Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]([CH:12]=O)[S:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.FC(F)(F)C(O)=O.[Cl:21][C:22]1[CH:37]=[CH:36][C:25]([C:26]([NH:28][CH2:29][CH:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)=[O:27])=[CH:24][C:23]=1[O:38][CH3:39].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.C[N+](C)(C)C>C(#N)C>[Cl:21][C:22]1[CH:37]=[CH:36][C:25]([C:26]([NH:28][CH2:29][CH:30]2[CH2:31][CH2:32][N:33]([CH2:12][C:9]3[S:10][CH:11]=[C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[CH:8]=3)[CH2:34][CH2:35]2)=[O:27])=[CH:24][C:23]=1[O:38][CH3:39]
Reactant: O=Cc1cc(-c2ccccc2)cs1
Reactant: COc1cc(C(=O)NCC2CCNCC2)ccc1Cl
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C[N+](C)(C)C
Solvent: CC#N
Solvent: CC(=O)O
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(C(=O)NCC2CCN(Cc3cc(-c4ccccc4)cs3)CC2)ccc1Cl
Reaction time: 18 h
Yield: 76.7 %

Procedure:
A mixture of 4-phenylthiophene-2-carbaldehyde (0.074 g) and the compound prepared in Example 11 (0.075 g) and acetic acid (0.023 mL) in acetonitrile (1 mL) was stirred at room temperature for 30 minutes. Tetramethylammonium triacetoxyborohydride (0.156 g) was added and the reaction was stirred for 18 hours. The mixture was partitioned between a saturated aqueous sodium bicarbonate solution and ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and concentrated. The residue was purified by column chromatography on silica gel (ethyl acetate:hexane=9:1) to obtain the title compound (0.066 g) having the following physical data.
Reaction SMILES: [F:1][C:2]1[C:3]([N:9]=[CH:10][N:11]([CH3:13])[CH3:12])=[N:4][C:5]([OH:8])=[N:6][CH:7]=1.[CH3:14][C:15]1[CH:23]=[CH:22][CH:21]=[C:20]([CH3:24])[C:16]=1[C:17](Cl)=[O:18]>N1C=CC=CC=1>[CH3:14][C:15]1[CH:23]=[CH:22][CH:21]=[C:20]([CH3:24])[C:16]=1[C:17]([N:6]1[CH:7]=[C:2]([F:1])[C:3]([N:9]=[CH:10][N:11]([CH3:13])[CH3:12])=[N:4][C:5]1=[O:8])=[O:18]
Reactant: Cc1cccc(C)c1C(=O)Cl
Reactant: CN(C)C=Nc1nc(O)ncc1F
Solvent: c1ccncc1
Product: Cc1cccc(C)c1C(=O)n1cc(F)c(N=CN(C)C)nc1=O
Temperature: 40 °C
Yield: 36.9 %

Procedure:
To an 8 mL screw-cap vial were added pyridine (2 mL), N′-(5-fluoro-2-hydroxy-pyrimidin-4-yl)-N,N-dimethylformamidine (100 mg, 0.54 mmol), and 2,6-dimethylbenzoyl chloride (102 mg, 0.60 mmol). The mixture was heated to 40° C. for 2 h, evaporated to dryness, and partitioned between ethyl acetate (EtOAc) and water (H2O). The organic phase was dried over magnesium sulfate (MgSO4), filtered, evaporated, and the residue was purified by reverse phase chromatography to yield the title compound as a white solid (63 mg, 37%): mp 120-150° C.; 1H NMR (300 MHz, CDCl3) δ 8.81 (s, 1H), 8.22 (d, J=6.04 Hz, 1H), 7.23-7.17 (m, 1H), 7.07-7.01 (m, 2H), 3.27 (s, 3H), 3.24 (s, 3H), 2.24 (s, 6H); ESIMS m/z 317 ([M+H]+).
