Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]([N:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)/[CH:3]=[CH:4]/[CH:5]1[C:10]([CH3:12])([CH3:11])[CH2:9][CH2:8][CH:7]=[C:6]1[CH3:13].[CH3:20][I:21]>CO>[I-:21].[CH3:20][N+:14]1([CH:2]([CH3:1])/[CH:3]=[CH:4]/[CH:5]2[C:10]([CH3:12])([CH3:11])[CH2:9][CH2:8][CH:7]=[C:6]2[CH3:13])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]1
Reactant: CI
Reactant: CC1=CCCC(C)(C)C1/C=C/C(C)N1CCCCC1
Solvent: CO
Product: CC1=CCCC(C)(C)C1/C=C/C(C)[N+]1(C)CCCCC1
Product: [I-]
Yield: 28.1 %

Procedure:
To a solution of 1-[1-methyl-3-(2,6,6-trimethyl-2-cyclohexenyl)-2(trans)-propenyl]piperidine (3.0 g) in a small amount of absolute methanol was added methyliodide (2.1 g) under cooling, and the reaction mixture was allowed to stand over night. The solvent of the reaction mixture was distilled off under reduced pressure, and the residue was dissolved in dil. hydrochloric acid. The aqueous solution was washed with ether, and then adjusted to an alkalinity by adding sodium bicarbonate. The aqueous solution was extracted with chloroform, and the chloroform layer was washed with water. After drying the chloroform layer, the solvent was distilled off under reduced pressure. The residue was dissolved in methanol and thereto was added ether, and then the mixture was allowed to stand under cooling. Precipitated crystals were gathered by filtration and recrystallized from a mixed solvent of methanol and ether to give crystals (1.3 g) of 1-methyl-1-[1-methyl-3-(2,6,6-trimethyl-2-cyclohexenyl)-2(trans)-propenyl]piperidinium iodide, m.p. 156°-158° C.
Reaction SMILES: [CH:1]1([N:7]2[CH2:13][C:12]([F:15])([F:14])[C:11](=[O:16])[N:10]([CH3:17])[C:9]3[CH:18]=[N:19][C:20]([NH:22][C:23]4[CH:31]=[CH:30][C:26]([C:27](O)=[O:28])=[CH:25][C:24]=4[O:32][CH3:33])=[N:21][C:8]2=3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C[N:35](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Cl-].[NH4+]>>[CH:1]1([N:7]2[CH2:13][C:12]([F:14])([F:15])[C:11](=[O:16])[N:10]([CH3:17])[C:9]3[CH:18]=[N:19][C:20]([NH:22][C:23]4[CH:31]=[CH:30][C:26]([C:27]([NH2:35])=[O:28])=[CH:25][C:24]=4[O:32][CH3:33])=[N:21][C:8]2=3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCCC1)CC(F)(F)C(=O)N2C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Product: COc1cc(C(N)=O)ccc1Nc1ncc2c(n1)N(C1CCCCC1)CC(F)(F)C(=O)N2C

Procedure:
The title compound was synthesized from 4-(9-cyclohexyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b][1,4]diazepin-2-ylamino)-3-methoxybenzoic acid as described in the General procedure for amide bond synthesis using HATU and ammonium chloride. The final compound was purified by reverse phase HPLC and basified to give the free base. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.10-1.41 (m, 3H) 1.54-1.86 (m, 7H) 3.32 (s, 3H) 3.93 (s, 3H) 4.17 (t, J=12.5 Hz, 2H) 4.44-4.55 (m, 1H) 7.33 (s, 1H) 7.55 (d, J=8.3 Hz, 1H) 7.59 (s, 1H) 7.99 (s, 1H) 8.13 (d, J=8.1 Hz, 1H) 8.24 (s, 1H) 8.61 (s, 1H). [M+H] calc'd for C22H26F2N6O3 461. found 461.
