Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:13][CH2:12][C@H:11]([C:14]3[C:15](=[O:26])[C:16]4[C:21]([C:22](=[O:25])[C:23]=3Cl)=[CH:20][CH:19]=[CH:18][CH:17]=4)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[OH-:27].[Na+]>CO.O>[CH:18]1[CH:19]=[CH:20][C:21]2[C:22]([C:23]([OH:27])=[C:14]([C@@H:11]3[CH2:10][CH2:9][C@@H:8]([C:5]4[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=4)[CH2:13][CH2:12]3)[C:15](=[O:26])[C:16]=2[CH:17]=1)=[O:25]
Reactant: [OH-]
Reactant: O=C1C(Cl)=C([C@H]2CC[C@H](c3ccc(Cl)cc3)CC2)C(=O)c2ccccc21
Agent: [Na+]
Solvent: CO
Solvent: O
Product: O=C1C(O)=C([C@H]2CC[C@H](c3ccc(Cl)cc3)CC2)C(=O)c2ccccc21
Temperature: 2.5 °C

Procedure:
6.0 g of trans-2-[4-(4-chlorophenyl)cyclohexyl]-3-chloro-1,4-naphthoquinone (trans-isomer of Formula IV) as obtained in Example 3 was suspended in 120 ml methanol. 6.0 g sodium hydroxide dissolved in 60 ml water was added drop-wise to the suspension under heating over a period of 20 minutes. Further, it was refluxed for 45 minutes and cooled to 0-5° C. and filtered. The filtrate was acidified with 50% aqueous hydrochloric acid to precipitate the product. The precipitated product was filtered, and recrystallized from acetonitrile to obtain 4 g (70% yield) atovaquone.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:8])[CH2:4][C:5](=O)[CH3:6].[F:9][C:10]([F:27])([F:26])[C:11]1[CH:12]=[C:13]([C:21](=O)[CH:22](Br)[CH3:23])[CH:14]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:16]=1.[CH:28]1([CH2:34][NH2:35])[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1>>[CH3:1][O:2][C:3]([C:4]1[C:22]([CH3:23])=[C:21]([C:13]2[CH:12]=[C:11]([C:10]([F:27])([F:26])[F:9])[CH:16]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:14]=2)[N:35]([CH2:34][CH:28]2[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]2)[C:5]=1[CH3:6])=[O:8]
Reactant: NCC1CCCCC1
Reactant: COC(=O)CC(C)=O
Reactant: CC(Br)C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Product: COC(=O)c1c(C)c(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)n(CC2CCCCC2)c1C

Procedure:
The title compound was prepared according to example 68, using 3-oxo-butyric acid methyl ester as compound of formula R, 1-(3,5-bis-trifluoromethyl-phenyl)-2-bromo-propan-1-one as compound of formula S and cyclohexanemethylamine, as R3—(CH2)m—NH2, MS (EI) 461.2 (M)+.
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[F:13][C:14]1[CH:15]=[C:16]([C:48]2[C:49]([C:54]#[N:55])=[CH:50][CH:51]=[CH:52][CH:53]=2)[CH:17]=[CH:18][C:19]=1[CH2:20][C:21]1[C:22](=[O:47])[N:23]([C@H:33]2[CH2:38][CH2:37][C@H:36]([O:39][C:40]3([C:43]([OH:46])([CH3:45])[CH3:44])[CH2:42][CH2:41]3)[CH2:35][CH2:34]2)[C:24]2[N:25]([N:30]=[CH:31][N:32]=2)[C:26]=1[CH2:27][CH2:28][CH3:29]>O.C(OCC)(=O)C>[F:13][C:14]1[CH:15]=[C:16]([C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][C:49]=2[C:54]2[NH:3][C:4](=[O:7])[O:5][N:55]=2)[CH:17]=[CH:18][C:19]=1[CH2:20][C:21]1[C:22](=[O:47])[N:23]([C@H:33]2[CH2:34][CH2:35][C@H:36]([O:39][C:40]3([C:43]([OH:46])([CH3:45])[CH3:44])[CH2:41][CH2:42]3)[CH2:37][CH2:38]2)[C:24]2[N:25]([N:30]=[CH:31][N:32]=2)[C:26]=1[CH2:27][CH2:28][CH3:29]
Reactant: O=C([O-])O
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2F)c(=O)n([C@H]2CC[C@H](OC3(C(C)(C)O)CC3)CC2)c2ncnn12
Reactant: [NH3+]O
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Solvent: CCOC(C)=O
Product: CCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2F)c(=O)n([C@H]2CC[C@H](OC3(C(C)(C)O)CC3)CC2)c2ncnn12
Temperature: 40 °C
Reaction time: 0.5 h

