Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[NH:6][C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.C1(C)C=CC=CC=1.[C:23](#[N:26])[CH:24]=[CH2:25]>C1C=CC=CC=1>[CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[N:6]([CH2:25][CH2:24][C:23]#[N:26])[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1
Reactant: C=CC#N
Reactant: Cc1ccc2[nH]c3c(c2c1)CN(C)CC3
Solvent: c1ccccc1
Solvent: Cc1ccccc1
Product: Cc1ccc2c(c1)c1c(n2CCC#N)CCN(C)C1
Reaction time: 0.25 h
Yield: 52.6 %

Procedure:
2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (1.5 g, 7.5 mmol) was taken in 20 ml of benzene: toluene mixture (1:1) along with acrylonitrile (1 ml, 15 mmol), cooled to 0° C., followed by addition of triton base (0.3 ml). The contents were stirred for 15 min. Acrylonitrile and triton base (same amount) were added and stirred at RT for 1 h. The reaction was monitored by TLC and LCMS. On completion of the reaction, reaction mixture was quenched with water, extracted with ethyl acetate, dried over anhydrous sodium sulfate and evaporated under reduced pressure to obtain solid material, which was crystallized using diethyl ether to yield 3-(2,8-dimethyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)propanenitrile (yield: 1 g). 1H NMR (CDCl3) 7.25 (s, 1H), 7.18-7.15 (d, 1H), 7.08-7.03 (d, 1H), 4.38-4.32 (t, 2H), 3.70-3.65 (m, 2H), 2.95-2.90 (m, 4H), 2.78-2.70 (t, 2H), 2.58 (s, 3H), 2.45 (s, 3H).
Reaction SMILES: C([O:5][C:6](=[O:31])[C@@H:7]([CH:28]([CH3:30])[CH3:29])[N:8]([CH2:23][CH2:24][CH:25]([CH3:27])[CH3:26])[S:9]([C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[CH:15][CH:16]=[C:17]([OH:22])[CH:18]=2)[CH:13]=1)(=[O:11])=[O:10])(C)(C)C>Cl.C(OCC)(=O)C>[CH2:23]([N:8]([S:9]([C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[CH:15][CH:16]=[C:17]([OH:22])[CH:18]=2)[CH:13]=1)(=[O:11])=[O:10])[C@@H:7]([C:6]([OH:31])=[O:5])[CH:28]([CH3:30])[CH3:29])[CH2:24][CH:25]([CH3:27])[CH3:26]
Reactant: CC(C)CCN([C@@H](C(=O)OC(C)(C)C)C(C)C)S(=O)(=O)c1ccc2cc(O)ccc2c1
Agent: Cl
Solvent: CCOC(C)=O
Product: CC(C)CCN([C@@H](C(=O)O)C(C)C)S(=O)(=O)c1ccc2cc(O)ccc2c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 89.3 %

Procedure:
N-Isoamyl-N-(6-hydroxy naphthalene-2-sulfonyl)-D-valine tert-butyl ester (0.33 g, 0.74 mmol) is dissolved in 4 N hydrochloric acid in ethyl acetate (50 mL), and the reaction is allowed to stir at ambient temperature for 16 h. The solvent is removed in vacuo, and the residue is purified by column chromatography (15% hexanes-ethyl acetate) to afford the title compound as a colorless oil (0.26 g, 90% yield). LCMS (m/z): (394.24, M+1; 392.27, M−1).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:14]([NH:16][CH2:17][C:18]2[C:19](=[O:26])[NH:20][C:21]([CH3:25])=[CH:22][C:23]=2[CH3:24])=[O:15])[C:5]2[CH:6]=[N:7][N:8]([CH:11]([CH3:13])[CH3:12])[C:9]=2[CH:10]=1.[N:27]1[CH:32]=[CH:31][CH:30]=[C:29](B(O)O)[CH:28]=1.C(=O)(O)[O-].[Na+]>COCCOC.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[CH3:24][C:23]1[CH:22]=[C:21]([CH3:25])[NH:20][C:19](=[O:26])[C:18]=1[CH2:17][NH:16][C:14]([C:4]1[C:5]2[CH:6]=[N:7][N:8]([CH:11]([CH3:13])[CH3:12])[C:9]=2[CH:10]=[C:2]([C:29]2[CH:28]=[N:27][CH:32]=[CH:31][CH:30]=2)[CH:3]=1)=[O:15]
Reactant: OB(O)c1cccnc1
Reactant: Cc1cc(C)c(CNC(=O)c2cc(Br)cc3c2cnn3C(C)C)c(=O)[nH]1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])O
Solvent: ClCCl
Solvent: COCCOC
Solvent: O
Product: Cc1cc(C)c(CNC(=O)c2cc(-c3cccnc3)cc3c2cnn3C(C)C)c(=O)[nH]1
Temperature: 120 °C
Yield: 61.4 %

