Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:5]2[O:9][N:8]=[C:7]([C:10]3[C:15]([Cl:16])=[CH:14][CH:13]=[CH:12][C:11]=3[Cl:17])[C:6]=2[CH2:18][O:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]3[CH:27]=[C:28]4[C:33](=[CH:34][CH:35]=3)[C:32]([C:36]([O:38]C)=[O:37])=[CH:31][CH:30]=[CH:29]4)=[CH:22][CH:21]=2)[CH2:4][CH2:3][CH2:2]1.O1CCCC1.[OH-].[Na+]>CO>[CH:1]1([C:5]2[O:9][N:8]=[C:7]([C:10]3[C:15]([Cl:16])=[CH:14][CH:13]=[CH:12][C:11]=3[Cl:17])[C:6]=2[CH2:18][O:19][C:20]2[CH:21]=[CH:22][C:23]([C:26]3[CH:27]=[C:28]4[C:33](=[CH:34][CH:35]=3)[C:32]([C:36]([OH:38])=[O:37])=[CH:31][CH:30]=[CH:29]4)=[CH:24][CH:25]=2)[CH2:2][CH2:3][CH2:4]1
Reactant: COC(=O)c1cccc2cc(-c3ccc(OCc4c(-c5c(Cl)cccc5Cl)noc4C4CCC4)cc3)ccc12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1cccc2cc(-c3ccc(OCc4c(-c5c(Cl)cccc5Cl)noc4C4CCC4)cc3)ccc12
Temperature: 120 °C
Yield: 88.7 %

Procedure:
To a solution of methyl 6-[4-({[5-cyclobutyl-3-(2,6-dichlorophenyl)-4-isoxazolyl]methyl}oxy)phenyl]-1-naphthalenecarboxylate (65 mg, 0.116 mmol) in a 2:1 mixture of tetrahydrofuran and methanol (1.5 mL) was added 1N sodium hydroxide (0.175 mL, 0.175 mmol). The solution was heated in a microwave reactor at 120° C. for 500 seconds. The solution was concentrated and water was added followed by 0.175 mL of 1N HCl. The solution was extracted twice with ethyl acetate. The combined organic phases were washed one time with brine and concentrated. Ether was added and the solution was again concentrated to dryness to afford the title compound as a white solid (56 mg, 89%). 1H-NMR (DMSO-d6,) δ 13.14 (s, 1H), 8.88 (d, J=9 Hz, 1H), 8.20-8.16 (m, 2H), 8.09 (d, J=9 Hz, 1H), 7.90 (d, J=9 Hz, 1H), 7.69-7.49 (m, 6H), 6.90 (d, J=9 Hz, 2H), 4.83 (s, 2H), 4.00 (quintet, J=9 Hz, 1H), 2.43-2.34 (m, 4H), 2.10-1.92 (m, 2H). HRMS C31H23Cl2NO4 m/z 544.10769 (M+H)+Cal; 544.10747 (M+H)+Obs.
