Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: B(F)(F)F.CCOCC.[CH:10]1([CH2:13][C@@H:14]2[O:22][CH2:21][C:17]3=[N:18][O:19][CH2:20][C@@H:16]3[CH2:15]2)[CH2:12][CH2:11]1.[F:23][C:24]1[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:25]=1I.C([Li])CCC>C1(C)C=CC=CC=1>[CH:10]1([CH2:13][C@@H:14]2[O:22][CH2:21][C@:17]3([C:27]4[CH:26]=[CH:25][C:24]([F:23])=[CH:29][C:28]=4[F:30])[NH:18][O:19][CH2:20][C@@H:16]3[CH2:15]2)[CH2:11][CH2:12]1
Reactant: Fc1ccc(I)c(F)c1
Reactant: C1O[C@@H](CC2CC2)C[C@H]2CON=C12
Agent: FB(F)F
Agent: [Li]CCCC
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: Fc1ccc([C@]23CO[C@@H](CC4CC4)C[C@H]2CON3)c(F)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Boron trifluoride diethyl etherate (5.4 g, 17.9 mmol) was added drop-wise to a solution of rel-(3aR,5S)-5-(cyclopropylmethyl)-3,3a,4,5-tetrahydro-7H-pyrano[3,4-c][1,2]oxazole (C69) (2.7 g, 14.9 mmol) in toluene (100 mL) at an internal temperature of −72.5° C. The reaction mixture was stirred at −73° C. to −76° C. for 30 minutes, then treated with 2,4-difluoro-1-iodobenzene (98%, 4.3 g, 17.9 mmol) in one portion. While the reaction temperature was maintained below −73° C., n-butyllithium (2.5 M in hexanes, 6.0 mL, 14.9 mmol) was added in a drop-wise manner over 15 minutes. The reaction mixture was stirred at −73° C. to −75° C. for 1.5 hours, then was quenched with saturated aqueous ammonium chloride solution (10 mL) at −74° C. and allowed to warm to room temperature. The resulting mixture was extracted with ethyl acetate (300 mL), and the aqueous layer was extracted with additional ethyl acetate (250 mL and 100 mL); the combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. Chromatography on silica gel (Gradient: 0% to 10% ethyl acetate in petroleum ether) afforded the product as a yellow oil. Yield: 1.85 g, 6.25 mmol, 42%. LCMS m/z 296 [M+H+]. 1H NMR (400 MHz, CDCl3) δ 7.92 (q, J=8.3 Hz, 1H), 6.88 (dt, J=8.2, 2.4 Hz, 1H), 6.80 (dt, J=10.4, 2.4 Hz, 1H), 6.31 (br s, 1H), 4.11 (dd, J=12.8, 1.6 Hz, 1H), 3.80 (d, J=12.8 Hz, 1H), 3.70 (d, J=7.2 Hz, 1H), 3.61-3.67 (m, 1H), 3.52-3.55 (m, 1H), 3.04-3.09 (m, 1H), 1.94 (dd, J=14.0, 6.8 Hz, 1H), 1.59-1.67 (m, 2H), 1.45 (q, J=15.1 Hz, 1H), 1.25 (quintet, J=6.9 Hz, 1H), 0.74-0.85 (m, 1H), 0.45-0.53 (m, 2H), 0.08-0.13 (m, 2H).
