Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.[CH:9]1([CH2:12]Br)[CH2:11][CH2:10]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[CH:9]1([CH2:12][S:8][C:5]2[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=2)[CH2:11][CH2:10]1
Reactant: Sc1ccc(Br)cc1
Reactant: BrCC1CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Brc1ccc(SCC2CC2)cc1

Procedure:
4-Bromothiophenol (106.12 g, 561 mmol), cyclopropylmethyl bromide (83.3 g, 617 mmol) and potassium carbonate (85.2 g, 617 mmol) were stirred in DMF (400 mL) overnight. The mixture was diluted with water (1.5 L) and the product extracted into hexanes (2×1 L). The combined organic extracts were dried (MgSO4) and concentrated to give 4-bromophenyl cyclopropylmethyl sulphide as an oil (130.7 g, quantitative). The aforementioned sulphide (10 g, 41 mmol) was dissolved in THF (400 mL) and cooled to −78° C. n-Butyllithium (51 mL of a 1.6 M solution in hexanes) was added dropwise. On completion of addition, the mixture was stirred for a further 15 min before dropwise addition of DMF. The reaction mixture was stirred for 18 h, allowing to warm to room temperature. The reaction was quenched by addition of satd. NH4Cl(aq) followed by water. The product was extracted into diethyl ether (×2) and the combined organic layers were dried (MgSO4) and concentrated. Purification by chromatography on silica eluting with 5 to 10% ethyl acetate in hexane gave the title compound (5.50 g, 70% yield). 1H NMR δ (360 MHz, CDCl3) δ 9.92 (1H, s), 7.76 (2H, d, J=8.4 Hz), 7.38 (2H, d, J=8.2 Hz), 2.97 (2H, d, J=7.0 Hz), 1.14-1.08 (1H, m), 0.67-0.62 (2H, m) 0.35-0.30 (2H, m).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:9]2[C:14](=[O:15])[C:13]([O:16][C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)=[C:12]([C:24]3[CH:29]=[CH:28][C:27]([S:30](C)(=[O:32])=[O:31])=[CH:26][CH:25]=3)[CH:11]=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8].[NH3:34]>>[F:1][C:2]1[CH:3]=[C:4]([N:9]2[C:14](=[O:15])[C:13]([O:16][C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)=[C:12]([C:24]3[CH:29]=[CH:28][C:27]([S:30]([NH2:34])(=[O:32])=[O:31])=[CH:26][CH:25]=3)[CH:11]=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: N
Reactant: CS(=O)(=O)c1ccc(-c2cnn(-c3ccc(F)c(F)c3)c(=O)c2Oc2ccc(F)cc2)cc1
Product: NS(=O)(=O)c1ccc(-c2cnn(-c3ccc(F)c(F)c3)c(=O)c2Oc2ccc(F)cc2)cc1

Procedure:
The product from Example 109 was converted to the title sulfonamide according to the method of Example 384 (yield: 110 mg, 45.7%). mp 224-226° C. 1H NMR (300 MHz, CDCl3) δ 4.86 (br s, 2H), 6.89-7.03 (m, 4H), 7.19-7.30 (m, 1H), 7.45-7.52 (m, 1H), 7.56-7.66 (m, 1H), 7.79 (d, J=9 Hz, 2H), 8.04 (d, J=9 Hz, 1H), 8.08 (s, 1H). MS (DCI/NH3) m/z 474 (M+H)+, 491 (M+NH4)+. Anal. calc. for C22H14F3N3O4S.0.25H2O: C, 55.32; H, 2.93; N, 8.80. Found: C, 55.26; H, 3.11; N, 8.58.
Reaction SMILES: [S:1](Cl)([CH3:4])(=[O:3])=[O:2].[OH:6][CH2:7][CH:8]1[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9]1.C(N(CC)CC)C>C(Cl)Cl>[CH3:4][S:1]([O:6][CH2:7][CH:8]1[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9]1)(=[O:3])=[O:2]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCC(CO)C1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(COS(C)(=O)=O)C1
Reaction time: 0.33 h

