Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][CH2:6][C@H:7]([CH3:10])[CH2:8]O)([CH3:4])([CH3:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:30]N1C(=O)CCC1=O>C(Cl)Cl>[C:1]([O:5][CH2:6][C@H:7]([CH3:10])[CH2:8][Br:30])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: C[C@H](CO)COC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: C[C@H](CBr)COC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 25.8 g. (0.176 mole) of (R)-(+)-3-tert. butoxy-2-methyl-1-propanol and 50.5 g. (0.193 mole) of triphenylphosphine in 105 ml. of CH2Cl2 was stirred while 32.8 g. (0.184 mole) of N-bromosuccinimide was added in portions, keeping the temperature below 30° C. with occasional ice bath cooling. The resulting solution was stirred at room temperature for one hour then most of the solvent was distilled under a water aspirator pressure using a Vigreaux column. The product was distilled from the residue using a short distilling head giving 0.7 g. of forerun b.p. 58°-62° C. (23 mm Hg) and then the main fraction (31.1 g.) b.p. 62°-69° C. (14-18 mm Hg). The total distillate (31.8 g.) was chromatographed on 450 g. of silica gel. Elution with 19:1 parts by volume and 9:1 parts by volume hexane-ether yielded the pure (S)-(+)-3-tert. butoxy-2-methyl- 1-bromopropane which was distilled giving 26 g. (70.6%) of colorless liquid, b.p. 71° C. (16 mm Hg); [α]25D+23.32° (c 4.23, C6H6).
Reaction SMILES: [C:1]([C:3]1([C:6]([OH:8])=O)[CH2:5][CH2:4]1)#[N:2].CCN(C(C)C)C(C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[CH3:45][N:46]1[CH:50]=[C:49]([C:51]2[N:52]=[C:53]3[C:58]([NH:59][C@H:60]4[C@@H:64]([CH3:65])[CH2:63][NH:62][CH2:61]4)=[C:57]([C:66]([NH2:68])=[O:67])[CH:56]=[N:55][N:54]3[CH:69]=2)[CH:48]=[N:47]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:1]([C:3]1([C:6]([N:62]2[CH2:63][C@H:64]([CH3:65])[C@H:60]([NH:59][C:58]3[C:53]4[N:54]([CH:69]=[C:51]([C:49]5[CH:48]=[N:47][N:46]([CH3:45])[CH:50]=5)[N:52]=4)[N:55]=[CH:56][C:57]=3[C:66]([NH2:68])=[O:67])[CH2:61]2)=[O:8])[CH2:5][CH2:4]1)#[N:2]
Reactant: C[C@H]1CNC[C@H]1Nc1c(C(N)=O)cnn2cc(-c3cnn(C)c3)nc12
Reactant: N#CC1(C(=O)O)CC1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@H]1CN(C(=O)C2(C#N)CC2)C[C@H]1Nc1c(C(N)=O)cnn2cc(-c3cnn(C)c3)nc12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 59.4 %

Procedure:
To a solution of cyanocyclopropanecarboxylic acid (3.67 mg, 0.033 mmol) in DCM (330 μl) were added DIEA (14.41 μl, 0.083 mmol) and BOP (17.52 mg, 0.040 mmol). The solution was stirred at room temperature for 10 minutes. 2-(1-Methyl-1H-pyrazol-4-yl)-8-(((3S,4S)-4-methylpyrrolidin-3-yl)amino)imidazo[1,2-b]pyridazine-7-carboxamide, TFA (15 mg, 0.033 mmol) was added. The reaction mixture was stirred at room temperature for another 30 min and concentrated to give an orange oil. The oil was partitioned between ethyl acetate and water. The organic layer was washed with (sat.) sodium chloride, dried with sodium sulfate, filtered and concentrated. The crude product was purified via preparative LCMS (prep. LCMS Method A) to afford 8-(((3S,4S)-1-(1-cyanocyclopropanecarbonyl)-4-methylpyrrolidin-3-yl)amino)-2-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-b]pyridazine-7-carboxamide (8.5 mg, 0.020 mmol, 59.4% yield) as an off-white solid. 