Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]([O:9][CH3:10])=[O:8].ClC(OCC)=[O:13].[OH-].[Na+].Cl.P(Br)(Br)Br>O.O1CCOCC1>[NH:1]1[C:2]2[CH:6]=[CH:5][S:4][C:3]=2[C:7](=[O:8])[O:9][C:10]1=[O:13]
Reactant: COC(=O)c1sccc1N
Reactant: CCOC(=O)Cl
Agent: BrP(Br)Br
Agent: Cl
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: O=c1[nH]c2ccsc2c(=O)o1
Temperature: 25 °C
Reaction time: 48 h
Yield: 100 %

Procedure:
A mixture of methyl 3-aminothiophene-2-carboxylate (63 mmol, 10.0 g) and ethyl chloroformate (50 ml) was refluxed for 2 hrs and then evaporated to dryness. The residue was dissolved in ethanol (130 ml) and sodium hydroxide (NaOH, 65 mmol, 3.84 g) in water (35 ml) was added. After stirring at room temperature for 48 hrs the mixture was acidified with 1M HCl and diluted with water. The precipitate was collected, washed with water, dried under vacuum and recrystallized from toluene/heptane resulting in 3-ethoxycarbonylamino-thiophene-2-carboxylic acid, (10.2 g, 73%). This acid, (23.2 nanol, 5.0 g), and phosphorus tribromide (12 mmol, 1.14 ml) were dissolved in 1,4-dioxane (50 ml). The mixture was stirred at 100° C. for 2 hrs and then cooled before it was concentrated on a rotary evaporator. The precipitate formed upon addition of toluene was isolated by filtration giving 1H-thieno[3,2-d][1,3]oxazine-2,4-dione (3.96. g, 100%). This intermediate (20.6 mmol, 3.5 g) was dissolved in DMA (40 ml) and cooled on an ice-bath. NaH (22.7 mmol, 780 mg) was added followed by addition of methyl iodide (25 mmol, 1.6 ml). The mixture was stirred at room temperature overnight and then diethyl malonate (25 mmol, 3.85 ml) and NaH (22.7 mmol, 780 mg) were added. After the addition the mixture was heated at 85° C. for 2 hrs and then the mixture was cooled. Water was added and the mixture was acidified with 1 M HCl and extracted with chloroform. The extract was dried, concentrated, and chromatographed (SiO2, chloroform/methanol/acetic acid; 40/1/0.1) to yield the title compound (1.4 g, 26%).
Reaction SMILES: [N:1]1([CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[O:17][C:18]4[CH:24]=[C:23](B5OC(C)(C)C(C)(C)O5)[CH:22]=[CH:21][C:19]=4[N:20]=3)=[CH:12][CH:11]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.FC(F)(F)S(O[C:40]1[CH:41]2[CH:43]([C:44](=[O:56])[N:45]([CH2:47][C:48]3[CH:53]=[CH:52][C:51]([O:54][CH3:55])=[CH:50][CH:49]=3)[N:46]=1)[CH2:42]2)(=O)=O>>[CH3:55][O:54][C:51]1[CH:50]=[CH:49][C:48]([CH2:47][N:45]2[N:46]=[C:40]([C:23]3[CH:22]=[CH:21][C:19]4[N:20]=[C:16]([C:13]5[CH:14]=[CH:15][C:10]([O:9][CH2:8][CH2:7][N:1]6[CH2:6][CH2:5][O:4][CH2:3][CH2:2]6)=[CH:11][CH:12]=5)[O:17][C:18]=4[CH:24]=3)[CH:41]3[CH:43]([CH2:42]3)[C:44]2=[O:56])=[CH:53][CH:52]=1
Reactant: CC1(C)OB(c2ccc3nc(-c4ccc(OCCN5CCOCC5)cc4)oc3c2)OC1(C)C
Reactant: COc1ccc(CN2N=C(OS(=O)(=O)C(F)(F)F)C3CC3C2=O)cc1
Product: COc1ccc(CN2N=C(c3ccc4nc(-c5ccc(OCCN6CCOCC6)cc5)oc4c3)C3CC3C2=O)cc1

