Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH2:9][C:10]([O:12]CC)=O)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:15][NH:16][NH2:17]>C(O)(C)C>[CH3:15][N:16]1[C:10](=[O:12])[CH2:9][C:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[N:17]1
Reactant: CCOC(=O)CC(=O)c1ccccc1
Reactant: CNN
Solvent: CC(C)O
Product: CN1N=C(c2ccccc2)CC1=O
Temperature: 20 °C
Reaction time: 2 h

Procedure:
Ethyl benzoylacetate (1,538 g. 8 moles) dissolved in isopropanol (6l) is placed in a 12 l flask under an atmosphere of nitrogen. Methylhydrazine (410 g, 8.7 moles, 98%) in isopropanol (800 ml) is added with stirring in a dropwise manner to the ethyl benzoylacetate solution prewarmed to about 80° C. During the addition the external heating is removed. Seeding of the reaction mixture with the product at the point of one-third addition of methylhydrazine causes a copious precipitate of product. This procedure eliminates a large exotherm from occurring at a later stage. After the addition is complete, the reaction mixture is held at about 80° C. for 2 hours. Cooling the slurry to 20° C. and filtering off the solid, a yield of 1,131 g (81%) of product after drying with a melting point equal to 211° C. is obtained.
Reaction SMILES: C(O[C:6]([N:8](C)[C@@H:9]([CH2:13][C:14]([CH3:17])([CH3:16])C)[C:10](O)=O)=[O:7])(C)(C)C.[F:19][C:20]([F:37])([F:36])[C:21]1[CH:22]=[CH:23][C:24]([N:27]2[CH2:31][C@@H]3[C@@H](N)CC[C@@H]3C2)=[N:25][CH:26]=1.FC(F)(F)[C:40]1N=[C:44]([N:46]2C[C@@H]3[C@@H](N)CC[C@@H]3[CH2:47]2)[CH:43]=[CH:42][CH:41]=1>>[CH3:47][NH:46][C@H:44]([C:6]([NH:8][C@@H:9]1[C@@H:13]2[C@@H:14]([CH2:16][N:27]([C:24]3[CH:23]=[CH:22][C:21]([C:20]([F:19])([F:36])[F:37])=[CH:26][N:25]=3)[CH2:31]2)[CH2:17][CH2:10]1)=[O:7])[CH2:43][CH2:42][CH2:41][CH3:40]
Reactant: N[C@H]1CC[C@@H]2CN(c3ccc(C(F)(F)F)cn3)C[C@@H]21
Reactant: CN(C(=O)OC(C)(C)C)[C@@H](CC(C)(C)C)C(=O)O
Reactant: N[C@H]1CC[C@@H]2CN(c3cccc(C(F)(F)F)n3)C[C@@H]21
Product: CCCC[C@H](NC)C(=O)N[C@H]1CC[C@@H]2CN(c3ccc(C(F)(F)F)cn3)C[C@@H]21

Procedure:
The title compound was prepared by substituting N-(tert-butoxycarbonyl)-N-methyl-L-norleucine for (S)-2-(tert-butoxycarbonyl(methyl)amino)-4,4-dimethylpentanoic acid and (3aR,4S,6aS)-2-(5-(trifluoromethyl)pyridin-2-yl)octahydrocyclopenta[c]pyrrol-4-amine from Example 262 Step B for (3aR,4S,6aS)-2-(6-(trifluoromethyl)pyridin-2-yl)octahydrocyclopenta[c]pyrrol-4-amine in the procedure described in Example 587: 1H NMR (500 MHz, pyridine-d5) δ ppm 8.64-8.59 (m, 1H), 8.27 (d, J=7.5, 1H), 7.68 (dd, J=8.9, 2.5, 1H), 6.39 (d, J=8.9, 1H), 4.47-4.39 (m, 1H), 3.83 (d, J=10.5, 1H), 3.71-3.64 (m, 1H), 3.62-3.54 (m, 1H), 3.33 (d, J=8.5, 1H), 3.19 (dd, J=6.9, 6.2, 1H), 2.81-2.70 (m, 2H), 2.44 (s, 3H), 2.21-2.13 (m, 1H), 2.16-2.03 (m, 1H), 2.01-1.90 (m, 1H), 1.86 (ddt, J=13.3, 10.3, 5.9, 1H), 1.77-1.64 (m, 2H), 1.55-1.37 (m, 3H), 1.32-1.20 (m, 2H), 0.83 (t, J=7.3, 3H); MS (ESI+) m/z 399 (M+H)+.
Reaction SMILES: [CH:1]12[O:6][CH:5]1[CH2:4][N:3]([C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8])[CH2:2]2.[Cu](C#N)[C:18]#N.C[Mg]Br>C1COCC1>[OH:6][C@H:5]1[C@H:1]([CH3:18])[CH2:2][N:3]([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])[CH2:4]1
Reactant: O=C(OCc1ccccc1)N1CC2OC2C1
Reactant: N#C[Cu]C#N
Agent: C[Mg]Br
Solvent: C1CCOC1
Product: C[C@@H]1CN(C(=O)OCc2ccccc2)C[C@H]1O
Temperature: -20 °C
Reaction time: 1 h
Yield: 89.3 %

