Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[Li]CCCC.Br[C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1>C1COCC1.[Cl-].[Cl-].[Zn+2].[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:19][O:18][C:15]1[CH:16]=[CH:17][C:12]([C:2]2[S:1][CH:5]=[CH:4][N:3]=2)=[CH:13][CH:14]=1
Reactant: c1cscn1
Reactant: COc1ccc(Br)cc1
Agent: [Pd]
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1ccc(-c2nccs2)cc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 123 %

Procedure:
To a solution of thiazole (3.0 g, 16 mmol) in THF (75 ml) was added n-BuLi (2.5 M in hexane, 11 ml, 27.3 mmol) at −78° C. dropwise, and stirred at −78° C. for 30 min. ZnCl2 (10.7 g, 78.3 mmol) was added at −78° C. in portions. The resulting mixture was stirred at −78° C. for 30 min, and room temperature for 1.5 h. To this solution was added 4-bromoanisole (1.60 g, 8.5 mmol) and terakis(triphenylphosphine)-palladium (0). The reaction mixture was heated to 65° C. for 16 h. After the catalyst was filtered off, the filtrate was concentrated in vacuo. The residue was purified by a column chromatography on silica gel with 25% ethyl acetate in hexane to yield the title product (2 g, 67%); 1H NMR (400 MHz, CDCl3) δ 7.90 (d, J=9.2 Hz, 2H), 7.81 (d, J=3.2 Hz, 1H), 7.25 (d, J=3.2 Hz, 1H), 6.95 (d, J=9.2 Hz, 2H), 3.86 (s, 3H); MS (ESI+) 192 (M+1, 100).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[O:5][C:4](=[O:12])[CH:3]=1.C=O.[CH3:15][C:16]1(C)O[C:21](=O)[CH2:20][C:18](=[O:19])[O:17]1.C([O-])(=O)C.[NH4+]>C(O)C>[CH2:16]([O:17][C:18](=[O:19])[CH2:20][CH2:21][C:3]1[C:4](=[O:12])[O:5][C:6]2[C:11]([C:2]=1[OH:1])=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH3:15]
Reactant: O=c1cc(O)c2ccccc2o1
Reactant: CC1(C)OC(=O)CC(=O)O1
Agent: C=O
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CCO
Product: CCOC(=O)CCc1c(O)c2ccccc2oc1=O
Temperature: 25 °C
Yield: 37.3 %

Procedure:
A solution of 4-hydroxy-chromen-2-one (2.0 g), aqueous formaldehyde (37%, 0.37 g), Meldrum's acid (1.77 g) and ammonium acetate (0.95 g) in ethanol (75 mL) was heated to reflux for 6 hours, then cooled to room temperature. The reaction mixture was conc. in vacuo to give the crude as yellow oil, which was purified by column chromatography to provide 3-(4-Hydroxy-2-oxo-2H-chromen-3-yl)-propionic acid ethyl ester as colorless oil (1.2 g).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([NH:15][C:16]2[C:21]([C:22]([F:25])([F:24])[F:23])=[CH:20][CH:19]=[CH:18][C:17]=2[F:26])=[C:6]([CH2:8][C:9]([O:11]C(C)C)=[O:10])[CH:7]=1>CS(O)(=O)=O>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([NH:15][C:16]2[C:21]([C:22]([F:23])([F:24])[F:25])=[CH:20][CH:19]=[CH:18][C:17]=2[F:26])=[C:6]([CH2:8][C:9]([OH:11])=[O:10])[CH:7]=1
Reactant: Cc1ccc(Nc2c(F)cccc2C(F)(F)F)c(CC(=O)OC(C)C)c1
Agent: CS(=O)(=O)O
Product: Cc1ccc(Nc2c(F)cccc2C(F)(F)F)c(CC(=O)O)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Isopropyl 5-methyl-2-(2′-fluoro-6′-trifluoromethylanilino)phenylacetate (2.9 g, 8.4 mmol) is dissolved in methanesulfonic acid (25 ml) and stirred at room temperature for 8 hours. The reaction mixture is slowly added to 200 ml of ice in a beaker. After the ice has melted, the solution is stirred to produce a white solid which is isolated by filtration. The solid is flash chromatographed on silica-gel using 35% EtOAc as an eluant to give 5-methyl-2-(2′-fluoro-6′-trifluoromethylanilino)phenylacetic acid as a white solid, m.p. 155-156°.
Reaction SMILES: [I:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9](S(C)(=O)=O)[N:8]([CH2:16][CH2:17][O:18][CH3:19])[C:7]2=[O:20].[C:21]([NH2:25])([CH3:24])([CH3:23])[CH3:22].[OH-].[Na+]>CS(C)=O>[C:21]([NH:25][C:9]1[N:8]([CH2:16][CH2:17][O:18][CH3:19])[C:7](=[O:20])[C:6]2[C:11](=[C:2]([I:1])[CH:3]=[CH:4][CH:5]=2)[N:10]=1)([CH3:24])([CH3:23])[CH3:22]
Reactant: COCCn1c(S(C)(=O)=O)nc2c(I)cccc2c1=O
Reactant: CC(C)(C)N
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Product: COCCn1c(NC(C)(C)C)nc2c(I)cccc2c1=O
Temperature: 80 °C
Yield: 70 %

