Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([OH:11])=[O:10])[CH:5]=[CH:6][CH:7]=1.Cl.[CH3:13]O>>[CH3:13][O:10][C:9](=[O:11])[CH2:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=1
Reactant: CO
Reactant: O=C(O)Cc1cccc(Br)c1
Agent: Cl
Product: COC(=O)Cc1cccc(Br)c1
Temperature: 58 °C
Yield: 96 %

Procedure:
3-bromophenylacetic acid (10000 mg, 46.50 mmol) was dissolved in methanol (200 mL) at room temperature and concentrated hydrochloric acid (4 mL) was added. The resulting solution was heated at 58° C. for 2 h then cooled to room temperature at which time the volatiles were removed in vacuo. The crude material was dissolved in ethyl acetate and the solution was carefully poured into a saturated aqueous sodium bicarbonate solution. The phases were separated and the combined organic extracts were dried over magnesium sulfate and concentrated under reduced pressure. The crude product was purified by MPLC (Biotage) with a gradient of 4 to 35% AcOEt/hexanes to give (3-bromo-phenyl)-acetic acid methyl ester as a colorless oil (10250 mg, 96%). GC-MS (MH+230 RT=9.34 min).
Reaction SMILES: [OH:1][CH2:2][C:3]12[CH2:10][CH2:9][C:6]([C:11]3[NH:19][C:18]4[C:17](=[O:20])[N:16]([CH2:21][CH2:22][CH3:23])[C:15](=[O:24])[NH:14][C:13]=4[N:12]=3)([CH2:7][CH2:8]1)[CH2:5][CH2:4]2.[H-].[Na+].Br[C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][N:29]=1>CN(C=O)C>[Cl:34][C:31]1[CH:32]=[CH:33][C:28]([O:1][CH2:2][C:3]23[CH2:8][CH2:7][C:6]([C:11]4[NH:19][C:18]5[C:17](=[O:20])[N:16]([CH2:21][CH2:22][CH3:23])[C:15](=[O:24])[NH:14][C:13]=5[N:12]=4)([CH2:9][CH2:10]2)[CH2:5][CH2:4]3)=[N:29][CH:30]=1
Reactant: Clc1ccc(Br)nc1
Reactant: CCCn1c(=O)[nH]c2nc(C34CCC(CO)(CC3)CC4)[nH]c2c1=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCn1c(=O)[nH]c2nc(C34CCC(COc5ccc(Cl)cn5)(CC3)CC4)[nH]c2c1=O
Temperature: 120 °C

Procedure:
To a solution of 8-(4-hydroxymethyl-bicyclo[2.2.2]oct-1-yl)-1-propyl-3,7-dihydro-purine-2,6-dione (0.2 g, 0.60 mmol) in DMF (4 ml) was added NaH (60% dispersion in mineral oil, 0.079 g, 1.98 mmol) at room temperature followed by 2-bromo-5-chloro-pyridine and maintained at 120° C. overnight. Reaction mixture was concentrated under reduced pressure quenched with water and was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulphate and concentrated under vacuum. The crude product was purified by column chromatography using 2% methanol in dichloromethane as solvent system.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:8]2[O:12][N:11]=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[Br:13]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:13][CH2:1][C:2]1[CH:3]=[C:4]([C:8]2[O:12][N:11]=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cccc(-c2ccno2)c1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: BrCc1cccc(-c2ccno2)c1

