Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CCN=C=NCCCN(C)C.[OH:12][CH2:13][C@H:14]1[CH2:19][CH2:18][CH2:17][C:16](=[O:20])[N:15]1[CH2:21][C:22]#[C:23][CH2:24][O:25][CH2:26][C:27]#[N:28].CS(C)=O.FC(F)(F)C([O-])=O.[NH+]1C=CC=CC=1>C1C=CC=CC=1>[CH:13]([C@H:14]1[CH2:19][CH2:18][CH2:17][C:16](=[O:20])[N:15]1[CH2:21][C:22]#[C:23][CH2:24][O:25][CH2:26][C:27]#[N:28])=[O:12]
Reactant: N#CCOCC#CCN1C(=O)CCC[C@@H]1CO
Agent: CCN=C=NCCCN(C)C
Agent: O=C([O-])C(F)(F)F
Agent: c1cc[nH+]cc1
Solvent: c1ccccc1
Solvent: CS(C)=O
Product: N#CCOCC#CCN1C(=O)CCC[C@@H]1C=O
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
EDCI (288 mg, 1.50 mmol) was added to a solution of [4-((R)-2-hydroxymethyl-6-oxo-piperidin-1-yl)-but-2-ynyloxy]-acetonitrile (118 mg, 0.50 mmol) in benzene (4 mL). The reaction mixture was cooled to 0° C. and DMSO (0.14 mL, 2.0 mmol) was added. After 5 min at 0° C., pyridinium trifluoroacetate (106 mg, 0.55 mmol) was added. The reaction was allowed to warm to rt and then was stirred at rt for 3 h. The solution was decanted from the oily residue and the residue was washed with benzene (3×5 mL). The combined benzene phases were concentrated in vacuo to afford crude [4-((R)-2-formyl-6-oxo-piperidin-1-yl)-but-2-ynyloxy]-acetonitrile, which was used without further purification.
Reaction SMILES: OS(O)(=O)=O.[CH3:6][C:7]1C=CC(S(O)(=O)=O)=CC=1.[C:17]1([C:23]2([C:29]([OH:31])=[O:30])[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CCO>[CH2:6]([O:30][C:29]([C:23]1([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:24][CH2:25][NH:26][CH2:27][CH2:28]1)=[O:31])[CH3:7]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: O=C(O)C1(c2ccccc2)CCNCC1
Agent: O=S(=O)(O)O
Solvent: CCO
Product: CCOC(=O)C1(c2ccccc2)CCNCC1

