Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][CH2:5][CH2:6][S:7][C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1.C(N(CC)CC)C.[CH2:21]([CH:23]([CH2:27][CH2:28][CH2:29][CH3:30])[C:24]([Cl:26])=[O:25])[CH3:22]>C(Cl)Cl>[ClH:26].[CH2:21]([CH:23]([CH2:27][CH2:28][CH2:29][CH3:30])[C:24]([NH:3][CH2:4][CH2:5][CH2:6][S:7][C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1)=[O:25])[CH3:22]
Reactant: NCCCSc1ccncc1
Reactant: CCCCC(CC)C(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCC(CC)C(=O)NCCCSc1ccncc1
Yield: 92.8 %

Procedure:
To a solution of 800 mg (3.32 mmol) of 4-(3-aminopropylthio)pyridine dihydrochloride and 2.22 ml (15.9 mmol) of triethylamine in 30 ml of methylene chloride was added 0.69 ml (3.98 mmol) of 2-ethylhexanoyl chloride under ice-cooling with stirring and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was washed with an aqueous saturated sodium bicarbonate solution and water and dried. The solvent was distilled off. The residue was purified by column chromatography (eluent: ethyl acetate) to obtain 1.02 g of the desired compound (free base) (quant., pale yellow oil).
Reaction SMILES: [C:1]([C:5]1[S:9][C:8]([N:10]=[C:11]=[O:12])=[N:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:13][NH:14][CH2:15][CH:16]=[O:17]>C1C=CC=CC=1>[CH3:13][N:14]([CH2:15][CH:16]=[O:17])[C:11]([NH:10][C:8]1[S:9][C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])=[N:6][N:7]=1)=[O:12]
Reactant: CC(C)(C)c1nnc(N=C=O)s1
Reactant: CNCC=O
Solvent: c1ccccc1
Product: CN(CC=O)C(=O)Nc1nnc(C(C)(C)C)s1
Reaction time: 0.08 h

Procedure:
A mixture of 5-t-butyl-1,3,4-thiadiazol-2-yl isocyanate dimer (6 grams), the dimethyl acetal of 2-methylaminoacetaldehyde (3.9 grams) and benzene (50 ml) was charged into a glass reaction flask equipped with a mechanical stirrer and reflux condenser. The reaction mixture was heated at reflux, with stirring for a period of about 5 minutes. After this time the reaction mixture was stripped of benzene to yield an oil which solidified upon standing. The resulting solid was then recrystallized from pentane to yield the desired product the dimethyl acetal of 2-[1-methyl-3-(5-t-butyl-1,3,4-thiadiazol-2-yl)ureido]acetaldehyde having a melting point of 80° to 82° C.
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[N:10]=2)[N:5]=[CH:4][C:3]=1[NH2:14].C(=O)(O)[O-].[Na+]>CO.[Pd]>[CH3:13][O:12][C:9]1[N:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]=[CH:4][C:3]([NH2:14])=[CH:2]2
Reactant: COc1ccc2ncc(N)c(Br)c2n1
Agent: [Pd]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: COc1ccc2ncc(N)cc2n1
Reaction time: 1 h
Yield: 60.5 %