Reaction SMILES: Cl[CH2:2][C:3]1[NH:12][C:11](=[O:13])[C:10]2[C:5](=[CH:6][C:7]([C:14]([O:16][CH3:17])=[O:15])=[CH:8][CH:9]=2)[N:4]=1.[CH2:18]([N:20](CC)[CH2:21][CH3:22])[CH3:19].C(NCC)C>CN(C=O)C>[CH2:18]([N:20]([CH2:2][C:3]1[NH:12][C:11](=[O:13])[C:10]2[C:5](=[CH:6][C:7]([C:14]([O:16][CH3:17])=[O:15])=[CH:8][CH:9]=2)[N:4]=1)[CH2:21][CH3:22])[CH3:19]
Reactant: CCN(CC)CC
Reactant: COC(=O)c1ccc2c(=O)[nH]c(CCl)nc2c1
Solvent: CN(C)C=O
Solvent: CCNCC
Product: CCN(CC)Cc1nc2cc(C(=O)OC)ccc2c(=O)[nH]1
Temperature: 100 °C
Reaction time: 3 h
Yield: 82.3 %

Procedure:
To a solution of methyl 2-(chloromethyl)-4-oxo-3,4-dihydroquinazoline-7-carboxylate (160 mg, 0.63 mmol) in DMF (3 mL) was added triethylamine (0.176 mL, 1.27 mmol) and diethylamine (0.33 mL, 3.17 mmol). The reaction mixture was heated to 100° C. and stirred for 3 h. The mixture was then cooled to rt and concentrated. The residue was purified by flash silica gel chromatography (0% to 10% MeOH/DCM) to afford methyl 2-[(diethylamino)methyl]-4-oxo-3,4-dihydroquinazoline-7-carboxylate (0.15 g, 81%). LC-MS: (FA) ES+ 290.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][C@H:6]([CH2:8][OH:9])[CH2:5][N:4]([C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:11])[C@H:3]1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[CH3:26][O:27][C:28]1[CH:35]=[CH:34][C:33]([O:36][C:37]([F:40])([F:39])[F:38])=[CH:32][C:29]=1[CH:30]=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl>[CH2:13]([O:12][C:10]([N:4]1[CH2:5][C@@H:6]([CH2:8][OH:9])[CH2:7][C@H:2]([NH:1][CH2:30][C:29]2[CH:32]=[C:33]([O:36][C:37]([F:38])([F:39])[F:40])[CH:34]=[CH:35][C:28]=2[O:27][CH3:26])[C@@H:3]1[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)=[O:11])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: COc1ccc(OC(F)(F)F)cc1C=O
Reactant: N[C@H]1C[C@H](CO)CN(C(=O)OCc2ccccc2)[C@H]1c1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: COc1ccc(OC(F)(F)F)cc1CN[C@H]1C[C@H](CO)CN(C(=O)OCc2ccccc2)[C@H]1c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 121.5 %

Procedure:
To a stirred solution of (2S*,3S*,5S*)-3-amino-1-benzyloxycarbonyl-5-hydroxymethyl-2-phenylpiperidine (0.50 g, 1.36 mmol)) and 2-methoxy-5-trifluoromethoxybenzaldehyde (0.37 g, 1.70 mmol) in CH2Cl2 (20.0 ml) was added NaB(OAc)3H (0.43 g, 2.04 mmol) portionwise. The reaction mixture was stirred at room temperature for 3 hours, and then basified with sat. Na2CO3 aq. solution. The mixture was extracted with CH2Cl2. The combined extracts were dried (Na2SO4), and concentrated in vacuo to give a red oil (0.90 g), which solidified spontaneously on standing in a refrigerator (4 C.). This was flash chromatographed over SiO2 (Merck Kieselgel 60, 18.0 g). Elution with CH2Cl2 --MeOH (300:1/200:1/100:1) gave title compound (0.678 g, 91.6%) as a colorless syrup. IRmax (film): 3450(s), 1698(s), 1682(s), 1670(s), 1498(s), 1230(br., s), 1160(br., s), 1030(s), 738(s), 700(s) cm31 1 ; 1H-NMR δ: 7.44-7.21(m, 9H), 7.18(br.s, 1H), 7.04(br.d, J=8.8 Hz, 1H), 7.00(br.s, 1H), 6.92(d, J=8.8 Hz, 1H), 5.40-5.27(m, 1H), 5.17(d, J=121.5 Hz, 1H), 5.05(d, J=12.5 Hz, 1H), 4.03(br.d, J=13.9 Hz, 1H), 3.74(d, J=13.9 Hz, 1H), 3.70-3.41(m, 4H), 3.62(s, 3H), 3.23-3.11(m, 1H), 2.20-1.95(m, 2H), 1.70-1.45(m, 3H) ppm.