Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:6][CH:5]=[C:4]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]([N:16]3[CH2:24][C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[CH2:17]3)=[O:15])=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.[CH:25](=O)[CH:26]([CH3:28])[CH3:27].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C.O.C(OCC)(=O)C.C(=O)(O)[O-].[Na+]>[CH2:25]([N:1]1[CH2:2][CH:3]=[C:4]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]([N:16]3[CH2:17][C:18]4[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=4)[CH2:24]3)=[O:15])=[CH:9][CH:8]=2)[CH2:5][CH2:6]1)[CH:26]([CH3:28])[CH3:27]
Reactant: CC(C)C=O
Reactant: O=C(Nc1ccc(C2=CCNCC2)cc1)N1Cc2ccccc2C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)CN1CC=C(c2ccc(NC(=O)N3Cc4ccccc4C3)cc2)CC1
Reaction time: 8 h

Procedure:
In a 4 mL were mixed N-(4-(1,2,3,6-tetrahydropyridin-4-yl)phenyl)isoindoline-2-carboxamide (50 mg, 0.157 mmol) and isobutyraldehyde (0.014 ml, 0.157 mmol) in anhydrous dichloroethane (2 ml) at room temperature. Sodium triacetoxyborohydride (46.4 mg, 0.219 mmol) was added, and reaction was stirred overnight. The reaction mixture was diluted with water, ethyl acetate and saturated aqueous sodium bicarbonate. The layers were separated and the organic layer was washed with brine. The organic layer was diluted with methanol, dried with sodium sulfate, filtered and concentrated. The residue was purified by flash chromatography to provide the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.35 (s, 1H), 7.53-7.55 (m, 2H), 7.30-7.38 (m, 6H), 6.06-6.08 (m, 1H), 4.77 (s, 4H), 3.01-3.03 (m, 2H), 2.57 (t, J=5.6 Hz, 2H), 2.41-2.47 (m, 2H), 2.14 (d, J=7.3 Hz, 2H), 1.77-1.88 (m, 1H), 0.88 (d, J=6.5 Hz, 6H); MS (ESI(−)) m/e 374 (M−H)−.
Reaction SMILES: ClC1C=C([N+]([O-])=O)C=CC=1N=NC1C=C(C)C(N=NC2C3C(=CC=CC=3)C=C(NC3C=CC=CC3=C=O)C=2O)=CC=1[S:42]([F:45])(=[O:44])=[O:43].C[C:47]1[CH:52]=[CH:51][C:50](S(F)(=O)=O)=[CH:49][C:48]=1[N:57]=[N:58][C:59]1[CH:64]=[CH:63][C:62]([N:65]=[N:66][C:67]2[C:76]3[C:71](=CC=CC=3)[CH:70]=[C:69](NC3C=CC=CC3=C=O)[C:68]=2O)=[C:61]([O:87][CH2:88]C)[CH:60]=1.FS(C1C=C(N=NC2C=C(OC)C(N=NC3C4C(=CC=CC=4)C=C(NC4C5C(=CC=CC=5)C=CC4=C=O)C=3O)=CC=2OC)C=CC=1)(=O)=[O:92].CC1C=CC(S(F)(=O)=O)=CC=1N=NC1C2C(=CC=CC=2)C(N=NC2C3C(=CC=CC=3)C=C(NC3C=CC=CC3=C=O)C=2O)=CC=1>>[OH:92][C:70]1[CH:69]=[CH:68][C:67]([N:66]=[N:65][C:62]2[CH:63]=[CH:64][C:59]([N:58]=[N:57][C:48]3[CH:49]=[CH:50][C:51]([S:42]([F:45])(=[O:44])=[O:43])=[CH:52][CH:47]=3)=[CH:60][C:61]=2[O:87][CH3:88])=[CH:76][CH:71]=1
Reactant: COc1cc(N=Nc2c(O)c(NC3C(=C=O)C=Cc4ccccc43)cc3ccccc23)c(OC)cc1N=Nc1cccc(S(=O)(=O)F)c1
Reactant: Cc1cc(N=Nc2ccc([N+](=O)[O-])cc2Cl)c(S(=O)(=O)F)cc1N=Nc1c(O)c(NC2C=CC=CC2=C=O)cc2ccccc12
Reactant: CCOc1cc(N=Nc2cc(S(=O)(=O)F)ccc2C)ccc1N=Nc1c(O)c(NC2C=CC=CC2=C=O)cc2ccccc12
Agent: Cc1ccc(S(=O)(=O)F)cc1N=Nc1ccc(N=Nc2c(O)c(NC3C=CC=CC3=C=O)cc3ccccc23)c2ccccc12
Product: COc1cc(N=Nc2ccc(S(=O)(=O)F)cc2)ccc1N=Nc1ccc(O)cc1

Procedure:
1-(2-chloro-4-nitrophenylazo)-5-methyl-2-fluorosulphonyl-4-(2-hydroxy-3-(carbonyl (N-phenyl) amino) naphth-1-ylazo) benzene; 1-(2-methyl-5-fluorosulphonylphenylazo)-3-ethoxy-4-(2-hydroxy-3-(carbonyl (N-phenyl) amino) naphth-1-ylazo) benzene; 1-(3-fluorosulphonylphenylazo)-2,5-dimethoxy-4-(2-hydroxy-3-(carbonyl(N-naphth-1-yl)amino)naphth-1-ylazo)benzene; and 1-(2-methyl-5-fluorosulphonylphenylazo)-4-(2-hydroxy-3-(carbonyl(N-phenyl)amino)naphth-1-ylazo)naphthalene and these form a further feature of the present invention.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1)#[N:2].[OH-].[Na+].O.Cl[CH:14]([F:16])[F:15]>O1CCCC1>[F:15][CH:14]([F:16])[O:9][C:6]1[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=1
Reactant: FC(F)Cl
Reactant: N#Cc1ccc(O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: N#Cc1ccc(OC(F)F)cc1
Temperature: 25 °C
Reaction time: 1.25 h
Yield: 36.6 %

Procedure:
Under a dry argon atmosphere a mixture of 10.0 g (0.084 mole) of 4-cyanophenol, 33.6 g (0.84 mole) of sodium hydroxide, 110 ml of water, and 130 ml of tetrahydrofuran was stirred in a Morton flask and heated at reflux. During 1.25 hour, 8.6 g (0.99 mole) of chlorodifluoromethane was added to the reaction mixture. After complete addition, the mixture was allowed to cool to room temperature and was stirred for approximately 18 hours. The reaction mixture was poured into 500 g of ice water, the resulting mixture filtered, and the filtrate extracted with three 300 ml portions of diethyl ether. The ether extracts were combined, dried over anhydrous potassium carbonate, and filtered. The filtrate was evaporated under reduced pressure to give an oil which crystallized upon standing. The product was recrystallized from toluene/methylcyclohexane to give 5.2 g of 4-difluoromethoxybenzonitrile as a white solid, m.p. 36°-37° C.
Reaction SMILES: [F:1][C:2]1[C:10]([O:11][CH3:12])=[CH:9][CH:8]=[CH:7][C:3]=1C(O)=O.C([N:16](C(C)C)CC)(C)C.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.C(OCC)(=O)C>Cl.C(O)(C)(C)C.C1(C)C=CC=CC=1>[F:1][C:2]1[C:10]([O:11][CH3:12])=[CH:9][CH:8]=[CH:7][C:3]=1[NH2:16]
Reactant: CCN(C(C)C)C(C)C
Reactant: COc1cccc(C(=O)O)c1F
Agent: Cl
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CC(C)(C)O
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: COc1cccc(N)c1F
Reaction time: 1 h
Yield: 72.3 %

Procedure:
A solution of 2-fluoro-3-methoxybenzoic acid (5.00 g, 29.39 mmol) and diisopropylethylamine (4.56 g, 35.27 mmol) in a mixture of anhydrous toluene (25 mL) and anhydrous tert-butanol (25 mL) was stirred over activated 4 A molecular sieves (4 g) for 1 h. Diphenyl phosphoryl azide (9.71 g, 35.27 mmol) was added and the mixture was heated at reflux for 15 h. The reaction mixture was cooled and filtered. To the filtrate was added ethyl acetate (200 mL) and the solution was washed with water (2×100 mL) and brine (100 mL). The organic phase was separated and dried over MgSO4. Filtration followed by concentration under reduced pressure gave crude tert-butyl 2-fluoro-3-methoxyphenylcarbamate. The crude product was dissolved in a solution of 6M HCl in ethyl acetate (20 mL, 0.12 mol) and the mixture stirred at rt for 2 h. The resulting precipitate was filtered and dried. The solid was taken up in a saturated aqueous solution of sodium hydrogen carbonate (50 mL) and the mixture extracted with dichloromethane (2×100 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to afford 2-fluoro-3-methoxyaniline (3.00 g, 72%) as brown oil, which was taken on without further purification. 1H NMR (400 MHz, DMSO-d6) δ 6.80-7.02 (m, 3H), 3.82 (s, 3H); LC-MS (ESI) m/z 142 (M+H)+.
Reaction SMILES: [CH:1]1([C:6]2[NH:14][C:13]3[C:12](=[O:15])[N:11]([CH2:16][CH2:17][CH3:18])[C:10](Cl)=[N:9][C:8]=3[N:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[CH3:21][O:22][C:23](=[O:32])[C:24]1[CH:29]=[CH:28][C:27]([CH2:30][NH2:31])=[CH:26][CH:25]=1.C(N(C(C)C)CC)(C)C.O>CN1CCCC1=O>[CH3:21][O:22][C:23](=[O:32])[C:24]1[CH:29]=[CH:28][C:27]([CH2:30][NH:31][C:10]2[N:11]([CH2:16][CH2:17][CH3:18])[C:12](=[O:15])[C:13]3[NH:14][C:6]([CH:1]4[CH2:5][CH2:4][CH2:3][CH2:2]4)=[N:7][C:8]=3[N:9]=2)=[CH:26][CH:25]=1
Reactant: COC(=O)c1ccc(CN)cc1
Reactant: CCCn1c(Cl)nc2nc(C3CCCC3)[nH]c2c1=O
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN1CCCC1=O
Product: CCCn1c(NCc2ccc(C(=O)OC)cc2)nc2nc(C3CCCC3)[nH]c2c1=O
Temperature: 150 °C
Yield: 50.2 %

Procedure:
To a solution of 8-cyclopentyl-2-chloro-1-propyl-1,7-dihydro-purin-6-one (0.15 g, 0.535 mmol) in N-methyl-pyrrolidone (1 ml) was added methyl-4-(amino methyl)benzoate hydrochloride (0.216 g, 1.07 mmol) followed by diisopropylethylamine (242 mg, 1.874 mmol) and the resulting reaction mixture was heated at 150° C. overnight. To the reaction mixture was added water and the product was extracted with ethyl acetate. The ethyl acetate layer was dried over anhydrous sodium sulphate and concentrated under vacuum. The crude product was purified by preparative TLC using 5% methanol in dichloromethane as solvent system to give the product (0.11 g, 50%) as an off white solid.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[Cl:6][C:7]1[CH:12]=[CH:11][N:10]2[N:13]=[C:14]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[CH:15]=[C:9]2[CH:8]=1.[OH-].[NH4+].CN(C)[CH:27]=[O:28]>>[Cl:6][C:7]1[CH:12]=[CH:11][N:10]2[N:13]=[C:14]([C:16]3[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=3)[C:15]([CH:27]=[O:28])=[C:9]2[CH:8]=1
Reactant: CN(C)C=O
Reactant: Fc1ccc(-c2cc3cc(Cl)ccn3n2)cc1
Agent: [NH4+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Product: O=Cc1c(-c2ccc(F)cc2)nn2ccc(Cl)cc12
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Phosphorous oxychloride (0.6 mL, 6.4 mmol) was added to N,N-dimethylformamide (10 mL) and the resulting mixture stirred at room temperature for 10 minutes. 5-Chloro-2-(4-fluorophenyl)pyrazolo[1,5-α]pyridine (1.0 g, 4.1 mmol) was added and the reaction mixture was stirred at room temperature for 12 hours. The reaction mixture was poured into ice-water and neutralized to pH 7 with aquous ammonium hydroxide. The resulting slurry was extracted with dichloromethane (3×40 mL). The combined organics were washed with brine, dried (magnesium sulfate), filtered and concentrated to give, after recrystallization from acetonitrile, 5-chloro-2-(4-fluorophenyl)pyrazolo [1,5-α]pyridine-3-carbaldehyde (0.95 g, 85%) as a white solid. 1H-NMR (CDCl3): δ10.07 (s, 1H), 8.49 (d, 1H), 8.44 (d, 1H), 7.78 (q, 2H), 7.22 (t, 2H), 7.07 (dd, 1H); MS m/z 275 (M+1).
Reaction SMILES: S(=O)(=O)(O)O.COC(=O)[NH:9][CH2:10][C@H:11]([CH2:16][C:17](=[O:27])N[C@H](C1C=CC=CC=1)C)[CH2:12][CH:13]([CH3:15])[CH3:14].[OH-:29].[Na+]>>[CH3:15][CH:13]([CH2:12][C@H:11]([CH2:10][NH2:9])[CH2:16][C:17]([OH:27])=[O:29])[CH3:14]
Reactant: [OH-]
Reactant: COC(=O)NC[C@H](CC(=O)N[C@@H](C)c1ccccc1)CC(C)C
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: CC(C)C[C@H](CN)CC(=O)O
Temperature: 117.5 °C
Yield: 40.4 %

Procedure:
A 0.2 1 reactor was loaded with 70% sulfuric acid (200 g) containing compound 26 (10 g, 0.031 mole), and was heated to 115-120° C. for 5-10 hours, and then cooled to room temperature, i.e., about 20° to about 25° C. An aqueous 40% sodium hydroxide solution was added in an amount sufficient to provide a pH of 1. The solution was then extracted with 35 ml of iso-butanol, the organic layer was separated, and Bu3N was added in an amount sufficient to provide a pH of 4. The (S)-Pregabalin was precipitated, filtered, and washed with 10 ml of iso-butanol. After drying at 55° C. under vacuum, (S)-Pregabalin was obtained as white crystals in a 40.4% yield. Purity: 99.95% area by HPLC.
Reaction SMILES: C([O:5]O)(C)(C)C.[CH3:7][O:8][C:9]([C:11]1[C@H:12]2[CH2:24][CH:23]=[C:22]([CH2:25][OH:26])[C@@H:13]2[C@H:14]([O:17][C:18](=[O:21])[NH:19][CH3:20])[O:15][CH:16]=1)=[O:10].S([O-])([O-])(=O)=S.[Na+].[Na+]>ClCCl.[V]>[CH3:7][O:8][C:9]([C:11]1[C@H:12]2[CH2:24][C@@H:23]3[O:5][C@@:22]3([CH2:25][OH:26])[C@@H:13]2[C@H:14]([O:17][C:18](=[O:21])[NH:19][CH3:20])[O:15][CH:16]=1)=[O:10]
Reactant: CC(C)(C)OO
Reactant: CNC(=O)O[C@@H]1OC=C(C(=O)OC)[C@H]2CC=C(CO)[C@H]12
Agent: [V]
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CNC(=O)O[C@@H]1OC=C(C(=O)OC)[C@H]2C[C@@H]3O[C@@]3(CO)[C@H]12
Reaction time: 0.33 h
Yield: 89 %

Procedure:
85 mg of vanadium oxyacetylacetonate were dissolved in dichloromethane followed by dropping 7.1 ml of t-butylhydroperoxide (3.0 M, 2,2,4-trimethylpentane solution) and stirring for 20 minutes. Next, a dichloromethan solution of 3.0 g of (1S,4aS,7aR)-7-(hydroxymethyl)-1-(methylcarbamoyloxy)-1,4a,5,7a-tetrahydrocyclopenta[c]pyrane-4-carboxylic acid methylester was dropped thereinto followed by stirring for 17 hours at room temperature. The reaction mixture was poured into saturated aqueous sodium thiosulfate solution and extracted with ethyl acetate. After washing the organic phase with brine, it was dried over magnesium sulfate. After distilling off the solvent under reduced pressure, the residue was purified by silica gel chromatography to obtain colorless needles from the hexane-ether eluate in the form of (1S,4aS,6S,7R,7aR)-6,7-epoxy-7-(hydroxymethyl)-1-(methylcarbamoyloxy)-1,4a,5,6,7,7a-hexahydrocyclopenta[c]pyrane-4-carboxylic acid methylester (2.9 g, yield: 89%). The physicochemical properties of this compound are described in Table 9, Compound No. 45.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[C:13]=1[C:19]1[N:24]=[CH:23][CH:22]=[CH:21][N:20]=1)=[O:11].Br[C:26]1[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][N:27]=1>>[Cl:32][C:29]1[CH:30]=[CH:31][C:26]([NH:1][CH2:2][C@@H:3]2[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]2[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[C:13]=2[C:19]2[N:20]=[CH:21][CH:22]=[CH:23][N:24]=2)=[O:11])=[N:27][CH:28]=1
Reactant: C[C@@H]1CCCN(C(=O)c2cccc(F)c2-c2ncccn2)[C@@H]1CN
Reactant: Clc1ccc(Br)nc1
Product: C[C@@H]1CCCN(C(=O)c2cccc(F)c2-c2ncccn2)[C@@H]1CNc1ccc(Cl)cn1

Procedure:
The title compound was prepared following the same general protocol as described for Example A44 using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(3-fluoro-2-(pyrimidin-2-yl)phenyl)methanone and 2-bromo-5-chloropyridine. ESI-MS (m/z): 440 [M+1]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[NH:9][C:10]1[N:14]([CH3:15])[C:13]2[C:16]3[CH2:17][C:18]([CH3:28])([CH3:27])[O:19][C:20]=3[C:21]([C:23](OC)=[O:24])=[CH:22][C:12]=2[N:11]=1.[F:29][C:30]([F:39])([F:38])[C:31]1[CH:32]=[CH:33][C:34]([NH2:37])=[N:35][CH:36]=1.C[Al](C)C>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[NH:9][C:10]1[N:14]([CH3:15])[C:13]2[C:16]3[CH2:17][C:18]([CH3:28])([CH3:27])[O:19][C:20]=3[C:21]([C:23]([NH:37][C:34]3[CH:33]=[CH:32][C:31]([C:30]([F:38])([F:29])[F:39])=[CH:36][N:35]=3)=[O:24])=[CH:22][C:12]=2[N:11]=1
Reactant: COC(=O)c1cc2nc(Nc3c(F)cccc3Cl)n(C)c2c2c1OC(C)(C)C2
Reactant: Nc1ccc(C(F)(F)F)cn1
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: Cn1c(Nc2c(F)cccc2Cl)nc2cc(C(=O)Nc3ccc(C(F)(F)F)cn3)c3c(c21)CC(C)(C)O3
Yield: 19 %

Procedure:
The title compound was prepared by following the procedure as described for Example-137 using methyl 2-((2-chloro-6-fluorophenyl)amino)-1,7,7-trimethyl-7,8-dihydro-1H-benzofuro[4,5-d]imidazole-5-carboxylate (step-7 of Intermediate-49, 0.100 g, 0.247 mmol) and 5-(trifluoromethyl)pyridin-2-amine (0.053 g, 0.371 mmol), trimethyl aluminium (2M solution in toluene) (1 mL) and dry toluene (5.0 mL) to afford 0.025 g of the desired product. 1HNMR (DMSO-d6): δ 1.61 (s, 6H), 3.49 (s, 2H), 3.57 (s, 3H), 7.17-7.31 (m, 4H), 8.22 (d, J=9 Hz, 1H), 8.44 (d, J=9 Hz, 1H), 8.75 (s, 1H), 8.79 (s, 1H), 10.39 (s, 1H), 10.55 (s, 1H); MS [M+H]+: 534.21.
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[CH:3]([OH:8])[C:4]([F:7])([F:6])[F:5].N1C=CC=CC=1.[Cl-].[C:18]([O:25][CH2:26][CH:27]([CH2:32][CH3:33])[CH2:28][CH2:29][CH2:30][CH3:31])(=[O:24])/[CH:19]=[CH:20]\[C:21]([O-])=[O:22].C(OCC)(=O)C>C(#N)C>[C:18]([O:25][CH2:26][CH:27]([CH2:32][CH3:33])[CH2:28][CH2:29][CH2:30][CH3:31])(=[O:24])/[CH:19]=[CH:20]\[C:21]([O:8][CH:3]([C:4]([F:7])([F:6])[F:5])[C:2]([F:10])([F:9])[F:1])=[O:22]
Reactant: OC(C(F)(F)F)C(F)(F)F
Reactant: CCCCC(CC)COC(=O)/C=C\C(=O)[O-]
Agent: [Cl-]
Solvent: CC#N
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CCCCC(CC)COC(=O)/C=C\C(=O)OC(C(F)(F)F)C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 13.9 %

Procedure:
1,1,1,3,3,3-Hexafluoro-2-propanol (HFIP, 33.7 g, 201 mmol) and pyridine (17.9 mL, 220 mmol) were dissolved in acetonitrile (80 mL) and added dropwise with mono(2-ethylhexyl) maleate chloride (41.8 g, 220 mmol), while the internal temperature was kept at 20° C. or lower by cooling the solution on an ice bath. After completion of the addition, the reaction mixture was stirred at room temperature for 1hour and added with ethyl acetate, and the organic phase was washed with 1 mol/L aqueous hydrochloric acid and a saturated sodium chloride aqueous solution. Then, the organic layer was collected, and the organic solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/chloroform=10/0 to 7/3 (v/v)) to obtain the target compound (10.6 g, yield: 14%) as a colorless transparent oily compound.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10]([C:12](=[O:14])[CH3:13])=[CH:9][CH:8]=[CH:7]2.[BH4-].[Na+].CC(C)=O>C(O)C>[OH:14][CH:12]([C:10]1[CH:9]=[CH:8][CH:7]=[C:6]2[C:11]=1[C:2]([OH:1])=[CH:3][CH:4]=[CH:5]2)[CH3:13]
Reactant: CC(=O)c1cccc2cccc(O)c12
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: CC(C)=O
Product: CC(O)c1cccc2cccc(O)c12
Reaction time: 0.5 h
Yield: 95.1 %

Procedure:
1040 g of 8'-hydroxy-1'-acetonaphthone was dissolved in 8.5 liters of ethanol, to which 131 g of sodium borohydride was added while ice-cooling in order not to allow the temperature of the reaction solution to exceed 30° C. After agitation for 30 minutes at room temperature, excess sodium borohydride was decomposed with 1 liter of acetone. The reaction solution was concentrated under reduced pressure, after which 4 liters of 1N hydrochloric acid was added, followed by extraction with ethyl acetate. The resultant organic phase was washed with a saturated saline solution to remove the excess acid. After drying with anhydrous magnesium sulfate, the solvent was distilled off and a small amount of hexane was added to the resultant residue for crystallization. The crystals were collected by filtration to obtain 1000 g of the captioned compound as light brown crystals.
Reaction SMILES: [CH:1]1([N:7]2[CH2:11][CH2:10][CH2:9][CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:12]([I:16])[CH2:13][CH2:14][CH3:15].C(=O)(O)[O-].[K+]>CO>[I-:16].[CH2:12]([N+:7]1([CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[CH2:11][CH2:10][CH2:9][CH2:8]1)[CH2:13][CH2:14][CH3:15]
Reactant: CCCCI
Reactant: C1CCC(N2CCCC2)CC1
Agent: O=C([O-])O
Agent: [K+]
Solvent: CO
Product: CCCC[N+]1(C2CCCCC2)CCCC1
Product: [I-]
Temperature: 25 °C
Reaction time: 48 h
Yield: 86.4 %

Procedure:
To a solution of 50 gm (0.326 mole) of N-cyclohexylpyrrolidine in 600 ml anhydrous methanol, 120 gm (0.652 mole) of butyl iodide is added. The reaction is mechanically stirred for 48 hours at room temperature. Then, an additional equivalent of butyl iodide and one equivalent (33.7 gm; 0.326 mole) of potassium bicarbonate are added and the reaction is stirred at refluxing temperature for 72 hours. The reaction mixture is concentrated under reduced pressure on a rotary evaporator to give an off-white-colored solid material. The solids are rinsed several times with chloroform and filtered after each rinse. All the chloroform rinses are combined and concentrated to give a white powder whose NMR data is acceptable for the desired quaternary ammonium iodide salt. The reaction affords 95 gm (86% yield) of the product. The iodide salt is purified by recrystallization. This is done by completely dissolving the iodide salt in acetone and then precipitating by the addition of ethyl ether to the acetone solution. The procedure gives 87 gm of white powder with very clean 1H and 13C-NMR spectra for the product (N-butyl-N-cyclohexylpyrrolidinium iodide).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:20][CH3:21])=[C:6]([C:8]([CH3:19])([CH3:18])[CH2:9][C:10](N2CCOCC2)=[O:11])[CH:7]=1.[CH3:22][Li]>C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:20][CH3:21])=[C:6]([C:8]([CH3:18])([CH3:19])[CH2:9][C:10](=[O:11])[CH3:22])[CH:7]=1
Reactant: COc1ccc(F)cc1C(C)(C)CC(=O)N1CCOCC1
Reactant: [Li]C
Solvent: C1CCOC1
Product: COc1ccc(F)cc1C(C)(C)CC(C)=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 3-(5-fluoro-2-methoxyphenyl)-3-methyl-1-morpholin-4-ylbutan-1-one (0.59 g) in THF (1 mL) stirred under argon and cooled on dry ice/acetone was added methyl lithium (1.4 M in pentane, 2 mL) over 2 minutes. The mixture was stirred for 30 minutes and quenched with EtOH (0.3 mL). The mixture was warmed to room temperature and 1 mL of water was added. The organic phase was separated, washed, dried, filtered, and evaporated. The residue was fractionated over a short column of silica gel (eluent: hexanes-methylene chloride (1:1)) to give the title compound as an oil (0.36 g).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[C@H:5]([CH2:14][C:15]1[CH:20]=[CH:19][C:18](O)=[CH:17][CH:16]=1)[NH:6]C(OC(C)(C)C)=O)[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH3:29][OH:30].C(Cl)Cl.[CH3:34][N:35]([CH:37]=O)C>>[C:29]1([O:30][C:18]2[CH:17]=[CH:16][C:15]([CH2:14][C@H:5]([NH2:6])[C:4]([O:3][CH2:1][CH3:2])=[O:22])=[CH:20][CH:19]=2)[C:20]2[C:15](=[CH:16][CH:34]=[N:35][CH:37]=2)[CH:14]=[CH:5][N:6]=1
Reactant: CO
Reactant: CCOC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OC(C)(C)C
Reactant: CN(C)C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: CCOC(=O)[C@@H](N)Cc1ccc(Oc2nccc3ccncc23)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 71 %

Procedure:
A mixture of N-(BOC)-(S)-tyrosine ethyl ester (1.79 g, 5.80 (mmol) potassium carbonate (0.80 g, 5.80 mmol) and Intermediate 12 (1.0 g, 6.08 mmol) in dry DMF (10 ml) was stirred at room temperature for 18 h, and at 40° for 18 h. The DMF was removed in vacuo and the residue partitioned between EtOAc (80 ml) and 10% aqueous Na2CO3 (20 ml). The phases were separated and the aqueous layer re-extracted with EtOAc (2×20 ml). The combined organic extracts were washed with brine (10 ml), dried (Na2SO4) and evaporated in vacuo to afford a new colourless oil. Chromatography (silica; 2.5% MeOH/DCM) afforded reasonably pure N-t-butoxycarbonyl protected title compound (1.81 g, 71%). This material was dissolved in EtOAc (40 ml) and HCl gas was bubbled through the stirred solution for 1 min. then the mixture was stirred for an additional 0.5 h. The volatiles were removed in vacuo affording a yellow solid which was partitioned between EtOAc (80 ml) and saturated aqueous NaHCO3 (20 ml). The phases were separated and the aqueous layer re-extracted with EtOAc (2×20 ml). The combined organic extracts were washed with brine (10 ml), dried (Na2SO4) and evaporated in vacuo. The obtained oil was chromatographed (silica; 5% MeOH/DCM) to afford the title compound as a near colourless oil (0.87 g, 62%) δH (CDCl3) 9.77 (1H, s), 8.75 (1H, d, J. 5.8 Hz), 8.10 (1H, d, J 5.8 Hz), 7.58 (1H, d, J 5.8 Hz), 7.29 (2H, d, J 8.4 Hz), 7.25 (1 H, d, J 5.9 Hz), 7.21 (2H, d, J 8.4 Hz), 4.22 (2H, q, J 7/1 Hz), 3.80-3.70 (1H, obscured m), 3.15 (1H, dd, J 13.6, 5.1 Hz), 2.88 (1H, dd, J 13.6, 8.0 Hz) 1.30 (3H, t, J 7.1 Hz) and 0.78 (2H, br s); m/z (ES+, 70V) 324 (MH+).
Reaction SMILES: [C@H:1]1([OH:8])[CH2:6][CH2:5][CH2:4][C@H:3]([OH:7])[CH2:2]1.[C:9](OC=C)(=[O:11])[CH3:10].[C:15]([O:19]C)(C)(C)[CH3:16]>>[C:9]([O:7][C@H:3]1[CH2:4][CH2:5][CH2:6][C@@H:1]([O:8][C:15](=[O:19])[CH3:16])[CH2:2]1)(=[O:11])[CH3:10]
Reactant: C=COC(C)=O
Reactant: O[C@H]1CCC[C@H](O)C1
Reactant: COC(C)(C)C
Product: CC(=O)O[C@@H]1CCC[C@H](OC(C)=O)C1
Reaction time: 24 h
Yield: 23 %

Procedure:
30 g of a 60 to 40 mixture of cis/trans-cyclohexane-1,3-diol are dissolved in 900 ml of methyl tert-butyl ether, 100 ml of vinyl acetate are added and 1.7 g of lipase (Chirazyme L1 lyo.) are added (20° C.). After 24 h, the protein is filtered off and the solvent is removed. The remaining oil is taken up in 1000 ml of cyclohexane and washed four times with 150 ml of water. The organic phase is removed on a rotary evaporator. 10 g of cis-1,3-diacetoxycyclohexane are obtained as an oil (23% yield based on the cis/trans mixture, 95% cis).