Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:6]([N+:7]([O-:9])=[O:8])=[C:5]([Br:10])[NH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+].Br[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([CH2:27]Br)[CH:22]=1>CN(C)C=O.O>[Br:1][C:2]1[C:6]([N+:7]([O-:9])=[O:8])=[C:5]([Br:10])[N:4]([CH2:27][C:23]2[CH:24]=[CH:25][CH:26]=[C:21]([CH2:20][N:3]3[C:2]([Br:1])=[C:6]([N+:7]([O-:9])=[O:8])[C:5]([Br:10])=[N:4]3)[CH:22]=2)[N:3]=1
Reactant: BrCc1cccc(CBr)c1
Reactant: O=[N+]([O-])c1c(Br)n[nH]c1Br
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1c(Br)nn(Cc2cccc(Cn3nc(Br)c([N+](=O)[O-])c3Br)c2)c1Br
Reaction time: 0.83 h

Procedure:
13.54 g of 3,5-dibromo-4-nitropyrazole, 11.1 g potassium carbonate, 0.8 g of potassium iodide and 6.6 g α, α′-dibromo-m-xylene are heated to 100° C. in 40 ml of dimethyl formamide. After 50 minutes the reaction mixture is allowed to cool and poured into 400 ml water. The precipitate is filtered, washed with water and dried in vacuum.
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[C:16]([O:19][CH:20]([C:29]([CH3:36])([CH3:35])[CH2:30][O:31][C:32](=[O:34])[CH3:33])[C:21]([NH:23][CH2:24][CH2:25][C:26]([OH:28])=[O:27])=[O:22])(=[O:18])[CH3:17].[CH:37]1[C:42]([N+:43]([O-:45])=[O:44])=[CH:41][CH:40]=[C:39](O)[CH:38]=1>O1CCCC1>[C:16]([O:19][CH:20]([C:29]([CH3:36])([CH3:35])[CH2:30][O:31][C:32](=[O:34])[CH3:33])[C:21]([NH:23][CH2:24][CH2:25][C:26]([O:28][C:39]1[CH:38]=[CH:37][C:42]([N+:43]([O-:45])=[O:44])=[CH:41][CH:40]=1)=[O:27])=[O:22])(=[O:18])[CH3:17]
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: CC(=O)OCC(C)(C)C(OC(C)=O)C(=O)NCCC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: C1CCOC1
Product: CC(=O)OCC(C)(C)C(OC(C)=O)C(=O)NCCC(=O)Oc1ccc([N+](=O)[O-])cc1
Yield: 32.3 %

