Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([OH:26])([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[N:25]=[CH:24][CH:23]=[CH:22][N:21]=3)=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:27]I.[H-].[Na+]>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][C:11]([O:26][CH3:27])([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[N:25]=[CH:24][CH:23]=[CH:22][N:21]=3)=[CH:16][CH:15]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CI
Reactant: CC(C)(C)OC(=O)N1CCC(O)(c2ccc(-c3ncccn3)cc2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC1(c2ccc(-c3ncccn3)cc2)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
4-Hydroxy-4-(4-pyrimidin-2-yl-phenyl)-piperidine-1-carboxylic acid tert-butyl ester 81 (138 mg, 0.39 mmol) was dissolved in DMF (2 mL) and cooled to 0° C. MeI (0.1 mL) was added followed by the addition of NaH (26 mg, 60% suspension in mineral oil). After 30 min at 0° C., the reaction was quenched with sat. NH4Cl and extracted with ethyl acetate. The combined organic layers was washed with brine, dried and concentrated in vacuo. The residue was purified with prep TLC plates (developing with 50% ethyl acetate/hexanes) to yield a colorless film (80 mg) as the title compound.
Reaction SMILES: [CH2:1]([OH:13])[C@H:2]([OH:12])[C@@H:3](O)[C@H:4]([OH:10])[C:5]([C:7]([OH:9])=[O:8])=[O:6].O=C[C@@H]([C@H]([C@@H]([C@@H](CO)O)O)O)O>>[O:8]=[C:7]1[O:9][C@H:3]([C@H:2]([CH2:1][OH:13])[OH:12])[C:4]([OH:10])=[C:5]1[OH:6]
Reactant: O=C(O)C(=O)[C@@H](O)[C@H](O)[C@@H](O)CO
Agent: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Product: O=C1O[C@H]([C@@H](O)CO)C(O)=C1O

Procedure:
Two derivatives of the original strain, Alicyclobacillus sp. NA-21, MA-10, and MB-6 were sequentially obtained by conventional mutagenesis followed by the selection steps described below. From the original strain, MA-10 was selected as a strain having tolerance against a higher 2-keto-L-gulonic acid concentration (about a 1% (w/v) improvement from 10% (w/v), at 60° C. and pH 2.5) after ultraviolet irradiation. Subsequently, from MA-10, MB-6 was selected as a strain having tolerance against a higher temperature (about a 2° C. improvement from 60° C., at 11% (w/v) of 2-keto-L-gulonic acid and pH 2.5) after treatment with N-methyl-N′-nitro-N-nitrosoguanidine. L-Ascorbic acid productivities were compared among the original strain, MA-10 and MB-6 by the same living-cell reaction described above at 62° C. and pH 2.5, using 11% (w/v) of 2-keto-L-gulonic acid and a medium containing ×0.5 conc. of LM101d salt base, 0.25%(w/v) of D-glucose, ×0.1 conc. of MM, ×0.05 conc. of VM and ×0.005 conc. of AM. The original strain, MA-10, and MB-6 produced 2.02, 2.22, and 2.80 g/L of L-ascorbic acid at 23 hours, respectively. The aerobic blank and the anaerobic control produced 1.63 and 1.94 g/L of L-ascorbic acid, respectively.
Reaction SMILES: C[O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:13]3[CH:18]=[CH:17][C:16]([O:19]C)=[CH:15][CH:14]=3)[CH:9]=2)[CH:4]=1.B(Br)(Br)Br>>[OH:19][C:16]1[CH:17]=[CH:18][C:13]([C:8]2[CH:9]=[C:10]3[C:5](=[CH:6][CH:7]=2)[CH:4]=[C:3]([OH:2])[CH:12]=[CH:11]3)=[CH:14][CH:15]=1
Reactant: COc1ccc(-c2ccc3cc(OC)ccc3c2)cc1
Agent: BrB(Br)Br
Product: Oc1ccc(-c2ccc3cc(O)ccc3c2)cc1
Yield: 98 %

Procedure:
The compound is prepared by reaction of 2-methoxy-6-(4-methoxyphenyl)-naphthalene (150 mg, 0.57 mmol, 1 eq) with boron tribromide (3.4 ml, 3.4 mmol, 3 eq) according to method G. Purification by column chromatography with hexane/ethyl acetate 9/1 as the eluent yields the desired product in a yield of 98%, 132 mg.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[C:11]([O:16][CH3:17])[CH:10]=1.C([O-])([O-])=O.[Cs+].[Cs+].C(OCC)(=O)C.C1(C(O)=O)C2C(=CC=CC=2)C=CC=1>C1C=CC=CC=1.FC(F)(F)S([O-])(=O)=O.[Cu+].C1(C)C=CC=CC=1>[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[C:11]([O:16][CH3:17])[CH:10]=1
Reactant: Ic1ccccc1
Reactant: COc1cc(Cl)ccc1O
Agent: [Cu+]
Agent: O=C(O)c1cccc2ccccc12
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: c1ccccc1
Product: COc1cc(Cl)ccc1Oc1ccccc1
Temperature: 110 °C

Procedure:
Iodobenzene (7.35 mmol), 4-chloro-2-methoxyphenol (14.7 mmol), Cs2CO3 (32.3 mmol), copper(I) trifluoromethanesulfonate benzene complex (0.735 mmol, 5.0 mol % Cu), ethyl acetate (0.125 mmol, 5.0 mol %), 1-naphthoic acid (32.3 mmol), molecular sieves 4A (1.8 g) and toluene (15 mL) were added to an oven-dried 50 mL two-necked round-bottomed flask. The flask was sealed with a rubber septum, purged with nitrogen, and the temperature raised to 110° C. overnight and monitored by thin layer chromatography. The solution was cooled to room temperature, followed by the addition of 50 mL dichloromethane. The solution was filtered and then washed with a 5% sodium hydroxide aqueous solution. The aqueous layer was then extracted with dichloromethane and the combined organic layers washed with brine (NaCl). The organic phase was dried over anhydrous Mg2SO4 and concentrated under vacuum to give the crude product. Purification by flash chromatography on silica gel afforded the analytically pure compound (3): 1H NMR (300 MHz) (CDCl3): δ 7.35-6.94 (m, 8H), 3.86 (s, 3H).
Reaction SMILES: C(OC(C1N=C(C2[CH2:16][CH2:15][N:14]([C:17](=[O:29])[CH2:18][N:19]3[C:23]([CH3:24])=[CH:22][C:21]([C:25]([F:28])([F:27])[F:26])=[N:20]3)[CH2:13][CH2:12]2)SC=1)=O)C.Cl.N1(C2SC=C(C(O)=O)N=2)CCNCC1.Cl.[N:46]1([C:52]2[S:53][CH:54]=[C:55]([C:57]([O:59][CH2:60][CH3:61])=[O:58])[N:56]=2)CCNCC1.C(=O)([O-])[O-].[K+].[K+]>ClCCl.C(N(CC)CC)C>[CH2:60]([O:59][C:57]([C:55]1[N:56]=[C:52]([N:46]2[CH2:12][CH2:13][N:14]([C:17](=[O:29])[CH2:18][N:19]3[C:23]([CH3:24])=[CH:22][C:21]([C:25]([F:26])([F:27])[F:28])=[N:20]3)[CH2:15][CH2:16]2)[S:53][CH:54]=1)=[O:58])[CH3:61]
Reactant: CCOC(=O)c1csc(C2CCN(C(=O)Cn3nc(C(F)(F)F)cc3C)CC2)n1
Reactant: CCOC(=O)c1csc(N2CCNCC2)n1
Agent: Cl
Agent: O=C(O)c1csc(N2CCNCC2)n1
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)c1csc(N2CCN(C(=O)Cn3nc(C(F)(F)F)cc3C)CC2)n1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
5-Methyl-3-(trifluoromethyl)-1H-pyrazole-1-acetyl chloride (1.05 g, 2.5 mmol) (prepared as described in Example 19, step B) was dissolved in 10 mL of dichloromethane and added to a mixture of 2-(1-piperazinyl)-4-thiazolecarboxylate monohydrochloride (1.0 g, 3.0 mmol) (i.e. the product of Example 30, Step B) and powdered anhydrous potassium carbonate (2.2 g, 15.9 mmol) in 20 mL of dichloromethane at 0° C. The reaction mixture was allowed to warm to room temperature and stirred for 3 h. Then triethylamine (2 mL) was added to the reaction mixture, and the stirring was continued for an additional 30 minutes. The reaction mixture was diluted with dichloromethane, washed with 1 N aqueous hydrochloric acid, water, saturated aqueous solution of sodium bicarbonate and brine, and dried over magnesium sulfate. The filtered residue was evaporated in vacuo to give 1.0 g of a white foam. The resulting foam was slurried in 1-chlorobutane and filtered to give 0.83 g of the title compound as a white solid.