Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[CH2:5]([C:21]1[C:26](=[O:27])[CH:25]=[C:24]([CH3:28])[NH:23][C:22]=1[CH3:29])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].C(=O)([O-])[O-].[Na+].[Na+]>S(=O)(=O)(O)O>[CH2:5]([C:21]1[C:26](=[O:27])[C:25]([N+:1]([O-:4])=[O:2])=[C:24]([CH3:28])[NH:23][C:22]=1[CH3:29])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: CCCCCCCCCCCCCCCCc1c(C)[nH]c(C)cc1=O
Reactant: O=[N+]([O-])O
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: CCCCCCCCCCCCCCCCc1c(C)[nH]c(C)c([N+](=O)[O-])c1=O
Temperature: 80 °C

Procedure:
Premixed nitric acid (d 1.5, 0.15 g) and sulfuric acid (0.05 g) was added dropwise at 5-10° C. to 4 (58 mg) in sulphuric acid (d 1.64, 0.5 g). The reaction mixture was heated at 80° C. for 1 hr then cooled and added to ice. Saturated aqueous sodium carbonate was added until effervescence ceased. The reaction mixture was extracted with portions of ethyl ether. The combined organic phase was dried over anhydrous MgSO4 and concentrated under diminished pressure to afford a crude residue Elution with hexane/ethyl acetate gave 3-hexadecyl-2,6-dimethyl-5-nitropyridin-4(1H)-one (14) as a yellow oil: yield 41 mg (62%); silica gel TLC Rf 0.60 (1:1 hexane/ethyl acetate); 1H NMR (400 MHz, CDCl3) δ 0.82-0.85 (m, 3H), 1.21-1.29 (m, 28H), 2.33 (s, 3H), 2.39 (s, 3H) and 2.46-2.52 (m, 2H).
Reaction SMILES: [C:1]1([C:7]2(C(O)=O)CCC[CH2:8]2)C=[CH:5][CH:4]=[CH:3][CH:2]=1.CC(C)C(C1C=CC=CC=1)[C:18]([NH:20][C@@H:21]1[C@H:28]2[C@H:24]([CH2:25][N:26]([CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[C:32]([C:36]([F:39])([F:38])[F:37])[CH:31]=3)[CH2:27]2)[CH2:23][CH2:22]1)=[O:19].C(N1C[C@H]2C(N)CC[C@H]2C1)C1C=CC=CC=1>>[CH2:1]([CH:2]([CH2:3][CH2:4][CH3:5])[C:18]([NH:20][C@@H:21]1[C@H:28]2[C@H:24]([CH2:25][N:26]([CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[C:32]([C:36]([F:37])([F:38])[F:39])[CH:31]=3)[CH2:27]2)[CH2:23][CH2:22]1)=[O:19])[CH2:7][CH3:8]
Reactant: CC(C)C(C(=O)N[C@H]1CC[C@H]2CN(Cc3cccc(C(F)(F)F)c3)C[C@H]21)c1ccccc1
Reactant: O=C(O)C1(c2ccccc2)CCCC1
Agent: NC1CC[C@H]2CN(Cc3ccccc3)C[C@@H]12
Product: CCCC(CCC)C(=O)N[C@H]1CC[C@H]2CN(Cc3cccc(C(F)(F)F)c3)C[C@H]21

