Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:4]1[CH:19]=[CH:18][C:7]([CH2:8][C:9]2[C:14]([CH3:15])=[CH:13][C:12]([CH3:16])=[CH:11][C:10]=2[OH:17])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Cl[CH2:27][C:28](=[O:30])[CH3:29].[I-].[K+]>CC(C)=O.O>[CH:1]([C:4]1[CH:19]=[CH:18][C:7]([CH2:8][C:9]2[C:14]([CH3:15])=[CH:13][C:12]([CH3:16])=[CH:11][C:10]=2[O:17][CH2:27][C:28]([CH3:29])=[O:30])=[CH:6][CH:5]=1)([CH3:3])[CH3:2]
Reactant: CC(=O)CCl
Reactant: Cc1cc(C)c(Cc2ccc(C(C)C)cc2)c(O)c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: CC(=O)COc1cc(C)cc(C)c1Cc1ccc(C(C)C)cc1
Yield: 73 %

Procedure:
A mixed solution of 2-(4-isopropylbenzyl)-3,5-dimethylphenol obtained in Reference Example 148 (1.0 g, 3.93 mmol), potassium carbonate (1.30 g, 9.44 mmol), chloroacetone (436 mg, 4.72 mmol) and potassium iodide (100 mg) in acetone (15 mL) was heated under reflux for 16 hours. Water was added to the reaction solution, which was extracted with ethyl acetate. The combined organic layer was washed with a saturated brine, dried over anhydrous sodium sulfate, filtered, and then concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:4) to obtain 888 mg (yield 73%) of the title compound. Oily matter.
Reaction SMILES: [Si:1]([O:18][CH2:19][C:20]1[N:21]=[CH:22][NH:23][CH:24]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:26]([CH3:28])=[CH2:27].C(N)CN.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.[Cu](I)I>[Si:1]([O:18][CH2:19][C:20]1[N:21]=[CH:22][N:23]([CH2:28][CH:26]=[CH2:27])[CH:24]=1)([C:14]([CH3:17])([CH3:15])[CH3:16])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)[Si](OCc1c[nH]cn1)(c1ccccc1)c1ccccc1
Reactant: C=C(C)Br
Agent: I[Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: NCCN
Solvent: C1COCCO1
Product: C=CCn1cnc(CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)c1

Procedure:
4-(tert-Butyldiphenylsilyloxymethyl)-1H-imidazole (1.000 g), 2-bromo-1-propene (1.04 mL), ethylenediamine (0.40 mL), copper iodide (0.28 g) and tripotassium phosphate (1.30 g) were suspended in dioxane (10 mL), and reacted in a microwave reactor (product name: Initiator, manufactured by Biotage, Ltd.) at 140° C. for 5 hours. The reaction solution was filtered using Celite to filter off the insolubles, followed by concentration of the mother liquor. The resulting residue was purified by flash chromatography (ethyl acetate/hexane=10%→100%) using silica gel column (product name: Hi-Flash column 3 L, manufactured by Yamazen Corporation) to afford the title compound (0.350 g).
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:15][CH:16]([C:21]2[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=2)[C:17]([F:20])([F:19])[F:18])=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([N+:12]([O-])=O)=[CH:7][CH:6]=2.[Cl-].[NH4+]>C(O)C.O.[Fe]>[Cl:1][C:2]1[C:3]([O:15][CH:16]([C:21]2[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=2)[C:17]([F:19])([F:20])[F:18])=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([NH2:12])=[CH:7][CH:6]=2
Reactant: O=[N+]([O-])c1ccc2nc(OC(c3cccnc3)C(F)(F)F)c(Cl)nc2c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: Nc1ccc2nc(OC(c3cccnc3)C(F)(F)F)c(Cl)nc2c1
Temperature: 80 °C
Reaction time: 1 h
Yield: 61.8 %

