccccc3ccc2c2ccccc12
Reactant: CCc1cc2c3ccccc3c(C=O)cc2c2ccccc12
Agent: CC(N)(CO)CO
Product: CCc1cc2c3ccccc3c(CNC(C)(CO)COS(C)(=O)=O)cc2c2ccccc12

Procedure:
Using the reductive amination procedure outlined in 1C, 12-ethyl-6-chrysenecarbaldehyde (15A) and 2-amino-2-methyl-1,3-propanediol (Aldrich) gave 2-(((12-ethyl-6-chrysenyl)methyl)amino)-2-methyl-1,3-propanediol methanesulfonate mp 189°-192° (dec), (EtOH/Et2O), (C,H,N,S).
Reaction SMILES: Br[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][NH:6]2.[NH2:11][CH:12]([C:14]1[C:15]([O:28][CH3:29])=[C:16]([N:22]2[CH2:26][CH2:25][CH2:24][C:23]2=[O:27])[C:17]([CH3:21])=[C:18]([Cl:20])[CH:19]=1)[CH3:13].C(N(CC)C(C)C)(C)C>C(O)(C)C>[Cl:20][C:18]1[C:17]([CH3:21])=[C:16]([N:22]2[CH2:26][CH2:25][CH2:24][C:23]2=[O:27])[C:15]([O:28][CH3:29])=[C:14]([CH:12]([NH:11][C:2]2[N:10]=[CH:9][N:8]=[C:7]3[C:3]=2[N:4]=[CH:5][NH:6]3)[CH3:13])[CH:19]=1
Reactant: Brc1ncnc2[nH]cnc12
Reactant: COc1c(C(C)N)cc(Cl)c(C)c1N1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: COc1c(C(C)Nc2ncnc3[nH]cnc23)cc(Cl)c(C)c1N1CCCC1=O
Temperature: 90 °C

Procedure:
A mixture of 6-bromo-9H-purine (8.5 mg, 0.043 mmol), 1-[3-(1-aminoethyl)-5-chloro-2-methoxy-6-methylphenyl]pyrrolidin-2-one (11 mg, 0.039 mmol), and N,N-diisopropylethylamine (0.014 mL, 0.078 mmol) in isopropyl alcohol (0.1 mL) was heated at 90° C. under nitrogen overnight. The mixture was evaporated and the resulting mixture was purified on RP-HPLC (XBridge C18 Column, eluting with a gradient of acetonitrile in water with 0.2% ammonium hydroxide, at flow rate of 30 mL/min) to give the desired product. LCMS calculated for C19H22ClN6O2 (M+H)+: m/z=401.1. found: 401.1.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:12])=[C:4]([CH:8]=[CH:9][C:10]=1[F:11])[C:5]([OH:7])=[O:6].OS(O)(=O)=O.[N+:18]([O-])([OH:20])=[O:19]>>[Cl:1][C:2]1[C:3]([F:12])=[C:4]([CH:8]=[C:9]([N+:18]([O-:20])=[O:19])[C:10]=1[F:11])[C:5]([OH:7])=[O:6]
Reactant: O=C(O)c1ccc(F)c(Cl)c1F
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: O=C(O)c1cc([N+](=O)[O-])c(F)c(Cl)c1F
Reaction time: 3 h
Yield: 94.4 %

Procedure:
3-Chloro-2,4-difluoro-benzoic acid 1a (3.00 g, 15.6 mmol) is added to a stirred solution of concentrated H2SO4 (16 mL) and fuming nitric acid (0.85 mL, 20.3 mmol). After 3 hours a precipitate forms. The yellow slurry is poured onto ice water (100 mL). The aqueous mixture is extracted with diethyl ether (3×). The organic extracts are dried (Na2SO4) and concentrated under reduced pressure to give 3.50 g (95%) of clean desired product as a pale yellow solid.
Reaction SMILES: [O:1]([CH2:8][CH2:9][CH2:10][C:11]([OH:13])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.C(Cl)(=O)C(C)(C)C.[C@@H:28]1([NH2:38])[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH2:31][CH2:30][CH2:29]1>C(Cl)Cl>[O:1]([CH2:8][CH2:9][CH2:10][C:11]([NH:38][C@@H:28]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH2:31][CH2:30][CH2:29]1)=[O:13])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)CCCOc1ccccc1
Reactant: N[C@H]1CCCc2ccccc21
Agent: CC(C)(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(CCCOc1ccccc1)N[C@H]1CCCc2ccccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 115.4 %

