Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([F:15])[CH:14]=1)[N:11]=[C:10](O)[CH:9]=[CH:8]2)(=[O:3])[CH3:2].O=P(Cl)(Cl)[Cl:19]>CN(C=O)C>[C:1]([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([F:15])[CH:14]=1)[N:11]=[C:10]([Cl:19])[CH:9]=[CH:8]2)(=[O:3])[CH3:2]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CC(=O)Oc1cc(F)c2nc(O)ccc2c1
Solvent: CN(C)C=O
Product: CC(=O)Oc1cc(F)c2nc(Cl)ccc2c1
Temperature: 80 °C

Procedure:
To a solution of 8-fluoro-2-hydroxyquinolin-6-yl acetate (550 mg) in DMF (6 mL) was added POCl3 (0.6 mL). Then, the mixture was heated at 80° C. over a couple of hours. After aqueous work-up, the desired product, 2-chloro-8-fluoroquinolin-6-yl acetate (380 mg) was obtained by flash silica column chromatography.
Reaction SMILES: [CH3:1][N:2]([CH3:16])[S:3]([C:6]1[CH:7]=[C:8]([CH:13]=[CH:14][CH:15]=1)[C:9](OC)=[O:10])(=[O:5])=[O:4].[NH2:17][NH2:18]>CO>[NH:17]([C:9]([C:8]1[CH:7]=[C:6]([S:3]([N:2]([CH3:16])[CH3:1])(=[O:5])=[O:4])[CH:15]=[CH:14][CH:13]=1)=[O:10])[NH2:18]
Reactant: COC(=O)c1cccc(S(=O)(=O)N(C)C)c1
Reactant: NN
Solvent: CO
Product: CN(C)S(=O)(=O)c1cccc(C(=O)NN)c1
Temperature: 65 °C
Yield: 40 %

Procedure:
Methyl 3-(N,N-dimethylsulfamoyl)benzoate (150 mg, 0.617 mmol) was added to hydrazine (29.6 mg, 0.925 mmol) in methanol (10 mL) and refluxed for 8 h at 65° C. Following cooling, the reaction was monitored by TLC. After completion of the reaction, the solvent was removed by vacuum and the compound was purified by column chromatography affording the title compound (60 mg). 1H NMR (400 MHz, CDCl3): δ 8.11 (s, 1H), 8.01 (d, 1H, J=8.4 Hz), 7.92 (d, 1H, J=8.0 Hz), 7.65 (t, 1H, J=8.0 Hz), 2.73 (5, 6H). ESI-MS: 244.0 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]2[CH:5]=[CH:6][C:7]3[CH:16]=[CH:15][CH:14]=[CH:13][C:8]=3[C:9]=2[C:10](=[O:12])[CH:11]=1.[I:17]I.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(#N)C>[I:17][C:11]1[C:10](=[O:12])[C:9]2[C:8]3[CH:13]=[CH:14][CH:15]=[CH:16][C:7]=3[CH:6]=[CH:5][C:4]=2[S:3][C:2]=1[CH3:1]
Reactant: II
Reactant: Cc1cc(=O)c2c(ccc3ccccc32)s1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CC#N
Product: Cc1sc2ccc3ccccc3c2c(=O)c1I
Temperature: 60 °C
Reaction time: 4 h
Yield: 74 %

