Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:31]([F:34])([F:33])[F:32])=[C:6]([CH:30]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:23]=[CH:22][N:21]=[C:20]([N:24]4[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]4)[CH:19]=3)=[CH:17][C:9]1=2.[C:35](Cl)(=[O:37])[CH3:36].C(N(CC)CC)C>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:31]([F:32])([F:34])[F:33])=[C:6]([CH:30]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:23]=[CH:22][N:21]=[C:20]([N:24]4[CH2:25][CH2:26][N:27]([C:35](=[O:37])[CH3:36])[CH2:28][CH2:29]4)[CH:19]=3)=[CH:17][C:9]1=2
Reactant: FC(F)(F)c1ccc(Cl)cc1CN1CCNc2ncc(-c3ccnc(N4CCNCC4)c3)cc21
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(=O)N1CCN(c2cc(-c3cnc4c(c3)N(Cc3cc(Cl)ccc3C(F)(F)F)CCN4)ccn2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 56 %

Procedure:
To a solution of 1-[5-chloro-2-(trifluoromethyl)benzyl]-7-(2-piperazin-1-yl-pyridin-4-yl)-1,2,3,4-tetrahydro-pyrido[2,3-b]pyrazine (63 mg, 0.000129 mol) in anhydrous DMF (1 mL) was added acetyl chloride (0.012 mL) and triethylamine (0.020 mL). The mixture was stirred at room temperature under nitrogen overnight and then concentrated. The residue was purified on normal phase silica gel chromatography to give the title compound as a yellow solid (56% yield). m.p.=241° C., LCMS: m/z=531.31 (M+H+), 1H-NMR (CDCl3, 400 MHz) δ 2.15 (3H, s), 3.47 (2H, m), 3.52 (2H, m), 3.57 (2H, m), 3.62 (2H, m), 3.73 (4H, m), 4.61 (2H, s), 5.25 (1H, bs), 6.55 (2H, m), 6.69 (1H, d, J=5.3 Hz), 7.37 (1H, d, J=8.3 Hz), 7.52 (1H, s), 7.65 (1H, d, J=8.3 Hz), 7.78 (1H, bs), 8.12 (1H, d, J=5.3 Hz).
Reaction SMILES: BrCCCCCO[C:8]1[CH:21]=[CH:20][C:11]([C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:13])=[CH:10][CH:9]=1.CNC.O>C(O)C>[C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)(=[O:13])[C:11]1[CH:20]=[CH:21][CH:8]=[CH:9][CH:10]=1
Reactant: O=C(c1ccccc1)c1ccc(OCCCCCBr)cc1
Agent: CNC
Solvent: CCO
Solvent: O
Product: O=C(c1ccccc1)c1ccccc1

Procedure:
A solution of 3.0 g of 4-[(5-bromopentyl)oxy]benzophenone in 30 ml of ethanol was heated to 90° in a pressure tube for 1.5 hours with 16 ml of a 33 percent solution of dimethylamine in ethanol. After cooling the mixture was poured into water and extracted three times with ethyl acetate. The organic phases, dried over sodium sulphate, were evaporated and the residue was chromatographed on neutral aluminium oxide (activity grade III) with hexane:ethyl acetate 7:3). There were obtained 2.69 g (97%) of 4- (5-(dimethylamino)pentyl)oxy]benzophenone as a colorless oil.
Reaction SMILES: [C:1]([NH:5][NH:6][C:7](=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[F:15][C:16]([F:24])([F:23])/[C:17](/[CH3:22])=[CH:18]\[C:19](Cl)=[O:20].C(Cl)(=O)C(Cl)=O.FC(F)(F)/C(/C)=C\C(O)=O>C1(C)C=CC=CC=1>[C:1]([N:5]([C:19](=[O:20])/[CH:18]=[C:17](\[C:16]([F:24])([F:23])[F:15])/[CH3:22])[NH:6][C:7](=[O:14])[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: C/C(=C/C(=O)Cl)C(F)(F)F
Reactant: CC(C)(C)NNC(=O)c1ccccc1
Agent: C/C(=C/C(=O)O)C(F)(F)F
Agent: O=C(Cl)C(=O)Cl
Solvent: Cc1ccccc1
Product: C/C(=C/C(=O)N(NC(=O)c1ccccc1)C(C)(C)C)C(F)(F)F
Reaction time: 0.5 h

