Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[S:13][C:12]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:11][C:10]=2[N+:19]([O-:21])=[O:20])=[CH:4][CH:3]=1.[CH:22]1[C:34]2[CH:33]([CH2:35][O:36][C:37](Cl)=[O:38])[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[C:26]=2[CH:25]=[CH:24][CH:23]=1.N1C=CC=CC=1>C(Cl)Cl>[CH:22]1[C:34]2[CH:33]([CH2:35][O:36][C:37]([NH:1][C:2]3[CH:3]=[CH:4][C:5]([S:8][C:9]4[S:13][C:12]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:11][C:10]=4[N+:19]([O-:21])=[O:20])=[CH:6][CH:7]=3)=[O:38])[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[C:26]=2[CH:25]=[CH:24][CH:23]=1
Reactant: O=C(Cl)OCC1c2ccccc2-c2ccccc21
Reactant: CCOC(=O)c1cc([N+](=O)[O-])c(Sc2ccc(N)cc2)s1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)c1cc([N+](=O)[O-])c(Sc2ccc(NC(=O)OCC3c4ccccc4-c4ccccc43)cc2)s1
Temperature: 25 °C
Reaction time: 18 h
Yield: 100 %

Procedure:
A suspension of the product of Example 430B (0.500 g, 1.541 mmol) and 9-fluorenylmethoxycarbonyl chloride (0.478 g, 1.849 mmol) in methylene chloride (10 mL) under a nitrogen atmosphere was treated with pyridine (0.25 mL, 3.083 mmol), and the resulting solution stirred for 18 hours at room temperature. The reaction was diluted with methylene chloride (50 mL) and washed with 1N aqueous HCl (50 mL) then water (50 mL). The organic was dried over magnesium sulfate, filtered, and concentrated by rotary evaporation. Purification by silica gel flash chromatography eluting with methylene chloride afforded the title compound as a bright yellow solid (0.842 g, quantitative). 1H NMR (300 MHz, DMSO-D6) δ ppm 1.23 (t, J=7.17 Hz, 3 H) 4.24 (q, J=7.23 Hz, 2 H) 4.35 (t, J=6.43 Hz, 1 H) 4.57 (d, J=6.25 Hz, 2 H) 7.29-7.50 (m, 4 H) 7.69 (s, 4 H) 7.77 (d, J=7.35 Hz, 2 H) 7.92 (d, J=7.35 Hz, 2 H) 8.11 (s, 1 H) 10.15 (s, 1 H); MS (ESI+) m/z 564 (M+NH4)+, 569 (M+Na)+.
Reaction SMILES: C[O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]([F:22])([F:21])[F:20])(=[O:12])=[O:11])[CH2:7][N:6]1[C:23]1[N:24]([CH2:29][C:30]([F:33])([F:32])[F:31])[N:25]=[C:26]([CH3:28])[CH:27]=1)=[O:4].[OH-].[Li+]>>[CH3:28][C:26]1[CH:27]=[C:23]([N:6]2[CH2:7][C@H:8]([S:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[C:19]([F:21])([F:20])[F:22])(=[O:12])=[O:11])[CH2:9][C@H:5]2[C:3]([OH:4])=[O:2])[N:24]([CH2:29][C:30]([F:31])([F:33])[F:32])[N:25]=1
Reactant: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2C(F)(F)F)CN1c1cc(C)nn1CC(F)(F)F
Agent: [Li+]
Agent: [OH-]
Product: Cc1cc(N2C[C@H](S(=O)(=O)c3ccccc3C(F)(F)F)C[C@H]2C(=O)O)n(CC(F)(F)F)n1

