Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([CH3:9])[CH:3]=1.[CH3:10][NH:11][CH2:12][CH2:13][OH:14]>Cl.O>[CH3:8][C:6]1[CH:7]=[C:2]([N:11]([CH2:12][CH2:13][OH:14])[CH3:10])[CH:3]=[C:4]([CH3:9])[N:5]=1
Reactant: CNCCO
Reactant: Cc1cc(Cl)cc(C)n1
Agent: Cl
Solvent: O
Product: Cc1cc(N(C)CCO)cc(C)n1
Yield: 88.8 %

Procedure:
A solution of 4-chloro-2,6-dimethylpyridine (849 mg, 6 mmol), (J. Het. Chem. 1990, 1841), in 2-(methylamino)ethanol (1.35 g, 18 mmol) and 3M ethereal hydrogen chloride (3 drops) was heated at 140° C. for 1 hour. The reaction mixture was allowed to cool and was diluted with water. The insolubles were removed by filtration and the aqueous filtrate was poured onto a suspension of magnesium sulphate (50 g) in ethyl acetate (100 ml). The insolubles were removed by filtration and the filtrate dried (MgSO4) and the solvent removed by evaporation. The solid residue was triturated with ether, collected by filtration and dried under vacuum at 50° C. to give 2-(N-(2,6-dimethyl-4-pyridyl)-N-methylamino)ethanol (960 mg, 90%).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:20]Br.O[CH2:23][C:24]1[C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=2[O:26][CH:25]=1>C(Cl)(Cl)(Cl)Cl>[Br:20][CH2:23][C:24]1[C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=2[O:26][CH:25]=1
Reactant: OCc1coc2ccccc12
Reactant: BrBr
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClC(Cl)(Cl)Cl
Product: BrCc1coc2ccccc12
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 81.7 %

Procedure:
To a stirring solution of 912 mg (3.48 mmol, 1.2 equiv) of triphenylphosphine in 5 mL of CCl4 at 0° C. is added 165 μL (3.19 mmol, 1.1 equiv) of Br2. The resulting orange-yellow suspension is stirred 10 min at 0° C., then a solution of 430 mg (2.90 mmol) of 3-hydroxymethylbenzofuran, prepared as in Intermediate 19, in 5 mL of CCl4 is added over 2 min. The resulting solution is stirred 1.5 h at RT, and the solvent is removed in vacuo. Purification of the residue by silica gel flash column chromatography using hexane/EtOAc 20/1 as eluent afforded 500 mg of the title compound as a clear, colorless oil: 1H NMR (CDCl3, 300 MHz) δ7.71 (m, 2H), 7.50 (m, 1H), 7.37 (m, 2H), 4.62 (s, 2H); Rf =0.67 in hexane/EtOAc 5/1.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:20][O:21][CH2:22][CH3:23])[N:14]([CH2:15][C:16]([CH3:19])([OH:18])[CH3:17])[C:10]=2[C:9]2[N:8]=[CH:7][C:6](Br)=[CH:5][C:4]=2[N:3]=1.[N:25]1([C:30]([C:32]2[CH:33]=[C:34](B(O)O)[CH:35]=[CH:36][CH:37]=2)=[O:31])[CH2:29][CH2:28][CH2:27][CH2:26]1.C(=O)([O-])[O-].[K+].[K+].COCCOC>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:20][O:21][CH2:22][CH3:23])[N:14]([CH2:15][C:16]([CH3:19])([OH:18])[CH3:17])[C:10]=2[C:9]2[N:8]=[CH:7][C:6]([C:36]3[CH:35]=[CH:34][CH:33]=[C:32]([C:30]([N:25]4[CH2:26][CH2:27][CH2:28][CH2:29]4)=[O:31])[CH:37]=3)=[CH:5][C:4]=2[N:3]=1
Reactant: O=C(c1cccc(B(O)O)c1)N1CCCC1
Reactant: CCOCc1nc2c(N)nc3cc(Br)cnc3c2n1CC(C)(C)O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: CCOCc1nc2c(N)nc3cc(-c4cccc(C(=O)N5CCCC5)c4)cnc3c2n1CC(C)(C)O
Temperature: 110 °C
Yield: 27.5 %