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]1[C:17](=[O:18])[O:16][C:14](=[O:15])[CH2:13]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH3:20][O:21][C:22](=[O:32])[C@H:23]([CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[NH2:24].C(=O)([O-])[O-].[K+].[K+].O>C(O)(=O)C>[CH3:20][O:21][C:22](=[O:32])[C@H:23]([CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[NH:24][C:17](=[O:18])[C@H:12]([CH2:13][C:14](=[O:15])[OH:16])[NH:11][C:9]([O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:10]
Reactant: COC(=O)[C@@H](N)Cc1ccccc1
Reactant: O=C1C[C@H](NC(=O)OCc2ccccc2)C(=O)O1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: O
Product: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(=O)O)NC(=O)OCc1ccccc1
Reaction time: 3 h

Procedure:
To 24.9 g (0.1 mole) of N-benzyloxycarbonyl-L-aspartic acid anhydride in 100.4 g of acetic acid were added 21.6 g (0.1 mole) of L-phenylalanine methyl ester hydrochloride and 7.6 g (0.055 mole) of potassium carbonate. The reaction was carried out for 3 hours with stirring at 15°-20.C. Thereafter 75.3 g of water was added and the mixture was stirred for one hour at 15°-20.C. The precipitated crystals were filtered, washed and dried to obtain crystals of N-benzyloxycarbonyl-α-L-aspartyl-phenylalanine methyl ester. Analysis of HPLC revealed that the crystals had an α-isomer:β-isomer ratio of 99.6:0.4. The yield of the α-isomer was 28.6 g. In the filtrate, 7.2 g of the α-isomer and 6.2 g of the β-isomer were present.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:11][CH2:10][C:9]2[C:4](=[C:5]([N:12]3[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]3)[CH:6]=[CH:7][CH:8]=2)[CH2:3]1.C(N(CC)CC)C.[CH:26]1([C:32](Cl)=[O:33])[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1>C(Cl)Cl>[CH3:18][N:15]1[CH2:16][CH2:17][N:12]([C:5]2[CH:6]=[CH:7][CH:8]=[C:9]3[C:4]=2[CH2:3][C@H:2]([NH:1][C:32]([CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)=[O:33])[CH2:11][CH2:10]3)[CH2:13][CH2:14]1
Reactant: O=C(Cl)C1CCCCC1
Reactant: CN1CCN(c2cccc3c2C[C@H](N)CC3)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN1CCN(c2cccc3c2C[C@H](NC(=O)C2CCCCC2)CC3)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 43.4 %

Procedure:
To an ice-cooled solution of (R)-2-amino-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydronaphthalene (110 mg, 0.46 mmol) and triethylamine (92 μL, 0.66 mmol) in methylene chloride (20 mL) was added dropwise cyclohexanecarbonyl chloride (67 μL, 0.46 mmol) in methylene chloride (5 mL). After the addition the reaction was allowed to stir at ambient temperature for 10 min and then washed with dilute aqueous sodium hydrogen carbonate. The organic phase was separated, dried (Na2SO4), filtered and evaporated in vacuo and the residue was purified on a silica gel column using chloroform/ethanol saturated with NH3 (100:3) as the eluent. This gave 71 mg (45% yield) of the title compound as white crystals: mp 183-184° C.; [α]21D +12° (c 1.0, chloroform); EIMS (70 eV) m/z (relative intensity) 355 (56, M+).
