Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:3]([F:14])=[CH:4][CH:5]=[C:6]2[C:11]=1[NH:10][C:9](=O)[C:8]([CH3:13])=[N:7]2.[C:15]([NH2:19])([CH3:18])([CH3:17])[CH3:16]>CS(C)=O.CCOC(C)=O.C([O-])(O)=O.[Na+]>[Br:1][C:2]1[C:3]([F:14])=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([NH:19][C:15]([CH3:18])([CH3:17])[CH3:16])[C:8]([CH3:13])=[N:7]2
Reactant: CC(C)(C)N
Reactant: Cc1nc2ccc(F)c(Br)c2[nH]c1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: Cc1nc2ccc(F)c(Br)c2nc1NC(C)(C)C
Temperature: 100 °C
Yield: 83 %

Procedure:
A mixture of 5-bromo-3-chloro-6-fluoro-2-methylquinoxaline (600) (5.00 g, 18.15 mmol) and tert-butylamine (Alfa-Aesar, Ward Hill, Ma) (9.62 mL, 91 mmol) in DMSO (50 mL) in a sealed tube was heated at 100° C. for 2 h. After cooling to RT, the mixture was diluted with EtOAc and saturated NaHCO3 (aq.). The layers were separated and the aq. layer was extracted with EtOAc (3×). The combined organic layers were washed with water and brine and dried over anhydrous Na2SO4, filtered and concentrated. The crude material was absorbed onto a plug of silica gel and purified by silica gel chromatography (0-20% EtOAc in hexanes) to provide 8-bromo-N-(tert-butyl)-7-fluoro-3-methylquinoxalin-2-amine (605a) (4.70 g, 15.06 mmol, 83% yield) as an orange solid. 1H NMR (400 MHz, CDCl3) δ ppm 7.71 (1H, dd, J=9.0, 5.7 Hz), 7.14 (1H, t, J=8.6 Hz), 4.82 (1H, br. s.), 2.51 (3H, s), 1.64 (9H, s). 19F NMR (376 MHz, CDCl3) δ ppm −103.85 (s, 1F). m/z (ESI, +ve) 312.0, 314.0 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[C:6]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)=[C:5]2[C:15](=O)[N:16]([CH2:19][CH2:20][C:21]3[CH:30]=[CH:29][C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[N:22]=3)[C:17](=[O:18])[C:4]2=[CH:3]1>C(O)(=O)C.[Zn]>[CH3:1][N:2]1[C:7](=[O:8])[C:6]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)=[C:5]2[CH2:15][N:16]([CH2:19][CH2:20][C:21]3[CH:30]=[CH:29][C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[N:22]=3)[C:17](=[O:18])[C:4]2=[CH:3]1
Reactant: Cn1cc2c(c(N3CCOCC3)c1=O)C(=O)N(CCc1ccc3ccccc3n1)C2=O
Agent: [Zn]
Solvent: CC(=O)O
Product: Cn1cc2c(c(N3CCOCC3)c1=O)CN(CCc1ccc3ccccc3n1)C2=O
Reaction time: 8 h
Yield: 6.1 %

