Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[CH:12][C:5]([C:6](N(OC)C)=[O:7])=[CH:4][N:3]=1.[H-].C([Al+]CC(C)C)C(C)C.C1(C)C=CC=CC=1>O1CCCC1>[Cl:1][C:2]1[N:3]=[CH:4][C:5]([CH:6]=[O:7])=[CH:12][CH:13]=1
Reactant: CON(C)C(=O)c1ccc(Cl)nc1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: O=Cc1ccc(Cl)nc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 93.2 %

Procedure:
Corey, E. J.; Loh, T-P.; Achyutha Rao, S.; Daley, D. C.; Sarshar, S. J. Org. Chem. 1993, 58, 5600-5602. In a flame-dried flask under nitrogen a solution of 6-Chloro-N-methoxy-N-methyl-nicotinamide (5 g, 25 mmol) in tetrahydrofuran (50 mL) was cooled in an ice bath. A 1.5 M solution of diisobutylaluminum hydride in toluene (24.9 mL, 37 mmol) was added at a rate keeping the internal temperature of the reaction below 20° C. The reaction then stirred for 3 hours at room temperature. The completed reaction was cooled in an ice bath and carefully quenched with 1N hydrochloric acid. Stirring continued for 15 minutes more without the ice bath. The reaction mixture was extracted with ethyl acetate; the extracts were washed with brine, dried over magnesium sulfate, filtered and the filtrate was concentrated in vacuo to yield a yellow solid (3.3 g). The solids were dissolved in ether and filtered through diatomaceous earth to remove some insoluble material. The filtrate was diluted with hexanes and petroleum ether and the named compound was allowed to crystallize out over night. The precipitate was collected and dried (850 mg, 24%). Melting point 77-78° C. Second crop was collected and dried (375 mg, 11%).
Reaction SMILES: O[N:2]=[C:3]([NH2:5])[CH3:4].[C:6]([O:10][CH3:11])(=[O:9])[C:7]#[CH:8]>CO>[CH3:4][C:3]1[NH:5][C:7]([C:6]([O:10][CH3:11])=[O:9])=[CH:8][N:2]=1
Reactant: CC(N)=NO
Reactant: C#CC(=O)OC
Solvent: CO
Product: COC(=O)c1cnc(C)[nH]1
Temperature: 25 °C

Procedure:
A solution of N′-hydroxyethanimidamide (65 g, 880 mmol) in anhydrous methanol (2 L) was treated with methyl propiolate (100 g, 1.19 mol), and the reaction was heated at reflux for 4 hours. The reaction mixture was concentrated in vacuo, and the residue was diluted with diphenyl ether (1 L) and heated at reflux for 4 hours. The hot solution was filtered, and the filtrate was cooled to room temperature and diluted with hexanes (2 L). The resulting solid was washed with diethyl ether (1 L), to afford the product as a brown solid. Yield: 60 g, 430 mmol, 49%.
