Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:6][N:5]=[C:4]2[N:14]([CH2:23][C:24](O)=[O:25])[N:15]=[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:3]=12.[F:27][C:28]([F:37])([F:36])[CH2:29][N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1.C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C=O)C.CCOC(C)=O>[Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:6][N:5]=[C:4]2[N:14]([CH2:23][C:24]([N:33]3[CH2:32][CH2:31][N:30]([CH2:29][C:28]([F:36])([F:37])[F:27])[CH2:35][CH2:34]3)=[O:25])[N:15]=[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:3]=12
Reactant: FC(F)(F)CN1CCNCC1
Reactant: O=C(O)Cn1nc(-c2ccccc2)c2c(Cl)c(-c3ccccc3)nnc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Cn1nc(-c2ccccc2)c2c(Cl)c(-c3ccccc3)nnc21)N1CCN(CC(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 29.5 %

Procedure:
To a suspension of 2-(4-chloro-3,5-diphenyl-1H-pyrazolo[3,4-c]pyridazin-1-yl)acetic acid (100 mg, 0.27 mmol) in DMF (2 mL) were added 1-(2,2,2-trifluoroethyl)piperazine (50 mg, 0.30 mmol), diisopropylethylamine (DIPEA) (105 μL, 0.60 mmol) and 2-(7-aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU) (125 mg, 0.33 mmol). The solution obtained was stirred at room temperature for 18 h then diluted with EtOAc. The organic phase was washed with water and brine, dried (MgSO4) and concentrated in vacuo. The resultant residue was purified by preparative HPLC yielding Compound 56 as a solid (41 mg).
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]([CH2:7]Cl)=[CH:5][N:6]=1.Cl[C:10]1C(CCl)=CC=C(Cl)[N:11]=1>C(Cl)Cl>[Cl:1][C:2]1[S:3][C:4]([CH2:7][NH:11][CH3:10])=[CH:5][N:6]=1
Reactant: ClCc1ccc(Cl)nc1Cl
Reactant: ClCc1cnc(Cl)s1
Solvent: ClCCl
Product: CNCc1cnc(Cl)s1

Procedure:
The reaction procedure of Reference Example 11 was repeated except that crude 2-chloro-5-chloromethyl-thiazole was used in lieu of 2,6-dichloro-3-pyridylmethyl chloride and that CH2Cl2 was used as the extractant. The procedure gave the title compound as a crude oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]2[C:13]([C:14]([O-:16])=O)=[C:12]([CH3:17])[NH:11][C:10]([CH3:18])=[C:9]2[C:19]([O:21][CH2:22][CH2:23][C:24]#[N:25])=[O:20])[CH:5]=[CH:6][CH:7]=1.Cl.CN(C)CCCN=C=NCC.[C:38]1([N:44]2[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]2)[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1.C(=O)([O-])O.[Na+]>CN(C)C1C=CN=CC=1.ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]2[C:13]([C:14]([N:47]3[CH2:48][CH2:49][N:44]([C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=4)[CH2:45][CH2:46]3)=[O:16])=[C:12]([CH3:17])[NH:11][C:10]([CH3:18])=[C:9]2[C:19]([O:21][CH2:22][CH2:23][C:24]#[N:25])=[O:20])[CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: CC1=C(C(=O)[O-])C(c2cccc(Cl)c2)C(C(=O)OCCC#N)=C(C)N1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CC1=C(C(=O)OCCC#N)C(c2cccc(Cl)c2)C(C(=O)N2CCN(c3ccccc3)CC2)=C(C)N1

