Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:20]([OH:22])=O)[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.C(Cl)(=O)OCC.[NH2:36][C:37]1[S:38][CH:39]=[N:40][N:41]=1>C(Cl)(Cl)Cl>[CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:20]([NH:36][C:37]1[S:38][CH:39]=[N:40][N:41]=1)=[O:22])[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1nncs1
Reactant: O=C(N[C@@H](Cc1ccccc1)C(=O)O)OCc1ccccc1
Agent: CCOC(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: O=C(N[C@@H](Cc1ccccc1)C(=O)Nc1nncs1)OCc1ccccc1
Yield: 71.2 %

Procedure:
Using the same procedure as in Example 1(i), 10 g of N-benzyloxycarbonyl-L-phenylalanine, 3.3 g of triethylamine, 3.7 g of ethyl chlorocarbonate and 3.5 g of 2-amino-1,3,4-thiadiazole were reacted in chloroform to obtain 9.1 g (yield: 71%) of 2-(N-benzyloxycarbonyl-L-phenylalanylamino)-1,3,4-thiadiazole as white crystals of mp: 78°-83° C. and [α]D20 : +28.0° (C=1.2, MeOH).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[CH2:4][CH2:5][CH2:6][C:7](=O)[N:8]([C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-])=O)=[CH:12][C:11]=1[N+:19]([O-])=O)[CH3:9].[H][H].[ClH:26]>[Pd].CO>[ClH:26].[CH3:1][O:2][C:3](=[O:23])[CH2:4][CH2:5][CH2:6][C:7]1[N:8]([CH3:9])[C:10]2[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][C:11]=2[N:19]=1
Reactant: COC(=O)CCCC(=O)N(C)c1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: COC(=O)CCCc1nc2cc(N)ccc2n1C
Yield: 92 %

Procedure:
A one-liter Buchi reactor was charged with 20 grams of 4-[(2,4-dinitro-phenyl)-methyl-carbamoyl]-butyric acid methyl ester, 1.0 g of palladium on carbon (dry basis, 10% Pd), and 180 mL of methanol at ambient temperature. The resulting mixture was subjected to hydrogenation at 40 psi overnight (ca. 18 hours) with a hydrogen mass transfer coefficient (kLa) of 0.12 to 0.28. The reaction mixture was filtered through a thin pad of Celite® 540. To the filtrate was added 2.8 mL of concentrated hydrochloric acid (1.1 eq vs. starting material). The resulting mixture was stirred under reflux for 3.5 hours. Approximately ¾ amount of solvent was removed under reduced pressure. Then warm tetrahydrofuran (THF) (150 mL) was added while vigorously stirring. The precipitate was collected by filtration and dried overnight under vacuum to afford a coffee-colored solid (16.1 g, yield 92%) with a purity of 98 Area % by HPLC analysis (HPLC Method B). 1H NMR (400 MHz, DMSO-d6) δ 7.83 (d, J=8.8 Hz, 1H), 7.50 (s, 1H), 7.27 (d, J=8.6 Hz, 1H), 3.91 (s, 3H), 3.58 (s, 3H), 3.17 (t, J=7.7 Hz, 2H), 2.53 (t, J=7.3 Hz, 2H, overlapped partially with DMSO), 2.07 (quint, J=7.5 Hz, 2H); LC/MS (ESI, m/z) 248 (M+1).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C:5]([C@:7]12[CH2:42][CH2:41][C@@H:40]([C:43]([CH3:45])=[CH2:44])[C@@H:8]1[C@@H:9]1[C@@:22]([CH3:25])([CH2:23][CH2:24]2)[C@@:21]2([CH3:26])[C@@H:12]([C@:13]3([CH3:39])[C@@H:18]([CH2:19][CH2:20]2)[C:17]([CH3:28])([CH3:27])[C:16]([C:29]2[CH:38]=[CH:37][C:32]([C:33]([O:35][CH3:36])=[O:34])=[CH:31][CH:30]=2)=[CH:15][CH2:14]3)[CH2:11][CH2:10]1)=[O:6].[C:46]([O:50][CH3:51])(=[O:49])[CH:47]=[CH2:48]>CO>[CH3:36][O:35][C:33]([C:32]1[CH:31]=[CH:30][C:29]([C:16]2[C:17]([CH3:27])([CH3:28])[C@H:18]3[C@:13]([CH3:39])([CH2:14][CH:15]=2)[C@@H:12]2[C@:21]([CH3:26])([C@@:22]4([CH3:25])[C@H:9]([CH2:10][CH2:11]2)[C@H:8]2[C@H:40]([C:43]([CH3:45])=[CH2:44])[CH2:41][CH2:42][C@:7]2([C:5]([NH:4][CH2:3][CH2:2][N:1]([CH2:31][CH2:32][C:33]([O:35][CH3:36])=[O:34])[CH2:48][CH2:47][C:46]([O:50][CH3:51])=[O:49])=[O:6])[CH2:24][CH2:23]4)[CH2:20][CH2:19]3)=[CH:38][CH:37]=1)=[O:34]
Reactant: C=C(C)[C@@H]1CC[C@]2(C(=O)NCCN)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Reactant: C=CC(=O)OC
Solvent: CO
Product: C=C(C)[C@@H]1CC[C@]2(C(=O)NCCN(CCC(=O)OC)CCC(=O)OC)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 20 °C
Reaction time: 3 h
Yield: 192.5 %

