Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]([O:13][CH2:14][CH2:15][CH2:16][CH2:17]/[CH:18]=[CH:19]\[CH2:20]/[CH:21]=[CH:22]\[CH2:23]/[CH:24]=[CH:25]\[CH2:26]/[CH:27]=[CH:28]\[CH2:29]/[CH:30]=[CH:31]\[CH2:32][CH3:33])([CH2:11][CH3:12])[C:4]([O:6]C(C)(C)C)=[O:5])[CH3:2]>C(O)=O>[CH2:1]([C:3]([O:13][CH2:14][CH2:15][CH2:16][CH2:17]/[CH:18]=[CH:19]\[CH2:20]/[CH:21]=[CH:22]\[CH2:23]/[CH:24]=[CH:25]\[CH2:26]/[CH:27]=[CH:28]\[CH2:29]/[CH:30]=[CH:31]\[CH2:32][CH3:33])([CH2:11][CH3:12])[C:4]([OH:6])=[O:5])[CH3:2]
Reactant: CC/C=C\C/C=C\C/C=C\C/C=C\C/C=C\CCCCOC(CC)(CC)C(=O)OC(C)(C)C
Solvent: O=CO
Product: CC/C=C\C/C=C\C/C=C\C/C=C\C/C=C\CCCCOC(CC)(CC)C(=O)O
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 73.6 %

Procedure:
A mixture of formic acid (5 ml) and tert-butyl 2-ethyl-2-((5Z,8Z,11Z,14Z,17Z)-icosa-5,8,11,14,17-pentaen-1-yloxy)butanoate (250 mg, 0.55 mmol) was stirred vigorously under nitrogen at room temperature for 4.5 hours. The formic acid was removed in vacuo. The residue was purified by flash chromatography on silica gel using increasingly polar mixtures of heptane and ethyl acetate (100:0→80:20) as eluent. Concentration of the appropriate fractions afforded 163 mg (74% yield) of the title compound as an oil. 1H NMR (300 MHz, CDCl3): δ 0.86 (t, 6H), 0.99 (t, 3H), 1.36-1.57 (m, 2H), 1.68 (dd, 2H), 1.73-1.98 (m, 4H), 2.11 (tt, 4H), 2.70-3.01 (m, 8H), 3.39 (t, 2H), 5.20-5.56 (m, 10H). MS (electrospray): 481.4 [M+Na]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[C:12](=[CH:13][C:14]([O:18][CH3:19])=[CH:15][CH:16]=3)[C:11](=O)[NH:10][N:9]=2)=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:23])=O>>[Cl:23][C:11]1[C:12]2[C:17](=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=2)[C:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)=[N:9][N:10]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1ccc2c(-c3ccc(F)cc3)n[nH]c(=O)c2c1
Product: COc1ccc2c(-c3ccc(F)cc3)nnc(Cl)c2c1

Procedure:
This compound is obtained according to the procedure described in 1.3. by reacting 4-(4-fluorophenyl)-7-methoxy-2H-phthalazin-1-one with phosphoryl chloride.
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][N:6]([C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=[C:11]([C:19]3[CH:24]=[C:23]([F:25])[C:22]([O:26]CC4C=CC=CC=4)=[C:21]([F:34])[CH:20]=3)[N:10]=2)[CH2:5][CH2:4]1)[CH3:2].Cl>CO.[Pd]>[CH2:1]([N:3]1[CH2:8][CH2:7][N:6]([C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=[C:11]([C:19]3[CH:24]=[C:23]([F:25])[C:22]([OH:26])=[C:21]([F:34])[CH:20]=3)[N:10]=2)[CH2:5][CH2:4]1)[CH3:2]
Reactant: CCN1CCN(c2nc(-c3cc(F)c(OCc4ccccc4)c(F)c3)cc3ccccc23)CC1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CCN1CCN(c2nc(-c3cc(F)c(O)c(F)c3)cc3ccccc23)CC1
Yield: 64.9 %