Procedure:
The preparation is carried out analogously to Example 136c from 2-[4-(2-morpholin-4-yl-ethoxy)-phenyl]-6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzoxazole and 4-(4-methoxy-benzyl)-5-oxo-3,4-diaza-bicyclo[4.1.0]hept-2-en-2-yl trifluoromethanesulphonate.
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH3:7])=[C:5]([C:8]([NH:10][C:11]2[CH:33]=[CH:32][C:14]([O:15][C:16]3[CH:21]=[CH:20][N:19]=[C:18]([NH:22][C:23](=O)[O:24]C4C=CC=CC=4)[CH:17]=3)=[C:13]([F:34])[CH:12]=2)=[O:9])[C:4](=[O:35])[N:3]1[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.[CH3:42][NH:43][CH3:44]>CN1C(=O)CCC1>[CH3:42][N:43]([CH3:44])[C:23](=[O:24])[NH:22][C:18]1[CH:17]=[C:16]([O:15][C:14]2[CH:32]=[CH:33][C:11]([NH:10][C:8]([C:5]3[C:4](=[O:35])[N:3]([C:36]4[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=4)[N:2]([CH3:1])[C:6]=3[CH3:7])=[O:9])=[CH:12][C:13]=2[F:34])[CH:21]=[CH:20][N:19]=1
Reactant: CNC
Reactant: Cc1c(C(=O)Nc2ccc(Oc3ccnc(NC(=O)Oc4ccccc4)c3)c(F)c2)c(=O)n(-c2ccccc2)n1C
Solvent: CN1CCCC1=O
Product: Cc1c(C(=O)Nc2ccc(Oc3ccnc(NC(=O)N(C)C)c3)c(F)c2)c(=O)n(-c2ccccc2)n1C
Temperature: 40 °C
Yield: 27 %

Procedure:
A mixture of phenyl (4-(4-(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamido)-2-fluorophenoxy)pyridin-2-yl)carbamate (100 mg, 0.18 mmol), NMP (5 mL) and aqueous dimethylamine (0.045 mL, 33%) was heated at 40° C. for 2 hours. The solvent was evaporated under reduced pressure at 40° C., and then diluted with EtOAc (20 mL). The precipitate was collected by filtration to give the title compound as a white solid (25 mg, 27%).
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:17])[C@@H:5]([CH2:7][C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[NH:10][CH:9]=1)[NH2:6].[CH:18]1[C:23]([CH:24]=O)=[CH:22][C:21]2[O:26][CH2:27][O:28][C:20]=2[CH:19]=1.C(=O)(O)[O-].[Na+]>CN(C)C(=O)C.O>[CH3:2][O:3][C:4]([C@@H:5]1[NH:6][C@H:24]([C:23]2[CH:18]=[CH:19][C:20]3[O:28][CH2:27][O:26][C:21]=3[CH:22]=2)[C:9]2[NH:10][C:11]3[C:16]([C:8]=2[CH2:7]1)=[CH:15][CH:14]=[CH:13][CH:12]=3)=[O:17]
Reactant: O=Cc1ccc2c(c1)OCO2
Reactant: COC(=O)[C@H](N)Cc1c[nH]c2ccccc12
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: COC(=O)[C@H]1Cc2c([nH]c3ccccc23)[C@@H](c2ccc3c(c2)OCO3)N1
Temperature: 25 °C
Yield: 64 %

