Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O.Cl.[Cl:3][C:4]1[CH:5]=[C:6]([C:14]2[O:18][N:17]=[C:16]([C:19]3[CH:20]=[CH:21][CH:22]=[C:23]4[C:27]=3[NH:26][CH:25]=[C:24]4[CH2:28][CH2:29][N+:30]([O-])=O)[N:15]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH:11]([CH3:13])[CH3:12]>CCOC(C)=O.CO.[Fe]>[Cl:3][C:4]1[CH:5]=[C:6]([C:14]2[O:18][N:17]=[C:16]([C:19]3[CH:20]=[CH:21][CH:22]=[C:23]4[C:27]=3[NH:26][CH:25]=[C:24]4[CH2:28][CH2:29][NH2:30])[N:15]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH:11]([CH3:12])[CH3:13]
Reactant: CC(C)Oc1ccc(-c2nc(-c3cccc4c(CC[N+](=O)[O-])c[nH]c34)no2)cc1Cl
Agent: [Fe]
Agent: Cl
Solvent: O
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(C)Oc1ccc(-c2nc(-c3cccc4c(CCN)c[nH]c34)no2)cc1Cl
Yield: 71.7 %

Procedure:
Water (20 mL) and concentrated HCl solution (10 mL) were added to a solution of 7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-3-(2-nitroethyl)-1H-indole (D83) (2.1 g) in EtOAc (70 mL) and methanol (150 mL). The mixture was heated to reflux and stirred efficiently. Fe (6.0 g) was added in portions. After the addition was complete, the reaction mixture was refluxed for 8 hours. The solid was filtered off and the filtrate was concentrated and then basified with saturated NaHCO3 solution. The solid was filtered off and the filtrate was extracted with dichloromethane (200 mL). The organic layer was washed with water and brine, and then dried over MgSO4. Removal of the solvent gave the product 2-[7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1H-indol-3-yl]ethanamine (D84) (1.4 g) as a yellow foam solid. No further purification was carried out. MS (ES): C21H21ClN4O2 requires 396; found 397.2 (M+H+).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:20]([Br:24])(Br)(Br)[Br:21].[CH:25]1([N:28]2[CH2:37][C:36]([CH3:39])([CH3:38])[C:35]3[C:30](=[CH:31][CH:32]=[C:33]([CH:40]=O)[CH:34]=3)[CH2:29]2)[CH2:27][CH2:26]1.C(OCC)(=O)C>ClCCl.CCCCCC>[Br:21][C:20]([Br:24])=[CH:40][C:33]1[CH:34]=[C:35]2[C:30](=[CH:31][CH:32]=1)[CH2:29][N:28]([CH:25]1[CH2:26][CH2:27]1)[CH2:37][C:36]2([CH3:39])[CH3:38]
Reactant: BrC(Br)(Br)Br
Reactant: CC1(C)CN(C2CC2)Cc2ccc(C=O)cc21
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCCCCC
Product: CC1(C)CN(C2CC2)Cc2ccc(C=C(Br)Br)cc21
Reaction time: 0.5 h

