Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][CH2:2][CH:3]1[CH2:8][NH:7][CH2:6][CH2:5][N:4]1[CH3:9].Br[C:11]1[CH:12]=[CH:13][C:14]([N+:17]([O-:19])=[O:18])=[N:15][CH:16]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[F:1][CH2:2][CH:3]1[CH2:8][N:7]([C:11]2[CH:16]=[N:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=2)[CH2:6][CH2:5][N:4]1[CH3:9]
Reactant: CN1CCNCC1CF
Reactant: O=[N+]([O-])c1ccc(Br)cn1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CN1CCN(c2ccc([N+](=O)[O-])nc2)CC1CF
Temperature: 25 °C
Yield: 84.5 %

Procedure:
A 100-mL single-neck round-bottomed flask equipped with a magnetic stirrer and reflux condenser was charged with 1,4-dioxane (50 mL), 336d (1.6 g, 12.1 mmol), 5-bromo-2-nitropyridine (3.7 g, 18.2 mmol), and cesium carbonate (9.9 g, 30.2 mmol). After bubbling nitrogen through the resulting solution for 30 min, Xantphos (700 mg, 0.12 mmol) and tris(dibenzylideneacetone)-dipalladium(0) (550 mg, 0.06 mmol) were added. After three cycles of vacuum/argon flash, the reaction mixture was heated at reflux for 15 h. After this time the reaction was cooled to room temperature, filtered, and concentrated to afford a black solid as a crude product, which was further purified by column chromatography eluting with 100:1 methylene chloride/methanol to afford 336e as a yellow solid (2.6 g, 76%). MS: [M+H]+ 255. 1H NMR (500 MHz, MeOD) δ 8.20 (m, 2H), 7.52 (dd, J=9, 1H), 4.72 (m, 0.5H), 4.64 (m, 1H), 4.56 (m, 0.5H), 4.01 (m, 1H), 3.94 (m, 1H), 3.19 (m, 1H), 3.06 (m, 1H), 3.00 (m, 1H), 2.50 (m, 2H), 2.46 (s, 3H).
Reaction SMILES: [C:1]1([N:7]2[CH:11]=[C:10]([CH2:12][OH:13])[N:9]=[C:8]2[S:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[N+]1([O-])CCOCC1>C(#N)C.[Ru]([O-])(=O)(=O)=O.C([N+](CCC)(CCC)CCC)CC>[C:1]1([N:7]2[CH:11]=[C:10]([CH:12]=[O:13])[N:9]=[C:8]2[S:14][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: OCc1cn(-c2ccccc2)c(Sc2ccccc2)n1
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: CC#N
Product: O=Cc1cn(-c2ccccc2)c(Sc2ccccc2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 54.4 %

Procedure:
To a solution of [1-phenyl-2-(phenylthio)-1H-imidazol-4-yl]methanol (740 mg) in acetonitrile (50 mL) were added tetra-n-propylammonium perruthenate (185 mg), N-methylmorpholine N-oxide (1.42 g) and molecular sieves 4A powder (5 g), and the mixture was stirred at room temperature for 2 hr. The reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent:hexane-ethyl acetate=3:2) to give the title compound as a pale-yellow oil (yield 400 mg, 54%).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:9][C:8]2([CH2:18][C:17](=[O:19])[C:16]3[C:11](=[CH:12][CH:13]=[C:14](/[CH:20]=[CH:21]/[C:22]([NH:24][O:25]C4CCCCO4)=[O:23])[CH:15]=3)[O:10]2)[CH2:7]1)=[O:5])[CH3:2].Cl>C(Cl)Cl.O1CCOCC1>[CH2:1]([O:3][C:4]([N:6]1[CH2:9][C:8]2([CH2:18][C:17](=[O:19])[C:16]3[C:11](=[CH:12][CH:13]=[C:14](/[CH:20]=[CH:21]/[C:22]([NH:24][OH:25])=[O:23])[CH:15]=3)[O:10]2)[CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CC2(CC(=O)c3cc(/C=C/C(=O)NOC4CCCCO4)ccc3O2)C1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: CCOC(=O)N1CC2(CC(=O)c3cc(/C=C/C(=O)NO)ccc3O2)C1
Yield: 60 %

