Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[S:3][CH:4]=[C:5]([C:7]([OH:9])=O)[N:6]=1.ClC(N(C)C)=C(C)C.[F:18][C:19]1[C:27]2[C:26]([NH2:28])=[CH:25][C:24]([C:29]3[CH:37]=[C:36]([F:38])[CH:35]=[C:34]4[C:30]=3[CH:31]=[CH:32][N:33]4S(C3C=CC([N+]([O-])=O)=CC=3)(=O)=O)=[CH:23][C:22]=2[N:21](S(C2C=CC=CC=2)(=O)=O)[N:20]=1.N1C=CC=CC=1.[OH-].[Na+].Cl>C1COCC1.C(O)(C)C.CS(C)=O>[F:18][C:19]1[C:27]2[C:22](=[CH:23][C:24]([C:29]3[CH:37]=[C:36]([F:38])[CH:35]=[C:34]4[C:30]=3[CH:31]=[CH:32][NH:33]4)=[CH:25][C:26]=2[NH:28][C:7]([C:5]2[N:6]=[C:2]([CH3:1])[S:3][CH:4]=2)=[O:9])[NH:21][N:20]=1
Reactant: Nc1cc(-c2cc(F)cc3c2ccn3S(=O)(=O)c2ccc([N+](=O)[O-])cc2)cc2c1c(F)nn2S(=O)(=O)c1ccccc1
Reactant: Cc1nc(C(=O)O)cs1
Agent: CC(C)=C(Cl)N(C)C
Agent: Cl
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CC(C)O
Solvent: c1ccncc1
Product: Cc1nc(C(=O)Nc2cc(-c3cc(F)cc4[nH]ccc34)cc3[nH]nc(F)c23)cs1
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
2-Methyl-1,3-thiazole-4-carboxylic acid was dissolved in THF (0.2 ml) and (1-chloro-2-methyl-1-propen-1-yl)dimethylamine (0.013 ml, 0.1 mmol) was added. The mixture was shaken, then left to stand for 30 mins. 3-fluoro-6-{6-fluoro-1-[(4-nitrophenyl)sulfonyl]-1H-indol-4-yl}-1-(phenylsulfonyl)-1H-indazol-4-amine (0.1 mmol) was dissolved in THF (0.4 ml) and added to the reaction mixture, followed by pyridine (0.016 ml, 0.2 mmol). The reaction mixture was shaken and then left to stand for 1 hour. A further portion of 2-methyl-1,3-thiazole-4-carboxylic acid was dissolved in THF (0.2 ml) and (1-chloro-2-methyl-1-propen-1-yl)dimethylamine (0.013 ml, 0.1 mmol) was added. The mixture was shaken, then left to stand for 20 mins before being added to the ongoing reaction mixture above, along with further pyridine (0.097 ml, 1.2 mmol). The mixture was shaken and left to stand for 30 mins. A further portion of 2-methyl-1,3-thiazole-4-carboxylic acid was dissolved in THF (0.2 ml) and (1-chloro-2-methyl-1-propen-1-yl)dimethylamine (0.013 ml, 0.1 mmol) was added. The mixture was shaken, then left to stand for 20 mins before being added to the ongoing reaction mixture above, along with further pyridine (0.097 ml, 1.2 mmol). The mixture was shaken and left to stand for 30 mins, then evaporated by blow down under a stream of nitrogen. The crude reaction mixture was dissolved in isopropanol (0.3 ml) and NaOH (2M aqueous, 0.3 ml) was added. The mixture was stood for 60 h at room temperature. Further NaOH (2M aqueous, 0.3 ml) was added and the mixture was heated to 80° C. for 1 hour. The reaction mixture was neutralised with HCl (2 M, aq.) and blown down under a stream of nitrogen. The crude material was dissolved in DMSO (0.5 ml), filtered and purified by Mass Directed Auto Prep on an Xbridge column using Acetonitrile/Water with a formic acid modifier (Method F). The solvent was evaporated in vacuo using the Genevac. The residue was dissolved in DMSO (0.5 ml) and further purified by formic acid MDAP (as above), over an extended run time. The product-containing fractions were blown down under a stream of nitrogen to give the title compound (11 mg). LCMS (Method D) Rt=1.16 min, MH+=410.
