Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1](C1C=C2C(COC2=O)=CC=1)[CH3:2].[C:13]1([S:19]([CH2:22][C:23]2[C:28]([C:29]([O:31][CH2:32][CH3:33])=[O:30])=[C:27]([O:34][CH3:35])[C:26](Br)=[CH:25][CH:24]=2)(=[O:21])=[O:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(B(CC)CC)C>>[C:13]1([S:19]([CH2:22][C:23]2[C:28]([C:29]([O:31][CH2:32][CH3:33])=[O:30])=[C:27]([O:34][CH3:35])[C:26]([CH2:1][CH3:2])=[CH:25][CH:24]=2)(=[O:21])=[O:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CCc1ccc2c(c1)C(=O)OC2
Reactant: CCOC(=O)c1c(CS(=O)(=O)c2ccccc2)ccc(Br)c1OC
Agent: CCB(CC)CC
Product: CCOC(=O)c1c(CS(=O)(=O)c2ccccc2)ccc(CC)c1OC

Procedure:
Prepared by proceeding in a similar manner to Intermediate 18, starting from ethyl 6-(benzenesulphonylmethyl)-3-bromo-2-methoxybenzoate (Intermediate 61) and triethylborane.
Reaction SMILES: [Cr](O)(O)(=O)=O.S(=O)(=O)(O)O.[OH2:11].[OH:12][CH2:13][CH2:14][CH2:15][O:16][CH2:17][C:18](=[O:38])[CH2:19][C:20]([O:22][CH2:23][CH2:24][CH:25]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:21]>CC(C)=O.C(OCC)(=O)C>[C:13]([CH2:14][CH2:15][O:16][CH2:17][C:18](=[O:38])[CH2:19][C:20]([O:22][CH2:23][CH2:24][CH:25]([C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:21])([OH:11])=[O:12]
Reactant: O=C(COCCCO)CC(=O)OCCC(c1ccccc1)c1ccccc1
Reactant: O
Agent: O=[Cr](=O)(O)O
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: O=C(O)CCOCC(=O)CC(=O)OCCC(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
625 mg (6.25 mmol) of chromic acid, 0.65 ml of concentrated sulfuric acid and 2.9 ml of water were added to 1.36 g (3.66 mmol) of 3,3-diphenylpropyl 4-(3-hydroxypropoxy)-3-oxobutanoate in 17 ml of acetone, and they were stirred at room temperature for 1.5 hours. After the addition of water and extraction with ethyl acetate, the organic layer was washed with water and then saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by the silica gel chromatography (hexane/ethyl acetate=1/1) to obtain the title compound.
Reaction SMILES: [OH:1][C@H:2]1[CH2:21][CH2:20][C@@:19]2([CH3:22])[C:4](=[CH:5][CH2:6][C@@H:7]3[C@@H:18]2[CH2:17][CH2:16][C@@:15]2([CH3:23])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C:12](=[O:14])[CH3:13])[CH2:3]1.[O:24]=[O:25]>>[O:24]([C@:4]12[CH2:3][C@@H:2]([OH:1])[CH2:21][CH2:20][C@:19]1([CH3:22])[C@@H:18]1[C@H:7]([C@H:8]3[C@:15]([CH3:23])([CH2:16][CH2:17]1)[C@@H:11]([C:12](=[O:14])[CH3:13])[CH2:10][CH2:9]3)[CH:6]=[CH:5]2)[OH:25]
Reactant: CC(=O)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Reactant: O=O
Product: CC(=O)[C@H]1CC[C@H]2[C@@H]3C=C[C@@]4(OO)C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C

Procedure:
3β-Hydroxy-5-pregnen-20-one 1 reacts with singlet oxygen to yield 5α-hydroperoxy-3β-hydroxy-6-pregnene-20-one 2. This hydroperoxide undergoes a rearrangement when in chloroform solution to yield 7α-hydroperoxy-3β-hydroxy-5-pregnene-17-one, 3. Treatment of the hydroperoxide with zinc and acetic acid yields 3β,7α-dihydroxy-5-pregnen-20-one 4. ##STR27##
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH:5]([C:7]1[CH:12]=[CH:11][C:10]([N:13]2[CH:17]=[CH:16][CH:15]=[N:14]2)=[CH:9][CH:8]=1)O)[CH3:2].S(Cl)([Cl:21])=O>>[CH2:1]([O:3][C:4](=[O:18])[CH:5]([C:7]1[CH:12]=[CH:11][C:10]([N:13]2[CH:17]=[CH:16][CH:15]=[N:14]2)=[CH:9][CH:8]=1)[Cl:21])[CH3:2]
Reactant: O=S(Cl)Cl
Reactant: CCOC(=O)C(O)c1ccc(-n2cccn2)cc1
Product: CCOC(=O)C(Cl)c1ccc(-n2cccn2)cc1

