Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si:1]([O:8][C@H:9]([C:42]1[CH:47]=[CH:46][C:45]([F:48])=[CH:44][CH:43]=1)[CH2:10][S:11][C@H:12]1[C:15](=[O:16])[N:14]([C:17]2[CH:22]=[CH:21][C:20]([C:23]#[C:24][CH2:25][NH:26][S:27]([CH3:30])(=[O:29])=[O:28])=[CH:19][CH:18]=2)[C@@H:13]1[C:31]1[CH:41]=[CH:40][C:34]([O:35][CH2:36][C:37](O)=[O:38])=[CH:33][CH:32]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].CN1CCOCC1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[NH2:78][CH2:79][C:80]([NH:82][C@@H:83]([C:91]([OH:93])=[O:92])[CH2:84][CH:85]1[CH2:90][CH2:89][CH2:88][CH2:87][CH2:86]1)=[O:81]>CN(C=O)C>[Si:1]([O:8][C@H:9]([C:42]1[CH:47]=[CH:46][C:45]([F:48])=[CH:44][CH:43]=1)[CH2:10][S:11][C@H:12]1[C:15](=[O:16])[N:14]([C:17]2[CH:18]=[CH:19][C:20]([C:23]#[C:24][CH2:25][NH:26][S:27]([CH3:30])(=[O:29])=[O:28])=[CH:21][CH:22]=2)[C@@H:13]1[C:31]1[CH:32]=[CH:33][C:34]([O:35][CH2:36][C:37]([NH:78][CH2:79][C:80]([NH:82][C@@H:83]([C:91]([OH:93])=[O:92])[CH2:84][CH:85]2[CH2:90][CH2:89][CH2:88][CH2:87][CH2:86]2)=[O:81])=[O:38])=[CH:40][CH:41]=1)([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:2])[CH3:3]
Reactant: CC(C)(C)[Si](C)(C)O[C@@H](CS[C@H]1C(=O)N(c2ccc(C#CCNS(C)(=O)=O)cc2)[C@@H]1c1ccc(OCC(=O)O)cc1)c1ccc(F)cc1
Reactant: NCC(=O)N[C@H](CC1CCCCC1)C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)O[C@@H](CS[C@H]1C(=O)N(c2ccc(C#CCNS(C)(=O)=O)cc2)[C@@H]1c1ccc(OCC(=O)NCC(=O)N[C@H](CC2CCCCC2)C(=O)O)cc1)c1ccc(F)cc1
Temperature: 30 °C
Reaction time: 0.08 h

Procedure:
{4-[(2R,3R)-3-{[(2R)-2-{[tert-butyl(dimethyl)silyl]oxy}-2-(4-fluorophenyl)ethyl]thio}-(4-{3-[(methylsulfonyl)amino]prop-1-yn-1-yl}phenyl)-4-oxoazetidin-2-yl]phenoxy}acetic acid (Method 8) (25.1 mg, 0.040 mmol) was dissolved in DMF (1 ml, dry). N-methylmorpholine (13 μl, 121 mmol) was added and the reaction mixture was stirred at 30° C. for five minutes. TBTU (20.1 mg, 0.063 mmol) was added and the reaction mixture was stirred at 30° C. for 1 hour. Glycyl-3-cyclohexyl-D-alanine (12.5 mg, 0.055 mmol) was added and the reaction mixture was stirred for 2 hours. The reaction mixture was purified with preparative HPLC on a C8 column. A gradient from 10 to 100% MeCN in 0.1M NH4OAc buffer was used as eluent. Most of the MeCN was removed under reduced pressure. The residue was diluted with water and lyophilised to give the title compound, M/z: 921 (M−1).
Reaction SMILES: C([O:8][C:9](=[O:17])[CH2:10][C@@H:11]([OH:16])[CH2:12][C:13]([NH2:15])=[O:14])C1C=CC=CC=1.N1C=CN=C1.[Si:23](Cl)([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24]>CN(C)C=O.ClCCl.CCCCCCC>[Si:23]([O:16][C@H:11]([CH2:10][C:9]([OH:8])=[O:17])[CH2:12][C:13]([NH2:15])=[O:14])([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24]
Reactant: NC(=O)C[C@H](O)CC(=O)OCc1ccccc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCCCCCC
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)O[C@@H](CC(N)=O)CC(=O)O
Temperature: 5 °C

