Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][P:4]([C:9]([P:30](=[O:37])([O:34]CC)[O:31]CC)=[CH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17]#[C:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])(=[O:8])[O:5]CC)C.C[Si](Br)(C)C.O1CCCC1.O>C(Cl)Cl.[2H]C([2H])(Cl)Cl>[C:17]([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[CH:10]=[C:9]([P:30](=[O:31])([OH:34])[OH:37])[P:4](=[O:3])([OH:5])[OH:8])#[C:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]
Reactant: CCCCCCCCCCCC#Cc1ccccc1C=C(P(=O)(OCC)OCC)P(=O)(OCC)OCC
Agent: C[Si](C)(C)Br
Agent: [2H]C([2H])(Cl)Cl
Solvent: C1CCOC1
Solvent: O
Solvent: ClCCl
Product: CCCCCCCCCCCC#Cc1ccccc1C=C(P(=O)(O)O)P(=O)(O)O
Reaction time: 5 h
Yield: 78.5 %

Procedure:
Tetraethyl[2-[2-(1-tridecynyl)phenyl]ethenylidene]bisphosphonate (1.26 g, 2.28 mmol) prepared according to Example 9 was dissolved in a mixture of CH2Cl2 -CD2Cl2 (12 ml, 1.73:1). Trimethylsilyl bromide (1.3 ml, 9.85 mmol) was added, and the reaction was stirred for 5 hours. At this time additional trimethylsilyl bromide (0.2 ml, 1.5 mmol) was added. The progress of the reaction was monitored by 1H and 31P NMR, until no additional change occurred. 1H NMR was more useful in this regard, particularly the low field doublet of doublets. At the end of 8 hours, the solvent was removed under reduced pressure and the resulting oil was placed on the vacuum line. Tetrahydrofuran (10 ml) and water (0.25 ml, 13.9 mmol) were added and stirred for 20 hours, then removed under reduced pressure. NMR showed at least two species to be present, so the tetrahydrofuran-water treatment was repeated. After stripping, the residue was recrystallized from heptane as a white solid, 0.793 g, 1.79 mmol, 78.5% yield; mp 141°-142° C.; 1H NMR (CD3OD) ∂ 0.89 (m, 3H), 1.20 to 1.55 (m, 16H), 1.63 (quintet, J=7.4 Hz, 2H), 2.46 (t, J=7.1 Hz, 2H), 7.24 to 7.42 (m, 3H), 7.98 (m, 1H), 8.42 (dd, J=46.4, 29.0 Hz, 1H); FAB mass spectrum m/z 443 (M+H)+.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH:9]1[CH2:14][CH2:13][N:12]([C:15]2[C:20]([C:21]#[C:22][C:23]3[CH:24]=[N:25][C:26]([NH2:29])=[CH:27][CH:28]=3)=[C:19]([CH3:30])[N:18]=[CH:17][N:16]=2)[CH2:11][CH2:10]1)(C)(C)C.Cl>C(Cl)Cl.CO.O1CCOCC1>[NH2:7][CH2:8][CH:9]1[CH2:14][CH2:13][N:12]([C:15]2[C:20]([C:21]#[C:22][C:23]3[CH:28]=[CH:27][C:26]([NH2:29])=[N:25][CH:24]=3)=[C:19]([CH3:30])[N:18]=[CH:17][N:16]=2)[CH2:11][CH2:10]1
Reactant: Cc1ncnc(N2CCC(CNC(=O)OC(C)(C)C)CC2)c1C#Cc1ccc(N)nc1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Solvent: ClCCl
Product: Cc1ncnc(N2CCC(CN)CC2)c1C#Cc1ccc(N)nc1
Temperature: 50 °C

