Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][CH:5]([N:12]([CH2:33][CH2:34][CH2:35][CH2:36][N:37]([CH2:41][CH2:42][CH3:43])[CH2:38][CH2:39][CH3:40])[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][N:21]=CC2C=CC(C(F)(F)F)=CC=2)=[CH:16][CH:15]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)(=[O:3])[CH3:2].Cl>C(O)C>[C:1]([O:4][CH:5]([N:12]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][NH2:21])=[CH:16][CH:15]=1)[CH2:33][CH2:34][CH2:35][CH2:36][N:37]([CH2:38][CH2:39][CH3:40])[CH2:41][CH2:42][CH3:43])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)(=[O:3])[CH3:2]
Reactant: CCCN(CCC)CCCCN(Cc1ccc(CN=Cc2ccc(C(F)(F)F)cc2)cc1)C(OC(C)=O)c1ccccc1
Agent: Cl
Solvent: CCO
Product: CCCN(CCC)CCCCN(Cc1ccc(CN)cc1)C(OC(C)=O)c1ccccc1
Temperature: 0 °C
Yield: 71.3 %

Procedure:
In a 50 ml recovery flask, 517 mg (0.87 mmol, 1.0 equivalent) of {(4-dipropylaminobutyl)-[4-(4-trifluoromethylbenzylidene)aminomethylbenzyl]}amino}benzyl acetate (32) was dissolved in 5.2 ml of ethanol. The solution was cooled to 0° C. After the dropwise addition of 5.2 ml of 2N hydrochloric acid over about five minutes, the mixture was reacted at 0° C. for 5.6 hours. The reaction solution was extracted five times with 25 ml of chloroform. The aqueous layer was slowly added with 50 ml of chloroform and 40 ml of a 3N sodium hydroxide aqueous solution to make the mixture basic. The mixture was subjected to phase separation, and then extracted three times with 25 ml of chloroform. The extract was dried over anhydrous sodium sulfate, filtered, and concentrated, thereby obtaining 272.9 mg of [(4-aminomethylbenzyl)-(4-dipropylaminobutyl)amino]benzyl acetate (39) as a slightly yellow oily substance (yield: 72%). [HPLC: 97% (HPLC measurement conditions B)]
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]([CH2:18][N:19]3[CH2:24][CH2:23][CH:22]([N:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)[CH2:21][CH2:20]3)=[C:16]([C:31]([OH:33])=O)[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([S:34]([CH3:37])(=[O:36])=[O:35])[CH:14]=3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[F:38][C:39]([F:49])([F:48])[C@H:40]([NH2:47])[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1.C(N(CC)C(C)C)(C)C.C(P1(=O)OP(=O)(CCC)OP(=O)(CCC)O1)CC>ClCCl.O.C([O-])(O)=O.[Na+]>[Br:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]([CH2:18][N:19]3[CH2:24][CH2:23][CH:22]([N:25]4[CH2:26][CH2:27][O:28][CH2:29][CH2:30]4)[CH2:21][CH2:20]3)=[C:16]([C:31]([NH:47][C@H:40]([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[C:39]([F:38])([F:48])[F:49])=[O:33])[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([S:34]([CH3:37])(=[O:35])=[O:36])[CH:14]=3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)c1ccc2nc(-c3cccc(Br)c3)c(CN3CCC(N4CCOCC4)CC3)c(C(=O)O)c2c1
Reactant: N[C@H](c1ccccc1)C(F)(F)F
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc2nc(-c3cccc(Br)c3)c(CN3CCC(N4CCOCC4)CC3)c(C(=O)N[C@H](c3ccccc3)C(F)(F)F)c2c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 87.6 %