1H NMR (500 MHz, DMSO-d6, 2 rotamers) δ 10.74 (d, J=8.4 Hz, 1H), 10.69 (d, J=8.9 Hz, 1H), 8.48 (br. s., 1H), 8.47 (br. s., 1H), 8.28 (s, 1H), 8.27 (s, 1H), 8.12 (s, 2H), 8.01 (br. s., 2H), 7.88 (s, 1H), 7.87 (s, 1H), 7.41 (br. s., 2H), 6.00-5.88 (m, 1H), 5.82 (d, J=5.9 Hz, 1H), 4.25 (dd, J=10.9, 5.0 Hz, 1H), 4.13 (dd, J=10.2, 7.7 Hz, 2H), 3.92 (d, J=3.5 Hz, 1H), 3.88 (s, 6H), 3.79 (dd, J=12.6, 5.2 Hz, 1H), 3.69 (dd, J=12.1, 7.7 Hz, 1H), 3.58 (s, 1H), 3.54-3.50 (m, 1H), 2.80-2.74 (m, 1H), 2.72-2.65 (m, 1H), 1.64-1.52 (m, 6H), 1.50-1.45 (m, 1H), 1.39-1.34 (m, 1H), 1.08 (d, J=6.9 Hz, 3H), 1.04 (d, J=6.9 Hz, 3H). HPLC/LCMS (Method F): m/z 434.10 ([M+H]+), Rt. 1.066 min.
Reaction SMILES: [OH:1][CH2:2][C:3]1[C:17]([CH3:18])=[CH:16][CH:15]=[CH:14][C:4]=1[CH2:5][O:6][C:7]1[CH:8]=[C:9]([OH:13])[CH:10]=[CH:11][CH:12]=1.[CH3:19][N:20]1[C:29](=[O:30])[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[N:22]=[C:21]1[CH2:31]Cl.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[OH:1][CH2:2][C:3]1[C:17]([CH3:18])=[CH:16][CH:15]=[CH:14][C:4]=1[CH2:5][O:6][C:7]1[CH:8]=[C:9]([CH:10]=[CH:11][CH:12]=1)[O:13][CH2:31][C:21]1[N:20]([CH3:19])[C:29](=[O:30])[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[N:22]=1
Reactant: Cn1c(CCl)nc2ccccc2c1=O
Reactant: Cc1cccc(COc2cccc(O)c2)c1CO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1cccc(COc2cccc(OCc3nc4ccccc4c(=O)n3C)c2)c1CO
Temperature: 60 °C
Reaction time: 5 h

Procedure:
To a solution of 3-(2-hydroxymethyl-3-methyl-benzyloxy)-phenol (87 mg, 0.38 mmol, example 100) and (3-methyl-4-oxo-3,4-dihydro-quinazolin-2-yl)-methyl chloride (94 mg, 0.45 mmol, example 99) in DMF (1 mL) is added powdered K2CO3 (78 mg, 0.5 mmol). The resulting mixture is warmed to 60° C. and stirred at this temperature for 5 h. This mixture is cooled to room temperature, diluted with ethyl acetate, washed with water and brine, dried over MgSO4 and concentrated. The residue is purified by flash chromatography (silica, 40% ethyl acetate/30% dichloromethane in hexanes) to give the title compound as a foam. MS (ESI) 417 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[N:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl[C:19]1[C:28]2[C:23](=[CH:24][C:25]([O:31][CH2:32][CH2:33][CH2:34][N:35]3[CH2:40][CH2:39][O:38][CH2:37][CH2:36]3)=[C:26]([O:29][CH3:30])[CH:27]=2)[N:22]=[CH:21][N:20]=1.[Cl-].[NH4+]>CN(C=O)C.C(OCC)(=O)C>[CH3:30][O:29][C:26]1[CH:27]=[C:28]2[C:23](=[CH:24][C:25]=1[O:31][CH2:32][CH2:33][CH2:34][N:35]1[CH2:40][CH2:39][O:38][CH2:37][CH2:36]1)[N:22]=[CH:21][N:20]=[C:19]2[O:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[N:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1
Reactant: COc1cc2c(Cl)ncnc2cc1OCCCN1CCOCC1
Reactant: Oc1ccc2cncnc2c1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1cc2c(Oc3ccc4cncnc4c3)ncnc2cc1OCCCN1CCOCC1
Temperature: 100 °C
Yield: 83.1 %

Procedure:
7-Hydroxyquinazoline (87 mg, 0.6 mmol) and potassium carbonate (110 mg, 0.8 mmol) were added to 4-chloro-6-methoxy-7-(3-morpholinopropoxy)quinazoline (180 mg, 0.53 mmol), (prepared as described for the starting material in Example 1), in suspension in DMF (3 ml) under an argon atmosphere. The reaction mixture was heated to 100° C. for 90 minutes. Upon cooling to ambient temperature the reaction was diluted with ethyl acetate and a saturated ammonium chloride solution. The aqueous phase was re-extracted with ethyl acetate, the organic phases combined, dried (MgSO4) and the solvent evaporated. The residue was purified by flash chromatography using a gradient of methanol/dichloromethane (3/97, 4/96, 5/95). Evaporation of the solvent and trituration of the solid with ether gave 6-methoxy-7-(3-morpholinopropoxy)-4-(quinazolin-7-yloxy)quinazoline (197 mg, 83%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](B(O)O)[CH:5]=[CH:6][CH:7]=1.Br[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1.C(=O)([O-])[O-].[K+].[K+]>C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Pd].O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: OB(O)c1cccc(Cl)c1
Reactant: Brc1ccccn1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: Clc1cccc(-c2ccccn2)c1
Temperature: 80 °C
Yield: 55 %

Procedure:
This Example was carried out in the same manner as Example 1, except that 5.0 g (0.032 mol) of 3-chloro-phenyl boronic acid, 10.0 g (0.064 mol) of 2-bromopyridine, 150□ of tetrahydrofuran and 2M potassium carbonate solution (20□) were added and then 0.37 g (3 mol %) of palladium tetrakistriphenylphosphine [(pd(PPh3)4] was used as a catalyst. Finally, after the resulting solution was heated to reflux at 80° C. for 24 hours, the 2-(3-chloro-phenyl)pyridine was isolated. The yield was 55%.
Reaction SMILES: Cl.[NH2:2][OH:3].C(=O)([O-])O.[Na+].[CH3:9][O:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[N:16]([CH2:20][C:21]1[N:26]=[C:25]([C:27]#[N:28])[CH:24]=[CH:23][CH:22]=1)[C:15]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[CH:14]2.O>CS(C)=O>[CH3:9][O:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[N:16]([CH2:20][C:21]1[N:26]=[C:25]([C:27](=[N:2][OH:3])[NH2:28])[CH:24]=[CH:23][CH:22]=1)[C:15]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[CH:14]2
Reactant: COc1ccc2c(c1)cc(-c1ccccc1)n2Cc1cccc(C#N)n1
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: COc1ccc2c(c1)cc(-c1ccccc1)n2Cc1cccc(C(N)=NO)n1
Temperature: 50 °C
Reaction time: 1 h
Yield: 99.1 %

Procedure:
To a suspension of hydroxylamine hydrochloride (233 mg) in dimethylsulfoxide (1.7 mL) was added sodium hydrogen carbonate (338 mg), and this mixture was stirred at 50° C. for 1 hour. Subsequently, 6-(5-methoxy-2-phenylindol-1-ylmethyl)pyridine-2-carbonitrile (114 mg) was added thereto, followed by stirring at 80° C. overnight. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure to obtain the title compound (124 mg). 1H-NMR (DMSO-d6) δ ppm: 3.76 (3H, s), 5.51 (2H, s), 5.65 (2H, br s), 6.59 (1H, s), 6.70-6.85 (2H, m), 7.11 (1H, d, J=2.4 Hz), 7.32 (1H, d, J=8.9 Hz), 7.35-7.70 (7H, m), 9.92 (1H, s).
