Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH:20]1([NH:23][C:24](=[O:44])[C:25]2[CH:30]=[CH:29][C:28]([CH3:31])=[C:27]([N:32]3[C:41](=[O:42])[C:40]4[C:35](=[CH:36][CH:37]=[C:38](I)[CH:39]=4)[N:34]=[CH:33]3)[CH:26]=2)[CH2:22][CH2:21]1.[C:45]([O:49][CH3:50])(=[O:48])[CH:46]=[CH2:47].C(N(CC)CC)C>O1CCCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH:20]1([NH:23][C:24]([C:25]2[CH:30]=[CH:29][C:28]([CH3:31])=[C:27]([N:32]3[C:41](=[O:42])[C:40]4[C:35](=[CH:36][CH:37]=[C:38](/[CH:47]=[CH:46]/[C:45]([O:49][CH3:50])=[O:48])[CH:39]=4)[N:34]=[CH:33]3)[CH:26]=2)=[O:44])[CH2:22][CH2:21]1
Reactant: C=CC(=O)OC
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-n1cnc2ccc(I)cc2c1=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)/C=C/c1ccc2ncn(-c3cc(C(=O)NC4CC4)ccc3C)c(=O)c2c1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
Palladium acetate (0.02 g) and triphenylphosphine (0.038 g) was added to a stirred mixture N-cyclopropyl-3-(6-iodo-4-oxoquinazolin-3(4H)-yl)-4-methylbenzamide (0.20 g), methyl acrylate (0.4 ml) and triethylamine (0.63 ml) in anhydrous tetrahydrofuran (15 ml) under an argon atmosphere. The mixture was heated to 60° C. and stirred for 2 hours. The reaction mixture was evaporated, dissolved in ethyl acetate (100 ml) and washed with water (100 ml) and brine (100 ml). The organic phase was dried (magnesium sulphate) and evaporated and the residue purified by column chromatography on a silica column using initially iso-hexane and then a 1:1 mixture of iso-hexane and ethyl acetate as eluent. There was thus obtained the title compound (0.14 g); NMR Spectrum: (DMSOd6) 0.57 (m, 2H), 0.70 (m, 2H), 2.17 (s, 3H), 2.86 (m, 1H), 3.76 (s, 3H), 6.80 (d, 1H), 7.55 (m, 2H), 7.63 (m, 1H), 7.86 (m, 2H), 8.31 (m, 1H), 8.37 (s, 1H), 8.45 (m, 2H); Mass Spectrum: M+H+ 404.
Reaction SMILES: O[CH2:2][CH2:3][CH:4]1[CH2:9][CH2:8][N:7]([C:10](=[O:12])[CH3:11])[CH2:6][CH2:5]1.C(Br)(Br)(Br)[Br:14].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1C=CN=C1>ClCCl>[Br:14][CH2:2][CH2:3][CH:4]1[CH2:9][CH2:8][N:7]([C:10](=[O:12])[CH3:11])[CH2:6][CH2:5]1
Reactant: CC(=O)N1CCC(CCO)CC1
Reactant: BrC(Br)(Br)Br
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(=O)N1CCC(CCBr)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 1-[4-(2-hydroxy-ethyl)-piperidin-1-yl]-ethanone (0.500 g, 2.92 mmol) in dichloromethane (15 mL) was added carbon tetrabromide 1.45 g, 4.38 mmol), triphenyl phosphine (0.728 g, 2.77 mmol) and imidazole (0.398 g, 5.84 mmol) at 0° C. The temperature of the reaction mixture was slowly raised to room temperature and stirring continued at rt for 18 h. The reaction was diluted with dichloromethane and washed with water. The organic layer was dried (Na2SO4), filtered, and the solvent was evaporated. The product was chromatographed over silica gel using gradient of 0-10% methanol in dichloromethane. GC-MS m/z 235.
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:25])[NH:4][N:5]=[C:6]([N+:22]([O-:24])=[O:23])[C:7]=1[NH:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH2:19][CH2:20][CH3:21])[CH:11]=1.[CH:26](I)([CH3:28])[CH3:27].C(=O)([O-])[O-].[K+].[K+]>C(C(C)=O)C>[CH:26]([N:4]1[C:3](=[O:25])[C:2]([Cl:1])=[C:7]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH2:19][CH2:20][CH3:21])[CH:11]=2)[C:6]([N+:22]([O-:24])=[O:23])=[N:5]1)([CH3:28])[CH3:27]
Reactant: CC(C)I
Reactant: CCCOc1cc(CNc2c([N+](=O)[O-])n[nH]c(=O)c2Cl)ccc1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCCOc1cc(CNc2c([N+](=O)[O-])nn(C(C)C)c(=O)c2Cl)ccc1OC
Reaction time: 1.5 h