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][CH2:10][C@@H:11]2[O:15][C:14](=[O:16])[N:13]([C:17]3[CH:22]=[CH:21][C:20]([N:23]4[CH2:28][CH2:27][O:26][CH2:25][C:24]4=[O:29])=[CH:19][CH:18]=3)[CH2:12]2)=[O:8])=[CH:4][CH:3]=1.CN(C=O)C.[H-].[Na+].[Cl:37][CH2:38][CH2:39][CH2:40][C:41](Cl)=[O:42]>O.C(OCC)(=O)C>[Cl:1][C:2]1[S:6][C:5]([C:7]([N:9]([C:41](=[O:42])[CH2:40][CH2:39][CH2:38][Cl:37])[CH2:10][C@@H:11]2[O:15][C:14](=[O:16])[N:13]([C:17]3[CH:18]=[CH:19][C:20]([N:23]4[CH2:28][CH2:27][O:26][CH2:25][C:24]4=[O:29])=[CH:21][CH:22]=3)[CH2:12]2)=[O:8])=[CH:4][CH:3]=1
Reactant: O=C(NC[C@H]1CN(c2ccc(N3CCOCC3=O)cc2)C(=O)O1)c1ccc(Cl)s1
Reactant: O=C(Cl)CCCCl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(CCCCl)N(C[C@H]1CN(c2ccc(N3CCOCC3=O)cc2)C(=O)O1)C(=O)c1ccc(Cl)s1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
1 g (2.3 mmol) of 5-chloro-N-({(5S)-2-oxo-3-[4-(3-oxomorpholin-4-yl)phenyl]-1,3-oxazolidin-5-yl}methyl)thiophene-2-carboxamide [compound (A)] is dissolved in 100 ml of abs. DMF under argon. 110 mg (4.6 mmol) of sodium hydride (98% strength) are added, and the mixture is stirred at RT for 20 min. Then 4.37 g (30.97 mmol) of chlorobutanoyl chloride are added, keeping the reaction temperature at RT. The reaction mixture is stirred at RT for 16 h and is then admixed with 25 ml of water added gradually with cooling. Subsequently, 300 ml of ethyl acetate are added and a further 50 ml of water. The phases are separated and the ethyl acetate phase is concentrated in vacuo. The residue is stirred up with ethyl acetate and filtered. The mother liquor is concentrated and the residue is purified by flash chromatography on silica gel with toluene/ethanol 5:1 as eluent. The appropriate fractions which contain the target compound and also those which contain a bis-acylated compound formed after enolization are combined and the solvent is removed. The residue is admixed with a saturated solution of hydrogen chloride in dichloromethane and stirred at RT overnight. This is followed by concentrating in vacuo and the residue is again purified by flash chromatography on silica gel with toluene/ethanol 6:1 as eluent. The appropriate fractions are concentrated and the residue is lyophilized from dioxane to obtain 94 mg (7.5% of theory) of the target compound.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH2:17][CH:18]3[CH2:23][CH2:22][CH2:21][NH:20][CH2:19]3)[C:9]=2[C:10]=1[CH3:11])=[O:5])[CH3:2].[N:24]1[CH:29]=[CH:28][CH:27]=[C:26]([CH:30]=O)[CH:25]=1.C(O)(=O)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C1COCC1.C(OCC)(=O)C>[CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH2:17][CH:18]3[CH2:23][CH2:22][CH2:21][N:20]([CH2:30][C:26]4[CH:25]=[N:24][CH:29]=[CH:28][CH:27]=4)[CH2:19]3)[C:9]=2[C:10]=1[CH3:11])=[O:5])[CH3:2]
Reactant: O=Cc1cccnc1
Reactant: CCOC(=O)c1oc2cccc(OCC3CCCNC3)c2c1C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CCOC(=O)c1oc2cccc(OCC3CCCN(Cc4cccnc4)C3)c2c1C
Temperature: 25 °C
Reaction time: 4 h

Procedure:
3-Methyl-4-(piperidin-3-ylmethoxy)-benzofuran-2-carboxylic acid ethyl ester (700 mg), pyridine-3-aldehyde (700 μl) and acetic acid (1 ml) were dissolved in THF (20 ml). The solution was stirred at room temperature for four hours. To the solution was added NaB(OAc)3H (1.4 g) and the resulting suspension was stirred overnight at room temperature. The reaction mixture was diluted with ethyl acetate and washed with saturated sodium hydrogencarbonate solution and brine. The organic solvent was dried over anhydrous sodium sulfate and evaporated to dryness. The residue was purified by silica gel column chromatography developed by dichloromethane-methanol to give 3-methyl-4-(1-pyridin-3-ylmethyl-piperidin-3-ylmethoxy)-benzofuran-2-carboxylic acid ethyl ester (777 mg) as a colorless oil. FAB-MS: m/z 409 (MH+); 1H-NMR (CDCl3): δ 1.15-2.30 (7H, m), 1.44 (3H, t, J=7 Hz), 2.58 (3H, s), 2.80 (1H, br d, J=11 Hz), 2.96 (1H, br d, J=8 Hz), 3.48 (1H, d, J=13.5 Hz), 3.57 (1H, d, J=13.5 Hz), 3.89 (1H, dd, J1=9 Hz, J2=8 Hz), 3.96 (1H, dd, J1=9 Hz, J2=5 Hz), 4.43 (2H, q, J=7 Hz), 6.57 (1H, d, J=8 Hz), 7.10 (1H, d, J=8 Hz), 7.21 (1H, dd, J1=8 Hz, J2=5 Hz), 7.28 (1H, t, J=8 Hz), 7.67 (1H, br d, J=8 Hz), 8.49 (1H, dd, J1=5 Hz, J2=1.5 Hz), 8.54 (1H, d, J=1.5 Hz).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH2:3][CH:2]1C(O)=O.[NH2:13][C:14]1[CH:15]=[CH:16][C:17]([CH3:37])=[C:18]([NH:20][C:21](=[O:36])[C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([CH2:28][N:29]3[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]3)[CH:23]=2)[CH:19]=1.CN([CH:41]=[O:42])C>CC(C)=O>[CH3:35][N:32]1[CH2:31][CH2:30][N:29]([CH2:28][C:24]2[CH:23]=[C:22]([CH:27]=[CH:26][CH:25]=2)[C:21]([NH:20][C:18]2[CH:19]=[C:14]([NH:13][C:41]([C:8]3[CH:7]=[CH:6][C:5]4[O:1][CH2:2][CH2:3][C:4]=4[CH:9]=3)=[O:42])[CH:15]=[CH:16][C:17]=2[CH3:37])=[O:36])[CH2:34][CH2:33]1
Reactant: O=C(O)C1Cc2ccccc2O1
Reactant: CN(C)C=O
Reactant: Cc1ccc(N)cc1NC(=O)c1cccc(CN2CCN(C)CC2)c1
Solvent: CC(C)=O
Product: Cc1ccc(NC(=O)c2ccc3c(c2)CCO3)cc1NC(=O)c1cccc(CN2CCN(C)CC2)c1
Temperature: 25 °C
Reaction time: 66 h

Procedure:
2,3-Dihydrobenzofuran-2-carboxylic acid (0.109 g) was added to a stirred mixture of N-(5-amino-2-methylphenyl)-3-(4-methylpiperazin-1-ylmethyl)benzamide (0.15 g), diisopropyethyllamine (0.232 ml), 2-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate(V) (0.253 g) and DMF (10 ml) and the mixture was stirred at ambient temperature for 66 hours. The mixture was partitioned between methylene chloride and water. The organic phase was washed with a saturated aqueous solution of sodium bicarbonate and evaporated. The residue was purified by column chromatography on an ion exchange column (isolute SCX column from International Sorbent Technology Limited, Hengoed, Mid-Glamorgan, UK) using a 99:1 mixture of methanol and a saturated aqueous ammonium hydroxide solution as eluent. The product so obtained was dissolved in acetone and precipitated by the addition of isohexane. There was thus obtained the title compound (0.089 g); NMR Spectrum: (DMSOd6) 2.15 (s, 3H), 2.2 (s, 3H), 2.30-2.45 (m, 8H), 3.25 (t, 2H), 3.55 (s, 2H), 4.6 (t, 2H), 6.85-6.9 (m, 1H), 7.18-7.22 (m, 1H), 7.4-7.66 (m, 3H), 7.75-7.9 (m, 5H), 9.85 (s, 1H), 10.0 (s, 1H); Mass Spectrum: M+H+ 485.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[CH:9]([CH2:11][N+:12]([O-])=O)[O:8][B:7]([OH:15])[C:6]=2[C:5]([O:16][CH2:17][CH2:18][CH2:19][OH:20])=[CH:4][CH:3]=1.[H][H]>N.[Ni]>[ClH:1].[NH2:12][CH2:11][CH:9]1[O:8][B:7]([OH:15])[C:6]2[C:5]([O:16][CH2:17][CH2:18][CH2:19][OH:20])=[CH:4][CH:3]=[C:2]([Cl:1])[C:10]1=2
Reactant: [H][H]
Reactant: O=[N+]([O-])CC1OB(O)c2c(OCCCO)ccc(Cl)c21
Agent: [Ni]
Agent: N
Product: Cl
Product: NCC1OB(O)c2c(OCCCO)ccc(Cl)c21
Yield: 241.2 %

Procedure:
4-Chloro-7-(3-hydroxy-propoxy)-3-nitromethyl-3H-benzo[c][1,2]oxaborol-1-ol (105 mg, 0.35 mmol) in methanolic ammonia solution (2 M, 20 mL) was added Ra/Ni (0.15 g, 2800 Nickel slurry in water) and the reaction vessel was pressurized to 40 psi with hydrogen overnight at room temperature. The resultant mixture was filtered through a pad of Celite® and washed with EtOAc. The filtrate was concentrated in vacuo and the residue was added water (1 mL), followed by conc HCl to pH 1. The heterogeneous mixture was lyophilized provide the title compound (130 mg, quantitative) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 9.14 (br. s., 1H), 8.36 (br. s., 3H), 7.49 (d, J=8.2 Hz, 1H), 6.99 (d, J=8.2 Hz, 1 H), 5.40 (d, J=7.0 Hz, 1H), 4.40 (br. s., 1H), 4.10 (br. s., 2H), 3.59 (br. s., 2H), ˜3.30 (hidden, 1H), 2.89 (br. s., 1H), 1.89 (br. s, 2H); MS (ESI) m/z=272 (M+1, positive); HPLC purity: 96.92% (MaxPlot 200-400 nm), 97.96% (220 nm).
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([NH:8][C:9]2[CH:18]=[C:17]3[C:12]([CH:13]=[CH:14][CH:15]=[N:16]3)=[CH:11][CH:10]=2)=[CH:4][C:3]=1[C:19]1[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=1.[CH3:29][O:30][C:31]1[CH:36]=[CH:35][C:34](B(O)O)=[CH:33][CH:32]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.CCOC(C)=O>[CH3:29][O:30][C:31]1[CH:36]=[CH:35][C:34]([C:2]2[N:7]=[N:6][C:5]([NH:8][C:9]3[CH:18]=[C:17]4[C:12]([CH:13]=[CH:14][CH:15]=[N:16]4)=[CH:11][CH:10]=3)=[CH:4][C:3]=2[C:19]2[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=2)=[CH:33][CH:32]=1
Reactant: FC(F)(F)c1ccc(-c2cc(Nc3ccc4cccnc4c3)nnc2Cl)cc1
Reactant: COc1ccc(B(O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: COc1ccc(-c2nnc(Nc3ccc4cccnc4c3)cc2-c2ccc(C(F)(F)F)cc2)cc1
Temperature: 100 °C
Reaction time: 4 h

Procedure:
To a solution of [6-chloro-5-(4-trifluoromethylphenyl)pyridazin-3-yl]-[quinolin-7-yl]amine, Example 88, (100 mg, 0.3 mmol) in dioxane (2 mL) was added 4-methoxyphenylboronic acid (46 mg, 0.3 mmol, Aldrich), followed by the addition of 2M aq Na2CO3 (0.2 mL, 0.4 mmol) and Pd[PPh3]4 (35 mg, 0.03 mmol, Aldrich). The mixture was flushed with N2 and heated under at 100° C. under N2 atmosphere for 24 h. The reaction mixture was cooled to room temperature, additional amounts of 2M aq Na2CO3 (0.2 mL, 0.4 mmol), 4-methoxyphenyl-boronic acid (46 mg, 0.3 mmol) and Pd[PPh3]4 (35 mg, 0.03 mmol) were added and the mixture was heated at 100° C. with stirring under N2 atmosphere for 4 h. The reaction mixture was cooled to room temperature, diluted with EtOAc (50 mL) and washed with 5% Na2CO3. The organic layer was dried over Na2SO4, filtered and the solvent evaporated in vacuo. The residue was purified by column chromatography, eluting with MeOH:CH2Cl2 (1:19), to give the title compound as a tan crystalline solid. MS (ESI, pos. ion) m/z: 473 (M+1). MP: 215-217° C.
Reaction SMILES: [CH:1]([C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=1)=O.C[Si](C)(C)CCOCN1C=CN=C1C=O.[NH2:28][CH2:29][CH2:30][CH2:31][CH2:32][NH:33][C:34](=[O:40])[O:35][C:36]([CH3:39])([CH3:38])[CH3:37]>>[C:36]([O:35][C:34]([NH:33][CH2:32][CH2:31][CH2:30][CH2:29][NH:28][CH2:1][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=1)=[O:40])([CH3:39])([CH3:38])[CH3:37]
Reactant: CC(C)(C)OC(=O)NCCCCN
Reactant: COC(=O)c1ccc(C=O)cc1
Agent: C[Si](C)(C)CCOCn1ccnc1C=O
Product: COC(=O)c1ccc(CNCCCCNC(=O)OC(C)(C)C)cc1

Procedure:
The same procedure as a series of reactions of Example 1 was carried out, except that methyl 4-formylbenzoate was used in place of 1-({[2-(trimethylsilyl)ethyloxy]methyl}-1H-imidazole-2-carboaldehyde and 1,1-dimethylethyl (4-aminobutyl)carbamate was used in place of {[4-(methyloxy)phenyl]methyl}amine, to obtain the title compound having the following physical properties.
Reaction SMILES: O.[F:2][C:3]1[C:22]([N:23]2[C:28](=[O:29])[CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[N:25]([CH3:34])[C:24]2=[O:35])=[CH:21][C:6]([O:7][C:8]2[C:9]([O:14][CH:15]([C:17]([O:19][CH3:20])=[O:18])[CH3:16])=[N:10][CH:11]=[CH:12][CH:13]=2)=[C:5]([N+:36]([O-])=O)[CH:4]=1>C(O)(=O)C.[Fe]>[NH2:36][C:5]1[CH:4]=[C:3]([F:2])[C:22]([N:23]2[C:28](=[O:29])[CH:27]=[C:26]([C:30]([F:31])([F:33])[F:32])[N:25]([CH3:34])[C:24]2=[O:35])=[CH:21][C:6]=1[O:7][C:8]1[C:9]([O:14][CH:15]([C:17]([O:19][CH3:20])=[O:18])[CH3:16])=[N:10][CH:11]=[CH:12][CH:13]=1
Reactant: COC(=O)C(C)Oc1ncccc1Oc1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c(F)cc1[N+](=O)[O-]
Agent: [Fe]
Solvent: O
Solvent: CC(=O)O
Product: COC(=O)C(C)Oc1ncccc1Oc1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c(F)cc1N
Reaction time: 1 h

Procedure:
To a mixture of 0.21 g of iron powder, 3 ml of acetic acid, and 0.3 ml of water was added dropwise a solution of 3-{4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrim idin-1-yl]-2-nitrophenoxy}-2-{1-(methoxycarbonyl)ethoxy}pyridine in 1.2 ml of acetic acid, while the temperature of the reaction mixture was kept at 35° C. or lower. After completion of the dropwise addition, the mixture was stirred for 1 hour and then filtered through Celite. The filtrate was diluted with ethyl acetate. The mixture was neutralized with saturated aqueous sodium bicarbonate solution. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated. The residue was subjected to silica gel chromatography to give 0.16 g of 3-{2-amino-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}-2-{1-(methoxycarbonyl)ethoxy}pyridine as a mixture of diastereoisomers.
Reaction SMILES: Cl.[S:2]1[C:6]([NH2:7])=[CH:5][C:4]2[CH:8]=[CH:9][CH:10]=[CH:11][C:3]1=2.[C:12]([C:14]1[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=1)#[N:13]>N1C=CC=CC=1.C(Cl)Cl>[S:2]1[C:6]([NH:7][S:20]([C:17]2[CH:16]=[CH:15][C:14]([C:12]#[N:13])=[CH:19][CH:18]=2)(=[O:22])=[O:21])=[CH:5][C:4]2[CH:8]=[CH:9][CH:10]=[CH:11][C:3]1=2
Reactant: N#Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Nc1cc2ccccc2s1
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: N#Cc1ccc(S(=O)(=O)Nc2cc3ccccc3s2)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 77.6 %

Procedure:
To a stirred solution of compound 1-C (0.927 g, 5.0 mmol) in pyridine (10 mL) and methylene chloride (5 mL), cooled on an ice bath, was added 4-cyanobenzene-1-sulfonyl chloride (1.01 g, 5.0 mmol) portion-wise over 3 min. The reaction was allowed to warm slowly to ambient temperature and allowed to stir for 72 h. The reaction mixture was concentrated under reduced pressure, the crude residue was partitioned between EtOAc (100 mL) and 1N HCl (25 mL), the layers separated, the organic phase washed with brine (25 mL), dried over MgSO4, filtered and evaporated in vacuo. The crude residue was purified by flash column chromatography (SiO2) eluting with an EtOAc-heptane gradient to afford 1.22 g of compound 389-A as a tan-brown powder. 1H-NMR (DMSO-d6): δ 6.91 (s, 1H), 7.33-7.21 (m, 2H), 7.69-7.64 (m, 1H), 7.82-7.76 (m, 1H), 7.99-7.93 (m, 2H), 8.11-8.05 (m, 2H), 11.49 (br s, 1H); MS: m/z 313.1 (M-H)−.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[C:18]([C:23]([F:26])([F:25])[F:24])[CH:17]=1.C(N(CC)CC)C.ClC(Cl)(O[C:38](=[O:44])OC(Cl)(Cl)Cl)Cl.[CH3:46][C:47]1[N:48]=[C:49]([CH:52]([NH2:54])[CH3:53])[S:50][CH:51]=1>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:38]([NH:54][CH:52]([C:49]2[S:50][CH:51]=[C:47]([CH3:46])[N:48]=2)[CH3:53])=[O:44])=[C:18]([C:23]([F:25])([F:26])[F:24])[CH:17]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: Cc1csc(C(C)N)n1
Reactant: COc1cc2nccc(Oc3ccc(N)c(C(F)(F)F)c3)c2cc1OC
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COc1cc2nccc(Oc3ccc(NC(=O)NC(C)c4nc(C)cs4)c(C(F)(F)F)c3)c2cc1OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 79.8 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2-(trifluoromethyl)aniline (30 mg) was dissolved in chloroform (1 ml) and triethylamine (0.1 ml) to prepare a solution. A solution of triphosgene (35 mg) in chloroform (0.2 ml) was then added to the solution, and the mixture was stirred at room temperature for one hr. Next, a solution of 1-(4-methyl-1,3-thiazol-2-yl)-1-ethylamine (35 mg) in chloroform (0.2 ml) was added thereto, and the mixture was stirred at room temperature for 10 hr. The stirred mixture was purified by chromatography on silica gel using chloroform/methanol for development to give the title compound (35 mg, yield 80%).