Procedure:
N'-t-butyl-N-benzoylhydrazine (1.0 g,) in 2 ml toluene was added dropwise to a solution of beta-trifluoromethylcrotonyl chloride (prepared by addition of oxalyl chloride (1.3 g) to a solution of 1.5 g beta-trifluoromethylcrotonic acid in 5 ml toluene at 23° C.). After 30 min. at 23° C., the reaction mixture was partitioned between saturated aqueous sodium bicarbonate (20 ml) and ether (20 ml). The ether layer was evaporated under reduced pressure to about 10 ml and the excess hydrazine was removed by filtration. The filtrate was evaporated to give N'-t-butyl-N-benzoyl-N'-(beta-trifluoromethylcrotonyl)hydrazine as a colorless oil.
Reaction SMILES: C([O:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([O:19][CH3:20])[N:17]=2)[N:12]=[CH:11][C:10]=1[NH2:21])C1C=CC=CC=1.ClCCl>[Pd].CO>[NH2:21][C:10]1[CH:11]=[N:12][C:13]2[C:18]([C:9]=1[OH:8])=[N:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2
Reactant: COc1ccc2ncc(N)c(OCc3ccccc3)c2n1
Agent: [Pd]
Solvent: ClCCl
Solvent: CO
Product: COc1ccc2ncc(N)c(O)c2n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 28.7 %

Procedure:
10% Palladium on activated carbon (76 mg, 0.07 mmol, 0.1 eq) is added at room temperature to a stirred solution of 4-benzyloxy-6-methoxy-[1,5]naphthyridin-3-ylamine (200 mg, 0.71 mmol, 1.0 eq) in methanol (20 mL). The resulting mixture is stirred under hydrogen flow (3 bars) at room temperature for 16 hours. The catalyst is then removed by filtration and the solution is concentrated to give a residue that is purified by column chromatography (silica gel, eluent: dichloromethane:methanol, 50:1 to 10:1, v/v) to afford 3-amino-6-methoxy-[1,5]naphthyridin-4-ol as a yellow solid (39 mg, 29% yield).
Reaction SMILES: [C@H]1(C[N:12]2[CH2:17][CH2:16][CH:15]([NH:18][C:19]([C:21]3[NH:22][C:23]4[C:28]([CH:29]=3)=[C:27]([O:30][CH2:31][C:32]3[C:36]5[C:37]([O:41][CH3:42])=[CH:38][CH:39]=[CH:40][C:35]=5[O:34][CH:33]=3)[CH:26]=[CH:25][CH:24]=4)=[O:20])[CH2:14][CH2:13]2)[C@@H]2N(CCCC2)CCC1.Cl.Cl.Cl.NC1CCN([CH2:53][CH2:54][N:55]2[CH2:60][CH2:59][C@H:58]([OH:61])[C@@H:57]([CH3:62])[CH2:56]2)CC1>>[OH:61][C@H:58]1[CH2:59][CH2:60][N:55]([CH2:54][CH2:53][N:12]2[CH2:17][CH2:16][CH:15]([NH:18][C:19]([C:21]3[NH:22][C:23]4[C:28]([CH:29]=3)=[C:27]([O:30][CH2:31][C:32]3[C:36]5[C:37]([O:41][CH3:42])=[CH:38][CH:39]=[CH:40][C:35]=5[O:34][CH:33]=3)[CH:26]=[CH:25][CH:24]=4)=[O:20])[CH2:14][CH2:13]2)[CH2:56][C@@H:57]1[CH3:62]
Reactant: COc1cccc2occ(COc3cccc4[nH]c(C(=O)NC5CCN(C[C@@H]6CCCN7CCCC[C@H]67)CC5)cc34)c12
Reactant: C[C@H]1CN(CCN2CCC(N)CC2)CC[C@@H]1O
Agent: Cl
Product: COc1cccc2occ(COc3cccc4[nH]c(C(=O)NC5CCN(CCN6CC[C@H](O)[C@@H](C)C6)CC5)cc34)c12

