Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[NH:11][C:12]([C:20]2[CH:29]=[CH:28][CH:27]=[C:26]3[C:21]=2[N:22]=[C:23]([NH:31][CH2:32][C:33]([F:36])([F:35])[F:34])[C:24]([CH3:30])=[N:25]3)=[CH:13][C:14]=1[C:15]([O:17]CC)=[O:16])=[O:7])([CH3:4])([CH3:3])[CH3:2]>O1CCOCC1.O.CCOCC>[C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[NH:11][C:12]([C:20]2[CH:29]=[CH:28][CH:27]=[C:26]3[C:21]=2[N:22]=[C:23]([NH:31][CH2:32][C:33]([F:34])([F:35])[F:36])[C:24]([CH3:30])=[N:25]3)=[CH:13][C:14]=1[C:15]([OH:17])=[O:16])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)c1cc(-c2cccc3nc(C)c(NCC(F)(F)F)nc23)[nH]c1CNC(=O)OC(C)(C)C
Solvent: CCOCC
Solvent: O
Solvent: C1COCCO1
Product: Cc1nc2cccc(-c3cc(C(=O)O)c(CNC(=O)OC(C)(C)C)[nH]3)c2nc1NCC(F)(F)F
Temperature: 110 °C
Yield: 85.3 %

Procedure:
A glass microwave reaction vessel was charged with ethyl 2-(((tert-butoxycarbonyl)amino)methyl)-5-(2-methyl-3-((2,2,2-trifluoroethyl)amino)quinoxalin-5-yl)-1H-pyrrole-3-carboxylate (301b) (380 mg, 0.75 mmol) and LiOH monohydrate (157 mg, 3.74 mmol) in dioxane (5 mL) and water (2.5 mL). The tube was sealed and the reaction mixture was stirred and heated at 110° C. for 3 h. After cooling to RT, the reaction mixture was diluted with Et2O and water and the layers were separated. The Et2O layer was discarded. The aq. layer was acidified with 2 M HCl (aq.) and extracted with EtOAc (3×). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated to give 2-(((tert-butoxycarbonyl)amino)methyl)-5-(2-methyl-3-((2,2,2-trifluoroethyl)amino)quinoxalin-5-yl)-1H-pyrrole-3-carboxylic acid (308 mg, 0.64 mmol) as an orange solid. m/z (ESI, +ve) 480.2 (M+H)+. The orange solid (308 mg) was dissolved in 4 mL of dioxane and treated with a 4 M solution of HCl in 1,4-dioxane (4.68 mL, 18.72 mmol) at RT. The reaction mixture was stirred at RT overnight and was then concentrated. The solid was suspended with 1/1 Et2O/hexanes and collected by filtration to give 2-(aminomethyl)-5-(2-methyl-3-((2,2,2-trifluoroethyl)amino)quinoxalin-5-yl)-1H-pyrrole-3-carboxylic acid hydrochloride (301c) (255 mg, 0.61 mmol, 82% yield) as a red solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.30 (br. s., 1H), 8.37 (t, J=5.77 Hz, 2H), 7.95 (dt, J=7.48, 0.76 Hz, 1H), 7.77 (t, J=6.16 Hz, 1H), 7.71 (dt, J=7.97, 0.81 Hz, 1H), 7.46 (t, J=7.82 Hz, 1H), 7.42 (dd, J=2.35, 0.39 Hz, 1H), 4.38-4.49 (m, 2H), 4.34 (q, J=5.35 Hz, 2H), 2.60 (s, 3H). 19F NMR (377 MHz, DMSO-d6) δ ppm −69.61 (s, 3F). m/z (ESI, +ve) 363.0 (M-NH2)′.
Reaction SMILES: C([O:3][CH2:4][CH2:5][N:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]=[C:8]([C:16]([NH:18][C:19]2[NH:23][N:22]=[N:21][N:20]=2)=[O:17])[C:7]1=[O:24])=O.[OH-].[Na+].Cl>O>[OH:3][CH2:4][CH2:5][N:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]=[C:8]([C:16]([NH:18][C:19]2[NH:23][N:22]=[N:21][N:20]=2)=[O:17])[C:7]1=[O:24]
Reactant: O=COCCn1c(=O)c(C(=O)Nc2nnn[nH]2)nc2ccccc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(Nc1nnn[nH]1)c1nc2ccccc2n(CCO)c1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
4(2-Formyloxyethyl)-3,4-dihydro-3-oxo-N(1H-tetrazol-5-yl)-2-quinoxalinecarboxamide (Example 20d) (1.85 g) in water (100 ml) was treated with sodium hydroxide (5.9 ml., 2N) and the solution was stirred for 30 minutes at room temperature. Hydrochloric acid (6 ml., 2N) was added and the solid was collected and crystallised from aqueous dimethylformamide and dried. It had m.p. 269° (d).
Reaction SMILES: [CH2:1]([O:3][P:4]([NH:9][C@H:10]1[C@H:15]([CH3:16])[CH2:14][CH2:13][N:12](C(OCC2C=CC=CC=2)=O)[CH2:11]1)([O:6][CH2:7][CH3:8])=[O:5])[CH3:2].[H][H]>CO.[Pd]>[CH3:16][C@@H:15]1[CH2:14][CH2:13][NH:12][CH2:11][C@H:10]1[NH:9][P:4](=[O:5])([O:6][CH2:7][CH3:8])[O:3][CH2:1][CH3:2]
Reactant: CCOP(=O)(N[C@@H]1CN(C(=O)OCc2ccccc2)CC[C@H]1C)OCC
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CCOP(=O)(N[C@@H]1CNCC[C@H]1C)OCC
Temperature: 25 °C
Reaction time: 1 h
Yield: 100.7 %

