Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[CH2:9][C:10]1[N:11]([CH3:23])[C:12]([C:15](=[O:22])[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:13][CH:14]=1)[NH2:5].N1C=CC=CC=1.[C:30]([O:33][CH2:34][CH2:35][S:36](Cl)(=[O:38])=[O:37])(=[O:32])[CH3:31]>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([NH:5][S:36]([CH2:35][CH2:34][O:33][C:30](=[O:32])[CH3:31])(=[O:38])=[O:37])[CH:6]=[CH:7][C:8]=1[CH2:9][C:10]1[N:11]([CH3:23])[C:12]([C:15](=[O:22])[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[CH:13][CH:14]=1
Reactant: Cn1c(Cc2ccc(N)cc2F)ccc1C(=O)c1ccccc1
Reactant: CC(=O)OCCS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)OCCS(=O)(=O)Nc1ccc(Cc2ccc(C(=O)c3ccccc3)n2C)c(F)c1
Yield: 57.7 %

Procedure:
3-Fluoro-4-[5-benzoyl-1-methyl-1H-pyrrol-2-ylmethyl]aniline (0.75 g, 2.43 mmol) [prepared as described in Example 1, but substituting ethyl 1,4-dimethylpyrrole-2-acetate with methyl 1-methylpyrrole-2-acetate in Step (a)], and pyridine (0.39 ml, 4.88 mmol) were dissolved in methylene chloride (8 ml). 2-Acetoxyethanesulfonyl chloride (681 mg, 3.65 mmol) was added to the solution and after 15 min, the reaction mixture was partitioned between ethyl acetate and water. The organic layer was separated, washed with brine, dried over sodium sulfate and concentrated to dryness. Purification of the residue by flash chromatography (hexane-ethyl acetate, 3:2) gave N-{3-fluoro-4-[5-benzoyl-1-methyl-1H-pyrrol-2-ylmethyl]-phenyl}-2-(acetoxy)ethanesulfonamide, (643 mg, 58%) as a solid. ##STR57##
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[C:10]([F:13])([F:12])[F:11].[CH3:14][C:15]1[NH:16][CH:17]=[CH:18][N:19]=1>>[CH3:14][C:15]1[N:16]([C:2]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=2[C:10]([F:13])([F:12])[F:11])[CH:17]=[CH:18][N:19]=1
Reactant: Cc1ncc[nH]1
Reactant: N#Cc1ccc(Cl)c(C(F)(F)F)c1
Product: Cc1nccn1-c1ccc(C#N)cc1C(F)(F)F

Procedure:
The title compound is prepared using an analogous method as described in Example 1.1, utilising 4-chloro-3-(trifluoromethyl)-benzonitrile (Lancaster Synthesis GmbH) and 2-methyl-imidazole (Fluka, Buchs, Switzerland), with a reaction temperature of 145° C. for 38 hours.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6](=[C:11]([C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[CH:23]=1)[C:12]1[CH:17]=[CH:16][C:15]([S:18]([CH3:21])(=[O:20])=[O:19])=[CH:14][CH:13]=1)[CH2:7][C:8](O)=[O:9])=[O:5])[CH3:2].CO>O1CCCC1>[F:28][C:24]1[CH:23]=[C:22]([C:11]([C:12]2[CH:13]=[CH:14][C:15]([S:18]([CH3:21])(=[O:20])=[O:19])=[CH:16][CH:17]=2)=[C:6]([CH2:7][CH2:8][OH:9])[C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH:27]=[CH:26][CH:25]=1
Reactant: CCOC(=O)C(CC(=O)O)=C(c1ccc(S(C)(=O)=O)cc1)c1cccc(F)c1
Solvent: C1CCOC1
Solvent: CO
Product: CCOC(=O)C(CCO)=C(c1ccc(S(C)(=O)=O)cc1)c1cccc(F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.3 %