Procedure:
(E)-3-[1′-Ethyloxycarbonyl-4-oxo-spiro(chromane-2,3′-azetidine)-6-yl]-N-(tetrahydro-pyran-2-yloxy)-acrylamide (110 mg, 0.26 mmol) in DCM (8 ml) was treated with 4 M HCl in dioxane (1 ml) as described in Example 30, Step C, giving (E)-3-[1′-ethyloxycarbony-4-oxo-spiro(chromane-2,3′-azetidine)-6-yl]-N-hydroxy-acrylamide (54 mg, hydrochloride salt) as a white solid.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7]([NH:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.Cl[C:22](=[O:30])[CH2:23][CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26]>O1CCCC1.O>[CH2:7]([N:14]([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:22](=[O:30])[CH2:23][CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CCOC(=O)CNCc1ccccc1
Reactant: CCOC(=O)CCC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)CCC(=O)N(CC(=O)OCC)Cc1ccccc1
Yield: 85.6 %

Procedure:
Potassium carbonate (110.4 g, 0.97 mol) was added in one portion to a solution of ethyl 2-(benzylamino)acetate (78 g, 0.4 mol) in tetrahydrofuran (500 mL) and water (200 mL). Ethyl 4-chloro-4-oxobutanoate (72.7 g, 0.485 mol) in anhydrous tetrahydrofuran (200 mL) was then added dropwise over a period of 1 hour to the mixture. The mixture was filtered, and the filtrate was washed with ethyl acetate. After the solvent was removed by evaporation, standard extractive workup with ethyl acetate (100 mL) to afford the title product as a yellow oil (110 g; yield=80%). LC-MS: m/z=322 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:15]([NH2:17])=[O:16])=[CH:4][C:5]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[NH:7][C:6]=2[N:14]=1.[H-].[Na+].Br[CH:21]([CH3:23])[CH3:22]>CN(C=O)C>[NH2:1][C:2]1[C:3]([C:15]([NH2:17])=[O:16])=[CH:4][C:5]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[N:7]([CH:21]([CH3:23])[CH3:22])[C:6]=2[N:14]=1
Reactant: NC(=O)c1cc2c(nc1N)[nH]c1ccccc12
Reactant: CC(C)Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)n1c2ccccc2c2cc(C(N)=O)c(N)nc21
Reaction time: 0.17 h

Procedure:
To a solution of 2-amino-9H-pyrido[2,3-b]indole-3-carboxamide (5, 122 mg, 0.540 mmol) in DMF (5 mL) was added NaH (110 mg, 2.75 mmol) and the reaction was stirred for 10 min. 2-Bromopropane (111 μL, 0.688 mmol) was added and the mixture was stirred at RT for another 2.5 h. The reaction was quenched with water (50 mL), poured into a separatory funnel containing EtOAc (150 mL), the mixture was shaken and the layers were separated. The organic layer was washed with brine (100 mL), dried, filtered and concentrated. The crude product was purified by silica gel chromatography (MeOH/CH2Cl2 gradient) to yield 2-amino-9-isopropyl-9H-pyrido[2,3-b]indole-3-carboxamide as a white powder (13, 30 mg, 21%). NH4OAc standard conditions. DAD Retention time=6.95 min. M+H=269. 1H NMR (300 MHz, DMSO-d6): 8.72 (s, 1H), 7.82 (d, J=7.8 Hz, 1H), 7.61 (d, J=8.1 Hz, 1H), 7.54 (br s, 2H), 7.29 (ddd, J=8.4, 8.4, 1.2 Hz, 1H), 7.17 (ddd, J=7.5, 7.5, 0.9 Hz, 1H), 5.23 (septet, J=6.9 Hz, 1H), 1.60 (d, J=6.9 Hz, 6H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[C:14](O)=[N:13][CH:12]=[N:11][C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Cl)(Cl)(Cl)[Cl:39]>ClCCCl>[C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[C:14]([Cl:39])=[N:13][CH:12]=[N:11][C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: ClC(Cl)(Cl)Cl
Reactant: CC(C)(C)OC(=O)N1CCc2c(O)ncnc2C1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N1CCc2c(Cl)ncnc2C1
Temperature: 70 °C
Reaction time: 2.5 h
Yield: 86.7 %

