Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[N:6]([NH:7][S:8]([CH3:11])(=[O:10])=[O:9])[C:5](=[O:12])[CH2:4][S:3]1.[Cl:13][C:14]1[CH:32]=[CH:31][C:17]([CH2:18][N:19]2[C:27]3[C:22](=[CH:23][C:24]([CH:28]=O)=[CH:25][CH:26]=3)[C:21]([F:30])=[N:20]2)=[C:16]([C:33]([F:36])([F:35])[F:34])[CH:15]=1.C(CN)O>>[Cl:13][C:14]1[CH:32]=[CH:31][C:17]([CH2:18][N:19]2[C:27]3[C:22](=[CH:23][C:24](/[CH:28]=[C:4]4/[C:5](=[O:12])[N:6]([NH:7][S:8]([CH3:11])(=[O:10])=[O:9])[C:2](=[O:1])[S:3]/4)=[CH:25][CH:26]=3)[C:21]([F:30])=[N:20]2)=[C:16]([C:33]([F:36])([F:35])[F:34])[CH:15]=1
Reactant: O=Cc1ccc2c(c1)c(F)nn2Cc1ccc(Cl)cc1C(F)(F)F
Reactant: CS(=O)(=O)NN1C(=O)CSC1=O
Solvent: NCCO
Product: CS(=O)(=O)NN1C(=O)S/C(=C\c2ccc3c(c2)c(F)nn3Cc2ccc(Cl)cc2C(F)(F)F)C1=O

Procedure:
N-[(5Z)-5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-3-fluoro-1H-indazol-5-yl}methylidene)-2,4-dioxo-1,3-thiazolidin-3-yl]methanesulfonamide was prepared from N-(2,4-dioxothiazolidin-3-yl)methanesulfonamide (from Example 360) and 1-[4-chloro-2-(trifluoromethyl)benzyl]-3-fluoro-1H-indazol-5-carbaldehyde following General Procedure F. The compound was converted to the corresponding ethanolamine salt following General Procedure T.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][C:11]([OH:13])=O)([O-:3])=[O:2].P(Cl)(Cl)(Cl)=O.Cl.[Cl:20][C:21]1[C:22]([CH2:31][NH2:32])=[N:23][CH:24]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:26]=1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[Cl:20][C:21]1[C:22]([CH2:31][NH:32][C:11](=[O:13])[CH2:10][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N+:1]([O-:3])=[O:2])=[N:23][CH:24]=[C:25]([C:27]([F:30])([F:28])[F:29])[CH:26]=1
Reactant: O=C(O)Cc1ccccc1[N+](=O)[O-]
Reactant: NCc1ncc(C(F)(F)F)cc1Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Product: O=C(Cc1ccccc1[N+](=O)[O-])NCc1ncc(C(F)(F)F)cc1Cl
Reaction time: 8 h

Procedure:
To a stirred suspension of 2-nitrophenylacetic acid (0.36 g) in dry toluene (5 ml) at room temperature was added phosphoryl chloride (0.37 g) and stirring was continued overnight. Meanwhile a solution of the amine was prepared, (3-Chloro-5-trifluoromethyl-2-pyridyl)methylamine hydrochloride (0.49 g) in dry toluene (5 ml) and triethylamine (1.23 g) was stirred at room temperature for 1 hour and then filtered. The solid was washed with dry toluene and the combined filtrates were added dropwise to the above suspension of acid chloride with ice-cooling. After addition, the mixture was stirred at room temperature overnight. Dichloromethane was added and the mixture was washed with water. The aqueous layer was separated and back-extracted with dichloromethane. The combined organic extracts were washed with saturated sodium bicarbonate solution, then brine, then dried (MgSO4), and the solvent removed. The resulting residue was purified by silica gel chromatography eluting with ethyl acetate/light petroleum (b.p. 40-60° C.) to give the title product, m.p. 123-4° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][N:15]2[C@H:10]([CH2:11][O:12][C@@:13]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[C:21]([C:26]#[N:27])[C:20]=3[CH3:28])(O)[CH2:14]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][N:15]2[C@H:10]([CH2:11][O:12][C:13]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[C:21]([C:26]#[N:27])[C:20]=3[CH3:28])=[CH:14]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1c([C@]2(O)CN3CCN(C(=O)OC(C)(C)C)C[C@H]3CO2)ccc(F)c1C#N
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1c(C2=CN3CCN(C(=O)OC(C)(C)C)C[C@H]3CO2)ccc(F)c1C#N
Temperature: 25 °C

