Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH2:4][CH:5]=O)[CH2:3][CH2:2]1.ClCCl.[CH2:10]([O:12][C:13]([C@H:15]1[C@@H:20]([NH2:21])[C@H:19]2[CH2:22][C@@H:16]1[CH2:17][CH2:18]2)=[O:14])[CH3:11].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO.C(O)(=O)C>[CH2:10]([O:12][C:13]([C@H:15]1[C@@H:20]([NH:21][CH2:5][CH2:4][CH:1]2[CH2:2][CH2:3]2)[C@H:19]2[CH2:22][C@@H:16]1[CH2:17][CH2:18]2)=[O:14])[CH3:11]
Reactant: CCOC(=O)[C@@H]1[C@H]2CC[C@H](C2)[C@@H]1N
Reactant: O=CCC1CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCOC(=O)[C@@H]1[C@H]2CC[C@H](C2)[C@@H]1NCCC1CC1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 84.9 %

Procedure:
A 1.4 M solution of cyclopropylacetaldehyde in dichloromethane (prepared as described in Example 23a, 3.4 mL, 4.76 mmol) was added to a solution of (1S,2R,3S,4R)-3-amino-bicyclo[2.2.1]heptane-2-carboxylic acid ethyl ester (prepared as described in Example 6k, 580 mg, 3.17 mmol) in anhydrous methanol (15 mL) at 25° C. under a nitrogen atmosphere. After stirring for 20 min, glacial acetic acid (0.6 mL) was added. The solution was cooled to 0° C., sodium triacetoxyborohydride (1.7 g, 7.93 mmol) was added, and the resulting mixture was stirred at 25° C. for 20 h. The reaction mixture was quenched with saturated aqueous sodium bicarbonate solution (25 mL) and was extracted with ethyl acetate (3×60 mL). The combined organic layers were washed with saturated aqueous brine solution, dried over sodium sulfate and filtered. The filtrate was concentrated in vacuo to afford the desired product, (1S,2R,3S,4R)-3-(2-cyclopropyl-ethylamino)-bicyclo[2.2.1]heptane-2-carboxylic acid ethyl ester (676.4 mg, 2.69 mmol, 84.9%), as a yellow oil. LC-MS (ESI) calcd for C15H25NO2 251.19. found 252.0 [M+H+].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:9][C:10]2([C:23](N)=[O:24])[CH2:15][CH2:14][N:13]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:12][CH2:11]2)[CH:6]=[CH:7][CH:8]=1.[OH-:26].[K+].Cl.[OH-].[Na+]>O.C(O)CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:9][C:10]2([C:23]([OH:26])=[O:24])[CH2:11][CH2:12][N:13]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:14][CH2:15]2)[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(NC2(C(N)=O)CCN(Cc3ccccc3)CC2)c1
Reactant: [OH-]
Agent: Cl
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: OCCO
Product: COc1cccc(NC2(C(=O)O)CCN(Cc3ccccc3)CC2)c1

Procedure:
A mixture of 100 parts of 4-[N-(3-methoxyphenyl)amino]-1-(phenylmethyl)-4-piperidinecarboxamide, 49.5 parts of potassium hydroxide and 974 parts of 1,2-ethanediol is stirred and refluxed for 24 hours. After cooling, the reaction mixture is poured onto 1500 parts of water and acidified with a concentrated hydrochloric acid solution. The whole is strongly alkalized with a sodium hydroxide solution and the layers are separated. The aqueous phase is concentrated, whereupon the product is separated as an oil. The supernatant aqueous phase is decanted and the residual oil is taken up in a sodium hydroxide solution. The precipitated product is filtered off and dissolved in water. The solution is acidified with acetic acid till pH=6. The precipitated product is filtered off and warmed in ethanol. It is filtered off again, washed with ethanol and 2,2'-oxybispropane and dissolved in boiling N,N-dimethylformamide. The solution is filtered and the product is allowed to crystallized from the filtrate. It is filtered off, washed successively with N,N-dimethylformamide, water and ethanol, and dried, yielding 4-[N-(3-methoxyphenyl)amino]-1-(phenylmethyl)- 4-piperidinecarboxylic acid; mp. 211.1° C.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:11])[C@H:5]([C@H:7]([CH2:9][CH3:10])[CH3:8])[NH2:6].[O-]S([O-])(=O)=O.[Mg+2].[O:18]1[CH:22]=[CH:21][CH:20]=[C:19]1[CH:23]=O.CCN(CC)CC.[BH4-].[Na+]>CO.C1COCC1>[O:18]1[CH:22]=[CH:21][CH:20]=[C:19]1[CH2:23][NH:6][C@@H:5]([C@@H:7]([CH3:8])[CH2:9][CH3:10])[C:4]([O:3][CH3:2])=[O:11]
Reactant: CC[C@H](C)[C@H](N)C(=O)OC
Reactant: O=Cc1ccco1
Agent: Cl
Agent: O=S(=O)([O-])[O-]
Agent: [BH4-]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CO
Product: CC[C@H](C)[C@H](NCc1ccco1)C(=O)OC
Yield: 71 %

Procedure:
Synthesized according to the general procedure as described in Example 1a using L-isoleucine methyl ester hydrochloride (2.5 gm, 1 equiv), THF (30 mL), MgSO4 (2.8 gm, 1.7 equiv), 2-furaldehyde (2.27 mL, 2 equiv), and Et3N (1.91 mL, 1 equiv), sodium borohydride (1.04 gm, 2 equiv), and methanol (40 mL) to give 11p (2.2 gm, 71%) in FIG. 2. 1H NMR (500 MHz, CDCl3): δ 0.86-0.92 (6H, m), 1.16-1.26 (1H, m), 1.48-1.58 (1H, m), 1.68-1.74 (1H, m), 1.78-1.98 (1H, bs), 3.16 (1H, d, J=5.85 Hz), 3.67 (1H, d, J=14.15 Hz), 3.71 (3H, s), 3.82 (1H, d, J=14.4 Hz), 6.19 (1H, d, J=3.17 Hz), 6.32 (1H, d, J=2.68 Hz), 7.37 (1H, d, J=1.95 Hz). ESI-MS: 248.1 (M+23).
Reaction SMILES: Br[C:2]1[S:6][C:5]([C:7]2[N:11]3[N:12]=[C:13]([CH3:21])[CH:14]=[C:15]([CH:16]([CH2:19][CH3:20])[CH2:17][CH3:18])[C:10]3=[N:9][C:8]=2[CH3:22])=[C:4]([CH3:23])[CH:3]=1.C([Li])CCC.C1COCC1.Br[C:35]1[CH:39]=[CH:38][N:37]([CH3:40])[N:36]=1>[Cl-].[Cl-].[Zn+2].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]>[CH2:17]([CH:16]([C:15]1[C:10]2[N:11]([C:7]([C:5]3[S:6][C:2]([C:35]4[CH:39]=[CH:38][N:37]([CH3:40])[N:36]=4)=[CH:3][C:4]=3[CH3:23])=[C:8]([CH3:22])[N:9]=2)[N:12]=[C:13]([CH3:21])[CH:14]=1)[CH2:19][CH3:20])[CH3:18]
Reactant: CCC(CC)c1cc(C)nn2c(-c3sc(Br)cc3C)c(C)nc12
Reactant: Cn1ccc(Br)n1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [Cl-]
Solvent: C1CCOC1
Product: CCC(CC)c1cc(C)nn2c(-c3sc(-c4ccn(C)n4)cc3C)c(C)nc12
Yield: 9.8 %

