Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[N:6]2[N:7]=[C:8](Cl)[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1.[NH2:12][CH2:13][CH2:14][CH2:15][OH:16].C(Cl)Cl.CO.[NH4+].[OH-]>>[Br:1][C:2]1[N:6]2[N:7]=[C:8]([NH:12][CH2:13][CH2:14][CH2:15][OH:16])[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1
Reactant: Clc1ccc2ncc(Br)n2n1
Reactant: NCCCO
Agent: [NH4+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Product: OCCCNc1ccc2ncc(Br)n2n1

Procedure:
Prepared from 3-bromo-6-chloroimidazo[1,2-b]pyridazine and 3-amino-1-propanol according to general procedure 1 providing the amino compound (493 mg, 84%) as a yellow solid: Rf=0.56 (CH2Cl2/MeOH/NH4OH, 160:18:2); 1H NMR (500 MHz, CD3OD) δ 7.56 (d, J=9.7 Hz, 1H), 7.41 (s, 1H), 6.71 (d, J=9.7 Hz, 1H), 3.71 (t, J=6.3 Hz, 2H), 3.50 (t, J=6.8 Hz, 2H), 1.93 (quin, J=6.6 Hz, 2H); ES-MS: (M+H)=271, 273 m/z.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:15])=[C:11](F)[CH:12]=3)[C:7](=[O:16])[C:6]([C:17]([OH:19])=[O:18])=[CH:5]2)[CH2:3][CH2:2]1.[CH2:20]([NH:22][CH2:23][C:24]1([OH:30])[CH2:29][CH2:28][CH2:27][NH:26][CH2:25]1)[CH3:21]>>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:15])=[C:11]([N:26]4[CH2:27][CH2:28][CH2:29][C:24]([CH2:23][NH:22][CH2:20][CH3:21])([OH:30])[CH2:25]4)[CH:12]=3)[C:7](=[O:16])[C:6]([C:17]([OH:19])=[O:18])=[CH:5]2)[CH2:3][CH2:2]1
Reactant: O=C(O)c1cn(C2CC2)c2cc(F)c(F)cc2c1=O
Reactant: CCNCC1(O)CCCNC1
Product: CCNCC1(O)CCCN(c2cc3c(cc2F)c(=O)c(C(=O)O)cn3C2CC2)C1

Procedure:
1-Cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid is reacted analogously to Example 1 with 3-ethylaminomethyl-3-hydroxypiperidine to give 1-cyclopropyl-7-(3-ethylaminomethyl-3-hydroxy-1-piperidinyl)-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid of melting point 199°-203° C. (with decomposition).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](/[C:12](=[N:16]\[O:17][CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)/[C:13](O)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].[NH2:24][C:25]1[S:26][C:27]2[CH:33]=[CH:32][CH:31]=[CH:30][C:28]=2[N:29]=1.C(N(CC)C(C)C)(C)C>C(#N)C>[S:26]1[C:27]2[CH:33]=[CH:32][CH:31]=[CH:30][C:28]=2[N:29]=[C:25]1[NH:24][C:13](=[O:14])/[C:12](/[C:4]1[CH:5]=[CH:6][C:7]([S:8]([CH3:11])(=[O:10])=[O:9])=[C:2]([Cl:1])[CH:3]=1)=[N:16]/[O:17][CH:18]1[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]1
Reactant: CS(=O)(=O)c1ccc(/C(=N\OC2CCCCC2)C(=O)O)cc1Cl
Reactant: Nc1nc2ccccc2s1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CS(=O)(=O)c1ccc(/C(=N\OC2CCCCC2)C(=O)Nc2nc3ccccc3s2)cc1Cl
Reaction time: 2 h
Yield: 56.4 %

