Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[N:12][N:11]3[C:14](=[O:17])[NH:15][N:16]=[C:10]3[C:9]=2[C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)=[CH:4][CH:3]=1.[C:25]1([N:31]2[C:35](Cl)=[N:34][N:33]=[N:32]2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.C(OCC)(=O)C.Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[N:12][N:11]3[C:14](=[O:17])[N:15]([C:35]4[N:31]([C:25]5[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=5)[N:32]=[N:33][N:34]=4)[N:16]=[C:10]3[C:9]=2[C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)=[CH:4][CH:3]=1
Reactant: O=c1[nH]nc2c(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3)cnn12
Reactant: Clc1nnnn1-c1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=c1n(-c2nnnn2-c2ccccc2)nc2c(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3)cnn12
Temperature: 80 °C
Yield: 10 %

Procedure:
To a stirred solution of 7,8-bis(4-chlorophenyl)-[1,2,4]triazolo[4,3-b]pyridazin-3(2H)-one, (50 mg, 0.14 mmol), prepared as described in Example 1, in 0.7 mL of DMF was added N-phenyl-5-chlorotetrazole (25 mg, 0.14 mmol) and 19 mg of K2CO3. The resulting red solution was heated at 80° C. for 4 days and, upon cooling to room temp, the mixture was diluted with 50 mL of ethyl acetate and 50 mL of 1N HCl. The layers were extracted, and the organic layer was washed with 50 mL of saturated aqueous NaCl. The organic layer was dried over MgSO4, filtered and evaporated to an orange solid. The material was purified via silica gel column chromatography followed by reverse phase HPLC to give the title compound, 7,8-bis(4-chlorophenyl)-2-(1-phenyl-1H-tetrazol-5-yl)-[1,2,4]triazolo[4,3-b]pyridazin-3(2H)-one, (7 mg, 10%) yield as a yellow solid. LCMS Anal. Calc'd for C24H14Cl2N8O, 500.07, [M+H] 501 observed; 1H NMR (400 MHz, CD3CN) δ 8.30 (s, 1H), 7.69-7.55 (m, 5H), 7.39 (dt, 2H, J=2.1, 6.6 Hz), 7.28 (dt, 2H, J=1.9, 8.6 Hz), 7.23 (dt, 2H, J=2.2, 8.6 Hz), 7.06 (dt, 2H, J=2.1, 8.7 Hz).
Reaction SMILES: [Mg].II.Br[CH2:5][CH2:6][CH:7]([CH3:9])[CH3:8].CON(C)[C:13]([C:15]1[CH:19]=[CH:18][S:17][CH:16]=1)=[O:14]>C(OCC)C>[CH3:8][CH:7]([CH3:9])[CH2:6][CH2:5][C:13]([C:15]1[CH:19]=[CH:18][S:17][CH:16]=1)=[O:14]
Reactant: CON(C)C(=O)c1ccsc1
Reactant: CC(C)CCBr
Agent: II
Agent: [Mg]
Solvent: CCOCC
Product: CC(C)CCC(=O)c1ccsc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 19.4 %

Procedure:
Magnesium powder (1.49 g, 61.3 mmol) was added to dry diethyl ether (100 ml) under nitrogen atmosphere. One iodine crystal (catalytic) was added, followed by 1-bromo-3-methylbutane (6.3 ml, 52.6 mmol). The reaction was initiated by sonication at 30° C. and was allowed to spontaneously reflux. Once the exothermic reaction had subsided, the mixture was added by cannulation to a solution of thiophene-3-carboxylic acid methoxy-methyl-amide (7.50 g, 43.8 mmol) in dry diethyl ether (10 ml). Once addition was complete, the mixture was stirred at room temperature for 2 hours. The reaction mixture was then washed with saturated ammonium chloride (2×150 ml), dried (Na2SO4) and concentrated in vacuo. The crude yellow oil was purified by silica gel chromatography to yield the title compound as a colourless oil (1.55 g, 19%). 8H (d6 DMSO): 0.88 (6H, d), 1.49 (2H, q), 1.56 (1H, m), 2.90 (2H, t), 7.49 (1H, d), 7.59 (1H, d), 8.50 (1H, s).
Reaction SMILES: [CH2:1]1[CH:8]2[N:4]([C:5](=[O:9])[CH2:6][CH2:7]2)[C:3](=[O:10])[CH2:2]1.Cl.C.[OH2:13]>>[O:9]=[C:5]1[NH:4][CH:8]([CH2:1][CH2:2][C:3]([OH:10])=[O:13])[CH2:7][CH2:6]1
Reactant: O=C1CCC2CCC(=O)N12
Reactant: O
Agent: Cl
Product: O=C(O)CCC1CCC(=O)N1
Temperature: 100 °C