Reaction SMILES: [NH2:1][C@H:2]([C:12]([OH:14])=[O:13])[CH2:3][CH2:4][C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8].[C:15]([O-:18])(O)=[O:16].[Na+]>O.O1CCOCC1>[NH:1]([C:15]([O:18][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:16])[C@H:2]([C:12]([OH:14])=[O:13])[CH2:3][CH2:4][C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:8])[CH3:9]
Reactant: O=C([O-])O
Reactant: CC(C)(C)OC(=O)CC[C@H](N)C(=O)O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)CC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
H-Glu(OtBu)-OH (Rf(BuOH/AcOH/H2O 4:1:1 v/v/v): 0.52, [α]D=+9.3° C.=1.05 H2O, mp: 181° C. (dec.); lit24: [α]D=+9.8° C.=2 H2O, mp: 182° C.) (2.0 g, 9.85 mmol), NaHCO3 (1.86 g, 22.2 mmol, 2.25 eq.) were dissolved in H2O (40 mL) and Boc2O25 (2.36 g, 10.8 mmol, 1.10 eq.) dissolved in dioxane (20 mL) was added. The reaction mixture became turbid and gas evolution started. After 3 hrs of stirring at room temperature, the reaction mixture was partially evaporated in vacuo. The aqueous solution was acidified with 10% citric acid and the precipitating oil was taken up into EtOAc (three extractions 20 mL). The EtOAc layer was subsequently washed with H2O (five times 30 mL), saturated NaCl (three times 30 mL) and dried on Na2SO4. The residue obtained after evaporation in vacuo was an oil which crystallized slowly. Yield: 2.91 g (98%), Rf(BuOH/AcOH/H2O 4:1:1 v/v/v): 0.87, Rf(CH2Cl2/MeOH 9:1 v/v): 0.17, [α]D=−10.3° C.=0.93 MeOH, mp: 98-99° C. (lit26: [α]D=−10.9° C.=1 MeOH, mp:101-102° C.), 1H NMR (CDCl3): δ=1.44 (s, 18H, Boc/OtBu (2×9H)); 1.99/2.18 (dm, 2H, β-CH2); 2.38 (m, 2H, γ-CH2); 4.34 (m, 1H, α-CH); 5.23 (d, 1H, NH).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.Cl.[CH3:36][NH:37][O:38][CH3:39].C(N(CC)CC)C>ClCCl>[CH3:39][O:38][N:37]([CH3:36])[C:10]([C@@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCc1ccccc1)C(=O)O
Reactant: CNOC
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CON(C)C(=O)[C@H](CCc1ccccc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 12 h
Yield: 92.5 %

Procedure:
A solution of (S)-2-tert-butoxycarbonylamino-4-phenylbutyric acid (500 g, 179 mmol), EDC (37.8 g, 197 mmol), HOBT (41.1 g, 269 mmol) and N,O-dimethylhydroxylamine hydrochloride (19.2 g, 197 mmol) in, dichloromethane (500 mL) was cooled in an ice bath and then treated with a solution of triethylamine (27.5 mL, 197 mmol) in dichloromethane (150 mL). The ice bath was removed and the reaction mixture was stir at room temperature for approximately 12 hours. The mixture was concentrated by rotary evaporation and the residue was treated with ethyl acetate (450 mL), water (300 mL) and saturated sodium bicarbonate until all solids were dissolved. The ethyl acetate layer was separated and washed sequentially with saturated sodium bicarbonate (100 mL), water (100 mL), 1N hydrochloric acid (100 mL), water (100 mL) and brine (50 mL). The solution was dried over anhydrous magnesium sulfate and concentrated to provide tert-butyl (S)-1-(N-methoxy-N-methylcarbamoyl)-3-phenylpropylcarbamate (53.41 g, 93% yield) as a clear, colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[NH:8][N:9]=[CH:10][C:3]=12.[H-].[Na+].[CH2:13]([O:20][CH2:21]Cl)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CN(C=O)C>[CH2:13]([O:20][CH2:21][N:8]1[C:4]2=[N:5][CH:6]=[CH:7][C:2]([Cl:1])=[C:3]2[CH:10]=[N:9]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: Clc1ccnc2[nH]ncc12
