Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][C:10]2[CH:15]=[C:14]([O:16]C)[C:13]([O:18]C)=[C:12]([O:20][CH3:21])[CH:11]=2)=[CH:4][CH:3]=1.O>C(Cl)Cl>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([S:8][CH2:9][C:10]2[CH:11]=[C:12]([O:20][CH3:21])[C:13]([OH:18])=[C:14]([OH:16])[CH:15]=2)=[CH:6][CH:7]=1
Reactant: COc1cc(CSc2ccc(O)cc2)cc(OC)c1OC
Solvent: O
Solvent: ClCCl
Product: COc1cc(CSc2ccc(O)cc2)cc(O)c1O
Temperature: -78 °C
Reaction time: 2 h
Yield: 77 %

Procedure:
3,4,5-Trimethoxybenzyl 4-hydroxyphenyl thioether (3g, 9.8 mmol) prepared as described in Example 1 was dissolved in 60 ml of dry methylene chloride, and cooled to -78° C. Then 2.8 ml (29.5 mmol) of borontribromide in 10 ml of methylene chloride was added dropwise to the above solution. After stirring for 2 hr, the solution was warmed to room temperature, and stirred for another 2 hr (monitored by TLC). Then, the reaction mixture was cooled to 0° C., and added dropwise 50 ml of water. The methylene chloride layer was separated. The crude product, obtained after drying over magnesium sulfate and concentration, was purified on silica gel column chromatography (ethyl acetate/n-hexane=2:1). 3,4-Dihydroxy-5-methoxybenzyl 4-hydroxyphenyl thioether (2.1 g, 77% yield) was obtained as a light yellow solid.
Reaction SMILES: C=O.[C:3](O)(=O)C.[NH:7]1[CH2:12][CH2:11][O:10][CH:9]([C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=2)[CH2:8]1>CO>[CH3:3][N:7]1[CH2:12][CH2:11][O:10][CH:9]([C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=2)[CH2:8]1
Reactant: Oc1ccc(C2CNCCO2)cc1
Reactant: CC(=O)O
Agent: C=O
Solvent: CO
Product: CN1CCOC(c2ccc(O)cc2)C1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 92.4 %

Procedure:
A 36% aqueous formaldehyde solution (20.1 mg, 2.51 mmol), 0.029 ml (0.502 mmol) of acetic acid, and 53.2 mg (0.251 mmol) of triacetoxysodium borohydride were successively added to a solution of 15 mg (0.084 mmol) of the title compound produced in step (iv) of Reference Example 12 in methanol (0.7 ml), and the mixture was stirred at room temperature for 15 min. Thereafter, the reaction solution was purified by preparative thin layer chromatography (chloroform:methanol:28% aqueous ammonia=9:2:0.2) to give 15 mg (yield 93%) of the title compound.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][CH:8]1[CH2:13][N:12]2[N:14]=[C:15]([CH2:17][O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:16]=[C:11]2[C:10](=O)[NH:9]1>C1COCC1.CCOC(C)=O>[CH3:7][CH:8]1[CH2:13][N:12]2[N:14]=[C:15]([CH2:17][O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:16]=[C:11]2[CH2:10][NH:9]1
Reactant: CC1Cn2nc(COc3ccccc3)cc2C(=O)N1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC1Cn2nc(COc3ccccc3)cc2CN1
Temperature: 25 °C
Reaction time: 60 h
Yield: 95.3 %

