Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[CH3:9].[C:10](O)(=[O:12])[CH3:11].C(OC(=O)C)(=O)C>>[Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:10](=[O:12])[CH3:11])=[CH:4][C:3]=1[CH3:9]
Reactant: CC(=O)O
Reactant: Cc1cc(N)ccc1Br
Solvent: CC(=O)OC(C)=O
Product: CC(=O)Nc1ccc(Br)c(C)c1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 94 %

Procedure:
To a stirring solution of 4-bromo-3-methylaniline (4.3 g, 23.11 mmol) in acetic acid (2 mL, 23.11 mmol) at room temperature was added acetic anhydride (2.62 mL, 27.7 mmol). The reaction mixture was refluxed for 30 min, cooled to room temperature and then poured into 20 mL of ice water while allowing to stir for 5 min. The aqueous suspension was filtered, and the solid was washed with water, dissolved in CH2Cl2 and then dried over sodium sulfate. The organic layer was filtered and concentrated under reduced pressure to yield Intermediate 1B (4.96 g, 21.73 mmol, 94% yield) as an off-white solid. MS (ES): m/z=229.9 [M+H]+.
Reaction SMILES: C1([O:7][C:8](=O)[N:9]([C:19]2[CH:24]=[C:23]([O:25][C:26]3[CH:31]=[CH:30][C:29]([NH:32][C:33]([C:35]4([C:38](=[O:46])[NH:39][C:40]5[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=5)[CH2:37][CH2:36]4)=[O:34])=[C:28]([F:47])[CH:27]=3)[CH:22]=[CH:21][N:20]=2)C(OC2C=CC=CC=2)=O)C=CC=CC=1.[CH3:49][N:50]1[CH2:55][CH2:54][N:53]([CH:56]2[CH2:61][CH2:60][NH:59][CH2:58][CH2:57]2)[CH2:52][CH2:51]1>CN(C)C=O>[F:47][C:28]1[CH:27]=[C:26]([O:25][C:23]2[CH:22]=[CH:21][N:20]=[C:19]([NH:9][C:8]([N:59]3[CH2:58][CH2:57][CH:56]([N:53]4[CH2:52][CH2:51][N:50]([CH3:49])[CH2:55][CH2:54]4)[CH2:61][CH2:60]3)=[O:7])[CH:24]=2)[CH:31]=[CH:30][C:29]=1[NH:32][C:33]([C:35]1([C:38]([NH:39][C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=2)=[O:46])[CH2:37][CH2:36]1)=[O:34]
Reactant: O=C(Oc1ccccc1)N(C(=O)Oc1ccccc1)c1cc(Oc2ccc(NC(=O)C3(C(=O)Nc4ccccc4)CC3)c(F)c2)ccn1
Reactant: CN1CCN(C2CCNCC2)CC1
Solvent: CN(C)C=O
Product: CN1CCN(C2CCN(C(=O)Nc3cc(Oc4ccc(NC(=O)C5(C(=O)Nc6ccccc6)CC5)c(F)c4)ccn3)CC2)CC1
Reaction time: 5 h
Yield: 29.7 %

Procedure:
To a solution of [4-(3-fluoro-4-{[1-(phenylcarbamoyl)cyclopropanecarbonyl]amino}phenoxy)pyridin-2-yl]-N-(phenoxycarbonyl)carbamic acid phenyl ester (100 mg) in N,N-dimethylformamide (2.0 ml) was added 1-methyl-4-(piperidin-4-yl)piperazine (114 mg) at room temperature, followed by stirring for 5 hr. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with a saturated aqueous solution of ammonium chloride and brine in this order, and dried over anhydrous sodium sulfate. The solvent was concentrated under reduced pressure. The resultant residue was purified by silica gel column chromatography (Fuji Silysia NH, eluent; ethyl acetate, then ethyl acetate:methanol=95:5). Fractions containing the target compound were concentrated under reduced pressure. A solid was precipitated by addition of diethyl ether to the resultant residue. The solid was collected by filtration. The solid was dried under aeration to provide the titled compound as white powder (28.3 mg, 30%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10](Cl)(=[O:12])=[O:11])([O-:3])=[O:2].[NH2:14][CH2:15][CH2:16][CH2:17][N:18]1[CH:22]=[CH:21][CH:20]=[N:19]1.C(C)#N.O.C(=O)([O-])[O-].[K+].[K+]>C(C)#N.C(OCC)(=O)C>[N:18]1([CH2:17][CH2:16][CH2:15][NH:14][S:10]([C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N+:1]([O-:3])=[O:2])(=[O:12])=[O:11])[CH:22]=[CH:21][CH:20]=[N:19]1
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Reactant: NCCCn1cccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: O
Product: O=[N+]([O-])c1ccccc1S(=O)(=O)NCCCn1cccn1
Temperature: 25 °C
Yield: 86.7 %

