Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].C([O:10][C:11]1[CH:16]=[CH:15][C:14](O)=[CH:13][CH:12]=1)C1C=CC=CC=1.FC(F)(F)S([O:23][CH2:24][C:25]([F:37])([F:36])[C:26]([F:35])([F:34])[C:27]([F:33])([F:32])[CH2:28][O:29][CH2:30][CH3:31])(=O)=O.[O-]S(C(F)(F)F)(=O)=O>COCCOC>[CH2:30]([O:29][CH2:28][C:27]([F:32])([F:33])[C:26]([F:34])([F:35])[C:25]([F:36])([F:37])[CH2:24][O:23][C:14]1[CH:15]=[CH:16][C:11]([OH:10])=[CH:12][CH:13]=1)[CH3:31]
Reactant: CCOCC(F)(F)C(F)(F)C(F)(F)COS(=O)(=O)C(F)(F)F
Reactant: Oc1ccc(OCc2ccccc2)cc1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: CCOCC(F)(F)C(F)(F)C(F)(F)COc1ccc(O)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 17.2 %

Procedure:
2.8 g of 60% sodium hydride in mineral oil was added to 100 ml of dry 1,2-dimethoxyethane. The mixture was stirred, and 10 g (0.0499 moles) of 4-benzyloxyphenol was added. The resulting solution was stirred for 30 minutes more, then was cooled down to room temperature using an ice bath. 19 g (0.0511 moles) of 5-ethoxy-2,2,3,3,4,4-hexafluoropentyl trifluoromethanesulfonate (prepared essentially as in Example 3) was then added slowly. When the triflate addition was complete, the ice bath was removed, and the product-containing mixture was stirred at room temperature overnight. The solvent was then removed under reduced pressure, and 200 ml of water, followed by 150 ml of diethyl ether, were added sequentially with stirring. Once all of the solids had dissolved, two homogeneous liquid layers formed. The layers were separated, and the aqueous layer was extracted twice with 150 ml aliquots of diethyl ether. The resulting ether layers were then combined, were washed once with 125 ml of 1 N aqueous sodium hydroxide and twice with 150 ml aliquots of deionized water, were dried using anhydrous magnesium sulfate, and were stripped to dryness using a rotary evaporator. The resulting solid was dissolved in ethanol and was hydrogenated for 18 hours at 60 psi (3100 torr) in the presence of a 10%-palladium-on-carbon catalyst. When the hydrogenation was complete, the catalyst solid was removed by filtration, and the solvent from the filtrate was removed using a rotary evaporator. The resulting material was purified using chromatography on silica gel (2.5% methanol in chloroform) to yield 2.85 g of 4-(5-ethoxy-2,2,3,3,4,4-hexafluoropentoxy)phenol.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[CH:6][C:5]([Br:9])=[CH:4][C:3]=1[C:10]([F:13])([F:12])[F:11].O.O.[C:16](O)(=[O:20])[C:17](O)=[O:18]>Cl.[OH-].[Na+]>[Br:9][C:5]1[CH:6]=[C:7]2[C:2]([NH:1][C:16](=[O:20])[C:17](=[O:18])[NH:8]2)=[C:3]([C:10]([F:13])([F:11])[F:12])[CH:4]=1
Reactant: Nc1cc(Br)cc(C(F)(F)F)c1N
Reactant: O=C(O)C(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=c1[nH]c2cc(Br)cc(C(F)(F)F)c2[nH]c1=O
Temperature: 25 °C
Yield: 71.4 %

