Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11]([C@@H:13]([OH:21])[CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:12])[CH2:7][CH2:6]1.[H-].[Na+].[CH3:24][CH2:25][CH2:26][CH2:27][C@@H:28](Br)[C:29]([OH:31])=[O:30].N#N>C1COCC1.CC(O)=O.CO>[CH3:1][O:2][CH2:3][O:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11]([C@@H:13]([O:21][C@@H:28]([CH2:27][CH2:26][CH2:25][CH3:24])[C:29]([OH:31])=[O:30])[CH2:14][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)=[O:12])[CH2:7][CH2:6]1
Reactant: CCCC[C@@H](Br)C(=O)O
Reactant: COCOC1CCN(C(=O)[C@@H](O)Cc2ccccc2)CC1
Agent: N#N
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: CO
Product: CCCC[C@H](O[C@@H](Cc1ccccc1)C(=O)N1CCC(OCOC)CC1)C(=O)O
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 43 %

Procedure:
The resultant compound of Example 82(b) (1.45 g, 4.95 mmol), in 10 ml THF was added dropwise to the cooled suspension of sodium hydride (60% dispersion in oil, 0.5 g, 11.2 mmol) in 4 ml THF (0°-5° C.). The suspension was stirred for 20 mins at 0°-5° C. and then warmed up to room temperature and stirred for additional 1 h. Solution of D-2-bromohexanoic acid in 6 ml THF was added dropwise to the cooled suspension (0°-5° C.) at N2 atmosphere. It was then allowed to warm up to room temperature and stirred overnight. Quenched with cold H2O and extracted with ethylacetate to remove undesired starting material. It was acidified with 1M sodium hydrogen sulfate and extracted with chloroform. After filtration and evaporation, the crude product was purified on silica gel, eluted with CH2Cl2 : CH3OH: AcOH (19.4=0.3:0.3) to obtain 0.79 g of desired acid (43% yield).
Reaction SMILES: CC(C)([O-])C.[K+].[CH3:7][S:8]([CH3:11])(=[O:10])=[O:9].[NH2:12][C:13]([CH3:30])([CH3:29])[CH2:14][CH2:15][N:16]1[C:24]2[C:19](=[CH:20][C:21]([C:25](OC)=[O:26])=[CH:22][CH:23]=2)[CH:18]=[CH:17]1.C(O)(C(F)(F)F)=O>CS(C)=O>[NH2:12][C:13]([CH3:30])([CH3:29])[CH2:14][CH2:15][N:16]1[C:24]2[C:19](=[CH:20][C:21]([C:25](=[O:26])[CH2:7][S:8]([CH3:11])(=[O:10])=[O:9])=[CH:22][CH:23]=2)[CH:18]=[CH:17]1
Reactant: COC(=O)c1ccc2c(ccn2CCC(C)(C)N)c1
Reactant: CS(C)(=O)=O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(N)CCn1ccc2cc(C(=O)CS(C)(=O)=O)ccc21
Temperature: 70 °C
Reaction time: 16 h

