Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[CH2:5][CH2:4][S:3][CH:2]1[C:6]1[CH:7]=[C:8]([OH:13])[CH:9]=[C:10]([CH:12]=1)[OH:11].[C:14]1(O)([CH3:23])[CH2:19][CH2:18][CH:17]([C:20]([CH3:22])=[CH2:21])[CH:16]=[CH:15]1.C1C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(Cl)Cl>[S:1]1[CH2:5][CH2:4][S:3][CH:2]1[C:6]1[CH:7]=[C:8]([OH:13])[C:9]2[CH:18]3[CH2:19][C:14]([CH3:23])=[CH:15][CH2:16][CH:17]3[C:20]([CH3:22])([CH3:21])[O:11][C:10]=2[CH:12]=1
Reactant: C=C(C)C1C=CC(C)(O)CC1
Reactant: Oc1cc(O)cc(C2SCCS2)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: c1ccccc1
Product: CC1=CCC2C(C1)c1c(O)cc(C3SCCS3)cc1OC2(C)C

Procedure:
In the third step of the process 5-(1,3-dithiolan-2-yl)resorcinol (V) is reacted with p-mentha-2,8-dien-1-ol having the formula ##STR10## in a suitable liquid reaction medium such as benzene or methylene chloride in the presence of an acid, such as p-toluenesulfonic acid, to induce the condensation. The procedures for this type of reaction are disclosed in Helv. Chim. Acta, 52, 1102 (1969). An elevated temperature, such as the reflux temperature, promotes the reaction and brings it to completion in less than one hour. The desired 3-(1,3-dithiolan-2-yl)-6a,7,10,10a-tetrahydro-6,6,9-trimethyl-6H-dibenzo[b,d]pyran-1-ol (VI) is then obtained from the reaction mixture, and purified, using routine operations.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:4]=[C:5]([SH:9])[CH:6]=[CH:7][CH:8]=1.[OH-].[Na+].Cl[CH2:15][CH2:16][C:17]#[N:18]>O>[F:11][C:2]([F:1])([F:10])[C:3]1[CH:4]=[C:5]([S:9][CH2:15][CH2:16][C:17]#[N:18])[CH:6]=[CH:7][CH:8]=1
Reactant: FC(F)(F)c1cccc(S)c1
Reactant: N#CCCCl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: N#CCCSc1cccc(C(F)(F)F)c1

Procedure:
A solution of 15.9 g (0.09 mol) of 3-trifluoromethylthiophenol and 3.8 g (0.095 mol) of sodium hydroxide pellets in 100 ml of water is heated at 65°-70° C and 8.5 g (0.095 mol) of β-chloropropionitrile are added dropwise whilst stirring. The mixture is heated for a quarter of an hour to the reflux temperature and is then cooled and extracted with ether, and the extract is washed with water and dried with magnesium sulphate. This gives 3-(3-trifluoromethylphenylthio)-propionitrile, which is not isolated.
Reaction SMILES: [Li+].[OH-].C[O:4][C:5](=[O:15])[C:6]1[CH:14]=[CH:13][C:9]([C:10]([NH2:12])=[O:11])=[CH:8][CH:7]=1.CO.O>C1COCC1>[C:5]([OH:15])(=[O:4])[C:6]1[CH:14]=[CH:13][C:9]([C:10]([NH2:12])=[O:11])=[CH:8][CH:7]=1
Reactant: COC(=O)c1ccc(C(N)=O)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: NC(=O)c1ccc(C(=O)O)cc1
Yield: 44.3 %

Procedure:
LiOH (26 mg, 0.6 mmol) was added to a stirred solution of terephthalamic acid methyl ester (73 mg, 0.41 mmol) in THF:MeOH:water mixture (3:1:1, 1 mL) and the resulting mixture was stirred at room temperature overnight. The THF and MeOH were then evaporated and the resulting residue was acidified to pH 2 using 10% citric acid solution. The product was extracted using EtOAc. The organic layer was washed with saturated brine solution, dried over Na2SO4 and concentrated under reduced pressure to afford 30 mg (53.6% yield) of terephthalamic acid. LCMS Purity: 92.2%.
Reaction SMILES: [O:1]=[C:2]1[C:7]2[CH:8]=[CH:9][O:10][C:6]=2[C:5]([CH2:11][C:12](OC)=O)=[CH:4][NH:3]1.[C-]#[N:17].[Na+].CS(C)=O>C(OCC)(=O)C>[O:1]=[C:2]1[C:7]2[CH:8]=[CH:9][O:10][C:6]=2[C:5]([CH2:11][C:12]#[N:17])=[CH:4][NH:3]1
Reactant: COC(=O)Cc1c[nH]c(=O)c2ccoc12
Reactant: [C-]#N
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: N#CCc1c[nH]c(=O)c2ccoc12
Temperature: 25 °C
Yield: 97.9 %

