Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([C:15]2[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:16]=2[O:22][CH3:23])(O)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(S(F)(F)[F:30])CC.C([O-])(O)=O.[Na+]>ClCCl>[CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([C:15]2[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:16]=2[O:22][CH3:23])([F:30])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(Cl)cc1C1(O)CCN(Cc2ccccc2)CC1
Reactant: CCN(CC)S(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COc1ccc(Cl)cc1C1(F)CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 1-benzyl-4-(5-chloro-2-methoxy-phenyl)-piperidin-4-ol (4b, 17 g, 0.05 mol) in dry dichloromethane (70 mL) was added dropwise DAST (10 g, 0.061 mol) at −78° C. under N2 atmosphere. The mixture was stirred at this temperature for 1 h and then warmed to room temperature slowly. NaHCO3 (sat., aq., 200 mL) was carefully added dropwise to quench the reaction. The separated aqueous was extracted with dichloromethane (150 mL×3), the combined extracts was washed with water and brine, dried over Na2SO4, concentrated to dryness. The residue was titrated with petroleum ether and the precipitated solid was filtered and washed with petroleum ether to afford 1-benzyl-4-(5-chloro-2-methoxy-phenyl)-4-fluoro-piperidine 4c as white powder.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:13][C:12]([C:14]3[S:15][CH:16]=[CH:17][CH:18]=3)=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.O1CCC[CH2:20]1.C([Li])CCC.COS(OC)(=O)=O>C([Li])CCC.O>[CH3:20][C:16]1[S:15][C:14]([C:12]2[S:13][C:9]([C:6]3[CH:5]=[CH:4][C:3]([S:2][CH3:1])=[CH:8][CH:7]=3)=[CH:10][CH:11]=2)=[CH:18][CH:17]=1
Reactant: C1CCOC1
Reactant: CSc1ccc(-c2ccc(-c3cccs3)s2)cc1
Agent: [Li]CCCC
Solvent: COS(=O)(=O)OC
Solvent: O
Product: CSc1ccc(-c2ccc(-c3ccc(C)s3)s2)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Under a nitrogen atmosphere, a stirred solution of 0.82 gram (0.003 mole) of 5-(4-methylthiophenyl)[2,2'-bithienyl] in 100 ml of freshly distilled tetrahydrofuran was cooled to 0° C. and 1.4 ml of n-butyllithium (2.6M in hexanes) was added dropwise via syringe during a ten minute period. Upon completion of addition the reaction mixture stirred at 0° C. for 30 minutes, then at ambient temperature for three hours. The reaction mixture was recooled to 0° C. and an additional five drops of n-butyllithium was added. The reaction mixture stirred at 0° C. for one hour then 0.32 ml (0.0034 mole) of dimethylsulfate was added. Upon completion of addition the reaction mixture was stirred at ambient temperature for 16 hours. The reaction mixture was taken up in 70 ml of water and the organic layer was separated. The aqueous layer was washed with three 25 ml portions of chloroform. The organic layers were combined and washed, first with water, then with an aqueous solution saturated with sodium chloride. The organic layer was dried with sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to yield 0.78 gram of 5'-methyl-5-(4-methylthiophenyl)[2,2'-bithienyl]; m.p. 145°-147° C.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([N:7]([C:17]([O:19][CH2:20][C:21]([Cl:24])([Cl:23])[Cl:22])=[O:18])[C@H:8]([C:13]([O:15][CH3:16])=[O:14])[CH2:9][CH:10]([CH3:12])[CH3:11])[S:4][N:3]=1.[Br:25]Br>C(Cl)Cl.CC(O)=O>[Br:25][C:6]1[C:2]([CH3:1])=[N:3][S:4][C:5]=1[N:7]([C:17]([O:19][CH2:20][C:21]([Cl:23])([Cl:24])[Cl:22])=[O:18])[C@H:8]([C:13]([O:15][CH3:16])=[O:14])[CH2:9][CH:10]([CH3:12])[CH3:11]
