Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:4]1[CH2:5][C@@H:6]2[C@H:9]([CH:10]=1)[C:8](=[CH:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:7]2)[CH:2]=[CH2:3].N12CCCN=C1CCCCC2.P([O-])(O)(O)=O.[K+].[N+:36]([CH3:39])([O-:38])=[O:37]>>[CH2:1]([C:4]1[CH2:5][C@@H:6]2[C@H:9]([CH:10]=1)[C@@:8]([CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])([CH2:39][N+:36]([O-:38])=[O:37])[CH2:7]2)[CH:2]=[CH2:3]
Reactant: C=CCC1=C[C@@H]2C(=CC(=O)OC(C)(C)C)C[C@@H]2C1
Reactant: C[N+](=O)[O-]
Agent: O=P([O-])(O)O
Agent: [K+]
Solvent: C1CCC2=NCCCN2CC1
Product: C=CCC1=C[C@H]2[C@@H](C1)C[C@]2(CC(=O)OC(C)(C)C)C[N+](=O)[O-]
Temperature: 55 °C
Reaction time: 7 h

Procedure:
Tert-butyl(±)-(1S,5R)-3-allylbicyclo[3.2.0]hept-3-en-6-ylideneacetate (0.63 g, 2 mmol) was dissolved in nitromethane (5 mL). To the solution, 1,8-diazabicyclo[5.4.0]undec-7-ene (0.45 mL, 3 mmol) was added, and the mixture was heated with stirring at 50 to 60° C. for 7 hours. The mixture was allowed to cool, and a saturated aqueous solution of potassium dihydrogen phosphate was then added thereto, followed by extraction with ethyl acetate. Then, the organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography to obtain the compound of interest as a colorless oil substance (367.0 mg, 60%).
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:13]=[CH:12][N:11]=[C:10]([O:14][CH2:15]/[CH:16]=[CH:17]\[CH2:18][NH2:19])[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:20][C:21]1[O:22][CH:23]=[CH:24][C:25]=1[C:26](O)=[O:27]>>[N:1]1([CH2:7][C:8]2[CH:13]=[CH:12][N:11]=[C:10]([O:14][CH2:15]/[CH:16]=[CH:17]\[CH2:18][NH:19][C:26]([C:25]3[CH:24]=[CH:23][O:22][C:21]=3[CH3:20])=[O:27])[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cc1occc1C(=O)O
Reactant: NC/C=C\COc1cc(CN2CCCCC2)ccn1
Product: Cc1occc1C(=O)NC/C=C\COc1cc(CN2CCCCC2)ccn1
Yield: 77 %

Procedure:
Following a procedure similar to that described in Example 13, but using 4-(4-piperidinomethyl-2-pyridyloxy)-cis-2-butenylamine and 2-methylfuran-3-carboxylic acid as starting materials, in relative proportions similar to those used in that Example, the title compound was obtained as an oil in a 77% yield.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N:8]1[CH2:12][CH2:11][NH:10][C:9]1=[O:13].Br[C:15]1[CH:20]=[CH:19][C:18]([F:21])=[C:17]([C:22]([F:25])([F:24])[F:23])[CH:16]=1.N[C@@H]1CCCC[C@H]1N.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[Cu](I)I.O1CCOCC1>[F:21][C:18]1[CH:19]=[CH:20][C:15]([N:10]2[CH2:11][CH2:12][N:8]([C:3]3[CH:4]=[N:5][CH:6]=[CH:7][C:2]=3[CH3:1])[C:9]2=[O:13])=[CH:16][C:17]=1[C:22]([F:23])([F:24])[F:25]
Reactant: Cc1ccncc1N1CCNC1=O
Reactant: Fc1ccc(Br)cc1C(F)(F)F
Agent: I[Cu]I
Agent: N[C@@H]1CCCC[C@H]1N
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Product: Cc1ccncc1N1CCN(c2ccc(F)c(C(F)(F)F)c2)C1=O
Yield: 60.2 %

