Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[N:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][CH:7]=[C:6]2[C:13]1[N:14]=[N:15][N:16]([CH2:18][CH2:19][CH2:20][N:21]2C(=O)C3C(=CC=CC=3)C2=O)[CH:17]=1.O.NN.Cl.C(N(CC)CC)C.[O:43]=[C:44]1[NH:49][C:48]2[CH:50]=[C:51]([S:54](Cl)(=[O:56])=[O:55])[CH:52]=[CH:53][C:47]=2[S:46][CH2:45]1>C(O)C.C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[N:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][CH:7]=[C:6]2[C:13]1[N:14]=[N:15][N:16]([CH2:18][CH2:19][CH2:20][NH:21][S:54]([C:51]2[CH:52]=[CH:53][C:47]3[S:46][CH2:45][C:44](=[O:43])[NH:49][C:48]=3[CH:50]=2)(=[O:56])=[O:55])[CH:17]=1
Reactant: COc1ccc2nccc(-c3cn(CCCN4C(=O)c5ccccc5C4=O)nn3)c2n1
Reactant: O=C1CSc2ccc(S(=O)(=O)Cl)cc2N1
Agent: Cl
Agent: NN
Solvent: CCO
Solvent: O
Solvent: CCN(CC)CC
Product: COc1ccc2nccc(-c3cn(CCCNS(=O)(=O)c4ccc5c(c4)NC(=O)CS5)nn3)c2n1
Reaction time: 1 h
Yield: 29.3 %

Procedure:
To a suspension of 2-{3-[4-(6-Methoxy-[1,5]naphthyridin-4-yl)-[1,2,3]triazol-1-yl]-propyl)-isoindole-1,3-dione (180 mg, 0.43 mmole) in ethanol (3 mL) was added hydrazine hydrate (23 μL, 0.48 mmole) and the mixture was brought to reflux for 3 hours. After cooling 0.1 mL of 6N aqueous HCl was added to dissolve the product. The mixture was filtered and the filtrate was concentrated to dryness to afford the crude amine hydrochloride (85 mg). This material was suspended in chloroform (3 mL) and treated with triethylamine (0.18 mL, 1.3 mmole), followed by 3-oxo-3,4-dihydro-2H benzo[1,4]thiazine-6-sulfonyl chloride (100 mg, 0.4 mmole). After stirring 1 hour the mixture was diluted with chloroform, washed with saturated aqueous NaHCO3, dried (MgSO4), and chromatographed on silica (0–5% methanovchloroform) to provide the title compound as an off-white solid (60 mg, 27%). 1H NMR (400 MHz, DMSO-d6): 10.83 (br s, 1 H); 9.05 (s, 1 H); 8.84 (d, 1H); 8.37 (d, 1H); 8.29 (d, 1H); 7.85 (m, 1H); 7.46 (d, 1H); 7.24–7.42 (m, 3H); 4.60 (m, 2H); 4.17 (s, 3H); 3.53 (s, 2H); 2.80 (m, 2H); 2.14 (m, 2H). LC-MS (ES) m/e 512 (M+H)+.
