Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH3:11])[C:5]([N+:8]([O-])=O)=[CH:6][CH:7]=1.[H][H]>C(OCC)(=O)C.[Pd]>[F:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([CH3:11])[CH:3]=1
Reactant: Cc1cc(F)ccc1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Cc1cc(F)ccc1N
Yield: 92.3 %

Procedure:
A solution of 9.0 g (58 mmole) of 3-fluoro-6-nitrotoluene in 200 ml of ethyl acetate was hydrogenated at room temperature with 60 psi of hydrogen gas using 0.9 g of 5% palladium on charcoal as catalyst. The solution was filtered and concentrated to give 6.7 g of 4-fluoro-2-methylaniline as an oil. A mixture of 1.33 g of the oil and 1.57 of phthalic anhydride was heated at 160° C. for 30 minutes and cooled. The resultant solid was washed with methanol and air dried to give 1.96 of the phthalimide derivative of 4-fluoro-2-methylaniline, m.p. 189.5-190.5° C. [Analysis. Calc'd. for C15H10NFO2: C,70.58; H, 3.95; N, 5.49; S, 7.44. Found: C, 70.68; H,3.95; N, 5.42; F, 7.39.] Bromination of the methyl group was effected by heating at reflux under an incandescent light source a mixture of 567 mg (2.22 mmole) of the phthalimide derivative, 435 mg of N-bromosuccinimide, and 59 mg of benzoyl peroxide in 25 ml of carbon tetrachloride. After one hour the mixture was cooled to room temperature, filtered, and concentrated in vacuo to give 720 mg of the crude bromomethyl phthalimide derivative. Using the general method of Example 1 with 284 mg of this bromomethyl phthalimide derivative instead of 2-(chloromethyl)-N,N-dimethylaniline in isopropyl alcohol produced the phthalimide derivative of 2-[(1H-benzimidazol-2-ylthio)methyl]-4-fluorobenzenamine. The residue from the dichloromethane extraction (as in Example 1) was washed with diethyl ether and purified by column chromatography, giving 190 mg of the phthalimide derivative as a white solid. Using the method of Example 3 with 104 mg (0.248 mmole) of this phthalimide derivative of 2-[(1H-benzimidazol-2-ylthio)methyl]-4-fluorobenzenamine instead of the title product of Example 2 produced the corresponding sulfoxide. The reaction mixture was diluted with dichloromethane, washed with aqueous sodium bicarbonate, dried over sodium sulfate, filtered, and concentrated in vacuo to give 119 mg of the sulfoxide as an oil. The sulfoxide was stirred in a solution of 0.14 ml of hydrazine hydrate in 5 ml of ethanol for two hours to remove the phthalimide group. The mixture was concentrated in vacuo to a solid, which was washed sequentially with 3% aqueous ammonium hydroxide and water, and air-dried to give 50 mg of the title compound: m.p. 184-185° C. Analysis. Calc'd. for C14H12N3FOS: C, 58.12; H, 4.18; N, 14.52; F, 6.57. Found: C, 58.11; H, 4.21; N, 14.54; F,6.34.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[O:14][C:13]([C:15]#[N:16])=[CH:12][CH:11]=1)([O-:3])=[O:2].[CH3:17][O-:18].[Na+]>CO>[N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[O:14][C:13]([C:15](=[NH:16])[O:18][CH3:17])=[CH:12][CH:11]=1)([O-:3])=[O:2]
Reactant: N#Cc1ccc(-c2ccccc2[N+](=O)[O-])o1
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=N)c1ccc(-c2ccccc2[N+](=O)[O-])o1
Reaction time: 2 h
Yield: 1331.1 %