Procedure:
Using the same reaction conditions as in Example 14, 1-(4-methyl-pyridin-3-yl)-imidazolidin-2-one (I-14b: 150 mg, 0.847 mmol) was reacted with 4-bromo-1-fluoro-2-trifluoromethyl-benzene (247 mg, 1.016 mmol), 1,4-dioxane (15 mL), copper iodide (16 mg, 0.0842 mmol), trans-1,2-diamino cyclohexane (0.0289 g, 0.2456 mmol) and potassium phosphate (0.538 g, 2.537 mmol) to afford the crude product. Purification by column chromatography on silica gel (1% MeOH in CHCl3) afforded 173 mg of the product (60.27% yield).
Reaction SMILES: [CH2:1]([NH:8][CH2:9][CH2:10][CH2:11]O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:13]([CH:15]1[O:17][CH2:16]1)[Cl:14]>>[CH2:1]([N:8]1[CH2:9][CH2:10][CH2:11][CH2:16][O:17][CH:15]1[CH2:13][Cl:14])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OCCCNCc1ccccc1
Reactant: ClCC1CO1
Product: ClCC1OCCCCN1Cc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 23.7 %

Procedure:
A solution of 3-benzylamino-propan-1-ol (14 g, 88.0 mmol) and epichlorohydrin (81.4 g, 880 mmol) was heated to 40° C. After stirring for 3 h the reaction was cooled and excess epichlorohydrin was removed by evaporation in vacuo. Sulfuric acid (10 mL) was added slowly, then the reaction flask was placed in a preheated oil bath at 150° C. Stirring proceeded for 1 h, then the reaction was allowed to cool to room temperature and quenched with the addition of ice. The mixture was adjusted to a basic pH with 10% aqueous Na2CO3 solution and extracted with EtOAc (3×300 mL). The combined organic layers were dried over anhydrous MgSO4, filtered, and dried under reduced pressure. The resulting residue was purified by flash chromatography (70:28:2 hexanes/CH2Cl2/2M NH4OH aq) to afford 5 g of a light yellow oil.
Reaction SMILES: [CH3:1][NH:2][CH3:3].C(N(CC)CC)C.[Br:11][C:12]1[CH:17]=[CH:16][C:15]([S:18](Cl)(=[O:20])=[O:19])=[CH:14][CH:13]=1>C1COCC1.ClCCl.C(OCC)(=O)C>[Br:11][C:12]1[CH:17]=[CH:16][C:15]([S:18]([N:2]([CH3:3])[CH3:1])(=[O:20])=[O:19])=[CH:14][CH:13]=1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Reactant: CNC
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CN(C)S(=O)(=O)c1ccc(Br)cc1
Temperature: 0 °C
Yield: 97 %

Procedure:
Place dimethylamine (5.25 mL of a 2.0 M solution in THF, 10.4 mmol), triethylamine (2.04 mL, 14.68 mmol) and dichloromethane (30 mL) in a round bottom flask. Cool this solution to 0° C., while stirring, and add a solution of 4-bromobenzenesulfonyl chloride (2.5 g, 9.78 mmol) in dichloromethane (30 mL). Add additional dichloromethane (10 mL) and stir the reaction overnight, letting it warm to ambient temperature. Concentrate the reaction in vacuo. Take up the resulting solid in ethyl acetate and filter. Evaporate the filtrate in vacuo and dry the resulting solid by vacuum to give 2.50 g of 4-bromo-N,N-dimethyl-benzenesulfonamide (97%).
Reaction SMILES: C([O:9][CH2:10][C:11]1([CH2:17][F:18])[O:16][CH2:15][CH2:14][CH2:13][O:12]1)(=O)C1C=CC=CC=1.[OH-].[Na+].[Cl-].[NH4+]>CO>[F:18][CH2:17][C:11]1([CH2:10][OH:9])[O:16][CH2:15][CH2:14][CH2:13][O:12]1
Reactant: O=C(OCC1(CF)OCCCO1)c1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Product: OCC1(CF)OCCCO1
Reaction time: 0.08 h
Yield: 89.3 %