Procedure:
A suspension of 1-[4-amino-7-bromo-2-(ethoxymethyl)-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl]-2-methylpropan-2-ol (1.2 g, 3.0 mmol), (3-pyrrolidinylcarbonylphenyl)boronic acid (0.800 g, 3.65 mmol), potassium carbonate (1.4 g, 10.0 mmol), dichlorobis(triphenylphosphine)palladium(II)(0.021 g, 0.030 mmol), DME (13 mL), and water (7 mL) was stirred under a nitrogen atmosphere in a pressure vessel. The vessel was then sealed and heated at 110° C. for 16.5 hours and allowed to cool to room temperature. The volatiles were removed under reduced pressure. The residue was diluted with methanol, and silica gel was added. The mixture was concentrated under reduced pressure. The residue was purified by automated flash chromatography (FLASH 40+M silica cartridge, eluting with 10% to 25% methanol in ethyl acetate). The resulting material was concentrated twice from acetonitrile and then triturated with acetonitrile (100 mL) to provide a solid. The solid was isolated by filtration, washed with acetonitrile, and dried in a vacuum oven at 65° C. to provide 403 mg of 1-{4-amino-2-(ethoxymethyl)-7-[3-(pyrrolidin-1-ylcarbonyl)phenyl]-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl}-2-methylpropan-2-ol as a white solid, mp 185-187° C.
Reaction SMILES: [CH3:1][C:2]([CH3:32])=[CH:3][C@H:4]([C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18]2[CH:27]=[CH:26][C:25]3[C:24]([CH3:29])([CH3:28])[CH2:23][CH2:22][C:21]([CH3:31])([CH3:30])[C:20]=3[CH:19]=2)=[CH:12][CH:11]=1)[CH2:5][C:6]([O:8]C)=[O:7].[OH-].[Na+]>O.CCO>[CH3:1][C:2]([CH3:32])=[CH:3][C@H:4]([C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18]2[CH:27]=[CH:26][C:25]3[C:24]([CH3:29])([CH3:28])[CH2:23][CH2:22][C:21]([CH3:31])([CH3:30])[C:20]=3[CH:19]=2)=[CH:12][CH:11]=1)[CH2:5][C:6]([OH:8])=[O:7]
Reactant: COC(=O)C[C@H](C=C(C)C)c1ccc(OCc2ccc3c(c2)C(C)(C)CCC3(C)C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C)=C[C@@H](CC(=O)O)c1ccc(OCc2ccc3c(c2)C(C)(C)CCC3(C)C)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of compound 33.2 (0.15 mmol) and sodium hydroxide (0.8 mmol) in water (1 mL) and EtOH (3 mL) is stirred at room temperature overnight. EtOH is removed under reduced pressure, and the remaining solution acidified with 1N HCl to pH 3-5 and then diluted with EtOAc (70 mL), washed with saturated brine, dried over anhydrous Na2SO4, concentrated under reduced pressure, and purified by column chromatography (silica gel; 1:9 MeOH/DCM) to yield compound 33.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[N:6][C:5]([OH:8])=[CH:4][CH:3]=1.[OH-].[Na+].[CH3:11]I>>[NH2:1][C:2]1[CH:3]=[CH:4][C:5](=[O:8])[N:6]([CH3:11])[N:7]=1
Reactant: Nc1ccc(O)nn1
Reactant: CI
Agent: [Na+]
Agent: [OH-]
Product: Cn1nc(N)ccc1=O
Temperature: 85 °C
Reaction time: 2.5 h
Yield: 23.9 %

