Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[C:10]2[O:9][CH:8]=[CH:7][C:6]=2[CH:5]=[C:4]([N+:11]([O-:13])=[O:12])[CH:3]=1.[CH3:14]C1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.[Sn](C)(C)(C)C.CCN(CC)CC>CN(C=O)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:14][C:2]1[C:10]2[O:9][CH:8]=[CH:7][C:6]=2[CH:5]=[C:4]([N+:11]([O-:13])=[O:12])[CH:3]=1
Reactant: O=[N+]([O-])c1cc(I)c2occc2c1
Reactant: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: C[Sn](C)(C)C
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1cc([N+](=O)[O-])cc2ccoc12
Temperature: 100 °C
Reaction time: 0.05 h

Procedure:
7-Iodo-5-nitro-benzofuran (6.5 g, 22.1 mmol), Pd(OAc)2 (1 g, 3.9 mmol), P(o-tolyl)3, Me4Sn, Et3N were dissolved in DMF (40 mL) and portioned out in 13 tubes and heated at 100° C. for 10 min each using controlled microwave energy. The reaction mixtures were combined and filtered and the solvent was evaporated. The crude material was purified using flash chromatography (using a gradient of isohexane—10% EtOAc in isohexane). Yield: 2.82 g (70%) of 7-methyl-5-nitro-1-benzofuran. 1H NMR (400 MHz, CDCl3) δ ppm 2.51-2.64 (m, 3H) 6.90 (d, J=2.3 Hz, 1H) 7.77 (d, J=2.3 Hz, 1H) 8.04 (d, J=1.3 Hz, 1H) 8.37 (d, J=2.3 Hz, 1H); HPLC 96% Rt=2.31 min (System A; 10-97% in 3 min ACE column). MS (ESI+) for C9H7NO3 m/z 178 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:21]=[CH:20][C:16]([C:17]([OH:19])=O)=[CH:15][CH:14]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:22]([O:24]CC)=[O:23].BrC1N=C(N)C=CC=1.[Cl:35][C:36]1[CH:41]=[CH:40][C:39]([C:42]2[CH:46]=[C:45]([NH2:47])[NH:44][N:43]=2)=[CH:38][CH:37]=1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:21]=[CH:20][C:16]([C:17](=[O:19])[NH:47][C:45]3[NH:44][N:43]=[C:42]([C:39]4[CH:40]=[CH:41][C:36]([Cl:35])=[CH:37][CH:38]=4)[CH:46]=3)=[CH:15][CH:14]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:22]([OH:24])=[O:23]
Reactant: Nc1cc(-c2ccc(Cl)cc2)n[nH]1
Reactant: CCOC(=O)C1CCOc2cc(Oc3ccc(C(=O)O)cc3)c(Cl)cc21
Agent: Nc1cccc(Br)n1
Product: O=C(Nc1cc(-c2ccc(Cl)cc2)n[nH]1)c1ccc(Oc2cc3c(cc2Cl)C(C(=O)O)CCO3)cc1

Procedure:
Prepared according to the method of Example 39, substituting 4-(6-cyano-4-(methoxycarbonyl)chroman-7-yloxy)benzoic acid in Step A with 4-(6-chloro-4-(ethoxycarbonyl)chroman-7-yloxy)benzoic acid and 6-bromopyridin-2-amine with 3-(4-chlorophenyl)-1H-pyrazol-5-amine. MS (apci) m/z=524.1 (M+H).
Reaction SMILES: S(Cl)([Cl:3])=O.[Cl:5][C:6]1[CH:11]=[CH:10][C:9]([CH:12]=[CH:13][S:14](O)(=[O:16])=[O:15])=[C:8]([O:18][CH3:19])[CH:7]=1.C(OCC)(=O)C>CN(C=O)C>[Cl:5][C:6]1[CH:11]=[CH:10][C:9]([CH:12]=[CH:13][S:14]([Cl:3])(=[O:16])=[O:15])=[C:8]([O:18][CH3:19])[CH:7]=1
Reactant: COc1cc(Cl)ccc1C=CS(=O)(=O)O
Reactant: O=S(Cl)Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1cc(Cl)ccc1C=CS(=O)(=O)Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 38.7 %