Procedure:
A 1M solution of lithium aluminum hydride in THF (2.14 mL, 2.14 mmol) was added dropwise to a stirred solution of rac-6-methyl-2-phenoxymethyl-6,7-dihydro-5H-pyrazolo[1,5-a]pyrazin-4-one (0.5 g, 1.94 mmol) in THF (12 mL) under N2 at 0° C. The reaction mixture was stirred at room temperature for 2.5 days and diluted with AcOEt. Na2SO4.10H2O was added at 0° C. and the mixture stirred for 15 minutes at 0° C., filtered through a pad of diatomaceous earth and then washed with additional AcOEt. The solvents were evaporated in vacuo to yield rac-6-methyl-2-phenoxymethyl-4,5,6,7-tetrahydro-pyrazolo[1,5-a]pyrazine (0.45 g, 84% yield) as an oil that crystallized upon standing, and that was used in the next step without further purification.
Reaction SMILES: [F:1][C:2]([F:30])=[C:3]([F:29])[C:4]([F:28])([F:27])[O:5][C:6]([F:26])([F:25])[C:7]([F:24])([F:23])[C:8]([F:22])([F:21])[O:9][C:10]1[C:15]([F:16])=[C:14]([F:17])[C:13]([F:18])=[C:12]([F:19])[C:11]=1[F:20].O=O.S([O-])([O-])(=O)=[O:34].[Ca+2]>C(C(Cl)(F)F)(Cl)(Cl)F>[F:30][C:2]1([F:1])[O:34][C:3]1([F:29])[C:4]([F:27])([F:28])[O:5][C:6]([F:26])([F:25])[C:7]([F:23])([F:24])[C:8]([F:21])([F:22])[O:9][C:10]1[C:11]([F:20])=[C:12]([F:19])[C:13]([F:18])=[C:14]([F:17])[C:15]=1[F:16]
Reactant: O=S(=O)([O-])[O-]
Reactant: FC(F)=C(F)C(F)(F)OC(F)(F)C(F)(F)C(F)(F)Oc1c(F)c(F)c(F)c(F)c1F
Agent: O=O
Agent: [Ca+2]
Solvent: FC(F)(Cl)C(F)(Cl)Cl
Product: Fc1c(F)c(F)c(OC(F)(F)C(F)(F)C(F)(F)OC(F)(F)C2(F)OC2(F)F)c(F)c1F
Temperature: 0 °C
Yield: 31 %

Procedure:
A 100-ml metal tube lined with stainless steel and charged with 105.3 g (0.22 mol) of perfluoro(7-phenoxy-4-oxa-1-heptene) was heated at 140° while oxygen was pressured in intermittently until no pressure drop was observed. The liquid product mixture was fractionated to afford 78.5 g of distillate, bp 37°-70° (3 min). The distillate was shaken with 1 liter of ice water, and then 25 ml of CFCl2CF2Cl and some calcium sulfate were added to hasten separation. The lower layer was dried over calcium sulfate and fractionated to give 33.3 g (31%) of perfluoro(7-phenoxy-1,2-epoxy-4-oxaheptane), bp 55° (1.9 mm). IR (CCl4): 6.47 (epoxide ring), 6.58 (aromatic C=C), 8-9μ (CF, C-O). NMR (CCl4): 19F -84.1 (m, 2F, OCF2), -84.6 (m, 2F, OCF2), -129.0 (s, 2F, CF2), -151.8 (m, 2F, arom. CF), -155.1 (t, JFF 21.0 Hz, 1F, arom. CF), -156.6 (t, JFF 17.9 Hz, 1F, ring CF), and -161.7 ppm (m, 2F, arom. CF), with AB groupings at -7382, -7534, -7566, and -7719 Hz (m, 2F) for CF2 adjacent to epoxide ring and at -10381 and -10424 Hz (d of t, JFF 18.8, 9.8 Hz, 1F) and --10600 and -10642 Hz (d, JFF 17.3 Hz, 1F) for epoxide CF2.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[CH:5][C:6]([S:11][CH3:12])=[C:7]([CH2:9][NH2:10])[CH:8]=1.C(N(CC)CC)C.C(OC(OC(C)(C)C)=O)(OC(C)(C)C)=[O:21].Cl>O1CCCC1>[ClH:2].[Cl:2][C:3]1[CH:4]=[CH:5][C:6]([S:11]([CH3:12])=[O:21])=[C:7]([CH2:9][NH2:10])[CH:8]=1
Reactant: CSc1ccc(Cl)cc1CN
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CS(=O)c1ccc(Cl)cc1CN
Reaction time: 2 h
Yield: 139.2 %