Procedure:
To solution of benzyl 6-oxa-3-azabicyclo[3.1.0]hexane-3-carboxylate (9.6 g, 43.8 mmol) in THF (150 mL) was added copper cyanide (3.92 g, 43.8 mmol) and the resulting suspension was cooled to −20° C. with dry ice-ice-water-acetone bath. Methylmagnesium bromide (3 M in diethylether) (29.2 mL, 88 mmol) was added via syringe dropwise and the resulting mixture was stirred at this temperature for 1 h. At this time, TLC analysis of the resulting slurry (after quenching an aliquot with MeOH) indicated total comsumption of substrate to give a single, more polar component. At this time, the reaction was carefully quenched at −20° C. by a slow dropwise addition of 50 mL of sat. aq. ammonium chloride. The cooling bath was removed and the mixture was allowed to stir vigorously for 1 h while warming to rt. Solid was removed by vacuum filtration through Celite and the filter cake was rinsed with dichloromethane (80 mL×3). The resulting two layers of the filtrate were separated and the aqueous portion was extracted with dichloromethane (80 mL). The combined organic portions were washed with brine and dried over magnesium sulfate, filtered and concentrated to afford the title compound as a clear oil (9.2 g, 39.1 mmol, 89% yield). HPLC (method B) retention time=2.64 min. and LCMS (m+1)=236.2.
Reaction SMILES: [C:1]([OH:6])(=[O:5])[C:2]([OH:4])=[O:3].[CH2:7]([O:14][NH:15][CH:16]1[CH2:21][NH:20][CH:19]([C:22]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:23])[CH2:18][CH2:17]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(=O)(O)[O-].[K+].O.O.C(O)(=O)C(O)=O>C(OCC)(=O)C.O.CO>[C:1]([OH:6])(=[O:5])[C:2]([OH:4])=[O:3].[CH2:7]([O:14][NH:15][C@H:16]1[CH2:21][NH:20][C@H:19]([C:22]([O:24][CH2:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)=[O:23])[CH2:18][CH2:17]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=C(OCc1ccccc1)C1CCC(NOCc2ccccc2)CN1
Agent: O=C(O)C(=O)O
Agent: O=C([O-])O
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CO
Product: O=C(OCc1ccccc1)[C@@H]1CC[C@@H](NOCc2ccccc2)CN1
Temperature: 45 °C