Procedure:
This compound is synthesized analogously to example 1 from 4-(4-methoxy-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid 122 (see example 94) and amine 14.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8](=[N:10][O:11][CH2:12][CH2:13][O:14][C:15]2[CH:28]=[CH:27][C:18]([CH2:19][CH:20]3[S:24][C:23](=[O:25])[NH:22][C:21]3=[O:26])=[CH:17][CH:16]=2)[CH3:9])[CH:5]=[CH:6][CH:7]=1.[C:29](OC(=O)C)(=[O:31])[CH3:30]>N1C=CC=CC=1>[C:29]([O:1][C:2]1[CH:3]=[C:4]([C:8](=[N:10][O:11][CH2:12][CH2:13][O:14][C:15]2[CH:28]=[CH:27][C:18]([CH2:19][CH:20]3[S:24][C:23](=[O:25])[NH:22][C:21]3=[O:26])=[CH:17][CH:16]=2)[CH3:9])[CH:5]=[CH:6][CH:7]=1)(=[O:31])[CH3:30]
Reactant: CC(=NOCCOc1ccc(CC2SC(=O)NC2=O)cc1)c1cccc(O)c1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)Oc1cccc(C(C)=NOCCOc2ccc(CC3SC(=O)NC3=O)cc2)c1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A mixture of 0.30 g of 5-(4-{2-[1-(3-hydroxyphenyl)ethylideneaminooxy]ethoxy}benzyl)thiazolidine-2,4-dione (prepared as described in Example 50), 0.092 ml of acetic anhydride and 15 ml of pyridine was stirred at room temperature for 1.5 hours. At the end of this time, the solvent was removed by distillation under reduced pressure, and then the resulting residue was diluted with water and then extracted with ethyl acetate. The extract was washed with 1N aqueous hydrochloric acid and with an aqueous solution of sodium chloride, in that order, after which it was dried over anhydrous magnesium sulfate. The solvent was then removed by distillation under reduced pressure, and the residue was purified by column chromatography through silica gel, using a 1:2 by volume mixture of ethyl acetate and hexane as the eluent, to give 0.23 g of the title compound, melting at 30°-50° C. (softening point).
Reaction SMILES: Cl.[NH2:2][OH:3].C(=O)([O-])[O-].[Na+].[Na+].[CH2:10]([O:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][C:31](Cl)=[O:32])=[CH:19][CH:18]=1)[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].O>C(Cl)Cl>[CH2:10]([O:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][C:31]([NH:2][OH:3])=[O:32])=[CH:19][CH:18]=1)[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: CCCCCCOc1ccc(CCCCCCCCC(=O)Cl)cc1
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CCCCCCOc1ccc(CCCCCCCCC(=O)NO)cc1
Yield: 10.8 %

Procedure:
To a cold, stirring suspension of 1.2 gms hydroxylamine hydrochloride and 1.7 gms sodium carbonate in 40 ml CH2Cl2 was added dropwise 4.2 gms 9(4-hexyloxyphenyl)nonanoyl chloride. The mixture was stirred for 1/2 hr in the cold, then 2 ml water was added, and the reaction was stirred at room temperature overnight. The suspension was then diluted with CH2Cl2, washed three times with water and once with NaCl solution, then dried over MgSO4. The drying agent was filtered off and the solvent was removed in vacuo to give a solid which was crystallized from CHCl3 :hexanes and then hexanes. Impurities were still present by thin layer chromatography, so the solid was dissolved in 3:1 benzene:hexanes, shaken with 150 gms silica gel, and the silica gel washed with ethyl acetate. The solid remaining on evaporation of the solvent was purified by column chromatography on silica gel with 30% ethyl acetate:CHCl3. The main fraction had Rf=0.4 by thin layer chromatography. The residue from the collected fractions was crystallized twice from CH2Cl2 to give 0.45 gms product of m.p. 94°-6°.
Reaction SMILES: Cl.Br[C:3]1[C:4]([O:9][C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)=[CH:12][CH:11]=2)=[N:5][CH:6]=[CH:7][CH:8]=1.CN(C1CCCCC1)C1CCCCC1.[C:37]1(=[O:42])[CH2:41][CH2:40][CH:39]=[CH:38]1>O1CCOCC1.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>[N:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[NH:16][C:13]1[CH:14]=[CH:15][C:10]([O:9][C:4]2[C:3]([C:39]3[CH2:40][CH2:41][C:37](=[O:42])[CH:38]=3)=[CH:8][CH:7]=[CH:6][N:5]=2)=[CH:11][CH:12]=1
Reactant: O=C1C=CCC1
Reactant: Brc1cccnc1Oc1ccc(Nc2ccccn2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CN(C1CCCCC1)C1CCCCC1
Agent: Cl
Solvent: C1COCCO1
Product: O=C1C=C(c2cccnc2Oc2ccc(Nc3ccccn3)cc2)CC1
Temperature: 23 °C
Reaction time: 0.25 h