Procedure:
A mixture of 4-hydroxy-5,8-dihydro-6H-pyrido[3,4-d]pyrimidine-7-carboxylic acid tert-butyl ester (1.4 g, 5.6 mmol) and triphenylphosphine (2.9 g, 11.1 mmol) was stirred in DCE (41 mL) until the solution became clear, and then carbon tetrachloride (1.6 mL, 16.7 mmol) was added. The reaction mixture was heated to 70° C. and stirred for 2.5 hours. The volatiles were removed in vacuo and the crude material was directly purified by flash chromatography on silica gel (0-50% EtOAc/heptanes) to afford the title compound as an off-white solid (1.31 g, 87% yield). MS (ESI) m/e (M+H+): 269.73
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([NH2:7])[S:5][CH:6]=1.[Si:8]([O:15][C:16]1[CH:17]=[C:18]([S:22][C:23]2[CH:28]=[CH:27][N:26]=[C:25](Cl)[CH:24]=2)[CH:19]=[CH:20][CH:21]=1)([C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:10])[CH3:9].P([O-])([O-])([O-])=O.[K+].[K+].[K+].O>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>[Si:8]([O:15][C:16]1[CH:17]=[C:18]([S:22][C:23]2[CH:28]=[CH:27][N:26]=[C:25]([NH:7][C:4]3[S:5][CH:6]=[C:2]([CH3:1])[N:3]=3)[CH:24]=2)[CH:19]=[CH:20][CH:21]=1)([C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:10])[CH3:9]
Reactant: CC(C)(C)[Si](C)(C)Oc1cccc(Sc2ccnc(Cl)c2)c1
Reactant: Cc1csc(N)n1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1csc(Nc2cc(Sc3cccc(O[Si](C)(C)C(C)(C)C)c3)ccn2)n1
Yield: 31.6 %

Procedure:
Using the method of Example 3, Step B, 4-methylthiazol-2-amine (9.20 mL, 3.68 mmol), 4-(3-(tert-butyldimethylsilyloxy)phenylthio)-2-chloropyridine (1.42 g, 4.05 mmol), potassium phosphate (0.859 g, 4.05 mmol), tris(dibenzylideneacetone)-dipalladium (0) (0.0842 g, 0.0920 mmol) and 4,5-bis(diphenylphosphino)-9,9-dimethyl-9H-xanthene (0.0585 g, 0.101 mmol) were reacted in toluene (10 mL) and water (3 mL) to afford N-(4-(3-(tert-butyldimethylsilyloxy)phenylthio)pyridin-2-yl)-4-methylthiazol-2-amine (0.500 g, 28.5% yield) as yellow solid. 1H NMR (CDCl3) δ 8.08 (d, 1H), 7.27 (t, 1H), 7.12 (dt, 1H), 7.00 (t, 1H), 6.90 (m, 1H), 6.56 (dd, 1H), 6.47 (d, 1H), 6.32 (d, 1H), 2.23 (d, 3H), 0.96 (s, 9H), 0.18 (s, 6H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:31])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][C:13]2[CH:18]=[CH:17][C:16]([CH:19]([NH:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C:20]([OH:22])=O)=[CH:15][CH:14]=2)=[CH:8][CH:7]=1.[CH2:32]([N:34](CC)[CH2:35]C)C.CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F.CNC>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:31])[CH2:4][CH2:5][C:6]1[CH:7]=[CH:8][C:9]([O:12][C:13]2[CH:14]=[CH:15][C:16]([CH:19]([NH:23][C:24]([O:26][C:27]([CH3:29])([CH3:28])[CH3:30])=[O:25])[C:20](=[O:22])[N:34]([CH3:35])[CH3:32])=[CH:17][CH:18]=2)=[CH:10][CH:11]=1
Reactant: COC(=O)CCc1ccc(Oc2ccc(C(NC(=O)OC(C)(C)C)C(=O)O)cc2)cc1
Reactant: CCN(CC)CC
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: CNC
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Product: COC(=O)CCc1ccc(Oc2ccc(C(NC(=O)OC(C)(C)C)C(=O)N(C)C)cc2)cc1
Temperature: 25 °C
Yield: 87.1 %