Procedure:
The starting compound is obtained in the following manner: 2.46 g (10 mmoles) of 4-(pyrazol-1-yl) mandelic acid ethyl ester and 10 ml of thionyl chloride are heated to 40° C. for 10 minutes, the excess thionyl chloride is distilled off. α-chloro-4-(pyrazol-1-yl) phenylacetic acid ethyl ester (oil) is obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH2:11][CH2:12][N:13]([CH3:15])[CH2:14][C:5]=3[C:4]=2[CH:3]=1.[CH3:16][C:17]1[C:18]([NH:25][C:26](=[O:28])[CH3:27])=[N:19][CH:20]=[C:21]([CH:23]=[CH2:24])[CH:22]=1.[OH-].[K+]>CN1C(=O)CCC1>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:24][CH2:23][C:21]3[CH:22]=[C:17]([CH3:16])[C:18]([NH:25][C:26](=[O:28])[CH3:27])=[N:19][CH:20]=3)[C:6]3[CH2:11][CH2:12][N:13]([CH3:15])[CH2:14][C:5]=3[C:4]=2[CH:3]=1
Reactant: C=Cc1cnc(NC(C)=O)c(C)c1
Reactant: CN1CCc2[nH]c3ccc(Cl)cc3c2C1
Agent: [K+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Product: CC(=O)Nc1ncc(CCn2c3c(c4cc(Cl)ccc42)CN(C)CC3)cc1C

Procedure:
The title compound is prepared from a mixture of 8-chloro-2,3,4,5-tetrahydro-2-methyl-1H-pyrido[4,3-b]indole, N-(3-methyl-5-vinylpyridin-2-yl)acetamide and KOH (5-7 equiv) in NMP at a temperature ranging between 25 deg C. to 100 deg C. The product obtained is isolated by preparative HPLC.
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([N:15]1[CH2:20][C:19](=[O:21])[N:18]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[Cl:28])[CH2:17][C:16]1([CH3:30])[CH3:29])=O)(C)(C)C>C(Cl)Cl>[Cl:28][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[N:18]1[CH2:17][C:16]([CH3:29])([CH3:30])[NH:15][CH2:20][C:19]1=[O:21]
Reactant: CC(C)(C)OC(=O)N1CC(=O)N(c2ccccc2Cl)CC1(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC1(C)CN(c2ccccc2Cl)C(=O)CN1
Reaction time: 0.5 h
Yield: 98.5 %

Procedure:
7.0 ml of trifluoroacetic acid (91 mmol) was added to a solution of 3.07 g of 4-(2-chlorophenyl)-2,2-dimethyl-5-oxopiperazine-1-carboxylic acid t-butyl ester obtained in Example (1j) (9.1 mmol) in methylene chloride (14 ml) at room temperature, and the mixture was stirred at the same temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure. A saturated sodium bicarbonate aqueous solution was added, followed by extraction with methylene chloride. Then, the organic layer was dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent:methylene chloride/methanol=10/1) to obtain 2.14 g of the title compound (yield: 98%).
Reaction SMILES: [O:1]1[CH2:5][CH2:4][NH:3][C:2]1=[O:6].ClC(Cl)(Cl)[C:9]([O:11][CH2:12][CH3:13])=[O:10]>CN(C)C1C=CN=CC=1>[C:9]([N:3]1[CH2:4][CH2:5][O:1][C:2]1=[O:6])([O:11][CH2:12][CH3:13])=[O:10]
Reactant: O=C1NCCO1
Reactant: CCOC(=O)C(Cl)(Cl)Cl
Agent: CN(C)c1ccncc1
Product: CCOC(=O)N1CCOC1=O
Temperature: 120 °C
Yield: 88.7 %

Procedure:
A mixture of 2-oxazolidinone (9.0 g, 0.10 mole) and 25 ml (0.18 mole) of ethyl trichloroacetate were heated to 120° C. in an oil bath. A small amount (ca 50 mg) of 4-dimethylaminopyridine was added to the stirred solution, during which time vigorous reflux began. After removing most of the chloroform by a Dean-Stark trap, the dark solution was allowed to cool to room temperature. Bulb to bulb distillation at 105° C.-120° C. (0.05 mm) yielded 14.1 g (0.0887 mole, 89 percent yield) of the product as a clear liquid which solidified to a colorless solid (mp 40° C.-44° C.) on standing at room temperature. Spectral data confirmed its structure.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:8][NH:9][CH2:10][CH2:11][OH:12]>>[CH3:8][N:9]([CH2:10][CH2:11][OH:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: CNCCO
Reactant: Clc1ccccn1
Product: CN(CCO)c1ccccn1

Procedure:
The reaction of 2-chloropyridine with 2-(N-methyl amino)ethanol provides 2-(N-methyl-N-(2-pyridyl)amino)ethanol (II), which on coupling reaction with 4-fluorobenzaldehyde (III) in an aprotic polar solvent with an alkali metal hydroxide or an alkali metal alkoxide as base yields 4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzaldehyde (IV) with an 88% yield (Reaction I).
Reaction SMILES: [C:1]1([NH:7][C:8]([C:10]2[N:11]=[C:12]3[CH:17]=[CH:16][C:15]([CH:18]=C)=[CH:14][N:13]3[CH:20]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.I([O-])(=O)(=O)=[O:22].[Na+].C(O)(C)(C)C.O>C1COCC1.[Os](=O)(=O)(=O)=O.C(OCC)(=O)C>[CH:18]([C:15]1[CH:16]=[CH:17][C:12]2[N:13]([CH:20]=[C:10]([C:8]([NH:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[O:9])[N:11]=2)[CH:14]=1)=[O:22]
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: C=Cc1ccc2nc(C(=O)Nc3ccccc3)cn2c1
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: O=Cc1ccc2nc(C(=O)Nc3ccccc3)cn2c1
Temperature: 20 °C
Reaction time: 20 h
Yield: 66.2 %

Procedure:
A suspension of 150 mg of N-phenyl-6-vinylimidazo[1,2-a]pyridine-2-carboxamide, 232 μl of osmium tetroxide and 167.5 mg of sodium periodate in a mixture of 6 ml of THF, 3 ml of t-butanol and 3 ml of water is stirred at 20° C. for 20 hours and then for a further 48 hours while adding, on 4 occasions, an additional 100 μl of osmium tetroxide and 80 mg of sodium periodate. The reaction mixture is poured into 50 ml of water and extraction is carried out twice with 50 ml of ethyl acetate. The combined organic phases are washed with a saturated aqueous sodium chloride solution, separated by settling, dried and concentrated to dryness under reduced pressure. The residue is chromatographed on silica, elution being carried out with a mixture of cyclohexane and ethyl acetate (gradient from 0 to 50%), to give 100 mg of 6-formyl-N-phenylimidazo[1,2-a]pyridine-2-carboxamide in the form of a white solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Si:8]([CH3:11])([CH3:10])[CH3:9])[CH:3]=1.[Li]CCCC.CN([CH:20]=[O:21])C.Cl>CCOCC.O>[CH3:9][Si:8]([CH3:11])([CH3:10])[C:4]1[CH:3]=[C:2]([CH:7]=[CH:6][CH:5]=1)[CH:20]=[O:21]
Reactant: CN(C)C=O
Reactant: C[Si](C)(C)c1cccc(Br)c1
Agent: Cl
Agent: [Li]CCCC
Solvent: O
Solvent: CCOCC
Product: C[Si](C)(C)c1cccc(C=O)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 46.6 %