Procedure:
4-Phenoxybutanoic acid (1.05 g, 5.8 mmol, Lancaster) and triethylamine (2.4 mL, 17.4 mmol) in anhydrous CH2Cl2 (25 mL) were treated with pivaloyl chloride (0.75 mL, 6.1 mmol) at 0° C. After stirring for 1 hour, the reaction mixture was treated with (1S)-1,2,3,4-tetrahydro-1-naphthalenylamine (1.0 mL, 6.9 mmol) and the reaction mixture was allowed to warm to room temperature and stir for 16 hours. The reaction mixture was diluted with CH2Cl2, washed with 1N HCl, saturated NaHCO3, brine, dried (Na2SO4), filtered and the filtrate concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, 40% ethyl acetate/hexanes) to provide the title compound as a colorless oil (2.07 g).
Reaction SMILES: [NH2:1][C:2]1[N:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.N1CC[CH2:15][C@H:11]1[C:12](O)=O.CC(C)=O>CCO>[CH3:15][C:11]1[CH:12]=[CH:4][C:3]2[C:2](=[N:9][CH:8]=[CH:7][CH:6]=2)[N:1]=1
Reactant: Nc1ncccc1C=O
Reactant: O=C(O)[C@@H]1CCCN1
Solvent: CC(C)=O
Solvent: CCO
Product: Cc1ccc2cccnc2n1
Reaction time: 8 h
Yield: 887.8 %

Procedure:
To a suspension of 2-aminonicotinaldehyde (732 mg, 6 mmol) and L-proline (69 mg, 0.6 mmol) in EtOH (15 mL) was added acetone (1.74 g, 30 mmol). Then the mixture was heated at reflux and stirred for 8 h. The resulting mixture was concentrated under reduced pressure to give a residue, which was washed with water (10 mL) and extracted with DCM (15 mL×3). The combined organic layers were washed with brine (10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to afford the crude product 2-methyl-1,8-naphthyridine as a yellow solid (768 mg). MS (ESI): m/z 145 [M+H]+. See e.g., Bioorg. Med. Chem. Lett., 2005, 15, 2679-84.
Reaction SMILES: [OH:1][C:2]1[C:7]2[C@@:8]3([OH:45])[C@@:21]([O:25][CH3:26])([C@H:22]([OH:24])[CH2:23][C:6]=2[CH:5]=[C:4]([CH3:46])[C:3]=1[C:47]([O:49][CH3:50])=[O:48])[C:20](=[O:27])[C:19]1[C:10](=[CH:11][C:12]2[C:13](=[O:43])[C:14]([NH:30][C@@H:31]4[C@H:36]([O:37][CH3:38])[C@H:35]([OH:39])[C@@H:34]([O:40][CH3:41])[C@H:33]([CH3:42])[O:32]4)=[CH:15][C:16](=O)[C:17]=2[C:18]=1[OH:28])[C:9]3=[O:44].[CH3:51][O:52][CH2:53][CH2:54][NH2:55]>CO>[OH:1][C:2]1[C:7]2[C@@:8]3([OH:45])[C@@:21]([O:25][CH3:26])([C@H:22]([OH:24])[CH2:23][C:6]=2[CH:5]=[C:4]([CH3:46])[C:3]=1[C:47]([O:49][CH3:50])=[O:48])[C:20](=[O:27])[C:19]1[C:10](=[CH:11][C:12]2[C:13](=[O:43])[C:14]([NH:30][C@@H:31]4[C@H:36]([O:37][CH3:38])[C@H:35]([OH:39])[C@@H:34]([O:40][CH3:41])[C@H:33]([CH3:42])[O:32]4)=[CH:15]/[C:16](=[N:55]\[CH2:54][CH2:53][O:52][CH3:51])/[C:17]=2[C:18]=1[OH:28])[C:9]3=[O:44]
Reactant: COC(=O)c1c(C)cc2c(c1O)[C@]1(O)C(=O)c3cc4c(c(O)c3C(=O)[C@]1(OC)[C@H](O)C2)C(=O)C=C(N[C@H]1O[C@@H](C)[C@H](OC)[C@@H](O)[C@H]1OC)C4=O
Reactant: COCCN
Solvent: CO
Product: COCC/N=C1\C=C(N[C@H]2O[C@@H](C)[C@H](OC)[C@@H](O)[C@H]2OC)C(=O)c2cc3c(c(O)c21)C(=O)[C@]1(OC)[C@H](O)Cc2cc(C)c(C(=O)OC)c(O)c2[C@]1(O)C3=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 32 %