Procedure:
216 mg (0.60 mmol) of mono(2-cyanoethyl) 4-(3-chlorophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate, 147 mg (0.76 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, 0.14 ml (0.92 mmol) of 1-phenylpiperazine and 25 mg (0.20 mmol) of 4-dimethylaminopyridine were stirred in 10 ml of dichloromethane at room temperature for 4 days. A saturated aqueous sodium hydrogencarbonate solution was added to the reaction mixture. After the extraction with dichloromethane, the organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by the silica gel chromatography (chloroform/methanol=100/1) to obtain the title compound
Reaction SMILES: N[C:2]1[CH:3]=[C:4]([CH3:12])[C:5]([CH2:8][CH2:9][CH2:10][NH2:11])=[N:6][CH:7]=1.N([O-])=O.[Na+].[OH-].[NH4+].[BrH:19]>O.[Cu]>[NH2:11][CH2:10][CH2:9][CH2:8][C:5]1[C:4]([CH3:12])=[CH:3][C:2]([Br:19])=[CH:7][N:6]=1
Reactant: Cc1cc(N)cnc1CCCN
Reactant: Br
Agent: [Cu]
Agent: O=N[O-]
Agent: [NH4+]
Solvent: O
Product: Cc1cc(Br)cnc1CCCN
Reaction time: 1 h

Procedure:
5-Amino-2-(3-aminopropyl)-3-methylpyridine (8.05 g) in hydrobromic acid (48%, 75 ml) and water (8 ml) wasreacted with cuprous bromide (8.73 g) and copper bronze (0.29 g). A solution of sodium nitrite (5.1 g) in water (8 ml) was added at 5°-8° C. over 40 minutes, the reaction mixture was allowed to stir at 5°-8° C. for one hour and then stirred at room temperature for 3 hours. The cooled reaction mixture was then basified with ammonium hydroxide (70 ml), which was then extracted with chloroform 3×150 ml. The chloroform extracts were then washed with fresh ammonium hydroxide and water (70 ml of each) till no more blue colour was visible in the aqueous layer. Chloroform extracts were dried over magnesium sulphate, filtered and concentrated to dryness to give the title compound (8.2 g) as an amber oil.
Reaction SMILES: [CH3:1]/[C:2](/[CH2:9][CH2:10][CH:11]=[C:12]([CH3:14])[CH3:13])=[CH:3]\[CH2:4][CH2:5][CH2:6][CH2:7]O.C(N(CC)CC)C.CS(Cl)(=O)=O.S([O-])(=O)(=O)C.[Na+].[I-:33]>C(Cl)Cl.CC(C)=O.CCOCC>[CH3:1]/[C:2](/[CH2:9][CH2:10][CH:11]=[C:12]([CH3:14])[CH3:13])=[CH:3]\[CH2:4][CH2:5][CH2:6][CH2:7][I:33]
Reactant: CC(C)=CCC/C(C)=C/CCCCO
Reactant: [I-]
Agent: CS(=O)(=O)Cl
Agent: CS(=O)(=O)[O-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: ClCCl
Solvent: CCOCC
Product: CC(C)=CCC/C(C)=C/CCCCI
Temperature: 25 °C
Reaction time: 1 h
Yield: 85 %

Procedure:
A solution of 1.80 g (9.20 mmol) of Part A (E)-6,10-dimethyl-5,9-undecadien-1-ol in 50 mL of methylene chloride and 2.00 mL (14.3 mmol) of triethylamine at 0° C. was treated with 1.14 g (10.00 mmol) of methanesulfonyl chloride dropwise over 0.2 hours. The reaction mixture was stirred for 1.0 hour when it was quenched with saturated aqueous NH4Cl solution and diluted with ether. The organic fraction was washed with saturated NaHCO3, brine, dried (Na2SO4) and evaporated to provide a crude colorless oil. The crude mesylate (~9.0 mmol) was diluted with 50 mL of acetone and treated with 4.05 g (27.00 mmol) of NaI, refluxed for 5 hours, and cooled to room temperature. The mixture was diluted with 250 mL of ether and extracted with NaHS03, brine, dried (MgSO4) and concentrated to provide a pale yellow oil. The oil was purified by flash chromatography (180 g of silica gel) eluting with hexane to provide 2.60 g (85%) of title iodide as a colorless oil.
Reaction SMILES: CC(C)([O-])C.[Na+].Br[C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][C:9]=1[O:16][CH3:17].[NH:18]1[CH2:22][CH2:21][CH2:20][CH2:19]1>C1(C)C=CC=CC=1.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[N:18]1([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][C:9]=2[O:16][CH3:17])[CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: COc1ccc(Br)c(OC)c1
Reactant: C1CCNC1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Solvent: O
Product: COc1ccc(N2CCCC2)c(OC)c1
Temperature: 100 °C
Yield: 62.7 %

