Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[C:12]([CH2:15]Br)=[C:11]([C:17]3[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:19][CH:18]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[F:27][C:28]1[CH:33]=[CH:32][C:31]([OH:34])=[CH:30][CH:29]=1.C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[C:12]([CH2:15][O:34][C:31]3[CH:32]=[CH:33][C:28]([F:27])=[CH:29][CH:30]=3)=[C:11]([C:17]3[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:19][CH:18]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1
Reactant: Oc1ccc(F)cc1
Reactant: CS(=O)(=O)c1ccc(-c2cnn(-c3ccc(F)cc3)c(=O)c2CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CS(=O)(=O)c1ccc(-c2cnn(-c3ccc(F)cc3)c(=O)c2COc2ccc(F)cc2)cc1
Temperature: 23 °C
Reaction time: 2 h
Yield: 72 %

Procedure:
To a homogeneous solution of 2-(4-fluorophenyl)-4-bromomethyl-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone, Example 194F, (107 mg, 0.246 mmol) and 4-fluorophenol (30.3 mg, 0.270 mmol) dissolved in acetone (4 mL) was added powdered K2CO3 (37.3 mg, 0.270 mmol). The mixture was stirred at 23° C. for 2 hours, filtered through a bed of Celite®, and concentrated in vacuo. The residue was chromatographed (flash silica gel, ethyl acetate/hexanes 3:2) to provide the product (yield: 83 mg, 72%). mp 65-80° C. 1H NMR (300 MHz, CDCl3) δ 3.12 (s, 3H), 4.94 (s, 2H), 6.78-6.86 (m, 2H), 6.91-7.00 (m, 2H), 7.15-7.24 (m, 2H), 7.65-7.72 (m, 2H), 7.74 (d, J=8.7 Hz, 2H), 7.93 (s, 1H), 8.08 (d, J=8.7 Hz, 2H). MS (APCI+) m/z 469 (M+H)+. Anal. calc. for C24H18F2N2O4S: C, 61.53; H, 3.87; N, 5.97. Found: C, 61.22; H, 3.63; N, 5.64.
Reaction SMILES: [CH2:1]([N:8]1[C:12]([CH:13]=[C:14]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH2:16][CH:15]2C2C=CC=CC=2)=[CH:11][N:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:29]1(C2C3C(=CC=CC=3)C(=O)C2)[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1>>[CH2:1]([N:8]1[C:12]([CH:13]=[C:14]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:16]([CH:29]3[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]3)[CH2:15]2)=[CH:11][N:10]=[CH:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CC(C2CCCCC2)c2ccccc21
Reactant: C(=C1c2ccccc2CC1c1ccccc1)c1cncn1Cc1ccccc1
Product: C(=C1CC(C2CCCCC2)c2ccccc21)c1cncn1Cc1ccccc1

Procedure:
1-Benzyl-5-(3-cyclohexylindan-1-ylidenemethyl)-1H-imidazole was prepared as 1-benzyl-5-(2-phenylindan-1-ylidenemethyl)-1H-imidazole above except that 3-cyclo-hexylindan-1-one was used as a starting material. The crude product as its hydro-chloride salt was used in the next step without purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]2[C:9]3[CH2:14][CH2:13][N:12]([CH2:15][C:16](=O)[CH3:17])[CH2:11][C:10]=3[C:19](=[O:21])[O:20][C:5]=2[CH:4]=1.[CH2:22]([NH2:24])[CH3:23]>>[CH2:22]([NH:24][CH:16]([CH3:17])[CH2:15][N:12]1[CH2:13][CH2:14][C:9]2[C:6]3[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][C:5]=3[O:20][C:19](=[O:21])[C:10]=2[CH2:11]1)[CH3:23]
Reactant: COc1ccc2c3c(c(=O)oc2c1)CN(CC(C)=O)CC3
Reactant: CCN
Product: CCNC(C)CN1CCc2c(c(=O)oc3cc(OC)ccc23)C1
Yield: 43.2 %

