Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][C:10]([C:13]2[N:14]([CH3:39])[C:15]3[C:20]([N:21]=2)=[C:19]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[N:18]=[C:17]([N:28]2[C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=4[N:30]=[C:29]2[CH2:37][CH3:38])[N:16]=3)(O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].COCCN(S(F)(F)[F:50])CCOC>C1COCC1>[CH2:37]([C:29]1[N:28]([C:17]2[N:16]=[C:15]3[C:20]([N:21]=[C:13]([C:10]4([F:50])[CH2:11][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9]4)[N:14]3[CH3:39])=[C:19]([N:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)[N:18]=2)[C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=2[N:30]=1)[CH3:38]
Reactant: COCCN(CCOC)S(F)(F)F
Reactant: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C3(O)CN(C(=O)OC(C)(C)C)C3)n(C)c2n1
Solvent: C1CCOC1
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C3(F)CN(C(=O)OC(C)(C)C)C3)n(C)c2n1
Temperature: 5 °C
Reaction time: 0.25 h
Yield: 79.2 %

Procedure:
To a solution of 3-[2-(2-ethylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purin-8-yl]-3-hydroxy-azetidine-1-carboxylic acid tert-butyl ester (300 mg, 0.56 mmol) in THF (2 mL) at 5° C. was added a solution of bis-(2-methoxyethyl)aminosulfur trifluoride (275 μL, 0.62 mmol, 50% solution in THF) in THF (3 mL). The resulting mixture was allowed to stir at 5° C. for 15 min then warmed to r.t. and stirred for a further 15 min. The reaction mixture was partitioned between sat. aq. NaHCO3 and DCM, the organic phase dried (phase separator) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, EtOAc:cyclohexane, 35-85%) affording 828 as a pale yellow solid (238 mg, 79%). LCMS (method I): RT 4.65 min, [M+H]+ 537.4. 1H NMR (DMSO, 400 MHz): δ 8.05-8.04 (1 H, m), 7.64-7.64 (1 H, m), 7.26-7.25 (2 H, m), 4.77 (2 H, dd, J=20.08, 10.62 Hz), 4.60-4.10 (4 H, brd s), 4.48 (2 H, dd, J=21.54, 10.50 Hz), 3.79 (4 H, t, J=4.55 Hz), 3.76 (3 H, d, J=1.32 Hz), 3.28-3.27 (2 H, m), 1.42 (9 H, s), 1.34 (3 H, t, J=7.46 Hz)
Reaction SMILES: C([O-])(=O)C.[NH4+:5].[CH3:6][C:7]1[N:12]=[C:11](OC2C=CC=CC=2)[C:10]2[N:20]=[CH:21][N:22]([CH2:23][CH2:24][O:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:9]=2[C:8]=1[CH3:32]>ClCCl>[CH3:6][C:7]1[N:12]=[C:11]([NH2:5])[C:10]2[N:20]=[CH:21][N:22]([CH2:23][CH2:24][O:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:9]=2[C:8]=1[CH3:32]
Reactant: Cc1nc(Oc2ccccc2)c2ncn(CCOc3ccccc3)c2c1C
Reactant: [NH4+]
Agent: CC(=O)[O-]
Solvent: ClCCl
Product: Cc1nc(N)c2ncn(CCOc3ccccc3)c2c1C
Temperature: 150 °C

Procedure:
A sealed tube containing ammonium acetate (12.7 g) and 6,7-dimethyl-4-phenoxy-1-(2-phenoxyethyl)-1H-imidazo[4,5-c]pyridine (1.27 g) from Part E was heated to 150° C. for 36 hours. HPLC and TLC analysis indicated that the reaction was complete. The reaction was allowed to cool to room temperature. The resulting reaction mixture was then dissolved in dichloromethane (DCM) and washed with 20% aqueous sodium hydroxide. The basic layer was washed with DCM and the combined organic layers were dried with magnesium sulfate and concentrated under reduced pressure. The resulting oil was passed through a silica gel column using 95/5 dichloromethane/methanol as the eluant. The product was recrystallized from isopropyl alcohol, and the resulting white solid was dried under vacuum to provide 6,7-dimethyl-1-(2-phenoxyethyl)-1H-imidazo[4,5-c]pyridin-4-amine, m.p. 197.0-199.0° C.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[C:8](=O)[N:7]2[CH2:10][CH2:11][NH:12][CH2:13][CH:6]2[C:5](=O)[NH:4]1.B.C1COCC1.Cl>CO>[CH2:5]1[NH:4][CH:3]([CH2:2][OH:1])[CH2:8][N:7]2[CH2:10][CH2:11][NH:12][CH2:13][CH:6]12
Reactant: O=C1NC(CO)C(=O)N2CCNCC12
Agent: B
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Product: OCC1CN2CCNCC2CN1
Temperature: 80 °C
Yield: 93.3 %

