Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C@@:2]12[C@H:11]3[CH2:12][CH2:13][C@:14]4([CH3:25])[C:18]([C:19]5[CH:20]=[CH:21][CH:22]=[N:23][CH:24]=5)=[CH:17][CH2:16][C@H:15]4[C@@H:10]3[CH2:9][CH:8]=[C:7]1[CH2:6][C@@H:5]([OH:26])[CH2:4][CH2:3]2.[C:27](OC(=O)C)(=[O:29])[CH3:28]>C(N(CC)CC)C>[CH3:28][C:27]([O:26][C@@H:5]1[CH2:6][C:7]2[C@@:2]([CH3:1])([C@@H:11]3[C@@H:10]([CH2:9][CH:8]=2)[C@@H:15]2[CH2:16][CH:17]=[C:18]([C:19]4[CH:20]=[CH:21][CH:22]=[N:23][CH:24]=4)[C@@:14]2([CH3:25])[CH2:13][CH2:12]3)[CH2:3][CH2:4]1)=[O:29]
Reactant: CC(=O)OC(C)=O
Reactant: C[C@]12CC[C@H](O)CC1=CC[C@@H]1[C@@H]2CC[C@]2(C)C(c3cccnc3)=CC[C@@H]12
Solvent: CCN(CC)CC
Product: CC(=O)O[C@H]1CC[C@@]2(C)C(=CC[C@@H]3[C@@H]2CC[C@]2(C)C(c4cccnc4)=CC[C@@H]32)C1

Procedure:
In one embodiment of the invention, abiraterone is acetylated by using acetic anhydride in the presence of a base, preferably triethylamine, and purified in hexane and ethanol to give pure abiraterone acetate of formula (I) with an overall yield up to 43-45% from the DHEA and a high purity (up to 99.0% by HPLC). In this embodiment, charcoal and a chelating resin are advantageously added to the hexane and ethanol solution of abiraterone acetate; the reaction mixture is then filtered and the pure active ingredient is crystallized. Suitable chelating resins that can be used in the invention are immobilized resins such as complex phenol-formaldehyde based resins; the Hokuetsu brand type MA-A resin (available from Ajinomoto) being preferred.
Reaction SMILES: [C:1]([O:4][C:5](=[O:7])[CH3:6])(=O)[CH3:2].[CH3:8][C@@:9]12[C@H:18]3[CH2:19][CH2:20][C@:21]4([CH3:32])[C:25]([C:26]5[CH:27]=[CH:28][CH:29]=[N:30][CH:31]=5)=[CH:24][CH2:23][C@H:22]4[C@@H:17]3[CH2:16][CH:15]=[C:14]1[CH2:13][C@@H](O)C[CH2:10]2.CO.C(=O)([O-])[O-].[Na+].[Na+]>C(OCC)(=O)C>[CH3:6][C:5]([O:4][C@@H:1]1[CH2:13][C:14]2[C@@:9]([CH3:10])([C@@H:18]3[C@@H:17]([CH2:16][CH:15]=2)[C@@H:22]2[CH2:23][CH:24]=[C:25]([C:26]4[CH:27]=[CH:28][CH:29]=[N:30][CH:31]=4)[C@@:21]2([CH3:32])[CH2:20][CH2:19]3)[CH2:8][CH2:2]1)=[O:7]
Reactant: C[C@]12CC[C@H](O)CC1=CC[C@@H]1[C@@H]2CC[C@]2(C)C(c3cccnc3)=CC[C@@H]12
Reactant: CC(=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(=O)O[C@H]1CC[C@@]2(C)C(=CC[C@@H]3[C@@H]2CC[C@]2(C)C(c4cccnc4)=CC[C@@H]32)C1
Temperature: 70 °C
Reaction time: 2 h

