Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][C@H:5]([CH3:20])[CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[C:15](=[O:16])[CH:14]=[C:13]([NH2:17])[N:12]([CH3:18])[C:11]1=[O:19])(=[O:3])[CH3:2].[CH2:21]=[C:22]1O[C:24](=[O:25])[CH2:23]1>ClCCCl>[C:1]([O:4][C@H:5]([CH3:20])[CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[C:15](=[O:16])[C:14]2[C:24](=[O:25])[CH:23]=[C:22]([CH3:21])[NH:17][C:13]=2[N:12]([CH3:18])[C:11]1=[O:19])(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@H](C)CCCCn1c(=O)cc(N)n(C)c1=O
Reactant: C=C1CC(=O)O1
Solvent: ClCCCl
Product: CC(=O)O[C@H](C)CCCCn1c(=O)c2c(=O)cc(C)[nH]c2n(C)c1=O
Temperature: 25 °C
Yield: 48.5 %

Procedure:
A mixture of (R)-3-(5-acetoxyhexyl)-6-amino-1-methyluracil (500 mg, 1.77 mmol), 1,2-dichloroethane (5 ml) and diketene (0.14 ml, 1.77 mmol) was heated at reflux for 18 hours. Another portion of diketene (0.2 ml) was added and the mixture was heated at reflux for an additional 18 hours. After cooling to room temperature, the mixture was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with ethyl acetate-hexane (1:1) to provide (R)-3-(5-acetoxyhexyl)-1,7-dimethylpyrido[2,3-d]pyrimidine-2,4,5(1H,3H,8H)-trione (300 mg, 49% yield) as an oil. 1H NMR (300 MHz, CDCl3) δ 1.20 (d, 3H), 1.25-1.71 (m, 6H), 2.00 (s, 3H), 2.46 (s, 3H), 3.62 (s, 3H), 4.00 (t, 2H), 4.86 (sextet, 1H), 6.49 (s, 1H), 12.15 (s, 1H). 13C NMR (75 MHz, CDCl3) δ 19.64, 20.96, 22.46, 25.02, 27.19, 29.15, 35.19, 40.67, 70.29, 94.48, 105.71, 150.09, 150.73, 164.92, 165.18, 167.82, 170.15.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[F:11])[NH:7][C:6]([C:12]1[CH:13]=[CH:14][C:15]([O:19][CH3:20])=[C:16]([NH2:18])[CH:17]=1)=[CH:5]2.[N:21]([C:24]1[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=1)=[C:22]=[S:23]>O1CCCC1>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[F:11])[NH:7][C:6]([C:12]1[CH:13]=[CH:14][C:15]([O:19][CH3:20])=[C:16]([NH:18][C:22]([NH:21][C:24]3[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=3)=[S:23])[CH:17]=1)=[CH:5]2
Reactant: COc1ccc(-c2cc3cc(F)c(F)cc3[nH]2)cc1N
Reactant: S=C=Nc1cccnc1
Solvent: C1CCOC1
Product: COc1ccc(-c2cc3cc(F)c(F)cc3[nH]2)cc1NC(=S)Nc1cccnc1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
The product from Example 3, 5-(5,6-difluoro-1H-indol-2-yl)-2-methoxy-phenylamine (0.277 g, 1.0 mmol) was mixed with 3-isothiocyanatopyridine (0.146 g, 1.07 mmol) in tetrahydrofuran (10 mL) and was heated briefly to 50° C. and then allowed to stand overnight at room temperature. The tetrahydrofuran was removed on the rotary evaporator to give a solid. The solid was triturated with hexanes/ethyl acetate, 1/1, v/v and was triturated a second time with hexanes/ethyl acetate, 4/1, v/v to give the product (0.309 g), mp 128-130° C.
Reaction SMILES: Br[C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][N:3]=1.C([Li])CCC.CCCCCC.[CH3:20][C:21]1[CH:22]=[C:23]([O:26][C:27]=1[CH3:28])[CH:24]=[O:25].O>O1CCCC1>[CH3:20][C:21]1[CH:22]=[C:23]([CH:24]([C:2]2[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][N:3]=2)[OH:25])[O:26][C:27]=1[CH3:28]
Reactant: Cc1cccnc1Br
Reactant: Cc1cc(C=O)oc1C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Solvent: CCCCCC
Product: Cc1cccnc1C(O)c1cc(C)c(C)o1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 66.8 %