Procedure:
The title compound was prepared by substituting 2-propylpentanoic acid for 1-phenylcyclopentanecarboxylic acid and (3aS*,4S*,6aR*)-2-(3-(trifluoromethyl)benzyl)octahydrocyclopenta[c]pyrrol-4-amine from Example 122 Step E for (3aS*,6aR*)-2-benzyloctahydrocyclopenta[c]pyrrol-4-amine in the procedure described for Example 1: 1H NMR (500 MHz, pyridine-d5) δ ppm 7.94 (d, J=6.9, 1H), 7.72 (s, 1H), 7.62 (d, J=7.7, 1H), 7.56 (d, J=7.7, 1H), 7.47 (t, J=7.7, 1H), 4.48 (dt, J=7.3, 14.6, 1H), 3.52 (d, J=13.0, 1H), 3.48 (d, J=13.0, 1H), 2.84 (ddd, J=3.0, 7.7, 16.7, 1H), 2.74 (dd, J=3.1, 9.5, 1H), 2.52-2.45 (m, 1H), 2.38-2.34 (m, 2H), 2.27 (dd, J=7.6, 9.5, 1H), 2.22 (td, J=4.6, 9.5, 1H), 1.90 (dt, J=7.3, 11.5, 1H), 1.84-1.75 (m, 2H), 1.73-1.61 (m, 2H), 1.48-1.27 (m, 6H), 1.20-1.08 (m, 1H), 0.88 (t, J=7.0, 3H), 0.83 (t, J=7.1, 3H); MS (ESI+) m/z 411 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]([C:18]2[CH:23]=[CH:22][C:21]([O:24][C:25]([F:28])([F:27])[F:26])=[CH:20][CH:19]=2)([OH:17])[CH:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)=[CH:6][CH:5]=1.[CH3:31][C:32]([NH:34][C:35]1[CH:40]=[CH:39][C:38]([CH2:41]Cl)=[CH:37][CH:36]=1)=[O:33].C(N(CC)C(C)C)(C)C>CS(C)=O>[CH3:31][C:32]([NH:34][C:35]1[CH:40]=[CH:39][C:38]([CH2:41][N:14]2[CH2:15][CH2:16][CH:11]([C:10]([C:7]3[CH:6]=[CH:5][C:4]([O:3][C:2]([F:29])([F:1])[F:30])=[CH:9][CH:8]=3)([C:18]3[CH:23]=[CH:22][C:21]([O:24][C:25]([F:28])([F:26])[F:27])=[CH:20][CH:19]=3)[OH:17])[CH2:12][CH2:13]2)=[CH:37][CH:36]=1)=[O:33]
Reactant: OC(c1ccc(OC(F)(F)F)cc1)(c1ccc(OC(F)(F)F)cc1)C1CCNCC1
Reactant: CC(=O)Nc1ccc(CCl)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CC(=O)Nc1ccc(CN2CCC(C(O)(c3ccc(OC(F)(F)F)cc3)c3ccc(OC(F)(F)F)cc3)CC2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 64.4 %

Procedure:
To a stirred solution of 0.4 gram (0.0008 mole) of 4-[bis(4-trifluoromethoxyphenyl)hydroxymethyl]piperidine in 10 mL of dimethyl sulfoxide was added a mixture of 0.2 gram (0.0008 mole) of 4-(methylcarbonylamino)phenylmethyl chloride and 0.6 mL (0.003 mole) of N,N-diisopropylethylamine. Upon completion of addition, the reaction mixture was stirred at ambient temperature for about 18 hours. After this time the reaction mixture was partitioned between an aqueous solution saturated with sodium bicarbonate and ethyl acetate. The organic layer was separated and washed with an aqueous solution saturated with sodium chloride. The organic layer was then concentrated under reduced pressure to a residue, which was subjected to column chromatography on silica gel, with methylene chloride and mixtures of 10-50% acetone in methylene chloride as eluants. The product-containing fractions were combined and concentrated under reduced pressure, yielding about 0.3 gram of N-[4-(methylcarbonylamino)phenylmethyl]-4-[bis(4-trifluoromethoxyphenyl)hydroxymethyl]piperidine. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [H-].[Na+].[OH:3][C@@H:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][C@H:5]1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[CH3:23]I.O>CN(C=O)C>[CH3:23][O:3][C@@H:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][C@H:5]1[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: CI
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](O)[C@H](c2ccccc2)C1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CO[C@@H]1CCN(C(=O)OC(C)(C)C)C[C@H]1c1ccccc1
Temperature: 22 °C
Reaction time: 0.5 h
Yield: 101.8 %