Procedure:
(Step 3) To a solution of 1-[5-chloro-2-(methylsulfanyl)phenyl]methanamine hydrochloride obtained in Step 2 (5.11 g) and triethylamine (4.61 g) in tetrahydrofuran (150 ml) was added di-t-butyl dicarbonate (6.47 g) at room temperature. The mixture was stirred at the same temperature for 2 hr, treated with 1N hydrochloric acid, and extracted with ethyl acetate. The extract was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was dissolved in ethyl acetate (200 ml), and m-chloroperbenzoic acid (5.62 g, containing water: Wako Pure Chemical Industries, Ltd.) was added at 0° C. The mixture was stirred at the same temperature for 2 hr, and treated with aqueous sodium hydrogen carbonate solution. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by basic silica gel column chromatography (ethyl acetate:hexane=2:1). The obtained residue was dissolved in methanol (100 ml), and 4N hydrogen chloride-ethyl acetate solution (10 ml) was added. The mixture was stirred at 60° C. for 30 min, and concentrated under reduced pressure to give 1-[5-chloro-2-(methylsulfinyl)phenyl]methanamine hydrochloride (3.81 g) as a solid.
Reaction SMILES: [C:1]([CH:3]=[CH:4][C:5]1[CH:14]=[CH:13][CH:12]=[CH:11][C:6]=1[C:7]([O:9][CH3:10])=[O:8])#[N:2].FC(F)(F)C(O)=O.[CH2:22]([N:29]([CH2:33][Si](C)(C)C)[CH2:30]OC)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>ClCCl>[CH2:22]([N:29]1[CH2:30][C@@H:3]([C:1]#[N:2])[C@H:4]([C:5]2[CH:14]=[CH:13][CH:12]=[CH:11][C:6]=2[C:7]([O:9][CH3:10])=[O:8])[CH2:33]1)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: COC(=O)c1ccccc1C=CC#N
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)c1ccccc1[C@@H]1CN(Cc2ccccc2)C[C@H]1C#N

Procedure:
In a 50 mL round bottom flask were combined methyl 2-(2-cyanovinyl)benzoate (Example 1A, 11.03 g, 58.9 mmol) trifluoroacetic acid (0.045 mL, 0.589 mmol) and dichloromethane (100 mL). N-Benzyl-1-methoxy-N-((trimethylsilyl)methyl)methanamine (64.8 mmol) was added as a solution in dichloromethane (100 mL) dropwise over 15 minutes while stirring under argon. The reaction was stirred at room temperature for 20 hours, then quenched with aqueous sodium bicarbonate and extracted with dichloromethane. The organic washes were combined and washed with brine, dried over Na2SO4, filtered, and the solvent was removed in vacuo to provide the crude product. The mixture of isomers was added to a silica gel column and was eluted with ethyl acetate/hexanes (gradient 0-20%, 40 minutes) to provide the title compound as the faster eluting (less polar) isomer. 1H NMR (500 MHz, CDCl3) δ ppm 2.82 (dd, 1H, J=9.09 Hz, J=7.81 Hz), 2.88 (dd, 1H, J=9.74 Hz, J=4.27 Hz), 2.99-3.03 (m, 1H), 3.05-3.09 (m, 1H), 3.29 (t, 1H, J=8.37 Hz), 3.71 (m, 2H), 3.94 (s, 3H), 4.51 (ddd, 1H, J=8.29 Hz, J=6.36 Hz, J=4.35 Hz), 7.25-7.40 (m, 6H), 7.50 (dt, 1H, J=7.65 Hz, J=1.45 Hz), 7.62 (d, 1H, J=7.24 Hz), 7.81 (dd, 1H, J=7.89 Hz, J=1.29 Hz); MS (DCI+) m/z 321.2 [M+H]+.
Reaction SMILES: Br[CH2:2][C:3]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][C:4]=1[C:5]([O:7]CC)=O.[CH:17]([C:20]1[CH:26]=[CH:25][C:23]([NH2:24])=[CH:22][CH:21]=1)([CH3:19])[CH3:18].C(N(CC)C(C)C)(C)C>C(O)C>[CH:17]([C:20]1[CH:26]=[CH:25][C:23]([N:24]2[CH2:2][C:3]3[C:4](=[CH:10][C:11]([N+:14]([O-:16])=[O:15])=[CH:12][CH:13]=3)[C:5]2=[O:7])=[CH:22][CH:21]=1)([CH3:19])[CH3:18]
Reactant: CCOC(=O)c1cc([N+](=O)[O-])ccc1CBr
Reactant: CC(C)c1ccc(N)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: CC(C)c1ccc(N2Cc3ccc([N+](=O)[O-])cc3C2=O)cc1
Temperature: 110 °C
Yield: 75.1 %

