Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][CH:4](OCC)[CH2:5][O:6][C:7]1[CH:16]=[CH:15][C:10]([C:11]([O:13][CH3:14])=[O:12])=[CH:9][CH:8]=1)C.S(=O)(=O)(O)O>O1CCOCC1>[CH:4]([CH2:5][O:6][C:7]1[CH:16]=[CH:15][C:10]([C:11]([O:13][CH3:14])=[O:12])=[CH:9][CH:8]=1)=[O:3]
Reactant: CCOC(COc1ccc(C(=O)OC)cc1)OCC
Agent: O=S(=O)(O)O
Solvent: C1COCCO1
Product: COC(=O)c1ccc(OCC=O)cc1
Temperature: 70 °C
Reaction time: 6 h
Yield: 92.9 %

Procedure:
Methyl 4-(2,2-diethoxyethoxy)benzoate (36.29 g) was dissolved in dioxane (100 ml), added thereto 2N sulfuric acid (200 ml), and the mixture was heated with stirring at 70° C. for 6 hours. After concentrated under reduced pressure to about half volume, it was diluted with water in two fold, and concentrated again under reduced pressure. The precipitate was collected by filtration, and washed successively with aqueous sodium hydrogencarbonate solution and water to give methyl 4-formylmethoxybenzoate (24.39 g). mp. 58°-60° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1B(O)O.Br[C:13]1[CH:22]=[C:21]([O:23][CH3:24])[C:20]2[NH:19][CH2:18][C@@H:17]3[CH2:25][N:26](C(OC(C)(C)C)=O)[CH2:27][C@@H:16]3[C:15]=2[CH:14]=1>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:13]1[CH:22]=[C:21]([O:23][CH3:24])[C:20]2[NH:19][CH2:18][C@@H:17]3[CH2:25][NH:26][CH2:27][C@@H:16]3[C:15]=2[CH:14]=1
Reactant: COc1cc(Br)cc2c1NC[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]21
Reactant: OB(O)c1ccc(Cl)cc1Cl
Product: COc1cc(-c2ccc(Cl)cc2Cl)cc2c1NC[C@@H]1CNC[C@H]21

Procedure:
Following the procedures described in Example 12, except that 2,4-dichlorophenylboronic acid was used instead of phenylboronic acid, (±)-cis-tert-butyl 8-bromo-6-methoxy-3,3a,4,5-tetrahydro-1H-pyrrolo[3,4-c]quinoline-2(9bH)-carboxylate from Example 11, Part A was converted into the title compound of Example 15. 1H NMR (CDCl3): δ 7.48 (s, 1H), 7.34-7.25 (m, 2H), 6.76 (s, 1H), 6.74 (s, 1H), 4.55 (broad s, 1H), 3.87 (s, 3H), 3.65-3.57 (m, 1H), 3.50-3.25 (overlapping m, 4H), 3.13-2.97 (m, 2H), 2.75-2.65 (m, 1H). LRMS (ES)+: 349.3/351.3 (M+H)+.