Procedure:
Prepared by the method described for Example 51 from 1,2,3,4-tetrahydro-8-methoxy-3-(2-oxopropyl)-5H-[1]benzopyrano[3,4-c]pyridin-5-one (14.9 g, 0.052 moles) and ethylamine (5 ml, 0.07 moles). Recrystallization from ethyl acetate gave the product (7.1 g), mp 97°-100° C.
Reaction SMILES: [CH:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH2:14]1N2CCN(CC2)C1>CCOC(C)=O.O>[CH3:14][N:12]1[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:5]2[C:13]1=[CH:1][CH:2]=[CH:3][CH:4]=2
Reactant: C1CN2CCN1CC2
Reactant: c1ccc2c(c1)[nH]c1ccccc12
Solvent: O
Solvent: CCOC(C)=O
Product: Cn1c2ccccc2c2ccccc21
Temperature: 92.5 °C
Yield: 961.2 %

Procedure:
To a solution of carbazole (1.03 g, 6.16 mmol) in DMC (10 mL), DABCO (0.069 g, 0.62 mmol) is added and the resulting solution is heated to 90-95° C. for 24 h. The reaction is cooled to RT, and diluted with EtOAc (40 mL) and H2O (40 mL). The organic layer is separated and washed in sequence with H2O (50 mL), 10% aqueous citric acid (2×40 mL) and H2O (3×40 mL). The organic layer is dried over anhydrous Na2SO4, filtered and concentrated under vacuum to give 9-methylcarbazole (about 1.08 g, 97%) as a beige solid: 1H NMR (CDCl3) δ8.06 (d, 2H), 7.43 (t, 2H), 7.31 (d, 2H), 7.20 (t, 2H), 3.71 (s, 3H); 13C NMR (CDCl3) δ141.0, 125.7, 122.8, 120.3, 118.9, 108.5, 29.0; MS m/z 181 [M+1]+.
Reaction SMILES: [CH2:1]([CH:3]([C:6]1[C:7]2[N:8]([CH:16]=[C:17]([CH3:19])[N:18]=2)[N:9]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:11]=1)[CH2:4][CH3:5])[CH3:2].C1C(=O)N([I:27])C(=O)C1>CC#N.CCOC(C)=O>[CH2:1]([CH:3]([C:6]1[C:7]2[N:8]([C:16]([I:27])=[C:17]([CH3:19])[N:18]=2)[N:9]=[C:10]([C:12]([F:13])([F:15])[F:14])[CH:11]=1)[CH2:4][CH3:5])[CH3:2]
Reactant: CCC(CC)c1cc(C(F)(F)F)nn2cc(C)nc12
Reactant: O=C1CCC(=O)N1I
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CCC(CC)c1cc(C(F)(F)F)nn2c(I)c(C)nc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 97 %

Procedure:
A solution of 8-(1-ethyl-propyl)-2-methyl-6-trifluoromethyl-imidazo[1,2-b]pyridazine (0.18 g, 0.67 mmol) in CH3CN (5 mL) is treated with NIS (0.18 g, 0.80 mmol), and stirred at rt overnight. It is diluted with EtOAc (50 mL), washed with 5% Na2SO3 (2×25 mL); dried (Na2SO4), filtered and concentrated to give the title compound (0.26 g, 0.65 mmol, 98%). 1H NMR (CDCl3): δ 0.85 (t, J=7.0 Hz, 6H), 1.79-1.92 (m, 4H), 2.59 (s, 3H), 3.30-3.43 (m, 1H), 7.09 (s, 1H). ES-MS (m/z): calcd for C13H15F31N3 (M+H)+: 398.2. found: 398.1.
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:6]=[C:7]([S:16][C:17]([S:20][C:21]2[CH:26]=[C:25]([C:27]([CH3:30])([CH3:29])[CH3:28])[C:24]([OH:31])=[C:23]([C:32]([CH3:35])([CH3:34])[CH3:33])[CH:22]=2)([CH3:19])[CH3:18])[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])[CH3:3].I[CH2:37][C:38]([O:40][CH2:41][CH3:42])=[O:39].[F-].[K+]>CN(C)C=O.CCOCC>[CH2:41]([O:40][C:38](=[O:39])[CH2:37][O:11][C:10]1[C:9]([C:12]([CH3:13])([CH3:14])[CH3:15])=[CH:8][C:7]([S:16][C:17]([S:20][C:21]2[CH:22]=[C:23]([C:32]([CH3:35])([CH3:34])[CH3:33])[C:24]([OH:31])=[C:25]([C:27]([CH3:30])([CH3:29])[CH3:28])[CH:26]=2)([CH3:18])[CH3:19])=[CH:6][C:5]=1[C:2]([CH3:1])([CH3:3])[CH3:4])[CH3:42]
Reactant: CCOC(=O)CI
Reactant: CC(C)(Sc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1)Sc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Agent: [F-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CCOC(=O)COc1c(C(C)(C)C)cc(SC(C)(C)Sc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)cc1C(C)(C)C
Reaction time: 24 h
Yield: 27.4 %

