Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si:1]([O:8][CH2:9][CH:10]1[O:15][CH2:14][CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].N1C(C)=CC=CC=1C.FC(F)(F)S(O[Si](C)(C)C)(=O)=O>ClCCl>[Si:1]([O:8][CH2:9][CH:10]1[O:15][CH2:14][CH2:13][NH:12][CH2:11]1)([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCOC(CO[Si](C)(C)C(C)(C)C)C1
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCC1CNCCO1
Temperature: 0 °C
Yield: 79.7 %

Procedure:
To a round bottom flask charged with (+/−)-tert-butyl 2-(((tert-butyldimethylsilyl)oxy)methyl)morpholine-4-carboxylate (3.04 g, 9.17 mmol) in dichloromethane (45.8 ml) and cooled to 0° C. was added 2,6-lutidine (2.136 ml, 18.34 mmol). Trimethylsilyl trifluoromethanesulfonate (3.31 ml, 18.34 mmol) was added drop wise over 5 min. The reaction was slowly warmed to room temperature over 4 h. The reaction mixture was quenched by the addition of saturated aqueous sodium bicarbonate and dichloromethane. The mixture was transferred to a separatory funnel and the aqueous layer was extracted with dichloromethane (3×). The combined organics were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The crude residue was purified by column chromatography on the ISCO system (0-10% MeOH/CH2Cl2). (+/−)-2-(((tert-Butyldimethylsilyl)oxy)methyl)morpholine (1.692 g) was isolated as a clear oil.
Reaction SMILES: C[C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5].ClCl.[ClH:18].[CH:19](O)(C)C>>[Cl:18][CH2:19][C:14]1[CH:15]=[CH:2][C:3]([C:4]([C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=2)=[O:5])=[CH:12][CH:13]=1
Reactant: CC(C)O
Reactant: Cc1ccccc1C(=O)c1ccccc1
Reactant: Cl
Agent: ClCl
Product: O=C(c1ccccc1)c1ccc(CCl)cc1
Reaction time: 7 h
Yield: 57 %

Procedure:
The amount of 912 grams (4.65 moles) of methyl benzophenone was then melted and heated to 100°-110° C. in a two-liter, two-necked, round bottom flask with magnetic stirring. Chlorine gas was introduced through a gas dispersion tube immersed below the liquid at a rate such that the characteristic greenish color of chlorine was not detectable in the exiting stream of hydrogen chloride. Initially the reaction was exothermic and no additional external heating was required. After about seven hours the theoretical uptake in weight (160 g) had occured. The hot melt was poured into 6 liters of isopropyl alcohol. This mixture was chilled to -5° to 0° C. and the precipitated solid was removed by suction filtration to provide 618 grams (57% yield) of 4-(chloromethyl)benzophenone, mp 109°-111° C. A carbonyl band at 1670 cm-1 was noted in the infrared spectrum.
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([OH:9])[CH2:5][C:6]([CH3:8])=[CH2:7].[Br:16][C:17]1[CH:22]=[CH:21][C:20]([C@@H:23]([N:25]=[C:26]=[O:27])[CH3:24])=[CH:19][CH:18]=1.C1CCN2C(=NCCC2)CC1>C1COCC1.CCOC(C)=O>[Br:16][C:17]1[CH:18]=[CH:19][C:20]([C@@H:23]([N:25]2[CH2:2][CH2:3][C@:4]([CH2:5][C:6]([CH3:8])=[CH2:7])([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[O:9][C:26]2=[O:27])[CH3:24])=[CH:21][CH:22]=1
Reactant: C=C(C)CC(O)(CCCl)c1ccccc1
Reactant: C[C@H](N=C=O)c1ccc(Br)cc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C=C(C)C[C@]1(c2ccccc2)CCN([C@@H](C)c2ccc(Br)cc2)C(=O)O1
Yield: 30.1 %

Procedure:
A mixture of 1-chloro-5-methyl-3-phenylhex-5-en-3-ol (2.9 g, 13 mmol), (S)-1-bromo-4-(1-isocyanatoethyl)benzene (3.5 g, 16 mmol), and DBU (8 g, 33 mmol) in THF (80 mL) was heated at reflux overnight. The mixture was diluted with EtOAc, and washed with 1N aq HCl. The aqueous phase was extracted with EtOAc (3×), and the combined organic phase was dried over Na2SO4. After the solvents were evaporated, the crude product was purified by column chromatography to give (R)-3-((S)-1-(4-bromophenyl)-ethyl)-6-(2-methylallyl)-6-phenyl-1,3-oxazinan-2-one (1.62 g, yield: 30%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:27])[CH2:5][N:6]1[C:10]([C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH2:26][CH2:25][C:20]4(OCCO4)[CH2:19][CH2:18]3)=[CH:13][CH:12]=2)=[N:9][N:8]=[N:7]1)[CH3:2].[NH2:28][CH2:29][C@@H:30]([C:32]1[CH:33]=[CH:34][C:35]([OH:43])=[C:36]([NH:38][S:39]([CH3:42])(=[O:41])=[O:40])[CH:37]=1)[OH:31]>>[OH:31][C@H:30]([C:32]1[CH:33]=[CH:34][C:35]([OH:43])=[C:36]([NH:38][S:39]([CH3:42])(=[O:41])=[O:40])[CH:37]=1)[CH2:29][NH:28][CH:20]1[CH2:19][CH2:18][N:17]([C:14]2[CH:15]=[CH:16][C:11]([C:10]3[N:6]([CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:27])[N:7]=[N:8][N:9]=3)=[CH:12][CH:13]=2)[CH2:26][CH2:25]1
Reactant: CCOC(=O)Cn1nnnc1-c1ccc(N2CCC3(CC2)OCCO3)cc1
Reactant: CS(=O)(=O)Nc1cc([C@@H](O)CN)ccc1O
Product: CCOC(=O)Cn1nnnc1-c1ccc(N2CCC(NC[C@H](O)c3ccc(O)c(NS(C)(=O)=O)c3)CC2)cc1

Procedure:
The title compound was prepared from ethyl{5-[4-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)phenyl]-1H-tetraazol-1-yl}acetate (which was obtained in Example 48) and N-[5-((1R)-2-amino-1-hydroxy-ethyl)-2-hydroxy-phenyl]-methanesulfonamide (which was obtained in Example 10) according to the procedures of Example 34 and Example 73 as a white solid; mp >140° C. (decomposed); 1H NMR (300 MHz, DMSO-d6) δ 1.17 (t, J=7.1 Hz, 3H), 1.20-1.40 (m, 2H), 1.80-1.95 (m, 2H), 2.50-3.50 (m, 5H), 2.89 (s, 3H), 3.70-3.90 (m, 2H), 4.11 (q, J=7.1 Hz, 2H), 4.47 (dd, J=7.8, 4.4 Hz, 1H), 5.60 (brs, 2H), 6.79 (d, J=8.2 Hz, 1H), 6.96 (dd, J=8.2, 2.0 Hz, 1H), 7.07 (d, J=8.9 Hz, 2H), 7.16 (d, J=2.0 Hz, 1H), 7.56 (d, J=8.9 Hz, 2 H); MS (ES) m/z: 560.2 (MH+); HRMS Calcd. for C21H28N7O4S(MH+): 560.2286. Found: 560.2282.
Reaction SMILES: [NH2:1][C@@H:2]([CH3:19])[CH2:3][N:4]1[CH:8]=[CH:7][C:6]([C:9]2[CH:16]=[C:15]([F:17])[C:12]([C:13]#[N:14])=[C:11]([F:18])[CH:10]=2)=[N:5]1.[CH:20]([C:23]1[N:27]=[C:26]([C:28](O)=[O:29])[O:25][N:24]=1)([CH3:22])[CH3:21].C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C>CN(C=O)C>[C:13]([C:12]1[C:11]([F:18])=[CH:10][C:9]([C:6]2[CH:7]=[CH:8][N:4]([CH2:3][C@@H:2]([NH:1][C:28]([C:26]3[O:25][N:24]=[C:23]([CH:20]([CH3:22])[CH3:21])[N:27]=3)=[O:29])[CH3:19])[N:5]=2)=[CH:16][C:15]=1[F:17])#[N:14]
Reactant: C[C@H](N)Cn1ccc(-c2cc(F)c(C#N)c(F)c2)n1
Reactant: CC(C)c1noc(C(=O)O)n1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)c1noc(C(=O)N[C@@H](C)Cn2ccc(-c3cc(F)c(C#N)c(F)c3)n2)n1
Yield: 2 %