Procedure:
3-Methyl-1H-benzo[f]thiochromen-1-one (1.0 mmol, 176 mg), iodine (1.2 mmol, 305 mg) and ceric ammonium nitrate (1.1 mmol, 603 mg) were dissolved in acetonitrile (4.0 mL), and the solution was stirred under a nitrogen atmosphere at 60° C. for 4 hours. After the disappearance of the starting materials was confirmed by thin-layer chromatography, the reaction solution was poured into a solution of a 10% saturated aqueous sodium thiosulfate solution under ice-cooling to terminate the reaction. The organic substances were extracted with methylene chloride, the obtained organic layer was dried over magnesium sulfate, and the solvents were evaporated under reduced pressure. The residue was purified by silica gel column chromatography, and the title compound (0.74 mmol, 260 mg) was obtained in a 74% yield.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[CH:5]=[C:4]([C:14]2[CH:19]=[CH:18][N:17]=[C:16]([NH:20][CH3:21])[N:15]=2)[CH:3]=1.C(N(CC)C(C)C)(C)C.[C:31]([C:35]1[CH:43]=[CH:42][C:38]([C:39](Cl)=[O:40])=[CH:37][CH:36]=1)([CH3:34])([CH3:33])[CH3:32]>CN(C)C(=O)C>[C:31]([C:35]1[CH:36]=[CH:37][C:38]([C:39]([NH:1][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=3)[CH:5]=[C:4]([C:14]3[CH:19]=[CH:18][N:17]=[C:16]([NH:20][CH3:21])[N:15]=3)[CH:3]=2)=[O:40])=[CH:42][CH:43]=1)([CH3:34])([CH3:32])[CH3:33]
Reactant: CC(C)(C)c1ccc(C(=O)Cl)cc1
Reactant: CNc1nccc(-c2cc(N)c3cc(OC)ccc3c2)n1
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: CNc1nccc(-c2cc(NC(=O)c3ccc(C(C)(C)C)cc3)c3cc(OC)ccc3c2)n1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 4-(4-amino-6-methoxy-2-naphthyl)-N-methylpyrimidin-2-amine (33) (252 mg, 0.900 mmol), N,N-dimethylacetamide (4 mL) was treated with N,N-diisopropylethylamine (0.9 mL, 5.2 mmol) followed by 4-(tert-butyl)benzoyl chloride (181 mg, 0.9 mmol) and stirred for 16 hours at room temperature. The mixture was partitioned between ethyl acetate (150 mL) and water (120 mL). The aqueous layer was removed and the organic layer was washed with water (2×100 mL), dried over anhydrous sodium sulfate, filtered, concentrated (rotary) and dried under high vacuum to afford the crude desired product, which was purified by reverse phase chromatography on preparative LC/UV/MS system using a mass triggered fractionation. Compound was eluted from the HPLC column (Maccel 120-10-C18 SH 10 μm 20 mmID×50 mm) at 88 mL/min with acetonitrile/water gradient using 0.1% FA as a modifier. 4-tert-butyl-N-{7-methoxy-3-[2-(methylamino)pyrimidin-4-yl]-1-naphthyl}benzamide (184) was isolated as an off-white solid (95 mg). M.p.=231-232° C.; 400 MHz 1H NMR (DMSO-d6) δ: 10.39 (s, 1H), 8.59 (s, 1H), 8.34-8.39 (m, 2H), 8.06 (m, 3H), 7.61 (d, J=6.7 Hz, 2H), 7.31 (m, 3H), 7.16 (s, 1H), 3.87 (s, 3H), 3.34 (br s, 3H), 1.36 (s, 9H); Experimental Elemental Analysis (0.23 equivalents of formic acid)=72.52% C, 6.15% H, 12.21% N; Calculated Elemental Analysis 72.50% C, 6.36% H, 12.42% N; LCMS (m/z): 442 [M+H].
Reaction SMILES: [CH2:1]([C@:3]1([OH:28])[C:25]2[CH:24]=[C:23]3[N:10]([CH2:11][C:12]4[C:13]3=[N:14][C:15]3[CH:16]=[C:17]([F:22])[CH:18]=[CH:19][C:20]=3[CH:21]=4)[C:9](=[O:26])[C:8]=2[CH2:7][O:6][C:5](=[O:27])[CH2:4]1)[CH3:2].[CH:29](=O)[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38]C>>[CH2:29]([C:21]1[C:20]2[CH:19]=[CH:18][C:17]([F:22])=[CH:16][C:15]=2[N:14]=[C:13]2[C:23]3[N:10]([CH2:11][C:12]=12)[C:9](=[O:26])[C:8]1[CH2:7][O:6][C:5](=[O:27])[CH2:4][C@@:3]([CH2:1][CH3:2])([OH:28])[C:25]=1[CH:24]=3)[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38]
Reactant: CCCCCCCCCCC=O
Reactant: CC[C@@]1(O)CC(=O)OCc2c1cc1n(c2=O)Cc2cc3ccc(F)cc3nc2-1
Product: CCCCCCCCCCc1c2c(nc3cc(F)ccc13)-c1cc3c(c(=O)n1C2)COC(=O)C[C@]3(O)CC

Procedure:
The product of Example 84 is treated with undecanal according to a procedure similar to Stage 95e in order to produce the expected solid.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[CH:11]=[CH:12][NH:13]3)O1.Br[C:20]1[C:25]([F:26])=[CH:24][CH:23]=[CH:22][C:21]=1[F:27].C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.[Pd].C(OCC)(=O)C>[F:26][C:25]1[CH:24]=[CH:23][CH:22]=[C:21]([F:27])[C:20]=1[C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[CH:11]=[CH:12][NH:13]2
Reactant: CC1(C)OB(c2cccc3[nH]ccc23)OC1(C)C
Reactant: Fc1cccc(F)c1Br
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: Fc1cccc(F)c1-c1cccc2[nH]ccc12
Temperature: 110 °C
Reaction time: 8 h
Yield: 91.5 %

Procedure:
To a mixture of 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-indole (11.34 g, 46.6 mmol), and 1-bromo-2,6-difluorobenzene (9 g, 46.6 mmol) in 1,2-dimethoxyethane (204 mL) were added Palladium catalyst Pd(PPh3)4 (1.62 g, 1.4 mmol) and the freshly prepared sodium carbonate solution (15.19 g in 66 mL of water). The system was degassed and then charged with nitrogen. The degas procedure was repeated for three times. The mixture was stirred under nitrogen at 110° C. oil bath for overnight. TLC showed the completion of the coupling reaction. The mixture was cooled to room temperature, diluted with ethyl acetate, and separated from water layer. The ethyl acetate solution was washed with brine, and dried over Na2SO4. After filtration, the solvents were evaporated, and the crude product was purified by a silica gel column to give 9.77 g (91%) of 4-(2,6-difluoro-phenyl)-1H-indole.
Reaction SMILES: O=[N+]([O-])[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[Ce+4].[NH4+].[NH4+].C(#N)C.C[O:32][C:33]1[C:41]([O:42][CH3:43])=[C:40]([O:44][CH3:45])[C:39]([O:46]C)=[C:38]2[C:34]=1[CH2:35][CH:36]([CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][OH:56])[CH2:37]2>O>[OH:56][CH2:55][CH2:54][CH2:53][CH2:52][CH2:51][CH2:50][CH2:49][CH2:48][CH:36]1[CH2:35][C:34]2[C:33](=[O:32])[C:41]([O:42][CH3:43])=[C:40]([O:44][CH3:45])[C:39](=[O:46])[C:38]=2[CH2:37]1
Reactant: COc1c2c(c(OC)c(OC)c1OC)CC(CCCCCCCCO)C2
Agent: O=[N+]([O-])[O-]
Agent: [Ce+4]
Agent: [NH4+]
Solvent: O
Solvent: CC#N
Product: COC1=C(OC)C(=O)C2=C(CC(CCCCCCCCO)C2)C1=O
Reaction time: 0.25 h
Yield: 26.2 %

Procedure:
A water (1.0 ml) solution of CAN (463 mg, 0.845 mmols) was dropwise added to an acetonitrile (3.0 ml) solution of 8-(4,5,6,7-tetramethoxyindan-2-yl)octanol (138 mg, 0.338 mmols) with cooling with ice and stirring was continued for 15 minutes. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, and then dried. The solvent was evaporated out in vacuo, and the resulting crude product was purified by silica gel column chromatography (hexane:ethyl acetate=4:1 to 2:1) followed by recrystallization from hexane-diethyl ether to obtain the entitled compound (29.8 mg) as crystals.
Reaction SMILES: [CH:1]1([CH2:4][C:5]2[C:6]([OH:16])=[C:7]([CH:12]=[CH:13][C:14]=2[OH:15])[C:8](OC)=[O:9])[CH2:3][CH2:2]1.[Cl-].[NH4+:18]>>[CH:1]1([CH2:4][C:5]2[C:6]([OH:16])=[C:7]([CH:12]=[CH:13][C:14]=2[OH:15])[C:8]([NH2:18])=[O:9])[CH2:3][CH2:2]1
Reactant: COC(=O)c1ccc(O)c(CC2CC2)c1O
Reactant: [NH4+]
Agent: [Cl-]
Product: NC(=O)c1ccc(O)c(CC2CC2)c1O

Procedure:
The compound of Example 15 is heated at 50° C. in a saturated ammonium chloride solution overnight. The reaction mixture is thoroughly extracted with ethyl acetate, and the solvent dried (Na2SO4) and evaporated in vacuo to afford the crude product. Chromatographic purification or silica gel using ethyl acetate/hexane (4:6) as eluant affords the product.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]([C:8]#[C:9][CH2:10][CH2:11][N:12]2[CH:16]=[CH:15][N:14]=[N:13]2)=[N:6][CH:7]=1>C(OCC)(=O)C.[Pd]>[Br:1][C:2]1[CH:3]=[N:4][C:5]([CH2:8][CH2:9][CH2:10][CH2:11][N:12]2[CH:16]=[CH:15][N:14]=[N:13]2)=[N:6][CH:7]=1
Reactant: Brc1cnc(C#CCCn2ccnn2)nc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Brc1cnc(CCCCn2ccnn2)nc1

Procedure:
5-Bromo-2-(4-[1,2,3]triazol-1-yl-but-1-ynyl)-pyrimidine (0.350 g, 1.26 mmol) is dissolved in ethyl acetate (3 ml) and hydrogenated for 2 h at r.t. in the presence of palladium on charcoal (10%, 175 mg). The reaction mixture is filtered and concentrated in vacuo to yield 5-Bromo-2-(4-[1,2,3]triazol-1-yl-butyl)-pyrimidine as a beige solid. Yield 290 mg (82%)
Reaction SMILES: [CH2:1]([NH:10][C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[H-].[Na+].[Cl:19][CH:20]=[CH:21][CH2:22]Cl.[I-].[Na+]>CN(C)P(=O)(N(C)C)N(C)C.O>[Cl:19][CH:20]=[CH:21][CH2:22][N:10]([CH2:1][CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[C:11](=[O:16])[C:12]([F:14])([F:15])[F:13]
Reactant: O=C(NCC=Cc1ccccc1)C(F)(F)F
Reactant: ClC=CCCl
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: O=C(N(CC=CCl)CC=Cc1ccccc1)C(F)(F)F
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 250 g of N-cinnamyltrifluoroacetamide in 1 liter of hexamethylphosphoric acid triamide (HMPT) is added dropwise with ice-cooling and stirring under a nitrogen atmosphere, to a suspension of 27 g of sodium hydride in 400 ml of HMPT. After the evolution of gas has ceased, a solution of 130 g of 1,3-dichloropropene and 1 g of sodium iodide in 1 liter of HMPT is added dropwise and the mixture stirred for 16 hours at room temperature. The reaction mixture is then poured on to water and extracted with ether. The ethereal solution is dried over sodium sulphate, evaporated and the oily residue chromatographed on 3.5 kg of silica gel with toluene to yield N-(3-chloro-2-propenyl)-N-cinnamyl-trifluoroacetamide as an oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:12]2[N:13]=[C:14]([NH:17]C(=O)C)[NH:15][CH:16]=2)[CH:5]=[CH:6][C:7]=1[C:8]([F:11])([F:10])[F:9].OS(O)(=O)=O.[K]>CO.O>[F:1][C:2]1[CH:3]=[C:4]([C:12]2[N:13]=[C:14]([NH2:17])[NH:15][CH:16]=2)[CH:5]=[CH:6][C:7]=1[C:8]([F:11])([F:9])[F:10]
Reactant: CC(=O)Nc1nc(-c2ccc(C(F)(F)F)c(F)c2)c[nH]1
Agent: O=S(=O)(O)O
Agent: [K]
Solvent: O
Solvent: CO
Product: Nc1nc(-c2ccc(C(F)(F)F)c(F)c2)c[nH]1
Temperature: 25 °C

Procedure:
To a stirred solution of Step 1 intermediate (1.1 g, 3.829 mmol) in a mixture of methanol (20 ml) and water (20 ml) was added conc. H2SO4 (2 ml) and the resulting mixture was refluxed for 24 h. The reaction mixture was cooled to room temperature, saturated solution of potassium carnonate was added and extracted with ethyl acetate (2×50 ml). The organic layers were combined and dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure. The residue obtained after the evaporation of the solvent was purified by silica gel column chromatography using 5% methanol in chloroform to obtain 290 mg of the product as a yellow solid; 1H NMR (300 MHz, DMSO-d6): δ 5.55 (br s, 2H), 7.32 (s, 1H), 7.59-7.67 (m, 3H), 11.30 (br s, 1H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[CH:5]=[C:4]([CH2:14][S:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)(=[O:17])=[O:16])[N:3]=1.O.CC1(C)C(C)(C)OB([C:33]2[CH:38]=[CH:37][C:36]([NH2:39])=[CH:35][CH:34]=2)O1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C.C(COC)OC.C(O)C>[N:8]1([C:6]2[CH:5]=[C:4]([CH2:14][S:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)(=[O:17])=[O:16])[N:3]=[C:2]([C:33]3[CH:38]=[CH:37][C:36]([NH2:39])=[CH:35][CH:34]=3)[N:7]=2)[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1
Reactant: CC1(C)OB(c2ccc(N)cc2)OC1(C)C
Reactant: O=S(=O)(Cc1cc(N2CCOCC2)nc(Cl)n1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: CN(C)C=O
Product: Nc1ccc(-c2nc(CS(=O)(=O)c3ccccc3)cc(N3CCOCC3)n2)cc1
Temperature: 90 °C

Procedure:
4-{2-Chloro-6-[(phenylsulfonyl)methyl]pyrimidin-4-yl}morpholine (3.3 g, 9.33 mmol) was dissolved in a solution of 18% DMF in a mixture of 7:3:2 dimethoxyethane:water:ethanol (36 mL). [4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]amine (3.07 g, 13.99 mmol), 2M sodium carbonate solution (12 mL) and dichlorobis(triphenylphosphine) palladium catalyst (328 mg, 0.47 mmol) were then added and the reaction refluxed at 90° C. for 2 hours under a nitrogen atmosphere. The reaction was allowed to cool to room temp then partitioned between ethyl acetate (20 mL) and water (20 mL). The organics were dried over magnesium sulphate, filtered and concentrated in vacuo. The crude oil was dissolved in DCM and filtered to remove insoluble material. A beige solid precipitated from the filtrates and the filtrates were filtered again. The solid was analysed and found to be the desired material (2.2 g).
Reaction SMILES: Cl[C:2]1[C:3]([CH3:14])=[C:4]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)[CH:5]=[CH:6][CH:7]=1.[C-]#N.[N:17]1C=CC=C[CH:18]=1.[OH-].[NH4+]>[Cu].C(Cl)Cl>[C:18]([C:2]1[C:3]([CH3:14])=[C:4]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)[CH:5]=[CH:6][CH:7]=1)#[N:17]
Reactant: c1ccncc1
Reactant: Cc1c(Cl)cccc1-c1cccnc1
Agent: [Cu]
Agent: [C-]#N
Agent: [NH4+]
Solvent: ClCCl
Product: Cc1c(C#N)cccc1-c1cccnc1
Temperature: 195 °C
Yield: 85.8 %

Procedure:
A mixture of 7.5 g (0.012 mol) of 3-(3-chloro-2-methylphenyl)pyridine and 1.7 g (0.018 mol) of copper I cyanide in 1.45 g (0.018 mol) of pyridine was heated at 195° C. for 18 hours. The reaction mixture was cooled to 50° C., and 40 mL of methylene chloride was added with stirring. The mixture was placed in a separatory funnel, and 75 mL of methylene chloride and 75 mL of a 35% aqueous solution of ammonium hydroxide were added. The mixture was shaken for five minutes, then passed through a fiber glass filter paper. The layers were separated, and the aqueous layer was washed with two portions of 40 mL each of methylene chloride. The combined organic layers were washed with three portions of 40 mL each of a 35% aqueous solution of ammonium hydroxide. The organic layer was dried with magnesium sulfate, filtered, and the filtrate concentrated under reduced pressure to give 2.0 g of 3 -(3-cyano-2-methylphenyl)pyridine.
Reaction SMILES: [O:1]1[CH:6]([CH2:7][NH2:8])[CH2:5][O:4][C:3]2[CH:9]=[CH:10][CH:11]=[CH:12][C:2]1=2.C([O:17][C:18]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[C:26]1[CH:31]=[CH:30][C:29]([CH2:32][N:33]2[C:41]3[C:36](=[CH:37][C:38]([C:42](O)=[O:43])=[CH:39][CH:40]=3)[C:35]([CH3:45])=[C:34]2[CH3:46])=[CH:28][CH:27]=1)=[O:19])(C)(C)C>>[O:1]1[CH:6]([CH2:7][NH:8][C:42]([C:38]2[CH:37]=[C:36]3[C:41](=[CH:40][CH:39]=2)[N:33]([CH2:32][C:29]2[CH:28]=[CH:27][C:26]([C:21]4[C:20]([C:18]([OH:19])=[O:17])=[CH:25][CH:24]=[CH:23][CH:22]=4)=[CH:31][CH:30]=2)[C:34]([CH3:46])=[C:35]3[CH3:45])=[O:43])[CH2:5][O:4][C:3]2[CH:9]=[CH:10][CH:11]=[CH:12][C:2]1=2
Reactant: NCC1COc2ccccc2O1
Reactant: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)OC(C)(C)C)cc2)c2ccc(C(=O)O)cc12
Product: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)O)cc2)c2ccc(C(=O)NCC3COc4ccccc4O3)cc12

Procedure:
The title compound was prepared following the same general protocol as described in Steps 8-9, Example 1, using (2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methanamine and 1-((2′-(tert-butoxycarbonyl)biphenyl-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylic acid. LC-MS 547 (M+H).
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:9])=[N:4][C:5]([OH:8])=[CH:6][CH:7]=1.[O:10]1[CH2:15][CH2:14][CH:13](O)[CH2:12][CH2:11]1>>[Br:1][C:2]1[C:3]([CH3:9])=[N:4][C:5]([O:8][CH:13]2[CH2:14][CH2:15][O:10][CH2:11][CH2:12]2)=[CH:6][CH:7]=1
Reactant: OC1CCOCC1
Reactant: Cc1nc(O)ccc1Br
Product: Cc1nc(OC2CCOCC2)ccc1Br

Procedure:
The title compound was prepared from 3-bromo-6-hydroxy-2-methylpyridine and tetrahydro-4H-pyran-4-ol in analogy to Example 9c): colorless solid.
Reaction SMILES: CC([CH2:5][N:6]([CH2:10][CH2:11][NH:12][C:13]1[N:14]=[C:15]([C:32]2[CH:37]=[C:36]([C:38]([NH:40][CH:41]([CH3:43])[CH3:42])=[O:39])[CH:35]=[CH:34][C:33]=2[CH3:44])[C:16]2[CH2:21][NH:20][C:19](=[O:22])[N:18]([C:23]3[C:28]([F:29])=[CH:27][CH:26]=[CH:25][C:24]=3[F:30])[C:17]=2[N:31]=1)C(=O)[O-])(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:30][C:24]1[CH:25]=[CH:26][CH:27]=[C:28]([F:29])[C:23]=1[N:18]1[C:17]2[N:31]=[C:13]([NH:12][CH2:11][CH2:10][NH:6][CH3:5])[N:14]=[C:15]([C:32]3[CH:37]=[C:36]([CH:35]=[CH:34][C:33]=3[CH3:44])[C:38]([NH:40][CH:41]([CH3:42])[CH3:43])=[O:39])[C:16]=2[CH2:21][NH:20][C:19]1=[O:22]
Reactant: Cc1ccc(C(=O)NC(C)C)cc1-c1nc(NCCN(CC(C)(C)C)C(=O)[O-])nc2c1CNC(=O)N2c1c(F)cccc1F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CNCCNc1nc(-c2cc(C(=O)NC(C)C)ccc2C)c2c(n1)N(c1c(F)cccc1F)C(=O)NC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 72 %

Procedure:
To a solution of 1,1-dimethylethyl(2-{[8-(2,6-difluorophenyl)-4-(2-methyl-5-{[(1-methylethyl)amino]carbonyl}phenyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-2-yl]amino}ethyl)methylcarbamate (18 mg, 0.030 mmol) in DCM (5 mL) was added TFA (0.05 mL). The reaction mixture was stirred at room temperature overnight, quenched with triethylamine (0.2 mL) at −78° C. The residue was mixed with H2O (5.0 mL). The organic layer was separated and the aqueous layer was extracted with DCM (3×15 mL). The combined organic phases were washed with saturated aq. NaCl, dried over Na2SO4, filtered, and concentrated. Purification via a CombiFlash system (90% CH2Cl2/7% MeOH/3% NH4OH) then afforded the title compound (11 mg, 73%). LC-MS (ES) m/z 510 (M+H)+; 1H-NMR(MeOD) δ 1.27 (d, 6H), 2.26 (s, 3H), 2.30 (s, 3H), 2.56 (m, 2H), 3.22 (m, 2H), 4.11 (s, 2H), 4.23 (m, 1H), 7.15 (t, 2H), 7.46 (d, 1H), 7.52 (m, 1H), 7.69 (s, 1H), 7.85 (d, 1H).
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2)[S:6][CH:7]=1.[NH:16]1[CH:20]=[CH:19][N:18]=[CH:17]1.[I-].[K+].[OH-].[Na+]>CC(O)(CC)C>[CH3:15][O:14][C:11]1[CH:12]=[CH:13][C:8]([C:5]2[S:6][CH:7]=[C:3]([CH2:2][N:16]3[CH:20]=[CH:19][N:18]=[CH:17]3)[N:4]=2)=[CH:9][CH:10]=1
Reactant: c1c[nH]cn1
Reactant: COc1ccc(-c2nc(CCl)cs2)cc1
Agent: [I-]
Agent: [K+]
Agent: [Na+]
Solvent: CCC(C)(C)O
Product: COc1ccc(-c2nc(Cn3ccnc3)cs2)cc1
Temperature: 120 °C
Reaction time: 5 h
Yield: 91 %

Procedure:
A suspension of 2.40 g (10 mmol) 4-chloromethyl-2-(4-methoxy-phenyl)-thiazole, 1.02 g (15 mmol) imidazole, 0.17 g (1 mmol) potassium iodide and 0.60 g (15 mmol) sodium hydroxide in 25 ml 2-methyl-2-butanol was stirred at 120° C. for 5 h. After evaporation, the residue was quenched with water and extracted with ethyl acetate. The extract was dried and concentrated to yield 2.47 g (91%) 1-[2-(4-methoxy-phenyl)-thiazol-4-ylmethyl]-imidazole as beige crystals, melting at 89-90° C.
Reaction SMILES: C(O[CH:4]=[C:5]([C:11](=[O:22])[C:12]1[CH:17]=[C:16]([F:18])[C:15]([F:19])=[C:14]([Br:20])[C:13]=1F)[C:6]([O:8][CH2:9][CH3:10])=[O:7])C.BrC1C(F)=C(C=C(F)C=1F)C(CC(OCC)=O)=O.[NH2:41][C:42]1[CH:47]=[CH:46][C:45]([F:48])=[C:44]([NH:49][C:50]([CH3:53])([CH3:52])[CH3:51])[N:43]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(Cl)(Cl)Cl>[Br:20][C:14]1[C:15]([F:19])=[C:16]([F:18])[CH:17]=[C:12]2[C:13]=1[N:41]([C:42]1[CH:47]=[CH:46][C:45]([F:48])=[C:44]([NH:49][C:50]([CH3:53])([CH3:52])[CH3:51])[N:43]=1)[CH:4]=[C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[C:11]2=[O:22]
Reactant: CCOC=C(C(=O)OCC)C(=O)c1cc(F)c(F)c(Br)c1F
Reactant: CC(C)(C)Nc1nc(N)ccc1F
Agent: CCOC(=O)CC(=O)c1cc(F)c(F)c(Br)c1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(-c2ccc(F)c(NC(C)(C)C)n2)c2c(Br)c(F)c(F)cc2c1=O
Temperature: 90 °C
Reaction time: 0.42 h

Procedure:
To 1 ml of chloroform solution of ethyl 3-ethoxy-2-(3-bromo-2,4,5-trifluorobenzoyl)acrylate prepared from 0.65 g of ethyl 3-bromo-2,4,5-trifluorobenzoylacetate by normal process was added 0.3 g of 2-amino-6-(t-butylamino)-5-fluoropyridine. The solution was concentrated under reduced pressure to obtain yellowish orange solid residue. To this residue were added 0.4 g of anhydrous potassium carbonate and 2 ml of N,N-dimethylformamide, and the mixture was stirred at 90° C. for 25 minutes and allowed to cool. The solution was separated by adding 25 ml of chloroform and 400 ml of distilled water, and the chloroform layer was washed with 400 ml of distilled water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. After adding 2 ml of ethanol, the solution was and allowed to stand. The precipitate was dispersed in ethanol and collected by filtration, and washed with ethanol and diisopropylether successively to obtain 0.53 g of the title compound as a pale yellow powder.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:17]3[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=3)=[N:10][N:11]3[CH2:16][CH2:15][CH2:14][NH:13][C:12]=23)=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:30](OC(=O)C)(=[O:32])[CH3:31]>ClCCCl>[C:30]([N:13]1[CH2:14][CH2:15][CH2:16][N:11]2[N:10]=[C:9]([C:17]3[CH:18]=[CH:19][N:20]=[CH:21][CH:22]=3)[C:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)=[C:12]12)(=[O:32])[CH3:31]
Reactant: CC(=O)OC(C)=O
Reactant: Fc1ccc(-c2c(-c3ccncc3)nn3c2NCCC3)cc1
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: CC(=O)N1CCCn2nc(-c3ccncc3)c(-c3ccc(F)cc3)c21

Procedure:
A mixture of 3-(4-fluorophenyl)-2-(pyridin-4-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine (100 mg), triethylamine (0.4 ml) and acetic anhydride (0.2 ml) in dry 1,2-dichloroethane (3 ml) was refluxed for 2 days. The reaction mixture was cooled and concentrated in vacuo. The residue was dissolved in dichloromethane and the solution was washed with an aqueous saturated sodium bicarbonate solution and brine, dried and concentrated in vacuo. The residue was purified by column chromatography on silica gel and the obtained oil was crystallized from diisopropyl ether to give 4-acetyl-3-(4-fluorophenyl)-2-(pyridin-4-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine (60 mg).