Reaction SMILES: [O:1]([C:8]1[CH:27]=[CH:26][C:11]([O:12][C:13]2[CH:18]=[CH:17][N:16]=[CH:15][C:14]=2[C:19]2[CH:20]=[C:21]([CH:23]=[CH:24][CH:25]=2)[NH2:22])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:35](Cl)(=[O:38])[CH:36]=[CH2:37]>CN1CCCC1=O.ClCCl>[O:1]([C:8]1[CH:9]=[CH:10][C:11]([O:12][C:13]2[CH:18]=[CH:17][N:16]=[CH:15][C:14]=2[C:19]2[CH:20]=[C:21]([NH:22][C:35](=[O:38])[CH:36]=[CH2:37])[CH:23]=[CH:24][CH:25]=2)=[CH:26][CH:27]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1cccc(-c2cnccc2Oc2ccc(Oc3ccccc3)cc2)c1
Reactant: C=CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: CN1CCCC1=O
Solvent: ClCCl
Product: C=CC(=O)Nc1cccc(-c2cnccc2Oc2ccc(Oc3ccccc3)cc2)c1
Temperature: 0 °C
Reaction time: 8 h
Yield: 36.7 %

Procedure:
Into a 20 mL vial was placed 3-(4-(4-phenoxyphenoxy)pyridin-3-yl)aniline (30.00 mg, 0.08 mmol), N,N-diethylethanamine (0.02 mL, 0.17 mmol) suspended in 1-methylpyrrolidin-2-one (0.35 mL) and dichloromethane (2.00 mL). The resulting mixture was cooled to 0° C. Added acryloyl chloride (0.02 mL, 0.25 mmol). The ice bath was left to melt and the reaction mixture was stirred at rt overnight. The reaction mixture was purified using Biotage column chromatography eluting 0-40% MeOH in EtOAc. Fractions containing the desired product were combined and concentrated. Purified using prep-HPLC eluting 25-55% CH3CN in 0.1% TFA in H2O. Fractions containing the desired product were combined and lyophilized overnight to afford N-(3-(4-(4-phenoxyphenoxy)pyridin-3-yl)phenyl)acrylamide as a white solid (12.00 mg, 35% yield). HPLC purity: 100%, RT=4.235 min. MS: m/z=409 [M+H]+, RT=3.38 min. 1H-NMR (DMSO-d6) δ 10.23 (s, 1H), 8.52 (s, 1H), 8.43 (d, 1H), 7.95 (s, 1H), 7.71 (d, 1H), 7.44-7.33 (m, 4H), 7.19 (d, 2H), 7.13 (t, 1H), 7.09 (d, 2H), 7.02 (d, 2H), 6.80 (d, 1H), 6.45 (dd, 1H), 6.26 (d, 1H), 5.75 (d, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](I)[CH:5]=[CH:4][C:3]=1[N:9]1[CH:14]=[C:13]([O:15][CH3:16])[C:12](=[O:17])[C:11]([C:18]2[N:22]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[N:21]=[CH:20][CH:19]=2)=[N:10]1.Cl.[F:30][C:31]([F:38])([F:37])[CH:32]1[CH2:36][CH2:35][NH:34][CH2:33]1.CC([O-])(C)C.[Na+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:1][C:2]1[CH:7]=[C:6]([N:34]2[CH2:35][CH2:36][CH:32]([C:31]([F:38])([F:37])[F:30])[CH2:33]2)[CH:5]=[CH:4][C:3]=1[N:9]1[CH:14]=[C:13]([O:15][CH3:16])[C:12](=[O:17])[C:11]([C:18]2[N:22]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[N:21]=[CH:20][CH:19]=2)=[N:10]1
Reactant: FC(F)(F)C1CCNC1
Reactant: COc1cn(-c2ccc(I)cc2F)nc(-c2ccnn2-c2ccccc2)c1=O
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: C1COCCO1
Product: COc1cn(-c2ccc(N3CCC(C(F)(F)F)C3)cc2F)nc(-c2ccnn2-c2ccccc2)c1=O
Temperature: 90 °C
Yield: 45.3 %

Procedure:
A mixture of 1-(2-fluoro-4-iodophenyl)-5-methoxy-3-(1-phenyl-1H-pyrazol-5-yl)pyridazin-4(1H)-one (300 mg, 0.61 mmol), 3-(trifluoromethyl)pyrrolidine hydrochloride (130 mg, 0.74 mmol), NaOt-Bu (154 mg, 1.6 mmol), Xantphos (28 mg, 0.049 mmol) and Pd2(dba)3 (11 mg, 0.012 mmol) in 1,4-dioxane (4 mL) was heated to 90° C. for 12 h under Ar. The mixture was extracted with AcOEt, dried over Na2SO4, filtered, concentrated in vacuo and purified by column chromatography on basic silica gel (hexane/AcOEt=10/90 to 0/100) to yield the title compound (138 mg, 45% yield) as a pale green solid: 1H NMR (300 MHz, CDCl3): δ ppm 2.17-2.42 (2H, m), 3.01-3.21 (1H, m), 3.30-3.63 (4H, m), 3.89 (3H, s), 6.11 (1H, dd, J=8.9, 2.4 Hz), 6.20-6.37 (2H, m), 7.24 (1H, d, J=1.9 Hz), 7.33-7.47 (5H, m), 7.71 (1H, d, J=2.3 