Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si](OC[C:20]1([C:36]#[N:37])[CH2:24][CH:23]=[CH:22][N:21]1[C:25]1[CH:30]=[CH:29][C:28]([C:31]([O:33][CH2:34][CH3:35])=[O:32])=[CH:27][CH:26]=1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.[O:56]1CCC[CH2:57]1>>[CH2:34]([O:33][C:31]([C:28]1[CH:27]=[CH:26][C:25]([N:21]2[C:22]([CH2:57][OH:56])=[CH:23][CH:24]=[C:20]2[C:36]#[N:37])=[CH:30][CH:29]=1)=[O:32])[CH3:35]
Reactant: CCOC(=O)c1ccc(N2C=CCC2(C#N)CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)cc1
Reactant: C1CCOC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Product: CCOC(=O)c1ccc(-n2c(C#N)ccc2CO)cc1

Procedure:
To a solution of 2-tert-butyldiphenylsilyloxymethyl-1-(4-ethoxycarbonylphenyl)pyrrole-2-carbonitrile (1.9 g) in tetrahydrofuran (19 ml) was added tetrabutylammonium fluoride (5.6 ml, 1M tetrahydrofuran solution) through syringe at ambient temperature. The mixture was stirred for half an hour at the same temperature and concentrated in vacuo. The residue was dissolved in ethyl acetate and the solution was washed with aqueous hydrochloric acid, water and brine, and then dried, and concentrated in vacuo. The oily residue was chromatographed on silica gel (elution by ethyl acetate/n-hexane =1/1) to give 1-(4-ethoxycarbonylphenyl)-5-hydroxymethylpyrrole-2-carbonitrile (702.5 mg) as an oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][CH:3]=1.CCCCCC.C([Li])CCC.[CH2:20]([C@H:23]1[CH2:28][CH2:27][C@H:26]([C:29]([F:33])=[C:30](F)[F:31])[CH2:25][CH2:24]1)[CH2:21][CH3:22].Cl>C(OCC)C>[F:1][C:2]1[CH:7]=[CH:6][C:5](/[C:30](/[F:31])=[C:29](/[C@H:26]2[CH2:27][CH2:28][C@H:23]([CH2:20][CH2:21][CH3:22])[CH2:24][CH2:25]2)\[F:33])=[CH:4][CH:3]=1
Reactant: CCC[C@H]1CC[C@H](C(F)=C(F)F)CC1
Reactant: Fc1ccc(I)cc1
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Product: CCC[C@H]1CC[C@H](/C(F)=C(\F)c2ccc(F)cc2)CC1
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
Into a 300 cc four-necked flask, 5.59 g (25.2 mmol) of 4-fluroiodobenzene and 30 cc of dry ethyl ether were charged and cooled to -78° C. Then, 17 cc (27.8 mmol) of a n-hexane solution of n--C4H9Li (1.63 mol/l) was dropwise added thereto over a period of 15 minutes. Further, the mixture was stirred at -78° C. for one hour. Then, 3.8 cc (25.5 mmol) of N,N,N',N'-tetramethylene ethylenediamine was added thereto. Further, a dry diethyl ether (10 cc) solution containing 1.3 g (6.31 mmol) of 2-(trans-4-n-propylcyclohexyl)-1,1,2-trifluoroethylene obtained in Example 1, was dropwise added thereto over a period of 30 minutes. Further, the mixture was reacted at the same temperature for one hour, and then stirred at room temperature for one hour. Then, 50 cc of 1N hydrochloric acid was added thereto. The organic layer was separated. The aqueous layer was extracted with n-hexane, and the extract was combined with the organic layer. The combined organic layer was washed with water and dried. Further, the solvent was distilled off. The obtained crude solution was purified by silica gel column chromatography to obtain a solid. This solid was recrystallized from methanol to obtain 0.71 g (yield: 40%) of (E)-1-(4-fluorophenyl)-2-(trans-4-n-propylcyclohexyl)-1,2-difluoroethylene.
Reaction SMILES: [CH3:1][CH:2]1[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[N:12]=[C:11]([NH:13][C:14]2[C:15]3[N:16]([CH:30]=[CH:31][N:32]=3)[N:17]=[C:18]([C:20]3[CH:29]=[CH:28][C:23]([C:24]([O:26]C)=[O:25])=[CH:22][CH:21]=3)[CH:19]=2)[CH:10]=[CH:9][CH:8]=1.[OH-].[Na+]>O1CCOCC1.O>[CH3:1][CH:2]1[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[N:12]=[C:11]([NH:13][C:14]2[C:15]3[N:16]([CH:30]=[CH:31][N:32]=3)[N:17]=[C:18]([C:20]3[CH:29]=[CH:28][C:23]([C:24]([OH:26])=[O:25])=[CH:22][CH:21]=3)[CH:19]=2)[CH:10]=[CH:9][CH:8]=1
Reactant: COC(=O)c1ccc(-c2cc(Nc3cccc(N4CCCC4C)n3)c3nccn3n2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CC1CCCN1c1cccc(Nc2cc(-c3ccc(C(=O)O)cc3)nn3ccnc23)n1
Temperature: 40 °C
Reaction time: 4 h
Yield: 87.5 %