Procedure:
To a solution of 8-iodo-3-(2-methoxyethyl)-2-(methylthio)quinazolin-4(3H)-one (715a; 1.33 g, 3.54 mmol) in 100 mL of DCM at 0° C. was added 3-chloroperoxybenzoic acid (77% max., 1.47 g, 6.56 mmol) and the resulting mixture was stirred for 1 h at 0° C. It was diluted with 50 mL of DCM, washed with 2×15 mL of sat NaHCO3. The DCM layer was dried over Na2SO4 and concentrated to give a yellow solid as a mixture (715b) of 8-iodo-3-(2-methoxyethyl)-2-(methylsulfonyl)quinazolin-4(3H)-one and 8-iodo-3-(2-methoxyethyl)-2-(methylsulfinyl)quinazolin-4(3H)-one. To the crude mixture (715b) in a sealable glass vessel was added tert-butylamine (3.72 mL, 35.4 mmol) and 5 mL of DMSO. The glass vessel was sealed and heated in an oil bath at 80° C. for 3 h. It was treated with 10 mL of 0.5 N NaOH, and extracted with 2×35 mL of EtOAc. The organic extracts were dried over Na2SO4 and concentrated. The residue was stirred in 25 mL of ether. The insoluble solid was filtered and rinsed with 2×10 mL of ether. The filtrate was concentrated and the residue was purified on a silica gel column (30-80% EtOAc in hexanes) to afford 2-(tert-butylamino)-8-iodo-3-(2-methoxyethyl)quinazolin-4(3H)-one (715) (0.99 g, 2.467 mmol, 70% yield for 2 steps) as a yellow crystalline solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.16 (1H, dd, J=7.5, 1.5 Hz), 7.94 (1H, dd, J=7.8, 1.4 Hz), 6.92 (1H, t, J=7.7 Hz), 6.46 (1H, s), 4.23 (2H, t, J=4.8 Hz), 3.66 (2H, t, J=4.7 Hz), 3.35 (3H, s), 1.58 (9H, s). m/z (ESI, +ve) 401.9 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[O:13])[C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1.[F:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[N:21]=[C:22]=[O:23]>CN(C)C=O>[F:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[NH:21][C:22](=[O:23])[NH:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[O:13])[C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1
Reactant: CCOC(=O)C(=O)c1csc(N)n1
Reactant: O=C=Nc1ccccc1F
Solvent: CN(C)C=O
Product: CCOC(=O)C(=O)c1csc(NC(=O)Nc2ccccc2F)n1

Procedure:
Following a procedure similar to that described in Preparation 1, the desired compound was prepared from 5 g of ethyl 2-aminothiazol-4-ylglyoxylate, 4.87 g of o-fluorophenyl isocyanate and 30 ml of dimethylformamide. The resulting product was a pale yellow powder having the following physical properties.
Reaction SMILES: [CH3:1][CH:2]([CH3:9])[CH2:3][CH2:4][CH2:5][C:6](Cl)=[O:7].[F:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[O:17][CH3:18]>[N+](C1C=CC=CC=1)([O-])=O>[F:10][C:11]1[CH:16]=[C:15]([C:6](=[O:7])[CH2:5][CH2:4][CH2:3][CH:2]([CH3:9])[CH3:1])[CH:14]=[CH:13][C:12]=1[O:17][CH3:18]
Reactant: CC(C)CCCC(=O)Cl
Reactant: COc1ccccc1F
Solvent: O=[N+]([O-])c1ccccc1
Product: COc1ccc(C(=O)CCCC(C)C)cc1F
Temperature: 0 °C