Procedure:
The hydrogenated compound 31 (4.0 g, 9.3 mmol) was dissolved in CH2Cl2 (60 mL) and stirred at room temperature under an atmosphere of argon. Triethylamine (1.56 mL, 11.0 mmol) and BOP reagent (4.53 g, 10.0 mmol) were added and the reaction mixture was stirred for 15 min. Dimethylamine (2.0 M solution in THF, 23.3 mL, 47.0 mmol) was added and the resulting solution was stirred at room temp for about 2-3 h. The solvent was removed under reduced pressure and the resulting oil was taken up in EtOAc (200 mL). The organic layer was extracted with 0.5 N NaOH (1×30 mL), water (2×100 mL) and brine (1×100 mL). Drying and concentration of the organic layer gave the desired amide 32 (3.7 g, 87%). 1H NMR (400 MHz, DMSO-d6): 7.34 (d, J=8.4 Hz, 2H), 7.24 (d, J=8.4 Hz, 2H), 7.11 (d, J=8.0 Hz, 2H), 6.93 (overlapped d, J=8.8 Hz, 2H), 6.92 (overlapped d, J=8.0 Hz, 2H), 5.50 (d, J=8.0 Hz, 1H), 3.59 (s, 3H), 2.90 (s, 3H), 2.80-2.84 (m. 5H), 2.63 (t, J=7.6 Hz, 2H), 1.37 (s, 9H).
Reaction SMILES: [C:1](N)(=O)C.[O:5]=[C:6]1[N:10]([C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH2:18][N:19]([C:23](=[O:29])[CH2:24][O:25]C(=O)C)[CH2:20][CH2:21][CH:22]=3)=[C:13]([F:30])[CH:12]=2)[CH2:9][C@H:8]([CH2:31][NH:32][C:33](=[O:35])[CH3:34])[O:7]1>>[OH:25][CH2:24][C:23]([N:19]1[CH2:1][CH:18]=[C:17]([C:14]2[CH:15]=[CH:16][C:11]([N:10]3[CH2:9][C@H:8]([CH2:31][NH:32][C:33](=[O:35])[CH3:34])[O:7][C:6]3=[O:5])=[CH:12][C:13]=2[F:30])[CH2:22][CH2:21][CH2:20]1)=[O:29]
Reactant: CC(N)=O
Reactant: CC(=O)NC[C@H]1CN(c2ccc(C3=CCCN(C(=O)COC(C)=O)C3)c(F)c2)C(=O)O1
Product: CC(=O)NC[C@H]1CN(c2ccc(C3=CCN(C(=O)CO)CCC3)c(F)c2)C(=O)O1