Reaction SMILES: [CH2:1]1[C@@H:6](O)[C@@H:5](O)[C@H:4](O)[CH2:3][C@@:2]1([C:11]([OH:13])=[O:12])O.C(OCC)C>S1(CCCC1)(=O)=O>[C:11]([OH:13])(=[O:12])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:1]=1
Reactant: O=C(O)[C@]1(O)C[C@@H](O)[C@@H](O)[C@H](O)C1
Solvent: CCOCC
Solvent: O=S1(=O)CCCC1
Product: O=C(O)c1ccccc1
Temperature: 210 °C

Procedure:
The reaction is performed using the following set-up and procedure: quinic acid (20 mmol) was first dissolved in sulfolane at room temperature in a 50 ml three neck flask fitted with a fractioning column connected to a collecting flask through a U-shaped tube. The temperature in the reaction mixture is indicated by an immersed thermometer and nitrogen is bubbled through the mixture using a perforated tube immersed in the solution. Formic acid is then added and the mixture is heated over a preheated oil bath to 200-220° C. for a sufficient period of time. After that, the procedure is repeated adding another aliquot of formic acid. The reaction can be monitored by 1H NMR taking aliquots from the reaction mixture. Eventually the conversion of quinic acid is complete. Benzoic acid is isolated from the reaction mixture by extraction with ethyl ether and isolated removing the solvent at reduced pressure to give the product in a yield of over 75%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[CH:11](O)[CH3:12].S(Cl)([Cl:16])=O>>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[CH:11]([Cl:16])[CH3:12]
Reactant: COc1ccc(C(C)O)c(OC)c1
Reactant: O=S(Cl)Cl
Product: COc1ccc(C(C)Cl)c(OC)c1

Procedure:
Starting, for example, from 1-(2,4-dimethoxy-phenyl)-ethanol and treating same with thionyl chloride there can be obtained 1-(2,4-dimethoxy-phenyl)-ethyl chloride which can be converted by reaction with potassium cyanide and subsequent methylation with sodium amide and methyl iodide into 2-(2,4-dimethoxy-phenyl)-2-methyl-propionitrile. Alkaline hydrolysis of the nitrile group and subsequent reduction of the carboxyl group with lithium aluminum hydride gives 2-(2,4-dimethoxy-phenyl)-2-methyl-propanol which, by treatment with hydrobromic acid/glacial acetic acid and subsequent cyclization of the resulting 2-(2,4-dihydroxy-phenyl)-2-methyl-propyl bromide with potassium carbonate in acetone, yields 3,3-dimethyl-6-hydroxy-2,3-dihydrobenzofuran.
Reaction SMILES: C(NC1C=CC(C2C=C3C(CN([C@@H](C(C)C)C(O)=O)C3=O)=CC=2)=CC=1)(=O)C1C=CC=CC=1.[CH3:33][C:34]1[O:38][C:37]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)=[N:36][C:35]=1[C:45]([NH:47][C:48]1[CH:53]=[CH:52][C:51]([C:54]2[CH:62]=[C:61]3[C:57]([CH2:58][N:59]([CH:64]4[CH2:69][CH2:68][CH2:67][CH:66]([C:70]([O:72]C)=[O:71])[CH2:65]4)[C:60]3=[O:63])=[CH:56][CH:55]=2)=[CH:50][CH:49]=1)=[O:46]>>[CH3:33][C:34]1[O:38][C:37]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)=[N:36][C:35]=1[C:45]([NH:47][C:48]1[CH:49]=[CH:50][C:51]([C:54]2[CH:62]=[C:61]3[C:57]([CH2:58][N:59]([CH:64]4[CH2:69][CH2:68][CH2:67][CH:66]([C:70]([OH:72])=[O:71])[CH2:65]4)[C:60]3=[O:63])=[CH:56][CH:55]=2)=[CH:52][CH:53]=1)=[O:46]
Reactant: COC(=O)C1CCCC(N2Cc3ccc(-c4ccc(NC(=O)c5nc(-c6ccccc6)oc5C)cc4)cc3C2=O)C1
Agent: CC(C)[C@@H](C(=O)O)N1Cc2ccc(-c3ccc(NC(=O)c4ccccc4)cc3)cc2C1=O
Product: Cc1oc(-c2ccccc2)nc1C(=O)Nc1ccc(-c2ccc3c(c2)C(=O)N(C2CCCC(C(=O)O)C2)C3)cc1
Yield: 72 %

Procedure:
The compound of example 553 was prepared analogous to compound of example 98 by hydrolysis of compound of example 552.