Procedure:
A mixture of 6-aminopyridazin-3-ol (2 g, 18.00 mmol), NaOH (0.720 g, 18.00 mmol) and MeI (1.126 mL, 18.00 mmol) was stirred for 2.5 hr at 85° C. under Ar. The reaction mixture was concentrated. The crude material was purified by silica gel column chromatography (NH3 1%/CH2Cl2/MeOH 4-7%) to afford the title product (538 mg, 4.30 mmol, 24% yield) as a yellow solid. tR: 0.25 min (LC-MS 2); ESI-MS: 126 [M+H]+ (LC-MS 2); Rf=0.36 (CH2Cl2/MeOH 9:1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:9]=[C:10]([F:30])[CH:11]=[C:12]2[C:17]=1[O:16][CH:15]([CH2:18]OS(C1C=CC(C)=CC=1)(=O)=O)[CH2:14][CH2:13]2.[N-:31]=[N+:32]=[N-:33].[Na+]>CS(C)=O>[N:31]([CH2:18][CH:15]1[CH2:14][CH2:13][C:12]2[C:17](=[C:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])[CH:9]=[C:10]([F:30])[CH:11]=2)[O:16]1)=[N+:32]=[N-:33]
Reactant: Cc1ccc(S(=O)(=O)OCC2CCc3cc(F)cc(-c4ccccc4Cl)c3O2)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CS(C)=O
Product: [N-]=[N+]=NCC1CCc2cc(F)cc(-c3ccccc3Cl)c2O1
Reaction time: 0.17 h
Yield: 94.5 %

Procedure:
A solution of toluene-4-sulfonic acid 8-(2-chloro-phenyl)-6-fluoro-chroman-2-ylmethyl ester (253 mg, 0.566 mmol) and sodium azide (147 mg, 2.264 mmol) in anhydrous dimethyl sulfoxide (8 mL) was heated to 70° C. under nitrogen for 20 hours. The cooled reaction mixture was quenched by the addition of water (30 mL) and the resulting suspension stirred vigorously for 10 minutes. The mixture was then partitioned between ethyl acetate (100 mL) and water (100 mL), the organic phase separated, washed with water (100 mL) and saturated brine (100 mL), dried over magnesium sulfate, filtered and concentrated under reduced pressure to afford 170 mg (95%) of 2-azidomethyl-8-(2-chloro-phenyl)-6-fluoro-chroman a colorless syrup.
Reaction SMILES: O1C=C(CN)N=C1.[CH3:8][N:9]1[CH:13]=[C:12]([CH2:14][NH2:15])[CH:11]=[N:10]1.[F:16][C:17]1[CH:38]=[CH:37][C:20]([CH2:21][N:22]2[CH2:26][CH2:25][N:24]([C:27]3[CH:28]=[C:29]([CH:33]=[CH:34][N:35]=3)[C:30](O)=[O:31])[C:23]2=[O:36])=[CH:19][CH:18]=1>>[F:16][C:17]1[CH:18]=[CH:19][C:20]([CH2:21][N:22]2[CH2:26][CH2:25][N:24]([C:27]3[CH:28]=[C:29]([CH:33]=[CH:34][N:35]=3)[C:30]([NH:15][CH2:14][C:12]3[CH:11]=[N:10][N:9]([CH3:8])[CH:13]=3)=[O:31])[C:23]2=[O:36])=[CH:37][CH:38]=1
Reactant: Cn1cc(CN)cn1
Reactant: O=C(O)c1ccnc(N2CCN(Cc3ccc(F)cc3)C2=O)c1
Agent: NCc1cocn1
Product: Cn1cc(CNC(=O)c2ccnc(N3CCN(Cc4ccc(F)cc4)C3=O)c2)cn1
Yield: 23 %

