Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7](=O)[CH2:8][CH:9]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:10](=O)[CH3:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][CH2:28][CH2:29][C:30]([OH:32])=[O:31])=[CH:23][CH:22]=1>C(O)(=O)C>[CH3:11][C:10]1[N:20]([C:21]2[CH:22]=[CH:23][C:24]([CH2:27][CH2:28][CH2:29][C:30]([OH:32])=[O:31])=[CH:25][CH:26]=2)[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[CH:8][C:9]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Nc1ccc(CCCC(=O)O)cc1
Reactant: CC(=O)C(CC(=O)c1ccccc1)c1ccccc1
Solvent: CC(=O)O
Product: Cc1c(-c2ccccc2)cc(-c2ccccc2)n1-c1ccc(CCCC(=O)O)cc1
Reaction time: 6 h

Procedure:
A soln of 1,3-diphenyl-pentane-1,4-dione (104 mg; 0.412 mmol) and 4-(4-amino-phenyl)-butyric acid (89 mg; 0.497 mmol) in acetic acid (2 mL) was heated at 120° C. After 6 h, the reaction was concentrated on a rotary evaporator. Ethyl acetate (5 mL) was added and this washed with H2O (1×2 mL) and satd NaCl (1×3 mL). The organic portion was dried (MgSO4) and filtered through silica with an EtOAc wash. Crude product was adsorbed onto silica (0.3 g) then purified by MPLC (12 g of silica using a 0→50% EtOAc in hexanes gradient). Pure product was obtained as a white solid (115 mg; 71%). 1H NMR (CDCl3) δ 7.54-7.49 (m, 2H), 7.44-7.38 (m, 2H), 7.26-7.07 (m, 10H), 6.56 (s, 1H), 2.72 (t, J=7.6 Hz, 2H), 2.40 (t, J=7.4 Hz, 2H), 2.25 (s, 3H), 2.00 (m, 2H); LC-MS (ESI−) 394 ([M−H]−).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][N:9]=[C:10]([CH3:16])[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:4]([N+:17]([O-:19])=[O:18])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O.Br[CH2:32][CH2:33][CH2:34][O:35][CH3:36]>O>[CH3:36][O:35][CH2:34][CH2:33][CH2:32][O:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][N:9]=[C:10]([CH3:16])[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:4]([N+:17]([O-:19])=[O:18])[CH:3]=1
Reactant: CCOC(=O)C(C)=NNc1ccc(O)cc1[N+](=O)[O-]
Reactant: COCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C(C)=NNc1ccc(OCCCOC)cc1[N+](=O)[O-]
Temperature: 60 °C
Reaction time: 15 h
Yield: 42.4 %

Procedure:
To a mixture of ethyl 2-[(4-hydroxy-2-nitrophenyl)hydrazono]propanoate (6.81 g), potassium carbonate (3.52 g) and N,N-dimethylformamide (100 mL) was added 1-bromo-3-methoxypropane (3.90 g) at 60° C., and the mixture was stirred at 60° C. for 15 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4), and concentrated. The obtained residue was subjected to silica gel column chromatography, and eluted with hexane-ethyl acetate (4:1-1:1, volume ratio) to give the title compound (3.67 g, yield 42%) as orange crystals.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][CH2:11][NH:10][CH2:9]2)=[CH:4][C:3]=1[O:14][CH3:15].[C:16]1([CH2:22][CH2:23][C:24](Cl)=O)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1(C)C=CC=CC=1.O1CCCC1>[C:16]1([CH2:22][CH2:23][CH2:24][N:10]2[CH2:11][CH2:12][CH2:13][CH:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[C:3]([O:14][CH3:15])[CH:4]=3)[CH2:9]2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C(Cl)CCc1ccccc1
Reactant: COc1cc(C2CCCNC2)ccc1F
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: COc1cc(C2CCCN(CCCc3ccccc3)C2)ccc1F
Yield: 95.8 %