Procedure:
To a solution of (6R,6aS,14aR)-methyl 1,6,8,14a-tetrahydroxy-11-((2S,3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-3-methyl-7,9,12,14-tetraoxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxylate (100 mg, 0.14 mmol) in methanol (3 mL) was added 2-methoxyethanamine (107 mg, 1.43 mmol). The reaction mixture was stirred at room temperature under nitrogen for 3 h. The reaction was quenched by adding saturated ammonium chloride solution (15 mL). Then it was extracted with chloroform (75 mL) and washed with water (2×25 mL). The organic layer was separated, dried (MgSO4), filtered and concentrated to give the crude product. The crude material was purified by preparative TLC (silica gel, 90:10 chloroform/methanol) to afford (6R,6aS,14aR,E)-methyl 1,6,8,14a-tetrahydroxy-11-((2S,3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-9-(2-methoxyethylimino)-3-methyl-7,12,14-trioxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxylate (33.8 mg, 31.2%) as a dark blue solid: 1H NMR (500 MHz, CDCl3) δ 11.95 (s, 1H), 7.93 (s, 1H), 6.91 (d, J=8.5 Hz, 1H), 6.49 (s, 1H), 6.05 (s, 1H), 5.27 (s, 1H), 4.99 (t, J=8.0 Hz, 1H), 4.74-4.69 (m, 2H), 3.83 (s, 4H), 3.79 (s, 4H), 3.72-3.69 (m, 4H), 3.65-3.59 (m, 4H), 3.57-3.55 (m, 1H), 3.40 (s, 3H), 3.37 (s, 3H), 3.14 (t, J=9.1 Hz, 1H), 2.48 (d, J=3.8 Hz, 1H), 2.37 (s, 3H), 1.58 (br s, 1H), 1.37 (d, J=6.1 Hz, 3H); MS (ESI+) m/z 755 (M+H); HPLC 88.9% (AUC), tR=11.14 min.
Reaction SMILES: [I-:1].[Na+].[CH:3]([C:5]1[CH:12]=[CH:11][C:8]([CH2:9]Cl)=[CH:7][CH:6]=1)=[CH2:4]>CC(C)=O>[CH:3]([C:5]1[CH:12]=[CH:11][C:8]([CH2:9][I:1])=[CH:7][CH:6]=1)=[CH2:4]
Reactant: C=Cc1ccc(CCl)cc1
Reactant: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: C=Cc1ccc(CI)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.4 %

