Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([Cl:12])[C:3]=1[C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[N:19]=[C:18]([NH:23][C@@H:24]1[CH2:28][NH:27][CH2:26][C@@H:25]1[NH:29][C:30](=[O:33])[CH:31]=[CH2:32])[N:17]=[CH:16]2.[CH2:34]([N:36]=[C:37]=[O:38])[CH3:35]>ClCCl>[C:30]([NH:29][C@@H:25]1[C@H:24]([NH:23][C:18]2[N:17]=[CH:16][C:15]3[C:20](=[CH:21][CH:22]=[C:13]([C:3]4[C:2]([Cl:1])=[C:7]([O:8][CH3:9])[CH:6]=[C:5]([O:10][CH3:11])[C:4]=4[Cl:12])[CH:14]=3)[N:19]=2)[CH2:28][N:27]([C:37]([NH:36][CH2:34][CH3:35])=[O:38])[CH2:26]1)(=[O:33])[CH:31]=[CH2:32]
Reactant: CCN=C=O
Reactant: C=CC(=O)N[C@H]1CNC[C@H]1Nc1ncc2cc(-c3c(Cl)c(OC)cc(OC)c3Cl)ccc2n1
Solvent: ClCCl
Product: C=CC(=O)N[C@H]1CN(C(=O)NCC)C[C@H]1Nc1ncc2cc(-c3c(Cl)c(OC)cc(OC)c3Cl)ccc2n1
Reaction time: 0.75 h
Yield: 76.3 %

Procedure:
To a solution of N-((3S,4R)-4-((6-(2,6-dichloro-3,5-dimethoxyphenyl)quinazolin-2-yl)amino)pyrrolidin-3-yl)acrylamide (0.040 g, 0.082 mmol) in dichloromethane (1.5 mL) at 0° C. was added TEA (0.014 mL, 0.098 mmol) and ethyl isocyanate (0.008 mL, 0.098 mmol) and the reaction was stirred for 45 mins. LC-MS indicated complete consumption of SM. The reaction mixture was purified by silica gel chromatography to yield (3S,4R)-3-acrylamido-4-((6-(2,6-dichloro-3,5-dimethoxyphenyl)quinazolin-2-yl)amino)-N-ethylpyrrolidine-1-carboxamide (0.035 g, 76%). MS (ES+) C26H28Cl2N6O4 requires: 558, found: 559.
Reaction SMILES: [C:1]([C:9]1[C:10]([OH:21])=[CH:11][CH:12]=[C:13]2[C:18]=1[O:17][C:16](=[O:19])[CH:15]=[C:14]2[CH3:20])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:23][C:24]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:25].C([O-])([O-])=O.[K+].[K+]>CC#N>[C:24]([C:23]1[O:21][C:10]2=[CH:11][CH:12]=[C:13]3[C:18]([O:17][C:16](=[O:19])[CH:15]=[C:14]3[CH3:20])=[C:9]2[C:1]=1[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)(=[O:25])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: Cc1cc(=O)oc2c(C(=O)c3ccccc3)c(O)ccc12
Reactant: O=C(CBr)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cc1cc(=O)oc2c1ccc1oc(C(=O)c3ccccc3)c(-c3ccccc3)c12