Reactant: BrBr
Reactant: COC(=O)[C@H](CC(C)C)N(C(=O)OCC(Cl)(Cl)Cl)c1cc(C)ns1
Solvent: CC(=O)O
Solvent: ClCCl
Product: COC(=O)[C@H](CC(C)C)N(C(=O)OCC(Cl)(Cl)Cl)c1snc(C)c1Br
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of methyl N-(3-methylisothiazol-5-yl)-N-[(2,2,2-trichloroethoxy)carbonyl]-L-leucinate (28.5 g, 68 mmol) in CH2Cl2 (250 mL) and AcOH (125 mL) was added bromine (8.5 mL, 165 mmol). The resulting red solution was stirred at room temperature for 4 h. A further aliquot of bromine (8.5 mL, 165 mmol) was added and the resulting solution was stirred at room temperature for 18 h. The reaction mixture was partitioned between EtOAc and water+aqueous NaHSO3 until the decolorization was complete. The organic layer was dried over Na2SO4 and concentrated in vacuo. The crude product was purified by flash chromatography using EtOAc in hexane to afford methyl N-(4-bromo-3-methylisothiazol-5-yl)-N-[(2,2,2-trichloroethoxy)carbonyl]-L-leucinate as a yellow syrup.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:12]2[CH:17]([CH2:18][CH3:19])[S:16][C:15](=[O:20])[NH:14][N:13]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH2:10]C.Cl[CH2:22][CH2:23][N:24]1[CH2:29][CH2:28]O[CH2:26][CH2:25]1>>[N:24]1([CH2:29][CH2:28][N:14]2[N:13]=[C:12]([C:5]3[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=3)[CH:17]([CH2:18][CH3:19])[S:16][C:15]2=[O:20])[CH2:25][CH2:26][CH2:22][CH2:23]1
Reactant: ClCCN1CCOCC1
Reactant: CCOc1ccc(C2=NNC(=O)SC2CC)cc1OC
Product: CCC1SC(=O)N(CCN2CCCC2)N=C1c1ccc(OC)c(OC)c1

Procedure:
of 5-(3-methoxy-4-ethoxyphenyl)-6-ethyl-3,6-dihydro-1,3,4-thiadiazin-2-one with 1-chloro-2-morpholinoethane:
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([OH:14])[CH2:13][CH2:12][NH:11][CH2:10]2)=[CH:5][C:4]=1[CH3:15].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)C(C)C)C.[CH3:47][C:48]1[CH:53]=[CH:52][C:51]([C:54]2[C:58]([C:59](O)=[O:60])=[CH:57][O:56][N:55]=2)=[CH:50][CH:49]=1>CN(C=O)C>[F:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([OH:14])[CH2:13][CH2:12][N:11]([C:59]([C:58]3[C:54]([C:51]4[CH:52]=[CH:53][C:48]([CH3:47])=[CH:49][CH:50]=4)=[N:55][O:56][CH:57]=3)=[O:60])[CH2:10]2)=[CH:5][C:4]=1[CH3:15]
Reactant: Cc1ccc(-c2nocc2C(=O)O)cc1
Reactant: Cc1cc(C2(O)CCNC2)ccc1F
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(-c2nocc2C(=O)N2CCC(O)(c3ccc(F)c(C)c3)C2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 80.9 %

Procedure:
A solution of 3-(4-fluoro-3-methylphenyl)pyrrolidin-3-ol hydrochloride (9 mg, 0.039 mmol), TBTU (15 mg, 0.047 mmol, 1.2 equ.) and N-ethyl-N-isopropylpropan-2-amine (14 μL, 0.079 mmol, 2 equ.) in DMF (0.3 mL) was added to 3-(4-methylphenyl)isoxazole-4-carboxylic acid (8 mg, 0.039 mmol) and the reaction mixture was stirred at rt for 2 h. The solvent was evaporated and the crude product was purified by RP-HPLC. After evaporation of the solvents the product was dried in vacuum to yield the title compound (12 mg). MS (ESI, pos. ion) m/z calcd for C22H21FN2O3: 380.1536, found 380.1532.