Reactant: ClCOCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Clc1ccnc2c1cnn2COCc1ccccc1
Yield: 58.3 %

Procedure:
4-Chloro-1H-pyrazolo[3,4-b]pyridine (371 mg, 2.42 mmol) was dissolved in anhydrous DMF (1 mL), and sodium hydride (60%, 116 mg, 2.42 mmol) was added thereto. The resulting mixture was stirred under ice-cooling for 30 minutes, and then benzyloxymethyl chloride (0.48 mL, 3.39 mmol) was added thereto. The resulting mixture was stirred under ice-cooling for 1 hour and concentrated under reduced pressure. The residue was partitioned between ethyl acetate (80 mL) and saturated brine (20 mL). The aqueous layer was further extracted with ethyl acetate (70 mL). The combined organic layer was washed with saturated brine, dried, and concentrated. The residue was purified by silica-gel column chromatography (Fuji Silysia, BW300, 70 g, n-hexane:EtOAc=5:1) to give 1-benzyloxymethyl-4-chloro-1H-pyrazolo[3,4-b]pyridine as a light-yellow syrup (386 mg, yield: 58%).
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:12]=[CH:11][C:6]2[NH:7][C:8](=O)[NH:9][C:5]=2[CH:4]=1.O=P(Cl)(Cl)[Cl:17]>>[Cl:17][C:8]1[NH:7][C:6]2[CH:11]=[CH:12][C:3]([C:2]([F:14])([F:13])[F:1])=[CH:4][C:5]=2[N:9]=1
Reactant: O=c1[nH]c2ccc(C(F)(F)F)cc2[nH]1
Reactant: O=P(Cl)(Cl)Cl
Product: FC(F)(F)c1ccc2[nH]c(Cl)nc2c1

Procedure:
Reflux 5-trifluoromethyl-1,3-dihydro-benzimidazol-2-one (17 g; Meanwell et al. (1995) J. Org. Chem. 60(6):1565-1582) for 14 hours in POCl3 (200 mL). Evaporate the solvent in vacuo, then carefully neutralize with saturated NaHCO3, and extract with EtOAc. Dry over Na2SO4, concentrate under vacuum, and purify by flash chromatography (1 :1 hexanes/EtOAc) to obtain 2-chloro-5-trifluoromethyl-1H-benzimidazole.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:16])[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:4]([CH3:17])[CH:3]=1.C1(N=C=NC2CCCCC2)CCCCC1.C1C=CC=CC=1.P(=O)(O)(O)O.[CH3:44][S:45]([CH3:47])=O>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:16])[C:10](=[S:45]([CH3:47])[CH3:44])[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:4]([CH3:17])[CH:3]=1
Reactant: CCOC(=O)CC(=O)Nc1ccc(Br)cc1C
Reactant: CS(C)=O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=P(O)(O)O
Solvent: c1ccccc1
Product: CCOC(=O)C(C(=O)Nc1ccc(Br)cc1C)=S(C)C
Temperature: 25 °C

Procedure:
A mixture of 30.0 grams (0.10 mole) of ethyl 3-[(4-bromo-2-methylphenyl)amino]-3oxopropanoate, 51.58 grams (0.25 mole) of 1,3-dicyclohexylcarbodiimide, 100 milliliters of benzene and 100 milliliters of dimethyl sulfoxide was stirred at ambient temperature and a solution of 4.9 grams (0.05 mole) of anhydrous phosphoric acid in 10 milliliters of dimethyl sulfoxide added dropwise. After a few minutes an exothermic reaction occurred with separation of a white solid and an increase in temperature from 25° C. to 35° C. The reaction mixture was then stirred for an approximate 16-hour period at ambient temperature. The mixture was then diluted with 500 milliliters of ethyl acetate and by-product 1,3-dicyclohexylurea removed by filtration. The filtrate was washed with several portions of water, dried over MgSO4, filtered and freed of solvent under reduced pressure to give a yellow solid. This was crystallized from ethyl acetate-hexane (1:1) to give 15.8 grams (0.04 mole) of ethyl 3 -[(4-bromo-2-methylphenyl)amino]-2-(dimethylsulfuranylidene)-3-oxopropanoate having a melting point of 143° C.-150° C. Recrystallization of a small sample gave a white solid of melting point 146° C.-149° C. Elemental analysis of the product indicated the following:
Reaction SMILES: [Br:1][CH2:2][C:3]([NH:5][C:6]1[N:7]=[N:8][CH:9]=[CH:10][CH:11]=1)=[O:4].[OH:12][C@@H:13]1[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14]1>C(#N)C>[Br-:1].[OH:12][CH:13]1[CH2:17][CH2:16][N@@+:15]([CH3:18])([CH2:2][C:3](=[O:4])[NH:5][C:6]2[N:7]=[N:8][CH:9]=[CH:10][CH:11]=2)[CH2:14]1
Reactant: O=C(CBr)Nc1cccnn1
Reactant: CN1CC[C@@H](O)C1
Solvent: CC#N
Product: C[N@@+]1(CC(=O)Nc2cccnn2)CCC(O)C1
Product: [Br-]
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A stirred suspension of 2-bromo-N-pyridazin-3-yl-acetamide (0.5 g, 2.31 mmol) in acetonitrile (10 ml) is treated with (R)-3-hydroxy-1-methyl pyrrolidine (0.234 g, 2.31 mmol). The suspension is stirred at room temperature for 2 hours and then filtered and washed with acetonitrile to yield the titled compound.
Reaction SMILES: [C:1]([C:5]1[CH:11]=[C:10]([OH:12])C=[CH:8][C:6]=1[OH:7])([CH3:4])([CH3:3])[CH3:2].[CH2:13]([O:15][C:16]([C:18]([P:25]([O:30][CH2:31][CH3:32])(=[O:29])[O:26][CH2:27][CH3:28])([CH2:20][CH:21]=[C:22]([CH3:24])[CH3:23])[CH3:19])=[O:17])[CH3:14].[CH3:33]COCC>>[C:1]([C:5]1[C:6]([OH:7])=[CH:8][C:23]([C:22]([CH3:33])([CH3:24])[CH2:21][CH2:20][C:18]([C:16]([O:15][CH2:13][CH3:14])=[O:17])([P:25]([O:26][CH2:27][CH3:28])(=[O:29])[O:30][CH2:31][CH3:32])[CH3:19])=[C:10]([OH:12])[CH:11]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cc(O)ccc1O
Reactant: CCOCC
Reactant: CCOC(=O)C(C)(CC=C(C)C)P(=O)(OCC)OCC
Product: CCOC(=O)C(C)(CCC(C)(C)c1cc(O)c(C(C)(C)C)cc1O)P(=O)(OCC)OCC

Procedure:
41.4 Parts of 2-t-butylhydroquinone, 15.3 parts of diethyl 2-ethoxycarbonyl-5-methyl-hex-4-ene-2-phosphonate, and 5.0 parts of Fulmont®237 are stirred at 130° C. for 24 hours. The cooled reaction is diluted with ether, washed with 10% sodium hydroxide solution and then with water. After stripping off the ether, the residual oil is distilled and gives a fraction b0.4 89°-156° C. and a residue. This residue is chromatographed on a column established from 150 parts silica, and an initial solvent mixture comprising petroleum-ether (b.p. 40°-60° C.) and 5% ethylacetate. Column elution is carried out by increasing the percentage of ether, and ultimately with 50% ether present, diethyl 5-(4'-t-butyl-2',5'-dihydroxyphenyl)-2-ethoxycarbonyl-5-methyl-hexane-2-phosphonate is obtained as a viscous oil with the following percentage composition by weight.