Procedure:
A suspension of N-(4-(3-bromopyridin-2-yloxy)phenyl)pyridin-2-amine hydrochloride (600 mg, 1.585 mmol) in Dioxane (4 mL) was treated with n-methyldicyclohexylamine (1.008 mL, 4.75 mmol, 3.0 equiv). The reaction was stirred at 23° C. for 15 min, followed by the addition of 2-cyclopenten-1-one (0.641 mL, 7.92 mmol, 5.0 equiv) and bis(tri-tert-butylphosphine)palladium (0) (81 mg, 0.158 mmol, 0.1 equiv). The reaction vessel was capped, degassed and backfilled with argon, and heated at 105° C. After 6 h, the reaction was cooled to 23° C., diluted with EtOAc (100 mL) and washed with water (75 mL) and brine (75 mL), dried over MgSO4, concentrated in vacuo and purified by silica gel chromatography (eluant: 0.5-3% methanol/dichloromethane), affording 3-(2-(4-(pyridin-2-ylamino)phenoxy)pyridin-3-yl)cyclopent-2-enone. MS (ESI, pos. ion) m/z: 344.1 (M+1). IC50 (uM) 0.015.
Reaction SMILES: [Cl:1][C:2]([Cl:6])=[CH:3][CH2:4][NH2:5].[Cl:7][CH:8]([Cl:12])[C:9](Cl)=[O:10]>>[Cl:1][C:2]([Cl:6])=[CH:3][CH2:4][NH:5][C:9](=[O:10])[CH:8]([Cl:12])[Cl:7]
Reactant: NCC=C(Cl)Cl
Reactant: O=C(Cl)C(Cl)Cl
Product: O=C(NCC=C(Cl)Cl)C(Cl)Cl

Procedure:
By reaction of the N-(3,3-dichloroallyl)amine with the dichloroacetyl chloride, as in Example 1, there was obtained N-(3,3-dichloroallyl)dichloroacetamide.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([O:13][CH3:14])=[CH:5][C:4]=1[CH2:15][CH2:16][CH2:17]I.[C-:19]#[N:20].[Na+].O>CS(C)=O>[CH3:1][O:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([O:13][CH3:14])=[CH:5][C:4]=1[CH2:15][CH2:16][CH2:17][C:19]#[N:20]
Reactant: COc1cc(CCCI)c(OC)c2ccccc12
Reactant: [C-]#N
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: COc1cc(CCCC#N)c(OC)c2ccccc12
Yield: 92.3 %

Procedure:
A solution of 5.08 g of 3-(1,4-dimethoxy-2-naphthyl)propyl iodide (prepared as described in Preparation 30), and 0.70 g of sodium cyanide in 60 ml of dry dimethyl sulfoxide was stirred at 60° C. (external temperature) for 80 minutes. At the end of this time, the reaction mixture was cooled and poured into water, after which it was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate and the solvent was removed by distillation under reduced pressure. The resulting residue was purified by column chromatography through silica gel, using a 4:1 by volume mixture of hexane and ethyl acetate as the eluent, to give 3.36 g of the title compound as a colorless oil.
Reaction SMILES: C[N:2](C)[CH:3]=[CH:4][C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=2)[N:8]=1)=O.Cl.[CH:26]1([CH2:29][NH:30]N)[CH2:28][CH2:27]1.CCN(CC)CC.Cl>CO>[CH:26]1([CH2:29][N:30]2[C:5]([C:7]3[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]4[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=4)[N:8]=3)=[CH:4][CH:3]=[N:2]2)[CH2:28][CH2:27]1
Reactant: NNCC1CC1
Reactant: CN(C)C=CC(=O)c1nn(-c2cccc(C(F)(F)F)c2)ccc1=O
Agent: Cl
Solvent: CO
Solvent: CCN(CC)CC
Product: O=c1ccn(-c2cccc(C(F)(F)F)c2)nc1-c1ccnn1CC1CC1
Temperature: 25 °C
Yield: 43.7 %

