Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([NH:18][C:19](=[O:36])[C:20]2[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH2:28][CH2:29][N:30]3[CH2:34][CH2:33][CH2:32][CH:31]3[CH3:35])=[CH:22][CH:21]=2)([C:14](OC)=[O:15])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Li+].[OH-].[Na+].Cl.C(=O)([O-])[O-].[K+].[K+]>O1CCCC1.ClCCl.O>[CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([NH:18][C:19](=[O:36])[C:20]2[CH:21]=[CH:22][C:23]([O:26][CH2:27][CH2:28][CH2:29][N:30]3[CH2:34][CH2:33][CH2:32][CH:31]3[CH3:35])=[CH:24][CH:25]=2)([CH2:14][OH:15])[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)C1(NC(=O)c2ccc(OCCCN3CCCC3C)cc2)CCN(Cc2ccccc2)CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [BH4-]
Solvent: C1CCOC1
Solvent: O
Solvent: ClCCl
Product: CC1CCCN1CCCOc1ccc(C(=O)NC2(CO)CCN(Cc3ccccc3)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 72 %

Procedure:
A solution of methyl 1-benzyl-4-({4-[3-(2-methylpyrrolidin-1-yl)propoxy]benzoyl}amino)piperidine-4-carboxylate ax60 (0.93 g, 1.89 mmol) in dry tetrahydrofurane (20 ml) is cooled to 0° C. and lithium borohydride (1.4 ml, 2.83 mmol, 2 M in tetrahydrofurane) is added dropwise. The mixture is then stirred at room temperature overnight. The reaction mixture is then cooled to 0° C. and water (1.4 ml) and 1 N sodium hydroxide (1.4 ml) are added. After stirring for 20 minutes at 20° C., the mixture is concentrated and the residue is taken up in acetone (30 ml). The solution is cooled to 0° C., then 1 N hydrochloric acid (9.45 ml, 9.45 mmol) is added and the mixture is stirred at room temperature for 1 hour and concentrated to afford a pink oil. This oil is taken up in dichloromethane and treated with a saturated solution of potassium carbonate to reach pH 10. Dichloromethane is removed under reduced pressure and the aqueous phase is extracted twice with ethyl acetate. The combined organic extracts are dried over magnesium sulfate, filtered and concentrated to give 0.63 g of N-[1-benzyl-4-(hydroxymethyl)piperidin-4-yl]-4-[3-(2-methylpyrrolidin-1-yl)propoxy]benzamide ax62.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[C:9](=O)[CH:8]([CH3:11])[CH2:7][S:6]1)=[O:4].Cl.[NH2:13]O.CCOCC>C(#N)C>[NH2:13][C:9]1[C:8]([CH3:11])=[CH:7][S:6][C:5]=1[C:3]([O:2][CH3:1])=[O:4]
Reactant: NO
Reactant: COC(=O)C1SCC(C)C1=O
Agent: Cl
Solvent: CCOCC
Solvent: CC#N
Product: COC(=O)c1scc(C)c1N

Procedure:
2-Methoxycarbonyl-4-methyl-3-oxotetrahydrothiophene (l.74 g) was dissolved in acetonitrile (13 ml) and the resulting solution was brought to the boil. To this was added hydroxylamine hydrochloride (0.69 g) and the mixture was refluxed for 5 hours. The reaction mixture was cooled in ice and dry ether (50 ml) added whereby a sticky precipitate was produced which was filtered off with the aid of kieselguhr. The kieselguhr was slurried with water and filtered, and the filtrate was basified with ammonia and extracted with ether (2 ×). The combined extracts were dried over sodium sulphate, filtered and evaporated to give the title compound, 1.lg (64%) mp 82°-83°.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([NH2:6])=[O:5].O=[CH:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([O:15][CH3:16])=[O:14]>>[O:5]=[C:4]1[CH2:3][NH:2][CH:8]([CH2:9][CH2:10][CH2:11][CH2:12][C:13]([O:15][CH3:16])=[O:14])[NH:6]1
Reactant: NCC(N)=O
Reactant: COC(=O)CCCCC=O
Agent: Cl
Product: COC(=O)CCCCC1NCC(=O)N1

