Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[N:10][S:11][C:12]=2[CH3:13])=[CH:4][CH:3]=1.BrN1C(=[O:20])CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[N:10][S:11][C:12]=2[CH:13]=[O:20])=[CH:6][CH:7]=1
Reactant: Cc1snnc1-c1ccc(F)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: O=Cc1snnc1-c1ccc(F)cc1
Reaction time: 6 h
Yield: 5.4 %

Procedure:
A mixture of 4-(4-fluorophenyl)-5-methyl-1,2,3-thiadiazole (6.19 g), N-bromosuccinimide (12.4 g), 2,2′-azobis(isobutyronitrile) (100 mg) and carbon tetrachloride (100 ml) was stirred for 6 hrs. with heating under reflux. The reaction mixture was washed with water, dried over anhydrous magnesium sulfate and concentrated. Sodium acetate (30 g) and acetic acid (100 ml) were added to the residue and the mixture was stirred for 12 hrs. with heating under reflux. 6N Hydrochloric acid (50 ml) was added and the mixture was further stirred for 1 hr. with heating under reflux. The reaction mixture was concentrated, poured into a saturated aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to give 4-(4-fluorophenyl)-1,2,3-thiadiazole-5-carbaldehyde (360 mg, yield 5.4%) as pale-yellow crystals from a fraction eluted with hexane-ethyl acetate (2:1, v/v).
Reaction SMILES: N(OC(C)(C)C)=O.N[C:9]1[N:13]([C:14]2[C:19]([Cl:20])=[CH:18][C:17]([C:21]([F:24])([F:23])[F:22])=[CH:16][C:15]=2[Cl:25])[N:12]=[C:11]([C:26]#[N:27])[C:10]=1[S:28][CH2:29][CH3:30].C(Br)(Br)[Br:32]>>[Br:32][C:9]1[N:13]([C:14]2[C:19]([Cl:20])=[CH:18][C:17]([C:21]([F:24])([F:23])[F:22])=[CH:16][C:15]=2[Cl:25])[N:12]=[C:11]([C:26]#[N:27])[C:10]=1[S:28][CH2:29][CH3:30]
Reactant: CCSc1c(C#N)nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c1N
Reactant: BrC(Br)Br
Agent: CC(C)(C)ON=O
Product: CCSc1c(C#N)nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c1Br
Temperature: 20 °C
Reaction time: 3 h

Procedure:
90% Tertiary-butyl nitrite (27.9 ml) was slowly added to a stirred solution of 5-amino-1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-4-ethylthio-1H-pyrazole-3-carbonitrile (49.8 g) in bromoform (600 ml) at 0-5° C. The mixture was stirred for three hours whilst warming to 20° C. evaporated and re-evaporated after addition of hexane/ethyl acetate (1:1) to give 5-bromo-1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-4-ethylthio-1H-pyrazole-3-carbonitrile (32.65 g), showing 93.3 area % purity by HPLC and with a retention time of 11.26 minutes on a 25.0 cm by 4.6 mm SUPELCOSIL LC-18 column, eluting with CH3CN/H2O (3: 1) solvent at 1 ml/minute. By proceeding in a similar manner the following compound was prepared:
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:11][CH3:12])=[C:4]([NH2:13])[N:3]=1.[CH2:14]([NH2:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[CH2:14]([NH:21][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:11][CH3:12])=[C:4]([NH2:13])[N:3]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CCn1cnc2c(N)nc(Cl)nc21
Reactant: NCc1ccccc1
Product: CCn1cnc2c(N)nc(NCc3ccccc3)nc21

Procedure:
A mixture of 2-chloro-9-ethyl-9H-purin-6-ylamine (0.2 g, 1.01 mmol), a compound of formula (3), and 3 mL of benzylamine was heated in a steel bomb at 130° C. for 24 hours. The amine was removed from the reaction mixture by evaporation under reduced pressure, and the residue was chromatographed on a silica gel column, eluting with chloroform/methanol (95:5), to give pure 2-benzylamino-9-ethyl-9H-purin-6-ylamine, a compound of formula (4).
Reaction SMILES: [OH:1][CH2:2][CH:3]([CH2:5][OH:6])[OH:4]>C(O)(=O)C>[CH2:2]([OH:1])[C@@H:3]([C@H:5]([C@@H:2]([CH2:3][OH:4])[OH:1])[OH:6])[OH:4]
Reactant: OCC(O)CO
Solvent: CC(=O)O
Product: OC[C@@H](O)[C@H](O)[C@@H](O)CO