Procedure:
To a solution of 3.10 g (7.34 mmol) {1-[5-(6-amino-pyridin-3-ylethynyl)-6-methyl-pyrimidin-4-yl]-piperidin-4-ylmethyl}-carbamic acid tert-butyl ester in 20 mL DCM and 20 mL MeOH at RT is added 2.75 mL (11.0 mmol) 4 M HCl in dioxane. The reaction is to stirred over night at 50° C. The solvent is removed under reduced pressure and the residue is taken up in a small amount of MeOH. The precipitated product is filtered off and washed with few MeOH. After drying 3.06 g (95%) of the desired product is obtained.
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C@@H:19]([C:42]([OH:44])=[O:43])[CH2:20][CH2:21][CH2:22][CH2:23][NH:24][C:25]([O:27][CH2:28][CH:29]3[C:41]4[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=4[C:35]4[C:30]3=[CH:31][CH:32]=[CH:33][CH:34]=4)=[O:26])=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.O[N:46]1[C:50](=[O:51])[CH2:49][CH2:48][C:47]1=[O:52].Cl.C(N=C=NCCCN(C)C)C.C(N(C(C)C)CC)(C)C>C(OC(=O)C)C.CN(C)C=O>[CH:10]1[C:11]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C@@H:19]([C:42]([O:44][CH:48]3[CH2:49][C:50](=[O:51])[NH:46][C:47]3=[O:52])=[O:43])[CH2:20][CH2:21][CH2:22][CH2:23][NH:24][C:25]([O:27][CH2:28][CH:29]3[C:30]4[CH:31]=[CH:32][CH:33]=[CH:34][C:35]=4[C:36]4[C:41]3=[CH:40][CH:39]=[CH:38][CH:37]=4)=[O:26])=[O:17])[C:13]3[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=3)[C:6]=2[CH:7]=[CH:8][CH:9]=1
Reactant: O=C1CCC(=O)N1O
Reactant: O=C(NCCCC[C@@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O)OCC1c2ccccc2-c2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C1CC(OC(=O)[C@@H](CCCCNC(=O)OCC2c3ccccc3-c3ccccc32)NC(=O)OCC2c3ccccc3-c3ccccc32)C(=O)N1

Procedure:
To a stirred solution of N,N'-bis-(9-fluorenylmethyloxycarbonyl)-D-lysine (12.0 g) in 360 ml of an ethylacetate:dimethylformamide (35:1) mixture are added N-hydroxysuccinimide (3.1 g), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (5.2 g) and diisopropylethylamine (2.0 ml). After 15 hours the solution is washed successively with dilute hydrochloric acid, water, saturated sodium bicarbonate solution, and brine, dried over magnesium sulfate, and concentrated in vacuo to about 20 ml. The solution is added to hexane (1 l.) and the precipitate is collected and dried to afford the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH3:13])=[C:11]([C:14]([OH:16])=O)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[NH2:17][C:18]1[CH:19]=[CH:20][C:21]([N:26]2[CH2:30][CH2:29][CH2:28][CH2:27]2)=[C:22]([CH:25]=1)[C:23]#[N:24]>>[C:23]([C:22]1[CH:25]=[C:18]([NH:17][C:14]([C:11]2[CH:10]=[N:9][N:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[C:12]=2[CH3:13])=[O:16])[CH:19]=[CH:20][C:21]=1[N:26]1[CH2:30][CH2:29][CH2:28][CH2:27]1)#[N:24]
Reactant: Cc1c(C(=O)O)cnn1-c1ccc(F)cc1
Reactant: N#Cc1cc(N)ccc1N1CCCC1
Product: Cc1c(C(=O)Nc2ccc(N3CCCC3)c(C#N)c2)cnn1-c1ccc(F)cc1
Yield: 48.1 %

Procedure:
By the reaction and treatment in the same manner as in Example 64 using 1-(4-fluorophenyl)-5-methylpyrazole-4-carboxylic acid (1.2 g) and 5-amino-2-pyrrolidinobenzonitrile (0.8 g), the title compound (0.8 g) was obtained, melting point: 185° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[S:9][C:10]1[N:11]([CH3:15])[CH:12]=[CH:13][N:14]=1)[NH2:5].Cl.N1C=CC=CC=1.Cl[C:24]1[C:29]([C:30]#[N:31])=[CH:28][N:27]=[C:26]2[S:32][CH:33]=[CH:34][C:25]=12>C(OCCO)C>[Cl:1][C:2]1[CH:3]=[C:4]([NH:5][C:24]2[C:29]([C:30]#[N:31])=[CH:28][N:27]=[C:26]3[S:32][CH:33]=[CH:34][C:25]=23)[CH:6]=[CH:7][C:8]=1[S:9][C:10]1[N:11]([CH3:15])[CH:12]=[CH:13][N:14]=1
Reactant: Cn1ccnc1Sc1ccc(N)cc1Cl
Reactant: N#Cc1cnc2sccc2c1Cl
Agent: Cl
Solvent: c1ccncc1
Solvent: CCOCCO
Product: Cn1ccnc1Sc1ccc(Nc2c(C#N)cnc3sccc23)cc1Cl
Yield: 26.6 %

