Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][P:4](Cl)[O:5]CC)C.[CH2:9]([Mg]Cl)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.O.Cl>C(OCC)C>[CH2:9]([PH:4](=[O:3])[OH:5])[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CCOP(Cl)OCC
Reactant: Cl[Mg]CCc1ccccc1
Agent: Cl
Solvent: O
Solvent: CCOCC
Product: O=[PH](O)CCc1ccccc1
Temperature: 5 °C
Reaction time: 8 h
Yield: 57.6 %

Procedure:
Diethylchlorophosphite (15.6 g, 0.1 mol) in 100 mL of dry diethyl ether was cooled to 5° C. under an atmosphere of nitrogen. Phenethylmagnesium chloride (100 mL, 0.1 mol, 1.0 M in THF) was added dropwise over 2 hours while maintaining a temperature between 0-10° C. A thick white slurry formed and stirred at room temperature overnight. The mixture was filtered under a nitrogen atmosphere and the filtrate evaporated under reduced pressure to give a clear and colorless liquid. The liquid was stirred as 15 mL of water was added followed by 0.5 mL of concentrated hydrochloric acid. An exothermic reaction was observed and stirring continued for 15 minutes followed by extraction with ethyl acetate. The organics were combined, washed with brine, dried (MgSO4) and evaporated. The clear liquid was brought up in sodium hydroxide (40 mL, 2.0 M NaOH), stirred for 1 hour and washed once with diethyl ether. The aqueous layer was acidified to pH 1.0 with concentrated hydrochloric acid and extracted with ethyl acetate. The organics were combined, dried (MgSO4) and evaporated to give phenethylphosphinic acid (1,R=CH2CH2Ph, R1=H) (9.8 g, 58%) as a clear light yellow oil.
Reaction SMILES: [N:1]1([C:6](=[O:24])[CH2:7][C:8]2[C:9]([C:17]3[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=3)=[N:10][N:11]3[CH:16]=[CH:15][CH:14]=[N:13][C:12]=23)C=CN=C1.N>O1CCCC1.O>[CH3:23][C:20]1[CH:19]=[CH:18][C:17]([C:9]2[C:8]([CH2:7][C:6]([NH2:1])=[O:24])=[C:12]3[N:13]=[CH:14][CH:15]=[CH:16][N:11]3[N:10]=2)=[CH:22][CH:21]=1
Reactant: Cc1ccc(-c2nn3cccnc3c2CC(=O)n2ccnc2)cc1
Agent: N
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(-c2nn3cccnc3c2CC(N)=O)cc1
Reaction time: 16 h
Yield: 41.3 %

Procedure:
A stirred slurry of 3.2 g (0.010 mole) of 3-[2-(1H-imidazole-1-yl)-2-oxoethyl]-2-(4-methylphenyl)pyrazolo[1,5-a]pyrimidine (prepared from 2-(4-methylphenyl)pyrazolo[1,5-a]pyrimidine-3-acetic acid and 1,1'-carbonyldiimidazol) in 20 ml of dry tetrahydrofuran was treated with 3 ml of ammonia in 10 ml of dry tetrahydrofuran. After stirring for 16 hours, the reaction mixture was diluted with 100 ml of water and the precipitated solid collected by filtration (1.6 g). The crude product was recrystallized from acetonitrile to yield 1.1 g (40.9%) of pale yellow crystals, mp 225°-226° C.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([OH:12])=O)=[CH:5][CH:4]=1.O1CCCC1.ON1C2C=CC=CC=2N=N1.[F:30][C:31]1[C:36]([C:37]2[C:41]([C:42]3[CH:47]=[CH:46][N:45]=[CH:44][CH:43]=3)=[CH:40][NH:39][N:38]=2)=[C:35]([F:48])[CH:34]=[CH:33][C:32]=1[NH2:49]>>[F:30][C:31]1[C:36]([C:37]2[C:41]([C:42]3[CH:47]=[CH:46][N:45]=[CH:44][CH:43]=3)=[CH:40][NH:39][N:38]=2)=[C:35]([F:48])[CH:34]=[CH:33][C:32]=1[NH:49][C:10](=[O:12])[CH2:9][C:6]1[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:14])[F:13])=[CH:8][CH:7]=1
Reactant: O=C(O)Cc1ccc(C(F)(F)F)cc1
Reactant: Nc1ccc(F)c(-c2n[nH]cc2-c2ccncc2)c1F
