Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1](C(OC(C)(C)C)=O)([CH2:3][C:4]([NH:6][C@H:7]([C:12]([NH:14][C@H:15]([C:20]([NH2:22])=[O:21])[CH2:16][CH2:17][S:18][CH3:19])=[O:13])[CH2:8][CH:9]([CH3:11])[CH3:10])=[O:5])[CH3:2].Cl>C(O)(=O)C>[NH:1]([CH2:3][C:4]([NH:6][C@H:7]([C:12]([NH:14][C@H:15]([C:20]([NH2:22])=[O:21])[CH2:16][CH2:17][S:18][CH3:19])=[O:13])[CH2:8][CH:9]([CH3:11])[CH3:10])=[O:5])[CH3:2]
Reactant: CSCC[C@H](NC(=O)[C@H](CC(C)C)NC(=O)CN(C)C(=O)OC(C)(C)C)C(N)=O
Agent: Cl
Solvent: CC(=O)O
Product: CNCC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCSC)C(N)=O
Yield: 100 %

Procedure:
Condensation of BocSarOPFP (3.43 g.) and HLeu-MetNH2 (Example 1, 2.98 g.) by the activated ester method gave BocSar-Leu-MetNH2 in 75% yield. De-t-butoxycarbonylation of BocSar-Leu-MetNH2 (3.04 g.) using hydrogen chloride in acetic acid gave HSar-Leu-MetNH2 in 100% yield.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:36]=[CH:37][CH:38]=1)[CH2:6][N:7]([C:29]1[CH:34]=[CH:33][C:32]([OH:35])=[CH:31][CH:30]=1)[CH:8]1[CH2:13][CH2:12][N:11]([CH:14]([CH3:28])[CH2:15][CH2:16][NH:17][C:18](=[O:27])[C:19]2[C:24]([CH3:25])=[CH:23][CH:22]=[CH:21][C:20]=2[CH3:26])[CH2:10][CH2:9]1)#[N:2].CCN(CC)CC.Cl[C:47]([O:49][CH3:50])=[O:48]>C(Cl)Cl>[CH3:50][O:49][C:47](=[O:48])[O:35][C:32]1[CH:33]=[CH:34][C:29]([N:7]([CH2:6][C:5]2[CH:36]=[CH:37][CH:38]=[C:3]([C:1]#[N:2])[CH:4]=2)[CH:8]2[CH2:13][CH2:12][N:11]([CH:14]([CH3:28])[CH2:15][CH2:16][NH:17][C:18](=[O:27])[C:19]3[C:24]([CH3:25])=[CH:23][CH:22]=[CH:21][C:20]=3[CH3:26])[CH2:10][CH2:9]2)=[CH:30][CH:31]=1
Reactant: COC(=O)Cl
Reactant: Cc1cccc(C)c1C(=O)NCCC(C)N1CCC(N(Cc2cccc(C#N)c2)c2ccc(O)cc2)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)Oc1ccc(N(Cc2cccc(C#N)c2)C2CCN(C(C)CCNC(=O)c3c(C)cccc3C)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.9 %