Procedure:
To a slurry of benzyl 5-[(benzyloxy)amino]piperidine-2-carboxylate ethanedioate (1:1) (10 g, 23.3 mmol, 3:1, SR:SS) in ethyl acetate (70 ml) was added a solution of potassium bicarbonate (9.3 g, 93 mmol, 4 eq) in water (90 ml). The mixture was stirred until all the solids had dissolved. The layers were separated and the aqueous layer was extracted with ethyl acetate (30 ml). The combined organic layers were washed with water (50 ml) and concentrated under vacuum below 40° C. to a final volume of 40 ml. The solution was passed through a filter and warmed to 45° C. Methanol (20 ml) at 40° C. was added, followed by a freshly prepared solution of oxalic acid dihydrate (3.67 g, 29.1 mmol) in methanol (10 ml). The mixture was cooled and the product was isolated by filtration. The solid was washed with an ethyl acetate/methanol mixture, then with ethyl acetate. The solid was dried to give benzyl (2S,5R)-5-[(benzyloxy)amino]piperidine-2-carboxylate ethanedioate (1:1) as a single isomer (7.0 g, 16.3 mmol, 70%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][C:10](=[S:19])[NH:11][C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.[H-].[Na+].[H][H].[CH:24](Br)([CH3:26])[CH3:25]>CN(C)C=O.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]([S:19][CH:24]([CH3:26])[CH3:25])[NH:11][C:12]=2[C:13]2[CH:14]=[CH:15][N:16]=[CH:17][CH:18]=2)=[CH:6][CH:7]=1
Reactant: [H][H]
Reactant: Fc1ccc(-c2[nH]c(=S)[nH]c2-c2ccncc2)cc1
Reactant: CC(C)Br
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)Sc1nc(-c2ccc(F)cc2)c(-c2ccncc2)[nH]1
Reaction time: 3 h
Yield: 15.2 %

Procedure:
To 8.0 g of 4-(4-fluorophenyl)-5-(4-pyridyl)-1H-imidazole-2-thione in 100 ml of dimethylformamide was added 1.56 g of sodium hydride (50% in mineral oil). The mixture was stirred until the evolution of hydrogen ceased. At this point 3.9 g of isopropyl bromide was added with a syringe. After stirring for 3 hours the mixture was poured into water, filtered and air dried. Trituration with ether, filtering and drying gave 5.73 g. Recrystallizing a 3.0 g sample from ethanol gave 1.4 g of the title compound, m.p. 263°-264°.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[O:3][C:4]1[CH:5]=[C:6]([CH:15]=[CH:16][CH:17]=1)[O:7][C:8]1[CH:9]=[C:10]([CH:12]=[CH:13][CH:14]=1)[NH2:11].[F:20][C:21]([F:34])([O:25][C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=1)[CH:29]=O)[CH:22]([F:24])[F:23].C(O[BH-](O[C:45](=[O:47])[CH3:46])OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClC(Cl)C>[F:1][C:2]([F:18])([F:19])[O:3][C:4]1[CH:5]=[C:6]([CH:15]=[CH:16][CH:17]=1)[O:7][C:8]1[CH:9]=[C:10]([N:11]([CH2:29][C:28]2[CH:31]=[CH:32][CH:33]=[C:26]([O:25][C:21]([F:34])([F:20])[CH:22]([F:24])[F:23])[CH:27]=2)[CH2:46][C@@H:45]([OH:47])[C:2]([F:19])([F:18])[F:1])[CH:12]=[CH:13][CH:14]=1
Reactant: Nc1cccc(Oc2cccc(OC(F)(F)F)c2)c1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: O=Cc1cccc(OC(F)(F)C(F)F)c1
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Product: O[C@H](CN(Cc1cccc(OC(F)(F)C(F)F)c1)c1cccc(Oc2cccc(OC(F)(F)F)c2)c1)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 165.6 %

Procedure:
To a solution of 3-(3-trifluoromethoxyphenoxy)aniline (1.0 g, 3.7 mmol) from EX-19B and 3-(1,1,2,2-tetrafluoroethoxy)benzaldehyde (0.83 g, 3.7 mmol) in 18.5 mL of dichloroethane was added sodium triacetoxyborohydride (1.0 g, 4.7 mmol) and glacial acetic acid (0.25 mL, 4.3 mmol). The reaction mixture was stirred at room temperature overnight then quenched with saturated aqueous sodium bicarbonate and extracted with methylene chloride. The organic layer was dried over MgSO4 and concentrated in vacuo to give 1.8 g (100%) of the desired [3-(3-trifluoromethoxy-phenoxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]amine product as a yellow oil, which was greater than 90% pure by reverse phase HPLC analysis. HRMS calcd. for C22H16F7NO3: 476.1097 [M+H]+, found: 476.1069. This material was carried on to the next step without further purification.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11](=[O:16])[CH:10]=[CH:9]2.[NH2:17][CH2:18][CH:19]([OH:21])[CH3:20]>CC(O)C>[OH:21][CH:19]([CH3:20])[CH2:18][NH:17][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11](=[O:16])[CH:10]=[CH:9]2
Reactant: O=c1ccc2cc(OCCCCl)ccc2[nH]1
Reactant: CC(O)CN
Solvent: CC(C)O
Product: CC(O)CNCCCOc1ccc2[nH]c(=O)ccc2c1