Procedure:
A mixture of 2,3-diamino-5-bromobenzotrifluoride (150 mg, 0.612 mmol) and oxalic acid dihydrate (81 mg, 0.643 mmol, used as received) in 2N HCl (4 mL) was refluxed at 120°-5° C. for 3 h, then cooled to room temperature. The mixture was centrifuged and the liquid layer was removed. The yellow solid was washed twice by cold water (2×2 mL), collected by filtration, and dried at 60° C. for 2 h, affording 150 mg of crude title compound (81.9%) as a red powder. The crude compound was dissolved in 1N NaOH (6 mL) and filtered. The filtrate was acidified to pH=6, affording 135 mg of title compound. Recrystallization from DMSO/H2O gave 125 mg of pure title compound (68.3%) as red microcrystals. Mp: 307°-9° C. (dec. from 290° C.). IR (KBr, cm-1) 3412, 3250, 1756, 1706, 1606; 1H NMR (DMSO-d6): δ7.514 (d, 1H, J=1.5 Hz); 7.556 (d, 1H, J=1.5 Hz); 11.342 (s, 1H); 12.220 (s, 1H). HRMS: calcd for C9H4BrF3N2O2 (M+) m/z: 307.9407; found: 307.9420.
Reaction SMILES: [C:1]([O:5][C:6](=[O:9])[CH2:7][OH:8])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[N+](C1C=CC([O:21][C:22]([N:24]2[C:33]3[C:28](=[CH:29][C:30]([C:34]([F:37])([F:36])[F:35])=[CH:31][CH:32]=3)[C@@H:27]([NH:38][C:39]3[N:44]=[CH:43][C:42]([N:45]4[CH2:50][CH2:49][O:48][CH2:47][CH2:46]4)=[CH:41][N:40]=3)[CH2:26][C@H:25]2[CH2:51][CH3:52])=O)=CC=1)([O-])=O.C(=O)([O-])O.[Na+]>O1CCCC1.C(OCC)(=O)C>[C:1]([O:5][C:6]([CH2:7][O:8][C:22]([N:24]1[C:33]2[C:28](=[CH:29][C:30]([C:34]([F:35])([F:37])[F:36])=[CH:31][CH:32]=2)[C@@H:27]([NH:38][C:39]2[N:44]=[CH:43][C:42]([N:45]3[CH2:46][CH2:47][O:48][CH2:49][CH2:50]3)=[CH:41][N:40]=2)[CH2:26][C@H:25]1[CH2:51][CH3:52])=[O:21])=[O:9])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC[C@@H]1C[C@H](Nc2ncc(N3CCOCC3)cn2)c2cc(C(F)(F)F)ccc2N1C(=O)Oc1ccc([N+](=O)[O-])cc1
Reactant: CC(C)(C)OC(=O)CO
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC[C@@H]1C[C@H](Nc2ncc(N3CCOCC3)cn2)c2cc(C(F)(F)F)ccc2N1C(=O)OCC(=O)OC(C)(C)C
Temperature: 50 °C

Procedure:
Hydroxyacetic acid tert-butyl ester (70 mg) and sodium hydride (60%; 21 mg) were added to a solution of the compound obtained in Example 21 (1) above (200 mg) in tetrahydrofuran (3 ml) and the mixture was stirred at 50° C. for an hour. The reaction mixture was cooled to room temperature, a saturated sodium hydrogen carbonate aqueous solution and ethyl acetate were added and the organic layer was separated, washed with a saturated brine, dried over magnesium sulfate and concentrated in vacuo. The resulting residue was purified by column chromatography (NH-silica gel; hexane:ethyl acetate=9:1→3:2) to give the titled compound (183 mg). MS (m/z): 566 [M+H]+.
Reaction SMILES: C[O:2][C:3](=O)[CH:4]=[CH:5][C:6]1[NH:7][C:8](=[O:30])[C:9]2[C:10]3[N:19]([CH3:20])[C:18]([NH:21][C:22]4[C:27]([Cl:28])=[CH:26][CH:25]=[CH:24][C:23]=4[Cl:29])=[N:17][C:11]=3[CH:12]=[CH:13][C:14]=2[C:15]=1[CH3:16].C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[Cl:28][C:27]1[CH:26]=[CH:25][CH:24]=[C:23]([Cl:29])[C:22]=1[NH:21][C:18]1[N:19]([CH3:20])[C:10]2[C:9]3[C:8](=[O:30])[NH:7][C:6]([CH:5]=[CH:4][CH2:3][OH:2])=[C:15]([CH3:16])[C:14]=3[CH:13]=[CH:12][C:11]=2[N:17]=1
Reactant: COC(=O)C=Cc1[nH]c(=O)c2c(ccc3nc(Nc4c(Cl)cccc4Cl)n(C)c32)c1C
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: Cc1c(C=CCO)[nH]c(=O)c2c1ccc1nc(Nc3c(Cl)cccc3Cl)n(C)c12
Temperature: -78 °C
Yield: 33.9 %