Procedure:
A mixture of 5-(2-nitrophenyl)-2-furonitrile (92 g, 0.43 mole) and anhydrous methanol (1000 ml) was heated to 55° and sodium methoxide (1.5 g) was added. The steam bath was removed, the solution was stirred for 2 hours and stored overnight at room temperature. The solution was poured into ice water (1000 ml) and stirred for 1 hour. The product was collected by filtration and air dried to yield 91 g (86%) of methyl 5-(2-nitrophenyl)-2-furancarboximidate. A sample was recrystallized from isopropanol, m.p. 107°-108°.
Reaction SMILES: [NH:1]([CH2:6][C:7]([OH:9])=[O:8])[CH2:2][C:3]([OH:5])=[O:4].[OH-].[Na+].[C:12]([O:16][CH3:17])(=[O:15])[CH:13]=[CH2:14].Cl>O>[C:3]([CH2:2][N:1]([CH2:6][C:7]([OH:9])=[O:8])[CH2:14][CH2:13][C:12]([O:16][CH3:17])=[O:15])([OH:5])=[O:4]
Reactant: O=C(O)CNCC(=O)O
Reactant: C=CC(=O)OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COC(=O)CCN(CC(=O)O)CC(=O)O
Reaction time: 6 h
Yield: 96 %

Procedure:
133 g (1.00 mol) of iminodiacetic acid were dissolved in 530 ml of water, and the solution was adjusted to pH 7.0 with 40.5 g (1.00 mol) of solid NaOH. 86.0 g (1.00 mol) of methyl acrylate were added dropwise to this solution at 20° C., and the mixture was then stirred for 6 h. The methyl acrylate content after this time had fallen to 0.6% of the initial amount, and the pH was adjusted to 2 by adding 98.5 ml of concentrated HCl. Methyl N,N-bis(carboxymethyl)-3-aminopropionate separated out as colorless precipitate overnight at 5° C. Filtering off and drying resulted in 210 g (corresponding to a yield of 96% of theory) of a pure product of melting point 141° C.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][CH2:5][OH:6].[CH:7]1([C:10]2[N:15]=[C:14]([C:16]([NH:18][C:19]3[CH:27]=[N:26][CH:25]=[CH:24][C:20]=3[C:21](O)=[O:22])=[O:17])[C:13]([NH:28][C:29]3[CH:30]=[N:31][CH:32]=[N:33][CH:34]=3)=[CH:12][CH:11]=2)[CH2:9][CH2:8]1>>[OH:6][CH2:5][CH2:4][CH2:3][N:2]([CH3:1])[C:21]([C:20]1[CH:24]=[CH:25][N:26]=[CH:27][C:19]=1[NH:18][C:16]([C:14]1[C:13]([NH:28][C:29]2[CH:34]=[N:33][CH:32]=[N:31][CH:30]=2)=[CH:12][CH:11]=[C:10]([CH:7]2[CH2:8][CH2:9]2)[N:15]=1)=[O:17])=[O:22]
Reactant: CNCCCO
Reactant: O=C(O)c1ccncc1NC(=O)c1nc(C2CC2)ccc1Nc1cncnc1
Product: CN(CCCO)C(=O)c1ccncc1NC(=O)c1nc(C2CC2)ccc1Nc1cncnc1
Yield: 34 %

Procedure:
According to the general method described in step 3 of example 53, reaction of 3-methylamino-propan-1-ol with 3-{[6-cyclopropyl-3-(pyrimidin-5-ylamino)-pyridine-2-carbonyl]-amino}-isonicotinic acid provided the title compound (34%) as amorphous yellow solid.
Reaction SMILES: [Cl:1]C1C=CC(N)=CC=1[N+]([O-])=O.C(Cl)(Cl)Cl.ClC1C=CC(N[S:24]([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])(=[O:26])=[O:25])=CC=1[N+]([O-])=O>N1C=CC=CC=1>[CH2:27]([S:24]([Cl:1])(=[O:26])=[O:25])[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42]
Reactant: Nc1ccc(Cl)c([N+](=O)[O-])c1
Reactant: CCCCCCCCCCCCCCCCS(=O)(=O)Nc1ccc(Cl)c([N+](=O)[O-])c1
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: CCCCCCCCCCCCCCCCS(=O)(=O)Cl

