Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC1(C)O[CH:5]([CH2:7][N:8]2[C:13]([C:14]([O:16]CC)=[O:15])=[CH:12][C:11]3[CH:19]=[CH:20][S:21][C:10]=3[S:9]2(=[O:23])=[O:22])[CH2:4][O:3]1.O.FC(F)(F)C(O)=O>>[OH:3][CH2:4][CH:5]1[O:16][C:14](=[O:15])[C:13]2[N:8]([S:9](=[O:22])(=[O:23])[C:10]3[S:21][CH:20]=[CH:19][C:11]=3[CH:12]=2)[CH2:7]1
Reactant: CCOC(=O)C1=Cc2ccsc2S(=O)(=O)N1CC1COC(C)(C)O1
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: O=C1OC(CO)CN2C1=Cc1ccsc1S2(=O)=O
Yield: 193.5 %

Procedure:
A solution of the product from Step B (18 g, 21.4 mmol) in a water/trifluoroacetic acid mixture (1:9) was stirred for 12 h. The solid which formed was collected by filtration, washed with hexane, and dried to give 11.9 g (86%) of a colorless solid: mp 210°-212° C.
Reaction SMILES: [C:1]([C:3]1([NH:6][C:7](=[O:35])[C@H:8]([CH2:30][C:31]([F:34])([CH3:33])[CH3:32])[NH:9][C@@H:10]([C:15]2[CH:20]=[CH:19][C:18](B3OC(C)(C)C(C)(C)O3)=[CH:17][CH:16]=2)[C:11]([F:14])([F:13])[F:12])[CH2:5][CH2:4]1)#[N:2].Br[C:37]1[CH:42]=[CH:41][C:40]([C@@H:43]([OH:47])[CH:44]([F:46])[F:45])=[CH:39][CH:38]=1.C(=O)(O)[O-].[Na+].ClCCl.OC(C(O)(C)C)(C)C>CN(C)C=O.C(OCC)C.C(OCC)(=O)C>[C:1]([C:3]1([NH:6][C:7](=[O:35])[C@H:8]([CH2:30][C:31]([F:34])([CH3:33])[CH3:32])[NH:9][C@@H:10]([C:15]2[CH:16]=[CH:17][C:18]([C:37]3[CH:38]=[CH:39][C:40]([C@@H:43]([OH:47])[CH:44]([F:46])[F:45])=[CH:41][CH:42]=3)=[CH:19][CH:20]=2)[C:11]([F:13])([F:14])[F:12])[CH2:4][CH2:5]1)#[N:2]
Reactant: CC(C)(F)C[C@H](N[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)C(F)(F)F)C(=O)NC1(C#N)CC1
Reactant: O[C@H](c1ccc(Br)cc1)C(F)F
Agent: CC(C)(O)C(C)(C)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)(F)C[C@H](N[C@@H](c1ccc(-c2ccc([C@@H](O)C(F)F)cc2)cc1)C(F)(F)F)C(=O)NC1(C#N)CC1
Temperature: 0 °C
Reaction time: 16 h

Procedure:
The boronate ester of step 3 of example 1 (20 g, 40 mmoles) and the aryl bromide of step 2 of example 1 (11.4 g, 48 mmoles) were dissolved in dimethylformamide (400 mL) followed by an aqueous solution of sodium bicarbonate (60 mL, 120 mmoles). Nitrogen was then bubbled through a pipette for 15 minutes. [1,1-Bis(diphenylphosphine)ferrocene]dichloropalladium(II), 1:1 complex with dichloromethane (PdCl2dppf.CH2Cl2, 2.4 g, 3 mmoles) was added and the reaction mixture immersed in an oil bath at 80° C. for 16 hours under a nitrogen atmosphere. Most of the dimethylformamide was removed under the rotovap at low pressure (45° C., approx 1-5 mm Hg). The residue was dissolved in ethyl acetate (400 mL) and filtered onto a pad of Celite. The filtrate was concentrated under reduced pressure. The residue was taken-up in approx 10 mL of dichloromethane and separated by flash chromatography. The most pure fractions were swished in hexanes (100 mL) at 0° C. overnight three times and flashed again (90% hexanes; 10% ethyl acetate to 45 hexanes; 55% ethyl acetate). After evaporation of the volatiles under reduced pressure, the solid was stirred in hexanes for 2 days. The product still contained 4% of pinacol so the batch was divided in two. Fraction A was dissolved in a minimum of isopropyl alcohol with gentle warming. Hexanes were added until the solution was a bit cloudy and let cool down. White crystals appeared and the reaction was further cooled to 0° C. for 15 minutes. The solids were collected by filtration to obtain the product not contaminated with pinacol. Fraction B was stirred in 20% diethyl ether; 1% ethyl acetate; 79% hexanes (100 mL) for 3 hours at room temperature. The solids were collected by filtration was contaminated with only approximately 1% pinacol by 1H NMR. The enantiomeric excess was verified chiral AD-RH using 32% acetonitrile; 68% water; 0.1% formic acid; isocratic (24 min for enantiomer and 27 minutes for desired molecule). (MH)+ ESI=528.0.
Reaction SMILES: [C:1]1([C:7]2[C:15]3[CH:14]=[CH:13][C:12]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[CH2:11][C:10]=3[N:9](COCC[Si](C)(C)C)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(C2C3C=CC(C4C=CC=CC=4)(C4C=CC=CC=4)CC=3NN2COCC[Si](C)(C)C)C=CC=CC=1.Cl>C(O)C.O>[C:1]1([C:7]2[C:15]3[CH:14]=[CH:13][C:12]([C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=4)([C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=4)[CH2:11][C:10]=3[NH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C[Si](C)(C)CCOCn1nc(-c2ccccc2)c2c1CC(c1ccccc1)(c1ccccc1)C=C2
Agent: C[Si](C)(C)CCOCN1NC2=C(C=CC(c3ccccc3)(c3ccccc3)C2)C1c1ccccc1
Agent: Cl
Solvent: CCO
Solvent: O
Product: C1=CC(c2ccccc2)(c2ccccc2)Cc2[nH]nc(-c3ccccc3)c21
Temperature: 65 °C
Reaction time: 4 h
Yield: 51.5 %

Procedure:
A mixture of 0.16 g of 3,6,6-triphenyl-1-(2-trimethylsilanylethoxymethyl)-6,7-dihydro-1H-indazole and 3,6,6-triphenyl-2-(2-trimethylsilanylethoxymethyl)-6,7-dihydro-1H-indazole is dissolved in 3.4 cm3 of ethanol and 1 cm3 of water, and 3.4 cm3 of an approximately 2N ethanolic solution of hydrogen chloride are then added. The solution is stirred for about 4 hours at a temperature in the region of 65° C. The reaction mixture is concentrated to dryness under reduced pressure (13 kPa). The residue is taken up in 50 cm3 of water, and the pH is brought to about 10 by addition of aqueous 0.1N sodium hydroxide solution. After extraction with three times 50 cm3 of ethyl acetate, the combined organic phases are washed with 50 cm3 of aqueous 0.1N sodium hydroxide solution, 50 cm3 of water and 50 cm3 of saturated aqueous sodium chloride solution, dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (13 kPa). After flash chromatography on a column of silica [eluent: dichloromethane], 0.06 g of 3,6,6-triphenyl-6,7-dihydro-1H-indazole is thus obtained in the form of a solid, the characteristics of which are as follows:
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]2[N:16]=[CH:15][N:14]=[C:13]3[C:9]=2[NH:10][C:11](=[O:17])[NH:12]3)[CH2:4][CH2:3]1.[C:18]1([CH2:24][CH:25]=O)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(O)(=O)C.ClCCCl.CO>[CH2:25]([NH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]2[N:16]=[CH:15][N:14]=[C:13]3[C:9]=2[NH:10][C:11](=[O:17])[NH:12]3)[CH2:4][CH2:3]1)[CH2:24][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=CCc1ccccc1
Reactant: NC1CCN(c2ncnc3[nH]c(=O)[nH]c23)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Solvent: ClCCCl
Solvent: CC(=O)O
Product: O=c1[nH]c2ncnc(N3CCC(NCCc4ccccc4)CC3)c2[nH]1
Temperature: 25 °C
Reaction time: 2 h
Yield: 10.3 %

Procedure:
A mixture of 6-(4-aminopiperidin-1-yl)-7,9-dihydropurin-8-one (Example 4B, 0.045 g, 0.20 mmol), phenylacetaldehyde (0.025 ml, 0.20 mmol), NaBH(OAc)3 (0.065 g, 0.30 mmol) and acetic acid (5 drops) in 1,2-dichloroethane (2 ml) and MeOH (0.5 ml) was stirred at room temperature for 2 hours. The solution was absorbed onto a 5 g SCX-II acidic resin cartridge and eluted with MeOH, then 1M NH3-MeOH. The basic eluant was concentrated. Preparative thin layer chromatography (t.l.c.), eluting with 1% NH3 (aq)/9% MeOH/90% CH2Cl2 gave the product as an off white solid (0.007 g, 10%). LC/MS: (LCT) Rt 3.62 [M+H]+ 339.
Reaction SMILES: [CH3:1]I.[CH2:3]([O:5][C:6](=[O:22])[C:7](=[C:13]([SH:21])[NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH3:4].[Na]>CN(C=O)C>[CH2:11]([O:10][C:8](=[O:9])[C:7](=[C:13]([S:21][CH3:1])[NH:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[C:6]([O:5][CH2:3][CH3:4])=[O:22])[CH3:12]
Reactant: CCOC(=O)C(C(=O)OCC)=C(S)Nc1ccccc1
Reactant: CI
Agent: [Na]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C(=O)OCC)=C(Nc1ccccc1)SC
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.9 %

Procedure:
Over a 30 min period, methyl iodide (17.7 g, 125 mmol) was added dropwise to a solution of sodium 2-(mercapto-phenylamino-methylene)-malonic acid diethyl ester (33 g, 104 mmol) in DMF (100 mL) cooled in an ice bath. The mixture was stirred at room temperature for 1 h, and then poured into ice water (300 mL). The resulting solid was collected via filtration, washed with water and dried to give 2-(methylsulfanyl-phenylamino-methylene)-malonic acid diethyl ester as a pale yellow solid (27 g, 84%).
Reaction SMILES: OC(C(F)(F)F)=O.[C:8]1([C:14]2[CH:19]=[CH:18][N:17]=[C:16]([N:20]3[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)[N:15]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[F:26][C:27]([F:43])([F:42])[C:28]1[O:32][N:31]=[C:30]([C:33]2[CH:34]=[C:35]([CH:39]=[CH:40][CH:41]=2)[C:36](O)=[O:37])[N:29]=1>>[C:8]1([C:14]2[CH:19]=[CH:18][N:17]=[C:16]([N:20]3[CH2:25][CH2:24][N:23]([C:36]([C:35]4[CH:39]=[CH:40][CH:41]=[C:33]([C:30]5[N:29]=[C:28]([C:27]([F:42])([F:26])[F:43])[O:32][N:31]=5)[CH:34]=4)=[O:37])[CH2:22][CH2:21]3)[N:15]=2)[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: O=C(O)c1cccc(-c2noc(C(F)(F)F)n2)c1
Reactant: c1ccc(-c2ccnc(N3CCNCC3)n2)cc1
Solvent: O=C(O)C(F)(F)F
Product: O=C(c1cccc(-c2noc(C(F)(F)F)n2)c1)N1CCN(c2nccc(-c3ccccc3)n2)CC1
Yield: 53 %

Procedure:
This compound was synthesized from 4-phenyl-2-(piperazin-1-yl)pyrimidine TFA salt and 3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzoic acid as described for example 37 step 3 (100 mg, yield 53%). 1H NMR (400 MHz, MeOD) δ 8.31-8.25 (m, 5H), 7.78-7.72 (m, 2H), 7.47-7.45 (m, 3H), 6.77-6.75 (d, J=6.3 Hz, 1H), 3.99-3.87 (m, 6H), 3.66 (s, 2H). MS (ESI) m/z: Calculated for C24H19F3N6O2: 480.15. found: 481.2 (M+H)+
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][CH:8]([CH3:18])[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[C:12]([OH:17])[CH:11]=1)([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[K+].[K+].[CH2:26]([O:28][C:29](=[O:33])[CH:30](Br)Br)[CH3:27]>CN(C=O)C>[CH2:26]([O:28][C:29]([CH:30]1[O:16][C:13]2[CH:14]=[CH:15][C:10]([CH2:9][CH:8]([NH:7][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:19])[CH3:18])=[CH:11][C:12]=2[O:17]1)=[O:33])[CH3:27]
Reactant: CCOC(=O)C(Br)Br
Reactant: CC(Cc1ccc(O)c(O)c1)NC(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)C1Oc2ccc(CC(C)NC(=O)OC(C)(C)C)cc2O1
Temperature: 120 °C
Yield: 25.4 %

Procedure:
To 1.30 g (4.6 mmol) of 3C was added 40 ml of anhydrous DMF followed by 2.5 g (18 mmol) of anhydrous K2CO3, 2.5 g of 3 A° molecular sieves and 2.3 mL (17.7 mmol) of ethyldibromoacetate. The reaction mixture was heated at 120° C. for 3 hours under argon atmosphere and concentrated under reduced pressure. To the residue 100 mL of water and 75 mL of ethyl acetate were added and filtered. The filtrate was transferred to a separatory funnel and the organic layer was separated. The aqueous layer was extracted with 4×50 mL of ethyl acetate. All the organic layers were combined, dried (Na2SO4) and concentrated. The residue was purified by silica gel column chromatography using 20% ethyl acetate in hexane to give 413 mg (1.17 mmol, 26%) of 3D as a colorless gum (M+Na, 374).
Reaction SMILES: [OH:1][C:2]1[C:11]([CH3:12])=[C:10]2[C:5]([C:6]([CH3:26])=[C:7]([CH2:14][N:15]3[C:19](=[O:20])[C:18]4=[CH:21][CH:22]=[CH:23][CH:24]=[C:17]4[C:16]3=[O:25])[C:8](=[O:13])[O:9]2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+].[Cl:35][C:36]([CH2:38]Cl)=[CH2:37]>CN(C=O)C.C(Cl)Cl>[Cl:35][C:36](=[CH2:37])[CH2:38][O:1][C:2]1[C:11]([CH3:12])=[C:10]2[C:5]([C:6]([CH3:26])=[C:7]([CH2:14][N:15]3[C:16](=[O:25])[C:17]4=[CH:24][CH:23]=[CH:22][CH:21]=[C:18]4[C:19]3=[O:20])[C:8](=[O:13])[O:9]2)=[CH:4][CH:3]=1
Reactant: C=C(Cl)CCl
Reactant: Cc1c(CN2C(=O)c3ccccc3C2=O)c(=O)oc2c(C)c(O)ccc12
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: C=C(Cl)COc1ccc2c(C)c(CN3C(=O)c4ccccc4C3=O)c(=O)oc2c1C
Temperature: 25 °C

Procedure:
A slurry of 7-hydroxy-4,8-dimethyl-3-phthalimidomethylcoumarin (649 mg, 1.86 mmol), potassium carbonate (320 mg, 2.60 mmol), potassium iodide (15 mg, 0.093 mmol), and 2,3-dichloro-1-propene (0.20 mL, 2.23 mmol) in DMF (15 mL) was stirred at 55-65° C. for 8 hours, allowed to cool to room temperature, then chilled in an ice water bath. The solid was filtered off to obtain the first crop of crude product (1.09 g). Half of the solvent was removed from the filtrate and after chilling, a second crop of crystals was obtained (33 mg). The solids were combined, dissolved in CH2Cl2, and washed with water several times. The organic layer was dried and evaporated to give 7-(beta-chloroallyloxy)-4,8-dimethyl-3-phthalimidomethylcoumarin, a white solid (690 mg, 87%). 1H NMR (CDCl3): δ7.66-7.83 (m, 4H), 7.49 (d, J=9.1 Hz, 1H), 6.79 (d, J=8.8 Hz, 1H), 5.56 (s, 1H), 5.47 (s, 1H), 4.91 (s, 2H), 4.67 (s, 2H), 2.59 (s, 3H), 2.32 (s, 3H).
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[C:10]([N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1)([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.[Cu]>[CH:4]([C:3]1[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=1[N:20]1[CH2:19][CH2:18][N:17]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:22][CH2:21]1)=[O:5]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=Cc1ccccc1F
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(c2ccccc2C=O)CC1
Temperature: 150 °C
Yield: 28.1 %

Procedure:
To a solution of 2-fluorobenzaldehyde (Aldrich) (1 g, 8.1 mmol) in DMF (14 mL) was added 1-Boc-piperazine (Lancaster) (2.3 g, 12 mmol). The resulting solution was treated with copper (Aldrich Chemical Company) (50 mg, 0.8 mmol) and K2CO3 (Aldrich) (5.1 g, 37 mmol) The suspension was heated in a sealed tube at 150° C. for 18 h. After cooling to RT, the reaction mixture was partitioned between EtOAc and brine. The aqueous layer was extracted twice with EtOAc and the combined EtOAc layers were washed with water, dried over Na2SO4, filtered and concentrated in vacuo. The crude compound was purified on a Biotage 40M column (12% EtOAc in hexanes) to give tert-butyl 4-(2-formylphenyl)piperazinecarboxylate (0.66 g) as a yellow oil. MS m/z: 291 (M+H). Calc'd for C16H22N2O3: 290.36.
Reaction SMILES: [C:1]([O:4][CH:5]([CH2:9][CH2:10][S:11][CH3:12])[C:6]([OH:8])=O)(=[O:3])[CH3:2].S(Cl)(Cl)=O.C(N(CC)CC)C.[CH2:24]([NH2:36])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35]>ClCCl>[C:1]([O:4][CH:5]([CH2:9][CH2:10][S:11][CH3:12])[C:6]([NH:36][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])=[O:8])(=[O:3])[CH3:2]
Reactant: CSCCC(OC(C)=O)C(=O)O
Reactant: CCCCCCCCCCCCN
Solvent: CCN(CC)CC
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: CCCCCCCCCCCCNC(=O)C(CCSC)OC(C)=O
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
To a solution of 2-acetoxy-4-(methylthio)butanoic acid (17.1 g, 89 mmol) in dichloromethane (350 mL) at 0° C. was added thionyl chloride (32.4 mL, 445 mmol) dropwise over 1 hr. The reaction was stirred at 0° C. for 1.5 hrs then the cooling bath was removed and the reaction was warmed to room temperature with stirring for 3 hrs. The solvent was evaporated and the resulting oil was dried under high vacuum for 1 hr to give an orange oil. A solution of the resulting oil in dichloromethane (˜30 mL) was added to a solution of triethylamine (24.8 mL, 178 mmol) and dodecylamine (20.5 mL, 89 mmol) in dichloromethane (150 mL) at 0° C. and the reaction was allowed to warm to room temperature with stirring overnight. The reaction was evaporated, re-dissolved in EtOAc (300 mL) and washed with 1N HCl (3×150 mL), saturated sodium bicarbonate (3×150 mL), and brine (1×150 mL). The organic layer was dried over magnesium sulfate, filtered and evaporated to give an oil. The oil was purified by silica gel chromatography with 0-40% EtOAc/heptane to give a yellow oil. (22.5 g, 70%). m/z 360 (MH+).
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]2[C:9]([N:10]=1)=[CH:8][C:7]([C:11]([OH:13])=O)=[C:6]([C:14]([OH:16])=[O:15])[N:5]=2>C(OC(=O)C)(=O)C>[CH3:1][C:2]1[O:3][C:4]2[C:9]([N:10]=1)=[CH:8][C:7]1[C:11]([O:16][C:14](=[O:15])[C:6]=1[N:5]=2)=[O:13]
Reactant: Cc1nc2cc(C(=O)O)c(C(=O)O)nc2o1
Solvent: CC(=O)OC(C)=O
Product: Cc1nc2cc3c(nc2o1)C(=O)OC3=O
Temperature: 70 °C
Yield: 97 %

Procedure:
A suspension of 2-methyloxazolo[5,4-b-]pyridine-5,6-dicarboxylic acid (4.84 g, 0.0218 mol) in acetic anhydride (150 mL) is slowly heated to 70° C. at which point all the solids dissolve forming a yellow solution. The reaction mixture is heated at 70° C. overnight, cooled to room temperature, and concentrated in vacuo. Xylene is added to remove excess acetic anhydride by codistillation. 2-Methyloxazolo[5,4-b]pyridine-5,6-dicarboxylic anhydride is obtained as a pale yellow solid in 97% yield melting point 194°-196° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:21]2[CH:22]=[N:23][N:24]3[CH:29]=[CH:28][C:27]([N:30]4[C@H:34]5[C:35]6[CH:36]=[CH:37][CH:38]=[CH:39][C:40]=6[CH2:41][C@H:33]5[O:32][C:31]4=[O:42])=[N:26][C:25]=23)[CH:5]=[CH:6][C:7]=1[C:8]1[N:12]=[CH:11][N:10](COCC[Si](C)(C)C)[N:9]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([C:21]2[CH:22]=[N:23][N:24]3[CH:29]=[CH:28][C:27]([N:30]4[C@H:34]5[C:35]6[CH:36]=[CH:37][CH:38]=[CH:39][C:40]=6[CH2:41][C@H:33]5[O:32][C:31]4=[O:42])=[N:26][C:25]=23)[CH:5]=[CH:6][C:7]=1[C:8]1[N:12]=[CH:11][NH:10][N:9]=1
Reactant: C[Si](C)(C)CCOCn1cnc(-c2ccc(-c3cnn4ccc(N5C(=O)O[C@@H]6Cc7ccccc7[C@@H]65)nc34)cc2F)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1O[C@@H]2Cc3ccccc3[C@@H]2N1c1ccn2ncc(-c3ccc(-c4nc[nH]n4)c(F)c3)c2n1
Temperature: 25 °C
Reaction time: 6 h
Yield: 10 %

Procedure:
To (3aS,8aR)-3-(3-(3-fluoro-4-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-3-yl)phenyl)pyrazolo[1,5-a]pyrimidin-5-yl)-3,3a,8,8a-tetrahydro-2H-indeno[1,2-d]oxazol-2-one (45 mg, 0.077 mmol) in DCM (5 mL) was added TFA (1 mL) and the reaction was stirred at ambient temperature for 6 hours. The reaction was concentrated to dryness and the residue dissolved in MeOH and added to 2N HCl in ether. After concentration, the residue was purified by reverse phase chromatography (SP4, 12M, water/CH3CN 100:0 to 0:100, 20 column volumes) to yield (3aS,8aR)-3-(3-(3-fluoro-4-(1H-1,2,4-triazol-3-yl)phenyl)pyrazolo[1,5-a]pyrimidin-5-yl)-3,3a,8,8a-tetrahydro-2H-indeno[1,2-d]oxazol-2-one (3.5 mg, 10% yield) as a pale yellow solid. LCMS (APCI+) m/z 454.2 [M+H]+.
Reaction SMILES: [OH-].[Na+].N[C@H:4](C(O)=O)[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.N[C@H](C(O)=[O:22])CC(C)C.N[C@H](C(O)=O)CC1C2C(=CC=CC=2)NC=1.N[C@H](C(O)=O)[C@H](CC)C.COC1C=CC(C[C@@H](C(O)=O)N)=CC=1>O1CCOCC1.O>[C:5]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)(=[O:22])[CH3:4]
Reactant: CC(C)C[C@H](N)C(=O)O
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Agent: CC[C@H](C)[C@H](N)C(=O)O
Agent: COc1ccc(C[C@H](N)C(=O)O)cc1
Agent: N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O
Solvent: C1COCCO1
Solvent: O
Product: CC(=O)c1ccccc1

Procedure:
200 μl (50 μmol) of a 0.25 M solution of each of the isatins listed in Table 1, in dioxane; 200 μl (50 μmol) of a 0.25 M solution of the α-amino acids listed in Table 2, in water (including 1 equivalent of sodium hydroxide for the L-phenylalanine, L-leucine, O-benzyl-(D,L)-serine, L-tryptophan, L-isoleucine, and O-methyl-L-tyrosine); and 400 μl (50 μmol) of a 0.125 M solution containing the chalcones produced by reaction of the arylaldehydes and acetophenone compounds of Tables 3 and 4, in dioxane, were combined in 1 ml perfume vials. The vials were capped and heated at 80° C. overnight. The solvent was then evaporated under reduced pressure and the resulting products were all recovered in greater than 85% purity according to high pressure liquid chromatography (HPLC) and mass spectroscopy (MS) experiments.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:19]([NH2:20])=[CH:18][C:6]2[CH2:7][CH2:8][CH2:9][CH:10]([N:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)[CH2:11][C:5]=2[CH:4]=1.CS([C:24]1[N:29]=[CH:28][C:27]2=[CH:30][CH:31]=[C:32]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=3[O:39][CH3:40])[N:26]2[N:25]=1)=O>>[CH3:1][O:2][C:3]1[C:19]([NH:20][C:24]2[N:29]=[CH:28][C:27]3=[CH:30][CH:31]=[C:32]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=4[O:39][CH3:40])[N:26]3[N:25]=2)=[CH:18][C:6]2[CH2:7][CH2:8][CH2:9][CH:10]([N:12]3[CH2:13][CH2:14][O:15][CH2:16][CH2:17]3)[CH2:11][C:5]=2[CH:4]=1
Reactant: COc1ccccc1-c1ccc2cnc(S(C)=O)nn12
Reactant: COc1cc2c(cc1N)CCCC(N1CCOCC1)C2
Product: COc1cc2c(cc1Nc1ncc3ccc(-c4ccccc4OC)n3n1)CCCC(N1CCOCC1)C2
Yield: 6.6 %

Procedure:
Following a procedure analogous to 251c, 3-Methoxy-6-morpholin-4-yl-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-ylamine (0.164 g, 0.59 mmol) and 2-methanesulfinyl-7-(2-methoxy-phenyl)-pyrrolo[2,1-f][1,2,4]triazine (85 mg, 0.30 mol) were converted to the title compound (19.6 mgs). 1H-NMR (DMSO-d6) δ 8.70 (s, 1H), 8.16 (s, 1H), 8.02 (d, J=7.4 Hz, 1H), 7.45-7.41 (m, 2H), 7.50-7.45 (m, 2H), 7.14-7.07 (m, 2H), 7.03 (d, J=4.9 Hz, 1H), 6.71 (s, 1H), 3.90 (s, 3H), 3.86 (s, 3H), 3.79-3.74 (m, 4H), 2.91-2.50 (complex series of m, 7H), 2.40 (t, J=10.6 Hz, 1H), 2.16-2.00 (m, 2H), 1.80-1.70 (m, 1H), 1.43-1.33 (m, 1H); LC/MS (ESI+): 500.17 (M+H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:11][C:12]2[C:21]3[C:16](=[CH:17][C:18]([O:24][CH2:25][CH2:26][CH2:27]Cl)=[C:19]([O:22][CH3:23])[CH:20]=3)[N:15]=[CH:14][N:13]=2)=[C:4]2[O:10][CH2:9][O:8][C:5]2=[N:6][CH:7]=1.[CH2:29]([N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1)[C:30]#[CH:31].[I-].[K+]>CC(N(C)C)=O>[Cl:1][C:2]1[C:3]([NH:11][C:12]2[C:21]3[C:16](=[CH:17][C:18]([O:24][CH2:25][CH2:26][CH2:27][N:35]4[CH2:36][CH2:37][N:32]([CH2:29][C:30]#[CH:31])[CH2:33][CH2:34]4)=[C:19]([O:22][CH3:23])[CH:20]=3)[N:15]=[CH:14][N:13]=2)=[C:4]2[O:10][CH2:9][O:8][C:5]2=[N:6][CH:7]=1
Reactant: COc1cc2c(Nc3c(Cl)cnc4c3OCO4)ncnc2cc1OCCCCl
Reactant: C#CCN1CCNCC1
Agent: [I-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: C#CCN1CCN(CCCOc2cc3ncnc(Nc4c(Cl)cnc5c4OCO5)c3cc2OC)CC1
Temperature: 80 °C
Yield: 68.3 %

Procedure:
A mixture of 4-(5-chloro-2,3-methylenedioxypyrid-4-ylamino)-7-(3-chloropropoxy)-6-methoxyquinazoline (0.08 g), 1-prop-2-ynylpiperazine (0.047 g), potassium iodide (0.01 g) and DMA (2 ml) was stirred and heated to 80° C. for 3.5 hours. The solvent was evaporated and the residue was partitioned between methylene chloride and a saturated aqueous ammonium chloride solution. The organic phase was dried over magnesium sulphate and evaporated. The residue was purified by column chromatography on silica using a 19:1 mixture of methylene chloride and methanol and then a 9:1 mixture of methylene chloride and a saturated methanolic ammonia solution as eluent. The resulting gum was triturated under diethyl ether. There was thus obtained the title compound as a solid (0.066 g); NMR Spectrum: (DMSOd6 and CF3CO2D) 2.3 (m, 2H), 3.2-3.6 (br m, 10H), 3.75 (s, 1H), 3.95 (br s, 2H), 4.0 (s, 3H), 4.35 (m, 2H), 6.3 (s, 2H), 7.4 (s, 1H), 7.9 (s, 1H), 8.15 (s, 1H), 8.95 (s, 1H); Mass Spectrum: M+H+ 511 and 513.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:8])[CH2:5][C:6]#[N:7])[CH3:2].[H-].[Na+].[O:11]=[C:12]1[C:24]2[C:19](=[N:20][C:21](C#N)=[C:22]([C:25]#[N:26])[N:23]=2)[C:18]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]1=2.CO>CN(C=O)C>[C:6]([C:5]([C:21]1[N:20]=[C:19]2[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[C:12](=[O:11])[C:24]2=[N:23][C:22]=1[C:25]#[N:26])=[C:4]([O:3][CH2:1][CH3:2])[OH:8])#[N:7]
Reactant: CCOC(=O)CC#N
Reactant: N#Cc1nc2c(nc1C#N)-c1ccccc1C2=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Product: CCOC(O)=C(C#N)c1nc2c(nc1C#N)C(=O)c1ccccc1-2
Reaction time: 0.5 h
Yield: 97.3 %

Procedure:
Ethylcyanoacetate (110 mg, 0.970 mmol) was dissolved, under inert atmosphere, in dry DMF (1 ml) and NaH (39 mg, 0.970 mmol) was added in one portion. After 30 min, a solution of 1 (150 mg, 0.646 mmol) in dry DMF (2 ml) was added dropwise. After 15 min MeOH was added and the solution stirred for 10 min. The solvents were evaporated and the crude purified by flash chromatography (EtOAc:MeOH 9:1) affording 22 as a dark red solid (200 mg, 97%).