Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:10]([N:12]2[CH2:17][CH2:16][N:15]([C:18]3[C:23]([CH3:24])=[CH:22][C:21]([CH3:25])=[CH:20][N:19]=3)[CH2:14][CH2:13]2)=[O:11])=[C:6]([CH:9]=1)[C:7]#[N:8].[S:26]1(=[O:32])(=[O:31])[CH2:30][CH2:29][CH2:28][NH:27]1.C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>[Cl-].[Na+].O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O1CCOCC1>[CH3:24][C:23]1[C:18]([N:15]2[CH2:16][CH2:17][N:12]([C:10]([C:5]3[CH:4]=[CH:3][C:2]([N:27]4[CH2:28][CH2:29][CH2:30][S:26]4(=[O:32])=[O:31])=[CH:9][C:6]=3[C:7]#[N:8])=[O:11])[CH2:13][CH2:14]2)=[N:19][CH:20]=[C:21]([CH3:25])[CH:22]=1
Reactant: O=S1(=O)CCCN1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(Br)cc3C#N)CC2)c(C)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: C1COCCO1
Solvent: O
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4CCCS4(=O)=O)cc3C#N)CC2)c(C)c1
Yield: 71.3 %

Procedure:
To a mixture of 5-bromo-2-[4-(3,5-dimethylpyridin-2-yl)piperazine-1-carbonyl]benzonitrile (599 mg) described in Preparation Example 187, isothiazolidine 1,1-dioxide (236 mg), 4,5-bisdiphenylphosphanyl-9,9-dimethyl-9H-xanthene (130 mg), palladium acetate (34 mg) and cesium carbonate (733 mg) was added 1,4-dioxane (2 mL), and the mixture was stirred with heating under reflux for 2 hr. The reaction mixture was cooled, saturated brine was added and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by column chromatography (ethyl acetate:hexane) to give the title compound (470 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([CH2:28][CH3:29])[C:12]([NH:17][C@@H:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:20][C@@H:19]2O)=[N:13][C:14]=1[CH2:15][CH3:16].BrC1N=C(CC)C(NC2C3C(=C[C:45]([O:49]C)=CC=3)CC2)=NC=1CC>[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.COCCOC>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([CH2:28][CH3:29])[C:12]([NH:17][CH:18]2[C:26]3[C:21](=[CH:22][C:23]([O:49][CH3:45])=[CH:24][CH:25]=3)[CH2:20][CH2:19]2)=[N:13][C:14]=1[CH2:15][CH3:16]
Reactant: CCc1nc(-c2ccc(Cl)cc2Cl)c(CC)nc1N[C@@H]1c2ccccc2C[C@@H]1O
Reactant: CCc1nc(NC2CCc3cc(OC)ccc32)c(CC)nc1Br
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: COCCOC
Product: CCc1nc(-c2ccc(Cl)cc2Cl)c(CC)nc1NC1CCc2cc(OC)ccc21

Procedure:
Following the procedure for the preparation of (1R,2S)-1-{[5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-yl]amino}-2,3-dihydro-1H-inden-2-ol but substituting 5-bromo-3,6-diethyl-N-(5-methoxy-2,3-dihydro-1H-inden-1-yl)pyrazin-2-amine, ethylene glycol dimethyl ether and tetrakis(triphenylphosphine) palladium and making non-critical variations provided the title compound as a oil: 1H NMR (CDCl3) δ) 1.28, 1.95, 2.51, 2.65, 2.80, 2.95, 3.02, 3.85, 4.14, 4.65, 5.73, 6.82, 6.87, 7.28–7.35, 7.5; HRMS (FAB) calcd for C24H25Cl2N3O+H 442.1453, found 442.1450.
Reaction SMILES: O.O.O.O.O.O.[N+]([O-])([O-])=[O:8].[Co+2:11].[N+]([O-])([O-])=[O:13].O.O.O.O.O.O.O.O.O.[N+]([O-])([O-])=[O:26].[Al+3:29].[N+]([O-])([O-])=[O:31].[N+]([O-])([O-])=[O:35].C(=O)([O-])[O-].[NH4+].[NH4+]>O>[O-2:8].[O-2:13].[O-2:26].[O-2:31].[O-2:35].[Al+3:29].[Al+3:29].[Co+2:11].[Co+2:11]
Reactant: O=[N+]([O-])[O-]
Agent: [Co+2]
Agent: O=C([O-])[O-]
Agent: [Al+3]
Solvent: O
Product: [O-2]
Reaction time: 3 h

Procedure:
In 300 ml of pure water were dissolved 29 g of cobalt nitrate hexahydrate and 75 g of aluminum nitrate nonahydrate. A solution of 38.4 g of ammonium carbonate dissolved in 100 ml of pure water was gradually added thereto with stirring to form a gel-form precipitate. The precipitate was washed with pure water three times, dried at 100° C. overnight and calcined at 600° C. in an air stream. The calcined material was then calcined at 800° C. in a muffle furnace for 3 hours to a cobalt aluminate catalyst having a blue color.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][CH:7]([CH:12]1[CH2:17][CH2:16][CH2:15][O:14][CH2:13]1)[CH2:6][C:5]2=O.[CH3:19][C:20]([S:23]([NH2:25])=[O:24])([CH3:22])[CH3:21]>CC1CCCO1.CCOC(C)=O.O.[O-]CC.[Ti+4].[O-]CC.[O-]CC.[O-]CC>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][CH:7]([CH:12]1[CH2:17][CH2:16][CH2:15][O:14][CH2:13]1)[CH2:6][C:5]2=[N:25][S:23]([C:20]([CH3:22])([CH3:21])[CH3:19])=[O:24]
Reactant: CC(C)(C)S(N)=O
Reactant: O=C1CC(C2CCCOC2)Oc2ccc(Br)cc21
Agent: [Ti+4]
Agent: CC[O-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC1CCCO1
Product: CC(C)(C)S(=O)N=C1CC(C2CCCOC2)Oc2ccc(Br)cc21
Temperature: 130 °C
Reaction time: 0.25 h
Yield: 90.1 %

Procedure:
6-Bromo-2-(tetrahydro-2H-pyran-3-yl)chroman-4-one (Intermediate 27, 1.5 g, 4.82 mmol) and 2-methylpropane-2-sulfinamide (1.052 g, 8.68 mmol) were dissolved in dry 2-methyl-tetrahydrofuran (12 mL). Neat titanium ethoxide (1.788 mL, 8.68 mmol) was added. The resulting mixture was heated by MW at 130° C. for 60 min. The mixture was diluted with EtOAc (150 mL) and water (40 mL) was added dropwise during vigorous stirring of the reaction mixture. The stirring was continued for 15 min. The solid was decanted and the mixture filtered through a pad of diatomaceous earth. The organic layer was separated, dried over MgSO4 and vacuum filtered directly through a pad of silica (approx. 10 g) and concentrated in vacuo to give the title compound (1.8 g, 90% yield). MS (ES+) m/z 414 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[CH3:9][CH:10]([CH3:13])[C:11]#[N:12].C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[NH4+].[Cl-]>C1(C)C=CC=CC=1>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([C:10]([CH3:13])([CH3:9])[C:11]#[N:12])=[N:3][CH:4]=1
Reactant: CC(C)C#N
Reactant: Brc1ccc(Br)nc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: Cc1ccccc1
Product: CC(C)(C#N)c1ccc(Br)cn1

Procedure:
To a solution of 2,5-dibromopyridine (5.0 g, 21 mmol) and 2-methylpropanenitrile (1.6 g, 23 mmol) in toluene (50 mL) under nitrogen was added NaHMDS (12 mL, 23 mmol, 2.0M in THF) dropwise at 0° C. The resulting solution was stirred at ambient temperature overnight before the addition of saturated aqueous NH4Cl (20 mL). The resulting mixture was extracted with EtOAc (3×30 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The crude residue was purified by MPLC on Silica gel (eluting with 1-3% EtOAc/hexane) to afford the title compound as a light yellow solid. 1H NMR (300 MHz, CDCl3) δ 8.65 (s, 1H), 7.85 (d, J=8.7 Hz, 1H), 7.51 (d, J=8.7 Hz, 1H), 1.75 (s, 6H). MS ESI [M+H]+ m/z 225.227.