Procedure:
To a flask containing (3S,9aS or 9aR)-3-(hydroxymethyl)tetrahydro-2H-pyrazino[1,2-a]pyrazine-1,4(3H,6H)-dione (D83, 217 mg) was added 1M BH3-THF solution (10.9 mL) and the reaction was brought to reflux (80° C.) overnight. The reaction flask was cooled to 0° C. and treated with 20 mL of MeOH and conc. HCl (2.5 mL). The resulting solution was heated to 60° C. for 4 h. The reaction was checked by direct MS (m/z=172 (M+1), 184 (M+BH3)). The reaction mixture was purified by SCX, obtaining 174 mg of the title compound.
Reaction SMILES: [C:1]1([C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4])[OH:2].Cl[C:10](=[CH:15][C:16]([F:19])([F:18])[F:17])[C:11]([F:14])([F:13])[F:12]>[OH-].[Na+]>[F:12][C:11]([F:14])([F:13])[CH2:10][C:15]1([C:16]([F:19])([F:18])[F:17])[O:4][C:3]2[CH:5]=[CH:6][CH:7]=[CH:8][C:1]=2[O:2]1
Reactant: FC(F)(F)C=C(Cl)C(F)(F)F
Reactant: Oc1ccccc1O
Agent: [Na+]
Agent: [OH-]
Product: FC(F)(F)CC1(C(F)(F)F)Oc2ccccc2O1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
11 g of pyrocatechol were dissolved in 200 ml of dimethylfomamide, and 18 g of 45% strength by weight aqueous sodium hydroxide solution were added. 20 g of 2-chloro-1,1,1,4,4,4-hexafluoro-2-butene were added dropwise at 75° C. to the mixture. Stirring was continued for 30 minutes at 75° C. The mixture was then poured into 500 ml of ice-water and extracted with diethyl ether. The organic phase was washed with water, dried with magnesium sulphate and concentrated. Finally, the product was distilled under a high vacuum. The yield was 15 g (=56%) the boiling point was 60° C. at 10 mbar. The NMR spectra showed the following characteristic absorptions: 19F-NMR: -59.0 and -84.6 ppm; 1H-NMR: 3.02 ppm.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:23]([F:26])([F:25])[F:24])[CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([S:19]([NH2:22])(=[O:21])=[O:20])=[CH:15][CH:14]=1)[N:8]=[CH:7]2.[F:27][C:28]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][N:29]=1.C(=O)([O-])[O-].[K+].[K+]>COCCOC.C(OCC)(=O)C>[F:27][C:28]1[N:29]=[CH:30][C:31]([C:2]2[CH:3]=[C:4]([C:23]([F:26])([F:24])[F:25])[CH:5]=[C:6]3[C:11]=2[N:10]=[C:9]([NH:12][C:13]2[CH:14]=[CH:15][C:16]([S:19]([NH2:22])(=[O:21])=[O:20])=[CH:17][CH:18]=2)[N:8]=[CH:7]3)=[CH:32][CH:33]=1
Reactant: OB(O)c1ccc(F)nc1
Reactant: NS(=O)(=O)c1ccc(Nc2ncc3cc(C(F)(F)F)cc(Br)c3n2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: NS(=O)(=O)c1ccc(Nc2ncc3cc(C(F)(F)F)cc(-c4ccc(F)nc4)c3n2)cc1