Procedure:
To a solution of COMPOUND 117 (43 mg, 0.083 mmol) in CH2Cl2 (2 mL) were added Et3N (0.04 mL, 0.29 mmol) followed by methyl chloroformate (14 μL, 0.19 mmol) and the mixture was stirred at room temperature overnight to afford COMPOUND 139 as a white solid (41 mg, 86%) following work-up and purification. 1H NMR (CDCl3) δ 0.91-1.14 (m, 2H), 1.00 (d, 3H, J=6.0 Hz), 1.50-1.55 (m, 1H), 1.70-1.74 (m, 3H), 2.15 (t, 1H, J=12.0 Hz), 2.31 (s, 6H), 2.55 (t, 1H, J=10.8 Hz), 2.74-2.91 (m, 3H), 3.24-3.32 (m, 1H), 3.57-3.63 (m, 1H), 3.78 (s, 2H), 3.86 (s, 3H), 3.86-3.90 (m, 1H), 6.51 (d, 2H, J=8.1 Hz), 6.92-7.05 (m, 5H), 7.43-7.53 (m, 4H), 8.37-8.38 (m, 1H). 13C NMR (CDCl3) δ 13.80, 19.54, 29.34, 30.72, 31.34, 40.23, 43.96, 48.84, 52.54, 55.68, 57.14, 60.94, 112.96, 114.36, 119.30, 122.04, 127.69, 128.78, 129.65, 130.33, 130.94, 131.25, 134.49, 139.04, 142.38, 143.01, 146.78, 155.24, 170.23. ES-MS m/z 569 (M+H). Anal. Calcd. for C34H40N4O4.0.5H2O: C, 70.69; H, 7.15; N, 9.70. Found. C, 70.64; H, 7.02; N, 9.65.
Reaction SMILES: [NH2:1][C:2]1[N:11]=[CH:10][C:9]2[C:8]([NH:12][C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([Br:19])[CH:14]=3)=[N:7][CH:6]=[N:5][C:4]=2[CH:3]=1.CCN(CC)CC.[C:27](Cl)(=[O:30])[CH:28]=[CH2:29]>CN(C1C=CN=CC=1)C.O>[Br:19][C:15]1[CH:14]=[C:13]([NH:12][C:8]2[C:9]3[CH:10]=[N:11][C:2]([NH:1][C:27](=[O:30])[CH:28]=[CH2:29])=[CH:3][C:4]=3[N:5]=[CH:6][N:7]=2)[CH:18]=[CH:17][CH:16]=1
Reactant: Nc1cc2ncnc(Nc3cccc(Br)c3)c2cn1
Reactant: C=CC(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: O
Product: C=CC(=O)Nc1cc2ncnc(Nc3cccc(Br)c3)c2cn1
Temperature: 20 °C
Reaction time: 4 h
Yield: 7 %

Procedure:
To a stirred solution of 7-amino-4-[(3-bromophenyl)amino]pyrido[4,3-d]pyrimidine (J Med Chem, 1995;38:3780) (140 mg, 0.46 mmol), DMAP (14 mg) and Et3N (excess, 2.0 mL) at 0° C. under N2 was added acryloyl chloride (4.8 mol eq., 182 μL) dropwise over 4 hours. The reaction was then stirred at 20° C. diluted with water and extracted with EtOAc. The combined organic extracts were washed with brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure before being chromatographed on silica gel eluting with MeOH/CH2Cl2/EtOAc (5:45:50), to give N-[4-[(3-bromophenyl)amino]pyrido[4,3-d]pyrimidin-7-yl]-acrylamide (12 mg, 7%) as a cream powder, mp (CH2Cl2/hexane) 215-220° C. (dec).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][CH:20]=1)[O:5][CH2:6][C:7](=NOC)[CH2:8][P:9](=[O:14])([O:12][CH3:13])[O:10][CH3:11].ClC1C=C(C=CC=1)[O:25]CC(=NNC(N)=O)CP(=O)(OC)OC.C(OCC)(=O)C.CO>C1(C)C=CC=CC=1.C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][CH:20]=1)[O:5][CH2:6][C:7](=[O:25])[CH2:8][P:9](=[O:14])([O:12][CH3:13])[O:10][CH3:11]
Reactant: CON=C(COc1cccc(Cl)c1)CP(=O)(OC)OC
Reactant: COP(=O)(CC(COc1cccc(Cl)c1)=NNC(N)=O)OC
Solvent: CCOC(C)=O
Solvent: CO
Solvent: ClCCl
Product: COP(=O)(CC(=O)COc1cccc(Cl)c1)OC

Procedure:
The process described in Example 1 was repeated, using a solution in toluene of dimethyl 3-(3-chlorophenoxy)-2-methoxyiminopropylphosphonate in place of a solution in toluene of dimethyl 3-(3-chlorophenoxy)-2-semicarbazonopropylphosphonate, to give dimethyl 3-(3-chlorophenoxy)-2-oxopropylphosphonate, RF = 0.29 (ethyl acetate), RF = 0.58 (5% v/v methanol in methylene dichloride).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[CH3:9])[NH2:5].Br[CH2:11][CH2:12][CH2:13][Cl:14].C(N(CC)CC)C.Cl>C(C(C)=O)C.O>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[CH3:9])[NH:5][CH2:11][CH2:12][CH2:13][Cl:14]
Reactant: ClCCCBr
Reactant: Cc1ccc(N)cc1Cl
Agent: Cl
Solvent: CCC(C)=O
Solvent: CCN(CC)CC
Solvent: O
Product: Cc1ccc(NCCCCl)cc1Cl
Temperature: 26.5 °C
Reaction time: 24 h
Yield: 157.1 %