Procedure:
A mixture of trans-benzyl 3-(diethoxyphosphorylamino)-4-methylpiperidine-1-carboxylate (0.95 g, 2.5 mmol) and 10% Pd/C (0.13 g, 0.12 mmol) in methanol (30 mL) was charged with 1 atmosphere hydrogen and stirred at room temperature for 1 hour. The catalyst was removed by filtration and washed with methanol (20 mL). The filtrate was concentrated in vacuo to give diethyl trans-4-methylpiperidin-3-ylphosphoramidate (0.63 g, 100%) as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:32]=[CH:33][C:34]=1[F:35])[CH2:5][N:6]1[CH2:15][CH2:14][C:13]2[C:8](=[C:9]([OH:30])[C:10](=[O:29])[N:11]3[CH2:21][CH2:20][CH2:19][CH2:18][N:17]([CH2:22][CH2:23][O:24]C(=O)C)[C:16](=[O:28])[C:12]3=2)[C:7]1=[O:31].[OH-].[Li+]>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:32]=[CH:33][C:34]=1[F:35])[CH2:5][N:6]1[CH2:15][CH2:14][C:13]2[C:8](=[C:9]([OH:30])[C:10](=[O:29])[N:11]3[CH2:21][CH2:20][CH2:19][CH2:18][N:17]([CH2:22][CH2:23][OH:24])[C:16](=[O:28])[C:12]3=2)[C:7]1=[O:31]
Reactant: CC(=O)OCCN1CCCCn2c(c3c(c(O)c2=O)C(=O)N(Cc2ccc(F)c(Cl)c2)CC3)C1=O
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C1c2c(c3n(c(=O)c2O)CCCCN(CCO)C3=O)CCN1Cc1ccc(F)c(Cl)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 11-(3-chloro-4-fluorobenzyl)-9-hydroxy-2-[2-(acetyloxy)ethyl]-3,4,5,6,12,13-hexahydro-2H[1,4]diazocino[2,1-a]-2,6-naphthyridine-1,8,10(11H)-trione (50 mg, 0.1 mmol) and aqueous lithium hydroxide (0.5 mL, 1M) in THF was stirred at room temperature for 1 hour. The product mixture was concentrated under vacuum. The residue was subjected to reverse phase column chromatography on C-18 stationary phase eluted with a 95-5% water-acetonitrile gradient. Collection and lyophilization of appropriate fractions afforded the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:11])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].[C:12](=O)([O-])[O-].[Cs+].[Cs+].CI.O>CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]([O:11][CH3:12])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9]
Reactant: O=C([O-])[O-]
Reactant: O=[N+]([O-])c1ccc(O)cc1Br
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CI
Product: COc1ccc([N+](=O)[O-])c(Br)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 94 %