Reaction SMILES: [CH:1]1[C:6]([OH:7])=[CH:5][CH:4]=[CH:3][C:2]=1[CH3:8].[C:9](OC(=O)C)(=[O:11])[CH3:10].N1C=CC=CC=1.Cl>O>[C:9]([O:7][C:6]1[CH:1]=[C:2]([CH3:8])[CH:3]=[CH:4][CH:5]=1)(=[O:11])[CH3:10]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1cccc(O)c1
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: CC(=O)Oc1cccc(C)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 96.2 %

Procedure:
Meta-cresol (1 g, 9.0 mmol) and acetic anhydride (1.1 g, 10.8 mmol) were mixed in the presence of pyridine (3 ml) as a base at 0° C., and gradually heated to room temperature. After 30 minutes, 10˜15 ml of water is added thereto, and the mixture was neutralized by adding 1N HCl (30 ml) in three portions. The resultant mixture was extracted with organic solvent, washed, dried and purified by using column chromatography (eluent: hexane/ethyl acetate=6/1) to obtain 1.3 g (96%) of compound (3).
Reaction SMILES: [C:1]([NH:3][C:4](=[N:7][CH2:8][CH2:9][S:10][CH2:11][C:12]1[N:13]=[CH:14][NH:15][C:16]=1[CH3:17])SC)#[N:2].[NH2:18][CH2:19][CH2:20][NH2:21]>>[C:1]([NH:3][C:4]([NH:18][CH2:19][CH2:20][NH2:21])=[N:7][CH2:8][CH2:9][S:10][CH2:11][C:12]1[N:13]=[CH:14][NH:15][C:16]=1[CH3:17])#[N:2]
Reactant: CSC(=NCCSCc1nc[nH]c1C)NC#N
Reactant: NCCN
Product: Cc1[nH]cnc1CSCCN=C(NC#N)NCCN

Procedure:
Reaction of N-cyano-N'-[2-((5-methyl-4-imidazolyl)-methylthio)ethyl]-S-methylisothiourea with excess 1,2-diaminoethane at room temperature gave N-cyano-N'-(2-aminoethyl)-N"-[2-((5-methyl-4-imidazolyl)methylthio)ethyl]guanidine, m.p. 164°-167°.
Reaction SMILES: CN(C=O)C.[CH2:6]([O:10][CH2:11][CH2:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:21]=[CH:22][C:23]3[N:29]([CH2:30][C:31]4[N:32]([CH3:36])[CH:33]=[CH:34][N:35]=4)[CH2:28][CH2:27][C:26]([C:37]([OH:39])=O)=[CH:25][C:24]=3[CH:40]=2)=[CH:16][CH:15]=1)[CH2:7][CH2:8][CH3:9].S(Cl)(Cl)=O.[CH3:45][N:46]([CH2:53][C:54]1[CH:60]=[CH:59][C:57]([NH2:58])=[CH:56][CH:55]=1)[CH:47]1[CH2:52][CH2:51][O:50][CH2:49][CH2:48]1>O1CCCC1.O.C(N(CC)CC)C>[CH2:6]([O:10][CH2:11][CH2:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:21]=[CH:22][C:23]3[N:29]([CH2:30][C:31]4[N:32]([CH3:36])[CH:33]=[CH:34][N:35]=4)[CH2:28][CH2:27][C:26]([C:37]([NH:58][C:57]4[CH:59]=[CH:60][C:54]([CH2:53][N:46]([CH3:45])[CH:47]5[CH2:52][CH2:51][O:50][CH2:49][CH2:48]5)=[CH:55][CH:56]=4)=[O:39])=[CH:25][C:24]=3[CH:40]=2)=[CH:16][CH:15]=1)[CH2:7][CH2:8][CH3:9]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCN3Cc2nccn2C)cc1
Reactant: CN(Cc1ccc(N)cc1)C1CCOCC1
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CN(C)C4CCOCC4)cc2)CCN3Cc2nccn2C)cc1
Reaction time: 1 h
Yield: 32.6 %

Procedure:
One droplet of DMF was added to a solution of 7-(4-butoxyethoxyphenyl)-1-[(1-methylimidazol-2-yl)methyl]-2,3-dihydro-1-benzazepine-4-carboxylic acid (140 mg) in tetrahydroturan (10 ml). Then, thionyl chloride (41 mg) was added at 0° C., the temperature was returned to room temperature, and the mixture was stirred under nitrogen atmosphere for 1 hour. Then, this mixture was added to a solution of 4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]aniline (75 mg) and triethylamine (346 mg) in tetrahydrofuran (30 ml) at 0° C. The suspension was stirred under nitrogen atmosphere at room temperature overnight, to the mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried with magnesium sulfate. The solvent was evaporated under reduced pressure, the resulting residue was separated and purified with basic silica gel column chromatography (ethyl acetate), which was recrystallized from hexane-ethyl acetate to give 7-(4-butoxyethoxyphenyl)-1-[(1-methylimidazol-2-yl)methyl]-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (Compound 67) (65 mg) as yellow crystals.
