Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([F:16])([CH2:14][OH:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CC(C)([O-])C.[K+].[CH2:23]([C:27]1[N:28]=[N:29][C:30](Cl)=[CH:31][C:32]=1[C:33]1[CH:38]=[CH:37][C:36]([O:39][CH:40]2[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]2)=[CH:35][CH:34]=1)[CH2:24][CH2:25][CH3:26]>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][C:11]([CH2:14][O:15][C:30]2[N:29]=[N:28][C:27]([CH2:23][CH2:24][CH2:25][CH3:26])=[C:32]([C:33]3[CH:34]=[CH:35][C:36]([O:39][CH:40]4[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]4)=[CH:37][CH:38]=3)[CH:31]=2)([F:16])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCCCc1nnc(Cl)cc1-c1ccc(OC2CCCCC2)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(F)(CO)CC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCCCc1nnc(OCC2(F)CCN(C(=O)OC(C)(C)C)CC2)cc1-c1ccc(OC2CCCCC2)cc1
Reaction time: 0.5 h
Yield: 33.2 %

Procedure:
To a stirred solution of 4-fluoro-4-hydroxymethyl-piperidine-1-carboxylic acid tert-butyl ester (0.5 mmol, 0.116 g) in THF (2 mL) at room temperature was added potassium tert-butoxide (0.5 mmol, 0.5 mL, 1M solution in THF) and continued stirring for 30 min. 3-Butyl-6-chloro-4-(4-cyclohexyloxy-phenyl)-pyridazine (Example 14, 0.5 mmol, 0.172 g) was taken THF (1 mL) and added to the reaction and stirred for 10 h at room temperature. The reaction was quenched with slow addition of water (2 mL) and the product was extracted with ethyl acetate (2×5 mL), Organic layer was washed with water (5 mL), brine (5 mL), dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified on a SiO2 cartridge with 30% ethyl acetate in hexanes to provide 4-[6-butyl-5-(4-cyclohexyloxy-phenyl)-pyridazin-3-yloxymethyl]-4-fluoro-piperidine-1-carboxylic acid tert-butyl ester (90 mg).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][C:9](Cl)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:12]([O:16][C:17](=[O:36])[NH:18][CH:19]1[CH2:24][CH2:23][N:22]([S:25]([C:28]2[CH:33]=[CH:32][C:31]([NH2:34])=[C:30]([Cl:35])[CH:29]=2)(=[O:27])=[O:26])[CH2:21][CH2:20]1)([CH3:15])([CH3:14])[CH3:13]>N1C=CC=CC=1.C(Cl)Cl>[C:12]([O:16][C:17](=[O:36])[NH:18][CH:19]1[CH2:20][CH2:21][N:22]([S:25]([C:28]2[CH:33]=[CH:32][C:31]([NH:34][C:9](=[O:10])[CH2:8][CH2:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[C:30]([Cl:35])[CH:29]=2)(=[O:27])=[O:26])[CH2:23][CH2:24]1)([CH3:15])([CH3:13])[CH3:14]
Reactant: O=C(Cl)CCc1ccccc1
Reactant: CC(C)(C)OC(=O)NC1CCN(S(=O)(=O)c2ccc(N)c(Cl)c2)CC1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)NC1CCN(S(=O)(=O)c2ccc(NC(=O)CCc3ccccc3)c(Cl)c2)CC1
Temperature: 60 °C
Reaction time: 12 h
Yield: 12.3 %

Procedure:
3-Phenyl propionyl chloride (0.29 g, 1.76 mmol) was added in one portion to a solution of [1-(4-amino-3-chloro-benzenesulfonyl)-piperidin-4-yl]-carbamic acid tert-butyl ester (0.57 g, 1.4 mmol) in Pyridine (5 ml) and the mixture was heated to 60° C. The mixture was stirred at this temperature under a nitrogen atmosphere for 12 hours. After this time the mixture was diluted with DCM (100 ml) and washed sequentially with HCl (1M solution, 50 ml), NaOH (1M solution, 50 ml) and brine (50 ml). The organic layer was separated, dried (MgSO4), filtered and concentrated. The resulting residue was purified by flash column chromatography (elution: 98% DCM, 2% Methanol) to give the title compound (0.09 g, 8% yield) as a white powder. Tr=2.41 min, m/z (ES+) (M+Na)+ 545.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([S:12]([NH2:15])(=[O:14])=[O:13])[CH:3]=1.CO[CH:18]1[CH2:22][CH2:21][CH:20](OC)O1>C(O)(=O)C>[NH2:15][S:12]([C:4]1[CH:3]=[C:2]([N:1]2[CH:18]=[CH:22][CH:21]=[CH:20]2)[CH:11]=[CH:10][C:5]=1[C:6]([O:8][CH3:9])=[O:7])(=[O:13])=[O:14]
Reactant: COC(=O)c1ccc(N)cc1S(N)(=O)=O
Reactant: COC1CCC(OC)O1
Solvent: CC(=O)O
Product: COC(=O)c1ccc(-n2cccc2)cc1S(N)(=O)=O
Temperature: 110 °C
Reaction time: 1.5 h