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: O=C(Cc1ccc(C(F)(F)F)cc1)Nc1ccc(F)c(-c2n[nH]cc2-c2ccncc2)c1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To (4-trifluoromethyl-phenyl)-acetic acid (49 mg, 0.24 mmol) in anhydrous tetrahydrofuran (3 mL) 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (63 mg, 0.24 mmol) was added, after 10 minutes 1-hydroxybenzotriazole (38 mg, 0.28 mmol) and after 30 minutes 2,4-difluoro-3-(4-pyridin-4-yl-1H-pyrazol-3-yl)-phenylamine (60 mg, 0.22 mmol) (prepared as described in Example 22) were added. The reaction was stirred under nitrogen atmosphere at room temperature overnight to yield a mixture of mono- and bis-amide (3:1 ratio at 254 nm). The reaction was concentrated under reduced pressure and the residue was dissolved in ethyl acetate, washed successively with NaHCO3 saturated solution and the organic layer was dried over anhydrous sodium sulfate and filtered. The monoamide derivative was isolated by silica gel column chromatography eluting with ethanol 7% in methylene chloride.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:20][Si:21]([C:24]#[CH:25])([CH3:23])[CH3:22].[C:26]1([S:32]([C:35]2[CH:36]=[C:37](OS(C(F)(F)F)(=O)=O)[C:38](=[O:44])[N:39]3[C:43]=2[CH2:42][CH2:41][CH2:40]3)(=[O:34])=[O:33])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C(N(CC)CC)C.C1(C)C=CC=CC=1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:26]1([S:32]([C:35]2[CH:36]=[C:37]([C:25]#[C:24][Si:21]([CH3:23])([CH3:22])[CH3:20])[C:38](=[O:44])[N:39]3[C:43]=2[CH2:42][CH2:41][CH2:40]3)(=[O:34])=[O:33])[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: O=c1c(OS(=O)(=O)C(F)(F)F)cc(S(=O)(=O)c2ccccc2)c2n1CCC2
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: C[Si](C)(C)C#Cc1cc(S(=O)(=O)c2ccccc2)c2n(c1=O)CCC2
Temperature: 25 °C

Procedure:
Pyridinone derivative (P) can also be derivatized to form pyridinone derivative (W) by the organometallic coupling of (trimethylsilyl)acetylene as shown in Reaction Scheme XIII. A similar result in Reaction Scheme XIII can be obtained for the corresponding derivative of pyridinone (E). wherein Z, R2, R3, and R4 are as defined in Reaction Scheme VI. Reagents for the organometallic coupling include PdCl2(PPh3)2 and Cul or other suitable organometallic reagents. The organometallic coupling is accomplished by combining the halogenated pyridinone derivative with (trimethylsilyl)acetylene and triphenylphosphine, PdCl2(PPh3)2 and Cul and then heating at 120 degrees Celcius for 72 hours. The preparation of pyridinone derivative (W) is illustrated by a procedure described by Padwa A., Sheehan S. M., and Straub C. S., J. Org. Chem. 1999, 64: 8648-8659 for an isomunchnone-based method for the synthesis of highly substituted 2(1H)-pyridones, the entirety of which is hereby incorporated by reference. The authors describe the palladium catalyzed coupling of (trimethylsilyl)acetylene with a triflate to provide a (trimethylsilyl)acetylene substituted compound. The specific preparation procedure employed by the authors involved the addition of Cul, followed by PdCl2(PPh3)2 to a solution containing triphenylphosphine in triethylamine. To this solution was added (trimethylsilyl)acetylene in toluene followed by the addition of trifluoromethanesulfonic acid 8-phenylsulfonyl-5-oxo-1,2,3,5-tetrahydroindolizin-6-yl ester. The mixture was heated at 115 degrees Celcius for 1 hour, cooled to room temperature, poured into ice water, extracted with CH2Cl2, washed with brine, and dried over Na2SO4. The organic extracts were filtered and concentrated under reduced pressure. The crude residue was subjected to flash silica gel chromatography to yield 8-phenylsulfonyl-6-trimethylsilanylethynyl-2,3-dihydro-1H-indolizin-5-one.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][C:7]=1[C:8]([NH:10][C:11]1[CH:12]=[CH:13][C:14]([C:18]([N:20]2[C:26]3[CH:27]=[CH:28][C:29]([Cl:31])=[CH:30][C:25]=3[CH:24]([OH:32])[CH2:23][CH2:22][CH2:21]2)=[O:19])=[C:15]([CH3:17])[CH:16]=1)=[O:9].N1C=CC=CC=1.Cl[C:40]([O:42][CH2:43][Cl:44])=[O:41]>ClCCl>[C:40](=[O:41])([O:32][CH:24]1[CH2:23][CH2:22][CH2:21][N:20]([C:18](=[O:19])[C:14]2[CH:13]=[CH:12][C:11]([NH:10][C:8](=[O:9])[C:7]3[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=3[CH3:1])=[CH:16][C:15]=2[CH3:17])[C:26]2[CH:27]=[CH:28][C:29]([Cl:31])=[CH:30][C:25]1=2)[O:42][CH2:43][Cl:44]