Procedure:
106 mg of 5-(3-methylphenyl)isoxazole, 119 mg of N-bromosuccinimide and 2 mg of benzoyl peroxide were dissolved in 10 ml of carbon tetrachloride, and the solution was refluxed for 3 hours with stirring. After cooling, the precipitate was separated by filtration, and concentrated under reduced pressure to give 5-(3-bromomethylphenyl)isoxazole as a pale yellow oily product.
Reaction SMILES: [C:1]([C:3]1[C:4]([Cl:18])=[N:5][C:6](Cl)=[CH:7][C:8]=1[C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=1[CH3:16])#[N:2].[NH:19]1[CH2:24][CH2:23][S:22][CH2:21][CH2:20]1>CO>[Cl:18][C:4]1[C:3]([C:1]#[N:2])=[C:8]([C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=2[CH3:16])[CH:7]=[C:6]([N:19]2[CH2:24][CH2:23][S:22][CH2:21][CH2:20]2)[N:5]=1
Reactant: Cc1cc(F)ccc1-c1cc(Cl)nc(Cl)c1C#N
Reactant: C1CSCCN1
Solvent: CO
Product: Cc1cc(F)ccc1-c1cc(N2CCSCC2)nc(Cl)c1C#N
Reaction time: 18 h
Yield: 88.4 %

Procedure:
Crude 3-cyano-2,6-dichloro-4-(4-fluoro-2-methylphenyl)pyridine, (32.44 g, 115.4 mmol) and 300 mL of methanol were added to a 500-mL, 3-necked flask (equipped with a 25-mL pressure-equilibrating addition funnel/dry N2 adapter, septum with teflon-coated thermocouple, and teflon paddle stirrer/glass shaft). Thiomorpholine (23.0 mL, 25.0 g, 242 mmol, 2.10 equiv) was added dropwise over a period of 22 minutes via the addition funnel, and the resulting mixture was stirred at 20–25° C. for 18 hours. The precipitate was filtered, washed with 30 mL of methanol, and dried to afford 35.47 g (88.4%) of 2-chloro-3-cyano-4-(4-fluoro-2-methylphenyl)-6-(thiomorpholino)pyridine as a beige solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=O.[NH2:11][C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[N:15][C:16]([O:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:17][CH:18]=2)[N:13]=1>O.C(#N)C>[O:22]([C:16]1[N:15]=[C:14]2[C:19]([CH:20]=[CH:21][C:12]([NH:11][C:5](=[O:7])[C:4]3[CH:8]=[CH:9][CH:10]=[C:2]([Br:1])[CH:3]=3)=[N:13]2)=[CH:18][CH:17]=1)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: O=C(O)c1cccc(Br)c1
Reactant: Nc1ccc2ccc(Oc3ccccc3)nc2n1
Solvent: CC#N
Solvent: O
Product: O=C(Nc1ccc2ccc(Oc3ccccc3)nc2n1)c1cccc(Br)c1
Temperature: 4 °C
Yield: 51.7 %

Procedure:
The procedure is analogous to that described in Example 1, but starting with 3-bromobenzoic acid (6 g), N,N'-carbonyldiimidazole (4.9 g) and 2-amino-7-phenoxy-1,8-naphthyridine (5.9 g). The product obtained by precipitation in water (9.8 g; m.p. 188°-192° C.) is dissolved in acetonitrile (300 cc). After cooling for 1 hour at 4° C., the crystallized solid is separated by filtration, washed with acetonitrile (3×10 cc) and dried at 40° C. under reduced pressure (0.07 kPa). N-(7-Phenoxy-1,8-naphthyridin-2-yl)-3-bromobenzamide (5.4 g), m.p. 194° C., is obtained.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C@@H:9]([CH2:14][CH2:15][CH2:16][C:17](OC)=[O:18])[C:10]([O:12][CH3:13])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].CC(C[Al]CC(C)C)C.O>C(OCC)C>[C:24]([O:23][C:21]([N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[C@H:9]([C:10]([O:12][CH3:13])=[O:11])[CH2:14][CH2:15][CH2:16][CH:17]=[O:18])=[O:22])([CH3:26])([CH3:27])[CH3:25]
Reactant: COC(=O)CCC[C@@H](C(=O)OC)N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Agent: CC(C)C[Al]CC(C)C
Solvent: CCOCC
Solvent: O
Product: COC(=O)[C@H](CCCC=O)N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Temperature: -70 °C
Reaction time: 1.5 h
Yield: 103 %

