Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:10]([NH:13][C:14]2[CH:19]=[CH:18][N:17]3[N:20]=[CH:21][C:22]([C:23]([OH:25])=O)=[C:16]3[N:15]=2)[CH2:11][OH:12])[C:5]([O:8][CH3:9])=[N:6][CH:7]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.C(N(CC)CC)C.Cl.[Cl:55][CH2:56][CH2:57][CH2:58][NH2:59]>C(Cl)Cl.CN(C=O)C>[Cl:55][CH2:56][CH2:57][CH2:58][NH:59][C:23]([C:22]1[CH:21]=[N:20][N:17]2[CH:18]=[CH:19][C:14]([NH:13][C@@H:10]([C:4]3[C:5]([O:8][CH3:9])=[N:6][CH:7]=[C:2]([F:1])[CH:3]=3)[CH2:11][OH:12])=[N:15][C:16]=12)=[O:25]
Reactant: NCCCCl
Reactant: COc1ncc(F)cc1[C@@H](CO)Nc1ccn2ncc(C(=O)O)c2n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1ncc(F)cc1[C@@H](CO)Nc1ccn2ncc(C(=O)NCCCCl)c2n1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 101.4 %

Procedure:
To a suspension of (S)-5-(1-(5-fluoro-2-methoxypyridin-3-yl)-2-hydroxyethylamino)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (50 mg, 0.14 mmol) in DCM (2 mL) was added HOBt (44 mg, 0.29 mmol) followed by EDCI (83 mg, 0.43 mmol). The heterogeneous mixture was stirred at ambient temperature for 10 minutes then treated with triethylamine (100 μL, 0.72 mmol) followed by 3-chloro-propylamine hydrochloride (56 mg, 0.43 mmol). The mixture was stirred for 2 hours, then DMF (2 mL) was added and stirring was continued for 48 hours. The mixture was partitioned between saturated NH4Cl solution (20 mL) and EtOAc (20 mL) and the layers were separated. The aqueous layer was extracted with EtOAc (2×10 mL) and the combined organic phases were washed with water (5×10 mL) and brine (10 mL), then dried over Na2SO4, filtered and concentrated to afford (S)-N-(3-chloropropyl)-5-(1-(5-fluoro-2-methoxypyridin-3-yl)-2-hydroxyethylamino)pyrazolo[1,5-a]pyrimidine-3-carboxamide (60 mg, 99% yield) as a pale yellow foam which was used without further purification. MS (apci) m/z=423.0 (M+H).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:8]2([OH:18])[CH2:17][CH2:16][C:11]3([O:15][CH2:14][CH2:13][O:12]3)[CH2:10][CH2:9]2)=[N:6][CH:7]=1.C([Mg]Cl)(C)C.C1(P(C2C=CC=CC=2)CCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Cl[C:53]1[CH:58]=[N:57][CH:56]=[CH:55][N:54]=1>C1COCC1.C/C(/[O-])=C/C(C)=O.C/C(/[O-])=C/C(C)=O.[Ni+2]>[N:54]1[CH:55]=[CH:56][N:57]=[CH:58][C:53]=1[C:2]1[CH:3]=[CH:4][C:5]([C:8]2([OH:18])[CH2:17][CH2:16][C:11]3([O:15][CH2:14][CH2:13][O:12]3)[CH2:10][CH2:9]2)=[N:6][CH:7]=1
Reactant: OC1(c2ccc(Br)cn2)CCC2(CC1)OCCO2
Reactant: Clc1cnccn1
Agent: [Ni+2]
Agent: CC(=O)/C=C(/C)[O-]
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: OC1(c2ccc(-c3cnccn3)cn2)CCC2(CC1)OCCO2
Reaction time: 1 h
Yield: 19.1 %

