Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([NH2:22])([CH3:21])[C:3]1[CH:8]=[CH:7][C:6]([C:9]([F:20])([F:19])[C:10]([F:18])([F:17])[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:5][CH:4]=1.[S:23]([CH2:27][CH2:28][OH:29])([OH:26])(=[O:25])=[O:24]>C(O)(C)C>[CH3:21][C:2]([NH2:22])([CH3:1])[C:3]1[CH:8]=[CH:7][C:6]([C:9]([F:19])([F:20])[C:10]([F:17])([F:18])[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:5][CH:4]=1.[S:23]([CH2:27][CH2:28][OH:29])([O-:26])(=[O:25])=[O:24]
Reactant: O=S(=O)(O)CCO
Agent: CC(C)(N)c1ccc(C(F)(F)C(F)(F)c2ccccc2)cc1
Solvent: CC(C)O
Product: O=S(=O)([O-])CCO

Procedure:
α,α-Dimethyl-4-(α,α,β,β-tetrafluorophenethyl)-benzylamine, 4.1 g. (0.0132 mole), was dissolved in 20 ml. of isopropyl alcohol and the solution treated with 3.7 ml. of 3.8M isethionic acid. Crystallization of the isethionate started after dilution with 400 ml. of absolute ether. The product was collected after several hours at room temperature, washed with absolute ether, and dissolved in 300 ml. of benzene. Water was removed azeotropically by distilling 200 ml. of benzene. The product was precipitated from the residual solution by dilution with 200 ml. of absolute ether; 5.8 g., m.p. 134.5°-136°. Recrystallization from 50 ml. of isopropyl alcohol - 200 ml. of absolute ether gave m.p. 135°-136.5°.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:25]([O:27]CC)=O)[C:5]2[C:6](=O)[CH:7]([C:18]3[N:19]([CH3:23])[CH:20]=[CH:21][N:22]=3)[CH:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[NH:9][C:10]=2[CH:11]=1.O.[NH2:31][NH2:32]>CO>[Cl:1][C:2]1[CH:11]=[C:10]2[NH:9][CH:8]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:7]([C:18]3[N:19]([CH3:23])[CH:20]=[CH:21][N:22]=3)[C:6]3=[N:31][NH:32][C:25](=[O:27])[C:4]([CH:3]=1)=[C:5]23
Reactant: CCOC(=O)c1cc(Cl)cc2c1C(=O)C(c1nccn1C)C(c1ccccc1)N2
Reactant: NN
Solvent: O
Solvent: CO
Product: Cn1ccnc1C1c2n[nH]c(=O)c3cc(Cl)cc(c23)NC1c1ccccc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 14 %

Procedure:
To a solution of ethyl 7-chloro-3-(1-methyl-1H-imidazol-2-yl)-4-oxo-2-phenyl-1,2,3,4-tetrahydroquinoline-5-carboxylate (429 mg, 1.05 mmol) in methanol (15 mL) was added hydrazine monohydrate (2 mL). The mixture was stirred at 25° C. for 5 hr. The resulting mixture was concentrated under reduced pressure to a volume of 10 ml and then filtered, giving 58 mg of solid (yield 14%). LC-MS (ESI) m/z: 378 (M+1)+; 379 (M+2)+. 1H-NMR (400 MHz, DMSO-d6) δ (ppm): 3.42 (s, 3H), 4.69 (d, J=10.0 Hz, 1H), 4.98 (d, J=10.4 Hz, 1H), 5.76 (s, 1H), 6.73 (s, 1H), 6.89 (s, 1H), 7.14 (s, 1H), 7.27 (dd, 4H), 7.38 (d, J=6.4 Hz, 2H), 7.62 (s, 1H), 12.36 (s, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:38])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:27]=[C:26]([CH2:28][OH:29])[CH:25]=[C:24]([Br:30])[CH:23]=2)[C:10]=1[CH2:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH3:2].I[CH2:40][CH3:41].[H-].[Na+]>CN(C)C=O.O.[Cl-].[Na+].O>[CH2:1]([O:3][C:4](=[O:38])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:27]=[C:26]([CH2:28][O:29][CH2:40][CH3:41])[CH:25]=[C:24]([Br:30])[CH:23]=2)[C:10]=1[CH2:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH3:2]
Reactant: CCI
Reactant: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(Br)cc(CO)c2)c1CCC(=O)OCC
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOCc1cc(Br)cc(OCCCCCCc2cccc(OCCCC(=O)OCC)c2CCC(=O)OCC)c1
Reaction time: 5 h
Yield: 52.7 %

