Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:49])[NH:4][C@H:5]([C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@H:12]1[C:16]1[NH:17][CH:18]=[C:19]([C:21]2[CH:26]=[CH:25][C:24]([C:27]3[CH:32]=[CH:31][C:30]([NH:33][C:34]([C:36]4[CH:37]=[N:38][C:39]([N:42]5[CH2:47][CH2:46][NH:45][CH2:44][C@H:43]5[CH3:48])=[CH:40][CH:41]=4)=[O:35])=[CH:29][CH:28]=3)=[CH:23][CH:22]=2)[N:20]=1)=[O:10])[CH:6]([CH3:8])[CH3:7].[CH3:50][C:51]1([CH3:57])[CH2:53][C@@H:52]1[C:54](O)=[O:55].CN(C)C=O.F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>>[CH3:1][O:2][C:3](=[O:49])[NH:4][C@H:5]([C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@H:12]1[C:16]1[NH:17][CH:18]=[C:19]([C:21]2[CH:26]=[CH:25][C:24]([C:27]3[CH:32]=[CH:31][C:30]([NH:33][C:34]([C:36]4[CH:37]=[N:38][C:39]([N:42]5[CH2:47][CH2:46][N:45]([C:54]([C@H:52]6[CH2:53][C:51]6([CH3:57])[CH3:50])=[O:55])[CH2:44][C@H:43]5[CH3:48])=[CH:40][CH:41]=4)=[O:35])=[CH:29][CH:28]=3)=[CH:23][CH:22]=2)[N:20]=1)=[O:10])[CH:6]([CH3:8])[CH3:7]
Reactant: CC1(C)C[C@@H]1C(=O)O
Reactant: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1nc(-c2ccc(-c3ccc(NC(=O)c4ccc(N5CCNC[C@H]5C)nc4)cc3)cc2)c[nH]1)C(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1nc(-c2ccc(-c3ccc(NC(=O)c4ccc(N5CCN(C(=O)[C@H]6CC6(C)C)C[C@H]5C)nc4)cc3)cc2)c[nH]1)C(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 57.8 %