Reaction SMILES: C1(C2CC(=O)NN=2)CCCCC1.ClC1C2C(=CC=CC=2)[N+]([O-])=CC=1.Cl[C:26]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[NH:29]/[C:28](=[C:36]2/[C:37]([CH:42]3[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]3)=[N:38][NH:39][C:40]/2=[O:41])/[CH:27]=1.[C:48]([NH:51][C:52]1[CH:57]=[CH:56][C:55]([SH:58])=[CH:54][CH:53]=1)(=[O:50])[CH3:49]>C(OC(=O)C)(=O)C.C(O)C>[CH:42]1([C:37]2=[N:38][NH:39][C:40](=[O:41])/[C:36]/2=[C:28]2\[NH:29][C:30]3[C:35]([C:26]([S:58][C:55]4[CH:54]=[CH:53][C:52]([NH:51][C:48](=[O:50])[CH3:49])=[CH:57][CH:56]=4)=[CH:27]\2)=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]1
Reactant: CC(=O)Nc1ccc(S)cc1
Reactant: O=C1NN=C(C2CCCCC2)/C1=C1\C=C(Cl)c2ccccc2N1
Agent: O=C1CC(C2CCCCC2)=NN1
Agent: [O-][n+]1ccc(Cl)c2ccccc21
Solvent: CCO
Solvent: CC(=O)OC(C)=O
Product: CC(=O)Nc1ccc(SC2=C/C(=C3/C(=O)NN=C3C3CCCCC3)Nc3ccccc32)cc1
Temperature: 180 °C

Procedure:
3-Cyclohexyl-3-oxo-propionic acid ethyl ester (0.5 g, 2.52 mmol) was stirred in ethanol and acetic acid (10:1, 2:0.2 mL), and treated with hydrazine (0.095 mL, 3.03 mmol). After 18 hrs, the resulting solid was filtered off and washed with a minimum amount of ethanol to yield 3-cyclohexyl-1H-pyrazol-5(4H)-one. Then, the 3-cyclohexyl-1H-pyrazol-5(4H)-one (0.2 g, 1.23 mmol) and 4-chloroquinoline N-oxide (1.23 mmol) were stirred in acetic anhydride (20 mL) at ambient temperature for 60-90 minutes. The reaction mixture was concentrated and the resulting solid filtered off and washed with a minimum amount of ether. (Z)-4-(4-chloroquinolin-2(1H)-ylidene)-3-cyclohexyl-1H-pyrazol-5(4H)-one (0.05 g, 0.13 mmol) was dissolved in ethanol (1.5 mL) and 4-acetamidothiophenol (0.023 g, 0.13 mmol) was added. The reaction mixture was heated to 180° C. using a microwave reactor for 5-10 minutes. The solid was filtered and washed with ethanol to yield Example 48. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.88-1.00 (m, 2H) 1.26-1.38 (m, 2H) 1.58 (d, J=10.61 Hz, 6H) 2.10 (s, 3H) 2.33 (t, J=9.47 Hz, 1H) 6.87 (s, 1H) 7.62-7.72 (m, 3H) 7.89 (t, J=7.83 Hz, 4H) 8.17 (d, J=8.34 Hz, 1H) 10.37 (s, 1H); ESI-MS: m/z calc'd for C26H26N4O2S 458.58. found 459.1 (M+H)+.
Reaction SMILES: [O:1]1[C:5]2[C:6]([C:10](O)=[O:11])=[CH:7][CH:8]=[CH:9][C:4]=2[CH2:3][CH2:2]1.COC(Cl)=O.[BH4-].[Na+].Cl.C1C=C[NH+]=CC=1.[O-][Cr](Cl)(=O)=O>C1COCC1.O.C(OCC)C>[O:1]1[C:5]2[C:6]([CH:10]=[O:11])=[CH:7][CH:8]=[CH:9][C:4]=2[CH2:3][CH2:2]1
Reactant: O=C(O)c1cccc2c1OCC2
Agent: O=[Cr](=O)([O-])Cl
Agent: COC(=O)Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Solvent: CCOCC
Product: O=Cc1cccc2c1OCC2
Reaction time: 0.5 h
Yield: 60.7 %

Procedure:
2,3-Dihydrobenzofuran-7-carboxylic acid (820 mg, 5 mmol) was dissolved in THF (10 mL). To the solution was added TEA (0.7 mL, 5 mmol) and methylchloroformate (0.43 mL, 5 mmol). The solution was stirred for 0.5 hour. The white precipitates were removed by filtration, the filtrate was added to a solution of NaBH4 (437 mg, 12.5 mmol) in H2O (5 mL). The resulting solution was stirred overnight. The reaction mixture was neutralized with 2 M aqueous HCl solution and then extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous Na2SO4 and concentrated in vacuo. The crude alcohol was dissolved in DCM. To the solution was added PCC (1.83 g, 7.5 mmol). The mixture was stirred for 2 hours at room temperature and diluted with diethyl ether, then ether layers were decanted. Combined organic layer was filtered though a layer of Celite®. The filtrate was concentrated to give crude product. The crude was purified from column with 10% EtOAc/hexane to afford 450 mg of 2,3-dihydrobenzofuran-7-carbaldehyde as a slightly yellow solid. HPLC 4.3 min.
