Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC(O)=O.COC1CCC(OC)O1.FC(F)(F)C(O)=O.[F:21][C:22]([F:60])([F:59])[O:23][C:24]1[CH:25]=[C:26]([CH:30]2[N:34](C3C=CC(OC(F)(F)F)=CC=3)[C:33](=[O:46])[C:32](NC3C=CC(OC(F)(F)F)=CC=3)=[CH:31]2)[CH:27]=[CH:28][CH:29]=1.FC(F)(F)OC1C=CC(N2C(C3C=CC=C(OC(F)(F)F)C=3)CC(=O)C2=O)=CC=1.C[C@@H](N)C1C=CC=CC=1>C1COCC1.C1(C)C=CC=CC=1.O>[F:60][C:22]([F:21])([F:59])[O:23][C:24]1[CH:25]=[C:26]([C@H:30]2[NH:34][C:33](=[O:46])[CH:32]=[CH:31]2)[CH:27]=[CH:28][CH:29]=1
Reactant: O=C1C(Nc2ccc(OC(F)(F)F)cc2)=CC(c2cccc(OC(F)(F)F)c2)N1c1ccc(OC(F)(F)F)cc1
Agent: COC1CCC(OC)O1
Agent: C[C@@H](N)c1ccccc1
Agent: O=C1CC(c2cccc(OC(F)(F)F)c2)N(c2ccc(OC(F)(F)F)cc2)C1=O
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: O=C1C=C[C@@H](c2cccc(OC(F)(F)F)c2)N1
Temperature: 35 °C
Reaction time: 18 h
Yield: 73.7 %

Procedure:
Add HOAc (11.5 mL, 201 mmol), 2,5-dimethoxytetrahydrofuran (9.8 mL, 75.5 mmol), water (56 mL), and trifluoroacetic acid (7.6 mL, 100.6 mmol) sequentially to a solution of (±)-5-(3-trifluoromethoxy-phenyl)-1-(4-trifluoromethoxy-phenyl)-3-(4-trifluoromethoxy-phenylamino)-1,5-dihydro-pyrrol-2-one (29.1 g, 50.3 mmol) in THF (180 mL). Heat the reaction mixture to 35° C. for 22 hours. Observe significant formation of (±)-1-(4-trifluoromethoxy-phenyl)-5-(3-trifluoromethoxy-phenyl)-pyrrolidine-2,3-dione (LC-MS ESI m/z: 420 (M+H)+, Tr=4.23 min., method 1). Cool the reaction mixture to room temperature and add toluene (200 mL) in a single portion. Wash the mixture with water and then pH 9 buffer. Separate layers and observe that the aqueous layer is pH=7. Filter through sodium sulfate and add (R)-(+)-α-methyl benzylamine (12.9 mL, 100.6 mmol). Stir the solution at ambient temperature for 18 hours. Concentrate the reaction mixture and purify by silica gel chromatography (5-15% EtOAc-hexane) to yield 1-(4-trifluoromethoxy-phenyl)-3-(R)-1-phenyl-ethylamino)-5(S)-(3-trifluoromethoxy-phenyl)-1,5-dihydro-pyrrol-2-one (9.01 g, 34%) as a yellow oil, LC-MS ESI m/z: 523 (M+H)+, Tr=5.57 min., method 1 and 1-(4-trifluoromethoxy-phenyl)-3-(R)-1-phenyl-ethylamino)-5(R)-(3-trifluoromethoxy-phenyl)-1,5-dihydro-pyrrol-2-one (11.1 g, 42%) as an orange solid, LC-MS ESI m/z: 523 (M+H)+, Tr=5.49 min., method 1.
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2Cl)[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.[CH3:14][N:15]1CCCC1=O.Cl>O>[C:1]1([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[C:14]#[N:15])[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1
Reactant: CN1CCCC1=O
Reactant: Clc1ccccc1C1=CCCCC1
Agent: Cl
Solvent: O
Product: N#Cc1ccccc1C1=CCCCC1
Yield: 68 %