Reaction SMILES: [CH:1]1([N:4]([CH:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)[C:5]([C:7]2[CH:8]=[N:9][C:10]([C:13]3[CH:18]=[CH:17][C:16]([CH2:19][C:20]#[N:21])=[CH:15][CH:14]=3)=[N:11][CH:12]=2)=[O:6])[CH2:3][CH2:2]1.Cl[C:29]1[N:34]=[CH:33][C:32]([CH2:35][CH3:36])=[CH:31][N:30]=1>>[CH:1]1([N:4]([CH:22]2[CH2:23][CH2:24][N:25]([C:29]3[N:34]=[CH:33][C:32]([CH2:35][CH3:36])=[CH:31][N:30]=3)[CH2:26][CH2:27]2)[C:5]([C:7]2[CH:8]=[N:9][C:10]([C:13]3[CH:14]=[CH:15][C:16]([CH2:19][C:20]#[N:21])=[CH:17][CH:18]=3)=[N:11][CH:12]=2)=[O:6])[CH2:3][CH2:2]1
Reactant: N#CCc1ccc(-c2ncc(C(=O)N(C3CCNCC3)C3CC3)cn2)cc1
Reactant: CCc1cnc(Cl)nc1
Product: CCc1cnc(N2CCC(N(C(=O)c3cnc(-c4ccc(CC#N)cc4)nc3)C3CC3)CC2)nc1

Procedure:
The title compound is prepared from 2-(4-cyanomethyl-phenyl)-pyrimidine-5-carboxylic acid cyclopropyl-piperidin-4-yl amide and 2-chloro-5-ethylpyrimidine following a procedure analogous to that described in Example 3. LC (method 3): tR=1.84 min; Mass spectrum (ESI+): m/z=468 [M+H]+.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17]C(C)(C)C)=O)[CH2:11][CH2:10]2)=[O:8])=[CH:5][N:4]=[CH:3]1.[C:22](O)(C(F)(F)F)=O.C(OC(=O)C)(=O)C>C(Cl)Cl>[CH3:1][N:2]1[C:6]([C:7]([CH:9]2[CH2:14][CH2:13][N:12]([C:15](=[O:17])[CH3:22])[CH2:11][CH2:10]2)=[O:8])=[CH:5][N:4]=[CH:3]1
Reactant: O=C(O)C(F)(F)F
Reactant: Cn1cncc1C(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Solvent: CC(=O)OC(C)=O
Solvent: ClCCl
Product: CC(=O)N1CCC(C(=O)c2cncn2C)CC1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
A homogeneous yellow solution of tert-butyl 4-(1-methyl-1H-imidazole-5-carbonyl)piperidine-1-carboxylate (10.1 g, 34.4 mmol; Intermediate 53, step b) in DCM (172 mL) was treated with TFA (26.4 mL, 344 mmol) and stirred at room temperature for 2.5 hours. The reaction was concentrated, toluene (2×100 mL) was added and the mixture concentrated again and the resulting clear light amber residue was taken up in DCM (344 mL) and TEA (23.9 mL, 172 mmol). Acetic anhydride (3.91 mL, 41.3 mmol) was added dropwise and the reaction stirred at room temperature for 1 hour. The reaction was concentrated under high vacuum and the residue flash chromatographed using 95:5 DCM/MeOH with 2% TEA as eluent. The combined fractions were concentrated, dissolved in DCM (200 mL), and washed with water (2×200 mL) to remove TEA. The organic layer was dried (Na2SO4), filtered, and concentrated, and the residue was triturated with MTBE (75 mL) at reflux for 15 min and then allowed to cool to room temperature. The mixture was filtered and the off-white filter cake was washed with MTBE (2×3 mL) to provide, after air drying at 100° C., the title compound as an off-white fine powder.
Reaction SMILES: [CH3:1][CH:2]([C@@H:15]1[C@:32]2([CH3:33])[C@H:18]([C:19]3[C@H:29]([CH2:30][CH2:31]2)[C@:27]2([CH3:28])[C:22]([CH2:23][C@@H:24]([O:39][C:40]([O:42][CH3:43])=[O:41])[CH2:25][C@@H:26]2[O:34][C:35]([O:37][CH3:38])=[O:36])=[CH:21][CH:20]=3)[CH2:17][CH2:16]1)[CH2:3]OS(C1C=CC(C)=CC=1)(=O)=O.[I-:44].[Na+]>CC(C)=O>[I:44][CH2:3][CH:2]([CH3:1])[C@@H:15]1[C@:32]2([CH3:33])[C@H:18]([C:19]3[C@H:29]([CH2:30][CH2:31]2)[C@:27]2([CH3:28])[C:22]([CH2:23][C@@H:24]([O:39][C:40]([O:42][CH3:43])=[O:41])[CH2:25][C@@H:26]2[O:34][C:35]([O:37][CH3:38])=[O:36])=[CH:21][CH:20]=3)[CH2:17][CH2:16]1