Procedure:
Acetic anhydride (70 g) is added to a suspension of Abiraterone (16 g) in ethyl acetate (48 mL) The mixture is heated to 70° C. until the reaction is complete (about 20 h); the temperature is then reduced to about 50° C. and methanol (28 mL) is added. The resulting mixture is maintained under stirring for 2 h, cooled to room temperature, and ethyl acetate (110 mL) and an aqueous solution of sodium carbonate (450 mL) are added. The phases are separated and the organic phase is treated with decolourising carbon. The organic phase is then concentrated under vacuum and the concentrate is taken up with acetonitrile (about 80 mL) to obtain a sandy solid, which is isolated by filtration (at 0-5° C.) and dried under vacuum at 40° C. for 8 h (about 15 g).
Reaction SMILES: C([CH:4]1[N:9](N=O)[CH2:8][C:7]2[CH:12]=[CH:13][S:14][C:6]=2[CH:5]1O)(O)=O.FC(F)(F)C(O)=O.N>>[S:14]1[C:6]2[CH:5]=[CH:4][N:9]=[CH:8][C:7]=2[CH:12]=[CH:13]1
Reactant: O=NN1Cc2ccsc2C(O)C1C(=O)O
Agent: N
Solvent: O=C(O)C(F)(F)F
Product: c1cc2sccc2cn1
Temperature: 25 °C
Yield: 56 %

Procedure:
11.4 g of the derivative of the formula (IV) of Example 2 is added portionwise to 55 cc trifluoroacetic acid stirred at room temperature. The temperature rises from 19° C. to 24° C., and russet fumes are evolved. The material is allowed to cool to room temperature; the reaction mixture is then poured over ice, made basic by addition of concentrated aqueous ammonia and extracted with diisopropyl ether. The organic extracts are washed with water, dried over sodium sulfate and evaporated to dryness. Distillation in vacuo of the residue gives 3.8 g (Yield: 56%) thieno[3,2-c]pyridine.
Reaction SMILES: O[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].P(Cl)(Cl)(Cl)(Cl)[Cl:12]>O=P(Cl)(Cl)Cl>[Cl:12][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9]
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: O=[N+]([O-])c1cnccc1O
Solvent: O=P(Cl)(Cl)Cl
Product: O=[N+]([O-])c1cnccc1Cl
Yield: 117.7 %

Procedure:
To a solution of 4-hydroxy-3-nitro-pyridine (2 g, 14 mmol) in POCl3 (6 mL) was added PCl5 (2.5 g, 12 mmol). The mixture was heated to reflux for 3 hours. The solvent was evaporated and the residue was cooled with ice-water and vigorously stirred with water (3 mL) and CHCl3 (6 mL). The aqueous was extracted CHCl3 (5×5 mL). The organic phase was combined and dried over MgSO4. After filtration, the solvent was removed to afford the product 4-Chloro-3-nitro-pyridine (2.24 g, 99%). 1H NMR (CDCl3, 400 Hz) δ 9.13 (s, 1H), 8.70 (d, J=5.2 Hz, 1H), 7.55 (d, J=5.6 Hz, 1H). MS (ESI+) [M+H]+ 159.
Reaction SMILES: [C:1]1([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8](=[O:23])[O:9][CH:10]1[CH2:15][CH2:14][N:13](CC2C=CC=CC=2)[CH2:12][CH2:11]1.C(O)=O>CO.[Pd]>[C:1]1([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8](=[O:23])[O:9][CH:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1
Reactant: O=C(Nc1ccccc1-c1ccccc1)OC1CCN(Cc2ccccc2)CC1
Agent: [Pd]
Solvent: CO
Solvent: O=CO
Product: O=C(Nc1ccccc1-c1ccccc1)OC1CCNCC1
Reaction time: 18 h
Yield: 69.3 %