Procedure:
To a 0.050 M solution of 4-(8-bromo-6-(trifluoromethyl)quinazolin-2-ylamino)benzenesulfonamide (1.0 eq) in DME was added 2-fluoro-5-pyridineboronic acid (3.0 eq), (dppf)Pd(II)Cl2-CH2Cl2 (0.050 eq) and 2M aqueous potassium carbonate (8.0 eq). The mixture was microwaved at 120° C. for 10 min and then diluted with ethyl acetate and filtered through a pad of silica gel. The filtrate was concentrated to give the desired product which was used without further purification. ES/MS m/z 464 (MH+).
Reaction SMILES: [NH2-:1].[Na+].[CH3:3][C:4]1([C:17]([O:19]CC)=O)[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]1>O1CCCC1>[NH2:1][C:17]([C:4]1([CH3:3])[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]1)=[O:19]
Reactant: [NH2-]
Reactant: CCOC(=O)C1(C)CCN(C(=O)OC(C)(C)C)CC1
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(C)(C(N)=O)CC1
Temperature: 35 °C
Reaction time: 3 h

Procedure:
A 500-mL flask equipped with an N2 inlet/temperature probe, overhead stirrer and an addition funnel was charged with sodium amide (13.3 g, 327.3 mmol) and tetrahydrofuran (110 g) then warmed to 35° C. Through the addition funnel was slowly charged the tetrahydrofuran/toluene solution of Example 8 (35.57 g, 130.9 mmol). The addition funnel was rinsed with tetrahydrofuran (12 g). The reaction temperature was adjusted to 50° C. and the reaction was stirred for 3 hours before an HPLC sample was taken that showed the reaction was complete. In a separate flask equipped with an overhead stirred and a thermocouple was charged water (142 g), acetic acid (31.5 g) and toluene (54 g). The resulting mixture was then chilled to 0° C. The heterogeneous reaction mixture was quenched by addition to the acetic acid/toluene mixture while maintaining the temperature below 25° C. The reaction flask was rinsed with toluene (14 g) and water (14 g), which were added to the quench flask. The pH of the quench mixture was 6.04. The pH of the mixture was adjusted to 7.5 using 50% NaOH solution (11 g). The aqueous layer was extracted with 1:1 toluene/tetrahydrofuran (50 g). The organic layers were combined, filtered through a fritted glass filter and concentrated to a total volume of about 75 mL. The residue was diluted with toluene (125 g) and concentrated to a total volume of about 100 mL. Solid had formed during the distillations. The mixture was cooled to 0° C. and stirred for 1 hour. The mixture was filtered and the solid was washed with three portions of cold toluene and dried under vacuum to give the title compound. 1H NMR (400 MHz, CDCl3) δ ppm 1.23 (s, 3H) 1.37-1.51 (m, 2H) 1.44 (s, 9H) 1.88-1.98 (m, 2H) 3.19-3.32 (m, 2H) 3.51-3.68 (m, 2H) 5.56-5.76 (m, 2H).
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]([CH3:18])=[N:7][O:8][C:9]=1[C:10]1[CH:15]=[CH:14][C:13]([Br:16])=[C:12]([CH3:17])[CH:11]=1)=[O:4].[Li+].[OH-]>>[Br:16][C:13]1[CH:14]=[CH:15][C:10]([C:9]2[O:8][N:7]=[C:6]([CH3:18])[C:5]=2[C:3]([OH:4])=[O:2])=[CH:11][C:12]=1[CH3:17]
Reactant: COC(=O)c1c(C)noc1-c1ccc(Br)c(C)c1
Agent: [Li+]
Agent: [OH-]
Product: Cc1cc(-c2onc(C)c2C(=O)O)ccc1Br

Procedure:
5-(4-Bromo-3-methyl-phenyl)-3-methyl-isoxazole-4-carboxylic acid methyl ester (7.26 g, 23.4 mmol) was hydrolyzed with 1N aqueous LiOH. Acidic work-up provided the title compound.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:24]3[C:19](=[CH:20][C:21]([O:27][CH2:28][CH3:29])=[C:22]([O:25][CH3:26])[CH:23]=3)[C@@H:18]3[C@@H:13]([CH2:14][CH2:15][C@@H:16]([OH:30])[CH2:17]3)[N:12]=2)=[CH:7][N:6]=1)=N.O.P(=O)(O)(O)[OH:33].P([O-])([O-])(O)=O.[Na+].[Na+]>C1COCC1>[CH2:28]([O:27][C:21]1[CH:20]=[C:19]2[C:24]([C:11]([C:8]3[CH:9]=[CH:10][C:5]([C:3]([OH:2])=[O:33])=[N:6][CH:7]=3)=[N:12][C@H:13]3[C@@H:18]2[CH2:17][C@H:16]([OH:30])[CH2:15][CH2:14]3)=[CH:23][C:22]=1[O:25][CH3:26])[CH3:29]
Reactant: O=P(O)(O)O
Reactant: CCOc1cc2c(cc1OC)C(c1ccc(C(=N)OC)nc1)=N[C@@H]1CC[C@@H](O)C[C@H]21
Agent: O=P([O-])([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCOc1cc2c(cc1OC)C(c1ccc(C(=O)O)nc1)=N[C@@H]1CC[C@@H](O)C[C@H]21
Temperature: 60 °C
Reaction time: 18 h