Procedure:
Zinc (0.375 g, 5.74 mmol) was added to a solution of 5-methyl-7-morpholin-4-yl-2-(2-quinolin-2-yl-ethyl)-5H-pyrrolo[3,4-c]pyridine-1,3,6-trione (0.8 g, 1.91 mmol, see Example 1) in acetic acid (15 ml) and the reaction was stirred for 8 h under reflux. The solvent was removed and the resulting mixture was purified via preparative HPLC (Waters system, eluent: MeCN/ammonium acetate buffer (gradient: 10:90 to 80:20 over 20 min), column: Hanbon Benetnach C18, 10 μm, 21.2×250 mm) to afford the title compound (47 mg, 6% yield).
Reaction SMILES: [CH3:1][N:2]([CH3:23])[C:3](=[O:22])[CH2:4][CH2:5][N:6]1[C:18]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]=[CH:10][C:9]=2[N:8]=[C:7]1[CH2:19][CH2:20][CH3:21].C1C=C(Cl)C=C(C(OO)=O)C=1.C1(S(Cl)(=O)=O)C=CC=CC=1.[OH-].[NH4+:46]>>[NH2:46][C:10]1[C:9]2[N:8]=[C:7]([CH2:19][CH2:20][CH3:21])[N:6]([CH2:5][CH2:4][C:3]([N:2]([CH3:1])[CH3:23])=[O:22])[C:18]=2[C:17]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N:11]=1
Reactant: CCCc1nc2cnc3ccccc3c2n1CCC(=O)N(C)C
Reactant: [NH4+]
Agent: O=C(OO)c1cccc(Cl)c1
Agent: O=S(=O)(Cl)c1ccccc1
Agent: [OH-]
Product: CCCc1nc2c(N)nc3ccccc3c2n1CCC(=O)N(C)C

Procedure:
N,N-Dimethyl-3-(2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)propanamide (2.40 g, 7.73 mmol) was treated with mCPBA (3.11 g, 13.5 mmol), ammonium hydroxide (40 mL), and benzenesulfonyl chloride (1.92 mL, 15.1 mmol) according to the method described in Part D of Example 36. The crude product was purified by column chromatography on silica gel (eluting with 93:7 dichloromethane:methanol) to provide 0.097 g of 3-(4-amino-2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)-N,N-dimethylpropanamide as a tan powder, mp 207-209° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:24]([CH3:25])=[C:11]3[N:12]=[C:13]([CH3:23])[C:14]([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[C:15](O)[N:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1.CN(C)C1C=CC=CC=1.O=P(Cl)(Cl)[Cl:37]>>[Cl:37][C:15]1[N:10]2[N:9]=[C:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)[C:24]([CH3:25])=[C:11]2[N:12]=[C:13]([CH3:23])[C:14]=1[CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOC(=O)Cc1c(C)nc2c(C)c(-c3cccc(Cl)c3)nn2c1O
Solvent: CN(C)c1ccccc1
Product: CCOC(=O)Cc1c(C)nc2c(C)c(-c3cccc(Cl)c3)nn2c1Cl
Temperature: 120 °C
Reaction time: 0.5 h
Yield: 98.4 %

Procedure:
A suspension of ethyl 2-(2-(3-chlorophenyl)-7-hydroxy-3,5-dimethylpyrazolo[1,5-a]pyrimidin-6-yl)acetate (11.5 g, 20.78 mmol), N,N-dimethylaniline (5.04 g, 41.6 mmol) and POCl3 (40 ml, 429 mmol) was heated (120° C. oil bath) for 3 hrs. The reaction was then concentrated in-vacuo and the dark residue taken up in EtOAc (75 mL) and stirred with ice-water (75 mL) for 30 min. The organic layer was washed with water (2×50 mL). The combined aqueous layers were extracted with EtOAc (50 mL) and the combined organic layers washed with brine (50 mL), dried (Na2SO4), filtered and concentrated to give a brown solid. The crude product was purified by silica gel flash column chromatography, eluting with 10%-30% EtOAc in hexane. Product fractions were pooled and concentrated under reduced pressure, affording the purified product, ethyl 2-(7-chloro-2-(3-chlorophenyl)-3,5-dimethylpyrazolo[1,5-a]pyrimidin-6-yl)acetate (8.3 g, 20.45 mmol, 98% yield) as an off-white powdery solid. 1H NMR (500 MHz, CDCl3) δ: 7.87 (t, J=1.7 Hz, 1H), 7.74 (dt, J=7.3, 1.5 Hz, 1H), 7.44-7.36 (m, 2H), 4.21 (q, J=7.1 Hz, 2H), 3.89 (s, 2H), 2.62 (s, 3H), 2.52 (s, 3H), 1.28 (t, J=7.2 Hz, 3H).
Reaction SMILES: C(O)CC.Cl.[CH3:6][O:7][NH2:8].[O:9]1[CH:13]=[CH:12][C:11]([C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[CH2:22][O:23][C:24]2[CH:29]=[C:28]([CH3:30])[CH:27]=[CH:26][C:25]=2[CH3:31])=O)=[N:10]1>O>[CH3:6][O:7][N:8]=[C:14]([C:11]1[CH:12]=[CH:13][O:9][N:10]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[CH2:22][O:23][C:24]1[CH:29]=[C:28]([CH3:30])[CH:27]=[CH:26][C:25]=1[CH3:31]
Reactant: Cc1ccc(C)c(OCc2ccccc2C(=O)c2ccon2)c1
Reactant: CON
Agent: Cl
Solvent: O
Solvent: CCCO
Product: CON=C(c1ccon1)c1ccccc1COc1cc(C)ccc1C

Procedure:
n-Propanol (2 ml) and methoxyamine hydrochloride (0.50 g, 6 mmol) were added to 2-(2,5-dimethylphenoxymethyl)phenyl isoxazol-3-yl ketone (0.64 g, 2 mmol), and the mixture was stirred under reflux for 17 hours. After completion of the reaction, water (100 ml) was added, the mixture was extracted with dichloromethane. The dichloromethane layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure, and the residue was purified by silica gel chromatography (benzene/n-hexane) to give 2-(2,5-dimethylphenoxymethyl)phenyl isoxazol-3-yl ketone O-methyloxime (a mixture of isomers A/B) (0.55 g, 81.8%) as colorless crystals. mp. 104-108° C.
Reaction SMILES: [Mg].C[O:3][C:4]1[C:12]2[O:13][C:14]([CH:16]=[CH:17][C:11]=2[CH:10]=[C:6]2[CH:7]=[CH:8][O:9][C:5]=12)=[O:15]>C1C=CC=CC=1>[CH:7]1[C:6]2=[CH:10][C:11]3[CH:17]=[CH:16][C:14](=[O:15])[O:13][C:12]=3[C:4]([OH:3])=[C:5]2[O:9][CH:8]=1
Reactant: COc1c2occc2cc2ccc(=O)oc12
Agent: [Mg]
Solvent: c1ccccc1
Product: O=c1ccc2cc3ccoc3c(O)c2o1
Temperature: 165 °C
Reaction time: 0.25 h

Procedure:
To a suspension of magnesium (0.97 g, 0.04 mol) in dry benzene (75 ml) iodine (10.2 g, 0.04 mol) was added over a period of 1 hour. Then 75 ml of dry benzene was added and the mixture was refluxed for 1 hour. The next day, 8-methoxypsoralen (Sigma Cat. No. M 3501) (4.3 g, 0.02 mol) was added, and after stirring for 15 minutes, the solvent was evaporated under vacuum at 120° C. until the residue was practically dry. It was then further heated at 165° C. for 2 hours. The resulting solid was decomposed with dilute sulphuric acid and filtered. The solid was washed with water, suspended in dilute bisulfite solution, filtered again, washed with water and finally crystallized from dioxane and yielded colourless crystals (3.75 g), m.p. 246° C.
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH:6]([CH2:9][CH3:10])[CH2:7][CH3:8])=[O:4].[Br:11][CH2:12][C:13]([OH:15])=[O:14].[K].CCOCC>CN(C)C=O>[Br:11][CH2:12][C:13]([O:15][CH2:2][C:3]([O:5][CH:6]([CH2:9][CH3:10])[CH2:7][CH3:8])=[O:4])=[O:14]
Reactant: CCC(CC)OC(=O)CBr
Reactant: O=C(O)CBr
Agent: [K]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CCC(CC)OC(=O)COC(=O)CBr
Temperature: 0 °C

Procedure:
Bromoacetic acid, 3-pentyl ester (330 g, 1.6 mole) was dissolved in 300 ml of dimethylformamide. Bromoacetic acid, potassium salt (142 g) was added portionwise with stirring and the mixture was stirred overnight. It was then poured into 1 liter of ice-cold water and 500 ml of ether was added. After washing with water, NaHCO3 solution and drying with MgSO4, the ether was evaporated. On distillation 156 g of the starting ester was recovered and 103.5 g of the title compound (boiling point 160°-162° C. at 12 mm of Hg) was obtained.
Reaction SMILES: Br[CH2:2][C:3]1[C:4]([C:20]2[CH:25]=[CH:24][C:23]([S:26](=[O:33])(=[O:32])[N:27]=[CH:28][N:29]([CH3:31])[CH3:30])=[CH:22][CH:21]=2)=[C:5]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[S:6][C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1.[CH3:34][NH:35][CH3:36]>C1C=CC=CC=1>[Cl:14][C:11]1[CH:10]=[CH:9][C:8]([C:7]2[S:6][C:5]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:4]([C:20]3[CH:21]=[CH:22][C:23]([S:26](=[O:33])(=[O:32])[N:27]=[CH:28][N:29]([CH3:31])[CH3:30])=[CH:24][CH:25]=3)[C:3]=2[CH2:2][N:35]([CH3:36])[CH3:34])=[CH:13][CH:12]=1
Reactant: CNC
Reactant: CCOC(=O)c1sc(-c2ccc(Cl)cc2)c(CBr)c1-c1ccc(S(=O)(=O)N=CN(C)C)cc1
Solvent: c1ccccc1
Product: CCOC(=O)c1sc(-c2ccc(Cl)cc2)c(CN(C)C)c1-c1ccc(S(=O)(=O)N=CN(C)C)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 53.4 %

Procedure:
To a stirred suspension of Ethyl 4-(bromomethyl)-5-(4-chlorophenyl)-3-(4-(N-((dimethylamino)methylene)sulfamoyl)phenyl)thiophene-2-carboxylate (compound 35b, 2.20 g, 3.86 mmol) in benzene (30 ml), dimethyl amine (0.69 g, 7.6 ml 2M solution in THF, 15.4 mmol) was added at 0° C. in a drop wise manner. The reaction mixture was then stirred at room temperature (about 25° C.) for 16 hr. The progress of the reaction was monitored by TLC. The reaction mixture was then concentrated to obtain the crude product as semi-solid (2.38 g). The crude product so obtained was purified by column chromatography over silica gel (100-200 mesh) using 1.2% methanol in DCM as an eluent to obtain the title compound (1.1 g, 53.39%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[OH:10])[CH:5]=[O:6].[Cl:11][C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][C:19]=1[Cl:20])[CH2:15]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(C)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[Cl:11][C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][C:19]=1[Cl:20])[CH2:15][O:10][C:9]1[CH:8]=[CH:7][C:4]([CH:5]=[O:6])=[CH:3][C:2]=1[F:1]
Reactant: OCc1ccc(Cl)c(Cl)c1
Reactant: O=Cc1ccc(O)c(F)c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: O=Cc1ccc(OCc2ccc(Cl)c(Cl)c2)c(F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 80 %

Procedure:
3-Fluoro-4-hydroxybenzaldehyde (400 mg, 2.85 mmol), 3,4-dichlorobenzyl alcohol (665 mg, 3.76 mmol), and triphenylphosphine (980 mg, 3.74 mmol) were dissolved in tetrahydrofuran (8 mL), and a diethyl azodicarboxylate toluene solution (2.2 M, 1.71 mL, 3.76 mmol) was slowly added dropwise thereto at room temperature, and then, the resulting mixture was stirred under a nitrogen atmosphere at room temperature for 2 hours. The solvent in the reaction solution was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=100:0 to 95:5 (v/v)), whereby the objective title compound was obtained as a colorless oily substance (680 mg, yield: 80%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1[CH:14]=[C:13]([N:15]2[C:19]3[CH:20]=[CH:21][C:22]([C:24]4[CH:25]=[N:26][N:27]([CH3:29])[CH:28]=4)=[CH:23][C:18]=3[N:17]=[CH:16]2)[CH:12]=[C:11]([NH2:30])[CH:10]=1.[CH2:31]([S:33](Cl)(=[O:35])=[O:34])[CH3:32]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1[CH:14]=[C:13]([N:15]2[C:19]3[CH:20]=[CH:21][C:22]([C:24]4[CH:25]=[N:26][N:27]([CH3:29])[CH:28]=4)=[CH:23][C:18]=3[N:17]=[CH:16]2)[CH:12]=[C:11]([NH:30][S:33]([CH2:31][CH3:32])(=[O:35])=[O:34])[CH:10]=1
Reactant: CCS(=O)(=O)Cl
Reactant: Cn1cc(-c2ccc3c(c2)ncn3-c2cc(N)cc(-c3cc(F)ccc3F)c2)cn1
Product: CCS(=O)(=O)Nc1cc(-c2cc(F)ccc2F)cc(-n2cnc3cc(-c4cnn(C)c4)ccc32)c1
Yield: 16.2 %

Procedure:
The compound was prepared from 2′,5′-difluoro-5-(5-(1-methyl-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-1-yl)-[1,1′-biphenyl]-3-amine (70 mg, 0.175 mmol) using the procedure of Example 2(b) and ethanesulfonyl chloride (26 mg, 0.21 mmol, 1.2 eq.) to give the pure product in 16.2% yield (14 mg). NMR (400 MHz, DMSO-D6): δ10.35 (s, 1H), 8.80 (s, 1H), 8.23 (s, 1H), 8.00 (s, 1H), 7.96 (s, 1H), 7.70 (d, 1H), 7.65-7.60 (m, 4H), 7.51 (s, 2H), 7.49-7.39 (m, 1H), 3.88 (s, 3H), 3.30 (q, 2H), 1.26 (t, 3H), LC-MS (ESI): Calculated mass: 493.53; Observed mass: 494.2 [M+H]+ (rt: 0.1.33 min).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([OH:7])=O.[CH2:12]1[C@H:21]2[C@H:16]([CH2:17][CH2:18][C:19]3[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=32)[NH:15][CH2:14][CH2:13]1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>>[CH2:12]1[C@H:21]2[C@H:16]([CH2:17][CH2:18][C:19]3[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=32)[N:15]([C:5]([C:4]2[CH:8]=[CH:9][C:10]([CH3:11])=[C:2]([OH:1])[CH:3]=2)=[O:7])[CH2:14][CH2:13]1
Reactant: c1ccc2c(c1)CC[C@@H]1NCCC[C@H]21
Reactant: Cc1ccc(C(=O)O)cc1O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: Cc1ccc(C(=O)N2CCC[C@@H]3c4ccccc4CC[C@@H]32)cc1O
Yield: 77 %

Procedure:
The title compound is prepared from 3-hydroxy-4-methyl-benzoic acid and cis-1,2,3,4,4a,5,6,10b-octahydro-benzo[f]quinoline following a procedure analogous to that described in Example 1 [2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexa-fluorophosphate is used]. Yield: 77% of theory; LC (method 4): tR=2.00 min; Mass spectrum (ESI+): m/z=322 [M+H]+.
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:15])[CH2:4][O:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][OH:14].CC(N(C)C)=O.Cl[CH2:23][C:24]1[CH:32]=[C:30]([CH3:31])[CH:29]=[C:27]([CH3:28])[C:25]=1[CH3:26]>C1COCC1.C(OC)(C)(C)C.CCCCCC>[CH3:23][C:24]1[CH:32]=[C:30]([CH3:31])[CH:29]=[C:27]([CH3:28])[C:25]=1[CH2:26][CH:13]([OH:14])[CH2:12][O:11][CH2:10][CH2:9][O:8][CH2:7][CH2:6][O:5][CH2:4][CH2:3][OH:15]
Reactant: OCCOCCOCCOCCO
Reactant: Cc1cc(C)c(C)c(CCl)c1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: COC(C)(C)C
Solvent: CCCCCC
Product: Cc1cc(C)c(CC(O)COCCOCCOCCO)c(C)c1
Temperature: 40 °C
Reaction time: 17 h

Procedure:
95% Sodium hydride (40.85 g, 1.6 moles) was placed into a 3 L flask under argon and THF (1.2 L) at −10° C. was added. Dry tetraethylene glycol (500.0 g, 2.57 moles) was added slowly. The pot temperature was maintained below 15° C. during the addition. Once the NaH had reacted, a homogeneous solution resulted. 18C6 (3.9 g) and dimethyl-acetamide (DMAC, 500 mL) was added. Chloroisodurene (TMB-Cl, 98.6 g, 0.58 mole) dissolved in THF (500 mL) was added to pot over about 4 h. The reaction mixture was stirred for about 17 h at about 40° C. under argon. The reaction was monitored by tlc on silica gel plates, eluting with 10% MeOH/CH2Cl2 vs TMB-Cl. The reaction was complete; the TMB-Cl was consumed. The solvent was removed in vacuo; the resulting oil was extracted with CH2Cl2 (700 mL) and water (300 mL). The CH2Cl2 layer was separated, dried over MgSO4, filtered through fluted filter paper and concentrated in vacuo to leave an oil. A column was prepared with 600 g of silica gel and hexane as needed. The crude product was placed onto column with hexane and a minimum of t-butylmethyl ether (TBME, 100 mL) to make a clean transfer. The column was eluted with hexane (4 L) and then as follows: (2 L) 10% TBME/hexane; (2 L) 20% TBME/hexane; (4 L) TBME/hexane; (3 L) 40% TBME/hexane, and (2 L) TBME. Like fractions containing product were combined and concentrated in vacuo to give 140.2 g (73%). The product was characterized by nmr. 1H NMR[400 MHz, DMSO(d6)] □6.81 (s, 2H), 4.56 (t, 1H), 4.45 (s, 2H), 3.57-3.45 (m, 14H), 3.41 (t, 2H), 2.28 (s, 6H), 2.22 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([CH:8]([C:13]2[C:18]([F:19])=[CH:17][CH:16]=[CH:15][C:14]=2[F:20])[C:9](=[O:12])[C:10]#[CH:11])=[CH:4][CH:3]=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:11]=[CH:10][C:9](=[O:12])[C:8]=2[C:13]2[C:18]([F:19])=[CH:17][CH:16]=[CH:15][C:14]=2[F:20])[N:7]=1
Reactant: C#CC(=O)C(c1ccc(Cl)nn1)c1c(F)cccc1F
Solvent: Cc1ccccc1
Product: O=c1ccn2nc(Cl)ccc2c1-c1c(F)cccc1F

Procedure:
A solution of 1-(6-chloropyridazin-3-yl)-1-(2,6-difluorophenyl)but-3-yn-2-one (10.2 g) in toluene was heated to 90° C. for 3 hours. LCMS analysis revealed the reaction was complete and the reaction was concentrated to yield a solid. The crude material was purified via silica gel chromatography (CH2Cl2/EtOAc/MeOH) to yield the title compound.
Reaction SMILES: [C:1]([O:6][CH3:7])(=[O:5])[C@@H:2]([CH3:4])[OH:3].C(N(CC)CC)C.Cl.CN(C)C.[C:20]1([CH3:30])[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1>C(#N)C>[CH3:30][C:20]1[CH:25]=[CH:24][C:23]([S:26]([O:3][C@H:2]([CH3:4])[C:1]([O:6][CH3:7])=[O:5])(=[O:28])=[O:27])=[CH:22][CH:21]=1
Reactant: COC(=O)[C@@H](C)O
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)C
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COC(=O)[C@@H](C)OS(=O)(=O)c1ccc(C)cc1
Yield: 87.2 %

Procedure:
A solution of methyl (R)-(+)-lactate (6.66 g) in acetonitrile (33 ml) was cooled to 5° C. and triethylamine (9.8 ml) added followed by trimethylamine hydrochloride (0.62 g). A separate solution of p-toluenesulfonyl chloride (11.6 g) in acetonitrile (33 ml) was added dropwise over 20 min maintaining the temperature below 5° C. The reaction mixture was filtered and concentrated. Diethylether and water were added and the organic fraction dried (MgSO4) and concentrated in vacuo to give the sub-title compound as a yellow oil (13.71 g).
Reaction SMILES: C(O)(C(F)(F)F)=O.CC([N:12]([C:16]([CH3:39])([CH3:38])[C:17]([NH:19][C:20]1[CH:21]=[N:22][C:23]([O:26][C:27]2[CH:36]=[CH:35][CH:34]=[C:33]3[C:28]=2[CH2:29][CH:30]([CH3:37])[CH2:31][O:32]3)=[CH:24][CH:25]=1)=[O:18])C(=O)[O-])(C)C>ClCCl>[CH3:39][C:16]([C:17]([NH:19][C:20]1[CH:21]=[N:22][C:23]([O:26][C:27]2[CH:36]=[CH:35][CH:34]=[C:33]3[C:28]=2[CH2:29][CH:30]([CH3:37])[CH2:31][O:32]3)=[CH:24][CH:25]=1)=[O:18])([CH3:38])[NH2:12]
Reactant: CC1COc2cccc(Oc3ccc(NC(=O)C(C)(C)N(C(=O)[O-])C(C)(C)C)cn3)c2C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC1COc2cccc(Oc3ccc(NC(=O)C(C)(C)N)cn3)c2C1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 90.1 %

Procedure:
In a 50 ml round-bottomed flask 1,1-dimethylethyl[1,1-dimethyl-2-({6-[(3-methyl-3,4-dihydro-2H-chromen-5-yl)oxy]-3-pyridinyl}amino)-2-oxoethyl]carbamate (Intermediate 120, 104.0 mg) was dissolved in dichloromethane (6 ml) to give a pale yellow solution. The reaction mixture was cooled at 0° C. and TFA (2 ml, 26.0 mmol) was added. The reaction mixture was stirred at 0° C. After 2 h 30 min, the mixture was evaporated under vacuum to give the crude product which was charged on a 5 g SCX cartridge. It was then flushed with 40 ml of methanol followed by 40 ml of a 2M solution of ammonia in methanol. The ammonia eluate was evaporated under vacuum to give the title compound as a colourless oil (72.6 mg).
Reaction SMILES: [C:1]1([S:7]([OH:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl-].[Cl-].[Ca+2].[F:13][C:14]1[CH:29]=[CH:28][C:17]([O:18][CH2:19][C@@H:20]([OH:27])[CH2:21][CH2:22][CH2:23][CH2:24][CH:25]=O)=[CH:16][CH:15]=1>C(Cl)Cl>[C:1]1([S:7]([CH:25]2[CH2:24][CH2:23][CH2:22][CH2:21][C@@H:20]([CH2:19][O:18][C:17]3[CH:28]=[CH:29][C:14]([F:13])=[CH:15][CH:16]=3)[O:27]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=S(O)c1ccccc1
Reactant: O=CCCCC[C@H](O)COc1ccc(F)cc1
Agent: [Ca+2]
Agent: [Cl-]
Solvent: ClCCl
Product: O=S(=O)(c1ccccc1)C1CCCC[C@@H](COc2ccc(F)cc2)O1
Temperature: 0 °C
Reaction time: 3 h
Yield: 81 %

Procedure:
25% HCl was added dropwise to sodium salt of benzenesulfinic acid (5 g, 30.5 mmol) until the solid dissolved. The reaction mixture was extracted with EtOAc, dried over Na2SO4 and concentrated to give benzenesulfinic acid (3.9 g, 90%). To an ice-cold mixture of benzene sulfinic acid (1.8 g, 12.4 mmol) and CaCl2, (1.4 g, 12.5 mmol) in dry methylene chloride (50 ml) was added dropwise a solution of (6S)-7-(4-fluorophenoxy)-6-hydroxy-heptanal (2 g, 8.3 mmol) in methylene chloride (10 ml). The reaction mixture was stirred for 3 hours and filtered through celite, and washed with methylene chloride. The combined organic layer was washed with saturated aqueous Na2CO3, water, brine and dried over Na2SO4. Solvent was removed under reduced pressure and the residue was purified by silica gel chromatography using EtOAC-hexane (1:6) as eluent to give (2RS,7S)-2-(benzenesulfonyl)-7-(4-fluorophenoxymethyl)oxepane (2.45 g, 80.8%); 1H-NMR (CDCl3, 200 Hz): δ 1.39-2.20 (m, 7H), 2.5 (m, 1H), 3.57-3.90 (m, 2H), 4.45 (m, 1H), 4.72 (dd, J=6.6, 12.0 Hz, 1H), 6.57-7.00 (m, 4H), 7.36-7.96 (m, 5H).
Reaction SMILES: N1C=CN=C1.[OH:6][CH2:7][CH2:8][CH2:9][NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14].[CH3:18][C:19]([Si:22](Cl)([CH3:24])[CH3:23])([CH3:21])[CH3:20].CCOC(C)=O.CCCCCC>ClCCl>[C:13]([O:12][C:11](=[O:17])[NH:10][CH2:9][CH2:8][CH2:7][O:6][Si:22]([C:19]([CH3:21])([CH3:20])[CH3:18])([CH3:24])[CH3:23])([CH3:14])([CH3:16])[CH3:15]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CC(C)(C)OC(=O)NCCCO
Agent: c1c[nH]cn1
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CC(C)(C)OC(=O)NCCCO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 84.2 %

Procedure:
11.6 g (1.3 eq) imidazole were added to a solution of 23 g (1 eq) tert-butyl 3-hydroxypropyl-carbamate in 230 ml dichloromethane. The reaction solution was stirred for 10 min at room temperature and then cooled to 0° C. 21.79 g (1.1 eq) TBDMSCl were added to this solution at 0° C. and on completion of the addition the mixture was stirred for 1 h at room temperature. The reaction course was monitored by thin-layer chromatography (30% EtOAc/hexane). Once the conversion was complete, the reaction mixture was filtered over celite and the filtrate mixed with 200 ml water and extracted with dichloromethane. The combined organic phases were dried over Na2SO4. Following removal of the solvent under reduced pressure, 32 g (84%) of product were obtained in the form of an oil.
Reaction SMILES: [NH2:1][CH:2]([C:10]1[C:11]([O:18][CH3:19])=[N:12][CH:13]=[CH:14][C:15]=1[O:16][CH3:17])[CH2:3][CH2:4][CH2:5][C:6]([O:8]C)=O.[CH3:20][C:21]1[S:22][CH:23]=[C:24]([C:26]2[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=2)[CH:29]=O)[N:25]=1>>[CH3:19][O:18][C:11]1[C:10]([CH:2]2[N:1]([CH2:29][C:28]3[CH:31]=[CH:32][CH:33]=[C:26]([C:24]4[N:25]=[C:21]([CH3:20])[S:22][CH:23]=4)[CH:27]=3)[C:6](=[O:8])[CH2:5][CH2:4][CH2:3]2)=[C:15]([O:16][CH3:17])[CH:14]=[CH:13][N:12]=1
Reactant: COC(=O)CCCC(N)c1c(OC)ccnc1OC
Reactant: Cc1nc(-c2cccc(C=O)c2)cs1
Product: COc1ccnc(OC)c1C1CCCC(=O)N1Cc1cccc(-c2csc(C)n2)c1

Procedure:
Prepared according to the described general procedure 1 (GP1) by reaction of methyl 5-amino-5-(2,4-dimethoxypyridin-3-yl)pentanoate with commercially available 3-(2-methylthiazol-4-yl)benzaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.71 min.; [M+H]+: 423.95 g/mol.