Procedure:
In a 25 mL sealable tube under nitrogen were combined 6-bromo-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-(1-methylethyl)-1H-indazole-4-carboxamide (120 mg, 0.29 mmol) and 3-pyridinylboronic acid (53 mg, 0.43 mmol) in DME/water (3 mL: 1 mL). PdCl2(dppf)-CH2Cl2 (11.7 mg, 0.014 mmol) was added and the resulting mixture was degassed with nitrogen for 10 min. Sodium bicarbonate (72.5 mg, 0.86 mmol) was added and the insoluble mixture was heated in a microwave at 120° C. for 20 min. It was evaporated and the residue was dissolved in DCM and purified by SiO2 chromatography (eluent: gradient 100% DCM to 80:20:2 DCM/MeOH/NH4OH). Fractions were evaporated. DMF was added along with some water and the solids that precipitated were filtered, washed with water and hexanes and dried to afford the title compound (74 mg, 61%) as a light grey solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.54 (s, 1H) 9.11 (d, J=2.02 Hz, 1H) 8.66 (t, J=4.80 Hz, 1H) 8.61 (dd, J=4.80, 1.26 Hz, 1H) 8.42 (s, 1H) 8.28 (dt, J=8.02, 1.93 Hz, 1H) 8.25 (s, 1H) 7.93 (s, 1H) 7.54 (dd, J=7.83, 4.80 Hz, 1H) 5.89 (s, 1H) 5.19 (dt, J=13.14, 6.57 Hz, 1H) 4.40 (d, J=4.80 Hz, 2H) 2.22 (s, 3H) 2.12 (s, 3H) 1.52 (s, 3H) 1.50 (s, 3H). MS(ES) [M+H]+ 416.1.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[Cl-].[Al+3].[Cl-].[Cl-].[N+]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([O-])=O>>[C:1]([C:14]1[CH:15]=[CH:16][C:17]2[C:12](=[CH:17][CH:12]=[CH:13][CH:14]=2)[CH:13]=1)(=[O:3])[CH3:2]
Reactant: O=[N+]([O-])c1ccccc1
Reactant: CC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Product: CC(=O)c1ccc2ccccc2c1

Procedure:
One such method by which they can be prepared involves the reaction of an unsubstituted or substituted naphthalene with acetyl chloride in nitrobenzene in the presence of about three molar equivalents of aluminum chloride to afford the corresponding 2-acetylnaphthlene derivative. The resulting derivative is heated with morpholine in the presence of sulfur at 150° C; the resulting product is refluxed with concentrated hydrochloric acid to furnish the corresponding 2-naphthylacetic acid derivative.
Reaction SMILES: [CH:1]1([C:6]#[CH:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.O1CCCC1.C([Li])CCC.CCCCCC.C1(C#C)CCCC1.[Li].O(C1C=CC=CC=1)[C:33]#[N:34]>>[CH:1]1([C:6]#[C:7][C:33]#[N:34])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C#CC1CCCC1
Reactant: N#COc1ccccc1
Agent: [Li]
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: N#CC#CC1CCCC1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 83.9 %