Procedure:
Dr. Ho et al. of Purdue University have obtained ethanol in high yields from xylose in the presence of glucose using the Saccharomyces yeast 424A (LNH-ST) strain capable of producing ethanol in high yields from xylose. As a result of this Example, the R-WT strain was found to have the highest xylose fermentability in the presence of glucose. This yeast strain was compared with the 424A (LNH-ST) strain of the Dr. Ho et al in terms of xylose fermentability. For this purpose, the R-WT strain was anaerobically cultured in a complete medium (YPDX2 medium) with sugar composition (25.0 g/l glucose and 15.0 g/l xylose) almost the same as that in the fermentation experiment conducted by Dr. Ho et al., and then xylose fermentability was examined (see FIG. 7). According to Dr. Ho et al., mixed sugar containing 25.5 g/l glucose and 17.0 g/l xylose was fermented using the 424A (LNH-ST) strain. Thus, glucose was completely consumed within 3 hours and 80% of the total xylose was consumed after 48 hours. As a result, 15.1 g/l ethanol was produced after 48 hours and the ethanol yield from the total sugar consumption was 75.7%. Also, glycerol, which is an intermediate metabolite, was produced in a small amount, but almost no acetic acid was produced and xylitol was never produced at all. R-WT was examined, as in FIG. 7. Glucose was completely consumed within 6 hours. The time taken for this consumption has a little longer than that taken by the 424A (LNH-ST) strain, but most xylose (98% of the total xylose) was consumed after 24 hours, which was a half of the time taken by the 424A (LNH-ST) strain. As a result, 16.5 g/l ethanol was produced after 24 hours and the ethanol yield from the total sugar consumption reached 77.9%. (The ethanol yield from the total xylose consumption was 76.1%.) Also, glycerol and xylitol, which are intermediate metabolites, were produced in small amounts (1.7 g/l or less), but almost no acetic acid was produced. Therefore, it was suggested that the R-WT strain is superior to the 424A (LNH-ST) strain, which is a recombinant yeast strain reported to have the best xylose fermentability with regard to all factors including xylose consumption rate, ethanol production rate, and ethanol yield. That is, it was suggested that the R-WT strain has markedly better xylose fermentability in the presence of glucose than that of the xylose-fermenting yeast strains reported so far.
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[C:13]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])(=[O:15])[CH3:14].Br[CH2:22][C:23]1[C:24]([Cl:37])=[N:25][C:26]([Cl:36])=[CH:27][C:28]=1[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[Cl:35]>C1COCC1.[Cl-].[Na+].O.C(OCC)(=O)C.C(O)(=O)C>[Cl:37][C:24]1[C:23]([CH2:22][CH2:14][C:13]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[C:28]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[Cl:35])[CH:27]=[C:26]([Cl:36])[N:25]=1
Reactant: Clc1cc(-c2ccccc2Cl)c(CBr)c(Cl)n1
Reactant: CC(=O)OC(C)(C)C
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CCc1c(-c2ccccc2Cl)cc(Cl)nc1Cl
Reaction time: 0.25 h
Yield: 90.9 %