Procedure:
To a solution of 3-bromo-4-nitrophenol (4.1 g) in N,N-dimethylformamide (40 ml) were sequentially added cesium carbonate (9.2 g) and methyl iodide (1.5 ml), and the solution was stirred overnight at room temperature. Water was added thereto, the solution was stirred, extracted with ethyl acetate, then sequentially washed with water and brine, dried over anhydrous magnesium sulfate, and then the solvent was evaporated in vacuo. The residue was purified by silica gel column chromatography (hexane-ethyl acetate system) to provide 2-bromo-4-methoxy-1-nitrobenzene (4.1 g). Synthesized from 7-benzyloxy-3-bromo-1,2-dihydronaphthalene and 2-bromo-4-methoxy-1-nitrobenzene according to an analogous synthetic method to Preparation Example 107, 7-benzyloxy-3-(5-methoxy-2-nitrophenyl)-1,2-dihydronaphthalene (3.4 g) was used according to an analogous synthetic method to Example 30 to provide the title compound (1.6 g).
Reaction SMILES: [F:1][CH:2]([F:24])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12]#[CH:13])=[C:7]2[N:6]=[C:5]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=2)[CH:4]=1.Br[C:26]1[C:27]([F:37])=[CH:28][C:29]([F:36])=[C:30]([S:32]([NH2:35])(=[O:34])=[O:33])[CH:31]=1>>[F:24][CH:2]([F:1])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12]#[C:13][C:26]3[C:27]([F:37])=[CH:28][C:29]([F:36])=[C:30]([S:32]([NH2:35])(=[O:33])=[O:34])[CH:31]=3)=[C:7]2[N:6]=[C:5]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=2)[CH:4]=1
Reactant: NS(=O)(=O)c1cc(Br)c(F)cc1F
Reactant: C#Cc1cnn2c(C(F)F)cc(-c3cccc(C(F)(F)F)c3)nc12
Product: NS(=O)(=O)c1cc(C#Cc2cnn3c(C(F)F)cc(-c4cccc(C(F)(F)F)c4)nc23)c(F)cc1F

Procedure:
The title compound was prepared from 7-difluoromethyl-3-ethynyl-5-(3-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.2) (169 mg, 0.5 mmol) and commercially available 5-bromo-2,4-difluoro-benzenesulfonamide (136 mg, 0.5 mmol) according to general procedure II. Obtained as a yellow solid (76 mg, 29%). MS (ISN) 527.0 [(M−H)−]; mp 277° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:11])=[C:4]([CH2:8][C:9]#[N:10])[CH:5]=[CH:6][CH:7]=1.B.CO>C1COCC1>[Cl:1][C:2]1[C:3]([F:11])=[C:4]([CH2:8][CH2:9][NH2:10])[CH:5]=[CH:6][CH:7]=1
Reactant: N#CCc1cccc(Cl)c1F
Agent: B
Solvent: C1CCOC1
Solvent: CO
Product: NCCc1cccc(Cl)c1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 85.1 %

Procedure:
To a solution of (3-chloro-2-fluoro-phenyl)-acetonitrile (1.48 g, 8.8 mmol) in anhydrous THF (20 mL) was added a solution of borane (20 mL, 1M in THF) dropwise. The resulting reaction mixture was heated at reflux temperature for 2 hours. After cooling to room temperature, MeOH was added and the mixture was stirred at room temperature for additional 30 min. After removal of volatiles under reduced pressure, desired title product (1.30 g, 90%) was obtained as oil. MS: 174.0 (M+H)+.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH2:15][C:16]#[N:17])=[CH:10][CH:9]=1>C1COCC1>[NH2:17][CH2:16][CH2:15][CH:14]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:23])([CH3:22])[CH3:24])[C:11]1[CH:10]=[CH:9][C:8]([Cl:7])=[CH:13][CH:12]=1
Reactant: CC(C)(C)OC(=O)NC(CC#N)c1ccc(Cl)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC(CCN)c1ccc(Cl)cc1
Temperature: 20 °C
Reaction time: 2 h
Yield: 100.4 %