Procedure:
The route shown in Scheme 1 exemplifies synthesis of the coumarin compounds of the present invention. Triethylamine is added to a solution of 7-hydroxy-4-methyl-chromen-2-one (i) and a benzoyl chloride (ii) in THF at room temperature. The reaction mixture is stirred at room temperature overnight and filtered. The filtrate is concentrated to afford a 7-benzoyloxy-4-methyl-coumarin (iii). A mixture of compound (iii) and finely powdered aluminum chloride is heated at 170° C. for 2 hours to afford an 8-benzoyl-7-hydroxy-4-methyl-chromen-2-one (iv). A mixture of compound (iv), 2-bromoacetophenone (v), and K2CO3 in CH3CN is refluxed overnight. The reaction mixture is filtered and the filtrate is concentrated. The residue is purified by column chromatography to afford a pure 8-benzoyl-4-methyl-9-phenyl-furo[2,3-h]chromen-2-one (vi).
Reaction SMILES: Br[C:2]1[CH:21]=[CH:20][C:5]2[N:6]=[C:7]([NH:10][C@H:11]3[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[CH2:13][CH2:12]3)[O:8][CH2:9][C:4]=2[CH:3]=1.[CH:22]1(B(O)O)[CH2:24][CH2:23]1.C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C1(C)C=CC=CC=1.[Pd].O>[CH:22]1([C:2]2[CH:21]=[CH:20][C:5]3[N:6]=[C:7]([NH:10][C@H:11]4[C:19]5[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=5)[CH2:13][CH2:12]4)[O:8][CH2:9][C:4]=3[CH:3]=2)[CH2:24][CH2:23]1
Reactant: OB(O)C1CC1
Reactant: Brc1ccc2c(c1)COC(N[C@@H]1CCc3ccccc31)=N2
Agent: [Pd]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: O=P([O-])([O-])[O-]
Solvent: Cc1ccccc1
Solvent: O
Product: c1ccc2c(c1)CC[C@H]2NC1=Nc2ccc(C3CC3)cc2CO1
Yield: 45.3 %

Procedure:
A stirred mixture of (6-bromo-4H-benzo[d][1,3]oxazin-2-yl)-(R)-indan-1-yl-amine (Example 32) (171.6 mg, 0.5 mmol), cyclopropylboronic acid (85.9 mg, 1.0 mmol), tricyclohexylphosphine (28 mg, 0.1 mmol), potassiumphosphate (371.5 mg, 1.75 mmol) and palladium actetate (11.2 mg, 0.05 mmol) in toluene (2 ml) and water (0.1 ml) was heated in a sealed tube at 110° C. for 17 h. The reaction mixture was poured into water (20 ml), extracted with ethyl acetate (2×30 ml). The combined organic layers were washed with water (20 ml) and brine (20 ml), dried (magnesium sulfate) and evaporated. Further purification by flash chromatography (ethyl acetate/heptane) on silica gel and crystallization (dichloromethane/heptane) yielded the title compound as colorless gum (69 mg, 41%). MS (ISP): m/e=305.2 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]1([O:20][CH3:21])[CH:8]2[CH:9]=[CH:10][CH:4]1[CH2:5][N:6]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1)[CH2:7]2>CCOC(C)=O.[OH-].[OH-].[Pd+2]>[CH3:21][O:20][C:3]1([O:2][CH3:1])[CH:4]2[CH2:10][CH2:9][CH:8]1[CH2:7][N:6]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1)[CH2:5]2
Reactant: COc1ccc(CN2CC3C=CC(C2)C3(OC)OC)cc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: COc1ccc(CN2CC3CCC(C2)C3(OC)OC)cc1
Reaction time: 4 h

Procedure:
8,8-Dimethoxy-3-(4-methoxy-benzyl)-3-aza-bicyclo[3.2.1]oct-6-ene (5.92 g, 20.5 mmol) was dissolved in EtOAc (50 mL) in a 250 mL Parr bottle. To this was added catalytic 20% Pd(OH)2/C (Pearlman's catalyst, 500 mg) and the mixture was shaken under 40 psi of H2 for 4 h or until judged complete by TLC. The reaction was filtered through a Celite pad and concentrated to a yellow oil (4.88 g, 82%). (TLC 5% MeOH/CH2Cl2, (NH3) Rf 0.60); 1H NMR (400 MHz, CDCl3) δ 7.21 (d, J=8.3 Hz, 2H), 6.81 (d, J=8.3 Hz, 2H), 3.76 (s, 3H), 3.43 (s, 2H), 3.21 (s, 3H), 3.15 (s, 3H), 2.48 (dd, J=10.3, 3.3 Hz, 2H), 2.36 (d, J=10.3 Hz, 2H), 2.02 (br s, 2H), 1.65 (m, 4H); GCMS m/z 291 (M)+.
Reaction SMILES: Cl.[C:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[NH2:17])=[CH:7][CH:6]=1)(=[O:4])[CH3:3].[CH3:18][N:19]([CH3:22])[C:20]#[N:21]>C1C(O)=CC=CC=1C>[C:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[NH:17][C:20]([N:19]([CH3:22])[CH3:18])=[NH:21])=[CH:7][CH:6]=1)(=[O:4])[CH3:3]
Reactant: CC(=O)c1ccc(-c2ccccc2N)cc1
Reactant: CN(C)C#N
Agent: Cl
Solvent: Cc1cccc(O)c1
Product: CC(=O)c1ccc(-c2ccccc2NC(=N)N(C)C)cc1