Procedure:
Potassium tert. butoxide (741 mg, 6.62 mmol) is added in two batches to a solution of dimethylsulphone (661 mg, 7.03 mmol) in 5 ml DMSO. After 10 minutes stirring at RT a solution of methyl 1-(3-amino-3-methyl-butyl)-indole-5-carboxylate (Component IV) (520 mg, 2.00 mmol) in 2 ml DMSO is added dropwise over 10 minutes. The reaction mixture is stirred for 16 hours at 70° C., acidified with TFA while cooling with ice and chromatographed on Microsorb C18-reverse-phase [acetonitrile (0.1% TFA)/water (0.13% TFA)=10:90→100:0]. Then the residue is chromatographed again on silica gel (DCM/methanol/ammonia=90:9:1).
Reaction SMILES: C(O)(C)(C)C.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[CH2:28]([O:35][C@H:36]1[C@H:41]([O:42][CH2:43][C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[C@@H:40]([O:50][CH2:51][C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=2)[C@H:39]([C:58]2[CH:63]=[CH:62][C:61]([Cl:64])=[C:60]([CH2:65][C:66]3[CH:71]=[CH:70][C:69]([CH2:72][CH3:73])=[CH:68][CH:67]=3)[CH:59]=2)[C@@H:38]([OH:74])[C@@H:37]1[CH2:75][O:76][CH2:77][C:78]1[CH:83]=[CH:82][CH:81]=[CH:80][CH:79]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.S([O-])([O-])=O.[Na+].[Na+].C(=O)(O)[O-].[Na+]>ClCCl.C(OCC)(=O)C.[Cl-].[Na+].O>[CH2:28]([O:35][C@H:36]1[C@H:41]([O:42][CH2:43][C:44]2[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=2)[C@@H:40]([O:50][CH2:51][C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=2)[C@H:39]([C:58]2[CH:63]=[CH:62][C:61]([Cl:64])=[C:60]([CH2:65][C:66]3[CH:67]=[CH:68][C:69]([CH2:72][CH3:73])=[CH:70][CH:71]=3)[CH:59]=2)[C:38](=[O:74])[C@@H:37]1[CH2:75][O:76][CH2:77][C:78]1[CH:79]=[CH:80][CH:81]=[CH:82][CH:83]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: CCc1ccc(Cc2cc([C@@H]3[C@@H](O)[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)ccc2Cl)cc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: O=S([O-])[O-]
Solvent: CC(C)(C)O
Solvent: CCOC(C)=O
Solvent: O
Product: CCc1ccc(Cc2cc([C@@H]3C(=O)[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)ccc2Cl)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 52 %

Procedure:
To a solution of tert-butanol (28.2 μL, 296 μMol) in dichloromethane (4 mL) was added Dess-Martin Periodinane [1,1,1-tris(acetyloxy)-1,1-dihydro-1,2-benziodoxol-3-(1H)-one] (116 mg, 274 μMol), and the resulting mixture was stirred under argon at room temperature for 10 minutes. A solution of alcohol 4 (R=Et, mixture of isomers) in dichloromethane (2 mL) was added to the mixture and stirred at room temperature for 3 hours. The mixture was diluted with 4 mL ethyl acetate and stirred vigorously with aqueous 1.5:1:1 saturated sodium sulfite:saturated sodium bicarbonate:brine (3.5 mL) for a period of 1 hour. The phases were separated and the aqueous phase was re-extracted with ethyl acetate (3 mL). The combined organics were washed with brine (2 mL), dried (anhydrous Na2SO4), filtered, and evaporated. Preparative TLC using dichloromethane as the developing solvent afforded 91 mg (52%) of compound 14 as a white solid. 1H NMR (300 MHz, CDCl3) δ 7.35-6.90 (m, 25H), 6.80 (m, 2H), 4.96 (m, 3H), 4.55 (m, 4H), 4.11 (m, 3H), 3.94 (m, 2H), 3.79 (m, 3H), 3.47 (s, 1H), 2.83 (m, 1H), 2.62 (q, J=7.8 Hz, 2H), 1.16 (t, J=7.5 Hz, 3H). LC-ESI-MS m/z 766 (M+H), 788 (M+Na).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([OH:13])=O)[CH:10]=1)[NH:7][CH:6]=[CH:5]2.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)C(C)C)(C)C.[C:45]([C:49]1[CH:67]=[CH:66][C:52]([CH2:53][NH:54][CH2:55][CH:56]([C:58]2[CH:63]=[CH:62][C:61]([Cl:64])=[C:60]([Cl:65])[CH:59]=2)[OH:57])=[CH:51][CH:50]=1)([CH3:48])([CH3:47])[CH3:46]>CN(C=O)C.O>[C:45]([C:49]1[CH:67]=[CH:66][C:52]([CH2:53][N:54]([CH2:55][CH:56]([C:58]2[CH:63]=[CH:62][C:61]([Cl:64])=[C:60]([Cl:65])[CH:59]=2)[OH:57])[C:11]([C:9]2[CH:10]=[C:2]([Cl:1])[CH:3]=[C:4]3[C:8]=2[NH:7][CH:6]=[CH:5]3)=[O:13])=[CH:51][CH:50]=1)([CH3:48])([CH3:46])[CH3:47]
Reactant: CC(C)(C)c1ccc(CNCC(O)c2ccc(Cl)c(Cl)c2)cc1
Reactant: O=C(O)c1cc(Cl)cc2cc[nH]c12
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CC(C)(C)c1ccc(CN(CC(O)c2ccc(Cl)c(Cl)c2)C(=O)c2cc(Cl)cc3cc[nH]c23)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 44.8 %

