Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][P:6]([CH:13]([F:27])[C:14]1[CH:26]=[CH:25][C:17]([CH2:18][CH:19]([C:21]([O:23]C)=[O:22])[NH2:20])=[CH:16][CH:15]=1)([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>O1CCOCC1>[C:9]([O:8][P:6]([CH:13]([F:27])[C:14]1[CH:15]=[CH:16][C:17]([CH2:18][CH:19]([C:21]([OH:23])=[O:22])[NH2:20])=[CH:25][CH:26]=1)([O:5][C:1]([CH3:3])([CH3:4])[CH3:2])=[O:7])([CH3:10])([CH3:11])[CH3:12]
Reactant: COC(=O)C(N)Cc1ccc(C(F)P(=O)(OC(C)(C)C)OC(C)(C)C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CC(C)(C)OP(=O)(OC(C)(C)C)C(F)c1ccc(CC(N)C(=O)O)cc1
Temperature: 25 °C
Reaction time: 0.42 h

Procedure:
To compound 21 (690 mg, 1.71 mmol) in dioxane (17 mL) is added 1N NaOH (8.6 mL, 5 eq.) and stirred at ambient temperature (25 minutes), yielding a solution of crude 4-[bis(tert-Butoxy)phosphoryl-fluoromethyl]-D,L-phenylalanine (22), which is not isolated. The pH is adjusted to 8 by bubbling in CO2 gas, Fmoc-OBT (673 mg, 1.88 mmol) is added and the mixture stirred at ambient temperature (3 hours). Ice-cold 5% citric acid (30 mL) is added and the resultant solution is extracted with CHCl3 (3×30 mL). The combined extracts are dried (MgSO4) and evaporated under reduced pressure to yield crude 23 (1.48 g). Purification by silica gel chromatography affords pure 23 as a colorless foam (407 mg, 40%).
Reaction SMILES: Br.[CH2:2]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]([OH:14])=[O:13])=[CH:7][CH:6]=1)[CH3:3].Cl.[CH2:16](O)[CH3:17]>>[CH2:2]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]([O:14][CH2:16][CH3:17])=[O:13])=[CH:7][CH:6]=1)[CH3:3]
Reactant: CCO
Reactant: CCNc1ccc(CC(=O)O)cc1
Agent: Br
Agent: Cl
Product: CCNc1ccc(CC(=O)OCC)cc1

Procedure:
Ethyl iodide (35.1 g) was gradually added dropwise to a mixed liquid of ethyl 4-(N-benzenesulfonyl)aminophenylacetate (60 g), potassium carbonate (39 g), and acetone (500 ml) while stirring and refluxing it. Then, the mixture was refluxed for 2 hours with stirring. The mixture was cooled, and the precipitated crystals were removed by filtration. The filtrate was distilled for removal of the solvent. The residue was dissolved in benzene, and the solution was washed in water, followed by drying over magnesium sulfate. The dried product was distilled to remove the solvent, and the residue was recrystallized from n-hexane to obtain 64.3 g (m.p. 99.8°-100.8° C.) of ethyl 4-(N-ethyl-N-benzeneslfonyl) aminophenylacetate as prismatic crystals. Subsequently, 48% hydrobromic acid (380 ml) and phenol (64.3 g) were added to the ethyl ester, and the mixture was refluxed for 4 hours. While being cooled, the refluxed mixture was washed with benzene, and distilled to remove the aqueous layer. To the residue was added benzene, and the mixture was distilled to remove moisture and crude 4-(N-ethyl)aminophenylacetic acid hydrobromide was obtained. Then, ethanol (300 ml) was added to the hydrobromide. While being cooled, the mixture was saturated with hydrogen chloride gas. With the introduction of hydrogen chloride gas, the mixture was refluxed for 4 hours. After the reaction, the solvent was distilled off. The residue was dissolved in water, and the solution was washed with ether. The aqueous layer was neutralized with potassium carbonate while cooling the layer with ice, and extracted with ether. The extract was dried over magnesium sulfate. After the solvent was distilled off, the residue was vacuum-distilled to obtain 26.8 g of the desired N-ethyl-4-ethoxycarbonylmethylaniline as a fraction boiling at 112.5° C. at 0.02 mmHg.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[O:14][C:13]([SH:15])=[N:12][N:11]=3)=[CH:9][C:4]=2[CH:3]=[CH:2]1.[CH3:16][O:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22]Cl)=[CH:20][CH:19]=1>>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[O:14][C:13]([S:15][CH2:22][C:21]4[CH:24]=[CH:25][C:18]([O:17][CH3:16])=[CH:19][CH:20]=4)=[N:12][N:11]=3)=[CH:9][C:4]=2[CH:3]=[CH:2]1
Reactant: Sc1nnc(-c2ccc3occc3c2)o1
Reactant: COc1ccc(CCl)cc1
Product: COc1ccc(CSc2nnc(-c3ccc4occc4c3)o2)cc1
Yield: 87 %

