Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[S:3][CH2:4][C:5]([C:8]([CH3:11])([CH3:10])[CH3:9])=[N:6][N:7]=1.C(N(CC)CC)C.[CH3:19][O:20][C:21]1[CH:29]=[CH:28][CH:27]=[C:26]([O:30][CH3:31])[C:22]=1[C:23](Cl)=[O:24].O>O1CCOCC1>[CH3:9][C:8]([C:5]1[CH2:4][S:3][C:2]([NH:1][C:23](=[O:24])[C:22]2[C:26]([O:30][CH3:31])=[CH:27][CH:28]=[CH:29][C:21]=2[O:20][CH3:19])=[N:7][N:6]=1)([CH3:11])[CH3:10]
Reactant: COc1cccc(OC)c1C(=O)Cl
Reactant: CC(C)(C)C1=NN=C(N)SC1
Solvent: O
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: COc1cccc(OC)c1C(=O)NC1=NN=C(C(C)(C)C)CS1
Temperature: 25 °C
Reaction time: 3 h
Yield: 12.8 %

Procedure:
To a solution of 1.71 g of 2-amino-5-(1,1-dimethylethyl)-6H-1,3,4-thiadiazine and 1.01 g triethylamine in 18 ml dioxane was added 2.11 g of 2,6-dimethoxybenzoyl chloride. The reaction mixture was stirred at room temperature for 3 hours and poured into 100 ml water. The solid was collected and recrystallized from ethanol. The second crop of material provided 0.43 g of N-[5-(1,1-dimethylethyl)-6H-1,3,4-thiadiazin-2-yl]-2,6-dimethoxybenzamide. mp=175°-177° C.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:14]=[C:13]([CH:15]([OH:20])[CH2:16][CH2:17][CH2:18][CH3:19])[CH:12]=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.[CH3:23][O:24][C:25](=[O:34])[CH2:26][C:27]1[CH:32]=[CH:31][C:30](O)=[CH:29][CH:28]=1.P(CCCC)(CCCC)CCCC>C1COCC1>[F:22][C:2]([F:21])([F:1])[C:3]1[CH:4]=[CH:5][C:6]([C:9]2[N:14]=[C:13]([CH:15]([O:20][C:30]3[CH:31]=[CH:32][C:27]([CH2:26][C:25]([O:24][CH3:23])=[O:34])=[CH:28][CH:29]=3)[CH2:16][CH2:17][CH2:18][CH3:19])[CH:12]=[CH:11][CH:10]=2)=[CH:7][CH:8]=1
Reactant: CCCCC(O)c1cccc(-c2ccc(C(F)(F)F)cc2)n1
Reactant: COC(=O)Cc1ccc(O)cc1
Agent: CCCCP(CCCC)CCCC
Solvent: C1CCOC1
Product: CCCCC(Oc1ccc(CC(=O)OC)cc1)c1cccc(-c2ccc(C(F)(F)F)cc2)n1
Temperature: 25 °C
Reaction time: 0.02 h
Yield: 63.8 %

Procedure:
To a solution of 1-{6-[4-(trifluoromethyl)phenyl]-2-pyridinyl}-1-pentanol (349 mg, 1.13 mmol) in dry THF (22.5 mL) at 0° C. (ice/water bath) under nitrogen was added methyl-4-hydroxyphenylacetate (187 mg, 1.13 mmol) followed after 1 minute by ADDM (578 mg, 2.25 mmol) in one portion. The resulting orange cloudy mixture was stirred for 3 minutes and then treated with nBu3P (562 μL, 2.26 mmol) drop-wise over 1 minute. The resulting pale yellow/orange mixture was then allowed to warm slowly to rt over 64 hours. The cloudy mixture was then reduced under vacuum and the residue partitioned between EtOAc (50 mL) and water (50 mL) and the layers separated. The aqueous was then re-extracted with EtOAc (50 mL) and the combined organic layer washed with brine (100 mL) dried (MgSO4), filtered and reduced to give an oil which was purified by SPE (silica) eluting with cyclohexane:EtOAc (gradient 100:1 to 5:1) to give the title compound (330 mg).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([F:11])([F:10])[F:9])[N:3]=1.C([Li])CCC.[C:17]([N:24]1[CH2:29][CH2:28][C:27](=[O:30])[CH2:26][CH2:25]1)([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18].O>O1CCCC1>[C:20]([O:19][C:17]([N:24]1[CH2:29][CH2:28][C:27]([OH:30])([C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([F:11])([F:10])[F:9])[N:3]=2)[CH2:26][CH2:25]1)=[O:18])([CH3:23])([CH3:21])[CH3:22]
Reactant: FC(F)(F)c1cccc(Br)n1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(O)(c2cccc(C(F)(F)F)n2)CC1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 97.7 %

