Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(C)C=CC=CC=1.[CH3:8][N:9]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16](C(O)=O)[CH:17]=2)[CH2:12][CH2:11][C:10]1=[O:22].C1(P([N:37]=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.C(O)(C)(C)C>C(N(CC)CC)C>[NH2:37][C:16]1[CH:17]=[C:18]2[C:13]([CH2:12][CH2:11][C:10](=[O:22])[N:9]2[CH3:8])=[CH:14][CH:15]=1
Reactant: CN1C(=O)CCc2ccc(C(=O)O)cc21
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CC(C)(C)O
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CN1C(=O)CCc2ccc(N)cc21
Reaction time: 14 h
Yield: 46.6 %

Procedure:
Into 10 ml of toluene was suspended 200 mg of 1-methyl-2-oxo-1,2,3,4-tetrahydroquinoline-7-carboxylic acid, and then 268 mg of diphenylphosphoryl azide (DPPA), 722 mg of tert-butyl alcohol, and 0.135 ml of triethylamine were added thereto, followed by 14 hours of stirring under reflux with heating. After cooling, the reaction solution was concentrated under reduced pressure, water was added to the residue, and the organic layer was extracted with ethyl acetate. After the organic layer was dried over anhydrous sodium sulfate, the solvent was removed by evaporation. To the residue was added 5 ml of a 4M ethyl acetate solution of hydrochloric acid, followed by 7 hours of stirring at room temperature. Then, the reaction solution was concentrated under reduced pressure. To the residue was added a saturated aqueous sodium hydrogen carbonate, and the organic layer was extracted with chloroform. After the organic layer was dried over anhydrous sodium sulfate, the solvent was removed by evaporation. The obtained residue was purified by silica gel column chromatography (chloroform:methanol:aqueous ammonia) to obtain 80 mg of 7-amino-1-methyl-3,4-dihydroquinolin-2(1H)-one as a white solid.
Reaction SMILES: [F:1][C@@H:2]1[C@@H:7]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([F:16])[CH:9]=2)[CH2:6][CH2:5][N:4](C(OC(C)(C)C)=O)[CH2:3]1.[ClH:24]>O1CCOCC1>[ClH:24].[F:1][C@@H:2]1[C@@H:7]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([F:16])[CH:9]=2)[CH2:6][CH2:5][NH:4][CH2:3]1
Reactant: COc1ccc([C@H]2CCN(C(=O)OC(C)(C)C)C[C@@H]2F)cc1F
Agent: Cl
Solvent: C1COCCO1
Product: COc1ccc([C@H]2CCNC[C@@H]2F)cc1F
Temperature: 25 °C

Procedure:
To a stirring solution of (3R,4R)-tert-butyl 3-fluoro-4-(3-fluoro-4-methoxyphenyl)piperidine-1-carboxylate (38 mg, 0.12 mmol, E-2, the second eluting enantiomer from step F) in 3 mL of 1,4-dioxane at 0° C. was added 2 mL of 4M HCl in 1,4-dioxane (8 mmol) and the mixture was allowed to warm up to rt over 12 h. The solvent was removed under reduced pressure to to obtain (3R,4R)-3-Fluoro-4-(3-fluoro-4-methoxyphenyl)piperidine hydrochloride (30 mg) as a semi-solid which was used without further purification. LCMS (Method K) RT=0.59 min, m/z 228, m/z 419 (M+H+); 1H NMR (400 MHz, methanol-d4) δ ppm 6.99-7.22 (m, 3H) 4.73-4.84 (m, 1H) 3.89 (s, 3H) 3.67-3.78 (m, 2H) 3.41-3.52 (m, 1H) 3.00-3.25 (m, 3H) 2.09-2.26 (m, 1H) 1.88-2.08 (m, 1H).
Reaction SMILES: [CH2:1]([C:3]1[C:8]([CH3:9])=[CH:7][N+:6]([O-])=[C:5]([CH3:11])[C:4]=1[CH3:12])[CH3:2].[C:13]([O:16]C(=O)C)(=[O:15])[CH3:14]>>[C:13]([O:16][CH2:11][C:5]1[C:4]([CH3:12])=[C:3]([CH2:1][CH3:2])[C:8]([CH3:9])=[CH:7][N:6]=1)(=[O:15])[CH3:14]
Reactant: CCc1c(C)c[n+]([O-])c(C)c1C
Reactant: CC(=O)OC(C)=O
Product: CCc1c(C)cnc(COC(C)=O)c1C
Temperature: 25 °C
Yield: 76 %