Procedure:
To a solution of the material from Step 2 (7.51 g, 19.08 mmol) in diethyl ether (95 mL) at −78° C. was slowly added 1.0 M Dibal-H (26.7 mL, 26.7 mmol) in hexanes. The reaction mixture was stirred at −70° C. for 90 minutes. Water (10 mL) was slowly added, and the reaction mixture was allowed to warm up to room temperature and aged for 30 minutes. Additional water (20 mL) was added, aged for 10 minutes with vigorous stirring. 8 g of celite was added to the reaction mixture, aged at room temperature for 5 minutes, filtered on a short pad of celite, rinsed with tert-butyl methyl ether (10×). The filtrate was washed with brine, dried over MgSO4, filtered and concentrated in vacuo to afford 7.06 g of the title compound that was used without further purification.
Reaction SMILES: Br[C:2]1[C:15]2[C:6](=[C:7]3[C:12](=[CH:13][CH:14]=2)[C:11]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:10][CH:9]=[N:8]3)[N:5]=[CH:4][CH:3]=1.[Li]CCCC.[B:27](OC)([O:30]C)[O:28]C.Cl>C1COCC1.CCCCCC>[C:16]1([C:11]2[C:12]3[C:7]([N:8]=[CH:9][CH:10]=2)=[C:6]2[C:15]([C:2]([B:27]([OH:30])[OH:28])=[CH:3][CH:4]=[N:5]2)=[CH:14][CH:13]=3)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: COB(OC)OC
Reactant: Brc1ccnc2c1ccc1c(-c3ccccc3)ccnc12
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: OB(O)c1ccnc2c1ccc1c(-c3ccccc3)ccnc12
Temperature: -39 °C
Reaction time: 0.5 h

Procedure:
4-Bromo-7-phenyl-1,10-phenanthroline (1.42 g) is dissolved in THF solvent (15 mL). The mixture is cooled to −39° C. and added over a period of 20 minutes to an n-hexane solution of n-BuLi (1.5 M; 3.12 mL) which has been cooled to −78° C. The reaction mixture is stirred for 30 minutes, followed by the addition of trimethyl borate (0.49 mL) in THF at −39° C. is added over a period of 20 minutes. The reaction mixture is maintained at −78° C. for one hour, then allowed to warn to room temperature over a day. The reaction mixture is acidified with cold 2N HCl extracted with ether. The organic layer is extracted with 1 N NaOH and filtered. To the filtrate is added 2 N HCl at 0° C. to yield a precipitate, which is filtered, washed, dried and re-crystallized from ethanol to give the desired product.
Reaction SMILES: [C:1](=[O:6])=[N:2][C:3](Cl)=[O:4].[CH3:7][C:8]1[O:12][C:11]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=2)=[N:10][C:9]=1[CH2:23][O:24][C:25]1[CH:26]=[C:27](/[C:31](/[CH2:36][CH3:37])=[CH:32]\[CH2:33][NH:34][OH:35])[CH:28]=[CH:29][CH:30]=1.Cl>C1COCC1>[CH3:7][C:8]1[O:12][C:11]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:21])([F:20])[F:22])=[CH:15][CH:14]=2)=[N:10][C:9]=1[CH2:23][O:24][C:25]1[CH:26]=[C:27](/[C:31](/[CH2:36][CH3:37])=[CH:32]/[CH2:33][N:34]2[C:3](=[O:4])[NH:2][C:1](=[O:6])[O:35]2)[CH:28]=[CH:29][CH:30]=1
Reactant: CC/C(=C/CNO)c1cccc(OCc2nc(-c3ccc(C(F)(F)F)cc3)oc2C)c1
Reactant: O=C=NC(=O)Cl
Agent: Cl
Solvent: C1CCOC1
Product: CC/C(=C\Cn1oc(=O)[nH]c1=O)c1cccc(OCc2nc(-c3ccc(C(F)(F)F)cc3)oc2C)c1
Reaction time: 0.5 h
Yield: 63.8 %

