Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([CH3:10])[C:5](Br)=[CH:4][N:3]=1.[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:20]=[C:21](B(O)O)[CH:22]=[CH:23][CH:24]=2)=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Pd]>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([CH3:10])[C:5]([C:21]2[CH:22]=[CH:23][CH:24]=[C:19]([C:16]3[CH:15]=[CH:14][C:13]([Cl:12])=[CH:18][CH:17]=3)[CH:20]=2)=[CH:4][N:3]=1
Reactant: Cc1c(Br)cnc(N)c1C#N
Reactant: OB(O)c1cccc(-c2ccc(Cl)cc2)c1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: Cc1c(-c2cccc(-c3ccc(Cl)cc3)c2)cnc(N)c1C#N

Procedure:
This compound is prepared in a manner analogous to that of Step D of 5 Example 4, using 1.7 grams (0.008 mole) of 2-amino-5-bromo-3-cyano-4-methylpyridine, 2.9 grams (0.012 mole) of 3-(4-chlorophenyl)phenylboronic acid, 4.3 grams (0.031 mole) of potassium carbonate and 0.3 gram of tetrakis(triphenylphosphine)palladium(O) in 150 mL of toluene, yielding 2-amino-3-cyano-4-methyl-5-[3-(4-chlorophenyl)phenyl]pyridine.
Reaction SMILES: CO[C:3](=[O:13])[C:4]1[C:9]([I:10])=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:11]Br.[CH3:14][O:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20][NH2:21])=[CH:18][CH:17]=1.C([O-])([O-])=O.[K+].[K+].C(OCC)(=O)C>C1(C)C=CC=CC=1.CCCCCC>[I:10][C:9]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:4]=1[C:3](=[O:13])[N:21]([CH2:20][C:19]1[CH:22]=[CH:23][C:16]([O:15][CH3:14])=[CH:17][CH:18]=1)[CH2:11]2
Reactant: COc1ccc(CN)cc1
Reactant: COC(=O)c1c(I)cccc1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: COc1ccc(CN2Cc3cccc(I)c3C2=O)cc1
Temperature: 100 °C
Reaction time: 2 h
Yield: 31.6 %

Procedure:
A mixture of 2-bromomethyl-6-iodo-benzoic acid methyl ester (0.245 g, 0.7 mmol), 4-methoxy-benzylamine (0.104 mL, 0.8 mmol), and K2CO3 (0.207 g, 1.5 mmol) in toluene (5 mL) was heated with stirring at 100° C. for 2 h. Workup and silica gel column chromatography using 30% ethyl acetate in hexane afforded 7-iodo-2-(4-methoxy-benzyl)-2,3-dihydro-isoindol-1-one (0.084 g, 31%). 1H NMR (300 MHz, CDCl3): δ (ppm) 3.78 (s, 3H), 4.14 (s, 2H), 4.74 (s, 2H), 6.84 (d, 2H), 7.14-7.40 (m, 4H), 7.91 (d, 1H). GC-MS: m/z 379 (M)+.
Reaction SMILES: CCCC[N+](CCCC)(CCCC)CCCC.[F-].C([Si]([C:26]#[C:27][C:28]1[C:33]([CH2:34][C:35]([O:37][CH3:38])=[O:36])=[CH:32][CH:31]=[CH:30][N:29]=1)(CC)CC)C.CCOC(C)=O>C1COCC1.C([O-])(O)=O.[Na+]>[C:27]([C:28]1[C:33]([CH2:34][C:35]([O:37][CH3:38])=[O:36])=[CH:32][CH:31]=[CH:30][N:29]=1)#[CH:26]
Reactant: CC[Si](C#Cc1ncccc1CC(=O)OC)(CC)CC
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])O
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C#Cc1ncccc1CC(=O)OC
Temperature: 0 °C
Reaction time: 0.03 h