Procedure:
A mixture of hydroxylammonium chloride (0.059 g), sodium hydrogen carbonate (0.094 g) and dimethyl sulfoxide (2 mL) was stirred at 40° C. for 30 min, 3′-fluoro-4′-{[4-(trans-4-{[1-(1-hydroxy-1-methylethyl)cyclopropyl]oxy}cyclohexyl)-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile (0.032 g) was added and the mixture was stirred at 90° C. for 24 hr and then at room temperature for 40 hr. Ethyl acetate and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was dissolved in tetrahydrofuran (1 mL). N,N′-Carbonyldiimidazole (0.011 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.010 mL) were added, and the mixture was stirred at room temperature for 30 min. Ethyl acetate and water were added to the reaction mixture, and the mixture was acidified with 1 M hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.017 g, 47%).
Reaction SMILES: Cl.[F:2][C:3]1([F:9])[CH2:8][CH2:7][CH2:6][NH:5][CH2:4]1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:17][CH2:18][CH2:19][O:20][Si:21]([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22].O>CN(C=O)C.C(OCC)(=O)C>[Si:21]([O:20][CH2:19][CH2:18][CH2:17][N:5]1[CH2:6][CH2:7][CH2:8][C:3]([F:9])([F:2])[CH2:4]1)([C:24]([CH3:25])([CH3:26])[CH3:27])([CH3:23])[CH3:22]
Reactant: FC1(F)CCCNC1
Reactant: CC(C)(C)[Si](C)(C)OCCCBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](C)(C)OCCCN1CCCC(F)(F)C1
Temperature: 50 °C

Procedure:
To a solution of 3,3-difluoropiperidine hydrochloride (518 mg) in DMF (15 mL) was added cesium carbonate (3.21 g) and (3-bromopropoxy)-tert-butyldimethylsilane (0.838 mL). The resulting reaction mixture was heated to 50° C. for 1.5 hours before cooling back to room temperature. Water and ethyl acetate were added to the reaction mixture. The mixture was extracted with ethyl acetate (2×). The combined organics were washed with water (2×), brine, dried over magnesium sulfate, filtered and concentrated. Purification by flash chromatography (ISCO, 0 to 40% ethyl acetate in hexanes with 1% triethylamine) gave the desired product (612 mg). 1H NMR (400 MHz, CDCl3): δ (ppm) 4.20 (t, 1H), 3.71-3.64 (m, 2H), 3.46 (t, 1H), 2.62 (t, 1H), 2.50-2.47 (m, 1H), 2.44-2.42 (m, 1H), 2.05-1.98 (m, 1H), 1.91-1.82 (m, 2H), 1.77-1.67 (m, 4H), 0.89 (d, 9H), 0.05 (s, 3H), 0.04 (s, 3H).
Reaction SMILES: C[O:2][CH:3]=[C:4]1[CH2:9][CH2:8][CH:7]([C:10]2[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[CH:12][CH:11]=2)[CH2:6][CH2:5]1.O1CCCC1>O>[C:14]([C:13]1[CH:16]=[CH:17][C:10]([C@H:7]2[CH2:8][CH2:9][C@H:4]([CH:3]=[O:2])[CH2:5][CH2:6]2)=[CH:11][CH:12]=1)#[N:15]
Reactant: COC=C1CCC(c2ccc(C#N)cc2)CC1
Solvent: O
Solvent: C1CCOC1
Product: N#Cc1ccc([C@H]2CC[C@H](C=O)CC2)cc1

