Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[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[N:17]1[CH2:22][CH2:21][CH:20]([CH2:23][N:24]2[CH2:28][CH2:27][CH2:26][CH2:25]2)[CH2:19][CH2:18]1.[Cl:29][C:30]1[CH:31]=[C:32](B(O)O)[CH:33]=[CH:34][C:35]=1[OH:36]>>[Cl:29][C:30]1[CH:31]=[C:32]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[CH:7][C:6]([C:12](=[O:16])[CH:13]([CH3:15])[CH3:14])=[C:5]3[N:17]2[CH2:18][CH2:19][CH:20]([CH2:23][N:24]3[CH2:25][CH2:26][CH2:27][CH2:28]3)[CH2:21][CH2:22]2)[CH:33]=[CH:34][C:35]=1[OH:36]
Reactant: CC(C)C(=O)c1cnc2ccc(Br)cc2c1N1CCC(CN2CCCC2)CC1
Reactant: OB(O)c1ccc(O)c(Cl)c1
Product: CC(C)C(=O)c1cnc2ccc(-c3ccc(O)c(Cl)c3)cc2c1N1CCC(CN2CCCC2)CC1
Yield: 56.5 %

Procedure:
Following general procedure D, 1-{6-bromo-4-[4-(pyrrolidin-1-ylmethyl)piperidin-1-yl]quinolin-3-yl}-2-methylpropan-1-one (30 mg, 0.068 mmol) was reacted with 3-chloro-4-hydroxyphenylboronic acid (17 mg, 0.100 mmol) to afford the desired product (18.9 mg, 56%) as an off-white solid: 1H NMR (500 MHz, CD3OD) δ 8.75 (s, 1H), 8.28 (d, J=1.2 Hz, 1H), 8.06-7.99 (m, 2H), 7.70 (d, J=2.3 Hz, 1H), 7.54 (dd, J=8.4, 2.3 Hz, 1H), 7.06 (d, J=8.4 Hz, 1H), 3.54-3.41 (m, 3H), 3.23-3.11 (m, 6H), 3.03 (d, J=6.8 Hz, 2H), 2.11-1.93 (m, 7H), 1.74-1.62 (m, 2H), 1.26 (d, J=6.9 Hz, 6H); ESI MS m/z 492 [C29H34ClN3O2+H]+; HPLC>99% (AUC), tR=10.93 min.
Reaction SMILES: [BH4-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([N+:24]([O-:26])=[O:25])[C:7]([OH:23])=[C:8]([C:10]([C:12]2[CH:17]=[C:16]([Cl:18])[CH:15]=[C:14]([N+:19]([O-:21])=[O:20])[C:13]=2[OH:22])=[O:11])[CH:9]=1.Cl>C(O)C.O>[Cl:3][C:4]1[CH:5]=[C:6]([N+:24]([O-:26])=[O:25])[C:7]([OH:23])=[C:8]([CH:10]([OH:11])[C:12]2[CH:17]=[C:16]([Cl:18])[CH:15]=[C:14]([N+:19]([O-:21])=[O:20])[C:13]=2[OH:22])[CH:9]=1
Reactant: O=C(c1cc(Cl)cc([N+](=O)[O-])c1O)c1cc(Cl)cc([N+](=O)[O-])c1O
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: O=[N+]([O-])c1cc(Cl)cc(C(O)c2cc(Cl)cc([N+](=O)[O-])c2O)c1O
Temperature: 0 °C
Reaction time: 8 h
Yield: 89.5 %