Procedure:
Mesyl chloride (106 μL, 1.37 mmol) was added to a stirred solution of tert-butyl 3-(hydroxymethyl)pyrrolidine-1-carboxylate (250 mg, 1.242 mmol) and triethylamine (225 μL, 1.62 mmol) in DCM at 0° C. After 20 min, the reaction mixture was diluted with DCM, washed with brine, dried (sodium sulfate) and concentrated in vacuo to afford the title compound i-14a. 1H NMR (500 MHz, CDCl3): δ 4.19 (m, 2H), 3.20-3.60 (m, 3H), 3.17 (m, 1H), 3.05 (s, 3H), 2.65 (m, 1H), 2.07 (m, 1H), 1.74 (m, 1H), 1.48 (s, 9H).
Reaction SMILES: [C:1]([O-:8])(=[O:7])/[CH:2]=[CH:3]/[C:4]([O-:6])=[O:5].[NH4+:9].[NH4+].S([O-])([O-])(=O)=O.[Mg+2].SC(O)C>>[NH2:9][C@H:2]([C:1]([OH:8])=[O:7])[CH2:3][C:4]([OH:6])=[O:5]
Reactant: O=C([O-])/C=C/C(=O)[O-]
Reactant: [NH4+]
Agent: CC(O)S
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Product: N[C@@H](CC(=O)O)C(=O)O

Procedure:
The stoichiometry of our immobilized aspartase, prepared as described in the previous examples, was determined using a 1 g column of immobilized aspartase, approximately 5,000 units per gram activity, operating at 40° C. The feedstock was 1.5 molar ammonium fumarate at pH 8.5 containing 10-3 molar each of magnesium sulfate and mercaptoethanol. The contents of the flask was circulated upflow through the jacketed column with the effluent being returned to the feed flask. The amount of fumaric acid consumed and aspartic acid formed was measured at various times using high-pressure liquid chromatography with results being summarized in Table 3.
Reaction SMILES: [C:1](=O)([O-:3])[OH:2].[Na+].[CH3:6][N:7]1[S:16](=[O:18])(=[O:17])[C:11]2[CH:12]=[C:13]([Cl:15])[S:14][C:10]=2[C:9]([OH:19])=[C:8]1[C:20]([NH:22][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][N:28]=1)=[O:21]>O.C(O)C>[C:1](=[O:3])=[O:2].[CH3:6][N:7]1[S:16](=[O:18])(=[O:17])[C:11]2[CH:12]=[C:13]([Cl:15])[S:14][C:10]=2[C:9]([OH:19])=[C:8]1[C:20]([NH:22][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][N:28]=1)=[O:21]
Reactant: O=C([O-])O
Agent: CN1C(C(=O)Nc2ccccn2)=C(O)c2sc(Cl)cc2S1(=O)=O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: O=C=O

Procedure:
8 g of sodium hydrogencarbonate was dissolved in 120 g of water and mixed with a suspension of 32 g lornoxicam in 600 g of ethanol. While forming gaseous carbon dioxide, lornoxicam dissolved. 100 g of Pharmacoat 606W was added and dissolved. 212 g of sodium hydrogen carbonate was admixed and dissolved. The solution obtained was mixed with Avicel in a lab size mixer. The wet mixture was dried and then magnesium stearate and polyplasdone XL were admixed in the lab scale mixer.
Reaction SMILES: [Br:1][C:2]1[S:3][C:4]([C:8]([OH:10])=O)=[C:5]([CH3:7])[N:6]=1.CN1CCOCC1.ClC(OCC(C)C)=O.[N:26]1[CH:31]=[CH:30][CH:29]=[C:28]([CH2:32][NH2:33])[CH:27]=1>ClCCl.C(OCC)(=O)C>[Br:1][C:2]1[S:3][C:4]([C:8]([NH:33][CH2:32][C:28]2[CH:27]=[N:26][CH:31]=[CH:30][CH:29]=2)=[O:10])=[C:5]([CH3:7])[N:6]=1
Reactant: NCc1cccnc1
Reactant: Cc1nc(Br)sc1C(=O)O
Agent: CC(C)COC(=O)Cl
Solvent: CN1CCOCC1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: Cc1nc(Br)sc1C(=O)NCc1cccnc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 57 %

