Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([SH:5])[CH2:2][CH2:3][CH3:4].C[O-].[Na+].Cl.Cl[CH:11]([N:21]1[CH:25]=[CH:24][N:23]=[CH:22]1)[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=1[Cl:20].[NH4+].[OH-]>CO.C(OCC)(=O)C.O>[CH2:1]([S:5][CH:11]([N:21]1[CH:25]=[CH:24][N:23]=[CH:22]1)[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=1[Cl:20])[CH2:2][CH2:3][CH3:4]
Reactant: Clc1ccc(CC(Cl)n2ccnc2)c(Cl)c1
Reactant: CCCCS
Agent: C[O-]
Agent: Cl
Agent: [NH4+]
Solvent: O
Solvent: CO
Solvent: CCOC(C)=O
Product: CCCCSC(Cc1ccc(Cl)cc1Cl)n1ccnc1
Reaction time: 0.5 h

Procedure:
Butyl mercaptan, 4.32 g (0.048 mole), was added to a solution of 2.376 g (0.044 mole) sodium methoxide in 100 ml of methanol and the mixture stirred 30 minutes followed by addition of 10.0 g (0.032 mole) of 1-(α-chloro-2,4-dichlorophenethyl) imidazole hydrochloride in 100 ml methanol. The total mixture was heated to reflux for 4 hours. After cooling, the mixture was poured into an excess of H2O and the organic layer extracted with ether. The combined ether extracts were washed with 10% NaOH, with H2O, then dried over MgSO4, and filtered. Dry HCl gas was passed through the ether solution to give an oily liquid. Trituration of the oily salt in ethyl acetate was not successful in giving a solid product. The oily salt was dissolved in methanol, treated with excess NH4OH, and converted back to the free base. A total of 4.35 g (42.3%) of the free base was recovered. H1 nmr: DMSO δ TMS 7.38 (m, 6H, aryl/imidazole; 4.6 (m, 3H, CH/CH2), 0.6 to 2.76 (m, 9H, C4H9).
Reaction SMILES: [C:1]1([S:7]([C:10]([CH:19]2[CH2:31][C:22]3[NH:23][C:24]4[CH:25]=[CH:26][C:27]([Cl:30])=[CH:28][C:29]=4[C:21]=3[CH2:20]2)([F:18])[C:11]2[O:15][N:14]=[C:13]([CH2:16][NH2:17])[N:12]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CCN(C(C)C)C(C)C.[C:41](Cl)(=[O:48])[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1>C1COCC1>[C:1]1([S:7]([C:10]([CH:19]2[CH2:31][C:22]3[NH:23][C:24]4[CH:25]=[CH:26][C:27]([Cl:30])=[CH:28][C:29]=4[C:21]=3[CH2:20]2)([F:18])[C:11]2[O:15][N:14]=[C:13]([CH2:16][NH:17][C:41](=[O:48])[C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)[N:12]=2)(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: NCc1noc(C(F)(C2Cc3[nH]c4ccc(Cl)cc4c3C2)S(=O)(=O)c2ccccc2)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: O=C(NCc1noc(C(F)(C2Cc3[nH]c4ccc(Cl)cc4c3C2)S(=O)(=O)c2ccccc2)n1)c1ccccc1
Reaction time: 2 h
Yield: 52.2 %

