Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1CCC[CH2:2]1.C([N-]C(C)C)(C)C.[Li+].C1CCCCC1.[Cl:20][C:21]1[CH:30]=[CH:29][C:28]2[C:23](=[C:24]([O:31][CH3:32])[CH:25]=[CH:26][CH:27]=2)[N:22]=1.CN(C=O)C>C1COCC1>[Cl:20][C:21]1[C:30]([CH:2]=[O:1])=[CH:29][C:28]2[C:23](=[C:24]([O:31][CH3:32])[CH:25]=[CH:26][CH:27]=2)[N:22]=1
Reactant: C1CCOC1
Reactant: COc1cccc2ccc(Cl)nc12
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: C1CCCCC1
Product: COc1cccc2cc(C=O)c(Cl)nc12
Reaction time: 0.67 h

Procedure:
To a cooled solution of lithium diisopropylamide mono(tetrahydrofuran), 1.5 M sol. in cyclohexane (25.82 mL, 38.73 mmol) in 72 mL of THF at −75° C. was added a solution of 2-chloro-8-methoxyquinoline (5.0000 g, 25.82 mmol) in 26 mL of THF dropwise over 35 min (10:00 am˜10:35 am) with stirring and keeping the temperature below −65° C. After 40 min, to the cooled mixture was added DMF (2.999 mL, 38.73 mmol) dropwise and the mixture was stirred at −72° C. for 30 min. After 30 min, the reaction was quenched with NH4Cl (20 mL) and partitioned between EtOAc (150 mL) and water (100 mL). The combined organic layers were washed with water (100 mL×1), brine (100 mL×2), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a yellow solid. The yellow solid was purified by flash column chromatography on a silica gel column using 20% of EtOAc in hexane as eluent to give 2-chloro-8-methoxyquinoline-3-carbaldehyde as a yellow solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 10.38 (1 H, s), 8.92 (1 H, s), 7.79 (1 H, dd, J=8.4, 1.0 Hz), 7.67 (1 H, t, J=8.0 Hz), 7.44 (1 H, dd, J=7.8, 1.2 Hz), 4.00 (3 H, s); LC-MS (ESI) m/z 222.1 [M+H]+.
Reaction SMILES: CC1C=CC(S(O[C:12]2[C:21]3[C:20](=[O:22])[N:19]([CH2:23][C:24]4[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=4)[C:18](=[O:32])[N:17]([C:33]4[CH:38]=[CH:37][C:36]([I:39])=[CH:35][C:34]=4[F:40])[C:16]=3[N:15]([CH3:41])[C:14](=[O:42])[C:13]=2[CH3:43])(=O)=O)=CC=1.N1C(C)=CC=CC=1C.[NH2:52][C:53]1[CH:54]=[C:55]([CH:59]=[CH:60][CH:61]=1)[C:56]([OH:58])=[O:57].O>CC(N(C)C)=O>[F:40][C:34]1[CH:35]=[C:36]([I:39])[CH:37]=[CH:38][C:33]=1[N:17]1[C:16]2[N:15]([CH3:41])[C:14](=[O:42])[C:13]([CH3:43])=[C:12]([NH:52][C:53]3[CH:54]=[C:55]([CH:59]=[CH:60][CH:61]=3)[C:56]([OH:58])=[O:57])[C:21]=2[C:20](=[O:22])[N:19]([CH2:23][C:24]2[CH:25]=[CH:26][C:27]([O:30][CH3:31])=[CH:28][CH:29]=2)[C:18]1=[O:32]
Reactant: Nc1cccc(C(=O)O)c1
Reactant: COc1ccc(Cn2c(=O)c3c(OS(=O)(=O)c4ccc(C)cc4)c(C)c(=O)n(C)c3n(-c3ccc(I)cc3F)c2=O)cc1
Solvent: O
Solvent: CC(=O)N(C)C
Solvent: Cc1cccc(C)n1
Product: COc1ccc(Cn2c(=O)c3c(Nc4cccc(C(=O)O)c4)c(C)c(=O)n(C)c3n(-c3ccc(I)cc3F)c2=O)cc1
Temperature: 130 °C
Yield: 73.5 %