Procedure:
A mixture of methyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(2-aminoethylcarbamoyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate (20 mg, 0.033 mmol) and methyl acrylate (8.40 mg, 0.098 mmol) in methanol (1 mL) was stirred at 20° C. for 3 hours. LCMS indicated the mono-substitution. Methyl acrylate (8.40 mg, 0.098 mmol) was added to the reaction mixture again. The reaction mixture was stirred for 16 hours. The reaction mixture was quenched with distilled water, extracted with DCM (3×3 mL). All the extracts were combined, dried over sodium sulfate, filtered and concentrated under reduced pressure to provide the title compound as a white solid (25 mg, 98%). LCMS: m/e 787.48 (M+H)+, 2.67 min (method 1).
Reaction SMILES: O=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[O:5][C:4]([C:12]([OH:14])=[O:13])=[CH:3]1>[Pd].C(O)(=O)C.C(OCC)(=O)C>[O:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH2:2][CH2:3][CH:4]1[C:12]([OH:14])=[O:13]
Reactant: O=C(O)c1cc(=O)c2ccccc2o1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: O=C(O)C1CCc2ccccc2O1
Yield: 96.2 %

Procedure:
A mixture of the compound from Example 19 (20.0 g, 105 mmol), and palladium on activated carbon (Pd 10%, 2.0 g) in acetic acid (200 mL) was placed under hydrogen pressure (60 psig) in a Parr hydrogenation apparatus. After 22.5 hours the mixture was removed from the hydrogen atmosphere and filtered through a pad of Celite. The Celite pad was washed with ethyl acetate (800 mL), and the combined filtrate concentrated to give a brown oil. The oil was dissolved in ethyl acetate (500 mL) and extracted with saturated aqueous NaHCO3 solution (4×125 mL). The aqueous phase was acidified to pH=2 with concentrated HCl and extracted with ethyl acetate (4×100 mL). The combined organic phase was washed with saturated aqueous sodium chloride solution (100 mL), dried (MgSO4), and concentrated to give a colorless solid (18.0 g, 96%). Mp 97.5-99° C.; 1H NMR (DMSO-d6, 300 MHz) δ 12.96 (br s, 1 H), 7.03 (m, 2 H), 6.78 (m, 2 H), 4.74 (dd, J=6.4 Hz, 3.9 Hz, 1 H), 2.73 (m, 1 H), 2.63 (m, 1 H), 2.03 (m, 2 H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](B(O)O)[CH:5]=[CH:6][CH:7]=1.COC1C=CC=C(OC)C=1C1C=CC=CC=1P(C1CCCCC1)C1CCCCC1.C(=O)([O-])[O-].[K+].[K+].Cl[C:47]1[C:52]([NH2:53])=[CH:51][CH:50]=[C:49]([CH3:54])[N:48]=1>CC([O-])=O.CC([O-])=O.[Pd+2].O.C(#N)C>[F:1][C:2]1[CH:3]=[C:4]([C:47]2[C:52]([NH2:53])=[CH:51][CH:50]=[C:49]([CH3:54])[N:48]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: OB(O)c1cccc(F)c1
Reactant: Cc1ccc(N)c(Cl)n1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: O
Solvent: CC#N
Product: Cc1ccc(N)c(-c2cccc(F)c2)n1
Temperature: 78 °C
Reaction time: 4 h