Procedure:
To a solution of 8-(5-bromopyridin-2-yl)-1,4-dioxaspiro[4.5]decan-8-ol (0.50 g, 1.59 mmol) in THF (7.5 mL) was dropwise added isopropyl magnesium chloride (2 M in THF, 1.8 mL) at rt. After stirred for 1 hour, the solution was degassed with N2 three times. To another degassed solution of THF (2.5 mL) at rt was added nickel acetylacetonate (20 mg, 0.080 mmol) and 1,2-bis(diphenylphosphino)-ethane (32 mg, 0.080 mmol) under N2 flush. After stirred for 10 mins, 2-chloropyrazine (0.155 mL, 1.59 mmol) was added in, and the resulting mixture was stirred for 30 minutes. The mixture was then transferred to a freshly prepared solution of the Grignard reagent prepared previously. The mixture was stirred at rt for 18 hours, and was quenched with saturated NH4Cl solution. The aqueous solution was extracted with ethyl acetate, and the combined organic phase was washed with saline solution (2×50 mL), dried over MgSO4, concentrated in vacuo. The residue was chromatographed on SiO2, eluted with hexane/ethyl acetate (1 to 1), and the appropriate fractions were collected to provide 8-(5-pyrazin-2-ylpyridin-2-yl)-1,4-dioxaspiro[4.5]decan-8-ol (95 mg, 19%) as an oil. LCMS: 314.2 (M+H+, 100%).
Reaction SMILES: [C:1]([C:3]1[N:8]=[C:7]([CH2:9][CH2:10][CH2:11][CH2:12][C:13]([O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])=[O:14])[CH:6]=[CH:5][CH:4]=1)#[N:2].[C:22](OC)(=[O:30])[C:23]1[C:24](=[CH:26][CH:27]=[CH:28][CH:29]=1)[SH:25].C(N(CC)CC)C>C1(C)C=CC=CC=1>[O:30]=[C:22]1[C:23]2[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=2[S:25][C:1]([C:3]2[N:8]=[C:7]([CH2:9][CH2:10][CH2:11][CH2:12][C:13]([O:15][CH2:16][CH2:17][Si:18]([CH3:20])([CH3:19])[CH3:21])=[O:14])[CH:6]=[CH:5][CH:4]=2)=[N:2]1
Reactant: COC(=O)c1ccccc1S
Reactant: C[Si](C)(C)CCOC(=O)CCCCc1cccc(C#N)n1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: C[Si](C)(C)CCOC(=O)CCCCc1cccc(-c2nc(=O)c3ccccc3s2)n1
Yield: 26.1 %

Procedure:
2-(Trimethylsilyl)ethyl 5-(6-cyano-2-pyridyl)valerate (1.0 g, 3.3 mmol) and methyl thiosalicylate (0.85 g, 5.0 mmol) were dissolved in toluene (4 ml), and triethylamine (0.85 ml, 8.4 mmol) was added thereto. The reaction mixture was refluxed for 10 hrs and subjected to a silica gel (75 g) column chromatography. The fractions eluted with hexane-ethyl acetate (4:1, v/v) were collected and concentrated to give the titled compound (0.38 g, 27%) as white crystals.
Reaction SMILES: [Cl:1][CH:2]([Cl:6])[C:3](Cl)=[O:4].[CH3:7][CH:8]1[NH:13][C:12]2[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=2[O:10][CH2:9]1.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC=CC=1.O.C(OCC)(=O)C>[Cl:1][CH:2]([Cl:6])[C:3]([N:13]1[C:12]2[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=2[O:10][CH2:9][CH:8]1[CH3:7])=[O:4]
Reactant: O=C(Cl)C(Cl)Cl
Reactant: CC1COc2ccccc2N1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: c1ccccc1
Solvent: O
Product: CC1COc2ccccc2N1C(=O)C(Cl)Cl
Reaction time: 0.5 h
Yield: 83 %