Procedure:
Reaction of dry 4'-acetyl-2-aminobiphenyl hydrochloride (2.6 g) with N,N-dimethylcyanamide (2.5 ml) in m-cresol (7 ml) at 80° C. for 5 hours gave N-(4'-acetyl-2-biphenylyl)-N',N'-dimethylguanidine (2.3 g) as a colourless solid (m.p. 174°-175° C.) which was recrystallised from a mixture of acetone and hexane.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[C:13](=[O:17])[CH2:12][CH2:11][CH2:10]2)(=O)=O.[Cl-].[Li+].[Cl-].[F-].[NH4+]>CN(C)C=O.C(OCC)(=O)C>[C:7]1([C:7]2[CH:8]=[C:9]3[C:14](=[CH:15][CH:16]=2)[C:13](=[O:17])[CH2:12][CH2:11][CH2:10]3)[CH2:8][CH2:9][CH2:14][CH2:15][CH:16]=1
Reactant: O=C1CCCc2cc(OS(=O)(=O)C(F)(F)F)ccc21
Agent: [Cl-]
Agent: [F-]
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C1CCCc2cc(C3=CCCCC3)ccc21
Temperature: 120 °C
Reaction time: 4 h
Yield: 113.9 %

Procedure:
3,4-Dihydro-6-trifluoromethylsulfonyloxy-1(2H)-naphthalenone (5.30 g, 18.0 mmol) was dissolved in 50 ml of N,N-dimethylformamide in an argon atmosphere, and 8.69 g (23.4 mmol) of 1-cyclohexenyltributyltin, 2.28 g (54.0 mmol) of lithium chloride and 0.63 g (0.90 mmol) of bistriphenylphosphinepalladium chloride were added to the solution. The mixture was stirred at 120° C. for 4 hours. The reaction product was cooled to room temperature, and ethyl acetate and a 2M-ammonium fluoride aqueous solution were added thereto, followed by stirring the mixture at room temperature overnight. The precipitate was filtered through Celite, and the filtrate was extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride aqueous solution, and dried over anhydrous magnesium sulfate. After the solvent was distilled off under reduced pressure, the residue was purified by silica-gel column chromatography (eluent: a mixture of 2% ethyl acetate and hexane) to obtain 2.32 g of the above-mentioned compound (yield 57%).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH2:4][C:5]2([C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:16]4[CH:17]=[C:18]([CH:22]=[CH:23][CH:24]=4)[C:19]([NH2:21])=O)[CH:14]=3)[O:9][CH:8]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH2:7]2)[N:6]=1.CCN(C(C)C)C(C)C.C(OC(C(F)(F)F)=O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:1][C:2]1[S:3][CH2:4][C:5]2([C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:16]4[CH:17]=[C:18]([CH:22]=[CH:23][CH:24]=4)[C:19]#[N:21])[CH:14]=3)[O:9][CH:8]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH2:7]2)[N:6]=1
Reactant: NC(=O)c1cccc(-c2ccc3c(c2)C2(CSC(N)=N2)CC(c2ccccc2)O3)c1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: N#Cc1cccc(-c2ccc3c(c2)C2(CSC(N)=N2)CC(c2ccccc2)O3)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 8 %

