Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [P:1]([O:19][CH2:20][CH2:21][N:22]1[C:30]2[C:25](=[CH:26][C:27]([O:31][C:32]3[CH:37]=[CH:36][C:35]([F:38])=[CH:34][C:33]=3[CH2:39][NH:40][C:41]([NH:43][C:44]3[N:48]([C:49]4[CH:54]=[CH:53][C:52]([CH3:55])=[CH:51][CH:50]=4)[N:47]=[C:46]([C:56]([CH3:59])([CH3:58])[CH3:57])[CH:45]=3)=[O:42])=[CH:28][CH:29]=2)[CH:24]=[N:23]1)([O:11]CC1C=CC=CC=1)([O:3]CC1C=CC=CC=1)=[O:2].C1CC=CCC=1>CCO.CO.[Pd]>[P:1]([O:19][CH2:20][CH2:21][N:22]1[C:30]2[C:25](=[CH:26][C:27]([O:31][C:32]3[CH:37]=[CH:36][C:35]([F:38])=[CH:34][C:33]=3[CH2:39][NH:40][C:41]([NH:43][C:44]3[N:48]([C:49]4[CH:50]=[CH:51][C:52]([CH3:55])=[CH:53][CH:54]=4)[N:47]=[C:46]([C:56]([CH3:59])([CH3:58])[CH3:57])[CH:45]=3)=[O:42])=[CH:28][CH:29]=2)[CH:24]=[N:23]1)([OH:11])([OH:3])=[O:2]
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)NCc2cc(F)ccc2Oc2ccc3c(cnn3CCOP(=O)(OCc3ccccc3)OCc3ccccc3)c2)cc1
Agent: [Pd]
Solvent: CO
Solvent: CCO
Solvent: C1=CCC=CC1
Product: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)NCc2cc(F)ccc2Oc2ccc3c(cnn3CCOP(=O)(O)O)c2)cc1
Yield: 80.9 %

Procedure:
Dibenzyl 2-(5-(2-((3-(3-tert-butyl-1-p-tolyl-1H-pyrazol-5-yl)ureido)methyl)-4-fluorophenoxy)-1H-indazol-1-yl)ethyl phosphate (1.920 g, 2.35 mmol) was suspended in EtOH (0.05M, 50 mL) and cyclohexa-1,4-diene (3.56 ml, 82.14 mmol) and 10% Pd/C (20%/weight, 0.384 g) were added. The reaction mixture was refluxed overnight. The reaction mixture was filtered through GF paper and washed with MeOH. The organic layers were concentrated under reduced pressure to afford the crude material, which was dissolved in MeOH and passed through a Gellman acrodisk (0.45 um) filter to remove trace of palladium contamination. After evaporation of the solvent, the resulting gum was triturated in CH3CN and solids formed were collected by filtration and dried under high vacuum for 3 hours to provide 1.21 g (89%) of the desired compound. MS (APCI+) m/z 637 (M+1) was detected. 1H NMR (400 MHz, DMSO-d6) δ 8.30 (s, 1H), 8.00 (s, 1H), 7.71 (d, 1H, J=9 Hz), 6.88-7.37 (m, 10H), 6.24 (s, 1H), 4.61 (br, 1H), 4.28 (d, 2H, J=5.7 Hz), 4.19 (dd, 2H, J=5.2 Hz), 2.35 (s, 3H), 1.25 (s, 9H).
