Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O-:2].[Na+].[F:4][C:5]1[C:10](F)=[C:9]([CH:12]=[O:13])[CH:8]=[CH:7][C:6]=1[C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=1>CO>[F:4][C:5]1[C:10]([O:2][CH3:1])=[C:9]([CH:12]=[O:13])[CH:8]=[CH:7][C:6]=1[C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=1
Reactant: O=Cc1ccc(-c2ccc(F)cc2)c(F)c1F
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1c(C=O)ccc(-c2ccc(F)cc2)c1F
Temperature: 25 °C
Yield: 97.8 %

Procedure:
Sodium methoxide (28% methanol solution, 7.37 g) was added at room temperature to a methanol (160 mL) solution of 2,3,4′-trifluorobiphenyl-4-carbaldehyde (6.01 g), and the mixture was heated to reflux for 18 hours in a nitrogen atmosphere. The reaction mixture was cooled to room temperature, and then, the solvent was distilled off under reduced pressure. The obtained residue was diluted with ethyl acetate and water, followed by extraction with ethyl acetate. The obtained organic layer was washed with water and saturated saline in this order and dried over anhydrous magnesium sulfate, and then, the solvent was distilled off under reduced pressure to obtain the title compound (6.18 g).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6](=[O:8])[CH3:7].[H-].[Na+].[N:11]([C:14]1[CH:15]=[CH:16][C:17]([CH3:33])=[C:18]([C:20]2[C:21](=[O:32])[N:22]([CH3:31])[C:23]3[C:28]([CH:29]=2)=[CH:27][N:26]=[C:25]([CH3:30])[CH:24]=3)[CH:19]=1)=[C:12]=[S:13].[CH3:34]I>CN(C=O)C>[CH3:31][N:22]1[C:23]2[C:28](=[CH:27][N:26]=[C:25]([CH3:30])[CH:24]=2)[CH:29]=[C:20]([C:18]2[CH:19]=[C:14]([NH:11]/[C:12](/[S:13][CH3:34])=[CH:7]/[C:6](=[O:8])[C:2]3[S:1][CH:5]=[CH:4][N:3]=3)[CH:15]=[CH:16][C:17]=2[CH3:33])[C:21]1=[O:32]
Reactant: Cc1cc2c(cn1)cc(-c1cc(N=C=S)ccc1C)c(=O)n2C
Reactant: CC(=O)c1nccs1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CS/C(=C\C(=O)c1nccs1)Nc1ccc(C)c(-c2cc3cnc(C)cc3n(C)c2=O)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 1-(thiazol-2-yl)ethanone (24.0 mg, 0.2 mmol) and NaH (16.0 mg, 0.4 mmol, 60% in mineral oil) in DMF (1 mL) was added 3-(5-isothiocyanato-2-methylphenyl)-1,7-dimethyl-1,6-naphthyridin-2(1H)-one 19 (64.5 mg, 0.2 mmol) at rt. The reaction was stirred for 1 h at rt. Then MeI (29 mg, 0.20 mmol) was added. The reaction was quenched with water after 10 min and extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated to yield crude (Z)-1,7-dimethyl-3-(2-methyl-5-(1-(methylthio)-3-oxo-3-(thiazol-2-yl)prop-1-enylamino)phenyl)-1,6-naphthyridin-2(1H)-one 32 which was used without purification. MS m/z 463.1 (M+1).
Reaction SMILES: C[Si](Cl)(C)C.[I-].[Na+].C(#N)C.O[CH:12]([C:31]1[CH:43]=[CH:42][C:34]([O:35][CH2:36][C:37]([O:39][CH2:40][CH3:41])=[O:38])=[C:33]([CH3:44])[CH:32]=1)[CH2:13][CH2:14][C:15]1[S:19][C:18]([C:20]2[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=2)=[N:17][C:16]=1[CH3:30]>C1CCCCC1>[CH2:40]([O:39][C:37](=[O:38])[CH2:36][O:35][C:34]1[CH:42]=[CH:43][C:31]([CH2:12][CH2:13][CH2:14][C:15]2[S:19][C:18]([C:20]3[CH:21]=[CH:22][C:23]([C:26]([F:28])([F:27])[F:29])=[CH:24][CH:25]=3)=[N:17][C:16]=2[CH3:30])=[CH:32][C:33]=1[CH3:44])[CH3:41]
Reactant: CCOC(=O)COc1ccc(C(O)CCc2sc(-c3ccc(C(F)(F)F)cc3)nc2C)cc1C
Agent: C[Si](C)(C)Cl
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Solvent: C1CCCCC1
Product: CCOC(=O)COc1ccc(CCCc2sc(-c3ccc(C(F)(F)F)cc3)nc2C)cc1C
Temperature: 21 °C
Reaction time: 18 h