Procedure:
A mixture of (2-(fluoromethyl)-1,3-dioxan-2-yl)methyl benzoate (2.22 g, 8.73 mmol), methanol (20 ml) and a 1N-aqueous sodium hydroxide solution (13.1 ml) was stirred at room temperature overnight. Ammonium chloride was added to the reaction mixture, which was concentrated. The residue was suspended in tetrahydrofuran and ethyl acetate, and then magnesium sulfate was added and the mixture was stirred for 5 minutes. After NH silica gel filtration was performed, the filtrate was concentrated to obtain the title compound (1.17 g, 89.3%) as a colorless liquid.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH:12]3[NH:14][CH:9]2[CH2:10][CH2:11]3)=[CH:4][N:3]=1.[OH-:15].[K+]>C(O)(C)(C)C>[OH:15][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH:12]3[NH:14][CH:9]2[CH2:10][CH2:11]3)=[CH:4][N:3]=1
Reactant: [OH-]
Reactant: Fc1ccc(C2CC3CCC2N3)cn1
Agent: [K+]
Solvent: CC(C)(C)O
Product: Oc1ccc(C2CC3CCC2N3)cn1
Yield: 50 %

Procedure:
Compound 53 (8.5 mg, 0.044 mmol) was dissolved in 1 ml tert-butanol. To this solution was added 1 ml 2M potassium hydroxide. After reflux for 20 hours and evaporation of butanol, the mixture was adjusted with 1M hydrochloric acid to pH 6-7. Evaporation of solvent in vacuo and purification of product with silica gel preparative thin layer chromatography developing with 20% 7N ammonia methanol in chloroform gave 4.2 mg compound 77 as an oil. Yield 50%. MS(CI) 191(M+1). 1H-NMR (CDCl3) δ 2.554 (br.s., 1H, H2), 3.503; 3.743 (2br.s., 2H, H1,4).
Reaction SMILES: [CH3:1][N:2]([N:12]1[CH2:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][C:18]=2[N+:21]([O-])=O)[C:13]1=[O:24])[C@H:3]([C:9]([OH:11])=[O:10])[CH2:4][CH2:5][C:6](=[O:8])[NH2:7]>CO.[Pd]>[CH3:1][N:2]([N:12]1[CH2:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][C:18]=2[NH2:21])[C:13]1=[O:24])[C@H:3]([C:9]([OH:11])=[O:10])[CH2:4][CH2:5][C:6](=[O:8])[NH2:7]
Reactant: CN([C@@H](CCC(N)=O)C(=O)O)N1Cc2c(cccc2[N+](=O)[O-])C1=O
Agent: [Pd]
Solvent: CO
Product: CN([C@@H](CCC(N)=O)C(=O)O)N1Cc2c(N)cccc2C1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 88143.9 %

Procedure:
A mixture of methyl N-(1-oxo-4-nitroisoindolin-2-yl)-L-glutamine (6.4 g, 0.02 mmol) and 5% Pd/C (0.6 g) in methanol (100 mL) was stirred under hydrogen (40 psi) at ambient temperature for two hours. The Pd catalyst was filtered off through a pad of Celite. After concentration of the filtrate, the resulting oily residue was triturated with MTBE (30 mL), which yielded a solid after standing at ambient temperature for one hour. The off-white solid was filtered, washed with MTBE (30 mL), and dried to furnish the title compound (5.4 g, 93% yield).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:22][CH2:21][C:11]3([CH2:15][NH:14][C@H:13]([C:16]([O:18]CC)=[O:17])[CH2:12]3)[CH2:10][CH2:9]2)[CH:5]=[C:4]([O:23][C@H:24]([C:29]2[CH:34]=[CH:33][C:32]([C:35]3[CH:40]=[CH:39][C:38]([CH3:41])=[C:37]([CH3:42])[CH:36]=3)=[CH:31][C:30]=2[C:43]2[CH:48]=[CH:47][CH:46]=[C:45]([S:49]([CH3:52])(=[O:51])=[O:50])[CH:44]=2)[C:25]([F:28])([F:27])[F:26])[N:3]=1.[Li+].[OH-]>>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:9][CH2:10][C:11]3([CH2:15][NH:14][C@H:13]([C:16]([OH:18])=[O:17])[CH2:12]3)[CH2:21][CH2:22]2)[CH:5]=[C:4]([O:23][C@H:24]([C:29]2[CH:34]=[CH:33][C:32]([C:35]3[CH:40]=[CH:39][C:38]([CH3:41])=[C:37]([CH3:42])[CH:36]=3)=[CH:31][C:30]=2[C:43]2[CH:48]=[CH:47][CH:46]=[C:45]([S:49]([CH3:52])(=[O:51])=[O:50])[CH:44]=2)[C:25]([F:28])([F:26])[F:27])[N:3]=1
Reactant: CCOC(=O)[C@@H]1CC2(CCN(c3cc(O[C@H](c4ccc(-c5ccc(C)c(C)c5)cc4-c4cccc(S(C)(=O)=O)c4)C(F)(F)F)nc(N)n3)CC2)CN1
Agent: [Li+]
Agent: [OH-]
Product: Cc1ccc(-c2ccc([C@@H](Oc3cc(N4CCC5(CC4)CN[C@H](C(=O)O)C5)nc(N)n3)C(F)(F)F)c(-c3cccc(S(C)(=O)=O)c3)c2)cc1C

Procedure:
Hydrolysis of (S)-ethyl 8-(2-amino-6-((R)-1-(3,4-dimethyl-3″-(methylsulfonyl)-[1,1′:3′,1″-terphenyl]-4′-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate using the LiOH general method provided the title compound as an off-white solid.
Reaction SMILES: N1C=CN=C1.[C:6]([CH2:8][CH:9]([OH:16])[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])#[N:7].[C:17]([Si:21](Cl)([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)([CH3:20])([CH3:19])[CH3:18].O>ClCCl>[C:6]([CH2:8][CH:9]([O:16][Si:21]([C:17]([CH3:20])([CH3:19])[CH3:18])([C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])#[N:7]
Reactant: CCOC(=O)CC(O)CC#N
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: c1c[nH]cn1
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)CC(CC#N)O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C

Procedure:
Imidazole (6.5 g, 0.095 mol) was added to a chilled solution (−5 to −10° C.) of ethyl 4-cyano-3-hydroxybutanoate (10 g, 0.063 mol) in dichloromethane (100 ml) under stirring, followed by tert-butyl diphenyl silyl chloride (15.7 g, 0.057 mol). After stirring for 4 hours at room temperature, water (250 ml) was added to the reaction mixture and layers separated. The aqueous layer was extracted with dichloromethane (100 ml) and combined with the organic layer. The combined organic layer was evaporated to give title compound.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([O:11][CH3:12])[N:10]=1)[C:5]([OH:7])=[O:6].[CH2:13]([NH2:17])[CH2:14][CH:15]=[CH2:16]>O.C(O)(=O)CC(CC(O)=O)(C(O)=O)O.[O-]S([O-])(=O)=O.[Cu+2]>[CH2:13]([NH:17][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([O:11][CH3:12])[N:10]=1)[C:5]([OH:7])=[O:6])[CH2:14][CH:15]=[CH2:16]
Reactant: C=CCCN
Reactant: COc1cc(C(=O)O)cc(Cl)n1
Agent: [Cu+2]
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=S(=O)([O-])[O-]
Solvent: O
Product: C=CCCNc1cc(C(=O)O)cc(OC)n1
Temperature: 140 °C
Reaction time: 36 h