Procedure:
N-(Chlorocarbonyl)isocyanate (0.12 ml, 1.5 mmol) was added dropwise to a cold (-5° C.) mixture of (Z)-N-(3-{3-[5-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-ylmethoxy]-phenyl}-pent-2-enyl)-hydroxylamine (0.65 g, 1.5 mmol) in THF (10 ml). The mixture was stirred for 30 minutes, then poured into HCl (1N) and extracted with EtOAc. The organic extracts were dried over MgSO4. Evaporation and purification by flash chromatography on acid washed (5% H3PO4 /MeOH) silica gel (hexane/EtOAc 2/1) gave a white solid (0.48 g, 64% yield, mp 126°-127° C.). Analysis for: C25H22F3N3O5Calc'd: C, 59.88; H, 4.42; N, 8.38 Found: C, 60.03; H, 4.55; N, 8.03
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:10])[C@H:5]([C@@H:7]([CH3:9])[OH:8])[NH2:6].[CH3:11][O:12][C:13]1[CH:14]=[C:15]([CH:19]=[CH:20][C:21]=1[N+:22]([O-:24])=[O:23])[C:16](O)=[O:17].CCN=C=NCCCN(C)C.Cl.C(N(CC)C(C)C)(C)C>CN(C1C=CN=CC=1)C.ClCCl>[CH3:2][O:3][C:4](=[O:10])[C@H:5]([C@@H:7]([CH3:9])[OH:8])[NH:6][C:16](=[O:17])[C:15]1[CH:19]=[CH:20][C:21]([N+:22]([O-:24])=[O:23])=[C:13]([O:12][CH3:11])[CH:14]=1
Reactant: COc1cc(C(=O)O)ccc1[N+](=O)[O-]
Reactant: COC(=O)[C@@H](N)[C@@H](C)O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)[C@@H](NC(=O)c1ccc([N+](=O)[O-])c(OC)c1)[C@@H](C)O
Yield: 94.6 %

Procedure:
The same operation as in Example (102a) was performed using threonine methyl ester hydrochloride (2.88 g, 17 mmol), 3-methoxy-4-nitrobenzoic acid (3 g, 15.2 mmol), WSC hydrochloride (3.83 g, 20 mmol), DMAP (0.18 g, 1.5 mmol), N,N-diisopropylethylamine (2.58 g, 20 mmol) and dichloromethane (40 mL). The resulting residue was purified by silica gel column chromatography (elution solvent: ethyl acetate/hexane=1/2, 1/1, 2/1, 1/0) to obtain 4.49 g of the title compound as a light yellow amorphous solid (95%).
Reaction SMILES: N[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[CH3:11].[N+]([O-])([O-])=O.[Na+].[BrH:17]>O.[Cu]Br>[Br:17][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[CH3:11]
Reactant: Cc1cc(C(=O)O)ccc1N
Reactant: Br
Agent: [Cu]Br
Agent: O=[N+]([O-])[O-]
Agent: [Na+]
Solvent: O
Product: Cc1cc(C(=O)O)ccc1Br
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A suspension of compound of Example 1a (73 g, 0.483 mol) in water (411 mL) and 47% HBr (486 mL) was stirred at 25° C. for 1 h and then the reaction mixture was cooled to −2° C. A solution of sodium nitrate (32 g, 0.463 mol) in water (100 mL) was added to the reaction mixture over a period of 15 min, maintaining the temperature at −1° C. to −2° C. The reaction mixture was stirred at −1° C. to −2° C. for 1.5 h. The reaction mixture was added slowly to a suspension of copper(I)bromide (73 g, 0.508 mol) in water (73 mL) and aqueous HBr (73 mL). The reaction mixture was stirred at 25° C. for 1 h and then digested at 70° C. for 1 h. The solid was filtered, washed with water till the pH of the filtrate was 7 and dried to obtain the title compound. Yield: 94 g (90%); 1H NMR (DMSO-d6, 300 MHz): δ 2.37 (s, 3H, CH3), 7.64 (m, 2H, Ar), 7.87 (s, 1H, Ar); MS: m/e (ES−) 214 (M−1).
Reaction SMILES: [Br-].[CH3:2][C:3]1([CH3:36])[CH2:12][CH2:11][C:10]([CH3:14])([CH3:13])[C:9]2[CH:8]=[C:7]([CH:15]([P+](C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[CH3:16])[CH:6]=[CH:5][C:4]1=2.[CH3:37][C:38]1[CH:45]=[C:44]([CH3:46])[CH:43]=[CH:42][C:39]=1[CH:40]=O>>[CH3:16]/[C:15](/[C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[C:3]([CH3:36])([CH3:2])[CH2:12][CH2:11][C:10]2([CH3:14])[CH3:13])=[CH:40]\[C:39]1[CH:42]=[CH:43][C:44]([CH3:46])=[CH:45][C:38]=1[CH3:37]
Reactant: CC(c1ccc2c(c1)C(C)(C)CCC2(C)C)[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Cc1ccc(C=O)c(C)c1
Agent: [Br-]
Product: C/C(=C\c1ccc(C)cc1C)c1ccc2c(c1)C(C)(C)CCC2(C)C