Procedure:
(S)-Benzyl-3-hydroxyglutaramate (100 g) was dissolved in dimethyl formamide. To this Imidazole (35 g) was added and the solution was cooled to 5° C. To this a solution of tert-butyldimethylsilylchloride (68.5 g) dissolved in dimethyl formamide (250 ml) was added under cooling. The mixture was warmed to 20-25° C. and stirred. The reaction mixture was cooled and quenched with water. To the reaction mixture ethyl acetate and water was added and stirred. The layers were separated and the organic phase was washed thrice with water. To the organic phase Palladium on charcoal (5%, 1 g) was added and stirred under hydrogen atmosphere (˜2.8 Kg). Palladium was removed by filtration. The filtrate was mixed with water and adjusted pH to ˜9.0 by using Aq ammonia solution. The reaction mass was stirred and layers were separated. The aqueous phase was washed with dichloromethane and dichloromethane was added to aqueous phase. The reaction mass was cooled to 5° C. and pH was adjusted to 4.0 with Aq phosphoric acid. The reaction mass was stirred and layers were separated. The organic phase was washed with water and dried over sodium sulphate. The organic layer was evaporated under vacuum to yield residue. Residue was dissolved in dichloromethane and to this solution heptane was added, stirred, filtered and dried to yield (S)-3-(tert-butyl dimethylsilyloxy)glutaric acid monoamide.
Reaction SMILES: [CH2:1]([N:4]([CH2:22][CH2:23][CH3:24])[C:5]([C:7]1[CH:8]=[C:9]([CH:14]=[C:15]([C:17]2[NH:18][CH:19]=[CH:20][N:21]=2)[CH:16]=1)[C:10]([O:12]C)=[O:11])=[O:6])[CH2:2][CH3:3].[OH-].[Li+]>O1CCCC1.CO.O>[CH2:22]([N:4]([CH2:1][CH2:2][CH3:3])[C:5]([C:7]1[CH:8]=[C:9]([CH:14]=[C:15]([C:17]2[NH:21][CH:20]=[CH:19][N:18]=2)[CH:16]=1)[C:10]([OH:12])=[O:11])=[O:6])[CH2:23][CH3:24]
Reactant: CCCN(CCC)C(=O)c1cc(C(=O)OC)cc(-c2ncc[nH]2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CCCN(CCC)C(=O)c1cc(C(=O)O)cc(-c2ncc[nH]2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of the ester from step 1 (260 mg, 0.79 mmol) in 2:1:1 tetrahydrofuran/methanol/water (8 mL) is added lithium hydroxide (140 mg, 3.3 mmol). The reaction mixture is stirred at room temperature for 2 h, and concentrated under reduced pressure. The residue is partitioned between water (10 mL) and diethyl ether (10 mL). The aqueous layer is acidified to pH 4–5 with 1 N hydrochloric acid and extracted with 3:1 chloroform/2-propanol (3×30 mL). The combined organic layers are dried (sodium sulfate), filtered, and concentrated under reduced pressure to provide the title compound. 1H NMR (300 MHz, CD3OD) δ 8.64 (s, 1H), 8.10 (s, 1H), 8.01 (s, 1H), 7.28 (s, 2H), 3.52 (m, 2H), 3.26 (m, 2H), 1.75 (m, 2H), 1.59 (m, 2H), 1.02 (t, J=7 Hz, 3H), 0.75 (t, J=7 Hz, 3H).
Reaction SMILES: [NH2:1][C@H:2]([C:11]([OH:13])=[O:12])[CH2:3][C:4](=[O:10])[O:5][C:6]([CH3:9])([CH3:8])[CH3:7].C[Si](C([Si](C)(C)C)C(N)=O)(C)C.CN1CCOCC1.C(OC(Cl)=O)C(C)C.Cl.[NH2:42][C@H:43]([C:47]([NH:49][C@H:50]([C:52](O)=[O:53])[CH3:51])=[O:48])[CH:44]([CH3:46])[CH3:45]>CN(C=O)C.C1COCC1>[NH2:42][C@H:43]([C:47]([NH:49][C@H:50]([C:52]([NH:1][C@H:2]([C:11]([OH:13])=[O:12])[CH2:3][C:4](=[O:10])[O:5][C:6]([CH3:9])([CH3:7])[CH3:8])=[O:53])[CH3:51])=[O:48])[CH:44]([CH3:45])[CH3:46]
Reactant: CC(C)(C)OC(=O)C[C@H](N)C(=O)O
Reactant: CC(C)[C@H](N)C(=O)N[C@@H](C)C(=O)O
Agent: CC(C)COC(=O)Cl
Agent: C[Si](C)(C)C(C(N)=O)[Si](C)(C)C
Agent: Cl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CC(C)[C@H](N)C(=O)N[C@@H](C)C(=O)N[C@@H](CC(=O)OC(C)(C)C)C(=O)O
Temperature: -15 °C
Reaction time: 0.67 h