Procedure:
A mixture comprising 500 mg of 4-chloro-5-(3-n-propoxy-4-methoxybenzylamino)-6-nitro-3(2H)pyridazinone (Compound No. 22) prepared in Example 2, 691 mg of isopropyl iodide, 562 mg of anhydrous potassium carbonate and 25 ml of methyl ethyl ketone, was refluxed under stirring for 1.5 hours. The solvent was distilled off under reduced pressure, and water was added to the residue thereby obtained. The mixture was extracted with diethyl ether. The extract was washed with a saturated sodium chloride aqueous solution and dried over sodium sulfate. Then, the solvent was distilled off. The residual oily substance thereby obtained was crystallized from a solvent mixture of diethyl ether-n-hexane, to obtain 435 mg of the above identified compound having a melting point of from 82.5° to 84° C. as yellow crystals.
Reaction SMILES: [C:1]1([CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8]([CH3:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CO[CH:19](OC)[N:20]([CH3:22])[CH3:21].C(O)C>CCOCC>[CH3:19][N:20]([CH3:22])[CH:21]=[CH:10][C:8](=[O:9])[CH:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: COC(OC)N(C)C
Reactant: CC(=O)C(c1ccccc1)c1ccccc1
Solvent: CCOCC
Solvent: CCO
Product: CN(C)C=CC(=O)C(c1ccccc1)c1ccccc1
Temperature: -10 °C

Procedure:
A mixture of 21.0 g of 1,1-diphenylacetone and 40 ml of N,N-dimethylformamide dimethyl acetal in a 300 ml round bottom flask was heated in an oil bath at 120° C. for 8 hours with ethanol being distilled over. The reaction mixture was cooled and evaporated in vacuo to give an oil. The oil was boiled up in 50 ml of ether then cooled at -10° C. and gave a heavy precipitate. The precipitate was collected, washed with ether, then air dried and gave 21.5 g of crude product. A 5.0 g portion was recrystallized from 50 ml of 2-propanol, then cooled at room temperature. The material was collected and dried at 60° C. and gave 1.7 g of the desired product, mp 93°-94° C.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([F:11])[C:7]=1[CH:8]1[CH2:10][CH2:9]1.C(=O)([O-])[O-].[Na+].[Na+].[F:18][C:19]1[CH:20]=[C:21](B(O)O)[CH:22]=[C:23]2[C:28]=1[N:27]1[C:29]([CH3:32])=[N:30][N:31]=[C:26]1[CH2:25][CH2:24]2>COCCOC.O>[CH:8]1([C:7]2[C:6]([F:11])=[CH:5][N:4]=[CH:3][C:2]=2[C:21]2[CH:22]=[C:23]3[C:28](=[C:19]([F:18])[CH:20]=2)[N:27]2[C:29]([CH3:32])=[N:30][N:31]=[C:26]2[CH2:25][CH2:24]3)[CH2:10][CH2:9]1
Reactant: Fc1cncc(Br)c1C1CC1
Reactant: Cc1nnc2n1-c1c(F)cc(B(O)O)cc1CC2
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: Cc1nnc2n1-c1c(F)cc(-c3cncc(F)c3C3CC3)cc1CC2
Temperature: 25 °C