Procedure:
To a stirred mixture of trimethylsilylchloride (0.15 ml), sodium iodide (0.175 g) and acetonitrile (0.061 ml) was added a solution of ethyl [4-(1-hydroxy-3-{4-methyl-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}propyl)-2-methylphenoxy]acetate (intermediate 12, 0.096 g) in cyclohexane (1 ml). The reaction mixture was stirred at 21° C. for 18 hours and then refluxed for 2 hours. The reaction mixture was partitioned between water and ethyl acetate; the aqueous layer separated and extracted twice more with ethyl acetate. The organic solutions were combined and were dried with brine and over magnesium sulfate and concentrated. The product isolated after evaporation of the solvent was further purified by flash chromatography using cyclohexane: ethyl acetate (7:1) as eluent to give the title compound as a pale yellow gum.
Reaction SMILES: [CH3:1][C@@:2]12[C@@H:10]([OH:11])[CH2:9][CH2:8][C@H:7]1[C@@H:6]1[CH2:12][CH2:13][C:14]3[C@@:20]([CH3:21])([C@H:5]1[CH2:4][CH2:3]2)[CH2:19][CH2:18][C:16](=[O:17])[CH:15]=3.CC(=[O:34])C(Cl)CCCCCCCC.O>N1C=CC=CC=1.CC(C)=O>[CH3:1][C@@:2]12[C@@H:10]([OH:11])[CH2:9][CH2:8][C@H:7]1[C@@H:6]1[CH2:12][CH2:13][C:14]3[C@@:20]([CH3:21])([C@H:5]1[CH2:4][CH2:3]2)[CH2:19][CH2:18][C:16](=[O:17])[CH:15]=3.[CH3:1][CH:2]([CH2:3][CH2:4][CH2:5][CH2:20][CH2:19][CH2:18][CH2:16][CH3:15])[C:10](=[O:34])[O-:11]
Reactant: CCCCCCCCC(Cl)C(C)=O
Agent: C[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@]43C)[C@@H]1CC[C@@H]2O
Solvent: c1ccncc1
Solvent: O
Solvent: CC(C)=O
Product: CCCCCCCCC(C)C(=O)[O-]
Temperature: -10 °C
Reaction time: 2 h

Procedure:
To a solution of 2 g testosterone in a mixture of 8 ml pyridine and 8 ml acetone, cooled to -10° C., was added dropwise in a nitrogen atmosphere a solution of 4 ml α-methyl-decanoyl-chloride in 12 ml acetone. The mixture was stirred for 16 hours at 0° C., whereafter 4 ml pyridine and 8 ml water were added to the mixture. The mixture was stirred for 1 hour at 0° C. and 2 hours at 45° C. and then poured out in 200 ml ice-water. Extraction with diethylether neutralisation of the extracts, evaporation of the diethylether and chromatography of the residue on silicagel with toluene/ethylacetate 8/2 gave 3.0 g testosterone α-methyl-caprate in the form of an oil with [α]D20 =+77.0° (in methylenechloride) and εmol 16.800 (λmax 240 mμ).
Reaction SMILES: [Si:1]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]#[C:27][CH2:28][CH2:29][CH2:30][CH2:31][O:32]C1CCCCO1)([C:14]([CH3:17])([CH3:16])[CH3:15])([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.CC1C=CC(S([O-])(=O)=O)=CC=1.C1C=C[NH+]=CC=1>>[Si:1]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]#[C:27][CH2:28][CH2:29][CH2:30][CH2:31][OH:32])([C:14]([CH3:16])([CH3:17])[CH3:15])([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)[Si](OCCCCCCCC#CCCCCOC1CCCCO1)(c1ccccc1)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Product: CC(C)(C)[Si](OCCCCCCCC#CCCCCO)(c1ccccc1)c1ccccc1
Yield: 91.4 %