Procedure:
A suspension of the product of Example 12 (100 mg, 0.22 mmol) in THF (7 mL) was cooled to −78° C. Sodium bis(trimethylsilyl)amide (1M in THF, 0.44 mmol) was added dropwise. The bright red solution was warmed to 0° C. for 15 minutes, then lithium aluminum hydride (1M in THF, 2.6 mmol) was added and the orange solution was warmed to room temperature for 0.5 h. The mixture was cooled to 0° C., quenched with saturated ammonium chloride and extracted with ethyl acetate. Column chromatography (3-6% MeOH—CH2Cl2) provided the title compound (32 mg, 34%), mp 298-300° C.; MS(ES) 429, 431 (MH+).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:20]([Br:24])(Br)(Br)[Br:21].[CH3:25][N:26]1[C:31]([C:32]([F:35])([F:34])[F:33])=[CH:30][C:29](=[O:36])[N:28]([C:37]2[CH:38]=[CH:39][C:40]3[S:44][N:43]=[C:42]([CH:45]=O)[C:41]=3[CH:47]=2)[C:27]1=[O:48]>C(Cl)Cl>[Br:21][C:20]([Br:24])=[CH:45][C:42]1[C:41]2[CH:47]=[C:37]([N:28]3[C:29](=[O:36])[CH:30]=[C:31]([C:32]([F:35])([F:34])[F:33])[N:26]([CH3:25])[C:27]3=[O:48])[CH:38]=[CH:39][C:40]=2[S:44][N:43]=1
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2ccc3snc(C=O)c3c2)c1=O
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2ccc3snc(C=C(Br)Br)c3c2)c1=O
Yield: 83.4 %