Procedure:
Asp(OtBu)OH (2.51 g) was dissolved in 40 mL of dry DMF under argon and 8.2 mL of bis(trimethylsilyl)acetamide (BSA) and the reaction was allowed to stir 40 minutes. In a separate flask, Mu-Val-Ala-OH (4.0 g) was dissolved in 200 mL of dry THF under argon and the resulting solution was cooled to -15° C. and one equivalent of N-methylmorpholine was added followed by one equivalent of isobutylchloroformate and the resulting mixture was allowed to stir 20 minutes and then the first reaction was then poured into the second reaction and both were maintained at -15° C. for one hour and then allowed to come slowly to room temperature and to stir overnight. The reaction was poured into 150 mL of 1N HCl and extracted with 2×200 mL of ethyl acetate. The combined organic fractions were washed with 15 mL 1N HCl, brine (50 mL), dried over MgSO4 (with decolorizing carbon), filtered, and the solvents were removed under reduced pressure to yield 4.89 g of Mu-Val-Ala-Asp(OtBu)OH.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]([OH:9])=O)=[CH:3][CH:2]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[Mg+].[C:23]([O:29][CH2:30][CH3:31])(=[O:28])[CH2:24]C([O-])=O.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCCC1.O.C(OCC)(=O)C>[O:9]=[C:7]([C:4]1[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=1)[CH2:24][C:23]([O:29][CH2:30][CH3:31])=[O:28]
Reactant: CCOC(=O)CC(=O)[O-]
Reactant: O=C(O)c1ccncc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [Mg+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC(=O)CC(=O)c1ccncc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 17 %

Procedure:
To a solution of 4-pyridinecarboxylic acid (50.0 g, 406 mmol) in tetrahydrofuran (250 ml) was added 1,1′-carbonylbis-1H-imidazole (72.5 g, 447 mmol), and the mixture was stirred at room temperature for 30 min. To the reaction solution was added monoethyl malonate magnesium salt (82.9 g, 487 mmol), and the mixture was heated under reflux for 30 min. To the reaction solution were added ethyl acetate (200 ml) and water (200 ml), and citric acid was added until the pH of the aqueous layer became 7. The reaction solution was extracted with ethyl acetate (400 ml×2). The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was washed with diisopropyl ether-hexane and recrystallized from diisopropyl ether-hexane to give ethyl 3-oxo-3-(4-pyridyl)propionate (13.3 g, 17%).
Reaction SMILES: Cl[C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=3)=[C:9]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[O:8][C:4]=2[N:5]=[CH:6][N:7]=1.[CH2:25]([O:27][CH:28]([O:33][CH2:34][CH3:35])[CH2:29][CH2:30][CH2:31][NH2:32])[CH3:26].CCN(C(C)C)C(C)C>CN(C=O)C>[CH2:34]([O:33][CH:28]([O:27][CH2:25][CH3:26])[CH2:29][CH2:30][CH2:31][NH:32][C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=3)=[C:9]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[O:8][C:4]=2[N:5]=[CH:6][N:7]=1)[CH3:35]
Reactant: CCOC(CCCN)OCC
Reactant: COc1ccc(-c2c(-c3ccccc3)oc3ncnc(Cl)c23)cc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(CCCNc1ncnc2oc(-c3ccccc3)c(-c3ccc(OC)cc3)c12)OCC