Procedure:
Dissolved 4-bromo-6-(methyloxy)-1,5-naphthyridin-3-amine (as prepared in WO2006081179 A1) (372 mg, 1.464 mmol) in methanol. Added sodium bicarbonate (246 mg, 2.93 mmol) followed by 10% palladium on carbon (312 mg, 0.293 mmol). The mixture was flushed with nitrogen and hydrogenated under balloon pressure for 1 h. After 1 h, filtered reaction mixture and concentrated to afford 155 mg (0.885 mmol, 60%) of the title compound as a white solid. 1H NMR (400 MHz, CHLOROFORM-d) d ppm 4.05 (s, 3H) 6.90 (d, J=9.09 Hz, 1H) 7.38 (br. s., 1H) 8.16 (d, J=8.84 Hz, 1H) 8.54 (br. s., 1H).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([P:19]([CH3:22])([CH3:21])=[O:20])=[CH:15][CH:14]=2)[N:3]=1.C(N(CC)CC)C.[C:30]12([CH2:40][NH2:41])[CH2:39][CH:34]3[CH2:35][CH:36]([CH2:38][CH:32]([CH2:33]3)[CH2:31]1)[CH2:37]2>C(O)C>[CH3:21][P:19]([C:16]1[CH:17]=[CH:18][C:13]([NH:12][C:4]2[N:3]=[C:2]([NH:41][CH2:40][C:30]34[CH2:39][CH:34]5[CH2:33][CH:32]([CH2:38][CH:36]([CH2:35]5)[CH2:37]3)[CH2:31]4)[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=2)=[CH:14][CH:15]=1)([CH3:22])=[O:20]
Reactant: NCC12CC3CC(CC(C3)C1)C2
Reactant: CP(C)(=O)c1ccc(Nc2ncc(C(F)(F)F)c(Cl)n2)cc1
Solvent: CCO
Solvent: CCN(CC)CC
Product: CP(C)(=O)c1ccc(Nc2ncc(C(F)(F)F)c(NCC34CC5CC(CC(C5)C3)C4)n2)cc1
Yield: 73 %

Procedure:
To a solution of 4-chloro-N-[4-(dimethylphosphoryl)phenyl]-5-(trifluoromethyl)pyrimidin-2-amine (prepared as in Example 1: 40 mg, 0.12 mmol) in 2 mL of ethanol was added 50 L of triethylamine and 1-Adamantanemethylamine (19 mg, 0.12 mmol). The mixture was microwave at 120 degrees for 20 minutes. The reaction mixture was filtered through a syringe filter and purified by prep-HPLC (Waters Sunfire C18 column with ACN/water mobile phases) to yield a white solid as product (40 mg, 73% yield.) MS/ES+: m/z=479
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[CH:6]2.C([BH3-])#N.[Na+].[OH-].[Na+]>C(O)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH2:7][CH2:6]2
Reactant: COc1ccc2[nH]ccc2c1
Agent: [BH3-]C#N
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: COc1ccc2c(c1)CCN2
Temperature: 11 °C
Yield: 99.1 %

Procedure:
5-Methoxyindole (50 g, 0.34 mol) was dissolved in glacial acetic acid (500 mL) in a 3 L 3-necked flask fitted with a mechanical stirrer, a dropping funnel and a thermometer. The solution was cooled to 10-12° C. with an ice bath and sodium cyanoborohydride (64 g, 1.0 mol) was added in portions while ensuring the temperature remained at or below 15-16° C. After the addition was complete the cooling bath was removed and the reaction was warmed to ambient temperature for 0.5 hour. TLC (1:1 EtOAc/hexane) confirmed a complete reaction. The reaction was cooled to 5-10° C. and 50% aqueous sodium hydroxide was added until the pH was 8-10. The product oiled out and was extracted with ethyl acetate (3×700 mL). The combined organic layers were washed with water (2×500 mL) and brine (400 mL), dried over anhydrous potassium carbonate, filtered and concentrated to afford 5-methoxyindoline (50 g, 0.337 mol, 99% yield) as a thick oil. This product was used without further purification. The structure was corroborated by NMR spectroscopy.
Reaction SMILES: C([O:4][C:5]1[CH:17]=[CH:16][C:15]2[C:14]3[C:9](=[CH:10][C:11]([O:18]C(=O)C)=[CH:12][CH:13]=3)[CH:8]([CH3:22])[C:7]=2[CH:6]=1)(=O)C.O.[OH-].[Li+].Cl>C(O)CO>[OH:4][C:5]1[CH:17]=[CH:16][C:15]2[C:14]3[C:9](=[CH:10][C:11]([OH:18])=[CH:12][CH:13]=3)[CH:8]([CH3:22])[C:7]=2[CH:6]=1
Reactant: CC(=O)Oc1ccc2c(c1)C(C)c1cc(OC(C)=O)ccc1-2
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: OCCO
Solvent: O
Product: CC1c2cc(O)ccc2-c2ccc(O)cc21
Yield: 84.2 %