Procedure:
Sodium borohydride (3.5 g) was added portionwise to a stirred solution of bis(5-chloro-2-hydroxy-3-nitrophenyl) ketone (10 g) in ethanol (150 ml) the solution being maintained at a temperature of 0° C. On completion of the addition the temperature of the solution was allowed to rise to ambient temperature and the mixture was stirred overnight at ambient temperature. The solution was diluted with water, acidified with hydrochloric acid and the product extracted into ethyl acetate. The solvent was removed by distillation under reduced pressure to give bis-(5-chloro-2-hydroxy-3-nitrophenyl)methyl alcohol (9.0 g) which on recrystallisation from ethanol/hexane had a melting point of 180° C.
Reaction SMILES: [Ni:1].[CH2:2]([N+:6]([CH2:15][CH2:16][CH2:17][CH3:18])([CH2:11][CH2:12][CH2:13][CH3:14])[CH2:7][CH2:8][CH2:9][CH3:10])[CH2:3][CH2:4][CH3:5].Cl[C:20]1[C:25]([Cl:26])=[C:24](Cl)[C:23](Cl)=[C:22]([SH:29])[C:21]=1[SH:30]>>[Ni:1].[CH2:15]([N+:6]([CH2:2][CH2:3][CH2:4][CH3:5])([CH2:7][CH2:8][CH2:9][CH3:10])[CH2:11][CH2:12][CH2:13][CH3:14])[CH2:16][CH2:17][CH3:18].[Cl:26][C:25]1[CH:20]=[C:21]([SH:30])[C:22]([SH:29])=[CH:23][CH:24]=1.[Cl:26][C:25]1[CH:20]=[C:21]([SH:30])[C:22]([SH:29])=[CH:23][CH:24]=1
Reactant: Sc1c(S)c(Cl)c(Cl)c(Cl)c1Cl
Agent: [Ni]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Product: Sc1ccc(Cl)cc1S

Procedure:
Ni-bis(3,4,5,6-tetrachlorobenzene-1,2-dithiol-tetrabutyl ammonium salt
Reaction SMILES: N([O-])=O.[Na+].[C:5]1([C@@H:11]([NH:13][C:14]2[N:19]=[C:18]([N:20]3[C:24]4[CH:25]=[C:26]([NH2:29])[CH:27]=[CH:28][C:23]=4[N:22]=[CH:21]3)[CH:17]=[CH:16][N:15]=2)[CH3:12])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[N-:30]=[N+:31]=[N-].[Na+]>O.C(O)(=O)C.C(OCC)(=O)C>[C:5]1([C@@H:11]([NH:13][C:14]2[N:19]=[C:18]([N:20]3[C:24]4[CH:25]=[C:26]([N:29]=[N+:30]=[N-:31])[CH:27]=[CH:28][C:23]=4[N:22]=[CH:21]3)[CH:17]=[CH:16][N:15]=2)[CH3:12])[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: [N-]=[N+]=[N-]
Reactant: C[C@H](Nc1nccc(-n2cnc3ccc(N)cc32)n1)c1ccccc1
Agent: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: O
Product: C[C@H](Nc1nccc(-n2cnc3ccc(N=[N+]=[N-])cc32)n1)c1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 73.7 %