Procedure:
Lithium aluminium hydride (0.712 mL, 0.71 mmol) was added dropwise to tert-butyl 1-(4-chlorophenyl)-2-cyanoethylcarbamate (Intermediate 24) (200 mg, 0.71 mmol) in THF (4 mL) at 20° C. under nitrogen. The resulting solution was stirred at 20° C. for 2 hours. The reaction mixture was quenched with NaOH (1M) (1 mL) and the solution was filtered. The solution was diluted with EtOAc (20 mL), and washed with water 2× (10 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford tert-butyl 3-amino-1-(4-chlorophenyl)propylcarbamate (203 mg, 100%) as a gum. m/z (ESI+) (M+H)+=285; HPLC tR=2.33 min.
Reaction SMILES: [C:1]([S:4][CH2:5][CH:6]([CH2:10][CH2:11][CH2:12][NH:13][C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=1)=[O:15])[C:7]([OH:9])=O)(=[O:3])[CH3:2].[C:26]([NH:29][CH:30]([C:36]([OH:38])=[O:37])[CH2:31]SC(=O)C)(=O)[CH3:27]>>[C:6]([O:38][C:36](=[O:37])[C@@H:30]1[CH2:31][CH2:27][CH2:26][N:29]1[C:7](=[O:9])[CH:6]([CH2:5][S:4][C:1](=[O:3])[CH3:2])[CH2:10][CH2:11][CH2:12][NH:13][C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=1)=[O:15])([CH3:10])([CH3:7])[CH3:5]
Reactant: COc1ccc(COC(=O)NCCCC(CSC(C)=O)C(=O)O)cc1
Reactant: CC(=O)NC(CSC(C)=O)C(=O)O
Product: COc1ccc(COC(=O)NCCCC(CSC(C)=O)C(=O)N2CCC[C@H]2C(=O)OC(C)(C)C)cc1

Procedure:
By substituting 2-acetylthiomethyl-5-(p-methoxybenzyloxycarbonylamino)pentanoic acid for the N,S-diacetyl-D,L-cysteine in the procedure of Example 53, N-[2-acetylthiomethyl-5-(p-methoxybenzyloxycarbonylamino)pentanoyl]-L-proline tert-butyl ester is obtained.
Reaction SMILES: CO/[CH:3]=[CH:4]/[C:5]([O:7][Si](C)(C)C)=[CH2:6].[C:12](#[N:15])[CH:13]=[CH2:14].Cl.C1COCC1>C1C=CC=CC=1>[O:6]=[C:5]1[CH2:7][CH2:14][C:13]([C:12]#[N:15])=[CH:3][CH2:4]1
Reactant: C=CC#N
Reactant: C=C(/C=C/OC)O[Si](C)(C)C
Agent: Cl
Solvent: C1CCOC1
Solvent: c1ccccc1
Product: N#CC1=CCC(=O)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
In a sealed tube, {[(3E)-4-methoxybuta-1,3-dien-2-yl]oxy}(trimethyl)silane (5.65 mL, 29.0 mmol) and acrylonitrile (1.91 mL, 29.0 mmol) were combined in benzene (9.67 mL), heated to reflux, and allowed to stir for 16 hours. The reaction mixture was then cooled to ambient temperature and the volatiles were removed in vacuo (23° C. water bath). The residue was stirred into a mixture of 1N aqueous HCl (29.0 mL, 29.0 mmol) and THF (9.67 mL). After being stirred at ambient temperature for 3 hours, the reaction mixture was extracted with diethyl ether. The organic layer was washed with de-ionized water (2×), brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo (23° C. water bath). The residue was purified by MPLC on silica gel (using a gradient elution of 0-50% hexanes/acetone). Desired fractions were identified, combined and concentrated in vacuo (23° C. water bath) to afford the title compound.
Reaction SMILES: [C:1]([NH:4][C:5]1[N:9]([CH2:10][C:11](OCC)=[O:12])[N:8]=[C:7]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)[C:6]=1[C:23]#[C:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)(=[O:3])[CH3:2].[BH4-].[Na+]>C(O)C.CO>[F:22][C:19]1[CH:20]=[CH:21][C:16]([C:7]2[C:6]([C:23]#[C:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[C:5]([NH:4][C:1](=[O:3])[CH3:2])[N:9]([CH2:10][CH2:11][OH:12])[N:8]=2)=[CH:17][CH:18]=1
Reactant: CCOC(=O)Cn1nc(-c2ccc(F)cc2)c(C#Cc2ccccc2)c1NC(C)=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: CO
Product: CC(=O)Nc1c(C#Cc2ccccc2)c(-c2ccc(F)cc2)nn1CCO
Temperature: 25 °C
Reaction time: 16 h
Yield: 72.5 %