Reaction SMILES: C(O)(C(F)(F)F)=O.[CH:8]([C:11]1[N:12]=[C:13]([C:16]2[CH:25]=[C:24]([O:26][CH:27]3[CH2:45][CH:44]4[N:29]([C:30](=[O:65])[N:31](CC5C=CC(OC)=CC=5)[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH:37]=[CH:38][CH:39]5[C:41]([C:47]([NH:49][S:50]([CH:53]6[CH2:55][CH2:54]6)(=[O:52])=[O:51])=[O:48])([NH:42][C:43]4=[O:46])[CH2:40]5)[CH2:28]3)[C:23]3[C:18](=[C:19]([CH3:68])[C:20]([O:66][CH3:67])=[CH:21][CH:22]=3)[N:17]=2)[S:14][CH:15]=1)([CH3:10])[CH3:9].O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH:8]([C:11]1[N:12]=[C:13]([C:16]2[CH:25]=[C:24]([O:26][CH:27]3[CH2:45][CH:44]4[N:29]([C:30](=[O:65])[NH:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH:37]=[CH:38][CH:39]5[C:41]([C:47]([NH:49][S:50]([CH:53]6[CH2:55][CH2:54]6)(=[O:52])=[O:51])=[O:48])([NH:42][C:43]4=[O:46])[CH2:40]5)[CH2:28]3)[C:23]3[C:18](=[C:19]([CH3:68])[C:20]([O:66][CH3:67])=[CH:21][CH:22]=3)[N:17]=2)[S:14][CH:15]=1)([CH3:10])[CH3:9]
Reactant: COc1ccc(CN2CCCCCC=CC3CC3(C(=O)NS(=O)(=O)C3CC3)NC(=O)C3CC(Oc4cc(-c5nc(C(C)C)cs5)nc5c(C)c(OC)ccc45)CN3C2=O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: O
Product: COc1ccc2c(OC3CC4C(=O)NC5(C(=O)NS(=O)(=O)C6CC6)CC5C=CCCCCCNC(=O)N4C3)cc(-c3nc(C(C)C)cs3)nc2c1C
Reaction time: 0.5 h
Yield: 73 %

Procedure:
TFA (10 mL) was added to a solution of N-[[18-[2-[4-(isopropyl)thiazol-2-yl]-7-methoxy-8-methylquinolin-4-yloxy]-2,15-dioxo-14-(4-methoxybenzyl)-3,14,16-triazatricyclo[14.3.0.04,6]nonadec-7-en-4-yl]carbonyl](cyclopropyl)sulfonamide (90) in DCM (20 mL). After 30 min at room temperature, water (20 mL) was added to the reaction mixture and the pH was adjusted to 3-4 with NaHCO3. The organic layer was washed with brine, dried (Na2SO4), filtered and evaporated. The residue was purified by column chromatography (gradient MeOH/CH2Cl2, 0:1 to 1:99, then AcOEt/CH2Cl2 1:1) to afford 313 mg (73%) of the desired title product 91 as a yellowish solid: m/z=751 (M+H)+. 1H-NMR (CDCl3): 0.88-1.64 (m, 16H), 1.96 (m, 2H), 2.52 (m, 1H), 2.68 (m s, 5H), 2.79-2.92 (m, 3H), 3.18 (m, 1H), 3.63-3.69 (m, 2H), 3.86 (m, 1H), 3.97 (s, 3H), 4.34 (m, 1H), 4.59 (m, 1H), 5.08 (m, 1H), 5.40 (m, 1H), 5.80 (m, 1H), 6.73 (s, 1H), 7.03 (s, 1H), 7.21 (d, J=8.9 Hz, 1H), 7.26 (br s, 1H), 7.47 (s, 1H), 7.92 (d, J=8.9 Hz, 1H), 10.20 (br s, 1H).
Reaction SMILES: S(Cl)(Cl)=O.S1C=CC=C1CC(O)=O.S1C=CC=C1CC(Cl)=O.[CH3:23][O:24][C:25]1[CH:26]=[C:27]2[C:32](=[CH:33][C:34]=1[O:35][CH3:36])[N:31]=[CH:30][N:29]=[C:28]2[O:37][C:38]1[CH:44]=[CH:43][C:41]([NH2:42])=[CH:40][CH:39]=1.[S:45]1[CH:49]=[CH:48][CH:47]=[C:46]1[CH2:50][C:51]([N:53]=[C:54]=[S:55])=[O:52]>C1(C)C=CC=CC=1.C(O)C>[CH3:23][O:24][C:25]1[CH:26]=[C:27]2[C:32](=[CH:33][C:34]=1[O:35][CH3:36])[N:31]=[CH:30][N:29]=[C:28]2[O:37][C:38]1[CH:44]=[CH:43][C:41]([NH:42][C:54]([NH:53][C:51](=[O:52])[CH2:50][C:46]2[S:45][CH:49]=[CH:48][CH:47]=2)=[S:55])=[CH:40][CH:39]=1
Reactant: COc1cc2ncnc(Oc3ccc(N)cc3)c2cc1OC
Reactant: O=C(Cc1cccs1)N=C=S
Agent: O=C(Cl)Cc1cccs1
Agent: O=C(O)Cc1cccs1
Solvent: CCO
Solvent: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: COc1cc2ncnc(Oc3ccc(NC(=S)NC(=O)Cc4cccs4)cc3)c2cc1OC
Temperature: 100 °C
Reaction time: 2 h
Yield: 57 %

Procedure:
Toluene (20 ml) and thionyl chloride (1 ml) were added to commercially available 2-(2-thienyl)acetic acid (40 mg), and the mixture was heated at 100° C. for one hr. The solvent was removed by distillation, and 2-(2-thienyl)ethanoyl isothiocyanate was prepared using the resultant 2-(2-thienyl)ethanoyl chloride as a starting compound according to the description of the literature. 4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]aniline (50 mg) was dissolved in toluene (5 ml) and ethanol (1 ml) to prepare a solution. A solution of 2-(2-thienyl)ethanoyl isothiocyanate in ethanol (1 ml) was then added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (46 mg, yield 57%).
Reaction SMILES: F[C:2]1[C:3]([CH3:22])=[N:4][C:5]2[C:10]([N:11]=1)=[C:9]([C:12]1[NH:20][C:19]3[CH2:18][CH2:17][NH:16][C:15](=[O:21])[C:14]=3[CH:13]=1)[CH:8]=[CH:7][CH:6]=2.[CH2:23]([NH2:27])[CH2:24][CH2:25][CH3:26].CO.C(Cl)Cl>CS(C)=O>[CH2:23]([NH:27][C:2]1[C:3]([CH3:22])=[N:4][C:5]2[C:10]([N:11]=1)=[C:9]([C:12]1[NH:20][C:19]3[CH2:18][CH2:17][NH:16][C:15](=[O:21])[C:14]=3[CH:13]=1)[CH:8]=[CH:7][CH:6]=2)[CH2:24][CH2:25][CH3:26]
Reactant: CCCCN
Reactant: Cc1nc2cccc(-c3cc4c([nH]3)CCNC4=O)c2nc1F
Solvent: CS(C)=O
Solvent: CO
Solvent: ClCCl
Product: CCCCNc1nc2c(-c3cc4c([nH]3)CCNC4=O)cccc2nc1C
Temperature: 75 °C
Yield: 12.9 %

Procedure:
Prepared similar to that described in Example 131 using 2-(3-fluoro-2-methylquinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (Example 126; 41.5 mg, 0.140 mmol) and butan-1-amine (0.042 mL, 0.420 mmol) in DMSO (1.0 mL), heating at 75° C. for 45 min. Chromatographic purification (silica gel, 0-100% EtOAc/hexanes, then 0-10% MeOH/DCM) furnished 2-(3-(butylamino)-2-methylquinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (6.28 mg, 0.018 mmol, 13% yield) as a yellow solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 12.15 (1H, br. s.), 7.88 (1H, d, J=7.4 Hz), 7.56 (1H, d, J=8.0 Hz), 7.27-7.36 (2H, m), 7.13 (1H, d, J=1.6 Hz), 6.94 (1H, br. s.), 3.52 (2H, q, J=6.7 Hz), 3.44 (2H, td, J=6.7, 2.0 Hz), 2.87 (2H, t, J=6.7 Hz), 2.53 (3H, s), 1.72 (2H, quin, J=7.4 Hz), 1.47 (2H, sxt, J=7.3 Hz), 0.94 (3H, t, J=7.3 Hz). m/z (ESI, +ve) 350.1 (M+H)+.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([CH2:15][OH:16])[CH:14]=1)[C:11](=[O:17])[N:10]([C:18]1[CH:23]=[CH:22][CH:21]=[C:20](Cl)[C:19]=1[CH2:25][OH:26])[N:9]=[CH:8]2)([CH3:4])([CH3:3])[CH3:2].[CH3:27][N:28]1[CH:32]=[C:31](B2OC(C)(C)C(C)(C)O2)[CH:30]=[C:29]1[C:42]([NH2:44])=[O:43].B1(B2OC(C)(C)C(C)(C)O2)OC(C)(C)C(C)(C)O1.B([O-])([O-])[O-].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O.O1CCOCC1>[C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([CH2:15][OH:16])[CH:14]=1)[C:11](=[O:17])[N:10]([C:18]1[C:19]([CH2:25][OH:26])=[C:20]([C:31]3[CH:30]=[C:29]([C:42]([NH2:44])=[O:43])[N:28]([CH3:27])[CH:32]=3)[CH:21]=[CH:22][CH:23]=1)[N:9]=[CH:8]2)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1cc(CO)c2c(=O)n(-c3cccc(Cl)c3CO)ncc2c1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cc1C(N)=O
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Solvent: O
Solvent: C1COCCO1
Product: Cn1cc(-c2cccc(-n3ncc4cc(C(C)(C)C)cc(CO)c4c3=O)c2CO)cc1C(N)=O
Temperature: 125 °C
Reaction time: 0.5 h
Yield: 15.8 %

Procedure:
To a 15 mL tube were added 6-tert-butyl-2-[3-chloro-2-(hydroxymethyl)phenyl]-8-(hydroxymethyl)phthalazin-1(2H)-one (39 mg, 0.105 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrole-2-carboxamide (26.2 mg, 0.105 mmol, prepared from Intermediate-3 and bis(pinacolato)diboron under the same condition of borate formation described in the preparation of Intermediate-4), X-Phos (4.99 mg, 0.0105 mmol) and tris-potassium phosphate (55.5 mg, 0.262 mmol). Dioxane (5 mL) and water (0.5 mL) were added followed by the addition of Pd2(dba)3 (4.79 mg, 0.00523 mmol). The mixture was purged with argon and then heated to 125° C. with stirring for 30 minutes. Additional Pd2(dba)3 (6.0 mg, 0.00655 mmol) was added and the mixture was further stirred at 125° C. for 30 minutes. The mixture was extracted with dichloromethane and water. The organic layer was washed with brine and dried over sodium sulfate. Solvents were evaporated and the residue was purified by flash column chromatography (12 g silica gel, 0% to 10% methanol in dichloromethane). The desired fraction was further purified by preparative TLC (silica gel, dichloromethane/methanol/ammonium hydroxide 90/10/1) to give 4-[3-(6-tert-butyl-8-hydroxymethyl-1-oxo-1H-phthalazin-2-yl)-2-hydroxymethyl-phenyl]-1-methyl-1H-pyrrole-2-carboxylic acid amide as a light yellow powder (7.6 mg, 15.8% yield). LC/MS clacd for C26H28N4O4 (m/e) 460.21, obsd 459.0 (M−H, ES−). 