Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C:15]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[NH:9][C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2.[CH3:17][CH:18]1[NH:22][C:21](=O)[CH2:20][CH2:19]1.P(Cl)(Cl)(Cl)=O>>[CH3:1][C:2]1([CH3:16])[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:8]=2[N:9]([C:21]2[CH2:20][CH2:19][CH:18]([CH3:17])[N:22]=2)[C:10]2[C:15]1=[CH:14][CH:13]=[CH:12][CH:11]=2
Reactant: CC1(C)c2ccccc2Nc2ccccc21
Reactant: CC1CCC(=O)N1
Solvent: O=P(Cl)(Cl)Cl
Product: CC1CCC(N2c3ccccc3C(C)(C)c3ccccc32)=N1
Yield: 11 %

Procedure:
Reaction of 9,9-dimethylacridan, 5-methyl-2-pyrrolidinone and phosphorus oxychloride according to the procedure of Example 1 provides the free base 9,9-DIMETHYL-10-(5-METHYL-1-PYRROLIN-2-YL)ACRIDAN as a distillable oil, b.p. 160°-180° C. at 0.15 mm Hg. in 11% yield. Conversion of the free base to the hydrochloride salt affords 9,9-DIMETHYL-10-(5-METHYL-1-PYRROLIN-2-YL)ACRIDAN HYDROCHLORIDE, m.p. 232.5°-234.5° C. (dec.) (corr.), by trituration with hot benzene.
Reaction SMILES: [CH3:1][Si:2](Cl)([CH3:4])[CH3:3].[CH2:6]1[O:12][CH2:11][C@@H:9]([OH:10])[C@H:7]1[OH:8].C(N(CC)CC)C>CN(C1C=CN=CC=1)C.ClCCl>[CH3:1][Si:2]([CH3:4])([CH3:3])[O:8][CH:7]1[CH:9]([O:10][Si:2]([CH3:4])([CH3:3])[CH3:1])[CH2:11][O:12][CH2:6]1
Reactant: O[C@@H]1COC[C@@H]1O
Reactant: C[Si](C)(C)Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[Si](C)(C)OC1COCC1O[Si](C)(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 107.6 %

Procedure:
TMSCl (8.0 mL, 63.32 mmol) was added dropwise to a solution of 1,4-anhydroerythritol (3.0 g, 28.81 mmol), triethylamine (9.2 mL, 66.0 mmol) and DMAP (few crystals) in dichloromethane (200 mL) at 0° C. The reaction was allowed to slowly warm to room temperature over 1 h and then stirred for an additional 3 h. The solid was filtered and the filtrate concentrated to give a solid. The solid was then filtered through a short silica gel column eluting with 33% hexanes in ethyl ether. Removal of solvents under reduced pressure provided 3,4-bis-trimethylsilanyloxy-tetrahydro-furan (7.7 g, ˜100%) as a colorless liquid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11](O)[CH2:10][C@H:9]1[CH2:14][O:15][Si:16]([C:29]([CH3:32])([CH3:31])[CH3:30])([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:33]1(=[O:43])[NH:37][C:36](=[O:38])[C:35]2=[CH:39][CH:40]=[CH:41][CH:42]=[C:34]12.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([N:37]2[C:36](=[O:38])[C:35]3=[CH:39][CH:40]=[CH:41][CH:42]=[C:34]3[C:33]2=[O:43])[CH2:10][C@H:9]1[CH2:14][O:15][Si:16]([C:29]([CH3:30])([CH3:32])[CH3:31])([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CC(C)(C)OC(=O)N1C[C@@H](O)C[C@H]1CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1C[C@@H](N2C(=O)c3ccccc3C2=O)C[C@H]1CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Temperature: 25 °C
Reaction time: 18 h
Yield: 68.4 %