Procedure:
Combine methyl (4-oxo-4,5-dihydrofuro[3,2-c]pyridin-7-yl)acetate (4.42 g, 21.3 mmol), sodium cyanide (5.22 g, 106 mmol), and dimethylsulfoxide (44 mL) and heat at 80° C. for 1 hour. Cool to room temperature, pour into ethyl acetate, wash sequentially with water, saturated aqueous sodium bicarbonate, and saturated aqueous sodium chloride, dry over magnesium sulftate, filter, and concentrate under reduced pressure to provide the desired compound (3.63 g, 63%).
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:27])[N:4]([C:10]2[CH:15]=[C:14]([C:16]3[CH:21]=[CH:20][N:19]=[C:18]([C:22]([OH:25])([CH3:24])[CH3:23])[N:17]=3)[CH:13]=[CH:12][C:11]=2[CH3:26])[C:5]([CH3:9])=[N:6][C:7]=1[OH:8].Cl[CH2:29][C:30]1[CH:35]=[CH:34][C:33]([F:36])=[C:32]([CH3:37])[C:31]=1[F:38].C(=O)([O-])[O-].[K+].[K+].C1OCCOCCOCCOCCOCCOC1>CN(C)C=O>[Cl:1][C:2]1[C:3](=[O:27])[N:4]([C:10]2[CH:15]=[C:14]([C:16]3[CH:21]=[CH:20][N:19]=[C:18]([C:22]([OH:25])([CH3:23])[CH3:24])[N:17]=3)[CH:13]=[CH:12][C:11]=2[CH3:26])[C:5]([CH3:9])=[N:6][C:7]=1[O:8][CH2:29][C:30]1[CH:35]=[CH:34][C:33]([F:36])=[C:32]([CH3:37])[C:31]=1[F:38]
Reactant: Cc1c(F)ccc(CCl)c1F
Reactant: Cc1ccc(-c2ccnc(C(C)(C)O)n2)cc1-n1c(C)nc(O)c(Cl)c1=O
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccc(-c2ccnc(C(C)(C)O)n2)cc1-n1c(C)nc(OCc2ccc(F)c(C)c2F)c(Cl)c1=O
Temperature: 60 °C
Yield: 36.5 %

Procedure:
To a solution of Intermediate 1 (50 mg, 0.13 mmol) in N,N-dimethylformamide (1.5 mL) was added 1-chloromethyl-2,4-difluoro-3-methyl-benzene from Step C (23 mg, 0.13 mmol), potassium carbonate (36 mg, 0.26 mmol) and 18-crown-6 (3 mg). The slurry was heated at 60° C. for three hours. After cooling to room temperature, the reaction was partitioned between ethyl acetate and water. The organic layer was washed with water and brine and dried over magnesium sulfate. The slurry was filtered and concentrated in vacuo. The crude material was purified using normal phase chromatography (ethyl acetate/heptane) to provide the title compound as a colorless oil (25 mg, 37% yield). MS (M+H): 527; 1H NMR (400 MHz, chloroform-d) δ ppm, 1.64 (s, 6H), 2.18 (s, 3H), 2.19 (s, 3H), 2.21 (s, 3H), 5.45-5.59 (m, 2H), 6.88-6.92 (m, 1H), 7.34-7.40 (m, 1H), 7.55-7.58 (m, 2H), 7.93 (s, 1H), 8.14 (d, J=7.83 Hz, 1H), 8.78 (d, J=5.09, 1H).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[CH:8][C:7]([F:11])=[CH:6][CH:5]=2.[H-].[Na+].Cl[C:15]1[N:16]=[C:17]([N:34]2[CH2:39][CH2:38][O:37][CH2:36][CH2:35]2)[C:18]2[S:23][C:22]([CH2:24][N:25]3[CH2:30][CH2:29][CH:28]([N:31]([CH3:33])[CH3:32])[CH2:27][CH2:26]3)=[CH:21][C:19]=2[N:20]=1>CN(C=O)C.O.[Cl-].[Na+]>[F:11][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]([C:15]1[N:16]=[C:17]([N:34]3[CH2:35][CH2:36][O:37][CH2:38][CH2:39]3)[C:18]3[S:23][C:22]([CH2:24][N:25]4[CH2:26][CH2:27][CH:28]([N:31]([CH3:33])[CH3:32])[CH2:29][CH2:30]4)=[CH:21][C:19]=3[N:20]=1)[C:2]([CH3:1])=[CH:10]2
Reactant: CN(C)C1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1
Reactant: Cc1cc2cc(F)ccc2[nH]1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc2cc(F)ccc2n1-c1nc(N2CCOCC2)c2sc(CN3CCC(N(C)C)CC3)cc2n1
Temperature: 150 °C
Yield: 10.4 %