Reactant: O=C(Cl)OCCl
Reactant: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2CCCC(O)c3cc(Cl)ccc32)c(C)c1
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2CCCC(OC(=O)OCCl)c3cc(Cl)ccc32)c(C)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Tolvaptan (5.0 g) and pyridine (1.1 ml) were suspended in dichloromethane (50 ml). Chloromethyl chloroformate (1.1 ml) was added thereto under cooling with ice, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was washed with water, dried over anhydrous sodium sulfate. After filtration and concentration under reduced pressure, the residue was purified by silica gel flash chromatography (n-hexane:ethyl acetate=70:30→50:50). The purified product was concentrated under reduced pressure to obtain 6.1 g of chloromethyl {7-chloro-1-[2-methyl-4-(2-methyl-benzoylamino)-benzoyl]-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl} carbonate as white amorphous solid.
Reaction SMILES: [CH2:1]([C:11]1[NH:15][C:14]2[CH:16]=[CH:17][CH:18]=[CH:19][C:13]=2[N:12]=1)[C:2]1[NH:6][C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[N:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:26](Cl)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>CN(C)C=O>[CH2:1]([C:2]1[N:6]([CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[N:3]=1)[C:11]1[N:12]([CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:13]2[CH:19]=[CH:18][CH:17]=[CH:16][C:14]=2[N:15]=1
Reactant: c1ccc2[nH]c(Cc3nc4ccccc4[nH]3)nc2c1
Reactant: ClCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: c1ccc(Cn2c(Cc3nc4ccccc4n3Cc3ccccc3)nc3ccccc32)cc1
Yield: 19.4 %

Procedure:
To a flask were added 2.0 g 2,2′-methylenebis(1H-benzimidazole), 2.8 g potassium carbonate, 100 ml N,N-dimethylformamide and the mixture was stirred under nitrogen. 2.5 g benzyl chloride were added and the mixture was heated to 70 C for 16 hours. Another 0.7 g benzyl chloride was added and the reaction was heated to 70 C for another 20 hours. The reaction was cooled to 22 C, quenched with 150 ml water and the product was extracted with ethyl acetate and washed with water. Following removal of solvent, the product was recrystallized from 10 ml ethanol, then 10 ml acetonitrile with 1 ml of water. The product was filtered and dried resulting in 0.67 g tan solid.
Reaction SMILES: [O:1]1[C@H:3]2[CH2:4][CH:5]3[C@:18]([CH3:20])([CH2:19][C@@H:2]12)[C@@H:17]1[C@H:8]([C@H:9]2[C@@:13]([CH2:15][CH2:16]1)([CH3:14])[C:12](=[O:21])[CH2:11][CH2:10]2)[CH2:7][CH2:6]3.O.[NH:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1>ClCCl>[OH:1][C@@H:3]1[C@@H:2]([N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)[CH2:19][C@@:18]2([CH3:20])[CH:5]([CH2:6][CH2:7][C@@H:8]3[C@@H:17]2[CH2:16][CH2:15][C@@:13]2([CH3:14])[C@H:9]3[CH2:10][CH2:11][C:12]2=[O:21])[CH2:4]1
Reactant: C[C@]12C[C@H]3O[C@H]3CC1CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Reactant: C1CNCCN1
Solvent: ClCCl
Solvent: O
Product: C[C@]12C[C@H](N3CCNCC3)[C@@H](O)CC1CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Temperature: 150 °C
Yield: 64.5 %

Procedure:
To compound 22 (202 mg, 0.70 mmol) was added water (1 mL) and piperazine (3.5 g, 41 mmol). The solution was subsequently heated at 150° C. over a period of 24 h. The resulting mixture was diluted with dichloromethane (50 mL) and washed with water, dried with Na2SO4, filtered and evaporated under reduced pressure. The crude compound was purified by flash chromatography (DCM/MeOH: 9:1 containing 0.5% of TEA) to yield compound 23 (169 mg, 65%). 1H NMR (CDCl3) δ: 0.87 (s, 18-CH3 and 19-CH3), 0.73-2.17 (residual CH and CH2), 2.45, 2.64 and 2.91 (3m, 4×CH2N and 2α-CH), 3.85 (m, 3β-CH).