Procedure:
To a solution of 2-bromo-4-methylthiazole-5-carboxylic acid (2.25 g, 10.00 mmol) and 4-methylmorpholine (1.25 g, 11.00 mmol) in anhydrous dichloromethane (80 mL) was added iso-butyl chloroformate (1.3 mL, 10.0 mmol) dropwise at 0° C. The reaction mixture was stirred at ambient temperature for 2 hours, cooled to 0° C. and pyridin-3-ylmethanamine (1.23 g, 12.00 mmol) was added dropwise. The reaction mixture was stirred at ambient temperature for 4 hours, diluted with ethyl acetate (100 mL) and washed with saturated aqueous sodium bicarbonate (50 mL) and brine (50 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (ethyl acetate) to afford the title compound as a yellow solid (1.78 g, 56%): 1H NMR (300 MHz, CDCl3) δ 8.55-8.48 (m, 2H), 7.70-7.64 (m, 1H), 7.29-7.26 (m, 1H), 6.36 (t, J=5.8 Hz, 1H), 4.56 (d, J=5.8 Hz, 2H), 2.63 (s, 3H); MS (ES+) m/z 312.1 (M+1), 314.1 (M+1).
Reaction SMILES: [H-].[Na+].[C:3]([O:14]C)(=O)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]([CH3:12])([CH3:11])[CH3:10].[C:16]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)(=[O:18])[CH3:17]>C1COCC1>[C:19]1([C:16](=[O:18])[CH2:17][C:3]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]([CH3:10])([CH3:11])[CH3:12])=[O:14])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: COC(=O)CCCCCC(C)(C)C
Reactant: CC(=O)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)CCCCCC(=O)CC(=O)c1ccccc1
Temperature: 25 °C
Yield: 25.8 %

Procedure:
A round bottom flask equipped with mechanical stirring, a nitrogen inlet, a thermometer, and an addition funnel was charged with 60% sodium hydride in mineral oil (50 g, 1.24 mol), THF (500 mL), and methyl neodecanoate (229 g, 1.23 mol), and the mixture was stirred at room temperature. Acetophenone (74 g, 0.62 mol) was added over 45 min. The temperature was slowly raised to 60° C. and maintained at that temperature for 24 hr. A sample was withdrawn, and analysis indicated the reaction was perhaps 1/4 complete. The reaction mixture was stirred at 60° C. for a total of eight days, continuously and slowly evolving hydrogen gas. Methanol was added to quench excess sodium hydride, followed by dilute sulfuric acid. The separated organic phase was washed with water, and volatiles were removed under vacuum. The residue was diluted with heptane and washed with 10% potassium hydroxide, then with water, and the volatiles removed under vacuum to leave 267 g. This was distilled, giving a heart cut at about 130° C. at a pressure of 0.1 mm Hg. Thin layer chromatography indicated the presence of some acetophenone plus two major components of similar size. The heart cut was purified by flash chromatography. Heptane elution provided 48 g of the less polar component, which was distilled at 165° C. at 1 mm Hg to give 44 g (0.16 mol, 26% yield) of 1-phenyl-3-neononyl-1,3-propanedione. Toluene elution provided 21 g of the more polar component, which was shown to be dypnone.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[C:11]1([NH2:17])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.CCN(CC)CC>CN1C(=O)CCC1>[N+:8]([C:7]1[C:2]([NH:17][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[N:3][CH:4]=[CH:5][CH:6]=1)([O-:10])=[O:9]
Reactant: Nc1ccccc1
Reactant: O=[N+]([O-])c1cccnc1Cl
Solvent: CCN(CC)CC
Solvent: CN1CCCC1=O
Product: O=[N+]([O-])c1cccnc1Nc1ccccc1
Temperature: 100 °C
Reaction time: 1.5 h
Yield: 52.6 %

Procedure:
A mixture of 2-chloro-3-nitropyridine (3.49 g, 22.0 mmol), phenylamine (2 mL, 22.0 mmol) and Et3N (3.1 mL, 22.0 mmol) in NMP (7 mL) was stirred at 100° C. for 1.5 h under a nitrogen atmosphere. Additional amounts of Et3N (0.2 mL) and of phenylamine (0.1 mL) were added and the stirring was continued for further 30 min. The mixture was then partitioned between EtOAc and water. The aqueous phase was further extracted with EtOAc and the combined organic layers were washed with brine, then dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, gradient 10-100% DCM in pentane) affording (3-Nitropyridin-2-yl)phenylamine as a red crystalline solid (2.49 g, 58%). LCMS: RT 3.53 min [M+H]+ 216.0.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[NH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C(OCC)(=O)C>[NH:11]([C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Nc1ccccc1
Reactant: O=[N+]([O-])c1cccnc1Cl
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1cccnc1Nc1ccccc1
Temperature: 100 °C
Reaction time: 1 h
Yield: 90.9 %