Procedure:
3-Bromo-4-cyclopropyl-5-fluoropyridine (462 mg, 2.14 mmol) was dissolved in a mixture of DME (3.55 mL) and water (3.55 mL). Sodium carbonate (226 mg, 2.14 mmol), (9-fluoro-1-methyl-4,5-dihydro-[1,2,4]triazolo[4,3-a]quinolin-7-yl)boronic acid (1-6, 176 mg, 0.71 mmol) and tetrakis triphenylphosphine palladium catalyst (4.11 mg, 3.6 mop were added. The mixture was deoxygenated under reduced pressure, flushed with nitrogen and heated under reflux for 18 h. After cooling to room temperature, ethyl acetate (10 mL) and water (10 mL) were added and the organic layer was separated. The water phase was extracted with ethyl acetate (2×10 mL). The combined organic phases were washed with brine, dried over Na2SO4, filtered over a short plug of Celite® and evaporated under reduced pressure. The crude compound was purified using preparative thin layer chromatography (ethyl acetate/ethanol 6:4) in order to yield the title compound as a white solid; 1H NMR (CD3SOCD3, 500 MHz) δ 8.49 (d, J=2.5 Hz, 1H), 8.35 (s, 1H), 7.60 (dd, J=1.8, 12.0 Hz, 1H), 7.52 (d, J=1.8 Hz, 1H), 3.80 (br. s, 4H), 2.54-2.52 (m, 3H), 1.96-1.95 (m, 1H), 0.89-0.87 (m, 2H), 0.68-0.67 (m, 2H); MS (ESI): m/z=338.97 [M+H]+.
Reaction SMILES: [F:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[C:4]([F:9])[C:3]=1[NH:10][C:11]1[C:16]([C:17]2[N:25]=[CH:24][N:23]=[C:22]3[C:18]=2[N:19]=[CH:20][N:21]3[CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][O:27]2)=[CH:15][CH:14]=[CH:13][N:12]=1.[CH3:32][C:33]1[O:37][C:36]([S:38](Cl)(=[O:40])=[O:39])=[CH:35][CH:34]=1.N1C=CC=CC=1>ClCCl>[F:1][C:2]1[C:3]([NH:10][C:11]2[C:16]([C:17]3[N:25]=[CH:24][N:23]=[C:22]4[C:18]=3[N:19]=[CH:20][N:21]4[CH:26]3[CH2:31][CH2:30][CH2:29][CH2:28][O:27]3)=[CH:15][CH:14]=[CH:13][N:12]=2)=[C:4]([F:9])[CH:5]=[CH:6][C:7]=1[NH:8][S:38]([C:36]1[O:37][C:33]([CH3:32])=[CH:34][CH:35]=1)(=[O:40])=[O:39]
Reactant: Nc1ccc(F)c(Nc2ncccc2-c2ncnc3c2ncn3C2CCCCO2)c1F
Reactant: Cc1ccc(S(=O)(=O)Cl)o1
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)Nc2ccc(F)c(Nc3ncccc3-c3ncnc4c3ncn4C3CCCCO3)c2F)o1
Temperature: 50 °C
Reaction time: 2 h
Yield: 85 %

Procedure:
The 2,6-difluoro-N1-(3-(9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)pyridin-2-yl)benzene-1,3-diamine (50 mg, 0.120 mmol) prepared at Step 9 was added and dissolved into dichloromethane solvent. 5-methylfuran-2-sulfonyl chloride (24 mg, 0.130 mmol) and pyridine (11 uL, 0.130 mmol) were added into the reaction solution and stirred at 50° C. for 2 hours. After the reaction, the reactant was washed with 1N aqueous hydrochloric acid solution and salt water. After extraction with dichloromethane, the organic layer was dried with sulfuric anhydride magnesium and vacuum concentrated, and then refined by means of column chromatography, so that 58 mg of the target compound, N-(2,4-difluoro-3-(3-(9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)pyridin-2-ylamino)phenyl)-5-methylfuran-2-sulfonamide (percentage yield: 85%), was obtained.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[C:10]1([NH:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(P(C(C)(C)C)C(C)(C)C)(C)(C)C>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd]>[C:6]([C:5]1[CH:8]=[CH:9][C:2]([N:16]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:3][CH:4]=1)#[N:7]
Reactant: c1ccc(Nc2ccccc2)cc1
Reactant: N#Cc1ccc(Br)cc1
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: N#Cc1ccc(N(c2ccccc2)c2ccccc2)cc1
Reaction time: 1 h
Yield: 97.3 %