Procedure:
Dicyclohexylcarbodiimide (15.5 g) was added to a solution of 22.6 g of 3-[N-(2,4-diacetoxy-3,3-dimethyl-1-oxobutyl)amino]propionic acid and 10.4 g of p-nitrophenol in 500 ml of tetrahydrofuran, and the mixture was stired for one night. After completion of the reaction, insoluble matter was removed and the solvent was distilled off under reduced pressure. The residue was dissolved in ethyl acetate. The resulting solution was washed with saturated aqueous sodium bicarbonate solution, with water and then with saturated saline, and dried over anhydrous sodium sulfate. After removing the solvent by evaporation, 10.2 g of the objectived compound was obtained as a residue (yield: 32%).
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[C:10]([CH3:11])=[CH:9][C:8]([C:12]2[NH:21][C:20](=[O:22])[C:19]3[C:14](=[CH:15][C:16]([O:25][CH3:26])=[CH:17][C:18]=3[O:23][CH3:24])[N:13]=2)=[CH:7][C:6]=1[CH3:27].C([O-])(O)=O.[Na+].O.[CH3:34][N:35]([CH:37]=O)C>>[N:35]1([CH2:2][CH2:3][O:4][C:5]2[C:10]([CH3:11])=[CH:9][C:8]([C:12]3[NH:21][C:20](=[O:22])[C:19]4[C:14](=[CH:15][C:16]([O:25][CH3:26])=[CH:17][C:18]=4[O:23][CH3:24])[N:13]=3)=[CH:7][C:6]=2[CH3:27])[CH2:37][CH2:7][CH2:6][CH2:5][CH2:10][CH2:34]1
Reactant: COc1cc(OC)c2c(=O)[nH]c(-c3cc(C)c(OCCBr)c(C)c3)nc2c1
Reactant: CN(C)C=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: COc1cc(OC)c2c(=O)[nH]c(-c3cc(C)c(OCCN4CCCCCC4)c(C)c3)nc2c1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
To a suspension of 2-[4-(2-bromo-ethoxy)-3,5-dimethyl-phenyl]-5,7-dimethoxy-3H-quinazolin-4-one (0.22 g, 0.50 mmol) in DMF (2 mL) was added hexamethyleneimine(azepane) (0.22 mL, 2.0 mmol) and the reaction mixture was stirred at room temperature for 17 hours. Saturated aqueous NaHCO3 solution (2 mL) was added and stirred for 2 hours. Water (10 mL) was added and stirred for another 0.5 hours. The solid was filtered, washed with water, and dried under vacuum to give the title compound as a white solid. Yield: 0.22 g (95%). MP 198-199° C. 1H NMR (400 MHz, CD3OD): δ 7.70 (s, 2H), 6.79 (s, 1H), 6.55 (s, 1H), 3.97 (t, J=6.0 Hz, 2H), 3.92 (s, 3H), 3.91 (s, 3H), 2.98 (t, J=6.0 Hz, 2H), 2.82 (t, J=5.2 Hz, 4H), 2.37 (s, 6H), 1.72 (m, 4H), 1.66 (m, 4H). MS (ES+) m/z: 452.27 (M+1). Analysis calculated for C26H33N3O4 (451.56), %: C, 69.16; H, 7.37; N, 9.31. Found, %: C, 68.94; H, 6.90; N, 9.30.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[CH2:15][CH2:14][CH2:13][N:11]3[CH:12]=2)=[CH:4][CH:3]=1.C([Li])CCC.[CH2:21]([Sn:25](Cl)([CH2:30][CH2:31][CH2:32][CH3:33])[CH2:26][CH2:27][CH2:28][CH3:29])[CH2:22][CH2:23][CH3:24]>O1CCCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]3[CH2:15][CH2:14][CH2:13][N:11]3[C:12]=2[Sn:25]([CH2:26][CH2:27][CH2:28][CH3:29])([CH2:30][CH2:31][CH2:32][CH3:33])[CH2:21][CH2:22][CH2:23][CH3:24])=[CH:6][CH:7]=1
Reactant: Fc1ccc(-c2cn3c(n2)CCC3)cc1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1c(-c2ccc(F)cc2)nc2n1CCC2
Temperature: -30 °C

Procedure:
To a -78° C. solution of 2-(4-fluorophenyl)-6,7-dihydro-[5H]-pyrrolo[1,2-a]imidazole (2.0 g, 0.010 mole) in 60 ml of tetrahydrofuran (THF) is added 4.0 ml of 2.5M n-butyllithium. The solution is warmed to -30° C. for 20 minutes and then tributyltin chloride (3.3 g, 0.01 mole) in THF is added. The reaction is allowed to warm gradually to 20° C. and then is quenched with saturated ammonium chloride. Further workup and purification on silica as described in Example 6b yields the titled compound.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[S:5]1[C:9]2[S:10][CH:11]=[CH:12][C:8]=2[CH:7]=[C:6]1[C:13]([O:15][CH3:16])=[O:14].[F:17][C:18]1[CH:26]=[CH:25][C:21]([C:22](Cl)=[O:23])=[CH:20][CH:19]=1.Cl>C(Cl)Cl.O>[F:17][C:18]1[CH:26]=[CH:25][C:21]([C:22]([C:11]2[S:10][C:9]3[S:5][C:6]([C:13]([O:15][CH3:16])=[O:14])=[CH:7][C:8]=3[CH:12]=2)=[O:23])=[CH:20][CH:19]=1
Reactant: COC(=O)c1cc2ccsc2s1
Reactant: O=C(Cl)c1ccc(F)cc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: O
Product: COC(=O)c1cc2cc(C(=O)c3ccc(F)cc3)sc2s1
Temperature: 20 °C
Reaction time: 3 h
Yield: 79.5 %

