Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:11]([C:12]3[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=3)[CH:10]([CH2:19][CH2:20][CH:21]([C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)[OH:22])[C:9]2=[O:30])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[I:37][CH:38](I)[CH2:39][CH2:40][CH2:41][CH2:42][CH3:43]>CN(C)C=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH:11]([C:12]3[CH:13]=[CH:14][C:15]([O:18][CH2:43][CH2:42][CH2:41][CH2:40][CH2:39][CH2:38][I:37])=[CH:16][CH:17]=3)[CH:10]([CH2:19][CH2:20][CH:21]([C:23]3[CH:24]=[CH:25][C:26]([F:29])=[CH:27][CH:28]=3)[OH:22])[C:9]2=[O:30])=[CH:6][CH:7]=1
Reactant: CCCCCC(I)I
Reactant: O=C1C(CCC(O)c2ccc(F)cc2)C(c2ccc(O)cc2)N1c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C1C(CCC(O)c2ccc(F)cc2)C(c2ccc(OCCCCCCI)cc2)N1c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
100 mg of 1-(4-fluorophenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]-4-(4 hydroxyphenyl)azetidin-2-one are dissolved in 10 ml of absolute dimethylformamide. 80 mg of powdered potassium carbonate and 0.25 ml of diiodohexane are then added. The reaction solution is stirred at room temperature overnight. After concentration using a rotary evaporator and oil pump vacuum at 40° C., the residue is purified using an SiO2 cartridge (n-heptene; n-heptane/ethyl acetate 4:1). The product is obtained as an oil. C30H32F2INO3 (619) MS (ESI): M+-18
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C:5]1[N:14]=[C:13]([NH:15][CH:16]2[CH2:21][CH2:20][N:19]([CH2:22][C:23]3[C:28]([O:29][CH3:30])=[CH:27][CH:26]=[CH:25][C:24]=3[N:31]([CH3:33])[CH3:32])[CH2:18][CH2:17]2)[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]=1.[CH:34]([N:37]=[C:38]=[O:39])([CH3:36])[CH3:35]>ClCCl>[CH3:33][N:31]([CH3:32])[C:24]1[CH:25]=[CH:26][CH:27]=[C:28]([O:29][CH3:30])[C:23]=1[CH2:22][N:19]1[CH2:20][CH2:21][CH:16]([NH:15][C:13]2[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[N:6]=[C:5]([NH:4][CH2:3][CH2:2][NH:1][C:38]([NH:37][CH:34]([CH3:36])[CH3:35])=[O:39])[N:14]=2)[CH2:17][CH2:18]1
Reactant: COc1cccc(N(C)C)c1CN1CCC(Nc2nc(NCCN)nc3ccccc23)CC1
Reactant: CC(C)N=C=O
Solvent: ClCCl
Product: COc1cccc(N(C)C)c1CN1CCC(Nc2nc(NCCNC(=O)NC(C)C)nc3ccccc23)CC1

Procedure:
A solution of Compound 125 (15 mg, 0.03 mmol) and isopropyl isocyanate (2.8 mg, 0.03 mmol) in dichloromethane (2 mL) was stirred at room temperature for 1 h. The product (Compound 126) was purified by Neutral alumina Prep TLC plate using 10% MeOH and 90% CH2Cl2 solution as eluent.
Reaction SMILES: C(O)(C)(C)C.[H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:12][C:13]1([CH3:22])[C@@H:15]([C:16](Cl)=[O:17])[C@@H:14]1[C:19](=[O:21])[CH3:20].[Cl-].[Na+]>O1CCCC1.CCOCC>[CH3:12][C:13]1([CH3:22])[C@@H:15]([CH:16]=[O:17])[C@@H:14]1[C:19](=[O:21])[CH3:20]
Reactant: CC(=O)[C@H]1[C@H](C(=O)Cl)C1(C)C
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: C1CCOC1
Solvent: CC(C)(C)O
Solvent: CCOCC
Product: CC(=O)[C@H]1[C@H](C=O)C1(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 60.4 %