Procedure:
14 ml of nitrobenzene are cooled in an ice-bath and then mixed in succession with 3.8 g of AICl3 and 3.7 g of 5-methyl-hexanoyl chloride in 5 ml of nitrobenzene. The mixture is stirred and then treated with 2.7 ml of 2-fluoro-anisole. The solution is stirred overnight, then poured into ice-water and extracted with methylene chloride. The extracts are washed with water and 10% aqueous NaCl solution, and thereafter dried and concentrated and recrystallized using pentane. 5.31 g of 1-(3-fluoro-4-methoxy-phenyl)-5-methyl-hexan-1-one, MS: m/e 238 (M+), are obtained.
Reaction SMILES: [F:1][C:2]([F:20])([C:16]([F:19])([F:18])[F:17])[CH2:3][CH2:4][N:5]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[C:7]([C:14]#[N:15])=[N:6]1.ClC1C=CC=C(C(OO)=[O:29])C=1>C(O)(=O)C>[C:14]([C:7]1[C:8]2[C:9](=[N+:10]([O-:29])[CH:11]=[CH:12][CH:13]=2)[N:5]([CH2:4][CH2:3][C:2]([F:1])([F:20])[C:16]([F:17])([F:18])[F:19])[N:6]=1)#[N:15]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: N#Cc1nn(CCC(F)(F)C(F)(F)F)c2ncccc12
Solvent: CC(=O)O
Product: N#Cc1nn(CCC(F)(F)C(F)(F)F)c2c1ccc[n+]2[O-]
Temperature: 75 °C
Reaction time: 6 h

Procedure:
1-(3,3,4,4,4-pentafluorobutyl)-1H-pyrazolo[3,4-b]pyridine-3-carbonitrile, as described in Step D of Example 158 (1.818 g, 6.26 mmol) and 3-chloroperbenzoic acid (7.1 g, 31.68 mmol, 77%) in acetic acid (20 mL) were stirred at 75° C. for 6 hours. The reaction was then evaporated under reduced pressure to remove acetic acid. To the residue was added a mixture of hexane/ethyl acetate (2/1, 200 mL total) and the pH adjusted to 7.0˜7.5 with aq. K2CO3 at 0° C. The water layer was extracted with hexane/ethyl acetate (2/1, 2×60 mL). The combined organic layer was dried over MgSO4 and evaporated under reduced pressure. The residue was purified by silica gel column chromatography using hexanes/ethyl acetate eluent to give the desired product as a white solid. 1H NMR (500 MHz, CDCl3): δ 2.86 (m, 2H); 5.44 (t, J=7.3 Hz, 2H); 7.31 (t, J=8.2 Hz, 1H); 7.80 (d, J=8.4 Hz, 1H); 8.38 (d, J=5.1 Hz, 1H). m/z=307.02 (M+H).
Reaction SMILES: Cl.Cl.[CH2:3]([NH:6][C:7]1=[N:8][C:9](=[O:19])[S:10]/[C:11]/1=[CH:12]\[CH:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)[C:4]#[CH:5].C(N(C(C)C)C(C)C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[CH3:53][N:54]1[C:62]2[C:57](=[CH:58][CH:59]=[CH:60][CH:61]=2)[CH:56]=[C:55]1[C:63](O)=[O:64]>CN(C=O)C.O>[CH3:53][N:54]1[C:62]2[C:57](=[CH:58][CH:59]=[CH:60][CH:61]=2)[CH:56]=[C:55]1[C:63]([N:16]1[CH2:17][CH2:18][CH:13](/[CH:12]=[C:11]2/[C:7]([NH:6][CH2:3][C:4]#[CH:5])=[N:8][C:9](=[O:19])[S:10]/2)[CH2:14][CH2:15]1)=[O:64]
Reactant: Cn1c(C(=O)O)cc2ccccc21
Reactant: C#CCNC1=NC(=O)S/C1=C\C1CCNCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C#CCNC1=NC(=O)S/C1=C\C1CCN(C(=O)c2cc3ccccc3n2C)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 44 %