Procedure:
Sodium iodide (1.2 equiv., 59 g, 0.39 mol) was dissolved in acetone (200 ml) and 4-vinylbenzyl chloride (50 g, 0.33 mol) was added to a reaction flask. The mixture was stirred at room temperature overnight. The reaction mixture was filtered and acetone removed under reduced pressure. The resulting product was dissolved in hexane, filtered, and the solvent removed under reduced pressure. The monomer was isolated as a red, slightly viscous liquid (68 g, yield 84%). 1H NMR (CDCl3) δ (ppm) 4.47 (s, 2H), 5.25 (d, 1H), 5.74 (d, 1H), 6.65 (dd, 1H), 7.34 (m, 4H).
Reaction SMILES: [ClH:1].F[C:3]1[CH:8]=[C:7]([C@@H:9]2[O:14][CH2:13][CH2:12][NH:11][CH2:10]2)[CH:6]=[CH:5][C:4]=1[NH:15][C:16]([C:18]1[CH:19]=[N:20][N:21]([C:23]2[CH:28]=[N:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[N:24]=2)[CH:22]=1)=[O:17].Cl.[Cl:34]C1C=C(NC(=O)C2C=CN=C(OCC)C=2)C=CC=1[C@H]1OCCNC1>>[ClH:34].[Cl:1][C:8]1[CH:3]=[C:4]([NH:15][C:16]([C:18]2[CH:19]=[N:20][N:21]([C:23]3[CH:28]=[N:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[N:24]=3)[CH:22]=2)=[O:17])[CH:5]=[CH:6][C:7]=1[C@@H:9]1[O:14][CH2:13][CH2:12][NH:11][CH2:10]1
Reactant: CCOc1cc(C(=O)Nc2ccc([C@@H]3CNCCO3)c(Cl)c2)ccn1
Reactant: O=C(Nc1ccc([C@H]2CNCCO2)cc1F)c1cnn(-c2cncc(C(F)(F)F)n2)c1
Agent: Cl
Product: O=C(Nc1ccc([C@H]2CNCCO2)c(Cl)c1)c1cnn(-c2cncc(C(F)(F)F)n2)c1

Procedure:
In analogy to example 83, step a) using 1-(6-Trifluoromethyl-pyrazin-2-yl)-1H-pyrazole-4-carboxylic acid (prepared as described in example 125) instead of 2-(trifluoromethyl)-4-pyridinecarboxylic acid (CAS 131747-41-6) and (−)-(S)-2-(4-Amino-2-chloro-phenyl)-morpholine-4-carboxylic acid tert-butyl ester (described in example 91) instead of (+)—(R)-2-(4-Amino-2-fluoro-phenyl)-morpholine-4-carboxylic acid tert-butyl ester.
Reaction SMILES: [CH2:1]([Mg]Br)[CH3:2].[C:5]1([S:15]([N:18]2[CH2:23][CH2:22][CH:21]([C:24](OC)=[O:25])[CH2:20][CH2:19]2)(=[O:17])=[O:16])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7][CH:6]=1>O1CCCC1.CC(C)[O-].CC(C)[O-].CC(C)[O-].C[Ti+3]>[C:5]1([S:15]([N:18]2[CH2:19][CH2:20][CH:21]([C:24]3([OH:25])[CH2:2][CH2:1]3)[CH2:22][CH2:23]2)(=[O:16])=[O:17])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7][CH:6]=1
Reactant: CC[Mg]Br
Reactant: COC(=O)C1CCN(S(=O)(=O)c2cccc3ccccc23)CC1
Agent: C[Ti+3]
Agent: CC(C)[O-]
Solvent: C1CCOC1
Product: O=S(=O)(c1cccc2ccccc12)N1CCC(C2(O)CC2)CC1
Temperature: 25 °C
Yield: 35.2 %