Procedure:
A mixture of ethyl 2-(bromomethyl)-5-nitrobenzoate (1.88 g, 6.52 mmol), 4-isopropylaniline (1.11 mL, 7.83 mmol) and N,N-diisopropylethylamine (1.36 mL, 7.83 mmol) in ethanol (75 mL) was heated in a sealed tube at 110° C. overnight. After this time, the mixture was cooled to room temperature and the solid collected by filtration to afford 2-(4-isopropylphenyl)-6-nitroisoindolin-1-one (1.45 g, 75%) as a yellow solid: mp 225-227° C.; 1H NMR (300 MHz, CDCl3) δ 8.77 (d, J=2.0 Hz, 1H) 8.48 (dd, J=8.3, 2.1 Hz, 1H), 7.76-7.69 (m, 3H), 7.32 (d, J=8.6 Hz, 2H), 2.94 (sept, J=6.9 Hz, 1H), 1.28 (d, J=6.9 Hz, 6H); ESI MS m/z 297 [M+H]+.
Reaction SMILES: [OH2:1].Cl[C:3]1[C:13]([N+:14]([O-:16])=[O:15])=[CH:12][CH:11]=[C:10]([Cl:17])[C:4]=1[C:5]([N:7]([CH3:9])[CH3:8])=[O:6].[H-].[Na+].Cl>O1CCCC1>[Cl:17][C:10]1[C:4]([C:5]([N:7]([CH3:9])[CH3:8])=[O:6])=[C:3]([OH:1])[C:13]([N+:14]([O-:16])=[O:15])=[CH:12][CH:11]=1
Reactant: CN(C)C(=O)c1c(Cl)ccc([N+](=O)[O-])c1Cl
Reactant: O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN(C)C(=O)c1c(Cl)ccc([N+](=O)[O-])c1O
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 59.4 %

Procedure:
3.2 ml (177.6 mmol, 4.2 eq) of water and 11.04 g (41.96 mmol; 1.0 eq) of 2,6-dichloro-N,N-dimethyl-3-nitrobenzamide (41.96 mmol; 1.00 eq.) in solution in 130.00 ml of tetrahydrofuran were added to a suspension of 7.16 g (179.01 mmol; 4.3 eq) of sodium hydride in 250 ml of tetrahydrofuran cooled to 0° C. After 10 minutes, the reaction medium was stirred at ambient temperature for 19 hours. The reaction medium was hydrolyzed with a 1 N aqueous hydrochloric acid solution and extracted with ethyl acetate. The organic phase was washed with a 1 N aqueous hydrochloric acid solution, dried over anhydrous sodium sulfate, filtered and concentrated. The residue (11.82 g) was chromatographed on silica gel (300 g prepacked column, eluent heptane/ethyl acetate from 40 to 80% of ethyl acetate, 150 ml/min). 6.10 g of 6-chloro-2-hydroxy-N,N-dimethyl-3-nitrobenzamide were obtained in the form of a yellow solid. Yield=59%.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][CH2:11][C:12](O)=O)=[CH:2]1.O.ON1C2C=CC=CC=2N=N1.C(N=C=NC(C)C)(C)C.Cl.[OH:36][C:37]1[CH:38]=[CH:39][C:40]2[O:45][CH2:44][C@H:43]([CH2:46][NH2:47])[O:42][C:41]=2[CH:48]=1>CN(C=O)C>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][CH2:11][CH2:12][NH:47][CH2:46][CH:43]2[CH2:44][O:45][C:40]3[CH:39]=[CH:38][C:37]([OH:36])=[CH:48][C:41]=3[O:42]2)=[CH:2]1
Reactant: NC[C@H]1COc2ccc(O)cc2O1
Reactant: O=C(O)CCc1c[nH]c2ccccc12
Agent: CC(C)N=C=NC(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: Oc1ccc2c(c1)OC(CNCCCc1c[nH]c3ccccc13)CO2
Temperature: 25 °C
Reaction time: 2 h
Yield: 59.9 %