Procedure:
A mixture composed of the above 4-ethyl-2,3,5-trimethylpyridine 1-oxide (3.84 g) and acetic anhydride (50 mL) was heated under reflux for 30 minutes. After leaving to cool to room temperature, the reaction solution was concentrated under reduced pressure. The residue was dissolved in chloroform and then washed with a saturated sodium bicarbonate solution. The organic layer was dried over anhydrous magnesium sulfate, and then the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate-hexane) to obtain the title compound (3.64 g, 76%) as an oil.
Reaction SMILES: Cl[C:2]1[N:3]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:4]2[C:9]([C:10]=1[CH:11]=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=2.[C:19]([O:23][C:24]([N:26]1[CH2:32][CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)=[O:25])([CH3:22])([CH3:21])[CH3:20]>>[C:19]([O:23][C:24]([N:26]1[CH2:32][CH2:31][CH2:30][N:29]([C:2]2[N:3]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:4]3[C:9]([C:10]=2[CH:11]=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=3)[CH2:28][CH2:27]1)=[O:25])([CH3:22])([CH3:20])[CH3:21]
Reactant: O=Cc1c(Cl)n(-c2ccccc2)c2ccccc12
Reactant: CC(C)(C)OC(=O)N1CCCNCC1
Product: CC(C)(C)OC(=O)N1CCCN(c2c(C=O)c3ccccc3n2-c2ccccc2)CC1
Yield: 87 %