Procedure:
In the same manner as in Example 1 and using 5-(1-benzofuran-5-yl)-1,3,4-oxadiazole-2-thiol instead of 5-(benzothiazol-6-yl)-1,3,4-oxadiazole-2-thiol and 4-methoxybenzyl chloride instead of 3-(trifluoromethyl)benzyl chloride, the title compound (yield 87%) was obtained as colorless crystals.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH:5]([CH2:11][CH2:12][CH2:13][C:14](Cl)([F:16])[F:15])[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2].N12CCCN=C1CCCCC2>C1(C)C=CC=CC=1>[CH2:9]([O:8][C:6](=[O:7])[CH:5]([CH2:11][CH2:12][CH:13]=[C:14]([F:16])[F:15])[C:4]([O:3][CH2:1][CH3:2])=[O:18])[CH3:10]
Reactant: CCOC(=O)C(CCCC(F)(F)Cl)C(=O)OCC
Solvent: C1CCC2=NCCCN2CC1
Solvent: Cc1ccccc1
Product: CCOC(=O)C(CCC=C(F)F)C(=O)OCC

Procedure:
150 g of 2-(4-chloro-4,4-difluoro-but-1-yl)malonic acid diethyl ester, 160 g of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) and 250 ml of toluene are stirred for 15 hours at reflux temperature. After cooling, 200 ml of toluene are added and the reaction mixture is washed with 500 ml of water and then with 500 ml of 2N NaCl solution, dried over sodium sulfate and the solvent is evaporated off. The residue is distilled at 65° and 0.052 mbar. The title product is obtained in the form of a colourless oil.
Reaction SMILES: [O:1]=[S:2]1(=[O:19])[NH:7][CH2:6][CH2:5][CH2:4][N:3]1[C:8]1[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][C:9]=1[CH3:18].[K].[CH3:21]C(C)([O-])C.CI>CN(C=O)C>[O:19]=[S:2]1(=[O:1])[N:7]([CH3:21])[CH2:6][CH2:5][CH2:4][N:3]1[C:8]1[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][C:9]=1[CH3:18]
Reactant: CC(C)(C)[O-]
Reactant: COC(=O)c1ccc(N2CCCNS2(=O)=O)c(C)c1
Agent: [K]
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(N2CCCN(C)S2(=O)=O)c(C)c1
Temperature: 40 °C
Reaction time: 5 h