Procedure:
36.6 g (0.495 mol) of tert.-butanol were added dropwise, at 20°-30° C., to a mixture of 6.3 g (0.165 mol) of lithium aluminum hydride and 100 ml of tetrahydrofuran in the course of 1 hour. The mixture was subsequently stirred for 2 hours at room temperature and was then added dropwise, at -50° to -60° C., to a solution of 26.1 g (0.15 mol) of trans-3,3-dimethyl-2-acetyl-cyclopropanecarboxylic acid chloride in 75 ml of tetrahydrofuran. When the addition was complete, the mixture was subsequently stirred for 1 hour, without cooling, and poured onto a mixture of 30 ml of concentrated sodium chloride and 300 g of ice, and extraction was carried out by shaking with twice 400 ml of ether. The organic phases were washed first with 50 ml of saturated sodium bicarbonate solution and then with 100 ml of water, dried over sodium sulphate and evaporated in vacuo. 12.7 g (62% of theory) of trans-3,3-dimethyl-2-acetyl-cyclopropanecarboxaldehyde were obtained, by vacuum distillation of the residue, in the form of a colorless oil having a boiling point of 80° -86° C./10 mbar.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:11]3([N:15]=[C:14]([NH2:16])[C:13]([CH3:17])=[N:12]3)[CH2:10][CH:9]([CH:18]3[CH2:23][CH2:22][O:21][C:20]([CH3:25])([CH3:24])[CH2:19]3)[O:8][C:5]2=[CH:6][CH:7]=1.[Cl:26][C:27]1[CH:28]=[C:29](B(O)O)[CH:30]=[CH:31][CH:32]=1.C([O-])([O-])=O.[K+].[K+].O1CCOCC1>C(Cl)Cl.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Br:1][C:2]1[CH:3]=[C:4]2[C:11]3([N:15]=[C:14]([NH2:16])[C:13]([CH3:17])=[N:12]3)[CH2:10][CH:9]([CH:18]3[CH2:23][CH2:22][O:21][C:20]([CH3:25])([CH3:24])[CH2:19]3)[O:8][C:5]2=[CH:6][CH:7]=1.[Cl:26][C:27]1[CH:32]=[C:31]([C:2]2[CH:3]=[C:4]3[C:11]4([N:15]=[C:14]([NH2:16])[C:13]([CH3:17])=[N:12]4)[CH2:10][CH:9]([CH:18]4[CH2:23][CH2:22][O:21][C:20]([CH3:24])([CH3:25])[CH2:19]4)[O:8][C:5]3=[CH:6][CH:7]=2)[CH:30]=[CH:29][CH:28]=1
Reactant: OB(O)c1cccc(Cl)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC1=NC2(CC(C3CCOC(C)(C)C3)Oc3ccc(Br)cc32)N=C1N
Solvent: ClCCl
Solvent: C1COCCO1
Product: CC1=NC2(CC(C3CCOC(C)(C)C3)Oc3ccc(-c4cccc(Cl)c4)cc32)N=C1N
Temperature: 130 °C
Yield: 68.5 %