Procedure:
Add sodium hydride (2.19 g, 54.75 mmol) in one portion to a solution of (−)trans-tert-butyl 4-hydroxy-3-phenyl-piperidine-1-carboxylate (11.8 g, 42.12 mmol) in DMF (168.5 mL) at 0° C. under a nitrogen atmosphere. Stir the mixture for 30 min and then add methyl iodide (3.15 mL, 50.54 mmol) dropwise. Stir the mixture at 0° C. for 1 minute and warm to 22° C. for 1 hour. Add additional sodium hydride (303 mg, 12.6 mmol), stir for 15 min, and then add methyl iodide (0.52 mL, 8.4 mmol) slowly. Stir the mixture at 22° C. for 1 hour, cool to 0° C. for 1 hour and add water (118 mL) carefully. Filter the resulting suspension, rinse the solid with water and dry the solid in the vacuum oven (45° C., 60 mbar) to obtain the title compound as a white solid (12.5 g, 99%). MS (m/z): 192 (M-Boc+1), 236 (M-tBu+1).
Reaction SMILES: [CH2:1]([NH:4][C:5](=[O:8])[CH2:6][OH:7])[CH2:2][CH3:3].[H-].[Na+].Cl[CH:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14](=[O:21])[N:13]1[C:22]1[CH:31]=[CH:30][C:29]2[C:24](=[N:25][C:26]([Cl:32])=[CH:27][CH:28]=2)[N:23]=1>O1CCCC1>[Cl:32][C:26]1[N:25]=[C:24]2[C:29]([CH:30]=[CH:31][C:22]([N:13]3[C:14](=[O:21])[C:15]4[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=4)[CH:12]3[O:7][CH2:6][C:5]([NH:4][CH2:1][CH2:2][CH3:3])=[O:8])=[N:23]2)=[CH:28][CH:27]=1
Reactant: CCCNC(=O)CO
Reactant: O=C1c2ccccc2C(Cl)N1c1ccc2ccc(Cl)nc2n1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCNC(=O)COC1c2ccccc2C(=O)N1c1ccc2ccc(Cl)nc2n1
Yield: 56.3 %

Procedure:
The procedure is as in Example 22, but starting with N-propylglycolamide (9.4 g) in tetrahydrofuran (375 cc), an oily suspension (50% by weight; 3.3 g) of sodium hydride and 3-chloro-2-(7-chloro-1,8-naphthyridin-2-yl)-1-isoindolinone (15 g). After recrystallization in acetonitrile, [2-(7-chloro-1,8-naphthyridin-2-yl)-3-oxo-1isoindolinyloxy]-N-propylacetamide (10.5 g), m.p. 167° C., is obtained.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][C:5]=1[C:14](=[O:25])[NH:15][C:16]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([CH3:18])[CH3:17])([O-])=O>CO.C(OCC)(=O)C.[Pd]>[NH2:1][C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][C:5]=1[C:14](=[O:25])[NH:15][C:16]([C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)([CH3:18])[CH3:17]
Reactant: COC(=O)c1ccc([N+](=O)[O-])c(C(=O)NC(C)(C)c2ccccc2)c1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: COC(=O)c1ccc(N)c(C(=O)NC(C)(C)c2ccccc2)c1
Reaction time: 5 h
Yield: 100.6 %