Procedure:
2-Chloro-1-phenyl-1H-indole-3-carboxaldehyde is reacted with [1,4]diazepane-1-carboxylic acid tert-butyl ester as described in Example 1 to afford 4-(3-formyl-1-phenyl-1H-indole-2-yl)-[1,4]diazepane-1-carboxylic acid tert-butyl ester (87% yield) as a yellow solid. LC/MS MS 420 (M+H); RT 3.55 min; NMR (CDCl3): 10.25 (1H, s), 8.27 (1 H, d), 7.46-7.66 (3H, m), 7.37 (2H, d), 7.22-7.30 (1H, t), 7.16(1 H, t), 6.96 (1 H, d), 3.25-3.45 (8H, m), 1.56 (2H, m), 1.44(9H, s).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]([OH:12])[CH:9]=[C:8]2[C:3]=1[C:4]([CH2:14][CH2:15][CH3:16])=[CH:5][C:6](=[O:13])[O:7]2.[Cl-].[Al+3].[Cl-].[Cl-].[N+](C1C=CC=CC=1)([O-])=O.[C:30](Cl)(=[O:33])[CH2:31][CH3:32]>C(=S)=S.C(OCC)(=O)C.CCCCCC>[OH:1][C:2]1[CH:11]=[C:10]([OH:12])[C:9]([C:30](=[O:33])[CH2:31][CH3:32])=[C:8]2[C:3]=1[C:4]([CH2:14][CH2:15][CH3:16])=[CH:5][C:6](=[O:13])[O:7]2
Reactant: CCC(=O)Cl
Reactant: CCCc1cc(=O)oc2cc(O)cc(O)c12
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=[N+]([O-])c1ccccc1
Solvent: CCCCCC
Solvent: S=C=S
Product: CCCc1cc(=O)oc2c(C(=O)CC)c(O)cc(O)c12
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A three-neck flask (500 mL) equipped with an efficient methanical stirrer, thermometer and addition funnel was charged with 5,7-dihydroxy-4-propylcoumarin, 2, (25.0 g, 0.113 mol), aluminum chloride (62.1 g; 0.466 mol), and nitrobenzene (150 mL) and the mixture was stirred until a solution was obtained, which was cooled to 0° C. in an ice bath. A solution of propionyl chloride (15.2 g; 0.165 mol) in carbon disulfide (50 mL) was added dropwise at such a rate that the reaction temperature was maintained at 8°-10° C. Addition was completed over a period of 1 hour with vigorous stirring. The reaction was monitored by TLC using a mobile phase of 50% ethyl acetate/hexane. After three hours, an additional portion of propionyl chloride (2.10 g; 0.0227 mol) in carbon disulfide (10 mL) was added. Immediately after the TLC analysis indicated the total consumption of starting material, the reaction mixture was poured onto ice, and allowed to stand overnight. The nitrobenzene was removed by steam distillation, and the remaining solution was extracted several times with ethyl acetate. The extracts were combined and dried over Na2SO4. The crude product obtained by evaporation in vacuo was purified by chromatography on a silica gel column eluting with 50% ether/hexane to provide the desired propionylated coumarin 3, mp (corr) 244°-246° C. 1H-NMR (DMSO-d6) δ 0.96 (3H, t, J=7.3 Hz, CH3); 1.10 (3H, t, J=7.2 Hz, CH3); 1.60 (2H, m, CH2); 2.88 (2H, t, J=7.7 Hz, CH2); 3.04 (2H, q, J=7.2 Hz, CH2); 5.95 (1H, s, H3); 6.31 (1H, s, H6); 11.07 (1H, s, OH); 11.50 (1H, s, OH); MS (EI): 277 (6.6, M+1); 276 (9.0, M+); 247 (100, M--C2H5); IR (KBr): 3239 (s and broad, OH); 1693 (s, C=O), 1625 and 1593 (s) cm-1 ; Anal. calcd. for C15H16O5 : C, 65.21; H, 5.84; Found: c, 64.92; H, 5.83. The isomer assignment was made by analogy to precedent.15
Reaction SMILES: [CH:1]([N:4]1[C:8]([CH:9]2[C:18](=O)[C:17]3[C:16]([C:20]([O:22]CC)=O)=[CH:15][CH:14]=[CH:13][C:12]=3[NH:11][CH:10]2[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:7][N:6]=[CH:5]1)([CH3:3])[CH3:2].O.[NH2:32][NH2:33]>CO>[CH:1]([N:4]1[C:8]([CH:9]2[C:18]3=[N:32][NH:33][C:20](=[O:22])[C:16]4[CH:15]=[CH:14][CH:13]=[C:12]([C:17]=43)[NH:11][CH:10]2[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:7][N:6]=[CH:5]1)([CH3:2])[CH3:3]
Reactant: NN
Reactant: CCOC(=O)c1cccc2c1C(=O)C(c1cncn1C(C)C)C(c1ccccc1)N2
Solvent: CO
Solvent: O
Product: CC(C)n1cncc1C1c2n[nH]c(=O)c3cccc(c23)NC1c1ccccc1
Temperature: 50 °C
Reaction time: 8 h
Yield: 13 %

Procedure:
A suspension of ethyl 3-(1-isopropyl-1H-imidazol-5-yl)-4-oxo-2-phenyl-1,2,3,4-tetrahydroquinoline-5-carboxylate (770 mg, 1.9 mmol) and hydrazine monohydrate (6 ml, 85%) were added in methanol (10 mL) and stirred at 50° C. overnight. The mixture was filtered, and the white solid was washed with methanol and dried to give 9-(1-isopropyl-1H-imidazol-5-yl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one (90 mg, yield 13%). 1H-NMR (400 MHz, DMSO-d6) δ (ppm): 0.82-0.84 (d, J=6.8 Hz, 3H), 1.27-1.29 (d, J=6.4 Hz, 3H), 3.30-3.33 (t, J=6.6 Hz, 1H), 4.67-4.70 (d, J=11.2 Hz, 1H), 4.92-4.95 (d, J=11.2 Hz, 1H), 6.80 (s, 1H), 7.01 (s, 1H), 7.16-7.18 (s, 1H), 7.24-7.28 (m, 3H), 7.31 (s, 1H), 7.36-7.39 (m, 3H), 7.55-7.59 (m, 1H); LC-MS (ESI) m/z: 372 (M+1)+.
Reaction SMILES: [CH3:1][N:2]([CH3:24])[C:3](=[O:23])[C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:14]=[CH:13][N:12]=[C:11]2[C:15]2[CH:19]=[CH:18][S:17][CH:16]=2)=[C:6]([N+:20]([O-])=O)[CH:5]=1.C(O)(=O)C.[O-]S([O-])(=S)=O.[Na+].[Na+].N>O1CCCC1.C(OCC)(=O)C.O>[NH2:20][C:6]1[CH:5]=[C:4]([CH:9]=[CH:8][C:7]=1[N:10]1[CH:14]=[CH:13][N:12]=[C:11]1[C:15]1[CH:19]=[CH:18][S:17][CH:16]=1)[C:3]([N:2]([CH3:24])[CH3:1])=[O:23]
Reactant: CN(C)C(=O)c1ccc(-n2ccnc2-c2ccsc2)c([N+](=O)[O-])c1
Agent: N
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CN(C)C(=O)c1ccc(-n2ccnc2-c2ccsc2)c(N)c1
Reaction time: 3.3 h