Procedure:
The resulting 1-(4-ethylpiperazin-1-yl)-3-(4-benzyloxy-3,5-difluorophenyl)isoquinoline (6.44 g) was converted into a hydrochloride in a conventional manner. The hydrochloride was dissolved in methanol (200 ml), followed by the addition of 10% palladium/carbon catalyst (0.48 g), and then the catalytic reduction was conducted at atmospheric pressure overnight. The catalyst was filtered off, while the solvent was evaporated. Water was added to the resulting residue, followed by the addition of an aqueous solution of saturated sodium bicarbonate, and the mixture was extracted with chloroform. The extract was washed with brine, dried over magnesium sulfate, and the solvent was evaporated, to give obtain 1-(4-ethylpiperazin-1-yl)-3-(3,5-difluoro-4-hydroxyphenyl)isoquinoline (3.36 g) as a pale brown amorphous. Sodium hydride (0.04 g) was washed with n-hexane, suspended in N,N-dimethylformamide (2 ml) and stirred under ice-cooling. The above-described 1-(4-ethylpiperazin-1-yl)-3-(3,5-difluoro-4-hydroxyphenyl)isoquinoline (0.30 g) dissolved in N,N-dimethylformamide (2 ml) was added thereto, and the mixture was stirred at room temperature for 50 min. The mixture was again ice-cooled, followed by the addition of 2-methoxyethyl bromide (115 ml), and the mixture was stirred in nitrogen atmosphere at 50° C. overnight. Water was added to the reaction solution, and then it was extracted with ethyl acetate. The extract was washed with water and brine, and dried over magnesium sulfate. The solvent was evaporated, and the resulting residue was purified by silica gel column chromatography (chloroform/methanol system), to give 0.26 g of the free compound of the title compound as a brown viscous oil.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[C:7](=[O:21])[C:8]3[C:13]([S:14](=[O:18])(=[O:17])[C:15]=2[CH:16]=1)=[CH:12][CH:11]=[C:10]([O:19][CH3:20])[CH:9]=3)#[N:2].[CH2:22](N)[CH2:23][NH2:24].C[O-].[Na+]>CO>[NH:2]1[CH2:22][CH2:23][N:24]=[C:1]1[C:3]1[CH:16]=[C:15]2[C:6](=[CH:5][CH:4]=1)[C:7](=[O:21])[C:8]1[CH:9]=[C:10]([O:19][CH3:20])[CH:11]=[CH:12][C:13]=1[S:14]2(=[O:18])=[O:17]
Reactant: COc1ccc2c(c1)C(=O)c1ccc(C#N)cc1S2(=O)=O
Reactant: NCCN
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1ccc2c(c1)C(=O)c1ccc(C3=NCCN3)cc1S2(=O)=O
Temperature: 0 °C

Procedure:
To 5.0 g (0.017 mol) of 3-cyano-7-methoxythioxanthen-9-one 10,10-dioxide was added ethylenediamine, 10.8 g (0.18 mol), and sodium methoxide, (0.098 g, 0.002 mol), in methanol, 70 ml, and the mixture was refluxed for 70.5 hr. The mixture was then poured into ice water, 400 ml, and the precipitate was filtered and washed with water then was recrystallized from ethanol, DMSO and H2O to provide 1.1 g of 6-(2-imidazolin-2-yl)-2-methoxythioxanthen-9-one-10,10-dioxide with m.p. 220°-224° C.; TLC on silica gel (ethanol), Rf =0.44.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([S:16][CH3:17])=[CH:12][CH:11]=1.[Mg].II.[C:21](OC(=O)C)(=[O:23])[CH3:22]>[Cl-].[NH4+]>[CH3:17][S:16][C:13]1[CH:14]=[CH:15][C:10]([CH2:9][CH2:8][O:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][C:21](=[O:23])[CH3:22])=[CH:11][CH:12]=1
Reactant: CC(=O)OC(C)=O
Reactant: CSc1ccc(CCOCCCCCBr)cc1
Agent: II
Agent: [Cl-]
Agent: [Mg]
Product: CSc1ccc(CCOCCCCCC(C)=O)cc1
Reaction time: 2 h
Yield: 49.1 %