Procedure:
n-Butyllithium in hexanes (1.6M, 18 ml, 28.8 mmol) was added to di-isopropylamine (4.1 ml, 29.25 mmol) in dry THF (200 ml) at −10° under nitrogen. After 5 min. the solution was cooled to −70° and tert-butyl acetate (3.9 ml, 28.93 mmol) added dropwise. After stirring at −70° for 15 min. under nitrogen, 3-(bromomethyl)-2,6-dichloro-4-(2-chlorophenyl)pyridine (2.44 g, 6.942 mmol) in dry THF (18 ml) was added dropwise over 10 min., and the mixture stirred at −70° for 1 h. Glacial acetic acid (2.3 ml) was added, the temperature allowed to rise to 22° and brine (200 ml) and ethyl acetate (100 ml) added. The phases were separated and the aqueous further extracted with ethyl acetate (150 ml). The extracts were dried (Na2SO4), evaporated in vacuo and the residue purified by flash chromatography over silica eluting with cyclohexane-ethyl acetate (100:0-50:50) to give the title compound as a viscous gum (2.44 g, 91%).
Reaction SMILES: [CH3:1][C:2]1([CH3:32])[CH2:7][C:6](=O)[CH2:5][C:4]([CH3:10])([CH3:9])[P:3]1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17]1[C:22]([CH:23]([CH3:25])[CH3:24])=[CH:21][C:20]([CH:26]([CH3:28])[CH3:27])=[CH:19][C:18]=1[CH:29]([CH3:31])[CH3:30].O.NN.[OH-].[K+]>>[CH3:32][C:2]1([CH3:1])[CH2:7][CH2:6][CH2:5][C:4]([CH3:9])([CH3:10])[P:3]1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17]1[C:18]([CH:29]([CH3:30])[CH3:31])=[CH:19][C:20]([CH:26]([CH3:28])[CH3:27])=[CH:21][C:22]=1[CH:23]([CH3:25])[CH3:24]
Reactant: CC(C)c1cc(C(C)C)c(-c2ccccc2P2C(C)(C)CC(=O)CC2(C)C)c(C(C)C)c1
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: CC(C)c1cc(C(C)C)c(-c2ccccc2P2C(C)(C)CCCC2(C)C)c(C(C)C)c1
Temperature: 200 °C
Reaction time: 5 h
Yield: 97.3 %

Procedure:
A flask was charged with 1.05 g of 2,2,6,6-tetramethyl-1-(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphinan-4-one (2.33 mmol, 1.0 equiv), the atmosphere was sparged with argon and 12 mL of argon-sparged diethylene glycol was added. The flask was mounted with a Dean-Stark trap and condenser to collect distillate. The mixture was charged with 1.05 mL of hydrazine hydrate (55 wt % hydrazine, 11.7 mmol, 5 equiv) and 0.77 g of potassium hydroxide (88 wt %, 12.1 mmol, 5 equiv) and the mixture was immersed in an oil bath at 115° C. under an argon atmosphere. The temperature of the bath was gradually increased to 200° C. over two hours and kept at that temperature for 5 h. The reaction mixture was cooled to room temperature under argon gas. The reaction mixture was partitioned between heptane and water. The organic solution was washed once with 0.1 M aqueous hydrochloric acid, once with 10 wt % aqueous sodium carbonate and once with water. The organic solution was concentrated in vacuo with gentle heating and the residue dried in vacuo to give 0.99 g of 2,2,6,6-tetramethyl-1-(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphinane (97 area % by HPLC, 94% yield) as a white solid. 1H NMR (C6D6, 500 MHz), δ=0.93 (d, 6H, J=10 Hz), 1.11 (d, 6H, J=7 Hz), 1.13 (d, 6H, J=19 Hz), 1.23 (d, 6H, J=7 Hz), 1.31-1.26 (m, 2H), 1.42 (d, 6H, J=7 Hz), 1.57-1.50 (m, 1H), 1.65-1.57 (m, 1H), 1.88-1.83 (m, 2H), 2.79 (sept, 2H, J=7 Hz), 2.84 (sept, 1H, J=7 Hz), 7.12-7.11 (m, 2H), 7.22 (s, 2H), 7.27-7.24 (m, 1H), 7.98-7.93 (m, 1H); 31P NMR (C6D6, 202 MHz), δ ppm −0.4 (br singlet).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:12]3[O:13][C:14]4[CH:20]=[C:19]([CH2:21][C:22]([O:24]C)=[O:23])[CH:18]=[CH:17][C:15]=4[N:16]=3)=[CH:7][N:8]2[CH3:11])=[CH:4][CH:3]=1.C1COCC1.[OH-].[Na+]>Cl>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:12]3[O:13][C:14]4[CH:20]=[C:19]([CH2:21][C:22]([OH:24])=[O:23])[CH:18]=[CH:17][C:15]=4[N:16]=3)=[CH:7][N:8]2[CH3:11])=[CH:4][CH:3]=1
Reactant: COC(=O)Cc1ccc2nc(-c3cn(C)c4cc(F)ccc34)oc2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cn1cc(-c2nc3ccc(CC(=O)O)cc3o2)c2ccc(F)cc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 86.9 %