Procedure:
To a solution of 5 g (21.89 mmol) of 1-bromo-3-trimethylsilylbenzene prepared according to the protocol described in the preceding step, in 40 mL of anhydrous Et2O, cooled to 0° C. and maintained under a nitrogen atmosphere, are added dropwise, with stirring and over 30 minutes, 16.36 mL (26.18 mmol) of BuLi (1.6M/hexane). Stirring is continued at 0° C. for a further 30 minutes, and the mixture is then maintained at room temperature for 90 minutes. 2.69 mL (34.91 mmol) of DMF, diluted with 17 mL of anhydrous Et2O, are then introduced into the reaction mixture. After stirring for 3 hours at room temperature, the reaction mixture is hydrolysed at 0° C. by successive addition of 10 mL of concentrated HCl solution and 100 mL of water. The product is extracted with 3×50 mL of CH2Cl2. The combined organic phases are washed with 100 mL of water, dried over Na2SO4, filtered and evaporated under reduced pressure. The crude reaction product is purified by flash chromatography on a column of silica gel, eluting with a gradient of from 10 to 20% of CH2Cl2 in heptane to give 1.82 g of the expected 3-trimethylsilylbenzaldehyde in the form of a yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[C:3]=1[C:4]([N:6]=[C:7]=[O:8])=[O:5].[CH:14]1([C:17](=[N:25][O:26][CH2:27][C:28]2[CH:34]=[CH:33][C:31]([NH2:32])=[CH:30][CH:29]=2)[C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)[CH2:16][CH2:15]1>C(OCC)C>[F:1][C:2]1[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[C:3]=1[C:4]([NH:6][C:7]([NH:32][C:31]1[CH:33]=[CH:34][C:28]([CH2:27][O:26][N:25]=[C:17]([CH:14]2[CH2:16][CH2:15]2)[C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)=[CH:29][CH:30]=1)=[O:8])=[O:5]
Reactant: Nc1ccc(CON=C(c2ccc(Cl)cc2)C2CC2)cc1
Reactant: O=C=NC(=O)c1c(F)cccc1F
Solvent: CCOCC
Product: O=C(NC(=O)c1c(F)cccc1F)Nc1ccc(CON=C(c2ccc(Cl)cc2)C2CC2)cc1
Reaction time: 3 h

Procedure:
36.6 g of 2,6-difluorobenzoylisocyanate in 50 ml of dry diethyl ether were added to a solution of 59.0 g 4-(α-cyclopropyl-4-chlorobenzylideneaminooxymethyl)aniline in 700 ml of dry diethylether with external cooling at 0°-10° C. After stirring for 3 hours at 0°-10° C. the formed precipitate was sucked off, washed with diethyl ether, and dried. The product obtained in a yield of 76.0 g was chromatographed over silica, chloroform being used as an eluent. The desired product was isolated in a yield of 60,7 g having a purity of at least 95% (PMR). The product obtained had a melting range of 145°-175° C. and comprised the syn- and anti-form in approximately equal amounts. In another experiment the desired product was obtained as a mixture of the syn- and anti-form in a ratio of 85:15; melting point 187°-191° C.
Reaction SMILES: [CH2:1]([N:3]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[C:5]([C:17]2[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][CH:18]=2)=[N:4]1)[CH3:2].Br[C:27]1[CH:32]=[CH:31][N:30]=[C:29]2[NH:33][CH:34]=[CH:35][C:28]=12.C(=O)([O-])[O-].[K+].[K+]>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.O1CCOCC1>[CH2:1]([N:3]1[CH:7]=[C:6]([C:27]2[CH:32]=[CH:31][N:30]=[C:29]3[NH:33][CH:34]=[CH:35][C:28]=23)[C:5]([C:17]2[CH:18]=[CH:19][C:20]([N+:23]([O-:25])=[O:24])=[CH:21][CH:22]=2)=[N:4]1)[CH3:2]
Reactant: Brc1ccnc2[nH]ccc12
Reactant: CCn1cc(B2OC(C)(C)C(C)(C)O2)c(-c2ccc([N+](=O)[O-])cc2)n1
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: [K+]
Solvent: C1COCCO1
Product: CCn1cc(-c2ccnc3[nH]ccc23)c(-c2ccc([N+](=O)[O-])cc2)n1
Temperature: 25 °C
Yield: 80 %

Procedure:
A solution of 1-ethyl-3-(4-nitrophenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (7.5 mmol), 4-bromo-1H-pyrrolo[2,3-b]pyridine (Ref. Org. Lett. 5(26), 5023-5024, 2003) (6.3 mmol), and tetrakis(triphenylphosphine)palladium(0) (0.25 mmol) in a 1:1 solution of 1,4-dioxane (12 mL):2M potassium carbonate (12 mL) was stirred for 18 h at 100° C. in a sealed tube. Upon cooling to room temperature, product precipitated out of solution which was filtered and dried to provide the title product as a light yellow powder (80%). ESMS [M+H]+: 334.2
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([CH:10]=[O:11])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[H-].[Na+].CI.[C:16](OCC)(=O)C>CN(C=O)C>[CH3:16][N:1]1[C:9]2[C:4](=[CH:5][C:6]([CH:10]=[O:11])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: CCOC(C)=O
Reactant: O=Cc1ccc2[nH]ccc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: CN(C)C=O
Product: Cn1ccc2cc(C=O)ccc21
Reaction time: 0.5 h
Yield: 91 %