Procedure:
To a solution of probucol (0.5 g, 0.97 mmol) in dimethylformamide (1.5 mL) were added ethyl iodoacetate (0.31 g, 1.45 mmol) and 40% potassium fluoride on alumina (0.7 g, 4.8 mmol). The mixture was stirred for 24 hours and then diluted with ether (25 mL), filtered and washed with water (2×5 mL). The ether layer was dried over MgSO4, filtered and concentrated. Silica gel chromatography (hexanes/ether 5:95) yielded 160 mg of {2,6-di-tert-butyl-4-[1-(3,5-di-tert-butyl-4-hydroxy-phenylsulfanyl)-1-methyl-ethylsulfanyl]-phenoxy}-acetic acid ethyl ester which was used directly for the next step of reaction.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1I.C[Si](C)(C)[C:14]([F:17])([F:16])[F:15].[F-].[K+]>CN(C)C=O.C(OCC)C.[Cu]I>[Cl:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1[C:14]([F:17])([F:16])[F:15]
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: O=[N+]([O-])c1ccc(I)c(Cl)c1
Agent: [Cu]I
Agent: [F-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: O=[N+]([O-])c1ccc(C(F)(F)F)c(Cl)c1

Procedure:
A solution of 3-chloro-4-iodo-nitrobenzene (2.26 g), trimethyl(trifluoromethyl)silane (5.68 g), copper(I) iodide (2.28 g), and potassium fluoride (0.56 g) in N,N-dimethylformamide (8 mL) is heated in a sealed tube to 80° C. for 40 hours. The solution is then cooled, diluted with diethyl ether, filtered through diatomaceous earth, and the filtrate is washed successively with water, saturated aqueous sodium chloride, and then dried over anhydrous sodium sulfate. The solvent is removed under reduced pressure and the residue is chromatographed over silica gel (1% diethyl ether in hexanes followed by 10% ethyl acetate in hexanes is used as the eluant) to provided the desired product as a colorless oil.
Reaction SMILES: C1O[C:4]2([C:7]([OH:15])([C:8]3[CH:13]=[CH:12][C:11]([I:14])=[CH:10][CH:9]=3)[C:6]([CH3:16])=[CH:5]2)[O:3]C1.OS(O)(=O)=O>C1COCC1.O.CCOCC>[OH:15][C:7]1([C:8]2[CH:9]=[CH:10][C:11]([I:14])=[CH:12][CH:13]=2)[C:4](=[O:3])[CH:5]=[C:6]1[CH3:16]
Reactant: CC1=CC2(OCCO2)C1(O)c1ccc(I)cc1
Agent: O=S(=O)(O)O
Solvent: C1CCOC1
Solvent: O
Solvent: CCOCC
Product: CC1=CC(=O)C1(O)c1ccc(I)cc1
Reaction time: 4 h
Yield: 87 %