Procedure:
Anhydrous aluminium chloride (136 g) is added in small portions, over a period of 30 minutes, to a mixture of methyl thieno[2,3-b]thiophene-2-carboxylate (40.3 g) and 4-fluorobenzoyl chloride (32.3 g) in methylene chloride (1000 cc) at about 25° C. The reaction mixture is stirred for 3 hours at a temperature of about 20° C. and then hydrolysed, with care, by the addition over a period of 30 minutes of 0.5N aqueous hydrochloric acid (500 cc), the internal temperature being maintained at about 20° C. by external cooling with a bath of cold water. The methylene chloride solution is diluted with methylene chloride (5000 cc), decanted off, washed three times with distilled water (total 3000 cc), three times with a saturated aqueous sodium bicarbonate solution (total 1000 cc), and again three times with distilled water (total 3000 cc), then dried over anhydrous sodium sulphate in the presence of decolourizing charcoal (1 g), filtered and evaporated. The residue is triturated in diethyl ether (250 cc), the resulting crystals are filtered off, washed three times with diethyl ether (total 375 cc) and dried under reduced pressure (20 mm Hg) at a temperature of about 20° C. in the presence of potassium hydroxide pellets. Methyl 5-(4-fluorobenzoyl)-thieno[2,3-b]thiophene-2-carboxylate (51.8 g), melting at 220° C., is thus obtained.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=[O:14])=[CH:11][C:10]=1[Cl:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Si](C)(C)[C:20]([F:23])([F:22])[F:21].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.Cl>C1COCC1.C(OCC)(=O)C>[CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]([OH:14])[C:20]([F:23])([F:22])[F:21])=[CH:11][C:10]=1[Cl:17])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1ccc(OCc2ccccc2)c(Cl)c1
Reactant: C[Si](C)(C)C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: OC(c1ccc(OCc2ccccc2)c(Cl)c1)C(F)(F)F
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 4-benzyloxy-3-chlorobenzaldehyde (4.9 g, 20 mmol) and trimethyl(trifluoromethyl)silane (4.4 mL, 30 mmol) in THF (0.10 L) was added a solution tetrabutylammonium fluoride (1.0 M in THF, 2.0 mL). After the reaction was stirred at 25° C. for 3 h, it was acidified with 2 N HCl to pH 2, diluted with ethyl acetate and washed with brine. The organic phase was dried and concentrated and the residue was purified by chramotography on silica gel eluting with 8:2 hexane:ethyl acetate to give 1-(4-benzyloxy-3-chlorophenyl)-2,2,2-trifluoroethanol.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:25][C:26]([C:28]2[S:29][CH:30]=[CH:31][CH:32]=2)=[NH:27])[CH:5]=[C:6]2[C:11]=1[N:10]([CH2:12][CH2:13][N:14](C)[C:15](=O)OC1C=CC=CC=1)[CH2:9][CH2:8][CH2:7]2.[OH-].[Na+]>C(O)C.O>[F:1][C:2]1[CH:3]=[C:4]([NH:25][C:26]([C:28]2[S:29][CH:30]=[CH:31][CH:32]=2)=[NH:27])[CH:5]=[C:6]2[C:11]=1[N:10]([CH2:12][CH2:13][NH:14][CH3:15])[CH2:9][CH2:8][CH2:7]2
Reactant: CN(CCN1CCCc2cc(NC(=N)c3cccs3)cc(F)c21)C(=O)Oc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CNCCN1CCCc2cc(NC(=N)c3cccs3)cc(F)c21
Reaction time: 3 h
Yield: 22.9 %

Procedure:
To a stirred solution of phenyl 2-(8-fluoro-6-(thiophene-2-carboximidamido)-3,4-dihydroquinolin-1(2H)-yl)ethyl(methyl)carbamate (400 mg, 0.884 mmol) in Ethanol (11 ml) was added sodium hydroxide (354 mg, 8.84 mmol) as a solution in Water (5.5 ml). The resulting mixture was stirred at reflux and monitored by TLC. After 3 h, the reaction mixture showed some formation of product, and some starting material. Due to the formation of some side product, the reaction was stopped, diluted with water and extracted with dichloromethane (3×). The combined organics were dried, filtered and concentrated, then chromatographed in 0-10% (2M NH3 in MeOH) in dichloromethane, giving the desired N-(8-fluoro-1-(2-(methylamino)ethyl)-1,2,3,4-tetrahydroquinolin-6-yl)thiophene-2-carboximidamide (67 mg, 0.202 mmol, 22.80% yield).1NMR (DMSO-d6) δ 7.71 (d, J=3, 1H); 7.58 (d, J=5 Hz, 1H); 7.07 (dd, J=5 Hz, 3 Hz, 1H); 6.48-6.43 (m, 2H); 6.41 (brd, J=15 Hz, 1H); 6.34 (s, 1H); 3.09 (m, 4H); 2.73-2.64 (m, 4H); 2.31 (s, 3H); 1.77-1.72 (m, 2H). EI-MS (m/z, %): 332 (M+, 9), 288 (100).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][C:9]2[C:14]([C:15]=1[OH:16])=[CH:13][CH:12]=[C:11]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH:10]=2)=[O:5])[CH3:2].[Br:25]N1C(=O)CCC1=O>C(#N)C>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([Br:25])[C:9]2[C:14]([C:15]=1[OH:16])=[CH:13][CH:12]=[C:11]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH:10]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ncc2cc(OCc3ccccc3)ccc2c1O
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Product: CCOC(=O)c1nc(Br)c2cc(OCc3ccccc3)ccc2c1O
Temperature: 70 °C
Yield: 74.6 %