Reaction SMILES: [F:1][C:2]1[C:7]2[N:8]([CH3:18])[C:9](=[O:17])[C:10]3[C:15]([C:6]=2[CH:5]=[CH:4][C:3]=1[O:19][CH2:20][C:21]([NH:27]C(=O)OC(C)(C)C)([CH3:26])[CH2:22][CH:23]([CH3:25])[CH3:24])=[CH:14][CH:13]=[N:12][C:11]=3[CH3:16].Cl.O1CCOCC1>CO>[NH2:27][C:21]([CH3:26])([CH2:22][CH:23]([CH3:24])[CH3:25])[CH2:20][O:19][C:3]1[CH:4]=[CH:5][C:6]2[C:15]3[C:10](=[C:11]([CH3:16])[N:12]=[CH:13][CH:14]=3)[C:9](=[O:17])[N:8]([CH3:18])[C:7]=2[C:2]=1[F:1]
Reactant: Cc1nccc2c1c(=O)n(C)c1c(F)c(OCC(C)(CC(C)C)NC(=O)OC(C)(C)C)ccc21
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: Cc1nccc2c1c(=O)n(C)c1c(F)c(OCC(C)(N)CC(C)C)ccc21
Temperature: 0 °C
Reaction time: 2 h
Yield: 5.7 %

Procedure:
To a solution of tert-butyl (1-((7-fluoro-4,6-dimethyl-5-oxo-5,6 dihydrobenzo[c][2,7]naphthyridin-8-yl)oxy)-2,4-dimethylpentan-2-yl)carbamate (200 mg, 0.424 mmol) in MeOH (6 mL) at 0° C. was added 4M HCl in 1,4-dioxane (3 mL, 99.0 mmol). The reaction mixture was stirred at 0° C. for 2 h. After 2 h, the reaction mixture was concentrated under reduced pressure to afford crude product which was purified by preparative HPLC to afford 8-((2-amino-2,4-dimethylpentyl)oxy)-7-fluoro-4,6-dimethylbenzo[c][2,7]naphthyridin-5(6H)-one (10 mg, 0.024 mmol, 6% yield) as an off-white solid. LC/MS (ESI) m/e 372.0 [(M+H)+, calcd for C21H27FN3O2 372.2]; LC/MS retention time (method G): tR=1.99 min. HPLC retention time (method A): tR=8.37 min; HPLC retention time (method B): tR=9.72 min. 1H NMR (400 MHz, METHANOL-d4) δ ppm 8.58 (d, J=6 Hz, 1H), 8.22 (dd, J=9.2 Hz, J=2 Hz, 1H), 8.14 (d, J=6 Hz, 1H), 7.23 (m, 1H), 4.31 (d, J=10 Hz, 1H), 4.23 (d, J=10.4 Hz, 1H), 3.88 (d, J=9.2 Hz, 3H), 3.06 (s, 3H), 1.90 (m, 2H), 1.73 (m, 1H), 1.52 (s, 3H), 1.05 (m, 6H).
Reaction SMILES: [C:1]([C:4]1[CH:8]=[C:7]([CH3:9])[O:6][C:5]=1[CH3:10])(=[O:3])[CH3:2].[C:11]([OH:15])(=[O:14])[CH:12]=O>O>[CH3:10][C:5]1[O:6][C:7]([CH3:9])=[CH:8][C:4]=1[C:1](=[O:3])/[CH:2]=[CH:12]/[C:11]([OH:15])=[O:14]
Reactant: O=CC(=O)O
Reactant: CC(=O)c1cc(C)oc1C
Solvent: O
Product: Cc1cc(C(=O)/C=C/C(=O)O)c(C)o1
Yield: 14.2 %

Procedure:
As in Example 1, one starts out with 9 g of 3-acetyl 2.5-dimethylfuran (J. Am. Chem. Soc., 70 739 (1948)), 6 g glyoxylic acid and 6 cm3 water. Following chromatography on silica (eluent: petroleum ether-ethyl acetate (2-8), recrystallization in ethyl acetate, 1.8 g of the expected product is obtained. MP=144°-147° C.