Procedure:
3-Chloro-4-methylaniline (10.0 g, 70.6 mmol), 1-bromo-3-chloropropane (34.7 mL, 55.6 g, 353 mmol) and triethylamine (21.4 g, 212 mmol) were charged. The mixture was stirred at 25-28° C. for 24 hrs. Water (50 mL) and methyl ethyl ketone (25 mL) were added for partitioning. The organic layer was washed twice with water (50 mL). Conc. hydrochloric acid (35 mL, 5.7 eq) was dropwise added to the organic layer under ice-cooling. The mixture was stirred at room temperature for 1 hr. The crystals were collected by filtration, washed with diisopropyl ether (10 mL) and dried in vacuo at 50° C. to give the title compound (14.12 g, yield 78.5%) as pale-yellow crystals.
Reaction SMILES: [Si:1](Cl)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[N:9]1([C:13]([C:15]2[CH:16]=[C:17]([Cl:36])[C:18]([O:21][C:22]3[CH:23]=[C:24]([CH:28]=[C:29]([O:31][C@@H:32]([CH3:35])[CH2:33][OH:34])[CH:30]=3)[C:25]([OH:27])=[O:26])=[N:19][CH:20]=2)=[O:14])[CH2:12][CH2:11][CH2:10]1.N12CCCN=C1CCCCC2>C(#N)C>[N:9]1([C:13]([C:15]2[CH:16]=[C:17]([Cl:36])[C:18]([O:21][C:22]3[CH:23]=[C:24]([CH:28]=[C:29]([O:31][C@@H:32]([CH3:35])[CH2:33][O:34][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])[CH:30]=3)[C:25]([OH:27])=[O:26])=[N:19][CH:20]=2)=[O:14])[CH2:12][CH2:11][CH2:10]1
Reactant: C[C@@H](CO)Oc1cc(Oc2ncc(C(=O)N3CCC3)cc2Cl)cc(C(=O)O)c1
Reactant: CC(C)(C)[Si](C)(C)Cl
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: C[C@@H](CO[Si](C)(C)C(C)(C)C)Oc1cc(Oc2ncc(C(=O)N3CCC3)cc2Cl)cc(C(=O)O)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 60.6 %

Procedure:
tert-Butyldimethylsilyl chloride (2.78 g, 18.4 mmol) was added to a mixture of 3-{[5-(azetidin-1-ylcarbonyl)-3-chloropyridin-2-yl]oxy}-5-{[(1S)-2-hydroxy-1-methylethyl]oxy}benzoic acid (3.74 g, 9.19 mmol) and 1,8-diazabicyclo(5,4,0)undec-7-ene (2.75 mL, 7.36 mmol) in acetonitrile (40 mL) and stirred at RT for 24 hours. The solvent was removed in vacuo and water (80 mL) added to the resultant oil. The mixture was adjusted to pH 10 with 1M sodium bicarbonate solution and washed with ether to remove any impurities. The aqueous layer was adjusted to pH 3 with 1M citric acid and extracted into ethyl acetate (2×100 mL). The combined organics were washed with brine (50 mL), dried (MgSO4), filtered and reduced in vacuo to give the desired compound as a white foam (2.9 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]([O:12][CH3:13])=[C:10]([O:14][CH3:15])[C:9]([O:16][CH3:17])=[C:8]2[C:4]=1[CH2:5][CH:6]([CH2:18][CH2:19][CH2:20][O:21][C:22]1[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][CH:23]=1)[CH2:7]2.Cl.[CH3:32][NH2+:33][CH3:34].O.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>C1COCC1.C(OCC)(=O)C>[CH3:32][N:33]([CH3:34])[C:26](=[O:27])[C:25]1[CH:29]=[CH:30][C:22]([O:21][CH2:20][CH2:19][CH2:18][CH:6]2[CH2:5][C:4]3[C:8](=[C:9]([O:16][CH3:17])[C:10]([O:14][CH3:15])=[C:11]([O:12][CH3:13])[C:3]=3[O:2][CH3:1])[CH2:7]2)=[CH:23][CH:24]=1
Reactant: C[NH2+]C
Reactant: COc1c2c(c(OC)c(OC)c1OC)CC(CCCOc1ccc(C(=O)O)cc1)C2
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1c2c(c(OC)c(OC)c1OC)CC(CCCOc1ccc(C(=O)N(C)C)cc1)C2
Temperature: 25 °C
Reaction time: 12 h
Yield: 99.5 %