Procedure:
A solution of TBAF (1 M solution in THF; 0.207 mL, 0.207 mmol) was added to a solution of methyl 2-(2-((triethylsilyl)ethynyl)pyridin-3-yl)acetate (I119) (50.0 mg, 0.173 mmol) in THF (2 mL) at 0° C. The reaction was stirred for 2 minutes at 0° C. then diluted with saturated NaHCO3 (20 mL). EtOAc (20 mL) was then added and the layers separated. The aqueous layer was extracted with EtOAc (2×20 mL) then the combined organic layers were washed with water 20 mL), brine (20 mL) and dried over Na2SO4. The solvent was removed in vacuo to yield a brown oily residue. The oil was purified using column chromatography on silica gel (0-55% EtOAc in cyclohexane) to afford the title compound (I120) (25.9 mg, 86%) as an orange oil; 1H NMR (400 MHz, CDCl3) δ 8.52 (dd, J=4.8, 1.6 Hz, 1H), 7.65 (dd, J=7.9, 1.6 Hz, 1H), 7.29-7.24 (m, peak obscured by solvent), 3.87 (s, 2H), 3.72 (s, 3H), 3.35 (s, 1H). LCMS Method C: rt 4.74 min; m/z 176 [M+H]+.
Reaction SMILES: Br[Si](C)(C)C.[CH:6]1(/[CH:12]=[C:13](\[CH2:27][P:28]([O:34]CC)([CH2:30][CH:31]([CH3:33])[CH3:32])=[O:29])/[C:14]([O:16][CH:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:19](=[O:20])[O:18]2)=[O:15])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.C(OCC)(=O)C.[Cl-].[NH4+]>ClCCl.ClCCl.CO.C(O)(=O)C>[CH:6]1(/[CH:12]=[C:13](\[CH2:27][P:28]([OH:34])([CH2:30][CH:31]([CH3:32])[CH3:33])=[O:29])/[C:14]([O:16][CH:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:19](=[O:20])[O:18]2)=[O:15])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: CCOP(=O)(C/C(=C\C1CCCCC1)C(=O)OC1OC(=O)c2ccccc21)CC(C)C
Agent: C[Si](C)(C)Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: ClCCl
Product: CC(C)CP(=O)(O)C/C(=C\C1CCCCC1)C(=O)OC1OC(=O)c2ccccc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 34.6 %

Procedure:
Under an atmosphere of argon, 29 μl (0.22 millimole) of bromotrimethylsilane was added to a solution of 48 mg (0.11 millimole) of phthalidyl (Z)-3-cyclohexyl-2-(ethoxyisobutylphosphinoyl)methylpropenoate in 0.50 ml of dry dichloromethane, and the mixture was stirred at room temperature for 18 hours. To the reaction mixture were added 2.0 ml of ethyl acetate and 3.0 ml of a saturated aqueous solution of ammonium chloride, and the mixture was stirred at room temperature for 30 minutes. A saturated aqueous solution of ammonium chloride (3 ml) was added to the reaction mixture, and the mixture was extracted three times with 8 ml of ethyl acetate each time. The combined organic layers were dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by preparative thin-layer chromatography [silica gel 60 F254 made by E. Merck & Co.; dichloromethane/methanol/acetic acid (30:1:1)]to give 16 mg (yield 35%) of the captioned compound as a colorless oil. On standing, this compound solidified.
Reaction SMILES: [CH3:1][C:2]1[C:3]2[CH:12]=[CH:11][CH:10]=[CH:9][C:4]=2[S:5][C:6]=1[CH:7]=O.[N:13]1([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[CH3:1][C:2]1[C:3]2[CH:12]=[CH:11][CH:10]=[CH:9][C:4]=2[S:5][C:6]=1[CH2:7][N:16]1[CH2:15][CH2:14][N:13]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:18][CH2:17]1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Cc1c(C=O)sc2ccccc12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1c(CN2CCN(C(=O)OC(C)(C)C)CC2)sc2ccccc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 3-methylbenzo[b]thiophene-2-carbaldehyde (0.029 mol) in dry DCM (100 mL) is added t-butyl piperazine-1-carboxylate (0.0319 mol), and the mixture is stirred at RT for 1 h. 0.042 Mol of NaBH(OAc)3 is added in portions, and the reaction mixture is stirred overnight at RT. The resulting solution is concentrated under vacuum, and the residue is partitioned between DCM and aqueous sodium bicarbonate solution. The organic phase is separated, washed with water, dried (MgSO4) and evaporated in vacuo. The residue is purified by column chromatography on silica gel by eluting with DCM/MeOH (9/1) to afford t-butyl 4-((3-methylbenzo[b]thiophen-2-yl)methyl)piperazine-1-carboxylate.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[NH2:11][C:12]1[C:17]([C:18]([F:21])([F:20])[F:19])=[CH:16][C:15]([CH2:22][CH2:23][C:24]([N:26]2[C@H:30]([CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH2:29][O:28][C:27]2=[O:38])=[O:25])=[CH:14][C:13]=1[Cl:39].Br[CH2:41][C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43].[NH4+].[Cl-]>C1COCC1>[NH2:11][C:12]1[C:17]([C:18]([F:19])([F:20])[F:21])=[CH:16][C:15]([CH2:22][C@H:23]([C:24]([N:26]2[C@H:30]([CH2:31][C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)[CH2:29][O:28][C:27]2=[O:38])=[O:25])[CH2:41][C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])=[CH:14][C:13]=1[Cl:39]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: Nc1c(Cl)cc(CCC(=O)N2C(=O)OC[C@H]2Cc2ccccc2)cc1C(F)(F)F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)C[C@H](Cc1cc(Cl)c(N)c(C(F)(F)F)c1)C(=O)N1C(=O)OC[C@H]1Cc1ccccc1
Temperature: -78 °C
Reaction time: 2 h