Procedure:
To a mixture of 3-fluorophenylboronic acid (1.6 g, 12 mmol), S—PHOS (0.304 g, 0.74 mmol), potassium carbonate (3.41 g, 25 mmol), 2-chloro-6-methylpyridin-3-amine 16 (1.3 g, 9.1 mmol), and Pd(OAc)2 (0.085 g, 0.38 mmol) was added acetonitrile (14 mL) and water (9 mL). The reaction mixture was degassed by bubbling nitrogen through the solution for 10 min and the reaction mixture was heated to 78° C. After 4 h, the reaction mixture was diluted with EtOAc, washed with brine (1×), dried over MgSO4, filtered, and concentrated. Purification by flash column chromatography on silica gel (10% to 50% EtOAc in hexanes) gave 2-(3-fluorophenyl)-6-methylpyridin-3-amine.
Reaction SMILES: [F:1][C:2]1[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[C:3]=1[CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[C:13]([O:14]C)[C:8]=2[N:7]=[C:6]1[C:16]1[C:21]([F:22])=[CH:20][CH:19]=[CH:18][C:17]=1[F:23].Br>[Br-].C([N+](C)(C)C)CCCCCCCCCCCCCCC.C(O)(=O)C>[F:1][C:2]1[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[C:3]=1[CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[C:13]([OH:14])[C:8]=2[N:7]=[C:6]1[C:16]1[C:17]([F:23])=[CH:18][CH:19]=[CH:20][C:21]=1[F:22]
Reactant: COc1cccc2c1nc(-c1c(F)cccc1F)n2Cc1c(F)cccc1F
Agent: Br
Agent: CCCCCCCCCCCCCCCC[N+](C)(C)C
Agent: [Br-]
Solvent: CC(=O)O
Product: Oc1cccc2c1nc(-c1c(F)cccc1F)n2Cc1c(F)cccc1F
Yield: 85.9 %