Procedure:
2-Bromo-3-methylpyridine (1.53 g) was dissolved in tetrahydrofuran (40 ml) under an argon atmosphere to prepare a solution. A 1.6M n-butyllithium/n-hexane solution (5.7 ml) was added dropwise to the solution at −78° C., and the mixture was then stirred at −78° C. for 30 min. A solution of 4,5-dimethylfurfural (1.00 g) in tetrahydrofuran (20 ml) was added dropwise thereto, and the temperature of the mixture was raised to room temperature while stirring. Water was added to the reaction solution to stop the reaction. The solvent was removed by distillation under the reduced pressure, water was added to the residue, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by column chromatography using hexane-ethyl acetate to give (4,5-dimethylfuran-2-yl)-(3-methyl-pyridin-2-yl)-methanol (1.17 g, yield 61%).
Reaction SMILES: C([SiH2][O:6][C:7](C1C=CC=CC=1)(C1C=CC=CC=1)[C:8]1[CH:20]=[CH:19][C:11]2[C:12]([CH2:15][C:16]([NH2:18])=[O:17])=[CH:13][O:14][C:10]=2[CH:9]=1)(C)(C)C.C([O:35][C:36](=O)[C:37]([C:39]1[C:47]2[C:42](=[CH:43][CH:44]=[C:45]([F:48])[CH:46]=2)[N:41]([CH3:49])[CH:40]=1)=O)C.CC(C)([O-])C.[K+]>C1COCC1>[F:48][C:45]1[CH:46]=[C:47]2[C:42](=[CH:43][CH:44]=1)[N:41]([CH3:49])[CH:40]=[C:39]2[C:37]1[C:36](=[O:35])[NH:18][C:16](=[O:17])[C:15]=1[C:12]1[C:11]2[CH:19]=[CH:20][C:8]([CH2:7][OH:6])=[CH:9][C:10]=2[O:14][CH:13]=1
Reactant: CC(C)(C)[SiH2]OC(c1ccccc1)(c1ccccc1)c1ccc2c(CC(N)=O)coc2c1
Reactant: CCOC(=O)C(=O)c1cn(C)c2ccc(F)cc12
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: Cn1cc(C2=C(c3coc4cc(CO)ccc34)C(=O)NC2=O)c2cc(F)ccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 72.7 %

Procedure:
To a solution of the 2-[6-(tert-butyl-diphenyl-silanyloxymethyl)-benzofuran-3-yl]-acetamide (0.36 g, 0.81 mmol) and (5-fluoro-1-methyl-1H-indol-3-yl)-oxo-acetic acid ethyl ester (0.20 g, 0.81 mmol) in dry THF (8 mL) was added a 1.0 M solution of potassium tert-butoxide in THF (6.49 mL) at 0° C. The reaction was stirred for 30 min, allowed to warm to room temperature and stirred for additional 30 min. The reaction was quenched with water, and diluted with EtOAc. The organic solution was washed with brine, then dried over Na2SO4 and concentrated. The residue was dissolved in THF and a 1.0 M solution of TBAF in THF (1.22 mL) was added at room temperature. The mixture was stirred for 2 h. The solution was quenched with NH4Cl and stirred for 5 min. The solvent was removed and the residue was dissolved in dichloromethane and washed twice with water and brine. The organic phase was dried over Na2SO4 and concentrated. The residue was purified by column chromatography (methanol:dichloromethane; 5:95 to 1:9) to give the 3-(5-fluoro-1-methyl-1H-indol-3-yl)-4-(6-hydroxymethyl-benzofuran-3-yl)-pyrrole-2,5-dione as an orange solid (0.23 g, 72%). 1H NMR (DMSO-d6, 400 MHz) 3.88 (s, 3H), 4.52 (d, J=5.7 Hz, 2H), 5.24 (t, J=5.7 Hz, 1H), 6.53 (dd, J=2.3, 10.3 Hz, 1H), 6.84 (d, J=8.1 Hz, 1H), 6.89 (d, J=8.2 Hz, 1H), 6.95 (dt, J=2.4, 9.1 Hz, 1H), 7.49 (dd, J=4.5, 9.5 Hz, 1H), 7.54 (s, 1H), 8.02 (s, 1H), 8.24 (s, 1H), 11.19 (s, 1H). 13C NMR (DMSO-d6, 100 MHz) 33.7, 63.1, 104.27, 104.31, 103.1, 106.3, 109.4, 110.5, 110.8, 111.7, 112.2, 112.3, 121.5, 121.9, 122.9, 124.5, 126.4, 126.5, 132.6, 133.9, 136.2, 140.6, 147.4, 154.9, 156.5, 172.2, 172.5.
Reaction SMILES: I[CH2:2][C@H:3]([NH:8][S:9]([C:12]1[CH:18]=[CH:17][C:15]([CH3:16])=[CH:14][CH:13]=1)(=[O:11])=[O:10])[CH2:4][C:5]([OH:7])=[O:6].[N-:19]=[N+:20]=[N-:21].[Na+]>CC#N.O>[CH2:14]([O:7][C:5](=[O:6])[CH2:4][C@@H:3]([NH:8][S:9]([C:12]1[CH:18]=[CH:17][C:15]([CH3:16])=[CH:14][CH:13]=1)(=[O:11])=[O:10])[CH2:2][N:19]=[N+:20]=[N-:21])[CH:15]([CH3:17])[CH3:16]
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1ccc(S(=O)(=O)N[C@@H](CI)CC(=O)O)cc1
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: Cc1ccc(S(=O)(=O)N[C@@H](CN=[N+]=[N-])CC(=O)OCC(C)C)cc1
Temperature: 80 °C
Reaction time: 6 h
Yield: 196.4 %