Procedure:
A mixture of 14.25 g of p-[4-(methoxymethylene)cyclohexyl]benzonitrile (purity 96.1%) and 200 ml of tetrahydrofuran/2N hydrochloric acid (vol. 4:1) was heated to reflux for 30 minutes. The reaction mixture was subsequently poured into 300 ml of water and extracted three times with 200 ml of diethyl ether each time. The organic phases were washed with 200 ml of water, dried over magnesium sulphate and concentrated. There were thus obtained 13.75 g (103%) of crude product of 4-(p-cyanophenyl)cyclohexanecarboxaldehyde (trans/cis ratio about 3:1) as a colourless, slowly crystallizing oil. Recrystallization of this material from 1.3 l of hexane gave 3.71 g (29%) of trans-4-(p-cyanophenyl)cyclohexanecarboxaldehyde (purity 99.5%) as long, colourless needles of m.p. 57.1° C. The mother liquor was concentrated to a volume of 1 l and again set aside for crystallization, there being obtained as the second crystallizate 1.20 g of colourless needles containing 97% of trans-aldehyde and 3 % of cis-aldehyde. The separated mother liquor was now concentrated, the residue was again heated to reflux for 30 minutes in 100 ml of tetrahydrofuran/2N hydrochloric acid (vol. 4:1) and the mixture was then worked-up in the same manner as on the first occasion. The crude product obtained was combined with the second crystallizate (1.2 g) and recrystallized from 900 ml of hexane, whereby 3.56 g (28%) of trans-4-(p-cyanophenyl)cyclohexanecarboxaldehyde (purity 99.7%) could again be isolated as long, colourless needles. The mother liquor (containing 4.2 g of crude product) was no longer worked-up. Total yield after two cycles: 7.27 g (57%) of trans-4-(p-cyanophenyl)cyclohexanecarboxaldehyde; m.p. 57.1° C.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([C:9]([OH:11])=[O:10])[CH2:5][CH2:4]1.[C:12]1([CH3:22])[CH:17]=[CH:16][C:15](S(O)(=O)=O)=[CH:14][CH:13]=1.C(O)C1C=CC=CC=1>C1(C)C=CC=CC=1>[CH2:22]([O:10][C:9]([C@H:6]1[CH2:5][CH2:4][C@H:3]([CH2:2][NH2:1])[CH2:8][CH2:7]1)=[O:11])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: NC[C@H]1CC[C@H](C(=O)O)CC1
Solvent: OCc1ccccc1
Solvent: Cc1ccccc1
Product: NC[C@H]1CC[C@H](C(=O)OCc2ccccc2)CC1
Temperature: 25 °C

Procedure:
50 g (0.318 moles) trans-4-(aminomethyl)-cyclohexane carboxylic acid, 61.7 g (0.324 moles) p-toluenesulfonic acid, 250 mL (2.4 moles) benzyl alcohol, and 250 mL toluene were combined and stirred at room temperature. The mixture was refluxed for 24 hours and the liberated water removed azeotropically by means of a Dean and Stark apparatus. A clear solution was obtained after 5 hours of refluxing. The solution was allowed to cool to room temperature and the product crystallized. The mixture was vacuum filtered, washed with ether and dried in a vacuum oven to give 128.12 g (96% yield). 1H NMR (CD3OD) δ1.05 (m, 2H), 1.43 (m, 2H), 1.59 (m, 1H) 1.85 (m, 2H), 2.03 (m, 2H), 2.33 (m, 1H), 2.35 (s, 3H), 2.75 (d, 2H), 5.09 (s, 2H), 7.23 (d, 2H), 7.32 (m, 5H), 7.69 (d, 2H). M.P. 154°-156° C. See, Greenstein and Winitz, Chemistry of the Amino Acids. 2:942 (1986).
Reaction SMILES: [C:1]([N:6]1[C@H:11]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[CH2:10][O:9][CH2:8][C@@H:7]1/[CH:19]=[CH:20]/[C:21](OC)=O)(=[O:5])CC=C.C(N1[C@H](C2C=CC(Cl)=CC=2)COC[C@@H]1/C=C\C(OC)=O)(=O)CC=C.C(N(CC)CC)C.[H][H]>Cl[Ru](=C1N(C2C(C)=CC(C)=CC=2C)CCN1C1C(C)=CC(C)=CC=1C)(Cl)(=CC1C=CC=CC=1)[P](C1CCCCC1)(C1CCCCC1)C1CCCCC1.ClCCl.CO.[Pt]=O>[Cl:18][C:15]1[CH:14]=[CH:13][C:12]([C@@H:11]2[CH2:10][O:9][CH2:8][C@@H:7]3[CH2:19][CH2:20][CH2:21][C:1](=[O:5])[N:6]23)=[CH:17][CH:16]=1
Reactant: [H][H]
Reactant: C=CCC(=O)N1[C@@H](/C=C/C(=O)OC)COC[C@H]1c1ccc(Cl)cc1
Agent: Cc1cc(C)c(N2CCN(c3c(C)cc(C)cc3C)C2=[Ru](Cl)(Cl)(=Cc2ccccc2)[P](C2CCCCC2)(C2CCCCC2)C2CCCCC2)c(C)c1
Agent: O=[Pt]
Agent: C=CCC(=O)N1[C@@H](/C=C\C(=O)OC)COC[C@H]1c1ccc(Cl)cc1
Solvent: CO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C1CCC[C@H]2COC[C@@H](c3ccc(Cl)cc3)N12
Reaction time: 0.17 h

Procedure:
Grubbs catalyst 2nd generation (21.3 mg) was added to a solution of methyl 3-[(3S,5R)-4-but-3-enoyl-5-(4-chlorophenyl)morpholin-3-yl]-(E)-acrylate and methyl 3-[(3S,5R)-4-but-3-enoyl-5-(4-chlorophenyl)morpholin-3-yl]-(Z)-acrylate (87.9 mg) in dichloromethane (10 mL), and the reaction solution was heated under reflux in a nitrogen atmosphere for 1.5 hours. The reaction solution was returned to room temperature. Triethylamine (500 μL) was added to the reaction solution, which was then stirred for 10 minutes. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (heptane-ethyl acetate system) to obtain a crude product. Platinum oxide (6.02 mg) was added to a solution of the crude product in methanol (3 mL), and the reaction solution was stirred in a hydrogen atmosphere at room temperature for one hour. The reaction solution was filtered through celite, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent solvent: heptane-ethyl acetate system) to obtain 48.7 mg of the title compound. The property values of the compound are as follows.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][CH:9]([OH:13])[CH2:10]2)=[CH:5][CH:4]=1.[CH3:14][C:15](O)=[O:16]>S(=O)(=O)(O)O>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][CH:9]([O:13][C:15](=[O:16])[CH3:14])[CH2:10]2)=[CH:5][CH:4]=1
Reactant: COc1ccc2c(c1)CC(O)CC2
Reactant: CC(=O)O
Agent: O=S(=O)(O)O
Product: COc1ccc2c(c1)CC(OC(C)=O)CC2
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
7-Methoxy-1,2,3,4-tetrahydro-naphthalen-2-ol (4.48 g, from step A) is taken up in AcOH (15 mL) and cooled to 0° C. Concentrated sulfuric acid (10 drops) is added. The mixture is stirred at 0° C. for 20 min and then warmed to room temperature over 10 min. The mixture is partitioned between ice-cold 1 N NaOH and EtOAc. The organic layer is dried over MgSO4 and concentrated to afford acetic acid 7-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl ester as a red solid: 1H NMR (CDCl3) δ 7.01 (d, J=8.0 Hz, 1H), 6.71 (d, J=8.0 Hz, 1H), 6.60 (s, 1H), 5.19 (m, 1H), 3.77 (s, 3H), 3.08 (dd, J=16.0, 8.0 Hz, 1H), 2.90-2.70 (m, 3H), 2.05 (s, 3H), 2.05-1.88 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[O:14][CH2:13][CH2:12][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10][C@H:9]2[CH2:22][OH:23])=[CH:4][C:3]=1[F:24].C(N(CC)CC)C.[CH3:32][S:33](Cl)(=[O:35])=[O:34]>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[O:14][CH2:13][CH2:12][N:11]([C:15]([O:17][C:18]([CH3:20])([CH3:19])[CH3:21])=[O:16])[CH2:10][C@H:9]2[CH2:22][O:23][S:33]([CH3:32])(=[O:35])=[O:34])=[CH:4][C:3]=1[F:24]
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(Cl)c(F)c2)[C@H](CO)C1
Reactant: CS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(Cl)c(F)c2)[C@H](COS(C)(=O)=O)C1
Reaction time: 3 h

Procedure:
To a solution of tert-butyl (6S,7R)-7-(4-chloro-3-fluorophenyl)-6-(hydroxymethyl)-1,4-oxazepane-4-carboxylate (4.50 g) in THF (41.7 mL) were added triethylamine (3.49 mL) and methanesulfonyl chloride (1.94 mL) under ice-cooling, and the mixture was stirred for 3 hr. To the reaction mixture was added distilled water, and the mixture was extracted with ethyl acetate. The extract was washed with distilled water and brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (6.01 g).
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5]/[CH:6]=[CH:7]\[CH:8]=[CH:9]/[CH2:10][CH2:11][CH2:12][CH2:13]Br.[N:15]1[C:24]2[CH2:23][CH2:22][CH2:21][CH2:20][C:19]=2[CH:18]=[CH:17][CH:16]=1>C(#N)C>[Br-:1].[Br-:1].[CH2:2]([N+:15]1[C:24]2[CH2:23][CH2:22][CH2:21][CH2:20][C:19]=2[CH:18]=[CH:17][CH:16]=1)[CH2:3][CH2:4][CH2:5]/[CH:6]=[CH:7]\[CH:8]=[CH:9]/[CH2:10][CH2:11][CH2:12][CH2:13][N+:15]1[C:24]2[CH2:23][CH2:22][CH2:21][CH2:20][C:19]=2[CH:18]=[CH:17][CH:16]=1
Reactant: c1cnc2c(c1)CCCC2
Reactant: BrCCCC/C=C\C=C/CCCCBr
Solvent: CC#N
Product: C(/C=C\CCCC[n+]1cccc2c1CCCC2)=C/CCCC[n+]1cccc2c1CCCC2
Product: [Br-]

Procedure:
cis-cis-1,12-Dibromo-dodeca-5,7-diene was added to a solution of 5,6,7,8-tetrahydro-quinoline (3 mmol) in acetonitrile and the solution refluxed for 24 hours. The acetonitrile was removed in vacuum and the resulting residue was partitioned between ether and water. The aqueous layer was washed extensively with ether until no quinoline left in the aqueous layer. The resulting aqueous solution of the product was lyophilized to yield the pure product. (75%). 1HNMR (300 MHz, D2O, ppm), 8.35 (d, J=6.3, 2H), 7.97 (d, J=8.1, 2H), 7.52 (dd, J=8.1, J=6.3, 2H), 6.16-6.22 (m, 2H), 5.32-5.42 (m, 2H), 4.30 (t, J=7.8, 4H), 2.92 (t, J=6.2, 4H), 2.79 (t, J=6.2, 4H), 2.09 (q, J=7.2, 4H), 1.60-1.83 (m, 12H), 1.36 (p, J=7.5, 4H).
Reaction SMILES: N([O-])=O.[Na+].N[C:6]1[CH:7]=[CH:8][C:9]2[N:15]([CH3:16])[C:14](=[O:17])[CH:13]3[CH2:18][CH2:19][CH2:20][N:12]3[CH2:11][C:10]=2[CH:21]=1.Cl.C(=O)([O-])[O-:24].[Na+].[Na+]>O>[OH:24][C:6]1[CH:7]=[CH:8][C:9]2[N:15]([CH3:16])[C:14](=[O:17])[CH:13]3[CH2:18][CH2:19][CH2:20][N:12]3[CH2:11][C:10]=2[CH:21]=1
Reactant: O=C([O-])[O-]
Reactant: CN1C(=O)C2CCCN2Cc2cc(N)ccc21
Agent: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: CN1C(=O)C2CCCN2Cc2cc(O)ccc21
Reaction time: 0.33 h

Procedure:
A solution of 3.5 g. of sodium nitrite in 30 ml. of water is added over a 30 minute period at 90°-95°C. to a rapidly stirred solution of 11.5 g. of 7-amino-1,2,3,5,10,11a- hexahydro-10-methyl-11H-pyrrolo[2,1-c] [1,4]benzodiazepin-11- one in 600 ml. of 0.05N hydrochloric acid. The solution is held at this temperature for 20 minutes longer, cooled, treated with an excess of sodium carbonate and the crude product is extracted into benzene. The benzene solution is concentrated to remove the solvent and the residue is purified by partition chromatography in order to obtain the pure 1,2,3,5,10,11a- hexahydro-7-hydroxy-10-methyl-11H-pyrrolo[2,1-c] [1,4]benzodiazepin- 11-one.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:13][CH2:14][CH2:15][N:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)=[C:6]2[C:11]=1[NH:10][C:9](=O)[CH:8]=[CH:7]2.O=P(Cl)(Cl)[Cl:24].[Cl-].C([NH+](CC)CC)C>C(#N)C>[Cl:24][C:9]1[CH:8]=[CH:7][C:6]2[C:11](=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=2[O:13][CH2:14][CH2:15][N:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[N:10]=1
Reactant: O=c1ccc2c(OCCN3CCCCC3)ccc(Cl)c2[nH]1
Reactant: O=P(Cl)(Cl)Cl
Agent: CC[NH+](CC)CC
Agent: [Cl-]
Solvent: CC#N
Product: Clc1ccc2c(OCCN3CCCCC3)ccc(Cl)c2n1
Temperature: 120 °C
Reaction time: 3 h
Yield: 77.9 %

Procedure:
8-chloro-5-(2-(piperidin-1-yl)ethoxy)quinolin-2(1H)-one (275 mg, 0.9 mmol, 1 eq.) was placed in acetonitrile (2.3 mL) in the presence of POCl3 (418 μL, 4.5 mmol, 5 eq.) and triethylammonium chloride (1 g, 4.5 mmol, 5 eq.). The reaction mixture was stirred at 120° C. during 3 hours. The mixture was then concentrated under reduced pressure and, after adding water to the residue (5 mL), was stirred at room temperature during 30 minutes. Then the resulting precipitate was washed with water and filtered to give 2,8-dichloro-5-(2-(piperidin-1-yl)ethoxy)quinoline (228 mg, 100%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[C@@H:12]([CH:13]([CH3:15])[CH3:14])[CH2:11][O:10][C:9]2=[O:16])[CH:5]=[CH:4][N:3]=1.[F:17][C:18]1[CH:33]=[CH:32][C:21]([O:22][C:23]2[N:28]=[CH:27][C:26]([C@@H:29]([NH2:31])[CH3:30])=[CH:25][CH:24]=2)=[CH:20][CH:19]=1.CCN(C(C)C)C(C)C>CS(C)=O>[F:17][C:18]1[CH:19]=[CH:20][C:21]([O:22][C:23]2[N:28]=[CH:27][C:26]([C@@H:29]([NH:31][C:2]3[N:7]=[C:6]([N:8]4[C@@H:12]([CH:13]([CH3:15])[CH3:14])[CH2:11][O:10][C:9]4=[O:16])[CH:5]=[CH:4][N:3]=3)[CH3:30])=[CH:25][CH:24]=2)=[CH:32][CH:33]=1
Reactant: C[C@H](N)c1ccc(Oc2ccc(F)cc2)nc1
Reactant: CC(C)[C@H]1COC(=O)N1c1ccnc(Cl)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CC(C)[C@H]1COC(=O)N1c1ccnc(N[C@@H](C)c2ccc(Oc3ccc(F)cc3)nc2)n1
Temperature: 107.5 °C
Yield: 14 %