Reactant: COC(=O)O[C@@H]1CC2=CC=C3[C@@H]4CC[C@H](C(C)COS(=O)(=O)c5ccc(C)cc5)[C@@]4(C)CC[C@@H]3[C@@]2(C)[C@@H](OC(=O)OC)C1
Reactant: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: COC(=O)O[C@@H]1CC2=CC=C3[C@@H]4CC[C@H](C(C)CI)[C@@]4(C)CC[C@@H]3[C@@]2(C)[C@@H](OC(=O)OC)C1
Yield: 77.2 %

Procedure:
To a solution of 53 mg of 20-methyl-1α,3β-bis-(methoxycarbonyloxy)-21-p-toluenesulfonyloxypregna-5,7 -diene in 5 ml of acetone was added 120 mg of sodium iodide and the mixture was heated under reflux for 4 hours. The reaction mixture was cooled, then the acetone was distilled off under reduced pressure, water was added to the residue, and the resulting mixture was extracted with diethyl ether. The extract was washed with water, an aqueous solution of sodium thiosulfate, water, an aqueous solution of sodium hydrogen carbonate and an aqueous solution of sodium chloride, then dried over sodium sulfate and concentrated. Purification of the residue by silica gel column chromatography gave 38 mg of 21-iodo-20-methyl-1α,3β-bis(methoxycarbonyloxy)-pregna-5,7-diene.
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]([NH:11][CH2:12][C@@H:13]2[CH2:17][CH2:16][CH2:15][N:14]2C(OC(C)(C)C)=O)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O)(C(F)(F)F)=O>ClCCl>[NH:14]1[CH2:15][CH2:16][CH2:17][C@H:13]1[CH2:12][NH:11][C:9](=[O:10])[O:8][CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1CNC(=O)OCc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(NC[C@@H]1CCCN1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 1,1-dimethylethyl (2S)-2-[({[(phenylmethyl)oxy]carbonyl}amino)methyl]-1-pyrrolidinecarboxylate (D113, 2.23 g, 6.67 mmol) in 16 mL of dichloromethane, cooled to 0° C., were added 4 mL of TFA. The reaction mixture was allowed to warm-up to r.t. and then it was stirred at this temperature for 30 mins. The title compound was isolated as a colourless oil after purification by SCX (1.36 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:49]=[CH:50][CH:51]=1)[CH2:5][N:6]1[C:10]([CH3:11])=[C:9]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[C:18]([C:21]4[CH:26]=[CH:25][C:24]([N:27]5[CH2:32][CH2:31][N:30]([CH2:33][CH2:34][N:35]([CH3:37])[CH3:36])[CH2:29][CH2:28]5)=[CH:23][CH:22]=4)[CH:19]=3)[N:14](S(C3C=CC(C)=CC=3)(=O)=O)[CH:13]=2)[C:8]([CH3:48])=[N:7]1.[OH-].[Li+]>C1COCC1.CO.O>[F:1][C:2]1[CH:3]=[C:4]([CH:49]=[CH:50][CH:51]=1)[CH2:5][N:6]1[C:10]([CH3:11])=[C:9]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[C:18]([C:21]4[CH:22]=[CH:23][C:24]([N:27]5[CH2:32][CH2:31][N:30]([CH2:33][CH2:34][N:35]([CH3:37])[CH3:36])[CH2:29][CH2:28]5)=[CH:25][CH:26]=4)[CH:19]=3)[NH:14][CH:13]=2)[C:8]([CH3:48])=[N:7]1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3c(C)nn(Cc4cccc(F)c4)c3C)c3cc(-c4ccc(N5CCN(CCN(C)C)CC5)cc4)cnc32)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: Cc1nn(Cc2cccc(F)c2)c(C)c1-c1c[nH]c2ncc(-c3ccc(N4CCN(CCN(C)C)CC4)cc3)cc12
Yield: 22.9 %

Procedure:
Using similar reaction conditions as described in step-iii of intermediate 1, 2-(4-(4-(3-(1-(3-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl) piperazin-1-yl)-N,N-dimethylethanamine (190 mg, 0.269 mmol) was hydrolyzed by lithium hydroxide (113 mg, 2.69 mmol), THF/Methanol/water (12/6/3 ml) to afford 34 mg (23% yield) of the titled compound. 1H NMR (CD3OD, 300 MHz): δ 8.432-8.426 (d, 1H), 7.835-7.829 (d, 1H), 7.512-7.475 (m, 2H), 7.367-7.324 (m, 1H), 7.069-6.968 (m, 3H), 6.878-6.845 (m, 1H), 5.349 (s, 2H), 3.68-3.48 (m, 2H), 3.162-3.12 (t, 2H), 2.967 (t, 1H), 2.82-2.715 (m, 8H), 2.206-2.166 (d, 6H), 1.923 (s, 1H). MS: m/z=552.2 (M+1); HPLC: 94.87% in method B.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][C:14]=1[O:15][CH3:16])[C:9]([OH:11])=[O:10].[N:17]([O-:19])=[O:18].[Na+].C(O)(=O)C.[N+]([O-])(O)=O>O>[CH3:16][O:15][C:14]1[C:6]([O:5][CH2:4][CH2:3][CH2:2][Cl:1])=[CH:7][C:8]([C:9]([OH:11])=[O:10])=[C:12]([N+:17]([O-:19])=[O:18])[CH:13]=1
Reactant: O=N[O-]
Reactant: COc1ccc(C(=O)O)cc1OCCCCl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: O=[N+]([O-])O
Product: COc1cc([N+](=O)[O-])c(C(=O)O)cc1OCCCCl
Temperature: 40 °C
Yield: 927.7 %

Procedure:
In a 50 mL volume glass flask equipped with a stirrer, a thermometer and a dropping funnel were placed 9.57 g (38.7 mmol) of 3-(3-chloropropoxy)-4-methoxybenzoic acid (purity: 99%) obtained in Reference Example III-13, 0.27 g (3.87 mmol) of sodium nitrite, and 12.5 mL of acetic acid. The resulting mixture was heated to 40° C. under stirring. To the reaction mixture was dropwise added slowly 16.2 g (154.8 mmol) of nitric acid (60 wt. %), and the mixture was heated at the same temperature for 5 hours. After the reaction was complete, 20 mL of water was added to the reaction mixture, and the aqueous mixture was cooled to 20° C., precipitating a crystalline product. The crystalline product was collected by filtration, washed successively with 30 mL of water and 30 mL of n-heptane, and dried under reduced pressure, to give 10.4 g (isolated yield: 92.0%, purity: 99% in terms of area percentage determined by high performance liquid chromatography) of 4-methoxy-5-(3-chloropropoxy)-2-nitrobenzoic acid as a white crystalline product. 4-Methoxy-5-(3-chloropropoxy)-2-nitrobenzoic acid had the following characteristics.
Reaction SMILES: Br[CH:2]1[C:6](=[O:7])[C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)=[C:4]([N:18]([CH3:20])[CH3:19])[O:3]1.C1OCCOCCOCCOCCOCCOC1.[F-:39].[K+]>C(#N)C>[F:39][CH:2]1[C:6](=[O:7])[C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)=[C:4]([N:18]([CH3:20])[CH3:19])[O:3]1
Reactant: CN(C)C1=C(c2cccc(C(F)(F)F)c2)C(=O)C(Br)O1
Reactant: [F-]
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Solvent: CC#N
Product: CN(C)C1=C(c2cccc(C(F)(F)F)c2)C(=O)C(F)O1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