Procedure:
400 mg (1.41 mmol) methyl 4-(1,1-dioxo-[1,2,6]-thiadiazinan-2-yl)-3-methyl-benzoate dissolved in 4 ml DMF at 40° C. are combined with 240 mg (2.14 mmol) potassium-tert.-butoxide and 96 μl (1.54 mmol) methyl iodide and stirred for 5 hours at 40° C. The reaction solution is evaporated down i. vac., combined with water and the aqueous phase is extracted with ethyl acetate. The combined organic phases are dried over sodium sulphate and evaporated down i. vac.
Reaction SMILES: [CH2:1]([C:7]([OH:9])=[O:8])[C@H:2]([OH:6])[C:3]([OH:5])=[O:4].[CH3:10][C:11]1C=CC(S([O-])(=O)=O)=C[CH:12]=1.C1C=C[NH+]=CC=1>COC(OC)(C)C>[CH3:10][C:11]1([CH3:12])[O:6][C@@H:2]([CH2:1][C:7]([OH:9])=[O:8])[C:3](=[O:5])[O:4]1
Reactant: O=C(O)C[C@H](O)C(=O)O
Reactant: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: COC(C)(C)OC
Product: CC1(C)OC(=O)[C@H](CC(=O)O)O1
Reaction time: 48 h
Yield: 2850.2 %

Procedure:
To a suspension of L-(−)-Malic acid (100.0 g, 0.74 mol) in 2,2-dimethoxy propane (200 mL) was added PPTS (2.60 g, 15.11 mmol) at room temperature (25° C.). The reaction mixture stirred at same temperature over a period of 48 h. The resulting mixture was partitioned between water (1.0 L) and dichloromethane (2.5 L), the aqueous layer was extracted twice with dichloromethane (2×500 mL). The combined organic layers dried (Na2SO4) and concentrated under reduced pressure to obtain colourless solid (75.0 g, 58%).
Reaction SMILES: [C:1]([C:4]1[C:5]([C:19](=[O:21])[CH3:20])=[C:6]([CH3:18])[N:7]([C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[C:12]([Cl:17])[CH:11]=2)[C:8]=1[CH3:9])(=[O:3])[CH3:2].Br[CH2:23][CH3:24].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[C:1]([C:4]1[C:5]([C:19](=[O:21])[CH3:20])=[C:6]([CH3:18])[N:7]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:23][CH3:24])=[C:12]([Cl:17])[CH:11]=2)[C:8]=1[CH3:9])(=[O:3])[CH3:2]
Reactant: CCBr
Reactant: CC(=O)c1c(C(C)=O)c(C)n(-c2ccc(O)c(Cl)c2)c1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOc1ccc(-n2c(C)c(C(C)=O)c(C(C)=O)c2C)cc1Cl
Temperature: 50 °C
Reaction time: 1 h

Procedure:
To a solution of 1-[4-acetyl-1-(3-chloro-4-hydroxy-phenyl)-2,5-dimethyl-1H-pyrrol-3-yl]-ethanone (prepared as outline in Example 57; 80 mg, 0.27 mmol) in 3 mL of dry DMF was added bromoethane (54 mg, 0.5 mmol) and K2CO3 powder (50 mg). The resulting reaction mixture was warmed to 50° C. and stirred for 1 h. It was quenched by addition of 20 mL of H2O, extracted with diethyl ether (20 mL×2). The combined organic extracts were washed with brine (50 mL), dried (MgSO4), filtered, and concentrated in vacuo to afford 1-[4-acetyl-1-(3-chloro-4-ethoxy-phenyl)-2,5-dimethyl-1H-pyrrol-3-yl]-ethanone: MS (ESI) 302 (M+H)+.
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].[CH:25]([C:27]1[CH:32]=[CH:31][C:30]([C:33]2[CH:37]=[C:36]([C:38]([NH2:40])=[O:39])[O:35][N:34]=2)=[CH:29][CH:28]=1)=O.C([O-])([O-])=O.[Na+].[Na+]>ClC(Cl)C.CC(O)=O>[N:1]1([CH2:25][C:27]2[CH:28]=[CH:29][C:30]([C:33]3[CH:37]=[C:36]([C:38]([NH2:40])=[O:39])[O:35][N:34]=3)=[CH:31][CH:32]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: NC(=O)c1cc(-c2ccc(C=O)cc2)no1
Reactant: c1ccc2c(c1)CCCN2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Product: NC(=O)c1cc(-c2ccc(CN3CCCc4ccccc43)cc2)no1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 67.7 %