Procedure:
Glycinamide hydrochloride (6.73 g, 0.061 mol) and methyl 6-oxohexanoate (8.8 ml, 0.061 mol) were reacted together according to the procedure of example 2, to give 0.93 (7.6%) of the title compound, m.p. 58°-60° C. (with decomposition). NMR (DMSO-d6): deltaH =8.10 (b.s., 1H, CONH); 4.50-4.15 (c.a., 1H, NHCHNH); 3.55 (s, 3H, COOCH3); 3.20 (b.s., 1H, CH2NHCH); 3.05 (s, 2H, NHCH2CO); 2.45-2.10 (c.a., 2H, CH2COO); 1.80-1.10 (c.a., 6H, CH2CH2CH2CH2COO). MS (E.I., 70 eV, 1.5 mA) m/z=200 (M+), 169 (M-OCH3)+, 85 (C3H5N2O)+.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C([O:9][C:10](=O)[C:11]([F:14])([F:13])[F:12])C>CO>[F:12][C:11]([F:14])([F:13])[C:10]([N:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1)=[O:9]
Reactant: C1CNCCN1
Reactant: CCOC(=O)C(F)(F)F
Solvent: CO
Product: O=C(N1CCNCC1)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 57.8 %

Procedure:
To a solution of piperazine (1.444 g, 16.8 mmol) in MeOH (10 mL) was added trifluroacetic acid ethyl ester (2.0 mL, 16.8 mmol) and the mixture stirred at room temperature overnight. The reaction was concentrated and purified by column chromatography on silica gel (CH2Cl2/MeOH, 9:1) to afford the desired mono-protected piperazine adduct (1.77 g, 58%) as a pale yellow oil. 1H NMR (CDCl3) δ 1.70 (br s, 1H), 2.90–2.94 (m, 4H), 3.56–3.59 (m, 2H), 3.64–3.67 (m, 2H).
Reaction SMILES: Cl[C:2]1[C:3]([CH3:23])=[C:4]([N:11]2[CH2:16][CH2:15][CH:14]([N:17]3[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)[CH2:13][CH2:12]2)[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].[CH3:24][O-:25].[Na+].O>CN(C=O)C>[CH3:23][C:3]1[C:2]([O:25][CH3:24])=[C:7]([N+:8]([O-:10])=[O:9])[CH:6]=[CH:5][C:4]=1[N:11]1[CH2:16][CH2:15][CH:14]([N:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)[CH2:13][CH2:12]1
Reactant: C[O-]
Reactant: Cc1c(N2CCC(N3CCCCC3)CC2)ccc([N+](=O)[O-])c1Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1c([N+](=O)[O-])ccc(N2CCC(N3CCCCC3)CC2)c1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 106.7 %

Procedure:
To 1′-(3-chloro-2-methyl-4-nitrophenyl)-1,4′-bipiperidine (0.50 g, 1.5 mmol) in DMF (15 mL) was added sodium methoxide (0.97 g, 1.8 mmol) at 0° C., and the mixture was stirred at rt overnight. The mixture was poured into H2O, extracted with EtOAc, washed with H2O, dried and concentrated to provide the title compound of step B (0.53 g, 1.6 mmol, 100% crude). 1H NMR (400 MHz, CDCl3) δ ppm 1.41-1.50 (m, 2H), 1.61-1.71 (m, 4H), 1.70-1.81 (m, 2H), 1.91-2.01 (m, 2H), 2.25 (s, 3H), 2.35-2.45 (m, 1H), 2.51-2.60 (m, 4H), 2.65-2.75 (m, 2H), 3.21-3.30 (m, 2H), 3.9 (s, 3H), 6.75 (d, J=9.2 Hz, 1H), 7.75 (d, J=9.2 Hz, 1H).
Reaction SMILES: [F:1][C:2]1[CH:26]=[CH:25][C:5]([O:6][CH2:7][C:8]2[N:9]=[C:10]3[CH:15]=[CH:14][N:13]([C:16]4[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=4)[C:12](=[O:23])[N:11]3[CH:24]=2)=[CH:4][CH:3]=1.[H][H]>CCO.[Ni]>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][CH2:7][C:8]2[N:9]=[C:10]3[CH2:15][CH2:14][N:13]([C:16]4[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=4)[C:12](=[O:23])[N:11]3[CH:24]=2)=[CH:25][CH:26]=1
Reactant: [H][H]
Reactant: O=c1n(-c2ccc(F)cc2)ccc2nc(COc3ccc(F)cc3)cn12
Agent: [Ni]
Solvent: CCO
Product: O=C1N(c2ccc(F)cc2)CCc2nc(COc3ccc(F)cc3)cn21
Yield: 45.2 %

