Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH:4]1[CH2:6][CH:5]1[C:7]1[C:17]([F:18])=[CH:16][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:9]([F:19])[C:8]=1[F:20])(O)=[O:2].B.C(OCC)(=O)C.Cl>O1CCCC1.O>[OH:2][CH2:1][CH:4]1[CH2:6][CH:5]1[C:7]1[C:17]([F:18])=[CH:16][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:9]([F:19])[C:8]=1[F:20]
Reactant: CCOC(=O)c1cc(F)c(C2CC2C(=O)O)c(F)c1F
Agent: B
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cc(F)c(C2CC2CO)c(F)c1F
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 77.1 %

Procedure:
In 60 ml of anhydrous tetrahydrofuran was dissolved 6.00 g of ethyl 4-(2-carboxycyclopropyl)-2,3,5-trifluorobenzoate. To the resulting solution was added 42 ml of a 1M solution of borane in tetrahydrofuran with ice-cooling. The resulting mixture was stirred for 1.5 hours at room temperature. The reaction mixture was added to a mixture of 100 ml of ethyl acetate and 100 ml of water. The resulting mixture was adjusted to pH 1 with 2N hydrochloric acid. The organic layer was separated, washed with water and a saturated aqueous sodium chloride solution in this order, and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue obtained was purified by a column chromatography (eluant: toluene/ethyl acetate=4/1) to obtain 4.40 g (yield: 77.1%) of ethyl 4-(2-hydroxymethylcyclopropyl)-2,3,5-trifluorobenzoate.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:8])=[N:6][CH:7]=1.ClC1C=CC=C(C(OO)=[O:17])C=1.C([O-])(O)=O.[Na+]>C(Cl)(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:8])=[N+:6]([O-:17])[CH:7]=1
Reactant: Cc1ccc(Br)cn1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: Cc1ccc(Br)c[n+]1[O-]
Temperature: 25 °C

Procedure:
A solution of 5-bromo-2-methylpyridine (10 g, 58.13 mmol) and meta-chloroperbenzoic acid (mCPBA, 30 g, 174.39 mmol) in CHCl3 (160 mL) was heated at 60° C. for 16 h. The mixture was cooled to rt and neutralized with satd. NaHCO3. The resulting mixture was extracted with DCM. The organic layers were combined and washed with brine and dried (MgSO4). The solvent was removed in vacuo. The crude was purified by silica gel chromatography (EtOAc/hexanes) to obtain the title compound.
Reaction SMILES: C([O:7][CH2:8][CH2:9][C@H:10]1[C@H:14]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[O:13][C:12]([CH2:24][CH3:25])([CH2:22][CH3:23])[O:11]1)(=O)C(C)(C)C.C[O-].[Na+]>CO.CCOC(C)=O>[CH2:15]([C@@H:14]1[O:13][C:12]([CH2:22][CH3:23])([CH2:24][CH3:25])[O:11][C@H:10]1[CH2:9][CH2:8][OH:7])[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: CCC1(CC)O[C@@H](CCOC(=O)C(C)(C)C)[C@H](Cc2ccccc2)O1
Agent: C[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Product: CCC1(CC)O[C@@H](CCO)[C@H](Cc2ccccc2)O1
Temperature: 45 °C
Reaction time: 14 h
Yield: 92.3 %

Procedure:
To a stirred solution of (2-((4S,5S)-5-benzyl-2,2-diethyl-1,3-dioxolan-4-yl)ethyl pivalate (Preparation example 246, 1.0 g, 2.87 mmol) in MeOH (10 mL) was added NaOMe (0.47 g, 8.61 mmol) and then warm to 45° C. The mixture was stirred for 14 h. The resulting mixture was diluted with EtOAc, washed with water, dried over MgSO4, filtered, and concentrated under reduced pressure. The crude compound was purified by a silica gel column to produce the title compound (0.7 g, 80˜95%);
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([F:9])[C:3]=1[NH2:4].S(Cl)([Cl:13])(=O)=O>C(O)(=O)C>[Cl:13][C:7]1[CH:8]=[C:2]([F:1])[C:3]([NH2:4])=[C:5]([F:9])[CH:6]=1
Reactant: Nc1c(F)cccc1F
Reactant: O=S(=O)(Cl)Cl
Solvent: CC(=O)O
Product: Nc1c(F)cc(Cl)cc1F
Temperature: 80 °C