Procedure:
Under an argon atmosphere 63.24 mL (63.24 mmol) of a sodium-bis(trimethylsilyl)-amide solution (1 M in THF) was added dropwise to a solution of 22.5 g (52.71 mmol) of (R)-3-[3-(4-amino-3-chloro-5-trifluoromethyl-phenyl)-propionyl]-4-benzyl-oxazolidin-2-one in 105 mL THF which had been cooled to −78° C. and the mixture was stirred for 2 h at −78° C. 38.9 mL (263.5 mmol) of tert.butyl bromoacetate were added dropwise to the reaction mixture at −78° C., this was stirred for a further 24 h at −78° C. and then heated to RT. After the addition of 200 mL of a saturated NH4Cl solution the mixture was extracted twice with 300 mL of EtOAc, the combined org. phases were dried over Na2SO4 and evaporated down i. vac. The residue remaining was purified by chromatography on silica gel. The desired product was obtained in the form of a yellow oil.
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1Br)([CH3:4])([CH3:3])[CH3:2].[F:15][C:16]1[CH:17]=[C:18](B(O)O)[CH:19]=[CH:20][C:21]=1[CH3:22].C(O)(C)C.C(=O)([O-])[O-].[Na+].[Na+].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>[C:1]([O:5][C:6]([C:7]1[C:8]([C:18]2[CH:19]=[CH:20][C:21]([CH3:22])=[C:16]([F:15])[CH:17]=2)=[CH:9][CH:10]=[CH:11][CH:12]=1)=[O:14])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)c1ccccc1Br
Reactant: Cc1ccc(B(O)O)cc1F
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: CC(C)O
Product: Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1F
Temperature: 90 °C
Reaction time: 17 h
Yield: 76.6 %

Procedure:
Compound A (80.0 g, 311 mmol) and 3-fluoro-4-methylphenylboronic acid (52.7 g, 342 mmol) were suspended in isopropyl alcohol (260 mL, 3.5 mol). A solution of sodium carbonate (56.1 g, 529 mmol) in water (260 mL, 15 mol) was added and the mixture was degassed under nitrogen. Tetrakis(triphenylphosphine)palladium(0) (3.6 g, 3.1 mmol) was then added and the mixture was stirred at 90° C. for 17 hours. The mixture was concentrated under reduced pressure and suspended in water (200 mL). The aqueous phase was extracted with EtOAc (600 mL) and separated. The organic phase was washed with saturated aqueous NaCl and concentrated under reduced pressure. The recovered oil was purified by silica gel chromatography (4-6% 5×120 g column) to yield compound B as a clear oil (68.2 g).
Reaction SMILES: [Br:1][C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][C:7](=O)[C:6]=2[CH:5]=[N:4][CH:3]=1.[NH3:13].CO.[BH4-].[Na+]>CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[Br:1][C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][CH:7]([NH2:13])[C:6]=2[CH:5]=[N:4][CH:3]=1
Reactant: N
Reactant: O=C1CCCc2c(Br)cncc21
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: [BH4-]
Solvent: CO
Product: NC1CCCc2c(Br)cncc21
Temperature: 0 °C
Reaction time: 2 h
Yield: 85 %

Procedure:
4-Bromo-6,7-dihydroisoquinolin-8(5H)-one (intermediate B-11 [C]) (4.81 g, 21.3 mmol), titanium (IV) isopropoxide (12.1 g, 42.6 mmol) and ammonia, 2.0 M solution in MeOH (53.2 mL, 106 mmol) were stirred at room temperature for 5 h. The reaction was cooled to 0° C. and NaBH4 (1.21 g, 31.9 mmol) was added portionwise over 10 min; the resulting mixture was stirred at room temperature for an additional 2 h. The reaction was quenched by pouring it into aq ammonium hydroxide 25%, the precipitate was filtered and washed with EtOAc (3×, each time suspended in AcOEt and stirred for 5 min). The organic layer was separated and the remaining aqueous layer was extracted with EtOAc. The combined organic extracts were extracted with 1 M HCl. The acidic aqueous extracts were washed with ethyl acetate (1×), then treated with aqueous sodium hydroxide (2 M) to give pH 10-12 and extracted with EtOAc (3×). The combined organic extracts were washed with brine, dried (Na2SO4), and concentrated in vacuo to afford the title compound (4.11 g, 85%) as brown solid. MS: 225 (M+, 1Br).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([N:16]2[CH:20]=[C:19]([C:21]([O:23]CC)=[O:22])[CH:18]=[N:17]2)[CH:6]=[CH:7][C:8]=1[O:9][CH2:10][CH:11]([CH2:14][CH3:15])[CH2:12][CH3:13])#[N:2].[OH-].[Na+].O.C(O)(=O)C>C(O)C>[C:1]([C:3]1[CH:4]=[C:5]([N:16]2[CH:20]=[C:19]([C:21]([OH:23])=[O:22])[CH:18]=[N:17]2)[CH:6]=[CH:7][C:8]=1[O:9][CH2:10][CH:11]([CH2:14][CH3:15])[CH2:12][CH3:13])#[N:2]
Reactant: CCOC(=O)c1cnn(-c2ccc(OCC(CC)CC)c(C#N)c2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Solvent: CCO
Product: CCC(CC)COc1ccc(-n2cc(C(=O)O)cn2)cc1C#N
Temperature: 70 °C
Yield: 26 %

Procedure:
To a solution (10 ml) of ethyl 1-(3-cyano-4-(2-ethylbutoxy)phenyl)pyrazole-4-carboxylate (0.88 g) in ethanol was added 2 N aqueous sodium hydroxide solution (1.5 ml) with siring and the mixture was heated at 70° C. for 1 hour. After the completion of the reaction, the reaction mixture was poured into water and neutralized with acetic acid. The precipitated crystals were recrystallized from ethyl acetate to give 0.21 g of 1-(3-cyano-4-(2-ethylbutoxy)phenyl)pyrazole-4-carboxylic acid, melting point 180-182° C.
Reaction SMILES: Cl[C:2]1[C:7]2[CH2:8][N:9]([CH2:12][C:13]3[CH:14]=[N:15][C:16]([N:20]4[CH:24]=[CH:23][CH:22]=[N:21]4)=[C:17]([CH3:19])[CH:18]=3)[C:10](=[O:11])[C:6]=2[CH:5]=[CH:4][N:3]=1.[CH:25]([O:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:26]>>[CH3:19][C:17]1[CH:18]=[C:13]([CH2:12][N:9]2[C:10](=[O:11])[C:6]3[CH:5]=[CH:4][N:3]=[C:2]([C:25]([O:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)=[O:26])[C:7]=3[CH2:8]2)[CH:14]=[N:15][C:16]=1[N:20]1[CH:24]=[CH:23][CH:22]=[N:21]1
Reactant: Cc1cc(CN2Cc3c(ccnc3Cl)C2=O)cnc1-n1cccn1
Reactant: O=COc1ccccc1
Product: Cc1cc(CN2Cc3c(ccnc3C(=O)Oc3ccccc3)C2=O)cnc1-n1cccn1
Yield: 75 %