Procedure:
In 3 ml of acetic acid, 300 mg (1.3 mmol) of methyl 4-amino2-(aminosulfonyl)benzoate and 0.23 ml of 2,5-dimethoxytetrahydrofuran were dissolved, followed by stirring at 110° C. for 1.5 hours. Acetic acid was then distilled off, followe by the addition of 30 ml of ice water. After the mixture thus obtained wa stirred for 20 minutes, the resulting precipitate was collected by filtration and dried in air. The brown solid thus obtained was purified b column chromatography, using silica gel ("Wako Gel C300", trade name; product of Wako Pure Chemical Industries, Ltd.) and dichloromethane, thereby obtaining the title compound as a white solid. Yield: 175.7 mg (48%). Its physicochemical properties are shown in Table 7.
Reaction SMILES: [Li].[O:2]([CH2:5][CH3:6])CC.IC.[CH3:9][CH:10]([N:12]1[CH2:17][CH2:16][C:15]([NH:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)(C(O)=O)[CH2:14][CH2:13]1)[CH3:11]>O>[CH3:11][CH:10]([N:12]1[CH2:17][CH2:16][C:15]([C:5](=[O:2])[CH3:6])([NH:21][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:14][CH2:13]1)[CH3:9]
Reactant: CCOCC
Reactant: CC(C)N1CCC(Nc2ccccc2)(C(=O)O)CC1
Agent: [Li]
Solvent: CI
Solvent: O
Product: CC(=O)C1(Nc2ccccc2)CCN(C(C)C)CC1
Temperature: 5 °C
Reaction time: 1.5 h
Yield: 33.5 %

Procedure:
To a stirred mixture of 13.8 parts of lithium and 140 parts of 1,1'-oxybisethane is added dropwise a mixture of 156 parts of iodomethane and 140 parts of 1,1'-oxybisethane while nitrogen gas is introduced. After the addition is complete, there are added 420 parts of 1,1'-oxybisethane and stirring is continued at reflux temperature till all lithium has reacted (about 15 minutes). Then there are added portionwise 26.25 parts of 1-(1-methylethyl)-4-(phenylamino)-4-piperidinecarboxylic acid (exothermic reaction: reflux temperature is maintained) while nitrogen gas is still introduced. Upon completion, stirring at reflux is continued for 1.50 hours. After the nitrogen gas introduction is stopped, the reaction mixture is cooled to 5° C. and decomposed by pouring onto 600 parts of water. The organic phase is separated, washed with water, dried, filtered and evaporated. The residue is purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (95:5 by volume), saturated with ammonia, as eluent. The pure fractions are collected and the eluent is evaporated. The residue is crystallized from petroleumether at 0° C. The product is filtered off and dried, yielding 8.7 parts (33.5%) of 1-[1-(1-methylethyl)-4-(phenylamino)-4-piperidinyl]ethanone; mp. 107.1° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:19]3[C:14](=[CH:15][C:16]([OH:20])=[CH:17][CH:18]=3)[C:13]([C:21]#[N:22])=[CH:12]2)=[CH:7][CH:6]=1)[CH3:2].[S:24]1[CH:28]=[CH:27][CH:26]=[C:25]1[CH2:29]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N=C=NC(C)C)(C)C>O1CCCC1>[CH2:1]([O:3][C:4](=[O:23])[C:5]1[CH:6]=[CH:7][C:8]([N:11]2[C:19]3[C:14](=[CH:15][C:16]([O:20][CH2:29][C:25]4[S:24][CH:28]=[CH:27][CH:26]=4)=[CH:17][CH:18]=3)[C:13]([C:21]#[N:22])=[CH:12]2)=[CH:9][CH:10]=1)[CH3:2]
Reactant: CCOC(=O)c1ccc(-n2cc(C#N)c3cc(O)ccc32)cc1
Reactant: OCc1cccs1
Agent: CC(C)N=C=NC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc(-n2cc(C#N)c3cc(OCc4cccs4)ccc32)cc1
Reaction time: 3 h