Procedure:
To a stirred solution of H2SO4 (1.62 g, 16.56 mmol) in EtOH (200 mL), 4-phenyl-4-piperidinecarboxylic acid 4-methylbenzenesulfonate (25 g, 66.23 mmol) was added and the mixture was stirred and refluxed for 12 h. Excess ethanol was evaporated at reduced pressure and the residue was poured into a mixture of ice and 6N NaOH. The pH was adjusted to 10-11 by adding more 6N NaOH and extracted with CH2Cl2 (3×100 mL). The combined CH2Cl2 extracts were dried (MgSO4) and the solvent evaporated to leave the desired product as a colorless viscous oil, the 1H-NMR showed it to be pure (14.68 g, 95%) and was used without any further purification.
Reaction SMILES: [N:1]1[C:6]2[NH:7][CH2:8][CH2:9][CH2:10][C:11](=[O:12])[C:5]=2[CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[Cl:20][C:21]1[CH:29]=[C:28]([N+:30]([O-:32])=[O:31])[CH:27]=[CH:26][C:22]=1[C:23](Cl)=O>ClCCl>[Cl:20][C:21]1[CH:29]=[C:28]([N+:30]([O-:32])=[O:31])[CH:27]=[CH:26][C:22]=1[CH2:23][N:7]1[CH2:8][CH2:9][CH2:10][C:11](=[O:12])[C:5]2[CH:4]=[CH:3][CH:2]=[N:1][C:6]1=2
Reactant: O=C1CCCNc2ncccc21
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C1CCCN(Cc2ccc([N+](=O)[O-])cc2Cl)c2ncccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 6,7,8,9-tetrahydro-5Hpyrido[2,3-b]azepin-5-one and 0.234 g of triethylamine in 6 ml of dichloromethane is added 0.506 g of 2-chloro-4-nitrobenzoyl chloride in 2 ml of dichloromethane. The mixture is stirred at room temperature overnight under argon. The solution is washed with H2O, 10% NaHCO3 and dried (MgSO4). The solvent is removed to give a brown oil which crystallizes. The mixture is chromatographed on silica with a waters Prep-500 instrument with ethyl acetate-hexane (1:1) as solvent to Give 2.4 g of off-white crystals, m.p. 162°-164 C. (identified as O-2-chloro-4-nitrobenzoyl derivative (2-chloro-4-nitro-benzoyl enolate of product) and 0.80 g of product as crystals, m.p. slowly decomposes 160°-220° C.
Reaction SMILES: [NH:1]([CH2:5][CH2:6][OH:7])[CH2:2][CH2:3][OH:4].[C:8]([C:12]1[CH:13]=[C:14]([CH:18]=[C:19]([C:22]([CH3:25])([CH3:24])[CH3:23])[C:20]=1[OH:21])[C:15](Cl)=[O:16])([CH3:11])([CH3:10])[CH3:9]>O1CCCC1.C1C=CC=CC=1>[OH:4][CH2:3][CH2:2][N:1]([CH2:5][CH2:6][O:7][C:15](=[O:16])[C:14]1[CH:18]=[C:19]([C:22]([CH3:23])([CH3:24])[CH3:25])[C:20]([OH:21])=[C:12]([C:8]([CH3:11])([CH3:10])[CH3:9])[CH:13]=1)[C:15](=[O:16])[C:14]1[CH:13]=[C:12]([C:8]([CH3:11])([CH3:10])[CH3:9])[C:20]([OH:21])=[C:19]([C:22]([CH3:25])([CH3:24])[CH3:23])[CH:18]=1
Reactant: CC(C)(C)c1cc(C(=O)Cl)cc(C(C)(C)C)c1O
Reactant: OCCNCCO
Solvent: C1CCOC1
Solvent: c1ccccc1
Product: CC(C)(C)c1cc(C(=O)OCCN(CCO)C(=O)c2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)cc(C(C)(C)C)c1O
Reaction time: 1 h

Procedure:
To a cold (5° C.) solution of 3 moles of diethanolamine in tetrahydrofuran was added dropwise a solution of 3,5-di-t-butyl-4-hydroxybenzoyl chloride in benzene. The reaction mixture was stirred for about 1 hour, washed with water, separating the benzene layer from the aqueous layer. The benzene solution was evaporated to yieldan oil, which, after crystallization with aqueous ethanol, yielded a white solid. Small amounts of by-product compounds of Examples 1 and 3 were removed by fractional crystallization to yield N-hydroxyethyl-N-(3',5'-di-t-butyl-4'-hydroxybenzoyloxyethyl)-3,5-di-t-butyl-4-hydroxybenzamide; melting point 174°-178° C. When testedby the procedure of Example 2, the sample containing this compound lasted 1,200 hours, about 2.2 times as long as the control.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1.C([O-])([O-])=O.[K+].[K+].[CH2:18]([CH:20]1[O:22][CH2:21]1)Cl>>[F:1][C:2]([F:10])([F:11])[C:3]1[CH:4]=[CH:5][C:6]([O:9][CH2:18][CH:20]2[O:22][CH2:21]2)=[CH:7][CH:8]=1
Reactant: Oc1ccc(C(F)(F)F)cc1
Reactant: ClCC1CO1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: FC(F)(F)c1ccc(OCC2CO2)cc1
Temperature: 120 °C
Reaction time: 4 h

Procedure:
A mixture of 4-trifluoromethyl phenol (2 g), K2CO3 (2.04 g) and epichlorohydrin (10 mL) was stirred at 120° C. for 4 hrs. After completion of reaction, the solid was filtered, filtrate was Diluted with water (50 mL) and extracted with ethylacetate (3×25 mL). Organic layer was washed with Distilled water (3×100 mL) and concentrated to an oil, which was purified on silica gel column using hexane:ethylacetate (9:1) as eluant, to given required compound 2.42 g (90%) yield.
Reaction SMILES: CN(C)C=O.[CH3:6][O:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][C:17]=1[O:18][CH2:19][C:20]([F:23])([F:22])[F:21])[N:14]=[CH:13][NH:12][C:11]2=O.S(Cl)([Cl:27])=O>>[Cl:27][C:11]1[C:10]2[C:15](=[CH:16][C:17]([O:18][CH2:19][C:20]([F:23])([F:22])[F:21])=[C:8]([O:7][CH3:6])[CH:9]=2)[N:14]=[CH:13][N:12]=1
Reactant: COc1cc2c(=O)[nH]cnc2cc1OCC(F)(F)F
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: COc1cc2c(Cl)ncnc2cc1OCC(F)(F)F
Yield: 97 %