Procedure:
A mixture of 19.3 g. (0.1 mol) o-(1-cyclohexenyl)-chlorobenzene and 16.4 g. (0.18 mol) cuprous cyanide in 100 ml. N-methylpyrrolidinone was heated to 200° C. for 15 hours. For working up, the brown-black product was introduced into a solution of 40 g. ferric chloride, 10 ml. concentrated hydrochloric acid and 60 ml. water and the mixture heated for 0.5 hours to 60° to 70° C. The N-methylpyrrolidinone phase was separated off and the aqueous phase was extracted several times with toluene. The combined organic phases were successively washed with 2N hydrochloric acid, water and 10% aqueous sodium hydroxide solution and subsequently dried with anhydrous sodium sulphate and evaporated. Fractional distillation gave the desired benzonitrile derivative. Yield 68% of theory; b.p. 90-92° C./0.1 mm.Hg; nD26 =1.5648.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][O:5][CH2:6][C:7](=[O:29])[C@@H:8]1[C@:25]2([CH3:26])[C@H:11]([C@H:12]3[C@H:22]([C:23](=[O:27])[CH2:24]2)[C@:20]2([CH3:21])[C@H:15]([CH2:16][C:17](=[O:28])[CH2:18][CH2:19]2)[CH2:14][CH2:13]3)[CH2:10][CH2:9]1>O.Cl.Cl.Cl[Ir](Cl)(Cl)Cl>[Cl:1][CH2:2][CH2:3][CH2:4][O:5][CH2:6][C:7](=[O:29])[C@@H:8]1[C@:25]2([CH3:26])[C@H:11]([C@H:12]3[C@H:22]([C:23](=[O:27])[CH2:24]2)[C@:20]2([CH3:21])[C@H:15]([CH2:16][C@H:17]([OH:28])[CH2:18][CH2:19]2)[CH2:14][CH2:13]3)[CH2:10][CH2:9]1
Reactant: C[C@]12CCC(=O)C[C@@H]1CC[C@H]1[C@@H]3CC[C@H](C(=O)COCCCCl)[C@@]3(C)CC(=O)[C@@H]12
Agent: Cl[Ir](Cl)(Cl)Cl
Agent: Cl
Solvent: O
Product: C[C@]12CC[C@@H](O)C[C@@H]1CC[C@H]1[C@@H]3CC[C@H](C(=O)COCCCCl)[C@@]3(C)CC(=O)[C@@H]12
Yield: 48.9 %

Procedure:
The less polar residue, crude 21-(3'-chloropropoxy)-5α-pregnane-3,11,20-trione (1.1 g.) was treated with `stock` chloroiridic acid solution. The mixture was then refluxed for 24 hours, cooled and partitioned between water and ether. The organic layer was washed with water, dried (Na2SO4) and evaporated. The residue was subjected to preparative t.l.c. EtOAc/petrol 1:1 to give title compound (0.54 g.) as a white foam, [α]D + 73° (c 1.3).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([Br:15])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.[C:16]1(=O)[CH2:21][CH2:20][C:19](=O)[CH2:18][CH2:17]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[CH:16]1[CH:21]=[CH:20][C:19]([N:8]([C:9]2[CH:14]=[CH:13][C:12]([Br:15])=[CH:11][CH:10]=2)[C:5]2[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=2)=[CH:18][CH:17]=1
Reactant: O=C1CCC(=O)CC1
Reactant: Brc1ccc(Nc2ccc(Br)cc2)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: Brc1ccc(N(c2ccccc2)c2ccc(Br)cc2)cc1
Yield: 91 %