Procedure:
Ethylmagnesium bromide (0.110 mL, 3.0 M in THF, 0.330 mmol) was added dropwise to a stirring solution of methyl 1-(naphthalen-1-ylsulfonyl)piperidine-4-carboxylate (0.100 g, 0.30 mmol) and methyltitanium triisopropoxide (0.300 mL, 1.0 M in THF, 0.300 mmol) in tetrahydrofuran (3 mL) at 0° C. The reaction mixture was allowed to warm to ambient temperature over 2 h then quenched with water (15 mL). The resulting flocculent solution was diluted with ethyl acetate (15 mL) and filtered through Celite. The filtrate was extracted with ethyl acetate (2×10 mL). The combined organic extracts were dried over anhydrous sodium sulfate and concentrated in vacuo. The resulting residue was purified by column chromatography on SiO2 eluted with hexanes/ethyl acetate (1:1) to yield 0.035 g (35%) of the title compound as a white foam. 1H NMR (400 MHz, Chloroform-d) δ, ppm: 0.36-0.41 (m, 2 H), 0.67-0.71 (m, 2H), 0.90-0.98 (m, 1 H), 1.72 (dd, J=13.89, 1.26 Hz, 2 H), 2.49 (td, J=12.51, 2.53 Hz, 2 H), 3.91-4.02 (m, 2 H), 7.54-7.60 (m, 3 H), 7.92 (d, J=8.34 Hz, 1 H), 8.06 (d, J=8.08 Hz, 1 H), 8.21 (d, J=7.33 Hz, 1 H), 8.76 (s, 1 H); ESI-MS: m/z 332.3 (M+H)+.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[Cl:9][C:10]1[CH:11]=[C:12]([CH:34]=[CH:35][CH:36]=1)[CH2:13][C:14]1[C:15]([C:19]([NH:21][C@H:22]([C:24]2[CH:33]=[CH:32][C:27]([C:28]([O:30][CH3:31])=[O:29])=[CH:26][CH:25]=2)[CH3:23])=[O:20])=[CH:16][S:17][CH:18]=1.C(Cl)Cl.CC(O)=O>C([O-])(O)=O.[Na+]>[Br:1][C:18]1[S:17][CH:16]=[C:15]([C:19]([NH:21][C@H:22]([C:24]2[CH:33]=[CH:32][C:27]([C:28]([O:30][CH3:31])=[O:29])=[CH:26][CH:25]=2)[CH3:23])=[O:20])[C:14]=1[CH2:13][C:12]1[CH:34]=[CH:35][CH:36]=[C:10]([Cl:9])[CH:11]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1ccc([C@H](C)NC(=O)c2cscc2Cc2cccc(Cl)c2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: COC(=O)c1ccc([C@H](C)NC(=O)c2csc(Br)c2Cc2cccc(Cl)c2)cc1
Reaction time: 16 h

Procedure:
N-Bromosuccinimide (43.0 mg, 0.242 mmol) was added to methyl 4-[(1S)-1-({[4-(3-chlorobenzyl)-3-thienyl]carbonyl}amino)ethyl]benzoate from Example 3, Step 4 (50.0 mg, 0.121 mmol) in 1:1 CH2Cl2/AcOH (1.2 mL). After 16 h, the reaction was slowly poured in 5% aq. NaHCO3. The aqueous layer was extracted with CHCl3 and the combined organics were washed with 5% aq. NaHCO3, sat. Na2S2O3 and brine, dried (Na2SO4) and concentrated. The crude product was purified by Combi Flash chromatography system (0-2% EtOAc/CHCl3 in 15 min.) to afford the desired product as a brown solid.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:10][C:11]1[CH:20]=[C:14]2[C:15](=[O:19])[NH:16][CH2:17][CH2:18][N:13]2[N:12]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Br[CH2:22][CH:23]1[CH2:25][CH2:24]1>CN(C=O)C.O>[CH2:3]([O:10][C:11]1[CH:20]=[C:14]2[C:15](=[O:19])[N:16]([CH2:22][CH:23]3[CH2:25][CH2:24]3)[CH2:17][CH2:18][N:13]2[N:12]=1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: O=C1NCCn2nc(OCc3ccccc3)cc21
Reactant: BrCC1CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C1c2cc(OCc3ccccc3)nn2CCN1CC1CC1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 78.5 %