Procedure:
A solution of 2-(4-fluoro-phenoxymethyl)-6-(4-fluoro-phenyl)-6H-imidazo[1,2-c]pyrimidin-5-one (0.1 g, 0.28 mmol) in EtOH (25 mL) was hydrogenated in a H-cube reactor (1 mL/min, 30 mm Raney nickel cartridge, 35° C., full hydrogen mode, 3 cycles) and then (1 mL/min, 30 mm Raney nickel cartridge, 40° C., full hydrogen mode, 3 cycles). The solvent was evaporated in vacuo and the crude product was purified by flash column chromatography (silica; AcOEt in DCM with a gradient of 50/50 to 75/25). The desired fractions were collected and the solvents evaporated in vacuo to yield 2-(4-fluoro-phenoxymethyl)-6-(4-fluoro-phenyl)-7,8-dihydro-6H-imidazo[1,2-c]pyrimidin-5-one (45 mg, 45% yield). 1H NMR (500 MHz, CDCl3) δ ppm 3.29 (t, J=6.6 Hz, 2H), 4.00 (t, J=6.6 Hz, 2H), 4.98 (s, 2H), 6.92-7.01 (m, 4H), 7.10-7.18 (m, 2H), 7.29-7.36 (m, 2H), 7.56 (s, 1H).
Reaction SMILES: [CH3:1][C:2]1[C:7]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:6][CH:5]=[CH:4][N+:3]=1[O-].[CH3:16][C:17]([O:19]C(C)=O)=[O:18]>>[O:8]([C:7]1[C:2]([CH2:1][O:19][C:17](=[O:18])[CH3:16])=[N:3][CH:4]=[CH:5][CH:6]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CC(=O)OC(C)=O
Reactant: Cc1c(Oc2ccccc2)ccc[n+]1[O-]
Product: CC(=O)OCc1ncccc1Oc1ccccc1
Yield: 28 %

Procedure:
A solution of 2-methyl-3-phenoxy-pyridine 1-oxide (0.690 g, 3.40 mmol) in Ac2O (3.4 mL) stirred at 80° C. for 3 h. The solution was concentrated and the resulting residue was diluted with CH2Cl2 (30 mL). The organic layer was washed with saturated aqueous NaHCO3 (2×30 mL), dried (MgSO4), and concentrated. Purification by column chromatography on silica gel with hexanes/Et2O (1:1) afforded acetic acid 3-phenoxy-pyridin-2-ylmethyl ester as a clear oil (0.234 g, 28%). 1H NMR (CDCl3) δ 2.07 (s, 3H), 5.34 (s, 2H), 7.00 (d, 2H, J=8.0 Hz), 7.13-7.23 (m, 2H), 7.36 (m, 2H), 8.39 (dd, 1H, J=3.4, 2.1 Hz).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[CH:8][C:7]([NH:11][C:12]1[CH:17]=[CH:16][N:15]=[C:14]3[CH:18]=[C:19]([C:21]([OH:23])=O)[S:20][C:13]=13)=[CH:6][CH:5]=2.[NH:24]1[CH2:28][CH2:27][CH2:26][C@@H:25]1[C:29]([OH:32])([CH3:31])[CH3:30]>>[OH:32][C:29]([C@H:25]1[CH2:26][CH2:27][CH2:28][N:24]1[C:21]([C:19]1[S:20][C:13]2[C:14](=[N:15][CH:16]=[CH:17][C:12]=2[NH:11][C:7]2[CH:6]=[C:5]3[C:4](=[CH:9][CH:8]=2)[NH:3][C:2]([CH3:10])=[CH:1]3)[CH:18]=1)=[O:23])([CH3:31])[CH3:30]
Reactant: CC(C)(O)[C@H]1CCCN1
Reactant: Cc1cc2cc(Nc3ccnc4cc(C(=O)O)sc34)ccc2[nH]1
Product: Cc1cc2cc(Nc3ccnc4cc(C(=O)N5CCC[C@@H]5C(C)(C)O)sc34)ccc2[nH]1