Procedure:
A solution of 2-methyl-5-fluoroindole (0.164 g) in DMF (6 mL) was cooled to 0° C. then sodium hydride (0.066 g) added. After 30 min [1-(2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-piperidin-4-yl]-dimethyl-amine (0.395 g) was added. The reaction vessel was sealed and heated at 150° C. After 3 h the reaction mixture was cooled to room temperature and diluted with water and saturated aqueous sodium chloride solution. The resulting residual oil was separated from the aqueous layer, and then purified by chromatography (silica, 0 to 20% of a 49:1 MeOH:NH4OH mixture in dichloromethane) to furnish 119 (0.053 g, 10%) as a yellow solid. MS m/e 509 [M+H]+; 1H NMR (300 MHz, DMSO-d6) δ ppm 1.33-1.57 (m, 2H) 1.74 (d, 2H) 2.08 (t, 3H) 2.18 (s, 6H) 2.64 (s, 3H) 2.95 (d, 2H) 3.74-3.87 (m, 6H) 3.89-4.04 (m, 4H) 6.42 (s, 1H) 6.98-7.20 (m, 1H) 7.37 (m, 1H) 7.43 (s, 1H) 8.03 (m, 1H).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[N:7][CH:8]=[C:9]([C:10]#[N:11])[C:4]=2[CH:3]=[CH:2]1.[H-].[Na+].Cl[CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20]>C1COCC1>[CH3:20][Si:19]([CH3:22])([CH3:21])[CH2:18][CH2:17][O:16][CH2:15][N:1]1[C:5]2[CH:6]=[N:7][CH:8]=[C:9]([C:10]#[N:11])[C:4]=2[CH:3]=[CH:2]1
Reactant: N#Cc1cncc2[nH]ccc12
Reactant: C[Si](C)(C)CCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCn1ccc2c(C#N)cncc21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 57.8 %

Procedure:
To a solution of 1H-pyrrolo[2,3-c]pyridine-4-carbonitrile (618 mg, 4.32 mmol) in anhydrous THF (30 mL) at 0° C. was slowly added NaH (60% in mineral oil, 346 mg, 8.64 mmol). After stirring at 0° C. for 30 min, (2-(chloromethoxy)ethyl)trimethylsilane (865 mg, 5.19 mmol) was added followed by stirring at RT for 1 h. The reaction mixture was quenched with ice water (50 ml) and extracted with EtOAc (50 mL×3). The combined extracts were dried over (MgSO4) filtered, and concentrated under reduced pressure. The residue was purified by SiO2 chromatography eluting with petroleum ether:EtOAc (3:1) to afford 683 mg (57.9%) of 1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-c]pyridine-4-carbonitrile as a yellow solid. MS (ESI): m/z=274.2 [M+1]+.
Reaction SMILES: [CH2:1]([C@@:4]1([CH2:37][O:38]CC[Si](C)(C)C)[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:6]([C@@H:24]([CH2:34][CH3:35])[CH2:25][N:26]([CH3:33])[S:27]([CH:30]2[CH2:32][CH2:31]2)(=[O:29])=[O:28])[C:5]1=[O:36])[CH:2]=[CH2:3].B(F)(F)F>C(Cl)Cl>[CH2:1]([C@@:4]1([CH2:37][OH:38])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:6]([C@@H:24]([CH2:34][CH3:35])[CH2:25][N:26]([CH3:33])[S:27]([CH:30]2[CH2:32][CH2:31]2)(=[O:28])=[O:29])[C:5]1=[O:36])[CH:2]=[CH2:3]
Reactant: C=CC[C@@]1(COCC[Si](C)(C)C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@@H](CC)CN(C)S(=O)(=O)C2CC2)C1=O
Agent: FB(F)F
Solvent: ClCCl
Product: C=CC[C@@]1(CO)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@@H](CC)CN(C)S(=O)(=O)C2CC2)C1=O
Yield: 98.2 %