Reaction SMILES: [I-].C(N1C=C[N+:11]([C:14]2[N:22]=[C:21]([Cl:23])[N:20]=[C:19]3[C:15]=2[N:16]=[CH:17][N:18]3[C@@H:24]2[O:38][C@H:37]([CH2:39][O:40]C(C3C=CC(C)=CC=3)=O)[C@@H:26]([O:27]C(C3C=CC(C)=CC=3)=O)[CH2:25]2)=C1CCC)C1C=CC=CC=1.N.CO>O.CO>[NH2:11][C:14]1[N:22]=[C:21]([Cl:23])[N:20]=[C:19]2[C:15]=1[N:16]=[CH:17][N:18]2[C@@H:24]1[O:38][C@H:37]([CH2:39][OH:40])[C@@H:26]([OH:27])[CH2:25]1
Reactant: CCCc1n(Cc2ccccc2)cc[n+]1-c1nc(Cl)nc2c1ncn2[C@H]1C[C@H](OC(=O)c2ccc(C)cc2)[C@@H](COC(=O)c2ccc(C)cc2)O1
Agent: N
Agent: [I-]
Solvent: CO
Solvent: O
Product: Nc1nc(Cl)nc2c1ncn2[C@H]1C[C@H](O)[C@@H](CO)O1
Yield: 108.9 %

Procedure:
Treatment of 3-benzyl-1-{2-chloro-9-[2-deoxy-3,5-di-O-(p-toluoyl)-β-D-erythro-pentofuranosyl]purin-6-yl}-2-propylimidazolium iodide (0.83 g, crude) with NH3/MeOH (26%, 50 mL) at 60° C. followed by ion exchange chromatography (Dowex 1×2 [OH−], H2O/MeOH) by method 3 gave cladribine (0.31 g, quantitative). Recrystallization from EtOH gave a white solid (0.153 g, 54%), and the residue from the mother liquor was recrystallized from H2O to give a second crop (0.015 g, 59% total): mp>300° C.; UV (MeOH) max 212, 265 nm (∈ 24 000, 14 600), min 229 nm (∈ 2000); 1H NMR (500 MHz, DMSO-d6) δ 8.36 (s, 1H), 7.83 (br, 2H), 6.26 (t, J=6.7 Hz, 1H), 5.32 (d, J=4.3 Hz, 1H), 4.97 (t, J=5.5 Hz, 1H), 4.38 (s, 1H), 3.85 (s, 1H), 3.57-3.61 (m, 1H), 3.48-3.53 (m, 1H), 2.62-2.67 (m, 1H), 2.25-2.29 (m, 1H); 13C NMR (125 MHz, DMSO-d6) δ 157.5, 153.6, 150.8, 140.5, 118.8, 88.6, 84.2, 71.4, 62.3, 38.0; HRMS m/z 285.0615 (M+ [C10H12ClN5O3]=285.0629). Anal. Calcd for C10H12ClN5O3: C, 42.04; H, 4.23; N, 24.51. Found: C, 41.87; H, 4.50; N, 24.39.