Procedure:
To a stirred solution of 44 mg (0.095 mmol) of (RS,SR)-C-{5-[benzenesulfonyl-(7-chloro-1,2,3,4-tetrahydro-cyclopenta[b]indol-2-yl)-fluoro-methyl]-[1,2,4]oxadiazol-3-yl}-methylamine in 5 mL of THF, 19 μL (0.114 mmol, 1.2 eq) of Huenig's base and 11 μL (0.095 mmol, 1 eq) of benzoyl chloride were added at 0° C. After 2 hours, the reaction mixture was quenched by addition of an aqueous solution of NaHCO3 and extracted with CH2Cl2. The combined organic phases were dried over Na2SO4, filtered and evaporated. Column chromatography on silica gel EtOAc/Heptane 1:1 gave 28 mg (51%) of (RS,SR)-N-{5-[benzenesulfonyl-(7-chloro-1,2,3,4-tetrahydro-cyclopenta[b]indol-2-yl)-fluoro-methyl]-[1,2,4]oxadiazol-3-ylmethyl}-benzamide as a white solid, MS: 565 (M).
Reaction SMILES: O[CH2:2][C:3]1[N:4]=[CH:5][N:6]([C:8]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:7]=1.S(Cl)([Cl:29])=O>ClCCl>[Cl:29][CH2:2][C:3]1[N:4]=[CH:5][N:6]([C:8]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:7]=1
Reactant: OCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: ClCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 114.1 %

Procedure:
To a suspension of 4-hydroxymethyl-1-tritylimidazole (6.13 g, 18 mmol) in dichloromethane (75 mL), cooled using an ice/water, was added dropwise thionyl chloride (5.0 g, 42 mmol) over 6 min. The ice/water bath was removed and the reaction was stirred for an additional 30 min. The DCM and SOCl2 were removed under reduced pressure. The resulting solid was triturated with diisopropyl ether (200 mL), collected by filtration and dried in vacuo to give 7.37 g (>100%) of 83% pure 4-(chloromethyl)-1-trityl-1H-imidazole; retention time, 7.33 min.; column: YMC ODS-A (3 μm, 50×4.6 mm); gradient: 10% to 100% B in A over 10 min. at 1.25 mL/min. Solvent A: 0.1% TFA in water, Solvent B: 0.1% TFA in AcCN. LC/MS: ESI (M+H)+=359.2.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]2[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH:16]2[O:28][CH2:29][CH2:30][O:31]S(C2C=CC(C)=CC=2)(=O)=O)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:42][C:43]1[CH:48]=[CH:47][C:46]([CH2:49][CH2:50][NH:51][C:52](=[O:54])[CH3:53])=[C:45](O)[CH:44]=1>>[C:52]([NH:51][CH2:50][CH2:49][C:46]1[CH:45]=[CH:44][C:43]([F:42])=[CH:48][C:47]=1[O:31][CH2:30][CH2:29][O:28][CH:16]1[CH:15]([C:12]2[CH:13]=[CH:14][C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[CH:10][CH:11]=2)[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:25])([CH3:26])[CH3:27])=[O:22])[CH2:17]1)(=[O:54])[CH3:53]
Reactant: CC(=O)NCCc1ccc(F)cc1O
Reactant: Cc1ccc(S(=O)(=O)OCCOC2CN(C(=O)OC(C)(C)C)CCC2c2ccc(OCc3ccccc3)cc2)cc1
Product: CC(=O)NCCc1ccc(F)cc1OCCOC1CN(C(=O)OC(C)(C)C)CCC1c1ccc(OCc2ccccc2)cc1

Procedure:
Analogously to Method G, 6.7 g of tert-butyl 4-(4-benzyloxyphenyl)-3-[2-(toluene-4-sulphonyloxy)ethoxy]piperidine-1-carboxylate and 4.54 g of N-[2-(4-fluoro-2-hydroxyphenyl)ethyl]acetamide (Example 112b) are reacted. The title compound is obtained as a yellowish oil. Rf=0.16 (2:1 EtOAc-heptane); Rt=5.44.
Reaction SMILES: [C:1]1([CH3:19])[CH:6]=[CH:5][C:4]([C:7]2[O:8][C:9]3[CH:15]=[CH:14][C:13]([C:16]([OH:18])=O)=[CH:12][C:10]=3[N:11]=2)=[CH:3][CH:2]=1.CN(C(O[N:28]1N=N[C:30]2[CH:31]=[CH:32]C=N[C:29]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.C(N)CCC>CN(C)C=O.C(OCC)(=O)C>[CH2:29]([NH:28][C:16]([C:13]1[CH:14]=[CH:15][C:9]2[O:8][C:7]([C:4]3[CH:3]=[CH:2][C:1]([CH3:19])=[CH:6][CH:5]=3)=[N:11][C:10]=2[CH:12]=1)=[O:18])[CH2:30][CH2:31][CH3:32]
Reactant: Cc1ccc(-c2nc3cc(C(=O)O)ccc3o2)cc1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCCCN
Solvent: CCOC(C)=O
Product: CCCCNC(=O)c1ccc2oc(-c3ccc(C)cc3)nc2c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 21.6 %