Procedure:
Analogously as described for Example 35 acidic acid (2R,4aR,10bR)-6-(6-cyano-pyridin-3-yl)-9-ethoxy-8-methoxy-1,2,3,4,4a,10b-hexahydro-phenanthridin-2-yl ester (compound 172) is converted in a first step into the corresponding imino ester 5-((2R,4aR,10bR)-9-ethoxy-2-hydroxy-8-methoxy-1,2,3,4,4a,10b-hexahydro-phenanthridin-6-yl)-pyridine-2-carboximidic acid methyl ester. In a second step, 443 mg (1.08 mmol) of 5-((2R,4aR,10bR)-9-ethoxy-2-hydroxy-8-methoxy-1,2,3,4,4a,10b-hexahydro-phenanthridin-6-yl)-pyridine-2-carboximidic acid methyl ester are dissolved in 3 ml of THF. A solution of 51 mg (2.16 mmol) LICH.H2O is added and the solution stirred at 60° C. for 18 hrs. The pH is adjusted to 5 using phosphoric acid and Disodiumhydrogenphosphate. The solvent is removed and the solid residue extracted with chloroform/methanol. After filtering off and removing the volatiles 350 mg (82%) of the title compound are obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][CH:4]=1.[C:10]([C:15](=[CH:21]OCC)[C:16]([O:18][CH2:19][CH3:20])=[O:17])(=[O:14])[CH2:11][CH2:12][CH3:13]>>[C:10]([C:15](=[CH:21][NH:7][C:6]1[CH:8]=[CH:9][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)[C:16]([O:18][CH2:19][CH3:20])=[O:17])(=[O:14])[CH2:11][CH2:12][CH3:13]
Reactant: COc1ccc(N)cc1
Reactant: CCCC(=O)C(=COCC)C(=O)OCC
Product: CCCC(=O)C(=CNc1ccc(OC)cc1)C(=O)OCC
Yield: 131.9 %

Procedure:
4-Methoxyaniline (25 g) and ethyl 2-butyryl-3-ethoxyacrylate (57 g) were heated together on a rotary evaporator (bath temp 100°) for 1 hour to give ethyl 2-butyryl-3-(4-methoxyphenylamino)acrylate (78 g) as an orange oil.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]([C:8]2[N:12]([CH3:13])[C:11]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][N:16]=3)=[CH:10][C:9]=2[CH3:22])=[O:7])=[CH:4][CH:3]=1.[CH3:25][N:26]=[C:27]=[O:28]>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([C:8]2[N:12]([CH3:13])[C:11]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([NH:21][C:27]([NH:26][CH3:25])=[O:28])=[CH:17][N:16]=3)=[CH:10][C:9]=2[CH3:22])=[O:7])=[CH:23][CH:24]=1
Reactant: Cc1cc(Cc2ccc(N)cn2)n(C)c1C(=O)c1ccc(Cl)cc1
Reactant: CN=C=O
Solvent: C1CCOC1
Product: CNC(=O)Nc1ccc(Cc2cc(C)c(C(=O)c3ccc(Cl)cc3)n2C)nc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 68.7 %

Procedure:
{2-{5-(4-Chlorobenzoyl)-1,4-dimethyl-1H-pyrrol-2-ylmethyl]pyridin-5-yl}amine (0.3 g, 0.88 mmol) was dissolved in THF (4 ml), and the solution was cooled to 0° C. Methyl isocyanate (0.062 ml, 1.06 mmol) was added and the reaction mixture was stirred overnight at ambient temperature. Additional methyl isocyanate (0.062 ml) was added and the mixture was stirred for an additional 24 h. The reaction mixture was concentrated under vacuum and the residue was crystallized from hexane-chloroform to give 1-{2-[5-(4-chlorobenzoyl)-1,4-di-methyl-1H-pyrrol-2-ylmethyl]pyridin-5-yl}-3-methylurea (240 mg, 69%), mp 234.0-235.5° C.
Reaction SMILES: [I:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:16])=[C:6]([CH:15]=1)[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1.N1C=CN=C1.[C:22]([Si:26]([CH3:29])([CH3:28])Cl)([CH3:25])([CH3:24])[CH3:23]>CN(C)C=O>[I:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:16])=[C:6]([CH:15]=1)[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][Si:26]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:29])[CH3:28])=[CH:10][CH:9]=1
Reactant: Cc1ccc(I)cc1Cc1ccc(O)cc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: Cc1ccc(I)cc1Cc1ccc(O[Si](C)(C)C(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To an ice cooled solution of 4-(5-iodo-2-methyl-benzyl)phenol (12.0 g) and imidazole (3.2 g) in dimethylformamide (40 mL) is added tert-butyldimethyl-chlorosilane (6.1 g). The ice-bath is removed and the solution is stirred at ambient temperature overnight. The solution is diluted with ethyl acetate and washed twice with hydrochloric acid (1 mol/L). The organic phase is dried (sodium sulphate) and concentrated in vacuo. The residue is purified by chromatography on silica gel (cyclohexane/ethyl acetate 1:0->20:1).
Reaction SMILES: [CH2:1]([C:3]1[N:8]=[CH:7][N:6]=[C:5](O)[C:4]=1[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH3:2].P(Cl)(Cl)([Cl:17])=O.[OH-].[Na+]>O>[Cl:17][C:5]1[C:4]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[C:3]([CH2:1][CH3:2])[N:8]=[CH:7][N:6]=1
Reactant: CCOC(=O)c1c(O)ncnc1CC
Reactant: O=P(Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCOC(=O)c1c(Cl)ncnc1CC
Temperature: 90 °C
Reaction time: 3 h
Yield: 43.8 %

Procedure:
Ethyl 6-ethyl-4-hydroxypyrimidine-5-carboxylate (7.30 g, 37.21 mmol) was stirred under ice-cooling. Phosphorus oxychloride (11.41 g, 74.41 mmol) was added dropwise to it. After the addition, the mixture was stirred at 90° C. for 3 hours. After cooling to room temperature, the mixture was poured into ice-cooled water and adjusted to pH 10 with an aqueous solution of sodium hydroxide. The resulting mixture was extracted with methylene chloride and dried over magnesium sulfate, and the solvent was evaporated. The residue was purified by column chromatography on silica gel eluting with n-hexane/ethyl acetate (=8/2) to give the desired ethyl 4-chloro-6-ethylpyrimidine-5-carboxylate (3.50 g, 44%).
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][CH:12]=[CH:11][C:3]=1[O:4][CH:5](Cl)[CH:6]([OH:9])[CH2:7][CH3:8].[CH2:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:18][CH2:17][NH:16]1.O.Cl>C(O)CCC>[OH2:4].[ClH:1].[Cl:1][C:2]1[CH:14]=[CH:13][CH:12]=[CH:11][C:3]=1[O:4][CH2:5][CH:6]([OH:9])[CH2:7][CH2:8][CH:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:18][CH2:17][NH:16]1
Reactant: c1ccc2c(c1)CCNC2
Reactant: CCC(O)C(Cl)Oc1ccccc1Cl
Agent: Cl
Solvent: O
Solvent: CCCCO
Product: OC(CCC1NCCc2ccccc21)COc1ccccc1Cl