Reaction SMILES: [N:1]1([CH2:10][CH2:11][O:12][C:13]2[CH:45]=[CH:44][C:16]([CH2:17][CH:18]3[S:22][C:21](=[O:23])[N:20](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[C:19]3=[O:43])=[CH:15][CH:14]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][N:8]=2)[CH:3]=[CH:2]1.FC(F)(F)C(O)=O>C(Cl)Cl>[N:1]1([CH2:10][CH2:11][O:12][C:13]2[CH:14]=[CH:15][C:16]([CH2:17][CH:18]3[S:22][C:21](=[O:23])[NH:20][C:19]3=[O:43])=[CH:44][CH:45]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][N:8]=2)[CH:3]=[CH:2]1
Reactant: O=C1SC(Cc2ccc(OCCn3ccc4cccnc43)cc2)C(=O)N1C(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1NC(=O)C(Cc2ccc(OCCn3ccc4cccnc43)cc2)S1
Yield: 55.8 %

Procedure:
A procedure similar to that described in Example 2 was repeated, except that 2.50 g of 5-{4-[2-(7-azaindol-1-yl)ethoxy]benzyl}-3-triphenylmethylthiazolidine-2,4-dione (prepared as described in Preparation 19), 50 ml of methylene chloride and 3.1 ml of trifluoroacetic acid were used, to give 0.84 g of the title compound, melting at 200.0-202.4° C.
Reaction SMILES: Cl.N[C:3]1[CH:4]=[CH:5][C:6]2[O:11][C:10]([CH3:13])([CH3:12])[CH:9]([CH3:14])[C:8](=[O:15])[C:7]=2[CH:16]=1.N([O-])=O.[Na+].[C-:21]#[N:22].[K+]>C(O)C.O>[C:21]([C:3]1[CH:4]=[CH:5][C:6]2[O:11][C:10]([CH3:13])([CH3:12])[CH:9]([CH3:14])[C:8](=[O:15])[C:7]=2[CH:16]=1)#[N:22]
Reactant: CC1C(=O)c2cc(N)ccc2OC1(C)C
Reactant: [C-]#N
Agent: Cl
Agent: O=N[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: CC1C(=O)c2cc(C#N)ccc2OC1(C)C
Temperature: 90 °C
Yield: 77 %

Procedure:
A mixture of of 6-nitro-2,2,3-trimethyl-3,4-dihydro-2H-1-benzopyran-4-one (23.5 g, 0.1 mol) and 10% palladium on carbon (2 g) in methanol was stirred under an atmosphere of hydrogen at 40°-50° C. for five hours at atmospheric pressure. The solution was then filtered, and the solvent removed from the filtrate under reduced pressure to give 21 g of 6-amino-2,2,3-trimethyl-3,4-dihydro-2H-1-benzopyran-4-one as an oil. B. To a mixture of water (293 ml) and concentrated hydrochloric acid (25.7 ml) at 0° C. was added a solution of 6-amino-2,2,3-trimethyl-3,4-dihydro-2H-1-benzopyran-4-one (20.5 g, 0.1 mol) in ethanol (140 ml). A solution of sodium nitrite (7.6 g, 0.11 mol) in water (90 ml) was then added, such that the temperature did not rise above 0° C. After fifteen minutes at 0° C., the reaction mixture was poured into a solution containing potassium cyanide (58.6 g, 0.90 mol) and cuprous cyanide (80.61 g, 0.90 mol) in water at 90° C., whilst maintaining the temperature of the reaction above 70° C. The resulting mixture was heated at 90° C. for one hour and then cooled to 20° C., extracted with ethyl acetate and the extract washed with water. The organic layer was separated and the solvent removed under reduced pressure. The residue was chromatographed on silica gel, eluting with dichloromethane/acetone (99/1) to give 16.58 g of 6-cyano-2,2,3-trimethyl-3,4-dihydro-2H-1-benzopyran-4-one, 1H NMR (CDCl3): δ 1.2 (d, 3H), 1.30 (s, 3H), 1.5 (s, 3H), 2.8 (q, 1H), 7.0 (d, 1H), 7.70 (d, 1H), 8.1 (s, 1H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][N:3]=1.[NH:9]1[CH2:14][CH2:13][CH:12]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:11][CH2:10]1.C1CCN2C(=NCCC2)CC1.CCOC(C)=O>CS(C)=O>[CH3:8][C:5]1[CH:6]=[CH:7][C:2]([N:9]2[CH2:10][CH2:11][CH:12]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:20])([CH3:19])[CH3:21])[CH2:13][CH2:14]2)=[N:3][CH:4]=1