Reaction SMILES: [CH3:1][C@@H:2]1[NH:7][CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3]1.CCN(C(C)C)C(C)C.[F:24][C:25]([F:38])([F:37])[O:26][C:27]1[CH:32]=[CH:31][C:30]([S:33](Cl)(=[O:35])=[O:34])=[CH:29][CH:28]=1.Cl>ClCCl>[CH3:1][C@@H:2]1[N:7]([S:33]([C:30]2[CH:29]=[CH:28][C:27]([O:26][C:25]([F:24])([F:37])[F:38])=[CH:32][CH:31]=2)(=[O:35])=[O:34])[CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:13])([CH3:12])[CH3:14])=[O:9])[CH2:3]1
Reactant: C[C@H]1CN(C(=O)OC(C)(C)C)CCN1
Reactant: O=S(=O)(Cl)c1ccc(OC(F)(F)F)cc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C[C@H]1CN(C(=O)OC(C)(C)C)CCN1S(=O)(=O)c1ccc(OC(F)(F)F)cc1
Yield: 90.9 %

Procedure:
To a solution of 1,1-dimethylethyl(3S)-3-methyl-1-piperazinecarboxylate (500 mg, 2.497 mmol) in dichloromethane (20 ml) was added DIPEA (0.654 ml, 3.74 mmol) and then portionwise addition of 4-[(trifluoromethyl)oxy]benzenesulfonyl chloride (0.445 ml, 2.62 mmol) at room temperature and the resultant mixture stirred under an atmosphere of argon for 16 hours. The reaction was worked up by the addition of 1M HCl solution (75 mL) and dichloromethane (75 mL), the layers were separated and the organic layer was then washed with 2M NaOH solution (75 mL). The organic phase was separated, dried (MgSO4) and concentrated to dryness to give 1,1-dimethylethyl(3S)-3-methyl-4-({4-[(trifluoromethyl)oxy]phenyl}sulfonyl)-1-piperazinecarboxylate (963 mg, 2.269 mmol). This was dissolved in 1,4-dioxane (4 mL), HCl (4M in 1,4-Dioxane) (2.269 mL, 9.08 mmol) was added and the resultant mixture stirred under an atmosphere of argon for 2 h. After this time a white precipitate had formed so methanol (5 ml) was added to solubilize the precipitate and the reaction stirred for a further 30 min. The reaction was concentrated to dryness giving a white solid which was triturated with Et2O and the solid isolated by filtration under vacuum to give the title compound (585 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:3]=1[O:4][C:5]1[C:10]([C:11]([N:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[NH:16][CH2:15][CH2:14]2)=[O:12])=[CH:9][C:8]([F:23])=[CH:7][N:6]=1.[CH2:29]([O:31][C:32](=[O:35])[CH:33]=O)[CH3:30].C1(C)C=CC=CC=1.C([Sn](Cl)(Cl)CCCC)CCC.C1([SiH3])C=CC=CC=1>>[CH2:29]([O:31][C:32](=[O:35])[CH2:33][N:16]1[C:17]2[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:13]([C:11]([C:10]2[C:5]([O:4][C:3]3[CH:24]=[C:25]([Cl:28])[CH:26]=[CH:27][C:2]=3[Cl:1])=[N:6][CH:7]=[C:8]([F:23])[CH:9]=2)=[O:12])[CH2:14][CH2:15]1)[CH3:30]
Reactant: CCOC(=O)C=O
Reactant: O=C(c1cc(F)cnc1Oc1cc(Cl)ccc1Cl)N1CCNc2ccccc21
Agent: CCCC[Sn](Cl)(Cl)CCCC
Agent: [SiH3]c1ccccc1
Solvent: Cc1ccccc1
Product: CCOC(=O)CN1CCN(C(=O)c2cc(F)cnc2Oc2cc(Cl)ccc2Cl)c2ccccc21
Temperature: 100 °C
Yield: 34 %

Procedure:
To [2-(2,5-dichloro-phenoxy)-5-fluoro-pyridin-3-yl]-(3,4-dihydro-2H-quinoxalin-1-yl)-methanone (200 mg, 0.478 mmol, 1.0 equiv; Example 147) was added a 50% solution of glyoxylic acid ethylester in toluene (1.03 g, 1 mL, 1.913 mmol, 4.0 equiv; [CAS RN 924-44-7]), dibutyltin dichloride (14.6 mg, 0.048 mmol, 0.1 equiv; [CAS RN 683-18-1]) and phenylsilane (103.8 mg, 118 μL, 0.956 mmol, 2.0 equiv; [CAS RN 694-53-1]). The reaction mixture was heated by microwave irradiation to 100° C. for 30 min. Removal of the solvent mixture under reduced pressure and purification by preparative HPLC on reversed phase (Xterra® PrepMSC 18, 5 μm, 19×50 mm column equipped with a Gilson Liquid Handler 215 autosampler, two Rainin Dynamax® SD-300 pumps, a Sedex ELSD 75 lightscatter and a Dionex UVD 340S UV detector) eluting with a gradient of acetonitrile/water provided 82.7 mg (34%) of the title compound as a light yellow solid. MS (ISP): 504.3 [M+H]+.