Procedure:
A solution of 16.3 mg of NaNO2 in 0.5 mL of H2O was added to a 5° C. solution of 78 mg of 2-[(S)-1-phenylethylamino]-4-[6-aminobenzimidazol-1-yl]pyrimidine in 2 mL acetic acid. The solution was cooled to 0° C. and stirred for 0.5 hours. A solution of 23 mg of NaN3 in 0.5 mL H2O was added and stirred for one hour. The solution was diluted with 100 mL of ethyl acetate and washed with water, saturated NaHCO3 and brine. The organic phase was dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography eluting with methanol in methylene chloride to give 62 mg of the title compound. RF: 0.6 (5% MeOH in CH2Cl2). 1H NMR (300 MHz, CD3OD): δ1.57 (d, J=7 Hz, 3H), 5.18 (q, J=8 Hz, 1H), 6.88 (d, J=6 Hz, 1H), 7.05 (dd, J=2.5, 9 Hz, 1H), 7.18 (m, 1H), 7.29 (t, J=6 Hz, 2H), 7.43 (d, J=9 Hz, 2H), 7.65 (d, J=9 Hz, 1H), 8.02 (m, 1H), 8.3 (d, J=6 Hz, 1H), 8.69 (b s, 1H). Mass Spectrum (CH3CN-TFA-NH4HCO2-ESI): 357.2 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][N:6]([N:11]([CH3:45])[C:12](=[O:44])[CH2:13][N:14]([C:31]1[CH:36]=[CH:35][C:34]([C:37]3[N:41]=[C:40]([CH3:42])[O:39][N:38]=3)=[CH:33][C:32]=1[CH3:43])[CH2:15][C:16]([NH:18][CH2:19][CH2:20][N:21](C(OC(C)(C)C)=O)[CH2:22][CH3:23])=[O:17])[CH2:5]2.[ClH:46].O1CCOCC1.Cl.C(OCC)(=O)C>ClCCl.C(Cl)(Cl)Cl>[ClH:46].[ClH:46].[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][N:6]([N:11]([CH3:45])[C:12](=[O:44])[CH2:13][N:14]([C:31]1[CH:36]=[CH:35][C:34]([C:37]3[N:41]=[C:40]([CH3:42])[O:39][N:38]=3)=[CH:33][C:32]=1[CH3:43])[CH2:15][C:16]([NH:18][CH2:19][CH2:20][NH:21][CH2:22][CH3:23])=[O:17])[CH2:5]2
Reactant: CCN(CCNC(=O)CN(CC(=O)N(C)N1Cc2ccc(F)cc2C1)c1ccc(-c2noc(C)n2)cc1C)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Solvent: C1COCCO1
Product: CCNCCNC(=O)CN(CC(=O)N(C)N1Cc2ccc(F)cc2C1)c1ccc(-c2noc(C)n2)cc1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 86 %

Procedure:
The compound (3.62 g, 5.80 mmol) obtained in step A was dissolved in dichloromethane (12 ml), 4N hydrochloric acid-dioxane solution (12 ml) was added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with chloroform, and the organic layer was washed with 1N aqueous sodium hydroxide solution, and dried over sodium sulfate. The insoluble material was filtered off, and the solution was concentrated under reduced pressure. The obtained oil was dissolved in diethyl ether (58 ml), and 4N hydrochloric acid-ethyl acetate (3.14 ml, 12.6 mmol) was added to allow precipitation of a solid. This was collected by filtration, washed with diethyl ether, and dried under reduced pressure to give the title compound (2.96 g, yield 86%) as a pale-yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][C:7]2[N:15]=[CH:14][CH:13]=[CH:12][C:8]=2[C:9]([OH:11])=O)=[CH:4][CH:3]=1.CN(C)C=O.C(Cl)(=O)C(Cl)=O.Cl.[F:30][C:31]1[CH:38]=[C:37]([OH:39])[CH:36]=[CH:35][C:32]=1[CH2:33][NH2:34]>ClCCl.C(N(CC)CC)C>[F:30][C:31]1[CH:38]=[C:37]([OH:39])[CH:36]=[CH:35][C:32]=1[CH2:33][NH:34][C:9](=[O:11])[C:8]1[CH:12]=[CH:13][CH:14]=[N:15][C:7]=1[O:6][C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:17][CH:16]=1
Reactant: O=C(O)c1cccnc1Oc1ccc(F)cc1
Reactant: NCc1ccc(O)cc1F
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(NCc1ccc(O)cc1F)c1cccnc1Oc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 2-(4-fluoro-phenoxy)-nicotinic acid (20.47 g) were added anhydrous dichloromethane (200 mL), dimethylformamide (2 mL), and oxalyl chloride (2.0 M in dichloromethane, 46.10 mL) were then added. The solution was cooled in a dry ice/acetone bath. Triethylamine (24.5 mL) and 2-fluoro-4-hydroxy-benzylamine hydrochloride (7.81 g) were then added. The solution was allowed to warm to ambient temperature and stir overnight. The reaction was then diluted with 200 mL dichloromethane and washed with 100 mL water. The organic phase was dried over magnesium sulfate and concentrated in vacuo. The crude product was then taken up in a solution of tetrahydrofuran (50 mL) and methanol (25 mL). Lithium hydroxide (5.26 g) in water (25 mL) were then added to the mixture, and the reaction was allowed to stir overnight at ambient temperature. The solution was then concentrated in vacuo. The resulting residue was taken up in 100 mL water, and acidified with conc. aq. HCl to pH 4. The aqueous layer was then extracted with ethyl acetate (3×300 mL). The combined organics were dried over magnesium sulfate and concentrated in vacuo. Recrystallization from methanol yielded pure title compound (9.75 g)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][CH:11]=O)[CH:5]=[CH:6][C:7]=1[Cl:8].[CH3:13][C:14]([S@@:17]([NH2:19])=[O:18])([CH3:16])[CH3:15].[O-]S([O-])(=O)=O.[Mg+2]>C(Cl)Cl.CC1C=CC(S(O)(=O)=O)=CC=1.N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10]/[CH:11]=[N:19]/[S@:17]([C:14]([CH3:16])([CH3:15])[CH3:13])=[O:18])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CC(C)(C)[S@@](N)=O
Reactant: O=CCCc1ccc(Cl)c(Cl)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(C)[S@](=O)/N=C/CCc1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 80.2 %