Procedure:
Following the general procedure of EXAMPLE 71, and making non-critical variations but substituting (S)-N-[[2-oxo-3-[3-fluoro-4-1-[(acetoxy)acetyl]-2,3,4,7-tetrahydro-1H-azepin-5-yl]phenyl]-5-oxazolidinyl]methyl]acetamide (EXAMPLE 75, Step 3) for (S)-(-)-N-[[2-oxo-3-[3-fluoro-4-[1-[(acetoxy)acetyl]-5,6-dihydro-2H-pyridin-3yl]phenyl]-5-oxazolidinyl]methyl]acetamide, the title compound is obtained, NMR (CDCl3, 400 MHz, mixture of rotamers) 7.41, 7.09-7.18, 6.07, 6.00, 5.87, 4.78, 4.25, 4.21, 4.05, 3.92, 3.87, 3.78, 3.67, 3.51, 2.63, 2.03 and 1.97 δ and HRMS calculated for C20H24F1N3O5 : 405.1700. Found: 405.1694.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9](B2OC(C)(C)C(C)(C)O2)[C:8]2[N:7]3[CH2:20][CH2:21][NH:22][C:23](=[O:24])[C:6]3=[C:5]([CH3:25])[C:4]=2[CH:3]=1.Br[C:27]1[S:28][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:30][N:31]=1>>[F:1][C:2]1[CH:10]=[C:9]([C:27]2[S:28][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:30][N:31]=2)[C:8]2[N:7]3[CH2:20][CH2:21][NH:22][C:23](=[O:24])[C:6]3=[C:5]([CH3:25])[C:4]=2[CH:3]=1
Reactant: FC(F)(F)c1cnc(Br)s1
Reactant: Cc1c2n(c3c(B4OC(C)(C)C(C)(C)O4)cc(F)cc13)CCNC2=O
Product: Cc1c2n(c3c(-c4ncc(C(F)(F)F)s4)cc(F)cc13)CCNC2=O

Procedure:
The title compound, off-white solid (16 mg, 22%), MS (ISP) m/z=370.4 [(M+H)+], mp 263° C., was prepared in accordance with the general method of example 171, step B from 8-fluoro-10-methyl-6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (Example 171, step A) (68.8 mg, 0.2 mmol) and commercially available 2-bromo-5-trifluoromethyl-thiazole (69.6 mg, 0.3 mmol).
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([NH2:9])=[C:4]([NH2:10])[CH:3]=1.C([O:15][C:16](=O)[CH2:17][C:18]([C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([C:26]2[CH:31]=[CH:30][N:29]=[C:28]([CH3:32])[CH:27]=2)[CH:21]=1)=O)(C)(C)C>C1(C)C(C)=CC=CC=1>[F:1][C:2]1[C:7]([F:8])=[CH:6][C:5]2[NH:9][C:16](=[O:15])[CH2:17][C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]4[CH:31]=[CH:30][N:29]=[C:28]([CH3:32])[CH:27]=4)[CH:21]=3)=[N:10][C:4]=2[CH:3]=1
Reactant: Nc1cc(F)c(F)cc1N
Reactant: Cc1cc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)ccn1
Solvent: Cc1ccccc1C
Product: Cc1cc(-c2cccc(C3=Nc4cc(F)c(F)cc4NC(=O)C3)c2)ccn1