Procedure:
To 1.60 g of N,N-dimethyl-3-nitro-4-[2-(3-thienyl)-1H-imidazol-1-yl]benzamide, 5.8 mL of acetic acid and 5.8 mL of water were added, and dissolved under heating. To the solution 3.25 g of 85% sodium hyposulfite was added little by little, followed by 3.3 hours' heating under reflux. The reaction liquid was cooled with ice, to which ethyl acetate was added, and then 25% aqueous ammonia was added little by little to render the same weakly alkaline. Tetrahydrofuran was added and whereby separated organic layer was recovered, which was washed with brine and dried over magnesium sulfate. Distilling the solvent off, 769 mg of the title compound was obtained.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12](C(F)(F)F)[C:11](C)=[CH:10][C:9]=1[NH:19][C:20](=[O:36])[CH2:21][C:22](=O)[C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([C:29]2[CH:34]=[N:33][CH:32]=[CH:31][N:30]=2)[CH:24]=1)(C)(C)C.[C:38](O)([C:40]([F:43])([F:42])[F:41])=O>C(Cl)Cl>[CH3:12][C:11]1[C:38]([C:40]([F:43])([F:42])[F:41])=[CH:13][C:8]2[N:7]=[C:22]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]4[CH:34]=[N:33][CH:32]=[CH:31][N:30]=4)[CH:24]=3)[CH2:21][C:20](=[O:36])[NH:19][C:9]=2[CH:10]=1
Reactant: O=C(O)C(F)(F)F
Reactant: Cc1cc(NC(=O)CC(=O)c2cccc(-c3cnccn3)c2)c(NC(=O)OC(C)(C)C)cc1C(F)(F)F
Solvent: ClCCl
Product: Cc1cc2c(cc1C(F)(F)F)N=C(c1cccc(-c3cnccn3)c1)CC(=O)N2

Procedure:
The title compound was prepared from {4-methyl-2-[3-oxo-3-(3-pyrazin-2-yl-phenyl)-propionylamino]-5-trifluoromethyl-phenyl}-carbamic acid tert-butyl ester (Example M85) (0.28 g, 0.54 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light yellow solid (146 mg, 68%).
Reaction SMILES: [OH:1][C:2]1[CH:15]=[CH:14][C:13]2[C:12](=[O:16])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5](=[O:17])[C:4]=2[CH:3]=1.[C:18](Cl)(=[O:22])[C:19]([CH3:21])=[CH2:20]>N1C=CC=CC=1>[C:18]([O:1][C:2]1[CH:15]=[CH:14][C:13]2[C:12](=[O:16])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5](=[O:17])[C:4]=2[CH:3]=1)(=[O:22])[C:19]([CH3:21])=[CH2:20]
Reactant: C=C(C)C(=O)Cl
Reactant: O=C1c2ccccc2C(=O)c2cc(O)ccc21
Solvent: c1ccncc1
Product: C=C(C)C(=O)Oc1ccc2c(c1)C(=O)c1ccccc1C2=O
Temperature: 25 °C
Reaction time: 20 h
Yield: 58 %