Procedure:
In analogy to the procedure described in example 253e, (2S,4R)-1-[5-methyl-2-(2,2,2-trifluoro-ethyl)-2H-pyrazol-3-yl]-4-(2-trifluoromethyl-benzenesulfonyl)-pyrrolidine-2-carboxylic acid methyl ester was saponified in the presence of lithium hydroxide to give the title compound as yellow solid. MS (ESI): m/z=486.2 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:9][OH:10])=[C:6]([OH:8])[CH:7]=1>C(Cl)Cl.[O-2].[Mn+4].[O-2]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:9]=[O:10])=[C:6]([OH:8])[CH:7]=1
Reactant: OCc1ccc(Cl)cc1O
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: O=Cc1ccc(Cl)cc1O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
The subtitle compound was prepared by using 5-chloro-2-hydroxymethylphenol (prepared from the method of Vargha. et. al Acta. Chim. Acad. Hung., 4, 1954, 345-360) (5 g) which was dissolved in DCM (200 ml) and manganese (iv) oxide (10 g) added. The mixture was stirred at room temperature for 16 hours. The mixture was filtered through celite and the filtrate concentrated under reduced pressure to give a brown solid. Yield 3.48 g.
Reaction SMILES: [CH:1]1([C:4]2[C:5]([N:24]([C:29]3[CH:30]=[CH:31][C:32]([N+:40]([O-])=O)=[C:33]([CH2:35][C:36]([O:38][CH3:39])=[O:37])[CH:34]=3)[S:25]([CH3:28])(=[O:27])=[O:26])=[CH:6][C:7]3[O:11][C:10]([C:12]4[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=4)=[C:9]([C:19](=[O:22])[NH:20][CH3:21])[C:8]=3[CH:23]=2)[CH2:3][CH2:2]1>C1COCC1.[Pd]>[NH2:40][C:32]1[CH:31]=[CH:30][C:29]([N:24]([C:5]2[C:4]([CH:1]3[CH2:2][CH2:3]3)=[CH:23][C:8]3[C:9]([C:19](=[O:22])[NH:20][CH3:21])=[C:10]([C:12]4[CH:13]=[CH:14][C:15]([F:18])=[CH:16][CH:17]=4)[O:11][C:7]=3[CH:6]=2)[S:25]([CH3:28])(=[O:27])=[O:26])=[CH:34][C:33]=1[CH2:35][C:36]([O:38][CH3:39])=[O:37]
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(c3ccc([N+](=O)[O-])c(CC(=O)OC)c3)S(C)(=O)=O)c(C3CC3)cc12
Agent: [Pd]
Solvent: C1CCOC1
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(c3ccc(N)c(CC(=O)OC)c3)S(C)(=O)=O)c(C3CC3)cc12
Yield: 65 %

Procedure:
A solution of methyl 2-(5-(N-(5-cyclopropyl-2-(4-fluorophenyl)-3-(methyl-carbamoyl)benzofuran-6-yl)methylsulfonamido)-2-nitrophenyl)acetate (1.00 g, 1.68 mmol) in THF (10 mL) was subjected to atmospheric hydrogenation in the presence of 20% palladium on charcoal. After 10 hours the reaction vessel was purged with nitrogen, catalyst removed by filtration through Celite, and the filtrate concentrated to dryness at reduced pressure. The crude material was subjected to flash chromatography (silica gel, hexane/EtOAc) to give the title compound in 65% yield. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.84-7.92 (m, 2H) 7.68 (s, 1H) 7.39 (s, 1H) 7.23-7.30 (m, 3H) 7.18 (t, J=8.60 Hz, 2H) 6.66 (d, J=8.40 Hz, 1H) 5.84 (d, J=4.49 Hz, 1H) 4.11-4.19 (m, 2H) 3.68 (s, 3H) 3.52 (s, 2H) 3.14-3.20 (m, 3H) 2.94-3.02 (m, 3H) 2.21-2.30 (m, 1H) 0.96 (br. s., 2H). LCMS (m/z, ES+)=566 (M+H+).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].C(O)(=O)C.C(O)(=O)C.[I:19]C1C=CC=CC=1.II>CN(C)C=O.COC(C)(C)C.Cl.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([I:19])[C:3]=1[C:4]([OH:6])=[O:5]
Reactant: O=C(O)c1ccccc1Br
Reactant: Ic1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cl
Solvent: CN(C)C=O
Solvent: CC(=O)O
Solvent: COC(C)(C)C
Product: O=C(O)c1c(Br)cccc1I
Temperature: 100 °C
Reaction time: 8 h
Yield: 74.3 %

