Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Na].[C:2]([O:10]CC)(=[O:9])[CH2:3][C:4]([O:6]CC)=[O:5].CS(O[CH2:18][CH2:19][CH2:20][CH2:21][C:22]#[CH:23])(=O)=O.O>C(O)C>[CH2:23]([CH:3]([C:4]([OH:6])=[O:5])[C:2]([OH:10])=[O:9])[CH2:22][CH2:21][CH2:20][C:19]#[CH:18]
Reactant: C#CCCCCOS(C)(=O)=O
Reactant: CCOC(=O)CC(=O)OCC
Agent: [Na]
Solvent: O
Solvent: CCO
Product: C#CCCCCC(C(=O)O)C(=O)O
Reaction time: 0.5 h

Procedure:
Sodium (1.2 g) was dissolved in dry ethanol (200 ml). Diethyl malonate (7.8 ml) was added and the mixture was stirred for 30 minutes and hex-5-ynyl methanesulphonate (9.0 g) was added. The mixture was stirred and refluxed for 1 hour. The mixture was cooled and the volume was reduced in vacuo. The mixture was poured into water and the aqueous mixture was extracted with diethyl ether. The ethereal extracts were washed with water and dried over anhydrous magnesium sulphate. The solvent was removed in vacuo. The crude ester was added to a solution of aqueous sodium hydroxide solution (100 ml of 15% solution) and methanol (50 ml) and the mixture was stirred at 20° for 24 hours. The mixture was extracted with diethyl ether. The aqueous alkaline phase was acidified with hydrochloric acid and the mixture was extracted with diethyl ether. The ethereal extracts were dried over anhydrous magnesium sulphate. The solvent was removed in vacuo. 2-(Hex-5-ynyl)malonic acid was obtained as a colourless solid (4.5 g) and was used without further purification.
Reaction SMILES: C(OP([CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])(OCC)=O)C.[H-].[Na+].[CH2:19]([O:26][C:27]1[CH:34]=[CH:33][C:30]([CH:31]=O)=[CH:29][CH:28]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>O1CCCC1>[CH2:19]([O:26][C:27]1[CH:28]=[CH:29][C:30](/[CH:31]=[CH:9]/[C:10]([O:12][C:13]([CH3:14])([CH3:15])[CH3:16])=[O:11])=[CH:33][CH:34]=1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: CCOP(=O)(CC(=O)OC(C)(C)C)OCC
Reactant: O=Cc1ccc(OCc2ccccc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)/C=C/c1ccc(OCc2ccccc2)cc1
Temperature: 0 °C
Yield: 93.7 %

Procedure:
To a solution (100 mL) of tert-butyl diethylphosphonoacetate (13.8 g, 51.8 mmol) in tetrahydrofuran was added 60% sodium hydride (2.45 g, 61.2 mmol) with stirring at 0° C., and the mixture was stirred at the same temperature for 15 min. Then, to this mixture was added dropwise a solution (138 mL) of 4-(benzyloxy)benzaldehyde (10 g, 47.1 mmol) in tetrahydrofuran with stirring at 0° C., and the mixture was stirred at room temperature for 3 hrs. The reaction mixture was concentrated, and the residue was diluted with ethyl acetate, and washed with 5% aqueous potassium hydrogensulfate solution and saturated brine. The ethyl acetate layer was dried over magnesium sulfate, and concentrated under reduced pressure to give the title compound (13.7 g, yield 94%) as colorless crystals.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl[C:10]1[N:15]=[C:14]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([N:23]3[CH:27]=[C:26]([CH3:28])[N:25]=[CH:24]3)=[C:19]([O:29][CH3:30])[CH:18]=2)[CH:13]=[CH:12][CH:11]=1>>[CH3:30][O:29][C:19]1[CH:18]=[C:17]([NH:16][C:14]2[CH:13]=[CH:12][CH:11]=[C:10]([N:2]([CH3:1])[C:3]3[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=3)[N:15]=2)[CH:22]=[CH:21][C:20]=1[N:23]1[CH:27]=[C:26]([CH3:28])[N:25]=[CH:24]1
Reactant: COc1cc(Nc2cccc(Cl)n2)ccc1-n1cnc(C)c1
Reactant: CNc1ccccc1
Product: COc1cc(Nc2cccc(N(C)c3ccccc3)n2)ccc1-n1cnc(C)c1