Reaction SMILES: [CH:1]([C:3]1[C:8]([C:9]2[C:10]([CH:18]=[O:19])=[CH:11][C:12]3[O:16][CH2:15][O:14][C:13]=3[CH:17]=2)=[C:7]([O:20][CH3:21])[C:6]([O:22][CH3:23])=[C:5]([O:24][CH3:25])[CH:4]=1)=[O:2].[BH4-].[Na+].O.C(OCC)(=O)C>CO>[OH:2][CH2:1][C:3]1[C:8]([C:9]2[C:10]([CH2:18][OH:19])=[CH:11][C:12]3[O:16][CH2:15][O:14][C:13]=3[CH:17]=2)=[C:7]([O:20][CH3:21])[C:6]([O:22][CH3:23])=[C:5]([O:24][CH3:25])[CH:4]=1
Reactant: COc1cc(C=O)c(-c2cc3c(cc2C=O)OCO3)c(OC)c1OC
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: O
Product: COc1cc(CO)c(-c2cc3c(cc2CO)OCO3)c(OC)c1OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.7 %

Procedure:
To a solution of crude 6-(6-formyl-2,3,4-trimethoxyphenyl)benzo[d][1,3]dioxole-5-carbaldehyde (265 mg, 0.77 mmol) in methanol (7 mL) was added sodium borohydride (80 mg, 2.1 mmol) and the solution was stirred at room temperature for 1 hour. Water (30 mL) and ethyl acetate (30 mL) were then added to the reaction, the layers were separated and the aqueous layer was extracted with ethyl acetate (2×30 mL). The combined extracts were dried over Na2SO4 and filtered. The solvent was removed in vacuo and the residue was purified by flash chromatography over silica gel (40 g), eluting with hexane-ethyl acetate (1:2), followed by crystallisation (ethyl acetate), which yielded (6-(6-(hydroxymethyl)-2,3,4-trimethoxyphenyl)benzo[d][1,3]dioxol-5-yl)methanol as a white solid (230 mg, 86%); m.p. 123-124° C.; High Resolution Mass Spectrometry Found: M+Na+ 371.1105 (C18H20O7Na requires 371.1107); NMR Spectrum δH (300 MHz, CDCl3) 7.00 (2H, s, 7-H), 6.88 (1H, s, 4-H), 6.63 (1H, s, 5′-H), 6.04 (2H, s, 2-H), 4.30 (2H, m, CH2OH), 4.21 (2H, m, CH2OH), 3.93 (3H, s, OCH3), 3.91 (3H, s, OCH3), 3.62 (3H, s, OCH3); NMR Spectrum δC (75 MHz, CDCl3) 56.4, 61.4, 61.5 (CH2), 63.1 (CH2), 63.7, 101.7, 108.7, 110.4, 110.6, 126.6, 129.1, 133.8, 135.5, 142.0, 147.5, 147.8, 151.4, 153.5; νmax/cm−1 (thin film) 3254, 2944, 2889, 1603, 1480, 1410, 1328, 1235, 1146, 1111, 1033, 928; m/z (ES) 412 (MNa2H2O+, 100%), 371 (MNa+, 60); Rf(hexane-ethyl acetate 1:2) 0.14.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[Cl:7][C:8]1[CH:9]=[CH:10][C:11]([C:16](OCC)=[O:17])=[N:12][C:13]=1[O:14][CH3:15].O>O1CCCC1>[Cl:7][C:8]1[CH:9]=[CH:10][C:11]([CH:16]=[O:17])=[N:12][C:13]=1[O:14][CH3:15]
Reactant: CCOC(=O)c1ccc(Cl)c(OC)n1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: COc1nc(C=O)ccc1Cl
Reaction time: 0.17 h
Yield: 82.8 %

Procedure:
Lithium aluminum hydride (2.54 g) was added in small portions to a solution of ethyl 5-chloro-6-methoxypyridine-2-carboxylate (22.3 g) in tetrahydrofuran (223 mL) under ice-cooling, and the mixture was stirred at the same temperature for 10 minutes. Water was added to the reaction solution under ice-cooling. After filtration through celite, the filtrate was concentrated under reduced pressure. Brine was added to the residue, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and filtered, after which the filtrate was concentrated under reduced pressure. Manganese dioxide (116.4 g) was added to a solution of the residue in chloroform (223 mL), and the mixture was stirred at 60° C. for one hour. The reaction solution was filtered through celite, and the filtrate was concentrated under reduced pressure. The resulting residue was suspended with hexane, stirred and then filtered. The filtrate was concentrated under reduced pressure. The same operation was further repeated three times. The resulting solids were combined and dried under reduced pressure to give the title compound as a white solid (14.7 g, 83%).