Procedure:
A stirred, cooled (ice-bath) solution of triphenyl phosphine (0.53 g, 2 mmol) in anhydrous dichloromethane was treated with carbon tetrabromide (0.35 g, 1 mmol) under argon. After 0.5 h, a solution of 2-cyclopropyl-4,4-dimethyl-1,2,3,4-tetrahydroisoquinoline-6-carboxaldehyde (Intermediate 25, 0.13 g, 0.57 mmol) in dichloromethane (2 mL) was cannulated into the reaction mixture. After 1.5 h between 0° C. and 10° C. , the reaction mixture was subjected to flash column chromatography over silica gel (230-400 mesh) using 3-5% ethyl acetate in hexane as the eluent to afford the title compound as a viscous, pale yellow oil (0.18 g, 82%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[CH:9]=2)[N:5]=[C:4]([CH2:15][CH3:16])[N:3]=1.[NH2:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22][OH:23])=[CH:20][CH:19]=1>C(O)(=O)C.C(=O)(O)[O-].[Na+]>[Cl:14][C:10]1[CH:9]=[C:8]([C:6]2[N:5]=[C:4]([CH2:15][CH3:16])[N:3]=[C:2]([NH:17][C:18]3[CH:25]=[CH:24][C:21]([CH2:22][OH:23])=[CH:20][CH:19]=3)[N:7]=2)[CH:13]=[CH:12][CH:11]=1
Reactant: Nc1ccc(CO)cc1
Reactant: CCc1nc(Cl)nc(-c2cccc(Cl)c2)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: CCc1nc(Nc2ccc(CO)cc2)nc(-c2cccc(Cl)c2)n1
Temperature: 75 °C
Yield: 16 %

Procedure:
2-Chloro-4-(3-chlorophenyl)-6-ethyl-1,3,5-triazine (0.140 g, 0.55 mmol) and 4-aminobenzyl alcohol (0.135 g, 1.1 mmol) were suspended in acetic acid (5 mL). The mixture was heated to 75° C. for 1 h. The reaction was cooled, diluted with saturated aqueous sodium bicarbonate, and extracted with ethyl acetate. The combined organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by column chromatography (silica, dichloromethane/ethyl acetate) and then triturated with hexanes to afford the title compound (0.030 g, 16%) as a yellow solid. MW=340.81. 1H NMR (DMSO-d6, 500 MHz) δ 10.24 (s, 1H), 8.42-8.31 (m, 2H), 7.75-7.68 (m, 3H), 7.61 (t, J=7.5 Hz, 1H), 7.36-7.28 (m, 2H), 5.11 (t, J=5.5 Hz, 1H), 4.48 (d, J=5.5 Hz, 2H), 2.78 (q, J=7.5 Hz, 2H), 1.32 (t, J=7.5 Hz, 3H); APCI MS m/z 341 [M+H]+.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][C@@H:13]([OH:21])[CH2:14][CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)=[CH:7][C:6]=1[NH:22][C:23](=[O:39])[CH2:24][CH:25]1[C:38]2[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=2[O:32][C:31]2[C:26]1=[CH:27][CH:28]=[CH:29][CH:30]=2)([CH3:4])([CH3:3])[CH3:2].[C:40]([O:47][CH2:48][C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1)(=[O:46])[CH2:41][CH2:42][C:43](O)=[O:44].Cl.C(N=C=NCCCN(C)C)C>CN(C1C=CN=CC=1)C.O1CCCC1.C(OCC)(=O)C>[C:43]([O:21][C@H:13]([CH2:12][CH2:11][C:8]1[CH:9]=[CH:10][C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])=[C:6]([NH:22][C:23](=[O:39])[CH2:24][CH:25]2[C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][C:31]=3[O:32][C:33]3[C:38]2=[CH:37][CH:36]=[CH:35][CH:34]=3)[CH:7]=1)[CH2:14][CH:15]1[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]1)(=[O:44])[CH2:42][CH2:41][C:40]([O:47][CH2:48][C:49]1[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=1)=[O:46]
Reactant: O=C(O)CCC(=O)OCc1ccccc1
Reactant: CC(C)(C)c1ccc(CC[C@@H](O)CC2CCCCC2)cc1NC(=O)CC1c2ccccc2Oc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)c1ccc(CC[C@H](CC2CCCCC2)OC(=O)CCC(=O)OCc2ccccc2)cc1NC(=O)CC1c2ccccc2Oc2ccccc21
Temperature: 25 °C
Reaction time: 17 h