Procedure:
To a solution of D-Tryptophan methyl ester hydrochloride (100 g) in N,N-Dimethyl acetamide (500 ml), added Piperonal (65 g) and heated the reaction mass to 65–70° C. for 30–35 hours for completion of reaction. Reaction mass is then diluted with water, basified with sodium bicarbonate solution and extracted twice with dichloromethane (2×750 ml). The organic layer is then treated with aqueous hydrochloric acid (1000 ml). Dichloromethane is evaporated and the reaction mass is stirred for 6–10 hours at 55–60° C. Cooled the reaction mass to an ambient temperature and filtered the crude title compound in hydrochloride salt form. Then wet crude mass is charged in sodium bicarbonate solution and extracted twice with dichloromethane (2×750 ml). Dichloromethane layer is distilled out and the residual material is dissolved in Toluene and crystallized by addition of anti solvent like cyclohexane to get title compound (88.0 g).
Reaction SMILES: [NH:1]1[CH2:7][CH2:6][CH2:5][CH:4]=[CH:3][C:2]1=[O:8].N1CCC=CCC1=O.[H-].[Na+].[CH2:19](Br)[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]>C1COCC1.O>[CH2:30]([N:1]1[CH2:7][CH2:6][CH:5]=[CH:4][CH2:3][C:2]1=[O:8])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH3:19]
Reactant: O=C1C=CCCCN1
Reactant: CCCCCCCCCCCCBr
Agent: O=C1CC=CCCN1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCCCCCCCCCCCN1CCC=CCC1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 11.4 g (0.102 mol) of a mixture of azacyclohept-3-ene-2-one and azacyclohept-4-ene-2-one (Example 3-C) in THF was added dropwise to a suspension of 4.8 g (107 mmol) of sodium hydride (50% oil dispersion) in THF. The mixture was stirred at room temperature for 1 hour, 25.4 g (0.102 mol) of dodecyl bromide was added, and the solution was refluxed for 5 hours. The mixture was cooled, water was added, and the solvent was removed in vacuo. The residue was dissolved in CH2Cl2, washed with water, the organic phase dried over MgSO4 and concentrated in vacuo to yield an oil which was Kugelrohr distilled to give 15.5 g of a crude product. This material was subjected to flash chromatography (silica gel; 9:1 petroleum ether/ether V/V) to give 1-dodecylazacyclohept-4-ene-2-one, Rf =0.45; GC retention time 7.4 min. GC conditions identical to Example 3-D.
Reaction SMILES: Br[C:2]1[C:3]([F:10])=[C:4]([NH2:9])[CH:5]=[CH:6][C:7]=1[F:8].C([Sn](CCCC)(CCCC)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1)CCC.[Cl-].[Li+]>O1CCCC1.[Cu]I>[F:10][C:3]1[C:2]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)=[C:7]([F:8])[CH:6]=[CH:5][C:4]=1[NH2:9]
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Reactant: Nc1ccc(F)c(Br)c1F
Agent: [Cu]I
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Nc1ccc(F)c(-c2ccccn2)c1F
Temperature: 25 °C
Yield: 10.7 %

Procedure:
A mixture of 3-bromo-2,4-difluorophenylamine (5.2 g, 25 mmol), 2-tri-n-butylstannylpyridine (11.0 g, 30 mmol), lithium chloride (10.6 g, 250 mmol) and copper(I) iodide (476 mg, 2.5 mmol) in tetrahydrofuran (100 ml) was degassed with nitrogen for 20 min before adding tetrakis(triphenylphosphine)palladium(0). The reaction was then heated at reflux for 5 days. The mixture was cooled to ambient temperature then partitioned between ethyl acetate and 10% ammonium hydroxide. The organics were washed with water, brine, dried over anhydrous magnesium sulfate, filtered and pre-adsorbed onto silica. Purification by chromatography on silica eluting with isohexane (containing 0.5% triethylamine) on a gradient of ethyl acetate (20-50%) gave 2,4-difluoro-3-(pyridin-2-yl)phenylamine as a brown oil (550 mg, 11%): δH (400 MHz, CDCl3) 3.65 (2H, br), 6.74-6.84 (2H, m), 7.31 (1H, ddd, J 7, 5 and 1), 7.46-7.51 (1H, m), 7.78 (1H, ddd, J 8, 8 and 2), 8.74-8.77 (1H, m); m/z (ES+) 207 (M++H).
Reaction SMILES: [CH2:1]1[O:12][CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].[CH3:13][CH:14]([NH2:17])[CH2:15][NH2:16]>>[CH2:15]([NH:16][CH2:1][CH:2]([OH:12])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[CH:14]([NH:17][CH2:1][CH:2]([OH:12])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[CH3:13]
Reactant: CC(N)CN
Reactant: CCCCCCCCCC1CO1
Product: CCCCCCCCCC(O)CNCC(C)NCC(O)CCCCCCCCC