Procedure:
To 2-p-tolylbenzo[d]oxazole-5-carboxylic acid (100 mg, 0.39 mmol) in dry dimethylformamide (10 mL) was added HATU (165 mg, 0.44 mmol) and diisopropylethylamine (206 μL, 1.18 mmol). The mixture was then stirred at room temperature for 10 min. Butan-1-amine (43 μL, 0.44 mmol) was then added and the resulting mixture was stirred at room temperature for 16 h. Ethyl acetate was added and the organic layer was washed three times with water. The combined organic layers were dried over anhydrous MgSO4 and evaporated. The resulting solid was purified by column chromatography eluting with ethyl acetate/hexanes 40:60 v/v to afford 26 mg (11%) of the title compound (LCMS RT=6.81 min, MH+ 309.1)
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[CH:3]([OH:27])[CH2:4][NH:5][C:6]([C:8]1[C:13]([N:14]2C(C)=CC=C2C)=[CH:12][C:11]([C:21]([F:24])([F:23])[F:22])=[C:10]([O:25][CH3:26])[N:9]=1)=[O:7].Cl.NO>CCO.O>[F:29][C:2]([F:1])([F:28])[CH:3]([OH:27])[CH2:4][NH:5][C:6]([C:8]1[C:13]([NH2:14])=[CH:12][C:11]([C:21]([F:22])([F:24])[F:23])=[C:10]([O:25][CH3:26])[N:9]=1)=[O:7]
Reactant: COc1nc(C(=O)NCC(O)C(F)(F)F)c(-n2c(C)ccc2C)cc1C(F)(F)F
Agent: Cl
Agent: NO
Solvent: O
Solvent: CCO
Product: COc1nc(C(=O)NCC(O)C(F)(F)F)c(N)cc1C(F)(F)F
Temperature: 25 °C