Procedure:
A solution of N-((S)-2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-2-oxo-3-((2-(trimethylsilyl)ethoxy)methyl)piperidin-1-yl)butyl)-N-methylcyclopropanesulfonamide (Example 414, Step D, 1.85 g, 2.72 mmol) in DCM was treated with boron trifluoride (diethyl etherate, purified, redistilled, 0.672 ml, 5.44 mmol) for 2 hours. The reaction mixture was diluted with DCM and washed with satd NaCl. The organic extract was dried over Na2SO4, filtered and concentrated in vacuo to give the crude material as an oil. The product was purified by chromatography on a RediSep® pre-packed silica gel column (Teledyne Isco, Lincoln, Nebr.) (12 g), eluting with a gradient of 0% to 80% EtOAc in hexane, to provide the intermediate N-((S)-2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-(hydroxymethyl)-2-oxopiperidin-1-yl)butyl)-N-methylcyclopropanesulfonamide (1.55 g, 2.67 mmol, 98% yield) as an oil which was used directly in the next reaction.
Reaction SMILES: [CH:1]1([N:5]2[CH2:10][CH2:9][CH:8]([O:11][C:12]3[CH:17]=[CH:16][C:15]([C:18]4[N:19]([CH3:31])[C:20](=[O:30])[C:21]5[CH:27]=[CH:26][N:25]=[C:24]([O:28]C)[C:22]=5[N:23]=4)=[CH:14][CH:13]=3)[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.B(F)(F)F.[OH-].[Na+]>ClCCl.C(OCC)(=O)C>[CH:1]1([N:5]2[CH2:6][CH2:7][CH:8]([O:11][C:12]3[CH:17]=[CH:16][C:15]([C:18]4[N:19]([CH3:31])[C:20](=[O:30])[C:21]5[CH:27]=[CH:26][NH:25][C:24](=[O:28])[C:22]=5[N:23]=4)=[CH:14][CH:13]=3)[CH2:9][CH2:10]2)[CH2:2][CH2:3][CH2:4]1
Reactant: COc1nccc2c(=O)n(C)c(-c3ccc(OC4CCN(C5CCC5)CC4)cc3)nc12
Agent: FB(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: Cn1c(-c2ccc(OC3CCN(C4CCC4)CC3)cc2)nc2c(=O)[nH]ccc2c1=O
Temperature: 0 °C
Yield: 62 %

Procedure:
2-{4-[(1-Cyclobutylpiperidin-4-yl)oxy]phenyl}-8-methoxy-3-methylpyrido[3,4-d]pyrimidin-4(3H)-one (500 mg, 1.19 mmol) was dissolved in dichloromethane (1 ml), and with stirring at 0° C., boron trifluoride (1.0 M in CH2Cl2, 3.9 mL) was added thereto, then gradually heated up to room temperature, and stirred at that temperature for 20 hours. The reaction solution was diluted with ethyl acetate, and with cooling with ice, this was poured into aqueous 1 N sodium hydroxide solution, and extracted with ethyl acetate. The organic layer was washed with saturated saline water, and dried with magnesium sulfate. The solvent was evaporated off, and the residue was purified through silica gel column chromatography (chloroform/methanol=1/0 to 9/1 and its polarity was stepwise increased up to 5/1) to obtain the intended compound (300 mg, 62%) as a pale yellow solid.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]=[CH2:10])=[CH2:2].C(C=CC1C=CC=CC=1)C>>[CH2:9]1[C:4]2[C:3](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH2:1][CH2:2][CH2:10]1
Reactant: C=Cc1ccccc1C=C
Agent: CCC=Cc1ccccc1
Product: c1ccc2c(c1)CCCC2