Procedure:
A solution of 11.97 g (0.0519 mol) of o-nitrobenzenesulfonyl chloride in 90 ml of cyanomethane was added slowly over several minutes to a cold (7° C.) solution of 10.7 g (0.0540 mol) of N-(3-aminopropyl)-pyrazole in a 3:1 cyanomethane/water solution containing 16.6 g (0.12 mol) of potassium carbonate, under nitrogen. The resulting reaction solution was warmed to room temperature and allowed to react. When the reaction was complete, as determined by thin layer chromatography, the reaction solution was poured into approximately 450 ml of ethyl acetate. The resulting aqueous and organic layers were separated and the organic layer was washed with both an aqueous potassium carbonate solution and an aqueous sodium chloride solution and then reduced to dryness under reduced pressure to provide an oil. This oil was purified using column chromatography (8000 ml of a gradient eluent of from 0 to 5% methanol in methylene chloride). The fractions containing the desired product were combined, reduced to dryness under reduced pressure and then recrystallized from a 1:2 ethyl acetate/diethyl ether solution to provide 13.97 g of the desired subtitled intermediate (m.p. 105°109° C.).
Reaction SMILES: [Br:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][N:3]=1.Br[CH2:10][CH2:11][F:12].C([O-])([O-])=O.[K+].[K+]>C(#N)C>[Br:1][C:2]1[C:7]([O:8][CH2:10][CH2:11][F:12])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: FCCBr
Reactant: Oc1cccnc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: FCCOc1cccnc1Br
Yield: 68 %

Procedure:
A mixture of 2-bromopyridin-3-ol 27 (0.1 mmol), 1-bromo-2-fluoroethane (0.2 mmol) and K2CO3 (0.4 mmol) in acetonitrile were stirred at refluxing for one day until TLC indicated that the reaction was complete, and then filter, dried and concentrated under reduce pressure. The crude product was purified with column chromatography to afforded 28 (yield, 68%). 1H NMR (CDCl3): δ 4.25-4.34 (m, 2H), 4.73-4.89 (m, 2H), 7.20-7.22 (m, 2H), 8.01 (s, 1H).
Reaction SMILES: [Si]([O:8][C@@H:9]1[CH2:13][CH2:12][C@H:11]([CH2:14][CH2:15][CH2:16][CH2:17][PH:18](=[O:22])[O:19][CH2:20][CH3:21])[CH2:10]1)(C(C)(C)C)(C)C.[H][H]>O=[Pt]=O>[OH:8][C@@H:9]1[CH2:13][CH2:12][C@H:11]([CH2:14][CH2:15][CH2:16][CH2:17][PH:18](=[O:22])[O:19][CH2:20][CH3:21])[CH2:10]1
Reactant: [H][H]
Reactant: CCO[PH](=O)CCCC[C@H]1CC[C@@H](O[Si](C)(C)C(C)(C)C)C1
Agent: O=[Pt]=O
Product: CCO[PH](=O)CCCC[C@H]1CC[C@@H](O)C1

Procedure:
A related strategy was applied to the synthesis of (±)-(cis-3-aminocyclopentanyl)methylphosphinic acid (Scheme 3). However, in this synthesis, a Mitzanobu reaction was performed at the start of the sequence on isopropyl (±)-(3-hydroxycyclopentenyl)methylphosphinate (3) to yield (±)-isopropyl (3-aminocyclopentenyl)methylphosphinate (8). The amine was then protected as the t-butyloxycarbonylamide (BOC) (9) which provided the steric bulk to direct the approach of the hydrogen. The hydrogenation was carried out over PtO2 at 40 psi affording the (±)-cis-N-butyloxycarbonyl cyclopentane (10) in quantitative yield and a diastereomeric excess of 95:5 cis:trans. The minor diastereoisomer could be separated by silica gel chromatography.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:9]([Cl:12])=[CH:10][CH:11]=1)[CH:7]=O)([O-:3])=[O:2].[CH2:13]([O:15][C:16](=[O:21])[CH2:17][C:18](=[NH:20])[NH2:19])[CH3:14]>C(O)C>[CH2:13]([O:15][C:16]([C:17]1[CH:7]([C:6]2[C:9]([Cl:12])=[CH:10][CH:11]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[C:17]([C:16]([O:15][CH2:13][CH3:14])=[O:21])=[C:18]([NH2:19])[NH:20][C:18]=1[NH2:19])=[O:21])[CH3:14]
Reactant: O=Cc1cc([N+](=O)[O-])ccc1Cl
Reactant: CCOC(=O)CC(=N)N
Solvent: CCO
Product: CCOC(=O)C1=C(N)NC(N)=C(C(=O)OCC)C1c1cc([N+](=O)[O-])ccc1Cl
Yield: 48 %

Procedure:
Upon boiling a solution of 9.3 g 3-nitro-6-chlorobenzaldehyde and 13.0 g amidinoacetic acid ethyl ester in 150 ml ethanol for 2 hours, 2,6-diamino-4-(3-nitro-6-chlorophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid diethyl ester of m.p. 130°C (ethanol) is obtained. Yield: 48% of theory.
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][C:4]=1[CH2:10][CH2:11][O:12][CH2:13][C:14]([NH2:16])=[NH:15].[Cl:17][C:18]1[C:19]([C:24](O)=[O:25])=[N:20][CH:21]=[CH:22][N:23]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.O>[F:2][C:3]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][C:4]=1[CH2:10][CH2:11][O:12][CH2:13][C:14]([NH:16][C:24]([C:19]1[C:18]([Cl:17])=[N:23][CH:22]=[CH:21][N:20]=1)=[O:25])=[NH:15]
Reactant: O=C(O)c1nccnc1Cl
Reactant: N=C(N)COCCc1cc(F)ccc1F
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: N=C(COCCc1cc(F)ccc1F)NC(=O)c1nccnc1Cl
Temperature: 25 °C
Reaction time: 4.5 h

Procedure:
2-[2-(2,5-Difluoro-phenyl)-ethoxy]-acetamidine hydrochloride (158 mg, 0.631 mmol) was dissolved in DMF (3 ml) and 3-chloro-2-pyrazine-carboxylic acid (100 mg, 0.631 mmol), TBTU (213 mg, 0.662 mmol) and DIPEA (565 μl, 3.15 mmol) were added. The reaction mixture was stirred at ambient temperature for 4.5 h. Then water was added and the mixture was extracted three times with CH2Cl2. The combined organic extracts were washed with water and brine, dried (Na2SO4) and evaporated. The crude title compound (195 mg, brown gum) was used for the next reaction step without further purification. MS: m/e=355.2 [M+H+].
Reaction SMILES: [CH2:1]([O:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]2[NH:17][CH:16]=[C:15]([C:18]3[CH:23]=[CH:22][C:21]([O:24]C(=O)C)=[CH:20][CH:19]=3)[S:14]2)=[CH:9][CH:8]=1)[CH2:2][CH2:3][CH2:4][CH3:5].[OH-].[K+]>CO>[CH2:1]([O:6][C:7]1[CH:8]=[CH:9][C:10]([N:13]2[NH:17][CH:16]=[C:15]([C:18]3[CH:19]=[CH:20][C:21]([OH:24])=[CH:22][CH:23]=3)[S:14]2)=[CH:11][CH:12]=1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCCOc1ccc(N2NC=C(c3ccc(OC(C)=O)cc3)S2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CCCCCOc1ccc(N2NC=C(c3ccc(O)cc3)S2)cc1