Procedure:
To 1-(2,6-difluorobenzyl)-2-(2,6-difluorophenyl)-4-methoxylbenzimidazole (Example 46) (0.30 g, 0.78 mmol) and hexadecyltrimethylammonium bromide (0.30 g) dissolved in acetic acid (9.0 mL) was added HBr (1.0 mL). After refluxing for 7 h, the reaction was concentrated. The residue was then diluted with EtOAc, and washed with NaHCO3 (sat. aq) and NaCl (sat. aq). The combined washing were dried (Na2SO4), filtered, and concentrated. The crude product was purified by flash chromatography eluting with 2% methanol/CH2Cl2 and recrystallization from diethylether, yielding 1-(2,6-Difluorobenzyl)-2-(2,6-difluorophenyl)-4-hydroxylbenzimidazole (0.25 g, 0.67 mmol, 86% yield). M.p. 257-259° C. 1H NMR (200 MHz, CD2Cl2): δ7.57 (m, 1H, H4′), 7.25 (m, 1H, H4″), 7.17 (dd, J=7.9, 8.3 Hz, 1H, H6), 7.12 (m, 2H, H3′,5′), 6.99 (d, J=8.3 Hz, 1H, H7), 6.82 (m, 2H, H3″,5″), 6.73 (dd, J=7.9, 1.0 Hz, H5), 5.35 (s, 2H, CH2PhF2).
Reaction SMILES: Cl.[F:2][C:3]1[CH:22]=[CH:21][C:6]([O:7][C:8]2[CH:9]=[C:10]([CH:18]=[CH:19][CH:20]=2)[CH:11]=[C:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[CH:5][CH:4]=1.[CH3:23][C:24]1[C:28]([CH3:29])=[C:27]([NH:30][C:31](=O)[O:32]C2C=CC=CC=2)[O:26][N:25]=1>>[CH3:23][C:24]1[C:28]([CH3:29])=[C:27]([NH:30][C:31]([N:15]2[CH2:14][CH2:13][C:12](=[CH:11][C:10]3[CH:18]=[CH:19][CH:20]=[C:8]([O:7][C:6]4[CH:5]=[CH:4][C:3]([F:2])=[CH:22][CH:21]=4)[CH:9]=3)[CH2:17][CH2:16]2)=[O:32])[O:26][N:25]=1
Reactant: Cc1noc(NC(=O)Oc2ccccc2)c1C
Reactant: Fc1ccc(Oc2cccc(C=C3CCNCC3)c2)cc1
Agent: Cl
Product: Cc1noc(NC(=O)N2CCC(=Cc3cccc(Oc4ccc(F)cc4)c3)CC2)c1C
Yield: 116.3 %

Procedure:
Following the procedure in Example 1, Step 6, 4-[3-(4-fluoro-phenoxy)-benzylidene]-piperidine hydrochloride (200 mg, 0.625 mmol, from Example 18, Step 3) and phenyl 3,4-dimethylisoxazol-5-ylcarbamate (160 mg, 0.40 mmol) were used to provide the title compound (196 mg). MS (APCI 10 V) AP+ 422.2, 284.2, AP− 420.2; 1H NMR (400 MHz, CD3OD) δ ppm 1.83 (s, 3H) 2.18 (s, 3H) 2.42 (td, J=5.76, 1.10 Hz, 2H) 2.51 (td, J=5.88, 1.13 Hz, 2H) 3.47-3.52 (m, 2H) 3.57-3.63 (m, 2H) 6.40 (s, 1H) 6.77-6.84 (m, 2H) 6.94-6.98 (m, J=7.78, 1.45, 0.77, 0.77 Hz, 1H) 6.98-7.03 (m, 2H) 7.05-7.13 (m, 2H) 7.29 (t, J=7.85 Hz, 1H).
Reaction SMILES: [NH2:1][C@H:2]([C:5]([OH:7])=[O:6])[CH2:3][OH:4].[OH-].[Na+].[CH:10](=O)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[BH4-].[Na+]>C(OCC)C>[CH2:10]([NH:1][C@H:2]([C:5]([OH:7])=[O:6])[CH2:3][OH:4])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: N[C@@H](CO)C(=O)O
Reactant: O=Cc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Product: O=C(O)[C@H](CO)NCc1ccccc1
Temperature: 5 °C
Yield: 39.3 %