Procedure:
6-Bromo-2-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-5′-methylspiro[chroman-4,2′-imidazol]-4′-amine (Isomeric mixture 1 from Example 49 Step 4, 0.08 g, 0.20 mmol), 3-chlorophenylboronic acid (0.046 g, 0.30 mmol), [1,1′-bis(diphenylphosphino)ferrocene]palladium(II) chloride (0.015 g, 0.02 mmol), 2 M aq. K2CO3 solution (0.197 mL, 0.39 mmol) and 1,4-dioxane (1.5 mL) were mixed in a vial and heated in a microwave reactor at 130° C. for 20 min. When cooled to r.t. the mixture was diluted with DCM, washed with water and dried over Na2SO4. The filtrate was concentrated and the product purified by preparative chromatography to yield Isomeric mixture 1 of the title compound (30 mg, 35% yield): 1H NMR (500 MHz, CDCl3) δ ppm 1.28 (m, 7 H), 1.48 (m, 3 H), 1.64 (d, 1 H), 1.91 (t, 1 H), 2.11 (m, 1 H), 2.40 (s, 3 H), 2.51 (t, 1 H), 3.74 (td, 1 H), 3.85 (td, 1 H), 4.48 (dd, 1 H), 6.81 (d, 1 H), 7.01 (d, 1 H), 7.26 (m, 1 H), 7.32 (d, 2 H), 7.40 (m, 2 H); MS (ES+) m/z 438 [M+H]1.
Reaction SMILES: [CH3:1][Si:2]([CH3:16])([CH3:15])[C:3]1[CH:4]=[C:5]([C:9]2([CH3:14])OCC[O:10]2)[CH:6]=[CH:7][CH:8]=1.Cl>CC(C)=O>[CH3:15][Si:2]([CH3:1])([CH3:16])[C:3]1[CH:4]=[C:5]([C:9](=[O:10])[CH3:14])[CH:6]=[CH:7][CH:8]=1
Reactant: CC1(c2cccc([Si](C)(C)C)c2)OCCO1
Agent: Cl
Solvent: CC(C)=O
Product: CC(=O)c1cccc([Si](C)(C)C)c1
Yield: 97.7 %

Procedure:
To a solution of the title compound of Step B (11.2 g) in acetone (400 mnL) was added an aqueous solution of 1N hydrochloric acid (6 mL) and the mixture was heated at reflux overnight. After cooling, the mixture was concentrated under reduced pressure and the resulting residue was dissolved in diethyl ether and dried (MgSO4). The drying agent was removed by filtration and the solvent was removed under reduced pressure to give a yellow oil. The crude product was combined with another batch of crude product prepared in the same manner and purified by distillation (47 Pa, 58-59° C.) to afford 8.9 g of the title compound of Step C as an oil. 1H NMR (CDCl3): δ 8.11 (s,1H), 7.92 (d,1H), 7.7 (d,1H), 7.47 (t,1H), 2.62 (s,3H), 0.30 (s,8H).
Reaction SMILES: [C:1]([C:5]1[CH:12]=[CH:11][C:8]([CH2:9]Br)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[Br:13][C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][CH:22]=1)[NH:19][CH:18]=[CH:17]2>>[Br:13][C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][CH:22]=1)[N:19]([CH2:9][C:8]1[CH:11]=[CH:12][C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:6][CH:7]=1)[CH:18]=[CH:17]2
Reactant: Brc1ccc2[nH]ccc2c1
Reactant: CC(C)(C)c1ccc(CBr)cc1
Product: CC(C)(C)c1ccc(Cn2ccc3cc(Br)ccc32)cc1

Procedure:
The title compound was prepared from 4-(tert-butyl)benzyl bromide (180 g, 768 mmol) and 5-bromoindole (152 g, 768 mmol) in substantially the same manner, as described in Step 1 of Example 25. The product (257 g, 97%) was obtained as a yellow solid, mp: 108-109° C. Mass spectrum (ESI, [M+H]+) m/z 342. 1HNMR (400 MHz, DMSO-d6): δ 7.73 (s, 1H), 7.55 (s, 1H), 7.44 (d, 1H, J=8.71 Hz), 7.30 (d, 2H, J=7.96 Hz), 7.19 (d, 1H, J=8.71 Hz), 7.10 (d, 2H, J=7.63 Hz), 6.46 (s, 1H), 5.36 (s, 2H), and 1.21 ppm (s, 9H).
Reaction SMILES: NC1[S:3][C:4]2[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:5]=2[N:6]=1.[OH-].[K+].Cl>O>[NH2:6][C:5]1[CH:7]=[CH:8][C:9]([O:11][CH3:12])=[CH:10][C:4]=1[SH:3]
Reactant: COc1ccc2nc(N)sc2c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: COc1ccc(N)c(S)c1
Reaction time: 0.5 h