Procedure:
To a solution of 4-hydroxy-4-p-iodophenyl-3-methyl-2-cyclobuten-1-one ethylene acetal (80 mg, 0.23 mmol dissolved in THF:H2O (3:1, 8 ml) was added dropwise 1N H2SO4 (3 ml) at room temperature. The reaction mixture was stirred for 4 h. The mixture was then diluted with ether (10 ml), and the organic fraction was separated from the aqueous phase by repeated extractions with ether (2×5 ml). The ether layer was dried over Na2SO4 and concentrated in vacuo to give a pale yellow oil (62 mg, 87%). 1H NMR (CDCl3) δ7.80 (d, J=9 Hz, 2H), 7.15 (d, J=9 Hz, 2H), 6.40 (s, 1H), 3.10 (s, 1H), 2.20 (s,3H).
Reaction SMILES: [Si]([O:8][C@@H:9]1[C@H:13]([O:14][Si](C(C)(C)C)(C)C)[C@@H:12]([CH2:22][O:23][Si](C(C)(C)C)(C)C)[O:11][C@H:10]1[N:31]1[C:40]2[N:39]=[CH:38][N:37]=[C:35]([NH2:36])[C:34]=2[N:33]=[C:32]1[C:41]1[CH:42]=[N:43][CH:44]=[CH:45][CH:46]=1)(C(C)(C)C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[N:43]1[CH:44]=[CH:45][CH:46]=[C:41]([C:32]2[N:31]([C:40]3[N:39]=[CH:38][N:37]=[C:35]([NH2:36])[C:34]=3[N:33]=2)[C@@H:10]2[O:11][C@H:12]([CH2:22][OH:23])[C@@H:13]([OH:14])[C@H:9]2[OH:8])[CH:42]=1
Reactant: CC(C)(C)[Si](C)(C)OC[C@H]1O[C@@H](n2c(-c3cccnc3)nc3c(N)ncnc32)[C@H](O[Si](C)(C)C(C)(C)C)[C@@H]1O[Si](C)(C)C(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: Nc1ncnc2c1nc(-c1cccnc1)n2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Reaction time: 8 h

Procedure:
A solution of 2′,3′,5′-tris-O-(tert-butyldimethylsilyl)-8-(3-pyridinyl)adenosine (16c) (0.56 g, 0.82 mmol) and TBAF (0.85 g, 3.26 mmol) in THF (31 ml) under argon was stirred at room temperature overnight. The solvent was distilled off and the residual material dissolved in MeOH (10 ml). The solution was left at 0° C. overnight and the title compound isolated by filtration. 13C NMR: (75 MHz, DMSO); δ 62.27 (C-5′), 71.13/71.62 (C-2′, C-3′), 86.95/89.27 (C-4, C-1), 119.33/123.69/125.71/137.20/148.20/149.80/149.85/150.88/152.33/156.34 (C-5, C-5″, C-3″, C-4″, C-6, C-8, C-6″, C-2″, C-2, C-4). MS (EI): 344 (M, 2%), 255 (5), 241 (5), 213 (22), 212 (100), 211 (5) 185 (12), 104 (12).
Reaction SMILES: O=CC[CH:4]1[CH2:13][C:12](=O)[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[O:5]1.O.[NH2:16][CH2:17][C@@H:18]([OH:20])[CH3:19].[C:21]1(C)C=CC=C[CH:22]=1>C1(C)C=CC(S(O)(=O)=O)=CC=1>[N:16]1([CH2:17][C@@H:18]([OH:20])[CH3:19])[CH:22]=[CH:21][C:13]2[CH2:4][O:5][C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][C:11]=3[C:12]1=2
Reactant: Cc1ccccc1
Reactant: O=CCC1CC(=O)c2ccccc2O1
Reactant: C[C@H](O)CN
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: C[C@H](O)Cn1ccc2c1-c1ccccc1OC2
Reaction time: 0.58 h
Yield: 76 %