Procedure:
Prepared in analogy to example 62 from N-methylaniline and (6-chloro-pyridin-2-yl)-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-amine. The title compound was obtained as a brownish solid (Yield=16%). MS ISP (m/e): 386.2 (100) [(M+H)+]. 1H NMR (DMSO-D6, 300 MHz): δ (ppm)=9.06 (s, 1H), 7.68 (d, 1H), 7.61 (s, 1H), 7.50-7.35 (m, 3H), 7.35-7.15 (m, 4H), 7.09 (, 1H), 6.99 (s, 1H), 6.19 (d, 1H), 5.95 (d, 1H), 3.70 (s, 3H), 3.44 (s, 3H), 2.14 (s, 3H).
Reaction SMILES: Cl[CH2:2][C:3]([C:5]1[CH:6]=[C:7]([CH:11]([O:32]C2CCCCO2)[C:12]2[CH:31]=[CH:30][C:15]([CH2:16][O:17][C:18]3[CH:23]=[CH:22][C:21]([C:24](=[O:27])[CH2:25][CH3:26])=[C:20]([OH:28])[C:19]=3[CH3:29])=[CH:14][CH:13]=2)[CH:8]=[CH:9][CH:10]=1)=O.[NH2:39][C:40]([NH2:42])=[S:41].C1(C)C=CC(S(O)(=O)=O)=CC=1>C(O)C>[NH2:42][C:40]1[S:41][CH:2]=[C:3]([C:5]2[CH:6]=[C:7]([CH:11]([OH:32])[C:12]3[CH:31]=[CH:30][C:15]([CH2:16][O:17][C:18]4[CH:23]=[CH:22][C:21]([C:24](=[O:27])[CH2:25][CH3:26])=[C:20]([OH:28])[C:19]=4[CH3:29])=[CH:14][CH:13]=3)[CH:8]=[CH:9][CH:10]=2)[N:39]=1
Reactant: NC(N)=S
Reactant: CCC(=O)c1ccc(OCc2ccc(C(OC3CCCCO3)c3cccc(C(=O)CCl)c3)cc2)c(C)c1O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Product: CCC(=O)c1ccc(OCc2ccc(C(O)c3cccc(-c4csc(N)n4)c3)cc2)c(C)c1O
Yield: 52.1 %