Procedure:
The preparation was carried out analogously to K. Haga et al, Bull. Chem. Soc. Jpn., 1986, 59, 803-7: 3.10 g (10.4 mmol) of bis(4-bromophenyl)amine (J. Berthelot et al, Can. J. Chem., 1989, 67, 2061), 1.28 g of cyclohexane-1,4-dione (11.4 mmol) and 2.17g (11.4 mmol) of p-toluenesulfonic acid hydrate were heated in 50 ml of toluene on a water separator. After a reaction time of 12 hours, the solvent was removed and the product was purified by column chromatography (hexane/ethyl acetate 4:1). 3.82 g (9.46 mmol, 91%) of 4,4′-dibromotriphenylamine were obtained as a viscous oil.
Reaction SMILES: [Cl:1][C:2]1[C:3](OS(O)(=O)=O)=[C:4]2[C:9](=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:11]=1)[NH:8][C:7](=[O:16])[C:6]([C:17]([CH:19]1[CH2:21][CH2:20]1)=[O:18])=[C:5]2C.[CH3:28][O:29][CH:30]([O:33][CH3:34])[CH2:31][NH2:32]>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([C:12]([F:13])([F:14])[F:15])[CH:11]=1)[NH:8][C:7](=[O:16])[C:6]([C:17]([CH:19]1[CH2:20][CH2:21]1)=[O:18])=[C:5]2[NH:32][CH2:31][CH:30]([O:33][CH3:34])[O:29][CH3:28]
Reactant: Cc1c(C(=O)C2CC2)c(=O)[nH]c2c(C(F)(F)F)cc(Cl)c(OS(=O)(=O)O)c12
Reactant: COC(CN)OC
Solvent: C1CCOC1
Product: COC(CNc1c(C(=O)C2CC2)c(=O)[nH]c2c(C(F)(F)F)cc(Cl)cc12)OC
Temperature: 25 °C
Reaction time: 24 h
Yield: 80 %

Procedure:
6-Chloro-3-cyclopropanecarbonyl-4-methylsulfoxy-8-trifluormethyl-2-quinolinone (377 mg, 1 mmol) and 2,2-dimethoxyethylamine (105 mg, 1 mmol) were dissolved in tetrahydrofurane (20 ml) and stirred for 24 hr at room temperature. After completion of reaction, solvent was removed under reduced pressure and residue was recrystallized from ethanol to give desired product (335 mg, yield: 80%).
Reaction SMILES: [CH2:1]([C:3]1[N:4]=[C:5]([C:8]2[CH:9]=[CH:10][C:11]([O:14][CH2:15][CH2:16][CH2:17][OH:18])=[N:12][CH:13]=2)[S:6][CH:7]=1)[CH3:2].[CH3:19][O:20][C:21](=[O:34])[C@H:22]([N:24]1[C:32]2[C:27](=[CH:28][C:29](O)=[CH:30][CH:31]=2)[CH:26]=[CH:25]1)[CH3:23].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>ClCCl>[CH3:19][O:20][C:21](=[O:34])[C@H:22]([N:24]1[C:32]2[C:27](=[CH:28][C:29]([O:18][CH2:17][CH2:16][CH2:15][O:14][C:11]3[CH:10]=[CH:9][C:8]([C:5]4[S:6][CH:7]=[C:3]([CH2:1][CH3:2])[N:4]=4)=[CH:13][N:12]=3)=[CH:30][CH:31]=2)[CH:26]=[CH:25]1)[CH3:23]
Reactant: CCc1csc(-c2ccc(OCCCO)nc2)n1
Reactant: COC(=O)[C@@H](C)n1ccc2cc(O)ccc21
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCc1csc(-c2ccc(OCCCOc3ccc4c(ccn4[C@H](C)C(=O)OC)c3)nc2)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 68.2 %

Procedure:
A solution of 3-[5-(4-ethyl-thiazol-2-yl)-pyridin-2-yloxy]-propan-1-ol (Example 73, 7.0 g, 0.025 mol), (R)-2-(5-hydroxy-indol-1-yl)-propionic acid methyl ester (Example 8, 4.961 g, 0.023 mol), and triphenylphosphine (7.716 g, 0.029 mol) in dichloromethane (60 mL) was treated with a solution of 1,1′-(azodicarbonyl)-dipiperidine (7.423 g, 0.029 mol) in dichloromethane (45 mL) slowly over 25 minutes while maintaining the temperature around 25° C. The resulting suspension was stirred at rt for 18 h. Upon completion, the solvent was removed under vacuum and the crude product was purified by silica gel chromatography using a gradient of 5-35% ethyl acetate/hexanes to give 7.3 g (69%) of the title compound as a beige solid. The product was characterized as in Example 69.
Reaction SMILES: [Br:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][C@@H:7]([CH2:12][CH3:13])[C:8](OC)=[O:9])=[CH:4][CH:3]=1.[BH4-].[Na+]>C(O)C>[Br:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][C@@H:7]([CH2:12][CH3:13])[CH2:8][OH:9])=[CH:4][CH:3]=1
Reactant: CC[C@H](Oc1ccc(Br)cc1)C(=O)OC
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CC[C@@H](CO)Oc1ccc(Br)cc1
Yield: 77.5 %