Procedure:
0.2 mol of 2-hydroxyanthraquinone is dissolved in 600 ml of pyridine under an inert gas in a 1,000 ml brown glass flask with a dropping funnel and thermometer. 0.24 mol of methacryloyl chloride is then added dropwise in the course of 15 minutes, with ice-cooling. After the mixture has been stirred at room temperature for 20 hours, the pyridine is removed on a rotary evaporator. The crude crystalline product is suspended in 500 ml of 0.1 N HCl, the suspension is filtered, the solid is taken up in water again and, after washing with sodium bicarbonate solution and water, the crude product is dried in vacuo. Yield of crude product: 90% of theory. Recrystallisation of the crude product from ethylene glycol monomethyl ether gives a 58% yield of 2-anthraquinonyl methacrylate as a yellow crystalline product; melting point: 184-186° C. ε254 =50200, ε325 =5200 in ethanol.
Reaction SMILES: C([Li])CCC.[F:6][C:7]([F:22])([F:21])[C:8]1[CH:20]=[CH:19][CH:18]=[CH:17][C:9]=1[O:10]C1CCCCO1.CN(C)CCN(C)C.CN(C)[CH:33]=[O:34]>C(OCC)C.O>[OH:10][C:9]1[C:8]([C:7]([F:6])([F:21])[F:22])=[CH:20][CH:19]=[CH:18][C:17]=1[CH:33]=[O:34]
Reactant: FC(F)(F)c1ccccc1OC1CCCCO1
Reactant: CN(C)C=O
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: O
Product: O=Cc1cccc(C(F)(F)F)c1O
Temperature: -20 °C
Reaction time: 0.5 h
Yield: 192.1 %

Procedure:
A n-butyl lithium-1.58M n-hexane solution (65.9 ml, 104 mmol) was added dropwise to a solution of 2-[2-(trifluoromethyl)phenoxy]tetrahydro-2H-pyrane (21.4 g, 86.8 mmol) which was synthesized according to the method described in literature (Miller, J. A. et al., J. Org. Chem. 1993, vol. 58, pp. 2637-2639) and N,N,N′,N′-tetramethylethylenediamine (15.7 ml, 104 mmol) in diethyl ether (230 ml) at −20° C. over 10 minutes. After the reaction mixture was stirred at −20° C. for 30 minutes, it was further stirred at room temperature for 40 minutes. After the reaction mixture was cooled to −30° C. and N,N-dimethylformamide (13.5 ml, 174 mmol) was added thereto, the mixture was further stirred at room temperature for 1 hour. After the reaction mixture was carefully poured into cooled water and the mixture was extracted with ethyl acetate (three times), the organic layer was successively washed with 1N hydrochloric acid, a 5% aqueous sodium hydrogencarbonate solution, water (twice) and a saturated aqueous NaCl solution and dried with anhydrous sodium sulfate. The residue obtained by removing the solvent under reduced pressure was purified by silica gel column chromatography (eluting solvent: n-hexane/ethyl acetate=20/1-10/1). The obtained 2-(tetrahydro-2H-pyran-2-yloxy)-3-(trifluoromethyl)benzaldehyde as a pale yellow oil was left to stand at room temperature overnight to give 2-hydroxy-3-(trifluoromethyl)benzaldehyde as a pale yellow solid (31.7 g, yield: 96%).
Reaction SMILES: Cl.[CH2:2]1[C:7]2([CH2:12][CH2:11][CH:10]([CH2:13][C:14]([O:16][CH3:17])=[O:15])[CH2:9][CH2:8]2)[CH2:6][CH2:5][NH:4][CH2:3]1.CCN(C(C)C)C(C)C.Cl[C:28]([O:30][CH:31]1[CH:38]2[CH2:39][CH:34]3[CH2:35][CH:36]([CH2:40][CH:32]1[CH2:33]3)[CH2:37]2)=[O:29].Cl>C(Cl)Cl>[CH3:17][O:16][C:14](=[O:15])[CH2:13][CH:10]1[CH2:11][CH2:12][C:7]2([CH2:2][CH2:3][N:4]([C:28]([O:30][CH:31]3[CH:32]4[CH2:40][CH:36]5[CH2:35][CH:34]([CH2:39][CH:38]3[CH2:37]5)[CH2:33]4)=[O:29])[CH2:5][CH2:6]2)[CH2:8][CH2:9]1
Reactant: O=C(Cl)OC1C2CC3CC(C2)CC1C3
Reactant: COC(=O)CC1CCC2(CCNCC2)CC1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)CC1CCC2(CC1)CCN(C(=O)OC1C3CC4CC(C3)CC1C4)CC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.3 %

Procedure:
A vial was charged with methyl 2-(3-azaspiro[5.5]undecan-9-yl)acetate HCl salt (31 mg, 0.12 mmol) and DIEA (45 μL, 0.25 mmol). A solution of 2-adamantyl chloroformate (25 mg, 0.12 mmol) in CH2Cl2 (2 mL) was added and the mixture was stirred overnight at rt. A 10-mL Chem-Elut cartridge was wetted with 5% aq HCl (6 mL) and allowed to stand for 5 min. The reaction mixture was applied to the cartridge and eluted with ether (20 mL). The eluate was evaporated to dryness and the residue was purified by preparative HPLC to afford (2-adamantyl) 9-(2-methoxy-2-oxoethyl)-3-azaspiro[5.5]undecane-3-carboxylate (35 mg, 74%). LC-MS Method 1 tR=2.52 min, m/z=404; 1H NMR (CDCl3) δ=1.05-2.10 (27H), 2.23 (d, 2H), 3.41 (m, 4H), 3.69 (s, 3H), 4.82 (s, 1H).
Reaction SMILES: [C:1](Cl)(=O)C.[CH3:5][C:6]1[C:7]2[CH:17]=[CH:16][CH:15]=[CH:14][C:8]=2[O:9][C:10]=1[C:11]([OH:13])=[O:12]>CO>[CH3:1][O:12][C:11]([C:10]1[O:9][C:8]2[CH:14]=[CH:15][CH:16]=[CH:17][C:7]=2[C:6]=1[CH3:5])=[O:13]
Reactant: CC(=O)Cl
Reactant: Cc1c(C(=O)O)oc2ccccc12
Solvent: CO
Product: COC(=O)c1oc2ccccc2c1C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Acetylchloride (6.7 mL, 91 mmol) was added dropwise to 750 mL dry methanol cooled on an ice-bath under N2 atmosphere. After completion of the addition, the solution was stirred at RT for 30 min. Subsequently, 16.0 g (90 mmol) 3-methyl benzo[b]furan-2-carboxylic acid was added and the solution was refluxed for 17 h under N2 atmosphere. The solution was cooled on an ice-bath to 0° C. and 500 mL ice-cold water was added. The resulting white precipitate was collected by filtration and washed with cold methanol. Yield: 16.1 g (94%) of a white solid. 1H-NMR (200 MHz, CDCl3): δ 7.72 (d, J=8 Hz, 1H), 7.60 (t, J=8 Hz, 1H), 7.53 (t, J=8 Hz, 1H), 7.41 (d, J=8 Hz, 1H), 4.08 (s, 3H), 2.73 (s, 3H) ppm.
Reaction SMILES: CI.[Cl:3][C:4]1[CH:5]=[C:6]2[C:12]([C:13]3[N:18]=[C:17]([NH:19][CH:20]4[CH2:25][CH2:24][CH2:23][CH:22]([OH:26])[CH2:21]4)[C:16]([F:27])=[CH:15][N:14]=3)=[CH:11][N:10]([S:28]([C:31]3[CH:36]=[CH:35][C:34]([CH3:37])=[CH:33][CH:32]=3)(=[O:30])=[O:29])[C:7]2=[N:8][CH:9]=1.Cl[C:39]1C=C2C(C3N=C(NC4CCC[C@H](O)C4)C(F)=CN=3)=CN(S(C3C=CC(C)=CC=3)(=O)=O)C2=NC=1.S([O-])([O-])(=O)=O.[Ca+2]>[Ag]=O>[Cl:3][C:4]1[CH:5]=[C:6]2[C:12]([C:13]3[N:18]=[C:17]([NH:19][C@H:20]4[CH2:25][CH2:24][CH2:23][CH:22]([O:26][CH3:39])[CH2:21]4)[C:16]([F:27])=[CH:15][N:14]=3)=[CH:11][N:10]([S:28]([C:31]3[CH:32]=[CH:33][C:34]([CH3:37])=[CH:35][CH:36]=3)(=[O:30])=[O:29])[C:7]2=[N:8][CH:9]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3ncc(F)c(NC4CCCC(O)C4)n3)c3cc(Cl)cnc32)cc1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3ncc(F)c(NC4CCC[C@H](O)C4)n3)c3cc(Cl)cnc32)cc1
Agent: O=[Ag]
Agent: O=S(=O)([O-])[O-]
Agent: [Ca+2]
Solvent: CI
Product: COC1CCC[C@H](Nc2nc(-c3cn(S(=O)(=O)c4ccc(C)cc4)c4ncc(Cl)cc34)ncc2F)C1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a suspension of methyl iodide (0.20 g, 0.41 mmol) and 3-[[2-[5-chloro-1-(p-tolylsulfonyl)pyrrolo[2,3-b]pyridin-3-yl]-5-fluoro-pyrimidin-4-yl]amino]-cyclohexanol, 27a, (0.47 g, 2.04 mmol) was added silver oxide (0.578 g, 4.07 mmol and calcium sulfate (0.28 g, 2.04 (mmol). The reaction mixture was stirred at room temperature for 18 h. The mixture was filtered through celite and the resulting filtrate was concentrated in vacuo. The resulting crude mixture was purified by silica gel chromatography to afford 120 mg of the desired product, 27b.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([C:12]#[N:13])[N:3]=1.[NH:14]1[CH2:18][CH2:17][CH:16]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[CH2:15]1.CCN(CC)CC>CN1C(=O)CCC1>[C:12]([C:4]1[N:3]=[C:2]([N:14]2[CH2:18][CH2:17][CH:16]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:24])([CH3:23])[CH3:25])[CH2:15]2)[C:11]2[C:6]([CH:5]=1)=[CH:7][CH:8]=[CH:9][CH:10]=2)#[N:13]
Reactant: N#Cc1cc2ccccc2c(Cl)n1
Reactant: CC(C)(C)OC(=O)NC1CCNC1
Solvent: CN1CCCC1=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NC1CCN(c2nc(C#N)cc3ccccc23)C1
Temperature: 160 °C