Procedure:
The title compound was prepared by acylation of 995 mg (4.75 mmole) of the 3-(4-fluoro-3-methoxyphenyl)piperidine from Preparation 8, Part B, with 1.2 g (7.13 mmole) of 3-phenylpropionyl chloride in toluene, followed by reduction with 831 mg (21.9 mmole) of lithium aluminum hydride in tetrahydrofuran, substantially according to the procedure of Preparation 3. This afforded 1.49 g (96% yield) of the title compound.
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:6]=[C:7]([CH2:16][CH2:17][C:18]([NH:20][NH2:21])=[O:19])[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])[CH3:3].C(=O)(O)[O-].[Na+].[N:27]#[C:28]Br>O1CCOCC1.O.C(OCC)(=O)C>[NH2:27][C:28]1[O:19][C:18]([CH2:17][CH2:16][C:7]2[CH:6]=[C:5]([C:2]([CH3:1])([CH3:3])[CH3:4])[C:10]([OH:11])=[C:9]([C:12]([CH3:13])([CH3:14])[CH3:15])[CH:8]=2)=[N:20][N:21]=1
Reactant: N#CBr
Reactant: CC(C)(C)c1cc(CCC(=O)NN)cc(C(C)(C)C)c1O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)c1cc(CCc2nnc(N)o2)cc(C(C)(C)C)c1O
Reaction time: 5 h
Yield: 59 %

Procedure:
A solution of 3,5-bis(1,1-dimethylethyl)-4-hydroxybenzenepropanoic acid hydrazide (0.50 g, 1.71 mmol) in dioxane (15 mL) is added to a solution of sodium bicarbonate (0.16 g, 1.88 mmol) in water (4 mL). Cyanogen bromide (0.20 g, 1.88 mmol) is then added in 4 equal portions at 1-minute intervals, and stirring is continued for 5 hours. The reaction mixture is diluted with ethyl acetate and sequentially washed with aqueous sodium bicarbonate, water, and brine. Drying the organic phase over magnesium sulfate and evaporation provides a solid which is crystallized from ethyl acetate/hexane followed by methanol/water to give 0.32 g (59%) of 4-[2-(5-amino-1,3,4-oxadiazol-2-yl)ethyl]-2,6-bis(1,1-dimethylethyl)phenol, mp 220.0°-221.0° C.
Reaction SMILES: [K].[OH:2][CH2:3][N:4]1[C:9](=[O:10])[NH:8][C:7](=[O:11])[CH:6]=[N:5]1.[C:12]1([C:22](Cl)=[O:23])[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][CH:13]=1.C(O)(=O)C>N1C=CC=CC=1.O.C(OCC)(=O)C>[C:12]1([C:22]([O:2][CH2:3][N:4]2[C:9](=[O:10])[NH:8][C:7](=[O:11])[CH:6]=[N:5]2)=[O:23])[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][CH:13]=1
Reactant: O=c1cnn(CO)c(=O)[nH]1
Reactant: O=C(Cl)c1cccc2ccccc12
Agent: [K]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: O
Product: O=C(OCn1ncc(=O)[nH]c1=O)c1cccc2ccccc12
Reaction time: 8 h

Procedure:
A potassium salt of 2-hydroxymethyl-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine (1.81 g) is suspended in pyridine (20 ml). The mixture is ice-cooled and dropwise added with 1-naphthylcarbonyl chloride (2.48 g). After the completion of the addition, the reaction mixture is allowed to stand overnight. The pyridine is removed in vacuo from the mixture to give the residue. The residue is dissolved in water, and the resultant aqueous solution is acidified with acetic acid. The acidic aqueous solution is added with ethyl acetate (50 ml) and water (20 ml), and the ethyl acetate layer is separated and evaporated to dryness under reduced pressure. The residue is recrystallized from ethanol to give 2-(1-naphthylcarbonyloxymethyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine (Compound No. 43). Yield, 1.44 g (82%). M.P., 134.0° C.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[Br:7][CH2:8][CH2:9][CH2:10]Br.[C:12]1([SH:18])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>CC(CC)=O>[Br:7][CH2:8][CH2:9][CH2:10][S:18][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: BrCCCBr
Reactant: Sc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: BrCCCSc1ccccc1
Reaction time: 18 h