Procedure:
Prepared according to the method described in Example 4b) from (2S)-2-(4-bromophenoxy)butanoic acid, methyl ester (7.53 g, Example 87a)) and sodium borohydride (1.09 g) in ethanol (100 ml). After work up, crude material was purified by flash column chromatography over silica eluting with dichloromethane to give the sub-title compound as an oil (5.24 g).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[C:10]2[CH:11]=[C:12]([F:16])[C:13]([F:15])=[CH:14][C:9]=2[O:8][CH2:7][C:6]1=[O:17].[CH:18]1([CH2:21][O:22][CH:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)[CH2:20][CH2:19]1.[Na+].[I-].C([O-])([O-])=O.[K+].[K+]>CC#N>[CH:18]1([CH2:21][O:22][CH:23]2[CH2:28][CH2:27][N:26]([CH2:2][CH2:3][CH2:4][N:5]3[C:10]4[CH:11]=[C:12]([F:16])[C:13]([F:15])=[CH:14][C:9]=4[O:8][CH2:7][C:6]3=[O:17])[CH2:25][CH2:24]2)[CH2:19][CH2:20]1
Reactant: O=C1COc2cc(F)c(F)cc2N1CCCCl
Reactant: C1CC(OCC2CC2)CCN1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: O=C1COc2cc(F)c(F)cc2N1CCCN1CCC(OCC2CC2)CC1
Reaction time: 20 h
Yield: 43.8 %

Procedure:
A 4 mL vial was charged with 4-(3-chloropropyl)-6,7-difluoro-4H-benzo[1,4]oxazin-3-one (0.077 g, 0.3 mmol), 4-cyclopropylmethoxypiperidine (0.047 g, 0.3 mmol), NaI (0.075 g, 0.5 mmol), and K2CO3 (0.069 g, 0.5 mmol) in MeCN (0.5 mL) and shaken at 60° for 20 h. The reaction mixture was quenched with water and the product extracted into EtOAc. The combined organic layers were dried over Na2SO4, filtered, and concentrated. The product was purified by cation exchange column chromatography followed by flash column chromatography (SiO2; EtOAc) to give the title compound (0.050 g, 44%). 1H NMR (CDCl3) d 6.98-6.93 (m, 1H), 6.66-6.62 (m, 1H), 4.39 (s, 2H), 3.74 (t, J=7.2 Hz, 2H), 3.20-3.15 (m, 1H), 3.11 (d, J=6.9 Hz, 2H), 2.61-2.55 (m, 2H), 2.21 (t, J=6.8 Hz, 2H), 2.00-1.96 (m, 2H), 1.79-1.63 (m, 4H), 1.52-1.46 (m, 2H), 0.89-0.85 (m, 1H), 0.38-0.33 (m, 2H), 0.04-0.00 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:11])[CH2:9][CH3:10])=[CH:4][CH:3]=1.[Br:12]Br>ClCCl.Br.BrBr>[Br:12][CH:9]([CH3:10])[C:8]([C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1)=[O:11]
Reactant: CCC(=O)c1ccc(Cl)cc1
Reactant: BrBr
Agent: Br
Solvent: ClCCl
Product: CC(Br)C(=O)c1ccc(Cl)cc1
Reaction time: 0.25 h