Procedure:
(E)-(3-Chloro-4-methanesulfonyl-phenyl)-cyclohexyloxyimino-acetic acid (prepared as in Example 9, 112 mg, 0.31 mmol), 2-aminobenzothiazole (47 mg, 0.31 mmol) and N,N-diisopropylethylamine (163 μL, 0.93 mmol) were combined in acetonitrile (1.25 mL) and cooled in an ice bath. O-(7-Azabenzotriazole-1-yl)-N,N,N′N′-tetramethyluronium hexafluorophosphate (118 mg, 0.31 mmol) was added and the ice bath was removed. After stirring 2 h, the reaction mixture was evaporated in vacuo. The residue was treated with saturated aqueous sodium bicarbonate solution (1 mL) and extracted with chloroform (2×3 mL). The combined organic phases were dried over sodium sulfate and evaporated in vacuo. The residue was purified by flash column chromatography (Merck silica gel 60, 40-63 μm; 60% ethyl acetate/hexanes) to afford (E)-N-benzothiazol-2-yl-2-(3-chloro-4-methanesulfonyl-phenyl)-2-cyclohexyloxyimino-acetamide (86 mg, 56%) as a white solid after lyophilization from aqueous acetonitrile: LC-MS (ESI) m/e calcd for C22H22ClN3O4S2 [M+] 491.07, found 492 [M+H+]; H1-NMR (400 MHz, CDCl3) δ ppm 1.26-1.64 (m, 6H, 3×CH2), 1.75 (m, 2H, 2×CH of CH2), 2.00 (m, 2H, 2×CH of CH2), 3.32 (s, 3 H, SO2CH3), 4.36 (m, 1 H, OCH), 7.35 (brt, 1 H, Ar), 7.48 (brt, 1 H, Ar), 7.65 (dd, Jo=8.2, Jm=1.5 Hz, 1 H, Ar), 7.76 (d, Jm=1.5 Hz, 1 H, Ar), 7.83 (brt, 2H, Ar), 8.23 (d, Jo=8.2 Hz, 1 H, Ar), 10.24 (s, 1 H, NH).
Reaction SMILES: [CH:1]([NH:4][C@H:5]([C:9]([OH:11])=[O:10])[CH:6]([CH3:8])[CH3:7])([CH3:3])[CH3:2].[C:12](Cl)(Cl)=[O:13]>O1CCOCC1>[CH:1]([N:4]1[CH:5]([CH:6]([CH3:7])[CH3:8])[C:9](=[O:11])[O:10][C:12]1=[O:13])([CH3:2])[CH3:3]
Reactant: O=C(Cl)Cl
Reactant: CC(C)N[C@H](C(=O)O)C(C)C
Solvent: C1COCCO1
Product: CC(C)C1C(=O)OC(=O)N1C(C)C

Procedure:
Finely ground N-isopropyl valine (31 mmol) in 150 ml dioxane is heated to 38°-40° and excess carbonyl chloride is slowly passed in over 4-5 hours. Dry air is then passed through the reaction for 18 hours, after which the dioxane is removed at 40° (20 mm) to yield 3,4-diisopropyl-oxazolidine-2,5-dione.
Reaction SMILES: Br[C:2]1[S:6][C:5]([CH:7]2[CH2:12][CH2:11][O:10][CH2:9][CH2:8]2)=[CH:4][C:3]=1[CH3:13].C([Li])CCC.[CH2:19]([CH:21]([C:24]1[C:25]2[N:26]([C:31](I)=[C:32]([CH3:34])[N:33]=2)[N:27]=[C:28]([CH3:30])[CH:29]=1)[CH2:22][CH3:23])[CH3:20]>[Cl-].[Cl-].[Zn+2].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:19]([CH:21]([C:24]1[C:25]2[N:26]([C:31]([C:2]3[S:6][C:5]([CH:7]4[CH2:12][CH2:11][O:10][CH2:9][CH2:8]4)=[CH:4][C:3]=3[CH3:13])=[C:32]([CH3:34])[N:33]=2)[N:27]=[C:28]([CH3:30])[CH:29]=1)[CH2:22][CH3:23])[CH3:20]
Reactant: Cc1cc(C2CCOCC2)sc1Br
Reactant: CCC(CC)c1cc(C)nn2c(I)c(C)nc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Product: CCC(CC)c1cc(C)nn2c(-c3sc(C4CCOCC4)cc3C)c(C)nc12
Yield: 11.5 %