Procedure:
Divinylbenzene (Polysciences 1892) (Note that this material is only 50% divinylbenzene. The other 50% is ethyl styrene).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]#[C:9][Mg]Cl.[CH2:12](Cl)/[CH:13]=[CH:14]/[CH3:15].[Cl-].[NH4+].Cl>O1CCCC1.[Cu]Cl>[Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]#[C:9][CH2:12]/[CH:13]=[CH:14]/[CH3:15]
Reactant: C/C=C/CCl
Reactant: ClCCCCCCC#C[Mg]Cl
Agent: Cl[Cu]
Agent: Cl
Agent: [Cl-]
Solvent: C1CCOC1
Product: C/C=C/CC#CCCCCCCCl
Reaction time: 1.5 h
Yield: 75.6 %

Procedure:
A Grignard mixture containing 3 moles of 8-chloro-1-octynyl magnesium chloride in 900 g of tetrahydrofuran was introduced into a reaction vessel and agitated for several minutes with addition of 3 g of copper (I) chloride. Thereafteer, 271.5 g (3 moles) of (E)-2-butenyl chloride were added dropwise to the mixture which was kept at a temperature not to exceed 65° C. followed by further continued agitation for 1.5 hours to complete the reaction. Thereafter, 800 g of an aqueous solution containing 5% ammonium chloride and 5% hydrogen chloride were added to the reaction mixture to effect the hydrolysis. The mixture was then subjected to phase separation and the organic phase was freed from tetrahydrofuran and then to rectification distillation to give 451 g of 1-chloro-(E)-10-dodecen-7-yne having a purity of 95%. The yield of this compound was 72% of the theoretical value.
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][C:3]=1[CH2:4][N:5]1[C:9](CC#N)=[C:8]([Cl:13])[N:7]=[C:6]1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.Cl.[C:28]([OH:31])(=[O:30])[CH3:29].O>C(O)C>[Cl:1][C:2]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][C:3]=1[CH2:4][N:5]1[C:9]([CH2:29][C:28]([OH:31])=[O:30])=[C:8]([Cl:13])[N:7]=[C:6]1[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: N#CCc1c(Cl)nc(-c2ccccc2)n1Cc1cc([N+](=O)[O-])ccc1Cl
Reactant: CC(=O)O
Agent: Cl
Solvent: O
Solvent: CCO
Product: O=C(O)Cc1c(Cl)nc(-c2ccccc2)n1Cc1cc([N+](=O)[O-])ccc1Cl

Procedure:
1.9 g of 1-(2-chloro-5-nitrobenzyl)-4-chloro-5-cyanomethyl-2-phenylimidazole was boiled in a mixed solution of 12 ml of concentrated hydrochloric acid and 12 ml of glacial acetic acid for 3 hours. The reaction solution was concentrated to dryness under reduced pressure, and 50 ml of water was added to the residue, resulting in the formation of a colorless powder. The residue was dissolved in 30 ml of heated ethanol, and 30 ml of water was added. Upon cooling, there was obtained 1.7 g of 1-(2-chloro-5-nitrobenzyl)-4-chloro-2-phenylimidazole-5-acetic acid as colorless, prism-formed crystals. m.p. 200°-205° C.
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]([C:15]([C:17]([OH:30])([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH2:28][OH:29])=[CH:22][CH:21]=2)[CH3:18])=[O:16])([OH:14])[CH3:13])=[CH:7][CH:6]=1.[CH3:31][S:32](Cl)(=[O:34])=[O:33].C(N(CC)CC)C>C1COCC1>[S:32]([O:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]([C:15]([C:17]([OH:30])([CH2:19][C:20]2[CH:21]=[CH:22][C:23]([O:26][CH2:27][CH2:28][O:29][S:32]([CH3:31])(=[O:34])=[O:33])=[CH:24][CH:25]=2)[CH3:18])=[O:16])([OH:14])[CH3:13])=[CH:7][CH:6]=1)([CH3:31])(=[O:34])=[O:33]
Reactant: CS(=O)(=O)Cl
Reactant: CC(O)(Cc1ccc(OCCO)cc1)C(=O)C(C)(O)Cc1ccc(OCCO)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(O)(Cc1ccc(OCCOS(C)(=O)=O)cc1)C(=O)C(C)(O)Cc1ccc(OCCOS(C)(=O)=O)cc1
Temperature: 2 °C

Procedure:
A 1000 ml three-necked round bottom flask is charged with a solution of 224.26 g (1 Mol) of 4-(2-Hydroxyethoxy)phenyl 2-hydroxy-2-propyl-ketone (Darocure® 2959) in 400 mL of THF and 114.55 g (1 mol) of methanesulfonyl chloride are added to the solution at room temperature. After cooling to 2° C., 101.2 g (1 mol) of triethylamine (TEA) and 200 mL of THF are added to the solution over a 30 min-period under stirring. Slightly exothermal reaction is observed. The reaction mixture is then filtered through a G3 glass frit filter and the TEA hydrochloride washed 2× with THF on the filter. The filtrate is evaporated at 60° C./200 mbar using a Rotavapor. The resulting yellow oil is then dissolved in 800 mL of CH2Cl2. The organic phase is washed 1× with 400 mL of deionized water, 2× with 400 mL of acidic water (pH˜1) and finally with 400 mL of deionized water. The organic phase is dried over MgSO4, filtered and concentrated to constant weight by evaporating the CH2Cl2 under reduced pressure at a Rotavapor to give crude 4-(2-mesyloxyethoxy)phenyl-2-hydroxy-2-propyl-ketone.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[CH:10]=[CH:9][CH:8]=[C:7]3[NH:12][CH:13]([C:21]4[CH:28]=[CH:27][C:24]([CH:25]=O)=[CH:23][CH:22]=4)[CH:14]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)[C:5]([C:6]=23)=[N:4][NH:3]1.C(O)(=O)C.[N:33]1(C(OC(C)(C)C)=O)[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCl>[C:15]1([CH:14]2[C:5]3=[N:4][NH:3][C:2](=[O:1])[C:11]4[CH:10]=[CH:9][CH:8]=[C:7]([C:6]=43)[NH:12][CH:13]2[C:21]2[CH:22]=[CH:23][C:24]([CH2:25][N:33]3[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]3)=[CH:27][CH:28]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=Cc1ccc(C2Nc3cccc4c(=O)[nH]nc(c34)C2c2ccccc2)cc1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: O=c1[nH]nc2c3c(cccc13)NC(c1ccc(CN3CCNCC3)cc1)C2c1ccccc1
Reaction time: 8 h
Yield: 53.8 %

Procedure:
A solution of 4-(3-oxo-9-phenyl-3,7,8,9-tetrahydro-2H-pyrido[4,3,2-de]phthalazin-8-yl)benzaldehyde (200 mg, 0.54 mmol) in dichloromethane (30 mL) was added acetic acid (196 mg, 3.24 mmol) and tert-butyl piperazine-1-carboxylate (304 mg, 1.63 mmol) at room temperature and stirred overnight. Then NaBH(OAc)3 (173 mg, 0.81 mmol) was added to the mixture at 0° C., stirred for one day. The reaction mixture was quenched with aqueous sodium bicarbonate, extracted with dichloromethane. The combined organic layer was washed by brine, dried over anhydrous sodium sulfate, concentrated to give the crude product which was purified by flash chromatography to obtain a solution. To the solution obtained (concentrated to about 50 mL) was added conc. HCl (10 mL) at room temperature and stirred overnight. The mixture was extracted with ethyl acetate for three times, the aqueous phase was concentrated to give 9-phenyl-8-(4-(piperazin-1-ylmethyl)phenyl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one (127 mg, yield 46%). 1H NMR (400 MHz, DMSO-d6) δ (ppm): 3.47 (br s, 7H), 3.60 (m, 1H), 4.32 (s, 2H), 4.38 (d, 1H), 4.83 (d, 1H), 5.41 (br s, 2H), 7.19 (m, 6H), 7.24 (m, 3H), 7.55 (m, 4H), 9.87 (br s, 2H), 12.20 (s, 1H); LC-MS (ESI) m/z: 438(M+1)+.
Reaction SMILES: [CH2:1]([N:3]1[C:15]2[CH:14]=[CH:13][C:12]([C:16](=[O:18])[CH3:17])=[CH:11][C:10]=2[C:9]2[C:4]1=[CH:5][CH:6]=[C:7]([C:19](=[O:27])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH3:26])[CH:8]=2)[CH3:2].[C:28](OCC)(=[O:30])[CH3:29].CC(C)([O-])C.[K+].Cl>O>[CH2:1]([N:3]1[C:15]2[CH:14]=[CH:13][C:12]([C:16](=[O:18])[CH2:17][C:28](=[O:30])[CH3:29])=[CH:11][C:10]=2[C:9]2[C:4]1=[CH:5][CH:6]=[C:7]([C:19](=[O:27])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH3:26])[CH:8]=2)[CH3:2]
Reactant: CCn1c2ccc(C(C)=O)cc2c2cc(C(=O)c3ccccc3C)ccc21
Reactant: CCOC(C)=O
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Product: CCn1c2ccc(C(=O)CC(C)=O)cc2c2cc(C(=O)c3ccccc3C)ccc21
Temperature: 25 °C
Yield: 43.5 %

Procedure:
A one liter four-necked flask equipped with a stirrer, a nitrogen inlet tube, a reflex condenser, and a thermometer was charged with 35.54 g of 1-[9-ethyl-6-(2-methylbenzoyl)-9H-carbazol-3-yl]ethanone, 264.33 g of ethyl acetate, and 33.66 g of potassium t-butoxide, and the mixture was refluxed in a nitrogen atmosphere for 5 hours. After cooling to room temperature, 100 ml of ion exchanged water and 100 ml of 6N hydrochloric acid were successively added, followed by stirring. The organic phase was separated and washed with a sodium chloride aqueous solution until neutral. A hundred fifty milliliters of n-hexane was added thereto, followed by cooling with ice for crystallization. The solid precipitated was collected by filtration by suction and dried under reduced pressure to give 17.29 g (43%) of pale yellow crystals, which had a melting point of 148° C. and was identified by various analyses to be β-diketone compound No. 3 having a carbazolyl group.
Reaction SMILES: [Al].[Na].[N:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:22][CH2:23][CH3:24])=[C:16]([O:19][CH2:20][CH3:21])[CH:17]=3)[CH:12]=[C:11]([C:25](OC)=[O:26])[C:10]=2[C:29](OC)=[O:30])=[CH:5][CH:4]=1.[OH-].[Na+].O>C1(C)C=CC=CC=1.O1CCCC1.C(Cl)Cl>[N:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:22][CH2:23][CH3:24])=[C:16]([O:19][CH2:20][CH3:21])[CH:17]=3)[CH:12]=[C:11]([CH2:25][OH:26])[C:10]=2[CH2:29][OH:30])=[CH:5][CH:4]=1
Reactant: CCOc1cc2cc(C(=O)OC)c(C(=O)OC)c(-c3ccncc3)c2cc1OCC
Agent: [Al]
Agent: [Na+]
Agent: [Na]
Solvent: C1CCOC1
Solvent: O
Solvent: ClCCl
Product: CCOc1cc2cc(CO)c(CO)c(-c3ccncc3)c2cc1OCC
Temperature: -10 °C
Yield: 91.4 %

Procedure:
To tetrahydrofuran (25 ml) is added a 3.4 M solution of sodium aluminum bis(methoxyethxoy) hydride in toluene (18.0 ml), and the mixture is cooled to -10° C. To the mixture is added dropwise a suspension of 1-(4-pyridyl)-2,3-bis(methoxycarbonyl)-6,7-diethoxynaphthalene (10.0 g) in tetrahydrofuran (25 ml) over a period of 15 minutes. The reaction solution is warmed, and stirred under ice-cooling for 1.5 hour, and thereto is added a 15% aqueous sodium hydroxide solution (3.7 ml). To the reaction mixture are added water and methylene chloride, and the insoluble materials are removed by filtration. The filtrate is extracted with methylene chloride, and the extract is washed, dried, and concentrated to give 1-(4-pyridyl)-2,3-bis(hydroxymethyl)-6,7-diethoxynaphthalene (7.89 g).