Procedure:
To a solution of 4-[3-[6-(3-bromo-5-hydroxymethyl-phenoxy)-hexyl]-2-(2-ethoxycarbonyl-ethyl)-phenoxy]-butyric acid ethyl ester (1.0 g, 1.68 mmol) in N,N-dimethylformamide (10 mL) was added iodoethane (403 μL, 5.04 mmol) and sodium hydride, 60% dispersion in mineral oil (202 mg. 5.04 mmol) at room temperature. The resulting suspension was stirred for 5 h. Then, the reaction mixture was diluted with water and brine. The organic compound was extracted into ethyl acetate and the combined organic extracts were washed with brine solution. The organic layers were dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure. The crude material was purified by column chromatography (Isco™ 40 g) with 0-30% ethyl acetate/hexanes as eluting solvents to afford the title compound (550 mg, 53%) as a colorless oil.
Reaction SMILES: C[O:2][C:3](=[O:29])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][N:11]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[N:13]([CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[Cl:27])[C:12]1=[O:28].[OH-].[Na+]>>[Cl:27][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[CH2:20][N:13]1[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[N:11]([CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][C:3]([OH:29])=[O:2])[C:12]1=[O:28]
Reactant: COC(=O)CCCCCCCn1c(=O)n(Cc2ccccc2Cl)c2ccccc21
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)CCCCCCCn1c(=O)n(Cc2ccccc2Cl)c2ccccc21

Procedure:
The product is produced as described in example 22 from 6.4 g. of 8-[3-(2-chlorobenzyl)-2-oxo-benzimidazolin-1-yl]-caprylic acid methyl ester and 1.2 g. of sodium hydroxide.
Reaction SMILES: [O-]P([O-])([O-])=O.[K+].[K+].[K+].[CH2:9]([NH2:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.I[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[CH3:24].C(O)CO>[Cu]I.CCCCCC.C(OCC)(=O)C.C(O)CCC>[C:19]1([CH3:24])[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[NH:16][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: Cc1ccccc1I
Reactant: NCc1ccccc1
Agent: [Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CCCCO
Solvent: OCCO
Solvent: CCCCCC
Product: Cc1ccccc1NCc1ccccc1
Yield: 68.9 %

Procedure:
The general procedure under argon was followed using copper(I) iodide (19 mg, 0.10 mmol), K3PO4 (425 mg, 2.00 mmol), benzylamine (131 μL, 1.20 mmol), 2-Iodotoluene (127 μl, 1.00 mmol), ethylene glycol (111 mL, 2.00 mmol) and 1-butanol (1.0 mL) at 100° C. Column chromatography using a solvent mixture (hexane/ethyl acetate=20/1, Rf=0.5) afforded N-(2-tolyl)benzylamine (136 mg, 69% isolated yield) as colorless liquid. The spectral data (1H NMR) matched with the literature references and GC analysis indicated >95% purity. See Maccarone, E.; Mamo, A.; Torre, M. J. Org. Chem. 1979, 44, 1143-1146.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][C:9](Cl)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=[O:26])[CH2:20][CH2:21][C:22]([O:24]C)=[O:23])=[CH:15][CH:14]=1>>[O:26]=[C:19]([C:16]1[CH:15]=[CH:14][C:13]([NH:12][C:9](=[O:10])[CH2:8][CH2:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[CH:18][CH:17]=1)[CH2:20][CH2:21][C:22]([OH:24])=[O:23]
Reactant: COC(=O)CCC(=O)c1ccc(N)cc1
Reactant: O=C(Cl)CCc1ccccc1
Product: O=C(O)CCC(=O)c1ccc(NC(=O)CCc2ccccc2)cc1
Yield: 73.8 %