Procedure:
Using a procedure similar to Example 25, 4-(5-bromo-4-methyl-thiophen-2-yl)-tetrahydropyran (0.83 g, 3.19 mmol), 1.56 M n-Bu-Li (2.04 mL, 3.19 mmol), ZnCl2 (6.4 mL, 3.19 mmol), 8-(1-ethyl-propyl)-3-iodo-2,6-dimethyl-imidazo[1,2-b]pyridazine (0.50 g, 1.56 mmol) and Pd(PPh3)4 (0.092 g, 0.008 mmol) furnish the title compound (0.072 g, 0.18 mmol, 11%). Spectrum identical to that from Method A.
Reaction SMILES: [CH3:1][CH:2]([O:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1)[CH2:3][CH3:4].Cl[CH2:14][CH2:15][NH:16][C:17](=[O:20])[O:18][CH3:19].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH3:1][CH:2]([O:5][C:6]1[CH:7]=[CH:8][C:9]([O:12][CH2:14][CH2:15][NH:16][C:17](=[O:20])[O:18][CH3:19])=[CH:10][CH:11]=1)[CH2:3][CH3:4]
Reactant: COC(=O)NCCCl
Reactant: CCC(C)Oc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCC(C)Oc1ccc(OCCNC(=O)OC)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 4-(1-methylpropoxy)phenol (9.2 mmol), methyl 2-chloroethylcarbamate (11.9 mmol), and potassium carbonate (18.4 mmol) in 20 ml of dimethylformamide (DMF) is heated at 85° for 18 hours. The reaction mixture is cooled to room temperature (RT), poured into water and extracted with ether. The combined ether extracts are washed with water until neutral, followed with brine and dried over calcium sulfate. The solvent is removed in vacuo and the residue is placed under high vacuum at 80° for ca. 2 hours to remove the excess methyl 2-chloroethylcarbamate. Purification by preparative thin layer chromatography (prep. TLC) gives methyl N-{2-[4-(1-methylpropoxy)phenoxy]ethyl}carbamate.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:6][NH:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]([OH:5])=[O:4].[ClH:15].[CH3:16]O>>[ClH:15].[ClH:15].[CH3:16][O:4][C:3](=[O:5])[CH:2]([NH2:1])[CH2:6][NH:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: N[C@@H](CNCc1ccccc1)C(=O)O
Reactant: CO
Agent: Cl
Product: COC(=O)C(N)CNCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.5 %

Procedure:
To 1N HCl/MeOH (50 mL) at 0° C. was added (S)-2-Amino-3-benzylamino-propanoic acid(0.5 g, 2.57 mmol). Reaction was stirred at room temperature overnight. Volatiles were removed to give the product 2-Amino-3-benzylamino-propanoic acid methyl ester dihydrochloride salt as a white solid (0.7 g, 97.5%). MS: m/z=209 M+1
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:14]2[CH2:18][C@H:17]([CH2:19][NH:20][C:21](=[O:23])[CH3:22])[O:16][C:15]2=[O:24])[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1.[C:25](=[O:28])([O-])[O-].[K+].[K+]>CN(C)C=O>[F:1][C:2]1[CH:3]=[C:4]([N:14]2[CH2:18][C@H:17]([CH2:19][NH:20][C:21](=[O:23])[CH3:22])[O:16][C:15]2=[O:24])[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][N:11]([C:15]([N:14]2[CH2:18][CH2:25][O:28][CH2:3][CH2:4]2)=[O:16])[CH2:10][CH2:9]1
Reactant: CC(=O)NC[C@H]1CN(c2ccc(N3CCNCC3)c(F)c2)C(=O)O1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)NC[C@H]1CN(c2ccc(N3CCN(C(=O)N4CCOCC4)CC3)c(F)c2)C(=O)O1
Yield: 82.5 %

Procedure:
(S)-N-[3-[3-Fluoro-4-[piperazin-1-yl]phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide (154 mg, 0.4587 mmol) was treated with morphonylcarbonylchloride (82 mg, 0.5504 mmol) and anhydrous potassium carbonate (190 mg, 1.376 mmol) in dimethylformamide (10 ml). The reaction mixture was allowed to react at 30° C. for 8 hrs, after which the reaction mixture was extracted with ethylacetate and water. The organic phase was separated and evaporated under reduced pressure to afford crude product. The crude was purified by column chromatography using silica gel using ethylacetate and methanol (9:1) as the eluent to afford pure title compound as colourless solid (85 mg).
Reaction SMILES: [H-].[Na+].[C:3](#[N:7])[CH2:4][C:5]#[N:6].I[C:9]1[CH:16]=[CH:15][C:12]([CH:13]=[O:14])=[CH:11][CH:10]=1>C(#N)C>[C:5]([CH:4]([C:3]#[N:7])[C:9]1[CH:16]=[CH:15][C:12]([CH:13]=[O:14])=[CH:11][CH:10]=1)#[N:6]
Reactant: N#CCC#N
Reactant: O=Cc1ccc(I)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CC#N
Product: N#CC(C#N)c1ccc(C=O)cc1
Reaction time: 66 h

