Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=1.[NH2:9][CH:10]([CH2:13][CH3:14])[CH2:11][OH:12]>O1CCOCC1>[Cl:8][C:6]1[N:5]=[CH:4][N:3]=[C:2]([NH:9][CH:10]([CH2:13][CH3:14])[CH2:11][OH:12])[CH:7]=1
Reactant: Clc1cc(Cl)ncn1
Reactant: CCC(N)CO
Solvent: C1COCCO1
Product: CCC(CO)Nc1cc(Cl)ncn1

Procedure:
4,6-Dichloropyrimidine (5.0 g) and 2-amino-1-butanol (6.5 mL) were heated under reflux in 1,4-dioxane (26 mL) for 1 hour. The reaction mixture was evaporated, and the resulting residue was purified by silica gel column chromatography (ethyl acetate:n-hexane=1:10) to give the title compound (5.6 g) as a pale orange oil.
Reaction SMILES: Cl.[N+:2]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]2[CH2:19][CH2:18][NH:17][CH2:16][C:15]2=[O:20])(=[O:13])=[O:12])=[CH:7][CH:6]=1)([O-:4])=[O:3].[N:21]1([CH2:30][C:31](O)=[O:32])[CH:29]=[C:27]([CH3:28])[C:25](=[O:26])[NH:24][C:22]1=[O:23]>>[N+:2]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]2[CH2:19][CH2:18][N:17]([C:31](=[O:32])[CH2:30][N:21]3[CH:29]=[C:27]([CH3:28])[C:25](=[O:26])[NH:24][C:22]3=[O:23])[CH2:16][C:15]2=[O:20])(=[O:13])=[O:12])=[CH:7][CH:6]=1)([O-:4])=[O:3]
Reactant: O=C1CNCCN1S(=O)(=O)c1ccc([N+](=O)[O-])cc1
Reactant: Cc1cn(CC(=O)O)c(=O)[nH]c1=O
Agent: Cl
Product: Cc1cn(CC(=O)N2CCN(S(=O)(=O)c3ccc([N+](=O)[O-])cc3)C(=O)C2)c(=O)[nH]c1=O
Yield: 95.6 %

Procedure:
The title compound (151 mg, 95%) was synthesized by reaction of 1-(4-nitro-benzenesulfonyl)-piperazin-2-one HCl salt (113 mg, 0.35 mmol) with (thymin-1-yl)-acetic acid (64 mg, 0.35 mmol) as per the procedure of example 64. 1H-NMR (500 MHz; DMSO-d6) δ 11.31 (s, 0.6H), 11.29 (s, 0.4H), 8.44 (d, 2H), 8.29 (d, 2H), 7.34 (s, 0.6H), 7.27 (s, 0.4H), 4.64 (s, 1.2H), 4.55 (s, 0.8H), 4.33 (s, 0.8H), 4.18 (s, 1.2H), 4.14 (t, 1.2H), 4.00 (t, 0.8H), 3.90 (t, 1.2H), 3.80 (t, 0.8H), 1.74 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][S:9][C:10]2[NH:14][C:13]3=[CH:15][S:16][CH:17]=[C:12]3[N:11]=2)=[N:6][CH:7]=1.Cl[C:19]([O:21][CH:22]=[CH2:23])=[O:20]>>[CH:22]([O:21][C:19]([N:11]1[C:12]2=[CH:17][S:16][CH:15]=[C:13]2[N:14]=[C:10]1[S:9][CH2:8][C:5]1[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][N:6]=1)=[O:20])=[CH2:23]
Reactant: Cc1ccc(CSc2nc3cscc3[nH]2)nc1
Reactant: C=COC(=O)Cl
Product: C=COC(=O)n1c(SCc2ccc(C)cn2)nc2cscc21
Yield: 41.5 %