Procedure:
The title compound is prepared in 75% yield (240 mg, brown solid) from 4-chloro-2-((5-methyl-6-(1H-pyrazol-1-yl)pyridin-3-yl)methyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (250 mg, 0.74 mmol, Intermediate-70) and phenyl formate (180 mg, 1.5 mmol) in a similar manner to Intermediate-91.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][C:9]1[CH:22]=[CH:21][C:12]([CH2:13][S:14][CH2:15][C@@H:16]([C:18]([OH:20])=[O:19])[NH2:17])=[CH:11][CH:10]=1.C(Cl)Cl.[C:26]([S:34][CH2:35][C@@H:36]([CH3:49])[C:37](OC1C=CC([N+]([O-])=O)=CC=1)=[O:38])(=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>CN(C)C=O>[C:26]([S:34][CH2:35][C@@H:36]([CH3:49])[C:37]([NH:17][C@@H:16]([CH2:15][S:14][CH2:13][C:12]1[CH:11]=[CH:10][C:9]([CH3:8])=[CH:22][CH:21]=1)[C:18]([OH:20])=[O:19])=[O:38])(=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: C[C@H](CSC(=O)c1ccccc1)C(=O)Oc1ccc([N+](=O)[O-])cc1
Reactant: Cc1ccc(CSC[C@H](N)C(=O)O)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(CSC[C@H](NC(=O)[C@H](C)CSC(=O)c2ccccc2)C(=O)O)cc1
Yield: 68.9 %

Procedure:
Triethylamine (0.464 ml) is added to a solution of S-(4-methylbenzyl)-L-cysteine (reference compound No. 2-1, 500 mg) in a mixed solvent of methylene chloride (20 ml)/dimethylformamide (5 ml) under ice-cooling, and the mixture is stirred. 4-Nitrophenyl (2S)-3-benzoylthio-2-methylpropionate (reference compound No. 1-1, 919 mg) is added to the system of reaction, and the system is stirred overnight. The system of reaction is further stirred overnight at 40° to 50° C. After the reaction is completed, the mixture is concentrated under reduced pressure, a 10%, aqueous citric acid solution is added to the residue, and the whole is extracted with ethyl acetate. The organic layer is washed with water and a saturated sodium chloride solution successively, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue is purified by silica gel column chromatography to give 660 mg (68.9%) of the titled compound. (Compound No. 1-1)
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([CH3:12])[CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH3:13])[CH:3]=1.[F:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][C:22]=1[F:23])[CH2:18][NH2:19]>>[F:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][C:22]=1[F:23])[CH2:18][NH:19][C:2]1[C:11]2[C:6](=[C:7]([CH3:12])[CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH3:13])[CH:3]=1
Reactant: Cc1cc(Cl)c2cccc(C)c2n1
Reactant: NCc1ccc(F)c(F)c1
Product: Cc1cc(NCc2ccc(F)c(F)c2)c2cccc(C)c2n1

Procedure:
Preparation was made using a similar procedure as described in example 1, method 1.3. Starting materials were 4-chloro-2-methyl-8-methylquinoline and 3,4-difluorobenzylamine.
Reaction SMILES: [CH3:1][C:2]1([CH2:13][O:14][C:15]2[CH:20]=[CH:19][C:18]([N:21]3[CH2:26][CH2:25][N:24]([C:27]([O:29]C(C)(C)C)=[O:28])[CH2:23][CH2:22]3)=[CH:17][CH:16]=2)[O:6][C:5]2=[N:7][C:8]([N+:10]([O-:12])=[O:11])=[CH:9][N:4]2[CH2:3]1.FC(F)(F)C(O)=O.[Cl:41][C:42]1[CH:43]=[C:44]([CH:47]=[CH:48][C:49]=1[Cl:50])[CH2:45]O.C(N1C=CN=C1)(N1C=CN=C1)=O>C(Cl)Cl.CN(C=O)C.O>[CH3:1][C:2]1([CH2:13][O:14][C:15]2[CH:20]=[CH:19][C:18]([N:21]3[CH2:22][CH2:23][N:24]([C:27]([O:29][CH2:45][C:44]4[CH:47]=[CH:48][C:49]([Cl:50])=[C:42]([Cl:41])[CH:43]=4)=[O:28])[CH2:25][CH2:26]3)=[CH:17][CH:16]=2)[O:6][C:5]2=[N:7][C:8]([N+:10]([O-:12])=[O:11])=[CH:9][N:4]2[CH2:3]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(OCC3(C)Cn4cc([N+](=O)[O-])nc4O3)cc2)CC1
Reactant: OCc1ccc(Cl)c(Cl)c1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: CC1(COc2ccc(N3CCN(C(=O)OCc4ccc(Cl)c(Cl)c4)CC3)cc2)Cn2cc([N+](=O)[O-])nc2O1
Temperature: 25 °C
Reaction time: 3 h
Yield: 69.1 %