Procedure:
15.5 ml (0.155 mol) of borane/methyl sulphide complex are added dropwise to a solution of 31.5 g (0.0775 mol) of 3-ethoxycarbonyl-4-(3-fluorophenyl)-4-(4-methanesulphonylphenyl)-3-butenoic acid, prepared in Example 11, in 90 ml of anhydrous tetrahydrofuran. The mixture is stirred at room temperature for 8 hours and 23.5 ml of methanol are added dropwise. The mixture is evaporated to dryness under vacuum and the residue is taken up with ethyl acetate and then treated with an aqueous solution of 7.6 g of potassium carbonate. The organic phase is decanted and then dried over magnesium sulphate and evaporated to dryness under vacuum to give 29.3 g of ethyl 3-(3-fluorophenyl)-3-(4-methanesulphonylphenyl)-2-(2-hydroxyethyl)-2-propenoate in the form of a viscous oil, which is used as such in the next step.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([OH:10])=[CH:9][C:4]=2[O:3][CH2:2]1.C([Mg]Cl)(C)C.[F:16][C:17]([F:30])([F:29])[C:18]1[CH:19]=[CH:20][CH:21]=[C:22]2[C:26]=1[NH:25][C:24](=[O:27])[C:23]2=[O:28]>O1CCCC1>[OH:28][C:23]1([C:7]2[C:8]([OH:10])=[CH:9][C:4]3[O:3][CH2:2][O:1][C:5]=3[CH:6]=2)[C:22]2[C:26](=[C:18]([C:17]([F:16])([F:29])[F:30])[CH:19]=[CH:20][CH:21]=2)[NH:25][C:24]1=[O:27]
Reactant: Oc1ccc2c(c1)OCO2
Reactant: O=C1Nc2c(cccc2C(F)(F)F)C1=O
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: O=C1Nc2c(C(F)(F)F)cccc2C1(O)c1cc2c(cc1O)OCO2
Temperature: 25 °C
Reaction time: 4 h
Yield: 175 %

Procedure:
To a solution of 1,3-benzodioxol-5-ol (9.63 g, 69.7 mmol) in anhydrous tetrahydrofuran (200 mL) was added dropwise a solution of isopropyl magnesium chloride (92.9 mmol, 46.5 mL, 2.0 M solution in tetrahydrofuran) over 30 min at 0° C. 7-Trifluoromethylisatin (4.00 g, 22.0 mmol) was added in one portion. The reaction mixture was stirred at ambient temperature for 4 h and the reaction was quenched by the addition of 10% aqueous hydrochloric acid (25.0 mL) and the mixture was concentrated in vacuo to dryness. The residue was diluted with ethyl acetate (200 mL), washed with saturated ammonium chloride (3×30.0 mL), brine (3×30.0 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to dryness. The residue was triturated with hot diethyl ether to afford 3-hydroxy-3-(6-hydroxy-1,3-benzodioxol-5-yl)-7-(trifluoromethyl)-1,3-dihydro-2H-indol-2-one (13.6 g, 83%): 1H NMR (300 MHz, DMSO-d6) δ 10.65 (s, 1H), 9.21 (s, 1H), 7.38 (d, J=7.8 Hz, 1H), 7.22 (s, 1H), 7.07 (d, J=7.2 Hz, 1H), 6.95 (dd, J=7.7, 7.7 Hz, 1H), 6.57 (s, 1H), 6.17 (s, 1H), 5.89 (d, J=6.2 Hz, 2H); 13C NMR (75 MHz, DMSO-d6) δ 179.2, 148.6, 147.3, 141.0, 139.9, 135.7, 127.9, 125.3, 124.3, 121.7, 119.8, 110.1, 107.2, 101.2, 97.7, 73.9; MS (ES−) m/z 352.2 (M−1).
Reaction SMILES: [CH:1]([C:3]([NH:6][C:7](=[O:16])[C:8]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][C:9]=1[F:15])([CH3:5])[CH3:4])=[O:2].[CH3:17][Mg]Br.[Cl-].[NH4+]>C1COCC1>[OH:2][CH:1]([CH3:17])[C:3]([NH:6][C:7](=[O:16])[C:8]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][C:9]=1[F:15])([CH3:5])[CH3:4]
Reactant: C[Mg]Br
Reactant: CC(C)(C=O)NC(=O)c1ccc(F)cc1F
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(O)C(C)(C)NC(=O)c1ccc(F)cc1F
Temperature: 25 °C
Yield: 86 %