Procedure:
Powdered anhydrous potassium carbonate (4.3 kg, 31 moles) was added to a mixture of 1,3-dibromopropane (6.55 kg, 32 moles), thiophenol (1.2 kg, 10.9 moles) and methylethylketone (9 L). The alkylation was carried out under a hood in a 22 liter flask equipped with a mechanical stirrer, heating mantle, and 2 reflux condensers. Nitrogen gas was passed over the top of the condensers. Within 30 minutes the mixture had generated enough heat to attain reflux. Reflux was then maintained for another 30 to 60 minutes. The mixture was permitted to come to room temperature over an 18 hour period. The solvent layer was siphoned off and filtered through celite. The salts were filtered and washed with acetone. The filtrates were concentrated. The residue was vacuum distilled. Three fractions were collected:
Reaction SMILES: O[CH2:2][C:3]1[N:4]=[C:5]2[CH:10]=[C:9]([S:11][C:12]3[CH:17]=[CH:16][C:15]([NH:18][C:19]([CH:21]4[CH2:23][CH2:22]4)=[O:20])=[CH:14][CH:13]=3)[N:8]=[C:7]([NH:24][C:25]3[CH:29]=[C:28]([CH3:30])[NH:27][N:26]=3)[N:6]2[CH:31]=1.[CH3:32][NH2:33]>>[CH3:30][C:28]1[NH:27][N:26]=[C:25]([NH:24][C:7]2[N:6]3[CH:31]=[C:3]([CH2:2][NH:33][CH3:32])[N:4]=[C:5]3[CH:10]=[C:9]([S:11][C:12]3[CH:17]=[CH:16][C:15]([NH:18][C:19]([CH:21]4[CH2:23][CH2:22]4)=[O:20])=[CH:14][CH:13]=3)[N:8]=2)[CH:29]=1
Reactant: CN
Reactant: Cc1cc(Nc2nc(Sc3ccc(NC(=O)C4CC4)cc3)cc3nc(CO)cn23)n[nH]1
Product: CNCc1cn2c(Nc3cc(C)[nH]n3)nc(Sc3ccc(NC(=O)C4CC4)cc3)cc2n1

Procedure:
The title compound was synthesized using N-(4-(2-(hydroxymethyl)-5-(5-methyl-1H-pyrazol-3-ylamino)imidazo[1,2-c]pyrimidin-7-ylthio)phenyl)cyclopropanecarboxamide and methyl amine using the procedure described in Example 283. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.82 (d, J=5.56 Hz, 4H) 1.82 (dt, J=12.06, 5.97 Hz, 1H) 2.11 (s, 3H) 3.28 (s, 3H) 4.03 (s, 2H) 5.84 (s, 1H) 6.49 (s, 1H) 7.53 (d, J=8.08 Hz, 2H) 7.75 (d, J=8.08 Hz, 2H) 8.27 (s, 1H) 10.48 (s, 1H) 12.12 (s, 1H); ESI-MS: m/z calc'd for C22H24N8OS 448.54; found 449.4 (M+H)+
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[CH2:7][CH:6]([C:8](O)=[O:9])[CH2:5][CH2:4][O:3]1.C(Cl)(=O)C([Cl:15])=O>C(Cl)Cl.CN(C=O)C>[CH3:1][C:2]1([CH3:11])[CH2:7][CH:6]([C:8]([Cl:15])=[O:9])[CH2:5][CH2:4][O:3]1
Reactant: CC1(C)CC(C(=O)O)CCO1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC1(C)CC(C(=O)Cl)CCO1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 2,2-dimethyltetrahydro-2H-pyran-4-carboxylic acid (530 mg, 3.35 mmol) in 10 mL of DCM at 0° C. was added 1 drop of DMF followed by oxalyl chloride (0.33 mL, 3.69 mmol) and the reaction stirred at RT for 3 hrs. The reaction was then concentrated and used with out further purification.
Reaction SMILES: [C:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:13][N:14]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:15](Cl)=[O:16]>ClCCl>[C:1]([O:5][C:6]1[CH:7]=[CH:8][C:9]([O:12][C:15](=[O:16])[N:14]([CH3:13])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:10][CH:11]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(C(=O)Cl)c1ccccc1
Reactant: CC(C)(C)Oc1ccc(O)cc1
Solvent: ClCCl
Product: CN(C(=O)Oc1ccc(OC(C)(C)C)cc1)c1ccccc1