Procedure:
To a stirred solution of cis-1tert-butoxycarbonyl-(2S)-(tert-butyldiphenylsilyloxy)methyl-4-hydroxypyrrolidine (1.82 mg, 4.0 mmol), phthalimide (647 mg, 4.4 mmol), and Ph3P (1.26 g, 4.8 mmol) in THF (20 ml) was added DIAD (889 mg, 4.4 mmol) at 0° C. The reaction mixture was stirred at room temperature for 18 hr. The mixture was concentrated in vacuo. The residue was purified by column chromatography on silica gel with n-hexane-EtOAc (5/1, v/v) as eluent to give N-[cis-1tert-butoxycarbonyl-(2S)-(tert-butyldiphenylsilyloxy)methyl-4-pyrrolidinyl]phthalimide (1.6 g, 69%) as an amorphous solid. 1H-NMR (CDCl3) δ 1.07 (s, 9H), 1.30 and 1.44 (each s, total 9H), 2.27–2.37 (m, 1H), 2.94–2.96 (m, 1H), 3.81–4.09 (m, 51H), 4.72 (m, 1H), 7.37–7.38 (m, 6H), 7.67–7.74 (m, 6H), 7.84–7.86 (m, 2H).
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([CH3:11])=[CH:4][N:3]=1.[NH2:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][OH:21])=[CH:15][CH:14]=1>>[CH3:11][C:5]1[CH:6]=[C:7]([N+:8]([O-:10])=[O:9])[C:2]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][OH:21])=[CH:15][CH:14]=2)=[N:3][CH:4]=1
Reactant: Cc1cnc(Cl)c([N+](=O)[O-])c1
Reactant: Nc1ccc(CCO)cc1
Product: Cc1cnc(Nc2ccc(CCO)cc2)c([N+](=O)[O-])c1

Procedure:
The title compound was prepared according to the procedure described in step 3 of Example 1 from 2-chloro-5-methyl-3-nitropyridine and 4-aminophenylethyl alcohol.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][CH2:8][C:9]1([C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=2)[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1.Cl.Cl[CH2:24][CH2:25][CH2:26][N:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[N:27]1([CH2:26][CH2:25][CH2:24][O:21][C:18]2[CH:19]=[CH:20][C:15]([C:9]3([CH2:8][NH:7][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=4)[CH2:10][CH2:11][O:12][CH2:13][CH2:14]3)=[CH:16][CH:17]=2)[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1
Reactant: Oc1ccc(C2(CNc3ccccn3)CCOCC2)cc1
Reactant: ClCCCN1CCCCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: c1ccc(NCC2(c3ccc(OCCCN4CCCCC4)cc3)CCOCC2)nc1
Yield: 76.3 %

Procedure:
4-{4-[(pyridin-2-ylamino)methyl]tetrahydro-2H-pyran-4-yl}phenol (200 mg, 0.704 mmol), 3-chloropropylpiperidine hydrochloride (152 mg, 0.775 mmol) and potassium carbonate (204 mg, 1.48 mmol) were stirred in DMF (1 ml) at 45° C. for 24 hours until complete. The reaction was then partitioned between ethyl acetate (40 ml) and water (40 ml). The organic layer was separated, dried over sodium sulphate and concentrated in vacuo to give a solid. The solid was purified by preparative HPLC to give the title compound (220 mg, 76%) as a white solid. 1H NMR (400 MHz, CDCl3) δ 1.44-1.55 (m, 2H), 1.64-1.78 (m, 4H), 1.85-2.00 (m, 2H), 2.08-2.18 (m, 4H), 2.52-2.70 (m, 6H), 3.48 (d, 2H), 3.52-3.62 (m, 2H), 3.78-3.85 (m, 2H), 4.02 (t, 2H), 6.21 (d, 1H), 6.50 (t, 1H), 6.90 (d, 2H), 7.24 (d, 2H), 7.34 (t, 1H), 8.01 (d, 1H). LRMS APCI+ m/z 410 [MH]+.
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@@H:16]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C@H:15]([CH2:25][O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:14][C@@H:11]([O:12][CH3:13])[C@@H:10]1OS(C(F)(F)F)(=O)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N-:42]=[N+:43]=[N-:44].C([N+](CCCC)(CCCC)CCCC)CCC>C1C=CC=CC=1>[N:42]([C@H:10]1[C@H:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C@@H:16]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C@H:15]([CH2:25][O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:14][C@H:11]1[O:12][CH3:13])=[N+:43]=[N-:44]
Reactant: CO[C@@H]1O[C@@H](COCc2ccccc2)[C@H](OCc2ccccc2)[C@@H](OCc2ccccc2)[C@H]1OS(=O)(=O)C(F)(F)F
Reactant: [N-]=[N+]=[N-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: c1ccccc1
Product: CO[C@@H]1O[C@@H](COCc2ccccc2)[C@H](OCc2ccccc2)[C@@H](OCc2ccccc2)[C@@H]1N=[N+]=[N-]
Temperature: 25 °C
Reaction time: 72 h