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:10]=[C:9]([SH:11])[CH:8]=[C:7]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:6]=1[OH:16])([CH3:4])[CH3:3].[O-]CC.[Na+].[Na].[CH3:22][C@@H:23]1[O:25][C@H:24]1[CH3:26]>C(O)C>[CH3:13][C:12]([C:7]1[CH:8]=[C:9]([S:11][CH:23]([CH3:22])[CH:24]([OH:25])[CH3:26])[CH:10]=[C:5]([C:2]([CH3:1])([CH3:3])[CH3:4])[C:6]=1[OH:16])([CH3:15])[CH3:14]
Reactant: CC(C)(C)c1cc(S)cc(C(C)(C)C)c1O
Reactant: C[C@@H]1O[C@H]1C
Agent: CC[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CCO
Product: CC(O)C(C)Sc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Temperature: 5 °C
Reaction time: 1 h

Procedure:
2,6-bis(1,1-Dimethylethyl)-4-mercaptophenol (18.2 g, 0.076 mole) was added to a solution of sodium ethoxide freshly prepared from sodium (3.5 g, 0.15 mole) in ethyl alcohol (100 ml) and stirred for 1 hour. After cooling to 5° C. with an ice bath, trans-2,3-epoxybutane (5.0 g, 0.069 mole) was added and the ice bath removed. After stirring for 5.5 hours the reaction mixture was poured into ten percent hydrochloric acid (50 ml). The ethyl alcohol was removed using a rotary evaporator and the aqueous residue extracted with ethyl acetate (2X75 ml). The extracts were combined, dried over sodium sulfate, filtered, and concentrated to an orange oil. The product was purified by chromatography on silica to give a yellow solid which was recrystallized from hexane to give a white solid, m.p. ca. 73° C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:14]([F:17])([F:16])[F:15])[CH2:3][CH2:2]1.[CH:18]1([CH2:21][CH2:22][NH:23][C:24]([C:26]2[N:27]=[N:28][C:29](Cl)=[CH:30][CH:31]=2)=[O:25])[CH2:20][CH2:19]1.C([O-])([O-])=O.[K+].[K+]>[N+](CCCC)(CCCC)(CCCC)CCCC.[I-].O1CCOCC1>[CH:18]1([CH2:21][CH2:22][NH:23][C:24]([C:26]2[N:27]=[N:28][C:29]([N:1]3[CH2:2][CH2:3][CH:4]([NH:7][C:8]4[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=4[C:14]([F:15])([F:16])[F:17])[CH2:5][CH2:6]3)=[CH:30][CH:31]=2)=[O:25])[CH2:20][CH2:19]1
Reactant: FC(F)(F)c1ccccc1NC1CCNCC1
Reactant: O=C(NCCC1CC1)c1ccc(Cl)nn1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: C1COCCO1
Product: O=C(NCCC1CC1)c1ccc(N2CCC(Nc3ccccc3C(F)(F)F)CC2)nn1
Yield: 57 %

Procedure:
A mixture of piperidin-4-yl-(2-trifluoromethylphenyl)amine (0.380 g, 1.55 mmol), 6-chloropyridazine-3-carboxylic acid (2-cyclopropylethyl)amide (0.276 g, 1.00 mmol), K2CO3 (0.277 g, 2.0 mmol) and n-Bu4NI (10 mg) in dioxane (10 mL) was heated to reflux overnight, then concentrated. The residue was purified by flash chromatography to give 6-[4-(2-trifluoromethylphenylamino)piperidin-1-yl]pyridazine-3-carboxylic acid (2-cyclopropylethyl)amide (0.247 g). MS (ES+) m/z 434.3 (M+1).