Procedure:
35.5 g of 2,6-difluoroaniline were mixed with 200 ml of concentrated acetic acid, and the mixture was heated to 80° C. 42.4 g of sulfuryl chloride were mixed with approximately the same amount of concentrated acetic acid, and the mixture was added dropwise to the heated solution. The mixture was then heated at reflux for six hours. After cooling, the solution was concentrated under reduced pressure and the residue was stirred with water and pentane. The solid residue was filtered off and washed with water. The resulting solid was admixed with 200 ml of concentrated hydrochloric acid and heated at reflux for two hours. After cooling, the solution was carefully made slightly alkaline using aqueous sodium hydroxide solution, and the mixture was extracted three times with 100 ml of ethyl acetate each time. The organic phase was dried over sodium sulfate and freed from the solvent. Yield: 40 g;
Reaction SMILES: [SH:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([OH:11])=[O:10])[CH:5]=[CH:6][CH:7]=1.Cl[CH2:13][C:14](=[O:16])[CH3:15].C(N(CC)C(C)C)(C)C.O>C1COCC1>[O:16]=[C:14]([CH3:15])[CH2:13][S:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([OH:11])=[O:10])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)Cc1cccc(S)c1
Reactant: CC(=O)CCl
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)CSc1cccc(CC(=O)O)c1

Procedure:
3-Mercaptophenylacetic acid (3.0 g, 17.9 mmol) and chloroacetone (1.5 mL, 18.8 mmol) were combined in THF (100 mL) then a solution of N,N-diisopropylethylamine (10.9 mL, 62.7 mmol) in THF (100 mL) was added by addition funnel over the course of 20 minutes at room temperature. After 2 hours H2O (100 mL) was added and the reaction mixture was worked up to give the title compound as a solid.
Reaction SMILES: C(Br)CCC.[Cl:6][C:7]1[C:12]2[C:13](=[O:18])[O:14][C:15](=[O:17])[NH:16][C:11]=2[CH:10]=[CH:9][CH:8]=1.N1[C:24]2N=C[CH:27]=[CH:28][C:23]=2[C:22](=O)OC1=O>>[Cl:6][C:7]1[C:12]2[C:13](=[O:18])[O:14][C:15](=[O:17])[N:16]([CH2:27][CH2:28][CH:23]([CH3:24])[CH3:22])[C:11]=2[CH:10]=[CH:9][CH:8]=1
Reactant: O=c1[nH]c2ncccc2c(=O)o1
Reactant: O=c1[nH]c2cccc(Cl)c2c(=O)o1
Solvent: CCCCBr
Product: CC(C)CCn1c(=O)oc(=O)c2c(Cl)cccc21

Procedure:
The title compound was prepared according to the procedure of Example 1B substituting 1-bromo-3-methylbutane for n-butyl bromide and substituting the product of Example 101A for the product of Example 1A (0.610 g, 45%). MS (DCI) m/z 285 (M+NH4)+.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5]([S:13](Cl)(=[O:15])=[O:14])[CH:6]=[C:7]([Cl:12])[CH:8]=2)[N:3]=1.[NH2:17][C:18]1[CH:26]=[CH:25][C:21]([C:22]([OH:24])=[O:23])=[CH:20][CH:19]=1.N1C=CC=CC=1>C1COCC1>[NH2:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5]([S:13]([NH:17][C:18]3[CH:26]=[CH:25][C:21]([C:22]([OH:24])=[O:23])=[CH:20][CH:19]=3)(=[O:15])=[O:14])[CH:6]=[C:7]([Cl:12])[CH:8]=2)[N:3]=1
Reactant: Nc1ccc(C(=O)O)cc1
Reactant: Nc1ccc2cc(Cl)cc(S(=O)(=O)Cl)c2n1
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: Nc1ccc2cc(Cl)cc(S(=O)(=O)Nc3ccc(C(=O)O)cc3)c2n1
Temperature: 30 °C
Reaction time: 8 h

Procedure:
A mixture of 2-amino-6-chloroquinoline-8-sulfonyl chloride (500 mg, 1.8 mmol), 4-aminobenzoic acid (300 mg, 2.2 mmol) and pyridine (1 mL) in 10 mL of THF was stirred at 30° C. overnight, when LCMS indicated that the reaction was complete. The resulting mixture was concentrated, and the residue was purified by a standard method to yield the title compound. LCMS (m/z): 378.8 (M+1)+
Reaction SMILES: S(Cl)(Cl)=O.[OH:5][C:6]1[CH:7]=[C:8]([CH2:12][C:13]([OH:15])=[O:14])[CH:9]=[CH:10][CH:11]=1.[CH3:16]O>>[OH:5][C:6]1[CH:7]=[C:8]([CH2:12][C:13]([O:15][CH3:16])=[O:14])[CH:9]=[CH:10][CH:11]=1
Reactant: CO
Reactant: O=C(O)Cc1cccc(O)c1
Solvent: O=S(Cl)Cl
Product: COC(=O)Cc1cccc(O)c1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 94 %

Procedure:
Thionyl chloride (17 mL, 0.64 mol) was added dropwise to methanol at 0° C. After the completion of the addition, the reaction mixture was stirred at 0° C. for 10 min., and then 3-hydroxyphenylacetic acid (25 g, 0.16 mol) was added. The resulting reaction mixture was stirred at room temperature for 2 h. Volatiles were removed and the residue was partitioned between water and ethyl acetate. The organic layer was separated, washed with H2O, NaHCO3, and NaCl (sat.) and dried over Na2SO4. The crude product was purified on a silica gel column with 20% EtOAc in hexane to give methyl 3-hydroxyphenylacetate as a colorless oil (25 g, 94% yield).
Reaction SMILES: [CH2:1]([C:3]1[NH:8][CH:7]=[N:6][C:5](=O)[C:4]=1[CH3:10])[CH3:2].P(Cl)(Cl)([Cl:13])=O>>[Cl:13][C:5]1[C:4]([CH3:10])=[C:3]([CH2:1][CH3:2])[N:8]=[CH:7][N:6]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCc1[nH]cnc(=O)c1C
Product: CCc1ncnc(Cl)c1C
Temperature: 25 °C
Yield: 84.3 %

Procedure:
6-Ethyl-5-methyl-4(1H)-pyrimidinone (Intermediate 40, 1.382 g, 10 mmol) was added to a stirred solution of phosphorus oxychloride (4.66 ml, 50.0 mmol) and the reaction mixture was heated under reflux for 2 hours. After this time the reaction mixture was cooled to room temperature, the solvent was removed under reduced pressure. The viscous residue was dissolved in DCM and the resulting residue was poured into a stirred mixture of ice and 2M aqueous hydrochloric acid and the extracted with DCM (×3). The DCM layers were combined dried suing a hydrophobic frit and evaporated under reduced pressure to give the product, 4-chloro-6-ethyl-5-methylpyrimidine (1.32 g, 8.43 mmol) as an oil. m/z (ES+) 157/159 (M+1).
Reaction SMILES: [Na].[NH2:2][C:3]1[C:8]([N+:9]([O-:11])=[O:10])=[CH:7][CH:6]=[C:5](Cl)[N:4]=1.[CH3:13][OH:14]>>[NH2:2][C:3]1[C:8]([N+:9]([O-:11])=[O:10])=[CH:7][CH:6]=[C:5]([O:14][CH3:13])[N:4]=1
Reactant: CO
Reactant: Nc1nc(Cl)ccc1[N+](=O)[O-]
Agent: [Na]
Product: COc1ccc([N+](=O)[O-])c(N)n1

Procedure:
1.65 g (0.0717 mol; 2 equivalents (eq)) of sodium are dissolved in 100 cm3 of methanol. 6.2 g (35.7 mmol) of 2-amino-6-chloro-3-nitropyridine are added and the solution is brought to reflux for 8h. The methanol is evaporated under reduced pressure and the residue is taken up in the minimum amount of water (20 cm3). The solution is extracted with 100 cm3 of ethyl ether. The ether phase is washed with water (20 cm3), separated by settling, dried over MgSO4, decolored with animal charcoal and evaporated on a rotary evaporator to give a 1 st crop. The aqueous phase is extracted under the same conditions with 2 times 50 cm3 of ethyl acetate, giving a 2nd and 3rd crop.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:16]=[CH:15][C:6]([CH:7](Cl)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:5][CH:4]=1.[C-:17]#[N:18].[K+].[Cl-]>CC#N.C1OCCOC2C(=CC=CC=2)OCCOCCOC2C(=CC=CC=2)OC1>[CH3:1][O:2][C:3]1[CH:16]=[CH:15][C:6]([CH:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:17]#[N:18])=[CH:5][CH:4]=1
Reactant: COc1ccc(C(Cl)c2ccccc2)cc1
Reactant: [C-]#N
Agent: [Cl-]
Agent: [K+]
Agent: c1ccc2c(c1)OCCOCCOc1ccccc1OCCOCCO2
Solvent: CC#N
Product: COc1ccc(C(C#N)c2ccccc2)cc1
Temperature: 25 °C
Yield: 96.6 %

Procedure:
To a solution of p-methoxybenzhydryl chloride (27.00 g, 0.116 mol) in dry CH3CN (200 mL) was added dibenzo-18-crown-6 (2.12 g) followed by dry KCN (8.02 g, 0.123 mol), and the stirred mixture was refluxed for 66 h. After this time, the reaction mixture was cooled to room temperature and the solid was removed by filtration. The filtrate was evaporated under vacuum. The resulting solid was dissolved in CH2Cl2 (50 mL) and the solution flushed through a silica gel column (230-400 mesh, 60 g) using CH2Cl2. The eluent was evaporated and the residue was titurated with heptane to precipitate the product. The precipitate was collected and washed with heptane to give a solid. 1H--NMR analysis of this solid showed that it was a mixture of starting chloride and product. Therefore, the heptane filtrates were evaporated and the solids were recombined, giving a total of 25.03 g of material. This solid was reacted again as described above, except that the reflux period was extended 48 h. Afterwards, the reaction mixture was worked up as described above to give the title nitrile (18.56 g, 72%) as a yellowish white solid. The structure was confirmed by 1H--NMR in CDCl3.
Reaction SMILES: [CH2:1]([N:3]([CH2:21][CH3:22])[C:4]1[CH:20]=[CH:19][C:7]([C:8]([C:10]2[C:11]([C:16]([OH:18])=[O:17])=[N:12][CH:13]=[CH:14][N:15]=2)=O)=[CH:6][CH:5]=1)[CH3:2].[C:23]1([NH:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(OC(=O)C)(=O)C>>[CH2:21]([N:3]([CH2:1][CH3:2])[C:4]1[CH:20]=[CH:19][C:7]([C:8]2([N:29]([C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:10]3=[N:15][CH:14]=[CH:13][N:12]=[C:11]3[C:16](=[O:17])[O:18]2)=[CH:6][CH:5]=1)[CH3:22]
Reactant: c1ccc(Nc2ccccc2)cc1
Reactant: CCN(CC)c1ccc(C(=O)c2nccnc2C(=O)O)cc1
Solvent: CC(=O)OC(C)=O
Product: CCN(CC)c1ccc(C2(N(c3ccccc3)c3ccccc3)OC(=O)c3nccnc32)cc1
Reaction time: 72 h

Procedure:
A mixture of 0.1 g. of 3-[4-(diethylamino)benzoyl]-2-pyrazinecarboxylic acid, 0.1 g. of diphenylamine and 2 ml. of acetic anhydride was warmed for several hours and then allowed to stand for three days. The product, 7-[4-(diethylamino)phenyl]-7-(diphenylamino)furo[3,4-b]pyrazine-5(7H)-one was isolated by column chromatography as a light orange solid, m.p. 140°-142.6° C. A toluene solution of this product contacted with acidic clay or phenolic resin developed a red image.
Reaction SMILES: C([N:4]1[CH2:9][CH2:8][CH:7]([O:10][C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][C:12]=2[CH3:20])[CH2:6][CH2:5]1)(=O)C.[ClH:21].C(O)C>O>[ClH:21].[N+:17]([C:14]1[CH:15]=[CH:16][C:11]([O:10][CH:7]2[CH2:8][CH2:9][NH:4][CH2:5][CH2:6]2)=[C:12]([CH3:20])[CH:13]=1)([O-:19])=[O:18]
Reactant: CC(=O)N1CCC(Oc2ccc([N+](=O)[O-])cc2C)CC1
Agent: Cl
Solvent: CCO
Solvent: O
Product: Cc1cc([N+](=O)[O-])ccc1OC1CCNCC1

Procedure:
To 1-acetyl-4-(4-nitro-2-methylphenyloxy)piperidine (11.8 g) were added conc. hydrochloric acid (15 ml), ethanol (15 ml) and water (15 ml) and the mixture was heated under reflux overnight. The reaction mixture was concentrated under reduced pressure, the residue thus obtained was washed with ethyl ether and crystals were filtered off to obtain 4-(4-nitro-2-methylphenyloxy)piperidine hydrochloride (8.3 g) as white crystals, m.p. 204°-226° C.
Reaction SMILES: F[C:2]1[C:7]([C:8]2[N:13]=[C:12]([CH3:14])[N:11]=[C:10]([N:15]([CH2:25][C:26]3[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=3)[CH2:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=3)[N:9]=2)=[CH:6][C:5]([CH2:34][N:35]2[CH2:40][CH2:39][O:38][CH2:37][CH2:36]2)=[CH:4][N:3]=1.[F:41][C:42]1[CH:43]=[C:44]([NH2:50])[CH:45]=[N:46][C:47]=1[O:48][CH3:49].C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>C1COCC1.O>[F:41][C:42]1[CH:43]=[C:44]([NH:50][C:2]2[C:7]([C:8]3[N:13]=[C:12]([CH3:14])[N:11]=[C:10]([N:15]([CH2:25][C:26]4[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=4)[CH2:16][C:17]4[CH:18]=[CH:19][C:20]([O:23][CH3:24])=[CH:21][CH:22]=4)[N:9]=3)=[CH:6][C:5]([CH2:34][N:35]3[CH2:40][CH2:39][O:38][CH2:37][CH2:36]3)=[CH:4][N:3]=2)[CH:45]=[N:46][C:47]=1[O:48][CH3:49]
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(CN4CCOCC4)cnc3F)n2)cc1
Reactant: COc1ncc(N)cc1F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(CN4CCOCC4)cnc3Nc3cnc(OC)c(F)c3)n2)cc1
Temperature: -20 °C
Yield: 15.5 %

Procedure:
A mixture of 4-(2-fluoro-5-(morpholinomethyl)pyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (0.500 g, 0.918 mmol) and 5-fluoro-6-methoxypyridin-3-amine (0.261 g, 1.836 mmol) in THF (20 mL) was cooled to −20° C. and treated with a 1.0 M solution of lithium bis(trimethylsilyl)amide (3.21 mL, 3.21 mmol) added dropwise. The mixture was allowed to slowly warm to ambient temperature over 1 h. The reaction mixture was diluted with water (50 mL) and extracted with CH2Cl2 (3×50 mL). The combined organic extracts were dried over sodium sulfate and concentrated to give the crude product as a tan solid. This was purified by chromatography through a SiliCycle SiliaSep pre-packed silica-gel column (80 gram) eluting with a gradient of 0% to 100% EtOAc in hexane over 30 min to give 4-(2-(5-fluoro-6-methoxypyridin-3-ylamino)-5-(morpholinomethyl)pyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (0.095 g) as a tan oil. This was treated with trifluoroacetic acid (1.8 mL, 23.36 mmol) and trifluoromethanesulfonic acid (0.2 mL, 2.252 mmol) and heated at 70° C. for 20 min. The mixture was cooled to ambient temperature and concentrated to give a tan oil. This was dissolved in DCM (10 mL) and allowed to stir for 5 min, then sodium carbonate (1.6 g) was slowly added to the mixture and stirred vigorously for 20 min. The mixture was filtered and concentrated. The mixture was diluted with ethyl acetate and filtered. The filtrate was concentrated and the residue was diluted with diethyl ether (20 mL) and placed in a sonicator for 2 min. The precipitate was collected by filtration. The solid was recrystallized from hot ethyl acetate to give 4-(2-(5-fluoro-6-methoxypyridin-3-ylamino)-5-(morpholinomethyl)pyridin-3-yl)-6-methyl-1,3,5-triazin-2-amine (0.025 g, 0.059 mmol, 6.39% yield) as a tan solid. 1H NMR (400 MHz, d6-DMSO) δ 11.94 (s, 1H); 8.72 (s, 1H); 8.41 (s, 1H); 8.36 (d, J=12.91 Hz, 1H); 8.24 (s, 1H); 7.90 (s, 1H); 7.75 (s, 1H); 3.93 (s, 3H); 3.57 (s, 4H); 3.43 (s, 2H); 2.44 (s, 7H). m/z (ESI, +ve ion) 427 (M+H)+.
Reaction SMILES: [C:1]([O:12][CH3:13])(=[O:11])[C:2]1[CH:10]=[CH:9][CH:8]=[C:4]([C:5]([O-:7])=O)[CH:3]=1.[CH3:14][C:15]1[N:16]=[C:17]([CH2:20][NH:21][CH:22]([CH3:24])[CH3:23])[S:18][CH:19]=1>CCN(CC)CC.O=S(Cl)Cl.C(Cl)Cl>[CH:22]([N:21]([CH2:20][C:17]1[S:18][CH:19]=[C:15]([CH3:14])[N:16]=1)[C:5]([C:4]1[CH:3]=[C:2]([CH:10]=[CH:9][CH:8]=1)[C:1]([O:12][CH3:13])=[O:11])=[O:7])([CH3:24])[CH3:23]
Reactant: Cc1csc(CNC(C)C)n1
Reactant: COC(=O)c1cccc(C(=O)[O-])c1
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1cccc(C(=O)N(Cc2nc(C)cs2)C(C)C)c1
Temperature: 90 °C
Reaction time: 0.5 h
Yield: 93 %

Procedure:
Et3N (1 drop, catalytic) was added to a stirred suspension of mono-Methyl isophthalate (0.294 mmol, 1.0 eq) in 2 ml SOCl2 under Ar. The mixture was heated to reflux at 90° C. for 2 h. The reaction was cooled to RT, and the solvent was removed in vacuo. The residue was placed under an Ar atmosphere and dissolved in 2 ml anh CH2Cl2. The resulting solution was treated with a solution of N-((4-methylthiazol-2-yl)methyl)propan-2-amine (0.294 mmol, 1.0 eq made from reductive amination of 4-methylthiazole-2-carbaldehyde with isopropylamine) dissolved in 1 ml anh CH2Cl2 under Ar. After stirring at RT for 30 min, the reaction was treated with ET3N (0.294 mmol, 1 eq). After stirring at RT for 30 min, the reaction is poured into a seperatory funnel, washed with sat. NaHCO3 (×1), water (×3), brine (×1), and dried over Na2SO4. The inorganics were removed via filtration, and the solvent was removed in vacuo yielding the crude product in 93% yield.
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][NH:4][C:3]1=[CH:7][N+:8]([O-:10])=[O:9].[C:11]1([CH3:23])[CH:16]=[CH:15][C:14]([S:17]([N:20]=[C:21]=[O:22])(=[O:19])=[O:18])=[CH:13][CH:12]=1>C(Cl)Cl.CCOCC>[CH3:1][N:2]1[CH2:6][CH2:5][NH:4][C:3]1=[C:7]([N+:8]([O-:10])=[O:9])[C:21]([NH:20][S:17]([C:14]1[CH:15]=[CH:16][C:11]([CH3:23])=[CH:12][CH:13]=1)(=[O:19])=[O:18])=[O:22]
Reactant: CN1CCNC1=C[N+](=O)[O-]
Reactant: Cc1ccc(S(=O)(=O)N=C=O)cc1
Solvent: ClCCl
Solvent: CCOCC
Product: Cc1ccc(S(=O)(=O)NC(=O)C(=C2NCCN2C)[N+](=O)[O-])cc1
Reaction time: 8 h

Procedure:
A solution of 1.43 g of 1A in 20 ml of methylene chloride was treated with 1.99 g of p-tolylsulfonyl isocyanate at room temperature. After a brief period of exothermicity, the mixture was held at room temperature overnight. The mixture then was diluted with 20 ml of dry ether and filtered to give 1, as a white powder, m.p.: 155°- 157°.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1.[C:10]([O:14][C:15](ON=C(C1C=CC=CC=1)C#N)=[O:16])([CH3:13])([CH3:12])[CH3:11]>O1CCOCC1.O>[C:10]([O:14][C:15]([NH:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1)=[O:16])([CH3:13])([CH3:12])[CH3:11]
Reactant: CC(C)(C)OC(=O)ON=C(C#N)c1ccccc1
Reactant: NCCN1CCNCC1
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)NCCN1CCNCC1

Procedure:
1-(2-aminoethyl)piperazine (1.29 g, 10 mmol) is dissolved in 20 mL of dioxane: water (1:1) mixture and 2-(tert-butoxycarbonyloxyimino)-2-phenylacetonitrile (2.46 g, 10 mmol) is added. The mixture is then stirred until no starting material is detected on thin layer chromatography. The obtained mixture is fractionally separated by silica gel chromatography, followed by RP-HPLC to obtain 1-[2-tert-butoxycarbonylaminoethyl]piperazine. Following the procedure of Example 6, but replacing 1-benzylpiperazine with 1-[2-tert-butoxycarbonylaminoethyl]piperazine, provides the desired compound. The product of Example 3 (2.1 g, 2.03 mmol), 1-[2-tert-butoxycarbonylaminoethyl]piperazine (1.396 g, 6.09 mmol), and triethylamine (0.85 mL, 6.09 mmol) in 10 mL of methylene chloride are used. The obtained product (1.0 g) is treated with 48%-HF (4 mL) in 35 mL of acetonitrile in the procedure described in Example 5, followed by a carefully deprotection of N-tert-butoxycarbonyl group with 10% trifluoroacetic acid to obtain the pure title compound.
Reaction SMILES: [CH:1]1[C:9]([Br:10])=[CH:8][N:7]2[C:3](=[N:4][CH:5]=[CH:6]2)[CH:2]=1.C[O:12][C:13]1[C:18]2C=CNC=2N=C(N)[N:14]=1.N1C=CC=CC=1.CC(OCC1C2C(=CC=CC=2)C(COC(C)=O)=C2C=1C=CC=C2)=O>CN(C1C=CN=CC=1)C.C(Cl)Cl>[Br:10][C:9]1[CH:1]=[CH:2][C:3]2[N:7]([CH:6]=[C:5]([NH:14][C:13](=[O:12])[CH3:18])[N:4]=2)[CH:8]=1
Reactant: COc1nc(N)nc2[nH]ccc12
Reactant: Brc1ccc2nccn2c1
Agent: CC(=O)OCc1c2ccccc2c(COC(C)=O)c2ccccc12
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)Nc1cn2cc(Br)ccc2n1
Temperature: 35 °C
Reaction time: 3 h
Yield: 49.4 %

Procedure:
To a 100 mL round-bottomed flask was added 6-bromoH-imidazo[1,2-a]pyridin-2-amine (0.771 g, 3.6 mmol), DCM (30 mL), pyridine (0.44 mL, 5.5 mmol), acetic anhyride (0.41 mL, 4.4 mmol) and DMAP (0.0022 g, 0.018 mmol). The mixture was stirred at 35° C. for 3 h. After cooling to rt, the mixture was concentrated and then taken up in water (100 mL) and extracted with 25% iPrOH/CHCl3 (3×75 mL). The combined extracts were washed with brine (75 mL), dried (Na2SO4) and concentrated in vacuo. The residue was dissolved in MeOH (2 M in NH3)/CH2Cl2 and concentrated onto silica. Purification by silica gel chromatography MeOH (2 M in NH3)/CH2Cl2) afforded the title compound as an orange solid (0.452 g, 49%). MS (ESI, positive ion) m/z: 254 (M(79Br)+1).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH:15]1[C:20]([C:21](=[O:29])[NH:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=2)=[C:19]([CH3:30])[NH:18][C:17]([CH3:31])=[C:16]1[C:32]([O:34][CH2:35][CH2:36][CH2:37][CH2:38][N:39]1[C:43]([CH3:44])=[N:42][N:41]=[C:40]1[CH3:45])=[O:33])C1C=CC=CC=1>C(O)C.[Pd]>[OH2:8].[CH3:31][C:17]1[NH:18][C:19]([CH3:30])=[C:20]([C:21](=[O:29])[NH:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=2)[CH:15]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[OH:8])[C:16]=1[C:32]([O:34][CH2:35][CH2:36][CH2:37][CH2:38][N:39]1[C:40]([CH3:45])=[N:41][N:42]=[C:43]1[CH3:44])=[O:33]
Reactant: CC1=C(C(=O)Nc2ccccn2)C(c2ccccc2OCc2ccccc2)C(C(=O)OCCCCn2c(C)nnc2C)=C(C)N1
Agent: [Pd]
Solvent: CCO
Product: CC1=C(C(=O)Nc2ccccn2)C(c2ccccc2O)C(C(=O)OCCCCn2c(C)nnc2C)=C(C)N1
Product: O
Reaction time: 4 h
Yield: 90.8 %

Procedure:
4-(2-Benzyloxyphenyl)-2,6-dimethyl-3-[4-(3,5-dimethyl-1,2,4-triazol-4yl)butoxycarbonyl]-5-(N-pyrid-2-ylcarbamoyl)-1,4-dihydropyridine (0.3 g--see Example 11) was dissolved in ethanol (10 ml) containing 10% palladium-on-charcoal and the mixture was hydrogenated at room temperature under pressure (30 p.s.i.=206.8 kPa) for 4 hours. The catalyst was filtered off and the filtrate evaporated under vacuum. The residue was then chromatographed on silica gel eluting with EtOAc containing 15% Et2NH and the fractions containing the product were combined and evaporated to give the title compound, (0.12 g, 47%), m.p. 125°-135°.