Procedure:
A 5 L 3-neck round bottom flask was charged with L-serine (313 g, 3.0 mol) and 2N sodium hydroxide solution (1.5 L). Stirring was begun and benzaldehyde (322.4 g, 3.0 mol) added. After 15 minutes at room temperature the solution was cooled to 5° C. and sodium borohydride (35.0 g, 0.93 mol) was added in small portions so as to maintain the temperature below 10° C. Once the addition was complete the solution was allowed to warm to room temperature and stir for 2 h. At this point, a second portion of benzaldehyde (322.4 g, 3.0 mol) was added and the solution stirred for 15 minutes. The solution was cooled to 5° C. and sodium borohydride (35.0 g, 0.93 mol) added, again maintaining the temperature below 10° C. The reaction mixture was then warmed to room temperature and stirred for 2 h. Diethyl ether (1 L) was added, the solution stirred 5–10 minutes and the ether layer separated. The pH of the aqueous layer was then adjusted to 6 with 37% hydrochloric acid. Filtration of the resulting solids and recrystallization of the wet cake from water afforded 230 g (40%) of (S)-(+)-N-benzylserine after drying at 45° C. overnight.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH:11]2[CH2:17][CH2:16][CH2:15][CH2:14][N:13]([O:18][C:19]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:12]2=[O:38])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:39][O:40][C:41]1[CH:46]=[CH:45][C:44]([OH:47])=[CH:43][CH:42]=1.C([O-])([O-])=O.[K+].[K+]>CC(N(C)C)=O.CCOC(C)=O>[CH3:39][O:40][C:41]1[CH:46]=[CH:45][C:44]([O:47][C:2]2[CH:7]=[CH:6][C:5]([S:8]([CH:11]3[CH2:17][CH2:16][CH2:15][CH2:14][N:13]([O:18][C:19]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:12]3=[O:38])(=[O:10])=[O:9])=[CH:4][CH:3]=2)=[CH:43][CH:42]=1
Reactant: O=C1C(S(=O)(=O)c2ccc(F)cc2)CCCCN1OC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: COc1ccc(Oc2ccc(S(=O)(=O)C3CCCCN(OC(c4ccccc4)(c4ccccc4)c4ccccc4)C3=O)cc2)cc1
Temperature: 100 °C

Procedure:
A Mixture of 3-(4-fluoro-benzenesulfonyl)-1-trityloxy-azepan-2-one prepared from step F (18.9 mg, 0.0357 mmol), 4-methoxy-phenol (19.2 mg, 0.154 mmol) and K2CO3 (38.1 mg, 0.275 mmol) in anhydrous DMA (1.5 mL) was stirred and heated at 100° C. for overnight. The reaction mixture was diluted with EtOAc and washed sequentially with water and saturated NaCl solution. The organic phase was then dried over anhydrous Na2SO4 and concentrated under reduced pressure to gave a crude material, which was then purified by a column chromatography (0˜25% EtOAc in hexane). MS: 656.5 (M+Na)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[CH:4]=[CH:5][C:6]1[CH:7]=[N:8][C:9]([O:12][CH3:13])=[CH:10][CH:11]=1.C(Cl)Cl>[Pd].CCO>[CH3:1][O:2][C:3](=[O:14])[CH2:4][CH2:5][C:6]1[CH:7]=[N:8][C:9]([O:12][CH3:13])=[CH:10][CH:11]=1
Reactant: COC(=O)C=Cc1ccc(OC)nc1
Agent: [Pd]
Solvent: ClCCl
Solvent: CCO
Product: COC(=O)CCc1ccc(OC)nc1
Yield: 97.3 %