Procedure:
To methyl (2-(6-fluoro-1-methyl-3-indolyl)-6-benzoxazolyl)acetate (889 mg, 2.63 mmol) were added THF (25 ml) and 0.25N NaOH (15.8 ml, 3.95 mmol). The resulting mixture was stirred at room temperature for 4 hours. The reaction mixture was poured in 1N HCl (30 ml). The crystals thus precipitated were collected by filtration under reduced pressure, washed with water, and dried under reduced pressure to give (2-(6-fluoro-1-methyl-3-indolyl)-6-benzoxazolyl)acetic acid (741 mg, 87%) as a brown solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[CH2:6]O.S(Cl)([Cl:15])=O>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[CH2:6][Cl:15]
Reactant: COc1ccc(CO)cc1OC
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: COc1ccc(CCl)cc1OC
Temperature: 0 °C

Procedure:
3,4-dimethoxybenzyl alcohol (20 g, 119 mmol) was dissolved in toluene (60 ml) and cooled to 0° C. Thionyl chloride (7.48 g, 61.4 mmol) was added dropwise to the cooled solution of the alcohol over a period of 30 minutes, and the reaction was maintained at 0° C. for an additional 30 minutes. The reaction was quenched by pouring onto an ice/water mix (100 ml), and the organic phase was separated. The aqueous phase was then extracted into toluene (2×20 ml) and the combined toluene solution was dried over anhydrous sodium sulfate. The toluene was removed at reduced pressure to afford an oil which solidified upon standing, with a yield of 21 g. The material was characterized as a single spot by thin layer chromatography (TLC).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([O:10][CH3:11])=[O:9])=[N:6][CH:7]=1.[H-].[Na+].Br[C:15]1[C:19]2[CH:20]=[CH:21][C:22]([O:24][CH3:25])=[CH:23][C:18]=2[S:17](=[O:26])[C:16]=1[C:27]1[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=1>CN(C=O)C>[CH3:25][O:24][C:22]1[CH:21]=[CH:20][C:19]2[C:15]([O:1][C:2]3[CH:3]=[CH:4][C:5]([C:8]([O:10][CH3:11])=[O:9])=[N:6][CH:7]=3)=[C:16]([C:27]3[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=3)[S:17](=[O:26])[C:18]=2[CH:23]=1
Reactant: COc1ccc(C2=C(Br)c3ccc(OC)cc3S2=O)cc1
Reactant: COC(=O)c1ccc(O)cn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OC2=C(c3ccc(OC)cc3)S(=O)c3cc(OC)ccc32)cn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 52.6 %