Procedure:
A suspension (partial solution) of 25 g of dihydro-1H-pyrrolizine-3,5(2H,6H)-dione (III) in 150 ml of deionized water is treated with 0.1 ml of concentrated hydrochloric acid. The mixture is heated to reflux (100° C.) for 80 hours. Charcoal (0.5 g) is added and the mixture is filtered through filter aid. The solution is concentrated at reduced pressure, the 5-oxo-2-pyrrolidinepropanoic acid crystallizes and is isolated by filtration. After drying in vacuo the 5-oxo-2-pyrrolidinepropanoic acid has a melting point of 125°-127° C.
Reaction SMILES: [Cl:1][C:2]1[C:24]([Cl:25])=[CH:23][CH:22]=[CH:21][C:3]=1[CH2:4][NH:5][C:6]1[C:11]([N+:12]([O-])=O)=[CH:10][CH:9]=[C:8]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[N:7]=1.[CH3:26][C:27](O)=O>[Fe]>[Cl:1][C:2]1[C:24]([Cl:25])=[CH:23][CH:22]=[CH:21][C:3]=1[CH2:4][N:5]1[C:6]2=[N:7][C:8]([N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[CH:9][CH:10]=[C:11]2[N:12]=[C:26]1[CH3:27]
Reactant: O=[N+]([O-])c1ccc(N2CCOCC2)nc1NCc1cccc(Cl)c1Cl
Reactant: CC(=O)O
Agent: [Fe]
Product: Cc1nc2ccc(N3CCOCC3)nc2n1Cc1cccc(Cl)c1Cl
Temperature: 25 °C
Yield: 30 %

Procedure:
To a refluxed solution of N-(2,3-dichlorobenzyl)-6-morpholino-3-nitropyridin-2-amine (1.15 g, 3 mmol) in CH3COOH (100 mL) was added iron powder (504 mg, 9 mmol) in portions. The mixture was then refluxed for 16 h and cooled to room temperature. It was filtered and the filtrate was concentrated in vacuo. The residue was then purified by chromatography on silica gel eluting with EtOAc/Pet ether=1/1 to afford the desired product as a pale solid (352 mg, 30%). LC/MS: MS (ES+) m/e 377 (MH+); 1H NMR (300 MHz, DMSO-d6) δ ppm 2.41 (s, 3H), 3.36 (t, J=4.8 Hz, 4H), 3.67 (t, J=4.8 Hz, 4H), 5.46 (s, 2H), 6.63 (d, J=8.1 Hz, 1H), 6.72 (d, J=8.7 Hz, 1H), 7.28 (t, J=8.1 Hz, 1H), 7.59 (d, J=8.1 Hz, 1H), 7.78 (d, J=8.7 Hz, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](Br)=[CH:4][N:3]=1.C([Li])CCC.[CH3:14][C:15]([CH3:17])=[O:16]>C(OCC)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:15]([OH:16])([CH3:17])[CH3:14])=[CH:4][N:3]=1
Reactant: CC(C)=O
Reactant: Brc1ccc(Br)nc1
Agent: [Li]CCCC
Solvent: CCOCC
Product: CC(C)(O)c1ccc(Br)nc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 2,5-dibromopyridine in diethyl ether (5 mL/mmol) was cooled to −78° C., and n-butyllithium 2.5M in hexanes (1.05 eq) was added slowly. After 2 hrs in the cold, acetone (1.3 eq) was added and stirring was continued for 1 hour. The resulting mixture was quenched with saturated aqueous ammonium chloride solution, warmed to room temperature, and partitioned between ether and water. The crude product from the organic phase was triturated with 1:1 ether-hexane and filtered to afford the 2-bromo-5-(1-hydroxy-1-methylethyl)pyridine compound as a solid.
Reaction SMILES: [C:1](/[CH:3]=[C:4](\[O-])/[C:5]([O:7][CH2:8][CH3:9])=[O:6])#[N:2].[K+].Cl.[CH2:13]([O:20][C:21]1[CH:22]=[C:23]([NH:27][NH2:28])[CH:24]=[CH:25][CH:26]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(O)C>[NH2:2][C:1]1[N:27]([C:23]2[CH:24]=[CH:25][CH:26]=[C:21]([O:20][CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:22]=2)[N:28]=[C:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH:3]=1
Reactant: NNc1cccc(OCc2ccccc2)c1
Reactant: CCOC(=O)/C([O-])=C/C#N
Agent: Cl
Agent: [K+]
Solvent: CCO
Product: CCOC(=O)c1cc(N)n(-c2cccc(OCc3ccccc3)c2)n1
Temperature: 25 °C
Yield: 67.8 %

