Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[CH2:7][NH:6][CH2:5][CH2:4][N:3]1[C@@H:8]1[CH2:17][CH2:16][C:15]2[CH:14]=[C:13]([C:18]#[N:19])[CH:12]=[CH:11][C:10]=2[CH2:9]1.O=[C:21]1[CH2:30][CH2:29][C:28]2[CH:27]=[C:26]([C:31]#[N:32])[CH:25]=[CH:24][C:23]=2[CH2:22]1>>[O:1]=[C:2]1[CH2:7][N:6]([CH:21]2[CH2:30][CH2:29][C:28]3[CH:27]=[C:26]([C:31]#[N:32])[CH:25]=[CH:24][C:23]=3[CH2:22]2)[CH2:5][CH2:4][N:3]1[C@@H:8]1[CH2:17][CH2:16][C:15]2[CH:14]=[C:13]([C:18]#[N:19])[CH:12]=[CH:11][C:10]=2[CH2:9]1
Reactant: N#Cc1ccc2c(c1)CC[C@@H](N1CCNCC1=O)C2
Reactant: N#Cc1ccc2c(c1)CCC(=O)C2
Product: N#Cc1ccc2c(c1)CCC(N1CCN([C@@H]3CCc4cc(C#N)ccc4C3)C(=O)C1)C2

Procedure:
The title compound was prepared from (6R)-6-(2-Oxopiperazin-1-yl)-5,6,7,8-tetrahydronaphthalene-2-carbonitrile and 6-Oxo-5,6,7,8-tetrahydronaphthalene-2-carbonitrile following essentially the same procedure as Example 6. The product was purified by mass-directed reverse phase HPLC (AcCN-Water with 0.1% TFA). LC-MS (IE, m/z): 411 [M+1]+.
Reaction SMILES: C=[C:2]1[CH2:7][C:6]2([CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH2:8]2)[O:5][CH2:4][CH2:3]1.I([O-])(=O)(=O)=[O:21].[Na+].O>O1CCOCC1.O.[Os](=O)(=O)(=O)=O.O>[O:21]=[C:2]1[CH2:7][C:6]2([CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH2:8]2)[O:5][CH2:4][CH2:3]1
Reactant: C=C1CCOC2(CCN(C(=O)OC(C)(C)C)CC2)C1
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC2(CC1)CC(=O)CCO2
Temperature: 25 °C
Reaction time: 2 h
Yield: 59.5 %

Procedure:
To a solution of Compound 29a (1.6 g, 5.99 mmol) in a mixture of dioxane-water (32.9 mL and 11 mL respectively) under stirring at r.t. was added a 4% sol. of osmium tetroxide in water (0.762 μL, 0.125 mmol). After 2 h, was added portionwise milled sodium metaperiodate (2.56 g, 12 mmol) affording a suspension that tended to become clear gray from brownish. After 4 h H2O was added, extracting with EtOAc, washing with H2O, drying over Na2SO4, evaporating the solvent to dryness. The residual tawny semi-solid was purified by means of automated flash chromatography (SP1®TM-Biotage; Petroleum Ether-EtOAc 7:3) to give 0.96 g of the title compound as a grey solid. Yield: 59.5%
Reaction SMILES: [CH:1]1([C:7]2[CH:8]=[CH:9][C:10]([O:13]C)=[N:11][CH:12]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Br[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=1>>[Cl:23][C:20]1[CH:21]=[CH:22][C:17]([CH2:16][N:11]2[CH:12]=[C:7]([CH:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)[CH:8]=[CH:9][C:10]2=[O:13])=[CH:18][CH:19]=1
Reactant: COc1ccc(C2CCCCC2)cn1
Reactant: Clc1ccc(CBr)cc1
Product: O=c1ccc(C2CCCCC2)cn1Cc1ccc(Cl)cc1
Yield: 66.7 %