Procedure:
In a manner similar to that described in Example 3, 3-phenyl-propionyl chloride (0.057 g, 0.00034 mol) was allowed to react with 4-(4-amino-phenyl)-4-oxo-butyric acid, methyl ester (0.052 g, 0.00025 mol), and the resulting intermediate was hydrolyzed to give 0.060 g of 4-oxo-4-[4-(3-phenyl-propionylamino)-phenyl]-butyric acid as an off-white solid; MS-(AP+) MH+326.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:13]=[C:12]([NH:14][C:15]([C:17]2[N:18]([CH3:27])[N:19]=[C:20]([C:23]([CH3:26])([CH3:25])[CH3:24])[C:21]=2[Cl:22])=O)[C:11]([N+:28]([O-])=O)=[CH:10][CH:9]=1>C(O)(=O)C.[Fe]>[C:23]([C:20]1[C:21]([Cl:22])=[C:17]([C:15]2[NH:28][C:11]3[C:12]([N:14]=2)=[N:13][C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])=[CH:9][CH:10]=3)[N:18]([CH3:27])[N:19]=1)([CH3:26])([CH3:25])[CH3:24]
Reactant: Cn1nc(C(C)(C)C)c(Cl)c1C(=O)Nc1nc(-c2ccccc2Cl)ccc1[N+](=O)[O-]
Agent: [Fe]
Solvent: CC(=O)O
Product: Cn1nc(C(C)(C)C)c(Cl)c1-c1nc2nc(-c3ccccc3Cl)ccc2[nH]1
Temperature: 100 °C
Reaction time: 0.17 h

Procedure:
A solution of 5-tert-butyl-4-chloro-2-methyl-2H-pyrazole-3-carboxylic acid [6-(2-chloro-phenyl)-3-nitro-pyridin-2-yl]-amide (157 mg, 0.350 mmol, prepared as described in the previous step) in acetic acid (5 mL) was treated with iron powder (97.8 mg, 1.75 mmol) and heated to 100° C. for 3 h. The cooled mixture then was concentrated in vacuo, taken up in water (50 mL) and extracted twice with EtOAc (50 mL). The combined extracts were dried over MgSO4 and concentrated in vacuo. The residue was purified on a 12-g SEPRA Si 50 SPE column (Isco system: Flow rate=15 mL/min; Eluent=EtOAc/hexanes, 1:99 v/v for 10 min, then 1:99 to 3:17 v/v over 40 min) to yield 2-(5-tert-butyl-4-chloro-2-methyl-2H-pyrazol-3-yl)-5-(2-chloro-phenyl)-1H-imidazo[4,5-b]pyridine as a white solid. Mass Spectrum (LCMS, APCI pos.): Calculated for C20H19Cl2N5: 400.1 (M+H); Measured: 400.2.
Reaction SMILES: [CH3:1][S:2][C:3]1[N:11]=[C:10]2[C:6]([NH:7][CH:8]=[N:9]2)=[C:5](Cl)[N:4]=1.[NH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(N(CC)CC)C>C(O)CCC>[CH3:1][S:2][C:3]1[N:11]=[C:10]2[C:6]([NH:7][CH:8]=[N:9]2)=[C:5]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:4]=1
Reactant: Nc1ccccc1
Reactant: CSc1nc(Cl)c2[nH]cnc2n1
Solvent: CCN(CC)CC
Solvent: CCCCO
Product: CSc1nc(Nc2ccccc2)c2[nH]cnc2n1
Reaction time: 8 h