Procedure:
34.3 g (0.19 mol) of 2-amino-6-methoxy-benzothiazole and 140 g (2.5 mol) of 85% potassium hydroxide are refluxed in 350 ml of water for 5 hours. Then the mixture is cooled and neutralised with 200 ml of concentrated hydrochloric acid. The mixture is stirred for a further 30 minutes, the precipitate formed is suction filtered, washed with water and dried in vacuo. Yield: 24.0 g (81.4% of theory). The following is obtained analogously to Example B:
Reaction SMILES: [NH2:1][OH:2].C1COCC1.Cl.[CH3:9][N:10]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([S:19]([N:22]2[CH:26]=[CH:25][C:24](/[CH:27]=[CH:28]/[C:29]([Cl:31])=[O:30])=[CH:23]2)(=[O:21])=[O:20])=[CH:15][CH:14]=1)[CH3:11].CC(C)=O>C(#N)C>[ClH:31].[CH3:9][N:10]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([S:19]([N:22]2[CH:26]=[CH:25][C:24](/[CH:27]=[CH:28]/[C:29]([NH:1][OH:2])=[O:30])=[CH:23]2)(=[O:21])=[O:20])=[CH:15][CH:14]=1)[CH3:11]
Reactant: CN(C)Cc1ccc(S(=O)(=O)n2ccc(/C=C/C(=O)Cl)c2)cc1
Reactant: NO
Agent: Cl
Solvent: C1CCOC1
Solvent: CC(C)=O
Solvent: CC#N
Product: CN(C)Cc1ccc(S(=O)(=O)n2ccc(/C=C/C(=O)NO)c2)cc1
Temperature: 9 °C
Reaction time: 0.5 h

Procedure:
A second reaction vessel was charged with aqueous hydroxylamine (50%, 42.8 kg, 647 mol) and THF (40.0 L). The above prepared solution of (E)-3-[1-(4-dimethylaminomethyl-benzenesulfonyl)-1H-pyrrol-3-yl]-acryloyl chloride hydrochloride was added at 18-30° C. over a period of 2-4 h. After stirring for 20-40 min, acetone (47.6 L, 647 mmol) was added at 17-25° C. within 45-90 min. The reaction mixture was stirred for 30 min and acetonitrile (570.0 L) was added over a period of 1-2 h. The suspension was stirred at 17-25° C. for at least 4 h, cooled to 5-13° C. and stirred for 1-2 h. The solid was centrifuged and was used without further drying in the subsequent free basing step.
Reaction SMILES: [Li].N.[F:3][C:4]([F:38])([F:37])[C:5]([OH:36])([CH2:10][CH2:11][CH2:12][C@H:13]([C@@H:15]1[C@:32]2([CH3:33])[C@H:18]([C@H:19]3[C@H:29]([CH2:30][CH2:31]2)[C@:27]2([CH3:28])[C:22](=[CH:23][C:24](=[O:35])[C@@H:25]4[O:34][C@@H:26]42)[CH:21]=[CH:20]3)[CH2:17][CH2:16]1)[CH3:14])[C:6]([F:9])([F:8])[F:7].[NH4+].[Cl-]>C1COCC1>[F:3][C:4]([F:37])([F:38])[C:5]([OH:36])([CH2:10][CH2:11][CH2:12][C@H:13]([C@@H:15]1[C@:32]2([CH3:33])[C@H:18]([C@H:19]3[C@H:29]([CH2:30][CH2:31]2)[C@:27]2([CH3:28])[C:22]([CH2:23][C@H:24]([CH2:25][C@@H:26]2[OH:34])[OH:35])=[CH:21][CH2:20]3)[CH2:17][CH2:16]1)[CH3:14])[C:6]([F:7])([F:9])[F:8]
Reactant: C[C@H](CCCC(O)(C(F)(F)F)C(F)(F)F)[C@H]1CC[C@H]2[C@@H]3C=CC4=CC(=O)[C@@H]5O[C@@H]5[C@]4(C)[C@H]3CC[C@]12C
Agent: N
Agent: [Cl-]
Agent: [Li]
Solvent: C1CCOC1
Product: C[C@H](CCCC(O)(C(F)(F)F)C(F)(F)F)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](O)C[C@H](O)[C@]4(C)[C@H]3CC[C@]12C
Reaction time: 1 h
Yield: 61.1 %