Procedure:
To a solution of methyl 4-nitro-3-[(2-phenylpropan-2-yl)carbamoyl]benzoate (0.12 g, 0.35 mmol) in methanol (2.5 mL) and ethyl acetate (2.5 mL) was added 10% palladium on carbon (12 mg). The mixture was purged with H2 gas (3×) and stirred under an atmosphere of H2 for 5 h. The reaction mixture was then filtered through Celite, washed with MeOH and concentrated. The residue was purified by flash silica gel chromatography (50% to 100% EtOAc/hexanes) to afford methyl 4-amino-3-[(2-phenylpropan-2-yl)carbamoyl]benzoate (0.11 g, 99%). LC-MS: (FA) ES+ 313.
Reaction SMILES: [Br:1][C:2]1[C:3]([Cl:11])=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=O.[F:12][C:13]([F:25])([C:18]1[CH:24]=[CH:23][C:21]([NH2:22])=[CH:20][CH:19]=1)[C:14]([F:17])([F:16])[F:15]>>[Br:1][C:2]1[C:3]([Cl:11])=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([NH:22][C:21]1[CH:20]=[CH:19][C:18]([C:13]([F:12])([F:25])[C:14]([F:15])([F:16])[F:17])=[CH:24][CH:23]=1)=[O:9]
Reactant: Nc1ccc(C(F)(F)C(F)(F)F)cc1
Reactant: O=C(O)c1cnc(Cl)c(Br)c1
Product: O=C(Nc1ccc(C(F)(F)C(F)(F)F)cc1)c1cnc(Cl)c(Br)c1

Procedure:
The title compound was prepared in an analogous fashion to that described in Stage 185.2 using 5-bromo-6-chloro-nicotinic acid and 4-pentafluoroethyl-aniline to afford a white crystalline solid. HPLC (Condition 4) tR=6.61 min, UPLC-MS (Condition 3) tR=1.32 min, m/z=429 [M−H]−.
Reaction SMILES: [S:1]1[C:5]([CH:6]=O)=[CH:4][N:3]=[CH:2]1.[NH:8]1[CH:12]=[CH:11][CH:10]=[CH:9]1>C(O)(=O)CC>[S:1]1[C:5]([C:6]2[C:12]3[NH:8][C:9]([C:6]([C:5]4[S:1][CH:2]=[N:3][CH:4]=4)=[C:9]4[N:8]=[C:12]([C:6]([C:5]5[S:1][CH:2]=[N:3][CH:4]=5)=[C:9]5[NH:8][C:12](=[C:6]([C:5]6[S:1][CH:2]=[N:3][CH:4]=6)[C:9]6[CH:10]=[CH:11][C:12]=2[N:8]=6)[CH:11]=[CH:10]5)[CH:11]=[CH:10]4)=[CH:10][CH:11]=3)=[CH:4][N:3]=[CH:2]1
Reactant: c1cc[nH]c1
Reactant: O=Cc1cncs1
Solvent: CCC(=O)O
Product: C1=Cc2nc1c(-c1cncs1)c1ccc([nH]1)c(-c1cncs1)c1nc(c(-c3cncs3)c3ccc([nH]3)c2-c2cncs2)C=C1
Temperature: 25 °C
Yield: 23.2 %

Procedure:
A 250-mL three-necked flask equipped with a condenser and charged with propionic acid (60 mL) was heated to reflux. 5-Thiazolecarboxaldehyde (1, 373 mg, 3.30 mmol), pyrrole (230 μL, 3.32 mmol), and an additional 5 mL of propionic acid were added. After 3.5 h at reflux, the mixture was cooled to room temperature while exposed to a stream of air. The solvent was removed in vacuo, the residue was redissolved in CHCl3/MeOH/concentrated NH4OH (6:3:1; 100 mL), and the solvent was removed in vacuo. The residue was adsorbed onto silica gel (3 g) and purified by column chromatography (gradient elution, 1-2% MeOH/CH2Cl2) to provide porphyrin 6 (123 mg, 14%) as a solid: 1H NMR (300 MHz, CDCl3) δ −2.70 (s, 2H), 8.67 (s, 4H), 9.02 (s, 8H), 9.38 (s, 4H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])[C@H:4]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([N+]([O-])=O)=[CH:22][CH:21]=1)[NH:5]C(C1(CCNC(=O)C)CCCC1)=S.O.ClCCl.CC(C)=O>CO.C(OCC)(=O)C.[Cl-].[NH4+].[Zn]>[CH3:1][O:2][C:3](=[O:29])[C@H:4]([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[NH2:5]
Reactant: COC(=O)[C@H](Cc1ccc([N+](=O)[O-])cc1)NC(=S)C1(CCNC(C)=O)CCCC1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CO
Product: COC(=O)[C@@H](N)Cc1ccccc1
Reaction time: 0.33 h
Yield: 207.3 %

Procedure:
To a suspension of N-[[1-[2-(acetylamino)ethyl]cyclopentyl]thioxomethyl]-4-nitro-L-phenylalanine methyl ester (740 mg, 1.75 mmol), zinc dust (1.14 g, 17.5 mmol) and ammonium chloride (1.41 g, 26.3 mmol) in methanol (20 mL) was added H2O (10 mL) slowly over 5 min. After stirring for 20 min, the reaction mixture was diluted with ethyl acetate (80 mL) and sat. ammonium chloride solution (25 mL). The separated aqueous layer was back-extracted with ethyl acetate (3×25 mL) and the organic layers were combined, dried over Na2SO4, filtered and concentrated in vacuo. The residual oil was dried under high vacuum for 2 h to give the crude amine (750 mg) which was by flash silica gel column chromatography (dichloromethane-acetone 2:1) to furnish 4-amino-N-[[1-[2-acetylamino)ethyl]cyclopentyl]thioxomethyl]-L-phenylalanine methyl ester (650 mg, 95%). HR MS: Obs. mass, 392.2016. Calcd. mass, 392.2008 (M+H).
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[CH:3]1[CH2:8][NH:7][CH2:6][CH2:5][NH:4]1.[CH:11]1([N:14]2[C:23]3[C:18](=[CH:19][C:20]([F:25])=[C:21](F)[CH:22]=3)[C:17](=[O:26])[C:16]([C:27]([OH:29])=[O:28])=[CH:15]2)[CH2:13][CH2:12]1>N1C=CC=CC=1>[CH:11]1([N:14]2[C:23]3[C:18](=[CH:19][C:20]([F:25])=[C:21]([N:7]4[CH2:6][CH2:5][NH:4][CH:3]([C:2]([F:10])([F:9])[F:1])[CH2:8]4)[CH:22]=3)[C:17](=[O:26])[C:16]([C:27]([OH:29])=[O:28])=[CH:15]2)[CH2:12][CH2:13]1
Reactant: O=C(O)c1cn(C2CC2)c2cc(F)c(F)cc2c1=O
Reactant: FC(F)(F)C1CNCCN1
Solvent: c1ccncc1
Product: O=C(O)c1cn(C2CC2)c2cc(N3CCNC(C(F)(F)F)C3)c(F)cc2c1=O
Temperature: 77 °C
Reaction time: 3 h

Procedure:
A 0.55 g portion of 2-(trifluoromethyl)piperazine was dissolved in 14 ml of pyridine. To this was added 265 mg of 1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid. The mixture was stirred for 3 hours at 77° C.. The pyridine was removed by repeated evaporation with toluene. The residue was triturated with hot methanol. The resulting solid was collected, washed with methanol and ether and dried, giving 105 mg of the desired product as a colorless solid.
Reaction SMILES: [CH3:1][C:2]([C:10]1[CH:11]=[CH:12][CH:13]=[C:14]2[C:19]=1[N:18]=[C:17]([CH3:20])[CH:16]=[CH:15]2)([CH3:9])[CH2:3][C:4](OCC)=[O:5].[H-].[H-].[H-].[H-].[Li+].[Al+3].O.O.O.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Na+].[Na+]>C1COCC1>[CH3:9][C:2]([C:10]1[CH:11]=[CH:12][CH:13]=[C:14]2[C:19]=1[N:18]=[C:17]([CH3:20])[CH:16]=[CH:15]2)([CH3:1])[CH2:3][CH2:4][OH:5]
Reactant: CCOC(=O)CC(C)(C)c1cccc2ccc(C)nc12
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc2cccc(C(C)(C)CCO)c2n1
Temperature: 0 °C
Reaction time: 3 h
Yield: 100.5 %