Procedure:
Thionyl chloride (8.1 mL, 111.19 mmol) was added dropwise at 0° C. to a solution of 2-(4-chloro-2-methoxy-phenyl)-ethenesulfonic acid (5.53 g, 22.24 mmol) in DMF (10 mL). The reaction mixture was stirred at RT for 3 h and then was poured onto crushed ice. Ethyl acetate (50 mL) was added to the mixture. The organic phase was separated, washed with brine (3×20 mL), dried over MgSO4 and concentrated under reduced pressure. The oily residue was purified on silica gel using hexane/ethyl acetate, 4:1 to give the target compound which was then recrystallized from pentane/diethyl ether to afford the title compound (2.30 g, 61% over 3 steps) as a white solid.
Reaction SMILES: [CH:1]([Si:3]([CH:6]=[CH2:7])(Cl)Cl)=[CH2:2].[CH3:8][C:9]([CH3:12])([O-:11])[CH3:10].[K+].[Cl-].[K+]>CCCCCC>[CH:1]([Si:3]([CH:6]=[CH2:7])([O:11][C:9]([CH3:12])([CH3:10])[CH3:8])[O:11][C:9]([CH3:12])([CH3:10])[CH3:8])=[CH2:2]
Reactant: C=C[Si](Cl)(Cl)C=C
Reactant: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CCCCCC
Product: C=C[Si](C=C)(OC(C)(C)C)OC(C)(C)C
Reaction time: 17 h
Yield: 56.5 %

Procedure:
306 g (2.00 mol) of divinyldichlorosilane, 539 g (4.80 mol) of potassium tert-butoxide and 3.0 L of dry hexane were charged in a 5 L four-necked flask equipped with a dropping funnel and a mechanical stirrer in a stream of nitrogen, and reaction was carried out for 17 hours under reflux with hexane. After completion of the reaction, potassium chloride residue as a by-product was removed by filtration, and the obtained filtrate was distilled under reduced pressure to obtain 257 g (1.13 mol) of divinyl di-tert-butoxysilane as an aimed product. The yield was 56.5%.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=O)[C:5]([OH:11])=[CH:4][CH:3]=1.[Cl:12][C:13]1[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][C:14]=1[NH2:15]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([CH:10]=1)[C:7]([NH:15][C:14]1[CH:16]=[C:17]([C:20]([F:21])([F:22])[F:23])[CH:18]=[CH:19][C:13]=1[Cl:12])=[O:9]
Reactant: Nc1cc(C(F)(F)F)ccc1Cl
Reactant: O=C(O)c1cc(Cl)ccc1O
Product: O=C(Nc1cc(C(F)(F)F)ccc1Cl)c1cc(Cl)ccc1O
Yield: 49.1 %

Procedure:
Using 5-chlorosalicylic acid and 2-chloro-5-(trifluoromethyl)aniline as the raw materials, the same operation as the example 16 gave the title compound.
Reaction SMILES: [CH2:1]([Mg]Br)[CH2:2][CH3:3].[CH3:6][O:7][C:8]([CH3:17])(C)[CH2:9][CH2:10][CH2:11][CH:12]([CH3:15])[CH:13]=[CH2:14]>O1CCCC1.[Cl-].[Cl-].C1([Ti+2]C2C=CC=C2)C=CC=C1>[CH3:17][C:8]1([O:7][CH3:6])[CH:9]=[CH:10][CH:11]=[C:12]([CH3:15])[CH:13]1[CH2:14][CH2:3][CH2:2][CH2:1][CH2:17][CH2:8][CH2:9][CH2:10][CH2:11][CH:12]([CH3:15])[CH3:13]
Reactant: CCC[Mg]Br
Reactant: C=CC(C)CCCC(C)(C)OC
Agent: C1=CC([Ti+2]C2C=CC=C2)C=C1
Agent: [Cl-]
Solvent: C1CCOC1
Product: COC1(C)C=CC=C(C)C1CCCCCCCCCC(C)C
Temperature: 25 °C