Procedure:
5.3 ml (55 mmoles) of dichloroacetyl chloride are added dropwise, at a temperature of 20° to 25° C. and while stirring, to a suspension of 7.5 g (50 mmoles) of 2,3-dihydro-3-methyl-1,4-benzoxazine and 5.8 g (55 mmoles) of sodium carbonate in 120 ml of benzene. The reaction mixture is then stirred at the same temperature for 30 minutes and is then taken up in a mixture of water and ethyl acetate. The organic phase is washed with saturated sodium chloride solution, dried over sodium sulfate and evaporated. Crystallising the residue from diisopropyl ether gives 10.8 g of 4-dichloroacetyl-2,3-dihydro-3-methyl-1,4-benzoxazine, melting point 105°-107° C.
Reaction SMILES: [OH-].[K+].Cl[C:4]1[C:13]2[C:8](=[CH:9][C:10]([O:16][CH3:17])=[C:11]([O:14][CH3:15])[CH:12]=2)[N:7]=[CH:6][CH:5]=1.[OH:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([OH:25])[CH:20]=1>>[CH3:15][O:14][C:11]1[CH:12]=[C:13]2[C:8](=[CH:9][C:10]=1[O:16][CH3:17])[N:7]=[CH:6][CH:5]=[C:4]2[O:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([OH:25])[CH:20]=1
Reactant: COc1cc2nccc(Cl)c2cc1OC
Reactant: Oc1cccc(O)c1
Agent: [K+]
Agent: [OH-]
Product: COc1cc2nccc(Oc3cccc(O)c3)c2cc1OC
Temperature: 140 °C
Reaction time: 1 h
Yield: 78 %

Procedure:
Potassium hydroxide (14 mg, 0.25 mmol) and 4-chloro-6,7-dimethoxyquinoline (50 mg, 0.22 mmol), (prepared as described for the starting material in Example 2), were added to 1,3-dihydroxybenzene (1 g, 9 mmol) melted at 140° C. under argon. After stirring for 1 hour at 140° C., the mixture was partitioned between ethyl acetate and water and 2M hydrochloric acid was added to adjust the aqueous phase to pH4. The organic layer was washed with water, brine, dried (MgSO4) and the volatiles were removed by evaporation. The residue was purified by column chromatography eluting with methylene chloridelethyl acetate (6/4 increasing to 3/7). The purified product was triturated with ether, collected by filtration and dried under vacuum to give 6,7-dimethoxy-4-(3-hydroxyphenoxy)quinoline (51 mg 78%).
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]([C:19]([O:21]CC)=[O:20])=[C:5]([O:7][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:15]([F:18])([F:17])[F:16])[N:6]=1.[Li+].[OH-].[OH-].[Na+].C(OCC)C>O1CCCC1>[Cl:1][C:2]1[S:3][C:4]([C:19]([OH:21])=[O:20])=[C:5]([O:7][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:15]([F:17])([F:16])[F:18])[N:6]=1
Reactant: CCOC(=O)c1sc(Cl)nc1OCc1ccccc1C(F)(F)F
Agent: [Li+]
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOCC
Product: O=C(O)c1sc(Cl)nc1OCc1ccccc1C(F)(F)F
Yield: 84.8 %

Procedure:
Ethyl 2-chloro-4-({[2-(trifluoromethyl)phenyl]methyl}oxy)-1,3-thiazole-5-carboxylate (0.535 g, 1.46 mmol) was dissolved in 15 mL of tetrahydrofuran with stirring, and 15 mL of 1N LiOH solution was added via pipet. The mixture was stirred for 18 hours, and poured into 0.1 N NaOH and diethyl ether. The layers were separated, and the aqueous layer was acidified to pH 2 with concentrated HCl. The mixture was filtered and the white solid was washed with water. The solid was air dried, collected, and dried further under vacuum to yield 0.418 g (85%) of 2-chloro-4-({[2-(trifluoromethyl)phenyl]methyl}oxy)-1,3-thiazole-5-carboxylic acid. 1H NMR (400 MHz, DMSO-d6) δ 13.22 (br s, 1H), 7.83-7.70 (m, 3H), 7.58 (m, 1H), 5.59 (s, 2H).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[F:15])=[N:6][CH:7]=1.[O:16]1CCC[CH2:17]1.C([Li])CCC.CN(C)C=O>O>[F:15][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[O:8][C:5]1[N:6]=[CH:7][C:2]([CH:17]=[O:16])=[CH:3][CH:4]=1
Reactant: Fc1ccccc1Oc1ccc(Br)cn1
Reactant: C1CCOC1
Agent: [Li]CCCC
Solvent: O
Solvent: CN(C)C=O
Product: O=Cc1ccc(Oc2ccccc2F)nc1
Temperature: 0 °C
Yield: 53 %