Procedure:
2-bromobenzoic acid (20.1 g, 100 mmol), palladium(II) acetate (1.12 mg, 5 mmol), iodobenzene diacetate (38.64 g, 120 mmol) and elemental iodine (30.48 g, 120 mmol) were dissolved in N,N-dimethylformamide (240 mL) and stirred overnight at 100° C. The reaction mixture was cooled to room temperature, diluted with methyl-tert-butylether and 2M hydrochloric acid and washed with 10% aqueous solution of sodium metabisulphite. Organic phase was extracted with 2M sodium hydroxide and the resulting basic aqueous phase was acidified with concentrated aqueous hydrochloric acid and re-extracted with methyl-tert-butylether. The solvent was removed under reduced pressure affording 2-bromo-6-iodobenzoic acid (24.3 g, 74% yield), which was used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]([C:6]([NH:8][C:9]2[S:10][CH:11]=[C:12]([CH2:14][C:15]([OH:17])=O)[N:13]=2)=[O:7])=[CH:4][CH:3]=1.Cl.[N:21]1([CH2:27][CH2:28][N:29]2[CH2:33][CH2:32][O:31][C:30]2=[O:34])[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([NH:8][C:9]2[S:10][CH:11]=[C:12]([CH2:14][C:15](=[O:17])[N:24]3[CH2:25][CH2:26][N:21]([CH2:27][CH2:28][N:29]4[CH2:33][CH2:32][O:31][C:30]4=[O:34])[CH2:22][CH2:23]3)[N:13]=2)=[O:7])=[CH:18][CH:19]=1
Reactant: O=C(O)Cc1csc(NC(=O)c2ccc(Cl)cc2)n1
Reactant: O=C1OCCN1CCN1CCNCC1
Agent: Cl
Product: O=C(Nc1nc(CC(=O)N2CCN(CCN3CCOC3=O)CC2)cs1)c1ccc(Cl)cc1

Procedure:
In analogy to example 1.3, [2-(4-chloro-benzoylamino)-thiazol-4-yl]-acetic acid (example 1.2) was coupled with 3-[2-(1-piperazinyl)ethyl]-2-oxazolidinone hydrochloride (CAS 52548-39-7) to give 4-chloro-N-[4-(2-oxo-2-{4-[2-(2-oxo-oxazolidin-3-yl)-ethyl]-piperazin-1-yl}-ethyl)-thiazol-2-yl]-benzamide, using general procedure C. White amorphous solid. MS 478.4 ([M+H]+)
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:14]=[N:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([CH:21]=[CH2:22])=[CH:17][CH:16]=3)=[N:11]2)=[CH:6][CH:5]=1.C12BC(CCC1)CCC2.[OH-:34].[Na+].OO>O1CCCC1.O>[F:24][C:2]([F:1])([F:23])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:14]=[N:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][OH:34])=[CH:17][CH:16]=3)=[N:11]2)=[CH:6][CH:5]=1
Reactant: [OH-]
Reactant: C=Cc1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Agent: B1C2CCCC1CCC2
Agent: OO
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: OCCc1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 71.6 %