Procedure:
The title compound was synthesized from (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2,6-difluorobenzonitrile (0.168 g, 0.64 mmol), 3-isopropyl-1,2,4-oxadiazole-5-carboxylic acid (0.1 g, 0.64 mmol), HOBt (0.13 g, 0.96 mmol), DIPEA (0.335 mL, 1.92 mmol) and EDCI (0.184 g, 0.96 mmol) using DMF as solvent using the method of Example 34(d). Yield of the title compound 5 mg. 1H NMR (400 MHz; MeOD): δ 1.27 (d, 3H), 1.36 (d, 6H), 3.16 (m, 1H), 4.39 (m, 2H), 4.58 (m, 1H), 6.80 (d, 1H), 7.62 (m, 2H), 7.72 (d, 1H).
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[C:19]([F:30])[CH:20]=[C:21]([C:22]4[C:27]([CH3:28])=[CH:26][CH:25]=[CH:24][C:23]=4[CH3:29])[C:15]=3[O:14]2)(=O)=O)=CC=1.[CH3:31][NH2:32]>CO>[CH3:29][C:23]1[CH:24]=[CH:25][CH:26]=[C:27]([CH3:28])[C:22]=1[C:21]1[C:15]2[O:14][CH:13]([CH2:12][NH:32][CH3:31])[CH2:17][C:16]=2[CH:18]=[C:19]([F:30])[CH:20]=1
Reactant: Cc1ccc(S(=O)(=O)OCC2Cc3cc(F)cc(-c4c(C)cccc4C)c3O2)cc1
Reactant: CN
Solvent: CO
Product: CNCC1Cc2cc(F)cc(-c3c(C)cccc3C)c2O1

Procedure:
The title compound was prepared (0.147 g, 65%) following the general procedure of Example 390 as a white solid, hydrochloride salt from (+)-[7-(2,6-dimethylphenyl)-5-fluoro-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (0.50 g, 1.2 mmol) and methylamine (0.372 g, 12.0 mmol). [α]D25=+1.6 (c 10.0 in methanol); mp 169-170° C.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[CH2:6][C:5]2[CH:9]=[C:10]3[C:15](=[CH:16][C:4]=2[S:3]1(=[O:18])=[O:17])[CH2:14][CH2:13][CH2:12][CH2:11]3.[H-].[Na+].[H][H].[C:23]1([N:29]=[C:30]=[O:31])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>O1CCCC1>[CH3:1][N:2]1[C:7](=[O:8])[CH:6]([C:30]([NH:29][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:31])[C:5]2[CH:9]=[C:10]3[C:15](=[CH:16][C:4]=2[S:3]1(=[O:17])=[O:18])[CH2:14][CH2:13][CH2:12][CH2:11]3
Reactant: O=C=Nc1ccccc1
Reactant: [H][H]
Reactant: CN1C(=O)Cc2cc3c(cc2S1(=O)=O)CCCC3
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN1C(=O)C(C(=O)Nc2ccccc2)c2cc3c(cc2S1(=O)=O)CCCC3
Temperature: 20 °C
Yield: 49.3 %

Procedure:
A solution of 5 g (19 mmol) 3,4,6,7,8,9-hexahydro-2-methyl-3-oxo-2H-naphtho[2,3-e]-1,2-thiazine 1,1-dioxide in 100 mL tetrahydrofuran was added to a suspension of 0.7 g (29 mmol) sodium hydride in 50 mL tetrahydrofuran at −5° C. under N2. After termination of the hydrogen formation 5.7 g (48 mmol) phenylisocyanate dissolved in 50 mL tetrahydrofuran were added at −5° C. After stirring at room temperature (approx. 20° C.) the resulting mixture was quenched with ice/water and by addition of dilute HCl and then extracted with CH2Cl2 (2 times). The combined CH2Cl2 extracts were washed, dried and concentrated to give 6 g crude product. This material was recrystallized from ethanol to give 3.6 g 3,4,6,7,8,9-hexahydro-2-methyl-3-oxo-2H-naphtho[2,3-e]-1,2-thiazine-4-carboxanilide 1,1-dioxide.
Reaction SMILES: [CH:1]([C:4]1[CH:10]=[CH:9][CH:8]=[C:7]([CH:11]([CH3:13])[CH3:12])[C:5]=1[NH2:6])([CH3:3])[CH3:2].F[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[N+:21]([O-:23])=[O:22].[F-].[K+]>O>[CH:11]([C:7]1[CH:8]=[CH:9][CH:10]=[C:4]([CH:1]([CH3:3])[CH3:2])[C:5]=1[NH:6][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[N+:21]([O-:23])=[O:22])([CH3:13])[CH3:12]
Reactant: O=[N+]([O-])c1ccccc1F
Reactant: CC(C)c1cccc(C(C)C)c1N
Agent: [F-]
Agent: [K+]
Solvent: O
Product: CC(C)c1cccc(C(C)C)c1Nc1ccccc1[N+](=O)[O-]
Temperature: 180 °C
Yield: 47.9 %

Procedure:
2,6-diisopropylaniline (25 g, 141 mmol), 2-fluoronitrobenzene (10 g, 70 mmol), and potassium fluoride (6.2 g, 106 mmol) were mixed in a one-neck flask. The mixture was heated up to 180° C. under nitrogen for 48 hours. After cooled to room temperature, water (200 mL) was added. The mixture was then extracted with dichloromethane (200 mL) for three times. The solvent was evaporated and the residue was purified by column chromatography using 20% of dichloromethane in hexanes. 10 g of desired product was obtained.
Reaction SMILES: [CH:1]([N:4]([CH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1)[CH2:5][CH2:6]O)([CH3:3])[CH3:2].S(Cl)([Cl:16])=O>C1C=CC=CC=1>[ClH:16].[CH:1]([N:4]([CH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1)[CH2:5][CH2:6][Cl:16])([CH3:3])[CH3:2]
Reactant: O=S(Cl)Cl
Reactant: CC(C)N(CCO)C1CCCCC1
Solvent: c1ccccc1
Product: CC(C)N(CCCl)C1CCCCC1
Product: Cl
Temperature: 25 °C

Procedure:
6.0 Grams of the above alcohol compound obtained was dissolved in 100 ml of dry benzene, and to this solution was added dropwise 3.2 ml of thionyl chloride with stirring at room temperature. The mixture was heated under refulx for 4 hours. The reaction mixture was concentrated under reduced pressure, and the residue was triturated with diethyl ether. The precipitated crystals were collected by filtration to obtain 7.4 g of 2-(N-isopropylcyclohexylamino)ethyl chloride hydrochloride having a melting point of 99°-103° C.
Reaction SMILES: [CH2:1]1[O:8]C(=O)C[O:4][C:2]1=[O:3].[CH3:9][C@@H:10]1[O:17]C(=O)[C@H](C)[O:13][C:11]1=[O:12].CCCCC(C([O-])=O)CC.CCCCC(C([O-])=O)CC.[Sn+2].C(O)CCCCCCCCCCC>C1(C)C=CC=CC=1>[C:2]([OH:4])(=[O:3])[CH2:1][OH:8].[C:11]([OH:13])(=[O:12])[CH:10]([CH3:9])[OH:17]
Reactant: C[C@@H]1OC(=O)[C@H](C)OC1=O
Reactant: O=C1COC(=O)CO1
Agent: CCCCC(CC)C(=O)[O-]
Agent: [Sn+2]
Solvent: CCCCCCCCCCCCO
Solvent: Cc1ccccc1
Product: CC(O)C(=O)O
Product: O=C(O)CO
Temperature: 220 °C
Reaction time: 2 h

Procedure:
1161 g (10 mols) of glycolide and 1441 g (10 mols) of L-lactide were placed in a glass reactor, and 10 ml of a toluene solution containing 0.26 g of stannous octoate and 9.0 g of lauryl alcohol were added to the reactor. Afterward, deaeration was carried out for 2 hours under reduced pressure, and the atmosphere in the reactor was then replaced with a nitrogen gas. This mixture was heated at 220° C. for 2 hours with stirring under the nitrogen atmosphere. While the temperature was maintained as it was, the deaeration was slowly performed by means of a vacuum pump through an exhaust pipe to reduce the pressure in the reactor to 3 mm Hg. One hour after the start of the deaeration, the monomers and low-molecular substances were not extracted any more, and the interior of the reactor was replaced with nitrogen and a resultant glycolic acid-lactic acid copolymer (hereinafter referred to as "PLGA") was then taken out.
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[C:21]([C:26]#[N:27])=[CH:22][CH:23]=[CH:24][CH:25]=3)=[CH:16][CH:15]=2)[C:7](=[O:12])[CH:8]=[C:9]([CH3:11])[N:10]=1)[CH2:2][CH2:3][CH3:4].[Br:28]Br>C(O)(=O)C.C(OCC)(=O)C>[Br:28][C:8]1[C:7](=[O:12])[N:6]([CH2:13][C:14]2[CH:15]=[CH:16][C:17]([C:20]3[C:21]([C:26]#[N:27])=[CH:22][CH:23]=[CH:24][CH:25]=3)=[CH:18][CH:19]=2)[C:5]([CH2:1][CH2:2][CH2:3][CH3:4])=[N:10][C:9]=1[CH3:11]
Reactant: BrBr
Reactant: CCCCc1nc(C)cc(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CCCCc1nc(C)c(Br)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 70 °C
Reaction time: 2 h
Yield: 88 %

Procedure:
To a solution of 4′-[(2-butyl-4-methyl-6-oxopyrimidin-1(6H)-yl)methyl]biphenyl-2-carbonitrile (1.8 g) in acetic acid (40 mL) was added bromine (0.77 mL), and the mixture was stirred at 70° C. for 2 hr. The reaction mixture was allowed to cool to room temperature. The mixture was diluted with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound (1.96 g, 88%) as a colorless solid.
Reaction SMILES: [C:1]([NH:9][C:10]1[CH:11]=[CH:12][C:13]([Cl:30])=[C:14]([NH:16][C:17](=[O:29])[C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][C:19]=2[N+:26]([O-])=O)[CH:15]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.C(O)(=O)C.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C.[Fe]>[C:1]([NH:9][C:10]1[CH:11]=[CH:12][C:13]([Cl:30])=[C:14]([NH:16][C:17](=[O:29])[C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][C:19]=2[NH2:26])[CH:15]=1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(C(=O)Nc2cc(NC(=O)c3ccccc3)ccc2Cl)c([N+](=O)[O-])c1
Agent: [Fe]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: CC(=O)O
Product: COc1ccc(C(=O)Nc2cc(NC(=O)c3ccccc3)ccc2Cl)c(N)c1
Temperature: 25 °C
Yield: 46 %

Procedure:
Iron powder (2.79 g) was added to a stirred suspension of N-(5-benzamido-2-chlorophenyl)-4-methoxy-2-nitrobenzamide (2.13 g) in a mixture of ethanol (100 ml), water (20 ml) and acetic acid (4 ml). The mixture was stirred and heated to reflux for 6 hours. The mixture was cooled to ambient temperature. Water (50 ml) was added and the resultant mixture was basified by the addition of sodium carbonate. The mixture was filtered and the filtrate was evaporated. The residue was triturated under water. The resultant solid was isolated and dried under vacuum at 40° C. There was thus obtained the title compound (0.911 g);
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[N:7]2[N:8]=[C:9]([N:12]3[CH2:17][CH2:16][CH:15]([OH:18])[CH2:14][CH2:13]3)[CH:10]=[CH:11][C:6]2=[N:5][N:4]=1.[H-].[Na+].Cl[C:24]1[CH:25]=[CH:26][C:27]([C:30]#[N:31])=[N:28][CH:29]=1>CN(C=O)C.CO>[F:20][C:2]([F:1])([F:19])[C:3]1[N:7]2[N:8]=[C:9]([N:12]3[CH2:17][CH2:16][CH:15]([O:18][C:24]4[CH:25]=[CH:26][C:27]([C:30]#[N:31])=[N:28][CH:29]=4)[CH2:14][CH2:13]3)[CH:10]=[CH:11][C:6]2=[N:5][N:4]=1
Reactant: N#Cc1ccc(Cl)cn1
Reactant: OC1CCN(c2ccc3nnc(C(F)(F)F)n3n2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Product: N#Cc1ccc(OC2CCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)cn1
Temperature: 50 °C
Reaction time: 18 h
Yield: 27.2 %

Procedure:
A solution of 1-[3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4-ol (150 mg, 0.52 mmol) and sodium hydride (60% dispersion in oil, 22.98 mg, 0.57 mmol) in DMF (5 mL) was stirred for 30 minutes at ambient temperature under nitrogen. 5-Chloropicolinonitrile (80 mg, 0.57 mmol) was added to the reaction mixture. The resulting solution was stirred at 50° C. for 18 hours. The reaction mixture was diluted with a few drops of MeOH. The crude product was purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5μ silica, 19 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 1% ammonia) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford 5-[[1-[3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4-yl]oxy]pyridine-2-carbonitrile (55.0 mg, 27%) as a solid.
Reaction SMILES: O[CH2:2][C:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])=O.[Cl-].[CH2:14]([NH3+:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(O)C.O.[CH2:26]([NH2:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[CH2:14]([NH:21][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[NH:33][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: [NH3+]Cc1ccccc1
Reactant: NCc1ccccc1
Reactant: O=C(CO)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: [Cl-]
Solvent: O
Solvent: CCO
Product: OC[C@H]1OC(NCc2ccccc2)[C@@H](NCc2ccccc2)[C@@H](O)[C@@H]1O
Reaction time: 8 h

Procedure:
To a mixture of D-(−)-fructose (50 g, 277.5 mmol) in benzyl amine (100 ml) was added benzyl ammonium chloride (30 g, 208 mmol) at room temperature. The mixture was stirred for 6 hours, at which time ethanol (50 ml) was added to make the mixture homogenous. After stirring overnight, another portion of ethanol (50 ml) was added resulting in a homogenous mixture. After 2 hours, water (150 ml) was added and the stirring was continued for 3 hours. The resulting suspension was separated by filtration, and the filtered material was washed with cold aqueous ethanol and dried under vacuum to constant weight, giving 21.3 g of title compound as a white solid. The mother liquor contained N,N′-dibenzyl-1,2-diamino-1,2-dideoxy-D-mannopyranose along with N,N′-dibenzyl-1,2-diamino-1,2-dideoxy-D-glucopyranose.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([CH:8]2[CH2:10][CH2:9]2)[CH:5]=[C:4]([CH3:11])[N:3]=1.[CH3:12][C:13]1([CH3:28])[CH2:17][C:16]2[CH:18]=[CH:19][CH:20]=[C:21]([S:22]([N:25]=[C:26]=[O:27])(=[O:24])=[O:23])[C:15]=2[O:14]1>C(Cl)Cl>[CH:8]1([C:6]2[CH:5]=[C:4]([CH3:11])[N:3]=[C:2]([NH:1][C:26]([NH:25][S:22]([C:21]3[C:15]4[O:14][C:13]([CH3:28])([CH3:12])[CH2:17][C:16]=4[CH:18]=[CH:19][CH:20]=3)(=[O:23])=[O:24])=[O:27])[N:7]=2)[CH2:10][CH2:9]1
Reactant: CC1(C)Cc2cccc(S(=O)(=O)N=C=O)c2O1
Reactant: Cc1cc(C2CC2)nc(N)n1
Solvent: ClCCl
Product: Cc1cc(C2CC2)nc(NC(=O)NS(=O)(=O)c2cccc3c2OC(C)(C)C3)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of 0.47 g of 2-amino-4-cyclopropyl-6-methylpyrimidine in 15 ml of methylene chloride is added one g of the sulfonyl isocyanate prepared in Example 4. After stirring at room temperature overnight, the suspension is concentratd in vacuo, and the residue is triturated with 1-chlorobutane and filtered to give the subject compound.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.C(=O)=O.CC(C)=O.CC([Si](C)(C)O[CH:26]1[CH2:34][CH:29]2[O:30][C:31](=[O:33])[CH2:32][CH:28]2[CH:27]1CCC(O[Si](C(C)(C)C)(C)C)CCCCC)(C)C.[CH3:53][Si:54]([CH3:57])([CH3:56])Cl>O1CCCC1>[CH3:53][Si:54]([CH3:57])([CH3:56])[O:33][C:31]1[O:30][C:29]2=[CH:34][CH:26]=[CH:27][CH:28]2[CH:32]=1
Reactant: C[Si](C)(C)Cl
Reactant: CCCCCC(CCC1C(O[Si](C)(C)C(C)(C)C)CC2OC(=O)CC21)O[Si](C)(C)C(C)(C)C
Agent: O=C=O
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: CC(C)=O
Solvent: C1CCOC1
Product: C[Si](C)(C)OC1=CC2C=CC=C2O1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
To a solution of 4.5 ml of diisopropylamine in 50 ml of dry THF (tetrahydrofuran) cooled to 0° C. was added dropwise over a period of twenty minutes 19.6 ml of n-butyllithium (1.5M in hexane). After stirring an additional five minutes at 0° C. the solution was cooled to -40° C. (dry ice/acetone) after which time a solution of 13.1 g (0.0263 mol) of [3aR-[3a alpha,4alpha(3S*), 5beta,6a alpha]]-hexahydro-5-[[(1,1-dimethylethyl)dimethylsilyl]-oxy]-4-[3-[[(1,1-dimethylethyl)dimethylsilyl]oxy]octyl)-2H-cyclopenta[b]furan-2-one dissolved in 100 ml of THF was added slowly while maintaining the temperature at -40° C. After five minutes at this temperature 4.5 ml of trimethylchlorosilane was added rapidly. The cooling bath was then removed and the reaction allowed to warm to 15 C. The solvent was then removed under vacuum and the residue treated with 50 ml of dry ether. The mixture was then filtered through a cintered glass filter and the solvent evaporated under high vacuum to produce [3aR-[3a alpha, 4alpha (3S*), 5 beta, 6a alpha]]-4,5,6,6a-tetrahydro-5-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-4-[3-[[1,1-dimethylethyl)dimethylsilyl]oxy]-octyl]-2-[(trimethylsilyl)oxy]-3aH-cyclopenta[b]furan. This compound was then dissolved at 0° C. in 50 ml of dry CH2Cl2 containing 5.26 g of KHCO3, followed by the slow addition of 5.0 g of xenon difluoride. The mixture was then stirred for an additional 0.5 hr at 0° C. and then poured into 500 ml of ice water followed by extraction with CH2Cl2. The organic layer was separated, dried, and the solvent removed under reduced pressure. The residue (9.1 g) was then chromatographed on 500 g of silica gel (2% by volume ethyl acetate/98% by volume petroleum ether to 10% ethyl acetate/90% by volume petroleum ether) and afforded 2.2 g of starting material and 7 g (51.5% yield) of [3S-[3alpha,3a alpha,4alpha(3S*),5beta,6a alpha]]-hexahydro-3-fluoro-5-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-4-[3-[[(1,1-dimethylethyl)dimethylsilyl]oxy]octyl]-2H-cyclopenta[b]furan-2-one as a colorless liquid [α]D25 -29.35 (CHCl3, C=0.726).
Reaction SMILES: [CH3:1][C@@:2]12[C:8]([CH3:10])([CH3:9])[C@@H:5]([CH2:6][CH2:7]1)[C:4](=O)[C:3]2=O.COP([CH2:19][C:20](=O)[C:21]1([C:24]([F:27])([F:26])[F:25])[CH2:23][CH2:22]1)(=O)OC.O.[NH2:30][NH2:31]>>[CH3:1][C@@:2]12[C:8]([CH3:10])([CH3:9])[C@@H:5]([CH2:6][CH2:7]1)[C:4]1[C:3]2=[N:30][N:31]=[C:20]([C:21]2([C:24]([F:27])([F:26])[F:25])[CH2:23][CH2:22]2)[CH:19]=1
Reactant: COP(=O)(CC(=O)C1(C(F)(F)F)CC1)OC
Reactant: NN
Reactant: CC1(C)[C@H]2CC[C@]1(C)C(=O)C2=O
Solvent: O
Product: CC1(C)[C@H]2CC[C@]1(C)c1nnc(C3(C(F)(F)F)CC3)cc12

Procedure:
yellow solid. MS (ESI): 297.1 (MH+). Prepared from (1S,4R)-1,7,7-trimethyl-bicyclo[2.2.1]heptane-2,3-dione, [[2-Oxo-2-(1-trifluoromethyl-cyclopropyl)-ethyl]-phosphonic acid dimethyl ester, hydrazine monohydrate.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])C.C(O)=O.[N:11]1([C:17]2[CH:26]=[CH:25][CH:24]=[C:23]3[C:18]=2[CH2:19][CH2:20][C:21](=[O:27])[NH:22]3)[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1.ClCCl>O>[CH:1]([N:14]1[CH2:15][CH2:16][N:11]([C:17]2[CH:26]=[CH:25][CH:24]=[C:23]3[C:18]=2[CH2:19][CH2:20][C:21](=[O:27])[NH:22]3)[CH2:12][CH2:13]1)=[O:3]
Reactant: O=C1CCc2c(cccc2N2CCNCC2)N1
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: O
Solvent: O=CO
Product: O=CN1CCN(c2cccc3c2CCC(=O)N3)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 1.22 ml of acetic anhydride and 0.5 ml of formic acid was stirred at 50°-60° C. for 2 hours. After cooling to room temperature, 1.0 g of 5-piperazinyl-3,4-dihydrocarbostyril was added portionwise to the reaction mixture, during which operation the product was solidified. To the solids was added 5 ml of dichloromethane and the mixture was stirred at room temperature for 2 hours. Then, a large amount of water was added thereto and the mixture was extracted with chloroform. After washing with water, the extract was dried over anhydrous sodium sulfate followed by removal of chloroform by distillation. Recrystallization of the residue from methanol gave 420 mg of 5-(4-formyl-1-piperazinyl)-3,4-dihydrocarbostyril, m.p. 263°-265° C., colorless granules.