Reaction SMILES: [NH:1]1[CH:8]=[N:7][C:5]([NH2:6])=[N:4][C:2]1=[O:3].C[Si](N[Si](C)(C)C)(C)C.C[Si](Cl)(C)C.[Si](OS(C(F)(F)F)(=O)=O)(C)(C)C.C(O[C@@H:39]1[O:51][C@H:50]([CH2:52][O:53]C(=O)C)[C@@H:45]([O:46]C(=O)C)[C@H:40]1[O:41]C(=O)C)(=O)C>C(#N)C>[C@@H:39]1([N:1]2[CH:8]=[N:7][C:5]([NH2:6])=[N:4][C:2]2=[O:3])[O:51][C@H:50]([CH2:52][OH:53])[C@@H:45]([OH:46])[C@H:40]1[OH:41]
Reactant: Nc1nc[nH]c(=O)n1
Reactant: CC(=O)OC[C@H]1O[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: C[Si](C)(C)Cl
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: CC#N
Product: Nc1ncn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c(=O)n1
Reaction time: 20 h

Procedure:
A mixture of 5-azacytosine, HMDS, and TMSCl in acetonitrile is heated to reflux for 20 hours under an inert atmosphere. TMS-triflate and 1,2,3,5-tetra-O-acetyl-β-D-ribofuranose are then added directly to the silylated 5-azacytosine in acetonitrile. The addition is performed at ambient temperature and under an inert atmosphere. The reaction mixture is maintained under stirring for 20 hours, then the acetonitrile is removed under vacuum. The solids are then dissolved in dichloromethane, and the mixture is poured over a pre-cooled (0–5° C.) sodium bicarbonate solution (10%). The resulting mixture is extracted with dichloromethane. The combined organic extract is washed with cooled (0–5° C.) 10% sodium bicarbonate and brine, then dried over magnesium sulfate, filtered, and the filtrate concentrated in vacuum to dryness. The off-white foam is dissolved in methanol and treated with a solution of 25% sodium methoxide in methanol. The suspension is stirred at ambient temperature for 15 hours, then the solid is filtered off, washed with methanol and anhydrous ether, then dried in vacuum. The crude 5-azacytidine is further purified from DMSO and methanol (for details see Example 4).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=[CH:5][C:4]=1[N:13]1[C:18](=[O:19])[CH:17]([CH3:20])[O:16][C:15]2[CH:21]=[C:22]([S:25]([N:28](CC3C=CC(OC)=CC=3)[C:29]3[S:30][CH:31]=[CH:32][N:33]=3)(=[O:27])=[O:26])[CH:23]=[CH:24][C:14]1=2.[CH3:43][Si]([N-][Si](C)(C)C)(C)C.[Li+].CI.[Cl-].[NH4+].FC(F)(F)C(O)=O>C1COCC1>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([C:9]([F:11])([F:10])[F:12])[CH:6]=[CH:5][C:4]=1[N:13]1[C:18](=[O:19])[C:17]([CH3:43])([CH3:20])[O:16][C:15]2[CH:21]=[C:22]([S:25]([NH:28][C:29]3[S:30][CH:31]=[CH:32][N:33]=3)(=[O:26])=[O:27])[CH:23]=[CH:24][C:14]1=2
Reactant: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(c2)OC(C)C(=O)N3c2ccc(C(F)(F)F)cc2OC)cc1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [Li+]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CI
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(C(F)(F)F)ccc1N1C(=O)C(C)(C)Oc2cc(S(=O)(=O)Nc3nccs3)ccc21
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
4-(2-Methoxy-4-(trifluoromethyl)phenyl)-N-(4-methoxybenzyl)-2-methyl-3-oxo-N-(thiazol-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide (from the product of Step 2 in Example 263; 110 mg, 0.178 mmol) was dissolved in THF (710 μl) in a 5 mL vial and cooled to 0° C. Lithium bis(trimethylsilyl)amide (1.0 m solution in THF, 69.1 μl, 0.355 mmol) was added dropwise, followed by methyl iodide (16.65 μl, 0.266 mmol), and the reaction was stirred for 30 min at 0° C. until reaction was complete by LCMS. Saturated ammonium chloride solution (aq; 5 mL) was added to the reaction mixture and it was warmed to RT, then extracted with EtOAc (3×5 mL), dried organics over Na2SO4, filtered and concentrated via rotary evaporation. Crude 4-(2-methoxy-4-(trifluoromethyl)phenyl)-N-(4-methoxybenzyl)-2,2-dimethyl-3-oxo-N-(thiazol-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide was dissolved in DCM (177 μl) then treated with 2,2,2-trifluoroacetic acid (328 μl, 4.42 mmol) and stirred at rt for 30 min until reaction was complete by LCMS. The reaction mixture was concentrated and purified via reverse-phase HPLC with a Waters-Xbridge C18, 19×100 mm, 10 μm column with a gradient 5-95% acetonitrile and water with 0.1% TFA modifier to yield title compound. m/z ESI 514.0 (M+H)+.