Reaction SMILES: C[Sn](C)(C)[C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][CH:9]=[C:10]2[N:13]2[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]2)=[CH:5][CH:4]=1.[CH3:22][NH:23][S:24]([C:27]1[CH:28]=[C:29](Br)[CH:30]=[CH:31][CH:32]=1)(=[O:26])=[O:25].C(N(CC)CC)C.[Cl-].[Li+]>CN(C=O)C.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:22][NH:23][S:24]([C:27]1[CH:28]=[C:29]([C:3]2[CH:12]=[C:11]3[C:6]([CH:7]=[CH:8][CH:9]=[C:10]3[N:13]3[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]3)=[CH:5][CH:4]=2)[CH:30]=[CH:31][CH:32]=1)(=[O:25])=[O:26]
Reactant: CNS(=O)(=O)c1cccc(Br)c1
Reactant: CN1CCN(c2cccc3ccc([Sn](C)(C)C)cc23)CC1
Agent: Cl[Pd]Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CNS(=O)(=O)c1cccc(-c2ccc3cccc(N4CCN(C)CC4)c3c2)c1
Temperature: 25 °C

Procedure:
7-Trimethylstannyl-1-(4-methyl-1-piperazinyl)-naphthalene (0.25 g, 0.67 mmol), 3-methylaminosulfonyl-1-bromobenzene (0.18 g, 0.72 mmol), triethylamine (0.45 mL, 3.23 mmol), lithium chloride (0.088 g, 2.07 mmol), and bis (triphenylphosphine) palladium chloride (0.025 g, 0.036 mmol) were combined in DMF (12.5 mL) and heated to 110° to 110° C. for 45 minutes. The reaction was cooled to room temperature and 1 N aqueous lithium chloride (20 mL) was added. The mixture was extracted with ether (2x). The combined organic layer was washed with 1N lithium chloride and brine; then it was dried over magnesium sulfate and concentrated to an orange oil. Flash chromatography on silica gel (1×6 inches) with an ethyl acetate/hexane gradient of from 50 to 75% followed by continued elution with ethyl acetate and finally 5% methanol/ethyl acetate 0.11 g (42%) of the title product. The sample was recrystallized from ethyl acetate for analysis: mp 147.5°-148° C. Analysis calculated for C22H25N3O2S: C, 66.81; H, 6.31; N, 10.62. Found: C, 66.32; H, 6.16; N, 10.41.
Reaction SMILES: Cl.[S:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7]1([N:17]2[CH2:20][CH2:19][CH2:18]2)[CH2:16][CH2:15][C:10]2(OCC[O:11]2)[CH2:9][CH2:8]1.CCOC(C)=O.CCCCCC>CO>[N:17]1([C:7]2([C:3]3[S:2][CH:6]=[CH:5][CH:4]=3)[CH2:16][CH2:15][C:10](=[O:11])[CH2:9][CH2:8]2)[CH2:18][CH2:19][CH2:20]1
Reactant: c1csc(C2(N3CCC3)CCC3(CC2)OCCO3)c1
Agent: Cl
Solvent: CCCCCC
Solvent: CO
Solvent: CCOC(C)=O
Product: O=C1CCC(c2cccs2)(N2CCC2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 77.2 %

Procedure:
50 ml 6N hydrochloric acid were added to a solution of 1-(8-(thiophen-2-yl)-1,4-dioxaspiro[4.5]decan-8-yl)azetidine (10 g) in 100 ml methanol at 0° C. and the reaction mixture was stirred for 1 hour at room temperature. The reaction course was monitored by thin-layer chromatography (75% EtOAc/hexane). Once the conversion was complete the methanol was removed by distillation and the residue was mixed with water (150 ml) and extracted with ethyl acetate (2×100 ml). The combined organic phases were dried over Na2SO4. Following removal of the solvent under reduced pressure the residue was taken up in cold water (150 ml) and the solution was stirred for 1 hour and then filtered. The residue that was retained was taken up in ethyl acetate and dried over Na2SO4. Following removal of the solvent under reduced pressure, the desired product (6.5 g, 78%) was obtained in the form of a brown solid.
Reaction SMILES: [Li+].[B-](CC)(CC)CC.[NH2:9][C:10]1[CH:11]=[C:12]([C:16]2[CH2:17][C@@H:18]3[N:24]([CH:25]=2)[C:23](=[O:26])[C:22]2[CH:27]=[C:28]([O:70][CH3:71])[C:29]([O:31][CH2:32][CH2:33][CH2:34][O:35][C:36]4[C:67]([O:68][CH3:69])=[CH:66][C:39]5[C:40](=[O:65])[N:41]6[CH:56]=[C:55]([C:57]7[CH:62]=[CH:61][C:60]([O:63][CH3:64])=[CH:59][CH:58]=7)[CH2:54][C@H:42]6[C:43](=O)[N:44](COCC[Si](C)(C)C)[C:38]=5[CH:37]=4)=[CH:30][C:21]=2[N:20](COCC[Si](C)(C)C)[C:19]3=O)[CH:13]=[CH:14][CH:15]=1>C1COCC1.O>[NH2:9][C:10]1[CH:11]=[C:12]([C:16]2[CH2:17][C@@H:18]3[N:24]([CH:25]=2)[C:23](=[O:26])[C:22]2[CH:27]=[C:28]([O:70][CH3:71])[C:29]([O:31][CH2:32][CH2:33][CH2:34][O:35][C:36]4[C:67]([O:68][CH3:69])=[CH:66][C:39]5[C:40](=[O:65])[N:41]6[CH:56]=[C:55]([C:57]7[CH:62]=[CH:61][C:60]([O:63][CH3:64])=[CH:59][CH:58]=7)[CH2:54][C@H:42]6[CH:43]=[N:44][C:38]=5[CH:37]=4)=[CH:30][C:21]=2[N:20]=[CH:19]3)[CH:13]=[CH:14][CH:15]=1
Reactant: COc1ccc(C2=CN3C(=O)c4cc(OC)c(OCCCOc5cc6c(cc5OC)C(=O)N5C=C(c7cccc(N)c7)C[C@H]5C(=O)N6COCC[Si](C)(C)C)cc4N(COCC[Si](C)(C)C)C(=O)[C@@H]3C2)cc1
Agent: CC[B-](CC)CC
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(C2=CN3C(=O)c4cc(OC)c(OCCCOc5cc6c(cc5OC)C(=O)N5C=C(c7cccc(N)c7)C[C@H]5C=N6)cc4N=C[C@@H]3C2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 77.8 %

Procedure:
A solution of superhydride (0.56 mL, 0.56 mmol, 1.0 M in THF) was added dropwise to a solution of the SEM dilactam (18)(0.271 g, 0.27 mmol) in dry THF (10 mL) at −78° C. under a nitrogen atmosphere. After 1 hr a further aliquot of superhydride solution (0.13 ml, 0.13 mmol) was added and the reaction mixture was allowed to stir for another 0.5 hr, at which time LC-MS indicated that reduction was complete. The reaction mixture was diluted with water and allowed to warm to room temperature. The reaction mixture was partitioned between chloroform and water, the layers were separated and the aqueous layer extracted with additional chloroform (emulsions). Finally the combined organic phase was washed with brine and dried over magnesium sulphate. The reduced product was dissolved in methanol, chloroform and water and allowed to stir in the presence of silica gel for 72 hours The crude product was subjected to flash column chromatography (methanol/chloroform gradient) to afford the desired imine product (150 mg, 0.21 mmol, 77%) after removal of excess eluent from selected fractions.
Reaction SMILES: [CH2:1]([C@H:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:7](=[O:16])[C@H:6]([O:17][Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19])[C@H:5]1[O:25][Si:26]([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27])[CH:2]=[CH2:3].C(O)(=O)[C@H]([C@@H](C(O)=O)O)[OH:35].[OH-].[Na+].OO>O1CCCC1.C(OCC)(=O)C.O>[CH2:9]([N:8]1[C@H:4]([CH2:1][CH2:2][CH2:3][OH:35])[C@H:5]([O:25][Si:26]([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:27])[CH3:28])[C@@H:6]([O:17][Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:19])[CH3:20])[C:7]1=[O:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=C(O)[C@@H](O)[C@H](O)C(=O)O
Reactant: C=CC[C@@H]1[C@H](O[Si](C)(C)C(C)(C)C)[C@@H](O[Si](C)(C)C(C)(C)C)C(=O)N1Cc1ccccc1
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)O[C@H]1[C@@H](CCCO)N(Cc2ccccc2)C(=O)[C@@H]1O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
100 g of (3R*,4S*,5R*)-5-allyl-1-benzyl-3,4-bis(tert-butyidimethylsilyloxy)-2-pyrrolidinone which had been prepared according to the procedure described in J. Org. Chem. 60, 103-108 (1995) by using D-tartaric acid as the starting material was added to 670 ml of tetrahydrofuran, and cooled with ice. Then, 87.1 ml of a 1.0M solution of borane-tetrahydrofuran complex in tetrahydrofuran was added thereto. After this mixture was stirred at room temperature for 1 hour, 7 ml of water was added dropwise thereto, and 33.4 ml of a 5N aqueous solution of sodium hydroxide was added at a time. Then, 33.4 ml of a 30% aqueous solution of hydrogen peroxide was added thereto at such a rate as to give a reaction temperature of 30-50° C., followed by stirring overnight. Thereafter, water and ethyl acetate were added to the reaction mixture so as to extract the product in an organic layer. After this organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (using chloroform as the eluent) to obtain 33.4 g of (3R*,4S*,5R*)-1-benzyl-3,4-bis(tert-butyidimethylsilyloxy)-5-(3-hydroxypropyl)-2-pyrrolidinone.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C@@H:4](/[CH:5]=[C:6](/[F:12])\[C:7](=[O:11])[O:8][CH2:9][CH3:10])[C@H:3]1[C:13]([OH:15])=[O:14].[CH2:17]([N:20]1[CH2:24][C:23](=[O:25])[N:22]([CH2:26]O)[C:21]1=[O:28])[C:18]#[CH:19]>C(Cl)(Cl)Cl>[CH3:16][C:2]1([CH3:1])[C@@H:4](/[CH:5]=[C:6](/[F:12])\[C:7](=[O:11])[O:8][CH2:9][CH3:10])[C@H:3]1[C:13]([O:15][CH2:26][N:22]1[C:23](=[O:25])[CH2:24][N:20]([CH2:17][C:18]#[CH:19])[C:21]1=[O:28])=[O:14]
Reactant: C#CCN1CC(=O)N(CO)C1=O
Reactant: CCOC(=O)/C(F)=C\[C@H]1[C@@H](C(=O)O)C1(C)C
Solvent: ClC(Cl)Cl
Product: C#CCN1CC(=O)N(COC(=O)[C@@H]2[C@H](/C=C(/F)C(=O)OCC)C2(C)C)C1=O

Procedure:
Using the procedure of Example 1, (1R,cis) 2,2-dimethyl-3(E)-[2-fluoro-3-oxo-3-ethoxy-propenyl]-cyclopropane-1-carboxylic acid and 3-(2-propynyl)-2,5-dioxoimidazolidinyl-methanol were reacted to obtain 3-(2-propynyl)-2,5-dioxoimidazolidinyl-methyl (1R,cis) 2,2-dimethyl-3(E)-[2-fluoro-3-oxo-3-ethoxy-propenyl)-cyclopropane-1-carboxylate with a specific rotation of [α]D20 =+12°±2° (c=0.5% in chloroform).
Reaction SMILES: [C:1]([O:7][C@@H:8]1[C@@H:14]([O:15][C:16](=[O:21])[C:17]([CH3:20])([CH3:19])[CH3:18])[C@H:13]([O:22][C:23](=[O:28])[C:24]([CH3:27])([CH3:26])[CH3:25])[C@@H:12]([CH2:29][O:30][C:31](=[O:36])[C:32]([CH3:35])([CH3:34])[CH3:33])[O:11][CH:9]1[OH:10])(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].CC(C)([O-])C.[K+].C([O:50][C:51](=[O:54])[CH2:52]Br)C1C=CC=CC=1.C1(C)C=CC=CC=1>[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC.CC(N(C)C)=O>[C:1]([O:7][C@@H:8]1[C@@H:14]([O:15][C:16](=[O:21])[C:17]([CH3:18])([CH3:20])[CH3:19])[C@H:13]([O:22][C:23](=[O:28])[C:24]([CH3:27])([CH3:26])[CH3:25])[C@@H:12]([CH2:29][O:30][C:31](=[O:36])[C:32]([CH3:35])([CH3:34])[CH3:33])[O:11][CH:9]1[O:10][CH2:52][C:51]([OH:54])=[O:50])(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3]
Reactant: CC(C)(C)C(=O)OC[C@H]1OC(O)[C@H](OC(=O)C(C)(C)C)[C@@H](OC(=O)C(C)(C)C)[C@@H]1OC(=O)C(C)(C)C
Reactant: O=C(CBr)OCc1ccccc1
Agent: CC(C)(C)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Solvent: CC(=O)N(C)C
Solvent: Cc1ccccc1
Product: CC(C)(C)C(=O)OC[C@H]1OC(OCC(=O)O)[C@H](OC(=O)C(C)(C)C)[C@@H](OC(=O)C(C)(C)C)[C@@H]1OC(=O)C(C)(C)C
Temperature: 0 °C

Procedure:
A mixture that consists of 54.1 g (100 mmol) of 2,3,4,6-tetra-O-pivaloyl-glucopyranose, 1.39 g (5 mmol) of tetrabutylammonium chloride and 11.22 g of potassium-t-butoxide (100 mmol) in 500 ml of dimethylacetamide is cooled to 0° C. At 0° C., 34.36 g (150 mmol) of 2-bromoacetic acid benzyl ester is added in drops over 20 minutes while being stirred vigorously. It is stirred for one hour at 0° C. Then, 250 ml of toluene is added thereto, solid is filtered out, it is evaporated to the dry state in a vacuum, the residue is taken up in 500 ml of ethanol, mixed with 5 g of palladium (10%) on activated carbon and hydrogenated until the hydrogen absorption is completed. Catalyst is filtered out, it is rewashed with a little ethanol and the combined organic solutions are evaporated to the dry state in a vacuum. The residue is chromatographed on silica gel (mobile solvent: dichloromethane/n-hexane/ethanol/acetic acid=20:5:3:0.5). The product-containing fractions are concentrated by evaporation, dissolved in 400 ml of ethyl acetate and shaken out three times with 200 ml of water. Then, the organic phase is separated and evaporated to the dry state in a vacuum.
Reaction SMILES: [CH2:1]([Li])[CH2:2]CC.C([Si](C)(C)C)#C.[N:12]12[CH2:19][CH2:18][CH:15]([CH2:16][CH2:17]1)[C:14](=[O:20])[CH2:13]2.CO>CCCCC.O1CCCC1>[C:1]([C:14]1([OH:20])[CH:15]2[CH2:18][CH2:19][N:12]([CH2:17][CH2:16]2)[CH2:13]1)#[CH:2]
Reactant: [Li]CCCC
Reactant: O=C1CN2CCC1CC2
Agent: C#C[Si](C)(C)C
Solvent: CCCCC
Solvent: C1CCOC1
Solvent: CO
Product: C#CC1(O)CN2CCC1CC2
Temperature: -70 °C
Reaction time: 1 h

Procedure:
A solution of n-butyl lithium (100 ml of a 2M solution in pentane) was added portion-vise over a period of 20 minutes to a stirred solution of ethynyltrimethylsilane (19.6 g) in dry tetrahydrofuran (400 ml) at -70° C. The mixture was stirred for 1 hour at -70° C. A solution of 3-quinuclidinone (2.4 g) in dry tetrahydrofuran (100 ml) was then added to the mixture and the mixture stirred for 1 hour at -70° C. Methanol (1 ml) was then added to the mixture and the mixture allowed to warm to room temperature. The solvents were removed by evaporation. Methanol (500 ml) and potassium carbonate (40 g) were added to the residue and the mixture was stirred for 1 hour. The solvent was removed by evaporation. The residue was triturated with water (500 ml) and then dried in vacuo to give 3-ethynyl-3-hydroxy-quinuclidine as a solid, m.p. 193-197° C.; NMR (DMSO-d6): 1.5-1.3(1H, m), 1.4-1.6(1H, m), 1.7-1.95(3H, m), 2.55-2.8(5H, m), 2.95(1H, d), 3.3(1H, d) and 5.4(1H, s); m/z 152 (M+H).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[N:4]([C:15](=[O:18])[NH:16][N:17]=2)[N:5]=[CH:6][C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1.[F:19][C:20]([F:30])([F:29])[C:21]1[CH:28]=[CH:27][C:24]([CH2:25]Br)=[CH:23][CH:22]=1.C([O-])([O-])=O.[K+].[K+].CCOC(C)=O>CN(C=O)C>[F:19][C:20]([F:29])([F:30])[C:21]1[CH:28]=[CH:27][C:24]([CH2:25][N:16]2[C:15](=[O:18])[N:4]3[N:5]=[CH:6][C:7]([C:8]4[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=4)=[C:2]([Cl:1])[C:3]3=[N:17]2)=[CH:23][CH:22]=1
Reactant: FC(F)(F)c1ccc(CBr)cc1
Reactant: O=c1[nH]nc2c(Cl)c(-c3ccc(Cl)cc3)cnn12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=c1n(Cc2ccc(C(F)(F)F)cc2)nc2c(Cl)c(-c3ccc(Cl)cc3)cnn12
Temperature: 55 °C
Reaction time: 2 h
Yield: 74 %

Procedure:
To a stirring suspension of 8-chloro-7-(4-chlorophenyl)-[1,2,4]triazolo[4,3-b]pyridazin-3(2H)-one (1.12 g, 4.0 mmol) and 4-(trifluoromethyl)benzyl bromide (1.24 g, 5.2 mmol) in DMF (15 mL) at RT under argon was added K2CO3 (0.83 g, 5.2 mmol). The resulting mixture was heated at 55° C. for 2 h. After 2 h, HPLC/MS analysis indicated the reaction was complete. The reaction mixture was cooled to RT and EtOAc (100 mL) was added. The resulting mixture was washed with saturated NaCl (50 mL×2). The organic layer was dried (Na2SO4), filtered and concentrated under vacuum with co-evaporation of toluene (10 mL×2) to obtain a dark yellow solid. This crude product was washed with MeOH (10 mL×2), then dried under vacuum at room temperature for 3 h to obtain the title compound, 2-(4-(trifluoromethyl)benzyl)-8-chloro-7-(4-chlorophenyl)-[1,2,4]triazolo[4,3-b]pyridazin-3(2H)-one (1.3 g, 74%) as a yellow solid. MS [M+H]+ 439; HPLC retention time=3.92 min; 1HNMR (400 MHz, CDCl3) δ 9.00 (s, 1H), 7.45-7.61 (m, 8H), 5.32 (s, 2H).