Procedure:
The title compound was prepared from 7-(2-methyl-1H-indol-5-ylamino)-thieno[3,2-b]pyridine-2-carboxylic acid and (R)-2-pyrrolidin-2-yl-propan-2-ol by a procedure analogous to Example 21B. MS: 435.2; HPLC Rf: 4.656 min.; HPLC purity: 97%.
Reaction SMILES: CCN(C(C)C)C(C)C.[Br:10][C:11]1[CH:12]=[C:13]2[C:18](Cl)=[C:17]([C:20]([NH2:22])=[O:21])[CH:16]=[N:15][N:14]2[CH:23]=1.Cl.[NH2:25][C@@H:26]([C@H:28]([C:31]1[O:32][CH:33]=[C:34]([C:36]([NH2:38])=[O:37])[N:35]=1)[CH2:29][CH3:30])[CH3:27]>CN(C=O)C>[Br:10][C:11]1[CH:12]=[C:13]2[C:18]([NH:25][C@@H:26]([C@H:28]([C:31]3[O:32][CH:33]=[C:34]([C:36]([NH2:38])=[O:37])[N:35]=3)[CH2:29][CH3:30])[CH3:27])=[C:17]([C:20](=[O:21])[NH2:22])[CH:16]=[N:15][N:14]2[CH:23]=1
Reactant: CC[C@@H](c1nc(C(N)=O)co1)[C@@H](C)N
Reactant: NC(=O)c1cnn2cc(Br)cc2c1Cl
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC[C@@H](c1nc(C(N)=O)co1)[C@@H](C)Nc1c(C(N)=O)cnn2cc(Br)cc12
Temperature: 90 °C
Yield: 93.7 %

Procedure:
DIPEA (1.08 ml, 6.21 mmol) was added in one portion to a solution of 6-bromo-4-chloropyrrolo[1,2-b]pyridazine-3-carboxamide (568 mg, 2.07 mmol) and 2-((2R,3R)-2-aminopentan-3-yl)oxazole-4-carboxamide hydrochloride (532 mg, 2.28 mmol) in DMF (6.9 ml). The reaction was heated to 90° C. overnight before evaporating in vacuo and treating the residue with water to precipitate 2-((2R,3R)-2-((6-bromo-3-carbamoylpyrrolo[1,2-b]pyridazin-4-yl)amino)pentan-3-yl)oxazole-4-carboxamide (843 mg, 1.94 mmol, 94% yield) which was used immediately in the next reaction. 1H NMR (400 MHz, CCl3D) δ 8.00 (s, 1H), 7.81 (s, 1H), 7.34 (d, J=1.5 Hz, 1H), 6.76 (d, J=1.5 Hz, 1H), 4.51-4.37 (m, 1H), 2.90 (dt, J=9.6, 4.9 Hz, 1H), 1.78-1.53 (m, 2H), 1.08 (d, J=6.4 Hz, 3H), 0.65 (t, J=7.4 Hz, 3H). LC/MS: M+H+337.08, ret. time=0.84 min. Column: Waters Acquity UPLC BEH C18, 2.1×50 mm, 1.7-μm particles; Mobile Phase A: 5:95 acetonitrile:water with 0.05% TFA; Mobile Phase B: 95:5 acetonitrile:water with 0.05% TFA; Temperature: 50° C.; Gradient: 0-100% B over 3 minutes, then a 0.75-minute hold at 100% B; Flow: 1.11 mL/min.
Reaction SMILES: Cl.[C:2]([NH:7][NH2:8])([CH2:5][CH3:6])([CH3:4])[CH3:3].[C:9]([O:16][CH2:17][CH:18]=[CH2:19])(=[O:15])[CH2:10][CH2:11][C:12]([CH3:14])=O.[OH-].[Na+]>O>[C:2]([NH:7][N:8]=[C:12]([CH3:14])[CH2:11][CH2:10][C:9]([O:16][CH2:17][CH:18]=[CH2:19])=[O:15])([CH2:5][CH3:6])([CH3:4])[CH3:3]
Reactant: C=CCOC(=O)CCC(C)=O
Reactant: CCC(C)(C)NN
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: C=CCOC(=O)CCC(C)=NNC(C)(C)CC
Temperature: 25 °C