Procedure:
To a solution of 1.2 g of lithium in 80 ml of liquid ammonia (distilled over Na) was added 443 mg of the epoxide (4) in THF (70 ml) dropwise during 1 hr under dry ice-acetone bath cooling and then the reaction mixture was stirred for 1 hr at reflux. The reaction mixture was recooled by dry ice-acetone bath and to this was added solid NH4Cl (12 g) in small portions during 1 hr, then refluxed for 3 hr. After bubbling argon gas to remove NH3, water was added to the reaction mixture and this was extracted with AcOEt. The extract was submitted to silica gel column chromatography. The fraction eluted with n-hexane and AcOEt (1:2) afforded 274 mg (65%) of the triol (5), mp 201°-202° C. (from CHCl3), MS Calcd. for C27H40F6O3 : 526.2879. Found: 526.2878. NMR(CDCl3) and acetone-D6 δ0.69(s, 18-H3), 0.93(d, J=6 Hz, 21-H3), 1.03(s, 19-H3), 3.83(1H, m, 1-H), 4.00(1H, m, 3-H), 5.53(1H, m, 6-H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]=1OS(C(F)(F)F)(=O)=O)[C:5]([O:7][CH2:8][CH3:9])=[O:6].[F:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][C:23]=1B(O)O.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.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>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH:10]=[CH:11][C:12]=1[C:23]1[CH:24]=[C:25]([O:28][CH3:29])[CH:26]=[CH:27][C:22]=1[F:21]
Reactant: COc1ccc(F)c(B(O)O)c1
Reactant: CCOC(=O)c1ccc(OS(=O)(=O)C(F)(F)F)c(Cl)c1
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: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(-c2cc(OC)ccc2F)c(Cl)c1
Temperature: 100 °C

Procedure:
A reaction mixture of ethyl 3-chloro-4-(trifluoromethylsulfonyloxy)benzoate (T1.5) (3.00 g, 9.02 mmol), 2-fluoro-5-methoxyphenylboronic acid (commercially available from Aldrich) (1.84 g, 10.8 mmol), tetrakis(triphenylphosphine)palladium (0.521 g, 0.451 mmol) and potassium carbonate (2.49 g, 18.0 mmol) in DMF (20 mL), was purged with N2 three times and then heated at 100° C. for 4 hours. The reaction was cooled to room temperature, and EtOAc (130 mL) was added. The mixture was then washed with brine (30×4 mL). The organic layer was dried over MgSO4. The residue was purified by CombiFlash® silica gel column (eluting with hexane/EtOAc; 85/15) to give T1.6. 1H NMR (400 MHz, CDCl3) δ ppm 8.08 (d, 1H), 7.90 (d, 1H), 7.33 (dd, 1H), 6.96-7.02 (m, 1H), 6.82-6.85 (m, 1H), 6.74 (d, 1H), 4.33 (q, 2H), 4.31 (s, 3H), 1.34 (t, 3H). MS ESI (pos.) m/e: 309.1 (M+H)+.
Reaction SMILES: C(NC(C)C)(C)C.I[C:9]1[C:14]2[O:15][CH2:16][O:17][C:13]=2[C:12]([NH:18][C:19]2[C:28]3[C:23](=[CH:24][C:25]([O:31][CH2:32][CH2:33][CH2:34][N:35]4[CH2:40][CH2:39][O:38][CH2:37][CH2:36]4)=[C:26]([O:29][CH3:30])[CH:27]=3)[N:22]=[CH:21][N:20]=2)=[CH:11][CH:10]=1.[CH2:41]([O:44][CH3:45])[C:42]#[CH:43]>C(OCC)(=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu](I)I>[CH3:30][O:29][C:26]1[CH:27]=[C:28]2[C:23](=[CH:24][C:25]=1[O:31][CH2:32][CH2:33][CH2:34][N:35]1[CH2:40][CH2:39][O:38][CH2:37][CH2:36]1)[N:22]=[CH:21][N:20]=[C:19]2[NH:18][C:12]1[C:13]2[O:17][CH2:16][O:15][C:14]=2[C:9]([C:43]#[C:42][CH2:41][O:44][CH3:45])=[CH:10][CH:11]=1
Reactant: C#CCOC
Reactant: COc1cc2c(Nc3ccc(I)c4c3OCO4)ncnc2cc1OCCCN1CCOCC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CC(C)NC(C)C
Solvent: CCOC(C)=O
Product: COCC#Cc1ccc(Nc2ncnc3cc(OCCCN4CCOCC4)c(OC)cc23)c2c1OCO2
Temperature: 25 °C
Reaction time: 16 h
Yield: 30.6 %