Procedure:
To a suspension of potassium (Z)-1-cyano-3-ethoxy-3-oxoprop-1-en-2-olate (3.73 g, 20.82 mmol) in ethanol (100 mL) was added (3-(benzyloxy)phenyl)hydrazine hydrochloride (Preparation 61, 5.22 g, 20.82 mmol) and the reaction was heated at reflux for 24 hours. The reaction was cooled to room temperature, the solid was filtered and the filtrate was concentrated in vacuo. The residue was purified using silica gel column chromatography eluting with 20-40% EtOAc in heptanes to afford the title compound (4.76 g, 68%).
Reaction SMILES: [NH2:1][CH:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:11]3[CH:12]=[CH:13][C:14](=[O:17])[NH:15][N:16]=3)[CH:8]=2)[CH2:3]1.C(N(CC)CC)C.[CH2:25]([S:29](Cl)(=[O:31])=[O:30])[CH2:26][CH2:27][CH3:28]>CN(C)C=O>[CH2:25]([S:29]([NH:1][CH:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:11]3[CH:12]=[CH:13][C:14](=[O:17])[NH:15][N:16]=3)[CH:8]=2)[CH2:3]1)(=[O:31])=[O:30])[CH2:26][CH2:27][CH3:28]
Reactant: NC1Cc2ccc(-c3ccc(=O)[nH]n3)cc2C1
Reactant: CCCCS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCCCS(=O)(=O)NC1Cc2ccc(-c3ccc(=O)[nH]n3)cc2C1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 72.9 %

Procedure:
In 50 ml of dimethylformamide were dissolved 1.14 g of 2-amino-5-[pyridazin-3(2H)-on-6-yl]indane and 0.8 g of triethyl amine, and 1.25 g of n-butanesulfonyl chloride was added thereto. The mixture was stirred at 50° C for 30 minutes and then stirred at room temperature overnight. The solvent was removed, water was added to the residue, and crystals precipitated were collected by filtration. The resulting crystals were recrystallized from methanol to obtain 1.27 g of 2-n-butylsulfonylamino-5-[pyridazin-3(2H)-on-6-yl]indane.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:18]2[C:17](=O)[O:16]C(C)(C)[O:14][C:13]=2[CH:12]=[C:11]([O:22][CH3:23])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].C([Al+]CC(C)C)C(C)C>ClCCl.C1(C)C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([O:22][CH3:23])[CH:12]=[C:13]([OH:14])[C:18]=1[CH:17]=[O:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cc(OCc2ccccc2)c2c(c1)OC(C)(C)OC2=O
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: COc1cc(O)c(C=O)c(OCc2ccccc2)c1
Temperature: -78 °C
Reaction time: 3 h
Yield: 73.5 %

Procedure:
A solution of 5-(benzyloxy)-7-methoxy-2,2-dimethyl-4H-benzo[d][1,3]dioxin-4-one (Example 1B, 6.76 g, 21.5 mmol) in dichloromethane (120 mL) was cooled to −78° C. and treated with 43 mL (64.5 mmol) of a 1.5 M solution of diisobutylaluminum hydride in toluene added dropwise over 20 min. The resulting mixture was then stirred at −78° C. for 3 h. The reaction mixture was quenched by the careful addition of methanol (5 mL) added dropwise over 15 min, followed by 1N hydrochloric acid (50 mL) added dropwise over 15 min. The cooling bath was then removed and an additional 150 mL of 1N hydrochloric acid was added over 20 min. The mixture was then stirred at 22° C. for 2 h and diluted with dichloromethane (400 mL). The organic phase was collected and the aqueous phase (pH ˜1) was extracted with dichloromethane (3×50 mL). The combined organic extracts were washed with brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residual oil was diluted with tetrahydrofuran (70 mL), treated with 10 mL of 0.1N hydrochloric acid and stirred at 20° C. for 2 h. The reaction mixture was diluted with ethyl acetate (300 mL), washed with brine, dried over anhydrous magnesium sulfate, evaporated in vacuo to give a clear oil. Chromatography on silica gel (4×13 cm, elution toluene) gave 4.08 g (73% yield) of the title aldehyde as a clear oil which solidified on standing. LC (Method C): 2.237 min. HRMS (ESI) calcd for C15H15O4 [M+H]+ m/z 259.0965. found 259.1153. 1H NMR (CDCl3, 600 MHz) δ 3.80 (s, 3H), 5.07 (s, 2H), 5.97 (d, J=2.1 Hz, 1H), 6.01 (d, J=2.1 Hz, 1H), 7.3-7.4 (m, 5H), 10.15 (s, 1H), 12.49 (s, 1H).
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[NH:16]1[C:20](=[O:21])[CH2:19][CH2:18][C@H:17]1[C:22]([OH:24])=O.OC1C2N=NNC=2C=CC=1.[NH:35]1[CH2:40][CH2:39][O:38][CH2:37][CH2:36]1>ClCCl>[N:35]1([C:22]([C@H:17]2[NH:16][C:20](=[O:21])[CH2:19][CH2:18]2)=[O:24])[CH2:40][CH2:39][O:38][CH2:37][CH2:36]1
Reactant: O=C1CC[C@@H](C(=O)O)N1
Reactant: C1COCCN1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Oc1cccc2[nH]nnc12
Solvent: ClCCl
Product: O=C1CC[C@@H](C(=O)N2CCOCC2)N1
Temperature: 25 °C

Procedure:
To a mixture of 48 g dicyclohexylcarbodiimide, 30 g commercially available L-pyroglutamic acid and 3.1 g hydroxybenzotriazole 20.2 g of morpholine were added in 170 ml dichloromethane at about −15° C. The mixture was allowed to warm to room temperature. The suspension was filtered and diluted with 290 ml THF. The mixture was concentrated to obtain a suspension, which was filtered yielding 41 g of (S)-5-(morpholine-4-carbonyl)pyrrolidin-2-one.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[N:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)[CH:6]=1.O.[OH-].[Na+]>C(O)(=O)C>[N+:1]([C:13]1[CH:12]=[C:11]([C:7]2[CH:6]=[N:5][CH:10]=[CH:9][CH:8]=2)[CH:16]=[CH:15][C:14]=1[OH:17])([O-:4])=[O:2]
Reactant: Oc1ccc(-c2cccnc2)cc1
Reactant: O=[N+]([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: O=[N+]([O-])c1cc(-c2cccnc2)ccc1O
Temperature: 60 °C
Yield: 43.4 %

Procedure:
Nitric acid (60 μL, 1.0 mmol) was added to a solution of 4-pyridin-3-yl-phenol (164 mg, 0.96 mmol) in acetic acid (2.8 mL). The mixture was heated at 60° C. for 30 min and the solution turned orange/brown in color. Upon cooling, water was added (3 mL) and 6 N NaOH (aq) was added until the solution was basic. The solution was extracted with ethyl acetate (3×) and then the aqueous phase was concentrated. The crude residue was washed with boiling methanol to afford 90 mg (43%) of 2-nitro-4-pyridin-3-yl-phenol as an orange solid: mp>300° C., MS (Cl) m/z 217.1 (M+1).
Reaction SMILES: [C:1]([O:8]CC)(=O)[C:2]([O:4]CC)=O.[Br:11][C:12]1[C:13]([NH2:20])=[C:14]([NH2:19])[CH:15]=[C:16]([Br:18])[CH:17]=1.C>[OH-].[Na+]>[Br:11][C:12]1[CH:17]=[C:16]([Br:18])[CH:15]=[C:14]2[C:13]=1[NH:20][C:2](=[O:4])[C:1](=[O:8])[NH:19]2
Reactant: CCOC(=O)C(=O)OCC
Reactant: Nc1cc(Br)cc(Br)c1N
Agent: [Na+]
Agent: [OH-]
Product: O=c1[nH]c2cc(Br)cc(Br)c2[nH]c1=O
Temperature: 25 °C

Procedure:
The title compound was prepared using an adaptation of the method of Cheeseman. (Cheeseman, G. W. H. J. Chem. Soc. 1171 (1962)). A mixture of diethyl oxalate (2.19 g, 15.0 mmol) and 3,5-dibromo-1,2-diaminobenzene (400 mg, 1.50 mmol) was heated to reflux under N2 for 6 h. The reaction was allowed to cool to room temperature and the pale brown shiny solid collected by vacuum filtration and rinsed with EtOH (20 mL) and air dried to give 264 mg (55%). A portion of this solid (150 mg) was taken and dissolved in 20 mL 1N NaOH with heating. The solution was treated with activated charcoal and filtered through a pad of Celite. The resulting solution was carefully acidified with 2N HCl (pH=1). Pale yellow needles slowly formed in the solution and were collected by vacuum filtration, rinsed with 20 mL of H2O) and dried under vacuum (0.1 torr, 78° C.) to yield 50.0 mg of powdery white solid, mp 356°-358° C. (dec). 1H NMR (d6 -DMSO) δ7.21 (d, 1H, J=2.1, H-8), 7.53 (d, 1H, J=2.1, H-6), 11.1 (br s, 1H, NH), 12.1 (br s, 1H, NH). EIMS m/z 322 (M+4, 51.3), 320 (M+2, bp), 318 (M+, 53.9), 294 (32.2), 292 (62.6), 290 (28.7), 185 (24.3), 183 (25.2). EIHRMS calc. for C8H4Br2N2O2 317.8641, found 317.8642.
Reaction SMILES: [H-].[Na+].[CH3:3][PH:4](=[O:8])[O:5][CH2:6][CH3:7].Br[CH2:10][CH:11]1[CH2:13][CH2:12]1.O>O1CCCC1>[CH:13]1([CH2:12][P:4]([CH3:3])(=[O:8])[O:5][CH2:6][CH3:7])[CH2:11][CH2:10]1
Reactant: BrCC1CC1
Reactant: CCO[PH](C)=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCOP(C)(=O)CC1CC1
Reaction time: 3 h

Procedure:
A suspension of 2.22 g of sodium hydride (80% in oil) in 50 ml of anhydrous tetrahydrofuran under an inert atmosphere at 20° is treated with 50 ml of an anhydrous tetrahydrofuran solution of 7.24 g of ethyl (methyl)phosphinate at such a rate so that the temperature does not exceed 25°. After the addition is complete the resulting suspension is stirred for 1 hour at room temperature before slow addition of 10.0 g of bromomethylcyclopropane. The reaction mixture is stirred for a further 3 hours at 20° cooled in an ice/water bath and 100 ml of water added carefully. The clear solution is then partitioned between dichloromethane and water. Separation of the organic layer followed by drying and removal of the solvent affords a pale yellow oil. Distillation under high vacuum affords ethyl cyclopropylmethyl(methyl)phosphinate of b.p. 100° C. (10-1 mbar); 1H-NMR (CDCl3): δ (ppm)=4.04 (2H, m, CH2OP) 1.66 (2H, d, CH2P), 1.47 (3H, d, CH3), 1.30 (3H, t, CH3) 0.88 (1H, m, CH), 0.55 (2H, m, CH2), 0.15 (2H, m, CH2).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[O:17][CH3:18])=[CH2:10].C[Li].CI.O1CC[CH2:25][CH2:24]1>CCOCC>[CH3:18][O:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[C:9]([C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[O:2][CH3:1])([CH2:24][CH3:25])[CH3:10]
Reactant: C=C(c1ccccc1OC)c1ccccc1OC
Reactant: C1CCOC1
Agent: [Li]C
Solvent: CCOCC
Solvent: CI
Product: CCC(C)(c1ccccc1OC)c1ccccc1OC
Reaction time: 2 h

Procedure:
1,1-Bis(2-methoxyphenyl)ethene (5.6 g) was dissolved in 25 ml of tetrahydrofuran and 25 ml of a 1.3 M solution of methyl lithium in ether was added dropwise with stirring. The solution became dark red and exothermed After 2 hours, 5.0 ml of methyl iodide was added slowly with stirring. The solution again exothermed. When all of the methyl iodide had been added the starting material was found to be completely consumed and replaced by a single product by gas-liquid chromatography. About 300 ml of ether was added and the resulting solution was extracted with 100 ml of water and then 100 ml of brine, dried over magnesium sulfate, filtered, and concentrated by evaporation under reduced pressure to obtain 5.46 g (88 percent of theory) of the title compound as a pale yellow crystalline solid melting at 49°-52° C. The proton and carbon NMR and infrared spectra were consistent with the assigned structure.
Reaction SMILES: [CH:1]([N:4]1[C:8](=[O:9])[C:7](=[O:10])[N:6]=[C:5]1SC)([CH3:3])[CH3:2].[Cl:13][C:14]1[CH:15]=[C:16]([NH:21][C:22]([NH2:24])=[NH:23])[CH:17]=[CH:18][C:19]=1[Cl:20]>C(Cl)(Cl)Cl>[Cl:13][C:14]1[CH:15]=[C:16]([NH:21][C:22]([N:24]=[C:5]2[NH:6][C:7](=[O:10])[C:8](=[O:9])[N:4]2[CH:1]([CH3:3])[CH3:2])=[NH:23])[CH:17]=[CH:18][C:19]=1[Cl:20]
Reactant: N=C(N)Nc1ccc(Cl)c(Cl)c1
Reactant: CSC1=NC(=O)C(=O)N1C(C)C
Solvent: ClC(Cl)Cl
Product: CC(C)N1C(=O)C(=O)NC1=NC(=N)Nc1ccc(Cl)c(Cl)c1
Temperature: 50 °C
Yield: 39.9 %

Procedure:
To the solution of dione 11 (0.712 g, 3.83 mmol) in 80 ml of dry CHCl3 was added guanidine 14 (0.74 g, 3.64 mmol) and the reaction mixture was heated in an oil-bath at 50° C. for 16 hours. The solid precipitates were collected, washed sequentially with H2O, CH3OH and CHCl3 to afford the compound 3 as a light yellow solid (0.497 g, 40%). mp 233° C. 1H NMR (600 MHz, DMSO-d6): δ 7.77 (d, J=2.2 Hz, 1H), 7.68 (d, J=8.6 Hz, 1H), 7.31 (dd, J=8.6 and 2.2 Hz, 1H), 4.38 (m, 1H), 1.33 (d, J=6.7 Hz, 6H). 13C NMR: δ 172.24, 170.65, 162.14, 160.08, 132.13, 131.76, 126.96, 125.00, 44.44, 20.54. IR: 3277, 3140, 1752, 1725, 1553, 1464, 1317, 996, 808, 754 cm−1. Anal. (C13H13Cl2N5O2): C, 45.63; H, 3.83; N, 19.94. Found: C, 45.40; H, 3.71; N, 19.94.
Reaction SMILES: [C:1]1([C:7]2[CH2:16][CH2:15][C:14]3[C:9](=[CH:10][CH:11]=[C:12]([O:17][CH3:18])[CH:13]=3)[C:8]=2[CH:19]([C:21]2[CH:26]=[CH:25][C:24]([O:27][CH2:28][CH2:29][N:30]3[CH2:34][CH2:33][CH2:32][CH2:31]3)=[CH:23][CH:22]=2)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[ClH:35].[C:36](OCC)(=O)C>>[ClH:35].[C:1]1([C:7]2[CH:16]=[CH:15][C:14]3[C:9](=[CH:10][CH:11]=[C:12]([O:17][CH3:18])[CH:13]=3)[C:8]=2[CH2:19][C:21]2[CH:26]=[CH:25][C:24]([O:27][CH2:28][CH2:29][N:30]3[CH2:31][CH2:32][CH2:33][CH2:34][CH2:36]3)=[CH:23][CH:22]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COc1ccc2c(c1)CCC(c1ccccc1)=C2C(O)c1ccc(OCCN2CCCC2)cc1
Reactant: CCOC(C)=O
Agent: Cl
Product: COc1ccc2c(Cc3ccc(OCCN4CCCCC4)cc3)c(-c3ccccc3)ccc2c1
Reaction time: 0.01 h
Yield: 89 %

Procedure:
To a solution of the product of Example 7 (8.7 g, 18.5 mmol) stirring in ethyl acetate (100 mL) was added a saturated solution of hydrochloric acid gas in ethyl acetate (250 mL). After 0.5 min, the resulting solution was concentrated to give 8.0 g (89%) of the desired product as a white foam which was used without further purification: 1H-NMR (300 MHz, DMSO) δ 7.70-7.85 (m, 4H), 7.30-7.50 (m, 7H), 7.10 (s, 1H), 6.80-7.00 (m, 2H), 4.25-4.40 (m, 4H), 4.00-4.20 (br s, 3H), 3.35-3.55 (m, 4H), 2.85-3.55 (m, 2H), 1.70-1.90 (m, 4H), 1.30-1.45 (m, 2H); Anal. Calc'd for: C, 76.29; H, 7.02; N, 2.87. Found: C, 76.56; H, 7.18; N, 2.91; MS (FD) m/e 452 (M+-hydrochloric acid).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:14]=[C:15]([CH2:19][OH:20])[CH:16]=[CH:17][CH:18]=1.[H-].[Na+].F[C:24]1[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[C:25]=1[CH:26]=[O:27]>CN(C=O)C>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:14]=[C:15]([CH:16]=[CH:17][CH:18]=1)[CH2:19][O:20][C:24]1[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:33])([F:35])[F:34])[C:25]=1[CH:26]=[O:27]
Reactant: O=Cc1c(F)cccc1C(F)(F)F
Reactant: OCc1cccc(OCc2ccc3ccccc3n2)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=Cc1c(OCc2cccc(OCc3ccc4ccccc4n3)c2)cccc1C(F)(F)F
Temperature: 90 °C
Reaction time: 0.33 h

