Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O.C1(C)C=CC=CC=1.[OH:39][C:40]1[CH:45]=[CH:44][C:43]([CH2:46][C:47](=[O:49])[CH3:48])=[CH:42][CH:41]=1.[C:50]([O:54][C:55]([N:57]1[CH2:62][CH2:61][CH:60](O)[CH2:59][CH2:58]1)=[O:56])([CH3:53])([CH3:52])[CH3:51]>O1CCCC1>[C:50]([O:54][C:55]([N:57]1[CH2:62][CH2:61][CH:60]([O:39][C:40]2[CH:41]=[CH:42][C:43]([CH2:46][C:47](=[O:49])[CH3:48])=[CH:44][CH:45]=2)[CH2:59][CH2:58]1)=[O:56])([CH3:53])([CH3:51])[CH3:52]
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: CC(=O)Cc1ccc(O)cc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CC(=O)Cc1ccc(OC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 58.6 %

Procedure:
A solution of triphenylphosphine (18.5 g, 70.6 mmol) and 40% DEAD in toluene (12.3 g, 70.6 mmol) in 125.0 mL of tetrahydrofuran was cooled to 0° C. under N2 as a solution of 1-(4-hydroxy-phenyl)-propan-2-one (6.54 g, 43.6 mmol) and 4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (10.7 g, 53.2 mmol) in 125.0 mL of tetrahydrofuran was added dropwise via addition funnel. After stirred at rt overnight, the solvent was evaporated. The residue was stirred in hexane/EtOAc, the solid formed was filtered. The hexane/EtOAC solution was concentrated and purified by ISCO graduate chromatography (hexane-20% EtOAc in hexane) to give 4-[4-[2-oxo-propyl)-phenoxy]-piperidine-1-carboxylic acid tert-butyl ester (8.52 g, 59%).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Cl[C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][N:9]=1.[CH3:17][CH:18]1[CH2:23][NH:22][CH2:21][CH2:20][NH:19]1>CN(C)C=O>[CH3:17][CH:18]1[NH:19][CH2:20][CH2:21][N:22]([C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][N:9]=2)[CH2:23]1
Reactant: CC1CNCCN1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC1CN(c2ccc([N+](=O)[O-])cn2)CCN1
Reaction time: 1 h

Procedure:
872 mg (6.31 mmol) of potassium carbonate were added to a solution of 500 mg (3.15 mmol) of 2-chloro-5-nitropyridine in 7 ml of dimethylformamide. After that, a solution of 350 mg (3.32 mmol) of 2-methylpiperazine in 3 ml of dimethylformamide was slowly added dropwise to the reaction mixture while cooling with ice (exothermic reaction). The reaction mixture was stirred for 1 hour while cooling with ice and then stirred overnight at room temperature. After the solvent had been evaporated to dryness, the residue was taken up in water and this mixture was extracted three times with diethyl ether. The combined organic phases were dried over sodium sulfate, filtered and evaporated to dryness, with 3-methyl-1-(5-nitropyridin-2-yl)piperazine (Yield: 650 mg, 89% of theory) being obtained.
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[C:9]3[C:14](=[CH:15][CH:16]=2)[NH:13][C:12](=O)[NH:11][C:10]3=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[ClH:19].C(N(CC)CC)C.O=P(Cl)(Cl)[Cl:29]>>[Cl:19][C:12]1[N:11]=[C:10]([Cl:29])[C:9]2[C:14](=[CH:15][CH:16]=[C:7]([N:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)[CH:8]=2)[N:13]=1
Reactant: O=c1[nH]c(=O)c2cc(N3CCCCC3)ccc2[nH]1
Reactant: Cl
Reactant: O=P(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Product: Clc1nc(Cl)c2cc(N3CCCCC3)ccc2n1
Yield: 91 %