Procedure:
To a oven dried 500 mL 3-neck round bottom flask equipped with a stir bar, a nitrogen inlet, a 125 mL addition funnel and a thermocouple, cyclopentylacetylene (7, 15.0 g, 0.143 mol) and anhydrous tetrahydrofuran (THF, 170 mL, 2.10 mol) were added at room temperature. The resulting solution was then cooled to −78° C. before a solution of 2.5 M n-butyllithium in hexane (63.1 mL, 0.158 mol, 1.1 equiv) was added dropwise over 25 min. The resulting lithium cyclopentylacetylene solution was stirred at −78° C. for 15 minutes before a solution of crude cyanatobenzene (6, 25.0 g, 0.210 mol, 1.5 equiv) in anhydrous tetrahydrofuran (THF, 30.0 mL, 0.400 mol) was added dropwise via a canula at −78° C. The resulting reaction mixture was stirred at −78° C. for an additional 10 min before the cooling batch was removed and the reaction mixture was allowed to gradually warm to room temperature and stirred at room temperature for 1-2 h. When the reaction was deemed complete, the reaction mixture was quenched with a 6 N aqueous sodium hydroxide solution (NaOH, 200 mL) and a 20% aqueous brine solution (200 mL). The aqueous solution was treated with ethyl acetate (EtOAc, 200 mL) before the two layers were separated. The organic layer was dried over magnesium sulfate (MgSO4), filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (SiO2, 0 to 5% ethyl acetate/hexane gradient elution) to afford 3-cyclopentylpropiolonitrile (8, 14.3 g, 17.0 g theoretical, 84% yield for two steps) as a yellow to orange oil. For 8: 1H NMR (DMSO-d6, 400 MHz) δ 2.97 (m, 1H), 1.97 (m, 2H), 1.64 (m, 4H), 1.56 (m, 2H).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:18])[CH:7]=[C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[O:9]2)=[CH:4][CH:3]=1.Br[CH2:20][CH2:21][CH2:22][CH:23]=[CH2:24].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:24]([O:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:18])[CH:7]=[C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[O:9]2)=[CH:4][CH:3]=1)[CH2:23][CH2:22][CH:21]=[CH2:20]
Reactant: C=CCCCBr
Reactant: O=c1cc(-c2ccccc2)oc2cc(O)ccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=CCCCOc1ccc2c(=O)cc(-c3ccccc3)oc2c1
Reaction time: 6 h
Yield: 98.6 %

Procedure:
A yellow suspension of 7-hydroxyflavone (25.66 g, 0.108 mol), 5-bromo-1-pentene (17.88 g, 14.2 ml, 0.12 mol), and anhydrous, powdered potassium carbonate (30.40 g, 0.22 mol) in acetone (500 ml) was stirred and heated at reflux for 24 hours. The tlc (thin layer chromatography), on silica gel eluted with 20% of hexane in ether, indicated that the reaction was incomplete. Additional 1.5 ml of 5-bromo-1-pentene was added and refluxing was continued for 6 hours and cooled. The solid was filtered and the filtrate was evaporated under vacuum to give a yellow solid 32.63 g, 97% yield. Recrystallization from isopropyl alcohol gave white crystals, mp 104.5°-106° C.; 55% yield (pure).
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[C:24]([F:25])=[C:23]([NH2:26])[C:9]2[C:10](=[O:22])[CH:11]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([NH2:20])=[C:16]([F:21])[CH:15]=3)[O:13][C:8]=2[C:7]=1[F:27])(=[O:3])[CH3:2].[Br:28][CH2:29][CH2:30][C:31](O)=[O:32].Cl.CN(C)CCCN=C=NCC.O>CN(C)C=O>[C:1]([O:4][CH2:5][C:6]1[C:24]([F:25])=[C:23]([NH2:26])[C:9]2[C:10](=[O:22])[CH:11]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([NH:20][C:31](=[O:32])[CH2:30][CH2:29][Br:28])=[C:16]([F:21])[CH:15]=3)[O:13][C:8]=2[C:7]=1[F:27])(=[O:3])[CH3:2]
Reactant: CC(=O)OCc1c(F)c(N)c2c(=O)cc(-c3ccc(N)c(F)c3)oc2c1F
Reactant: O=C(O)CCBr
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)OCc1c(F)c(N)c2c(=O)cc(-c3ccc(NC(=O)CCBr)c(F)c3)oc2c1F
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 27 %