Procedure:
A stirred solution of p-chloropropiophenone (2.0 g, 11.9 mmol) in dichloromethane (35 mL) was treated with one drop of 48% HBr and one drop of bromine. When the color had discharged, bromine (608 μL, 1.90 gm, 11.9 mmol) was added dropwise. The solution was stirred until 15 min after the color had fully discharged, then the mixture was concentrated under reduced pressure to give the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5].[Cl:16][C:17]1[C:22]([N+:23]([O-:25])=[O:24])=[CH:21][CH:20]=[CH:19][N:18]=1.Cl.CCCCCC>C(Cl)Cl>[ClH:16].[N+:23]([C:22]1[C:17]([NH:1][C:2]2[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=2[C:4]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)=[O:5])=[N:18][CH:19]=[CH:20][CH:21]=1)([O-:25])=[O:24]
Reactant: O=[N+]([O-])c1cccnc1Cl
Reactant: Nc1ccccc1C(=O)c1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: CCCCCC
Product: O=C(c1ccccc1)c1ccccc1Nc1ncccc1[N+](=O)[O-]
Temperature: 150 °C
Reaction time: 0.75 h
Yield: 8.2 %

Procedure:
A mixture of 56.0 g (0.28 mole) of 2-aminobenzophenone and 49.6 g (0.31 mole) of 2-chloro-3-nitropyridine was heated in an oil bath with stirring at 150° C. for 45 minutes. After cooling, an 8.7 g portion of the product was dissolved in 45 ml of methylene chloride, hydrogen chloride gas was added for 15 min and 100 ml of hexane was added. After stirring for 20 min, solid was collected and washed twice with 1:3 mixture of methylene chloride to hexanes. After drying in air, 8.2 g (81.6%) product was obtained.
Reaction SMILES: C1(C)C=CC(S(O[CH2:11][CH2:12][CH:13]([C:20]([F:23])([F:22])[F:21])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])(=O)=O)=CC=1.[OH:25][C:26]1[CH:36]=[CH:35][C:29]([C:30]([O:32][CH2:33][CH3:34])=[O:31])=[CH:28][CH:27]=1.[H-].[Na+]>CN(C=O)C>[F:21][C:20]([F:22])([F:23])[CH:13]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH2:12][CH2:11][O:25][C:26]1[CH:27]=[CH:28][C:29]([C:30]([O:32][CH2:33][CH3:34])=[O:31])=[CH:35][CH:36]=1
Reactant: CCCCCCC(CCOS(=O)(=O)c1ccc(C)cc1)C(F)(F)F
Reactant: CCOC(=O)c1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCCCC(CCOc1ccc(C(=O)OCC)cc1)C(F)(F)F
Temperature: 130 °C
Yield: 60.4 %

Procedure:
345 mg of 3-trifluoromethylnonyl p-toluenesulfonate obtained in Step 1), 166 mg of ethyl p-hydroxybenzoate and 1 ml of dimethylformamdie (DMF) were placed in a round-bottomed flask, and 80 mg of sodium hydride (60%) was added thereto together with DMF, followed by 6 hours of stirring at 130° C. After the reaction, DMF was distilled off under a reduced pressure, and water was added, followed by extraction with methylene chloride. The methylene chloride solution was dried with magnesium sulfate, followed by distilling-off of the solvent and purification by thin layer chromatography with benzene as the developer to obtain 205 mg of ethyl p-(3-trifluoromethylnonyloxy)-benzoate (yield: 60.5%).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1.[CH:13]([C:16]1[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=1)([CH3:15])[CH3:14]>>[CH:13]([C:16]1[CH:21]=[CH:20][C:19]([S:22]([NH:1][C:2]2[S:3][CH:4]=[C:5]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=2)(=[O:24])=[O:23])=[CH:18][CH:17]=1)([CH3:15])[CH3:14]
Reactant: CCOC(=O)Cc1csc(N)n1
Reactant: CC(C)c1ccc(S(=O)(=O)Cl)cc1
Product: CCOC(=O)Cc1csc(NS(=O)(=O)c2ccc(C(C)C)cc2)n1