Hz), 7.77 (1H, d, J=1.9 Hz); MS Calcd.: 499; MS Found: 500 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)=[CH:13][C:12]([C@@H:25]2[CH2:27][C@H:26]2[NH2:28])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:29][CH2:30][CH:31]=O>C(Cl)Cl>[CH2:1]([O:8][C:9]1[C:14]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:22])([F:23])[F:24])=[CH:17][CH:16]=2)=[CH:13][C:12]([C@@H:25]2[CH2:27][C@H:26]2[NH:28][CH2:31][CH2:30][Cl:29])=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N[C@@H]1C[C@H]1c1ccc(OCc2ccccc2)c(-c2ccc(C(F)(F)F)cc2)c1
Reactant: O=CCCl
Solvent: ClCCl
Product: FC(F)(F)c1ccc(-c2cc([C@@H]3C[C@H]3NCCCl)ccc2OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 53.9 %

Procedure:
To a solution of (trans)-2-(6-(benzyloxy)-4′-(trifluoromethyl)biphenyl-3-yl)cyclopropanamine (520 mg, 2.08 mmol) in DCM (6 mL), 4° A molecular sieves was added followed by chloroacetaldehyde (0.33 mL, 2.5 mmol) and stirred at RT for 1 h. After completion, monitored by TLC, the reaction mixture was cooled at −10° C. and Na(CN)BH3 (157 mg, 2.5 mmol) was added and stirred at RT for 2 h. After completion, the reaction mixture was quenched with NH4Cl (5%) and filtered through a pad of celite. The filtrate was extracted with DCM (2×20 mL), combined extracts were washed with water (20 mL), dried over anhydrous Na2SO4, filtered and evaporated. The residue was purified by flash column chromatography by using EtOAc: Pet ether to get (trans)-2-(6-(benzyloxy)-4′-(trifluoromethyl)biphenyl-3-yl)-N-(2-chloroethyl)cyclopropanamine (500 mg, 83.3%) as a liquid.
Reaction SMILES: Cl[C:2]1[CH:3]=[N:4][N:5]2[CH:10]=[CH:9][C:8]([N:11]3[CH:15]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=4)[CH2:14][O:13][C:12]3=[O:22])=[N:7][C:6]=12.C(=O)([O-])[O-].[Na+].[Na+].[F:29][C:30]1[CH:35]=[C:34](B2OC(C)(C)C(C)(C)O2)[CH:33]=[CH:32][C:31]=1[C:45]1[N:49]=[CH:48][N:47]([CH2:50][O:51][CH2:52][CH2:53][Si:54]([CH3:57])([CH3:56])[CH3:55])[N:46]=1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O>[F:29][C:30]1[CH:35]=[C:34]([C:2]2[CH:3]=[N:4][N:5]3[CH:10]=[CH:9][C:8]([N:11]4[CH:15]([C:16]5[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=5)[CH2:14][O:13][C:12]4=[O:22])=[N:7][C:6]=23)[CH:33]=[CH:32][C:31]=1[C:45]1[N:49]=[CH:48][N:47]([CH2:50][O:51][CH2:52][CH2:53][Si:54]([CH3:57])([CH3:56])[CH3:55])[N:46]=1
Reactant: CC1(C)OB(c2ccc(-c3ncn(COCC[Si](C)(C)C)n3)c(F)c2)OC1(C)C
Reactant: O=C1OCC(c2ccccn2)N1c1ccn2ncc(Cl)c2n1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Product: C[Si](C)(C)CCOCn1cnc(-c2ccc(-c3cnn4ccc(N5C(=O)OCC5c5ccccn5)nc34)cc2F)n1
Temperature: 80 °C
Reaction time: 3 h
Yield: 48.5 %

Procedure:
To a solution of 3-(3-chloropyrazolo[1,5-a]pyrimidin-5-yl)-4-(pyridin-2-yl)oxazolidin-2-one (0.42 g, 1.3 mmol) in dioxanes was added sodium carbonate solution (2.0 M, 3.3 ml, 6.7 mmol) and 3-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazole (0.61 g, 1.5 mmol) and the reaction bubbled with nitrogen for 30 minutes, followed by the addition of XPHOS (0.63 g, 1.3 mmol) and Pd2 dba3 (1.2 g, 1.3 mmol), and the reaction stirred at 80° C. for 3 hours. The reaction was poured into water and extracted into EtOAc. The combined organic layers were washed with brine, dried over MgSO4 and concentrated in vacuo. The crude material was purified by normal phase chromatography using a gradient eluent from 25% EtOAc in hexane to EtOAc to yield 3-(3-(3-fluoro-4-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-3-yl)phenyl)pyrazolo[1,5-a]pyrimidin-5-yl)-4-(pyridin-2-yl)oxazolidin-2-one (0.36 g, 0.63 mmol, 47% yield).