Procedure:
To a 0.10 formula weight of sodium hydride suspended in 1 L acetonitrile in an atmosphere of dry argon is added 0.11 mole malononitrile dissolved in 0.10 L acetonitrile while adequate external cooling is applied to maintain the temperature of the reaction mixture in the range 0° C. to 10° C. To this mixture 0.05 formula weight of 4-iodobenzaldehyde is added followed by a solution of 0,005 formula weight of tetrakis(triphenylphosphene)palladium[0] in 0.50L argon-saturated acetonitrile. The resulting mixture is refluxed under argon with rapid stirring for 66 hours. The resulting mixture is concentrated in vacuo to a volume of 100 ml and the resulting mixture is treated with 500 ml ethyl ether. The salt which precipitated is removed by filtration and, while not with ether, suspended in 0.5 L water. The resulting suspension is acidified to pH=1.0 with concentrated hydrochloric acid to precipitate the 4-(dicyanomethyl)benzaldehyde.
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:5].[CH3:17][N:18]([CH3:27])[C:19]1[CH:26]=[CH:25][C:22]([CH:23]=O)=[CH:21][CH:20]=1>C(O)C>[CH3:17][N:18]([CH3:27])[C:19]1[CH:26]=[CH:25][C:22]([CH:23]2[N:6]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)[C:4](=[O:5])[C:3]3[C:2](=[CH:16][CH:15]=[CH:14][CH:13]=3)[NH:1]2)=[CH:21][CH:20]=1
Reactant: CN(C)c1ccc(C=O)cc1
Reactant: Nc1ccccc1C(=O)Nc1ccccc1
Solvent: CCO
Product: CN(C)c1ccc(C2Nc3ccccc3C(=O)N2c2ccccc2)cc1

Procedure:
9.6 g (0.4 mol) Magnesium, 0.1 g iodine and 180 ml anhydrous (sodium dried) diethyl ether were placed in a 2 liter flask equipped with magnetic stirrer, condenser, dropping funnel containing 62.4 g (0.4 mol) ethyl iodide and drying (CaCl2) tubes. The ethyl iodide was added dropwise slowly until the reaction started. The magnetic stirrer was then started and the remaining ethyl iodide added over a period of about 3/4 hr. It was not found necessary to apply external cooling. Stirring was continued for a further 1/2 hr at ambient temperature to ensure completion of reaction. To the resulting solution 18.6 g (0.2 mol) of aniline were added dropwise over a period of about 1/2 hr. and stirring was again continued at ambient temperature for a further 1/2 hr. To this mixture 15.1 g (0.1 mol) methyl 2-aminobenzoate were added dropwise over a period of about 1/2 hr. The reaction mixture became relatively viscous (a quantity e.g. 80 ml anhydrous diethyl ether can be added to this mixture and the stirring can be supplemented by manual agitation). Stirring, or manual agitation, was continued for about one hour. A saturated aqueous solution of ammonium chloride was then added to quench the reaction, about 300 to 350 ml is usually adequate. This mixture was thoroughly stirred and the aqueous and organic phases were separated. The aqueous phase was washed with fresh diethyl ether (ca 100 ml.) and the ethereal solutions were combined, washed with water and dried over anhydrous magnesium sulphate. The intermediate, 2-amino-N-phenylbenzamide was isolated by evaporating off the ether solvent. This crude 2-amino-N-phenylbenzamide (21 g; 0.1 mol; 99% theory based on methyl 2-aminobenzoate) had a melting point of 95° C. 10.6 g (0.05 mol) of the 2-amino-N-phenylbenzamide and 7.46 g (0.05 mol) of 4-dimethylaminobenzaldehyde were heated under reflux in 100 ml ethanol for 5 hrs. The reaction mixture was allowed to cool and the product slowly crystallised out. The crystals were filtered off to give 13 g (0.038 mol; 76% theory) of a pale yellow solid. The title compound, recrystyallised from methanol, had a melting point of 195° C. The IR and NMR spectra of this purified product were taken, as described above. The compound was also imaged onto CF paper to give an intense yellow-gold colour. The UV-visible reflectance spectrum of this colouration was measured. The results of spectral analysis were as follows:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[C:12]([O:16][CH3:17])[C:13]=1[O:14][CH3:15])[CH:6]=[CH:7][C:8](Cl)=[O:9].C(N(CC)CC)C.[CH2:25]([NH:28][C:29]([CH:31]([N:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1)[CH3:32])=[O:30])[CH2:26][CH3:27]>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[C:12]([O:16][CH3:17])[C:13]=1[O:14][CH3:15])[CH:6]=[CH:7][C:8]([N:36]1[CH2:35][CH2:34][N:33]([CH:31]([C:29]([NH:28][CH2:25][CH2:26][CH3:27])=[O:30])[CH3:32])[CH2:38][CH2:37]1)=[O:9]
Reactant: COc1cc(C=CC(=O)Cl)cc(OC)c1OC
Reactant: CCCNC(=O)C(C)N1CCNCC1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCCNC(=O)C(C)N1CCN(C(=O)C=Cc2cc(OC)c(OC)c(OC)c2)CC1
Temperature: 25 °C