Procedure:
To a solution of Intermediate 16A (1.0 g, 4.9 mmol) in CH2Cl2 (5 mL) was added (S)-2-methylpropane-2-sulfinamide (0.72 g, 5.9 mmol) followed by the addition of pyridine 4-methylbenzenesulfonate (0.062 g, 0.25 mmol) and MgSO4 (2.96 g, 24.6 mmol). The reaction mixture was stirred at rt for 18 h, and then filtered through a celite pad. The filtrate was concentrated under reduced pressure and the residue was purified by ISCO chromatography (EtOAc/Hexanes 0-30% over 15 min, column 80 g, flow rate 85 mL/min) to give Intermediate 16B (1.20 g, 3.93 mmol, 80.0% yield) as a white solid. HPLC/MS (Method D) RT=1.13 min, [M+1]+ 306.0.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[Cl:11])[C:5](Cl)=[O:6].[CH3:12][NH:13][CH2:14][C:15]([CH3:23])([N:20]([CH3:22])[CH3:21])[CH2:16][CH2:17][CH2:18][CH3:19]>C1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[Cl:11])[C:5]([N:13]([CH3:12])[CH2:14][C:15]([CH3:23])([N:20]([CH3:21])[CH3:22])[CH2:16][CH2:17][CH2:18][CH3:19])=[O:6]
Reactant: O=C(Cl)c1ccc(Cl)c(Cl)c1
Reactant: CCCCC(C)(CNC)N(C)C
Solvent: c1ccccc1
Product: CCCCC(C)(CN(C)C(=O)c1ccc(Cl)c(Cl)c1)N(C)C

Procedure:
A solution of 3,4-dichlorobenzoyl chloride (1.048 g., 5 mmole) in dry benzene (25 ml.) was added to a solution of N-methyl-2-methyl-2-dimethylamino hexylamine (0.754 g., 4.4 mmole) in dry benzene (25 ml.) and the solution heated under reflux for 1 hr. The cooled solution was washed with 2N sodium hydroxide solution (4 × 100 ml.), water (4 × 100 ml.), dried (Na2SO4) and evaporated to a colourless oil (1.612 g.). The oil was dissolved in benzene, chromatographed on a column of alumina (25 × 3.0 cm.) eluting with benzene/ether 1:1, and fractions (9 × 100 ml.) were collected. Fractions 2-8 were combined and, on evaporation, afforded 3,4-dichloro-N-methyl-N-[2-methyl-2-dimethylamino-hexyl]benzamide as a colourless oil (1.282 g., 84%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1)[NH2:5].[I:13]N1C(=O)CCC1=O>C(O)(=O)C.C(OCC)(=O)C>[Br:1][C:2]1[C:3]([I:13])=[C:4]([CH:6]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:8]=1)[NH2:5]
Reactant: Nc1cc(Br)cc(C(F)(F)F)c1
Reactant: O=C1CCC(=O)N1I
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: Nc1cc(C(F)(F)F)cc(Br)c1I
Temperature: 25 °C
Reaction time: 8 h
Yield: 68.3 %