Reaction SMILES: COC1C=CC(C[N:8](CC2C=CC(OC)=CC=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)=CC=1.N1C=CC=CC=1.[C:47](Cl)(Cl)=[S:48].[CH2:51]([N:53]1[CH2:58][CH2:57][N:56]([C:59]([C:61]2[CH:66]=[CH:65][C:64]([CH3:67])=[C:63]([NH2:68])[CH:62]=2)=[O:60])[CH2:55][CH2:54]1)[CH3:52]>ClCCl>[CH2:51]([N:53]1[CH2:54][CH2:55][N:56]([C:59]([C:61]2[CH:66]=[CH:65][C:64]([CH3:67])=[C:63]([NH:68][C:47]([N:27]3[C:17]4[N:18]=[C:19]([N:21]5[CH2:22][CH2:23][O:24][CH2:25][CH2:26]5)[N:20]=[C:15]([C:12]5[CH:13]=[N:14][C:9]([NH2:8])=[N:10][CH:11]=5)[C:16]=4[CH2:29][CH2:28]3)=[S:48])[CH:62]=2)=[O:60])[CH2:57][CH2:58]1)[CH3:52]
Reactant: S=C(Cl)Cl
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4)cn2)cc1
Reactant: CCN1CCN(C(=O)c2ccc(C)c(N)c2)CC1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCN1CCN(C(=O)c2ccc(C)c(NC(=S)N3CCc4c(-c5cnc(N)nc5)nc(N5CCOCC5)nc43)c2)CC1
Temperature: 80 °C
Reaction time: 4 h
Yield: 38.6 %

Procedure:
A dichloromethane solution (3 ml) of bis-(4-methoxy-benzyl)-[5-(2-morpholin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl)-pyrimidin-2-yl]-amine (100 mg, 0.185 mmol), pyridine (30 μl, 0.37 mmol) and thiophosgene (28 μl, 0.37 mmol) was stirred for 40 minutes. This was concentrated and dried under reduced pressure, and subsequently (4-ethyl-piperazin-1-yl)-(3-amino-4-methyl-phenyl)-methanone (90 mg, 0.390 mmol) obtained in Step B was added, followed by stirring in dichloromethane (3 ml) for 16 hours. The reaction mixture was washed with aqueous ammonium chloride solution, and subsequently dried over sodium sulfate. The drying agent was removed, followed by concentration and drying. To this, TFA (2 ml) was added, followed by stirring at 80° C. for 4 hours. After TFA was removed under reduced pressure, dichloromethane was added, followed by washing with sodium hydrogencarbonate aqueous solution. The organic layer was dried over sodium sulfate, filtered and concentrated, to obtain a crude product. Purification by silica gel column chromatography (dichloromethane/methanol=10/1) afforded 4-(2-amino-pyrimidin-5-yl)-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidine-7-carbothioic acid [5-(4-ethyl-piperazine-1-carbonyl)-2-methyl-phenyl]-amide (42 mg, 39%) as a pale yellow powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH2:20][CH2:19][C@@:18]2([CH3:21])[C:5](=[CH:6][CH2:7][C@@H:8]3[C@@H:17]2[CH2:16][CH2:15][C@@:13]2([CH3:14])[C@H:9]3[CH2:10][CH2:11][C:12]2=[C:22]([N+:33]#[C-:34])[S:23]([C:26]2[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=2)(=[O:25])=[O:24])[CH:4]=1.[CH2:35](I)[CH3:36]>>[CH3:1][O:2][C:3]1[CH2:20][CH2:19][C@@:18]2([CH3:21])[C:5](=[CH:6][CH2:7][C@@H:8]3[C@@H:17]2[CH2:16][CH2:15][C@@:13]2([CH3:14])[C@H:9]3[CH2:10][CH:11]=[C:12]2[C:22]([N+:33]#[C-:34])([S:23]([C:26]2[CH:27]=[CH:28][C:29]([CH3:32])=[CH:30][CH:31]=2)(=[O:25])=[O:24])[CH2:35][CH3:36])[CH:4]=1