Procedure:
The title compound was prepared from commercially available 4,5-difluoro-1,2-phenylendiamine (400 mg, 2.78 mmol) and 3-[3-(2-methyl-pyridin-4-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K12) (864 mg, 2.78 mmol) in xylene (15 ml) under reflux conditions for 1.5 h according to the general procedure M. Obtained as a light brown solid (780 mg, 77%).
Reaction SMILES: I[CH:2]([CH3:4])[CH3:3].C(=O)([O-])[O-].[K+].[K+].[I:11][C:12]1[CH:17]=[C:16]([O:18][CH3:19])[N:15]=[CH:14][C:13]=1[OH:20]>CC(C)=O>[I:11][C:12]1[C:13]([O:20][CH:2]([CH3:4])[CH3:3])=[CH:14][N:15]=[C:16]([O:18][CH3:19])[CH:17]=1
Reactant: CC(C)I
Reactant: COc1cc(I)c(O)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1cc(I)c(OC(C)C)cn1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
At 0° C., 758 mg (4.5 mmol) of 2-iodopropane and 948 mg (6.9 mmol, 2 eq.) of potassium carbonate were added to a solution of 861 mg (3.4 mmol) of 4-iodo-6-methoxypyridin-3-ol in 15 ml of acetone and the mixture was stirred at 80° C. overnight and concentrated under reduced pressure. After addition of water/ethyl acetate and phase separation, the aqueous phase was extracted with ethyl acetate. The combined organic phases were dried (sodium sulphate), filtered and concentrated under reduced pressure. Yield: 741 mg (73% of theory)
Reaction SMILES: C(O[C:4]([C:6]1[C:11](=[O:12])[N:10]([CH2:13][CH2:14][CH:15]([CH3:17])[CH3:16])[N:9]2[CH:18]=[CH:19][CH:20]=[C:8]2[C:7]=1[OH:21])=O)C.[NH2:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][C:24]=1[S:31]([NH2:34])(=[O:33])=[O:32]>C(O)C>[OH:21][C:7]1[C:8]2[N:9]([CH:18]=[CH:19][CH:20]=2)[N:10]([CH2:13][CH2:14][CH:15]([CH3:16])[CH3:17])[C:11](=[O:12])[C:6]=1[C:4]1[NH:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][C:24]=2[S:31](=[O:32])(=[O:33])[N:34]=1
Reactant: COc1ccc(N)c(S(N)(=O)=O)c1
Reactant: CCOC(=O)c1c(O)c2cccn2n(CCC(C)C)c1=O
Solvent: CCO
Product: COc1ccc2c(c1)S(=O)(=O)N=C(c1c(O)c3cccn3n(CCC(C)C)c1=O)N2
Temperature: 180 °C
Yield: 45 %

Procedure:
4-Hydroxy-1-(3-methyl-butyl)-2-oxo-1,2-dihydro-pyrrolo[1,2-b]pyridazine-3-carboxylic acid ethyl ester (Example 1f, 0.040 g, 0.14 mmol) was mixed with 2-amino-5-methoxy-benzenesulfonamide (Example 2b, 0.0235 g, 0.14 mmol) and the resulting mixture was heated to 180° C. for 20 min. The resulting crude oil was allowed to cool to 25° C. and ethanol (0.5 mL) was added and sonicated to afford a tan precipitate, which was collected and dried in vacuo. The crude solid was dissolved in 1.0 M aqueous potassium hydroxide solution (0.5 mL) and heated to 110° C. for 12 h. The reaction mixture was allowed to cool to 25° C. and 10% aqueous hydrochloric acid solution (0.5 mL) was added and the resulting white precipitate was collected. The crude solid was washed with methanol and dried in vacuo to afford the desired product, 4-hydroxy-3-(7-methoxy-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-1-(3-methyl-butyl)-pyrrolo[1,2-b]pyridazin-2-one (0.027 g, 0.063 mmol, 47% yield) as a white solid. 1HNMR (400 MHz, DMSO-d6) δ 1.07 (6H, d, J=6.4 Hz), 1.69 (1H, m), 1.78 (1H, m), 3.89 (3H, s), 4.39 (2H, t, J=7.6 Hz), 6.60 (1H, dd, J1=4.4 Hz, J2=2.8 Hz), 7.04 (1H, d, J=4.4 Hz), 7.05 (1H, dd, J1=4.8 Hz, J2=2.0 Hz), 7.25 (1H, m), 7.17 (1H, m), 7.39 (1H, d, J=2.0 Hz); LC-MS (ESI) calcd for C19H22N4O5S 430.49. found 431.33 [M+H+].
Reaction SMILES: C[O:2][C:3](=[O:31])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][NH:9][C:10]1[C:11]2[C:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[C:17]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[O:16][C:12]=2[N:13]=[CH:14][N:15]=1.[OH-].[Na+].Cl>CO.C1COCC1.O>[C:19]1([C:18]2[C:11]3[C:10]([NH:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][C:3]([OH:31])=[O:2])=[N:15][CH:14]=[N:13][C:12]=3[O:16][C:17]=2[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: COC(=O)CCCCCNc1ncnc2oc(-c3ccccc3)c(-c3ccccc3)c12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)CCCCCNc1ncnc2oc(-c3ccccc3)c(-c3ccccc3)c12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Dissolve 27.5 mg (0.066 mmol) 6-[(5,6-diphenylfuro[2,3-d]pyrimidin-4-yl)amino]hexanoic acid methyl ester in 0.1 ml methanol, 0.05 ml THF and one drop of water and add 0.09 ml 2.5 M sodium hydroxide solution. Stir the mixture for 1 h at RT and then lightly acidify with 1 N hydrochloric acid. Extract the aqueous phase three times with dichloromethane. Combine the organic phases and dry over magnesium sulphate, concentrate by vacuum evaporation and dry the residue at high vacuum. 25 mg (96.1% of theor.) of the target compound is obtained.
Reaction SMILES: C[O-].CO.[C:5]1([OH:11])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[C:12]([N:20]1[CH2:25][CH2:24][CH:23]([CH2:26]Cl)[CH2:22][CH2:21]1)(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(OCC)C>[C:12]([N:20]1[CH2:25][CH2:24][CH:23]([CH2:26][O:11][C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH2:22][CH2:21]1)(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C(c1ccccc1)N1CCC(CCl)CC1
Reactant: Oc1ccccc1
Agent: C[O-]
Solvent: CCOCC
Solvent: CO
Product: O=C(c1ccccc1)N1CCC(COc2ccccc2)CC1
Reaction time: 12 h
Yield: 51.9 %