Reaction SMILES: [CH3:1][O:2][C:3]([C@@:5]12[CH2:11][CH2:10][C@:9]1([CH2:12][O:13]CC1C=CC=CC=1)[CH2:8][N:7]([C@@H:21]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH3:22])[C:6]2=[O:29])=[O:4].O1CCCC1.[H][H]>[C].[Pd].C(O)C>[CH3:1][O:2][C:3]([C@@:5]12[CH2:11][CH2:10][C@:9]1([CH2:12][OH:13])[CH2:8][N:7]([C@@H:21]([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[CH3:22])[C:6]2=[O:29])=[O:4]
Reactant: [H][H]
Reactant: COC(=O)[C@@]12CC[C@]1(COCc1ccccc1)CN([C@H](C)c1ccccc1)C2=O
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: COC(=O)[C@@]12CC[C@]1(CO)CN([C@H](C)c1ccccc1)C2=O

Procedure:
A 10% palladium-carbon catalyst (50% wet, 200 mg) was added to a solution of (1S,5R)-5-benzyloxymethyl-2-oxo-3-[(1R)-1-phenylethyl]-3-azabicyclo[3.2.0]heptane-1-carboxylic acid methyl ester (1.82 g, 4.62 mmol) in ethanol (20 mL)-tetrahydrofuran (20 mL), and the mixture was stirred in a hydrogen atmosphere at 40° C. for 2.5 hours. After removing the catalyst by filtration, the filtrate was concentrated to give the title compound as colorless crystals.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1F)[CH:5]=[O:6].[CH3:11][C:12]1[N:13]=[CH:14][NH:15][CH:16]=1.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[N:15]1[CH:16]=[C:12]([CH3:11])[N:13]=[CH:14]1)[CH:5]=[O:6]
Reactant: O=Cc1ccc(F)c(F)c1
Reactant: Cc1c[nH]cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1cn(-c2ccc(C=O)cc2F)cn1
Temperature: 90 °C
Reaction time: 6 h
Yield: 17.6 %

Procedure:
To a solution of 3,4-difluorobenzaldehyde (40.0 g) in DMF (533 mL), 4-methylimidazole (46.4 g) and potassium carbonate (78.0 g) were added at room temperature, and the reaction solution was stirred at 90° C. for six hours. The reaction solution was left to cool to room temperature. Ethyl acetate was added to the reaction solution, which was then sequentially washed with water and brine. The resulting organic layer was dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: heptane-ethyl acetate system) and solidified with tert-butyl methyl ether to obtain 10.1 g of the title compound. The property values of the compound are as follows.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:8]=[C:7]([C:9](N)=[O:10])[CH:6]=[CH:5][C:4]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[OH-:20].[K+].O>C(O)C>[F:1][C:2]([F:19])([F:18])[C:3]1[CH:8]=[C:7]([C:9]([OH:20])=[O:10])[CH:6]=[CH:5][C:4]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: [OH-]
Reactant: NC(=O)c1ccc(-c2ccccc2)c(C(F)(F)F)c1
Agent: [K+]
Solvent: CCO
Solvent: O
Product: O=C(O)c1ccc(-c2ccccc2)c(C(F)(F)F)c1
Temperature: 90 °C
Yield: 47.8 %

Procedure:
The reaction was split into 4, using a quarter of the reagents shown in each: to a mixture of 4-bromo-3-(trifluoromethyl)benzonitrile (4 g, 16.00 mmol), phenylboronic acid (3.90 g, 32.0 mmol) and potassium carbonate (6.63 g, 48.0 mmol) in DMF (64 ml) was added palladium tetrakistriphenylphosphine(0) (1.849 g, 1.600 mmol). Each reaction was heated in the microwave at 150° C. for 30 minutes. The combined reaction mixtures were filtered through Celite®, washed with EtOAc and the solvent removed in vacuo. The residue was partitioned between EtOAc (100 ml) and water (100 ml) and the organic phase washed with sodium bicarbonate solution (100 ml). The organic phase was dried (MgSO4), filtered and the solvent removed in vacuo. The brown oil was triturated with DCM and filtered to give a pale yellow solid, 2-(trifluoromethyl)-4-biphenylcarboxamide (2.47 g) which was used without further purification. To 