Procedure:
A mixture of 2-(3-bromophenyl)-6-(methylsulfonyl)-3-{[4-(4-morpholinyl)-1-piperidinyl]methyl}-4-quinolinecarboxylic acid (0.250 g, 0.398 mmol), [(1R)-2,2,2-trifluoro-1-phenylethyl]amine (0.093 g, 0.438 mmol), and N,N-diisopropylethylamine (77 μL, 0.438 mmol) in dichloromethane (3.98 mL) was cooled to 0° C., and 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphorinane 2,4,6-trioxide (0.356 mL of 50% solution in ethyl acetate, 0.597 mmol) was added dropwise. The mixture was stirred at 0° C. for 2 h, warmed to room temperature, and stirred overnight. The mixture was diluted with water (2 mL) and saturated aqueous NaHCO3 (1 mL) was added. After stirring for 30 min, the organic phase was removed, passed over a phase separator, and concentrated in vacuo. The residue was dissolved in acetonitrile, and water was added slowly until the mixture became cloudy. The solid precipitate was collected by filtration, washed with water, and dried to afford 2-(3-bromophenyl)-6-(methylsulfonyl)-3-{[4-(4-morpholinyl)-1-piperidinyl]methyl}-N-[(1R)-2,2,2-trifluoro-1-phenylethyl]-4-quinolinecarboxamide (0.260 g, 88% yield). MS (m/z) 747.1 (M+H+).
Reaction SMILES: O.[Cl:2][C:3]1[CH:18]=[C:17]([F:19])[C:16]([N:20]2[C:25](=[O:26])[CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[N:22]([CH3:31])[C:21]2=[O:32])=[CH:15][C:4]=1[O:5][C:6]1[C:11]([N+:12]([O-])=O)=[CH:10][CH:9]=[CH:8][N:7]=1>C(O)(=O)C.[Fe]>[NH2:12][C:11]1[C:6]([O:5][C:4]2[CH:15]=[C:16]([N:20]3[C:25](=[O:26])[CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[N:22]([CH3:31])[C:21]3=[O:32])[C:17]([F:19])=[CH:18][C:3]=2[Cl:2])=[N:7][CH:8]=[CH:9][CH:10]=1
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(Oc3ncccc3[N+](=O)[O-])c(Cl)cc2F)c1=O
Agent: [Fe]
Solvent: CC(=O)O
Solvent: O
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(Oc3ncccc3N)c(Cl)cc2F)c1=O
Temperature: 35 °C
Reaction time: 2 h
Yield: 95.7 %

Procedure:
To a mixture of 3.8 g of an iron powder, 50 ml of acetic acid and 5 ml of water was added a solution of 3.8 g of 2-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}-3-nitropyridine in 5.0 ml of acetic acid dropwise while maintaining the temperature of the reaction solution at 35° C. or lower. After completion of the addition, the mixture was stirred for 2 hours, then, the reaction solution was filtrated through Celite, and diluted with ethyl acetate. The mixture was neutralized with saturated aqueous sodium bicarbonate solution, the organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated, then, the resulted residue was subjected to silica gel chromatography to obtain 3.4 g of 3-amino-2-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}pyridine.
Reaction SMILES: [F:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11](=[O:28])[CH2:12][CH2:13][C:14]1[N:15]=[C:16]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([OH:27])[CH:20]=2)[O:17][CH:18]=1.[CH2:29](Br)[CH:30]([CH3:32])[CH3:31]>>[F:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11](=[O:28])[CH2:12][CH2:13][C:14]1[N:15]=[C:16]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH2:29][CH:30]([CH3:32])[CH3:31])[CH:20]=2)[O:17][CH:18]=1
Reactant: COc1ccc(-c2nc(CCC(=O)c3ccccc3OCCF)co2)cc1O
Reactant: CC(C)CBr
Product: COc1ccc(-c2nc(CCC(=O)c3ccccc3OCCF)co2)cc1OCC(C)C