Procedure:
To a solution of 1 g of 5b (2.27 mmol) in 10 ml of CH3CN and 2 ml of water, NaN3 (0.592 g, 9.11 mmol) was added. The resulting suspension was stirred at 80° C. for 6 hours, then the solvent was removed under vacuum and the crude residue was diluted with water and extracted twice with ether. The organic layer was dried over anhydrous Na2SO4, and finally evaporated to obtain 0.790 g of crude product as a light yellow wax which was used without further purification with a yield of 98%;
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][N:3]=1.[CH2:8]=[O:9]>CCOCC>[OH:9][CH2:8][CH2:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][N:3]=1
Reactant: Cc1ccncn1
Reactant: C=O
Solvent: CCOCC
Product: OCCc1ccncn1

Procedure:
A mixture of 4-methylpyrimidine (10 g, 106 mmol) and para-formaldehyde (3 g) was stirred in a 50 mL sealed capacity pressure vessel at 165° C. for 3.5 hours. After cooling, ether was added and the solvents evaporated to afford an oil. This was purified by silica column chromatography using a Flashmaster system, eluting with dichloromethane, then chloroform, ether, and finally ethyl acetate. The ethyl acetate fractions were evaporated to afford the title compound as an oil.
Reaction SMILES: [NH2:1][C@H:2]1[C@@H:7]([CH2:8]O)[CH2:6][CH2:5][N:4]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:3]1.C(N(CC)CC)C.[N+:24]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[S:33](Cl)(=[O:35])=[O:34])([O-:26])=[O:25]>C(Cl)Cl>[N+:24]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[S:33]([N:1]1[C@H:2]2[C@H:7]([CH2:6][CH2:5][N:4]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:3]2)[CH2:8]1)(=[O:35])=[O:34])([O-:26])=[O:25]
Reactant: CC(C)(C)OC(=O)N1CC[C@H](CO)[C@H](N)C1
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CC[C@@H]2CN(S(=O)(=O)c3ccccc3[N+](=O)[O-])[C@@H]2C1
Temperature: 25 °C
Reaction time: 20 h
Yield: 69.6 %