Procedure:
Following the procedure as described in Example 14, making variations as required to replace oxazol-4-ylmethanamine with (1-methyl-1H-pyrazol-4-yl)methanamine to react with 2-(3-(4-fluorobenzyl)-2-oxoimidazolidin-1-yl)isonicotinic acid, 2-(3-(4-fluorobenzyl)-2-oxoimidazolidin-1-yl)-N-((1-methyl-1H-pyrazol-4-yl)methyl)isonicotinamide was obtained as a colorless solid in 23% yield: mp 165-166° C.; 1HNMR (300 MHz, CDCl3) δ 8.52 (s, 1H), 8.34 (d, J=5.1 Hz, 1H), 7.44-7.37 (m, 3H), 7.27-7.22 (m, 2H), 7.04-6.98 (m, 2H), 6.70 (br s, 1H), 4.45-4.41 (m, 4H), 4.03 (t, J=8.1 Hz, 2H), 3.84 (s, 3H), 3.36 (t, J=8.1 Hz, 2H); 13C NMR (75 MHz, CDCl3) δ 165.5, 164.0, 160.7, 157.0, 152.9, 148.2, 143.0, 138.9, 132.1, 132.0, 129.9, 129.8, 116.0, 115.9, 115.6, 109.0, 47.2, 41.3, 41.0, 39.0, 34.5; MS (ES+) m/z 408.9 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.[Br:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22]Br)=[CH:16][CH:15]=1.CN(C)P(N(C)C)(N(C)C)=O>O>[Br:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][NH:1][C:2]2[CH:3]=[CH:4][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:11][CH:12]=2)=[CH:16][CH:15]=1
Reactant: CCOC(=O)c1ccc(N)cc1
Reactant: BrCCOc1ccc(Br)cc1
Solvent: O
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCOC(=O)c1ccc(NCCOc2ccc(Br)cc2)cc1

Procedure:
A mixture of 26.4 g of ethyl p-aminobenzoate, 22.4 g of 2-bromoethyl p-bromophenyl ether and 80 ml of hexamethylphosphoramide is heated at 100°-110° C. for 20 hours. The mixture is chilled, diluted with 25 ml of water, chilled and filtered. The solid is washed with 100 ml of ethanol-water (1:1), with 25 ml of ethanol and with water to give tan crystals, mp 128°-133° C. Recrystallization from ethanol gives yellow crystals, mp 135.5°-137° C.
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:23]([N:24]2[CH2:29][CH2:28][C:27]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)([OH:30])[CH2:26][CH2:25]2)=[C:22]2[C:17]([CH:18]=[CH:19][CH:20]=[N:21]2)=[C:16]([Cl:37])[CH:15]=1)[CH3:13].C(N(CC)C(C)C)(C)C>C(O)C>[Cl:37][C:16]1[CH:15]=[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])[C:23]([N:24]2[CH2:25][CH2:26][C:27]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)([OH:30])[CH2:28][CH2:29]2)=[C:22]2[C:17]=1[CH:18]=[CH:19][CH:20]=[N:21]2
Reactant: CC(N)c1cc(Cl)c2cccnc2c1N1CCC(O)(c2ccccc2)CC1
Reactant: Brc1ncnc2[nH]cnc12
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: CC(Nc1ncnc2[nH]cnc12)c1cc(Cl)c2cccnc2c1N1CCC(O)(c2ccccc2)CC1

Procedure:
A mixture of 6-bromo-9H-purine (0.036 g, 0.18 mmol), 1-[7-(1-aminoethyl)-5-chloroquinolin-8-yl]-4-phenylpiperidin-4-ol (0.035 g, 0.092 mmol), and N,N-diisopropylethylamine (0.032 mL, 0.18 mmol) in ethanol (0.32 mL) was heated at reflux under nitrogen overnight. The mixture was evaporated and the resulting residue was purified on a RP-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile in water with 0.2% ammonium hydroxide, at a flow rate of 30 mL/min) to give the product as the free base. LCMS calculated for C27H27ClN7O (M+H)+: m/z=500.2; Found: 500.1.
Reaction SMILES: CS(O)(=O)=O.[NH2:6][C:7]1[C:8](=[O:19])[N:9]2[CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][CH2:11][N:10]2[C:17]=1[NH2:18].[NH2:20][C:21]1[C:22]([Cl:29])=[C:23]([OH:28])[C:24]([CH3:27])=[CH:25][CH:26]=1.N.OO>O.C(O)C>[NH2:18][C:17]1[N:10]2[CH2:11][CH2:12][N:13]([CH3:16])[CH2:14][CH2:15][N:9]2[C:8](=[O:19])[C:7]=1[N:6]=[C:26]1[CH:25]=[C:24]([CH3:27])[C:23](=[O:28])[C:22]([Cl:29])=[C:21]1[NH2:20]
Reactant: Cc1ccc(N)c(Cl)c1O
Reactant: CN1CCn2c(N)c(N)c(=O)n2CC1
Agent: CS(=O)(=O)O
Agent: N
Agent: OO
Solvent: CCO
Solvent: O
Product: CC1=CC(=Nc2c(N)n3n(c2=O)CCN(C)CC3)C(N)=C(Cl)C1=O