Procedure:
To a solution of 7-(acetoxymethyl)-5-amino-2-[4-amino-3-fluorophenyl]-6,8-difluoro-4H-1-benzopyran-4-one (1.51 g, 4.00 mmol) in dimethylformamide (40 mL) were added 3-bromopropionic acid (3.06 g, 20.0 mmol) and 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (3.83 g, 20.0 mmol), and the mixture was stirred at room temperature for 45 minutes. Water was added thereto and the mixture was extracted with ethyl acetate. Purification by silica gel column chromatography (6:1 chloroform/acetate) gave 7-(acetoxymethyl)-5-amino-2-[4-[(3-bromopropionyl)amino]-3-fluorophenyl]-6,8-difluoro-4H-1-benzopyran-4-one (554 mg, 27%).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][C:9]([OH:11])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN(C=O)C.[Cl:17][C:18]1[CH:19]=[C:20]([C:24]2[C:29]([NH2:30])=[C:28]([CH3:31])[N:27]=[C:26]([S:32][CH3:33])[N:25]=2)[CH:21]=[CH:22][CH:23]=1.N1C=CC=CC=1>S(Cl)(Cl)=O>[Cl:17][C:18]1[CH:19]=[C:20]([C:24]2[C:29]([NH:30][C:9](=[O:11])[CH2:8][CH2:7][C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[C:28]([CH3:31])[N:27]=[C:26]([S:32][CH3:33])[N:25]=2)[CH:21]=[CH:22][CH:23]=1
Reactant: CSc1nc(C)c(N)c(-c2cccc(Cl)c2)n1
Reactant: O=C(O)CCc1ccccc1
Solvent: c1ccncc1
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: CSc1nc(C)c(NC(=O)CCc2ccccc2)c(-c2cccc(Cl)c2)n1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
51.4 mg (0.342 mmol) of 3-phenylpropionic acid was dissolved in 1 ml of thionyl chloride. A catalytic amount of DMF was added and stirred at room temperature for 3 hours. After the solvent was evaporated under reduced pressure, 45.4 mg (0.171 mmol) of 4-(3-chlorophenyl)-6-methyl-2-(methylthio)-5-pyrimidinamine and 1 ml of pyridine were added and stirred at 50° C. overnight. After the solvent was evaporated under reduced pressure, the reaction mixture was diluted with ethyl acetate and washed with saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by the silica gel chromatography (hexane/ethyl acetate=10/1 to 1/1) to obtain the title compound.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=1.[CH3:10][O:11][C:12]([C:14]1[CH:15]=[CH:16][C:17]2[C:21]([CH2:22]Br)=[CH:20][S:19][C:18]=2[CH:24]=1)=[O:13].O>CN(C)C=O>[CH3:10][O:11][C:12]([C:14]1[CH:15]=[CH:16][C:17]2[C:21]([CH2:22][O:3][C:4]3[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=3)=[CH:20][S:19][C:18]=2[CH:24]=1)=[O:13]
Reactant: COC(=O)c1ccc2c(CBr)csc2c1
Reactant: Oc1cccnc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc2c(COc3cccnc3)csc2c1
Reaction time: 0.5 h
Yield: 36.2 %

Procedure:
Sodium hydride (0.12 g of 50% dispersion in mineral oil) was added to a solution of 3-hydroxypyridine (0.24 g) in dry N,N-dimethylformamide (5 ml) and the mixture was stirred for 30 minutes. 3-Bromomethylbenzo[b]thiophene-6-carboxylic acid methyl ester (0.71 g) in a small volume of N,N-dimethylformamide was added and the mixture was stirred at room temperature for 2 hours and then poured into water. The mixture was extracted several times with ethyl acetate and the combined extracts were washed with water and dried (Na2SO4). Evaporation of the solvent gave a gummy solid which was chromatographed on silica gel. Elution with chloroform first gave some impurity followed by pure product. Evaporation of the product containing fractions gave 3-(3-pyridyloxymethyl)benzo[b]thiophene-6-carboxylic acid methyl ester (0.27 g) which was used directly in the next stage.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][N:5]1[C:13]([O:14]C)=[N:12][C:11]2[C:6]1=[N:7][C:8]([O:17][CH2:18][CH2:19][CH2:20][CH3:21])=[N:9][C:10]=2[NH2:16].Cl.N>CO.O1CCOCC1>[NH2:16][C:10]1[N:9]=[C:8]([O:17][CH2:18][CH2:19][CH2:20][CH3:21])[N:7]=[C:6]2[C:11]=1[NH:12][C:13](=[O:14])[N:5]2[CH2:4][CH2:3][CH2:2][Cl:1]
Reactant: CCCCOc1nc(N)c2nc(OC)n(CCCCl)c2n1
Agent: Cl
Agent: N
Solvent: CO
Solvent: C1COCCO1
Product: CCCCOc1nc(N)c2[nH]c(=O)n(CCCCl)c2n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The product of step (vi) (29.8 g) was dissolved in MeOH (60 ml) and treated with 4M hydrogen chloride in dioxane (60 ml). The mixture was stirred at rt for 2 hours, cooled to 0° C. and neutralised with 3.5% aqueous ammonia solution. The solid was filtered off, washed with water then MeOH and dried Yield 27.2 g.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.[CH3:8][Si:9]([CH2:12][CH2:13][O:14][CH2:15]Cl)([CH3:11])[CH3:10].C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C>[CH3:8][Si:9]([CH2:12][CH2:13][O:14][CH2:15][N:5]1[CH:6]=[CH:7][C:2](=[O:1])[CH:3]=[CH:4]1)([CH3:11])[CH3:10]
Reactant: Oc1ccncc1
Reactant: C[Si](C)(C)CCOCCl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: C[Si](C)(C)CCOCn1ccc(=O)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-hydroxypyridine (3.0 g, 32 mmol) and trimethylsilylethoxymethyl chloride (5.5 mL, 32 mmol) in 30 mL of acetonitrile was added cesium carbonate (11 g, 34 mmol). After stirring at room temperature overnight, the reaction mixture was partitioned between brine (100 mL) and ethyl acetate (100 mL). The organic layer was separated and aqueous layer extracted with ethyl acetate (3×100 mL). The combined extracts were dried over anhydrous sodium sulfate, filtered, and concentrated to dryness to give the title compound contaminated with some O-alkylated product. 1H NMR (500 MHz, CD3OD): δ 7.92 (d, 2H), 6.49 (d, 2H), 5.28 (s, 2H), 3.62 (t, 2H), 0.96 (t, 2H), 0.024 (s, 9H).
Reaction SMILES: [N:1]([N:3]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[S:7][CH2:6][CH2:5][CH2:4]1)=O.[H-].[H-].[H-].[H-].[Li+].[Al+3].O.[OH-].[Na+]>C1COCC1>[S:7]1[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[N:3]([NH2:1])[CH2:4][CH2:5][CH2:6]1
Reactant: O=NN1CCCSc2ccccc21
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: NN1CCCSc2ccccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 59.1 %

