Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([Mg]Br)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].Br[C:10]1[CH:14]=[CH:13][S:12][C:11]=1[C:15]1[S:16][CH:17]=[CH:18][C:19]=1Br.Cl>C(OCC)C.Cl[Ni]1(Cl)[P](C2C=CC=CC=2)(C2C=CC=CC=2)CCC[P]1(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:1]([C:10]1[CH:14]=[CH:13][S:12][C:11]=1[C:15]1[S:16][CH:17]=[CH:18][C:19]=1[CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: Brc1ccsc1-c1sccc1Br
Reactant: CCCCCC[Mg]Br
Agent: Cl[Ni]1(Cl)[P](c2ccccc2)(c2ccccc2)CCC[P]1(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: CCOCC
Product: CCCCCCc1ccsc1-c1sccc1CCCCCC
Yield: 100.1 %

Procedure:
Hexylmagnesium bromide (100 ml, 2 M solution in diethyl ether, 200 mol) was added dropwise to a solution of 3,3′-dibromo-2,2′-bithiophene (15 g, 46.6 mmol) and Ni(dppp)Cl2 (0.5 g, 0.1 mmol) in 100 ml of diethyl ether at 0° C. The reaction was slightly exothermic and a red brown coloration was observed. After stirred and heated for 24 h, the reaction mixture was cautiously poured into a mixture of crushed ice and diluted HCl solution and extracted with ether. The combined extracts were dried over anhydrous MgSO4 and filtered. After removal of the solvent, the residue was vacuum-distilled to give a clear viscous oil (15.6 g, 81%). 1H-NMR (CDCl3, ppm): δ7.25 (d, 2H, J=5 Hz), 6.96 (d, 2H, J=5 Hz), 2.50 (t, 4H), 1.54 (m, 4H), 1.23 (m, 12H), 0.85 (t, 6H).
Reaction SMILES: [CH3:1][CH2:2][C@@:3]1([OH:27])[C:8](=[O:9])[O:7][CH2:6][C:5]2[C:10]([N:12]3[C:16](=[CH:17][C:4]1=2)[C:15]1[NH:18][C:19]2[C:25](=[CH:26][C:14]=1[CH2:13]3)[CH:24]=[CH:23][C:21](=O)[CH:20]=2)=[O:11].C[OH:29].C(Cl)(Cl)Cl>FC(F)(F)C(O)=O>[CH3:1][CH2:2][C@@:3]1([OH:27])[C:8](=[O:9])[O:7][CH2:6][C:5]2[C:10]([N:12]3[C:16](=[CH:17][C:4]1=2)[C:15]1[N:18]=[C:19]2[C:25]([CH:24]=[C:23]([OH:29])[CH:21]=[CH:20]2)=[CH:26][C:14]=1[CH2:13]3)=[O:11]
Reactant: CC[C@@]1(O)C(=O)OCc2c1cc1n(c2=O)Cc2cc3ccc(=O)cc-3[nH]c2-1
Reactant: CO
Solvent: O=C(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Product: CC[C@@]1(O)C(=O)OCc2c1cc1n(c2=O)Cc2cc3cc(O)ccc3nc2-1

Procedure:
Naturally available mixture of 10 and 11-hydroxy camptothecin (1.0 g) is dissolved in anhydrous trifluoroacetic acid (5 ml) and anhydrous methanol (10 ml) to form a homogeneous solution of the quaternized components of the mixture. The homogeneous solution is then absorbed over enough silica gel (60A; 60-230 mesh) to form a thick slurry. This slurry is dried by evaporating methanol and excess acid in vacuo on a rotary evaporator, leaving a powdery mass. The powder is then loaded over a pre-equilibrated silica gel column using chloroform. The column is washed using 1000 ml of a solvent mixture of 80% chloroform-20% methanol to remove non polar impurities, occluded trifluoroacetic acid and 11-hydroxycamptothecin (fraction A). Elution is then continued with chloroform-methanol-triethyl amine (in the approximate ratio of 1:1:0.01) and the band migrating away from the origin is collected using this eluent (Fraction B). Fractions A and B are evaporated separately and analyzed. Fraction B corresponds to the 10-hydroxy camptothecin isolate.