Procedure:
Stir 600 mg (1.78 mmol) 4-chloro-5-(4-methoxyphenyl)-6-phenylfuro[2,3-d]pyrimidine, 344.7 mg (2.14 mmol) 4-aminobutyraldehyde-diethylacetal and 0.465 ml (2.67 mmol) DIEA in 5 ml DMF overnight at 80° C. After cooling, purify the mixture directly by preparative RP-HPLC (gradient acetonitrile/water). 746 mg (90.7% of theor.) of the target compound is obtained.
Reaction SMILES: Br[CH:2](Br)[C:3](=O)[C:4]([F:7])([F:6])[F:5].C([O-])(=O)C.[Na+].Br.Br.[NH2:17][CH2:18][C:19]([NH2:21])=[NH:20].[OH-].[Na+]>O.CO>[NH2:21][C:19]1[CH:18]=[N:17][CH:2]=[C:3]([C:4]([F:7])([F:6])[F:5])[N:20]=1
Reactant: O=C(C(Br)Br)C(F)(F)F
Reactant: N=C(N)CN
Agent: Br
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: Nc1cncc(C(F)(F)F)n1
Temperature: 20 °C

Procedure:
A mixture of 6.6 g. of 3,3-dibromo-1,1,1-trifluoropropanone, 60 ml. of water, and 6.6 g. sodium acetate was refluxed for about 10 minutes. The solution thus obtained was cooled and added dropwise to a solution of 6 g. of aminoacetamidine dihydrobromide in 90 ml. of methanol cooled to a temperature of about -30° C., followed by the addition of a solution of 3.6 g. of sodium hydroxide pellets in 25 ml. of water. The reaction mixture was stirred and warmed gradually to about 20° C. over a period of about two hours. The reaction product mixture was concentrated in vacuo to remove the methanol, and the residue extracted with ethyl acetate. There was obtained product weighing 3.6 g. and having a melting point of about 133°-136° C. after recrystallization from a mixture of benzene and hexane. The product was identified by NMR spectrum and elemental analyses as 2-amino-6-trifluoromethylpyrazine.
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:4]=[C:5]([NH:9][C:10](=[O:39])[NH:11][CH2:12][C:13]([N:15]([CH:22]([C:30]2[CH:35]=[CH:34][C:33]([N+:36]([O-])=O)=[CH:32][CH:31]=2)[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:14])[CH:6]=[CH:7][CH:8]=1.C(O)C.C(=O)(O)[O-].[Na+]>[Fe].O>[NH2:36][C:33]1[CH:34]=[CH:35][C:30]([CH:22]([N:15]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:13](=[O:14])[CH2:12][NH:11][C:10]([NH:9][C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([CH3:2])[CH:4]=2)=[O:39])[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[CH:31][CH:32]=1
Reactant: Cc1cccc(NC(=O)NCC(=O)N(c2ccccc2)C(C(=O)OC(C)(C)C)c2ccc([N+](=O)[O-])cc2)c1
Agent: [Fe]
Agent: Cl
Agent: O=C([O-])O
Solvent: O
Solvent: CCO
Product: Cc1cccc(NC(=O)NCC(=O)N(c2ccccc2)C(C(=O)OC(C)(C)C)c2ccc(N)cc2)c1
Yield: 40.4 %

Procedure:
0.68 g of iron powder and 0.5 cm3 of concentrated hydrochloric acid are added to a suspension of 2.1 g of tert-butyl (RS)-2-{2-[3-(3methylphenyl)ureido]-N-phenylacetamido}-2-(4-nitrophenyl)acetate in 40 cm3 of a mixture of ethanol and water (50/50 by volume) heated under reflux. The reaction mixture is kept under reflux for 4 hours and after cooling it is rendered alkaline to pH 8 using a saturated aqueous sodium bicarbonate solution. The insoluble product is removed by filtration and the filtrate is extracted with 3 times 100 cm3 of dichloromethane. The organic extracts are washed with twice 100 cm3 of water, dried over magnesium sulphate and concentrated to dryness under reduced pressure (2.7 kPa) at 40° C. The oily residue obtained is purified by chromatography on 100 g of silica (0.04-0.063 mm) contained in a column 3 cm in diameter [eluent: methanol/dichloromethane (1/99 by volume)], using an excess pressure of 40 kPa of nitrogen and collecting 10-cm3 fractions. Fractions 8 to 14 are combined and concentrated to dryness under reduced pressure (2.7 kPa) at 40° C. After recrystallization from isopropyl ether, 0.8 g of tert-butyl (RS)-2-(4-aminophenyl)-2-{2-[3-(3-methylphenyl)ureido]-N-phenylacetamido}acetate melting at 108° C. is obtained.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[C:8]3[NH:16][N:15]=[N:14][C:9]=3[N:10]=[C:11]([NH2:13])[N:12]=2)=[CH:4][CH:3]=1.[Br:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH2:25]Br)[N:20]=1>CCCCCC.CCOC(C)=O>[Br:17][CH2:18][C:19]1[N:20]=[C:21]([CH2:25][N:14]2[C:9]3[N:10]=[C:11]([NH2:13])[N:12]=[C:7]([C:5]4[O:6][C:2]([CH3:1])=[CH:3][CH:4]=4)[C:8]=3[N:16]=[N:15]2)[CH:22]=[CH:23][CH:24]=1
Reactant: BrCc1cccc(CBr)n1
Reactant: Cc1ccc(-c2nc(N)nc3nn[nH]c23)o1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: Cc1ccc(-c2nc(N)nc3c2nnn3Cc2cccc(CBr)n2)o1