Procedure:
Using the compound obtained in Example 271 and isobutyl bromide, white powdery 1-[2-(2-fluoroethoxy)phenyl]-3-[2-(3-isobutoxy-4-methoxyphenyl)oxazol-4-yl]propan-1-one was obtained following the procedure of Example 3.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]2[C:17]([O:24][C@@H:25]3[O:51][C@H:50]([CH2:52][O:53][C:54](=[O:59])[C:55]([CH3:58])([CH3:57])[CH3:56])[C@@H:42]([O:43][C:44](=[O:49])[C:45]([CH3:48])([CH3:47])[CH3:46])[C@H:34]([O:35][C:36](=[O:41])[C:37]([CH3:40])([CH3:39])[CH3:38])[C@H:26]3[O:27][C:28](=[O:33])[C:29]([CH3:32])([CH3:31])[CH3:30])=[N:18][NH:19][C:20]=2[CH:21]([CH3:23])[CH3:22])=[C:11]([CH3:60])[CH:10]=1)C1C=CC=CC=1>O1CCCC1.[C].[Pd]>[OH:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]2[C:17]([O:24][C@@H:25]3[O:51][C@H:50]([CH2:52][O:53][C:54](=[O:59])[C:55]([CH3:58])([CH3:57])[CH3:56])[C@@H:42]([O:43][C:44](=[O:49])[C:45]([CH3:47])([CH3:46])[CH3:48])[C@H:34]([O:35][C:36](=[O:41])[C:37]([CH3:38])([CH3:39])[CH3:40])[C@H:26]3[O:27][C:28](=[O:33])[C:29]([CH3:32])([CH3:30])[CH3:31])=[N:18][NH:19][C:20]=2[CH:21]([CH3:23])[CH3:22])=[C:11]([CH3:60])[CH:10]=1
Reactant: Cc1cc(OCc2ccccc2)ccc1Cc1c(O[C@@H]2O[C@H](COC(=O)C(C)(C)C)[C@@H](OC(=O)C(C)(C)C)[C@H](OC(=O)C(C)(C)C)[C@H]2OC(=O)C(C)(C)C)n[nH]c1C(C)C
Agent: [Pd]
Solvent: C1CCOC1
Product: Cc1cc(O)ccc1Cc1c(O[C@@H]2O[C@H](COC(=O)C(C)(C)C)[C@@H](OC(=O)C(C)(C)C)[C@H](OC(=O)C(C)(C)C)[C@H]2OC(=O)C(C)(C)C)n[nH]c1C(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 99.8 %

Procedure:
4-[(4-Benzyloxy-2-methylphenyl)methyl]-5-isopropyl-3-(2,3,4,6-tetra-O-pivaloyl-β-D-glucopyranosyloxy)-1H-pyrazole (5 g) was dissolved in tetrahydrofuran (18 mL). To the solution was added 10% palladium-carbon powder (500 mg), and the mixture was stirred at room temperature under a hydrogen atmosphere for 3 hours. The insoluble material was removed by filtration, and the solvent of the filtrate was removed under reduced pressure to give the title compound (4.45 g).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([O:19][C:20]3[CH:25]=[CH:24][C:23]([N+:26]([O-])=O)=[CH:22][C:21]=3[F:29])=[CH:14][CH:15]=[N:16]2)=[CH:11][C:10]=1[O:30][CH3:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.NN>C1COCC1.[Ni]>[CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([O:19][C:20]3[CH:25]=[CH:24][C:23]([NH2:26])=[CH:22][C:21]=3[F:29])=[CH:14][CH:15]=[N:16]2)=[CH:11][C:10]=1[O:30][CH3:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cc2c(Oc3ccc([N+](=O)[O-])cc3F)ccnc2cc1OCc1ccccc1
Agent: [Ni]
Agent: NN
Solvent: C1CCOC1
Product: COc1cc2c(Oc3ccc(N)cc3F)ccnc2cc1OCc1ccccc1
Reaction time: 0.5 h

Procedure:
To a stirring solution of 7-(benzyloxy)-4-(2-fluoro-4-nitrophenoxy)-6-methoxyquinoline (Step 1, 4.5 g, 10.7 mmol) and hydrazine (2 mL, 61 mmol) in THF (200 mL) was added Raney 2400 nickel (1 mL slurry in water). The suspension was stirred for 30 min. The mixture was filtered through a bed of Celite®, then solvents were removed under reduced pressure to afford the title compound. Calc'd Mass for C23H19FN2O3, 390, MS (M+1) 391.
Reaction SMILES: [F:1][C:2]1[CH:23]=[CH:22][C:5]([C:6]([NH:8][C:9]2[S:10][C:11]3[C:17]([CH:18]=[CH2:19])=[CH:16][CH:15]=[C:14]([O:20][CH3:21])[C:12]=3[N:13]=2)=[O:7])=[CH:4][CH:3]=1>CO.[Pd]>[CH2:18]([C:17]1[C:11]2[S:10][C:9]([NH:8][C:6](=[O:7])[C:5]3[CH:22]=[CH:23][C:2]([F:1])=[CH:3][CH:4]=3)=[N:13][C:12]=2[C:14]([O:20][CH3:21])=[CH:15][CH:16]=1)[CH3:19]
Reactant: C=Cc1ccc(OC)c2nc(NC(=O)c3ccc(F)cc3)sc12
Agent: [Pd]
Solvent: CO
Product: CCc1ccc(OC)c2nc(NC(=O)c3ccc(F)cc3)sc12
Reaction time: 2 h