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH2:8][OH:9])=[CH:6][CH:5]=[C:4]([Cl:10])[N:3]=1.N1C=CN=C1.[Si:16](Cl)([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17].O>CN(C=O)C>[Si:16]([O:9][CH2:8][C:7]1[C:2]([Cl:1])=[N:3][C:4]([Cl:10])=[CH:5][CH:6]=1)([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17]
Reactant: OCc1ccc(Cl)nc1Cl
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCc1ccc(Cl)nc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.1 %

Procedure:
To a solution of (2,6-dichloropyridin-3-yl)methanol (from Step A above, 6.3 g) in DMF was added imidazole (3.06 g) and t-butyldimethylsilyl chloride (6.02 g) at 0° C. The mixture was warmed to room temperature and stirred for 1 h before poured into water. The solution was extracted with ethyl acetate. The organic layer was washed with water (5×), brine, dried over MgSO4 and concentrated. The residue was purified by silica gel (hexanes/ethyl acetate) to give the title compound (8.7 g).
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[C:10]([O:12][CH2:13][CH:14]([CH3:16])[CH3:15])[CH:9]=[CH:8][C:7]=1[C:17](=[N:36]O)[C:18]1[CH:19]=[CH:20][C:21]([O:31][CH2:32][CH:33]([CH3:35])[CH3:34])=[C:22]([CH2:24][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH:23]=1)[CH:2]([CH3:4])[CH3:3].[BH4-].[Na+].Cl.C(=O)(O)[O-].[Na+]>CO.O.O.O.O.O.O.[Ni](Cl)Cl.C(Cl)Cl.O>[NH2:36][CH:17]([C:7]1[CH:8]=[CH:9][C:10]([O:12][CH2:13][CH:14]([CH3:16])[CH3:15])=[CH:11][C:6]=1[O:5][CH2:1][CH:2]([CH3:3])[CH3:4])[C:18]1[CH:19]=[CH:20][C:21]([O:31][CH2:32][CH:33]([CH3:34])[CH3:35])=[C:22]([CH2:24][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH:23]=1
Reactant: CCOC(=O)CCc1cc(C(=NO)c2ccc(OCC(C)C)cc2OCC(C)C)ccc1OCC(C)C
Agent: Cl[Ni]Cl
Agent: Cl
Agent: O=C([O-])O
Solvent: CO
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)CCc1cc(C(N)c2ccc(OCC(C)C)cc2OCC(C)C)ccc1OCC(C)C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 85.2 %

Procedure:
At 5° C., 5.56 g of nickel (II) chloride hexahydrate is added to a solution of 6.00 g of ethyl 3-{5-[(2,4-diisobutoxyphenyl)(hydroxyimino)methyl]-2-isobutoxyphenyl}propanoate in 60 ml of methanol. Then, 4.42 g of sodium borohydride is portionwise added over a period of one hour. Water is added to the reaction mixture, and then 6 mol/L hydrochloric acid is dropwise added and stirred at ambient temperature for 10 minutes. pH is adjusted to 9 with saturated aqueous solution of sodium bicarbonate, methylene chloride is added, and the organic layer is separated. The organic layer thus obtained is washed with water and saturated aqueous solution of sodium chloride successively and dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. Thus, 4.97 g of ethyl 3-{5-[amino(2,4-diisobutoxyphenyl)methyl]-2-isobutoxyphenyl}propanoate is obtained as a brown oily product.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([OH:32])([CH2:26][N:27]1[CH:31]=[N:30][N:29]=[N:28]1)[C:10]([C:13]1[N:18]=[CH:17][C:16](/[CH:19]=[CH:20]/[C:21](OCC)=[O:22])=[CH:15][CH:14]=1)([F:12])[F:11].[H-].C([Al+]CC(C)C)C(C)C.[BH4-].[Na+]>C(Cl)Cl.CO>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([OH:32])([CH2:26][N:27]1[CH:31]=[N:30][N:29]=[N:28]1)[C:10]([C:13]1[N:18]=[CH:17][C:16](/[CH:19]=[CH:20]/[CH2:21][OH:22])=[CH:15][CH:14]=1)([F:12])[F:11]
Reactant: CCOC(=O)/C=C/c1ccc(C(F)(F)C(O)(Cn2cnnn2)c2ccc(F)cc2F)nc1
Agent: CC(C)C[Al+]CC(C)C
Agent: [BH4-]
Agent: [H-]
Solvent: ClCCl
Solvent: CO
Product: OC/C=C/c1ccc(C(F)(F)C(O)(Cn2cnnn2)c2ccc(F)cc2F)nc1
Temperature: 0 °C
Yield: 57.2 %

Procedure:
To a stirred solution of (E)-ethyl 3-(6-(2-(2,4-difluorophenyl)-1,1-difluoro-2-hydroxy-3-(1H-tetrazol-1-yl)propyl)pyridin-3-yl)acrylate (4; 150 mg, 0.332 mmol) in dry CH2Cl2 (5 mL) was added diisobutylaluminum hydride (DIBAL-H, 1.6 M in toluene; 0.42 mL, 0.66 mmol) at −78° C. and maintained for 2 h under inert atmosphere. After completion of reaction (by TLC), the reaction was quenched with CH3OH (2 mL) and the obtained heterogeneous mixture was then filtered through a pad of Celite®. The filtrate was concentrated under reduced pressure to obtain the residue. The residue was dissolved in CH3OH (4 mL), and the mixture was stirred at 0° C. under inert atmosphere. Sodium borohydride (NaBH4; 18.9 mg, 0.499 mmol) was added to the stirring solution, and the mixture was maintained at the same temperature for 30 min. The reaction mixture was quenched with satd NH4Cl solution (5 mL) and extracted with EtOAc (3×20 mL). The organic extracts were washed with water (20 mL) and brine (20 mL), dried over anhydrous Na2SO4 and then concentrated in vacuo. Purification by silica gel column chromatography (eluting with 65-75% EtOAc/hexanes) yielded 43 (80 mg, 0.19 mmol, 58%). 1H NMR (500 MHz, CDCl3): δ 8.75 (s, 1H), 8.51 (s, 1H), 7.79 (dd, J=8.5, 2.0 Hz, 1H), 7.52 (d, J=8.5 Hz, 1H), 7.36-7.31 (m, 1H), 6.78-6.74 (m, 1H), 6.68 (br s, OH), 6.67-6.63 (m, 2H), 6.54-6.49 (m, 1H), 5.58 (d, J=14.5 Hz, 1H), 5.11 (d, J=14.5 Hz, 1H), 4.41-4.39 (m, 2H), 3.45 (br s, OH). MS (ESI): m/z 410 [M+H]+. HPLC: 99%.