Procedure:
Heat a solution of 1-(4-{4-[[3-(2-chloro-acetyl)-phenyl]-(tetrahydro-pyran-2-yloxy)-methyl]-benzyloxy}-2-hydroxy-3-methyl-phenyl)-propan-1-one (0.250 mg, 0.466 mmol) and thiourea (71 mg, 0.931 mmol) in ethanol (0.20 M) overnight at 70° C. Add p-toluenesulfonic acid (10 mg) and stir overnight. Evaporate solvents and chromatograph residue. Major fraction isolated was the title compound (0.115 g, 0.243 mmol, 52%): 1H NMR (400 MHz, DMSO-d6) δ 1.09 (t, J=10.5 Hz, 3H), 2.02 (s, 3H), 3.03 (q, J=14.4 Hz, 2H), 5.20 (s, 2H), 5.75 (s, 1H), 6.70 (d, J=9.0 Hz, 1H), 7.14 (s, 1H), 737 (d, J=6.43 Hz, 1H), 7.42 (m, 6H), 7.60 (m, 1H), 7.80 (m, 2H), 12.89 (s, 1H). MS (m/z): 473 (M−H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([NH:11][C:12]3[N:17]=[C:16]([O:18][CH2:19][C:20]([F:23])([F:22])[F:21])[N:15]=[C:14]([NH:24][C:25]4[CH:33]=[CH:32][C:28]([C:29](O)=[O:30])=[CH:27][CH:26]=4)[N:13]=3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.Cl.[NH2:57][C@@H:58]([CH2:63][NH:64][C:65]([O:67][C:68]([CH3:71])([CH3:70])[CH3:69])=[O:66])[C:59]([O:61][CH3:62])=[O:60].CCN(C(C)C)C(C)C>CN(C=O)C>[C:68]([O:67][C:65]([NH:64][CH2:63][C@H:58]([NH:57][C:29](=[O:30])[C:28]1[CH:27]=[CH:26][C:25]([NH:24][C:14]2[N:13]=[C:12]([NH:11][C:8]3([C:5]4[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=4)[CH2:9][CH2:10]3)[N:17]=[C:16]([O:18][CH2:19][C:20]([F:23])([F:21])[F:22])[N:15]=2)=[CH:33][CH:32]=1)[C:59]([O:61][CH3:62])=[O:60])=[O:66])([CH3:71])([CH3:70])[CH3:69]
Reactant: COC(=O)[C@@H](N)CNC(=O)OC(C)(C)C
Reactant: O=C(O)c1ccc(Nc2nc(NC3(c4ccc(Cl)cc4)CC3)nc(OCC(F)(F)F)n2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@H](CNC(=O)OC(C)(C)C)NC(=O)c1ccc(Nc2nc(NC3(c4ccc(Cl)cc4)CC3)nc(OCC(F)(F)F)n2)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 4-(4-(1-(4-chlorophenyl)cyclopropylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzoic acid (50 mg) in DMF (2 mL) was added O-(benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium tetrafluoroborate (23.82 mg) and (S)-methyl 2-amino-3-(tert-butoxycarbonylamino)propanoate hydrochloride (18.90 mg) and iPr2NEt (0.052 ml). After stirring at rt for 4 h, the mixture was purified by preparative HPLC to give (S)-methyl 3-(tert-butoxycarbonylamino)-2-(4-(4-(1-(4-chlorophenyl)cyclopropylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzamido)propanoate.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:27])[NH:10][C@H:11]1[CH2:16][CH2:15][C@@H:14]([NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:13][C@@H:12]1[CH:25]=[CH2:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B1C2CCCC1CCC2.C1C[O:40]CC1>>[CH2:1]([O:8][C:9](=[O:27])[NH:10][C@H:11]1[CH2:16][CH2:15][C@@H:14]([NH:17][C:18]([O:20][C:21]([CH3:22])([CH3:23])[CH3:24])=[O:19])[CH2:13][C@@H:12]1[CH2:25][CH2:26][OH:40])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=C[C@H]1C[C@H](NC(=O)OC(C)(C)C)CC[C@@H]1NC(=O)OCc1ccccc1
Reactant: C1CCOC1
Agent: B1C2CCCC1CCC2
Product: CC(C)(C)OC(=O)N[C@@H]1CC[C@H](NC(=O)OCc2ccccc2)[C@@H](CCO)C1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
The compound [(1S,2R,4R)-[4-tert-butoxycarbonylamino-2-(vinyl)-cyclohexyl]-carbamic acid benzyl ester (0.82 g, 2.2 mmol) was dissolved in THF (15 mL). The resultant solution was cooled to 0° C. and charged with 9-BBN (11 mL of a 0.5 M solution in THF). The mixture was stirred for 20 h at RT and then quenched sequentially with aqueous sodium acetate (0.6 g in 1.5 mL water) and 30% hydrogen peroxide (1.5 mL). This was stirred at RT for 14 h and partitioned between EtOAc and sat. NaHCO3. The aqueous phase was extracted with EtOAc, and the combined organic extracts were washed with brine, dried (Na2SO4), filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography to afford [(1S,2R,4R)-[4-tert-butoxycarbonylamino-2-(hydroxyethyl)-cyclohexyl]-carbamic acid benzyl ester (0.42 g) as a white foam. MS found: (M+H)+=393.
Reaction SMILES: [CH3:1][C:2]1[N:6]2[C:7](=[O:19])[C:8]3[NH:9][CH:10]=[N:11][C:12]=3[N:13]([CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[C:5]2=[N:4][N:3]=1.[Br:20]N1C(=O)CCC1=O>C1COCC1>[Br:20][C:10]1[NH:9][C:8]2[C:7](=[O:19])[N:6]3[C:2]([CH3:1])=[N:3][N:4]=[C:5]3[N:13]([CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[C:12]=2[N:11]=1
Reactant: CCCCCn1c2nc[nH]c2c(=O)n2c(C)nnc12
Reactant: O=C1CCC(=O)N1Br
Solvent: C1CCOC1
Product: CCCCCn1c2nc(Br)[nH]c2c(=O)n2c(C)nnc12
Temperature: 70 °C
Yield: 31 %