Procedure:
2-(4-n-pentyloxyphenyl)-5-(4-acetyloxyphenyl)-thiadiazole 4.0 g (0.01 moles) was suspended in 40 mL methanol and mixed with a solution of 2.0 g KOH in 90 mL methanol. The mixture was heated for 2 hours under reflux. The solvent was subsequently distilled off in a rotary evaporator and the residue dissolved in 50 mL water. The solution was acidified with 5% HCl, and the precipitate formed was filtered off with suction and recrystallized from ethanol.
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[C:7]([CH3:13])([CH3:12])[CH2:8][C:9]([OH:11])=[O:10])([CH3:4])([CH3:3])[CH3:2].C(Cl)CCl.O[C@H:20]1[CH2:37][CH2:36][C@@:35]2([CH3:38])[C@@H:22]([CH2:23][CH2:24][C@:25]3([CH3:52])[C@@H:34]2[CH2:33][CH2:32][C@H:31]2[C@@:26]3([CH3:51])[CH2:27][CH2:28][C@@:29]3(/[CH:46]=[CH:47]/[C:48]([OH:50])=[O:49])[CH2:41][C:40](=[O:42])[C:39]([CH:43]([CH3:45])[CH3:44])=[C:30]32)[C:21]1([CH3:54])[CH3:53]>CN(C1C=CN=CC=1)C.ClCCl>[C:1]([O:5][C:6](=[O:14])[C:7]([CH3:13])([CH3:12])[CH2:8][C:9]([O:11][C@H:20]1[CH2:37][CH2:36][C@@:35]2([CH3:38])[C@@H:22]([CH2:23][CH2:24][C@:25]3([CH3:52])[C@@H:34]2[CH2:33][CH2:32][C@H:31]2[C@@:26]3([CH3:51])[CH2:27][CH2:28][C@@:29]3(/[CH:46]=[CH:47]/[C:48]([OH:50])=[O:49])[CH2:41][C:40](=[O:42])[C:39]([CH:43]([CH3:45])[CH3:44])=[C:30]32)[C:21]1([CH3:53])[CH3:54])=[O:10])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)C(C)(C)CC(=O)O
Reactant: CC(C)C1=C2[C@H]3CC[C@@H]4[C@@]5(C)CC[C@H](O)C(C)(C)[C@@H]5CC[C@@]4(C)[C@]3(C)CC[C@@]2(/C=C/C(=O)O)CC1=O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: ClCCCl
Product: CC(C)C1=C2[C@H]3CC[C@@H]4[C@@]5(C)CC[C@H](OC(=O)CC(C)(C)C(=O)OC(C)(C)C)C(C)(C)[C@@H]5CC[C@@]4(C)[C@]3(C)CC[C@@]2(/C=C/C(=O)O)CC1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 80.4 %