Procedure:
The product of Example 61D (39.8 mmol) in CH2Cl2 (200 mL) at 0° C. was treated with triethylamine (16.7 mL, 0.120 mol) followed by 2-nitrobenzenesulfonyl chloride (19.5 g, 88.0 mmol). The ice-bath was removed and the solution stirred at ambient temperature for 20 hours. The mixture was concentrated under reduced pressure and the residue dissolved in a mixture of ethanol and 5% aqueous NaOH (2:1, 200 mL). The mixture was stirred for 30 minutes, concentrated under reduced pressure, diluted with ethyl acetate (200 mL) and the layers were separated. The organic layer was dried over Na2SO4, filtered, and the filtrate concentrated under reduced pressure. The residue was purified via chromatography (SiO2, 50% ethyl acetate/hexanes) to provide the title compound (11.0 g, 27.7 mmol, 70% yield for two steps). MS (DCI/NH3) m/z 415 (M+NH4)+.
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]2[N:10]=[C:11]([NH:21][C:22]3[CH:27]=[CH:26][C:25]([N:28]4[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]4)=[CH:24][CH:23]=3)[C:12]([C:18]([NH2:20])=[O:19])=[N:13][C:14]=2[C:15]([CH3:17])=[CH2:16])[CH2:4][CH2:3]1.C(O)C>[Pd].C1COCC1>[OH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]2[N:10]=[C:11]([NH:21][C:22]3[CH:27]=[CH:26][C:25]([N:28]4[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]4)=[CH:24][CH:23]=3)[C:12]([C:18]([NH2:20])=[O:19])=[N:13][C:14]=2[CH:15]([CH3:16])[CH3:17])[CH2:4][CH2:3]1
Reactant: C=C(C)c1nc(C(N)=O)c(Nc2ccc(N3CCN(C)CC3)cc2)nc1N[C@H]1CC[C@H](O)CC1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: CC(C)c1nc(C(N)=O)c(Nc2ccc(N3CCN(C)CC3)cc2)nc1N[C@H]1CC[C@H](O)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a mixture of 5-[(trans-4-hydroxycyclohexyl)amino]-6-isopropenyl-3-{[4-(4-methylpiperazin-1-yl)phenyl]amino}pyrazine-2-carboxamide (Example 342) (205 mg), ethanol (20 mL) and THF (10 mL), 10% palladium on carbon (100 mg) was added under a hydrogen atmosphere and stirred at room temperature for 18 hours. After the catalyst was separated by filtration, the solvent was distilled off, and the residue was purified by basic silica gel column chromatography (eluent: chloroform). The resulting yellow solid was washed with ethyl acetate to give 5-[(trans-4-hydroxycyclohexyl)amino]-6-isopropyl-3-{[4-(4-methylpiperazin-1-yl)phenyl]amino}pyrazine-2-carboxamide (136 mg) as a yellow solid.
Reaction SMILES: N([O-])=O.[Na+].[N:5]1([CH2:10][CH2:11][N:12]2[C:20]3[C:15](=[CH:16][C:17](N)=[CH:18][CH:19]=3)[CH:14]=[N:13]2)[CH2:9][CH2:8][CH2:7][CH2:6]1.[BrH:22]>O>[Br:22][C:17]1[CH:16]=[C:15]2[C:20](=[CH:19][CH:18]=1)[N:12]([CH2:11][CH2:10][N:5]1[CH2:9][CH2:8][CH2:7][CH2:6]1)[N:13]=[CH:14]2
Reactant: Nc1ccc2c(cnn2CCN2CCCC2)c1
Reactant: Br
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: Brc1ccc2c(cnn2CCN2CCCC2)c1
Temperature: 100 °C
Reaction time: 0.25 h
Yield: 25 %

Procedure:
A solution of NaNO2 (0.20 g, 2.8 mmol) in H2O (5 mL) was cooled in a wet ice bath and treated with a solution of 1-(2-(pyrrolidin-1-yl)ethyl)-1H-indazol-5-amine (0.65 g, 2.8 mmol) in 48% aqueous HBr (2 mL). The resulting mixture was added to a pre-heated solution of CuBr (0.49 g, 3.4 mmol) in 48% aqueous HBr (2 mL) at 100° C. After stirring at 100° C. for 15 min, the dark mixture was allowed to cool. The solids were isolated by filtration, washed with 1N NaOH, and dried under vacuum. Purification by flash column chromatography (silica gel, CH2Cl2/MeOH, 95:5 to 90:10 gave the title compound (0.21 g, 25%) as a brown solid: ESI MS m/z 294 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:10]([Br:11])=[C:9]([Br:12])[N:8]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:7]=1[CH2:20]Br)=[O:5])[CH3:2].[CH2:22]([O:24][C:25](=[O:35])[CH2:26][NH:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH3:23]>>[CH2:1]([O:3][C:4]([C:6]1[C:10]([Br:11])=[C:9]([Br:12])[N:8]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:7]=1[CH2:20][N:27]([C:28]([O:30][C:31]([CH3:32])([CH3:34])[CH3:33])=[O:29])[CH2:26][C:25]([O:24][CH2:22][CH3:23])=[O:35])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(Br)c(Br)n(Cc2ccccc2)c1CBr
Reactant: CCOC(=O)CNC(=O)OC(C)(C)C
Product: CCOC(=O)CN(Cc1c(C(=O)OCC)c(Br)c(Br)n1Cc1ccccc1)C(=O)OC(C)(C)C