Procedure:
Triphenylphosphine (0.354 g, 0.00138 mol) is added to a solution of carbon tetrabromide (0.223 g, 0.000676 mol) in methylene chloride. The resultant mixture is stirred at room temperature for 10 minutes and treated dropwise with a solution of 5-[3,6-dihydro-3-methyl-2,6-dioxo-4-(trifluoromethyl)-1(2H)-pyrimidinyl]-1,2-benzisothiazole-3-carboxaldehyde (0.200 g, 0.000563 mol) in methylene chloride. The resultant mixture is stirred 20 minutes and concentrated in vacuo. The resultant residue is purified by flash column chromatography using silica gel and 10:1 methylene chloride/ethyl acetate to give the title product as a white solid (0.240 g, 83.6%, mp 260-262° C.) which is identified by NMR and IR spectral analyses.
Reaction SMILES: [NH2:1][C@@H:2]1[C:26](=[O:27])[N:4]2[C:5]([C:23]([OH:25])=[O:24])=[C:6]([CH:9]([S:17][C:18]3[NH:22][N:21]=[N:20][N:19]=3)[CH2:10][CH2:11][NH:12][S:13]([CH3:16])(=[O:15])=[O:14])[CH2:7][S:8][C@H:3]12.[C:28](OC(=N)N(C(C)C)C(C)C)([CH3:31])([CH3:30])[CH3:29]>C(Cl)Cl>[C:28]([O:24][C:23]([C:5]1[N:4]2[C:26](=[O:27])[C@@H:2]([NH2:1])[C@H:3]2[S:8][CH2:7][C:6]=1[CH:9]([S:17][C:18]1[NH:19][N:20]=[N:21][N:22]=1)[CH2:10][CH2:11][NH:12][S:13]([CH3:16])(=[O:15])=[O:14])=[O:25])([CH3:31])([CH3:30])[CH3:29]
Reactant: CC(C)N(C(=N)OC(C)(C)C)C(C)C
Reactant: CS(=O)(=O)NCCC(Sc1nnn[nH]1)C1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)C1=C(C(CCNS(C)(=O)=O)Sc2nnn[nH]2)CS[C@@H]2[C@H](N)C(=O)N12
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a suspension of 21.8 g (0.05 mol) of 7β-amino-3-[1-(2-methanesulfonamidoethyl)tetrazol-5-ylthiomethyl]-3-cephem-4-carboxylic acid in 500 ml of methylene chloride is added over a 30 minute interval a solution of 30.0 g (0.15 mol) of O-t-butyldiisopropylpseudourea in 100 ml of methylene chloride. The mixture is stirred at ambient temperature for 72 hours. The precipitate is removed by filtration and the filtrate is evaporated to a residue which is taken up in 200 ml of benzene and filtered again. The filtrate is extraced with three 100 ml portions of cold 1N hydrochloric acid. The aqueous extracts are layered with ethyl acetate and the pH is adjusted to 7.5 by addition of solid sodium bicarbonate. The organic layer is separated and the aqueous phase extracted with two 150 ml portions of ethyl acetate. The combined extracts are dried (MgSO4), filtered and evaporated to dryness to give 7β-amino-3-[1-(2-methanesulfonamidoethyl)tetrazol-5-ylthiomethyl]-3-cephem-4-carboxylic acid t-butyl ester.
Reaction SMILES: Cl[C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)=[CH:9][S:8][C:4]=2[N:5]=[CH:6][N:7]=1.[NH2:18][CH2:19][CH2:20][CH2:21][O:22][C:23]1[CH:24]=[C:25]([NH:29][C:30](=[O:32])[CH3:31])[CH:26]=[CH:27][CH:28]=1.C(N(C(C)C)CC)(C)C>CN(C)C=O>[F:17][C:14]1[CH:15]=[CH:16][C:11]([C:10]2[C:3]3[C:2]([NH:18][CH2:19][CH2:20][CH2:21][O:22][C:23]4[CH:24]=[C:25]([NH:29][C:30](=[O:32])[CH3:31])[CH:26]=[CH:27][CH:28]=4)=[N:7][CH:6]=[N:5][C:4]=3[S:8][CH:9]=2)=[CH:12][CH:13]=1
Reactant: Fc1ccc(-c2csc3ncnc(Cl)c23)cc1
Reactant: CC(=O)Nc1cccc(OCCCN)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(=O)Nc1cccc(OCCCNc2ncnc3scc(-c4ccc(F)cc4)c23)c1
Temperature: 120 °C
Yield: 75.8 %

Procedure:
A mixture of 4-chloro-5-(4-fluorophenyl)thieno[2,3-d]pyrimidine (100 mg, 0.378 mmol), N-[3-(3-amino-propoxy)-phenyl]-acetamide (94 mg, 0.45 mmol), diisopropylethylamine (147 mg, 1.14 mmol) and N,N-dimethylformamide (3.0 mL) was warmed to 120° C. for 20 minutes by microwave irradiation. The solvent was then concentrated in vacuo and the residue was dissolved in ethyl acetate (50 mL) and washed with of aqueous sodium bicarbonate (2×30 mL). The organic layer was concentrated in vacuo and purified by column chromatography over silica gel using 1% methanol in dichloromethane as eluant to give 125 mg (73%) of N-[3-(3-{[5-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]amino}propoxy)phenyl]acetamide as a white solid. MS [M+H] 437.1, 1H NMR (CDCl3) 6 (ppm) 8.50 (s, 1H), 7.41-7.36 (m, 2H), 7.25 (s, 1H), 7.21 (t, J=8.1 Hz, 1H), 7.07-6.95 (m, 3H), 6.94 (d, J=8.1 Hz, 1H), 6.55 (d, J=8.4 Hz, 1H), 5.01 (b, 1H), 3.89 (t, J=6.0 Hz, 2H), 3.64 (m, 2H), 2.19 (s, 3H), 1.98 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[C:13]#[C:14][C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][CH:23]=1)[C:18](O)=[O:19].F[B-](F)(F)F.[N:29]1(OC(N(C)C)=[N+](C)C)[C:33]2[CH:34]=[CH:35][CH:36]=CC=2N=N1.NCC1CC1.C(N(C(C)C)C(C)C)C>CN(C)C=O>[CH:34]1([CH2:33][NH:29][C:18](=[O:19])[C:17]2[CH:21]=[CH:22][CH:23]=[C:15]([C:14]#[C:13][C:3]3[C:4]([C:7]4[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=4)=[N:5][O:6][C:2]=3[CH3:1])[CH:16]=2)[CH2:36][CH2:35]1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: Cc1onc(-c2ccccc2)c1C#Cc1cccc(C(=O)O)c1
Agent: F[B-](F)(F)F
Agent: NCC1CC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1onc(-c2ccccc2)c1C#Cc1cccc(C(=O)NCC2CC2)c1
Temperature: 25 °C
Reaction time: 1.75 h
Yield: 86.9 %

