Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([C:10]2[O:11][C:12]3[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[C:27](O)=[O:28])=[CH:15][C:13]=3[CH:14]=2)[S:8][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[S:37]([NH2:40])(=[O:39])=[O:38].Cl.CN(C)CCCN=C=NCC>CN(C)C1C=CN=CC=1.CN(C)C=O>[C:1]([C:5]1[N:6]=[C:7]([C:10]2[O:11][C:12]3[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[C:27]([NH:40][S:37]([C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=4[CH3:30])(=[O:38])=[O:39])=[O:28])=[CH:15][C:13]=3[CH:14]=2)[S:8][CH:9]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)c1csc(-c2cc3cc(OCc4ccccc4C(=O)O)ccc3o2)n1
Reactant: Cc1ccccc1S(N)(=O)=O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Product: Cc1ccccc1S(=O)(=O)NC(=O)c1ccccc1COc1ccc2oc(-c3nc(C(C)(C)C)cs3)cc2c1
Temperature: 0 °C
Yield: 101.7 %

Procedure:
A solution of 4-tert-butyl-2-[5-(2-carboxyphenylmethoxy)benzofuran-2-yl]thiazole (0.2 g), 2-methylbenzenesulfonamide (0.11 g), 4-dimethylaminopyridine (0.12 g) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.19 g) in N,N-dimethylformamide (10 ml) was stirred at ambient temperature for 1 day. The resulting mixture was poured into ice-water. The resulting precipitates were collected by filtration and washed with water. The crude compound was subjected to column chromatography on silica gel and eluted with a mixture of chloroform and methanol (40:1). The fractions containing object compound were combined and concentrated under reduced pressure to give an oil. The oil was crystallized with ethanol and filtered to give 4-tert-butyl-2-{5-[2-(2-methylbenzenesulfonamidocarbonyl)phenylmethoxy]benzofuran-2-yl}thiazole (0.28 g).
Reaction SMILES: [C:1]([OH:10])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].O.[OH-].[Li+:13].O>CC(O)C>[C:1]([O-:10])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].[Li+:13]
Reactant: O=C(O)c1ccccc1O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)O
Product: O=C([O-])c1ccccc1O
Yield: 70.3 %

Procedure:
To a flask were added 10.0 g salicylic acid, 2.9 g lithium hydroxide monohydrate, 20 ml of water and 100 ml 2-propanol. The mixture was heated to 50 C for 1.5 hours and then cooled and the solvent was removed under reduced pressure. The product was slurried in 25 ml diethyl ether, filtered and washed with diethyl ether. After drying, 7.0 g of a white solid was obtained.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:6][CH2:5][N:4]([C:7]2[CH:12]=[CH:11][C:10]([N+:13]([O-])=O)=[C:9]([C:16]([F:19])([F:18])[F:17])[CH:8]=2)[CH2:3]1>[Pd]>[CH3:1][C@H:2]1[CH2:6][CH2:5][N:4]([C:7]2[CH:12]=[CH:11][C:10]([NH2:13])=[C:9]([C:16]([F:19])([F:17])[F:18])[CH:8]=2)[CH2:3]1
Reactant: C[C@H]1CCN(c2ccc([N+](=O)[O-])c(C(F)(F)F)c2)C1
Agent: [Pd]
Product: C[C@H]1CCN(c2ccc(N)c(C(F)(F)F)c2)C1
Reaction time: 8 h
Yield: 95.4 %

Procedure:
A flask charged with (S)-3-methyl-1-(4-nitro-3-(trifluoromethyl)phenyl)pyrrolidine (1 g, 3.646 mmol) and palladium (100 mg, 0.9397 mmol) was flushed with N2 followed by evacuating under vacuum. Methanol (10 mL) was added under inert atmosphere followed by evacuating under vacuum. The reaction placed under an atmosphere of hydrogen and the reaction was stirred overnight. Pd/C was removed by filtration and solvent was removed under reduced pressure to give (S)-4-(3-methylpyrrolidin-1-yl)-2-(trifluoromethyl)aniline (850 mg, 95%) MS 245.0 m/z (MH+).
Reaction SMILES: C([O:8][C:9]([C:11]1[N:12]=[C:13]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[O:14][C:15]=1[CH2:16][CH3:17])=[O:10])C1C=CC=CC=1>C(O)C.[Pd]>[CH2:16]([C:15]1[O:14][C:13]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[N:12][C:11]=1[C:9]([OH:10])=[O:8])[CH3:17]
Reactant: CCc1oc(-c2ccccc2)nc1C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: CCc1oc(-c2ccccc2)nc1C(=O)O