Procedure:
To a solution of 3-bromo-5-(trifluoromethyl)aniline (5.00 g) in acetic acid (40 mL) was added N-iodosuccinimide (5.16 g) at 0° C., and the mixture was stirred overnight at room temperature under nitrogen atmosphere. The reaction mixture was diluted with ethyl acetate, washed with 10% aqueous sodium thiosulfate solution, saturated aqueous sodium bicarbonate solution and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (5.21 g). 1H NMR (300 MHz, CDCl3) δ 4.58 (2H, brs), 6.84 (1H, d, J=1.1 Hz), 7.23 (1H, d, J=1.1 Hz).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][Cl:11])[C:3]([OH:5])=[O:4].[C:12](ON1C(=O)CCC1=O)([O:14][CH2:15][CH:16]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22]2[C:17]1=[CH:18][CH:19]=[CH:20][CH:21]=2)=[O:13]>O1CCOCC1.C([O-])(O)=O.[Na+]>[CH:27]1[C:28]2[CH:16]([CH2:15][O:14][C:12]([NH:1][C@@H:2]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][Cl:11])[C:3]([OH:5])=[O:4])=[O:13])[C:17]3[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:23]=2[CH:24]=[CH:25][CH:26]=1
Reactant: N[C@@H](CCCCCCl)C(=O)O
Reactant: O=C(OCC1c2ccccc2-c2ccccc21)ON1C(=O)CCC1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: O=C(N[C@@H](CCCCCCl)C(=O)O)OCC1c2ccccc2-c2ccccc21
Temperature: 0 °C
Reaction time: 4 h
Yield: 113.8 %

Procedure:
The amine, (S)-2-amino-7-chloroheptanoic acid (-)-pseudoephedrinyl amide (1.8 mmol, 0.59 g) (for reference, Myers, A. G. et al. J. Am. Chem. Soc. 1995, 117, 8488), was dissolved in 7.2 mL of a heterogeneous mixture (1:1 v/v) of dioxane and saturated aqueous NaHCO3. The mixture was degassed under reduced pressure, placed under nitrogen and chilled to 0° C. To the mixture was added Fmoc-OSu (2.2 mmol, 0.73 g) in four equivalent portions over 15 min. Another 1 mL of dioxane was added to improve solubility of the Fmoc-OSu. The mixture was allowed to stir 20 min at 0° C. and 4 h at 20° C. After the mixture was concentrated under reduced pressure, it was extracted into AcOEt (250 mL). The organic layer was washed with saturated aqueous NaHCO3 (3×5 mL), saturated NaCl (3×5 mL) and dried (MgSO4). After the solvent was removed under reduced pressure, the residue obtained was purified by silica gel chromatography (AcOEt/hexanes:40/60%). The protected compound was obtained as a white foam (0.823 g, 83%) after removal of solvents under reduced pressure: [α]D25 -503.7° (c 0.01, CHCl3), Rf 0.25 (AcOEt/hexanes:1/1).
Reaction SMILES: [H-].[Na+].[CH2:3]([N:10]1[CH2:15][CH2:14][CH2:13][C@H:12]([OH:16])[CH2:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.F[C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=1>CN(C=O)C>[CH2:3]([N:10]1[CH2:15][CH2:14][CH2:13][C@H:12]([O:16][C:18]2[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=2)[CH2:11]1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: O[C@H]1CCCN(Cc2ccccc2)C1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(O[C@H]2CCCN(Cc3ccccc3)C2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.8 %