Procedure:
To a solution of ethyl 3-methyl-3-(2-methylquinolin-8-yl)butanoate (0.66 g, 2.43 mmol) in THF (3 mL) was added 1.0 N LAH (3.65 mL, 3.65 mmol) in THF at 0° C. and stirred at 0° C. for 3 hours. Sodium sulfate decahydrate (2.0 g) was added and stirred at ambient temperature for 30 minutes. The solid was removed by filtration and washed with ethyl acetate (30 mL). The filtrate was concentrated under reduced pressure to give 3-methyl-3-(2-methylquinolin-8-yl)butan-1-ol (0.56 g, 100%) as a solid.
Reaction SMILES: [ClH:1].[Cl:2][CH2:3][CH2:4][NH:5][CH2:6][CH2:7]Cl.[F:9][C:10]1[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][C:11]=1[CH3:17].C(=O)([O-])[O-].[K+].[K+]>C(O)C>[ClH:2].[ClH:1].[F:9][C:10]1[CH:15]=[CH:14][C:13]([N:16]2[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]2)=[CH:12][C:11]=1[CH3:17]
Reactant: ClCCNCCCl
Reactant: Cc1cc(N)ccc1F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: Cc1cc(N2CCNCC2)ccc1F
Reaction time: 24 h
Yield: 12.1 %

Procedure:
A solution of 56.3 g (0.315 mol) of bis(2-chloroethyl)amine hydrochloride and 35.9 g (0.287 mol) of 4-fluoro-3-methylbenzeneamine in 500 mL of absolute ethanol was heated at reflux for 24 h under a nitrogen atmosphere. The mixture was cooled and 65.3 g (0.473 mol) of anhydrous potassium carbonate was added and heating was continued for 24 h. The hot mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was triturated with ethyl acetate to yield a crude solid. This solid was converted to the base and purified by column chromatography using 500 g of silica gel on a 30 cm×10 cm column, eluted with methanol. The fractions containing the product were combined and concentrated. The residue was partitioned between water and ethyl ether. The ethyl ether layer was washed with water, dried (MgSO4) and concentrated under reduced pressure to yield 9.3 g (14%) of a light-pink oil. A portion of the oil was converted to the dihydrochloric acid salt and the solid was recrystallized from 2-propanol to yield a white solid, mp 188°-191° C.
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][C:8]2([CH3:12])[CH3:11])=[CH:4][CH:3]=1.C([Li])CCC.[N:18]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])=[N:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21]>O1CCCC1>[CH3:11][C:8]1([CH3:12])[C:9]2[C:5](=[CH:4][CH:3]=[C:2]([N:18]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[NH:19][C:20]([O:22][C:23]([CH3:24])([CH3:25])[CH3:26])=[O:21])[CH:10]=2)[CH2:6][CH2:7]1
Reactant: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Reactant: CC1(C)CCc2ccc(Br)cc21
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NN(C(=O)OC(C)(C)C)c1ccc2c(c1)C(C)(C)CC2
Temperature: 25 °C
Yield: 37.2 %

