Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([NH:12][CH:13]([CH3:15])[CH3:14])[C:9]2[C:8](=[O:16])[N:7]([CH3:17])[CH:6]=[N:5][C:4]=2[CH:3]=1.CC1(C)C(C)(C)OB([C:26]2[CH:31]=[CH:30][C:29]([NH:32][CH2:33][CH2:34][N:35]3[CH2:40][CH2:39][O:38][CH2:37][CH2:36]3)=[C:28]([S:41]([CH3:44])(=[O:43])=[O:42])[CH:27]=2)O1.C([O-])([O-])=O.[Na+].[Na+].C(#N)C>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[O:38]1[CH2:37][CH2:36][N:35]([CH2:34][CH2:33][NH:32][C:29]2[CH:30]=[CH:31][C:26]([C:2]3[N:11]=[C:10]([NH:12][CH:13]([CH3:15])[CH3:14])[C:9]4[C:8](=[O:16])[N:7]([CH3:17])[CH:6]=[N:5][C:4]=4[CH:3]=3)=[CH:27][C:28]=2[S:41]([CH3:44])(=[O:42])=[O:43])[CH2:40][CH2:39]1
Reactant: CC1(C)OB(c2ccc(NCCN3CCOCC3)c(S(C)(=O)=O)c2)OC1(C)C
Reactant: CC(C)Nc1nc(Cl)cc2ncn(C)c(=O)c12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: CC(C)Nc1nc(-c2ccc(NCCN3CCOCC3)c(S(C)(=O)=O)c2)cc2ncn(C)c(=O)c12
Temperature: 140 °C

Procedure:
7-Chloro-5-(isopropylamino)-3-methylpyrido[4,3-d]pyrimidin-4(3H)-one (60 mg, 0.24 mmol), crude 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(methylsulfonyl)-N-(2-morpholinoethyl)benzenamine (240 mg, ˜0.28 mmol), Pd(PPh3)4 (28 mg, 0.024 mmol) and Na2CO3 (102 mg, 0.96 mol) in a mixed solvent of acetonitrile (4 mL) and H2O (4 mL) were added to a 20 mL microwave tube and sealed. The tube was then heated in a Microwave Reactor at 140° C. for 10 minutes. The solvent was removed and the crude product purified by silica column using 7% MeOH in DCM to give the final product as a pale solid. ESI-MS m/z 501.2 (MH+); 1H NMR (DMSO-d6) δ 8.71 (d, J=7.2 Hz, 1H), 8.46 (d, J=2.4 HZ, 1H), 8.40 (s, 1H), 8.26 (d, J=8.8 Hz, 1H), 7.04 (s, 1H), 6.97 (d, J=8.8 Hz, 1H), 6.77 (t, J=4.8 Hz, 1H), 3.59 (m, 4H), 3.42 (s, 3H), 3.33 (m, 4H), 3.20 (s, 3H), 2.62 (m, 2H), 2.44 (s, 3H), 1.29 (d, J=6.4 Hz, 6H).
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:6]=[C:7](/[CH:11]=C/C(Cl)=O)[CH:8]=[CH:9][CH:10]=1)[CH2:2][CH3:3].[OH:16]C1C=C(C=CC=1)C=O.ICCC>>[CH2:1]([O:4][C:5]1[CH:6]=[C:7]([CH:8]=[CH:9][CH:10]=1)[CH:11]=[O:16])[CH2:2][CH3:3]
Reactant: O=Cc1cccc(O)c1
Reactant: CCCOc1cccc(/C=C/C(=O)Cl)c1
Solvent: CCCI
Product: CCCOc1cccc(C=O)c1

Procedure:
For example, (E)-3-(3'-propyloxyphenyl)-2-propenoyl chloride, used in Example 3 (i), can be prepared from commercially available 3-hydroxybenzaldehyde by reacting 3-hydroxybenzaldehyde with 1-iodopropane to give 3-propyloxy benzaldehyde. 3-Propyloxy benzaldehyde is then reacted with malonic acid to give the corresponding propenonic acid which is subsequently converted into (E)-3-(3'-propyloxyphenyl)-2-propenoyl chloride by reaction with oxalyl chloride.
Reaction SMILES: [Li].[CH3:2][CH:3]([CH3:7])[C:4]([OH:6])=[O:5].C([N-]C(C)C)(C)C.[Li+].[CH2:16]([O:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.Cl>O1CCCC1>[CH2:16]([O:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][C:3]([CH3:7])([CH3:2])[C:4]([OH:6])=[O:5])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CC(C)C(=O)O
Reactant: BrCCCCCCCCCCOCc1ccccc1
Agent: CC(C)[N-]C(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(CCCCCCCCCCOCc1ccccc1)C(=O)O
Yield: 46 %

Procedure:
According to the method reported by George R. Newkome et al.: Synthesis, 1975, 517, lithium dianion of 2-methylpropionic acid was generated from lithium diisopropylamide in tetrahydrofuran under a nitrogen atmosphere. After the dropwise addition thereto of 18 g of 10-benzyloxydecanyl bromide at -20° C., the mixture was reacted at 45° C. for 2 hours. The reaction mixture was then mixed with cold dilute hydrochloric acid and extracted with ether, and the separated ether layer was washed with dilute hydrochloric acid and then with water. The separated layer was then dried over salt cake and evaporated to dryness to leave a crude oily material which in turn was recrystallized from petroleum ether, producing 8.4 g (yield 46%) of 12-benzyloxy-2,2-dimethyldodecanoic acid as colorless crystal. M.P. 53° to 55° C.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH:13]([OH:23])[CH2:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=1)=[O:7])(C)(C)C.[C:24]([O:28][C:29]([N:31]1[CH2:38][CH2:37][CH2:36][C@H:32]1C(O)=O)=[O:30])([CH3:27])([CH3:26])[CH3:25]>>[C:24]([O:28][C:29]([N:31]1[CH2:38][CH2:37][CH2:36][C@H:32]1[C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH:13]([OH:23])[CH2:14][O:15][C:16]1[CH:17]=[CH:18][C:19]([Cl:22])=[CH:20][CH:21]=1)=[O:7])=[O:30])([CH3:27])([CH3:25])[CH3:26]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(O)COc1ccc(Cl)cc1
Product: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)N1CCC[C@H]1C(O)COc1ccc(Cl)cc1
Yield: 59.2 %

Procedure:
By the same procedure as in Example 26-D), while using (2S)-1-(tert-butoxycarbonyl)-2-[2-(4-chlorophenoxy)-1-hydroxyethyl]pyrrolidine (2.80 g) and N-(tert-butoxycarbonyl)-L-proline (1.94 g), there was obtained 2.13 g of the title compound.
Reaction SMILES: [NH:1]([C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4])[NH2:2].C(N(CC)CC)C.[Cl:17][C:18]1[N:19]=[CH:20][C:21]([C:24](Cl)=[O:25])=[N:22][CH:23]=1>ClCCl>[Cl:17][C:18]1[N:19]=[CH:20][C:21]([C:24]([NH:2][NH:1][C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4])=[O:25])=[N:22][CH:23]=1
Reactant: CC(C)(C)OC(=O)NN
Reactant: O=C(Cl)c1cnc(Cl)cn1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NNC(=O)c1cnc(Cl)cn1
Reaction time: 16 h

Procedure:
1,1-dimethylethyl hydrazinecarboxylate (2.59 g, 19.58 mmol) and triethylamine (2.98 mL, 21.36 mmol) were dissolved in Dichloromethane (DCM) (50 mL). 5-chloro-2-pyrazinecarbonyl chloride (I47) (3.15 g, 17.80 mmol) dissolved in Dichloromethane (DCM) (50 mL) was added dropwise at 0° C. and the mixture allowed to reach room temperature over 16 hr. Solvents were removed in vacuo and the residue was partitioned between ethyl acetate (100 mL) and saturated sodium bicarbonate solution (50 mL). The aqueous phase was extracted with ethyl acetate (3×100 mL), combined extracts were washed with brine (100 mL) dried over anhydrous sodium sulfate and concentrated to a crude solid (5.05 g). The product was purified by flash chromatography (Isolera, 100 g, 0-100% Methanol:Dichloromethane (1:9)/Dichloromethane) to afford product in 4.63 g.
Reaction SMILES: C([BH3-])#N.[Na+].[C:5]([C:7]1[CH:14]=[CH:13][C:10]([CH:11]=O)=[CH:9][CH:8]=1)#[N:6].[F:15][C:16]([F:20])([F:19])[CH2:17][NH2:18].C(O)(=O)C>CO>[F:15][C:16]([F:20])([F:19])[CH2:17][NH:18][CH2:11][C:10]1[CH:13]=[CH:14][C:7]([C:5]#[N:6])=[CH:8][CH:9]=1
Reactant: NCC(F)(F)F
Reactant: N#Cc1ccc(C=O)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: N#Cc1ccc(CNCC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.8 %

Procedure:
Add sodium cyanoborohydride (957 mg, 15.24 mmol) to a stirred solution of 4-cyanobenzaldehyde (500 mg, 3.81 mmol), 2,2,2-trifluoroethylamine (0.3 mL, 3.81 mmol) and acetic acid (0.44 mL, 7.62 mmol) in methanol (5 mL). Stir the mixture overnight at room temperature. Partition the mixture between 1N aqueous NaOH and DCM. Extract the aqueous phase twice with DCM. Dry the combined organic extracts over MgSO4, filter and concentrate in vacuo to obtain the desired intermediate (749 mg, 92%) suitable for use without further purification. MS (ES+) m/z: 215 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]([CH2:14][CH3:15])[CH2:7][NH:8][C@H:9]([C:11]([OH:13])=[O:12])[CH3:10])=[O:5])[CH3:2].C(N(CC)CC)C.Cl[C:24]([O:26][CH2:27][CH3:28])=[O:25]>CC(C)=O>[CH2:1]([O:3][C:4]([CH:6]([CH2:14][CH3:15])[CH2:7][N:8]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[C@H:9]([C:11]([OH:13])=[O:12])[CH3:10])=[O:5])[CH3:2]
Reactant: CCOC(=O)C(CC)CN[C@@H](C)C(=O)O
Reactant: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: CCOC(=O)C(CC)CN(C(=O)OCC)[C@@H](C)C(=O)O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a suspension of N-[2-(ethoxycarbonyl)butyl]alanine (21.7 g, 100 mmol) in acetone (250 mL) was added a solution of triethylamine (27.7 mL, 20.2 g, 200 mmol) in acetone (50 mL) followed by ethyl chloroformate (24.8 mL, 28.2 g, 260 mmol) at 0-5° C. After stirring for 2 h at ambient temperature the solvent was evaporated and the residue was stirred with a mixture of water (200 mL) and concentrated hydrochloric acid (2 mL) for 8 h at ambient temperature. The mixture was extracted with ethyl acetate (200 mL) and the solution in ethyl acetate was extracted with cold aqueous sodium hydroxide solution [prepared from ice (100 g) and aqueous sodium hydroxide solution (1N, 200 mL)]. Concentrated hydrochloric acid (15 mL) was added to the aqueous layer and the mixture was extracted with ethyl acetate (200 mL). After drying and evaporation N-[2-(ethoxycarbonyl)butyl]-N-ethoxycarbonylalanine (23.8 g, 82%) was obtained as a yellow oil which can be used in the next reaction without further purification.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:9](=[N:11][OH:12])[NH2:10])=[N:4][C:5]([Br:8])=[CH:6][N:7]=1.C(N(CC)CC)C.[C:20](Cl)(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(Cl)Cl>[NH2:1][C:2]1[C:3]([C:9](=[N:11][O:12][C:20](=[O:27])[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[NH2:10])=[N:4][C:5]([Br:8])=[CH:6][N:7]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: NC(=NO)c1nc(Br)cnc1N
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: NC(=NOC(=O)c1ccccc1)c1nc(Br)cnc1N
Reaction time: 1 h
Yield: 69.8 %

Procedure:
3-amino-6-bromo-N′-hydroxypyrazine-2-carboximidamide (770 mg, 3.318 mmol) was suspended in DCM (10 mL) and triethylamine (369.3 mg, 508.7 μL, 3.650 mmol) followed by benzoyl chloride (513.1 mg, 423.7 μL, 3.650 mmol) were added. After 1 hour, the solvent was removed in vacuo and the residue triturated with MeOH. The resultant filtrate was filtered off to furnish the product as an off-white solid (779 mg, 70% Yield).
Reaction SMILES: Cl.[OH:2][CH:3]1[O:11][C@H:10]([CH2:12][OH:13])[C@@H:8]([OH:9])[C@H:6]([OH:7])[C@H:4]1[NH2:5].C(N(CC)CC)C.[F:21][C:22]([F:29])([F:28])[C:23](OCC)=[O:24]>CO>[F:21][C:22]([F:29])([F:28])[C:23]([NH:5][C@@H:4]1[C@@H:6]([OH:7])[C@H:8]([OH:9])[C@@H:10]([CH2:12][OH:13])[O:11][CH:3]1[OH:2])=[O:24]
Reactant: N[C@H]1C(O)O[C@H](CO)[C@@H](O)[C@@H]1O
Reactant: CCOC(=O)C(F)(F)F
Agent: Cl
Solvent: CO
Solvent: CCN(CC)CC
Product: O=C(N[C@H]1C(O)O[C@H](CO)[C@@H](O)[C@@H]1O)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
160 g (0.742 mole) of D-(+)-glucosamine hydrochloride were dissolved in 2200 ml of methanol (99.6% purity), and 187.9 g (1.86 mole) of triethylamine were added to the resulting solution. 115.9 g of ethyl trifluoroacetate were then added dropwise to the resulting mixture, whilst ice-cooling, after which the mixture was stirred overnight at room temperature. At the end of this time, the mixture was concentrated by evaporation under reduced pressure, and then benzene (250 ml twice) and ethyl acetate (250 ml) were repeatedly added to the residue, which was then concentrated by evaporation under reduced pressure and then finally dried sufficiently in vacuo. The whole of the resulting crude trifluoroacetyl compound was used in the subsequent step (b) without purification.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([C:9]2[CH2:13][CH2:12][C:11]3([CH2:17][CH2:16][N:15]([CH3:18])[C:14]3=[O:19])[N:10]=2)[CH:3]=1.CC1(C)C(C)(C)OB([C:28]2[CH:35]=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:33]=[CH:32][C:29]=2[C:30]#[N:31])O1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.ClCCl.C1(C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)[Pd][P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:8][C:6]1[CH:7]=[C:2]([C:28]2[CH:35]=[C:34]([C:36]([F:37])([F:39])[F:38])[CH:33]=[CH:32][C:29]=2[C:30]#[N:31])[CH:3]=[C:4]([C:9]2[CH2:13][CH2:12][C:11]3([CH2:17][CH2:16][N:15]([CH3:18])[C:14]3=[O:19])[N:10]=2)[N:5]=1
Reactant: Cc1cc(Br)cc(C2=NC3(CC2)CCN(C)C3=O)n1
Reactant: CC1(C)OB(c2cc(C(F)(F)F)ccc2C#N)OC1(C)C
Agent: c1ccc([P]([Pd][P](c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Solvent: ClCCl
Product: Cc1cc(-c2cc(C(F)(F)F)ccc2C#N)cc(C2=NC3(CC2)CCN(C)C3=O)n1
Temperature: 120 °C
Yield: 32 %

Procedure:
To a solution of 2-(4-bromo-6-methyl-2-pyridyl)-7-methyl-1,7-diazaspiro[4.4]non-1-en-6-one (which may be prepared as described in Description 13) (180 mg, 0.5600 mmol) in 1,2-dimethoxyethane (3 mL) and water (1 mL) was added 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4-(trifluoromethyl)benzonitrile (182.56 mg, 0.6100 mmol) and sodium carbonate (177.65 mg, 1.68 mmol). The reaction mixture was degassed with nitrogen and then treated with bis(triphenylphosphine)palladium (II) dichloride (19.61 mg, 0.0300 mmol). The reaction was heated in the microwave at 120° C. for 15 minutes. The reaction mixture was diluted with dichloromethane and water. After separation of the layers, the aqueous phase was re-extracted with dichloromethane and the combined organic phases passed through a hydrophobic frit. The solvent was evaporated and the residue purified by silica gel chromatography to afford 2-[2-methyl-6-(7-methyl-6-oxo-1,7-diazaspiro[4.4]non-1-en-2-yl)-4-pyridyl]-4-(trifluoromethyl)-benzonitrile (D14) as a colourless solid (74 mg);
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:6]=[C:7]([C:13]2[CH2:17][C:16](=[O:18])[NH:15][N:14]=2)[CH:8]=[CH:9][C:10]=1[O:11][CH3:12].Cl[C:20]1[C:29]2[C:24](=[CH:25][C:26]([O:32][CH2:33][CH2:34][CH2:35][N:36]3[CH2:41][CH2:40][O:39][CH2:38][CH2:37]3)=[C:27]([O:30][CH3:31])[CH:28]=2)[N:23]=[CH:22][N:21]=1>CN(C=O)C.[Cl-].[NH4+]>[CH3:3][O:4][C:5]1[CH:6]=[C:7]([C:13]2[NH:14][N:15]=[C:16]([O:18][C:20]3[C:29]4[C:24](=[CH:25][C:26]([O:32][CH2:33][CH2:34][CH2:35][N:36]5[CH2:37][CH2:38][O:39][CH2:40][CH2:41]5)=[C:27]([O:30][CH3:31])[CH:28]=4)[N:23]=[CH:22][N:21]=3)[CH:17]=2)[CH:8]=[CH:9][C:10]=1[O:11][CH3:12]
Reactant: COc1cc2c(Cl)ncnc2cc1OCCCN1CCOCC1
Reactant: COc1ccc(C2=NNC(=O)C2)cc1OC
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: COc1ccc(-c2cc(Oc3ncnc4cc(OCCCN5CCOCC5)c(OC)cc34)n[nH]2)cc1OC
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 57.5 %

Procedure:
Sodium hydride (40 mg, 1 mmol, prewashed with THF) was added to a suspension of 3-(3,4-dimethoxyphenyl)-4,5-dihydro-1H-pyrazol-5-one (220 mg, 1 mmol) in DMF (3 ml) under nitrogen. After stirring for 20 minutes at ambient temperature, 4-chloro-6-methoxy-7-(3-morpholinopropoxy)quinazoline (134 mg, 0.4 mmol), (prepared as described for the starting material in Example 2), was added and the mixture was heated for 30 minutes at 60° C. After cooling, the mixture was diluted with saturated aqueous ammonium chloride solution and partitioned between methylene chloride and water. The organic layer was washed with water, brine, dried (MgSO4) and the volatiles were removed by evaporation. The residue was purified by column chromatography eluting with methylene chloride/ethyl acetate/methanol (1/10 followed by 5/4/1). The volatiles were removed by evaporation and the residual solid was collected by filtration, washed with ether and dried under vacuum to give 4-(5-(3,4-dimethoxyphenyl)pyrazol-3-yloxy)-6-methoxy-7-(3-morpholinopropoxy)quinazoline (120 mg, 57%).
Reaction SMILES: [F-].[K+].O1CCCOO1.[C:9]([C:13]([C:15]([F:18])([F:17])[F:16])=[O:14])([F:12])([F:11])[F:10].[CH:19]([C:28](F)(F)F)([C:24]([F:27])([F:26])[F:25])[C:20]([F:23])([F:22])[F:21]>CC(N(C)C)=O.CN(C)C=O>[F:10][C:9]([F:12])([F:11])[C:13]([C:15]([F:18])([F:17])[F:16])=[O:14].[F:21][C:20]([F:23])([F:22])[C:19](=[CH2:28])[C:24]([F:27])([F:26])[F:25]
Reactant: FC(F)(F)C(C(F)(F)F)C(F)(F)F
Agent: C1COOOC1
Agent: O=C(C(F)(F)F)C(F)(F)F
Agent: [F-]
Solvent: CC(=O)N(C)C
Solvent: CN(C)C=O
Product: C=C(C(F)(F)F)C(F)(F)F

Procedure:
Following the procedure of Example 1, 100 g (0.274 mole) ##STR5## 3.5 g anhydrous KF, 60 g (2.02 mole) trioxane (α-trioxymethylene), 50 mL dimethylformamide and 100 mL dimethylacetamide were heated from 100° C. to 143° C. over a 25 hour period. The cold trap yielded 29.4 g crude product which on GC analysis indicated that 15 g (0.09 mole) was CF3COCF3, 4.4 g (0.027 mole) was (CF3)2C=CH2 and 5.0 g (0.023 mole) was (CF3)3CH. The yields of hexafluoroacetone and hexafluoroisobutylene were 16.4% and 4.9% respectively based on starting hexafluorothioacetone dimer.
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([N:10]1[CH2:13][CH:12]([OH:14])[CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4].CS(O[CH2:20][C:21]1[CH:22]=[N:23][C:24]([C:27]2[S:35][C:34]3[C:29](=[N:30][CH:31]=[CH:32][C:33]=3[O:36][C:37]3[CH:42]=[CH:41][C:40]([NH:43][C:44]([NH:46][CH:47]4[CH2:49][CH2:48]4)=[O:45])=[CH:39][C:38]=3[F:50])[CH:28]=2)=[CH:25][CH:26]=1)(=O)=O>CN(C=O)C>[CH:47]1([NH:46][C:44](=[O:45])[NH:43][C:40]2[CH:41]=[CH:42][C:37]([O:36][C:33]3[CH:32]=[CH:31][N:30]=[C:29]4[CH:28]=[C:27]([C:24]5[N:23]=[CH:22][C:21]([CH2:20][O:14][CH:12]6[CH2:13][N:10]([C:8]([O:7][C:3]([CH3:6])([CH3:4])[CH3:5])=[O:9])[CH2:11]6)=[CH:26][CH:25]=5)[S:35][C:34]=34)=[C:38]([F:50])[CH:39]=2)[CH2:49][CH2:48]1
Reactant: CC(C)(C)OC(=O)N1CC(O)C1
Reactant: CS(=O)(=O)OCc1ccc(-c2cc3nccc(Oc4ccc(NC(=O)NC5CC5)cc4F)c3s2)nc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CC(OCc2ccc(-c3cc4nccc(Oc5ccc(NC(=O)NC6CC6)cc5F)c4s3)nc2)C1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 32 %

Procedure:
To a stirred suspension of NaH (271 mg, 60% dispersion in mineral oil, 6.72 mmol) in DMF (2 mL) at 0° C. was added tert-butyl-3-hydroxyazetidine-1-carboxylate (1.0 g, 5.65 mmol). After 30 min, a solution of 403 (1.13 mmol) in DMF (6 mL) and KI (183 mg, 1.13 mmol) were added at 0° C. The reaction mixture was heated to 80° C. for 30 min. The reaction was then quenched by addition of water and the mixture was extracted with AcOEt/MeOH. The organic phase was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified via Biotage [linear gradient 0-10%, (methanol/dichloromethane: SiliaFlash 25 g cartridge]. Title compound 404 was obtained as a beige solid (221 mg, 32% yield for 2 steps). 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.71 (s, 1H), 8.62 (d, J=2.4 Hz, 1H), 8.52 (d, J=5.2 Hz, 1H), 8.37 (s, 1H), 8.28 (d, J=8.0 Hz, 1H), 7.94 (dd, J=8.0, 2.0 Hz, 1H), 7.73 (dd, J=13.6, 2.4 Hz, 1H), 7.38 (t, J=9.0 Hz, 1H), 7.23-7.18 (m, 1H), 6.64 (d, J=5.2 Hz, 1H), 6.57 (brd, 1H), 4.53 (s, 2H), 4.42-4.36 (m, 1H), 4.09-4.00 (m, 2H), 3.77-3.68 (m, 2H), 2.59-2.50 (m, 1H), 1.37 (s, 9H), 0.68-0.62 (m, 2H), 0.47-0.41 (m, 2H). MS (m/z): 606.48 (M+H).
Reaction SMILES: C1(C)C=CC(S(O[CH2:11][CH2:12][C:13]2([CH3:30])[CH2:22][CH2:21][C:20]3[C:15](=[C:16]([CH3:29])[C:17]([CH3:28])=[C:18]([O:24][CH2:25][O:26][CH3:27])[C:19]=3[CH3:23])[O:14]2)(=O)=O)=CC=1.[NH:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1.CCCCCC.C(OCC)(=O)C.C(Cl)(Cl)Cl.CO>C1(C)C=CC=CC=1>[CH3:27][O:26][CH2:25][O:24][C:18]1[C:19]([CH3:23])=[C:20]2[C:15](=[C:16]([CH3:29])[C:17]=1[CH3:28])[O:14][C:13]([CH2:12][CH2:11][N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1)([CH3:30])[CH2:22][CH2:21]2
Reactant: COCOc1c(C)c(C)c2c(c1C)CCC(C)(CCOS(=O)(=O)c1ccc(C)cc1)O2
Reactant: C1CNCCN1
Solvent: ClC(Cl)Cl
Solvent: CCCCCC
Solvent: CO
Product: COCOc1c(C)c(C)c2c(c1C)CCC(C)(CCN1CCNCC1)O2
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
2-(6-Methoxymetoxy-2,5,7,8-tetramethylchroman-2-yl)ethyl p-toluenesulfonate (compound 4) (16.01 g, 35.7 mmol) was diluted in 200 mL of toluene, and piperazine (6.15 g, 71.4 mmol) was added to it, as shown in FIG. 5. The reaction solution was heated at reflux. TLC (silica gel 60 F254 plates; hexane:ethyl acetate (2:1) and chloroform:methanol (4:1)) indicated the reaction to be complete after 2.5 hours, and therefore, it was worked-up as follows: The reaction solution was cooled to room temperature (RT) which caused residual piperazine to precipitate out, and the piperazine was removed by filtration. The filter cake was rinsed with toluene, and this rinsing was combined with the filtrate. The filtrate was concentrated to an oil which weighed 15.79 g. The oil was diluted with chloroform (25 mL), and it was decanted onto a silica gel column (230-400 mesh, 60 Å) that had been prepared with chloroform:methanol (6:1) slurry. The flash column bed measured ˜5 cm×30 cm. The flash column was eluted with the following mobile phase systems: 1) CHCl3:MeOH (6:1); 3 L; -collected 40×˜30 mL fractions, followed by 8×˜100 mL fractions; 2) CHCl3:MeOH (2:1); 1.8 L; -collected 4×200 mL fractions, followed by 2×400 mL fractions; and 3) CHCl3:MeOH (1:1); 0.8 L; -collected 2×400 mL fractions. Based upon the TLC results of each fraction, appropriate fractions were combined and concentrated to a clear oil which weighed 10.70 g. The compound was characterized by NMR and MS as follows: 1) C-NMR (CDCl3): 12.25, 12.80, 13.68, 20.99, 24.42, 32.07, 36.59, 46.48, 54.42, 55.19, 57.88, 74.35, 99.89, 117.69, 123.28, 126,51, 128.45, 147.25, 148.16 ppm; 2) H-NMR (CDCl3): 1.23 (s, 3H), 1.78 (m, 5H), 2.05 (s, 3H), 2.12 (s, 3H), 2.16 (s, 3H), 2.39 (b, 4H), 2.48 (t, 2H), 2.57 (t, 2H), 286 (t, 4H), 3.59 (s, 3H), 4.82 (s, 2H) ppm; and 3) MS (ESI): 363.3 [M+H]+.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[C:5]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:4]=1.[CH2:19](Cl)[CH:20]1[O:24][CH2:23][CH2:22][CH2:21]1.[H-].[Na+]>CN(C=O)C.[N+](CCCC)(CCCC)(CCCC)CCCC.[Br-]>[CH3:10][O:9][C:7](=[O:8])[C:6]1[CH:11]=[CH:12][C:3]([CH2:2][O:1][CH2:19][CH:20]2[CH2:21][CH2:22][CH2:23][O:24]2)=[CH:4][C:5]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: COC(=O)c1ccc(CO)cc1-c1ccccc1
Reactant: ClCC1CCCO1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [H-]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(COCC2CCCO2)cc1-c1ccccc1
Temperature: 130 °C
Reaction time: 0.5 h
Yield: 2.9 %

Procedure:
A solution of 4-hydroxymethyl-2-phenylbenzoic acid, methyl ester (1.94 g, 8.00 mmol), prepared as in Example 158C, and tetrahydrofurfuryl chloride (1.18 g, 9.60 mmol) in DMF (4 mL) was added to a mixture of NaH (6.40 g, 16.0 mmol) (rinsed with THF just prior to use), KI (1.33 g, 9.00 mmol), and Bu4NBr (2.60 g, 0.800 mmol). An exothermic reaction including gas evolution was observed. The mixture was stirred 30 minutes and then heated to 130° C. for 3.5 hours. The reaction mixture was quenched by the addition of a few drops of methanol and then treated with H2O. The mixture was extracted with 2:1 ether-ethyl acetate and ether (2×). The combined organic extracts were rinsed with H2O (4×) and chromatography eluting 20% ethyl acetate-hexane) afforded the desired compound (74.9 mg) as an oil shown to be 89% pure by 1H NMR.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[Li+].[CH3:17]C([N-]C(C)C)C.IC>C1COCC1.C(OCC)C>[CH3:17][C:8]1([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:9][CH2:10][C:5]2([O:4][CH2:3][CH2:2][O:1]2)[CH2:6][CH2:7]1
Reactant: CC(C)[N-]C(C)C
Reactant: CCOC(=O)C1CCC2(CC1)OCCO2
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CI
Solvent: CCOCC
Product: CCOC(=O)C1(C)CCC2(CC1)OCCO2
Temperature: -78 °C
Reaction time: 1 h
Yield: 129.5 %

Procedure:
Ethyl 1,4-dioxaspiro[4,5]decane-8-carboxilate (2) (5.8 g) was dissolved under a nitrogen atmosphere in dry THF (60 mL) and cooled in a dry ice/isopropanol bath to −78° C. LDA (2M solution in THF/n-heptane/ethylbenzene, 20 mL, 40 mmol) was added dropwise to the stirred solution and the mixture was allowed to warm to room temperature for 30 minutes. The reaction mixture was again cooled to −78° C. and to it was added a solution of iodomethane (5.5 g, 39 mmol) in dry THF (15 mL) using a syringe pump over 20 minutes. This mixture was stirred at −78° C. for 1 h. The reaction mixture was allowed to reach room temperature. The reaction mixture was then diluted with ethyl ether (100 mL) and the organic layer was washed with saturated aqueous ammonium chloride solution (2×50 mL) and brine (1×50 mL), then dried over magnesium chloride, filtered, and concentrated in vacuo to give a yellow-brown oil (8 g). The oil was purified by flash column chromatography [petroleum ether-ethyl ether (2:1)] to give 3 (5.22 g, 85%) as a colorless oil: 1H NMR (CDCl3) δ 4.14 (2H, q, J=7.1 Hz), 3.93 (4H, s), 2.13 (2H, m), 1.64 (6H, m), 1.25 (3H, t, J=7.1 Hz), 1.18 (3H, s); 13C NMR (CDCl3) δ 177.2, 108.7, 64.4, 60.6, 42.5, 33.1, 32.3, 26.2, 14.4.