Procedure:
3-Indolepropionic acid (1.4 g, 7.4 mmole), 1-hydroxybenzotriazole hydrate (1.2 g, 8.9 mmole) and 1,3-diisopropylcarbodiimide (2.8 ml, 17.8 mmole) were combined in 100 ml of DMF and stirred at room temperature for 2 hours under a nitrogen atmosphere. To this was added dropwise (S)-7-hydroxy-2,3-dihydro-1,4-benzodioxin-2-methanamine hydrochloride (1.6 g, 7.4 mmole) in 50 ml of DMF and the mixture was further stirred for 24 hours. The solvent was removed and the residue partitioned between dichloromethane and water. The separated dichloromethane layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuum. The residue was chromatographed on a silica gel column using ethyl acetate as the eluant. Fractions containing product were concentrated and washed with a minimum amount of THF to remove a by-product and to give 1.5 g (60%) of the desired product, (S)-(7-hydroxy-2,3-dihydro-benzo[1,4]dioxin-2-ylmethyl)-4-(1H-indol-3-yl)-propanamide, as a white fluffy solid.
Reaction SMILES: [P:1]([O:38]C(C)(C)C)([O:33]C(C)(C)C)([O:3][CH2:4][CH:5]1[O:9][N:8]=[C:7]([C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][C:19]([N:22]4[CH2:26][C@H:25]([CH2:27][NH:28][C:29](=[O:31])[CH3:30])[O:24][C:23]4=[O:32])=[CH:18][CH:17]=3)=[CH:12][CH:11]=2)[CH2:6]1)=[O:2].FC(F)(F)C(O)=O>ClCCl>[P:1]([OH:33])([OH:38])([O:3][CH2:4][CH:5]1[O:9][N:8]=[C:7]([C:10]2[CH:11]=[CH:12][C:13]([C:16]3[CH:17]=[CH:18][C:19]([N:22]4[CH2:26][C@H:25]([CH2:27][NH:28][C:29](=[O:31])[CH3:30])[O:24][C:23]4=[O:32])=[CH:20][CH:21]=3)=[CH:14][CH:15]=2)[CH2:6]1)=[O:2]
Reactant: CC(=O)NC[C@H]1CN(c2ccc(-c3ccc(C4=NOC(COP(=O)(OC(C)(C)C)OC(C)(C)C)C4)cc3)cc2)C(=O)O1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(=O)NC[C@H]1CN(c2ccc(-c3ccc(C4=NOC(COP(=O)(O)O)C4)cc3)cc2)C(=O)O1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