Procedure:
Ex-38A: Method A: A mixture of 2,4-dimethoxyaniline (1.0 g, 6.53 mmol), 1,4-dibromobutane (1.41 g, 6.53 mmol) and potassium carbonate (3.61 g, 26.1 mmol) in N,N-dimethylformamide (70 mL) was heated at 150° C. overnight. The reaction mixture was concentrated under reduced pressure. The residue was taken up in a mixture of water and ethyl acetate. After the mixture was partitioned, the aqueous solution was extracted with ethyl acetate. The combined solution of ethyl acetate was washed with saturated sodium bicarbonate, brine, dried over sodium sulfate and concentrated. The residue was purified by flash chromatography. Elution with ethyl acetate and hexane (1:2, v/v) gave 1-pyrrolidin-1-yl-2,4-dimethoxybenzene as a brown oil (0.85 g, 63%). 1H-NMR (300 MHz, CDCl3) δ 6.76 (d, J=8.9 Hz, 1H), 6.49 (d, J=2.7 Hz, 1H), 6.41 (dd, J=2.7, 8.9 Hz, 1H), 3.84 (s, 3H), 3.78 (s, 3H), 3.18–3.14 (m, 4H), 1.95–1.90 (m, 4H). Method B: Sodium tert-butoxide was charged to a mixture of 1-bromo-2,4-dimethoxybenzene (3.03 g, 14.0 mmol), pyrrolidine (1.75 mL, 20.9 mmol), tris(dibenzylideneacetone)dipalladium (Pd2(dba)3) (0.26 g, 0.28 mmol) and rac-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (BINAP) (0.35 g, 0.56 mmol) in degassed toluene (60 mL). The reaction mixture was heated at 100° C. under N2 for 17 h. After cooling to room temperature, the reaction mixture was diluted with water (60 mL) and partitioned. The aqueous solution was further extracted with ethyl acetate. The combined ethyl acetate and toluene was washed with saturated sodium bicarbonate, brine, dried over sodium sulfate and concentrated. The crude product was purified by flash chromatography with ethyl acetate and hexane (1:2, v/v) to give 1-pyrrolidin-1-yl-2,4-dimethoxybenzene as a brown oil (1.82 g, 63%).
Reaction SMILES: [Cl:1][C:2]1[C:7](=[O:8])[CH:6]=[CH:5][NH:4][C:3]=1[N:9]=[C:10]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[F:29][C:30]1[CH:31]=[C:32]([N+:37]([O-:39])=[O:38])[CH:33]=[CH:34][C:35]=1F.O>CN(C=O)C.CCO>[Cl:1][C:2]1[C:3]([N:9]=[C:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[N:4][CH:5]=[CH:6][C:7]=1[O:8][C:35]1[CH:34]=[CH:33][C:32]([N+:37]([O-:39])=[O:38])=[CH:31][C:30]=1[F:29]
Reactant: O=c1cc[nH]c(N=C(c2ccccc2)c2ccccc2)c1Cl
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCO
Product: O=[N+]([O-])c1ccc(Oc2ccnc(N=C(c3ccccc3)c3ccccc3)c2Cl)c(F)c1
Temperature: 90 °C
Reaction time: 2 h
Yield: 32.73 %