Procedure:
A 60% dispersion of sodium hydride in mineral oils (8.14 mg, 0.2 mmol) was added to a stirred solution of 2-(benzyloxy)-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one (0.045 g, 0.18 mmol) in DMF (2.7 mL) at 0° C. The mixture was stirred at 0° C. for 15 minutes. Then (bromomethyl)cyclopropane (22 μL, 0.22 mmol) was added at 0° C. The mixture was stirred at 0° C. for 1 hour and then allowed to warm to room temperature and stirred for 16 hours. The mixture was diluted with water and extracted with AcOEt. The organic layer was separated, washed with a saturated solution of NH4Cl, dried (Na2SO4), filtered and the solvents evaporated in vacuo. The crude product was purified by flash column chromatography (silica; AcOEt in DCM 0/100 to 20/80). The desired fractions were collected, the solvents evaporated in vacuo and the residue was triturated with DIPE to yield 2-(benzyloxy)-5-(cyclopropylmethyl)-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one (42 mg, 76% yield) as a white solid. C17H19N3O2. 1H NMR (500 MHz, CDCl3) δ ppm 0.25-0.36 (m, 2H), 0.51-0.62 (m, 2H), 0.98-1.08 (m, 1H), 3.43 (d, J=6.9 Hz, 2H), 3.83 (dd, J=6.9, 5.5 Hz, 2H), 4.23 (dd, J=6.9, 5.5 Hz, 2H), 5.20 (s, 2H), 6.26 (s, 1H), 7.29-7.35 (m, 1H), 7.37 (t, J=7.4 Hz, 2H), 7.41-7.48 (m, 2H).
Reaction SMILES: [CH2:1]([NH:8][C:9]1[C:10]2[C:15]([N:16]=[C:17]3[C:22]=1[CH:21]([OH:23])[CH2:20][CH2:19][CH2:18]3)=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)(O)[O-].[Na+].[Br:29][CH2:30][CH2:31]O>FC(F)(F)C(O)=O>[CH2:1]([NH:8][C:9]1[C:10]2[C:15]([N:16]=[C:17]3[C:22]=1[CH:21]([O:23][CH2:31][CH2:30][Br:29])[CH2:20][CH2:19][CH2:18]3)=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OC1CCCc2nc3ccccc3c(NCc3ccccc3)c21
Reactant: OCCBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: BrCCOC1CCCc2nc3ccccc3c(NCc3ccccc3)c21
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 71 %

Procedure:
To a suspension of 9-benzylamino-1,2,3,4-tetrahydroacridin-1ol (7.20 g) in 2-bromoethanol (45 ml) was added 40 drops of trifluoroacetic acid. The reaction mixture was stirred at ambient temperature for 20 mins, added to iced sodium bicarbonate solution, and the suspension was extracted with ethyl acetate. The combined organic extracts were washed with water, saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and evaporated. The residue was purified by flash chromatography (ethyl acetate→1% triethylamine/ethyl acetate) to give 6.85 g (71%) of product. Recrystallization from cyclohexane gave the analytical sample, mp 89°-91° C.
Reaction SMILES: [NH2:1][CH2:2][P:3]([OH:6])(=[O:5])[OH:4].[F:7][C:8]([F:21])([F:20])[C:9]1[CH:10]=[C:11]([N+:17]([O-:19])=[O:18])[C:12](Cl)=[CH:13][C:14]=1[Cl:15]>O.C(O)C>[N+:17]([C:11]1[CH:10]=[C:9]([C:8]([F:7])([F:20])[F:21])[C:14]([Cl:15])=[CH:13][C:12]=1[NH:1][CH2:2][P:3]([OH:6])(=[O:4])[OH:5])([O-:19])=[O:18]
Reactant: NCP(=O)(O)O
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)c(Cl)cc1Cl
Solvent: O
Solvent: CCO
Product: O=[N+]([O-])c1cc(C(F)(F)F)c(Cl)cc1NCP(=O)(O)O
Temperature: 120 °C
Yield: 68.2 %