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH:3]([NH:11][S:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)(=[O:14])=[O:13])[CH2:2]1.[Cl:21][C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=1)[CH:25]=O>>[Cl:21][C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=1)[CH2:25][N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH:3]([NH:11][S:12]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)(=[O:13])=[O:14])[CH2:2]1
Reactant: O=S(=O)(NC1CNc2ccccc2C1)c1ccccc1
Reactant: O=Cc1cccc(Cl)c1
Product: O=S(=O)(NC1Cc2ccccc2N(Cc2cccc(Cl)c2)C1)c1ccccc1

Procedure:
The title compound was prepared from 162B and 3-chlorobenzaldehyde by procedures analogous to those described in Example 22A. HPLC: 99% at 3.94 min (retention time) (Conditions: Phenom Prime S5, C18 (4.6×50 mm); Eluted with 0% to 100% B, 4 min gradient (A=90% H2O−10% MeOH−0.1% TFA and B=10% H2O−90% MeOH−0.1% TFA); Flow rate at 4.0 mL/min, UV detection at 220 nm). MS (ES): m/z 413 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[CH2:5][CH:6]([C:9]1[CH:10]=[N:11][C:12]([CH3:15])=[N:13][CH:14]=1)[CH:7]=[CH2:8])[CH3:2].B1C2CCCC1CCC2.C([O-])(O)=[O:27].[Na+]>O>[CH2:1]([O:3][C:4](=[O:16])[CH2:5][CH:6]([C:9]1[CH:10]=[N:11][C:12]([CH3:15])=[N:13][CH:14]=1)[CH2:7][CH2:8][OH:27])[CH3:2]
Reactant: O=C([O-])O
Reactant: C=CC(CC(=O)OCC)c1cnc(C)nc1
Agent: B1C2CCCC1CCC2
Agent: [Na+]
Solvent: O
Product: CCOC(=O)CC(CCO)c1cnc(C)nc1
Reaction time: 18 h

Procedure:
To a stirred solution of 2-4 (422 mg, 1.92 mmol) in TBF was added 5.75 mL of 9-BBN (0.5 M/THF). After 18 hours, a slurry of NaBO3 (2.35 g) and NaHCO3 (2.42 g) in H2O (10 mL) was added and the mixture stirred vigorously for 1 hour. The mixture was extracted with CHCl3, washed with brine, and dried over MgSO4. Following evaporative removal of the solvent, the residue was chromatographed (silica gel, 3% EtOH/EtOAc) to give 2-5 as a clear oil.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH:14]([O:17][CH3:18])[O:15][CH3:16])[CH:9]=2)[CH:5]=[CH:4][N:3]=1.[NH2:19][CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=1>>[CH3:16][O:15][CH:14]([O:17][CH3:18])[C:10]1[CH:9]=[C:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:19][CH2:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=3)[N:7]=2)[CH:13]=[CH:12][CH:11]=1
Reactant: COC(OC)c1cccc(-c2ccnc(Cl)n2)c1
Reactant: NCCc1ccc(O)cc1
Product: COC(OC)c1cccc(-c2ccnc(NCCc3ccc(O)cc3)n2)c1
Yield: 35 %

Procedure:
Intermediate 26 was coupled with tyramine following procedure F. The product was purified by flash chromatography using 99:1 CH2Cl2:MeOH as eluent. Yield: 35%. LC-MS showed the product had the expected M+H+ of 366.