Procedure:
A solution of 5-nitroso-2,3,4,5-tetrahydro-1,5-benzothiazepine (32.21 g, 0.166 mol) in THF (650 mL) was added dropwise to LAH (1.0M in THF, 166 mL) under N2 such that the temperature did not rise above 27-29° C. Once the addition was complete, the mixture was stirred at room temperature for 1 hr. It was cooled in an ice bath and treated with H2O (7.3 mL) added dropwise, followed by 1N NaOH (32.4 mL). Once at room temperature, the mixture was filtered and the filtrate was evaporated under reduced pressure. The residue was taken up in CH2Cl2 (200 mL) washed with H2O, and dried over MgSO4, and stripped of solvent under reduced pressure to yield 29.42 g (98%) of the crude product. Purification by column chromatography (EtOAc) afforded 17.69 g (59% yield) of 3,4-dihydro-1,5-benzothiazepin-5(2H)-amine as a liquid which was converted to the HCl salt, m.p. 202° C. (decomposition). (M+H)+ 180.
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:7]2[CH:14]=[CH:13][C:10]([CH:11]=[O:12])=[CH:9][CH:8]=2)[CH:4]=[CH:5][N:6]=1.CN(C)C=O.[C-]#N.[Na+].[C:23](#[N:27])[CH:24]=[CH:25][CH3:26]>O>[CH3:1][C:2]1[N:3]([C:7]2[CH:14]=[CH:13][C:10]([C:11](=[O:12])[CH:25]([CH3:26])[CH2:24][C:23]#[N:27])=[CH:9][CH:8]=2)[CH:4]=[CH:5][N:6]=1
Reactant: Cc1nccn1-c1ccc(C=O)cc1
Reactant: CC=CC#N
Agent: [C-]#N
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1nccn1-c1ccc(C(=O)C(C)CC#N)cc1
Temperature: 30 °C