Procedure:
3.3 g (30 mmol) of aminomethanephosphonic acid in 120 ml of water and 120 ml of ethanol are introduced together with 3.37 g (31.8 mmol) of soda and mixed with 7.8 g (97%, 30 mmol) of 3-trifluoromethyl-4,6-dichloronitrobenzene, and it is refluxed for 4 hours at 120° C. bath temperature. After removing the ethanol in a rotary evaporator, it is extracted three times with 100 ml of ethyl acetate. The organic phase is washed with a little water. It contains starting material and is discarded. The collected aqueous phase is adjusted acidic with 4N hydrochloric acid to pH 1 and extracted three times with 100 ml of ethyl acetate each. The organic phase is washed with water, dried, filtered and concentrated by evaporation. 6.85 g (68% of theory) of N-(2-nitro-4-trifluoromethyl-5-chloro-phenyl)-aminomethanephosphonic acid of melting point 207.3° C. is obtained.
Reaction SMILES: BrC1C=CC(C[N:7]([S:36]([CH3:39])(=[O:38])=[O:37])[NH:8][C:9](=[O:35])[C@@H:10]([C@@H:15]([C:25](=[O:34])[NH:26][O:27]C2CCCCO2)[CH2:16]/[CH:17]=[CH:18]/[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:11][CH:12]([CH3:14])[CH3:13])=CC=1.O1CCCCC1OC([C@H]([C@@H](CC(C)C)C(NNS(C)(=O)=O)=O)C/C=C/C1C=CC=CC=1)=O.[Br:74][C:75]1[CH:82]=[CH:81][C:78]([CH2:79]Br)=[CH:77][CH:76]=1>>[Br:74][C:75]1[CH:82]=[CH:81][C:78]([CH2:79][C@@:10]([C@@H:15]([C:25](=[O:34])[NH:26][OH:27])[CH2:16][CH:17]=[CH:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)([CH2:11][CH:12]([CH3:14])[CH3:13])[C:9]([NH:8][NH:7][S:36]([CH3:39])(=[O:37])=[O:38])=[O:35])=[CH:77][CH:76]=1
Reactant: BrCc1ccc(Br)cc1
Reactant: CC(C)C[C@@H](C(=O)NN(Cc1ccc(Br)cc1)S(C)(=O)=O)[C@H](C/C=C/c1ccccc1)C(=O)NOC1CCCCO1
Agent: CC(C)C[C@@H](C(=O)NNS(C)(=O)=O)[C@H](C/C=C/c1ccccc1)C(=O)OC1CCCCO1
Product: CC(C)C[C@](Cc1ccc(Br)cc1)(C(=O)NNS(C)(=O)=O)[C@H](CC=Cc1ccccc1)C(=O)NO

Procedure:
The (E)-2′-(4-bromobenzyl)-2(R)-[1(S)-[(tetrahydro-2(RS)-pyranyloxy)carbamoyl]-4-phenyl-3-butenyl]-2′-(methanesulphonyl)-4-methylvalerohydrazide used as the starting material was prepared in an analogous manner to that described in Example 15, part (iii), starting from (E)-(2R)-[1(S)-[(tetrahydro-2(RS)-pyranyloxy)carbanoyl]-4-phenyl-3-butenyl]-2′-(methanesulphonyl)-4-methylvalerohydrazide by reaction with 4-bromobenzyl bromide.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:13]([OH:15])=[O:14])[CH:7]=[C:8]([CH:12]=1)[C:9]([OH:11])=[O:10])([O-:3])=[O:2].Br[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH2:17]([O:14][C:13]([C:6]1[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:12]=[C:8]([C:9]([O:11][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH3:17])=[O:10])[CH:7]=1)=[O:15])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]
Reactant: O=C(O)c1cc(C(=O)O)cc([N+](=O)[O-])c1
Reactant: CCCCCCCCCCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCCCOC(=O)c1cc(C(=O)OCCCCCCCCCCCCCC)cc([N+](=O)[O-])c1
Yield: 74 %