Reaction SMILES: CC(O)(C)[C:3]#[C:4][C:5]1[S:6][C:7]([C:10]#[C:11][C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)=[CH:8][CH:9]=1.[OH-].[K+].CC(C)=O.C1COCC1.CCCCCC>CO.C1(C)C=CC=CC=1>[C:4]([C:5]1[S:6][C:7]([C:10]#[C:11][C:12]2[CH:13]=[CH:14][N:15]=[CH:16][CH:17]=2)=[CH:8][CH:9]=1)#[CH:3]
Reactant: CC(C)(O)C#Cc1ccc(C#Cc2ccncc2)s1
Agent: [K+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: CO
Solvent: C1CCOC1
Product: C#Cc1ccc(C#Cc2ccncc2)s1
Yield: 69.92 %

Procedure:
A distillation apparatus was set up and 2-{3-methyl-3-hydroxybutynyl}-5-{2-(4pyridyl)ethynyl}thiophene (8.50 g, 31.84 mmol), KOH (1.78 g, 21.84 mmol) in 25 ml of methanol and 200 ml of toluene were added to the distillation flask. The flask was heated to about 90° C. until all the acetone formed in the reaction and the methanol were collected in the receiving flask (total heating time, about 1.5 to 2 hours). The toluene was removed under reduced pressure and the reddish residue was purified by chromatography on silica gel using 2:8 THF/petroleum ether as the eluting solvent to obtain 4.65 g (69.92% yield) of light yellow solid. TLC (3:7 THF/hexane): Rf =0.28, mp=134.5°-135.5° C. FTIR (cm-1): 3304 (H--C≡C), 2206 (C≡C). Elemental analysis: Calculated for C13H7NS (mw 209.26): C, 74.61; H, 3.37; N, 6.70. Found: C, 74.54; H, 3.19; N, 6.72. DSC thermogram of the monomer showed a melting transition at 138° C. and a transition for thermal curing of the terminal C≡C at 144.67° C. TGA thermogram showed about 10-20% weight loss at the terminal C≡C cure temperature (about 150° C.) after which there was little weight loss up to about 400° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:8]2[CH:12]=[CH:11][C:10]([C:13]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([C@@H:22]4[O:27][CH2:26][CH2:25][N:24](C(OC(C)(C)C)=O)[CH2:23]4)=[CH:18][CH:17]=3)=[O:14])=[N:9]2)=[N:4][CH:5]=[CH:6][N:7]=1.Cl>O1CCOCC1>[ClH:1].[Cl:1][C:2]1[C:3]([N:8]2[CH:12]=[CH:11][C:10]([C:13]([NH:15][C:16]3[CH:17]=[CH:18][C:19]([C@@H:22]4[O:27][CH2:26][CH2:25][NH:24][CH2:23]4)=[CH:20][CH:21]=3)=[O:14])=[N:9]2)=[N:4][CH:5]=[CH:6][N:7]=1
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(NC(=O)c3ccn(-c4nccnc4Cl)n3)cc2)C1
Agent: Cl
Solvent: C1COCCO1
Product: O=C(Nc1ccc([C@H]2CNCCO2)cc1)c1ccn(-c2nccnc2Cl)n1
Temperature: 60 °C
Reaction time: 1.5 h

Procedure:
(S)-tert-Butyl 2-(4-(1-(3-chloropyrazin-2-yl)-1H-pyrazole-3-carboxamido)phenyl)morpholine-4-carboxylate (44 mg, 90.7 μmol) was dissolved in dioxane (0.35 ml) and a solution of HCl in dioxane (340 μl, 1.36 mmol) was added and the reaction mixture was stirred at 60° C. for 90 min.
Reaction SMILES: [Na].[Cl:2][C:3]1[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:4]=1[O:5][C:6]1[CH:11]=[CH:10][C:9]([O-:12])=[CH:8][CH:7]=1.[CH2:18]([O:20][C:21](=[O:33])[CH:22]([C:28](=[O:32])[CH:29](Cl)[CH3:30])[C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH3:19]>CS(C)=O>[CH2:26]([O:25][C:23](=[O:24])[CH:22]([C:28](=[O:32])[CH:29]([O:12][C:9]1[CH:8]=[CH:7][C:6]([O:5][C:4]2[CH:13]=[CH:14][C:15]([Cl:17])=[CH:16][C:3]=2[Cl:2])=[CH:11][CH:10]=1)[CH3:30])[C:21]([O:20][CH2:18][CH3:19])=[O:33])[CH3:27]
Reactant: [O-]c1ccc(Oc2ccc(Cl)cc2Cl)cc1
Reactant: CCOC(=O)C(C(=O)OCC)C(=O)C(C)Cl
Agent: [Na]
Solvent: CS(C)=O
Product: CCOC(=O)C(C(=O)OCC)C(=O)C(C)Oc1ccc(Oc2ccc(Cl)cc2Cl)cc1
Temperature: 60 °C
Reaction time: 48 h
Yield: 63.9 %

Procedure:
27.7 g of sodium-4-(2',4'-dichloro-phenoxy)-phenolate and 25.1 g of diethyl-2-chloro-propionyl-malonate are dissolved in 150 ml of dimethyl sulfoxide and the reaction mixture is stirred at 60° C. for 48 hours under stirring. The reaction mixture is filtered and the filtrate is evaporated. The residue is dissolved in 100 ml of benzene and washed successively with 100 ml of a saturated aqueous sodium hydrogen carbonate solution and water. The benzene solution is evaporated. Thus 30 g of the desired compound are obtained, yield 61%.
Reaction SMILES: [F:1][C:2]1[C:3]([CH:16]=[CH:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[C:4]([CH:9]=[CH:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:5]=[C:6]([F:8])[CH:7]=1>C(OCC)(=O)C.[Pd]>[F:1][C:2]1[C:3]([CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[C:4]([CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: CCOC(=O)C=Cc1cc(F)cc(F)c1C=CC(=O)OCC
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC(=O)CCc1cc(F)cc(F)c1CCC(=O)OCC
Yield: 121.7 %

Procedure:
Ethyl 3-{3,5-difluoro-2-[2-(ethoxycarbonyl)vinyl]phenyl}acrylate (5.7 g, 18.4 mmol) in 250 mL of ethyl acetate was hydrogenated at 60 psi over 10% palladium on carbon (0.57 g) for 4 hours and then the mixture was filtered through Celite. Evaporation of the solvent gave ethyl 3-{3,5-difluoro-2-[2-(ethoxycarbonyl)ethyl]phenyl}propionate (5.73 g, 22.4 mmol) as a colorless oil.
Reaction SMILES: [OH:1][CH2:2][CH:3]([N:7]([CH2:15][CH:16]=[CH2:17])[C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])[CH2:4][CH:5]=[CH2:6].C(N(CC)CC)C.[N+:25]([C:28]1[CH:36]=[CH:35][C:31]([C:32](Cl)=[O:33])=[CH:30][CH:29]=1)([O-:27])=[O:26]>CN(C)C1C=CN=CC=1.ClCCl.C(=O)([O-])O.[Na+]>[N+:25]([C:28]1[CH:29]=[CH:30][C:31]([C:32]([O:1][CH2:2][CH:3]([N:7]([C:8]([O:9][C:10]([CH3:11])([CH3:12])[CH3:13])=[O:14])[CH2:15][CH:16]=[CH2:17])[CH2:4][CH:5]=[CH2:6])=[O:33])=[CH:35][CH:36]=1)([O-:27])=[O:26]
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Reactant: C=CCC(CO)N(CC=C)C(=O)OC(C)(C)C
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CCC(COC(=O)c1ccc([N+](=O)[O-])cc1)N(CC=C)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 58.1 %

Procedure:
To a mixture of tert-butyl [1-(hydroxymethyl)but-3-en-1-yl]prop-2-en-1-ylcarbamate (15.0 g) produced above, triethylamine (19.0 g) and dichloromethane (150 mL) was added N,N-dimethylpyridin-4-amine (0.7 g). To the mixture was added dropwise a solution of 4-nitrobenzoyl chloride (14.2 g) in dichloromethane (30 mL), and the mixture was stirred at 0° C. for 30 min. The reaction mixture was diluted with saturated aqueous sodium hydrogen carbonate, the mixture was extracted with dichloromethane, and the extract was dried over anhydrous sodium sulfate. Insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/petroleum ether) to give the title compound (14.1 g).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:15][CH3:16])[CH:11]=2)[CH:6]=1)=[O:4].CN([CH:20]=[O:21])C.O=P(Cl)(Cl)Cl.C([O-])([O-])=O.[Na+].[Na+]>>[CH3:1][O:2][C:3]([C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:15][CH3:16])[C:11]=2[CH:20]=[O:21])[CH:6]=1)=[O:4]
Reactant: CN(C)C=O
Reactant: COC(=O)c1ccc2cc(OC)ccc2c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Product: COC(=O)c1ccc2c(C=O)c(OC)ccc2c1
Temperature: 80 °C
Reaction time: 48 h
Yield: 62.8 %

Procedure:
To a stirred solution of 6-methoxy-2-naphthoic acid methyl ester (10.3 g, 47.6 mmol) in DMF (36.9 mL, 476 mmol) at 5° C. was added POCl3 (44.4 mL, 476 mmol) dropwise. The reaction mixture was heated to 80° C. After 2 days at this temperature, the reaction was poured into ice/H2O (400 mL). The solution was made basic with addition of solid Na2CO3. The resulting mixture was extracted with EtOAc (2×400 mL). The organic layer was washed with brine (80 mL) and dried (MgSO4). After concentration, the residue was recrystallized from MeOH:H2O to afford the product (7.30 g, 63%) as a solid; 1H NMR (DMSO-d6) δ3.91 (s, 3H), 4.11 (s, 3H), 7.72 (d, J=9.3 Hz, 1H), 8.10 (dd, J=2.0, 9.0 Hz, 1H), 8.53 (d, J=9.2 Hz, 1H), 8.66 (d, J=1.8 Hz, 1H), 9.17 (d, J=9.0 Hz, 1H), 10.76 (s, 1H).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][C:11]2[C:12]([C:17]([CH:19]3[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]3)=O)=[N:13][CH:14]=[CH:15][CH:16]=2)[CH:6]=[CH:7][CH:8]=1.F.B(F)(F)F>>[Cl:2][C:3]1[CH:8]=[CH:7][C:6]2[C:17](=[C:19]3[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]3)[C:12]3=[N:13][CH:14]=[CH:15][CH:16]=[C:11]3[CH2:10][CH2:9][C:5]=2[CH:4]=1
Reactant: CN1CCC(C(=O)c2ncccc2CCc2cccc(Cl)c2)CC1
Agent: Cl
Agent: F
Agent: FB(F)F
Product: CN1CCC(=C2c3ccc(Cl)cc3CCc3cccnc32)CC1
Yield: 93.8 %

Procedure:
To a solution of [3-[2-(3-chlorophenyl)ethyl]-2-pyridinyl]-1-methyl-4-piperidinyl methanone hydrochloride (59.0 g; 0.15 mol) in 120 mL (120 g; 6.0 mol) of hydrofluoric acid at -35° C. was added boron trifluoride (44.3 g; 0.66 mol) over 1 h. The reaction was quenched using ice water and potassium hydroxide to a final pH of 10. The product was extracted into toluene which was washed with water and brine. The toluene solution was concentrated to a residue which was triturated with hot hexanes. Insoluble salts were removed by filtration and the filtrate was concentrated to give as a main product 45.7 g (HPLC purity 96%, yield 91%) of 8-chloro-6,11-dihydro- 11-(1-methyl-4-piperidinylidene)-5H-benzo[5,6]cyclohepta[1,2-b]pyridine as an off-white solid: mp 116°-119° C.; NMR (200 MHz, CDCl3)δ2.0-2.2 (m,2H), 2.27 (s,3H), 2.3-2.6 (m,4H), 2.6-3.0 (m,4H), 3.3-3.6 (m,2H), 7.0-7.2 (m,4H), 7.44 (dd,1H,J=8, 2 Hz), 8.42 (dd,1H,J=3, 2 Hz); mass spectrum, m/e (rel intensity) 327M+3 (28), 325M+1 (100) Anal. Calcd. for C20H21N2Cl: C,73.94; H,6.52; N,8.63; Cl,10.92. Found: C,73.88; H,6.48; N,8.69; Cl10.80. This material was found to include the two corresponding fluoro-substituted compound of the invention as discussed further below.
Reaction SMILES: Cl[C:2]1[C:7]2[CH:8]=[CH:9][N:10]([CH2:11][CH3:12])[C:6]=2[CH:5]=[C:4]([Cl:13])[N:3]=1.[OH-:14].[Na+].Cl>O1CCOCC1>[Cl:13][C:4]1[NH:3][C:2](=[O:14])[C:7]2[CH:8]=[CH:9][N:10]([CH2:11][CH3:12])[C:6]=2[CH:5]=1
Reactant: CCn1ccc2c(Cl)nc(Cl)cc21
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: C1COCCO1
Product: CCn1ccc2c(=O)[nH]c(Cl)cc21
Temperature: 160 °C
Yield: 32.8 %

Procedure:
A microwave reaction vial was charged with 4,6-dichloro-1-ethyl-1H-pyrrolo[3,2-c]pyridine (200 mg, 0.930 mmol), a 2M aqueous sodium hydroxide solution (10 mL) and 1,4-dioxane (3 mL). The vial was sealed and then heated in the microwave at 160° C. for 30 min. At this time, the resulting mixture was acidified to pH 6.5 with a 4M aqueous hydrochloric acid solution and then concentrated in vacuo. The residue was diluted with ethanol. The solids were removed by filtration, and the filtrate was concentrated in vacuo. Flash chromatography (10/1 methylene chloride/methanol) afforded 6-chloro-1-ethyl-1,5-dihydro-pyrrolo[3,2-c]pyridine-4-one (60 mg, 32.8%). LC-MS calcd. for C9H9ClN2O [(M)+] 196, obsd. 196.9.
Reaction SMILES: [CH:1]([C:4]1[C:5]([O:16][CH2:17][CH2:18][CH2:19][CH3:20])=[C:6](B(O)O)[CH:7]=[C:8]([CH:10]([CH3:12])[CH3:11])[CH:9]=1)([CH3:3])[CH3:2].[C:21]([C:24]1[S:28][C:27]2[CH:29]=[CH:30][CH:31]=[C:32](I)[C:26]=2[CH:25]=1)(=[O:23])[CH3:22].C(=O)([O-])[O-].[Na+].[Na+].O>C1(C)C=CC=CC=1.C(O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:21]([C:24]1[S:28][C:27]2[CH:29]=[CH:30][CH:31]=[C:32]([C:6]3[CH:7]=[C:8]([CH:10]([CH3:12])[CH3:11])[CH:9]=[C:4]([CH:1]([CH3:2])[CH3:3])[C:5]=3[O:16][CH2:17][CH2:18][CH2:19][CH3:20])[C:26]=2[CH:25]=1)(=[O:23])[CH3:22]
Reactant: CCCCOc1c(B(O)O)cc(C(C)C)cc1C(C)C
Reactant: CC(=O)c1cc2c(I)cccc2s1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCO
Product: CCCCOc1c(-c2cccc3sc(C(C)=O)cc23)cc(C(C)C)cc1C(C)C

Procedure:
A mixture of 1.08 mmol of 3,5-di-iso-propyl-2-n-butoxy phenylboronic acid, 1.62 mmol of 2-acetyl-4-iodo benzo[b]thiophene (see Example 14, step A) and 62 mg (0.05 mmol) of Pd(PPh3)4, 1 mL of 2N aqueous sodium carbonate in 9 mL of toluene and 4 mL ethanol was heated to reflux. After complexion (TLC), water was added and the solution was extracted with ethyl acetate. The organic layer is dried over MgSO4 and after evaporation of the solvents, the crude oil was purified over a short silica plug (eluent: 10/90=ethyl acetate/hexane) to afford 2-acetyl-4-(2-n-butoxy-3,5-di-iso-propylphenyl)-benzo[b]thiophene.