1H-NMR (300 MHz, CDCl3)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]2[C:7](=[O:10])[CH2:8][O:9][C:5]=2[C:4]=1[C:13]#[C:14][CH2:15][N:16]1[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]1.[NH:29]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:31]([CH:38]=O)=[N:30]1.N1CCCCC1>CO>[NH:29]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:31](/[CH:38]=[C:8]2\[O:9][C:5]3[C:4]([C:13]#[C:14][CH2:15][N:16]4[CH2:17][CH2:18][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:20][CH2:21]4)=[C:3]([O:2][CH3:1])[CH:12]=[CH:11][C:6]=3[C:7]\2=[O:10])=[N:30]1
Reactant: O=Cc1n[nH]c2ccccc12
Reactant: COc1ccc2c(c1C#CCN1CCN(C(=O)OC(C)(C)C)CC1)OCC2=O
Solvent: C1CCNCC1
Solvent: CO
Product: COc1ccc2c(c1C#CCN1CCN(C(=O)OC(C)(C)C)CC1)O/C(=C\c1n[nH]c3ccccc13)C2=O
Temperature: 60 °C
Reaction time: 2 h
Yield: 94.2 %

Procedure:
A solution of tert-butyl 4-[3-(6-methoxy-3-oxo-2,3-dihydrobenzofuran-7-yl)prop-2-ynyl]piperazine-1-carboxylate (0.0500 g, 0.129 mmol) in methanol (3 mL) was added with 1H-indazole-3-carboxaldehyde (0.0198 g, 0.136 mmol) and piperidine (0.0877 g, 0.103 mmol), and the mixture was stirred at 60° C. for 2 hours. The reaction mixture was concentrated, and the resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain tert-butyl (Z)-4-(3-{2-[(1H-indazol-3-yl)methylene]-6-methoxy-3-oxo-2,3-dihydrobenzofuran-7-yl}prop-2-ynyl)piperazine-1-carboxylate (0.0625 g, 94%).
Reaction SMILES: Br[C:2]1[C:3]([CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:4][CH:5]=[CH:6][CH:7]=1.C([O-])([O-])=O.[K+].[K+].F[B-](F)(F)F.C1([PH+](C2CCCCC2)C2CCCCC2)CCCCC1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CN(C)C(=O)C>[CH:7]1[C:2]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[CH2:9][CH2:8][C:3]=2[N:4]=[CH:5][CH:6]=1
Reactant: Brc1cccnc1CCc1ccccc1
Agent: [Pd+2]
Agent: C1CCC([PH+](C2CCCCC2)C2CCCCC2)CC1
Agent: CC(=O)[O-]
Solvent: CC(=O)N(C)C
Product: c1ccc2c(c1)CCc1ncccc1-2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
N,N-Dimethylacetamide (15 mL) is added to a flask charged with a stir bar, 3-bromo-2-phenethyl-pyridine (3.34 g), freshly dried K2CO3 (3.52 g), palladium(II) acetate (0.14 g), and tricyclohexylphosphonium tetrafluoroborate (0.47 g) and kept under argon atmosphere at room temperature. The flask is put into a 150° C. hot oil bath and the mixture is stirred therein for 2 h. After cooling the mixture to room temperature, the solvent is evaporated and the residue is chromatographed twice on silica gel (1. dichloromethane/methanol 98:2; 2. cyclohexane/ethyl acetate 90:10→50:50) to afford the title compound as an oil. Yield: 1.51 g (65% of theory); LC (method 1): tR=1.83 min; Mass spectrum (ESI+): m/z=182 [M+H]+.