Procedure:
A suspension of 3-(6-methoxy-pyridin-3-yl)-acrylic acid methyl ester (1.2 g, 6.21 mmol, 1 eq) and Pd/C, 10% (330 mg, 0.05 eq, 10%) was stirred in a DCM (15 ml)/absolute EtOH (15 ml) solvent mixture under hydrogen atmosphere for 1 hour at room temperature. Palladium was filtered off over a celite pad, the solvent was evaporated and obtained was 3-(6-methoxy-pyridin-3-yl)-propionic acid methyl ester (1.18 g, yield=93%, purity=95%) in form of yellowish oil. MS: [M+H]+=196.15 1H NMR (300 MHz; CDCl3) δ/ppm 2.59 (t, J=7.75 Hz, 2H), 2.88 (t, J=7.75 Hz, 2H), 3.67 (s, 3H), 3.91 (s, 3H), 6.68 (d, J=8.46 Hz, 1H), 7.42 (dd, J=7.42 Hz, J=2.40 Hz, 1H), 8.00 (d, J=2.40 Hz, 1H)
Reaction SMILES: [N:1]([CH:4]1[CH2:10][CH2:9][C:8]2[CH:11]=[CH:12][C:13]([O:15][CH3:16])=[CH:14][C:7]=2[NH:6][C:5]1=[O:17])=[N+:2]=[N-:3].[OH-].[K+].Br[CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.O1CCCC1>[N:1]([CH:4]1[CH2:10][CH2:9][C:8]2[CH:11]=[CH:12][C:13]([O:15][CH3:16])=[CH:14][C:7]=2[N:6]([CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[C:5]1=[O:17])=[N+:2]=[N-:3]
Reactant: CCOC(=O)CBr
Reactant: COc1ccc2c(c1)NC(=O)C(N=[N+]=[N-])CC2
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(=O)CN1C(=O)C(N=[N+]=[N-])CCc2ccc(OC)cc21
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
3-Azido-8-methoxy-2,3,4,5-tetrahydro-1H-[1]-benzazepin-2-one (5 g) was added in one portion to a stirred suspension of potassium hydroxide (1.3 g) and tetrabutylammonium bromide (0.7 g) in tetrahydrofuran (50 ml) maintained at 0° under a nitrogen atmosphere. Stirring was continued for 5 minutes, then a solution of ethyl bromoacetate (3.6 g) in tetrahydrofuran (15 ml) was added during 5 minutes. The reaction mixture was allowed to warm to room temperature while stirring for an additional 2 hours. The reaction mixture was filtered and the tetrahydrofuran was removed at reduced pressure. The residue was partitioned between water (50 ml) and ether (100 ml). The organic phase was washed with 2N hydrochloric acid (10 ml), dried over magnesium sulfate and the solvent removed under reduced pressure to give 3-azido-1-ethoxycarbonylmethyl-8-methoxy-2,3,4,5-tetrahydro-1H-[1]-benzazepin-2-one, m.p. 90°-91°.
Reaction SMILES: [C:1]1([CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8]([CH3:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:17]([C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([CH:26]([CH3:28])[CH3:27])[C:21]=1[N:29]=[C:30]=[O:31])([CH3:19])[CH3:18].C([N-]C(C)C)(C)C.[Li+]>>[CH3:19][CH:17]([C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([CH:26]([CH3:27])[CH3:28])[C:21]=1[NH:29][C:30](=[O:31])[CH2:10][C:8](=[O:9])[CH:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[CH3:18]
Reactant: CC(C)c1cccc(C(C)C)c1N=C=O
Reactant: CC(=O)C(c1ccccc1)c1ccccc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Product: CC(C)c1cccc(C(C)C)c1NC(=O)CC(=O)C(c1ccccc1)c1ccccc1

Procedure:
The title compound, mp 153°-155° C., was prepared from 1,1-diphenylacetone (5.0 g, 0.023 mol), 2,6-diisopropylphenyl isocyanate (4.6 g, 0.023 mol) and lithium diisopropylamide (0.023 mol) using the procedure described in Example 1.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[Cl:5][C:6]1[CH:14]=[C:13]2[C:9]([CH:10]=[C:11]([C:15]([OH:17])=[O:16])[NH:12]2)=[CH:8][CH:7]=1>C(OC(=O)C)(=O)C>[Cl:5][C:6]1[CH:14]=[C:13]2[C:9]([C:10]([N+:1]([O-:4])=[O:2])=[C:11]([C:15]([OH:17])=[O:16])[NH:12]2)=[CH:8][CH:7]=1
Reactant: O=[N+]([O-])O
Reactant: O=C(O)c1cc2ccc(Cl)cc2[nH]1
Solvent: CC(=O)OC(C)=O
Product: O=C(O)c1[nH]c2cc(Cl)ccc2c1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 2 h
Yield: 56 %