Reaction SMILES: O.Cl.[N+:3]([C:6]1[CH:7]=[C:8]([CH:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)[OH:14])[CH:9]=[CH:10][C:11]=1[Cl:12])([O-:5])=[O:4]>[O-2].[O-2].[O-2].[Cr+6].C(O)(=O)C>[N+:3]([C:6]1[CH:7]=[C:8]([CH:9]=[CH:10][C:11]=1[Cl:12])[C:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=1)=[O:14])([O-:5])=[O:4]
Reactant: O=[N+]([O-])c1cc(C(O)c2ccccn2)ccc1Cl
Agent: [Cr+6]
Agent: Cl
Agent: [O-2]
Solvent: CC(=O)O
Solvent: O
Product: O=C(c1ccc(Cl)c([N+](=O)[O-])c1)c1ccccn1
Temperature: 0 °C

Procedure:
A solution of 27 g. (0.27 mol) of chromium trioxide in 250 ml. of water was added to a solution of 80 g. (0.266 mol) of 3-nitro-4-chlorophenyl-2-pyridyl methanol hydrochloride in 800 ml. of 75% acetic acid at 45° C. and the mixture was heated to 75° C. for 1 hr. The resulting dark green solution was poured into 3 liters of ice-water. The resulting product was filtered off, washed with water, dissolved in methylene chloride, dried with sodium sulfate and concentrated in vacuo to yield 2-(3-nitro-4-chlorobenzoyl)pyridine as white microneedles, mp. 98° -99° C. (cyclohexane).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:14]([OH:16])=O)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[NH2:17][CH2:18][CH2:19][CH2:20][N:21]1[CH2:26][CH2:25][CH:24]([C:27]2[CH:28]=[C:29]([NH:34][C:35](=[O:39])[CH:36]([CH3:38])[CH3:37])[CH:30]=[CH:31][C:32]=2[F:33])[CH2:23][CH2:22]1>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([C:14]([NH:17][CH2:18][CH2:19][CH2:20][N:21]3[CH2:22][CH2:23][CH:24]([C:27]4[CH:28]=[C:29]([NH:34][C:35](=[O:39])[CH:36]([CH3:38])[CH3:37])[CH:30]=[CH:31][C:32]=4[F:33])[CH2:25][CH2:26]3)=[O:16])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]2)=[CH:6][CH:7]=1
Reactant: O=C(O)C1(c2ccc(Cl)cc2)CCCCC1
Reactant: CC(C)C(=O)Nc1ccc(F)c(C2CCN(CCCN)CC2)c1
Solvent: ClC(Cl)Cl
Product: CC(C)C(=O)Nc1ccc(F)c(C2CCN(CCCNC(=O)C3(c4ccc(Cl)cc4)CCCCC3)CC2)c1

Procedure:
Example 130 was prepared from 1-(4-chlorophenyl)cyclohexanecarboxylic acid and N-{3-[1-(3-aminopropyl)-4-piperidinyl]-4-fluorophenyl}-2-methylpropanamide according to the procedures described in Scheme 9: 1H NMR (400 MHz, CDCl3) δ 7.45–7.40 (m, 1H), 7.34–7.29 (m, 3H), 7.24–7.16 (m, 3H), 6.88 (t, 1H, J=8.7 Hz), 6.77–6.72 (m, 1H), 3.21 (q, 2H, J=5.6 Hz), 2.87–2.81 (m, 2H), 2.74–2.65 (m, 1H), 2.44 (septet, 1H, J=6.7 Hz), 2.28–2.21 (m, 4H), 1.92–1.76 (m, 4H), 1.69–1.69 (m, 4H), 1.56–1.47 (m, 8H), 1.18 (d, 6H, J=6.7 Hz); ESMS m/e: 542.2 (M+H)+; Anal. Calc. for C31H41ClFN3O2.HCl.0.20 CHCl3: C, 62.20; H, 7.06; N, 6.97. Found: C, 62.24; H, 7.03; N, 6.79.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[CH:5]([N:11]1[CH:15]=[CH:14][CH:13]=[CH:12]1)[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2].[Cl:17][C:18]([Cl:23])([Cl:22])[C:19](Cl)=[O:20]>C(Cl)(Cl)Cl>[CH2:9]([O:8][C:6](=[O:7])[CH:5]([N:11]1[CH:12]=[CH:13][CH:14]=[C:15]1[C:19](=[O:20])[C:18]([Cl:23])([Cl:22])[Cl:17])[C:4]([O:3][CH2:1][CH3:2])=[O:16])[CH3:10]
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Reactant: CCOC(=O)C(C(=O)OCC)n1cccc1
Solvent: ClC(Cl)Cl
Product: CCOC(=O)C(C(=O)OCC)n1cccc1C(=O)C(Cl)(Cl)Cl
Yield: 89 %

Procedure:
To a solution of 2-(pyrrol-1-yl)malonic acid diethyl ester (100.0 g) in chloroform (100 ml) was added trichloroacetyl chloride (161.4 g), and the resulting mixture was refluxed for 15 hours. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in ethyl acetate. The solution was washed with 10% aqueous sodium carbonate solution and then with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and evaporated under reduced pressure. The residue was recrystallized from isopropyl ether to give the title compound (146.4 g, 89.0%) as colorless crystals, mp 67°-69° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[NH:6][N:7]=[C:8]([N+:10]([O-:12])=[O:11])[CH:9]=1)=[O:4].I[CH2:14][CH3:15].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH3:1][O:2][C:3]([C:5]1[N:6]([CH2:14][CH3:15])[N:7]=[C:8]([N+:10]([O-:12])=[O:11])[CH:9]=1)=[O:4]
Reactant: COC(=O)c1cc([N+](=O)[O-])n[nH]1
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCn1nc([N+](=O)[O-])cc1C(=O)OC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 5-nitro-2H-pyrazole-3-carboxylic acid methyl ester (525, 2.50 g, 0.0146 mol) in N,N-dimethylformamide (62.5 mL) were added iodoethane (1.2 mL, 0.016 mol) and potassium carbonate (4.17 g, 0.0301 mol) under an atmosphere of nitrogen. The reaction was stirred at room temperature overnight. The reaction was poured into water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 20% to 100% ethyl acetate in hexane to give a white solid (526, 1.3 g, 44.7%).
Reaction SMILES: C(O)C.[OH-].[K+].[C:6]1([CH2:12][CH2:13][N:14]2[C:18]([Br:19])=[C:17]([C:20]([O:22]CC)=[O:21])[C:16]([N:25]([CH2:44][CH2:45][CH3:46])[CH2:26][C:27]3[CH:32]=[CH:31][C:30]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=4[C:39]4[NH:43][N:42]=[N:41][N:40]=4)=[CH:29][CH:28]=3)=[N:15]2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>O>[C:6]1([CH2:12][CH2:13][N:14]2[C:18]([Br:19])=[C:17]([C:20]([OH:22])=[O:21])[C:16]([N:25]([CH2:44][CH2:45][CH3:46])[CH2:26][C:27]3[CH:32]=[CH:31][C:30]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=4[C:39]4[NH:43][N:42]=[N:41][N:40]=4)=[CH:29][CH:28]=3)=[N:15]2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: CCCN(Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1)c1nn(CCc2ccccc2)c(Br)c1C(=O)OCC
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCCN(Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1)c1nn(CCc2ccccc2)c(Br)c1C(=O)O
Yield: 94.1 %

Procedure:
5 ml of ethanol, 5 ml of water and 226 mg of potassium hydroxide were added to 206 mg of N-[1-(2-phenylethyl)-4-ethoxycarbonyl-5-bromopyrazol-3-yl]-N-[(2'-(1H-tetrazol-5-yl)-biphenyl-4-yl)methyl]-n-propylamine, and heated under reflux for 5 hours. Ethanol was distilled off under reduced pressure, and 10 ml of water were added to the reaction mixture, which was then made acidic with concentrated hydrochloric acid. The resultant was extracted with 50 ml of dichloromethane. After dried over magnesium sulfate, the extract was concentrated under reduced pressure and dried to obtain 185 mg of the intended compound as a pale yellow, amorphous solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:5]=[CH:6][CH:7]=1.[Br:14]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:14][CH:8]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=1)[C:9]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)Cc1cccc(Cl)c1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)C(Br)c1cccc(Cl)c1