Procedure:
2-methylthio-6-chloropurine (10 g, 50 mmol), aniline (7.7 g, 63 mmol) and triethylamine (35 ml, 250 mmol) were refluxed in butanol (400 ml) for 2 h. Butanol was removed in vacuo and water (290 ml) added to the cooled residue. pH was adjusted to 8.0, the mixture was left at −16° C. overnight. Filtration and drying over phosphorus pentoxide in vacuo gave 10 g crude yellow-green product. The product was chromatographically purified (250 g silica, Fisons, chloroform); eluted with chloroform/methanol (97/3, v/v). Appropriate fractions were dried in vacuo, re-crystallised from ethanol with decolourisation by active carbon. After drying to constant weight over P2O5, yield 5.76 g, (46%), HPLC purity >98%. TLC: chloroform/methanol (9/1, v/v), no contaminants.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:28]=[CH:27][C:8]2[N:9]=[C:10]([C:12]3[CH:26]=[CH:25][C:15]([CH2:16]P(=O)(OCC)OCC)=[CH:14][CH:13]=3)[S:11][C:7]=2[CH:6]=1.[Cl:29][C:30]1[CH:37]=[CH:36][C:33]([CH:34]=O)=[CH:32][C:31]=1[N+:38]([O-:40])=[O:39]>C1COCC1>[Cl:29][C:30]1[CH:37]=[CH:36][C:33]([CH:34]=[CH:16][C:15]2[CH:14]=[CH:13][C:12]([C:10]3[S:11][C:7]4[CH:6]=[C:5]([O:4][CH3:3])[CH:28]=[CH:27][C:8]=4[N:9]=3)=[CH:26][CH:25]=2)=[CH:32][C:31]=1[N+:38]([O-:40])=[O:39]
Reactant: O=Cc1ccc(Cl)c([N+](=O)[O-])c1
Reactant: CCOP(=O)(Cc1ccc(-c2nc3ccc(OC)cc3s2)cc1)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc2nc(-c3ccc(C=Cc4ccc(Cl)c([N+](=O)[O-])c4)cc3)sc2c1
Yield: 46.4 %

Procedure:
Prepared as described in the Alkene Formation section using sodium hydride (60% dispersion in mineral oil, 0.077 g, 1.92 mmol), diethyl 4-(6-methoxybenzothiazol-2-yl)benzylphosphonate (0.5 g, 1.28 mmol) and 4-chloro-3-nitrobenzaldehyde (0.26 g, 1.41 mmol) in dry THF (20 ml) to give the title compound (0.251 g, 46%) as pale orange needles after work-up and recrystallisation from 1,2-dichloroethane.
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][N:21]=[CH:20][CH:19]=2)[N:17]=1>>[N:21]1[CH:20]=[CH:19][C:18]([C:16]2[N:17]=[C:12]([NH:6][CH2:5][C:4]3[CH:7]=[CH:8][C:9]([Cl:10])=[C:2]([Cl:1])[CH:3]=3)[C:13]3[CH:26]=[C:25]([Cl:27])[S:24][C:14]=3[N:15]=2)=[CH:23][CH:22]=1
Reactant: NCc1ccc(Cl)c(Cl)c1
Reactant: Clc1cc2c(Cl)nc(-c3ccncc3)nc2s1
Product: Clc1cc2c(NCc3ccc(Cl)c(Cl)c3)nc(-c3ccncc3)nc2s1