Procedure:
In a mixed solvent of ethanol (19.5 mL) and water (9.75 mL) was dissolved 3-chloro-6-nitro-2-(2,2,2-trifluoro-1-(pyridin-3-yl)ethoxy)quinoxaline (975 mg, 2.53 mmol) obtained in Step 2. To the solution were added iron (0) (425 mg, 7.60 mmol) and ammonium chloride (68.0 mg, 1.27 mmol) and the mixture was stirred at 80° C. for 1 hour. The reaction mixture was filtered through Celite and the filtrate was extracted with ethyl acetate. Washing with saturated brine and drying over anhydrous magnesium sulfate were performed. After filtration, the solvent in the filtrate was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=1/0 to 0/1) to give 3-chloro-2-(2,2,2-trifluoro-1-(pyridin-3-yl)ethoxy) quinoxaline-6-amine (555 mg, 62% yield).
Reaction SMILES: Cl[CH:2]([CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)[C:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[O:5][C:4]=1[CH2:12][CH3:13].[NH2:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]([N:29]([CH3:37])[CH2:30][CH2:31][C:32]([O:34]CC)=[O:33])=[O:28])=[CH:23][CH:22]=1>>[CH:14]1([CH:2]([NH:20][C:21]2[CH:22]=[CH:23][C:24]([C:27]([N:29]([CH3:37])[CH2:30][CH2:31][C:32]([OH:34])=[O:33])=[O:28])=[CH:25][CH:26]=2)[C:3]2[C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=3[O:5][C:4]=2[CH2:12][CH3:13])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: CCOC(=O)CCN(C)C(=O)c1ccc(N)cc1
Reactant: CCc1oc2ccccc2c1C(Cl)C1CCCCC1
Product: CCc1oc2ccccc2c1C(Nc1ccc(C(=O)N(C)CCC(=O)O)cc1)C1CCCCC1

Procedure:
Using 3-[chloro(cyclohexyl)methyl]-2-ethyl-1-benzofuran (300 mg) synthesized above and ethyl 3-{[(4-aminophenyl)carbonyl](methyl)amino}propanoate (270 mg) synthesized in Example 2(2) and in the same manner as in Example A22(4), the title object compound (287 mg, 57%) was obtained as a white solid.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:16]=[CH:17][CH:18]=1)[CH2:6][S:7][C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=1)[CH:11]=[O:12].C1(C)C=CC(S([CH2:28][N+:29]#[C-:30])(=O)=O)=CC=1.C(=O)([O-])[O-].[K+].[K+]>>[O:12]1[C:11]([C:10]2[CH:9]=[C:8]([S:7][CH2:6][C:5]3[CH:4]=[C:3]([CH:18]=[CH:17][CH:16]=3)[CH2:2][OH:1])[CH:15]=[CH:14][CH:13]=2)=[CH:30][N:29]=[CH:28]1
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Reactant: O=Cc1cccc(SCc2cccc(CO)c2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: OCc1cccc(CSc2cccc(-c3cnco3)c2)c1
Yield: 84.3 %

Procedure:
When the same reaction as in Referential Example 33 was carried out except using 172 mg of the resulting aldehyde compound, 130 mg of p-toluenesulfonylmethyl isocyanide and 92 mg of potassium carbonate, 167 mg (yield 84%) of the captioned compound wss obtained.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]([C:10]2[C:11](Cl)=[N:12][C:13]([Cl:16])=[N:14][CH:15]=2)=O)[CH:5]=[CH:6][CH:7]=1.[NH2:18][NH2:19]>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([C:8]2[C:10]3[C:11](=[N:12][C:13]([Cl:16])=[N:14][CH:15]=3)[NH:19][N:18]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: NN
Reactant: O=C(c1cccc(Br)c1)c1cnc(Cl)nc1Cl
Solvent: C1CCOC1
Product: Clc1ncc2c(-c3cccc(Br)c3)n[nH]c2n1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of crude (3-bromo-phenyl)-(2,4-dichloro-pyrimidin-5-yl)-methanone (from Example 37 supra) (1 g, 3.0 mmol) in THF (70 mL), 85% hydrazine (0.45 g, 7.64 mmol) was added dropwise at room temperature. The mixture was stirred for additional 20 minutes at room temperature and then heated at 50° C. for another 20 minutes. The solvent was removed under reduced pressure, and the residue was washed with water (5 mL), petroleum ether (10 mL) and dried to give 3-(3-bromo-phenyl)-6-chloro-1H-pyrazolo[3,4-d]pyrimidine as yellow solid. (Yield 0.848 g, 91.3%).
Reaction SMILES: [F:1][C:2]1([F:14])[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][C:10]([CH3:13])([NH2:12])[CH3:11])[CH2:4][CH2:3]1.[C:15](ON1C(=O)CCC1=O)([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16]>C1COCC1>[F:14][C:2]1([F:1])[CH2:3][CH2:4][N:5]([CH2:8][CH2:9][C:10]([NH:12][C:15](=[O:16])[O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)([CH3:11])[CH3:13])[CH2:6][CH2:7]1
Reactant: CC(C)(N)CCN1CCC(F)(F)CC1
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Solvent: C1CCOC1
Product: CC(C)(CCN1CCC(F)(F)CC1)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 69.7 %