Reaction SMILES: [C:1](N1C=CN=C1)(N1C=CN=C1)=[O:2].N12CCCN=C1CCCCC2.[CH2:24]([O:26][C:27]1[CH:28]=[N:29][C:30]([N:33]2[C:38](=[O:39])[C:37]([CH2:40][C:41]3[CH:42]=[CH:43][C:44]([C:47]4[CH:56]=[CH:55][CH:54]=[CH:53][C:48]=4[C:49](=[N:51][OH:52])[NH2:50])=[N:45][CH:46]=3)=[C:36]([CH2:57][CH2:58][CH3:59])[N:35]=[C:34]2[CH:60]([CH3:62])[CH3:61])=[N:31][CH:32]=1)[CH3:25].Cl>O1CCCC1.ClCCl>[CH2:24]([O:26][C:27]1[CH:28]=[N:29][C:30]([N:33]2[C:38](=[O:39])[C:37]([CH2:40][C:41]3[CH:42]=[CH:43][C:44]([C:47]4[CH:56]=[CH:55][CH:54]=[CH:53][C:48]=4[C:49]4[NH:50][C:1](=[O:2])[O:52][N:51]=4)=[N:45][CH:46]=3)=[C:36]([CH2:57][CH2:58][CH3:59])[N:35]=[C:34]2[CH:60]([CH3:62])[CH3:61])=[N:31][CH:32]=1)[CH3:25]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CCCc1nc(C(C)C)n(-c2ncc(OCC)cn2)c(=O)c1Cc1ccc(-c2ccccc2C(N)=NO)nc1
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCCc1nc(C(C)C)n(-c2ncc(OCC)cn2)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)nc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 90.8 %

Procedure:
Process 6: 1,1′-Carbonyldiimidazole (130 mg, 0.80 mmol) and 1,8-diazabicyclo[5.4.0]undeca-7-ene (122 mg, 0.80 mmol) were added to dichloromethane (4 mL) and tetrahydrofuran (4 mL) mixture solution of 2-{5-{[1-(5-ethoxypyrimidin-2-yl)-2-isopropyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}pyridin-2-yl}-N′-hydroxybenzimidamide (212 mg, 0.40 mmol) and stirred for 3 hours at room temperature. Once the reaction is completed, 1 M hydrochloric acid solution was added to the reaction mixture, which was then extracted with chloroform. The organic layer was washed with water, dried over anhydrous sodium sulfate, and concentrated in vacuo. The obtained residues were subjected to silica gel column chromatography (chloroform/methanol=20:1) to give 3-{2-{5-{[1-(5-ethoxypyrimidin-2-yl)-2-isopropyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}pyridin-2-yl}phenyl}-1,2,4-oxadiazol-5(4H)-one (201 mg, 91%) as white amorphous.
Reaction SMILES: C([O:3][C:4](=[O:16])[CH2:5][C@H:6]1[C:14]2[C:9](=[CH:10][C:11]([OH:15])=[CH:12][CH:13]=2)[CH2:8][CH2:7]1)C.C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:24][CH2:25][O:26][C:27]1[CH:39]=[CH:38][C:30]2[C:31]([C:34](F)(F)F)=[N:32][O:33][C:29]=2[C:28]=1[CH2:40][CH2:41][CH3:42]>CN(C=O)C.O>[CH3:34][C:31]1[C:30]2[CH:38]=[CH:39][C:27]([O:26][CH2:25][CH2:24][O:15][C:11]3[CH:10]=[C:9]4[C:14](=[CH:13][CH:12]=3)[C@H:6]([CH2:5][C:4]([OH:3])=[O:16])[CH2:7][CH2:8]4)=[C:28]([CH2:40][CH2:41][CH3:42])[C:29]=2[O:33][N:32]=1
Reactant: CCOC(=O)C[C@@H]1CCc2cc(O)ccc21
Reactant: CCCc1c(OCCBr)ccc2c(C(F)(F)F)noc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCc1c(OCCOc2ccc3c(c2)CC[C@H]3CC(=O)O)ccc2c(C)noc12
Temperature: 60 °C
Reaction time: 10 h

Procedure:
Ethyl[(1S)-5-hydroxy-2,3-dihydro-1H-inden-1-yl]acetate (Example 6) (62.4 mg, 0.28 mmol) was dissolved in DMF (5 mL), and Cs2CO3 (111 mg, 0.34 mmol), and 3 drops of water were added. 6-(2-bromoethoxy)-7-propyl-3-(trifluoromethyl)1,2-benzisoxazole (100 mg, 0.28 mmol) was added and the reaction mixture was stirred for 10 h at 60° C. The solvent was removed under reduced pressure, and the crude product was taken up in EtOAc, filtered through silica gel, and the filtrate was concentrated under reduced pressure. The crude product was dissolved in THF (2 mL), and LiOH (0.5 M aqueous solution, 0.9 mL) and MeOH (4 drops) were added. After stirring for 18 h at 50° C. the reaction mixture was concentrated under reduced pressure. Water and HCl (1 N aqueous solution) were added until the mixture was acidic which was followed by extraction using EtOAc. The product was purified by silica gel filtration (gradient 1:6 EtOAc/Hexane to 100% EtOAc), yielding 12 mg (9% over 2 steps) of the title compound as white crystals. 1H NMR (300 MHz, CD3OD): δ 0.91 (t, 3H), 1.70 (m, 3H), 2.33 (m, 2H), 2.68 (m, 2H), 2.87 (m, 3H), 3.46 (m, 1H), 4.33 (m, 2H), 4.48 (m, 2H), 6.73 (dd, 1H), 6.82 (d, 1H), 7.11 (d, 1H), 7.34 (d, 1H), 7.67 (d, 1H).
Reaction SMILES: C[O:2][C:3]([C:5]1[S:35][C:8]2[N:9]=[CH:10][N:11]=[C:12]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=3[O:21][C@H:22]3[CH2:26][CH2:25][CH2:24][C@@H:23]3[NH:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[C:7]=2[C:6]=1[CH3:36])=[O:4].[OH-].[Na+].Cl>CO.O>[C:31]([O:30][C:28]([NH:27][C@H:23]1[CH2:24][CH2:25][CH2:26][C@@H:22]1[O:21][C:15]1[CH:16]=[C:17]([F:20])[CH:18]=[CH:19][C:14]=1[NH:13][C:12]1[C:7]2[C:6]([CH3:36])=[C:5]([C:3]([OH:4])=[O:2])[S:35][C:8]=2[N:9]=[CH:10][N:11]=1)=[O:29])([CH3:34])([CH3:32])[CH3:33]
Reactant: COC(=O)c1sc2ncnc(Nc3ccc(F)cc3O[C@H]3CCC[C@@H]3NC(=O)OC(C)(C)C)c2c1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1c(C(=O)O)sc2ncnc(Nc3ccc(F)cc3O[C@H]3CCC[C@@H]3NC(=O)OC(C)(C)C)c12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 2.4 g (1S,2S) 4-[2-(2-tert-butoxycarbonylamino-cyclopentyloxy)-4-fluoro-phenylamino]-5-methyl thieno[2,3-d]pyrimidine-6-carboxylic acid methyl ester and 20 ml 1M sodium hydroxide solution in 50 ml MeOH was stirred at rt overnight. To the reaction mixture was added 20 ml 1M hydrochloric acid until a pH range of 2-3 was reached. The mixture was diluted with water and filtrated. The solid was dried in vacuo at 50° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:17][CH2:18][NH2:19])[CH:6]=[CH:7][C:8]=1[O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(N(CC)CC)C.O1CCCC1.[CH3:32][C:33]1[CH:38]=[CH:37][C:36]([CH2:39][C:40](Cl)=[O:41])=[CH:35][CH:34]=1>O>[CH2:10]([O:9][C:8]1[CH:7]=[CH:6][C:5]([CH2:17][CH2:18][NH:19][C:40](=[O:41])[CH2:39][C:36]2[CH:37]=[CH:38][C:33]([CH3:32])=[CH:34][CH:35]=2)=[CH:4][C:3]=1[O:2][CH3:1])[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: Cc1ccc(CC(=O)Cl)cc1
Reactant: COc1cc(CCN)ccc1OCc1ccccc1
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1cc(CCNC(=O)Cc2ccc(C)cc2)ccc1OCc1ccccc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 154.9 %

Procedure:
15.26 g (59.3 mmol) of crude 2-(3-methoxy-4-benzyloxyphenyl)ethylamine, 9.09 g (89.0 mmol) of triethylamine and 100 ml of tetrahydrofuran were mixed and cooled to about 0° C. and then 5.44 g (32.28 mmol) of (4-methylphenyl)acetyl chloride was added dropwise thereto. The mixture was stirred at 0° C. for 30 minutes and further at room temperature for 3 hours. Water was added to the reaction mixture, which was followed by extracted with ethyl acetate, washed with 5% hydrochloric acid and saturated brine subsequently, dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The residue was washed with hexane and dried to give 19.48 g of N-[2-(4-benzyloxy-3-methoxyphenyl)ethyl]-2-(4-methylphenyl)acetamide.
Reaction SMILES: [CH3:1][C:2]1[N:24]=[C:5]2[N:6]=[C:7]([C:16]3[CH:23]=[CH:22][C:19]([CH:20]=O)=[CH:18][CH:17]=3)[C:8]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)=[CH:9][N:4]2[N:3]=1.Cl.[NH:26]1[CH2:31][CH2:30][CH:29]([C:32]2[N:33]=[C:34]([C:37]3[CH:42]=[CH:41][CH:40]=[C:39]([C:43]([F:46])([F:45])[F:44])[N:38]=3)[NH:35][N:36]=2)[CH2:28][CH2:27]1.CCN(CC)CC.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>CN1C(=O)CCC1.CC(O)=O>[CH3:1][C:2]1[N:24]=[C:5]2[N:6]=[C:7]([C:16]3[CH:23]=[CH:22][C:19]([CH2:20][N:26]4[CH2:27][CH2:28][CH:29]([C:32]5[N:33]=[C:34]([C:37]6[CH:42]=[CH:41][CH:40]=[C:39]([C:43]([F:45])([F:46])[F:44])[N:38]=6)[NH:35][N:36]=5)[CH2:30][CH2:31]4)=[CH:18][CH:17]=3)[C:8]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)=[CH:9][N:4]2[N:3]=1
Reactant: Cc1nc2nc(-c3ccc(C=O)cc3)c(-c3ccccc3)cn2n1
Reactant: FC(F)(F)c1cccc(-c2nc(C3CCNCC3)n[nH]2)n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: CCN(CC)CC
Solvent: CC(=O)O
Product: Cc1nc2nc(-c3ccc(CN4CCC(c5n[nH]c(-c6cccc(C(F)(F)F)n6)n5)CC4)cc3)c(-c3ccccc3)cn2n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 4-(2-methyl-6-phenyl-[1,2,4]triazolo[1,5-a]pyrimidin-5-yl)benzaldehyde (300 mg, 0.95 mmol) and 2-(5-piperidin-4-yl-2H-[1,2,4]triazol-3-yl)-6-trifluoromethyl-pyridine hydrochloride salt (662 mg, 1.43 mmol) in NMP (8.1 mL) was treated with Et3N (0.32 mL), followed by AcOH (98 μL) and the mixture was stirred overnight at rt. NaBH(OAc)3 (222 mg) was added and the mixture stirred for 3 hours. The mixture was partitioned between CH2Cl2 and saturated aqueous NaHCO3 solution, the organic phase washed with brine and concentrated in vacuo. The crude product was purified by preparative HPLC to give the title compound.
Reaction SMILES: NC[CH2:3][CH2:4][NH:5][CH2:6][C:7]1[NH:8][C:9]2[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=2[N:11]=1.[CH3:16][N:17]=[C:18]=S.N1C2C=CC=CC=2NC=1CNC[CH2:32][CH2:33][NH:34][C:35]([NH:38][C:39]#[N:40])=[N:36]C>>[N:8]1[C:9]2[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=2[NH:11][C:7]=1[CH2:6][NH:5][CH2:4][CH2:3][NH:36][C:35]([NH:38][C:39]#[N:40])=[N:34][CH2:33][CH2:32][N:17]([CH3:18])[CH3:16]
Reactant: CN=C(NC#N)NCCCNCc1nc2ccccc2[nH]1
Reactant: CN=C=S
Reactant: NCCCNCc1nc2ccccc2[nH]1
Product: CN(C)CCN=C(NC#N)NCCNCc1nc2ccccc2[nH]1

Procedure:
Using in the above procedure, 2-[(3-aminopropyl)aminomethyl]benzimidazole (prepared by reacting 2-chloromethylbenzimidazole with 1,3-diaminopropane) and methyl isothiocyanate, the product is N-[3-(2-benzimidazolylmethylamino)propyl]-N'-cyano-N"-methylguanidine.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[O:15][C:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[N:17][N:18]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O.N>C(Cl)Cl.CO>[C:19]1([C:16]2[O:15][C:14]([CH:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)=[N:18][N:17]=2)[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2nnc(-c3ccccc3)o2)CC1
Agent: N
Solvent: CO
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: c1ccc(-c2nnc(C3CCNCC3)o2)cc1
Reaction time: 1 h
Yield: 100.1 %

Procedure:
To a solution of 4-(5-phenyl-[1,3,4]oxadiazol-2-yl)-piperidine-1-carboxylic acid tert-butyl ester (795 mg, 2.41 mmol, 1.0 eq) in CH2Cl2 was added TFA (1.5 mL, 19.5 mmol, 8 eq). The reaction was stirred for 1 h and 7 N NH3 in MeOH (2 mL) was added dropwise for the pH to reach 7. The solvent was evaporated in vacuo giving the title product as a white solid (553 mg) which was used without further purification for the next step. MS (m/z, MH+): 230.3
Reaction SMILES: [CH2:1]([N:3](CC)CC)C.CN.[CH2:10]([C:12]1[N:13]=[C:14]([C:17]2[CH:22]=[C:21]([NH:23][C:24]([NH:26][CH2:27][CH3:28])=[O:25])[N:20]=[CH:19][C:18]=2[C:29]2[CH:30]=[N:31][CH:32]=[C:33]([C:35](O)=[O:36])[CH:34]=2)[S:15][CH:16]=1)[CH3:11].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CO.CN(C=O)C>[CH2:27]([NH:26][C:24]([NH:23][C:21]1[N:20]=[CH:19][C:18]([C:29]2[CH:30]=[N:31][CH:32]=[C:33]([C:35]([NH:3][CH3:1])=[O:36])[CH:34]=2)=[C:17]([C:14]2[S:15][CH:16]=[C:12]([CH2:10][CH3:11])[N:13]=2)[CH:22]=1)=[O:25])[CH3:28]
Reactant: CCNC(=O)Nc1cc(-c2nc(CC)cs2)c(-c2cncc(C(=O)O)c2)cn1
Reactant: CCN(CC)CC
Agent: CN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CO
Solvent: CN(C)C=O
Product: CCNC(=O)Nc1cc(-c2nc(CC)cs2)c(-c2cncc(C(=O)NC)c2)cn1
Reaction time: 0.17 h

Procedure:
Triethylamine (30.6 mg, 0.30 mmol) and methanamine (0.075 mL, 0.15 mmol), (2M soln in methanol) were added to a solution of 4′-(4-ethylthiazol-2-yl)-6′-(3-ethylureido)-3,3′-bipyridine-5-carboxylic acid (Example 99, 60 mg, 0.15 mmol) in DMF (1.5 mL). The solution was stirred for 10 minutes and then 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate(V) (57.4 mg, 0.15 mmol) was added. The resulting light yellow solution was stirred at room temperature for one hour. A small aliquat was withdrawn and analyzed by LCMS. Since the reaction was not complete, one more equivalent of methylamine solution and HATU were added. The analysis and addition of methylamine and HATU was repeated 3-4 times, however, the reaction did not go to completion. It was then diluted with water and extracted with ethylacetate 2-3 times. The extract was washed with water (3 times), brine and dried over magnesium sulfate, then concentrated to give the title compound as an off-white solid, which was triturated with acetonitrile and lyophilized to remove excess solvent (15 mg). MS (ES) MH+: 411 for C20H22N6O2S; NMR: 1.08 (t, 3H); 1.11 (t, 3H); 2.64 (q, 2H); 2.79 (d, 3H); 3.17-3.22 (m, 2H); 7.40 (s, 1H); 7.66 (s, 1H); 8.12 (d, 1H); 8.16 (s, 1H); 8.28 (s, 1H); 8.55 (s, 1H); 8.68 (s, 1H); 8.99 (d, 1H); 9.02 (s, 1H); 9.44 (s, 1H).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([N+:10]([O-:12])=[O:11])=[C:6]([CH:9]=1)[C:7]#[N:8].[O:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH:14]1[N:19]1[C:23](B2OC(C)(C)C(C)(C)O2)=[CH:22][CH:21]=[N:20]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O.C(C1C=CC=C(C(C)C)C=1N1C=CN(C2C(C(C)C)=CC=CC=2C(C)C)C1=[Pd-3](Cl)(Cl)C1C(Cl)=CC=CN=1)(C)C>[N+:10]([C:5]1[CH:4]=[CH:3][C:2]([C:23]2[N:19]([CH:14]3[CH2:15][CH2:16][CH2:17][CH2:18][O:13]3)[N:20]=[CH:21][CH:22]=2)=[CH:9][C:6]=1[C:7]#[N:8])([O-:12])=[O:11]
Reactant: N#Cc1cc(Cl)ccc1[N+](=O)[O-]
Reactant: CC1(C)OB(c2ccnn2C2CCCCO2)OC1(C)C
Agent: CC(C)c1cccc(C(C)C)c1-n1ccn(-c2c(C(C)C)cccc2C(C)C)c1=[Pd-3](Cl)(Cl)c1ncccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1cc(-c2ccnn2C2CCCCO2)ccc1[N+](=O)[O-]

Procedure:
5-Chloro-2-nitrobenzonitrile (1.5 g), 1-(tetrahydro-2H-pyran-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (2.74 g), PEPPSI ((1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene) (3-chloropyridyl)palladium(ii) dichloride) (0.11 g), K2CO3 (2.27 g) in DMF (30 ml) and water (3 ml) was stirred under argon at 90° C. for 2.5 h. After pouring the mixture to water, it was extracted with EtOAc. Combined organic phases were washed with 5% NaHCO3, water and brine, dried with Na2SO4 and evaporated. The residue was triturated with ethanol. The precipitate was filtered and washed with water. Yield 1.96 g. 1H-NMR (400 MHz; d6-DMSO): δ 1.50-1.65 (m, 3H), 1.83-1.87 (m, 1H), 1.95-1.99 (m, 1H), 2.33-2.42 (m, 1H), 3.60-3.67 (m, 1H), 3.95-4.00 (m, 1H), 5.34 (d, 1H), 6.82 (d, 1H), 7.68 (d, 1H), 8.11 (dd, 1H), 8.32 (d, 1H), 8.54 (d, 1H).