Reaction SMILES: C[O:2][C:3](=[O:25])[C@@H:4]([N:11]1[CH2:15][C:14]2=[CH:16][C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:22]=3[O:23][CH:13]2[C:12]1=[O:24])[CH2:5][CH:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1.[OH-].[Li+].CCOCC>C1COCC1.O>[CH:6]1([CH2:5][C@H:4]([N:11]2[CH2:15][C:14]3[CH2:16][C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][C:22]=4[O:23][C:13]=3[C:12]2=[O:24])[C:3]([OH:25])=[O:2])[CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: COC(=O)[C@H](CC1CCCC1)N1CC2=Cc3ccccc3OC2C1=O
Agent: [Li+]
Agent: [OH-]
Solvent: CCOCC
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)[C@H](CC1CCCC1)N1CC2=C(Oc3ccccc3C2)C1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 81 %

Procedure:
To a magnetically stirred mixture of (S)-3-Cyclopentyl-2-(3-oxo-3,3a-dihydro-1H-chromeno[2,3-c]pyrrol-2-yl)-propionic acid methyl ester (0.64 g, 1.88 mmol) in THF (9 mL) and water (3 mL) was added lithium hydroxide (0.102 g, 2.44 mmol). After addition was complete the mixture was stirred at 25° C. for 2 hours. The reaction mixture was poured into water and ether and the layers separated. The aqueous layer was made acidic with 2N HCl and extracted with three portions of ethyl acetate. The combined ethyl acetate fractions were washed with a saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated to afford (S)-3-Cyclopentyl-2-(3-oxo-3,9-dihydro-1H-chromeno[2,3-c]pyrrol-2-yl)-propionic acid as a white solid, 500 mg (81% yield). ESI-LRMS m/e calcd for C19H21NO4 [M+] 327, found 328 [M+H+]. (Note: The double bond isomerizes during the course of the reaction based on NMR spectrum)
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]([C:13]2[N:14]=[CH:15][N:16]([C:18]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:17]=2)([OH:12])[CH:9]([CH3:11])[CH3:10])[CH:5]=[CH:6][CH:7]=1.C(B(CC)[C:40]1[CH:41]=[N:42][CH:43]=[CH:44][CH:45]=1)C>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>[CH3:10][CH:9]([CH3:11])[C:8]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([C:40]2[CH:41]=[N:42][CH:43]=[CH:44][CH:45]=2)[CH:3]=1)([C:13]1[N:14]=[CH:15][N:16]([C:18]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:17]=1)[OH:12]
Reactant: CC(C)C(O)(c1cccc(Br)c1)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: CCB(CC)c1cccnc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: CC(C)C(O)(c1cccc(-c2cccnc2)c1)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Yield: 65.3 %

Procedure:
By the reaction in the same manner as in Example 4-(ii) using 1-(3-bromophenyl)-2-methyl-1-(1-trityl-1H-imidazol-4-yl)-1-propanol (1.01 g), diethyl(3-pyridyl)borane (0.497 g) and tetrakis(triphenylphosphine)palladium(0) (0.170 g), the title compound (0.657 g) was obtained as a pale-yellow amorphous powder.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[Cl:7][C:8]1[CH:9]=[C:10]([C:14]2[N:22]([CH2:23][C:24]([OH:26])=O)[C:17]3=[N:18][CH:19]=[CH:20][CH:21]=[C:16]3[N:15]=2)[CH:11]=[CH:12][CH:13]=1.[NH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=1.C(N(CC)CC)C>CN(C)C=O>[Cl:7][C:8]1[CH:9]=[C:10]([C:14]2[N:22]([CH2:23][C:24]([NH:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=3)=[O:26])[C:17]3=[N:18][CH:19]=[CH:20][CH:21]=[C:16]3[N:15]=2)[CH:11]=[CH:12][CH:13]=1