Procedure:
To 1-(4-(trifluoromethoxy)phenyl)-3-(4-vinylphenyl)-1H-1,2,4-triazole (C43) (2.0 g, 6.0 mmol) in tetrahydrofuran (50 mL) was added 9-borabicyclo(3.3.1)nonane (24 mL, 12.1 mmol), and the reaction was stirred at room temperature for 4.5 hours. Sodium hydroxide (3 N, 4.0 mL, 12.0 mmol) was added, followed by hydrogen peroxide (30% wt, 1.5 mL, 15.1 mmol). The light green solution was stirred at room temperature overnight. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated to give a light green oil. The crude compound was purified by flash column chromatography using 0-50% ethyl acetate/hexanes as eluent to afford the title compound as a white solid (1.5 g, 69%): mp 85-98° C.; 1H NMR (400 MHz, DMSO-d6) δ 9.37 (s, 1H), 8.06 (d, J=9.0 Hz, 2H), 8.01 (d, J=8.1 Hz, 2H), 7.61 (dd, J=9.2, 1.0 Hz, 2H), 7.41-7.30 (m, 2H), 4.69 (t, J=5.2 Hz, 1H), 3.65 (td, J=7.0, 5.1 Hz, 2H), 2.79 (t, J=6.9 Hz, 2H); 13C NMR (101 MHz, DMSO-d6) δ 162.18, 147.08, 143.70, 141.45, 135.72, 129.39, 128.23, 127.93, 125.96, 122.57, 121.10, 61.90, 61.90; 19F NMR (376 MHz, DMSO-d6) δ −56.98; ESIMS m/z 349 ([M+H]+).
Reaction SMILES: CC(C)([O-])C.[K+].[C:7]([O:11][C:12]([N:14]([CH2:21][C:22](=[O:24])[CH3:23])[CH2:15][C:16](OCC)=[O:17])=[O:13])([CH3:10])([CH3:9])[CH3:8]>CCOCC>[O:24]=[C:22]1[CH2:23][C:16](=[O:17])[CH2:15][N:14]([C:12]([O:11][C:7]([CH3:8])([CH3:9])[CH3:10])=[O:13])[CH2:21]1
Reactant: CCOC(=O)CN(CC(C)=O)C(=O)OC(C)(C)C
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1CC(=O)CC(=O)C1
Reaction time: 3 h
Yield: 60.6 %

Procedure:
To a cooled solution (0° C.) of potassium tert-butoxide (112.0 mL, 112.0 mmol) was added via addition funnel over 1.5 h, a solution 120 (26.41 g, 101.9 mmol) in ether (200 mL). The mixture was stirred for an additional 3 h. The precipitate was filtered off and washed with ether. The solid was dissolved in water and the pH was adjusted to ca. 4 with HOAc. The solids were filtered, washed with water, and dried to afford 13.16 g (60.6%) of tert-butyl 3,5-dioxopiperidine-1-carboxylate (122).
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8]Cl)[CH:3]=1.Cl.[CH3:11][O:12][NH2:13].C(N(CC)CC)C>C(#N)C>[CH3:11][O:12][NH:13][CH2:8][C:4]1[CH:3]=[N:2][CH:7]=[CH:6][CH:5]=1
Reactant: ClCc1cccnc1
Reactant: CON
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CONCc1cccnc1
Temperature: 50 °C
Reaction time: 15 h
Yield: 18.1 %

Procedure:
In 200 ml of acetonitrile was suspended 6.6 g (0.04 mole) of 3-pyridylmethyl chloride hydrochloride, followed by addition of 10 g (0.12 mole) of O-methyl-hydroxylamine hydrochloride and 16.2 g (0.16 mole) of triethylamine. The mixture was stirred at 50° C. for 15 hours. The insoluble matter was filtered off and the filtrate was concentrated. The residue was subjected to silica gel column chromatography, using EtOH-CHCl3 (1:10) as an eluent. The procedure gave 1.0 g of the title compound as a yellow oil.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C@@H:3]([O:9][C:10](=[O:24])[C@:11]([CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1)([OH:17])[C:12]1S[CH:14]=[CH:15][CH:16]=1)[CH2:2]2.[CH:25]1([C@@](O)(C2C=CC=CC=2)C(O)=O)CCCC[CH2:26]1>>[N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C@@H:3]([O:9][C:10](=[O:24])[C@:11]([CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1)([OH:17])[C:12]1[CH:26]=[CH:25][CH:14]=[CH:15][CH:16]=1)[CH2:2]2
Reactant: O=C(O)[C@](O)(c1ccccc1)C1CCCCC1
Reactant: O=C(O[C@H]1CN2CCC1CC2)[C@](O)(c1cccs1)C1CCCCC1
Product: O=C(O[C@H]1CN2CCC1CC2)[C@](O)(c1ccccc1)C1CCCCC1