Procedure:
Mesyl-Cl (17.2 mL, 221 mmol) was added dropwise to a stirred, <5° C. internal temperature mixture of (3R,9aS)-3-(3-Cyano-4-fluoro-2-methyl-phenyl)-3-hydroxy-hexahydro-pyrazino[2,1-c][1,4]oxazine-8-carboxylic acid tert-butyl ester (66.6 g, 170 mmol) and triethylamine (71.1 mL, 510 mmol) in CH2Cl2 (1000 mL) (exotherm occurs, so must keep addition slow), and the reaction was allowed to warm to room temperature for 30 minutes, by which time reaction was complete. The solution was washed with 500 mL 10% w/w NaHCO3 aqueous solution. The organics were dried over MgSO4, filtered and concentrated. The resulting material was taken up in a minimal amount of EtOAc (125 mL) with some heating (solution kept<50° C.) until all solids dissolved. The solution was allowed to cool with stirring, then dropwise overnight 350 mL hexanes was added. By the next morning the solution had clarified and there was considerable powder. The solids were collected by filtration and washed with 20% EtOAc/Hexanes, providing product. The mother liquors were concentrated until precipitate appeared, which was filtered to give additional (S)-3-(3-Cyano-4-fluoro-2-methyl-phenyl)-6,7,9,9a-tetrahydro-1H-pyrazino[2,1-c][1,4]oxazine-8-carboxylic acid tert-butyl ester.
Reaction SMILES: C(O[C:4]([CH3:13])=[CH:5][C:6](=O)[C:7]([O:9][CH2:10][CH3:11])=[O:8])C.[C:14]([CH2:16][C:17]([NH2:19])=[O:18])#[N:15].C(=O)([O-])[O-].[K+].[K+].Cl>CC(C)=O>[C:14]([C:16]1[C:17](=[O:18])[NH:19][C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:5][C:4]=1[CH3:13])#[N:15]
Reactant: N#CCC(N)=O
Reactant: CCOC(=O)C(=O)C=C(C)OCC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)c1cc(C)c(C#N)c(=O)[nH]1
Temperature: 85 °C
Reaction time: 0.5 h
Yield: 65.8 %

Procedure:
To a stirred solution of ethyl 4-ethoxy-2-oxopent-3-enoate (22.5 g, 121 mmol) and 2-cyanoacetamide (9.0 g, 107 mmol) in acetone (250 mL) was added potassium carbonate (15.8 g, 114 mmol). The reaction was refluxed (85° C. oil bath) for 10 hr (the reaction formed a thick ppt. in a deep red solution). The slurry was added to cold 1 N HCl (230 mL) in ice. After stirring for 30 min. the suspension was filtered, washed with water and dried under vacuum to give the product ethyl 5-cyano-4-methyl-6-oxo-1,6-dihydropyridine-2-carboxylate (14.51 g, 70.4 mmol, 65.7% yield) as a light pink solid.
Reaction SMILES: I[C:2]1[CH:3]=[N:4][N:5]([CH:7]2[CH2:12][CH2:11][CH:10]([N:13]3[CH2:16][CH:15]([NH:17][C:18]([CH2:20][NH:21][C:22](=[O:33])[C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=4)=[O:19])[CH2:14]3)[CH2:9][CH2:8]2)[CH:6]=1.[Si:34]([C:38]#[CH:39])([CH3:37])([CH3:36])[CH3:35].CCN(CC)CC>CN(C=O)C.[Cu]I>[F:30][C:29]([F:32])([F:31])[C:25]1[CH:24]=[C:23]([CH:28]=[CH:27][CH:26]=1)[C:22]([NH:21][CH2:20][C:18](=[O:19])[NH:17][CH:15]1[CH2:16][N:13]([CH:10]2[CH2:11][CH2:12][CH:7]([N:5]3[CH:6]=[C:2]([C:39]#[C:38][Si:34]([CH3:37])([CH3:36])[CH3:35])[CH:3]=[N:4]3)[CH2:8][CH2:9]2)[CH2:14]1)=[O:33]
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CN(C2CCC(n3cc(I)cn3)CC2)C1
Reactant: C#C[Si](C)(C)C
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C[Si](C)(C)C#Cc1cnn(C2CCC(N3CC(NC(=O)CNC(=O)c4cccc(C(F)(F)F)c4)C3)CC2)c1