Procedure:
To (S)-3-(2-chloropyrimidin-4-yl)-4-isopropyloxazolidin-2-one (28 mg, 0.116 mmol) was added (S)-1-(6-(4-fluorophenoxy)pyridin-3-yl)ethanamine (46.7 mg, 0.174 mmol), DMSO (0.6 ml) and Hunig's Base (0.071 ml, 0.406 mmol). The reaction was heated at 105-110° C. for 24 hours or until done by LCMS. The reaction was let cool, 0.5 ml of DMSO was added, filtered, purified by prep LC and lyophilized to give 7.1 mg of (S)-3-(2-((S)-1-(6-(4-fluorophenoxy)pyridin-3-yl)ethylamino)pyrimidin-4-yl)-4-isopropyloxazolidin-2-one as the TFA Salt. LCMS m/z 438.2 (M+H)+, Rt 0.82 min.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:28][CH2:29]CS([O-])(=O)=O)[CH2:13][CH2:12][N:11]([C:14](=[O:27])[C:15]3[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=3)[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].[N:35]1[CH:40]=[CH:39][CH:38]=[C:37]([C:41]2([C:47]([NH2:49])=[O:48])[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]2)[CH:36]=1.C(OCC)(=O)C>CO.ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:28][CH2:29][N:44]3[CH2:45][CH2:46][C:41]([C:37]4[CH:36]=[N:35][CH:40]=[CH:39][CH:38]=4)([C:47]([NH2:49])=[O:48])[CH2:42][CH2:43]3)[CH2:13][CH2:12][N:11]([C:14](=[O:27])[C:15]3[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=3)[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: COc1cc(C(=O)N2CCC(CCCS(=O)(=O)[O-])(c3ccc(Cl)c(Cl)c3)C2)cc(OC)c1OC
Reactant: NC(=O)C1(c2cccnc2)CCNCC1
Solvent: CCOC(C)=O
Solvent: CO
Solvent: ClCCl
Product: COc1cc(C(=O)N2CCC(CCN3CCC(C(N)=O)(c4cccnc4)CC3)(c3ccc(Cl)c(Cl)c3)C2)cc(OC)c1OC

Procedure:
Prepare by the method of example 88.6 using 2-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl-methanesulfonate (3.2 g, 6 mmol) and 4-(pyridin-3-yl)-piperidine-4-carboxylic acid amide (1.03 g, 5 mmol). Chromatograph on silica gel eluting sequentially with ethyl acetate, 4% methanol/dichloromethane, 6% methanol/dichloromethane, 8% methanol/dichloromethane, and then 10% methanol/dichloromethane to give the title compound: Rf =0.32 (silica gel, 10% methanol/dichloromethane).
Reaction SMILES: CSC.S([O:9][CH3:10])(OC)(=O)=O.[CH2:11]([S:14][C:15]1([C:18]([CH:20]=[CH:21][C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=2[Cl:29])=O)[CH2:17][CH2:16]1)[CH2:12][CH3:13].[OH-].[K+].OO>C(O)(C)(C)C>[Cl:29][C:23]1[CH:24]=[C:25]([Cl:28])[CH:26]=[CH:27][C:22]=1[CH:21]=[CH:20][C:18]1([C:15]2([S:14][CH2:11][CH2:12][CH3:13])[CH2:16][CH2:17]2)[CH2:10][O:9]1
Reactant: COS(=O)(=O)OC
Reactant: CCCSC1(C(=O)C=Cc2ccc(Cl)cc2Cl)CC1
Agent: OO
Agent: [K+]
Agent: [OH-]
Solvent: CSC
Solvent: CC(C)(C)O
Product: CCCSC1(C2(C=Cc3ccc(Cl)cc3Cl)CO2)CC1
Reaction time: 14 h
Yield: 89.2 %