Procedure:
With the procedure of Example 1, the reaction of 3,4-dichlorobenzylamine with 4-chloro-2-(pyridin-4-yl)-6-chloro-thieno-[2,3-d]-pyrimidine yields 2-(pyridin-4-yl)-4-(3,4-dichlorobenzylamino)-6-chloro-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH3:28])[CH2:10][CH2:11][N:12]1[CH2:17][CH2:16][N:15](C(OCC2C=CC=CC=2)=O)[CH2:14][CH2:13]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>C(O)C.[C].[Pd]>[CH3:28][C@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[CH2:10][CH2:11][N:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1
Reactant: C[C@@H](CCN1CCN(C(=O)OCc2ccccc2)CC1)NC(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CCO
Product: C[C@@H](CCN1CCNCC1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of benzyl 4-{(3S)-3-[(tert-butoxycarbonyl)amino]butyl}piperazine-1-carboxylate (1.10 g) in ethanol (10 mL) was added 10% palladium carbon (1.50 g), and the mixture was stirred at room temperature for 30 min under a hydrogen atmosphere. The reaction mixture was filtered, and the filtrate was evaporated under reduced pressure to give tert-butyl [(1S)-1-methyl-3-(piperazin-1-yl)propyl]carbamate. By a method similar to Example 1, steps F to H, and using the obtained compound, the title compound was obtained.
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:4]=[C:5]([OH:10])[CH:6]=[C:7]([CH3:9])[CH:8]=1.[N:11]([O-])=[O:12].[Na+]>C(O)C.O>[CH3:2][C:3]1[CH:4]=[C:5]([OH:10])[CH:6]=[C:7]([CH3:9])[C:8]=1[N:11]=[O:12]
Reactant: Cc1cc(C)cc(O)c1
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Cc1cc(O)cc(C)c1N=O
Temperature: 0 °C
Yield: 71.6 %

Procedure:
750 ml of concentrated HCl are added to a solution of 3,5-dimethyl phenol (80.6 g) in 750 ml of 95% ethyl alcohol. The mixture is cooled to 0° C. in an ice/methanol bath. While maintaining the temperature of the reaction mixture below 5° C., a solution of NaNO2 (69.0 g) in 150 ml of H2O is added dropwise to the reaction mixture. The mixture is stirred at 0° C. for more than an hour and then poured into 9 liters of water. The aqueous mixture is filtered to give a yellow solid which is recrystallized from hot methanol and filtered to give 71.45 grams of a yellow solid, M.P. 180°-181° C. (dec.).
Reaction SMILES: [Cl-].[CH:2]1([C:6]2[S:7][CH:8]=[C:9]([CH2:11][P+](C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[N:10]=2)[CH2:5][CH2:4][CH2:3]1.[H-].[Na+].[N+:33]([C:36]1[CH:37]=[C:38]([CH:41]=[CH:42][CH:43]=1)[CH:39]=O)([O-:35])=[O:34]>O1CCCC1.C(Cl)Cl>[CH:2]1([C:6]2[S:7][CH:8]=[C:9](/[CH:11]=[CH:39]/[C:38]3[CH:41]=[CH:42][CH:43]=[C:36]([N+:33]([O-:35])=[O:34])[CH:37]=3)[N:10]=2)[CH2:3][CH2:4][CH2:5]1
Reactant: c1ccc([P+](Cc2csc(C3CCC3)n2)(c2ccccc2)c2ccccc2)cc1
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: O=[N+]([O-])c1cccc(/C=C/c2csc(C3CCC3)n2)c1
Yield: 70.4 %

Procedure:
A slurry of 1.8 g of [(2-cyclobutyl-4-thiazolyl)methyl] triphenylphosphonium chloride, in 80 ml of tetrahydrofuran was sealed under a positive argon atmosphere and the mixture cooled with an ice bath. Sodium hydride (0.2 g; 50% oil dispersion) was added and stirring and cooling continued for 30 min afterwhich 0.6 g of 3-nitrobenzaldehyde was added. The cooling bath was removed and the mixture was stirred at room temperature for 1 hr. The mixture was then filtered, condensed in vacuo and the residual materials taken up in 100 ml of methylene chloride. This solution was then washed with water, dried (MgSO4) and condensed in vacuo to yield 0.8 g of (E)-2-cyclobutyl-4-[2-(3-nitrophenyl)ethenyl]thiazole; m.p. 112°-115° C.
Reaction SMILES: Br[C:2]1[S:3][C:4]2[CH:10]=[C:9]([C:11]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH3:23])[CH:15]=3)=[O:12])[CH:8]=[CH:7][C:5]=2[N:6]=1.[C:24]([N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1)([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25].C(N(C(C)C)CC)(C)C>CN1CCCC1=O.O>[CH3:23][O:22][C:16]1[CH:15]=[C:14]([NH:13][C:11]([C:9]2[CH:8]=[CH:7][C:5]3[N:6]=[C:2]([N:34]4[CH2:33][CH2:32][N:31]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:36][CH2:35]4)[S:3][C:4]=3[CH:10]=2)=[O:12])[CH:19]=[CH:18][C:17]=1[O:20][CH3:21]
Reactant: COc1ccc(NC(=O)c2ccc3nc(Br)sc3c2)cc1OC
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Solvent: O
Product: COc1ccc(NC(=O)c2ccc3nc(N4CCN(C(=O)OC(C)(C)C)CC4)sc3c2)cc1OC
Reaction time: 18 h