Procedure:
To a solution of 3-(5-methyl-3-phenyl-isoxazol-4-ylethynyl)-benzoic acid (250 mg; 0.82 mmol) in N,N-dimethylformamide (4.8 mL) was added 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (318 mg, 0.99 mmol) at 0° C. After stirring for 15 min at this temperature, aminomethylcyclopropane (86 μl, 0.99 mmol) and N-ethyldiisopropylamine (0.85 mL, 4.94 mmol) were added and the reaction mixture was allowed to warm to ambient temperature. After 1.75 h stirring at ambient temperature, it was extracted with dichloromethane (300 mL) and aqueous sodium carbonate (2 M, 75 mL). The combined organic layers were washed with brine (75 mL), dried over sodium sulfate and concentrated. Purification by chromatography (SiO2, heptane:ethyl acetate=95:5 to 0:100) afforded the title compound (254 mg, 87%) as a white solid. MS: m/e=357.1 [M+H]+.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]1[S:10][CH:11]=[C:12]([C:14]2[CH:15]=[C:16]3[C:21](=[CH:22][CH:23]=2)[N:20]=[CH:19][N:18]=[C:17]3[NH:24][C:25]2[CH:30]=[CH:29][C:28]([O:31][C:32]3[CH:33]=[N:34][C:35]([CH3:38])=[CH:36][CH:37]=3)=[C:27]([CH3:39])[CH:26]=2)[N:13]=1)(C)(C)C.Cl.C(=O)([O-])[O-].[K+].[K+]>CCOC(C)=O.O>[NH2:7][CH2:8][C:9]1[S:10][CH:11]=[C:12]([C:14]2[CH:15]=[C:16]3[C:21](=[CH:22][CH:23]=2)[N:20]=[CH:19][N:18]=[C:17]3[NH:24][C:25]2[CH:30]=[CH:29][C:28]([O:31][C:32]3[CH:33]=[N:34][C:35]([CH3:38])=[CH:36][CH:37]=3)=[C:27]([CH3:39])[CH:26]=2)[N:13]=1
Reactant: Cc1ccc(Oc2ccc(Nc3ncnc4ccc(-c5csc(CNC(=O)OC(C)(C)C)n5)cc34)cc2C)cn1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1ccc(Oc2ccc(Nc3ncnc4ccc(-c5csc(CN)n5)cc34)cc2C)cn1
Yield: 67.9 %