Procedure:
Methyl 3,4,6-tri-O-benzyl-2-O-trifluoromethanesulfonyl-α-L-mannopyranoside (6) (12.23 g) was dissolved in dehydrated benzene (400 ml), tetrabutylammonium azide [(n-Bu)4NN3] (29.16 g) was added thereto under an argon atmosphere. After 3 days, (n-Bu)4NN3 (3.61 g) was further added thereto. The mixture was stirred at room temperature for an additional 11 days (14 days in total). The reaction mixture was charged to a silica gel column as such to effect purification by silica gel column chromatography combined with preparative thin-layer chromatography, whereby a target product was obtained (yield: 3.58 g, yield ratio: 36%).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[C:8]1(B(O)O)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:8]1([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: OB(O)c1ccccc1
Reactant: Clc1ccccn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: c1ccc(-c2ccccn2)cc1
Yield: 70.3 %

Procedure:
2-Chloropyridine (10 g, 88.0 mmol), phenylboronic acid (12.9 g, 105.7 mmol), tetrakis(triphenylphosphine)palladium (0) (5.0 g, 5 mol %) and 2M Na2CO3 (50 mL) were all dissolved in ethylene glycol dimethylether (200 mL) at room temperature, under an atmosphere of nitrogen. The mixture was refluxed for 48 hours. Ethylene glycol dimethylether was evaporated in vacuo to give a red oil, which was partitioned between water (10 mL) and EtOAc (10 mL). The EtOAc layer was separated and the aqueous layer was further extracted with EtOAc (10 mL×2). The combined EtOAc layers were dried (MgSO4) and concentrated in vacuo to a red oil. Purification by flash column chromatography (iso-hexaneethyl acetate 1:5-silica) gave the title product as a colourless oil (9.6 g, 70%).
Reaction SMILES: [C:1]1([C:7]2[CH2:8][CH2:9][N:10]([CH2:13][CH2:14][CH2:15][N:16]3[CH:24]([OH:25])[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[C:17]3=[O:26])[CH2:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[C:29]1([CH2:35][C:36](Cl)=[O:37])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.[C:39]([OH:44])(=[O:43])[C:40]([OH:42])=[O:41]>CN(C)C=O.C(C(C)=O)C>[C:39]([OH:44])(=[O:43])[C:40]([OH:42])=[O:41].[C:29]1([CH2:35][C:36]([O:26][CH:17]2[C:18]3[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:24](=[O:25])[N:16]2[CH2:15][CH2:14][CH2:13][N:10]2[CH2:9][CH:8]=[C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH2:12][CH2:11]2)=[O:37])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: O=C(Cl)Cc1ccccc1
Reactant: O=C1c2ccccc2C(O)N1CCCN1CC=C(c2ccccc2)CC1
Agent: O=C(O)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: CCC(C)=O
Solvent: CN(C)C=O
Product: O=C(Cc1ccccc1)OC1c2ccccc2C(=O)N1CCCN1CC=C(c2ccccc2)CC1
Reaction time: 2 h
Yield: 61.8 %

Procedure:
A solution of 2-[3-(4-phenyl-1,2,3,6-tetrahydro-1pyridyl)propyl]-3-hydroxy-1-isoindolinone (7 g) in anhydrous dimethylformamide (75 cc) is added to a suspension of sodium hydride (as a 50% suspension in oil) (1 g) in anhydrous dimethylformamide (25 cc) at a temperature close to 20° C. in the course of 10 minutes and agitation is continued for 2 hours. Then, 3.5 g of phenylacetyl chloride is added in the course of 5 minutes, and agitation is continued for a further 20 hours. The suspension obtained is poured into distilled water (100 cc) and extracted with methylene chloride (4×50 cc). The organic extracts are combined, dried over anhydrous magnesium sulphate, filtered and concentrated to dryness under reduced pressure (20 mm Hg; 2.7 kPa) at 40° C. The residue obtained is dissolved in methyl ethyl ketone (30 cc). A solution of oxalic acid (1.1 g) in methyl ethyl ketone (15 cc) is added and agitation continued for 1 hour at a temperature close to 20° C. The precipitate formed is separated by filtration. 4.2 g of 3-phenylacetoxy-2-[3-(4-phenyl-1,2,3,6-tetrahydro-1pyridyl)propyl]-1-isoindolinone oxalate are thus obtained, melting at 134° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:21][CH2:20][C:10]2[C:11]3[C:12](=[O:19])[CH2:13][CH2:14][C:15]=3[C:16](I)=[CH:17][C:9]=2[CH2:8][CH2:7]1)=[O:5])[CH3:2].[H][H]>CCO.[Pd]>[CH2:1]([O:3][C:4]([N:6]1[CH2:21][CH2:20][C:10]2[C:11]3[C:12](=[O:19])[CH2:13][CH2:14][C:15]=3[CH:16]=[CH:17][C:9]=2[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCc2cc(I)c3c(c2CC1)C(=O)CC3
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)N1CCc2ccc3c(c2CC1)C(=O)CC3
Yield: 81 %