Procedure:
To a solution of tetrahydroquinoline (20 μL, 0.16 mmol) in dichloroethane (1 mL) was added Na(OAc)3BH (88 mg, 0.415 mmol). The mixture was stirred at room temperature under argon for 20 min. A slurry of 3-(4-formyl-phenyl)-isoxazole-5-carboxylic acid amide (which may be prepared as described in Preparation of Intermediate 20; 20 mg, 0.093 mmol) in dichloroethane (1 mL) was added, followed by AcOH (20 μL). The reaction mixture was stirred at room temperature overnight. 1 M Na2CO3 solution was added and the mixture was extracted with CHCl3 (3×25 mL). The combined organic layers were washed with brine, dried (Na2SO4), evaporated, and purified by chromatography (11-20% acetone/CH2Cl2) to give 3-[4-(3,4-dihydro-2H-quinolin-1-ylmethyl)-phenyl]-isoxazole-5-carboxylic acid amide (21 mg, 45%) as a white powder. 1H NMR (300 MHz, DMSO-d6) δ ppm 8.35 (br. s., 1H), 7.97 (br. s., 1H), 7.84 (d, J=8.2 Hz, 2H), 7.47-7.57 (m, 1H), 7.38 (d, J=7.8 Hz, 2H), 6.72-6.93 (m, 2H), 6.36-6.50 (m, 2H), 4.53 (s, 2H), 3.34-3.43 (m, 2H), 2.73 (t, J=6.2 Hz, 2H), 1.93 (dt, J=11.2, 5.7 Hz, 2H).
Reaction SMILES: [C:1]([O:9][CH2:10][CH2:11][OH:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:13](Cl)(=[O:31])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]/[CH:21]=[CH:22]\[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]>>[C:13]([O:12][CH2:11][CH2:10][O:9][C:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)(=[O:31])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]/[CH:21]=[CH:22]\[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]
Reactant: O=C(OCCO)c1ccccc1
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)Cl
Product: CCCCCCCC/C=C\CCCCCCCC(=O)OCCOC(=O)c1ccccc1

Procedure:
2-Benzoyloxyethyl oleate was prepared by the procedure of Example 1 from 16 gms (0.1 mole) of ethylene glycol monobenzoate and 30 gms (0.1 mole) of oleoyl chloride. The structure of the final product was characterized on the basis of NMR and IR spectral analyses as described in Example 1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:12][C@@:11]3([CH2:16][C@@H:15]([C:17](O)=[O:18])[N:14]([C:20](=[O:35])[C@@H:21]([NH:26][C:27]([O:29][CH:30]4[CH2:34][CH2:33][CH2:32][CH2:31]4)=[O:28])[C:22]([CH3:25])([CH3:24])[CH3:23])[CH2:13]3)[O:10][C:9]2=[O:36])[CH:5]=[CH:6][CH:7]=1.[NH2:37][C@@H:38]([CH2:47][CH2:48][CH3:49])[CH:39]([OH:46])[C:40]([NH:42][CH:43]1[CH2:45][CH2:44]1)=[O:41]>>[CH:30]1([O:29][C:27](=[O:28])[NH:26][C@@H:21]([C:22]([CH3:25])([CH3:23])[CH3:24])[C:20]([N:14]2[C@H:15]([C:17](=[O:18])[NH:37][C@@H:38]([CH2:47][CH2:48][CH3:49])[CH:39]([OH:46])[C:40]([NH:42][CH:43]3[CH2:44][CH2:45]3)=[O:41])[CH2:16][C@:11]3([O:10][C:9](=[O:36])[N:8]([C:4]4[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=4)[CH2:12]3)[CH2:13]2)=[O:35])[CH2:34][CH2:33][CH2:32][CH2:31]1
Reactant: CC(C)(C)[C@H](NC(=O)OC1CCCC1)C(=O)N1C[C@@]2(C[C@H]1C(=O)O)CN(c1cccc(Cl)c1)C(=O)O2
Reactant: CCC[C@H](N)C(O)C(=O)NC1CC1
Product: CCC[C@H](NC(=O)[C@@H]1C[C@@]2(CN(c3cccc(Cl)c3)C(=O)O2)CN1C(=O)[C@@H](NC(=O)OC1CCCC1)C(C)(C)C)C(O)C(=O)NC1CC1
Yield: 36 %