Procedure:
To 6-Piperidin-1-yl-1H-quinazoline-2,4-dione (522 mg, 2.13 mmol) and triethyl amine hydrochloride (1.2 g, 8.5 mmol) was added POCl3 (20 mL) and the solution was heated to 120 C for 72 h. POCl3 was removed in vacuum and the resulting brown oil was quenched with ice water and treated with saturated NaHCO3, to afford a tan solid. Filtration and drying in vacuum gave title compound 550 mg (91% yield). HPLC tr=8.56 min (100%), FIA m/z 282.1 (M+H), HNMR (500 MHz, dmso): δ 8.05–8.00 (1H, d), 7.85–7.80 (1H, d), 7.20 (1H s), 5.50–4.40 (4H, m), 1.70–1.60 (6H, m).
Reaction SMILES: [C:1]([C:3]1[NH:4][CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:9]=2[Cl:15])[N:7]=1)#[N:2].[H-].[Na+].[CH3:18][N:19]([CH3:26])[P:20](Cl)([N:22]([CH3:24])[CH3:23])=[O:21].O>O1CCCC1>[CH3:18][N:19]([P:20]([N:22]([CH3:24])[CH3:23])([N:4]1[CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:9]=2[Cl:15])[N:7]=[C:3]1[C:1]#[N:2])=[O:21])[CH3:26]
Reactant: N#Cc1nc(-c2ccc(Cl)cc2Cl)c[nH]1
Reactant: CN(C)P(=O)(Cl)N(C)C
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CN(C)P(=O)(N(C)C)n1cc(-c2ccc(Cl)cc2Cl)nc1C#N
Reaction time: 2 h

Procedure:
A solution of 2-cyano-4-(2,4-dichlorophenyl)imidazole (1.0 g) in tetrahydrofuran (30 ml) was treated with sodium hydride (0.16 g of 80% dispersion in oil) at 0°. A solution of tetramethylphosphorodiamidic chloride (0.89 g) in tetrahydrofuran (10 ml) was added dropwise and the mixture stirred for 11/2 hours under nitrogen. It was then poured into water, stirred, and the precipitate filtered, dried and recrystalllsed from toluene/hexane to give 1-[bis(dimethylamino)phosphinyl]-2-cyano-4-(2,4-dichlorophenyl)imidazole, m.p. 140.5°-1°. (Compound 6).
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Br:21]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:21][CH2:20][C:17]1[CH:18]=[CH:19][C:14]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])=[CH:15][CH:16]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(C)OC(=O)c1ccccc1-c1ccc(CBr)cc1
Temperature: 25 °C
Yield: 81.8 %

Procedure:
To a solution of 2-t-butoxycarbonyl-4'-methylbiphenyl (25.3 g, 95 mmol) in CCl4 (200 ml) were added freshly opened N-bromosuccinimide (17.6 g, 0.099 mole) and dibenzoyl peroxide (2.28 g, 0.0094 moles). The mixture was refluxed for 4 hours, cooled to room temperature and filtered. The filtrate was washed with sat. NaHSO3 (1×50 ml), sat. NaHCO3 (1×50 ml), water (1×50 ml), sat. NaCl (1×50 ml) and dried over MgSO4. The solution was filtered, and concentrated in vacuo. The residue was dissolved in 100 ml of hot hexane. Crystallization gradually took place as the solution cooled. The flask was finally cooled to -20° C. and the precipitate recovered by filtration. The solid was washed with ice cold hexanes and dried in vacuo to give 27 g (88%) of a white solid. 1H-NMR (CDCl3): 1.23 (s, 9H), 4.53 (s, 2H), 7.2-7.5 (m, 7H), 7.68 (d, 1H).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[OH:7][C:8]([C:11]1[N:12]=[C:13]([CH2:27][CH2:28][CH3:29])[NH:14][C:15]=1[C:16]([O:18][CH2:19][C:20]1[O:21][C:22](=[O:26])[O:23][C:24]=1[CH3:25])=[O:17])([CH3:10])[CH3:9].[C:30]([N:49]1[C:53]([C:54]2[CH:59]=[CH:58][CH:57]=[CH:56][C:55]=2[C:60]2[CH:67]=[CH:66][C:63]([CH2:64]Br)=[CH:62][CH:61]=2)=[N:52][N:51]=[N:50]1)([C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>CN(C)C(=O)C.C(OCC)(=O)C>[OH:7][C:8]([C:11]1[N:12]=[C:13]([CH2:27][CH2:28][CH3:29])[N:14]([CH2:64][C:63]2[CH:62]=[CH:61][C:60]([C:55]3[CH:56]=[CH:57][CH:58]=[CH:59][C:54]=3[C:53]3[N:49]([C:30]([C:43]4[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=4)([C:37]4[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=4)[C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[N:50]=[N:51][N:52]=3)=[CH:67][CH:66]=2)[C:15]=1[C:16]([O:18][CH2:19][C:20]1[O:21][C:22](=[O:26])[O:23][C:24]=1[CH3:25])=[O:17])([CH3:9])[CH3:10]
Reactant: CCCc1nc(C(C)(C)O)c(C(=O)OCc2oc(=O)oc2C)[nH]1
Reactant: BrCc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: CCCc1nc(C(C)(C)O)c(C(=O)OCc2oc(=O)oc2C)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Temperature: 60 °C
Yield: 49.7 %