Procedure:
The mixture of 4-[3-(4,5,6,7-tetramethoxyindan-2-yl)propoxy]benzoic acid (2.00 g), dimethylammonium hydrochloride (783 mg), 1-ethyl-3-(3-dimethylaminopropyl)carboduimide hydrochloride (1.84 g), 1-hydroxybenzotriazole monohydrate (1.47 g), and triethylamine (4.01 ml) in THF (40 ml) was stirred at room temperature for 12 hr. The reaction mixture was diluted with ethyl acetate and the organic layer was washed with water and saturated aqueous sodium chloride and dried. The solvent was removed in vacuo. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:2 to ethyl acetate) to yield the entitled compound (2.12 g) as an oil.
Reaction SMILES: C([O:8][C:9]1[CH:31]=[CH:30][C:12]([CH:13]([OH:29])[CH2:14][NH:15][CH2:16][CH2:17][O:18][C:19]2[CH:24]=[CH:23][C:22]([OH:25])=[C:21]([C:26](=[O:28])[NH2:27])[CH:20]=2)=[CH:11][CH:10]=1)C1C=CC=CC=1>CO.[Pd]>[C:26]([C:21]1[CH:20]=[C:19]([CH:24]=[CH:23][C:22]=1[OH:25])[O:18][CH2:17][CH2:16][NH:15][CH2:14][CH:13]([OH:29])[C:12]1[CH:30]=[CH:31][C:9]([OH:8])=[CH:10][CH:11]=1)(=[O:28])[NH2:27]
Reactant: NC(=O)c1cc(OCCNCC(O)c2ccc(OCc3ccccc3)cc2)ccc1O
Agent: [Pd]
Solvent: CO
Product: NC(=O)c1cc(OCCNCC(O)c2ccc(O)cc2)ccc1O

Procedure:
A solution of 7.2 g of 4-benzyloxy-α-[N-[2-(3-carbamoyl-4-hydroxy-phenoxy)-ethyl]-aminomethyl]-benzyl alcohol in 200 ml of methanol is hydrogenated analogously to Example 7 in the presence of palladium-on-charcoal catalyst (5%). Evaporation of the filtered solution yields crude α-[N-[2-(3-carbamoyl-4-hydroxy-phenoxy)-ethyl]aminomethyl]-4-hydroxybenzyl alcohol, which after recrystallisation from methanol/isopropanol melts at 194°-196°.
Reaction SMILES: [CH3:1][CH:2]([N:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[NH:8][C:7](=[O:15])[CH2:6][C:5]1=[O:16])[CH3:3].C(=O)([O-])[O-].[Cs+].[Cs+].[F:23][C:24]([F:28])([F:27])[CH2:25]I.C(=O)([O-])O.[Na+]>CN(C)C=O>[CH3:3][CH:2]([N:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]([CH2:25][C:24]([F:28])([F:27])[F:23])[C:7](=[O:15])[CH2:6][C:5]1=[O:16])[CH3:1]
Reactant: FC(F)(F)CI
Reactant: CC(C)N1C(=O)CC(=O)Nc2ccccc21
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)N1C(=O)CC(=O)N(CC(F)(F)F)c2ccccc21
Temperature: 80 °C
Yield: 58.6 %

