Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7](C#N)=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:10][Mg+].[Br-].Cl.[C:14](=[O:17])(O)[O-].[Na+]>O1CCCC1>[C:14]([C:7]1[C:2]([Cl:1])=[N:3][CH:4]=[CH:5][CH:6]=1)(=[O:17])[CH3:10]
Reactant: C[Mg+]
Reactant: O=C([O-])O
Reactant: N#Cc1cccnc1Cl
Agent: Cl
Agent: [Br-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(=O)c1cccnc1Cl
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To a solution of 2-chloro-3-cyanopyridine (139 mg) in tetrahydrofuran (5 mL) at 0° C. was added dropwise a solution of MeMgBr (3M in ether, 0.67 mL). The resultant mixture was warmed to room temperature and stirred for 3 hr. The reaction solution was cooled to 0° C. and to it was added aqueous HCl solution (2M, 5 mL). The reaction solution was then stirred an additional 16 hr at room temperature and then neutralized by the addition of saturated sodium bicarbonate (NaHCO3) solution. The reaction solution was filtered to remove any precipitates and the filtrate was washed with ethyl acetate (3×10 mL) and aqueous brine (NaCl) solution (10 mL). The organic layer was dried over sodium sulfate (Na2SO4), filtered and concentrated in vacuo to give 3-acetyl-2-chloropyridine as a yellow powder which was used without further purification. The title compound (3-Methyl-1H-pyrazolo[3,4-b]pyridine) was synthesized from 3-acetyl-2-chloropyridine according to the procedure outlined in Example 2.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([NH:19][C:20]2[CH:25]=[C:24]([CH3:26])[CH:23]=[CH:22][N:21]=2)[C:5]2[N:10]([CH2:11][CH2:12][O:13][CH2:14][CH3:15])[N:9]=[C:8]([C:16](O)=[O:17])[C:6]=2[N:7]=1.[CH3:27][S:28]([NH2:31])(=[O:30])=[O:29].Cl.CN(C)CCCN=C=NCC>CN(C)C1C=CN=CC=1.CN(C)C=O>[Cl:1][C:2]1[N:3]=[C:4]([NH:19][C:20]2[CH:25]=[C:24]([CH3:26])[CH:23]=[CH:22][N:21]=2)[C:5]2[N:10]([CH2:11][CH2:12][O:13][CH2:14][CH3:15])[N:9]=[C:8]([C:16]([NH:31][S:28]([CH3:27])(=[O:30])=[O:29])=[O:17])[C:6]=2[N:7]=1
Reactant: CS(N)(=O)=O
Reactant: CCOCCn1nc(C(=O)O)c2nc(Cl)nc(Nc3cc(C)ccn3)c21
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Product: CCOCCn1nc(C(=O)NS(C)(=O)=O)c2nc(Cl)nc(Nc3cc(C)ccn3)c21
Temperature: 25 °C
Reaction time: 60 h

Procedure:
The carboxylic acid of Step 8 (1.0 g, 2.70 mmol), methanesulphonamide (330 mg, 3.5 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (660 mg, 3.5 mmol) and 4-dimethylaminopyridine (390 mg, 3.5 mmol) were dissolved in N,N-dimethylformamide (10 mL) and the reaction mixture stirred at room temperature for 60 hours. Additional methanesulphonamide (165 mg, 1.7 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (330 mg, 1.7 mmol) and 4-dimethylaminopyridine (195 mg, 1.7 mmol) were added and the reaction mixture stirred for a further 20 hours. Further methanesulphonamide (165 1.7 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (330 mg, 1.7 mmol) and 4-dimethylaminopyridine (195 mg 1.7 mmol) were added and the reaction mixture stirred for a final 18 hours. The reaction mixture was concentrated in vacuo and the residue partitioned between dichloromethane (25 mL) and water (25 mL). The organic phase was separated, washed with water (2×25 mL), dried over magnesium sulphate and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with dichloromethane:methanol:acetic acid 100:0:0 to 96:3.5:0.5. The crude product was triturated in warm ethyl acetate (10 mL) to yield the title product, 290 mg.