Procedure:
To a solution of ethyl 2-(5-acetamido-3-(4-fluorophenyl)-4-(phenylethynyl)-1H-pyrazol-1-yl)acetate (1 g, 2.5 mmol) in ethanol (40 mL) and methanol (10 ml) was added sodium borohydride (466 mg, 12.3 mmol and the reaction stirred at room temperature for 16 h. The reaction mixture was concentrated in vacuo and the residue was dissolved in CH2Cl2 and washed with a dilute NH4Cl solution. The aqueous was extracted with CH2Cl2 and the combined organic extracts were dried over MgSO4, filtered and evaporated. The crude product was suspended in CH2Cl2 (20 ml), heated to reflux, allowed to cool and the product was filtered and dried in vacuo to give N-(3-(4-fluorophenyl)-1-(2-hydroxyethyl)-4-(phenylethynyl)-1H-pyrazol-5-yl)acetamide as a white solid (659 mg), which was used as such in the subsequent step.
Reaction SMILES: [C:1]1([P:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N+:20]([C:23]1[CH:54]=[CH:53][C:26]([CH2:27][O:28][C:29](=[O:52])[CH:30]([N:32]2[C@H:35]([S:36][C:37](=[O:39])[CH3:38])[C@@H:34]([O:40][C:41](=[O:50])[CH2:42][O:43][C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)[C:33]2=[O:51])Cl)=[CH:25][CH:24]=1)([O-:22])=[O:21]>O1CCOCC1>[N+:20]([C:23]1[CH:24]=[CH:25][C:26]([CH2:27][O:28][C:29](=[O:52])[C:30]([N:32]2[C@H:35]([S:36][C:37](=[O:39])[CH3:38])[C@@H:34]([O:40][C:41](=[O:50])[CH2:42][O:43][C:44]3[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=3)[C:33]2=[O:51])=[P:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[CH:53][CH:54]=1)([O-:22])=[O:21]
Reactant: CC(=O)S[C@@H]1[C@@H](OC(=O)COc2ccccc2)C(=O)N1C(Cl)C(=O)OCc1ccc([N+](=O)[O-])cc1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: CC(=O)S[C@@H]1[C@@H](OC(=O)COc2ccccc2)C(=O)N1C(C(=O)OCc1ccc([N+](=O)[O-])cc1)=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 8 h

Procedure:
786 mg of triphenylphosphine and 3 g of poly-Hunig base are added to a solution of 960 mg of 2-[(3S,4R)-4-acetylthio-3-phenoxyacetoxy-2-oxoazetidin-1-yl]-2-chloroacetic acid p-nitrobenzyl ester in 40 ml of dioxan and the mixture is stirred overnight at 50° under nitrogen. The poly-Hunig base is removed by filtration and the filtrate is concentrated by evaporation in vacuo. The residue is chromatographed over silica gel with toluene/ethyl acetate (9:1, 4:1 and 1:1) and yields the title compound. IR spectrum (in methylene chloride): characteristic absorption bands at 5.7, 5.9, 6.17, 6.55 and 7.45 μ.
Reaction SMILES: [CH2:1]([C:3]1([CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:12][CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8](B3OC(C)(C)C(C)(C)O3)[CH:9]=2)[C:4]1=[O:22])[CH3:2].Br[C:30]1[CH:35]=[CH:34][C:33]([N+:36]([O-:38])=[O:37])=[CH:32][N:31]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>C(O)C.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.C1(C)C=CC=CC=1>[CH2:1]([C:3]1([CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:12][CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:30]3[CH:35]=[CH:34][C:33]([N+:36]([O-:38])=[O:37])=[CH:32][N:31]=3)[CH:9]=2)[C:4]1=[O:22])[CH3:2]
Reactant: O=[N+]([O-])c1ccc(Br)nc1
Reactant: CCOC(=O)CC1(CC)CCc2cc(B3OC(C)(C)C(C)(C)O3)ccc2C1=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: [Cs+]
Solvent: CCO
Solvent: O
Solvent: Cc1ccccc1
Product: CCOC(=O)CC1(CC)CCc2cc(-c3ccc([N+](=O)[O-])cn3)ccc2C1=O
Temperature: 100 °C
Reaction time: 48 h
Yield: 66.3 %