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH:9]([OH:11])[CH3:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(C)C=CC=CC=1.[C:19](O)(=[O:21])[CH3:20].Cl>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[C:19]([O:11][CH:9]([CH2:8][CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH3:10])(=[O:21])[CH3:20]
Reactant: CC(O)CCc1ccccc1
Reactant: CC(=O)O
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: CC(=O)OC(C)CCc1ccccc1
Yield: 98.3 %

Procedure:
Into a four-necked flask provided with a thermometer and a stirrer, 150 g (1 mol) of 4-phenyl-2-butanol (XXX-35), 500 ml of toluene and 200 ml of pyridine were charged. 122.4 g (1.2 mol) of anhydrous acetic acid and 1 g of 4-dimethylaminopyridine were further added thereto to react them for 4 hours, while temperature being maintained at 40°-50° C. After completion of the reaction, the reaction mixture was poured into 500 ml of 4N hydrochloric acid solution, extracted and fractionated, and then an organic layer was washed with 1N hydrochloric acid, water, 5% sodium bicarbonate solution and water in the order. The thus-obtained organic layer was concentrated under a reduced pressure to obtain 189 g of 2-acetoxy-4-phenylbutane (XXIX-35) with yield of 98.5%.
Reaction SMILES: [CH2:1]([C:4]12[CH2:19][C:18](=O)[CH:11]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:17]=31)[C:10]1[C:5]2=[CH:6][CH:7]=[CH:8][CH:9]=1)[CH:2]=[CH2:3].NN.[OH-].[Na+]>C(O)COCCOCCO.O>[CH2:1]([C:4]12[CH2:19][CH2:18][CH:11]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:17]=31)[C:10]1[C:5]2=[CH:6][CH:7]=[CH:8][CH:9]=1)[CH:2]=[CH2:3]
Reactant: C=CCC12CC(=O)C(c3ccccc31)c1ccccc12
Agent: NN
Agent: [Na+]
Agent: [OH-]
Solvent: OCCOCCOCCO
Solvent: O
Product: C=CCC12CCC(c3ccccc31)c1ccccc12
Temperature: 150 °C
Reaction time: 2.5 h

Procedure:
A mixture of 9-β-propenyl-9,10-dihydro-9,10-ethanoanthracene-11-one (280 mg), hydrazine (0.2 ml) and sodium hydroxide in triethyleneglycol was stirred at 150° C. for 30 minutes and at 190° - 200° C. for 2.5 hours. The reaction mixture was diluted with water and extracted with benzene. The organic layer was washed with water, dried over anhydrous sodium sulfate and evaporated to dryness. The residue was purified over silica gel chromatography to give 9-β-propenyl-9,10-dihydro-9,10-ethanoanthracene, M.P. 42° - 43° C.
Reaction SMILES: Br[C:2]1[S:19][C:5]2[CH2:6][N:7]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH:9]([CH3:11])[O:10][C:4]=2[C:3]=1[CH:20]([CH3:22])[CH3:21].[CH3:23]B(O)O.P([O-])([O-])([O-])=O.[K+].[K+].[K+].COCCOC>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.O>[CH3:11][CH:9]1[CH2:8][N:7]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:6][C:5]2[S:19][C:2]([CH3:23])=[C:3]([CH:20]([CH3:22])[CH3:21])[C:4]=2[O:10]1
Reactant: CC1CN(C(=O)OC(C)(C)C)Cc2sc(Br)c(C(C)C)c2O1
Reactant: CB(O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: Cc1sc2c(c1C(C)C)OC(C)CN(C(=O)OC(C)(C)C)C2
Yield: 81.8 %

Procedure:
A solution of tert-butyl 7-bromo-2-methyl-8-(1-methylethyl)-2,3-dihydrothieno[2,3-f][1,4]oxazepine-4(5H)-carboxylate (390 mg), methylboronic acid (239 mg), potassium phosphate (849 mg), tetrakis(triphenylphosphine)palladium (116 mg) and DME (4 mL) was stirred at 80° C. for 20 hr, the reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (solvent gradient; 3→7% ethyl acetate/hexane) to give the title compound (266 mg, 82%) as a solid.
Reaction SMILES: [O-]P([O-])([O-])=O.[K+].[K+].[K+].[NH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][OH:15].C(O)CO.I[C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=1.N>C(O)CCC.O.[Cu]I>[CH3:28][O:27][C:24]1[CH:25]=[CH:26][C:21]([NH:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][OH:15])=[CH:22][CH:23]=1
Reactant: NCCCCCO
Reactant: COc1ccc(I)cc1
Agent: [Cu]I
Agent: N
Agent: O=P([O-])([O-])[O-]
Solvent: O
Solvent: CCCCO
Solvent: OCCO
Product: COc1ccc(NCCCCCO)cc1
Temperature: 100 °C
Reaction time: 14 h
Yield: 84.6 %

Procedure:
An oven-dried resealable 15 mL Schlenk tube was charged with CuI (9.5 mg, 0.0499 mmol, 5.0 mol %), K3PO4 (440 mg, 2.07 mmol), evacuated and backfilled with argon. 5-Amino-1-pentanol (135 μL, 1.24 mmol), ethylene glycol (0.11 mL, 1.97 mmol), and a solution of 4-iodoanisole (235 mg, 1.00 mmol) in 1-butanol (1.0 mL) were added under argon. The Schlenk tube was sealed with a Teflon valve and the reaction mixture was stirred magnetically at 100° C. for 14 h. The resulting thick, yellow-brown suspension was allowed to reach room temperature, poured into a solution of 30% aq ammonia (1 mL) in water (20 mL), and extracted with 3×15 mL of CH2Cl2. The organic phase was dried (Na2SO4), concentrated, and the residue was purified by flash chromatography on silica gel (2×15 cm; ethyl acetate; 15 mL fractions). Fractions 6-15 provided 177 mg (85% yield) of the product as a pale tan oil. 1H NMR (400 MHz, CDCl3): δ 6.80−6.74 (m, 2H), 6.60−6.54 (m, 2H), 3.74 (s, 3H), 3.65 (t, J=6.4 Hz, 2H), 3.07 (t, J=7.0 Hz, 2H), 2.5 (br s, 2H), 1.68−1.55 (m, 4H), 1.52−1.41 (m, 2H). 13C NMR (100 MHz, CDCl3): δ 151.9, 142.6, 114.8, 114.0, 62.7, 55.8, 44.9, 32.4, 29.4, 23.3. IR (neat, cm−1): 3350, 1511, 1233, 1036, 820. Anal. Calcd. for C12H19NO2: C, 68.87; H, 9.15. Found: C, 68.93; H, 9.12.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[CH2:10][CH2:11][CH2:12][NH:13][C:14](=[O:25])[C@@H:15]([NH:18]C(=O)C(F)(F)F)[CH2:16][CH3:17].O1CCCC1.CO.[OH-].[Na+]>ClCCl>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[CH2:10][CH2:11][CH2:12][NH:13][C:14](=[O:25])[C@@H:15]([NH2:18])[CH2:16][CH3:17]
Reactant: CC[C@H](NC(=O)C(F)(F)F)C(=O)NCCCc1cc2ccccc2[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: ClCCl
Product: CC[C@H](N)C(=O)NCCCc1cc2ccccc2[nH]1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A 20 mL cintillation vial was charged with (S)—N-(3-(1H-indol-2-yl)propyl)-2-(2,2,2-trifluoroacetamido)butanamide (48.2 mg, 0.136 mmol), tetrahydrofuran (0.68 mL), and methanol (0.18 mL). 3N Sodium hydroxide (0.14 mL, 0.407 mmol) was added and the resulting mixture stirred at room temperature for 18 h. The resulting mixture was then diluted with dichloromethane and extracted with 1 N HCl. The aqueous layer was neutralized to pH 8 and extracted with dichlormethane. The organic layer was dried with MgSO4, filtered, and concentrated in vacuo. The resulting solid was taken up in water and lyophilized to yield (S)—N-(3-(1H-indol-2-yl)propyl)-2-aminobutanamide. 1H NMR (300 MHz, CDCl3) δ7.52 (d, J=7.6 Hz, 1H), 7.38 (d, J=8.0 Hz, 1H), 7.01-7.13 (m, 2H), 6.22 (s, 1H), 3.30-3.49 (m, 3H), 2.72-2.77 (m, 2H), 1.83-1.96 (m, 3H), 1.58-1.66 (m, 1H), and 0.98 (t, J=7.4 Hz, 3H); MS (ES+) 260 (M+1).
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[NH:7][CH2:8][CH2:9][CH2:10][CH2:11][NH:12][CH:13]([C:15]1[CH:20]=[N:19][CH:18]=[CH:17][N:16]=1)[CH3:14])([CH3:4])([CH3:3])[CH3:2].[CH3:22][C:23]1[C:24]([CH:29]=O)=[N:25][CH:26]=[CH:27][CH:28]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[C:1]([O:5][C:6](=[O:21])[NH:7][CH2:8][CH2:9][CH2:10][CH2:11][N:12]([CH2:29][C:24]1[C:23]([CH3:22])=[CH:28][CH:27]=[CH:26][N:25]=1)[CH:13]([C:15]1[CH:20]=[N:19][CH:18]=[CH:17][N:16]=1)[CH3:14])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(NCCCCNC(=O)OC(C)(C)C)c1cnccn1
Reactant: Cc1cccnc1C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1cccnc1CN(CCCCNC(=O)OC(C)(C)C)C(C)c1cnccn1
Yield: 63 %

Procedure:
Using General Procedure B: Reaction of [4-(1-pyrazin-2-yl-ethylamino)-butyl]-carbamic acid tert-butyl ester and 3-methyl-pyridine-2-carbaldehyde in CH2Cl2 with NaBH(OAc)3 gave {4-[(3-methyl-pyridin-2-ylmethyl)-(1-pyrazin-2-yl-ethyl)-amino]-butyl}-carbamic acid tert-butyl ester (229 m, 63%) as an oil. 1H NMR (CDCl3) δ 1.26-1.39 (m, 6H), 1.43 (s, 9H), 1.50 (d, 1H, J=7.0 Hz), 2.30 (s, 3H), 2.90-2.96 (m, 2H), 4.05 (s, 2H), 4.08 (d, 1H, J=7.0 Hz) 7.10 (dd, 1H, J=7.5, 4.8 Hz), 7.41 (d, 1H, J=7.5 Hz), 8.37 (dd, 1H, J=5.1, 1.2 Hz), 8.39 (s, 1H), 8.48-8.50 (m, 1H), 8.63 (d, 1H, J=1.5 Hz).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH:12](O)[C:13]([OH:15])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[O:24][CH3:25].S(=O)(=O)(O)O>C(O)(=O)C>[CH2:1]([O:8][C:9]([NH:11][CH:12]([C:22]1[CH:21]=[CH:20][C:19]([O:24][CH3:25])=[C:18]([CH3:17])[CH:23]=1)[C:13]([OH:15])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(NC(O)C(=O)O)OCc1ccccc1
Reactant: COc1ccccc1C
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: COc1ccc(C(NC(=O)OCc2ccccc2)C(=O)O)cc1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.7 %

Procedure:
To a solution of benzyloxycarbonylamino-hydroxy-acetic acid (5.9 g, 26.2 mmol) (prepared according to the procedure of E. H. W. Bohme, et al., J. Med. Chem, 1980, 23, 405-412) and 2-methylanisole (3.2 g, 26.2 mmol) in acetic acid (150 mL) was added concentrated sulfuric acid (15 mL). The mixture was stirred at room temperature for 1 hour, then poured into ice/water and extracted with ethyl acetate (2×200 mL). The combined organic extracts were dried over sodium sulfate and concentrated to give an oily residue. The residue was triturated in hexanes, the precipitate formed was collected by filtration and dried overnight to give crude benzyloxycarbonylamino-(4-methoxy-3-methyl-phenyl)-acetic acid as a white solid (8.6 g, 100%).
Reaction SMILES: [Li+].[OH-].[CH3:3][CH:4]([CH3:34])/[CH:5]=[CH:6]\[C@@H:7]([N:13]1[CH2:18][CH2:17][C@@H:16]([CH2:19][C:20]([O:22]C)=[O:21])[CH2:15][C@H:14]1[C:24]1[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=1)[CH2:8][CH2:9][CH:10]([CH3:12])[CH3:11].Cl>O.C1COCC1>[CH3:3][CH:4]([CH3:34])/[CH:5]=[CH:6]\[C@@H:7]([N:13]1[CH2:18][CH2:17][C@@H:16]([CH2:19][C:20]([OH:22])=[O:21])[CH2:15][C@H:14]1[C:24]1[CH:25]=[CH:26][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:28][CH:29]=1)[CH2:8][CH2:9][CH:10]([CH3:11])[CH3:12]
Reactant: COC(=O)C[C@@H]1CCN([C@H](/C=C\C(C)C)CCC(C)C)[C@H](c2ccc(C(F)(F)F)cc2)C1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)/C=C\[C@H](CCC(C)C)N1CC[C@@H](CC(=O)O)C[C@H]1c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 85.6 %

Procedure:
A solution of LiOH (60 mg, 2.5 mmol) in H2O (1 ml) was added to a stirred solution of methyl {(2S,4R)-1-[(1S,2Z)-4-methyl-1-(3-methylbutyl)pent-2-en-1-yl]-2-[4-(trifluoromethyl)phenyl]piperidin-4-yl}acetate (Example 2, Step 1, 210 mg, 0.46 mmol) in THF (2 ml) at RT. The mixture was stirred at RT for 18 hrs, then at 60° C. for 3 hrs. After cooling to RT 2N HCl was added and the THF was removed in vacuo. The residue was partitioned between CH2Cl2 and H2O. The pH of the aqueous layer was adjusted to ˜pH7 with saturated aqueous NaHCO3. The aqueous layer was extracted with CH2Cl2 (×3). The combined extracts were dried (Na2SO4) filtered and evaporated. The residue was purified by chromatography (silica, 4-10% MeOH/CH2Cl2) to give the acid (173 mg) as a colourless foam. 1H NMR (500 MHz, CD3OD): δ 0.69 (3H, d, J 6.6), 0.81-0.87 (9H, m), 1.04-1.18 (2H, m), 1.25 (1H, q, J 12.1), 1.34-1.46 (3H, m), 1.56-1.68 (2H, m), 1.82-1.89 (3H, m), 2.13-2.21 (2H, m), 2.60 (1H, t, J 11.5), 3.23 (1H, brd, J 10), 3.38 (1H, q, J 8.7), 3.63 (1H, d, J 9.6), 5.28 (1H, t, J 10.6), 5.37 (1H, t, J 10.6), 7.53 (2H, d, J 7.7), 7.65 (2H, t, J 8.2); M/Z (ES+) 440 (MH+).
Reaction SMILES: [C:1]1([C:7](=[O:15])[CH2:8][C@@H:9]2[CH2:14][CH2:13][CH2:12][NH:11][CH2:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2([C:27](O)=O)[CH2:26][CH2:25][CH2:24]2)=[CH:19][CH:18]=1.CN([P+](Br)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C(Cl)Cl.O.CCOCC.C1COCC1.CCOC(C)=O.CCCCCC>[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2([CH2:27][N:11]3[CH2:12][CH2:13][CH2:14][CH:9]([CH2:8][C@@H:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[OH:15])[CH2:10]3)[CH2:26][CH2:25][CH2:24]2)=[CH:19][CH:18]=1
Reactant: O=C(C[C@@H]1CCCNC1)c1ccccc1
Reactant: O=C(O)C1(c2ccc(Cl)cc2)CCC1
Agent: CN(C)[P+](Br)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Al+3]
Solvent: ClCCl
Solvent: CCOCC
Solvent: O
Product: O[C@@H](CC1CCCN(CC2(c3ccc(Cl)cc3)CCC2)C1)c1ccccc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 76.3 %

Procedure:
(S)-[1-Phenyl-2-piperidin-3-yl-ethanone] (142 mg, 0.70 mmol) and 1-(4-Chloro-phenyl)-cyclobutanecarboxylic acid (148 mg, 0.70 mmol) were dissolved in 5 mL of methylene chloride and treated with the amide coupling agent BROP (1.05 mmol), and diisopropylethylamine (2.1 mmol). The mixture was kept at room temperature overnight, diluted with 20 mL of water, and 50 mL of ether. Extractive workup gave, after concentration of the organic layers in vacuo and chromatography on silica gel using a EtOAc-hexane gradient column, the desired amide intermediate 2-{1-[1-(4-Chloro-phenyl)-cyclobutanecarbonyl]-piperidin-3-yl}-1-phenyl-ethanone (254 mg, 92%). This amide was dissolved in 10 mL of THF at 0° C. and excess lithium aluminum hydride (245 mg) was added. The solution was heated to reflux for 5 minutes, cooled to 0° C., and quenched by dropwise addition of 1.5 mL 1M NaOH. Additional THF (10 mL) was added, and the suspension was stirred at room temperature for 30 minutes and then filtered though a plug of sodium sulfate. The solution thus obtained was concentrated in vacuo and the residue was purified by flash chromatography on silica gel using as eluent a gradient of ethyl acetate in hexane containing 1% ammonium hydroxide. 205 mg of (S)-[2-{1-[1-(4-Chloro-phenyl)-cyclobutylmethyl]-piperidin-3-yl}-1-phenyl-ethanol], 182, was obtained (83%). 1H and 13C NMR data was consistent with the assigned structure. Data for this compound as a mixture of diastereomers: MS 384 (M++1).
