Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[CH:2]([C:4]1[C:17]2[S:16](=[O:19])(=[O:18])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[O:9][C:8]=2[CH:7]=[CH:6][CH:5]=1)[CH3:3].Cl(O)(=O)(=O)=O>C(O)(=O)C.[OH-].[OH-].[Pd+2]>[CH2:2]([C:4]1[C:17]2[S:16](=[O:19])(=[O:18])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[O:9][C:8]=2[CH:7]=[CH:6][CH:5]=1)[CH3:3]
Reactant: CC(O)c1cccc2c1S(=O)(=O)c1ccccc1O2
Agent: [Pd+2]
Agent: [O-][Cl+3]([O-])([O-])O
Agent: [OH-]
Solvent: CC(=O)O
Product: CCc1cccc2c1S(=O)(=O)c1ccccc1O2

Procedure:
A solution of 1-(1-hydroxyethyl)phenoxathiin 10,10-dioxide (590.2) g) in acetic acid (5.4 L) containing 70% aqueous perchloric acid (250 mL) was blanketed with nitrogen and 65 g of Pearlman's catalyst (20% palladium hydroxide on carbon, Aldrich Chemical Co., Milwaukee, Wis.) was added. The atmosphere above the reaction mixture was replaced by successive evacuation and flushing with nitrogen, and then the nitrogen was displaced by successive evacuations and flushing with hydrogen. The reaction mixture was then stirred vigorously and hydrogen was added until no more was taken up. The catalyst was filtered off and rinsed with acetic acid. The combined acetic acid solutions were diluted to approximately 23.5 L with water and stirred overnight at room temperature. The resulting off-white solid was collected by filtration, washed with water (2 L) and dried at 50° C. in a vacuum oven, giving 1-ethylphenoxathiin 10,10-dioxide. After recrystallization from ethyl acetate/hexanes it had a melting point of 114°-115° C. Recrystallization from ethyl acetate/pentane appeared to give a different crystalline form, mp 101°-103° C.
Reaction SMILES: [CH:1](Cl)=[CH:2][CH:3]=[CH:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].C(Cl)CCCCCCC=CC=CC.[C:27]([O-:30])(=[O:29])[CH3:28].[K+].C(O)(=O)C>C(OCC)(=O)C.O>[C:27]([O:30][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH:8]=[CH:9][CH:10]=[CH:11][CH3:12])(=[O:29])[CH3:28]
Reactant: CCCCCCCCC=CC=CCl
Reactant: CC(=O)[O-]
Agent: CC=CC=CCCCCCCCCl
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: O
Product: CC=CC=CCCCCCCCOC(C)=O
Reaction time: 1 h

Procedure:
The particulars of the conversion of the dodecadienyl chloride to the alcohol that is CM pheromone are set forth below. To a 100 mL glass round-bottomed flask equipped with a reflux condenser, a stir bar and a nitrogen atmosphere were added 1.0 g (5 mmol) of 8,10-dodecadien-1-yl chloride, 8.1 g (8.3 mmol) potassium acetate and 40 ml of glacial acetic acid. This mixture was placed in a 150° C. oil bath for 76 hours, after which time GC analysis indicated that the reaction was >98% complete. The reaction mixture was poured into 100 ml of water and ice and stirred for one hour. Ethyl acetate (100 ml) was added and the organic phase was separated from the aqueous phase. The organic phase was washed with 4×50 mL of sodium bicarbonate-saturated water until the pH of the water was neutral, dried with sodium sulfate, filtered and the organic solvent was removed under reduced pressure to yield 8,10-dodecadienyl acetate as a yellow liquid. This acetate was dissolved into 30 ml of methanol and 1 ml of 6 M sodium hydroxide and stirred at room temperature for two hours. Methanol was removed under reduced pressure, 10 mL of heptane and 1 mL of 1 M HCl were added and the aqueous phase removed. The organic phase was placed in a -20° C. freezer for 18 hours. White crystals were removed by filtration to yield 200 mg of E,E-8,10-dedecadienol. Gas chromatography, 1H NMR and 13C NMR analysis of the product were identical to a standard sample of E,E-8,10-dodecadienol.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].[CH2:9]([OH:12])[C:10]#[CH:11].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N)CCC>C1COCC1.CC([O-])=O.CC([O-])=O.[Pd+2].[Cu]I>[OH:12][CH2:9][C:10]1[O:8][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[CH:11]=1
Reactant: Oc1ccccc1I
Reactant: C#CCO
Agent: [Cu]I
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCCCN
Solvent: C1CCOC1
Product: OCc1cc2ccccc2o1
Temperature: 40 °C

Procedure:
2-Iodophenol (500 mg, 2.27 mmol), propargyl alcohol (265 μl, 4.54 mmol), Pd(OAc)2, (5.1 mg, 0.03 mmol), triphenylphosphine (12 mg, 0.046 mmol), n-butylamine (450 μL, 4.5 mmol) and CuI (8.6 mg, 0.045 mmol) were combined in 4.5 mL of THF and the mixture was heated at 40° C. under nitrogen for 36 h. The mixture was cooled to room temperature and the solvents were removed in vacuo and the residue purified by SiO2 column chromatography on 100 g of silica gel, eluting with 20% ethyl acetate in hexanes. 2-(Hydroxymethyl)benzofuran was obtained by concentration of the product containing fractions. [Kudu, N. G.; Pal, M.; Mahanty, J. S.; Dasgupta, F. K. JCS Chem. Com. 1992, 41]
Reaction SMILES: Br[C:2]1[C:3]([OH:12])=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[B:13]1(B2OC(C)(C)C(C)(C)O2)[O:17]C(C)(C)C(C)(C)[O:14]1.C([O-])(=O)C.[K+].C(Cl)Cl>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.[Fe+2].O1CCOCC1>[O:12]=[C:3]1[C:2]([B:13]([OH:17])[OH:14])=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4]1
Reactant: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Reactant: Oc1nc2ccccc2cc1Br
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: C1COCCO1
Solvent: ClCCl
Product: O=c1[nH]c2ccccc2cc1B(O)O
Temperature: 90 °C
Reaction time: 8 h
Yield: 71.2 %

Procedure:
To a microwave vial was added 3-bromo-2-hydroxyquinoline (50 mg, 0.223 mmol), bis(pinacolato)diboron (113 mg, 0.446 mmol), potassium acetate (66 mg, 0.669 mmol), PdCl2(dppf). CH2Cl2 (18.22 mg, 0.022 mmol), and dppf (12.37 mg, 0.022 mmol), followed by addition of 1,4-dioxane (6 mL). The reaction mixture was purged with N2 and stirred under N2 atmosphere at 90° C. overnight. The reaction mixture was filtered through a disposable filter funnel, concentrated in vacuo, and purified by silica gel chromotography (10% to 60% EtOAc in heptane) to afford (2-oxo-1,2-dihydroquinolin-3-yl)boronic acid (30 mg, MS: 190.1 [M+H+].)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]1[CH:11]=[N:12][C:13]([CH:15]=O)=[CH:14][C:5]2=1.[OH-].[NH4+:18].II.[O-]S([O-])(=S)=O.[Na+].[Na+]>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]1[CH:11]=[N:12][C:13]([C:15]#[N:18])=[CH:14][C:5]2=1
Reactant: [NH4+]
Reactant: O=Cc1cc2c(cn1)[nH]c1ccc(Br)cc12
Agent: II
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: C1CCOC1
Product: N#Cc1cc2c(cn1)[nH]c1ccc(Br)cc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
6-bromo-9H-pyrido[3,4-b]indole-3-carbaldehyde (30 mg, 0.11 mmol) was suspended in 100 ul of THF. Ammonium hydroxide (1 mL) and iodine (31 mg, 0.12 mmol) were added and the mixture was stirred at room temperature for 1 hour. Upon completion, Na2S2O3 (5 ml) was added and was extracted 3× with diethyl ether. Material was used in the next step without further purification.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]([S:12][C:13]2[S:14][C:15]([CH2:19][C:20]([O:22]CC)=[O:21])=[C:16]([CH3:18])[N:17]=2)=[N:8][CH:9]=[CH:10][CH:11]=1)=[O:5])C.CO.[OH-].[Na+]>O>[C:20]([CH2:19][C:15]1[S:14][C:13]([S:12][C:7]2[C:6]([C:4]([OH:5])=[O:3])=[CH:11][CH:10]=[CH:9][N:8]=2)=[N:17][C:16]=1[CH3:18])([OH:22])=[O:21]
Reactant: CCOC(=O)Cc1sc(Sc2ncccc2C(=O)OCC)nc1C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1nc(Sc2ncccc2C(=O)O)sc1CC(=O)O
Temperature: 0 °C
Reaction time: 3 h
Yield: 85.4 %