Procedure:
The title compound was prepared from 4-tert-butoxy-phenol and N-methyl-N-phenylcarbamoyl chloride. The crude product was subjected to flash chromatography (Quad 12/25, flash 12, dichloromethane) followed by a recrystallization from ethanol (41%, crystals). HPLC-MS m/z=300.3 (M+1), Rt: 4.7 min.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=1[CH:4]=[O:5].[CH2:13]([O:15][C:16](=[O:27])[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([OH:26])[CH:19]=1)[CH3:14].C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1>[CH2:13]([O:15][C:16](=[O:27])[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([O:26][C:2]2[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=2[CH:4]=[O:5])[CH:19]=1)[CH3:14]
Reactant: CCOC(=O)Cc1ccc(OC)c(O)c1
Reactant: O=Cc1cc([N+](=O)[O-])ccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: CCOC(=O)Cc1ccc(OC)c(Oc2ccc([N+](=O)[O-])cc2C=O)c1
Temperature: 100 °C
Reaction time: 24 h

Procedure:
2-Fluoro-5-nitrobenzaldehyde (8.8 g, 52 mmol), (3-hydroxy-4-methoxy-phenyl)-acetic acid ethyl ester (10.0 g, 48 mmol), and potassium carbonate (10.0 g, 69 mmol) were combined in 1,4-dioxane (150 mL), and the reaction was stirred at 100° C. for 24 hours. The mixture was worked up to give the title compound.
Reaction SMILES: [Br:1][C:2]1[C:3](N)=[N:4][CH:5]=[C:6]([F:8])[CH:7]=1.[Br:10]Br.N([O-])=O.[Na+].S([O-])([O-])=O.[Na+].[Na+]>Br.O>[Br:10][C:3]1[C:2]([Br:1])=[CH:7][C:6]([F:8])=[CH:5][N:4]=1
Reactant: Nc1ncc(F)cc1Br
Reactant: BrBr
Agent: Br
Agent: O=N[O-]
Agent: O=S([O-])[O-]
Solvent: O
Product: Fc1cnc(Br)c(Br)c1
Temperature: -5 °C
Yield: 50 %

Procedure:
At 60° C., 3-bromo-5-fluoro-pyridin-2-ylamine (56) (1.91 g, 0.01 mol) was dissolved in 48% hydrobromic acid (30 mL). After cooling to −5° C., bromine (3.24 g, 0.02 mol) was added dropwise over 5 min. A solution of sodium nitrite (1.01 g, 0.02 mol) in water (3 mL) was then added at a rate to keep the temperature of the reaction mixture between −5° C. and 0° C. When finished, the temperature was allowed to reach 25° C. The bromine was reduced with an excess of solid sodium sulfite, and the reaction mixture was extracted with EtOAc (3×50 mL). The combined organic extracts were washed with water (30 mL), brine (30 mL), dried over Na2SO4 and filtered. The filtrate was evaporated in vacuo and the residue was purified by flash column chromatography on silica gel (10% to 20% EtOAc in petroleum ether) to give 2,3-dibromo-5-fluoro-pyridine (57) (1.27 g, 5.0 mmol, 50% yield) as a yellow solid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][O:11][C:12]1[C:16]([C:17](=O)[NH2:18])=[C:15]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[O:14][N:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].P(Cl)(Cl)(Cl)=O>CN(C)C=O>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][O:11][C:12]1[C:16]([C:17]#[N:18])=[C:15]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[O:14][N:13]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCCOc1noc(-c2ccccc2)c1C(N)=O
Solvent: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCCOc1noc(-c2ccccc2)c1C#N
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 77.7 %