Procedure:
A suspension of 249 mg (0.474 mmol) of (R)-N-[2-t-butyl- 5-(4-cyclohexyl-3-hydroxybutyl)phenyl]-2-(9H-xanthen-9-yl)acetamide (prepared as described in Example 100), 218 mg (1.05 mmol) of benzyl hydrogen succinate, 76 mg (0.62 mmol) of 4-(N,N-dimethylamino)pyridine and 256 mg (1.34 mmol) of 1-ethyl-3-(3'-dimethylaminopropyl)carbodiimide hydrochloride in 5 ml of tetrahydrofuran was stirred for 17 hours at room temperature. At the end of this time, the reaction mixture was diluted with ethyl acetate, and the diluted mixture was washed with 2N aqueous hydrochloric acid, with water, with a saturated aqueous solution of sodium hydrogencarbonate and with a saturated aqueous solution of sodium chloride, in that order. The organic phase was then dried over anhydrous magnesium sulfate, and the solvent was removed by distillation under reduced pressure. The resulting residue was purified by column chromatography through 20 g of silica gel, using a 1:9 by volume mixture of ethyl acetate and hexane as the eluent, to give 352 mg (a quantitative yield) of the title compound as a glassy material.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13]([CH:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:22])[CH:11]=2)[CH:6]=1.[CH3:24][O:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[N:32]=[C:33]=[O:34]>C(Cl)Cl.O>[CH3:1][O:2][C:3](=[O:23])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13]([CH:16]2[CH2:17][CH2:18][N:19]([C:33](=[O:34])[NH:32][C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=3[O:25][CH3:24])[CH2:20][CH2:21]2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:22])[CH:11]=2)[CH:6]=1
Reactant: COC(=O)Cc1cc2ccc(F)cc2c(C2CCNCC2)c1C
Reactant: COc1ccccc1N=C=O
Solvent: O
Solvent: ClCCl
Product: COC(=O)Cc1cc2ccc(F)cc2c(C2CCN(C(=O)Nc3ccccc3OC)CC2)c1C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 87.4 %

Procedure:
To a solution of (6-fluoro-3-methyl-4-piperidin-4-yl-naphthalen-2-yl)-acetic acid methyl ester (which may be prepared as described above; 83.6 mg, 0.265 mmol) in methylene chloride (8.0 mL) was added 2-methoxyphenyl isocyanate (71 μL, 0.53 mmol) at room temperature under nitrogen. The resulting light brown solution was stirred at room temperature for 10 minutes. The reaction mixture was diluted with water (˜25 mL) and the resulting mixture was extracted with methylene chloride (2×30 mL). The combined organic layers were washed with saturated aqueous NaHCO3, dried over anhydrous Na2SO4, filtered and concentrated to a light yellow film. Flash chromatography (0-60% ethyl acetate in hexanes) provided {6-fluoro-4-[1-(2-methoxy-phenylcarbamoyl)-piperidin-4-yl]-3-methyl-naphthalen-2-yl}-acetic acid methyl ester (107.6 mg, 87%) as a colorless film. MS cald. for C27H30FN2O4 [(M+H)+]: 465, obsd. 465.3.
Reaction SMILES: [F:1][C:2]([F:23])([C:7]([F:22])([F:21])[C:8]([F:20])([F:19])[C:9]([F:18])([F:17])[C:10]([F:16])([F:15])[C:11]([F:14])([F:13])[F:12])[C:3](OC)=[O:4].[NH3:24].[NH4+]>O1CCCC1>[F:1][C:2]([F:23])([C:7]([F:22])([F:21])[C:8]([F:20])([F:19])[C:9]([F:18])([F:17])[C:10]([F:16])([F:15])[C:11]([F:14])([F:13])[F:12])[C:3]([NH2:24])=[O:4]
Reactant: COC(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reactant: N
Agent: [NH4+]
Solvent: C1CCOC1
Product: NC(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Temperature: 45 °C
Reaction time: 12 h
Yield: 99 %