Procedure:
A 53.6 g. portion of ethyl m-chlorophenylacetate (prepared by esterification of the corresponding acid), 51.5 g. of N-bromosuccinimide and one gram of benzoyl peroxide in 1.25 liters of carbon tetrachloride is stirred with a Nichrome metal stirrer and refluxed for 20 hours. The mixture is cooled, filtered and concentrated to an orange oil. Vacuum distillation yields the product ethyl α-bromo-m-chlorophenylacetate.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[CH:9]1([CH2:15]C2C=CC=CC=2O)[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.C1(C)C=CC=CC=1>O1CCCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:15][CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)=[CH:4][CH:3]=1
Reactant: Oc1ccc(Br)cc1
Reactant: Oc1ccccc1CC1CCCCC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: Brc1ccc(OCC2CCCCC2)cc1
Yield: 54.6 %

Procedure:
To a solution of 4-bromophenol (6.0 g, 34.7 mmol), cyclohexylmethylphenol (4.3 ml, 34.7 mmol) and triphenylphosphine (9.1 g, 34.7 mmol) in tetrahydrofuran (100 ml) was added slowly a 40% solution of diethyl azodicarboxylate in toluene (15.1 ml, 34.7 mmol) in portions at 0° C. with stirring, and then the resulting mixture was stirred at room temperature for 3 hours. After stirring, the reaction mixture was evaporated in vacuo, and hexane was added to the residue. After filtration, the filtrate was evaporated in vacuo once again, and the residue was purified by chromatography on a silica gel column using a mixed solvent of ethyl acetate and hexane (1:20) as the eluent to afford 1-bromo-4-(cyclohexylmethoxy)benzene (5.1 g, yield: 54%).
Reaction SMILES: [CH2:1]([N:3]1[C:7]([NH:8][C:9]2[C:10](=[CH:14][C:15]([S:18]([C:21]([F:24])([F:23])[F:22])(=[O:20])=[O:19])=[CH:16][CH:17]=2)[C:11](O)=O)=[CH:6][CH:5]=[N:4]1)[CH3:2].[NH4+].[OH-].O=P(Cl)(Cl)[Cl:29]>>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]3[C:10]([C:11]([Cl:29])=[C:6]2[CH:5]=[N:4]1)=[CH:14][C:15]([S:18]([C:21]([F:24])([F:23])[F:22])(=[O:20])=[O:19])=[CH:16][CH:17]=3)[CH3:2]
Reactant: CCn1nccc1Nc1ccc(S(=O)(=O)C(F)(F)F)cc1C(=O)O
Reactant: O=P(Cl)(Cl)Cl
Agent: [NH4+]
Agent: [OH-]
Product: CCn1ncc2c(Cl)c3cc(S(=O)(=O)C(F)(F)F)ccc3nc21

Procedure:
A mixture of N-(1-ethylpyrazol-5-yl) -5-(trifluoromethylsulfonyl)anthranilic acid and POCl3 (30 mL) was heated on a steam bath overnight. The reaction mixture was poured onto ice-water and then was neutralized with NH4OH. The resulting solid was collected by filtration, washed with water, dissolved in CH2Cl2, dried over MgSO4, filtered and stripped. The residue was purified by column chromatography on silica gel eluting with 10% ethyl acetate/hexane to afford 1.0 g of 1-ethyl-4-chloro-6-(trifluoromethylsulfonyl)-1H-pyrazolo[3,4-b]quinoline.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH:25]=O)=[C:5]([C:21]([O:23][CH3:24])=[O:22])[CH:6]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N+:18]([O-:20])=[O:19])[C:7]=1[C:8]([O:10][CH3:11])=[O:9].Cl.[NH2:28][OH:29].C([O-])(=O)C.[Na+]>C(O)(=O)C>[CH3:1][C:2]1[NH:3][C:4]([CH:25]=[N:28][OH:29])=[C:5]([C:21]([O:23][CH3:24])=[O:22])[CH:6]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N+:18]([O-:20])=[O:19])[C:7]=1[C:8]([O:10][CH3:11])=[O:9]