Procedure:
To a solution of (5Z)-4-(prop-2-yn-1-ylamino)-5-(piperidin-4-ylmethylidene)-1,3-thiazol-2(5H)-one dihydrochloride (200 mg) in DMF (3 mL) were added N-ethyl-N-(1-methylethyl)propan-2-amine (0.56 mL), O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (283 mg) and 1-methyl-1H-indole-2-carboxylic acid (135 mg). The reaction mixture was stirred at room temperature overnight, water was added, and the mixture was extracted with ethyl acetate/tetrahydrofuran. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was recrystallized from ethyl acetate/heptane to give the title compound (111 mg).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:13][C@H:12]([CH2:14][NH:15][C:16](=[O:18])[CH3:17])[O:11][C:10]2=[O:19])[CH:5]=[CH:6][C:7]=1I.[CH3:20][C:21]1([CH3:28])[C:25]([CH3:27])([CH3:26])[O:24][BH:23][O:22]1.C(N(CC)CC)C>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[F:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:13][C@H:12]([CH2:14][NH:15][C:16](=[O:18])[CH3:17])[O:11][C:10]2=[O:19])[CH:5]=[CH:6][C:7]=1[B:23]1[O:24][C:25]([CH3:27])([CH3:26])[C:21]([CH3:28])([CH3:20])[O:22]1
Reactant: CC(=O)NC[C@H]1CN(c2ccc(I)c(F)c2)C(=O)O1
Reactant: CC1(C)OBOC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CC(=O)NC[C@H]1CN(c2ccc(B3OC(C)(C)C(C)(C)O3)c(F)c2)C(=O)O1
Temperature: 25 °C
Yield: 94.1 %

Procedure:
A suspension of (5S)—N-[3-(3-fluoro-4-iodo-phenyl)-2-oxo-oxazolidin-5-ylmethyl]-acetamide 1010 (20.0 g, 52.8 mmol, prepared as described in Example 1, above) in anhydrous 1,4-dioxane (130 mL) was treated with 4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (10.2 g, 11.6 mL, 80.0 mmol, 1.5 equiv) and triethylamine (16.0 g, 22.4 mL, 158.4 mmol, 3.0 equiv) at room temperature. The resulting reaction mixture was degassed three times under a steady stream of argon before being treated with dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium (II) (Pd(dppf)2Cl2, 1.32 g, 1.6 mmol, 0.03 equiv) at room temperature. The resulting reaction mixture was degassed three times under a steady stream of argon before being warmed to reflux for 7 h. When HPLC/MS showed the reaction was complete, the reaction mixture was cooled to room temperature before being treated with water (100 mL) and ethyl acetate (100 mL). The two layers were separated, and the aqueous layer was extracted with ethyl acetate (2×50 mL). The combined organic extracts were washed with water (2×50 mL) and saturated aqueous NaCl (50 mL), dried over MgSO4, and concentrated in vacuo. The residual brown oil was further dried in vacuo to afford the (5S)—N-{3-[3-fluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-2-oxo-oxazolidin-5-ylmethyl}acetamide 1037 (18.8 g, 94%) as brown solids. This product was directly used in subsequent reactions without further purification. C18H24BFN2O5, HPLC/MS (ESI) m/e 379 (M++H).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][OH:5].[H-].[Na+].[Br:8][C:9]1[C:10](Cl)=[N:11][CH:12]=[C:13]([N+:15]([O-:17])=[O:16])[CH:14]=1>C1COCC1>[Br:8][C:9]1[C:10]([O:5][CH2:4][CH2:3][O:2][CH3:1])=[N:11][CH:12]=[C:13]([N+:15]([O-:17])=[O:16])[CH:14]=1
Reactant: COCCO
Reactant: O=[N+]([O-])c1cnc(Cl)c(Br)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCCOc1ncc([N+](=O)[O-])cc1Br
Temperature: 25 °C
Reaction time: 1 h
Yield: 74.2 %