Reaction SMILES: [OH:1][CH:2]([C:4]1[CH:42]=[CH:41][C:7]([CH2:8][N:9]2[C:14](=[O:15])[C:13]([CH2:16][C:17]3[CH:22]=[CH:21][C:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[C:29]4[NH:33][C:32](=[O:34])[O:31][N:30]=4)=[CH:19][CH:18]=3)=[C:12]([CH2:35][CH2:36][CH3:37])[N:11]3[N:38]=[CH:39][N:40]=[C:10]23)=[CH:6][CH:5]=1)[CH3:3]>[O-2].[O-2].[Mn+4].C(Cl)Cl>[C:2]([C:4]1[CH:5]=[CH:6][C:7]([CH2:8][N:9]2[C:14](=[O:15])[C:13]([CH2:16][C:17]3[CH:18]=[CH:19][C:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[C:29]4[NH:33][C:32](=[O:34])[O:31][N:30]=4)=[CH:21][CH:22]=3)=[C:12]([CH2:35][CH2:36][CH3:37])[N:11]3[N:38]=[CH:39][N:40]=[C:10]23)=[CH:41][CH:42]=1)(=[O:1])[CH3:3]
Reactant: CCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2)c(=O)n(Cc2ccc(C(C)O)cc2)c2ncnn12
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: CCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2)c(=O)n(Cc2ccc(C(C)=O)cc2)c2ncnn12
Temperature: 25 °C
Reaction time: 16 h
Yield: 86.3 %

Procedure:
A mixture of 4-[4-(1-hydroxyethyl)benzyl]-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one (0.5 g), manganese dioxide (2.3 g) and methylene chloride (20 mL) was stirred at room temperature for 16 hr. The insoluble material was filtered off through celite, and the filtrate was concentrated. The obtained residue was purified by silica gel column chromatography to give the title compound as colorless crystals (0.43 g, 85%).
Reaction SMILES: C[O:2][C:3]([C:5]1[C:18]2[CH2:17][CH2:16][C@H:15]3[C@@H:10]([CH2:11][CH2:12][CH2:13][N:14]3[CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:9]=2[CH:8]=[CH:7][CH:6]=1)=O.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C(OCC)C>[CH2:19]([N:14]1[C@@H:15]2[C@H:10]([C:9]3[CH:8]=[CH:7][CH:6]=[C:5]([CH2:3][OH:2])[C:18]=3[CH2:17][CH2:16]2)[CH2:11][CH2:12][CH2:13]1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: COC(=O)c1cccc2c1CC[C@H]1[C@H]2CCCN1Cc1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: OCc1cccc2c1CC[C@H]1[C@H]2CCCN1Cc1ccccc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of trans-4-benzyl-1,2,3,4,4a,5,6,10b-octahydro-benzo[f]quinolin-7-carboxylic acid methyl ester (1.9 g, 5.67 mmol) in 50 mL of dry diethyl ether was cooled to 0° C. Solid lithium aluminum hydride (1.5 g, 39.5 mmol) was then added in small portions. The mixture was stirred for 1 hour at 0° C. The reaction was then terminated by the addition of water (1 mL), 15% sodium hydroxide solution (1 mL) and finally water (3 mL). The resulting mixture was filtered through a pad of Celite, dried (magnesium sulfate) and evaporated to dryness. The residue was chromatographed on a silica column with methanol:dichloromethane (1:19 (v/v)) as eluant. The solvents from the collected fractions containing pure 48 were evaporated yielding 1.5 g (86%) as an oil.