Procedure:
A mixture of 11.8 g. (0.05 mole) of 1-(2-chlorophenoxy)-2-hydroxybutyl chloride, 13.3 g. (0.1 mole) of 1,2,3,4-tetrahydroisoquinoline and 100 ml. of n-butanol was heated in a steel bomb at 120° C. for 24 hr. The reaction mixture was filtered at room temperature, the filtrate was mixed with 200 ml. 3N hydrochloric acid and extracted twice with 100 ml. isopropyl ether. The aqueous acidic solution was made basic and extracted with isopropyl ether and treated with ethereal hydrogen chloride. Recrystallization with isopropanol yielded 6 g. of the hydrochloride hydrate of the product which melted at 118°-120° C.
Reaction SMILES: [CH3:1][CH:2]([O:4][CH2:5][CH2:6][CH2:7][NH:8][CH2:9][C:10]1[S:14][C:13](B(O)O)=[CH:12][CH:11]=1)[CH3:3].Br[C:19]1[CH:20]=[C:21]2[C:25](=[C:26]([C:28]([NH2:30])=[O:29])[CH:27]=1)[NH:24][CH:23]=[C:22]2[CH:31]1[CH2:36][CH2:35][N:34]([S:37]([CH2:40][CH3:41])(=[O:39])=[O:38])[CH2:33][CH2:32]1.C([O-])([O-])=O.[K+].[K+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:40]([S:37]([N:34]1[CH2:33][CH2:32][CH:31]([C:22]2[C:21]3[C:25](=[C:26]([C:28]([NH2:30])=[O:29])[CH:27]=[C:19]([C:13]4[S:14][C:10]([CH2:9][NH:8][CH2:7][CH2:6][CH2:5][O:4][CH:2]([CH3:3])[CH3:1])=[CH:11][CH:12]=4)[CH:20]=3)[NH:24][CH:23]=2)[CH2:36][CH2:35]1)(=[O:39])=[O:38])[CH3:41]
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(Br)cc23)CC1
Reactant: CC(C)OCCCNCc1ccc(B(O)O)s1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4ccc(CNCCCOC(C)C)s4)cc23)CC1
Yield: 9 %

Procedure:
Following the general procedure of 5-(5-{[(2-ethylbutyl)amino]methyl}-2-thienyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide, (5-formyl-2-thienyl)boronic acid (50 mg, 0.32 mmol), {3-[(1-methylethyl)oxy]propyl}amine (38 mg, 0.32 mmol), and NaCNBH3 (40 mg, 0.64 mmol) were reacted to give 30 mg of crude {5-[({3-[(1-methylethyl)oxy]propyl}amino)methyl]-2-thienyl}boronic acid. The crude {5-[({3-[(1-methylethyl)oxy]propyl}amino)methyl]-2-thienyl}boronic acid was then reacted with 5-bromo-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide (65 mg, 0.157 mmol), K2CO3 (130 mg, 0.942 mmol), and tetrakis(triphenylphosphine)palladium(0) (9 mg, 0.0079 mmol). After purification on an Agilent MDAP twice as shown in preparation of 5-(5-{[(2-ethylbutyl)amino]methyl}-2-thienyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide, the impure title compound was washed with a 20:4:1 mixture of hexanes/EtOAc/MeOH (2.5 mL) to give 7.6 mg of the title compound (9%).
Reaction SMILES: [CH2:1]([OH:4])[CH:2]=[CH2:3].[H-].[Na+].Cl[C:8]1[C:12]([C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)=[N:11][S:10][N:9]=1.O>O1CCCC1>[CH2:1]([O:4][C:8]1[C:12]([C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)=[N:11][S:10][N:9]=1)[CH:2]=[CH2:3]
Reactant: C=CCO
Reactant: Clc1nsnc1-c1cccnc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: C=CCOc1nsnc1-c1cccnc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of allyl alcohol (650 mg, 9 mmol) and sodium hydride (310 mg,9 mmol) in dry tetrahydrofuran was added a solution of 3-(3-chloro-1,2,5-thiadiazol-4-yl)pyridine (590 mg, 3 mmol) in dry tetrahydrofuran. The reaction mixture was stirred at room temperature for 1 h. Water was added and the mixture was extracted with ether. The ether phase was dried and evaporated to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5](Cl)=[O:6].[N+:11]([C:14]1[CH:15]=[C:16]([CH:18]=[C:19]([O:21][C:22]2[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=2)[CH:20]=1)[NH2:17])([O-:13])=[O:12].O>CN(C)C1C=CN=CC=1.C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([NH:17][C:16]1[CH:18]=[C:19]([O:21][C:22]2[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=2)[CH:20]=[C:14]([N+:11]([O-:13])=[O:12])[CH:15]=1)=[O:6]
Reactant: Nc1cc(Oc2cccnc2)cc([N+](=O)[O-])c1
Reactant: O=C(Cl)c1cccc(Cl)c1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: O
Product: O=C(Nc1cc(Oc2cccnc2)cc([N+](=O)[O-])c1)c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 88.1 %