Procedure:
A mixture of 1.0 g (5.3 mmol) 2-chloro-6-methoxy-isonicotinic acid, 4.4 g (53 mmol, 86% pure by NMR) but-3-enylamine and 85 mg (0.53 mmol) CuSO4 in 10 ml H2O is stirred in a pressurized reaction vessel for 36 h at 140° C. The reaction mixture is diluted with an 0.5 M aqueous citric acid and extracted two times with EtOAc. The combined extracts are washed with citric acid solution, water and brine, dried over Na2SO4, filtered and the solvent is evaporated. Chromatography on silica gel yields the title compound as an off-white powder.
Reaction SMILES: [C:1]([C:5]1[NH:9][C:8]([C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)=[C:7](I)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[C:17]1(B(O)O)[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][CH:18]=1.C([O-])(O)=O.[Na+].O>C1(C)C=CC=CC=1.CCO>[C:1]([C:5]1[NH:9][C:8]([C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)=[C:7]([C:19]2[CH:18]=[CH:17][C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH:20]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1nc(I)c(-c2ccncc2)[nH]1
Reactant: OB(O)c1cccc2ccccc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: Cc1ccccc1
Product: CC(C)(C)c1nc(-c2ccc3ccccc3c2)c(-c2ccncc2)[nH]1

Procedure:
In a heavy-walled pressure vessel 4-(2-tert-Butyl-5-iodo-3-H-imidazol-4-yl)-pyridine (100 milligrams (hereinafter “mg”), 0.3 mmol) and tetrakis-triphenylphosphine palladium (0) catalyst was dissolved in toluene (2-3 ml) and argon was bubbled through the solution while the other reagents were added: 1-naphthyl boronic acid (86 mg, 0.5 mmol), solid NaHCO3 (84 mg), water (500 uL), EtOH (500 uL). The vessel was sealed and the reaction heated to 100° overnight. The reaction mixture was partitioned between 5% NaHCO3 and EtOAc and extracted several times with EtOAc. The combined organic layers were washed with brine, dried over MgSO4, filtered, and evaporated. The crude product was chromatographed on silica gel (chromatotron, eluting with 1-4% MeOH/CH2Cl2) to give the title compound as a yellow solid. (58 mg, 59%). mp 218-220°; MS m/e: 328 [M+H]+, 326 [M−H]−; 1H NMR(400 MHz, CDCl3) δ 9.63(br s, 1H), 8.16(app d, J=4.8 Hz, 2H), 7.92(br d, J=8.3 Hz, 2H), 7.64 (br d, 1H), 7.52 (m, 3H), 7.41 (t, J=6 Hz, 1H), 7.29 (br s, 2H), 1.49 (s, 9H).
Reaction SMILES: [CH2:1]([Li])CCCCC.[Li+].CC([N-]C(C)C)C.[Br:16][C:17]1[CH:25]=[CH:24][C:20]([C:21]([OH:23])=[O:22])=[C:19]([CH3:26])[CH:18]=1.C=O.Cl>C1COCC1>[Br:16][C:17]1[CH:18]=[C:19]2[C:20](=[CH:24][CH:25]=1)[C:21](=[O:23])[O:22][CH2:1][CH2:26]2
Reactant: Cc1cc(Br)ccc1C(=O)O
Reactant: [Li]CCCCCC
Agent: C=O
Agent: CC(C)[N-]C(C)C
Agent: Cl
Solvent: C1CCOC1
Product: O=C1OCCc2cc(Br)ccc21
Temperature: -40 °C
Reaction time: 0.5 h