Reaction SMILES: C(O)(=O)C.[CH2:5]([C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=1)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[N+:24]([O-])([OH:26])=[O:25]>O>[N+:24]([C:21]1[CH:22]=[C:17]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH:18]=[CH:19][C:20]=1[OH:23])([O-:26])=[O:25]
Reactant: CCCCCCCCCCCCc1ccc(O)cc1
Reactant: O=[N+]([O-])O
Solvent: O
Solvent: CC(=O)O
Product: CCCCCCCCCCCCc1ccc(O)c([N+](=O)[O-])c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 310 g of acetic acid and 262 g (1 mole) of 4-dodecyl phenol maintained at 20° C. is slowly added with stirring 76 ml (1.2 moles) of HNO3 in 40 ml of water. After 30 minutes, ice water (800 ml) is added to the reaction vessel and the resulting mixture is extracted with methylene chloride. The methylene chloride phase is withdrawn and washed successively with water, an aqueous solution of NaHCO3 (5 percent) and water. The methylene chloride is then removed under vacuum to obtain the desired 2-nitro-4-dodecylphenol. A solution of 46 g (0.15 mole) of the nitrated phenol, 550 ml of absolute ethanol and 1.2 g of platinum oxide is maintained at 20° C. under 50 psi of hydrogen for 23 hours. The reaction mixture is filtered and then subjected to vacuum to remove solvent. Essentially quantitative yield of the desired 2-amino-4-dodecylphenol is recovered. A solution of 200 ml of acetone, 200 ml of water and 38.8 g (0.14 mole) of the amino phenol is stirred with 200 ml of a carbonate form (CO3=) quaternary ammonium styrene/divinyl benzene, ion exchange resin sold by The Dow Chemical Company under the trade name, Dowex® SBR, forty-nine ml (0.787 mole) of methyl iodide is added to the aforementioned solution through a dry ice condenser. After refluxing the reaction mixture with stirring for 20 hours, the mixture is filtered and excess methyl iodide is removed under vacuum. The resulting solution is contacted with the hydroxide form of the aforementioned ion exchange resin to provide the desired quaternary ammonium zwitterion.
Reaction SMILES: [S-:1][C:2]#[N:3].[NH4+].[C:5](Cl)(=[O:12])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[NH2:14][C:15]1[CH:19]=[CH:18][NH:17][N:16]=1>CC(C)=O>[NH:17]1[CH:18]=[CH:19][C:15]([NH:14][C:2]([NH:3][C:5](=[O:12])[C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)=[S:1])=[N:16]1
Reactant: Nc1cc[nH]n1
Reactant: O=C(Cl)c1ccccc1
Reactant: N#C[S-]
Agent: [NH4+]
Solvent: CC(C)=O