Procedure:
To a solution of methyl 5-hydroxypyridine-2-carboxylate (0.273 g, 1.78 mmol) in DMF (6.84 mL) at room temperature was added sodium hydride (60% suspension in oil, 0.043 g, 1.78 mmol) and the resulting mixture was stirred at room temperature for 30 mins. After 30 min at room temperature 3-bromo-6-methoxy-2-(4-methoxyphenyl)benzothiophene 1-oxide (0.5 g, 1.37 mmol) was added and the reaction was heated to 80° C. for 18 h. Upon completion the reaction was cooled to room temperature, quenched with water and extracted with DCM. The organic layers were combined, passed through a phase separator and concentrated in vacuo to give the crude product, which was purified by column chromatography (SiO2, 0-75% EtOAc/heptane) to afford methyl 5-((6-methoxy-2-(4-methoxyphenyl)-1-oxidobenzo[b]thiophen-3-yl)oxy)picolinate (314 mg, 0.72 mmol, 52% yield). 1H NMR (400 MHz, CDCl3) δ ppm=3.73 (s, 3H), 3.84 (s, 3 H), 3.90-3.92 (m, 3 H), 6.79-6.86 (m, 2 H), 6.91 (dd, J=8.59, 2.53 Hz, 1 H), 7.03 (d, J=8.59 Hz, 1 H), 7.30 (dd, J=8.59, 3.03 Hz, 1 H), 7.48 (d, J=2.53 Hz, 1 H), 7.55-7.60 (m, 2 H), 7.95 (d, J=8.59 Hz, 1 H), 8.55 (d, J=2.02 Hz, 1 H), LC/MS (m/z, MH+): 438.2.
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[CH2:11]([NH:27][C:28]1[CH:35]=[CH:34][C:31]([C:32]#N)=[CH:30][CH:29]=1)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26].C[OH:37]>C1(C)C=CC=CC=1.ClCCl>[CH2:11]([NH:27][C:28]1[CH:35]=[CH:34][C:31]([CH:32]=[O:37])=[CH:30][CH:29]=1)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: CCCCCCCCCCCCCCCCNc1ccc(C#N)cc1
Reactant: CO
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCCCCCCNc1ccc(C=O)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Di-isobutylaluminum hydride (54-ml., 25% solution in toluene) is added with stirring to a solution of p-hexadecylaminobenzonitrile (11.4 g.) under a nitrogen atmosphere. The temperature rises to 40° C. during the addition which takes 30 minutes and the reaction is then stirred for 1 hour. A solution of methanol in toluene (50 ml., 1:1) is added over 30 minutes and the mixture is poured into vigorously stirred ice-cold aqueous sulfuric acid (500 ml., 5%). After 10 minutes diatomaceous earth (30 g.) is added, the mixture filtered and the organic layer separated. The aqueous solution is extracted twice with toluene (100 ml.) and the combined organic layers are washed with aqueous sodium bicarbonate, dried over magnesium sulfate, decolorized with charcoal, filtered and evaporated in vacuo to give a light yellow crystalline solid. The crude product is dissolved in dichloromethane and filtered through hydrated magnesium silicate (80 g.) to give a white crystalline material on removal of the solvent. The product is recrystallized from dichloromethane/hexanes giving colorless fine needles (6.0 g.), m.p. 84°-85° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([CH2:12][N:13]1[CH:17]=[C:16]([C:18]([NH:20][CH2:21][C:22]3[C:23]([CH3:37])=[CH:24][C:25]([NH:29]C(=O)OCCCC)=[N:26][C:27]=3[CH3:28])=[O:19])[CH:15]=[N:14]1)=[CH:7][CH:6]=2.C(Cl)Cl>CO>[NH2:29][C:25]1[N:26]=[C:27]([CH3:28])[C:22]([CH2:21][NH:20][C:18]([C:16]2[CH:15]=[N:14][N:13]([CH2:12][C:8]3[CH:9]=[C:10]4[C:5](=[CH:6][CH:7]=3)[N:4]=[CH:3][C:2]([Cl:1])=[CH:11]4)[CH:17]=2)=[O:19])=[C:23]([CH3:37])[CH:24]=1
Reactant: CCCCOC(=O)Nc1cc(C)c(CNC(=O)c2cnn(Cc3ccc4ncc(Cl)cc4c3)c2)c(C)n1
Solvent: CO
Solvent: ClCCl
Product: Cc1cc(N)nc(C)c1CNC(=O)c1cnn(Cc2ccc3ncc(Cl)cc3c2)c1

Procedure:
To a solution of tent-Butyl 5-((1-((3-chloroquinolin-6-yl)methyl)-1H-pyrazole-4-carboxamido)methyl)-4,6-dimethylpyridin-2-ylcarbamate (125 mg, 0.240 mmol) in DCM (1 ml) Tri fluoro acetic acid (0.092 ml, 1.200 mmol) was added at rt. The reaction was stirred for 2 h at II. The reaction mixture was concentrated under vacuum to afford crude title compound. The crude product was dissolved in MeOH and filtered over a PL-HCO3-cartridge (MP-resin, VARIAN) to afford pure title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:11]2[CH:12]=[C:13]3[C:18](=[CH:19][CH:20]=2)[CH:17]=[C:16]([C:21](OCC)=[O:22])[CH:15]=[CH:14]3)[CH:5]=[C:6]2[O:10][CH2:9][O:8][C:7]=12.CC(C[AlH]CC(C)C)C>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([C:11]2[CH:12]=[C:13]3[C:18](=[CH:19][CH:20]=2)[CH:17]=[C:16]([CH2:21][OH:22])[CH:15]=[CH:14]3)[CH:5]=[C:6]2[O:10][CH2:9][O:8][C:7]=12
Reactant: CCOC(=O)c1ccc2cc(-c3cc(Br)c4c(c3)OCO4)ccc2c1
Agent: CC(C)C[AlH]CC(C)C
Solvent: Cc1ccccc1
Product: OCc1ccc2cc(-c3cc(Br)c4c(c3)OCO4)ccc2c1
Temperature: 25 °C
Yield: 100 %