Procedure:
To a stirred solution of 1-(2-fluoro-4-iodophenyl)-3-(4-methoxybenzyl)-6,8-dimethyl-2,4,7-trioxo-1,2,3,4,7,8-hexahydropyrido[2,3-d]pyrimidin-5-yl 4-methylbenzene sulfonate (2a) (2.0 gm, 2.79 mmol) in DMA (5 ml) was added 2,6-lutidine (0.98 ml, 8.36 mmol) and 3-aminobenzoic acid (1.147 gm, 8.36 mmol). The reaction mixture was heated at 130° C. for 16 h. The reaction mixture was cooled to room temperature and water was added followed by extraction with Ethyl acetate. The organic phase was dried over sodium sulphate. The solvent was evaporated in vacuo and the residual solid was purified by silica gel column chromatography, eluting with Hexane:Ethyl acetate (1:1), to yield the titled compound (2b) (1.4 g)
Reaction SMILES: Br[C:2]1[CH:33]=[CH:32][C:5]([C:6]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][N:17]3[CH2:22][CH2:21][N:20]([C:23](=[O:31])[C:24]4[CH:29]=[CH:28][C:27](Br)=[CH:26][CH:25]=4)[CH2:19][CH2:18]3)[CH2:10][CH2:9]2)=[O:7])=[CH:4][CH:3]=1.[CH3:34][O:35][C:36]1[CH:37]=[C:38](B(O)O)[CH:39]=[C:40]([O:46][CH3:47])[C:41]=1[O:42][CH2:43][CH2:44][CH3:45]>>[CH3:34][O:35][C:36]1[CH:37]=[C:38]([C:2]2[CH:33]=[CH:32][C:5]([C:6]([N:8]3[CH2:9][CH2:10][N:11]([CH2:14][CH2:15][CH2:16][N:17]4[CH2:18][CH2:19][N:20]([C:23](=[O:31])[C:24]5[CH:25]=[CH:26][C:27]([C:38]6[CH:37]=[C:36]([O:35][CH3:34])[C:41]([O:42][CH2:43][CH2:44][CH3:45])=[C:40]([O:46][CH3:47])[CH:39]=6)=[CH:28][CH:29]=5)[CH2:21][CH2:22]4)[CH2:12][CH2:13]3)=[O:7])=[CH:4][CH:3]=2)[CH:39]=[C:40]([O:46][CH3:47])[C:41]=1[O:42][CH2:43][CH2:44][CH3:45]
Reactant: CCCOc1c(OC)cc(B(O)O)cc1OC
Reactant: O=C(c1ccc(Br)cc1)N1CCN(CCCN2CCN(C(=O)c3ccc(Br)cc3)CC2)CC1
Product: CCCOc1c(OC)cc(-c2ccc(C(=O)N3CCN(CCCN4CCN(C(=O)c5ccc(-c6cc(OC)c(OCCC)c(OC)c6)cc5)CC4)CC3)cc2)cc1OC
Yield: 100 %

Procedure:
By similar procedures applied in Example 2, from 3.00 g (5.19 mmol) of 1,3-bis [4-(4-bromobenzoyl)-1-piperazinyl]propane and 3.00 g (12.5 mmol) of 3,5-dimethoxy-4-propoxyphenylboronic acid, 4.20 g of 1,3-bis[4[4-(3,5-dimethoxy-4-propoxyphenyl) benzoyl]-1-piperazinyl]propane was obtained as a colorless oil (quantitative yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:18])[C:5]([NH2:17])=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=1[F:16].[C:19](O)([C:21]([F:24])([F:23])[F:22])=O>Cl>[Cl:1][C:2]1[C:7]([O:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=2[F:16])=[CH:6][C:5]2[NH:17][C:19]([C:21]([F:24])([F:23])[F:22])=[N:18][C:4]=2[CH:3]=1
Reactant: O=C(O)C(F)(F)F
Reactant: Nc1cc(Cl)c(Oc2ccc(F)cc2F)cc1N
Agent: Cl
Product: Fc1ccc(Oc2cc3[nH]c(C(F)(F)F)nc3cc2Cl)c(F)c1
Yield: 57 %