Procedure:
According to Scheme 26 Step 4: The title compound was prepared according to Example 6 Step 2, from 5-cyclohexyl-2-methoxypyridine (1 eq, 0.30 mmol. 57 mg) and 1-(bromomethyl)-4-chlorobenzene (1.5 eq, 0.44 mmol, 92 mg), then purified by chromatography over silicagel (AIT Flashsmart prepacked column 5 g SiO2, CH2Cl2/MeOH 98/2) then recrystallized in pentane/diisopropyl ether, yielding the title compound (0.20 mmol, 0.09 g, 68%) as a beige solid.
Reaction SMILES: C(O)(=O)C.C(O)(=O)C.O[CH2:10][C:11]1[CH:12]2[CH:20]=[CH:19][C:15]([CH3:21])([C:16]=1[CH2:17]O)[C:14](=[O:22])[C:13]2([CH3:24])[CH3:23]>[Pd].C(O)(C)C>[CH3:21][C:15]12[CH2:19][CH2:20][CH:12]([C:11]([CH3:10])=[C:16]1[CH3:17])[C:13]([CH3:24])([CH3:23])[C:14]2=[O:22]
Reactant: CC12C=CC(C(CO)=C1CO)C(C)(C)C2=O
Agent: [Pd]
Solvent: CC(C)O
Solvent: CC(=O)O
Product: CC1=C(C)C2(C)CCC1C(C)(C)C2=O
Temperature: 80 °C
Reaction time: 0.07 h
Yield: 119.9 %

Procedure:
To a 450 ml Parr mini-pressure reactor is charged 15 grams of 5,6-bis(hydroxymethyl)-1,3,3-trimethylbicyclo[2.2.2]-octa-5,7-dien-2-one diacetate produced according to Example IV, 60 ml of isopropyl alcohol and 0.3 grams of 10% palladium on charcoal. After flushing with nitrogen and hydrogen, the hydrogen is charged to a pressure of 195 psig while maintaining the reaction mass temperature at 22°-27° C. Within four minutes, the pressure drops to 140 psig and holds steady for six minutes. Hydrogen is again charged to 195 psig and the temperature is gradually raised to 80° C. At 80° C. the pressure beings to drop. The temperature is raised to 85° C. and maintained at 85° C. until the pressure holds constant at 102 psig (1.7 hours). After cooling to room temperature, the reaction mass is filtered and the toluene is removed in vacuo to yield 10.1 grams of 1,3,3,5,6-pentamethyl-bicyclo[2.2.2]octa-5-en-2-one. This material is identical to that prepared from 2,6,6-trimethylcyclohexa-2,4-dien-1-one and 2-butyne according to Examples I and II, supra.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[CH3:16][C:17]1[CH:18]=[C:19]([OH:24])[CH:20]=[CH:21][C:22]=1[CH3:23].[OH-].[Na+]>COCCOCCOC>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH3:15])[N:5]=[CH:4][CH:3]=[C:2]2[O:24][C:19]1[CH:20]=[CH:21][C:22]([CH3:23])=[C:17]([CH3:16])[CH:18]=1
Reactant: Cc1ccc(O)cc1C
Reactant: COc1cc2nccc(Cl)c2cc1OC
Agent: [Na+]
Agent: [OH-]
Solvent: COCCOCCOC
Product: COc1cc2nccc(Oc3ccc(C)c(C)c3)c2cc1OC
Temperature: 180 °C
Reaction time: 1.5 h
Yield: 57.8 %

Procedure:
4-Chloro-6,7-dimethoxyquinoline (200 mg) and 3,4-dimethylphenol (274 mg) were suspended in diethylene glycol dimethyl ether (0.1 ml), and the suspension was stirred at 180° C. for 1.5 hr. The reaction solution was cooled to room temperature, an aqueous sodium hydroxide solution was added to the reaction solution, and the mixture was extracted with chloroform. The chloroform layer was then washed with saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by column chromatography on silica gel using acetone-chloroform to give 6,7-dimethoxy-4-(3,4-dimethylphenoxy)quinoline (160 mg, yield 58%).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][N:3]=1.[Br:12]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N.CCCCCC>C(Cl)(Cl)(Cl)Cl>[Br:12][CH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][N:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1ccc(C)nc1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: CCCCCC
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1ccc(CBr)nc1
Temperature: 25 °C
Yield: 35.5 %