Procedure:
A solution of 1.9 g of (RS)-2-(2-oxoethyl)-4-chromanone and 80 mg of p-toluenesulfonic acid in 70 ml of anhydrous toluene was heated on a water separator. A solution of 3.0 g of (S)-1-amino-2-propanol in 20 ml of anhydrous toluene was added dropwise to the boiling solution over a period of 5 minutes. Subsequently, the mixture was boiled for an additional 35 minutes, during which the solvent was reduced to a volume of 20 ml. The cooled reaction mixture was purified by column chromatography on silica gel (ethyl acetate/toluene 2:3). 1.73 g (76%) of (S)-1-(1,4-dihydro-[1]benzopyrano[4,3-b]pyrrol-1-yl)-propan-2-ol were obtained as a yellow oil.
Reaction SMILES: [CH3:1][NH:2][CH3:3].[CH2:4]([O:6][C:7](=[O:22])[CH2:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([CH:19]=O)=[CH:16][CH:17]=2)[CH:12]=[CH:11][C:10]=1[Cl:21])[CH3:5].C([BH3-])#N.[Na+].C(O)(=O)C>C1COCC1.CO>[CH2:4]([O:6][C:7](=[O:22])[CH2:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([CH2:19][N:2]([CH3:3])[CH3:1])=[CH:16][CH:17]=2)[CH:12]=[CH:11][C:10]=1[Cl:21])[CH3:5]
Reactant: CNC
Reactant: CCOC(=O)Cc1c(Cl)ccc2cc(C=O)ccc12
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: CO
Product: CCOC(=O)Cc1c(Cl)ccc2cc(CN(C)C)ccc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Dimethylamine (5.6 M solution in EtOH, 0.28 ml, 1.53 mmol) is added under an atmosphere of argon to a solution of (2-chloro-6-formyl-naphthalen-1-yl)-acetic acid ethyl ester (284 mg, 1.02 mmol) in THF (10 ml). The mixture is stirred at RT for 18 h, before a solution of sodium cyanoborohydride (78 mg, 1.23 mmol) in MeOH (2 ml) and glacial acetic acid (0.29 ml, 5.13 mmol) are added. After stirring at RT for 1 h, TLC analysis indicates complete consumption of starting material. The reaction mixture is diluted with water and adjusted to pH 8-9 by the addition of conc. aq. NaHCO3 solution. Extraction with EtOAc, washing with brine, drying over Na2SO4 and removal of solvent yields the crude reaction product. Purification by FCC (CH2Cl2/EtOH/NH3 190:9:1) affords the title compound. 1H NMR (CDCl3, 400 MHz): δ 1.26 (t, J=9 Hz, 3H), 2.30 (s, 6H), 3.59 (s, 2H), 4.18 (q, J=9 Hz, 2H), 4.30 (s, 2H), 7.49 (d, J=10 Hz, 1H), 7.54-7.58 (m, 1H), 7.69-7.76 (m, 2H), 7.91 (d, J=10 Hz, 1H). ES+-MS: 306.4, 308.3 [M+H]+.
Reaction SMILES: [H-].[Na+].[OH:3][NH:4][C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8].[H][H].[C:14]1([CH2:24]Cl)[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][CH:15]=1>CN(C)C=O.O>[C:14]1([CH2:24][O:3][NH:4][C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8])[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][CH:15]=1
Reactant: ClCc1cccc2ccccc12
Reactant: CC(C)(C)OC(=O)NO
Reactant: [H][H]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)NOCc1cccc2ccccc12
Yield: 38.9 %

Procedure:
Under a nitrogen atmosphere, a suspension of 1.6 grams (0.041 mole) of 60% sodium hydride (in mineral oil) in dimethylformamide was stirred, and 5.4 grams (0.041 mole) of 1,1-dimethylethyl N-hydroxycarbamate was carefully added portionwise. Upon completion of the evolution of hydrogen, 5.8 grams (0.032 mole) of naphth-1-ylmethyl chloride was added. Upon completion of addition, the reaction mixture was stirred for about 30 minutes. After this time the reaction mixture was poured into 200 ml of water. The mixture was extracted with 200 ml of diethyl ether. The ether extract was washed with three 50 ml portions of water. The organic layer was concentrated under reduced pressure to a residual oil. The oil was purified by column chromatography on silica gel. Elution was accomplished with mixtures of 5% to 20% diethyl ether in petroleum ether. The appropriate fractions were combined and concentrated under reduced pressure, yielding 3.4 grams of 1,1-dimethylethyl N-(naphth-1-ylmethoxy)carbamate. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:12][C:11]([C:13](Cl)=[O:14])=[N:10][C:9]=2[C:16]2[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=2)=[CH:4][C:3]=1[OH:22].[CH3:23][N:24]([CH3:28])[CH2:25][CH2:26][NH2:27].C(N(CC)CC)C>ClCCl>[NH3:10].[CH3:23][N:24]([CH3:28])[CH2:25][CH2:26][NH:27][C:13]([C:11]1[NH:12][C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([OH:22])[CH:4]=2)=[C:9]([C:16]2[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=2)[N:10]=1)=[O:14]
Reactant: CN(C)CCN
Reactant: O=C(Cl)c1nc(-c2ccncc2)c(-c2ccc(Cl)c(O)c2)[nH]1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(C)CCNC(=O)c1nc(-c2ccncc2)c(-c2ccc(Cl)c(O)c2)[nH]1
Product: N
Temperature: 25 °C
Reaction time: 8 h
Yield: 34.6 %