Procedure:
To a solution of 4-(tert-butoxy)-3,3-dimethyl-4-oxobutanoic acid (122 mg, 0.604 mmol), DMAP (123 mg, 1.007 mmol) and EDC (193 mg, 1.007 mmol) in dichloromethane (12 mL) stirred at room temp for 30 min was added (E)-3-((3aS,5aR,5bR,7aR,9S,11aR,11bR,13aS)-9-hydroxy-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-3a-yl)acrylic acid (100 mg, 0.201 mmol). The reaction mixture was stirred at 25° C. for 3 h. The produce was extracted with DCM (15 mL*3), the combined organic phase was washed with brine (20 mL), dried, and the solvent removed under reduced pressure to give 110 mg of residue as light yellow solid which was used in the next reaction without further purification.
Reaction SMILES: [CH2:1]([C:8]1[NH:12][N:11]=[C:10]([C:13]2[S:17][C:16]([C:18]([OH:20])=O)=[C:15]([CH3:21])[CH:14]=2)[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.C(N(CC)C(C)C)(C)C.[NH2:53][CH2:54][C:55]1[CH:56]=[N:57][CH:58]=[CH:59][CH:60]=1>CN(C)C=O.C(OCC)(=O)C>[CH2:1]([C:8]1[NH:12][N:11]=[C:10]([C:13]2[S:17][C:16]([C:18]([NH:53][CH2:54][C:55]3[CH:56]=[N:57][CH:58]=[CH:59][CH:60]=3)=[O:20])=[C:15]([CH3:21])[CH:14]=2)[N:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cc(-c2n[nH]c(Cc3ccccc3)n2)sc1C(=O)O
Reactant: NCc1cccnc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(-c2n[nH]c(Cc3ccccc3)n2)sc1C(=O)NCc1cccnc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 65.7 %

Procedure:
To a stirred mixture of 5-(5-benzyl-1H-1,2,4-triazol-3-yl)-3-methylthiophene-2-carboxylic acid (0.13 g, 0.43 mmol), 1-hydroxybenzotriazole (0.088 g, 0.65 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.13 g, 0.65 mmol) in anhydrous N,N-dimethylformamide (2 mL) was added N,N-diisopropylethylamine (0.23 mL, 1.30 mmol), followed by the addition of 3-(aminomethyl)pyridine (0.044 mL, 0.44 mmol). The resulting reaction mixture was stirred at ambient temperature for 18 h, and diluted with ethyl acetate (75 mL). The organic layer was washed with saturated aqueous sodium bicarbonate (3×35 mL) and water (35 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography eluted with 10% methanol in dichloromethane to afford the title compound as a colorless foam (0.11 g, 67%): mp 82° C. (dec.); 1H NMR (300 MHz, DMSO-d6) δ 8.66 (t, J=5.6 Hz, 1H), 8.55 (s, 1H), 8.46 (s, 1H), 7.73 (d, J=7.9 Hz, 1H), 7.42-7.20 (m, 8H), 4.44 (d, J=5.6 Hz, 2H), 4.10 (s, 2H), 2.43 (s, 3H); MS (ES+) m/z 390.3 (M+1).
Reaction SMILES: C([O:8][C:9]1[C:14]2[N:15]=[C:16]([CH3:19])[N:17]([CH3:18])[C:13]=2[CH:12]=[C:11]([N:20]([CH3:24])[C:21](=[O:23])[CH3:22])[CH:10]=1)C1C=CC=CC=1.C(O)(=O)C>C(O)C.[Pd]>[OH:8][C:9]1[C:14]2[N:15]=[C:16]([CH3:19])[N:17]([CH3:18])[C:13]=2[CH:12]=[C:11]([N:20]([CH3:24])[C:21](=[O:23])[CH3:22])[CH:10]=1
Reactant: CC(=O)N(C)c1cc(OCc2ccccc2)c2nc(C)n(C)c2c1
Agent: [Pd]
Solvent: CCO
Solvent: CC(=O)O
Product: CC(=O)N(C)c1cc(O)c2nc(C)n(C)c2c1
Yield: 102.1 %

Procedure:
A solution of 3.1 g (18.9 mmol) N-(7-benzyloxy-2,3-dimethy-3H-benzimidazol-5-yl)-N-methyl-acetamide and 1.2 ml acetic acid in 600 ml ethanol was hydrogenated over 1.2 g 10%. Pd/C in an autoclave (5 bar H2) at 50° C. for 18 h. The catalyst was filtered off and the filtrate was concentrated in vacuo to afford 4.5 g (100%) of the title compound as a yellow solid.
Reaction SMILES: [I:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].S(=O)(=O)(O)O.[CH3:19]O>>[I:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([O:6][CH3:19])=[O:5]
Reactant: O=C(O)c1cccc([N+](=O)[O-])c1I
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1cccc([N+](=O)[O-])c1I
Yield: 95 %