Procedure:
Pd(PPh3)4 (0.479 g, 0.414 mmol) was added to a solution of 4E (3.2 g, 8.28 mmol), 2-bromo-5-nitropyridine (1.84 g, 9.11 mmol) and cesium carbonate (8.1 g, 24.85 mmol) in a mixture of ethanol (4 mL), water (4 mL) and toluene (80 mL) under argon atmosphere. The resulting mixture was degassed for further 10 min and stirred at 100° C. for 48 h. The solvent was removed under reduced pressure, and the residue was partitioned between ethyl acetate and water. The separated organic layer was treated with saturated NaCl solution, dried over sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The crude product was triturated in ethanol to afford the title compound (2.1 g, 66%) as a solid. 1H NMR (300 MHz, CDCl3): δ 9.52 (d, J=2.7 Hz, 1H), 8.56 (dd, J1=2.1 Hz, J2=8.4 Hz, 1H), 8.21 (d, J=8.4 Hz, 1H), 7.97 (m, 3H), 4.11 (q, J=7.5 Hz, 2H), 3.23-3.12 (m, 1H), 3.06-2.93 (m, 2H), 2.56-2.46 (m, 2H), 2.14-2.07 (m, 1H), 1.85-1.61 (m, 2H), 1.22 (t, J=6.9 Hz, 3H), 0.94 (t, J=7.8 Hz, 3H). ESI-MS m/z=383 (M+H).
Reaction SMILES: [CH2:1]([C:4]1[S:5][CH:6]=[CH:7][CH:8]=1)[CH2:2][CH3:3].[Br:9]N1C(=O)CCC1=O>CN(C)C=O>[Br:9][C:6]1[S:5][C:4]([CH2:1][CH2:2][CH3:3])=[CH:8][CH:7]=1
Reactant: CCCc1cccs1
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Product: CCCc1ccc(Br)s1
Yield: 89.3 %

Procedure:
A solution of 2-propylthiophene (1.00 g, 7.92 mmol) and N-bromosuccinimide (1.55 mg, 8.71 mmol) in N,N-Dimethylformamide (60 mL) was heated at 65° C. for 4 hours. The reaction mixture was concentrated in vacuo. The residue was dissolved in cyclohexane (20 mL) and successively washed with a 5% sodium thiosulfate solution (15 mL) and brine (15 mL). The organic layer was dried over sodium sulfate and concentrated in vacuo to provide 2-bromo-5-propylthiophene (11a) (1.45 g, 7.07 mmol, 89%) which was used without further purification.
Reaction SMILES: C(O)(C(F)(F)F)=O.C(OC(C(F)(F)F)=O)(C(F)(F)F)=O.[C:21]([CH2:24][CH2:25][CH2:26][CH2:27][N:28]1[C:36]2[C:31](=[CH:32][CH:33]=[C:34]([C:37]([OH:39])=[O:38])[CH:35]=2)[C:30]([CH:40]2[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]2)=[CH:29]1)(O)=[O:22]>O>[CH:40]1([C:30]2[C:31]3[C:36](=[CH:35][C:34]([C:37]([OH:39])=[O:38])=[CH:33][CH:32]=3)[N:28]3[CH2:27][CH2:26][CH2:25][CH2:24][C:21](=[O:22])[C:29]=23)[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]1
Reactant: O=C(O)CCCCn1cc(C2CCCCC2)c2ccc(C(=O)O)cc21
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: O=C(O)c1ccc2c(C3CCCCC3)c3n(c2c1)CCCCC3=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 118.5 %

Procedure:
A mixture of TFA (1.0 mL) and TFAA (469 mg, 2.232 mmol) was added dropwise to 1-(4-carboxybutyl)-3-cyclohexyl-1H-indole-6-carboxylic acid (365 mg, 1.063 mmol) at 0° C. The reaction mixture was then warmed to rt. and stirred for 4 hr. Water was then added slowly to quench the reaction and a precipitate formed. This was collected by filtration to provide the product as a yellow-greenish solid, (410 mg, >100% yield). MS m/z 326(MH+); 1H NMR (500 MHz, CD3OD) □ ppm 1.39–1.50 (m, 3 H) 1.73–2.14 (m, 11 H) 2.88 (m, 2 H) 3.45 (m, 1 H) 4.46 (m, 2 H) 7.73 (dd, J=8.54, 1.22 Hz, 1 H) 7.98 (d, J=8.55 Hz, 1 H) 8.21 (s, 1 H).
Reaction SMILES: [C:1]([C:5]1[CH:13]=[CH:12][C:8]([C:9](O)=[O:10])=[CH:7][C:6]=1[N+:14]([O-:16])=[O:15])([CH3:4])([CH3:3])[CH3:2].[NH3:17].C(OCC)(=O)C.CCCCCC>C(#N)C.C(OCC)(=O)C.CCCCCC>[C:1]([C:5]1[CH:13]=[CH:12][C:8]([C:9](=[O:10])[NH2:17])=[CH:7][C:6]=1[N+:14]([O-:16])=[O:15])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccc(C(=O)O)cc1[N+](=O)[O-]
Reactant: N
Solvent: CC#N
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CC(C)(C)c1ccc(C(N)=O)cc1[N+](=O)[O-]
Reaction time: 1 h
Yield: 84.8 %