Procedure:
3-Chlorobenzoyl chloride (79 mg, 0.45 mmol, 1.05 eq), 4-dimethylaminopyridine (55 mg, 0.45 mmol, 1.05 eq) and 3-nitro-5-(pyridin-3-yloxy)aniline (0.1 g, 0.43 mmol, 1 eq) were dissolved in CH2Cl2 (5 mL) and stirred at rt for 18 h. Water was added and the organic layer separated, dried (MgSO4), filtered, and concentrated in vacuo to afford 140 mg (88%) of the title compound as a yellow solid: 1H NMR (400 MHz, DMSO-d6) δ 10.78 (s, 1H), 8.58 (t, J=1.9 Hz, 1H), 8.53 (d, J=2.8 Hz, 1H), 8.50 (dd, J=4.6, 1.0 Hz, 1H), 8.01 (t, J=1.8 Hz, 1H), 7.91-7.87 (m, 2H), 7.70-7.65 (m, 2H), 7.60-7.56 (m, 2H), 7.53 (dd, J=8.4, 4.7 Hz, 1H); ES-MS [M+1]+: 370.1.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([O:13][C:14]2[CH:35]=[CH:34][C:17]([O:18][CH2:19][C:20]3[N:24]([CH2:25][CH2:26][OH:27])[C:23]4[CH:28]=[CH:29][C:30]([C:32]#[N:33])=[CH:31][C:22]=4[N:21]=3)=[CH:16][CH:15]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].CI.[C:40](O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCCC1>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([O:13][C:14]2[CH:35]=[CH:34][C:17]([O:18][CH2:19][C:20]3[N:24]([CH2:25][CH2:26][O:27][CH3:40])[C:23]4[CH:28]=[CH:29][C:30]([C:32]#[N:33])=[CH:31][C:22]=4[N:21]=3)=[CH:16][CH:15]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(OCc3nc4cc(C#N)ccc4n3CCO)cc2)C1
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: C1CCOC1
Product: COCCn1c(COc2ccc(OC3CCN(C(=O)OC(C)(C)C)C3)cc2)nc2cc(C#N)ccc21
Reaction time: 0.5 h

Procedure:
To a solution of 2-[4-(1-tert-butoxycarbonylpyrrolidin-3-yloxy)-phenoxymethyl]-5-cyano-1-(2-hydroxyethyl)benzimidazole (270 mg) in tetrahydrofuran (5 ml) was added 60% sodium hydride (271 mg) at room temperature, and the mixture was stirred for 30 min. Thereto was added methyl iodide (0.105 ml), and the mixture was stirred for 24 hours. After completion of the reaction, 10% aqueous citric acid solution was added and the mixture was extracted with ethyl acetate and washed with saturated brine. The organic layer was dried over anhydrous magnesium sulfate and the solvent was evaporated. The obtained residue was purified by silica gel column chromatography (hexane:acetone=4:1) and dried under reduced pressure to give the title compound (199 mg).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][CH2:8][N:9]2[CH2:23][CH2:22][N:12]3[C:13]4[C:18]([NH:19][C:20](=[O:21])[CH:11]3[CH2:10]2)=[CH:17][CH:16]=[CH:15][CH:14]=4)=[CH:3][CH:2]=1.O.Cl.[H][H]>O=[Pt]=O.C(O)C>[NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][CH2:8][N:9]2[CH2:23][CH2:22][N:12]3[C:13]4[C:18]([NH:19][C:20](=[O:21])[CH:11]3[CH2:10]2)=[CH:17][CH:16]=[CH:15][CH:14]=4)[CH2:3][CH2:2]1
Reactant: O=C1Nc2ccccc2N2CCN(CCc3ccncc3)CC12
Reactant: [H][H]
Agent: O=[Pt]=O
Agent: Cl
Solvent: CCO
Solvent: O
Product: O=C1Nc2ccccc2N2CCN(CCC3CCNCC3)CC12

Procedure:
A solution of 2,3,4,4a-tetrahydro-3-[2-(4-pyridinyl)ethyl]-1H-pyrazino[1,2-a]quinoxalin-5(6H)-one in 120 ml. water and 60 ml. ethanol containing 13 ml. conc. hydrochloric acid was placed in a Parr hydrogenation apparatus, with 1.2 g. PtO2, under 45 psi. of hydrogen and shaken till pressure drop ceased. After filtering off catalyst the solvents were removed under vacuum and the residue crystallized from hot ethanol. Product filtered off, washed (ethanol), and dried. Dissolved in hot methanol which was displaced by ethanol by boiling off lower boiling solvent. Yield: 4.0 g. of the title compound as the dihydrochloride salt, m.p. 238°-240° C.