Procedure:
A mixture of 2,7-diacetyloxy-9-methylfluorene (12 g), lithium hydroxide monohydrate (3.42 g) and ethylene glycol (120 mL) was refluxed for one hour by heating. The reaction mixture was poured into 6M-hydrochloric acid and extracted with ethyl acetate. The organic layer was sufficiently washed with water and then dried on anhydrous magnesium sulfate. The solvent was distilled off from this organic layer under reduced pressure to obtain 2,7-dihydroxy-9-methylfluorene (7.24 g) of light brown crystal. Melting point: 191.5-196.3° C.
Reaction SMILES: N1CCCC1.[OH:6][C:7]1[C:8]([C:13](=[O:15])[CH3:14])=[N:9][N:10]([CH3:12])[CH:11]=1.C([N:23]1[CH2:28][CH2:27][CH2:26][CH2:25][C:24]1=O)(OC(C)(C)C)=O>CO>[CH3:12][N:10]1[CH:11]=[C:7]2[O:6][C:26]3([CH2:27][CH2:28][NH:23][CH2:24][CH2:25]3)[CH2:14][C:13](=[O:15])[C:8]2=[N:9]1
Reactant: CC(=O)c1nn(C)cc1O
Reactant: CC(C)(C)OC(=O)N1CCCCC1=O
Solvent: C1CCNC1
Solvent: CO
Product: Cn1cc2c(n1)C(=O)CC1(CCNCC1)O2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Pyrrolidine (3.0 g, 3.5 mL, 42 mmol) was added to a solution of 1-(4-hydroxy-1-methyl-1H-pyrazol-3-yl)ethanone (5.93 g, 42.3 mmol) in methanol (50 mL). The mixture was stirred at room temperature for 2 hours before addition of N-Boc-piperidone (8.43 g, 42.3 mmol). The mixture was stirred at room temperature overnight before concentration to dryness. The crude material was purified by CombiFlash (120 g column, 30-50% EtOAc/hexanes gradient) to afford desired product containing unreacted starting material. This material was triturated with 30% EtOAc/hexanes, the solids were filtered and air dried to afford tert-butyl 2′-methyl-7′-oxo-6′,7′-dihydro-1H,2′H-spiro[piperidine-4,5′-pyrano[3,2-c]pyrazole]-1-carboxylate (6.8 g, 50%).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[C:9]([N:10]=1)=[CH:8][CH:7]=[C:6]([O:11][C:12]1[CH:13]=[C:14]([NH:20][C:21](=[O:33])[C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]4([C:31]#[N:32])[CH2:30][CH2:29]4)[CH:23]=3)[CH:15]=[CH:16][C:17]=1[O:18][CH3:19])[N:5]=2.Cl.Cl.[CH3:36][N:37]1[CH2:42][CH2:41][N:40]([CH2:43][C:44](O)=[O:45])[CH2:39][CH2:38]1.Cl.C(N=C=NCCCN(C)C)C.CO>N1C=CC=CC=1.CN(C)C1C=CN=CC=1>[C:31]([C:28]1([C:24]2[CH:23]=[C:22]([CH:27]=[CH:26][CH:25]=2)[C:21]([NH:20][C:14]2[CH:15]=[CH:16][C:17]([O:18][CH3:19])=[C:12]([O:11][C:6]3[N:5]=[C:4]4[S:3][C:2]([NH:1][C:44](=[O:45])[CH2:43][N:40]5[CH2:41][CH2:42][N:37]([CH3:36])[CH2:38][CH2:39]5)=[N:10][C:9]4=[CH:8][CH:7]=3)[CH:13]=2)=[O:33])[CH2:30][CH2:29]1)#[N:32]
Reactant: CN1CCN(CC(=O)O)CC1
Reactant: COc1ccc(NC(=O)c2cccc(C3(C#N)CC3)c2)cc1Oc1ccc2nc(N)sc2n1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: c1ccncc1
Solvent: CO
Product: COc1ccc(NC(=O)c2cccc(C3(C#N)CC3)c2)cc1Oc1ccc2nc(NC(=O)CN3CCN(C)CC3)sc2n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 70.2 %

Procedure:
To a solution of N-{3-[(2-amino[1,3]thiazolo[5,4-b]pyridin-5-yl)oxy]-4-methoxyphenyl}-3-(1-cyanocyclopropyl)benzamide (457 mg, 998 μmol) produced in Example C1(vii) in pyridine (10 mL) were added (4-methylpiperazin-1-yl)acetic acid dihydrochloride (474 mg, 2.05 mmol), N,N-dimethylpyridine-4-amine (51.3 mg, 420 μmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (403 mg, 2.10 mmol), and the mixture was stirred at room temperature for 2 hr. Methanol (10 mL) was added to the reaction solution, and the mixture was stirred for 30 min. The solvent was evaporated under reduced pressure. The residue was dissolved in ethyl acetate (100 mL) and tetrahydrofuran (10 mL), and the solution was washed with 0.1N hydrochloric acid (50 mL), saturated aqueous sodium hydrogen carbonate solution (50 mL) and saturated brine (50 mL). The earlier 0.1N hydrochloric acid washing solution was neutralized (pH 7.0) with 1N aqueous sodium hydroxide solution, and extracted with ethyl acetate (50 mL×2). The combined organic layer was dried over anhydrous magnesium sulfate, the insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (ethyl acetate/methanol=100/0→80/20), and recrystallized from a mixture of ethyl acetate and diisopropyl ether to give the title compound (419 mg, 70%) as colorless crystals.
Reaction SMILES: [CH3:1][N:2]([CH3:25])[CH:3]([CH3:24])[CH2:4][C:5]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:6][CH2:7][C:8]([O:10]C)=[O:9].C(=O)([O-])[O-].[K+].[K+].CO.Cl>O>[CH3:25][N:2]([CH3:1])[CH:3]([CH3:24])[CH2:4][C:5]([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[CH2:6][CH2:7][C:8]([OH:10])=[O:9]
Reactant: COC(=O)CCC(CC(C)N(C)C)(c1ccccc1)c1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: CC(CC(CCC(=O)O)(c1ccccc1)c1ccccc1)N(C)C
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of methyl 6-dimethylamino-4,4-diphenyl-heptanoate (obtained above), potassium carbonate (500 mg), methanol (5 ml) and water (1 ml) was stirred at room temperature for 24 hours. The reaction mixture was diluted with water, acidified with 1N HCl to pH 1, and extracted with chloroform (3×). The combined extracts were washed with water and brine (once each). After drying over magnesium sulfate, the solution was rotary evaporated to yield 40 mg of 6-dimethylamino-4,4-diphenyl-heptanoic acid.
Reaction SMILES: [Cl-].[NH4+].O.[N+:4]([C:7]1[CH:8]=[CH:9][C:10]([N:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)=[C:11]([CH:14]=1)[C:12]#[N:13])([O-])=O>[Fe].C(O)C>[NH2:4][C:7]1[CH:8]=[CH:9][C:10]([N:15]2[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]2)=[C:11]([CH:14]=1)[C:12]#[N:13]
Reactant: N#Cc1cc([N+](=O)[O-])ccc1N1CCCCC1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: N#Cc1cc(N)ccc1N1CCCCC1
Temperature: 65 °C
Reaction time: 0.5 h
Yield: 95.4 %

Procedure:
2-Chloro-5-nitrobenzonitrile (20 g) and piperidine (9.34 g) were added to acetonitrile (100 ml) and the mixture was stirred at the refluxing temperature for 1 hr. The solvent was evaporated under reduced pressure. Diisopropyl ether was added to the residue to allow crystallization and the crystals were recrystallized from methanol to give 5-nitro-2-piperidinobenzonitrile (17 g). Subsequently, ammonium chloride (1.6 g) and iron powder (8.4 g) were added to a mixed solvent of water (40 ml) and ethanol (120 ml) and the mixture was heated to 65° C. 5-Nitro-2-piperidinobenzonitrile (10 g) was added by portions over 20 min and the mixture was stirred at the refluxing temperature for 30 min. The reaction mixture was ice-cooled and the reaction solution was filtrated. The solvent was evaporated under reduced pressure. An aqueous sodium hydroxide solution was added and the mixture was extracted with toluene. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. Diisopropyl ether was added to the residue to allow crystallization and the crystals were recrystallized from a mixed solvent of ethyl acetate-n-hexane to give the title compound (8.3 g). melting point: 148-149° C.
Reaction SMILES: Cl[C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[CH2:11]([O:13][C:14]1[CH:15]=[C:16]([NH2:23])[C:17](=[CH:21][CH:22]=1)[C:18](O)=[O:19])[CH3:12]>>[CH2:11]([O:13][C:14]1[CH:15]=[C:16]2[C:17]([C:18](=[O:19])[N:6]3[C:5]4[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=4[NH:3][C:2]3=[N:23]2)=[CH:21][CH:22]=1)[CH3:12]
Reactant: CCOc1ccc(C(=O)O)c(N)c1
Reactant: Clc1nc2ccccc2[nH]1
Product: CCOc1ccc2c(=O)n3c(nc2c1)[nH]c1ccccc13

Procedure:
3-Ethoxybenzimidazo[2,1-b]quinazolin-12(6H)one is prepared with 2-chlorobenzimidazole and 4-ethoxyanthranilic acid.
Reaction SMILES: CCN(C(C)C)C(C)C.[O:10]1[CH2:15][CH2:14][CH:13]([CH2:16][NH2:17])[CH2:12][CH2:11]1.[C:18](OC(=O)C)(=[O:20])[CH3:19]>C(Cl)Cl>[O:10]1[CH2:15][CH2:14][CH:13]([CH2:16][NH:17][C:18](=[O:20])[CH3:19])[CH2:12][CH2:11]1
Reactant: CC(=O)OC(C)=O
Reactant: NCC1CCOCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)NCC1CCOCC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
PS-DIEA (Argonaut Technologies, 1.35 g, 4.5 mmol) is added to a mixture of C-(tetrahydropyran-4-yl)methylamine (345 mg, 3.0 mmol) in CH2Cl2 (20 ml) at ambient temperature. Acetic anhydride (367 mg, 3.6 mmol) is added to the mixture. After stirring at ambient temperature for 18 hours, methylisocyanate polystyrene (Novabiochem, 1.84 g, 3.0 mmol) and N-(2-aminoethyl)aminomethyl polystyrene (Novabiochem, 1.07 g, 3.0 mmol) are added. After stirring at room temperature for 4 h, the resins are removed by filtration, and the resins are washed with dichloromethane. The filtrate and washing are combined, and the solvent is removed by evaporation in vacuo to give N-(tetrahydropyran-4-ylmethyl)acetamide.
Reaction SMILES: [CH:1]([S:4]([C:7]1[N:11]=[CH:10][NH:9][N:8]=1)(=[O:6])=[O:5])([CH3:3])[CH3:2].[CH2:12]([N:15]([CH2:19][CH2:20][CH3:21])[C:16](Cl)=[O:17])[CH2:13][CH3:14]>>[CH2:12]([N:15]([CH2:19][CH2:20][CH3:21])[C:16]([N:9]1[CH:10]=[N:11][C:7]([S:4]([CH:1]([CH3:3])[CH3:2])(=[O:6])=[O:5])=[N:8]1)=[O:17])[CH2:13][CH3:14]
Reactant: CC(C)S(=O)(=O)c1nc[nH]n1
Reactant: CCCN(CCC)C(=O)Cl
Product: CCCN(CCC)C(=O)n1cnc(S(=O)(=O)C(C)C)n1

Procedure:
In an analogous manner to that described in Example 20, 3-isopropylsulphonyl-1,2,4-triazole was reacted with dipropylcarbamoyl chloride (4 hours reflux) to give 1-dipropylcarbamoyl-3-isopropylsulphonyl-1,2,4-triazole, m.p. 61° .varies. 63°C. Elemental analysis satisfactory.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[OH:9].[Cl:10]C1C=CC=CC=1O>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:10])[CH:5]=[C:4]([Cl:8])[C:3]=1[OH:9]
Reactant: Oc1ccccc1Cl
Reactant: Oc1c(Cl)cccc1Cl
Product: Oc1c(Cl)cc(Cl)cc1Cl

Procedure:
The selectivity was 0.73 mol of 2,6-dichlorophenol mol of ortho-chlorophenol introduced.
Reaction SMILES: [CH3:1][N:2]([CH3:19])[CH:3]1[CH2:8][CH2:7][C:6]([C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([NH2:18])[CH:16]=3)[NH:11][CH:10]=2)=[CH:5][CH2:4]1.I.CS[C:23]([C:25]1[S:26][CH:27]=[CH:28][CH:29]=1)=[NH:24]>C(O)C>[CH3:1][N:2]([CH3:19])[CH:3]1[CH2:8][CH2:7][C:6]([C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([NH:18][C:23]([C:25]4[S:26][CH:27]=[CH:28][CH:29]=4)=[NH:24])[CH:16]=3)[NH:11][CH:10]=2)=[CH:5][CH2:4]1
Reactant: CSC(=N)c1cccs1
Reactant: CN(C)C1CC=C(c2c[nH]c3ccc(N)cc23)CC1
Agent: I
Solvent: CCO
Product: CN(C)C1CC=C(c2c[nH]c3ccc(NC(=N)c4cccs4)cc23)CC1
Reaction time: 24 h
Yield: 93.5 %

Procedure:
A solution of compound 113 (0.18 g, 0.704 mmol) in dry ethanol (10 mL) was treated with thiophene-2-carboximidothioic acid methyl ester hydroiodide (0.4 g, 1.409 mmol) at room temperature and stirred for 24 h. Solvent was evaporated and crude was diluted with sat. NaHCO3 solution (20 mL) and product was extracted into CH2Cl2 (2 25 mL). The combined CH2Cl2 layer was washed with brine (20 mL) and dried (Na2SO4). Solvent was evaporated and crude was purified by column chromatography (2 M NH3 in methanol: CH2Cl2, 1:9) to obtain compound 114 (0.24 g, 90%) as a solid. mp 113-115° C.; 1H NMR (DMSO-d6) δ 1.42-1.53 (m, 1H), 1.97-2.02 (m, 1H), 2.08-2.22 (m, 8H), 2.31-2.60 (m, 3H), 6.03 (s, 1H), 6.21 (brs, 2H), 6.65 (dd, 1H, J=1.2, 8.4 Hz), 7.09 (t, 1H, J=4.2 Hz), 7.20 (s, 1H), 7.28-7.31 (m, 2H), 7.58 (d, 1H, J=4.5 Hz), 7.71 (d, 1H, J=2.7 Hz), 10.88 (s, 1H), ESI-MS m/z (%): 365 (MH+, 39), 320 (38), 183 (76), 160 (100); ESI-HRMS calculated for C21H25N4S (MH+), Calculated: 365.1813: Observed: 365.1794.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][C:5]1[N:9]([CH3:10])[C:8]([CH2:11][CH3:12])=[N:7][CH:6]=1.[CH3:13][N:14]1[N:18]=[N:17][C:16]([C:19]2[CH:24]=[C:23]([CH3:25])[C:22](O)=[C:21]([CH3:27])[CH:20]=2)=[N:15]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[CH3:13][N:14]1[N:18]=[N:17][C:16]([C:19]2[CH:20]=[C:21]([CH3:27])[C:22]([O:1][CH2:2][CH2:3][CH2:4][C:5]3[N:9]([CH3:10])[C:8]([CH2:11][CH3:12])=[N:7][CH:6]=3)=[C:23]([CH3:25])[CH:24]=2)=[N:15]1
Reactant: CCc1ncc(CCCO)n1C
Reactant: Cc1cc(-c2nnn(C)n2)cc(C)c1O
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCc1ncc(CCCOc2c(C)cc(-c3nnn(C)n3)cc2C)n1C
Temperature: 20 °C
Yield: 119.2 %

Procedure:
A mixture of 5-(3-hydroxypropyl)-1-methyl-2-ethylimidazole (150 mg, 0.89 mmol), 4-(2-methyl-tetrazol-5-yl)-2,6-dimethylphenol (200 mg, 0.98 mmol), and triphenylphosphine (257 mg, 0.98 mmol) was dissolved in 10 ml of THF under nitrogen at 0° C. To the above solution was added at 0° C. DEAD (170.5 mg, 0.98 mmol) and the mixture was stirred for 2 h allowing the mixture to warm to 20° C. The solvent was removed in vacuo, and the residue was purified by silica column chromatography (20 cm column, ethyl acetate/hexane, 1/1-3/1; methylene chloride/methanol 30/1-10/1) to afford 376 mg (quantitative) of 5-[3-[4-(2-methyl-tetrazol-5-yl)-2,6-dimethylphenoxy]-propyl]-1-methyl-2-ethyl-imidazole, as a white crystalline solid, m.p. 96°-98° C. (recrystallization from methylene chloride/hexane).
Reaction SMILES: [Cl:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([NH:11][C:12]3[N:17]=[C:16]([N:18]4[CH:22]=[C:21]([CH2:23][N:24]5[CH2:27][CH:26]([OH:28])[CH2:25]5)[C:20]([CH3:29])=[N:19]4)[CH:15]=[CH:14][N:13]=3)[CH:9]=2)[N:4]([CH3:30])[CH:3]=1.[CH3:31][S:32](O)(=[O:34])=[O:33]>CO>[CH3:31][S:32]([O:28][CH:26]1[CH2:25][N:24]([CH2:23][C:21]2[C:20]([CH3:29])=[N:19][N:18]([C:16]3[CH:15]=[CH:14][N:13]=[C:12]([NH:11][C:8]4[CH:9]=[C:10]5[C:5](=[CH:6][CH:7]=4)[N:4]([CH3:30])[CH:3]=[C:2]5[Cl:1])[N:17]=3)[CH:22]=2)[CH2:27]1)(=[O:34])=[O:33]
Reactant: CS(=O)(=O)O
Reactant: Cc1nn(-c2ccnc(Nc3ccc4c(c3)c(Cl)cn4C)n2)cc1CN1CC(O)C1
Solvent: CO
Product: Cc1nn(-c2ccnc(Nc3ccc4c(c3)c(Cl)cn4C)n2)cc1CN1CC(OS(C)(=O)=O)C1
Temperature: 25 °C
Yield: 54 %

Procedure:
To a slurry of 1-((1-(2-(3-chloro-1-methyl-1H-indol-5-ylamino)pyrimidin-4-yl)-3-methyl-1H-pyrazol-4-yl)methyl)azetidin-3-ol, Compound No. 144 (127 mg, 0.3 mmol) in methanol, was added 1 equivalant of methanesulfonic acid at room temperature. After being stirred at room temperature, the resulting solids were collected by filtration, rinsed with cold methanol and then vacuum dried to give 85 mg (54%) of the desired compound 181 as a pale yellow solid. MS (ESI) m/z 424 [M+H]+; 1H NMR (300 MHz, DMSO-d6) δ 9.9 (br s, 1H), 9.98 (s, 1H), 8.66 (s, 1H), 8.53 (d, 1H, J=5.4 Hz), 7.92 (S, 1H), 7.53˜7.51 (m, 3H), 7.19 (d, 1H, J=5.4 Hz), 4.45˜4.50 (m, 1H), 4.32˜4.38 (m, 2H), 4.22˜4.28 (m, 2H), 3.85˜3.91 (m, 2H), 3.79 (s, 3H), 2.36 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:18]=[C:17]([N+:19]([O-])=O)[CH:16]=[CH:15][C:3]=1[O:4][C:5]1[C:10]2[C:11]([NH2:14])=[N:12][O:13][C:9]=2[CH:8]=[CH:7][CH:6]=1.O.O.[Sn](Cl)Cl.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C>[NH2:19][C:17]1[CH:16]=[CH:15][C:3]([O:4][C:5]2[C:10]3[C:11]([NH2:14])=[N:12][O:13][C:9]=3[CH:8]=[CH:7][CH:6]=2)=[C:2]([F:1])[CH:18]=1
Reactant: Nc1noc2cccc(Oc3ccc([N+](=O)[O-])cc3F)c12
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: Nc1ccc(Oc2cccc3onc(N)c23)c(F)c1
Temperature: 70 °C