Procedure:
To a solution of methyl 6-methylnicotinate (6.3 g) in carbon tetrachloride (100 mL) is added successively N-bromosuccinimide (8.9 g) and 2,2′-azobisisobutyronitrile (342 mg), and the mixture is refluxed under heating for 6 hours. After cooling to room temperature, to the reaction mixture is added n-hexane (300 mL) and the insoluble materials are removed by filtration. The filtrate is concentrated in vacuo and the resultant crude product is purified by column chromatography on silica gel (Solvent; n-hexane:ethyl acetate=10:1) and stirred in n-hexane to give methyl 6-(bromomethyl)nicotinate (3.4 g, yield; 35%) as colorless crystals.
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:9][C:10]1[N:11]=[C:12](Cl)[C:13]2[CH:18]=[C:17]([CH3:19])[S:16][C:14]=2[N:15]=1>>[Cl:9][C:10]1[N:11]=[C:12]([NH:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:13]2[CH:18]=[C:17]([CH3:19])[S:16][C:14]=2[N:15]=1
Reactant: Cc1cc2c(Cl)nc(Cl)nc2s1
Reactant: NCc1ccccc1
Product: Cc1cc2c(NCc3ccccc3)nc(Cl)nc2s1

Procedure:
Following the procedure of Example 1, the reaction of benzylamine with 2,4-dichloro-6-methyl-thieno-[2,3-d]-pyrimidine yields 2-chloro-6-methyl-4-benzylamino-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [OH-].[Li+].[CH2:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][CH2:5][N:4]1[C:13](=[O:34])[CH2:14][CH2:15][C:16]1[CH:33]=[CH:32][C:19]([O:20][CH2:21][C:22]2[CH:31]=[CH:30][CH:29]=[CH:28][C:23]=2[C:24]([O:26]C)=[O:25])=[CH:18][CH:17]=1>O.C1COCC1>[CH2:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][CH2:5][N:4]1[C:13](=[O:34])[CH2:14][CH2:15][C:16]1[CH:33]=[CH:32][C:19]([O:20][CH2:21][C:22]2[CH:31]=[CH:30][CH:29]=[CH:28][C:23]=2[C:24]([OH:26])=[O:25])=[CH:18][CH:17]=1
Reactant: COC(=O)c1ccccc1COc1ccc(CCC(=O)N2CCc3ccccc3C2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1ccccc1COc1ccc(CCC(=O)N2CCc3ccccc3C2)cc1
Yield: 89.1 %

Procedure:
Lithium hydroxide (14.4 mg, 0.6 mmol) dissolved in water (1 ml) was added into 70377 methyl 2-({4-[3-(3,4-dihydroisoquinolin-2(1H)-yl)-3-oxopropyl]phenoxy}methyl)benzoate (129 mg, 0.3 mmol) in THF (2 ml). The mixture was put in a microwave oven (Smith Synthesizer) and irradiated at 150° C. for 7 minutes and then evaporated to remove THF. The residue was acidified with 1% hydrochloric acid, pH˜5, and extracted with ethyl acetate (×2). The extracts were combined and dried (magnesium sulphate) and evaporated. Chromatography of the residue on a column (ISOLUTE® SI, 2 g/6 ml) using DCM, MeOH/DCM (1:99) as eluant gave 111 mg the desired product yield 89%.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]([N:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:12])[C:5]([OH:7])=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)CC)(C)C.[Br:49][C:50]1[CH:51]=[C:52]([CH2:56][CH:57]([NH2:68])[C:58]2[NH:62][C:61]3[CH:63]=[CH:64][C:65]([Cl:67])=[CH:66][C:60]=3[N:59]=2)[CH:53]=[CH:54][CH:55]=1.BrCl>O1CCCC1.ClCCl.C(O)C>[Br:49][C:50]1[CH:51]=[C:52]([CH2:56][CH:57]([NH:68][C:5](=[O:7])[C:4]2[CH:8]=[CH:9][C:10]([C:11]([N:13]3[CH2:17][CH2:16][CH2:15][CH2:14]3)=[O:12])=[C:2]([CH3:1])[CH:3]=2)[C:58]2[NH:62][C:61]3[CH:63]=[CH:64][C:65]([Cl:67])=[CH:66][C:60]=3[N:59]=2)[CH:53]=[CH:54][CH:55]=1
Reactant: NC(Cc1cccc(Br)c1)c1nc2cc(Cl)ccc2[nH]1
Reactant: Cc1cc(C(=O)O)ccc1C(=O)N1CCCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: ClBr
Agent: F[B-](F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1cc(C(=O)NC(Cc2cccc(Br)c2)c2nc3cc(Cl)ccc3[nH]2)ccc1C(=O)N1CCCC1