Procedure:
0.32 mmol of 8,9-diamino-3-methyl-2,3,4,5-tetrahydro-1H,7H-pyrazolo[1,2-a][1,2,5]triazepin-7-one methanesulfonate was dissolved in a mixture of water and ethanol (7.5 ml/1.5 ml). This solution was admixed with 0.32 mmol of 3-amino-2-chloro-6-methylphenol, then with 1.8 ml of concentrated aqueous ammonia, then with 9 ml of hydrogen peroxide.
Reaction SMILES: C(Cl)(=O)[C:2](Cl)=[O:3].CN(C)C=O.[Cl:12][C:13]1[CH:14]=[C:15]([C:23]2[O:27][N:26]=[C:25]([C:28]3[CH:29]=[CH:30][CH:31]=[C:32]4[C:36]=3[NH:35][CH:34]=[CH:33]4)[N:24]=2)[CH:16]=[CH:17][C:18]=1[O:19][CH:20]([CH3:22])[CH3:21]>ClCCl>[Cl:12][C:13]1[CH:14]=[C:15]([C:23]2[O:27][N:26]=[C:25]([C:28]3[CH:29]=[CH:30][CH:31]=[C:32]4[C:36]=3[NH:35][CH:34]=[C:33]4[CH:2]=[O:3])[N:24]=2)[CH:16]=[CH:17][C:18]=1[O:19][CH:20]([CH3:21])[CH3:22]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC(C)Oc1ccc(-c2nc(-c3cccc4cc[nH]c34)no2)cc1Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)Oc1ccc(-c2nc(-c3cccc4c(C=O)c[nH]c34)no2)cc1Cl
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of oxalyl chloride (1.1 mL) in dichloromethane (60 mL) at 0° C. was added a solution of N,N-dimethylformamide (1.16 mL) in dichloromethane (30 mL) dropwise during 30 mins. The reaction mixture was stirred at this temperature for 15 minutes. A solution of 7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1H-indole (D51) (3.5 g) in dichloromethane (60 mL) was added in one portion. The mixture was warmed to room temperature slowly. After stirred at room temperature for 5 hours, dichloromethane was evaporated off. Ethyl acetate (300 mL), water (100 mL) and concentrated HCl solution (5 mL) was added to the residue. The obtained mixture was stirred for 30 minutes. KOH was added to basify the solution to pH value about 8. The organic layer was separated, washed with water and brine, dried over MgSO4. Filtration and evaporation afforded the product 7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1H-indole-3-carbaldehyde (D71) (4.0 g). δH (DMSO-d6, 400 MHz): 1.37 (6H, d), 4.87-4.93 (1H, m), 7.43-7.47 (2H, m), 8.07 (1H, dd), 8.21 (1H, dd), 8.37 (1H, d), 8.40-8.41 (2H, m), 10.06 (1H, s), 11.98 (1H, br s). MS (ES): C20H16ClN3O3 requires 381; found 382.1 (M+H+).
Reaction SMILES: Cl[C:2]1[N:24]=[C:23]([CH3:25])[CH:22]=[CH:21][C:3]=1[C:4]([C:6]1[CH:11]=[C:10]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:9]([OH:16])=[C:8]([C:17]([CH3:20])([CH3:19])[CH3:18])[CH:7]=1)=O.O.[NH2:27][NH2:28]>N1C=CC=CC=1>[C:12]([C:10]1[CH:11]=[C:6]([C:4]2[C:3]3[C:2](=[N:24][C:23]([CH3:25])=[CH:22][CH:21]=3)[NH:28][N:27]=2)[CH:7]=[C:8]([C:17]([CH3:19])([CH3:18])[CH3:20])[C:9]=1[OH:16])([CH3:15])([CH3:13])[CH3:14]
Reactant: Cc1ccc(C(=O)c2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)c(Cl)n1
Reactant: NN
Solvent: c1ccncc1
Solvent: O
Product: Cc1ccc2c(-c3cc(C(C)(C)C)c(O)c(C(C)(C)C)c3)n[nH]c2n1
Yield: 81.2 %