Procedure:
A 3-1, four-necked, round-bottomed flask equipped with stirrer, thermometer, reflux condenser with bubble counter and inlet gas-tube, is charged with 658 g (1.74 mol) of methyl perfluoroheptanoate and 1.5 l tetrahydrofurane. A stream of ammonia is passed from a pressure tank into the stirring solution. The ammonia feed rate is such that a negligible amount of gas is observed exiting the reactor as observed in the bubble counter. Temperature of the mixture increases to 40-50° C. Ammonium supply is continued until the temperature begins to decrease and an increasing volume of gas is observed exiting the reactor in the bubble counter. After ending the ammonia supply, the mixture is left to stand for 12 hr. Solvent is removed under reduced pressure, yielding 626 g p perfluoroheptanoic acid amide (99%), mp 127-128° C.
Reaction SMILES: [O:1]1[CH:5]2[C:6]([O:8][C:9](=[O:10])[CH:2]1[CH2:3][CH2:4]2)=O.[NH2:11][CH2:12][CH2:13][CH2:14][CH2:15][N:16]1[CH2:21][CH2:20][N:19]([C:22]2[CH:27]=[N:26][CH:25]=[C:24]([Cl:28])[N:23]=2)[CH2:18][CH2:17]1>C(Cl)Cl>[Cl:28][C:24]1[N:23]=[C:22]([N:19]2[CH2:18][CH2:17][N:16]([CH2:15][CH2:14][CH2:13][CH2:12][N:11]3[C:6](=[O:8])[CH:5]4[O:1][CH:2]([CH2:3][CH2:4]4)[C:9]3=[O:10])[CH2:21][CH2:20]2)[CH:27]=[N:26][CH:25]=1
Reactant: O=C1OC(=O)C2CCC1O2
Reactant: NCCCCN1CCN(c2cncc(Cl)n2)CC1
Solvent: ClCCl
Product: O=C1C2CCC(O2)C(=O)N1CCCCN1CCN(c2cncc(Cl)n2)CC1
Reaction time: 0.5 h

Procedure:
Tetrahydrofuran-2,5-dicarboxylic anhydride (1.26 g., 8.8 mmole) and 1-(4-aminobutyl)-4-(6-chloro-2-pyrazinyl)piperazine (2.37 g., 8.8 mmole) were combined and stirred for 30 minutes in 200 ml. of methylene chloride. The solvent was removed in vacuum and replaced with 300 ml. of xylene. The mixture as refluxed for 48 hours with water removal via a Dean-Stark trap. After cooling, the mixture was filtered through 75 g. of silica gel and the column rinsed with 5% ethanol/chloroform. The product was concentrated in vacuum and recrystallized from isopropanol with addition of 4N isopropanolic HCl. 0.60 Grams of the title compound was obtained as the monohydrochloride; m.p. 233°-235° C. (d).
Reaction SMILES: [CH:1]([C:3]1[CH:11]=[CH:10][CH:9]=[CH:8][C:4]=1[C:5]([OH:7])=[O:6])=[O:2].[CH3:12][C:13](=[CH:15][CH2:16][CH2:17][CH:18]([CH2:20][CH2:21]O)[CH3:19])[CH3:14].C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[CH:1]([C:3]1[CH:11]=[CH:10][CH:9]=[CH:8][C:4]=1[C:5]([O:7][CH2:21][CH2:20][CH:18]([CH3:19])[CH2:17][CH2:16][CH:15]=[C:13]([CH3:14])[CH3:12])=[O:6])=[O:2]
Reactant: CC(C)=CCCC(C)CCO
Reactant: O=Cc1ccccc1C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CC(C)=CCCC(C)CCOC(=O)c1ccccc1C=O
Reaction time: 0.25 h
Yield: 15.6 %

Procedure:
A solution of 7.50 g (50.0 mmol) 2-formylbenzoic acid, 4.88 g (40.0 mmol) 4-dimethyl aminopyridine (DMAP) and 15.60 g (100.0 mmol) citronellol in 75 ml dichloromethane was cooled in an ice bath before addition of a solution of 11.35 g (55.0 mmol) dicyclohexylcarbodiimide (DCC) in 25 ml dichloromethane for 15 min. The reaction medium was maintained with stirring at 0° for 15 min, then at 20° for 48 h. The precipitate formed during the reaction was filtered and the filtrate washed with HCl (10%, 2×) and with a saturated Na2CO3 solution (2×). The organic phase was dried over Na2SO4, concentrated and chromatographed twice (SiO2, ethyl toluene/ethyl acetate 19:1 and SiO2, toluene) to give 2.25 g (16%) 3,7 dimethyl-6-octenyl 2-formylbenzoate in the pure state in the form of a colourless oil.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:9]2[N:10]=[C:11]([NH2:20])[S:12][C:13]=2[C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)[CH:5]=[C:6]([CH3:8])[CH:7]=1.Cl[CH2:22][C:23](Cl)=[O:24].[CH3:26][N:27](C)C(=O)C>>[NH2:27][C:26]1[N:10]2[C:9]([C:4]3[CH:5]=[C:6]([CH3:8])[CH:7]=[C:2]([CH3:1])[CH:3]=3)=[C:13]([C:14]3[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=3)[S:12][C:11]2=[N:20][C:23](=[O:24])[CH:22]=1
Reactant: Cc1cc(C)cc(-c2nc(N)sc2-c2ccncc2)c1
Reactant: CC(=O)N(C)C
Reactant: O=C(Cl)CCl
Product: Cc1cc(C)cc(-c2c(-c3ccncc3)sc3nc(=O)cc(N)n23)c1
Temperature: 80 °C
Reaction time: 14 h
Yield: 18 %

Procedure:
To a solution of [4-(3,5-dimethylphenyl)-5-(4-pyridyl)-1,3-thiazol-2-yl)amine (1.0 g) in N,N-dimethylacetamide (10 mL) was added chloroacetyl chloride (0.60 g) and the mixture was stirred at 80° C. for 14 hours. N,N-Dimethylacetamide was distilled off under reduced pressure and the resultant residue was dissolved in dimethylsulfoxide (5 mL). To this solution was added sodium cyanate (0.24 g) and the mixture was stirred at room temperature for 14 hours. An aqueous solution of sodium hydrogen carbonate was added to the reaction mixture and the mixture was extracted with a mixed solvent of ethyl acetate-tetrahydrofuran (1:1). The extract was washed with brine, dried over anhydrous sodium sulfate and filtered. The solvent was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (hexane-tetrahydrofuran, 1:1) and recrystallized from ethanol to obtain the title compound (0.22 g, yield 18%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13](O)=[CH:14][CH:15]=[N:16]2)=[CH:11][C:10]=1[O:20][CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O=P(Cl)(Cl)[Cl:24]>>[Cl:24][C:13]1[C:12]2[C:17](=[CH:18][C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[C:10]([O:20][CH3:21])[CH:11]=2)[N:16]=[CH:15][CH:14]=1
Reactant: COc1cc2c(O)ccnc2cc1OCc1ccccc1
Reactant: O=P(Cl)(Cl)Cl
Product: COc1cc2c(Cl)ccnc2cc1OCc1ccccc1

Procedure:
7-Benzyloxy-6-methoxy-quinolin-4-ol (WO2006108059) (1 g) was refluxed with POCl3 (8 ml) for 3 hours. The reaction was evaporated and dissolved into DCM (80 ml) that was washed with ice water followed by brine. The organic layer was dried with Na2SO4 and evaporated to dryness to give a dark yellow solid as 4-chloro-7-benzyloxy-6-methoxy-quinoline that was mixed with 5-aminoindole (600 mg) in isopropanol (15 ml). The mixture was refluxed for one hour and cooled to RT and the precipitate was filtered to give the product as 4-(1H-indol-5-ylamino)-7-benzyloxy-6-methoxy-quinoline (710 mg). This product was mixed with Pd/C (10%, 100 mg) in EtOH (80 ml) and hydrogenated at 50 psi for 8 hours to give a gray suspension that was evaporated to dryness as 4-(1H-indol-5-ylamino)-7-hydroxy-6-methoxy-quinoline (˜85% purity) for next step without further purification.
Reaction SMILES: [Br:1]Br.[Br:3][C:4]1[C:12]2[O:11][CH2:10][CH2:9][C:8]=2[CH:7]=[C:6]([CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:5]=1>C(O)(=O)C.[Fe]>[Br:1][C:5]1[C:6]([CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:7][C:8]2[CH2:9][CH2:10][O:11][C:12]=2[C:4]=1[Br:3]
Reactant: CCOC(=O)CCc1cc(Br)c2c(c1)CCO2
Reactant: BrBr
Agent: [Fe]
Solvent: CC(=O)O
Product: CCOC(=O)CCc1cc2c(c(Br)c1Br)OCC2
Temperature: 50 °C
Reaction time: 5 h
Yield: 53.1 %

Procedure:
Bromine (0.80 g, 5.01 mmol) was added dropwise to a mixture of ethyl 3-(7-bromo-2,3-dihydrobenzofuran-5-yl)propionate (1.0 g, 3.34 mmol) and iron (10 mg) in acetic acid (10 ml) and the reaction mixture was stirred at 50° C. for 5 hours. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. Water was added to the residue and the organic matter was extracted with ethyl acetate. The extract was washed with a saturated aqueous sodium bicarbonate solution, a saturated aqueous sodium chloride solution and water and then dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:3) to give 0.67 g (yield: 53%) of the target compound.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH3:11])(=[O:10])=[O:9])=[CH:4][C:3]=1[C:12]([N:14]1[CH2:19][CH2:18][N:17]([C:20]2[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=2)[CH2:16][CH2:15]1)=[O:13].[CH2:30]([NH2:34])[CH:31]([CH3:33])[CH3:32]>>[CH2:30]([NH:34][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH3:11])(=[O:10])=[O:9])=[CH:4][C:3]=1[C:12]([N:14]1[CH2:19][CH2:18][N:17]([C:20]2[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=2)[CH2:16][CH2:15]1)=[O:13])[CH:31]([CH3:33])[CH3:32]
Reactant: CC(C)CN
Reactant: CS(=O)(=O)c1ccc(I)c(C(=O)N2CCN(c3ccc(C(F)(F)F)cc3)CC2)c1
Product: CC(C)CNc1ccc(S(C)(=O)=O)cc1C(=O)N1CCN(c2ccc(C(F)(F)F)cc2)CC1
Yield: 49 %

Procedure:
The title compound was prepared according to the procedure described for example 301 from (2-Iodo-5-methanesulfonyl-phenyl)-[4-(4-trifluoromethyl-phenyl)-piperazin-1-yl]-methanone (compound CK) and Isobutylamine (49% yield, off white foam, MS (m/e): 484.5 (M+H, 100%)
Reaction SMILES: C(OC(=O)[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[N:19]=[C:20]4[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH3:28])=[CH:22][N:21]4[C:29]=3[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)(C)(C)C.Cl.O1CCOCC1>CO.C(Cl)Cl>[CH2:27]([O:26][C:23]1[CH:24]=[CH:25][C:20]2[N:21]([C:29]([C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)=[C:18]([C:15]3[CH:16]=[CH:17][C:12]([C:8]4([NH2:7])[CH2:9][CH2:10][CH2:11]4)=[CH:13][CH:14]=3)[N:19]=2)[CH:22]=1)[CH3:28]
Reactant: CCOc1ccc2nc(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)c(-c3ccccc3)n2c1
Agent: Cl
Solvent: ClCCl
Solvent: CO
Solvent: C1COCCO1
Product: CCOc1ccc2nc(-c3ccc(C4(N)CCC4)cc3)c(-c3ccccc3)n2c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 18.7 %