Reaction SMILES: [C:1]([C:4]1[N:5]=[C:6]([CH2:37][CH3:38])[C:7]([O:24][CH:25]2[CH2:29][CH2:28][N:27](C(OC(C)(C)C)=O)[CH2:26]2)=[N:8][C:9]=1[NH:10][C:11]1[CH:16]=[CH:15][C:14]([N:17]2[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]2)=[CH:13][CH:12]=1)(=[O:3])[NH2:2].FC(F)(F)C(O)=O>ClCCCl>[CH2:37]([C:6]1[N:5]=[C:4]([C:1]([NH2:2])=[O:3])[C:9]([NH:10][C:11]2[CH:12]=[CH:13][C:14]([N:17]3[CH2:18][CH2:19][N:20]([CH3:23])[CH2:21][CH2:22]3)=[CH:15][CH:16]=2)=[N:8][C:7]=1[O:24][CH:25]1[CH2:29][CH2:28][NH:27][CH2:26]1)[CH3:38]
Reactant: CCc1nc(C(N)=O)c(Nc2ccc(N3CCN(C)CC3)cc2)nc1OC1CCN(C(=O)OC(C)(C)C)C1
Solvent: ClCCCl
Solvent: O=C(O)C(F)(F)F
Product: CCc1nc(C(N)=O)c(Nc2ccc(N3CCN(C)CC3)cc2)nc1OC1CCNC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 73.8 %

Procedure:
To a mixture of tert-butyl 3-[(5-carbamoyl-3-ethyl-6-{[4-(4-methylpiperazin-1-yl)phenyl]amino}pyrazin-2-yl)oxy]pyrrolidine-1-carboxylate (355 mg) and 1,2-dichloroethane (6 mL) was added trifluoroacetic acid (2 mL) under ice-cooling, followed by stirring at room temperature for 12 hours. The reaction mixture was concentrated, then diluted with chloroform, and neutralized with a 10% aqueous potassium carbonate solution. After extraction with chloroform, the organic phase was dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was purified by silica gel column chromatography (eluent; chloroform:methanol:28% aqueous ammonia=1:0:0-100:10:1), and dried under reduced pressure to obtain 6-ethyl-3-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-5-(pyrrolidin-3-yloxy)pyrazine-2-carboxamide (212 mg) as a yellow solid.
Reaction SMILES: [CH2:1]([N:3]=[C:4]=[O:5])[CH3:2].[NH2:6][C:7]1[CH:17]=[C:16]([NH:18][C:19]2[CH:20]=[C:21]([CH3:25])[CH:22]=[CH:23][CH:24]=2)[C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:9][N:8]=1>O1CCOCC1.CCOC(C)=O>[CH2:1]([NH:3][C:4](=[O:5])[NH:6][C:7]1[CH:17]=[C:16]([NH:18][C:19]2[CH:20]=[C:21]([CH3:25])[CH:22]=[CH:23][CH:24]=2)[C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:9][N:8]=1)[CH3:2]
Reactant: CCN=C=O
Reactant: CCOC(=O)c1cnc(N)cc1Nc1cccc(C)c1
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CCNC(=O)Nc1cc(Nc2cccc(C)c2)c(C(=O)OCC)cn1
Temperature: 100 °C

Procedure:
Ethyl isocyanate (0.898 mL, 1.49 mmol), was added to a solution of compound vi (0.270 g, 0.99 mmol) in 1,4-dioxane (5 mL). The reaction mixture was warmed to 100° C. for 48 h, cooled to room temperature and reduced in vacuo. The resulting orange residue was re-dissolved in EtOAc (15 mL) and reduced in vacuo on to SiO2. Column chromatography (SiO2), eluting with 2:1 Hexanes-EtOAc, gave the desired compound vii. (0.145 g, 0.424 mmol, 43%) as an off-white solid, 1H NMR (300 MHz, DMSO-d6): δ 9.62 (1H, br s), 9.19 (1H, br s), 8.62 (1H, s), 7.85 (1H, br t), 7.31 (1H, t, J 7.7), 7.23 (1H, s), 7.13-7.07 (2H, m), 7.03 (1H, d, J 7.2), 4.31 (2H, q, J 7.2), 3.13 (2H, dq, J 6.7 and 7.2), 2.33 (3H, s), 1.33 (3H, t, J 7.2), 1.05 (3H, t, J 7.2); [M+H]+ m/z=343.1.