Procedure:
To an ice-cooled soluton of acetic anhydride (90 ml) and concentrated nitric acid (70%, 10.3 ml) was added 6-chloroindole-2-carboxylic acid (H. W. Ridon and J. C. Tweddle, J. Chem.Soc., 1955, 3499: 18.16 g, 92.84 mmol) portion wise over 20 min. The mixture was stirred for 2 h at 0° C. and the resulting precipitates collected by filtration and washed with a mixture of dichloromethane/hexane (1:1) to give 12.6 g (56%) of the title compound as a yellow solid. 1H-NMR (DMSO-d6) δ: 13.41(1H, br s), 8.04 (1H, d, J=8.8 Hz), 7.62 (1H, d, 1.8 Hz), 7.44 (1H, dd, J=1.8, 8.8 Hz)
Reaction SMILES: O1CCCOB1[C:7]1[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=1[C:9]#[N:10].Br[C:16]1[CH:22]=[C:21]([C:23]([CH3:26])([CH3:25])[CH3:24])[CH:20]=[CH:19][C:17]=1[NH2:18].C([O-])([O-])=O.[K+].[K+].C1(C)C=CC=CC=1>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.C(O)C>[C:23]([C:21]1[CH:22]=[CH:16][C:17]2[C:19](=[C:7]3[C:8](=[C:9]([NH2:10])[N:18]=2)[CH:11]=[CH:12][CH:13]=[CH:14]3)[CH:20]=1)([CH3:26])([CH3:24])[CH3:25]
Reactant: N#Cc1ccccc1B1OCCCO1
Reactant: CC(C)(C)c1ccc(N)c(Br)c1
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: CCO
Solvent: Cc1ccccc1
Product: CC(C)(C)c1ccc2nc(N)c3ccccc3c2c1
Yield: 35.4 %

Procedure:
35.7 g (190 mmol) 2-(1,3,2-dioxaborinan-2-yl)benzonitrile, 31.9 g (158 mmol) 2-bromo-4-(tertbutyl)aniline, 3.6 g (3.16 mmol) tetrakis(triphenylphosphine)palladium(0) and 59.0 g (427 mmol) K2CO3 were heated to reflux in a 2 L flask containing 400 ml toluene and 300 mL ethanol. The reaction mixture was heated for 19 hours under constant N2 purge. HPLC of the reaction mixture indicated consumption of the starting aniline. The mixture was cooled and then filtered to remove the base. The base was washed with EtOAc to remove trace organic. The combined filtrate was evaporated down to give impure oil. The oil was purified on a column of silica using 95/5/0.05 CH2Cl2/MeOH/NH4OH as eluent to obtain separation. The product fractions were evaporated of solvent and the resultant residue recrystallized from CH2Cl2/hexanes to yield 14.0 g of the target compound as white solids (35.5% yield, confirmed by GC-MS).
Reaction SMILES: [CH2:1]([N:3]([C@H:17]1[CH2:22][CH2:21][C@H:20]([OH:23])[CH2:19][CH2:18]1)[S:4]([C:7]1[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=1)(=[O:6])=[O:5])[CH3:2].[Br:24][CH2:25][CH2:26][CH2:27][CH2:28]Br>>[Br:24][CH2:25][CH2:26][CH2:27][CH2:28][O:23][C@H:20]1[CH2:19][CH2:18][C@H:17]([N:3]([CH2:1][CH3:2])[S:4]([C:7]2[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:14])[F:15])=[CH:9][CH:8]=2)(=[O:5])=[O:6])[CH2:22][CH2:21]1
Reactant: BrCCCCBr
Reactant: CCN([C@H]1CC[C@H](O)CC1)S(=O)(=O)c1ccc(C(F)(F)F)cc1
Product: CCN([C@H]1CC[C@H](OCCCCBr)CC1)S(=O)(=O)c1ccc(C(F)(F)F)cc1