Reactant: NO
Reactant: COC(=O)C1=C(C)NC(C=O)=C(C(=O)OC)C1c1ccccc1[N+](=O)[O-]
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Product: COC(=O)C1=C(C)NC(C=NO)=C(C(=O)OC)C1c1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
A mixture of dimethyl 2-methyl-4-(2-nitrophenyl)-6-formyl-1,4-dihydropyridine-3,5-dicarboxylate (3.6 g), hydroxylamine hydrochloride (764 mg) and sodium acetate (1.06 g) in acetic acid (20 ml) was stirred at room temperature for 45 minutes to form dimethyl 2-methyl-4-(2-nitrophenyl)-6-hydroxyiminomethyl-1,4-dihydropyridine-3,5-dicarboxylate. To the reaction mixture was added acetic anhydride (3.37 g) and the mixture was stirred at room temperature for 15 minutes and then heated at 100° C. for 3 hours with stirring. After removal of the acetic acid, the residue was adjusted to pH 7.5 with an aqueous sodium bicarbonate solution and extracted with ethyl acetate. The extract was washed twice with water and saturated aqueous sodium chloride solution, dried over magnesium sulfate and evaporated to dryness under reduced pressure. The resultant oil (3.80 g) was chromatographed on a column of silica-gel (110 g) and eluted with a mixture of benzene and ethyl acetate (9:1, v/v) to give crystals (2.05 g), which were recrystallized from a mixture of ethyl acetate (12 ml) and n-hexane (6 ml) to give yellow granules of dimethyl 2-methyl-4-(2-nitrophenyl)-6-cyano-1,4-dihydropyridine-3,5-dicarboxylate (1.19 g), mp 170.5° to 171.5° C.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[C:17]([O:19][CH3:20])=[O:18])[CH2:7][CH2:6]1.[N+](C1C=CC([O:30][C:31]([N:33]2[CH:37]([C:38]3[CH:43]=[C:42]([F:44])[CH:41]=[C:40]([F:45])[CH:39]=3)[CH2:36][O:35][C:34]2=[O:46])=O)=CC=1)([O-])=O>C1COCC1>[CH3:20][O:19][C:17](=[O:18])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[N:8]1[CH2:9][CH2:10][N:5]([CH2:4][CH2:3][CH2:2][NH:1][C:31]([N:33]2[CH:37]([C:38]3[CH:39]=[C:40]([F:45])[CH:41]=[C:42]([F:44])[CH:43]=3)[CH2:36][O:35][C:34]2=[O:46])=[O:30])[CH2:6][CH2:7]1
Reactant: COC(=O)c1ccccc1N1CCN(CCCN)CC1
Reactant: O=C1OCC(c2cc(F)cc(F)c2)N1C(=O)Oc1ccc([N+](=O)[O-])cc1
Solvent: C1CCOC1
Product: COC(=O)c1ccccc1N1CCN(CCCNC(=O)N2C(=O)OCC2c2cc(F)cc(F)c2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 75.2 %

Procedure:
To a solution of 1-(3-amino-propyl)-4-(2-carbomethoxyphenyl)-piperazine (25 mg, 0.090 mmol) in 10 mL of THF, 4-(3,5-difluorophenyl)-2-oxo-oxazolidine-3-carboxylic acid-4-nitro-phenyl ester(30 mg, 0.082 mmol) was added and the resulting yellow solution was stirred under argon atmosphere for 2 h at room temperature. The solvent was removed in vacuo and the residue was purified by column chromatography over silica gel with 1:1 hexane/EtOAc followed by 1:9 MeOH/EtOAc (Rf=0.75, MeOH/EtOAc=1:3 ) to obtain 2-[4-(3-{[4-(3,5-difluoro-phenyl)-2-oxo-oxazolidine-3-carbonyl]-amino)-propyl)-piperazin-1-yl]-benzoic acid methyl ester (31 mg, 69%). The compound was dissolved in CH2Cl2 (3 mL) and was treated with 1N HCl in ether (1 mL). The solvent was removed in vacuo to give the corresponding hydrochloride salt as a yellow solid. M.P. 93-96° C.; [α]D=+45.3, (c=0.29, MeOH); Anal. Calcd. For C25H30N4O 5F2Cl2 .0.58 CH2Cl2: C, 50.48; H, 5.16; N, 9.20. Found: C, 50.46; H, 5.56; N, 8.91.