2-(trifluoromethyl)-4-biphenylcarboxamide (2 g, 7.54 mmol) in ethanol (80 ml) was added potassium hydroxide (4.23 g, 75 mmol) and water and the mixture heated to 90° C. for 18 hrs. The reaction mixture was concentrated in vacuo and the residue partitioned between DCM (100 ml) and 2M HCl (100 ml). The organic phase was isolated and dried (hydrophobic frit phase separator) and the solvent removed in vacuo to give the crude product. Chromatographic purification using the Biotage Horizon, reverse phase cartridge, eluting 5-100% MeCN in water to give the title compound as an off-white solid (960 mg). LCMS (ES−): C14H9F3O2 requires 266; found 265 [M−H+]
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:12])=[C:4]([S:8](Cl)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.N1C=CC=CC=1.[NH2:19][C:20]1[CH:29]=[CH:28][C:23]2[N:24]=[C:25]([CH3:27])[O:26][C:22]=2[CH:21]=1.C([O-])(O)=O.[Na+]>ClCCl>[Cl:1][C:2]1[C:3]([CH3:12])=[C:4]([S:8]([NH:19][C:20]2[CH:29]=[CH:28][C:23]3[N:24]=[C:25]([CH3:27])[O:26][C:22]=3[CH:21]=2)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1nc2ccc(N)cc2o1
Reactant: Cc1c(Cl)cccc1S(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1nc2ccc(NS(=O)(=O)c3cccc(Cl)c3C)cc2o1
Reaction time: 0.08 h
Yield: 65.2 %

Procedure:
To a solution of 3-chloro-2-methylbenzenesulphonyl chloride (163 mg, 0.723 mmol) in dichloromethane (3 mL) was added pyridine (140 μL, 1.72 mmol) and the mixture was stirred under N2 for 5 min, after which time 6-amino-2-methylbenzoxazole (102 mg, 0.688 mmol) was added. The resulting mixture was stirred for 1 h at room temperature, then saturated NaHCO3 solution was added (8 mL) and the mixture was extracted into ethyl acetate (15 mL). The organic phase was washed with brine, dried (Na2SO4), filtered and evaporated to give a residue that was purified using flash chromatography to afford a white solid (151 mg, 65%), single spot at Rf 10.50 (60:40 hexane:ethyl acetate). mp 127.1-127.5° C., HPLC purity 97% (tR 2.05 min in 10% water-acetonitrile). 1H NMR (CDCl3): δ 7.85 (1H, dd, J=8.1, 1.1 Hz), 7.53 (1H, dd, J=8.1, 1.3 Hz), 7.45 (1H, d, J=8.4 Hz), 7.27 (1H, d, J=2.2 Hz), 7.17 (1H, t, J=7.9 Hz), 6.93 (1H, s, N—H), 6.86 (1H, dd, J=8.4, 2.2 Hz), 2.71 (3H, s), 2.58 (3H, s). LCMS: 335.14 (M−). FAB-MS (MH+, C15H13ClN2O3S): calcd 337.0413, found 337.0406.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][CH2:9][C:10]([N:12]([CH:19]([CH3:21])[CH3:20])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:11].[C:22](Cl)(=[O:27])[CH2:23][C:24](Cl)=[O:25]>C1COCC1>[O:25]=[C:24]1[N:8]([CH2:9][C:10]([N:12]([CH:19]([CH3:21])[CH3:20])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:11])[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[NH:1][C:22](=[O:27])[CH2:23]1
Reactant: O=C(Cl)CC(=O)Cl
Reactant: CC(C)N(C(=O)CNc1ccccc1N)c1ccccc1
Solvent: C1CCOC1
Product: CC(C)N(C(=O)CN1C(=O)CC(=O)Nc2ccccc21)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 46.7 %

Procedure:
To a stirred solution of 10 g (37.14 mmol) of 2-(2-Aminophenylamino)-N-isopropyl-N-phenyl acetamide, prepared as in Intermediate 45, in 100 mL of THF is added 5.2 g (37.14 mmol, 1 equiv.) of malonyl dichloride. The resulting solution is stirred at RT for 2 h and the solvent removed in vacuo. Purification by silica gel flash column chromatography using hexane/EtOAc 1/1 as eluent afforded 6.1 g of the title compound as an oil: 1H NMR (CDCl3, 300 MHz) δ9.65 (s, 1H), 7.4 (bd, 1H, J=9), 7.30-6.93 (m, 7H), 5.09-4.95 (m, 1H), 4.42 (d, 1H, J=16), 3.68 (d, 1H, J=17), 3.36 (d, 2H, J=4), 1.09 (d, 6H, J=7).
Reaction SMILES: [CH:1]([OH:3])=O.C(OC(=O)C)(=O)C.[CH3:11][C:12]1[CH:18]=[C:17]([CH3:19])[CH:16]=[C:15]([CH3:20])[C:13]=1[NH2:14]>ClCCl>[CH:1]([NH:14][C:13]1[C:15]([CH3:20])=[CH:16][C:17]([CH3:19])=[CH:18][C:12]=1[CH3:11])=[O:3]
Reactant: Cc1cc(C)c(N)c(C)c1
Reactant: O=CO
Solvent: CC(=O)OC(C)=O
Solvent: ClCCl
Product: Cc1cc(C)c(NC=O)c(C)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of formic acid (14.361 g, 0.312 mol) and acetic anhydride (12.659 g, 0.124 mol) was stirred at room temperature for 1 h under an argon atmosphere. This mixture was added to a solution of 2,4,6-trimethylaniline (13.521 g, 0.1 mol) in dry dichloromethane (60 ml) at such a rate that the temperature of the reaction mixture was kept between 5 and 10° C. The reaction was stirred at room temperature for 16 h and then refluxed for 4 h. The solvent was evaporated under reduced pressure, the residue was dissolved in CHCl3 (200 mL) and washed with a saturated aqueous NaHCO3 solution (3×200 mL), and water (200 mL). The organic layer was dried over Na2SO4 and the solvent was evaporated under reduced pressure. The remaining yellow solid was washed with hot diethyl ether (2×50 mL) to afford N-formyl-2,4,6-trimethylaniline 8c1 as a white solid (11.42 g, 70%). 1H NMR (CDCl3, 300 MHz): δ=8.39-8.03 (m, 1H, CHO), 7.26-6.91 (m, 2H), 6.75 (broad s, 1H, NH), 2.29-2.21 (m, 9H); 13C{1H} NMR (CDCl3, 75 MHz): δ=165.48, 160.05, 137.75, 137.61, 135.37, 135.16, 130.92, 130.74, 129.53, 129.16, 21.15, 21.12, 18.84, 18.64; HRMS (FAB+) calculated for C10H14NO [M]+ 164.1075, observed 164.1116. 1 (a) Arduengo, A. J.; Goerlich, J. R.; Marshall, W. J. Liehigs Ann./Recited 1997, 365-374. (b) J. Liebscher, Methoden der Organischen Chemie (Hauben-Weyl) 4th ed. (Ed.: E. Schaumann), Georg Thieme Verlag, New York, 1994 Band E 8b, Heratrene III/Part 2, p. 48. (c) Hromatka, O. U.S. Pat. No. 2,160,867, 1939.
Reaction SMILES: [CH:1]1([CH2:4][NH:5][CH2:6][CH2:7][C:8]([OH:10])=[O:9])[CH2:3][CH2:2]1.[CH:11]([C:13]1[CH:21]=[CH:20][C:16]([C:17](O)=[O:18])=[CH:15][CH:14]=1)=[O:12].F[P-](F)(F)(F)(F)F.Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1>CN(C=O)C.C(N(C(C)C)CC)(C)C>[CH:1]1([CH2:4][N:5]([C:17](=[O:18])[C:16]2[CH:20]=[CH:21][C:13]([CH:11]=[O:12])=[CH:14][CH:15]=2)[CH2:6][CH2:7][C:8]([OH:10])=[O:9])[CH2:3][CH2:2]1
Reactant: O=C(O)CCNCC1CC1
Reactant: O=Cc1ccc(C(=O)O)cc1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=Cc1ccc(C(=O)N(CCC(=O)O)CC2CC2)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To the above resin bound N-(cyclopropylmethyl) 3-aminopropionic acid (50 mg) was added 200 μmol 4-formylbenzoic acid (30 mg) dissolved in a mixture of 430 μL DMF and 70 μL diisopropylethylamine followed by 200 μmol bromo-tris-pyrrolidinophosphonium hexafluorophosphate (PyBrOP, 93 mg) dissolved in 500 μL DMF. The mixture was shaken at 25° C. for 4 hours followed by filtration and washing of the resin with 3×1 mL DMF and 1 mL trimethylorthoformate.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[CH2:16][N:15]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:14][CH2:13][CH2:12][C:7]=3[N:8]([CH3:11])[C:9]=2[CH:10]=1.[Cl:24][C:25]1[CH:39]=[C:38]([Cl:40])[CH:37]=[CH:36][C:26]=1[CH2:27][O:28][C:29]1[CH:34]=[CH:33][NH:32][C:31](=[O:35])[CH:30]=1>>[Cl:24][C:25]1[CH:39]=[C:38]([Cl:40])[CH:37]=[CH:36][C:26]=1[CH2:27][O:28][C:29]1[CH:34]=[CH:33][N:32]([C:2]2[CH:3]=[CH:4][C:5]3[C:6]4[CH2:16][N:15]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:14][CH2:13][CH2:12][C:7]=4[N:8]([CH3:11])[C:9]=3[CH:10]=2)[C:31](=[O:35])[CH:30]=1
Reactant: Cn1c2c(c3ccc(Br)cc31)CN(C(=O)OC(C)(C)C)CCC2
Reactant: O=c1cc(OCc2ccc(Cl)cc2Cl)cc[nH]1
Product: Cn1c2c(c3ccc(-n4ccc(OCc5ccc(Cl)cc5Cl)cc4=O)cc31)CN(C(=O)OC(C)(C)C)CCC2
Yield: 44.9 %

Procedure:
tert-Butyl 8-bromo-6-methyl-3,4,5,6-tetrahydroazepino[4,3-b]indole-2(1H)-carboxylate (155 mg, 0.411 mmol) and 4-(2,4-dichlorobenzyloxy)pyridin-2(1H)-one (110 mg, 0.411 mmol) were reacted following the procedure for Example 2 (step d) to provide the title compound (105 mg, 45%) as a yellow foam: ESI MS m/z 568 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1([C:5]2[N:10]=[C:9]([NH:11][CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)[C:8]3=[C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH:20]=[CH:21][N:7]3[N:6]=2)[CH2:4][CH2:3]1.N1C=CC=CC=1.[C:34](Cl)(=[O:36])[CH3:35]>C(Cl)Cl>[C:22]1([C:19]2[CH:20]=[CH:21][N:7]3[C:8]=2[C:9]([NH:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[N:10][C:5]([C:2]2([NH:1][C:34](=[O:36])[CH3:35])[CH2:3][CH2:4]2)=[N:6]3)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CC(=O)Cl
Reactant: NC1(c2nc(NCc3ccccn3)c3c(-c4ccccc4)ccn3n2)CC1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)NC1(c2nc(NCc3ccccn3)c3c(-c4ccccc4)ccn3n2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 37.3 %

Procedure:
To a stirred solution of 2-(1-aminocyclopropyl)-5-phenyl-N-(pyridin-2-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (60.0 mg, 0.168 mmol)) in DCM (15 mL) was added pyridine (0.0200 mL, 0.253 mmol) followed by acetyl chloride (0.0140 mL, 0.202 mmol) and the reaction mixture stirred at RT for 2 h then concentrated under reduced pressure. The residue was dissolved in ethyl acetate (100 mL) and washed with water (2×30 mL). The combined organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC (Condition B-111 as described in general methods) to give N-(1-(5-phenyl-4-((pyridin-2-ylmethyl)amino)pyrrolo[2,1-f][1,2,4]triazin-2-yl)cyclopropyl)acetamide (25.0 mg, 37.3%) as white solid. LCMS Condition B-34: retention time 2.14 min, [M+1]=399.0. HPLC Condition B-31: retention time 6.09 min, Purity 99.83%. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.93-1.01 (m, 2H), 1.35-1.41 (m, 2H), 1.85 (s, 3H), 4.68 (d, J=4.8 Hz, 2H), 6.68 (d, J=2.7 Hz, 1H), 6.99 (t, J=4.9 Hz, 1H), 7.27 (dd, J=6.5 Hz, J=4.9 Hz, 1H), 7.36 (d, J=7.8 Hz, 1H), 7.40-7.48 (m, 1H), 7.48-7.57 (m, 4H), 7.67 (d, J=2.7 Hz, 1H), 7.76 (td, J=7.7 Hz, J=1.7 Hz, 1H), 8.37-8.41 (m, 1H), 8.44 (s, 1H).
Reaction SMILES: [CH3:1][Mg]Br.[F:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[N:12]=[N:13][N:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17]([N:24]3[CH2:29][CH2:28][C:27](=[O:30])[CH2:26][CH2:25]3)=[N:16][C:15]=12>O1CCCC1.O.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>[F:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[N:12]=[N:13][N:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17]([N:24]3[CH2:25][CH2:26][C:27]([OH:30])([CH3:1])[CH2:28][CH2:29]3)=[N:16][C:15]=12
Reactant: O=C1CCN(c2nc3c(-c4ccccc4F)nnn3c3ccccc23)CC1
Reactant: C[Mg]Br
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: O
Solvent: C1CCOC1
Product: CC1(O)CCN(c2nc3c(-c4ccccc4F)nnn3c3ccccc23)CC1
Reaction time: 2 h
Yield: 46.8 %

Procedure:
Methylmagnesium bromide (3M in diethyl ether, 0.24 ml, 0.72 mmol) was added to a stirred solution of 3-(2-fluorophenyl)-5-(4-oxopiperidin-1-yl)-[1,2,3]triazolo[1,5-α]quinazoline (Example 22) (0.107 g, 0.3 mmol) in dry tetrahydrofuran (2 ml) at room temperature under nitrogen. After stirring for 2 h, the mixture was diluted with water (20 ml) and 1M aqueous citric acid (5 ml). The mixture was extracted with dichloromethane (20 ml) and the organic extract was dried (Na2SO4), filtered and concentrated. Preparative thin layer chromatography on silica, eluting with 2% methanol:dichloromethane, gave 3-(2-fluorophenyl)-5-(4-hydroxy-4-methylpiperidin-1-yl)-[1,2,3]triazolo[1,5-α]quinazoline (0.053 g, 47%). δH (360 MHz; CDCl3) 1.38 (3H, s), 1.75-1.85 (2H, m), 1.90-2.00 (2H, m), 3.56-3.64 (2H, m), 3.83-3.89 (2H, m), 7.20-7.30 (2H, m), 7.30-7.40 (1H, m), 7.60 (1H, dd, J=7 and 7), 7.88 (1H, dd, J=7 and 7), 8.02 (1H, d, J=7), 8.15 (1H, dd, J=7 and 7), 8.68 (1H, d, J=7); m/z (ES+) 378 (M+H+).
Reaction SMILES: [ClH:1].C([N:9]([C:25]([CH3:28])([CH3:27])[CH3:26])[CH2:10][C:11]([C:13]1[CH:22]=[C:17]([C:18]([O:20][CH3:21])=[O:19])[C:16]([O:23][CH3:24])=[CH:15][CH:14]=1)=[O:12])C1C=CC=CC=1.[H][H]>C(O)C.[Pd]>[ClH:1].[C:25]([NH:9][CH2:10][CH:11]([C:13]1[CH:22]=[C:17]([C:18]([O:20][CH3:21])=[O:19])[C:16]([O:23][CH3:24])=[CH:15][CH:14]=1)[OH:12])([CH3:28])([CH3:27])[CH3:26]
Reactant: COC(=O)c1cc(C(=O)CN(Cc2ccccc2)C(C)(C)C)ccc1OC
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: COC(=O)c1cc(C(O)CNC(C)(C)C)ccc1OC
Yield: 91.5 %

Procedure:
5-(N-Benzyl-N-tert.butylglycyl)-o-anisic acid, methyl ester, hydrochloride (4.05g) in ethanol (60 ml) was added to a pre-reduced suspension of 10% Pd/C (1.0g) in ethanol (15 ml) and hydrogenated until uptake ceased (hydrogen uptake was 441.cc). The catalyst was filtered off and the filtrate evaporated to dryness to afford 5-(2-tert.butylamino-1-hydroxyethyl)-o-anisic acid, methyl ester, hydrochloride as a white crystalline solid (2.9g) m.p. 189°-194° .