Procedure:
To a solution of n-propylmagnesium bromide (0.25 mole) in tetrahydrofuran (200 ml) was added 7-methoxy-3,7-dimethyl-1-octene (42.5 g) and biscyclopentadienyl titanium dichloride (1.25 g). After the vigorous reaction subsided, the mixture was heated in an oil bath (75°) for 19 hours. Aliquot quench at this point indicated ~50% conversion. The Grignard exchange product was transferred to a separatory funnel, and added dropwise to p-isopropylbenzyl chloride (21 g) in THF (300 ml) containing cuprous chloride (2.5 g) cooled at 0° to -10° while stirring. On warming to room temperature overnight, the reaction was then quenched with aqueous ammonium chloride and extracted with pentane. The pentane extracts were distilled to give product (2,6-dimethyl-2-methoxy-9-isopropylphenylnonane) (12.5 g; bp 150°-152° /0.25-0.3 torr) contaminated with some p, p'-diisopropylbibenzyl.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1)#[CH:2].C([Mg]Br)C.[CH3:13][C:14]1([CH3:23])[CH2:19][C:18]([CH3:21])([CH3:20])[CH2:17][C:16](=[O:22])[CH2:15]1.C(OCC)(=O)C>C1COCC1>[CH3:20][C:18]1([CH3:21])[CH2:19][C:14]([CH3:23])([CH3:13])[CH2:15][C:16]([C:2]#[C:1][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=2)([OH:22])[CH2:17]1
Reactant: CC1(C)CC(=O)CC(C)(C)C1
Reactant: C#Cc1ccccn1
Agent: CC[Mg]Br
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC1(C)CC(C)(C)CC(O)(C#Cc2ccccn2)C1
Temperature: 25 °C
Yield: 9.7 %

Procedure:
To a solution of 2-ethynylpyridine (1.0 g, 10 mmol) in TMF at −78° C. was added a 1.0 M solution of ethyl magnesium bromide in THF (10 mL, 10 mmol). After stirring at reduced temperature for 30 minutes a solution of 3,3,5,5-tetramethylcyclohexanone (1.5 g, 10 mmol) in THF was added rapidly. The mixture was allowed to warm to ambient temperature over 16 hours, then partitioned between water and ethyl acetate. The organic layer was dried over anhydrous Na2SO4, and concentrated in vacuo. The resultant product was purified by flash column chromatography on silica gel eluting with 1:1 hexane:ethyl acetate to afford 3,3,5,5-tetramethyl-1-(2-pyridinylethynyl)cyclohexanol (250 mg, 10% yield) as a white solid. M.p. 126-127° C. 1H NMR (DMSO-d6, 300 MHz) δ 8.57 (m, 1H), 7.64 (m, 1H), 7.39 (d, J=5 Hz, 1H), 7.22 (m, 1H), 1.91 (d, J=9 Hz, 2H), 1.71 (d, J=9 Hz, 2H), 1.26 (s, 2H), 1.14 (s, 6H), 1.09 (s, 6H).
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: C1COCCO1
Solvent: CC(=O)O
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-propylbenzene. To a solution of 3-(3,4-dimethoxypheny) 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: [Cl:1][C:2]1[S:3][CH:4]=[CH:5][CH:6]=1.C([Li])CCC.[CH2:12]1[O:15][C@H:13]1[CH3:14]>O1CCCC1>[Cl:1][C:2]1[S:3][C:4]([CH2:12][C@@H:13]([OH:15])[CH3:14])=[CH:5][CH:6]=1
Reactant: Clc1cccs1
Reactant: C[C@H]1CO1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C[C@H](O)Cc1ccc(Cl)s1
Temperature: -30 °C
Reaction time: 1 h

Procedure:
A solution of 2-chlorothiophene (8.17 g) in tetrahydrofuran (80 ml) is cooled to -30° C. and 1.6M n-butyllithium in hexanes (43.0 ml) is added dropwise. The mixture is stirred at -30° C. for about 1 hour, (S)-propylene oxide (4.00 g) is added, and the mixture is warmed to 0° C. and stirred at that temperature for about 3 hours. The reaction is quenched with saturated aqueous ammonium chloride solution, diluted with ether, and the layers separated. The organic layer is washed with brine, dried over magnesium sulfate, and concentrated in vacuo to give the desired product.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[Br:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19]2[C:24](=[O:25])[C:23]([CH3:27])([CH3:26])[S:22][C:21]([CH3:29])([CH3:28])[C:20]2=[O:30])=[C:15]([CH2:31][CH3:32])[CH:14]=1>ClCCl.O>[Br:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19]2[C:24](=[O:25])[C:23]([CH3:26])([CH3:27])[S:22](=[O:9])[C:21]([CH3:29])([CH3:28])[C:20]2=[O:30])=[C:15]([CH2:31][CH3:32])[CH:14]=1
Reactant: CCc1cc(Br)ccc1C1C(=O)C(C)(C)SC(C)(C)C1=O
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Solvent: O
Product: CCc1cc(Br)ccc1C1C(=O)C(C)(C)S(=O)C(C)(C)C1=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 54.6 %

Procedure:
A solution of 3-chloroperbenzoic acid (2.45 g, 0.0142 mol) in dichloromethane (40 ml) is added to a pre-cooled solution (0° C.) of 4-(4-bromo-2-ethylphenyl)-2,2,6,6-tetramethyl-thiopyran-3,5-dione (3.5 g, 0.0095 mol) in dichloromethane (100 ml). The reaction mixture is stirred at 0° C. for one hour and then allowed to come to room temperature. The reaction mixture is stirred at room temperature for one hour, diluted with water (100 ml) and separated. The organic phase is collected, and the aqueous layer is extracted with dichloromethane (2×50 ml). The organic phases are combined, washed with water, and dried over anhydrous sodium sulfate. The mixture is filtered, and the filtrate is evaporated under reduced pressure. The residue is purified by column chromatography on silica gel to give 4-(4-bromo-2-ethylphenyl)-2,2,6,6-tetramethyl-1-oxo-dihydrothiopyran-3,5-dione as a white solid (2.0 g).
Reaction SMILES: [C:1]([CH2:3]P(=O)(OCC)OCC)#[N:2].[H-].[Na+].O=[C:15]([C:26](=[O:75])[NH:27][C:28]1[CH:29]=[N:30][N:31]([CH2:53][CH2:54][O:55][C:56]([C:69]2[CH:74]=[CH:73][CH:72]=[CH:71][CH:70]=2)([C:63]2[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=2)[C:57]2[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=2)[C:32]=1[NH:33][C:34]([C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)([C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[CH2:16][CH2:17][NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22].O>O1CCCC1>[C:1](/[CH:3]=[C:15](/[C:26]([NH:27][C:28]1[CH:29]=[N:30][N:31]([CH2:53][CH2:54][O:55][C:56]([C:63]2[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=2)([C:69]2[CH:74]=[CH:73][CH:72]=[CH:71][CH:70]=2)[C:57]2[CH:58]=[CH:59][CH:60]=[CH:61][CH:62]=2)[C:32]=1[NH:33][C:34]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)([C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)=[O:75])\[CH2:16][CH2:17][NH:18][C:19](=[O:25])[O:20][C:21]([CH3:22])([CH3:23])[CH3:24])#[N:2]
Reactant: CC(C)(C)OC(=O)NCCC(=O)C(=O)Nc1cnn(CCOC(c2ccccc2)(c2ccccc2)c2ccccc2)c1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCOP(=O)(CC#N)OCC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCC/C(=C\C#N)C(=O)Nc1cnn(CCOC(c2ccccc2)(c2ccccc2)c2ccccc2)c1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 83.3 %

Procedure:
To a stirred solution of diethyl (cyanomethyl)phosphonate (311 mg) in tetrahydrofuran (13 ml) was added sodium hydride (70.3 mg, 60% oil suspension) under nitrogen atmosphere at 0° C., and the mixture was stirred for 45 minutes with warming to room temperature. tert-Butyl [3,4-dioxo-4-({5-(tritylamino)-1-[2-(trityloxy)ethyl]-1H-pyrazol-4-yl}amino)butyl]carbamate (1.32 g) was added to the mixture and the stirring was continued for 30 minutes. Water was added to the reaction mixture and the whole mixture was extracted with ethyl acetate. The extract was washed with water and brine and dried over anhydrous magnesium sulfate. Concentration under reduced pressure gave tert-butyl {(3E)-4-cyano-3-[({5-(tritylamino)-1-[2-(trityloxy)ethyl]-1H-pyrazol-4-yl}amino)carbonyl]-3-buten-1-yl}carbamate (1.13 g).
Reaction SMILES: C(O[CH:5]([CH2:12][CH3:13])[CH:6]([N+]([O-])=O)[CH2:7][CH3:8])(=O)C.[N+:14]([CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])#[C-:15].C1CCN2C(=NCCC2)CC1.Cl>C1COCC1>[CH2:12]([C:5]1[C:6]([CH2:7][CH3:8])=[CH:15][NH:14][C:16]=1[C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH3:13]
Reactant: [C-]#[N+]CC(=O)OCC
Reactant: CCC(OC(C)=O)C(CC)[N+](=O)[O-]
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: CCOC(=O)c1[nH]cc(CC)c1CC
Temperature: 25 °C
Reaction time: 12 h
Yield: 93.6 %

Procedure:
After 4-acetoxy-3-nitrohexane (11.34 g, 60 mmol) had been added to a reaction vessel, air in the vessel was replaced with nitrogen, and dry-THF (150 ml) and ethyl isocyanoacetate (7.28 ml, 66 mmol) were added. Then, DBU (20.76 ml, 144 mmol) was slowly dropwise added while being cooled on an ice bath, and stirred at room temperature for 12 hours. After the completion of the reaction, 1N hydrochloric acid was added, and extracted with chloroform, and the extract was washed with water and a saturated salt solution. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. After that, the concentrated product was purified by means of silica gel column chromatography to yield ethyl 3,4-diethylpyrrole-2-carboxylate (10.97 g, 94% yield).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[N:9]=[CH:8][N:7]([CH2:11][CH2:12][CH3:13])[C:6]=2[C:5](=[O:14])[NH:4][C:3]1=[O:15].[OH-].[Na+].Br[CH2:19][CH2:20][CH2:21][CH2:22][C:23](=[O:25])[CH3:24]>CO.O>[O:25]=[C:23]([CH3:24])[CH2:22][CH2:21][CH2:20][CH2:19][N:4]1[C:5](=[O:14])[C:6]2[N:7]([CH2:11][CH2:12][CH3:13])[CH:8]=[N:9][C:10]=2[N:2]([CH3:1])[C:3]1=[O:15].[CH3:1][N:2]1[C:10]2[N:9]=[CH:8][N:7]([CH2:11][CH2:12][CH3:13])[C:6]=2[C:5](=[O:14])[NH:4][C:3]1=[O:15]
Reactant: CC(=O)CCCCBr
Agent: CCCn1cnc2c1c(=O)[nH]c(=O)n2C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCCn1cnc2c1c(=O)n(CCCCC(C)=O)c(=O)n2C

Procedure:
437.2 g of 3-methyl-7-propylxanthine are suspended in a mixture of 240 g of methanol and 321 g of water and induced to dissolve at elevated temperature with 160 g of 50% strength sodium hydroxide solution, and subsequently at the boiling point 358 g of 1-bromo-5-hexanone are added and the mixture is heated to reflux for 41/2 hours. After cooling, unreacted 3-methyl-7-propylxanthine is separated off and the alcohol is removed by distillation. The aqueous solution is adjusted to pH 11 with sodium hydroxide solution and extracted with methylene chloride. 1-(5-Oxohexyl)-3-methyl-7-propylxanthine is obtained with melting point 69°-70° C. in approximately 90% yield (based on reacted 3-methyl-7-propylxanthine) from the residue of the methylene chloride solution after recrystallization from 5.2 of diisopropyl ether.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([C:17]2[CH:22]=[CH:21][C:20]([Br:23])=[CH:19][CH:18]=2)(CC=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+].[CH:26]([OH:29])(C)C>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([C:17]2[CH:18]=[CH:19][C:20]([Br:23])=[CH:21][CH:22]=2)([CH2:26][OH:29])[CH2:10][CH2:9]1)=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: CC(C)O
Reactant: CC(C)(C)OC(=O)N1CCC(CC=O)(c2ccc(Br)cc2)CC1
Agent: [BH4-]
Agent: [Na+]
Product: CC(C)(C)OC(=O)N1CCC(CO)(c2ccc(Br)cc2)CC1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of 1.78 g of 4-(4-bromo-phenyl)-4-hydroxymethyl-piperidine-1-carboxylic acid tert-butyl ester from Step 3 (4.85 mmol, 1 eq) in 25 mL of isopropanol was added NaBH4 (0.201 g, 5.33 mmol, 1.1 eq). The mixture was stirred at room temperature for 20 h and then quenched by the addition of aqueous HCl (20 mL) to pH ˜3. The solvent was removed by rotary evaporation and the resulting aqueous mixture was extracted with three 50 mL portions of ethyl acetate. The organic extracts were combined and washed with saturated brine and dried over Na2SO4. Filtration and concentration by rotary evaporation gave the crude product which was purified by flash column chromatography eluting with a gradient of 5-20% ethyl acetate in hexane to give 1.36 g of the title compound 4-(4-bromo-phenyl)-4-hydroxymethyl-piperidine-1-carboxylic acid tert-butyl ester 49 as a pale foam. 1H NMR (300 MHz, CDCl3): δ 7.38-7.18 (m, 4H), 4.35-4.19 (br. d, 2H), 2.83-2.76 (t, 2H), 2.70-2.58 (m, 1H), 1.86-1.78 (d, 2H), 1.70-1.58 (m, 3H), 1.50 (s, 9H).
Reaction SMILES: [N:1]([O-:3])=[O:2].F[B-](F)(F)F.[NH:9]1[C:17]2[C:12](=[CH:13][C:14]([OH:18])=[CH:15][CH:16]=2)[CH:11]=[N:10]1.O>C(#N)C>[N+:1]([C:13]1[C:14]([OH:18])=[CH:15][CH:16]=[C:17]2[C:12]=1[CH:11]=[N:10][NH:9]2)([O-:3])=[O:2]
Reactant: O=N[O-]
Reactant: Oc1ccc2[nH]ncc2c1
Agent: F[B-](F)(F)F
Solvent: CC#N
Solvent: O
Product: O=[N+]([O-])c1c(O)ccc2[nH]ncc12
Temperature: 0 °C
Reaction time: 2 h
Yield: 44.8 %