Procedure:
The similar procedures in Example 1 by using 15.5 g of 4-(2-chloro-6-methylnicotinoyl)-2,6-di-tertiary butylphenol, 9.7 g of hydrazine hydrate and 85 ml of pyridine are carried out, and then the obtained crude crystals are recrystallized from ethanol to give 11.8 g of 3-(3,5-di-tertiary butyl-4-hydroxyphenyl)-6-methyl-1H-pyrazolo[3,4-b]pyridine as white crystals, melting at 239°-240° C.
Reaction SMILES: [CH:1]([C:3]1[C:8]([N+:9]([O-])=O)=[CH:7][CH:6]=[CH:5][N:4]=1)=[CH2:2].[H][H]>C(O)C.[Pd]>[CH2:1]([C:3]1[C:8]([NH2:9])=[CH:7][CH:6]=[CH:5][N:4]=1)[CH3:2]
Reactant: C=Cc1ncccc1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCc1ncccc1N
Yield: 57.3 %

Procedure:
A solution of 2-vinyl-3-nitropyridine (0.75 g, 5.0 mMol) from step 1 above dissolved in 50 mL of ethanol and 100 mg of 10% palladium on carbon was shaken under 55 psi of hydrogen using a parr hydrogenation apparatus until hydrogen uptake ceased. The mixture was filtered through a bed of celite and the filtrate concentrated in vacuo. The residue was purified by flash silica gel chromatography using 1% then 2% methanol in methylene chloride as an eluent to afford the title compound as a white crystalline solid (0.35 g).
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[NH:11][CH2:12][CH2:13][NH:14][CH2:15][C:16]1[CH:17]=[C:18]([C:22]([N:24]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)=[O:23])[CH:19]=[CH:20][CH:21]=1)([CH3:3])[CH3:2].[C:30]([O-])([O-])=O.[K+].[K+].IC>CN(C=O)C>[CH:1]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[NH:11][CH2:12][CH2:13][N:14]([CH2:15][C:16]1[CH:17]=[C:18]([C:22]([N:24]2[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]2)=[O:23])[CH:19]=[CH:20][CH:21]=1)[CH3:30])([CH3:3])[CH3:2]
Reactant: O=C([O-])[O-]
Reactant: CC(C)Oc1ccccc1NCCNCc1cccc(C(=O)N2CCCCC2)c1
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: CC(C)Oc1ccccc1NCCN(C)Cc1cccc(C(=O)N2CCCCC2)c1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 45.2 %

Procedure:
To a solution of (3-{[2-(2-isopropoxy-phenylamino)-ethylamino]-methyl}-phenyl)-piperidin-1-yl-methanone (Example 1; 0.032 g, 0.081 mmol) in DMF (0.8 mL) was added K2CO3 (0.022 g, 0.16 mmol) and iodomethane (0.03 g, 0.2 mmol), and the resulting suspension was stirred at 25° C. for 45 min. The suspension was partitioned with EtOAc (20 mL) and H2O (20 mL), and the organic layer was washed with brine (20 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure. The crude residue was purified by preparative TLC (2% CH3OH/CH2Cl2) to provide a colorless oil (0.015 g, 47%). MS (ESI): mass calculated for C26H35N3O2, 409.27. m/z found, 410.5 [M+H]+, 432.4 [M+Na]+. 1H NMR (CDCl3, 400 MHz): 7.46 (d, J=7.6 Hz, 1H), 7.36-7.31 (m, 2H), 7.27-7.25 (m, 1H), 6.84 (dt, J=7.8, 1.3 Hz, 1H), 6.78 (dt, J=7.8, 1.3 Hz, 1H), 6.63 (dt, J=7.8, 1.6 Hz, 1H), 6.58 (dt, J=7.8, 1.6 Hz, 1H), 4.53 (hept, J=6.1 Hz, 1H), 3.70 (br s, 2H), 3.60 (br s, 2H), 3.31 (br s, 2H), 3.20 (t, J=6.1 Hz, 2H), 2.73 (t, J=6.1 Hz, 2H), 2.20 (s, 3H), 1.62-1.46 (m, 6H), 1.37 (d, J=6.1 Hz, 6H).
Reaction SMILES: [Cu][C:2]#[N:3].Br[C:5]1[CH:10]=[CH:9][C:8]([S:11]([F:16])([F:15])([F:14])([F:13])[F:12])=[CH:7][C:6]=1[N+:17]([O-:19])=[O:18]>CN(C)C=O.O>[N+:17]([C:6]1[CH:7]=[C:8]([S:11]([F:16])([F:12])([F:13])([F:14])[F:15])[CH:9]=[CH:10][C:5]=1[C:2]#[N:3])([O-:19])=[O:18]
Reactant: N#C[Cu]
Reactant: O=[N+]([O-])c1cc(S(F)(F)(F)(F)F)ccc1Br
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1ccc(S(F)(F)(F)(F)F)cc1[N+](=O)[O-]
Temperature: 14 °C
Reaction time: 1.25 h
Yield: 95.1 %

Procedure:
Copper (I) cyanide (5.05 g) was added to a stirred solution of 4-bromo-3-nitro-phenylsulphur pentafluoride (18.5 g) in N,N-dimethylformamide and heated at 14° C. for 4 hours. A mixture of ferric chloride (20.0 g),concentrated hydrochloric acid and water was added at 105° C. and heating continued for 1.25 hours. The cooled mixture was diluted with water, extracted (ether) and the organic phase washed (water), dried (magnesium sulphate) and evaporated to give 2-nitro-4-pentafluorosulphanylbenzonitrile (14.7 g), m.p.57-59° C.
Reaction SMILES: [N+:1]([O:4][C@@H:5]([CH2:12][O:13][N+:14]([O-:16])=[O:15])[CH2:6][CH2:7][CH2:8][C:9]([OH:11])=[O:10])([O-:3])=[O:2].[C:17](Cl)(=O)[C:18]([Cl:20])=O.C(=O)C>CN(C)C=O.ClCCl.[Cl-].[Zn+2].[Cl-]>[N+:1]([O:4][C@@H:5]([CH2:12][O:13][N+:14]([O-:16])=[O:15])[CH2:6][CH2:7][CH2:8][C:9]([O:11][CH:18]([Cl:20])[CH3:17])=[O:10])([O-:3])=[O:2]
Reactant: O=C(O)CCC[C@H](CO[N+](=O)[O-])O[N+](=O)[O-]
Reactant: O=C(Cl)C(=O)Cl
Agent: CC=O
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(Cl)OC(=O)CCC[C@H](CO[N+](=O)[O-])O[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a dichloromethane (10 mL) solution of (5R)-5,6-bis(nitrooxy)hexanoic acid (292 mg, 1.22 mmol) was added oxalyl chloride (0.54 mL, 6.12 mmol), followed by a few drops of N,N-dimethylformamide. After bubbling has stopped, the reaction mixture was concentrated in vacuo to afford a yellow slurry, which was redissolved in dichloromethane (5 mL). This solution was added to a mixture of zinc chloride (166 mg, 1.22 mmol) and acetaldehyde (0.15 mL, 2.66 mmol) in dichloromethane (5 mL) at 0° C. The reaction mixture turned cloudy immediately. It was warmed up to room temperature, stirred for 1 hour, and concentrated in vacuo to afford the crude product. Chromatography over silica eluting with ethyl acetate/hexanes afforded the diastereomeric 1-chloroethyl (5R)-5,6-bis(nitrooxy)hexanoate as a colorless liquid. 1H NMR (500 MHz, CDCl3) δ 6.54 (q, J=5.8 Hz, 1H, D1), 6.54 (q, J=5.8 Hz, 1H, D2), 5.25-5.35 (m, 1H), 4.76 (dd, J=3.1, 13.0 Hz, 1H, D1), 4.76 (dd, J=3.0, 12.8 Hz, 1H, D2), 4.49 (dd, J=6.5, 12.9 Hz, 1H, D1), 4.49 (dd, J=6.4, 13.1 Hz, 1H, D2), 2.4-2.5 (m, 2H), 1.7-1.9 (m, 7H).
Reaction SMILES: C[N:2](C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH:20]([OH:22])[CH3:21])[CH:15]=2)[N:8]=1)=O.[F:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[NH:31]N>>[F:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[N:31]1[C:5]([C:7]2[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([CH:20]([OH:22])[CH3:21])[CH:15]=3)[N:8]=2)=[CH:4][CH:3]=[N:2]1
Reactant: NNc1ccccc1F
Reactant: CC(O)c1cccc(-n2ccc(=O)c(C(=O)/C=C/N(C)C)n2)c1
Product: CC(O)c1cccc(-n2ccc(=O)c(-c3ccnn3-c3ccccc3F)n2)c1