Procedure:
2-Bromo-N-(3,4-dimethoxyphenyl)benzo[d]thiazole-6-carboxamide (612.2 mg, 1.56 mmol), N-Boc piperazine (300.8 mg, 1.61 mmol) and diisopropylethylamine (0.3 mL, 1.72 mmol) in N-methyl-2-pyrrolidinone (5.5 mL) was stirred at 120° C. (oil bath) for 4 h, then at room temperature for 18 h. The resulting mixture was diluted with water and the solid separated from the solution. The solid was collected by filtration, dissolved in ethyl acetate, washed with water (2×), then dried, filtered and concentrated. The resulting residue was purified by flash chromatography, eluting with 5% methanol in chloroform to yield tert-butyl 4-(6-(3,4-dimethoxyphenylcarbamoyl)benzo[d]thiazol-2-yl)piperazine-1-carboxylate as a brown glassy solid.
Reaction SMILES: [NH2:1][N:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][C:5](=[O:12])[N:4]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([CH:20](OCC)OCC)[CH:14]=2)[C:3]1=[O:27].[CH2:28]([SH:32])[CH:29]([SH:31])[CH3:30]>C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC=CC=1>[NH2:1][N:2]1[C:7]([C:8]([F:9])([F:10])[F:11])=[CH:6][C:5](=[O:12])[N:4]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([CH:20]3[S:31][CH:29]([CH3:30])[CH2:28][S:32]3)[CH:14]=2)[C:3]1=[O:27]
Reactant: CC(S)CS
Reactant: CCOC(OCC)c1cc(-n2c(=O)cc(C(F)(F)F)n(N)c2=O)ccc1Cl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CC1CSC(c2cc(-n3c(=O)cc(C(F)(F)F)n(N)c3=O)ccc2Cl)S1
Yield: 81.2 %

Procedure:
2.5 g (6.1 mmol) of 1-amino-3-(4-chloro-3-diethoxymethyl-phenyl)-2,4-dioxo-6-trifluoromethyl-1,2,3,4-tetrahydropyrimidine, 2.0 g (18 mmol) of 1,2-propanedithiol and 50 mg of p-toluenesulfonic acid were refluxed in 100 mi of anhydrous toluene for six hours. After cooling, the mixture was washed with 10% strength sodium hydrogen carbonate solution and water, dried over sodium sulfate, concentrated and dried for 48 hours at reduced pressure. 2.1 g (80%) of a colorless oil were thus obtained, which is a 1:1 mixture of the two diastereomers.
Reaction SMILES: [N+:1]([C:4]1[C:10]([CH2:11][CH3:12])=[C:9]([N+:13]([O-:15])=[O:14])[CH:8]=[C:7]([CH3:16])[C:5]=1[NH2:6])([O-])=O.[S-2].[Na+].[Na+]>>[NH2:6][C:5]1[C:7]([CH3:16])=[CH:8][C:9]([N+:13]([O-:15])=[O:14])=[C:10]([CH2:11][CH3:12])[C:4]=1[NH2:1]
Reactant: CCc1c([N+](=O)[O-])cc(C)c(N)c1[N+](=O)[O-]
Agent: [Na+]
Agent: [S-2]
Product: CCc1c([N+](=O)[O-])cc(C)c(N)c1N