Procedure:
To a mixture of 33.6 g of 4-(2-methyl-1-imidazolyl)benzaldehyde and 400 ml of dimethylformamide under a nitrogen atmosphere was added 0.78 g of sodium cyanide and then with stirring at 30° C. 10.7 g of 2-butenenitrile was added dropwise. The reaction mixture was stirred at 25° C. under nitrogen for another 16 hours. Following the addition of one liter of water the mixture was extracted with chloroform, and the chloroform phase was washed with water, dried over sodium sulfate, and concentrated. The residue was purified by column chromatography (silica gel/chloroform) and then reprecipitated with chloroform/hexane.
Reaction SMILES: Cl[C:2]1([CH2:10][C:11]([Cl:14])([Cl:13])[Cl:12])[C:5]2([CH2:8][CH2:7][CH2:6]2)[CH2:4][C:3]1=[O:9]>[Zn].C(O)=O>[Cl:12][C:11]([Cl:13])([Cl:14])[CH2:10][CH:2]1[C:5]2([CH2:8][CH2:7][CH2:6]2)[CH2:4][C:3]1=[O:9]
Reactant: O=C1CC2(CCC2)C1(Cl)CC(Cl)(Cl)Cl
Agent: [Zn]
Solvent: O=CO
Product: O=C1CC2(CCC2)C1CC(Cl)(Cl)Cl
Temperature: 30 °C
Reaction time: 2 h

Procedure:
18 g of 1-chloro-1-(2',2',2'-trichloroethyl)spiro(3.3)-heptan-2-one is placed into 200 ml of formic acid, and 8.5 g of zinc dust is added portionwise in such a way that the temperature does not exceed 30° C. The reaction mixture is afterwards stirred for two hours at 30° C. and then filtered. The filtrate is concentrated by evaporation; water is added and the mixture is extracted with diethyl ether. The ethereal phase is washed with water, with aqueous sodium carbonate solution and again with water; it is dried over sodium sulphate and concentrated by evaporation. The residue is distilled at 75°-80° C./0.03-0.05 Torr to yield 1-(2',2',2'-trichloroethyl)spiro(3.3)heptan-2-one of the formula ##STR12## as a clear liquid.
Reaction SMILES: [Mg].[C:2]12([C:12]3[CH:13]=[CH:14][C:15](Br)=[C:16]([CH3:18])[CH:17]=3)[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([CH2:5]3)[CH2:3]1)[CH2:9]2.[C:20]12([C:30]3[CH:35]=[CH:34][C:33](Br)=[CH:32][CH:31]=3)[CH2:29][CH:24]3[CH2:25][CH:26]([CH2:28][CH:22]([CH2:23]3)[CH2:21]1)[CH2:27]2.Cl>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCCC1>[C:2]12([C:12]3[CH:13]=[CH:14][C:15]([C:33]4[CH:32]=[CH:31][C:30]([C:20]56[CH2:21][CH:22]7[CH2:28][CH:26]([CH2:25][CH:24]([CH2:23]7)[CH2:29]5)[CH2:27]6)=[CH:35][CH:34]=4)=[C:16]([CH3:18])[CH:17]=3)[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([CH2:5]3)[CH2:3]1)[CH2:9]2
Reactant: Brc1ccc(C23CC4CC(CC(C4)C2)C3)cc1
Reactant: Cc1cc(C23CC4CC(CC(C4)C2)C3)ccc1Br
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Agent: [Mg]
Solvent: C1CCOC1
Product: Cc1cc(C23CC4CC(CC(C4)C2)C3)ccc1-c1ccc(C23CC4CC(CC(C4)C2)C3)cc1
Yield: 79 %

Procedure:
In a 1 L recovery flask, 3.19 g of magnesium (131 mmol), g of 5-(1-adamantyl)-2-bromotoluene (131 mmol), 200 mL of tetrahydrofuran and a stirrer were charged and refluxed under a nitrogen atmosphere for two hours to prepare a Grignard reagent. Next, in another 1 L recovery flask, 38.2 g of 4-(1-adamantyl)-bromobenzene (131 mmol), 9.19 mg of bis(triphenylphosphine)palladium dichloride (13.1 mmol), 300 mL of tetrahydrofuran and a stirrer were charged. A tetrahydrofuran solution, which is the above-prepared Grignard reagent, was added thereto under nitrogen flow and the mixture was refluxed for 12 hours. Then, 60 mL of 10% hydrochloric acid aqueous solution was added thereto and the mixture was refluxed for 30 minutes. After an aqueous layer was separated and removed therefrom, the reaction solution was washed with 200 mL of saturated sodium hydrogencarbonate aqueous solution, followed by removal of solvent under reduced pressure. Solid thus obtained was refined by alumina column chromatography, thus obtaining 45.1 g of 4,4′-di(1-adamantyl)-2-methyl-1,1′-biphenyl (103.5 mmol; yield: 79.0%).
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][N:7]([N:10]=O)[CH2:6][C@@H:5]1[CH3:12])(=[O:3])[CH3:2]>O.C(O)(=O)C.[Zn]>[C:1]([N:4]1[CH2:9][CH2:8][N:7]([NH2:10])[CH2:6][C@@H:5]1[CH3:12])(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCN(N=O)C[C@@H]1C
Agent: [Zn]
Solvent: O
Solvent: CC(=O)O
Product: CC(=O)N1CCN(N)C[C@@H]1C
Temperature: 55 °C
Reaction time: 2 h
Yield: 99.6 %