Procedure:
A suspension of 2.48 g (7.67 mmol) of 7-benzyloxy-4-hydroxy-isoquinoline-3-carboxylic acid ethyl ester and 1.43 g (8.0 mmol) of N-bromosuccinimide in 25 mL of acetonitrile was heated to 70° C. for ten minutes. The reaction was cooled and a white solid precipitated out of solution. The solid was collected by filtration through a medium glass fritted filter and washed with cold acetonitrile to give 2.3 g of the title compound; MS (ESI+): 402.2, 404.2 e/z (M+1, 79Br/81Br)
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[S:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13].C(OCC)C.[H-].[Na+].[CH2:24](Br)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>CN(C)C=O>[CH2:24]([N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[S:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: CCOC(=O)CSc1nc2ccccc2[nH]1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CCOC(=O)CSc1nc2ccccc2n1Cc1ccccc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 31 %

Procedure:
To a stirred solution of ethyl 2-(1H-benzo[d]imidazol-2-ylthio)acetate 4a (11.2 g, 47.6 mmol, 1.0 eq.) in 10:1 diethyl ether:dimethylformamide (450 mL) at 0° C., was added 60% sodium hydride in mineral oil (2.09 g, 52.3 mmol, 1.1 eq.), and the reaction was stirred at 0° C. for 20 minutes. Benzyl bromide (9.78 g, 57.1 mmol, 1.2 eq.) was added at 0° C., and the reaction was stirred with warming to room temperature for 16 hours. The reaction mixture was quenched with methanol (100 mL) and concentrated in vacuo. The residue was taken into hot chloroform (400 mL) and filtered. The filtrate was washed with water (200 mL), 1M HCl (200 mL) and brine (200 mL). The organic layer was dried over magnesium sulfate and concentrated in vacuo. Purification by flash chromatography (10% EtOAc:90% petroleum ether) gave 4b as a pale-yellow solid (4.82 g, 30%).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:19]([Cl:20])=[CH:18][C:17]([C:21](=[O:23])[CH3:22])=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.Cl>CCOC(C)=O>[ClH:20].[Cl:20][C:19]1[CH:18]=[C:17]([C:21](=[O:23])[CH3:22])[CH:16]=[N:15][C:14]=1[N:11]1[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1
Reactant: CC(=O)c1cnc(N2CCN(C(=O)OC(C)(C)C)CC2)c(Cl)c1
Agent: Cl
Solvent: CCOC(C)=O
Product: CC(=O)c1cnc(N2CCNCC2)c(Cl)c1

Procedure:
A mixture of 4-(5-acetyl-3-chloro-pyridin-2-yl)-piperazine-1-carboxylic acid tert-butyl ester from step (c) above (0.65 g, 1.92 mmol) and satd. solution of HCl in EtOAc (50 mL) was stirred at room temperature for 4 h. The solution was evaporated in vacuo to give the title compound as a white solid. MS (ESI, pos. ion) m/z: 240 (M+1).
Reaction SMILES: [N:1]([C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[C:6]([N+:11]([O-:13])=[O:12])[CH:5]=1)=[C:2]=[S:3].[CH3:14][C:15]1[CH:21]=[C:20]([CH3:22])[CH:19]=[C:18]([CH3:23])[C:16]=1[NH2:17]>CO>[C:15]1([CH3:14])[CH:21]=[C:20]([CH3:22])[CH:19]=[C:18]([CH3:23])[C:16]=1[NH:17][C:2]([NH:1][C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[C:6]([N+:11]([O-:13])=[O:12])[CH:5]=1)=[S:3]
Reactant: Cc1cc(C)c(N)c(C)c1
Reactant: Cc1ccc(N=C=S)cc1[N+](=O)[O-]
Solvent: CO
Product: Cc1cc(C)c(NC(=S)Nc2ccc(C)c([N+](=O)[O-])c2)c(C)c1
Yield: 71.4 %