Procedure:
A solution of 5-ethyl-2-phenyl-oxazole-4-carboxylic acid benzyl ester (1 g, 3.25 mmol) in 30 mL of ethanol was hydrogenated at 30 psi with 10% Pd/C (200 mg) at room temperature for two hours. The reaction mixture was filtered through a celite plug, evaporated and placed under high vacuum to give 5-ethyl-2-phenyl-oxazole-4-carboxylic acid, that was used without further purification. LCMS calcd for C12H11NO3 (m/e) 217, obsd 218 (M+H).
Reaction SMILES: [F:1][C:2]1[C:3](F)=[C:4]2[O:9][CH2:8][CH:7]([CH3:10])[N:6]3[CH:11]=[C:12]([C:17]([OH:19])=[O:18])[C:13](=[O:16])[C:14]([CH:15]=1)=[C:5]23.[NH2:21][C:22]1[CH:30]=[CH:29][CH:28]=[C:27]2[C:23]=1[CH2:24][NH:25][CH2:26]2>CN(C=O)C>[NH2:21][C:22]1[CH:30]=[CH:29][CH:28]=[C:27]2[C:23]=1[CH2:24][N:25]([C:3]1[C:2]([F:1])=[CH:15][C:14]3[C:13](=[O:16])[C:12]([C:17]([OH:19])=[O:18])=[CH:11][N:6]4[CH:7]([CH3:10])[CH2:8][O:9][C:4]=1[C:5]=34)[CH2:26]2
Reactant: CC1COc2c(F)c(F)cc3c(=O)c(C(=O)O)cn1c23
Reactant: Nc1cccc2c1CNC2
Solvent: CN(C)C=O
Product: CC1COc2c(N3Cc4cccc(N)c4C3)c(F)cc3c(=O)c(C(=O)O)cn1c23
Yield: 53.9 %

Procedure:
157 mg of 9,10-difluoro-2,3-dihydro-3-methyl-7-oxo-7H-pyrido[1,2,3-de][1,4]-benzoxazine-6-carboxylic acid, 242 mg of 4-aminoisoindoline, and 1.5 ml of anhydrous DMF were processed in the same manner as in Example 2 to produce 119 mg of the target compound.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[C:3]1[CH2:7][N:8]1[C:13]2[CH:14]=[C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[S:16][C:12]=2[C:11](=[O:23])[N:10]([CH:24]2[CH2:29][CH2:28][N:27](C(OC(C)(C)C)=O)[CH2:26][CH2:25]2)[C:9]1=[O:37].[ClH:38]>O1CCOCC1>[ClH:38].[CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[C:3]1[CH2:7][N:8]1[C:13]2[CH:14]=[C:15]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[S:16][C:12]=2[C:11](=[O:23])[N:10]([CH:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[C:9]1=[O:37]
Reactant: Cn1ccnc1Cn1c(=O)n(C2CCN(C(=O)OC(C)(C)C)CC2)c(=O)c2sc(-c3ccccc3)cc21
Agent: Cl
Solvent: C1COCCO1
Product: Cn1ccnc1Cn1c(=O)n(C2CCNCC2)c(=O)c2sc(-c3ccccc3)cc21