Procedure:
Dimethylformamide (0.1 ml) was added dropwise to a solution of 6-methoxy-7-(2,2,2-trifluoroethoxy)-3,4-dihydroquinazolin-4-one (15.8 g, 57.7 mmol) in thionyl chloride (200 ml) and the reaction was heated at reflux for 6 hours. The reaction was cooled, excess thionyl chloride was removed in vacuo and the residue was azeotroped with toluene (2×50 ml) to remove the last of the thionyl chloride. The residue was taken up in dichloromethane (550 ml), the solution was washed with saturated aqueous sodium hydrogen carbonate solution (2×250 ml) and the organic phase was dried over magnesium sulphate. Solvent evaporation in vacuo yielded 4-chloro-6-methoxy-7-(2,2,2-trifluoroethoxy)quinazoline (16.3 g, 97% yield) as a cream solid:
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH:3]=1.Cl.[NH2:14][C:15]1[CH:16]=[C:17]2[C:30](=[CH:31][CH:32]=1)[CH2:29][C:19]1([C:27]3[C:22](=[N:23][CH:24]=[CH:25][CH:26]=3)[NH:21][C:20]1=[O:28])[CH2:18]2>CC(O)C>[O:28]=[C:20]1[NH:21][C:22]2=[N:23][CH:24]=[CH:25][CH:26]=[C:27]2[C:19]21[CH2:18][C:17]1[C:30](=[CH:31][CH:32]=[C:15]([NH:14][C:2]3[N:7]=[CH:6][N:5]=[C:4]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH:3]=3)[CH:16]=1)[CH2:29]2
Reactant: Nc1ccc2c(c1)CC1(C2)C(=O)Nc2ncccc21
Reactant: CCOC(=O)c1cc(Cl)ncn1
Agent: Cl
Solvent: CC(C)O
Product: CCOC(=O)c1cc(Nc2ccc3c(c2)CC2(C3)C(=O)Nc3ncccc32)ncn1
Temperature: 25 °C

Procedure:
0.10 g (0.55 mmol) ethyl 6-chloropyrimidine-4-carboxylate and 13 μL (50 μmol) 4M HCl were added to 0.16 g (0.60 mmol) 5-amino-1,3-dihydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-one in 1.0 mL 2-propanol. The reaction mixture was refluxed for 2 h, then cooled to RT and the resulting solid was filtered off and dried.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][C:5]1[CH:15]=[CH:14][CH:13]=[C:7]2[C:8]([NH:10][C:11](=[O:12])[C:6]=12)=[O:9].[NH:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1>C(OCC)C>[N:16]1([CH2:2][CH2:3][CH2:4][C:5]2[CH:15]=[CH:14][CH:13]=[C:7]3[C:8]([NH:10][C:11](=[O:12])[C:6]=23)=[O:9])[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1
Reactant: O=C1NC(=O)c2c(CCCBr)cccc21
Reactant: C1COCCN1
Solvent: CCOCC
Product: O=C1NC(=O)c2c(CCCN3CCOCC3)cccc21