Procedure:
In analogy to Example 15 1.5 g of crude product were obtained from 2.1 g (8 mmol) of 2-(5-methyl-2-picolylmercapto)-1H-thieno[3,4-d]imidazole and 0.85 g (0.72 ml, 8 mmol) of vinyl chloroformate and were chromatographed on SiO2 (CH2Cl2 /MeOH 50:1). 1.1 g of title compound were obtained by crystallization from diisopropyl ether. Melting point 78°-80° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[CH2:5][CH:4]([C:6]([C:8]2[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][CH:9]=2)=[O:7])[CH2:3]1.Cl.[NH2:19][CH2:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23].O.N1(O)C2C=CC=CC=2N=N1.C(N(CC)CC)C>O1CCCC1>[CH3:17][C:2]1([CH3:1])[CH2:3][CH:4]([C:6]([C:8]2[CH:9]=[CH:10][C:11]([C:12]([NH:19][CH2:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[O:14])=[CH:15][CH:16]=2)=[O:7])[CH2:5]1
Reactant: CCOC(=O)CCN
Reactant: CC1(C)CC(C(=O)c2ccc(C(=O)O)cc2)C1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)CCNC(=O)c1ccc(C(=O)C2CC(C)(C)C2)cc1
Reaction time: 16 h
Yield: 63.6 %

Procedure:
Tetrahydrofuran (138 mL) was added to a vial containing 4-(3,3-dimethylcyclobutanecarbonyl)benzoic acid (3.20 g, 14.0 mmol), ethyl 3-aminopropanoate hydrochloride (3.17 g, 20.7 mmol) and 1,2,3-benzotriazol-1-ol monohydrate (2.22 g, 14.5 mmol). Triethylamine (9.11 mL, 4.75 mmol) was then added. The reaction was stirred for 16 h, and was then concentrated. Purification by column chromatography (0-35% ethyl acetate in heptane) afforded impure ethyl 3-(4-(3,3-dimethylcyclobutanecarbonyl)benzamido)propanoate (4.22 g, approximately 8.90 mmol pure) as an oil. MS (M+1) 332.2.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:9]=[C:8]([NH2:10])[CH:7]=[CH:6][C:5]=1[OH:11].[Cl:12][C:13]1[CH:18]=[C:17]([N+]([O-])=O)[CH:16]=[CH:15][N:14]=1>CN(C=O)C>[Cl:12][C:13]1[CH:18]=[C:17]([O:11][C:5]2[CH:6]=[CH:7][C:8]([NH2:10])=[CH:9][C:4]=2[F:3])[CH:16]=[CH:15][N:14]=1
Reactant: O=[N+]([O-])c1ccnc(Cl)c1
Reactant: Nc1ccc(O)c(F)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Nc1ccc(Oc2ccnc(Cl)c2)c(F)c1
Temperature: 90 °C
Reaction time: 0.5 h
Yield: 76.3 %

Procedure:
Sodium hydride (60%, 0.104 g, 2.60 mmol, 1.1 eq) was added to a solution of 2-fluoro-4-aminophenol (0.30 g, 2.36 mmol, 1.0 eq) in DMF (6.5 mL) at room temperature and the reaction mixture was stirred for 30 minutes. 2-Chloro-4-nitropyridine (Aldrich, 0.374 g, 2.36 mmol, 1.0 eq) was added and the reaction mixture was heated to 90° C. for 12 h. The reaction mixture was cooled to room temperature, quenched with saturated aqueous NaCl solution and extracted with ethyl acetate (3×70 mL). The combined organic extracts were washed with 10% aq. LiCl solution (3×70 mL), dried over Na2SO4, filtered and the filtrate concentrated in vacuo to afford the title compound (0.430 g, 76%) which was used without further purification. 1H NMR (DMSO-d6) δ 8.27 (d, 1H, J=5.7 Hz), 6.90-7.04 (m, 3H), 6.42-6.54 (m, 2H), 5.54 (s, 2H); MS(ESI+) m/z 239 (M+H)+; HRMS (ESI+) calcd.: 239.0387, found: 239.0391.
Reaction SMILES: Cl.Cl.[N:3]1([CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:22]=[C:21]3[C:16]([CH2:17][CH2:18][NH:19][CH2:20]3)=[CH:15][CH:14]=2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.CCN(CC)CC.[C:30](Cl)(=[O:32])[CH3:31]>C(Cl)Cl>[N:3]1([CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:22]=[C:21]3[C:16]([CH2:17][CH2:18][N:19]([C:30](=[O:32])[CH3:31])[CH2:20]3)=[CH:15][CH:14]=2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: c1cc2c(cc1OCCCN1CCCCC1)CNCC2
Reactant: CC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)N1CCc2ccc(OCCCN3CCCCC3)cc2C1
Reaction time: 5.5 h