Procedure:
To a mixture of 737 mg (2.09 mmol) of the title compound of Example 1, 70 ml of methanol, and 30 ml of water chilled to 0° C. in an ice bath was added 210 mg (5.22 mmol, 2.5 equivalents) of sodium hydroxide. After the sodium hydroxide had dissolved, the ice bath was removed and the mixture was allowed to stir at room temperature for 3 hours. The solvent was removed by rotary evaporation and the residue was diluted with water, chilled to 0° C. in an ice bath, and acidified with aqueous 6N HCl solution until precipitation had ceased. The precipitate was collected by filtration (washed with cold water) and was dried under vacuum to yield 554 mg (85%) of the title compound, mp 233°-235° C. 1H NMR (DMSO-d6): δ 2.29 (3H, s), 3.85 (2H, s), 7.38 (1H, dd, J=8, 5), 8.33 (1H, d, J=8), 8.63 (1H, d, J=5). FAB MS (m/e): 311 (M+ +1), 265, 233, 119 (base).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([S:12](=[O:25])(=[O:24])[NH:13][C:14]2[CH:15]=[CH:16][C:17]3[CH2:21][O:20][B:19]([OH:22])[C:18]=3[CH:23]=2)=[C:6]([CH2:8][C:9]([OH:11])=O)[CH:7]=1.[CH2:26]([NH2:28])[CH3:27].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>CN(C=O)C.CCOC(C)=O>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([S:12](=[O:24])(=[O:25])[NH:13][C:14]2[CH:15]=[CH:16][C:17]3[CH2:21][O:20][B:19]([OH:22])[C:18]=3[CH:23]=2)=[C:6]([CH2:8][C:9]([NH:28][CH2:26][CH3:27])=[O:11])[CH:7]=1
Reactant: Nc1ccc(S(=O)(=O)Nc2ccc3c(c2)B(O)OC3)c(CC(=O)O)c1
Reactant: CCN
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CCNC(=O)Cc1cc(N)ccc1S(=O)(=O)Nc1ccc2c(c1)B(O)OC2
Reaction time: 3 h

Procedure:
To the mixture of 2-(5-amino-2-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)sulfamoyl)phenyl)acetic acid (500 mg, 1.4 mmol) and ethyl amine (2.1 mg, 4.2 mmol) in DMF (5 ml), added PyBOP (730 mg, 1.4 mmol) then triethyl amine (0.4 ml, 3 mmol). Stirring was kept for 3 hours. Diluted with EtOAc, washed with 1N HCl, water and brine. Dried over anhydrous sodium sulfate. Concentrated, the residue was dissolved in DMSO and purified by prep HPLC (SunFire Prep C18 OBD 5 uM 30×50 mm column). The title compound was obtained as white powder. MS calcd for (C17H20BN3O5S): 389.12. MS found (ESI negative): (M−H)−=388.1. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 9.86 (s, 1H), 9.15 (br, 1H), 7.98 (m, 1H), 7.41 (s, 1H), 7.39 (d, J=8.8 Hz, 1H), 7.21 (d, J=8 Hz, 1H), 7.09 (dd, J=8.4 Hz, 1H), 6.44 (d, J=2 Hz, 1H), 6.33 (dd, J=8.8 Hz, 1H), 4.85 (s, 2H), 3.75 (s, 2H), 3.09 (m, 1H), 1.02 (t, J=7.2 Hz, 3H).
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[N:6][CH:5]=[CH:4][N:3]=1.[Cl:9][C:10]1[CH:15]=[CH:14][C:13](B(O)O)=[CH:12][CH:11]=1.[F-].[K+]>C1(C)C=CC=CC=1.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>[Cl:8][C:7]1[C:2]([C:13]2[CH:14]=[CH:15][C:10]([Cl:9])=[CH:11][CH:12]=2)=[N:3][CH:4]=[CH:5][N:6]=1
Reactant: Clc1nccnc1Cl
Reactant: OB(O)c1ccc(Cl)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [F-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: Clc1ccc(-c2nccnc2Cl)cc1
Reaction time: 17.5 h
Yield: 43.6 %

Procedure:
Couple 2,3-dichloropyrazine (0.302 g, 2.03 mmol) and 4-chlorophenylboronic acid (0.320 g, 2.05 mmol), using tetrakis(triphenylphosphine)palladium(0) (0.124 g, 0.107 mmol), and potassium fluoride (0.355 g, 6.11 mmol) in toluene (19 mL) and water (5 mL), at 100° C. for 17.5 hr. Cool the reaction, partition the layers and extract the aqueous layer with ethyl acetate. Wash the combined organic layers with saturated aqueous sodium chloride, dry (magnesium sulfate), concentrate and purify (silica gel chromatography, eluting with 0:100 to 35:65 ethyl acetate:hexanes), to give 2-chloro-3-(4-chlorophenyl)-pyrazine (0.199 g, 44%).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([CH3:13])=[CH:7][C:8](=O)[NH:9]2)=[CH:4][CH:3]=1.[NH4+].[OH-].O=P(Cl)(Cl)[Cl:18]>>[Cl:18][C:8]1[CH:7]=[C:6]([CH3:13])[C:5]2[C:10](=[CH:11][C:2]([Cl:1])=[CH:3][CH:4]=2)[N:9]=1
Reactant: Cc1cc(=O)[nH]c2cc(Cl)ccc12
Reactant: O=P(Cl)(Cl)Cl
Agent: [NH4+]
Agent: [OH-]
Product: Cc1cc(Cl)nc2cc(Cl)ccc12
Temperature: 0 °C
Yield: 72 %

Procedure:
A solution of quinolone 13 (10 g; 51.6 mmol) in 90 ml of POCl3 was refluxed for 2 hours. After cooling, the mixture was poured into 300 g ice-water and neutralized with NH4OH. The resultant precipitate was filtered off and washed with cold H2O. The crude product was recrystallized from 95% ethanol to obtain 8.95 g (72%) of 14. 1H NMR (CDCl3): δ 2.71 (s, 3H); 7.28 (d, 1H); 7.55 (d, 1H); 7.92 (d, 1H); 8.08 (d, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([O:13][CH3:14])[CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[C:7]2[CH3:12].C(=O)([O-])[O-].[Na+].[Na+].[Br:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27](Cl)=[O:28]>CC(C)=O>[Br:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]([NH:1][C:2]1[CH:3]=[C:4]([O:13][CH3:14])[CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[C:7]2[CH3:12])=[O:28]
Reactant: O=C(Cl)CCCCCBr
Reactant: COc1cc(N)c2nccc(C)c2c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)=O
Product: COc1cc(NC(=O)CCCCCBr)c2nccc(C)c2c1
Yield: 61 %

Procedure:
To a mixture of 9.4 g (0.05 mol) of 8-amino-6-methoxy-4-methylquinoline and 8.7 g (0.082 mol) of anhydrous sodium carbonate in 60 ml of acetone was added dropwise a solution of 6-bromohexanoylchloride in 35 ml of acetone. The mixture was heated under reflux for 4 hours, cooled and filtered. The filter cake was washed with with chloroform and the filtrate and wash were combined and concentrated in vacuo to dryness. The residual solid was recrystallized first from ethanol and then from 85% aqueous ethanol to give 10.8 g (61%) of product, mp 111°-113°.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:13]([C:14]([OH:16])=O)=[C:12]([CH3:17])[O:11][N:10]=1.[NH2:18][C:19]1[CH:26]=[C:25]([N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)[C:24]([Cl:33])=[CH:23][C:20]=1[C:21]#[N:22].C(O)(C(F)(F)F)=O.C(Cl)CCl>CN(C1C=CN=CC=1)C.C(Cl)Cl>[NH2:18][C:19]1[CH:26]=[C:25]([N:27]2[CH2:28][CH2:29][N:30]([C:14]([C:13]3[C:9]([C:4]4[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=4[O:2][CH3:1])=[N:10][O:11][C:12]=3[CH3:17])=[O:16])[CH2:31][CH2:32]2)[C:24]([Cl:33])=[CH:23][C:20]=1[C:21]#[N:22]
Reactant: COc1ccccc1-c1noc(C)c1C(=O)O
Reactant: N#Cc1cc(Cl)c(N2CCNCC2)cc1N
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: ClCCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccccc1-c1noc(C)c1C(=O)N1CCN(c2cc(N)c(C#N)cc2Cl)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 52 %

Procedure:
The reaction mixture of 3-(2-methoxyphenyl)-5-methylisoxazole-4-carboxylic acid (10.00 mg, 0.043 mmol), 2-amino-5-chloro-4-(piperazin-1-yl)benzonitrile, 2 TFA (16.6 mg, 0.036 mmol), EDC (9.59 mg, 0.050 mmol) and DMAP (8.73 mg, 0.071 mmol) in DCM (1 mL) was stirred at room temperature overnight. The product was purified by preparative HPLC (0.1% TFA MeOH/H2O) to give 11 mg (52% yield) of the title compound. 1H-NMR (CDCl3, 400 MHz): δ 7.59 (1H, dd, J1=7.5 Hz, J2=1.8 Hz), 7.52-7.46 (1H, m), 7.33 (1H, s), 7.13-6.97 (2H, m), 6.06 (1H, s), 3.84 (2H, s), 3.80 (3H, s), 3.25 (2H, s), 2.98 (2H, s), 2.57 (3H, s), 2.43 (2H, s).
Reaction SMILES: Br.[C:2]([O:5][C@H:6]1[C@@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@H:10]([O:16][C:17](=[O:19])[CH3:18])[C@@H:9]([CH2:20][O:21][C:22](=[O:24])[CH3:23])[O:8][C@@H:7]1[S:25][C:26](=N)N)(=[O:4])[CH3:3].IC[CH2:31][C:32]([OH:34])=[O:33].C(=O)([O-])[O-].[K+].[K+].S(S([O-])=O)([O-])(=O)=O.[K+].[K+].Cl>CC(C)=O.O.C(Cl)(Cl)Cl>[C:2]([O:5][C@H:6]1[C@@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@H:10]([O:16][C:17](=[O:19])[CH3:18])[C@@H:9]([CH2:20][O:21][C:22](=[O:24])[CH3:23])[O:8][C@@H:7]1[S:25][CH2:26][CH2:31][C:32]([OH:34])=[O:33])(=[O:4])[CH3:3]
Reactant: CC(=O)OC[C@H]1O[C@H](SC(=N)N)[C@@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: O=C(O)CCI
Agent: Br
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: ClC(Cl)Cl
Solvent: CC(C)=O
Solvent: O
Product: CC(=O)OC[C@H]1O[C@H](SCCC(=O)O)[C@@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 99.1 %

Procedure:
A mixture of 2-S-(2,3,4,6-tetra-O-acetyl-α-D-mannopyranosyl)-2-thiopseudourea hydrobromide (1) (90 g, 0.185 mol), freshly crystallized 3-iodopropionic acid (37 g, 0.199 mol), potassium carbonate (29.6 g, 0.215 mol), and potassium metabisulfite (37 g, 0.167 mol) in acetone (150 ml) and water (150 ml) is stirred for 45 minutes at room temperature. Hydrochloric acid (5%, 700 ml) and chloroform (700 ml) are added to the mixture. The organic layer is separated and washed with water, dried, and evaporated in vacuo to an oil (80 g, quantitative yield) that is used, without further purification, for the preparation of 3.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[C:6]([Cl:11])[C:3]=1[CH:4]=[O:5].C([O-])([O-])=O.[K+].[K+].[N+:18]([CH3:21])([O-:20])=[O:19]>>[Cl:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[C:6]([Cl:11])[C:3]=1[CH:4]([OH:5])[CH2:21][N+:18]([O-:20])=[O:19]
Reactant: C[N+](=O)[O-]
Reactant: O=Cc1c(Cl)cc(F)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: O=[N+]([O-])CC(O)c1c(Cl)cc(F)cc1Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 2,6-dichloro-4-fluorobenzaldehyde (10.0 g, 51.8 mmol), nitromethane (2 mL) and K2CO3 (3.57 g, 25.9 mmol) was stirred at room temperature for 2 h. The reaction mixture was quenched with water and extracted with EtOAc (2×100 mL). The combined organic layers were washed with water (2×50 mL) and brine (20 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure to provide compound A31-1 (26.0 g, crude) as yellow gum. The crude product was used in the next step without purification.
Reaction SMILES: COC1C=CC(CC[C@@H](O)C)=CC=1.[O:14]([CH2:21][C:22](=[O:24])[CH3:23])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>COC1C=CC(CCC(=O)C)=CC=1>[O:14]([CH2:21][C@@H:22]([OH:24])[CH3:23])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CC(=O)COc1ccccc1
Agent: COc1ccc(CCC(C)=O)cc1
Agent: COc1ccc(CC[C@H](C)O)cc1
Product: C[C@H](O)COc1ccccc1

Procedure:
Phenyl ring-containing 2-butanone derivatives were reduced to the corresponding (S)-alcohols with excellent stereoselectivities and moderate to excellent yields (Table 4). 4-Phenyl-2-butanone (1a) was reduced stereoselectively to produce (S)-4-phenyl-2-butanol ((S)-1b) with excellent chemical and optical yields. The â-diketone 1-phenyl-1,3-butadione (2a) was reduced regio- and stereoselectively to furnish the monohydroxy ketone (S)-3-hydroxy-1-phenyl-1-butanone ((S)-2b) with excellent yield and ee, leaving the other keto group at C-1 intact. (E)-4-Phenyl-3-butene-2-one (3a) was reduced with moderate yield and excellent optical purity to produce the allylic alcohol (S)-4-phenyl-3-butene-2-ol ((S)-3b). The presence of the methoxy group at the para position of the phenyl ring in 4-(4-methoxyphenyl)-2-butanone (4a) affected the ee of the produced (S)-4-(4-methoxyphenyl)-2-butanol ((S)-4-b) (91% ee), which was lower than for (S)-1b. Phenoxy-2-propanone (5a) was reduced with very high yield and optical purity to produce the corresponding (S)-phenoxy-2-propanol ((S)-5b). When the R-chloroketone, 3-chloro-4-(4-chlorophenyl)-2-butanone (6a), was reduced with W110A TESADH, (+)-(2S,3R)-3-chloro-4-(4-chlorophenyl)-2-butanol ((+)-(2S,3R)-6b) was produced with high enantioselectivity (>99% ee) and diastereoselectivity (92:8 mixture of anti- and syn-R-chlorohydrins).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]#[N:9])[CH:5]=[CH:4][CH:3]=1.[OH:10][CH:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]1.C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1)(C)(C)C>C1(C)C=CC=CC=1.CC([O-])=O.CC([O-])=O.[Pd+2]>[C:8]([C:6]1[N:7]=[C:2]([O:10][CH:11]2[CH2:12][CH2:13][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:15][CH2:16]2)[CH:3]=[CH:4][CH:5]=1)#[N:9]
Reactant: N#Cc1cccc(Br)n1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCC(Oc2cccc(C#N)n2)CC1
Temperature: 130 °C

Procedure:
6-Bromo-2-pyridinecarbonitrile (1.00 g, 5.46 mmol), tert-butyl 4-hydroxypiperidine-1-carboxylate (1.10 g, 5.46 mmol), Pd(OAc)2 (61 mg, 0.27 mmol), 2-(di-t-butylphosphino)biphenyl (98 mg, 0.328 mmol) and Cs2(CO3) (3.56 g, 10.93 mmol) were mixed in toluene (20 ml). The reaction was stirred under an N2 atmosphere and heated to 130° C. on an oil bath for 24 h. The solvent was evaporated in vacuo and the remaining separated between EtOAc (500 ml) and water (500 ml). The aqueous phase was extracted with EtOAc (500 ml). The combined organic phases were washed with water (500 ml), dried with Na2SO4 (s), filtered and evaporated in vacuo. Purification by silica gel flash chromatography using a 40 g Biotage column with a gradient of 5-30% EtOAc in heptane giving the title compound as a white solid. Yield: 605 mg (37%). 1H NMR (400 MHz, CDCl3) δ 7.63 (dd, 1H, J=8.4 Hz, J=7.3 Hz), 7.25 (d, 1H, J=7.3 Hz), 6.90 (d, 1H, J=8.4 Hz), 5.21 (m, 1H), 3.74 (m, 2H), 3.25 (m, 2H), 1.95 (m, 2H), 1.68 (m, 2H), 1.44 (s, 9H).
Reaction SMILES: C([CH:3]([C:14]1[C:19]([CH:20]([CH3:22])[CH3:21])=[C:18]([O:23][CH3:24])[N:17]=[C:16]([O:25][CH3:26])[N:15]=1)[C:4]1[CH:5]=[C:6]([C:12]#[N:13])[CH:7]=[C:8]([CH:11]=1)[C:9]#[N:10])#N.[H-].[Na+].CN(C=[O:33])C>>[CH:20]([C:19]1[C:14]([C:3]([C:4]2[CH:5]=[C:6]([C:12]#[N:13])[CH:7]=[C:8]([CH:11]=2)[C:9]#[N:10])=[O:33])=[N:15][C:16]([O:25][CH3:26])=[N:17][C:18]=1[O:23][CH3:24])([CH3:22])[CH3:21]
Reactant: CN(C)C=O
Reactant: COc1nc(OC)c(C(C)C)c(C(C#N)c2cc(C#N)cc(C#N)c2)n1
Agent: [H-]
Agent: [Na+]
Product: COc1nc(OC)c(C(C)C)c(C(=O)c2cc(C#N)cc(C#N)c2)n1
Reaction time: 0.5 h
Yield: 8 %

Procedure:
To a solution of 5-[cyano-(5-isopropyl-2,6-dimethoxy-pyrimidin-4-yl)-methyl]-isophthalonitrile (0.2457 g, 0.707 mmol) in DMF (2.4 mL) was added 60% sodium hydride (0.031 g, 0.778 mmol) and stirred for 30 min. Oxygen was bubbled into reaction mixture for 4 h. The reaction was quenched with saturated ammonium chloride solution and pH was adjusted to ˜6.0 with 1N HCl. Mixture was extracted with ethyl acetate and organic layer was washed with water (2×), dried (MgSO4) and concentrated. The resulting residue was purified by flash column chromatography (silica gel, 10 to 50% ethyl acetate/hexane) to give a white foam (0.018 g, 8%). 1H NMR (300 MHz, CDCl3): δ 8.32 (s, 2H); 8.08 (s, 1H), 4.05 (s, 3H), 3.89 (s, 3H), 3.0-2.8 (m, 1H), 1.19 (s, 3H), 1.42 (s, 3H). Mass spectrum: 337.2 (M+H)+.
Reaction SMILES: [C:1]([OH:24])(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]/[CH:13]=[CH:14]\[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].[CH2:25]([CH2:27][NH2:28])O>CCCC[O-].CCCC[O-].CCCC[O-].CCCC[O-].[Ti+4]>[CH2:2]([C:1]1[O:24][CH2:25][CH2:27][N:28]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH:13]=[CH:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CCCCCCCC/C=C\CCCCCCCCCCCC(=O)O
Reactant: NCCO
Agent: [Ti+4]
Agent: CCCC[O-]
Product: CCCCCCCCC=CCCCCCCCCCCCC1=NCCO1

Procedure:
Following the procedure of Example 10, erucic acid was reacted with ethanolamine in the presence of titanium tetrabutylate as catalyst to form 2-(12-heneicosenyl)-2-oxazoline. The quantities used were as follows:
Reaction SMILES: C[O:2][C:3](=O)[C@@H:4]([N:16]1[C:22](=[O:23])[CH2:21][CH2:20][N:19]([C:24](=[O:33])[NH:25][C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([Cl:32])[CH:27]=2)[C@H:18]([CH3:34])[CH2:17]1)[CH2:5][CH2:6][N:7]1[CH2:14][CH2:13][C:10]2([CH2:12][CH2:11]2)[C@H:9]([OH:15])[CH2:8]1.[BH4-].[Li+]>>[Cl:32][C:28]1[CH:27]=[C:26]([NH:25][C:24]([N:19]2[CH2:20][CH2:21][C:22](=[O:23])[N:16]([C@H:4]([CH2:3][OH:2])[CH2:5][CH2:6][N:7]3[CH2:14][CH2:13][C:10]4([CH2:12][CH2:11]4)[C@H:9]([OH:15])[CH2:8]3)[CH2:17][C@H:18]2[CH3:34])=[O:33])[CH:31]=[CH:30][CH:29]=1
Reactant: COC(=O)[C@H](CCN1CCC2(CC2)[C@H](O)C1)N1C[C@@H](C)N(C(=O)Nc2cccc(Cl)c2)CCC1=O
Agent: [BH4-]
Agent: [Li+]
Product: C[C@@H]1CN([C@H](CO)CCN2CCC3(CC3)[C@H](O)C2)C(=O)CCN1C(=O)Nc1cccc(Cl)c1
Yield: 46 %

Procedure:
In analogy to the procedure described in intermediate 6A, (S)-2-[(R)-4-(3-chloro-phenylcarbamoyl)-3-methyl-7-oxo-[1,4]diazepan-1-yl]-4-((S)-4-hydroxy-6-aza-spiro[2.5]oct-6-yl)-butyric acid methyl ester was reduced with lithium borohydride (2 h) to give 46% of the title compound as white solid. MS: 479.4 (MH+, 1Cl).