Reaction SMILES: O(S(C)(=O)=O)S(C)(=O)=O.[CH2:10]([O:12][C:13]([C:15]1[N:16]=[C:17]([Br:32])[N:18]([CH:29]([CH3:31])[CH3:30])[C:19]=1C(C1C=CC(Cl)=CC=1)O)=[O:14])[CH3:11].[Cl:33][C:34]1[CH:35]=[CH:36][C:37]([CH3:41])=[C:38]([CH:40]=1)[NH2:39]>C(Cl)Cl.C(Cl)Cl.O>[CH2:10]([O:12][C:13]([C:15]1[N:16]=[C:17]([Br:32])[N:18]([CH:29]([CH3:30])[CH3:31])[C:19]=1[N:39]([C:37]1[CH:36]=[CH:35][C:34]([Cl:33])=[CH:40][CH:38]=1)[C:38]1[CH:40]=[C:34]([Cl:33])[CH:35]=[CH:36][C:37]=1[CH3:41])=[O:14])[CH3:11]
Reactant: Cc1ccc(Cl)cc1N
Reactant: CCOC(=O)c1nc(Br)n(C(C)C)c1C(O)c1ccc(Cl)cc1
Agent: CS(=O)(=O)OS(C)(=O)=O
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)c1nc(Br)n(C(C)C)c1N(c1ccc(Cl)cc1)c1cc(Cl)ccc1C
Temperature: 5 °C
Reaction time: 0.25 h

Procedure:
Ms2O (3.6 g, 20.9 mmol) was added to a stirred solution of 2-bromo-5-[(4-chlorophenyl)-hydroxy-methyl]-1-isopropyl-1H-imidazole-4-carboxylic acid ethyl ester (intermediate B; 4.2 g, 20.9 mmol) and TEA (5.3 g, 52.0 mmol) in DCM (80 mL) at 5° C. and the reaction mixture was stirred at 5° C. for 15 min. 5-Chloro-2-methyl aniline (2.2 g, 15.7 mmol) was then added. The reaction mixture was allowed to reach rt in 45 min and stirred at rt for 2 h. The reaction mixture was diluted in DCM/water, extracted twice with DCM and the combined organic extracts were washed with brine, dried (Na2SO4) and concentrated. The crude was purified by flash chromatography (silica gel, EtOAc/hexanes 2:8) to afford the title compound as a white foam; ESI-MS: 526.2 [M+H]+ (LC-MS 2); 1H-NMR (DMSO-d6, 400 MHz) δ ppm 1.15 (dd, J=9.97, 4.11 Hz, 2 H) 1.15 (s, 1 H) 1.24 (t, J=7.23 Hz, 3 H) 1.45 (d, J=7.04 Hz, 3 H) 2.17 (s, 3 H) 4.24 (quin, J=6.74 Hz, 2 H) 4.83-5.04 (m, 1 H) 5.92 (d, J=5.47 Hz, 1 H) 6.47 (bs, 1 H) 6.63 (dd, J=7.82, 1.95 Hz, 1H) 6.79 (bs, 1H) 7.04 (d, J=8.21 Hz, 1 H) 7.26 (m, J=8.60 Hz, 2 H) 7.43 (m, J=8.60 Hz, 2 H).
