Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([CH3:4])([O-:3])=[O:2].[H-].[Na+].[O-]S([O-])(=O)=O.[Mg+2].[CH3:13][O:14][C:15](=[O:25])[C:16]1[C:21]([F:22])=[CH:20][C:19]([Br:23])=[CH:18][C:17]=1F>CS(C)=O>[CH3:13][O:14][C:15](=[O:25])[C:16]1[C:17]([CH2:4][N+:1]([O-:3])=[O:2])=[CH:18][C:19]([Br:23])=[CH:20][C:21]=1[F:22]
Reactant: COC(=O)c1c(F)cc(Br)cc1F
Reactant: C[N+](=O)[O-]
Agent: O=S(=O)([O-])[O-]
Agent: [H-]
Agent: [Mg+2]
Solvent: CS(C)=O
Product: COC(=O)c1c(F)cc(Br)cc1C[N+](=O)[O-]
Reaction time: 0.25 h

Procedure:
Nitromethane (10 mL, 169 mmol, 8 equiv.) is added cautiously to a suspension of sodium hydride (4.05 g, 169 mmol, 8 equiv.) and MgSO4 (40 g) in DMSO (100 mL) at rt and the resulting slurry is stirred for 0.25 h. To the resulting yellow slurry is added 4-bromo-2,6-difluorobenzoic acid methyl ester (5.3 g, 21 mmol) and the mixture is stirred at rt for 3 days at which point all the starting material has been consumed. Water (200 mL) and 6M HCl (50 mL) is added followed by DCM (200 mL). More water (500 mL) is added to yield a clear biphasic system. The aqueous layer is extracted with DCM (3×100 mL), the DCM layers are then combined, washed with saturated NaHCO3 and brine, and dried over MgSO4. Evaporation of the solvent affords an orange solid containing 64% of the desired material, used without further purification. LCMS; Rt=1.27 min (64%).
Reaction SMILES: [NH:1]([C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])[C@H:2]([C:9]([OH:11])=O)[CH2:3][O:4][C:5]([CH3:8])([CH3:7])[CH3:6].ON1C(=O)CCC1=O.C1(N=C=NC2CCCCC2)CCCCC1.[NH2:45][C@H:46]([C:64]([NH:66][C@H:67]([C:72]([OH:74])=[O:73])[CH2:68][CH:69]([CH3:71])[CH3:70])=[O:65])[CH2:47][CH2:48][CH2:49][NH:50][C:51](=[NH:63])[NH:52][S:53]([C:56]1[CH:62]=[CH:61][C:59]([CH3:60])=[CH:58][CH:57]=1)(=[O:55])=[O:54]>O1CCCC1.CN(C)C=O.C(N(CC)CC)C>[NH:1]([C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])[C@H:2]([C:9]([NH:45][C@H:46]([C:64]([NH:66][C@H:67]([C:72]([OH:74])=[O:73])[CH2:68][CH:69]([CH3:70])[CH3:71])=[O:65])[CH2:47][CH2:48][CH2:49][NH:50][C:51](=[NH:63])[NH:52][S:53]([C:56]1[CH:62]=[CH:61][C:59]([CH3:60])=[CH:58][CH:57]=1)(=[O:55])=[O:54])=[O:11])[CH2:3][O:4][C:5]([CH3:6])([CH3:7])[CH3:8]
Reactant: CC(C)(C)OC[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: Cc1ccc(S(=O)(=O)NC(=N)NCCC[C@H](N)C(=O)N[C@@H](CC(C)C)C(=O)O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=C1CCC(=O)N1O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)NC(=N)NCCC[C@H](NC(=O)[C@H](COC(C)(C)C)NC(=O)OCc2ccccc2)C(=O)N[C@@H](CC(C)C)C(=O)O)cc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 72.5 %

Procedure:
In 250 ml of tetrahydrofuran are dissolved 23.7 g (80.4 millimoles) of Z-Ser(But)-OH and 10.2 g of N-hydroxysuccinimide, and the solution is cooled to 0° C. and 16.6 g of dicyclohexylcarbodiimide is added to the solution. The mixture is stirred for 3 hours at the above temperature and then stirred in a low temperature chamber overnight. The formed precipitate is removed by filtration and the filtrate is concentrated under reduced pressure. The obtained oily substance is dissolved in 100 ml of dimethylformamide. This solution is mixed with a solution formed by dissolving 35.5 g (80.4 millimoles) of H-Arg(Tos)-Leu-OH prepared according to the process (ii) of Example 8 in 200 ml of dimethylformamide and adding 11.2 ml of triethylamine to the solution, and the mixture is stirred for 6 hours at 6° C., overnight in a low temperature chamber and for 5 hours at room temperature. The insoluble substances are removed by filtration and the filtrate is concentrated under reduced pressure. The residue is extracted with 700 ml of ethyl acetate, washed with 2% citric acid and water and dried with magnesium sulfate. The dried filtrate is concentrated under reduced pressure and ether is added to the residue to effect solidification. The solid is dissolved in a mixed liquid of chloroform and methanol, and the solution is concentrated under reduced pressure. Solidification is effected by ethyl acetate to obtain 41.9 g of intended Z-Ser(But)-Arg(Tos)-Leu-OH (the yield being 73%).
Reaction SMILES: [CH2:1]([CH2:4][PH:5](Cl)=[O:6])[CH:2]=[CH2:3].[O-:8][C:9]#[N:10].[Na+]>C(#N)C>[CH2:1]([CH2:4][PH:5]([N:10]=[C:9]=[O:8])=[O:6])[CH:2]=[CH2:3]
Reactant: C=CCC[PH](=O)Cl
Reactant: N#C[O-]
Agent: [Na+]
Solvent: CC#N
Product: C=CCC[PH](=O)N=C=O
Reaction time: 5.5 h
Yield: 70.6 %

Procedure:
166 g (1.2 mol) of allylmethylphosphinic acid chloride were dissolved in 300 ml of acetonitrile and heated with 78 g (1.2 mol) of sodium cyanate to 50°-55° C. while stirring. After 5.5 hours, the precipitate was filtered off by suction and washed with acetonitrile. The filtrate was then concentrated and the residue distilled at a temperature of 78°-80° C. and at a pressure of 25 Pa. 123 g of allylmethylphosphinic acid isocyanate (71% of theory) were obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[N:23][C:5]2[N:6](COCC[Si](C)(C)C)[C:7]3[CH:12]=[N:11][C:10]([C:13]#[N:14])=[CH:9][C:8]=3[C:4]=2[C:3]=1[N:25]1[CH2:29][CH2:28][C@H:27]([OH:30])[CH2:26]1.Br.[OH-].[Na+].Cl>O1CCOCC1>[Cl:1][C:2]1[CH:24]=[N:23][C:5]2[NH:6][C:7]3[CH:12]=[N:11][C:10]([C:13]#[N:14])=[CH:9][C:8]=3[C:4]=2[C:3]=1[N:25]1[CH2:29][CH2:28][C@H:27]([OH:30])[CH2:26]1
Reactant: C[Si](C)(C)CCOCn1c2cnc(C#N)cc2c2c(N3CC[C@H](O)C3)c(Cl)cnc21
Agent: Br
Agent: Cl
Agent: [Na+]
Solvent: C1COCCO1
Product: N#Cc1cc2c(cn1)[nH]c1ncc(Cl)c(N3CC[C@H](O)C3)c12
Temperature: 55 °C
Yield: 63.7 %

Procedure:
(S)-3-Chloro-4-(3-hydroxypyrrolidin-1-yl)-9-((2-(trimethylsilyl)ethoxy)methyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile (100 mg, 0.2 mmol) was dissolved in 1,4-dioxane (0.3 mL) and then treated with 48% HBr(aq) (0.3 mL) and heated at 55° C. for 20 minutes. The cooled reaction mixture was then basified to pH ˜12 by dropwise addition of 6N sodium hydroxide and then immediately acidified to pH ˜8-9 by dropwise addition of concentrated hydrochloric acid, producing a cloudy precipitate. The solid was collected by centrifugation, dissolved in dimethylsulfoxide (2 mL), and purified by preparative HPLC [5-85% methanol in water (0.1% ammonium hydroxide) over 30 min, 35 mL/min] to afford the title compound as a pale off-white solid (40 mg, 60% over two steps). 1H NMR (400 MHz, d6-DMSO) δ 8.95 (s, 1H), 8.56 (s, 1H), 8.45 (s, 1H), 5.27 (s, 1H), 4.54 (s, 1H), 3.88 (m, 1H), 3.78 (dd, J=10.5, 4.6, 1H), 3.66 (td, J=9.0, 4.5, 1H), 3.50 (d, J=10.3, 1H), 2.34-2.19 (m, 1H), 2.06-1.95 (m, 1H), NH signals not observed. LCMS (Method D): RT=8.57 min, M+H+=314.0.
Reaction SMILES: [C:1]([OH:5])(=[O:4])[CH2:2]O.[Cl:6][C:7]1[CH:16]=[CH:15][C:10]([O:11][CH2:12][CH:13]=[O:14])=[C:9]([CH3:17])[CH:8]=1.B(F)(F)F.CCOCC>CCOCC.O1CCCC1>[Cl:6][C:7]1[CH:16]=[CH:15][C:10]([O:11][CH2:12][CH:13]2[O:5][C:1](=[O:4])[CH2:2][O:14]2)=[C:9]([CH3:17])[CH:8]=1
Reactant: O=C(O)CO
Reactant: Cc1cc(Cl)ccc1OCC=O
Agent: FB(F)F
Solvent: C1CCOC1
Solvent: CCOCC
Product: Cc1cc(Cl)ccc1OCC1OCC(=O)O1
Reaction time: 24 h
Yield: 62.6 %

Procedure:
A solution containing 2.5g (0.033 mole) of glycolic acid, 4.2g (0.025 mole) of 4-chloro-2-methylphenoxyacetaldehyde and 10g (0.07 mole) of boron trifluoride etherate in 50 ml of ether and 30 ml of tetrahydrofuran was allowed to stand at room temperature for 24 hours. The dark solution was washed with aqueous sodium bicarbonate, dried and concentrated to dryness. Recrystallization from ether-hexane gave 3.8g of 2-(4-chloro-2-methylphenoxymethyl)-1,3-dioxolan-4-one having a melting point of 42°-44°.
Reaction SMILES: [CH2:1]([NH:8][C:9](=[O:19])[C:10]1[CH:15]=[C:14]([O:16]C)[CH:13]=[C:12]([I:18])[CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B(Br)(Br)Br.C(OCC)C>ClCCl.C(=O)=O.CC(C)=O>[CH2:1]([NH:8][C:9](=[O:19])[C:10]1[CH:11]=[C:12]([I:18])[CH:13]=[C:14]([OH:16])[CH:15]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc(I)cc(C(=O)NCc2ccccc2)c1
Agent: BrB(Br)Br
Agent: O=C=O
Solvent: CC(C)=O
Solvent: CCOCC
Solvent: ClCCl
Product: O=C(NCc1ccccc1)c1cc(O)cc(I)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of N-benzyl-3-iodo-5-methoxy-benzamide (4.7 g) in anhydrous dichloromethane (100 mL) was cooled to −78° C. in dry ice/acetone bath under flow of argon and a BBr3 solution (38.4 mL of 1 M solution in dichloromethane) was added dropwise. After the addition was completed, the reaction mixture was stirred at room temperature overnight. The reaction mixture was cooled in an ice bath and then quenched by a dropwise addition of methanol. Then it was diluted with ethyl acetate, washed with water and brine, dried over anhydrous sodium sulfate and concentrated to remove the solvents. The title compound was obtained by trituration with diethyl ether and hexanes (4.1 g, 90% yield).
Reaction SMILES: [OH-].[Na+].CC1C=CC(S(O[C:14]2[C:20](=[O:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)(=O)=O)=CC=1.[CH3:22][C:23]([C:26]([NH2:28])=[NH:27])([CH3:25])[CH3:24].Cl.[NH4+].[Cl-]>O.C1(C)C=CC=CC=1.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH3:22][C:23]([C:26]1[NH:28][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:20](=[O:21])[C:14]=2[N:27]=1)([CH3:25])[CH3:24]
Reactant: Cc1ccc(S(=O)(=O)Oc2cccccc2=O)cc1
Reactant: CC(C)(C)C(=N)N
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [Br-]
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)(C)c1nc2c(=O)ccccc2[nH]1
Temperature: 30 °C
Yield: 103.8 %

Procedure:
To a mixture of sodium hydroxide 30% in water (12.06 g) and toluene (20 mL), tropolone tosylate (2.5 g), tert-butylcarbamidine hydrochloride (1.236 g) and tetrabutylammonium bromide (1.167 g) were added successively and the RM was stirred and heated at 30° C. for 1 hour. The reaction mixture was cooled down to room temp, diluted with an excess of sat. aq. NH4Cl solution and then extracted with EtOAc (3×50 ml). The combined organics were dried (hydrophobic frit) and concentrated under vacuum. The residue was purified by reverse phase chromatography using an acetonitrile-0.1% TFA:water-0.1% TFA (5%-95% gross gradient). The desired fractions were combined and concentrated under vacuum to yield the title compound (1.9 g). LC/MS MH+ 203, Rt 0.62 min (2 minute run).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[C:4]([CH3:12])[N:3]=1.[Br:13][C:14]1[CH:20]=[C:19]([CH:21]([CH3:23])[CH3:22])[CH:18]=[CH:17][C:15]=1[NH2:16].C(OCC)(=O)C>O1CCOCC1>[Br:13][C:14]1[CH:20]=[C:19]([CH:21]([CH3:22])[CH3:23])[CH:18]=[CH:17][C:15]=1[NH:16][C:2]1[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[C:4]([CH3:12])[N:3]=1
Reactant: COC(=O)c1cc(C)nc(Cl)n1
Reactant: CC(C)c1ccc(N)c(Br)c1
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: COC(=O)c1cc(C)nc(Nc2ccc(C(C)C)cc2Br)n1
Temperature: 25 °C

Procedure:
A mixture of 2-chloro-4-carbomethoxy-6-methylpyrimidine (47 g, 252 mmol) and 2-bromo-4-(2-propyl)aniline (54.0 g, 252 mmol) in dioxane (400 mL) was stirred at reflux temperature for 20 h under a nitrogen atmosphere. The reaction mixture was cooled to ambient temperature and concentrated on a rotary evaporator. The residue was treated with a saturated sodium bicarbonate solution and extracted three times with ethyl acetate. The combined organic layers were dried over magnesium sulfate and filtered. Solvent was removed in vacuo to provide a red oil. Column chromatography (ethyl acetate:hexanes::1:1) gave the title product as a crude oil. Recrystallization from ether-hexanes, collection by filtration and drying in vacuo afforded the title compound as a solid (42.8 g, 47% yield): mp 75-76° C.; NMR (CDCl3, 300 MHz): 8.4 (d, 1H, J=8); 7.65 (br s, 1H), 7.4 (d, 1H, J=1), 7.3 (s, 1H), 7.2 (dd, 1H, J=8,1), 4.0 (s, 3H), 2.85 (septet, 1H, J=7), 2.5 (br s, 3H), 1.25 (d, 6H, J=7); Anal.(C16H18BrN3O2): C, 52.76, H, 4.98, N, 11.54, Br, 21.94; Found: C, 52.71, H, 4.99, N, 11.38, Br, 21.83.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]([I:12])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[Cl:13]N1C(=O)CCC1=O>C(O)(=O)C>[Cl:13][C:9]1[C:10]([I:12])=[CH:11][C:2]([OH:1])=[C:3]([CH:8]=1)[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1ccc(I)cc1O
Reactant: O=C1CCC(=O)N1Cl
Solvent: CC(=O)O
Product: COC(=O)c1cc(Cl)c(I)cc1O
Temperature: 100 °C

Procedure:
A mixture of methyl 2-hydroxy-4-iodobenzoate (10.0 g, 36.0 mmol, from Aldrich) and N-chlorosuccinimide (5.76 g, 43.2 mmol) in acetic acid (40 mL) was heated at 100° C. for 1 hour and then cooled to room temperature overnight. The precipitate was collected by filtration and washed with ethyl acetate and then air dried to give the desired product. In addition, the filtrate was concentrated to dryness and partitioned between water and ethyl acetate. The organic phase was separated, washed with brine, dried over sodium sulfate and concentrated to dryness. The residue was purified on silica gel, eluting with 0 to 20% ethyl acetate in hexane, to give additional desired product (total 9.03 g, 82%). LCMS calculated for C8H7ClIO3 (M+H)+: m/z=312.9; Found: 313.0.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:28]=[CH:29][CH:30]=1)[CH2:5][N:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]([CH2:15][CH:16]([OH:26])[CH2:17][O:18][C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)[C:7]1=[NH:27].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.[C:77]1([C:90]2[CH:95]=[CH:94][CH:93]=[CH:92][CH:91]=2)[CH:82]=[CH:81][CH:80]=[CH:79][C:78]=1[CH2:83][N:84]1[CH2:89][CH2:88][NH:87][CH2:86][CH2:85]1.C([O-])([O-])=O.[Cs+].[Cs+]>C1(C)C=CC=CC=1.CC([O-])=O.CC([O-])=O.[Pd+2]>[C:77]1([C:90]2[CH:95]=[CH:94][CH:93]=[CH:92][CH:91]=2)[CH:82]=[CH:81][CH:80]=[CH:79][C:78]=1[CH2:83][N:84]1[CH2:85][CH2:86][N:87]([C:2]2[CH:3]=[C:4]([CH:28]=[CH:29][CH:30]=2)[CH2:5][N:6]2[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[N:8]([CH2:15][CH:16]([OH:26])[CH2:17][O:18][C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)[C:7]2=[NH:27])[CH2:88][CH2:89]1
Reactant: c1ccc(-c2ccccc2CN2CCNCC2)cc1
Reactant: N=c1n(Cc2cccc(Br)c2)c2ccccc2n1CC(O)COc1ccc(F)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: N=c1n(Cc2cccc(N3CCN(Cc4ccccc4-c4ccccc4)CC3)c2)c2ccccc2n1CC(O)COc1ccc(F)cc1
Temperature: 95 °C
Yield: 7.4 %

Procedure:
To a degassed solution of 1-[3-(3-bromo-benzyl)-2-imino-2,3-dihydro-benzoimidazol-1-yl]-3-(4-fluoro-phenoxy)-propan-2-ol (0.100 g, 0.21 mmol) in toluene (3 ml) at rt under nitrogen was added Pd(OAc)2 (1 mg, 4.45 μmop and BINAP (5 mg, 8.03 μmol). Nitrogen was bubbled through the mixture for 10 min before a degassed solution of 1-biphenyl-2-ylmethyl-piperazine (64 mg, 0.25 mmol) in toluene (1 ml) was introduced. After 5 min Cs2CO3 (1.39 g, 4.27 mmol) was added. During all additions nitrogen was continuously bubbled through the reaction. Once the additions were completed the reaction vessel was sealed and then heated to 95° C. where it was maintained for 1d. After this time, the reaction was cooled to rt and additional Pd(OAc)2 (1 mg, 4.45 □mol) and BINAP (5 mg, 8.03 □mol) were added. The reaction was then returned to 95° C. where it was maintained for 3 d. The suspension was then cooled to rt, filtered through Celite® and the collected solids were washed with dichloromethane. The combined filtrate and washings were concentrated under reduced pressure and the crude product was purified by preparative HPLC twice. The purified product was partitioned between a saturated solution of NaHCO3 and dichloromethane and the organic phase was separated. The aqueous layer was extracted with additional dichloromethane and then the combined organic fractions were washed with brine, dried (Na2SO4), filtered and concentrated under reduced pressure to provide 1-{3-[3-(4-biphenyl-2-ylmethyl-piperazin-1-yl)-benzyl]-2-imino-2,3-dihydro-benzoimidazol-1-yl}-3-(4-fluoro-phenoxy)-propan-2-ol (10 mg, 7%). HPLC-MS 642 [M+1]+, 322.
Reaction SMILES: [CH3:1][C@@:2]1([CH2:13][N:14]2[CH2:19][CH2:18][N:17]([NH:20]C(=O)OC(C)(C)C)[CH2:16][CH2:15]2)[O:6][C:5]2=[N:7][C:8]([N+:10]([O-:12])=[O:11])=[CH:9][N:4]2[CH2:3]1.FC(F)(F)C(O)=O.C(N(CC)CC)C.[CH3:42][C:43]([C:45]1[CH:50]=[CH:49][C:48]([Cl:51])=[CH:47][CH:46]=1)=O>C(O)C.C(Cl)Cl>[Cl:51][C:48]1[CH:49]=[CH:50][C:45]([C:43](=[N:20][N:17]2[CH2:16][CH2:15][N:14]([CH2:13][C@:2]3([CH3:1])[O:6][C:5]4=[N:7][C:8]([N+:10]([O-:12])=[O:11])=[CH:9][N:4]4[CH2:3]3)[CH2:19][CH2:18]2)[CH3:42])=[CH:46][CH:47]=1
Reactant: CC(C)(C)OC(=O)NN1CCN(C[C@@]2(C)Cn3cc([N+](=O)[O-])nc3O2)CC1
Reactant: CC(=O)c1ccc(Cl)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: CCO
Product: CC(=NN1CCN(C[C@@]2(C)Cn3cc([N+](=O)[O-])nc3O2)CC1)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 17.9 %

Procedure:
A mixture of tert-butyl (S)-[4-(2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazol-2-ylmethyl)-piperazin-1-yl]carbamate prepared in Example 503 (200 mg, 0.52 mmol), trifluoroacetic acid (2 ml) and methylene chloride (4 ml) was stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in methylene chloride (4 ml) and then neutralized with triethylamine (4 ml, 28.7 mmol). To the neutralized solution, a solution of 4-chloroacetophenone (97 mg, 0.63 mmol) in ethanol (4 ml) was added followed by stirring under reflux for 4 hours. The reaction mixture was allowed to return to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane/acetone=3/1) to afford (S)-N-[1-(4-chlorophenyl)ethylidene]-N-[4-(2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazol-2-ylmethyl)piperazin-1-yl]amine (39 mg, yield 18%) as a light yellow powder.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][C:7](/[CH:11]=[N:12]/[OH:13])=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1.ClN1C(=O)CCC1=O.[CH2:22]([Sn:26]([CH2:33][CH2:34][CH2:35][CH3:36])([CH2:29][CH2:30][CH2:31][CH3:32])[C:27]#[CH:28])[CH2:23][CH2:24][CH3:25]>CN(C=O)C>[CH2:33]([Sn:26]([CH2:29][CH2:30][CH2:31][CH3:32])([CH2:22][CH2:23][CH2:24][CH3:25])[C:27]1[O:13][N:12]=[C:11]([C:7]2[CH:6]=[C:5]3[C:10](=[CH:9][CH:8]=2)[CH:1]=[N:2][CH:3]=[CH:4]3)[CH:28]=1)[CH2:34][CH2:35][CH3:36]
Reactant: C#C[Sn](CCCC)(CCCC)CCCC
Reactant: O/N=C/c1ccc2cnccc2c1
Agent: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Product: CCCC[Sn](CCCC)(CCCC)c1cc(-c2ccc3cnccc3c2)no1
Temperature: 5 °C
Reaction time: 0.17 h
Yield: 31.1 %

Procedure:
To a solution of (E)-isoquinoline-6-carbaldehyde oxime (2.14 g, 12.4 mmol) in 60 mL of DMF at 0° C. was added 1-chloropyrrolidine-2,5-dione (1.66 g, 12.4 mmol) (commercially available from Aldrich). The mixture was stirred for 10 minutes and then heated to 5° C. After 2½ hours, the DMF was removed by rotary evaporation. The residue was dissolved in 100 mL of THF and chilled to 0° C. To this mixture was added tributyl(ethynyl)stannane (4.50 g, 14.3 mmol) (commercially available from Aldrich). TEA (3.81 mL, 27.3 mmol) was then added dropwise. The mixture was gradually warmed to room temperature over 12 hours. The reaction was quenched with 50 mL of aqueous NH4Cl and diluted with 50 mL of water. The mixture was partitioned in a separatory funnel. The aqueous portion was extracted twice with 100 mL of EtOAc, and the combined organic layers were washed with 100 mL of brine and dried over MgSO4. Filtration and concentration under reduced pressure, followed by flash chromatography on silica gel (5% to 30% EtOAc/hexanes), afforded 6-(5-(tributylstannyl)isoxazol-3-yl)isoquinoline (1.87 g, 31.0% yield) as a yellow oil. 1H NMR (400 MHz, CDCl3) δ ppm 9.29 (s, 1H), 8.58 (d, J=5.8 Hz, 1H), 8.26 (s, 1H), 8.14 (dd, J=1.3 Hz, 8.5 Hz, 1H), 8.05 (d, J=8.5 Hz, 1H), 7.72 (d, J=5.7 Hz, 1H), 6.83 (s, 1H), 1.65-1.57 (m, 6H), 1.38 (q, 7.3 Hz, 6H), 1.23 (t, J=8.2 Hz, 6H), 0.92 (t, 7.2 Hz, 9H).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[C:7]([C:9]1[CH:14]=[CH:13][C:12]([CH2:15][N:16]2[C:20]([CH2:21][CH2:22][CH2:23][OH:24])=[CH:19][N:18]=[CH:17]2)=[CH:11][CH:10]=1)#[N:8].C(N(CC)CC)C>C(Cl)Cl.CS(C)=O>[C:7]([C:9]1[CH:10]=[CH:11][C:12]([CH2:15][N:16]2[C:20]([CH2:21][CH2:22][CH:23]=[O:24])=[CH:19][N:18]=[CH:17]2)=[CH:13][CH:14]=1)#[N:8]
Reactant: N#Cc1ccc(Cn2cncc2CCCO)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: N#Cc1ccc(Cn2cncc2CCC=O)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 0.14 ml of dimethylsulfoxide in 5 ml of methylene chloride is cooled to -78° under N2 and 0.1 ml of oxalyl chloride is added dropwise. After 30 min, a solution of 0.24 g of 1-(p-cyanophenylmethyl)-5-(3-hydroxypropyl)-1H-imidazole in 1 ml of methylene chloride and 0.2 ml of dimethylsulfoxide is added slowly. The reaction mixture is stirred at -78° for 2 h and 1 ml of triethylamine is added slowly. The reaction mixture is allowed to warm slowly to room temperature, diluted with 30 ml of methylene chloride and washed three times with 10 ml of water. The organic phase is dried over sodium sulfate and evaporated to yield the title compound (a) as an oil, NMR (60 MHZ): δ5.15 (s, 2H), 9.65 (s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](B(O)O)[CH:5]=[CH:4][N:3]=1.C([O-])([O-])=O.[Na+].[Na+].Br[C:18]1[N:23]=[C:22]([C:24]2[N:28]3[N:29]=[C:30]([N:33]4[CH2:37][CH2:36][CH2:35][C@@H:34]4[C:38]4[CH:43]=[CH:42][CH:41]=[C:40]([F:44])[CH:39]=4)[CH:31]=[CH:32][C:27]3=[N:26][CH:25]=2)[CH:21]=[CH:20][CH:19]=1>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[F:1][C:2]1[CH:7]=[C:6]([C:18]2[CH:19]=[CH:20][CH:21]=[C:22]([C:24]3[N:28]4[N:29]=[C:30]([N:33]5[CH2:37][CH2:36][CH2:35][C@@H:34]5[C:38]5[CH:43]=[CH:42][CH:41]=[C:40]([F:44])[CH:39]=5)[CH:31]=[CH:32][C:27]4=[N:26][CH:25]=3)[N:23]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Fc1cccc([C@H]2CCCN2c2ccc3ncc(-c4cccc(Br)n4)n3n2)c1
Reactant: OB(O)c1ccnc(F)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Product: Fc1cccc([C@H]2CCCN2c2ccc3ncc(-c4cccc(-c5ccnc(F)c5)n4)n3n2)c1
Temperature: 110 °C

Procedure:
In step 16-3, 2-fluoropyridin-4-ylboronic acid (97%) (9.6 g, 66 mmol), Pd(dppf)Cl2 (1.3 g, 1.65 mmol) and 2N Na2CO3 (50 mL, 99 mmol) were added to a suspension of (R)-3-(6-bromopyridin-2-yl)-6-(2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazine (16-2) (14.5 g, 33 mmol) in 1,4-dioane (250 mL). The mixture was degassed for 15 minute using N2 and then heated at 110° C. for 3 hours. The mixture was filtered through a celite pad and rinsed with ethyl acetate (EtOAc). The filtrate was washed with brine, dried over Na2SO4, and concentrated to give (R)-3-(2′-fluoro-2,4′-bipyridin-6-yl)-6-(2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazine (16-3) as a dark oil, which was used in the next step without further purification. LC/MS: 455.2 (M+H+).
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[N:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][C:21](O)=[O:22])[CH:15]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>CN(C=O)C.O.C(OCC)(=O)C>[C:1]([N:8]1[CH2:9][CH2:10][N:11]([C:21](=[O:22])[CH2:20][C:16]2[CH:15]=[N:14][CH:19]=[CH:18][CH:17]=2)[CH2:12][CH2:13]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: O=C(O)Cc1cccnc1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(C(=O)Cc2cccnc2)CC1
Reaction time: 3 h
Yield: 69.1 %

Procedure:
1-Boc-piperazine (12 g, 64 mmol), 3-pyridylacetic acid (8.85 g, 64 mmol), and HOBt (8.64 g, 64 mmol) were dissolved in DMF. To this solution, EDCI (14.7 g, 76.8 mmol) was added in portions. The mixture became homogenous and was stirred for 3 h. The mixture was diluted with water and ethyl acetate. The layers were separated, and the aqueous layer extracted with ethyl acetate. The organic layers were washed with water and brine, dried (Na2SO4), filtered, and concentrated to provide a yellow solid. The crude product was purified by recrystallization from hexanes:dichloromethane to provide 1-Boc-4-[(3-pyridinyl)acetyl]piperazine (13.5 g, 69%) as a white solid.