Reaction SMILES: [CH3:1][C:2]([CH3:21])([CH3:20])[CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH:17]=[CH:18][CH:19]=1)[C:9]([N:12]1[CH:16]=[N:15][CH:14]=[N:13]1)=[N:10][OH:11].[H-].[Na+].I[CH:25]([CH3:27])[CH3:26].O>CN(C)C=O>[CH:25]([O:11][N:10]=[C:9]([N:12]1[CH:16]=[N:15][CH:14]=[N:13]1)[C:8]1[CH:17]=[CH:18][CH:19]=[C:6]([O:5][CH2:4][CH2:3][C:2]([CH3:21])([CH3:20])[CH3:1])[CH:7]=1)([CH3:27])[CH3:26]
Reactant: CC(C)I
Reactant: CC(C)(C)CCOc1cccc(C(=NO)n2cncn2)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)ON=C(c1cccc(OCCC(C)(C)C)c1)n1cncn1
Temperature: 80 °C
Reaction time: 0.33 h
Yield: 75.7 %

Procedure:
To a solution of 1.6 g (5.6 mmol) of 1-[3-(3,3-dimethylbutoxy)benzohydroximoyl]-1H-1,2,4-triazole dissolved in 100 ml of N,N-dimethylformamide was added 0.16 g (6.7 mmol) of sodium hydride. The mixture was stirred for 20 minutes at 80° C. And then allowed to sit and cool naturally to about 50° C. To the mixture was added 1.1 g (6.5 mmol) of 2-iodopropane and stirred for 1 hour at about 50° C. The reaction mixture was allowed to sit and cool naturally to room temperature. The cooled mixture was poured into water and extracted with ethyl acetate. After being washed with water, the organic layer was dried over anhydrous magnesium sulfate. The solvent in the organic layer was removed under reduced pressure. The residue was purified by column chromatography, thus obtaining 1.4 g (yield: 87%) of the desired product having a refractive index of [nD20 ] 1.5289 at 20° C.
Reaction SMILES: [CH3:1][C:2]([CH3:21])([CH3:20])[C:3]([NH:5][C:6]1[NH:7][C:8](=O)[C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[NH:11][C:10]=2[N:18]=1)=[O:4].P(Cl)(Cl)([Cl:24])=O>>[Cl:24][C:8]1[C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[NH:11][C:10]=2[N:18]=[C:6]([NH:5][C:3](=[O:4])[C:2]([CH3:21])([CH3:20])[CH3:1])[N:7]=1
Reactant: CC(C)(C)C(=O)Nc1nc2[nH]c3ccccc3c2c(=O)[nH]1
Reactant: O=P(Cl)(Cl)Cl
Product: CC(C)(C)C(=O)Nc1nc(Cl)c2c(n1)[nH]c1ccccc12
Yield: 59 %

Procedure:
In a 50 mL R.B.F. was placed 5 (56 mg, 0.17 mmol) and phosphoryl trichloride (15 mL). The mixture was stirred and heated at reflux for 4 hours. The phosphoryl trichloride was evaporated under reduced pressure using a vacuum aspirator. The resulting residue was cooled in an ice and water mixture, and neutralized with ammonium hydroxide solution to yield a precipitate that was filtered and dried over P2O5. The filterate was extracted with chloroform and dried over sodium sulfate. The dry precipitate and filterate were combined and evaporated to provide 35 mg of 6 as a brown solid in 59% yield. Compound 6 was used without further purification for the subsequent step. TLC Rf 0.65 (chloroform-methanol 10:1); mp 234° C.; 1H NMR (DMSO-d6) δ 1.24 (s, 9H, C(CH3)3), 7.36-8.17 (m, 4H, Ar—H), 10.25 (s, 1H, 2-NH, exch), 12.55 (s, 1H, 9-NH, exch). Anal. Calculated (C15H15ClN4O. 0.15H2O): C, 58.98; H, 5.04; N, 18.34; Cl, 11.60. Found: C, 59.00; H, 5.09; N, 17.97; Cl, 11.83.