Procedure:
According to the procedure described for compound B92 tert-butyl 4-{1-[(1-methyl-1H-imidazol-2-yl)methyl]-2,4-dioxo-6-phenyl-1,4-dihydrothieno[3,2-d]pyrimidin-3(2H)-yl}piperidine-1-carboxylate (1.00 g, compound B71) and a solution of hydrogen chloride in 1,4-dioxane (5.0 ml, 6.8 M) are reacted in 1,4-dioxane (25 ml) to afford the title compound as a solid.
Reaction SMILES: C(O[CH:4](OCC)[CH2:5][Br:6])C.[NH2:10][C:11]1[CH:16]=[C:15]([CH3:17])[CH:14]=[C:13](Br)[N:12]=1.C(OCC)(=O)C>O>[Br:6][C:5]1[N:12]2[CH:13]=[CH:14][N:10]=[C:11]2[CH:16]=[C:15]([CH3:17])[CH:4]=1
Reactant: Cc1cc(N)nc(Br)c1
Reactant: CCOC(CBr)OCC
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1cc(Br)n2ccnc2c1
Temperature: 90 °C
Reaction time: 3 h
Yield: 76 %

Procedure:
A mixture of bromoacetaldehyde diethyl acetal (20 mL), concentrated hydrobomic acid (5 mL) and water (20 mL) is heated at 90° C. for 1.5 h. The reaction mixture is poured into 250 mL of water and 50 g sodium bicarbonate is gradually added. 2-Amino-6-bromo-4-methylpyridine (3 g, 0.016 mol) is then added and the mixture is stirred at room temperature for 3 h. Ethyl acetate (100 mL) and water (50 mL) are added. The organic layer is separated and extracted with hydrochloric acid (1N, 3×100 mL). The combined aqueous layer is neutralized with ammonium hydroxide at 0° C. and extracted with dichloromethane (3×200 mL). The combined organic layer is dried over sodium sulfate. Evaporation of the solvent gave 5-bromo-7-methylimidazo[1,2-a]pyridine (2.95 g, 76%) as a white solid, m.p. 53-54° C.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([N:8]2[N:12]=[N:11][C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[NH:19]1[CH:23]=[CH:22][N:21]=[CH:20]1.C(=O)([O-])[O-].[K+].[K+].NC1CCCCC1N.Cl.CCOCC>C(Cl)Cl.CCOCC.[Cu]I>[N:19]1([C:2]2[CH:3]=[C:4]([N:8]3[N:12]=[N:11][C:10]([C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=4)=[N:9]3)[CH:5]=[CH:6][CH:7]=2)[CH:23]=[CH:22][N:21]=[CH:20]1
Reactant: Ic1cccc(-n2nnc(-c3ccccn3)n2)c1
Reactant: c1c[nH]cn1
Agent: [Cu]I
Agent: Cl
Agent: NC1CCCCC1N
Solvent: ClCCl
Solvent: CCOCC
Product: c1ccc(-c2nnn(-c3cccc(-n4ccnc4)c3)n2)nc1
Temperature: 100 °C