Procedure:
12.0 g (74.0 mmol) of N,N'-carbonyldiimidazole were added to a suspension of 15.03 g (67.3 mmol) of 4-t-butyl-3-nitrobenzoic acid in 150 ml of acetonitrile, and the resulting mixture was stirred for 1 hour, after which 20 ml (0.31 mol) of aqueous ammonia were added. The reaction mixture was stirred for 30 minutes, after which it was concentrated by evaporation under reduced pressure, and the concentrate was dissolved in ethyl acetate. The organic phase was washed with water, with 2N aqueous hydrochloric acid, with water, with a saturated aqueous solution of sodium hydrogencarbonate and with a saturated aqueous solution of sodium chloride, in that order, after which it was dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure, and the resulting residue was purified by column chromatography through 150 g of silica gel, using a gradient elution method, with mixtures of ethyl acetate and hexane ranging from 1:1 to 2:1 by volume as the eluent, to give 12.68 g (yield 85%) of the title compound as crystals, melting at 114°-115° C. (from ethyl acetate-hexane).
Reaction SMILES: C1(C(C2CCCCCCCCC2)=C(C2CCCCCCCCC2)C([O-])=O)CCCCCCCCC1.C(O)(=O)C(C)=C.[C:42]([O:47][CH2:48][CH2:49][O:50][CH2:51][CH2:52]OC12CC3CC(CC(C3)C1)C2)(=[O:46])[C:43]([CH3:45])=[CH2:44]>>[C:42]([O:47][CH2:48][CH2:49][O:50][CH2:51][CH3:52])(=[O:46])[C:43]([CH3:45])=[CH2:44]
Reactant: C=C(C)C(=O)OCCOCCOC12CC3CC(CC(C3)C1)C2
Agent: C=C(C)C(=O)O
Agent: O=C([O-])C(=C(C1CCCCCCCCC1)C1CCCCCCCCC1)C1CCCCCCCCC1
Product: C=C(C)C(=O)OCCOCC

Procedure:
In the same way as the embodiment 1, synthesis of terpolymer was performed using 3.4 grams (0.0166 mols) of tricyclodecanylacrylate, 0.7 grams (0.0083 mols) of methacrylic acid, and 5 grams (0.0166 mols) of adamantyloxyethoxyethyl methacrylate, which is a compound having been obtained in the synthesis example 7, in place of ethoxyethyl methacrylate. As a result, there was obtained 5.4 grams of poly (tricyclodecylacrylate-adamantyloxyethoxyethyl methacrylate-methacrylic acid). The yield was 60%.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[N:13]3[C:14]([CH2:17][N:18]4C(=O)C5=CC=CC=C5C4=O)=[CH:15][N:16]=[C:12]3[CH2:11][N:10]=[C:9]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:8]=2[CH:35]=1)([O-:3])=[O:2].O.NN>C(O)C>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[N:13]3[C:14]([CH2:17][NH2:18])=[CH:15][N:16]=[C:12]3[CH2:11][N:10]=[C:9]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:8]=2[CH:35]=1)([O-:3])=[O:2]
Reactant: O=C1c2ccccc2C(=O)N1Cc1cnc2n1-c1ccc([N+](=O)[O-])cc1C(c1ccccc1)=NC2
Agent: NN
Solvent: O
Solvent: CCO
Product: NCc1cnc2n1-c1ccc([N+](=O)[O-])cc1C(c1ccccc1)=NC2

Procedure:
In the manner given in Example 28, 8-nitro-1-(phthalimidomethyl)-6-phenyl-4H-imidazo[1,2-a][1,4]-benzodiazepine is reacted at room temperature with hydrazine hydrate, dissolved in ethanol to give 8-nitro-1-(aminomethyl)-6-phenyl-4H-imidazo[1,2-a][1,4]benzodiazepine.