Procedure:
A solution of 3-[3-(dimethylamino)prop-2-enoyl]-1-[3-(trifluoromethyl)phenyl]pyridazin-4(1H)-one (675 mg, 2 mmol), cyclopropylmethylhydrazine hydrochloride (490 mg, 4 mmol), and Et3N (0.558 mL, 4 mmol) in MeOH (20 mL) was refluxed for 2 h. After cooling to room temperature, the reaction mixture was poured into 1 M HCl aqueous solution and extracted with AcOEt. The extract was washed with brine, dried over MgSO4, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography eluting with AcOEt and recrystallized from hexane/AcOEt to give the title compound (315 mg, 44% yield) as a pale yellow solid: mp 155-157° C.; 1H NMR (300 MHz, CDCl3): δ ppm 0.35-0.44 (2H, m), 0.45-0.57 (2H, m), 1.24-1.40 (1H, m), 4.37 (2H, d, J=6.8 Hz), 6.76 (1H, d, J=7.9 Hz), 7.37 (1H, d, J=1.9 Hz), 7.61 (1H, d, J=1.9 Hz), 7.68-7.74 (2H, m), 7.78-7.83 (1H, m), 7.94 (1H, s), 8.28 (1H, d, J=7.9 Hz). Anal. Calcd for C18H15F3N4O: C, 60.00; H, 4.20; N, 15.55. Found: C, 60.07; H, 4.24; N, 15.56.
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[OH:6][C:7]1[CH:19]=[CH:18][CH:17]=[CH:16][C:8]=1[O:9][CH2:10][CH:11]1[NH:15][CH2:14][CH2:13][S:12]1>ClCCCl>[Cl:1][CH2:2][C:3]([N:15]1[CH2:14][CH2:13][S:12][CH:11]1[CH2:10][O:9][C:8]1[CH:16]=[CH:17][CH:18]=[CH:19][C:7]=1[OH:6])=[O:4]
Reactant: O=C(Cl)CCl
Reactant: Oc1ccccc1OCC1NCCS1
Solvent: ClCCCl
Product: O=C(CCl)N1CCSC1COc1ccccc1O
Temperature: -30 °C