Procedure:
Crude 4-(4,4-difluoropiperidin-1-yl)-2-methylbutan-2-amine (6.56 g, 31.8 mmol) was dissolved into THF (100 mL). To this solution was added CbzOSu (7.93 g, 1 equiv, 31.8 mmol) in one portion. The reaction was left to stir at room temperature for 1 d. The solvent was removed and the residue was taken up in a mixture of ethyl acetate (150 mL) and water (100 mL). The layers were separated and the organic layer washed with 1 M sodium carbonate (2×50 mL), 1M HCl (50 mL), and brine (100 mL). The organic layer was dried over anhydrous MgSO4, filtered and concentrated to a colorless oil which solidified on standing. The crude solid was purified on an ISCO purification system with gradient elution from 0-6% methanol. The desired fractions were collected and concentrated to give a white solid (7.54 g, 69.7%). 1H NMR (CDCl3, 400 MHz): δ 1.35 (s, 6H), 1.68-1.72 (t, J=6.8, 4H), 1.92-2.05 (m, 4H), 2.16-2.20 (m, 2H), 2.48-2.52 (t, J=6.8, 4H), 2.53-2.58 (m, 4H), 5.04 (s, 2H), 6.70 (s, 1H), 7.27-7.40 (m, 5H). LRMS (ESI+) for C18H26F2N2O2 (340.1); Found: 341 (MH+).
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[C:7]([CH2:27][O:28][CH3:29])[NH:8][C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4].C(=O)([O-])[O-].[Cs+].[Cs+].I[CH2:37][C:38]([CH3:41])([CH3:40])[CH3:39].CN(C)C(=O)C>C(OCC)(=O)C>[CH2:1]([C:5]1[N:6]=[C:7]([CH2:27][O:28][CH3:29])[N:8]([CH2:37][C:38]([CH3:41])([CH3:40])[CH3:39])[C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(COC)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: CC(C)(C)CI
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: CCCCc1nc(COC)n(CC(C)(C)C)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 130 °C
Reaction time: 2 h
Yield: 30 %

Procedure:
A mixture of 4′-{[4-butyl-2-(methoxymethyl)-6-oxo-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile (5 g), cesium carbonate (8.4 g), 1-iodo-2,2-dimethylpropane (3.4 mL) and N,N-dimethylacetamide (50 mL) was stirred at 130° C. for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with 5% aqueous potassium hydrogen sulfate solution 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 colorless solid (1.76 g, 30%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]([O:10][C:11](=[O:18])[CH2:12][C:13]2[S:14][CH:15]=[CH:16][CH:17]=2)[CH2:7][S:8][CH:9]=1)=[O:4].S(Cl)(Cl)(=O)=O>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[C:6]([O:10][C:11](=[O:18])[CH2:12][C:13]2[S:14][CH:15]=[CH:16][CH:17]=2)=[CH:7][S:8][CH:9]=1)=[O:4]
Reactant: COC(=O)C1=CSCC1OC(=O)Cc1cccs1
Solvent: ClC(Cl)Cl
Solvent: O=S(=O)(Cl)Cl
Product: COC(=O)c1cscc1OC(=O)Cc1cccs1
Yield: 75 %