Procedure:
To a suspension of NaH (0.83 g, 37 mmol) in DMF (10 mL) was added 1-benzyl-(3S)-3-hydroxypiperidine (4.1 g, 21.5 mmol), and the resulting reaction mixture was stirred at ambient temperature for 2 hours. 4-Fluoronitrobenzene (2.5 mL, 23.6 mmol) in DMF (10 mL) was then added to the mixture dropwise. The resulting reaction mixture was stirred at ambient temperature for 2 hours. After removal of DMF in vacuo, the crude mixture was dissolved in ethyl acetate (200 mL), washed with water (100 mL×3), brine (100 mL), to give a yellow oil. Purification using silical gel chromatography column afforded 1-benzyl-(3S)-3-(4-nitrophenoxy)piperidine (6.5 g, 97% yield) as a yellow oil.
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:24]=[CH:23][C:12]([CH2:13][NH:14][C:15]2[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[CH:17][CH:16]=2)=[CH:11][CH:10]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[S:25]1[CH:29]=[CH:28][CH:27]=[C:26]1[C:30](Cl)=[O:31].Cl>>[Si:1]([O:8][C:9]1[CH:24]=[CH:23][C:12]([CH2:13][N:14]([C:15]2[CH:16]=[CH:17][C:18]([C:19]#[N:20])=[CH:21][CH:22]=2)[C:30]([C:26]2[S:25][CH:29]=[CH:28][CH:27]=2)=[O:31])=[CH:11][CH:10]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: O=C(Cl)c1cccs1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(CNc2ccc(C#N)cc2)cc1
Agent: Cl
Product: CC(C)(C)[Si](C)(C)Oc1ccc(CN(C(=O)c2cccs2)c2ccc(C#N)cc2)cc1
Temperature: 25 °C
Reaction time: 19 h
Yield: 76.2 %

Procedure:
The procedure of Preparation Example 8 was repeated, except that 195 mg of 4-[N-(4-tert-butyldimethylsilyloxybenzyl)amino]benzonitrile was used in place of 4-[N-(4-benzyloxybenzyl)amino]phenol, and 84 mg of 2-thiophenecarbonyl chloride was used in place of methanesulfonyl chloride. The resulting mixture was stirred at room temperature for 19 hours. After the reaction mixture was poured into dilute hydrochloric acid, the product was extracted with ethyl acetate. After the extract was successively washed with a saturated aqueous solution of sodium hydrogen carbonate and a saturated aqueous solution of sodium chloride, and dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. The resulting crude product was purified by TLC (using a 3:1 mixture of hexane and ethyl acetate as the developing solvent) to obtain 196 mg of N-(4-tert-butyldimethylsilyloxybenzyl)-N-(4-cyanophenyl)-2-thiophenecarboxamide.
Reaction SMILES: O.[F:2][C:3]1[CH:8]=[C:7]([N+:9]([O-])=O)[C:6]([O:12][C:13]2[C:14]([O:19][CH2:20][C:21]([O:23][CH3:24])=[O:22])=[N:15][CH:16]=[CH:17][CH:18]=2)=[CH:5][C:4]=1[NH:25][C:26](=[O:28])[CH3:27]>C(O)(=O)C.C(OCC)(=O)C.[Fe]>[NH2:9][C:7]1[C:6]([O:12][C:13]2[C:14]([O:19][CH2:20][C:21]([O:23][CH3:24])=[O:22])=[N:15][CH:16]=[CH:17][CH:18]=2)=[CH:5][C:4]([NH:25][C:26](=[O:28])[CH3:27])=[C:3]([F:2])[CH:8]=1
Reactant: COC(=O)COc1ncccc1Oc1cc(NC(C)=O)c(F)cc1[N+](=O)[O-]
Agent: [Fe]
Solvent: CC(=O)O
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)COc1ncccc1Oc1cc(NC(C)=O)c(F)cc1N
Temperature: 45 °C
Reaction time: 1 h
Yield: 91.4 %