Procedure:
Prepared analogously to Example 1g from 3-methyl-4-(pyrrolidin-1-ylcarbonyl)benzoic acid, TBTU, diisopropylethylamine, and rac.-2-(3-bromophenyl)-1-(5-chloro-1H-benzimidazol-2-yl)ethylamine in tetrahydrofuran. Yield: %; Rf value: 0.52 (silica gel: dichloromethane/ethanol=9:1); C28H26BrClN4O2 (565.90); mass spectrum: (M+H)+=565/567/569 (bromo-chlorine isotope).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:20][CH3:21])=[C:6]([C:8]([CH3:19])([CH3:18])[CH2:9][C:10]([C:14]([F:17])([F:16])[F:15])([OH:13])CO)[CH:7]=1.I([O-])(=O)(=O)=O.[Na+]>CO.CCOCC.CCCCCC>[F:17][C:14]([F:15])([F:16])[C:10](=[O:13])[CH2:9][C:8]([C:6]1[CH:7]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=1[O:20][CH3:21])([CH3:19])[CH3:18]
Reactant: COc1ccc(F)cc1C(C)(C)CC(O)(CO)C(F)(F)F
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: CCOCC
Solvent: CCCCCC
Solvent: CO
Product: COc1ccc(F)cc1C(C)(C)CC(=O)C(F)(F)F
Reaction time: 4 h
Yield: 87.6 %