Procedure:
To a solution of N-(1-formyl-1-methylethyl)-2,4-difluorobenzamide obtained in Example 32 (1.14 g, 5 mmol) in THF (10 ml) was added 0.9 M methyl magnesium bromide in THF (13 ml, 12 mmol) dropwise at −20° C. The reaction mixture was warmed gradually to room temperature over 2 hours and added to 10% aqueous ammonium chloride (100 ml). The resulting mixture was extracted with ethyl acetate, washed with saturated aqueous NaHCO3 and brine, dried over MgSO4, concentrated under a reduced pressure and the residue was crystallized from hexane/ethyl acetate to give the title compound (1.05 g; 86%).
Reaction SMILES: FC(F)(F)C(O)=O.[Br:8][C:9]1[CH:10]=[C:11]([CH:20]=[CH:21][CH:22]=1)[C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=O.[BH4-].[Na+].[OH-].[Na+]>C(Cl)Cl>[CH2:12]([C:11]1[CH:20]=[CH:21][CH:22]=[C:9]([Br:8])[CH:10]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: O=C(c1ccccc1)c1cccc(Br)c1
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Brc1cccc(Cc2ccccc2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 92.8 %

Procedure:
Under a nitrogen atmosphere, into a cold (10° C.) solution of trifluoroacetic acid (240 mL) was added a solution of 3-bromobenzophenone (11 g, 42.1 mmol) in CH2Cl2 (120 mL) over 10 minutes, followed by slow addition of NaBH4-pellets (19 g) over 1 hour. The reaction mixture was stirred at room temperature for 18 h, poured into ice, basified with NaOH (50%) to pH 8 and extracted with ether. The organic extracts were combined, dried over MgSO4, treated with charcoal and filtered. The filtrate was concentrated in vacuo to give 1-benzyl-3-bromobenzene as an oil (9.65 g, 92% yield) MS m/e (M+H)+ 248; 1H NMR (400 MHZ, DMSOd6) δ 3.89 (s, 2H,), 7.19-7.39 (m, 9H).
Reaction SMILES: [NH2:1][C:2]([CH3:32])([CH3:31])[C:3]#[C:4][C:5]1[CH:10]=[CH:9][C:8]([C@@H:11]([N:13]2[CH2:18][CH2:17][C@:16]([CH2:25][C:26]([OH:29])([CH3:28])[CH3:27])([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[O:15][C:14]2=[O:30])[CH3:12])=[CH:7][CH:6]=1.[CH3:33][S:34](Cl)(=[O:36])=[O:35]>>[OH:29][C:26]([CH3:27])([CH3:28])[CH2:25][C@@:16]1([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[O:15][C:14](=[O:30])[N:13]([C@H:11]([C:8]2[CH:9]=[CH:10][C:5]([C:4]#[C:3][C:2]([NH:1][S:34]([CH3:33])(=[O:36])=[O:35])([CH3:31])[CH3:32])=[CH:6][CH:7]=2)[CH3:12])[CH2:18][CH2:17]1
Reactant: C[C@@H](c1ccc(C#CC(C)(C)N)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Reactant: CS(=O)(=O)Cl
Product: C[C@@H](c1ccc(C#CC(C)(C)NS(C)(=O)=O)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O