Procedure:
Under a nitrogen atmosphere, a solution of tetrafluoroborate nitrite (110 mg, 0.783 mmol) in acetonitrile (3 ml) was added dropwise to a suspension of the 1H-indazol-5-ol (100 mg, 0.745 mmol) obtained in Reference Example 4 in acetonitrile (4.0 ml) at −35° C. over a period of 10 minutes, and the resulting mixture was slowly heated to 0° C. After 2 hours, the reaction solution was poured into water and extracted with ethyl acetate. The extract solution was concentrated under reduced pressure and the resulting residue was purified by a silica gel column chromatography (eluent: hexane/ethyl acetate). The residue purified was concentrated under reduced pressure and the resulting residue was washed with ethanol/diisopropyl ether by repulping to obtain 4-nitro-1H-indazol-5-ol (59.8 mg, 45%).
Reaction SMILES: [CH3:1][N:2]([CH3:30])[CH2:3][CH2:4][N:5]([CH2:18][CH2:19][NH:20][C:21]1[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][N:22]=1)S(C1C=CC=CC=1[N+]([O-])=O)(=O)=O.C([O-])([O-])=O.[K+].[K+].C1(S)C=CC=CC=1>O.CN(C=O)C>[CH3:1][N:2]([CH3:30])[CH2:3][CH2:4][NH:5][CH2:18][CH2:19][NH:20][C:21]1[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][N:22]=1
Reactant: CN(C)CCN(CCNc1ccc([N+](=O)[O-])cn1)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: Sc1ccccc1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CN(C)CCNCCNc1ccc([N+](=O)[O-])cn1
Temperature: 23 °C
Reaction time: 12 h

Procedure:
To a suspension of resin-bound [2-(dimethylamino)ethyl]{2-[(5-nitro(2-pyridyl))-amino]ethyl}[(2-nitrophenyl)sulfonyl]amine (3.0 g, 2.1 mmol) and DMF (30 mL) at 23° C. was added H2O (2 drops), K2CO3 (2.9 g, 21 mmol) and PhSH (2.2 mL, 21 mmol). The resulting mixture was shaken at 23° C. for 12 h, filtered, washed with NMP, H2O and CH2Cl2 and air dried to yield polymer-bound dimethyl[2-({2-[(5-nitro(2-pyridyl))amino]-ethyl}amino)ethyl]amine.
Reaction SMILES: [CH2:1]([C:7]1[C:8](=[O:12])[CH2:9][CH2:10][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[N+:13]([CH3:16])([O-:15])=[O:14].[OH-].C([N+](C)(C)C)C1C=CC=CC=1>O1CCOCC1>[CH2:1]([CH:7]1[CH:11]([CH2:16][N+:13]([O-:15])=[O:14])[CH2:10][CH2:9][C:8]1=[O:12])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCC1=CCCC1=O
Reactant: C[N+](=O)[O-]
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [OH-]
Solvent: C1COCCO1
Product: CCCCCCC1C(=O)CCC1C[N+](=O)[O-]

Procedure:
In a 2-L flask fitted with a reflux condenser, is placed 332 g of 2-n-hexyl-2-cyclopentenone, 183 g of nitromethane, 30 ml of 40% methanolic solution of benzyltrimethylammonium hydroxide (Triton B) and 200 ml of dry dioxane. The reaction mixture is refluxed for 23 hours. The solvent is distilled off under a reduced pressure and the residue is dissolved in 1 L of ether. The ether solution is washed successively with dilute hydrochloric acid, water and sodium bicarbonate solution and dried over anhydrous sodium sulphate. The solvent is removed at atmospheric pressure and the residue is distilled through a short Vigreux column. After a lower boiling fraction (35 g, 65°C/0.2 mm) consisting of 2-n-hexyl-2-cyclopentenone, the product is collected at 135°C/0.3 mm, yield 365 g (80%), nD20 1.4733.