Procedure:
Following the procedure applied in the synthesis of analog 25, 1-tert-butyldiphenylsilyloxy-13-(tetrahydro-2H-pyran-2-yloxy)tridec-8-yne (10.0 g, 18.70 mmol) was deprotected with PPTS to give 13-(tert-butyldiphenylsilyloxy)tridec-5-yn-1-ol (7.70 g, 91%) as a colorless syrup. TLC:EtOAc/hexanes (3:7), Rf˜0.43; 1H NMR (300 MHz) δ 7.64-7.68 (m, 4H), 7.34-7.42 (m, 6H), 3.62 (t, J=5.6 Hz, 4H), 2.06-2.22 (m, 4H), 1.50-1.64 (m, 14H), 1.04 (s, 9H); 13C NMR (100 MHz) δ 135.82, 134.37, 129.76, 127.85, 80.93, 80.04, 64.21, 62.63, 32.77, 32.09, 29.33, 29.13, 29.10, 27.14, 25.92, 25.63, 19.47, 19.0, 18.81. HRMS calcd for C29H43O2Si [M+1]+ 451.3032, found 451.3032.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH:10]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14](Br)[CH:13]=1)[OH:11].[CH3:19][O:20][C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=1.C(=O)([O-])[O-].[K+].[K+].O>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.C1(C)C=CC=CC=1.C(O)C>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH:10]([C:12]1[CH:13]=[C:14]([C:24]2[CH:25]=[CH:26][C:21]([O:20][CH3:19])=[CH:22][CH:23]=2)[CH:15]=[CH:16][CH:17]=1)[OH:11]
Reactant: OC(c1cccc(Br)c1)c1nc2ccccc2s1
Reactant: COc1ccc(B(O)O)cc1
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: [K+]
Solvent: O
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1ccc(-c2cccc(C(O)c3nc4ccccc4s3)c2)cc1
Temperature: 25 °C

Procedure:
A mixture of benzothiazol-2-yl(3-bromophenyl)methanol (200 mg), 4-methoxy-phenylboronic acid (142 mg), tetrakis(triphenylphosphine)palladium (50 mg), potassium carbonate (259 mg), water (4 mL), ethanol (1 mL) and toluene (9 mL) is purged with argon and refluxed for one night. After cooling at room temperature, the mixture is diluted with water and diethylether. The organic phase is dried over magnesium sulfate and concentrated under reduced pressure. The residue is purified by column chromatography (heptane/ethyl acetate 2/1) to afford benzothiazol-2-yl(4′-methoxybiphenyl-3-yl)methanol as a beige solid.
Reaction SMILES: [C:1]1([CH:7]=[C:8]2[C:13](=[O:14])[C:12](=[CH:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:11][S:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:22][C:23]1[S:24][CH2:25][CH2:26][N:27]=1>CC(C)=O>[S:24]1[CH2:25][CH2:26][N:27]=[C:23]1[NH:22][C:13]1([OH:14])[C:8](=[CH:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:9][S:10][CH2:11][C:12]1=[CH:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: NC1=NCCS1
Reactant: O=C1C(=Cc2ccccc2)CSCC1=Cc1ccccc1
Solvent: CC(C)=O
Product: OC1(NC2=NCCS2)C(=Cc2ccccc2)CSCC1=Cc1ccccc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 92.5 %

Procedure:
A slurry of tetrahydro-3,5-bis-(phenylmethylene)-4H-thiopyran-4-one (5.5 g, 18.9 mmole) in 200 ml of acetone is treated with a solution of 2-amino-2-thiazoline (2.0 g, 19.6 mmole, filtered) in 100 ml of acetone at room temperature. The mixture never becomes homogeneous, but the nature of the solids change (yellow to white). After stirring at room temperature for 2 days, the starting ketone remains as evidenced by tlc. Additional 2-amino-2-thiazoline (1 g, 9.8 mmole, filtered) in 50 ml of acetone is added and the mixture is heated at reflux temperature for 1 day. Upon cooling to room temperature, filtration and washing with acetone affords a combined yield of 6.9 g (92.5%) of product in two crops, m.p. 171°-172.5°).
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]([CH3:54])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([O:50]O)[CH:46]([O:52]O)[CH2:45]2)[CH:7]([CH3:55])[CH2:6][CH2:5][C:4]1=[O:56])[CH3:2].N1C=CN=C1.[C:62]([Si:66](Cl)([CH3:68])[CH3:67])([CH3:65])([CH3:64])[CH3:63]>C(Cl)Cl.C(OCC)(=O)C>[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]([CH3:54])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([O:50][Si:66]([C:62]([CH3:65])([CH3:64])[CH3:63])([CH3:68])[CH3:67])[CH:46]([OH:52])[CH2:45]2)[CH:7]([CH3:55])[CH2:6][CH2:5][C:4]1=[O:56])[CH3:2]
Reactant: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(OO)C(OO)C3)C(C)CCC1=O)C(C)CC2OC
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: 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)(C)C)C(O)C3)C(C)CCC1=O)C(C)CC2OC
Temperature: 25 °C
Reaction time: 72 h
Yield: 28.3 %