Procedure:
To a mixture of 3.6 g of an iron powder, 10 ml of acetic acid and 1 ml of water was added a solution of 3.67 g of N-[2-fluoro-5-{2-(methoxycarbonyl)methoxy-3-pyridyloxy}-4-nitrophenyl]acetamide in 12 ml of acetic acid and 2 ml of ethyl acetate, dropwise while maintaining the temperature of the reaction solution at 45° C. or lower. After completion of the addition, the mixture was stirred for 1 hour at 40° C., then, the reaction mixture was filtrated through Celite, and concentrated. The residue was diluted with saturated aqueous sodium bicarbonate solution, and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium bicarbonate solution, dried over anhydrous magnesium sulfate, and concentrated. Then, the resulted residue was washed with diisopropyl ether to obtain 3.09 g of N-[4-amino-2-fluoro-5-{2-(methoxycarbonyl)methoxy-3-pyridyl oxy}phenyl]acetamide.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[N:10]=[C:9]([NH:11][C:12](=[O:14])[CH3:13])[S:8][C:5]2=[N:6][CH:7]=1.[CH3:15][O:16][C:17]1[CH:26]=[C:25]2[C:20]([C:21]([N:27]3[CH2:33][C:32]4[CH:34]=[C:35](B(O)O)[CH:36]=[CH:37][C:31]=4[O:30][CH2:29][CH2:28]3)=[N:22][CH:23]=[N:24]2)=[CH:19][CH:18]=1>>[CH3:21][N:27]([CH2:33][C:23]1[N:22]=[C:21]([N:27]2[CH2:33][C:32]3[CH:34]=[C:35]([C:2]4[CH:3]=[C:4]5[N:10]=[C:9]([NH:11][C:12](=[O:14])[CH3:13])[S:8][C:5]5=[N:6][CH:7]=4)[CH:36]=[CH:37][C:31]=3[O:30][CH2:29][CH2:28]2)[C:20]2[C:25](=[CH:26][C:17]([O:16][CH3:15])=[CH:18][CH:19]=2)[N:24]=1)[CH3:28]
Reactant: CC(=O)Nc1nc2cc(Br)cnc2s1
Reactant: COc1ccc2c(N3CCOc4ccc(B(O)O)cc4C3)ncnc2c1
Product: COc1ccc2c(N3CCOc4ccc(-c5cnc6sc(NC(C)=O)nc6c5)cc4C3)nc(CN(C)C)nc2c1

Procedure:
Synthesized according to the method of example 5 using N-(6-bromothiazolo[5,4-b]pyridin-2-yl)acetamide (J. Heterocyclic Chemistry 2003, 40, 261) and {4-[7-(methyloxy)quinazolin-4-yl]-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl}boronic acid (reagent preparation 23) in step 1. 1H NMR (400 MHz, d6-DMSO) δ 12.60 (s, 1H), 8.86 (d, 1H), 8.45 (d, 1H), 8.23-8.07 (m, 2H), 7.70 (dd, 1H), 7.27-7.17 (m, 2H), 7.02 (d, 1H), 5.43 (s, 2H), 4.65-4.57 (m, 2H), 4.46 (s, 2H), 4.43-4.37 (m, 2H), 3.94 (s, 3H), 2.73 (s, 6H), 2.25 (s, 3H); MS (EI) for C29H29N7O3S: 556 (MH+).
Reaction SMILES: C(N(CC)CC)C.[CH3:8][N+:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11][C:10]=1[CH3:19].CC1C=CC(S(O)(=O)=O)=CC=1.[Cl:31][C:32]([Cl:53])([Cl:52])[C:33]1[N:38]=[C:37]([C:39]([Cl:42])([Cl:41])[Cl:40])[N:36]=[C:35]([C:43]2[CH:51]=[CH:50][C:46]([C:47](Cl)=[O:48])=[CH:45][CH:44]=2)[N:34]=1.O>C1(C)C=CC=CC=1.C(Cl)Cl>[Cl:42][C:39]([Cl:40])([Cl:41])[C:37]1[N:38]=[C:33]([C:32]([Cl:53])([Cl:31])[Cl:52])[N:34]=[C:35]([C:43]2[CH:44]=[CH:45][C:46]([C:47]([CH:19]=[C:10]3[CH:11]=[CH:12][C:13]4[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=4)[N:9]3[CH3:8])=[O:48])=[CH:50][CH:51]=2)[N:36]=1
Reactant: Cc1ccc2ccccc2[n+]1C
Reactant: O=C(Cl)c1ccc(-c2nc(C(Cl)(Cl)Cl)nc(C(Cl)(Cl)Cl)n2)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CN1C(=CC(=O)c2ccc(-c3nc(C(Cl)(Cl)Cl)nc(C(Cl)(Cl)Cl)n3)cc2)C=Cc2ccccc21
Temperature: 25 °C