Procedure:
2-[2-(3-Iodophenyl)-2H-tetrazol-5-yl]pyridine (520 mg, 1.5 mmol), imidazole (133 mg, 2.0 mmol), potassium carbonate (435 mg, 3.2 mmol), copper (I) iodide (57 mg, 0.3 mmol) and 1,2-diamino cyclohexane (90 μL, 0.8 mmol) were weighed into a flask and flushed with Ar(g). Dry dioxane (0.7 mL) was added and the reaction mixture heated at 100° C. for 18 h. The reaction mixture was then poured into NH4OH (10% in H2O), NH4Cl (sat aq) (1/1, 10 mL) and shaken with EtOAc (30 mL). The organic layer was separated and the aqueous layer extracted with EtOAc (3×30 mL), the combined organics were dried over Na2SO4, filtered and concentrated onto silica gel. Purification by liquid chromatography on silica gel (hexane:EtOAc=90:10) gave a yellow solid. This was recrystallized from EtOAc/Hexane to give yellow crystals which were dissolved in CH2Cl2/Et2O and HCl in ether (1.5 equiv) was added. The resulting precipitate was filtered off to afford 2-{2-[3-(1H-imidazol-1-yl)phenyl]-2H-tetrazol-5-yl}pyridine as a yellow solid. 1H NMR ((CD3)2SO, 300 MHz) δ 9.94 (s, 1H), 8.23-8.84 (m, 1H), 8.68-8.69 (m, 1H), 8.48-8.49 (m, 1H), 8.39-8.42 (m, 1H), 8.30-8.33 (m, 1H) 8.07-8.13 (m, 2H), 7.97-8.03 (m, 2H), 7.63-7.67 (m, 1H). MS (ESI) 262.2 (MH-N2)+.
Reaction SMILES: [CH2:1]([N:8]1[C:13]2[NH:14][N:15]=[C:16]([NH:17][CH3:18])[C:12]=2[C:11](=[O:19])[N:10]([CH2:20][CH2:21][CH2:22][CH3:23])[C:9]1=[O:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CI.[C:27](=O)([O-])[O-].[K+].[K+]>>[CH2:1]([N:8]1[C:13]2=[N:14][N:15]([CH3:27])[C:16]([NH:17][CH3:18])=[C:12]2[C:11](=[O:19])[N:10]([CH2:20][CH2:21][CH2:22][CH3:23])[C:9]1=[O:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: CCCCn1c(=O)c2c(NC)n[nH]c2n(Cc2ccccc2)c1=O
Agent: [K+]
Solvent: CI
Product: CCCCn1c(=O)c2c(NC)n(C)nc2n(Cc2ccccc2)c1=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 56.3 %

Procedure:
A mixture of 7-benzyl-5-butyl-3-methylaminopyrazolo[3,4-d]pyrimidine-4,6(5H,7H)-dione (1.5 g, 4.58 mM), methyl iodide (0.48 ml, 6 mM) and potassium carbonate (0.82 g, 6 mM) was stirred at room temperature for 12 hours. The mixture was concentrated to dryness and the residue was extracted with chloroform and water. The organic layer was washed with water, dried (MgSO4) and concentrated to dryness to give a solid. Recrystallization from 80% ethanol gave colorless needles (0.88 g, 50%), m.p. 146°-148° C.
Reaction SMILES: [C:1]([C:4]1[CH:13]=[C:12]2[C:7]([CH:8]=[C:9]([NH:37][C:38]([O:40][CH2:41][C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)=[O:39])[C:10]([C:14]([NH:16][C:17]3[CH:18]=[N:19][CH:20]=[CH:21][C:22]=3[N:23]3[CH2:28][CH2:27][CH2:26][C@H:25]([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[CH2:24]3)=[O:15])=[N:11]2)=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[CH2:48]1COCC1>C[Mg]Br.CCOC(C)=O.Cl>[C:32]([O:31][C:30]([NH:29][C@H:25]1[CH2:26][CH2:27][CH2:28][N:23]([C:22]2[CH:21]=[CH:20][N:19]=[CH:18][C:17]=2[NH:16][C:14]([C:10]2[C:9]([NH:37][C:38](=[O:39])[O:40][CH2:41][C:42]3[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=3)=[CH:8][C:7]3[C:12](=[CH:13][C:4]([C:1]([OH:3])([CH3:48])[CH3:2])=[CH:5][CH:6]=3)[N:11]=2)=[O:15])[CH2:24]1)=[O:36])([CH3:35])([CH3:34])[CH3:33]
Reactant: C1CCOC1
Reactant: CC(=O)c1ccc2cc(NC(=O)OCc3ccccc3)c(C(=O)Nc3cnccc3N3CCC[C@H](NC(=O)OC(C)(C)C)C3)nc2c1
Agent: C[Mg]Br
Agent: Cl
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N[C@H]1CCCN(c2ccncc2NC(=O)c2nc3cc(C(C)(C)O)ccc3cc2NC(=O)OCc2ccccc2)C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 92 %

