Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:12]=[C:11](O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1.P(Br)(Br)([Br:18])=O>>[F:1][C:2]([F:15])([F:14])[C:3]1[CH:12]=[C:11]([Br:18])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1
Reactant: Oc1cc(C(F)(F)F)nc2ccccc12
Reactant: O=P(Br)(Br)Br
Product: FC(F)(F)c1cc(Br)c2ccccc2n1

Procedure:
2-Trifluoromethyl cinchoninic acid, and substituted 2-trifluoromethyl cinchoninic acids, are known plant growth regulating materials. Such compounds can be prepared, as disclosed by B. M. Pinder and A. Burger (J. Med. Chem, 11, pp 267-269 (1968)), by condensation of aniline, or a substituted aniline, with ethyl 4,4,4-trifluoroacetoacetate in the presence of polyphosphoric acid to produce a 2-trifluoromethyl-4-hydroxyquinoline from which the desired 2-trifluoromethyl cinchoninic acid can be obtained by two alternative procedures. In the first of such procedures, the 2-trifluoromethyl-4-hydroxyquinoline is brominated with phosphorus oxybromide to produce the corresponding 2-trifluoromethyl-4-bromoquinoline which is then reacted with n-butyllithium to produce a lithioquinoline which can in turn be treated with dry carbon dioxide to produce the desired 2-trifluoromethyl cinchoninic acid. In the second of such procedures, the 2-trifluoromethyl-4-hydroxyquinoline is chlorinated with phosphorus oxychloride and the resulting 2-trifluoromethyl-4-chloroquinoline is reacted with cuprous cyanide in N-methylpyrrolidone to convert it to the corresponding nitrile which is then hydrolyzed to the desired 2-trifluoromethyl cinchoninic acid. However, not only are both these procedures complex and involved, but they produce yields of only about 35% and involve the use of corrosive materials such as phosphorus oxybromide and phosphorus oxychloride as well as air- and water-sensitive materials such a butyllithium and copper cyanide.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][CH2:8][C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[NH:11][CH:10]=2)=[CH:3][CH:2]=1.[CH2:18]([C:22]1([N:29]([CH3:31])[CH3:30])[CH2:27][CH2:26][C:25](=O)[CH2:24][CH2:23]1)[CH2:19][CH2:20][CH3:21].FC(F)(F)S(O)(=O)=O>ClCCl>[CH2:18]([C:22]1([N:29]([CH3:31])[CH3:30])[CH2:27][CH2:26][C:25]([C:10]2[NH:11][C:12]3[C:17]([C:9]=2[CH2:8][CH2:7][C:4]2[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=2)=[CH:16][CH:15]=[CH:14][CH:13]=3)([C:10]2[NH:11][C:12]3[C:17]([C:9]=2[CH2:8][CH2:7][C:4]2[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=2)=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH2:24][CH2:23]1)[CH2:19][CH2:20][CH3:21]
Reactant: CCCCC1(N(C)C)CCC(=O)CC1
Reactant: c1ccc2c(CCc3ccncc3)c[nH]c2c1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: ClCCl
Product: CCCCC1(N(C)C)CCC(c2[nH]c3ccccc3c2CCc2ccncc2)(c2[nH]c3ccccc3c2CCc2ccncc2)CC1
Temperature: 25 °C
Reaction time: 67 h