Procedure:
1-Benzyl-4-piperidyl N-(2-biphenylyl)carbamate (12.5 g, 32.3 mmol) was dissolved in anhydrous methanol (150 mL) and formic acid (25 mL, 660 mmol) and the solution was flushed with gaseous nitrogen for 15 min. 10% Palladium on carbon (3 g) was added and the reaction mixture was stirred under nitrogen atmosphere. After 18 h, the reaction mixture was filtered through CeliteR and the filtrate was concentrated to give a yellow solid. The solid was partitioned between 0.1 N hydrochloric acid (300 mL) and diethyl ethr (300 mL). The aqueous layer was washed with diethyl ether and then basified with 1 N sodium hydroxide solution to pH 12. A white solid precipitated out which was extracted into ethyl acetate. The ethyl acetate layer was dried over magnesium sulfate and evaporated to dryness to give 4-piperidyl N-(2-biphenylyl)carbamate as a colorless solid (6.63 g, 69%). MS=296.9 MH+.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][CH:14]=1)[CH2:5][N:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:22][CH2:23][CH2:24][C:25]#[N:26].O>CN(C)C=O>[N:6]1([CH2:5][C:4]2[CH:3]=[C:2]([CH:14]=[CH:13][CH:12]=2)[O:1][CH2:22][CH2:23][CH2:24][C:25]#[N:26])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11]1
Reactant: N#CCCCBr
Reactant: Oc1cccc(CN2CCCCC2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: N#CCCCOc1cccc(CN2CCCCC2)c1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
A mixture of N-3-hydroxybenzylpiperidine (9.55 g) and anhydrous potassium carbonate (13.8 g) in dimethylformamide (100 ml) was stirred at ambient temperature for 17 hours. 4-Bromobutyronitrile (5 ml) was added and the mixture stirred at ambient temperature for 24 hours. Water (10 volumes) was added and the resulting mixture extracted with ethyl acetate. The extracts were washed with water, dried and the solvent removed to leave an oil which was purified by distillation (190°-200° C./0.1 mm) or by chromatography on a column packed with an activated magnesium silicate (sold under the trade name FLORISIL) to give 4-(3-piperidinomethylphenoxy)butyronitrile as an oil.
Reaction SMILES: [CH3:1][C@@:2]([OH:30])([C:26]([CH3:29])([CH3:28])[CH3:27])[C@@H:3]1[C@@:8]2([O:24][CH3:25])[C@@H:9]3[O:23][C:18]4=[C:19]([OH:22])[CH:20]=[CH:21][C:16]5=[C:17]4[C@:10]43[CH2:11][CH2:12][NH:13][C@H:14]([CH2:15]5)[C@@:5]4([CH2:6][CH2:7]2)[CH2:4]1.C(=O)(O)[O-].[Na+].[CH:36]1([CH2:39]Br)[CH2:38][CH2:37]1.CN(C=O)C>CO.O>[CH3:1][C@@:2]([OH:30])([C:26]([CH3:29])([CH3:28])[CH3:27])[C@@H:3]1[C@:8]2([O:24][CH3:25])[C@@H:9]3[O:23][C:18]4=[C:19]([OH:22])[CH:20]=[CH:21][C:16]5=[C:17]4[C@:10]43[CH2:11][CH2:12][N:13]([CH2:39][CH:36]3[CH2:38][CH2:37]3)[C@H:14]([CH2:15]5)[C@@:5]4([CH2:6][CH2:7]2)[CH2:4]1
Reactant: BrCC1CC1
Reactant: CO[C@]12CC[C@@]3(C[C@@H]1[C@](C)(O)C(C)(C)C)[C@H]1Cc4ccc(O)c5c4[C@@]3(CCN1)[C@H]2O5
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Solvent: O
Product: CO[C@@]12CC[C@@]3(C[C@@H]1[C@](C)(O)C(C)(C)C)[C@H]1Cc4ccc(O)c5c4[C@@]3(CCN1CC1CC1)[C@H]2O5
Temperature: 90 °C
Reaction time: 0.17 h
Yield: 56.1 %

Procedure:
A mixture of 11.5 g of norbuprenorphine, 4.6 g of sodium bicarbonate, 4.85 g of cyclopropylmethyl bromide (1% butenyl bromide in it by GC) and 46 ml of dry DMF is heated in an oilbath at 80-100° C. for 4 hours until the reaction is substantially complete. The reaction mixture is transferred to a dropping funnel, with minimal DMF as a wash. The reaction mixture is added over 5 minutes to 160 ml of water, with mechanical stirring. (Adding water to the reaction yields a gum). The mixture is stirred for about 10 minutes and filtered. The filter cake is washed with 20 ml water. The HPLC will show about 90% by area of desired product, and 0.2-0.5% of an N-butenyl substituted impurity. The resulting product is dried, yielding about 12 g. The resulting product is boiled in 30 ml of methanol for about 30 minutes, cooled, and filtered to yield about 7.3 g buprenorphine.
Reaction SMILES: [Br:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]3[N:7]([CH:11]=[C:12](I)[N:13]=3)[CH2:8][CH2:9][O:10][C:4]=2[CH:3]=1.C[Si](C)(C)N[Si](C)(C)C.C[N:27]([CH:29]=[O:30])C>[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[Br:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]3[N:7]([CH:11]=[C:12]([C:29]([NH2:27])=[O:30])[N:13]=3)[CH2:8][CH2:9][O:10][C:4]=2[CH:3]=1
Reactant: CN(C)C=O
Reactant: Brc1ccc2c(c1)OCCn1cc(I)nc1-2
Agent: Cl[Pd]Cl
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: NC(=O)c1cn2c(n1)-c1ccc(Br)cc1OCC2
Temperature: 70 °C
Reaction time: 0.08 h
Yield: 62 %

Procedure:
9-Bromo-2-iodo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine (1.5 g, 3.8 mmol) and bis(triphenylphosphine) palladium(II) chloride (142 mg, 0.202 mmol), DMF (45 mL) and hexamethyldisilazane (4.34 mL, 20.6 mmol) were mixed. The entire solution was purged with a CO balloon and sealed with the CO balloon attached. The reaction flask was heated at 70° C. for 2 h. LC/MS indicated clean conversion. Cooled to room temp and poured into 1 N HCl (30 mL). Stirred for 5 min and neutralized with sat. aq. NaHCO3 soln. Extracted three times with EtOAc, dried over MgSO4, filtered and concentrated in vacuo. Triturated with IPA and the solids were collected after filtration and EtOAc wash. This provided 734 mg (62% yield) of 9-bromo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2-carboxamide as a tan solid. LC/MS (ESI+): m/z 310 (M+H). 1H NMR (400 MHz, CDCl3) δ 8.36 (d, J=8.5, 1H), 7.63 (s, 1H), 7.24 (dd, J=7.2, 4.2, 1H), 7.09-6.99 (m, 1H), 4.51-4.36 (m, 4H).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]Br)=[CH:4][C:3]=1[F:10].[C-:11]#[N:12].[Na+]>C(O)C>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][C:11]#[N:12])=[CH:4][C:3]=1[F:10]
Reactant: [C-]#N
Reactant: Fc1cc(CBr)ccc1Br
Agent: [Na+]
Solvent: CCO
Product: N#CCc1ccc(Br)c(F)c1
Yield: 155.7 %

Procedure:
A solution of 4-bromo-3-fluorobenzyl bromide (12.2 g, 0.03 moles) in ethanol (100 ml) is added with NaCN (2 g, 0.04 moles) and refluxed for 2 hours. The mixture is concentrated under vacuum; the resulting residue is taken up with water, then extracted with ethyl acetate. The organic phase is washed with brine, dried over sodium sulfate and concentrated under vacuum to give a dark oil (10 g), which is subjected to chromatography on a silica gel column (150 g), eluting with hexane:ethyl ether 7:3, to afford the product in the solid form.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]Br)=[CH:4][C:3]=1[F:10].[C-:11]#[N:12].[K+]>CCO>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:11]#[N:12])=[CH:4][C:3]=1[F:10]
Reactant: [C-]#N
Reactant: Fc1cc(CBr)ccc1Br
Agent: [K+]
Solvent: CCO
Product: N#CCc1ccc(Br)c(F)c1
Temperature: 60 °C
Reaction time: 3 h
Yield: 79.4 %

Procedure:
To a solution of 1-bromo-4-(bromomethyl)-2-fluorobenzene (1 g, 3.73 mmol) in EtOH (30 mL) was added KCN (0.243 g, 3.73 mmol). The resulting mixture was stirred at 60° C. After 3 h, LCMS analysis showed the starting material had disappeared. The solvent was removed in vacuo. The residue was dissolved in EA (80 mL) was washed with H2O (30 mL) and brine (30 mL). The organic layer was dried and concentrated to give the crude product, which was purified by silica column chromatography (PE/EA=10/1) to yield a white solid of 2-(4-bromo-3-fluorophenyl)acetonitrile (0.78 g, 2.96 mmol, 79.0% yield): 1H NMR (400 MHz, CD3OD) δ 7.63 (t, J=7.8 Hz, 1H), 7.24 (d, J=9.2 Hz, 1H), 7.12 (d, J=9.6 Hz, 1H), 3.92 (s, 2H); ES-LCMS m/z 214.0 (M+H).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Br[C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=1.[CH2:28]([OH:32])[CH2:29][C:30]#[CH:31]>C(N(CC)CC)C.C(OC)(C)(C)C.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[F:27][C:24]1[CH:25]=[CH:26][C:21]([C:31]#[C:30][CH2:29][CH2:28][OH:32])=[CH:22][CH:23]=1
Reactant: Fc1ccc(Br)cc1
Reactant: C#CCCO
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: COC(C)(C)C
Solvent: O
Solvent: CCN(CC)CC
Product: OCCC#Cc1ccc(F)cc1
Reaction time: 5 h
Yield: 86 %

Procedure:
1 g of bis-(triphenylphosphine)-palladium(II) chloride, 3.8 g of copper(I) iodide and 8.7 g of triphenylphosphine were added in succession to a solution of 100 g of 4-bromofluorobenzene in 350 ml of triethylamine. The mixture was heated to reflux temperature, after which 43.4 g of 3-butynol were added dropwise in the course of 20 minutes at this temperature (about100° C.). Stirring was carried out for a further 5 hours at this temperature. After the mixture had cooled, the triethylamine was distilledoff. The residue was taken up in methyl tert-butyl ether and water. The aqueous phase was extracted twice more with methyl tert-butyl ether, and the combined organic extracts were washed in succession with 1 N hydrochloric acid and with 10% strength by weight sodium bicarbonate solution and dried over sodium sulfate. After removal of the solvent, the crude product was distilled under greatly reduced pressure. Yield: 86%.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH3:5].[OH:6][C:7]1[CH:14]=[CH:13][C:10]([CH:11]=[O:12])=[CH:9][CH:8]=1>>[CH2:2]([O:6][C:7]1[CH:14]=[CH:13][C:10]([CH:11]=[O:12])=[CH:9][CH:8]=1)[CH2:3][CH2:4][CH3:5]
Reactant: O=Cc1ccc(O)cc1
Reactant: CCCCBr
Product: CCCCOc1ccc(C=O)cc1

Procedure:
4-Butoxybenzaldehyde was prepared according to the method of Example 1, part a, except using 1-bromobutane instead of benzylbromide and using 4-hydroxybenzaldehyde instead of 4-hydroxyacetophenone.
Reaction SMILES: C([O:3][C:4](=[O:24])[C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[N:17]=[C:16]([C:18]3[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=3)[CH:15]=[CH:14][N:13]=2)=[CH:7][CH:6]=1)C.[OH-].[Na+].O.Cl>C(O)C>[N:20]1[CH:21]=[CH:22][CH:23]=[C:18]([C:16]2[CH:15]=[CH:14][N:13]=[C:12]([NH:11][C:8]3[CH:9]=[CH:10][C:5]([C:4]([OH:24])=[O:3])=[CH:6][CH:7]=3)[N:17]=2)[CH:19]=1
Reactant: CCOC(=O)c1ccc(Nc2nccc(-c3cccnc3)n2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)c1ccc(Nc2nccc(-c3cccnc3)n2)cc1
Temperature: 25 °C

Procedure:
4-(4-pyridin-3-yl-pyrimidin-2-ylamino)-benzoic acid ethyl ester prepared in Preparation 8 (19.6 g, 59.6 mmole) and 2N-sodium hydroxide (190 ml) were added to a reaction vessel under the solvent of water (190 ml) and ethanol (190 ml), mixed under reflux and cooled to RT, and pH thereof was adjusted to 1˜2 with hydrochloride solution. The mixture was mixed for 1 hr, and filtered to give the titled compound as yellow solid.
Reaction SMILES: CO[C:3]([O:6][CH3:7])([CH3:5])[CH3:4].OC[C@@H:10]1[NH:14][C:13](=[O:15])[CH2:12][CH2:11]1>C1(C)C=CC=CC=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH3:5][C:3]1([CH3:4])[N:14]2[C:13](=[O:15])[CH2:12][CH2:11][C@@H:10]2[CH2:7][O:6]1
Reactant: COC(C)(C)OC
Reactant: O=C1CC[C@H](CO)N1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CC1(C)OC[C@H]2CCC(=O)N21
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
The reaction was equipped with a Dean-Stark then 2,2-dimethoxypropane (17.09 mL, 139 mmol) was added to a stirred mixture of (R)-(−)-5-(hydroxymethyl)-2-pyrrolidinone (5.353 g, 46.5 mmol) and p-toluenesulfonic acid monohydrate (0.126 g, 0.662 mmol) in toluene (100 mL). The reaction mixture was refluxed for 1.5 h and allowed to stir at room temperature overnight. Solvent was evaporated to afford (R)-3,3-dimethyltetrahydropyrrolo[1,2-c]oxazol-5(3H)-one (7.22 g, 100% yield) as a light yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 4.18 (tt, J=8.8, 6.2 Hz, 1H), 4.00 (dd, J=8.1, 5.8 Hz, 1H), 3.40 (t, J=8.6 Hz, 1H), 2.69 (ddd, J=16.4, 12.1, 8.6 Hz, 1H), 2.33 (dd, J=16.3, 9.1 Hz, 1H), 2.02-2.11 (m, 1H), 1.73 (tt, J=12.1, 8.9 Hz, 1H), 1.53 (s, 3H), 1.33 (s, 3H). m/z (ESI, +ve) 156 (M+H).
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[NH:7][C:6](=[O:8])[CH2:5][CH2:4]1.CO[C:11](OC)([CH3:13])[CH3:12]>C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH3:12][C:11]1([CH3:13])[N:7]2[C:6](=[O:8])[CH2:5][CH2:4][C@@H:3]2[CH2:2][O:1]1
Reactant: COC(C)(C)OC
Reactant: O=C1CC[C@H](CO)N1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CC1(C)OC[C@H]2CCC(=O)N21
Yield: 102.5 %

Procedure:
To a stirred suspension of (R)-(−)-5-(hydroxymethyl)-2-pyrrolidinone (2.20 g, 19.11 mmol) and p-toluenesulfonic acid (0.018 g, 0.096 mmol) in toluene (54.6 ml), 2,2-dimethoxypropane (7.02 ml, 57.3 mmol) was added and the reaction was refluxed for 2 h. The reaction was equipped with a Dean-Stark then 2,2-dimethoxypropane (7.02 ml, 57.3 mmol) was added and the reaction was refluxed overnight. Solvent was evaporated to afford (R)-3,3-dimethyltetrahydropyrrolo[1,2-c]oxazol-5(3H)-one (3.04 g, 19.59 mmol, 103% yield) as yellow oil. 1H NMR (400 MHz, CDCl3) δ 4.27 (tt, J=6.01, 9.00 Hz, 1H), 4.09 (dd, J=5.65, 8.24 Hz, 1H), 3.43-3.50 (m, 1H), 2.81 (ddd, J=8.53, 12.19, 16.65 Hz, 1H), 2.55 (ddd, J=1.01, 9.15, 16.64 Hz, 1H), 2.13-2.23 (m, 1H), 1.72-1.80 (m, 1H), 1.66-1.72 (m, 3H), 1.48 (s, 3H).
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[CH3:6][O:7][CH:8]([O:12][CH3:13])[CH2:9][NH:10][CH3:11].C(=O)([O-])[O-].[K+].[K+].O>CC1CCCO1>[Cl:1][CH2:2][C:3]([N:10]([CH2:9][CH:8]([O:12][CH3:13])[O:7][CH3:6])[CH3:11])=[O:4]
Reactant: CNCC(OC)OC
Reactant: O=C(Cl)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC1CCCO1
Solvent: O
Product: COC(CN(C)C(=O)CCl)OC

Procedure:
195 ml chloroacetyl chloride in 200 ml 2-methyltetrahydrofuran are added dropwise at 2° C. within one hour to a mixture of 300 ml (methylamino)-acetaldehyde dimethylacetal, 1200 ml 2-methyltetrahydrofuran and 1200 ml saturated potassium carbonate solution. After 40 min 1450 ml of water are added and the phases are separated. The aqueous phase is extracted with 600 ml 2-methyltetrahydrofuran. The combined organic phases are dried on sodium sulphate and evaporated down. 451 g product remain.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[C@@H:5]([C@H:7]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[OH:8])[OH:6])[CH3:2].BrN1C(C)(C)C(=O)N(Br)C1=O.N(C(C)(CC(OC)(C)C)C#N)=NC(C)(CC(C)(OC)C)C#N>C(O)(=O)C>[O:6]=[C:5]([C:4]([O:3][CH2:1][CH3:2])=[O:14])[C:7](=[O:8])[C:9]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: CCOC(=O)[C@H](O)[C@@H](O)C(=O)OCC
Agent: CC1(C)C(=O)N(Br)C(=O)N1Br
Agent: COC(C)(C)CC(C)(C#N)N=NC(C)(C#N)CC(C)(C)OC
Solvent: CC(=O)O
Product: CCOC(=O)C(=O)C(=O)C(=O)OCC
Temperature: 55 °C
Reaction time: 3 h