Procedure:
A mixture of (3-chloro-4-[(1-methyl-1H-imidazol-2-yl)sulfanyl]aniline (135 mg, 0.57 mmol), pyridine hydrochloride (66 mg, 0.57 mmol) and 4-chlorothieno[2,3-b]pyridine-5-carbonitrile (0.1 g, 0.52 mmol) in 4 mL of 2-ethoxyethanol is heated at reflux for 24 hours. The solution is cooled and the solvent is evaporated. The resultant residue is treated with a minimum amount of methanol and the product is purified by flash column chromatography eluting with 3% methanol in dichloromethane. The fractions containing product are combined and concentrated. Ethyl acetate is added and the insoluble material collected by filtration to provide 55 mg of 4-[(3-chloro-4-[(1-methyl-1H-imidazol-2-yl)thio]phenyl)amino]thieno[2,3-b]pyridine-5-carbonitrile as a tan solid, mp>240° C.; 1H NMR (DMSO-d6) δ 3.61 (s, 3H), 6.53 (d, J=9 Hz, 1H), 7.15 (m, 1H), 7.17 (s, 1H), 7.44 (m, 1H), 7.52 (s, 1H), 7.54 (s, 1H), 7.81 (d, J=6 Hz, 1H), 8.53 (s, 1H), 9.76 (s, 1H); MS 396.2 (M−H)−.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[C:6]([NH2:11])[CH:5]=1.C1C[O:16][CH2:15]C1.C(C1NC=CN=1)(C1NC=CN=1)=O.Cl>O>[CH3:1][O:2][C:3]([C:4]1[CH:9]=[CH:8][C:7]2[NH:10][C:15](=[O:16])[NH:11][C:6]=2[CH:5]=1)=[O:12]
Reactant: COC(=O)c1ccc(N)c(N)c1
Reactant: C1CCOC1
Agent: Cl
Agent: O=C(c1ncc[nH]1)c1ncc[nH]1
Solvent: O
Product: COC(=O)c1ccc2[nH]c(=O)[nH]c2c1
Temperature: 23 °C
Reaction time: 16 h

Procedure:
To a solution of 3,4-diamino-benzoic acid methyl ester (5.00 g, 30.1 mmol) and THF (40 mL), was added carbonyl diimidazole (7.32 g, 45.1 mmol) at 0° C. The mixture stirred for 16 h, and allowed to warm to 23° C. A solution of 1M aq. HCl (50 mL) was added at 0° C., followed by water (70 mL) and the mixture was stirred for 1 h. The resulting precipitate was filtered and dried under reduced pressure for 18 h to yield the titled compound, which was used in the next step without further purification (5.45 g, 94%). MS (ESI/CI): mass calcd. for C9H8N2O3, 192.1; m/z found, 193.1 [M+H]+. 1H NMR (400 MHz, CDCl3): 11.01 (s, 1H), 10.84 (s, 1H), 7.63 (dd, J=8.2, 1.6 Hz, 1H), 7.47 (s, 1H), 7.02 (d, J=8.2 Hz, 1H), 3.82 (s, 3H).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([NH:10][CH:11](C2C=CC(OC)=C(OC)C=2)[C:12]([OH:14])=[O:13])[CH:7]=[CH:8][CH:9]=1)(=[O:3])[NH2:2].[Cl:25][C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][C:27]=1[O:35][CH3:36].NC1C=C(C=CC=1[F:47])C(N)=O.O.C(O)(=O)C=O>>[C:1]([C:4]1[CH:9]=[CH:8][C:7]([F:47])=[C:6]([NH:10][CH:11]([C:29]2[CH:30]=[CH:31][C:26]([Cl:25])=[C:27]([O:35][CH3:36])[CH:28]=2)[C:12]([OH:14])=[O:13])[CH:5]=1)(=[O:3])[NH2:2]
Reactant: NC(=O)c1ccc(F)c(N)c1
Reactant: COc1ccc(C(Nc2cccc(C(N)=O)c2)C(=O)O)cc1OC
Reactant: COc1cc(B(O)O)ccc1Cl
Agent: O=CC(=O)O
Solvent: O
Product: COc1cc(C(Nc2cc(C(N)=O)ccc2F)C(=O)O)ccc1Cl
Yield: 37 %