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Reactant: Cc1ccc(Br)nc1
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Solvent: C1CCC2=NCCCN2CC1
Product: Cc1ccc(N2CCC(NC(=O)OC(C)(C)C)CC2)nc1
Temperature: 110 °C
Reaction time: 2.5 h
Yield: 13.8 %

Procedure:
A solution of 2-bromo-5-methylpyridine (1.00 g, 5.8 mmol), tert-butyl piperidine-4-ylcarbamate (1.28 g, 6.39 mmol) and TEA (1.21 ml, 8.72 mmol) in DMSO (5 ml) was heated at 110° C., After 17 h the reaction mixture was heated at 130° C. for 4 h before more TEA (0.40 ml, 2.91 mmol) was added. After 2.5 h, DBU (1.73 ml, 11.63 mmol) was added and the reaction mixture heated at 110° C. for 17 h. The reaction mixture was then allowed to cool to rt and EtOAc was added. The reaction mixture was washed with brine and evaporated to dryness. The residue was purified using the Biotage SPI eluting with 25% EtOAc in pet. ether 40-60° C. to give the title compound (0.233 g, 14%) as a solid. 1H NMR (500 MHz, CDCl3): 8.02 (d, 1H), 7.31 (dd, 1H), 6.62 (d, 1H), 4.48 (bs, 1H), 4.16-4.10 (m, 2H), 3.68 (bs, 1H), 2.95 (dt, 2H), 2.20 (s, 3H), 2.08-2.00 (m, 2H), 1.48-1.40 (m, 9H). 13C NMR (CDCl3): 158.1, 155.4, 147.9, 138.6, 122.3, 107.5, 79.5, 48.4, 45.1, 32.3, 28.7, 17.5. Mass Spectrum: M+H 292.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:16][C:17]2[C:22]([C:23]#[N:24])=[CH:21][N:20]=[C:19]3[S:25][C:26]4[CH2:27][N:28](C(OC(C)(C)C)=O)[CH2:29][CH2:30][C:31]=4[C:18]=23)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1.Cl.O1CCOCC1>CC(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([NH:16][C:17]2[C:22]([C:23]#[N:24])=[CH:21][N:20]=[C:19]3[S:25][C:26]4[CH2:27][NH:28][CH2:29][CH2:30][C:31]=4[C:18]=23)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1
Reactant: CC(C)(C)OC(=O)N1CCc2c(sc3ncc(C#N)c(Nc4ccc(OCc5ccccn5)c(Cl)c4)c23)C1
Agent: Cl
Solvent: C1COCCO1
Solvent: CC(C)O
Product: N#Cc1cnc2sc3c(c2c1Nc1ccc(OCc2ccccn2)c(Cl)c1)CCNC3
Temperature: 80 °C

Procedure:
tert-Butyl 4-{[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino}-3-cyano-5,8-dihydrothieno[2,3-b:5,4-c′]dipyridine-7(6H)-carboxylate from Example 56A (210 mg, 0.34 mmol) was dissolved in 2-propanol, and 4 M gaseous hydrogen chloride in dioxane (0.17 mL, 0.67 mmol) was added. The mixture was heated to 80° C. for 3 h. The precipitate was collected by suction filtration and dissolved in diluted aqueous sodium hydroxide solution. Some methanol was added, and the mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate, and the solvent was evaporated. The title compound was crystallized from dichloromethane/diethyl ether to yield 116 mg (77%).
Reaction SMILES: [CH2:1]([C@H:3]1[CH2:8][O:7][CH2:6][CH2:5][NH:4]1)[CH3:2].Cl[C:10]1[O:11][C:12]2[C:13](=[C:15]([C:20]([O:22][CH3:23])=[O:21])[CH:16]=[C:17]([Cl:19])[CH:18]=2)[N:14]=1>>[Cl:19][C:17]1[CH:18]=[C:12]2[O:11][C:10]([N:4]3[CH2:5][CH2:6][O:7][CH2:8][C@@H:3]3[CH2:1][CH3:2])=[N:14][C:13]2=[C:15]([C:20]([O:22][CH3:23])=[O:21])[CH:16]=1
Reactant: CC[C@H]1COCCN1
Reactant: COC(=O)c1cc(Cl)cc2oc(Cl)nc12
Product: CC[C@H]1COCCN1c1nc2c(C(=O)OC)cc(Cl)cc2o1

Procedure:
Following general procedure GP-A, (S)-3-ethylmorpholine and methyl 2,6-dichlorobenzoxazole-4-carboxylate were coupled to provide (S)-methyl 6-chloro-2-(3-ethylmorpholino)benzoxazole-4-carboxylate. MS consistent.
Reaction SMILES: Cl[C:2]1[CH:10]=[C:9]2[C:5]([C:6](=[O:20])[N:7](CCC3C=CN=CC=3)[C:8]2=[O:11])=[CH:4][C:3]=1S(N)(=O)=O.ClC1C=C2C(=O)NC(=O)C2=CC=1S(=O)(=O)N.NCCC1C=CN=CC=1>>[O:20]=[C:6]1[C:5]2[C:9](=[CH:10][CH:2]=[CH:3][CH:4]=2)[C:8](=[O:11])[NH:7]1
Reactant: NS(=O)(=O)c1cc2c(cc1Cl)C(=O)N(CCc1ccncc1)C2=O
Agent: NCCc1ccncc1
Agent: NS(=O)(=O)c1cc2c(cc1Cl)C(=O)NC2=O
Product: O=C1NC(=O)c2ccccc21
Yield: 93 %

Procedure:
6-Chloro-2,3-dihydro-1,3-dioxo-2-[2-(4-pyridinyl)ethyl]-1H-isoindole-5-sulfonamide. Reaction of a mixture of 4-chloro-5-sulfamoylphthalimide and 4-(2-aminoethyl)pyridine according to the procedure of Example 1(a) afforded a 93% yield of the 1,3-dioxoisoindole intermediate. Crystallization of this material from dimethylformamide provided analytically pure 6-chloro-2,3-dihydro-1,3-dioxo-2-[2-(4-pyridinyl)ethyl]-1H-isoindole-5-sulfonamide, m.p. 277°-278° (dec.).
Reaction SMILES: [OH:1][CH:2]([CH2:20][CH3:21])[C:3]([C:5]1[CH:19]=[CH:18][C:8]2[N:9]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[O:11][C:7]=2[CH:6]=1)=O.[NH:22]([C:24](OCC)=[O:25])[NH2:23].[Na]>Cl.C(O)C>[CH2:20]([CH:2]1[O:1][C:24](=[O:25])[NH:22][N:23]=[C:3]1[C:5]1[CH:19]=[CH:18][C:8]2[N:9]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[O:11][C:7]=2[CH:6]=1)[CH3:21]
Reactant: CCOC(=O)NN
Reactant: CCC(O)C(=O)c1ccc2nc(-c3ccccc3)oc2c1
Agent: Cl
Agent: [Na]
Solvent: CCO
Product: CCC1OC(=O)NN=C1c1ccc2nc(-c3ccccc3)oc2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
50 mg (178 μmol) 2-hydroxy-1-(2-phenyl-benzoxazol-6-yl)-butan-1-one are refluxed together with 20.36 mg (196 μmol) ethyl hydrazinoformate, 1 drop of 0.1N hydrochloric acid and 500 μl ethanol for 10 min, then the solvent is completely removed i. V. The residue is dissolved in 2 ml dry ethanol. 40 mg (1740 μmol) sodium are dissolved in 1.2 ml dry ethanol and added dropwise to the first solution, the mixture is stirred overnight at RT, then separated by RP-HPLC.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N:22]([CH3:29])[CH:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)[C:5]([CH3:21])=[C:6]([CH:20]=1)[C:7]([NH:9][CH2:10][C:11]1[C:12](=[O:19])[NH:13][C:14]([CH3:18])=[CH:15][C:16]=1[CH3:17])=[O:8].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C.[C:59](O)(=[O:64])[C:60]([CH3:63])([CH3:62])[CH3:61]>CN(C=O)C.O>[Br:1][C:2]1[CH:3]=[C:4]([N:22]([CH3:29])[CH:23]2[CH2:28][CH2:27][N:26]([C:59](=[O:64])[C:60]([CH3:63])([CH3:62])[CH3:61])[CH2:25][CH2:24]2)[C:5]([CH3:21])=[C:6]([CH:20]=1)[C:7]([NH:9][CH2:10][C:11]1[C:12](=[O:19])[NH:13][C:14]([CH3:18])=[CH:15][C:16]=1[CH3:17])=[O:8]
Reactant: Cc1cc(C)c(CNC(=O)c2cc(Br)cc(N(C)C3CCNCC3)c2C)c(=O)[nH]1
Reactant: CC(C)(C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(C)c(CNC(=O)c2cc(Br)cc(N(C)C3CCN(C(=O)C(C)(C)C)CC3)c2C)c(=O)[nH]1
Reaction time: 18 h
Yield: 49.1 %

Procedure:
To a stirred solution of 5-bromo-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-methyl-3-(methyl(piperidine-4-yl)amino)benzamide (0.05 g, 0.112 mmol) in DMF (2 mL), EDCI.HCl (0.064 g, 0.336 mmol), HOBt (0.03 g, 0.22 mmol), triethyl amine (0.03 g, 0.336 mmol) and pivalic acid (0.023 g, 0.224 mmol) were added at room temperature and stirred at same temperature for 18 h. On completion, water was added and extracted with 10% MeOH/DCM. Combined organic layers were dried, concentrated giving crude material; which then purified by column chromatography to afford the desired compound (0.03 g, 56%). LCMS: 545.20 (M+1)+; HPLC: 98.60% (@ 254 nm) (Rt; 6.355; Method: Column: YMC ODS-A 150 mm×4.6 mm×5μ; Mobile Phase: A; 0.05% TFA in water/B; 0.05% TFA in acetonitrile; Inj. Vol: 10 μL, Col. Temp.: 30° C.; Flow rate.: 1.4 mL/min.; Gradient: 5% B to 95% B in 8 min, Hold for 1.5 min, 9.51-12 min 5% B); 1H NMR (DMSO-d6, 400 MHz) δ 11.46 (s, 1H), 8.20 (t, 1H, J=4.4 Hz), 7.25 (d, 1H, J=2.8 Hz), 7.05 (d, 1H, J=1.2 Hz), 5.85 (s, 1H), 4.23-4.25 (m, 4H), 3.00 (m, 1H), 2.76 (t, 2H, J=12.4 Hz), 2.54 (s, 3H), 2.18 (s, 3H), 2.14 (s, 3H), 2.10 (s, 3H), 1.62-1.65 (m, 2H), 1.42-1.48 (m, 2H), 1.18 (s, 9H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:31]=[CH:32][C:33]=1[NH:34][C:35]([NH:37][C:38]1[CH:43]=[C:42]([CH3:44])[CH:41]=[CH:40][C:39]=1[F:45])=[O:36])[O:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]([C:12]2[NH:16][CH:15]=[C:14]([C:17]([N:19]3[CH2:24][CH2:23][N:22]([CH2:25][C:26]([O:28]CC)=[O:27])[CH2:21][CH2:20]3)=[O:18])[CH:13]=2)[CH:7]=1.