Procedure:
20.00 g of 3,4,5-trimethoxycinnamoyl chloride and 11.77 ml of triethylamine are added with ice cooling to a solution of 12.90 g of 1-[1-(propylaminocarbonyl)ethyl]piperazine in 200 ml of chloroform and stirred at room temperature for one-half an hour.
Reaction SMILES: Br[C:2]1[C:3]2[N:4]([CH:18]=[CH:19][N:20]=2)[N:5]=[C:6]([C:8]2[CH:9]=[C:10]([CH:15]=[CH:16][CH:17]=2)[C:11]([O:13][CH3:14])=[O:12])[CH:7]=1.[CH3:21][CH:22]1[CH2:26][CH2:25][CH:24]([CH3:27])[N:23]1[C:28]1[N:33]=[C:32]([NH2:34])[CH:31]=[CH:30][CH:29]=1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.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]>[CH3:21][CH:22]1[CH2:26][CH2:25][CH:24]([CH3:27])[N:23]1[C:28]1[N:33]=[C:32]([NH:34][C:2]2[C:3]3[N:4]([CH:18]=[CH:19][N:20]=3)[N:5]=[C:6]([C:8]3[CH:9]=[C:10]([CH:15]=[CH:16][CH:17]=3)[C:11]([O:13][CH3:14])=[O:12])[CH:7]=2)[CH:31]=[CH:30][CH:29]=1
Reactant: CC1CCC(C)N1c1cccc(N)n1
Reactant: COC(=O)c1cccc(-c2cc(Br)c3nccn3n2)c1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: COC(=O)c1cccc(-c2cc(Nc3cccc(N4C(C)CCC4C)n3)c3nccn3n2)c1
Temperature: 100 °C
Yield: 56.5 %

Procedure:
A mixture of methyl 3-(8-bromoimidazo[1,2-b]pyridazin-6-yl)benzoate (0.2 g, 0.6 mmol), 6-(2,5-dimethylpyrrolidin-1-yl)pyridin-2-amine (116 mg, 0.6 mmol), Pd2(dba)3 (0.036 g, 0.06 mmol), BINAP (0.076 g, 0.12 mmol) and Cs2CO3 (0.59 g, 1.8 mmol) in dioxane (5 mL) was heated to 100° C. for 15 h in a sealed tube under N2 atmosphere then concentrated in vacuo. The residue was purified by chromatography (silica gel, 10 g, 200˜300 mesh, dichloromethane:MeOH=100:1) to afford methyl 3-(8-(6-(2,5-dimethylpyrrolidin-1-yl)pyridin-2-ylamino)imidazo[1,2-b]pyridazin-6-yl)benzoate (150 mg, 56%) as a brown solid. LC-MS: [M+1]+=443, tR=2.092 min.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[OH:9].C1N2CN3CN(C2)CN1C3.S(=O)(=O)(O)O.FC(F)(F)[C:27](O)=[O:28]>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([CH:27]=[O:28])[C:3]=1[OH:9]
Reactant: Oc1ccc(F)cc1F
Reactant: O=C(O)C(F)(F)F
Agent: C1N2CN3CN1CN(C2)C3
Agent: O=S(=O)(O)O
Product: O=Cc1cc(F)cc(F)c1O
Temperature: 75 °C
Reaction time: 0.5 h