Reaction SMILES: [CH2:1]([O:3]C=O)C.CC[O-].[Na+].[CH3:10][C:11]([CH3:24])([C:13](=[O:23])[CH2:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=1)[CH3:12].Cl>C(O)C>[OH:3][CH:1]=[C:14]([O:15][C:16]1[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=1)[C:13](=[O:23])[C:11]([CH3:24])([CH3:10])[CH3:12]
Reactant: CCOC=O
Reactant: CC(C)(C)C(=O)COc1ccc(F)cc1
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CC(C)(C)C(=O)C(=CO)Oc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 96 h
Yield: 35.7 %

Procedure:
163 g (2.2 mol) of formic acid ethyl ester were added dropwise to a solution of 136 g of sodium ethylate in 1,500 ml of ethanol at 0° C. 420 g (2 mol) of 2,2-dimethyl-4-(4-fluorophenoxy)-butan-3-one were then slowly stirred in at 0° C. After a reaction time of 24 hours at 0° C., the mixture was allowed to warm to room temperature and was subsequently stirred at this temperature for a further 96 hours. The reaction mixture was poured onto 5,000 ml of ice-water and the organic phase was separated off by extracting with chloroform. Unreacted starting material could be isolated from this chloroform solution and re-used. The aqueous phase was acidified with 10% strength hydrochloric acid, while cooling, and the oil which separated out was taken up in chloroform. The chloroform phase was dried over sodium sulphate and concentrated by distilling off the solvent in vacuo. The oil which remained was distilled in vacuo. 170 g (83% of theory, relative to unreacted product) of 1-hydroxy-2-(4-fluorophenoxy)-4,4-dimethyl-penten-3-one of boiling point 101°-102° C./0.6 mm Hg (nD20 =1.5132) were obtained.
Reaction SMILES: Cl.[CH3:2][NH:3][CH2:4][CH2:5][CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8].C(N(CC)CC)C.CC(O)C.Cl[C:24]1[N:33]=[C:32]([NH:34][CH2:35][C:36]2[CH:41]=[CH:40][C:39]3[O:42][CH2:43][O:44][C:38]=3[CH:37]=2)[C:31]2[C:26](=[CH:27][CH:28]=[C:29]([C:45]#[N:46])[CH:30]=2)[N:25]=1>CN(C)C=O>[CH2:10]([O:9][C:7]([CH2:6][CH2:5][CH2:4][N:3]([C:24]1[N:33]=[C:32]([NH:34][CH2:35][C:36]2[CH:41]=[CH:40][C:39]3[O:42][CH2:43][O:44][C:38]=3[CH:37]=2)[C:31]2[C:26](=[CH:27][CH:28]=[C:29]([C:45]#[N:46])[CH:30]=2)[N:25]=1)[CH3:2])=[O:8])[CH3:11]
Reactant: N#Cc1ccc2nc(Cl)nc(NCc3ccc4c(c3)OCO4)c2c1
Reactant: CCOC(=O)CCCNC
Agent: Cl
Solvent: CC(C)O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)CCCN(C)c1nc(NCc2ccc3c(c2)OCO3)c2cc(C#N)ccc2n1
Temperature: 25 °C
Yield: 77.6 %

Procedure:
858 mg of ethyl N-methyl-4-aminobutyrate hydrochloride, 238 mg of triethylamine, 4 ml of 2-propanol and 2 ml of N,N-dimethylformamide were added to 400 mg of 2-chloro-4-(3,4-methylenedioxybenzyl)amino-6-cyanoquinazoline. The obtained mixture was refluxed for 1 hour, cooled to room temperature and filtered. The filtrate was distilled under a reduced pressure to remove the solvent and the residue was recrystallized (from ethanol/water) to give 410 mg of the title compound.
Reaction SMILES: [C:1]([O:13][CH3:14])(=[O:12])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]([O-:11])=O.CN(C)C=O.C(Cl)(=O)C(Cl)=O.[CH2:26]([Mg]Br)[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32].Cl>C1(C)C=CC=CC=1.[Fe+3].O1CCCC1>[O:11]=[C:9]([CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][C:1]([O:13][CH3:14])=[O:12]
Reactant: CCCCCCC[Mg]Br
Reactant: COC(=O)CCCCCCCC(=O)[O-]
Agent: [Fe+3]
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CCCCCCCC(=O)CCCCCCCC(=O)OC
Temperature: 60 °C
Reaction time: 2 h
Yield: 78 %

Procedure:
Under a nitrogen atmosphere, monomethyl azelate (6.70 g, 33.1 mmol), commercially available from Tokyo Chemical Industry Co., Ltd., was dissolved in toluene (60 mL), N,N-dimethylformamide (DMF, 25.6 μL, 0.331 mmol) was added thereto, and the solution was warmed to 60° C. While maintaining the temperature at 60° C., a solution of oxalyl chloride (2.94 mL, 34.8 mmol) in toluene (7.0 mL) was added dropwise over 10 minutes. After completion of the dropwise addition, the mixture was stirred at 60° C. for 2.0 hours. Toluene and oxalyl chloride were distilled off under reduced pressure, and subsequently tetrahydrofuran (THF, 67 mL) was added to distill off the solvent. Under a nitrogen atmosphere, this crude product was dissolved in THF (50 mL), tris(2,4-pentadionato) iron (III) (Fe(acac)3, 0.585 g, 0.166 mmol) was added thereto, and the solution was cooled to −40° C. Subsequently, a dilution of n-heptyl magnesium bromide (1 M solution in THF, 36.4 mL, 36.4 mmol) with THF (30 mL) was added dropwise over 1 hour. After completion of the dropwise addition, the mixture was stirred at −40° C. for 1.5 hours. To the reaction solution was added 0.5 M aqueous hydrochloric acid solution (40 mL) to stop the reaction, and the solution was extracted with ethyl acetate. The aqueous layer was washed with ethyl acetate, and the organic layers were combined, washed sequentially with water, a saturated sodium bicarbonate aqueous solution, and a saturated brine and dried over anhydrous sodium sulfate. After the organic layer was filtered and the solvent was distilled off, the resulting residue was purified with SP1 (SiO2 cartridge, 10% ethyl acetate/n-hexane, Rf=0.2) to obtain methyl 9-oxo-hexadecanoate (No. 4984860; 7.33 g, 78% yield).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:6][C:5]=1[O:16][CH2:17][C:18]([F:21])([F:20])[F:19])([O-:3])=[O:2].[H-].[Na+].Br[CH2:25][CH2:26][CH2:27][CH2:28]Br.[NH4+].[Cl-]>CN(C=O)C>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:28][CH2:27][CH2:26][CH2:25]2)=[CH:6][C:5]=1[O:16][CH2:17][C:18]([F:19])([F:20])[F:21])([O-:3])=[O:2]
Reactant: BrCCCCBr
Reactant: CCOC(=O)Cc1ccc([N+](=O)[O-])c(OCC(F)(F)F)c1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: CCOC(=O)C1(c2ccc([N+](=O)[O-])c(OCC(F)(F)F)c2)CCCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 94.6 %

Procedure:
Ethyl 2-(4-nitro-3-(2,2,2-trifluoroethoxy)phenyl)acetate (0.5 g, mmol) was dissolved in 10 mL anhydrous DMF and NaH (60% wt. in oil, 0.13 g, mmol) was added at 0° C. The reaction mixture was stirred for 0.5 h at 25° C. and 1,4-dibromobutane (0.24 g, mmol) was added drop wise at 0° C. The reaction mixture was stirred at 0° C. for 1 h and saturated NH4Cl solution (10 mL) was added. The reaction mixture was extracted with EtOAc (3×20 mL) and the combined organic phases were washed with water (3×20 mL) and brine (20 mL), dried over MgSO4, filtered and concentrated under reduced pressure to give ethyl 1-(4-nitro-3-(2,2,2-trifluoroethoxy)phenyl)cyclopentane carboxylate (380 mg) as a colorless oil.