Procedure:
To a solution of 17-ethyl-1-hydroxy-12-[2'-(3", 4"-dihydroxycyclohexyl)-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 (Example 2, 3.01 g) in dry methylene chloride (70 ml) was added an excess of imidazole (809 mg) followed by tertbutyldimethylsilyl chloride (716 mg). After 3 days of stirring at room temperature, the mixture was diluted with ethyl acetate which in turn was washed with 1N HCl, saturated sodium bicarbonate and brine, dried over magnesium sulfate and purified by flash chromatography (ethyl acetate:hexane (1:3)) to give the title compound (941 mg). 1H NMR consistent with the desired structure.
Reaction SMILES: [CH3:1][O:2]/[N:3]=[C:4](\[C:11]([NH:13][C@@H:14]1[C:17](=[O:18])[N:16]2[C:19]([C:32]([O-:34])=[O:33])=[C:20]([CH2:23][S:24][C:25]([C:27]3[O:31][CH:30]=[CH:29][CH:28]=3)=[O:26])[CH2:21][S:22][C@H:15]12)=[O:12])/[C:5]1[N:9]=[C:8]([NH2:10])[S:7][CH:6]=1.[Na+].[Cl-:36].[Na+].Cl.C(OC(C)C)(C)C>O.C1COCC1>[CH3:1][O:2]/[N:3]=[C:4](\[C:11]([NH:13][C@@H:14]1[C:17](=[O:18])[N:16]2[C:19]([C:32]([OH:34])=[O:33])=[C:20]([CH2:23][S:24][C:25]([C:27]3[O:31][CH:30]=[CH:29][CH:28]=3)=[O:26])[CH2:21][S:22][C@H:15]12)=[O:12])/[C:5]1[N:9]=[C:8]([NH2:10])[S:7][CH:6]=1.[ClH:36]
Reactant: CO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)[O-])=C(CSC(=O)c3ccco3)CS[C@H]12)c1csc(N)n1
Reactant: [Cl-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CC(C)OC(C)C
Solvent: C1CCOC1
Product: CO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)O)=C(CSC(=O)c3ccco3)CS[C@H]12)c1csc(N)n1

Procedure:
To a suspension of crystalline Ceftiofur sodium (10 g) in water (30 ml) was added THF (87 ml) at 10-30° C. To that sodium chloride (14 g) was added. pH of the solution was adjusted to 2.5-3.5. Organic layer pH was adjusted to 0.5-1.5 using conc. HCl. Addition of diisopropyl ether followed by filtration yielded pure title compound.]
Reaction SMILES: [CH3:1][O:2][C:3]([F:11])([F:10])[C:4]([F:9])([F:8])[C:5]([NH2:7])=O.N1C=CC=CC=1.FC(F)(F)C(OC(=O)C(F)(F)F)=O>COCCOCCOC>[CH3:1][O:2][C:3]([F:11])([F:10])[C:4]([F:9])([F:8])[C:5]#[N:7]
Reactant: COC(F)(F)C(F)(F)C(N)=O
Solvent: c1ccncc1
Solvent: COCCOCCOC
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: COC(F)(F)C(F)(F)C#N
Reaction time: 2 h
Yield: 77.5 %

Procedure:
A solution of 52.5 g (0.30 mol) of the amide from Part A in 200 ml of diglyme was stirred at -10° while 47.5 g (0.60 mol) of pyridine and then 63.0 g (0.30 mol) of trifluoroacetic anhydride were added. The cooling bath was removed, and the mixture was stirred at about 25° for 2 h. Evaporation of volatiles to 40° (4.5 mm) gave 42.7 g of crude product, which was distilled to afford 36.5 g (77%) of 3-methoxytetrafluoropropionitrile, b.p. 53°. IR (neat): 3.36 and 3.48 (sat'd CH), 4.42 (CN), 8-10μ (CF, C--O). NMR: 1H 3.78 ppm (s, OCH3): 19F -93.2 (t, JFF 6.3 Hz, 2F, CH2) and -108.8 ppm (t, JFF 6.3 Hz, 2F, CF2). Elemental analysis was consistent with the formula C4H3F4NO. ##STR54##
Reaction SMILES: [CH2:1]([N:8]([CH2:21][C:22]1[CH:39]=[CH:38][C:25]([O:26][C:27]2[CH:28]=[C:29]([CH:35]=[CH:36][CH:37]=2)[O:30][CH2:31][C:32]([OH:34])=O)=[CH:24][CH:23]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])[C:10]=1[CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.C([O:43][C:44](=[O:48])[CH2:45][CH2:46][NH2:47])C>>[CH2:1]([N:8]([CH2:21][C:22]1[CH:39]=[CH:38][C:25]([O:26][C:27]2[CH:28]=[C:29]([CH:35]=[CH:36][CH:37]=2)[O:30][CH2:31][C:32]([NH:47][CH2:46][CH2:45][C:44]([OH:48])=[O:43])=[O:34])=[CH:24][CH:23]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][S:16]([CH3:19])(=[O:17])=[O:18])[C:10]=1[CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1c(NS(C)(=O)=O)cccc1N(Cc1ccccc1)Cc1ccc(Oc2cccc(OCC(=O)O)c2)cc1
Reactant: CCOC(=O)CCN
Agent: Cl
Product: Cc1c(NS(C)(=O)=O)cccc1N(Cc1ccccc1)Cc1ccc(Oc2cccc(OCC(=O)NCCC(=O)O)c2)cc1

Procedure:
The product from Example 62C and β-alanine ethyl ester hydrochloride were processed as described in Example 104B to provide the title compound. 1H NMR (300 MHz, DMSO-d6) δ8.97 (s, 1 H), 8.10 (t, 1 H), 7.24 (m, 8 H), 6.99 (m, 5 H), 6.71 (m, 1 H), 6.55 (m, 2 H), 4.43 (s, 2 H), 4.06 (s, 2 H), 4.03 (s, 2 H), 3.31 (dd, 2 H), 2.88 (s, 3 H), 2.40 (t, 4 H), 2.07 (s, 2 H); MS (APCI) m/z 618 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[N:6]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[NH:4][C:3]=1[CH:13]=[O:14].CI.[C:17](=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[Cl:1][C:2]1[N:6]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:4]([CH3:17])[C:3]=1[CH:13]=[O:14]
Reactant: O=C([O-])[O-]
Reactant: O=Cc1[nH]c(-c2ccccc2)nc1Cl
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CI
Product: Cn1c(-c2ccccc2)nc(Cl)c1C=O
Reaction time: 1 h

Procedure:
1 g (4.8 mmol) of 5-chloro-2-phenyl-3H-imidazole-4-carbaldehyde, 0.824 g (5.8 mmol) of methyl iodide and 1.338 g (9.7 mmol) of potassium carbonate in 50 ml of DMF were stirred at room temperature for 4 h. The reaction mixture was poured onto 200 ml of water, the resulting mixture stirred for 1 h, and the product was filtered off with suction and dried. Yield: 820 mg.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][S:5]([O:8][CH2:9][C:10]([CH3:32])([CH3:31])[C@@H:11]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:12]([O:14][CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1)=[O:13])(=[O:7])=[O:6].[N-:33]=[N+:34]=[N-:35].[Na+]>CS(C)=O>[N:33]([CH2:2][CH2:3][CH2:4][S:5]([O:8][CH2:9][C:10]([CH3:32])([CH3:31])[C@@H:11]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:12]([O:14][CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1)=[O:13])(=[O:7])=[O:6])=[N+:34]=[N-:35]
Reactant: CC(C)(COS(=O)(=O)CCCCl)[C@@H](OCc1ccccc1)C(=O)OCCN1CCOCC1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CC(C)(COS(=O)(=O)CCCN=[N+]=[N-])[C@@H](OCc1ccccc1)C(=O)OCCN1CCOCC1