Procedure:
3-Bromopropylphthalimide (536 mg; 2.0 mmoles) and morpholine (0.35 ml; 4.0 mmoles) were dissolved in anhydrous ethyl ether (5 ml). Reaction times and process as per Example 1.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9]([NH2:13])=[CH:10]2)=[CH:5][CH:4]=1.C(N(CC)CC)C.[C:23](Cl)(=[O:25])[CH3:24]>ClCCl>[F:1][C:2]([F:14])([F:15])[C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9]([NH:13][C:23](=[O:25])[CH3:24])=[CH:10]2)=[CH:5][CH:4]=1
Reactant: CC(=O)Cl
Reactant: Nc1ccc2ccc(C(F)(F)F)cc2c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)Nc1ccc2ccc(C(F)(F)F)cc2c1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of 7-trifluoromethyl-2-aminonaphthalene (550 mg, 2.60 mmol) and triethylamine (1.09 mL, 7.81 mmol) in dichloromethane (10 mL) at room temperature is added acetyl chloride (0.222 mL, 3.13 mmol) dropwise. After stirring at room temperature for 1.5 hours, the mixture is partitioned between dichloromethane and water. The organic layer is washed with 0.1 M citric acid solution, brine, dried (MgSO4) and concentrated by rotary evaporator to give 7-trifluoromethyl-2-acetamidonaphthalene as a light yellow solid.
Reaction SMILES: [C:1]1([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:6]=[CH:5][C:4]([CH2:7]O)=[CH:3][CH:2]=1.[BrH:15]>O>[Br:15][CH2:7][C:4]1[CH:5]=[CH:6][C:1]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:2][CH:3]=1
Reactant: OCc1ccc(-c2ccccc2)cc1
Reactant: Br
Solvent: O
Product: BrCc1ccc(-c2ccccc2)cc1
Temperature: 10 °C
Reaction time: 3 h
Yield: 98.5 %

Procedure:
A mixture of biphenyl-4-yl-methanol (250 mg, 1.35 mmol) and aqueous HBr (48%) (3 mL) was stirred at 10° C. for 3 hrs. After completion of the reaction, the mixture was diluted with cold water, extracted with ethyl acetate and dried over sodium sulfate. The organic layer collected was concentrated under reduced pressure to afford 330 mg (98.5% Yield) 4-bromomethyl-biphenyl. 4-Bromomethyl-biphenyl (120 mg, 0.485 mmol) was added to a stirred mixture of 2-amino-1-[4-(2-chloro-phenoxy)-piperidin-1-yl]-ethanone hydrochloride (134 mg, 0.44 mmol) (prepared according to Step 1 and 5 of the General Scheme), LiOH.H2O (40 mg, 0.97 mmol) and 4 Å molecular sieves (350 mg) in DMF (4 mL) and stirring was continued overnight. The reaction mixture was filtered and filtrate was diluted with cold water, extracted with ethyl acetate and organic layer was dried over sodium sulfate. The organic layer was concentrated under reduced pressure. Purification by column chromatography (using neutral alumina and 5% MeOH in DCM as eluent) to afford 22 mg (11.4% Yield) of 2-[(biphenyl-4-ylmethyl)-amino]-1-[4-(2-chloro-phenoxy)-piperidin-1-yl]-ethanone. LC/MS [M+H]+: 435, 90.56%. 1H NMR (CDCl3): δ7.64-7.52 (m, 4H), 7.5-7.3 (m, 6H), 7.24-7.15 (dt, 1H), 7.0-6.86 (m, 2H), 4.6 (q, 1H), 4.0-3.8 (m, 3H), 3.7-3.6 (m, 3H), 3.5 (s, 2H), 3.4-3.3 (m, 1H), 2.0-1.8 (m, 4H).
Reaction SMILES: [ClH:1].Cl.[F:3][C:4]1[CH:23]=[CH:22][C:7]([CH2:8][CH:9]2[CH2:14][CH2:13][CH:12]([NH:15][C@H:16]3[C@H:20]([NH2:21])[CH2:19][O:18][CH2:17]3)[CH2:11][CH2:10]2)=[CH:6][CH:5]=1.C(N(CC)CC)C.[C:31]([C:34]1[CH:35]=[C:36]([N:40]=[C:41]=[O:42])[CH:37]=[CH:38][CH:39]=1)(=[O:33])[CH3:32]>ClCCl>[ClH:1].[C:31]([C:34]1[CH:35]=[C:36]([NH:40][C:41]([NH:21][C@H:20]2[C@H:16]([NH:15][CH:12]3[CH2:11][CH2:10][CH:9]([CH2:8][C:7]4[CH:6]=[CH:5][C:4]([F:3])=[CH:23][CH:22]=4)[CH2:14][CH2:13]3)[CH2:17][O:18][CH2:19]2)=[O:42])[CH:37]=[CH:38][CH:39]=1)(=[O:33])[CH3:32]
Reactant: N[C@@H]1COC[C@H]1NC1CCC(Cc2ccc(F)cc2)CC1
Reactant: CC(=O)c1cccc(N=C=O)c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)c1cccc(NC(=O)N[C@@H]2COC[C@H]2NC2CCC(Cc3ccc(F)cc3)CC2)c1
Yield: 61.2 %

Procedure:
To a stirring solution of (3S,4S)-N3-[4-(4-fluorobenzyl)cyclohexyl]tetrahydro-3,4-furandiamine dihydrochloride (20 mg, 0.055 mmol) and triethylamine (100 μL, 0.72 mmol) in dichloromethane (1 mL) was added 3-acetylphenyl isocyanate (7.1 mg, 0.050 mmol). The resulting solution was immediately concentrated, and the resulting residue was purified by flash column chromatography (100% ethyl acetate then 5% triethylamine in ethyl acetate then 10% methanol in ethylacetate containing 5% triethylamine) to yield the desired urea (15 mg, 60%) as an oily white solid. MS (ESI) 454 (M+H).
Reaction SMILES: C1(C)C=CC=CC=1.[CH3:8][C:9]([NH2:17])([CH3:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[Cl:18][CH:19]([C:23]([CH3:26])([CH3:25])[CH3:24])[C:20](Cl)=[O:21]>N1C=CC=CC=1>[CH3:8][C:9]([NH:17][C:20](=[O:21])[CH:19]([C:23]([CH3:26])([CH3:25])[CH3:24])[Cl:18])([CH3:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CC(C)(N)c1ccccc1
Reactant: CC(C)(C)C(Cl)C(=O)Cl
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: CC(C)(NC(=O)C(Cl)C(C)(C)C)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 88.6 %

Procedure:
Into a 200 ml four-necked flask, there were charged toluene (100 ml), α,α-dimethylbenzylamine (9 g) and pyridine (5.8 g), and α-chloro-tert-butylacetyl chloride (11.3 g) was dropwise added thereto while stirring at room temperature. Stirring was continued for 3 hours. The reaction mixture was washed with water to remove pyridine hydrochloride. After the toluene layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The obtained residue was recrystallized from ethanol to give 15.8 g of N-(α,α-dimethylbenzyl)-α-chloro-tert-butylacetamide. M.P., 159°-160° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:16]([CH3:17])=[CH:15][CH:14]=[C:13]([C:18]([OH:20])=O)[CH:12]=2)=[CH:7][CH:6]=1)=[O:4].C(Cl)(=O)C(Cl)=O.[CH2:27]([NH2:30])[CH2:28][CH3:29]>C(Cl)(Cl)Cl>[CH3:17][C:16]1[C:11]([C:8]2[CH:7]=[CH:6][C:5]([C:3]([O:2][CH3:1])=[O:4])=[CH:10][CH:9]=2)=[CH:12][C:13]([C:18]([NH:30][CH2:27][CH2:28][CH3:29])=[O:20])=[CH:14][CH:15]=1
Reactant: COC(=O)c1ccc(-c2cc(C(=O)O)ccc2C)cc1
Reactant: CCCN
Agent: O=C(Cl)C(=O)Cl
Solvent: ClC(Cl)Cl
Product: CCCNC(=O)c1ccc(C)c(-c2ccc(C(=O)OC)cc2)c1
Reaction time: 0.75 h

Procedure:
4′-(Methoxycarbonyl)-6-methyl-1,1′-biphenyl-3-carboxylic acid (190 mg, 0.7 mmol) and oxalyl chloride (70 μl, 0.77 mol) in chloroform (4 ml) were stirred at room temperature for 15 min. Propylamine (200 μl) was added and stirring continued for 45 min. The reaction was quenched with water (4 ml), the phases separated and the organic phase passed through an aminopropyl SPE eluting with chloroform. After evaporation of the solvent this gave methyl 6′-methyl-3′-[(propylamino)carbonyl]1,1′-biphenyl-4-carboxylate (216 mg). LCMS: retention time 3.26 min, MH+312.
Reaction SMILES: [CH2:1]([N:3]([CH2:14][CH3:15])[C:4]([CH:6]1[CH2:11][CH2:10][CH2:9][CH:8](Br)[C:7]1=O)=[O:5])[CH3:2].[F:16][CH2:17][CH2:18][NH:19][C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=1>CC(O)C.[Cl-].[Zn+2].[Cl-]>[CH2:1]([N:3]([CH2:14][CH3:15])[C:4]([CH:6]1[C:7]2[C:25]3[C:20](=[CH:21][CH:22]=[C:23]([F:26])[CH:24]=3)[N:19]([CH2:18][CH2:17][F:16])[C:8]=2[CH2:9][CH2:10][CH2:11]1)=[O:5])[CH3:2]
Reactant: FCCNc1ccc(F)cc1
Reactant: CCN(CC)C(=O)C1CCCC(Br)C1=O
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CC(C)O
Product: CCN(CC)C(=O)C1CCCc2c1c1cc(F)ccc1n2CCF
Temperature: 50 °C
Reaction time: 3 h
Yield: 10 %

Procedure:
A mixture of 3-bromo-2-oxo-cyclohexanecarboxylic acid diethylamide (35; prepared according to Example 7(c)) (336 mg, 1.2 mmol) and (2-fluoro-ethyl)-(4-fluoro-phenyl)-amine (38) (383 mg, 2.4 mmol) was stirred under N2 at 50° C. for 3 h and the reaction turned brown. The resulting mixture was dissolved in propan-2-ol (2 mL) and dry zinc chloride (491 mg, 3.6 mmol) was added. The mixture was heated to reflux under N2 for 16 h and then concentrated in vacuo. The residue was dissolved in ethyl acetate (20 mL) and washed with 2 N HCl (10 mL), water (2×10 mL) and aqueous potassium carbonate solution (2×5 mL) then dried and concentrated in vacuo. The crude material was triturated with diethyl ether to afford 40 mg (10%) of 6-fluoro-9-(2-fluoro-ethyl)-2,3,4,9-tetrahydro-1H-carbazole-4-carboxylic acid diethylamide (non-radioactive imaging agent 9) as white solid. The structure was confirmed by 1H NMR (300 MHz, CDCl3) δH 1.13 (3H, t, J=9 Hz, N(CH2CH3)2), 1.30 (3H, t, J=9 Hz, N(CH2CH3)2), 1.55-2.14 (4H, m, 2- and 3-CH2), 2.78-2.86 (2H, m, 1-CH2), 3.36-3.67 (4H, m, N(CH2CH3)2), (1H, m, 4-CH), 4.30 (2H, dm, J=21 Hz, NCH2CH2F), 4.60 (2H, dm, J=41 Hz, NCH2CH2F), 6.75-6.95 (2H, m, NCCHCHCFCH), and 7.05-7.15 (1H, m, NCCHCHCFCH.
Reaction SMILES: [CH3:1][C:2]12[CH2:11][CH2:10][CH2:9][C:8]([CH3:13])([CH3:12])[CH:7]1[CH2:6][CH2:5][CH:4]([OH:14])[CH2:3]2.CC(CC)=O.CC(C)[O-].[Al+3].CC(C)[O-].CC(C)[O-].[Cl-].[Al+3].[Cl-].[Cl-]>C1(C)C=CC=CC=1>[CH3:1][C:2]12[CH2:11][CH2:10][CH2:9][C:8]([CH3:13])([CH3:12])[CH:7]1[CH2:6][CH2:5][C:4](=[O:14])[CH2:3]2
Reactant: CC1(C)CCCC2(C)CC(O)CCC12
Agent: CC(C)[O-]
Agent: [Al+3]
Agent: [Cl-]
Solvent: Cc1ccccc1
Solvent: CCC(C)=O
Product: CC1(C)CCCC2(C)CC(=O)CCC12

Procedure:
A mixture of 19.6 g. of 1,7,7-trimethylbicyclo[4.4.0]decan-3-ol, prepared according to the description of Example 1, paragraph (b) 72 g. of methylethylketone, 50 ml. of toluene, 10.5 g. of aluminium isopropoxide and 2 g. of aluminum chloride was heated to the boil for 6 hours. After cooling the mixture was stirred with 200 ml. of 10% H2SO4 and extracted with toluene. The extract was treated as usual and gave by distillation 8.2 g. of the bicycloketone, b.p. 85°-90°/0.001 Torr.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@H:12]1[C:16](=[O:33])[NH:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20](B2OC(C)(C)C(C)(C)O2)[CH:19]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:35]1[CH:43]=[C:42]2[C:38]([CH:39]=[CH:40][NH:41]2)=[CH:37][CH:36]=1.C([O-])(O)=O.[Na+].CN(C=O)C>CO>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@H:12]1[C:16](=[O:33])[NH:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([C:35]2[CH:43]=[C:42]3[C:38]([CH:39]=[CH:40][NH:41]3)=[CH:37][CH:36]=2)[CH:19]=1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Brc1ccc2cc[nH]c2c1
Reactant: CC1(C)OB(c2cccc(NC(=O)[C@@H]3CCCN3C(=O)OCc3ccccc3)c2)OC1(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Product: O=C(Nc1cccc(-c2ccc3cc[nH]c3c2)c1)[C@@H]1CCCN1C(=O)OCc1ccccc1
Temperature: 70 °C

Procedure:
A solution of (S)-2-[3-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenylcarbamoyl]-pyrrolidine-1-carboxylic acid benzyl ester (90 mg, 0.2 mmol), 6-Bromo-1H-indole (1 eq., 49 mg), Pd[P(Ph)3]4 (5 mol %, 10 mg), in methanol (4 mL), NaHCO3 (sat. aq., 600 uL) and DMF (800 uL) was degassed and heated to 70° C. overnight in a sealed vial. The reaction was cooled, filtered and the solvents removed. The resulting mixture was redissolved in 5 ml of 90% DMF, 10% water with 0.1% TFA and purified by reverse phase HPLC to give the products. Yield 5.7 mg. MS: 440.3 (M+H). H1-NMR (DMSO-d6): δ (ppm) 11.1 (s, 1H), 10.1 (s, 1H), 8.0 (m, 1H), 7.6-7.2 (m, 12H), 7.0 (m, 2H), 6.4 (m, 1H), 5.0 (m, 2H), 4.4 (m, 1H), 3.5 (m, 1H), 2.2 (m, 1H), 1.9 (m, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[N:10]=[C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19](=O)[CH3:20])[N:14]=1)[CH3:12].[CH3:22][Si:23]([CH3:33])([CH3:32])[O:24][C:25]1[CH:31]=[CH:30][C:28]([NH2:29])=[CH:27][CH:26]=1>C1(C)C=CC=CC=1>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[N:10]=[C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19](=[N:29][C:28]2[CH:27]=[CH:26][C:25]([O:24][Si:23]([CH3:33])([CH3:32])[CH3:22])=[CH:31][CH:30]=2)[CH3:20])[N:14]=1)[CH3:12]
Reactant: CC(=O)c1cccc(C(C)=Nc2c(C)cc(C)cc2C)n1
Reactant: C[Si](C)(C)Oc1ccc(N)cc1
Solvent: Cc1ccccc1
Product: CC(=Nc1ccc(O[Si](C)(C)C)cc1)c1cccc(C(C)=Nc2c(C)cc(C)cc2C)n1

Procedure:
Monoimine (1, 1.4 g, 5 mmol) and 4-trimethylsiloxy-aniline (8, 906 mg, 5 mmol) were dissolved in 50 ml of toluene. To this solution 4 Å molecular sieves were added. After standing at room temperature for 4 days with addition of more molecular sieves the reaction mixture was filtered and the solvent was removed in vacuo. The product was washed with a small amount of methanol. Yield 1.4 g (63%) of mixed diimine (9). 1H NMR (CDCl3) δ 8.42 (dd, 1H), 8.33 (dd, 1H), 7.86 (t, 1H), 6.88 (s, 2H), 6.86 (d, 2H), 6.74 (d, 2H), 2.42 (s, 3H), 2.28 (s, 3H), 2.21 (s, 3H), 2.00 (s, 6H), 0.27 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([S:9]([N:12]([CH2:14][CH2:15]Cl)[CH3:13])(=[O:11])=[O:10])=[C:4]([C:17]([F:20])([F:19])[F:18])[CH:3]=1.[F:21][C:22]1[CH:36]=[CH:35][C:25]2[NH:26][C:27]([CH:29]3[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]3)=[N:28][C:24]=2[CH:23]=1>>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([S:9]([N:12]([CH2:14][CH2:15][N:32]2[CH2:31][CH2:30][CH:29]([C:27]3[NH:26][C:25]4[CH:35]=[CH:36][C:22]([F:21])=[CH:23][C:24]=4[N:28]=3)[CH2:34][CH2:33]2)[CH3:13])(=[O:11])=[O:10])=[C:4]([C:17]([F:20])([F:19])[F:18])[CH:3]=1
Reactant: Fc1ccc2[nH]c(C3CCNCC3)nc2c1
Reactant: CN(CCCl)S(=O)(=O)c1cc(Cl)c(Cl)cc1C(F)(F)F
Product: CN(CCN1CCC(c2nc3cc(F)ccc3[nH]2)CC1)S(=O)(=O)c1cc(Cl)c(Cl)cc1C(F)(F)F