Reaction SMILES: [I:1]N1C(=O)CCC1=O.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH3:21][O:22][C:23](=[O:45])[C:24]1[C:29]([NH:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[F:37])=[CH:28][N:27]=[CH:26][C:25]=1[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=1[F:44]>>[CH3:21][O:22][C:23](=[O:45])[C:24]1[C:29]([NH:30][C:31]2[CH:36]=[CH:35][C:34]([I:1])=[CH:33][C:32]=2[F:37])=[CH:28][N:27]=[CH:26][C:25]=1[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=1[F:44]
Reactant: O=C1CCC(=O)N1I
Reactant: COC(=O)c1c(Nc2ccccc2F)cncc1-c1ccccc1F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: COC(=O)c1c(Nc2ccc(I)cc2F)cncc1-c1ccccc1F
Temperature: 60 °C
Reaction time: 8 h
Yield: 78.5 %

Procedure:
N-iodosuccinimide (400 mg, 1.76 mmol) and p-toluenesulfonic acid monohydrate (670 mg, 3.53 mmol) were added to a solution of 3-(2-fluoro-phenyl)-5-(2-fluoro-phenylamino)-isonicotinic acid methyl ester (480 mg, 1.41 mmol), and stirred overnight at 60° C. The reaction mixture was quenched with Na2S2O3 (1 mL, 10% aqueous solution), diluted with CH2Cl2, and filtered through an Extrelut column. The column was washed with CH2Cl2, and the filtrate was concentrated. The crude product was purified via Biotage eluting with a gradient of 0 to 55% EtOAc in hexanes to afford the desired product (516 mg, 78%). LC-MS (M+H=467, obsd.=467).
Reaction SMILES: C(O[CH2:5][C:6]1[CH:11]([C:12]([OH:14])=[O:13])[N:10]2[C:15](=[O:27])[CH:16]([NH:17][C:18](=[O:26])[CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C@H:9]2[S:8][CH:7]=1)(=O)C.[F:28][C:29]([F:34])([F:33])[C:30]([OH:32])=[O:31]>C1(C)C=CC=CC=1>[C:20]1([CH2:19][C:18]([NH:17][CH:16]2[C:15](=[O:27])[N:10]3[CH:11]([C:12]([OH:14])=[O:13])[C:6]([CH2:5][O:31][C:30](=[O:32])[C:29]([F:34])([F:33])[F:28])=[CH:7][S:8][C@H:9]23)=[O:26])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CC(=O)OCC1=CS[C@@H]2C(NC(=O)Cc3ccccc3)C(=O)N2C1C(=O)O
Reactant: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Product: O=C(Cc1ccccc1)NC1C(=O)N2C(C(=O)O)C(COC(=O)C(F)(F)F)=CS[C@H]12
Reaction time: 0.25 h

Procedure:
A solution of 0.8 g of 3-acetoxymethyl-7-(N-phenylacetyl-amino)-ceph-2-em-4ξ-carboxylic acid in 4 ml of trifluoroacetic acid is left to stand for 15 minutes at room temperature and is then diluted with an equal quantity of toluene. The volatile constituents are evaporated under reduced pressure and at room temperature. The residue is taken up in 100 ml of chloroform and the mixture is filtered. The filtrate is concentrated to a small volume under reduced pressure and cooled. The resulting solid material is filtered off and yields 7-(N-phenylacetyl-amino)-3-trifluoroacetoxymethyl-ceph-2-em-4ξ-carboxylic acid, melting at 139° - 140°C; infrared absorption spectrum (in mineral oil): characteristic bands at 3.01μ, 5.60μ, 5.65μ, 5.73μ, 5.77μ, 6.02μ and 6.54μ. A further quantity of the desired product can be obtained by further concentration and cooling of the filtrate.