Procedure:
To a mixture of tert-butyl [(3S)-1-(3-{[(7-acetyl-3-{[(benzyloxy)carbonyl]amino}quinolin-2-yl)carbonyl]amino}pyridin-4-yl)piperidin-3-yl]carbamate (0.100 g, 0.156 mmol) in THF (4.0 mL), methylmagnesium bromide in THF (3.0 M, 0.43 mL, 1.3 mmol) was added slowly at 0° C. under nitrogen. The reaction mixture was stirred at 0° C. for 1 h and was then allowed to warm to room temperature. The reaction mixture was diluted with EtOAc (10 mL), and 1 M HCl was slowly added to adjust the pH to 7. The aqueous layer was extracted twice with EtOAc. The organic extracts were combined, dried over Na2SO4, filtered and concentrated under reduced pressure to give the sub-title compound (94 mg, 92%). LCMS calc. for C36H43N6O6 (M+H)+: m/z=655.2. Found: 655.1.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([OH:8])=O.C(N1C=CN=C1)(N1C=CN=C1)=O.[Cl-].[Mg+2].[Cl-].[CH2:24]([O:26][C:27](=[O:32])[CH2:28]C([O-])=O)[CH3:25].[K+]>O1CCCC1.O>[O:8]=[C:6]([C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)[CH2:28][C:27]([O:26][CH2:24][CH3:25])=[O:32]
Reactant: O=C(O)c1cccs1
Reactant: CCOC(=O)CC(=O)[O-]
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [Cl-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)CC(=O)c1cccs1
Temperature: 25 °C
Reaction time: 1 h
Yield: 78.1 %

Procedure:
To a suspension of 2-thiophenecarboxylic acid (6.48 g, 50.57 mmol) in tetrahydrofurane (100 ml) at 5. was added 1,1′-Carbonyldiimidazole (8.61 g, 53.09 mmol) by portions. The mixture was allowed to warm to room temperature, and the stirring was continued for 1 hour. The reaction mixture was added into a suspension mixture of magnesium chloride (4.86 g, 51.07 mmol) and potassium 3-ethoxy-3-oxopropanoate (12.91 g, 75.85 mmol) in tetrahydrofurane (50 ml). After being stirred at 50. for 2 hours and at room temperature overnight, the reaction mixture was poured into water , and then extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica-gel (ethyl acetate/ hexane, 15/85) to give ethyl 3-oxo-3-(2-thienyl)propanoate (7.83 g, 78% yield) as a yellow oil.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH:6]([NH:8][C:9]1[S:10][CH:11]=[C:12]([C:14](=[N:18][O:19][CH2:20][CH2:21][O:22][CH:23]=[O:24])[C:15]([OH:17])=O)[N:13]=1)=[O:7].[NH2:25][CH:26]1[C:43](=[O:44])[N:28]2[C:29]([C:40]([OH:42])=[O:41])=[C:30]([CH2:33][S:34][C:35]3[S:36][CH:37]=[N:38][N:39]=3)[CH2:31][S:32][C@H:27]12.CC(C)(C)C(N)=O>C(OCC)(=O)C.O.CN(C)C=O>[CH:6]([NH:8][C:9]1[S:10][CH:11]=[C:12]([C:14](=[N:18][O:19][CH2:20][CH2:21][O:22][CH:23]=[O:24])[C:15]([NH:25][CH:26]2[C:43](=[O:44])[N:28]3[C:29]([C:40]([OH:42])=[O:41])=[C:30]([CH2:33][S:34][C:35]4[S:36][CH:37]=[N:38][N:39]=4)[CH2:31][S:32][C@H:27]23)=[O:17])[N:13]=1)=[O:7]
Reactant: NC1C(=O)N2C(C(=O)O)=C(CSc3nncs3)CS[C@H]12
Reactant: O=CNc1nc(C(=NOCCOC=O)C(=O)O)cs1
Agent: CC(C)(C)C(N)=O
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Solvent: CCOC(C)=O
Product: O=CNc1nc(C(=NOCCOC=O)C(=O)NC2C(=O)N3C(C(=O)O)=C(CSc4nncs4)CS[C@H]23)cs1
Yield: 31.5 %