Reaction SMILES: Br[C:2]1[CH:31]=[CH:30][C:5]2[C:6]3[N:7]([CH:11]=[C:12]([C:14]4[N:18]([C:19]5[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=5[Cl:25])[N:17]=[C:16]([NH:26][C:27](=[O:29])[OH:28])[N:15]=4)[N:13]=3)[CH2:8][CH2:9][O:10][C:4]=2[CH:3]=1.[Cl:32][C:33]1[CH:38]=[CH:37][C:36](B(O)O)=[CH:35][CH:34]=1.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:25][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[N:18]1[C:14]([C:12]2[N:13]=[C:6]3[C:5]4[CH:30]=[CH:31][C:2]([C:36]5[CH:37]=[CH:38][C:33]([Cl:32])=[CH:34][CH:35]=5)=[CH:3][C:4]=4[O:10][CH2:9][CH2:8][N:7]3[CH:11]=2)=[N:15][C:16]([NH:26][C:27](=[O:29])[OH:28])=[N:17]1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: O=C(O)Nc1nc(-c2cn3c(n2)-c2ccc(Br)cc2OCC3)n(-c2ccccc2Cl)n1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)Nc1nc(-c2cn3c(n2)-c2ccc(-c4ccc(Cl)cc4)cc2OCC3)n(-c2ccccc2Cl)n1
Temperature: 120 °C
Reaction time: 4 h
Yield: 42.2 %

Procedure:
5-(9-Bromo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-2-yl)-1-(2-chlorophenyl)-1H-1,2,4-triazol-3-ylcarbamic acid (600 mg, 1.2 mmol), 4-chlorophenylboronic acid (374 mg, 2.4 mmol), Pd(dppf)Cl2(97.9 mg, 0.12 mmol) and Cs2CO3 (469 mg, 1.44 mmol) were dissolved in dioxane/H2O (3:1, 30 ml). The resulting mixture was bubbled with N2 for 10 min and then sealed to stir at 120° C. for 4 h under N2. The reaction mixture was filtered. The filtrate was concentrated and purified by HPLC to give 1-(2-chlorophenyl)-5-(9-(4-chlorophenyl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-2-yl)-1H-1,2,4-triazol-3-ylcarbamic acid (270 mg, 21%). 1H NMR (DMSO, 400 MHz) δ 10.65 (s, 1H), 7.74 (s, 1H), 7.70 (d, J=8.4 Hz, 3H), 7.67-7.61 (m, 3H), 7.54 (t, 1H), 7.47 (d, J=8.4 Hz, 2H), 7.27-7.22 (m, 2H), 7.45-7.43 (m, 4H)
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH:6]=[C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH3:15])[CH:9]=2)[CH2:4][CH2:3]1.Cl[CH2:17][CH2:18][CH2:19]Br.[I-].[Na+]>>[CH3:15][O:14][C:10]1[CH:9]=[C:8]([C:5]23[CH2:19][CH2:18][CH2:17][C:4]2=[CH:3][N:2]([CH3:1])[CH2:7][CH2:6]3)[CH:13]=[CH:12][CH:11]=1
Reactant: COc1cccc(C2=CCN(C)CC2)c1
Reactant: ClCCCBr
Agent: [I-]
Agent: [Na+]
Product: COc1cccc(C23CCCC2=CN(C)CC3)c1

Procedure:
Following the procedure set out in Example 47, 1-methyl-4-(3-methoxyphenyl)-1,2,3,6-tetrahydropyridine was reacted with 3-chloropropylbromide and sodium iodide to afford 4a-(3-methoxyphenyl)-2-methyl-3,4,4a,5,6,7-hexahydro-2-pyrindine. B.P. 132°-134° C. at 0.1 torr.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][OH:14].[OH:15][C:16]1[CH:23]=[CH:22][C:19]([CH:20]=[O:21])=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.C(C(C)=O)C>[OH:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][O:15][C:16]1[CH:23]=[CH:22][C:19]([CH:20]=[O:21])=[CH:18][CH:17]=1
Reactant: OCCCCCCCCCCCCBr
Reactant: O=Cc1ccc(O)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CCC(C)=O
Product: O=Cc1ccc(OCCCCCCCCCCCCO)cc1

Procedure:
A mixture of 12-bromododecan-1-ol (15 g, 57 mmol, see Example 1 above), 4-hydroxy-benzaldehyde (6.9 g, 57 mmol), potassium carbonate (excess), potassium iodide (trace) and tetra-n-butylammonium iodide (trace) was heated at reflux in methyl ethyl ketone (50 ml) for 16 hours. After cooling, the solids were filtered off and washed with acetone. The combined organic fractions were evaporated to dryness. Diethyl ether was added to the resultant oil and the solution was stored at 4° C. The title compound precipitated and was collected by filtration.