Procedure:
This compound is prepared analogously to (S)-cyclohexyl-hydroxy-thiophen-2-yl-acetic acid (R)-(1-aza-bicyclo[2.2.2]oct-3-yl)ester by replacing (S)-cyclohexyl-hydroxy-thiophen-2-yl-acetic acid with (R)-cyclohexyl-hydroxy-phenyl-acetic acid.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:10]([O:12][CH3:13])=[O:11])[CH:8]=2)[CH:3]=[CH:2]1.C(=O)([O-])[O-].[K+].[K+].[CH3:20][C:21]1[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[CH:23][CH:22]=1>CC(=O)CCC>[S:27]([N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:10]([O:12][CH3:13])=[O:11])[CH:8]=2)[CH:3]=[CH:2]1)([C:24]1[CH:25]=[CH:26][C:21]([CH3:20])=[CH:22][CH:23]=1)(=[O:29])=[O:28]
Reactant: COC(=O)c1ccc2cc[nH]c2c1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCC(C)=O
Product: COC(=O)c1ccc2ccn(S(=O)(=O)c3ccc(C)cc3)c2c1
Temperature: 80 °C
Reaction time: 16 h
Yield: 91.2 %

Procedure:
To a solution of methyl indole-6-carboxylate (2.1 g) of 2-pentanone (40 mL), potassium carbonate (6.5 g) and 4-methylbenzenesulfonyl chloride (4.4 g) were added at room temperature, and then the reaction mixture was stirred at 80° C. for 16 hours. After cooling to room temperature, the insoluble materials were filtered, and the filtrate was concentrated under reduced pressure. To the obtained residue, a mixed solvent of ethyl acetate-hexane was added, and the obtained solid was filtered, and washed with hexane to give the titled compound (3.6 g) as a white solid.
Reaction SMILES: [F:1][C:2]1[C:3]([C:9]2[CH:14]=[C:13]([NH:15][C:16]3[C:17]4[C:18](=[CH:22][NH:23][N:24]=4)[N:19]=[CH:20][CH:21]=3)[CH:12]=[CH:11][N:10]=2)=[N:4][C:5]([CH3:8])=[CH:6][CH:7]=1.Br[CH2:26][CH2:27][OH:28].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.O.C(#N)C.O>[F:1][C:2]1[C:3]([C:9]2[CH:14]=[C:13]([NH:15][C:16]3[C:17]4[C:18](=[CH:22][N:23]([CH2:26][CH2:27][OH:28])[N:24]=4)[N:19]=[CH:20][CH:21]=3)[CH:12]=[CH:11][N:10]=2)=[N:4][C:5]([CH3:8])=[CH:6][CH:7]=1
Reactant: OCCBr
Reactant: Cc1ccc(F)c(-c2cc(Nc3ccnc4c[nH]nc34)ccn2)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CC#N
Solvent: CN(C)C=O
Product: Cc1ccc(F)c(-c2cc(Nc3ccnc4cn(CCO)nc34)ccn2)n1
Temperature: 120 °C
Yield: 8.7 %

Procedure:
N-(3′-Fluoro-6′-methyl-2,2′-bipyridin-4-yl)-2H-pyrazolo[4,3-b]pyridin-7-amine (21 mg, 0.066 mmol), 2-bromoethanol (8.19 mg, 0.066 mmol) and cesium carbonate (42.7 mg, 0.131 mmol) were combined in DMF (5 mL). The mixture was heated at 120° C. for 30 minutes, then cooled and purified by preparative HPLC using a Phenomenex Gemini Prep 5 μm C18, 75×30 mm column eluting with a gradient of 20-70% 10 mmol NH4HCO3 in 20/80 (v/v) water/acetonitrile in 10 mmol NH4HCO3 in water to afford 2-(7-(3′-fluoro-6′-methyl-2,2′-bipyridin-4-ylamino)-2H-pyrazolo[4,3-b]pyridin-2-yl)ethanol (2.1 mg, 8.79% yield). 2-(7-(3′-Fluoro-6′-methyl-2,2′-bipyridin-4-ylamino)-1H-pyrazolo[4,3-b]pyridin-1-yl)ethanol containing fractions were concentrated and subsequently purified by preparative HPLC using a Sunfire Prep 5 μm C18, 75×30 mm column eluting with a gradient of 5-40% acetonitrile (containing 0.035% TFA) in water (containing 0.05% TFA) to afford the title compound as TFA salts.
Reaction SMILES: N1C=CC=C(CO)C=1.O[N:10]1[C:14](=[O:15])[C:13]2=[CH:16][CH:17]=[CH:18][CH:19]=[C:12]2[C:11]1=[O:20]>>[C:14]1(=[O:15])[NH:10][C:11](=[O:20])[C:12]2=[CH:19][CH:18]=[CH:17][CH:16]=[C:13]12
Reactant: O=C1c2ccccc2C(=O)N1O
Agent: OCc1cccnc1
Product: O=C1NC(=O)c2ccccc21
Yield: 81.3 %