Procedure:
Bis(Triphenyl-phosphine)palladium(II) chloride (94 mg), copper iodide (19 mg) and diisopropylamine (68 mg) were added to a stirred solution of N-(7-iodo-1,3-benzodioxol-4-yl)-6-methoxy-7-(3-morpholin-4-ylpropoxy)quinazolin-4-amine (200 mg) and methyl propargyl ether (47 mg) in ethyl acetate (5 mls) at −20° C. The reaction was allowed to warm to ambient temperature and stirred over 16 hours. The reaction mixture was partitioned between ethyl acetate and saturated NaHCO3. The organic layer was washed with water and saturated brine and dried over magnesium sulfate. The product was purified by column chromatography on silica using a gradient of 0-10% methanol/methylene chloride as eluent. The resultant yellow gum was dissolved in minimal methylene chloride, diluted with diethyl ether and precipitated as an HCl salt by the addition of 1.0 M ethereal hydrogen chloride. The resultant solid was centrifuged and washed with diethyl ether (3 times) and dried to give the title compound as a yellow solid (55 mg); NMR Spectrum: DMSOd6) 2.29-2.36 (m, 2H); 3.03-3.14 (m, 2H); 3.24 -3.31 (m, 2H), 3.32 (s, 3H), 3.43-3.54 (m, 2H), 3.76-3.86 (m, 2H), 3.94 -4.00 (m, 5H), 4.31 (t, 2H), 4.35 (s, 2H), 6.13 (s, 2H), 6.98 (d, 1H), 7.02 (d, 1H), 7.40 (s, 1H), 8.27 (s, 1H), 8.80 (s, 1H); Mass Spectrum: M+H+ 507.11
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[CH:13]=[CH:14][O:15]C)[N:9]=[CH:8][CH:7]=[CH:6]2>Cl.O1CCCC1.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[CH2:13][CH:14]=[O:15])[N:9]=[CH:8][CH:7]=[CH:6]2
Reactant: COC=Cc1cc2ncccc2cc1OC
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1cc2cccnc2cc1CC=O
Temperature: 70 °C
Reaction time: 2 h
Yield: 110 %

Procedure:
1.41 g of 6-methoxy-7-(2-methoxyvinyl)quinoline was dissolved in 40 ml of 2 N hydrochloric acid-tetrahydrofuran (1:1), and the obtained mixture was then stirred at 70° C. for 2 hours. The reaction solution was cooled to a room temperature. It was diluted with ethyl acetate and then washed with a saturated sodium bicarbonate aqueous solution and a saturated sodium chloride aqueous solution. The organic layer was dried over magnesium sulfate and then concentrated under a reduced pressure, so as to obtain 1.45 g of (6-methoxyquinolin-7-yl)acetaldehyde containing triphenylphosphine oxide. This compound was used in the following reaction without further purification.
Reaction SMILES: [NH2:1][N:2]=[CH:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][CH2:12][CH2:13][C:14]([NH:16][CH:17]([CH2:22][S:23]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:24])[CH2:18][C:19]([OH:21])=[O:20])=[O:15])=[CH:6][CH:5]=1.C(O)(=[O:33])C.OO>O>[NH2:1][N:2]=[CH:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][CH2:12][CH2:13][C:14]([NH:16][CH:17]([CH2:22][S:23]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)(=[O:33])=[O:24])[CH2:18][C:19]([OH:21])=[O:20])=[O:15])=[CH:6][CH:5]=1
Reactant: NN=Cc1ccc(CCCCC(=O)NC(CC(=O)O)CS(=O)c2ccccc2)cc1
Reactant: CC(=O)O
Agent: OO
Solvent: O
Product: NN=Cc1ccc(CCCCC(=O)NC(CC(=O)O)CS(=O)(=O)c2ccccc2)cc1
Reaction time: 24 h

Procedure:
(±)-3-[[5-[4-(Aminoiminomethyl)phenyl]-1-oxopentyl]amino]-4-[(phenylsulfinyl)]butanoic acid (2.5 g) was dissolved in 10 ml water and 5 ml acetic acid followed by the addition of 5 ml 30% H2O2. The oxidation was allowed to proceed for 24 h. after which the reaction mixture was purified by reverse phase chromatography (water/acetonitrile) and lyophilized to give 1.6 g of the title compound as a white solid: 1H NMR (d6 -DMSO) δ1.48 (m, 2H), 1.56 (m, 2H), 1.75 (m, 2H), 2.10 (m, 2H), 2.41 (m, 2H), 2.68 (m, 2H), 3.9 (m, 1H), 4.02 (m, 2H), 7.35 (m, 9H), 7.7 (bd, 1H, J=7.9 Hz), 9.05 (bs, 2H), 9.3 (bs, 2H); MS (FAB) m/e 446.2 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:17])[CH2:9][C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.[BH4-].[Na+].O>CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:17])[CH2:9][C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)=[CH:4][CH:3]=1
Reactant: O=C(Cc1ccc(Cl)cc1)c1ccc(Cl)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: OC(Cc1ccc(Cl)cc1)c1ccc(Cl)cc1
Temperature: 0 °C

Procedure:
A solution of 1,2-di(4-chlorophenyl)ethan-1-one (known compound) and sodium borohydride in methanol is stirred at ambient temperature for about three hours. After this time, the reaction mixture is cooled, and water is carefully added to destroy excess sodium borohydride. The mixture is cooled to 0° C. and neutralized with concentrated hydrochloric acid. The mixture is concentrated under reduced pressure to remove some of the methanol. The concentrate is taken up in ethyl acetate and washed with an aqueous solution saturated with sodium chloride. The organic layer is dried with sodium sulfate, filtered, and concentrated under reduced pressure, yielding the subject compound.
Reaction SMILES: C[O:2][CH:3](OC)[C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[NH:22][C:20]3[C:21]4[C:12](=[N:13][NH:14][C:15](=[O:23])[C:16]=4[CH:17]=[CH:18][CH:19]=3)[CH:11]2[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:6][CH:5]=1.C(=O)([O-])[O-].[K+].[K+]>Cl>[O:23]=[C:15]1[C:16]2[CH:17]=[CH:18][CH:19]=[C:20]3[NH:22][CH:10]([C:7]4[CH:6]=[CH:5][C:4]([CH:3]=[O:2])=[CH:9][CH:8]=4)[CH:11]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[C:12]([C:21]=23)=[N:13][NH:14]1
Reactant: COC(OC)c1ccc(C2Nc3cccc4c(=O)[nH]nc(c34)C2c2ccccc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: O=Cc1ccc(C2Nc3cccc4c(=O)[nH]nc(c34)C2c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 73 %