Procedure:
Prepared from 7-(5-methyl-2-furyl)-1H-[1,2,3]triazolo[4,5-d]pyrimidin-5-ylamine and 2,6-bis(bromomethyl)pyridine by the alkylation method described in Example 36; NMR δH (400 MHz, DMSO) 2.46 (3H, s), 4.64 (2H, s), 5.75 (2H, s), 6.50 (1H, d, J 3.5 Hz), 7.04 (1H, d, J 8.0 Hz), 7.31 (2H, s), 7.49 (1H, d, J 7.5 Hz), 7.80 (1H, t, J 7.5 Hz), 7.88 (1H, d, J 3.5 Hz). TLC (Hexane:EtOAc (1:1)) Rf=0.28**
Reaction SMILES: [C:1]1([C:7](=O)[CH2:8][CH2:9][CH2:10][CH2:11][C:12]([C-:14]2[CH:18]=[CH:17][CH:16]=[CH:15]2)=[O:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH-:20]1[CH:24]=[CH:23][CH:22]=[CH:21]1.[Fe+2:25].[H-].[Na+].O>[Na]>[C-:14]1([C:12]([C:11]2[CH2:10][CH2:9][CH2:8][C:7]=2[C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[O:13])[CH:18]=[CH:17][CH:16]=[CH:15]1.[CH-:20]1[CH:24]=[CH:23][CH:22]=[CH:21]1.[Fe+2:25]
Reactant: O=C(CCCCC(=O)[c-]1cccc1)c1ccccc1
Agent: [Fe+2]
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: O=C(C1=C(c2ccccc2)CCC1)[c-]1cccc1

Procedure:
6-Phenyl-6-oxohexanoylferrocene (5.61g; 15 mmole) in sodium dried dioxane (150 ml) was heated under reflux with sodium hydride (0.72g; 30 m mole) for 3 hr. The mixture was cooled and treated carefully with water (200 ml) when a brown solid precipitated, which was filtered off to yield 4.3g (76%) of nearly pure 1-ferrocenoyl-2-phenylcyclopentene. An analytical sample (3.7g; 69%) was obtained by one recrystallization from cyclohexane. mp 163°-164°.
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].[F:6][C:7]([F:22])([F:21])[C:8]([N:10]1[CH2:16][CH2:15][C:14]2[CH:17]=[CH:18][CH:19]=[CH:20][C:13]=2[CH2:12][CH2:11]1)=[O:9]>ClCCl>[F:22][C:7]([F:6])([F:21])[C:8]([N:10]1[CH2:11][CH2:12][C:13]2[CH:20]=[CH:19][C:18]([S:2]([Cl:1])(=[O:5])=[O:3])=[CH:17][C:14]=2[CH2:15][CH2:16]1)=[O:9]
Reactant: O=S(=O)(O)Cl
Reactant: O=C(N1CCc2ccccc2CC1)C(F)(F)F
Solvent: ClCCl
Product: O=C(N1CCc2ccc(S(=O)(=O)Cl)cc2CC1)C(F)(F)F
Reaction time: 48 h

Procedure:
Chlorosulphonic acid (10.4 ml, 0.156 mol) was added dropwise to a stirred, cold solution of the product from (b) above (5.85 g, 11.7 mmol) in dichloromethane, whilst ensuring that the temperature of the reaction mixture was held between -12 and -8° C. After 2 days at room temperature, the reaction solution was poured onto ice and the aqueous phase separated and extracted with dichloromethane. The combined organic extracts were dried (MgSO4) and evaporated under reduced pressure to provide an oil (7.9 g) which was purified by chromatography on silica gel, using a mixture of hexane and ether (1:3) as eluent, to give the title compound as a colourless oil which eventually solidified. Crystallisation of a sample from diisopropyl ether produced a white solid, m.p. 87°-88° C. Found: C,41.75; H,3.18; N,3.92. C12H11F3ClNO3S requires C,42.17; H,3.24; N,4.10%.
Reaction SMILES: C([Li])CCCCC.[CH3:8][O:9][C:10]([NH:12][C@@H:13]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:14]([O:16]C)=O)=[O:11].Cl[Si](C)(C)C.Br[CH2:31][Cl:32].Cl>CCCCCC.O1CCCC1.O>[CH2:18]([C@H:13]([NH:12][C:10](=[O:11])[O:9][CH3:8])[C:14](=[O:16])[CH2:31][Cl:32])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: ClCBr
Reactant: COC(=O)N[C@@H](Cc1ccccc1)C(=O)OC
Agent: C[Si](C)(C)Cl
Agent: Cl
Agent: [Li]CCCCCC
Solvent: CCCCCC
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)N[C@@H](Cc1ccccc1)C(=O)CCl
Yield: 70 %

Procedure:
15.4 ml of a 2.6 molar solution of hexyllithium in hexane were added dropwise at -80° C. to a solution of 9.50 g of methyl (S)-2-methoxycarbonylamino-3-phenyl-propionate in 60 ml of tetrahydrofuran. Subsequently, the mixture was treated with 5.60 ml of chlorotrimethylsilane. The resulting suspension was stirred and treated with 3.22 ml of bromochloromethane. Subsequently, 18.4 ml of hexyllithium solution were added. The solution was treated at -80° C. with 11 ml of 20% methanolic hydrochloric acid, warmed to 22° and diluted with 100 ml of water and 40 ml of tetrahydrofuran. The phases were separated and the organic phase was washed with saturated sodium chloride solution, dried and concentrated. The residue was recrystallized from ethyl acetate and hexane and the crystallizate was dried, there being obtained 7.20 g (70%) of pure methyl (S)-(1-benzyl-3-chloro-2-oxo-propyl)-carbamate, m.p. 122°-123° C. IR (KBr): 3336s (NH), 1737s and 1686s (C=O), 1535s (amide II).
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]([N:11]2[CH2:16][CH2:15][CH:14]([O:17][Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19])[CH2:13][CH2:12]2)=[N:9][CH:10]=1)=[O:4].CN(C)CCN(C)C.CC1(C)CCCC(C)(C)N1.C([Li])CCC.[I:48]I.O.O.O.O.O.S([O-])([O-])(=O)=S.[Na+].[Na+]>O1CCCC1>[CH3:1][NH:2][C:3]([C:5]1[C:6]([I:48])=[CH:7][C:8]([N:11]2[CH2:16][CH2:15][CH:14]([O:17][Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19])[CH2:13][CH2:12]2)=[N:9][CH:10]=1)=[O:4]
Reactant: CNC(=O)c1ccc(N2CCC(O[Si](C)(C)C(C)(C)C)CC2)nc1
Reactant: II
Agent: CC1(C)CCCC(C)(C)N1
Agent: CN(C)CCN(C)C
Agent: O=S([O-])([O-])=S
Solvent: C1CCOC1
Solvent: O
Product: CNC(=O)c1cnc(N2CCC(O[Si](C)(C)C(C)(C)C)CC2)cc1I
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 72.8 %

Procedure:
To a solution of 500 mg (1.43 mmol) 4-(tert-butyl-dimethyl-silanyloxy)-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-carboxylic acid methylamide, 1.7 ml (11 mmol) N,N,N′,N′-tetramethyl-ethylenediamine and 1.0 ml (5.7 mmol) 2,2,6,6-tetramethylpiperidine in 9.5 ml dry tetrahydrofuran 7.2 ml (11 mmol) of a 1.6 M solution of n-butyllithium in hexanes were added dropwise during 10 min. at −78° C. under argon. The resulting solution was stirred at −78° C. for 30 min., warmed to −20° C. and stirred at this temperature for 3 h. After cooling the reaction mixture to −78° C. a solution of 2.92 g (11.5 mmol) iodine in 7 ml dry tetrahydrofuran was added dropwise under argon. The resulting suspension was kept at −78° C. for 2 h and subsequently allowed to warm to room temperature over 1 h. The suspension was poured into a solution of 12.4 g (50.0 mmol) sodium thiosulfate pentahydrate in 50 ml ice-water. The resulting yellow suspension was extracted with two 250-ml portions of tert-butyl methyl ether. The combined organic extracts were washed with 2 portions of a saturated aqueous ammonium chloride solution, dried with sodium sulfate and concentrated. Flash chromatography afforded 495 mg (72.8 %) of the title compound as an off-white amorphous mass.
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][C:15](=[O:18])[CH2:14][CH2:13]3)[CH:10]=[CH:11][C:6]2=[N:5][N:4]=1.Br[C:22]1[CH:29]=[CH:28][CH:27]=[CH:26][C:23]=1[C:24]#[N:25]>>[OH:18][C:15]1([C:22]2[CH:29]=[CH:28][CH:27]=[CH:26][C:23]=2[C:24]#[N:25])[CH2:16][CH2:17][N:12]([C:9]2[CH:10]=[CH:11][C:6]3[N:7]([C:3]([C:2]([F:1])([F:19])[F:20])=[N:4][N:5]=3)[N:8]=2)[CH2:13][CH2:14]1
Reactant: N#Cc1ccccc1Br
Reactant: O=C1CCN(c2ccc3nnc(C(F)(F)F)n3n2)CC1
Product: N#Cc1ccccc1C1(O)CCN(c2ccc3nnc(C(F)(F)F)n3n2)CC1
Yield: 24 %

Procedure:
A mixture of 1-[3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4-one and 2-bromobenzonitrile was allowed to react by the method of Example 315 to give 2-[4-hydroxy-1-[3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4-yl]benzonitrile in 24% yield.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]1[CH:24]=[CH:23][C:6]([O:7][C:8]2[CH:9]=[C:10]([CH:20]=[CH:21][CH:22]=2)[CH2:11]P(=O)(OCC)OCC)=[CH:5][CH:4]=1.[H-].[Na+].[C:29]([O:33][C:34]([N:36]1[CH2:41][CH2:40][C:39](=O)[CH2:38][CH2:37]1)=[O:35])([CH3:32])([CH3:31])[CH3:30].O>C1COCC1.O1CCOCCOCCOCCOCC1>[F:26][C:2]([F:1])([F:25])[C:3]1[CH:4]=[CH:5][C:6]([O:7][C:8]2[CH:9]=[C:10]([CH:20]=[CH:21][CH:22]=2)[CH:11]=[C:39]2[CH2:40][CH2:41][N:36]([C:34]([O:33][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:35])[CH2:37][CH2:38]2)=[CH:23][CH:24]=1
Reactant: CCOP(=O)(Cc1cccc(Oc2ccc(C(F)(F)F)cc2)c1)OCC
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: C1COCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(=Cc2cccc(Oc3ccc(C(F)(F)F)cc3)c2)CC1
Reaction time: 0.5 h
Yield: 91.8 %

Procedure:
Diethyl 3-(4-(trifluoromethyl)phenoxy)benzylphosphonate (1.7 g, 4.4 mmol) from Step 3 and 1,4,7,10,13-pentaoxacyclopentadecane (15-Crown-5, 0.02 mL, 0.10 mmol) were combined in THF (10 mL). Sodium hydride (195 mg, 60% dispersion in mineral oil, 4.9 mmol) was added. The reaction was stirred for 30 min and then a solution of 4-oxo-piperidine-1-carboxylic acid tert-butyl ester (875 mg, 4.9 mmol) in THF (5 mL) was added. After 16 h, water was added and the layers were separated. The aqueous layer was extracted with EtOAc (2×200 mL) and the combined organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (10%, EtOAc:heptane) to afford the title compound (1.75 g, 92% yield) as a thick oil.