Procedure:
Using a procedure analogous to Example 31, 3-(5-bromo-3-methyl-thiophen-2-yl)-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine (0.40 g, 1.02 mmol), 1.42 M n-Bu-Li (0.75 mL, 1.07 mmol), 0.5 M ZnCl2 in THF (2.14 mL, 1.07 mmol), 3-bromo-1-methyl-1H-pyrazole (Pavlik, J.; Kurzweil, E.; J. Org. Chem., 1991, 56, 22, 6313) (0.20 g, 1.22 mmol) and PdCl2(dppf) (0.037 g, 0.051 mmol) furnish the title compound (0.041 g, 0.10 mmol, 10%). 1H NMR (CDCl3) δ 0.90 (t, J=7.5 Hz, 6H), 1.75-1.94 (m, 4H), 2.15 (s, 3H), 2.51 (s, 3H), 2.52 (s, 3H), 3.31-3.41 (m, 1H), 3.95 (s, 3H), 6.47 (d, J=2.2 Hz, 1H), 6.67 (s, 1H), 7.25 (s, 1H), 7.36 (d, J=2.2 Hz, 1H). LC/MS (m/z): calcd. for C22H27N5S (M+H)+: 394.3; found: 394.2.
Reaction SMILES: [Si]([O:8][C@@H:9]1[C@H:13]([O:14][Si](C(C)(C)C)(C)C)[C@@H:12]([CH2:22][O:23][CH3:24])[O:11][C@H:10]1[N:25]1[CH:33]=[N:32][C:31]2[C:26]1=[N:27][C:28]([CH2:49][CH2:50][NH:51][CH2:52][CH:53]1[CH2:58][CH2:57][CH2:56][CH2:55][CH2:54]1)=[N:29][C:30]=2[NH:34][CH2:35][CH:36]([C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[CH:53]1([CH2:52][NH:51][CH2:50][CH2:49][C:28]2[N:27]=[C:26]3[C:31]([N:32]=[CH:33][N:25]3[C@H:10]3[C@H:9]([OH:8])[C@H:13]([OH:14])[C@@H:12]([CH2:22][O:23][CH3:24])[O:11]3)=[C:30]([NH:34][CH2:35][CH:36]([C:37]3[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=3)[C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)[N:29]=2)[CH2:54][CH2:55][CH2:56][CH2:57][CH2:58]1
Reactant: COC[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(CCNCC4CCCCC4)nc32)[C@H](O[Si](C)(C)C(C)(C)C)[C@@H]1O[Si](C)(C)C(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: COC[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(CCNCC4CCCCC4)nc32)[C@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 24 h
Yield: 46.6 %

Procedure:
N-(9-[(2R,3R,4R,5R)-3,4-Bis{[tert-butyl(dimethyl)silyl]oxy}-5-(methoxymethyl)tetrahydro-2-furanyl]-2-{2-[(cyclohexylmethyl)amino]ethyl}-9H-purin-6-yl)-N-(2,2-diphenylethyl)amine (210 mg, 0.25 mmol) (preparation 23) was dissolved in stirred tetrahydrofuran (1 ml) and a 1M solution of tetra-n-butylammonium fluoride in tetrahydrofuran (1 ml, 1 mmol) added. The reaction mixture was stirred at room temperature for 24 hr. The solvent was removed under reduced pressure and the residue partitioned between dilute aqueous sodium hydroxide solution and ethyl acetate. The organic layer was separated and the aqueous phase extracted with ethyl acetate. The ethyl acetate phases were combined and dried with anhydrous magnesium sulfate. The solvent was removed under reduced pressure and the residue purified by column chromatography on silica gel eluting with a solvent gradient of dichloromethane:methanol:ammonia (94:6:0.6) increasing in polarity to (91:9:0.9). This gave the title compound (70 mg) as a powder. MS: 601 (MH+).
Reaction SMILES: [CH2:1]([C:8]#[N:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li]CCCC.[C:15]([N:22]1[CH2:27][CH2:26][C:25](=[O:28])[CH2:24][CH2:23]1)([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16]>C1COCC1>[C:8]([CH:1]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:25]1([OH:28])[CH2:24][CH2:23][N:22]([C:15]([O:17][C:18]([CH3:20])([CH3:19])[CH3:21])=[O:16])[CH2:27][CH2:26]1)#[N:9]
Reactant: N#CCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(O)(C(C#N)c2ccccc2)CC1
Reaction time: 0.5 h

Procedure:
Benzyl cyanide (2.96 ml, 25.6 mmol) in THF (125 ml) was cooled to −78° C. nBuLi (16.17 ml, 25.9 mmol) was added dropwise over 20 min via syringe pump, and the reaction stirred for 30 min. 1-BOC-4-piperidone (5.10 g, 25.6 mmol) in THF (20 ml) was added over 20 min via syringe pump and the reaction stirred for 2.5 hours. While still cold, the reaction was quenched with satd. NH4Cl and allowed to warm overnight. The mixture was partitioned between CH2Cl2 and satd. NH4Cl, the aqueous portion extracted 3×CH2Cl2, and the organic portion dried (Na2SO4) then concentrated in vacuo. The resulting material was carried on without further purification.
Reaction SMILES: [C:1]([N:5]([CH2:37][C:38]([O:40][CH2:41][CH3:42])=[O:39])[NH:6][C:7]1[C:12]([F:13])=[CH:11][N:10]=[C:9]([C:14]2[C:22]3[C:17](=[N:18][CH:19]=[C:20]([C:23]([F:26])([F:25])[F:24])[CH:21]=3)[N:16](S(C3C=CC(C)=CC=3)(=O)=O)[CH:15]=2)[N:8]=1)([CH3:4])([CH3:3])[CH3:2].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.CCOC(C)=O>C1COCC1.[Cl-].[Na+].O>[C:1]([N:5]([CH2:37][C:38]([O:40][CH2:41][CH3:42])=[O:39])[NH:6][C:7]1[C:12]([F:13])=[CH:11][N:10]=[C:9]([C:14]2[C:22]3[C:17](=[N:18][CH:19]=[C:20]([C:23]([F:26])([F:24])[F:25])[CH:21]=3)[NH:16][CH:15]=2)[N:8]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)CN(Nc1nc(-c2cn(S(=O)(=O)c3ccc(C)cc3)c3ncc(C(F)(F)F)cc23)ncc1F)C(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC(=O)CN(Nc1nc(-c2c[nH]c3ncc(C(F)(F)F)cc23)ncc1F)C(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of ethyl 2-(1-tert-butyl-2-(5-fluoro-2-(1-tosyl-5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl)hydrazinyl)ethanoate, 154a, (0.54 g, 0.89 mmol) in THF (20 mL) was added tetrabutylammonium fluoride (1.78 mL of 1 M, 1.78 mmol). The reaction mixture was stirred at room temperature for 30 minutes. The reaction mixture was diluted into EtOAc and brine. The organic phase was dried over MgSO4, filtered and concentrated in vacuo. The resulting residue was purified via silica gel chromatography (70% EtOAc/Hexanes) to afford 300 mg of the desired product. 1H NMR (400 MHz, CDCl3) δ 10.59 (s, 1H), 9.55 (s, 1H), 8.66 (s, 1H), 8.29 (d, J=2.2 Hz, 1H), 8.13 (dd, J=3.8, 1.5 Hz, 1H), 7.14 (s, 1H), 4.20-4.04 (m, 2H), 3.85 (s, 2H), 1.28 (d, J=9.1 Hz, 9H), 1.19 (dt, J=7.1, 3.6 Hz, 3H). LCMS Gradient 10-90%, 0.1% formic acid, 5 minutes, C18/ACN, Retention Time=2.93 min, (M+H) 455.43.
Reaction SMILES: C([O:5][C:6](=[O:26])[CH2:7][O:8][C:9]1[CH:14]=[C:13]([C:15]([O:17][CH3:18])=[O:16])[C:12]([N+:19]([O-:21])=[O:20])=[C:11]([C:22]([O:24][CH3:25])=[O:23])[CH:10]=1)(C)(C)C.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[C:22]([C:11]1[CH:10]=[C:9]([CH:14]=[C:13]([C:15]([O:17][CH3:18])=[O:16])[C:12]=1[N+:19]([O-:21])=[O:20])[O:8][CH2:7][C:6]([OH:26])=[O:5])([O:24][CH3:25])=[O:23]
Reactant: COC(=O)c1cc(OCC(=O)OC(C)(C)C)cc(C(=O)OC)c1[N+](=O)[O-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: O
Product: COC(=O)c1cc(OCC(=O)O)cc(C(=O)OC)c1[N+](=O)[O-]

Procedure:
To a solution of 3.28 g. of tert-butyl-(3,5-dicarbomethoxy-4-nitrophenoxy)acetate in 20 ml. of benzene are added 100 mg. of p-toluenesulfonic acid monohydrate. The solution is stirred and refluxed for 30 min. After this time, the reaction is cooled and the precipitate collected. Yield 2.4 g.; m.p. 151°-152° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][CH2:14][CH2:15][O:16][Si:17]([C:30]([CH3:33])([CH3:32])[CH3:31])([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:10](O)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:34]([O:38][C:39]([N:41]1[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]1)=[O:40])[CH2:35][CH2:36][CH3:37].C(N1CCOCC1)C.[B-](F)(F)(F)F.CCOC(C(C#N)=NOC(N(C)C)=[N+](C)C)=O>CN(C=O)C.C(OCC)(=O)C>[CH2:34]([O:38][C:39]([N:41]1[CH2:46][CH2:45][N:44]([C:10](=[O:11])[C@@H:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:13][CH2:14][CH2:15][O:16][Si:17]([C:30]([CH3:33])([CH3:32])[CH3:31])([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:43][CH2:42]1)=[O:40])[CH2:35][CH2:36][CH3:37]
Reactant: CCCCOC(=O)N1CCNCC1
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)C(=O)O
Agent: CCN1CCOCC1
Agent: CCOC(=O)C(C#N)=NOC(N(C)C)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCCOC(=O)N1CCN(C(=O)[C@H](CCCO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)NC(=O)OC(C)(C)C)CC1
Reaction time: 12 h

Procedure:
To a solution of 1.61 g (S)-2-tert-Butoxycarbonylamino-5-(tert-butyl-diphenyl-silanyloxy)-pentanoic acid in 8 ml DMF were added 1.02 g piperazine-1-carboxylic acid butyl ester hydrotrifluoroacetate, 1.7 ml N-ethylmorpholine and 1.1 g TOTU. After stirring for 12 h the solution was diluted with ethyl acetate and subsequently washed with aqueous LiCl (4%), 0.1 M HCl and saturated aqueous NaHCO3. The crude product obtained after evaporation of the solvent was used without further purification. Yield: 1.80 g.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)=[CH:4][N:3]=1.[C:18]([NH:21][NH2:22])(=O)[CH3:19]>C(O)CCC>[CH3:19][C:18]1[N:3]2[CH:4]=[C:5]([C:8]3[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=3)[CH:6]=[CH:7][C:2]2=[N:22][N:21]=1
Reactant: CC(=O)NN
Reactant: FC(F)(F)c1cccc(-c2ccc(Cl)nc2)c1
Solvent: CCCCO
Product: Cc1nnc2ccc(-c3cccc(C(F)(F)F)c3)cn12

Procedure:
A mixture of 2 g. of 2-chloro-5-[3-(trifluoromethyl)phenyl]pyridine and two equivalents of acetylhydrazine in n-butanol is heated at reflux for 48 hours to give the product of the Example as crystals, m.p. 185°-187° C.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([OH:12])=[C:4]([C:13]([NH:15][CH2:16][C:17]([OH:19])=[O:18])=[O:14])[N:3]=1.[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([SH:27])=[CH:23][CH:22]=1>>[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([S:27][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]([OH:12])=[C:4]([C:13]([NH:15][CH2:16][C:17]([OH:19])=[O:18])=[O:14])[N:3]=2)=[CH:23][CH:22]=1
Reactant: O=C(O)CNC(=O)c1nc(Cl)c2ccccc2c1O
Reactant: Sc1ccc(Cl)cc1
Product: O=C(O)CNC(=O)c1nc(Sc2ccc(Cl)cc2)c2ccccc2c1O

Procedure:
The title compound was prepared from [(1-chloro-4-hydroxy-isoquinoline-3-carbonyl)-amino]-acetic acid (U.S. Pat. No. 6,093,730) and 4-chlorobenzenethiol under conditions analogous to Example D-110; MS (+) m/z 389.06 (M+1)
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:11]2[CH:12]=[C:13]([C:16]3[C:17]([C:40]4[CH:45]=[CH:44][C:43]([O:46]COCC[Si](C)(C)C)=[CH:42][CH:41]=4)=[N:18][N:19]([C:21]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH:20]=3)[CH:14]=[CH:15][C:10]2=[N:9][CH:8]=1.CN(C)P(N(C)C)N(C)C.C(OCC)(=O)C.[Cl-].[NH4+]>[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC.O>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:11]2[CH:12]=[C:13]([C:16]3[C:17]([C:40]4[CH:41]=[CH:42][C:43]([OH:46])=[CH:44][CH:45]=4)=[N:18][N:19]([C:21]([C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=4)([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)[CH:20]=3)[CH:14]=[CH:15][C:10]2=[N:9][CH:8]=1
Reactant: C[Si](C)(C)CCOCOc1ccc(-c2nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cc2-c2ccc3ncc(-c4ccccn4)n3c2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: CN(C)P(N(C)C)N(C)C
Agent: [Cl-]
Solvent: O
Solvent: CCOC(C)=O
Product: Oc1ccc(-c2nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cc2-c2ccc3ncc(-c4ccccn4)n3c2)cc1
Temperature: 80 °C
Reaction time: 2 h
Yield: 100.1 %

Procedure:
A mixture of 1.23 g 3-(pyridin-2-yl)-6-{3-[4-(2-trimethylsilanylethoxymethoxy)phenyl]-1-trityl-1H-pyrazol-4-yl}imidazo[1,2-a]pyridin (compound in Example 352), 8.5 mL tetrabutylammoniumchloride (1 M tetrahydrofuran solution) and 10 mL hexamethyl phosphorous acid triamide was stirred at 80° C. for 2 hours. Ethyl acetate, an aqueous saturated ammonium chloride solution and water were added to the reaction solution, and the organic layer was separated. The organic layer was dried over anhydrous sodium sulfate, the solvent was evaporated, the resulting residue was triturated with diisopropyl ether, and the crystals were collected by filtration to give 1.01 g of the title compound as white crystals.
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]1[C:9](=[O:10])[N:8]2[CH:11]=[CH:12][CH:13]=[CH:14][C:7]2=[N:6][C:5]=1[CH3:15].[NH:16]1[CH2:21][CH2:20][CH:19]([NH:22][C:23]2[N:24]([CH2:32][C:33]3[CH:38]=[N:37][CH:36]=[CH:35][N:34]=3)[C:25]3[C:30]([N:31]=2)=[CH:29][N:28]=[CH:27][N:26]=3)[CH2:18][CH2:17]1.C(=O)([O-])[O-].[Na+].[Na+].CN(C)C(=O)C>O>[CH3:15][C:5]1[N:6]=[C:7]2[CH:14]=[CH:13][CH:12]=[CH:11][N:8]2[C:9](=[O:10])[C:4]=1[CH2:3][CH2:2][N:16]1[CH2:17][CH2:18][CH:19]([NH:22][C:23]2[N:24]([CH2:32][C:33]3[CH:38]=[N:37][CH:36]=[CH:35][N:34]=3)[C:25]3[C:30]([N:31]=2)=[CH:29][N:28]=[CH:27][N:26]=3)[CH2:20][CH2:21]1
Reactant: Cc1nc2ccccn2c(=O)c1CCCl
Reactant: c1cnc(Cn2c(NC3CCNCC3)nc3cncnc32)cn1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: Cc1nc2ccccn2c(=O)c1CCN1CCC(Nc2nc3cncnc3n2Cc2cnccn2)CC1
Temperature: 90 °C
Yield: 31.6 %

Procedure:
A mixture of 1.45 parts of 3-(2-chloroethyl)-2-methyl-4H-pyrido-[1,2-a]pyrimidin-4-one, 2 parts of N-(4-piperidinyl)-9-(2-pyrazinylmethyl)-9H-purin-8-amine, 1 part of sodium carbonate and 45 parts of N,N-dimethylacetamide was stirred and heated overnight at 90° C. The reaction mixture was poured into water. The product was extracted with trichloromethane. The extract was dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol, saturated with ammonia, (95:5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from acetonitrile. The product was filtered off and dried, yielding 0.9 parts (31.6%) of 2-methyl-3-[2-[4-[[9-(2-pyrazinylmethyl)-9H-purin-8-yl]amino]-1-piperidinyl]-ethyl]-4H-pyrido[1,2-a]pyrimidin-4-one; mp. 180.1° C. (compound 87).
Reaction SMILES: Br[C:2]1[C:3]([CH3:16])=[N:4][N:5]([C:7]2[CH:12]=[CH:11][N:10]=[C:9]3[NH:13][CH:14]=[CH:15][C:8]=23)[CH:6]=1.[C:17]([C:19]1[CH:20]=[C:21](B(O)O)[CH:22]=[CH:23][CH:24]=1)#[N:18].C(=O)([O-])[O-].[Na+].[Na+].COCCOC.O>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>[CH3:16][C:3]1[C:2]([C:23]2[CH:24]=[C:19]([CH:20]=[CH:21][CH:22]=2)[C:17]#[N:18])=[CH:6][N:5]([C:7]2[CH:12]=[CH:11][N:10]=[C:9]3[NH:13][CH:14]=[CH:15][C:8]=23)[N:4]=1
Reactant: Cc1nn(-c2ccnc3[nH]ccc23)cc1Br
Reactant: N#Cc1cccc(B(O)O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: Cc1nn(-c2ccnc3[nH]ccc23)cc1-c1cccc(C#N)c1
Temperature: 130 °C
Reaction time: 4 h
Yield: 41.8 %

Procedure:
A mixture of 4-(4-bromo-3-methyl-1H-pyrazol-1-yl)-1H-pyrrolo[2,3-b]pyridine (0.032 g, 0.00012 mol), (3-cyanophenyl)boronic acid (0.027 g, 0.00018 mol), sodium carbonate (0.032 g, 0.00030 mol) and tetrakis(triphenylphosphine)palladium(0) (7.0 mg, 0.0000060 mol) in 1,2-dimethoxyethane (0.3 mL, 0.003 mol) and water (0.3 mL, 0.02 mol) was heated at 130° C. (a liquid resulted, but with two layers) for 4 h. The reaction mixture then was cooled to room temperature (rt), filtered and was washed with water (×2) and dimethyl ether (DME) (×2) to give the product as a pale orange solid (15 mg, 44% yield).
Reaction SMILES: C(N(CCCC)CCCC)CCC.[S:14]1[CH:18]=[CH:17][CH:16]=[C:15]1[CH2:19][C:20]([NH:22][C@@H:23]1[C:35](=[O:36])[N:25]2[C:26]([C:32]([OH:34])=[O:33])=[C:27]([CH2:30]O)[CH2:28][S:29][C@H:24]12)=[O:21].[SH:37][C:38]1[N:42]([CH3:43])[N:41]=[N:40][N:39]=1.O>C(OCC)(=O)C>[S:14]1[CH:18]=[CH:17][CH:16]=[C:15]1[CH2:19][C:20]([NH:22][C@@H:23]1[C:35](=[O:36])[N:25]2[C:26]([C:32]([OH:34])=[O:33])=[C:27]([CH2:30][S:37][C:38]3[N:42]([CH3:43])[N:41]=[N:40][N:39]=3)[CH2:28][S:29][C@H:24]12)=[O:21]
Reactant: Cn1nnnc1S
Reactant: O=C(Cc1cccs1)N[C@@H]1C(=O)N2C(C(=O)O)=C(CO)CS[C@H]12
Solvent: O
Solvent: CCCCN(CCCC)CCCC
Solvent: CCOC(C)=O
Product: Cn1nnnc1SCC1=C(C(=O)O)N2C(=O)[C@@H](NC(=O)Cc3cccs3)[C@H]2SC1
Temperature: -20 °C
Yield: 83.9 %

Procedure:
To 10 ml of ethyl acetate were added 0.540 g of 7β-(2-thienylacetamido)-3-hydroxymethyl-3-cephem-4-carboxylic acid tri-n-butylamine salt and 0.175 g of 5-mercapto-1-methyl-1H tetrazole and, under cooling at -20° C. and stirring, a solution of 0.370 g of methyl o-phenylene phosphorochloridate in 5 ml of ethyl acetate was added. The mixture was stirred under ice-cooling for 1.5 hours and 10 ml of water was added. After phase separation, 20 ml of water was added to the organic layer and the mixture was adjusted to pH 9.0. The aqueous layer was taken and washed with 5 ml of ethyl acetate. To the aequous layer was added 20 ml of ethyl acetate and the mixture was adjusted to pH 2.0. After phase separation, the organic layer was washed with saturated aqueous sodium chloride and dried over anhydrous sodium sulfate. The ethyl acetate was distilled off under reduced pressure and ether was added. The powdery precipitate was collected by filtration to give 0.380 g (yield 84.1%) of 7β-(2-thienylacetamido)-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid. The IR and NMR spectra of this product were identical with those of the authentic sample.
Reaction SMILES: [Li+].CC([N-]C(C)C)C.[Cl:9][C:10]1[CH:15]=[CH:14][N:13]=[C:12]2[N:16]([S:19]([C:22]3[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=3)(=[O:21])=[O:20])[CH:17]=[CH:18][C:11]=12.[Sn:29](Cl)([CH2:38][CH2:39][CH2:40][CH3:41])([CH2:34][CH2:35][CH2:36][CH3:37])[CH2:30][CH2:31][CH2:32][CH3:33].O>C1COCC1.CCOC(C)=O>[Cl:9][C:10]1[CH:15]=[CH:14][N:13]=[C:12]2[N:16]([S:19]([C:22]3[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=3)(=[O:21])=[O:20])[C:17]([Sn:29]([CH2:34][CH2:35][CH2:36][CH3:37])([CH2:38][CH2:39][CH2:40][CH3:41])[CH2:30][CH2:31][CH2:32][CH3:33])=[CH:18][C:11]=12
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(Cl)ccnc32)cc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1cc2c(Cl)ccnc2n1S(=O)(=O)c1ccc(C)cc1
Temperature: -78 °C
Yield: 79 %

Procedure:
Add LDA (1.5 equiv., 0.74 mL, 1.47 mmol) dropwise in the space of 5 min to azaindole 25 (0.3 g, 0.98 mmol) in THF (15 mL), stirred at −78° C., under N2. After stirring the reaction medium for 0.5 h, add Bu3SnCl dropwise (475 mg, 400 μL, 1.47 mmol) and stir the reaction medium for a further 0.5 h. Then allow the reaction medium to return to room temperature, stop the reaction with H2O, dilute with EtOAc (200 mL), wash with brine, dry (MgSO4) and concentrate. The residue is submitted to flash chromatography to give 26 (0.46 g, 79%) as a colorless oil: 1H NMR (CDCl3) δ 8.15 (d, 1H, J=5.1 Hz), 7.97 (dd, 2H, J=8.0, 1.5 Hz), 7.27 (d, 2H, J=8.4 Hz), 7.09 (d, 1H, J=5.2 Hz), 6.75 (s, 1H), 2.36 (s, 3H), 1.65-1.20 (m, 12H), 0.93 (t, 9H), TLC (EtOAc at 40%/heptane) Rf=0.65.