Reactant: O=C(O)Cn1c(-c2cccc(Cl)c2)nc2cccnc21
Reactant: Nc1ccccn1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(Cn1c(-c2cccc(Cl)c2)nc2cccnc21)Nc1ccccn1
Temperature: 0 °C
Yield: 15.8 %

Procedure:
Under a nitrogen atmosphere, oxalyl chloride (2.38 g, 0.019 mole) was added slowly dropwise to a stirred and chilled (15°-20° C.) solution of 2-(3-chlorophenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid (4.70 g, 0.016 mole) in 50 ml of dimethylformamide. The reaction mixture was stirred at ambient temperature for 1/2 hr., then warmed to 60°-65° C. for 5 hrs. This acylchloride solution was added dropwise under nitrogen to a stirred and chilled (15°-20° C.) solution of 2-aminopyridine (1.76 g, 0.019 mole), triethylamine (1.89 g, 0.019 mole), and 30 ml of dimethylformamide. The reaction mixture was stirred at room temperature over the weekend. The reaction mixture was poured into 400 ml of ice water and extracted with ethyl acetate (3×). The ethyl acetate layers were washed with 5% potassium hydroxide (2×50 ml), water (2×50 ml), dried, and filtered. The residue was treated with isopropyl alcohol and excess ethereal hydrogen chloride to give solid which was recrystallized twice from isopropyl alcohol-isopropyl ether and once from isopropyl alcohol. The solid was collected by filtration, washed with cold isopropyl alcohol, then isopropyl alcohol-water, and dried under high vacuum for 2 days to give 0.92 g (15.8%) of title compound, mp 165°-66° C.
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=1)(=[O:6])[OH:5])[CH3:2].C(Cl)(=O)C(Cl)=O.[C:24]1([CH2:30][CH2:31][CH2:32]O)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.FC(F)(F)C1C=C(C=CC=1)CP(=O)(OCC)OCl.C(N(CC)CC)C>C(Cl)Cl.CN(C=O)C>[F:16][C:14]([F:17])([F:15])[C:10]1[CH:9]=[C:8]([CH:13]=[CH:12][CH:11]=1)[CH2:7][P:4](=[O:5])([O:6][CH2:32][CH2:31][CH2:30][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[O:3][CH2:1][CH3:2]
Reactant: OCCCc1ccccc1
Reactant: CCOP(=O)(O)Cc1cccc(C(F)(F)F)c1
Agent: CCOP(=O)(Cc1cccc(C(F)(F)F)c1)OCl
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCOP(=O)(Cc1cccc(C(F)(F)F)c1)OCCCc1ccccc1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
3-trifluoromethylbenzylphosphonic acid mono ethyl ester (1.5 g, 5.6 mmol) was dissolved in 20 mL of CH2Cl2 and cooled to 0° C. under nitrogen. After the oxalyl chloride (8.46 mmol) had been added, 0.04 mL of DMF was slowly added in 3 portions, and the resultant mixture was stirred at room temperature for 3 hours. Evaporation in vacuo gave the crude acid chloride which was used without further purification. 3-Phenyl-1-propanol (0.76 g, 5.6 mmol), in 15 mL of CH2Cl2, was added to a cold mixture of crude chloro ethyl 3-trifluoromethylbenzylphosphonate (5.6 mmol), triethylamine (0.85 g, 8.4 mmol), and CH2Cl2 (20 mL) cooled at 0° C. The resultant reaction mixture was allowed to stir at room temperature for 4 hours. Evaporation of the volatile components gave a quantitative yield of the expected product. Purification by column chromatography (silica gel, 25% ethyl acetate/hexane) gave 1.66 g (52.3%) of analytically pure product as a pale yellow oil. D.C.I.M.S.[MH+, 387].
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:24]=[CH:25][C:26]=1[F:27])[CH2:5][C@H:6]1[CH2:11][C@@H:10]([C:12](=[O:19])[CH2:13][C:14](OCC)=[O:15])[CH2:9][CH2:8][N:7]1[C:20]([O:22][CH3:23])=[O:21].[OH-].[Na+].[NH2:30]O.Cl>CO.O>[F:1][C:2]1[CH:3]=[C:4]([CH:24]=[CH:25][C:26]=1[F:27])[CH2:5][C@H:6]1[CH2:11][C@@H:10]([C:12]2[O:19][NH:30][C:14](=[O:15])[CH:13]=2)[CH2:9][CH2:8][N:7]1[C:20]([O:22][CH3:23])=[O:21]
Reactant: CCOC(=O)CC(=O)[C@H]1CCN(C(=O)OC)[C@@H](Cc2ccc(F)c(F)c2)C1
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COC(=O)N1CC[C@H](c2cc(=O)[nH]o2)C[C@@H]1Cc1ccc(F)c(F)c1
Temperature: -40 °C
Reaction time: 0.33 h
Yield: 66.4 %

Procedure:
Cis-methyl 2-(3,4-difluorobenzyl)-4-(3-ethoxy-3-oxopropanoyl)piperidine-1-carboxylate (2.233 g, 5.82 mmol) was dissolved in MeOH (20 mL) and cooled to −40° C. under nitrogen. Sodium hydroxide (0.233 g, 5.82 mmol) dissolved in water (2.000 mL) was added during 10 min and the yellow solution continued to stir at −40° C. for 20 min. Hydroxylamine (50% by weight in water, 0.357 mL, 5.82 mmol) was added during 8 min. The resulting solution was stirred at −40° C. for 3 h. The mixture was then rapidly poured into a prewarmed (80° C.) solution of 6 M hydrogen chloride (30 mL, 180.00 mmol) and the mixture continued to stir at 80° C. for 20 min. The solvent was evaporated and DCM/water added. The phases were separated and the organic phase passed through a phase separator and evaporated to yield a yellow semi-solid. The compound was purified by preparative HPLC in 3 injections on a XBridge C18 column (10 μm 250×50 ID mm) using a gradient of 0-25% Acetonitrile in H2O/MeCN/NH3 95/5/0.2 buffer over 20 minutes with a flow of 100 mL/min. Cis-methyl 2-(3,4-difluorobenzyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate (1.361 g, 66%) was isolated as a white solid. 1H NMR (400 MHz, cdcl3) δ 1.84-2.14 (m, 4H), 2.52-2.62 (m, 1H), 2.71-2.80 (m, 1H), 2.95-3.05 (m, 1H), 3.09-3.20 (m, 1H), 3.64 (s, 3H), 3.95-4.06 (m, 1H), 4.20-4.30 (m, 1H), 5.74 (s, 1H), 6.77-6.83 (m, 1H), 6.90-6.98 (m, 1H), 6.98-7.09 (m, 1H). MS m/z 353 (M+H)+
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1)[N:6]=[C:5]2[NH:18][CH3:19].C(O[C:24](=[O:26])[CH3:25])(=O)C>C(O)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1)[N:6]=[C:5]2[N:18]([CH3:19])[C:24](=[O:26])[CH3:25]
Reactant: CC(=O)OC(C)=O
Reactant: CNc1nc(-c2cccnc2)nc2ccc(Br)cc12
Solvent: CC(=O)O
Product: CC(=O)N(C)c1nc(-c2cccnc2)nc2ccc(Br)cc12
Temperature: 195 °C
Yield: 52.2 %

Procedure:
To a solution of 6-bromo-N-methyl-2-(pyridin-3-yl)quinazolin-4-amine (1.20 g, 3.81 mmol) in acetic acid (10 mL) was added acetic anhydride (1.94 g, 19.0 mmol) and stirred at 195° C. using microwave for 6 h. The reaction mixture was checked by LC-MS, no starting material was observed, ice was added into the reaction. The precipitate was collected by filtration and washed with water. The product was dried at 60° C. to give N-(6-bromo-2-(pyridin-3-yl)quinazolin-4-yl)-N-methylacetamide (711 mg, 52%) as a light brown powder. 1H NMR (300 MHz, CDCl3) δ 9.76 (dd, J=2.2, 0.8 Hz, 1H), 8.85-8.79 (m, 1H), 8.76 (dd, J=4.8, 1.7 Hz, 1H), 8.09 (dd, J=1.8, 0.8 Hz, 1H), 8.05-8.01 (m, 2H), 7.46 (ddd, J=8.0, 4.8, 0.8 Hz, 1H), 3.52 (s, 3H), 2.11 (s, 3H).