Procedure:
A suspension of 0.97 g of potassium carbonate in 100 ml of N,N-dimethylacetamide was warmed at 60° C., and then a solution of 1.14 g of (5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl 4-(1-hydroxy-1-methylethyl)-2-propylimidazole-5-carboxylate (prepared as described in Preparation 31) and 2.35 g of 4-[2-(trityltetrazol-5-yl)phenyl]benzyl bromide in 50 ml of N,N-dimethylacetamide was added dropwise to the warm suspension, whilst stirring. The reaction mixture was stirred at 60° C. for 3.5 hours, and it was then diluted with ethyl acetate. The ethyl acetate layer was separated, washed with water and dried over anhydrous magnesium sulfate, and then the solvent was removed by distillation under reduced pressure. The resulting residue was purified by column chromatography through silica gel, using a 1:1 by volume mixture of hexane and ethyl acetate as the eluent, to give 1.4 g of the title compound as an amorphous solid. This product was crystallized from diisopropyl ether, to give pure title compound, melting at 98°-99° C. (with decomposition).
Reaction SMILES: [I:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[CH2:11]([NH:14][CH2:15][CH2:16][CH3:17])[CH2:12][CH3:13]>>[CH2:11]([N:14]([CH2:15][CH2:16][CH3:17])[C:6](=[O:7])[C:5]1[CH:9]=[CH:10][C:2]([I:1])=[CH:3][CH:4]=1)[CH2:12][CH3:13]
Reactant: O=C(Cl)c1ccc(I)cc1
Reactant: CCCNCCC
Product: CCCN(CCC)C(=O)c1ccc(I)cc1

Procedure:
as an orange oil (11.51 g) t.l.c. (ER) Rf 0.48 was prepared from 4-iodobenzoyl chloride (10.0 g) and dipropylamine (4.10 g) according to the method of Intermediate 20.
Reaction SMILES: [NH2:1][CH:2]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[C:3]([OH:5])=O.N1C=CC=C[CH:13]=1.[C:18](OC(=O)C)(=[O:20])[CH3:19]>>[C:18]([NH:1][CH:2]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[C:3](=[O:5])[CH3:13])(=[O:20])[CH3:19]
Reactant: CCCCCCC(N)C(=O)O
Reactant: c1ccncc1
Reactant: CC(=O)OC(C)=O
Product: CCCCCCC(NC(C)=O)C(C)=O