Procedure:
120 mg (0.41 mmol) of 4-(2-fluoro-4-nitrophenoxy)-1,2-benzisoxazole-3-amine (from example VI) and 468 mg (2.07 mmol) of tin(II) chloride dihydrate are dissolved in 8 ml of ethyl acetate and heated at 70° C. for 4 hours. After cooling to room temperature, the reaction solution is adjusted to pH 9 using saturated sodium bicarbonate solution, which gives a colorless precipitate. 5 g of kieselguhr are added to the suspension, and the mixture is filtered. The filtrate is extracted repeatedly with ethyl acetate. The combined organic phases are washed with water and dried over sodium sulfate. Removal of the solvent under reduced pressure gives the product.
Reaction SMILES: [N:1]1[C:10]2[C@H:9]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][N:16]3[C:24](=[O:25])[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[C:17]3=[O:26])[CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.C(OC([N:34]1[C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][C:37]=2[N:36]=[C:35]1[CH2:43]Cl)=O)(C)(C)C.C(N(C(C)C)CC)(C)C>C(#N)C.[I-].[K+]>[NH:34]1[C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][C:37]=2[N:36]=[C:35]1[CH2:43][N:11]([C@H:9]1[C:10]2[N:1]=[CH:2][CH:3]=[CH:4][C:5]=2[CH2:6][CH2:7][CH2:8]1)[CH2:12][CH2:13][CH2:14][CH2:15][N:16]1[C:24](=[O:25])[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17]1=[O:26]
Reactant: CC(C)(C)OC(=O)n1c(CCl)nc2ccccc21
Reactant: O=C1c2ccccc2C(=O)N1CCCCN[C@@H]1CCCc2cccnc21
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: O=C1c2ccccc2C(=O)N1CCCCN(Cc1nc2ccccc2[nH]1)[C@@H]1CCCc2cccnc21
Temperature: 50 °C
Reaction time: 22 h
Yield: 111.7 %

Procedure:
To a solution of 2-{4-[(R)-(5,6,7,8-tetrahydro-quinolin-8-yl)amino]-butyl}-isoindole-1,3-dione (135.3 g, 0.39 mol) and 2-chloromethyl-benzimidazole-1-carboxylic acid tert-butyl ester (103 g, 0.39 mol) in acetonitrile (780 mL) at room temperature was added diisopropylethylamine (101 mL, 0.58 mol) and potassium iodide (6.4 g, 0.04 mol) and the mixture heated to 50° C. for 3 hours. The mixture was then concentrated under reduced pressure and redissolved in methyl t-butyl ether (500 mL) and water (500 mL). The pH was adjusted to 2 with 6N HCl then the phases were separated. The aqueous layer was washed with methyl t-butyl ether (500 mL). The aqueous phase was stirred for 22 hours, adding 6N HCl as needed to maintain pH=2. The solution was basified to pH 10-11 with ION NaOH and extracted with toluene (2×1.5 L). The organic phase was washed with 1N NaOH (1×200 mL) and brine (1×200 mL). The organic phase was dried (Na2SO4), filtered and concentrated under reduced pressure to give 2-{4-[(R)-(1H-benzimidazol-2-ylmethyl)-5,6,7,8-tetrahydro-quinolin-8-yl-amino]-butyl}-isoindole-1,3-dione (209 g). 1H NMR (300 MHz, CDCl3, δ ppm) 0.75-1.75 (series of m, 5H), 1.80-2.10 (2m, 2H), 2.15-2.25 (m, 1H), 2.55-2.90 (m, 4H), 3.52 (t, 2H, J=7.0 Hz), 3.95-4.10 (m, 1H), 4.01 (d, 1H, J=17.0 Hz), 4.11 (d, 1H, J=17.0 Hz), 7.10-7.30 (m, 4H), 7.39 (d, 1H, J=7.5 Hz), 7.50-7.55 (m, 1H), 7.60-7.70 (m, 2H), 7.70-7.80 (m, 2H), 8.60 (d, 1H, J=3.5 Hz).