Procedure:
25B was prepared in a procedure similar to that of 1A using 25A, 19B and glyoxylic acid monohydrate. Yield: 37%. 1H NMR (400 MHz, Methanol-d4) δ ppm 3.88 (s, 3H) 5.21 (s, 1H) 7.03-7.12 (m, 3H) 7.13-7.19 (m, 1H) 7.25 (d, J=1.76 Hz, 1H) 7.33 (d, J=7.91 Hz, 1H), LCMS: 353 (M+1).
Reaction SMILES: [NH2:1][N:2]=[CH:3][NH:4][C:5]1[CH:29]=[CH:28][C:8]([C:9]([NH:11][C:12]2[CH:13]=[CH:14][C:15]3[O:20][CH:19]([CH2:21][C:22]([O:24]CC)=[O:23])[CH2:18][CH2:17][C:16]=3[CH:27]=2)=[O:10])=[CH:7][CH:6]=1.[OH-].[Na+]>C(O)C>[NH2:1][N:2]=[CH:3][NH:4][C:5]1[CH:29]=[CH:28][C:8]([C:9]([NH:11][C:12]2[CH:13]=[CH:14][C:15]3[O:20][CH:19]([CH2:21][C:22]([OH:24])=[O:23])[CH2:18][CH2:17][C:16]=3[CH:27]=2)=[O:10])=[CH:7][CH:6]=1
Reactant: CCOC(=O)CC1CCc2cc(NC(=O)c3ccc(NC=NN)cc3)ccc2O1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: NN=CNc1ccc(C(=O)Nc2ccc3c(c2)CCC(CC(=O)O)O3)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
0.08 g (0.2 mmol) of the ester from Example 64 were dissolved in 30 ml ethanol followed by addition of 0.4 ml aqueous 2 N sodium hydroxide solution. The mixture was stirred at room temperature for two days, and the mixture was concentrated to dryness under reduced pressure. The residue was dissolved in water, and the solution was neutralized with acetic acid, while the title acid precipitated. It was filtered with suction, washed with water, and dried in vacuo. Yield: 0.045 g (61%) of a beige crystalline solid, m.p. 258-260° C.
Reaction SMILES: [O:1]([C:8]1[CH:15]=[C:12]([CH:13]=O)[C:11]([OH:16])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH:23]([CH:25]=[CH2:26])=[O:24].O>O1CCOCC1>[O:1]([C:8]1[CH:9]=[CH:10][C:11]2[O:16][CH2:26][C:25]([CH:23]=[O:24])=[CH:13][C:12]=2[CH:15]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1cc(Oc2ccccc2)ccc1O
Reactant: C=CC=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: O=CC1=Cc2cc(Oc3ccccc3)ccc2OC1

Procedure:
A mixture of 5-phenoxysalicylaldehyde (15.0 g, 70.0 mmol, see example 2d) and potassium carbonate (19.4 g, 140.0 mmol) in 250 ml of 1,4-dioxane is treated with acrolein (4.32 g, 77.0 mmol) under nitrogen. The mixture is heated at reflux for 6 hours. Water is added and the mixture is extracted with dichloromethane. The organic layer is dried (MgSO4) and evaporated. The residue is purified by flash chromatography (silica gel, 10% EtOAc/hexane) to give 6-phenoxy-2H-1-benzopyran-3-carboxaldehyde, as a fluorescent solid.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11])[C:5]#[N:6].[Br:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[OH:20].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[Br:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[O:20][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11])[C:5]#[N:6]
Reactant: Oc1ccccc1Br
Reactant: N#Cc1ccc([N+](=O)[O-])c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1ccc([N+](=O)[O-])c(Oc2ccccc2Br)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 92.5 %

Procedure:
To a solution of 3-fluoro-4-nitrobenzonitrile (6.3 g; 37.93 mmol) and 2-bromophenol (4.4 mL; 37.94 mmol) in DMF (50 mL) was added potassium carbonate (6.29 g; 45.51 mmol). The mixture was stirred for 5 h at rt. Water (100 mL) was added, and a precipitate formed. The solid was separated via filtration, washed with water, and dried to yield 11.20 g (92.5%) of 3-(2-bromo-phenoxy)-4-nitrobenzonitrile, 1a.
Reaction SMILES: Cl.[CH3:2][NH:3][OH:4].C[O-].[Na+].[O:8]([C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[O:21][CH:20]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH2:19]/[C:18]/2=[N:31]/[C:32]#[N:33])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>CO>[CH3:2][N:3]1[C:32]([NH2:33])=[N:31][C:18]2([C:17]3[C:22](=[CH:23][CH:24]=[C:15]([O:8][C:9]4[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=4)[CH:16]=3)[O:21][CH:20]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH2:19]2)[O:4]1
Reactant: CNO
Reactant: N#C/N=C1/CC(c2ccccc2)Oc2ccc(Oc3ccccc3)cc21
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CN1OC2(CC(c3ccccc3)Oc3ccc(Oc4ccccc4)cc32)N=C1N
Reaction time: 0.17 h
Yield: 51.6 %

Procedure:
To a solution of methylhydroxylamine HCl salt (83.6 mg, 1 mmol) in anhydrous MeOH (11 mL) was added NaOMe (25% in MeOH (Wt. %), 0.2 mL, 0.9 mmol), followed by (Z)—N-(6-phenoxy-2-phenylchroman-4-ylidene)cyanamide (340 mg, 1 mmol). After stirring for 10 min, the solvent was removed in vacuo. The residue was redissolved in DCM (30 mL) The mixture was filter, and the solvent was removed to give the residue, which was purified by column chromatography to give 2′-methyl-6-phenoxy-2-phenyl-2′H-spiro[chroman-4,5′-[1, 2, 4]oxadiazol]-3′-amine (200 mg, 52%). 1H-NMR (CDCl3): 2.41-2.66 (m, 1H), 2.65 (m, 1H), 2.75 (m, 1H), 3.32 (m, 3H), 5.35 (m, 1H), 6.95 (m, 2H), 7.06 (m, 1H), 7.20 (m, 2H), 7.42 (m, 3H), 7.48 (m, 3H), 7.51 (m, 2H).
Reaction SMILES: [CH:1]1[C:18]2[C:19]3[C:24]4[C:3](=[CH:4][CH:5]=[C:6]5[C:23]=4[C:22]4[C:9](=[CH:10][CH:11]=[C:12]6[C:21]=4[C:20]=3[C:15](=[CH:16][CH:17]=2)[CH:14]=[CH:13]6)[CH:8]=[CH:7]5)[CH:2]=1.[C:25]1(=[O:31])[O:30][C:28](=[O:29])[CH2:27][CH2:26]1.[Cl-].[Al+3].[Cl-].[Cl-]>[N+](C1C=CC=CC=1)([O-])=O.C1(C)C(C)=CC=CC=1.C1COCC1>[C:2]1([C:25]([CH2:26][CH2:27][C:28]([OH:30])=[O:29])=[O:31])[C:3]2[C:24]3[C:19]4[C:18](=[CH:17][CH:16]=[C:15]5[C:20]=4[C:21]4[C:12](=[CH:11][CH:10]=[C:9]6[C:22]=4[C:23]=3[C:6](=[CH:5][CH:4]=2)[CH:7]=[CH:8]6)[CH:13]=[CH:14]5)[CH:1]=1
Reactant: O=C1CCC(=O)O1
Reactant: c1cc2ccc3ccc4ccc5ccc6ccc1c1c2c3c4c5c61
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=[N+]([O-])c1ccccc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1C
Product: O=C(O)CCC(=O)c1cc2ccc3ccc4ccc5ccc6ccc1c1c6c5c4c3c21
Reaction time: 4 h
Yield: 82 %