Procedure:
The title compound was prepared using the procedure described in Example 1 using 4,5-dichloro-N-(2-chloroethyl)-N-methyl-2-trifluoromethyl-benzenesulfonamide (D12) and 4-(5-fluoro 1H benzimidazol-2-yl)piperidine (D17). MH+ 581/583/585.
Reaction SMILES: [CH:1]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[CH2:8][N:7]([C:16]#[N:17])[CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[Na].[CH:19]([OH:22])([CH3:21])[CH3:20]>>[CH:1]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[CH2:8][N:7]([C:16](=[NH:17])[O:22][CH:19]([CH3:21])[CH3:20])[CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)O
Reactant: N#CN1Cc2ccccc2-c2ccccc2C1
Agent: [Na]
Product: CC(C)OC(=N)N1Cc2ccccc2-c2ccccc2C1

Procedure:
starting from 5,7-dihydro-6H-dibenz[c,e]azepine-6-carbonitrile and sodium isopropylate in isopropanol there is obtained isopropyl 5,7-dihydro-6H-dibenz[c,e]azepine-6-carboximidate and therefrom with hydrochloric acid in alcohol there is obtained the hydrochloride, m.p. 158° C. (with decomposition);
Reaction SMILES: [OH:1][C:2]1([C:8]2[S:9][C:10]([S:13][C:14]3[CH:23]=[CH:22][C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[CH:15]=3)=[CH:11][CH:12]=2)[CH2:6][CH2:5][O:4][CH:3]1[CH3:7].[CH3:24]I>>[CH3:24][O:1][C:2]1([C:8]2[S:9][C:10]([S:13][C:14]3[CH:23]=[CH:22][C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[CH:15]=3)=[CH:11][CH:12]=2)[CH2:6][CH2:5][O:4][CH:3]1[CH3:7]
Reactant: CC1OCCC1(O)c1ccc(Sc2ccc3ccccc3c2)s1
Reactant: CI
Product: COC1(c2ccc(Sc3ccc4ccccc4c3)s2)CCOC1C
Yield: 75 %

Procedure:
Using the procedure described in Example 1, (2RS,3RS)-3-hydroxy-2-methyl-3-[5-(naphth-2-ylthio)thien-2-yl]tetrahydrofuran was reacted with methyl iodide to give (2RS,3RS)-3-methoxy-2-methyl-3-[5-(naphth-2-ylthio)thien-2-yl]tetrahydrofuran in 75% yield as an oil.
Reaction SMILES: C[O:2][C:3](OC)([O:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[CH:8][N:7]=1)[CH3:4].O1CCOCC1.S(=O)(=O)(O)O>O>[C:6]1([O:5][C:3](=[O:2])[CH3:4])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[CH:8][N:7]=1
Reactant: COC(C)(OC)Oc1nccc2ccccc12
Agent: O=S(=O)(O)O
Solvent: O
Solvent: C1COCCO1
Product: CC(=O)Oc1nccc2ccccc12
Temperature: 85 °C
Yield: 57.4 %

Procedure:
A mixture of 1-isoquinolinyloxyacetaldehyde dimethyl acetal (0.93 g, 4 mmol), dioxane (10 mL), water (15 mL) and conc. sulfuric acid (2 mmol) was heated at 85° C. for 2 h, then was quenched with saturated aqueous sodium hydrogen carbonate (100 mL). The resulting mixture was extracted with dichloromethane (2×100 mL) and the combined organic extracts were washed with saturated aqueous sodium hydrogen carbonate (50 mL), dried over sodium sulfate and evaporated in vacuo to give the title compound (0.43 g, 57%).