Procedure:
To a solution of 3-(2′-amino-2-phenyl-5′H-spiro[chroman-4,4′-thiazole]-6-yl)benzamide (20 mg, 0.048 mmol) and DIEA (21 mg, 0.096 mmol) in CH2Cl2 was added TFAA (0.2 mL) at 0. The mixture was stirred at room temperature for 1 h and concentrated to give the residue, which was purified by preparative TLC to give 3-(2′-amino-2-phenyl-5′H-spiro[chroman-4,4′-thiazole]-6-yl)benzonitrile (1.53 mg, 8%). 1H-NMR (MeOD): 2.27 (m, 2H), 3.36 (m, 1H), 3.84 (m, 1H), 5.24 (m, 1H), 6.92 (m, 1H), 7.31 (m, 4H), 7.48 (m, 4H), 7.81 (m, 3H).
Reaction SMILES: C([O:4][C:5]1[C@:6]2([CH2:23][CH2:22][C@H:21]3[C@@H:12]([CH2:13][CH2:14][C:15]4[CH:16]=[C:17]([O:24][CH3:25])[CH:18]=[CH:19][C:20]=43)[C@@H:9]2[CH2:10][CH:11]=1)[CH2:7][CH3:8])(=O)C.C(COC(=O)[O-])C=C.C[O-].C([Sn+](CCCC)CCCC)CCC>C(#N)C.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:25][O:24][C:17]1[CH:18]=[CH:19][C:20]2[C@@H:21]3[C@H:12]([C@H:9]4[C@@:6]([CH2:23][CH2:22]3)([CH2:7][CH3:8])[C:5](=[O:4])[CH:11]=[CH:10]4)[CH2:13][CH2:14][C:15]=2[CH:16]=1
Reactant: CC[C@]12CC[C@@H]3c4ccc(OC)cc4CC[C@H]3[C@@H]1CC=C2OC(C)=O
Agent: [Pd+2]
Agent: C=CCCOC(=O)[O-]
Agent: CC(=O)[O-]
Solvent: CC#N
Solvent: O
Product: CC[C@]12CC[C@@H]3c4ccc(OC)cc4CC[C@H]3[C@@H]1C=CC2=O

Procedure:
3.4 g of 17-acetoxy-3-methoxy-18-methyl-1,3,5(10),16-estratetraene is refluxed for 1.5 hours in 50 ml of acetonitrile with 2.3 ml of allylmethylcarbonate, 220 mg of palladium acetate and 580 microliters of tributyltin methoxide. The reaction mix is then diluted with water, extracted with dichloromethane and concentrated under vacuum. After chromatographic purification, 2.1 g of 3-methoxy-18-methyl-1,3,5(10),15-estratetraen-17-one with a melting point of 158°-160° C. is obtained.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[I:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][C:21]([OH:23])=[O:22])=[CH:16][CH:15]=1.I[CH2:25][CH:26]1[CH2:30][CH2:29][CH2:28][CH2:27]1>O1CCCC1.CN1CCCN(C)C1=O>[CH:26]1([CH2:25][CH:20]([C:17]2[CH:16]=[CH:15][C:14]([I:13])=[CH:19][CH:18]=2)[C:21]([OH:23])=[O:22])[CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: O=C(O)Cc1ccc(I)cc1
Reactant: ICC1CCCC1
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: CN1CCCN(C)C1=O
Solvent: C1CCOC1
Product: O=C(O)C(CC1CCCC1)c1ccc(I)cc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 57.8 %