Procedure:
A mixture of 11.21 g (70 mmol) of 2-chloro-3-nitropyridine and 19.56 g (210 mmol) of aniline was heated under stirring at 100° C. for 1 h. The reaction liquid was cooled to room temperature and dissolved in ethyl acetate. The solution was washed with an aqueous citric acid solution and then with water. After drying over magnesium sulfate, the solvent was distilled off under reduced pressure and the residue was recrystallized from ethyl acetate/n-hexane to obtain 13.7 g of the title compound.
Reaction SMILES: [OH-:1].[K+].[C:3]1(=[O:10])[CH2:8][CH2:7][CH2:6][CH2:5][C:4]1=O.Br[CH2:12][C:13](=O)[C:14]([O:16]CC)=[O:15].[OH-].[Na+]>CO.O>[O:10]=[C:3]1[C:4]2[C:13]([C:14]([OH:16])=[O:15])=[CH:12][O:1][C:5]=2[CH2:6][CH2:7][CH2:8]1
Reactant: [OH-]
Reactant: O=C1CCCCC1=O
Reactant: CCOC(=O)C(=O)CBr
Agent: [K+]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: O=C(O)c1coc2c1C(=O)CCC2
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
4-Oxo-4,5,6,7-tetrahydrobenzofuran-3-carboxylic acid was prepared as follows: To a stirred solution of potassium hydroxide (28.06 g, 0.5 mol) in methyl alcohol (100 mL) under nitrogen at 0° C. was added dropwise a solution of cyclohexanedione (56.07 g, 0.5 mol) in methyl alcohol (100 mL). The mixture was stirred at 0° C. for 0.5 h, then a solution of ethyl bromopyruvate (66 mL, 0.525 mol) in methyl alcohol(100 mL) was added dropwise. After allowing the mixture to stir at ambient temperature for 17 h, a 50% aqueous sodium hydroxide solution (60 mL) was added dropwise and stirring continued an additional 7 h. After dilution with water, the solution was acidified and the methanol removed in vacua. Ice water was added and the precipitate filtered and dried in vacuo to afford 4-oxo-4,5,6,7-tetrahydrobenzofuran-3 -carboxylic acid. m.p. 137-138° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]([OH:25])([C@H:16]([C:18]1[C:23]([F:24])=[CH:22][N:21]=[CH:20][N:19]=1)[CH3:17])[CH2:10][N:11]1[CH:15]=[N:14][CH:13]=[N:12]1.N1C=NN=N1.C(N(C(C)C)[P:35]([O:44][CH2:45][C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)[O:36][CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)(C)C.ClC1C=C(C=CC=1)C(OO)=[O:60]>CN(C)C1C=CN=CC=1.C(Cl)Cl>[P:35]([O:25][C@@:9]([C:3]1[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=1[F:1])([C@H:16]([C:18]1[C:23]([F:24])=[CH:22][N:21]=[CH:20][N:19]=1)[CH3:17])[CH2:10][N:11]1[CH:15]=[N:14][CH:13]=[N:12]1)([O:36][CH2:37][C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1)([O:44][CH2:45][C:46]1[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=1)=[O:60]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C[C@@H](c1ncncc1F)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Reactant: CC(C)N(C(C)C)P(OCc1ccccc1)OCc1ccccc1
Agent: CN(C)c1ccncc1
Agent: c1nnn[nH]1
Solvent: ClCCl
Product: C[C@@H](c1ncncc1F)[C@@](Cn1cncn1)(OP(=O)(OCc1ccccc1)OCc1ccccc1)c1ccc(F)cc1F
Temperature: 25 °C
Yield: 60 %