Procedure:
In a manner analogous to that described in Example 1, from [1-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)ethyl]-triphenylphosphonium bromide and 2,4-dimethyl-benzaldehyde there can be obtained 6-[(E)-α,2,4-trimethylstyryl]-1,2,3,4-tetrahydro-1,1,4,4-tetramethylnaphthalene of melting point 54°-56° C.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[CH2:9][CH:8]2[O:10][CH2:11][CH2:12][O:13][CH:7]2[CH2:6]1.[F:14][C:15]1[CH:20]=[C:19]([Br:21])[CH:18]=[CH:17][C:16]=1[NH:22][C:23]1[C:32]2[C:27](=[CH:28][C:29]([O:34][CH3:35])=[C:30]([OH:33])[CH:31]=2)[N:26]=[CH:25][N:24]=1.C([O-])([O-])=O.[K+].[K+]>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C=O)C>[Br:21][C:19]1[CH:18]=[CH:17][C:16]([NH:22][C:23]2[C:32]3[C:27](=[CH:28][C:29]([O:34][CH3:35])=[C:30]([O:33][CH2:2][CH2:3][CH2:4][N:5]4[CH2:9][CH:8]5[O:10][CH2:11][CH2:12][O:13][CH:7]5[CH2:6]4)[CH:31]=3)[N:26]=[CH:25][N:24]=2)=[C:15]([F:14])[CH:20]=1
Reactant: ClCCCN1CC2OCCOC2C1
Reactant: COc1cc2ncnc(Nc3ccc(Br)cc3F)c2cc1O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CN(C)C=O
Product: COc1cc2ncnc(Nc3ccc(Br)cc3F)c2cc1OCCCN1CC2OCCOC2C1
Temperature: 80 °C
Yield: 54.2 %

Procedure:
A mixture of 6-(3-chloropropyl)hexahydro-2H-[1,4]dioxino[2,3-c]pyrrole (0.58 g, 2.82 mmol, 1.2 eq), 4-((2-fluoro-4-bromophenyl)amino)-7-methoxyquinazolin-6-ol (0.49 g, 1.35 mmol, 1.0 eq), anhydrous K2CO3 (0.56 g, 4.05 mmol, 3.0 eq) and tetrabutylammonium iodide (25 mg, 0.06 mmol, 0.05 eq) in DMF (8 mL) was heated at 80° C. for 11 h. The reaction mixture was cooled to room temperature and quenched with water (10 mL). The resulted mixture was diluted with EtOAc (20 mL) and the organic phase was separated from the mixture. The water phase was extracted with EtOAc (20 mL×3). The combined organic phases were dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated in vacuo and the residue was purified by a silica gel column chromatography (20:1 (v/v) CH2Cl2/CH3OH) to give the crude product, which was recrystallized from CH2Cl2/PE to afford the title compound as a pale yellow solid (0.39 g, 54.00%), HPLC: 96.20%. The compound was characterized by the following spectroscopic data: MS (ESI, pos. ion) m/z: 535.1 (M+1); 1H NMR (400 MHz, CDCl3) δ: 2.13 (2H, m), 2.77 (2H, t, J=7.2 Hz), 2.84 (2H, dd, J=6.4, 10.4 Hz), 2.95 (2H, dd, J=4.0, 10.4 Hz), 3.56 (2H, m), 3.80 (2H, m), 4.02 (3H, s), 4.10 (2H, m), 4.25 (2H, t, J=6.4 Hz), 7.13 (1H, s), 7.26-7.37 (3H, m), 8.38 (1H, t, J=8.4 Hz), 8.67 (1H, s) ppm.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4](=[O:24])[N:5]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:6]([CH:12]([O:14]C(=O)C)[CH3:13])=[N:7]2.C(=O)([O-])[O-].[K+].[K+].O>CO>[OH:14][CH:12]([C:6]1[N:5]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:4](=[O:24])[C:3]2[C:8](=[CH:9][CH:10]=[CH:11][C:2]=2[CH3:1])[N:7]=1)[CH3:13]
Reactant: CC(=O)OC(C)c1nc2cccc(C)c2c(=O)n1-c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: Cc1cccc2nc(C(C)O)n(-c3ccccc3)c(=O)c12
Reaction time: 0.33 h

Procedure:
Compound 180 (0.011 g, 0.034 mmol) was dissolved in methanol (2 mL), and potassium carbonate (0.012 g, 0.085 mmol) was added. The reaction mixture was stirred for 20 min, and then water (20 mL) was added. The mixture was extracted with ethyl acetate (3×10 mL) and the combined organic extracts were washed with saturated brine (10 mL). The organic solution was dried (MgSO4), filtered and concentrated under reduced pressure to give compound 181. ESI-MS m/z=281 (MH+). The reaction described above and compound 181 are shown below.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[CH3:11].S(=O)(=O)(O)O.[C:17]([O-])(O)=O.[Na+]>CO>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH3:17])=[O:7])=[CH:4][C:3]=1[CH3:11]
Reactant: Cc1cc(C(=O)O)ccc1Br
Reactant: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1ccc(Br)c(C)c1

Procedure:
4-Bromo-3-methylbenzoic acid (10 g) was suspended in methanol (50 ml) containing conc. sulphuric acid (2 ml). The mixture was heated to reflux for 18 h. On addition of 8% NaHCO3 (100 ml) to the cooled reaction, a solid was formed which was collected by filtration. Drying in vacuo at 40°-45° gave the title compound as a liquid which recrystallised on cooling (10.25 g) m.p. 39.5°-40.5° C.
Reaction SMILES: [N:1]1([CH2:5][CH2:6][CH2:7][N:8]2[C:16]([O:17]C)=[N:15][C:14]3[C:9]2=[N:10][C:11]([O:20][CH2:21][CH2:22][CH2:23][CH3:24])=[N:12][C:13]=3[NH2:19])[CH2:4][CH2:3][CH2:2]1.Cl.O1CCOCC1>CO>[NH2:19][C:13]1[N:12]=[C:11]([O:20][CH2:21][CH2:22][CH2:23][CH3:24])[N:10]=[C:9]2[C:14]=1[NH:15][C:16](=[O:17])[N:8]2[CH2:7][CH2:6][CH2:5][N:1]1[CH2:2][CH2:3][CH2:4]1
Reactant: CCCCOc1nc(N)c2nc(OC)n(CCCN3CCC3)c2n1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: CCCCOc1nc(N)c2[nH]c(=O)n(CCCN3CCC3)c2n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 104 %

Procedure:
9-[3-(1-Azetidinyl)propyl]-2-(butyloxy)-8-(methyloxy)-9H-purin-6-amine (13 mg, 0.039 mmol) was dissolved in methanol (3 ml) and 4M hydrogen chloride in 1,4-dioxane (0.243 ml, 0.972 mmol) was added and the mixture stirred at room temperature for 18 hours. The solvent was removed in vacuo and the residue was dissolved in methanol and loaded onto an aminopropyl SPE cartridge (2 g). The cartridge was eluted with methanol and the solvent removed to give the title compound as a white solid (13 mg).
Reaction SMILES: CCN=C=NCCCN(C)C.[F:12][C:13]1[CH:18]=[CH:17][C:16]([N:19]2[C:24](=[O:25])[C:23]([C:26]([OH:28])=O)=[CH:22][CH:21]=[N:20]2)=[CH:15][CH:14]=1.CCN(C(C)C)C(C)C.[CH3:38][O:39][C:40]1[CH:79]=[CH:78][C:43]([CH2:44][N:45]2[C:49]3=[N:50][CH:51]=[CH:52][C:53]([O:54][C:55]4[CH:60]=[CH:59][C:58]([NH2:61])=[CH:57][C:56]=4[F:62])=[C:48]3[C:47]([NH:63][C@H:64]3[CH2:69][CH2:68][N:67]([C:70]([O:72][C:73]([CH3:76])([CH3:75])[CH3:74])=[O:71])[CH2:66][C@H:65]3[F:77])=[N:46]2)=[CH:42][CH:41]=1.C1C=CC2N(O)N=NC=2C=1>C(Cl)Cl>[CH3:38][O:39][C:40]1[CH:41]=[CH:42][C:43]([CH2:44][N:45]2[C:49]3=[N:50][CH:51]=[CH:52][C:53]([O:54][C:55]4[CH:60]=[CH:59][C:58]([NH:61][C:26]([C:23]5[C:24](=[O:25])[N:19]([C:16]6[CH:15]=[CH:14][C:13]([F:12])=[CH:18][CH:17]=6)[N:20]=[CH:21][CH:22]=5)=[O:28])=[CH:57][C:56]=4[F:62])=[C:48]3[C:47]([NH:63][C@H:64]3[CH2:69][CH2:68][N:67]([C:70]([O:72][C:73]([CH3:76])([CH3:74])[CH3:75])=[O:71])[CH2:66][C@H:65]3[F:77])=[N:46]2)=[CH:78][CH:79]=1
Reactant: O=C(O)c1ccnn(-c2ccc(F)cc2)c1=O
Reactant: COc1ccc(Cn2nc(N[C@H]3CCN(C(=O)OC(C)(C)C)C[C@H]3F)c3c(Oc4ccc(N)cc4F)ccnc32)cc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1ccc(Cn2nc(N[C@H]3CCN(C(=O)OC(C)(C)C)C[C@H]3F)c3c(Oc4ccc(NC(=O)c5ccnn(-c6ccc(F)cc6)c5=O)cc4F)ccnc32)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 39 %

Procedure:
EDCI (43.6 mg, 0.227 mmol) was added to a stirred mixture of 2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxylic acid (53.2 mg, 0.227 mmol, prepared according to the procedure for Example 19, Step C), HOBt-hydrate (34.8 mg, 0.227 mmol) and DIEA (0.0792 ml, 0.455 mmol) in DCM (1 mL) at ambient temperature, and the reaction mixture was stirred for 15 minutes at ambient temperature. ±(3R*,4S*)-tert-Butyl 4-(1-(4-methoxybenzyl)-4-(4-amino-2-fluorophenoxy)-1H-pyrazolo[3,4-b]pyridin-3-ylamino)-3-fluoropiperidine-1-carboxylate (66 mg, 0.114 mmol) was then added. The resulting solution was stirred for 18 hours at ambient temperature. To a separate 1 dram vial was added an additional equivalent of the 2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxylic acid, HOBt, DIEA, and EDCI in DCM (0.5 mL). This mixture was stirred for 15 minutes, then added to the original reaction mixture, which was stirred for an additional day at ambient temperature. The crude reaction mixture was loaded directly on to a preparative TLC plate (2 mm thickness) and eluted with 10% MeOH/DCM (Rf=0.70). A second preparative TLC plate (1 mm thickness, Rf=0.17) eluting with 1:1 EtOAc/hexanes was utilized to obtain pure product (35 mg, 39%)
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3]([C:6]([O:8][CH3:9])=[O:7])=[CH:2]1.C(Cl)Cl.[C:13]1([CH3:22])[C:14]([C:19](Cl)=[O:20])=[CH:15][CH:16]=[CH:17][CH:18]=1.O>CCOCC>[CH3:22][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C:19]([C:5]1[NH:1][CH:2]=[C:3]([C:6]([O:8][CH3:9])=[O:7])[CH:4]=1)=[O:20]
Reactant: Cc1ccccc1C(=O)Cl
Reactant: COC(=O)c1cc[nH]c1
Solvent: ClCCl
Solvent: CCOCC
Solvent: O
Product: COC(=O)c1c[nH]c(C(=O)c2ccccc2C)c1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
Under nitrogen at room temperature, methyl pyrrole-3-carboxylate (2.5 g., 20 mmoles) was combined with 75 ml. of methylene chloride. o-Toluoyl chloride (3.09 g., 20 mmoles) in 25 ml. of methylene chloride was added, followed by stannic chloride (4.6 ml., 40 mmoles) added at a fast dropwise rate via a needle and syringe. Progress of the reaction was followed by thin layer chromatography (silica gel with ethyl acetate-1/hexane-5/5% acetic acid as eluant). After stirring at room temperature for 2.5 hours, the reaction was cooled with an ice-water bath while 75 ml. of water was added dropwise. After addition was complete, the mixture was stirred for 15 minutes at room temperature, approximately an equal volume of ether was added, the organic layer separated, washed in sequence with water, 1 N sodium hydroxide, water and saturated brine, dried over anhydrous sodium sulfate, filtered and evaporated to yield methyl 5-(2-methylbenzoyl)pyrrole-3-carboxylate.
Reaction SMILES: Br[C:2]1[C:3]2[N:4]([N:8]=[C:9]([Cl:11])[N:10]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][C:15]=1B(O)O>>[Cl:11][C:9]1[N:10]=[C:3]2[C:2]([C:15]3[CH:16]=[C:17]([C:20]([F:23])([F:22])[F:21])[CH:18]=[CH:19][C:14]=3[O:13][CH3:12])=[CH:7][CH:6]=[CH:5][N:4]2[N:8]=1
Reactant: Clc1nc2c(Br)cccn2n1
Reactant: COc1ccc(C(F)(F)F)cc1B(O)O
Product: COc1ccc(C(F)(F)F)cc1-c1cccn2nc(Cl)nc12

Procedure:
2-Chloro-8-(2-methoxy-5-trifluoromethyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridine was prepared from 8-bromo-2-chloro-[1,2,4]triazolo[1,5-a]pyridine (0.500 g, 2.15 mmol) and 2-methoxy-5-trifluoromethylbenzeneboronic acid (0.710 g, 3.23 mmol) in a manner analogous to Example 311a to give product (0.636 g, 90%). MS=328 (MH)+. 315b) 7-[8-(2-Methoxy-5-trifluoromethyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamino]-1,2,4,5-tetrahydro-3-benzazepine-3-carboxylic acid tert-butyl ester was prepared from 2-chloro-8-(2-methoxy-5-trifluoromethyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridine (0.630 g, 1.92 mmol) and 7-amino-1,2,4,5-tetrahydro-3-benzazepine-3-carboxylic acid tert-butyl ester (0.605 g, 2.31 mmol) in a manner analogous to Example 311b to give product (0.750 g, 71%). 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 9.56 (s, 1H), 8.79 (d, 1H), 7.95 (s, 1H), 7.82 (d, 1H), 7.65 (d, 1H), 7.42 (m, 3H), 7.05 (m, 2H), 3.85 (s, 3H), 3.42 (m, 4H), 2.75 (m, 4H), 1.41 (s, 9H): MS=554 (MH)+.