Procedure:
Following the general procedure for the preparation of azides of Description 16, 2-morpholin-4-ylethyl (2R)-4-[(3-chloropropyl)sulfonyloxy]-3,3-dimethyl-2-(phenylmethoxy)butanoate (26a) (0.41 g, 0.83 mmol) dissolved in 5 mL of anhydrous dimethyl sulfoxide (DMSO) was reacted with 0.12 g (1.7 mmol) of sodium azide (NaN3). After work-up, the crude material (26b) was used in the next step without further purification. MS (ESI) m/z 499.12 (M+H)+.
Reaction SMILES: Br[C:2]1[C:7]([N+]([O-])=O)=[CH:6][CH:5]=[C:4]([Br:11])[C:3]=1[OH:12].C[Si]([C:17]#[C:18][C:19]1([OH:27])[CH:24]2[CH2:25][CH2:26][N:21]([CH2:22][CH2:23]2)[CH2:20]1)(C)C>N1C=CC=CC=1>[Br:11][C:4]1[C:3]2[O:12][C:18]([C:19]3([OH:27])[CH:24]4[CH2:25][CH2:26][N:21]([CH2:22][CH2:23]4)[CH2:20]3)=[CH:17][C:2]=2[CH:7]=[CH:6][CH:5]=1
Reactant: O=[N+]([O-])c1ccc(Br)c(O)c1Br
Reactant: C[Si](C)(C)C#CC1(O)CN2CCC1CC2
Solvent: c1ccncc1
Product: OC1(c2cc3cccc(Br)c3o2)CN2CCC1CC2
Yield: 29.2 %

Procedure:
2,6-Dibromonitrophenol (3.0 g, 0.0119 mol), 3-[(trimethylsilyl)ethynyl]quinuclidin-3-ol (2.66 g, 0.0119 mol; obtained in Step 1), Cu2O (1.70 g, 0.0119 mol) and pyridine (200 mL) were added to a round bottom flask. The resulting mixture was heated at reflux overnight, filtered through Celite, and the solvent was evaporated. The residue was purified by chromatography on silica gel using ethyl acetate (250 mL) and methanol (500 mL) as eluents. The methanol fraction was evaporated to yield 1.12 g (29%) of the title compound. HPLC purity=90%, m/z=322 (M+H)+.
Reaction SMILES: O1CCCCC1.[C:7]1([C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C([Li])CCC.[C:25](=[O:27])=[O:26]>C1COCC1>[OH:19][C:16]1[CH:15]=[CH:14][C:13]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[CH:18][C:17]=1[C:25]([OH:27])=[O:26]
Reactant: O=C=O
Reactant: Oc1ccc(-c2ccccc2)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: C1CCOCC1
Product: O=C(O)c1cc(-c2ccccc2)ccc1O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2-hydroxy-5-phenylbenzoic acid was synthesized as follows. A solution of tetrahydropyran (THP)-protected 4-phenylphenol (474 mg. 2 mmol., prepared from 4-phenylphenol by standard methods described in Green and Wuts at pp. 31-34) in anhydrous THF (5 mL) was cooled to -78° C. and treated with n-Butyllithium (2 mL of 1.6M in hexanes). The reaction mixture was stirred and warmed to ambient temperature during which a tan suspension formed. After 2 hours, the reaction mixture was cooled to -78° C. and treated with excess anhydrous CO2 for several minutes. The reaction mixture was stirred and warmed to ambient temperature. After 2 hours, the reaction mixture was partitioned between ethyl ether and aqueous 1N NaOH. The aqueous layer was cooled to 0° C. with ice and acidified to pH 2 with aqueous 1N HCl. The aqueous solution was partitioned with methylene chloride. The organic layer was dried over magnesium sulfate. Concentration in vacuo yielded crude product as an off-white solid (258 mg, 2-hydroxy-5-phenylbenzoic acid). NMR spectroscopy of the crude material was consistent with the expected structure. 1H NMR (DMSO-d6) δ8.04 (d, J=3 Hz, 1H), 7.76 (dd, J=9, 3 Hz, 1H), 7.62 (d, J=7 Hz, 2H), 7.44 (t, J=7 Hz, 2H), 7.32 (t, J=7 Hz, 1H), 7.00 (d, J=9 Hz, 1H). Mass calculated: 466.5. Mass found 467.2. LC Gradient 25-45% acetonitrile over 13 minutes. LC retention time 3.5 minutes. The material was used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:13]=[C:14]=[O:15])[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].[ClH:16].Cl.[Cl:18][C:19]1[CH:36]=[CH:35][C:22]([CH2:23][CH2:24][N:25]2[CH2:30][CH2:29][N:28]([CH2:31][CH2:32][CH2:33][SH:34])[CH2:27][CH2:26]2)=[CH:21][CH:20]=1.C(N(CC)CC)C>C(Cl)Cl>[ClH:18].[ClH:16].[CH3:12][O:11][C:7]1[CH:6]=[C:5]([NH:13][C:14](=[SH:34][CH2:33][CH2:32][CH2:31][N:28]2[CH2:29][CH2:30][N:25]([CH2:24][CH2:23][C:22]3[CH:21]=[CH:20][C:19]([Cl:18])=[CH:36][CH:35]=3)[CH2:26][CH2:27]2)[OH:15])[CH:4]=[C:3]([O:2][CH3:1])[C:8]=1[O:9][CH3:10]
Reactant: SCCCN1CCN(CCc2ccc(Cl)cc2)CC1
Reactant: COc1cc(N=C=O)cc(OC)c1OC
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc(NC(O)=[SH]CCCN2CCN(CCc3ccc(Cl)cc3)CC2)cc(OC)c1OC
Yield: 46.4 %

Procedure:
The procedure described in Example 2 was followed, using 2.5 g of 3,4,5-trimethoxyphenyl isocyanate, 4.4 g of 3-[4-(4-chlorophenethyl)piperazin-1-yl]propanethiol dihydrochloride, 1.2 g of triethylamine and 50 ml of methylene chloride, to give 1.6 g (23% of theory) of N-(3,4,5-trimethoxyphenyl)-S-{3-[4-(4-chlorophenethyl)piperazin-1-yl]propyl}thiocarbamate dihydrochloride as a white crystalline solid, M.p. 239°-241° C.
Reaction SMILES: FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.C([N:23]1[CH2:30][CH2:29][C:28]2([CH3:34])[C:31]([CH3:33])([CH3:32])[CH:24]1[CH2:25][C:26]1[C:38]([OH:39])=[CH:37][CH:36]=[CH:35][C:27]=12)C1C=CC=CC=1.C(N(CC)CC)C>ClCCCl.CN(C)C1C=CN=CC=1.ClCCl>[CH:38](=[O:39])[C:26]1[CH:27]=[CH:28][CH:31]=[CH:24][CH:25]=1.[CH3:34][C@:28]12[C:31]([CH3:32])([CH3:33])[C@H:24]([NH:23][CH2:30][CH2:29]1)[CH2:25][C:26]1[C:38]([OH:39])=[CH:37][CH:36]=[CH:35][C:27]2=1
Reactant: CC12CCN(Cc3ccccc3)C(Cc3c(O)cccc31)C2(C)C
Agent: CN(C)c1ccncc1
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCCl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1(C)[C@H]2Cc3c(O)cccc3[C@]1(C)CCN2
Product: O=Cc1ccccc1

Procedure:
Trifluoromethanesulfonic anhydride (9.7 mL) is added to a solution of 3-benzyl-6,11,11-trimethyl-1,2,3,4,5,6-hexahydro-2,6-methano-benzo[d]azocin-10-ol (13.7 g, the compound may be obtained by reductive amination of benzaldehyde with (2R,6S)-6,11,11-trimethyl-1,2,3,4,5,6-hexahydro-2,6-methano-benzo[d]azocin-10-ol and NaHB(OAc)3 in 1,2-dichloroethane), triethylamine (43 mL), and 4-dimethylaminopyridine (50 mg) in dichloromethane (135 mL) chilled to −10° C. under argon atmosphere. The solution is stirred at ca. −5° C. for 30 min and then at room temperature overnight. The solution is added to ice-cold water and then aqueous ammonia solution is added. The resulting mixture is extracted with dichloromethane, the combined organic extracts are washed with water and dried (MgSO4). The solvent is removed under reduced pressure to give the crude product that is used without further purification.