Procedure:
To a solution of indole-5-carbaldehyde (1.0 g, 6.9 mmol) in DMF (15 mL) was added sodium hydride (303 mg of 60% dispersion in oil, 7.59 mmol) in 3 portions. The mixture was stirred for 30 mins. Methyl iodide (1.96 g, 13.8 mmol) was then added and the mixture was stirred overnight. Ethyl acetate (200 mL) was added and solution was washed with H2O (3×20 mL) and brine (25 mL) dried over MgSO4 and concentrated to afford N-methylindole-5-carboxaldehyde as an orange oil (1.0 g, 91%). 1H NMR (200 MHz, CDCl3) δ 10.05 (s, 1H), 8.09 (s, 1H), 7.90-7.80 (m, 1H), 7.35-7.15 (m, 2H), 6.85-6.80 (m, 1H), 3.95 (s, 3H).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][NH2:14].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[CH:48]([C:51]1[CH:56]=[CH:55][C:54]([N:57]2[CH2:61][CH2:60][CH:59]([C:62](O)=[O:63])[C:58]2=[O:65])=[CH:53][CH:52]=1)([CH3:50])[CH3:49]>CN(C=O)C>[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][NH:14][C:62]([CH:59]1[CH2:60][CH2:61][N:57]([C:54]2[CH:55]=[CH:56][C:51]([CH:48]([CH3:49])[CH3:50])=[CH:52][CH:53]=2)[C:58]1=[O:65])=[O:63]
Reactant: CC(C)c1ccc(N2CCC(C(=O)O)C2=O)cc1
Reactant: NCCc1c[nH]c2ccc(Cl)cc12
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Product: CC(C)c1ccc(N2CCC(C(=O)NCCc3c[nH]c4ccc(Cl)cc34)C2=O)cc1
Yield: 32.3 %

Procedure:
A mixture of 2-(5-chloro-1H-indol-3-yl)ethanamine hydrochloride (0.036 g; 0.146 mmol), PyBOP (0.113 g; 0.219 mmol), N,N-diisoprpylethylamine (0.075 mL; 0.437 mmol) and 1-(4-isopropylphenyl)-2-oxopyrrolidine-3-carboxylic acid (0.100 g; 0.425 mmol) was stirred in DMF (3 mL) overnight. The reaction mixture was partitioned between ethyl acetate and sodium hydrogen sulfate, the organic layer was washed with sodium carbonate, brine, dried and concentrated under reduced pressure. The crude mixture was purified flash chromatography on silica (eluent 20 to 100% ethyl acetate in heptane) to yield 0.020 g (32%) of the title compound as a white solid.
Reaction SMILES: C[O:2][C:3]([CH:5]1[CH2:10][CH2:9][CH:8]([NH:11][C:12]2[CH:30]=[CH:29][C:28]([N+:31]([O-:33])=[O:32])=[CH:27][C:13]=2[C:14]([NH:16][CH2:17][C:18]2[CH:26]=[CH:25][C:21]3[O:22][CH2:23][O:24][C:20]=3[CH:19]=2)=[O:15])[CH2:7][CH2:6]1)=[O:4].CO.[OH-].[Na+].Cl>O1CCCC1>[C:3]([CH:5]1[CH2:6][CH2:7][CH:8]([NH:11][C:12]2[CH:30]=[CH:29][C:28]([N+:31]([O-:33])=[O:32])=[CH:27][C:13]=2[C:14]([NH:16][CH2:17][C:18]2[CH:26]=[CH:25][C:21]3[O:22][CH2:23][O:24][C:20]=3[CH:19]=2)=[O:15])[CH2:9][CH2:10]1)([OH:4])=[O:2]
Reactant: COC(=O)C1CCC(Nc2ccc([N+](=O)[O-])cc2C(=O)NCc2ccc3c(c2)OCO3)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(NCc1ccc2c(c1)OCO2)c1cc([N+](=O)[O-])ccc1NC1CCC(C(=O)O)CC1
Temperature: 60 °C
Yield: 97 %

Procedure:
A mixture of 2-[4-(methoxycarbonyl)cyclohexylamino]-5-nitro-N-(1,3-benzodioxol-5-ylmethyl)benzamide (269 mg), methanol (10 mL), tetrahydrofuran (10 mL) and 1N-sodium hydroxide solution (5 mL) was stirred for an hour at 60° C. The mixture was acidified with 1N-hydrochloric acid to pH 4 and the organic solvent was removed by evaporation. The aqueous layer was diluted with water and extracted with chloroform. The extract was washed with brine, dried over magnesium sulfate and evaporated in vacuo. The residue was triturated with diisopropyl ether to give 2-(4-carboxycyclohexylamino)-5-nitro-N-(1,3-benzodioxol-5-ylmethyl)benzamide as yellow powders (253 mg).
Reaction SMILES: [CH2:1]([C:5]1[NH:6][C:7]2[CH:12]=[CH:11][N:10]=[CH:9][C:8]=2[N:13]=1)[CH2:2][CH2:3][CH3:4].Br[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[C:23]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])=[CH:24][CH:25]=[CH:26][CH:27]=2)=[CH:18][CH:17]=1.[H-].[Na+]>CO.CCOC(C)=O>[CH2:1]([C:5]1([CH2:5][CH2:1][CH2:2][CH3:3])[N:13]([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]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])=[CH:18][CH:17]=2)[C:8]2[CH:9]=[N:10][CH:11]=[CH:12][C:7]=2[NH:6]1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2cnccc2[nH]1
Reactant: CC(C)(C)OC(=O)c1ccccc1-c1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Product: CCCCC1(CCCC)Nc2ccncc2N1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1

Procedure:
2-butyl-3-[(2'-tert-butoxycarbonylbiphen-4-yl)methyl]-2-butyl-3H-imidazo[4,5-c]pyridine was prepared according to the procedure described in Example 1, Part A from 2-butylimidazo[4,5-c]pyridine (220 mg, 1.25 mmol), tert-butyl 4'-bromomethylbiphenyl-2-carboxylate (414 mg, 1.19 mmol), and NaH (1.88 mmol). Yield: 25 mg (5%) thick oil; Rf: 0.45 (SiO2 tlc, 1% MeOH/EtOAc); 1H NMR (250 MHz, CDCl3) δ 8.66 (s 1H), 8.42 (d, 1H, J=5.6 Hz), 7.78 (dd, 1H, J=7.5 1.4 Hz), 7.66 (d, 1H, J=5.5 Hz), 7.52-7.35 (m, 2H) 7.31-7.24 (m, 3H), 7.10 (d, 2H, J=8 Hz), 5.46 (s, 2H), 2.92 (t, 2H, J=7.5 Hz), 1.97- 1.80 (m, 2H), 1.55-1.39 (m, 2H), 1.21 (s, 9H), 0.96 (t, 3H, J=7.3 Hz).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[CH:5][C:6]2[N:15]3[C:11](=[N:12][N:13]=[C:14]3[C@H:16]3[CH2:21][CH2:20][C@H:19]([O:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH2:18][CH2:17]3)[CH2:10][NH:9][CH2:8][C:7]=2[CH:29]=1.C(N(CC)CC)C.[CH3:37][N:38]([CH3:43])[CH2:39][C:40](O)=[O:41].Cl.CN(C)CCCN=C=NCC>O1CCCC1>[Cl:2][C:3]1[CH:4]=[CH:5][C:6]2[N:15]3[C:11](=[N:12][N:13]=[C:14]3[C@H:16]3[CH2:17][CH2:18][C@H:19]([O:22][C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=4)[CH2:20][CH2:21]3)[CH2:10][N:9]([C:40](=[O:41])[CH2:39][N:38]([CH3:43])[CH3:37])[CH2:8][C:7]=2[CH:29]=1
Reactant: Clc1ccc2c(c1)CNCc1nnc([C@H]3CC[C@H](Oc4ccccc4)CC3)n1-2
Reactant: CN(C)CC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CN(C)CC(=O)N1Cc2cc(Cl)ccc2-n2c(nnc2[C@H]2CC[C@H](Oc3ccccc3)CC2)C1
Reaction time: 0.17 h

Procedure:
To a mixture of trans-8-chloro-1-(4-phenoxy-cyclohexyl)-5,6-dihydro-4H-2,3,5,10b-tetraaza-benzoazulene hydrochloride (0.179 g, 0.41 mmol) in tetrahydrofuran (2 ml) was added triethylamine (0.058 ml, 0.41 mmol). The suspension was stirred for 10 minutes. The ammonium salts were removed by filtration. The filtrate was concentrated in vacuo. The residue was redissolved in tetrahydrofuran (3 ml) followed by consecutive addition of N,N-dimethylglycine (0.056 g, 0.54 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.104 g, 0.54 mmol. Stirring for 18 h at 50° C. was followed by partitioning between water (50 ml) and dichloromethane (50 ml). The organic layer was separated. The aqueous layer was extracted with one 50-ml portion of dichloromethane. The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo. Purification by flash-chromatography with n-heptane/ethyl acetate as eluent gave the title compound (0.057 g, 28%) as white solid.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([C:13]([C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH2:23][N:24]3[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]3)=[CH:17][CH:16]=1)=[O:14])=[C:8]([C:30]1[CH:35]=[CH:34][C:33]([F:36])=[C:32]([F:37])[C:31]=1[F:38])[CH:7]=[CH:6]2.B(Br)(Br)Br.C(=O)(O)[O-].[Na+].C(Cl)(Cl)Cl.C(O)(C)C>C(Cl)Cl>[OH:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([C:13]([C:15]1[CH:16]=[CH:17][C:18]([O:21][CH2:22][CH2:23][N:24]3[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]3)=[CH:19][CH:20]=1)=[O:14])=[C:8]([C:30]1[CH:35]=[CH:34][C:33]([F:36])=[C:32]([F:37])[C:31]=1[F:38])[CH:7]=[CH:6]2
Reactant: COc1ccc2c(C(=O)c3ccc(OCCN4CCCCC4)cc3)c(-c3ccc(F)c(F)c3F)ccc2c1
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: O=C(c1ccc(OCCN2CCCCC2)cc1)c1c(-c2ccc(F)c(F)c2F)ccc2cc(O)ccc12
Temperature: 0 °C
Reaction time: 1 h
Yield: 74.3 %

Procedure:
Dissolve [6-methoxy-2-(2,3,4-trifluoro-phenyl)-naphthalen-1-yl]-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-methanone (880 mg, 1.69 mmol) in 100 mL methylene chloride and chill in ice. Add 4.0 mL of neat boron tribromide with swirling and stir in the ice bath for 30 minutes. Allow the mixture to come to room temperature and stir for an additional 1 hour. Carefully pour the mixture into a two-phase system consisting of saturated sodium bicarbonate solution and a 3/1 mixture of chloroform/isopropanol. Separate the organic layer, dry over 3 Å molecular sieves and evaporate to give 800 mg of slightly impure product. Purify on a silica gel column eluting with 3% methanol/methylene chloride to give 635 mg (74%) of the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]([C:8]2[O:9][C:10]3[CH:22]=[CH:21][CH:20]=[CH:19][C:11]=3[C:12]=2[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:7])=[CH:4][CH:3]=1.[CH2:25]([N:27]([CH2:31][CH3:32])[CH2:28][CH2:29]Cl)[CH3:26].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:25]([N:27]([CH2:31][CH3:32])[CH2:28][CH2:29][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([C:8]2[O:9][C:10]3[CH:22]=[CH:21][CH:20]=[CH:19][C:11]=3[C:12]=2[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:7])=[CH:23][CH:24]=1)[CH3:26]
Reactant: O=C(c1ccc(O)cc1)c1oc2ccccc2c1-c1ccccc1
Reactant: CCN(CC)CCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCN(CC)CCOc1ccc(C(=O)c2oc3ccccc3c2-c2ccccc2)cc1

Procedure:
(0.005 mol.) of 2-(4-hydroxybenzoyl)-3-phenylbenzofuran with 2.7 g. (0.02 mol.) of 2-diethylaminoethyl chloride in 50 ml. of acetone containing 2.7 g. (0.02 mol.) of potassium carbonate for 3 hours according to the procedure described in Example 1 gives the title compound.