In this example, a mixture containing 3 g of 2-bromo-3-oxo-4-(3-trifluoromethylphenyl)-5-dimethylamino-2,3-dihydrofuran, 0.26 of 18-Crown-6 ether and 1.11 g of potassium fluoride in 20 ml of acetonitrile was stirred at room temperature for about 30 minutes and then refluxed overnight (about 16 hours). The mixture was then cooled, filtered, and then concentrated by evaporation. The residue was chromatographed eluting with 3 vol. % tetrahydrofuran:97% chloroform affording the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:10](B3OC(C)(C)C(C)(C)O3)=[CH:9][N:8]([S:20]([C:23]3[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=3)(=[O:22])=[O:21])[C:5]2=[N:6][CH:7]=1.Cl[C:31]1[N:36]=[C:35]([NH:37][C@H:38]2[CH2:43][CH2:42][CH2:41][C@@H:40]([OH:44])[C@H:39]2[OH:45])[C:34]([F:46])=[CH:33][N:32]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C.CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:31]3[N:36]=[C:35]([NH:37][C@H:38]4[CH2:43][CH2:42][CH2:41][C@@H:40]([OH:44])[C@H:39]4[OH:45])[C:34]([F:46])=[CH:33][N:32]=3)=[CH:9][N:8]([S:20]([C:23]3[CH:24]=[CH:25][C:26]([CH3:29])=[CH:27][CH:28]=3)(=[O:22])=[O:21])[C:5]2=[N:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(B3OC(C)(C)C(C)(C)O3)c3cc(Cl)cnc32)cc1
Reactant: O[C@@H]1[C@H](O)CCC[C@@H]1Nc1nc(Cl)ncc1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: Cc1ccc(S(=O)(=O)n2cc(-c3ncc(F)c(N[C@H]4CCC[C@@H](O)[C@H]4O)n3)c3cc(Cl)cnc32)cc1
Temperature: 120 °C

Procedure:
To a deoxygenated solution of 5-chloro-1-(p-tolylsulfonyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[2,3-b]pyridine (0.22 g, 0.51 mmol) and (1R,2S,3S)-3-(2-chloro-5-fluoropyrimidin-4-ylamino)cyclohexane-1,2-diol, 31b, (0.08 g, 0.24 mmol) in acetonitrile (6 ml) was added 2M sodium carbonate (0.45 mL of 2 M solution, 0.894 mmol) and Pd(PPh3)4 (34.5 mg, 0.030 mmol). The reaction was sealed and heated to 120° C. for 15 minutes in the microwave. The rxn was diluted with EtOAc and filtered thru florisil. The solution was concentrated to crude and purified via silica gel chromatography (DCM to 20% MeOH/DCM) to give compound 31c (0.11 g) as a pink solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]Cl)=[CH:4][N:3]=1.[NH:10]1[CH:14]=[CH:13][N:12]=[CH:11]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:10]2[CH:14]=[CH:13][N:12]=[CH:11]2)=[CH:4][N:3]=1
Reactant: c1c[nH]cn1
Reactant: ClCc1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Clc1ccc(Cn2ccnc2)cn1
Temperature: 80 °C
Yield: 68.7 %

Procedure:
To a solution of 2-chloro-5-(chloromethyl)pyridine (500 mg, 3.08 mmole) in 4 mL of dry acetonitrile is added 420 mL (6.17 mmol) of imidazole followed by 852 mg (6.17 mmol) of potassium carbonate. The reaction is heated at 80° C. for 20 h. After cooling, the reaction mixture is quenched with 5 mL of water, extracted three-times with methylene chloride, and dried over sodium sulfate. Concentration of the solvent provided an oil which was purified by silica gel chromatography to provide 410 mg (69% yield) of 2-Chloro-5-imidazol-1-ylmethyl-pyridine. Diagnostic C13 NMR (100 MHz, CDCl3) 47.7, 119.2, 124.9, 130.6, 131.1, 137.5, 137.8, 148.6, 151.8; MS 194.2 (M+H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:25])=[C:4]([C:10]2[CH:14]=[C:13]([CH2:15][CH2:16][NH:17]C(=O)OC(C)(C)C)[O:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:17][CH2:16][CH2:15][C:13]1[O:12][N:11]=[C:10]([C:4]2[CH:5]=[CH:6][C:7]([C:8]#[N:9])=[C:2]([Cl:1])[C:3]=2[CH3:25])[CH:14]=1
Reactant: Cc1c(-c2cc(CCNC(=O)OC(C)(C)C)on2)ccc(C#N)c1Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1c(-c2cc(CCN)on2)ccc(C#N)c1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
tert-Butyl (2-(3-(3-chloro-4-cyano-2-methylphenyl)isoxazol-5-yl)ethyl)-carbamate (0.56 g, 1.55 mmol) was dissolved to DCM (20 ml). To this mixture was added TFA (1.15 ml) and stirred at RT overnight. The reaction mixture was evaporated to dryness and dissolved to diethyl ether. 1 M HCl in diethyl ether solution was added and the mixture was stirred at RT for 2 h. The HCl salt of the title compound (0.20 g) was filtered and dried. 1H-NMR (400 MHz; d6-DMSO): δ 2.50 (s, 3H), 2.92 (m, 2H), 3.22 (m, 2H), 6.88 (s, 1H), 7.65 (d, 1H), 7.98 (d, 1H), 8.23 (bs, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:31])[NH:10][CH2:11][CH2:12][CH2:13][N:14]([CH:21]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH2:24][CH2:23][CH2:22]2)[CH2:15][CH2:16][CH2:17][C:18](O)=[O:19])=[CH:4][CH:3]=1.[C:32]1([S:38]([NH2:41])(=[O:40])=[O:39])[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.CCN=C=NCCCN(C)C.Cl>C(Cl)Cl.CN(C1C=CN=CC=1)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:31])[NH:10][CH2:11][CH2:12][CH2:13][N:14]([CH:21]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH2:24][CH2:23][CH2:22]2)[CH2:15][CH2:16][CH2:17][C:18](=[O:19])[NH:41][S:38]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)(=[O:40])=[O:39])=[CH:4][CH:3]=1
Reactant: NS(=O)(=O)c1ccccc1
Reactant: O=C(O)CCCN(CCCNC(=O)Nc1ccc(Br)cc1)C1CCCc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: O=C(CCCN(CCCNC(=O)Nc1ccc(Br)cc1)C1CCCc2ccccc21)NS(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 21 %

Procedure:
To a mixture of 4-[[3-(4-bromophenylureido)propyl](1,2,3,4-tetrahydro-1-naphthyl)amino]butanoic acid (20 mg, 0.041 mmol) and benzenesulfonamide (7.0 mg, 0.045 mmol) in CH2Cl2 (1 ml) were added WSC.HCl (8.6 mg, 0.045 mmol) and DMAP (5.5 mg, 0.045 mmol), and the mixture was stirred at RT for 18 h. The reaction mixture was purified by preparative normal phase HPLC using linear gradients of (A) chloroform and (B) methanol (2-4% B, in 0-2 min; 4-5% B, in 2-6 min; 5% B, in 6-12 min) at a flow rate of 12 ml/min. Fractions containing the major peak were pooled and concentrated to afford 3-[[3-(4-bromophenylureido)propyl](1,2,3,4-tetrahydro-1-naphthyl)amino]-1-[(phenylsulfonyl)carbamoyl]propane (5.4 mg, 21%): MS(ES+) m/e 627 [M+H]+; 1H NMR (400 MHz, CDCl3) δ 8.27 (s, 1H), 8.05 (m, 2H), 7.50 (m, 3H), 7.44 (d, J=8.8 Hz, 2H), 7.31 (d, J=9.0 Hz, 2H), 7.23 (m, 3H), 7.15 (d, J=7.0 Hz, 1H), 7.02 (m, 1H), 6.92 (m, 1H), 4.72 (m, 1H), 3.73 (m, 1H), 3.58 (m, 1H), 3.21 (m, 1H), 2.96 (m, 1H), 2.79-2.65 (m, 5H), 2.57 (m, 1H), 2.17 (m, 1H), 2.03 (m, 1H), 1.94-1.66 (m, 4H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[CH:15]=[CH:14][C:13]([I:16])=[CH:12][N:11]3[CH:17]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:25][CH2:26][CH2:27][O:28][Si:29]([C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:31])[CH3:30].[Cl-].[Na+]>CN(C)C=O>[O:28]([CH2:27][CH2:26][CH2:25][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]3[CH:15]=[CH:14][C:13]([I:16])=[CH:12][N:11]3[CH:17]=2)=[CH:6][CH:7]=1)[Si:29]([C:32]([CH3:34])([CH3:33])[CH3:35])([CH3:30])[CH3:31]
Reactant: Oc1ccc(-c2cn3cc(I)ccc3n2)cc1
Reactant: CC(C)(C)[Si](C)(C)OCCCBr
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCCCOc1ccc(-c2cn3cc(I)ccc3n2)cc1
Temperature: 25 °C
Reaction time: 192 h
Yield: 50.3 %

Procedure:
2.00 g (corresponding to 5.95 mmol) of 2-(4′-hydroxyphenyl)-6-iodoimidazo[1,2-a]pyridine was dissolved in 30.0 mL of dimethylformamide, and 2.47 g (corresponding to 17.9 mmol) of potassium carbonate was added. Then, 1.51 g (corresponding to 5.95 mmol) of 1-bromo-3-(t-butyldimethylsiloxy)propane was added thereto. After the reaction mixture was stirred at room temperature for 8 days, it was supplemented with a saturated sodium chloride aqueous solution, and extracted three times with ethyl acetate. The combined ethyl acetate layers were dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (elution solvent: hexane/ethyl acetate=1/1) to obtain 1.52 g (corresponding to 2.99 mmol) of 2-[4′-(3″-t-butyldimethylsiloxypropoxy)phenyl]-6-iodoimidazo[1,2-a]pyridine (FIG. 10, Step 4).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:11]2[CH:16]=[CH:15][C:14]([O:17]C)=[CH:13][C:12]=2[CH3:19])=[C:8]([CH3:10])[CH:9]=1)=[O:4].B(Br)(Br)Br>ClCCl>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][C:12]=2[CH3:19])=[C:8]([CH3:10])[CH:9]=1)=[O:4]
Reactant: COC(=O)c1cc(C)c(-c2ccc(OC)cc2C)s1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: COC(=O)c1cc(C)c(-c2ccc(O)cc2C)s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.1 %

Procedure:
To a 0° C. solution of 5-(4-methoxy-2-methyl-phenyl)-4-methyl-thiophene-2-carboxylic acid methyl ester (540 mg, 2 mmol) in dichloromethane (30 mL) is added BBr3 in dichloromethane (1N, 5.0 mL) and the mixture is stirred at ambient temperature overnight. The reaction is quenched by addition of methanol and evaporated. The residue is purified by column chromatography on silica gel eluting with 0-20% EtOAc in hexanes to give the title compound (420 mg, 82%). 1H NMR (CDCl3): δ 7.62 (s, 1H), 7.10 (d, 1H, J=7.9 Hz), 6.76 (s, 1H), 6.70 (d, 1H, J=7.9 Hz), 4.79 (bs, 1H), 3.88 (s, 3H), 2.15 (s, 3H), 2.02 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH:8]([C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)[OH:9])=[N:4][CH:5]=[CH:6][N:7]=1>C1(C)C=CC=CC=1.O=[Mn]=O>[Cl:1][C:2]1[C:3]([C:8]([C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)=[O:9])=[N:4][CH:5]=[CH:6][N:7]=1
Reactant: OC(c1cccnc1)c1nccnc1Cl
Agent: O=[Mn]=O
Solvent: Cc1ccccc1
Product: O=C(c1cccnc1)c1nccnc1Cl
Temperature: 25 °C

Procedure:
MnO2 (1.82 g, 20.95 mmol) is added to a solution of (3-chloro-pyrazin-2-yl)-pyridin-3-yl-methanol (929 mg, 4.19 mmol) in toluene (35 ml), and the reaction heated at reflux for 2 hours. The reaction is allowed to cool to room temperature and filtered through a pad of celite, which is washed with toluene. The solvent is removed in vacuo to afford (3-Chloro-pyrazin-2-yl)-pyridin-3-yl-methanone as a pale brown solid which is used in step 3 with no further purification [M+H]+ 220.