Procedure:
To a 1 liter round bottom flask equipped with a magnetic stirrer and water-cooled condenser was added 760 grams (0.5 mole) of a 9.1% aqueous solution of t-amylhydrazine hydrochloride, 78 grams (0.5 mole) of allyl levulinate and 40 grams (0.5 mole) of 50% sodium hydroxide. The flask was placed in an oil bath on a magnetic stirrer and the contents stirred and heated to reflux. The reaction was refluxed gently for 3 hours and allowed to cool to room temperature. The organic layer was separated, dried over anhydrous sodium sulfate and the drying agent removed by filtration. The yellow liquid product weighed 116 grams (96.5% crude yield). The infrared spectrum of the product contained a strong band at 1718 cm-1 (carbonyl) and a weak band at 1620 cm-1 (C=N) indicating that the hydrazone band had formed and the ester group was still intact.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]2[N:14]([CH2:27][CH2:28][CH2:29][N:30]3[CH2:35][CH2:34][N:33]([C:36]4[C:41]([N+:42]([O-])=O)=[CH:40][CH:39]=[CH:38][C:37]=4[Cl:45])[CH2:32][CH2:31]3)[N:15]=[C:16]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=3)[C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(O)(=O)C.C([O-])(O)=O.[Na+]>CO.C(Cl)Cl.[Zn]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]2[N:14]([CH2:27][CH2:28][CH2:29][N:30]3[CH2:35][CH2:34][N:33]([C:36]4[C:37]([Cl:45])=[CH:38][CH:39]=[CH:40][C:41]=4[NH2:42])[CH2:32][CH2:31]3)[N:15]=[C:16]([C:17]3[CH:18]=[CH:19][C:20]([C:23]([F:25])([F:26])[F:24])=[CH:21][CH:22]=3)[C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCc2c(c(-c3ccc(C(F)(F)F)cc3)nn2CCCN2CCN(c3c(Cl)cccc3[N+](=O)[O-])CC2)C1
Agent: O=C([O-])O
Agent: [Na+]
Agent: [Zn]
Solvent: CO
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCc2c(c(-c3ccc(C(F)(F)F)cc3)nn2CCCN2CCN(c3c(N)cccc3Cl)CC2)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 360 mg (0.56 mmol) of 1-{3-[4-(2-chloro-6-nitro-phenyl)-piperazin-1-yl]-propyl}-3-(4-trifluoromethyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester in 4 mL of MeOH was treated with 182 mg (5 eq) of zinc dust and glacial acetic acid (1.57 mL, 50 eq) at 25° C. The reaction mixture was stirred at 25° C. for 1 h. The reaction mixture was then filtered through a pad of celite and concentrated to obtain a thick oil. The residue was taken up in CH2Cl2 (50 mL) and sat. NaHCO3 (20 mL). The organic layer was separated, washed with H2O (2×10 mL), dried over Na2SO4, and concentrated to afford 1-{3-[4-(2-amino-6-chloro-phenyl)-piperazin-1-yl]-propyl}-3-(4-trifluoromethyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester. TLC (silica, 10% MeOH/CH2Cl2): Rf=0.3. MS (electrospray): exact mass calculated for C31H38ClF3N6O2, 618.27; m/z found, 619.3 [M+H]+.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[C:9]([C@@H:10]3[CH2:12][C@H:11]3[CH:13]=O)[C:4]=2[CH2:3][CH2:2]1.Cl.[NH2:16]O.[OH-].[Na+].[H-].[H-].[H-].[H-].[Li+].[Al+3].Cl>O.C(OCC)(=O)C.C1COCC1.C(O)C>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[C:9]([C@@H:10]3[CH2:12][C@H:11]3[CH2:13][NH2:16])[C:4]=2[CH2:3][CH2:2]1
Reactant: O=C[C@@H]1C[C@H]1c1cccc2c1CCO2
Reactant: NO
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCO
Product: NC[C@@H]1C[C@H]1c1cccc2c1CCO2
Temperature: 25 °C
Reaction time: 2 h
Yield: 31.7 %