Procedure:
6-Bromo-1,1-dimethyl-indan (WO2005066115) 8g (4.32 g, 19.27 mmol) was dissolved in 40 mL of tetrahydrofuran and then butyllithium (15.67 mL, 1.6 mol/L, 25.05 mmol) was added dropwise at −78° C. After the reaction mixture was reacted for 40 minutes, a solution of di-tert-butyl azodicarboxylate (5.32 g, 23.12 mmol) in 30 mL of tetrahydrofuran was then added. The reaction mixture was reacted for another 3 hours at −78° C. The reaction was monitored by TLC until the disappearance of the starting materials and quenched with 5 mL of methanol. The mixture was warmed up to room temperature and filtered by silica gel. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography to obtain the title compound di-tert-butyl 1-(3,3-dimethyl-2,3-dihydro-1H-inden-5-yl)hydrazine-1,2-dicarboxylate 8h (2.70 g, yield 37.2%) as a yellow solid.
Reaction SMILES: [CH2:1]([C:5]1[N:14]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[C:28]#[N:29])=[CH:18][CH:17]=2)[C:8]2[C:9](=[O:13])[NH:10][CH:11]=[CH:12][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4].C[Sn]([N:34]=[N+:35]=[N-:36])(C)C>C1(C)C=CC=CC=1>[CH2:1]([C:5]1[N:14]([CH2:15][C:16]2[CH:17]=[CH:18][C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[C:28]3[NH:36][N:35]=[N:34][N:29]=3)=[CH:20][CH:21]=2)[C:8]2[C:9](=[O:13])[NH:10][CH:11]=[CH:12][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2cc[nH]c(=O)c2n1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: C[Sn](C)(C)N=[N+]=[N-]
Solvent: Cc1ccccc1
Product: CCCCc1nc2cc[nH]c(=O)c2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Reaction time: 96 h

Procedure:
A mixture of 800 mg of 2-butyl-3-(2'-cyano-biphenyl-4-ylmethyl)-4,5-dihydro-4-oxo-3H-imidazo[4,5-c]-pyridine, 515 mg of trimethyltin azide and 20 ml of toluene is boiled for 96 hours and evaporated. Chromatography of the residue (silica gel; methylene chloride/-methanol 9:1, then 85:15 and 80:20) yields 2-butyl-4,5-dihydro-4-oxo-3-[2'-(tetrazol-5-yl)biphenyl-4-ylmethyl]-3H-imidazo[4,5-c]pyridine , m.p.167°. The corresponding K salt is prepared therefrom in conventional manner.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:14][N:13]=[CH:12][C:11]=2[C:15](OCC)=[O:16])=[CH:6][CH:5]=1)([O-:3])=[O:2].[H-].C([Al+]CC(C)C)C(C)C.Cl>O1CCCC1>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([C:10]2[O:14][N:13]=[CH:12][C:11]=2[CH2:15][OH:16])=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: CCOC(=O)c1cnoc1-c1ccc([N+](=O)[O-])cc1
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(-c2oncc2CO)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 94.1 %

Procedure:
To a solution of ethyl 5-(4-nitrophenyl)isoxazole-4-carboxylate (9.06 g) in tetrahydrofuran (50 ml) was gently added diisobutylaluminum hydride (1.0 M tetrahydrofuran solution, 80 ml) at 0° C. and the mixture was stirred at room temperature for 30 min. The reaction mixture was poured into dilute hydrochloric acid and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated to give 5-(4-nitrophenyl)-4-isoxazolylmethanol (7.16 g, yield 94%) as colorless crystals. The crystals were recrystallized from ethyl acetate-hexane. melting point: 170–171° C.
Reaction SMILES: [OH-].[Na+].[CH3:3][C:4]([C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:17]=[CH:16][O:15][C:14]=2[C:18]([O-:20])=[O:19])=[CH:9][CH:8]=1)([CH3:6])[CH3:5]>O.O1CCCC1>[CH3:6][C:4]([C:7]1[CH:8]=[CH:9][C:10]([C:13]2[CH:17]=[CH:16][O:15][C:14]=2[C:18]([OH:20])=[O:19])=[CH:11][CH:12]=1)([CH3:3])[CH3:5]
Reactant: CC(C)(C)c1ccc(-c2ccoc2C(=O)[O-])cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)c1ccc(-c2ccoc2C(=O)O)cc1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
Sodium hydroxide (1.42 g) in water (17.75 ml) was added to a vigorously stirred solution of methyl 5-(4-(1,1-dimethylethyl)phenylfuran-2-carboxylate (4.579 g) in tetrahydrofuran (100 ml) and stirred at room temperature for 17 hours, the solvent was removed in vacuo and the residue dissolved in 10% sodium hydrogen carbonate solution (200 ml) then acidified with 2 M hydrochloric acid. The mixture was extracted with diethyl ether (3 x 200 ml), the ether washed with water and dried (MgSO4) The solvent was removed in vacuo to give 5-(4-(1,1-dimethylethyl)phenylfuran-2-carboxylic acid, m.p. 230° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:29])[NH:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][C:17]=1[F:18])[C:14](=[O:19])[N:13]([C:20]1[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=1)[CH:12]=[CH:11]2)([CH3:4])([CH3:3])[CH3:2].[C:30](=O)([O-])[O-].[Cs+].[Cs+].CI>CN(C=O)C>[C:1]([O:5][C:6](=[O:29])[N:7]([C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][C:17]=1[F:18])[C:14](=[O:19])[N:13]([C:20]1[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=1)[CH:12]=[CH:11]2)[CH3:30])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)OC(=O)Nc1cc2ccn(-c3ccc([N+](=O)[O-])cc3)c(=O)c2cc1F
Agent: [Cs+]
Solvent: CI
Solvent: CN(C)C=O
Product: CN(C(=O)OC(C)(C)C)c1cc2ccn(-c3ccc([N+](=O)[O-])cc3)c(=O)c2cc1F
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 91.4 %

