Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24](/[C:26](=[N:71]/[O:72][C:73]([C:86]2[CH:91]=[CH:90][CH:89]=[CH:88][CH:87]=2)([C:80]2[CH:85]=[CH:84][CH:83]=[CH:82][CH:81]=2)[C:74]2[CH:79]=[CH:78][CH:77]=[CH:76][CH:75]=2)/[C:27]([NH:29][C@@H:30]2[C:69](=[O:70])[N:32]3[C:33]([C:57]([O:59][CH2:60][C:61]4[CH:66]=[CH:65][C:64]([O:67][CH3:68])=[CH:63][CH:62]=4)=[O:58])=[C:34]([CH:37]=P(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[CH2:35][S:36][C@H:31]23)=[O:28])[N:25]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:92]1([CH:95]=O)[CH2:94][CH2:93]1>ClCCl>[C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24](/[C:26](=[N:71]/[O:72][C:73]([C:80]2[CH:81]=[CH:82][CH:83]=[CH:84][CH:85]=2)([C:74]2[CH:75]=[CH:76][CH:77]=[CH:78][CH:79]=2)[C:86]2[CH:87]=[CH:88][CH:89]=[CH:90][CH:91]=2)/[C:27]([NH:29][C@@H:30]2[C:69](=[O:70])[N:32]3[C:33]([C:57]([O:59][CH2:60][C:61]4[CH:62]=[CH:63][C:64]([O:67][CH3:68])=[CH:65][CH:66]=4)=[O:58])=[C:34](/[CH:37]=[CH:95]\[CH:92]4[CH2:93][CH2:94]4)[CH2:35][S:36][C@H:31]23)=[O:28])[N:25]=1)([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: COc1ccc(COC(=O)C2=C(C=P(c3ccccc3)(c3ccccc3)c3ccccc3)CS[C@@H]3[C@H](NC(=O)/C(=N\OC(c4ccccc4)(c4ccccc4)c4ccccc4)c4csc(NC(c5ccccc5)(c5ccccc5)c5ccccc5)n4)C(=O)N23)cc1
Reactant: O=CC1CC1
Solvent: ClCCl
Product: COc1ccc(COC(=O)C2=C(/C=C\C3CC3)CS[C@@H]3[C@H](NC(=O)/C(=N\OC(c4ccccc4)(c4ccccc4)c4ccccc4)c4csc(NC(c5ccccc5)(c5ccccc5)c5ccccc5)n4)C(=O)N23)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
4-Methoxyphenylmethyl 7β-[(Z)-2-(2-tritylaminothiazol-4-yl)-2-trityloxyiminoacetamido]-3-(triphenylphosphoranyliden)methyl-3-cephem-4-carboxylate (8.2 g) and cyclopropanecarboxaldehyde (5 ml) were dissolved in dichloromethane (40 ml), followed by stirring at room temperature for 16 hours. After the solvent was distilled off under reduced pressure, the residue was purified by chromatography on a silica gel column whereby the title compound (1.1 g) was obtained.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][NH2:9])=[CH:4][C:3]=1[O:10][CH3:11].CO[CH:14]([CH3:22])[C:15](OC)(OC)OC>C(O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:22]=[CH:14][CH:15]=[N:9]2)=[CH:4][C:3]=1[O:10][CH3:11]
Reactant: COC(C)C(OC)(OC)OC
Reactant: COc1cc(NN)ccc1Br
Solvent: CCO
Product: COc1cc(-n2cccn2)ccc1Br
Temperature: 70 °C
Reaction time: 1.5 h
Yield: 48.4 %

Procedure:
To a solution of (4-bromo-3-methoxyphenyl)hydrazine (62 g, 245 mmol) in ethanol (310 mL) was added tetramethoxypropane (40.2 g, 245 mmol) over a few minutes, and the mixture was heated to an internal temperature of 70° C. The mixture was stirred at 70° C. for 1.5 h then slowly cooled to RT. Ethanol was removed in vacuo and the residue was slurried in EtOAc. The residue was neutralized with 1M aqueous sodium hydroxide (˜700 mL) to cause precipitation. The biphasic mixture was filtered and the filtrate was extracted with EtOAc, dried over sodium sulfate and concentrated to provide 30 g of 1-(4-bromo-3-methoxyphenyl)-1H-pyrazole as a black solid (30 g, MS: 254 [M+H+].).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1.[CH3:11][C:12]1[N:13]=[CH:14][NH:15][CH:16]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:11][C:12]1[N:13]=[CH:14][N:15]([C:2]2[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=2)[CH:16]=1
Reactant: Cc1c[nH]cn1
Reactant: CC(=O)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)c1ccc(-n2cnc(C)c2)cc1
Temperature: 150 °C
Yield: 20 %

Procedure:
A mixture of 4'-fluoroacetophenone (13.8 g, 100 mmol), 4-methylimidazole (8.2 g, 100 ml) and potassium carbonate (20.7 g, 150 mmol) in dry dimethylformamide (190 ml) was heated at 150° C. for 23 hours. Most of the solvent was evaporated at reduced pressure and the residue was partitioned between ethyl acetate and brine. The organic layer was washed (3×) with brine, dried (magnesium sulphate) and evaporated to leave a sticky solid which was purified by flash chromatography (eluting 5% diethylamine in ethylacetate). Recrystallization from ethyl acetate/hexane afforded the title compound (yield 4 g, 20%), m.p. 100° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH2:9][CH2:8][CH:7]([N:15]([CH3:17])[CH3:16])[CH2:6][C:5]2=1.[CH:18]1([C:23](O)=[O:24])[CH2:22][CH2:21][CH2:20][CH2:19]1>>[CH:18]1([C:23]([NH:1][C:2]2[CH:3]=[C:4]3[C:12](=[CH:13][CH:14]=2)[NH:11][C:10]2[CH2:9][CH2:8][CH:7]([N:15]([CH3:17])[CH3:16])[CH2:6][C:5]3=2)=[O:24])[CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: CN(C)C1CCc2[nH]c3ccc(N)cc3c2C1
Reactant: O=C(O)C1CCCC1
Product: CN(C)C1CCc2[nH]c3ccc(NC(=O)C4CCCC4)cc3c2C1
Yield: 57.6 %

Procedure:
Beginning with 9.2 mg (0.040 mMol) 6-amino-3-(dimethyl)amino-1,2,3,4-tetrahydro-9H-carbazole and 11.6 mg (0.101 mMol) cyclopentanecarboxylic acid, 7.5 mg (53%) of the title compound were recovered as a light beige solid.
Reaction SMILES: CS([C:5]1[N:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:7][N:6]=1)(=O)=O.[CH:19]1([NH2:24])[CH2:23][CH2:22][CH2:21][CH2:20]1.CCN(CC)CC>C1COCC1>[CH:19]1([NH:24][C:5]2[N:10]=[CH:9][C:8]([C:11]#[C:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:7][N:6]=2)[CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: NC1CCCC1
Reactant: CS(=O)(=O)c1ncc(C#Cc2ccccc2)cn1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C(#Cc1cnc(NC2CCCC2)nc1)c1ccccc1
Temperature: 65 °C
Reaction time: 1 h

Procedure:
2-Methanesulfonyl-5-phenylethynyl-pyrimidine (100 mg, 3.11 mmol), cyclopentylamine (80 μl, 6.22 mmol) and Et3N (110 μl, 6.22 mmol) were suspended in 1 ml THF and stirred for 1 hour at 65° C. The reaction mixture was concentrated in vacuo and the residue was purified by flash chromatography by directly loading the crude material onto a silica gel column and eluting with (heptane:ethyl acetate 100:0→0:100). The desired compound was obtained as a white solid (85 mg, 83%), MS: m/e=264.2 (M+H+).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[C:4]([N+:11]([O-:13])=[O:12])[C:3]=1[N:14]=[N:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]([CH2:25][CH3:26])[CH2:23][CH3:24])=[CH:18][C:17]=1[NH:27][C:28](=[O:30])[CH3:29].C([O-])(=O)C.[Na+].[CH:36]([NH2:38])=O.C(OC(=O)C)(=O)C>[Cu](Cl)Cl.C(OCCCC)(=O)C>[C:36]([C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[C:4]([N+:11]([O-:13])=[O:12])[C:3]=1[N:14]=[N:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]([CH2:25][CH3:26])[CH2:23][CH3:24])=[CH:18][C:17]=1[NH:27][C:28](=[O:30])[CH3:29])#[N:38]
Reactant: NC=O
Reactant: CCN(CC)c1ccc(N=Nc2c(Br)cc([N+](=O)[O-])cc2[N+](=O)[O-])c(NC(C)=O)c1
Agent: Cl[Cu]Cl
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Solvent: CCCCOC(C)=O
Product: CCN(CC)c1ccc(N=Nc2c(C#N)cc([N+](=O)[O-])cc2[N+](=O)[O-])c(NC(C)=O)c1
Temperature: 110 °C
Reaction time: 0.25 h
Yield: 96 %

Procedure:
2-Bromo-4,6-dinitro-2'-acetylamino-4'-(N,N-diethylamino)azobenzene (2.4 parts), copper (II) chloride (0.67 parts), anhydrous sodium acetate (1.2 parts), formamide (1.8 parts), acetic anhydride (2.0 parts) and n-butyl acetate (44 parts) are mixed together and heated, with stirring, to 110° C. during 15 minutes. The temperature is maintained for 5 hours after which time the reaction is complete. The mixture is cooled to room temperature and poured into petroleum-ether (boiling range 60-80°) (400 parts). The precipitate is collected, washed with petroleum-ether (100 parts) and dried. 2-Cyano-4,6-dinitro-2'-acetylamino-4'-(N,N-diethylamino)azobenzene is obtained in 96% yield.
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([O:10][CH2:11][CH:12]([OH:22])[CH2:13][O:14][C:15]1[CH:21]=[CH:20][C:18]([NH2:19])=[CH:17][CH:16]=1)[CH3:9].[CH3:23][S:24][CH2:25][CH2:26][C:27](Cl)=[O:28]>CN(C)C=O>[CH3:23][S:24][CH2:25][CH2:26][C:27](=[O:28])[NH:19][C:18]1[CH:17]=[CH:16][C:15]([O:14][CH2:13][CH:12]([OH:22])[CH2:11][O:10][CH2:8][CH3:9])=[CH:21][CH:20]=1
Reactant: CCOCC(O)COc1ccc(N)cc1
Reactant: CSCCC(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOCC(O)COc1ccc(NC(=O)CCSC)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Dissolved in 4 ml of dimethylformamide were 1.46 g of triethylamine and 1.52 g of 4-(3-ethoxy-2-hydroxypropoxy)aniline. A 1.10 g quantity of 3-methylmercaptopropionyl chloride was added to the solution with ice-cooling. The mixture was stirred at room temperature for 12 hours and the reaction mixture was concentrated. The residue was extracted with chloroform and the chloroform layer was washed successively with 1N hydrochloric acid, a saturated aqueous solution of sodium hydrogencarbonate and water and concentrated. Ether was added to the residue and the crystals formed were filtered off to give 1.52 g of 2-{4-(3-ethoxy-2-hydroxypropoxy)phenylcarbamoyl}ethyl methyl sulfide in 67.4%, M.P. 79° to 81° C.
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.OS(O)(=O)=O.[OH-].[Na+].CC[O:18][CH2:19][CH3:20]>>[CH:2]1([C@@H:19]([OH:18])[CH2:20][NH:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: NCc1ccccc1
Reactant: CCOCC
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: O[C@@H](CNCc1ccccc1)C1CCCCC1
Yield: 74 %

Procedure:
Following removal of the solvent under reduced pressure, the β-aminosulfate from the reaction of 1-(R)-cyclohexyl-1,2-cyclic sulfate (0.206 g, 1 mmol) and benzylamine (0.214 g, 2 mmol) was stirred with 20% H2SO4 (5 mL) and ether (5 mL) at room temperature (refluxing of the two phase mixture expedites the hydrolysis) for 12 hours. The organic phase was discarded and the aqueous phase was adjusted to pH 10 with 20% aq. NaOH and extracted with ether (3×20 mL). The combined organic phases were washed with brine (20 mL) and dried over Na2SO4. Concentration gave 1(R)-cyclohexyl-2-benzylaminoethanol (0.117 g, 74%), mp. 56°-58° C., [α]22D=-1.2° (c 1, CHCI3 ; 1H NMR (CDCI3) δ 7.3 (S, 5 H), 3.75 (d, J 5.77 Hz, 2 H), 3.35 (m, 1 H), 2.75 (dd, J=2.5, 9.6 Hz, 2 H), 2.5 (dd, J 9.6, 13 Hz, 1 H), 1.9-1.5 (m, 5 H), 1.3-0.9 (m, 7 H).
Reaction SMILES: C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOC(/N=N/C(OCC)=O)=O.[C:32]([N:39]1[CH2:42][CH:41]([OH:43])[CH2:40]1)([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33].O[C:45]1[CH:46]=[N:47][CH:48]=[CH:49][CH:50]=1>C1COCC1>[C:35]([O:34][C:32]([N:39]1[CH2:42][CH:41]([O:43][C:45]2[CH:46]=[N:47][CH:48]=[CH:49][CH:50]=2)[CH2:40]1)=[O:33])([CH3:38])([CH3:37])[CH3:36]
Reactant: CC(C)(C)OC(=O)N1CC(O)C1
Reactant: Oc1cccnc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC(Oc2cccnc2)C1
Temperature: -20 °C
Reaction time: 0.17 h
Yield: 63.9 %

Procedure:
To 315 mg (1.2 mmol) of PPh3 in 5 mL of dry THF at −20° C. was added 189 μL (1.2 mmol) of DEAD dropwise. The solution was allowed to stir 10 min. at −20° C. After 10 min, a solution containing 173 mg (1 mmol) of N-Boc-3-hydroxyazetidine and 2 mL of dry THF was added dropwise. The solution was again allowed to stir 10 min at −20° C. After 10 min, to the solution was added 95 mg (1 mmol) of 3-hydroxypyridine at once. The solution was then slowly heated to 70° C. and allowed to stir at 70° C. overnight. Next day, solvent was removed under reduced pressure. The crude product was purified by flash chromatography (2:1, Hexane:Ethyl Acetate) to obtain 160 mg (64% yield) of a yellow oil: 1H NMR (300 MHz, CD3OD) δ 8.27 (1H, d, J=4.8 Hz), 8.18 (1H, d, J=2.7 Hz), 7.23 (1H, m), 7.05 (1H, m), 4.92 (1H, m), 4.34-4.00 (2H, AB, J=6.6, 9.7 Hz), 1.45 (9H, s).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=O)[CH:5]=[C:6]([F:8])[CH:7]=1.Cl.[NH2:14][C@H:15]([C:17]([C:19]1([NH2:44])[C:25](=[O:26])[N:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:23]2[CH:33]=[CH:34][CH:35]=[CH:36][C:22]=2[N:21]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[C:20]1=[O:43])=[O:18])[CH3:16]>>[F:8][C:6]1[CH:5]=[C:4]([CH2:9][C:10]([NH:14][C@H:15]([C:17]([C:19]2([NH2:44])[C:25](=[O:26])[N:24]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:23]3[CH:33]=[CH:34][CH:35]=[CH:36][C:22]=3[N:21]([C:37]3[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=3)[C:20]2=[O:43])=[O:18])[CH3:16])=[O:12])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: O=C(O)Cc1cc(F)cc(F)c1
Reactant: C[C@H](N)C(=O)C1(N)C(=O)N(c2ccccc2)c2ccccc2N(c2ccccc2)C1=O
Agent: Cl
Product: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)C1(N)C(=O)N(c2ccccc2)c2ccccc2N(c2ccccc2)C1=O

Procedure:
Following General Procedure I above using 3,5-difluorophenylacetic acid (Lancaster) and 3-(L-alaninyl)-amino-2,4-dioxo-1,5-bis-phenyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine hydrochloride (Example 8-W), the title compound was prepared as a white solid (melting point=139-141° C.). Purification was by flash chromatography eluting with CH2Cl2/EtOAc (1:1). Rf=0.46 (CH2Cl2/EtOAc, 1:1).
Reaction SMILES: [C:1]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[F:19])#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].C([Li])(CC)C.CN(C)[CH:27]=[O:28]>O1CCCC1.C(OCC)(=O)C>[F:19][C:14]1[C:13]([C:1]#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])=[CH:18][CH:17]=[CH:16][C:15]=1[CH:27]=[O:28]
Reactant: CCCCCCCCCCC#Cc1ccccc1F
Reactant: CN(C)C=O
Agent: [Li]C(C)CC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCCCCCCCCC#Cc1cccc(C=O)c1F
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 91 %

Procedure:
To a solution of 7.00 g (27.0 mmol) of 2-(1-dodecynyl)fluorobenzene in tetrahydrofuran (60 ml) at -78° C. was added slowly sec-butyllithium (1.3 M, cyclohexane) (21 ml). The mixture was stirred at -78° C. for 30 min, and dimethylformamide (2.8 ml) was added dropwise. The mixture was stirred for 5 min at -78° C. and allowed to warm to room temperature. The mixture was diluted with ethyl acetate and washed with water. The organic phase was separated, dried over anhydrous magnesium sulfate, filtered, and the filtrate concentrated in vacuo. The residue was flash chromatographed on silica gel (eluted with ethyl acetate/heptane/1:10). The appropriate fractions were collected and evaporated. The residue was chromatographed a second time over silica gel (eluted with dichloromethane) to afford 7.10 g (91%) of product.
Reaction SMILES: [BH4-].[Na+].[CH3:3][N:4]1[CH:8]=[CH:7][N:6]=[C:5]1[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=1)=[O:10].O>CO>[CH3:3][N:4]1[CH:8]=[CH:7][N:6]=[C:5]1[CH:9]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:19])([F:18])[F:20])[CH:12]=1)[OH:10]
Reactant: Cn1ccnc1C(=O)c1cccc(C(F)(F)F)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: Cn1ccnc1C(O)c1cccc(C(F)(F)F)c1
Reaction time: 0.5 h

Procedure:
0.6 g of sodium borohydride is added to a solution of 3.6 g of 1-methyl-α-(3-trifluoromethylphenyl) -1H-imidazole-2-methanone in 25 ml of methanol. The mixture is stirred for 30 minutes and 150 ml of water are added. The precipitate obtained is filtered off and washed with water. It is recrystallized from an ethanol/water mixture.
Reaction SMILES: N[C@H](C(O)=O)CCSC.[Br:10][C:11]1[CH2:17][N:16](CC2C=CC(OC)=CC=2OC)[C:15](=[O:29])[C@H:14]([NH:30][C:31](=[O:40])[O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH2:13][CH:12]=1>FC(F)(F)C(O)=O.ClCCl>[Br:10][C:11]1[CH2:17][NH:16][C:15](=[O:29])[C@H:14]([NH:30][C:31](=[O:40])[O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH2:13][CH:12]=1
Reactant: COc1ccc(CN2CC(Br)=CC[C@@H](NC(=O)OCc3ccccc3)C2=O)c(OC)c1
Agent: CSCC[C@H](N)C(=O)O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(N[C@@H]1CC=C(Br)CNC1=O)OCc1ccccc1
Reaction time: 18 h
Yield: 27.2 %

Procedure:
A solution of L-methionine (274 mg, 1.84 mmol) in trifluoroacetic acid (5 mL) was added to a solution of benzyl (3R)-6-bromo-1-(2,4-dimethoxybenzyl)-2-oxo-2,3,4,7-tetrahydro-1H-azepin-3-ylcarbamate (90 mg, 0.184 mmol) in dichloromethane (5 mL). After 18 h, the mixture was concentrated. Purification by reverse phase HPLC (C-18, 95% water/acetonitrile→5% water/acetonitrile with 0.1% trifluoroacetic acid) gave the title compound (17 mg). MS 339 (M+1).
Reaction SMILES: [C:1]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[Na].[CH3:13][C:14]([CH3:18])=[C:15]=[CH:16]Br.O>C(O)C>[CH3:13][C:14]([CH3:18])([C:15]#[CH:16])[CH:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[C:1]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: CC(C)=C=CBr
Agent: [Na]
Solvent: O
Solvent: CCO
Product: C#CC(C)(C)C(C(=O)OCC)C(=O)OCC

Procedure:
Diethyl malonate (34.8 g.) was added to a solution of sodium (5.0 g.) in ethanol (500 ml.) and the mixture stirred for a few minutes. 3,3-Dimethyl-1-bromoallene (32.0 g.) was then added dropwise at the ambient temperature after which the mixture was refluxed for 3 hours. The ethanolic solution obtained was poured into an excess of water and the mixture extracted with chloroform (3×200 ml.). The extracts were combined, dried with anhydrous sodium sulphate and evaporated and the residual oil distilled under reduced pressure to yield ethyl 3,3-dimethyl-2-ethoxycarbonylpent-4-ynoate, as an oil b.p. 56°-60°/0.1 mm. Hg.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:7]([OH:9])=[O:8])[S:5][CH:6]=1.OS(O)(=O)=O.[OH-].[Na+].[CH3:17]O>>[Br:1][C:2]1[CH:3]=[C:4]([C:7]([O:9][CH3:17])=[O:8])[S:5][CH:6]=1
Reactant: CO
Reactant: O=C(O)c1cc(Br)cs1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: COC(=O)c1cc(Br)cs1
Temperature: 50 °C
Reaction time: 12 h

Procedure:
To a solution of 4-bromo-2-thiophenecarboxylic acid (4 g, 19 mmol) in MeOH (100 mL) was added H2SO4 (5 mL) dropwise at 25° C. The solution was stirred for 12 h at 50° C. and was poured into ice-H2O and the pH was adjusted to ˜11 with aqueous NaOH. The aqueous phase was extracted several times with DCM and the combined organic fractions were dried over Na2SO4, concentrated and used directly (4.27 g, quant.): LCMS (ES) m/z 222 (M+H)+.
Reaction SMILES: [CH2:1]([C:3]([CH2:8][OH:9])([CH2:6][OH:7])[CH2:4][CH3:5])[OH:2].[C:10](OCC)(OCC)(OCC)[CH3:11].C1(C)C(S(O)(=O)=O)=CC=CC=1>>[CH2:4]([C:3]12[CH2:8][O:9][C:10]([CH3:11])([O:7][CH2:6]1)[O:2][CH2:1]2)[CH3:5]
Reactant: CCC(CO)(CO)CO
Reactant: CCOC(C)(OCC)OCC
Agent: Cc1ccccc1S(=O)(=O)O
Product: CCC12COC(C)(OC1)OC2
Temperature: 25 °C

Procedure:
Trimethylolpropane (268.0 g, 2.0 mol), triethyl orthoacetate (356.4 g, 2.20 mol) and toluene sulfonic acid (4.0 g) were charged into a oven dried round bottom flask equipped with a stirring bar, distillation head and under nitrogen. The resulting solution was heated until the theoretical amount od ethanol was collected. The reaction was cooled to room temperature. Fractional vacuum distillation afforded the product as a water clear liquid, boiling point 62.8-71.2° C. at 0.78-1.80 torr. Yield: 276.0 g (87.3%)
Reaction SMILES: [CH3:1][N:2]1[C:6]2[N:7]=[C:8]([CH2:47][CH2:48][CH3:49])[N:9]([CH2:10][C:11]3[CH:16]=[CH:15][C:14]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=4[C:23]4[N:27](C(C5C=CC=CC=5)(C5C=CC=CC=5)C5C=CC=CC=5)[N:26]=[N:25][N:24]=4)=[CH:13][CH:12]=3)[C:5]=2[C:4]([CH3:50])=[N:3]1.O>CC(O)=O>[CH3:1][N:2]1[C:6]2[N:7]=[C:8]([CH2:47][CH2:48][CH3:49])[N:9]([CH2:10][C:11]3[CH:12]=[CH:13][C:14]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=4[C:23]4[NH:24][N:25]=[N:26][N:27]=4)=[CH:15][CH:16]=3)[C:5]=2[C:4]([CH3:50])=[N:3]1
Reactant: CCCc1nc2c(c(C)nn2C)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CC(=O)O
Solvent: O
Product: CCCc1nc2c(c(C)nn2C)n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Reaction time: 2 h
Yield: 67.7 %

Procedure:
The material prepared in Step E (160 mg, 0.24 mmol) was dissolved in glacial HOAc (2.0 mL) at 50° C. and H2O was added dropwise until the solution just became cloudy (approx. 0.7 mL). The mixture was kept at 50° C. for 2 hours and then was evaporated to dryness under a stream of nitrogen. The residue so formed was purified by preparative tlc on 1000μ SiO2 plates developed with CHCl3 /MeOH/NH4OH (80:20:2) to give 67 mg (68%) of the title compound as its ammonium salt. 1H NMR (200 MHz, DMSO-d6)δ 6.82-7.80 (m), 5.21 (s), 3.66 (s), 2.70 (t, J=9 Hz), 1.93 (s), 1.52-1.76 (m), 0.89 (t, J=9 Hz). FAB-MS: 413 (M+ +1). Anal. Calcd for C23H24N8 ·NH3 ·0.6 H2O; C, 62.74; H, 6.46; N, 28.63; Found: C, 62.49; H, 6.24; N, 28.73.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]([CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[CH2:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:9]=[CH:8][C:3]=1[C:4]([O:6]C)=[O:5].[OH-].[Na+]>C1COCC1.CO>[OH:1][C:2]1[CH:11]=[C:10]([CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[CH2:20][CH2:21][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:9]=[CH:8][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: COC(=O)c1ccc(CCc2ccccc2CCc2ccccc2)cc1O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1ccc(CCc2ccccc2CCc2ccccc2)cc1O
Yield: 83.2 %

Procedure:
A solution of methyl 2-hydroxy-4-[2-(phenethyl)phenethyl]benzoate (0.25 g) in THF (5 ml) and methanol (5 ml) containing aqueous 2N sodium hydroxide (5 ml) was heated under reflux for 2 hours. The reaction mixture was evaporated to small volume and acidified with aqueous 2N hydrochloric acid. The mixture was extracted three times with ethyl acetate (25 ml each time) and the combined extracts were washed with brine and dried over anhydrous magnesium sulphate. The solid obtained on removal of the solvent was crystallised from a mixture of diethyl ether and hexane to give 2-hydroxy-4-[(2-phenethyl)phenethyl]benzoic acid (0.2 g), m.p. 134°-7° C.
Reaction SMILES: [OH:1][C:2]1[C:3]2[O:21][N:20]=[C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:4]=2[C:5]([C:13]#[C:14][Si](C)(C)C)=[N:6][C:7]=1[C:8](OCC)=[O:9].C[O-].[Na+].[NH2:31][CH2:32][C:33]([OH:35])=[O:34]>C(=O)(O)[O-].[Na+]>[C:13]([C:5]1[C:4]2[C:19]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)=[N:20][O:21][C:3]=2[C:2]([OH:1])=[C:7]([C:8]([NH:31][CH2:32][C:33]([OH:35])=[O:34])=[O:9])[N:6]=1)#[CH:14]
Reactant: NCC(=O)O
Reactant: CCOC(=O)c1nc(C#C[Si](C)(C)C)c2c(-c3ccccc3)noc2c1O
Agent: C[O-]
Agent: O=C([O-])O
Agent: [Na+]
Product: C#Cc1nc(C(=O)NCC(=O)O)c(O)c2onc(-c3ccccc3)c12
Temperature: 25 °C
Yield: 64.9 %

Procedure:
Ethyl 7-hydroxy-3-phenyl-4-((trimethylsilyl)ethynyl)isoxazolo[4,5-c]pyridine-6-carboxylate (200 mg, 0.53 mmol) was added to sodium methoxide solution (39.5 mL, 19.7 mmol, 0.5 M in MeOH) and the mixture was refluxed for 30 min. After the mixture was cooled to room temperature, glycine (1.98 g, 26.3 mmol) was added, and the mixture was refluxed for 48 h. The mixture was cooled to room temperature and the solvent was removed in vacuo. The residue was dissolved in 100 mL of water and hydrochloric acid was added until pH was 3. The precipitate was isolated by filtration and dried under vacuum to give 170 mg of crude solid. The solid was dissolved in 100 mL of saturated sodium bicarbonate solution and washed with EtOAc. The aqueous layer was acidified with concentrated hydrochloric acid to pH 3 and extracted with EtOAc. The solvent was concentrated in vacuo to give 116 mg of the title compound. MS: (−) m/z 336.28 (M−1).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([N+:30]([O-:32])=[O:31])[CH:25]=1>CN(C)C=O.O>[N+:30]([C:26]1[CH:25]=[C:24]([CH:29]=[CH:28][CH:27]=1)[CH2:23][NH:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:12])([CH3:14])[CH3:13])[CH:5]=[CH:6][CH:7]=1)([O-:32])=[O:31]
Reactant: O=[N+]([O-])c1cccc(CBr)c1
Reactant: CC(C)(C)OC(=O)Nc1cccc(N)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Nc1cccc(NCc2cccc([N+](=O)[O-])c2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 98.8 %

Procedure:
A solution of tert-butyl (3-aminophenyl)carbamate (0.51 g, 2.4 mmol) and potassium carbonate (0.61 g, 4.4 mmol) in N,N-dimethylformamide (7 mL) was treated with a solution of 1-(bromomethyl)-3-nitrobenzene (0.50 g, 2.3 mmol) in N,N-dimethylformamide (3 mL) and stirred at 25° C. for 16 h. The reaction mixture was diluted with water (80 mL) and extracted with ethyl acetate (3×75 mL). The combined organic layers were washed with water (3×50 mL) and brine (50 mL), dried over anhydrous sodium sulfate, filtered, and evaporated to give a crude residue. This material was purified by flash column chromatography to give the desired product (0.78 g, 88% [90% pure]) as a solid. LCMS for C18H22N3O4 (M+H)+: m/z=344.2.