Procedure:
2,4-Dinitro-3-ethyl-6-methylaniline (see Example 2) is treated with sodium sulfide to afford 1,2-diamino-3-ethyl-6-methyl-4-nitrobenzene. Treatment with cyanogen bromide affords to 2-amino-4-ethyl-7-methyl-5-nitrobenzimidazole. This is converted to 2-diazo-4-ethyl-7-methyl-5-nitrobenzimidazole tetrafuoroborate with sodium nitrite and tetrafluoroboric acid. Thermal decomposition of the diazonium salt gives 4-ethyl-2-fluoro-7-methyl-5-nitrobenzimidazole. Conversion to 4-ethyl-2-fluoro-5-(2-imidazolinylamino)benzimidazole is completed according to Scheme 5.
Reaction SMILES: [OH-].[Na+].[F:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1.[CH2:14]([CH:16]1[O:18][CH2:17]1)Cl.CCOC(C)=O>O>[F:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH:16]2[CH2:17][O:18]2)=[CH:9][CH:8]=1
Reactant: ClCC1CO1
Reactant: Oc1ccc(OCCF)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Product: FCCOc1ccc(OCC2CO2)cc1
Temperature: 100 °C
Yield: 48 %

Procedure:
A solution of NaOH (0.35 g) in 10 mL of water was added to a mixture of 4-(2-f luoroethoxy) phenol (1.10 g, 7.1 mmol) and epichlorohydrin (0.80 mL, 10.2 mmol). The mixture was heated at 100° C. for 3 h. After cooling, the mixture is taken up with AcOEt (50 mL). The organic phase was separated, washed with brine, dried over Na2SO4 and evaporated under reduced pressure. The crude residue was chromatographed (Petroleum ether/AcOEt, 4:1, as eluent) to afford pure compound in 48% yield. 1H NMR (CDCl3): δ 2.60-2.70 (m, 2H), 3.16 (m, 1H), 3.89-4.04 (m, 2H), 4.17-4.28 (m, 1H), 4.50-4.65 (m, 1H), 6.54 -6.60 (m, 2H), 6.84-6.87 (m, 2H).
Reaction SMILES: [CH2:1]([C:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([OH:14])=[O:13])=[CH:9][CH:10]=2)[NH:5][N:4]=1)[CH3:2].N1C2C(=CC=CC=2)[CH:17]=N1.CO>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH2:1]([C:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([O:14][CH3:17])=[O:13])=[CH:9][CH:10]=2)[NH:5][N:4]=1)[CH3:2]
Reactant: CCc1n[nH]c2cc(C(=O)O)ccc12
Reactant: c1ccc2[nH]ncc2c1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CO
Product: CCc1n[nH]c2cc(C(=O)OC)ccc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1.35 g (7.1 mmol) of 3-ethyl-1H-indazol-6-yl-carboxylic acid, [Marfat, A., et al., “Indazole Derivatives and Their Use as Inhibitors of Phosphodiesterase Type IV and the Production of Tumor Necrosis Factor TNF, U.S. Pat. No. 6,262,040], 2.9 mL (71 mmol) of methanol, and 0.95 g (7.8 mmol) of DMAP in 60 mL of CH2Cl2 was added 1.5 g (7.8 mmol) of EDCl—nHCl. This mixture was stirred at room temperature overnight, concentrated and the residue dissolved in 50 mL of ethyl acetate. The organic layer was successively washed with 40 mL of 1N HCl, 40 mL of water and 40 mL of brine, dried (Na2SO4), and concentrated. The residue was purified by chromatography over silica gel using a gradient of 35% to 50% ethyl acetate in hexanes over 20 minutes as eluant to yield 860 mg (4.2 mmol) of methyl 3-ethyl-1H-indazol-6-yl-carboxylate. 1H-NMR (CDCl3) δ 11.7 (s, 1H), 8.18 (s, 1H), 7.73 (apparent q, 9.0 Hz, 2H), 3.94 (s, 3H), 3.03 (q, 7.5 Hz, 2H), 1.42 (t, 7.5 Hz, 3H).
Reaction SMILES: Br[C:2]1[C:3]2[N:4]([N:8]=[C:9]([Cl:11])[N:10]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:12][S:13]([C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][CH:23]=1)[CH2:19][NH2:20])(=[O:15])=[O:14]>>[Cl:11][C:9]1[N:10]=[C:3]2[C:2]([NH:20][CH2:19][C:18]3[CH:21]=[CH:22][CH:23]=[C:16]([S:13]([CH3:12])(=[O:15])=[O:14])[CH:17]=3)=[CH:7][CH:6]=[CH:5][N:4]2[N:8]=1
Reactant: Clc1nc2c(Br)cccn2n1
Reactant: CS(=O)(=O)c1cccc(CN)c1
Product: CS(=O)(=O)c1cccc(CNc2cccn3nc(Cl)nc23)c1