Procedure:
A mixture of 1-chloroisoquinoline-3-carbonitrile (438 mg, 2.322 mmol), tert-butyl pyrrolidin-3-ylcarbamate (519 mg, 2.79 mmol) and Et3N (0.653 mL, 4.64 mmol) in NMP (3 mL) was heated at 160° C. for 30 minutes in a microwave reactor. The crude reaction mixture, which contained the title compound, was used directly in the next step.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([CH2:11][N:12]3[C:16]4=[N:17][C:18]([C:21]5[CH:29]=[CH:28][C:24]([C:25](O)=[O:26])=[CH:23][CH:22]=5)=[CH:19][CH:20]=[C:15]4[N:14]=[N:13]3)=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.CN(C=O)C.CCN=C=NCCCN(C)C.Cl.C(N(CC)CC)C.[NH2:54][CH:55]1[CH2:60][CH2:59][O:58][CH2:57][CH2:56]1>O>[N:1]1[C:10]2[C:5](=[CH:6][C:7]([CH2:11][N:12]3[C:16]4=[N:17][C:18]([C:21]5[CH:22]=[CH:23][C:24]([C:25]([NH:54][CH:55]6[CH2:60][CH2:59][O:58][CH2:57][CH2:56]6)=[O:26])=[CH:28][CH:29]=5)=[CH:19][CH:20]=[C:15]4[N:14]=[N:13]3)=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: NC1CCOCC1
Reactant: O=C(O)c1ccc(-c2ccc3nnn(Cc4ccc5ncccc5c4)c3n2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: O=C(NC1CCOCC1)c1ccc(-c2ccc3nnn(Cc4ccc5ncccc5c4)c3n2)cc1
Reaction time: 0.08 h
Yield: 20.5 %