Procedure:
The above general procedure was followed using 4-bromobenzonitrile (188 mg, 1.03 mmol) and diphenylamine (169 mg, 1.00 mmol) with 1 mol % Pd(dba)2 and 0.8 mol % tri-t-butylphosphine in 1.5 mL of toluene. After one hour, the reaction mixture was adsorbed onto silica gel and chromatographed with 50% toluene/hexanes to give 263 mg (97%) of N-(4-cyanophenyl)diphenylamine as a white solid. 1H NMR (500 MHz, C6D6) δ 6.97 (t, J=8 Hz, 4H), 6.92 (d, J=8.9 Hz, 2H), 6.86-6.83 (m, 6H), 6.56 (d, J=8.7 Hz, 2H). 13C NMR (125 MHz, C6D6) δ 151.3, 146.6, 133.2, 129.9, 126.1, 124.9, 120.5, 119.4, 104.0.
Reaction SMILES: [CH3:1][C:2](C)([O-])[CH3:3].[K+].[CH3:7][O:8][C:9]([C:11]1[N:12]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:13]2[C:18]([C:19]=1[OH:20])=[CH:17][C:16]([O:21][CH3:22])=[CH:15][CH:14]=2)=[O:10].BrC(C)C>CS(C)=O>[CH3:7][O:8][C:9]([C:11]1[N:12]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:13]2[C:18]([C:19]=1[O:20][CH:2]([CH3:3])[CH3:1])=[CH:17][C:16]([O:21][CH3:22])=[CH:15][CH:14]=2)=[O:10]
Reactant: COC(=O)c1c(O)c2cc(OC)ccc2n1-c1ccccc1
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CC(C)Br
Product: COC(=O)c1c(OC(C)C)c2cc(OC)ccc2n1-c1ccccc1
Reaction time: 0.75 h

Procedure:
A stirred mixture of 24.8 g (0.22 mole) of potassium tert-butoxide in 100 ml of dimethyl sulfoxide (under a nitrogen atmosphere) was placed in a cold water bath. A solution of 44.6 g (0.15 mole) of 3-hydroxy-5-methoxy-1-phenyl-1H-indole-2-carboxylic acid methyl ester [P. C. Unangst and M. E. Carethers, J. Heterocyclic Chem., 21, 709 (1984)] in 100 ml of dimethyl sulfoxide was added over 30 minutes. The new mixture was stirred for an additional 45 minutes, and 25.0 ml (32.8 g, 0.27 mole) of 2-bromopropane was added in one portion. The cooling bath was removed, and the mixture was stirred at room temperature for 45 hours, then added to 2.5 kg ice water. The crude ester intermediate was removed by extracting with dichloromethane (4×800 ml). The combined organic layers were washed with water (1×2.0 l), 5% aqueous sodium bicarbonate (2×2.0 l), and water again (1×2.0 l), before being dried with anhydrous sodium sulfate. Evaporation (vacuum) yielded a crude residue of 5-methoxy-3-(1-methylethoxy)-1-phenyl-1H-indole-2-carboxylic acid methyl ester.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[CH:5][S:6][CH:7]=1.[OH:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][C:24]=3[O:26][CH2:27][CH2:28][N:29]([CH3:33])[C:30](=[O:32])[CH3:31])[N:19]=[CH:18][N:17]=2)=[CH:11][C:10]=1[CH3:34]>>[CH3:33][N:29]([CH2:28][CH2:27][O:26][C:24]1[CH:23]=[CH:22][CH:21]=[C:20]2[C:25]=1[C:16]([NH:15][C:12]1[CH:13]=[CH:14][C:9]([O:8][CH2:2][C:3]3[N:4]=[CH:5][S:6][CH:7]=3)=[C:10]([CH3:34])[CH:11]=1)=[N:17][CH:18]=[N:19]2)[C:30](=[O:32])[CH3:31]
Reactant: ClCc1cscn1
Reactant: CC(=O)N(C)CCOc1cccc2ncnc(Nc3ccc(O)c(C)c3)c12
Product: CC(=O)N(C)CCOc1cccc2ncnc(Nc3ccc(OCc4cscn4)c(C)c3)c12
Yield: 5 %