Procedure:
A solution of diisopropylamine (11.2 mL, 80.13 mmol) in tetrahydrofuran (120 mL) cooled to −78° C. was treated with a 2.5M solution of n-butyllithium in hexanes (32 mL, 80.13 mmol). This solution was stirred at −78° C. for 30 min and then treated with a solution of (4-iodo-phenyl)-acetic acid (9.67 g, 36.9 mmol) in tetrahydrofuran (88 mL) and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (29 mL). The reaction mixture was allowed to stir at −78° C. for 1 h. At this time, the reaction was treated with iodomethylcyclopentane (8.53 g, 40.6 mmol). The reaction mixture was allowed to slowly warm to 25° C. where it was stirred at 25° C. for 18 h. At this time, the reaction mixture was quenched with water (5 mL) and then concentrated in vacuo. The residue was diluted with water (800 mL) and then acidified to pH=2 with concentrated hydrochloric acid. This solution was extracted with ethyl acetate (2×800 mL). The combined organic extracts were washed with water (1×600 mL) and a saturated aqueous sodium chloride solution (1×600 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 50/50 hexanes/ethyl acetate) afforded 3-cyclopentyl-2-(4-iodo-phenyl)-propionic acid (7.34 g, 57.8%) as a white solid: mp 105-107° C.; EI-HRMS m/e calcd for C14H17IO2 (M+) 344.0273, found 344.0275.
Reaction SMILES: [CH:1]1(/[C:6](/[N:12]2[CH:16]=[C:15]([C:17]3[C:18]4[CH:25]=[CH:24][N:23]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:33])([CH3:32])[CH3:31])[C:19]=4[N:20]=[CH:21][N:22]=3)[CH:14]=[N:13]2)=[CH:7]\[C:8]([O:10][CH3:11])=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.[H][H]>C(OCC)(=O)C>[CH:1]1([C@@H:6]([N:12]2[CH:16]=[C:15]([C:17]3[C:18]4[CH:25]=[CH:24][N:23]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:32])([CH3:31])[CH3:33])[C:19]=4[N:20]=[CH:21][N:22]=3)[CH:14]=[N:13]2)[CH2:7][C:8]([O:10][CH3:11])=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: [H][H]
Reactant: COC(=O)/C=C(\C1CCCC1)n1cc(-c2ncnc3c2ccn3COCC[Si](C)(C)C)cn1
Solvent: CCOC(C)=O
Product: COC(=O)C[C@@H](C1CCCC1)n1cc(-c2ncnc3c2ccn3COCC[Si](C)(C)C)cn1
Temperature: 25 °C
Reaction time: 19 h

Procedure:
A solution of (E)-methyl 3-cyclopentyl-3-(4-(7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)acrylate (21, 109 mg) in ethyl acetate (EtOAc, 5.0 mL) in a pressure glass tube was treated with the catalyst [Rh(COD)(+)-DuanPhos](BF4) (5.5 mg) under nitrogen before the reaction mixture was pressurized with hydrogen gas to 20 bar pressure. The reaction mixture was stirred at room temperature under this hydrogen pressure for 19 h. When HPLC analysis showed that the substrate was completely consumed, the reaction mixture was cooled down to room temperature. The enantiomeric excess of the reaction mixture was determined to be 97.9% ee (98.95% of the first peak, (S)-22; 1.05% of the second peak, (R)-22) by chiral HPLC analysis. The reaction mixture was then filtered through a thin silica gel pad and the pad was washed with ethyl acetate (EtOAc, 5 mL). The filtrate was then concentrated under reduced pressure to dryness. The resultant foamy solid (98 mg) was analyzed by chiral HPLC analysis and result showed a 97.9% of enantiomeric excess favoring the first peak (98.95% of the first peak, (S)-22; 1.05% of the second peak, (R)-22).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:40]=[CH:39][C:6]([CH2:7][N:8]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=2)[C:9]2[N:14]=[CH:13][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][NH:27][C:17]=4[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=3)=[CH:11][N:10]=2)=[CH:5][CH:4]=1.[H-].[Na+].[CH2:43](I)[CH3:44]>CN(C)C=O.O>[CH2:43]([N:27]1[C:17]2[N:18]=[C:19]([N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)[N:20]=[C:15]([C:12]3[CH:11]=[N:10][C:9]([N:8]([CH2:7][C:6]4[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:40][CH:39]=4)[CH2:30][C:31]4[CH:32]=[CH:33][C:34]([O:37][CH3:38])=[CH:35][CH:36]=4)=[N:14][CH:13]=3)[C:16]=2[CH2:29][CH2:28]1)[CH3:44]
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4)cn2)cc1
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCN1CCc2c(-c3cnc(N(Cc4ccc(OC)cc4)Cc4ccc(OC)cc4)nc3)nc(N3CCOCC3)nc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 86 %