Procedure:
A mixture of 2-iodo-3-nitrobenzoic acid (31.0 g, 106 mmol) and concentrated sulfuric acid (24.9 mL, 317 mmol) in methanol (600 mL) was heated under reflux for 12 hr. The solvent was evaporated under reduced pressure and the residue was extracted with methylene chloride. The extract was washed with saturated aqueous sodium hydrogen carbonate solution and water, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by recrystallization (chloroform/hexane) to give the title compound (31.0 g, yield 95%).
Reaction SMILES: [F:1][C:2]([F:37])([F:36])[O:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]([C:25]2[CH:30]=[CH:29][C:28]([O:31][C:32]([F:35])([F:34])[F:33])=[CH:27][CH:26]=2)[C:11]2([OH:24])[CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13][CH2:12]2)=[CH:6][CH:5]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[F:34][C:32]([F:33])([F:35])[O:31][C:28]1[CH:27]=[CH:26][C:25]([CH:10]([C:7]2[CH:8]=[CH:9][C:4]([O:3][C:2]([F:37])([F:1])[F:36])=[CH:5][CH:6]=2)[C:11]2([OH:24])[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)=[CH:30][CH:29]=1
Reactant: CC(C)(C)OC(=O)N1CCC(O)(C(c2ccc(OC(F)(F)F)cc2)c2ccc(OC(F)(F)F)cc2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: OC1(C(c2ccc(OC(F)(F)F)cc2)c2ccc(OC(F)(F)F)cc2)CCNCC1
Temperature: 25 °C

Procedure:
A mixture of 3.0 grams (0.0057 mole) of tert-butyl 4-{bis[4-(trifluoromethoxy)phenyl]methyl}-4-hydroxypiperidine carboxylate and 25 mL of methylene chloride was chilled in a wet ice bath. A solution of 2.63 mL trifluoro acetic acid and 5 mL methylene chloride was added dropwise to the reaction mixture during a 5-minute period. The wet ice bath was removed and the reaction mixture was allowed to warm to ambient temperature. The reaction mixture was then warmed to reflux, and allowed to cool to ambient temperature. The reaction mixture was concentrated under reduced pressure. The residue can then be dissolved in 100 mL methylene chloride and reacted with 200 mL of an aqueous solution saturated with sodium carbonate. The methylene chloride layer can then be separated, dried over magnesium sulfate, filtered and concentrated under reduced pressure to yield the subject compound.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH:11]([P:20]([O:25]CC)(=[O:24])[O:21]CC)[P:12]([O:17]CC)(=[S:16])[O:13]CC.C[Si](Br)(C)C>C(Cl)Cl>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH:11]([P:20]([OH:24])(=[O:21])[OH:25])[P:12]([OH:13])(=[S:16])[OH:17]
Reactant: CCOP(=O)(OCC)C(c1ccc2ccccc2c1)P(=S)(OCC)OCC
Agent: C[Si](C)(C)Br
Solvent: ClCCl
Product: O=P(O)(O)C(c1ccc2ccccc2c1)P(O)(O)=S
Temperature: 25 °C
Reaction time: 72 h
Yield: 86 %

Procedure:
Under an argon atmosphere, to a solution of 8.04 g (18 mmol) of tetraethyl 2-naphthylthiomethane-diphosphonate obtained in Example 1 in dry methylene chloride (100 ml) was added dropwise 27.56 g (180 mmol) of trimethylsilyl bromide at room temperature and then the mixture was stirred at room temperature for 72 hours. After the solvent and the excess trimethylsilyl bromide were distilled off under reduced pressure, the resulting residue was dissolved in a mixed solvent of water:methanol=5:95, and the solution was heated to reflux for 30 minutes, and the solvent was again distilled off under reduced pressure. The resulting residue was crystallized from acetone/methylene chloride and the obtained crystals were recrystallized from the same solvent to obtain the title compound as white crystals. The yield was 86%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:15]=[C:16]([O:20][CH3:21])[C:17]=1[O:18][CH3:19])[CH2:6][CH:7]([C:13]#[N:14])[C:8]([O:10][CH2:11][CH3:12])=[O:9].[C:22]([O:25][CH:26](OCC)[O:27][CH2:28][CH3:29])(=O)[CH3:23]>>[C:8]([C:7]([CH:26]([O:27][CH2:28][CH3:29])[O:25][CH2:22][CH3:23])([CH2:6][C:5]1[CH:15]=[C:16]([O:20][CH3:21])[C:17]([O:18][CH3:19])=[C:3]([O:2][CH3:1])[CH:4]=1)[C:13]#[N:14])([O:10][CH2:11][CH3:12])=[O:9]
Reactant: CCOC(=O)C(C#N)Cc1cc(OC)c(OC)c(OC)c1
Reactant: CCOC(OCC)OC(C)=O
Product: CCOC(=O)C(C#N)(Cc1cc(OC)c(OC)c(OC)c1)C(OCC)OCC
Temperature: 95 °C
Yield: 72.7 %

Procedure:
Ethyl 3,4,5-trimethoxybenzylcyanoacetate (5 g) was mixed with diethoxymethyl acetate (15 g) and heated at 95° C. overnight. The mixture was cooled and crystallized by addition of ether-hexane (1:1, 25 ml). The product was filtered and dried under reduced pressure giving 4.9 g (73%) of white solid, m.p. 95°-97° C.
Reaction SMILES: [C:1]([NH:9][C:10]1[S:11][CH2:12][C@@H:13]2[CH2:18][N:17]([C:19]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[O:20])[CH2:16][C@:14]2([C:29]2[S:30][C:31](Br)=[CH:32][CH:33]=2)[N:15]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:35]([N:39]1C=CN=C1)CCC.C1(C)C=CC=CC=1>C(OCC)(=O)C.O.[C-]#N.[C-]#N.[C-]#N.[C-]#N.[C-]#N.[C-]#N.[K+].[K+].[K+].[K+].[Fe+6].[Cu]I>[C:1]([NH:9][C:10]1[S:11][CH2:12][C@@H:13]2[CH2:18][N:17]([C:19]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[O:20])[CH2:16][C@:14]2([C:29]2[S:30][C:31]([C:35]#[N:39])=[CH:32][CH:33]=2)[N:15]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCCn1ccnc1
Reactant: O=C(NC1=N[C@@]2(c3ccc(Br)s3)CN(C(=O)OCc3ccccc3)C[C@H]2CS1)c1ccccc1
Agent: [Cu]I
Agent: [Fe+6]
Agent: [C-]#N
Solvent: CCOC(C)=O
Solvent: O
Solvent: Cc1ccccc1
Product: N#Cc1ccc([C@]23CN(C(=O)OCc4ccccc4)C[C@H]2CSC(NC(=O)c2ccccc2)=N3)s1
Temperature: 145 °C
Yield: 73.9 %