Procedure:
To a solution of 2-methoxyethanol (8.81 g, 9.13 ml, 116 mmol) in anhydrous THF (150ml) was added sodium hydride (4.63 g, 116 mmol) under nitrogen at 5° C. or below and the reaction mixture was stirred at 25° C. for 1 h. Then 3-bromo-2-chloro-5-nitropyridine (CAN 5470-17-7) (25 g, 105 mmol) was added drop wise at 25° C. and stirred at 25° C. for 1 h. Ice-water (150 ml) was added to the reaction mixture and extracted with ethyl acetate (500 mL). The combined organic layers was washed with water and brine, dried over Na2SO4 and evaporated under reduced pressure to get the crude residue (25.7 g). The crude was purified by column chromatography (15% ethyl acetate/hexane) to get the desired product (21.6 g, 74%) as light yellow solid; GC/MS (FID/EI): 100%, 276.0 (M)+.
Reaction SMILES: [CH:1]1([N:9]2[C:12](=[O:13])[C:11]([CH3:15])([CH3:14])[NH:10]2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:16][C:17]1[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=1[CH2:19]Br>>[Cl:16][C:17]1[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=1[CH2:19][N:10]1[C:11]([CH3:15])([CH3:14])[C:12](=[O:13])[N:9]1[CH:1]1[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC1(C)NN(C2CCCCCCC2)C1=O
Reactant: Clc1ccccc1CBr
Product: CC1(C)C(=O)N(C2CCCCCCC2)N1Cc1ccccc1Cl

Procedure:
2-Cyclooctyl-4,4-dimethyl-1,2-diazetidin-3-one and 2-chlorobenzyl bromide were used for a similar reaction and treatment as Process 6 of Example 1, and the title compound was obtained as a colorless oil.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C.[NH2:22][C@@H:23]([CH3:26])[CH2:24][OH:25]>O>[N+:8]([C:7]1[C:2]([NH:22][C@@H:23]([CH3:26])[CH2:24][OH:25])=[N:3][CH:4]=[CH:5][CH:6]=1)([O-:10])=[O:9]
Reactant: C[C@H](N)CO
Reactant: O=[N+]([O-])c1cccnc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C[C@@H](CO)Nc1ncccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 114.3 %

Procedure:
A 100-mL round bottomed flask equipped with a magnetic stir bar was charged with 2-chloro-3-nitropyridine (4.0 g, 25.2 mmol), potassium carbonate (4.18 g, 30.3 mmol), and DMF (25 mL). Next, (S)-2-aminopropane-1-ol (1.990 g, 26.5 mmol) was added at rt. The yellow mixture was stirred at rt for 45 min, then was heated to 50° C. for 22 h. Heating was discontinued, and after the mixture had cooled, it was diluted with water (50 mL) and extracted with ethyl acetate. The organic phase was separated and washed with 5% aqueous sodium chloride solution (3×25 mL). The combined aqueous layers were extracted with ethyl acetate. The combined organic phases were concentrated to yield (S)-2-(3-nitropyridin-2-ylamino)propane-1-ol (5.68 g, 28.8 mmol, 114%) as a dark yellow syrup. MS (ESI, pos. ion) m/z 198 [M+1]+.
Reaction SMILES: [CH:1]1([NH:4][C:5]([NH:7][C:8]2[CH:13]=[CH:12][C:11]([O:14][C:15]3[CH:20]=[CH:19][N:18]=[C:17]4[CH:21]=[C:22]([C:24]5[CH:29]=[CH:28][C:27]([CH2:30][NH:31][CH2:32][CH2:33][O:34][CH3:35])=[CH:26][N:25]=5)[S:23][C:16]=34)=[C:10]([F:36])[CH:9]=2)=[O:6])[CH2:3][CH2:2]1.Cl[C:38]([O:40][CH3:41])=[O:39].CCN(C(C)C)C(C)C>C1COCC1>[CH3:41][O:40][C:38](=[O:39])[N:31]([CH2:30][C:27]1[CH:26]=[N:25][C:24]([C:22]2[S:23][C:16]3[C:17](=[N:18][CH:19]=[CH:20][C:15]=3[O:14][C:11]3[CH:12]=[CH:13][C:8]([NH:7][C:5]([NH:4][CH:1]4[CH2:3][CH2:2]4)=[O:6])=[CH:9][C:10]=3[F:36])[CH:21]=2)=[CH:29][CH:28]=1)[CH2:32][CH2:33][O:34][CH3:35]
Reactant: COCCNCc1ccc(-c2cc3nccc(Oc4ccc(NC(=O)NC5CC5)cc4F)c3s2)nc1
Reactant: COC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COCCN(Cc1ccc(-c2cc3nccc(Oc4ccc(NC(=O)NC5CC5)cc4F)c3s2)nc1)C(=O)OC
Temperature: 25 °C
Reaction time: 18 h
Yield: 50.3 %