Procedure:
To a solution of {1-[4-(6-ethoxy-3-phenyl-imidazo[1,2-a]pyridin-2-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester (255 mg, 0.53 mmol) in MeOH (2.1 mL) and CH2Cl2 (3.4 mL) was added a 4 molar solution of HCl in dioxane (2.6 mL, 10.5 mmol, 20 equiv). The resulting solution was stirred at room temperature for 12 h, then was concentrated under reduced pressure. The remaining material was purified using MPLC (Isolute Flash NH2 reverse phase column; 100% CH2Cl2 for 5 min., gradient to 95% CH2Cl2: 5% MeOH over 15 minutes; gradient to 90% CH2Cl2: 10% MeOH over 15 min.; gradient to 80% CH2Cl2: 20% MeOH over 15 min.; and gradient to 75% CH2Cl2: 25% MeOH over 15 min.) to give 1-[4-(6-ethoxy-3-phenyl-imidazo[1,2-a]pyridin-2-yl)-phenyl]-cyclobutylamine (38 mg, 19%):
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([Br:9])[C:3]=1[NH2:4].[O:10]=[C:11]1[CH2:16][C:15](=O)[CH2:14][CH2:13][NH:12]1>>[Br:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([Br:9])[C:3]=1[NH:4][C:15]1[CH2:14][CH2:13][NH:12][C:11](=[O:10])[CH:16]=1
Reactant: O=C1CCNC(=O)C1
Reactant: Nc1c(Br)cccc1Br
Product: O=C1C=C(Nc2c(Br)cccc2Br)CCN1
Yield: 29.7 %

Procedure:
A mixture of 2,6-dibromoaniline (4.4 g) and 2,4-dioxopiperidine (2.0 g) was heated at 120° for 2.5 h. The mixture was then cooled (0°) and triturated with ether 9100 ml) to give a solid which was purified by FCC eluting with System A (100:8:1) to give the title compound (1.8 g), m.p. 240°-243°.
Reaction SMILES: [Br:1][CH:2](Br)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].[NH2:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:18][N:17]=1>>[BrH:1].[BrH:1].[CH2:2]([N:17]1[CH:18]=[C:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:20]=[CH:21][C:16]1=[NH:15])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][N:17]1[CH:18]=[C:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:20]=[CH:21][C:16]1=[NH:15]
Reactant: CCCCCCCCCCCC(Br)Br
Reactant: Nc1ccc(-c2ccccc2)cn1
Product: Br
Product: N=c1ccc(-c2ccccc2)cn1CCCCCCCCCCCCn1cc(-c2ccccc2)ccc1=N

Procedure:
The procedure is as before, with dibromododecane and 2-amino-5-phenylpyridine. The product obtained is purified by recrystallization in methanol. Its m.p.=185° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:11]O)[C:5]([O:9][CH3:10])=[N:6][C:7]=1[CH3:8].S(Cl)([Cl:15])=O>C(Cl)Cl>[Cl:15][CH2:11][C:4]1[C:5]([O:9][CH3:10])=[N:6][C:7]([CH3:8])=[C:2]([F:1])[CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: COc1nc(C)c(F)cc1CO
Solvent: ClCCl
Product: COc1nc(C)c(F)cc1CCl
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.9 %