Procedure:
Bis-(4-methoxy-benzyl)-[5-(2-morpholin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl)-pyrimidin-2-yl]-amine (54 mg) was dissolved in dimethylformamide (5 ml), and sodium hydride (60% mineral oil dispersion, 5 mg) was added under ice cooling, followed by stirring at room temperature for 30 minutes. After dropwise addition of ethyl iodide (9 μl), the reaction mixture was further stirred for 10 hours, and subsequently diluted with water (20 ml), followed by extraction with ethyl acetate (10 ml×2). The combined organic layers were washed with brine, and dried with sodium sulfate. After filtering off the drying agent, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate=20/0 to 10/1), to obtain [5-(7-ethyl-2-morpholin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl)-pyrimidin-2-yl]-bis-(4-methoxy-benzyl)-amine as a colorless solid (49 mg, 86%). The above colorless solid was dissolved in trifluoroacetic acid (2 ml), and concentrated sulfuric acid (1 drop) was added, followed by stirring at 100° C. for 1 hour. The solvent was concentrated under reduced pressure, and the resulting residue was diluted with water (2 ml), to filter the resulting precipitate, followed by washing with water. The crude product was purified by amino silica gel column chromatography (dichloromethane), to obtain a colorless powder (18 mg, 64%).
Reaction SMILES: CN1CCCC1=O.[NH2:8][C:9]1[C:14]([F:15])=[C:13]([Br:16])[C:12]([Cl:17])=[C:11](F)[N:10]=1.[CH3:19][C:20]([NH2:27])([CH3:26])[CH2:21][C:22]([CH3:25])([CH3:24])[CH3:23].C1C=CC=CC=1>CCCCCC>[NH2:8][C:9]1[C:14]([F:15])=[C:13]([Br:16])[C:12]([Cl:17])=[C:11]([NH:27][C:20]([CH3:26])([CH3:19])[CH2:21][C:22]([CH3:25])([CH3:24])[CH3:23])[N:10]=1
Reactant: CC(C)(C)CC(C)(C)N
Reactant: Nc1nc(F)c(Cl)c(Br)c1F
Solvent: CCCCCC
Solvent: c1ccccc1
Solvent: CN1CCCC1=O
Product: CC(C)(C)CC(C)(C)Nc1nc(N)c(F)c(Br)c1Cl
Temperature: 140 °C
Reaction time: 82 h
Yield: 46 %

Procedure:
To 6 ml of N-methylpyrrolidone were added 2.4 g of 2-amino-4-bromo-5-chloro-3,6-difluoropyridine and 3.5 g of 1,1,3,3-tetramethylbutylamine, and the mixture was stirred at 140° C. for 82 hours and allowed to cool. 50 ml of the mixed solution of benzene and n-hexane (1:1, v/v) was added, and the solution was washed twice with 400 ml of distilled water. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The brown oily residue was subjected to column chromatography (silica gel, 30 g; eluent: chloroform:n-hexane, 1:1) to obtain 1.6 g of the title compound as a colorless oily residue.
Reaction SMILES: O.[NH2:2][C:3]1[C:8]([N+:9]([O-])=O)=[CH:7][C:6]([C:12]2[N:13]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH:14]=[CH:15][CH:16]=2)=[C:5]([O:24][C:25]2[CH:30]=[CH:29][C:28]([S:31]([CH3:34])(=[O:33])=[O:32])=[CH:27][CH:26]=2)[CH:4]=1>[Pt].[C].CC(O)C>[NH2:2][C:3]1[C:8]([NH2:9])=[CH:7][C:6]([CH:12]2[CH2:16][CH2:15][CH2:14][N:13]2[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[C:5]([O:24][C:25]2[CH:26]=[CH:27][C:28]([S:31]([CH3:34])(=[O:33])=[O:32])=[CH:29][CH:30]=2)[CH:4]=1
Reactant: CC(C)(C)OC(=O)n1cccc1-c1cc([N+](=O)[O-])c(N)cc1Oc1ccc(S(C)(=O)=O)cc1
Agent: [Pt]
Solvent: O
Solvent: CC(C)O
Product: CC(C)(C)OC(=O)N1CCCC1c1cc(N)c(N)cc1Oc1ccc(S(C)(=O)=O)cc1
Temperature: 70 °C
Reaction time: 48 h

Procedure:
20 ml of water and 4 g of 5% platinum-carbon catalyst were added to a 2-propanol (200 ml) solution of 12 g of t-butyl 2-(4-amino-2-(4-methanesulfonyl-phenoxy)-5-nitro-phenyl)-pyrrole-1-carboxylate, and the reaction liquid was stirred under a hydrogen atmosphere of 50 kgf/cm2 at 70° C. for 2 days. The catalyst was removed through filtration through Celite, the solvent was evaporated away under reduced pressure, and the resulting residue was purified through silica gel column chromatography (developing solvent: chloroform/methanol=50/1) to obtain the entitled compound as a dark brown oily substance.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[CH2:6].C(N(CCCC)CCCC)CCC.F[B-](F)(F)F.C(P(C(C)(C)C)C(C)(C)C)(C)(C)C.[C:41]([NH:49][C:50]1[CH:62]=[C:61](Br)[CH:60]=[CH:59][C:51]=1[C:52]([O:54][C:55]([CH3:58])([CH3:57])[CH3:56])=[O:53])(=[O:48])[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(OCC)(=O)C.CN(C)C(=O)C>[C:41]([NH:49][C:50]1[CH:62]=[C:61](/[CH:6]=[CH:5]/[C:4]2[CH:7]=[CH:8][CH:9]=[C:2]([Cl:1])[CH:3]=2)[CH:60]=[CH:59][C:51]=1[C:52]([O:54][C:55]([CH3:57])([CH3:58])[CH3:56])=[O:53])(=[O:48])[C:42]1[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=1
Reactant: C=Cc1cccc(Cl)c1
Reactant: CC(C)(C)OC(=O)c1ccc(Br)cc1NC(=O)c1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Solvent: CCOC(C)=O
Solvent: CCCCN(CCCC)CCCC
Solvent: CC(=O)N(C)C
Product: CC(C)(C)OC(=O)c1ccc(/C=C/c2cccc(Cl)c2)cc1NC(=O)c1ccccc1
Temperature: 110 °C
Reaction time: 0.5 h