Procedure:
Chloroacetylchloride (2.5 ml) is added to a stirred solution of 2-[(o-hydroxyphenoxy)methyl]thiazolidine (6 g) in 1,2-dichloroethane (80 ml) and triethilamine (4.3 ml) cooled at -30° C. After the usual work-up 3-αchloroacetyl-2-[(o-hydroxyphenoxy)methyl]thiazolidine (5.7 g, from Et2O, m.p. 89°-91° C.) is obtained. A stirred solution of the latter compound in 1,2-dichloroethane (50 ml) is heated with solid potassium thioacetate (4 g). After 2 hours, the mixture is washed with water to give, after the usual work-up, 3-acetylthio-acetyl-2-[(o-hydroxyphenoxy)methyl]thiazolidine (6.4 g, from EtOH) m.p. 97°-99° C.
Reaction SMILES: [SH:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]([O:9]C)=O.Br.[NH2:12][CH2:13][CH2:14]Br.C[O-].[Na+]>C1(C)C=CC=CC=1.CO>[S:1]1[C:2]2[CH:6]=[CH:5][S:4][C:3]=2[C:7](=[O:9])[NH:12][CH2:13][CH2:14]1
Reactant: COC(=O)c1sccc1S
Reactant: NCCBr
Agent: Br
Agent: C[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CO
Product: O=C1NCCSc2ccsc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
(aca) Method A: 17.4 g of methyl 3-mercapto-thiophene-2-carboxylate were dissolved in 350 ml of toluene under an inert gas atmosphere, whereupon the solution was treated with 20.5 g of 2-aminoethyl bromide hydrobromide and then with 100 ml of 3N sodium methylate solution in methanol. The mixture was stirred at room temperature for 30 minutes and thereafter heated under reflux until the reaction finished. The mixture was evaporated in vacuo, the residue was taken up in 300 ml of water, acidified with 2N hydrochloric acid and the crystals were removed by filtration. By recrystallization from chloroform there was obtained 3,4-dihydro-thieno[2,3-f][1,4]thiazepin-5-(2H)-one as white crystals of m.p. 186°-188°.
Reaction SMILES: Cl[CH2:2][C:3](=[CH2:6])[C:4]#[N:5].[CH3:7][O:8][P:9]([CH2:13][CH2:14][OH:15])(=[O:12])[O:10][CH3:11].C(N(CC)CC)C>C1COCC1.C1C2NC3C(=CC=CC=3)SC=2C=CC=1>[CH3:7][O:8][P:9]([CH2:13][CH2:14][O:15][CH2:2][C:3](=[CH2:6])[C:4]#[N:5])([O:10][CH3:11])=[O:12]
Reactant: COP(=O)(CCO)OC
Reactant: C=C(C#N)CCl
Agent: c1ccc2c(c1)Nc1ccccc1S2
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C=C(C#N)COCCP(=O)(OC)OC
Temperature: 65 °C
Yield: 54.2 %

Procedure:
86.3 g (850 mmol) 2-(chloromethyl)-acrylonitrile are added dropwise at room temperature to a solution of 130.9 g (850 mmol) 2-hydroxyethylphosphonic acid dimethylester, 85.9 g (850 mmol) triethylamine (TEA) and 40 mg phenothiazine (stabilizer) in 1 l THF. Subsequently, the mixture is heated for 6 hours at 65° C. under reflux. 9.1 g (90 mmol) TEA and 9.1 g (90 mmol) 2-(chloromethyl)-acrylonitrile are once again added one after the other and the mixture is heated for a further 24 hours under reflux. After the reaction mixture has cooled, the formed deposit of TEA hydrochloride is filtered out and is washed twice with 50 ml THF. After the THF phases have been concentrated on the rotary evaporator, the residual raw product is taken up in 650 ml methylene chloride and washed twice with water. After it has been dried over anhydrous sodium sulphate, the mixture is concentrated and the residual liquid undergoes fractional distillation in the fine vacuum. 101.0 g (54% yield) of a colourless liquid results at b.p. 150° C. (0.05 mbar).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:5]2.[F:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=1)[CH2:20]Cl.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C)C=O>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:20][C:19]1[CH:22]=[CH:23][CH:24]=[C:17]([F:16])[CH:18]=1)[C:6]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:5]2
Reactant: Fc1cccc(CCl)c1
Reactant: CCOC(=O)c1cc2cc(F)ccc2[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2cc(F)ccc2n1Cc1cccc(F)c1
Temperature: 60 °C
Reaction time: 24 h
Yield: 61.8 %

Procedure:
A suspension of 0.207 g (1 mmol) of ethyl 5-fluoro-1H-indole-2-carboxylate, 0.173 g (1.2 mmol) of 3-fluorobenzyl chloride and 0.276 g (2 mmol) of potassium carbonate in 10 ml of dimethylformamide is stirred at 60° C. for 24 hours. The reaction mixture is subsequently cooled and is poured into a mixture of ice-cold water and of ethyl acetate. After settling, the organic phase is separated and then it is washed with two times 50 ml of water and then with 50 ml of a saturated sodium chloride solution. The solution is dried over magnesium sulfate and is filtered, and then the filtrate is concentrated under reduced pressure. 0.195 g of an oil is obtained, which oil is used as is in the following stage.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:36])=[C:9]([CH2:11][O:12][C:13]2[CH:33]=[CH:32][C:16]([CH2:17][O:18][C:19]3[CH:23]=[C:22]([CH2:24]O)[N:21]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[N:20]=3)=[CH:15][C:14]=2[O:34][CH3:35])[N:10]=1.C(P(CCCC)CCCC)CCC.[NH:50]1[CH:54]=[N:53][CH:52]=[N:51]1.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C(OCC)(=O)C.O1CCCC1>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:36])=[C:9]([CH2:11][O:12][C:13]2[CH:33]=[CH:32][C:16]([CH2:17][O:18][C:19]3[CH:23]=[C:22]([CH2:24][N:50]4[CH:54]=[N:53][CH:52]=[N:51]4)[N:21]([C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=4)[N:20]=3)=[CH:15][C:14]=2[O:34][CH3:35])[N:10]=1
Reactant: c1nc[nH]n1
Reactant: COc1cc(COc2cc(CO)n(-c3ccccc3)n2)ccc1OCc1nc(-c2ccco2)oc1C
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1cc(COc2cc(Cn3cncn3)n(-c3ccccc3)n2)ccc1OCc1nc(-c2ccco2)oc1C
Reaction time: 15 h
Yield: 85.1 %