Procedure:
A mixture of 2-bromo-6-(trifluoromethyl)pyridine (300 mg, 1.33 mmol) in tetrahydrofuran (10 mL) under a nitrogen atmosphere cooled to −78° C. was treated with n-butyl lithium (2M solution in tetrahydrofuran, 0.83 mL, 1.33 mmol). The mixture was stirred at −78° C. for 15 min. At this time, the reaction was treated with 1-boc-4-piperidone (265 mg, 1.33 mmol). The mixture was then allowed to slowly warm to 25° C. and was stirred at 25° C. for 1 h. At this time, the reaction was poured into water. The aqueous layer was extracted with ethyl acetate. The organics were washed with a saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered, and concentrated in vacuo to afford 4′-hydroxy-6-trifluoromethyl-3′,4′,5′,6′-tetrahydro-2′H-[2,4′]bipyridinyl-1′-carboxylic acid tert-butyl ester (450 mg, 98%) as a yellow oil; LRMS for C16H21F3N2O3 (M+H)+ at m/z=346. The NMR spectrum obtained on the sample is compatible with its structure.
Reaction SMILES: C[Si]([O:5][C:6]1[C:11]([C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:10][C:9]([C:16]([CH3:19])([CH3:18])[CH3:17])=[CH:8][C:7]=1[P:20]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)(C)C.[O:33]1[CH2:37][CH2:36][CH2:35][CH2:34]1.[Cl-:38].[Cl-].[Cl-].[Cl-].[Zr+4:42]>O1CCCC1>[Cl-:38].[Cl-:38].[C:21]1([P:20]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:7]2[CH:8]=[C:9]([C:16]([CH3:19])([CH3:18])[CH3:17])[CH:10]=[C:11]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:6]=2[O:5][Zr+2:42][O:33][C:37]2[C:36]([C:12]([CH3:13])([CH3:14])[CH3:15])=[CH:35][C:34]([C:16]([CH3:19])([CH3:18])[CH3:17])=[CH:28][C:27]=2[P:20]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:6]=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CC(C)(C)c1cc(P(c2ccccc2)c2ccccc2)c(O[Si](C)(C)C)c(C(C)(C)C)c1
Reactant: [Zr+4]
Reactant: C1CCOC1
Agent: [Cl-]
Product: CC(C)(C)c1cc(P(c2ccccc2)c2ccccc2)c(O[Zr+2]Oc2c(P(c3ccccc3)c3ccccc3)cc(C(C)(C)C)cc2C(C)(C)C)c(C(C)(C)C)c1
Temperature: -30 °C
Reaction time: 1 h
Yield: 58.1 %