Procedure:
A mixture of 2-amino-1-octanoic acid (I, 200 g, 1.26 mole) in acetic anhydride (960 ml), and pyridine (640 ml) was heated on a boiling water bath for 4 hr. The reaction mixture was evaporated in vacuo, and the residue was partitioned 6-8 times between 5% aqueous solution of NaHCO3 (400 ml) and ether (400 ml). The combined ethereal extracts were dried with anhydrous MgSO4 and evaporated to dryness to give crude 3-acetamidononan-2-one, 154 g (70%).
Reaction SMILES: [CH3:1][C:2]1([CH3:28])[CH2:7][CH2:6][C:5]([C:8]2[CH:13]=[C:12]([C:14](O)([CH3:16])[CH3:15])[CH:11]=[CH:10][C:9]=2[NH:18][C:19]([C:21]2[NH:22][CH:23]=[C:24]([C:26]#[N:27])[N:25]=2)=[O:20])=[CH:4][CH2:3]1.O=S(Cl)Cl.[NH:33]1[CH2:38][CH2:37][S:36][CH2:35][CH2:34]1.CCOC(C)=O>C(Cl)Cl>[CH3:1][C:2]1([CH3:28])[CH2:7][CH2:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]([CH3:16])([N:33]3[CH2:38][CH2:37][S:36][CH2:35][CH2:34]3)[CH3:15])[CH:11]=[CH:10][C:9]=2[NH:18][C:19]([C:21]2[NH:22][CH:23]=[C:24]([C:26]#[N:27])[N:25]=2)=[O:20])=[CH:4][CH2:3]1
Reactant: CC1(C)CC=C(c2cc(C(C)(C)O)ccc2NC(=O)c2nc(C#N)c[nH]2)CC1
Reactant: C1CSCCN1
Solvent: O=S(Cl)Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC1(C)CC=C(c2cc(C(C)(C)N3CCSCC3)ccc2NC(=O)c2nc(C#N)c[nH]2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 88 %

Procedure:
To a suspension of 4-cyano-1H-imidazole-2-carboxylic acid [2-(4,4-dimethyl-cyclohex-1-enyl)-4-(1-hydroxy-1-methyl-ethyl)-phenyl]-amide (as prepared in the previous step, 65 mg, 0.17 mmol) in 1.5 mL of DCM at 0° C. was added SOCl2 (38 μL, 0.52 mmol) under Ar. After stirring at RT for 1 h, the mixture was cooled back to 0° C. To the reaction was added thiomorpholine (172 μL, 1.72 mmol) and the resulting mixture was stirred at 0° C. for 1 h. After warming to RT, the mixture was treated with EtOAc (30 mL) and washed with H2O (2×10 mL) and brine (10 mL). The organic layer was dried over Na2SO4 and concentrated in vacuo. The residue was purified by silica gel chromatography (5% EtOAc/DCM then 1-2% MeOH/DCM) to afford the title compound (70 mg, 88%) as a white solid. 1H-NMR (CDCl3; 400 MHz): δ 11.90 (s, 1H), 9.65 (s, 1H), 8.28 (d, 1H, J=8.6 Hz), 7.74 (s, 1H), 7.45 (dd, 1H, J=8.6, 2.3 Hz), 7.33 (d, 1H, J=2.3 Hz), 5.78 (m, 1H), 2.77 (m, 4H), 2.65 (m, 4H), 2.29 (m, 2H), 2.12 (m, 2H), 1.60 (t, 2H, J=6.3 Hz), 1.33 (s, 6H), 1.12 (s, 6H). Mass spectrum (ESI-neg, m/z): Calcd. for C26H33N5OS, 462.2 (M−H). found 462.4.
Reaction SMILES: Cl[C:2]1[C:3](=[O:19])[N:4]([CH2:15][CH2:16][O:17][CH3:18])[S:5](=[O:14])(=[O:13])[C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[F:20][CH:21]([F:30])[O:22][C:23]1[CH:29]=[CH:28][C:26]([NH2:27])=[CH:25][CH:24]=1>>[F:20][CH:21]([F:30])[O:22][C:23]1[CH:24]=[CH:25][C:26]([NH:27][C:2]2[C:3](=[O:19])[N:4]([CH2:15][CH2:16][O:17][CH3:18])[S:5](=[O:14])(=[O:13])[C:6]=2[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[CH:28][CH:29]=1
Reactant: COCCN1C(=O)C(Cl)=C(c2ccccc2)S1(=O)=O
Reactant: Nc1ccc(OC(F)F)cc1
Product: COCCN1C(=O)C(Nc2ccc(OC(F)F)cc2)=C(c2ccccc2)S1(=O)=O