Procedure:
To a mixture of 28 ml of 30% sdium methanolate solution and 50 ml of methanol are added 14.1 g (0.15 mole) of phenol. The reaction mixture is evaporated in a vacuum and the residue is taken up in 120 ml of N,N-dimethyl formamide, 35.5 g (0.15 mole) of N-benzoyl-4chloromethylpiperidine are added thereto and the reaction mixture is stirred for 12 hours at 60°-70° C. After cooling, the reaction mixture is mixed with diethyl ether, washed with water and dilute aqueous sodium hydroxide solution, dried over anhydrous sodium sulfate and evaporated in a vacuum. The oily residue is triturated with diethyl ether/ligroin. There are obtained 23.0 g of N-benzoyl-4-phenoxymethylpiperidine (52% of theory); m.p. 95°-96° C.
Reaction SMILES: [CH3:1][CH:2]1[CH:9]2[CH:5]([CH2:6][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:8]2)[CH2:4][C:3]1=O.[CH2:18]([NH2:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.S([O-])([O-])(=O)=O.[Mg+2].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH2:18]([NH:25][CH:3]1[CH2:4][CH:5]2[CH2:6][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:8][CH:9]2[CH:2]1[CH3:1])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: NCc1ccccc1
Reactant: CC1C(=O)CC2CN(C(=O)OC(C)(C)C)CC21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: ClCCCl
Product: CC1C(NCc2ccccc2)CC2CN(C(=O)OC(C)(C)C)CC21
Reaction time: 60 h