Reaction SMILES: [CH2:1]([O:3][P:4]([C:9]([P:11](=[O:18])([O:15][CH2:16][CH3:17])[O:12][CH2:13][CH3:14])=[CH2:10])(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2].[C:19]([CH2:27][C:28](=[O:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C1CCN2C(=NCCC2)CC1>C1COCC1.C(OCC)(=O)C>[CH2:16]([O:15][P:11]([CH:9]([P:4](=[O:8])([O:5][CH2:6][CH3:7])[O:3][CH2:1][CH3:2])[CH2:10][CH:27]([C:19](=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:28](=[O:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)(=[O:18])[O:12][CH2:13][CH3:14])[CH3:17]
Reactant: O=C(CC(=O)c1ccccc1)c1ccccc1
Reactant: C=C(P(=O)(OCC)OCC)P(=O)(OCC)OCC
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOP(=O)(OCC)C(CC(C(=O)c1ccccc1)C(=O)c1ccccc1)P(=O)(OCC)OCC

Procedure:
Ethenylidenebisphosphonic acid tetraethyl ester (I, 3.00 g), dibenzoyl methane (II, 2.30 g), and DBU (0.25 ml) are heated to 50° in THF (20 ml) for 15 min. The reaction mixture is cooled, diluted with ethyl acetate, filtered through magnesium sulfate and concentrated under reduced pressure. The concentrate is chromatographed eluting with ethyl acetate, ethyl acetate/acetone (1/1). The appropriate fractions are pooled and concentrated to give the title compound, MS (m/e) 524 (M+), 419, 387, 373, 268 and 224; IR (neat) 2982, 1736, 1696, 1674, 1594, 1580, 1448, 1392 and 1253 cm-1 ; NMR (CDCl3) 8.07, 7.58, 7.46, 6.18, 4.17, 2.65 and 1.29 δ.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([O:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:6]=[CH:5][C:3]=1[NH2:4].Cl[C:25](Cl)([O:27]C(=O)OC(Cl)(Cl)Cl)Cl.[CH3:36][CH2:37][CH:38]([OH:42])[CH2:39][CH2:40][CH3:41].C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(N(CC)CC)C.C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:8]=[C:7]([O:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:6]=[CH:5][C:3]=1[NH:4][C:25](=[O:27])[O:42][CH:38]([CH2:37][CH3:36])[CH2:39][CH2:40][CH3:41]
Reactant: CCCC(O)CC
Reactant: COc1cc2ncnc(Oc3ccc(N)c(Cl)c3)c2cc1OC
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCC(CC)OC(=O)Nc1ccc(Oc2ncnc3cc(OC)c(OC)cc23)cc1Cl
Yield: 79.3 %

Procedure:
2-Chloro-4-[(6,7-dimethoxy-4-quinazolinyl)oxy]-aniline (50 mg) was added to toluene (5 ml), and triethylamine (0.5 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (68 mg) in methylene chloride was then added thereto, and the mixture was heated under reflux for 10 min. Next, 3-hexanol (24 mg) was added thereto, and the mixture was further stirred with heating under reflux for 3 hr. A saturated aqueous sodium bicarbonate solution was added to stop the reaction, and the reaction solution was then extracted with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution, water, and saturated brine in that order. The extract was dried over sodium sulfate and was then concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (55 mg, yield 69%).
Reaction SMILES: [OH:1][CH:2]([N:15]1[C:21](=[O:22])[C@@H:20]2[C@H:16]1[S:17][C:18]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[N:19]2)[C:3]([O:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=1)=[O:4].Br[CH2:31][C:32]([CH:34]1[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1)=[O:33].C(=O)([O-])[O-:41].[K+].[K+].C(OCC)(=O)C>CC(C)=O>[OH:1][CH:2]([N:15]1[C@H:16]([S:17][CH2:31][C:32]([CH:34]2[CH2:39][CH2:38][O:37][CH2:36][CH2:35]2)=[O:33])[C@H:20]([NH:19][C:18](=[O:41])[CH2:23][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:21]1=[O:22])[C:3]([O:5][CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][CH3:14])=[CH:11][CH:12]=1)=[O:4]
Reactant: O=C([O-])[O-]
Reactant: O=C(CBr)C1CCOCC1
Reactant: COc1ccc(COC(=O)C(O)N2C(=O)[C@H]3N=C(Cc4ccccc4)S[C@H]32)cc1
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: COc1ccc(COC(=O)C(O)N2C(=O)[C@@H](NC(=O)Cc3ccccc3)[C@H]2SCC(=O)C2CCOCC2)cc1
Reaction time: 0.33 h
Yield: 76 %

Procedure:
Crude 4-methoxybenzyl (2RS)-2-hydroxy-2-[(3R,4R)-4-mercapto-3-phenylacetamidoazetidin-2-on-1-yl acetate {prepared from 4-methoxybenzyl (2RS)-2-hydroxy-2-[(1R,5R)-3-benzyl-4-thia-2,6-diazabicyclo[3.2.0]hept-2-en-7-on-6-yl]acetate (8.35g, 20mmol)} was dissolved in acetone (25ml) and treated with a solution of 4-bromoacetyltetrahydropyran (G. H. Harnest and A. Burger, J. Amer. Chem. Soc., 1943, 65, 370) (4.4g, 20mmol). After 20min., potassium carbonate (1.38g, 10mmol) was added and the mixture stirred again for a further 45min. Excess ethyl acetate was then added and the organic solution washed with water, brine and dried over anhydrous MgSO4. Evaporation of solvent and chromatography of the residue on silica gel using 50% hexane in ethyl acetate to 100% ethyl acetate gave the title compound as a pale yellow foam (8.5g; 76%); vmax (CHCl3) 3420, 1780, 1750, 1680 and 1615cm-1. [Mass spectrum: +ve ion (3-nitrobenzyl alcohol, sodium acetate) MNa+ (579)].
Reaction SMILES: [CH:1]([N:4](CC)[CH:5](C)C)(C)C.[F:10][C:11]1[CH:24]=[C:23]([C:25]2[CH:26]=[N:27][C:28]3[N:29]([C:31]([C:34]4([C:37]5[CH:38]=[C:39]6[C:44](=[CH:45][CH:46]=5)[N:43]=[CH:42][CH:41]=[CH:40]6)[CH2:36][CH2:35]4)=[CH:32][N:33]=3)[CH:30]=2)[CH:22]=[CH:21][C:12]=1[C:13]([NH:15][CH:16]([CH3:20])[C:17](O)=[O:18])=[O:14].[CH3:47]NC.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C)C=O>[CH3:1][N:4]([CH3:5])[C:17](=[O:18])[CH:16]([NH:15][C:13](=[O:14])[C:12]1[CH:21]=[CH:22][C:23]([C:25]2[CH:26]=[N:27][C:28]3[N:29]([C:31]([C:34]4([C:37]5[CH:38]=[C:39]6[C:44](=[CH:45][CH:46]=5)[N:43]=[CH:42][CH:41]=[CH:40]6)[CH2:35][CH2:36]4)=[CH:32][N:33]=3)[CH:30]=2)=[CH:24][C:11]=1[F:10])[CH2:20][CH3:47]
Reactant: CNC
Reactant: CCN(C(C)C)C(C)C
Reactant: CC(NC(=O)c1ccc(-c2cnc3ncc(C4(c5ccc6ncccc6c5)CC4)n3c2)cc1F)C(=O)O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: CCC(NC(=O)c1ccc(-c2cnc3ncc(C4(c5ccc6ncccc6c5)CC4)n3c2)cc1F)C(=O)N(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
N,N-Diisopropylethylamine (31 μL, 0.18 mmol) was added to a mixture of 2-(2-fluoro-4-[3-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidin-6-yl]benzoylamino)propanoic acid (29.7 mg, 0.06 mmol), dimethylamine (4.0 mg, 0.09 mmol) and benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (40 mg, 0.09 mmol) in N,N-dimethylformamide (0.5 mL). The reaction mixture was stirred overnight at RT and purified by RP-HPLC (pH 10) to afford the desired product. LCMS: (M+H)=523.1.