Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH:3]([Si:6]([CH:11]([CH3:13])[CH3:12])([CH:8]([CH3:10])[CH3:9])[SH:7])([CH3:5])[CH3:4].FC(F)(F)S(O[C:20]1[CH:29]=[C:28]2[C:23]([CH2:24][CH2:25][CH:26]([C:30]([O:32][CH2:33][CH3:34])=[O:31])[O:27]2)=[CH:22][CH:21]=1)(=O)=O>C1(C)C=CC=CC=1.C1COCC1.[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>[CH:11]([Si:6]([CH:3]([CH3:5])[CH3:4])([CH:8]([CH3:10])[CH3:9])[S:7][C:20]1[CH:29]=[C:28]2[C:23]([CH2:24][CH2:25][CH:26]([C:30]([O:32][CH2:33][CH3:34])=[O:31])[O:27]2)=[CH:22][CH:21]=1)([CH3:13])[CH3:12]
Reactant: CCOC(=O)C1CCc2ccc(OS(=O)(=O)C(F)(F)F)cc2O1
Reactant: CC(C)[Si](S)(C(C)C)C(C)C
Agent: [Pd]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCOC(=O)C1CCc2ccc(S[Si](C(C)C)(C(C)C)C(C)C)cc2O1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of NaH (1.02 g, 25.6 mmol, 60% in mineral oil) in toluene (60 ml) was added triisopropylsilanethiol (4.24 g, 22.3 mmol). After stirring at room temperature for 30 min, to the mixture were added a solution of ethyl 7-{[(trifluoromethyl)sulfonyl]oxy}chromane-2-carboxylate (6.07 g, 17.1 mmol) in THF (60 ml) and tetrakis(triphenylphosphine) palladium (0.39 g, 0.34 mmol), and the mixture was degassed under N2. After heating at 90° C. for 1.5 h under N2, the solvents were evaporated and the residue was purified by column chromatography (EtOAc/Isooctane) to afford the title compound. Yield: 6.84 g. MS m/z (rel. intensity, 70 eV) 394 (M+, 27), 277 (52), 352 (26), 351 (bp), 251 (50).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[N:12]([C:21]([N:23]3[CH2:28][CH2:27][N:26](C(OC(C)(C)C)=O)[CH2:25][CH2:24]3)=[O:22])[C:11]([C:36]3[CH:41]=[CH:40][C:39]([C:42]([F:45])([F:44])[F:43])=[CH:38][C:37]=3[O:46][CH2:47][CH3:48])=[N:10]2)=[CH:5][CH:4]=1>O1CCOCC1>[ClH:2].[Cl:2][C:3]1[CH:4]=[CH:5][C:6]([CH:9]2[CH:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[N:12]([C:21]([N:23]3[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]3)=[O:22])[C:11]([C:36]3[CH:41]=[CH:40][C:39]([C:42]([F:44])([F:43])[F:45])=[CH:38][C:37]=3[O:46][CH2:47][CH3:48])=[N:10]2)=[CH:7][CH:8]=1
Reactant: CCOc1cc(C(F)(F)F)ccc1C1=NC(c2ccc(Cl)cc2)C(c2ccc(Cl)cc2)N1C(=O)N1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: C1COCCO1
Product: CCOc1cc(C(F)(F)F)ccc1C1=NC(c2ccc(Cl)cc2)C(c2ccc(Cl)cc2)N1C(=O)N1CCNCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98 %

Procedure:
Hydrochloric acid (10 mL, 40 mmol, 4 M in 1,4-dioxane) was added to a cooled (0° C.) solution of [4,5-bis-(4-chloro-phenyl)-2-(2-ethoxy-4-trifluoromethyl-phenyl)-4,5-dihydro-imidazol-1-yl]-[4-tert-butyloxycarbonylpiperazin-1-yl]-methanone in 1,4-dioxane (10 mL). The mixture was stirred at room temperature overnight. Evaporation of the solvent gave [4,5-bis-(4-chloro-phenyl)-2-(2-ethoxy-4-trifluoromethyl-phenyl)-4,5-dihydro-imidazol-1-yl]-(piperazin-1-yl)-methanone hydrochloride as an off-white solid (1.10 g, 98% yield).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([C:8]2(O)[CH2:13][CH2:12][CH:11]([N:14]([CH3:16])[CH3:15])[CH2:10][CH2:9]2)[CH:5]=[CH:4][CH:3]=1>C1(C)C=CC=CC=1>[Br:1][C:2]1[N:7]=[C:6]([C:8]2[CH2:13][CH2:12][CH:11]([N:14]([CH3:16])[CH3:15])[CH2:10][CH:9]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: CN(C)C1CCC(O)(c2cccc(Br)n2)CC1
Solvent: Cc1ccccc1
Product: CN(C)C1CC=C(c2cccc(Br)n2)CC1
Temperature: 25 °C
Yield: 80.5 %

Procedure:
Mix the above 1-(6-bromo-pyridin-2-yl)-4-dimethylamino-cyclohexanol (7 g, 23.4 mmol), p-toluenesulfonic acic monohydrate (15.3 g, 80.5 mmol), anhydrous toluene (600 mL). Heat at reflux for 16 hr. with a Dean Stark trap. Cool down to room temperature. Concentrate under reduced pressure. Partition between ethyl acetate and a 2M NaOH solution. Separate the organic layer, extract the aqueous layer twice with ethyl acetate. Combine the organic fractions, dry over sodium sulfate and concentrate to a residue. Purify the residue by chromatography (silica gel, 6% 2M NH3-MeOH in DCM) to yield (4-(6-bromo-pyridin-2-yl)-cyclohex-3-enyl)-dimethyl-amine (5.3 g, 81% yield): MS (ES): m/z=299 (M+H)+; 1H NMR (CDCl3): δ 7.45 (m, 1H), 7.27 (m, 2H), 6.72 (m, 1H), 2.69 (m, 1H), 2.45 (m, 3H), 2.33 (s, 6H), 2.21 (m, 2H), 1.58 (m, 1H).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][C@@H:6]([CH3:8])[CH2:5][N:4]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][C:10]=2[NH:15][C:16]([C:18]2[C:27]([NH:28]C(=O)OCC3C=CC=CC=3)=[CH:26][C:25]3[C:20](=[CH:21][C:22]([N:39]4[CH2:44][CH2:43][O:42][CH2:41][CH2:40]4)=[CH:23][CH:24]=3)[N:19]=2)=[O:17])[CH2:3]1>Br.CC(O)=O>[NH2:28][C:27]1[C:18]([C:16]([NH:15][C:10]2[CH:11]=[N:12][CH:13]=[CH:14][C:9]=2[N:4]2[CH2:5][C@H:6]([CH3:8])[CH2:7][C@H:2]([NH2:1])[CH2:3]2)=[O:17])=[N:19][C:20]2[C:25]([CH:26]=1)=[CH:24][CH:23]=[C:22]([N:39]1[CH2:40][CH2:41][O:42][CH2:43][CH2:44]1)[CH:21]=2
Reactant: C[C@@H]1C[C@H](N)CN(c2ccncc2NC(=O)c2nc3cc(N4CCOCC4)ccc3cc2NC(=O)OCc2ccccc2)C1
Agent: Br
Solvent: CC(=O)O
Product: C[C@@H]1C[C@H](N)CN(c2ccncc2NC(=O)c2nc3cc(N4CCOCC4)ccc3cc2N)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of benzyl {2-[({4-[(3S,5R)-3-amino-5-methylpiperidin-1-yl]pyridin-3-yl}amino)carbonyl]-7-morpholin-4-ylquinolin-3-yl}carbamate (0.002 g, 0.003 mmol) in 2 mL of 4 M HBr in AcOH solution was stirred at room temperature for 2 h. The solution was then concentrated under reduced pressure and the residue was treated with 4.5 mL of MeOH and 0.5 mL of NH4OH solution. The mixture was filtered and the filtrate was purified by preparative HPLC (XBridge™ C18 column, eluting with a gradient of MeCN/water containing 0.1% NH4OH, at a flow rate of 30 mL/min.) to afford the title compound. LCMS calc. for C25H32N7O2 [M+H]+: m/z=462.3. found: 462.3.
Reaction SMILES: [F:1][CH:2]([F:19])[O:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]2[N:16]=[CH:15][C:14]([CH:17]=[CH2:18])=[CH:13][N:12]=2)=[CH:6][CH:5]=1.[CH2:20]([O:27][C:28]1[CH:33]=[CH:32][C:31](I)=[CH:30][CH:29]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>C(#N)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C(Cl)(Cl)Cl.[Pd].[Pd]>[CH2:20]([O:27][C:28]1[CH:33]=[CH:32][C:31](/[CH:18]=[CH:17]/[C:14]2[CH:15]=[N:16][C:11]([NH:10][C:7]3[CH:8]=[CH:9][C:4]([O:3][CH:2]([F:1])[F:19])=[CH:5][CH:6]=3)=[N:12][CH:13]=2)=[CH:30][CH:29]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: C=Cc1cnc(Nc2ccc(OC(F)F)cc2)nc1
Reactant: Ic1ccc(OCc2ccccc2)cc1
Agent: [Pd]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CC#N
Solvent: ClC(Cl)Cl
Product: FC(F)Oc1ccc(Nc2ncc(/C=C/c3ccc(OCc4ccccc4)cc3)cn2)cc1
Temperature: 90 °C
Yield: 69.7 %

Procedure:
To a solution of N-(4-(difluoromethoxy)phenyl)-5-vinylpyrimidin-2-amine (0.102 g, 0.387 mmol) in ACN (3 mL) were added 1-(benzyloxy)-4-iodobenzene (0.1 g, 0.322 mmol), tris(dibenzylideneacetone)dipalladium(0) chloroform adduct (0.033 g, 0.032 mmol), tri-o-tolylphosphine (0.039 g, 0.129 mmol), and TEA (0.135 mL, 0.967 mmol). The reaction mixture was flushed with N2 and heated at 90° C. overnight. Solvent was evaporated, and the residue was dissolved in ethyl acetate, filtered through celite and concentrated. The crude product was purified by flash chromatography on silica gel using 30% ethyl acetate in hexanes to give (E)-5-(4-(benzyloxy)styryl)-N-(4-(difluoromethoxy)phenyl)pyrimidin-2-amine (0.1 g, 70%). 1H NMR (400 MHz, DMSO-d6) δ ppm 5.14 (s, 2H), 6.93-7.30 (m, 7H), 7.34-7.52 (m, 2H), 7.78-7.80 (m, 2H), 8.71 (s, 2H), 9.82 (s, 1H). LCMS: RT 1.18 min, (M+H)+446.6.
Reaction SMILES: P([O-])([O-])([O-])=O.C([NH:9][C@@H:10]1[C@@H:16]([OH:17])[C@H:15]([OH:18])[C@@H:14]([CH2:19][OH:20])[O:13][CH:11]1[OH:12])(=O)C>>[OH:12][CH:11]1[O:13][C@H:14]([CH2:19][OH:20])[C@@H:15]([OH:18])[C@H:16]([OH:17])[C@H:10]1[NH2:9]
Reactant: CC(=O)N[C@H]1C(O)O[C@H](CO)[C@@H](O)[C@@H]1O
Agent: O=P([O-])([O-])[O-]
Product: N[C@H]1C(O)O[C@H](CO)[C@@H](O)[C@@H]1O

Procedure:
An enzyme solution (0.1 ml) is added to 0.3 ml of 100 mM phosphate buffer (pH 7.8) containing 0.1 ml of 1% N-acetyl-D-glucosamine as a substrate, and the resultant mixture is incubated at 37° C. for 30 minutes. The amount of D-glucosamine formed is determined colorimetrically using indole-HCl according to the method of Z. Dische and E. Borenfreund [J. Biol. Chem., 184:517 (1950)]. One unit of the enzyme is defined as the amount of the enzyme which is capable of producing 1 μmol D-glucosamine from N-acetyl-D-glucosamine per minute at 37° C.
Reaction SMILES: C(O[C:4](=[O:30])[C@H:5]([O:7][C:8]1[CH:29]=[CH:28][C:11]2[C:12]3[N:16]([CH2:17][CH2:18][O:19][C:10]=2[CH:9]=1)[CH:15]=[C:14]([C:20]1[N:21]([CH:25]([CH3:27])[CH3:26])[N:22]=[CH:23][N:24]=1)[N:13]=3)[CH3:6])C.O.[OH-].[Li+].Cl.C[N:36](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Cl-].[NH4+].C(N(CC)CC)C>CO.O>[CH:25]([N:21]1[C:20]([C:14]2[N:13]=[C:12]3[C:11]4[CH:28]=[CH:29][C:8]([O:7][C@H:5]([CH3:6])[C:4]([NH2:36])=[O:30])=[CH:9][C:10]=4[O:19][CH2:18][CH2:17][N:16]3[CH:15]=2)=[N:24][CH:23]=[N:22]1)([CH3:26])[CH3:27]
Reactant: CCOC(=O)[C@@H](C)Oc1ccc2c(c1)OCCn1cc(-c3ncnn3C(C)C)nc1-2
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Solvent: CO
Solvent: CCN(CC)CC
Solvent: O
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(O[C@H](C)C(N)=O)cc1OCC2
Temperature: 50 °C
Reaction time: 1 h
Yield: 25.5 %

Procedure:
To a solution of (R)-2-[2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-yloxy]-propionic acid ethyl ester (315 mg, 0.77 mmol) in methanol (10 mL) was added water (1 mL) and lithium hydroxide monohydrate (46 mg, 1.15 mmol). The reaction mixture was heated at 50° C. for 16 h then HCl (1N, aq.) added until pH˜4. The reaction mixture was concentrated in vacuo. The resultant residue was dissolved in DMF (5 mL) and HATU (583 mg, 1.53 mmol), ammonium chloride (122 mg, 2.29 mmol) and triethylamine (320 μL, 2.29 mmol) added. The reaction mixture was stirred at RT for 1 h before being concentrated in vacuo. The residue was dissolved in ethyl acetate (10 mL) and the mixture washed with water, extracting with ethyl acetate (3×10 mL). The combined organic extracts were washed with brine, dried (MgSO4) and concentrated in vacuo. The resultant residue was subjected to flash chromatography (SiO2, gradient 0-10% methanol in ethyl acetate) and the product crystallised from acetonitrile to give 485 as a white solid (75 mg, 26%). LCMS: RT=3.25 min, [M+H]+=383
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]([C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[NH:17][C:16]([C:21]([N:23]2[CH2:28][CH2:27][CH:26]([O:29][CH3:30])[CH2:25][CH2:24]2)=[O:22])=[CH:15]3)=[O:11])[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[H-].[Na+].CS(O[CH2:38][C:39]([F:42])([F:41])[F:40])(=O)=O>CN(C)C=O>[CH:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]([C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[N:17]([CH2:38][C:39]([F:42])([F:41])[F:40])[C:16]([C:21]([N:23]2[CH2:28][CH2:27][CH:26]([O:29][CH3:30])[CH2:25][CH2:24]2)=[O:22])=[CH:15]3)=[O:11])[CH2:6][CH2:5]1)([CH3:3])[CH3:2]
Reactant: CS(=O)(=O)OCC(F)(F)F
Reactant: COC1CCN(C(=O)c2cc3cc(C(=O)N4CCN(C(C)C)CC4)ccc3[nH]2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC1CCN(C(=O)c2cc3cc(C(=O)N4CCN(C(C)C)CC4)ccc3n2CC(F)(F)F)CC1
Yield: 83 %

Procedure:
The title compound was synthesized in analogy to example 51, from [5-(4-isopropyl-piperazine-1-carbonyl)-1H-indol-2-yl]-(4-methoxy-piperidin-1-yl)-methanone (example 21), sodium hydride and 2,2,2-trifluoroethyl methanesulfonate in N,N-dimethylformamide, to give the desired product as a light brown foam (83%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8](Cl)=[O:9])=[C:6]([F:11])[C:5]([CH3:12])=[CH:4][CH:3]=1.C(P(CCCC)CCCC)CCC.[C:26]1([Mg]Br)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>O1CCCC1>[Cl:1][C:2]1[C:7]([C:8]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:9])=[C:6]([F:11])[C:5]([CH3:12])=[CH:4][CH:3]=1
Reactant: Br[Mg]c1ccccc1
Reactant: Cc1ccc(Cl)c(C(=O)Cl)c1F
Agent: CCCCP(CCCC)CCCC
Solvent: C1CCOC1
Product: Cc1ccc(Cl)c(C(=O)c2ccccc2)c1F
Reaction time: 0.75 h

Procedure:
Step 1 To a solution of 6-chloro-2-fluoro-3-methyl-benzoyl chloride (2.07 g, 10.0 mmol) in anhydrous tetrahydrofuran (50 ml), stirred under nitrogen in an acetonitrile/CO2 bath, was added tributyl phosphine (2.75 ml, 11.0 mmol). The mixture was stirred for 15 minutes before phenylmagnesium bromide (3M in diethyl ether, 3.67 ml, 11.0 mmol) was added dropwise. After 45 minutes, the reaction was quenched by addition of hydrochloric acid (2N, 50 ml). The mixture was extracted with ethyl acetate. The organic liquors were washed with sodium bicarbonate solution and brine, dried (MgSO4) and concentrated in vacuo. The residue was purified by silica chromatography eluting with 0-10% diethyl ether/petroleum ether furnishing (6-chloro-2-fluoro-3-methyl-phenyl)-phenyl-methanone as a yellow oil that slowly crystallised (1.12 g, ca. 80% pure). Trituration with petroleum ether produced an analytically pure sample. MS: [M+H]+ 249
Reaction SMILES: [OH-].[Na+].[Br:3][C:4]([Br:16])=[CH:5][CH2:6][CH:7]([CH:13]([CH3:15])[CH3:14])[C:8]([O:10]CC)=[O:9]>O.C(O)C>[Br:3][C:4]([Br:16])=[CH:5][CH2:6][CH:7]([CH:13]([CH3:14])[CH3:15])[C:8]([OH:10])=[O:9]
Reactant: CCOC(=O)C(CC=C(Br)Br)C(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(C)C(CC=C(Br)Br)C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 88 %

Procedure:
In a mixture of 7 g of water and 20 g of ethanol were dissolved 1.1 g of sodium hydroxide and 4.6 of the ethyl α-(3.3-dibromoallyl)isovalerate obtained above were added to the above solution. The mixture was stirred at room temperature overnight and, then, refluxed for 3 hours. The reaction mixture was then distilled to remove the ethanol and the residue was made acidic by the addition of dilute hydrochloric acid and extracted with diethyl ether. The ethereal layer was dried over anhydrous magnesium sulfate and the low-boiling fraction was distilled off. By the above procedure there were obtained 3.7 g of α-(3,3-dibromoallyl)isovaleric acid, the NMR spectrum of which is shown below [yield: 88% based on ethyl α-(3,3-dibromoallyl)isovalerate].
Reaction SMILES: Cl.[C:2](Cl)(=[O:9])[C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1.[NH2:11][C:12]([CH3:33])([CH3:32])[CH2:13][C:14]1[N:15]([CH2:28][CH2:29][O:30][CH3:31])[N:16]=[C:17]2[C:26]=1[C:25]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[N:19]=[C:18]2[NH2:27]>>[NH2:27][C:18]1[C:17]2=[N:16][N:15]([CH2:28][CH2:29][O:30][CH3:31])[C:14]([CH2:13][C:12]([NH:11][C:2](=[O:9])[C:3]3[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=3)([CH3:33])[CH3:32])=[C:26]2[C:25]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[N:19]=1
Reactant: COCCn1nc2c(N)nc3ccccc3c2c1CC(C)(C)N
Reactant: O=C(Cl)c1ccncc1
Agent: Cl
Product: COCCn1nc2c(N)nc3ccccc3c2c1CC(C)(C)NC(=O)c1ccncc1
Yield: 82.3 %

Procedure:
Using the method of Example 68, isonicotinoyl chloride hydrochloride (710 mg, 4.00 mmol) was reacted with 1-(2-amino-2-methylpropyl)-2-(2-methoxyethyl)-2H-pyrazolo[3,4-c]quinolin-4-amine (500 mg, 1.60 mmol, prepared as described in Example 590). The crude product was purified as described in Example 68 to provide 551 mg of N-{2-[4-amino-2-(methoxyethyl)-2H-pyrazolo[3,4-c]quinolin-1-yl]-1,1-dimethylethyl}isonicotinamide as a white solid, mp 166-168° C. MS (ESI) m/z 419 (M+H)+; Anal. Calcd for C23H26N6O2: C, 66.01; H, 6.26; N, 20.08. Found: C, 65.93; H, 6.41; N, 20.44.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:7]([CH3:22])([CH3:21])[C:8]3[C:13]([O:14][C:15]=2[C:16]=1C=O)=[CH:12][C:11]([O:19][CH3:20])=[CH:10][CH:9]=3.[CH:23]([O:30][CH2:31]C)([O:27][CH2:28]C)OCC.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(O)C>[CH3:31][O:30][CH:23]([O:27][CH3:28])[C:12]1[C:13]2[O:14][C:15]3[C:6](=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[CH:16]=3)[C:7]([CH3:21])([CH3:22])[C:8]=2[CH:9]=[CH:10][C:11]=1[O:19][CH3:20]
Reactant: COc1ccc2c(c1)Oc1c(ccc(OC)c1C=O)C2(C)C
Reactant: CCOC(OCC)OCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Solvent: O
Product: COc1ccc2c(c1)Oc1c(ccc(OC)c1C(OC)OC)C2(C)C

Procedure:
A solution of 24.15 g of 3,6-dimethoxy-9,9-dimethylxanthene-4-carboxaldehyde in 50 ml of absolute ethanol was treated with 50 ml of triethyl orthoformate. After the addition of 100 mg of p-toluenesulphonic acid monohydrate the mixture was boiled under reflux for 1 hour, then cooled and poured into ice-cold sodium bicarbonate solution, whereupon the mixture was extracted twice with 200 ml of ether each time. The combined extracts were washed neutral with water, dried over Na2SO4 and concentrated. The residue was purified on silica gel with hexane/ethyl acetate, whereby there were obtained 19.6 g of 3,6-dimethoxy-9,9-dimethylxanthene-4-carboxaldehyde dimethyl acetal as a pale yellow oil which crystallized slowly; m.p. 60°-62°, IR 2972, 1606, 1572, 1490 cm-1.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]2[N:11]([CH2:12][CH2:13][O:14][CH:15]([CH3:17])[CH3:16])[C:10]([CH3:19])([CH3:18])[CH2:9][N:5]2[C:6](=[O:8])[CH:7]=1.[NH:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1>>[CH:15]([O:14][CH2:13][CH2:12][N:11]1[C:4]2=[N:3][C:2]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)=[CH:7][C:6](=[O:8])[N:5]2[CH2:9][C:10]1([CH3:19])[CH3:18])([CH3:17])[CH3:16]
Reactant: C1COCCN1
Reactant: CC(C)OCCN1c2nc(Cl)cc(=O)n2CC1(C)C
Product: CC(C)OCCN1c2nc(N3CCOCC3)cc(=O)n2CC1(C)C
Yield: 60 %

Procedure:
150 mg of 7-chloro-1-(2-isopropoxyethyl)-2,2-dimethyl-2,3-dihydroimidazo[1,2-a]pyrimidin-5(1H)-one in 2 mL of morpholine are heated with the microwave oven to 80° C. for 45 mins. The crude is purified by flash chromatography on silica gel (CH2Cl2 100% to CH2Cl2/MeOH, 92/8). 0.085 g (yield=60%) of 1-(2-isopropoxyethyl)-2,2-dimethyl-7-(morpholin-4-yl)-2,3-dihydroimidazo[1,2-a]pyrimidin-5(1H)-one are obtained as a beige solid and including the following characteristics:
Reaction SMILES: [CH2:1]([Li])[CH3:2].[Cl:4][C:5]1[CH:6]=[C:7]([CH:24]=[CH:25][CH:26]=1)[C:8]([C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][N:19]([CH2:22][CH3:23])[CH2:20][CH3:21])=[CH:12][CH:11]=1)=[O:9].[Cl-].[NH4+]>CCOCC>[Cl:4][C:5]1[CH:6]=[C:7]([CH:24]=[CH:25][CH:26]=1)[C:8]([CH2:1][CH3:2])([OH:9])[C:10]1[CH:11]=[CH:12][C:13]([O:16][CH2:17][CH2:18][N:19]([CH2:20][CH3:21])[CH2:22][CH3:23])=[CH:14][CH:15]=1
Reactant: [Li]CC
Reactant: CCN(CC)CCOc1ccc(C(=O)c2cccc(Cl)c2)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Product: CCN(CC)CCOc1ccc(C(O)(CC)c2cccc(Cl)c2)cc1

Procedure:
To 125 ml. of a 0.8 molar ethereal ethyl lithium solution a solution of 13.3 g. of 3-chloro-4'-[2-(diethylamino)-ethoxy]-benzophenone in 160 ml. of ether is added dropwise, with stirring under argon atmosphere, at a temperature between -20° C. and -15° C. The reaction mixture is then stirred at room temperature for one hour, and is decomposed with a saturated aqueous ammonium chloride solution, under cooling. The aqueous phase is extracted with ether, the ethereal phases are combined and washed to neutral with water. After drying over anhydrous magnesium sulfate, ether is distilled off under reduced pressure. Crystallization of the solid residue from n-hexane yields 8.9 g. of the title compound, melting at 64° to 65° C.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[Cl:13][C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1.[F:20][C:21]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:22]=1[CH:23]=[O:24].[Cl-].[NH4+]>C(OCC)(=O)C.O1CCCC1>[Cl:13][C:14]1[CH:15]=[N:16][CH:17]=[CH:18][C:19]=1[CH:23]([C:22]1[CH:25]=[C:26]([F:29])[CH:27]=[CH:28][C:21]=1[F:20])[OH:24]
Reactant: Clc1cccnc1
Reactant: O=Cc1cc(F)ccc1F
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CC(C)NC(C)C
Product: OC(c1cc(F)ccc1F)c1ccncc1Cl
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 52 %

Procedure:
To a tetrahydrofuran solution (14 ml) of diisopropylamine (1.4 ml, 10 mmol) was added n-butyl lithium (6.3 ml, 1.59M hexane solution) at −78° C. and the mixture was stirred for 10 minutes. Then, 3-chloropyridine (1.13 g, 10 mmol) was added to the resulting mixture. Thirty minutes later, 2,5-difluorobenzaldehyde (1.09 ml, 10 mmol) was added to the mixture. The mixture was warmed gradually to 0° C., at which stirring was conducted for further 10 minutes. An aqueous solution of ammonium chloride was added and the mixture was diluted with ethyl acetate (80 ml). The organic layer obtained by separation was washed with brine and then dried. After filtration, the filtrate was concentrated under reduced pressure. The precipitate thus obtained was triturated with ethanol to yield the title compound (1.33 g, 52%).
Reaction SMILES: [CH2:1]([Mg]Cl)[CH3:2].[C:5]([O:9][C:10](=[O:23])[NH:11][C:12]1[S:13][CH:14]=[C:15]([C:17](=[O:22])N(OC)C)[N:16]=1)([CH3:8])([CH3:7])[CH3:6]>O1CCCC1>[C:5]([O:9][C:10](=[O:23])[NH:11][C:12]1[S:13][CH:14]=[C:15]([C:17](=[O:22])[CH2:1][CH3:2])[N:16]=1)([CH3:8])([CH3:6])[CH3:7]
Reactant: CC[Mg]Cl
Reactant: CON(C)C(=O)c1csc(NC(=O)OC(C)(C)C)n1
Solvent: C1CCOC1
Product: CCC(=O)c1csc(NC(=O)OC(C)(C)C)n1
Temperature: -70 °C
Reaction time: 1 h
Yield: 54.9 %

Procedure:
A solution of ethyl magnesium chloride (126 mL, 0.252 mol, 2 M in tetrahydrofuran) was stirred and cooled to −70° C. on a dry ice/acetone bath. A solution of [4-(methoxy-methyl-carbamoyl)-thiazol-2-yl]-carbamic acid tert-butyl ester (14.5 g, 0.0504 mol) in tetrahydrofuran (200 mL) was added dropwise over approximately 5 minutes. The mixture was stirred for 1 hour. The cooling bath was removed and stirring continued for an additional 2 hours. The mixture was poured into a mixture of ice and saturated aqueous ammonium chloride solution and then extracted with ethyl acetate. The organic extracts were combined, washed with brine, dried over magnesium sulfate and evaporated to give an off white solid which was purified by chromatography over a 350 g pad of silica gel eluted with 4:1 ethyl acetate/dichloromethane to afford (4-propionyl-thiazol-2-yl)-carbamic acid tert-butyl ester (7.09 g, 55%) as an off white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2Cl.[NH:18]1[CH2:23][CH2:22][CH:21]([CH2:24][N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)[CH2:20][CH2:19]1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[N:18]1[CH2:23][CH2:22][CH:21]([CH2:24][N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)[CH2:20][CH2:19]1
Reactant: C1CC(CN2CCOCC2)CCN1
Reactant: O=C(c1cnc2ccc(Br)cc2c1Cl)C1CC1
Product: O=C(c1cnc2ccc(Br)cc2c1N1CCC(CN2CCOCC2)CC1)C1CC1
Yield: 83.9 %

Procedure:
Following general procedure B, (6-bromo-4-chloroquinolin-3-yl)(cyclopropyl)methanone (144 mg, 0.460 mmol) was reacted with 4-(piperidin-4-ylmethyl)morpholine (102 mg, 0.552 mmol) to afford the desired product (177 mg, 84%) as a yellow solid: ESI MS m/z 458 [C23H28BrN3O2+H]+.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH:5]([CH3:7])[CH3:6].[C:8]1(=[O:18])[NH:12][C:11](=[O:13])[C:10]2=[CH:14][CH:15]=[CH:16][CH:17]=[C:9]12.[K].C(Cl)(Cl)Cl.O>CN(C=O)C>[CH3:6][CH:5]([CH3:7])[CH2:4][CH2:3][CH2:2][N:12]1[C:8](=[O:18])[C:9]2[C:10](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:11]1=[O:13]
Reactant: CC(C)CCCBr
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: CN(C)C=O
Solvent: O
Solvent: ClC(Cl)Cl
Product: CC(C)CCCN1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 1-bromo-4-methylpentane (5.0 g, 0.030 mol) in DMF (20 mL) was added potassium phthalimide (5.9 g, 0.032 mol) in one portion at room temperature. After stirring at room temperature of 1 hr, the mixture was heated at 55° C. for 16 hr. Chloroform (30 mL) was added to the reaction mixture and the resulting mixture was poured into water (100 mL). The aqueous phase was extracted with chloroform and the combined organic phase was washed with 0.25 M NaOH (aq) and water. The organic phase was dried (Na2SO4), filtered and concentrated in vacuo to give 2-(4-methylpentyl)-1H-isoindole-1,3(2H)-dione as a pale yellow oil. (M+H) 232, 2.80 min. (LC/MS method A).