Procedure:
The title compound was prepared from 4-chloro-2-(2-methoxyethyl)-5-phenylisothiazol-3(2H)-one 1,1-dioxide and 4-(difluoromethoxy)aniline in a similar manner as described for Examples 9 and 13. 1H NMR (400 MHz, CD3CN): δ 3.38 (s, 3H), 3.72 (t, 2H), 3.91 (t, 2H), 6.57 (t, 1H), 6.74-6.79 (m, 2H), 6.81-6.86 (m, 2H), 7.10-7.20 (m, 4H), 7.25-7.30 (m, 1H), 7.80 (bs, 1H); Mass Spectrum: M+H+ 425.
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[C:9]2[C:5]([C:6]([CH:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)=[CH:7][NH:8]2)=[CH:4][CH:3]=1.Cl[CH2:19][CH2:20][CH2:21][O:22][C:23]1[C:24]2[CH:25]=[CH:26][NH:27][C:28]=2[CH:29]=[CH:30][CH:31]=1.C(=O)([O-])[O-].[K+].[K+]>>[Cl:1][C:2]1[C:10]([Cl:11])=[C:9]2[C:5]([C:6]([CH:12]3[CH2:17][CH2:16][N:15]([CH2:19][CH2:20][CH2:21][O:22][C:23]4[CH:31]=[CH:30][CH:29]=[C:28]5[C:24]=4[CH:25]=[CH:26][NH:27]5)[CH2:14][CH2:13]3)=[CH:7][NH:8]2)=[CH:4][CH:3]=1
Reactant: Clc1ccc2c(C3CCNCC3)c[nH]c2c1Cl
Reactant: ClCCCOc1cccc2[nH]ccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Clc1ccc2c(C3CCN(CCCOc4cccc5[nH]ccc45)CC3)c[nH]c2c1Cl

Procedure:
The title compound was prepared in a fashion similar to that described in Example 192 from 6,7-dichloro-3-(piperidin-4-yl)-1H-indole (0.80 g, 3.0 mmol), 1-chloro-3-(1H-indole-4-oxy)propane (0.64 g, 3.1 mmol) and potassium carbonate (0.83 g, 6.0 mmol). The product was isolated as a tan foam. Yield 278 mg, 21%. mp 160°-165° C. FDMS m/e=441 (M+ of free base).
Reaction SMILES: Cl[C:2]1[N:10]=[C:9](Cl)[CH:8]=[C:7]([C:12]([F:15])([F:14])[F:13])[C:3]=1[C:4]([NH2:6])=O.[CH:16]([O:19][CH2:20][CH2:21][OH:22])([CH3:18])[CH3:17].[B:23]1([OH:33])[C:27]2[CH:28]=[CH:29][C:30]([OH:32])=[CH:31][C:26]=2[CH2:25][O:24]1>>[OH:33][B:23]1[C:27]2[CH:28]=[CH:29][C:30]([O:32][C:9]3[CH:8]=[C:7]([C:12]([F:15])([F:14])[F:13])[C:3]([C:4]#[N:6])=[C:2]([O:22][CH2:21][CH2:20][O:19][CH:16]([CH3:18])[CH3:17])[N:10]=3)=[CH:31][C:26]=2[CH2:25][O:24]1
Reactant: OB1OCc2cc(O)ccc21
Reactant: CC(C)OCCO
Reactant: NC(=O)c1c(C(F)(F)F)cc(Cl)nc1Cl
Product: CC(C)OCCOc1nc(Oc2ccc3c(c2)COB3O)cc(C(F)(F)F)c1C#N