Procedure:
The product of state (i) (5.00 g) in ER (7.0 ml) was added dropwise to magnesium turnings (0.384 g) with one crystal of iodine at room temperature under nitrogen with stirring. The stirred mixture was heated to reflux for 3 h under nitrogen and the solution of Grignard reagent was added slowly to a stirred solution of acetic anhydride (2.86 g) in ER (70 ml) over a period of 1 h maintaining the temperature between -60° and -70°. After a further 2 h at -60° to -70°, the reaction mixture was allowed to warm to -10° and treated with a saturated aqueous ammonium chloride solution (20 ml). The ER layer was separated and the aqueous phase was extracted with ER (3×40 ml). The combined extracts were washed with 2N sodium hydroxide (30 ml) and brine (30 ml). The washings were extracted with ER (3×40 ml) and these extracts, combined with the previous extracts were dried and evaporated. The residual oil (3.73 g) was purified by FCC eluting with ER-H (1:14→1:7) followed by ER-CX (1:7 to give the title compound (2.17 g).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:32])[C:7]([CH2:18][NH:19][C:20](=[O:31])OC3C=CC([N+]([O-])=O)=CC=3)=[CH:8][N:9]2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:4][CH:3]=1.[C:33]1([N:39]2[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]2)[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:32])[C:7]([CH2:18][NH:19][C:20]([N:42]3[CH2:43][CH2:44][N:39]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[CH2:40][CH2:41]3)=[O:31])=[CH:8][N:9]2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:4][CH:3]=1
Reactant: O=C(NCc1cn(-c2ccccc2)c2cc(Cl)ccc2c1=O)Oc1ccc([N+](=O)[O-])cc1
Reactant: c1ccc(N2CCNCC2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(NCc1cn(-c2ccccc2)c2cc(Cl)ccc2c1=O)N1CCN(c2ccccc2)CC1
Temperature: 25 °C

Procedure:
In a 25 mL round-bottomed flask, 4-nitrophenyl (7-chloro-4-oxo-1-phenyl-1,4-dihydroquinolin-3-yl)methylcarbamate (intermediate M) (0.05 g, 0.111 mmol), 1-phenylpiperazine (18.0 mg, 0.111 mmol) and N,N-diisopropylethylamine (43.1 mg, 58.2 μA, 333 mmol) were combined with methylene chloride (5 mL). The reaction mixture was stirred at room temperature. The crude product was purified using preparative reverse-phase HPLC, giving 4-phenyl-piperazine-1-carboxylic acid (7-chloro-4-oxo-1-phenyl-1,4-dihydro-quinolin-3-ylmethyl)-amide MS calcd. for C27H26ClN4O2 [(M+H)+] 473.2, obsd. 473.0.
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[CH:4]=O.FC1C=C(F)C=CC=1CO>[Ni]>[F:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[CH3:4]
Reactant: O=Cc1ccc(F)cc1F
Agent: [Ni]
Agent: OCc1ccc(F)cc1F
Product: Cc1ccc(F)cc1F
Yield: 68.6 %

Procedure:
DE-A 2,333,849 discloses that 2,4-difluorobenzaldehyde can be converted into 2,4-difluorobenzyl alcohol in a yield of 68.6% by hydrogenation over Raney nickel. Disadvantages of this process are not only the large amount of catalyst (31 g per mol) and the large amount of a solvent (1100 ml per mole) but also the unsatisfactory yield of 68.6%. These factors result in an unsatisfactory space-time yield. The aldehyde used was obtained here from the difficult-to-obtain 2,4-difluorotoluene by side-chain chlorination and subsequent hydrolysis.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][CH2:8][CH2:9][CH2:10]Cl)=[CH:3][CH:2]=1.[C:12]1([C:18]2[CH2:19][CH2:20][NH:21][CH2:22][CH:23]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(=O)(O)[O-].[K+]>C(#N)C>[C:12]1([C:18]2[CH2:23][CH2:22][N:21]([CH2:10][CH2:9][CH2:8][CH2:7][C:4]3[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=3)[CH2:20][CH:19]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: C1=C(c2ccccc2)CCNC1
Reactant: ClCCCCc1ccncc1
Agent: O=C([O-])O
Agent: [K+]
Solvent: CC#N
Product: C1=C(c2ccccc2)CCN(CCCCc2ccncc2)C1
Temperature: 25 °C
Yield: 84.2 %