Procedure:
L-Tartaric acid diethyl ester (2.0 g), acetic acid (20 ml), 1,3-dibromo-5,5-dimethylhydantoin (6.0 g) and 2,2′-azobis(4-methoxy-2,4-dimethylvaleronitrile) (30 mg) were mixed, and the reaction solution was stirred at 55° C. for 3 hours. The reaction solution was concentrated under reduced pressure until its volume became 10 ml to afford a solution of diethyl dioxobutanedioate in acetic acid as a yellow liquid.
Reaction SMILES: [N+:1]([C:4]1[CH:8]=[CH:7][NH:6][N:5]=1)([O-:3])=[O:2].[CH3:9][C:10]1([CH3:13])[CH2:12][O:11]1.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>C(OCC)(=O)C.O>[CH3:9][C:10]([OH:11])([CH3:13])[CH2:12][N:6]1[CH:7]=[CH:8][C:4]([N+:1]([O-:3])=[O:2])=[N:5]1
Reactant: CC1(C)CO1
Reactant: O=[N+]([O-])c1cc[nH]n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(O)Cn1ccc([N+](=O)[O-])n1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
A mixture of 3-nitro-1H-pyrazole (10.0 g, 88.43 mmol), 2,2-dimethyl-oxirane (15.7 mL, 176.9 mmol), potassium carbonate (18.2 g, 132 mmol) and DMF (100 mL) was stirred at 100° C. for 1 h, then stirred ON at rt. The mixture was then diluted with ethyl acetate and water, the organic layer was separated, dried over Na2SO4, and filtered. The resulting mixture was concentrated under reduced pressure to yield the crude product that was purified (50% EtOAc/heptane) to yield the product 2-methyl-1-(3-nitro-pyrazol-1-yl)-propan-2-ol as a waxy solid (4.88 g, 30%).
Reaction SMILES: [CH2:1]([CH:3]1[O:5][CH2:4]1)Cl.[OH-:6].[Na+]>O>[CH2:1]([O:6][CH2:1][CH:3]1[O:5][CH2:4]1)[CH:3]1[O:5][CH2:4]1
Reactant: [OH-]
Reactant: ClCC1CO1
Agent: [Na+]
Solvent: O
Product: C(OCC1CO1)C1CO1
Yield: 91.5 %

Procedure:
To a mixture of 382 g (4.13 moles) of epichlorohydrin and 86 g (0.21 mole) of bis(1,1,1,3,3,3-hexafluoro-2-hydroxyisopropyl)cyclohexane (Compound A) obtained in Reference Example 2 were added 16.8 g (0.42 mole) of sodium hydroxide and 2 ml of water. The mixture was heated with stirring and reacted with reflux for 10 hours. The resulting sodium chloride was removed by filtration with use of a glass filter and the excess of epichlorohydrin was distilled off at a reduced pressure. The residue was checked by gel permeation chromatography (GPC) to find that the compounds of the formula (1) in which n was 0, 1 and 2 were contained in 93:6:1 (ratio of area on chromatogram). Conditions for GPC: column, Shodex, KF-801, KF-802, each 30 cm, solvent, chloroform. The reside was distilled to obtain 50 g of diglycidyl ether of the compound of the formula (1) wherein n was zero, namely Compound A. The ether had a boiling point of 138° to 150° C./1 mmHg. ##STR15##
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][C:5]([N:11]2[C:15](=[O:16])[C:14]3[CH2:17][CH2:18][CH2:19][CH2:20][C:13]=3[C:12]2=[O:21])=[C:4]([F:22])[CH:3]=1.C(Cl)(Cl)Cl>C(O)(=O)C.[Fe]>[NH2:8][C:7]1[CH:6]=[C:5]([N:11]2[C:15](=[O:16])[C:14]3[CH2:17][CH2:18][CH2:19][CH2:20][C:13]=3[C:12]2=[O:21])[C:4]([F:22])=[CH:3][C:2]=1[Cl:1]
Reactant: O=C1C2=C(CCCC2)C(=O)N1c1cc([N+](=O)[O-])c(Cl)cc1F
Agent: [Fe]
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: Nc1cc(N2C(=O)C3=C(CCCC3)C2=O)c(F)cc1Cl
Yield: 51 %

Procedure:
A solution of N-(4-chloro-2-fluoro-5-nitrophenyl)-3,4,5,6-tetrahydrophthalimide (16.2 g) in acetic acid (200 ml) was dropwise added to a suspension of iron powder (14 g) in a 5% aqueous acetic acid (30 ml) at 90°-100° C. and refluxed for 1 hour. After being allowed to cool, chloroform was added to the resultant mixture, followed by filtration. The organic layer was separated from the filtrate, washed with a saturated sodium hydrogen carbonate solution, dried and concentrated. The residue was recrystallized from a mixture of ether and petroluem ether to give 7.5 g of N-(3-amino-4-chloro-6-fluorophenyl)-3,4,5,6-tetrahydrophthalimide. M.P., 144.5°-146.5° C.