Procedure:
30 ml (0.41 mol) of dimethyl sulphide and 43.5 g (0.35 mol) of dimethyl sulphate are added to 60 ml of tert.-butanol and allowed to stand at room temperature for 14 hours. A solution of 40 g (0.13 mol) of 2,4-dichlorophenyl-ethenyl 1-propylmercaptocyclopropyl ketone in 120 ml of tert.-butanol is initially added dropwise to the reaction mixture with stirring and then 39.1 g of potassium hydroxide powder is introduced, the temperature of the reaction mixture being held at 20° to 30° C. The mixture is stirred for a further 3 hours at 30° C., then the dimethyl sulphide is stripped off under reduced pressure and the reaction mixture is then poured into 70 ml of a 1% strength aqueous hydrogen peroxide solution. The mixture is extracted with ethyl acetate. The organic phase is washed using water and concentrated by stripping off the solvent under reduced pressure after drying over sodium sulphate. In this manner, 38.2 g (91% of theory) of 2-(2,4-dichlorophenylethenyl)-2-(1-propylmercaptocyclopropyl)-oxirane are obtained in the form of an oily product, which is further reacted without additional purification. ##STR78##
Reaction SMILES: [CH:1]([C:3]1[O:7][C:6](B(O)O)=[CH:5][CH:4]=1)=[O:2].Br[C:12]1[CH:17]=[CH:16][C:15]([S:18]([F:23])([F:22])([F:21])([F:20])[F:19])=[CH:14][CH:13]=1>O.[Ru](=O)=O>[F:19][S:18]([F:20])([F:21])([F:22])([F:23])[C:15]1[CH:14]=[CH:13][C:12]([C@H:6]2[O:7][C@@H:3]([CH2:1][OH:2])[CH2:4][CH2:5]2)=[CH:17][CH:16]=1
Reactant: O=Cc1ccc(B(O)O)o1
Reactant: FS(F)(F)(F)(F)c1ccc(Br)cc1
Agent: O=[Ru]=O
Solvent: O
Product: OC[C@H]1CC[C@@H](c2ccc(S(F)(F)(F)(F)F)cc2)O1

Procedure:
The requisite {cis-5-[4-(pentafluoro-λ6-sulfanyl)phenyl]tetrahydrofuran-2-yl}methanol was prepared via Suzuki reaction of (5-formylfuran-2-yl)boronic acid with 1-bromo-4-(pentafluoro-λ6-sulfanyl)benzene, followed by hydrogenation in the presence of ruthenium(IV) oxide hydrate.
Reaction SMILES: [Cl:1][C:2]1[C:14]([Cl:15])=[C:13]([O:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])[CH:12]=[C:11]2[C:3]=1[C:4]1[C:9]([CH2:22][CH3:23])([CH2:10]2)[CH2:8][CH2:7][C:6](=[O:24])[CH:5]=1.[O-][CH2:26][CH3:27]>C(O)C1C=CC=CC=1.C(Cl)Cl>[Cl:1][C:2]1[C:14]([Cl:15])=[C:13]([O:16][CH2:17][C:18]([O:20][CH2:21][C:27]2[CH:26]=[CH:4][CH:3]=[CH:2][CH:14]=2)=[O:19])[CH:12]=[C:11]2[C:3]=1[C:4]1[C:9]([CH2:22][CH3:23])([CH2:10]2)[CH2:8][CH2:7][C:6](=[O:24])[CH:5]=1
Reactant: CCC12CCC(=O)C=C1c1c(cc(OCC(=O)OC)c(Cl)c1Cl)C2
Reactant: CC[O-]
Solvent: OCc1ccccc1
Solvent: ClCCl
Product: CCC12CCC(=O)C=C1c1c(cc(OCC(=O)OCc3ccccc3)c(Cl)c1Cl)C2

Procedure:
Methyl [(5,6-dichloro-9a-ethyl-3-oxo-1,2,9,9a-tetrahydro-3H-fluoren-7-yl)oxy]acetate (Example 20, Step C) (5.8 g., 0.016 mole) is dissolved in a mixture of dry benzyl alcohol (50 ml) and methylene chloride (40 ml.) containing amberlite IRA 400 (ethoxide) (5-6 g.). The mixture is stirred magnetically at reflux for four hours and then filtered. The filtrate is concentrated in vacuo to give a yellow solid (5.3 g.) which upon trituration with ethanol and washing with ether yields the product.