Procedure:
To a solution of [7-Fluoro-2-(4-nitro-phenyl)-1-oxo-1,2-dihydro-isoquinolin-6-yl]-carbamic acid tert-butyl ester (0.36 g, 0.9 mmol) in dry DMF (9 mL) was added cesium carbonate (1.04 g, 3.19 mmol) followed by neat methyl iodide (0.064 mL, 1.03 mmol). The mixture was stirred at room temperature for 3.5 hr, extracted into ethyl acetate (150 mL), washed with water (2×50 mL) and brine (50 mL), dried over sodium sulfate, filtered, concentrated in vacuo and dried to give 0.34 g (93%) of pure [7-Fluoro-2-(4-nitro-phenyl)-1-oxo-1,2-dihydro-isoquinolin-6-yl]-methyl-carbamic acid tert-butyl ester. RP-HPLC: 5.89 min; ES-MS (M+H)+=414.0; 1H-NMR (DMSO-d6) δ (ppm): 1.33 (s, 9), 3.20 (s, 3), 6.75 (d, 1), 7.52 (d, 1), 7.80 (d, 2), 7.83 (d, 1), 7.93 (d, 1), 8.35 (d, 2).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][NH:7][CH:8]=1)([O-:3])=[O:2].Br[CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CC#N.C(Cl)Cl>[CH3:19][O:18][C:14]1[CH:13]=[C:12]([CH:17]=[CH:16][CH:15]=1)[CH2:11][CH2:10][N:6]1[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:8]=[N:7]1
Reactant: O=[N+]([O-])c1cn[nH]c1
Reactant: COc1cccc(CCBr)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClCCl
Solvent: CC#N
Product: COc1cccc(CCn2cc([N+](=O)[O-])cn2)c1
Temperature: 80 °C

Procedure:
To a solution of 4-nitro-1H-pyrazole (230 mg, 2.03 mmol) in MeCN (9.5 mL), 1-(2-bromo-ethyl)-3-methoxy-benzene (481 mg, 2.24 mmol) dissolved in MeCN (1.5 mL) and Cs2CO3 (729 mg, 2.24 mmol) was added. The resulting mixture was refluxed (80° C.) for 1.5 h, then the reaction mixture was allowed to reach rt. The mixture was diluted with DCM, filtered, the filter cake was washed with DCM and the filtrate was concentrated in vacuo to obtain 1-(3-methoxyphenethyl)-4-nitro-1H-pyrazole as a beige solid which was used in the next step without further purification. LC-MS conditions A: tR=0.86 min, [M+H]+=no ionization.