Procedure:
To a solution of compound 339 (220 mg, 0.433 mmol) and methyl chloroformate (50.2 μl, 0.65 mmol) in THF (4 ml) was added DIPEA (227 μl, 1.30 mmol) and the mixture was stirred at room temperature for 18 h. The solvent was removed under reduced pressure, the residue was triturated with MeOH and the solid suspension was collected by filtration and purified via Biotage (linear gradient 0-20%, methanol/dichloromethane; Snap 25 g column) to afford compound 340 (123.1 mg, 0.218 mmol, 50.2% yield) as a beige solid. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.70 (s, 1H), 8.56-8.50 (m, 2H), 8.33 (s, 1H), 8.25 (d, J=8.0 Hz, 1H), 7.84-7.77 (m, 1H), 7.73 (dd, J=13.6, 2.4 Hz, 1H), 7.38 (t, J=9.2 Hz, 1H), 7.20 (dd, J=8.8, 1.2 Hz, 1H), 6.65 (d, J=5.6 Hz, 1H), 6.56 (d, J=2.8 Hz, 1H), 4.54 (s, 2H), 3.64 (s, 2H), 3.44 (s, 3H), 3.22 (s, 2H), 2.59-2.51 (m, 1H), 0.69-0.62 (m, 2H), 0.46-0.40 (m, 2H). MS (m/z): 566.1 (M+H).
Reaction SMILES: [N:1]1[CH2:2][CH2:3][CH2:4][N:5]2[C:9]3[CH:10]=[C:11]([NH2:14])[CH:12]=[CH:13][C:8]=3[S:7][C:6]=12.C(O)(=O)C.[O-:19][C:20]#[N:21].[K+].[OH-].[NH4+]>O>[N:1]1[CH2:2][CH2:3][CH2:4][N:5]2[C:9]3[CH:10]=[C:11]([NH:14][C:20]([NH2:21])=[O:19])[CH:12]=[CH:13][C:8]=3[S:7][C:6]=12
Reactant: N#C[O-]
Reactant: Nc1ccc2c(c1)N1CCCN=C1S2
Agent: [K+]
Agent: [NH4+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: NC(=O)Nc1ccc2c(c1)N1CCCN=C1S2
Temperature: 10 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 3 parts of 3,4-dihydro-2-H-pyrimido[2,1-b]benzothiazol-7-amine in 16 parts of acetic acid are added 32 parts of water. Then there is added dropwise a solution of 1.46 parts of potassium cyanate in 32 parts of water (slightly exothermic reaction). Upon completion, stirring is continued overnight at room temperature. The reaction mixture is alkalized with ammonium hydroxide and the whole is stirred while cooling at 10° C. The precipitated product is filtered off and crystallized twice: first from 2-methoxyethanol and then from 1-butanol, yielding 0.6 parts of N-(3,4-dihydro-2H-pyrimido[2,1-b]benzothiazol-7-yl)urea; mp. 245.9° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13](=[O:14])[NH:12][N:11]3[C:15](=[O:26])[N:16]([CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])[N:17]=[C:10]3[C:9]=2[C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=2)=[CH:4][CH:3]=1.[F:34][C:35]([F:45])([F:44])[C:36]1[CH:43]=[CH:42][C:39]([CH2:40]Br)=[CH:38][CH:37]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[F:34][C:35]([F:44])([F:45])[C:36]1[CH:43]=[CH:42][C:39]([CH2:40][N:12]2[C:13](=[O:14])[C:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)=[C:9]([C:27]3[CH:28]=[CH:29][C:30]([Cl:33])=[CH:31][CH:32]=3)[C:10]3=[N:17][N:16]([CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])[C:15](=[O:26])[N:11]23)=[CH:38][CH:37]=1
Reactant: C[Si](C)(C)CCOCn1nc2c(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3)c(=O)[nH]n2c1=O
Reactant: FC(F)(F)c1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCn1nc2c(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3)c(=O)n(Cc3ccc(C(F)(F)F)cc3)n2c1=O
Temperature: 80 °C
Yield: 109.9 %