Procedure:
Condensation of 1-undecene oxide and 1-methyl-1,2-ethanediamine affords N,N'-(1,2-propylene)-bis[2-hydroxyundecylamine] (I: R = CH3 (CH2)8, R' = H, X = CH(CH3)CH2, Z = H).
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][N:6]([C:9]2[CH:14]=[CH:13][C:12]([NH:15]C(=O)OC(C)(C)C)=[C:11]([N+:23]([O-:25])=[O:24])[CH:10]=2)[CH2:5][CH2:4]1)[CH3:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:1]([N:3]1[CH2:8][CH2:7][N:6]([C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[C:11]([N+:23]([O-:25])=[O:24])[CH:10]=2)[CH2:5][CH2:4]1)[CH3:2]
Reactant: CCN1CCN(c2ccc(NC(=O)OC(C)(C)C)c([N+](=O)[O-])c2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCN1CCN(c2ccc(N)c([N+](=O)[O-])c2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 89 %

Procedure:
To a solution of tert-butyl 4-(4-ethylpiperazin-1-yl)-2-nitrophenylcarbamate (3.3 g, 9.43 mmol) in DCM (50 mL) was added TFA (20 mL) at 0° C., the resulting mixture was stirred for 3 hours at rt. After removal of all volatiles in vacuo, the residue was re-dissolved in DCM, neutralized with saturated aqueous K2CO3 and extracted with DCM. The combined extracts were concentrated to obtain the title compound (2.1 g, yield: 90%), which was used directly in the next step. 1H NMR (400 MHz, DMSO-d6) δ 1.02 (t, 3H), 2.36 (q, 2H), 2.47-2.49 (m, 4H) 2.97-3.00 (m, 4H), 6.97 (d, 1H), 7.20 (s, 2H), 7.25 (s, 1H), 7.34 (dd, 1H); MS (ESI): 251 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:4]([C:8]([C@@H:26]3[CH2:30][CH2:29][CH2:28][NH:27]3)=[N:9][C:10]=2[C:11]2[CH:25]=[CH:24][C:14]([C:15]([NH:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)=[O:16])=[CH:13][CH:12]=2)[CH:5]=[CH:6][N:7]=1.NC1C2N(C([C@@H]3CCCN3C(OCC3C=CC=CC=3)=O)=NC=2Br)C=CN=1.[F:57]C1C=CN=C(NC(=O)C2C=CC(B3OC(C)(C)C(C)(C)O3)=CC=2)C=1>>[NH2:1][C:2]1[C:3]2[N:4]([C:8]([C@@H:26]3[CH2:30][CH2:29][CH2:28][NH:27]3)=[N:9][C:10]=2[C:11]2[CH:25]=[CH:24][C:14]([C:15]([NH:17][C:18]3[CH:23]=[C:22]([F:57])[CH:21]=[CH:20][N:19]=3)=[O:16])=[CH:13][CH:12]=2)[CH:5]=[CH:6][N:7]=1
Reactant: Nc1nccn2c([C@@H]3CCCN3)nc(-c3ccc(C(=O)Nc4ccccn4)cc3)c12
Reactant: CC1(C)OB(c2ccc(C(=O)Nc3cc(F)ccn3)cc2)OC1(C)C
Agent: Nc1nccn2c([C@@H]3CCCN3C(=O)OCc3ccccc3)nc(Br)c12
Product: Nc1nccn2c([C@@H]3CCCN3)nc(-c3ccc(C(=O)Nc4cc(F)ccn4)cc3)c12
Yield: 93 %