Procedure:
Next, 0.98 g (2.11 millimole) of this 4,6-di-tert-butyl-2-diphenylphosphinophenyl trimethylsilyl ether was dissolved in 15 ml of dehydrated tetrahydrofuran under nitrogen flow, and the solution was cooled down to −30° C. Then, a dehydrated tetrahydrofuran solution of 0.4 g (1.06 millimole) of a zirconium tetrachloride tetrahydrofuran adduct was added thereto step by step, and the solution was stirred at a room temperature for one hour. Further, the solution was refluxed for 3 days by heating. The solvent was distilled off under reduced pressure, and the residue was recrystallized from dichloromethane/hexane, whereby obtained was 0.29 g (yield: 29.0%) of bis (2-diphenylphosphino-4,6-di-tert-butylphenoxy) zirconium dichloride.
Reaction SMILES: [CH2:1](O)[CH3:2].[N:4]1[CH:9]=[CH:8][C:7]([C:10]([NH:12][NH2:13])=[O:11])=[CH:6][CH:5]=1.Br[CH2:15][CH2:16][F:17].[OH-].[K+]>O.ClCCl>[F:17][CH2:16][CH2:15][N:13]1[CH2:2][CH2:1][O:11][C:10]([C:7]2[CH:8]=[CH:9][N:4]=[CH:5][CH:6]=2)=[N:12]1
Reactant: FCCBr
Reactant: CCO
Reactant: NNC(=O)c1ccncc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: FCCN1CCOC(c2ccncc2)=N1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To 60 ml of ethanol in a 250 ml round-bottom flask was added 25 grams of 4-pyridinecarboxylic acid hydrazide and 58 grams of 1-bromo-2-fluoroethane, to prepare a reaction mixture. After stirring the reaction mixture at room temperature for 15 minutes, a solution of 24 grams of potassium hydroxide in 60 ml of water was added dropwise to the reaction mixture. The resulting reaction mixture was heated to reflux for 3 hours. The reaction mixture was then allowed to cool to room temperature. To the cooled reaction mixture was added 100 ml of water and 200 ml of dichloromethane, to prepare a mixture with an aqueous layer and an organic layer. The organic layer was separated and extracted to leave an oil upon evaporation of the solvent. The oil was purified by column chromatography on silica gel using dichloromethane as the eluant, to produce 12 grams of 4-(2-fluoroethyl)-5,6-dihydro-2-(4-pyridinyl)-4H-1,3,4-oxadiazine as an oil.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[C:11](=[C:12]([CH2:15][CH2:16][CH3:17])[C:13]=1[OH:14])[N:10]=[C:9]([C:18](OC)=[O:19])[CH:8]=[C:7]2[Cl:22])(=[O:3])[CH3:2].[NH3:23]>Cl>[C:1]([C:4]1[CH:5]=[C:6]2[C:11](=[C:12]([CH2:15][CH2:16][CH3:17])[C:13]=1[OH:14])[N:10]=[C:9]([C:18]([NH2:23])=[O:19])[CH:8]=[C:7]2[Cl:22])(=[O:3])[CH3:2]
Reactant: N
Reactant: CCCc1c(O)c(C(C)=O)cc2c(Cl)cc(C(=O)OC)nc12
Agent: Cl
Product: CCCc1c(O)c(C(C)=O)cc2c(Cl)cc(C(N)=O)nc12

Procedure:
Methyl 6-acetyl-4-chloro-7-hydroxy-8-propylquinoline-2-carboxylate (2 g) was treated with ammonia saturated methanol in an autoclave at 100° C. for 24 hours. Removal of solvent afforded a solid which was boiled with 2 N HCl (100 ml) for 10 minutes, then cooled, and the precipitate was collected and identified as the sub-title compound by NMR.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]([CH3:14])[C:5]1[N:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][N:6]=1.[H-].[Na+].[CH2:17](I)[CH3:18]>C1COCC1.CN(C=O)C.CCOC(C)=O>[CH2:17]([O:1][CH2:2][CH2:3][N:4]([CH3:14])[C:5]1[N:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][N:6]=1)[CH3:18]
Reactant: CN(CCO)c1ncc([N+](=O)[O-])cn1
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CCOCCN(C)c1ncc([N+](=O)[O-])cn1
Reaction time: 8 h

Procedure:
(2-Hydroxy-ethyl)-methyl-(5-nitro-pyrimidin-2-yl)-amine (198 mg, 1 mmol) in THF (15 mL) and DMF (3 mL) was stirred with 60% NaH in oil (60 mg, 1.75 mmol) for 1 hr. The mixture was cooled and to this was added ethyl iodide. The reaction mixture was allowed to stir overnight. The mixture was diluted with EtOAc, extracted with H2O and dried over MgSO4. The EtOAc was filtered, evaporated to dryness and used without further purification. Yield: 75 mg. ES-MS calcd for C9H14N4O3 (m/e) 226.24, obsd 227 (M+H).
Reaction SMILES: [C:1](=O)([O-])[O-].[K+].[K+].[I-].[K+].[C:9](OC(=O)CCl)([CH3:12])([CH3:11])[CH3:10].[CH3:18][C:19]([CH3:21])=[O:20]>>[CH:1]#[C:12][C:9]1[CH:10]=[CH:21][C:19]([OH:20])=[CH:18][CH:11]=1
Reactant: CC(C)=O
Reactant: CC(C)(C)OC(=O)CCl
Reactant: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Product: C#Cc1ccc(O)cc1

Procedure:
50.0 g of the resin synthesized in Reference Example 4 was dissolved in 500 ml of acetone. After adding 12.6 g of potassium carbonate, 2.52 g of potassium iodide and 13.15 g of tert-butylchloroacetate, the solution obtained was refluxed for 10 hours. Thereafter, same post-treatment as that of Reference Example 5 was carried out to obtain poly(p-vinylphenol) wherein 1% of the hydroxyl groups were ethyletherified and 21% of the hydroxyl groups were tert-butoxycarbonylmethyletherified.
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:13][C:14]1[C:22]([N+:23]([O-:25])=[O:24])=[CH:21][C:20]([Br:26])=[CH:19][C:15]=1[C:16](O)=[O:17].Cl.[CH3:28][O:29][NH:30][CH3:31].O>C(Cl)Cl>[NH2:13][C:14]1[C:22]([N+:23]([O-:25])=[O:24])=[CH:21][C:20]([Br:26])=[CH:19][C:15]=1[C:16]([N:30]([O:29][CH3:28])[CH3:31])=[O:17]
Reactant: CNOC
Reactant: Nc1c(C(=O)O)cc(Br)cc1[N+](=O)[O-]
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Solvent: O
Product: CON(C)C(=O)c1cc(Br)cc([N+](=O)[O-])c1N
Temperature: 25 °C
Reaction time: 1 h
Yield: 35.9 %

Procedure:
1,1′-Carbonyldiimidazole (41 g) was added portionwise at room temperature to a mixture of 2-amino-5-bromo-3-nitro-benzoic acid (55 g) in DCM (700 ml). The mixture was stirred at room temperature for 1 hour. N-methoxy-methanamine hydrochloride (24.6 g) was added. The mixture was stirred at room temperature overnight and hydrolized with water. The precipitate was filtered off and the filtrate was decanted. The organic layer was dried, filtered and the solvent was evaporated till dryness. The residue was purified by column chromatography over silica gel (eluent: CH2Cl2/ethyl acetate 98/2). The pure fractions were collected and the solvent was evaporated. The precipitate was taken up in HCl 3N (250 ml). The mixture was stirred at room temperature for 4 hours. The precipitate was filtered off, washed with water and dried, yielding 23 g of 2-amino-5-bromo-N-methoxy-N-methyl-3-nitrobenzamide (interm. 55, mp. 129° C.)
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[CH2:5][N:6]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([N+:21]([O-:23])=[O:22])[CH:16]=1)[S:7]([NH:10]C(C)(C)C)(=[O:9])=[O:8])[CH3:2].[C:25]([OH:31])([C:27]([F:30])([F:29])[F:28])=[O:26]>O1CCOCC1>[CH2:1]([O:3][C:4](=[O:24])[CH2:5][N:6]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([N+:21]([O-:23])=[O:22])[CH:16]=1)[S:7]([NH2:10])(=[O:9])=[O:8])[CH3:2].[F:28][C:27]([F:30])([F:29])[C:25]([O-:31])=[O:26]
Reactant: O=C(O)C(F)(F)F
Reactant: CCOC(=O)CN(c1cccc([N+](=O)[O-])c1)S(=O)(=O)NC(C)(C)C
Solvent: C1COCCO1
Product: CCOC(=O)CN(c1cccc([N+](=O)[O-])c1)S(N)(=O)=O
Product: O=C([O-])C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
5 mmol of (3-nitro-phenyl-N-(t-butylaminosulfonyl)amino)-acetic acid ethyl ester is dissolved in 20 ml of 90% aqueous TFA and the mixture obtained is stirred for 1 hour at rt. The mixture obtained is diluted with dioxane and solvent is evaporated. (3-Nitro-phenyl-N-(aminosulfonyl)amino)-acetic acid ethyl ester in the form of a trifluoroacetate is obtained.
Reaction SMILES: [C:1]([NH:5][C:6]1[N:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]2=[N:8][C:7]=1[C:15]1[S:16][C:17]([C:20]#[C:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=2)=[CH:18][CH:19]=1)([CH3:4])([CH3:3])[CH3:2].O.[Cl:29][Si](C)(C)C>C(Cl)Cl>[ClH:29].[C:1]([NH:5][C:6]1[N:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]2=[N:8][C:7]=1[C:15]1[S:16][C:17]([C:20]#[C:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=2)=[CH:18][CH:19]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: C[Si](C)(C)Cl
Agent: CC(C)(C)Nc1c(-c2ccc(C#Cc3ccccn3)s2)nc2ccccn12
Solvent: ClCCl
Solvent: O
Product: Cl
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 6.93 g (18.6 mmol) of N-tert-butyl-2-(5-(pyridin-2-ylethynyl)thiophen-2-yl)imidazo[1,2-a]pyridin-3-amine (Example 94) in DCM (180 ml) was combined with 335 μl (18.6 mmol) of water and 2.35 ml (18.6 mmol) of chlorotrimethylsilane and stirred at RT for 16 h. The resultant precipitate was filtered out and dried under a vacuum at 40° C., 6.09 g (14.8 mmol, 80%) of N-tert-butyl-2-(5-(pyridin-2-ylethynyl)thiophen-2-yl)imidazo[1,2-a]pyridin-3-amine hydrochloride being obtained.
Reaction SMILES: [Li][CH2:2][CH2:3][CH2:4]C.[CH2:6]([O:10][S:11]([CH:14]1[CH2:16][CH2:15]1)(=[O:13])=[O:12])[CH2:7][CH2:8][CH3:9].[CH3:17]I>C1COCC1>[CH3:17][C:14]1([S:11]([O:10][CH2:6][C:7]2[CH:4]=[CH:3][CH:2]=[CH:9][CH:8]=2)(=[O:13])=[O:12])[CH2:16][CH2:15]1
Reactant: CI
Reactant: [Li]CCCC
Reactant: CCCCOS(=O)(=O)C1CC1
Solvent: C1CCOC1
Product: CC1(S(=O)(=O)OCc2ccccc2)CC1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 78.9 %

Procedure:
n-BuLi (0.78 g, 12.25 mmol) was added drop-wise at −78° C. to a solution of Butylcyclopropane sulfonate (2.0 g, 11.2 mmol) in THF (20 mL) and continued stirring at the same temperature for 10 min. CH3I (3.98 g, 28.0 mmol) was added at −78° C., allowed the reaction to warm to 0° C. with stirring for 30 min. The reaction mixture was quenched with ice cold water, diluted with ethylacetate (100 mL), organic layer collected was dried over anhydrous sodium sulphate and concentrated under reduced pressure to afford the crude. The crude was purified by column chromatography (using silica gel and 4% ethyl acetate in Hexane as eluent) to afford benzyl 1-methylcyclopropane-1-sulfonate (Int-48) (2.0 g, 93% yield). 1H NMR (300 MHz, CD3OD) δ 4.2-4.1 (2H, t), 1.7-1.6 (2H, m), 1.4 (3H, s), 1.5-1.3 (2H, m), 1.3-1.2 (2H, m), 1.0-0.9 (2H, m), 0.9 (3H, t) ppm.
Reaction SMILES: [N:1]1([C:14]([O:16][CH2:17][C:18]2[CH:23]=CC=C[CH:19]=2)=[O:15])[CH2:13][CH2:12][CH2:11][C@H:2]1[C:3](N[C@H](C(O)=O)C)=O.C(Cl)[Cl:25]>>[CH2:17]([O:16][C:14]([Cl:25])=[O:15])[CH:18]([CH3:23])[CH3:19].[CH3:14][N:1]1[CH2:3][CH2:2][CH2:11][CH2:12][CH2:13]1
Reactant: C[C@H](NC(=O)[C@@H]1CCCN1C(=O)OCc1ccccc1)C(=O)O
Reactant: ClCCl
Product: CC(C)COC(=O)Cl
Product: CN1CCCCC1

Procedure:
A suspension of 2.100 g (6.55 mmoles) of Z-(L)-Pro-(L)AlaOH (Sigma) in 80 ml of dry methylene chloride (CH2Cl2) was brought, under argon atmosphere, to a temperature of approximately -20° C. On stabilization of the temperature, the following were added in rapid succession: 0.850 ml (6.50 mmoles) of isobutylchloroformate (IBCF) and 0.790 ml (6.50 mmoles) of N-methylpiperidine (NMP), leaving the system under stirring for approximately 2 minutes. A solution pre-cooled to -15° C. for 30 minutes of 1.700 g (6.32 mmoles) of TrpOMe. HCl, prepared (according to Chan's method) from 1-Me-(DL)-TrpOH (Aldrich) and 0,770 ml (6.33 mmoles) of NMP in 25 ml of anhydrous N,N-dimethylformamide (DMF) was then added to the white suspension. Under stirring, the temperature of the system was allowed to rise to room temperature. After approximately 4 hours of reaction, the white precipitate was filtered away and washed with a little CH2Cl2. The latter was put back into the reaction solution of a yellowish colour, which was extracted in succession using 5% NaHCO3 (4×30 ml); saturated aqueous NaCl (2×30 ml); 4% KHSO4 (4×30 ml) and finally saturated aqueous NaCl (3×30 ml), discarding the aqueous phases. The organic phase extracted was left in a cold chamber under argon and on anhydrous Na2SO4 for 24 hours. The desiccant was then filtered away and the solution concentrated to a small volume under vacuum. The residual yellowish liquid was dripped under stirring into 150 ml of n-hexane, obtaining a large amount of white precipitate, which was filtered after resting for several hours in a cold chamber, leaving the white solid under vacuum on P2O5 for 12 hours. 2.700 g (85.0%) of a white solid were recovered, which on analysis was shown to be Z-(L)-Pro-(L)-Ala-(1)-Me-(DL)-TrpOMe. The two diastereoisomers were separated by flash-chromatography in an inverse phase (resin C18, eluant H2O/CH3CN 60:40), collecting and uniting the fractions of interest. On elimination under vacuum of most of the organic phase, an abundant white flocculent precipitation was obtained which, after several hours at rest in a cold chamber, was filtered under vacuum. The filtered solid was dried for 24 hours on P2O5 under vacuum. 1.0 g (31.5%) of an analytically pure white solid corresponding to Z-(L)-Pro-(L)-Ala-(1)-Me-(L)-TrpOMe were recovered.
Reaction SMILES: [O:1]1[CH2:5][CH:4]=[CH:3][C:2]1=[O:6].C(N(CC)CC)C.[Si:14](OS(C(F)(F)F)(=O)=O)([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15]>ClCCl>[Si:14]([O:6][C:2]1[O:1][CH:5]=[CH:4][CH:3]=1)([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15]
Reactant: O=C1C=CCO1
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)Oc1ccco1

Procedure:
To a freshly distilled solution of 2(5H)-furanone (2.86 g, 34 mmol) in dichloromethane (20 ml), distilled triethylamine (6.6 ml. 47.4 mmol) is added under argon at 0° C. and then rapidly followed by tert-butyldimehylsilyltrifluoromethane sulfonate (8.6 ml, 37.3 mmol) The reaction mixture is allowed to return to room temperature and the stirring is maintained for two hours. The solvent is then removed under reduced pressure and the oily residue is purified by flash chromatography on silica gel (ethyl acetate-heptane, 1:9) in order to thus obtain compound 10 (Z=O) in the form of a slightly colored oil (5.3 g, 79%). The spectroscopic data for this compound (1H and 13C NMR) are identical to those described in the literature (G. Rassu, Z. Zanardi, L. Battistini, E. Gaetani, G. Casiraghi, J. Med. Chem ., 1997, 40, 168).
Reaction SMILES: [CH:1](=[O:4])[CH2:2][OH:3].[C:5]([Si:9]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)Cl)([CH3:8])([CH3:7])[CH3:6].N1C=CN=C1>CN(C)C=O>[Si:9]([O:4][CH2:1][CH:2]=[O:3])([C:5]([CH3:8])([CH3:7])[CH3:6])([C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: O=CCO
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](OCC=O)(c1ccccc1)c1ccccc1

Procedure:
In the manner described in Example 14c, 5.15 g of glycolaldehyde and 26.78 ml of tert-butyldiphenylchlorosilane were reacted in the presence of 7.61 g of imidazole and 26 ml of absolute dimethylformamide whereby after column chromatography with ether/petroleum ether (1:2) 21.26 g of the title compound were obtained.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([Cl:21])=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[S:15]([CH:18]([CH3:20])[CH3:19])(=[O:17])=[O:16])[N:7]=1.[CH3:22][O:23][C:24]1[CH:30]=[C:29]([N:31]2[CH2:36][CH2:35][CH:34]([N:37]3[CH2:42][CH2:41][P:40]([CH3:44])(=[O:43])[CH2:39][CH2:38]3)[CH2:33][CH2:32]2)[CH:28]=[CH:27][C:25]=1[NH2:26].C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O>CC(O)C.ClCCl>[Cl:21][C:5]1[N:4]=[N:3][C:2]([NH:26][C:25]2[CH:27]=[CH:28][C:29]([N:31]3[CH2:36][CH2:35][CH:34]([N:37]4[CH2:42][CH2:41][P:40]([CH3:44])(=[O:43])[CH2:39][CH2:38]4)[CH2:33][CH2:32]3)=[CH:30][C:24]=2[O:23][CH3:22])=[N:7][C:6]=1[NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[S:15]([CH:18]([CH3:20])[CH3:19])(=[O:17])=[O:16]
Reactant: COc1cc(N2CCC(N3CCP(C)(=O)CC3)CC2)ccc1N
Reactant: CC(C)S(=O)(=O)c1ccccc1Nc1nc(Cl)nnc1Cl
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: CC(C)O
Solvent: ClCCl
Product: COc1cc(N2CCC(N3CCP(C)(=O)CC3)CC2)ccc1Nc1nnc(Cl)c(Nc2ccccc2S(=O)(=O)C(C)C)n1
Temperature: 25 °C

Procedure:
A mixture of 3,6-dichloro-N-[2-(propan-2-ylsulfonyl)phenyl]-1,2,4-triazin-5-amine (prepared as in Example 106: 0.7 mmol), 2-methoxy-4-[4-(4-methyl-4-oxido-1,4-azaphosphinan-1-yl)piperidin-1-yl]aniline (0.7 mmol) and camphorsulfonic acid (0.7 equiv.), is refluxed for 20-48 hours in 2-propanol. The reaction mixture is allowed to cool to room temperature, dissolved in dichloromethane and washed with an aqueous solution of Na2CO3. The dichloromethane extract is dried over MgSO4 and evaporated. The crude product is purified by Prep-HPLC.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH3:9])=[CH:4][CH:3]=1.Cl[C:19]1[N:24]=[C:23]([Cl:25])[C:22]([C:26]([F:29])([F:28])[F:27])=[CH:21][N:20]=1>ClCCCl.CC(O)(C)C.[Zn+2].[Br-].[Br-]>[Cl:25][C:23]1[C:22]([C:26]([F:28])([F:27])[F:29])=[CH:21][N:20]=[C:19]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([C@H:8]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH3:9])=[CH:4][CH:3]=2)[N:24]=1
Reactant: C[C@@H](NC(=O)OC(C)(C)C)c1ccc(N)cc1
Reactant: FC(F)(F)c1cnc(Cl)nc1Cl
Agent: [Br-]
Agent: [Zn+2]
Solvent: ClCCCl
Solvent: CC(C)(C)O
Product: C[C@@H](NC(=O)OC(C)(C)C)c1ccc(Nc2ncc(C(F)(F)F)c(Cl)n2)cc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
C2 (690 mg, 2.92 mmol) was dissolved in 10 mL DCE:t-BuOH (1:1 vol:vol), and the resultant solution was treated with ZnBr2 (1.97 g, 8.76 mmol) and 2,4-dichloro-5-(trifluoromethyl)pyrimidine (748 mg, 3.45 mmol). The resultant mixture was then treated drop-wise with TEA (406 ml, 2.92 mmol), and the mixture was allowed to stir at 25° C. for about 20 hours. The reaction mixture was concentrated, and the resultant residue was treated with EtOAc. The resultant solution was washed with water and brine, and dried over MgSO4. The mixture was then filtered, concentrated, and purified by column chromatography eluting with 22% EtOAc/Heptane. The product-containing eluents were combined and concentrated to provide C3 as a white solid. Yield: 680 mg, 56%. MS− 415.2. 1H NMR (500 MHz, DMSO) δ: 10.59 (s, 1H), 8.74 (s, 1H), 7.53 (d, 2H), 7.31 (d, 1H), 7.23 (d, 2H), 4.54 (m, 1H), 1.33 (s, 9H), 1.25 (d, 3H).