Procedure:
A solution of (±)-(trans)-2-(2,3-dihydrobenzofuran-4-yl)-cyclopropane-carboxaldehyde (2.6 g, 15 mmol), hydroxylamine hydrochloride (3.13 g, 45 mmol), ethanol (60 mL), water (40 mL), and 10N NaOH (4.5 mL, 45 mmol) was heated to reflux for 4 h. The solution was cooled to room temperature, diluted with water and ethyl acetate. The ethyl acetate layer was separated and washed sequentially with H2O and brine. The ethyl acetate extract was dried over K2CO3 and concentrated in vacuo. The residue was dissolved in THF (50 mL) and added dropwise to a -45° C. suspension of LAH (1.06 g, 28 mmol) in THF (100 mL), maintaining the temperature below -40° C. The reaction was warmed to room temperature and stirred for 2 h. The reaction was recooled to -45° C., and 1N HCl (50 mL) was cautiously added dropwise. The cooling bath was removed and the suspension was stirred at room temperature for 30 min. The resulting paste was then diluted with ethyl ether and extracted with 1N HCl. The acid extracts were combined, washed with ethyl ether, made basic with 50% NaOH, and extracted with dichloromethane. The dichloromethane extracts were combined, washed with brine, dried over K2CO3, and concentrated in vacuo to give a clear oil (900 mg, 40%).
Reaction SMILES: [O:1]1[CH2:28][CH:2]1[CH2:3][N:4]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[N:5]=[CH:6][C:7]1[CH:8]=[CH:9][C:10]2[N:11]([CH2:20][CH3:21])[C:12]3C([C:18]=2[CH:19]=1)=CC=C[CH:13]=3.C1(NN=CC2C=CC3N(CC)C4C(C=3C=2)=CC=CC=4)C=CC=CC=1.C1(NN=CC2C=CC(N(CC)CC)=CC=2)C=CC=CC=1.C=O>>[O:1]1[CH2:28][CH:2]1[CH2:3][N:4]([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[N:5]=[CH:6][C:7]1[CH:19]=[CH:18][C:10]([N:11]([CH2:12][CH3:13])[CH2:20][CH3:21])=[CH:9][CH:8]=1
Reactant: CCn1c2ccccc2c2cc(C=NN(CC3CO3)c3ccccc3)ccc21
Agent: C=O
Agent: CCN(CC)c1ccc(C=NNc2ccccc2)cc1
Agent: CCn1c2ccccc2c2cc(C=NNc3ccccc3)ccc21
Product: CCN(CC)c1ccc(C=NN(CC2CO2)c2ccccc2)cc1