Procedure:
The title compound was prepared following a procedure analogous to that described in Example 15 using (S)-3-((S)-1-(4-(3-amino-3-methylbut-1-ynyl)phenyl)ethyl)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-1,3-oxazinan-2-one and methanesulfonyl chloride. LC-MS Method 1 tR=1.53 min, m/z=513, 455; 1H NMR (CDCl3) 1.13 (s, 3H), 1.18 (s, 3H), 1.49 (d, 3H), 1.69 (s, 6H), 2.10-2.45 (5H), 2.83 (m, 1H), 3.14 (s, 3H), 5.66 (q, 1H), 6.92 (d, 2H), 7.17 (d, 2H), 7.30-7.40 (5H)
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][N:21]3[C:25]4=[N:26][C:27]([NH:30][C:31]5[CH:32]=[N:33][N:34]([CH3:36])[CH:35]=5)=[N:28][CH:29]=[C:24]4[CH:23]=[N:22]3)[CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O.C(Cl)Cl>>[CH3:36][N:34]1[CH:35]=[C:31]([NH:30][C:27]2[N:26]=[C:25]3[N:21]([CH2:20][C:16]4[CH:17]=[CH:18][CH:19]=[C:14]([N:11]5[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]5)[CH:15]=4)[N:22]=[CH:23][C:24]3=[CH:29][N:28]=2)[CH:32]=[N:33]1
Reactant: Cn1cc(Nc2ncc3cnn(Cc4cccc(N5CCN(C(=O)OC(C)(C)C)CC5)c4)c3n2)cn1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cn1cc(Nc2ncc3cnn(Cc4cccc(N5CCNCC5)c4)c3n2)cn1
Yield: 11.6 %

Procedure:
tert-Butyl-4-(3-((6-((1-methyl-1H-pyrazol-4-yl)amino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)phenyl)piperazine-1-carboxylate (1.10 g, 2.25 mmol) was treated with TFA/DCM (1:2, 12 mL) for 1 h at rt. After evaporation to dryness, the residue was purified by preparative HPLC to afford the title compound (103 mg, 0.26 mmol, 12% over two steps). 1H NMR (d6-DMSO) δ 9.83 (s, 1H), 8.90 (s, 1H), 8.08 (s, 1H), 8.04 (s, 1H), 7.58 (s, 1H), 7.18-7.06 (m, 1H), 7.00 (s, 1H), 6.84-6.75 (m, 1H), 6.73-6.58 (m, 1H), 5.48 (s, 2H), 3.84 (s, 3H), 2.99-2.91 (m, 4H), 2.79-2.71 (m, 4H), 2.22 (br s, 1H); LC-MS method B, (ES+) 390.1, RT=4.93 min.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:8][CH:9]([NH:15][C:16](=[O:34])[C:17]2[CH:22]=[CH:21][CH:20]=[N:19][C:18]=2[N:23]2[CH:27]=[CH:26][C:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[N:24]2)[CH:10]([OH:14])[C:11]([OH:13])=O)[CH:5]=[CH:6][CH:7]=1.[CH:35]1([NH2:38])[CH2:37][CH2:36]1>>[CH:35]1([NH:38][C:11](=[O:13])[CH:10]([OH:14])[CH:9]([NH:15][C:16](=[O:34])[C:17]2[CH:22]=[CH:21][CH:20]=[N:19][C:18]=2[N:23]2[CH:27]=[CH:26][C:25]([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)=[N:24]2)[CH2:8][C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=2)[CH2:37][CH2:36]1
Reactant: NC1CC1
Reactant: O=C(NC(Cc1cccc(F)c1)C(O)C(=O)O)c1cccnc1-n1ccc(-c2ccccc2)n1
Product: O=C(NC(Cc1cccc(F)c1)C(O)C(=O)NC1CC1)c1cccnc1-n1ccc(-c2ccccc2)n1

Procedure:
The reaction was carried out in analogy to reaction step 1.3 by reacting 4-(3-fluorophenyl)-2-hydroxy-3-(2-(3-phenyl-1H-pyrazol-1-yl)nicotinamido)butanoic acid with cyclopropylamine; ESI-MS [M+H]+: 500.2.
Reaction SMILES: [OH:1][CH2:2][C:3]([NH:6][C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=1)=S)([CH3:5])[CH3:4].[OH-].[Na+].C1(C)C=CC(S(Cl)(=O)=O)=CC=1>C1COCC1.O>[CH3:4][C:3]1([CH3:5])[CH2:2][O:1][C:7](=[N:9][C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=2)[NH:6]1
Reactant: CC(C)(CO)NC(=S)Nc1ccc([N+](=O)[O-])cc1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC1(C)COC(=Nc2ccc([N+](=O)[O-])cc2)N1
Temperature: 25 °C
Reaction time: 3 h
Yield: 95.6 %