Product: O=C(NC(=S)Nc1cc[nH]n1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of ammonium thiocyanate (17.8 g, 0.234 mol) in dry acetone (200 ml) at 0° C. under nitrogen is added benzoylchloride (30 g, 0.213 mol) over a period of 15 min. The reaction mixture is stirred at rt for 30 min and filtered. To the filtrate is added 3-aminopyrazole (14.1 g, 0.17 mol) dropwise and stirred 3 h at room temperature. The solvents are removed under vacuum and the residue is purified by flash chromatography using chloroform/methanol (9/1) as eluent. N-[(1H-pyrazol-3-ylamino)carbonothioyl]benzamide is isolated as a solid (22 g; 52%). M+ (ESI): 246.9. TLC—Chloroform/methanol (9/1): Rf−0.45.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:5][N:4]=[C:3]1[SH:13].O.[CH3:15]I>[OH-].[Na+].CCO>[CH3:1][N:2]1[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:5][N:4]=[C:3]1[S:13][CH3:15]
Reactant: Cn1c(S)nnc1-c1ccccc1
Reactant: CI
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CSc1nnc(-c2ccccc2)n1C
Reaction time: 0.25 h

Procedure:
To a solution of 4-methyl-5-phenyl-4H-1,2,4-triazole-3-thiol (2.00 g, 10 mmol) in NaOH 1.0 M in H2O (21 ml, 21 mmol) was added a solution of CH3I (0.98 mL, 16 mmol) in 6 mL EtOH. The reaction became cloudy and then clear. After 15 min, a white solid precipitated out of the reaction. The reaction was filtered, rinsing with water. The solid was collected and dried in vacuo to give 4-methyl-3-(methylthio)-5-phenyl-4H-1,2,4-triazole as a white solid. MS m/z=206 [M+H]+. Calc'd for C10H11N3S: 205.3.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C:20]([OH:22])=O)[C:14](=[O:23])[C@@H:13]2[CH3:24])=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8].[CH3:25][C@H:26]1[CH2:31][CH2:30][NH:29][CH2:28][C@H:27]1[OH:32]>>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C:20]([N:29]3[CH2:30][CH2:31][C@H:26]([CH3:25])[C@H:27]([OH:32])[CH2:28]3)=[O:22])[C:14](=[O:23])[C@@H:13]2[CH3:24])=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: C[C@H]1C(=O)N(CCC(=O)O)CCN1C(=O)Nc1ccc(Cl)c(Cl)c1
Reactant: C[C@H]1CCNC[C@H]1O
Product: C[C@H]1CCN(C(=O)CCN2CCN(C(=O)Nc3ccc(Cl)c(Cl)c3)[C@@H](C)C2=O)C[C@H]1O
Product: Cl

Procedure:
In analogy to the procedure described in Example 15, 3-[(S)-4-(3,4-dichloro-phenylcarbamoyl)-3-methyl-2-oxo-piperazin-1-yl]-propionic acid (intermediate 12) and 1.1 eq. (3S,4S)-4-methyl-piperidin-3-ol; hydrochloride (intermediate 3) gave the titled compound in 84% yield as off-white solid. MS: 471.3 (MH+, 2Cl).
Reaction SMILES: [CH:1]1([N:4]2[CH2:9][CH2:8][N:7]([C:10]3[S:11][C:12]4[CH:18]=[C:17]([CH:19]=O)[CH:16]=[CH:15][C:13]=4[N:14]=3)[CH2:6][CH2:5]2)[CH2:3][CH2:2]1.[CH:21]1([NH2:24])[CH2:23][CH2:22]1.CC(O)=O.[BH3-]C#N.[Na+]>C1COCC1.CO>[CH:21]1([NH:24][CH2:19][C:17]2[CH:16]=[CH:15][C:13]3[N:14]=[C:10]([N:7]4[CH2:8][CH2:9][N:4]([CH:1]5[CH2:3][CH2:2]5)[CH2:5][CH2:6]4)[S:11][C:12]=3[CH:18]=2)[CH2:23][CH2:22]1
Reactant: O=Cc1ccc2nc(N3CCN(C4CC4)CC3)sc2c1
Reactant: NC1CC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: CO
Product: c1cc2nc(N3CCN(C4CC4)CC3)sc2cc1CNC1CC1
Yield: 79.3 %

Procedure:
To a solution of 2-(4-cyclopropylpiperazin-1-yl)benzothiazole-6-carbaldehyde (400 mg, 1.39 mmol) and cyclopropylamine (159 mg, 2.78 mmol) in a 1:3 mixture of CH3OH and THF (40 mL) was added AcOH (417 mg, 6.95 mmol), followed by NaCNBH3 (140 mg, 2.22 mmol). The mixture was heated at reflux for 12 h and then the volatiles were evaporated. Water (10 mL) was added and the mixture was extracted with CH2Cl2 (3×15 mL). The combined organic extracts were dried (Na2SO4) and concentrated. The residue was purified by the preparative HPLC to give 362 mg (79%) of cyclopropyl-[2-(4-cyclopropylpiperazin-1-yl)-benzothiazol-6-ylmethyl]-amine as a trifluoroacetate salt.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[N:15]=[C:14]([C:16]3[CH:17]=[N:18][C:19]([NH2:22])=[N:20][CH:21]=3)[N:13]=[C:12]3[C:8]=2[N:9]=[CH:10][N:11]3[CH2:23][CH:24]2[CH2:28][CH2:27][NH:26][CH2:25]2)[CH2:3][CH2:2]1.C1C=CC2N([OH:38])N=NC=2C=1.C(N([CH:45]([CH3:47])C)CC)(C)C.Cl.CN(C)CCCN=C=NCC>CN(C=O)C.C(O)(=O)C>[NH2:22][C:19]1[N:20]=[CH:21][C:16]([C:14]2[N:13]=[C:12]3[C:8]([N:9]=[CH:10][N:11]3[CH2:23][CH:24]3[CH2:28][CH2:27][N:26]([C:45](=[O:38])[CH3:47])[CH2:25]3)=[C:7]([N:4]3[CH2:5][CH2:6][O:1][CH2:2][CH2:3]3)[N:15]=2)=[CH:17][N:18]=1
Reactant: Nc1ncc(-c2nc(N3CCOCC3)c3ncn(CC4CCNC4)c3n2)cn1
Reactant: CCN(C(C)C)C(C)C
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: CC(=O)N1CCC(Cn2cnc3c(N4CCOCC4)nc(-c4cnc(N)nc4)nc32)C1

Procedure:
5-(6-Morpholino-9-(pyrrolidin-3-ylmethyl)-9H-purin-2-yl)pyrimidin-2-amine (75 mg) was reacted with excess acetic acid, 2 eq HOBT, 5 eq diisopropylethylamine and 2 eq N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide Hydrochloride in 1 mL of DMF. Upon completion, the reaction was extracted with ethyl acetate and a saturated sodium bicarbonate solution. The organic layer was concentrated and purified via reverse phase HPLC to give 40.1 mg 108 as a white solid. MS (Q1) 424.2 (M)+.
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[CH:9][C:8]([S:11][CH2:12][CH2:13][CH3:14])=[CH:7][C:5]=1[NH2:6])([O-:3])=[O:2].FC(F)(F)C(O)=[O:18].ClC1C=CC=C(C(OO)=O)C=1.C(Cl)(Cl)Cl>C(Cl)Cl>[N+:1]([C:4]1[CH:10]=[CH:9][C:8]([S:11]([CH2:12][CH2:13][CH3:14])=[O:18])=[CH:7][C:5]=1[NH2:6])([O-:3])=[O:2]
Reactant: O=C(O)C(F)(F)F
Reactant: CCCSc1ccc([N+](=O)[O-])c(N)c1
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: CCCS(=O)c1ccc([N+](=O)[O-])c(N)c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Cool to 0°-5° C. a stirred solution of 2-nitro-5-propylthioaniline (21.2 g) in methylene chloride (350 ml) and add trifluoroacetic acid (11.40 g), followed by the dropwise addition of 85% m-chloroperbenzoic acid (22.34 g) in methylene chloride (450 ml). Stir 30 minutes at 0° C., then warm to room temperature and stir 3.5 hours. Add chloroform to dissolve the solids, and extract the mixture with 10% sodium carbonate solution three times, extract with water once, filter over magnesium sulfate, then evaporate the organic solvent in vacuo. Recrystallize the residue from methanol to obtain 2-nitro-5-propylsulfinylaniline, m.p. 128°-130° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH:8]([CH3:10])[CH3:9])[O:5][C:4](=[O:11])[C:3]=1C(=O)C(C)C>OS(O)(=O)=O>[OH:1][C:2]1[CH:7]=[C:6]([CH:8]([CH3:9])[CH3:10])[O:5][C:4](=[O:11])[CH:3]=1