Reaction SMILES: [C:1]([C:9]1[N:10](C(OCC)=O)[C:11]2[C:16]([C:17]=1[N:18]([CH3:20])[CH3:19])=[CH:15][CH:14]=[C:13]([Cl:21])[CH:12]=2)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(OCC)C.CCCCCC>[C:1]([C:9]1[NH:10][C:11]2[C:16]([C:17]=1[N:18]([CH3:19])[CH3:20])=[CH:15][CH:14]=[C:13]([Cl:21])[CH:12]=2)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)n1c(C(=O)c2ccccc2)c(N(C)C)c2ccc(Cl)cc21
Solvent: CCCCCC
Solvent: CCOCC
Product: CN(C)c1c(C(=O)c2ccccc2)[nH]c2cc(Cl)ccc12

Procedure:
The title compound was prepared according to the procedure described in step 2 of Example 2 from 2-benzoyl-6-chloro-1-ethoxycarbonyl-3-(N,N-dimethylamino)indole (step 1). m.p.: 178-180° C. (diethyl ether/hexane)
Reaction SMILES: ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.Cl.[CH3:24][NH:25][O:26][CH3:27].C(N(CC)CC)C.[CH2:35]([O:37][C:38]1[CH:39]=[C:40]([C:47]2[S:48][CH:49]=[C:50]([CH2:52][CH2:53][C:54]([OH:56])=O)[N:51]=2)[CH:41]=[CH:42][C:43]=1[O:44][CH2:45][CH3:46])[CH3:36]>ClCCl.O>[CH2:35]([O:37][C:38]1[CH:39]=[C:40]([C:47]2[S:48][CH:49]=[C:50]([CH2:52][CH2:53][C:54]([N:25]([O:26][CH3:27])[CH3:24])=[O:56])[N:51]=2)[CH:41]=[CH:42][C:43]=1[O:44][CH2:45][CH3:46])[CH3:36]
Reactant: CNOC
Reactant: CCOc1ccc(-c2nc(CCC(=O)O)cs2)cc1OCC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOc1ccc(-c2nc(CCC(=O)N(C)OC)cs2)cc1OCC
Temperature: 25 °C
Reaction time: 4 h
Yield: 85.5 %

Procedure:
1-hydroxybenzotriazole (22.91 g, 149.6 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (WSC) (28.68 g, 149.6 mmol), N,O-dimethylhydroxylamine hydrochloride (13.93 g, 136 mmol) and triethylamine (41.7 ml, 299.2 mmol) were added to a solution (1.0 l) of 3-[2-(3,4-diethoxyphenyl)thiazole-4-yl]propionic acid (43.71 g, 136 mmol) in dichloromethane, followed by stirring at room temperature for 4 hours. Water was added to separate the reaction mixture into layers, and the aqueous layer was further subjected to extraction with dichloromethane. The organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/3). The solvent was distilled off under reduced pressure, and the residue was recrystallized from an ethyl acetate/n-hexane mixed solvent, to thereby obtain 42.4 g (yield: 68%) of 3-[2-(3,4-diethoxyphenyl)thiazole-4-yl]-N-methoxy-N-methylpropionamide as colorless prisms.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:13]=[CH:12][CH:11]=[CH:10][C:6]=1[C:7](Cl)=[O:8])(=[O:3])[CH3:2].[NH2:14][C:15]1[C:26]([CH2:27][N:28]([CH2:31][CH3:32])[CH2:29][CH3:30])=[CH:25][C:18]([C:19]([O:21][CH2:22][CH2:23][OH:24])=[O:20])=[CH:17][C:16]=1[Br:33]>>[NH2:14][C:15]1[C:26]([CH2:27][N:28]([CH2:31][CH3:32])[CH2:29][CH3:30])=[CH:25][C:18]([C:19]([O:21][CH2:22][CH2:23][O:24][C:7](=[O:8])[C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=2[O:4][C:1](=[O:3])[CH3:2])=[O:20])=[CH:17][C:16]=1[Br:33]
Reactant: CCN(CC)Cc1cc(C(=O)OCCO)cc(Br)c1N
Reactant: CC(=O)Oc1ccccc1C(=O)Cl
Product: CCN(CC)Cc1cc(C(=O)OCCOC(=O)c2ccccc2OC(C)=O)cc(Br)c1N

Procedure:
This compound was prepared from 2-acetoxybenzoyl chloride and 1-[4-amino-3-bromo-5-diethylaminomethyl-benzoyloxy]-2-hydroxy-ethane analogous to Example 5. Oil.