Procedure:
Benzyl (4aR,7aR)-2-(benzoylamino)-7a-(5-bromothiophen-2-yl)-4a,5,7,7a-tetrahydropyrrolo[3,4-d][1,3]thiazine-6(4H)-carboxylate (3.88 g, 6.97 mmol), anhydrous potassium hexacyanoferrate (II) (2.57 g, 6.97 mmol) (prepared as cited in Schareina, T.; et al Synthesis, 2008, 20, 3351-3355), copper (I) iodide (398 mg, 2.09 mmol), 1-butylimidazole (2.8 mL, 20.9 mmol), and toluene (23 mL) are added to a 60 mL glass pressure tube fitted with a stirrer bar. A stream of nitrogen is passed over the mixture for a few minutes and the pressure tube is then sealed. The stirred mixture is heated at 145° C. for 18 hours. The resulting dark mixture is cooled to room temperature. The mixture is diluted with ethyl acetate (100 mL) and water (15 mL) and vacuum filtered through a pad of diatomaceous earth while rinsing with ethyl acetate (100 mL) and water (15 mL). The layers of the filtrate are separated and the organic layer is further washed with water (2×30 mL) and brine (30 mL). The organic phase is dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue is purified by silica gel flash chromatography eluting with a hexanes/ethyl acetate, gradient from 80:20 to 0:100, to give the title compound (2.59 g, 74%) as a white foam: ES/MS (m/z): 503.2 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12]N=[C:10](Cl)[CH:9]=2)[CH:5]=[C:4]([Cl:15])[C:3]=1[S:16]([NH:19][C:20]1[C:21]([CH3:27])=[N:22][N:23]([CH3:26])[C:24]=1[CH3:25])(=[O:18])=[O:17].[CH:28]([C:30]1C=CC(B(O)O)=CC=1)=[O:29].P([O-])([O-])([O-])=O.[K+].[K+].[K+].C(Cl)Cl>O=O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O>[CH3:26][N:23]1[C:24]([CH3:25])=[C:20]([NH:19][S:16]([C:3]2[C:4]([Cl:15])=[CH:5][C:6]([C:8]3[CH:13]=[CH:12][C:30]([CH:28]=[O:29])=[CH:10][CH:9]=3)=[CH:7][C:2]=2[Cl:1])(=[O:17])=[O:18])[C:21]([CH3:27])=[N:22]1
Reactant: O=Cc1ccc(B(O)O)cc1
Reactant: Cc1nn(C)c(C)c1NS(=O)(=O)c1c(Cl)cc(-c2ccnc(Cl)c2)cc1Cl
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=O
Solvent: ClCCl
Solvent: O
Product: Cc1nn(C)c(C)c1NS(=O)(=O)c1c(Cl)cc(-c2ccc(C=O)cc2)cc1Cl
Yield: 75.3 %

Procedure:
Prepared from the sulphonamide of intermediate 2 (1.0 g, 2.43 mmol), 4-formylphenylboronic acid (440 mg, 2.91 mmol), tribasic potassium phosphate (620 mg, 2.91 mmol), Pd(dppf)Cl2.DCM (100 mg, 0.12 mmol) and water (0.5 ml) in oxygen-free DMF (6.0 ml) at 130° C. for 1 h according to the method of intermediate 11, to give the title compound as a white solid (791 mg, 1.83 mmol, 75%). δH (D-6 DMSO, 300K) 10.12 (1H, s), 9.68 (1H, s), 8.31 (2H, d 7.1 Hz), 8.07 (2H, s), 8.01 (2H, d J 7.1 Hz), 3.58 (3H, s), 1.50 (3H, s), 1.75 (3H, s). m/z (ES+, 70V) 439.2 (MH+).
Reaction SMILES: [Br:1][C:2]1[NH:3][C:4]([C:11]([O:13][CH3:14])=[O:12])=[C:5]([C:7]([O:9][CH3:10])=[O:8])[N:6]=1.Br[CH2:16][CH:17]=[C:18]([CH3:20])[CH3:19].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Br:1][C:2]1[N:6]([CH2:16][CH:17]=[C:18]([CH3:20])[CH3:19])[C:5]([C:7]([O:9][CH3:10])=[O:8])=[C:4]([C:11]([O:13][CH3:14])=[O:12])[N:3]=1
Reactant: COC(=O)c1nc(Br)[nH]c1C(=O)OC
Reactant: CC(C)=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1nc(Br)n(CC=C(C)C)c1C(=O)OC
Temperature: 50 °C
Reaction time: 2 h

Procedure:
A mixture of 12.20 g (46 mmol) dimethyl 2-bromo-imidazole-4,5-dicarboxylate, 7.16 g (48 mmol) 1-bromo-3-methyl-2-butene and 7.19 g (52 mmol) potassium carbonate in 150 ml of dimethylformamide were stirred for two hours at 50° C. Then 100 ml of water were added, and the mixture was extracted three times with ethyl acetate. The extracts were dried and evaporated down. The crude product thus obtained was purified by column chromatography (silica gel; eluant: cyclohexane/ethyl acetate 4:1->2:1).