Reactant: CC(C)C(=O)c1c(O)cc(C(C)C)oc1=O
Agent: O=S(=O)(O)O
Product: CC(C)c1cc(O)cc(=O)o1
Temperature: 0 °C

Procedure:
A solution of 4-hydroxy-3-isobutyryl-6-isopropyl-pyran-2-one (10.26 g, 45.8 mmol) in conc. H2SO4 (40 mL) is stirred at 130° C. for 15 min. The dark reaction mixture is then cooled to 0° C., and crushed ice (˜200 g) is added with stirring. The resulting solution is extracted thrice with Et2O, and the combined extracts are dried over Na2SO4 and concentrated. The crude material is purified by flash chromatography on silica gel. Gradient elution with 3:2 hexanes-EtOAc, 1:1 EtOAc-hexanes, 2:1 EtOAc-hexanes, and 3:1 EtOAc-hexanes affords 4-hydroxy-6-isopropyl-pyran-2-one as a light yellow solid. 1H NMR (CDCl3, 300 MHz) δ 11.2 (br, 1H), 6.00 (d, J=1.8 Hz, 1H), 5.58 (d, J=1.8 Hz, 1H), 2.73 (sept, J=6.9 Hz, 1H), 1.22 (d, J=6.9 Hz, 1H) ppm.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[NH:7][C:6](=[O:8])[CH2:5][CH2:4]1.[CH3:9][C:10]([CH3:12])=O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1C=CC=CC=1>[CH3:9][C:10]1([CH3:12])[N:7]2[C:6](=[O:8])[CH2:5][CH2:4][C@@H:3]2[CH2:2][O:1]1
Reactant: CC(C)=O
Reactant: O=C1CCC(CO)N1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: O
Product: CC1(C)OC[C@H]2CCC(=O)N21

Procedure:
A mixture of 5-hydroxymethyl-2-pyrrolidone (0.4 g), acetone (5 ml) and p-toluenesulfonic acid (ca. 10 mg) was refluxed in 20 ml of benzene for 20 hours with a Dean-Stark water separator. After working up the reaction mixture, distillation (boiling point 70°-75° C. at 0.5 mm of Hg) yielded 0.2 g of (R)-tetrahydro-3,3-dimethyl-3H,5H-pyrrolo[1,2-c]oxazol-5-one as an oil.
Reaction SMILES: O=[CH:2][C@@H:3]([C@H:5]([C@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4].[CH2:13]([NH2:19])[C:14]1[O:18][CH:17]=[CH:16][CH:15]=1.[Cl:20][CH2:21][CH2:22][N:23]=[C:24]=[O:25]>>[Cl:20][CH2:21][CH2:22][NH:23][C:24]([N:19]([CH2:13][C:14]1[O:18][CH:17]=[CH:16][CH:15]=1)[CH:2]1[O:10][C@H:9]([CH2:11][OH:12])[C@H:7]([OH:8])[C@H:5]([OH:6])[C@H:3]1[OH:4])=[O:25]
Reactant: NCc1ccco1
Reactant: O=C[C@H](O)[C@@H](O)[C@@H](O)[C@H](O)CO
Reactant: O=C=NCCCl
Product: O=C(NCCCl)N(Cc1ccco1)C1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O
Yield: 60.2 %

Procedure:
5.5 g of D-galactose, 3.8 g of furfurylamine and 3.5 g of 2-chloroethyl isocyanate are treated in the same manner as described in Example 23-(1). 6.7 g of 1-(2-chloroethyl)-3-furfuryl-3-(D-galactopyranosyl)urea are thereby obtained as colorless powder.