Procedure:
To a mixture of the hydrochloride salt of ((S)-2-methyl-1-{(S)-2-[4-(4′-{[6-((R)-2-methyl-piperazin-1-yl)-pyridine-3-carbonyl]-amino}-biphenyl-4-yl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-propyl)-carbamic acid methyl ester (60.0 mg, 0.0775 mmol) and (S)-(+)-2,2-dimethylcyclopropane carboxylic acid (10.6 mg, 0.093 mmol) in N,N-dimethylformamide (1.5 mL, 19 mmol) at RT was added N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (35.4 mg, 0.093 mmol) and N,N-diisopropylethylamine (54.0 uL, 0.310 mmol). The reaction mixture was stirred at RT overnight, and then concentrated. The residue was redissolved in 1:1 acetic acid:water (6 mL), filtered and purified by reverse phase preparative HPLC. Desired fractions were combined and freeze dried to give a white solid 34.1 mg). (m/z): [M+H]+ calcd for C43H52N8O5 761.42 found 761.7. 1H NMR (CD3OD, 400 MHz) δ (ppm): 8.76 (s, 1H), 8.18-8.20 (m, 1H), 7.76-7.86 (m, 7H), 7.68-7.7 (m, 2H), 6.95-6.99 (m, 1H), 5.22-5.26 (t, 1H, J=16), 4.59-4.73 (m, 1H), 4.03-4.38 (m, 5H), 3.82-3.89 (m, 1H), 3.69-3.74 (m, 1H), 3.65 (s, 3H), 3.12-3.2 & 3.3-3.5 (m, total 2H), 2.53-2.6 (m, 1H), 2.0-2.3 (m, 4H), 1.75-1.78 & 1.82-1.85 (m, total 1H), 1.25 (s, 3H), 1.12 (s, 3H), 1.07-1.1 & 1.14-1.17 (m, total 1H), 0.96 (s, 3H), 0.88-0.96 & 1.21-1.27 (m, total 6H), 0.76-0.8 (m, 1H).
Reaction SMILES: [C:1]([C:10]1[CH:18]=[C:14]([C:15]([OH:17])=[O:16])[C:13]([OH:19])=[CH:12][CH:11]=1)(=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[CH3:20][C:21]([CH2:24][C:25]([C:28]1[CH:29]=[CH:30][C:31]([O:34][CH2:35][CH2:36][O:37][CH2:38][CH2:39][N+:40]([CH2:43][C:44]2[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=2)([CH3:42])[CH3:41])=[CH:32][CH:33]=1)([CH3:27])[CH3:26])([CH3:23])[CH3:22].C(=O)([O-])[O-]>CO>[CH3:23][C:21]([CH2:24][C:25]([C:28]1[CH:29]=[CH:30][C:31]([O:34][CH2:35][CH2:36][O:37][CH2:38][CH2:39][N+:40]([CH2:43][C:44]2[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=2)([CH3:41])[CH3:42])=[CH:32][CH:33]=1)([CH3:26])[CH3:27])([CH3:20])[CH3:22].[C:1]([C:10]1[CH:18]=[C:14]([C:15]([O-:17])=[O:16])[C:13]([OH:19])=[CH:12][CH:11]=1)(=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCC(=O)c1ccc(O)c(C(=O)O)c1
Agent: CC(C)(C)CC(C)(C)c1ccc(OCCOCC[N+](C)(C)Cc2ccccc2)cc1
Agent: O=C([O-])[O-]
Solvent: CO
Product: CCCCCCCC(=O)c1ccc(O)c(C(=O)[O-])c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2.2 g (8.4 mmol) of 5-octanoylsalicylic acid, dissolved beforehand in 100 ml of methanol, are added to a solution of 3.7 g (4.2 mmol) of benzethonium carbonate dissolved in 100 ml of methanol; the mixture is stirred for 1 hour at room temperature, the solution is then filtered and the filtrate is evaporated to dryness to give 5.5 g (98% yield) of benzethonium 5-octanoylsalicylate.
Reaction SMILES: C([O:3][C:4](=[O:20])[CH2:5][N:6]([C:8](=[O:19])[CH2:9][N:10]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH3:11])[CH3:7])C.[Li+].[OH-]>O.C1COCC1>[C:15]([O:14][C:12]([N:10]([CH3:11])[CH2:9][C:8]([N:6]([CH2:5][C:4]([OH:20])=[O:3])[CH3:7])=[O:19])=[O:13])([CH3:18])([CH3:17])[CH3:16]
Reactant: CCOC(=O)CN(C)C(=O)CN(C)C(=O)OC(C)(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CN(CC(=O)O)C(=O)CN(C)C(=O)OC(C)(C)C
Reaction time: 8 h
Yield: 90 %

Procedure:
A suspension of {[2-(tert-butoxycarbonyl-methyl-amino)-acetyl]-methyl-amino}-acetic acid ethyl ester (12.3 g, 42.7 mmol) and LiOH (8.9 g, 214 mmol) in H2O (20 mL) and THF (100 mL) was stirred overnight. Volatile solvent was removed under vacuum and the residue was extracted with ether (2×100 mL). The aqueous phase was acidified to pH 3 with dilute HCl solution, and then extracted with CH2Cl2 (2×300 mL). The combined organic layers were washed with brine, dried over Na2SO4 and concentrated under vacuum to give {[2-(tert-butoxycarbonyl-methyl-amino)-acetyl]-methyl-amino}-acetic acid as a colorless oil (10 g, 90%). 1H NMR (CDCl3) δ 7.17 (br s, 1H), 4.14-4.04 (m, 4H), 3.04-2.88 (m, 6H), 1.45-1.41 (m, 9H); ESI-MS 282.9 m/z (M+Na+).
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][C@@H:8]1[C:14](=[O:15])[NH:13][C:12]2[CH:16]=[CH:17][CH:18]=[CH:19][C:11]=2[NH:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[CH3:21][Si]([N-][Si](C)(C)C)(C)C.[Li+].IC>O1CCCC1.C(OCC)(=O)C>[C:1]([O:5][C:6](=[O:20])[NH:7][CH:8]1[C:14](=[O:15])[N:13]([CH3:21])[C:12]2[CH:16]=[CH:17][CH:18]=[CH:19][C:11]=2[NH:10][CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@H]1CNc2ccccc2NC1=O
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CI
Product: CN1C(=O)C(NC(=O)OC(C)(C)C)CNc2ccccc21
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 87 %

Procedure:
To a solution of 0.94 g (3.38 mmol) (S)-(2-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-yl)-carbamic acid tert-butyl ester dissolved in 20 ml of tetrahydrofurane at −78° C., 3.4 ml of lithium bis(trimethylsilyl)amide (1N solution in tetrahydrofurane) were added. The reaction mixture was stirred for 30 minutes at −78° C. and was allowed to reach room temperature. Iodomethane was slowly added and stirring was continued for 2 hours. The reaction mixture was diluted with ethyl acetate, washed with saturated NaHSO4 solution and separated. The aqueous phase was extracted twice with ethyl acetate (2×50 ml). The combined organic layers were washed with water (2×100 ml), with brine (1×100 ml), dried over MgSO4, filtered and evaporated. The residue was purified by chromatography (heptane/ethyl acetate=7:3) to yield 0.855 g (87%) of the product as a light yellow solid.
Reaction SMILES: [CH3:1][C:2]1[C:7]2=[N:8][CH:9]=[C:10]([C:13]3[N-:14][N:15]=[N:16][N:17]=3)[C:11](=[O:12])[N:6]2[CH:5]=[CH:4][CH:3]=1.[K+].[OH-].[K+]>O.Cl>[CH3:1][C:2]1[C:7]2=[N:8][CH:9]=[C:10]([C:13]3[NH:14][N:15]=[N:16][N:17]=3)[C:11](=[O:12])[N:6]2[CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cccn2c(=O)c(-c3nnn[n-]3)cnc12
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: Cc1cccn2c(=O)c(-c3nnn[nH]3)cnc12

Procedure:
Pemirolast free acid was prepared by dissolving pemirolast potassium in water and acidifying to pH 1 with 6M HCl which caused the free acid to precipitate from solution. The crystals formed were filtered, washed with water and dried under vacuum. Pemirolast potassium was in turn prepared analogously to the methodology described in Example 4 (steps Ia and Ib) below, using 2M KOH instead of 2M NaOH, and recrystallising from water:isopropanol in a 1:2, instead of a 2:1, ratio.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[H-].[Na+].Cl[C:12]1[CH:17]=[CH:16][N:15]=[C:14]([C:18]([NH:20][CH3:21])=[O:19])[CH:13]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH3:21][NH:20][C:18]([C:14]1[CH:13]=[C:12]([O:8][C:5]2[CH:6]=[CH:7][C:2]([NH2:1])=[CH:3][CH:4]=2)[CH:17]=[CH:16][N:15]=1)=[O:19]
Reactant: CNC(=O)c1cc(Cl)ccn1
Reactant: Nc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [H-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CNC(=O)c1cc(Oc2ccc(N)cc2)ccn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 70.1 %

Procedure:
A solution of 4-aminophenol (9.6 g, 88 mmol) in anhydrous DMF (100 mL) was treated with NaH (5.28 g of a 60% dispersion, 132 mmol), and the reddish-brown mixture was stirred at RT for 2 h. The contents were treated with 4-chloro-N-methylpicolinamide (15 g, 88 mmol) and K2CO3 (6.5 g, 44 mmol) and heated at 80° C. for 8 h. The mixture was cooled to RT and partitioned between EtOAc and brine. The aqueous phase was extracted with EtOAc. The combined organic layers were washed with brine (2×50 mL), dried (Na2SO4) and concentrated to afford 4-(4-amino-phenoxy)pyridine-2-carboxylic acid methylamide (15 g, 71% yield). 1H NMR (300 MHz, DMSO-d6): δ 8.71 (d, J=1.8 Hz, 1H), 8.43 (d, J=5.7 Hz, 1H), 7.32 (d, J=2.7 Hz, 1H), 7.06-7.03 (m, 1H), 6.76 (dd, J=8.7 Hz, 4H), 5.15 (s, 2H), 2.76 (d, J=4.8 Hz, 3H); MS (ESI) m/z: 244 (M+H+).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10](O)=[O:11])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[H-].[H-].[H-].[H-].[Li+].[Al+3].C1(C)C=CC=CC=1>O1CCCC1>[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([CH2:10][OH:11])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: O=C(O)c1ccc2[nH]ccc2c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: OCc1ccc2[nH]ccc2c1
Reaction time: 8 h

Procedure:
To a mechanically stirred solution of 1H-Indole-5-carboxylic acid (3-1, 20.01 g, 124 mmol) in tetrahydrofuran (500 mL) was added at ambient temperature slowly a solution of 1M-LAH in toluene (186 mL, 186 mmol, 1.5 equiv). The reaction mixture was heated at reflux for 1 h, quenched with ice, partitioned between EA and saturated aqueous NaHCO3. The organic layer was washed with brine, separated, dried (MgSO4) ans concentrated in vacuo. The crude product solidified upon standing under the reduced pressure. The crude solid was suspended in hexanes (200 mL) and ethyl acetate (10 mL), stirred overnight, collected by filtration and air-dried to afford the desired product as a light brown solid. 1H NMR (400 MHz, CDCl3) δ 8.24 (br s, 1H), 7.62 (s, 1H), 7.36 (d, 1H, J=8.4 Hz), 7.23 (d, 1H, J=8.4 Hz), 7.20 (s, 1H), 6.54 (s, 1H), 4.75 (s, 2H), 1.68 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][CH:8]([CH3:13])[C:9]2=[O:12])=[CH:5][CH:4]=1.[CH2:14](OC(OCC)OCC)[CH3:15]>C(O)C>[CH3:13][C:8]1[CH2:7][C:6]2[C:10]([C:9]=1[O:12][CH2:14][CH3:15])=[CH:11][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2
Reactant: CCOC(OCC)OCC
Reactant: COc1ccc2c(c1)C(=O)C(C)C2
Solvent: CCO
Product: CCOC1=C(C)Cc2ccc(OC)cc21

Procedure:
6-Methoxy-2-methylindanone [1.76 g (0.01 mole)] is dissolved in 6.5 ml of absolute ethanol (containing 20% anhydrous ether). This solution is stirred with 2.4 g (0.016 mole) of triethylorthoformate and a drop of redistilled BF3C2H5OC2H5 for about 72 hours. The reaction mixture is diluted with ether poured slowly into 8.1 ml. of 5.0% sodium hydroxide solution with crushed ice with stirring. Two layers separate and the organic layer is washed with cold water until neutral followed by saturated sodium chloride solution and dried over sodium sulfate. This is then filtered and the solvent removed and the residue distilled with 1 ml of benzene solution which contains about 47.5 mg of anhydrous p-toluene sulfonic acid to obtain 2-methyl-3-ethoxy-5-methoxyindene.
Reaction SMILES: Br[CH2:2][C:3]([CH:5]1[CH2:7][CH2:6]1)=O.CCO.[NH2:11][C:12]([NH2:14])=[S:13]>>[CH:5]1([C:3]2[N:11]=[C:12]([NH2:14])[S:13][CH:2]=2)[CH2:7][CH2:6]1
Reactant: O=C(CBr)C1CC1
Reactant: NC(N)=S
Solvent: CCO
Product: Nc1nc(C2CC2)cs1

Procedure:
To a 100 mL round-bottomed flask was added 2-bromo-1-cyclopropylethanone (7.9 g, 48 mmol), EtOH (70 mL, 1202 mmol), and thiourea (2.6 mL, 48 mmol). The solution was stirred at reflux for 6 hours. The reaction solution was cooled and concentrated under reduced pressure. The reaction mixture was diluted with water (200 mL), neutralized with NaHCO3, and extracted with EtOAc (3×100 mL). The organic extract was washed with saturated sodium chloride (1×100 mL), water (1×100 mL), dried over Na2SO4, filtered and concentrated in vacuo to give 4-cyclopropylthiazol-2-amine. The crude product was adsorbed onto a plug of silica gel and chromatographed through a Redi-Sep® pre-packed silica gel column (40 g), eluting with a gradient (5%→50% n 2 M NH3.MeOH in DCM), to provide 4-cyclopropylthiazol-2-amine (3.2 g, 48% yield), m/z (%): 141.3 (100%, M++H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1)[N:8]=[CH:7]2)([O-])=O>C(O)C.[Pt](=O)=O>[N:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[CH2:13][N:9]1[C:10]2[C:6](=[CH:5][C:4]([NH2:1])=[CH:12][CH:11]=2)[CH:7]=[N:8]1
Reactant: O=[N+]([O-])c1ccc2c(cnn2Cc2ccccn2)c1
Agent: O=[Pt]=O
Solvent: CCO
Product: Nc1ccc2c(cnn2Cc2ccccn2)c1

Procedure:
A solution of the compound from Example 60A (6.73 g, 26.5 mmol) in ethanol (70 mL) was stirred with platinum dioxide (200 mg) under a hydrogen atmosphere at normal pressure for 3 h. The catalyst was removed by suction filtration, and the solvent was removed in vacuo. The residue was triturated with tert-butyl methyl ether, and the product was collected by suction filtration to yield 5.1 g (86%) as white crystals.
Reaction SMILES: C1OCOC1CO.C12CC(C=C1)CC2C(OC)=O.C[O-].[Na+].[CH:22]12[CH2:28][CH:25]([CH:26]=[CH:27]1)[CH2:24][CH:23]2[C:29]([O:31][CH2:32][CH:33]1[CH2:37][O:36][CH2:35][O:34]1)=[O:30]>C1(C)C=CC=CC=1>[CH:22]12[CH2:28][CH:25]([CH2:26][CH2:27]1)[CH:24]=[C:23]2[C:29]([O:31][CH:32]1[CH2:33][O:34][CH2:35][O:36][CH2:37]1)=[O:30]
Reactant: O=C(OCC1COCO1)C1CC2C=CC1C2
Agent: COC(=O)C1CC2C=CC1C2
Agent: C[O-]
Agent: OCC1COCO1
Solvent: Cc1ccccc1
Product: O=C(OC1COCOC1)C1=CC2CCC1C2
Yield: 93 %

Procedure:
A mixture of 104 g of glycerol formal, 152 g of methyl 5-norbornene-2-carboxylate, 2.0 g of sodium methoxide and 300 ml of toluene was heated under reflux for 5 hours while gradually distilling off methanol formed during the reaction. After cooling, the reaction solution was washed with saturated sodium bicarbonate water, dried over anhydrous sodium sulfate, and concentrated in vacuum. It was further purified by vacuum distillation, obtaining 209 g of a mixture of (1,3-dioxolan-4-yl)methyl 5-norbornene-2-carboxylate and 1,3-dioxan-5-yl 5-norbornene-2-carboxylate (boiling point 111-115° C./530 Pa, yield 93%).
Reaction SMILES: [O:1]=[C:2]([CH2:9][C:10](=[O:13])[C:11]#[CH:12])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].B.C1COCC1.C1C2C(=CC=CC=2)C=CC=1CN1CCC[C@H]1CO>C1COCC1.CO>[OH:1][CH:2]([CH2:9][CH:10]([OH:13])[C:11]#[CH:12])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: C#CC(=O)CC(=O)CC(=O)OCC
Agent: B
Agent: OC[C@@H]1CCCN1Cc1ccc2ccccc2c1
Solvent: CO
Solvent: C1CCOC1
Product: C#CC(O)CC(O)CC(=O)OCC
Reaction time: 20 h

Procedure:
50 mg (0.27 mmol) of ethyl 3,5-dioxo-6-heptynoate was dissolved in 5 ml of THF and 52 ml of methanol. Then, with or without addition of aluminum tri-i-propoxide as a metal reagent, a reaction was conducted at 20° C. for 20 hours using 5.4 ml of a 1.0M BH3.THF solution and 6.2 mg (0.027 mmol) of the (S)-N-(β-naphthyl)methyl-2-pyrrolidine methanol (compound (S)-II-1) obtained in Example 1, to obtain ethyl 3,5-dihydroxy-6-heptynoate (VI-2) as oily desired product.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][C:14]#[N:15].[H][H]>[Co].C(CN)O>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][CH2:14][NH2:15]
Reactant: [H][H]
Reactant: Cc1oc(-c2ccccc2)nc1CC#N
Agent: [Co]
Solvent: NCCO
Product: Cc1oc(-c2ccccc2)nc1CCN
Yield: 102.3 %

Procedure:
This example was run in an analogous manner as example 5 but using 6.00 g (30 mmol) of (5-Methyl-2-phenyl-oxazol-4-yl)-acetonitrile in the presence of 0.60 g of wet Raney Cobalt catalyst (Johnson Matthey 8B0022, wet, ca. 50 weight %) in the presence of 40 μL of ethanolamine as modifier in a 185 mL autoclave at 70° C. under 9 bar of hydrogen pressure for 1.5 h. Removal of the catalyst by filtration, evaporation of the solvents and drying (50° C./10 mbar/2 h) afforded 6.21 g of 2-(5-Methyl-2-phenyl-oxazol-4-yl)-ethylamine with a purity of 90.3% (HPLC area %).
Reaction SMILES: B(Cl)(Cl)Cl.[C:5]1([OH:11])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[Cl-].[Al+3].[Cl-].[Cl-].[OH-].[Na+].CS[C:20]#[N:21]>ClCCCl>[C:20]([C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=1[OH:11])#[N:21]
Reactant: CSC#N
Reactant: Oc1ccccc1
Agent: ClB(Cl)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: N#Cc1ccccc1O
Temperature: 25 °C
Yield: 84 %

Procedure:
To 6 ml of a solution of 2.02M of boron trichloride in 1,2-dichloroethane were added a solution of 941 mg of phenol in 10 ml of 1,2-dichloroethane, 0.82 ml of methyl thiocyanate and 1.33 g of aluminium chloride under ice-cooling. After dissolving aluminium chloride with stirring at room temperature, the mixture was heated at 80° C. on an oil bath for 3 hr. After cooling, the reaction solution is poured into 33 ml of 4N aqueous sodium hydroxide and stirred at 75°-80° C. for 30 min. on an oil bath. The aqueous layer was washed with methylene chloride, acidified with 25 ml of 6N HCl and extracted with ether. Then, the ether layer was washed with 2N aqueous sodium carbonate, dried over anhydrous magnesium sulfate and concentrated to recover 39 mg of phenol. On the other hand, the sodium carbonate layer was acidified with 6N HCl and extracted with ether. The ether layer was dried over anhydrous magnesium sulfate and evaporated to remove the solvent. The crystalline residue (1.13 g) was recrystallized from methylene chloride-petroleum ether, whereby 1.002 g of 2-cyanophenol was obtained as colorless crystals melting at 97°-98° C.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH2:11]([Sn](CCCC)(CCCC)C=C)[CH2:12]CC.[Cl-].[Li+]>CN(C)C=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH:11]([C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1)=[CH2:12]
Reactant: O=[N+]([O-])c1cccnc1Cl
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: C=Cc1ncccc1[N+](=O)[O-]
Temperature: 90 °C
Yield: 39.6 %

Procedure:
Into a solution of the commercially available 2-chloro-3-nitropyridine (2 g, 12.6 mMol) in 5 mL of anhydrous N,N-dimethylformamide under inert atmosphere was added tributyl(vinyl)tin (4 mL, 13.87 mMol, 1.1 eq), lithium chloride (2.68 g, 50.46 mMol, 5 eq), and dichlorobis(triphenylphosphine)-palladium(II) (442 mg, 0.64 mMol, 5 Mol %). This was heated for 18 h at 90° C., concentrated in vacuo, and purified by flash silica gel chromatography using 10% ethyl acetate in hexanes as an eluent to afford the title compound as a brown oil (0.75 g).
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH2:11]([Sn](CCCC)(CCCC)C=C)[CH2:12]CC>[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(#N)C>[N+:8]([C:7]1[C:2]([CH:11]=[CH2:12])=[N:3][CH:4]=[CH:5][CH:6]=1)([O-:10])=[O:9]
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: O=[N+]([O-])c1cccnc1Cl
Agent: Cl[Pd]Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Solvent: CC#N
Product: C=Cc1ncccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 67 %

Procedure:
To an oven dried 20 mL of vial, was added 2-chloro-3-nitropyridine (0.793 g, 5 mmol), tetrabutylammonium chloride (1.390 g, 5.00 mmol), and bis(triphenylphosphine) palladium(II) chloride (0.351 g, 0.500 mmol). After addition of acetonitrile (10 ml) the resulting mixture was stirred at room temperature for 30 min while it was degassed by a flow of nitrogen through a needle inserted to the bottom of the vial. Tributyl(vinyl)tin (1.754 ml, 6.00 mmol) was added and the mixture was further degassed for 5 minutes. Vial was capped and heated at 90° C. for 2 hours. All solvents were removed. The residue was dissolved in dichloromethane and washed with brine. Organic layer was dried over Na2SO4, and filtered. Solvents were removed by roto-vap. Silica gel chromatography eluting ethyl acetate-hexanes afforded the title compound as dark brown oil in 67% yield. 1H NMR (500 MHz, CHLOROFORM-D) δ ppm 8.77 (dd, J=4.58, 1.53 Hz, 1 H) 8.18 (dd, J=8.24, 1.53 Hz, 1 H) 7.06-7.57 (m, 2 H) 6.63 (dd, J=16.79, 1.83 Hz, 1 H) 5.74 (dd, J=10.68, 1.83 Hz, 1 H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].CO.C[O-].[Na+].[F:15][C:16]([F:30])([F:29])[CH2:17]OS(C1C=CC(C)=CC=1)(=O)=O>CCCCCC.C1(C)C=CC=CC=1.C(OCC)(=O)C>[F:15][C:16]([F:30])([F:29])[CH2:17][O:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6]
Reactant: O=Cc1cccc(O)c1
Reactant: Cc1ccc(S(=O)(=O)OCC(F)(F)F)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCCCCC
Solvent: CO
Product: O=Cc1cccc(OCC(F)(F)F)c1
Temperature: 90 °C
Reaction time: 24 h
Yield: 25.7 %

Procedure:
EX-659A) 3-Hydroxybenzaldehyde (12.22 g, 0.10 mol) and 100 mL of anhydrous methanol were combined in a 250 mL round-bottom flask. Sodium methoxide was slowly added as a 25 wt. % solution in methanol (21.61 g, 0.10 mol), and the methanol was removed under vacuum. Then 2,2,2-trifluoroethyl-p-toluenesulfonate (25.42 g, 0.10 mol) was added, the flask was purged with nitrogen, and 100 mL of N-methyl pyrrolidine was added. The solution was stirred for 24 h at 90° C., quenched with water, and extracted with ether (3×). The combined ether layers were washed with 1 M NaOH (2×), water, and brine, dried over MgSO4, filtered, and evaporated to give 11.72 g of crude product. Chromatography over silica gel eluting with 0-10% ethyl acetate in hexane followed by a second chromatography with toluene gave 5.24 g (26%) of the desired 3-(2.2,2-trifluoroethoxy)benzaldehyde product as a pale oil. 1H NMR (C6D6) δ9.61 (s, 1H), 7.14 (d, 1H), 7.06 (s, 1H), 6.97 (t, 1H), 6.75 (m, 1H), 3.75 (m, 2H). 19F NMR (C6D6) δ−74.45 (t, 3F).
Reaction SMILES: [F:1][C:2]1[C:10]([F:11])=[C:9]([F:12])[C:8]([F:13])=[C:7]([F:14])[C:3]=1[C@H:4]1[O:6][CH2:5]1.[Br-:15].[Li+].P([O-])([O-])([O-])=O>O1CCCC1>[Br:15][CH2:5][C@@H:4]([C:3]1[C:2]([F:1])=[C:10]([F:11])[C:9]([F:12])=[C:8]([F:13])[C:7]=1[F:14])[OH:6]
Reactant: [Br-]
Reactant: Fc1c(F)c(F)c([C@@H]2CO2)c(F)c1F
Agent: O=P([O-])([O-])[O-]
Agent: [Li+]
Solvent: C1CCOC1
Product: O[C@@H](CBr)c1c(F)c(F)c(F)c(F)c1F
Temperature: 0 °C
Reaction time: 1 h
Yield: 81.9 %

Procedure:
To an ice-cooled solution of 10.51 g of (R)-(+)-2,3,4,5,6-pentafluorostyrene oxide in 100 ml of tetrahydrofuran, was added dropwise a solution of Li2CuBr4, which was prepared by adding 16.75 g of cupric bromide to a suspension of 13.03 g of lithium bromide suspended in 150 ml of tetrahydrofuran. After completion of addition, the solution was stirred for one hour in an ice bath, and for another two hours at room temperature. The resulted reaction mixture was poured into a 0.05 mol phosphate buffer, and was extracted with ether. The resultant extract was dried over magnesium sulfate, and the solvent was distilled off under reduced pressure, thereby obtaining 11.92 g of (R)-(-)-2-bromo-1-(pentafluorophenyl)ethanol containing 20% of (+)-2-bromo-2-(pentafluorophenyl)ethanol. This was subjected to isolation by silica gel column chromatography, thereby obtaining (R)-(-)-2-bromo-1-(pentafluorophenyl)ethanol and (+)-2-bromo-2-(pentafluorophenyl)ethanol respectively possessing the aforementioned physical properties.