Procedure:
The product from Step 2 (124 mg, 0.3 mmol) was suspended in dichioromethane (5 ml) and treated with a solution of N,N-dimethyl ethylenediamine (0.036 ml, 0.33 mmol), and triethylamine (0.125 ml, 0.9 mmol) in dichloromethane (1 ml). The reaction mixture was then stirred at room temperature overnight, washed saturated sodium bicarbonate solution (3 ml) and passed through a Varain Chem Elut hydromatric cartridge to remove the aqueous phase. The filtrate was then concentrated and purified by silica gel chromatography, eluting with 0.3:3:7 dichloromethane: ethanol:0.880 ammonia solution to afford the title compound (20 mg, 17%); MS(AP+) m/e 386/388 [M+H]+
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[N:6][CH:7]=1.[CH:16]1([C:19]2[CH:20]=[C:21]([C:44]([O:46][CH2:47][CH3:48])=[O:45])[C:22](=[O:43])[N:23]3[C:28]=2[C:27]([CH3:29])=[C:26]([Sn](CCCC)(CCCC)CCCC)[CH:25]=[CH:24]3)[CH2:18][CH2:17]1.O>CN(C=O)C.[Ag-]=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:11]([O:10][C:9]([NH:8][C:5]1[N:6]=[CH:7][C:2]([C:26]2[CH:25]=[CH:24][N:23]3[C:28]([C:27]=2[CH3:29])=[C:19]([CH:16]2[CH2:18][CH2:17]2)[CH:20]=[C:21]([C:44]([O:46][CH2:47][CH3:48])=[O:45])[C:22]3=[O:43])=[CH:3][CH:4]=1)=[O:15])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)OC(=O)Nc1ccc(Br)cn1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccn2c(=O)c(C(=O)OCC)cc(C3CC3)c2c1C
Agent: O=[Ag-]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc(C2CC2)c2c(C)c(-c3ccc(NC(=O)OC(C)(C)C)nc3)ccn2c1=O
Temperature: 100 °C
Reaction time: 0.08 h
Yield: 13.3 %

Procedure:
73 mg of tert-butyl (5-bromopyridin-2-yl)carbamate was dissolved in 1 ml of DMF. 62 mg of silver (I) oxide and 31 mg of tetrakis(triphenylphosphine)palladium were added to the obtained solution, and they were stirred at 100° C. in argon atmosphere for 5 minutes. 1 ml of a solution of 100 mg of ethyl 1-cyclopropyl-9-methyl-4-oxo-8-tributylstannyl-4H-quinolizine-3-carboxylate in DMF was added dropwise to the reaction mixture, and they were stirred at that temperature for 1 hour. The reaction mixture was poured into water. After the extraction with chloroform, the organic layer was washed with water and then dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified by the silica gel column chromatography (eluent: hexane/ethyl acetate=1/1) to obtain 11 mg of ethyl 8-(6-tert-butoxycarbonylaminopyridin-3-yl)-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate.
Reaction SMILES: [N+](=C)=[N-].[C:4]([C:7]([Cl:27])([CH2:17][CH2:18][CH2:19][CH:20]([OH:26])[CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15])(=[O:6])[CH3:5].[C:28](O)(=O)C>CCOCC>[C:4]([C:7]([Cl:27])([CH2:17][CH2:18][CH2:19][CH:20]([OH:26])[CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([O:16][CH3:28])=[O:15])(=[O:6])[CH3:5]
Reactant: CC(=O)O
Reactant: CCCCCC(O)CCCC(Cl)(CCCCCCC(=O)O)C(C)=O
Agent: C=[N+]=[N-]
Solvent: CCOCC
Product: CCCCCC(O)CCCC(Cl)(CCCCCCC(=O)OC)C(C)=O
Reaction time: 4 h

