Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C:4](=[O:20])[C:5]([CH:8]1[CH:10]([C:11]2[C:19]3[O:18][CH2:17][O:16][C:15]=3[CH:14]=[CH:13][CH:12]=2)[CH2:9]1)(O)C)C.S([O-])([O-])(=O)=S.[Na+].[Na+]>ClCCl>[CH2:15]([O:16][C:17](=[O:18])[C:4](=[O:20])[CH2:5][CH:8]1[CH:10]([C:11]2[C:19]3[O:18][CH2:17][O:16][C:15]=3[CH:14]=[CH:13][CH:12]=2)[CH2:9]1)[CH3:14]
Reactant: CCOC(=O)C(C)(O)C1CC1c1cccc2c1OCO2
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CCOC(=O)C(=O)CC1CC1c1cccc2c1OCO2
Reaction time: 6 h
Yield: 111.6 %

Procedure:
13.9 g of 1,1,1-triacetoxy-1,1-dihydro-1,2-benzodioxol-3(1H)-one (Dess-Martin-Periodinane, cf. D. B. Dess, J. C. Martin, J. Am. Chem. Soc. 1991, 113, 7277) is added to a solution of 4.55 g of 3-(benzo[1,3]dioxol-4-yl)-cyclopropyl-2-hydroxypropionic acid ethyl ester in 205 ml of dichlormethane. After 6 hours at room temperature, the batch is added to a saturated solution of sodium thiosulfate and extracted with ether. It is washed with water, saturated bicarbonate solution and brine, dried (Na2SO4) and concentrated by evaporation. The residue is purified by column chromatography on silica gel with hexane-ethyl acetate (100: 0→80:20). 2.52 g of 3-(benzo[1,3]dioxol-4-yl)-cyclopropyl-2-oxopropionic acid ethyl ester is obtained. The latter is stirred in 84 ml of a solution of 1N sodium hydroxide solution in ethanol/water 2:1 at room temperature for 12 hours. The batch is concentrated in a vacuum, and the remaining solution is extracted with diethyl ether. The aqueous phase is acidified with 1 M hydrochloric acid and extracted with diethyl ether. After drying and concentration by evaporation, 2.2 g of 3-(benzo[1,3]dioxol-4-yl)-cyclopropyl-2-oxopropionic acid is obtained as a yellowish oil.
Reaction SMILES: [K].[CH3:2][O:3][CH2:4][C:5]([CH:7]1[CH2:11][CH2:10][N:9]([C:12]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:13])[C:8]1=[O:22])=O.Cl.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[Br:36][C:37]1[CH:43]=[CH:42][C:40]([NH2:41])=[CH:39][CH:38]=1.C(=O)(O)[O-].[Na+]>C1CCCCC1.C1(C)C=CC=CC=1>[Br:36][C:37]1[CH:43]=[CH:42][C:40]([NH:41][C:5](=[C:7]2[CH2:11][CH2:10][N:9]([C:12]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[O:13])[C:8]2=[O:22])[CH2:4][O:3][CH3:2])=[CH:39][CH:38]=1
Reactant: Nc1ccc(Br)cc1
Reactant: COCC(=O)C1CCN(C(=O)OCc2ccccc2)C1=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Agent: O=C([O-])O
Solvent: Cc1ccccc1
Solvent: O
Solvent: C1CCCCC1
Product: COCC(Nc1ccc(Br)cc1)=C1CCN(C(=O)OCc2ccccc2)C1=O
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 61.6 %

Procedure:
Into a 100 mL eggplant-shaped flask were added benzyl 3-(2-methoxyacetyl)-2-oxopyrrolidine-1-carboxylate potassium salt (4.95 g) [mw. 329.39, 15.0 mmol], 1 mol/L hydrochloric acid (25 mL) [25 mmol] and toluene (50 mL), and the mixture was stirred for 20 min. After partitioning, the organic layer was dried over magnesium sulfate, filtered and concentrated under reduced pressure. To the concentrate were added toluene (19 mL), cyclohexane (57 mL), p-toluenesulfonic acid monohydrate (29.0 mg) [mw. 190.22, 0.15 mmol] and parabromoaniline (2.58 g) [mw. 172.02, 15.0 mmol]. Dean-Stark trap was set, and the mixture was subjected to dehydration reflux for 2 hr. After cooling to 25° C., 5 w/w % aqueous sodium bicarbonate solution (10 mL) was added to allow for partitioning. The organic layer was washed with water (10 mL), dried over magnesium sulfate, filtered and concentrated under reduced pressure. To the concentrate was added methanol (19 mL), and the mixture was dissolved. Activated carbon (0.5 g) was added, and the mixture was stirred. The activated carbon was filtered off, the mother liquor was concentrated under reduced pressure, and to the concentrate were added ethyl acetate (2 mL) and diisopropyl ether (20 mL). The mixture was left standing in a freezer at −16° C. overnight, and crystallization was confirmed. The mixture was aged at room temperature for 1 hr. After filtration under reduced pressure, the crystals were washed with ethyl acetate/diisopropyl ether (1/10), and dried under reduced pressure at 50° C. Yellow crystals, 4.12 g, yield 61.6%, 1H-NMR (500 MHz, CDCl3, TMS) δ 2.78 (t, J=7.7 Hz, 2H), 3.35 (s, 3H), 3.76-3.89 (m, 2H), 4.00 (s, 2H), 5.30 (s, 2H), 6.99 (d, J=8.8 Hz, 5H), 7.28-7.52 (m, 7H), 10.49 (s, 1H). 13C-NMR (125 MHz, CDCl3, CDCl3) δ 20.95, 43.60, 58.55, 67.74, 67.97, 99.87, 117.24, 124.08, 128.13, 128.58, 132.24, 135.78, 138.56, 149.72, 152.24, 169.92.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10]C(O)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)(Cl)=O.C[N:19](C)[CH:20]=[O:21]>CCOCC>[CH2:1]([O:8][CH2:9][CH2:10][N:19]=[C:20]=[O:21])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)CCOCc1ccccc1
Reactant: CN(C)C=O
Solvent: O=S(Cl)Cl
Solvent: CCOCC
Product: O=C=NCCOCc1ccccc1
Temperature: 5 °C
Reaction time: 0.5 h

Procedure:
To 3-benzyloxypropionic acid (129.6 g) in ether (310 ml) and N,N-dimethylformamide (4ml) was added thionyl chloride (155 ml). The solution was refluxed for 2 hours, and solvents and excess thionyl chloride were removed by evaporation in vacuo. Yield 132 g of 3-Benzyloxypropionic acid chloride as an oil. To an ice cooled solution of the thus prepared acid chloride (132 g) in acetone (450 ml) was added a cold solution of sodium azide (48.5 g) in water (200 ml) at 5° C. After additional stirring at 5° C. for 30 minutes, the mixture was poured into water and toluene, and the aqueous phase was extracted twice with toluene. The combined organic phases were washed with brine. After drying (magnesium sulfate) the solution was heated slowly to 85° C. on a steam bath until evolution of nitrogen ceased. The solvent was removed in vacuo leaving 108.4 g of 2-benzyloxyethylisocyanate as an oil. A mixture of 2-benzyloxy-ethylisocyanate (10 g) and diethanolamine (5.72 g) in dichloromethane (60 ml) was refluxed for 2.5 hours. After cooling to room temperature, the solution was washed with brine. Drying (magnesium sulfate) and evaporation of the solvent yielded 11.4 g of N-(2-benzyloxyethyl)-N',N'-di-(2-hydroxyethyl)-urea as an oil. A solution of the urea derivative (11.4 g) in dichloromethane (55 ml) was cooled to 5° C., and thionyl chloride (8.3 ml) was added at a temperature below 10° C. After the addition the mixture was refluxed for 1 hour and then left over night at room temperature. The solution was washed with cold sodium hydrogen carbonate solution and saturated sodium chloride solution, dried over magnesium sulfate and evaporated in vacuo. The residue was dissolved in 1,1,1-trichloroethane and refluxed for 3 hours. After cooling the solution was washed with sodium hydrogen carbonate solution, dried over magnesium sulfate and evaporated in vacuo, yilding 6.6 g of the title compound 22a as an oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]2[C:7](=[O:10])[CH2:8][O:9][C:5]=2[C:4]=1[CH2:13][CH2:14][CH2:15][N:16]1[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]1.[NH:29]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:31]([CH:38]=O)=[N:30]1.N1CCCCC1>CO>[NH:29]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:31](/[CH:38]=[C:8]2\[O:9][C:5]3[C:4]([CH2:13][CH2:14][CH2:15][N:16]4[CH2:17][CH2:18][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:20][CH2:21]4)=[C:3]([O:2][CH3:1])[CH:12]=[CH:11][C:6]=3[C:7]\2=[O:10])=[N:30]1
Reactant: COc1ccc2c(c1CCCN1CCN(C(=O)OC(C)(C)C)CC1)OCC2=O
Reactant: O=Cc1n[nH]c2ccccc12
Solvent: CO
Solvent: C1CCNCC1
Product: COc1ccc2c(c1CCCN1CCN(C(=O)OC(C)(C)C)CC1)O/C(=C\c1n[nH]c3ccccc13)C2=O
Temperature: 60 °C
Reaction time: 2 h
Yield: 46.2 %

Procedure:
A solution of tert-butyl 4-[3-(6-methoxy-3-oxo-2,3-dihydrobenzofuran-7-yl)propyl]piperazine-1-carboxylate (0.0642 g, 0.164 mmol) in methanol (3 mL) was added with 1H-indazole-3-carboxaldehyde (0.0264 g, 0.180 mmol) and piperidine (0.0112 g, 0.131 mmol), and the mixture was stirred at 60° C. for 2 hours. The reaction mixture was concentrated, and then the residue was purified by silica gel column chromatography (chloroform/methanol) to obtain tert-butyl (Z)-4-(3-{2-[(1H-indazol-3-yl)methylene]-6-methoxy-3-oxo-2,3-dihydrobenzofuran-7-yl}propyl)piperazine-1-carboxylate (0.0393 g, 46%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:9][CH:10]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:11]([OH:13])=[O:12])[CH:6]=[CH:7][CH:8]=1.C1C=CC2N(O)N=NC=2C=1.C1CCC(N=C=NC2CCCCC2)CC1.[N:45]12[CH2:52][CH2:51][CH:48]([CH2:49][CH2:50]1)[C@@H:47](O)[CH2:46]2>C1COCC1>[N:45]12[CH2:52][CH2:51][CH:48]([CH2:49][CH2:50]1)[C@@H:47]([O:12][C:11](=[O:13])[CH:10]([NH:9][C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:46]2
Reactant: COc1cccc(NC(C(=O)O)c2ccccc2)c1
Reactant: O[C@H]1CN2CCC1CC2
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: COc1cccc(NC(C(=O)O[C@H]2CN3CCC2CC3)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 52.2 %

Procedure:
(3-Methoxy-phenylamino)-phenyl-acetic acid (0.58 g, 2.25 mmol), HOBT (0.45 g, 2.93 mmol) and DCC (0.60 g, 2.93 mmol) are dissolved in THF (100 mL) and stirred at RT for 20 minutes. Then, (R)-quinuclidin-3-ol (0.57 g, 4.51 mmol) is added and the resulting reaction is stirred at the same temperature for one day. The solvent is evaporated, the residue is taken up with EtOAc and the insoluble is filtered off. The organic solution is washed with 1M K2CO3 and then with brine. The crude is purified by flash chromatography (DCM/MeOH=99/1 to 80:20) to obtain the title compound as a yellow solid (0.43 g, 52% yield, mixture of diastereoisomers).
Reaction SMILES: [CH2:1]([Si:3]([CH2:7][CH3:8])([CH2:5][CH3:6])Cl)[CH3:2].[CH3:9][NH:10][CH3:11]>C(OCC)C>[CH3:9][N:10]([Si:3]([CH2:7][CH3:8])([CH2:5][CH3:6])[CH2:1][CH3:2])[CH3:11]
Reactant: CC[Si](Cl)(CC)CC
Reactant: CNC
Solvent: CCOCC
Product: CC[Si](CC)(CC)N(C)C

Procedure:
Triethylchlorosilane, 75.4 g (0.5 mole), was added dropwise to a solution of 73 ml (1.1 mole) of dimethylamine in 500 ml diethyl ether at 10°-20°. A precipitate was removed by filtration, and the resulting filtrate distilled to provide 64.8 g of dimethylaminotriethylsilane as a colorless liquid, bp 88° (46 mm). A 47.8 g (0.3 mole) sample of the silane was added dropwise to a solution of 5 ml (0.09 mole) of sulfur tetrafluoride in 100 ml of ether cooled to -70°. The resulting mixture was allowed to warm to about 23° and stirred for one week. The resulting white solid precipitate was collected on a filter, washed with ether, and dried under nitrogen to give 6.8 g of tris(dimethylamino)sulfonium bifluoride as colorless crystals: mp 117°-120°; 19F NMR (CD3CN) δ-150.4 ppm; 1H NMR (CD3CN) δ+2.95 ppm.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:24]=[CH:23][C:6]([CH2:7][N:8]2[C:13]3[S:14][C:15]([CH:17]=O)=[CH:16][C:12]=3[C:11]3=[N:19][CH:20]=[N:21][N:10]3[C:9]2=[O:22])=[CH:5][CH:4]=1.Cl.[O:26]1[CH2:32][CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1.C(N(CC)CC)C.[Na]>ClCCl>[O:26]1[CH2:32][CH2:31][CH2:30][N:29]([CH2:17][C:15]2[S:14][C:13]3[N:8]([CH2:7][C:6]4[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:24][CH:23]=4)[C:9](=[O:22])[N:10]4[N:21]=[CH:20][N:19]=[C:11]4[C:12]=3[CH:16]=2)[CH2:28][CH2:27]1
Reactant: C1CNCCOC1
Reactant: COc1ccc(Cn2c(=O)n3ncnc3c3cc(C=O)sc32)cc1
Agent: Cl
Agent: [Na]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(Cn2c(=O)n3ncnc3c3cc(CN4CCCOCC4)sc32)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 51.7 %

Procedure:
8-((1,4-oxazepan-4-yOmethyl)-6-(4-methoxybenzyl)thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one (29). To a mixture of 6-(4-methoxybenzyl)-5-oxo-5,6-dihydrothieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidine-8-carbaldehyde (50 mg, 0.15 mmol) and 1,4-oxazepane hydrochloride (30 mg, 0.22 mmol) in dichloromethane (2 ml) was added triethylamine (25 μl, 0.18 mmol). After 5 minutes of stifling, sodium triacetoxyhydroborate (47 mg, 0.22 mmol) was added. The resulting mixture was stirred at room temperature. After 4 hours, the mixture was concentrated under reduced pressure. The resulting residue was taken up in DMSO (2 mL), filtered and purified directly by reverse phase chromatography to yield the above product (33 mg, 41%) as a white solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])[C:11]([C:20]([F:23])([F:22])[F:21])=[CH:10][C:9]=1[NH2:24])([CH3:4])([CH3:3])[CH3:2].C([O:30][C:31](=O)[CH2:32][C:33]([C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([C:41]2[CH:42]=[N:43][C:44]([CH:47]3[CH2:49][CH2:48]3)=[CH:45][CH:46]=2)[CH:36]=1)=[O:34])(C)(C)C>>[C:1]([O:5][C:6](=[O:25])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][C:16]([F:18])([F:17])[F:19])[C:11]([C:20]([F:22])([F:23])[F:21])=[CH:10][C:9]=1[NH:24][C:31](=[O:30])[CH2:32][C:33]([C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([C:41]2[CH:42]=[N:43][C:44]([CH:47]3[CH2:48][CH2:49]3)=[CH:45][CH:46]=2)[CH:36]=1)=[O:34])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-c2ccc(C3CC3)nc2)c1
Reactant: CC(C)(C)OC(=O)Nc1cc(OCC(F)(F)F)c(C(F)(F)F)cc1N
Product: CC(C)(C)OC(=O)Nc1cc(OCC(F)(F)F)c(C(F)(F)F)cc1NC(=O)CC(=O)c1cccc(-c2ccc(C3CC3)nc2)c1

Procedure:
The title compound was prepared from [2-amino-5-(2,2,2-trifluoro-ethoxy)-4-trifluoromethyl-phenyl]-carbamic acid tert-butyl ester (Example J6) (281 mg, 0.75 mmol) and 3-[3-(6-cyclopropyl-pyridin-3-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K21) (253 mg, 0.75 mmol) according to the general procedure M. Obtained as a yellow foam (344 mg, 72%).
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([C@H:6]([O:13][C:14]3[CH:15]=[CH:16][C:17]4[N:18]([C:20]([CH:23]([CH3:25])[CH3:24])=[N:21][N:22]=4)[CH:19]=3)[CH2:7][CH2:8][C@@H:9]2[NH2:12])=[CH:4][CH:3]=1.ClC(Cl)(Cl)C[O:29][C:30](=O)[NH:31][C:32]1[N:33]([CH3:41])[N:34]=[C:35]([C:37]([CH3:40])([CH3:39])[CH3:38])[CH:36]=1.CCN(C(C)C)C(C)C>O1CCOCC1.CCN(C(C)C)C(C)C>[C:37]([C:35]1[CH:36]=[C:32]([NH:31][C:30]([NH:12][C@@H:9]2[C:10]3[C:5](=[CH:4][CH:3]=[C:2]([F:1])[CH:11]=3)[C@H:6]([O:13][C:14]3[CH:15]=[CH:16][C:17]4[N:18]([C:20]([CH:23]([CH3:25])[CH3:24])=[N:21][N:22]=4)[CH:19]=3)[CH2:7][CH2:8]2)=[O:29])[N:33]([CH3:41])[N:34]=1)([CH3:40])([CH3:38])[CH3:39]
Reactant: Cn1nc(C(C)(C)C)cc1NC(=O)OCC(Cl)(Cl)Cl
Reactant: CC(C)c1nnc2ccc(O[C@@H]3CC[C@H](N)c4cc(F)ccc43)cn12
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CC(C)c1nnc2ccc(O[C@@H]3CC[C@H](NC(=O)Nc4cc(C(C)(C)C)nn4C)c4cc(F)ccc43)cn12
Yield: 63.1 %

Procedure:
Intermediate 19b (85.0 mg, 0.250 mmol) and (5-tert-butyl-2-methyl-2H-pyrazol-3-yl)-carbamic acid 2,2,2-trichloro-ethyl ester (US2004/192653, 99 mg, 0.300 mmol) were dissolved in 1,4-dioxane (3 mL) and DIPEA (70 μL, 0.400 mmol). The reaction was heated at reflux for 1.75 h, then more (5-tert-butyl-2-methyl-2H-pyrazol-3-yl)-carbamic acid 2,2,2-trichloro-ethyl ester (35 mg, 0.100 mmol) and DIPEA (3 drops) were added. After a further 4 h the mixture was concentrated in vacuo. The residue was purified by FCC, using 0-15% MeOH in DCM, to give impure product (82 mg). Further purification twice by HPLC (C18 X-select column, 40-98% MeCN in H2O, 0.1% HCO2H) gave the title compound as a white powder after freeze-drying (44 mg, 34%). LCMS (Method 5): Rt 3.83 min, m/z 520.1 [MH+]. 1H NMR (400 MHz, d6-DMSO): 1.21 (9H, s), 1.35-1.43 (6H, m), 1.85-2.25 (4H, m), 3.51-3.62 (4H, m), 4.80-4.91 (1H, m), 5.50-5.57 (1H, m), 6.02 (1H, s), 7.09 (1H, d, J 8.8), 7.11-7.17 (2H, m), 7.20 (1H, dd, J 9.6, 2.2), 7.44-7.50 (1H, m), 7.69 (1H, d, J 9.6), 8.22 (1H, br d), 8.40 (1H, s).
Reaction SMILES: C1(C(C2C=CC=CC=2)(O)C(O)=O)CCCCC1.[CH3:18][CH2:19][N:20]([CH2:23][C:24]#[C:25][CH2:26][O:27][C:28]([C@:30]([OH:43])([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[CH:31]1[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1)=[O:29])CC.C(OC(Cl)=O)C(C)C.C(O)C#C.C(N(C(C)C#CO)CC1C=CC(OC)=CC=1)C.C1(C(C2CCCCC2)(O)C(OC#CCCN(CC)CC2C=CC(OC)=CC=2)=O)C=CC=CC=1.C(Cl)(=O)OC(Cl)C>>[C:31]1([C@:30]([CH:37]2[CH2:38][CH2:39][CH2:40][CH2:41][CH2:42]2)([OH:43])[C:28]([O:27][CH2:26][C:25]#[C:24][CH2:23][NH:20][CH2:19][CH3:18])=[O:29])[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: CCN(CC)CC#CCOC(=O)[C@](O)(c1ccccc1)C1CCCCC1
Agent: C#CCO
Agent: CC(C)COC(=O)Cl
Agent: CC(Cl)OC(=O)Cl
Product: CCNCC#CCOC(=O)[C@@](O)(c1ccccc1)C1CCCCC1

Procedure:
The method according to claim 1, wherein said single enantiomer of cyclohexylphenyl glycolic acid is the (S) enantiomer, said alkyl chloroformate is isobutylchloroformate, said sidechain propargyl alcohol derivative of formula (III) is N-ethyl-N-(4-methoxybenzyl)aminobutynol, and said single enantiomer of structure (II) is N-ethyl-N-(4-methoxybenzyl)aminobutynyl phenylcyclohexyl-glycolate, which is treated with α-chloroethyl carbonochloridate to provide (S)-4-ethylamino-2-butynyl phenylcyclohexylglycolate.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:15]#[N:16])[C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[C:7]([O:12][CH3:13])[C:6]=2Br.O.O.[Sn](Cl)Cl.Cl>C(O)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]([C:15]#[N:16])[C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[C:7]([O:12][CH3:13])[CH:6]=2
Reactant: COc1ccc2cc(Br)cc(C#N)c2c1Br
Agent: Cl
Agent: Cl[Sn]Cl
Solvent: CC(=O)O
Solvent: O
Product: COc1ccc2cc(Br)cc(C#N)c2c1
Temperature: 100 °C
Reaction time: 2 h
Yield: 42.1 %

Procedure:
To slurry of 3,8-dibromo-7-methoxy-1-naphthonitrile (1.62 kg) and Tin (II) chloride dihydrate (1.24 kg, 5.50 mol) in acetic acid (5 L) is added conc. HCl (37% wt, 2.50 L) through a dropping funnel at 100° C. during a period of 2 h. The mixture is stirred at 100° C. for 4 h. Then, the mixture is cooled to room temperature. The solid is filtered, washed with 1% wt HCl (2×1.00 L), water (1.00 L) and dried to give the title compound as a white solid (524 g, 73%). 1H NMR (CDCl3): δ8.13 (d, 1H, J=1.8 Hz), 7.93 (d, 1H, J=1.9 Hz), 7.72 (d, 1H, J=9.0 Hz),7.41 (d, 1H, J=2.4 Hz), 7.28 (dd, 1H, J=2.4 Hz, 9.0 Hz), 3.99 (s, 3H).
Reaction SMILES: C(Cl)(Cl)Cl.[NH2:5][C:6]([CH3:13])([CH3:12])[CH2:7][NH:8][CH2:9][CH2:10][OH:11].[OH-:14].[Na+]>CC(C)=O.O>[OH:11][CH2:10][CH2:9][N:8]1[CH2:7][C:6]([CH3:13])([CH3:12])[NH:5][C:6]([CH3:13])([CH3:12])[C:7]1=[O:14]
Reactant: [OH-]
Reactant: CC(C)(N)CNCCO
Agent: [Na+]
Solvent: CC(C)=O
Solvent: ClC(Cl)Cl
Solvent: O
Product: CC1(C)CN(CCO)C(=O)C(C)(C)N1
Temperature: 5 °C

Procedure:
244.2 g (2.05 mol) of chloroform are added to 180 g (1.36 mol) of 2-(2-amino-2-methylpropylamino)ethanol in 1204 ml of acetone. The mixture is cooled to 5° C. under stirring and a solution of 327 g (8.18 mol) of sodium hydroxide in 327 ml of water is slowly added, the temperature of the mixture being maintained at 0°-5° C. during the addition. The mixture is then stirred at this temperature for further 2 hours and at room temperature for 15 hours. Subsequently, the pH of the aqueous solution is corrected to 11 and the mixture is stirred for further 4 hours. Then, the mixture is filtered and the residue is washed with acetone. The filtrate and the acetone of washing are collected and evaporated under vacuum (70° C./24 mbar). The residue is distilled giving a white oil with a boiling point of 115° C. at 2.66 mbar. After cooling a solid product with a melting point of 91°-93° C. is obtained.
Reaction SMILES: [CH3:1][N:2]([CH3:22])[C:3](=[O:21])[CH:4]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([OH:12])[CH:7]=1.F[C:24]1[CH:33]=[CH:32][C:27]([C:28]([O:30][CH3:31])=[O:29])=[CH:26][CH:25]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C.C(OCC)(=O)C>[C:16]([O:15][C:14]([NH:13][CH:4]([C:3]([N:2]([CH3:1])[CH3:22])=[O:21])[CH2:5][C:6]1[CH:7]=[C:8]([CH:9]=[CH:10][CH:11]=1)[O:12][C:24]1[CH:33]=[CH:32][C:27]([C:28]([O:30][CH3:31])=[O:29])=[CH:26][CH:25]=1)=[O:20])([CH3:17])([CH3:18])[CH3:19]
Reactant: COC(=O)c1ccc(F)cc1
Reactant: CN(C)C(=O)C(Cc1cccc(O)c1)NC(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(Oc2cccc(CC(NC(=O)OC(C)(C)C)C(=O)N(C)C)c2)cc1
Temperature: 100 °C
Reaction time: 4 h

Procedure:
tert-Butyl 1-(dimethylamino)-3-(3-hydroxyphenyl)-1-oxopropan-2-ylcarbamate (0.025 g, 0.081 mmol) and methyl 4-fluorobenzoate (Aldrich, Cat. #120707) (0.025 g, 0.16 mmol) were combined in acetonitrile (1.0 mL) with cesium carbonate (0.053 g, 0.16 mmol) in a sealed tube and heated to 100° C. After 4 h., the reaction was allowed to cool, diluted with ethyl acetate and washed with water, brine, dried over magnesium sulfate and concentrated under reduced pressure to give crude methyl 4-(3-(2-(tert-butoxycarbonylamino)-3-(dimethylamino)-3-oxopropyl)phenoxy)benzoate as a semi-solid. Analytical LCMS (M+H-Boc)+: m/z=342.9.
Reaction SMILES: C[O:2][C:3](=O)[CH:4]=[CH:5][C:6]1[CH:10]=[CH:9][N:8]([S:11]([C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)(=[O:13])=[O:12])[CH:7]=1.[Li+].[BH4-].CCCCCC.C(OCC)(=O)C>C1COCC1>[C:17]1([CH3:20])[CH:16]=[CH:15][C:14]([S:11]([N:8]2[CH:9]=[CH:10][C:6]([CH:5]=[CH:4][CH2:3][OH:2])=[CH:7]2)(=[O:13])=[O:12])=[CH:19][CH:18]=1
Reactant: COC(=O)C=Cc1ccn(S(=O)(=O)c2ccc(C)cc2)c1
Agent: [BH4-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: Cc1ccc(S(=O)(=O)n2ccc(C=CCO)c2)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 13 (3 g, 10 mmol) in 150 mL anhydrous THF was added LiBH4 (0.27 g, 12 mmol) under nitrogen and the mixture was stirred at room temperature for 24 h. The reaction was quenched by the addition of 1 M H2SO4 solution. The resulting solution was extracted with dichloromethane. The extracts were washed with saturated aqueous sodium bicarbonate, water and brine, dried over sodium sulphate, filtered and evaporated under vacuum to give light yellow solid which subjected to flash chromatography (silica gel, hexane:ethyl acetate=2:1) to afford 14.
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:11]=1)[C:7](Cl)=[N:8][OH:9].[C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)#[CH:13].N>>[F:1][C:2]1[CH:11]=[C:6]([C:7]2[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[O:9][N:8]=2)[CH:5]=[N:4][CH:3]=1
Reactant: ON=C(Cl)c1cncc(F)c1
Reactant: C#Cc1ccccc1
Agent: N
Product: Fc1cncc(-c2cc(-c3ccccc3)on2)c1

Procedure:
The titled compound was prepared according to Method CB using the product of product of Example 28B (88 mg, 0.5 mmol) and 1-ethynylbenzene (Aldrich, 52 mg, 0.5 mmol). 1H NMR (300 MHz, MeOH-d4) δ 7.39 (s, 1H), 7.49-7.60 (m, 3H), 7.88-7.97 (m, 2H), 8.17 (ddd, J=9.3, 2.9, 1.7 Hz, 1H), 8.60 (d, J=2.7 Hz, 1H), 8.97 (t, J=1.4 Hz, 1H) ppm; MS (DCI/NH3) m/z 241 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:6]([C:7](OCC)=[O:8])=[C:5]([C:12]2[CH2:17][CH2:16][CH:15]([CH3:18])[CH2:14][CH:13]=2)[S:4][N:3]=1.CC(C[AlH]CC(C)C)C>C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:6]([CH2:7][OH:8])=[C:5]([C:12]2[CH2:17][CH2:16][CH:15]([CH3:18])[CH2:14][CH:13]=2)[S:4][N:3]=1
Reactant: CCOC(=O)c1c(Cl)nsc1C1=CCC(C)CC1
Agent: CC(C)C[AlH]CC(C)C
Solvent: Cc1ccccc1
Product: CC1CC=C(c2snc(Cl)c2CO)CC1
Temperature: 20 °C
Yield: 35.5 %

Procedure:
Into a 25-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed ethyl 3-chloro-5-(4-methylcyclohex-1-en-1-yl)-1,2-thiazole-4-carboxylate (150 mg, 0.52 mmol, 1.00 equiv), toluene (3 mL). DIBAL-H (0.926 mL) was added dropwise at −78° C. with stirring. The resulting solution was allowed to warm to 20° C. and then stirred for 1 h. The reaction was then quenched by the addition of MeOH. The resulting mixture was concentrated under reduced pressure. The residue was applied to a silica gel column, eluting with ethyl acetate/petroleum ether (20:80), to afford 45 mg (35%) of [3-chloro-5-(4-methylcyclohex-1-en-1-yl)-1,2-thiazol-4-yl]methanol as colorless oil.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[CH2:3][NH:4][C:5](=S)[NH:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([S:13][CH3:14])[N:8]=1.[NH3:18]>CO>[F:1][C:2]([F:17])([F:16])[CH2:3][N:4]=[C:5]([NH2:18])[NH:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([S:13][CH3:14])[N:8]=1
Reactant: N
Reactant: CSc1nccc(NC(=S)NCC(F)(F)F)n1
Solvent: CO
Product: CSc1nccc(NC(N)=NCC(F)(F)F)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 4-[3-(2,2,2-trifluoroethyl)thioureido]-2-methylthiopyrimidine (2.15 g.), methanol (100 ml.), saturated ethanolic ammonia (10 ml.) and yellow mercuric oxide (4.3 g.) was stirred at room temperature for 2 hours and then filtered. The filtrate was evaporated to dryness and the residue recrystallised from ethanol to give 4-[2-(2,2,2-trifluoroethyl)guanidino]-2-methylthiopyrimidine (1.5 g.), m.p. 201°-202°.