[OH-].[Na+].O.Cl>CO>[F:1][C:2]1[CH:3]=[C:4]([CH:31]=[CH:32][C:33]=1[NH:34][C:35]([NH:37][C:38]1[CH:43]=[C:42]([CH3:44])[CH:41]=[CH:40][C:39]=1[F:45])=[O:36])[O:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]([C:12]2[NH:16][CH:15]=[C:14]([C:17]([N:19]3[CH2:20][CH2:21][N:22]([CH2:25][C:26]([OH:28])=[O:27])[CH2:23][CH2:24]3)=[O:18])[CH:13]=2)[CH:7]=1
Reactant: CCOC(=O)CN1CCN(C(=O)c2c[nH]c(-c3cc(Oc4ccc(NC(=O)Nc5cc(C)ccc5F)c(F)c4)ccn3)c2)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1ccc(F)c(NC(=O)Nc2ccc(Oc3ccnc(-c4cc(C(=O)N5CCN(CC(=O)O)CC5)c[nH]4)c3)cc2F)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirred solution of ethyl {4-[(5-{4-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrol-3-yl)carbonyl]piperazin-1-yl}acetate (175 mg, 0.28 mmol) in MeOH (8 ml) was added 1M NaOH solution (1 ml, 1 mmol). The mixture was stirred at room temperature for 16 hours and poured into 50 ml of water. 1M HCl was added dropwise with vigorous stirring until pH=7. The precipitates were filtered, washed with water and dried in vacuo to give {4-[5-{4-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrol-3-yl)carbonyl]piperazin-1-yl}acetic acid as white solid. Yield: 160 mg, 96%.
Reaction SMILES: [F:1][C:2]1[CH:25]=[C:24]([N+:26]([O-:28])=[O:27])[CH:23]=[CH:22][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12]([C:14]3[CH:21]=[CH:20][C:17]([CH:18]=O)=[CH:16][CH:15]=3)[S:13][C:6]=12.COC[CH2:32][O:33][CH2:34][CH2:35][O:36][CH2:37][CH2:38][O:39][CH2:40][CH2:41][NH2:42].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[F:1][C:2]1[CH:25]=[C:24]([N+:26]([O-:28])=[O:27])[CH:23]=[CH:22][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12]([C:14]3[CH:15]=[CH:16][C:17]([CH2:18][NH:42][CH2:41][CH2:40][O:39][CH2:38][CH2:37][O:36][CH2:35][CH2:34][O:33][CH3:32])=[CH:20][CH:21]=3)[S:13][C:6]=12
Reactant: O=Cc1ccc(-c2cc3nccc(Oc4ccc([N+](=O)[O-])cc4F)c3s2)cc1
Reactant: COCCOCCOCCOCCN
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: COCCOCCOCCNCc1ccc(-c2cc3nccc(Oc4ccc([N+](=O)[O-])cc4F)c3s2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 58 %

Procedure:
A suspension of 362 (0.90 g, 2.3 mmol), amine 363 (0.93 g, 5.7 mmol) [amine 363 has been synthesized according to the procedures used for the synthesis of amines 322 (scheme 18) and 326 (scheme 20)] and acetic acid (0.26 ml, 4.6 mmol) in dichloromethane (50 ml) was stirred for 1 h at room temperature. Then sodium triacetoxyborohydride (1.45 g, 6.85 mmol) was added and the mixture was stirred at r.t. for 16 h. A further amount of sodium triacetoxyborohydride (1.5 g) was then added, and stirring continued for 2 h. The reaction mixture was partitioned between dichloromethane and 1N HCl. The organic phase was discarded. The aqueous phase was basified (pH=13) with 3M NaOH, and extracted with dichloromethane. The organic extract was dried over anhydrous sodium sulfate, filtered, and concentrated to yield 364 (0.72 g, 58%) as a yellow solid. LRMS (M+H): 542.4