Procedure:
[3-(Quinolin-2-ylmethoxy)-phenyl]-methanol (300 mg, 1.13 mmol, example 48) is dissolved in DMF (6 mL) and sodium hydride (60%, 60 mg, 1.5 mmol) is added and allowed to stir 20 min. 2-Fluoro-6-(trifluoromethyl)benzaldehyde (0.30 mL, 2.2 mmol) is added and the reaction is heated at 90° C. for 5 h. The reaction is partitioned between ethyl acetate (200 mL) and water (200 mL), dried over magnesium sulfate, filtered, concentrated in vacuo and purified by column chromatography (silica, 25% ethyl acetate in hexanes) to provide the title compound; MS (ESI) 438 (M+H)+.
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.[CH2:29]([NH:31][CH2:32][CH3:33])[CH3:30].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[CH2:29]([N:31]([CH2:25][C:24]1[CH:27]=[CH:28][C:21]([CH:13]2[NH:12][C:7]3[C:6]4[C:5](=[N:4][NH:3][C:2](=[O:1])[C:11]=4[CH:10]=[CH:9][CH:8]=3)[CH:14]2[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:22][CH:23]=1)[CH2:32][CH3:33])[CH3:30]
Reactant: CCNCC
Reactant: O=Cc1ccc(C2Nc3cccc4c(=O)[nH]nc(c34)C2c2ccccc2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCN(CC)Cc1ccc(C2Nc3cccc4c(=O)[nH]nc(c34)C2c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 36.4 %

Procedure:
A mixture of 4-(3-oxo-9-phenyl-3,7,8,9-tetrahydro-2H-pyrido[4,3,2-de]phthalazin-8-yl)benzaldehyde (80 mg, 0.22 mmol), diethylamine (47 mg, 0.65 mmol) and acetic acid (39 mg, 0.65 mmol) in dichloromethane (50 mL) was stirred at room temperature for 60 min. Upon cooling the mixture to 0° C., sodium triacetoxyborohydride (69.3 mg, 0.33 mmol) was added. After the addition, the mixture was stirred at room temperature overnight. Dichloromethane was removed under reduced pressure. The crude product was purified by chromatography (silica gel, dichloromethane/Methanol=50:1) to give the title compound (34 mg, yield 36%). LC-MS (ESI) m/z: 425 (M+H)+. 1H-NMR (400 MHz, CD3OD) δ (ppm): 1.10 (t, 6H), 2.64 (q, 4H), 3.70 (s, 2H), 4.30 (d, J=8.0 Hz, 1H), 4.75 (d, J=8.0 Hz, 1H), 7.06-7.09 (m, 2H), 7.13-7.20 (m, 4 H), 7.22-7.29 (m, 4H), 7.54-7.56 (dd, J=8.0 Hz, 1H), 7.62-7.64 (m, 1H).
Reaction SMILES: [C:1]([CH:3]1[CH2:12][CH2:11][C:6]2([O:10][CH2:9][CH2:8][O:7]2)[CH2:5][CH2:4]1)#[CH:2].Br[C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)=[CH:16][CH:15]=1.C(N(CC)CC)C>C(OCC)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.[Cu]Br>[F:26][C:23]1[CH:22]=[CH:21][C:20]([C:17]2[CH:18]=[CH:19][C:14]([C:2]#[C:1][CH:3]3[CH2:12][CH2:11][C:6]4([O:7][CH2:8][CH2:9][O:10]4)[CH2:5][CH2:4]3)=[CH:15][CH:16]=2)=[CH:25][CH:24]=1
Reactant: C#CC1CCC2(CC1)OCCO2
Reactant: Fc1ccc(-c2ccc(Br)cc2)cc1
Agent: [Cu]Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: Fc1ccc(-c2ccc(C#CC3CCC4(CC3)OCCO4)cc2)cc1
Reaction time: 4.5 h

Procedure:
A mixture of 1.03 g of 8-ethynyl-1,4-dioxaspiro[4.5]decane, 1.197 g 4-bromo-4'-fluorobiphenyl, 0.11 g of tetrakis(triphenylphosphine)palladium, 0.041 g of copper(I) bromide and 45 ml of triethylamine was heated to boiling for 4.5 hours. After cooling the mixture was diluted with diethyl ether, washed twice with water, dried over sodium sulphate, filtered and concentrated. The crude 8-[(4'-fluoro-4-biphenylyl)ethynyl]-1,4-dioxaspiro[4.5]decane (1.82. g) obtained was purified by chromatography on 35 g of silica gel with hexane/ethyl acetate (vol. 9:1). Yield 1.30 g.