Reaction SMILES: ClCCl.[C:4]([OH:8])(=[O:7])[CH2:5]O.[Cl:9][C:10]1[CH:32]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:30]=[C:29]([F:37])[C:11]=1[O:12][C:13]1[CH:28]=[CH:27][C:16]2[N:17]([CH3:26])[C:18](=[O:25])[C:19]([CH3:24])([C:21]([OH:23])=[O:22])[O:20][C:15]=2[CH:14]=1>C(N(CC)CC)C>[Cl:9][C:10]1[CH:32]=[C:31]([C:33]([F:34])([F:35])[F:36])[CH:30]=[C:29]([F:37])[C:11]=1[O:12][C:13]1[CH:28]=[CH:27][C:16]2[N:17]([CH3:26])[C:18](=[O:25])[C:19]([CH3:24])([C:21]([O:23][CH2:5][C:4]([OH:8])=[O:7])=[O:22])[O:20][C:15]=2[CH:14]=1
Reactant: CN1C(=O)C(C)(C(=O)O)Oc2cc(Oc3c(F)cc(C(F)(F)F)cc3Cl)ccc21
Reactant: O=C(O)CO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN1C(=O)C(C)(C(=O)OCC(=O)O)Oc2cc(Oc3c(F)cc(C(F)(F)F)cc3Cl)ccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a dichloromethane solution (20 ml) of glycolic acid (0.3 g) and triethylamine (1.0 ml) was added an acid chloride (1.5 g) prepared as in Example 6 from 7-(2-chloro-6-fluoro-4-trifluoromethylphenoxy)-2,4-dimethyl-3,4-dihydro-3-oxo-2H-1,4-benzoxazine-2-carboxylic acid (Compound 25), and the mixture was stirred at room temperature for one hour. The reaction mixture was then concentrated under a reduced pressure, the residue was extracted twice with ethyl acetate (20 ml), and the extract was washed with water and then with saturated aqueous sodium chloride, and dried over magnesium sulfate, followed by evaporation of the solvent under a reduced pressure to obtain carboxymethyl 7-(2-chloro-6-fluoro-4-trifluoromethylphenoxy)-2,4-dimethyl-3,4-dihydro-3-oxo-2H-1,4-benzoxazine-2-carboxylate. The acid was dissolved in benzene (20 ml), thionyl chloride (0.9 g) was added thereto, and the mixture was heated under reflux for 3 hours. Then after an evaporation of the solvent under a reduced pressure, the residue was dissolved in dichloromethane (20 ml), ethylamine hydrochloride (0.6 g) and triethylamine (2 ml) were added thereto, and the mixture was stirred for one hour. The reaction mixture was then concentrated under a reduced pressure, and the residue was extracted twice with ethyl acetate (20 ml). The extract was washed with water and then with saturated aqueous sodium chloride, and dried over magnesium sulfate, followed by an evaporation of the solvent under a reduced pressure. The residue was purified by silica gel chromatography (eluant: n-hexane/ethyl acetate=3/1) to give 0.5 g of the title compound (colorless oil).
Reaction SMILES: Cl[C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1.[CH:16]1[CH:21]=[CH:20][C:19]([C@@H:22]([NH2:25])[CH2:23][OH:24])=[CH:18][CH:17]=1.C(Cl)(Cl)Cl>CO>[Cl:15][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[C:2]([NH:25][C@H:22]([C:19]1[CH:20]=[CH:21][CH:16]=[CH:17][CH:18]=1)[CH2:23][OH:24])[C:11]([C:12]([OH:14])=[O:13])=[CH:10]2
Reactant: O=C(O)c1cc2cc(Cl)ccc2nc1Cl
Reactant: N[C@@H](CO)c1ccccc1
Solvent: ClC(Cl)Cl
Solvent: CO
Product: O=C(O)c1cc2cc(Cl)ccc2nc1N[C@@H](CO)c1ccccc1
Yield: 23 %

Procedure:
In close analogy to the procedure described in Example 1, 2,6-dichloroquinoline-3-carboxylic acid is reacted with D-phenylglycinol to provide the title compound in 23% yield as yellow needles (flash chromatography on SiO2, eluent CHCl3, MeOH, AcOH—15, 1, 0.2).