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][CH2:10][O:11][C:12]1[CH:13]=[CH:14][C:15]2[C:16]3[N:17]([CH2:33][CH2:34][N:35]=3)[C:18]([NH:24][C:25]([C:27]3[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=3)=[O:26])=[N:19][C:20]=2[C:21]=1[O:22][CH3:23])(C)(C)C.C(#N)C>FC(F)(F)C(O)=O.ClCCl>[NH2:7][CH2:8][CH2:9][CH2:10][O:11][C:12]1[CH:13]=[CH:14][C:15]2[C:16]3[N:17]([CH2:33][CH2:34][N:35]=3)[C:18]([NH:24][C:25](=[O:26])[C:27]3[CH:32]=[CH:31][CH:30]=[N:29][CH:28]=3)=[N:19][C:20]=2[C:21]=1[O:22][CH3:23]
Reactant: COc1c(OCCCNC(=O)OC(C)(C)C)ccc2c1N=C(NC(=O)c1cccnc1)N1CCN=C21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: COc1c(OCCCN)ccc2c1N=C(NC(=O)c1cccnc1)N1CCN=C21
Temperature: 25 °C
Reaction time: 8 h
Yield: 60.6 %

Procedure:
tert-Butyl[3-({7-methoxy-5-[(pyridin-3-ylcarbonyl)amino]-2,3-dihydroimidazo[1,2-c]quinazolin-8-yl}oxy)propyl]carbamate (Step 1, 1.2 g, 2.3 mmol) was diluted in a mixture of trifluoroacetic acid (6 mL) and dichloromethane (24 mL). The mixture was stirred at rt overnight, then was concentrated in vacuo to afford a viscous yellow oil. Acetonitrile was added to the mixture, and the desired was isolated by vacuum filtration as a white solid (0.55 g, 60%). 1H NMR (DMSO-d6+2 drops TFA-d) δ: 2.13 (2H, m), 3.02 (2H, m), 4.01 (3H, s), 4.25 (2H, m), 4.35 (2H, t), 4.57 (2H, m), 7.45 (1H, d), 7.73 (1H, m), 7.92 (2H, br m), 8.06 (1H, d), 8.69 (1H, m), 8.87 (1H, m), 9.43 (1H, m).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:14]=[CH:13][N:12]([CH2:15][C@@H:16]([NH:18][C:19]([C:21]3[N:22]=[C:23]([CH3:26])[NH:24][CH:25]=3)=[O:20])[CH3:17])[N:11]=2)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].C(=O)([O-])[O-].[Cs+].[Cs+].I[CH2:34][CH2:35][F:36].O>C(#N)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:14]=[CH:13][N:12]([CH2:15][C@@H:16]([NH:18][C:19]([C:21]3[N:22]=[C:23]([CH3:26])[N:24]([CH2:34][CH2:35][F:36])[CH:25]=3)=[O:20])[CH3:17])[N:11]=2)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9]
Reactant: Cc1nc(C(=O)N[C@@H](C)Cn2ccc(-c3ccc(C#N)c(Cl)c3)n2)c[nH]1
Reactant: FCCI
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CC#N
Product: Cc1nc(C(=O)N[C@@H](C)Cn2ccc(-c3ccc(C#N)c(Cl)c3)n2)cn1CCF
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(S)—N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-2-methyl-1H-imidazole-4-carboxamide (100 mg, 0.271 mmol) suspended in acetonitrile (5 ml). Into the mixture, cesium carbonate (124 mg, 0.380 mmol) and 1-Iodo-2-fluoroethane (0.049 ml, 0.596 mmol) were added and the resulting mixture was stirred overnight at RT. Water (2 ml) was added and the mixture was evaporated. The product was purified with LC/MS-trigger. 1H-NMR (400 MHz; CDCl3): δ 1.23 (d, 3H), 2.42 (s, 3H), 4.12-4.23 (m, 2H), 4.30 (dd, 1H), 4.39 (dd, 1H), 4.51-4.61 (m, 1H), 4.58-4.73 (m, 2H), 6.61 (d, 1H), 7.49 (d, 1H), 7.51 (d, 1H), 7.62 (d, 1H), 7.77 (dd, 1H), 7.85 (dd, 1H), 8.00 (dd, 1H).