[3-(4′-{(5S)-5-[(Acetylamino)methyl]-2-oxo-1,3-oxazolidin-3-yl}-1,1′-biphenyl-4-yl)-4,5-dihydroisoxazol-5-yl]methyl di-tert-butyl phosphate (95 mg, 0.16 mmol) was dissolved in dichloromethane (1 ml) and trifluoroacetic acid (0.1 ml) was added. The solution was stirred for 1 h at ambient temperature, then concentrated in vacuo. Dichloromethane was added and the volatiles were removed in vacuo. This was repeated twice with dichloromethane and five times with diethyl ether. A pale yellow solid was obtained (78 mg) corresponding to the desired product.
Reaction SMILES: C(O[C:4]1[CH2:9][CH2:8][CH2:7][C:6](=[O:10])[CH:5]=1)C.[CH2:11]([Mg]Br)[CH3:12]>C(OCC)C.C(O[Ti](OC(C)C)(OC(C)C)OC(C)C)(C)C>[CH2:11]1[C:4]2([CH2:9][CH2:8][CH2:7][C:6](=[O:10])[CH2:5]2)[CH2:12]1
Reactant: CCOC1=CC(=O)CCC1
Reactant: CC[Mg]Br
Agent: CC(C)O[Ti](OC(C)C)(OC(C)C)OC(C)C
Solvent: CCOCC
Product: O=C1CCCC2(CC2)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
3-Ethoxycyclohex-2-enone (25 g) was dissolved in diethyl ether (500 mL), and tetraisopropoxytitanium (55 mL) was added, followed by the addition of ethyl magnesium bromide (3.0M in diethyl ether, 180 mL) over 30 minutes. The reaction was stirred at room temperature for another two hours, and quenched by the careful addition of water (250 mL). The mixture was filtered through diatomaceous earth, and rinsed with diethyl ether. The filtrate was transferred to a separatory funnel, the aqueous layer was drawn off, and p-toluenesulfonic acid monohydrate (2 g) was added to the organic layer, which was stirred at room temperature for two days. The reaction mixture was washed with saturated aqueous NaHCO3 and brine, then dried over Na2SO4. The mixture was filtered, and concentrated and chromatography on silica gel using 93/7 hexanes/ethyl acetate provided the title compound.
Reaction SMILES: [Br-:1].[Br-].[Br-].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[NH:22]1[C:30]2[CH2:29][CH2:28][CH2:27][C:26](=[O:31])[C:25]=2[CH:24]=[N:23]1>C(O)(=O)C>[Br:1][CH:27]1[CH2:28][CH2:29][C:30]2[NH:22][N:23]=[CH:24][C:25]=2[C:26]1=[O:31]
Reactant: O=C1CCCc2[nH]ncc21
Reactant: [Br-]
Agent: c1cc[nH+]cc1
Solvent: CC(=O)O
Product: O=C1c2cn[nH]c2CCC1Br
Yield: 90.7 %