Procedure:
Prepared in analogy to that of Example 1(c) from 1-benzyl-4,5-dibromo-2-bromomethyl-1H-pyrrole-3-carboxylic acid ethyl ester and tert-butoxycarbonylamino-acetic acid ethyl ester. The title compound, ESI MS (m/z): 623 (M+Na+).
Reaction SMILES: [C:1](Cl)(=[O:15])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].[NH2:17][CH2:18][CH2:19][CH2:20][N:21]1[CH2:26][CH2:25][N:24]([CH2:27][CH2:28][OH:29])[CH2:23][CH2:22]1.C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)(Cl)Cl>[OH:29][CH2:28][CH2:27][N:24]1[CH2:25][CH2:26][N:21]([CH2:20][CH2:19][CH2:18][NH:17][C:1](=[O:15])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[CH2:22][CH2:23]1
Reactant: NCCCN1CCN(CCO)CC1
Reactant: CCCCCCCCCCCCCC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CCCCCCCCCCCCCC(=O)NCCCN1CCN(CCO)CC1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A 50 mL chloroform solution of 6.21 g. (0.025 1 mol) of myristoyl chloride was added dropwise under argon to an ice cold 75 mL chloroform solution of 4.79 g. (0.0256 mol) of N-(3-aminopropyl)-N'-(2-hydroxyethyl)piperazine. After stirring for two hours, 100 mL of aqueous sodium carbonate was added and stirred for 30 minutes. The layers were separated and the chloroform layer was washed with aqueous sodium carbonate (2×125 mL) followed by water (2×75 mL). The chloroform layer was concentrated in vacuo and the remaining amber liquid was crystallized successively from ethyl acetate to yield 4.56 g. (45.6%) of the subject compound.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:4]=[C:5]([C:9]2[CH:18]=[N:17][C:12]3[O:13][CH2:14][CH2:15][NH:16][C:11]=3[CH:10]=2)[CH:6]=[CH:7][CH:8]=1.[Br:21][C:22]1[CH:23]=[C:24]([CH:28]=[C:29]([Br:33])[C:30]=1[O:31][CH3:32])[C:25](Cl)=[O:26].C(N(CC)CC)C>ClCCl>[Br:21][C:22]1[CH:23]=[C:24]([C:25]([N:16]2[CH2:15][CH2:14][O:13][C:12]3[N:17]=[CH:18][C:9]([C:5]4[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:19])([F:1])[F:20])[CH:4]=4)=[CH:10][C:11]2=3)=[O:26])[CH:28]=[C:29]([Br:33])[C:30]=1[O:31][CH3:32]
Reactant: FC(F)(F)c1cccc(-c2cnc3c(c2)NCCO3)c1
Reactant: COc1c(Br)cc(C(=O)Cl)cc1Br
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1c(Br)cc(C(=O)N2CCOc3ncc(-c4cccc(C(F)(F)F)c4)cc32)cc1Br
Yield: 95.9 %

Procedure:
By the same method as in the step c) of Example 45, 7-(3-trifluoromethyl-phenyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine (99 mg, 0.35 mmol), 3,5-dibromo-4-methoxy-benzoyl chloride (139 mg, 0.42 mmol) and triethylamine (98.5 μl, 0.71 mmol) were dissolved in dichloromethane (3 ml) and reacted at room temperature for 3 hours to obtain (3,5-dibromo-4-methoxy-phenyl)-[7-(3-trifluoromethyl-phenyl)-2,3-dihydro-pyrido[2,3-b][1,4]oxazin-1-yl]-methanone as white solid (192 mg, 95%).
Reaction SMILES: [C:1]1(/[CH:7]=[CH:8]/[S:9]([NH:12][C:13]2[CH:14]=[C:15]([CH:19]=[CH:20][C:21]([OH:23])=O)[CH:16]=[CH:17][CH:18]=2)(=[O:11])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:24]CCl>CN(C)C=O>[C:1]1(/[CH:7]=[CH:8]/[S:9]([NH:12][C:13]2[CH:14]=[C:15]([CH:19]=[CH:20][C:21]([Cl:24])=[O:23])[CH:16]=[CH:17][CH:18]=2)(=[O:11])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: ClCCl
Reactant: O=C(O)C=Cc1cccc(NS(=O)(=O)/C=C/c2ccccc2)c1
Solvent: CN(C)C=O
Product: O=C(Cl)C=Cc1cccc(NS(=O)(=O)/C=C/c2ccccc2)c1
Temperature: 40 °C
Reaction time: 1 h
Yield: 98.3 %

Procedure:
To a suspension of 3-{3-[(E)-2-phenylethenesulfonylamino]phenyl}acrylic acid (26a) (0.26 g, 0.79 mmol) in dichloromethane (3.5 ml) oxalyl chloride (0.21 ml, 2.37 mmol) and one drop of dimethylformamide were added. The reaction mixture was stirred at 40° C. for one hour and concentrated under reduced pressure to give crude title compound (0.27 g, 98%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-])=O)=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CO.[H][H]>[Pd].CCOC(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc([N+](=O)[O-])cn2)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(N)cn2)CC1
Temperature: 25 °C
Reaction time: 20 h
Yield: 98.1 %

Procedure:
Place 4-(5-nitro-pyridin-2-yl)-piperazine-1-carboxylic acid tert-butyl ester (1.14 g, 3.70 mmol) in 1:1 EtOAc:MeOH (20 mL). Add 10% Pd on carbon using EtOAc (5 mL). Purge the reaction and then add hydrogen. Repeat the purge/fill cycle twice and place the reaction under a balloon of hydrogen and stir at room temperature for 20 hours. Filter the reaction through a pad of Celite® and wash the filter cake with EtOAc. Collect the filtrate and concentrate under reduced pressure to yield 1.01 g (98%) of the title compound. MS(ES): m/z=279 [M+H].
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.S(OOS([O-])(=O)=O)([O-])(=O)=O.[NH4+].[NH4+].[CH3:21][C:22]#[N:23]>O>[CH:4]1[CH:5]=[C:21]2[C:22]([NH2:23])=[C:8]3[C:3](=[N:2][C:7]2=[CH:8][CH:3]=1)[CH:4]=[CH:5][CH:6]=[CH:7]3
Reactant: Nc1ccccc1
Reactant: CC#N
Agent: Cl
Agent: O=S(=O)([O-])OOS(=O)(=O)[O-]
Agent: [NH4+]
Solvent: O
Product: Nc1c2ccccc2nc2ccccc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
HCl (1.0 g) was dissolved in CH3CN (50 ml). To the suspension was added aniline (0.42 g) in CH3CN (10 ml), followed by water (50 ml). The solution was stirred at room temperature for 2 hours, but the solution did not become homogeneous. The solution was heated for 1 hour and then cooled to room temperature. To the solution was added ammonium persulphate (1.2 g) in water (10 ml) and the resulting mixture was stirred for 20 hours.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:18][C:12]3[C:13](=[O:17])[NH:14][N:15]=[CH:16][C:11]=3[CH:10]=2)=[CH:5][CH:4]=1.[H-].[Na+].CS(O[CH2:26][C:27]1[N:32]=[C:31]([O:33][CH2:34][C@@H:35]2[CH2:40][CH2:39][CH2:38][CH2:37][N:36]2[C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH:30]=[CH:29][CH:28]=1)(=O)=O.O>CN(C=O)C.C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[S:18][C:12]3[C:13](=[O:17])[N:14]([CH2:26][C:27]4[N:32]=[C:31]([O:33][CH2:34][C@@H:35]5[CH2:40][CH2:39][CH2:38][CH2:37][N:36]5[C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH:30]=[CH:29][CH:28]=4)[N:15]=[CH:16][C:11]=3[CH:10]=2)=[CH:7][CH:8]=1
Reactant: CC(C)(C)OC(=O)N1CCCC[C@H]1COc1cccc(COS(C)(=O)=O)n1
Reactant: COc1ccc(-c2cc3cn[nH]c(=O)c3s2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1ccc(-c2cc3cnn(Cc4cccc(OC[C@@H]5CCCCN5C(=O)OC(C)(C)C)n4)c(=O)c3s2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 2-(4-methoxyphenyl)thieno[2,3-d]pyridazin-7(6H)-one (455 mg, 1.76 mmol) in DMF (5 ml), was added NaH 60% (110 mg, 2.52 mmol) in small portions. The mixture was stirred at rt. for 10 min before addition of tert-butyl (2S)-2-{[(6-{[(methylsulfonyl)oxy]methyl}pyridin-2-yl)oxy]methyl}piperidine-1-carboxylate (672 mg, 1.68 mmol) dissolved in DMF (3 ml). The reaction was stirred at rt. for 16 h, water (150 ml) and DCM (150 ml) added and the phases separated. The aqueous phase was extracted with DCM (150 ml). The combined organic phases were dried through a phase separator and evaporated in vacuo. Purification by silica gel flash chromatography using a 40+M Biotage column with a gradient of 30-100% EtOAc in heptane yielded the title compound as a light yellow solid. Yield: 354 mg (36%). 1H NMR (400 MHz, CDCl3) δ 8.17 (s, 1H), 7.61 (m, 2H), 7.46 (t, 1H, J=7.8 Hz), 7.34 (s, 1H), 6.96 (m, 2H), 6.71 (d, 1H, J=7.3 Hz), 6.55 (d, 1H, J=8.2 Hz), 5.47 (s, 2H), 4.50 (m, 1H), 4.30 (m, 2H), 3.94 (d, 1H, J=10.7 Hz), 3.85 (s, 3H), 2.74 (t, 1H, J=12.2 Hz), 1.67-1.20 (m, 15H). MS (ESI+) 563.30 (M+1H+)
Reaction SMILES: [C:1]([NH:4][C:5]1([CH2:12][OH:13])[CH2:10][CH2:9][N:8]([CH3:11])[CH2:7][CH2:6]1)(=O)[CH3:2].[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[CH2:1]([NH:4][C:5]1([CH2:12][OH:13])[CH2:6][CH2:7][N:8]([CH3:11])[CH2:9][CH2:10]1)[CH3:2]
Reactant: CC(=O)NC1(CO)CCN(C)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCNC1(CO)CCN(C)CC1
Reaction time: 4 h
Yield: 77 %

Procedure:
4-acetamido-4-hydroxymethyl-1-methylpiperidine (1.6 g, 8.6 mmoles) in dry THF was refluxed in the presence of lithium aluminium hydride (3 g). After 4 hours, the mixture was poured into an ice-water bath and filtered through Celite. The solvent was evaporated and after evaporation of most of the water, the solution was extracted with chloroform, dried with magnesium sulfate and evaporated to yield 1.13 g (77% yield) of quite pure material. The product, 4-ethylamino-4-hydroxymethyl-1-methylpiperidine, so obtained, was used without further purification.
Reaction SMILES: [CH3:1][C:2]1([CH3:23])[CH2:6][O:5][C:4](=[O:7])[N:3]1[C:8]1[S:9][C:10]2[CH2:20][CH2:19][C:18]3[C:13](=[CH:14][CH:15]=[C:16]([C:21]#[N:22])[CH:17]=3)[C:11]=2[N:12]=1.BrNC(=O)CCC(N)=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl.C(OCC)(=O)C>[CH3:1][C:2]1([CH3:23])[CH2:6][O:5][C:4](=[O:7])[N:3]1[C:8]1[S:9][C:10]2[CH:20]=[CH:19][C:18]3[C:13](=[CH:14][CH:15]=[C:16]([C:21]#[N:22])[CH:17]=3)[C:11]=2[N:12]=1
Reactant: CC1(C)COC(=O)N1c1nc2c(s1)CCc1cc(C#N)ccc1-2
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: NC(=O)CCC(=O)NBr
Solvent: ClC(Cl)(Cl)Cl
Solvent: CCOC(C)=O
Product: CC1(C)COC(=O)N1c1nc2c(ccc3cc(C#N)ccc32)s1
Yield: 54.1 %

Procedure:
2-(4,4-Dimethyl-2-oxo-1,3-oxazolidin-3-yl)-4,5-dihydronaphtho[1,2-d][1,3]thiazole-7-carbonitrile (0.65 g, 2.0 mmol), prepared in step 5 of Example 6, N-bromosuccinamide (0.39 g, 2.2 mmol) and a catalytic amount of 2,2′-azobis(2-methylproprionitrile) were stirred in carbontetrachloride (68 mL) at reflux for 4 h. The reaction was diluted with ethyl acetate and washed with 10% sodium thiosulfate. The layers were separated and the organic layer was dried over anhydrous MgSO4, filtered and concentrated to give 0.64 g of crude product. Purification of the crude product on silica gel using a stepwise gradient of 6:1 to 1:1 hexane:ethyl acetate as the eluent gave 0.35 g of product that contained an impurity. Recrystallization from ethyl acetate afforded the title compound (0.02 g, 3%), mp>230° C.