Procedure:
Following the same procedure as Example 1 step 1 using (5S,8S)-3-(3-chlorophenyl)-7-((S)-2-(cyclopentyloxycarbonylamino)-3,3-dimethylbutanoyl)-2-oxo-1-oxa-3,7-diazaspiro[4.4]nonane-8-carboxylic acid (D3) (10 mg, 20 μmol) and (3S)-3-amino-N-cyclopropyl-2-hydroxyhexanamide (7 mg, 28 μmol) gave 5 mg (7.2 μmol) of Cyclopentyl-(2S)-1-((5S,8S)-3-(3-chlorophenyl)-8-((3S)-1-(cyclopropylamino)-2-hydroxy-1-oxohexan-3-ylcarbamoyl)-2-oxo-1-oxa-3,7-diazaspiro[4.4]nonan-7-yl)-3,3-dimethyl-1-oxobutan-2-ylcarbamate (E3). LC MS+: 690.38 at 3.31 min (10-90%, 3-5 min, Formic Acid).
Reaction SMILES: [CH3:1]C1CCCCO1.[OH:8][C:9]1([C:15]#[C:16][CH2:17][O:18][CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][O:20]2)[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1>>[OH:8][C:9]1(/[CH:15]=[CH:16]/[CH2:17][O:18][CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][O:20]2)[CH2:10][CH2:11][O:12][CH:13]([CH3:1])[CH2:14]1
Reactant: CC1CCCCO1
Reactant: OC1(C#CCOC2CCCCO2)CCOCC1
Product: CC1CC(O)(/C=C/COC2CCCCO2)CCO1

Procedure:
The desired compound was prepared according to the method of Example 3, step 1, except substituting 4-hydroxy-4-[3-tetrahydropyran-2-yloxy)-prop-1-ynyl]-2-methyltetrahydropyran, prepared as in step 1, for 4-hydroxy-4-[3-(tetrahydropyran-2-yloxy)-prop-1-ynyl]tetrahydropyran.
Reaction SMILES: [OH:1][C:2]1[CH2:7][C:6]([CH2:11][CH2:12][C:13]2[CH:17]=[CH:16][S:15][C:14]=2[CH2:18][OH:19])([CH:8]([CH3:10])[CH3:9])[O:5][C:4](=[O:20])[CH:3]=1.[NH2:21][C:22]1[C:27]([CH3:28])=[CH:26][C:25]([S:29]S(C2C=CC(C)=CC=2)(=O)=O)=[C:24]([C:40]([CH3:43])([CH3:42])[CH3:41])[CH:23]=1.CCN(CC)CC>C(#N)C>[NH2:21][C:22]1[C:27]([CH3:28])=[CH:26][C:25]([S:29][C:3]2[C:4](=[O:20])[O:5][C:6]([CH2:11][CH2:12][C:13]3[CH:17]=[CH:16][S:15][C:14]=3[CH2:18][OH:19])([CH:8]([CH3:9])[CH3:10])[CH2:7][C:2]=2[OH:1])=[C:24]([C:40]([CH3:43])([CH3:42])[CH3:41])[CH:23]=1
Reactant: Cc1ccc(S(=O)(=O)Sc2cc(C)c(N)cc2C(C)(C)C)cc1
Reactant: CC(C)C1(CCc2ccsc2CO)CC(O)=CC(=O)O1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1cc(SC2=C(O)CC(CCc3ccsc3CO)(C(C)C)OC2=O)c(C(C)(C)C)cc1N