Procedure:
To a mixture of 5-bromo-2-(2-fluoro-phenoxy)-pyridine (500 mg, 1.9 mmol) described in Manufacturing Example 74-1-1 and tetrahydrofuran (7 mL) was added n-butyl lithium (1.7 mL, 1.5 M n-hexane solution, 2.6 mmol) under nitrogen atmosphere at −78° C. N,N-dimethylformamide (0.29 mL, 3.7 mmol) was added to the reaction mixture at the same temperature, and the temperature was then gradually raised to 0° C. Water was added to the reaction solution, which was then extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, and was concentrated under a reduced pressure. The residue was purified by silica gel column chromatography (heptane:ethyl acetate=2:1) to obtain the title compound (210 mg, 53%).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH:11]([OH:13])[CH3:12])=[CH:3][CH:2]=1>ClCCl.[O-2].[Mn+2]>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11](=[O:13])[CH3:12])=[CH:3][CH:2]=1
Reactant: CC(O)c1ccnc2ccccc12
Agent: [Mn+2]
Agent: [O-2]
Solvent: ClCCl
Product: CC(=O)c1ccnc2ccccc12
Temperature: 25 °C
Yield: 100 %

Procedure:
To the mixture of manganese oxide (8.69 g, 100 mmol, Aldrich) in dichloromethane (80 mL) was added 1-quinolin-4-yl-ethanol (1.73 g, 10 mmol). The reaction mixture was refluxed for overnight and then cooled to room temperature. The solid was filtered out through Celite pad. The organic solution dried over anhydrous magnesium sulfate and concentrated via vacuo to give crude title compound as light yellow solid in 100% yield (1.71 g, 10.0 mmol).
Reaction SMILES: [N+:1]([C:4]([N+:13]([O-:15])=[O:14])([N+:10]([O-:12])=[O:11])[CH2:5][CH2:6][C:7](Cl)=[O:8])([O-:3])=[O:2].[F:16][C:17]([F:23])([F:22])[C:18]([NH:20][NH2:21])=[O:19].N1C=CC=CC=1.Cl>C(OCC)C>[N+:1]([C:4]([N+:13]([O-:15])=[O:14])([N+:10]([O-:12])=[O:11])[CH2:5][CH2:6][C:7]([NH:21][NH:20][C:18](=[O:19])[C:17]([F:23])([F:22])[F:16])=[O:8])([O-:3])=[O:2]
Reactant: NNC(=O)C(F)(F)F
Reactant: O=C(Cl)CCC([N+](=O)[O-])([N+](=O)[O-])[N+](=O)[O-]
Agent: Cl
Solvent: CCOCC
Solvent: c1ccncc1
Product: O=C(CCC([N+](=O)[O-])([N+](=O)[O-])[N+](=O)[O-])NNC(=O)C(F)(F)F
Reaction time: 0.05 h