Procedure:
To a solution of ethyl 6-[3-bromo-4,5-methylenedioxyphenyl]-2-naphthoate (18.32 g, 45.90 mmol) in 308 mL toluene at −78° C. under an atmosphere of argon was added DIBAL (92 mL, 1.5 M in toluene, 137.7 mmol) dropwise. After 1 hour the reaction mixture was quenched with ethyl acetate and the resulting mixture was allowed to warm to RT. The mixture was diluted with ethyl acetate and washed with 5% NH4Cl, water and brine. The organics were dried with magnesium sulfate, filtered and evaporated. The residue was passed through a short silica gel column (eluent: CH2Cl2) to give 16.40 g of 6-[3-bromo-4,5-methylenedioxyphenyl]-naphthalen-2-yl-methyl alcohol (100%). 1H NMR (300 MHz; CDCl3): δ 4.85 (s, 2H), 6.01 (s, 2H), 6.88 (s, 1H), 7.13 (s, 1H), 7.47 (dd, J1=4.0 Hz, J2=1.8 Hz, 1H), 7.50 (dd, J1=4.0 Hz, J2=1.8 Hz, 1H), 7.76–7.85 (m, 4H).
Reaction SMILES: C(O)(C(F)(F)F)=O.C(OC(=O)[NH:14][C@H:15]([C:18]1[CH:27]=[CH:26][C:25]2[C:20](=[CH:21][C:22]([O:28][CH3:29])=[CH:23][CH:24]=2)[CH:19]=1)[CH2:16][OH:17])(C)(C)C>C(Cl)Cl>[NH2:14][C@H:15]([C:18]1[CH:27]=[CH:26][C:25]2[C:20](=[CH:21][C:22]([O:28][CH3:29])=[CH:23][CH:24]=2)[CH:19]=1)[CH2:16][OH:17]
Reactant: COc1ccc2ccc([C@H](CO)NC(=O)OC(C)(C)C)cc2c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc2ccc([C@@H](N)CO)cc2c1
Yield: 99.1 %

Procedure:
A solution of TFA (8 mL) and (R)-[2-hydroxy-1-(7-methoxy-naphthalen-2-yl)-ethyl]-carbamic acid tert-butyl ester (1.268 g) in methylene chloride (24 mL) was stirred for 2 h. After concentration, the residue was neutralized with 10 N NaOH and extracted with methylene chloride. The organic layer was washed with brine, dried over Na2SO4, and concentrated to give the title compound as a solid (860 mg).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1([C:17]([OH:19])=O)[CH2:16][CH2:15][CH2:14][CH2:13]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.C(Cl)(=O)OCC.[NH2:33][C:34]1[S:35][CH:36]=[N:37][N:38]=1>C(Cl)(Cl)Cl>[CH2:1]([O:8][C:9]([NH:11][C:12]1([C:17]([NH:33][C:34]2[S:35][CH:36]=[N:37][N:38]=2)=[O:19])[CH2:16][CH2:15][CH2:14][CH2:13]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1nncs1
Reactant: O=C(NC1(C(=O)O)CCCC1)OCc1ccccc1
Agent: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: O=C(NC1(C(=O)Nc2nncs2)CCCC1)OCc1ccccc1
Yield: 63.8 %

Procedure:
10 g of N-benzyloxycarbonylcycloleucine, 3.9 g of triethylamine, 150 ml of chloroform, 4.1 g of ethyl chlorocarbonate and 3.9 g of 2-amino-1,3,4-thiadiazole were reacted in the same manner as in Example 1(i) to obtain 8.4 g (yield: 64%) of 2-(N-benzyloxycarbonyl-cycloleucylamino)-1,3,4-thiadiazole as white crystals having a melting point of 229°-233° C.
Reaction SMILES: C([O:3][C:4](=[O:23])[C:5]([CH2:15][C:16]1[CH:21]=[CH:20][C:19](O)=[CH:18][CH:17]=1)([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH2:6][CH3:7])C.[C:24]1([C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)[CH:29]=[CH:28][CH:27]=[C:26]([C:30]2[O:31][C:32]([CH3:48])=[C:33]([CH2:35][CH2:36][O:37]S(C3C=CC(C)=CC=3)(=O)=O)[N:34]=2)[CH:25]=1.C([O-])([O-])=O.[K+].[K+].[OH-].[Na+]>C(O)C>[C:24]1([C:49]2[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=2)[CH:29]=[CH:28][CH:27]=[C:26]([C:30]2[O:31][C:32]([CH3:48])=[C:33]([CH2:35][CH2:36][O:37][C:19]3[CH:20]=[CH:21][C:16]([CH2:15][C:5]([O:8][C:9]4[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=4)([CH2:6][CH3:7])[C:4]([OH:23])=[O:3])=[CH:17][CH:18]=3)[N:34]=2)[CH:25]=1
Reactant: CCOC(=O)C(CC)(Cc1ccc(O)cc1)Oc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)OCCc2nc(-c3cccc(-c4ccccc4)c3)oc2C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CCO
Product: CCC(Cc1ccc(OCCc2nc(-c3cccc(-c4ccccc4)c3)oc2C)cc1)(Oc1ccccc1)C(=O)O

Procedure:
A mixture of 2-(4-hydroxybenzyl)-2-phenoxybutyric acid ethyl ester (0.030 mmol) (see Ex. 40, Part C), toluene-4-sulfonic acid 2-(2-biphenyl-3-yl-5-methyloxazol-4-yl)ethyl ester (0.030 mmol) (see Ex. 2, Part F) and 325 mesh K2CO3 (0.084 g, 0.60 mmol) in ethanol (2 mL) was heated to reflux for 24 h under N2. Aqueous 5N NaOH (0.5 mL) and additional ethanol (1 mL) was added to the reaction mixture and it was heated at reflux for an additional 2 h. The reaction was cooled and the solvent removed in vacuo. The residue was acidified with aqueous 1 N HCl (5 mL), extracted with water and CH2Cl2 and the organic layer dried by passing it through a Varian Chem Elut 1003 cartridge. The solvent was removed in vacuo to give 2-{4-[2-(2-biphenyl-3-yl-5-methyl-oxazol-4-yl)-ethoxy]-benzyl}-2-phenoxy-butyric acid. 1H NMR (400 MHz, CDCl3) δ 8.30–8.20 (m, 1H), 7.96–7.93 (m, 1H), 7.68–7.63 (m, 3H), 7.53–7.43 (m, 3H), 7.39–7.34 (m, 1H), 7.32–7.24 (m, 2H), 7.09–7.05 (m, 1H), 7.02–6.97 (m, 4H), 6.78–6.73 (m, 2H), 4.20 (t, 2H, J=6.4 Hz), 3.29 (s, 2H), 3.01 (t, 2H, J=6.4 Hz), 2.39 (s, 3H), 2.14 (qd, 1H, J=14.8, 7.6 Hz), 2.08 (qd, 1H, J=14.8, 7.6 Hz), 0.91 (t, 3H, J=7.6 Hz.
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[NH2:15][C:16]1[C:21]([NH2:22])=[CH:20][CH:19]=[CH:18][N:17]=1.[C:23]([O:27][C:28]([N:30]1[CH2:35][CH2:34][C:33](=O)[CH2:32][CH2:31]1)=[O:29])([CH3:26])([CH3:25])[CH3:24]>ClC(Cl)C>[NH2:15][C:16]1[C:21]([NH:22][CH:33]2[CH2:34][CH2:35][N:30]([C:28]([O:27][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:29])[CH2:31][CH2:32]2)=[CH:20][CH:19]=[CH:18][N:17]=1
Reactant: Nc1cccnc1N
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: CC(C)(C)OC(=O)N1CCC(Nc2cccnc2N)CC1
Reaction time: 5 h
Yield: 33.2 %

Procedure:
Sodium triacetoxyborohydride (14.5 g, 68.7 mmol) was added to a solution of 2,3-diaminopyridine (5.00 g, 45.8 mmol) and N-(tert-butoxycarbonyl)-4-piperidone (9.58 g, 48.1 mmol) in dichloroethane (75 mL) at room temperature. After 5 h, additional sodium triacetoxyborohydride was added (1.8 g) and again after another 2.5 h. The reaction was stirred overnight, and quenched with 5% aqueous sodium hydroxide. This was extracted with methylene chloride, and washed with 5% aqueous sodium hydroxide, water and saturated sodium chloride solution. After drying over sodium sulfate, the solution was filtered and evaporated to give the crude product. This was purified by chromatography (silica gel, 3 to 5% methanol in methylene chloride gradient elution), which gave the title compound (4.44 g). MS 293 (M+1)