Reaction SMILES: Cl.[N:2]1([CH2:8][CH2:9][N:10]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[N:12]([C:19]([NH:21][C@H:22]([C:27](O)=[O:28])[C@H:23]([CH2:25][CH3:26])[CH3:24])=[O:20])[C:11]2=[O:30])[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1.C1N=[CH:34][N:33](C(N2C=NC=C2)=O)[CH:32]=1.CNC.O>CN(C=O)C>[CH3:32][N:33]([CH3:34])[C:27]([C@@H:22]([NH:21][C:19]([N:12]1[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[N:10]([CH2:9][CH2:8][N:2]2[CH2:3][CH2:4][O:5][CH2:6][CH2:7]2)[C:11]1=[O:30])=[O:20])[C@@H:23]([CH3:24])[CH2:25][CH3:26])=[O:28]
Reactant: CC[C@H](C)[C@H](NC(=O)n1c(=O)n(CCN2CCOCC2)c2ccccc21)C(=O)O
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: CNC
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: CC[C@H](C)[C@H](NC(=O)n1c(=O)n(CCN2CCOCC2)c2ccccc21)C(=O)N(C)C
Reaction time: 2 h
Yield: 54.6 %

Procedure:
To a solution of N-{[3-(2-morpholin-4-ylethyl)-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl]carbonyl}-L-isoleucine hydrochloride (Step 1, 62 mg, 0.14 mmol) in DMF (1 mL) was added CDI (27 mg, 0.17 mol) at rt. After 2 h, to the mixture was added aq. dimethylamine (40%, 20 μL) and stirred for further 14 h. Then to the mixture was added water (10 mL). The mixture was extracted with ethyl acetate (20 mL×2) and the combined organic layers were washed with brine (10 mL), dried over sodium sulfate, filtered and concentrated. The residue was purified by preparative TLC eluting with dichloromethane/methanol (10/1) to afford 33 mg (54%) of the title compound.
Reaction SMILES: C(O[CH:4](OCC)[CH2:5][N:6]([C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15])[C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=1)C.Cl.[OH:28][C:29]1[CH:30]=[C:31]([CH:35]=[CH:36][C:37]=1[OH:38])[CH2:32][CH2:33][NH2:34].C(O)CCC>O>[ClH:13].[CH2:17]([O:16][C:14]([N:6]([CH2:5][CH:4]1[C:35]2[C:31](=[CH:30][C:29]([OH:28])=[C:37]([OH:38])[CH:36]=2)[CH2:32][CH2:33][NH:34]1)[C:7]1[CH:8]=[CH:9][C:10]([Cl:13])=[CH:11][CH:12]=1)=[O:15])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: CCOC(CN(C(=O)OCc1ccccc1)c1ccc(Cl)cc1)OCC
Reactant: NCCc1ccc(O)c(O)c1
Agent: Cl
Solvent: CCCCO
Solvent: O
Product: O=C(OCc1ccccc1)N(CC1NCCc2cc(O)c(O)cc21)c1ccc(Cl)cc1
Yield: 111.3 %

Procedure:
N-benzyloxycarbonyl-p-chloroanilinoacetaldehyde diethyl acetal (10 g) and 3,4-dihydoxyphenethylamine hydrochloride (4.2 g) were added to a mixture of n-butyl alcohol (100 ml) and water (14 ml) and then the mixture was refluxed for 4 hours. The above-mentioned acetal (1 g) was added to the mixture and the resultant mixture was refluxed for 4 hours. The reaction mixture was concentrated to dryness under reduced pressure and the residue was washed with ethyl acetate and collected by filtration. The crystals were recrystallized from a mixture of methanol and ether to give 1-(N-benzyloxycarbonyl-p-chloroanilinomethyl)-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline hydrochloride (7.0 g), mp 210° to 212° C. (dec).