Procedure:
In analogy to example 11.11, trans-N-Ethyl-N-(4-hydroxy-cyclohexyl)-4-trifluoromethyl-benzenesulfonamide and 1,4-Dibromobutane were converted to yield trans-N-[4-(4-Bromo-butoxy)-cyclohexyl]-N-ethyl-4-trifluoromethyl-benzenesulfonamide as colorless oil, MS 470 (M—CH3,1Br).
Reaction SMILES: [C:1]([C:4]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)([CH2:14][CH2:15][CH2:16][CH:17]([O:23]CC1C=CC=CC=1)[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12])(=[O:3])[CH3:2]>CCO.[Pd]>[C:1]([C:4]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)([CH2:14][CH2:15][CH2:16][CH:17]([OH:23])[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12])(=[O:3])[CH3:2]
Reactant: CCCCCC(CCCC(CCCCCCC(=O)O)(C(C)=O)c1ccccc1)OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: CCCCCC(O)CCCC(CCCCCCC(=O)O)(C(C)=O)c1ccccc1
Reaction time: 2 h

Procedure:
8-Acetyl-8-phenyl-12-benzyloxyheptadecanoic acid (1.42 g., slightly impure) is dissolved in EtOH (50 ml.), and is hydrogenated over 10% palladium on carbon at atmospheric pressure and 25° C. The hydrogenation is stopped after 2 hours, the catalyst is filtered off, and the solvent is removed in vacuo to obtain the product as a crude viscous yellowish oil. This oil is chromatographed through a silica gel column (CHCl3) to obtain 8-acetyl-8-phenyl-12-hydroxyheptadecanoic acid as a virtually colorless oil (350 mg.).
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][C:8]([C:11]3[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=3)=[CH:7][CH2:6]2)[O:4][CH2:3][CH2:2]1>CO>[O:1]1[C:5]2([CH2:6][CH2:7][CH:8]([C:11]3[CH:12]=[CH:13][N:14]=[CH:15][CH:16]=3)[CH2:9][CH2:10]2)[O:4][CH2:3][CH2:2]1
Reactant: C1=C(c2ccncc2)CCC2(C1)OCCO2
Solvent: CO
Product: c1cc(C2CCC3(CC2)OCCO3)ccn1
Reaction time: 3 h
Yield: 84 %

Procedure:
4-(1,4-Dioxaspiro[4.5]dec-7-en-8-yl)pyridine (3.5 g, 16.1 mmol, 1 eq) was dissolved in MeOH (80 ml) and degassed for 15 min with argon. Pd(OH)2 (1.75 g, 50%) was added, and hydrogenation was carried out for 3 h at RT under balloon pressure (H2). After monitoring by thin-layer chromatography, the reaction mixture was filtered off over Celite and the filtrate was concentrated under reduced pressure. Yield: 84% (3.0 g, 13.6 mmol).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:11][C:10]([CH3:13])([CH3:12])[CH:9]3[O:14][CH:8]3[C:7]=2[CH:15]=1)#[N:2].[CH3:16][O:17][C:18]1[CH2:22][NH:21][C:20](=[O:23])[CH:19]=1.C(OC1CNC(=O)C=1)CCCCCCC>>[C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:11][C:10]([CH3:13])([CH3:12])[C@@H:9]([OH:14])[C@H:8]([N:21]3[CH2:22][C:18]([O:17][CH3:16])=[CH:19][C:20]3=[O:23])[C:7]=2[CH:15]=1)#[N:2]
Reactant: CC1(C)Oc2ccc(C#N)cc2C2OC21
Reactant: COC1=CC(=O)NC1
Agent: CCCCCCCCOC1=CC(=O)NC1
Product: COC1=CC(=O)N([C@@H]2c3cc(C#N)ccc3OC(C)(C)[C@H]2O)C1

Procedure:
Similarly, optionally replacing 6-cyano-3,4-dihydro-2,2-dimethyl-3,4-epoxy-2H-1-benzopyran with the appropriate compound of formula (2), and optionally replacing 4-methoxy-3-pyrrolin-2-one with the appropriate compound of formula (3), the following compounds of formula (I) are prepared: