Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl([O-])(=O)(=O)=O.[CH2:6]([CH:8]1[C:17]2[C:16]3[NH:18][C:19]4[C:24]([C:15]=3[CH2:14][CH2:13][N+:12]=2[CH2:11][CH2:10][CH2:9]1)=[CH:23][C:22]([Br:25])=[CH:21][CH:20]=4)[CH3:7].[OH-].[Na+].[C:28]([O:32][CH3:33])(=[O:31])[CH:29]=[CH2:30]>ClCCl.O>[CH3:28][O-:31].[CH2:6]([C:8]1([CH2:30][CH2:29][C:28]([O:32][CH3:33])=[O:31])[C:17]2[C:16]3=[N:18][C:19]4[C:24]([CH:15]3[CH2:14][CH2:13][N+:12]=2[CH2:11][CH2:10][CH2:9]1)=[CH:23][C:22]([Br:25])=[CH:21][CH:20]=4)[CH3:7]
Reactant: C=CC(=O)OC
Reactant: CCC1CCC[N+]2=C1c1[nH]c3ccc(Br)cc3c1CC2
Agent: [Na+]
Agent: [O-][Cl+3]([O-])([O-])[O-]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: CCC1(CCC(=O)OC)CCC[N+]2=C1C1=Nc3ccc(Br)cc3C1CC2
Product: C[O-]
Reaction time: 48 h
Yield: 64.5 %

Procedure:
7.00 g. (16.2 mmoles) of 1-ethyl-9-bromo-1,2,3,4,6,7-hexahydro-12H-indolo[2,3-a]quinolizin-5-ium perchlorate are dissolved in 160 ml. of dichloromethane, the solution is poured into a separatory funnel, and the mixture of 28 ml. of a 10% aqueous sodium hydroxide solution and 111 ml. of water is added. The two-phase mixture is shaken thoroughly, the organic phase is separated, dried over anhydrous potassium carbonate, and filtered. 8.90 g. (103.5 mmoles) of methyl acrylate are added to the filtrate, which is a dichloro-methane solution of the free base. The resulting mixture is allowed to stand at room temperature for 2 days, thereafter the solvent is evaporated in vacuo, and the oily residue is crystallized from methanol. In this way 4.70 g. (64.5%) of 1-ethyl-1-(2'-methoxycarbonylethyl)-9-bromo-1,2,3,4,6,7-hexahydro-7aH-indolo[2,3-a]quinolizin-5-ium methoxide are obtained in the form of orange red crystals; m.p.: 140°-142° C. (from methanol).
Reaction SMILES: OC[C:3]1[CH:7]=[CH:6][S:5][C:4]=1[CH2:8][CH2:9]O.C(N(C(C)C)CC)(C)C.S(Cl)([Cl:23])(=O)=O.Cl[CH2:26][Cl:27]>>[Cl:23][CH2:9][CH2:8][C:4]1[S:5][CH:6]=[CH:7][C:3]=1[CH2:26][Cl:27]
Reactant: OCCc1sccc1CO
Reactant: O=S(=O)(Cl)Cl
Reactant: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: ClCCc1sccc1CCl
Temperature: -3 °C
Reaction time: 0.5 h
Yield: 27 %

Procedure:
3.0 g of the compound obtained in Example 2 was dissolved in 57 mL of dichloromethane, and the resulting solution was cooled to −3° C. To the solution, 6.1 g of diisopropylethylamine and 3.1 g of sulfuryl chloride were added, and the resulting mixture was stirred for 30 min at the same temperature and for an hour at room temperature. 20 mL of dichloromethane was added to the reaction solution, and the resulting mixture was washed twice with 40 mL portions of water. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was subjected to a silica gel column chromatography (eluent, n-hexane:ethyl acetate=10:1) to obtain 1.0 g (yield of 27%) of the title compound as a colorless oil.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10][C:9]1=[O:18].CS[C:21](=[N:25][C:26]1[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=1)[NH:22][C:23]#[N:24].C(N(CC)CC)C>CN(C1C=CN=CC=1)C.N1C=CC=CC=1>[O:18]=[C:9]1[CH:10]=[CH:11][C:12]2[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:8]1[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:21]([NH:22][C:23]#[N:24])=[N:25][C:26]1[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=1
Reactant: CSC(=Nc1ccncc1)NC#N
Reactant: NCCCCCCn1c(=O)ccc2ccccc21
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: N#CNC(=Nc1ccncc1)NCCCCCCn1c(=O)ccc2ccccc21
Temperature: 60 °C
Reaction time: 8 h

Procedure:
A mixture of 1-(6-amino-1-hexyl)-1,2-dihydroquinoline-2-one (320 mg), S-methyl-N-cyano-N′-4-pyridyl-isothiourea (210 mg), triethylamine (0.31 ml), 4-(N,N-dimethylamino)-pyridine (7 mg) and pyridine (10 ml) was stirred overnight at 60° C. After cooling to room temperature the pyridine was removed by evaporation twice with toluene in vacuo and the residue was distributed between water and ethyl acetate. The organic phase was dried and evaporated to yield a crude product which was purified by chromatography on silica gel with ethyl acetate/methanol/aqueous ammonia (40:10:1.25) as eluent. The pure fractions were pooled, evaporated, triturated with ethyl acetate and dried in vacuo to give the title compound.
Reaction SMILES: [NH2:1][CH2:2][C:3]#[N:4].C(N(CC)CC)C.[CH2:12]([S:15](Cl)(=[O:17])=[O:16])[CH2:13][CH3:14]>ClCCCl>[C:3]([CH2:2][NH:1][S:15]([CH2:12][CH2:13][CH3:14])(=[O:17])=[O:16])#[N:4]
Reactant: CCCS(=O)(=O)Cl
Reactant: N#CCN
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: CCCS(=O)(=O)NCC#N
Temperature: 25 °C
Reaction time: 16 h
Yield: 70.4 %

Procedure:
Aminoacetonitrile (14.25 g, 92.5 mmoles) was dissolved in 1,2-dichloroethane (150 ml) and the reaction was placed under N2. Triethylamine (32.76 g, 324 mmoles) was added and the reaction was cooled to zero degrees Celsius. A solution of propane-1-sulfonyl chloride (13.19 g, 92.5 mmoles) in 1,2-dichloroethane (20 ml) was added dropwise and the reaction was allowed to warm to room temperature and was stirred for 16 hours. Thin-layer chromatography showed the presence of a new product with a higher Rf. The solvent was removed in vacuo and the crude product was submitted to flash chromatography (methylene chloride:ethyl acetate, 9:1) to yield 10.56 g of propane-1-sulfonic acid cyanomethyl-amide. 1HNMR (CDCl3): 5.40 (s, 1H), 4.11 (s, 2H), 3.15,(m, 2H), 1.89 (q, 2H), 1.10 (t, 3H).
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[CH2:7][CH2:6][NH:5][CH2:4]1.C(N(CC)CC)C.[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1.Cl>O1CCOCC1.O>[OH:1][CH2:2][C@H:3]1[CH2:7][CH2:6][N:5]([S:23]([C:20]2[CH:19]=[CH:18][C:17]([O:16][CH3:15])=[CH:22][CH:21]=2)(=[O:25])=[O:24])[CH2:4]1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Reactant: OC[C@H]1CCNC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Solvent: O
Product: COc1ccc(S(=O)(=O)N2CC[C@H](CO)C2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
The 3(S)-hydroxymethylpyrrolidine (0.9 g, 8.90 mmol), triethylamine (1.80 g, 17.8 mmol, 2.0 equiv) in 1,4-dioxane (30 mL) and water (10 mL) is stirred at room temperature and then 4-methoxyphenylsulfonyl chloride (2.02 g, 9.80 mmol, 1.10 equiv) is added. The resulting solution is stirred at room temperature for 3 h. and then the solution is acidified to pH~1 with 1 N HCl. The solution is poured into water and then extracted with CH2Cl2. The organic extracts are dried (Na2SO4) and concentrated to an oil. The oil is purified by chromatography using 1/1 hexane/EtOAc as the eluent to afford the desired product as a colorless oil.
Reaction SMILES: Br[C:2]1[C:3](=[O:16])[C:4]([CH3:15])([CH3:14])[O:5][C:6]=1[C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=1.CC1(C)C(C)(C)OB([C:25]2[CH:42]=[CH:41][C:28]([O:29][CH2:30][C:31]3[CH:40]=[CH:39][C:38]4[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=4)[N:32]=3)=[CH:27][CH:26]=2)O1.C([O-])([O-])=O.[Cs+].[Cs+]>C1(C)C=CC=CC=1.O>[Cl:13][C:10]1[CH:11]=[CH:12][C:7]([C:6]2[O:5][C:4]([CH3:15])([CH3:14])[C:3](=[O:16])[C:2]=2[C:25]2[CH:26]=[CH:27][C:28]([O:29][CH2:30][C:31]3[CH:40]=[CH:39][C:38]4[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=4)[N:32]=3)=[CH:41][CH:42]=2)=[CH:8][CH:9]=1
Reactant: CC1(C)OC(c2ccc(Cl)cc2)=C(Br)C1=O
Reactant: CC1(C)OB(c2ccc(OCc3ccc4ccccc4n3)cc2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: Cc1ccccc1
Solvent: O
Product: CC1(C)OC(c2ccc(Cl)cc2)=C(c2ccc(OCc3ccc4ccccc4n3)cc2)C1=O
Yield: 34.6 %

Procedure:
A solution of 4-bromo-5-(4-chlorophenyl)-2,2-dimethylfuran-3(2H)-one (1.0 g, 3.30 mmol), 2-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)methyl)quinoline (1.30 g, 3.60 mmol), and Cs2CO3 (5.37 g, 16.50 mmol) in toluene (10 mL) and water (5 mL) was degassed. Then, Pd(dppf)C2 (0.54 g, 0.601 mmol) was added under an inert atmosphere and the solution was degassed again. The reaction mixture was then refluxed for 2 h, filtered through a pad of Celite®, and the filtrate was diluted with EtOAc (40 mL). The combined organic layers were washed with water (20 mL) and brine (20 mL), dried over Na2SO4, filtered, and concentrated in vacuo to obtain the crude product. The crude material was purified via silica gel column chromatography to afford 5-(4-chlorophenyl)-2,2-dimethyl-4-(4-(quinolin-2-ylmethoxy)phenyl) furan-3(2H)-one (520 mg, 35%) as a pale yellow solid. 1H NMR (500 MHz, d6-DMSO): δ 8.44 (d, J=8.5 Hz, 1H), 8.02 (t, J=7.9 Hz, 2H), 7.81 (t, J=8.4 Hz, 1H), 7.70 (d, J=8.2 Hz, 1H), 7.63 (t, J=8.2 Hz, 1H), 7.58 (d, J=8.5 Hz, 2H), 7.52 (d, J=8.5 Hz, 2H), 7.18 (d, J=7.4 Hz, 2H), 7.11 (d, J=7.5 Hz, 2H), 5.39 (s, 2H), 1.44 (s, 6H). MS: [M+Na]: m/z=478.1, [M+H]: m/z=456.1. HPLC: 97%, Column: Acquity BEH-C-18, 50×2.1 mm, 1.7 um. Mobile Phase: 0.025% TFA in Water (A), AcN (B), Flow rate: 0.5 ml/min (Gradient).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:24]=[O:25])=[C:6]2[C:10]=1[N:9]=[C:8]1[CH:11]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=3[Cl:23])[O:12][CH2:13][CH2:14][CH2:15][N:7]21.[CH:26]1([Mg]Br)[CH2:28][CH2:27]1>O1CCCC1>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[CH:11]([C:16]4[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=4[Cl:23])[O:12][CH2:13][CH2:14][CH2:15][N:7]3[C:6]=2[C:5]([CH:24]([CH:26]2[CH2:28][CH2:27]2)[OH:25])=[CH:4][CH:3]=1
Reactant: Br[Mg]C1CC1
Reactant: O=Cc1ccc(Cl)c2nc3n(c12)CCCOC3c1ccc(Cl)cc1Cl
Solvent: C1CCOC1
Product: OC(c1ccc(Cl)c2nc3n(c12)CCCOC3c1ccc(Cl)cc1Cl)C1CC1
Reaction time: 0.5 h
Yield: 83 %

Procedure:
To a stirred solution of 10-chloro-1-(2,4-dichlorophenyl)-4,5-dihydro-1H,3H-[1,4]oxazepino[4,3-a]benzimidazole-7-carbaldehyde (88.1 mg, 0.223 mmol) in tetrahydrofuran (2 mL) was added a solution of cyclopropyl magnesium bromide in tetrahydrofuran (1.0 M, 357 μL, 0.357 mmol) at 0° C. After 0.5 h, the reaction mixture was quenched with aqueous ammonium chloride, diluted with ethyl acetate, washed with water and brine, dried over sodium sulfate, filtrated, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 10-50% ethyl acetate/n-hexane gradient mixture to give the title compound as a colorless solid (81.4 mg, 0.186 mmol, 83%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[CH2:5][CH2:6][C:7]1[CH:8]=[C:9]([C:15](=[O:22])[CH2:16][CH2:17][CH2:18][C:19]([OH:21])=[O:20])[CH:10]=[CH:11][C:12]=1[O:13]C)[CH3:2].Cl.N1C=CC=[CH:27][CH:26]=1>O>[CH2:26]([O:21][C:19](=[O:20])[CH2:18][CH2:17][CH2:16][C:15](=[O:22])[C:9]1[CH:10]=[CH:11][C:12]([OH:13])=[C:7]([CH2:6][CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:23])[CH:8]=1)[CH3:27]
Reactant: CCOC(=O)CCc1cc(C(=O)CCCC(=O)O)ccc1OC
Reactant: c1ccncc1
Agent: Cl
Solvent: O
Product: CCOC(=O)CCCC(=O)c1ccc(O)c(CCC(=O)OCC)c1
Temperature: 240 °C
Yield: 77.3 %

Procedure:
A mixture of 1.61 g (5.0 mmol) of 3-(3-ethoxy-3-oxopropyl)-4-methoxy-δ-oxobenzenepentanoic acid and 11.56 g (0.1 mol) of pyridine hydrochloride was heated at ca. 240° C. for 1.33 hr. After being cooled to room temperature, the reaction mixture was treated with 100 mL of water and extracted twice with ether and once with ethyl acetate. The organic extracts were processed in the usual manner to give 1.30 g of a tan solid which was dissolved in 120 mL of ethanol. To this solution was slowly added 30 drops of thionyl chloride. The resulting solution was heated at reflux for 7 hr and then kept at room temperature for ca. 65 hr. The solvent was removed in vacuo and the residue was purified by flash chromatography on 100 g of silica gel, eluting with 3:1 hexane-ethyl acetate, to give 1.44 g (85.6%) of the title compound as a light-tan solid, mp 68°-69° C.
Reaction SMILES: [N:1]1([C:6]2[CH:7]=[C:8]([C:12]3[N:16]4[CH:17]=[CH:18][C:19]([C:21]5[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=5)[CH:24]=O)=[CH:20][C:15]4=[N:14][CH:13]=3)[CH:9]=[CH:10][CH:11]=2)[CH:5]=[CH:4][CH:3]=[N:2]1.[CH3:29][N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>C(Cl)Cl.CCOC(C)=O>[CH3:29][N:30]1[CH2:35][CH2:34][N:33]([CH2:24][C:23]2[CH:22]=[C:21]([C:19]3[CH:18]=[CH:17][N:16]4[C:12]([C:8]5[CH:9]=[CH:10][CH:11]=[C:6]([N:1]6[CH:5]=[CH:4][CH:3]=[N:2]6)[CH:7]=5)=[CH:13][N:14]=[C:15]4[CH:20]=3)[CH:28]=[CH:27][CH:26]=2)[CH2:32][CH2:31]1
Reactant: CN1CCNCC1
Reactant: O=Cc1cccc(-c2ccn3c(-c4cccc(-n5cccn5)c4)cnc3c2)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CN1CCN(Cc2cccc(-c3ccn4c(-c5cccc(-n6cccn6)c5)cnc4c3)c2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 3-[3-(3-pyrazol-1-yl-phenyl)-imidazo[1,2-a]pyridin-7-yl]-benzaldehyde (Ex. 1.9) (1 eq, 0.110 mmol, 40 mg) in DCM (2 ml) is added methyl piperazine (2 eq, 0.220, 0.24 ml) and the reaction mixture is stirred at room temperature for 2 h. After this time sodium triacetoxyborohydride (1.5 eq, 0.165 mmol, 36.7 mg) and acetic acid (0.1 ml) are added to the reaction mixture and this is stirred for a further one hour. The reaction is diluted with EtOAc and the organic phase is washed with NaHCO3. The aqueous layer is further extracted with EtOAc. The combined organic layers are washed with brine, dried over MgSO4, filtered and the solvent removed in vacuo. The reaction mixture is purified by flash column chromatography eluting with 8:2 DCM/MeOH to yield 7-[3-(4-methyl-piperazine-1-ylmethyl)-phenyl]-3-(3-pyrazol-1-yl-phenyl)-imidazo-[1,2-a]pyridine as a yellow solid; [M+H]+=449
Reaction SMILES: [NH2:1][C@H:2]([C:6]([OH:8])=[O:7])[CH:3]([CH3:5])[CH3:4].[CH3:9][C:10](=O)[CH2:11][CH3:12].[H][H]>C(O)C.[Pd]>[CH:10]([NH:1][C@@H:2]([CH:3]([CH3:5])[CH3:4])[C:6]([OH:8])=[O:7])([CH2:11][CH3:12])[CH3:9]
Reactant: [H][H]
Reactant: CCC(C)=O
Reactant: CC(C)[C@H](N)C(=O)O
Agent: [Pd]
Solvent: CCO
Product: CCC(C)N[C@H](C(=O)O)C(C)C
Reaction time: 2.5 h
Yield: 54 %

Procedure:
A mixture of L-valine (29.29 g, 250 mmol), and 2-butanone (44.8 mL, 500 mmol, Aldrich Inc, Milwaukee, Wis.) was agitated in an atmosphere of hydrogen (pressure, 39-51 psi) at 45° C. in 500 mL ethanol in the presence of Pd/C (20%, 4 g) until the absorption of hydrogen had ceased. The mixture was filtered, and this ethanolic filtrate was set aside, then the filter cake washed with 450 mL 1 M HCl. The ethanolic filtrate was concentrated to dryness and the residue dissolved in the aqueous filtrate above, which was treated with concentrated aqueous sodium hydroxide (29.8%) to adjust the pH to 5.5, and the mixture concentrated to dryness under reduced pressure. The white solid thus obtained was extracted by stirring 2-3 hours vigorously with 250 mL methanol followed by filtration. This process was repeated several times. The combined extracts were concentrated under reduced pressure and the white solid thus obtained was triturated in warm acetone, filtered, and the solids washed with acetone and dried under vacuum to give 23.4 g (54%) of the pure titled compound as a white solid; mp >300° C. APCI-MS m/z 174.2 (MH+).
Reaction SMILES: [CH3:1][C@@:2]1([O:36][C:37](=[O:44])[C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[C@H:6]([O:7][C:8](=[O:15])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C@@H:5]([CH2:16][O:17][C:18](=[O:25])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[O:4][C@H:3]1[N:26]1[C:30]2=[CH:31][N:32]=[N:33][C:34](=O)[C:29]2=[N:28][CH2:27]1.C(N(CC)C1C=CC=CC=1)C.P(Cl)(Cl)[Cl:57]>>[Cl:57][C:34]1[N:33]=[N:32][CH:31]=[C:30]2[N:26]([C@@H:3]3[O:4][C@H:5]([CH2:16][O:17][C:18](=[O:25])[C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[C@@H:6]([O:7][C:8](=[O:15])[C:9]4[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=4)[C@@:2]3([CH3:1])[O:36][C:37](=[O:44])[C:38]3[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=3)[CH:27]=[N:28][C:29]=12
Reactant: ClP(Cl)Cl
Reactant: C[C@@]1(OC(=O)c2ccccc2)[C@H](OC(=O)c2ccccc2)[C@@H](COC(=O)c2ccccc2)O[C@H]1N1CN=C2C(=O)N=NC=C21
Solvent: CCN(CC)c1ccccc1
Product: C[C@@]1(OC(=O)c2ccccc2)[C@H](OC(=O)c2ccccc2)[C@@H](COC(=O)c2ccccc2)O[C@H]1n1cnc2c(Cl)nncc21

Procedure:
A solution containing the compound from Step A (300 mg, 0.50 mmol), the N,N-diethylaniline (1.2 mL) and freshly distilled phosphorus chloride (24 mL) was stirred at reflux for 1 hour. The reaction mixture was evaporated to dryness. Dichloromethane was added to the residue and the organic layer poured over cracked ice/water. The aqueous layer was extracted with dichloromethane. The organic layer was washed with sodium hydrogenocarbonate 5%, water and was evaporated to dryness. The crude product was purified on silica gel using diethyl ether/petrol ether (1/1) as eluant to give the title compound (295 mg) as a white powder.
Reaction SMILES: [CH3:1][CH:2]1[O:16][C:5]2=[CH:6][C:7]3[CH2:8][C:9](=[O:15])[N:10]([CH2:13][CH3:14])[C:11]=3[CH:12]=[C:4]2[CH2:3]1.[F:17][C:18]1[CH:23]=[CH:22][C:21]([N:24]=[C:25]=[O:26])=[CH:20][CH:19]=1>>[F:17][C:18]1[CH:23]=[CH:22][C:21]([NH:24][C:25]([CH:8]2[C:7]3[CH:6]=[C:5]4[O:16][CH:2]([CH3:1])[CH2:3][C:4]4=[CH:12][C:11]=3[N:10]([CH2:13][CH3:14])[C:9]2=[O:15])=[O:26])=[CH:20][CH:19]=1
Reactant: CCN1C(=O)Cc2cc3c(cc21)CC(C)O3
Reactant: O=C=Nc1ccc(F)cc1
Product: CCN1C(=O)C(C(=O)Nc2ccc(F)cc2)c2cc3c(cc21)CC(C)O3
Yield: 45 %

Procedure:
Following the procedure of Example 1 and employing 326 mg. (1.5 mmoles) of 2-methyl-5-ethyl-6-oxo-2,3,6,7-tetrahydrofuro[2,3-f]indole and 0.24 ml. (2.1 mmoles) of 4-fluorophenylisocyanate, 240 mg. (45% yield), m.p. 196°-197° C. of the desired product was obtained.
Reaction SMILES: [CH2:1]([C@H:4]([C@H:11]([OH:18])[C:12]([O:14][CH:15]([CH3:17])[CH3:16])=[O:13])[C:5]([O:7][CH:8]([CH3:10])[CH3:9])=[O:6])[CH:2]=[CH2:3].CCN(C(C)C)C(C)C.Br[C:29]1[CH:34]=[CH:33][C:32]([O:35][CH2:36][CH3:37])=[CH:31][CH:30]=1.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>CC#N.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:36]([O:35][C:32]1[CH:33]=[CH:34][C:29](/[CH:3]=[CH:2]/[CH2:1][C@H:4]([C@H:11]([OH:18])[C:12]([O:14][CH:15]([CH3:17])[CH3:16])=[O:13])[C:5]([O:7][CH:8]([CH3:10])[CH3:9])=[O:6])=[CH:30][CH:31]=1)[CH3:37]
Reactant: C=CC[C@@H](C(=O)OC(C)C)[C@H](O)C(=O)OC(C)C
Reactant: CCOc1ccc(Br)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CCOc1ccc(/C=C/C[C@@H](C(=O)OC(C)C)[C@H](O)C(=O)OC(C)C)cc1
Temperature: 25 °C
Yield: 97.9 %

Procedure:
To a solution of diisopropyl (2R,3S)-2-allyl-3-hydroxybutanedioate (3.0 g; 11.6 mmol; 1.0 eq.) and DIEA (3.86 mL; 28.9 mmol; 2.4 eq.) in CH3CN (30.0 mL) was added 4-bromophenetole (2.0 mL; 13.9 mmol; 1.2 eq.). To this solution was added a mixture of tri-o-tolylphosphine (0.35 g; 1.16 mmol; 0.1 eq.) and palladium(II) acetate (0.03 g; 0.12 mmol; 0.01 eq.) in CH3CN (3.0 mL) which was sonicated before the addition to the reaction mixture. The reaction was stirred under argon at reflux for 2.5 h, cooled to RT and the solvents were evaporated under reduce pressure. The resulting residue was then taken up in EtOAc and washed with an aqueous saturated solution of NaCl. Evaporation of the solvent gave an oil (4.3 g). Purification by chromatography (SiO2, gradient from 20/80 EtOAc/c-hex to 100/0 EtOAc/c-hex) gave the title product as a colorless oil (4.41 g, 100%). M+(ESI): 379.3. 1H NMR (CDCl3, 300 MHz) δ 7.14 (d, J=8.6 Hz, 2H), 6.70 (d, J=8.6 Hz, 2H), 6.46 (d, J=15.6 Hz, 1H), 6.00-5.86 (m, 1H), 5.05-4.83 (m, 2H), 4.13 (dd, J=7.0 Hz, J=3.0 Hz, 1H), 3.90 (q, J=7.0 Hz, 2H), 3.10 (d, J=7.2 Hz, 1H), 2.89-2.78 (m, 1H), 2.70-2.55 (m, 1H), 2.52-2.35 (m, 1H), 1.27 (t, J=7.0 Hz, 3H), 1.22-1.00 (m, 12H).
Reaction SMILES: [F:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11](=[O:28])[CH2:12][CH2:13][C:14]1[N:15]=[C:16]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([OH:27])[CH:20]=2)[O:17][CH:18]=1.Br[CH:30]([CH3:32])[CH3:31]>>[F:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11](=[O:28])[CH2:12][CH2:13][C:14]1[N:15]=[C:16]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH:30]([CH3:32])[CH3:31])[CH:20]=2)[O:17][CH:18]=1
Reactant: COc1ccc(-c2nc(CCC(=O)c3ccccc3OCCF)co2)cc1O
Reactant: CC(C)Br
Product: COc1ccc(-c2nc(CCC(=O)c3ccccc3OCCF)co2)cc1OC(C)C

Procedure:
Using the compound obtained in Example 271 and 2-bromopropane, white powdery 1-(2-fluoroethoxyphenyl)-3-[2-(3-isopropoxy-4-methoxyphenyl)oxazol-4-yl]propan-1-one was obtained following the procedure of Example 3.
Reaction SMILES: [NH2:1][C:2]1[C:10]([Cl:11])=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([O:12][CH3:13])[CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH2:26]1[C:33]2([CH2:34][CH2:35][NH2:36])[N:29]([CH2:30][CH2:31][CH2:32]2)[CH2:28][CH2:27]1.[NH4+].[OH-]>CO.C(Cl)(Cl)Cl.CN(C=O)C>[NH2:1][C:2]1[C:10]([Cl:11])=[CH:9][C:5]([C:6]([NH:36][CH2:35][CH2:34][C:33]23[CH2:26][CH2:27][CH2:28][N:29]2[CH2:30][CH2:31][CH2:32]3)=[O:8])=[C:4]([O:12][CH3:13])[CH:3]=1
Reactant: NCCC12CCCN1CCC2
Reactant: COc1cc(N)c(Cl)cc1C(=O)O
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [NH4+]
Agent: [OH-]
Solvent: CO
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: COc1cc(N)c(Cl)cc1C(=O)NCCC12CCCN1CCC2
Yield: 75.2 %

Procedure:
4-Amino-5-chloro-2-methoxybenzoic acid (1.0 g, 0.005 moles) and 1,1'-carbonyldi-imidazole (892 mg, 0.00055 moles) were suspended in the DMF (10 ml) and the mixture was stirred until solution occurred (three hours). At this time, tetrahydro-1H-pyrrolizin-7a(5H)-ethylamine [amine Heterocycles 16, 755, 1981](771 mg; 0,005 moles) was added and the mixture was stirred for 1 hour. Tlc 30% MeOH/CHCl3 /1/10% NH4OH indicated that the reaction was complete. Concentration afforded a residue which was partitioned between Et2O/H2O . The product crystallized. The solid was filtered and dissolved in CHCl3, washed with dilute K2CO3, dried over MgSO4 and concentrated to a solid. The solid was triturated with Et2O and converted to the HCl salt with MeOH/HCl to yield 1.27g (69%) of the product.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[S:9][CH:10]=[C:11]([C:13]3[C:14](=[O:23])[NH:15][C:16]4[C:21]([CH:22]=3)=[CH:20][CH:19]=[CH:18][CH:17]=4)[N:12]=2)[CH:5]=[CH:4][N:3]=1.NCC[N:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1>>[N:27]1([C:2]2[CH:7]=[C:6]([C:8]3[S:9][CH:10]=[C:11]([C:13]4[C:14](=[O:23])[NH:15][C:16]5[C:21]([CH:22]=4)=[CH:20][CH:19]=[CH:18][CH:17]=5)[N:12]=3)[CH:5]=[CH:4][N:3]=2)[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1
Reactant: NCCN1CCCCC1
Reactant: O=c1[nH]c2ccccc2cc1-c1csc(-c2ccnc(Cl)c2)n1
Product: O=c1[nH]c2ccccc2cc1-c1csc(-c2ccnc(N3CCCCC3)c2)n1
Temperature: 128 °C

Procedure:
A mixture of 3-[2-(2-chloro-pyridin-4-yl)-thiazol-4-yl]-1H-quinolin-2-one (Example 85, 60 mg, 0.18 mmol) and 1-(2-aminoethyl)piperidine (Aldrich-Sigma Company, 2 mL) was heated at 128° C. for 48 h. The reaction was quenched by addition of 10 mL of H2O. The precipitates were collected by filtration and purified by Gilson preparative HPLC to provide the title compound as a yellow solid after lyophilization. MS m/z: 389.3 (M+1). HRMS m/z: 389.1398 (M+H+, C22H20N4OS Calc'd 389.1431).
Reaction SMILES: B(Br)(Br)Br.Cl[C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]=[C:8]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[O:22]C)[N:7]=1.Cl.Cl.[CH3:26][N:27]1[CH2:32][CH2:31][CH2:30][CH:29]([NH2:33])[CH2:28]1.C(N(CC)CC)C>ClCCl.CN(C)C(=O)C>[CH3:26][N:27]1[CH2:32][CH2:31][CH2:30][CH:29]([NH:33][C:6]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]=[C:8]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[OH:22])[N:7]=2)[CH2:28]1
Reactant: CN1CCCC(N)C1
Reactant: COc1ccccc1-c1nc(Cl)c2ccccc2n1
Agent: BrB(Br)Br
Agent: Cl
Solvent: CC(=O)N(C)C
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN1CCCC(Nc2nc(-c3ccccc3O)nc3ccccc23)C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 69.4 %

Procedure:
Boron tribromide (7.4 mL, 1 M solution in dichloromethane, 7.4 mmol) was added to a solution of 4-chloro-2-(2-methoxy-phenyl)-quinazoline (0.200 g, 0.739 mmol) in dichloromethane (5 mL) at 0° C. After 24 hours the solution was poured into ice-water (200 mL) and extracted with dichloromethane (2×100 mL). The organic layers were combined, washed with brine (100 mL), dried (MgSO4) and concentrated to give a yellow solid that was used immediately without further purification. Half of the material (0.370 mmol) was dissolved in N,N-dimethylacetamide and 1-methylpiperidine-3-amine dihydrochloride (0.083 g, 0.444 mmol) was added. Triethylamine (258 μL, 1.850 mmol) was added and the reaction was stirred for 1 hour. The mixture was concentrated and purified by ion exchange chromatography on SCX-2 Isolute acidic resin (2 g), eluting with methanol and then 1 M ammonia in methanol. The basic fractions were combined and purified by silica column chromatography, eluting with 10% methanol in dichloromethane, to give the title compound as a yellow solid (0.103 g, 83%).