Procedure:
To a 2-L Chem-Glass reactor was added the crude 3-chloro-2-(diphenylmethyleneamino)pyridin-4(1H)-one (from above, now in DMF) and cesium carbonate (300.52 g, 923 mmol) followed by the addition of 3,4-difluoronitrobenzene (118.15 mL, 1065 mmol). The mixture was heated to approximately 90° C. with stirring for 2 h. The mixture was cooled to 25° C. with stirring for 10 min. To this solution was added water (1 L). The mixture was extracted with EtOAc (1 L) and the aqueous phase was discarded. The organics were concentrated to afford an oil. The oil was dissolved into EtOH (200 mL) (heating sometimes required). After the solution was allowed to stand at 25° C. for 4 h, a solid was collected by filtration to afford 3-chloro-N-(diphenylmethylene)-4-(2-fluoro-4-nitrophenoxy)pyridin-2-amine (104.00 g; 32.73% yield) as a yellow solid. 1H NMR (CDCl3) δ 6.52 (d, 1 H, J=5.6 Hz), 6.80 (dd, 1 H, J=8.1, 9.1 Hz), 7.21-7.60 (m, 8 H), 7.78-7.95 (m, 2 H), 8.00 (m, 1 H), 8.11 (dd, 1 H, J=2.5, 9.6 Hz), 8.17 (d, 1 H, J=5.6 Hz); MS (ESI+) m/z 448.01 (M+H)+.
Reaction SMILES: C1(C)C=CC=CC=1.C[N:9](C)C=O.N.Cl.Cl[CH2:16][CH2:17][N:18]([CH:20](Cl)[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH3:19]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.[OH-].[Na+]>[CH3:19][N:18]1[CH2:17][CH2:16][NH:9][CH:21]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:20]1
Reactant: CN(C)C=O
Reactant: CN(CCCl)C(Cl)Cc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: N
Solvent: Cc1ccccc1
Product: CN1CCNC(c2ccccc2)C1
Reaction time: 2 h
Yield: 58.7 %

Procedure:
A reactor was charged with 515 kg of toluene, 1320 kg of dimethylformamide, 41 kg of tetrabutylammonium bromide and 1392 kg of a 28% aqueous ammonia. A slurry mixture of 524.3 kg (pure content: 409.9 kg) of the wet crystals of N-(2-chloroethyl)-N-methyl-α-chloro-β-phenylethylamine hydrochloride obtained in Example 9 and 519.2 kg of toluene was introduced thereinto. A vessel in which the slurry mixture had been placed was washed with 178 kg of toluene, and the washing liquid was introduced into the reactor. The mixture was stirred at 40° to 44° C. for 2 hours, and the termination point of the reaction was confirmed by gas chromatography. A solution prepared by dissolving 109 kg of sodium hydroxide in 246.3 kg of a 25% aqueous sodium hydroxide was added thereto to adjust its pH to 11.7. The mixture was stirred at 45° to 47° C. for 2 hours, and allowed to separate into layers. To the aqueous layer was added a solution prepared by dissolving 31 kg of sodium hydroxide in 71 kg of a 25% aqueous sodium hydroxide, and the resulting mixture was stirred and extracted at 23° to 24° C. with 461 kg of toluene. Further, 461 kg of toluene was added to the aqueous layer with stirring to extract. The organic layers were combined, and the combined organic layer was dried over 76 kg of anhydrous magnesium sulfate. The organic layer was filtered, and the filtered residue was washed with 143 kg of toluene. The filtrate was concentrated under reduced pressure to distill off toluene. Further, dimethylformamide was distilled off under reduced pressure (450 to 720 Pa), and thereafter, 157.8 g of 1-methyl-3-phenylpiperazine was obtained as a main component (yield: 58.7%). Its boiling point was from 98° to 122° C. (0.2 to 2 kPa).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:31]=[CH:30][C:8]([O:9][C:10]2[CH:11]=[C:12]3[C:16](=[C:17]([O:19][CH2:20][CH:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[CH:18]=2)[NH:15][C:14]([C:27]([OH:29])=O)=[CH:13]3)=[CH:7][CH:6]=1)(=[O:4])=[O:3].Cl.C[N:34](C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.N>O.CN(C)C=O>[CH3:1][S:2]([C:5]1[CH:31]=[CH:30][C:8]([O:9][C:10]2[CH:11]=[C:12]3[C:16](=[C:17]([O:19][CH2:20][CH:21]4[CH2:22][CH2:23][O:24][CH2:25][CH2:26]4)[CH:18]=2)[NH:15][C:14]([C:27]([NH2:34])=[O:29])=[CH:13]3)=[CH:7][CH:6]=1)(=[O:3])=[O:4]
Reactant: CCN=C=NCCCN(C)C
Reactant: CS(=O)(=O)c1ccc(Oc2cc(OCC3CCOCC3)c3[nH]c(C(=O)O)cc3c2)cc1
Agent: Cl
Agent: N
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1ccc(Oc2cc(OCC3CCOCC3)c3[nH]c(C(N)=O)cc3c2)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 80.2 %