Procedure:
260 g (2.00 mol) of 2,4-difluorophenol are dissolved in 1.6 l of trifluoroacetic acid, and 560 g (4.00 mol) of hexamethylenetetramine are added in portions. After 30 min, the batch is warmed to 75° C. and stirred overnight. 2 l of 40 percent sulfuric acid are subsequently added at RT, the mixture is left to stir for 2.5 h, 1.5 l of ice-water are added, and the mixture is stirred for a further 30 min. The deposited precipitate is separated off, washed with water and taken up in dichloromethane. The resultant solution is dried over sodium sulfate and evaporated, giving 3,5-difluorosalicylaldehyde as a beige solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C@@H:6]([N:15]([C:21]([O:23][CH2:24][C:25]([Cl:28])([Cl:27])[Cl:26])=[O:22])[C@H:16]([C:18](O)=[O:19])[CH3:17])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:5])[CH3:2].C(Cl)(=O)C(Cl)=O.Cl.[CH2:36]([O:38][C:39](=[O:46])[C@@H:40]1[CH2:44][CH:43]([OH:45])[CH2:42][NH:41]1)[CH3:37].C(N(CC)CC)C>C(Cl)Cl.CN(C)C=O>[CH2:36]([O:38][C:39](=[O:46])[C@@H:40]1[CH2:44][CH:43]([OH:45])[CH2:42][N:41]1[C:18](=[O:19])[C@H:16]([CH3:17])[N:15]([C@H:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:21]([O:23][CH2:24][C:25]([Cl:27])([Cl:28])[Cl:26])=[O:22])[CH3:37]
Reactant: CCOC(=O)[C@@H]1CC(O)CN1
Reactant: CCOC(=O)[C@H](CCc1ccccc1)N(C(=O)OCC(Cl)(Cl)Cl)[C@@H](C)C(=O)O
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCOC(=O)[C@@H]1CC(O)CN1C(=O)[C@H](C)N(C(=O)OCC(Cl)(Cl)Cl)[C@@H](CCc1ccccc1)C(=O)OCC
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 40.7 %

Procedure:
To N-[(1S)-1-(ethoxycarbonyl)-3-phenylpropyl]-N-(2,2,2-trichloroethoxycarbonyl)-L-alanine (5.94 g, 13.07 mmol) in 50 ml methylene chloride, under N2, was added oxalyl chloride (5.70 ml, 65.33 mmol) and then N,N-dimethylformamide (20 uL). The solution was stirred 3.5 hours and concentrated in vacuo. The residue was diluted with 30 ml methylene chloride and cooled with an ice bath while under N2. To this solution was added portionwise a mixture of 4-hydroxy-L-proline ethyl ester hydrochloride (1.96 g, 10.05 mmol) and triethylamine (6.99 ml, 50.25 mmol) in 40 ml methylene chloride. After the addition was complete the solution was slowly warmed to room temperature, stirred 18 hours and concentrated in vacuo. The residue was dissolved in ether and washed with water, 10% HCl, 1N NaOH, and brine, and dried (MgSO4) and concentrated in vacuo. Chromatography of the residue on HPLC, using 50% ethyl acetate in hexanes as eluents, provided 2.44 g (41%) of the oily product.
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[N:13]1([CH2:18][C@@H:19]([O:26][C:27]2[CH:36]=[CH:35][C:34]3[C:33](=[O:37])[CH2:32][CH2:31][CH2:30][C:29]=3[C:28]=2[CH2:38][S:39][C:40]2[CH:41]=[C:42]([CH:46]=[CH:47][CH:48]=2)[C:43](O)=[O:44])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:17]=[CH:16][N:15]=[CH:14]1.[NH2:49][CH2:50][CH2:51][OH:52]>O>[OH:52][CH2:51][CH2:50][NH:49][C:43](=[O:44])[C:42]1[CH:46]=[CH:47][CH:48]=[C:40]([S:39][CH2:38][C:28]2[C:29]3[CH2:30][CH2:31][CH2:32][C:33](=[O:37])[C:34]=3[CH:35]=[CH:36][C:27]=2[O:26][C@@H:19]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:18][N:13]2[CH:17]=[CH:16][N:15]=[CH:14]2)[CH:41]=1
Reactant: NCCO
Reactant: O=C(O)c1cccc(SCc2c(O[C@H](Cn3ccnc3)c3ccccc3)ccc3c2CCCC3=O)c1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O
Product: O=C(NCCO)c1cccc(SCc2c(O[C@H](Cn3ccnc3)c3ccccc3)ccc3c2CCCC3=O)c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 81.2 %

Procedure:
A mixture of 1,1′-carbonyldiimidazole (49 mg, 0.30 mmol, 0.60M in DMF) and 3-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfanyl}benzoic acid (50 mg, 0.10 mmol, 0.20M in DMF) in a capped vial were placed in a heater-shaker at 55° C. for 20 min. It was removed from the heater-shaker and stood at room temperature. A solution of 2-aminoethanol (31 mg, 0.50 mmol, 1.0M in DMF) was added and the reaction mixture was further shaken at room temperature over-night. Water (6 ml) was added and the mixture was shaken at room temperature for 10 min. before being stored in refrigerator over-night. The precipitate was filtered, washed with cold water (2×0.5 ml) and dried in a vacuum oven at 40° C. until constant weight was obtained. 44 mg of the required benzamide was obtained as a beige solid: Low resolution mass spectrum (LC-MS, APCI) m/z 542 [M+H]+.
Reaction SMILES: C([Li])CCC.[CH:6]([C@H:9]1[CH2:13][O:12][C:11](=[O:14])[NH:10]1)([CH3:8])[CH3:7].[C:15]1([CH2:21][CH2:22][C:23](Cl)=[O:24])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[Cl-].[NH4+]>C1COCC1>[CH:6]([C@H:9]1[CH2:13][O:12][C:11](=[O:14])[N:10]1[C:23](=[O:24])[CH2:22][CH2:21][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([CH3:8])[CH3:7]
Reactant: CC(C)[C@H]1COC(=O)N1
Reactant: O=C(Cl)CCc1ccccc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)[C@H]1COC(=O)N1C(=O)CCc1ccccc1
Temperature: -55 °C
Reaction time: 0.5 h
Yield: 91.3 %

Procedure:
Add n-butyllithium (2.5 M solution in hexanes, 32 mL of, 80 mmol) to a solution of 4-(S)-isopropyloxazolidin-2-one (10.26 g, 79.4 mmol) in THF (250 mL) at −78° C. Stir 30 min. Add 3-phenylpropionyl chloride (13.2 mL, 89 mmol) over 4 min. Stir 2.5 h at −78° C., then warm to −55° C. and stir 2 h. Add saturated aqueous ammonium chloride (75 mL) and warm to room temperature. Extract with dichloromethane and wash extract with 1 N NaOH (200 mL), saturated aqueous sodium chloride, dry (magnesium sulfate) and concentrate. Add hexanes (50 mL), filter solids and dry under vacuum to give a white solid (18.94 g, 91%).
Reaction SMILES: [Li]CCCC.[CH3:6][C:7]([O-:10])(C)[CH3:8].[K+].[Cl:12][C:13]1[CH:14]=[C:15]([F:20])C=[C:17]([Cl:19])[CH:18]=1.C(=O)C>C1COCC1>[Cl:19][C:17]1[CH:18]=[C:13]([Cl:12])[CH:14]=[C:15]([F:20])[C:6]=1[CH:7]([OH:10])[CH3:8]
Reactant: CC(C)(C)[O-]
Reactant: Fc1cc(Cl)cc(Cl)c1
Agent: CC=O
Agent: [K+]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(O)c1c(F)cc(Cl)cc1Cl
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
A solution of n-BuLi (4.8 mL, 12 mmol, 2.5 M solution in hexane) was added to THF (50 mL) at −78° C. under nitrogen, followed by the addition of 1.0 M KOtBu in THF (12 mL, 12 mmol). The mixture was stirred at −78° C. for 30 min, then 3,5-dichlorofluorobenzene (1.65 g, 10.0 mmol) in THF (5 mL) was added slowly, and the resulting mixture was stirred at this temperature for 30 min. Then a solution of acetaldehyde (0.88 g, 20 mmol) in THF (5 mL) was added. The mixture was slowly warmed to rt. The mixture was quenched with water (10 mL), and diluted with EtOAc (50 mL). The organic phase was separated, washed with brine (10 mL), and dried over anhydrous sodium sulfate. The crude material was purified by silica gel chromatography (Hex:EtOAc=95:5→90:10) to give the title compound as a colorless oil. 1H NMR (CDCl3): δ=1.62 (d, J=6.8 Hz, 3H), 2.30 (br s, 1H, —OH), 5.35 (q, J=6.8 Hz, 1H), 7.05 (dd, J=10.6, 2.0 Hz, 1H), 7.20 (m, 1H).