Reaction SMILES: [CH3:1][C:2]([CH3:56])=[CH:3][CH2:4][CH2:5]/[C:6](/[CH3:55])=[CH:7]/[CH2:8][CH2:9]/[C:10](/[CH3:54])=[CH:11]/[CH2:12][CH2:13]/[C:14](/[CH3:53])=[CH:15]/[CH2:16][CH2:17]/[C:18](/[CH3:52])=[CH:19]/[CH2:20][CH2:21]/[C:22](/[CH3:51])=[CH:23]/[CH2:24][CH2:25]/[C:26](/[CH3:50])=[CH:27]/[CH2:28][CH2:29]/[C:30](/[CH3:49])=[CH:31]/[CH2:32][CH2:33]/[C:34](/[CH3:48])=[CH:35]/[CH2:36][CH2:37]/[C:38](/[CH3:47])=[CH:39]/[CH2:40][CH2:41]/[C:42](/[CH3:46])=[CH:43]/[CH2:44][OH:45].[C:57](Cl)(=[O:64])[C:58]1[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=1>N1C=CC=CC=1.CCCCCC>[C:57]([O:45][CH2:44][CH:43]=[C:42]([CH3:46])[CH2:41][CH2:40][CH:39]=[C:38]([CH3:47])[CH2:37][CH2:36][CH:35]=[C:34]([CH3:48])[CH2:33][CH2:32][CH:31]=[C:30]([CH3:49])[CH2:29][CH2:28][CH:27]=[C:26]([CH3:50])[CH2:25][CH2:24][CH:23]=[C:22]([CH3:51])[CH2:21][CH2:20][CH:19]=[C:18]([CH3:52])[CH2:17][CH2:16][CH:15]=[C:14]([CH3:53])[CH2:13][CH2:12][CH2:11][C:10]([CH3:54])=[CH:9][CH2:8][CH:7]=[C:6]([CH3:55])[CH2:5][CH2:4][CH:3]=[C:2]([CH3:56])[CH3:1])(=[O:64])[C:58]1[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=1
Reactant: CC(C)=CCC/C(C)=C/CC/C(C)=C/CC/C(C)=C/CC/C(C)=C/CC/C(C)=C/CC/C(C)=C/CC/C(C)=C/CC/C(C)=C/CC/C(C)=C/CC/C(C)=C/CO
Reactant: O=C(Cl)c1ccccc1
Solvent: c1ccncc1
Solvent: CCCCCC
Product: CC(C)=CCCC(C)=CCC=C(C)CCCC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CCOC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3.5 Grams of undecaprenol were dissolved in 30 ml of pyridine and the solution was added with a solution of 1.3 g of benzoyl chloride in pyridine dropwise over 30 minutes. After completion of the addition, the mixture was stirred at room temperature for one hour to complete the reaction. The reaction product was diluted with n-hexane, washed with water and concentrated. The concentrate was purified by chromatography with 50 g of silica gel in n-hexane/benzene solvent mixture as elution solvent to obtain a white waxy final product. Yield: 3.6 g.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:19][CH3:20])[CH:15]=2)[C:10]=1Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:22]1([CH2:29][CH2:30][O:31][C:32]2[CH:37]=[CH:36][C:35]([OH:38])=[CH:34][CH:33]=2)[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1.C(=O)([O-])[O-].[K+].[K+]>[Cu].N1C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:19][CH3:20])[CH:15]=2)[C:10]=1[O:38][C:35]1[CH:34]=[CH:33][C:32]([O:31][CH2:30][CH2:29][N:22]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)=[CH:37][CH:36]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc2c(Br)c(OCc3ccccc3)ccc2c1
Reactant: Oc1ccc(OCCN2CCCCCC2)cc1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccncc1
Product: COc1ccc2c(Oc3ccc(OCCN4CCCCCC4)cc3)c(OCc3ccccc3)ccc2c1
Yield: 42.4 %

Procedure:
Combine 2-benzyloxy-1-bromo-6-methoxy-naphthalene (31 g, 90 mmol), 4-(2-azepan-1-yl-ethoxy)-phenol (31 g, 132 mmol), copper bronze (12 g, 189 mmol), potassium carbonate (25 g, 181 mmol) and pyridine (400 ml). Heat the reaction mixture to reflux for 85 hours. Coot and filter the residue with celite and elute with methanol and methylene chloride (500 mL, V/V=1:5). Evaporate solvent under reduced pressure and chromatograph the residue on a silica gel column eluting the material with a step gradient of methanol/dichloromethane (0 to 10%) to get 19 g (43%) of 1-{2-[4-(2-benzyloxy-6-methoxy-naphthalen-1-yloxy)-phenoxy]ethyl}-azepane.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:31])[CH2:4][N:5]1[C:10](CC2C=CC=CC=2)=[CH:9][CH:8]=[C:7]([NH:18][C:19]([O:21][CH2:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26]C=2)=[O:20])[C:6]1=[O:30].[K+].[Br-]>>[CH3:1][O:2][C:3](=[O:31])[CH2:4][N:5]1[CH:10]=[CH:9][CH:8]=[C:7]([NH:18][C:19]([O:21][CH2:22][C:23]2[CH:24]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:20])[C:6]1=[O:30]
Reactant: COC(=O)Cn1c(Cc2ccccc2)ccc(NC(=O)OCCc2ccccc2)c1=O
Agent: [Br-]
Agent: [K+]
Product: COC(=O)Cn1cccc(NC(=O)OCc2ccccc2)c1=O

Procedure:
Methyl[6-benzyl-1,2-dihydro-2-oxo-3-(2-phenylethoxy)carbonylamino-1-pyridyl]acetate (49i), was isolated (88%) as a colorless solid: mp. 130°-133° C.; IR (KBr) 3363, 1746, 1732, 1651, 1604, 1515, 1368, 1231, 1212, 1185; 1H NMR (CDCl3) δ 8.00 (1H, d, J=7.0), 7.68 (1H, s), 7.36-7.10 (10H, m), 6.15 (1H, d, J=7.6), 4.7 (2H, s), 4.38 (2H, t, J=7.0), 3.88 (2H, s), 3.67 (3H, s), 2.98 (2H, t, J=7). ##STR132##
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([C:9]2[C:10](=[O:24])[CH:11]([CH:16](O)[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[CH2:12][C:13]=2[O:14][CH3:15])=[C:4]([CH3:25])[CH:3]=1.C(N(CC)CC)C.CS(Cl)(=O)=O.C(=O)([O-])[O-].[K+].[K+]>ClCCl>[Br:1][C:2]1[CH:3]=[C:4]([CH3:25])[C:5]([C:9]2[C:10](=[O:24])[C:11](=[CH:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[CH2:12][C:13]=2[O:14][CH3:15])=[C:6]([CH3:8])[CH:7]=1
Reactant: COC1=C(c2c(C)cc(Br)cc2C)C(=O)C(C(O)c2ccccn2)C1
Agent: CS(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC1=C(c2c(C)cc(Br)cc2C)C(=O)C(=Cc2ccccn2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-(4-bromo-2,6-dimethylphenyl)-5-(hydroxypyridin-2-ylmethyl)-3-methoxycyclopent-2-enone (7.2 g, 17.9 mmol) in dichloromethane (200 ml) at 0°C. is added triethylamine (7.0 ml, 53.8 mmol) dropwise, then methanesulfonyl chloride (6 ml, 53.8 mmol). The reaction mixture is allowed to warm to room temperature, then is stirred overnight and quenched with ice cold water. The organic phase is separated and the aqueous phase is extracted with ethyl acetate (100 ml×3). The combined organic fractions are concentrated in vacuo and the residue is re-dissolved in methanol (250 ml) and stirred for 10 minutes. To this suspension is then added potassium carbonate (8.1 g, 58.7 mmol), and the reaction mixture is stirred for 4-5 hours at 25-30°C. Volatile solvents are removed under vacuum and the crude product is diluted with distilled water and extracted with ethyl acetate (150 ml×3). The combined organic fractions are washed with distilled water, brine, then dried over sodium sulfate, filtered and the filtrate is concentrated in vacuo. The crude product is purified by flash column chromatography to afford 2-(4-bromo-2,6-dimethylphenyl)-3-methoxy-5-[1-pyridin-2-ylmethylidene]cyclopent-2-enone.