Procedure:
1.86 Parts of 3-thiolacetoxy-dihydrothiophene-4-carboxylic acid methyl ester are reacted with 1.76 parts by volume of sulfuryl chloride in 25 parts by volume of chloroform in the course of one hour at 0° C. The end product is isolated from the reaction mixture by the method described in Example 1c. 1.4 parts (75% of theory) of 3-thiolacetoxy-thiophene-4-carboxylic acid methyl ester of melting point 92°-95° C. are obtained.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[CH2:5][S:6]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][CH:18]([CH3:20])[CH3:19])=[CH:11][CH:10]=1)(=[O:8])=[O:7])[CH3:2].[CH2:22]([N:26]([CH2:30][CH2:31]Cl)[CH2:27][CH2:28]Cl)[CH2:23][CH2:24][CH3:25]>>[CH2:1]([O:3][C:4]([C:5]1([S:6]([C:9]2[CH:10]=[CH:11][C:12]([O:15][CH2:16][CH2:17][CH:18]([CH3:20])[CH3:19])=[CH:13][CH:14]=2)(=[O:7])=[O:8])[CH2:31][CH2:30][N:26]([CH2:22][CH2:23][CH2:24][CH3:25])[CH2:27][CH2:28]1)=[O:21])[CH3:2]
Reactant: CCCCN(CCCl)CCCl
Reactant: CCOC(=O)CS(=O)(=O)c1ccc(OCCC(C)C)cc1
Product: CCCCN1CCC(C(=O)OCC)(S(=O)(=O)c2ccc(OCCC(C)C)cc2)CC1

Procedure:
1-Butyl-4-[4-(3-methyl-butoxy)-benzenesulfonyl]-piperidine-4-carboxylic acid ethyl ester was prepared according to the general method outlined in example 83 starting from [4-(3-methyl-butoxy)-phenylsulfonyl]-acetic acid ethyl ester (6.2 g, 20 mmol) and butyl-bis-(2-chloro-ethyl)-amine (5.2 g, 22 mmol). Yield 7 g (79%); yellow oil; MS: 440 (M+H)+
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][C:16]2[S:17][CH:18]=[CH:19][CH:20]=2)=[CH:9][C:8]=1[CH3:21])[CH3:2].[Br:23]Br.O>C(O)(=O)C>[CH2:1]([O:3][C:4](=[O:22])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][C:16]2[S:17][C:18]([Br:23])=[CH:19][CH:20]=2)=[CH:9][C:8]=1[CH3:21])[CH3:2]
Reactant: BrBr
Reactant: CCOC(=O)COc1ccc(OCCc2cccs2)cc1C
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)COc1ccc(OCCc2ccc(Br)s2)cc1C
Reaction time: 0.25 h

Procedure:
A solution of ethyl[2-methyl-4-(2-thien-2-ylethoxy)phenoxy]acetate (intermediate 69, 0.306 g) in acetic acid (5 ml) was treated with bromine (0.180 g) at ambient temperature and the mixture stirred for 15 minutes. The mixture was poured into water and the resulting suspension extracted with diethyl ether. The organic layer was separated, dried over sodium sulfate and concentrated to give the title compound as a colourless oil.
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:8])[CH2:4][CH2:5][CH2:6][OH:7].[CH2:9](Cl)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>CN(C)C=O>[CH2:9]([O:7][CH2:6][CH2:5][CH2:4][CH2:3][OH:8])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: ClCc1ccccc1
Reactant: OCCCCO
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: OCCCCOCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
6 g (0.2 mol) of a sodium hydride dispersion (80% in white oil) are placed at room temperature in 120 ml of absolute dimethylformamide, and 22.2 ml (0.25 mol) of 1,4-butanediol are added dropwise. When the addition is complete, the mixture is stirred for a further 30 minutes at room temperature. 23.1 ml (0.2 mol) of benzyl chloride are then slowly added dropwise, a slight exothermic reaction being observed. The reaction mixture is stirred overnight at room temperature, water/ice is added, and the mixture is extracted twice with ether. The organic phases are washed with water and with saturated sodium chloride solution, combined, dried over MgSO4, filtered and concentrated by evaporation. The residue is subjected to fractional distillation under a water-jet vacuum over a 10 cm Vigreux column. 4-benzyloxybutanol is obtained, b.p.22 =161°-162°.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1([OH:22])[CH2:14][CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11][CH2:10]1.FC(F)(F)C(O)=O>C(Cl)Cl>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1([OH:22])[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CCC(O)(c2cccc(Cl)c2Cl)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: OC1(c2cccc(Cl)c2Cl)CCNCC1