Procedure:
A mixture of 4-(4-pyridinyl)-1-butylchloride (Example A) (0 76 g, 4.47 mmol), 1,2,3,6-tetrahydro-4-phenylpyridine (0.796 g, 5.0 mmol), and potassium bicarbonat (1.0 g, 10 mmol) in 5 mL of acetonitrile are heated to reflux for 8 hours. The reaction is cooled to room temperature and the acetonitrile removed in vacuo. The residue is partitioned between 50 mL of water and 50 mL of chloroform. The aqueous layer is extracted again with 50 mL of chloroform and the combined organic extracts are dried over sodium sulfate and the solvent removed in vacuo. The resulting residue is chromatographed on silica gel (2% to 3% methanol, 0.1% ammonia, chloroform) to obtain 1.10 g of 4-[4-(3,6-dihydro-4-phenyl-1(2H)-pyridinyl)-butyl]pyridine as a white solid; mp 89`
Reaction SMILES: [OH:1][C:2]1[CH:19]=[CH:18][C:5]2[C:6](=O)[CH2:7][C:8]([CH2:11][CH2:12][C:13]([O:15][CH3:16])=[O:14])([CH3:10])[O:9][C:4]=2[C:3]=1[CH2:20][CH2:21][CH3:22]>C(O)(=O)C.CO.[Pd]>[OH:1][C:2]1[CH:19]=[CH:18][C:5]2[CH2:6][CH2:7][C:8]([CH2:11][CH2:12][C:13]([O:15][CH3:16])=[O:14])([CH3:10])[O:9][C:4]=2[C:3]=1[CH2:20][CH2:21][CH3:22]
Reactant: CCCc1c(O)ccc2c1OC(C)(CCC(=O)OC)CC2=O
Agent: [Pd]
Solvent: CO
Solvent: CC(=O)O
Product: CCCc1c(O)ccc2c1OC(C)(CCC(=O)OC)CC2
Yield: 45.9 %

Procedure:
A solution of 4.1 g (13.4 mmole) of ester product of Example 4 in 100 ml of acetic acid and 50 ml of methanol was hydrogenated for 21 hours at 4 psi and room temperature using palladium on carbon as catalyst. The catalyst was filtered and the filtrate was evaporated to dryness. Chromatography of the residue on silica gel using 20% ethyl acetate/hexane as eluent gave 1.8 g of the title compound as an oil. Structure assignment was confirmed by nmr and infrared spectra.
Reaction SMILES: [C:1](Cl)(=[O:4])[CH2:2][CH3:3].[Br-:6].[OH:7][C@@H:8]1[C@@H:25]([N:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)[CH2:24][C@@:23]2([CH3:32])[C@@H:10]([CH2:11][CH2:12][C@@H:13]3[C@@H:22]2[CH2:21][CH2:20][C@@:18]2([CH3:19])[C@H:14]3[CH2:15][C@H:16]([N+:38]3([CH3:44])[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]3)[C@@H:17]2[O:33][C:34](=[O:37])[CH2:35][CH3:36])[CH2:9]1>ClCCl>[Br-:6].[N:26]1([C@H:25]2[CH2:24][C@@:23]3([CH3:32])[C@@H:10]([CH2:11][CH2:12][C@@H:13]4[C@@H:22]3[CH2:21][CH2:20][C@@:18]3([CH3:19])[C@H:14]4[CH2:15][C@H:16]([N+:38]4([CH3:44])[CH2:39][CH2:40][CH2:41][CH2:42][CH2:43]4)[C@@H:17]3[O:33][C:34](=[O:37])[CH2:35][CH3:36])[CH2:9][C@@H:8]2[O:7][C:1](=[O:4])[CH2:2][CH3:3])[CH2:27][CH2:28][O:29][CH2:30][CH2:31]1
Reactant: CCC(=O)Cl
Reactant: CCC(=O)O[C@H]1[C@@H]([N+]2(C)CCCCC2)C[C@H]2[C@@H]3CC[C@H]4C[C@H](O)[C@@H](N5CCOCC5)C[C@]4(C)[C@H]3CC[C@@]21C
Agent: [Br-]
Solvent: ClCCl
Product: CCC(=O)O[C@H]1C[C@@H]2CC[C@@H]3[C@H](CC[C@@]4(C)[C@H]3C[C@H]([N+]3(C)CCCCC3)[C@@H]4OC(=O)CC)[C@@]2(C)C[C@@H]1N1CCOCC1
Reaction time: 20 h