Procedure:
A solution of 1-(2-propyl)-1,5-benzodiazepine-2,4-dione (0.55 g, 0.0025 mole) in N,N-dimethylformamide (5 mL) at room temperature was treated with cesium carbonate (1.64 g, 0.005 mole) and trifluoroethyl iodide (1.06g, 0.005 mole), and heated to 80° C. for 2 hours. The reaction was cooled to room temperature and poured into a solution of saturated sodium hydrogen carbonate (100 mL) and extracted with ethyl acetate (3×50 mL). The organic layers were combined, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The residue was chromatographed on silica gel eluting with 1:1 ethyl acetate/hexane to give 440 mg of product.
Reaction SMILES: [F:1][C:2]1[C:22]([O:23][CH:24]([CH3:26])[CH3:25])=[CH:21][CH:20]=[C:19]([F:27])[C:3]=1[O:4][C:5]1[CH2:9][N:8]([C@@H:10]([CH2:14][CH:15]([CH3:17])[CH3:16])[C:11]([OH:13])=O)[C:7](=[O:18])[CH:6]=1.[CH3:28][C:29]1([CH3:41])[O:33][C@H:32]([CH2:34][N:35]2[CH:39]=[CH:38][C:37]([NH2:40])=[N:36]2)[CH2:31][O:30]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH3:28][C:29]1([CH3:41])[O:33][C@H:32]([CH2:34][N:35]2[CH:39]=[CH:38][C:37]([NH:40][C:11](=[O:13])[C@@H:10]([N:8]3[CH2:9][C:5]([O:4][C:3]4[C:19]([F:27])=[CH:20][CH:21]=[C:22]([O:23][CH:24]([CH3:25])[CH3:26])[C:2]=4[F:1])=[CH:6][C:7]3=[O:18])[CH2:14][CH:15]([CH3:16])[CH3:17])=[N:36]2)[CH2:31][O:30]1
Reactant: CC(C)C[C@@H](C(=O)O)N1CC(Oc2c(F)ccc(OC(C)C)c2F)=CC1=O
Reactant: CC1(C)OC[C@@H](Cn2ccc(N)n2)O1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)C[C@@H](C(=O)Nc1ccn(C[C@@H]2COC(C)(C)O2)n1)N1CC(Oc2c(F)ccc(OC(C)C)c2F)=CC1=O
Temperature: 0 °C
Yield: 64.4 %

Procedure:
To a solution of (S)-2-[4-(2,6-difluoro-3-isopropoxy-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid (0.530 g, 1.38 mmol) in N,N-dimethylformamide (10 mL) was added 1-((R)-2,2-dimethyl-[1,3]dioxolan-4-yl-methyl)-1H-pyrazol-3-ylamine (prepared as in Example 49, 0.354 g, 1.79 mmol) and benzotriazol-1-yl-oxy-tris(dimethylamino)phosphonium hexafluorophosphate (1.21 g, 2.73 mmol). The mixture was stirred at 0° C. and N,N-diisopropylethylamine (0.356 g, 2.75 mmol) was added. The mixture was stirred at room temperature for 5 h and the solvents were evaporated. The residue was treated with ethyl acetate and ammonium chloride solution, and the organic layer separated. The organic layer was washed with brine and dried over sodium sulfate. The solvents were evaporated and the residue was purified by ISCO flash chromatography (Teledyne Isco RediSep Flash Column 25 g, 10% to 70% ethyl acetate/hexanes) which afforded (S)-2-[4-(2,6-difluoro-3-isopropoxy-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid [1-((R)-2,2-dimethyl-[1,3]dioxolan-4-yl-methyl)-1H-pyrazol-3-yl]-amide (0.500 g, 64%) as a off-white solid.
Reaction SMILES: [Cl:1][C:2]1[C:7](I)=[CH:6][C:5]([NH:9][CH:10]([CH3:30])[C:11]([N:13]2[CH2:18][CH2:17][N:16]([CH:19]3[CH2:22][N:21]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:20]3)[CH2:15][CH2:14]2)=[O:12])=[C:4]([O:31][CH3:32])[CH:3]=1.[Br-].[CH:34]1([Zn+])[CH2:37][CH2:36][CH2:35]1.COC1C=CC=C(OC)C=1C1C=CC=CC=1P(C1CCCCC1)C1CCCCC1>C1COCC1.CC(O)=O.CC(O)=O.[Pd]>[Cl:1][C:2]1[C:7]([CH:34]2[CH2:37][CH2:36][CH2:35]2)=[CH:6][C:5]([NH:9][CH:10]([CH3:30])[C:11]([N:13]2[CH2:18][CH2:17][N:16]([CH:19]3[CH2:22][N:21]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:20]3)[CH2:15][CH2:14]2)=[O:12])=[C:4]([O:31][CH3:32])[CH:3]=1
Reactant: [Zn+]C1CCC1
Reactant: COc1cc(Cl)c(I)cc1NC(C)C(=O)N1CCN(C2CN(C(=O)OC(C)(C)C)C2)CC1
Agent: [Pd]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: [Br-]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: COc1cc(Cl)c(C2CCC2)cc1NC(C)C(=O)N1CCN(C2CN(C(=O)OC(C)(C)C)C2)CC1
Temperature: 65 °C
Reaction time: 16 h
Yield: 95.9 %