Procedure:
A mixture of 4-isothiocyanato-1-methyl-2-nitrobenzene (500 mg, 2.58 mmol) and 2,4,6-trimethylaniline (0.329 ml, 2.34 mmol) in methanol (10 ml) was refluxed for 4 h. The solvent was evaporated under vacuum. The residue was triturated with ether. The resulting solid was collected by filtration to afford 550 mg of the title compound.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][C@@H:6]([CH2:8][CH2:9][CH2:10][CH:11]=[CH2:12])[O:5][C@:4]([C@@H:15]2[CH2:19][S:18][C:17](=[O:20])[N:16]2[CH2:21][C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=2)([O:13][CH3:14])[CH2:3]1.[CH3:30]/[C:31](/[CH2:36][CH2:37][CH:38]=[CH2:39])=[CH:32]/[C:33](O)=[O:34].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>ClCCl>[CH3:14][O:13][C@:4]1([C@@H:15]2[CH2:19][S:18][C:17](=[O:20])[N:16]2[CH2:21][C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=2)[CH2:3][C@H:2]([NH:1][C:33](=[O:34])/[CH:32]=[C:31](/[CH3:30])\[CH2:36][CH2:37][CH:38]=[CH2:39])[CH2:7][C@@H:6]([CH2:8][CH2:9][CH2:10][CH:11]=[CH2:12])[O:5]1
Reactant: C=CCCC[C@@H]1C[C@@H](N)C[C@](OC)([C@@H]2CSC(=O)N2Cc2ccc(OC)cc2)O1
Reactant: C=CCC/C(C)=C\C(=O)O
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: ClCCCl
Product: C=CCCC[C@@H]1C[C@@H](NC(=O)/C=C(/C)CCC=C)C[C@](OC)([C@@H]2CSC(=O)N2Cc2ccc(OC)cc2)O1
Temperature: 25 °C
Reaction time: 96 h
Yield: 66.6 %

Procedure:
A solution of the title compound from Example 67 (155 mg, 0.368 mmol) in dichloromethane (5 mL) was treated with the title compound from Example 21 (58 mg, 0.42 mmol), HOBT (65 mg, 0.42 mmol), and EDC (78 mg, 0.41 mmol), and the mixture was stirred at room temperature for 4 days. The mixture was then concentrated and the residue was chromatographed on silica, eluting with ethyl acetate/hexanes, which afforded the title compound (133 mg, 67%) as a crystalline solid.
Reaction SMILES: [CH3:1][C:2]1[C:7]([C:8](O)=[O:9])=[CH:6][C:5]([S:11]([N:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)(=[O:13])=[O:12])=[CH:4][C:3]=1[C:19]1[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=1.[CH3:26][C:27]1[N:32]=[CH:31][C:30]([C@H:33]([NH2:35])[CH3:34])=[CH:29][N:28]=1.F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH3:1][C:2]1[C:7]([C:8]([NH:35][C@@H:33]([C:30]2[CH:29]=[N:28][C:27]([CH3:26])=[N:32][CH:31]=2)[CH3:34])=[O:9])=[CH:6][C:5]([S:11]([N:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)(=[O:13])=[O:12])=[CH:4][C:3]=1[C:19]1[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=1
Reactant: Cc1ccc(-c2cc(S(=O)(=O)N3CCCC3)cc(C(=O)O)c2C)cc1
Reactant: Cc1ncc([C@@H](C)N)cn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(-c2cc(S(=O)(=O)N3CCCC3)cc(C(=O)N[C@H](C)c3cnc(C)nc3)c2C)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A reaction vial was charged with 2,4′-dimethyl-5-(pyrrolidin-1-ylsulfonyl)biphenyl-3-carboxylic acid (40 mg, 0.11 mmol), (R)-1-(2-methylpyrimidin-5-yl)ethanamine (20 mg, 0.14 mmol), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (106 mg, 0.28 mmol), N,N-diisopropylethylamine (39 μL, 0.22 mmol) and N,N-dimethylformamide (1.33 mL), and the reaction mixture was stirred at room temperature overnight. The reaction mixture was purified by preparative HPLC to afford the compound as a light brown solid.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=[C:5]([C:9]2[N:10]=[CH:11][C:12]([NH2:15])=[N:13][CH:14]=2)[CH:6]=[CH:7][CH:8]=1.N1C=CC=CC=1.[Cl:24][C:25]1[CH:26]=[CH:27][C:28]([N+:34]([O-:36])=[O:35])=[C:29]([CH:33]=1)[C:30](Cl)=[O:31]>ClCCl>[Cl:24][C:25]1[CH:26]=[CH:27][C:28]([N+:34]([O-:36])=[O:35])=[C:29]([CH:33]=1)[C:30]([NH:15][C:12]1[CH:11]=[N:10][C:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:1])([F:16])[F:17])[CH:4]=2)=[CH:14][N:13]=1)=[O:31]
Reactant: Nc1cnc(-c2cccc(C(F)(F)F)c2)cn1
Reactant: O=C(Cl)c1cc(Cl)ccc1[N+](=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(Nc1cnc(-c2cccc(C(F)(F)F)c2)cn1)c1cc(Cl)ccc1[N+](=O)[O-]

Procedure:
Into a 50-mL round-bottom flask, was placed a solution of 5-(3-(trifluoromethyl)phenyl)pyrazin-2-amine (1.3 g, 5.43 mmol, 1.00 equiv) in dichloromethane (15 mL), and pyridine (2 mL). This was followed by dropwise addition of a solution of 5-chloro-2-nitrobenzoyl chloride (1.2 g, 5.45 mmol, 1.00 equiv) in dichloromethane (5 mL) with stirring. The resulting solution was stirred for 2 h at 25° C. in an oil bath. The resulting solution was diluted with 100 mL of dichloromethane. The resulting mixture was washed with 2×50 mL of hydrogen chloride (aq), dried over anhydrous sodium sulfate, and concentrated under vacuum. This resulted in 2 g (87%) of 5-chloro-2-nitro-N-(5-(3-(trifluoromethyl)phenyl)pyrazin-2-yl)benzamide as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[Cl:10])[CH2:5][NH2:6].Cl[C:12]1[C:13]2[CH:26]=[C:25]([Cl:27])[S:24][C:14]=2[N:15]=[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)[N:17]=1>>[N:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[C:16]1[N:17]=[C:12]([NH:6][CH2:5][C:4]2[CH:7]=[CH:8][C:9]([Cl:10])=[C:2]([Cl:1])[CH:3]=2)[C:13]2[CH:26]=[C:25]([Cl:27])[S:24][C:14]=2[N:15]=1
Reactant: Clc1cc2c(Cl)nc(-c3ccccn3)nc2s1
Reactant: NCc1ccc(Cl)c(Cl)c1
Product: Clc1cc2c(NCc3ccc(Cl)c(Cl)c3)nc(-c3ccccn3)nc2s1

Procedure:
With the procedure of Example 1, the reaction of 3,4-dichlorobenzylamine with 4-chloro-2-(pyridin-2-yl)-6-chloro-thieno-[2,3-d]-pyrimidine yields 2-(pyridin-2-yl)-4-(3,4-dichlorobenzylamino)-6-chloro-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[Al+3].[Cl-].[Cl-].[Cl-].[Cl:15][C:16]1[C:21]([Cl:22])=[CH:20][CH:19]=[CH:18][C:17]=1[O:23][CH3:24].Cl>ClCCCl>[F:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](=[O:5])[C:20]1[CH:19]=[CH:18][C:17]([O:23][CH3:24])=[C:16]([Cl:15])[C:21]=1[Cl:22]
Reactant: O=C(Cl)c1ccccc1F
Reactant: COc1cccc(Cl)c1Cl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: COc1ccc(C(=O)c2ccccc2F)c(Cl)c1Cl
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of 31.55 g of o-fluorobenzoyl chloride in 100 ml 1,2-dichloroethane, 26.54 g of AlCl3 was added over a 30 minute period. A solution of 32 g of 2,3-dichloroanisole in 50 ml of 1,2-dichloroethane was added dropwise. There was an evolution of gas and the temperature rose to 35°. The mixture was stirred 2 hours and then poured overa mixture of 100 ml concentrated HCl and 100 ml ice. The organic solvent was evaporated in vacuo and the mixture extracted with ether. The ether extract was washed with 10% K2CO3, washed withwater, and dried over Na2SO4, and the ether was evaporated to give a solid. Recrystallization of the solid from the ether-hexane mixturegave 38.69 g (70%) of 2'-fluoro-4-methoxy-2,3-dichlorobenzophenone, m.p. 74°-77°.
Reaction SMILES: [N+:1](=[C:3](C=O)[CH:4]=O)=[N-:2].[Cl-].[CH3:9][O:10][C:11]1[CH:12]=[C:13]([CH:15]=[CH:16][C:17]=1[O:18][CH3:19])[NH2:14]>>[CH3:9][O:10][C:11]1[CH:12]=[C:13]([N:14]2[CH:4]=[CH:3][N:1]=[N:2]2)[CH:15]=[CH:16][C:17]=1[O:18][CH3:19]
Reactant: COc1ccc(N)cc1OC
Reactant: [N-]=[N+]=C(C=O)C=O
Agent: [Cl-]
Product: COc1ccc(-n2ccnn2)cc1OC

Procedure:
The derivative (114m) was prepared with 80.0% of output, as of the reaction of diazomalonaldehyde with the 3,4-dimethoxyaniline chloride, thus obtaining an amorphous yellow solid with fusion point at 170.0-171.0° C.
Reaction SMILES: CON(CC)[C:4](=[O:21])[CH2:5][CH:6]1[CH2:11][CH2:10][N:9]([CH2:12][C:13]2[C:14]([O:19][CH3:20])=[N:15][CH:16]=[CH:17][CH:18]=2)[CH2:8][CH2:7]1.[S:24]1[CH:28]=[CH:27][CH:26]=[C:25]1[Li].[Cl-].[NH4+]>O1CCCC1>[CH3:20][O:19][C:14]1[C:13]([CH2:12][N:9]2[CH2:8][CH2:7][CH:6]([CH2:5][C:4](=[O:21])[C:25]3[S:24][CH:28]=[CH:27][CH:26]=3)[CH2:11][CH2:10]2)=[CH:18][CH:17]=[CH:16][N:15]=1
Reactant: [Li]c1cccs1
Reactant: CCN(OC)C(=O)CC1CCN(Cc2cccnc2OC)CC1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1ncccc1CN1CCC(CC(=O)c2cccs2)CC1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
0.50 g of N1-methoxy,N1-ethyl-2-[1-[(2-methoxy-3-pyridyl)methyl]-4-piperidyl]acetamide obtained in Example 55 was dissolved in 3 ml of tetrahydrofuran and 1.8 ml of a 1.0M (2-thienyl)-lithium in tetrahydrofuran was added dropwise thereinto at −78° C. After completion of the dropwise addition, the mixture was further stirred at −78° C. for 1 hour. An aqueous saturated ammonium chloride was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, and then dried over anhydrous magnesium sulfate. The solvent was evaporated, and the crude product was purified by silica gel column chromatography (ethyl acetate), to give 0.22 g of the title compound as a pale yellow oil. The NMR spectrum data of the title compound were agreed with those of Example 54.
Reaction SMILES: [C:1]([C:3]1[N:7]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:9]=2[C:15]([F:18])([F:17])[F:16])[N:6]=[CH:5][C:4]=1[C:19]([O:21]CC)=O)#[N:2].[CH3:24][NH2:25]>CN(C=O)C>[C:1]([C:3]1[N:7]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:9]=2[C:15]([F:17])([F:18])[F:16])[N:6]=[CH:5][C:4]=1[C:19]([NH:25][CH3:24])=[O:21])#[N:2]
Reactant: CN
Reactant: CCOC(=O)c1cnn(-c2ccc(Cl)cc2C(F)(F)F)c1C#N
Solvent: CN(C)C=O
Product: CNC(=O)c1cnn(-c2ccc(Cl)cc2C(F)(F)F)c1C#N
Temperature: 0 °C

Procedure:
A solution of 1.23 g of 5-cyano-1-[2-(trifluoromethyl)-4-chlorophenyl]-1H-pyrazole-4-carboxylic acid, ethyl ester and 8 ml of 40% aqueous monomethylamine in 20 ml of DMF was stirred at approximately 25° C. for 16 hours. The reaction mixture was poured into 150 ml of ice water and the precipitated solid was collected by filtration. The isolated material was recrystallized from ethanol to provide 535 mg of 5-cyano-1-[2-(trifluoromethyl)-4-chlorophenyl]-N-methyl-1H-pyrazole-4-carboxamide. MP=162.5°-164° C.