Procedure:
Propanoyl chloride (5.24 ml) was added to a solution of 1-[(2β,3α,5α,16β,17β)-3-hydroxy-2(4-morpholinyl)-17-(1-oxopropoxy)-androstan-16-yl]-1-methylpiperidinium bromide (2.62 g) in dichloro-methane (33 ml) and the solution was set aside at room temperature for 20 h. The solution was evaporated to dryness under reduced pressure to give a gum, which was taken up in dichloromethane (15 ml) and purified by chromatography on alumina (Fluka type 5016A) (62 g) to give 1-[(2β,3α,5α,16β,17β)-2-(4-morpholinyl)-3,17-bis(1-oxopropoxy)-androstan-16-yl]-1-methylpiperidinium bromide as a non-crystalline solid (1.99 g), [α]D20 =-16.7° (c 1.09 in CHCl3).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:9]2[N:14]([CH2:15][C:16]([NH:18][C:19]3[CH:20]=[C:21]4[C:42](=[CH:43][CH:44]=3)[CH2:41][C@:23]3([C:31]5[C:26](=[N:27][CH:28]=[CH:29][CH:30]=5)[N:25]([CH2:32][O:33][CH2:34][CH2:35][Si:36]([CH3:39])([CH3:38])[CH3:37])[C:24]3=[O:40])[CH2:22]4)=[O:17])[C:13](=[O:45])[C:12]([CH3:47])([CH3:46])[CH2:11][CH2:10]2)[CH:5]=[C:6]([F:8])[CH:7]=1.[H-].[Na+].I[CH3:51]>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([C@H:9]2[N:14]([CH2:15][C:16]([N:18]([CH3:51])[C:19]3[CH:20]=[C:21]4[C:42](=[CH:43][CH:44]=3)[CH2:41][C@:23]3([C:31]5[C:26](=[N:27][CH:28]=[CH:29][CH:30]=5)[N:25]([CH2:32][O:33][CH2:34][CH2:35][Si:36]([CH3:39])([CH3:37])[CH3:38])[C:24]3=[O:40])[CH2:22]4)=[O:17])[C:13](=[O:45])[C:12]([CH3:47])([CH3:46])[CH2:11][CH2:10]2)[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: CC1(C)CC[C@@H](c2cc(F)cc(F)c2)N(CC(=O)Nc2ccc3c(c2)C[C@@]2(C3)C(=O)N(COCC[Si](C)(C)C)c3ncccc32)C1=O
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C(=O)CN1C(=O)C(C)(C)CC[C@H]1c1cc(F)cc(F)c1)c1ccc2c(c1)C[C@@]1(C2)C(=O)N(COCC[Si](C)(C)C)c2ncccc21
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a stirred solution of 2-[(6S)-6-(3,5-difluorophenyl)-3,3-dimethyl-2-oxopiperidin-1-yl]-N-((2R)-2′-oxo-1′-{[2-(trimethylsilyl)ethoxy]methyl}-1,1′,2′,3-tetrahydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridin]-5-yl]acetamide from Step A (47 mg, 0.07 mmol) in DMF (1 mL) at 0° C. was added NaH (11 mg of a 60% dispersion in oil, 0.28 mmol). After 15 min, iodomethane (30 mg, 0.21 mmol) was added and the mixture was allowed to warm to ambient temperature and was stirred for 1 h. The reaction mixture was quenched with H2O (5 mL) and the precipitate was isolated by filtration, washed with H2O, and dried in vacuo to provide the title compound. MS: m/z=675 (M+1).
Reaction SMILES: [C:1](O[BH-](OC(=O)C)OC(=O)C)(=O)[CH3:2].[Na+].[NH:15]1[CH2:20][CH2:19][CH2:18][CH:17]([O:21][C:22]2[CH:23]=[C:24]3[C:29](=[CH:30][CH:31]=2)[C:28](=[O:32])[NH:27][CH:26]=[CH:25]3)[CH2:16]1.C(O)(=O)C.C(=O)C>CN(C)C=O>[CH2:1]([N:15]1[CH2:20][CH2:19][CH2:18][CH:17]([O:21][C:22]2[CH:23]=[C:24]3[C:29](=[CH:30][CH:31]=2)[C:28](=[O:32])[NH:27][CH:26]=[CH:25]3)[CH2:16]1)[CH3:2]
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: O=c1[nH]ccc2cc(OC3CCCNC3)ccc12
Agent: CC=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: CCN1CCCC(Oc2ccc3c(=O)[nH]ccc3c2)C1
Reaction time: 17 h

Procedure:
Sodium triacetoxyborohydride (45 mg, 1.8 mol) was added to a solution of 6-(piperidin-3-yloxy)-2H-isoquinolin-1-one (30 mg, 0.12 mmol), acetic acid (100 μl) and acetaldehyde (50 μl or 50 mg) in N, N-dimethylformamide (500 μl) and shaken for 17 hours. The reaction was quenched with water and methanol and passed down an SCX cartridge. The product was purified by preparative HPLC under basic conditions. The clean products were isolated by evaporation under reduced pressure to give 6-(1-ethyl-piperidin-3-yloxy)-2H-isoquinolin-1-one: El-MS: m/z=273.5[M+H]+.
Reaction SMILES: Br[CH2:2][C:3]1[NH:12][C:11](=[O:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1.[Cl:14][C:15]1[C:16]([O:38][CH3:39])=[CH:17][C:18]([O:36][CH3:37])=[C:19]([CH2:21][CH2:22][C:23]2([CH:31]3[CH2:35][CH2:34][CH2:33][CH2:32]3)[O:28][C:27](=[O:29])[CH2:26][C:25](=[O:30])[CH2:24]2)[CH:20]=1>>[Cl:14][C:15]1[C:16]([O:38][CH3:39])=[CH:17][C:18]([O:36][CH3:37])=[C:19]([CH2:21][CH2:22][C:23]2([CH:31]3[CH2:35][CH2:34][CH2:33][CH2:32]3)[O:28][C:27](=[O:29])[C:26]([CH2:2][C:3]3[NH:12][C:11](=[O:13])[C:10]4[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=4)[N:4]=3)=[C:25]([OH:30])[CH2:24]2)[CH:20]=1
Reactant: COc1cc(OC)c(CCC2(C3CCCC3)CC(=O)CC(=O)O2)cc1Cl
Reactant: O=c1[nH]c(CBr)nc2ccccc12
Product: COc1cc(OC)c(CCC2(C3CCCC3)CC(O)=C(Cc3nc4ccccc4c(=O)[nH]3)C(=O)O2)cc1Cl
Yield: 19 %

Procedure:
The title compound was prepared as described in Example B(53), using 2-(bromomethyl)-quinazolin-4(3H)-one (Example B(55), Step 1) in place of 5-(chloromethyl)-1,3-dimethyl-1H-1,2,4-triazole, and using 6-[2-(5-chloro-2,4-dimethoxyphenyl)ethyl]-6-cyclopentyldihydro-2H-pyran-2,4(3H)-dione in place of 6-[2-(3-chloro-4-methoxyphenyl)ethyl]-6-cyclopentyldihydro-2H-pyran-2,4(3H)-dione. Yield: 19%. 1H NMR (300 MHz, DMSO-d6) δ 1.33-1.74 (m, 8H), 1.99 (m, 1H), 2.23 (m, 1H), 2.37 (m, 1H), 2.45-2.53 (m, 2H, overlap with DMSO-d5), 2.58 (d, J=17.5 Hz, 1H), 2.78 (d, J=17.5 Hz, 1H), 3.59 (ABQ pattern, J=16.6 Hz, 2H), 3.73 (s, 3H), 3.84 (s, 3H), 6.69 (s, 1H), 7.01 (d, J=8 Hz, 1H), 7.13 (s, 1H), 7.42 (t, J=8 Hz, 1H), 7.57 (t, J=8 Hz, 1H), 8.03 (d, J=8 Hz, 1H). LC-MS (APCI) calcd for C29H31ClN2O6: 538.19; found (M+H+) 539.0 m/z.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[C:9]([O:10][CH2:11]OC)=[C:8]([O:14]C)[C:7]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]2[C:26]([O:27]C)=[C:25]([O:29][CH2:30]OC)[C:24]([CH2:33][CH2:34][OH:35])=[C:23]([O:36]C)[C:22]=2[O:38][CH2:39]OC)=[C:6]([O:42][CH2:43]OC)[C:5]=1[O:46]C.Cl.C(=O)([O-])O.[Na+].O=O>O1CCCC1.C(O)(C)C.CO.O1CCCC1.C(O)(C)C>[OH:1][CH2:2][CH2:3][C:4]1[C:5](=[O:46])[C:6]([O:42][CH3:43])=[C:7]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]2[C:26](=[O:27])[C:25]([O:29][CH3:30])=[C:24]([CH2:33][CH2:34][OH:35])[C:23](=[O:36])[C:22]=2[O:38][CH3:39])[C:8](=[O:14])[C:9]=1[O:10][CH3:11]
Reactant: COCOc1c(CCO)c(OC)c(OCOC)c(CCCCCc2c(OC)c(OCOC)c(CCO)c(OC)c2OCOC)c1OC
Agent: Cl
Agent: O=C([O-])O
Agent: O=O
Solvent: CO
Solvent: CC(C)O
Solvent: C1CCOC1
Product: COC1=C(CCO)C(=O)C(OC)=C(CCCCCC2=C(OC)C(=O)C(CCO)=C(OC)C2=O)C1=O
Temperature: 50 °C

Procedure:
402 Milligrams of 4,4'-pentamethylenebis[1-(2-hydroxyethyl)-2,5-dimethoxy-3,6-bis(methoxymethoxy)benzene] was dissolved in a mixed solvent of 4 ml of tetrahydrofuran with 4 ml of isopropanol, under ice-cooling conditions, 0.8 ml of tetrahydrofuran-isopropanol (1:1) solution containing 20% of hydrogen chloride was added thereto. The reaction mixture was heated at 50° C. on a water bath for 5 hours with stirring. The reaction mixture was concentrated, and to the residue obtained was added 10 ml of methanol and a small amount of sodium hydrogen carbonate, then whole mixture was heated at 50 to 60° C., on a water bath and oxygen gas was blown into the reaction mixture for 5 hours. After the reaction was completed, the reaction mixture was filtered, and concentrated, the residue obtained was treated by means of a preparative thin layer chromatography (silica gel plate: 20×20 cm, thickness 2 mm, 2 plates were used, developing solvent: ethyl acetate:benzene=1:1), then recrystallized from petroleum ether to obtain 305 mg of 5,5'-pentamethylenebis[2-(2-hydroxyethyl)-3,6-dimethoxy-1,4-benzoquinone] was obtained. Yellow needles crystals.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH2:11][C:12]#[CH:13])[CH:5]=1>C(N(CC)C1C=CC=CC=1)C.CCOCC>[CH3:1][O:2][C:3]([C:4]1[C:5]2[CH:13]=[CH:12][CH2:11][O:10][C:6]=2[CH:7]=[CH:8][CH:9]=1)=[O:14]
Reactant: C#CCOc1cccc(C(=O)OC)c1
Solvent: CCOCC
Solvent: CCN(CC)c1ccccc1
Product: COC(=O)c1cccc2c1C=CCO2
Temperature: 25 °C

Procedure:
A solution of 3-prop-2-ynyloxy-benzoic acid methyl ester (10.5 mmol) in N,N-diethylaniline (20 mL) is heated to reflux for 15 h. The mixture is cooled to RT, diluted with ether and washed with aq. HCl (5%) and brine. The solvents are removed in vacuo and the residue is purified by FC (heptane to heptane/EtOAc 95/5) to give the desired chromene derivative. 1H-NMR (CDCl3): δ=3.91 (s, 3H); 4.80 (bs, 2H); 5.93-5.98 (m, 1H); 6.99 (d, J=8.03 Hz, 1H); 7.16 (t, J=7.66 Hz, 1H); 7.34 (d, J=10.3 Hz, 1H); 7.50 (d, J=7.28 Hz, 1H).
Reaction SMILES: [CH:1]([N:4]([CH:11]([CH3:13])[CH3:12])[C:5](=[O:10])[CH2:6][C:7](=[O:9])[CH3:8])([CH3:3])[CH3:2].[OH-].[Na+].[Cl-].[C:17]1([N+:23]#[N:24])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>O>[CH:11]([N:4]([CH:1]([CH3:2])[CH3:3])[C:5](=[O:10])[C:6](=[N:24][NH:23][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:7](=[O:9])[CH3:8])([CH3:13])[CH3:12]
Reactant: CC(=O)CC(=O)N(C(C)C)C(C)C
Reactant: N#[N+]c1ccccc1
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(=O)C(=NNc1ccccc1)C(=O)N(C(C)C)C(C)C
Yield: 68.2 %