Procedure:
Triethylamine (17.4 pbw) are added dropwise at 15° C. to 14.1 pbw of 1,2-dimethyl-quinolinium-p-toluenesulfonate and 22.2 pbw of 4-(4,6-bis-trichloromethyl-s-triazin-2-yl)-benzoylchloride in 150 ml of dried toluene. The mixture is then allowed to warm to room temperature. After 1 hour the mixture is poured onto 600 pbw of water, admixed with 600 pbw of methylene chloride and extracted by shaking. Silica gel (100 pbw) is added to the dried organic phase and the mixture is stirred for 30 minutes. The silica gel is removed by filtration and the solvents are distilled off in vacuo the residue is recrystallized from 2-methoxyethanol, giving strong red crystals.
Reaction SMILES: Br.[NH2:2][C:3]1[C:11]([OH:12])=[CH:10][CH:9]=[CH:8][C:4]=1[C:5]([OH:7])=[O:6].[CH:13]1([C:17](Cl)=O)[CH2:16][CH2:15][CH2:14]1.C(N(CC)CC)C.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>ClCCl.O>[CH:13]1([C:17]2[O:12][C:11]3[C:3](=[C:4]([C:5]([OH:7])=[O:6])[CH:8]=[CH:9][CH:10]=3)[N:2]=2)[CH2:16][CH2:15][CH2:14]1
Reactant: Nc1c(O)cccc1C(=O)O
Reactant: O=C(Cl)C1CCC1
Agent: Br
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: O=C(O)c1cccc2oc(C3CCC3)nc12
Temperature: 25 °C
Reaction time: 12 h
Yield: 90.8 %

Procedure:
To a mixture of 2-amino-3-hydroxybenzoic acid hydrobromide (0.50 g, 2.13 mmol) and cyclobutanecarbonyl chloride (0.24 mL, 2.13 mmol) in dichloromethane (20 mL) was added triethylamine (0.90 mL, 6.41 mmol) dropwise, then the reaction mixture was stirred at room temperature for 12 h. The reaction mixture was diluted with dichloromethane, and then washed with 2 N HCl. The aqueous layer was extracted with dichloromethane. The combined organic layers were washed with brine, dried (Na2SO4), filtered and concentrated. The crude product was dissolved in toluene (8 mL) and the solution was treated with p-toluenesulfonic acid monohydrate (676 mg, 3.56 mmol). The reaction mixture was then heated to reflux for 5 h. The reaction was cooled to room temperature, poured into water and extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried (Na2SO4), filtered and concentrated. The crude product was purified by re-crystallization from ethyl acetate and hexanes to afford 2-cyclobutylbenzoxazole-4-carboxylic acid (420 mg, 73%) as a brown solid: 1H NMR (500 MHz, DMSO-d6) δ 12.96 (br s, 1H), 7.92 (dd, J=8.1, 0.8 Hz, 1H), 7.84 (dd, J=7.6, 0.8 Hz, 1H), 7.44 (t, J=7.9 Hz, 1H), 3.95-3.85 (m, 1H), 2.46-2.39 (m, 4H), 2.28-2.00 (m, 2H); MS (ESI+) m/z 218 (M+H).