Procedure:
A solution of diazomethane (approx. 2.5 g., 0.06 mole) in ether (100 ml.) is mixed with a solution of 8-acetyl-8-chloro-12-hydroxyheptadecanoic acid (10.9 g., 0.03 mole) in ether (50 ml.). The resulting solution is allowed to stand 4 hours at room temperature. Acetic acid is then added to destroy the excess diazomethane and the solution is washed with dilute sodium bicarbonate solution and water and dried over sodium sulfate. Evaporation of volatile materials at reduced pressure yields methyl 8-acetyl-8-chloro-12-hydroxyheptadecanoate, a colorless viscous oil.
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[CH2:7]/[N:8]=[CH:9]/[CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1)([CH3:4])([CH3:3])[CH3:2].[Cl:17][C:18]1[CH:19]=[C:20](/[CH:24]=[C:25](/[C:28]2[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=2)\[C:26]#[N:27])[CH:21]=[CH:22][CH:23]=1.C(N(CC)CC)C>ClCCl>[C:1]([O:5][C:6]([CH:7]1[CH:24]([C:20]2[CH:21]=[CH:22][CH:23]=[C:18]([Cl:17])[CH:19]=2)[C:25]([C:28]2[CH:29]=[CH:30][C:31]([Cl:34])=[CH:32][CH:33]=2)([C:26]#[N:27])[CH:9]([CH:10]2[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]2)[NH:8]1)=[O:16])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)C/N=C/C1CCCCC1
Reactant: N#C/C(=C\c1cccc(Cl)c1)c1ccc(Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)C1NC(C2CCCCC2)C(C#N)(c2ccc(Cl)cc2)C1c1cccc(Cl)c1
Yield: 37.3 %

Procedure:
In a manner similar to the method described in Example 1c, {[1-cyclohexyl-meth-(E)-ylidene]-amino}-acetic acid tert-butyl ester prepared in Example 50a (1.2 g, 5.3 mmol) was reacted with (Z)-3-(3-chloro-phenyl)-2-(4-chloro-phenyl)-acrylonitrile (1 g, 3.7 mmol) prepared in Example 1b, AgF (1.5 g, 12 mmol), and triethylamine (2 g, 20 mmol) in dichloromethane (100 mL) at room temperature for 20 h to give rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-cyclohexyl-pyrrolidine-2-carboxylic acid tert-butyl ester as a white foam (0.69 g, 38%).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[CH2:11]([O:17][C@H:18]([CH3:22])[C:19](Cl)=[O:20])[CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]>C(Cl)Cl.N1C=CC=CC=1.Cl>[CH2:11]([O:17][C@H:18]([CH3:22])[C:19]([O:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1)=[O:20])[CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: O=C(O)c1ccc(O)cc1
Reactant: CCCCCCO[C@H](C)C(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCCCCO[C@H](C)C(=O)Oc1ccc(C(=O)O)cc1
Yield: 46.4 %

Procedure:
To a solution of p-hydroxybenzoic acid (2.15 g, 15.6 mmol) in methylene chloride (30 ml) and pyridine (10 ml), a solution of (R)-2-n-hexyloxypropanoyl chloride (3.0 g, 15.6 mmol) in methylene chloride (20 ml) was added dropwise and then the mixture was refluxed for 7 hours. After cooling, the resultant mixture was taken up in dilute hydrochloric acid, extracted with ethyl ether; the organic extract was washed twice with dilute hydrochloric acid and with H2O for four times, and dried over anhydrous Na2SO4. The solvent was evaporated and the residue was recrystallized from n-hexane to afford 2.13 g of the title compound as white crystals; mp. 67.0°-72.0° C.
Reaction SMILES: [Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([NH2:9])=[CH:4][C:3]=1[CH3:10].[C:11](OC(=O)C)(=[O:13])[CH3:12]>C(Cl)Cl>[Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([NH:9][C:11](=[O:13])[CH3:12])=[CH:4][C:3]=1[CH3:10]
Reactant: Cc1cc(N)cc(C)c1Br
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Product: CC(=O)Nc1cc(C)c(Br)c(C)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 4-bromo-3,5-dimethyl-phenylamine (130 mg) in CH2Cl2 (4 mL) was added acetic anhydride (0.123 mL) at 0° C. The mixture was allowed to warm up to room temperature and stirred for 2 h. The mixture was concentrated under reduced pressure. The crude product was purified by column chromatography (SiO2, EtOAc:Hexane=10:90 to 60:40) to give N-(4-bromo-3,5-dimethyl-phenyl)-acetamide: MS (m/z) 244 (M+1); 1H NMR (CDCl3, 400 MHz) δ 7.24 (s, 2H), 2.35 (s, 6H), 2.13 (s, 3H).