Procedure:
The title compound was prepared as described in General Method 16b using 4-hydroxy-6-[2-(2-hydroxymethyl-thiophen-3-yl)-ethyl]-6-isopropyl-5,6-dihydro-pyran-2-one (Example E-24; 1 mmol), toluene-4-thiosulfonic acid S-(4-amino-2-tert-butyl-5-methyl-phenyl)ester (Example BB-11; 1.05 mmol), NEt3 (2.2 mmol) in acetonitrile (5 mL). The product was triturated from Et2O, mp 107-115° C. MS (APCI): 488 (M−H).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][C@H:12]([CH2:14]O)[C@H:11]2[O:16][C@@:17]([O:24][CH3:25])([CH3:23])[C@:18]([O:21][CH3:22])([CH3:20])[O:19][C@@H:10]2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:28])=O>C(Cl)(Cl)Cl>[CH2:1]([N:8]1[CH2:13][C@H:12]([CH2:14][Cl:28])[C@H:11]2[O:16][C@@:17]([O:24][CH3:25])([CH3:23])[C@:18]([O:21][CH3:22])([CH3:20])[O:19][C@@H:10]2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CO[C@@]1(C)O[C@@H]2[C@@H](CO)CN(Cc3ccccc3)C[C@H]2O[C@]1(C)OC
Reactant: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Product: CO[C@@]1(C)O[C@@H]2[C@@H](CCl)CN(Cc3ccccc3)C[C@H]2O[C@]1(C)OC
Yield: 83.8 %

Procedure:
To a solution of ((2S,3S,4aR,8R,8aR)-6-benzyl-2,3-dimethoxy-2,3-dimethyloctahydro-[1,4]dioxino[2,3-c]pyridine-8-yl)methanol (1) (2.5 g, 7.1 mmol) in chloroform (35 mL) was added thionyl chloride (1.3 mL, 18 mmol). The resulting mixture was heated at reflux for 4-8 hours until reaction was judged complete by TLC (98:2 CH2Cl2/2-PrOH). Solvent and excess reagent were evaporated in vacuo and the residue was chromatographed (98:2 CH2Cl2/2-PrOH) to give the title compound (2.2 g, 85%). Product was characterized via HPLC/MS (MH+=369). Purity was judged as >95%.
Reaction SMILES: O[CH:2]1[CH2:15][N:14]2[C:5](=[N:6][C:7]3[C:12]([C:13]2=[O:16])=[CH:11][CH:10]=[C:9]([C:17]#[C:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)[CH:8]=3)[CH2:4][CH2:3]1.CCN(S(F)(F)[F:31])CC>C(Cl)Cl>[F:31][CH:2]1[CH2:15][N:14]2[C:5](=[N:6][C:7]3[C:12]([C:13]2=[O:16])=[CH:11][CH:10]=[C:9]([C:17]#[C:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)[CH:8]=3)[CH2:4][CH2:3]1
Reactant: CCN(CC)S(F)(F)F
Reactant: O=c1c2ccc(C#Cc3ccccn3)cc2nc2n1CC(O)CC2
Solvent: ClCCl
Product: O=c1c2ccc(C#Cc3ccccn3)cc2nc2n1CC(F)CC2
Reaction time: 3 h