Procedure:
The title compound was prepared from ethyl 2-amino-4-thiazolylacetate and 4-isopropylbenzenesulfonyl chloride according to METHOD A, giving 0.57 g (78%) of a pink powder: MS (electrospray, [M−H]−) m/z 367.2.
Reaction SMILES: C[O:2][C:3](=[O:28])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][O:11][C:12]2[CH:27]=[CH:26][C:15]3[CH2:16][CH2:17][N:18]([CH:21]4[CH2:25][CH2:24][CH2:23][CH2:22]4)[CH2:19][CH2:20][C:14]=3[CH:13]=2)=[CH:6][CH:5]=1>CO.[OH-].[Na+].O>[CH:21]1([N:18]2[CH2:19][CH2:20][C:14]3[CH:13]=[C:12]([O:11][CH2:10][C:7]4[CH:8]=[CH:9][C:4]([C:3]([OH:28])=[O:2])=[CH:5][CH:6]=4)[CH:27]=[CH:26][C:15]=3[CH2:16][CH2:17]2)[CH2:22][CH2:23][CH2:24][CH2:25]1
Reactant: COC(=O)c1ccc(COc2ccc3c(c2)CCN(C2CCCC2)CC3)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1ccc(COc2ccc3c(c2)CCN(C2CCCC2)CC3)cc1
Temperature: 60 °C
Reaction time: 4 h

Procedure:
4-(3-Cyclopentyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yloxymethyl)-benzoic acid methyl ester (E88) (3.1 g, 8.1 mmol)) was dissolved in a mixture of methanol (90 ml), 2N sodium hydroxide (12 ml) and water (30 ml). The resulting mixture was stirred at 60° C. for 4 hours and then cooled to room temperature. The mixture was concentrated in vacuo to remove the organic solvents and then acidified to pH 6 (2N hydrochloric acid). The resulting precipitates were filtered, washed with water and dried under vacuum to afford the title compound (E89); MS (ES+) m/e 366 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[O:6][CH:5]([CH2:7][OH:8])[CH2:4][O:3]1.[H-].[Na+].[F:12][C:13]([F:27])([F:26])[C:14]1[CH:15]=[C:16]([CH:19]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:21]=1)[CH2:17]Br>CN(C=O)C.C1COCC1>[CH3:1][C:2]1([CH3:9])[O:6][CH:5]([CH2:7][OH:8])[CH2:4][O:3]1.[F:12][C:13]([F:27])([F:26])[C:14]1[CH:15]=[C:16]([CH:19]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:21]=1)[CH2:17][O:8][CH2:7][C:5]1[CH:4]=[C:20]([C:22]([F:23])([F:24])[F:25])[CH:21]=[C:14]([C:13]([F:12])([F:26])[F:27])[CH:15]=1
Reactant: FC(F)(F)c1cc(CBr)cc(C(F)(F)F)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: CC1(C)OCC(CO)O1
Product: FC(F)(F)c1cc(COCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)cc(C(F)(F)F)c1