Procedure:
According to Preparation 2: Tert-butyl 4-(2,3-dichlorophenyl)-4-hydroxypiperidine-1-carboxylate (3.0 g, 8.7 mmol), methylen chloride (50 ml), trifluoroacetic acid (10 ml). Yield: 0.88 g. MS m/z (rel. intensity, 70 eV) 246 (M+, 8), 245 (14), 212 (34), 210 (bp), 192 (67).
Reaction SMILES: CON(C)[C:4]([C:6]1[N:7]=[N:8][CH:9]=[CH:10][CH:11]=1)=[O:5].[CH3:13]C(O)=O.OO>C1COCC1>[N:8]1[CH:9]=[CH:10][CH:11]=[C:6]([CH:4]([OH:5])[CH3:13])[N:7]=1
Reactant: CON(C)C(=O)c1cccnn1
Reactant: CC(=O)O
Agent: OO
Solvent: C1CCOC1
Product: CC(O)c1cccnn1
Temperature: 30 °C
Reaction time: 10 h
Yield: 35 %

Procedure:
To a solution of compound 2 (300 mg, 0.6 mmol) in THF (15 mL) was added AcOH (1 mL) and H2O2 (3 mL). The reaction mixture was stirred at 30° C. for 10 h. The mixture was quenched with saturated NaHCO3 (6 mL) and then balanced between EtOAc (2×20 mL) and water (10 mL). The organic layers were collected and concentrated in vacuo to give the residue, which was purified by preparative TLC (petroleum ether:ethyl acetate=1:1) to give compound 3 (70 mg, 35%) as a colorless oil.
Reaction SMILES: C([N:8]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15][O:14][CH2:13][CH2:12][O:11][CH2:10][CH2:9]1)C1C=CC=CC=1.C(O)C>[Pd].[H][H]>[NH:8]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15][O:14][CH2:13][CH2:12][O:11][CH2:10][CH2:9]1
Reactant: c1ccc(CN2CCOCCOCCOCC2)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: C1COCCOCCOCCN1
Yield: 60 %

Procedure:
A quantity of the 1-benzyl-1-aza-4,7,10-trioxacyclododecane compound (3) prepared in Example 3 (45.1 g, 0.17 mol), ethanol (7 g), and 10% palladium on carbon (0.5 g) were shaken in hydrogen atmosphere at more than 50 psi (1 psi= 6.9×103Pa=0.07 kg cm-2). Hydrogen gas was recharged several times into the reaction chamber to keep the pressure elevated. Shaking was continued until the pressure lowering stopped (4 days). After the palladium carbon was filtered, the solvent was evaporated. The pure compound (4) was sublimed from the residue with gentle heating using a water bath (75°-77° C.; crude material melted at this temperature). The sublimate was white needles and was hygroscopic. Yield 60%; 1HNMR (D2O): δ 2.53-2.70 (t, 4H, N--CH2), 3.5-3.75 (m, 12H, O--CH2), no signal at 7.1 (Ar--H of benzyl group, possible contaminant).
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[C:15]([O:17][CH2:18][CH:19]=[C:20]([Cl:22])[Cl:21])[CH:14]=[C:13]([Cl:23])[C:3]=1[O:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][CH2:10][CH:11]=O.[Cl:24][C:25](Cl)(Cl)[C:26]([O:28][CH2:29][CH3:30])=[O:27].Cl>[Zn].CN(C)C=O>[Cl:23][C:13]1[CH:14]=[C:15]([O:17][CH2:18][CH:19]=[C:20]([Cl:21])[Cl:22])[CH:16]=[C:2]([Cl:1])[C:3]=1[O:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][CH2:10][CH:11]=[C:25]([Cl:24])[C:26]([O:28][CH2:29][CH3:30])=[O:27]
Reactant: CCOC(=O)C(Cl)(Cl)Cl
Reactant: O=CCOCCCCOc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl
Agent: Cl
Agent: [Zn]
Solvent: CN(C)C=O
Product: CCOC(=O)C(Cl)=CCOCCCCOc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl
Temperature: 25 °C
Yield: 5 %