Procedure:
To a solution of methyl 4-(8-(6-(2-methylpyrrolidin-1-yl)pyridin-2-ylamino)imidazo[1,2-b]pyridazin-6-yl)benzoate (220 mg, 0.51 mmol) in dioxane (10 mL) and water (9 mL) was added NaOH (200 mg, 5 mmol), then the mixture was heated to 40° C. with stirring for 4 h. The solution was concentrated to approximately 10 mL in vacuo and washed with dichloromethane (10 mL×3). Water (10 mL) was added and the solution was adjusted to pH=4 by the addition of concentrated HCl. The solid formed was filtered to give 4-(8-(6-(2-methylpyrrolidin-1-yl)pyridin-2-ylamino)imidazo[1,2-b]pyridazin-6-yl)benzoic acid (0.185 g, 87%) as a light yellow solid. 1H NMR (300 MHz, DMSO): δ 9.72 (s, 1H), 8.82 (s, 1H), 8.23 (s, 1H), 8.09-8.02 (m, 3H), 7.69 (s, 1H), 7.44 (t, 1H, J=7.5 Hz), 6.73 (d, 1H, J=7.5 Hz), 6.08 (d, 1H, J=8.4 Hz), 4.23-4.20 (m, 1H), 3.58-3.56 (m, 2H), 2.08-1.97 (m, 3H), 1.68 (s, 1H), 1.12 (d, 1H, J=6.3 Hz). LC-MS: [M+H]+, 415, tR=1.652 min, HPLC: 98.19% at 214 nm, 97.87% at 254 nm, tR=5.967 min.
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][N:14]([CH:17]2[CH2:20][N:19]([C:21]([C:23]3[CH:28]=[CH:27][C:26]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)=[CH:25][CH:24]=3)=[O:22])[CH2:18]2)[CH2:13][CH2:12]1)=O)C1C=CC=CC=1.[H][H]>[Pd]>[C:26]1([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:25]=[CH:24][C:23]([C:21]([N:19]2[CH2:20][CH:17]([N:14]3[CH2:15][CH2:16][NH:11][CH2:12][CH2:13]3)[CH2:18]2)=[O:22])=[CH:28][CH:27]=1
Reactant: O=C(OCc1ccccc1)N1CCN(C2CN(C(=O)c3ccc(-c4ccccc4)cc3)C2)CC1
Reactant: [H][H]
Agent: [Pd]
Product: O=C(c1ccc(-c2ccccc2)cc1)N1CC(N2CCNCC2)C1
Yield: 160.9 %

Procedure:
A mixture of compound 8e (1.7 g, 2.9 mmol), and 10% Palladium on carbon (300 mg) was hydrogenated (50 psi hydrogen gas) using a Parr apparatus for 18 h. The catalyst was removed by filtration, and the solvent concentrated under reduced pressure to afford crude compound 8f (1.5 g). MS m/z (M+H+) 322.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1B(O)O.C(=O)([O-])[O-].[Na+].[Na+].[CH2:19]([N:26]1[CH2:34][C:33]2([C:35]([O:37][CH3:38])=[O:36])[CH:28]([C:29](I)=[CH:30][CH2:31][CH:32]2[C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[CH2:27]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CO.COCCOC.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>[CH2:19]([N:26]1[CH2:34][C:33]2([C:35]([O:37][CH3:38])=[O:36])[CH:28]([C:29]([C:2]3[S:1][C:5]4[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=4[CH:3]=3)=[CH:30][CH2:31][CH:32]2[C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=2)[CH2:27]1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: COC(=O)C12CN(Cc3ccccc3)CC1C(I)=CCC2c1ccccc1
Reactant: OB(O)c1cc2ccccc2s1
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: [Na+]
Solvent: CO
Solvent: COCCOC
Product: COC(=O)C12CN(Cc3ccccc3)CC1C(c1cc3ccccc3s1)=CCC2c1ccccc1
Temperature: 25 °C