Procedure:
To a mixture of {3-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-methoxybenzyl)oxy]-1-phenyl-1H-pyrazol-5-yl}methanol (0.50 g), tributylphosphine (0.61 g), 1H-1,2,4-triazole (0.21 g) and tetrahydrofuran (80 mL) was added 1,1′-(azodicarbonyl)dipiperidine (0.75 g) at room temperature, and the mixture was stirred for 15 hrs. Ethyl acetate was added to the reaction mixture. The ethyl acetate layer was washed successively with 1N hydrochloric acid and saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to give 1-({3-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-methoxybenzyl)oxy]-1-phenyl-1H-pyrazol-5-yl}methyl)-1H-1,2,4-triazole as crystals (0.47 g, yield 85%) from a fraction eluted with ethyl acetate-hexane (2:1, v/v). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 95-96° C.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13]>CC(N(C)C)=O.C(OCC)(=O)C>[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][N:22]([C:2]2[N:3]=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=2)[CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:13])[CH3:14]
Reactant: FC(F)(F)c1cnnc(Cl)c1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCN(c2cc(C(F)(F)F)cnn2)CC1
Temperature: 100 °C
Reaction time: 3 h
Yield: 100 %

Procedure:
3-Chloro-5-trifluoromethyl-pyridazine (200 mg) was added to piperazine-1-carboxylic acid tert-butyl ester (231 mg) in dimethylacetamide (3 mL), and the reaction mixture was stirred at 100° C. for 3 hours. After such time, the reaction mixture was allowed to cool down to room temperature and diluted with ethyl acetate. The solid was filtered off and washed with ethyl acetate. The filtrate was then concentrated in vacuo and then purified by column chromatography (SiO2, Heptane/EtOAc) to yield the title compound as a white solid (364 mg). MS (m/e): 333.4 (M+H+, 100%)
Reaction SMILES: [C:1]1(C#C)C=CC=C[CH:2]=1.[C:9]1([C:16]#[C:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:10](Br)=[CH:11][CH:12]=[CH:13][CH:14]=1.C[Si](C#C)(C)C>>[C:9]1([C:16]#[C:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:1]#[CH:2]
Reactant: Brc1ccccc1C#Cc1ccccc1
Reactant: C#Cc1ccccc1
Agent: C#C[Si](C)(C)C
Product: C#Cc1ccccc1C#Cc1ccccc1

Procedure:
In an especially contemplated arm extension strategy depicted in FIG. 4, in which AD represents an admantane or diamantane group. Phenylacetylene is a starting molecule that is reacted (A1) with TBA (supra) to yield tetrakis(mono-tolanyl)-adamantane. Alternatively, phenylacetylene can be converted (B1) to tolanylbromide that is subsequently reacted (C1) with trimethylsilylacetylene to form tolanylacetylene. TBA can then be reacted (A2) with tolanylacetylene to tetrakis(bis-tolanyl)-adamantane. In a further extension reaction, tolanylacetylene is reacted (B2) with 1-bromo-4-iodobenzene to bistolanylbromide that is further converted (C2) to bistolanylacetylene. The so formed bistolanylacetylene may then be reacted (A3) with TBA to yield tetrakis(tristolanyl)-adamantane.