Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:17]([OH:19])=O)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CN1CCOCC1.C(OC(Cl)=O)C(C)C.[NH2:35][C:36]12[CH2:45][CH:40]3[CH2:41][CH:42]([CH2:44][C:38]([CH2:46][OH:47])([CH2:39]3)[CH2:37]1)[CH2:43]2>CN(C)C=O>[C:1]([NH:8][C@H:9]([C:17]([CH:37]1[C:36]2([NH2:35])[CH2:45][CH:40]3[CH2:41][CH:42]([CH2:44][C:38]1([CH2:46][OH:47])[CH2:39]3)[CH2:43]2)=[O:19])[CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Reactant: NC12CC3CC(C1)CC(CO)(C3)C2
Agent: CC(C)COC(=O)Cl
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)C1C2(N)CC3CC(C2)CC1(CO)C3
Temperature: -40 °C
Reaction time: 8 h

Procedure:
To a solution of 1.83 g of Boc-L-phenylalanine in 15 ml of dimethylformamide is added 0.76 of N-methylmorpholine. The reaction mixture is cooled to -40° C. and 0.90 ml of isobutylchloroformate is added with stirring. The reaction mixture is stirred for 15 minutes at a temperature below -10° C. then 1.04 g of 3-amino-1-adamantanemethanol is added. The reaction mixture is stirred for 15 minutes at -20° C. then stored overnight at 5° C. The dimethylformamide is removed under reduced pressure and the residue is dissolved in methylene chloride and water. The methylene chloride phase is separated and washed twice with 35 ml of water, 3 times with 35 ml of a 0.5 M potassium bisulfate solution, and twice with 35 ml of water and then dried over magnesium sulfate. The solvent is removed under reduced pressure, and the residue is purified by chromatography on Whatman 10 micron silica gel eluting with a gradient of 1:1 hexane-chloroform to chloroform to give Boc-L-phenylalanyl-3-amino-adamantanemethanol. 2.0 Grams of this product is dissolved in 5 ml of a 6 N solution of hydrogen chloride in dioxane. The reaction mixture is allowed to stand for 20 minutes at room temperature then the solvent is removed under reduced pressure at 30° C., and the residue is stirred with diethyl ether to give the product as a solid. The solid product is collected by filtration and dried under reduced pressure to give L-phenylalanyl-3-amino-1-adamantanemethanol hydrochloride which is represented by the following structure ##STR70## When an equivalent quantity of L-phenylalanyl-3-amino-1-adamantanemethanol hydrochloride is substituted for the methyl L-phenylalanyl-3-amino-1-adamantanecarboxylate hydrochloride of Example 4 and the procedures detailed in Examples 4 through 9 substantially repeated there is obtained L-tyrosyl-D-methionyl-glycyl-L-phenylalanyl-3-amino-1-adamantanemethanol hydrochloride which is represented by the following formula ##STR71##
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH3:12])=[N:7]2.[CH3:13][C:14]1[CH:15]=[CH:16][C:17]([S:21][C:22]2[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=2)=[C:18]([NH2:20])[CH:19]=1>>[CH3:12][C:6]1[N:7]=[C:8]2[C:3]([C:2]([NH:20][C:18]3[CH:19]=[C:14]([CH3:13])[CH:15]=[CH:16][C:17]=3[S:21][C:22]3[CH:23]=[CH:24][C:25]([CH3:28])=[CH:26][CH:27]=3)=[CH:11][CH:10]=[N:9]2)=[CH:4][CH:5]=1
Reactant: Cc1ccc2c(Cl)ccnc2n1
Reactant: Cc1ccc(Sc2ccc(C)cc2N)cc1
Product: Cc1ccc(Sc2ccc(C)cc2Nc2ccnc3nc(C)ccc23)cc1

Procedure:
The product from Example 1d (267 mg, 1.56 mmol) was reacted with the product from Example 47b (358 mg, 1.56 mmol) for 48 h following the procedure from Example 1g giving the crude title compound which was purified by HPLC with TFA providing the trifluoroacetic acid salt (347 mg, 46%). 1H NMR (300 MHz, DMSO-d6) δ ppm: 2.22 (s, 3H) 2.37 (s, 3H) 2.77 (s, 3H) 6.27 (d, J=7.35 Hz, 1H) 7.04 (d, J=7.72 Hz, 2H) 7.14 (m, 2H) 7.29 (m, 3H) 7.79 (d, J=8.82 Hz, 1H) 8.39 (d, J=6.99 Hz, 1H) 8.95 (d, J=8.46 Hz, 1H) 11.25 (br. s., 1H) 14.39 (br. s., 1H); MS (ESI+) m/z 372 (M+H)+.
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:13]=[CH:12][N:11]=[C:10]([O:14][CH2:15]/[CH:16]=[CH:17]\[CH2:18][NH:19][C:20](=[O:25])[CH2:21][CH2:22][CH2:23]Cl)[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[SH:26][CH2:27][CH2:28][OH:29]>>[N:1]1([CH2:7][C:8]2[CH:13]=[CH:12][N:11]=[C:10]([O:14][CH2:15]/[CH:16]=[CH:17]\[CH2:18][NH:19][C:20](=[O:25])[CH2:21][CH2:22][CH2:23][S:26][CH2:27][CH2:28][OH:29])[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: OCCS
Reactant: O=C(CCCCl)NC/C=C\COc1cc(CN2CCCCC2)ccn1
Product: O=C(CCCSCCO)NC/C=C\COc1cc(CN2CCCCC2)ccn1
Yield: 66 %

Procedure:
Following a procedure similar to that described in Example 1, but using N-[4-(4-piperidinomethyl-2-pyridyloxy) -cis-2-butenyl]-4-chlorobutyramide (prepared as described in Preparation 2) and 2-mercaptoethanol as starting materials, in relative proportions similar to those used in that Example, and carrying out the reaction at 80° C. for 5 hours, the title compound was obtained in a 66% yield.
Reaction SMILES: [N:1]1([C:7]2[N:12]=[C:11]3[N:13]=[C:14]([CH2:16][C:17]([O:19]CC)=O)[NH:15][C:10]3=[CH:9][CH:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[NH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[C:29]#[N:30]>>[NH2:30][C:29]1[C:24]2[C:23](=[CH:28][CH:27]=[CH:26][CH:25]=2)[NH:22][C:17](=[O:19])[C:16]=1[C:14]1[NH:13][C:11]2=[N:12][C:7]([N:1]3[CH2:2][CH2:3][O:4][CH2:5][CH2:6]3)=[CH:8][CH:9]=[C:10]2[N:15]=1
Reactant: N#Cc1ccccc1N
Reactant: CCOC(=O)Cc1nc2nc(N3CCOCC3)ccc2[nH]1
Product: Nc1c(-c2nc3ccc(N4CCOCC4)nc3[nH]2)c(=O)[nH]c2ccccc12

Procedure:
The title compound was synthesized as described in Example 45, Method E using ethyl 2-(5-morpholin-4-ylimidazolo[5,4-b]pyridin-2-yl)acetate and 2-aminobenzenecarbonitrile, with a modified workup procedure. After quenching with a saturated aqueous ammonium chloride solution, the two phases were separated and the aqueous phase extracted with EtOAc. Upon standing, a solid formed and precipitated out of the organic extracts. The precipitate, a dark brown solid, was filtered off and dried. Purification by reverse phase chromatography afforded the desired product as a reddish solid. LC/MS m/z 363.2 (MH+), Rt 2.20 minutes.
Reaction SMILES: [BrH:1].[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2(O)[CH2:13][S:12][C:11](=[N:14][C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([CH3:21])[C:16]=3[CH3:22])[N:10]2[CH3:23])=[CH:5][C:4]=1[S:25](=[O:30])(=[O:29])[N:26]([CH3:28])[CH3:27]>C(O)(=O)C>[BrH:1].[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]([CH3:23])[C:11](=[N:14][C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([CH3:21])[C:16]=3[CH3:22])[S:12][CH:13]=2)=[CH:5][C:4]=1[S:25](=[O:30])(=[O:29])[N:26]([CH3:28])[CH3:27]
Reactant: Cc1cccc(N=C2SCC(O)(c3ccc(Cl)c(S(=O)(=O)N(C)C)c3)N2C)c1C
Agent: Br
Solvent: CC(=O)O
Product: Cc1cccc(N=c2scc(-c3ccc(Cl)c(S(=O)(=O)N(C)C)c3)n2C)c1C

Procedure:
Obtained by a procedure analogous to that indicated in Example 1 (b), from 4-(4-chloro-3-dimethylsulfamoylphenyl)-3-methyl-2-(2,3-dimethylphenyl-imino)thiazolidin-4-ol hydrobromide, by boiling in glacial acetic acid for 2 hours and filtering off the crystals at room temperature. Colorless crystals from glacial acetic acid; melting point 256° C. (with decomposition).
Reaction SMILES: [N:1]1([CH2:7][CH2:8][NH2:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:10]([O:12][C:13]([C:15]1[C:16](=[O:35])[C:17]2[CH:22]=[N:21][C:20](S(C)(=O)=O)=[N:19][C:18]=2[N:27]([CH:29]2[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]2)[CH:28]=1)=[O:14])[CH3:11]>>[CH2:10]([O:12][C:13]([C:15]1[C:16](=[O:35])[C:17]2[CH:22]=[N:21][C:20]([NH:9][CH2:8][CH2:7][N:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)=[N:19][C:18]=2[N:27]([CH:29]2[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]2)[CH:28]=1)=[O:14])[CH3:11]
Reactant: NCCN1CCCCC1
Reactant: CCOC(=O)c1cn(C2CCCCC2)c2nc(S(C)(=O)=O)ncc2c1=O
Product: CCOC(=O)c1cn(C2CCCCC2)c2nc(NCCN3CCCCC3)ncc2c1=O

Procedure:
Using the procedure outlined in Example 28 Step F, the title compound was prepared from 2-piperidin-1-yl-ethylamine and 8-cyclohexyl-2-methanesulfonyl-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester (25 mg, 0.06 mmol). 8-Cyclohexyl-5-oxo-2-(2-piperidin-1-yl-ethylamino)-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester was obtained as a white solid (20 mg, 80%). Mass Spectrum (LCMS, ESI pos.) Calcd. For C23H33N5O3: 428.26 (M+H). Found: 428.3.
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH2:9][C:10](Cl)=[O:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Al+3].[Cl-].[Cl-].[Cl-].[CH2:17]([O:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH3:28])=[CH:22][C:21]=1[CH3:29])[CH3:18].C(Cl)Cl>C(Cl)(Cl)(Cl)Cl>[CH:1]1([CH2:7][CH2:8][CH2:9][C:10]([C:24]2[CH:25]=[C:20]([O:19][CH2:17][CH3:18])[C:21]([CH3:29])=[CH:22][C:23]=2[O:26][CH2:27][CH3:28])=[O:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOc1ccc(OCC)c(C)c1
Reactant: O=C(Cl)CCCC1CCCCC1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: ClC(Cl)(Cl)Cl
Product: CCOc1cc(C(=O)CCCC2CCCCC2)c(OCC)cc1C
Reaction time: 4 h
Yield: 75.6 %

Procedure:
4 g of 4-cyclohexylbutyryl chloride dissolved in 10 ml of CCl4 are added to a suspension of 2.9 g of AlCl3 in 40 ml of CCl4 at +4° C. 4.2 g of 2,5-diethoxytoluene in 20 ml of CCl4 are added dropwise. After 4 hours at +4° C., the reaction medium is poured into dilute ice-cold HCl solution. DCM is added, the phases are separated out by settling and the organic phase is then dried over MgSO4. After evaporation of the solvent, the product is purified by chromatography on silica H, eluting with toluene. 5.33 g of the expected compound are obtained: m.p.=49-50° C.
Reaction SMILES: [C:1]1(/[C:7](/[C:17]2[CH:22]=[CH:21][C:20]([CH:23]=[CH:24][C:25](O)=[O:26])=[CH:19][CH:18]=2)=[C:8](/[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)\[CH2:9][CH3:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:28][C:29]([F:42])([F:41])[C:30]1[CH:35]=[CH:34][C:33]([CH2:36][S:37]([NH2:40])(=[O:39])=[O:38])=[CH:32][CH:31]=1>>[C:1]1([C:7]([C:17]2[CH:22]=[CH:21][C:20]([CH:23]=[CH:24][C:25]([NH:40][S:37]([CH2:36][C:33]3[CH:32]=[CH:31][C:30]([C:29]([F:28])([F:41])[F:42])=[CH:35][CH:34]=3)(=[O:39])=[O:38])=[O:26])=[CH:19][CH:18]=2)=[C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:9][CH3:10])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC/C(=C(\c1ccccc1)c1ccc(C=CC(=O)O)cc1)c1ccccc1
Reactant: NS(=O)(=O)Cc1ccc(C(F)(F)F)cc1
Product: CCC(=C(c1ccccc1)c1ccc(C=CC(=O)NS(=O)(=O)Cc2ccc(C(F)(F)F)cc2)cc1)c1ccccc1

Procedure:
Prepared by coupling 1a and [(4-trifluoromethylphenyl)-methyl]sulfonamide (Synlett, 1997, 375) in accordance with Procedure 1, Method B described hereinabove. Yield (11%); 1H NMR (d6-DMSO) δ 11.69 (br s, 1H), 7.74 (d, J=8.0 Hz, 2H), 7.57–7.09 (m, 15H), 6.87 (d, J=8.1 Hz, 2H), 6.41 (d, J=15.7 Hz, 1H), 4.86 (s, 2H), 2.37 (q, J=7.3 Hz, 2H), 0.83 (t, J=7.3 Hz, 3H); APcI m/z: 576 (M+H+).
Reaction SMILES: [OH:1][CH:2]1[CH2:5][N:4]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH2:3]1.[N:13]1[CH:18]=[CH:17][C:16](O)=[CH:15][CH:14]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C.C1(C)C=CC=CC=1>C1COCC1>[N:13]1[CH:18]=[CH:17][C:16]([O:1][CH:2]2[CH2:3][N:4]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH2:5]2)=[CH:15][CH:14]=1
Reactant: CC(C)(C)OC(=O)N1CC(O)C1
Reactant: Oc1ccncc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CC(Oc2ccncc2)C1
Temperature: 55 °C
Reaction time: 8 h
Yield: 88.7 %

Procedure:
tert-Butyl 3-hydroxyazetidine-1-carboxylate (4.0 g) and pyridin-4-ol (1.8 g) were mixed with THF (50 ml), and triphenylphosphine (6.23 g) was added thereto. A 1.9 M DIAD/toluene solution (12.5 ml) was added dropwise, followed by stirring at 55° C. overnight. Triphenylphosphine (5 g) and a 1.9 M DIAD/toluene solution (10 ml) were added to the reaction mixture, followed by stirring at 55° C. overnight. The reaction mixture was concentrated under reduced pressure, and a liquid separation operation was carried out by the addition of EtOAc and 0.5 M hydrochloric acid. The aqueous layer was adjusted to a pH of around 10 by the addition of a 4 M aqueous NaOH solution, and extracted with CHCl3. The organic layer was dried over Na2SO4 and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (CHCl3/MeOH) to obtain tert-butyl 3-(pyridin-4-yloxy)azetidine-1-carboxylate (4.2 g).
Reaction SMILES: Cl.[CH2:2]([O:9][NH2:10])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(N(CC)CC)C.[CH3:18][N:19]([CH3:23])[C:20](Cl)=[O:21]>C1COCC1.CN(C1C=CN=CC=1)C>[CH3:18][N:19]([CH3:23])[C:20]([NH:10][O:9][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)=[O:21]
Reactant: CN(C)C(=O)Cl
Reactant: NOCc1ccccc1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CN(C)C(=O)NOCc1ccccc1
Yield: 42 %

Procedure:
To a stirred slurry of benzyloxyamine hydrochloride (3.19 g, 20 mmol) in the THF (40 ml) at room temperature under nitrogen was added triethylamine (6.13 ml). This slurry was stirred, and dimethylcarbamyl chloride (1.84 ml) was added rapidly. 4-(N,N-dimethylamino)pyridine (1.0 g, 0.4 equiv.) was added, and the mixture was stirred for 20 hours. The mixture was filtered, and the filtrate evaporated. Purification by chromatography on silica provided N,N-dimethyl-N'benzyloxyurea as a colorless oil (1.62 g, 42% yield).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[CH:13][C:14]([O:18][CH3:19])=[CH:15][CH:16]=3)[O:11][C:10](=[O:20])[CH:9]=2)[CH:5]=[CH:6][CH:7]=1.C[O-].[Na+].[CH2:24](Br)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>CO>[CH2:24]([O:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[CH:13][C:14]([O:18][CH3:19])=[CH:15][CH:16]=3)[O:11][C:10](=[O:20])[CH:9]=2)[CH:5]=[CH:6][CH:7]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: COc1ccc2c(-c3cccc(O)c3)cc(=O)oc2c1
Reactant: BrCc1ccccc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1ccc2c(-c3cccc(OCc4ccccc4)c3)cc(=O)oc2c1
Temperature: 45 °C
Reaction time: 3 h
Yield: 89 %

Procedure:
4-[3'-(hydroxy)phenyl]-7-methoxycoumarin (prepared as in Example 1 (ii) (268 g) and 95% sodium methoxide (102 g) were dissolved in methanol (3.00 L) and stirred while heating to 45° C. Benzyl bromide (314 g) was added and the reaction was heated to 60° C. A thick precipitate formed in the pink reaction mixture. After 3 hours, the slurry was cooled in an ice-water bath and filtered to collect the product, which was washed with methanol (500 mL) and water (1.0 L), then dried under vacuum (20 inches of Hg) at 70° C. to give 4-[3-(benzyloxy)phenyl]-7-methoxycoumarin (320 g, 89%).
Reaction SMILES: Cl.[NH:2]1[N:6]2[CH2:7][C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=3[CH:5]2[CH2:4][CH2:3]1.[N:14]#[C:15][NH2:16]>CCCCCO>[N:2]1([C:15](=[NH:14])[NH2:16])[N:6]2[CH2:7][C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=3[CH:5]2[CH2:4][CH2:3]1
Reactant: c1ccc2c(c1)CN1NCCC21
Reactant: N#CN
Agent: Cl
Solvent: CCCCCO
Product: N=C(N)N1CCC2c3ccccc3CN21
Reaction time: 2 h

Procedure:
3.92 g (0.02 mol) of 2,3,3a,8-tetrahydro-1H-pyrazolo[5,1-a]isoindole hydrochloride and 0.95 g of cyanamide in 20 ml of n-amyl alcohol are heated to boiling for 2 hours. After distilling out the solvent, the residue is taken up in boiling ethanol, active charcoal is added, and, after filtration, the filtrate is evaporated in vacuo. After recrystallisation from isopropanol/ethyl acetate, 2.4 g of the hydrochloride of 2,3,3a,8-tetrahydro-1H-pyrazolo[5,1-a]isoindole-1-carboximidamide are obtained. Melting point 233°-234° C.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([CH3:23])[C:13](=[O:22])[N:14]([C:15]4[C:16]([CH3:21])=[N:17][N:18]([CH3:20])[CH:19]=4)[C:5]=3[C:4]=2[CH:3]=1.[C:24]([C:26]1[CH:31]=[CH:30][C:29](B2OC(C)(C)C(C)(C)O2)=[CH:28][N:27]=1)#[N:25]>>[CH3:20][N:18]1[CH:19]=[C:15]([N:14]2[C:5]3[C:4]4[CH:3]=[C:2]([C:29]5[CH:30]=[CH:31][C:26]([C:24]#[N:25])=[N:27][CH:28]=5)[CH:11]=[CH:10][C:9]=4[N:8]=[CH:7][C:6]=3[N:12]([CH3:23])[C:13]2=[O:22])[C:16]([CH3:21])=[N:17]1
Reactant: CC1(C)OB(c2ccc(C#N)nc2)OC1(C)C
Reactant: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(Br)cc3c21
Product: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(-c4ccc(C#N)nc4)cc3c21

Procedure:
The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate A) and 2-cyanopyridine-5-boronic acid pinacol ester (Frontier Scientific, Logan, USA) to give the title compound as a brown solid. (HPLC: tR 2.42 min (Method A); M+H=396 MS-ES)
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C@H:5]1[CH2:10][CH2:9][C@H:8]([CH2:11][C:12]([NH:14][C@H:15]2[CH2:20][C:19]3[CH:21]=[CH:22][CH:23]=[C:24]([C:25]([OH:27])=[O:26])[C:18]=3[O:17][B:16]2[OH:28])=[O:13])[CH2:7][CH2:6]1.C(O)(=O)C.O=[CH:34][C@@H:35]([NH:37][C:38](=[O:44])[O:39][C:40]([CH3:43])([CH3:42])[CH3:41])[CH3:36].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO>[C:40]([O:39][C:38]([NH:37][C@@H:35]([CH3:36])[CH2:34][NH:1][CH2:2][CH2:3][NH:4][C@H:5]1[CH2:10][CH2:9][C@H:8]([CH2:11][C:12]([NH:14][C@H:15]2[CH2:20][C:19]3[CH:21]=[CH:22][CH:23]=[C:24]([C:25]([OH:27])=[O:26])[C:18]=3[O:17][B:16]2[OH:28])=[O:13])[CH2:7][CH2:6]1)=[O:44])([CH3:43])([CH3:42])[CH3:41]
Reactant: C[C@@H](C=O)NC(=O)OC(C)(C)C
Reactant: NCCN[C@H]1CC[C@H](CC(=O)N[C@H]2Cc3cccc(C(=O)O)c3OB2O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: C[C@@H](CNCCN[C@H]1CC[C@H](CC(=O)N[C@H]2Cc3cccc(C(=O)O)c3OB2O)CC1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To (R)-3-(2-(trans-4-(2-aminoethylamino)cyclohexyl)acetamido)-2-hydroxy-3,4-dihydro-2H-benzo[e][1,2]oxaborinine-8-carboxylic acid from Example 15 (92 mg) in MeOH (2 mL) was added TEA (70 μL), acetic acid (30 μL), (S)-tert-butyl 1-oxopropan-2-ylcarbamate (86 mg) and sodium triacetoxyborohydride (212 mg). The reaction mixture was stirred overnight at RT. Solvent was removed and the product was carried on to next step without further purification.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][OH:8].[CH:9]#[C:10][CH2:11][CH2:12][C:13]#[C:14][CH2:15][CH2:16][CH2:17][CH3:18].[Li].N>>[CH2:7]([OH:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][C:9]#[C:10][CH2:11][CH2:12][C:13]#[C:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: OCCCCCCBr
Reactant: C#CCCC#CCCCC
Agent: N
Agent: [Li]
Product: CCCCC#CCCC#CCCCCCCO

Procedure:
The use of a protected derivative of 6-bromohexanol can be avoided thus an excess of lithium 1,5-decadiyne in liquid ammonia is used and allowed to react directly with 6-bromohexanol to give 7,11-hexadecadiynol (bp 136°-138°/1 torr, nD21 1.4818). Acetylation with acetic anhydride or acetic acid-acetyl chloride converts the alcohol to the acetate.
Reaction SMILES: [CH3:1][C:2]1([CH3:27])[C:11]2[C:6](=[CH:7][C:8]([N+:23]([O-])=O)=[C:9]([NH:12][C:13](=O)[C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)[CH:10]=2)[NH:5][C:4](=[O:26])[CH2:3]1>[Pd].C(O)C>[CH3:1][C:2]1([CH3:27])[C:11]2[CH:10]=[C:9]3[NH:12][C:13]([C:14]4[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=4)=[N:23][C:8]3=[CH:7][C:6]=2[NH:5][C:4](=[O:26])[CH2:3]1
Reactant: COc1ccc(C(=O)Nc2cc3c(cc2[N+](=O)[O-])NC(=O)CC3(C)C)cc1
Agent: [Pd]
Solvent: CCO
Product: COc1ccc(-c2nc3cc4c(cc3[nH]2)C(C)(C)CC(=O)N4)cc1

Procedure:
6.8 g. (18.4 mmole) 4,4-dimethyl-6-(4-methoxy- benzoylamino)-7-nitro-1,2,3,4-tetrahydroquinolin-2-one were hydrogenated in 200 ml. ethanol in the presence of 0.6 g. 10% palladium on charcoal. After filtering off of the catalyst, the filtrate was mixed with 15 ml. concentrated hydrochloric acid and boiled under reflux for 20 hours. The evaporation residue was mixed with water and ammonia, extracted with methylene chloride/methanol (20:1 v/v), purified over silica gel (elution agent: methylene chloride/ammonia-saturated methanol; 20:1 v/v) and recrystallised from ethanol to give 3.5 g. (60% of theory) of the title compound; m.p. 235°-238° C.
Reaction SMILES: [CH3:1][C:2]([CH3:6])=[CH:3][CH2:4]O.[C:7]([O-:13])([O-])([O:9][CH2:10][CH3:11])[CH3:8].C1(O)C=CC=CC=1>>[CH3:1][C:2]([CH3:6])([CH:3]=[CH2:4])[CH2:8][C:7]([O:9][CH2:10][CH3:11])=[O:13]
Reactant: CCOC(C)([O-])[O-]
Reactant: CC(C)=CCO
Solvent: Oc1ccccc1
Product: C=CC(C)(C)CC(=O)OCC
Temperature: 25 °C
Reaction time: 9.5 h
Yield: 77.8 %

Procedure:
A mixture of 43 g (0.5 mole) of 3-methyl-2-buten-1-ol, 97 g (0.6 mole) of ethyl orthoacetate, and 7.0 g (0.075 mole) of phenol was heated at 135°-140° with stirring for 9-10 hours. Ethanol was distilled from the mixture as the reaction proceeded. When the evolution of ethanol had ceased, heating was discontinued and the mixture was allowed to cool to room temperature. The mixture was then dissolved in diethyl ether and the ethereal solution was treated with IN hydrochloric acid to decompose unreacted ethyl orthoacetate. The ethereal solution was then washed successively with a saturated aqueous solution of sodium bicarbonate and with water, then dried over magnesium sulfate. The dried solution was concentrated and distilled under reduced pressure to give 60.8 g (78% yield) of ethyl 3,3-dimethyl-4-pentenoate, b.p. 57°-60°/11 mm.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][C:5]1[C:6](=[O:19])[CH:7]=[C:8]([CH2:11][O:12][CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][O:14]2)O[CH:10]=1.O.[NH4+:21]>C(O)C>[OH:1][CH2:2][CH2:3][CH2:4][C:5]1[C:6](=[O:19])[CH:7]=[C:8]([CH2:11][O:12][CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][O:14]2)[NH:21][CH:10]=1
Reactant: [NH4+]
Reactant: O=c1cc(COC2CCCCO2)occ1CCCO
Solvent: CCO
Solvent: O
Product: O=c1cc(COC2CCCCO2)[nH]cc1CCCO
Reaction time: 0.5 h

Procedure:
To a solution of 1.2 g of 5-(3-hydroxypropyl)-2-((tetrahydro-2H-pyran-2-yloxy)methyl)-4H-pyran-4-one in 5 mL of ethanol, 16 mL of 25% ammonium water was added, and the mixture was heated under reflux while stirring for 9 hours 30 minutes. The solvent was distilled off under reduced pressure, and the resultant residue was purified by flash silica gel column chromatography using gradient elution with chloroform:methanol=95:5 to 90:10 to obtain 0.42 g of 5-(3-hydroxypropyl)-2-((tetrahydro-2H-pyran-2-yloxy)methyl)pyridin-4(1H)-one as a brown oily substance.
Reaction SMILES: [CH3:1][N:2](S(C1C=CC=CC=1)(=O)=O)[N:3]=[C:4](Cl)[C:5]1[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:6]=1[F:12].[Cl:23][C:24]1[CH:31]=[CH:30][C:27]([C:28]#[N:29])=[CH:26][C:25]=1[O:32][C:33]1[CH:38]=[CH:37][C:36]([C:39]([F:42])([F:41])[F:40])=[CH:35][N:34]=1.ClC1C=CC=CC=1Cl>C(Cl)(Cl)Cl.[Fe](Cl)(Cl)Cl>[Cl:23][C:24]1[CH:31]=[CH:30][C:27]([C:28]2[N:2]([CH3:1])[N:3]=[C:4]([C:5]3[C:6]([F:12])=[CH:7][CH:8]=[CH:9][C:10]=3[F:11])[N:29]=2)=[CH:26][C:25]=1[O:32][C:33]1[CH:38]=[CH:37][C:36]([C:39]([F:40])([F:41])[F:42])=[CH:35][N:34]=1
Reactant: N#Cc1ccc(Cl)c(Oc2ccc(C(F)(F)F)cn2)c1
Reactant: CN(N=C(Cl)c1c(F)cccc1F)S(=O)(=O)c1ccccc1
Agent: Cl[Fe](Cl)Cl
Solvent: ClC(Cl)Cl
Solvent: Clc1ccccc1Cl
Product: Cn1nc(-c2c(F)cccc2F)nc1-c1ccc(Cl)c(Oc2ccc(C(F)(F)F)cn2)c1
Temperature: 140 °C
Reaction time: 0.5 h
Yield: 24.6 %

Procedure:
A mixture of N-methyl-N-(benzenesulfonyl)-2,6-difluorobenzohydrazonoyl chloride (0.90 g), 4-chloro-3-(5-trifluoromethylpyridine-2-yloxy)benzonitrile (0.90 g), anhydrous iron (III) chloride (0.50 g) and o-dichlorobenzene (5 ml) is stirred at an oil bath temperature of 140° C. for 30 minutes. After cooling, it is dissolved in chloroform (100 ml) and washed with dilute hydrochloric acid, dilute aqueous solution of sodium hydroxide and saline. Then, it is dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The concentrate is purified by silica gel column chromatography using mixed solvent of hexaneethyl acetate as eluent to give 0.30 g of desired compound.