Procedure:
To a solution of 2,4-difluorophenol (1.9 g, 14.61 mmol) in DMSO (20 ml) was added 4,5-dichloro-2-nitroaniline (3 g, 14.49 mmol) and potassium carbonate (4 g, 28.94 mmol) with stirring overnight at 90° C. Then the reaction was quenched with water (200 ml) and extracted with ethyl acetate (3×100 ml) and the organic layers combined and dried over anhydrous magnesium sulfate. The organic layers were concentrated under vacuum to give a residue, which was purified by a silica gel column with 2%˜5% ethyl acetate in petroleum ether to produce 4-chloro-5-(4-fluoro-2-methylphenoxy)-2-nitroaniline as a yellow solid (1.3 g, 30%). Next, to a solution of 4-chloro-5-(2,4-difluorophenoxy)-2-nitroaniline (1.3 g, 4.32 mmol) in ethanol (20 ml) was added hydrogen chloride (conc. 1 ml) followed by the addition of Zn powder (1.7 g, 25.92 mmol) in portions at room temperature. The resulting solution was stirred for 4 h at 85° C. The resulting mixture was concentrated under vacuum and dissolved in water (150 ml), adjusted pH to 8 with aqueous sodium bicarbonate. The mixture was extracted with ethyl acetate (3×100 ml), dried and concentrated under reduced pressure to give a residue, which was purified by a silica gel column with 10%˜20% ethyl acetate in petroleum ether to produce 4-chloro-5-(2,4-difluorophenoxy)benzene-1,2-diamine as a light yellow solid (600 mg, 51%). Finally, a solution of 4-chloro-5-(2,4-difluorophenoxy)benzene-1,2-diamine (100 mg, 0.37 mmol) in hydrogen chloride (conc. 2 ml) and TFA (10 ml) was stirred overnight at 80° C. The solution was quenched with water (100 ml), adjusted pH value of the solution to 7 with aqueous sodium bicarbonate and extracted with ethyl acetate (3×50 ml) and the organic layers combined and dried over anhydrous magnesium sulfate. The solids were filtered out. The resulting mixture was concentrated under vacuum to give a residue, which was purified by a silica gel column with 5%˜10% ethyl acetate in petroleum ether to produce 5-chloro-6-(2,4-difluorophenoxy)-2-(trifluoromethyl)-1H-1,3-benzodiazole as a white solid (73.5 mg, 57%).
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].N1C=CC=CC=1.[CH2:15](Cl)[CH:16]=[CH:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C([O-])(O)=[O:26].[Na+]>C(Cl)Cl>[Br:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH:4][C:15](=[O:26])[CH:16]=[CH:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C([O-])O
Reactant: ClCC=Cc1ccccc1
Reactant: Nc1ccccc1Br
Agent: [Na+]
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(C=Cc1ccccc1)Nc1ccccc1Br
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-Bromoaniline (48.41 g, 281.4 mMol) was dissolved in 500 mL of anhydrous DCM under an atmosphere of dry N2. Pyridine (45.5 mL, 563 mMol) was then added and the reaction was subsequently cooled to 0° C. after which time cinnamyl chloride (46.9 g, 281.4 mMol) was added. The reaction mixture was slowly warmed up to ambient temperature and then stirred overnight at ambient temperature. The reaction was diluted with 300 mL of saturated aqueous NaHCO3 and then extracted with DCM. The DCM layer was then washed three times with 10% aqueous NaHSO4 followed by saturated aqueous NaHCO3 and finally brine. The DCM layer was then dried over Na2SO4, filtered and concentrated under vacuum to give 85.08 g of a tan solid as the title compound 61A.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH2:11])(=[O:10])=[O:9].[NH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1>O1CCOCC1>[NH2:11][S:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[N:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1)(=[O:10])=[O:9]
Reactant: C1CNCCN1
Reactant: NS(=O)(=O)c1ccccc1F
Solvent: C1COCCO1
Product: NS(=O)(=O)c1ccccc1N1CCNCC1
Temperature: 100 °C
Yield: 100 %

Procedure:
To a 50 mL flask containing 2-flourobenzene sulfonamide (200 mg, 1.14 mmol, 1 eq.) and piperazine (245 mg, 2.84 mmol, 2.5 eq) was added 20 mL of dioxane. The solution was heated to 100° C. for about 4 hours. More piperazine (200 mg, 2.32 mmol, 2 eq.) was added and the solution was heated to 100° C. for another 72 hours. The solution was concentrated to an oil and dissolved in 30 mL of 0.1 M pH 7.0 phosphate buffer. The aqueous solution was extracted with CH2Cl2 (3×30 mL). The combined organic extracts were dried over Na2SO4 and concentrated to yield about 275 mg (1.14 mmol, 100%) of the title compound. LRMS (ESI+): 242.1 (M+H).
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[CH2:16][CH2:15][N:14]([C:17]3[CH:18]=[CH:19][C:20]4[N:21]([C:23]([C:26]([F:29])([F:28])[F:27])=[N:24][N:25]=4)[N:22]=3)[CH2:13][CH2:12]2)=[CH:7][CH:6]=1.FC(F)(F)C1[N:36]2[N:37]=[C:38](N3CCC(C4C=CC(O)=CC=4)CC3)[CH:39]=[CH:40]C2=NN=1>>[N:37]1([CH2:2][CH2:3][O:4][C:5]2[CH:10]=[CH:9][C:8]([CH:11]3[CH2:16][CH2:15][N:14]([C:17]4[CH:18]=[CH:19][C:20]5[N:21]([C:23]([C:26]([F:29])([F:28])[F:27])=[N:24][N:25]=5)[N:22]=4)[CH2:13][CH2:12]3)=[CH:7][CH:6]=2)[CH:38]=[CH:39][CH:40]=[N:36]1
Reactant: FC(F)(F)c1nnc2ccc(N3CCC(c4ccc(OCCBr)cc4)CC3)nn12
Reactant: Oc1ccc(C2CCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)cc1
Product: FC(F)(F)c1nnc2ccc(N3CCC(c4ccc(OCCn5cccn5)cc4)CC3)nn12

Procedure:
The starting 6-[4-[4-(2-bromoethoxy)phenyl]piperidin-1-yl]-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine was obtained in 29% yield by an analogous method to Example 847, preparation of starting materials, starting from 4-[4-[3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-1-yl]phenol (obtained as described in Example 513, preparation of starting materials).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][C:11]1[CH:16]=[CH:15][C:14]([CH:17]=[O:18])=[CH:13][CH:12]=1)[C:5]#[N:6].OO.C(=O)([O-])[O-:22].[K+].[K+]>CS(C)=O>[F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][C:11]1[CH:16]=[CH:15][C:14]([CH:17]=[O:18])=[CH:13][CH:12]=1)[C:5]([NH2:6])=[O:22]
Reactant: O=C([O-])[O-]
Reactant: N#Cc1ccc(Oc2ccc(C=O)cc2)c(F)c1
Agent: OO
Agent: [K+]
Solvent: CS(C)=O
Product: NC(=O)c1ccc(Oc2ccc(C=O)cc2)c(F)c1
Yield: 99 %

Procedure:
Hydrolysis of the compound of step 1 using hydrogen peroxide and potassium carbonate in DMSO as described previously afford the above compound in 99% yield.
Reaction SMILES: [C:1]([OH:6])(=[O:5])[C:2]([OH:4])=[O:3].C(OC([NH:17][CH:18]1[CH2:23][CH2:22][N:21]([CH2:24][CH2:25][NH:26][C:27]([C:29]2[C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[N:31]([CH:38]([CH3:40])[CH3:39])[N:30]=2)=[O:28])[CH2:20][CH2:19]1)=O)C1C=CC=CC=1.[H][H]>[Pd].C(O)C>[C:1]([OH:6])(=[O:5])[C:2]([OH:4])=[O:3].[C:1]([OH:6])(=[O:5])[C:2]([OH:4])=[O:3].[NH2:17][CH:18]1[CH2:19][CH2:20][N:21]([CH2:24][CH2:25][NH:26][C:27]([C:29]2[C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[N:31]([CH:38]([CH3:40])[CH3:39])[N:30]=2)=[O:28])[CH2:22][CH2:23]1
Reactant: [H][H]
Reactant: CC(C)n1nc(C(=O)NCCN2CCC(NC(=O)OCc3ccccc3)CC2)c2ccccc21
Agent: [Pd]
Agent: O=C(O)C(=O)O
Solvent: CCO
Product: CC(C)n1nc(C(=O)NCCN2CCC(N)CC2)c2ccccc21

Procedure:
The product from Example 8, as the free base (8.71 g, 18.8 mmol), was reacted with hydrogen gas in the presence of 5% Pd/C (25° C./18 h/60 PSI) in an ethanol solution. After filtering the catalyst, the ethanol was evaporated to 5.0 g oil. Crystallization as the dioxalate salt from methanol/water provided colorless crystals. Mp 232° C. Mass spectrum, m+ =329. Anal (C22H31N5O9) theory C, 51.86; H, 6.13; N, 13.75; found C, 51.61; H, 6.04; N, 13.48.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=2)[CH:5]=[CH:4][N:3]=1.[CH2:18]([N:20]([CH2:23]C)[CH2:21]C)C.ClC(OC1C=CC=CC=1)=[O:27].CNC>O1CCCC1.CO>[N+:15]([C:12]1[CH:11]=[CH:10][C:9]([O:8][C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:1][C:18](=[O:27])[N:20]([CH3:23])[CH3:21])[CH:7]=2)=[CH:14][CH:13]=1)([O-:17])=[O:16]
Reactant: O=C(Cl)Oc1ccccc1
Reactant: Nc1cc(Oc2ccc([N+](=O)[O-])cc2)ccn1
Reactant: CCN(CC)CC
Agent: CNC
Solvent: CO
Solvent: C1CCOC1
Product: CN(C)C(=O)Nc1cc(Oc2ccc([N+](=O)[O-])cc2)ccn1
Reaction time: 0.5 h
Yield: 72.5 %

Procedure:
2-Amino-4-(4-nitrophenoxy)pyridine (761 mg) was dissolved in tetrahydrofuran (14 ml) under a nitrogen atmosphere, and then triethylamine (1.16 ml) and phenyl chloroformate (1.05 ml) were added dropwise while cooling in an ice water bath, followed by stirring for 30 min. To the reaction mixture was added 2 N dimethylamine (a solution in methanol) (6.95 ml), followed by stirring overnight. The reaction mixture was partitioned between ethyl acetate and a saturated aqueous solution of ammonium chloride. The organic layer was washed with a saturated aqueous solution of ammonium chloride, a saturated aqueous solution of sodium hydrogencarbonate, water and brine in this order, and dried over anhydrous sodium sulfate. The solvent was evaporated under a reduced pressure to give a residue, which was then purified by silica gel column chromatography (eluent; hexane:ethyl acetate=1:1 to 1:5). Fractions containing the target compound were concentrated under a reduced pressure to give a residue, which was then dried in vacuum to provide the titled compound (609 mg, 72.5%) as a brown solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:11]#[N:12])[C:5]2[CH:6]=[CH:7][NH:8][C:9]=2[CH:10]=1.Cl[C:14]1[C:23]2[C:18](=[CH:19][CH:20]=[C:21]([Cl:24])[CH:22]=2)[N:17]=[C:16]([CH3:25])[C:15]=1[CH3:26]>>[Br:1][C:2]1[CH:3]=[C:4]([C:11]#[N:12])[C:5]2[CH:6]=[CH:7][N:8]([C:14]3[C:23]4[C:18](=[CH:19][CH:20]=[C:21]([Cl:24])[CH:22]=4)[N:17]=[C:16]([CH3:25])[C:15]=3[CH3:26])[C:9]=2[CH:10]=1
Reactant: Cc1nc2ccc(Cl)cc2c(Cl)c1C
Reactant: N#Cc1cc(Br)cc2[nH]ccc12
Product: Cc1nc2ccc(Cl)cc2c(-n2ccc3c(C#N)cc(Br)cc32)c1C

Procedure:
Prepared according to procedure U using 6-bromo-1H-indole-4-carbonitrile (0.5 g, 2.26 mmol) and 4,6-dichloro-2,3-dimethylquinoline (0.5626 g, 2.49 mmol) to give 6-bromo-1-(6-chloro-2,3-dimethylquinolin-4-yl)-1H-indole-4-carbonitrile as a yellow solid: Mass Spectrum (ESI) m/e=410.0 [M+1 (79Br)] and 412.0 [M+1 (81Br)].
Reaction SMILES: [C:1]([NH:5][OH:6])([CH3:4])([CH3:3])[CH3:2].[Cl:7][C:8]1[CH:9]=[CH:10][C:11]([OH:16])=[C:12]([CH:15]=1)[CH:13]=O>CO.Cl>[Cl:7][C:8]1[CH:9]=[CH:10][C:11]([OH:16])=[C:12]([CH:13]=[N+:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[O-:6])[CH:15]=1
Reactant: O=Cc1cc(Cl)ccc1O
Reactant: CC(C)(C)NO
Agent: Cl
Solvent: CO
Product: CC(C)(C)[N+]([O-])=Cc1cc(Cl)ccc1O
Yield: 98.5 %

Procedure:
To a solution of tert-butylhydroxylamine (14.98 g, 168.4 mmol) in MeOH (160 mL) was added 5-chloro-2-hydroxybenzaldehyde (15.8 g, 129.5 mmol) and 3 drops of 37% hydrochloric acid. The resulting solution was refluxed through a Soxhlet apparatus containing molecular sieves (40 g) until no more aldehyde was detected by TLC. The solvent was removed in vacuo and the residue was recrystallized from EtOAc. The title compound was isolated in 98.5% yield as a crystalline solid, m.p. 143.4° C. (Rf=0.45 on a silica gel plate using 7:10 hexanes:EtOAc as an eluant).
Reaction SMILES: [C:1]1([N:7]=[C:8]2[NH:12][CH2:11][CH2:10][NH:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([Li])CCC.[C:18]1([CH3:28])[CH:23]=[CH:22][C:21]([S:24](Cl)(=[O:26])=[O:25])=[CH:20][CH:19]=1>C1COCC1.CCCCCC>[S:24]([N:12]1[CH2:11][CH2:10][NH:9][C:8]1=[N:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)([C:21]1[CH:22]=[CH:23][C:18]([CH3:28])=[CH:19][CH:20]=1)(=[O:26])=[O:25]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: c1ccc(N=C2NCCN2)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: Cc1ccc(S(=O)(=O)N2CCNC2=Nc2ccccc2)cc1
Temperature: -78 °C
Reaction time: 1.5 h

Procedure:
2-(Phenylimino)imidazolidine (0.773 g, 4.8 mmoles) is dissolved in dry THF (15 ml), cooled to -78° C. under nitrogen protected from moisture and 2.4 N butyllithium in hexane (2.0 ml) is added. Then p-toluenesulfonyl chloride (0.953 g, 5 mmoles) in THF (3 ml) at -78° C. is added. The mixture is stirred for 90 minutes and allowed to warm to ambient temperature. The volatiles are evaporated in vacuo and water and ether are added. Crystals separate in the ether layer which are filtered and recrystallized from isopropanol to remove some bistosyl derivative. The major product, confirmed by n.m.r is N'-Tosyl-2-(phenylimino)imidazolidine, (610 mg, 40%), m.p. 174°-177° C.
Reaction SMILES: [CH2:1]([C:3]1[NH:4][CH:5]=[CH:6][N:7]=1)[CH3:2].[F:8][C:9]([F:15])([F:14])[S:10]([OH:13])(=[O:12])=[O:11]>O>[F:8][C:9]([F:15])([F:14])[S:10]([O-:13])(=[O:12])=[O:11].[CH2:1]([C:3]1[NH:7][CH:6]=[CH:5][NH+:4]=1)[CH3:2]
Reactant: O=S(=O)(O)C(F)(F)F
Reactant: CCc1ncc[nH]1
Solvent: O
Product: CCc1[nH]cc[nH+]1
Product: O=S(=O)([O-])C(F)(F)F

Procedure:
2-ethylimidazole was solved with distilled water, in which an equimolar amount of trifluoromethanesulfonic acid was dropped and stirred while being cooled. The reaction product was predried at 100° C. and then vacuum-dried at 120° C., thus obtaining a target ionic conductor.
Reaction SMILES: Cl.CN.[F:4][C:5]1[C:13]([O:14][CH2:15][CH2:16][O:17][CH3:18])=[C:12]2[C:8]([CH:9]=[C:10]([C:19]3[S:20][CH:21]([CH2:24][C:25]([OH:27])=O)[CH2:22][N:23]=3)[NH:11]2)=[CH:7][C:6]=1[O:28][C:29]1[CH:30]=[N:31][C:32]([S:35]([CH3:38])(=[O:37])=[O:36])=[CH:33][CH:34]=1.O[N:40]1[C:44]2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O.C(N(CC)CC)C>[F:4][C:5]1[C:13]([O:14][CH2:15][CH2:16][O:17][CH3:18])=[C:12]2[C:8]([CH:9]=[C:10]([C:19]3[S:20][CH:21]([CH2:24][C:25]([NH:40][CH3:44])=[O:27])[CH2:22][N:23]=3)[NH:11]2)=[CH:7][C:6]=1[O:28][C:29]1[CH:30]=[N:31][C:32]([S:35]([CH3:38])(=[O:36])=[O:37])=[CH:33][CH:34]=1
Reactant: On1nnc2ccccc21
Reactant: COCCOc1c(F)c(Oc2ccc(S(C)(=O)=O)nc2)cc2cc(C3=NCC(CC(=O)O)S3)[nH]c12
Agent: CCN=C=NCCCN(C)C
Agent: CN
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CNC(=O)CC1CN=C(c2cc3cc(Oc4ccc(S(C)(=O)=O)nc4)c(F)c(OCCOC)c3[nH]2)S1
Temperature: 0 °C
Yield: 78.8 %

Procedure:
To an ice-cooled and stirred mixture of methylamine hydrochloride (35 mg) and triethylamine (0.072 mL) in N,N-dimethylformamide (7 mL) were added {2-[6-fluoro-7-(2-methoxyethoxy)-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}-1H-indol-2-yl]-4,5-dihydro-1,3-thiazol-5-yl}acetic acid (135 mg), 1-hydroxybenzotriazole (70 mg) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (100 mg). After stirring at 4° C. to room temperature for 15 h, the reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed successively with aqueous sodium hydrogen carbonate solution and brine, dried (MgSO4), filtered, and concentrated to give colorless crystals, which were recrystallized from tetrahydrofuran-ethyl acetate to give the title compound (109 mg, 79%) as colorless crystals. MS 537 (MH+). mp 151-152° C.
Reaction SMILES: [CH:1]1([C:5]2[N:6]=[C:7](/[CH:10]=[CH:11]/[C:12]3[CH:13]=[C:14]([NH2:18])[CH:15]=[CH:16][CH:17]=3)[S:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.C(O[C:23]1[CH:34]=[C:27]2[CH2:28][C:29]([O:31][C:32](=[O:33])[C:26]2=[CH:25][CH:24]=1)=[O:30])(=O)C>C1(C)C=CC=CC=1>[C:29]([O:31][C:24]1[CH:23]=[CH:34][C:27]([CH2:28][C:29]([NH:18][C:14]2[CH:15]=[CH:16][CH:17]=[C:12](/[CH:11]=[CH:10]/[C:7]3[S:8][CH:9]=[C:5]([CH:1]4[CH2:4][CH2:3][CH2:2]4)[N:6]=3)[CH:13]=2)=[O:30])=[C:26]([CH:25]=1)[C:32]([OH:31])=[O:33])(=[O:30])[CH3:28]
Reactant: Nc1cccc(/C=C/c2nc(C3CCC3)cs2)c1
Reactant: CC(=O)Oc1ccc2c(c1)CC(=O)OC2=O
Solvent: Cc1ccccc1
Product: CC(=O)Oc1ccc(CC(=O)Nc2cccc(/C=C/c3nc(C4CCC4)cs3)c2)c(C(=O)O)c1
Yield: 148.2 %

Procedure:
A mixture composed of 0.58g of (E)-3-[2-[4-(cyclobutyl)-2-thiazolyl]ethenyl]benzeneamine, 0.48g of 5-acetoxyhomophthalic anhydride and 50 ml of toluene was heated on a steam bath for 0.5 hr. The mixture was cooled and the solids that formed were isolated by filtration to yield 0.77 g of (E)-5-acetoxy-2-[2-[3-[2-[4-(cyclobutyl)-2-thiazolyl]ethenyl]phenylamino]-2-oxoethyl]benzoic acid; m.p. 176°-179° C. after trituration with hot acetonitrile.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11](Br)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[Mg].[F:16][CH2:17][CH2:18][C:19](=[O:21])[CH3:20].[NH4+].[Cl-]>CCOCC>[F:16][CH2:17][CH2:18][C:19]([C:11]1[CH:12]=[CH:13][C:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)=[CH:9][CH:10]=1)([OH:21])[CH3:20]
Reactant: CC(=O)CCF
Reactant: Fc1ccc(-c2ccc(Br)cc2)cc1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: CCOCC
Product: CC(O)(CCF)c1ccc(-c2ccc(F)cc2)cc1

Procedure:
A solution of 4'-fluoro-4-biphenylyl-magnesium bromide obtained from 2.51 g. of 4'-fluoro-4-bromo-biphenyl and 0.24 g. of magnesium in 100 ml. of ether is added dropwise, while stirring, at 20° to a solution of 0.9 g. of 1-fluorobutan-3-one in 40 ml. of ether, the mixture is stirred for a further 2 hours, the resulting alcoholate is decomposed with ice and saturated NH4Cl solution and the mixture is worked up in the customary manner to give 1-fluoro-3-(4'-fluoro-4-biphenylyl)-butan-3-ol, m.p. 90° - 92°.
Reaction SMILES: [F:1][C:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:15]([CH2:16][OH:17])=[C:14]([C:18]([F:21])([F:20])[F:19])[S:13][N:12]=2)=[CH:7][CH:6]=1)([F:4])[CH3:3].O[C:23]1[CH:28]=[CH:27][C:26]([CH2:29][CH2:30][C:31]([O:33]CC)=[O:32])=[C:25]([CH3:36])[C:24]=1[CH3:37]>>[F:4][C:2]([C:5]1[CH:6]=[CH:7][C:8]([C:11]2[C:15]([CH2:16][O:17][C:23]3[CH:28]=[CH:27][C:26]([CH2:29][CH2:30][C:31]([OH:33])=[O:32])=[C:25]([CH3:36])[C:24]=3[CH3:37])=[C:14]([C:18]([F:19])([F:20])[F:21])[S:13][N:12]=2)=[CH:9][CH:10]=1)([F:1])[CH3:3]
Reactant: CC(F)(F)c1ccc(-c2nsc(C(F)(F)F)c2CO)cc1
Reactant: CCOC(=O)CCc1ccc(O)c(C)c1C
Product: Cc1c(CCC(=O)O)ccc(OCc2c(-c3ccc(C(C)(F)F)cc3)nsc2C(F)(F)F)c1C

Procedure:
The title compound was prepared according to the procedure described in Example 1 starting following Step 5 and 6 coupling [3-[4-(1,1-difluoroethyl)phenyl]-5-(trifluoromethyl)-1,2-thiazol-4-yl]methanol and ethyl 3-(4-hydroxy-2,3-dimethylphenyl)propanoate followed by hydrolysis to afford the desired product as an off-white solid. 1H NMR (400 MHz, CD3OD) δ 7.79 (d, J=8.4 Hz, 2H), 7.63 (d, J=8.4 Hz, 2H), 6.97 (d, J=8.4 Hz, 1H), 6.710 (d, J=8.4 Hz, 1H), 5.12 (s, 2H), 2.92 (t, J=7.6 Hz, 2H), 2.52 (t, J=8.4 Hz, 2H), 2.23 (s, 3H), 2.05 (s, 3H), 1.90-2.02 (m, 3H). Mass spectrum (ESI, m/z): Calcd. for C24H22F5NO3S, 498.1 (M−H). found 498.1.