Procedure:
A mixture of tert-butyl 3-(4-(2-((4-chloro-5-iodo-2-methoxyphenyl)amino)propanoyl)piperazin-1-yl)azetidine-1-carboxylate (673 mg, 1.162 mmol), cyclobutylzinc bromide (5.11 mL, 2.556 mmol, 0.5 M in THF), Pd(Oac)2 (52 mg, 0.23 mmol), S-Phos (95 mg, 0.23 mmol) in THF (10 mL) was stirred at 65° C. under argon for 16 h. The mixture was allowed to cool to RT, quenched with aqueous NH4Cl solution and then extracted with ethyl acetate. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (ethyl acetate/petroleum ether=1:1) to afford the desired product (565 mg, 96% yield) as a light yellow solid. ESI-MS m/z: 507.6[M+H]+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][CH:13]=[CH:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].Br[CH:21]([CH3:26])[C:22]([O:24][CH3:25])=[O:23]>CN(C=O)C>[CH3:25][O:24][C:22](=[O:23])[CH:21]([N:14]1[C:15]2[C:11](=[CH:10][C:9]([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[CH:17][CH:16]=2)[CH:12]=[CH:13]1)[CH3:26]
Reactant: c1ccc(COc2ccc3[nH]ccc3c2)cc1
Reactant: COC(=O)C(C)Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C(C)n1ccc2cc(OCc3ccccc3)ccc21
Temperature: 25 °C
Reaction time: 6 h
Yield: 81.8 %

Procedure:
To a solution of 5-benzyloxyindole (13.5 g, 60.46 mmol) in DMF (300 mL) was added sodium hydride (60% dispersion in mineral oil, 3.63 g, 90.7 mmol). The resulting suspension was stirred at rt for 1 h after which methyl 2-bromopropionate (11.1 g, 66.51 mmol) was added. The resulting suspension was stirred at rt for 6 h. The reaction mixture was quenched with sat. aqueous ammonium chloride solution (25 mL), and diluted with 200 mL of EtOAc. The organic layer was washed with water three times. The aqueous layer was extracted again with EtOAc. The combined organic layers were dried over magnesium sulfate, filtered, and concentrated via rotary evaporation. The resulting brown oil was purified on silica gel (EtOAc/hexanes 1:1) to give the title compound as a brownish oil (15.3 g, 82%). LC/MS m/z 310 (M+H)+, RT 4.04 min. 1H NMR (400 MHz, Acetone-d6) δ 7.57 (d, 2H), 7.23-7.41 (m, 5H), 7.19 (d, 1H), 6.84 (d, 1H), 6.40 (d, 1H), 5.37 (q, 1H), 5.17 (s, 2H), 3.66 (s, 3H), 1.79 (d, 3H).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[CH:12]=[CH:11][C:9]([NH2:10])=[C:8]([CH3:13])[CH:7]=1.[CH3:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([C:22](=O)[CH2:23][CH2:24][C:25](=O)[CH2:26][CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:18][CH:17]=1>CCO.C(S([O-])(=O)=O)(F)(F)F.C(S([O-])(=O)=O)(F)(F)F.[Zn+2]>[NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[CH:12]=[CH:11][C:9]([N:10]2[C:22]([C:19]3[CH:20]=[CH:21][C:16]([O:15][CH3:14])=[CH:17][CH:18]=3)=[CH:23][CH:24]=[C:25]2[CH2:26][CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])=[C:8]([CH3:13])[CH:7]=1
Reactant: Cc1cc(-c2ncc[nH]2)ccc1N
Reactant: CCOC(=O)CCC(=O)CCC(=O)c1ccc(OC)cc1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Zn+2]
Solvent: CCO
Product: CCOC(=O)CCc1ccc(-c2ccc(OC)cc2)n1-c1ccc(-c2ncc[nH]2)cc1C
Temperature: 120 °C
Yield: 30.5 %

Procedure:
To a solution of 4-(1H-imidazol-2-yl)-2-methylaniline (Method #3) (1.0 g, 5.76 mmol) and ethyl 7-(4-methoxyphenyl)-4,7-dioxoheptanoate (25C) (2.03 g, 6.93 mmol) in EtOH (12 mL) was added Zn(OTf)2 (6.30 g, 17.34 mmol). The mixture was heated by microwave at 120° C. for 5 h. The solvent was removed under reduced pressure and the residue was dissolved in EA, washed with water and brine, dried over MgSO4, filtered, concentrated and purified by silica gel column chromatography (PE:EA=1:1) to afford ethyl 3-(1-(4-(1H-imidazol-2-yl)-2-methylphenyl)-5-(4-methoxyphenyl)-1H-pyrrol-2-yl)propanoate as a brown solid (755 mg, 30%).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][C@H:3]1[O:15][CH2:16][CH2:17][CH3:18].[Cl:19][C:20]1[N:21]=[C:22]([C:27](O)=[O:28])[NH:23][C:24]=1[CH2:25][CH3:26].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>ClCCl.CC(N(C)C)=O>[Cl:19][C:20]1[N:21]=[C:22]([C:27]([NH:1][C@H:2]2[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:12])([CH3:13])[CH3:14])=[O:9])[CH2:4][C@H:3]2[O:15][CH2:16][CH2:17][CH3:18])=[O:28])[NH:23][C:24]=1[CH2:25][CH3:26]
Reactant: CCCO[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@@H]1N
Reactant: CCc1[nH]c(C(=O)O)nc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CC(=O)N(C)C
Product: CCCO[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@@H]1NC(=O)c1nc(Cl)c(CC)[nH]1
Yield: 76.6 %

Procedure:
The same operation as in Example (106d) was performed using tert-butyl cis(±)-4-amino-3-propoxypiperidine-1-carboxylate obtained in Example (113d) (0.73 g, 2.8 mmol), 4-chloro-5-ethyl-1H-imidazole-2-carboxylic acid (85% content, 0.61 g, 2.98 mmol), WSC hydrochloride (1.15 g, 6 mmol), HOBt (0.61 g, 4.5 mmol), DMA (15 mL) and dichloromethane (15 mL). The resulting residue was purified by silica gel column chromatography (elution solvent: ethyl acetate/hexane=1/4, 2/3, 3/2, 4/1) to obtain 0.89 g of the title compound as a colorless solid (77%).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1)#[N:2].[CH3:9][O:10][C:11]1[CH:17]=[CH:16][C:14]([NH2:15])=[CH:13][CH:12]=1.[K+].[Br-]>>[CH3:9][O:10][C:11]1[CH:17]=[CH:16][C:14]([NH:15][C:1]([C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=2)=[NH:2])=[CH:13][CH:12]=1
Reactant: N#Cc1ccccn1
Reactant: COc1ccc(N)cc1
Agent: [Br-]
Agent: [K+]
Product: COc1ccc(NC(=N)c2ccccn2)cc1
Yield: 86.7 %