Procedure:
A solution of (2R,3S)-2-(2,4-difluorophenyl)-3-(5-fluoro-4-pyrimidinyl)-1-(1H-1,2,4-triazol-1-yl) butan-2-ol (the compound of Example 7, EP 0440372, also known as voriconazole, 17.0 g, 48.7 mmol), 4-dimethylaminopyridine (10.2 g, 83.5 mmol), 1H-tetrazole (10.2 g, 146 mmol) and dibenzyl diisopropylphosphoramidite (33.6 g, 97.4 mmol) in methylene chloride (100 ml) was stirred at reflux for 2 hours and a further 16 hours at room temperature under a nitrogen atmosphere. The reaction mixture was then washed with hydrochloric acid and then sodium bicarbonate, dried (MgSO4) and concentrated. The crude product phosphite was purified by column chromatography (silica gel, 300 g, eluting with 3:1 to 1:1 hexane:ethyl acetate gradient) to give a pale yellow oil. This was dissolved in methylene chloride (100 ml) and cooled to −10° C., whereupon a solution of 3-chloroperoxybenzoic acid (14.8 g, 57% w/w, 46.9 mmol) in methylene chloride (100 ml) was added maintaining the temperature below 0° C. The resulting mixture was allowed to warm to room temperature for 10 minutes before washing with aqueous sodium metabisulphite and sodium bicarbonate. After drying (MgSO4) and concentrating the crude product was purified by column chromatography (silica gel, 300 g, eluting with ethyl acetate) to give the subtitle compound as a viscous syrup (17.86 g, 60%).
Reaction SMILES: [F:1][C:2]1[C:10]([F:11])=[CH:9][C:8]([I:12])=[CH:7][C:3]=1[C:4](O)=[O:5].[CH:13]([N:16](C(C)C)[CH2:17]C)(C)C.C(Cl)(=O)C(C)(C)C.CNC>ClCCl.O>[F:1][C:2]1[C:10]([F:11])=[CH:9][C:8]([I:12])=[CH:7][C:3]=1[C:4]([N:16]([CH3:17])[CH3:13])=[O:5]
Reactant: CCN(C(C)C)C(C)C
Reactant: O=C(O)c1cc(I)cc(F)c1F
Agent: CC(C)(C)C(=O)Cl
Agent: CNC
Solvent: O
Solvent: ClCCl
Product: CN(C)C(=O)c1cc(I)cc(F)c1F
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 86.8 %

Procedure:
2,3 Difluoro-5-iodobenzoic acid (10.8 g, 38 mmol) was suspended in 80 mL of dry dichloromethane under nitrogen. Di-iso-propylethylamine (6.6 mL, 38 mmol) was added and the mixture was cooled to 0° C. Pivaloyl chloride (4.7 mL, 38 mmol) was added and the solution was stirred at 0° C. for 1.5 hrs. Dimethylamine was added (40% wt. solution in water, 10.6 mL, 83 mmol) and the reaction mixture was stirred for 5 hrs. The reaction was quenched with sodium bicarbonate and diluted with dichloromethane (50 mL). The layers were separated, the organic phase was washed with 1 N hydrochloric acid and brine. The organic phase was dried over magnesium sulfate and concentrated to give 10.3 g (33 mmol, 87%) of 2,3-difluoro-5-iodo-N,N-dimethyl-benzamide as a colorless solid. 1H NMR (500 MHz, DMSO-d6) δ 7.95 (ddd, J=10 Hz, J2=7.5 Hz, J3=2 Hz, 1H), 7.57 (dt, J=10 Hz, J2=2 Hz, 1H), 2.98 (s, 3H), 2.84 (s, 3H); MS: m/z 312 [MH+]
Reaction SMILES: [C:1]([Br:5])(Br)(Br)[Br:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C.[O:32]1[CH:36]=[CH:35][CH:34]=[C:33]1[CH:37]=O.C(=O)(O)[O-].[Na+]>C(Cl)Cl.O>[Br:2][C:1]([Br:5])=[CH:37][C:33]1[O:32][CH:36]=[CH:35][CH:34]=1
Reactant: O=Cc1ccco1
Reactant: BrC(Br)(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: BrC(Br)=Cc1ccco1
Reaction time: 0.08 h
Yield: 54.7 %

Procedure:
To a stirred solution of 9.6 g (29 mmol) of carbon tetrabromide in 120 mL of dry methylene chloride at 0° was added 15.2 g (58 mmol) of triphenylphosphine. After 15 min 3.0 mL (22.5 mmol) of triethylamine was added, and after stirring another 5 min at 0°, the reaction mixture was cooled to −78°. At this temperature 1.50 mL (22.5 mmol) of 2-furaldehyde was added quickly dropwise, and after addition was complete, the mixture was stirred a −70° for 30 min. The reaction mixture was poured onto a rapidly stirring saturated solution of sodium bicarbonate in water. The methylene chloride phase was removed and the aqueous layer was extracted with additional methylene chloride. The combined extracts were evaporated to a solid which was stirred in 500 mL of hexanes for 2 h. After filtration, the filtrate was concentrated to a volume of 50 mL and the filtered again to remove precipitated solid. Final evaporation of the filtrate afforded 3.1 g (58%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([O:15][CH2:16][CH:17]=[C:18]([Cl:20])[Cl:19])[CH:5]=[C:6]([Cl:14])[C:7]=1[O:8][CH2:9][CH2:10][CH2:11][NH:12][CH3:13].C(Cl)(Cl)Cl.[F:25][C:26]([F:37])([F:36])[C:27]1[CH:35]=[CH:34][C:30]([C:31](Cl)=[O:32])=[CH:29][CH:28]=1>C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([O:15][CH2:16][CH:17]=[C:18]([Cl:20])[Cl:19])[CH:5]=[C:6]([Cl:14])[C:7]=1[O:8][CH2:9][CH2:10][CH2:11][N:12]([CH3:13])[C:31](=[O:32])[C:30]1[CH:34]=[CH:35][C:27]([C:26]([F:37])([F:36])[F:25])=[CH:28][CH:29]=1
Reactant: CNCCCOc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl
Reactant: O=C(Cl)c1ccc(C(F)(F)F)cc1
Solvent: ClC(Cl)Cl
Solvent: CCOC(C)=O
Product: CN(CCCOc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl)C(=O)c1ccc(C(F)(F)F)cc1
Yield: 55 %

Procedure:
To a mixture of 0.42 g of 3,5-dichloro-1-(3,3-dichloro-2-propenyloxy)-4-(3-(methylamino)propyloxy)benzene, 0.18 ml of triethylamnine and 10 ml of chloroform was added 0.18 ml of 4-(trifluoromethyl)benzoyl chloride, while stirring under ice cooling. After stirring at room temperature for 6 hours, the reaction mixture was concentrated to give a residue. The residue was dissolved in 50 ml of ethyl acetate, and the ethyl acetate layer was successively washed with 10% hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and saturated saline solution, dried over anhydrous magnesium sulfate, and then concentrated to give a residue. The residue was subjected to silica gel chromatography, which afforded 0.35 g of 3,5-dichloro-1-(3,3-dichloro-2-propenyloxy)-4-(3-(N-methyl-4-(trifluoromethyl)benzamido)propyloxy)benzene (55% yield), nD24.5 1.5461.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([CH3:11])[CH:3]=1.[CH:12]1([NH2:15])[CH2:14][CH2:13]1.C(Cl)CCl>C(Cl)Cl>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:15][CH:12]2[CH2:14][CH2:13]2)=[O:8])=[C:4]([CH3:11])[CH:3]=1
Reactant: NC1CC1
Reactant: Cc1cc(Br)ccc1C(=O)O
Solvent: ClCCl
Solvent: ClCCCl
Product: Cc1cc(Br)ccc1C(=O)NC1CC1
Reaction time: 8 h
Yield: 73.1 %

Procedure:
To a stirred solution of 4-bromo-2-methylbenzoic acid (300 g, 1.4 mol) in DCM (8.4 L) at rt was added cyclopropanamine (79.64 g, 1.4 mol) and EDC (320.9 g, 1.67 mol) in one portion. After stirring overnight, the solution was washed with water and the aqueous phase was reextracted with DCM. The combined organic phases were dried over Na2SO4, filtered and evaporated. The remaining solid was triturated with diisopropyl ether, filtered, washed and dried in vaccuo to yield 260 g (73.4%) 4-bromo-N-cyclopropyl-2-methylbenzamide: 1H-NMR (300 MHz, CDCl3): δ=7.34 (s, 1H), 7.27 (d, 1H), 7.14 (d, 1H), 5.96 (bs, 1H), 2.85 (m, 1H), 2.38 (s, 3H), 0.85 (m, 2H), 0.59 (m, 2H) ppm.
Reaction SMILES: [C:1]1([CH3:18])[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[C:2]=1[C:9]1[C:14]([N+:15]([O-])=O)=[CH:13][CH:12]=[CH:11][N:10]=1>[H][H].[C].[Pd]>[C:1]1([CH3:18])[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[C:2]=1[C:9]1[C:14]([NH2:15])=[CH:13][CH:12]=[CH:11][N:10]=1
Reactant: Cc1cc(C)c(-c2ncccc2[N+](=O)[O-])c(C)c1
Reactant: [H][H]
Agent: [Pd]
Product: Cc1cc(C)c(-c2ncccc2N)c(C)c1
Yield: 106.5 %

Procedure:
Palladium-carbon (10%, 0.6 g) was added to a solution of 2-mesityl-3-nitropyridine (5.99 g, 23 mmol) methanol (120 mL), followed by stirring for one day in hydrogen atmospher. The mixture was filtered through Celite and evaporated, to give the title compound (5.2 g) as white crystals.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[NH:8][CH:9]=[CH:10][C:3]=12.[NH2:11][C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][C:13]=1[F:19].CCN(C(C)C)C(C)C.[H-].[Na+]>CN1C(=O)CCC1.O>[NH:8]1[C:4]2=[N:5][CH:6]=[CH:7][C:2]([O:18][C:15]3[CH:16]=[CH:17][C:12]([NH2:11])=[C:13]([F:19])[CH:14]=3)=[C:3]2[CH:10]=[CH:9]1
Reactant: Clc1ccnc2[nH]ccc12
Reactant: Nc1ccc(O)cc1F
Agent: [H-]
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN1CCCC1=O
Product: Nc1ccc(Oc2ccnc3[nH]ccc23)cc1F
Temperature: 250 °C
Yield: 18.7 %

Procedure:
To a solution of 4-chloro-1H-pyrrolo[2,3-b]pyridine (50 mg, 0.33 mmol, prepared according to Thibault, C. et al. Org. Lett. 2003, 5, 5023) in NMP (0.5 mL) were added 4-amino-3-fluorophenol (51 mg, 0.40 mmol) and DIEA (0.1 mL, 0.57 mmol). The mixture was heated at 250° C. in a microwave oven for 1 h and then cooled to room temperature. To the mixture was added NaH (10 mg, 0.4 mmol) and the mixture was again heated at 250° C. for 3 h. After cooling, the mixture was diluted with H2O and extracted with EtOAc. The organic layer was washed with H2O, brine, and dried over MgSO4. After filtration and concentration in vacuo, the residue was purified by flash column chromatography (ISCO RediSep® silica gel cartridge) to give the title compound (15 mg, 19%). MS (ESI) m/z 244.1 (M+H)+.
Reaction SMILES: [N+](C1C=CC(OC2C=CC([N+]([O-])=O)=CC=2)=CC=1)([O-])=O.[CH2:20]([O:27][C:28]([N:30]1[CH2:37][CH2:36][CH2:35][C@H:31]1[C:32]([OH:34])=O)=[O:29])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[NH2:38][C@H:39]([C:47]([OH:49])=[O:48])[CH2:40][CH2:41][CH2:42][NH:43][C:44](=[NH:46])[NH2:45]>O1CCOCC1.O>[CH2:20]([O:27][C:28]([N:30]1[CH2:37][CH2:36][CH2:35][C@H:31]1[C:32]([NH:38][C@H:39]([C:47]([OH:49])=[O:48])[CH2:40][CH2:41][CH2:42][NH:43][C:44](=[NH:45])[NH2:46])=[O:34])=[O:29])[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: O=C(O)[C@@H]1CCCN1C(=O)OCc1ccccc1
Reactant: N=C(N)NCCC[C@H](N)C(=O)O
Agent: O=[N+]([O-])c1ccc(Oc2ccc([N+](=O)[O-])cc2)cc1
Solvent: C1COCCO1
Solvent: O
Product: N=C(N)NCCC[C@H](NC(=O)[C@@H]1CCCN1C(=O)OCc1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 72 h
Yield: 96 %

Procedure:
To a solution of 37 g (0.1 mol) of p-nitrophenyl ether of benzyloxycarbonylproline in 360 ml of dioxane there is added a solution of 16 g (0.09 mole) of arginine in 160 ml of water under vigorous stirring. After two hours the solvent is evaporated and the residue is dissolved in 100 ml of dimethylformamide. The solution is stirred at room temperature (25° C.) for 72 hours and then poured into 1 liter of ethylacetate. After residence of the reaction mixture for 12 hours in a cooler the resulting precipitate is filtered-off, washed on the filter with ethylacetate and diethyl ether. After recrystallization of the product from a mixture of ethanol-diethyl ether (1:5) there are obtained 35 g (96%) of benzyloxycarbonyl-prolyl-arginine having the following properties: melting point 137°-140° C., [L]D20 -46.6° (c 1.0; H2O); Rf 0.53 (A, "Eastman"); 0.66 (B, "Eastman"), Ehis 0.56 (pH 2.4).