Procedure:
The solution of 7,8-bis(4-chlorophenyl)-2-((2-(trimethylsilyl)ethoxy)methyl)-[1,2,4]triazolo[4,3-b]pyridazine-3,6(2H,5H)-dione, (112 mg, 0.22 mmol), prepared as described in example 6B, 4-(trifluoromethyl)benzyl bromide (58 mg, 0.24 mmol), K2CO3 (91 mg, 0.66 mmol) in DMF (2 ml), was heated at 80° C. for 0.75 hour. After this time, the solution was cooled to RT and diluted with ethyl acetate. The resulting solution was washed with water. The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure to give the title compound, 5-(4-(trifluoromethyl)benzyl)-7,8-bis(4-chlorophenyl)-2-((2-(trimethylsilyl)ethoxy)methyl)-[1,2,4]triazolo[4,3-b]pyridazine-3,6(2H,5H)-dione, (160 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[NH:14][C:13](=O)[N:12]2[N:16]=[C:17]([CH:19]3[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]3)[N:18]=[C:11]2[CH:10]=1.C(=O)(O)[O-].[Na+].P(Cl)(Cl)([Cl:33])=O>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1>[Cl:33][C:13]1[N:12]2[N:16]=[C:17]([CH:19]3[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]3)[N:18]=[C:11]2[CH:10]=[C:9]([C:3]2[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=2[Cl:1])[N:14]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CN1CCC(c2nc3cc(-c4ccc(Cl)cc4Cl)[nH]c(=O)n3n2)CC1
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: O=C([O-])O
Agent: [Cl-]
Product: CN1CCC(c2nc3cc(-c4ccc(Cl)cc4Cl)nc(Cl)n3n2)CC1
Temperature: 120 °C
Reaction time: 3 h

Procedure:
270 mg (0.71 mmol) of 7-(2,4-dichlorophenyl)-2-(1-methylpiperidin-4-yl)[1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one (Example 48A) were initially charged in phosphorus oxychloride (2 ml), 650 mg (2.90 mmol) of benzyltriethylammonium chloride were added and the mixture was then stirred at 120° C. for 3 h. The reaction mixture was poured into saturated aqueous sodium bicarbonate solution (150 ml), and solid sodium bicarbonate was added until a pH of 7 had been reached. The solid was filtered off with suction and dried. This gave 190 mg (65% of theory) of the product as a solid.
Reaction SMILES: C(O[CH:5]([CH3:24])/[CH:6]=[CH:7]/[C:8]1[S:12][C:11]([O:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH:21]([CH3:23])[CH3:22])=[CH:16][CH:15]=2)=[N:10][CH:9]=1)(=O)C.[N-:25]=[N+:26]=[N-:27].[Na+].CCOCC.CCCCCC>O1CCCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[N:25]([CH:5]([CH3:24])/[CH:6]=[CH:7]/[C:8]1[S:12][C:11]([O:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH:21]([CH3:23])[CH3:22])=[CH:16][CH:15]=2)=[N:10][CH:9]=1)=[N+:26]=[N-:27]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(=O)OC(C)/C=C/c1cnc(Oc2ccc(OC(C)C)cc2)s1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: CCCCCC
Product: CC(/C=C/c1cnc(Oc2ccc(OC(C)C)cc2)s1)N=[N+]=[N-]
Temperature: 50 °C
Reaction time: 8 h
Yield: 57.2 %

Procedure:
To a solution of the product of Example 7E (155 mg, 0.45 mmole) in tetrahydrofuran (15 mL) was added sodium azide (32 mg, 0.5 mmole) and tetrakis(triphenylphosphine)palladium(0) (25 mg, 0.022 mmole) and heated at 50° C. After 2 hours additional sodium azide (23 mg, 0.35 mmole) was added and after 8 hours a third amount of sodium azide (40 mg, 0.61 mmole) was added and stirred at 50° C. overnight. The reaction mixture was added ether and hexane and the organic phase was washed twice with water followed by brine. The reaction mixture was dried over magnesium sulfate filtered and evaporated. The product was purified via silica column, using a gradient of 5-25% ethyl acetate in hexane and yielded 85 mg (57.6%) of clear oil. 1H NMR (300 MHz, CDCl3) δ ppm 7.13-7.22 (m, 2H) 7.10 (s, 1H) 6.86-6.98 (m, 2H) 6.58 (d, J=15.44 Hz, 1H) 5.69 (dd, J=15.63, 7.17 Hz, 1H) 4.42-4.62 (m, 1H) 3.96-4.23 (m, 1H) 1.35 (d, J=5.88 Hz, 6H) 1.33 (d, J=5.88 Hz, 3H). Mass spectrum DCI 331 (M+H)+.