Procedure:
To a solution of 31 mg (0.16 mmol) of 5-chloro-1H-indole-7-carboxylic acid and 51 mg of TBTU (0.16 mmol) in 2 ml DMF, were added 0.14 ml (0.79 mmol) of N,N-diisopropyl-ethyl amine. After stirring for 5 min at rt, 81 mg (0.16 mmol) of [rac]-(4-tert-butyl-benzyl)-[2-(3,4-dichloro-phenyl)-2-hydroxy-ethyl]-amine were added. After stirring for 17 h at rt, the reaction mixture was diluted with 20 ml water and extracted with EtOAc (2×). The combined organic phases were washed with water and brine, dried with magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (8 g silica gel; heptane/EtOAc 2:1) to give 38 mg (44%) of a light yellow foam. MS: 528 (M).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:5]=1[OH:13])([CH3:3])[CH3:2].[C:14]([O-])([O-])=O.[K+].[K+].IC>CC(C)=O>[CH:1]([C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:5]=1[O:13][CH3:14])([CH3:3])[CH3:2]
Reactant: O=C([O-])[O-]
Reactant: CC(C)c1cc([N+](=O)[O-])ccc1O
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: COc1ccc([N+](=O)[O-])cc1C(C)C
Temperature: 25 °C
Reaction time: 17 h
Yield: 89.3 %

Procedure:
2-Isopropyl-4-nitrophenol (4.7 g, 26 mmol) was dissolved in 100 mL of acetone, and 5.4 g (39 mmol) of K2CO3 was added, followed by 14.8 g (6.5 mL, 104 mmol) of iodomethane. The reaction flask was capped and the mixture was stirred at room temperature for 17 hours. The mixture was concentrated under reduced pressure, diluted with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried (MgSO4), filtered and concentrated under reduced pressure to afford 4.53 g of 3-isopropyl-4-methoxynitrobenzene.
Reaction SMILES: [C:1]([CH:4]1[CH2:8][CH2:7][CH2:6][C:5]1=O)(=O)[CH3:2].[NH2:10][C:11]1[NH:15][N:14]=[C:13]([CH2:16][OH:17])[N:12]=1>COCCO>[CH3:2][C:1]1[N:15]2[N:14]=[C:13]([CH2:16][OH:17])[N:12]=[C:11]2[N:10]=[C:5]2[CH2:6][CH2:7][CH2:8][C:4]=12
Reactant: CC(=O)C1CCCC1=O
Reactant: Nc1nc(CO)n[nH]1
Solvent: COCCO
Product: Cc1c2c(nc3nc(CO)nn13)CCC2
Temperature: 23 °C
Yield: 32.7 %

Procedure:
To a round bottomed flask was loaded 3.78 grams of 2-acetylcyclopentanone, 3.52 grams of (5-Amino-1H-[1,2,4]triazol-3-yl)-methanol and 50 ml 2-methoxyethanol. The mixture was refluxed for 18 hours. Then it was cooled down to 23° C. and concentrated to 5 ml. Then 50 ml ethyl ether was added and the precipitate was filtered and vacuum dried to yielded 2.0 grams of product. This compound was used directly for the next step. MS: 205.2 (M+H). H-NMR (DMSO): δ 5.55 (t, 1H, OH, J=6.2 Hz), 4.63 (d, 2H, J=6.2 Hz), 3.28 (m, 2H), 3.02 (t, 2H, CH2, J=6.8 Hz), 2.51 (s, 3H, CH3), 2.27 (m, 2H, CH2).
Reaction SMILES: [CH3:1][NH:2][C:3]1[N:8]=[C:7]([C:9]2[S:10][C:11]3[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=3[C:13](=[O:15])[N:14]=2)[CH:6]=[CH:5][CH:4]=1.[S:20]1[CH:24]=[CH:23][CH:22]=[C:21]1[C:25](Cl)=[O:26].CN(C)C(=O)C>O>[CH3:1][N:2]([C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([C:9]2[S:10][C:11]3[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=3[C:13](=[O:15])[N:14]=2)[N:8]=1)[C:25]([C:21]1[S:20][CH:24]=[CH:23][CH:22]=1)=[O:26]
Reactant: CNc1cccc(-c2nc(=O)c3ccccc3s2)n1
Reactant: O=C(Cl)c1cccs1
Solvent: CC(=O)N(C)C
Solvent: O
Product: CN(C(=O)c1cccs1)c1cccc(-c2nc(=O)c3ccccc3s2)n1
Temperature: 80 °C
Reaction time: 2 h
Yield: 81.9 %

Procedure:
A mixture of 2-(6-methylamino-2-pyridyl)-4H-1,3-benzothiazine-4-one (0.20 g, 0.74 mmol), 2-thiophenecarbonyl chloride (0.28 g, 1.9 mmol) and N,N-dimethylacetamide (10 ml) was stirred at 80° C. for 2 hrs. After cooling, the reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed successively with saturated aqueous sodium hydrogen carbonate solution and brine and dried. The solvent was evaporated. The residue was recrystallized from tetrahydrofuran-hexane to give the titled compound (0.23 g, 83%)
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][O:14][C:15]1[CH:16]=[C:17]([CH2:21][C:22]([OH:24])=[O:23])[CH:18]=[CH:19][CH:20]=1)=[O:7])([CH3:4])(C)C.CCOCC.C([O-])(O)=O.[Na+].C(Cl)(OCC1[C:51]2[C:46](=[CH:47][CH:48]=[CH:49][CH:50]=2)[C:45]2[C:40]1=[CH:41][CH:42]=[CH:43][CH:44]=2)=O>C(Cl)Cl.C(O)(C(F)(F)F)=O.O.O1CCOCC1>[C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][O:14][C:15]1[CH:16]=[C:17]([CH2:21][C:22]([OH:24])=[O:23])[CH:18]=[CH:19][CH:20]=1)([O:5][CH2:1][CH:4]1[C:44]2[C:45](=[CH:40][CH:41]=[CH:42][CH:43]=2)[C:46]2[C:51]1=[CH:50][CH:49]=[CH:48][CH:47]=2)=[O:7]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1COc1cccc(CC(=O)O)c1
Reactant: O=C(Cl)OCC1c2ccccc2-c2ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)Cc1cccc(OC[C@@H]2CCCN2C(=O)OCC2c3ccccc3-c3ccccc32)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 81 %

Procedure:
A mixture of the above (S)-3-(1-tert-butoxycarbonyl-2-pyrrolidinyl) methoxyphenyl acetic acid in CH2Cl2 (10 mL) and TFA (10 mL) was stirred for 1 hr at room temp. Et2O was added to the mixture and allowed to stand. Upper layer was removed by decantation to give an oil. A mixture of this oil in water (100 mL), dioxane (30 mL) and NaHCO3 (6.0 g) was added Fmoc-Cl (2.86 g, 11.1 mmol) and the mixture was stirred for 20 hr at room temp. The mixture was extracted with Et2O (×2), and the aqueous layer was acidified by the addition of 1 N HCl. The mixture was extracted with EtOAc. The extract was washed with water, brine, dried over MgSO4 and concentrated in vacuo to afford 5.08 g (81%) (S)-3-(1-Fmoc-2-pyrrolidinyl)methoxyphenylacetic acid as a viscous oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14](C(OCC2C=CC=CC=2)=O)[CH3:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([NH:14][CH3:15])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(C(=O)OCc1ccccc1)C1CCN(C(=O)OC(C)(C)C)CC1
Agent: [Pd]
Solvent: CO
Product: CNC1CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 2 h
Yield: 102657.6 %

Procedure:
To a solution of 4-(benzyloxycarbonyl-methyl-amino)-piperidine-1-carboxylic acid tert-butyl ester (5 g, 0.014 mmol) in MeOH (30 ml) was added under an inert atmosphere 10% Pd/C (500 mg). H2 was bubbled through the resulting suspension for 2 hrs. The reaction mixture was then stirred under 1 atm. of H2 for 2 hrs. Pd/C was filtered off and the solvent was removed under reduced pressure to give the expected 4-methylamino-piperidine-1-carboxylic acid tert-butyl ester (3.08 g, quant.).
Reaction SMILES: C([Mg]Br)C.[Mg].C(Br)C.[O:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH:10]1[O:15][C@@H:16]([CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[C:17]#[CH:18].[CH:24](OCC)([O:28][CH2:29][CH3:30])[O:25][CH2:26][CH3:27].[Cl-].[NH4+]>CCOCC>[CH2:26]([O:25][CH:24]([O:28][CH2:29][CH3:30])[C:18]#[C:17][C@@H:16]([O:15][CH:10]1[CH2:11][CH2:12][CH2:13][CH2:14][O:9]1)[CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH3:27]
Reactant: CCOC(OCC)OCC
Reactant: C#C[C@H](CCCCC)OC1CCCCO1
Agent: CC[Mg]Br
Agent: [Cl-]
Agent: [Mg]
Solvent: CCOCC
Solvent: CCBr
Product: CCCCC[C@@H](C#CC(OCC)OCC)OC1CCCCO1
Reaction time: 1 h

Procedure:
A solution of ethylmagnesium bromide in 400 ml. of ether is prepared in the usual manner from magnesium (12.2 g., 0.5 mole) and ethyl bromide (56.5 g., 0.52 mole). To this solution, (3S)-3-(2-tetrahydropyranyloxy)-1-octyne (88.2 g., 0.42 mole) is added dropwise with stirring during one hour. The reaction mixture is stirred an additional 45 minutes, and there is added triethyl orthoformate (81.4 g., 0.55 mole) dropwise during 30 minutes. The mixture is then refluxed 16 hours. It is poured into 500 ml. of iced saturated ammonium chloride solution. The oily product is taken up in ether, washed with water, dried over sodium sulfate and distilled to obtain (4S)-1,1-diethoxy-4-(2-tetrahydropyranyloxy)-2-nonyne.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:11][CH3:12])(=[O:10])=[O:9])=[CH:4][C:3]=1[N+:13]([O-:15])=[O:14].Cl.[F:17][C:18]([F:24])([F:23])[O:19][CH2:20][CH2:21][NH2:22]>C(N(CC)CC)C>[CH2:11]([S:8]([C:5]1[CH:6]=[CH:7][C:2]([NH:22][CH2:21][CH2:20][O:19][C:18]([F:24])([F:23])[F:17])=[C:3]([N+:13]([O-:15])=[O:14])[CH:4]=1)(=[O:10])=[O:9])[CH3:12]
Reactant: CCS(=O)(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: NCCOC(F)(F)F
Agent: Cl
Solvent: CCN(CC)CC
Product: CCS(=O)(=O)c1ccc(NCCOC(F)(F)F)c([N+](=O)[O-])c1

Procedure:
The title compound was prepared according to the procedure described in Step A of Example 5 from 1-chloro-4-(ethylsulfonyl)-2-nitrobenzene (Step C of Example 2), 2-(trifluoromethoxy)ethanamine hydrochloride (J. Org. Chem. 2001, 66, 1061-1063.) and triethylamine.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:8]#[N:9])=[N:4][CH:5]=[CH:6][N:7]=1.[CH3:10][C:11]1[CH:21]=[CH:20][C:14]([O:15][CH2:16][C:17](N)=[NH:18])=[CH:13][CH:12]=1.CC(C)=O.C(O)C>C(O)C>[NH2:9][C:8]1[C:3]2[C:2](=[N:7][CH:6]=[CH:5][N:4]=2)[N:1]=[C:17]([CH2:16][O:15][C:14]2[CH:20]=[CH:21][C:11]([CH3:10])=[CH:12][CH:13]=2)[N:18]=1
Reactant: Cc1ccc(OCC(=N)N)cc1
Reactant: N#Cc1nccnc1N
Solvent: CCO
Solvent: CC(C)=O
Product: Cc1ccc(OCc2nc(N)c3nccnc3n2)cc1

Procedure:
Obtained using the procedure described in section c of Example 2, starting with 6.9 g (0.057 mole) of 3-amino-2-pyrazinecarbonitrile and 14.1 g (0.086 mole) of 2-(4-methylphenoxy)acetamidine [prepared according to C. Djerassi and C. R. Scholz, U.S. Pat. No. 2,517,468; C.A. 1951, 45, 661f] in 350 ml of absolute ethanol. Refluxing time: 2 hours. Yld: 2.6 g (17%), m.p. 225°-227° C. (acetone/ethanol).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[CH:4][CH:3]=1.O1CCCC1.C(=O)([O-])[O-].[Na+].[Na+].[F:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1B(O)O>O>[F:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[CH:4][CH:3]=1
Reactant: COC(=O)Cc1ccc(Br)cc1
Reactant: OB(O)c1ccccc1F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)Cc1ccc(-c2ccccc2F)cc1

Procedure:
47.6 g (0.21 mol) of methyl 4-bromophenylacetate are introduced under argon into 400 ml of absolute tetrahydrofuran and, at room temperature, 320 ml of 1M sodium carbonate solution and 40 g (0.28 mol) of 2-fluorophenylboronic acid are added. Addition of 7.0 g (0.01 mol) of bis(triphenylphosphane)palladium(II) chloride is followed by heating under reflux for 18 h. Cooling is followed by dilution with 500 ml of water and extracted three times with 300 ml of ethyl acetate each time. The combined organic phases are washed with 400 ml each of saturated ammonium chloride solution, water and saturated sodium chloride solution, dried over magnesium sulfate and freed of solvent in vacuo. Example V is obtained after silica gel filtration (petroleum ether/ethyl acetate 10:1) as a colorless oil.
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[OH:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:17]2[C:22]=1[CH:21]=[CH:20][NH:19][CH:18]=2.C(N(CC)CC)C>C(Cl)Cl>[CH:18]1[C:17]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12](=[O:11])[C:22]=2[CH:21]=[CH:20][N:19]=1
Reactant: OC1=C2C=CNC=C2C=CC=C1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CS(C)=O
Product: O=c1ccccc2cnccc12
Temperature: -70 °C
Reaction time: 0.17 h
Yield: 93.9 %

Procedure:
Dimethylsulfoxide (9.37 g, 0.12 mole) was added dropwise to a stirred solution of oxalyl chloride (7.61 g, 0.060 mole) in methylene chloride (120 ml) maintained at betweeen -70° C. to -60° C. The mixture was stirred for 10 minutes at -70° C., then a solution of 5-hydroxycyclohepta[ 1,2-c]pyridine (10.00 g, 0.061 mole) and additional dimethylsulfoxide (12 ml) in methylene chloride (~115 ml) was added rapidly (~10 minutes) while maintaining the temperature of the reaction mixture at -70° C. After stirring for an additional 30 minutes at -75° C. to 60° C., a solid precipitate was present. Triethylamine (37.026 g, 0.366 mole) was added rapidly at -70° C. and the resulting yellow reaction mixture was stirred at -70° C. for ~10 minutes, then allowed to warm to room temperature. After about 48 hours at room temperature the reaction mixture was quenched with water (600 ml), the organic phase separated, then extracted with water (2X, 500 ml), aqueous sodium bicarbonate (5%, 2X, 500 ml), and brine. After drying, the organic layer was filtered through celite and concentrated by solvent evaporation to give 9.00 g of a brown oil. Distillation (90°-120° C., 0.03 mm) gave the desired product as a yellow liquid (07.41 g, 75%). The analytical sample was prepared by chromatography of ~0.1 g on a 20×20 cm preparative tlc plate eluting with a mixture of 35% ethanol - 65% methylene chloride.
Reaction SMILES: [C:1]([NH:8][CH2:9][C:10]([OH:12])=O)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[Br:13][C:14]1[CH:15]=[C:16]([CH:20]=[CH:21][CH:22]=1)[CH2:17][CH2:18][NH2:19].C(=O)([O-])O.[Na+].C(OCC)(=O)C>O1CCCC1.CN1CCOCC1.ClC(OCC(C)C)=O>[Br:13][C:14]1[CH:15]=[C:16]([CH:20]=[CH:21][CH:22]=1)[CH2:17][CH2:18][NH:19][C:10](=[O:12])[CH2:9][NH:8][C:1](=[O:2])[O:3][C:4]([CH3:5])([CH3:6])[CH3:7]
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: NCCc1cccc(Br)c1
Agent: CC(C)COC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NCC(=O)NCCc1cccc(Br)c1
Reaction time: 0.67 h

Procedure:
To a solution of N-Boc-glycine (175 mg) in tetrahydrofuran (1 mL), N-methylmorpholine (165 μL) and isobutyl chloroformate (131 μL) were added under ice cooling, and the mixture was stirred at the same temperature for 40 minutes. To the reaction mixture, 3-bromophenethylamine (100 μL) was added under ice cooling, and the mixture was stirred at room temperature for 5 hours. To the reaction mixture, saturated aqueous sodium hydrogencarbonate and ethyl acetate were added. The organic layer was separated, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to obtain tert-butyl (2-((3-bromophenethyl)amino)-2-oxoethyl)carbamate (R1, 290 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH2:11])[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.[C:12](OC(=O)C)(=[O:14])[CH3:13]>C1(C)C=CC=CC=1>[CH3:10][O:9][C:7]1[CH:6]=[C:5]([NH:11][C:12](=[O:14])[CH3:13])[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=1
Reactant: COc1cc(N)cc(OC)c1
Reactant: CC(=O)OC(C)=O
Solvent: Cc1ccccc1
Product: COc1cc(NC(C)=O)cc(OC)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 90486 %

Procedure:
To a solution of 3,5-dimethoxy-phenylamine (20 g, 0.131 mol) in toluene (110 mL) was added acetic anhydride (14 g, 0.137 mmol) at room temperature. The resulting mixture was stirred for 18 hours at room temperature. PE (55 mL) was added, the precipitate was filtered and washed with PE (100 mL) to obtain the title compound (24.2 g, yield: 95%). 1H-NMR (400 MHz, CDCl3) δ 2.16 (s, 3H), 3.77 (s, 6H), 6.23 (s, 1H), 6.75 (s, 2H), 7.20 (s, 1H).
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:18][CH:19]([C:24](=O)[CH3:25])[C:20](OC)=[O:21])=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.Cl.[CH:28]([NH:31][NH2:32])([CH3:30])[CH3:29]>Cl.C(O)C.CC(O)C.O>[CH:28]([N:31]1[C:20](=[O:21])[C:19]([NH:18][C:16](=[O:17])[O:15][CH2:14][CH:12]2[C:11]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=3[C:5]3[C:13]2=[CH:1][CH:2]=[CH:3][CH:4]=3)=[C:24]([CH3:25])[NH:32]1)([CH3:30])[CH3:29]
Reactant: COC(=O)C(NC(=O)OCC1c2ccccc2-c2ccccc21)C(C)=O
Reactant: CC(C)NN
Agent: Cl
Solvent: CCO
Solvent: O
Solvent: CC(C)O
Product: Cc1[nH]n(C(C)C)c(=O)c1NC(=O)OCC1c2ccccc2-c2ccccc21
Temperature: 25 °C

Procedure:
To a solution of methyl 2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-oxobutanoate (2.766 g, 7.83 mmol) in 1.25M HCl in ethanol (25 mL) was added isopropylhydrazine hydrochloride (1.298 g, 11.74 mmol). The reaction mixture was stirred at reflux. Upon completion the reaction mixture was cooled to room temperature and the solvent was removed under reduced pressure. The crude material was adsorbed onto silica and purification by chromatography using a gradient of 0-100% EtOAc in iso-hexane and 10% MeOH in EtOAc afforded crude material. The crude material was dissolved in IPA to which water was added to give a cloudy mixture that was sonicated and left to stand at room temperature. The resulting suspension was filtered and the solid dried under reduced pressure to afford the title compound;
Reaction SMILES: [CH3:1][C:2]1[NH:7][C:6](=[O:8])[NH:5][C:4](=[O:9])[CH:3]=1.Cl[CH2:11][CH2:12][CH2:13][C:14]([O:16][CH3:17])=[O:15]>CN(C)C=O>[CH3:17][O:16][C:14]([CH2:13][CH2:12][CH2:11][N:7]1[C:2]([CH3:1])=[CH:3][C:4](=[O:9])[N:5]([CH2:11][CH2:12][CH2:13][C:14]([O:16][CH3:17])=[O:15])[C:6]1=[O:8])=[O:15]
Reactant: Cc1cc(=O)[nH]c(=O)[nH]1
Reactant: COC(=O)CCCCl
Solvent: CN(C)C=O
Product: COC(=O)CCCn1c(C)cc(=O)n(CCCC(=O)OC)c1=O

Procedure:
40.4 g (0.2 mol) of the dipotassium salt of 6-methyluracil and 57.4 g (0.42 mol) of methyl 4-chlorobutyrate are stirred in 350 ml of dimethylformamide for 10 hours at 125° C. The mixture is filtered and the clear solution is concentrated to dryness, 48.2 g of the desired crude product being obtained as a yellowish semi-solid mass (73.8% of theory).