Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]([C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[NH:17][C:16]([C:21]([N:23]2[CH2:28][CH2:27][N:26]([S:29]([CH3:32])(=[O:31])=[O:30])[CH2:25][CH2:24]2)=[O:22])=[CH:15]3)=[O:11])[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[CH:33]1([CH2:36]Br)[CH2:35][CH2:34]1>>[CH:33]1([CH2:36][N:17]2[C:18]3[C:14](=[CH:13][C:12]([C:10]([N:7]4[CH2:8][CH2:9][N:4]([CH:1]([CH3:3])[CH3:2])[CH2:5][CH2:6]4)=[O:11])=[CH:20][CH:19]=3)[CH:15]=[C:16]2[C:21]([N:23]2[CH2:24][CH2:25][N:26]([S:29]([CH3:32])(=[O:30])=[O:31])[CH2:27][CH2:28]2)=[O:22])[CH2:35][CH2:34]1
Reactant: CC(C)N1CCN(C(=O)c2ccc3[nH]c(C(=O)N4CCN(S(C)(=O)=O)CC4)cc3c2)CC1
Reactant: BrCC1CC1
Product: CC(C)N1CCN(C(=O)c2ccc3c(c2)cc(C(=O)N2CCN(S(C)(=O)=O)CC2)n3CC2CC2)CC1
Yield: 54 %

Procedure:
The title compound was synthesized in analogy to example 3, from [5-(4-isopropyl-piperazine-1-carbonyl)-1H-indol-2-yl]-(4-methanesulfonyl-piperazin-1-yl)-methanone (example 1) and cyclopropylmethyl bromide to afford the desired product as a colorless foam (54%). MS (ISP): 516.2 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4](=[O:12])[C:5]2[S:10][C:9](=[O:11])[NH:8][C:6]=2[N:7]=1.C(O[CH:17]1[O:29][C@H:28]([CH2:30][O:31][C:32](=[O:34])[CH3:33])[C@@H:23]([O:24][C:25](=[O:27])[CH3:26])[C@H:18]1[O:19][C:20](=[O:22])[CH3:21])(=O)C>>[NH2:1][C:2]1[NH:3][C:4](=[O:12])[C:5]2[S:10][C:9](=[O:11])[N:8]([C@@H:17]3[O:29][C@H:28]([CH2:30][O:31][C:32](=[O:34])[CH3:33])[C@@H:23]([O:24][C:25](=[O:27])[CH3:26])[C@H:18]3[O:19][C:20](=[O:22])[CH3:21])[C:6]=2[N:7]=1
Reactant: Nc1nc2[nH]c(=O)sc2c(=O)[nH]1
Reactant: CC(=O)OC[C@H]1OC(OC(C)=O)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Product: CC(=O)OC[C@H]1O[C@@H](n2c(=O)sc3c(=O)[nH]c(N)nc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O

Procedure:
Compound 4 (10 g, 54.4 mmol) was glycosylated exactly as described for the synthesis of 6 except that the sugar used in this case was the 1,2,3,5-tetra-O-acetyl-D-ribofuranose (20.7 g, 65.1 mmol). After the usual workup the crude residue was flash chromatographed on silica gel using 10% methanol in dichloromethane. Yield of pure material 7.1 g (29%) as a dry foam or amorphous solid.
Reaction SMILES: Cl.C([O:9][P:10]([CH2:19][C@H:20]([OH:23])[CH2:21][NH2:22])([CH2:12][CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:11])C1C=CC=CC=1.C([NH:34][C@H:35]([C:40](O)=[O:41])[C@H:36]([CH2:38][CH3:39])[CH3:37])(OCC1C=CC=CC=1)=O>>[NH2:34][C@@H:35]([CH:36]([CH3:37])[CH2:38][CH3:39])[C:40]([NH:22][CH2:21][C@@H:20]([OH:23])[CH2:19][P:10]([CH2:12][CH:13]1[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]1)(=[O:11])[OH:9])=[O:41]
Reactant: CC[C@H](C)[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: NC[C@@H](O)CP(=O)(CC1CCCCC1)OCc1ccccc1
Agent: Cl
Product: CCC(C)[C@H](N)C(=O)NC[C@@H](O)CP(=O)(O)CC1CCCCC1

Procedure:
Step 4, Method B of Example 1 was substantially repeated in this Example 6 except for employing ((R)-3-amino-2-hydroxy-propyl)-cyclohexylmethyl-phosphinic acid benzyl ester hydrochloride and N-Cbz-L-isoleucine as the starting materials. Subsequent hydrogenation of the resulting benzyl ester in accordance with the procedures of Step 5, Method A of Example 1 and RP-HPLC purification yielded the title compound. 1H NMR (CD3OD, 300 MHz): δ 4.18-4.03 (m, 1H), 3.72 (d, 1H), 3.40-3.35 (m, 2H), 2.01-1.85 (m, 5H), 1.80-1.50 (m, 7H), 1.42-1.18 (m, 4H), 1.17-0.95 (m, 8H). 31P NMR (CD3OD, 300 MHz): δ 53.18. LCMS m/z: [M+H]+=349.2.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:47])[C@@H:10]([NH:23][C:24](=[O:46])[C@@H:25]([NH:38]C(OC(C)(C)C)=O)[CH2:26][CH2:27][CH2:28][CH2:29][NH:30]C(OC(C)(C)C)=O)[CH2:11][CH2:12][CH2:13][CH2:14][NH:15]C(OC(C)(C)C)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:48]>O1CCOCC1>[ClH:48].[ClH:48].[ClH:48].[CH2:1]([O:8][C:9](=[O:47])[C@@H:10]([NH:23][C:24](=[O:46])[C@@H:25]([NH2:38])[CH2:26][CH2:27][CH2:28][CH2:29][NH2:30])[CH2:11][CH2:12][CH2:13][CH2:14][NH2:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)NCCCC[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](CCCCNC(=O)OC(C)(C)C)C(=O)OCc1ccccc1
Agent: Cl
Solvent: C1COCCO1
Product: NCCCC[C@H](NC(=O)[C@@H](N)CCCCN)C(=O)OCc1ccccc1
Reaction time: 3 h

Procedure:
The above prepared (S)-2-((S)-2,6-bis-tert-butoxycarbonylamino-hexanoylamino)-6-tert-butoxycarbonylamino-hexanoic acid benzyl ester (4.516, 6.793 mmol) was dissolved in 4 mol/L HCl in dioxane. After a couple of min, gas evolved and a precipitate was formed. After 3 h at ambient temperature, the reaction mixture was carefully evaporated and scrupulously dried to yield 3.81 g of the title compound as an off-white foam which was used without further purification for Example 7. E. GalNAc Cluster benzyl ester above, MS (ISP) 365.3 [M+H]+.
Reaction SMILES: N1(CCS(N2CCC(C3[C:25]4[C:20](=[C:21]([C:31](N)=[O:32])[CH:22]=[C:23](C5C=CSC=5)[CH:24]=4)NC=3)CC2)(=O)=O)CCCC1.Br[C:35]1[CH:36]=[C:37]2[C:41](=[C:42]([C:44]([NH2:46])=[O:45])[CH:43]=1)[NH:40][CH:39]=[C:38]2[CH:47]1[CH2:52][CH2:51][N:50]([S:53]([CH2:56][CH2:57][CH2:58][N:59]([CH3:61])[CH3:60])(=[O:55])=[O:54])[CH2:49][CH2:48]1.OCC1C=C(B(O)O)C=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:60][N:59]([CH3:61])[CH2:58][CH2:57][CH2:56][S:53]([N:50]1[CH2:49][CH2:48][CH:47]([C:38]2[C:37]3[C:41](=[C:42]([C:44]([NH2:46])=[O:45])[CH:43]=[C:35]([C:25]4[CH:24]=[CH:23][CH:22]=[C:21]([CH2:31][OH:32])[CH:20]=4)[CH:36]=3)[NH:40][CH:39]=2)[CH2:52][CH2:51]1)(=[O:55])=[O:54]
Reactant: CN(C)CCCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(Br)cc23)CC1
Reactant: NC(=O)c1cc(-c2ccsc2)cc2c(C3CCN(S(=O)(=O)CCN4CCCC4)CC3)c[nH]c12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: OCc1cccc(B(O)O)c1
Product: CN(C)CCCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cccc(CO)c4)cc23)CC1

Procedure:
The title compound was prepared following the general procedure described in intermediate 16. Thus, 5-bromo-3-(1-{[3-(dimethylamino)propyl]sulfonyl}-4-piperidinyl)-1H-indole-7-carboxamide (150 mg, 0.32 mmol), [3-(hydroxymethyl)phenyl]boronic acid (195 mg, 1.27 mmol), Pd(PPh3)4 (31 mg, 10%) and cesium carbonate (220 mg, 0.64 mmol) were reacted to form the desired product which was purified by reverse phase HPLC eluting with 10% B to 80% B, where A=H2O (0.1% trifluoroacetic acid) and B=CH3CN (0.1% trifluoroacetic acid) to yield the desired product (230.0 mg, 36%).
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:56])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([O:50][Si](C)(C)C)[CH:46]([Cl:55])[CH2:45]2)[CH:7]([CH3:57])[CH2:6][CH2:5][C:4]1=[O:58])[CH3:2].C1(C)C=CC(S(O)(=O)=O)=CC=1>C(Cl)Cl>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:56])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([OH:50])[CH:46]([Cl:55])[CH2:45]2)[CH:7]([CH3:57])[CH2:6][CH2:5][C:4]1=[O:58])[CH3:2]
Reactant: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(O[Si](C)(C)C)C(Cl)C3)C(C)CCC1=O)C(C)CC2OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Product: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(O)C(Cl)C3)C(C)CCC1=O)C(C)CC2OC
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of 17-ethyl-1-hydroxy-12-[2'-(3"-chloro-4"-trimethylsilyloxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone (20 mg) in 1 ml of methylene chloride was added a solution of p-toluenesulfonic acid (200 μl, 1% solution in methanol) and stirred for 20 minutes at room temperature. Purification of the crude product by preparative tlc on silica gel (1:1 hexane:ethyl acetate) gave the title compound in quantitative yield.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]Cl)=[C:6]([C:12]([Cl:15])([Cl:14])[Cl:13])[CH:5]=1)([O-:3])=[O:2].[CH2:16]([NH2:19])[CH:17]=[CH2:18]>>[CH2:16]([NH:19][S:10][C:7]1[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][C:6]=1[C:12]([Cl:15])([Cl:14])[Cl:13])[CH:17]=[CH2:18]
Reactant: O=[N+]([O-])c1ccc(SCl)c(C(Cl)(Cl)Cl)c1
Reactant: C=CCN
Product: C=CCNSc1ccc([N+](=O)[O-])cc1C(Cl)(Cl)Cl
Yield: 94.6 %

Procedure:
As in Example 4, 61.4 g of 4-nitro-2-trichloromethylbenzenesulfenyl chloride is reacted with 23 g of allylamine. The hydrochloride is filtered off and the ether phase is concentrated. There is obtained 62 g (95% of theory) of N-allyl-4-nitro-2-trichloromethylphenylsulfenamide as a pale oil.
Reaction SMILES: C(OC([N:8]1[CH2:12][C:11]([CH3:14])([CH3:13])[CH2:10][CH:9]1[C:15](=[O:17])[NH2:16])=O)(C)(C)C.[ClH:18].C(OCC)C>O1CCOCC1>[ClH:18].[CH3:13][C:11]1([CH3:14])[CH2:12][NH:8][CH:9]([C:15]([NH2:16])=[O:17])[CH2:10]1
Reactant: CC1(C)CC(C(N)=O)N(C(=O)OC(C)(C)C)C1
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Product: CC1(C)CNC(C(N)=O)C1
Reaction time: 1.5 h
Yield: 95 %

Procedure:
A solution of 2-carbamoyl-4,4-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (1.2 g, 4.95 mmol) in dioxane (5 mL) was cooled to 10° C. Hydrogen chloride dissolved in dioxane (10 mL, 6.4 N) was added and the mixture was stirred for 1.5 hours. Diethylether (50 mL) was added to completely precipitate the product, which was filtered and dried to give the title compound (0.84 g, 95%) as colorless solid; MS (ESI) 143.0 [MH+].
Reaction SMILES: [OH-].[Na+].[N+:3]([C:6]1[CH:7]=[C:8]2[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[N:12](C(OC)=O)[C:9]2=[N:10][CH:11]=1)([O-:5])=[O:4].O.C(OCC)(=O)C>C1COCC1.CO>[N+:3]([C:6]1[CH:7]=[C:8]2[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[NH:12][C:9]2=[N:10][CH:11]=1)([O-:5])=[O:4]
Reactant: COC(=O)n1c(C(F)(F)F)cc2cc([N+](=O)[O-])cnc21
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1cnc2[nH]c(C(F)(F)F)cc2c1
Temperature: 40 °C
Yield: 87.3 %

Procedure:
Sodium hydroxide (4.2 mL, 4.2 mmol, 1M in water) was added to a solution of methyl 5-nitro-2-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridine-1-carboxylate (0.35 g, 1.19 mmol) in THF (6.9 mL) and methanol (1.7 mL) at room temperature. The reaction mixture was heated at 40° C. for 30 minutes. The reaction mixture was then cooled down and treated with water and ethyl acetate. The layers were then separated. The organic layers were washed twice with water, dried over sodium sulfate, filtered, and evaporated to afford 5-nitro-2-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridine (0.24 g, 86%), which was carried to the next step without further purification.
Reaction SMILES: [NH2:1][CH:2]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:3]1([N:8]([CH3:10])[CH3:9])[CH2:7][CH2:6][CH2:5][CH2:4]1.ClC1C(C(F)(F)F)=CC=CC=1C(NC(C1(N(C)C)CCCC1)C1C=CC=CC=1)=O.[CH3:46][O:47][C:48]1[CH:56]=[CH:55][CH:54]=[C:53]([CH3:57])[C:49]=1[C:50](O)=[O:51].O.ON1C2C=CC=CC=2N=N1.C1CCC(N=C=NC2CCCCC2)CC1>C(Cl)Cl>[CH3:9][N:8]([CH3:10])[C:3]1([CH:2]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[NH:1][C:50](=[O:51])[C:49]2[C:48]([O:47][CH3:46])=[CH:56][CH:55]=[CH:54][C:53]=2[CH3:57])[CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: CN(C)C1(C(N)c2ccccc2)CCCC1
Reactant: COc1cccc(C)c1C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)C1(C(NC(=O)c2cccc(C(F)(F)F)c2Cl)c2ccccc2)CCCC1
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCl
Product: COc1cccc(C)c1C(=O)NC(c1ccccc1)C1(N(C)C)CCCC1
Reaction time: 8 h

Procedure:
A mixture of {1-[amino(phenyl)methyl]cyclopentyl}dimethylamine D3 enantiomer 2 (0.220 g, 1 mmol), 2-methoxy-6-methylbenzoic acid (0.200 g, 1.2 mmol), 1-hydroxybenzotriazole hydrate (0.183 g, 1.2 mmol) and PS-DCC (1 g of 1.3 mmol/g loading, 1.3 mmol) in DCM (10 ml) was stirred vigorously overnight. The mixture was washed with saturated aqueous sodium hydrogen carbonate, the layers separated through a phase separation cartridge and the organic layer applied to an SCX cartridge. The cartridge was eluted with DCM (×2), and then methanol (×2) followed by 1M ammonia in methanol. Evaporation of the solvent afforded the title compound which was characterised. 1H NMR (CDCl3) δ: 1.00-1.10 (1H, m), 1.25-1.40 (1H, m), 1.40-1.60 (2H, m), 1.60-1.80 (2H, m), 1.80-2.00 (2H, m), 2.24 (6H, s), 2.28 (3H, s), 3.80 (3H, s), 5.17 (1H, d, J=6 Hz), 6.75 (1H, d, J=8 Hz), 6.79 (1H, d, J=8 Hz), 7.10 (1H, br s), 7.15-7.30 (4H, m), 7.44 (2H, m). Mass Spectrum (Electrospray LC/MS): Found 367 (MH+). C23H30N2O2 requires 366. Ret. time 1.92 min. The title product was converted to the corresponding hydrochloride salt (0.34 g, 85%).
Reaction SMILES: [CH3:1][N:2]1[C:11]2[C:6](=[CH:7][N:8]=[C:9]([CH3:12])[CH:10]=2)[CH:5]=[C:4]([C:13]2[CH:14]=[C:15]([CH:19]=[CH:20][C:21]=2[CH3:22])[C:16]([NH2:18])=[O:17])[C:3]1=[O:23].C(Cl)(=O)[C:25](Cl)=[O:26]>ClCCCl>[CH3:1][N:2]1[C:11]2[C:6](=[CH:7][N:8]=[C:9]([CH3:12])[CH:10]=2)[CH:5]=[C:4]([C:13]2[CH:14]=[C:15]([CH:19]=[CH:20][C:21]=2[CH3:22])[C:16]([N:18]=[C:25]=[O:26])=[O:17])[C:3]1=[O:23]
Reactant: Cc1cc2c(cn1)cc(-c1cc(C(N)=O)ccc1C)c(=O)n2C
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCCl
Product: Cc1cc2c(cn1)cc(-c1cc(C(=O)N=C=O)ccc1C)c(=O)n2C

Procedure:
3-(1,7-Dimethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-4-methylbenzamide 30 (310 mg, 1 mmol) is heated with oxalyl chloride (1 mL) in 1,2-dichloroethane (2 mL) at reflux for 2 h. Solvent is evaporated to give 31 as a white solid which is used without purification.
Reaction SMILES: [OH-].[Na+].[O:3]=[C:4]1[C:13]([NH:19][C:20](=[O:23])[CH2:21][CH3:22])([C:14]([O:16]CC)=[O:15])[CH2:12][C:11]2=[CH:24][CH:25]=[CH:26][C:9]3=[C:10]2[N:5]1[CH2:6][CH2:7][CH2:8]3>CO>[O:3]=[C:4]1[C:13]([NH:19][C:20](=[O:23])[CH2:21][CH3:22])([C:14]([OH:16])=[O:15])[CH2:12][C:11]2=[CH:24][CH:25]=[CH:26][C:9]3=[C:10]2[N:5]1[CH2:6][CH2:7][CH2:8]3
Reactant: CCOC(=O)C1(NC(=O)CC)Cc2cccc3c2N(CCC3)C1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCC(=O)NC1(C(=O)O)Cc2cccc3c2N(CCC3)C1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 93.9 %

Procedure:
Sodium hydroxide solution (10 mL of 4.0 N, 0.04 mol) was slowly added to ethyl 2,3,6,7-tetrahydro-3-oxo-2-((1-oxopropyl)amino)-1H,5H-benzo(ij)quinolizine-2-carboxylate (3.33 g, 0.010 tool) in methanol (50 mL). After stirring at room temperature for 30 minutes, the solvent was removed under reduced pressure. The resulting solid was dissolved in water (20 mL) and methanol (trace), neutralized with 4N HC1 (10 mL, 0.04 mol), cooled to -10° C., and the precipitate was filtered off and air dried to give 2.86 g of 2,3,6,7-tetrahydro-3-oxo-2-((1-oxopropyl) amino)-1H,5H-benzo(ij)quinolizine-2-carboxylic acid. This was refluxed in ethanol for 20 minutes to effect decarboxylation. The ethanol was removed under reduced pressure and the solid was crystallized from ethyl acetate:hexane to give 1.85 g of N-(2,3,6,7-tetrahydro-3-oxo-1H, 5H-benzo(ij)quinolizin-2-yl)propanamide, mp 149°-152° C. A sample was recrystallized for analysis; mp 152°-154° C. Anal. Calc'd for C15H18N2O2 : C, 69.74; H, 7.02; N, 10.85. Found: C, 69.33; H, 7.33; N, 10.68.
Reaction SMILES: C([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]=[C:13]([CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:14]([NH:17][S:18]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=3)(=[O:20])=[O:19])=[N:15][CH:16]=2)=[CH:7][CH:6]=1)(=O)C.[OH-].[Na+].Cl>CO>[CH2:29]([C:13]1[C:14]([NH:17][S:18]([CH2:21][C:22]2[CH:23]=[CH:24][C:25]([OH:28])=[CH:26][CH:27]=2)(=[O:20])=[O:19])=[N:15][CH:16]=[C:11]([C:8]2[CH:7]=[CH:6][C:5]([OH:4])=[CH:10][CH:9]=2)[N:12]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: CC(=O)Oc1ccc(-c2cnc(NS(=O)(=O)Cc3ccc(O)cc3)c(Cc3ccccc3)n2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=S(=O)(Cc1ccc(O)cc1)Nc1ncc(-c2ccc(O)cc2)nc1Cc1ccccc1
Temperature: 25 °C
Yield: 45.3 %

Procedure:
5-(4-Acetoxyphenyl)-3-benzyl-2-[(4-hydroxybenzyl)sulfonylamino]pyrazine (c-48) (105 mg, 214 μmol) was dissolved in methanol (2 mL) and to this was added 10% (w/v) aqueous solution of sodium hydroxide (1.0 mL) while stirring at room temperature and then stirred at 60° C. for 2 h. After cooling to room temperature, to this was added 2 M hydrochloric acid to stop the reaction, and extracted 3 times with ethyl acetate. The organic layer was washed with saturated brine and then dried over anhydrous sodium sulfate. After removing a anhydrous sodium sulfate by filtration, the filtrate was concentrated under reduced pressure with a rotary evaporator. The residue was purified by column chromatography (10 g, n-hexane/ethyl acetate=1/1). Recrystallization from n-hexane/ethyl acetate gave 3-benzyl-2-(4-hydroxybenzyl)sulfonylamino-5-(4-hydroxyphenyl)pyrazine (coelenterasulfonamide) (c-38) as a yellow solid (43.4 mg, 45.2%). Rf=0.29 (n-hexane/ethyl acetate=1/1). Mp. 194.5-196.5° C. 1H NMR (400 MHz, DMSO-d6) δ 4.22 (s, 2H), 4.78 (s, 2H), 6.70-6.77 (AA′BB′, 2H), 6.83-6.90 (AA′BB′, 2H), 7.10-7.21 (m, 3H), 7.23-7.31 (m, 4H), 7.85-7.95 (AA′BB′, 2H), 8.81 (s, 1H), 9.54 (s, 1H), 9.81 (s, 1H), 10.30 (s, 1H). 13C NMR. (67.8 MHz, DMSO-d6) δ 38.0, 59.1, 115.4 (2C), 115.8 (2C), 119.9, 126.3, 126.6, 127.7 (2C), 128.3 (2C), 129.0 (2C), 132.0 (2C), 135.9, 138.2, 144.4, 145.7, 146.4, 157.7, 158.8. IR (KBr, cm−1) 536, 602, 700, 835, 889, 1119, 1155, 1177, 1258, 1275, 1327, 1402, 1456, 1514, 1611, 3529, 3412, 3487. Anal. Calcd. For C24H21N3O4S: C, 64.41; H, 4.73; N, 9.39. Found: C, 64.28; H, 4.74; N, 9.28.
Reaction SMILES: [CH3:1][C:2]1[C:7]2[O:8][C@@:9]([CH2:13][CH2:14][CH2:15][CH:16]([CH2:18][CH2:19][CH2:20][CH:21]([CH2:23][CH:24]([CH3:26])[CH3:25])[CH3:22])[CH3:17])([CH3:12])[CH2:10][CH2:11][C:6]=2[C:5]([CH3:27])=[C:4]([O:28][C:29]([CH2:31][CH2:32][C:33]([OH:35])=[O:34])=[O:30])[C:3]=1[CH3:36].CCCCCCCC(OCC(O)CO)=O.C[C:53]1[CH:58]=[C:57]([OH:59])[CH:56]=[C:55]2[CH2:60][CH2:61][C@:62]([CH2:65][CH2:66][CH2:67][C@@H:68]([CH2:70][CH2:71][CH2:72][C@@H:73]([CH2:75][CH2:76][CH2:77][CH:78]([CH3:80])[CH3:79])[CH3:74])[CH3:69])([CH3:64])[O:63][C:54]=12.CC[C@H]1OC(=O)[C@H](C)[C@@H](O[C@@H]2O[C@@H](C)[C@H](O)[C@@](OC)(C)C2)[C@H](C)[C@@H](O[C@@H]2O[C@H](C)C[C@H](N(C)C)[C@H]2O)[C@@](OC)(C)C[C@@H](C)C(=O)[C@H](C)[C@@H](O)[C@@]1(O)C>C(O)C>[CH3:74][C@H:73]([CH2:75][CH2:76][CH2:77][CH:78]([CH3:80])[CH3:79])[CH2:72][CH2:71][CH2:70][C@H:68]([CH2:67][CH2:66][CH2:65][C@@:62]1([CH3:64])[O:63][C:54]2[CH:53]=[CH:58][C:57]([OH:59])=[CH:56][C:55]=2[CH2:60][CH2:61]1)[CH3:69].[CH3:1][C:2]1[C:7]2[O:8][C@@:9]([CH2:13][CH2:14][CH2:15][CH:16]([CH2:18][CH2:19][CH2:20][CH:21]([CH2:23][CH:24]([CH3:25])[CH3:26])[CH3:22])[CH3:17])([CH3:12])[CH2:10][CH2:11][C:6]=2[C:5]([CH3:27])=[C:4]([O:28][C:29]([CH2:31][CH2:32][C:33]([OH:35])=[O:34])=[O:30])[C:3]=1[CH3:36]
Reactant: Cc1cc(O)cc2c1O[C@](C)(CCC[C@H](C)CCC[C@H](C)CCCC(C)C)CC2
Agent: CCCCCCCC(=O)OCC(O)CO
Agent: CC[C@H]1OC(=O)[C@H](C)[C@@H](O[C@H]2C[C@@](C)(OC)[C@@H](O)[C@H](C)O2)[C@H](C)[C@@H](O[C@@H]2O[C@H](C)C[C@H](N(C)C)[C@H]2O)[C@](C)(OC)C[C@@H](C)C(=O)[C@H](C)[C@@H](O)[C@]1(C)O
Agent: Cc1c(C)c2c(c(C)c1OC(=O)CCC(=O)O)CC[C@@](C)(CCCC(C)CCCC(C)CC(C)C)O2
Solvent: CCO
Product: CC(C)CCC[C@@H](C)CCC[C@@H](C)CCC[C@]1(C)CCc2cc(O)ccc2O1

Procedure:
Clarithromycin was obtained as the free base from Wockhardt (Delhi, India). Vitamin E Succinate (VESA) was obtained from Eastman (Freeport Tenn.). Capmul® MCM was obtained from Abitec (Janesville Wis.); Poloxamer® 407 (Pluronic® F-127) from BASF (Parsippany N.J.); PEG-400 from Spectrum Chemicals (Gardenia Calif.), and d-δ-tocopherol from Sigma Chemicals (St Louis MO). An oil phase consisting of d-δ-tocopherol and Capmul MCM was prepared using 2 parts of δ-tocopherol. Surfactant and clarithromycin were then added as shown in the table below. Dry ethanol was used to dissolve the components at 70° C. and the ethanol was then removed under vacuum. A clear amber oil resulted, but upon cooling, oblong, “casket-lid” crystals of clarithromycin were observed. A tocol-soluble ion pair of this compound was then produced by addition of a stoichiometric equivalent of Vitamin E succinate (VESA) as the free acid. On re-dissolution in ethanol and cooling no crystals formed. The clarithromycin was now sufficiently soluble in the tocopherol oil to allow subsequent preparation of the emulsion. The oil was then re-heated to 45° C. and degassed immediately prior to emulsification as described below.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[C:8]([C:10]#[N:11])[CH:7]=[CH:6][C:5]=1[OH:12].[C:14]([O-])([O-])=O.[K+].[K+].CI>CC(C)=O>[CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[C:8]([C:10]#[N:11])[CH:7]=[CH:6][C:5]=1[O:12][CH3:14]
Reactant: COC(=O)c1cc(C#N)ccc1O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: COC(=O)c1cc(C#N)ccc1OC
Temperature: 65 °C
Yield: 42 %

Procedure:
To a mixture of methyl-2-hydroxy-5-cyano-benzoate (2.g, 5.6 mmol), K2CO3 (4.68 g, 16.8 mmol) in acetone (50 ml) was added methyl iodide (0.7 ml, 5.6 mmol). The reaction was then heated at 65° C. overnight resulting in formation of a solid which was filtered off whilst hot and washed with acetone to give 5-cyano-2-methoxy-benzoic acid methyl ester (0.45 g). The crude product was dissolved in THF (5 ml) and then treated with LiOH (0.108 g 0.26 mmol) in water (5 ml) and stirred at room temperature overnight. The reaction was acidified with 2M HCl and extracted EtOAc (×2). The organic portion dried (MgSO4) and reduced in vacuo to give 5-cyano-2-methoxy-benzoic acid (0.277 g). (LC/MS Acidic: Rt 2.92, [M+H]+ 178).
Reaction SMILES: C([O-])(=O)C.[NH4+].[CH2:6]([O:13][C:14]1[C:19]([O:20][CH3:21])=[CH:18][C:17]([C:22](=[O:24])[CH3:23])=[C:16]([N+:25]([O-])=O)[CH:15]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C1(C)C=CC=CC=1>[Fe].O>[NH2:25][C:16]1[CH:15]=[C:14]([O:13][CH2:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:19]([O:20][CH3:21])=[CH:18][C:17]=1[C:22](=[O:24])[CH3:23]
Reactant: COc1cc(C(C)=O)c([N+](=O)[O-])cc1OCc1ccccc1
Agent: [Fe]
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: Cc1ccccc1
Solvent: O
Product: COc1cc(C(C)=O)c(N)cc1OCc1ccccc1

Procedure:
A Mixture of iron powder (477 mmol, 27 g), ammonium acetate (500 mmol, 31.g), 1-(4-Benzyloxy-5-methoxy-2-nitro-phenyl)-ethanone (120 mmol, 36 g), toluene (500 ml) and water (500 ml) was refluxed overnight, or until completion. The mixture was filtered through celite and washed with EtOAc. The organic layer washed with water and Sat. NaCl, dried over Na2SO4, and concentrated to afford the product, 90%. 1H NMR (CDCl3): 7.408-7.298 (5H, m), 7.130 (1H, s), 6.155 (2H, br), 6.104 (1H, s), 5.134 (2H, s), 3.834 (3H, s), 2.507 (3H, s). LC/MS (M+1=272).
Reaction SMILES: [CH:1]1([C:4]2[O:8][N:7](C)[CH:6](NC=O)[N:5]=2)[CH2:3][CH2:2]1.[CH2:13]([N:15](CC)[CH2:16]C)C.C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl.O>[CH:1]1([C:4]2[O:8][N:7]=[C:6]([CH2:16][N+:15]#[C-:13])[N:5]=2)[CH2:2][CH2:3]1
Reactant: CN1OC(C2CC2)=NC1NC=O
Reactant: CCN(CC)CC
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: [C-]#[N+]Cc1noc(C2CC2)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A stirred solution of 5-cyclopropyl-3-formylamino-methyl-1,2,4-oxadiazole (60 mmol) and triethylamine (176 mmol) in CH2Cl2 (100 ml) was charged dropwise with POCL3 (60 mmol) at 0° C. The mixture was then left for 30 minutes with stirring at 0° C., whereafter a solution of Na2CO3 (60 mmol) in H2O (50 ml) was added. The mixture was heated to room temperature, whereafter the organic phase was separated, dried and evaporated in vacuo. The residue was treated with ether, decanted and the solution was evaporated to give the title compound as an oil. The oil was processed without any further purification. The compound was characterized by its IR absorbtion band at 2160 cm-1.