Procedure:
A 5 mL CH2Cl2 solution of 7-(3-piperidin-1-yl-propoxy)-1,2,3,4-tetrahydro-isoquinoline dihydrochloride (175 mg, 0.5 mmol) and NEt3 (0.25 mL, 1.7 mmol) is stirred under N2, a 1 mL CH2Cl2 solution of acetyl chloride (0.043 mL, 0.6 mmol) is added, and reaction is stirred at room temp. for 5-6 hours. Reaction mixture is quenched with MeOH, concentrated and the residue is purified by chromatography (SCX-MeOH wash, elute 2M NH3/MeOH; then (SiO2; 0-10% MeOH/CH2Cl2/1% NH4OH gradient) to give the product (90 mg, 58% yld). MS(ES+)317.1(M+H)+
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[OH:13][CH:14]([CH3:51])[C:15]([CH3:50])([CH3:49])[O:16][C:17]1[CH:22]=[CH:21][C:20]([N:23]2[C:28](=[O:29])[C:27]([CH2:30][C:31]3[CH:36]=[CH:35][C:34]([C:37]4[C:38]([C:43]#[N:44])=[CH:39][CH:40]=[CH:41][CH:42]=4)=[CH:33][CH:32]=3)=[C:26]([CH2:45][CH2:46][CH3:47])[N:25]=[C:24]2[CH3:48])=[CH:19][CH:18]=1>O.C(OCC)(=O)C>[OH:13][CH:14]([CH3:51])[C:15]([CH3:49])([CH3:50])[O:16][C:17]1[CH:22]=[CH:21][C:20]([N:23]2[C:28](=[O:29])[C:27]([CH2:30][C:31]3[CH:36]=[CH:35][C:34]([C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=4[C:43]4[NH:3][C:4](=[O:7])[O:5][N:44]=4)=[CH:33][CH:32]=3)=[C:26]([CH2:45][CH2:46][CH3:47])[N:25]=[C:24]2[CH3:48])=[CH:19][CH:18]=1
Reactant: O=C([O-])O
Reactant: [NH3+]O
Reactant: CCCc1nc(C)n(-c2ccc(OC(C)(C)C(C)O)cc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Solvent: O
Product: CCCc1nc(C)n(-c2ccc(OC(C)(C)C(C)O)cc2)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 68.9 %

Procedure:
A mixture of hydroxylammonium chloride (1.70 g), sodium hydrogen carbonate (2.62 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C. for 30 min, 4′-({1-[4-(2-hydroxy-1,1-dimethylpropoxy)phenyl]-2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl}methyl)biphenyl-2-carbonitrile (0.60 g) was added, and the mixture was stirred at 90° C. for 18 hr. The reaction mixture was allowed to cool to room temperature, ethyl acetate and water were added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was dissolved in tetrahydrofuran (6 mL). N,N′-carbonyldiimidazole (0.22 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.21 mL) were added, and the mixture was stirred at room temperature for 3 hr. The reaction mixture was diluted with ethyl acetate, washed with 1 M hydrochloric acid and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as a pale-yellow amorphous solid (0.46 g, 68%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:12]=[C:13](I)[C:14]4[C:19]([CH3:21])([CH3:20])[C:18](=[O:22])[NH:17][C:15]=4[N:16]=3)=[N:9][N:8]([CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[F:31])[C:5]2=[N:6][CH:7]=1.[F:32][C:33]([F:39])([F:38])[CH2:34][CH2:35][CH2:36][NH2:37]>CN1CCCC1=O>[F:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:12]=[C:13]([NH:37][CH2:36][CH2:35][CH2:34][C:33]([F:39])([F:38])[F:32])[C:14]4[C:19]([CH3:21])([CH3:20])[C:18](=[O:22])[NH:17][C:15]=4[N:16]=3)=[N:9][N:8]([CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[F:31])[C:5]2=[N:6][CH:7]=1
Reactant: NCCCC(F)(F)F
Reactant: CC1(C)C(=O)Nc2nc(-c3nn(Cc4ccccc4F)c4ncc(F)cc34)nc(I)c21
Solvent: CN1CCCC1=O
Product: CC1(C)C(=O)Nc2nc(-c3nn(Cc4ccccc4F)c4ncc(F)cc34)nc(NCCCC(F)(F)F)c21
Temperature: 150 °C

Procedure:
150 mg (0.186 mmol, approx. 66% purity) of the compound obtained in example 16A was dissolved in 1-methyl-2-pyrrolidone (3 ml) in a reaction vessel suitable for a microwave and 0.4 ml of 4,4,4-trifluorobutylamine was added. Then it was sealed with a corresponding septum and it was heated in the microwave at 150° C. for 3 h. After cooling, the reaction mixture was purified by preparative HPLC (acetonitrile:water (+0.05% formic acid) gradient). 47 mg of the title compound was obtained (48% of theor.).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([O:8][CH2:9][CH3:10])[C:5]([NH2:11])=[C:4]([NH2:12])[N:3]=1.[CH:13]([CH:15]=O)=O>C(O)C>[NH2:1][C:2]1[N:7]=[C:6]([O:8][CH2:9][CH3:10])[C:5]2[C:4](=[N:12][CH:13]=[CH:15][N:11]=2)[N:3]=1
Reactant: CCOc1nc(N)nc(N)c1N
Reactant: O=CC=O
Solvent: CCO
Product: CCOc1nc(N)nc2nccnc12
Yield: 206.4 %

Procedure:
To a solution of 2,5,6-triamino-4-ethoxy-pyrimidine (10.54 g, 62.37 mmoles) in ethanol (160 ml) was added glyoxal (40% solution in water, 2.7 ml, 18.6 mmoles). The reaction mixture was refluxed for 4 hours. Some insoluble material was filtered off. The filtrate was concentrated in vacuo and the residue purified by flash chromatography (silica, using a CH3OH/CH2Cl2 mixture (5:95) as the eluent), providing the pure title compound (7.34 g, yield: 62%). The spectral data of the product are identical with the literature data (W. Pfleiderer et al. cited supra).
Reaction SMILES: [S:1]([N:11]=[S:12]1[CH2:17][CH2:16][CH2:15][S:14](=[O:19])(=[O:18])[CH2:13]1)([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2].[Mn]([O-])(=O)(=O)=[O:21].[K+]>C(OC(=O)C)(=O)C>[S:1]([N:11]=[S:12]1(=[O:21])[CH2:17][CH2:16][CH2:15][S:14](=[O:18])(=[O:19])[CH2:13]1)([C:4]1[CH:5]=[CH:6][C:7]([CH3:8])=[CH:9][CH:10]=1)(=[O:3])=[O:2]
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: Cc1ccc(S(=O)(=O)N=S2CCCS(=O)(=O)C2)cc1
Agent: [K+]
Solvent: CC(=O)OC(C)=O
Product: Cc1ccc(S(=O)(=O)N=S2(=O)CCCS(=O)(=O)C2)cc1

Procedure:
A method as defined in claim 59 which includes the additional step of reacting said 1-tosylimino-1,3-dithiane-3,3-dioxide with potassium permanganate in acetic acid-acetic anhydride solution at about 20° to 30° C to yield the corresponding 1-tosylimino-1,3-dithiane-1,3,3-trioxide.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:13]([C:15]3[C:16]([O:34][CH2:35][CH3:36])=[C:17]([CH:23]4[CH2:26][N:25]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:24]4)[C:18]([F:22])=[C:19]([Cl:21])[CH:20]=3)[CH3:14])[N:9]=[C:10]([CH:11]=[CH2:12])[C:3]=12.C[N+]1([O-])CC[O:41]CC1.[OH2:45].CCOC(C)=O>C(O)(C)(C)C.[Os](=O)(=O)(=O)=O>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:13]([C:15]3[C:16]([O:34][CH2:35][CH3:36])=[C:17]([CH:23]4[CH2:24][N:25]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:26]4)[C:18]([F:22])=[C:19]([Cl:21])[CH:20]=3)[CH3:14])[N:9]=[C:10]([CH:11]([OH:41])[CH2:12][OH:45])[C:3]=12
Reactant: C[N+]1([O-])CCOCC1
Reactant: C=Cc1nn(C(C)c2cc(Cl)c(F)c(C3CN(C(=O)OC(C)(C)C)C3)c2OCC)c2ncnc(N)c12
Reactant: O
Agent: O=[Os](=O)(=O)=O
Solvent: CC(C)(C)O
Solvent: CCOC(C)=O
Product: CCOc1c(C(C)n2nc(C(O)CO)c3c(N)ncnc32)cc(Cl)c(F)c1C1CN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of tert-butyl 3-{3-[1-(4-amino-3-vinyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-ethoxy-6-fluorophenyl}azetidine-1-carboxylate (0.707 g, 1.37 mmol) in tert-butyl alcohol (8.6 mL) was added N-methylmorpholine N-oxide (176 mg, 1.50 mmol), water (4.3 mL), and osmium tetraoxide (20 mg, 0.080 mmol). The resulting mixture was stirred overnight at room temperature. Water was added to the reaction followed by EtOAc. The layers were separated and the aqueous extracted with EtOAc. The combined organics were washed with brine, dried over Na2SO4, filtered, and concentrated to give the crude product. LCMS calculated for C25H33ClFN6O5 (M+H)+: m/z=551.2; Found:551.2.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]#[N:10])[CH:5]=[CH:6][CH:7]=1.[CH3:11][O:12][C:13]1[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[CH:17][C:14]=1[CH:15]=O>C(O)C.[OH-].[Na+]>[C:9]([C:8](=[CH:15][C:14]1[CH:17]=[C:18]([O:23][CH3:24])[C:19]([O:21][CH3:22])=[CH:20][C:13]=1[O:12][CH3:11])[C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=1)#[N:10]
Reactant: N#CCc1cccc(Cl)c1
Reactant: COc1cc(OC)c(OC)cc1C=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1cc(OC)c(OC)cc1C=C(C#N)c1cccc(Cl)c1
Yield: 92.5 %

Procedure:
3-chlorophenylacetonitrile (purchased from Tokyo Kasei), 1.96 g (10.0 mmol), and 1.96 g (10.0 mmol) of 2,4,5-trimethoxybenzaldehyde (purchased from Lancaster) were dissolved in 10 ml of ethanol (purchased from Kokusan Kagaku) under heating, 2 drops of 20% aqueous sodium hydroxide solution was added to the solution and stirred over night, and the precipitate was crushed, and washed with ethanol twice and hexane twice, and dried to give 3.05 g (yield: 92.5%) of α-cyano-3-chloro-2',4',5'-trimethoxystilbene (as a yellow crystalline).
Reaction SMILES: C([C:3](Br)([CH2:9][CH3:10])[C:4](=O)[C:5]([O-:7])=[O:6])C.[F:12][C:13]([F:24])([F:23])[C:14]1[CH:22]=[CH:21][C:17]([C:18]([NH2:20])=[S:19])=[CH:16][CH:15]=1.[CH2:25](O)[CH3:26]>>[CH3:10][C:9]1[N:20]=[C:18]([C:17]2[CH:21]=[CH:22][C:14]([C:13]([F:12])([F:23])[F:24])=[CH:15][CH:16]=2)[S:19][C:3]=1[CH2:4][C:5]([O:7][CH2:25][CH3:26])=[O:6]
Reactant: CCC(Br)(CC)C(=O)C(=O)[O-]
Reactant: NC(=S)c1ccc(C(F)(F)F)cc1
Reactant: CCO
Product: CCOC(=O)Cc1sc(-c2ccc(C(F)(F)F)cc2)nc1C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of ethyl-3-bromooxopentanoate (O. G. Kulinkovich e.t al., Synthesis, 1986, 378–379) (1.26 g) in absolute ethanol (6 ml) was added 4-(trifluoromethyl)thiobenzamide (1.24 g). The reaction was heated to reflux and stirred at this temperature for 18 hours under nitrogen. The mixture was then allowed to cool to room temperature, prior to cooling in ice. This resulted in crystallization of the product which was filtered and washed with ice cold ethanol to afford the title compound as beige crystals.
Reaction SMILES: B(Br)(Br)Br.[Cl:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][CH2:14][CH2:15][O:16]C)=[C:8]([N+:18]([O-:20])=[O:19])[CH:7]=1>ClCCl>[Cl:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][CH2:14][CH2:15][OH:16])=[C:8]([N+:18]([O-:20])=[O:19])[CH:7]=1
Reactant: COCCCCc1ccc(Cl)cc1[N+](=O)[O-]
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=[N+]([O-])c1cc(Cl)ccc1CCCCO
Temperature: 25 °C
Reaction time: 8 h
Yield: 35 %

Procedure:
Boron tribromide (1.24 g, 4.925 mmol) was added to a cooled mixture of 4-chloro-1-(4-methoxy-butyl)-2-nitro-benzene (0.2 g, 0.995 mmol) in dichloromethane (10 mL) and the resulting mixture was stirred at room temperature overnight. The reaction mixture was extracted with ethyl acetate and the organic extracts were dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure to give 80 mg of 4-(4-chloro-2-nitro-phenyl)-butan-1-ol as an oil without further purifications.
Reaction SMILES: [Si]([O:18][CH2:19][C:20]1[C:21]([N:35]2[CH2:40][C@H:39]([CH3:41])[O:38][C@H:37]([CH3:42])[CH2:36]2)=[C:22]([F:34])[C:23]2[O:27][N:26]=[C:25]([C:28]([O:30]CC)=O)[C:24]=2[CH:33]=1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.[CH3:43][N:44]1[CH:48]=[CH:47][C:46]([CH2:49][NH2:50])=[N:45]1>>[CH3:42][C@@H:37]1[CH2:36][N:35]([C:21]2[C:20]([CH2:19][OH:18])=[CH:33][C:24]3[C:25]([C:28]([NH:50][CH2:49][C:46]4[CH:47]=[CH:48][N:44]([CH3:43])[N:45]=4)=[O:30])=[N:26][O:27][C:23]=3[C:22]=2[F:34])[CH2:40][C@H:39]([CH3:41])[O:38]1
Reactant: Cn1ccc(CN)n1
Reactant: CCOC(=O)c1noc2c(F)c(N3C[C@@H](C)O[C@@H](C)C3)c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)cc12
Product: C[C@@H]1CN(c2c(CO)cc3c(C(=O)NCc4ccn(C)n4)noc3c2F)C[C@H](C)O1

Procedure:
Starting materials: ethyl 5-((tert-butyldiphenylsilyloxy)methyl)-6-((2R,6S)-2,6-dimethylmorpholino)-7-fluorobenzo[d]isoxazole-3-carboxylate (Intermediate 204) and (1-methyl-1H-pyrazol-3-yl)methanamine
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Br[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]1[N:18]([C:19]2[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=2)[N:17]=[N:16][N:15]=1.O.[CH2:29]([C:31]1[CH:40]=[C:39]([O:41][CH2:42][C:43]2[CH:48]=[CH:47][C:46](B3OCC(C)(C)CO3)=[CH:45][CH:44]=2)[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[N:32]=1)[CH3:30]>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.C1(C)C=CC=CC=1.CO>[CH2:29]([C:31]1[CH:40]=[C:39]([O:41][CH2:42][C:43]2[CH:48]=[CH:47][C:46]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[C:14]3[N:18]([C:19]4[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=4)[N:17]=[N:16][N:15]=3)=[CH:45][CH:44]=2)[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[N:32]=1)[CH3:30]
Reactant: CCc1cc(OCc2ccc(B3OCC(C)(C)CO3)cc2)c2ccccc2n1
Reactant: O=[N+]([O-])c1ccc(-n2nnnc2-c2ccccc2Br)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CO
Product: CCc1cc(OCc2ccc(-c3ccccc3-c3nnnn3-c3ccc([N+](=O)[O-])cc3)cc2)c2ccccc2n1
Temperature: 60 °C
Yield: 58.2 %

Procedure:
A mixture of potassium carbonate (1.08 g; 7.8 mmol), 5-(2-bromophenyl)-1-(4-nitrophenyl)-1H-tetrazole (1.16 g; 3.2 mmol) (obtained as described in Procedure A, step (ii)), water (10 ml), toluene (10 ml), and methanol (10 ml) was heated to 60° C. to give a clear solution. Compound H (1.0 g; 2.6 mmol) and tetrakis(triphenylphosphine)palladium (0.06 g; 0.05 mmol) were added and the reaction mixture heated at reflux for 6 hours. The mixture was allowed to cool and further toluene (10 ml) added. The organic phase was separated and the aqueous phase extracted with toluene (2×20 ml). The combined organic phases were evaporated and the resultant solid recrystallised from toluene to give 2-ethyl-4-[(2'-(1-(4-nitrophenyl)-1H-tetrazol-5-yl)biphenyl-4-yl)methoxy]quinoline (A) as a solid (0.8 g); m.p. and NMR similar to that of the product of procedure A, part (v).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH3:11])=[CH:5][C:4]=1[O:12][CH3:13].C(C1C(=O)C(Cl)=C(Cl)C(=[O:19])C=1C#N)#N.C(O)(=O)C>O1CCOCC1>[CH3:13][O:12][C:4]1[CH:5]=[C:6]([CH:7]=[CH:8][C:3]=1[O:2][CH3:1])[CH:9]=[CH:10][CH:11]=[O:19]
Reactant: CCCc1ccc(OC)c(OC)c1
Reactant: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: CC(=O)O
Solvent: C1COCCO1
Product: COc1ccc(C=CC=O)cc1OC
Yield: 60 %

Procedure:
In order to study the contribution of the length of the conjugation bridge to the AR activity, compound Q110 with a four-conjugated-double bond linker and compound Q111 with a five-conjugated-double bond linker were synthesized and illustrated in Scheme 13. Compound Q110 was synthesized starting from 1,2-dimethoxy-4-propyl-benzene. To a solution of 3-(3,4-dimethoxyphenyl) propane in dry dioxane was added with DDQ (3.1 eq.) and catalytic amount of acetic acid. The mixture was sonicated for 2 h with TLC monitoring. After completion of the reaction, the solid was filtered out and the filtration was concentrated. The residue was dissolved in EtOAc and washed with water, 2% NaHCO3, and brine. The organic extract was dried over Na2SO4 and concentrated to afford a crude as yellow-brownish solid, which was purified with neutral alumina column chromatography and eluted with hexanes-ethyl acetate mixture to give a light yellow solid, 3,4-dimethoxycinnamaldehyde in 60% yield (B. P. Joshi et al., Tetrahedron, 62, 2590-2593, 2006). A solution of 2,4-petanedione (3 eq.) and B2O3 (1 eq.) in EtOAc was stirred at 40° C. for 0.5 h, 3,4-dimethoxycinnamaldehyde (1 eq.) and tributyl borane (1 eq.) were added. The resulting reaction mixture was stirred at 40° C. for 0.5 h. Butylamine (1.2 eq.) in EtOAc was added dropwise at the temperature and stirred at 40° C. for 16 h. To the red reaction mixture, 1% HCl aq was added and the mixture was stirred to 60° C. for 1 h. After cooling to rt, the aqueous was separated and the organic was washed with water to pH˜7 and dried over Na2SO4. The crude was purified by silica gel flash column chromatography to get the intermediate product 8-(3,4-Dimethoxy-phenyl)-4-hydroxy-octa-3,5,7-trien-2-one as an off-white solid. A solution of the intermediate (1 eq.) and B2O3 (0.7 eq.) in EtOAc was stirred at 70° C. for 0.5 h. 3,4-dimethoxybenzaldehyde (1 eq.) and trubutyl borane (1 eq.) were added and the reaction mixture was stirred at 70° C. for 0.5 h. Piperidine (1.2 eq.) in EtOAc was added dropwise and the reaction mixture was stirred at 88-90° C. for 1 h. After cooling to 60° C., 1% HCl aq was added and the mixture was stirred at 60° C. for 0.5 h. The reaction mixture was worked-up by following the procedure described above and the crude was purified by silica gel column chromatography to afford the desired product Q110 as a red solid. Amorphous, mp. 65-68° C., ESI MS m/z: 423.1 [M+H]+; 1H NMR (300 MHz, CDCl3) δ: 7.64-7.58 (d, 2H, H-1 and 2), 7.16-7.02 (4H, aromatic ring H and trans double bond H), 6.90-6.82 (4H, aromatic ring H), 6.53-6.48 (1H, trans double bond H), 6.18-6.12 (1H, trans double bond H), 5.75 (s, 1H, H-4), 3.94-3.92 (12H, —OCH3).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][NH2:33]>C(O)C>[C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][NH:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][NH2:33])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NCCCCCCN
Reactant: BrCCCCCCCCCCCCCCCCCCc1ccccc1
Solvent: CCO
Product: NCCCCCCNCCCCCCCCCCCCCCCCCCc1ccccc1

Procedure:
Following the procedure of Example XVI a solution of 15.8 grams (0.04 mole) of phenylstearyl bromide and 37.2 grams (0.32 mole) of hexamethylene diamine in 400 ml of ethanol was refluxed for three hours. After the same recovery procedure 15.2 grams (88.4% crude mass yield) of N-phenylstearyl hexamethylene diamine was obtained having the following analysis: