Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[OH:7][CH2:8][C:9]1[CH:10]=[C:11]([OH:15])[CH:12]=[CH:13][CH:14]=1.Br[CH2:17][CH:18]([O:22][CH2:23][CH3:24])[O:19][CH2:20][CH3:21]>CN(C=O)C>[CH2:20]([O:19][CH:18]([O:22][CH2:23][CH3:24])[CH2:17][O:15][C:11]1[CH:10]=[C:9]([CH2:8][OH:7])[CH:14]=[CH:13][CH:12]=1)[CH3:21]
Reactant: OCc1cccc(O)c1
Reactant: CCOC(CBr)OCC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(COc1cccc(CO)c1)OCC
Temperature: 25 °C

Procedure:
Cesium carbonate (7.87 g) was added to a solution of 3-(hydroxymethyl)phenol (2.5 g) and 2-bromo-1,1-diethoxyethane (3.97 g) in DMF (40 mL) and the resultant mixture was heated at 90° C. for 18 hours. The mixture was cooled to room temperature and partitioned between ethyl acetate and brine, the organic layer was washed twice with brine, dried over sodium sulphate, filtered and the solvent evaporated under reduced pressure. The crude product was purified by flash silica chromatography using 30% ethyl acetate in isohexane as solvent. Pure fractions were evaporated to dryness to afford the subtitled compound. Yield 1.9 g.
Reaction SMILES: [Cl-].[Mg+2].[Cl-].[O:4]=[C:5]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8].[F:19][C:20]1[CH:28]=[CH:27][C:23]([C:24](Cl)=[O:25])=[CH:22][CH:21]=1.Cl>O1CCCC1.C(OCC)(=O)C.N1C=CC=CC=1>[F:19][C:20]1[CH:28]=[CH:27][C:23]([C:24]([CH:6]([C:5](=[O:4])[CH2:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:25])=[CH:22][CH:21]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: CCOC(=O)CC(=O)Cc1ccccc1
Agent: Cl
Agent: [Cl-]
Agent: [Mg+2]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CCOC(=O)C(C(=O)Cc1ccccc1)C(=O)c1ccc(F)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 67.5 %

Procedure:
To a suspensin of magnesium chloride (1.46 g) in tetrahydrofuran (10 ml) was added a solution of ethyl 3-oxo-4-phenylbutanoate (2.0 g) in tetrahydrofuran (10 ml) and the mixture was cooled to 0° C., then pyridine (2.5 ml) was added. The mixture was stirred at 20° C. for 30 minutes, then a solution of 4-fluorobenzoyl chloride (2.44 g) in tetrahydrofuran (10 ml) was added at 0° C. After stirring at 20° C. for 2 hours, the mixure was partitoned between 0.5N hydrochloric acid and ethyl acetate. The organic layer was separated, washed with water and brine, dried over magnesium sulfate, and evaporated. The residue was chromatographed on silica gel eluting with a mixture of ethyl acetate and hexane (1:5) to give ethyl 2-(4-fluorobenzoyl)-3-oxo-4-phenylbutanoate (2.15 g) as an oil.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([CH2:7][C:8]([CH3:16])(C)[CH2:9][CH2:10][CH2:11][CH:12]([CH3:14])[CH3:13])[C:4]([OH:6])=[O:5].N[CH2:18]C(CCCCCC(C)C)C(O)=O.C1(C(OC2C(C(C)(C)C)=CC(C)=CC=2C(C)(C)C)=O)CC1>>[NH2:1][CH2:2][CH:3]([CH2:7][CH:8]([CH2:16][CH3:18])[CH2:9][CH2:10][CH2:11][CH:12]([CH3:13])[CH3:14])[C:4]([OH:6])=[O:5]
Reactant: CC(C)CCCCCC(CN)C(=O)O
Reactant: CC(C)CCCC(C)(C)CC(CN)C(=O)O
Agent: Cc1cc(C(C)(C)C)c(OC(=O)C2CC2)c(C(C)(C)C)c1
Product: CCC(CCCC(C)C)CC(CN)C(=O)O

Procedure:
A procedure similar to that of 2-Aminomethyl-4,4,8-trimethyl-nonanoic acid was utilized to prepare 2-Aminomethyl-8-methyl-nonanoic acid from 2,6-di-t-butyl-4-methylphenyl cyclopropylcarboxylate. m/z 230.2 (M+).
Reaction SMILES: [N:1]([O-:3])=O.[Na+].[CH3:5][O:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][O:12][C:13]1[N:18]=[C:17]([NH2:19])[N:16]=[C:15]([NH2:20])[CH:14]=1>O.C(O)(=O)C>[CH3:5][O:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][O:12][C:13]1[N:18]=[C:17]([NH2:19])[N:16]=[C:15]([NH2:20])[C:14]=1[N:1]=[O:3]
Reactant: O=N[O-]
Reactant: COCCOCCOc1cc(N)nc(N)n1
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: COCCOCCOc1nc(N)nc(N)c1N=O
Reaction time: 2 h
Yield: 349.9 %

Procedure:
A solution of 9.11 g (0.013 mol) of sodium nitrite in 40 ml of water was added in drops to a solution of 22.8 g (0.100 mol) of 6-[2-(2-methoxyethoxyl)ethoxy]pyrimidine-2,4-diamine in 200 ml of acetic acid (10% in water) over 1 h at 3-5° C. while stirring was performed. Then stirring was performed further for 2 h at room temperature. The resulting precipitate was sucked off, post-washed with water, and dried, whereby 6-[2-(2-methoxyethoxyl)ethoxy]-5-nitrosopyrimidine-2,4-diamine (11.7 g, 45%) was obtained as a purple solid.
Reaction SMILES: [C:1]([C:3]1([C:7]2(O)[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8]2)[CH2:6][CH2:5][CH2:4]1)#[N:2].O=P(Cl)(Cl)Cl.C(OCC)(=O)C>N1C=CC=CC=1>[C:1]([C:3]1([C:7]2[CH2:8][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:10][CH:11]=2)[CH2:6][CH2:5][CH2:4]1)#[N:2]
Reactant: CC(C)(C)OC(=O)N1CCC(O)(C2(C#N)CCC2)C1
Solvent: O=P(Cl)(Cl)Cl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N1CC=C(C2(C#N)CCC2)C1
Temperature: 60 °C
Reaction time: 12 h
Yield: 116.3 %

Procedure:
To a solution of Example 265A (2.4 g, 9 mmol) in pyridine (50 mL) was added POCl3 (8.4 mL, 90 mmol) dropwise and the solution was stirred at 60° C. for 12 hours. Pyridine was removed under reduced pressure and the solution was basified with 1 N NaOH. The aqueous layer was extracted with EtOAc (25 mL×3). The combined organic phases were washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography eluted with petroleum ether:ethyl acetate=20:1 to obtain the title compound (2.6 g, 44.3% yield) as a colorless oil. 1H NMR: (400 MHz, CDCl3): δ 5.80 (d, J=9.6 Hz, 1H), 4.26-4.17 (m, 4H), 2.66-2.59 (m, 2H), 2.45-2.38 (m, 2H), 2.34-2.24 (m, 1H), 2.10-2.00 (m, 1H), 1.49 (s, 9H).
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].C1COCC1.[CH3:16][O:17][N:18]([CH3:30])[S:19]([C:22]1[N:23]=[CH:24][N:25]2[CH:29]=[CH:28][S:27][C:26]=12)(=[O:21])=[O:20].[CH2:31]([Sn:35](Cl)([CH2:40][CH2:41][CH2:42][CH3:43])[CH2:36][CH2:37][CH2:38][CH3:39])[CH2:32][CH2:33][CH3:34].[Cl-].[NH4+]>C1COCC1.C(OCC)(=O)C>[CH3:16][O:17][N:18]([CH3:30])[S:19]([C:22]1[N:23]=[CH:24][N:25]2[CH:29]=[C:28]([Sn:35]([CH2:36][CH2:37][CH2:38][CH3:39])([CH2:40][CH2:41][CH2:42][CH3:43])[CH2:31][CH2:32][CH2:33][CH3:34])[S:27][C:26]=12)(=[O:20])=[O:21]
Reactant: CON(C)S(=O)(=O)c1ncn2ccsc12
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCC[Sn](CCCC)(CCCC)c1cn2cnc(S(=O)(=O)N(C)OC)c2s1
Reaction time: 0.5 h

Procedure:
A 1.0 N lithiumbis(trimethylsilyl)amide/THF solution (2.0 ml) was added to a solution of 0.44 g of 7-(N-methoxy-N-methylsulfamoyl)imidazo[5,1-b]thiazole in 9 ml of dry THF in an argon atmosphere at −40° C. The mixture was stirred at the same temperature for 30 min. Tri-n-butylstannyl chloride (0.58 ml) was added thereto. The mixture was stirred for 30 min. Further, a 1.0 N lithiumbis(trimethylsilyl)amide/THF solution (2.5 ml) was then added, followed by stirring for 30 min. Tri-n-butylstannyl chloride (0.1 ml) was added thereto. The mixture was stirred at the same temperature for 30 min. A saturated aqueous ammonium chloride solution was added thereto, and the ethyl acetate was then added, followed by washing with water and saturated brine in that order. The organic layer was dried over anhydrous magnesium sulfate. The solvent was removed by distillation. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate=1:2) to give 0.39 g of the title compound.
Reaction SMILES: [CH3:1][N:2]1[C@@H:7]([CH3:8])[CH2:6][NH:5][CH2:4][C@H:3]1[CH3:9].C(=O)([O-])[O-].[Cs+].[Cs+].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.Br[C:63]1[CH:64]=[CH:65][C:66]([O:78][CH2:79][C:80]2[CH:85]=[CH:84][CH:83]=[CH:82][CH:81]=2)=[C:67]([CH:77]=1)[C:68]([NH:70][C:71]1[CH:72]=[N:73][CH:74]=[CH:75][CH:76]=1)=[O:69]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:80]1([CH2:79][O:78][C:66]2[CH:65]=[CH:64][C:63]([N:5]3[CH2:6][C@H:7]([CH3:8])[N:2]([CH3:1])[C@H:3]([CH3:9])[CH2:4]3)=[CH:77][C:67]=2[C:68]([NH:70][C:71]2[CH:72]=[N:73][CH:74]=[CH:75][CH:76]=2)=[O:69])[CH:81]=[CH:82][CH:83]=[CH:84][CH:85]=1
Reactant: O=C(Nc1cccnc1)c1cc(Br)ccc1OCc1ccccc1
Reactant: C[C@@H]1CNC[C@H](C)N1C
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: C[C@@H]1CN(c2ccc(OCc3ccccc3)c(C(=O)Nc3cccnc3)c2)C[C@H](C)N1C

Procedure:
(2R,6S)-1,2,6-Trimethylpiperazine (105 mg, 0.52 mmol), cesium carbonate (680 mg, 2.09 mmol), BINAP (2.44 mg, 3.91 μmol) and Pd2(dba)3 (1.20 mg, 1.30 μmol) were added to 5-bromo-2-[(phenylmethyl)oxy]-N-3-pyridinylbenzamide (may be prepared as described in example 2; 200 mg, 0.52 mmol) in anhydrous toluene (5 ml), and the mixture was heated to reflux overnight. The reaction mixture was evaporated under reduced pressure. Water (50 ml) was added to the residue and the mixture was extracted with ethyl acetate (3×50 ml). The organics were combined and evaporated, and the residue purified by MDAP twice to yield the title compound. 180 mg.
Reaction SMILES: [C:1]([NH:4][C:5](=[O:12])[CH2:6][CH2:7][CH2:8][C:9]([OH:11])=[O:10])(=[O:3])[NH2:2].CS(O)(=O)=[O:15].OO>>[C:1]([NH:4][C:5](=[O:12])[CH2:6][CH2:7][CH2:8][C:9]([O:11][OH:15])=[O:10])(=[O:3])[NH2:2]
Reactant: NC(=O)NC(=O)CCCC(=O)O
Reactant: CS(=O)(=O)O
Agent: OO
Product: NC(=O)NC(=O)CCCC(=O)OO

Procedure:
11.3 g (0.065 mol) of N-carbamoylglutaramic acid, 21 g of methanesulfonic acid and 7.8 g (0.2 mol) of hydrogen peroxide (85% strength by weight) are reacted and worked up as described in Example 3.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][C:10]2[C:11]([C:18]3[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:19]=3[OH:25])=[N:12][N:13]([CH2:15][CH2:16][OH:17])[CH:14]=2)=[CH:4][CH:3]=1.[C:26]([N:33]1[CH2:38][CH2:37][CH2:36][CH2:35][C@@H:34]1[C:39](O)=[O:40])([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27].C(N=C=NC(C)C)(C)C.O[Li].O.C(O)(=O)C>CN(C)C1C=CN=CC=1.C1COCC1.O.C(OCC)(=O)C>[C:29]([O:28][C:26]([N:33]1[CH2:38][CH2:37][CH2:36][CH2:35][C@@H:34]1[C:39](=[O:40])[NH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][C:10]2[C:11]([C:18]3[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:19]=3[OH:25])=[N:12][N:13]([CH2:15][CH2:16][OH:17])[CH:14]=2)=[CH:4][CH:3]=1)=[O:27])([CH3:32])([CH3:31])[CH3:30]
Reactant: CC(C)(C)OC(=O)N1CCCC[C@@H]1C(=O)O
Reactant: Nc1ccc(C#Cc2cn(CCO)nc2-c2cc(Cl)ccc2O)cc1
Agent: CC(C)N=C=NC(C)C
Agent: CN(C)c1ccncc1
Agent: [Li]O
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCCC[C@@H]1C(=O)Nc1ccc(C#Cc2cn(CCO)nc2-c2cc(Cl)ccc2O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.6 %

Procedure:
A solution of 2-[4-(4-Amino-phenylethynyl)-1-(2-hydroxy-ethyl)-1H-pyrazol-3-yl]-4-chloro-phenol (2A) (7.08 g, 20.0 mmol), N-Boc-2(R)-piperidinecarboxylic acid (3A) (18.35 g, 80.0 mmol) and 4-dimethylaminopyridine (DMAP, 0.978 g, 8.0 mmol) in anhydrous THF (100 mL) was cooled to 0° C. with and ice-water bath. N,N′-Diisopropylcarbodiimide (DIPC, 12.39 mL, 80.0 mmol) was added slowly to the above solution. The ice-water bath was removed and the reaction mixture was stirred at rt overnight. Water (˜5 mL) and methanol (100 mL) were added. The mixture was cooled to 0° C. A solution of LiOH.H2O (17.0 g, 405 mmol) in water (60 mL) were added slowly. The mixture was stirred at 0° C. for 2 h. It was then neutralized with acetic acid (23 mL, 402 mmol). The mixture was diluted with ethyl acetate (˜200 mL), and washed with brine, and dried over sodium sulfate. It was filtered, concentrated and filtered again to remove diisopropylurea. The filtrate was purified with silica column chromatography eluting with hexanes-ethyl acetate (v/v 1/1, 2/3) to provide the title compound (4A, 8.2 g) as a yellowish solid in 72.6% yield. 1H NMR (CDCl3, 500 MHz) δ 10.59 (s, 1H), 8.67 (d, 1H, J=1.5 Hz), 8.40 (br s, 1H), 7.77 (s, 1H), 7.54 (s, 4H), 7.20 (dd, 1H, J=9.0, 1.5 Hz), 6.96 (d, 1H, J=9.0 Hz), 4.88 (s, 1H), 4.31 (t, 2H, J=4.5 Hz), 4.06 (t, 3H, J=4.5 Hz), 3.75 (br s, 1H), 2.87 (t, 1H, J=12.0 Hz), 2.34 (m, 3H), 1.90-1.20 (m, 15H). LCMS (ESI) m/z 587.15 (MNa+), 565.16 (MH+), 465.19 (100), 354.09; HPLC: tR=5.22 min.
Reaction SMILES: C[O:2][C:3](=[O:23])[C:4]1[CH:9]=[C:8]([N:10]([S:12]([CH:15]2[CH2:17][CH2:16]2)(=[O:14])=[O:13])[CH3:11])[N:7]=[C:6]([NH:18][C@H:19]([CH2:21][CH3:22])[CH3:20])[CH:5]=1.[OH-].[Na+].Cl>CO>[C@@H:19]([NH:18][C:6]1[CH:5]=[C:4]([CH:9]=[C:8]([N:10]([S:12]([CH:15]2[CH2:16][CH2:17]2)(=[O:13])=[O:14])[CH3:11])[N:7]=1)[C:3]([OH:23])=[O:2])([CH2:21][CH3:22])[CH3:20]
Reactant: CC[C@H](C)Nc1cc(C(=O)OC)cc(N(C)S(=O)(=O)C2CC2)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC[C@H](C)Nc1cc(C(=O)O)cc(N(C)S(=O)(=O)C2CC2)n1

Procedure:
Dissolve (S)-2-sec-butylamino-6-(cyclopropanesulfonyl-methylamino)-isonicotinic acid methyl ester (600 mg, 1.97 mmol) in methanol (18 mL). Slowly add 2 N NaOH (3 mL) and stir overnight at room temperature. Acidify the mixture to about pH=6 with 5 N HCl and concentrate. Dilute with ethyl acetate (30 mL) and wash the organic layer with saturated aqueous sodium chloride solution, dry (magnesium sulfate) and concentrate to give the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([CH2:12][C:13]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)=[O:14])[C:9]([OH:11])=O)=[CH:4][CH:3]=1.[NH2:21][C@@H:22]([CH:25]([CH3:27])[CH3:26])[CH2:23][OH:24].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>C(Cl)Cl.CCCCCC.CCOC(C)=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C@H:8]([CH2:12][C:13]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)=[O:14])[C:9]([NH:21][C@H:22]([CH2:23][OH:24])[CH:25]([CH3:27])[CH3:26])=[O:11])=[CH:6][CH:7]=1
Reactant: CC(C)[C@H](N)CO
Reactant: O=C(O)[C@@H](CC(=O)N1CCOCC1)c1ccc(F)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCCCCC
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)[C@@H](CO)NC(=O)[C@@H](CC(=O)N1CCOCC1)c1ccc(F)cc1
Temperature: 25 °C
Yield: 40.6 %

Procedure:
2-(S)-(4-Fluoro-phenyl)-4-morpholin-4-yl-4-oxo-butyric acid (2.00 g, 7.11 mmol, 1.0 eq.), 2-(S)-Amino-3-methyl-butan-1-ol (1.59 g, 7.33 mmol, 1.03 eq.) and HATU (2.41 g, 7.33 mmol, 1.03 mmol) were dissolved in CH2Cl2 and stirred at room temperature. Diisopropylethylamine (3.9 mL, 21.98 mmol, 3.1 eq.) was added via syringe and the reaction is monitored by LC/MS. Upon completion, there reaction was evaporated and is diluted with ethyl acetate (100 mL) and extracted with 0.5M HCl (2×30 mL), saturated NaHCO3, and brine. The organic layer is dried over MgSO4, filtered and evaporated. Column chromatography (0-100%) EtOAc in hexane gradient provided 2-(S)-(4-Fluoro-phenyl)-N-(1-(S)-hydroxymethyl-2-methyl-propyl)-4-morpholin-4-yl-4-oxo-butyramide as a clear oil (1.06 g, 2.89 mmol, 41%). HPLC-MS calcd. for C19H27FN2O4 (M+H+) 367.2, found 367.4; TLC (1:1 hexane/EtOAc) Rf=0.15.
Reaction SMILES: [OH:1][C:2]1[CH:30]=[CH:29][C:5]([C:6]([NH:8][C:9]2[CH:10]=[C:11]([NH:16][C:17]([C:19]3[CH:20]=[C:21]4[C:26](=[CH:27][CH:28]=3)[N:25]=[CH:24][CH:23]=[CH:22]4)=[O:18])[CH:12]=[CH:13][C:14]=2[CH3:15])=[O:7])=[CH:4][CH:3]=1.Cl[CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=1>>[N:34]1[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=1[CH2:32][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([NH:8][C:9]2[CH:10]=[C:11]([NH:16][C:17]([C:19]3[CH:20]=[C:21]4[C:26](=[CH:27][CH:28]=3)[N:25]=[CH:24][CH:23]=[CH:22]4)=[O:18])[CH:12]=[CH:13][C:14]=2[CH3:15])=[O:7])=[CH:29][CH:30]=1
Reactant: ClCc1ccccn1
Reactant: Cc1ccc(NC(=O)c2ccc3ncccc3c2)cc1NC(=O)c1ccc(O)cc1
Product: Cc1ccc(NC(=O)c2ccc3ncccc3c2)cc1NC(=O)c1ccc(OCc2ccccn2)cc1
Temperature: 40 °C
Yield: 72 %

Procedure:
Using an analogous procedure to that described in Example 7 except that the reaction mixture was heated to 70° C. for 48 hours rather than to 40° C. for 18 hours, N-[3-(4-hydroxybenzamido)-4-methylphenyl]quinoline-6-carboxamide was reacted with 2-chloromethylpyridine to give the title compound in 72% yield; NMR Spectrum: (DMSOd6) 2.22 (s, 3H), 5.28 (s, 2H), 7.16 (d, 2H), 7.22 (d, 1H), 7.34 (m, 1H), 7.53 (m, 1H), 7.62 (m, 2H), 7.85 (m, 2H), 7.95 (m, 1H), 8.12 (d, 1H), 8.23 (m, 1H), 8.52 (m, 1H), 8.59 (m, 2H), 9.0 (d, 1H), 10.48 (s, 1H); Mass Spectrum: M+H+ 489.
Reaction SMILES: [C:1]([CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH:11]1[C:15](=[O:16])[C:14](=[O:17])[CH2:13][C:12]1=[O:18])([O:3][CH3:4])=[O:2].CC1(CCC#C)OCCO1.O=C(C)CCC#CCCCC(O)=O.O=C(C)CCC#CCCCC(OC)=O.O=C(C)CC/C=C\CCCC([O-])=O.O=C(C)CC/C=C\CCCC(OC)=O.[C:83](OCC)(=[O:89])[C:84]([O:86][CH2:87][CH3:88])=[O:85]>>[C:1]([CH2:5][CH2:6][CH2:7]/[CH:8]=[CH:9]\[CH2:10][CH:11]1[C:15](=[O:16])[C:14](=[O:17])[CH:13]([C:83]([C:84]([O:86][CH2:87][CH3:88])=[O:85])=[O:89])[C:12]1=[O:18])([O:3][CH3:4])=[O:2]
Reactant: COC(=O)CCCC/C=C\C1C(=O)CC(=O)C1=O
Reactant: CCOC(=O)C(=O)OCC
Agent: C#CCCC1(C)OCCO1
Agent: CC(=O)CC/C=C\CCCC(=O)[O-]
Agent: CC(=O)CCC#CCCCC(=O)O
Product: CCOC(=O)C(=O)C1C(=O)C(=O)C(C/C=C\CCCC(=O)OC)C1=O

Procedure:
In a process for the synthesis of 2-(6-carbomethoxy-cis-hexenyl)-cyclopentane-1,3,4-trione by stepwise converting 2-methyl-2-(3-butynyl)-1,3-dioxolane to 9-oxo-5-decynoic acid, esterifying that acid to methyl 9-oxo-5-decynoate, reducing the latter to 9-oxo-cis-5-decenoate, condensing the methyl 9-oxo-cis-5-decenoate with diethyl oxalate to obtain 2-(6-carbomethoxy-cis-2-hexenyl)-5-ethoxalyl-cyclopentane-1,3,4-trione as an intermediate, and hydrolyzing the intermediate to obtain 2-(6-carbomethoxy-cis-hexenyl)-cyclopentane-1,3,4-trione, the improvement which comprises:
Reaction SMILES: Br[C:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][C:4]([C:12]([OH:14])=[O:13])([CH2:5]3)[CH2:3]1)[CH2:9]2.[Al+3].[Cl-:16].[Cl-].[Cl-]>ClC1C=CC=CC=1>[Cl:16][C:2]1[CH:11]=[CH:6][C:5]([C:2]23[CH2:11][CH:6]4[CH2:7][CH:8]([CH2:10][C:4]([C:12]([OH:14])=[O:13])([CH2:5]4)[CH2:3]2)[CH2:9]3)=[CH:4][CH:3]=1
Reactant: O=C(O)C12CC3CC(CC(Br)(C3)C1)C2
Reactant: [Cl-]
Agent: [Al+3]
Solvent: Clc1ccccc1
Product: O=C(O)C12CC3CC(C1)CC(c1ccc(Cl)cc1)(C3)C2
Temperature: 25 °C
Yield: 79.3 %

Procedure:
More specifically, adamantane-1-carboxylic acid (1) (45 g, 0.25 mol) was added to a mixture of AlCl3 (45 g, 0.34 mol) and Br2 (450 g) at 0° C. and stirred at 0-10° C. for 48 hrs, and then kept for 5 hrs at about 20° C. The mixture was then poured onto 500 g crushed ice, diluted with 300 mL of CHCl3 and decolorized with solid Na2S2O5. The aqueous phase was extracted twice with Et2O (50 mL each), and the combined organic phases were washed with H2O and extracted with 10% NaOH. The alkaline extraction was acidified with 2NH2SO4 and kept overnight to provide 49 g (yield=75.7%) of 3-bromoadamantane-1-carboxylic acid (2). Over a course of 0.5 hr, intermediate 2 (16.0 g, 61.7 mmol) in 50 mL of dry chlorobenzene was added at −10° C. to 100 mL of dry chlorobenzene containing 9.3 g (70 mmol) of AlCl3. The mixture was then warmed to room temperature for 1 hr, and then heated to 90° C. for 10 hr. The mixture was then poured onto 200 g of crushed ice and filtered to provide 14.2 g (yield=79.3%) of 3-(4-chlorophenyl)adamantane-1-carboxylic acid (3). Intermediate 3 (1 mmol) was added to a 50 mL round-bottom flask containing HPLC-grade toluene (20 mL), fitted with reflux condenser, and dry N2 was introduced. The mixture was stirred while thionyl chloride (SOCl2) (10 mmol) was added, and refluxed for 1 hr. The sample was then evaporated under a vacuum to produce intermediate 4,3-(4-chlorophenyl)adamantane-1-carbonyl chloride. Without further purification, intermediate 4 was added to 5 mL of a mixture containing 3-hydroxytyramine hydrochloride (5, 1 mmol), NaOH (1 mmol) and Na2CO3 (1 mmol) in 5 mL DMF under N2, and the mixture was stirred at 60° C. for 24 hr and then cool to room temperature. The mixture was evaporated under a vacuum, and 10% HCL was slowly added to the mixture until it reached a pH value of 1. The mixture was then extracted with 20 mL CHCl3, washed three times with water (10 mL each), dried with anhydrous Na2SO4, filtered and concentrated to give Compound 1 as white crystals (yield=83%) with a melting point of 146-148° C. 1H NMR (500 MHz, DMSO) δ 1.63-1.68 (m, 2H, Admant-H), 1.71-1.83 (m, 10H, Admant-H), 2.14 (s, 2H, Admant-H), 2.50-2.53 (m, 2H, CH2), 3.15-3.18 (t, J=7.5 Hz, 2H, NCH2), 3.40 (s, 1H, NH), 6.40-6.42 (d, J=10 Hz, 1H, Ar—H), 6.56 (s, 1H, Ar—H), 6.62-6.63 (d, J=5 Hz, 1H, Ar—H), 7.36-7.41 (m, 4H, Ar—H), 8.68 (s(br), 2H, OH). 13C NMR (500 MHz, DMSO) δ 28.8, 31.3, 35.0, 35.5, 36.3, 36.6, 38.3, 41.0, 41.3, 42.0, 44.3, 115.8, 116.4, 119.8, 127.4, 128.5, 130.7, 131.0, 149.6, 162.9, 176.8. Mass spectroscopy m/z (relative intensity) 426.18 (MH+, 100), 427.18 (68), 428.18 (75).
Reaction SMILES: C(NC1SC=C(C(=NOCCN2CCOCC2)C(O)=O)N=1)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[IH:40].N1C=CC=CC=1.C1(N=C=NC2CCCCC2)CCCCC1.C(OC[C:67]1[CH2:68][S:69][C@@H:70]2[CH:90](N)[C:89](=[O:92])[N:71]2[C:72]=1[C:73]([O:75]C(C1C=CC=CC=1)C1C=CC=CC=1)=[O:74])(=O)C>CN(C)C=O>[IH:40].[S:69]1[C@@H:70]2[CH2:90][C:89](=[O:92])[N:71]2[C:72]([C:73]([OH:75])=[O:74])=[CH:67][CH2:68]1
Reactant: CC(=O)OCC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(N)[C@H]2SC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: I
Agent: O=C(O)C(=NOCCN1CCOCC1)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: O=C(O)C1=CCS[C@@H]2CC(=O)N12
Reaction time: 0.17 h

Procedure:
A solution of 1 g of the product of Step A, 0.38 g of pyridine hydroiodide, 0.63 g of dicyclohexylcarbodiimide, 0.60 g of benzhydryl 3-acetoxymethyl-7-amino-ceph-3-eme-4-carboxylate and 5 ml of anhydrous dimethylformamide was stirred at room temperature for 30 minutes and was vacuum filtered to remove dicyclohexylurea. 100 ml of ether were added to the filtrate and the mixture was stirred for 10 minutes and was vacuum filtered. The product was rinsed with ether and was chromatographed over silica gel. Elution with a 7-1 ethyl acetate-ethanol mixture yielded 0.524 g of the syn isomer of benzhydryl 3-acetoxymethyl-7-[2-2tritylamino-4-thiazolyl)-2-(2-morpholinoethoxyimino)-acetamido]-ceph-3-eme-4-carboxylate hydroiodide melting at 167° C. (decomposition).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[N:7]1[C:11]2[CH:12]=[CH:13][C:14]([CH2:16][NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:15][C:10]=2[N:9]=[CH:8]1.[H-].[Na+].I[CH2:28][CH3:29]>CN(C=O)C>[CH2:28]([N:17]([CH2:16][C:14]1[CH:13]=[CH:12][C:11]2[N:7]([CH:2]3[CH2:3][CH2:4][CH2:5][CH2:6][O:1]3)[CH:8]=[N:9][C:10]=2[CH:15]=1)[C:18](=[O:24])[O:19][C:20]([CH3:21])([CH3:23])[CH3:22])[CH3:29]
Reactant: CCI
Reactant: CC(C)(C)OC(=O)NCc1ccc2c(c1)ncn2C1CCCCO1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCN(Cc1ccc2c(c1)ncn2C1CCCCO1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.42 h
Yield: 55.3 %

Procedure:
To a solution of 202 (600 mg, 1.81 mmol) in DMF (4.5 mL) at 0° C. was added NaH (101 mg, 2.54 mmol, 60% in oil). The reaction was warmed to RT and stirred for 25 min, then re-cooled to 0° C. and iodoethane (0.27 mL, 3.26 mmol) was added. The reaction was warmed to RT and stirred for 5 h. The reaction mixture was partitioned between EtOAc and H2O. The EtOAc extract was washed thrice with water, dried (Na2SO4), filtered and concentrated in vacuo. The crude residue was purified by SiO2 chromatography to afford 360 mg (55%) of tert-butyl ethyl((1-(tetrahydro-2H-pyran-2-yl)-1H-benzo[d]imidazol-5-yl)methyl)carbamate (208): MS (ESI) m/z=360.3 [M+1]+
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:10]2[CH:11]=[CH:12][C:13]([O:15][C:16]3[CH:21]=[CH:20][N:19]=[C:18](Cl)[N:17]=3)=[CH:14][C:9]=2[O:8][N:7]=1)=[O:5])[CH3:2].CCN(CC)CC>CN(C=O)C.[Pd]>[CH2:1]([O:3][C:4]([C:6]1[C:10]2[CH:11]=[CH:12][C:13]([O:15][C:16]3[CH:21]=[CH:20][N:19]=[CH:18][N:17]=3)=[CH:14][C:9]=2[O:8][N:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1noc2cc(Oc3ccnc(Cl)n3)ccc12
Agent: [Pd]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)c1noc2cc(Oc3ccncn3)ccc12

Procedure:
300 mg (0.938 mMol) 6-(2-chloro-pyrimidin-4-yloxy)-benzo[d]isoxazole-3-carboxylic acid ethyl ester in 3 ml DMF and 262 μl (1.88 mMol) Et3N are hydrogenated in presence of 120 mg Pd/C (10%; Engelhard 4505). The catalyst is filtered off, the filtrate concentrated, the residue re-dissolved in EtOAc and water, the aq. layer separated off and extracted with EtOAc. The organic layers are washed with water and brine, dried (Na2SO4) and concentrated. Chromatography (Combi Flash; hexane/EtOAc 9:1→4:1) gives the title compound: MS: [M+1]+=286; TLC(hexane/EtOAc 1:1): Rf=0.30.