Procedure:
6-(3-Chloropropoxy)carbostyril (5 g) and 1-amino-2-propanol (24 ml) are dissolved in 2-propanol (100 ml), and the mixture is refluxed for 4 hours. After the reaction mixture is allowed to cool, the precipitated crystals are collected by filtration, washed with ethanol, and dried to give 6-[3-(2-hydroxypropyl)aminopropoxy]carbostyril (3.1 g) as a white powder.
Reaction SMILES: [CH2:1]([Li])[CH2:2][CH2:3][CH3:4].[CH3:6][O:7][C:8]1[CH:9]=[CH:10][CH:11]=[C:12]2[C:17]=1[N:16]=C(C)C=[CH:13]2.IC>O1CCCC1>[CH2:3]([C:2]1[CH:1]=[CH:13][C:12]2[C:17](=[C:8]([O:7][CH3:6])[CH:9]=[CH:10][CH:11]=2)[N:16]=1)[CH3:4]
Reactant: [Li]CCCC
Reactant: COc1cccc2ccc(C)nc12
Solvent: C1CCOC1
Solvent: CI
Product: CCc1ccc2cccc(OC)c2n1
Temperature: -60 °C
Reaction time: 0.25 h

Procedure:
n-Butyllithium (1 ml, 1.6M in hexanes) was added dropwise to a stirred solution of 8-methoxy-2-methylquinoline (0.25 g) in tetrahydrofuran (4 ml) at -60° C. under an inert atmosphere. The resulting red solution was stirred at -60° C. for 15 minutes, and then warmed to -40° C. Iodomethane (0.27 ml) was then added dropwise and the reaction warmed slowly to room temperature with continued stirring for 12 hours. The reaction was quenched with brine (50 ml) and extracted with dichloromethane (2×5ml). The organic phases were combined, dried over magnesium sulphate and preadsorbed onto silica. Purification was achieved by column chromatography eluting with ethyl acetate to afford the title compound as a pale yellow solid (0.16 g).
Reaction SMILES: [NH:1]([C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15])[C@H:2]([C:10]([O:12]C)=[O:11])[CH2:3][C:4]1[CH:9]=[N:8][CH:7]=[CH:6][CH:5]=1.[OH-].[Na+].CO>C(#N)C>[NH:1]([C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15])[C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[N:8][CH:7]=[CH:6][CH:5]=1
Reactant: COC(=O)[C@H](Cc1cccnc1)NC(=O)OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Solvent: CO
Product: O=C(N[C@@H](Cc1cccnc1)C(=O)O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
5.5 g of Z-Pal-OMe (18.2 mMol) are dissolved in 100 ml of acetonitrile, mixed with 20 ml of 1N NaOH and stirred for 3 hours at ambient temperature. The mixture is neutralised by adding 20 ml of 1N NaOH, the solvent is largely removed on the rotary evaporator and the solid residue is mixed with ice cold water. After suction filtering the mixture is washed with a little water and the residue is dried in the desiccator whereby Z-Pal-OH is obtained in the form of white crystals. M.p.: 82° C.; [α]D20 (MeOH)=-9.4°.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:10])[C@H:4]([CH2:6][CH:7]([CH3:9])[CH3:8])[NH2:5].C(N(CC)CC)C.Cl[C:19]([O:21][CH2:22][CH:23]=[CH2:24])=[O:20]>ClCCl>[CH3:1][O:2][C:3](=[O:10])[C@H:4]([CH2:6][CH:7]([CH3:9])[CH3:8])[NH:5][C:19]([O:21][CH2:22][CH:23]=[CH2:24])=[O:20]
Reactant: C=CCOC(=O)Cl
Reactant: COC(=O)[C@@H](N)CC(C)C
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CCOC(=O)N[C@@H](CC(C)C)C(=O)OC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of leucine methyl ester (5 mmol) and triethylamine (10 mmol) in dichloromethane (50 ml) was cooled to 0° C. and treated dropwise with allyl chloroformate. After addition, the solution was stirred at ambient temperature for 2 h, diluted with dichloromethane, washed successively with 1N HCl and aqueous NaHCO3, dried over Na2 SO4, and concentrated to give the desired compound.
Reaction SMILES: [CH3:1][C:2]1[NH:6][CH:5]=[N:4][C:3]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C([O-])([O-])=O.[K+].[K+].[CH2:19](OS(C)(=O)=O)[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(#N)C>[CH3:1][C:2]1[N:6]([CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:5]=[N:4][C:3]=1[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1.[CH3:1][C:2]1[N:6]=[CH:5][N:4]([CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:3]=1[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: CS(=O)(=O)OCCc1ccccc1
Reactant: Cc1[nH]cnc1-c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cc1c(-c2ccccc2)ncn1CCc1ccccc1
Product: Cc1ncn(CCc2ccccc2)c1-c1ccccc1
Temperature: 25 °C

Procedure:
To a solution of 5-methyl-4-phenyl-1H-imidazole (example 103D) (1.02 g, 6.44 mmoles) in ACN (20 mL) are added K2CO3 (1.07 g, 7.72 mmoles) and methanesulfonic acid phenethyl ester (example 4D). The reaction mixture is heated at reflux overnight, then cooled to room temperature, filtered, cake washed with ACN and solvent is removed under reduced pressure. The residue is purified by silica gel chromatography using (toluene:acetone) (90:10) as eluent to give 5-methyl-1-phenethyl-4-phenyl-imidazole and 4-methyl-1-phenethyl-5-phenyl-imidazole.
Reaction SMILES: Br[C:2]1[CH:6]=[CH:5][S:4][C:3]=1[CH:7]=[O:8].[C:9]1(B(O)O)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>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>[C:9]1([C:2]2[CH:6]=[CH:5][S:4][C:3]=2[CH:7]=[O:8])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: OB(O)c1ccccc1
Reactant: O=Cc1sccc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: COCCOC
Product: O=Cc1sccc1-c1ccccc1
Temperature: 80 °C
Reaction time: 0.25 h
Yield: 33.7 %

Procedure:
3-Bromothiophene-2-carbaldehyde (3 g, 1.67 ml, 14.8 mmol, CAS RN 930-96-1) was dissolved in DME (180 mL) and the resulting solution was evacuated and purged with argon three times. Pd(Ph3P)4 (512 mg, 443 μmol) was added, the reaction flask purged again with argon and stirring was continued at RT for 15 min. Then 2M aqueous Na2CO3 solution was added (14.8 mL, 29.5 mmol) followed by phenylboronic acid (1.98 g, 16.2 mmol). Again the reaction flask was purged with argon and the reaction mixture was heated to 80° C. and stirred for 6.5 h. After evaporation of the solvent, the residue was taken up in Et2O and H2O and the layers were separated. The organic layer was dried over Na2SO4, filtered and evaporated. The crude residue was suspended in CH2Cl2 and n-heptane and the solid was filtered off. The filtrate was evaporated and the crude product purified by flash chromatography on silica gel (gradient EtOAc/n-heptane, 0% to 10%). The product-containing fractions were pooled and further purified by preparative HPLC to give the title compound as a yellow oil (0.939 g, 34%). MS (ESI): m/z=189.2 [M+H]+.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([C:16]2[N:17]=[C:18]3[N:22]([C:23]=2[CH:24]=[O:25])[CH2:21][CH2:20][S:19]3)[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+].C(O)(=O)C.O>C(O)C>[C:12]([C:9]1[CH:8]=[C:7]([C:16]2[N:17]=[C:18]3[N:22]([C:23]=2[CH2:24][OH:25])[CH2:21][CH2:20][S:19]3)[CH:6]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:10]=1[OH:11])([CH3:13])([CH3:14])[CH3:15]
Reactant: CC(C)(C)c1cc(-c2nc3n(c2C=O)CCS3)cc(C(C)(C)C)c1O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: CC(=O)O
Product: CC(C)(C)c1cc(-c2nc3n(c2CO)CCS3)cc(C(C)(C)C)c1O
Reaction time: 0.17 h
Yield: 74.6 %

Procedure:
In 10 ml of ethanol was dissolved 0.4 g of 6-(3,5-di-tert-butyl-4-hydroxyphenyl)-5-formyl-2,3-dihydroimidazo[2,1-b]thiazole and after adding 40 mg of sodium borohydride to the solution, the mixture was stirred for 10 minutes. To the reaction mixture were added 0.3 ml of acetic acid and 30 ml of water, and the crystals thus precipitated were recovered by filtration and recrystallized from aqueous ethanol to provide 0.3 g of 6-(3,5-di-tert-butyl-4-hydroxyphenyl)-5-hydroxymethyl-2,3-dihydroimidazo[2,1-b]thiazole.
Reaction SMILES: [CH3:1][C:2](OC(C)=O)=[O:3].[CH3:8][C:9]1[NH:10][C:11]([CH3:31])=[C:12]([C:27]([O:29][CH3:30])=[O:28])[CH:13]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([NH2:26])[CH:21]=2)[C:14]=1[C:15]([O:17][CH2:18][CH3:19])=[O:16]>N1C=CC=CC=1>[CH3:8][C:9]1[NH:10][C:11]([CH3:31])=[C:12]([C:27]([O:29][CH3:30])=[O:28])[CH:13]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([NH:26][C:2](=[O:3])[CH3:1])[CH:21]=2)[C:14]=1[C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: CCOC(=O)C1=C(C)NC(C)=C(C(=O)OC)C1c1cccc(N)c1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CCOC(=O)C1=C(C)NC(C)=C(C(=O)OC)C1c1cccc(NC(C)=O)c1

Procedure:
Under inert gas atmosphere Ac2O (43 mcl) is added to a stirred solution of (-)-2,6-dimethyl-3-carboethoxy-5-carbomethoxy-4-(3-aminophenyl)-1,4-dihydropyridine (100 mg) in pyridine (ml 1). 90 minutes after dilution with water (ml 50), extraction with AcOEt (3×10 ml) and crystallization from Et2O 70/EtOH 10, give mg 85 of +)-2,6-dimethyl-3-carboethoxy-5-carbomethoxy-4-(3-acetylaminophenyl)-1,4-dihydropyridine m.p. 197°-199° C. [α]D =+0.87°, [α]578 =+2.00°, [α]546 =+1.64° c=2.2 DMF.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH2:23][CH2:24][OH:25])[CH2:10][C:11]([N:13]([CH3:22])[C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)=[O:12])[CH:5]=[CH:6][C:7]=1[Cl:8].CCN(CC)CC.[CH3:33][S:34](Cl)(=[O:36])=[O:35]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH2:23][CH2:24][O:25][S:34]([CH3:33])(=[O:36])=[O:35])[CH2:10][C:11]([N:13]([CH3:22])[C:14]2[CH:15]=[CH:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=2)=[O:12])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: COc1ccc(N(C)C(=O)CC(CCO)c2ccc(Cl)c(Cl)c2)cc1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(N(C)C(=O)CC(CCOS(C)(=O)=O)c2ccc(Cl)c(Cl)c2)cc1

Procedure:
3,4-Dichloro-beta-(2-hydroxyethyl)-N-methyl-N-(4-methoxyphenyl)-benzene propanamide (2.0 g) in CH2Cl2 (50 mL) was cooled to -5° to -10° C. and treated sequentially with Et3N (0.911 mL), and methanesulfonyl chloride (0.64 mL). After two hours the reaction mixture was washed with water (100 mL), brine (100 mL) and the organic layer separated, dried over MgSO4, filtered and concentrated under reduced pressure to give the title compound (2.56 g).
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[CH:6][N:5]=[C:4]([NH2:9])[C:3]=1[N+:10]([O-:12])=[O:11].[Si:13]([O:20][C@@H:21]1[C@H:25]([CH2:26][O:27][Si:28]([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:30])[CH3:29])[CH2:24][C@@H:23]([NH2:35])[CH2:22]1)([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14].CCN(C(C)C)C(C)C>C(O)C>[Si:13]([O:20][C@@H:21]1[C@H:25]([CH2:26][O:27][Si:28]([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:29])[CH3:30])[CH2:24][C@@H:23]([NH:35][C:2]2[C:7]([Cl:8])=[CH:6][N:5]=[C:4]([NH2:9])[C:3]=2[N+:10]([O-:12])=[O:11])[CH2:22]1)([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14]
Reactant: Nc1ncc(Cl)c(Cl)c1[N+](=O)[O-]
Reactant: CC(C)(C)[Si](C)(C)OC[C@@H]1C[C@@H](N)C[C@@H]1O[Si](C)(C)C(C)(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: CC(C)(C)[Si](C)(C)OC[C@@H]1C[C@@H](Nc2c(Cl)cnc(N)c2[N+](=O)[O-])C[C@@H]1O[Si](C)(C)C(C)(C)C
Yield: 82.6 %

Procedure:
A solution of 4,5-dichloro-3-nitropyridin-2-amine (0.0365 g, 0.000175 mol) (Johansson, H; Lawitz, K; Nikitidis, G; Sjoe, P; Storm, P. PCT Int. Application WO2004/016611), (1R,3S,4S)-3-{[tert-butyl(dimethyl)silyl]oxy)-4-({[tert-butyl(dimethyl)silyl]-oxy}methyl)cyclopentanamine (0.0947 g, 0.000263 mol) and DIPEA (0.0907 g, 0.000702 mol) in ethanol (10.0 mL) was refluxed overnight. The reaction was concentrated and purified by flash chromatography (30% EtOAc/hexanes) to afford the title compound (0.0768 g, 82%) as a yellow solid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:10])[CH3:9].[N+:11]([C:14]1[CH:24]=[CH:23][C:17]([O:18][CH2:19][C:20](=O)[CH3:21])=[CH:16][CH:15]=1)([O-:13])=[O:12].N1CCCC1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1.O>[CH3:21][C:20]1([CH2:19][O:18][C:17]2[CH:23]=[CH:24][C:14]([N+:11]([O-:13])=[O:12])=[CH:15][CH:16]=2)[CH2:9][C:8](=[O:10])[C:3]2[C:2](=[CH:7][CH:6]=[CH:5][CH:4]=2)[O:1]1
Reactant: CC(=O)c1ccccc1O
Reactant: CC(=O)COc1ccc([N+](=O)[O-])cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1CCNC1
Solvent: O
Solvent: Cc1ccccc1
Product: CC1(COc2ccc([N+](=O)[O-])cc2)CC(=O)c2ccccc2O1
Yield: 54.6 %

Procedure:
2 g of o-hydroxyacetophenone, 2.85 g of 4-nitrophenoxyacetone, 2 g of pyrrolidine and 280 mg of p-toluenesufonic acid monohydrate were dissolved in 10 ml of toluene, and the mixture was heated under reflux for 3 hours in apparatus equipped with a water separator. At the end of this time, the reaction mixture was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. The solvent was then distilled off under reduced pressure. The residue was subjected to silica gel column chromatography eluted with a 3:1 by volume mixture of benzene and ethyl acetate, to afford 2.5 g of the title compound as a pale yellow oily substance.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([CH:11]=O)[S:10][C:3]=12.[NH:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1.C(O)(=O)C.C([BH3-])#N.[Na+]>CO.CO.CCOC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([CH2:11][N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[S:10][C:3]=12
Reactant: C1COCCN1
Reactant: O=Cc1cc2nccc(Cl)c2s1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Solvent: CCOC(C)=O
Product: Clc1ccnc2cc(CN3CCOCC3)sc12
Reaction time: 18 h
Yield: 29.4 %

Procedure:
To a solution of aldehyde 14 (scheme 3) (316 mg, 1.6 mmol) and morpholine (0.15 ml, 1.52 mmol) in MeOH (20 mL) was added acetic acid (0.88 ml, 15 mmol), followed by sodium cyanoborohydride (105 mg, 1.67 mmol). The resultant mixture was allowed to stir for 18 h, quenched with saturated aqueous potassium carbonate solution (5 mL), evaporated under reduced pressure and the residue was partitioned between EtOAc and water. The organic phase was dried over anhydrous sodium sulfate, concentrated to dryness and the remained solid was purified by column chromatography, eluents EtOAc/hexane (30:70), then MeOH/EtOAc (1:99), to afford the title compound 131 (120 mg, 29% yield). MS (m/z) 269.0/271.0 (M+H).