Procedure:
A solution of DIPA (4 M, 270 mL, 1080 mmol) in THF (900 mL) was cooled to −65° C. and HexLi (2.1 M, 505 mL, 1061 mmol) was added dropwise over 15 min maintaining the internal temp <−55° C. Upon completion the reaction mixture was warmed up to −40° C. where it was stirred 30 min. To the resulting solution of LDA was added 4-bromo-2-methylbenzoic acid (90 g, 419 mmol) slowly (over 15 min) as a solution in THF (400 mL) during which time the reaction mixture turned into a bright red suspension. The reaction mixture was stirred for 30 min at −40° C. and then warmed to 15° C. at which point paraformaldehyde (50.3 g, 1674 mmol) was added in 3 portions as a solid keeping the internal temperature (ice water bath) below <18° C. Stirring was then continued at room temperature for 1 hour during which time the mixture turned an orange-yellow colour. After a second hour of stirring, the vessel was immersed in an ice water bath and 3N HCl (650 mL) was added at such a rate to keep the internal temperature less than 30° C. The contents of the reaction vessel was subsequently transferred to a separatory funnel where it was extracted 3× 400 mL EtOAc and the combined organic phases were then concentrated to ˜800 mL total volume. To this was added Amberlyst 15 resin (12 g) and the resulting mixture stirred at 48° C. overnight (˜14 h). HPLC analysis the following morning indicated that cyclization to the desired halolactone was nearly complete. The resin was removed by filtration and the yellow solution concentrated to ˜200 mL total volume at which point the desired product began to crystallize as a yellow solid which was then collected by filtration. The cake was subsequently washed with MTBE (2× 80 mL) to give the first crop of product. Additional material was salvaged by washing the collected supernatant 2× with 200 mL 10% K2CO3,aq followed by 200 mL 1M H3PO4. After concentration to ˜100 mL the crystallized material was collected by filtration, washed with MTBE and then combined with the first crop of and dried to afford the title compound. LCMS: m/z 227, 229 (M+1)+;
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])[CH2:7][O:8][C:4]=2[C:3]=1[CH2:12][N:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]1.[O:26]1[CH2:31][CH2:30][N:29]([CH2:32][CH2:33][O:34][C:35]2[CH:36]=[C:37]3[C:41](=[CH:42][CH:43]=2)[NH:40][CH:39]=[C:38]3[CH:44]=O)[CH2:28][CH2:27]1>CO.N1CCCCC1>[OH:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])/[C:7](=[CH:44]/[C:38]3[C:37]4[C:41](=[CH:42][CH:43]=[C:35]([O:34][CH2:33][CH2:32][N:29]5[CH2:30][CH2:31][O:26][CH2:27][CH2:28]5)[CH:36]=4)[NH:40][CH:39]=3)/[O:8][C:4]=2[C:3]=1[CH2:12][N:13]1[CH2:14][CH2:15][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:17][CH2:18]1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2c(O)ccc3c2OCC3=O)CC1
Reactant: O=Cc1c[nH]c2ccc(OCCN3CCOCC3)cc12
Solvent: C1CCNCC1
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCN(Cc2c(O)ccc3c2O/C(=C\c2c[nH]c4ccc(OCCN5CCOCC5)cc24)C3=O)CC1
Temperature: 50 °C
Reaction time: 2 h
Yield: 78.6 %

Procedure:
A solution of tert-butyl 4-[(6-hydroxy-3-oxo-2,3-dihydrobenzofuran-7-yl)methyl]piperazine-1-carboxylate (0.067 g, 0.19 mmol) obtained in Example A16, Step 1 in methanol (5.0 mL) was added with 5-(2-morpholinoethoxy)-1H-indole-3-carboxaldehyde (0.044 g, 0.16 mmol). Then, the mixture was added with 5 drops of piperidine, and the mixture was stirred at 50° C. for 2 hours. The solvent was evaporated under reduced pressure, and then the residue was subjected to silica gel column chromatography (eluted with chloroform/methanol (95:5)) to obtain tert-butyl (Z)-4-[(6-hydroxy-2-{[5-(2-morpholinoethoxy)-1H-indol-3-yl]methylene}-3-oxo-2,3-dihydrobenzofuran-7-yl)methyl]piperazine-1-carboxylate (0.076 g, 81%).
Reaction SMILES: [O:1]1CCO[CH:2]1[C:6]1[CH:7]=[C:8]([C:12]2[N:16]=[C:15]([C:17]3[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=3)[NH:14][N:13]=2)[CH:9]=[CH:10][CH:11]=1.[CH3:24]I>>[CH3:24][N:13]1[C:12]([C:8]2[CH:7]=[C:6]([CH:11]=[CH:10][CH:9]=2)[CH:2]=[O:1])=[N:16][C:15]([C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=2)=[N:14]1
Reactant: CI
Reactant: Cc1ccc(-c2nc(-c3cccc(C4OCCO4)c3)n[nH]2)cc1
Product: Cc1ccc(-c2nc(-c3cccc(C=O)c3)n(C)n2)cc1

Procedure:
Using 3-(3-[1,3]dioxolan-2-yl-phenyl)-5-p-tolyl-1H-[1,2,4]triazole (mixture of tautomers) and methyl iodide the title compound was obtained as white solid (41% yield), MS: m/e=277.1 (M+).
Reaction SMILES: [F:1][CH:2]([O:7][C:8]1[CH:14]=[CH:13][C:11]([NH2:12])=[CH:10][CH:9]=1)[C:3]([F:6])([F:5])[F:4].Cl.[O-:16][C:17]#[N:18].[K+]>O>[F:1][CH:2]([O:7][C:8]1[CH:14]=[CH:13][C:11]([NH:12][C:17]([NH2:18])=[O:16])=[CH:10][CH:9]=1)[C:3]([F:4])([F:5])[F:6]
Reactant: Nc1ccc(OC(F)C(F)(F)F)cc1
Reactant: N#C[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Product: NC(=O)Nc1ccc(OC(F)C(F)(F)F)cc1
Reaction time: 0.5 h
Yield: 87.1 %

Procedure:
10 g of 4-tetrafluoroethoxyaniline, prepared as in Example 1, in 40 ml of water, and 10 ml of 1:1 HCl, were reacted with 3.9 g of potassium cyanate. The mixture was stirred for 30 minutes and the formed solid was filtered out, rinsed with cool water, and dried to give 10.5 g of the desired compound, having a melting point of 167°-168° C.
Reaction SMILES: [NH2:1][CH:2]([CH2:25][O:26][Si](C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1)[CH2:3][N:4]1[C:13]([C:14]#[N:15])=[C:12]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:22][CH3:23])[CH:10]=2)[C:5]1=[O:24]>C1COCC1>[NH2:1][CH:2]([CH2:25][OH:26])[CH2:3][N:4]1[C:13]([C:14]#[N:15])=[C:12]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:22][CH3:23])[CH:10]=2)[C:5]1=[O:24]
Reactant: COc1ccc2c(=O)n(CC(N)CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)c(C#N)c(-c3ccccc3)c2c1
Solvent: C1CCOC1
Product: COc1ccc2c(=O)n(CC(N)CO)c(C#N)c(-c3ccccc3)c2c1
Reaction time: 2 h

Procedure:
To a solution of 94 (37 mg, 0.063 mmol) in THF at room temperature was added 1M TBAY in THF (1.5 mL). After 2 h, the reaction mixture was partitioned between EtOAc and 1N HCl. The organic phase was washed once with 1N HCl. The combined aqueous phases were basified with NaOH, then extracted with CH2Cl2 (3×). Drying the organic phase (Na2SO4) and concentration gave a residue which was purified by high pressure flash chromatography (0-10% MeOH(NH3)/EtOAc) to give 95.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[O:7][CH2:6][N:5]([C:8]2[CH:17]=[C:16]3[C:11]([C:12](=[O:27])[N:13]4[C:24]5[C:19](=[CH:20][C:21]([F:25])=[CH:22][CH:23]=5)[C:18](=[O:26])[C:14]4=[N:15]3)=[CH:10][CH:9]=2)[CH2:4]1.[S:28](Cl)([C:31]1[CH:37]=[CH:36][C:34]([CH3:35])=[CH:33][CH:32]=1)(=[O:30])=[O:29].C(N(CC)CC)C>CN(C=O)C.C(Cl)(Cl)Cl>[S:28]([O:1][CH2:2][CH:3]1[O:7][CH2:6][N:5]([C:8]2[CH:17]=[C:16]3[C:11]([C:12](=[O:27])[N:13]4[C:24]5[C:19](=[CH:20][C:21]([F:25])=[CH:22][CH:23]=5)[C:18](=[O:26])[C:14]4=[N:15]3)=[CH:10][CH:9]=2)[CH2:4]1)([C:31]1[CH:37]=[CH:36][C:34]([CH3:35])=[CH:33][CH:32]=1)(=[O:30])=[O:29]
Reactant: O=C1c2cc(F)ccc2-n2c1nc1cc(N3COC(CO)C3)ccc1c2=O
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: Cc1ccc(S(=O)(=O)OCC2CN(c3ccc4c(=O)n5c(nc4c3)C(=O)c3cc(F)ccc3-5)CO2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 3-(5-hydroxymethyloxazolidin-3-yl)-8-fluoroindolo[2,1-b]-quinazoline-6,12-dione (0.1 mmol), tosyl chloride (0.12 mmol) and triethylamine (0.2 mmol) in dry DMF is allowed to stir at room temperature overnight. The reaction mixture is diluted with CHCl3, washed with 0.1N HCl, sodium bicarbonate solution, dried (MgSO4) and the solvent is evaporated to give 3-(5-tosyloxymethyloxazolidin-3-yl)-8-fluoroindolo[2,1-b]quinazoline-6,12-dione.
Reaction SMILES: Br[C:2]1[C:10]2[CH:9]([C:11]3[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=3)[CH2:8][NH:7][C:6](=[O:18])[C:5]=2[S:4][C:3]=1[N:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1.C(=O)([O-])[O-].[Cs+].[Cs+].O1CCO[CH2:33][CH2:32]1.C(OB(C=C)OCCCC)CCC>O.[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>[Cl:17][C:14]1[CH:15]=[CH:16][C:11]([CH:9]2[CH2:8][NH:7][C:6](=[O:18])[C:5]3[S:4][C:3]([N:19]4[CH2:24][CH2:23][O:22][CH2:21][CH2:20]4)=[C:2]([CH:32]=[CH2:33])[C:10]2=3)=[CH:12][CH:13]=1
Reactant: O=C1NCC(c2ccc(Cl)cc2)c2c1sc(N1CCOCC1)c2Br
Reactant: C1COCCO1
Agent: [Pd]
Agent: C=CB(OCCCC)OCCCC
Agent: O=C([O-])[O-]
Solvent: O
Product: C=Cc1c(N2CCOCC2)sc2c1C(c1ccc(Cl)cc1)CNC2=O
Temperature: 100 °C
Yield: 61.1 %

Procedure:
In a 20 mL microwave vial a mixture of 3-bromo-4-(4-chlorophenyl)-2-(morpholin-4-yl)-5,6-dihydrothieno[2,3-c]pyridin-7(4H)-one (493.0 mg, 1.152 mmol, single enantiomer of unknown configuration), dicesium carbonate (1.13 g, 3.46 mmol), 1,4-dioxane (4.0 mL, 51 mmol), water (1.41 mL, 78.4 mmol) and vinylboronic acid dibutyl ester (381 uL, 1.73 mmol) was degassed by bubbling argon through the mixture for 10 min. Tetrakis(triphenylphosphine)-palladium(0) (66.6 mg, 0.0576 mmol) was added, the vial was sealed, and the r×n was heated at 100° C. for 15 h. The reaction was cooled to rt, diluted with water, and extracted with EA twice. The combined organics were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The crude material was (dry loaded on Celite and purified using column chromatography on silica gel (40 g ISCO column, gradient 100% hexanes to 100% EA over 60 minutes) to give the title compound (264 mg yellow solid, 61%). Final purification of 50 mg of this material by HPLC gave 30 mg pure product as a white solid. LCMS: (FA) ES+ 375, 377. 1H NMR (400 MHz, DMSO) δ 7.48 (d, J=4.6 Hz, 1H), 7.42-7.32 (m, 2H), 7.09-7.00 (m, 2H), 6.38 (dd, J=18.0, 11.8 Hz, 1H), 5.37 (dd, J=18.0, 1.7 Hz, 1H), 5.17 (dd, J=11.8, 1.6 Hz, 1H), 4.36 (d, J=4.3 Hz, 1H), 3.90 (dd, J=12.8, 5.0 Hz, 1H), 3.76-3.69 (m, 4H), 3.29 (dd, J=11.7, 5.1 Hz, 1H), 3.05-3.00 (m, 2H), 2.99-2.92 (m, 2H).