Procedure:
To a solution of (5-fluoro-2-methoxy-6-methylpyridin-3-yl)methanol (20) (0.2 g, 1.16 mmol) in DCM was added thionyl chloride (0.278 g, 2.33 mmol). The reaction mixture was stirred for 2 h at RT. The solvent was evaporated under the reduced pressure and the reaction mixture was poured in to water (50 mL) and extracted with DCM (2×50 mL). The combined organic layer was washed with water, brine, dried over sodium sulfate, and concentrated at reduced pressure to yield to afford 3-(chloromethyl)-5-fluoro-2-methoxy-6-methylpyridine (21) as a pale yellow liquid (0.2 g) 90%.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[O:11][CH:12]=[CH:13][CH:14]=2)[C:5]([C:15]#[N:16])=[C:4](S(C)=O)[N:3]=1.[CH2:20]([OH:22])[CH3:21].C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[O:11][CH:12]=[CH:13][CH:14]=2)[C:5]([C:15]#[N:16])=[C:4]([O:22][CH2:20][CH3:21])[N:3]=1
Reactant: CS(=O)c1nc(N)c(C#N)c(-c2ccco2)c1C#N
Reactant: CCO
Solvent: COCCOC
Solvent: C1CCC2=NCCCN2CC1
Product: CCOc1nc(N)c(C#N)c(-c2ccco2)c1C#N
Reaction time: 2 h
Yield: 7.5 %

Procedure:
To a stirred suspension of 300 mg (1.10 mmol) 2-amino-4-furan-2-yl-6-methanesulfinyl-pyridine-3,5-dicarbonitrile in 15 ml dry DME were added 0.23 ml (3.86 mmol) ethanol and 0.25 ml (1.65 mmol) DBU and stirring continued for 2 hours at room temperature. The reaction mixture was then concentrated in vacuo. Chromatography (ethyl acetate/hexane 1/4) followed by trituration in ether/hexane afforded 21 mg (8%) 2-amino-6-ethoxy-4-furan-2-yl-pyridine-3,5-dicarbonitrile as a light yellow crystalline solid. EI-MS m/e (%): 254 (M+, 90), 226 (100), 198 (44), 143 (26).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([CH:8]([Br:10])[Br:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].C1(C)C=CC=CC=1.[Br:20]Br.[OH-].[Na+]>O>[N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([Br:20])([Br:9])[Br:10])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(C(Br)Br)cc1
Reactant: BrBr
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Product: O=[N+]([O-])c1ccc(C(Br)(Br)Br)cc1
Temperature: 50 °C
Reaction time: 10 h
Yield: 85 %

Procedure:
A solution of 100 parts of p-nitrobenzal bromide in 500 parts of toluene is added to a solution of 80 parts of bromine plus 160 parts of 50% sodium hydroxide in a 1,000 parts of water at 50° C. The mixture is stirred mechanically at 50° C for 10 hours. The toluene layer is separated; the water layer is extracted with 500 parts of toluene. The combined toluene layers are dried and evaporated to give 110 parts (85% yield) of p-nitrobenzotribromide, m.p. 74°-81° C.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH:6]=[C:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([CH:17]=O)[CH:15]=3)[NH:10][CH:9]=2)[CH2:4][CH2:3]1.[NH:19]1[CH2:25][C:23](=[O:24])[NH:22][C:20]1=[O:21].C([O-])(=O)C.[NH4+]>C(O)(=O)C>[CH3:1][N:2]1[CH2:7][CH:6]=[C:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([CH:17]=[C:25]4[NH:19][C:20](=[O:21])[NH:22][C:23]4=[O:24])[CH:15]=3)[NH:10][CH:9]=2)[CH2:4][CH2:3]1
Reactant: O=C1CNC(=O)N1
Reactant: CN1CC=C(c2c[nH]c3ccc(C=O)cc23)CC1
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Product: CN1CC=C(c2c[nH]c3ccc(C=C4NC(=O)NC4=O)cc23)CC1
Yield: 76 %

Procedure:
A mixture of the product from step (b) (2.4 g), hydantoin (Aldrich, 0.98 g) and ammonium acetate (0.74 g) in glac. acetic acid (2.4 ml) was heated at 120° C. for 4 hours. The mixture was cooled and the resulting precipitate filtered off and dried to give the desired product as a yellow solid (2.4 g).