Reaction SMILES: [C:1]([CH:4]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH:20]2[CH2:24][CH2:23][CH2:22][CH2:21]2)[CH:12]=1)[C:5](OCC)=[O:6])(=O)[CH3:2].O.[NH2:26][NH2:27]>C(O)C>[CH:20]1([O:19][C:13]2[CH:12]=[C:11]([CH:16]=[CH:15][C:14]=2[O:17][CH3:18])[CH2:10][C:4]2[C:5](=[O:6])[N:26]=[N:27][C:1]=2[CH3:2])[CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: CCOC(=O)C(Cc1ccc(OC)c(OC2CCCC2)c1)C(C)=O
Reactant: NN
Solvent: CCO
Solvent: O
Product: COc1ccc(CC2=C(C)N=NC2=O)cc1OC1CCCC1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 65.6 %

Procedure:
To a stirred solution of ethyl 2-acetyl-3-(3-cyclopentyloxy-4-methoxyphenyl)-propanoate (585 mg, 1.74 mmol) in absolute ethanol (10 ml) at 0° C. was added hydrazine monohydrate (87 mg, 1.74 mmol) in one portion. The resulting solution was stirred at 0° C. for 45 minutes and then refluxed at 80° C. for 3 hours. After cooling to room temperature, the reaction mixture was concentrated in vacuo and purified by flash chromatography (SiO2 ;methylene chloride/ethanol/ammonia (4:1:0.1)) to afford the title compound as a white solid (343 mg). m.p. 186-187° C.
Reaction SMILES: COC(=O)C(O)=CC(=O)N(CC1C=CC(F)=CC=1)C.C=O.[C:22]1([CH2:28][CH2:29][NH2:30])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[F:31][C:32]1[CH:50]=[CH:49][C:35]([CH2:36][N:37]([CH3:48])[C:38]([C:40]2[CH2:41]N(C)[C:43](=[O:46])[C:44]=2[OH:45])=[O:39])=[CH:34][CH:33]=1>>[F:31][C:32]1[CH:50]=[CH:49][C:35]([CH2:36][N:37]([CH3:48])[C:38]([C:40]2[CH2:41][N:30]([CH2:29][CH2:28][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:43](=[O:46])[C:44]=2[OH:45])=[O:39])=[CH:34][CH:33]=1
Reactant: CN1CC(C(=O)N(C)Cc2ccc(F)cc2)=C(O)C1=O
Reactant: NCCc1ccccc1
Agent: C=O
Agent: COC(=O)C(O)=CC(=O)N(C)Cc1ccc(F)cc1
Product: CN(Cc1ccc(F)cc1)C(=O)C1=C(O)C(=O)N(CCc2ccccc2)C1

Procedure:
3-[(4-Fluoro-benzyl)-methyl-carbamoyl]-2-hydroxy-acrylic acid methyl ester (Compound 1-D) was treated with paraformaldehyde and 2-phenyl-ethylamine as described in the preparation of Compound 1. HRMS (M+H) calcd for C21H22FN2O3: 369.1615. found: 369.1625. 1H NMR (500 MHz, CDCl3) δ: 2.92 (overlapping m, 5), 3.74 (t, 2, J=7), 3.92 (s, 2), 4.56 (s, 2), 7.01–7.29 (overlapping m, 9). 13C NMR (125 MHz, CDCl3) δ: 34.45, 34.60, 44.70, 49.42, 51.46, 109.12, 115.66, 115.83, 126.75, 128.63, 128.72, 129.26, 129.33, 132.09, 132.11, 138.18, 153.11, 161.38, 163.34, 164.79, 166.18.