Procedure:
Into a 500 ml Parr bottle, Intermediate 1 (11 g, 27.56 mmol) was added, followed by 5% Pd—C (700 mg) in EtOH (200 ml). The mixture was shaken over 50 psi hydrogen for 16 hours. The contents were filtered through celite and solvent evaporated in vacuo. The remaining residue was purified by silica-gel chromatography (gradient elution: 0 to 40% EtOAc in hexane) to give the title product as a white solid (6.1 g). 1H NMR (300 MHz, CDCl3) δ 7.31 (d, J=7.8 Hz, 1H); 7.22 (d, J=7.8 Hz, 1H); 4.16 (q, J=6.9 Hz, 2H); 3.62-3.60 (m, 6 μl); 3.05-2.96 (m, 4 μl); 2.70-2.66 (m, 2H); 1.27 (t, J=6.9 Hz, 3H; MS: ESI (positive): 274 (M+H).
Reaction SMILES: [CH:1]([O:3][CH2:4][CH2:5][OH:6])=[CH2:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[N:27]1[C:31](=[O:32])[C:30]2=[CH:33][CH:34]=[CH:35][CH:36]=[C:29]2[C:28]1=[O:37].CCOC(/N=N/C(OCC)=O)=O>O1CCCC1>[CH:1]([O:3][CH2:4][CH2:5][O:6][N:27]1[C:31](=[O:32])[C:30]2[C:29](=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:28]1=[O:37])=[CH2:2]
Reactant: C=COCCO
Reactant: O=C1c2ccccc2C(=O)N1O
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C=COCCON1C(=O)c2ccccc2C1=O
Temperature: 0 °C
Yield: 53 %

Procedure:
Ethylene glycol vinyl ether (9.88 g, 112 mmol), triphenylphosphine (29.4 g, 112 mmol), and N-hydroxyphthalimide (18.22 g, 111.7 mmol) were combined in 300 mL of anhydrous tetrahydrofuran and cooled to 0° C. (ice bath). Diethylazodicarboxylate (18.0 mL, 114 mmol) was added dropwise over 15 min and the resultant reaction mixture was allowed to warm to ambient temperature over 18 h. The reaction mixture was concentrated to a paste and the solids were filtered and washed with chloroform. The filtrate was further concentrated and filtered again, washing the solids with chloroform. The remaining chloroform solution was concentrated to an oil. The oil was dissolved in absolute ethanol (75 mL). Scratching with a glass rod induced crystallization. The crystals were collected and recrystallized from hot ethanol to afford colorless needles of 2-(2-vinyloxy-ethoxy)-isoindole-1,3-dione (13.8 g, 53% yield): 1H NMR (400 MHz, CDCl3) δ 7.85 (m, 2 H), 7.75 (m, 2 H), 6.46 (dd, J=14.3, 6.7 Hz, 1 H), 4.45 (m, 2H), 4.16 (dd, J=14.4, 2.2 Hz), 4.02 (m 3 H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9](=[O:23])[C:10]([CH3:22])([CH3:21])[O:11][C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CN(C=O)C.Cl[CH2:36][C:37]1[CH:42]=[CH:41][C:40]([CH3:43])=[CH:39][N:38]=1>O>[CH3:20][O:19][C:16]1[CH:17]=[CH:18][C:13]([C:12]2[O:11][C:10]([CH3:21])([CH3:22])[C:9](=[O:23])[C:8]=2[C:5]2[CH:4]=[CH:3][C:2]([O:1][CH2:36][C:37]3[CH:42]=[CH:41][C:40]([CH3:43])=[CH:39][N:38]=3)=[CH:7][CH:6]=2)=[CH:14][CH:15]=1
Reactant: Cc1ccc(CCl)nc1
Reactant: COc1ccc(C2=C(c3ccc(O)cc3)C(=O)C(C)(C)O2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(C2=C(c3ccc(OCc4ccc(C)cn4)cc3)C(=O)C(C)(C)O2)cc1
Temperature: 80 °C
Yield: 74.1 %

Procedure:
4-(4-Hydroxyphenyl)-5-(4-methoxyphenyl)-2,2-dimethylfuran-3(2H)-one (2.0, 6.5 mmol) was added to a mixture of cesium carbonate (10.5 g, 32.2 mmol) and DMF (50 mL) at RT under an atmosphere of nitrogen. The reaction mixture was stirred at RT for 30 min, upon which 2-(chloromethyl)-5-methylpyridine (1.36 g, 9.6 mmol) was added. The mixture was heated at 80° C. for 4 h (the reaction was monitored by TLC). The reaction mixture allowed to cool, diluted with water and extracted with EtOAc. The combined organics were dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography using 20% ethyl acetate in n-hexane and silica gel (230-400 mesh), to afford 5-(4-methoxyphenyl)-2,2-dimethyl-4-(4-((5-methylpyridin-2-yl)methoxy)phenyl)furan-3(2H)-one (2.0 g, 76.9%,) as an off-white solid. 1H NMR: 200 MHz, DMSO-d6: δ 8.4 (s, 1H), 7.6 (d, 1H), 7.55 (d, 2H), 7.4 (d, 1H), 7.2 (d, 2H), 7.1 (d, 2H), 7.0 (d, 2H), 5.2 (s, 2H) 3.8 (s, 3H), 2.3 (s, 3H), 1.45 (s, 6H). MS: [M+H]+: m/z=415.2. HPLC: (97.5%, Condition-A).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:19][CH2:20][CH2:21][N:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)=[CH:9][C:10]=2[N:12]2[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]2)[N:5]=[CH:4][N:3]=1.[ClH:27].[Cl:28][C:29]1[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][C:30]=1[NH2:31].Cl>C(O)(C)C>[ClH:1].[ClH:28].[ClH:27].[Cl:28][C:29]1[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][C:30]=1[NH:31][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:19][CH2:20][CH2:21][N:22]3[CH2:23][CH2:24][CH2:25][CH2:26]3)=[CH:9][C:10]=2[N:12]2[CH2:13][CH2:14][N:15]([CH3:18])[CH2:16][CH2:17]2)[N:5]=[CH:4][N:3]=1
Reactant: CN1CCN(c2cc(OCCN3CCCC3)cc3ncnc(Cl)c23)CC1
Reactant: COc1ccc(Cl)c(N)c1
Agent: Cl
Solvent: CC(C)O
Product: COc1ccc(Cl)c(Nc2ncnc3cc(OCCN4CCCC4)cc(N4CCN(C)CC4)c23)c1

Procedure:
Using an analogous procedure to that described in Example 5, 4chloro-5-(4-methylpiperazin-1-yl)-7-(2-pyrrolidin-1-ylethoxy)quinazoline (0.11 g) was reacted with 2-chloro-5-methoxyaniline hydrochloride (0.064 g) in the presence of a 6M solution of hydrogen chloride in isopropanol (0.05 ml) to give the title compound, as a trihydrochloride salt (0.092 g), a portion of which was converted into the free base using an analogous procedure to that described in Example 3. The free base gave the following characterising data: NMR Spectrum: (CDCl3) 1.8–1.9 (m, 4H), 2.32 (s, 3H), 2.48 (m, 2H), 2.65 (br s, 4H), 2.82 (d, 2H), 2.98 (m, 4H), 3.2 (d, 2H), 3.82 (s, 3H), 4.25 (m, 2H), 6.65 (m, 1H), 6.95 (m, 1H), 7.3 (d, 1H), 8.02 (d, 1H), 8.52 (s, 1H); Mass Spectrum: M+H+ 497 and 499.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:11](Br)=[CH:10][CH:9]=[C:8]([CH3:13])[N:7]=1)=[O:5])[CH3:2].[NH2:14][C:15]1[CH:16]=[N:17][N:18]([CH3:20])[CH:19]=1>[Pd]>[CH2:1]([O:3][C:4]([C:6]1[C:11]([NH:14][C:15]2[CH:16]=[N:17][N:18]([CH3:20])[CH:19]=2)=[CH:10][CH:9]=[C:8]([CH3:13])[N:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1nc(C)ccc1Br
Reactant: Cn1cc(N)cn1
Agent: [Pd]
Product: CCOC(=O)c1nc(C)ccc1Nc1cnn(C)c1

Procedure:
The Pd catalyzed coupling of 3-Bromo-6-methyl-pyridine-2-carboxylic acid ethyl ester and 4-Amino-1-methyl-pyrazole was performed in accordance with the general method of Example 78, step 3 to yield the title compound as an orange solid, MS (ISP): m/e=261.0 (M+H+).
Reaction SMILES: Cl.NO.[C:4]([C:6]1[CH:11]=[CH:10][C:9]([C:12](=[O:18])[CH:13]=[CH:14][N:15](C)C)=[CH:8][CH:7]=1)#[N:5]>CO.O>[O:18]1[C:12]([C:9]2[CH:10]=[CH:11][C:6]([C:4]#[N:5])=[CH:7][CH:8]=2)=[CH:13][CH:14]=[N:15]1
Reactant: CN(C)C=CC(=O)c1ccc(C#N)cc1
Agent: Cl
Agent: NO
Solvent: CO
Solvent: O
Product: N#Cc1ccc(-c2ccno2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 89.3 %

Procedure:
Hydroxylamine hydrochloride (21.40 g, 308 mmol) was added to a suspension of 1-(4-cyanophenyl)-3-dimethylaminopropen-1-one (55.96 g, 280 mmol) in MeOH (450 ml) and the reaction stirred at room temperature for 24 h. The reaction was diluted with water (400 ml) and the resultant precipitate collected by filtration, washed with water (5×150 ml) and dried in vacuo to give 4-(5-isoxazolyl)-benzonitrile as a pale yellow solid (42.53 g) m.p. 148-149°. δH (CDCl3) 8.35 (1H, d, J 1.8 Hz), 7.91 (2H, d, J 8.3 Hz), 7.77, (2H, d, J 8.3 Hz), 6.66 (1H, d, J 1.8 Hz).
Reaction SMILES: [C:1]([OH:9])(=[S:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[C:12]([O:16][C:17]([N:19]1[CH2:23][C@H:22](OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:21][C@H:20]1[C:35]([O:37][CH2:38][CH3:39])=[O:36])=[O:18])([CH3:15])([CH3:14])[CH3:13]>CN(C)C=O.[I-].[Na+]>[C:12]([O:16][C:17]([N:19]1[CH2:23][C@@H:22]([S:8][C:1](=[O:9])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:21][C@H:20]1[C:35]([O:37][CH2:38][CH3:39])=[O:36])=[O:18])([CH3:15])([CH3:14])[CH3:13]
Reactant: CCOC(=O)[C@@H]1C[C@@H](OS(=O)(=O)c2ccc(C)cc2)CN1C(=O)OC(C)(C)C
Reactant: OC(=S)c1ccccc1
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)[C@@H]1C[C@H](SC(=O)c2ccccc2)CN1C(=O)OC(C)(C)C
Temperature: 80 °C
Yield: 70.5 %

Procedure:
Next, 36.4 g of thiobenzoic acid was dissolved in 300 ml of dimethylformamide and cooled on an ice bath, to which was subsequently added 10.5 g of sodium hydride. To this were added 102 g of (2S,4R)-1-(t-butoxycarbonyl)-2-ethoxycarbonyl -4-(p-toluenesulfonyloxy)pyrrolidine dissolved in 200 ml of dimethylformamide and 37.5 g of sodium iodide, followed by heating at 80° C. for 3 hours. After concentration of the reaction mixture, the thus obtained residue was dissolved in .benzene, and the resulting organic layer was washed with 5% sodium bicarbonate aqueous solution, 10% citric acid aqueous solution and water in that order, followed by drying over sodium sulfate and subsequent evaporation of the solvent under a reduced pressure. The resulting residue was purified by a silica gel column chromatography to yield 66 g of (2S,4S)-1-(t-butoxycarbonyl)-2-ethoxycarbonyl -4-benzoylthiopyrrolidine.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.C([Li])CCC.[CH2:15]([N:22]1[CH2:27][CH2:26][C:25](=[O:28])[CH2:24][CH2:23]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[NH4+].[Cl-]>C1COCC1.CCCCCC>[CH2:15]([N:22]1[CH2:27][CH2:26][C:25]([C:2]2[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=2)([OH:28])[CH2:24][CH2:23]1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: COc1ccc(Br)cc1
Reactant: O=C1CCN(Cc2ccccc2)CC1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COc1ccc(C2(O)CCN(Cc3ccccc3)CC2)cc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 68.3 %

Procedure:
A solution of 44.8 g of 1-bromo-4-methoxybenzene in 700 ml of THF is cooled to −78° C., 168 ml of a 1.6M solution of n-butyllithium in hexane are added dropwise and the mixture is then stirred at −78° C. for 30 minutes. The solution of 45.3 g of 1-benzyl-4-piperidinone in 100 ml of THF is then added dropwise and the mixture is stirred at −78° C. for 2 hours. The reaction mixture is poured into 400 ml of saturated NH4Cl solution and extracted with ether, the organic phase is washed with water, with saturated NaCl solution and dried over MgSO4, and the solvent is evaporated off under vacuum. 48.6 g of the expected product are obtained after crystallization from hexane.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[O:15][CH2:14][CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11][CH:10]2[CH2:23][OH:24])[CH:5]=[CH:6][C:7]=1[Cl:8].Cl.C(O)C>C(O)C>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[O:15][CH2:14][CH2:13][NH:12][CH2:11][CH:10]2[CH2:23][OH:24])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CC(C)(C)OC(=O)N1CCOC(c2ccc(Cl)c(Cl)c2)C(CO)C1
Agent: Cl
Solvent: CCO
Product: OCC1CNCCOC1c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 135.5 %

Procedure:
To a solution of tert-butyl (6RS,7RS)-7-(3,4-dichlorophenyl)-6-(hydroxymethyl)-1,4-oxazepane-4-carboxylate (100 mg) in ethanol (0.5 mL) was added 2 N hydrogen chloride-ethanol solution (2.0 ml), and the mixture was stirred at room temperature for 24 hr. The crystals obtained by concentration under reduced pressure were recrystallized from ethyl acetate-ethanol to give the title compound (56.3 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N:11]3[N:14]=[CH:15][C:16]([C:17]#[CH:18])=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.Br[C:20]1[CH:21]=[CH:22][C:23]([O:35][CH3:36])=[C:24]([S:26]([NH:29][C:30]([CH3:34])([CH3:33])[CH2:31][OH:32])(=[O:28])=[O:27])[CH:25]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][N:11]3[N:14]=[CH:15][C:16]([C:17]#[C:18][C:20]4[CH:21]=[CH:22][C:23]([O:35][CH3:36])=[C:24]([S:26]([NH:29][C:30]([CH3:33])([CH3:34])[CH2:31][OH:32])(=[O:28])=[O:27])[CH:25]=4)=[C:10]3[N:9]=2)=[CH:6][CH:7]=1
Reactant: C#Cc1cnn2ccc(-c3ccc(Cl)cc3)nc12
Reactant: COc1ccc(Br)cc1S(=O)(=O)NC(C)(C)CO
Product: COc1ccc(C#Cc2cnn3ccc(-c4ccc(Cl)cc4)nc23)cc1S(=O)(=O)NC(C)(C)CO

Procedure:
The title compound was prepared from 5-(4-chloro-phenyl)-3-ethynyl-pyrazolo[1,5-a]pyrimidine (example C.6) (63 mg, 0.25 mmol) and 5-bromo-N-(2-hydroxy-1,1-dimethyl-ethyl)-2-methoxy-benzenesulfonamide (85 mg, 0.25 mmol) according to general procedure II. Obtained as a yellow solid (52 mg, 41%). MS (ISP) 511.1 [(M+H)+]; mp 264–266° C.