Procedure:
To a solution of 4-(5-hydroxy-3-cyanoindol-1-yl)benzoic acid ethyl ester and thiophene-2-methanol (0.057 g) and triphenylphosphine (0.012 g) in tetrahydrofuran (2.5 mL) was added diisopropylcarbodiimide (40% toluene solution, 0.18 mL) at room temperature, and this mixture was stirred for 3 hours. This reaction mixture was concentrated under reduced pressure. This residue was purified by column chromatography on silica gel (eluent: ethyl acetate/n-hexane=1/3) to give the title compound (0.10 g).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[NH:9][CH:8]=2)[CH2:3][CH2:2]1.C([O-])([O-])=O.[K+].[K+].[F:22][C:23]([F:32])([F:31])[C:24]1[CH:25]=[CH:26][C:27](Cl)=[N:28][CH:29]=1>CN(C=O)C>[NH:9]1[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:7]([CH:4]2[CH2:5][CH2:6][N:1]([C:27]3[CH:26]=[CH:25][C:24]([C:23]([F:32])([F:31])[F:22])=[CH:29][N:28]=3)[CH2:2][CH2:3]2)=[CH:8]1
Reactant: FC(F)(F)c1ccc(Cl)nc1
Reactant: c1ccc2c(C3CCNCC3)c[nH]c2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: FC(F)(F)c1ccc(N2CCC(c3c[nH]c4ccccc34)CC2)nc1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
3-piperidin-4-yl-1H-indole (0.5 g, 2.5 mmol) is suspended in 10 ml of DMF and is heated to 60° C. K2CO3 and 5-trifluoromethyl-2-chloropyridine (0.54 g, 3.0 mmol) are added and the reaction mixture is stirred at 95° C. for 1 hour. K2CO3 is removed by filtration and the filtrate is concentrated and purified with a silica gel flash column using heptane and ethyl acetate as the elutes.
Reaction SMILES: [H-].[Na+].[NH:3]1[CH2:8][CH2:7][CH2:6][CH2:5][C:4]1=[O:9].Br[CH2:11][C:12]1[CH:21]=[CH:20][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][CH:13]=1.[Cl-].[Na+]>CN(C=O)C>[O:9]=[C:4]1[CH2:5][CH2:6][CH2:7][CH2:8][N:3]1[CH2:11][C:12]1[CH:21]=[CH:20][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][CH:13]=1
Reactant: O=C1CCCCN1
Reactant: COC(=O)c1ccc(CBr)cc1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(CN2CCCCC2=O)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 99.9 %

Procedure:
60% sodium hydride (600 mg, 15.0 mmol) was suspended in DMF (30 mL), 2-piperidone (1.49 g, 15.0 mmol) was added thereto, followed by stirring at room temperature for 30 minutes. A solution of methyl 4-bromomethylbenzoate (2.29 g, 10.0 mmol) in DMF (10 mL) was added to the reaction mixture, followed by stirring at room temperature for 3 hours. The reaction mixture was poured into a saturated aqueous solution of sodium chloride, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and then the solvent was distilled away under reduced pressure. The resulting residue was purified through silica gel column chromatography (ethyl acetate:methanol=9:1) to afford methyl 4-[(2-oxopiperidino)methyl]benzoate (2.47 g 100%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C@H:9]([NH:11][C:12]1[CH:19]=[C:18]([N:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)[CH:17]=[CH:16][C:13]=1[C:14]#[N:15])[CH3:10].C(OC([N:33]1[CH2:38][CH2:37][CH2:36][CH2:35][C@@H:34]1[C:39](O)=[O:40])=O)(C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN1C(=O)CCC1>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C@H:9]([NH:11][C:12]1[CH:19]=[C:18]([N:20]2[CH2:25][CH2:24][N:23]([C:39]([C@H:34]3[CH2:35][CH2:36][CH2:37][CH2:38][NH:33]3)=[O:40])[CH2:22][CH2:21]2)[CH:17]=[CH:16][C:13]=1[C:14]#[N:15])[CH3:10]
Reactant: C[C@@H](Nc1cc(N2CCNCC2)ccc1C#N)c1ccc(Cl)cc1Cl
Reactant: CC(C)(C)OC(=O)N1CCCC[C@@H]1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H](Nc1cc(N2CCN(C(=O)[C@H]3CCCCN3)CC2)ccc1C#N)c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 76.2 %