Procedure:
Phthalimide-protected intermediate 2G was prepared from pyridin-3-ylmethanol and N-hydroxyphthalimide by a procedure analogous to Example 2A, Step 1 (3.22 g, 81.3% yield). ESI-MS: m/z 255.2 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:8]=[C:9](B3OCCCO3)[CH:10]=[CH:11][CH:12]=2)[C:5]2[CH:19]=[CH:20][CH:21]=[CH:22][C:4]=2[N:3]=1.Br[C:24]1[CH:25]=[C:26]2[C:30](=[CH:31][CH:32]=1)[NH:29][CH:28]=[CH:27]2>>[NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:24]3[CH:25]=[C:26]4[C:30](=[CH:31][CH:32]=3)[NH:29][CH:28]=[CH:27]4)[CH:8]=2)[C:5]2[CH:19]=[CH:20][CH:21]=[CH:22][C:4]=2[N:3]=1
Reactant: Brc1ccc2[nH]ccc2c1
Reactant: Nc1nc2ccccc2n1-c1cccc(B2OCCCO2)c1
Product: Nc1nc2ccccc2n1-c1cccc(-c2ccc3[nH]ccc3c2)c1

Procedure:
2-Amino-1-[3-(5-indolyl)phenyl]benzimidazole was prepared from 3-(2-amino-1-benzimidazolyl)-phenyl-1,3,2-dioxaborinane and 5-bromoindole according to method A. mp 120°-123° C.
Reaction SMILES: [CH2:1]([O:4][C:5]([NH:7][C@@:8]1([C:17]([OH:19])=[O:18])[CH2:13][CH2:12][C@@H:11]2[C@H:9]1[C@H:10]2[C:14]([OH:16])=[O:15])=[O:6])[CH:2]=[CH2:3].C(N=C=N[CH2:25][CH2:26][CH2:27]N(C)C)C.CN(C1C=CC=CN=1)C.C(O)C=C>C(Cl)Cl>[CH2:27]([O:15][C:14]([C@@H:10]1[C@@H:9]2[C@H:11]1[CH2:12][CH2:13][C@@:8]2([NH:7][C:5]([O:4][CH2:1][CH:2]=[CH2:3])=[O:6])[C:17]([OH:19])=[O:18])=[O:16])[CH:26]=[CH2:25]
Reactant: C=CCOC(=O)N[C@@]1(C(=O)O)CC[C@H]2[C@H](C(=O)O)[C@H]21
Reactant: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Solvent: C=CCO
Product: C=CCOC(=O)N[C@@]1(C(=O)O)CC[C@H]2[C@H](C(=O)OCC=C)[C@H]21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(1S,2S,5R,6S)-2-Allyloxycarbonylamino-bicyclo[3.1.0]hexane-2,6-dicarboxylic acid (13.4 g, 49.81 mmol, 1.0 equiv) was suspended in methylene chloride (400 mL). N-Ethyl-N′-dimethylaminopropylcarbodiimide (9.55 g, 49.81 mmol, 1.0 equiv) and dimethylaminopyridine (0.608 g, 4.98 mmol, 0.1 equiv) were added at room temperature under nitrogen. After a solution formed, allyl alcohol (3.4 mL, 2.89 g, 49.81 mmol, 1.0 equiv) was added and the mixture was stirred overnight at room temperature. The reaction mixture was diluted with methylene chloride and washed twice with water. The organic phase was dried over magnesium sulfate, filtered and concentrated. The title compound was obtained as an oil (44% yield).
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([C:10]2[O:11][C:12]3[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[CH2:27]Cl)=[CH:15][C:13]=3[CH:14]=2)[S:8][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[I-].[Na+].C(=O)([O-])[O-:32].[Na+].[Na+]>CS(C)=O>[C:1]([C:5]1[N:6]=[C:7]([C:10]2[O:11][C:12]3[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[CH:27]=[O:32])=[CH:15][C:13]=3[CH:14]=2)[S:8][CH:9]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1csc(-c2cc3cc(OCc4ccccc4CCl)ccc3o2)n1
Reactant: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CC(C)(C)c1csc(-c2cc3cc(OCc4ccccc4C=O)ccc3o2)n1
Temperature: 100 °C
Reaction time: 10 h
Yield: 50.6 %

Procedure:
A mixture of 4-tert-butyl-2-[5-(2-chloromethylphenylmethoxy)benzofuran-2-yl]thiazole (1.56 g), sodium iodide (0.50 g) and sodium carbonate (0.83 g) in dimethylsulfoxide (15 ml) was stirred at 100° C. for 10 hours. After being cooled, the resulting mixture was poured into ice-water and extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was subjected to column chromatography on silica gel and eluted with a mixture of ethyl acetate and toluene (1:20). The fractions containing object compound were combined and concentrates under reduced pressure to give 4-tert-butyl-2-[5-(2-formylphenylmethoxy)benzofuran-2-yl]thiazole (0.75 g).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][CH3:9])[N:5]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH:21]=[C:20]([CH3:22])[N:19]=[CH:18]3)=[C:13]([O:23][CH3:24])[CH:12]=2)[N:3]=1.[Cl:25][C:26]1[C:31]([OH:32])=[CH:30][CH:29]=[CH:28][N:27]=1>>[Cl:25][C:26]1[C:31]([O:32][C:2]2[N:7]=[C:6]([O:8][CH3:9])[N:5]=[C:4]([NH:10][C:11]3[CH:16]=[CH:15][C:14]([N:17]4[CH:21]=[C:20]([CH3:22])[N:19]=[CH:18]4)=[C:13]([O:23][CH3:24])[CH:12]=3)[N:3]=2)=[CH:30][CH:29]=[CH:28][N:27]=1
Reactant: Oc1cccnc1Cl
Reactant: COc1nc(Cl)nc(Nc2ccc(-n3cnc(C)c3)c(OC)c2)n1
Product: COc1nc(Nc2ccc(-n3cnc(C)c3)c(OC)c2)nc(Oc2cccnc2Cl)n1

Procedure:
The title compound was prepared from (4-chloro-6-methoxy-[1,3,5]triazin-2-yl)-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-amine and 2-chloro-3-hydroxypyridine in analogy to example 3. It was purified by column chromatography on Si—NH2 gel (Isolute) using ethyl acetate as eluent to give the title compound as a yellowish solid in 76% yield.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:12]([C:19]3[CH:24]=[CH:23][C:22]4[O:25][CH2:26][O:27][C:21]=4[CH:20]=3)[CH2:11][N:10]=2)=[CH:5][CH:4]=1.C([BH3-])#N.[Na+].Cl>CC1C(Br)=C(O)C(Br)=CC=1C1(C2C=C(Br)C(O)=C(Br)C=2C)OS(=O)(=O)C2C=CC=CC1=2.C(O)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:12]([C:19]3[CH:24]=[CH:23][C:22]4[O:25][CH2:26][O:27][C:21]=4[CH:20]=3)[CH2:11][NH:10]2)=[CH:5][CH:4]=1
Reactant: CCOC(=O)C1C(c2ccc(OC)cc2)=NCC1c1ccc2c(c1)OCO2
Agent: Cc1c(C2(c3cc(Br)c(O)c(Br)c3C)OS(=O)(=O)c3ccccc32)cc(Br)c(O)c1Br
Agent: Cl
Agent: [BH3-]C#N
Solvent: CCO
Product: CCOC(=O)C1C(c2ccc3c(c2)OCO3)CNC1c1ccc(OC)cc1
Reaction time: 0.5 h
Yield: 96.8 %

Procedure:
Into a 12-L flask equipped with magnetic stirring, addition funnel, temperature probe, and nitrogen inlet was charged 0.460 kg ethyl 2-(4-methoxyphenyl)-4-(3,4-methylenedioxyphenyl)-4,5-dihydro-3H-pyrrole-3-carboxylate (1.25 mol). The reaction vessel was degassed with nitrogen. Absolute 3.7 L ethanol and 1.12 L of THF were added. 31 mg bromocresol green and 94.26 g sodium cyanoborohydride (1.5 mol) were added. A solution containing 400 mL absolute ethanol and 200 mL of 12 M HCl was then added. The reaction mixture was stirred for 30 minutes after addition was complete. After the starting material was consumed, 0.5 L of 7% aq. NaHCO3 was added. The reaction mixture was concentrated and diluted with 5 L ethyl acetate. The organic layer was washed twice with 2 L of 7% aq. NaHCO3 and once with 2.5 L of 23% aq. NaCl, the dried over 190 g MgSO4, filtered, and concentrated to give 447 g of the title compound as a thick yellow oil.
Reaction SMILES: C([C:5]([Br:17])(CCCC)[C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=1)CCC.C1C=C(Cl)C=C(C(OO)=O)C=1.[S:29]([O-])([O-:31])=[O:30].[Na+].[Na+].C(OCC)(=O)C>C(Cl)Cl>[S:29](=[C:5]([Br:17])[C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=1)(=[O:31])=[O:30]
Reactant: O=S([O-])[O-]
Reactant: CCCCC(Br)(CCCC)c1ccc(F)cc1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: O=S(=O)=C(Br)c1ccc(F)cc1
Reaction time: 0.17 h
Yield: 98 %

Procedure:
To a solution of 8.5 g (25 mmol) of sulfide obtained from Step 3 in 200 mL of CH2Cl2 at 0° C. was added 15.9 g (60 mmol) of mCPBA (64% peracid). The resulting solution was stirred cold for 10 min, then was allowed to stirred ambient temperature for 5 hours. To the mixture was added 10% solution of sodium sulfite and ethyl acetate. The extract was washed several times with saturated Na2CO3, dried (MgSO4), and concentrated in vacuo to give 10.2 g (98%) of the desired product as a colorless oil: 1H NMR (CDCl3) d 0.91 (t, J=7.05 Hz, 6H), 1.03-1.4 (m, 8H), 1.65-1.82 (m, 2H), 1.90-2.05 (m, 2H), 3.54 (s, 2H), 5.01 (s, 2H), 7.04-7.23 (m, 1H), 7.30 (dd, J=8.87, 2.42 Hz, 1H), 8.03 (dd, J 8.86, 5.64, 1H), 9.49 (s, 1H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[N:3]=1.[CH2:9]([NH:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH2:10][CH2:11][CH3:12].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Br:8][C:4]1[N:3]=[C:2]([N:13]([CH2:14][CH2:15][CH2:16][CH3:17])[CH2:9][CH2:10][CH2:11][CH3:12])[CH:7]=[CH:6][CH:5]=1
Reactant: Brc1cccc(Br)n1
Reactant: CCCCNCCCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCN(CCCC)c1cccc(Br)n1
Temperature: 90 °C
Yield: 43 %

Procedure:
To a solution of 2,6-dibromopyridine (Aldrich, 1.42 g, 6.00 mmol) in DMF (2.0 mL) were added dibutylamine (Aldrich, 388 g, 3.00 mmol) and potassium carbonate (829 mg, 6.00 mmol). The reaction mixture was heated at 90° C. for 20 h. After cooling to room temperature, the reaction mixture was quenched by adding cold water. The mixture was extracted with DCM (3×), and the combined organic extracts were dried over Na2SO4, filtered and concentrated in vacuo to give a crude oil. Purification using flash column chromatography (eluting with DCM) provided the title compound (368 mg, 43%) as a light brown oil. 1H NMR (CDCl3) δ 0.22 (dd, J=8.4, 7.4 Hz, 1H), 6.62 (d, J=7.0 Hz, 1H), 6.33 (d, J=8.3 Hz, 1H), 3.49-3.37 (m, 4H), 1.65-1.52 (m, 4H), 1.44-1.30 (m, 4H), 0.98 (t, J=7.3 Hz, 6H); MS(ESI+) m/z 272.1 (M+H)+.