Procedure:
3-(2-(N-tert-Butoxycarbonylamino)ethoxy)-4-carbamoyl-5-phenylisoxazole (0.38 g) was dissolved in dimethylformamide (4 ml), and phosphorus oxychloride (0.11 ml) was added dropwise thereto at 5° C. under a nitrogen atmosphere, followed by stirring of the mixture at room temperature for 30 minutes. The reaction mixture was poured into ice-cold water and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous NaCl solution and dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=3/1) to obtain the title compound (0.28 g, 78%) as a colorless solid.
Reaction SMILES: [C:1]1(/[CH:7]=[CH:8]/[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Mg].[C:17](OC)(=[O:22])[C:18]([O:20][CH3:21])=[O:19].Cl>O1CCCC1>[C:1]1(/[CH:7]=[CH:8]/[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:17](=[O:22])[C:18]([O:20][CH3:21])=[O:19])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)C(=O)OC
Reactant: Brc1ccccc1/C=C/c1ccccc1
Agent: Cl
Agent: [Mg]
Solvent: C1CCOC1
Product: COC(=O)C(=O)c1ccccc1/C=C/c1ccccc1
Temperature: -15 °C
Reaction time: 0.5 h
Yield: 22.9 %

Procedure:
A solution of the Grignard reagent prepared from E-1-phenyl-2-(2 -bromophenyl)ethylene (8.56 g) and magnesium (0.96 g) in dry tetrahydrofuran (20 ml) was added dropwise over 30 minutes to a stirred solution of dimethyl oxalate (7.76 g) in dry tetrahydrofuran (70 ml) cooled to -15° C. The resulting mixture was stirred at about -15° C. for 30 minutes, then at room temperature for 1 hour, then poured into dilute hydrochloric acid and extracted with ether. The extracts were washed with water, dried and concentrated to give the crude product as a pale yellow oil (17.22 g). Purification by column chromatography using dichloromethane and petrol (1:1) as eluant then evaporative distillation (0.07 torr, oven temperature 170° C.) gave E-methyl 2-(2'-phenylethenyl)phenylglyoxalate (2.01 g, 23% yield) as a yellow oil, pure by GC, 1H nmr (CDCl3) : delta 3.78 (3H, s), 6.88 (centre of 2 doublets, each 1 H, J 16Hz) p.p.m.
Reaction SMILES: CO[C:3]([C:5]1[CH:6]=[CH:7][C:8]2[N:9]([CH:20]=[N:21][CH:22]=2)[C:10]=1[NH:11][C:12]1[CH:17]=[CH:16][C:15]([I:18])=[CH:14][C:13]=1[F:19])=[O:4].[CH:23]([O:25][CH2:26][CH2:27][O:28][NH2:29])=[CH2:24].C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>C1COCC1>[CH:23]([O:25][CH2:26][CH2:27][O:28][NH:29][C:3]([C:5]1[CH:6]=[CH:7][C:8]2[N:9]([CH:20]=[N:21][CH:22]=2)[C:10]=1[NH:11][C:12]1[CH:17]=[CH:16][C:15]([I:18])=[CH:14][C:13]=1[F:19])=[O:4])=[CH2:24]
Reactant: C=COCCON
Reactant: COC(=O)c1ccc2cncn2c1Nc1ccc(I)cc1F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: C=COCCONC(=O)c1ccc2cncn2c1Nc1ccc(I)cc1F
Temperature: 0 °C
Reaction time: 1 h
Yield: 61 %

Procedure:
To a solution of 5-(2-fluoro-4-iodophenylamino)imidazo[1,5-a]pyridine-6-carboxylic acid methyl ester (1.5 g, 3.64 mmol) and O-(2-vinyloxyethyl)hydroxylamine (749 mg, 7.28 mmol) in THF (30 mL) at 0° C. was added lithium bis(trimethylsilyl)amide as a solution in THF (18 mL, 1 M, 18 mmol) over 5 minutes. The reaction mixture was stirred at ˜0° C. for 1 hour before being quenched with saturated aqueous ammonium chloride. Volatile solvents were removed in vacuo and then diethyl ether (10 mL) and ethyl acetate (20 mL) added. The resultant mixture was sonicated causing a precipitate to form which was filtered off to give the title compound as a yellow solid (1.07 g, 61%). LCMS (Method B): RT=2.79 min, M+H+=483.
Reaction SMILES: [C:1]1([CH:8]=[CH:7][C:5]([OH:6])=[CH:4][CH:3]=1)[OH:2].[CH2:9](Br)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH:17]=[CH2:18].[OH-].[K+]>C(O)C.O>[CH2:18]([O:2][C:1]1[CH:8]=[CH:7][C:5]([OH:6])=[CH:4][CH:3]=1)[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH:10]=[CH2:9]
Reactant: Oc1ccc(O)cc1
Reactant: C=CCCCCCCCCBr
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: C=CCCCCCCCCOc1ccc(O)cc1
Yield: 36.4 %

Procedure:
Hydroquinone (37.65 g, 342 mmol) and dec-9-enyl bromide (25 g, 114 mmol) were dissolved in ethanol (150 ml) with warming under a nitrogen atmosphere. The solution was heated under reflux and a solution of potassium hydroxide (6.83 g, 121 mmol) in water (20 ml) was added dropwise over 1 h. The resulting suspension was heated under reflux (3 H) then poured on to water (500 ml) and extracted with ether (3×100 ml). The combined extracts were dried (MgSO4), evaporated in vacuo and the residue extracted with heptane (300 ml). On cooling, it afforded a first crop of the phenol (10.31 g). The remaining material was chromatographed (flash grade silica gel, petroleum ether 40-60° C./diethyl ether 3/2). 2 was isolated as white plates (Rf=0.57). Combined yield=15.61 g (55%). Mp=54° C.
Reaction SMILES: [H-].[Li+].[CH3:3][C:4]1([CH3:12])[C@H:6]([CH:7]=[O:8])[C@H:5]1[C:9]([OH:11])=[O:10].[CH3:13][O:14][CH2:15]Cl.C(=O)(O)[O-].[Na+]>O.O1CCCC1>[CH3:3][C:4]1([CH3:12])[C@H:6]([CH:7]=[O:8])[C@H:5]1[C:9]([O:11][CH2:13][O:14][CH3:15])=[O:10]
Reactant: COCCl
Reactant: CC1(C)[C@H](C=O)[C@H]1C(=O)O
Agent: O=C([O-])O
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: COCOC(=O)[C@@H]1[C@@H](C=O)C1(C)C
Temperature: 15 °C
Reaction time: 0.5 h
Yield: 45.2 %

Procedure:
A mixture of 1.64 g of lithium hydride and 25.6 g of (1R,trans) 2,2-dimethyl-3-formyl-cyclopropane-carboxylic acid and 25 ml of tetrahydrofuran was stirred at 15° C. for 30 minutes and then 18.2 g of a freshly prepared chloromethyl methyl ether (0.225 mols) were added thereto. The mixture was stirred at 20° C. for 4 hours and was then poured into a mixture of ice, water and sodium bicarbonate with stirring. The mixture was extracted with isopropyl ether and the organic phase was evaporated to dryness under reduced pressure. The residue was rectified under vacuum to obtain 15.15 g of methoxymethyl (1R,trans) 2,2-dimethyl-3-formyl-cyclopropane-carboxylate with a boiling point of 67° C. at 0.05 mm Hg.
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][CH2:24][N:23]1[C:27]1[N:32]=[C:31]([NH2:33])[CH:30]=[CH:29][CH:28]=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+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[CH3:21][CH:22]1[CH2:26][CH2:25][CH2:24][N:23]1[C:27]1[N:32]=[C:31]([NH:33][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:30]=[CH:29][CH:28]=1
Reactant: COC(=O)c1cccc(-c2cc(Br)c3nccn3n2)c1
Reactant: CC1CCCN1c1cccc(N)n1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: COC(=O)c1cccc(-c2cc(Nc3cccc(N4CCCC4C)n3)c3nccn3n2)c1
Temperature: 100 °C
Reaction time: 16 h
Yield: 64.4 %

Procedure:
A mixture of methyl 3-(8-bromoimidazo[1,2-b]pyridazin-6-yl)benzoate (288 mg, 0.87 mmol), 6-(2-methylpyrrolidin-1-yl)pyridin-2-amine (230 mg, 1.3 mmol), Pd2(dba)3 (50 mg, 0.087 mmol), BINAP (217 mg, 0.348 mmol), Cs2CO3 (851 mg, 2.61 mmol) and dioxane (20 mL) was heated to 100° C. with stirring for 16 h under N2. The solvent was removed in vacuo and the resulting mixture was purified by chromatography (silica gel, 200-300 mesh, CH2Cl2:MeOH=100:1) to give methyl 3-(8-(6-(2-methylpyrrolidin-1-yl)pyridine-2-ylamino)imidazo[1,2-b]pyridazin-6-yl)benzoate (240 mg, 64%) as a yellow solid. 1H NMR (300 MHz, CDCl3): δ 8.72 (s, 1H), 8.60 (s, 1H), 8.19-8.08 (m, 3H), 7.92 (s, 1H), 7.59-7.54 (m, 2H), 7.41 (t, 1H, J=8.1 Hz), 6.20 (d, 1H, J=7.5 Hz), 6.03 (d, 1H, J=8.1 Hz), 4.27-4.23 (m, 1H), 3.99 (s, 3H), 3.69-3.63 (m, 1H), 3.53-3.43 (m, 1H), 2.15-1.99 (m, 3H), 1.99 (brs, 1H), 1.21 (d, 3H, J=6.3 Hz). LC-MS: [M+H]+, 429, tR=2.055 min, HPLC: 96.86% at 214 nm, 96.95% at 254 nm, tR=3.763 min.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]([OH:9])=[O:8])[CH2:3][CH2:2]1.[OH-].[Na+].[CH2:12]([O:15][C:16](Cl)=[O:17])[CH:13]=[CH2:14]>C(Cl)Cl>[CH2:12]([O:15][C:16]([N:1]1[CH2:6][CH2:5][CH:4]([C:7]([OH:9])=[O:8])[CH2:3][CH2:2]1)=[O:17])[CH:13]=[CH2:14]
Reactant: C=CCOC(=O)Cl
Reactant: O=C(O)C1CCNCC1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: C=CCOC(=O)N1CCC(C(=O)O)CC1
Temperature: 2.5 °C
Reaction time: 2 h

Procedure:
To a solution of 4-piperidincarboxylic acid (25 g) in dry DCM (30 ml) a solution of NaOH 2N (207 ml) was added. The reaction mixture was then cooled to 0-5° and a solution of allylchloroformate (22 ml) in DCM (1 ml) was added over 40 min. The reaction was stirred at 0-5° C. for 2 h, then NaOH 2N (40 ml) was added and the organic phase was separated. The aqueous phase was washed with DCM, then acidified with H2SO4 conc. (10 ml) to pH2 and extracted with EA. The organic layer was washed with brine, dried and the solvent removed in vacuo to give the title compound as a colourless oil (39.5 g).
Reaction SMILES: C1(C[O:8][C:9](=[O:44])[C:10]2[CH:15]=[C:14]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([O:23][CH3:24])=[O:22])[CH:13]=[C:12]([O:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])[CH:11]=2)C=CC=CC=1.[H][H]>[Pd].C1COCC1>[CH2:26]([O:25][C:12]1[CH:11]=[C:10]([CH:15]=[C:14]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([O:23][CH3:24])=[O:22])[CH:13]=1)[C:9]([OH:44])=[O:8])[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43]
Reactant: CCCCCCCCCCCCCCCCCCOc1cc(OCCCCC(=O)OC)cc(C(=O)OCc2ccccc2)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCCCCCOc1cc(OCCCCC(=O)OC)cc(C(=O)O)c1
Yield: 97.3 %

Procedure:
A mixture of 11.3 g of 3-(octadecyloxy)-5-[(5-methoxy-5-oxopentyl)oxy]benzoic acid phenylmethyl ester and 1.5 g of 10% palladium on carbon in 250 ml of THF was stirred ina hydrogen atmosphere at room temperature for 4 hours. The catalyst was removed by filtration and the filtrate was concentrated at reduced pressure to a solid which was triturated with hexane and filtered to give 9.37 g (98% yield, mp 68°-70°) of 3-(octadecyloxy)-5-[(5-methoxy-5-oxopentyl) oxy]benzoic acid.