Procedure:
3-(2-pyridin-4-ylethyl)-1H-indole (667 mg, 3 mmol, synthesis cf. WO2008009415, indole unit Ind-14) together with 4-butyl-4-(dimethylamino)cyclohexanone (592 mg, 3 mmol, synthesis cf. WO2008009415, ketone unit Ket-4) was dissolved in dichloromethane (45 ml) and mixed with trifluoromethane sulphonic acid (0.553 ml, 6.3 mmol). The batch was stirred for 67 h at RT, and a brown oil separated out. For work up the reaction solution was mixed with 1N NaOH (10 ml) and THF (10 ml). The mixture was stirred a further 60 min. After separation of the phases the aqueous phase was extracted with dichloromethane (3×10 ml). The combined organic extracts were dried over Na2SO4 and then concentrated to low volume. The raw product obtained (1.24 g) was purified by column chromatography [silica gel 60 (100 g); ethyl acetate/methanol (10:1, 1200 ml), ethyl acetate/methanol (5:1, 600 ml) ethyl acetate/methanol (2:1, 700 ml), ethyl acetate/methanol (1:2, 750 ml), methanol (800 ml)].
Reaction SMILES: [N+:1]([CH3:4])([O-:3])=[O:2].C[O-].[Na+].[C:8]([Si:12]([CH3:33])([CH3:32])[O:13][CH2:14][CH2:15][C:16]([CH3:31])([CH3:30])[CH2:17]/[CH:18]=[C:19]1\[C:20](=[O:29])[NH:21][C:22]2[C:27]\1=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=2)([CH3:11])([CH3:10])[CH3:9].C(O)(=O)C>CO>[C:8]([Si:12]([CH3:32])([CH3:33])[O:13][CH2:14][CH2:15][C:16]([CH3:31])([CH3:30])[CH2:17][CH:18]([CH:19]1[C:27]2[C:22](=[CH:23][C:24]([Cl:28])=[CH:25][CH:26]=2)[NH:21][C:20]1=[O:29])[CH2:4][N+:1]([O-:3])=[O:2])([CH3:10])([CH3:9])[CH3:11]
Reactant: CC(C)(C/C=C1\C(=O)Nc2cc(Cl)ccc21)CCO[Si](C)(C)C(C)(C)C
Reactant: C[N+](=O)[O-]
Agent: C[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)(CCO[Si](C)(C)C(C)(C)C)CC(C[N+](=O)[O-])C1C(=O)Nc2cc(Cl)ccc21
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 64.6 %

Procedure:
To a solution of nitromethane (Aldrich) (0.21 g, 3.5 mmol) in methanol (20 mL) was slowly added a methanolic solution (Aldrich, 25 wt. %) of sodium methoxide (0.74 g, 3.5 mmol). After the mixture was stirred at room temperature for 10 min, a solution of E/Z-3-[5-(tert-butyl-dimethyl-silanyloxy)-3,3-dimethyl-pentylidene]-6-chloro-1,3-dihydro-indol-2-one (0.68 g, 1.7 mmol) in methanol (10 mL) was added. The reaction mixture was stirred at room temperature for 2 h, then acetic acid (0.6 g, 10 mmol) was added. The mixture was concentrated to a small volume, then the residue was partitioned between ethyl acetate and water. The organic layer was separated, the aqueous layer was extracted with ethyl acetate. The organic layers were combined, washed with saturated aqueous NaHCO3, brine, dried over MgSO4, and concentrated. The residue was purified by chromatography (EtOAc:hexanes=1:10) to give the racemic 3-[5-(tert-butyl-dimethyl-silanyloxy)-3,3-dim ethyl-1-nitromethyl-pentyl]-6-chloro-1,3-dihydro-indol-2-one as a white foam (0.5 g, 64%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.Cl.[CH:13]1C=CC=CC=1>CCOCC>[CH3:1][O:2][C:3](=[O:11])[C:4]([C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)=[CH2:13]
Reactant: COC(=O)Cc1ccccc1
Reactant: c1ccccc1
Agent: Cl
Solvent: CCOCC
Product: C=C(C(=O)OC)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 81 %

Procedure:
The compound was synthesized according to a literature method (Ames and Davey J. Chem. Soc. 1958, 1798). To a solution of phenylacetic acid methyl ester (13.58 ml, 100 mmol) in 35 ml of benzene was added diethyl glyoxalate (20.72 ml, 130 mmol). The solution was allowed to stir at room temperature for 1 hour at which point a solid mass was obtained. Suspending the mass in ether followed by filtration yielded a white powder. The white powder was then suspended in ether and acidified using 5% HCl. The aqueous layer was then removed and the ether layer was washed with saturated NaHCO3, H2O, and brine, dried over MgSO4 and then concentrated under reduced pressure. The resulting yellow oil was charged with 45 ml of 37% formaldehyde solution (in water) and 100 ml of water at room temperature. 40 g K2CO3 in 50 ml of water was added via addition funnel to the reaction mixture over a period of 30 minutes. The reaction was then stirred for a further 2 hours at room temperature. The resulting mixture was extracted with ether three times, and the resulting ethereal solution was washed with water, brine, dried over MgSO4, and subjected to Kugelrohr distillation (83° C., 0.5 mmHg) to afford the title compound as an oil (81% yield, 14.1 g). 1H NMR (CDCl3, 300 MHz) δ:7.50-7.30 (m, 5H), 6.35 (d, J=1.2 Hz, 1H), 5.90 (d, J=1.2 Hz, 1H), 4.31 (q, J=7.2 Hz, 2H), 1.36 (t, J=7.2 Hz, 3H) ppm.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[SH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH2:17]O.Cl>ClCCl>[S:10]1[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH2:17][O:7][CH:6]1[C:5]1[CH:8]=[CH:9][C:2]([OH:1])=[CH:3][CH:4]=1
Reactant: O=Cc1ccc(O)cc1
Reactant: OCc1ccccc1S
Agent: Cl
Solvent: ClCCl
Product: Oc1ccc(C2OCc3ccccc3S2)cc1

Procedure:
Following the same procedure as outlined in Example 1 step b), 4-hydroxybenzaldehyde (0.73 g, 5.95 mmol) and (2-mercaptophenyl)methanol (1 g, 7.14 mmol) in dichloromethane (30 ml) were treated with hydrogen chloride gas. After workup and chromatography, as in example 1 step b), the subtitle compound was obtained (0.91 g, 63%) as a white solid. 1H NMR (300 MHz, CDCl3, ppm) δ 5.04 (d, J=15 Hz, 1H); 5.10 (d, J=15 Hz, 1H); 5.19 (s, 1H); 6.02 (s, 1H); 6.76-6.81 (m, 2H); 6.96-7.03 (m, 1H); 7.04-7.19 (m, 3H); 7.35-7.42 (m, 2H): 13C NMR (75 MHz, CDCl3, ppm) δ 70.6; 82.8; 115.7; 125.1; 126.0, 127.5; 128.4; 129.9; 130.6; 133.1; 156.4; MS calculated for C14H12O2S+H 245 observed 245.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]#[CH:24])=[CH:17][CH:16]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Br:25][C:26]1[CH:31]=[CH:30][C:29](I)=[CH:28][CH:27]=1.N1CCCC1>Cl[Pd]Cl.O>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]#[C:24][C:29]2[CH:30]=[CH:31][C:26]([Br:25])=[CH:27][CH:28]=2)=[CH:17][CH:16]=1)=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: Brc1ccc(I)cc1
Reactant: C#CCOc1ccc(OCC2CCCN2C(=O)OC(C)(C)C)cc1
Agent: Cl[Pd]Cl
Solvent: O
Solvent: C1CCNC1
Product: CC(C)(C)OC(=O)N1CCCC1COc1ccc(OCC#Cc2ccc(Br)cc2)cc1
Yield: 33.8 %

Procedure:
General procedure A was followed using the product from step 3 Example 1 (266 mg, 0.803 mmol), p-bromo iodobenzene (156.5 mg, 0.669 mmol), PdCl2 (2.5 mg, 0.014 mmol), pyrrolidine (0.277 mL, 3.34 mmol), water (0.844 mL) to give the title compound (110 mg, 33.8%).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][N:6]2[C:11]([CH:12]([F:14])[F:13])=[CH:10][C:9]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=3)=[N:8][C:7]=12)#[CH:2].Br[C:26]1[CH:27]=[CH:28][C:29]([C:32]([NH2:34])=[O:33])=[N:30][CH:31]=1>>[F:13][CH:12]([F:14])[C:11]1[N:6]2[N:5]=[CH:4][C:3]([C:1]#[C:2][C:26]3[CH:27]=[CH:28][C:29]([C:32]([NH2:34])=[O:33])=[N:30][CH:31]=3)=[C:7]2[N:8]=[C:9]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:23])([F:24])[F:22])=[CH:17][CH:16]=2)[CH:10]=1
Reactant: NC(=O)c1ccc(Br)cn1
Reactant: C#Cc1cnn2c(C(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Product: NC(=O)c1ccc(C#Cc2cnn3c(C(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)cn1

Procedure:
The title compound was prepared from 3-ethynyl-7-difluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.2) (340 g, 1.0 mmol) and 5-bromo-pyridine-2-carboxylic acid amide (example B.47) (181 mg, 0.9 mmol) according to general procedure II. Obtained as a yellow solid (300 mg, 65%). MS (ISP) 458.1 [(M+H)+]; mp 276-277° C.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:15]=[CH:14][CH:13]=[CH:12][C:4]=1[CH2:5][CH:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1.N1CCC(NC2C=CC=CC=2C(F)(F)F)CC1.[CH:35]1([CH2:38][CH2:39][NH:40][C:41]([C:43]2[N:44]=[N:45][C:46](Cl)=[CH:47][CH:48]=2)=[O:42])[CH2:37][CH2:36]1>>[CH:35]1([CH2:38][CH2:39][NH:40][C:41]([C:43]2[N:44]=[N:45][C:46]([N:9]3[CH2:8][CH2:7][CH:6]([CH2:5][C:4]4[CH:12]=[CH:13][CH:14]=[CH:15][C:3]=4[C:2]([F:1])([F:16])[F:17])[CH2:11][CH2:10]3)=[CH:47][CH:48]=2)=[O:42])[CH2:37][CH2:36]1
Reactant: FC(F)(F)c1ccccc1CC1CCNCC1
Reactant: O=C(NCCC1CC1)c1ccc(Cl)nn1
Agent: FC(F)(F)c1ccccc1NC1CCNCC1
Product: O=C(NCCC1CC1)c1ccc(N2CCC(Cc3ccccc3C(F)(F)F)CC2)nn1
Yield: 35 %

Procedure:
Following the procedure as described in Example 1, making variations only as required to use 4-(2-trifluoromethylbenzyl)piperidine (Vice, S. et al J. Org. Chem. 2001, 66, 2487 and references therein) in place of piperidin-4-yl-(2-trifluoromethylphenyl)amine to react with 6-chloropyridazine-3-carboxylic acid (2-cyclopropylethyl)amide, the title compound was obtained as a white powder in 35% yield. 1H NMR (300 MHz, CDCl3) δ 7.98 (m, 1H), 7.96 (d, J=9.5 Hz, 1H), 7.63 (d, J=8 Hz, 1H), 7.46 (t, J=7.5 Hz, 1H), 7.33-7.26 (m, 2H), 6.93 (d, J=9.5 Hz, 1H), 4.48 (d, J=13.5 Hz, 2H), 3.51 (q, J=6.5 Hz, 2H), 2.97-2.88 (m, 2H), 2.74 (d, J=6.5 Hz, 2H), 2.03-1.86 (m, 1H), 1.78 (d, J=6.5 Hz, 2H), 1.49 (q, J=6.5 Hz, 2H), 1.41-1.27 (m, 2H), 0.79-0.67 (m, 1H), 0.48-0.37 (m, 2H), 0.10-0.05 (m, 2H). 13C NMR (75 MHz, CDCl3) δ 163.4, 160.0, 144.3, 138.6, 131.7, 131.5, 126.7, 126.4, 126.3, 126.2, 112.0, 45.3, 39.6, 39.4, 37.9, 34.6, 31.7, 8.7, 4.2. MS (ES+) m/z 433.1 (M+1).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[C:7]2[CH2:13][CH2:14][CH2:15][OH:16])([O-])=O.[CH2:17]([SH:19])[CH3:18].[NH4+].[Cl-].O>CN(C=O)C.C1COCC1.CCOC(C)=O.[Zn]>[NH2:1][C:4]1[C:5]([S:19][CH2:17][CH3:18])=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[C:7]2[CH2:13][CH2:14][CH2:15][OH:16]
Reactant: O=[N+]([O-])c1ccc2[nH]cc(CCCO)c2c1
Reactant: CCS
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: O
Product: CCSc1c(N)ccc2[nH]cc(CCCO)c12
Reaction time: 3 h
Yield: 20 %

Procedure:
A cold (10°-12° C.) mixture of 3-(5-nitro-3-indolyl)-1-propanol (Example 3: 2.2 g, 10.0 mmol), ethanethiol (7.4 ml, 0.1 mol) and Zn dust (2.0 g, 30.6 mmol) in dry DMF (20 ml) kept under argon was treated portionwise with NH4Cl which was added at 10 min interval for 3 h while temperature of the mixture was kept between 10°-12° C. After the addition was completed, the reaction mixture was stirred for 3 h and then diluted with THF:EtOAc (1:2, 45 ml) mixture followed by slow addition of water (40 ml). The mixture was filtered on a glass fiber filter and the two phases separated. The aqueous phase was extracted with EtOAc: THF (2:1, 3×40 ml) mixture The organic extracts were combined, washed with water (2×50 ml), dried (MgSO4) and concentrated in vacuo. The crude material was chromatographed on silica gel dry column using first a mixture of CH2Cl2 : EtOAc (3:17) and then EtOAc both containing Et3N (0.5%). Appropriate fractions were concentrated in vacuo affording 3-(5-amino-4-ethylthio-3-indolyl)-1-propanol (0.50 g, 20%); 1H NMR (DMSO-d6) δ (ppm): 10.48 (s, 1H, indolic NH), 7.08 (d, J=8.5 Hz, 1H, indolic H-7), 6.94 (d, J=2.3 Hz, 1H, indolic H-2), 6.59 (d, J=8.5 Hz, indolic H-6), 4.88 (bs, 2H, NH2), 4.37 (t, J=5.1 Hz, 1H, OH), 3.4-3.6 (m, 2H, H-1), 2.9-3.1 (m, 2H, H-3), 2.65 (q, J=7.4 Hz, 2H, SCH2CH3), 1.7-1.9 (m, 2H, H-2), 1.09 (t, J=7.4 Hz, 3H, SCH2CH3); also isolated was 3-(5-amino-3-indolyl)-1-propanol (1.0 g, 55%); 1H NMR (DMSO-d6) δ (ppm): 10.2 (s, 1H, indolic NH), 7.00 (d, J=8.4 Hz, 1H, indolic H-7), 6.88 (dd, J=2.2 Hz, indolic H-2), 6.63 (d, J=2.0 Hz, indolic H-4), 6.44 (dd, J=8.4 Hz, J=2.0 Hz, 1H, indolic H-6), 4.4-4.6 (m, 3H, NH2 and OH), 3.3-3.5 (m, 2H, H-1), 2.5-2.7 (m, 2H, H-3), 1.6-1.9 (m, 2H, H-2).
Reaction SMILES: ClC(Cl)(Cl)C(Cl)=O.[Cl:8][C:9]1([Cl:14])[CH2:12][C:11](=[O:13])[CH2:10]1.ClC1[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([O:24]O)=O)C=1.C(=O)([O-])O.[Na+].ClC(Cl)=C=O.[N+](=C)=[N-]>[Zn].ClCCl.C(O)(=O)C>[C:22]1(=[O:24])[CH2:18][CH2:19][CH2:20][CH2:21]1.[Cl:8][C:9]1([Cl:14])[CH2:12][C:11](=[O:13])[CH2:10]1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: C=[N+]=[N-]
Agent: O=C(Cl)C(Cl)(Cl)Cl
Agent: O=C([O-])O
Solvent: ClCCl
Solvent: CC(=O)O
Product: O=C1CCCC1

Procedure:
The compound (b) is reacted with trichloroacetyl chloride in a solvent such as diethyl ether, dimethoxyethane or tetrahydrofuran to give the dichlorocyclobutanone compound (f) (Alternatively, when it is reacted with diacetyl chloride, a monochloro-compound is obtained. The monochloro-compound can also be obtained by reacting with trichioroacetyl chloride, followed by treating with acetic acid.), and then the product is treated with a reducing agent such as zinc dust, whereby the cyclobutanone compound represented by the formula (g) can be obtained. The reaction temperature is preferably 10 to 50° C. When the compound (g) is treated with a peroxide such as 3-chloroperbenzoic acid in the presence of sodium hydrogen carbonate in a solvent such as dichloromethane, the lactone compound represented by the formula (h) can be obtained. The reaction temperature is preferably in the range of from room temperature to 40° C. When the compound (b) is treated with dichloroketene and diazomethane, a cyclopentanone compound in the formula (f) is obtained, and when the compound (g) is treated with diazomethane, a cyclopentanone compound in formula (g) is obtained. When the cyclopentanone compound is further treated with diazomethane, a cyclohexanone compound is obtained.
Reaction SMILES: II.[I-].[K+].[SH:5][C:6]1[S:7][C:8]2[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=2[N:10]=1.[OH-].[Na+]>O.C(O)C>[S:7]1[C:8]2[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=2[N:10]=[C:6]1[S:5][S:5][C:6]1[S:7][C:8]2[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=2[N:10]=1
Reactant: Sc1nc2ccccc2s1
Agent: II
Agent: [I-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: c1ccc2sc(SSc3nc4ccccc4s3)nc2c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 20 g of iodine and 115 g of potassium iodide in 400 ml of water is added dropwise to a solution of 30 g of 2-mercapto-benzothiazole and 1.6 g of sodium hydroxide in 800 ml of absolute ethanol. After completion of the addition, the mixture is stirred for 30 minutes at ambient temperature and the precipitate is then filtered off, washed with ethanol and then washed with ether.
Reaction SMILES: [CH3:1][C:2]1([CH3:39])[CH2:7][CH2:6][C:5]([C:8]2[CH:13]=[C:12]([CH2:14][CH2:15][S:16](=[O:20])(=[O:19])[NH:17][CH3:18])[CH:11]=[CH:10][C:9]=2[NH:21][C:22]([C:24]2[N:25](COCC[Si](C)(C)C)[CH:26]=[C:27]([C:29]#[N:30])[N:28]=2)=[O:23])=[CH:4][CH2:3]1.CO.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:1][C:2]1([CH3:39])[CH2:7][CH2:6][C:5]([C:8]2[CH:13]=[C:12]([CH2:14][CH2:15][S:16](=[O:20])(=[O:19])[NH:17][CH3:18])[CH:11]=[CH:10][C:9]=2[NH:21][C:22]([C:24]2[NH:25][CH:26]=[C:27]([C:29]#[N:30])[N:28]=2)=[O:23])=[CH:4][CH2:3]1
Reactant: CNS(=O)(=O)CCc1ccc(NC(=O)c2nc(C#N)cn2COCC[Si](C)(C)C)c(C2=CCC(C)(C)CC2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: CNS(=O)(=O)CCc1ccc(NC(=O)c2nc(C#N)c[nH]2)c(C2=CCC(C)(C)CC2)c1
Yield: 26.4 %

Procedure:
A solution of 97.0 mg (0.170 mmol) of 4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylic acid [2-(4,4-dimethyl-cyclohex-1-enyl)-4-(2-methylsulfamoyl-ethyl)-phenyl]-amide (as prepared in the previous step) in CH2Cl2 (30 mL) was treated with MeOH (1 mL) and TFA (10 mL) at RT for 1 h. MeOH (10 mL) was added and the solvents were removed in vacuo. The residue was purified by RP-HPLC (C18) with 40-100% CH3CN in 0.1% TFA/H2O over 30 min to afford 19.8 mg (26%) of the title compound as a white solid: 1H-NMR (CD3CN; 400 MHz): δ 9.41 (s, 1H), 8.24 (d, 1H, J=8.0 Hz), 7.91 (s, 1H), 7.22 (dd, 1H, J=8.0, 2.0 Hz), 5.79-5.74 (m, 1H), 5.08-5.00 (m, 1H), 3.34-3.27 (m, 2H), 3.06-2.99 (m, 2H), 2.70 (d, 3H, J=5.2 Hz), 2.35-2.28 (m, 2H), 2.10-2.05 (m, 2H), 1.59 (t, 2H, J=6.4 Hz), 1.10 (s, 6H). Mass spectrum (ESI, m/z): Calcd. for C22H27N5O3S, 442.2 (M+H). found 442.1.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:34]=[CH:33][C:8]([O:9][C:10]2[S:11][C:12]([C:15]3[S:19][C:18]([CH:20]([N:22]4C(=O)C5[C:24](=CC=CC=5)[C:23]4=[O:32])[CH3:21])=[CH:17][CH:16]=3)=[CH:13][N:14]=2)=[CH:7][CH:6]=1)([CH3:3])[CH3:2].O.NN.C(N(CC)CC)C.C(OC(=O)C)(=O)C>ClCCl.CCCCCC.C(OCC)(=O)C.CO.C(O)C>[CH:1]([O:4][C:5]1[CH:34]=[CH:33][C:8]([O:9][C:10]2[S:11][C:12]([C:15]3[S:19][C:18]([CH:20]([NH:22][C:23](=[O:32])[CH3:24])[CH3:21])=[CH:17][CH:16]=3)=[CH:13][N:14]=2)=[CH:7][CH:6]=1)([CH3:2])[CH3:3]
Reactant: CC(C)Oc1ccc(Oc2ncc(-c3ccc(C(C)N4C(=O)c5ccccc5C4=O)s3)s2)cc1
Agent: NN
Solvent: O
Solvent: CCO
Solvent: ClCCl
Product: CC(=O)NC(C)c1ccc(-c2cnc(Oc3ccc(OC(C)C)cc3)s2)s1
Reaction time: 2 h
Yield: 24.2 %

Procedure:
To a solution of Example 3C (200 mg, 0.41 mmol) at room temperature in dichloromethane (5 mL) was added hydrazine hydrate (197 uL, 4.1 mmol). Ethanol was added until a clear, single phase was formed. After an hour at room temperature, the solvent was removed under vacuum and the reaction mixture was thoroughly dried. To the resulting mixture was added dichloromethane (5 mL), triethylamine (300 uL, 2.15 mmol) and acetic anhydride (150 uL, 1.59 mmol). After two hours at room temperature, methanol was added and the solution was stirred for additional hour. The mixture was concentrated and the product was isolated via silica column chromatography (using a gradient of 25 to 75% ethyl acetate in hexane) and yielded 40 mg of the title compound. 1H NMR (300 MHz, CDCl3) δ ppm 7.16-7.23 (m, 3H) 6.83-6.95 (m, 4H) 5.66 (d, J=8.09 Hz, 1H) 5.25-5.43 (m, 1H) 4.52 (heptet, J=6.25 Hz, 1H) 2.00 (s, 3H) 1.57 (d, J=6.99 3 H) 1.35 (d, J=6.25 Hz, 6H), MS (DCI): m/z 403 (M+H).
Reaction SMILES: [C:1]([C:8]1NC=CN=1)([C:3]1[NH:4][CH:5]=[CH:6]N=1)=O.[C:13](O)(=[O:23])[C:14]1[CH:22]=[CH:21][C:20]2[O:19][CH2:18][O:17][C:16]=2[CH:15]=1.C(Cl)(=O)C1C=CC2OCOC=2C=1.N1CC=CCC1>>[O:19]1[C:20]2[CH:21]=[CH:22][C:14]([C:13]([N:4]3[CH2:5][CH:6]=[CH:8][CH2:1][CH2:3]3)=[O:23])=[CH:15][C:16]=2[O:17][CH2:18]1
Reactant: O=C(c1ncc[nH]1)c1ncc[nH]1
Reactant: O=C(O)c1ccc2c(c1)OCO2
Agent: C1=CCNCC1
Agent: O=C(Cl)c1ccc2c(c1)OCO2
Product: O=C(c1ccc2c(c1)OCO2)N1CC=CCC1

Procedure:
The product amide is made by the method employed for the preparation of Invention Compound V, which uses carbonyl diimidazole in order to activate piperonylic acid, or piperonyloyl chloride (available from Aldrich) can be combined with 1,2,3,6-tetrahydropyridine either in a suitable anhydrous solvent or without solvent. In either case, the isolation of product is performed in the same manner as done for Invention Compound V to give Invention Compound III as a white solid. EIMS m/z=231 (parent, 149 (base), and 121. 1H NMR δ 2.21 (br s, 2), 3.4-4.3 (br m, 4), 5.87 (m, 2), 6.00 (s, 2), 6.83 (d, 1, J=7.84 Hz), and 6.92-6.96 (dd and d, 2). 13C NMR δ 101.3 (--OCH2O--) and 169.9 ppm (carbonyl).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:19][OH:20])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:10]=[N:11][C:12]([C:15]([F:18])([F:17])[F:16])=[N:13][CH:14]=1.Cl[C:22]1[CH:23]=[C:24]2[N:31]([CH3:32])[C:30]([CH3:34])([CH3:33])[CH2:29][N:25]2[C:26](=[O:28])[N:27]=1>>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[N:13][C:12]([C:15]([F:17])([F:18])[F:16])=[N:11][CH:10]=1)[CH2:19][O:20][C:22]1[CH:23]=[C:24]2[N:31]([CH3:32])[C:30]([CH3:34])([CH3:33])[CH2:29][N:25]2[C:26](=[O:28])[N:27]=1
Reactant: CN1c2cc(Cl)nc(=O)n2CC1(C)C
Reactant: OCc1ccc(Oc2cnc(C(F)(F)F)nc2)c(F)c1
Product: CN1c2cc(OCc3ccc(Oc4cnc(C(F)(F)F)nc4)c(F)c3)nc(=O)n2CC1(C)C

Procedure:
The title compound was prepared by a procedure similar to that described for E9 starting from (3-fluoro-4-((2-(trifluoromethyl)pyrimidin-5-yl)oxy)phenyl)methanol and 7-chloro-1,2,2-trimethyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one.
Reaction SMILES: [Br:1][C:2]1[N:7]2[CH:8]=[C:9]([CH:11]=O)[N:10]=[C:6]2[C:5]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[N:4][CH:3]=1.[CH3:19][C:20]1[CH:29]=[CH:28][C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[N:21]=1.Br[Si](C)(C)C>CN(C=O)C>[Br:1][C:2]1[N:7]2[CH:8]=[C:9](/[CH:11]=[CH:19]/[C:20]3[CH:29]=[CH:28][C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[N:21]=3)[N:10]=[C:6]2[C:5]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[N:4][CH:3]=1
Reactant: Cc1ccc2ccccc2n1
Reactant: O=Cc1cn2c(Br)cnc(N3CCOCC3)c2n1
Agent: C[Si](C)(C)Br
Solvent: CN(C)C=O
Product: Brc1cnc(N2CCOCC2)c2nc(/C=C/c3ccc4ccccc4n3)cn12
Temperature: 25 °C
Yield: 93.3 %

Procedure:
To a solution of compound 2a (800 mg, 2.58 mmol) in DMF (10 mL) was added 2-methylquinoline (600 mg, 4.20 mmol) and bromotrimethylsilane (960 mg, 8.89 mmol). The reaction mixture was stirred in a 20 mL sealed tube at 90° C. for 4 h. After cooling to rt, the reaction was quenched with MeOH (20 mL). The solids were collected by filtration and washed with Et2O to obtain compound 2b as a red solid (1.05 g, 85% yield). Mass Spectrum (LCMS, ESI pos.): Calcd. for C21H18BrN5O: 436.1 (M+H). found: 436.1.