Procedure:
A Friedel-Crafts acylation of coronene was performed using the procedure of Clar and Zanders J. Chem. Soc. 2, (1958) 1577-1579, with the Coronene (100mg; FIG. 1, compound I) and succinic anhydride (73.4mg) were placed in a 10ml round-bottomed flask. Aluminum chloride (400mg) was dissolved in 3ml of nitrobenzene and injected slowly into the round-bottomed flask. The flask was then flushed with nitrogen and sealed. The mixture was stirred for four hours and cold 2M HCl (8ml) was added and the solution boiled for 10 minutes. A greenish-yellow precipitate was obtained. The crystals were filtered, washed with benzene, methanol and 2M HCl, and dried overnight under vacuum. The product (108mg; 82% yield) was recrystallized from xylene and judged pure using TLC analyses (Rf=0.53), using 50% ethanol/50% THF (v/v) as the developing solvent with silica gel G (40 micron) as the support medium. The keto-acid (FIG. 1, compound II) had a melting point of 243° C. IR and NMR analysis gave spectra consistent with the structure of the molecule, and in xylene had an absorption band at 444 nm, with ε340 in THF=24,914±80M-1 cm-1.
Reaction SMILES: [CH2:1]([C@H:4]1[CH2:9][CH2:8][C@H:7]([CH2:10][CH2:11][C@H:12]2[CH2:17][CH2:16][C@H:15]([CH:18]=O)[CH2:14][CH2:13]2)[CH2:6][CH2:5]1)[CH2:2][CH3:3].[Br-].[C:21]([C:23]1[CH:48]=[CH:47][C:26]([CH2:27][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[CH:25][CH:24]=1)#[N:22].C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1>[CH2:1]([C@H:4]1[CH2:9][CH2:8][C@H:7]([CH2:10][CH2:11][C@H:12]2[CH2:17][CH2:16][C@H:15]([CH:18]=[CH:27][C:26]3[CH:47]=[CH:48][C:23]([C:21]#[N:22])=[CH:24][CH:25]=3)[CH2:14][CH2:13]2)[CH2:6][CH2:5]1)[CH2:2][CH3:3]
Reactant: CCC[C@H]1CC[C@H](CC[C@H]2CC[C@H](C=O)CC2)CC1
Reactant: N#Cc1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Br-]
Agent: [K+]
Solvent: C1COCCO1
Product: CCC[C@H]1CC[C@H](CC[C@H]2CC[C@H](C=Cc3ccc(C#N)cc3)CC2)CC1
Reaction time: 72 h

Procedure:
A mixture of 5.6 g of trans-4-[2-(trans-4-propylcyclohexyl)ethyl]cyclohexanecarboxaldehyde, 10.6 g of p-cyanobenzyl-triphenylphosphonium bromide and 200 ml of dioxan was treated with 14.5 g of powdered potassium carbonate and the mixture was heated to boiling for 72 hours. After cooling, the mixture was filtered, the filtrate was concentrated and the residue was chromatographed on silica gel with hexane/diethyl ether (vol. 4:1), thereby obtaining 6.0 g of p-[2-[trans-4-[2-(trans-4-propylcyclohexyl)ethyl]cyclohexyl]vinyl]benzonitrile.
Reaction SMILES: [N:1]([C@@H:4]([CH:12]1[CH2:17][CH2:16][CH:15]([CH2:18][O:19][Si](C(C)C)(C(C)C)C(C)C)[CH2:14][CH2:13]1)[C:5]([N:7]1[CH2:11][CH2:10][S:9][CH2:8]1)=[O:6])=[N+:2]=[N-:3]>O.C(#N)C>[N:1]([C@@H:4]([CH:12]1[CH2:17][CH2:16][CH:15]([CH2:18][OH:19])[CH2:14][CH2:13]1)[C:5](=[O:6])[N:7]1[CH2:11][CH2:10][S:9][CH2:8]1)=[N+:2]=[N-:3]
Reactant: CC(C)[Si](OCC1CCC([C@H](N=[N+]=[N-])C(=O)N2CCSC2)CC1)(C(C)C)C(C)C
Solvent: CC#N
Solvent: O
Product: [N-]=[N+]=N[C@H](C(=O)N1CCSC1)C1CCC(CO)CC1
Reaction time: 2 h
Yield: 94.6 %