Procedure:
To a stirred solution of the (R)-2-(1-(2,4-dichlorophenyl)ethylamino)-4-(piperazin-1-yl)benzonitrile (0.080 g, 0.21 mmol) and (R)-1-(t-butoxycarbonyl)piperidine-2-carboxylic acid (0.049 g, 0.21 mmol) in 1-methyl pyyrolidinone (NMP) (1.0 mL) was added HATU (0.085 g, 0.22 mmol) and iPr2NEt (0.055 g, 0.43 mmol). The reaction mixture was stirred at room temperature for 2 h, and quenched with deionzied water. The aqueous layer was extracted with diethyl ether (2×10 mL). The organic layer was dried (Na2SO4), filtered, and concentrated in vacuo. The crude product was purified by flash chromatography (SiO2, 0-25% ethyl acetate in hexanes) to afford the desired product (0.095 g, 0.16 mmol, 77%).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][N:5]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]3[N:15]=[C:16]([N:29]4[CH2:37][CH2:36][C:31]5(OCC[O:32]5)[CH2:30]4)[C:17]4[CH2:22][CH2:21][CH:20]([C:23]5[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=5)[C:18]=4[N:19]=3)=[CH:9][C:8]=2[O:38][CH3:39])[CH:6]=1.Cl.CC(C)=O>C1COCC1>[Cl:1][C:2]1[N:3]=[CH:4][N:5]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]3[N:15]=[C:16]([N:29]4[CH2:37][CH2:36][C:31](=[O:32])[CH2:30]4)[C:17]4[CH2:22][CH2:21][CH:20]([C:23]5[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=5)[C:18]=4[N:19]=3)=[CH:9][C:8]=2[O:38][CH3:39])[CH:6]=1
Reactant: COc1cc(Nc2nc3c(c(N4CCC5(C4)OCCO5)n2)CCC3c2ccccc2)ccc1-n1cnc(Cl)c1
Agent: Cl
Solvent: C1CCOC1
Solvent: CC(C)=O
Product: COc1cc(Nc2nc3c(c(N4CCC(=O)C4)n2)CCC3c2ccccc2)ccc1-n1cnc(Cl)c1
Temperature: 60 °C
Yield: 5.3 %

Procedure:
The mixture of N-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-7-phenyl-4-(1,4-dioxa-7-azaspiro[4.4]nonan-7-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-amine (Example 205) (37 mg, 0.068 mmol) and HCl (272 μL, 0.272 mmol) in THF (339 μL) was heated at 60° C. overnight. Concentrated to remove THF and added Acetone (339 μL) and HCl (272 μL, 0.272 mmol) to the mixture. The mixture was heated at 60° C. for 6 h. The crude product was purified by Prep-HPLC (Solvent A=10% MeOH-90% H2O-0.1% TFA, Solvent B=90% MeOH-10% H2O-0.1% TFA. Column. PHENOMENEX LUNA 30×100 mm, S10, Flow rate: 40 ml/min, 35-100% B, 40 min) and then was purified by Prep-HPLC (Column: PHENOMENEX LUNA C18 30×100 mm, Solvent A=10 mM Ammonium Acetate in 95:5 H2O/ACN, Solvent B=10 mM Ammonium Acetate in 5:95 H2O/ACN. Flow rate: 40 ml/min, 30-100% B, 35 min) to get 1-(2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenylamino)-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)pyrrolidin-3-one (2.0 mg, 3.59 μmol, 5.29% yield).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:14](=[O:20])[C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:5]=[CH:6][C:7]=1[CH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1.[F:21][C:22](I)([F:24])[F:23]>[Cu].CN(C)C=O>[F:21][C:22]([F:24])([F:23])[C:2]1[CH:3]=[C:4]([C:14](=[O:20])[C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:5]=[CH:6][C:7]=1[CH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: CCOC(=O)C(=O)c1ccc(C2CCCCC2)c(Br)c1
Reactant: FC(F)(F)I
Agent: [Cu]
Solvent: CN(C)C=O
Product: CCOC(=O)C(=O)c1ccc(C2CCCCC2)c(C(F)(F)F)c1
Temperature: 140 °C
Reaction time: 5 h

Procedure:
To a solution of 0.01 moles of ethyl 3-bromo-4-cyclohexylphenylglyoxylate in 50 ml. of dimethylformamide is added 0.15 moles of trifluoromethyl iodide and 0.02 g. of copper powder. The reaction is shaken in a sealed tube for 5 hours at 140° C., cooled, and then filtered and evaporated in vacuo. 200 ml. of water is added to the residue and extracted with ether. The ether extract is dried, evaporated to dryness and distilled to obtain ethyl 3-trifluoromethyl-4-cyclohexylphenylglyoxylate.
Reaction SMILES: C([NH:4][C:5]1[CH:19]=[C:18]([Cl:20])[C:8]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([OH:17])=[O:16])=[C:7]([Cl:21])[CH:6]=1)(=O)C.[OH-].[K+]>CO.O>[NH2:4][C:5]1[CH:6]=[C:7]([Cl:21])[C:8]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([OH:17])=[O:16])=[C:18]([Cl:20])[CH:19]=1
Reactant: CC(=O)Nc1cc(Cl)c(OCCCCCC(=O)O)c(Cl)c1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Nc1cc(Cl)c(OCCCCCC(=O)O)c(Cl)c1
Reaction time: 0.5 h
Yield: 65.6 %

Procedure:
7.5 g (22.4 mmol) of 6-(4-acetylamino-2,6-dichlorophenoxy)hexanoic acid in 140 ml of 1 m potassium hydroxide solution in methanol/water (3:1) were boiled under reflux overnight. The methanol was removed in a rotary evaporator, and the residue was diluted with about 30 ml of water and acidified to pH 5 with glacial acetic acid. The mixture was stirred in an ice bath for 30 minutes and then filtered with suction. The crude product was subjected to column chromatography using n-heptane/ethyl acetate=1/1 and produced 4.3 g (14.7 mmol, 66%) of the required product.
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[C:5]([CH2:9][CH2:10]F)([F:8])([F:7])[F:6].Cl.[CH:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[F:6][C:5]([F:8])([F:7])[CH2:9][CH2:10][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: FCCC(F)(F)F
Reactant: c1ccccc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Product: FC(F)(F)CCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a slurry of 9.4 g AlCl3 in 90 mL benzene cooled in an ice bath, was added (over 18 minutes) a solution of 14.2 g of CF3CH2CH2F in 10 mL benzene. The mixture was stirred for an additional 0.5 hour at ice-bath temperature and 1 hour at room temperature. It was then poured into 50 g ice and 25 mL concentrated HCl, and the resulting solution stirred until the color disappeared. The benzene layer was separated, washed with 25 mL saturated NaCl and dried (Na2SO4). Distillation provided 1,1,1-trifluoro-3-phenylpropane (CH3CH2CH2Ph), bp 77-79° C. at 32 mm Hg. 1H NMR: 7.1(5H), 2.8(m) ppm. 19F NMR: -67.2 (t, J=9.7 Hz) ppm. This example shows the utility of CF3CH2CH2F. It illustrates that it can be used in a Friedel-Crafts reaction to make the same product as would be obtained if CF3CH=CH2 had been used.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7](=[O:13])[C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH:4]=[N:3]1.[CH3:14][Mg]Br.C(OCC)C.[Cl-].[NH4+]>C1COCC1>[OH:13][C:7]([C:5]1[CH:4]=[N:3][N:2]([CH3:1])[CH:6]=1)([CH3:14])[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: C[Mg]Br
Reactant: CCOC(=O)C(=O)c1cnn(C)c1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCOC(=O)C(C)(O)c1cnn(C)c1
Reaction time: 1 h

Procedure:
Under an argon atmosphere, to a solution of 500 mg of ethyl (1-methyl-1H-pyrazol-4-yl)(oxo)acetate that had been cooled in a dry ice-acetone bath in 7.5 ml of THF was added 1.56 ml of a 3.0 M methyl magnesium bromide/diethyl ether solution, followed by stirring for 1 hour. To the reaction mixture was added a saturated aqueous ammonium chloride solution, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate, and the solvent was then evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain 302 mg of ethyl 2-hydroxy-2-(1-methyl-1H-pyrazol-4-yl)propanoate.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[CH2:7][C:8]1[N:9](COCC[Si](C)(C)C)[C:10]2[C:15]([CH:16]=1)=[CH:14][CH:13]=[CH:12][CH:11]=2.[F:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]2[S:36][C:35]([CH3:37])=[N:34][C:33]=2[C:38](Cl)=[O:39])=[CH:28][CH:27]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O>C1COCC1>[F:25][C:26]1[CH:27]=[CH:28][C:29]([C:32]2[S:36][C:35]([CH3:37])=[N:34][C:33]=2[C:38]([N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]2[CH2:7][C:8]2[NH:9][C:10]3[C:15]([CH:16]=2)=[CH:14][CH:13]=[CH:12][CH:11]=3)=[O:39])=[CH:30][CH:31]=1
Reactant: C[Si](C)(C)CCOCn1c(CC2CCCCN2)cc2ccccc21
Reactant: Cc1nc(C(=O)Cl)c(-c2ccc(F)cc2)s1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1nc(C(=O)N2CCCCC2Cc2cc3ccccc3[nH]2)c(-c2ccc(F)cc2)s1

Procedure:
(RS)-1-[5-(4-Fluoro-phenyl)2-methyl-thiazol-4-yl]-1-{2-[1-(2-trimethylsilanyl-oxymethyl)-1H-indol-2-ylmethyl]-piperidin-1-yl}-methanone (130 mg) was prepared from (RS)-2-piperidin-2-ylmethyl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-indole, D68 (520 mg) and 5-(4-fluoro-phenyl)-2-methyl-thiazole-4-carbonyl chloride (512 mg) according to a procedure similar to that for Example 1. A stirring solution of the above amide (125 mg) in dry THF (5 ml) was treated with a solution of tetrabutylammonium fluoride (2.2 mmol) in THF (5 ml). Once tlc indicated the reaction had gone to completion, the reaction mixture was poured into water and the product extracted with ethyl acetate. The combined organics were washed with brine, dried (Na2SO4) and the solvent removed in vacuo. Chromatography (silica gel, 0-100% pentane-ethyl acetate followed by preparative tlc, 40% ethyl acetate-pentane) afforded the title compound as a white solid (2.5 mg).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]2[N:11]([CH:15]=[C:16]([CH2:18]Cl)[N:17]=2)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C-:20]#[N:21].[Na+]>CN(C)C=O>[CH2:1]([O:8][C:9]1[C:10]2[N:11]([CH:15]=[C:16]([CH2:18][C:20]#[N:21])[N:17]=2)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ClCc1cn2cccc(OCc3ccccc3)c2n1
Reactant: [C-]#N
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#CCc1cn2cccc(OCc3ccccc3)c2n1

Procedure:
A mixture of 1.79 g 8-benzyloxy-2-chloromethylimidazo[1,2-a]pyridine, 0.90 g sodium cyanide, and 15 ml dimethylformamide was heated on a steam bath for 1.5 hr. The mixture was cooled and evaporated in vacuo, the residue was taken up in chloroform (50 ml) and filtered through a pad of silica gel, the filtrate was evaporated in vacuo, and the residue recrystallized from acetonitrile to give the title compound (m.p. 148°-150°C.).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6](Cl)[C:5]([F:9])=[CH:4][N:3]=1.[CH2:10]([O:12][C:13]([NH:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][C:17]=1[OH:23])=[O:14])[CH3:11]>>[CH2:10]([O:12][C:13]([NH:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:2]2[N:7]=[C:6]([NH:20][C:19]3[CH:21]=[CH:22][C:16]([NH:15][C:13]([O:12][CH2:10][CH3:11])=[O:14])=[C:17]([OH:23])[CH:18]=3)[C:5]([F:9])=[CH:4][N:3]=2)=[CH:18][C:17]=1[OH:23])=[O:14])[CH3:11]
Reactant: CCOC(=O)Nc1ccc(N)cc1O
Reactant: Fc1cnc(Cl)nc1Cl
Product: CCOC(=O)Nc1ccc(Nc2ncc(F)c(Nc3ccc(NC(=O)OCC)c(O)c3)n2)cc1O

Procedure:
In like manner to N2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine, 2,4-dichloro-5-fluoropyrimidine and 4-ethoxycarbonylamino-3-hydroxyaniline were reacted to yield N2,N4-bis(4-ethoxycarbonylamino-3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine. 1H NMR (CD3OD): δ 7.86 (d, 1H J=4 Hz), 7.67 (m, 2H), 7.20 (dd, 1H, J=8 Hz, J=4.1 Hz), 7.13 (d, 1H), 6.90 (m, 2H), 4.2 (m, 4H), 1.32 (m, 6H); LCMS: ret. time: 20.92 min.; purity: 98%; MS (m/e): 487 (MH+).
Reaction SMILES: Br[CH2:2][C:3]1[C:4]([F:20])=[C:5]([O:10][C:11]2[CH:12]=[C:13]([CH:16]=[C:17]([Cl:19])[CH:18]=2)[C:14]#[N:15])[C:6]([Cl:9])=[CH:7][CH:8]=1.[NH3:21]>C(Cl)Cl.CO>[NH2:21][CH2:2][C:3]1[C:4]([F:20])=[C:5]([O:10][C:11]2[CH:12]=[C:13]([CH:16]=[C:17]([Cl:19])[CH:18]=2)[C:14]#[N:15])[C:6]([Cl:9])=[CH:7][CH:8]=1
Reactant: N
Reactant: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc(CBr)c2F)c1
Solvent: ClCCl
Solvent: CO
Product: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc(CN)c2F)c1
Reaction time: 2 h
Yield: 84 %

Procedure:
3-{[3-(Bromomethyl)-6-chloro-2-fluorophenyl]oxy}-5-chlorobenzonitrile (1.0 g, 2.6 mmol) was dissolved in CH2Cl2 (5 mL) and added dropwise to ammonia in methanol (7N, 25 mL). The reaction mixture was stirred for 2 h then the solvent was evaporated. The resulting oil was purified by column chromatography (CH-2Cl2/MeOH) to afford the title compound (0.7 g, 84%). 1H NMR (400 MHz, DMSO-d6): δ ppm 7.79 (s, 2H), 7.45-7.56 (m, 4H), 7.42 (t, 1H), 3.75 (s, 2H). MS: m/z 311.1 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C@@H:12]([C:16]([OH:18])=[O:17])[CH:13]([CH3:15])[CH3:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:19][C:20](=[CH2:22])[CH3:21].OS(O)(=O)=O>C(Cl)Cl.O1CCOCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([NH:11][C@@H:12]([C:16]([O:18][C:20]([CH3:22])([CH3:21])[CH3:19])=[O:17])[CH:13]([CH3:15])[CH3:14])(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: CC(C)[C@@H](NS(=O)(=O)c1ccc(F)cc1)C(=O)O
Reactant: C=C(C)C
Agent: O=S(=O)(O)O
Solvent: ClCCl
Solvent: C1COCCO1
Product: CC(C)[C@@H](NS(=O)(=O)c1ccc(F)cc1)C(=O)OC(C)(C)C

Procedure:
A solution of N-[(4-fluorophenyl)-sulfonyl]-D-valine from Example 1a (8.00 g, 29.1 mmol) in CH2Cl2 /dioxane was treated with isobutylene in the presence of H2SO4 at room temperature at a pressure of 18 psi. The reaction was quenched by adding the solution to a mixture of NaHCO3 (20 g) in water (300 mL) cooled in an ice bath. The mixture was extracted with ethyl acetate. The ethyl acetate layers were combined and washed with H2O and brine, dried over MgSO4, and concentrated to a solid. Recrystallization from diethyl ether/hexane afforded N-[(4-fluorophenyl)-sulfonyl]-D-valine, 1,1-dimethylethyl ester, as a white solid (6.99 g, 73%): MS MH+ calc'd for Cl5H22NO4SF: 332, found: 332. Anal. calc'd for Cl5H22NO4SF: C, 54.36; H, 6.69; N, 4.23. Found: C, 54.21; H, 6.86; N, 4.14.