Procedure:
To a solution of 3-methyl-9-pentyl-6,9-dihydro-5H-[1,2,4]triazolo[4,3-a]purin-5-one (1.0 g, 3.8 mmol) in THF (50 mL) was added N-bromosuccinimide (0.75 g, 4.2 mol). The mixture was heated at 70° C. for 1 h and concentrated in vacuum. The residue was taken up in water and EtOAc. The organic layer was separated and the aqueous layer was extracted with ethyl acetate three times. The combined organic layers were dried (MgSO4), filtered, and concentrated in vacuum. The residue was purified by preparative LCMS to provide the desired product as a white powder (0.4 g, 30% yield). 1HNMR (400 MHz, d6-DMSO): δ 4.18 (t, J=7.5 Hz, 2H), 2.71 (s, 3H), 1.79 (m, 2H), 1.29 (m, 4H), 0.84 (m, 3H). LCMS calculated for C12H16BrN6O(M+H): 339.1, 341.1; found: 339.1, 341.1.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[N:2]1.[H-].[Na+].Cl[C:13]1[N:14]=[C:15]([N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)[C:16]2[S:21][C:20]([CH2:22][N:23]3[CH2:28][CH2:27][CH:26]([N:29]([CH3:31])[CH3:30])[CH2:25][CH2:24]3)=[CH:19][C:17]=2[N:18]=1>CN(C=O)C.O>[N:1]1([C:13]2[N:14]=[C:15]([N:32]3[CH2:33][CH2:34][O:35][CH2:36][CH2:37]3)[C:16]3[S:21][C:20]([CH2:22][N:23]4[CH2:24][CH2:25][CH:26]([N:29]([CH3:31])[CH3:30])[CH2:27][CH2:28]4)=[CH:19][C:17]=3[N:18]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[N:2]1
Reactant: c1ccc2[nH]ncc2c1
Reactant: CN(C)C1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CN(C)C1CCN(Cc2cc3nc(-n4ncc5ccccc54)nc(N4CCOCC4)c3s2)CC1
Temperature: 150 °C
Reaction time: 0.25 h
Yield: 48.9 %

Procedure:
A solution of indazole (0.118 g) in DMF (8 mL) was cooled to 0° C. then sodium hydride (0.06 g) added. After 15 min, [1-(2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-piperidin-4-yl]-dimethyl-amine (0.395 g) was added and the reaction vessel sealed and heated at 150° C. After 1 h the reaction mixture was cooled to room temperature then diluted with water. The resulting precipitate was collected by filtration then purified by chromatography (silica, 0 to 20% of a 49:1 MeOH:NH4OH mixture in dichloromethane) to furnish 116 (0.233 g, 49%) as a white solid after trituration with ethyl acetate. MS m/e 478 [M+H]−; 1H NMR (300 MHz, DMSO-d6) δ ppm 1.41 (dd, J=11.68, 3.39 Hz, 2 H) 1.73 (d, J=10.93 Hz, 2 H) 2.07 (t, J=10.74 Hz, 3 H) 2.17 (s, 6 H) 2.94 (d, J=11.68 Hz, 2 H) 3.75-3.90 (m, 6 H) 3.93-4.13 (m, 4 H) 7.31 (t, J=7.54 Hz, 1 H) 7.39 (s, 1 H) 7.56 (dd, J=7.91, 6.40 Hz, 1 H) 7.88 (d, J=7.91 Hz, 1 H) 8.39 (s, 1 H) 8.68 (d, J=8.67 Hz, 1 H).
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][N:13]2[N:16]=[CH:17][C:18]([C:19]([O:21][CH3:22])=[O:20])=[C:12]2[CH:11]=1)(C(C)(C)C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-].C(OCC)(=O)C>C1COCC1>[OH:8][CH2:9][C:10]1[CH:15]=[CH:14][N:13]2[N:16]=[CH:17][C:18]([C:19]([O:21][CH3:22])=[O:20])=[C:12]2[CH:11]=1
Reactant: COC(=O)c1cnn2ccc(CO[Si](C)(C)C(C)(C)C)cc12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)c1cnn2ccc(CO)cc12
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of methyl 5-((tert-butyldimethylsilyloxy)methyl)pyrazolo[1,5-a]pyridine-3-carboxylate Y-5 (2.9 g, 9.1 mmol) in dry THF (20 mL) was added TBAF (3.5 g, 13.7 mmol). The reaction mixture was stirred at room temperature for 10 mins, then treated with ethyl acetate. The resulting mixture was washed with brine, dried over Na2SO4 and concentrated to afford the title compound (1.9 g).
Reaction SMILES: N[C:2]1[CH:3]=[CH:4][C:5]2[S:11][C:10]3[CH:12]=[C:13]([C:16]#[N:17])[CH:14]=[CH:15][C:9]=3[CH:8]=[CH:7][C:6]=2[CH:18]=1.S(=O)(=O)(O)[OH:20].N([O-])=O.[Na+]>O>[C:16]([C:13]1[CH:14]=[CH:15][C:9]2[CH:8]=[CH:7][C:6]3[CH:18]=[C:2]([OH:20])[CH:3]=[CH:4][C:5]=3[S:11][C:10]=2[CH:12]=1)#[N:17]
Reactant: O=S(=O)(O)O
Reactant: N#Cc1ccc2c(c1)Sc1ccc(N)cc1C=C2
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: N#Cc1ccc2c(c1)Sc1ccc(O)cc1C=C2
Temperature: 3 °C
Reaction time: 2 h

Procedure:
Suspend 50 mg. of the 3-cyano-8-aminodibenzo[b,f]thiepine from Example 18, Step 1, in 2 ml. of 10% sulfuric acid and cool to 3° C. Add dropwise 0.2 ml. of 10% aqueous sodium nitrite solution. Stir at 3° C. for 2 hours and allow to warm to 15° C. for 1 hour. Add the solution dropwise to 50 ml. of boiling 10% sulfuric acid and continue heating for 15 minutes. Dilute with cold water and filter. Wash the solids with water and dry to obtain the title product (m.p., 224°-227° C.).
Reaction SMILES: [N+:1]([O-:4])([O-:3])=[O:2].[N+]([O-])(O)=O.[C:9]([O:12][CH2:13][CH3:14])(=[O:11])C.CCOCC>C(OCC)(=O)C>[N+:1]([O-:4])([OH:3])=[O:2].[O:11]1[CH2:14][CH2:13][O:12][CH2:9]1
Reactant: O=[N+]([O-])[O-]
Reactant: CCOC(C)=O
Solvent: O=[N+]([O-])O
Solvent: CCOCC
Product: C1COCO1

Procedure:
analysis: C28H23Cl2N3O4 (MW 536.43) calc. C 62.69, H 4.32, N 7.83; found C 62.4, H 4.4, N 7.6. Nitrate formation: 1.93 g (3.6 mmol) of base were dissolved in 15 ml of ethyl acetate, and 3.6 ml of 1M HNO3 /ethyl acetate were added with stirring. Ether was subsequently added until no further precipitate was produced, and the precipitate was filtered off under suction. 2.05 g (yield of nitrate, 95.3% of theory) of cis-2-(2,4-dichlorophenyl)-2-(imidazol-1-ylmethyl)-4-[4-(benzoxazol-2-yl)benzyl)oxymethyl]-1,3-dioxolane nitrate were obtained; melting point 121°-2° C.,
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([C:8]([N:16]2[CH2:21][CH2:20][N:19](C(OC(C)(C)C)=O)[CH2:18][CH2:17]2)([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH3:9])[CH2:4][CH2:3]1.FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([C:8]([N:16]2[CH2:17][CH2:18][NH:19][CH2:20][CH2:21]2)([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH3:9])[CH2:4][CH2:3]1
Reactant: CN1CCC(C(C)(c2ccccc2)N2CCN(C(=O)OC(C)(C)C)CC2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN1CCC(C(C)(c2ccccc2)N2CCNCC2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 84.9 %

Procedure:
To a solution of tert-butyl 4-[1-(1-methylpiperidin-4-yl)-1-phenylethyl]piperazine-1-carboxylate 0.16 g (0.41 mmol) in methylene chloride (20 ml) was added trifluoroacetic acid (5 ml) and resulting mixture stirred at room temperature for 2 hours. The reaction mixture was concentrated, dissolved in methylene chloride and washed with saturated sodium bicarbonate and brine. The methylene chloride solution was dried over sodium sulfate and concentrated to give 0.1 g (yield 82%) of desired product.
Reaction SMILES: F[C:2]1[C:3]([N+:14]([O-:16])=[O:15])=[C:4]([N:8]2[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.CN(C=O)C.[N-:22]=[N+:23]=[N-:24].[Na+]>CCOC(C)=O>[N:22]([C:6]1[CH:7]=[CH:2][C:3]([N+:14]([O-:16])=[O:15])=[C:4]([N:8]2[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)[CH:5]=1)=[N+:23]=[N-:24]
Reactant: [N-]=[N+]=[N-]
Reactant: O=[N+]([O-])c1c(F)cccc1N1CCCCC1
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: [N-]=[N+]=Nc1ccc([N+](=O)[O-])c(N2CCCCC2)c1
Reaction time: 6 h
Yield: 74 %

Procedure:
To a solution of 1-(fluoro-2-nitro-phenyl)-piperidine (389 mg, 1.73 mmol, as prepared in the previous step) in 5, mL of DMF was added sodium azide (169 mg, 2.60 mmol) and the resultant mixture heated to 50° C. for 14 h, and then 80° C. for 6 h. The reaction was diluted with EtOAc (100 mL), washed with water (2×50 mL), dried (Na2SO4) and concentrated in vacuo. Purification by preparative TLC (50% EtOAc-hexane) afforded 316 mg (74%) of the title compound as a tan solid. Mass spectrum (ESI, m/z): Calcd. for C11H13N5O2, 248.1 (M+H), found 247.9.
Reaction SMILES: [NH:1]1[C:5](=[O:6])[CH2:4][CH2:3][C@H:2]1[C:7]([OH:9])=[O:8].S(Cl)(Cl)=O.[C:14](=O)(O)[O-].[Na+]>CO>[CH3:14][O:8][C:7](=[O:9])[C@@H:2]1[CH2:3][CH2:4][C:5](=[O:6])[NH:1]1
Reactant: O=C([O-])O
Reactant: O=C1CC[C@@H](C(=O)O)N1
Agent: [Na+]
Solvent: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)[C@@H]1CCC(=O)N1
Temperature: 25 °C
Reaction time: 16 h
Yield: 80 %

Procedure:
To a solution of L-pyroglutamic acid (32.7 g, 0.253 mol) in methanol (600 mL) was added thionyl chloride (2.40 mL, 32.9 mmol), and the resulting solution was stirred at room temperature for 16 h. The reaction mixture was neutralized to pH=7 with saturated aqueous sodium bicarbonate and concentrated in vacuo. The residue was dissolved in methylene chloride, washed with brine, dried over magnesium sulfate, and concentrated. The residue was distilled under high vacuum to give the product as a colorless oil (28.9 g, 80%), b.p. 118-126° C./0.35 mm Hg. 1H NMR (300 MHz, CDCl3): δ 2.36 (m, 4 H), 3.77 (s, 3 H), 4.27 (dd, 1 H, J=5.0, 8.4), 6.78 (s, 1 H).
Reaction SMILES: Cl.Cl.Cl.[NH2:4][C@@H:5]([C:11]([N:13]1[CH2:18][CH2:17][N:16]([CH:19]2[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]2)[CH2:15][CH2:14]1)=[O:12])[CH2:6][CH2:7][C:8](=[O:10])[OH:9].[NH:26]1[C:34]2[C:29](=[CH:30][CH:31]=[C:32]([C:35](O)=[O:36])[CH:33]=2)[CH:28]=[CH:27]1>>[NH:26]1[C:34]2[C:29](=[CH:30][CH:31]=[C:32]([C:35]([NH:4][C@@H:5]([C:11]([N:13]3[CH2:14][CH2:15][N:16]([CH:19]4[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]4)[CH2:17][CH2:18]3)=[O:12])[CH2:6][CH2:7][C:8](=[O:9])[OH:10])=[O:36])[CH:33]=2)[CH:28]=[CH:27]1
Reactant: O=C(O)c1ccc2cc[nH]c2c1
Reactant: CN1CCC(N2CCN(C(=O)[C@H](N)CCC(=O)O)CC2)CC1
Agent: Cl
Product: CN1CCC(N2CCN(C(=O)[C@@H](CCC(=O)O)NC(=O)c3ccc4cc[nH]c4c3)CC2)CC1

Procedure:
Using methods substantially equivalent to those described in Method D-1, the titled compound was prepared from 1-(D-glutamyl)-4-(1-methylpiperidin-4-yl)piperazine trihydrochloride and indole-6-carboxylic acid (46%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4](Cl)[CH:3]=1.[CH3:9][O-:10].[Na+].C1(C)C=CC=CC=1>O>[Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([O:10][CH3:9])[CH:3]=1
Reactant: Clc1cc(Br)ccn1
Reactant: C[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: COc1cc(Br)ccn1

Procedure:
4-Bromo-2-chloropyridine, sodium methoxide (1.6 equiv.) and toluene (6.1 volumes) were heated to 95° C. for 40 h. Toluene (6.1 volumes) and water (3 volumes) were added and the lower aqueous phase cut away. The organic was washed with water (1.5 volumes) and then the volatiles evaporated to give the title compound as an oil. HRMS (ES, M+H) Calcd 187.9711. Found 187.9711.
Reaction SMILES: [O-:1][S:2]([C:5]([F:8])([F:7])[F:6])(=[O:4])=[O:3].[C:9]1([C:15]2[CH:20]=[C:19]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH:18]=[C:17]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[O+]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[CH2:33]([C:41]1[CH:47]=[CH:46][C:44]([NH2:45])=[CH:43][CH:42]=1)[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40]>C(O)C>[O-:4][S:2]([C:5]([F:8])([F:7])[F:6])(=[O:3])=[O:1].[CH2:33]([C:41]1[CH:42]=[CH:43][C:44]([N+:45]2[C:15]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)=[CH:20][C:19]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:18][C:17]=2[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[CH:46][CH:47]=1)[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40]
Reactant: c1ccc(-c2cc(-c3ccccc3)[o+]c(-c3ccccc3)c2)cc1
Reactant: CCCCCCCCc1ccc(N)cc1
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: CCO
Product: CCCCCCCCc1ccc(-[n+]2c(-c3ccccc3)cc(-c3ccccc3)cc2-c2ccccc2)cc1

Procedure:
A 4.58-g portion (0.01 mole) of 2,4,6-triphenylpyrylium triflate is added to 200 ml of ethanol. To this solution, 2.05 g (0.01 mole) of p-n-octylaniline is added. The mixture is refluxed for about 20 hours. Upon removing the ethanol by rotating evaporation, an orange oil remains. To remove the last of the ethanol the oil is placed under high vacuum.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([CH2:8][OH:9])[CH:5]=[CH:4][CH:3]=1.CN(C=O)C.C([N:23]=[C:24]=[S:25])(=O)C1C=CC=CC=1>C(Cl)Cl>[OH:9][CH2:8][C:6]1[N:7]=[C:2]([NH:1][C:24]([NH2:23])=[S:25])[CH:3]=[CH:4][CH:5]=1
Reactant: Nc1cccc(CO)n1
Reactant: O=C(N=C=S)c1ccccc1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: NC(=S)Nc1cccc(CO)n1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
(6-Amino-pyridin-2-yl)-methanol (6-2, 1.00 g, 8.06 mmol) was dissolved in 20 mL anhydrous CH2Cl2 and 5 mL anhydrous DMF under N2. Benzoylisothiocyanate (1.19 mL, 8.86 mmol) was added and the reaction was stirred at room temperature fro 16 h. The reaction was concentrated in vacuo and to the resulting residue was added 24 mL 1M NaOH (aq) and 24 mL TEF. The resulting mixture was heated to reflux for 3 h. The THF was removed in vacuo and a white precipitate formed. The mixture was filtered and washed with water to provide the titled compound as a white solid. 1H NMR(DMSO-d6): δ10.58 (bs, 1H), 10.48 (bs, 1H), 8.84 (bs, 1H), 7.74 (t, 1H, J=8.1 Hz), 7.06 (d, 1H, J=7.5 Hz), 7.01 (d, 1H, J=8.1 Hz), 5.47 (t, 1H, J=5.9 Hz), 4.47 (d, 2H, J=5.7 Hz).
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[N:13]1([CH2:18][C@@H:19]([O:26][C:27]2[CH:36]=[CH:35][C:34]3[C:33](=[O:37])[CH2:32][CH2:31][CH2:30][C:29]=3[C:28]=2[CH2:38][S:39][C:40]2[CH:41]=[C:42]([CH:46]=[CH:47][CH:48]=2)[C:43](O)=[O:44])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:17]=[CH:16][N:15]=[CH:14]1.[NH2:49][CH2:50][CH2:51][OH:52]>O>[OH:52][CH2:51][CH2:50][NH:49][C:43](=[O:44])[C:42]1[CH:46]=[CH:47][CH:48]=[C:40]([S:39][CH2:38][C:28]2[C:29]3[CH2:30][CH2:31][CH2:32][C:33](=[O:37])[C:34]=3[CH:35]=[CH:36][C:27]=2[O:26][C@@H:19]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:18][N:13]2[CH:17]=[CH:16][N:15]=[CH:14]2)[CH:41]=1
Reactant: O=C(O)c1cccc(SCc2c(O[C@H](Cn3ccnc3)c3ccccc3)ccc3c2CCCC3=O)c1
Reactant: NCCO
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O
Product: O=C(NCCO)c1cccc(SCc2c(O[C@H](Cn3ccnc3)c3ccccc3)ccc3c2CCCC3=O)c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 81.2 %

Procedure:
A mixture of 1,1′-carbonyldiimidazole (49 mg, 0.30 mmol, 0.60M in DMF) and 3-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfanyl}benzoic acid (50 mg, 0.10 mmol, 0.20M in DMF) in a capped vial were placed in a heater-shaker at 55° C. for 20 min. It was removed from the heater-shaker and stood at room temperature. A solution of 2-aminoethanol (31 mg, 0.50 mmol, 1.0M in DMF) was added and the reaction mixture was further shaken at room temperature over-night. Water (6 ml) was added and the mixture was shaken at room temperature for 10 min. before being stored in refrigerator over-night. The precipitate was filtered, washed with cold water (2×0.5 ml) and dried in a vacuum oven at 40° C. until constant weight was obtained. 44 mg of the required benzamide was obtained as a beige solid: Low resolution mass spectrum (LC-MS, APCI) m/z 542 [M+H]+.