Procedure:
3-[(2S)-2-Azido-2-(4-{[(triisopropylsilyl)oxy]methyl}cyclohexyl)-ethanoyl]-1,3-thiazolidine (isomer II, 130 mg, 0.29 mmol) from Example 6, Step I was dissolved in 3 mL of 15% HF (45% in H2O) in acetonitrile and stirred for 2 h. The solvent was removed and the residue was dissolved in ethyl acetate and then neutralized with aqueous sodium bicarbonate. The organics were separated, dried (Na2SO4) and filtered. Evaporation of the solvent afforded 78 mg of {4-[(1S)-1-azido-2-oxo-2-(1,3-thiazolidin-3-yl)ethyl]cyclohexyl}methanol. A portion of this material (24 mg, 0.084 mmol) was dissolved in wet THF and triphenyl phosphine (26 mg, 0.1 mmol) was added to the solution. The mixture was heated in an oil bath at 60° C. for 5 h, cooled, concentrated and purified by preparative TLC on silica gel (eluent: 5 to 10% methanol in CH2Cl2) to give the title compound. 1H NMR (500 MHz, CD3OD, HCl salt) δ 4.71 (dd, 1H, J=3 and 6 Hz), 4.58 (d, 0.45H, J=9.2 Hz), 4.48 (d, 0.55H, J=9.2 Hz), 4.18 (d, 0.45H, J=5.9 Hz), 4.11 (d, 0.55H, J=5.9 Hz), 3.93 (m, 0.55H), 3.88 (m, 0.45H), 3.88 (m, 0.45H), 3.79 (m, 1H), 3.17 (m, 1H), 3.36 (d, 2H, J=6.1 Hz), 3.09 (m, 1H), 1.98–1.78 (m, 4H), 1.40 (m, 1H), 1.26 (m, 1H), 1.11(m, 1H), 1.01 (m, 2H). 3-[(2S)-2-Azido-2-(4-{[(triisopropylsilyl)oxy]methyl}cyclohexyl)-ethanoyl]-1,3-thiazolidine (isomer I, 78 mg) was converted to the title compound in a manner identical to that described for isomer II. 1H NMR (500 MHz, CD3OD, HCl salt) δ 4.71 (dd, 1H, J=8 and 10 Hz), 4.58 (dd, 0.45H, J=2 and 9 Hz), 4.48 (d, 0.55H, J=2 and 9 Hz), 4.20 (d, 0.45H, J=6.2 Hz), 4.12 (d, 0.55H, J=6.2 Hz), 3.96 (m, 0.55H), 3.88 (m, 0.45H), 3.88 (m, 0.45H), 3.79 (m, 1H), 3.55 (d, 2H, J=5.9 Hz), 3.14 (m, 1H), 3.09 (m, 1H), 1.98 (m, 1H), 1.80 (m, 3H), 1.58 (m, 3H), 1.39 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[S:9][CH:10]=[C:11]([CH2:13][C:14]([O:16]C)=[O:15])[N:12]=2)=[CH:4][CH:3]=1.[Li+].[OH-]>>[CH3:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[S:9][CH:10]=[C:11]([CH2:13][C:14]([OH:16])=[O:15])[N:12]=2)=[CH:4][CH:3]=1
Reactant: COC(=O)Cc1csc(-c2ccc(C)nc2)n1
Agent: [Li+]
Agent: [OH-]
Product: Cc1ccc(-c2nc(CC(=O)O)cs2)cn1

Procedure:
This material was prepared according to the procedure described for Example 24(b) using methyl 2-[2-(6-methyl-3-pyridyl)-1,3-thiazol-4-yl]acetate (Step a, 0.5 g, 2.0 mmol) and LiOH (2 N, 5.0 mL). The product was filtered and washed successively with CH2Cl2, EtOAc, and hexanes to afford the title compound as a white solid. MS m/z: 235 (M+1). Calc'd for C11H10N2O2S: 234.05.
Reaction SMILES: C(NC1C=CC(C2C=C3C(CN([C@@H](C(C)C)C(OC)=O)C3=O)=CC=2)=CC=1)(=O)C1C=CC=CC=1.[NH2:34][C:35]1[CH:40]=[CH:39][C:38]([C:41]2[CH:49]=[C:48]3[C:44]([CH2:45][N:46]([C@@H:51]([CH:56]([CH3:58])[CH3:57])[C:52]([O:54][CH3:55])=[O:53])[C:47]3=[O:50])=[CH:43][CH:42]=2)=[CH:37][CH:36]=1.[CH3:59][O:60][C:61]1[CH:62]=[C:63]([CH:67]=[C:68]([O:72][CH3:73])[C:69]=1[O:70][CH3:71])[C:64](Cl)=[O:65]>>[CH3:57][CH:56]([CH3:58])[C@H:51]([N:46]1[CH2:45][C:44]2[C:48](=[CH:49][C:41]([C:38]3[CH:37]=[CH:36][C:35]([NH:34][C:64](=[O:65])[C:63]4[CH:62]=[C:61]([O:60][CH3:59])[C:69]([O:70][CH3:71])=[C:68]([O:72][CH3:73])[CH:67]=4)=[CH:40][CH:39]=3)=[CH:42][CH:43]=2)[C:47]1=[O:50])[C:52]([O:54][CH3:55])=[O:53]
Reactant: COc1cc(C(=O)Cl)cc(OC)c1OC
Reactant: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(N)cc3)cc2C1=O
Agent: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)c4ccccc4)cc3)cc2C1=O
Product: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)c4cc(OC)c(OC)c(OC)c4)cc3)cc2C1=O
Yield: 89 %

Procedure:
The compound of example 143 was prepared analogous to compound of example 97 by reaction of compound of example 6 with 3,4,5-trimethoxy benzoyl chloride.
Reaction SMILES: [CH2:1]([C@@H:5]([C:22](=[O:29])[NH:23][CH2:24][C:25]([O:27]C)=[O:26])[NH:6][C:7](=[O:21])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH:2]([CH3:4])[CH3:3].O[Li].O>C1COCC1.O>[CH2:1]([C@@H:5]([C:22](=[O:29])[NH:23][CH2:24][C:25]([OH:27])=[O:26])[NH:6][C:7](=[O:21])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH:2]([CH3:4])[CH3:3]
Reactant: COC(=O)CNC(=O)[C@H](CC(C)C)NC(=O)CCCCCNC(=O)OC(C)(C)C
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Product: CC(C)C[C@H](NC(=O)CCCCCNC(=O)OC(C)(C)C)C(=O)NCC(=O)O
Reaction time: 3 h

Procedure:
To a solution of (9-methyl 13-isobutyl-2,2-dimethyl-4,11,14-trioxo-3-oxa-5,12,15-triazaheptadecan-17-oate (6w) in THF was added a solution of LiOH.H2O in water at room temperature. After 3 h, the reaction mixture was concentrated, diluted with water and acidified with a 1N aqueous solution of HCl to about pH 4-5. The mixture was stirred for 15 min and the white precipitate formed was filtered off, rinsed with water, and dried to afford (S)-13-isobutyl-2,2-dimethyl-4,11,14-trioxo-3-oxa-5,12,15-triazaheptadecan-17-oic acid (7w).
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C@@H:3]([O:9][C:10]([C:12]1([C:19]3[S:20][CH:21]=[CH:22][CH:23]=3)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)=[O:11])[CH2:2]2.[Br:24][CH2:25][C:26]([NH:28][C:29]1[CH:34]=[N:33][CH:32]=[CH:31][N:30]=1)=[O:27].C(OCC)C.CCCC(C)C>C(#N)C>[Br-:24].[N:30]1[CH:31]=[CH:32][N:33]=[CH:34][C:29]=1[NH:28][C:26]([CH2:25][N+:1]12[CH2:6][CH2:5][CH:4]([CH2:7][CH2:8]1)[C@@H:3]([O:9][C:10]([C:12]1([C:19]3[S:20][CH:21]=[CH:22][CH:23]=3)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)=[O:11])[CH2:2]2)=[O:27]
Reactant: O=C(CBr)Nc1cnccn1
Reactant: O=C(O[C@H]1CN2CCC1CC2)C1(c2cccs2)CCCCCC1
Solvent: CCOCC
Solvent: CCCC(C)C
Solvent: CC#N
Product: O=C(C[N+]12CCC(CC1)[C@@H](OC(=O)C1(c3cccs3)CCCCCC1)C2)Nc1cnccn1
Product: [Br-]
Reaction time: 8 h

Procedure:
1-Thiophen-2-yl-cycloheptanecarboxylic acid (R)-(1-aza-bicyclo[2.2.2]oct-3-yl)ester (Example 5d) (116 mg) and 2-bromo-N-pyrazin-2-yl-acetamide (Example 11a) (75 mg were dissolved in acetonitrile (2 mL) and left overnight. Diethyl ether (10 mL) and isohexane (8 mL) were added and the mixture was left to stand overnight. The resulting crystals were filtered off and washed with diethyl ether to afford the titled compound (117 mg).