Procedure:
Tert-butyl 4-[4-(2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazol-2-ylmethoxy)phenyl]-piperazine-1-carboxylate prepared in Example 131 (118 mg, 0.26 mmol) was dissolved in methylene chloride (5 ml). To the solution, trifluoroacetic acid (5 ml) was added, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure and added methylene chloride (2 ml) and triethylamine (2 ml). The solution was stirred at room temperature for 5 minutes and then concentrated under reduced pressure. The residue was dissolved in DMF (15 ml) and the solution was added a solution of 3,4-dichlorobenzyl alcohol (136 mg, 0.77 mmol) and 1,1′-carbonyldiimidazole (125 mg, 0.77 mmol) in DMF (5 ml) stirred at room temperature for 3 hours followed by stirring at room temperature overnight. The reaction mixture was poured into water and extracted with ethyl acetate. The organic phase was washed with a saturated saline solution, dried over magnesium sulfate and then filtered. The resulting filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methylene chloride/methanol=200/1) and crystallized from methylene chloride-isopropyl ether to afford 3,4-dichlorobenzyl 4-[4-(2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazol-2-ylmethoxy)phenyl]piperazine-1-carboxylate (101 mg, yield 70%) as a light yellow powder.
Reaction SMILES: CN(C=O)C.[C:6]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1I)(=[O:8])[CH3:7].[C:18]([OH:22])(=[O:21])[CH:19]=[CH2:20].C([O-])(=O)C.[Na+]>[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>[C:6]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[CH:20]=[CH:19][C:18]([OH:22])=[O:21])(=[O:8])[CH3:7]
Reactant: C=CC(=O)O
Reactant: CC(=O)Nc1ccc(F)cc1I
Agent: Cl[Pd]Cl
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)Nc1ccc(F)cc1C=CC(=O)O
Reaction time: 3 h
Yield: 78.7 %

Procedure:
To a 200-ml flask were added 40 ml of DMF, 20 g (0.0717 mole) of 2-acetylamino-5-fluoroiodobenzene, 5.85 g (0.0812 mole) of acrylic acid, 7.77 g (0.0947 mole) of anhydrous sodium acetate, 10 mg of palladium chloride and 30 mg of triphenylphosphine. This mixture was stirred at 125° to 130° C. for 3 hours and poured into 200 ml of water, and then a large amount of crystal precipitated. Sodium hydroxide was added to this aqueous solution containing the crystal while stirring the solution as it was, until the pH of the solution became 9.0 to obtain a uniform solution. Thereafter, 2 g of activated carbon was added to the solution, and after stirring at room temperature for 15 minutes, the insoluble matter was filtered off. The filtrate was acidified to a pH of 4.0 with conc. hydrochloric acid, and then white crystal precipitated. This crystal was filtered off and vacuum-dried to obtain 12.6 g of 2-acetylamino-5-fluorocinnamic acid. The yield was 78.5% of the theoretical value, and the melting point was 232° to 233° C. The 1H-NMR and IR of this compound were as follows:
Reaction SMILES: CC(C)([O-])C.[K+].[C:7]([O:16][CH2:17][CH3:18])(=[O:15])[CH2:8][CH2:9][C:10]([O:12]CC)=O.[Br:19][C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][CH:27]=1)[CH:23]=O.Cl.CC([O-])=O.[Na+].C([O-])([O-])=O.[K+].[K+]>CC(O)(C)C.C(OC(=O)C)(=O)C.O>[Br:19][C:20]1[CH:27]=[CH:26][CH:25]=[C:22]2[C:21]=1[C:10]([OH:12])=[CH:9][C:8]([C:7]([O:16][CH2:17][CH3:18])=[O:15])=[CH:23]2
Reactant: CCOC(=O)CCC(=O)OCC
Reactant: O=Cc1cccc(Br)c1
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Agent: Cl
Solvent: O
Solvent: CC(=O)OC(C)=O
Solvent: CC(C)(C)O
Product: CCOC(=O)c1cc(O)c2c(Br)cccc2c1
Temperature: 85 °C
Reaction time: 2 h