Procedure:
(4-{4-[3-Methyl-4-(6-methyl-pyridin-3-yloxy)-phenylamino]quinazolin-6-yl}-thiazol-2-ylmethyl)-carbamic acid ter-butyl ester (81 mg, 0.14 mmol) is treated with concentrated aqueous hydrochloric acid (0.5 ml) in EtOAc (6 ml). Reaction progress is followed by LC/MS. Upon reaction completion saturated aqueous potassium carbonate solution is added, the reaction mixture is diluted with water and thoroughly extracted with DCM and EtOAc. The combined organic extracts are dried (Na2SO4) and concentrated under reduced pressure to yield 45 mg (0.095 mmol, 68%) of clean desired product.
Reaction SMILES: [C:1]1([CH:7]([CH2:14][C:15]2[O:16][CH:17]=[C:18]([C:20]([NH:22][CH2:23][CH2:24][CH2:25][CH2:26][NH:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=3)=[O:21])[N:19]=2)[CH2:8][C:9]([O:11]CC)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Li+].[OH-]>C1COCC1.O>[C:1]1([CH:7]([CH2:14][C:15]2[O:16][CH:17]=[C:18]([C:20]([NH:22][CH2:23][CH2:24][CH2:25][CH2:26][NH:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=3)=[O:21])[N:19]=2)[CH2:8][C:9]([OH:11])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)CC(Cc1nc(C(=O)NCCCCNc2ccccn2)co1)c1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)CC(Cc1nc(C(=O)NCCCCNc2ccccn2)co1)c1ccccc1
Reaction time: 24 h
Yield: 82.8 %

Procedure:
To a solution of ethyl (±)-3-phenyl-4-[4-[[[4-(pyridin-2-yl)amino-1-butyl]amino]carbonyl]-1,3-oxazol-2-yl]butanoate (197 mg, 0.44 mmole) in 1:1 THF/H2O (4 mL) was added 1.0 N LiOH (0.66 mL, 0.66 mmole). After 24 hr, the mixture was washed with Et2O (2×2 mL), and the pH of the aqueous layer was adjusted to 6 using 10% HCl. The solution was chromatographed on a C-18 Mega Bond Elut® column (50 mL H2O then 50 mL 20% CH3CN/H2O). Fractions containing the product were pooled and lyophilized to give the title compound (154 mg, 83%) as a white powder: MS (ES) m/e 423 (M+H)+. Anal. Calcd for C23H26N4O4.0.75 H2O: C, 63.36; H, 6.36; N, 12.85. Found: C, 63.55; H, 6.27; N, 12.50.
Reaction SMILES: [BrH:1].[Br:2][C:3]1[CH:4]=[C:5]([N+:10]([O-:12])=[O:11])[C:6](N)=[N:7][CH:8]=1.BrBr.S([O-])([O-])=O.[Na+].[Na+].[OH-].[Na+]>>[Br:1][C:6]1[C:5]([N+:10]([O-:12])=[O:11])=[CH:4][C:3]([Br:2])=[CH:8][N:7]=1
Reactant: Nc1ncc(Br)cc1[N+](=O)[O-]
Reactant: Br
Agent: BrBr
Agent: O=S([O-])[O-]
Agent: [Na+]
Product: O=[N+]([O-])c1cc(Br)cnc1Br
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 58.9 %

Procedure:
Hydrogen bromide (48% in H2O, 13 mL) was stirred at 0° C., to which 5-bromo-3-nitropyridin-2-amine (5.0 g, 22.9 mmol) was dropwise added with its inner temperature kept at 5° C. or lower. After the addition, bromine (4.69 mL) and sodium sulfite (6.32 g) were added to it in that order. After stirred at 0° C. for 45 minutes, aqueous sodium hydroxide (9.16 g) solution (10 mL) was added thereto and stirred at room temperature for 1 hour. The resulting solid was taken out through filtration, washed with water and dried to obtain the intended compound (3.80 g, 58.9%).
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][C:8]=1[F:15].C[O:17][B:18](OC)[O:19]C.Cl>C1COCC1>[F:15][C:8]1[CH:9]=[C:10]([O:13][CH3:14])[CH:11]=[CH:12][C:7]=1[B:18]([OH:19])[OH:17]
Reactant: COB(OC)OC
Reactant: COc1ccc(Br)c(F)c1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1ccc(B(O)O)c(F)c1
Temperature: 25 °C