Procedure:
0.076 mL of 3-chlorostyrene, 0.19 mL of tributylamine, 2.9 mg of tri-tert-butylphosphine tetrafluoroborate and 4.5 mg of palladium acetate were added to 2.0 mL of N,N-dimethylacetamide solution containing 0.15 g of tert-butyl 2-(benzamido)-4-bromobenzoate at room temperature and stirred under nitrogen atmosphere at 110° C. for 4 hours and 30 minutes. After the reaction mixture was cooled to room temperature, 0.025 mL of 3-chlorostyrene, 2.9 mg of tri-tert-butylphosphine tetrafluoroborate and 4.5 mg of palladium acetate were added at room temperature and stirred under nitrogen atmosphere at 110° C. for 1 hour and 20 minutes. After the reaction mixture was cooled to room temperature, 10% citric acid aqueous solution and ethyl acetate were added. The organic layer was separated and dried over anhydrous magnesium sulfate after washed with 10% citric acid aqueous solution, a saturated sodium thiosulfate aqueous solution and a saturated sodium chloride aqueous solution sequentially, and the solvent was evaporated under reduced pressure. The obtained residue was purified with silica gel column chromatography [PSQ100B (spherical) manufactured by Fuji Silysia Chemical Ltd., eluent; hexane:ethyl acetate=10:1] to obtain 86 mg of tert-butyl 2-(benzamido)-4-((E)-2-(3-chlorophenyl)vinyl)benzoate as white solid.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[C:11]([F:14])([F:13])[F:12])[CH2:7][NH:6][CH2:5]2.[CH3:15][S:16]([C:19]1[CH:20]=[CH:21][C:22]([O:28][C@@H:29]([CH3:34])[C:30]([F:33])([F:32])[F:31])=[C:23]([CH:27]=1)[C:24](O)=[O:25])(=[O:18])=[O:17]>>[I:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[C:11]([F:12])([F:14])[F:13])[CH2:7][N:6]([C:24]([C:23]1[CH:27]=[C:19]([S:16]([CH3:15])(=[O:17])=[O:18])[CH:20]=[CH:21][C:22]=1[O:28][C@@H:29]([CH3:34])[C:30]([F:32])([F:33])[F:31])=[O:25])[CH2:5]2
Reactant: FC(F)(F)c1cc2c(cc1I)CNC2
Reactant: C[C@H](Oc1ccc(S(C)(=O)=O)cc1C(=O)O)C(F)(F)F
Product: C[C@H](Oc1ccc(S(C)(=O)=O)cc1C(=O)N1Cc2cc(I)c(C(F)(F)F)cc2C1)C(F)(F)F

Procedure:
Prepared in analogy to Example 1 from 5-Iodo-6-trifluoromethyl-2,3-dihydro-1H-isoindole and 5-Methanesulfonyl-2-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-benzoic acid (example B3). Yellow foam. MS (m/e): 607.0 (M+, 100%).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:9][C:10]([F:13])([F:12])[F:11])=[C:6]([NH2:8])[CH:7]=1.[Li]N([Si](C)(C)C)[Si](C)(C)C.[CH3:24][N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1>C1COCC1.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].C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2N(C)C)CCCCC1>[CH3:24][N:25]1[CH2:30][CH2:29][N:28]([C:2]2[CH:3]=[CH:4][C:5]([O:9][C:10]([F:13])([F:12])[F:11])=[C:6]([NH2:8])[CH:7]=2)[CH2:27][CH2:26]1
Reactant: CN1CCNCC1
Reactant: Nc1cc(Br)ccc1OC(F)(F)F
Agent: [Pd]
Agent: CN(C)c1ccccc1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1CCOC1
Product: CN1CCN(c2ccc(OC(F)(F)F)c(N)c2)CC1
Temperature: 25 °C
Yield: 63.9 %

Procedure:
Tris(dibenzilideneacetone)dipalladium, Pd2(dba)3 (1.1 g, 1.2 mmol), 2-dicyclohexylphosphino-2′-(N,N-dimethylamino)-biphenyl (0.94 g, 2.4 mmol), 5-bromo-2-trifluoromethoxy-phenylamine (30.7 g, 120 mmol) in THF (50 mL) were charged in a round-bottom flask flushed with argon. The flask was evacuated and backfilled with argon. LiN(TMS)2 solution (1M in THF, 288 mL) and N-methylpiperazine (26.7 mL, 194 mmol) were added and the reaction refluxed for 1 h. The reaction mixture was then allowed to cool to room temperature and filtered through a pad of celite. The organic phase was concentrated, the residue dissolved in DCM (200 ml) and washed with water (1×100 ml). The organic phases were dried over anhydrous Na2SO4, the solvent evaporated in vacuo and the crude solid was purified by flash chromatography on silica gel (eluant: DCM/EtOH 90/10) to afford 21.1 g of 5-(4-methyl-piperazin-1-yl)-2-trifluoromethoxy-phenylamine (64% yield) as a light brown powder.