Procedure:
To a stirred solution of 8-hydroxy-3-(pyridin-2-ylethynyl)-8,9-dihydro-6H-pyrido[2,1-b]quinazolin-11(7H)-one (100 mg, 0.315 mmol, 1 eq) in DCM was added excess DAST under N2 at −78° C. After stirring at the same temperature for 3 hours, the reaction mixture was quenched with water (20 mL) and extracted with ethyl acetate (3×20 mL). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure to give the desired product, which was purified by silica gel chromatography. MS (ESI): 320 (MH+); 1H NMR (300 MHz, DMSO-d6) δ 8.65-8.65 (d, J=3.30 Hz, 1H), 8.17-8.14 (d, J=8.16 Hz, 1H), 7.92-7.87 (t, J=7.5 Hz, 1H), 7.79 (s, 1H), 7.74-7.72 (d, J=7.71 Hz, 1H), 7.67-7.64 (d, J=8.04 Hz, 1H), 7.48-7.47 (m, 1H), 5.50-5.34 (d, J=48.6 Hz, 1H), 4.62-4.52 (t, J=15.9 Hz, 1H), 3.93-3.79 (dd, J=38.1, 15.3 Hz, 1H), 2.96-2.94 (m, 2H), 2.45-2.10 (m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:19][C:20]([CH:22]2[CH2:26][CH2:25][NH:24][C:23]2=[O:27])=[O:21])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[CH:15]=[C:16](I)[S:17][C:10]=12.[CH3:28][NH:29][C:30]([C:32]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=1)=[O:31].C([O-])([O-])=O.[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.COCCOC>[F:1][C:2]1[CH:3]=[C:4]([NH:19][C:20]([CH:22]2[CH2:26][CH2:25][NH:24][C:23]2=[O:27])=[O:21])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[CH:15]=[C:16]([C:35]3[CH:36]=[CH:37][C:32]([C:30](=[O:31])[NH:29][CH3:28])=[CH:33][CH:34]=3)[S:17][C:10]=12
Reactant: CNC(=O)c1ccc(B(O)O)cc1
Reactant: O=C1NCCC1C(=O)Nc1ccc(Oc2ccnc3cc(I)sc23)c(F)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CNC(=O)c1ccc(-c2cc3nccc(Oc4ccc(NC(=O)C5CCNC5=O)cc4F)c3s2)cc1
Temperature: 100 °C
Yield: 23.8 %

Procedure:
A round-bottomed flask was charged with N-(3-fluoro-4-(2-iodothieno[3,2-b]pyridin-7-yloxy)phenyl)-2-oxopyrrolidine-3-carboxamide (15.0 mg, 0.030 mmol), 4-(methyl carbamoyl)phenylboronic acid (16.2 mg, 0.091 mmol), tetrakis(triphenylphosphine)palladium (6.97 mg, 0.0060 mmol), Na2CO3 (0.0754 ml, 0.15 mmol) and DME (10 mL). The reaction mixture was stirred at 100° C. until the starting material had been consumed (4 hours). Then the reaction mixture was cooled to room temperature and partitioned between EtOAc (100 mL) and H2O (100 mL). The phases were separated and the aqueous phase was re-extracted with EtOAc (3×100 mL). The combined organic layers were dried (Na2SO4), filtered and concentrated to yield a crude product. The crude product was purified by silica gel chromatography (DCM/7 M NH3 in MeOH from 50/1 to 10/1, v/v) to give product (3.6 mg, 23.7%). LRMS (APCI pos): >99% purity, 254 nm, m/e 505 (M+1). 1H NMR (400 MHz, CD3OD) δ 8.47 (d, 1H), 7.84-8.00 (m, 6H), 7.32-7.46 (m, 2H), 6.65 (d, 1H), 3.38-3.56 (m, 3H), 2.95 (s, 3H), 2.34-2.62 (m, 2H).
Reaction SMILES: [CH:1]([CH:3]=O)=[O:2].[CH3:5][NH:6][CH2:7][CH2:8][NH:9][CH3:10]>O>[CH3:5][N:6]1[CH2:7][CH2:8][N:9]([CH3:10])[CH2:3][C:1]1=[O:2]
Reactant: O=CC=O
Reactant: CNCCNC
Solvent: O
Product: CN1CCN(C)C(=O)C1
Temperature: 25 °C
Yield: 92.7 %