Procedure:
7.0 g (0.038 mol) of N,N-diisopropyl-3-oxobutyramide, a solution of 5.3 g (0.133 mol) of NaOH in 58 ml of water and 0.04 mol of phenyldiazonium chloride were treated as described in preparation 8. The crude reaction mixture was purified by chromatography on silica gel (hexane/Et2O 95:5) obtaining 7.5 g of the title compound which was used as such in the subsequent step. M.p.=143°-145° C.
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH:24]([CH3:28])[C:25](=O)[CH3:26])=[CH:19][C:18]=1[CH3:29])[C:5]([NH:7][CH3:8])=[O:6].[CH3:30][O:31][NH2:32]>CO>[CH3:1][O:2][N:3]=[C:4]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH:24]([CH3:28])[C:25](=[N:32][O:31][CH3:30])[CH3:26])=[CH:19][C:18]=1[CH3:29])[C:5]([NH:7][CH3:8])=[O:6]
Reactant: CON
Reactant: CNC(=O)C(=NOC)c1ccccc1COc1ccc(OC(C)C(C)=O)cc1C
Solvent: CO
Product: CNC(=O)C(=NOC)c1ccccc1COc1ccc(OC(C)C(C)=NOC)cc1C
Temperature: 22.5 °C
Reaction time: 12 h

Procedure:
A solution of 21.7 g of the compound from Example 3 in 100 ml of methanol was admixed with 30.4 g of 30% strength aqueous methoxyamine solution and then stirred at 20-25° C. for 12 h. The solvent was distilled off and the residue was taken up in a mixture of methyl tert-butyl ether/water, and the phases were then separated. After drying, the solvent was removed from the organic phase. The residue gave 22 g of the title compound as a light-brown oil.
Reaction SMILES: [C:1]([C:5]1[C:6]([O:15]COCCOC)=[CH:7][C:8]([CH3:14])=[C:9]([CH:13]=1)[C:10]([OH:12])=[O:11])([CH3:4])([CH3:3])[CH3:2].[CH3:22]O>>[CH3:22][O:12][C:10](=[O:11])[C:9]1[CH:13]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:6]([OH:15])=[CH:7][C:8]=1[CH3:14]
Reactant: COCCOCOc1cc(C)c(C(=O)O)cc1C(C)(C)C
Reactant: CO
Product: COC(=O)c1cc(C(C)(C)C)c(O)cc1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 5-tert-butyl-4-(2-methoxy-ethoxymethoxy)-2-methyl benzoic acid from Example AAA (20.9 g, 70.5 mmol), MeOH (150 mL), and H2 SO4 (10 mL) was refluxed for 5 hours and stirred overnight at room temperature. The mixture was concentrated by half, diluted with H2O, and extracted with EtOAc. The combined extracts were washed with brine, dried (MgSO4), and concentrated to give the title compound. 1H NMR (CDCl3) δ 1.36 (s, 9 H), 2.48 (s, 3 H), 3.82 (s, 3 H), 6.48 (s, 1 H), 7.87 (s, 1 H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([NH:17]C(OC(C)(C)C)=O)[CH:12]=2)[O:8][N:7]=1)=[O:5])[CH3:2].FC(F)(F)C(O)=O>C(Cl)Cl>[NH2:17][C:13]1[CH:12]=[C:11]([C:9]2[O:8][N:7]=[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH:10]=2)[CH:16]=[CH:15][CH:14]=1
Reactant: CCOC(=O)c1cc(-c2cccc(NC(=O)OC(C)(C)C)c2)on1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1cc(-c2cccc(N)c2)on1
Yield: 200.3 %

Procedure:
5-(3-tert-butoxycarbonylamino-phenyl)-isoxazole-3-carboxylic acid ethyl ester (2.63 g, 0.00791 mole) in methylene chloride. (5 mL) was treated with trifluoroacetic acid (2.5 mL) at ambient temperature for 4 hours. The mixture was concentrated in vacuo to provide the titled compound (3.68 g).