Procedure:
A solution of 9.3 g (17.3 mmol) of benzothiophene-2-boronic acid trimeric anhydride in 100 cm3 of methanol and 400 cm3 of a 2N aqueous sodium carbonate solution are successively added to a solution of 22.36 g (47 mmol) of the levorotatory enantiomer of methyl (3aRS,4SR,7aRS)-2-benzyl-7-iodo-4-phenyl-1,2,3,4,5,7a-hexahydroisoindole-3a-carboxylate and of 6.03 g (5.2 mmol) of tetrakis(triphenylphosphine)palladium in 250 cm3 of 1,2-dimethoxyethane, the reaction mixture is then brought to reflux for two hours and stirring is maintained overnight at room temperature. After returning to a temperature in the region of 20° C., the reaction mixture is extracted with 800 cm3 of ethyl acetate and then the organic phase is washed with a saturated aqueous sodium chloride solution, dried over magnesium sulfate and concentrated under reduced pressure. The brown residue obtained is purified by flash chromatography on silica gel (230-400 mesh), elution being carried out with a cyclohexane/ethyl acetate (80/20 by volume) mixture. 11.04 g (50%) of the levorotatory enantiomer of methyl (3aRS,4SR,7aRS)-2-benzyl-4-phenyl-7-(2-benzothienyl)-1,2,3,4,5,7a-hexahydroisoindole-3a-carboxylate are thus obtained in the form of a yellow foam, the characteristics of which are as follows:
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=2[F:16])=[N:6][CH:7]=1.[Li]CCCC.[Br:22][C:23]1[CH:24]=[CH:25][C:26]([Cl:31])=[C:27]([CH:30]=1)[CH:28]=[O:29]>C1COCC1.CCCCCC>[Br:22][C:23]1[CH:24]=[CH:25][C:26]([Cl:31])=[C:27]([CH:28]([C:2]2[CH:7]=[N:6][C:5]([NH:8][C:9]3[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=3[F:16])=[CH:4][CH:3]=2)[OH:29])[CH:30]=1
Reactant: Fc1ccc(Nc2ccc(Br)cn2)c(F)c1
Reactant: O=Cc1cc(Br)ccc1Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: OC(c1ccc(Nc2ccc(F)cc2F)nc1)c1cc(Br)ccc1Cl
Reaction time: 0.33 h

Procedure:
(5-Bromo-pyridin-2-yl)-(2,4-difluoro-phenyl)-amine (3 g; 10.5 mmol) is dissolved in THF (70 ml) and cooled to −78 C. nBuLi (14.5 ml of a 1.5M solution in hexane; 23 mmol) is added dropwise and the resulting yellow suspension stirred or 20 min. 5-Bromo-2-chlorobenzaldehyde in THF (6 ml) is added at −78 C. After 5 min at −78 C, the reaction mixture is warmed to −50 C, poured on water and extracted with TBME twice. The combined organic phases are dried over Na2SO4 and evaporated to dryness. Purification via chromatography (SiO2; acetone/hexanes 6/94>12/88) yields the title compound as orange viscuous oil, (2.58 g; 58%) which is used in the next step. b) (5-Bromo-2-chloro-phenyl)-[6-(2,4-difluoro-phenylamino)-pyridin-3-yl]-methanone
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][C:5](=[C:8]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[CH:12]=[C:11](Br)[C:10]3[CH:20]=[CH:21][CH:22]=[CH:23][C:9]2=3)[CH2:4][CH2:3]1.[NH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1.C([Li])CCC.CCCCCC>>[CH3:1][N:2]1[CH2:7][CH2:6][C:5](=[C:8]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[CH:12]=[C:11]([N:24]3[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]3)[C:10]3[CH:20]=[CH:21][CH:22]=[CH:23][C:9]2=3)[CH2:4][CH2:3]1
Reactant: C1CCNCC1
Reactant: CN1CCC(=C2c3ccccc3C=C(Br)c3ccccc32)CC1
Agent: [Li]CCCC
Solvent: CCCCCC
Product: CN1CCC(=C2c3ccccc3C=C(N3CCCCC3)c3ccccc32)CC1

Procedure:
1-Methyl-4-(10-bromo-5H-dibenzo[a,d]cyclohepten-5-ylidene)piperidine, 7.32 g. (0.02 mole) is dissolved in 100 ml. of dry piperidine. To this solution is added slowly 25 ml. of a 1.6M solution of butyl lithium in hexane (0.04 mole) under anhydrous conditions and then stirred and refluxed for 8 hours under anhydrous conditions. The reaction is cooled and poured into 500 ml. of benzene and extracted 6 times with 100 ml. of water. The benzene is dried over anhydrous MgSO4, filtered, and the benzene removed on a rotary evaporator leaving 1-methyl-4-(10-(1-piperidyl)-5H-dibenzo[a,d]-cyclohepten-5-ylidene)piperidine as an oil which still has some solvent in it.
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][CH2:4][C:3]1=[O:7].C([N-]C(C)C)(C)C.[Li+].Br[CH2:17]/[CH:18]=[C:19](/[C:30]1[N:35]=[C:34]([O:36][CH3:37])[C:33]([Cl:38])=[CH:32][CH:31]=1)\[C:20]1[CH:25]=[CH:24][C:23]([C:26]([CH3:29])([CH3:28])[CH3:27])=[CH:22][CH:21]=1.O>O1CCCC1>[C:26]([C:23]1[CH:22]=[CH:21][C:20](/[C:19](/[C:30]2[CH:31]=[CH:32][C:33]([Cl:38])=[C:34]([O:36][CH3:37])[N:35]=2)=[CH:18]\[CH2:17][CH:4]2[CH2:5][CH2:6][N:2]([CH3:1])[C:3]2=[O:7])=[CH:25][CH:24]=1)([CH3:27])([CH3:28])[CH3:29]
Reactant: COc1nc(/C(=C/CBr)c2ccc(C(C)(C)C)cc2)ccc1Cl
Reactant: CN1CCCC1=O
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: COc1nc(/C(=C/CC2CCN(C)C2=O)c2ccc(C(C)(C)C)cc2)ccc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 93 %

Procedure:
A solution of N-methylpyrrolidone (0.7 mL) in tetrahydrofuran (3 mL) was stirred at −78° C. in a nitrogen atmosphere, during which a lithium diisopropylamide solution (2.2 M, 0.5 mL) was added dropwise thereto. The mixture was stirred at the same temperature for 30 minutes. A solution of 6-[(1E)-3-bromo-1-(4-tert-butylphenyl)prop-1-en-1-yl]-3-chloro-2-methoxypyridine (182 mg) in tetrahydrofuran (2 mL) was slowly added dropwise thereto, and the mixture was stirred at −78° C. for one hour. Water was added to the reaction solution, which was then warmed to room temperature and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and filtered, after which the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1→0:10) to give 3-[(2E)-3-(4-tert-butylphenyl)-3-(5-chloro-6-methoxypyridin-2-yl)prop-2-en-1-yl]-1-methylpyrrolidin-2-one as a colorless oil (176 mg, 93%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]3([CH2:17][CH2:16][N:15]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:14][CH2:13]3)[C:11](=[O:23])[NH:10][CH2:9]2)=[CH:4][CH:3]=1.[CH3:24]S(C)=O.[H-].[Na+].IC>C1C=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]3([CH2:17][CH2:16][N:15]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:14][CH2:13]3)[C:11](=[O:23])[N:10]([CH3:24])[CH2:9]2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)N1CCC2(CC1)C(=O)NCN2c1ccc(F)cc1
Reactant: CS(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: CI
Product: CCOC(=O)N1CCC2(CC1)C(=O)N(C)CN2c1ccc(F)cc1
Reaction time: 8 h
Yield: 88 %

Procedure:
To a stirred and cooled (below 5° C.) mixture of 16 parts of ethyl 1-(4-fluorophenyl)-4-oxo-1,3,8-triazaspiro[4,5]decane-8-carboxylate, 200 parts of dimethyl sulfoxide and 200 parts of benzene are added 3.5 parts of a sodium hydride dispersion 50%. After stirring for 1 hour at a temperature below 5° C., there are added dropwise 10 parts of iodomethane at this temperature. Upon completion, stirring is continued overnight at room temperature. The reaction mixture is poured onto water and the layers are separated. The aqueous phase is extracted with methylbenzene. The extract is washed with water, dried, filtered and evaporated, yielding 14.7 parts (88%) of ethyl 1-(4-fluorophenyl)-3-methyl-4-oxo-1,3,8-triazaspiro[4,5]decane-8-carboxylate as a residue.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[CH2:9][N+:8]([O-])=[C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[F:20])[C:6]=2[CH:21]=1.[F:22][C:23]([F:34])([F:33])[C:24]([O:26]C(=O)C(F)(F)F)=[O:25]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[CH:9]([O:26][C:24](=[O:25])[C:23]([F:34])([F:33])[F:22])[N:8]=[C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[F:20])[C:6]=2[CH:21]=1
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Reactant: O=C1C[N+]([O-])=C(c2ccccc2F)c2cc(Br)ccc2N1
Product: O=C1Nc2ccc(Br)cc2C(c2ccccc2F)=NC1OC(=O)C(F)(F)F
Reaction time: 1.5 h
Yield: 80 %

Procedure:
A 9.5-g (0.027 mole) portion of 7-bromo-5-(2-fluorophenyl)-1,3-dihydro-2H-1,4-benzodiazepin-2-one 4-oxide was added portion-wise to 50 ml of trifluoroacetic anhydride, and the reaction mixture was stirred for 90 minutes. The suspended solid that formed was collected on a filter, washed thoroughly with pentane and dried in a vacuum over KOH. There was obtained 9.72 g (80%) of 7-bromo-5-(2-fluorophenyl)-1,3-dihydro-3-trifluoroacetoxy-2H-1,4-benzodiazepin-2-one as an off-white crystalline powder: mp 175°-177° (dec.); 19F nmr (DMSO-d6) δ -74.6 ppm (s, 3F) and -112.7 ppm (m, 1F); 1H nmr (DMSO-d6) δ 6.34 ppm (s, 1H), 7.1-8.1 ppm (m, 7H), 11.5 ppm (NH).
Reaction SMILES: [Br:1]C1C=CC(CC(OCC)=O)=CC=1.Br[C:15]1[CH:24]=[C:23]2[C:18]([C:19]([CH3:27])([CH3:26])[CH2:20][CH2:21][C:22]2=[O:25])=[CH:17][CH:16]=1>>[Br:1][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][CH:15]=1)[C:22](=[O:25])[CH2:21][CH2:20][C:19]2([CH3:27])[CH3:26]
Reactant: CCOC(=O)Cc1ccc(Br)cc1
Reactant: CC1(C)CCC(=O)c2cc(Br)ccc21
Product: CC1(C)CCC(=O)c2ccc(Br)cc21

Procedure:
Important starting materials for the synthesis of the preferred compounds of the invention are 6-bromo-1,2,3,4-tetrahydro-1,1-dimethylnaphthalene (Compound F), 7-bromo-3,4-dihydro-4,4-dimethylnaphthalen-1-one (Compound G), and the isomeric bromo compound, 6-bromo-3,4-dihydro-4,4-dimethylnaphthalen-1(2H)-one (Compound H). Compound G can be obtained as described in J. Mez Chem. 1995, 38, 4764-4767, and as shown in Reaction Scheme 1. Thus, referring now specifically to Reaction Scheme 1, ethyl 3-bromophenylacetate (Compound B, made by esterification of 3-bromophenylacetic acid) is reduced with diisobutylaluminum hydride (DIBAL H) to yield (3-bromophenyl)acetaldehyde. (3-Bromophenyl)acetaldehyde is reacted in a Wittig reaction with (carbethoxymethylene)triphenylphosphorane to provide a mixture of E and Z ethyl 4-(3-bromophenyl)but-2-enoates. The latter compounds are hydrogenated to yield ethyl 4-(3-bromophenyl)butanoate (Compound D). Compound D is reacted with the Grignard reagent derived from methylbromide to give the tertiary alcohol 5-(3-bromophenyl)-2-methylpentan-2-ol (Compound E) (It should be apparent to those skilled in the art, that the choice of the Grignard reagent used in this reaction step determines the nature of the R1 substituent in the resulting compounds of the invention.) Compound E is then treated with acid to cyclize it and to form 6-bromo-1,2,3,4-tetrahydro-1,1-dimethylnaphthalene (Compound F). Compound F is oxidized with chromium trioxide to yield 7-bromo-3,4-dihydro-4,4-dimethylnaphthalen-1(2H)-one (Compound G). The isomeric compound, 6-bromo-3,4-dihydro-4,4-dimethylnaphthalen-1(2H)-one (Compound H) can be obtained, starting with ethyl (4-bromophenyl)acetate, in accordance with the sequence of reactions illustrated in Reaction Scheme 1 for Compound G. 6-Bromo-3,4-dihydro-4,4-dimethylnaphthalen-1(2H)-one (Compound H) can also be obtained in accordance with the published literature procedure: Mathur et al. Tetrahedron, 41, 1509-1516 (1985).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:19][CH2:20][CH2:21][CH2:22][N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)=[CH:9][C:10]=2[O:12][CH:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[N:5]=[CH:4][C:3]=1[C:29]#[N:30].[CH3:31][O:32][CH2:33][C:34]#[C:35][C:36]1[CH:42]=[CH:41][C:39]([NH2:40])=[C:38]2[O:43][CH2:44][O:45][C:37]=12.[ClH:46].CN(C)C(=N)N(C)C>C(O)CC.C(OCC)C>[ClH:1].[ClH:46].[C:29]([C:3]1[CH:4]=[N:5][C:6]2[C:11]([C:2]=1[NH:40][C:39]1[CH:41]=[CH:42][C:36]([C:35]#[C:34][CH2:33][O:32][CH3:31])=[C:37]3[O:45][CH2:44][O:43][C:38]=13)=[C:10]([O:12][CH:13]1[CH2:14][CH2:15][O:16][CH2:17][CH2:18]1)[CH:9]=[C:8]([O:19][CH2:20][CH2:21][CH2:22][N:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1)[CH:7]=2)#[N:30]
Reactant: N#Cc1cnc2cc(OCCCN3CCOCC3)cc(OC3CCOCC3)c2c1Cl
Reactant: COCC#Cc1ccc(N)c2c1OCO2
Agent: CN(C)C(=N)N(C)C
Agent: Cl
Solvent: CCCO
Solvent: CCOCC
Product: COCC#Cc1ccc(Nc2c(C#N)cnc3cc(OCCCN4CCOCC4)cc(OC4CCOCC4)c23)c2c1OCO2

Procedure:
A mixture of 4-chloro-3-cyano-7-(3-morpholin-4-ylpropoxy)-5-(tetrahydro-2H-pyran-4-yloxy)quinoline (125 mg) and 4-(3-methoxyprop-1-ynyl)-2,3-methylendioxyaniline (179 mg) in 1-propanol (8 ml) was treated with a 11.0M solution of hydrogen chloride in diethyl ether (0.30 ml) then stirred and heated at reflux for 1 hour. The mixture was allowed to cool and neutralised by the addition of tetramethylguanidine (0.10 ml). The resulting solution was evaporated to dryness and the residue was purified by chromatography on a Biotage silica cartridge (20 g) eluting with a gradient of methanol in dichloromethane (1–10%). The fractions containing the product were combined and evaporated. The residue was dissolved in ethanol (8 ml) and treated with 2 equivalents of hydrogen chloride (1.0M in diethyl ether). The title compound was thus obtained as a white solid (130 mg); NMR Spectrum: (DMSOd6, 300K) 1.87 (m, 2H), 2.10 (m, 2H), 2.31 (m, 2H), 3.11 (m, 2H), 3.30 (m, 2H), 3.36 (s, 3H), 3.50 (m, 4H), 3.87 (m, 4H), 3.97 (m, 2H), 4.32 (m, 2H), 4.37 (s, 2H), 5.10 (m, 1H), 6.18 (s, 2H), 1.05 (m, 3H), 7.13 (s, 1H), 8.87 (s, 1H), 10.43 (s, 1H), 11.34 (s, 1H); Mass Spectrum: M+H+ 601.
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[C:9]3[C:14](=[CH:15][CH:16]=2)[NH:13][C:12](=[O:17])[CH2:11][CH2:10]3)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Cl.Cl[C:20]1[C:29]2[C:24](=[CH:25][C:26]([O:32][CH3:33])=[C:27]([O:30][CH3:31])[CH:28]=2)[N:23]=[CH:22][N:21]=1.CN(C)C=O>C(N(CC)CC)C>[CH3:31][O:30][C:27]1[CH:28]=[C:29]2[C:24](=[CH:25][C:26]=1[O:32][CH3:33])[N:23]=[CH:22][N:21]=[C:20]2[N:4]1[CH2:5][CH2:6][N:1]([C:7]2[CH:8]=[C:9]3[C:14](=[CH:15][CH:16]=2)[NH:13][C:12](=[O:17])[CH2:11][CH2:10]3)[CH2:2][CH2:3]1
Reactant: COc1cc2ncnc(Cl)c2cc1OC
Reactant: O=C1CCc2cc(N3CCNCC3)ccc2N1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1cc2ncnc(N3CCN(c4ccc5c(c4)CCC(=O)N5)CC3)c2cc1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 34.8 %

Procedure:
To a mixture of 6-(1-piperazinyl)-3,4-dihydro-2(1H)-quinolinone (1.28 g), 4-chloro-6,7-dimethoxyquinazoline hydrochloride (1.43 g) and N,N-dimethylformamide (50 ml) was added triethylamine (560 mg) and the mixture was stirred for 8 hours at ambient temperature. The solvent was removed under reduced pressure and to the obtained residue were added water (20 ml), tetrahydrofuran (10 ml) and ethyl acetate (10 ml). The separated organic layer was washed with brine, dried over magnesium sulfate and concentrated. The residue was subjected to a column chromatography on silica gel (80 g) and eluted with 10% solution of methanol in chloroform. The fractions containing the object compound were combined and concentrated. The obtained residue was subjected to a column chromatography on alumina (60 g) and eluted with 5% solution of methanol in chloroform. The fractions containing the object compound were combined and concentrated to give 6-[4-(6,7-dimethoxyquinazolin-4-yl)-1-piperazinyl]-3,4-dihydro-2(1H)-quinolinone (0.8 g).
Reaction SMILES: [CH2:1]([CH:8]1[NH:14][CH2:13][CH2:12][S:11][C:10]2[C:15](=[O:20])[N:16]([CH3:19])[N:17]=[CH:18][C:9]1=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.I([O-])(=O)(=O)=[O:22].[Na+]>C(O)(=O)C.O>[CH2:1]([CH:8]1[NH:14][CH2:13][CH2:12][S:11](=[O:22])[C:10]2[C:15](=[O:20])[N:16]([CH3:19])[N:17]=[CH:18][C:9]1=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cn1ncc2c(c1=O)SCCNC2Cc1ccccc1
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: Cn1ncc2c(c1=O)S(=O)CCNC2Cc1ccccc1
Temperature: 0 °C
Yield: 63.2 %

Procedure:
To a solution of 0.84 g (2.92 mmol) of 5-benzyl-8-methyl-2,3,4,5-tetrahydro-9(8H)-pyridazino[4,5-b][1,5]thiazepinone in 7.5 ml of glacial acetic acid the solution of 0.75 g (3.6 mmol) of sodium metaperiodate in 6 ml of water are added dropwise while stirring and cooling with ice-water. The reaction mixture is stirred for 3 hours while cooling with ice-water. The obtained suspension is filtered and washed with a small amount of water. The aqueous phase is extracted with 3×20 ml of dichloromethane. The organic phase is washed with 2×5 ml of 10% aqueous sodium carbonate solution and then with 2×10 ml of water. The organic phase is dried and evaporated in vacuum. The residue is crystallized from a 9:1 mixture of ethyl acetate and methanol. In this way 0.56 g (63%) of the title compound is obtained with a melting point of 162-163° C.