Reaction SMILES: [CH:1]1([S:4][C:5]2[CH:20]=[CH:19][CH:18]=[CH:17][C:6]=2/[CH:7]=[N:8]/[CH2:9][CH2:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:3][CH2:2]1.CCN(CC)CC>C(Cl)Cl.Cl[Ti](Cl)(Cl)Cl>[CH:1]1([S:4][C:5]2[CH:20]=[CH:19][CH:18]=[CH:17][C:6]=2[CH:7]2[CH:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:10][CH2:9][NH:8]2)[CH2:2][CH2:3]1
Reactant: CCOC(=O)CCC/N=C/c1ccccc1SC1CC1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)C1CCNC1c1ccccc1SC1CC1
Reaction time: 3 h

Procedure:
To 58C (15 mmol) in CH2Cl2 (100 mL) at −15° C. was added Et3N (2.1 mL, 15 mmol) followed by TiCl4 (1.0 M in CH2Cl2, 30 mL, 30 mmol). The mixture was stirred from −15° C. to rt over 3.0 h before it was quenched with sat. K2CO3 (100 mL) at 0° C. and stirred at rt for 1.0 h. The mixture was filtered through a pad of wet Celite®, extracted with CH2Cl2 (3×40 mL). The organic layer was washed with water, dried over Na2SO4. A small portion of the dried organic layer was concentrated to give crude ethyl 2-(2-(cyclopropylthio)phenyl)pyrrolidine-3-carboxylate: 1H NMR indicated a mixture of cis and trans isomer in ca. 1:1 ratio. LC-MS 292 (M+H). To the above ethyl 2-(2-(cyclopropylthio)phenyl)pyrrolidine-3-carboxylate in CH2Cl2 was added Et3N (2.1 mL, 15 mmol) and di-tert-butyl dicarbonate (1.0 M in THF, 15 mL, 15 mmol). The mixture was stirred at rt over night before it was quenched with 0.5 N HCl (50 mL). The organic layer was washed with brine, dried (Na2SO4), filtered and concentrated. The resulting residue was purified via silica gel chromatography (0-30% ethyl acetate/hexanes) to provide 58D (3.3 g, 56%) as an oil. 1H NMR indicated a mixture of cis and trans isomer in 1:1 ratio. 1H NMR (400 MHz, CDCl3) δ ppm 0.66-0.75 (m, 2H) 0.87 (t, J=7.03 Hz, 3 H) 1.05-1.08 (m, 2H) 1.14-1.16 (s, 9H) 2.02-2.18 (m, 3H) 3.43-4.19 (m, 5H) 7.06-7.13 (m, 2H) 7.16-7.25 (m, 1H) 7.51-7.60 (m, 1H); LC-MS 292 (M+H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:6][C@H:7]3[NH:18][CH2:17][CH2:16][C@@:13]4([C:14]=2[CH:15]=1)[C@H:8]3[CH2:9][CH2:10][CH2:11][CH2:12]4.[OH-].[Na+].[CH:21]1[CH:26]=[CH:25][C:24]([CH2:27][O:28][C:29](Cl)=[O:30])=[CH:23][CH:22]=1>O1CCOCC1.O>[OH:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:6][C@H:7]3[N:18]([C:29]([O:28][CH2:27][C:24]4[CH:25]=[CH:26][CH:21]=[CH:22][CH:23]=4)=[O:30])[CH2:17][CH2:16][C@@:13]4([C:14]=2[CH:15]=1)[C@H:8]3[CH2:9][CH2:10][CH2:11][CH2:12]4
Reactant: Oc1ccc2c(c1)[C@@]13CCCC[C@H]1[C@@H](C2)NCC3
Reactant: O=C(Cl)OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: O=C(OCc1ccccc1)N1CC[C@]23CCCC[C@H]2[C@H]1Cc1ccc(O)cc13
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.1 %

Procedure:
To (+)-3-hydroxymorphinan (HM) hydrobromide (50.0 g, 154.2 mmol), sodium hydroxide (12.3 g, 308.4 mmol) in a mixture of 1,4-dioxane (200 mL) and water (200 mL) was added Cbz-Cl (24.2 mL, 169.6 mmol) dropwise at room temperature. The reaction mixture was stirred vigorously at room temperature overnight. After the reaction was completed, water (200 mL) was added. The mixture was extracted with diethyl ether (500 mL×2). The combined organics were dried over MgSO4, filtered, and evaporated under vacuum. Standing under high vacuum provided the title compound (57.7 g, 99%) as a light yellow solid. The compound was used for the next step without further purification.
Reaction SMILES: [C:1]([C:4]1[S:5][CH:6]=[CH:7][CH:8]=1)(=[O:3])[CH3:2].[CH3:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[N:18]=[C:19]3[N:23]([C:24]=2[CH:25]=O)[CH:22]=[CH:21][S:20]3)=[CH:13][CH:12]=1.[OH-].[Na+]>C(O)C.C(OCC)(=O)C.CCCCCC>[CH3:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[N:18]=[C:19]3[N:23]([C:24]=2/[CH:25]=[CH:2]/[C:1]([C:4]2[S:5][CH:6]=[CH:7][CH:8]=2)=[O:3])[CH:22]=[CH:21][S:20]3)=[CH:13][CH:12]=1
Reactant: COc1ccc(-c2nc3sccn3c2C=O)cc1
Reactant: CC(=O)c1cccs1
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CCO
Product: COc1ccc(-c2nc3sccn3c2/C=C/C(=O)c2cccs2)cc1
Temperature: 27 °C
Reaction time: 4 h
Yield: 69.9 %

Procedure:
To a stirred solution of 2-acetyl thiophene (126 mg, 1.0 mmol) and a 6-(4-methoxyphenyl) imidazo[2,1-b]thiazol-5-carbaldehyde (258 mg, 1.0 mmol) in ethanol (20 ml) 10% aqueous solution of NaOH was added (5 ml). The reaction mixture was stirred at room temperature 27° C. for 4 h and the reaction was monitored by TLC using ethyl acetate-hexane (3:7) as a solvent system. The solvent was evaporated under vacuum then the residue was dissolved in ethylacetate/water. The organic layer was washed with brine and evaporated. This was further purified by column chromatography using ethyl acetate:hexane (2:8) as a solvent system to obtain the pure product (16a) as yellow solid (256 mg, 70% yield). Mp: 169-172° C.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.S(Cl)(Cl)=O.[CH2:10]([S:17][CH2:18][C:19]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[OH:27])=O)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C(Cl)Cl>[OH:27][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[C:19]([C:2]1[NH:1][CH:5]=[CH:4][N:3]=1)=[CH:18][S:17][CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: c1c[nH]cn1
Reactant: O=C(CSCc1ccccc1)c1ccccc1O
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: Oc1ccccc1C(=CSCc1ccccc1)c1ncc[nH]1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a suspension of 4.08 g of imidazole and 30 ml of dry methylene chloride, 1.78 g of thionyl chloride was added with ice-cooling. After stirring the reaction mixture for 30 minutes, 2.58 g of 2-benzylthio-2'-hydroxyacetophenone was added, followed by further stirring at room temperature for 2 hours. Ice water was added to the reaction mixture, followed by extraction with methylene chloride. The organic, i.e., methylene chloride layer was washed with water, dried over magnesium sulfate and then concentrated. The residue was dissolved in chloroform and was then subjected to chromatography on a silica gel column. Upon concentration of the resultant eluate, there were obtained 180 mg of Isomer A (m.p. 196°-198° C.; Compound 1) and 1.0 g of Isomer B (m.p. 136.5°-138° C.; Compound 2) of 1-(2-hydroxyphenyl)-1-imidazolyl-2-benzylthioethylene (in formula (I), R1, R2, R3 =H, R4 =--SCH2C6H5), both, as colorless crystals.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[CH2:6][C@H:7]([C:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]([CH3:19])[CH:11]=1)[CH2:8][OH:9].CCN(CC)CC.[CH3:27][S:28](Cl)(=[O:30])=[O:29]>C(Cl)Cl.O>[O:1]1[CH2:5][CH2:4][O:3][CH:2]1[CH2:6][C@H:7]([C:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]([CH3:19])[CH:11]=1)[CH2:8][O:9][S:28]([CH3:27])(=[O:30])=[O:29]
Reactant: Cn1cc([C@H](CO)CC2OCCO2)c2ccccc21
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: Cn1cc([C@H](COS(C)(=O)=O)CC2OCCO2)c2ccccc21
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
(R)-Benzoic acid 2-(1-methyl-1H-indol-3-yl)-4-oxo-butyl ester (1.65 g, 5.10 mmol) was dissolved in CH2Cl2 (50 mL). This solution was treated with p-TSA (20 mg) and ethylene glycol (1.4 mL, 26 mmol). The reaction was stirred at room temperature overnight, at which time the organics were removed in vacuo. The solution was diluted with H2O (10 mL) and extracted with Et2O (3×20 mL). The collected organics were washed with brine, dried over Na2SO4 and concentrated in vacuo to provide (R)-benzoic acid 3-[1,3]dioxolan-2-yl-2-(1-methyl-1H-indol-3-yl)-propyl ester. The unpurified product was dissolved in MeOH/THF (18 mL/18 mL) and allowed to stir at room temperature for 10 min. To this was added a 4% NaOH/MeOH (18 mL) solution. The reaction was allowed to stir at room temperature for 1 h. The solution was diluted with H2O (10 mL) and extracted with Et2O (3×20 mL). The collected organics were washed with brine, dried over Na2SO4 and concentrated in vacuo to provide (R)-3-[1,3]dioxolan-2-yl-2-(1-methyl-1H-indol-3-yl)-propan-1-ol (600 mg, 2.30 mmol) after silica gel chromatography (50:50 Et2O/hexanes). 50% Et2O/hexanes). (R)-3-[1,3]Dioxolan-2-yl-2-(1-methyl-1H-indol-3-yl)-propan-1-ol (69.5 mg, 0.267 mmol) was dissolved in CH2Cl2 (8 mL) and Et3N (56 μl, 0.40 mmol). The reaction was cooled to 0° C. and treated with methanesulfonyl chloride (31 μl, 0.40 mmol). The reaction stirred for 1.5 h at this temperature then was allowed to warm to room temperature and stirred for an additional 10 min. The solution was diluted with H2O (5 mL) and extracted with Et2O (3×10 mL). The collected organics were washed with brine, dried over Na2SO4 and concentrated in vacuo to provide (R)-methanesulfonic acid 3-[1,3]dioxolan-2-yl-2-(1-methyl-1H-indol-3-yl)-propyl ester. Deoxygenation was performed following the method of Holder and Matturro (1977) J. Org. Chem. 42:2166.
Reaction SMILES: [N:1]1([CH2:10][C:11]([OH:13])=O)[CH:9]=[C:7]([CH3:8])[C:5](=[O:6])[NH:4][C:2]1=[O:3].C(Cl)Cl.[CH2:17]([O:19][C:20](=[O:28])[CH2:21][CH2:22][NH:23][CH2:24][C:25](=[O:27])[NH2:26])[CH3:18].C1CCC(N=C=NC2CCCCC2)CC1>CN(C=O)C.CN(C=O)C.C(Cl)Cl>[CH2:17]([O:19][C:20](=[O:28])[CH2:21][CH2:22][N:23]([CH2:24][C:25](=[O:27])[NH2:26])[C:11](=[O:13])[CH2:10][N:1]1[CH:9]=[C:7]([CH3:8])[C:5](=[O:6])[NH:4][C:2]1=[O:3])[CH3:18]
Reactant: CCOC(=O)CCNCC(N)=O
Reactant: Cc1cn(CC(=O)O)c(=O)[nH]c1=O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCOC(=O)CCN(CC(N)=O)C(=O)Cn1cc(C)c(=O)[nH]c1=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 61.4 %

Procedure:
DhbtOH (9.37 g, 57.4 mmol), N1-thyminyl acetic acid (10.57 g, 57.4 mmol) and CH2Cl2 (100 mL) were added to a solution of N-(carbamoylmethyl)-β-alanine ethylester (10.0 g, 57.4 mmol) in dry DMF (100 mL). The solution was cooled to 0° C. in an ice bath and a solution of DCC (1.90 g, 9.18 mmol) in DMF/CH2Cl2 (100 mL, 1:1 v/v) was added dropwise within 20 minutes. The ice bath was removed and after stirring for 1 hour at room temperature. The reaction mixture was filtered and the precipitate (DCU) was rinsed with CH2Cl2 (50 mL). The organic solution and the CH2Cl2 rinse were combined. A colorless precipitate formed overnight which was filtered and rinsed with CH2Cl2. The precipitate was dried in vacuo to give 12.0 g (61%) (mp 207-208° C.) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8][CH2:9][CH2:10][CH2:11]Cl)=[CH:6][CH:5]=[CH:4][N:3]=1.[Na].[S:14]1[CH2:18][C:17](=[O:19])[NH:16][C:15]1=[O:20].[I-].[Na+].O>CN(C)C=O>[NH2:1][C:2]1[C:7]([O:8][CH2:9][CH2:10][CH2:11][N:16]2[C:17](=[O:19])[CH2:18][S:14][C:15]2=[O:20])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: O=C1CSC(=O)N1
Reactant: Nc1ncccc1OCCCCl
Agent: [I-]
Agent: [Na+]
Agent: [Na]
Solvent: O
Solvent: CN(C)C=O
Product: Nc1ncccc1OCCCN1C(=O)CSC1=O
Temperature: 80 °C

Procedure:
To a suspension of 9.33 g (50 mmol) of 2-amino-3-(3-chloropropyloxy)pyridine and 6.97 g (50 mmol) of thiazolidine-2,4-dione sodium salt in 200 ml of N,N-dimethylformamide, 7.49 g (50 mmol) of sodium iodide was added, followed by refluxing at 80° C. for 16 hours. After cooling, the reaction mixture was poured into water, extracted with ethyl acetate, washed with water and dried, after which the solvent was distilled off. The residue was purified by column chromatography (eluent, n-hexane/ethyl acetate=1/4→ethyl acetate) to yield 8.14 g (60.9%, yellow solid) of the desired product.
Reaction SMILES: ClC1C=CC2N(C(C(C3C=[C:15]4[C:19](=CC=3F)[N:18]([CH3:23])[N:17]=[CH:16]4)=O)=CN=2)N=1.Cl[C:25]1[CH:26]=[CH:27][C:28]2[N:29]([C:31]([C:34]([C:37]3[CH:38]=[C:39]4[C:43](=[CH:44][C:45]=3[F:46])[N:42]([CH3:47])[N:41]=[CH:40]4)(O)[CH3:35])=[CH:32][N:33]=2)[N:30]=1.C[Mg]Br>C1COCC1.CCOC(C)=O>[F:46][C:45]1[CH:44]=[C:43]2[C:39]([CH:40]=[N:41][N:42]2[CH3:47])=[CH:38][C:37]=1[CH:34]([C:31]1[N:29]2[N:30]=[C:25]([C:15]3[CH:16]=[N:17][N:18]([CH3:23])[CH:19]=3)[CH:26]=[CH:27][C:28]2=[N:33][CH:32]=1)[CH3:35]
Reactant: Cn1ncc2cc(C(=O)c3cnc4ccc(Cl)nn34)c(F)cc21
Reactant: Cn1ncc2cc(C(C)(O)c3cnc4ccc(Cl)nn34)c(F)cc21
Agent: C[Mg]Br
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(c1cc2cnn(C)c2cc1F)c1cnc2ccc(-c3cnn(C)c3)nn12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(rac)-1-(6-Chloro-imidazo[1,2-b]pyridazin-3-yl)-1-(6-fluoro-1-methyl-1H-indazol-5-yl)-ethanol (6-Chloro-imidazo[1,2-b]pyridazin-3-yl)-(6-fluoro-1-methyl-1H-indazol-5-yl)-methanone (Stage 278.3, 3.7 g, 11.22 mmol) was dissolved in THF (250 mL) with heating under Argon. The solution was let to cool down and methylmagnesium bromide (3 M, 7.48 mL) was added. The mixture was stirred at rt for 1 h. It was then diluted with EtOAc and washed with a saturated NaHCO3 sol. The aqueous phase was extracted twice with EtOAc. The combined organics were washed with brine, dried over Na2SO4, filtered and evaporated. The residue was purified by flash chromatography (CombiFlash® Companion System®, with 120 g RediSep® silica gel column, DCM/MeOH=100:0->94:6 in 20 min). The collected fractions containing product were evaporated and the residue was dried under vacuum to afford the title compound (tR 1.14 min (conditions 2), MH+=346)
Reaction SMILES: O[CH2:2][CH2:3][NH:4][S:5]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:15]3[C:16]4[CH:29]=[CH:28][S:27][C:17]=4[C:18](=[O:26])[NH:19][C:20]=3[CH:21]=[CH:22][C:23]=2[O:24]C)=[CH:10][CH:9]=1)(=[O:7])=[O:6].[Br:30]B(Br)Br>>[Br:30][CH2:2][CH2:3][NH:4][S:5]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:15]3[C:16]4[CH:29]=[CH:28][S:27][C:17]=4[C:18](=[O:26])[NH:19][C:20]=3[CH:21]=[CH:22][C:23]=2[OH:24])=[CH:10][CH:9]=1)(=[O:7])=[O:6]
Reactant: COc1ccc2[nH]c(=O)c3sccc3c2c1-c1ccc(S(=O)(=O)NCCO)cc1
Reactant: BrB(Br)Br
Product: O=c1[nH]c2ccc(O)c(-c3ccc(S(=O)(=O)NCCBr)cc3)c2c2ccsc12
Yield: 90.9 %

Procedure:
Following General Procedure F, N-(2-hydroxyethyl)-4-(8-methoxy-4-oxo-4,5-dihydrothieno[2,3-c]quinolin-9-yl)benzenesulfonamide (1.7 g, 3.9 mmol) was reacted with tribromoborane (3.7 mL, 24 mmol) to afford the desired product (1.7 g, 91%) as an off-white solid: 1H NMR (500 MHz, DMSO-d6) δ 11.84 (s, 1H), 9.43 (s, 1H), 8.16 (t, J=5.9 Hz, 1H), 7.94 (d, J=8.3 Hz, 2H), 7.75 (d, J=5.4 Hz, 1H), 7.52 (d, J=8.3 Hz, 2H), 7.41 (d, J=8.9 Hz, 1H), 7.19 (d, J=8.9 Hz, 1H), 5.83 (d, J=5.4 Hz, 1H), 3.51 (t, J=6.4 Hz, 2H), 3.28 (q, J=6.2 Hz, 2H); ESI MS m/z 478 [C19H15BrN2O4S2+H]+; HPLC 98.5% (AUC), tR=15.23 min.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:20]=[CH:19][C:18]([C:21]4[CH:22]=[C:23]([CH:27]=[CH:28][C:29]=4[CH3:30])[C:24](O)=[O:25])=[CH:17][C:11]=3[C:12]=2[C:13](=[O:16])[NH:14][CH3:15])=[CH:4][CH:3]=1.[CH:31]1[CH:32]=[CH:33][C:34]2[N:39]([OH:40])N=[N:37][C:35]=2[CH:36]=1.[CH3:41]CN=C=NCCCN(C)C.Cl.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:20]=[CH:19][C:18]([C:21]4[CH:22]=[C:23]([C:24](=[O:25])[NH:37][C:35]5([C:34]6[CH:33]=[C:32]([CH3:31])[O:40][N:39]=6)[CH2:36][CH2:41]5)[CH:27]=[CH:28][C:29]=4[CH3:30])=[CH:17][C:11]=3[C:12]=2[C:13]([NH:14][CH3:15])=[O:16])=[CH:4][CH:3]=1
Reactant: CCN=C=NCCCN(C)C
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)O)ccc3C)cc12
Reactant: On1nnc2ccccc21
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)NC4(c5cc(C)on5)CC4)ccc3C)cc12
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a mixture of 3-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-4-methylbenzoic acid (0.15 g, 0.37 mmol, 1 eq), amine (0.06 g, 0.43 mmol, 1.2 eq), HOBT (0.084 g, 0.62 mmol, 1.7 eq), EDC.HCl (0.127 g, 0.087 mmol, 1.8 eq) in DCM at ambient temperature under nitrogen was added Diisopropylethylamine (0.239 g, 1.8 mmol, 5.0 eq). The clear mixture was stirred at ambient temperature for 12 h. LCMS showed the desired product. The mixture was concentrated, diluted with water and extracted with EtOAc. The organic layer is further washed with water, dried over sodium sulphate, filtered and then concentrated. The product obtained was further purified by column chromatography (neutral alumina) using 0.5% Methanol/DCM and preparative HPLC. Yield: 0.03 g (20%). 1H NMR (400 MHz, DMSO-d6): δ 1.24-1.29 (m, 4H), 2.29 (s, 3H), 2.32 (s, 3H), 2.81-2.82 (d, 3H, J=4.6 Hz), 6.05 (s, 1H), 7.38-7.44 (m, 4H), 7.57 (d, 1H, J=1.6 Hz), 7.75-7.82 (m, 3H), 7.97-8.0 (m, 2H), 8.46-8.47 (m, 1H), 9.24 (s, 1H). LCMS: (ES+) m/z=524.2 (M+H). LCMS Method: Column-Ascentis Express C18 (5×2.1 mm-2.7 μm) Mphase A: 2% ACN-98% H2O-10 mM NH4COOH Mphase B: 98% ACN-2% H2O-10 mM NH4COOH Flow: 1 mL/Min
Reaction SMILES: [F:1][C:2]1([F:11])[O:6][C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[O:3]1.[C:12]([O:18][CH3:19])(=[O:17])[CH2:13][C:14]([CH3:16])=[O:15].[C:20](OC(=O)C)(=O)C>>[F:11][C:2]1([F:1])[O:3][C:4]2[CH:10]=[CH:9][C:8]([C:16](=[CH2:20])[C:14](=[O:15])[CH2:13][C:12]([O:18][CH3:19])=[O:17])=[CH:7][C:5]=2[O:6]1
Reactant: FC1(F)Oc2ccccc2O1
Reactant: COC(=O)CC(C)=O
Reactant: CC(=O)OC(C)=O
Product: C=C(C(=O)CC(=O)OC)c1ccc2c(c1)OC(F)(F)O2
Reaction time: 24 h

Procedure:
50 mmol of 5-butyliminomethyl)-2,2-difluoro-1,3-benzodioxole and 50 mmol of methyl acetoacetate are added simultaneously to 80 ml of acetic anhydride and, after brief warming, the mixture is left to stand at room temperature for 24 hours. It is then hydrolyzed with 1 l of ice-water and the oil which has separated out is separated off, diluted with a little methylene chloride, dried and subsequently used as the crude product.