Procedure:
3-(2,5-Dimethyl-pyrrol-1-yl)-6-methoxy-5-trifluoromethyl-pyridine-2-carboxylic acid (3,3,3-trifluoro-2-hydroxy-propyl)-amide (350 mg, 0.823 mmol) was dissolved in EtOH (14 ml) and water (7 ml). Hyroxylamine hydrochloride (572 mg, 8.23 mmol) was added followed by TEA (167 mg, 1.646 mmol) and the mixture was heated at reflux overnight. After cooling the RT, the mixture was purified by reverse phase chromatography eluting with MeOH; water (0.1% TFA) to afford the title compound as a pale yellow solid; LC-MS Rt=4.20 min [M+H]+ 348.2 (Method 10minLC_v002)
Reaction SMILES: [O:1]=[C:2]1[CH:7]=[C:6]([CH2:8][NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH:5]=[CH:4][NH:3]1.C([O-])([O-])=O.[K+].[K+].Br[C:24]1[CH:29]=[CH:28][N:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=1.CN[C@@H]1CCCC[C@H]1NC>C1(C)C=CC=CC=1.[Cu]I.C(OCC)(=O)C>[O:1]=[C:2]1[CH:7]=[C:6]([CH2:8][NH:9][C:10](=[O:16])[O:11][C:12]([CH3:13])([CH3:15])[CH3:14])[CH:5]=[CH:4][N:3]1[C:24]1[CH:29]=[CH:28][N:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=1
Reactant: CC(C)(C)OC(=O)NCc1cc[nH]c(=O)c1
Reactant: FC(F)(F)c1cc(Br)ccn1
Agent: [Cu]I
Agent: CN[C@@H]1CCCC[C@H]1NC
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)NCc1ccn(-c2ccnc(C(F)(F)F)c2)c(=O)c1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a reaction vessel containing a stir bar was charged with tert-butyl (2-oxo-1,2-dihydropyridin-4-yl)methylcarbamate 56-4 (72 mg, 0.32 mmol), CuI (12 mg, 0.06 mmol), and K2CO3 (88 mg, 0.64 mmol). The reaction vessel was evacuated and backfilled with nitrogen. A solution of 4-bromo-2-(trifluoromethyl)pyridine 56-5 (94 mg, 0.42 mmol) and (1R,2R)—N1,N2-dimethylcyclohexane-1,2-diamine (9 mg, 0.06 mmol) in toluene (3 mL) was added via syringe. The reaction was stirred at room temperature for 20 minutes, then 110° C. overnight. The reaction mixture was diluted into ethyl acetate and filtered through celite pad to remove salt. The filtrate was dried and the residue was purified by silica gel flash chromatography, and eluted with 50% ethyl acetate to give tert-butyl (2-oxo-1-(2-(trifluoromethyl)pyridin-4-yl)-1,2-dihydropyridin-4-yl)methylcarbamate 56-6. MS m/z 370.2 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:26]=[CH:25][C:24]([O:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[CH:23][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][N:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)=[C:9]([O:21][CH3:22])[CH:8]=1)=[O:5].[CH2:34](OC(OCC)OCC)C>ClCCCl.C1CCN2C(=NCCC2)CC1>[CH3:22][O:21][C:9]1[CH:8]=[C:7]([N:6]2[C:4](=[O:5])[C:3]3[C:2](=[CH:26][CH:25]=[C:24]([O:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[CH:23]=3)[N:1]=[CH:34]2)[CH:12]=[CH:11][C:10]=1[O:13][CH2:14][CH2:15][N:16]1[CH2:17][CH2:18][CH2:19][CH2:20]1
Reactant: CCOC(OCC)OCC
Reactant: COc1cc(NC(=O)c2cc(Oc3ccccc3)ccc2N)ccc1OCCN1CCCC1
Solvent: ClCCCl
Solvent: C1CCC2=NCCCN2CC1
Product: COc1cc(-n2cnc3ccc(Oc4ccccc4)cc3c2=O)ccc1OCCN1CCCC1
Temperature: 80 °C

Procedure:
A solution of 2-amino-N-[3-methoxy-4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-5-phenoxy-benzamide [Example D1] (25 mg, 0.055 mmol) in 1,2-dichloroethane (1 ml) was treated with triethylorthoformate (2 ml) and the mixture heated to 80° C. for 16 hours. The mixture was cooled, 1 drop of DBU added and the mixture evaporated. The residue was subjected to flash chromatography on silica gel eluting with (methanol-dichloromethane-aqueous ammonia) to give the title compound;
Reaction SMILES: [CH:1]([Si:4]([CH:15](C)C)([CH:12](C)C)[C:5]1[CH2:10][CH:9]=[C:8]([CH3:11])[CH2:7][CH:6]=1)(C)C.C([O-])(O)=O.[Na+]>O.O.O.[Ru](Cl)(Cl)Cl.COCCO>[CH3:1][Si:4]([CH3:12])([CH3:15])[C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][CH:6]=1
Reactant: CC1=CCC([Si](C(C)C)(C(C)C)C(C)C)=CC1
Agent: Cl[Ru](Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCO
Solvent: O
Product: Cc1ccc([Si](C)(C)C)cc1
Temperature: 25 °C
Yield: 73 %