Procedure:
To a solution of example 8 (0.200 g, 0.524 mmol) in DMF (1 ml) HOBT (0.084 g, 0.629 mmol), EDC-HCl (0.250 g, 1.31 mmol) and triethylamine (0.2 ml, 1.57 mmol) were added and stirred for 5 min. 4-Aminotetrahydropyran (0.106 g, 1.04 mmol) was added at RT and the reaction mixture was stirred for 12 h. To the reaction mixture water was added and extracted with ethyl acetate, dried over sodium sulphate and concentrated under reduced pressure. The crude product was purified by column chromatography with methanol:dichloromethane to afford the title compound as an off-white solid (0.050 g, 20%). M.P.: 202-205° C. 1H-NMR (δ ppm, DMSO-d6, 400 MHz): 8.88 (dd, J=4.1, 1.6 Hz, 1H), 8.69 (d, J=8.8 Hz, 1H), 8.44 (d, J=7.5 Hz, 1H), 8.38 (d, J=7.7 Hz, 1H), 8.33 (d, J=8.5 Hz, 2H), 8.20 (d, J=8.8 Hz, 1H), 8.03-7.99 (m, 4H), 7.85 (dd, J=8.7, 1.9 Hz, 1H), 7.53 (dd, J=8.3, 4.2 Hz, 1H), 6.22 (s, 2H), 4.04 (m, 1H), 3.89 (d, J=9.7 Hz, 2H), 3.39 (t, J=10.0 Hz, 2H), 1.78 (d, J=10.5 Hz, 2H), 1.63 (m, 2H).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([O:20]C)=[O:19])=[CH:14][CH:13]=2)=[CH:8][CH:7]=1.[OH-].[Li+]>C1COCC1.O>[Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([OH:20])=[O:19])=[CH:14][CH:13]=2)=[CH:10][CH:11]=1
Reactant: COC(=O)c1ccc(-c2ccc(OCCCCl)cc2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1ccc(-c2ccc(OCCCCl)cc2)cc1
Yield: 82.3 %

Procedure:
The product from Example 10B (3.4 g, 11.2 mmol) and lithium hydroxide (1.2 g, 28.6 mmol) in THF:water (3:1, 52 mL) were stirred vigorously at ambient temperature for 24 hours. The volume of the mixture was reduced under reduced pressure and then extracted with hexanes (2×25 mL). The remaining aqueous phase was acidified to pH 2 and then extracted with ethyl acetate (3×50 mL). The ethyl acetate extract was evaporated under reduced pressure to provide the title compound as a solid (2.68 g).
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6]2[CH:8]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[S:10][C:5]=2[C:4](=[O:17])[N:3]1[CH:18]1[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]1.Cl[CH2:32][C:33]1[O:37][N:36]=[C:35]([CH2:38][CH3:39])[CH:34]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:38]([C:35]1[CH:34]=[C:33]([CH2:32][N:7]2[C:6]3[CH:8]=[C:9]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)[S:10][C:5]=3[C:4](=[O:17])[N:3]([CH:18]3[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]3)[C:2]2=[O:1])[O:37][N:36]=1)[CH3:39]
Reactant: CCc1cc(CCl)on1
Reactant: CC(C)(C)OC(=O)N1CCC(n2c(=O)[nH]c3cc(-c4ccccc4)sc3c2=O)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCc1cc(Cn2c(=O)n(C3CCN(C(=O)OC(C)(C)C)CC3)c(=O)c3sc(-c4ccccc4)cc32)on1

Procedure:
According to GP1 tert-butyl 4-(2,4-dioxo-6-phenyl-1,4-dihydrothieno[3,2-d]pyrimidin-3(2H)-yl)piperidine-1-carboxylate (750 mg; compound B50) is reacted with 5-(chloromethyl)-3-ethylisoxazole (255 mg; compound D3) in the presence of potassium carbonate (242 mg) in DMF (10 ml). Using WU1 the title compound is obtained as a solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([NH2:10])=[N:5][CH:6]=[C:7]([CH3:9])[N:8]=1.[C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[S:19](Cl)(=[O:21])=[O:20])#[N:12]>>[CH3:1][O:2][C:3]1[C:4]([NH:10][S:19]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[C:11]#[N:12])(=[O:21])=[O:20])=[N:5][CH:6]=[C:7]([CH3:9])[N:8]=1
Reactant: N#Cc1ccccc1S(=O)(=O)Cl
Reactant: COc1nc(C)cnc1N
Product: COc1nc(C)cnc1NS(=O)(=O)c1ccccc1C#N

Procedure:
Prepared by method of Example 1 using 3-methoxy-5-methyl-2-pyrazinamine and 2-cyanobenzenesulphonyl chloride.