Procedure:
To a mixture of 0.60 g of 4-(2,6-dichloro-4-(3,3-dichloro-2-propenyloxy)phenoxy)butyloxyacetaldehyde, 0.29 g of zinc dust and 10 ml of N,N-dimethylformamide was added ethyl trichloroacetate with stirring at room temperature. After stirring at room temperature for 2 hours, the reaction mixture was poured into 10 ml of diluted hydrochloric acid and extracted twice with diethyl ether. The diethyl ether layers were combined, washed with water, dried over magnesium sulfate and then evaporated to give a crude product. The crude product was subjected to silica gel chromatography, which afforded 0.04 g of 3,5-dichloro-1-(3,3-dichloro-2-propenyloxy)-4-(4-(3-chloro-3-ethoxycarbonyl-2-propenyloxy)butyloxy)benzene (yield, 5%), nD23.0 1.5348.
Reaction SMILES: [NH2:1][CH:2]([C:10]1[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[CH:12][C:11]=1[O:18][CH3:19])[CH2:3][CH2:4][CH2:5][C:6]([O:8]C)=O.[N:20]1[CH:25]=[CH:24][C:23]([C:26]2[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=2)[CH:29]=O)=[CH:22][CH:21]=1>>[CH3:19][O:18][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]([O:16][CH3:17])[C:10]=1[CH:2]1[N:1]([CH2:29][C:28]2[CH:31]=[CH:32][CH:33]=[C:26]([C:23]3[CH:22]=[CH:21][N:20]=[CH:25][CH:24]=3)[CH:27]=2)[C:6](=[O:8])[CH2:5][CH2:4][CH2:3]1
Reactant: COC(=O)CCCC(N)c1c(OC)cccc1OC
Reactant: O=Cc1cccc(-c2ccncc2)c1
Product: COc1cccc(OC)c1C1CCCC(=O)N1Cc1cccc(-c2ccncc2)c1

Procedure:
Prepared according to the described general procedure 1 (GP1) by reaction of methyl 5-amino-5-(2,6-dimethoxyphenyl)pentanoate with commercially available 3-(pyridin-4-yl)benzaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.59 min.; [M+H]+: 403.35 g/mol.
Reaction SMILES: C([O-])(=O)C.[Na+].[Br:6]Br.[Br:8][C:9]1[C:17]2[C:12](=[N:13][C:14]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[C:15]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:16]=2)[O:11][CH:10]=1.N12CCCN=C1CCCCC2>C(Cl)Cl>[Br:6][C:10]1[O:11][C:12]2=[N:13][C:14]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[C:15]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:16]=[C:17]2[C:9]=1[Br:8]
Reactant: CCOC(=O)c1cc2c(Br)coc2nc1C(=O)OCC
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Product: CCOC(=O)c1cc2c(Br)c(Br)oc2nc1C(=O)OCC
Temperature: 25 °C
Reaction time: 96 h