Procedure:
A mixture of 5-[4-(methylsulfonyl)phenoxy]-7-(tetrahydro-2H-pyran-4-ylmethoxy)-1H-indole-2-carboxylic acid (1.0 g), 1-[3-(dimethylamino)propyl-3-ethylcarbodiimide hydrochloride (0.9 g), 1-hydroxybenzotriazole (0.6 g) and N,N-dimethylformamide (15 mL) was stirred at room temperature for 15 min. 28% Aqueous ammonia solution (0.8 mL) was added to the reaction solution, and the mixture was stirred at room temperature for 2.5 hr. Water was added to the reaction solution, and the mixture was subjected to extraction with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, filtrated, and concentrated under reduced pressure. The obtained crude product was crystallized from a mixed solvent of ethanol-diethyl ether, and the obtained crystals were washed with diethyl ether to give the title compound (0.8 g, yield 83%) as colorless crystals. MS 445 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=O)[CH:5]=[CH:6][C:7]=1[Cl:8].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:37][C:38]1[S:39][CH:40]=[CH:41][N:42]=1.C(N(C(C)C)CC)(C)C>CN(C)C=O.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([NH:37][C:38]2[S:39][CH:40]=[CH:41][N:42]=2)=[O:12])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: Nc1nccs1
Reactant: O=C(O)Cc1ccc(Cl)c(Cl)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: O=C(Cc1ccc(Cl)c(Cl)c1)Nc1nccs1
Reaction time: 16 h
Yield: 69.6 %

Procedure:
To a solution of (3,4-dichloro-phenyl)-acetic acid (500 mg, 2.4 mmol)in N,N-dimethylformamide (15 mL) at 25° C. was added HBTU (1.02 g, 2.7 mmol), 2-aminothiazole (360 mg, 3.6 mmol) and diisopropylethylamine (1.25 mL, 7.2 mmol). The reaction mixture was stirred for 16 h, then was diluted with water (10 mL) and extracted with ethyl acetate (3×15 mL). The combined organic layers were washed in turn with water (1×10 mL), 1N sodium hydroxide (1×10 mL), 1 N hydrochloric acid (1×10 mL) and brine (1×10 mL), then were dried over sodium sulfate, filtered and evaporated under reduced pressure. The residual material was purified by flash chromatography (Merck Silica gel 60, 230-400 mesh, 50150 hexanes/ethyl acetate) to furnish rac-2-(3,4-dichloro-phenyl)-N-thiazol-2-yl-acetamide (480 mg, 70% yield) as a light yellow solid, mp 169.8-172.3° C. EI-HRMS m/e calcd for C11H8N2OSCl2 (M+) 285.9734, found 285.9734.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([N+:9]([O-:11])=[O:10])=[CH:7][CH:6]=[CH:5][C:4]=1B1OC(C)(C)C(C)(C)O1.Br[C:22]1[O:26][C:25]([C:27]([OH:29])=[O:28])=[CH:24][CH:23]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:1][O:2][C:3]1[C:8]([N+:9]([O-:11])=[O:10])=[CH:7][CH:6]=[CH:5][C:4]=1[C:22]1[O:26][C:25]([C:27]([OH:29])=[O:28])=[CH:24][CH:23]=1
Reactant: O=C(O)c1ccc(Br)o1
Reactant: COc1c(B2OC(C)(C)C(C)(C)O2)cccc1[N+](=O)[O-]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: COc1c(-c2ccc(C(=O)O)o2)cccc1[N+](=O)[O-]
Yield: 56.1 %

Procedure:
2-(2-Methoxy-3-nitro-phenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane 6a (10 g, 35.85 mmol), 5-bromofuran-2-carboxylic acid (5.47 g, 28.66 mmol), tetrakis(triphenylphosphine)palladium (2.07 g, 1.79 mmol) and sodium carbonate (7.60 g, 71.66 mmol) were dissolved in the solvent mixture of 200 mL of 1,4-dioxane and 30 mL of water. The reaction mixture was heated to reflux for 2.5 hours. The reaction was monitored by TLC until the disappearance of the starting materials. The mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was diluted with 150 mL of water and adjusted to pH 3 with 1 N hydrochloric acid. Then the mixture was filtered and the filter cake was washed with 50 mL of the solvent mixture of n-hexane/ethyl acetate (V/V=1:1). The residue was dried to obtain the title compound 5-(2-methoxy-3-nitro-phenyl)furan-2-carboxylic acid 9a (4.23 g, yield 56.1%) as a grey solid.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([B:9]2[O:17][C:14]([CH3:16])([CH3:15])[C:11]([CH3:13])([CH3:12])[O:10]2)=[CH:5][CH:4]=1.C(N(CC)CC)C.Cl[C:26]([O:28][C:29]1[CH:34]=[CH:33][C:32]([N+:35]([O-:37])=[O:36])=[CH:31][CH:30]=1)=[O:27]>C1COCC1.CCOC(C)=O>[C:26](=[O:27])([O:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([B:9]2[O:17][C:14]([CH3:16])([CH3:15])[C:11]([CH3:13])([CH3:12])[O:10]2)=[CH:7][CH:8]=1)[O:28][C:29]1[CH:30]=[CH:31][C:32]([N+:35]([O-:37])=[O:36])=[CH:33][CH:34]=1
Reactant: CC1(C)OB(c2ccc(CO)cc2)OC1(C)C
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC1(C)OB(c2ccc(COC(=O)Oc3ccc([N+](=O)[O-])cc3)cc2)OC1(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 60 %

Procedure:
4-(Hydroxymethyl)phenylboronic acid pinacol ester (0.5 g, 2.1 mmol) was dissolved in 20 mL of dry THF. Triethylamine (0.6 mL, 4.3 mmol) was added followed by 4-nitrophenyl chloroformate (0.47 g, 2.3 mmol) and the reaction was allowed to stir at room temperature for 1 h. The reaction was diluted with EtOAc and washed with 1.0 M HCl followed by saturated NaHCO3. The organic layer was dried over MgSO4, filtered and concentrated. Compound B2a was purified on a silica gel column eluting with 5% EtOAc in hexanes to give 0.51 g (1.3 mmol, 60% yield) as a white solid. 1H NMR (400 MHz, CDCl3) δ=8.25 (d, J=9.2 Hz, 2H), 7.85 (d, J=8.0 Hz, 2H), 7.43 (d, J=8.0 Hz, 2H), 7.36 (d, J=9.2 Hz, 2H), 5.31 (s, 2H), 1.35 (s, 12H). 13C NMR (100 MHz, CDCl3) δ=155.7, 152.7, 145.6, 137.2, 135.4, 127.9, 125.5, 122.0, 84.2, 71.0, 25.1. ESI-MS(+): m/z 417.19 [M+NH4]+, 422.20 [M+Na]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[Cl:9])[NH2:5].[C:10]([O:15][CH3:16])(=[O:14])[C:11]([CH3:13])=O>>[CH3:16][O:15][C:10](=[O:14])[C@H:11]([CH3:13])[NH:5][C:4]1[CH:6]=[CH:7][C:8]([Cl:9])=[C:2]([Cl:1])[CH:3]=1
Reactant: Nc1ccc(Cl)c(Cl)c1
Reactant: COC(=O)C(C)=O
Product: COC(=O)[C@H](C)Nc1ccc(Cl)c(Cl)c1

Procedure:
Following General Procedure AA above and using 3,4-dichloroaniline (Aldrich) and methyl pyruvate (Aldrich), the title compound was prepared as an oil. The reaction was monitored by tlc on silica gel (Rf=0.55 in 25% EtOAc/hexanes) and purification was by flash chromatography (silica gel using 25% EtOAc/hexanes as the eluant).
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([C:7]([CH3:10])([CH3:9])[CH3:8])[O:4][N:3]=1.[CH3:11][N:12]=[C:13]=[O:14].C(N(CC)CC)C>C1C=CC=CC=1>[CH3:11][NH:12][C:13]([NH:1][C:2]1[CH:6]=[C:5]([C:7]([CH3:10])([CH3:9])[CH3:8])[O:4][N:3]=1)=[O:14]
Reactant: CN=C=O
Reactant: CC(C)(C)c1cc(N)no1
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: CNC(=O)Nc1cc(C(C)(C)C)on1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.3 %

Procedure:
To a solution of 3-amino-5-t-butylisoxazole (16.82 g) in anhydrous benzene (140 ml), methyl isocyanate (8.90 g) and triethylamine (0.5 ml) are added. The resulting mixture is stirred at room temperature for about 8 hours, allowed to stand overnight and refluxed for 1 hour. After ice cooling, the reaction mixture is filtered to give a precipitate, which is recrystallized from ethyl acetate to give 1-methyl-3-(5-t-butyl-3-isoxazolyl)urea (21.61 g) as colorless needles melting at 187.0° to 187.5° C.
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[F:16][C:17]([F:27])([F:26])[O:18][C:19]1[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=1.CN(C1C=CC=CN=1)C.[CH2:37]([C@H:39]1[CH2:44][CH2:43][C@H:42]([C:45](O)=[O:46])[CH2:41][CH2:40]1)[CH3:38]>C1(C)C=CC=CC=1>[CH2:37]([C@H:39]1[CH2:44][CH2:43][C@H:42]([C:45]([O:25][C:22]2[CH:21]=[CH:20][C:19]([O:18][C:17]([F:26])([F:27])[F:16])=[CH:24][CH:23]=2)=[O:46])[CH2:41][CH2:40]1)[CH3:38]
Reactant: CC[C@H]1CC[C@H](C(=O)O)CC1
Reactant: Oc1ccc(OC(F)(F)F)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccccn1
Solvent: Cc1ccccc1
Product: CC[C@H]1CC[C@H](C(=O)Oc2ccc(OC(F)(F)F)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
First, 4.6 g of dicyclohexylcarbodiimide in 80 ml of toluene are added to a mixture of 4 g of 4-trifluoromethoxyphenol and 20 ml of toluene, 0.2 g of dimethylaminopyridine is then added, the mixture is stirred at room temperature for 1 hour, and 3.8 g of trans-4-ethylcyclohexanecarboxylic acid are then added. After work-up and purification by chromatography and/or crystallization, 4-(trifluoromethoxy)phenyl trans-4-ethylcyclohexanecarboxylate is obtained.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][C:10](=[O:14])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:15](Br)[CH:16]=[CH2:17].[H-].[Na+]>CN(C=O)C>[CH2:17]([N:11]1[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9][C:10]1=[O:14])[CH:16]=[CH2:15]
Reactant: C=CCBr
Reactant: CC(C)(C)OC(=O)N1CCNC(=O)C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCN1CCN(C(=O)OC(C)(C)C)CC1=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred solution of 4-tert-butyloxycarbonyl-2-piperazinone (10 g, 50 mmol) and allyl bromide (7.25 g, 60 mmol) in DMF (75 mL) at 0° C. was added sodium hydride (2.4 g of a 60% suspension in mineral oil, 60 mmol) in portions over a period of 10 min. The mixture was allowed to warm to ambient temperature and stirred for 18 h. The solvent was removed in vacuo and the residue was partitioned between EtOAc and water. The EtOAc layer was dried (MgSO4), filtered, and the solvent was removed in vacuo. The residue was purified by silica gel column chromatography using a gradient elution of 33%, 40%, 50%, 60% EtOAc in hexanes. Concentration of product-containing fractions in vacuo gave the title compound as an oil. HPLC RT=2.80 min (Method A), ES MS (M+H)=241, 1H NMR (400 MHz, CDCl3) δ 5.76 (ddt, 1H), 5.2 (overlapping doublets, 2H), 4.10 (s, 2H), 4.04 (d, J=6 Hz, 2H), 3.64 (t, J=7 Hz, 2 H), 3.50 (t, J=7 Hz, 2H), 1.47, (s, 9H).