Procedure:
3-Methanesulfonyl-benzylamine was prepared from 3-methanesulfonyl-benzonitrile (0.984 g, 5.43 mmol) in a manner analogous to Example 156b. Product isolated as a pale yellow oil (0.946 g, 94%). 1H NMR (400 MHz, CDCl3, δ, ppm): 7.93 (s, 1H), 7.83 (d, J=7.7 Hz, 1H), 7.64 (d, J=7.6 Hz, 1H), 7.54 (t, J=7.7 Hz, 1H), 4.00 (s, 2H), 3.06 (s, 3H). MS=186 (MH)+. 160 b) (2-Chloro-[1,2,4]triazolo[1,5-a]pyridin-8-yl)-(3-methanesulfonyl-benzyl)-amine was prepared from 8-bromo-2-chloro-[1,2,4]triazolo[1,5-a]pyridine (500.0 mg, 2.151 mmol) and 3-methanesulfonyl-benzylamine (450.0 mg, 2.429 mmol) in a manner analogous to Example 2d. Product isolated as a pale yellow solid (0.429 g, 59%). 1H NMR (400 MHz, CDCl3, δ, ppm): 7.97 (s, 1H), 7.93-7.87 (m, 2H), 7.68 (d, J=7.7 Hz, 1H), 7.58 (t, J=7.7 Hz, 1H), 6.85 (t, J=7.4 Hz, 1H), 6.35 (d, J=7.8 Hz, 1H), 5.51-5.44 (m, 1H), 4.59 (d, J=5.8 Hz, 2H), 3.07 (s, 3H). MS=337, 339 (MH)+. 160 c) N(8)-(3-Methanesulfonyl-benzyl)-N(2)-[4-(4-methyl-piperazin-1-yl)-phenyl]-[1,2,4]triazolo[1,5-a]pyridine-2,8-diamine was prepared from (2-chloro-[1,2,4]triazolo[1,5-a]pyridin-8-yl)-(3-methanesulfonyl-benzyl)-amine (75.0 mg, 0.223 mmol) and 4-(4-methyl-piperazin-1-yl)-phenylamine (47.0 mg, 0.246 mmol) with 2,2′-bis-dicyclohexylphosphanyl-biphenyl (23.0 mg, 0.0421 mmol) as the ligand in a manner analogous to Example 2d. Product isolated as a brown lyophilate as the trifluoroacetic acid salt (0.004 g, 4%). 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 9.50 (br s, 1H), 9.17 (s, 1H), 7.98-7.93 (m, 2H), 7.81 (d, J=8.0 Hz, 1H), 7.74 (d, J=7.8 Hz, 1H), 7.65-7.59 (m, 3H), 6.96 (d, J=8.9 Hz, 2H), 6.70 (t, J=7.5 Hz, 1H), 6.64 (br s, 1H), 6.32 (d, J=7.6 Hz, 1H), 4.65-4.60 (m, 2H), 3.72-3.65 (m, 2H), 3.23-3.13 (m, 6H), 2.92-2.82 (m, 6H). MS=492 (MH)+.