Procedure:
This intermediate was prepared, in an analogous manner as described for intermediate 2b, from (S)-benzyl 2-(8-amino-1-bromoimidazo[1,5-a]pyrazin-3-yl)pyrrolidine-1-carboxylate (Intermediate 1e) and N-(4-fluoropyridin-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (intermediate 4b) to afford the title compound (331 mg, 93%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7](Br)[CH:6]=1.[C:13]1(/[C:19](=[C:21]2/[C:22](=[O:30])[NH:23][C:24]3[C:29]/2=[CH:28][CH:27]=[CH:26][CH:25]=3)/[CH3:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[CH3:1][O:2][C:3](=[O:12])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([N:23]2[C:24]3[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=3)/[C:21](=[C:19](\[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)/[CH3:20])/[C:22]2=[O:30])[CH:6]=1
Reactant: COC(=O)Cc1cccc(Br)c1
Reactant: C/C(=C1\C(=O)Nc2ccccc21)c1ccccc1
Product: COC(=O)Cc1cccc(N2C(=O)/C(=C(\C)c3ccccc3)c3ccccc32)c1

Procedure:
The title compound was prepared in analogy to Example 1 starting from (3-bromo-phenyl)-acetic acid methyl ester (commercially available) and 3-[1-phenyl-eth-(E)-ylidene]-1,3-dihydro-indol-2-one. 1H NMR (400 MHz, DMSO-d6) δppm 2.77 (s, 3H) 3.65 (s, 3H) 3.81 (s, 2H) 6.08 (d, J=7.33 Hz, 1H) 6.66-6.72 (m, 2H) 7.11 (t, J=7.33 Hz, 1H) 7.35-7.44 (m, 5H) 7.51-7.61 (m, 4H).
Reaction SMILES: [N+:1]([C:4]1[N:5]=[C:6]2[N:11]([CH:12]=1)[CH2:10][CH:9]([NH2:13])[CH2:8][O:7]2)([O-:3])=[O:2].C(N(CC)CC)C.[Cl:21][CH2:22][C:23](Cl)=[O:24].C(=O)(O)[O-].[Na+]>CN(C=O)C>[Cl:21][CH2:22][C:23]([NH:13][C@@H:9]1[CH2:8][O:7][C:6]2=[N:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:12][N:11]2[CH2:10]1)=[O:24]
Reactant: O=C(Cl)CCl
Reactant: NC1COc2nc([N+](=O)[O-])cn2C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(CCl)N[C@@H]1COc2nc([N+](=O)[O-])cn2C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 48.4 %

Procedure:
Under argon protection, I-7-(S)-(2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine-6-amine (134 mg, 0.73 mmol) was dissolved in anhydrous DMF (2 mL), added triethylamine (0.3 mL, 2.18 mmol), added dropwise chloroacetyl chloride (0.082 mL, 1.09 mmol) at 0° C., stirred for 2 h at room temperature, added saturated sodium bicarbonate solution, extracted by ethyl acetate, followed by anhydrous sodium sulphate drying and suction filtration, spun dry solvents, separated by column chromatography to give 92 mg yellow viscous liquid, yield was 50%.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[C:9]([Br:11])[C:8](=[O:12])[N:7]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]#[N:21])=[CH:16][CH:15]=2)[C:6]=1[CH2:22]Br)=[O:4].[CH3:24][O:25][C:26](=[O:39])[CH2:27][NH:28][S:29]([C:32]1[CH:37]=[CH:36][C:35]([CH3:38])=[CH:34][CH:33]=1)(=[O:31])=[O:30].[I-].[Na+].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.[Cl-].[Na+].O.CCOC(C)=O>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[C:9]([Br:11])[C:8](=[O:12])[N:7]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]#[N:21])=[CH:16][CH:15]=2)[C:6]=1[CH2:22][N:28]([CH2:27][C:26]([O:25][CH3:24])=[O:39])[S:29]([C:32]1[CH:33]=[CH:34][C:35]([CH3:38])=[CH:36][CH:37]=1)(=[O:31])=[O:30])=[O:4]
Reactant: COC(=O)c1cc(Br)c(=O)n(Cc2ccc(C#N)cc2)c1CBr
Reactant: COC(=O)CNS(=O)(=O)c1ccc(C)cc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [I-]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)CN(Cc1c(C(=O)OC)cc(Br)c(=O)n1Cc1ccc(C#N)cc1)S(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 65.6 %