Reaction SMILES: [CH2:1]([S:3][C:4]1[C:9]([NH:10][C:11](=[O:19])OC2C=CC=CC=2)=[C:8]([S:20][CH2:21][CH3:22])[CH:7]=[C:6]([CH3:23])[N:5]=1)[CH3:2].C(N(CC)CC)C.[CH2:31]([NH:38][CH2:39][CH2:40][N:41]1[CH2:46][CH2:45][N:44]([CH2:47][CH2:48][OH:49])[CH2:43][CH2:42]1)[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37]>C1(C)C=CC=CC=1.O>[CH2:1]([S:3][C:4]1[C:9]([NH:10][C:11](=[O:19])[N:38]([CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[CH2:39][CH2:40][N:41]2[CH2:46][CH2:45][N:44]([CH2:47][CH2:48][OH:49])[CH2:43][CH2:42]2)=[C:8]([S:20][CH2:21][CH3:22])[CH:7]=[C:6]([CH3:23])[N:5]=1)[CH3:2]
Reactant: CCCCCCCNCCN1CCN(CCO)CC1
Reactant: CCSc1cc(C)nc(SCC)c1NC(=O)Oc1ccccc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: O
Product: CCCCCCCN(CCN1CCN(CCO)CC1)C(=O)Nc1c(SCC)cc(C)nc1SCC
Temperature: 80 °C
Reaction time: 2 h
Yield: 88.5 %

Procedure:
To a solution of this phenyl carbamate (1.46 g, 4.19 mmol) in toluene (20 ml) were added triethylamine (509 mg, 5.03 mmol) and 2-[4-(2-heptylaminoethyl)piperazin-1-yl]ethanol (1.14 g, 4.20 mmol) obtained in Example 16 and the mixture was stirred at 80° C. for 2 hours. The reaction solution was diluted with water and extracted with chloroform. The organic layer was washed with water and a saturated sodium chloride solution successively, dried over anhydrous sodium sulfate and concentrated in vacuo. The resulting residue was purified by a silica gel column chromatography (silica gel 100 g, developing solvent; chloroform:methanol=40:1 20:1) to provide 1.95 g (yield 88%) of N′-[2,4-bis(ethylthio)-6-methyl-3-pyridyl]-N-heptyl-N-[2-[4-(2-hydroxyethyl)piperazin-1-yl]ethyl]urea as pale yellow oil.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH:36][S:37]([CH3:40])(=[O:39])=[O:38])[C:8]([O:34][CH3:35])=[C:9]([NH:11][C:12]([C:14]2[N:15]([CH3:33])[C:16]3[C:21]([CH:22]=2)=[CH:20][CH:19]=[CH:18][C:17]=3[CH2:23][N:24]2[CH2:29][CH2:28][CH:27]([C:30]([OH:32])=O)[CH2:26][CH2:25]2)=[O:13])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:41][N:42]1[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]1>O1CCCC1>[C:1]([C:5]1[CH:6]=[C:7]([NH:36][S:37]([CH3:40])(=[O:38])=[O:39])[C:8]([O:34][CH3:35])=[C:9]([NH:11][C:12]([C:14]2[N:15]([CH3:33])[C:16]3[C:21]([CH:22]=2)=[CH:20][CH:19]=[CH:18][C:17]=3[CH2:23][N:24]2[CH2:29][CH2:28][CH:27]([C:30]([N:45]3[CH2:46][CH2:47][N:42]([CH3:41])[CH2:43][CH2:44]3)=[O:32])[CH2:26][CH2:25]2)=[O:13])[CH:10]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: CN1CCNCC1
Reactant: COc1c(NC(=O)c2cc3cccc(CN4CCC(C(=O)O)CC4)c3n2C)cc(C(C)(C)C)cc1NS(C)(=O)=O
Solvent: C1CCOC1
Product: COc1c(NC(=O)c2cc3cccc(CN4CCC(C(=O)N5CCN(C)CC5)CC4)c3n2C)cc(C(C)(C)C)cc1NS(C)(=O)=O

Procedure:
1-[2-(5-tert-butyl-3-methanesulphonylamino-2-methoxy-phenylcarbamoyl)-1-methyl-1H-indol-7-ylmethyl]-piperidine-4-carboxylic acid and 1-methylpiperazine are used as reactants. Tetrahydrofuran is used instead of N,N-dimethylformamide.