Reaction SMILES: [C:1]([N:4]1[CH:10]2[CH:8]([CH:9]2[CH2:11][O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:7]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)[C:6](=[O:28])[CH2:5]1)(=[O:3])[CH3:2].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].C1COCC1.[C:44](OCC)(=[O:50])[C:45](OCC)=[O:46].Cl>CN(C=O)C>[CH2:13]([O:12][CH2:11][CH:9]1[CH:10]2[CH:8]1[N:7]([CH2:20][C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=1)[C:6](=[O:28])[C:5]1[N:4]2[C:1](=[O:3])[CH:2]=[C:44]([OH:50])[C:45]=1[OH:46])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CC(=O)N1CC(=O)N(Cc2ccc(F)cc2)C2C(COCc3ccccc3)C21
Reactant: CCOC(=O)C(=O)OCC
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: O=C1c2c(O)c(O)cc(=O)n2C2C(COCc3ccccc3)C2N1Cc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a cold (0° C.) solution of 5-acetyl-2-(4-fluorobenzyl)-7-[(benzyloxy)-methyl]-2,5-diazabicyclo[4.1.0]heptane-3-one (700 mg, 1.83 mmol) in DMF (10 mL) under nitrogen, a solution of lithium bis(trimethylsilyl)amide in THF (1.0 M, 2.0 mL, 2.0 mmol) was added. After 30 min, diethyl oxalate (401 mg, 2.74 mmol) in DMF (2 mL) was added. After stirring for 1 h at room temperature, the resultant mixture was treated with additional lithium bis(trimethylsilyl)amide (1.0 M, 7.1 mL, 7.1 mmol), and stirred at room temperature overnight. The reaction mixture was treated with 1 N HCl, concentrated under vacuum. The residue was partitioned between brine and chloroform. The aqueous layer was extracted with chloroform twice. The combined organic phases were dried over sodium sulfate, filtered and concentrated. The residue was subjected to HPLC purification on C-18 stationary phase eluted with water/acetonitrile/TFA mobile phase. Collection and lyophilization of appropriate fractions provided the title compound.
Reaction SMILES: [OH:1][CH2:2][N:3]1[C:7](=[O:8])[C:6]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[NH:5][C:4]1=[O:21].[CH3:22][N:23]([CH3:28])[CH2:24][C:25](O)=[O:26].C1(N=C=NC2CCCCC2)CCCCC1>N1C=CC=CC=1>[CH3:22][N:23]([CH3:28])[CH2:24][C:25]([O:1][CH2:2][N:3]1[C:7](=[O:8])[C:6]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[NH:5][C:4]1=[O:21])=[O:26]
Reactant: O=C1NC(c2ccccc2)(c2ccccc2)C(=O)N1CO
Reactant: CN(C)CC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: c1ccncc1
Product: CN(C)CC(=O)OCN1C(=O)NC(c2ccccc2)(c2ccccc2)C1=O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Into a suitable reaction vessel containing 5 ml of pyridine, there is added one g (0.0035 mols) of 3-hydroxymethyl-diphenylhydantoin, 0.36 g (0.0035 mols) of N,N-dimethylglycine and 0.79 g (0.0035 mols) of dicyclohexylcarbodiimide (DCCI). The reaction mixture is stirred at room temperature for a period of approximately 24 hours, after which the final product, mp 128°-130°, yield 0.86 g (66.7%) is obtained.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:25][C:26]1[S:30][C:29]([C:31]([OH:33])=O)=[CH:28][CH:27]=1.[CH:34]([N:47]1[CH2:50][C:49]2([CH2:55][NH:54][CH2:53][CH2:52][O:51]2)[CH2:48]1)([C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.C(N(CC)CC)C>CN(C=O)C>[CH:34]([N:47]1[CH2:50][C:49]2([CH2:55][N:54]([C:31]([C:29]3[S:30][C:26]([CH3:25])=[CH:27][CH:28]=3)=[O:33])[CH2:53][CH2:52][O:51]2)[CH2:48]1)([C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1)[C:41]1[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=1
Reactant: c1ccc(C(c2ccccc2)N2CC3(CNCCO3)C2)cc1
Reactant: Cc1ccc(C(=O)O)s1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)N2CCOC3(C2)CN(C(c2ccccc2)c2ccccc2)C3)s1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
HATU (2.267 g) was added in one portion to a solution of 5-methylthiophene-2-carboxylic acid (0.652 g) and 2-benzhydryl-5-oxa-2,8-diazaspiro[3.5]nonane (example 33, step f) (1.35 g) and triethylamine (1.917 mL) in DMF (20 mL) at 0° C. The cooling bath was removed and the mixture stirred at room temperature for 2 hours. The mixture was partitioned between ethyl acetate and brine, the organic layer was washed twice with brine before being dried over sodium sulphate, filtered and the solvent removed under reduced pressure. The crude product was purified by flash silica chromatography, elution gradient 0.4 to 5% methanol in dichloromethane. Pure fractions were evaporated to dryness to afford the subtitled compound. Yield 1.5 g.