Procedure:
A solution of tert-butyl 4-methyl-5-oxohexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (10.7 g, 44.7 mmol) and benzyl amine (7.67 g, 71.5 mmol) in 1,2-dichloroethane (250 mL) was stirred at room temperature for 2 h. Anhydrous magnesium sulfate (20 g, 166 mmol) was added. The resultant suspension was stirred at room temperature for additional 2 h. Sodium triacetoxyborohydride (18.95 g, 89 mmol) was added. After 60 h at room temperature, the mixture was quenched with saturated sodium bicarbonate (100 mL) and extracted with ethyl acetate (3×150 mL). The combined organic extracts were washed with water, brine, dried (MgSO4) and concentrated. Silica gel chromatography, eluting with 0-8% methanol in dichloromethane, gave tert-butyl 5-(benzylamino)-4-methylhexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate as a mixture of stereoisomers (13.2 g), which was taken to the next reaction without separation.
Reaction SMILES: Cl[C:2]1[O:3][C:4]([C:7]2[N:8]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:9]3[C:14]([CH:15]=2)=[CH:13][CH:12]=[CH:11][CH:10]=3)=[CH:5][N:6]=1.[NH2:23][C:24]1[CH:25]=[C:26]([NH:30][S:31]([CH3:34])(=[O:33])=[O:32])[CH:27]=[CH:28][CH:29]=1>CC(O)C>[CH3:34][S:31]([NH:30][C:26]1[CH:25]=[C:24]([NH:23][C:2]2[O:3][C:4]([C:7]3[N:8]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:9]4[C:14]([CH:15]=3)=[CH:13][CH:12]=[CH:11][CH:10]=4)=[CH:5][N:6]=2)[CH:29]=[CH:28][CH:27]=1)(=[O:33])=[O:32]
Reactant: CC(C)(C)OC(=O)n1c(-c2cnc(Cl)o2)cc2ccccc21
Reactant: CS(=O)(=O)Nc1cccc(N)c1
Solvent: CC(C)O
Product: CC(C)(C)OC(=O)n1c(-c2cnc(Nc3cccc(NS(C)(=O)=O)c3)o2)cc2ccccc21
Temperature: 80 °C
Yield: 53.4 %

Procedure:
A mixture of tert-butyl 2-(2-chlorooxazol-5-yl)-1H-indole-1-carboxylate 21 (0.281 g, 0.883 mmol) and commercially available N-(3-aminophenyl)methanesulfonamide 6 (0.321 g, 1.723 mmol) in 2-propanol (20 mL) was heated to 80° C. for 14 h with stirring. Upon cooling, solvent was evaporated and silica column purified (Biotage) (Acetone/hexane as an eluent) to provide tert-butyl 2-(2-((3-(methylsulfonamido) phenyl)amino)oxazol-5-yl)-1H-indole-1-carboxylate 24 (0.221 g, 54% yield) as solid. MS (ES) m/z 469 (M+H+).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[CH:7]=O)([O-:3])=[O:2].[CH3:14][O:15][C:16]1[CH:17]=[C:18]([CH2:26][C:27]#[N:28])[CH:19]=[C:20]([O:24][CH3:25])[C:21]=1[O:22][CH3:23].[OH-].[Na+].ClCCl>O.[Cl-].C([NH2+]C)CCCCCCC>[N+:1]([C:4]1[CH:5]=[C:6](/[CH:7]=[C:26](/[C:18]2[CH:19]=[C:20]([O:24][CH3:25])[C:21]([O:22][CH3:23])=[C:16]([O:15][CH3:14])[CH:17]=2)\[C:27]#[N:28])[CH:9]=[CH:10][C:11]=1[O:12][CH3:13])([O-:3])=[O:2]
Reactant: COc1ccc(C=O)cc1[N+](=O)[O-]
Reactant: COc1cc(CC#N)cc(OC)c1OC
Agent: CCCCCCCC[NH2+]C
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: COc1ccc(/C=C(\C#N)c2cc(OC)c(OC)c(OC)c2)cc1[N+](=O)[O-]
Temperature: 0 °C
Yield: 72.4 %

Procedure:
3.0 g of 3-nitro-4-methoxybenzaldehyde, 3.4 g of 3,4,5-trimethoxyphenylacetonitrile, 800 mg of sodium hydroxide and 100 mg of octylmethylammonium chloride were dissolved in 15 ml of water and 15 ml of dichloromethane and reacted for 4 hours at room temperature. Ice water was added to the reaction liquid, which was then extracted three times each with dichloromethane. The extract was dried with anhydrous sodium sulfate and concentrated. The concentrated liquid was purified by crystallization (ethyl acetate) to obtain 4.4 g of the intended compound. The yield was 72%.