Procedure:
To 10 g (69.0 mmoles) of 40 percent glyoxal and 200 ml of distilled water is rapidly added 6.1 g (69.0 mmoles) of N,N'-dimethylethylenediamine. The solution is heated rapidly to reflux and heating maintained for 5 minutes. The dark brown solution is allowed to cool to room temperature and is then evaporated at 60° C. under water pump vacuum to a viscous brown oil. The oil is distilled in a short path distillation apparatus to yield 8.2 g (93 percent yield) of 1,4-dimethylpiperazin-2-one in the form of a yellow oil. Purity is greater than 99 percent by capillary gas chromatograph.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([NH:24][C:25]3[N:29]([C:30]([CH3:33])([CH3:32])[CH3:31])[N:28]=[CH:27][CH:26]=3)[N:19]=2)([C:14]([OH:16])=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:34]([O:38][CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)(=[O:37])[NH:35][NH2:36].Cl.CN(C)CCCN=C=NCC.O>C(Cl)(Cl)Cl>[CH2:39]([O:38][C:34]([NH:35][NH:36][C:14]([C:11]1([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([NH:24][C:25]3[N:29]([C:30]([CH3:33])([CH3:31])[CH3:32])[N:28]=[CH:27][CH:26]=3)[N:19]=2)[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9][CH2:10]1)=[O:16])=[O:37])[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1
Reactant: NNC(=O)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC(Cc2cccc(Nc3ccnn3C(C)(C)C)n2)(C(=O)O)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(Cc2cccc(Nc3ccnn3C(C)(C)C)n2)(C(=O)NNC(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 535 mg of 1-(tert-butoxycarbonyl)-4-((6-((1-tert-butyl-1H-pyrazol-5-yl)amino)pyridin-2-yl)methyl)piperidine-4-carboxylic acid in 10 ml of chloroform were added 214 mg of benzyl carbazate and 291 mg of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride at room temperature, followed by stirring the reaction mixture at room temperature for 2 hours. The reaction mixture was poured into water, and extracted with chloroform. The chloroform solution was dried over magnesium sulfate, and filtered. The filtrate was concentrated in vacuo. The resulting residue was purified by a silica gel column chromatography (eluent: hexane to hexane/ethyl acetate=10/1) to give the title compound as a pale brown solid.
Reaction SMILES: Cl[C:2]1([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[O:3]1.C(N(CC)CC)C.[CH2:26]([NH2:29])[CH2:27][CH3:28]>C(OCC)(=O)C>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([C:2]2([OH:3])[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[C:4](=[O:11])[N:29]2[CH2:26][CH2:27][CH3:28])=[CH:13][CH:14]=1
Reactant: O=C1OC(Cl)(c2ccc(Cl)cc2)c2ccccc21
Reactant: CCCN
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCCN1C(=O)c2ccccc2C1(O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 78.6 %

Procedure:
Distilled THF (20 mL) was added to 3-chloro-3-(4-chlorophenyl)-3H-isobenzofuran-1-one (535.4 mg, 1.91 mmol) followed by triethylamine (398.9 mg, 0.549 mL, 3.94 mmol) and n-propylamine (159.8 mg, 0.22 mL, 1.792 mmol). The mixture was stirred at room temperature under nitrogen for 4 hours and monitored by TLC. Upon completion the mixture was then extracted with EtOAc (15 mL) and washed with saturated sodium bicarbonate (3×10 mL), water (3×10 mL) and dried (Na2SO4). Recrysallisation from a minimum amount of boiling ethyl acetate and an excess of petrol yielded the title product as a white crystalline solid (425 mg, 1.409 mmol, 77%). 1H NMR: (300 Hz, CDCl3) δ ppm 0.76 (t, 3H, H11), 1.45 (m, 2H, H10), 2.86 (m, 1H, H9), 3.36 (m, 1H, H9′), 7.16 (d, 1H, H5), 7.38 (dd, 4H, H1-H4), 7.45 (m, 2H, H6-H7), 7.70 (d, 1H, H8). 13C NMR: (75 Hz, DMSO); δ 11.87 (N—CH2—CH2—CH3), 21.96 (N—CH2—CH2), 40.69 (N—CH2), 90.50 (O—C—N), 122.75, 122.99, 128.24, 128.76, 129.58, 131.04, 131.24, 132.73, 133.13, 139.94, 149.59 (Ar), 166.96 (C═O). Mp: 201.5-201.7° C. IR: 1466, 1608, 1664, 2968, 3157 cm−1.