Procedure:
In a 150-ml Schlenk flask, 1.18 g (4.5 mmol) of ruthenium chloride trihydrate, 5.6 g (22.5 mmol) of triisopropyl(4-methyl-1,4-cyclohexadienyl)silane, 0.38 g (4.5 mmol) of NaHCO3, and 11 ml of 2-methoxyethanol were added, and the mixture was allowed to react for 9 hours at 130° C. Subsequently, the mixture was left to cool to room temperature, and precipitated crystals were filtered. Thus, 1.4 g of objective [RuCl2 (4-(triisopropylsilyl)toluene)]2 was obtained at a yield of 73.0%.
Reaction SMILES: CO[C:3]([C:5]1[C:6]([OH:28])=[C:7]2[C:12](=[CH:13][N:14]=1)[N:11]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:10](=[O:21])[C:9]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[CH:8]2)=[O:4].[NH2:29][CH2:30][CH2:31][C:32]([OH:34])=[O:33].C[O-].[Na+]>>[OH:28][C:6]1[C:5]([C:3]([NH:29][CH2:30][CH2:31][C:32]([OH:34])=[O:33])=[O:4])=[N:14][CH:13]=[C:12]2[C:7]=1[CH:8]=[C:9]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:10](=[O:21])[N:11]2[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: COC(=O)c1ncc2c(cc(-c3ccccc3)c(=O)n2-c2ccccc2)c1O
Reactant: NCCC(=O)O
Agent: C[O-]
Agent: [Na+]
Product: O=C(O)CCNC(=O)c1ncc2c(cc(-c3ccccc3)c(=O)n2-c2ccccc2)c1O
Temperature: 25 °C
Yield: 86.2 %

Procedure:
A mixture of 5-hydroxy-2-oxo-1,3-diphenyl-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (30 mg, 0.081 mmol), β-alanine (431 mg, 4.84 mmol) and NaOMe solution (8 mL, 4.03 mmol, 0.5 M in MeOH) was refluxed for 16 h. After the mixture was cooled to r.t., the solvent was evaporated in vacuo. The residue was dissolved in water and washed several times with ether. The aqueous layer was acidified to pH 2 with 4 M HCl, and the resulting precipitate was isolated by filtration to give 30 mg of the title compound as a light yellow solid. MS: (+) m/z 430.27 (M+1).
Reaction SMILES: [CH2:1]([Li])[CH2:2][CH2:3]C.[I-].C([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)(C)C.[C:29]([O:33][C:34]([N:36]1[CH2:41][CH2:40][CH:39]([N:42]([CH3:51])[C:43]2[C:48]([CH:49]=O)=[CH:47][CH:46]=[CH:45][N:44]=2)[CH2:38][CH2:37]1)=[O:35])([CH3:32])([CH3:31])[CH3:30]>>[C:29]([O:33][C:34]([N:36]1[CH2:41][CH2:40][CH:39]([N:42]([CH3:51])[C:43]2[C:48]([CH:49]=[C:2]([CH3:3])[CH3:1])=[CH:47][CH:46]=[CH:45][N:44]=2)[CH2:38][CH2:37]1)=[O:35])([CH3:32])([CH3:31])[CH3:30]
Reactant: CN(c1ncccc1C=O)C1CCN(C(=O)OC(C)(C)C)CC1
Reactant: [Li]CCCC
Agent: CC(C)[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [I-]
Product: CC(C)=Cc1cccnc1N(C)C1CCN(C(=O)OC(C)(C)C)CC1

Procedure:
Following the general procedure of EXAMPLE 16 and making non-critical variations but starting with n-butyl lithium (1.6M, 3.9 ml, 6.26 mmol), isopropyltriphenylphosphonium iodide (2.71 g, 6.26 mmol), and 1-tert-butoxycarbonyl-4-[N-methyl-N-(3-(formyl)-2-pyridinyl)amino]piperidine (XXIV, EXAMPLE 26) (1.0 g, 3.13 mmol), the title compound is obtained, NMR (300 MHz, CDCl3) 1.30, 1.50-1.59, 1.64, 1.75, 2.42-2.50, 2.61, 3.40-3.50, 3.95-4.06, 5.88, 6.62, 7.18 and 7.95δ.
Reaction SMILES: [CH:1]1[C:6]2[C:7](=O)[NH:8][C:9]3[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=3[S:11][C:5]=2[CH:4]=[CH:3][CH:2]=1.[NH:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1>>[N:17]1([C:7]2[C:6]3[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=3[S:11][C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[N:8]=2)[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1
Reactant: C1CNCCN1
Reactant: O=C1Nc2ccccc2Sc2ccccc21
Product: c1ccc2c(c1)N=C(N1CCNCC1)c1ccccc1S2
Yield: 10.5 %

Procedure:
10H-Dibenzo[b,f][1,4]thiazepin-11-one (23 mg, 0.1 mmol) and piperazine (43 mg, 0.5 mmol) were reacted according to GP4 to give 3.1 mg of the title compound (160FE17A). MS (ESI) 296 (MH+). Purity for MH+ (UV/MS) 97/90.
Reaction SMILES: C(N(C(C)C)CC)(C)C.[OH:10][C:11]([C:39]1[CH:40]=[C:41]2[C:46](=[CH:47][CH:48]=1)[CH:45]=[C:44]([C:49]([NH:51][CH3:52])=[O:50])[CH:43]=[CH:42]2)([C:15]1[N:16]=[CH:17][N:18](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:19]=1)[CH2:12][CH2:13]O.CS(Cl)(=O)=O.[Cl-].[NH4+]>C(OCC)(=O)C.CO.O.CS(C)=O.C1COCC1>[OH:10][C:11]1([C:39]2[CH:40]=[C:41]3[C:46](=[CH:47][CH:48]=2)[CH:45]=[C:44]([C:49]([NH:51][CH3:52])=[O:50])[CH:43]=[CH:42]3)[C:15]2[N:16]([CH:17]=[N:18][CH:19]=2)[CH2:13][CH2:12]1
Reactant: CNC(=O)c1ccc2cc(C(O)(CCO)c3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)cn3)ccc2c1
Agent: CS(=O)(=O)Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CNC(=O)c1ccc2cc(C3(O)CCn4cncc43)ccc2c1
Temperature: 25 °C
Reaction time: 0.42 h
Yield: 80 %

Procedure:
20 mL of THF and 1.23 mL (3.14 mmol, 2 eq) of diisopropylethylamine were added to 2 g (3.523 mmol) of 6-[1,3-dihydroxy-1-(1-trityl-1H-imidazol-4-yl)propyl]-N-methyl-2-naphtamide. 20 mL of THF was further added. 0.35 mL (4.58 mmol, 1.3 eq) of methylsulfonyl chloride was added dropwise at 2˜3° C., and the mixture was stirred at 2˜3° C. for 25 minutes. 16 mL of dimethyl sulfoxide was added dropwise at 2˜3° C., and the mixture was stirred at 0˜3° C. for 45 minutes. 0.2 mL of methylsulfonyl chloride and 0.5 mL of diisopropylethylamine were added at 0˜3° C., and the mixture was stirred at 0˜3° C. for 20 minutes. 4 mL of water was added dropwise at 0˜8° C., and the layers were separated. The aqueous layer was re-extracted with 10 mL of ethyl acetate two times, the organic layers were combined, and washed with 4 mL of an aqueous saturated sodium chloride solution two times. The material was dried with magnesium sulfate, and concentrated under reduced pressure. The concentration residue was dissolved in 15 mL of acetonitrile, and the solution was stirred at 60˜63° C. for 20 minutes. To the reaction solution were added 4.5 mL of methanol and 1.23 mL (3.14 mmol, 2 eq) of diisopropylethylamine. The mixture was stirred at 60˜63° C. for 2 hours. After cooled to 25° C., 30 mL of an aqueous saturated ammonium chloride solution and 40 mL of ethyl acetate were added, and the layers were separated. The organic layer was back extracted with 10 mL of 0.5N hydrochloric acid-aqueous saturated ammonium chloride solution. The aqueous layers were combined, a pH was adjusted to 8 with a 30% aqueous sodium hydroxide solution, followed by stirring at 25° C. for 18 hours and 15 minutes, and at 0˜5° C. for 1 hour and 25 minutes. Crystals were filtered, and washed with water. Vacuum drying (50° C.) to a constant weight afforded 0.87 g. of 6-[7-hydroxy-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-7-yl]-N-methyl-2-naphthamide (yield 80%).
Reaction SMILES: [CH2:1]([N:8]([CH2:16][CH2:17][NH:18]C(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH2:9]/[CH:10]=[CH:11]/[C:12]([O:14][CH3:15])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O1CCOCC1>CO>[CH2:1]([N:8]1[CH2:16][CH2:17][NH:18][CH:10]([CH2:11][C:12]([O:14][CH3:15])=[O:13])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)/C=C/CN(CCNC(c1ccccc1)(c1ccccc1)c1ccccc1)Cc1ccccc1
Solvent: C1COCCO1
Solvent: CO
Product: COC(=O)CC1CN(Cc2ccccc2)CCN1
Temperature: 50 °C

Procedure:
To a solution of Example 12B (160 g, 326 mmol) in methanol (652 mL) was added 4 MHCl in dioxane (408 mL, 1630 mmol) and the mixture was heated at 50° C. for 3 hours. The solvent was then evaporated and water was added. A solid precipitates. The water layer was decanted and washed once with ethyl acetate. The solid was dissolved in ethyl acetate and extracted with water once. The water layers were combined and treated with 1N NaOH (1 L) until pH=10. The free amine was extracted twice with dichloromethane, dried over sodium sulfate and concentrated to afford the title compound. 1H NMR (500 MHz, DMSO-d6) δ ppm 7.34-7.20 (m, 5H), 3.57 (s, 3H), 3.42 (q, J=13.4 Hz, 2H), 2.96 (qd, J=2.7 Hz, 6.9 Hz, 1H), 2.78 (dt, J=2.9 Hz, 11.9 Hz, 1H), 2.69-2.60 (m, 2H), 2.55 (d, J=10.8 Hz, 1H), 2.30 (dd, J=3.2 Hz, 6.7 Hz, 2H), 1.92 (td, J=2.8 Hz, 10.6 Hz, 1H), 1.68 (t, J=10.0 Hz, 1H); MS (ESI) m/z 249.0 (M+H)+.
Reaction SMILES: C([CH:5]1[C@H:9]([O:10][CH3:11])[CH2:8][CH2:7][N:6]1[C:12]([O-])=O)(C)(C)C.CCOCC.[N+:20]([C:23]1[CH:30]=[CH:29][C:26](CBr)=[CH:25][CH:24]=1)([O-:22])=[O:21]>Cl>[CH3:11][O:10][CH:9]1[CH2:8][CH2:7][N:6]([CH2:12][C:26]2[CH:29]=[CH:30][C:23]([N+:20]([O-:22])=[O:21])=[CH:24][CH:25]=2)[CH2:5]1
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Reactant: CO[C@@H]1CCN(C(=O)[O-])C1C(C)(C)C
Agent: Cl
Solvent: CCOCC
Product: COC1CCN(Cc2ccc([N+](=O)[O-])cc2)C1
Reaction time: 0.5 h
Yield: 67.1 %

Procedure:
An amount of 1.8 g (9.02 mmol) of tert-butyl-(3R)-3-methoxypyrrolidin-1-yl carboxylate is stirred in concentrated hydrogen chloride (10 mL) for two hours. Anhydrous ether (100 mL) is added and stirred for additional 30 minutes. The ether is decanted and this is repeated three times. The mixture is neutralized with excess triethylamine and after evaporating to dryness, the mixture is re-dissolved in methylene chloride (100 mL) and 1.5 g (6.94 mmol) of 4-nitrobenzylbromide is added and refluxed for two hours. After cooling, the mixture is washed three times with aqueous sodium bicarbonate, dried over magnesium sulfate and evaporated to give 1.1 g (67% yield) of the nitro intermediates as a yellow oil.
Reaction SMILES: COC1C=[C:7]([C:9]2[CH:14]=[CH:13][C:12](N)=[C:11]([O:16]C)[CH:10]=2)[CH:6]=[CH:5][C:4]=1N.[OH-].[Na+]>>[CH:10]1[C:9]2[C:14](=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH:13]=[CH:12][C:11]=1[OH:16]
Reactant: COc1cc(-c2ccc(N)c(OC)c2)ccc1N
Agent: [Na+]
Agent: [OH-]
Product: Oc1ccc2ccccc2c1
Reaction time: 0.5 h

Procedure:
Silica particles were derivatized with o-dianisidine by Method No. 2. After drying, 1.0 gm of the carrier was diazotized with sodium nitrite. After diazotization the derivative was washed several times with borate (0.03M) buffered saline (0.15M) pH 8.0. The derivative was then reacted with 1.5 ml of T4 antisera (titer 1:10000) at 4°C. with stirring. The pH was maintained between 8.0 - 8.5 with 0.1N NaOH. After 30 minutes the pH stabilized at 8.2 and the reaction was stirred slowly at 4°C. overnight. After this time the composite gave a negative β-napthol test indicating no more remaining functional diazo groups. The preparation was then washed (4X) with phosphate-buffer (0.03M) saline (0.15M) containing 0.1% bovine serum albumin (PBS-BSA).
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([N+:13]([O-:15])=[O:14])[CH:7]=1)=[O:4].C(=O)([O-])[O-].[K+].[K+].[NH:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1>C1COCC1>[CH3:12][C:9]1[CH:10]=[CH:11][C:6]([NH:5][C:3](=[O:4])[CH2:2][N:22]2[CH2:26][CH2:25][CH2:24][CH2:23]2)=[CH:7][C:8]=1[N+:13]([O-:15])=[O:14]
Reactant: C1CCNC1
Reactant: Cc1ccc(NC(=O)CCl)cc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: Cc1ccc(NC(=O)CN2CCCC2)cc1[N+](=O)[O-]
Yield: 74.4 %

Procedure:
A solution of 2-chloro-N-(4-methyl-3-nitrophenyl)acetamide (1.0 g, 4.39 mmol), potassium carbonate (3.63 g, 26.3 mmol), pyrrolidine (0.93 g, 13.2 mmol, Aldrich), and catalytic Kl (˜100 mg, Aldrich) in anhydrous THF (50 mL) was heated for 3 hrs at 60° C. The solvent was removed under reduced pressure, residue redissolved in dichloromethane (100 mL), washed with water (100 mL) and purified by column chromatography (dichloromethane to 10% methanol/dichloromethane) to provide N-(4-methyl-3-nitrophenyl)-2-(1-pyrrolidinyl)acetamide (0.86 g, 75%). ESIMS (M+H)+=264.
Reaction SMILES: S(Cl)([Cl:3])=O.[ClH:5].Cl.[CH3:7][C@H:8]1[NH:13][C@@H:12]([CH3:14])[CH2:11][N:10]([CH2:15][CH2:16][CH2:17]O)[CH2:9]1>>[ClH:3].[ClH:5].[CH3:7][C@H:8]1[NH:13][C@@H:12]([CH3:14])[CH2:11][N:10]([CH2:15][CH2:16][CH2:17][Cl:5])[CH2:9]1
Reactant: C[C@@H]1CN(CCCO)C[C@H](C)N1
Reactant: O=S(Cl)Cl
Agent: Cl
Product: C[C@@H]1CN(CCCCl)C[C@H](C)N1

Procedure:
Thionyl chloride (300 g) was slowly added to 3-(3,5-cis-dimethylpiperazino)propanol dihydrochloride (200 g). The reaction was gently refluxed for an hour followed by removal of excess thionyl chloride by vacuum distillation. The resulting solid was washed with several portions of benzene then several portions of ether, m.p. 291°-292°.