Procedure:
100 mg of 4-fluoro-N-(4-methoxy-7-vinyl-benzothiazol-2-yl)-benzamide (0.3 mmol) were dissolved in methanol (100 ml) and Pd/C (4 mg) were added. The reaction mixture was hydrogenated for 2 hrs. After filtering and evaporation of the solvent the crude product was subjected to column chromatography (silica gel, eluent MeOH/CH2Cl2 1:9). The title compound was obtained in form of white crystals (79%); F.p.: 165-167° C.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH:13]1([C:19]([O:21][CH3:22])=[O:20])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1.[CH2:23]([O:30][C:31]1[CH:38]=[CH:37][CH:36]=[CH:35][C:32]=1[CH2:33]Cl)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>O1CCCC1>[CH2:23]([O:30][C:31]1[CH:38]=[CH:37][CH:36]=[CH:35][C:32]=1[CH2:33][C:13]1([C:19]([O:21][CH3:22])=[O:20])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: COC(=O)C1CCCCC1
Reactant: ClCc1ccccc1OCc1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: COC(=O)C1(Cc2ccccc2OCc2ccccc2)CCCCC1
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 69.5 %

Procedure:
Under anhydrous conditions and a nitrogen atmoshere a solution of 8.7 g (0.086 mole) diisopropylamine in 250 ml tetrahydrofuran was cooled to -78° C. and 1.6M n-butyllithium (53.75 ml, 0.086 mole) was added dropwise over ten minutes. The mixture was stirred for 45 minutes, allowed to warm to 0° C. and 12.2 g (0.086 mole) methyl cyclohexancarboxylate was added. Stirring was continued for 45 minutes and then 20 g (0.086 mole) 2-benzyloxybenzyl chloride in 20 ml tetrahydrofuran was added dropwise. The resulting mixture was stirred at room temperature for 24 hours, quenched by addition of 150 ml 3M acetic acid and stirred at room temperature for one week. The mixture was diluted with ethyl ether, washed with sodium bicarbonate solution, brine, dried (MgSO4) and concentrated to a yellow oil, 29.3 g. This was distilled to obtain 20.23 g (70%) of viscous oil, b.p. 135°-140° C. (0.4 Torr).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:20][C:21]1[CH:22]=[CH:23][C:24]([N+:28]([O-:30])=[O:29])=[C:25]([OH:27])[CH:26]=1.[C:31]([O:36][CH3:37])(=[O:35])[C@H:32]([CH3:34])O.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C(Cl)Cl>[Br:20][C:21]1[CH:22]=[CH:23][C:24]([N+:28]([O-:30])=[O:29])=[C:25]([CH:26]=1)[O:27][C@H:32]([CH3:34])[C:31]([O:36][CH3:37])=[O:35]
Reactant: O=[N+]([O-])c1ccc(Br)cc1O
Reactant: COC(=O)[C@H](C)O
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COC(=O)[C@@H](C)Oc1cc(Br)ccc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 94 %

Procedure:
Triphenylphosphine (624.0 mg, 2.38 mmol) was added at room temperature to a solution of 5-bromo-2-nitrophenol A-15 (400.0 mg, 1.83 mmol) and methyl(−)—(S)-lactate (0.149 mL, 1.56 mmol) in anhydrous methylene chloride (18.3 mL) under an atmosphere of argon. After 10 mins of stirring, the reaction mixture was cooled to 0° C. and diisopropyl azodicarboxylate (0.360 mL, 1.83 mmol) was added dropwise. The orange solution was warmed to room temperature, stirred for 12 h, then concentrated to ca. 1.0 mL, diluted with pentane (7 mL) and diethyl ether (8 mL), filtered and rinsed with diethyl ether-pentane (15 mL). The filtrate was concentrated to dryness under reduced pressure, and the residue was purified by flash column chromatography on silica gel (hexanes to ethyl acetate gradient) to give (R)-methyl 2-(5-bromo-2-nitrophenoxy)propanoate (R)-A-16 as a yellow solid (525.0 mg; Yield=94%). MS (ESI) [M+1]+ 304, 306.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][C@@H:13]([CH2:15][O:16][C:17]2[CH:25]=[CH:24][CH:23]=[CH:22][C:18]=2[C:19](O)=[O:20])[C@H:12]([C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[C:28]([Cl:33])[CH:27]=2)[O:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:34][S:35]([NH2:38])(=[O:37])=[O:36].Cl.CN(C)CCCN=C=NCC>CN(C=O)C.CN(C1C=CN=CC=1)C.C(OCC)(=O)C>[Cl:33][C:28]1[CH:27]=[C:26]([C@@H:12]2[O:11][CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:14][C@H:13]2[CH2:15][O:16][C:17]2[CH:25]=[CH:24][CH:23]=[CH:22][C:18]=2[C:19](=[O:20])[NH:38][S:35]([CH3:34])(=[O:37])=[O:36])[CH:31]=[CH:30][C:29]=1[Cl:32]
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(Cl)c(Cl)c2)[C@H](COc2ccccc2C(=O)O)C1
Reactant: CS(N)(=O)=O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(Cl)c(Cl)c2)[C@H](COc2ccccc2C(=O)NS(C)(=O)=O)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 34.6 %

Procedure:
To a solution of 2-{[(6S,7R)-4-(tert-butoxycarbonyl)-7-(3,4-dichlorophenyl)-1,4-oxazepan-6-yl]methoxy}benzoic acid (100 mg) in DMF (1 ml) were added methanesulfonamide (38.3 mg), N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (62.5 mg) and N,N-dimethyl-4-aminopyridine (49.2 mg) at room temperature, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate. The diluted solution was washed with distilled water and brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (hexane/ethyl acetate) to give the title compound (40 mg).
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[CH2:14][CH2:13][CH2:12][C:11]2(OCC[O:15]2)[C@@:10]1([CH3:26])[CH2:19][CH2:20][CH2:21][CH:22]([CH3:25])[CH2:23][OH:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(C)=O.S(=O)(=O)(O)O>O>[CH2:1]([O:8][C@@H:9]1[CH2:14][CH2:13][CH2:12][C:11](=[O:15])[C@@:10]1([CH3:26])[CH2:19][CH2:20][CH2:21][CH:22]([CH3:25])[CH2:23][OH:24])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(CO)CCC[C@@]1(C)[C@H](OCc2ccccc2)CCCC12OCCO2
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(C)=O
Product: CC(CO)CCC[C@]1(C)C(=O)CCC[C@H]1OCc1ccccc1
Yield: 99.8 %

Procedure:
A mixture of (2S*,3R*)-3-benzyloxy-1,1-ethylenedioxy-2-methyl-2-(4'-methyl-5'-hydroxypentyl)-cyclohexane (13.9 g, 0.0384 mol), acetone (150 ml), water (20 ml) and 0.002 N sulfuric acid (50 ml) is refluxed for 18 hours under a nitrogen atmosphere. The reaction mixture is cooled, the acetone evaporated under reduced pressure and the aqueous layer extracted with ether (3×500 ml). The combined organic layers are washed with saturated sodium bicarbonate (100 ml), saturated sodium chloride (2×200 ml) and dried (MgSO4). The solvents are removed to afford (2S*,3R*)-3-benzyloxy-2-methyl-2-(4'-methyl-5'-hydroxypentyl)-cyclohexanone (crude product, 12.2 g, 100%): ir (neat) 3484 (OH), 1709 cm-1 (CO); nmr (CDCl3)δ0.88 (d, J=6 Hz, 3H, -CH-CH3), 1.08 (s, 3H, CH3), 3.42 ##STR36## 4.50 (d of d, J=10 Hz, 2H, Ph-CH2 -O-), 7.2 (s, 5H, aromatic).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[N:20]=[CH:19][C:18]([CH2:21][O:22][C:23]2[C:28]([CH2:29]O)=[CH:27][CH:26]=[CH:25][N:24]=2)=[CH:17][CH:16]=1.[CH2:31]([N:33](CC)CC)C.CS(Cl)(=O)=O.[C-]#N.[Na+]>O.CS(C)=O.C(OCC)(=O)C>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[N:20]=[CH:19][C:18]([CH2:21][O:22][C:23]2[C:28]([CH2:29][C:31]#[N:33])=[CH:27][CH:26]=[CH:25][N:24]=2)=[CH:17][CH:16]=1
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc(COc2ncccc2CO)cn1
Reactant: CCN(CC)CC
Agent: CS(=O)(=O)Cl
Agent: [C-]#N
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1oc(-c2ccccc2)nc1COc1ccc(COc2ncccc2CC#N)cn1
Temperature: 25 °C
Reaction time: 3 h
Yield: 71 %

Procedure:
To a mixture of [2-[[6-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]-3-pyridyl]methoxy]-3-pyridyl]methanol (2.55 g), triethylamine (1.27 g) and ethyl acetate (200 mL) was dropwise added methanesulfonyl chloride (1.44 g) under ice-cooling and the mixture was stirred at room temperature for 3 hrs. The reaction mixture was washed successively with water, saturated aqueous sodium hydrogencarbonate and saturated brine, dried over anhydrous magnesium sulfate, and concentrated to give an oil. To a mixture of this oil and dimethyl sulfoxide (30 mL) was added an aqueous solution (3 mL) of sodium cyanide (0.77 g) at room temperature and the mixture was stirred at room temperature for 15 hrs. To the reaction mixture was added water and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The obtained residue was subjected to silica gel column chromatography to give crystals (1.85 g, 71%) of 2-[2-[[6-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]-3-pyridyl]methoxy]-3-pyridyl]acetonitrile from a fraction eluted with ethyl acetate-hexane (1:2, v/v). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 110-111° C.
Reaction SMILES: [ClH:1].[C:2]1(=[O:16])[N:6]([CH2:7][C:8](=[NH:10])O)[C:5](=[O:11])[C:4]2=[CH:12][CH:13]=[CH:14][CH:15]=[C:3]12.C(=O)([O-])[O-].[K+].[K+].[Cl-].[NH4+:24]>CO>[ClH:1].[C:2]1(=[O:16])[N:6]([CH2:7][C:8]([NH2:24])=[NH:10])[C:5](=[O:11])[C:4]2=[CH:12][CH:13]=[CH:14][CH:15]=[C:3]12
Reactant: N=C(O)CN1C(=O)c2ccccc2C1=O
Reactant: [NH4+]
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: CO
Product: N=C(N)CN1C(=O)c2ccccc2C1=O

Procedure:
A mixture of 2-phthalimidoacetimidate hydrochloride (6 g, Chem. Ber., 1964, 97, 528) and a saturated aqueous potassium carbonate solution (50 ml) was stirred at ambient temperature for 3 minutes and then extracted with chloroform. The organic phase was dried (Na2SO4) and evaporated. A mixture of the solid so obtained, ammonium chloride (1.4 g) and methanol (100 ml) was stirred at laboratory temperature for 18 hours. The mixture was evaporated to give 2-phthalimidoacetamidine hydrochloride, as a white solid (5.5 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])[C:5]2=[CH:14]OC.[N:17]1([CH2:23][C:24]2[CH:29]=[CH:28][C:27]([NH2:30])=[CH:26][CH:25]=2)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1>CN(C)C=O.C(OCC)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])[C:5]2=[CH:14][NH:30][C:27]1[CH:26]=[CH:25][C:24]([CH2:23][N:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)=[CH:29][CH:28]=1
Reactant: Nc1ccc(CN2CCCCC2)cc1
Reactant: COC=C1C(=O)NC(=O)c2ccc(Br)cc21
Solvent: CN(C)C=O
Solvent: CCOCC
Product: O=C1NC(=O)c2ccc(Br)cc2C1=CNc1ccc(CN2CCCCC2)cc1
Temperature: 115 °C
Yield: 84.6 %