Procedure:
A mixture of 1.0 g (4.7 mmol) of 5-nitroisophthalic acid, 3.1 ml (10.3 mmol) of 1-bromotetradecane and 2.0 g (15 mmol) of potassium carbonate in 40 ml of anhydrous DMF was stirred and heated at 100° for 20 hours. Water was added to the cooled reaction mixture and the resultant solid was filtered and recrystallized from methylene chloride-methanol to give 2.1 g (74% yield, mp 60°-61°) of 5-nitro-1,3-benzenedicarboxylic acid ditetradecyl ester.
Reaction SMILES: [Br:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][NH:7][C@H:8]([C:12]([OH:14])=[O:13])[CH:9]([CH3:11])[CH3:10])=[CH:4][CH:3]=1.C(=O)(O)[O-].[Na+].[C:22](Cl)(=[O:27])[CH2:23][CH2:24][CH2:25][CH3:26].O>C1COCC1>[Br:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][N:7]([C:22](=[O:27])[CH2:23][CH2:24][CH2:25][CH3:26])[C@H:8]([C:12]([OH:14])=[O:13])[CH:9]([CH3:11])[CH3:10])=[CH:4][CH:3]=1
Reactant: CC(C)[C@H](NCc1ccc(Br)cc1)C(=O)O
Reactant: CCCCC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCCCC(=O)N(Cc1ccc(Br)cc1)[C@H](C(=O)O)C(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 91.2 %

Procedure:
A mixture made up of 5 g (17.47 mmol) of N-(4-bromobenzyl)-L-valine and 5.9 g (70.24 mmol) of sodium bicarbonate in 50 mL of dry THF is left under stirring and under nitrogen atmosphere for one hour. The preceding suspension is cooled to 0° C. and to it is added over a period of 15 min. 4.2 mL (35.41 mmol) of valeroyl chloride. The mixture is then left to react at 20-25° C. for 3 h, 50 mL of water is added and the THF is distilled at low pressure. The resulting solution is taken to pH 2 with HCl 35% and the remains of THF distilled off completely. The solid obtained is filtered, washed with 50 mL of water and dried in a vacuum over to provide 5.9 g (91.2%) of N-(4-bromobenzyl)-N-valeryl-L-valine. The solid is recrystallised from a mixture of EtOH/H2O 2:1. M.p.=123° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][NH2:16])[CH2:10][CH2:9]1.[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[N:28]([C:29]([CH3:32])([CH3:31])[CH3:30])[N:27]=[C:26]([CH:33]=O)[CH:25]=2)=[CH:20][CH:19]=1>>[C:29]([N:28]1[C:24]([C:21]2[CH:20]=[CH:19][C:18]([Cl:17])=[CH:23][CH:22]=2)=[CH:25][C:26]([CH2:33][NH:16][CH2:15][CH2:14][N:11]2[CH2:10][CH2:9][N:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[F:1])[CH2:13][CH2:12]2)=[N:27]1)([CH3:32])([CH3:31])[CH3:30]
Reactant: NCCN1CCN(c2ccccc2F)CC1
Reactant: CC(C)(C)n1nc(C=O)cc1-c1ccc(Cl)cc1
Product: CC(C)(C)n1nc(CNCCN2CCN(c3ccccc3F)CC2)cc1-c1ccc(Cl)cc1
Yield: 74.2 %

Procedure:
Compound 70 was prepared using the same method as that of Example 1 except that 4-(2-fluorophenyl)piperazin-1-ylethylamine and 5-(4-chlorophenyl)-1-t-butylpyrazole-3-carbaldehyde were used.