Procedure:
To a stirred solution of solketal (0.151 mol) in DMF/THF (1:1, 300 ml) under a nitrogen atmosphere was added sodium hydride (1.2 equivalents of an 80% dispersion in mineral oil). The anion was allowed to form over one hour prior to addition of 3,5-bistrifluoromethylbenzyl bromide. The reaction was partitioned between ethyl acetate-saturated ammonium chloride after 1 h and the organic phase separated, dried (MgSO4), and concentrated to a yellow oil. Chromatography using pet. ether then 20% ethyl acetate-pet. ether as eluent gave 2,2-dimethyl- 1,3-dioxolane-4-methanol-3,5-bistrifluoromethylbenzyl ether as a yellow oil: (CDCl3) δ1.4 (3H, s), 1.45 (3H, s), 3.6-3.65 (2H, m), 3.7-3.8 (1H, m), 4.1-4.15 (1H, m), 4.3-4.4 (1H, m), 4.7 (2H, s), 7.8 (3H, s).
Reaction SMILES: [OH2:1].[Cl:2][C:3]1[CH:26]=[CH:25][C:6]([C:7]([NH:9][CH:10]2[C:15]([CH3:17])([CH3:16])[S:14][C:13](=[S:18])[N:12]([CH2:19][CH2:20][N:21]([CH3:23])[CH3:22])[C:11]2=[O:24])=[O:8])=[CH:5][CH:4]=1>C(OCC)(=O)C>[Cl:2][C:3]1[CH:26]=[CH:25][C:6]([C:7]([NH:9][C@H:10]([C:11]([OH:1])=[O:24])[C:15]([S:14][C:13](=[S:18])[NH:12][CH2:19][CH2:20][N:21]([CH3:23])[CH3:22])([CH3:17])[CH3:16])=[O:8])=[CH:5][CH:4]=1
Reactant: O
Reactant: CN(C)CCN1C(=O)C(NC(=O)c2ccc(Cl)cc2)C(C)(C)SC1=S
Solvent: CCOC(C)=O
Product: CN(C)CCNC(=S)SC(C)(C)[C@H](NC(=O)c1ccc(Cl)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 120 h

Procedure:
Water (10 ml) is added to a solution of 30 g of 5-(p-chlorobenzamido)-3-(2-dimethylaminoethyl)-6,6-dimethyl-2-thioxo-tetrahydro-2H-1,3-thiazin-4-one in 600 ml of ethyl acetate. The resulting mixture is stirred at room temperature for 5 days. The precipitate is collected by filtration, and washed with ethyl acetate. Thus is obtained N-(p-chlorobenzoyl)-S-(2-dimethylaminoethylthiocarbamoyl)-penicillamine as white crystals, melting at 142°-143° C. with decomposition.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][N:12]2[C:20](=[O:21])[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]2=[O:22])=[CH:6][CH:5]=1.C(N(CC)CC)C.[CH3:30][S:31](Cl)(=[O:33])=[O:32].C(=O)([O-])[O-].[K+].[K+]>C(C(C)=O)C>[O:21]=[C:20]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13](=[O:22])[N:12]1[CH2:11][CH2:10][C:7]1[CH:6]=[CH:5][C:4]([CH2:3][CH2:2][O:1][S:31]([CH3:30])(=[O:33])=[O:32])=[CH:9][CH:8]=1
Reactant: O=C1c2ccccc2C(=O)N1CCc1ccc(CCO)cc1
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCc1ccc(CCN2C(=O)c3ccccc3C2=O)cc1
Temperature: 2 °C
Reaction time: 1 h
Yield: 92 %

Procedure:
A solution of 2-{2-[4-(2-hydroxy-ethyl)phenyl]-ethyl}-isoindole-1,3-dione (Preparation 10, 21.0 g, 71.25 mmol) in methyl ethyl ketone (315 mL) was cooled to 0° C. Triethylamine (14.9 mL, 106.87 mmol) was added followed by the dropwise addition of methane sulfonyl chloride (6.07 mL, 78.37 mmol). The reaction was stirred at 0-4° C. for 1 hour and then allowed to warm to room temperature. An aqueous solution of potassium carbonate (1M, 210 mL) was added and the mixture stirred. The organic and aqueous layers were separated and the aqueous re-extracted with methyl ethyl ketone (50 mL). The combined organic layers were concentrated to 40 mL by distillation. Tert-butyl methyl ether (300 mL) was slowly added to the hot solution causing crystallisation to occur. The mixture was allowed to cool to room temperature and then allowed to stir for 72 hours. The solid was removed by filtration and washed with tert-butyl methyl ether (3×25 mL). The solid was dried in vacuo at 45° C. for 4 hours to yield the title compound as a light brown solid, in 92% yield, 24.6 g.
Reaction SMILES: [CH2:1]=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:9]([OH:13])(=[O:12])[CH:10]=[CH2:11].S([O-])(OCCCCCCCCCCCC)(=O)=O.[Na+].S(OOS([O-])(=O)=O)([O-])(=O)=O.[K+].[K+].[OH-].[NH4+]>O>[CH:1]([CH:11]=[CH:10][C:9]([OH:13])=[O:12])=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: C=CC(=O)O
Reactant: C=Cc1ccccc1
Agent: CCCCCCCCCCCCOS(=O)(=O)[O-]
Agent: O=S(=O)([O-])OOS(=O)(=O)[O-]
Agent: [K+]
Solvent: O
Product: O=C(O)C=CC=Cc1ccccc1