Procedure:
A mixture of 5-bromo-2-bromomethyl-1-(4-cyano-benzyl)-6-oxo-1,6-dihydro-pyridine-3-carboxylic acid methyl ester (2.27 g, 5.16 mmol), (toluene-4-sulfonylamino)-acetic acid methyl ester (1.23 g, 5.06 mmol), sodium iodide (1.55 g, 10.3 mmol) and potassium carbonate (1.43 g, 10.3 mmol) in DMF (40 mL) was stirred at r.t. for 16 h. Brine (100 mL) and EtOAc (150 mL) were added, and the resulting mixture was extracted with EtOAc. The organic layers were combined, washed with water and dried over MgSO4. After the solvent was evaporated in vacuo, the crude product was chromatographed (0-80% EtOAc/hexanes) to give 2 g of the title compound. MS: (+) m/z 602.09, 604.04 (M+1, 79/81Br).
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[CH:16]=[CH:17][C:18]([C:21]([OH:23])=O)=[N:19][CH:20]=1.[NH2:24][N:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1>>[N:25]1([NH:24][C:21]([C:18]2[CH:17]=[CH:16][C:15]([O:14][CH2:13][C:3]3[C:4]([C:7]4[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=4)=[N:5][O:6][C:2]=3[CH3:1])=[CH:20][N:19]=2)=[O:23])[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1
Reactant: Cc1onc(-c2ccccn2)c1COc1ccc(C(=O)O)nc1
Reactant: NN1CCOCC1
Product: Cc1onc(-c2ccccn2)c1COc1ccc(C(=O)NN2CCOCC2)nc1
Yield: 82 %

Procedure:
As described for example 7, 5-(5-methyl-3-pyridin-2-yl-isoxazol-4-ylmethoxy)-pyridine-2-carboxylic acid (81.6 mg, 0.26 mmol) was converted, using N-aminomorpholine instead of isopropylamine, to the title compound (85 mg, 82%), which was obtained as a white solid. MS: m/e=396.2 [M+H]+.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[Br:16])=[CH:13][C:12]([O:17][CH3:18])=[CH:11][CH:10]=2)=[O:5])C.[OH-].[Na+].CO.C(Cl)Cl.Cl>C1COCC1>[Br:16][C:15]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:17][CH3:18])[CH:13]=2)[N:8]=[CH:7][C:6]=1[C:4]([OH:5])=[O:3]
Reactant: CCOC(=O)c1cnc2ccc(OC)cc2c1Br
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc2ncc(C(=O)O)c(Br)c2c1
Reaction time: 24 h
Yield: 91.3 %

Procedure:
4-Bromo-6-methoxy-quinoline-3-carboxylic acid ethyl ester (41 g, 0.132 mole), partially dissolved in THF (600 mL), was treated dropwise with aqueous 2 M sodium hydroxide (198.4 mL, 0.396 mole). After 24 hr, the reaction was complete by TLC (2% MeOH/CH2Cl2). The mixture was neutralized with 5 M HCl then the THF was removed in vacuo. The residue was dissolved in water and acidified with 5 M HCl. The solid product was collected under suction, washed well with water, and dried in vacuo to give the title compound (34 g, 91%) as a white solid: MS (ES) m/e 282/284 (M+H)+.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][S:12](Cl)(=[O:14])=[O:13])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[NH2:16][C:17]1[S:18][CH:19]=[CH:20][N:21]=1>N1C=CC=CC=1>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][S:12]([NH:16][C:17]2[S:18][CH:19]=[CH:20][N:21]=2)(=[O:14])=[O:13])=[CH:7][CH:6]=1)(=[O:4])=[O:3]
Reactant: Nc1nccs1
Reactant: CS(=O)(=O)c1ccc(CS(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: CS(=O)(=O)c1ccc(CS(=O)(=O)Nc2nccs2)cc1
Reaction time: 48 h

Procedure:
To the solution of the title B compound, (4-methanesulfonyl-phenyl)-methanesulfonyl chloride (1.86 mmol, 0.5 g) in 5 mL of pyridine is added 2-aminothiazole (2.5 mmol, 0.25 g) and the mixture is stirred for 48 h. The reaction mixture is quenched with aqueous 1 N HCl and the product is taken up in EtOAc, dried and concentrated to afford C-(4-methanesulfonyl-phenyl)-N-thiazol-2-yl-methanesulfonamide.
Reaction SMILES: [C:1]([Br:5])(Br)(Br)[Br:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:25]([O:29][C:30]([N:32]1[C:41]2[C:36](=[CH:37][CH:38]=[C:39]([CH:42]([CH:48]=O)[CH2:43][CH2:44][CH2:45][CH2:46][CH3:47])[CH:40]=2)[C:35]([CH3:51])([CH3:50])[CH2:34][CH2:33]1)=[O:31])([CH3:28])([CH3:27])[CH3:26]>ClCCl>[C:25]([O:29][C:30]([N:32]1[C:41]2[C:36](=[CH:37][CH:38]=[C:39]([CH:42]([CH2:43][CH2:44][CH2:45][CH2:46][CH3:47])[CH:48]=[C:1]([Br:5])[Br:2])[CH:40]=2)[C:35]([CH3:50])([CH3:51])[CH2:34][CH2:33]1)=[O:31])([CH3:28])([CH3:27])[CH3:26]
Reactant: BrC(Br)(Br)Br
Reactant: CCCCCC(C=O)c1ccc2c(c1)N(C(=O)OC(C)(C)C)CCC2(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCCCCC(C=C(Br)Br)c1ccc2c(c1)N(C(=O)OC(C)(C)C)CCC2(C)C
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 31.5 %

Procedure:
To a solution of carbon tetrabromide (0.32 g, 0.96 mmole) in 5 mL of dichloromethane, at −20° C., was added triphenyl phosphine in 5 mL of dichloromethane. After stirring at 0° C. for 15 minutes reaction mixture was treated with a solution of 7-(1-formyl-hexyl)-4,4-dimethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid tert-butyl ester (0.18 g, 0.48 mmole, from Example 5 step 8) in 2 mL of dichloromethane. The reaction mixture was stirred at room temperature for 4 hours, quenched by the successive addition of 5 mL of water and 1.5 mL of saturated sodium bicarbonate. The phases were separated and aqueous phase was extracted with two 25 mL portions of dichloromethane. Organic phase was dried over MgSO4, filtered and concentrated in vacuo affording a brownish thick oil. The product was purified by flash chromatography (SiO2, 20% ethyl acetate in hexanes) to yield 0.08 g of 7-(3,3-dibromo-1-pentyl-allyl)-4,4-dimethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid tert-butyl ester as a colourless oil.
Reaction SMILES: [N+:1]([C:4]1[N:8]2[N:9]=[C:10]([SH:13])[CH:11]=[CH:12][C:7]2=[N:6][CH:5]=1)([O-:3])=[O:2].Cl[CH2:15][CH2:16][CH2:17][O:18][C:19]1[CH:24]=[CH:23][N:22]=[C:21]([CH2:25][OH:26])[C:20]=1[CH3:27].C(N(CC)CC)C.O>CN(C)C=O>[CH3:27][C:20]1[C:21]([CH2:25][OH:26])=[N:22][CH:23]=[CH:24][C:19]=1[O:18][CH2:17][CH2:16][CH2:15][S:13][C:10]1[CH:11]=[CH:12][C:7]2[N:8]([C:4]([N+:1]([O-:3])=[O:2])=[CH:5][N:6]=2)[N:9]=1
Reactant: Cc1c(OCCCCl)ccnc1CO
Reactant: O=[N+]([O-])c1cnc2ccc(S)nn12
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: Cc1c(OCCCSc2ccc3ncc([N+](=O)[O-])n3n2)ccnc1CO
Temperature: 25 °C
Yield: 69.5 %

Procedure:
570 mg (2.9 mmol) of 3-nitroimidazo[1,2-b]pyridazine-6-thiol, 500 mg (2.3 mmol) of [4-(3-chloropropoxy)-3-methylpyridin-2-yl]methanol and 0.4 ml (2.9 mmol) of triethylamine in 10 ml of dimethylformamide are heated to 100° C for 1 h under a nitrogen atmosphere. After cooling to room temperature, water (100 ml) is added and the mixture is extracted with 3×50 ml of ethyl acetate. The residual oil is crystallized from methanol. 600 mg (69%) of the title compound are isolated as a pale beige solid. M.p. 135-136° C.
Reaction SMILES: Cl[C:2]1[S:3][C:4]([C:7]#[N:8])=[CH:5][N:6]=1.[F:9][C:10]1[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=1[C:17]([OH:34])([CH2:28][N:29]1[CH:33]=[N:32][N:31]=[N:30]1)[C:18]([C:21]1[N:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=1)([F:20])[F:19].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.C(Cl)Cl>[F:9][C:10]1[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=1[C:17]([OH:34])([CH2:28][N:29]1[CH:33]=[N:32][N:31]=[N:30]1)[C:18]([C:21]1[N:26]=[CH:25][C:24]([O:27][C:2]2[S:3][C:4]([C:7]#[N:8])=[CH:5][N:6]=2)=[CH:23][CH:22]=1)([F:19])[F:20]
Reactant: N#Cc1cnc(Cl)s1
Reactant: Oc1ccc(C(F)(F)C(O)(Cn2cnnn2)c2ccc(F)cc2F)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CS(C)=O
Product: N#Cc1cnc(Oc2ccc(C(F)(F)C(O)(Cn3cnnn3)c3ccc(F)cc3F)nc2)s1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a magnetically stirred mixture of 2-chlorothiazole-5-carbonitrile (14.68 mg, 0.102 mmol) and 6-(2-(2,4-difluorophenyl)-1,1-difluoro-2-hydroxy-3-(1H-tetrazol-1-yl)propyl)pyridin-3-ol (V) (25 mg, 0.068 mmol) in dry DMSO (1 mL) was added potassium carbonate (18.71 mg, 0.135 mmol) in a dry 25 mL vial under N2 atmosphere. The reaction mixture was stirred at RT for 4 hours, then diluted with DCM and washed with 2N HCl/water. The organic extract was evaporated and purified on silica (ISCO, 12 gram column, gradient to 50% EtOAc/Hexanes over 15 minutes) to afford the title compound. Yield=18 mg (52.9%) of a yellow white foam. 1H NMR (400 MHz, CDCl3) δ 8.75 (s, 1H), 8.63 (d, J=2.5 Hz, 1H), 7.92 (dd, J=8.8, 2.8 Hz, 1H), 7.75 (s, 1H), 7.68 (d, J=8.5 Hz, 1H), 7.34 (td, J=8.9, 6.4 Hz, 1H), 6.90 (s, 1H), 6.82-6.73 (m, 1H), 6.73-6.64 (m, 1H), 5.59 (d, J=14.3 Hz, 1H), 5.16 (d, J=15.3 Hz, 1H), 1H-decoupled 19F NMR (376 MHz, CDCl3) δ−103.63 (d, J=16.3 Hz), −104.07 (dd, J=56.5, 10.2 Hz), −104.33 (d, J=16.3 Hz), −107.58 (t, J=6.8 Hz), −110.27 (d, J=39.5 Hz), −110.97 (d, J=40.9 Hz). MS (ESI): m/z 478.1 (M+H)+.