Procedure:
6-Bromo-4-methoxymethylene-4H-isoquinoline-1,3-dione (100 mg, 0.350 mmol) and 4-piperidin-1-ylmethyl-phenylamine (67 mg, 0.35 mmol) are suspended in 5 ml of dimethylformamide. Mixture is heated at 115° C. for 2 hours forming a homogeneous mixture. Mixture is cooled to room temperature and concentrated on high vacuum to yield an orange oil. Residue is taken up in ethyl ether causing an orange solid to form. Mixture is filtered, and residue washed with 50 ml of ethyl ether to afford the product as an orange solid (130 mg, 0.296 mmol, 85%); 1H NMR (DMSO-d6) δ 1.37-1.52 (m, 6H), 2.25-2.36 (m, 4H), 3.40 (s, 2H), 7.31 (d, J=8.4 Hz, 2H), 7.39 (dd, J=1.6, 8.4 Hz, 1H), 7.52 (d, J=8.5 Hz, 2H), 7.89 (d, J=8.4 Hz, 1H), 8.44 (d, J=1.6 Hz, 1H), 8.92 (d, J=12.8 Hz, 1H), 11.39 (s, 1H), 12.50 (d, J=12.7 Hz, 1H).
Reaction SMILES: [CH3:1][N:2]([CH3:7])[CH2:3][CH2:4][CH2:5][NH2:6].Cl[C:9]1[C:14]([Cl:15])=[CH:13][CH:12]=[CH:11][C:10]=1[N+:16]([O-:18])=[O:17]>C1(C)C=CC=CC=1>[Cl:15][C:14]1[CH:13]=[CH:12][CH:11]=[C:10]([N+:16]([O-:18])=[O:17])[C:9]=1[NH:6][CH2:5][CH2:4][CH2:3][N:2]([CH3:7])[CH3:1]
Reactant: CN(C)CCCN
Reactant: O=[N+]([O-])c1cccc(Cl)c1Cl
Solvent: Cc1ccccc1
Product: CN(C)CCCNc1c(Cl)cccc1[N+](=O)[O-]
Temperature: 125 °C
Reaction time: 13.5 h
Yield: 87.9 %

Procedure:
N,N-Dimethyl-1,3-propanediamine (5.125 g) was added to 2,3-dichloronitrobenzene (3.841 g) and stirred for 13.5 hours at 125° C. The reaction mixture, with toluene added thereto, was washed with saturated sodium hydrogencarbonate aqueous solution and saturated brine successively, dried over sodium sulfate anhydride, and concentrated. The residue (4.881 g) was purified by silica gel column chromatography (silica gel 100 g, chloroform:methanol=1:0-50:1), thereby yielding the entitled compound (4.53 g) as reddish orange oil.
Reaction SMILES: C[O:2][C:3](=[O:25])[CH2:4][C:5]1[CH:10]=[C:9]([OH:11])[CH:8]=[C:7]([O:12][C:13]2[CH:18]=[CH:17][C:16]([S:19]([CH2:22][CH3:23])(=[O:21])=[O:20])=[CH:15][C:14]=2[Cl:24])[CH:6]=1.CO.[Si](C=[N+]=[N-])(C)(C)[CH3:29]>C1(C)C=CC=CC=1>[Cl:24][C:14]1[CH:15]=[C:16]([S:19]([CH2:22][CH3:23])(=[O:21])=[O:20])[CH:17]=[CH:18][C:13]=1[O:12][C:7]1[CH:6]=[C:5]([CH2:4][C:3]([OH:2])=[O:25])[CH:10]=[C:9]([O:11][CH3:29])[CH:8]=1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: CCS(=O)(=O)c1ccc(Oc2cc(O)cc(CC(=O)OC)c2)c(Cl)c1
Solvent: CO
Solvent: Cc1ccccc1
Product: CCS(=O)(=O)c1ccc(Oc2cc(CC(=O)O)cc(OC)c2)c(Cl)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
The product from step (i) was taken up in toluene (3 ml) and methanol (1 ml) and TMS-diazomethane (0.6 ml, 2M in diethylether) added, the mixture stirred at RT for 3 h then evaporated under reduced pressure. The residue was taken up in THF (2 ml) and methanol (1 ml) then 3M NaOH (2 ml) added and the mixture stirred at RT for 2 h. The mixture was then acidified to pH 2 and extracted with ethyl acetate. The organics were dried (MgSO4), evaporated under reduced pressure and then passed onto a Varian NH2 resin (eluting with ethyl acetate, acetonitrile, methanol, DCM then 20% acetic acid in DCM). The acidic fraction was evaporated under reduced pressure and then purified by RPHPLC to give a white solid.