Reaction SMILES: [N:1]#[N:2].C([O:6][C@H:7]1[C@@H:12]([O:13]C(=O)C)[C@H:11]([O:17]C(=O)C)[C@@H:10]([CH2:21][O:22]C(=O)C)[O:9][C@@H:8]1[S:26][CH2:27][CH2:28][C:29]([NH:31][C@H:32]([C:66]([NH:68][C@H:69]([C:103]([NH:105][C@H:106]([C:140]([OH:142])=[O:141])[CH2:107][CH2:108][CH2:109][CH2:110][NH:111][C:112](=[O:139])[CH2:113][CH2:114][S:115][C@H:116]1[O:133][C@H:132]([CH2:134][O:135]C(=O)C)[C@@H:127]([O:128]C(=O)C)[C@H:122]([O:123]C(=O)C)[C@@H:117]1[O:118]C(=O)C)=[O:104])[CH2:70][CH2:71][CH2:72][CH2:73][NH:74][C:75](=[O:102])[CH2:76][CH2:77][S:78][C@H:79]1[O:96][C@H:95]([CH2:97][O:98]C(=O)C)[C@@H:90]([O:91]C(=O)C)[C@H:85]([O:86]C(=O)C)[C@@H:80]1[O:81]C(=O)C)=[O:67])[CH2:33][CH2:34][CH2:35][CH2:36][NH:37][C:38](=[O:65])[CH2:39][CH2:40][S:41][C@H:42]1[O:59][C@H:58]([CH2:60][O:61]C(=O)C)[C@@H:53]([O:54]C(=O)C)[C@H:48]([O:49]C(=O)C)[C@@H:43]1[O:44]C(=O)C)=[O:30])(=O)C>CO.O.C(N(CC)CC)C>[N:1]#[N:2].[C@H:8]1([S:26][CH2:27][CH2:28][C:29]([NH:31][C@H:32]([C:66]([NH:68][C@H:69]([C:103]([NH:105][C@H:106]([C:140]([OH:142])=[O:141])[CH2:107][CH2:108][CH2:109][CH2:110][NH:111][C:112](=[O:139])[CH2:113][CH2:114][S:115][C@H:116]2[O:133][C@H:132]([CH2:134][OH:135])[C@@H:127]([OH:128])[C@H:122]([OH:123])[C@@H:117]2[OH:118])=[O:104])[CH2:70][CH2:71][CH2:72][CH2:73][NH:74][C:75](=[O:102])[CH2:76][CH2:77][S:78][C@H:79]2[O:96][C@H:95]([CH2:97][OH:98])[C@@H:90]([OH:91])[C@H:85]([OH:86])[C@@H:80]2[OH:81])=[O:67])[CH2:33][CH2:34][CH2:35][CH2:36][NH:37][C:38](=[O:65])[CH2:39][CH2:40][S:41][C@H:42]2[O:59][C@H:58]([CH2:60][OH:61])[C@@H:53]([OH:54])[C@H:48]([OH:49])[C@@H:43]2[OH:44])=[O:30])[O:9][C@H:10]([CH2:21][OH:22])[C@@H:11]([OH:17])[C@H:12]([OH:13])[C@@H:7]1[OH:6]
Reactant: CC(=O)OC[C@H]1O[C@H](SCCC(=O)NCCCC[C@H](NC(=O)[C@H](CCCCNC(=O)CCS[C@H]2O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@@H]2OC(C)=O)NC(=O)[C@H](CCCCNC(=O)CCS[C@H]2O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@@H]2OC(C)=O)NC(=O)CCS[C@H]2O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@@H]2OC(C)=O)C(=O)O)[C@@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: N#N
Solvent: O
Solvent: CCN(CC)CC
Solvent: CO
Product: O=C(CCS[C@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@@H]1O)NCCCC[C@H](NC(=O)[C@H](CCCCNC(=O)CCS[C@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@@H]1O)NC(=O)[C@H](CCCCNC(=O)CCS[C@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@@H]1O)NC(=O)CCS[C@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@@H]1O)C(=O)O
Yield: 70.1 %

Procedure:
A solution of 15 (52 mg, 0.025 mmol) in methanol-water-triethylamine 5:4:1 (v/v/v, 1 ml) is kept for 3 hours at room temperature, and evaporated in vacuo to a residue that is put on a Sephadex G-15 column and eluted with water. Fractions 1-4 (12 ml), eluted after blue dextran, are collected and lyophilized to give 16 (25.1 mg, 71%): [α]D27 +96.2° (c 1.0, H2O); NMR (D2O)δ: 5.37 (s, 1H, H-1), 5.34 (s, 3H, H-1) 4.34 (2H), 4.18 (1H) (α-CH), 3.22 (m, ε-CH2), 2.93 (m, SCH2), 2.70 (t, 2H), 2.60 (t, 6H) (SCH2CH2), 1.34-1.94 (CCH2CH2CH2C).