Procedure:
The title compound was prepared from 2-cyanopyridine (8.46 g, 81 mmol) and 4-methoxyaniline (10 g, 81 mmol) by following the procedure described in preparation 10 (16 g, yield 86.7%, mp 73-75° C., purity 97.6% by HPLC). 1H-NMR (CDCl3):δ 3.81 (s, 3H), 5.5-6 (bs, 2H, D2O exchangeable), 6.91-6.98 (m, 4H), 7.37-7.4 (m, 1H), 7.79-7.83 (m, 1H), 8.39-8.41 (d, 1H), 8.56-8.57 (d, 1H). IR (KBr) cm−1: 3456, 3540, 3410, 1663. MS m/z:228.2 (M+).
Reaction SMILES: [C:1]([C:9]1[C:10]([CH:14]=O)=[CH:11][S:12][CH:13]=1)#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].C(O)(=O)[CH2:17][C:18]([OH:20])=[O:19]>>[C:1]([C:9]1[C:10](/[CH:14]=[CH:17]/[C:18]([OH:20])=[O:19])=[CH:11][S:12][CH:13]=1)#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: O=C(O)CC(=O)O
Reactant: CCCCCCC#Cc1cscc1C=O
Product: CCCCCCC#Cc1cscc1/C=C/C(=O)O
Yield: 41.5 %

Procedure:
Reaction of 4-(octynyl)-3-thiophenecarboxaldehyde (550 mg, 2.5 mmole) with malonic acid by the method described in Example 2 yielded the title compound 272 mg (41.5%) mp °C.; νmax (mull) 2600(vb), 1790, 1615, 940, 865, 835, 760; δ(CDCl3) 0.90(3H, distorted t), 1.40(8H, m), 2.37(2H, t, J=6 Hz), 6.23(1H, d, J=16 Hz), 7.22(1H, bs), 7.37(1H, bs), 7.77(1H, d, J=16 Hz), 10.3(1H, bs).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[CH:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[NH:8][CH2:7][CH2:6]2.[OH-].[Na+].C(=O)([O-])[O-].[K+].[K+]>C(O)(=O)C.[Pt]=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[NH:8][CH2:7][CH2:6]2
Reactant: CCOC(=O)C=C1NCCc2cc(OC)ccc21
Agent: O=[Pt]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)O
Product: CCOC(=O)CC1NCCc2cc(OC)ccc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 64 %

Procedure:
To a solution of ethyl (6-methoxy-3,4-dihydro-2H-isoquinolin-1-yliden)-acetate (7.56 g) obtained in step (b) of Example 187 in acetic acid (50 ml) was added platinum oxide (400 mg), and the resulting mixture was stirred for 3 hours at room temperature under a hydrogen atmosphere. After stirring, the reaction mixture was filtered through celite and evaporated in vacuo. The residue obtained was neutralized with 1N aqueous sodium hydroxide solution and potassium carbonate, and extracted with ethyl acetate (300 ml×2). The organic layer was washed with saturated aqueous sodium chloride solution (300 ml×1), dried over anhydrous sodium sulfate, filtered, and evaporated in vacuo to afford the crude product. The crude product was purified by chromatography on a silica gel column using a mixed solvent of ethyl acetate and methanol (1:0-5:1) as the eluent to afford the title compound (4.88 g) as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11]3[C:18]4[CH2:19][N:20](C(OCC)=O)[CH2:21][C:17]=4[S:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[F:8].[OH-].[K+].O>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11]3[C:18]4[CH2:19][NH:20][CH2:21][C:17]=4[S:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CCOC(=O)N1Cc2sc3ncnc(Nc4ccc(F)c(Cl)c4)c3c2C1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Fc1ccc(Nc2ncnc3sc4c(c23)CNC4)cc1Cl
Temperature: 80 °C
Reaction time: 14 h
Yield: 37.4 %

Procedure:
To a solution of ethyl 4-[(3-chloro-4-fluorophenyl)amino]-5,7-dihydro-6H-pyrrolo[3′,4′:4,5]thieno[2,3-d]pyrimidine-6-carboxylate from Example 22A (413 mg, 1.05 mmol) in ethanol (4 mL) was added a 10 M aqueous potassium hydroxide solution (2 mL), and the mixture was stirred for 14 h at 80° C. Subsequently, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed twice with water, dried over sodium sulfate, and the solvent was removed in vacuo. The residue was triturated with tert-butyl methyl ether, and the precipitate was collected by suction filtration to yield 126 mg (38%) of the title compound. The mother liquor was concentrated in vacuo and purified by preparative HPLC to yield further 35 mg (10%).