Procedure:
According to Scheme 1 Step 3: Pyridinium tribromide (25.7 mmol, 8.22 g) was added to a solution of 6,7-dihydro-1H-indazol-4(5H)-one (25.7 mmol, 3.50 g) in acetic acid (60 mL) and the reaction mixture was stirred under reflux for 2 hours. After evaporation of the solvent, the crude residue was partitioned between DCM and a saturated solution of Na2S2O3. The organic phase was washed with a saturated solution of Na2CO3 and with water, was dried over Na2SO4 and concentrated to yield 5-bromo-6,7-dihydro-1H-indazol-4(5H)-one (23.3 mmol, 5.00 g, 90%).
Reaction SMILES: Cl.[OH:2][CH:3]1[CH2:8][CH2:7][CH2:6][NH:5][CH2:4]1.[CH2:9](Cl)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH2:9]([N:5]1[CH2:6][CH2:7][CH2:8][CH:3]([OH:2])[CH2:4]1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: OC1CCCNC1
Reactant: ClCc1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: OC1CCCN(Cc2ccccc2)C1
Yield: 56.6 %

Procedure:
A mixture of 15.0 g of 3-hydroxypiperidine hydrochloride, 13.8 g of benzyl chloride, 22.1 g of triethylamine and 120 ml of toluene was stirred at reflux for 4 hours. The reaction mixture was filtered, and the filtrate was concentrated and distilled under reduced pressure to obtain 11.8 g of 1-benzyl-3-hydroxypiperidine (yield: 56.9%). b.p.: 125°-126° C./3.5 mmHg
Reaction SMILES: CC(C[Al]CC(C)C)C.[C:10]([O:14][C:15]([NH:17][CH:18]1[CH2:23][CH2:22][CH2:21][N:20]([C:24]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[O:25])[CH:19]1[CH2:34][C:35](OCC)=[O:36])=[O:16])([CH3:13])([CH3:12])[CH3:11].O>C1(C)C=CC=CC=1>[C:10]([O:14][C:15]([NH:17][CH:18]1[CH2:23][CH2:22][CH2:21][N:20]([C:24]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[O:25])[CH:19]1[CH2:34][CH2:35][OH:36])=[O:16])([CH3:13])([CH3:12])[CH3:11]
Reactant: CCOC(=O)CC1C(NC(=O)OC(C)(C)C)CCCN1C(=O)OCc1ccccc1
Agent: CC(C)C[Al]CC(C)C
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)(C)OC(=O)NC1CCCN(C(=O)OCc2ccccc2)C1CCO
Temperature: -78 °C
Yield: 67.4 %

Procedure:
1.0 M of a solution (3.15 mL) of Dibal-H in toluene was added dropwise to the compound 13 (440 mg) and toluene (8 mL) with stirring at −78° C. The reaction mixture was stirred at room temperature for 3 hours and then added water at 0° C. Generated salt was removed by filtration with Celite (trade name) and then the filtrate was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and then concentrated. The obtained residue was dissolved in methanol (2 mL) and then sodium borohydride (40 mg) was added into the solution. The reaction solution was stirred at room temperature for 20 minuets, added water and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, concentrated and obtained the title compound (267 mg) having the following physical properties.
Reaction SMILES: [CH3:1][CH:2]([CH3:14])[CH2:3][CH:4]=[C:5]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH:6]=O.[Cl-].[OH:16][NH3+:17].C(=O)([O-])[O-].[Na+].[Na+]>C(O)C.O>[CH3:1][CH:2]([CH3:14])[CH2:3][CH:4]=[C:5]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH:6]=[N:17][OH:16]
Reactant: [NH3+]O
Reactant: CC(C)CC=C(C=O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CC(C)CC=C(C=NO)c1ccccc1
Yield: 74.7 %

Procedure:
To a solution of 5-methyl-2-phenyl-2-hexenal (5.0 g, 27 mmol) and hydroxylammonium chloride (3.7 g, 53 mmol) in a mixture of 96% ethanol (20 ml) and water (5 ml) was carefully added a solution of sodium carbonate (11.2 g, 106 mmol) in water (30 ml). The resulting mixture was stirred for 2h, the precipitated compound was filtered off and suspended in dichloromethane (500 ml). The suspension was filtered and the solvent evaporated from the filtrate in vacuo to give 4.1 g of 5-methyl-2-phenyl-2-hexenal oxime.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([C:13]3[CH:18]=[CH:17][N:16]=[C:15]([C:19]#[N:20])[CH:14]=3)=[CH:11][NH:10][N:9]=2)=[CH:4][CH:3]=1.OO.C(=O)([O-])[O-:24].[K+].[K+].O>CS(C)=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]([C:13]3[CH:18]=[CH:17][N:16]=[C:15]([C:19]([NH2:20])=[O:24])[CH:14]=3)=[CH:11][NH:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: N#Cc1cc(-c2c[nH]nc2-c2ccc(F)cc2)ccn1
Agent: OO
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: NC(=O)c1cc(-c2c[nH]nc2-c2ccc(F)cc2)ccn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 283.4 %