Procedure:
Hexadecanesulfonylchloride, which was prepared by the method as described in J. M. Sprague, et al., J. Amer. Chem. Soc., Vol. 59, page 1837 (1937), was reacted with 2-chloro-5-aminonitrobenzene in a chloroform solution in the presence of pyridine to prepare 2-chloro-5-hexadecanesulfonamidonitrobenzene.
Reaction SMILES: [CH2:1]([S:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][C:28]([OH:30])=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O.[NH2:44][NH2:45]>C(O)CC>[CH2:1]([S:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][C:28]([NH:44][NH2:45])=[O:30])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: NN
Reactant: CCCCCCCCCCCCCCCCSCCCCCCCCCCC(=O)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CCCO
Product: CCCCCCCCCCCCCCCCSCCCCCCCCCCC(=O)NN
Temperature: 25 °C

Procedure:
22.1 Grams of 11-(hexadecylthio)undecanoic acid, 1.0 g of p-toluenesulfonic acid monohydrate and 200 ml of n-propanol were charged in a flask equipped with a stirrer, a condenser and a calcium chloride drying tube and refluxed with heating for 4 hours. Thereafter, to the solution was added 12.5 g of hydrazine monohydrate, followed by refluxing with heating for further 20 hours. The reaction mixture was cooled to room temperature and the precipitated crystal was filtered off under reduced pressure and washed with distilled water. The crystal was recrystallized from 2-propanol to obtain 16.0 g of the desired product. m.p. 108° C.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[Cl:10])([O-:3])=[O:2].[Cl:11][S:12](O)(=[O:14])=[O:13]>>[N+:1]([C:4]1[CH:9]=[C:8]([S:12]([Cl:11])(=[O:14])=[O:13])[CH:7]=[CH:6][C:5]=1[Cl:10])([O-:3])=[O:2]
Reactant: O=S(=O)(O)Cl
Reactant: O=[N+]([O-])c1ccccc1Cl
Product: O=[N+]([O-])c1cc(S(=O)(=O)Cl)ccc1Cl

Procedure:
On the other hand, those compounds of formula (1) wherein X is hydroxy and A is a sulfonamido group can be prepared by treating, for example, ortho-nitro-chlorobenzene with chlorosulfonic acid to obtain 3-nitro-4-chlorobenzenesulfonylchloride, followed by treatment with a primary or secondary amine to yield the corresponding 3-nitro-4-chlorobenzene sulfonamido derivative. This product is then treated with caustic soda to yield the 3-nitro-4-hydroxybenzene sulfonamide and subsequently reduced to the desired 3-amino-4-hydroxybenzene sulfonamide.
Reaction SMILES: CC(OC(=O)[NH:7][CH:8]([C:13]([NH:15][CH2:16][C:17]1[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=1)=[O:14])[CH:9]([CH3:12])[CH2:10][CH3:11])(C)C.[F:24][C:25]([F:30])([F:29])[C:26]([OH:28])=[O:27]>>[F:24][C:25]([F:30])([F:29])[C:26]([OH:28])=[O:27].[NH2:7][CH:8]([CH:9]([CH3:12])[CH2:10][CH3:11])[C:13]([NH:15][CH2:16][C:17]1[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=1)=[O:14]
Reactant: CCC(C)C(NC(=O)OC(C)(C)C)C(=O)NCc1cccnc1
Solvent: O=C(O)C(F)(F)F
Product: CCC(C)C(N)C(=O)NCc1cccnc1
Yield: 172.5 %

Procedure:
The title compound is prepared by the procedure of Example 2, using 2.0 g of product from Example 3 and 3.55 g of trifluoroacetic acid to give 3.6 g of the desired product as a tacky oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH:9]=[O:10])=[CH:7][CH:8]=1.[CH3:11][C:12](=[N:16][OH:17])[C:13](=O)[CH3:14].[ClH:18]>C(O)(=O)C>[ClH:18].[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:10][C:13]([CH3:14])=[C:12]([CH3:11])[N+:16]=2[O-:17])=[CH:5][CH:4]=1
Reactant: COc1ccc(C=O)cc1
Reactant: CC(=O)C(C)=NO
Agent: Cl
Solvent: CC(=O)O
Product: COc1ccc(-c2oc(C)c(C)[n+]2[O-])cc1
Reaction time: 3 h

Procedure:
A mixture of 68.07 g of anisaldehyde, 50.5 g of 2,3-butanedione mono-oxime and 150 ml of acetic acid was saturated with hydrogen chloride gas and the mixture was allowed to stand at room temperature for 3 hours. The solid product was collected and recrystallized from methanol to give 2-(4-methoxyphenyl)-4,5-dimethyloxazole N-oxide hydrochloride, m.p. 194°-196° C. The latter was converted to the free base for use in the next reaction by treatment with sodium bicarbonate solution.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7](Cl)[CH:6]=[CH:5]2.C[NH:14]CC1C=CC=CC=1>>[NH2:14][C:7]1[CH:6]=[CH:5][C:4]2[C:9](=[CH:10][CH:11]=[CH:2][CH:3]=2)[N:8]=1
Reactant: CNCc1ccccc1
Reactant: Clc1ccc2cc(Br)ccc2n1
Product: Nc1ccc2ccccc2n1

Procedure:
6-Bromo-2-chloroquinoline (200 mg, 0.8 mmol) and N-methylbenzylamine (2 mL) were heated at 120° C. for 16 hours. Extraction from 2M NaOH into DCM and drying on Na2SO4 gave the crude 2-aminoquinoline. This was converted, via Methods 3 and 5, to compound 204 (110 mg, 46%). [M−H]−=291.1 m/z. Activity: A
Reaction SMILES: [N+](C1C=CC([O:10][C:11](=O)/[CH:12]=[CH:13]/[CH:14]=[C:15]([C:26]2[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[C:28]([O:34][CH3:35])[CH:27]=2)[C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH3:25])[CH:17]=2)=CC=1)([O-])=O.[N:37]1[CH:42]=[CH:41][CH:40]=[C:39]([CH2:43][CH2:44][CH2:45][CH2:46][NH2:47])[CH:38]=1>O1CCCC1>[CH3:35][O:34][C:28]1[CH:27]=[C:26]([C:15]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH3:25])[CH:17]=2)=[CH:14]/[CH:13]=[CH:12]/[C:11]([NH:47][CH2:46][CH2:45][CH2:44][CH2:43][C:39]2[CH:38]=[N:37][CH:42]=[CH:41][CH:40]=2)=[O:10])[CH:31]=[CH:30][C:29]=1[O:32][CH3:33]
Reactant: COc1ccc(C(=C/C=C/C(=O)Oc2ccc([N+](=O)[O-])cc2)c2ccc(OC)c(OC)c2)cc1OC
Reactant: NCCCCc1cccnc1
Solvent: C1CCOC1
Product: COc1ccc(C(=C/C=C/C(=O)NCCCCc2cccnc2)c2ccc(OC)c(OC)c2)cc1OC
Yield: 71.8 %

Procedure:
As in Example 134, a solution of (E)-5,5-bis(3,4-dimethoxyphenyl)-2,4-pentadienoic acid 4-nitrophenyl ester (4.9 g) and 3-pyridinebutanamine (1.5 g) in tetrahydrofuran (25 mL) was stirred for 17 hours at room temperature and was then worked up in the usual manner. The crude amide was crystallized from ethyl acetate-hexane to provide 3.6 g of (E)-5,5-bis(3,4-dimethoxyphenyl)-N-[4-(3-pyridinyl)butyl]-2,4-pentadienamide mp 145°-146° C. Anal. Calculated for C30H34N2O5 : C, 71.69; H, 6.82; N, 5,57 Found: C, 71.33; H, 6.93; N, 5.72.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[CH2:7][CH2:6][CH2:5]2.[CH3:13][N:14]([CH3:23])[C:15]1[CH:22]=[CH:21][C:18]([CH:19]=O)=[CH:17][CH:16]=1.Cl.CO>O>[CH3:13][N:14]([CH3:23])[C:15]1[CH:22]=[CH:21][C:18]([CH:19]=[C:7]2[CH2:6][CH2:5][C:4]3[C:9](=[CH:10][CH:11]=[C:2]([OH:1])[CH:3]=3)[C:8]2=[O:12])=[CH:17][CH:16]=1
Reactant: CN(C)c1ccc(C=O)cc1
Reactant: O=C1CCCc2cc(O)ccc21
Agent: Cl
Solvent: O
Solvent: CO
Product: CN(C)c1ccc(C=C2CCc3cc(O)ccc3C2=O)cc1
Temperature: 25 °C
Yield: 48.9 %

Procedure:
After 6-hydroxy-1-tetralone 1.0 g and 4-dimethylaminobenzaldehyde 0.97 g were added to a mixture of concentrated hydrochloric acid 50 ml and methanol 75 ml, the mixture was refluxed for 1.5 hours and cooled to room temperature, and water 400 ml was added. The precipitated crystals were filtered. The crystals were dried over phosphorous pentoxide for six hours under reduced pressure to obtain the desired compound 0.885 g.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][N:6]2[C@@H:11]1[O:28][C@H:27]([CH2:29][O:30]C(=O)C)[C@@H:22]([O:23]C(=O)C)[C@H:17]([O:18]C(=O)C)[C@H:12]1[O:13]C(=O)C.[CH3:34][C:35]1[CH:43]=[CH:42][C:38]([C:39](Cl)=O)=[CH:37][CH:36]=1>>[F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]([CH2:34][C:35]1[CH:43]=[CH:42][C:38]([CH3:39])=[CH:37][CH:36]=1)=[CH:5][N:6]2[C@@H:11]1[O:28][C@H:27]([CH2:29][OH:30])[C@@H:22]([OH:23])[C@H:17]([OH:18])[C@H:12]1[OH:13]
Reactant: CC(=O)OC[C@H]1O[C@@H](n2ccc3c(F)cccc32)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: Cc1ccc(C(=O)Cl)cc1
Product: Cc1ccc(Cc2cn([C@@H]3O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)c3cccc(F)c23)cc1

Procedure:
4-Fluoro-1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)indole obtained in Example 2-(3) and 4-methylbenzoyl chloride were treated in a manner similar to Example 2-(4), (5), (6) and (7) to give the titled compound as a colorless powder. APCI-Mass m/Z 419 (M+NH4). 1H-NMR (DMSO-d6) δ 2.24 (3, 3H), 3.21-3.25 (m, 2H), 3.37-3.46 (m, 2H), 3.63-3.67 (m, 2H), 4.04 (s, 2H), 4.53 (t, J=5.5 Hz, 1H), 5.09 (d, J=5.1 Hz, 1H), 5.16 (d, J=5.0 Hz, 1H), 5.21 (d, J=5.1 Hz, 1H), 5.37 (d, J=9.0 Hz, 1H), 6.74 (dd, J=11.1, 7.9 Hz, 1H), 7.05-7.07 (m, 3H), 7.13-7.15 (m, 2H), 7.20 (s, 1H), 7.35 (d, J=8.3 Hz, 1H).
Reaction SMILES: FC(F)(F)C(O)=O.[Br:8][C:9]1[CH:10]=[CH:11][C:12]([O:27][CH3:28])=[C:13]([CH:15]([C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH:20]=[CH:19][CH:18]=2)O)[CH:14]=1.[OH-].[Na+]>C(Cl)Cl.O>[Br:8][C:9]1[CH:10]=[CH:11][C:12]([O:27][CH3:28])=[C:13]([CH:14]=1)[CH2:15][C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][CH:18]=1
Reactant: COc1ccc(Br)cc1C(O)c1cccc2ccccc12
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: ClCCl
Product: COc1ccc(Br)cc1Cc1cccc2ccccc12
Temperature: 25 °C
Reaction time: 19 h
Yield: 95.7 %

Procedure:
3.06 g (80.89 mmol, 10.48 eq.) NAB4 (granules) were added slowly to 50 ml Trifluoroacetic acid at 0° C. To this mixture a solution of 2.65 g (7.72 mmol) (5-Bromo-2-methoxy-phenyl)-napthalen-1-yl-methanol (62) in 30 ml dry CH2Cl2 was added which led to an brownish mixture. After stirring this mixture for 19 h at r.t. it was diluted with water and cooled again to 0° C. At this temperature NaOH-pellets were added carefully to adjust the pH to 10 before the solution was extracted with ether. The comb. org. fractions. were washed with brine, dried over Na2SO4 and evaporated. Column chromatography (CH2Cl2) yielded 2.42 g (7.39 mmol, 95.72%) 1-(5-Bromo-2-methoxy-benzyl)-naphthalene (63) as a pale yellow oil. Rf (CH2Cl2)=0.73. 1H-NMR (400 MHz, CDCl3): δ=3.84 (s, 3H, OMe), 4.35 (s, 2H), 6.76 (d, 1H, J=8.72 Hz), 6.91 (d, 1H, J=2.53 Hz), 7.20 (dm, 1H, J1=6.82 Hz), 7.26 (dd, 1H, J1=8.84 Hz, J2=2.53 Hz), 7.38 (m, 1H), 7.41-7.49 (m, 2H), 7.74 (d, 1H, J=8.34 Hz), 7.84 (m, 1H), 7.91 (m, 1H). MS (EI): m/z=329 (18), 328 (97), 327 (20), 326 (100), 248 (16), 247 (35), 232 (22), 231 (25), 216 (20), 215 (41), 203 (17), 202 (25), 142 (21), 141 (61), 115 (10), 101 (14). HR-MS (EI): Calcd. for C18H15BrO: 326.030626. Found: 326.030567.
Reaction SMILES: [CH3:1][C:2]([CH3:15])([CH2:12][CH:13]=C)[C:3](=[O:11])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.O=[O+][O-].O=O.CSC.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1CCN2C(=NCCC2)CC1>CO.C(Cl)Cl.CC(O)=O>[CH3:15][C:2]1([CH3:1])[C:3](=[O:11])[C:4]([C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=2)=[CH:13][CH2:12]1
Reactant: C=CCC(C)(C)C(=O)Cc1ccccc1
Agent: O=O
Agent: O=[O+][O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: CSC
Product: CC1(C)CC=C(c2ccccc2)C1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 79.6 %

Procedure:
A solution of the product of Step 2 (15 g) in 70 mL of MeOH and 50 mL of CH2Cl2 was treated with a stream of ozone/oxygen until the solution turned light blue. Dimethylsulfide (20 mL) was added and the reaction mixture was stirred for 2 h at room temperature and then treated with 5 g of triphenylphosphine for an additional 0.5 h. DBU (1 mL) was then added to the reaction mixture. After stirring for 1 h at room temperature, 1 mL of AcOH was added and the reaction mixture was concentrated. The residue was dissolved in 100 mL of 20:1 hexanes/EtOAc and the solution was filtered through a pad of silica gel. The filtrate was concentrated to give 11 g of the tite compound as a yellow oil.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:4]=[CH:5][C:6]([CH2:9][NH2:10])=[N:7][CH:8]=1.O[C:14]1[C:15]2[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([NH2:26])=[O:25])[C:16]=2[N:17]=[N:18][N:19]=1>>[F:12][C:2]([F:11])([F:1])[C:3]1[CH:4]=[CH:5][C:6]([CH2:9][NH:10][C:14]2[C:15]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([NH2:26])=[O:25])[C:16]=3[N:17]=[N:18][N:19]=2)=[N:7][CH:8]=1
Reactant: NCc1ccc(C(F)(F)F)cn1
Reactant: NC(=O)c1cccc2c(O)nnnc12
Product: NC(=O)c1cccc2c(NCc3ccc(C(F)(F)F)cn3)nnnc12

Procedure:
Compound 7 was prepared following general synthetic scheme 7 wherein (5-(trifluoromethyl)-pyridin-2-yl)methanamine was reacted with 4-hydroxybenzo[d][1,2,3]-triazine-8-carboxamide to give the title compound. LC-MS [349 (M+1)], 1H NMR (400 MHz, DMSO-d): δ 9.50 (t, 1H), 9.35 (s, 1H), 8.93 (s, 1H), 8.55 (d, 2H), 8.16 (dd, 1H), 8.05-8.01 (m, 2H), 7.65 (d, 1H), 5.07 (d, 2H).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[C:6]([N:11]3[C:15]([NH2:16])=[CH:14][CH:13]=[N:12]3)[CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[C:17]([C:21]1[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[CH:23][CH:22]=1)([CH3:20])([CH3:19])[CH3:18].C(=O)(O)[O-].[Na+]>CN(C1C=CN=CC=1)C.N1C=CC=CC=1>[C:17]([C:21]1[CH:26]=[CH:25][C:24]([S:27]([NH:16][C:15]2[N:11]([C:6]3[CH:7]=[CH:8][CH:9]=[C:10]4[C:5]=3[CH:4]=[CH:3][CH:2]=[N:1]4)[N:12]=[CH:13][CH:14]=2)(=[O:29])=[O:28])=[CH:23][CH:22]=1)([CH3:20])([CH3:18])[CH3:19]
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Cl)cc1
Reactant: Nc1ccnn1-c1cccc2ncccc12
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Product: CC(C)(C)c1ccc(S(=O)(=O)Nc2ccnn2-c2cccc3ncccc23)cc1
Temperature: 80 °C
Yield: 6.6 %

Procedure:
A stirred mixture of crude 1-(quinolin-5-yl)-1H-pyrazol-5-amine (0.080 g, 0.38 mmol), 4-t-butylbenzenesulfonyl chloride (0.13 g, 0.57 mmol), and DMAP (0.068 g, 0.57 mmol) in pyridine (1.5 mL) was heated at 80° C. for 2 h. After cooling to room temperature, aqueous saturated sodium bicarbonate was added to the reaction mixture and extracted with 2:1 chloroform/iPrOH. The organic layer was dried (Na2SO4), filtered, and concentrated in vacuo. The crude residue was purified by reverse phase HPLC(C18 column, acetonitrile-H2O with 0.1% TFA as eluent) to give the title compound as a white solid (0.010 g, 0.025 mmol, 7%). 1H NMR (400 MHz, CD3OD) δ 8.87 (dd, J=2.0, 4.4 Hz, 1H), 8.13 (d, J=8.4 Hz, 1H), 7.76 (dd, J=7.2, 8.8 Hz, 1H), 7.69 (d, J=2.4 Hz, 1H), 7.65-7.62 (m, 1H), 7.52-7.42 (m, 3H), 7.51 (d, J=8.8 Hz, 1H), 7.43 (d, J=8.8 Hz, 1H), 7.28 (dd, J=1.2, 7.2 Hz, 1H), 6.25 (s, 1H), 1.35 (s, 9H); MS: (ES) m/z calculated for C22H23N4O2S [M+H]+ 407.2. found 407.0.
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:6][C:5]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)=[CH:4][N:3]=1.C(Cl)(Cl)Cl.[C:27](Cl)(=[O:29])[CH3:28].C(=O)(O)[O-].[Na+]>N1C=CC=CC=1>[C:27]([NH:1][C:2]1[C:7]([CH2:8][C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)=[N:6][C:5]([C:15]2[CH:16]=[CH:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=2)=[CH:4][N:3]=1)(=[O:29])[CH3:28]
Reactant: CC(=O)Cl
Reactant: COc1ccc(-c2cnc(N)c(Cc3ccccc3)n2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: COc1ccc(-c2cnc(NC(C)=O)c(Cc3ccccc3)n2)cc1
Temperature: 25 °C
Yield: 32.9 %

Procedure:
Under an argon atmosphere, 2-amino-3-benzyl-5-(4-methoxyphenyl)pyrazine (c-11) (prepared by the method described in Adamczyk, M. et al., Org. Prep. Proced. Int., 33, 477-485 (2001)) (199 mg, 681 μmol) was dissolved in anhydrous pyridine (1.4 mL) and chloroform (4 mL) and cooled to 0° C. To this was added acetyl chloride (365 μL, 5.13 mmol) and stirred for an hour after warming to room temperature. To this was added saturated aqueous solution of sodium bicarbonate to stop the reaction, and extracted 3 times with dichloromethane. The organic layer was washed with saturated aqueous solution of sodium sulfate and dried over anhydrous sodium sulfate. After removing anhydrous sodium sulfate by filtration, the filtrate was concentrated under reduced pressure with a rotary evaporator. The residue was recrystallized from methanol to give 2-acetylamino-3-benzyl-5-(4-methoxyphenyl)pyrazine (c-24) as a colorless solid (74.6 mg, 32.9%). Rf=0.14 (n-hexane/ethyl acetate=3/2). UV (MeOH) λmax (log ε) 329.5 (4.18), 293 (4.18), 274 (4.16). UV (pH 7.4 PB) λmax (log ε) 328 (4.11), 289.5 (4.01), 270.5 (4.05). 1H NMR (400 MHz, DMSO-d6) δ 2.04 (s, 3H), 3.81 (s, 3H), 4.15 (s, 2H), 7.02-7.08 (AA′BB′, 2H), 7.15-7.22 (m, 3H), 7.23-7.29 (m, 2H), 8.00-8.05 (AA′BB′, 2H), 8.87 (s, 1H), 10.25 (s, 1H). IR (KBr, cm−1) 698, 744, 833, 1032, 1157, 1175, 1213, 1256, 1285, 1327, 1368, 1416, 1450, 1499, 1543, 1587, 1609, 1670, 3258. HRMS (FAB+) m/z 334.1557 (M+H, C20H20N3O2 requires 334.1556).
Reaction SMILES: [C:1]([C:5]1[NH:6][C:7]2[C:12]([CH:13]=1)=[C:11](F)[C:10]([N+:15]([O-:17])=[O:16])=[CH:9][CH:8]=2)([CH3:4])([CH3:3])[CH3:2].[C-:18]#[N:19].[K+].O>CS(C)=O>[C:1]([C:5]1[NH:6][C:7]2[CH:8]=[CH:9][C:10]([N+:15]([O-:17])=[O:16])=[C:11]([C:18]#[N:19])[C:12]=2[CH:13]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: [C-]#N
Reactant: CC(C)(C)c1cc2c(F)c([N+](=O)[O-])ccc2[nH]1
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CC(C)(C)c1cc2c(C#N)c([N+](=O)[O-])ccc2[nH]1
Temperature: 70 °C
Reaction time: 3 h
Yield: 53.2 %

Procedure:
To a solution of 2-tert-butyl-4-fluoro-5-nitro-1H-indole (4.0 g, 17 mmol) in DMSO (30 mL) was added KCN (3.4 g, 51 mmol). The mixture was stirred at 70° C. for 3 hours, and poured into water (80 mL) and extracted with ethyl acetate (50 mL×3). The combined organic layers were washed with brine, dried over anhydrous Na2SO4 and concentrated under vacuum. The residue was purified by column chromatography on silica gel (7% EtOAc in petroleum ether) to afford 2-tert-butyl-5-nitro-1H-indole-4-carbonitrile (2.2 g, 53%). 1H NMR (DMSO, 300 MHz) δ 12.23 (br s, 1 H), 8.09 (d, J=9.0 Hz, 1 H), 7.75 (d, J=9.0 Hz, 1 H), 6.50 (s, 1 H), 1.38 (s, 9 H). MS (ESI) m/z: 244.2 [M+H+].