Procedure:
The product was obtained starting from 3-((E)-3-Dimethylamino-acryloyl)-1-[3-(1-hydroxy-ethyl)-phenyl]-1H-pyridazin-4-one (A-36) and 2-fluoro-phenylhydrazine according to the method described for example 1. MS: M=377.1 (M+H)+
Reaction SMILES: [C:1]1([CH:7]([C:10]#[C:11][Si](C)(C)C)[CH2:8][OH:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C#C>C(O)C.O.[N+]([O-])([O-])=O.[Ag+]>[C:1]1([CH:7]([C:10]#[CH:11])[CH2:8][OH:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C[Si](C)(C)C#CC(CO)c1ccccc1
Agent: [Ag+]
Agent: C#C
Agent: O=[N+]([O-])[O-]
Solvent: O
Solvent: CCO
Product: C#CC(CO)c1ccccc1
Temperature: -5 °C
Reaction time: 0.5 h
Yield: 95.8 %

Procedure:
2-Phenyl-4-trimethylsilyl-but-3-yn-1-ol (Chem. Ber. (1988), 121, 1315-1320) (7.8 g) was dissolved in ethanol and the solution was cooled to -5° C. A solution of silver nitrate (8.9 g) in ethanol (60 ml) and water (21 ml) was added dropwise to the acetylene solution such that the temperature remained below 5° C. This precipitated the acetylene as the silver complex. A solution of potassium cyanide (17 g) in water (30 ml) was added dropwise to the stirred acetylene mixture and the resulting mixture was stirred at room temperature for 30 minutes. The mixture mainly dissolved and was diluted with water and extracted with ethyl acetate. The organic extracts were washed with brine, dried (MgSO4) and evaporated. The residue was purified on silica using 10% ethyl acetate in hexane as eluant to afford the title compound (5 g) as a colourless oil.
Reaction SMILES: [CH:1](=[O:10])[C:2]1[CH:9]=[CH:8][CH:7]=[C:4]([CH:5]=O)[CH:3]=1.[Cl:11][C:12]1[CH:21]=[C:20]2[C:15]([CH:16]=[CH:17][C:18]([CH3:22])=[N:19]2)=[CH:14][CH:13]=1>C(OC(=O)C)(=O)C.CCOCC>[Cl:11][C:12]1[CH:21]=[C:20]2[C:15]([CH:16]=[CH:17][C:18]([CH:22]=[CH:5][C:4]3[CH:3]=[C:2]([CH:9]=[CH:8][CH:7]=3)[CH:1]=[O:10])=[N:19]2)=[CH:14][CH:13]=1
Reactant: Cc1ccc2ccc(Cl)cc2n1
Reactant: O=Cc1cccc(C=O)c1
Solvent: CCOCC
Solvent: CC(=O)OC(C)=O
Product: O=Cc1cccc(C=Cc2ccc3ccc(Cl)cc3n2)c1
Temperature: 25 °C

Procedure:
A solution of isophthalaldehyde (4.0 g) and 7-chloroquinaldine (5.39 g) in acetic anhydride was heated at 125° C. in an oil bath for 48 hours. The reaction was cooled to room temperature, diluted with ether (30 mL) and the resulting suspension was stirred vigorously. The solid title compound was collected by filtration and was used as such in the next step.