Procedure:
8-(4-(Dimethoxymethyl)phenyl)-9-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one (89 mg, 0.22 mmol) and 20 ml of 3 N hydrochloric acid were added and the mixture was stirred at room temperature for 2 h. The resulting mixture was neutralized with potassium carbonate and then filtered to give 4-(3-oxo-9-phenyl-3,7,8,9-tetrahydro-2H-pyrido[4,3,2-de]phthalazin-8-yl)benzaldehyde (59, yield 73%). LC-MS (ESI) m/z: 368.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].Cl[C:15]1[N:16]=[CH:17][C:18]([C:21]([O:23]C)=[O:22])=[N:19][CH:20]=1.Cl.[OH-].[Na+]>CN(C=O)C.CO.O>[CH2:1]([O:8][CH2:9][CH2:10][O:11][C:15]1[N:16]=[CH:17][C:18]([C:21]([OH:23])=[O:22])=[N:19][CH:20]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCCOCc1ccccc1
Reactant: COC(=O)c1cnc(Cl)cn1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Solvent: O
Product: O=C(O)c1cnc(OCCOCc2ccccc2)cn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 34.3 %

Procedure:
To a solution of 2-(benzyloxy)ethanol (1.94 g) in DMF (60 mL) was added 60% sodium hydride (510 mg) under ice-cooling, followed by stirring at room temperature for 30 minutes, and methyl 5-chloropyrazine-2-carboxylate (2 g) was added thereto in one portion in an ice bath, followed by stirring at room temperature for 15 minutes. To the reaction mixture was added 1 M hydrochloric acid in an ice bath, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=3:1-1:1) to obtain a colorless oily substance. To a solution of the obtained colorless oily substance in methanol (50 mL) was added 1 M aqueous sodium hydroxide solution (15 mL) at room temperature, followed by stirring at room temperature for 2 hours. 1 M Hydrochloric acid was added to reaction mixture to adjust the pH to 2 under ice-cooling, followed by addition of water (about 200 mL). The resulting precipitate was collected by filtration while washing with a solvent (water:methanol=5:1), to obtain 5-[2-(benzyloxy)ethoxy]pyrazine-2-carboxylic acid (1.089 g) as a white solid.
Reaction SMILES: CO.C([C:6]1[C:7](=[O:17])[O:8][C:9]([OH:16])=[C:10](C(=O)C)[C:11]=1[OH:12])(=O)C>[Pd].O1CCCC1>[OH:12][C:11]1[CH2:10][C:9](=[O:16])[O:8][C:7](=[O:17])[CH:6]=1
Reactant: CC(=O)c1c(O)oc(=O)c(C(C)=O)c1O
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: O=C1C=C(O)CC(=O)O1
Reaction time: 16 h

Procedure:
A mixture of 3.5 g. (0.01 mol) of 1-nitro-3,5-bis-ethoxyoxamoylbenzene (prepared from 3,5-diaminonitrobenzene by reaction with ethoxyoxalyl chloride in pyridine) in 100 ml. of methanol was hydrogenated over 200 mg. of 10% palladium-on-carbon at 50 psi. Reduction was complete in 16 hours. To the mixture was added tetrahydrofuran (about 100 ml.) to dissolve the precipitate, the catalyst was filtered and to the filtrate containing 3,5-bis-ethoxyoxamoylaniline was added 2.12 g. (0.01 mol) of 3,5-diacetyl-4,6-dihydroxy-2H-pyran-2-one. This mixture was heated under reflux while 100 ml. of volatile solvent was collected by distillation. Heating was stopped, 50 ml. of methanol was added and the product collected by filtration, giving 5-acetyl-3-[3,5-bis-ethoxyoxamoylphenylamino)ethylidene]-4-hydroxy-2H-pyran-2,6(3H)-dione, m.p. 195° C.