Procedure:
To a solution of 1-(2-hydroxy-1,1-dimethyl-ethyl)-3-(4-nitro-phenyl)-thiourea (3.25 g, 12 mmol) in THF was added 0.5 M aqueous sodium hydroxide (60.4 mL, 30.2 mmol), followed by dropwise addition of a solution of p-toluenesulfonyl chloride (2.52 g, 13.2 mmol) in THF (20 mL). The mixture was stirred at r.t. for 3 h then diluted with water and extracted with ethyl acetate. The organic extracts were washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo to give (4,4-dimethyl-oxazolidin-2-ylidene)-(4-nitro-phenyl)-amine (2.7 g, 95%).
Reaction SMILES: C([O:8][C:9](=[O:16])[C@@H:10]([CH2:12][C:13]([OH:15])=[O:14])[OH:11])C1C=CC=CC=1.Cl.[C:18]([O:24]N)(=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20]>>[C:18]([O:24][O:8][C:9](=[O:16])[C@@H:10]([CH2:12][C:13]([OH:15])=[O:14])[OH:11])(=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20]
Reactant: CC(C)(C)C(=O)ON
Reactant: O=C(O)C[C@@H](O)C(=O)OCc1ccccc1
Agent: Cl
Product: CC(C)(C)C(=O)OOC(=O)[C@H](O)CC(=O)O
Yield: 89 %

Procedure:
D-Malic acid monobenzyl ester prepared as described by Example 1A was allowed to react with pivalyloxyamine hydrochloride according to the method described in the preceding examples (Part B) to provide in 89% yield O-pivalyloxy-D-malic acid hydroxyamate monobenzyl ester melting at about 75° to about 76° C.
Reaction SMILES: Cl[C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1OC.[C:11](OCC)(=[O:16])[CH2:12][C:13]([CH3:15])=O>>[CH3:15][C:13]1[CH2:12][C:11](=[O:16])[C:4]2[C:5](=[CH:7][CH:8]=[CH:2][CH:3]=2)[N:6]=1
Reactant: COc1cc(N)ccc1Cl
Reactant: CCOC(=O)CC(C)=O
Product: CC1=Nc2ccccc2C(=O)C1

Procedure:
Condensation of 4-chloro-3-methoxy aniline and ethyl acetoacetate followed by thermal cyclization provided 2-methyl-4-quinolone 1 via Conrad-Limpach synthesis. Iodination of 1 with iodine in saturated aqueous potassium iodide solution and n-butylamine provided the 3-iodo-4-quinolone 2. Copper-mediated coupling of 4-bromophenol and 4-trifluoromethoxyphenyl boronic acid with Hunig's base and pyridine afforded the diaryl ether 4. Reaction of the lithium anion of 4 with boron triisopropoxide followed by acidic hydrolysis of the resulting boronic ester provided the boronic acid 5. Suzuki-Miyaura reaction of the 3-iodo-4-quinolone 2 with the boronic acid 5 resulted in difficult to separate mixtures of quinolone starting material and product. This difficulty in separation was likely the result of a combination of pi-stacking and intermolecular hydrogen bonding typical of 4-quinolones. A functional group protection strategy involving the 4-position alcohol was devised that would alleviate this problem by mitigating intermolecular hydrogen bonding. To this end 4-O-carbonates and 4-O-acetates were prepared, but these were found to be labile under Suzuki-Miyaura reaction conditions. A more robust protecting group, a 4-O-ethyl ether, was shown to be stable under these reaction conditions, yet reactive enough to be selectively removed in the presence of an aryl methoxy moiety. The 3-iodo-quinolone 2 was reacted with ethyl iodide and potassium carbonate to give the corresponding ethyl ether 3. Suzuki-Miyaura coupling of 3 with 4-phenoxyphenylboronic acid using palladium tetrakis triphenylphosphine and aqueous potassium carbonate provided 3 in very good yield. ELQ-300 was obtained in quantitative yield by heating the ethyl ether 3 in 30% hydrobromic acid in acetic acid.
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][CH:14]([CH2:17][CH2:18][CH2:19][CH2:20][C@H:21]([NH:27][C@H:28]([C:30]([N:32]2[C@H:39]([C:40]([O:42]CC3C=CC=CC=3)=[O:41])[CH2:38][C@H:37]3[C@@H:33]2[CH2:34][CH2:35][CH2:36]3)=[O:31])[CH3:29])[C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:13][CH2:12]1)=O)C1C=CC=CC=1>C(O)C.[C].[Pd]>[NH:11]1[CH2:12][CH2:13][CH:14]([CH2:17][CH2:18][CH2:19][CH2:20][C@H:21]([NH:27][C@H:28]([C:30]([N:32]2[C@H:39]([C:40]([OH:42])=[O:41])[CH2:38][C@H:37]3[C@@H:33]2[CH2:34][CH2:35][CH2:36]3)=[O:31])[CH3:29])[C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:15][CH2:16]1
Reactant: CCOC(=O)[C@H](CCCCC1CCN(C(=O)OCc2ccccc2)CC1)N[C@@H](C)C(=O)N1[C@H](C(=O)OCc2ccccc2)C[C@@H]2CCC[C@@H]21
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)[C@H](CCCCC1CCNCC1)N[C@@H](C)C(=O)N1[C@H](C(=O)O)C[C@@H]2CCC[C@@H]21
Reaction time: 4 h