Procedure:
To a solution of 4.9 g (15.8 mmol) of the above 4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-trifluoromethylpentane-1,2-diol in 100 mL of MeOH was added 10 g (45.9 mmol) of sodium periodate. The mixture was stirred for 4 hours and was then diluted with 100 mL of ether and 100 mL of hexane, filtered through diatomaceous earth, and concentrated in vacuo. The crude residue was dissolved in hexane and passed through a pad of silica gel, eluting first with hexane then with EtOAc-hexane (2:98, then 4:96) to afford 3.85 g (87%) of 1,1,1-trifluoro-4-(5-fluoro-2-methoxyphenyl)-4-methylpentan-2-one as a clear oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH:16]3[CH2:17][CH2:18][CH2:19][CH:12]2[C:13](=[CH:23][N:24](C)C)[C:14](=O)[CH:15]3[CH2:20][CH3:21])(=[O:10])=[O:9])=[CH:4][CH:3]=1.O.[NH2:28]N>C(O)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH:16]3[CH2:17][CH2:18][CH2:19][CH:12]2[C:13]2[CH:23]=[N:24][NH:28][C:14]=2[CH:15]3[CH2:20][CH3:21])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: CCC1C(=O)C(=CN(C)C)C2CCCC1N2S(=O)(=O)c1ccc(Cl)cc1
Reactant: NN
Solvent: O
Solvent: CC(=O)O
Product: CCC1c2[nH]ncc2C2CCCC1N2S(=O)(=O)c1ccc(Cl)cc1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
To a solution of 9-(4-chloro-benzenesulfonyl)-2-dimethylaminomethylene-4-ethyl-9-aza-bicyclo[3.3.1]nonan-3-one crude mixture in glacial acetic acid (1 mL) followed by hydrazine monohydrate (0.5 mL). The reaction mixture was stirred at 100° C. for 1 h after which the solution was cooled to room temperature and quenched by the addition of a saturated aqueous NaHCO3 solution (until pH>7). The resulting solution was extracted with EtOAc (3×20 mL), the organic extracts were combined, dried (Na2SO4), filtered, concentrated and purified by silica gel column chromatography and preparative HPLC to give 12-(4-chloro-benzenesulfonyl)-7-ethyl-4,5,12-triaza-tricyclo[6.3.1.02,6]dodeca-2(6),3-diene as a white solid. Retention time (min)=1.896, Method [1], MS (ESI) 366.1 (M+H); 1H-NMR (300 MHz, CDCl3) δ 7.81-7.78 (m, 2H), 7.47-7.43 (m, 2H), 7.25 (s, 1H), 5.15 (b s, 1H), 4.27 (d, J=4.95 Hz, 1H), 2.56 (dd, J=9.34, 5.49 Hz, 1H), 2.10-1.22 (m, 8H), 1.02 (t, J=7.14 Hz, 3H) (major diastereomer); 1H-NMR (300 MHz, CDCl3) δ 7.68-7.66 (m, 2H), 7.35-7.32 (m, 2H), 7.22 (s, 1H), 5.28 (b s, 1H), 4.31 (d, J=5.5 Hz, 1H), 2.80-2.73 (m, 1H), 2.05-1.21 (m, 8H), 1.06 (t, J=7.69 Hz, 3H) (minor diastereomer).
Reaction SMILES: O[C:2]1([CH3:11])[CH:6]([CH2:7][CH:8]=[CH2:9])[C:5](=[O:10])[CH:4]=[CH:3]1.C(=O)([O-])[OH:13].[Na+]>>[CH2:7]([C:6]1[C:5](=[O:10])[CH2:4][CH:3]([OH:13])[C:2]=1[CH3:11])[CH:8]=[CH2:9]
Reactant: C=CCC1C(=O)C=CC1(C)O
Reactant: O=C([O-])O
Agent: [Na+]
Product: C=CCC1=C(C)C(O)CC1=O
Yield: 75 %

Procedure:
In 200 ml of a 5% aqueous sodium hydrogen-carbonate solution, was dissolved 29 g of 4-hydroxy-4-methyl-5-allyl-2-cylcopentenone. The solution was heated with stirring under reflux for one hour. After having been allowed to cool, the reaction mixture was extracted three times with chloroform. The extract solution was dried over anhydrous magnesium sulfate and freed from the chloroform by distillation. The residue was distilled in vacuo to obtain 21.7 g (75% yield) of 2-allyl-3-methyl-4-hydroxy-2-cyclopentenone boiling at 155° C./1 mmHg.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:6](=[CH:7][N:8]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[N:9]=2)[CH:5]=[C:4]([CH2:19][C@@H:20]([O:24][C:25]([N:27]2[CH2:32][CH2:31][CH:30]([C:33]3[C:34](=[O:43])[NH:35][C:36]4[C:41]([CH:42]=3)=[CH:40][CH:39]=[CH:38][CH:37]=4)[CH2:29][CH2:28]2)=[O:26])[C:21](O)=[O:22])[CH:3]=1.[NH2:44][C:45](=[N:51]O)[C:46]([O:48][CH2:49][CH3:50])=[O:47].Cl.CN(C)CCCN=C=NCC>COCCOCCOC>[O:43]=[C:34]1[C:33]([CH:30]2[CH2:29][CH2:28][N:27]([C:25]([O:24][C@@H:20]([C:21]3[O:22][N:51]=[C:45]([C:46]([O:48][CH2:49][CH3:50])=[O:47])[N:44]=3)[CH2:19][C:4]3[CH:3]=[C:2]([CH3:1])[C:10]4[C:6](=[CH:7][N:8]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:16])([CH3:17])[CH3:18])[N:9]=4)[CH:5]=3)=[O:26])[CH2:32][CH2:31]2)=[CH:42][C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[NH:35]1
Reactant: CCOC(=O)C(N)=NO
Reactant: Cc1cc(C[C@@H](OC(=O)N2CCC(c3cc4ccccc4[nH]c3=O)CC2)C(=O)O)cc2cn(COCC[Si](C)(C)C)nc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: COCCOCCOC
Product: CCOC(=O)c1noc([C@@H](Cc2cc(C)c3nn(COCC[Si](C)(C)C)cc3c2)OC(=O)N2CCC(c3cc4ccccc4[nH]c3=O)CC2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 33.9 %

Procedure:
A stirred solution of (R)-3-(7-methyl-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazol-5-yl)-2-(4-(2-oxo-1,2-dihydroquinolin-3-yl)piperidine-1-carbonyloxy)propanoic acid (28.5 mg, 0.0471 mmol) in anhydrous diglyme (2.5 mL) was treated with ethyl 2-amino-2-(hydroxyimino)acetate (6.54 mg, 0.0495 mmol) and 1-[3-(dimethylamino)propyl]3-ethylcarbodiimide hydrochloride (0.49 mg, 0.0495 mmol) at room temperature. The mixture was stirred overnight at room temperature and then overnight at 110° C. After cooling to room temperature and removal of the solvent in vacuo, the crude compound was purified using preparative HPLC to afford a tan gum (11.2 mg, 34%). 1H-NMR (CDCl3, 400 MHz) δ 8.0 (s,1H), 7.58 (s, 1H), 7.57 (s, 1H), 7.46 (m, 1H), 7.30 (s,1H), 7.24-7.20 (m, 2H), 6.93 (s,1H), 6.17-6.15 (m, 1H), 5.71 (s, 2H), 4.50-4.48 (m, 2H), 4.29-4.20 (m, 2H), 3.65-3.55 (m, 2H), 3.40-3.38 (m, 2H), 3.20-2.81 (m, 4H), 2.59 (s, 3 h), 2.03-1.72 (m, 4H), 1.44-1.38 (m, 3H), 0.95-0.86 (m, 2H), −0.045 (s, 9H).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][CH2:7][C:8]1[C:9]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[N:10][N:11]([CH2:13][C:14]2[CH:15]=[C:16]([CH:20]=[CH:21][CH:22]=2)[C:17](O)=[O:18])[CH:12]=1)=[O:5])[CH3:2].[F:29][C:30]([F:40])([F:39])[C:31]1[CH:38]=[CH:37][C:34]([CH2:35][NH2:36])=[CH:33][CH:32]=1.O.ON1C2C=CC=CC=2N=N1.CCN=C=NCCCN(C)C>O.CN(C)C=O>[C:23]1([C:9]2[C:8]([CH2:7][CH2:6][C:4]([O:3][CH2:1][CH3:2])=[O:5])=[CH:12][N:11]([CH2:13][C:14]3[CH:22]=[CH:21][CH:20]=[C:16]([C:17]([NH:36][CH2:35][C:34]4[CH:37]=[CH:38][C:31]([C:30]([F:39])([F:40])[F:29])=[CH:32][CH:33]=4)=[O:18])[CH:15]=3)[N:10]=2)[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: CCOC(=O)CCc1cn(Cc2cccc(C(=O)O)c2)nc1-c1ccccc1
Reactant: NCc1ccc(C(F)(F)F)cc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CCc1cn(Cc2cccc(C(=O)NCc3ccc(C(F)(F)F)cc3)c2)nc1-c1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 90.8 %

Procedure:
A mixture of 3-[4-(2-ethoxycarbonylethyl)-3-phenyl-1H-pyrazol-1-ylmethyl]benzoic acid (700 mg), 4-trifluoromethylbenzylamine (390 mg), 1-hydroxybenzotriazole monohydrate (340 mg), WSC (430 mg), and N,N-dimethylformamide (30 ml) was stirred at room temperature for 18 hours. The reaction mixture was poured into water, which was extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried (MgSO4), and concentrated. The residue was subjected to silica gel column chromatography, and ethyl 3-[3-phenyl-1-[3-(4-trifluoromethylbenzylaminocarbonyl)benzyl]-1H-pyrazol-4-yl]propionate (900 mg, yield: 91%) was obtained as an oily substance from the fraction eluted with acetone-hexane (1:2, volume ratio).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]([CH3:13])[CH3:12].C(=O)([O-])[O-].[K+].[K+].[CH3:20][C:21]1[CH:22]=[C:23]([N+:29]([O-:31])=[O:30])[CH:24]=[C:25]([CH3:28])[C:26]=1F.C(OCC)(=O)C>CS(C)=O.O>[CH:11]([C:5]1[C:4]2[C:8](=[CH:9][CH:10]=[C:2]([O:1][C:26]3[C:21]([CH3:20])=[CH:22][C:23]([N+:29]([O-:31])=[O:30])=[CH:24][C:25]=3[CH3:28])[CH:3]=2)[NH:7][CH:6]=1)([CH3:13])[CH3:12]
Reactant: Cc1cc([N+](=O)[O-])cc(C)c1F
Reactant: CC(C)c1c[nH]c2ccc(O)cc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: Cc1cc([N+](=O)[O-])cc(C)c1Oc1ccc2[nH]cc(C(C)C)c2c1
Temperature: 100 °C
Reaction time: 2 h

Procedure:
11.44 g (58.76 mmol) of 5-hydroxy-3-isopropyl-indole are dissolved in 350 ml of DMSO, 8.93 g (64.63 mmol) of potassium carbonate in solid form are introduced and subsequently 9.94 g (58.76 mmol) of 3,5-dimethyl-4-fluoronitrobenzene are added. The reaction solution is stirred for 2 hours at 100° C. under argon. Afterwards it is cooled to room temperature, 100 ml of ethyl acetate and 600 ml of H2O are added; ethyl acetate is separated off after phase separation and the aqueous phase is reextracted twice with ethyl acetate. The combined organic phases are washed twice with sodium chloride solution, dried over sodium sulphate, filtered and concentrated to dryness. The residue is purified by chromatography on silica gel by means of cyclohexane/ethyl acetate (10:1).
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]3[S:16][C:15]4[CH:17]=[CH:18][CH:19]=[CH:20][C:14]=4[C:13]=3[C:21](=[O:26])[CH2:22][CH:23]([CH3:25])[CH3:24])=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[O:27][CH2:28][C:29]#[N:30].[N-:31]=[N+:32]=[N-:33].[Na+].[Cl-].[NH4+].CN(C=O)C.Cl>O>[Br:1][C:2]1[C:3]([O:27][CH2:28][C:29]2[NH:33][N:32]=[N:31][N:30]=2)=[CH:4][CH:5]=[C:6]2[C:11]=1[CH:10]=[CH:9][C:8]([C:12]1[S:16][C:15]3[CH:17]=[CH:18][CH:19]=[CH:20][C:14]=3[C:13]=1[C:21](=[O:26])[CH2:22][CH:23]([CH3:25])[CH3:24])=[CH:7]2
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)CC(=O)c1c(-c2ccc3c(Br)c(OCC#N)ccc3c2)sc2ccccc12
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)CC(=O)c1c(-c2ccc3c(Br)c(OCc4nnn[nH]4)ccc3c2)sc2ccccc12
Temperature: 80 °C
Yield: 54.7 %

Procedure:
A mixture of {1-bromo-6-[3-(3-methyl-butyryl)-benzo[b]thiophen-2-yl]-naphthalen-2-yloxy}-acetonitrile (1.01 g, 2.11 mmol), sodium azide (0.687 g, 10.6 mmol) and ammonium chloride (0.570 g, 10.7 mmol) in DMF (10 mmol) was heated at 80° C. for two hours. After cooling to ambient temperature, the reaction mixture was poured into excess water and acidified with 2N hydrochloric acid. This was then extracted with ethyl acetate. The organic phase was washed with water and brine. It was then dried with anhydrous magnesium sulfate, filtered and solvent evaporated. Drying in vacuo at 78° C. for 12 hours yielded 1-{2-[5-bromo-6-(1H-tetrazol-5-ylmethoxy)-naphthalen-2-yl]-benzo[b]thiophen-3-yl}-3-methyl-butan-1-one as a yellow foam (0.602 g, 75%). Mass spectrum (+EI, [M+H]+) m/z 521/523. 1H NMR (500 MHz, DMSO-d6): δ16.7–17.2 (br, 1H), 8.24 (d, 1H, J=9.01 Hz), 8.16–8.19 (m, 2H), 8.08–8.10 (m, 1H), 7.95–7.97 (m, 1H), 7.75–7.79 (m, 2H), 7.46–7.52 (m, 2H), 5.77 (s, 2H), 2.32 (d, 2H, J=6.72 Hz), 1.95–2.02 (m, 1H), 0.65 ppm (d, 6H, J=6.57 Hz). Elemental Analysis for C25H21BrN4O2S: Calcd: C, 57.59; H, 4.06; N, 10.74; Found: C, 57.37; H, 4.12; N, 10.48.
Reaction SMILES: [C:1]([N:9]1[C:17]2[CH:16]=[CH:15][CH:14]=[C:13]3[CH:18]4[O:21][CH:19]4[CH2:20][CH:11]([C:12]=23)[CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C=CC=CC=1>C(OCC)(=O)C.[I-].[Zn+2].[I-]>[C:1]([N:9]1[C:17]2[CH:16]=[CH:15][CH:14]=[C:13]3[CH2:18][C:19](=[O:21])[CH2:20][CH:11]([C:12]=23)[CH2:10]1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(c1ccccc1)N1CC2CC3OC3c3cccc1c32
Agent: [I-]
Agent: [Zn+2]
Solvent: CCOC(C)=O
Solvent: c1ccccc1
Product: O=C1Cc2cccc3c2C(C1)CN3C(=O)c1ccccc1

Procedure:
Twenty grams of 1-benzoyl-4,5-epoxy-1,2,2a,3,4,5-hexahydrobenz[cd]indole were dissolved in 500 ml. of benzene. 7.7 g. of zinc iodide were added and the resulting mixture refluxed under nitrogen for about 1.5 hours. Thin layer chromatrography indicated one major spot slightly slower than the spot corresponding to starting material. The reaction mixture was cooled and then diluted with ethyl acetate. The resulting organic layer was washed with water, and with saturated aqueous sodium chloride and was then dried. Evaporation of the solvent yielded a residue comprising 1-benzoyl-4-keto-1,2,2a,3,4,5-hexahydrobenz[cd]indole formed in the above reaction. The residue was crystallized by trituration with ether containing a small amount of benzene, yielding crystals melting at 146°-149° C. (yield equals 16.9 g.)
Reaction SMILES: [OH:1][CH:2]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH2:3][CH2:4][C:5]([NH:7][CH3:8])=[O:6].[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>C(Cl)Cl>[CH3:8][NH:7][C:5](=[O:6])[CH2:4][CH2:3][C:2](=[O:1])[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: CNC(=O)CCC(O)c1ccccc1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CNC(=O)CCC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 81.9 %

Procedure:
A mixture of 4-hydroxy-N-methyl-4-phenyl-butyramide (4.50 g, 23.3 mmol), prepared in the previous step, and pyridinium chlorochromate (7.54 g, 35.0 mmol) in 200 ml of methylene chloride was stirred at room temperature for 2.5 hours. The reaction was poured onto 400 g of silica gel (230-400 mesh) and the material eluted with ethyl acetate-methylene chloride and then ethyl acetate. Isolation of the major component gave N-methyl-4-oxo-4-phenyl-butyramide (3.65 g, 82%) as an off-white solid, mp 80-82° C.