Procedure:
Sodium acetate (2.40 g, 0.0292 mol) and bromine (7.5 mL, 0.146 mol) are added to a solution of diethyl 3-bromofuro[2,3-b]pyridine-5,6-dicarboxylate (5.00 g, 0.0146 mol) in methylene chloride (150 mL). The mixture is stirred at room temperature for four days then washed with aqueous sodium bisulfate to remove unreacted bromine. The aqueous solution is then back extracted with methylene chloride. The organic solution is combined, dried over sodium sulfate and filtered. To the filtrate is added 1,8-diazabicyclo[5.4.0]undec-7-ene(4.4 mL, 0.032 mol), and the mixture is stirred at room temperature for one hour. The solution is then concentrated in vacuo. The residue is chromatographed over silica gel eluting with 20% ethyl acetate in hexane, yielding the crude 2,3-dibromofuro[2,3-b]pyridine as a white solid in 95% yields recrystallization from a methylene chloride-hexane mixture affords diethyl 2,3-dibromofuro[2,3-b]pyridine-5,6-dicarboxylate mp 96°-98° C. in 75.9% recrystallized yield.
Reaction SMILES: C(O[C:6](=[O:21])[N:7]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=1)[N:8]1[CH:12]=[CH:11][CH:10]=[CH:9]1)(C)(C)C.[CH2:22]([O:24][C:25](=[O:37])[CH:26](C(OCC)=O)[C:27](OCC)=[O:28])[CH3:23]>>[CH2:22]([O:24][C:25]([C:26]1[C:6](=[O:21])[N:7]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=2)[N:8]2[CH:9]=[CH:10][CH:11]=[C:12]2[C:27]=1[OH:28])=[O:37])[CH3:23]
Reactant: CC(C)(C)OC(=O)N(Cc1cccc(F)c1)n1cccc1
Reactant: CCOC(=O)C(C(=O)OCC)C(=O)OCC
Product: CCOC(=O)c1c(O)c2cccn2n(Cc2cccc(F)c2)c1=O

Procedure:
Prepared according to the thermal cyclization condition used in Example 1 step c) from (3-fluoro-benzyl)-pyrrol-1-yl-carbamic acid tert-butyl ester (1.0 eq.) and 2-ethoxycarbonyl-malonic acid diethyl ester (3.0 eq.). ESI (m/z): 331 (M+H)+.
Reaction SMILES: CS([C:4]1[CH:9]=[CH:8][N:7]=[C:6]([C:10]2[C:18]3[C:13](=[N:14][CH:15]=[CH:16][CH:17]=3)[NH:12][N:11]=2)[N:5]=1)=O.[N:19]1(C(OC(C)(C)C)=O)[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1.C(=O)([O-])[O-].[K+].[K+]>CN1C(=O)CCC1.CCOC(C)=O>[N:19]1([C:4]2[CH:9]=[CH:8][N:7]=[C:6]([C:10]3[C:18]4[C:13](=[N:14][CH:15]=[CH:16][CH:17]=4)[NH:12][N:11]=3)[N:5]=2)[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: CS(=O)c1ccnc(-c2n[nH]c3ncccc23)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: c1cnc2[nH]nc(-c3nccc(N4CCNCC4)n3)c2c1
Temperature: 125 °C
Reaction time: 1 h
Yield: 20.9 %

Procedure:
A mixture of 3-(4-methylsulfinylpyrimidin-2-yl)-1H-pyrazolo[5,4-b]pyridine (45 mg, 0.17 mmol), tert-butyl piperazine-1-carboxylate (100 mg, 0.53 mmol) and potassium carbonate (100 mg, 0.72 mmol) in NMP (0.5 ml) were stirred at 125° C. for 60 minutes in the microwave. The reaction mixture was diluted with EtOAc and washed with saturated aqueous sodium bicarbonate and brine. After drying over MgSO4 and concentration the residue was taken up in DCM (2 ml) and treated with TFA (1 ml). The reaction was allowed to stir at RT for 3 hours and concentrated in vacuo. and the resultant residue was purified by reverse phase preparative HPLC [Waters Sunfire C18, 10 uM, 100 A column, gradient 10%-95% B (solvent A: 0.05% TFA in water, solvent B: CH3CN) over 16 minutes at 25 mL/min]. The fractions were collected, passed through a sodium bicarbonate cartridge and freeze-dried to give the title compound as a pink solid (10 mg, 11% Yield).