Procedure:
In 50 ml of ethanol is dissolved 0.26 g of benzyl (S,S,S)-2-[N-[(S)-5-(1-benzyloxycarbonyl-4-piperidyl)-1-ethoxycarbonylpentyl)-L-alanyl]-2-azabicyclo[3,3,0]octane-3-carboxylate, and a catalytic reduction is carried out at ambient temperature and under atmospheric pressure using 0.2 g of 10% palladium-carbon (50% wet) as a catalyst. After the reaction is allowed to proceed for 4 hours, the catalyst is filtered off, and the filtrate is concentrated under reduced pressure to give (S,S,S)-2-[N-[(S)-5-(4-piperidyl)-1-ethoxycarbonylpentyl)-L-alanyl]-2-azabicyclo[3,3,0]octane-3-carboxylic acid as a colorless oil. This product is dissolved in 5 ml of 1N aqueous sodium hydroxide, and the solution is allowed to stand at room temperature for 1 hour, made weakly acidic with 1 ml of acetic acid and purified by XAD-2 column chromatography (0.15M aqueous ammonia-5% acetonitrile). The effluent is concentrated under reduced pressure, and the concentrate is lyophilized to give 0.15 g of (S,S,S)-2 -[N-[(S)-5-(4-piperidyl)-1-carboxypentyl]-L-alanyl]-2-azabicyclo[3,3,0]octane-3-carboxylic acid as a colorless powder.
Reaction SMILES: I[C:2]1[CH:21]=[CH:20][C:5]([CH2:6][O:7][C@@H:8]2[CH2:13][O:12][C:11]3=[N:14][C:15]([N+:17]([O-:19])=[O:18])=[CH:16][N:10]3[CH2:9]2)=[CH:4][CH:3]=1.[C:22]([Si](C)(C)C)#[CH:23]>CN(C=O)C.CCN(CC)CC.[Cu](I)I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:22]([C:2]1[CH:21]=[CH:20][C:5]([CH2:6][O:7][C@@H:8]2[CH2:13][O:12][C:11]3=[N:14][C:15]([N+:17]([O-:19])=[O:18])=[CH:16][N:10]3[CH2:9]2)=[CH:4][CH:3]=1)#[CH:23]
Reactant: C#C[Si](C)(C)C
Reactant: O=[N+]([O-])c1cn2c(n1)OC[C@@H](OCc1ccc(I)cc1)C2
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: C#Cc1ccc(CO[C@@H]2COc3nc([N+](=O)[O-])cn3C2)cc1
Reaction time: 0.5 h
Yield: 71.1 %

Procedure:
A mixture of iodide 43 (see Example 2C) (1.00 g, 2.49 mmol) and copper iodide (51 mg, 0.27 mmol) in DMF (10 mL) and Et3N (10 mL) was purged with N2. Ethynyltrimethylsilane (1.0 mL, 7.1 mmol) and PdCl2(PPh3)2 (93 mg, 0.13 mmol) were added and the mixture was stirred under N2 for 0.5 h. The resulting mixture was partitioned between EtOAc and water, the organic fraction was dried, and the solvent was removed. The residue was dissolved in THF (50 mL) and tetra-n-butylammonium fluoride (5 mL of a 1M solution in THF, 5 mmol) was added. The solution was stirred for 2 h and then concentrated. The residue was partitioned between EtOAc and water, and the organic fraction was dried and concentrated. Column chromatography of the residue on silca gel using gradient elution (1:1 hexanes EtOAc to EtOAc) gave (6S)-6-[(4-ethynylbenzyl)oxy]-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine (129) (0.530 g, 71%) as a white solid: mp 162-164° C.; 1H NMR [(CD3)2SO] δ 8.01 (s, 1H), 7.45 (d, J=8.3 Hz, 2H), 7.32 (d, J=8.3 Hz, 2H), 4.62-4.71 (m, 3H), 4.47 (d, J=11.9 Hz, 1H), 4.20-4.30 (m, 3H), 4.14 (s, 1H). Anal. (C15H13N3O4) C, H, N.
Reaction SMILES: [CH3:1][N:2]([CH2:4][CH2:5][CH2:6]Cl)[CH3:3].[Mg].[CH2:9]1[CH2:19][C:17](=O)[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10]1>O1CCCC1>[CH3:1][N:2]([CH3:3])[CH:4]([C:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:17][CH2:19][CH:9]=1)[CH2:5][CH3:6]
Reactant: CN(C)CCCCl
Reactant: O=C1CCCc2ccccc21
Agent: [Mg]
Solvent: C1CCOC1
Product: CCC(C1=CCCc2ccccc21)N(C)C
Reaction time: 1.5 h
Yield: 58 %

Procedure:
The Grignard reagent from 300 g (2.5 moles) of dimethylaminopropyl chloride and 60 g (2.5 moles) of magnesium turnings is prepared in 2 l. of tetrahydrofuran. To this is added 300 g (2.0 moles) of α-tetralone in 1 l. of tetrahydrofuran, at a rate to maintain reflux. After the addition the reflux is continued for 1.5 hours, then the mixture is cooled in ice and quenched with 500 ml of saturated ammonium chloride. The layers are separated, and the aqueous diluted with water and reextracted with ether. The organics are evaporated, then treated with a mixture of 350 ml of concentrated HCl and 1400 ml of glacial acetic acid at reflux for 1/2 hour. The solvents are removed in vacuo, and the residue taken up in water, and the aqueous extracted with benzene. Basification liberates the product which is extracted with benzene, dried over carbonate, the solvent evaporated, and the product distilled at 129° C, 0.3 mmHg to give 250 g (58%) of a light yellow liquid, 1-dimethylaminopropyl-3,4-dihydronaphthalene.
Reaction SMILES: [Cl:1][CH2:2][C:3]1[N:4]=[C:5]2[S:12][CH:11]=[N:10][N:6]2[C:7](=[O:9])[CH:8]=1.S(Cl)([Cl:16])(=O)=O>ClC(Cl)C>[Cl:16][C:8]1[C:7](=[O:9])[N:6]2[N:10]=[CH:11][S:12][C:5]2=[N:4][C:3]=1[CH2:2][Cl:1]
Reactant: O=S(=O)(Cl)Cl
Reactant: O=c1cc(CCl)nc2scnn12
Solvent: CC(Cl)Cl
Product: O=c1c(Cl)c(CCl)nc2scnn12
Temperature: 60 °C
Reaction time: 2 h

Procedure:
7-chloromethyl-5H-1,3,4-thiadiazolo[3,2-a]pyrimidine-5-one (10 g), prepared according to Example 1, was reacted with sulfuryl chloride (7.5 g) in dichloroethane (150 ml) under stirring at 60° C. for 2 hours. After cooling the precipitate was filtered then was suspended in water (500 ml) and neutralized by treatment with 35% NaOH. Filtration and washings with water gave 6-chloro-7-chloromethyl-5H-1,3,4-thiadiazolo[3,2-a]pyrimidine-5-one, m.p. 193°-195° C. (7.5 g), which was reacted with triphenylphosphine (9.1 g) in acetonitrile (125 ml) under stirring at reflux temperature for 20 hours. After cooling the precipitate was filtered and washed with ethyl acetate to give (6-chloro-5-oxo-5H-1,3,4-thiadiazolo[3,2-a]pyrimidine-7-yl)-methyl-triphenylphosphonium chloride (16 g), which was suspended in dimethylsulphoxide (60 ml) and treated dropwise with potassium terbutoxide (3.6 g) dissolved in dimethylsulphoxide (30 ml) at a temperature of about 20° C. The solution of the ylide so obtained was then reacted with benzaldehyde (6 g) at 80° C. for 8 hours. After cooling the solution was diluted with ice water and the precipitate was filtered and washed with water. Crystallization from chloroform-ethanol gave 3.4 g of 6-chloro-7-trans-(2-phenyl-ethenyl)-5H-1,3,4-thiadiazolo[3,2-a]pyrimidine-5-one, m.p. 265°-270° C. dec., N.M.R. (CF3COOD) δ p.p.m.: 7.45 (m) (3H, C-3, C-4 and C-5 phenyl protons), 7.53 (d) (1H, β-ethenyl proton), 7.66 (dd) (2H, C-2 and C-6 phenyl protons), 8.05 (d), (1H, α-ethenyl proton), 9.02 (s) (1H, C-2 proton); JHα↑Hβ =16 Hz.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][N:8]2[CH3:11])=[CH:4][C:3]=1[CH:12]([C:14]1[N:18]2[N:19]=[C:20]([C:23](=O)[CH3:24])[CH:21]=[CH:22][C:17]2=[N:16][CH:15]=1)[CH3:13].Cl.[NH:27]([C:29]([NH2:31])=[O:30])[NH2:28]>CO>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][N:8]2[CH3:11])=[CH:4][C:3]=1[CH:12]([C:14]1[N:18]2[N:19]=[C:20](/[C:23](=[N:28]/[NH:27][C:29]([NH2:31])=[O:30])/[CH3:24])[CH:21]=[CH:22][C:17]2=[N:16][CH:15]=1)[CH3:13]
Reactant: CC(=O)c1ccc2ncc(C(C)c3cc4cnn(C)c4cc3F)n2n1
Reactant: NNC(N)=O
Agent: Cl
Solvent: CO
Product: C/C(=N\NC(N)=O)c1ccc2ncc(C(C)c3cc4cnn(C)c4cc3F)n2n1
Temperature: 35 °C
Reaction time: 5 h
Yield: 34.1 %

Procedure:
To a solution of 1-(3-(1-(6-fluoro-1-methyl-1H-indazol-5-yl)ethyl)imidazo[1,2-b]pyridazin-6-yl)ethanone (35 mg, 0.104 mmol) in MeOH (4 mL), was added hydrazinecarboxamide hydrochloride (28.9 mg, 0.259 mmol). The reaction mixture was heated to 35° C. After stirring for 5 h, the solvent was removed and DCM was added to dilute the residue. The resulting mixture was then washed with brine, dried over Na2SO4, and concentrated in vacuo to give (E)-2-(1-(3-(1-(6-fluoro-1-methyl-1H-indazol-5-yl)ethyl)imidazo[1,2-b]pyridazin-6-yl)ethylidene)hydrazinecarboxamide (14 mg, 33%) as a white solid. 1H-NMR (400 MHz, DMSO-d6) δ ppm 9.64 (s, 1H), 8.14 (d, 1H), 7.93 (m, 2H), 7.74 (s, 1H), 7.51 (m, 2H), 4.93 (m, 1H), 3.96 (s, 3H), 2.13 (s, 3H), 1.76 (d, 3H). LCMS (method B): [MH]+=395, tR=2.32 min.