Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([NH:4][C:5]2[C:10]([C:11]#[N:12])=[CH:9][N:8]=[CH:7][CH:6]=2)[CH2:3][CH2:2]1.Br[CH2:14][C:15]([O:17][CH3:18])=[O:16].[H-].[Na+].[H][H]>>[CH3:18][O:17][C:15]([C:14]1[N:4]([CH:1]2[CH2:2][CH2:3]2)[C:5]2[CH:6]=[CH:7][N:8]=[CH:9][C:10]=2[C:11]=1[NH2:12])=[O:16]
Reactant: [H][H]
Reactant: N#Cc1cnccc1NC1CC1
Reactant: COC(=O)CBr
Agent: [H-]
Agent: [Na+]
Product: COC(=O)c1c(N)c2cnccc2n1C1CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 50.3 %

Procedure:
To a stirred solution of 4-cyclopropylamino-nicotinonitrile (2.15 g, 13.51 mmol) and methyl bromoacetate (1.53 mL, 16.21 mmol, 1.2 eq) at 0° C. was added sodium hydride (60% in mineral oil: 1.35 g, 33.78 mmol, 2.5 eq) portion wise over 15 min. After the evolution of hydrogen gas had subsided, the reaction mixture was warmed to ambient temperature and stirred under N2 for 16 h. The reaction mixture was quenched with saturated NH4Cl solution (10 mL) and poured into EtOAc. The biphasic layers were separated, and the organic layer was washed with 50% aq. brine, sat. NaHCO3 solution, and brine. The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo. The crude residue was absorbed onto silica and purified by flash column chromatography (silica, ISCO, 45 mL/min, 0 to 25% MeOH in EtOAc) to give the desired product as an orange solid (1.57 g, 50.3%). 1H-NMR (500 MHz, DMSO-d6) δ ppm 9.01 (d, J=1.0 Hz, 1H), 8.24 (t, J=5.1 Hz, 1H), 7.29 (dd, J=6.0 Hz, J=1.0 Hz, 1H), 6.34-6.09 (br s, 2H), 3.85 (s, 3H), 3.35 (m, 1H), 1.14-1.03 (m, 2H), 0.80-0.70 (m, 2H); LC-MS (method D): [M+H]+=232.0, RT=1.31 min.
Reaction SMILES: [NH2:1][CH:2]1[C:20](=[O:21])[N:4]2[C:5]([C:17]([OH:19])=[O:18])=[C:6]([CH:9]([S:11][C:12]3[NH:16][N:15]=[N:14][N:13]=3)[CH3:10])[CH2:7][S:8][C@H:3]12.C[Si](CC(N)=O)(C)C.P(Cl)(Cl)(Cl)=O.[CH:35]([NH:37][C:38]1[S:39][C:40]([Br:50])=[C:41]([C:43](=[N:47][O:48][CH3:49])[C:44](O)=[O:45])[N:42]=1)=[O:36]>C(OCC)(=O)C.CN(C)C=O>[CH:35]([NH:37][C:38]1[S:39][C:40]([Br:50])=[C:41]([C:43](=[N:47][O:48][CH3:49])[C:44]([NH:1][CH:2]2[C:20](=[O:21])[N:4]3[C:5]([C:17]([OH:19])=[O:18])=[C:6]([CH:9]([S:11][C:12]4[NH:13][N:14]=[N:15][N:16]=4)[CH3:10])[CH2:7][S:8][C@H:3]23)=[O:45])[N:42]=1)=[O:36]
Reactant: CC(Sc1nnn[nH]1)C1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Reactant: CON=C(C(=O)O)c1nc(NC=O)sc1Br
Agent: C[Si](C)(C)CC(N)=O
Solvent: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(C(C)Sc3nnn[nH]3)CS[C@H]12)c1nc(NC=O)sc1Br
Yield: 41.8 %

Procedure:
A solution of 7-amino-3-(1-methyl-1H-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid (660 mg.) and trimethylsilylacetamide (1.3 g.) in dry ethyl acetate (23 ml.) and a mixture of dimethylformamide (0.2 ml.), phosphoryl chloride (0.24 ml.), dry ethyl acetate (10 ml.) and 2-(2-formamido-5-bromothiazol-4-yl)-2-methoxyiminoacetic acid (syn isomer, 740 mg.) were treated in a similar manner to that of Example 1-(1) to give 7-[2-(2-formamido-5-bromothiazol-4-yl)-2-methoxyiminoacetamido]-3-(1-methyl-1H-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid (syn isomer, 520 mg.).
Reaction SMILES: [C:1](=[O:16])([O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)OC1C=CC=CC=1.[NH2:17][C@H:18]([C:26]([O-:28])=[O:27])[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C([N+]1C=CN(C)C=1)C.Cl>CC(=O)CC>[O:9]([C:1]([NH:17][C@H:18]([C:26]([OH:28])=[O:27])[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:16])[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: O=C(Oc1ccccc1)Oc1ccccc1
Reactant: N[C@@H](Cc1ccccc1)C(=O)[O-]
Agent: CC[n+]1ccn(C)c1
Agent: Cl
Solvent: CCC(C)=O
Product: O=C(N[C@@H](Cc1ccccc1)C(=O)O)Oc1ccccc1
Temperature: -20 °C

Procedure:
Under a nitrogen atmosphere, 430 mg (2 mmol) of diphenyl carbonate and 5 mL of 2-butanone were loaded into a round bottom flask having a volume of 100 mL, and then the mixture was stirred at −20° C. A solution prepared by dissolving 550 mg (2 mmol) of 1-ethyl-3-methylimidazolium phenylalanine salt in 15 mL of 2-butanone was slowly dropped to the solution, and then the mixture was stirred at −20° C. for 8 hours. After that, a 1M aqueous HCl solution was added to the mixture to terminate the reaction. The resultant was concentrated with an evaporator. Next, water was added to the concentrated product, and then the resultant was extracted with ethyl acetate. After that, the resultant was concentrated with an evaporator. Thus, a crude product was obtained. Next, the crude product was purified by column chromatography. Thus, N-phenoxycarbonyl-L-phenylalanine was obtained. An isolation amount and an isolation yield were 528.9 mg and 93%, respectively.
Reaction SMILES: [H-].[Na+].C(S)C.[H][H].C[O:9][C:10]1[C:11](OC)=[CH:12][C:13]2[S:19](=O)[CH2:18][CH2:17][CH2:16][CH2:15][C:14]=2[CH:21]=1>CN(C)C=O>[OH:9][C:10]1[CH:11]=[CH:12][C:13]2[S:19][CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[CH:21]=1
Reactant: [H][H]
Reactant: COc1cc2c(cc1OC)S(=O)CCCC2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCS
Product: Oc1ccc2c(c1)C=CC=CS2

Procedure:
Sodium hydride (8.8 g of a 50% w/w dispersion in oil) was added over 30 minutes to a solution of ethanethiol (20.8 g) in dry dimethylformamide at 0°. After evolution of hydrogen had ceased additional ethanethiol (8.8 ml) was added followed by 7,8-dimethoxy-2,3,4,5-tetrahydro-1-benzothiepin-1-oxide. The mixture was heated at reflux for 3 hours, cooled and the solvent was removed in vacuo. The residue was taken up in water (100 ml) and extracted with diethyl ether (2×100 ml). The aqueous solution was acidified with conc. hydrochloric acid, saturated with solid sodium chloride and extracted with chloroform (2×100 ml). The organic extract was dried (Na2SO4) and the solvent was removed in vacuo to give a cream coloured solid. This material was chromatographed on a silica gel column eluting with methylene chloride/methanol mixtures (gradient 0 to 3% v/v methanol) to give the 7-hydroxybenzothiepin (20.7 g), m.p. 165°-166°. Further elution of the column gave, after recrystallisation from methanol, the isomeric 8-hydroxybenzothiepin (2.25 g), m.p. 173°-175°.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([NH:10][C:11]([NH2:13])=[S:12])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.Br[CH2:15][C:16](=O)[C:17]([O:19]CC)=[O:18]>C(O)C>[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([NH:10][C:11]3[S:12][CH:15]=[C:16]([C:17]([OH:19])=[O:18])[N:13]=3)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: NC(=S)Nc1ccc2[nH]ccc2c1
Reactant: CCOC(=O)C(=O)CBr
Solvent: CCO
Product: O=C(O)c1csc(Nc2ccc3[nH]ccc3c2)n1

Procedure:
A solution of 5-aminoindole (8 g, 60.6 mmol) in acetone (150 mL) was reacted with benzoylisothiocyanate (9.88 g, 60. mmol) at RT for about 4 h. The resulting solid was filtered and treated with 2 N NaOH in THF (120 mL). The mixture was refluxed for about 6 h and allowed to warm to RT. The solvent was evaporated off under vacuum. The residue was diluted with water (20 mL) and neutralized to pH 7 with 1N HCl. The resulting solid was filtered and dried under vacuum to afford 5-indolylthiourea (55-2). 5-Indolyl thiourea (0.01 mol) and ethyl bromopyruvate (0.011 mol) were dissolved in 3 mL ethanol and held at reflux for 2 h. The reaction was cooled, the crystalline ethyl 2-(1H-indol-5-ylamino)thiazole-4-carboxylate (55-3) was collected by filtration and washed with ethanol. Refluxing the mixture of ethyl esters with the NaOH-ethanol solution gave 2-(1H-indol-5-ylamino)thiazole-4-carboxylic acid (55-4) which was used directly in next steps. To a mixture of the crude acid (2.5 mmol), EDCI (2.9 mmol), HOBt (2.6 mmol) and NMM (5.3 mmol) in CH2Cl2 (30 mL) was added HNCH3OCH3HCl salt (2.6 mmol) and stirring continued at RT for overnight. The reaction mixture was diluted with CH2Cl2 (20 mL) and sequentially washed with water, satd. NaHCO3, brine and dried over MgSO4. The solvent was removed under reduced pressure to yield a crude product, which was purified by column chromatography to obtain pure compound 2-(1H-indol-5-ylamino)-N-methoxy-N-methylthiazole-4-carboxamide (55-5) (45.6% yield for overall 5 steps). At −78° C., to a solution of 5-bromo-1,2,3-trimethoxybenzene (1.235 g, 5.0 mmol) in 30 mL THF was charged n-BuLi in hexane (2.5 N, 2.4 mL, 6 mmol) under Ar2 protection and stirred for 10 min Weinreb amide (1 mmol) in 10 ml, THF was added to lithium reagent and allowed to stir at RT for 2 h. The reaction mixture was quenched with satd. NH4Cl, extracted with ethyl ether, dried with MgSO4. The solvent was removed under reduced pressure to yield a crude product, which was purified by column chromatography to obtain pure compound 55 (51.7% yield). 1H NMR (300 MHz, CDCl3) δ 8.29 (br, 1H), 7.68 (d, 1H), 7.46 (s, 2H), 7.39 (s, 1H), 7.36 (s, 1H), 7.28˜7.26 (m, 1H), 7.15˜7.12 (m, 1H), 6.55 (m, 1H), 3.93 (s, 3H), 3.89 (s, 6H). MS (ESI) m/z 432.1 (M+Na)+, 408.0 (M−H)−.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[C:5](=[O:13])[C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1)[CH3:2].[H-].[Na+].Br[CH2:18][CH2:19][CH2:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([C:28](=[O:30])[CH3:29])=[C:24]([OH:31])[C:23]=1[CH2:32][CH2:33][CH3:34]>CN(C)C=O>[CH2:1]([O:3][C:4](=[O:14])[C:5](=[O:13])[C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:27]=[CH:26][C:25]([C:28](=[O:30])[CH3:29])=[C:24]([OH:31])[C:23]=2[CH2:32][CH2:33][CH3:34])=[CH:8][CH:7]=1)[CH3:2]
Reactant: CCOC(=O)C(=O)c1ccc(O)cc1
Reactant: CCCc1c(OCCCBr)ccc(C(C)=O)c1O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCc1c(OCCCOc2ccc(C(=O)C(=O)OCC)cc2)ccc(C(C)=O)c1O
Temperature: 50 °C
Reaction time: 0.25 h
Yield: 40.9 %

Procedure:
A mixture of 4-hydroxy-alpha-oxobenzeneacetic acid ethyl ester (0.776 g) in dimethylformamide (10 mL) under argon was treated with 55% sodium hydride (0.175 g), stirred for 15 minutes and then 1-[4-(3-bromopropoxy)-2-hydroxy-3-propylphenyl] ethanone (1.26 g) was added and rinsed in with a little dimethylformamide. The mixture was heated at 50° C. for 6 hours and worked up as in Example 20. The crude material was purified by HPLC (ethyl acetate-hexane; 1:4) to furnish 0.7 g of 4-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)propoxy]-alpha-oxobenzeneacetic acid ethyl ester as an oil.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([O:14][C:15]2[CH:20]=[CH:19][C:18]([S:21]([CH3:24])(=[O:23])=[O:22])=[CH:17][N:16]=2)[CH:5]=[C:6]2[C:10]=1[NH:9][C:8]([C:11]([OH:13])=[O:12])=[CH:7]2.O.[CH3:26]O>C1(C)C=CC=CC=1>[OH:1][C:2]1[CH:3]=[C:4]([O:14][C:15]2[CH:20]=[CH:19][C:18]([S:21]([CH3:24])(=[O:23])=[O:22])=[CH:17][N:16]=2)[CH:5]=[C:6]2[C:10]=1[NH:9][C:8]([C:11]([O:13][CH3:26])=[O:12])=[CH:7]2
Reactant: CS(=O)(=O)c1ccc(Oc2cc(O)c3[nH]c(C(=O)O)cc3c2)nc1
Reactant: CO
Solvent: Cc1ccccc1
Solvent: O
Product: COC(=O)c1cc2cc(Oc3ccc(S(C)(=O)=O)cn3)cc(O)c2[nH]1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 92 %

Procedure:
To a suspension of 7-hydroxy-5-{[5-(methylsulfonyl)pyridin-2-yl]oxy}-1H-indole-2-carboxylic acid (8.71 g) in a mixture of methanol (300 mL) and toluene (300 mL) was added dropwise 2M trimethylsilyldiazomethane diethyl ether solution (12.5 mL) at 0° C., and the mixture was stirred at 0° C. for 1.5 h. Furthermore 2M trimethylsilyldiazomethane diethyl ether solution (10 mL) was added to the mixture and the mixture was stirred at 0° C. for 1 h, which was repeated three times. And then 2M trimethylsilyldiazomethane diethyl ether solution (5 mL) was added and the mixture was stirred at 0° C. for 30 min, which was repeated two times. To quench the reaction, 1M hydrochloric acid (80 mL) was added to the mixture. Water was added to the mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, filtered and concentrated. The residual solid was washed with diethyl ether to give the title compound (8.25 g, 92%) as a purple solid. MS 363 (MH+).
Reaction SMILES: [CH2:1]([N:3]([CH2:17][CH3:18])[CH2:4][CH2:5][N:6]1[CH:14]([OH:15])[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]1[OH:16])[CH3:2].[CH3:19][O:20][S:21]([C:24]1[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=1)(=[O:23])=[O:22]>C1(C)C=CC=CC=1>[C:27]1([CH3:30])[CH:26]=[CH:25][C:24]([S:21]([O-:23])(=[O:20])=[O:22])=[CH:29][CH:28]=1.[O:16]=[C:7]1[C:8]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:14](=[O:15])[N:6]1[CH2:5][CH2:4][N+:3]([CH2:1][CH3:2])([CH2:17][CH3:18])[CH3:19]
Reactant: CCN(CC)CCN1C(O)c2ccccc2C1O
Reactant: COS(=O)(=O)c1ccc(C)cc1
Solvent: Cc1ccccc1
Product: CC[N+](C)(CC)CCN1C(=O)c2ccccc2C1=O
Product: Cc1ccc(S(=O)(=O)[O-])cc1

Procedure:
20.0 g (81.3 mmol) of 2-[2-(diethylamino)ethyl]-1H-isoindole-1,3(2H)-diol from stage 1 and 16.6 g (89.5 mmol) of p-toluenesulfonic acid methyl ester were refluxed in 250 ml toluene for 8 hours. After cooling, the white, crystalline solid was filtered out and rewashed with toluene. The product was then dried under a vacuum at 30° C. Yield: 10.3 g (29.3%); 1H-NMR (400 MHz, DMSO-d6): δ [ppm]=1.39 (t, 6H); 2.28 (s, 3H); 3.06 (s, 3H); 3.47 (m, 6H); 3.97 (q, 2H); 7.10 (d, 2H); 7.48 (d, 2H); 7.89 (m, 4H); 13C-NMR (400 MHz, DMSO-d6): δ [ppm]=8.1; 20.7; 30.5; 46.1; 55.5; 56.0; 123.2; 125.4; 128.0; 131.2; 134.5; 137.6; 145.6; 167.3.
Reaction SMILES: [SH2:1].[Na].Cl[CH:4]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH2:5][CH2:6][CH:7]=[O:8].C(OCC)(=O)C.O>CN(C)C=O>[C:9]1([CH:4]2[S:1][CH:7]([OH:8])[CH2:6][CH2:5]2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: S
Reactant: O=CCCC(Cl)c1ccccc1
Agent: [Na]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: OC1CCC(c2ccccc2)S1
Yield: 61.5 %

Procedure:
32 mg of anhydrous sodium hydrogen sulfide was added to a solution of 61 mg of 4-chloro-4-phenylbutanal in 1 mL of N,N-dimethylformamide at a temperature of 0° C. to 10° ° C. and the obtained mixture was then stirred at the same temperature as described above for 1 hour. Thereafter, ethyl acetate and water were added to the reaction mixture, and the water layer was then removed. The organic layer was washed with water, and was then dried over anhydrous sodium sulfate. After that, the solvent was distilled away under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=85/15 to 60/40), so as to obtain 37 mg of 5-phenylthiolan-2-ol in the form of a colorless oily product.
Reaction SMILES: C[N:2](C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]([F:24])([F:23])[F:22])[CH:15]=2)[N:8]=1)=O.[F:26][C:27]1([F:38])[O:31][C:30]2[CH:32]=[CH:33][C:34]([NH:36]N)=[CH:35][C:29]=2[O:28]1.N([O-])=O.[Na+].[Sn](Cl)Cl>>[F:38][C:27]1([F:26])[O:31][C:30]2[CH:32]=[CH:33][C:34]([N:36]3[C:5]([C:7]4[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]5[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]([F:24])([F:23])[F:22])[CH:15]=5)[N:8]=4)=[CH:4][CH:3]=[N:2]3)=[CH:35][C:29]=2[O:28]1
Reactant: CN(C)/C=C/C(=O)c1nn(-c2cccc(OC(F)(F)F)c2)ccc1=O
Reactant: NNc1ccc2c(c1)OC(F)(F)O2
Agent: Cl[Sn]Cl
Agent: O=N[O-]
Agent: [Na+]
Product: O=c1ccn(-c2cccc(OC(F)(F)F)c2)nc1-c1ccnn1-c1ccc2c(c1)OC(F)(F)O2

Procedure:
The product was obtained starting from 3-((E)-3-Dimethylamino-acryloyl)-1-(3-trifluoromethoxy-phenyl)-1H-pyridazin-4-one (A-6) and 2,2-difluoro-benzo[1,3]dioxol-5-yl-hydrazine (prepared from the corresponding amino derivative using sodium nitrite and tin(II) chloride as described in J. Med. Chem. 2003, 46, 4676-4686) according to the method described for example 91. MS: M=479.1 (M+H)+
Reaction SMILES: [CH2:1]([O:3][C@@H:4]([C@H:9](O)[C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][NH:23][CH3:24])[CH:17]=2)=[CH:12][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6])[CH3:2].C(N(CC)CC)C>FC(F)(F)C(O)=O>[CH2:1]([O:3][C@@H:4]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][NH:23][CH3:24])[CH:17]=2)=[CH:12][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6])[CH3:2]
Reactant: CCO[C@H](C(=O)OC)[C@H](O)c1ccc(-c2cccc(CNC)c2)cc1
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Product: CCO[C@@H](Cc1ccc(-c2cccc(CNC)c2)cc1)C(=O)OC
Temperature: 25 °C
Reaction time: 48 h
Yield: 10 %

Procedure:
19.6 g of the crude product methyl (2S,3R)-2-ethoxy-3-hydroxy-3-(3′-methylaminomethylbiphenyl-4-yl)propionate are dissolved in 200 ml of trifluoroacetic acid and 41.7 ml (297 mmol) of triethylamine are added. The reaction medium is stirred at room temperature for 48 hours and then extracted with ethyl acetate. The organic phase is decanted off, washed with a sodium hydroxide solution and then with a saturated aqueous sodium chloride solution, dried over magnesium sulphate, filtered and evaporated off. The residue obtained is purified by chromatography on a silica column eluted with a dichloromethane and methanol (95/5) mixture. 1.6 g (10%) of the expected product are obtained.
Reaction SMILES: [CH2:1]([N:5]=[C:6]=[O:7])[CH2:2][CH2:3][CH3:4].[NH2:8][C:9]1[C:18]2[N:19]=[C:20]([CH2:27][CH2:28][CH2:29][CH3:30])[N:21]([CH2:22][CH2:23][CH2:24][CH2:25][NH2:26])[C:17]=2[C:16]2[N:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:10]=1>>[NH2:8][C:9]1[C:18]2[N:19]=[C:20]([CH2:27][CH2:28][CH2:29][CH3:30])[N:21]([CH2:22][CH2:23][CH2:24][CH2:25][NH:26][C:6]([NH:5][CH2:1][CH2:2][CH2:3][CH3:4])=[O:7])[C:17]=2[C:16]2[N:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:10]=1
Reactant: CCCCc1nc2c(N)nc3cccnc3c2n1CCCCN
Reactant: CCCCN=C=O
Product: CCCCNC(=O)NCCCCn1c(CCCC)nc2c(N)nc3cccnc3c21
Yield: 65.8 %

Procedure:
Using the general method of Example 47, butyl isocyanate (54 μL, 0.48 mmol) was reacted with 4-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)butaneamine (0.15 g, 0.48 mmole) to provide 0.13 g of N-[4-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)butyl]-N′-butylurea as a white solid. Analysis: Calculated for C22H33N7O: %C, 64.21; %H, 8.08; %N, 23.82. Found: %C, 64.05; %H, 7.97; %N, 24.00.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:19]([OH:21])=O)[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]1)=[O:5])[CH3:2].ON1C2C=CC=CC=2N=N1.[CH3:32][NH:33][CH3:34].CCN=C=NCCCN(C)C.Cl>O.C1COCC1>[CH2:1]([O:3][C:4]([C:6]1([C:19](=[O:21])[N:33]([CH3:34])[CH3:32])[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CNC
Reactant: CCOC(=O)C1(C(=O)O)CCN(C(=O)OC(C)(C)C)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)C1(C(=O)N(C)C)CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 0.5 h

Procedure:
THF (5 ml) charged in to a R B flask followed by the addition of piperidine-1,4,4-tricarboxylic acid 1-tert-butyl ester 4-ethyl ester (0.5 g) and 1-hydroxybenzotriazole (0.38 g). Allowed to stir the reaction mixture at 25-300 C for 30 mins. Dimethylamine (0.75 mL) followed by EDC HCl (0.38 g) was added in to the above reaction mixture at 25-300 C. Allowed the reaction mixture to stir at 25-300 C for 1-2 hrs. Reaction is followed by TLC. The reaction mixture concentrated under vacuum using rota vapour and the product slurry obtained is suspended in D M Water (5 mL). The product extracted in to ethyl acetate (2×5 mL). The combined product layer dried with sodium sulphate and concentrated under vacuum to yield crude product which in turn purified by a column chromatography to yield pure 4-dimethylcarbamoyl-piperidine-1,4-dicarboxylic acid 1-tert-butyl ester 4-ethyl ester.
Reaction SMILES: [OH:1][CH2:2][CH:3]([OH:9])[CH2:4][CH2:5][CH2:6][CH2:7][OH:8].CO[CH:12](OC)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CN(C=O)C.C(OCC)(=O)C>[C:13]1([CH:12]2[O:9][CH:3]([CH2:4][CH2:5][CH2:6][CH2:7][OH:8])[CH2:2][O:1]2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: OCCCCC(O)CO
Reactant: COC(OC)c1ccccc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: OCCCCC1COC(c2ccccc2)O1
Temperature: 100 °C
Reaction time: 0.08 h
Yield: 66.3 %

Procedure:
To a solution of 1,2,6-trihydroxyhexane (10.0 g, 74.6 mmol) and benzaldehyde dimethylacetal (15.0 g, 98.7 mmol) in dry DMF (10 mL) was added Amberlyst 15 (5.0 g). The mixture was stirred at 100° C. for 5 min, then cooled and filtered. The filtrate was concentrated and residue obtained was re-dissolved in ethyl acetate. After being washed with water and brine, the solution was dried over Na2SO4. The crude product obtained after evaporation of the solvent was chromatographed on silica eluting with ethyl acetate. Concentration of the proper fractions afforded 11.0 g (66%) of the title product (a mixture of diastereomers) as a colorless oil: 1H NMR (CDCl3, 300 MHz, ppm) 7.48 (m, 2H), 7.39 (m, 3H), 5.92 (s, 0.4H), 5.80 (s, 0.6H), 4.3-4.1 (m, 2H), 3.64 (m, 3H), 1.8-1.4 (m, 6H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([CH:12]=NN=P(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[O:11])=[CH:5][CH:4]=1.N([O-])=[O:35].[Na+].Cl>O1CCCC1.O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][C:10]([CH:12]=[O:35])=[O:11])=[CH:7][CH:8]=1
Reactant: COc1ccc(CC(=O)C=NN=P(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(CC(=O)C=O)cc1
Reaction time: 0.5 h

Procedure:
A solution of 1.82 g of 1-(4-methoxyphenyl)-3-(triphenylphosphoranylidene-hydrazono)-acetone in 12 ml of tetrahydrofuran is mixed with 0.84 g of pulverized sodium nitrite and the mixture is diluted with 5 ml of water. The resulting suspension is cooled to 0°-5°, treated dropwise over the course of 7 minutes with 8.8 ml of 2N hydrochloric acid and then kept for a further 30 minutes at 0°-5°. The aqueous phase is twice washed with methylene chloride; the combined organic solutions are washed with a saturated aqueous sodium chloride solution, dried over sodium sulphate and evaporated under reduced pressure. The oily residue is chromatographed on 40 g of acid-washed silica gel. A small quantity of a by-product is eluted with benzene and, using 1200 ml of a 95:5-mixture of benzene and ethyl acetate, the 4-methoxybenzylglyoxal is obtained in the form of the hydrate, which is an oily product; infra-red absorption spectrum (in methylene chloride): characteristic bands at 2.96μ, 5.79-5.84μ, 6.23μ and 6.63μ. The anhydrous product melts at 139°-140° after recrystallisation from a mixture of chloroform and hexane; ultra-violet absorption spectrum:λmax 333 mμ (in ethanol or hydrochloric acid/ethanol) and λmax 367 mμ (in potassium hydroxide/ethanol); ethanol); infra-red absorption spectrum (in methylene chloride): characteristic bands at 3.00μ, 5.97μ, 6.09μ, 6.24μ, 6.61μ and 7.15μ.
Reaction SMILES: [CH3:1][C:2]([CH3:26])([CH3:25])[CH2:3][N:4]1[C:12]2[C:7](=[N:8][C:9]([C:13]3[CH:20]=[C:19]([CH:21]=[O:22])[CH:18]=[CH:17][C:14]=3[C:15]#[N:16])=[CH:10][CH:11]=2)[N:6]([CH3:23])[C:5]1=[O:24].[CH3:27][Mg]Br>C1COCC1.CO>[CH3:1][C:2]([CH3:26])([CH3:25])[CH2:3][N:4]1[C:12]2[C:7](=[N:8][C:9]([C:13]3[CH:20]=[C:19]([C@@H:21]([OH:22])[CH3:27])[CH:18]=[CH:17][C:14]=3[C:15]#[N:16])=[CH:10][CH:11]=2)[N:6]([CH3:23])[C:5]1=[O:24]
Reactant: C[Mg]Br
Reactant: Cn1c(=O)n(CC(C)(C)C)c2ccc(-c3cc(C=O)ccc3C#N)nc21
Solvent: CO
Solvent: C1CCOC1
Product: C[C@H](O)c1ccc(C#N)c(-c2ccc3c(n2)n(C)c(=O)n3CC(C)(C)C)c1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a round bottom flask, 2-[1-(2,2-dimethylpropyl)-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-5-yl]-4-formylbenzonitrile (30-1) (70 mg, 0.2 mmol) was added under nitrogen, dissolved in THF (1 mL), and cooled to −78° C. 3M methylmagnesium bromide (0.08 ml, 0.24 mmol) was added slowly to the cooled solution and allowed to stir for 30 minutes. The reaction was warmed to room temperature for 30 minutes until complete conversion over starting material. The mixture was diluted with methanol, and passed through a syringe filter. The solution was purified using reverse phase chromatography (10-100%, 0.1% TFA in H2O/Acetonitrile) and the desired fractions were collected and concentrated to produce 2-[1-(2,2-dimethylpropyl)-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-5-yl]-4-[(1S)-1-hydroxyethyl]benzonitrile (30-2). HRMS (M+H)+: observed=365.1976, calculated=365.1972.