Procedure:
First, an 80/20 styrene-acrylic acid copolymer was prepared by the emulsion copolymerization of 49.09 g of styrene with 14.7 g of acrylic acid. Sodium lauryl sulfate was used as the surfactant (1.53 g), potassium persulfate (0.17 g) as the initiator and ammonium hydroxide (dropwise) was used to adjust the pH to 4. Deoxygenated water (165 g) was used as the continuous phase. After polymerization, the material was found to contain both acrylic acid and styrene by FI-IR. This emulsion was found to contain 22% solids by weight.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][C@H:7]([CH3:12])[CH2:6][C:5]2=[O:13].Cl.NO.C([O-])([O-])=[O:18].[K+].[K+]>O>[F:1][C:2]1[CH:11]=[CH:10][C:9]([O:8][C@H:7]([CH3:12])[CH2:6][C:5]([OH:13])=[O:18])=[CH:4][CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: C[C@@H]1CC(=O)c2cc(F)ccc2O1
Agent: Cl
Agent: NO
Agent: [K+]
Solvent: O
Product: C[C@H](CC(=O)O)Oc1ccc(F)cc1
Temperature: 25 °C
Yield: 184.5 %

Procedure:
6-fluoro-2,3-dihydro-2-methylchromen-4-oxime (13). To a suspension of the ketone 12 (2.79 g, 15.5 mmol) was added a solution of hydroxylamine hydrochloride (2.09 g, 30 mmol) and K2CO3 (1.2 g, 8.75 mmol) in 18 mL of H2O. The reaction mixture was refluxed for four hours. After cooling to room temperature, the solution was removed under vacuum, and the residual solid was triturated with ice water. The crude product was recrystallized from EtOH to give 3.2 g (84%) of the white solid oxime 13, m.p. 102-105° C., 1H NMR (CDCl3) δ 7.58 (br s, 1H), 7.48 (dd, J=3.0, 9.5 Hz, 1H), 6.97 (ddd, J=3.0, 9.0, 8.0 Hz, 1H), 6.85 (dd, J=4.5, 9.0 Hz, 1H), 4.21-4.15 (m, 1H), 3.28 (dd, J=3.0, 17.0 Hz, 1H), 2.37 (dd, J=12.0, 17.0 Hz, 1H), 1.47 (d, J=6.5 Hz, 3H). EI-MS (m/z) 195 (M+). The reaction is shown as follows:
Reaction SMILES: S(Cl)(Cl)=O.[CH3:5][C:6]1[N:7]=[N:8][S:9][C:10]=1[CH2:11]O.C(=O)([O-])[O-].[K+].[K+].[C:19]1([SH:25])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CC(C)=O>[CH3:5][C:6]1[N:7]=[N:8][S:9][C:10]=1[CH2:11][S:25][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: Cc1nnsc1CO
Reactant: Sc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O=S(Cl)Cl
Product: Cc1nnsc1CSc1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 84.7 %

Procedure:
At an ice-cooled temperature, 3 ml of thionyl chloride was added to 0.50 g (3.8 mmol) of 4-methyl-1,2,3-thiadiazol-5-ylmethanol and stirred for 4 hours. Then, the reaction mixture was concentrated under reduced pressure, and 1.30 g (11.5 mmol) of potassium carbonate, 0.38 g (3.4 mmol) of thiophenol and 10 ml of acetone were added to the concentrate and reacted for 7 hours with heating under reflux. After the reaction was completed, the reaction mixture was cooled to room temperature, the precipitated matter was filtered off, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography using 5:1 mixture of n-hexane and ethyl acetate. Thus, 0.64 g of the objective compound was obtained.