Procedure:
To a mixture of (S)-1-acetyl-2-methyl-4-nitrosopiperazine (350 mg) in water (2 ml) and acetic acid (0.59 ml) was added zinc powder (401 mg) as portions during the period of 2 hours at 8-13° C. (exothermic reaction) with ice-water cooling bath. After removal of the bath, the temperature was raised till 55° C. and the reaction mixture was additionally stirred at 45° C. for 2 hours. The zinc residue was filtered off and washed with methanol (10 ml) on the Celite. The combined filtrate was added into dichloromethane (40 ml) and sodium hydroxide (409 mg) in water (6 ml) below 35° C. The resulting precipitate was filtered off with Celite and the residue was washed with chloroform (50 ml). The combined filtrate was washed with water, dried over magnesium sulfate and concentrated to give (S)-1-acetyl-4-amino-2-methylpiperazine (320 mg). This product was used for next step without purification.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[CH3:11][C@H:12]1[CH2:17][NH:16][CH2:15][CH2:14][NH:13]1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1>[CH3:11][C@@H:12]1[NH:13][CH2:14][CH2:15][N:16]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[N+:8]([O-:10])=[O:9])[CH2:17]1
Reactant: O=[N+]([O-])c1ccccc1Br
Reactant: C[C@H]1CNCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: C[C@H]1CN(c2ccccc2[N+](=O)[O-])CCN1
Yield: 479.1 %

Procedure:
To a solution of 2-bromo-1-nitrobenzene (0.6 g, 3.0 mmol) in 1,4-dioxane (15 mL) was added (S)-(+)-2-methylpiperazine (0.5 g, 0.5 mmol) and powdered K2CO3 (15.0 mmol, 1.5 g) and the resulting suspension was heated at reflux for 10 h. After the suspension was cooled, it was filtered through a sintered glass funnel and the solvent was evaporated in vacuo. The resulting residue was purified by column chromatography on silica gel (1:1 hexane/EtOAc followed by 4:1 EtOAc/MeOH) to yield (S)-(+)-3-methyl-1-(2-nitrophenyl)-piperazine as an orange oil (0.53 g, 80%).
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([CH:22]=[CH:23][C:24]=1[O:25]C)[O:7][C:8]1[C:13]([CH3:14])=[CH:12][C:11]([NH:15][C:16]2[NH:20][N:19]=[N:18][N:17]=2)=[CH:10][C:9]=1[CH3:21])([CH3:3])[CH3:2].B(Br)(Br)Br>O>[CH3:14][C:13]1[CH:12]=[C:11]([NH:15][C:16]2[NH:20][N:19]=[N:18][N:17]=2)[CH:10]=[C:9]([CH3:21])[C:8]=1[O:7][C:6]1[CH:22]=[CH:23][C:24]([OH:25])=[C:4]([CH:1]([CH3:3])[CH3:2])[CH:5]=1
Reactant: COc1ccc(Oc2c(C)cc(Nc3nnn[nH]3)cc2C)cc1C(C)C
Agent: BrB(Br)Br
Solvent: O
Product: Cc1cc(Nc2nnn[nH]2)cc(C)c1Oc1ccc(O)c(C(C)C)c1

Procedure:
4-[2,6-Dimethyl-4-(1H-tetrazol-5-ylamino)-phenoxy]-2-isopropyl-phenol was prepared from [4-(3-isopropyl-4-methoxy-phenoxy)-3,5-dimethyl-phenyl]-(1H-tetrazol-5-yl)-amine according to a procedure analogous to that described in EXAMPLE 2, Step B. Boron tribromide (1M in dichloromethane, 8.0 equiv) was used. After water addition, the mixture was extracted with ethyl acetate (3×10 ml). The combined organic phases were dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by preparative TLC (methanol:water:dichloromethane 25:3:72) to afford the title product of Example 4. MS (APCI+) Calc.: 339.4, Found: 340.1 (M+1).