Procedure:
n-Butyllithium (1.6 M solution in hexanes, 29.1 mmol, 18.2 mL) was added to 1-bromo-2-fluoro-4-methoxybenzene (24.4 mmol, 5.0 g) in THF (150 mL) at −78° C. under an atmosphere of nitrogen. After stirring for thirty minutes the trimethylborate (95.1 mmol, 10.8 mL) was added over twenty minutes. The reaction was allowed to warm to room temperature overnight while stirring. The solution was then acidified with HCl (3 M, 200 mL), and extracted into EtOAc. The EtOAc was then extracted with NaOH (1 N, 4×100 mL), which was subsequently acidified with concentrated HCl forming (2-fluoro-4-methoxyphenyl) boronic acid as a white precipitate. The white precipitate (2.04 g, 49%) was filtered and dried. 1H NMR (CD3OD, 300 MHz): 7.29 (1H, t, J 8.0 Hz), 6.73 (1H, dd, J 8.5 and 2.2 Hz), 6.62 (1H, dd, J 11.4 and 2.2 Hz), 3.78 (3H, s.)
Reaction SMILES: [OH:1][CH2:2][C:3]1[C:4]2[N:5]([CH:9]=[C:10]([C:12]([F:15])([F:14])[F:13])[N:11]=2)[CH:6]=[CH:7][CH:8]=1.[K+].[Br-]>>[F:15][C:12]([F:13])([F:14])[C:10]1[N:11]=[C:4]2[C:3]([CH:2]=[O:1])=[CH:8][CH:7]=[CH:6][N:5]2[CH:9]=1
Reactant: OCc1cccn2cc(C(F)(F)F)nc12
Agent: [Br-]
Agent: [K+]
Product: O=Cc1cccn2cc(C(F)(F)F)nc12
Yield: 96 %

Procedure:
From 3e: reaction time 6 h (yield: 96%); mp 98-100° C.; IR (KBr) 1709, 1164 cm−1; 1H NMR (200 MHz, CDCl3) δ 7.12 (t, 1H, J=7 Hz), 7.94 (d, 1H, J=7 Hz), 8.06 (s, 1H), 8.46 (d, 1H, J=7 Hz), 10.73 (s, 1H); 13C NMR (100 MHz, CDCl3) δ 112.3, 113.6, 118.6 (d, 1JF-C=267 Hz), 122.6, 124.8, 128.0, 131.1, 137.0 (q, 2JF-C=30 Hz), 144.2, 188.0; MS m/z 214 (M+, 39), 186 (100), 166 (52), 139 (25), 92 (22), 75 (55), 64 (26).
Reaction SMILES: [CH:1]1([CH2:7][O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]2[CH:23]=[CH:22][C:20]([NH2:21])=[CH:19][CH:18]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:24]([C:26]1([C:29](O)=[O:30])[CH2:28][CH2:27]1)#[N:25]>>[C:24]([C:26]1([C:29]([NH:21][C:20]2[CH:22]=[CH:23][C:17]([CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][O:8][CH2:7][CH:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)=[CH:18][CH:19]=2)=[O:30])[CH2:28][CH2:27]1)#[N:25]
Reactant: Nc1ccc(CCCCCCCCOCC2CCCCC2)cc1
Reactant: N#CC1(C(=O)O)CC1
Product: N#CC1(C(=O)Nc2ccc(CCCCCCCCOCC3CCCCC3)cc2)CC1
Yield: 98 %

Procedure:
General procedure E was used to convert 2.05 mmol of 13c and 3.08 mmol of 1-cyanocyclopropanecarboxylic acid to 2.01 mmol (98%) of the title compound.
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[F:13][C:14]1[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][CH:15]=1.[F:22][C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=1)[CH:26]=[O:27].[Cl-].[NH4+]>CCCCCC.O1CCCC1>[F:13][C:14]1[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][C:15]=1[CH:26]([C:25]1[CH:28]=[CH:29][CH:30]=[C:23]([F:22])[CH:24]=1)[OH:27]
Reactant: O=Cc1cccc(F)c1
Reactant: N#Cc1ccc(F)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: N#Cc1ccc(F)c(C(O)c2cccc(F)c2)c1
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
In an atmosphere of nitrogen gas, 76.3 ml of 1.56 M solution of n-butyllithium in hexane was added to a solution of 11.1 g of N,N-diisopropylamine in 200 ml tetrahydrofuran under ice-cooling, and the mixture was stirred at the same temperature for 15 minutes. After cooling to −78° C., a solution of 12.1 g of 4-fluorobenzonitrile in 40 ml tetrahydrofuran was added dropwise. After stirring at the same temperature for 45 minutes, 10.6 ml of 3-fluorobenzaldehyde was added dropwise. After stirring at the same temperature for 25 minutes, saturated aqueous ammonium chloride solution was added and the solvent was removed. To the residue was added 150 ml of ethyl acetate, and the mixture was sequentially washed with 1 N hydrochloric acid, water, saturated aqueous sodium hydrogencarbonate solution and brine, dried over anhydrous magnesium sulfate and the solvent was evaporated. The crude product was purified and separated by silica gel column chromatography (ethyl acetate:toluene=3:97 to 1:19), and the resulting crystals were recrystallized from diisopropyl ether-hexane, to give 12.7 g of the title compound as pale yellow needles.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH:9]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:10][C:11](=O)[CH:12]([CH3:14])[CH3:13])=[CH:4][CH:3]=1.[NH2:23][CH2:24][CH2:25][C@H:26]1[O:31][C:30]2([CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]2)[O:29][C@@H:28]([CH2:37][C:38]([O:40][CH2:41][C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)=[O:39])[CH2:27]1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:23]([CH2:24][CH2:25][C@H:26]3[O:31][C:30]4([CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]4)[O:29][C@@H:28]([CH2:37][C:38]([O:40][CH2:41][C:42]4[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=4)=[O:39])[CH2:27]3)[C:11]([CH:12]([CH3:14])[CH3:13])=[CH:10][C:9]=2[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:4][CH:3]=1
Reactant: CC(C)C(=O)CC(C(=O)c1ccc(F)cc1)c1ccccc1
Reactant: NCC[C@@H]1C[C@H](CC(=O)OCc2ccccc2)OC2(CCCCC2)O1
Product: CC(C)c1cc(-c2ccccc2)c(-c2ccc(F)cc2)n1CC[C@@H]1C[C@H](CC(=O)OCc2ccccc2)OC2(CCCCC2)O1

Procedure:
According to the same method as in Example 4-1, the title compound was synthesized using 1-(4-fluorophenyl)-5-methyl-2-phenyl-1,4-hexanedione and benzyl 2-((2R,4R)-4-(2-aminoethyl)-1,5-dioxaspiro[5.5]undecan-2-yl)acetate.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10]N=C(C(=O)CC)CC)([O-:3])=[O:2].[OH-:19].[Na+]>>[CH3:6][C:5]1[C:6]2[C:5](=[C:4]([N+:1]([O-:3])=[O:2])[CH:9]=[CH:8][CH:7]=2)[NH:10][C:4]=1[C:9](=[O:19])[CH2:8][CH3:7]
Reactant: [OH-]
Reactant: CCC(=O)C(CC)=NNc1ccccc1[N+](=O)[O-]
Agent: [Na+]
Product: CCC(=O)c1[nH]c2c([N+](=O)[O-])cccc2c1C
Temperature: 80 °C
Reaction time: 8 h
Yield: 10 %

Procedure:
A mixture of hexane-3,4-dione (2-nitrophenyl)hydrazone (3.13 g) and polyphosphoric acid (50 g) was stirred at 80° C. overnight. The reaction mixture was poured into ice water, neutralized with 50% aqueous sodium hydroxide solution, and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography and the title compound (0.29 g, yield 10%) was obtained as yellow crystals from a fraction eluted with ethyl acetate-hexane (1:2, volume ratio). melting point>164° C. (decomposition).