Procedure:
A solution of N-({1-[4-(4-Iodo-pyrazol-1-yl)-cyclohexyl]-azetidin-3-ylcarbamoyl}-methyl)-3-trifluoromethyl-benzamide (as prepared in Example 28, 120 mg, 0.20 mmol), TMS-acetylene (Fluka, 20 mg, 0.40 mmol), Pd(Cl2)dppf (Aldrich, 16 mg, 0.02 mmol), CuI (Aldrich, 3.8 mg, 0.02 mmol) and Et3N (56 uL, 0.40 mmol) in DMF (5 mL) was heated to 80° C. overnight. The reaction was purified column chromatography purification (0-100% ethyl acetate in hexanes with NH3 in MeOH) resulting in the title compound as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]2[CH:11]=[CH:12][C:13](I)=[CH:14][C:8]=2[CH:7]=1)=[O:5])[CH3:2].C([Mg]Br)(C)C.CN(C1C=CC=CN=1)[CH:23]=[O:24].Cl>C(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]2[CH:11]=[CH:12][C:13]([CH:23]=[O:24])=[CH:14][C:8]=2[CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc2cc(I)ccc2s1
Reactant: CN(C=O)c1ccccn1
Agent: CC(C)[Mg]Br
Agent: Cl
Solvent: ClCCl
Product: CCOC(=O)c1cc2cc(C=O)ccc2s1
Temperature: -40 °C
Reaction time: 2 h

Procedure:
To a solution of 5-iodo-benzo[b]thiophene-2-carboxylic acid ethyl ester (14.09 g, 42.42 mmol) at −40° C. was slowly added a solution of isopropylmagnesium bromide (0.7 M in THF, 85 mL, 59.5 mmol). The mixture was allowed to stir at −40° C. for 2 h and N-methyl-N-pyridin-2-yl-formamide (7.65 mL, 63.9 mmol) was added slowly. After warming to rt, the mixture was allowed to stir for additional 2.5 h. To the mixture was carefully added 250 mL of 1N HCl. After stirring for 10 min, the reaction mixture was diluted with CH2Cl2 (800 mL). The organic layer was separated, washed with 200 mL of saturated NaHCO3 and dried over Na2SO4. After filtration, the filtrate was concentrated and the residue was recrystallized from MeOH to give 5-formyl-benzo[b]thiophene-2-carboxylic acid ethyl ester as a yellow solid. 1H NMR (CDCl3, 200 MHz) δ 10.12 (s, 1H), 8.37 (s, 1H), 8.18 (s, 1H), 8.08-7.90 (m, 2H), 4.44 (q, J=7.2 Hz, 2H), 1.44 (t, J=7.4 Hz, 3H). MS (EI): cal'd 235.0 (MH+), exp 235.1 (MH+).
Reaction SMILES: [Cl:1][CH:2]([C:11]1[CH:16]=[CH:15][C:14]([C:17]#[N:18])=[CH:13][CH:12]=1)[CH2:3][CH2:4][CH2:5][C:6]1[N:7]=[CH:8][NH:9][CH:10]=1>C(Cl)(Cl)Cl>[ClH:1].[C:17]([C:14]1[CH:15]=[CH:16][C:11]([CH:2]2[N:7]3[CH:8]=[N:9][CH:10]=[C:6]3[CH2:5][CH2:4][CH2:3]2)=[CH:12][CH:13]=1)#[N:18]
Reactant: N#Cc1ccc(C(Cl)CCCc2c[nH]cn2)cc1
Solvent: ClC(Cl)Cl
Product: Cl
Product: N#Cc1ccc(C2CCCc3cncn32)cc1

Procedure:
A solution of 2.0 g of 4-[4-chloro-4-(p-cyanophenyl)-n-butyl]-1H-imidazole in 50 ml of chloroform is refluxed for 4 h under nitrogen, cooled and evaporated to yield the title compound.
Reaction SMILES: [CH3:1][S:2][CH2:3][CH2:4][C@@H:5]([OH:8])[CH2:6][OH:7].[C:9]1([CH3:19])[CH:14]=[CH:13][C:12]([S:15](Cl)(=[O:17])=[O:16])=[CH:11][CH:10]=1>N1C=CC=CC=1>[C:9]1([CH3:19])[CH:14]=[CH:13][C:12]([S:15]([O:7][CH2:6][C@H:5]([O:8][S:15]([C:12]2[CH:13]=[CH:14][C:9]([CH3:19])=[CH:10][CH:11]=2)(=[O:17])=[O:16])[CH2:4][CH2:3][S:2][CH3:1])(=[O:17])=[O:16])=[CH:11][CH:10]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CSCC[C@@H](O)CO
Solvent: c1ccncc1
Product: CSCC[C@H](COS(=O)(=O)c1ccc(C)cc1)OS(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
(R)-4-(Methylthio)-1,2-butanediol (0.4 g, 2.9 mmol) was dissolved in 5 ml of pyridine and cooled to 0°-5° C. p-Toluenesulfonyl chloride (1.65 g, 9.0 mmol) was added and, after 5 minutes, the cooling bath removed, and the mixture stirred at room temperature for 2 hours, at which point it was diluted with 15 ml of H2O and extracted with 20 ml of ethyl acetate. The organic extract was washed with saturated NaCl, dried (MgSO4) and stripped to yield 0.5 g of present, crude title product as an oil, all of which was used in the next step without further refinement; tlc Rf 0.53 (3:1 hexane:ethyl acetate), 0.25 (5:1 hexane:ethyl acetate).
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[N:6][C:7]([CH2:11][CH2:12][CH:13]=O)=[CH:8][CH:9]=2)[CH2:4][O:3]1.[OH:15][CH2:16][CH2:17][O:18][CH2:19][CH2:20][N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1>>[OH:15][CH2:16][CH2:17][O:18][CH2:19][CH2:20][N:21]1[CH2:26][CH2:25][N:24]([CH2:13][CH2:12][CH2:11][C:7]2[N:6]=[C:5]3[CH2:4][O:3][C:2](=[O:1])[C:10]3=[CH:9][CH:8]=2)[CH2:23][CH2:22]1
Reactant: OCCOCCN1CCNCC1
Reactant: O=CCCc1ccc2c(n1)COC2=O
Product: O=C1OCc2nc(CCCN3CCN(CCOCCO)CC3)ccc21
Yield: 78.7 %

Procedure:
In a process similar to that described in Preparation 8, 3-(5-Oxo-5,7-dihydro-furo[3,4-b]pyridin-2-yl)-propionaldehyde (76 mg, 0.4 mmol) and 1-[2-(2-hydroxyethoxy)ethyl]-piperazine (66 μL, 0.4 mmol) are reacted to provide the title compound as an oil (110 mg, 79%).
Reaction SMILES: CC(C)([O-])C.[K+].[OH:7][C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH3:18])[CH:15]=2)[N:10]([CH3:19])[C:9]=1[C:20]([O:22][CH3:23])=[O:21].Cl[CH2:25][C:26]#[N:27].O>CS(C)=O>[C:26]([CH2:25][O:7][C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH3:18])[CH:15]=2)[N:10]([CH3:19])[C:9]=1[C:20]([O:22][CH3:23])=[O:21])#[N:27]
Reactant: N#CCCl
Reactant: COC(=O)c1c(O)c2cc(OC)ccc2n1C
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: COC(=O)c1c(OCC#N)c2cc(OC)ccc2n1C
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 59.2 %

Procedure:
A suspension of potassium tert-butoxide (3.2 g, 29 mmol) in 60 mL of dimethyl sulfoxide is treated in portions with methyl 3-hydroxy-5-methoxy-1-methyl-1H-indole-2-carboxylate (5.6 g, 24 mmol; Unangst P. C., et al., J. Heterocyclic Chem., 24:811 (1987)). The mixture is stirred for 15 minutes, and chloroacetonitrile (4.8 mL, 5.7 g, 76 mmol) is added dropwise. The mixture is heated at 80° for 90 minutes, cooled, and added to 800 g of ice and water. The precipitated solid is filtered, washed with 10% methanol-water, and recrystallized from aqueous acetonitrile to give 3.9 g (60%) of product, mp 136°-137° C.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[Li:10]CCCC>CCCCCCC>[CH:1]1([Li:10])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: [Li]CCCC
Reactant: C1=Cc2ccccc2C1
Solvent: CCCCCCC
Product: [Li]C1C=Cc2ccccc21
Reaction time: 2 h
Yield: 99.2 %

Procedure:
All reactions involving air and or moisture sensitive compounds were conducted under nitrogen using standard Schlenk and cannula techniques, or in a glovebox. Reaction solvents were purified either using the system described by Pangborn et. al. in Organometallics 1996, v 15, p. 1518 or used directly after being stored over activated 4 Å molecular sieves. The aluminoxane used was a 10% MAO solution in toluene supplied by Albemarle which was used as received. The support used was silica Sylopol 2408 obtained from W.R. Grace. & Co. The support was calcined by fluidizing with air at 200° C. for 2 hours followed by nitrogen at 600° C. for 6 hours and stored under nitrogen. The phosphinimine catalyst compound (1,2-(n-propyl)(C6F5)Cp)Ti(N═P(t-Bu)3)Cl2 was made in a manner similar to the procedure given in U.S. Pat. No. 7,531,602 (see Example 2). The phosphinimine compound (1-C6F5CH2—Indenyl)((t-Bu)3P═N)TiCl2 was made as follows. To distilled indene (15.0 g, 129 mmol) in heptane (200 mL) was added BuLi (82 mL, 131 mmol, 1.6 M in hexanes) at room temperature. The resulting reaction mixture was stirred overnight. The mixture was filtered and the filter cake washed with heptane (3×30 mL) to give indenyllithium (15.62 g, 99% yield). Indenyllithium (6.387 g, 52.4 mmol) was added as a solid over 5 minutes to a stirred solution of C6F5CH2—Br (13.65 g, 52.3 mmol) in toluene (100 mL) at room temperature. The reaction mixture was heated to 50° C. and stirred for 4 h. The product mixture was filtered and washed with toluene (3×20 mL). The combined filtrates were evaporated to dryness to afford 1-C6F5CH2-indene (13.58 g, 88%). To a stirred slurry of TiCl4.2THF (1.72 g, 5.15 mmol) in toluene (15 mL) was added solid (t-Bu)3P═N—Li (1.12 g, 5 mmol) at room temperature. The resulting reaction mixture was heated at 100° C. for 30 min and then allowed to cool to room temperature. This mixture containing ((t-Bu)3P═N)TiCl3 (1.85 g, 5 mmol) was used in the next reaction. To a THF solution (10 mL) of 1-C6F5CH2-indene (1.48 g, 5 mmol) cooled at −78° C. was added n-butyllithium (3.28 mL, 5 mmol, 1.6 M in hexanes) over 10 minutes. The resulting dark orange solution was stirred for 20 minutes and then transferred via a double-ended needle to a toluene slurry of ((t-Bu)3P═N)TiCl3 (1.85 g, 5 mmol). The cooling was removed from the reaction mixture which was stirred for a further 30 minutes. The solvents were evaporated to afford a yellow pasty residue. The solid was re-dissolved in toluene (70 mL) at 80° C. and filtered hot. The toluene was evaporated to afford pure (1-C6F5CH2—Indenyl)((t-Bu)3P═N)TiCl2 (2.35 g, 74%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([CH3:14])[NH:12][CH:13]=1.Cl[CH:16]([F:18])[F:17]>O1CCCC1.[OH-].[Na+]>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([CH3:14])[N:12]([CH:16]([F:18])[F:17])[CH:13]=1
Reactant: FC(F)Cl
Reactant: Cc1nc(-c2ccc(Cl)cc2Cl)c[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1nc(-c2ccc(Cl)cc2Cl)cn1C(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 1.7 g (7.5 mmol) of 4-(2,4-dichlorophenyl)-2-methyl-1H-imidazole stirring in a mixture of 75 ml of tetrahydrofuran and 8 ml of 50% aqueous sodium hydroxide at room temperature, 8 ml of condensed chlorodifluoromethane was added dropwise from a gas addition funnel. The reaction mixture was stirred at ambient temperature overnight. After partitioning between an excess of ethyl acetate and water, the organic layer was separated, washed with water (3×) and brine, dried over magnesium sulfate, and evaporated in vacuo. The resulting dark red oil was flash chromatographed on silica gel (10:1-5:1-3:1-1:1 hexane/ethyl acetate) to give 940 mg of slightly impure 4-(2,4-dichlorophenyl)-1-difluoromethyl-2-methylimidazole, obtained as an oily solid residue and taken directly to the next step.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.C[O-].[Na+].F[C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[C:17]([CH3:24])[CH:16]=1.Cl>CO.O>[CH3:24][C:17]1[CH:16]=[C:15]([CH:20]=[CH:19][C:18]=1[N+:21]([O-:23])=[O:22])[O:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccc(O)cc1
Reactant: Cc1cc(F)ccc1[N+](=O)[O-]
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: O
Product: Cc1cc(Oc2ccc(C(=O)O)cc2)ccc1[N+](=O)[O-]
Temperature: 125 °C
Yield: 22.3 %

Procedure:
4-hydroxybenzoic acid (13.8 g, 0.1 mole) was dissolved in methanol and to this solution was added, sodium methoxide (10.8 g, 0.2 mole). The solution was then evaporated to dryness. To the resulting solid was added DMF (500 mL) followed by 4-fluoro-2-methyl-1-nitrobenzene (available from Aldrich under 5-fluoro-2-nitro-toluene) (10.2 mL 0.1 mole). The mixture was heated at 125° C. for 2 hours, cooled and poured into 3 L of water, acidified to pH2 with 2M HCl and extracted twice with ethyl acetate. The combined organic layers were washed with water, dried and evaporated to dryness. The resulting solid was triturated with ether to give 4-(3-methyl-4-nitro-phenoxy)-benzoic acid (compound 1) as a white solid 6.1 g (22% yield; melting point=187-190° C.).
Reaction SMILES: [N:1]1([C:7](Cl)=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[C:10]([CH2:12][C:13]1([N:17]2[CH:21]=[C:20]([C:22]3[CH:27]=[N:26][N:25]4[C:28]([C:31]5[CH:32]=[C:33]([NH:37][C:38]([NH:40][CH2:41][C:42]([F:45])([F:44])[F:43])=[O:39])[CH:34]=[CH:35][CH:36]=5)=[CH:29][N:30]=[C:24]4[CH:23]=3)[CH:19]=[N:18]2)[CH2:16][NH:15][CH2:14]1)#[N:11].C(N(CC)CC)C>CN(C)C=O.CO>[C:10]([CH2:12][C:13]1([N:17]2[CH:21]=[C:20]([C:22]3[CH:27]=[N:26][N:25]4[C:28]([C:31]5[CH:32]=[C:33]([NH:37][C:38]([NH:40][CH2:41][C:42]([F:44])([F:45])[F:43])=[O:39])[CH:34]=[CH:35][CH:36]=5)=[CH:29][N:30]=[C:24]4[CH:23]=3)[CH:19]=[N:18]2)[CH2:14][N:15]([C:7]([N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)=[O:8])[CH2:16]1)#[N:11]
Reactant: O=C(Cl)N1CCOCC1
Reactant: N#CCC1(n2cc(-c3cnn4c(-c5cccc(NC(=O)NCC(F)(F)F)c5)cnc4c3)cn2)CNC1
Solvent: CO
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: N#CCC1(n2cc(-c3cnn4c(-c5cccc(NC(=O)NCC(F)(F)F)c5)cnc4c3)cn2)CN(C(=O)N2CCOCC2)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Morpholine-4-carbonyl chloride (6.8 mg, 0.045 mmol) was added to a mixture of N-[3-(7-{1-[3-(cyanomethyl)azetidin-3-yl]-1H-pyrazol-4-yl}imidazo[1,2-b]pyridazin-3-yl)phenyl]-N′-(2,2,2-trifluoroethyl)urea (15.0 mg, 0.0303 mmol) and triethylamine (13 μL, 0.093 mmol) in N,N-dimethylformamide (0.5 mL) and methanol (0.1 mL). The reaction mixture was stirred at r.t. for 2 h. The mixture was purified by RP-HPLC (pH=10) to afford the desired product. LCMS (M+H)+: m/z=609.2.
Reaction SMILES: [N:1]1([NH2:14])[C:13]2[C:12]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[N:6]=[CH:5][C:4]=2[N:3]=[CH:2]1.CO[C:17](OC)([CH3:19])[CH3:18]>C(#N)C.C(O)(=O)C.C(Cl)(Cl)Cl>[N:1]1([N:14]=[C:17]([CH3:19])[CH3:18])[C:13]2[C:12]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[N:6]=[CH:5][C:4]=2[N:3]=[CH:2]1
Reactant: COC(C)(C)OC
Reactant: Nn1cnc2cnc3ccccc3c21
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Solvent: CC#N
Product: CC(C)=Nn1cnc2cnc3ccccc3c21
Temperature: 100 °C
Reaction time: 18 h
Yield: 100.1 %

Procedure:
A solution of 1H-imidazo[4,5-c]quinolin-1-amine (2.86 g, 15.5 mmol) in 60 mL of acetonitrile and 15 mL of glacial acetic acid was treated with 2,2-dimethoxypropane (9.53 mL, 77.5 mmol) and heated to 100° C. under an atmosphere of nitrogen. After 18 h, the reaction mixture was concentrated under reduced pressure to give a brown oil. The oil was dissolved in 100 mL of CHCl3 and washed with 5% Na2CO3 solution (2×30 mL), water (30 mL) and brine (30 mL). The organic portion was dried over Na2SO4, filtered and concentrated under reduced pressure to yield 3.48 g of N-(1H-imidazo[4,5-c]quinolin-1-yl)isopropylideneamine as a brown oil.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([C:6]([CH3:14])([CH3:13])[CH2:7][CH2:8][C:9]2=O)=[CH:4][CH:3]=1.[C:15]([Mg]Cl)([CH3:18])([CH3:17])[CH3:16].C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:32]([O:34]C([Sn](CCCC)(CCCC)CCCC)=C)[CH3:33]>O1CCCC1>[C:32]([C:2]1[CH:11]=[C:10]2[C:5]([C:6]([CH3:14])([CH3:13])[CH2:7][CH:8]=[C:9]2[C:15]([CH3:18])([CH3:17])[CH3:16])=[CH:4][CH:3]=1)(=[O:34])[CH3:33]
Reactant: CC1(C)CCC(=O)c2cc(Br)ccc21
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Reactant: CC(C)(C)[Mg]Cl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1CCOC1
Product: CC(=O)c1ccc2c(c1)C(C(C)(C)C)=CCC2(C)C

Procedure:
Reaction Scheme 9 discloses the preferred method of synthesis of a starting material from which certain examples for compounds of the invention within the scope of Formula 6 are preferably made. In accordance with this scheme 7-bromo-3,4-dihydro-4,4-dimethylnaphthalen-1(2H)-one (Compound G) is reacted with t-butylmagnesium chloride in tetrahydrofuran in the presence of 1,3-dimethyl-3,4,5,6-tetrahydro-2(H)-pyrimidinone (DMPU). Thereafter, the resulting intermediate tertiary alcohol is heated in the presence of acid (ρ-toluenesulfonic acid) to give 7-bromo-1-(1,1-dimethylethyl)-3,4-dihydro-4,4-diimethylnaphthalene (Compound C42). Compound C42 is reacted with 1-ethoxyvinyltributyltin (EVTB) in the presence of Pd(0) catalyst to yield after acidic work-up 7-acetyl-1-(1,1-dimethylethyl)-3,4-dihydro-4,4-dimethylnaphthalene (Compound C43). Compound C43 is subjected to a sequence of reactions of the type described above in connection with Reaction Scheme 8, starting with a Horner Emmons reaction with diethyl cyanomethylphosphonate, to eventually provide ethyl 7-[4,4-dimethyl-3,4-dihydro-1-(1,1-dimethylethyl)-naphth-7-yl]-3,7-dimethyl-hepta-2(E),4(E),6(E)-trienoate (Compound C46). Compound C46 of the invention is within the scope of Formula 6. ##STR31##