Procedure:
To 1.65 g (0.007 mole) of 4,4,4-trinitrobutyryl chloride in 15 mL of anhydrous diethyl ether stirred in a water bath at 15° C. was added 0.9 g (0.007 mole) of N-(trifluoroacetyl)hydrazine. Pyridine (0.6 mL, 0.007 mole) was added dropwise. After 3 minutes, dilute hydrochloric acid was added and the ether layer was separated and dried (Na2SO4). The volatiles were removed and the residue was stirred with water and then with CH2Cl2 to give the product N-(4,4,4-trinitrobutyryl)-N'-(trifluoroacetyl)hydrazine, 1.15 g (50%), mp 154°-156° C. Crystallization from 1,2-dichloroethane raised the melting point to 157°-159° C.; 1H NMR (acetone-d6 +D2O): 2.97 (t, 2H), 3.86 (t, 2H); IR (KBr): 3330, 3220 (NH), 1745, 1690 (C=O); 1610, 1590 (NO2); 1195 (C--F).
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[C:11]([CH2:13][CH2:14][N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)[CH:10]=[CH:9][C:8]=2[NH:21][C:22]([C:24]2[N:25](COCC[Si](C)(C)C)[C:26]([S:29][CH3:30])=[N:27][CH:28]=2)=[O:23])[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.[C:39]([OH:45])([C:41]([F:44])([F:43])[F:42])=[O:40]>C(Cl)Cl>[F:42][C:41]([F:44])([F:43])[C:39]([OH:45])=[O:40].[C:1]1([C:7]2[CH:12]=[C:11]([CH2:13][CH2:14][N:15]3[CH2:16][CH2:17][O:18][CH2:19][CH2:20]3)[CH:10]=[CH:9][C:8]=2[NH:21][C:22]([C:24]2[NH:25][C:26]([S:29][CH3:30])=[N:27][CH:28]=2)=[O:23])[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1
Reactant: CSc1ncc(C(=O)Nc2ccc(CCN3CCOCC3)cc2C2=CCCCC2)n1COCC[Si](C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CSc1ncc(C(=O)Nc2ccc(CCN3CCOCC3)cc2C2=CCCCC2)[nH]1
Temperature: 25 °C
Reaction time: 6 h
Yield: 36 %

Procedure:
To a solution of 2-methylsulfanyl-3-(2-trimethylsilanyl-ethoxymethyl)-3H-imidazole-4-carboxylic acid [2-cyclohex-1-enyl-4-(2-morpholin-4-yl-ethyl)-phenyl]-amide (100 mg, 0.18 mmol)(as prepared in the previous step) in 1 mL of DCM was added 1 mL of TFA and the mixture stirred at RT for 6 h. The mixture was concentrated and the title compound purified by RP-HPLC on a C18 column eluting with a linear gradient of 35-55% CH3CN in 0.1% TFA/H2O over 8 min to give 35 mg (36%) of a white solid. 1H-NMR (400 MHz, CD3OD): δ 8.22 (d, J=8.4 Hz, 1H), 7.71 (s, 1H), 7.20 (dd, J=8.4, 2.2 Hz, 1H), 7.12 (d, J=2.2 Hz, 1H), 5.79 (m, 1H), 4.07 (m 2H), 3.82 (m, 2H), 3.57 (m, 2H), 3.40 (m, 2H), 3.20 (m, 2H), 3.15 (m, 2H), 2.65 (s, 3H), 2.30-2.22 (m, 4H), 1.88-1.72 (m, 4H). Mass spectrum (ESI, m/z): Calcd. for C23H30N4O2S, 427.2 (M+H). found 427.1.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10]2[N:11]=[C:12]([CH2:15][N:16]3[CH:20]=[C:19]([C:21]([O:23]CC)=[O:22])[CH:18]=[N:17]3)[S:13][CH:14]=2)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[OH-].[Na+].Cl>O1CCCC1CCO.[Cl-].[Na+].O>[N+:1]([C:4]1[CH:5]=[C:6]([C:10]2[N:11]=[C:12]([CH2:15][N:16]3[CH:20]=[C:19]([C:21]([OH:23])=[O:22])[CH:18]=[N:17]3)[S:13][CH:14]=2)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: CCOC(=O)c1cnn(Cc2nc(-c3cccc([N+](=O)[O-])c3)cs2)c1
Agent: Cl
Agent: OCCC1CCCO1
Agent: [Cl-]
Solvent: O
Product: O=C(O)c1cnn(Cc2nc(-c3cccc([N+](=O)[O-])c3)cs2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.2 %

Procedure:
To a mixed solution of the compound (250 mg, 0.70 mmol) obtained in Example 25a in tetrahydrofuran-ethanol (v/v=1/1, 7 ml) was added 2N aqueous sodium hydroxide solution (1.4 mL, 2.8 mmol), and the mixture was stirred at room temperature overnight. The reaction mixture was neutralized with 1N aqueous hydrochloric acid solution, saturated brine was added, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the produced crude title compound was recrystallized (ethyl acetate-hexane) to give the title compound (227 mg, 98%) as colorless crystals.
Reaction SMILES: [Br:1][C:2]1[C:10]2[O:9][CH:8]=[C:7]([CH3:11])[C:6]=2[C:5]([F:12])=[C:4]([F:13])[CH:3]=1.C1C(=O)[N:18](Br)[C:16](=O)C1.[C-]#N.[Na+].[OH-].[Na+]>O.C(Cl)(Cl)(Cl)Cl>[Br:1][C:2]1[C:10]2[O:9][CH:8]=[C:7]([CH2:11][C:16]#[N:18])[C:6]=2[C:5]([F:12])=[C:4]([F:13])[CH:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1coc2c(Br)cc(F)c(F)c12
Agent: [C-]#N
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClC(Cl)(Cl)Cl
Product: N#CCc1coc2c(Br)cc(F)c(F)c12
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 36 %

Procedure:
To the compound (98.8 mg, 0.400 mmol) of Step 1 of Example 21, NBS (78.3 mg, 0.440 mmol), and a catalytic amount of BPO, carbon tetrachloride (4 mL) was added, and heated under reflux overnight. The resultant was returned to room temperature, and the solvent was distilled away under reduced pressure. The resulting residue was diluted with dichloromethane, washed with a saturated aqueous sodium hydrogen carbonate solution and saturated brine, and then dried over anhydrous magnesium sulfate. The solvent was distilled away under reduced pressure. The resulting residue was dissolved in acetonitrile (2 mL), and sodium cyanide (39.2 mg, 0.800 mmol) and water (0.2 mL) were added thereto, and stirred at 50° C. for 30 minutes. To the reaction solution, a 1 N sodium hydroxide aqueous solution was added. After concentrated under reduced pressure, the resultant was diluted with ethyl acetate, washed with water and saturated brine, and then dried over anhydrous magnesium sulfate. The solvent was distilled away under reduced pressure. The resulting residue was purified by silica gel chromatography to thus obtain the title compound.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]=[CH:7][C:8](O)=O.S(Cl)(Cl)=O.[N:15]1([CH2:21][CH2:22][OH:23])[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1(C)C=CC=CC=1.N1C=CC=CC=1.O1CCCC1.O>[OH:23][CH2:22][CH2:21][N:15]1[CH2:20][CH2:19][N:18]([CH2:8][CH:7]=[CH:6][C:2]2[O:1][CH:5]=[CH:4][CH:3]=2)[CH2:17][CH2:16]1
Reactant: OCCN1CCNCC1
Reactant: O=C(O)C=Cc1ccco1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O=S(Cl)Cl
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: OCCN1CCN(CC=Cc2ccco2)CC1

Procedure:
5.0 g (0.036 mol) 3-(2-furyl)acrylic acid was suspended in 100 ml toluene, followed by addition of 7.9 ml (0.108 mol) thionyl chloride. The mixture was refluxed for 1 h, cooled, evaporated and the residue stripped twice with toluene. The resulting acylchloride was redissolved in 25 ml toluene and added dropwise to a solution of 4.7 g (0.036 mol) 1-piperazineethanol in 25 ml toluene and 25 ml pyridine. The reaction mixture was stirred at reflux temperature for 1 h, then cooled, diluted with toluene and washed successively with one portion of 1N sodium hydroxide and three portions of water. Evaporation in vacuo left 3.4 g of an amber oil, which was redissolved in 75 ml of tetrahydrofuran and added dropwise to a solution of 1.32 g (0.035 mol) lithium aluminium hydride in 75 ml of tetrahydrofuran. The reaction mixture was stirred at room temperature for 1 h, cooled in an ice bath and hydrolyzed by dropwise addition of water. The precipitate was filtered off and washed with tetrahydrofuran. The filtrate was concentrated in vacuo and the residue redissolved in acetonitrile. A solution of maleic acid in acetonitrile was added and the precipitate collected by filtration. Recrystallization from isopropanol gave the 1-(2-hydroxyethyl)-4-[3-(2-furyl)-2-propenyl]-piperazine as the dimaleate salt, m.p. 165°-67° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:10]([C:26]([OH:28])=O)=[CH:11][C:12]3[N:16]([CH2:17][CH:18]4[CH2:23][CH2:22][CH2:21][CH2:20][O:19]4)[CH:15]=[N:14][C:13]=3[C:24]=2[F:25])=[C:4]([Cl:29])[CH:3]=1.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C.[CH:47]([O:49][CH2:50][CH2:51][O:52][NH2:53])=[CH2:48].CCN=C=NCCCN(C)C.Cl>CN(C)C=O.C(OCC)(=O)C.O>[CH:47]([O:49][CH2:50][CH2:51][O:52][NH:53][C:26]([C:10]1[C:9]([NH:8][C:5]2[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][C:4]=2[Cl:29])=[C:24]([F:25])[C:13]2[N:14]=[CH:15][N:16]([CH2:17][CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][O:19]3)[C:12]=2[CH:11]=1)=[O:28])=[CH2:48]
Reactant: O=C(O)c1cc2c(ncn2CC2CCCCO2)c(F)c1Nc1ccc(Br)cc1Cl
Reactant: C=COCCON
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C=COCCONC(=O)c1cc2c(ncn2CC2CCCCO2)c(F)c1Nc1ccc(Br)cc1Cl
Temperature: 25 °C
Yield: 29.9 %

Procedure:
6-(4-Bromo-2-chloro-phenylamino)-7-fluoro-3-(tetrahydro-pyran-2-ylmethyl)-3H-benzoimidazole-5-carboxylic acid 11r (0.11 g, 0.23 mmol) is dissolved in N,N-dimethylformamide (2 mL). HOBT (0.037 g, 0.27 mmol) and triethylamine (0.094 mL, 0.68 mmol) are added. Then O-(2-vinyloxy-ethyl)-hydroxylamine (0.028 g, 0.27 mmol) and EDCl (0.056 g, 0.29 mmol) are added and the reaction mixture is stirred at room temperature under N2 until HPLC shows the reaction is complete (2-3 days). The reaction mixture is poured into a separatory funnel, diluted with ethyl acetate and water and the layers separated. The ethyl acetate layer is washed successively with aqueous saturated NH4Cl (2×), brine (1×), aqueous saturated sodium bicarbonate (2×), water (1×), and brine (1×), dried (Na2SO4) and concentrated under reduced pressure. The resulting solid is purified by FCC (eluting with 15:1 methylene chloride:methanol) to yield 0.039 g (79%) of the pure desired product as an off-white solid. MS ESI (+) m/z 567, 569 (M+, Br pattern) detected.
Reaction SMILES: Cl.Cl.C([O:10][C:11]1[CH:20]=[C:19]2[C:14]([C:15]([NH:21][C:22]3[C:27]([Cl:28])=[CH:26][CH:25]=[C:24]4[O:29][CH2:30][O:31][C:23]=34)=[N:16][CH:17]=[N:18]2)=[CH:13][C:12]=1[O:32][CH3:33])C1C=CC=CC=1>FC(F)(F)C(O)=O>[Cl:28][C:27]1[C:22]([NH:21][C:15]2[C:14]3[C:19](=[CH:20][C:11]([OH:10])=[C:12]([O:32][CH3:33])[CH:13]=3)[N:18]=[CH:17][N:16]=2)=[C:23]2[O:31][CH2:30][O:29][C:24]2=[CH:25][CH:26]=1
Reactant: COc1cc2c(Nc3c(Cl)ccc4c3OCO4)ncnc2cc1OCc1ccccc1
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Product: COc1cc2c(Nc3c(Cl)ccc4c3OCO4)ncnc2cc1O
Yield: 111.5 %

Procedure:
A mixture of 7-benzyloxy 4-(6-chloro-2,3-methylenedioxyanilino)-6-methoxyquinazoline dihydrochloride (3.3 g) and trifluoroacetic acid (60 ml) was heated to reflux for 4 hours. The mixture was evaporated. The residue was diluted with water and methanol and the mixture was basified to pH 7.5 by the addition of a saturated aqueous sodium carbonate solution. The methanol was evaporated and the resultant solid was isolated and washed with water. There was thus obtained the title compound as a solid (2.5 g); NMR Spectrum: (DMSOd6 and CF3CO2D) 3.95 (s, 3H), 6.1 (s, 2H), 6.95 (d, 1H), 7.1 (m, 2H), 8.1 (s, 1H), 8.4 (s, 1H), 9.85 (br s, 1H), 10.7 (br s, 1H); Mass Spectrum: M+H+ 346 and 348.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([CH:17]3[CH2:20][N:19]([CH3:21])[CH2:18]3)=[CH:13][N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.[C:22]([O:25][CH2:26][C:27]1[C:32]([N:33]2[CH2:44][CH2:43][N:42]3[C:35](=[CH:36][C:37]4[CH2:38][C:39]([CH3:46])([CH3:45])[CH2:40][C:41]=43)[C:34]2=[O:47])=[CH:31][C:30]([F:48])=[CH:29][C:28]=1B1OC(C)(C)C(C)(C)O1)(=[O:24])[CH3:23].COCCOC.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.CO.O.C(OCC)(=O)C>[F:48][C:30]1[CH:29]=[C:28]([C:2]2[CH:3]=[C:4]([NH:10][C:11]3[CH:16]=[CH:15][C:14]([CH:17]4[CH2:20][N:19]([CH3:21])[CH2:18]4)=[CH:13][N:12]=3)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=2)[C:27]([CH2:26][O:25][C:22](=[O:24])[CH3:23])=[C:32]([N:33]2[CH2:44][CH2:43][N:42]3[C:35](=[CH:36][C:37]4[CH2:38][C:39]([CH3:45])([CH3:46])[CH2:40][C:41]=43)[C:34]2=[O:47])[CH:31]=1
Reactant: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)cc(F)cc1N1CCn2c(cc3c2CC(C)(C)C3)C1=O
Reactant: CN1CC(c2ccc(Nc3cc(Br)cn(C)c3=O)nc2)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: CO
Solvent: CCOC(C)=O
Solvent: O
Product: CC(=O)OCc1c(-c2cc(Nc3ccc(C4CN(C)C4)cn3)c(=O)n(C)c2)cc(F)cc1N1CCn2c(cc3c2CC(C)(C)C3)C1=O
Temperature: 130 °C
Yield: 31.3 %

Procedure:
A microwave tube equipped with a magnetic stirrer was charged with 5-bromo-1-methyl-3-(5-(1-methylazetidin-3-yl)pyridin-2-ylamino)pyridin-2(1H)-one (172a) (216 mg, 0.6 mmol), 230a (390 mg, 0.8 mmol), 1,2-dimethoxyethane (8 mL) and 1M aqueous sodium carbonate (2 mL). After bubbling N2 for 15 min, Pd(PPh3)4 (36 mg, 0.03 mmol) was added. The mixture was heated in microwave to 130° C. for 15 min. After this time, ethyl acetate (5 mL) and water (5 mL) were added. The separated aqueous layer was extracted with ethyl acetate (2×5 mL). The combined organics were washed with brine (10 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by column chromatography eluting with a gradient of methylene chloride-9:1 methylene chloride:methanol to afford a 30% yield (120 mg) of 271a.