Procedure:
4-(Diethylamino)benzaldehyde N-2,3-epoxypropyl-N-phenylhydrazone was prepared according to the preparation procedure above for 9-ethyl-3-carbazolecarboxaldehyde N-2,3-epoxypropyl-N-phenylhydrazone except that 9-ethyl-3-carbazolecarboxaldehyde phenylhydrazone was replaced by 4-(diethylamino)benzaldehyde phenylhydrazone and the product was recrystallized from diethyl ether. The yield of 4-(diethylamino)benzaldehyde N-2,3-epoxypropyl-N-phenylhydrazone was 69%. The product had a melting point of 79–80.5° C. when recrystallized from diethyl ether. A 1H-NMR spectrum was obtained in CDCl3 with the following results (δ in ppm, 250 MHz): δ=7.7–6.7 (m, 8H, Ar, CH═N); δ=6.6 (d, 2H, 2-H, 6-H of p-Ph); δ=4.4–3.6 (m, 2H, NCH2CH); δ=3.6–3.0 (m, 5H, CH2CH3, CH2CHCH2); δ=2.75 (m, 1H, ABX, cis-HA of CH2O); δ=2.55 (m, ABX, trans-HB of CH2O); δ=1.1 (t, J=7.0 Hz, 6H, CH3). An elemental analysis found the following weight percents of the elements: C, 74.45; H, 7.84; N, 12.72, which compares with the following calculated elemental weight percent for a compound with the formula C20H25N3O of: C, 74.27; H, 7.79; N, 12.99.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH:14]([C:16]2[N:17]=[N:18][N:19]([CH2:21][C:22]3[C:27]([Cl:28])=[CH:26][CH:25]=[CH:24][C:23]=3[Cl:29])[CH:20]=2)[OH:15])=[CH:4][CH:3]=1.[CH2:30]([O:32][C:33]([C:35]1([C:38]2[CH:43]=[CH:42][C:41](B3OC(C)(C)C(C)(C)O3)=[CH:40][CH:39]=2)[CH2:37][CH2:36]1)=[O:34])[CH3:31]>>[CH2:30]([O:32][C:33]([C:35]1([C:38]2[CH:43]=[CH:42][C:41]([C:2]3[CH:7]=[CH:6][C:5]([C:8]4[O:12][N:11]=[C:10]([CH3:13])[C:9]=4[CH:14]([C:16]4[N:17]=[N:18][N:19]([CH2:21][C:22]5[C:23]([Cl:29])=[CH:24][CH:25]=[CH:26][C:27]=5[Cl:28])[CH:20]=4)[OH:15])=[CH:4][CH:3]=3)=[CH:40][CH:39]=2)[CH2:36][CH2:37]1)=[O:34])[CH3:31]
Reactant: CCOC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1C(O)c1cn(Cc2c(Cl)cccc2Cl)nn1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4C(O)c4cn(Cc5c(Cl)cccc5Cl)nn4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 1, Step 10, using [5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-[1-(2,6-dichloro-benzyl)-1H-[1,2,3]triazol-4-yl]-methanol and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester.
Reaction SMILES: [CH3:1][N:2]([CH3:53])[CH2:3][CH2:4][S:5]([NH:8][C:9]1[CH:14]=[C:13]([C:15]2[C:23]3[C:22]([NH:24][C@H:25]([C:27]4[N:32]([C:33]5[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=5)[C:31](=[O:39])[C:30]5=[C:40]([CH3:43])[CH:41]=[CH:42][N:29]5[N:28]=4)[CH3:26])=[N:21][CH:20]=[N:19][C:18]=3[N:17](COCC[Si](C)(C)C)[CH:16]=2)[CH:12]=[C:11]([OH:52])[CH:10]=1)(=[O:7])=[O:6].FC(F)(F)C(O)=O.N>>[CH3:53][N:2]([CH3:1])[CH2:3][CH2:4][S:5]([NH:8][C:9]1[CH:14]=[C:13]([C:15]2[C:23]3[C:22]([NH:24][C@H:25]([C:27]4[N:32]([C:33]5[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=5)[C:31](=[O:39])[C:30]5=[C:40]([CH3:43])[CH:41]=[CH:42][N:29]5[N:28]=4)[CH3:26])=[N:21][CH:20]=[N:19][C:18]=3[NH:17][CH:16]=2)[CH:12]=[C:11]([OH:52])[CH:10]=1)(=[O:6])=[O:7]
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc4c3c(-c3cc(O)cc(NS(=O)(=O)CCN(C)C)c3)cn4COCC[Si](C)(C)C)n(-c3ccccc3)c(=O)c12
Agent: N
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccn2nc([C@H](C)Nc3ncnc4[nH]cc(-c5cc(O)cc(NS(=O)(=O)CCN(C)C)c5)c34)n(-c3ccccc3)c(=O)c12
Yield: 39.8 %

Procedure:
(S)-2-(Dimethylamino)-N-(3-hydroxy-5-(4-((1-(5-methyl-4-oxo-3-phenyl-3,4-dihydropyrrolo[2,1-f][1,2,4]triazin-2-yl)ethyl)amino)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl)ethanesulfonamide (15 mg, 0.02 mmol, 77% purity) was treated with trifluoroacetic acid (300 μl, 3.89 mmol) and a solution of ammonia (7N in methanol, 300 μl, 2.10 mmol) according to the method described in Example 27. The residue was purified using SP1® Purification System (0% to 40% dichloromethane methanol) to obtain 5 mg (52% yield) of the title compound.
Reaction SMILES: C(=O)([O-])[O-:2].[Li+].[Li+].[Li].[O-2:8].[O-2].[O-2].[O-2].[Co+2:12].[Co+3].[Co+3].[V+5:15].[Co]>>[O-2:2].[O-2:8].[O-2:2].[O-2:2].[Co+2:12].[Co+3:12].[Co+3:12].[V:15].[Co:12]
Reactant: O=C([O-])[O-]
Reactant: [V+5]
Agent: [Co+2]
Agent: [Co+3]
Agent: [Co]
Product: [V]

Procedure:
For the starting material, lithium carbonate (Li2CO3) was used as a lithium source, and (Cu0.999V0 001)3O4 which was a composite of tricobalt tetraoxide and vanadium (V) was used as a cobalt source. The composite of tricobalt tetraoxide and vanadium was obtained such that cobalt dissolved in an acid solution and vanadium were precipitated as a composite hydroxide and then were calcined at 300° C. Next, the lithium carbonate and the composite of tricobalt tetraoxide and vanadium were weighed out such that the molar ratio of Li to (Co+V) was 1, and there was then added MgF2 such that the fluorine content in the total amount of positive electrode active material was 0.01 mass %, and then the mixture was mixed. Subsequently, the mixture was calcined in an air atmosphere to obtain a calcined product of LiCo0.999V0 001O2 of a hexagonal crystal system containing fluorine and magnesium, and then the calcined product was ground in a mortar to an average particle size of 10 μm, thereby obtaining a positive electrode active material.
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32](Cl)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:35][CH2:36][CH3:37])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:38][N:39]1[CH2:44][CH2:43][N:42]([CH:45]2[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]2)[CH2:41][CH2:40]1>>[C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:48]3[CH2:47][CH2:46][CH:45]([N:42]4[CH2:41][CH2:40][N:39]([CH3:38])[CH2:44][CH2:43]4)[CH2:50][CH2:49]3)=[O:33])[C@@:13]([C:25]3[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=3)([CH3:24])[C@@:14]([C:17]3[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=3)([CH3:16])[N:15]=2)=[C:7]([O:35][CH2:36][CH3:37])[CH:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CN1CCN(C2CCNCC2)CC1
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)Cl
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(N2CCN(C)CC2)CC1

Procedure:
In a manner analogous to the method described in examples 8, (4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride (example 51) was coupled with 1-methyl-4-piperidin-4-yl-piperazine (Oakwood) to give the title compound. HR-MS (ES, m/z) calculated for C39H51Cl2N6O2 [(M+H)+] 705.3445, observed 705.3445.