Procedure:
To a solution of 4-[3-(4-fluorophenyl)-1H-pyrazol-4-yl]-2-pyridinecarbonitrile from step 2 (0.45 g, 0.0017 mol) in 10 mL of DMSO was added hydrogen peroxide (0.24 mL of 30% aqueous solution, 1.7 mmol) and potassium carbonate (0.04 g, 0.4 mmol) at 0° C. The mixture was stirred for 1 hour while allowing it to warm to room temperature. Water was added and the precipitate was collected by filtration and air-dried to give 0.32 g of 4-[3-(4-fluorophenyl)-1H-pyrazol-4-yl]-2-pyridinecarboxamide as a white solid (67% yield), mp: 230-231° C. Anal. Calc'd for C15H11FN4O: C, 63.83; H, 3.93; N, 19.85. Found C, 63.42; H, 3.66; N, 19.58.
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[CH:12][C:5]([C:6](N(OC)C)=[O:7])=[C:4]([F:14])[CH:3]=1.[CH3:15]COCC.C[Mg+].[Br-]>C(Cl)Cl>[Cl:1][C:2]1[CH:13]=[CH:12][C:5]([C:6](=[O:7])[CH3:15])=[C:4]([F:14])[CH:3]=1
Reactant: CON(C)C(=O)c1ccc(Cl)cc1F
Reactant: CCOCC
Agent: C[Mg+]
Agent: [Br-]
Solvent: ClCCl
Product: CC(=O)c1ccc(Cl)cc1F
Temperature: 25 °C

Procedure:
To a solution of the above benzamide (1 eq) in CH2Cl2 (0.5 M) at 0° C. was added 3M/Et2O MeMgBr (1.25 eq). The reaction mixture was slowly warmed to rt over a 2 hrs period, quenched with 0.5 M aqueous citric acid and extracted with Et2O. The combined organic layers were washed with brine, dried over MgSO4 and concentrated. The residue was purified by flash chromatography on silica gel eluted with 20% EtOAc/hexane to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([N:8]2[CH2:13][CH2:12][NH:11][C@@H:10]([CH3:14])[CH2:9]2)=[C:4]2[CH:15]=[N:16][CH:17]=[CH:18][C:3]=12.[C:19](Cl)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(N(CC)CC)C.C(=O)(O)[O-].[Na+].[OH-].[Na+]>ClCCl>[Cl:1][C:2]1[N:7]=[N:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:19]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[O:26])[C@@H:10]([CH3:14])[CH2:9]2)=[C:4]2[CH:15]=[N:16][CH:17]=[CH:18][C:3]=12
Reactant: C[C@H]1CN(c2nnc(Cl)c3ccncc23)CCN1
Reactant: O=C(Cl)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@H]1CN(c2nnc(Cl)c3ccncc23)CCN1C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 79.3 %

Procedure:
To (S)-1-chloro-4-(3-methylpiperazin-1-yl)pyrido[3,4-d]pyridazine 4 (0.190 g, 0.720 mmol) in dichloromethane (3 ml) was added benzoyl chloride (0.0920 ml, 0.792 mmol) and triethylamine (0.220 ml, 1.58 mmol). The reaction was stirred at 25° C. After 2 h, the reaction contents were poured into saturated sodium bicarbonate (6 mL). The aqueous layer was brought to pH 11 with 5 N NaOH and extracted with 10% methanol in dichloromethane (3×15 mL). Silica gel chromatography (gradient elution 30 to 60% EtOAc in hexanes with 2.5% TEA additive) afforded 210 mg of (S)-(4-(1-chloropyrido[3,4-d]pyridazin-4-yl)-2-methylpiperazin-1-yl)(phenyl)methanone 5. 1H NMR (CDCl3) δ 9.55 (s, 1H), 9.08 (d, J=5.9 Hz, 1H), 8.00 (d, J=5.1 Hz, 1H) 7.41-7.51 (m, 5H) 4.70 (m, 1H), 4.02 (app d, J=11.7 Hz, 1H), 3.86 (app d, J=12.1 Hz, 1H) 3.62-3.72 (m, 1H), 3.47 (dd, J=13.1, 3.3 Hz, 1H), 3.30 (td, J=12.6, 3.3 Hz, 1H), 1.61 (bs, 1H), 1.57 (d, J=6.3 Hz, 3H).