Procedure:
The procedure described in Example 3 was repeated using 4-(chloromethyl)-1,3-thiazole and N-[2-({4-[(4-hydroxy-3-methylphenyl)amino]quinazolin-5-yl}oxy)ethyl]-N-methylacetamide (obtained as described in Example 75, preparation of starting materials) to give the title compound as an off-white solid in 5% yield; NMR spectrum (DMSO-d6 373K) 1.94 (s, 3H), 2.24 (s, 3H), 2.99 (s, 3H), 3.87 (t, 2H), 4.46 (m, 2H), 5.25 (s, 2H), 7.08 (d, 1H), 7.17 (d, 1H), 7.35 (d, 1H), 7.47 (d, 1H), 7.54 (dd, 1H), 7.70 (m, 2H), 8.41 (s, 1H), 9.07 (d, 1H), 9.63 (s, 1H); Mass spectrum MH+ 464.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]([OH:8])=O)[N:3]=[N:2]1.[CH3:9][NH:10][CH2:11][CH2:12][CH:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][CH2:22][C:23]2[CH:28]=[C:27]([Cl:29])[CH:26]=[C:25]([Cl:30])[CH:24]=2)=[O:20])[CH2:15][CH2:14]1>>[CH3:9][N:10]([CH2:11][CH2:12][CH:13]1[CH2:14][CH2:15][N:16]([C:19]([O:21][CH2:22][C:23]2[CH:24]=[C:25]([Cl:30])[CH:26]=[C:27]([Cl:29])[CH:28]=2)=[O:20])[CH2:17][CH2:18]1)[C:6]([C:4]1[N:3]=[N:2][NH:1][CH:5]=1)=[O:8]
Reactant: O=C(O)c1c[nH]nn1
Reactant: CNCCC1CCN(C(=O)OCc2cc(Cl)cc(Cl)c2)CC1
Product: CN(CCC1CCN(C(=O)OCc2cc(Cl)cc(Cl)c2)CC1)C(=O)c1c[nH]nn1

Procedure:
The title compound was prepared analogously to Example 34, step 3 from 1H-1,2,3-triazole-4-carboxylic acid and 3,5-dichlorobenzyl 4-(2-(methylamino)ethyl)piperidine-1-carboxylate (Example 1, step 3) (200 mg, 0.579 mmol);
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[O:18]1[CH2:19][CH2:20][N:15]([C:11]2[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9][CH:10]=2)[CH2:16][CH2:17]1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: C1COCCN1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: CC(C)(C)OC(=O)N1CC=C(N2CCOCC2)CC1
Temperature: 25 °C

Procedure:
To a solution of tert-butyl-4-oxo-1-piperidine carboxylate (8.0 g, 40 mmol) and morpholine (3.6 g, 42 mmol) in benzene (16 mL) was added p-toluenesulfonic acid (40 mg) and the resulting solution was refluxed using a Dean-Stark trap for 24 h. After cooling to rt, the solution was concentrated under vacuum to afford the title compound a as a thick reddish-orange oil which was used without any further purification (11.1 g, ˜quant). 1H NMR (400 MHz, CDCl3): δ 7.36 (s, 1 H), 3.94 (br s, 2 H), 3.74 (m, 4 H), 3.54 (m, 2 H), 2.80 (m, 4 H), 2.16 (br s, 2 H), 1.47 (s, 9 H).
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[C:13]2[C:8](=[N:9][CH:10]=[N:11][C:12]=2[NH:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=3)=[C:17]([Cl:29])[CH:16]=2)[NH:7][N:6]=1.[CH2:30]([CH2:32][NH2:33])[OH:31]>>[Cl:29][C:17]1[CH:16]=[C:15]([NH:14][C:12]2[N:11]=[CH:10][N:9]=[C:8]3[NH:7][N:6]=[C:5]([O:4][CH2:3][CH2:2][NH:33][CH2:32][CH2:30][OH:31])[C:13]=23)[CH:20]=[CH:19][C:18]=1[O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=1
Reactant: NCCO
Reactant: ClCCOc1n[nH]c2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12
Product: OCCNCCOc1n[nH]c2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12
Yield: 28 %

Procedure:
The procedure described in Example 23 was repeated using 3-(2-chloroethoxy)-N-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine and ethanolamine to give the title compound in 28% yield; NMR Spectrum: 2.68 (t, 2H), 2.98-3.00 (m, 2H), 3.46-3.49 (m, 2H), 4.36 (t, 2H), 5.29 (s, 2H), 7.23 (d, 1H), 7.37 (t, 1H), 7.54-7.58 (m, 2H), 7.86-7.93 (m, 2H), 8.27 (s, 1H), 8.59 (d, 1H), 8.65 (br s, 1H); Mass Spectrum: 456 (MH+).
Reaction SMILES: [C:1]([N:6]1[CH2:16][CH2:15][C:9]2[N:10]=[N:11][C:12](Cl)=[CH:13][C:8]=2[CH2:7]1)(=[O:5])[CH2:2][CH2:3][CH3:4].C(O)(=O)/C=C\C(O)=O.ClC1[N:31]=[N:30]C2CCNCC=2C=1.C(Cl)(=O)CCC>C(#N)C>[C:1]([N:6]1[CH2:16][CH2:15][C:9]2[N:10]=[N:11][C:12]([NH:30][NH2:31])=[CH:13][C:8]=2[CH2:7]1)(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC(=O)N1CCc2nnc(Cl)cc2C1
Reactant: Clc1cc2c(nn1)CCNC2
Agent: CCCC(=O)Cl
Agent: O=C(O)/C=C\C(=O)O
Solvent: CC#N
Product: CCCC(=O)N1CCc2nnc(NN)cc2C1