Procedure:
A solution of potassium tert-butoxide (20.0 g, 0.78 mol) at 55° C. in t-BuOH (249 mL) was treated with a premixed solution of diethyl succinate (40.4 mL, 0.243 mol) and 3-bromobenzaldehyde (18.9 mL, 0.162 mol) dropwise. Upon completion of the addition, the reaction mixture was warmed to 85° C. and stirred for 2 h. After 2 h, the reaction mixture was cooled to 25° C. The reaction mixture was acidified to pH<4 with 2 N aqueous HCl and concentrated. The aqueous suspension was then extracted with ethyl acetate (3×). The organic layers were combined and washed with saturated aqueous NaHCO3 (5×). The basic aqueous washes were combined and reacidified with 2 N aqueous HCl to pH 1. Finally, the aqueous phase was extracted with ethyl acetate (3×). The organic layers were combined, dried over Na2SO4, and concentrated under reduced pressure, which afforded the desired half ester (39.1 g, 77%) as an orange oil. The half ester (39.1 g, 0.124 mol) was dissolved in acetic anhydride (178 mL) and NaOAc (18.7 g, 0.137 mol) was added. The reaction mixture was warmed to 140° C. and stirred for 6 h. Upon completion, the reaction mixture was cooled to 25° C. and poured into H2O. The aqueous layer was extracted with ethyl acetate (3×). The organic layers were combined, dried over Na2SO4, and concentrated under reduced pressure. The residue was dissolved in anhydrous ethanol (620 mL). K2CO3 (104 g, 0.624 mol) was added, and the reaction mixture was warmed at 80° C. for 1 h. The reaction mixture was cooled and acidified to pH 1 with 2 N aqueous HCl. The ethanol was removed under reduced pressure and the aqueous suspension was extracted with ethyl acetate (3×). The organic extracts were combined, dried over Na2SO4, and concentrated under reduced pressure. Flash chromatography (SiO2, 16×30 cm, 0-15% EtOAc/hexanes gradient elution) provided 7 (5.4 g, 15% over 3 steps) as a yellow solid and its 7-bromo isomer (12.4 g, 34% over 3 steps). 1H NMR (CDCl3, 500 MHz) δ 8.16 (s, 1H), 8.07 (s, 1H), 7.89 (d, J=6.5 Hz, 1H), 7.73 (d, J=6.5 Hz, 1H), 7.63 (s, 1H), 7.29 (t, J=10 Hz, 1H), 4.43 (q, J=6.0 Hz, 2H) 1.44 (t, J=6.0 Hz, 3H). 13C NMR (CDCl3, 125 MHz) δ 165.9, 152.7, 136.3, 133.6, 130.6, 129.2, 126.7, 123.6, 122.7, 115.2, 112.3, 61.3, 14.3. IR (film) νmax3367, 2979, 1690, 1227 cm−1. ESI-TOF HRMS m/z 294.9959 (M+H+, C13H11BrO3 requires 294.9964).
Reaction SMILES: [C:1]1([C:7]2[O:11][N:10]=[C:9]([O:12][CH2:13][C:14]([OH:16])=O)[C:8]=2[Br:17])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N+]([O-])(O)=O.[O:22]([CH2:26][CH2:27][NH2:28])[N+:23]([O-:25])=[O:24]>C(O)C>[O:22]([CH2:26][CH2:27][NH:28][C:14](=[O:16])[CH2:13][O:12][C:9]1[C:8]([Br:17])=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[O:11][N:10]=1)[N+:23]([O-:25])=[O:24]
Reactant: NCCO[N+](=O)[O-]
Reactant: O=C(O)COc1noc(-c2ccccc2)c1Br
Solvent: O=[N+]([O-])O
Solvent: CCO
Product: O=C(COc1noc(-c2ccccc2)c1Br)NCCO[N+](=O)[O-]
Yield: 64.2 %

Procedure:
Following a similar treatment to that in Example 2 and using 0.53 g of 5-phenyl-4-bromo-3-isoxazolyloxyacetic acid and 0.30 g of nitroxyethylamine nitrate, 0.44 g of the title compound was obtained as colorless needles (solvent for recrystallization; ethanol).