Procedure:
This compound was prepared from 2,6-dichloro-4-(trifluoromethyl)nicotinamide (obtained from Peakdale), 2-isopropoxyethanol, and benzo[c][1,2]oxaborole-1,5(3H)-diol in a similar manner to that of D230. 1H-NMR (400 MHz, DMSO-d6) δ (ppm) 1.72-1.75 (m, 2H), 2.05 (s, 3H), 2.38 (t, J=5.4 Hz, 2H), 4.03 (t, J=5.4 Hz, 2H), 5.03 (s, 2H), 7.13 (d, J=7.8 Hz, 1H), 7.2 (s, 1H), 8.61 (s, 1H), 9.36 (s, 1H).
Reaction SMILES: Br[C:2]1[CH:21]=[CH:20][C:5]2[N:6]3[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][C:7]3=[N:8][C:4]=2[CH:3]=1.[F:22][C:23]1[CH:24]=[CH:25][C:26]([CH2:29][O:30][C:31]2[CH:36]=[CH:35][NH:34][C:33](=[O:37])[CH:32]=2)=[N:27][CH:28]=1>>[F:22][C:23]1[CH:24]=[CH:25][C:26]([CH2:29][O:30][C:31]2[CH:36]=[CH:35][N:34]([C:2]3[CH:21]=[CH:20][C:5]4[N:6]5[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][C:7]5=[N:8][C:4]=4[CH:3]=3)[C:33](=[O:37])[CH:32]=2)=[N:27][CH:28]=1
Reactant: O=c1cc(OCc2ccc(F)cn2)cc[nH]1
Reactant: CC(C)(C)OC(=O)N1CCn2c(nc3cc(Br)ccc32)C1
Product: CC(C)(C)OC(=O)N1CCn2c(nc3cc(-n4ccc(OCc5ccc(F)cn5)cc4=O)ccc32)C1
Yield: 49.2 %

Procedure:
tert-Butyl 8-bromo-3,4-dihydropyrazino[1,2-a]benzimidazole-2(1H)-carboxylate (150 mg, 0.426 mmol) and 4-((5-fluoropyridin-2-yl)methoxy)pyridin-2(1H)-one (103 mg, 0.468 mmol) were reacted according to Example 18 (step g) to provide the title compound (103 mg, 47%) as a white solid: ESI MS m/z 492 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([CH2:9][C:10]2[CH:15]=[C:14]([O:16][CH3:17])[C:13]([O:18][CH3:19])=[C:12]([OH:20])[CH:11]=2)=[CH:4][N:3]=1.CC(C)([O-])C.[K+].[CH2:27]([O:29][CH:30]([O:34][CH2:35][CH3:36])[CH2:31][CH2:32]Cl)[CH3:28]>CS(C)=O>[NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([CH2:9][C:10]2[CH:15]=[C:14]([O:16][CH3:17])[C:13]([O:18][CH3:19])=[C:12]([O:20][CH2:32][CH2:31][CH:30]([O:34][CH2:35][CH3:36])[O:29][CH2:27][CH3:28])[CH:11]=2)=[CH:4][N:3]=1
Reactant: CCOC(CCCl)OCC
Reactant: COc1cc(Cc2cnc(N)nc2N)cc(O)c1OC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CCOC(CCOc1cc(Cc2cnc(N)nc2N)cc(OC)c1OC)OCC
Yield: 82.1 %

Procedure:
To a solution of 27.6 g, (0.1 mole) of 2,4-diamino-5-(3-hydroxy-4,5-dimethoxybenzyl)pyrimidine (D. E. Schwartz, W. Vetter, and G. Englert, Arzneim.-Forsch. (Drug Res.) 1970, 20, 1867; G. Rey-Bellet and R. Reiner, Helv. Chim. Acta 1970, 53, 945) in 400 mL of dry dimethyl sulfoxide was added 11.22 g (0.10 mole) of potassium t-butoxide. To the resulting suspension was added dropwise 17.92 g (0.107 mole) of β-chloropropionaldehyde diethylacetal. The mixture was heated at 65° overnight. The solvent was removed under vacuum and the residue was partitioned between 750 mL methylene chloride and 750 mL of 0.1N sodium hydroxide. The organic layer was separated and the aqueous layer was extracted with an additional 750 mL of methylene chloride. The organic layers were combined, washed with 750 mL of water, dried (MgSO4), and purified by flash column chromatography to yield 33.38 g (83%) of the title compound (mp 105°-106.5° ). Anal. Calcd for C20H30N4O5 : C, 59.10; H, 7.44; N, 13.78. Found: C, 58.71; H, 7.40; N, 13.58.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([C:12]([CH2:19][C:20]2[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=2)([CH2:16][C:17]#[CH:18])[C:13](O)=[O:14])(=[O:11])=[O:10])=[CH:5][CH:4]=1.Cl.[NH2:27][OH:28]>>[OH:28][NH:27][C:13](=[O:14])[C:12]([S:9]([C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)(=[O:11])=[O:10])([CH2:19][C:20]1[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=1)[CH2:16][C:17]#[CH:18]
Reactant: C#CCC(Cc1cccnc1)(C(=O)O)S(=O)(=O)c1ccc(OC)cc1
Reactant: NO
Agent: Cl
Product: C#CCC(Cc1cccnc1)(C(=O)NO)S(=O)(=O)c1ccc(OC)cc1
Yield: 25 %

Procedure:
2-(4-Methoxy-benzenesulfonyl)-2-pyridin-3-ylmethyl-pent-4-ynoic acid hydroxyamide was prepared according to the method as outlined in Example 1. Starting from 2-(4-methoxy-benzenesulfonyl)-2-pyridin-3-ylmethyl-pent-4-ynoic acid (0.29 g, 0.81 mmol) and hydroxylamine hydrochloride (0.70 m, 10 mmol), 0.065 g of the product was isolated. Yield 25%; off-white solid; mp 70° C.; MS: 375.0 (M+H)+; 1H NMR (300 MHz, DMSO-d6) δ 1.19 (brs, 1H), 2.90-3.00 (m, 2H), 3.55 (d, J=13.8 Hz, 1H), 3.67 (d, J=13.8 Hz, 1H), 3.89 (s, 3H), 7.18 (d, J=9.0 Hz, 2H), 7.75 (d, J=9.0 Hz, 2H), 7.80-7.89 (m, 1H), 8.35-8.40 (m, 1H), 8.70-8.80 (m, 2H), 11.1 (brs, 1H); IR (KBr, cm-1): 3168 m, 3095 s, 1670 m, 1593 s.
Reaction SMILES: [CH3:1][C:2]1([C:15]2[CH:24]=[CH:23][C:22]3[C:21]([CH3:26])([CH3:25])[CH2:20][CH2:19][C:18]([CH3:28])([CH3:27])[C:17]=3[CH:16]=2)[C:6]2[CH:7]=[C:8]([C:11]([O:13]C)=[O:12])[CH:9]=[CH:10][C:5]=2[O:4][CH2:3]1.[OH-].[Na+].[OH-].[Li+].O>C1COCC1>[CH3:1][C:2]1([C:15]2[CH:24]=[CH:23][C:22]3[C:21]([CH3:26])([CH3:25])[CH2:20][CH2:19][C:18]([CH3:28])([CH3:27])[C:17]=3[CH:16]=2)[C:6]2[CH:7]=[C:8]([C:11]([OH:13])=[O:12])[CH:9]=[CH:10][C:5]=2[O:4][CH2:3]1
Reactant: COC(=O)c1ccc2c(c1)C(C)(c1ccc3c(c1)C(C)(C)CCC3(C)C)CO2
Agent: [Li+]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC1(C)CCC(C)(C)c2cc(C3(C)COc4ccc(C(=O)O)cc43)ccc21
Temperature: 25 °C
Reaction time: 120 h

Procedure:
A mixture of methyl 3-methyl-3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-2H-1-benzofuran-5-carboxylate (510 mg, 1.35 mmol), sodium hydroxide (0.33 g, 7.9 mmol), lithium hydroxide (0.33 g, 7.9 mmol) and water in THF is stirred at room temperature for 5 days. The mixture is concentrated on a rotary evaporator under vacuum at 40° C. 10 ml of water and 10 ml of ethyl acetate are added. The mixture is acidified with concentrated hydrochloric acid solution to pH 1. After separation of the phases by settling, the organic phase is washed twice with 10 ml of water, dried over magnesium sulphate and concentrated on a rotary evaporator under vacuum at 40° C. The solid obtained is washed with heptane.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:20]=[CH:19][C:18]3[C:13](=[CH:14][CH:15]=[C:16]([O:21][CH3:22])[CH:17]=3)[C:12]=2[O:23][C:24]2[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].Cl.[N:32](=[CH:40][CH2:41]Cl)[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][Cl:39].[H-].[Na+]>CN(C)C=O>[ClH:39].[CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([C:11]2[CH:20]=[CH:19][C:18]3[C:13](=[CH:14][CH:15]=[C:16]([O:21][CH3:22])[CH:17]=3)[C:12]=2[O:23][C:24]2[CH:25]=[CH:26][C:27]([O:30][CH2:41][CH2:40][N:32]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=[CH:33]3)=[CH:28][CH:29]=2)=[CH:9][CH:10]=1)(=[O:3])=[O:4]
Reactant: ClCC=NCCCCCCCl
Reactant: COc1ccc2c(Oc3ccc(O)cc3)c(-c3ccc(S(C)(=O)=O)cc3)ccc2c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc2c(Oc3ccc(OCCN4C=CC=CC=C4)cc3)c(-c3ccc(S(C)(=O)=O)cc3)ccc2c1
Yield: 71.2 %

Procedure:
Stir a solution of 4-[2-(4-methanesulfonyl-phenyl)-6-methoxy-naphthalen-1-yloxy]-phenol (160 mg, 0.39 mmol), 2-(hexamethyleneimino)-ethyl chloride hydrochloride (140 mg, 0.69 mmol), 60% sodium hydride (47 mg, 1.18 mmol) and N,N-dimethylformamide (2 mL) for 18 hours at ambient temperature, then evaporate under reduced pressure. Dissolve the residue in dichloromethane and wash with water, dry with solid magnesium sulfate and chromatograph on silica gel with dichloromethane/methanol mixtures. Combine the fractions containing product and add 1N hydrogen chloride in diethyl ether (0.30 mL). Concentrate the resulting solution under reduced pressure to give 160 mg of the title compound (69%). Mass spectrum (ion spray): m/z=546 (M+H).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[S:10][CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[Li]CCCC.[CH3:16][S:17]SC>C1COCC1>[Cl:1][C:2]1[C:3]2[S:10][C:9]([S:17][CH3:16])=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: CSSC
Reactant: Clc1ncnc2ccsc12
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CSc1cc2ncnc(Cl)c2s1
Reaction time: 0.25 h
Yield: 82 %

Procedure:
To a solution of 20 (shown in the scheme 4) (200 mg, 1.18 mmol) in THF (11 mL) was added n-BuLi (566 μL, 1.42 mmol, 2.5M in THF) very slowly at −78° C. and the mixture was stirred for 15 min at the same conditions. A solutions of dimethyl disulfide (160 uL, 1.77 mmol) and Mel (110 μL, 1.77 mmol) in THF (1 mL) was added drop wise. The reaction mixture was stirred for 2 h at −78° C., quenched with saturated aqueus NH4Cl solution, and extracted with DCM. The extract was dried over anhydrous Na2SO4 and concentrated to afford the title compound 280 (210 mg, 82% yield) as a yellowish solid. MS (m/z): 217.0(M+H) (found).