Procedure:
The 6-butyryl-3-chloro-5,6,7,8-tetrahydropyrido[4,3-c]pyridazine, required as starting material, may be produced in a manner analogous to that described in Example 8(g), from 3-chloro-5,6,7,8-tetrahydropyrido[4,3-c]pyridazine maleate and butyric acid chloride. Reaction time 27 hours. M.P. 130°-133° from acetonitrile.
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([NH2:14])=[CH:11][CH:12]=2)[C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([CH3:15])[CH2:6][C:5]1([CH3:23])[CH3:22])(=[O:3])[CH3:2].[CH3:24][C:25]1[CH:26]=[N:27][CH:28]=[C:29]([CH:33]=1)[C:30](O)=[O:31].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>ClCCl>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([NH:14][C:30](=[O:31])[C:29]3[CH:33]=[C:25]([CH3:24])[CH:26]=[N:27][CH:28]=3)=[CH:11][CH:12]=2)[C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([CH3:15])[CH2:6][C:5]1([CH3:23])[CH3:22])(=[O:3])[CH3:2]
Reactant: CC(=O)N1c2ccc(N)cc2C(C)(c2ccccc2)CC1(C)C
Reactant: Cc1cncc(C(=O)O)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N1c2ccc(NC(=O)c3cncc(C)c3)cc2C(C)(c2ccccc2)CC1(C)C

Procedure:
Condensation of 1-acetyl-6-amino-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline (0.10 g) with 5-methyl nicotinic acid (0.13 g) under the agency of HATU (0.18 g) and N,N-diisopropylethylamine (0.28 ml) in dichloromethane (2 ml) was performed according to the method described in example 11.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](Br)[CH:5]=[CH:6][CH:7]=1.[Li]CCCC.[O:14]=[C:15]1[C@@H:19]([O:20][Si:21]([CH:28]([CH3:30])[CH3:29])([CH:25]([CH3:27])[CH3:26])[CH:22]([CH3:24])[CH3:23])[CH2:18][CH2:17][N:16]1[C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32]>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([C:15]2([OH:14])[C@@H:19]([O:20][Si:21]([CH:25]([CH3:26])[CH3:27])([CH:28]([CH3:29])[CH3:30])[CH:22]([CH3:24])[CH3:23])[CH2:18][CH2:17][N:16]2[C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)[Si](O[C@H]1CCN(C(=O)OC(C)(C)C)C1=O)(C(C)C)C(C)C
Reactant: Fc1cccc(Br)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)[Si](O[C@H]1CCN(C(=O)OC(C)(C)C)C1(O)c1cccc(F)c1)(C(C)C)C(C)C
Temperature: -22 °C
Reaction time: 2 h

Procedure:
In step 3-2, a solution of 3-fluoro-1-bromo benzene (4.0 g, 22.9 mmol) in THF (10 mL) was cooled to −60° C. To this solution n-BuLi in hexanes solution (1.6 M hexanes, 14.3 ml, 22.9 mmol) was added over 12 minutes allowing for a gradual temperature ramp (2° C./minute) until a net internal temperature of −40° C. was obtained and all the n-BuLi was added. The reaction mixture was then allowed to warm over a 30 minute period until an internal temperature of −22° C. was reached, then the resulting solution (dark in color) was cooled to −45° C. and then a solution of (S)-tert-butyl 2-oxo-3-(triisopropylsilyloxy)pyrrolidine-1-carboxylate (2.0 grams, 5.6 mmoles) in THF (10 mL) was added over 6 minutes (do not allow the internal temperature to exceed −40° C. during this addition event). The mixture was then allowed to warm to −20° C. over a 35 minute period and the temperature was then held at −20° C. for 2 hours. The reaction mixture was then quenched with cold saturated ammonium chloride aqueous solution (150 mL), warmed to room temperature and extracted with ethyl acetate (3×150 mL). The organic extracts were combined, concentrated using a rotary evaporator and purified using flash chromatography (5% ethyl acetate in hexanes to 10% ethyl acetate in hexanes over a 30 minute gradient) yielding the racemate of (3S)-tert-butyl 2-(3-fluorophenyl)-2-hydroxy-3-(triisopropylsilyloxy)pyrrolidine-1-carboxylate (3-2) as an oil. 1H NMR (400 MHz, D6 acetone) δ ppm 7.92-7.23 (m, 4H), 5.80 (br s, 1H), 5.10 (app t, J=8.2, 1H), 3.20-2.95 (m, 2H), 2.05-1.95 (m, 2H), 1.35 (s, 9H), 1.21-0.99 (m, 21H). LCMS observed m/z 737.5 major ion.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([B:9]2[O:13][C:12]([CH3:15])([CH3:14])[C:11]([CH3:17])([CH3:16])[O:10]2)=[CH:5][CH:4]=1.[CH3:18][N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1>ClCCl>[CH3:18][N:19]1[CH2:24][CH2:23][N:22]([CH2:2][C:3]2[CH:8]=[CH:7][C:6]([B:9]3[O:13][C:12]([CH3:15])([CH3:14])[C:11]([CH3:17])([CH3:16])[O:10]3)=[CH:5][CH:4]=2)[CH2:21][CH2:20]1
Reactant: CN1CCNCC1
Reactant: CC1(C)OB(c2ccc(CBr)cc2)OC1(C)C
Solvent: ClCCl
Product: CN1CCN(Cc2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Temperature: 25 °C

Procedure:
A solution of 2-(4-Bromomethyl-phenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (60 mg, 212 mmol) in N-methyl piperazine (0.5 mL) was heated at 70-75° C. for 3 h. The reaction mixture was cooled down to RT, diluted with dichloromethane (6 mL), washed with water (2×2 mL), brine (2 mL), dried over anhydrous sodium sulphate and concentrated in vacuo to yield 1-methyl-4-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxborolan-2-yl)-benzyl]-piperazine in reasonably good purity. This boronate ester was used for Suzuki coupling reaction with 3-(4-Iodo-benzyl)-5-(R)-phenyl)-oxazolidin-2-one (40 mg, 105 mmol), without any purification, as described in General Procedure (5). The desired product was isolated as a white solid (28 mg, 60%) by silica gel column chromatography. 1H NMR (300 MHz, CDCl3): δ 7.56 (m, 4H), 7.38 (m, 9H), 5.52 (t, 1H), 4.61 (d, 1H), 4.46 (d, 1H), 3.83 (t, 1H), 3.57 (s, 2H), 3.37 (dd, 1H), 2.53 (bs, 8H), 2.32 (s, 3H). (Note: where N-Boc protected piperazine was used as the base, the final product was obtained by cleaving off the Boc group using trifluoro acetic acid in dichloromethane.)
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[O:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH:12]1[O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]#N.S(=O)(=O)(O)[OH:27]>C1C=CC=CC=1.C(OCC)C>[O:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH:12]1[O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH:24]=[O:27]
Reactant: N#CCCCCCCOC1CCCCO1
Reactant: O=S(=O)(O)O
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: c1ccccc1
Solvent: CCOCC
Product: O=CCCCCCCOC1CCCCO1
Temperature: 10 °C
Reaction time: 0.5 h

Procedure:
Diisobutylaluminium hydride (19.4 g.) in dry benzene (50 ml.) was added dropwise at 10° C. to a stirred solution of 7-(2-tetrahydropyranyloxy)heptanenitrile (20.6 g.) in dry diethyl ether (200 ml.). The solution was stirred at 10° C. for 30 minutes and was then added to 2N aqueous sulphuric acid (300 ml.) at 0° C. The mixture was heated at 30° C. for 30 minutes, and then saturated with sodium chloride and the layers were separated. The aqueous layer was extracted with diethyl ether and the combined organic layers were washed with aqueous sodium bicarbonate, and then aqueous sodium chloride, and dried over sodium sulphate. The solvent was evaporated and the residue was distilled under reduced pressure to give 7-(2-tetrahydropyranyloxy)heptanal (12.7 g.), b.p. 78°-106° C./0.1 mm.Hg, nD25 1.456.