Procedure:
Dry N,N-dimethylformamide (1.2 g.), phosphoryl chloride (2.5 g.), 2-(2-formamidothiazol-4-yl)-2-(2-formyloxyethoxyimino)acetic acid (syn isomer, 3.8 g.) and dry ethyl acetate (49.7 ml.) were treated in a similar manner to that of Example 1-(1) to give an activated acid solution. The solution was added to a solution of 7-amino-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid (4.4 g.) and trimethylacetamide (12.3 g.) in dry ethyl acetate (90 ml.) at -10° C., and stirred at -5° to -10° C. for an hour. Water (50 ml.) was added to the resultant solution and allowed to stand at room temperature. The ethyl acetate layer was separated, washed with a saturated aqueous solution of sodium chloride and dried over magnesium sulfate. After concentrating the solution in vacuo, the residue was pulverized with diisopropyl ether. The precipitates were collected by filtration, washed with diisopropyl ether and dried to give 7-[2-(2 -formamidothiazol-4-yl)-2-(2-formyloxyethoxyimino)acetamido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer, 2.5 g.).
Reaction SMILES: [Br:1][C:2]1[N:6]2[C:7](Br)=[CH:8][N:9]=[CH:10][C:5]2=[N:4][CH:3]=1.[NH4+:12].[OH-]>C1COCC1.C(Cl)Cl.Cl>[Br:1][C:2]1[N:6]2[CH:7]=[CH:8][N:9]=[C:10]([NH2:12])[C:5]2=[N:4][CH:3]=1
Reactant: Brc1cncc2ncc(Br)n12
Reactant: [NH4+]
Agent: Cl
Agent: [OH-]
Solvent: C1CCOC1
Solvent: ClCCl
Product: Nc1nccn2c(Br)cnc12
Temperature: 50 °C
Yield: 50 %

Procedure:
To a solution of 3,5-dibromo-imidazo[1,2-a]pyrazine (D) (500 mg, 1.8 mmol) in THF (4 ml) was added NH4OH (4 ml). The mixture was heated at 50° C. in sealed tube overnight. Additional NH4OH (4 ml) was added to the reaction mixture and was heated at 50° C. in sealed tube overnight. The mixture was then cooled to rt, diluted with DCM (200 ml) and IN HCl (50 ml). The organic layer was washed with 10N NaOH, brine, dried and concentrated. The residue was purified on a silica gel column to afford 190 mg (yield 50%) of 3-bromo-imidazo[1,2-a]pyrazin-8-ylamine.
Reaction SMILES: C([O:3][C:4]([CH2:6][CH:7]1[NH:12][C:11]2[CH:13]=[C:14]([Cl:21])[C:15]([S:17](=[O:20])(=[O:19])[NH2:18])=[CH:16][C:10]=2[S:9](=[O:23])(=[O:22])[NH:8]1)=[O:5])C.[OH-].[Na+]>C(O)C>[C:4]([CH2:6][CH:7]1[NH:12][C:11]2[CH:13]=[C:14]([Cl:21])[C:15]([S:17](=[O:20])(=[O:19])[NH2:18])=[CH:16][C:10]=2[S:9](=[O:22])(=[O:23])[NH:8]1)([OH:5])=[O:3]
Reactant: CCOC(=O)CC1Nc2cc(Cl)c(S(N)(=O)=O)cc2S(=O)(=O)N1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: NS(=O)(=O)c1cc2c(cc1Cl)NC(CC(=O)O)NS2(=O)=O

Procedure:
Combine 3-ethoxycarbonylmethyl-6-chloro-7-sulfamoyl-3, 4-dihydro-1,2,4-benzothiadiazine-1,1-dioxide (7.7 g) with ethanol (EtOH) (250 ml) and 1N sodium hydroxide (NaOH) (70 ml) for 4 hours. Concentrate to 50 ml, add 1N hydrochloric acid (HCl) (70 ml), and extract with ethyl acetate (EtOAc). Dry the EtOAc extract over anhydrous magnesium sulfate and concentrate to obtain 3-carboxymethyl-6-chloro-7-sulfamoyl-3,4-dihydro-1, 2,4-benzothiadiazine-1,1-dioxide.
Reaction SMILES: FC(F)(F)C(O)=O.[OH:8][C:9]1[CH:43]=[CH:42][C:12]([O:13][CH2:14][CH2:15][CH:16]2[CH2:21][CH2:20][N:19]([C:22]3[CH:23]=[N:24][CH:25]=[C:26]([O:28][CH2:29][C@@H:30]4[CH2:34][CH2:33][CH2:32][N:31]4C(OC(C)(C)C)=O)[CH:27]=3)[CH2:18][CH2:17]2)=[CH:11][CH:10]=1>C(Cl)Cl.O>[NH:31]1[CH2:32][CH2:33][CH2:34][C@H:30]1[CH2:29][O:28][C:26]1[CH:27]=[C:22]([N:19]2[CH2:18][CH2:17][CH:16]([CH2:15][CH2:14][O:13][C:12]3[CH:42]=[CH:43][C:9]([OH:8])=[CH:10][CH:11]=3)[CH2:21][CH2:20]2)[CH:23]=[N:24][CH:25]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1COc1cncc(N2CCC(CCOc3ccc(O)cc3)CC2)c1
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Oc1ccc(OCCC2CCN(c3cncc(OC[C@@H]4CCCN4)c3)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 52 %

Procedure:
Trifluoroacetic acid (1.5 mL) was added slowly to a solution of 3-[4-[2-(4-hydroxyphenoxy)ethyl]-1-piperidinyl]-5-[[1-(tert-butoxycarbonyl)-2(S)-pyrrolidinyl]methoxy]pyridine (260 mg) in CH2Cl2/H2O (7.5/0.15 mL) at room temperature under N2. The solution was stirred overnight at room temperature. After removing the solvent, the residue was purified by preparative HPLC (column: SunFire Prep C18, 100×19 mm, 5 μm particle size; UV detection at 254 nm; flow 18 mL/min; mobile phase: A, water with 0.05% CF3COOH; B, CH3CN; 5% to 30% B in A in 6 min). The eluate was partially evaporated under reduced pressure (bath 30° C.) to remove CH3CN. The residue was basified with saturated aqueous NaHCO3 solution and extracted with EtOAc. The combined organic layers were washed with brine and dried over Na2SO4. After concentration in vacuo, the free base (108 mg, 58%) was obtained as a yellowish solid. LC-MS (ESI) m/z 398 (M+H+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:9])[C:5]([Cl:8])=[N:6][CH:7]=1.Br[C:11]1[C:12](Cl)=[N:13]C=C(O)[CH:16]=1.ClC(C)C#N.C(=O)([O-])[O-].[Cs+].[Cs+]>C1COCC1.CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([O:9][CH:11]([CH3:16])[C:12]#[N:13])[C:5]([Cl:8])=[N:6][CH:7]=1
Reactant: Oc1cc(Br)cnc1Cl
Reactant: Oc1cnc(Cl)c(Br)c1
Agent: CC(Cl)C#N
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CC(C#N)Oc1cc(Br)cnc1Cl
Reaction time: 0.05 h

Procedure:
A dry 5 mL, one neck round bottom flask was charged with a 95-5 mixture of 5-bromo-2-chloropyridin-3-ol and 3-bromo-2-chloropyridin-5-ol (0.2031 g, 0.9744 mmol), a stirbar, 2 mL dry DMF and 2-chloropropanenitrile (0.4310 ml, 4.872 mmol). To the mixture was added cesium carbonate (CS2CO3) (0.3492 g, 1.072 mmol), and the flask was sealed with a septa. The reaction was heated using a 100° C. oil bath for 4 h, and cooled. The DMF was diluted with 4 mL THF, and the slurry was loaded onto 5 g of SiO2 wet-packed with THF. The silica was eluted with 50 mL THF, and the eluted volume was concentrated in vacuo. A sample was scouted for prep purification using a 2.1×50 mm Xterra MS C18 column with a 3.5 μm particle size (PN 186000400); A=10 mM NH4 HCO3 in water, pH adjusted with concentrated NH4OH to 9.6; B=ACN; gradient: initial@1 mL/min, 10% B; 0→5 min@1 mL/min, linear gradient to 100% B; 5→6.9 min@1 mL/min, isocratic at 100% B; 6.9→6.95 min@1 mL/min, linear gradient to 10% B, 8 min end. A major peak was observed at 2.87 minutes. The sample was purified using a 30×100 mm Waters Xterra Prep C18 OBD column (100 Å pore diameter, 5 μm particle size, spherical shape, PN 186001942); Gradient: 0→5 min@35 mL/min, 10% B; 5→20 min@35 mL/min, linear gradient to 40% B; 20→24.9 min@35 mL/min, isocratic at 40% B; 25.0 min→29.9 min@35 mL/min, step to 100% B; 30→40 min@35 mL/min, step to 10% B; 40 min end. A=10 mM NH4 HCO3 in water, pH adjusted with concentrated NOH to 9.6; B=ACN. A band that eluted from 23.6 to 25.4 minutes was isolated. The solvent was removed in vacuo to afford 2-(5-bromo-2-chloropyridin-3-yloxy)propanenitrile and 2-(5-bromo-2-chloropyridin-3-yloxy)propanenitrile (0.1316 g).
Reaction SMILES: [CH2:1]([N:3]1[C:9]2[N:10]=[CH:11][CH:12]=[CH:13][C:8]=2[C:7](=[O:14])[N:6]([CH3:15])[C:5]2[CH:16]=[CH:17][C:18](OS(C(F)(F)F)(=O)=O)=[N:19][C:4]1=2)[CH3:2].[CH2:28]([N:30]1[CH:34]=[C:33](I)[CH:32]=[N:31]1)[CH3:29]>>[CH2:1]([N:3]1[C:9]2[N:10]=[CH:11][CH:12]=[CH:13][C:8]=2[C:7](=[O:14])[N:6]([CH3:15])[C:5]2[CH:16]=[CH:17][C:18]([C:33]3[CH:32]=[N:31][N:30]([CH2:28][CH3:29])[CH:34]=3)=[N:19][C:4]1=2)[CH3:2]
Reactant: CCn1cc(I)cn1
Reactant: CCN1c2ncccc2C(=O)N(C)c2ccc(OS(=O)(=O)C(F)(F)F)nc21
Product: CCN1c2ncccc2C(=O)N(C)c2ccc(-c3cnn(CC)c3)nc21

Procedure:
The title compound (a foam, mp 60°-62° C.) was prepared from 5,11-dihydro-11-ethyl-5-methyl-2-trifluoromethanesulfonyloxy-6H-dipyrido[3,2-b:2',3'-e][1,4]diazepin-6-one and N-ethyl-4-iodopyrazole in a manner analogous to that described in Example 1.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](=[O:16])[CH:13]([CH3:15])[CH3:14])=[C:5]2O.C(=O)(O)[O-].[Na+].C(OCC)(=O)C.P(Cl)(Cl)([Cl:31])=O>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](=[O:16])[CH:13]([CH3:15])[CH3:14])=[C:5]2[Cl:31]
Reactant: CC(C)C(=O)c1cnc2ccc(Br)cc2c1O
Reactant: O=P(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CC(C)C(=O)c1cnc2ccc(Br)cc2c1Cl
Temperature: 85 °C
Reaction time: 1.5 h
Yield: 89 %

Procedure:
1-(6-Bromo-4-hydroxyquinolin-3-yl)-2-methylpropan-1-one (16.0 g, 54.4 mmol) was added to phosphoryl chloride (160 mL) and the reaction was stirred at 85° C. for 1.5 h. The reaction mixture was cooled and slowly poured into a 2:1 solution of satd. aq. sodium bicarbonate/ethyl acetate at 0° C. The organic layer was separated and was washed with satd. aq. sodium bicarbonate and brine, dried over anhydrous sodium sulfate, filtered, and concentrated to afford the desired product (14.8 g, 89%) as a yellow solid: ESI MS m/z 312 [C13H11BrClNO+H]+.