Reactant: [C-]#[N+]C(=C1CC[C@H]2[C@@H]3CC=C4C=C(OC)CC[C@]4(C)[C@H]3CC[C@]12C)S(=O)(=O)c1ccc(C)cc1
Reactant: CCI
Product: [C-]#[N+]C(CC)(C1=CC[C@H]2[C@@H]3CC=C4C=C(OC)CC[C@]4(C)[C@H]3CC[C@]12C)S(=O)(=O)c1ccc(C)cc1

Procedure:
The title compound was prepared according to the method described in Example 8a starting from 3-methoxy-17-(isocyano-p-methylphenylsulfonylmethylene)-androsta-3,5-diene (954 mg, 2 mmol) and ethyl iodide (4.9 mmol). Yield: 900 mg (89%), m.p. 135°-150° C.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([N:5]2[CH:9]=[C:8]([C:10]3[CH:11]=[C:12]4[C:18]([CH:19]([C:21]5[C:26]([Cl:27])=[CH:25][CH:24]=[C:23]([F:28])[C:22]=5[Cl:29])[CH3:20])=[CH:17][NH:16][C:13]4=[N:14][CH:15]=3)[CH:7]=[N:6]2)[CH2:2]1.C(O)=O.[CH3:33][N:34]([C:36]([O:40]N1N=NC2C=CC=CC1=2)=[N+](C)C)[CH3:35].[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:33][N:34]([CH3:35])[C:36]([N:1]1[CH2:2][CH:3]([N:5]2[CH:9]=[C:8]([C:10]3[CH:11]=[C:12]4[C:18]([CH:19]([C:21]5[C:26]([Cl:27])=[CH:25][CH:24]=[C:23]([F:28])[C:22]=5[Cl:29])[CH3:20])=[CH:17][NH:16][C:13]4=[N:14][CH:15]=3)[CH:7]=[N:6]2)[CH2:4]1)=[O:40]
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: CC(c1c(Cl)ccc(F)c1Cl)c1c[nH]c2ncc(-c3cnn(C4CNC4)c3)cc12
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O=CO
Product: CC(c1c(Cl)ccc(F)c1Cl)c1c[nH]c2ncc(-c3cnn(C4CN(C(=O)N(C)C)C4)c3)cc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 5-(1-azetidin-3-yl-1H-pyrazol-4-yl)-3-[1-(2,6-dichloro-3-fluorophenyl)ethyl]-1H-pyrrolo[2,3-b]pyridine (6.0 mg, 0.014 mmol), formic acid (1.4 μL, 0.037 mmol), TBTU (8.95 mg, 0.0279 mmol), DIPEA (0.02 mL, 0.09 mmol) and DMF (1 mL) was stirred at rt for 30 min. The solution was used directly for HPLC purification. The fractions containing the material were concentrated in vacuo, redissolved in THF and treated with 5M NaOH (0.1 mL) at rt for 10 min. The solution was neutralized with HCl, and loaded into an SCX cartridge. MeOH was used to wash, and the material was ejected with 2M NH3 in MeOH to afford the title compound as a white solid. 1H NMR (400 MHz, CD3OD): δ=1.89 (d, J=7.1 Hz, 3 H), 2.92 (s, 6 H), 4.33-4.40 (m, 2 H), 4.42-4.50 (m, 2 H), 5.16-5.25 (m, 1 H), 5.25-5.35 (m, 1 H), 7.15-7.22 (m, 1 H), 7.37 (d, J=1.5 Hz, 1 H), 7.38-7.53 (m, 2 H), 7.68 (s, 1 H), 7.94 (s, 1 H), 8.33 (s, 1H). MS (ES+): m/z 501.06 (100) [MH+]. HPLC: tR=3.35 min (ZQ3, polar—5 min).