Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][CH:10]=[CH:11][CH:12]=2)=[CH:4][CH:3]=1.[Li]CCCC.[CH:18]([C@@H:20]1[N:24]([CH3:25])[C:23](=[O:26])[CH2:22][C@@H:21]1[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:19].[NH4+].[Cl-]>C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[S:9][C:10]([C@@H:18]([OH:19])[C@@H:20]3[N:24]([CH3:25])[C:23](=[O:26])[CH2:22][C@@H:21]3[C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)=[CH:11][CH:12]=2)=[CH:6][CH:7]=1
Reactant: Fc1ccc(-c2cccs2)cc1
Reactant: CN1C(=O)C[C@H](c2ccccc2)[C@@H]1C=O
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: CN1C(=O)C[C@H](c2ccccc2)[C@@H]1[C@H](O)c1ccc(-c2ccc(F)cc2)s1
Temperature: -20 °C
Reaction time: 1 h
Yield: 14.9 %

Procedure:
To a −65° C. solution of 2-(4-fluorophenyl)thiophene (Intermediate O; 853.6 mg, 5.79 mmol) in THF (5 mL) was added a solution of n-BuLi (2.5M in hexane, 1.8 mL, 4.5 mmol). The reaction mixture was allowed to warm to −20° C. over the period of 1 h. After cooling down to −65° C. again, a solution of (±)-(4R*,5R*)-5-formyl-1-methyl-4-phenylpyrrolidin-2-one (Intermediate Z, 6.38 mmol) in THF (5 mL) was added. The reaction mixture was stirred for 1 h, while allowing to warm to −20° C., then treated with a saturated NH4Cl solution (15 mL). The resulting mixture was extracted with EtOAc (4×15 mL), dried (MgSO4) and concentrated under reduced pressure. The crude brown solid was triturated (Et2O/hex) to give (±)-(4R*,5R*)-5-{(1S*) [5-(4-fluorophenyl)(2-thienyl)]hydroxymethyl}-1-methyl-4-phenylpyrrolidin-2-one (330 mg, 24%) as a fine brown solid: mp 110° C. (dec); TLC (EtOAc) Rf 0.52.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([OH:15])[CH:13]=2)[CH:8]=[CH:7]1)[CH3:2].[F:17][C:18]([F:40])([F:39])[CH2:19][N:20]1[C:24]([CH2:25][CH2:26]O)=[CH:23][C:22]([C:28]2[CH:33]=[CH:32][C:31]([O:34][C:35]([F:38])([F:37])[F:36])=[CH:30][CH:29]=2)=[N:21]1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>>[CH2:1]([O:3][C:4](=[O:16])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][CH2:26][CH2:25][C:24]3[N:20]([CH2:19][C:18]([F:40])([F:17])[F:39])[N:21]=[C:22]([C:28]4[CH:33]=[CH:32][C:31]([O:34][C:35]([F:37])([F:38])[F:36])=[CH:30][CH:29]=4)[CH:23]=3)[CH:13]=2)[CH:8]=[CH:7]1)[CH3:2]
Reactant: OCCc1cc(-c2ccc(OC(F)(F)F)cc2)nn1CC(F)(F)F
Reactant: CCOC(=O)Cn1ccc2ccc(O)cc21
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CCOC(=O)Cn1ccc2ccc(OCCc3cc(-c4ccc(OC(F)(F)F)cc4)nn3CC(F)(F)F)cc21

Procedure:
In analogy to the procedure described for example 3 c], (6-hydroxy-indol-1-yl)-acetic acid ethyl ester (example 2 e]) was reacted with 2-[2-(2,2,2-trifluoro-ethyl)-5-(4-trifluoromethoxy-phenyl)-2H-pyrazol-3-yl]-ethanol in the presence of di-tert-butyl azodicarboxylate and triphenylphosphine to give (6-{2-[2-(2,2,2-trifluoro-ethyl)-5-(4-trifluoromethoxy-phenyl)-2H-pyrazol-3-yl]-ethoxy}-indol-1-yl)-acetic acid ethyl ester as colorless oil.
Reaction SMILES: [NH2:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[OH-].[K+].CO.O.[C:14](=S)=[S:15]>>[SH:15][C:14]1[O:8][C:7]2[C:2]([N:1]=1)=[N:3][CH:4]=[CH:5][CH:6]=2
Reactant: Nc1ncccc1O
Reactant: S=C=S
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Sc1nc2ncccc2o1

Procedure:
A mixture of 2-amino-3-hydroxypyridine and MeOCS2K [prepared from potassium hydroxide (6.2 g), methanol (96 ml), water (17.4 ml) and carbon disulfide (7.1 g)] was refluxed for 20 hr and filtered. The filtrate was neutralized with acetic acid and the resulting precipitate was collected, washed with water and dried to give 2-mercapto-oxazolo[4,5-b]pyridine (8.2 g).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][O:10][CH3:11])=[CH:4][C:3]=1[O:12][CH2:13][O:14][CH3:15].CN(C)CCN(C)C.C([Li])CCC.[CH2:29]1[O:39][C:32]2([CH2:37][CH2:36][C:35](=[O:38])[CH2:34][CH2:33]2)[O:31][CH2:30]1.Cl>C1COCC1.C(OCC)(=O)C>[CH3:15][O:14][CH2:13][O:12][C:3]1[CH:4]=[C:5]([O:8][CH2:9][O:10][CH3:11])[CH:6]=[CH:7][C:2]=1[C:35]1([OH:38])[CH2:36][CH2:37][C:32]2([O:39][CH2:29][CH2:30][O:31]2)[CH2:33][CH2:34]1
Reactant: O=C1CCC2(CC1)OCCO2
Reactant: COCOc1ccc(Br)c(OCOC)c1
Agent: CN(C)CCN(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COCOc1ccc(C2(O)CCC3(CC2)OCCO3)c(OCOC)c1
Temperature: -78 °C
Reaction time: 1 h
Yield: 55.5 %

Procedure:
A round bottomed flask was loaded with 1-bromo-2,4-bis(methoxymethoxy)benzene (2.00 g) and THF (50 mL). N,N,N′,N′-Tetramethylethylene diamine (2.3 ml) was added and the solution was cooled to −78° C. n-Butyl lithium (9.5 ml, 1.6M in hexane) was added. The resulting solution was stirred for 1 hr at −78° C. and 1,4-cyclohexanedione monoethylene ketal (1.35 g) was added as a solution in THF (25 ml). The resulting solution was stirred at −78° C. for 1 hr and then allowed to warm to room temperature overnight. Hydrochloric acid (20 ml, 2M) was added and the reaction mixture stirred vigorously for 15 min. Ethyl acetate (100 ml) was added and the mixture poured into a separating funnel. The phases were separated and the aqueous phase was extracted with ethyl acetate (3×20 ml). The combined organic phases were washed with brine (20 ml), dried over anhydrous magnesium sulfate, filtered and concentrated affording an orange oil, which was purified by flash column chromatography (SiO2, ethyl acetate/petroleum ether, 45:55, v/v). The title product (1.42 g, 56%) was isolated as a colourless oil. m/z (ES+) 337 (M−H2O+H+); δH (CDCl3) 1.61-1.64(2H, m), 2.00-2.18(6H, m), 3.44(3H, s), 3.48(3H, s), 3.90-3.97(4H, m), 5.11(2H, s), 5.24(2H, s), 6.64(1H, dd), 6.82(1H, d), 7.20(1H, d).
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH:11]=[CH:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(=O)(=O)(O)[OH:14].O.[O-]S(OOS([O-])(=O)=O)(=O)=O.[Na+].[Na+]>CC(C)=O>[CH2:1]([N:8]1[CH2:12][CH:11]2[O:14][CH:10]2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S(=O)(O)O
Reactant: C1=CCN(Cc2ccccc2)C1
Agent: O=S(=O)([O-])OOS(=O)(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: c1ccc(CN2CC3OC3C2)cc1
Yield: 25.7 %

Procedure:
To a solution of 15.9 g (0.1 mol) of 1-benzyl-3-pyrroline, 12.0 g (0.12 mol) of 98% sulfuric acid, 15.0 g of water, and 60.0 g of acetone in a Pyrex round flask reactor, 47.6 g (0.20 mol) of Na2S2O8 (sodium peroxydisulfate produced by Mitsubishi Gas Chemical Industry Co., Ltd.) was added with stirring and allowed to react for 10 hours at room temperature with irradiation by 500 W Xe lamps (UXL-500D xenon lamp produced by Ushio). After completion, acetone was evaporated under reduced pressure, neutralized by NaOH (aq), and extracted with toluene and water. After the solvent was evaporated under reduced pressure, 4.5 g of 1-benzyl-3,4-epoxypyrrolidine (yield 23.3%) was obtained and 11.9 g (yield 75.0%) of 1-benzyl-3-pyrroline was recovered.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:33][C:32]([CH3:34])=[CH:31][C@@H:30]([CH2:35][CH:36]=[CH2:37])[C:28](=[O:29])[CH2:27][C@H:26]([OH:38])[C@@H:25]([CH3:39])[C@@H:24](/[C:40](/[CH3:51])=[CH:41]/[C@H:42]2[CH2:47][C@@H:46]([O:48][CH3:49])[C@H:45]([OH:50])[CH2:44][CH2:43]2)[O:23][C:21](=[O:22])[C@H:20]2[N:15]([CH2:16][CH2:17][CH2:18][CH2:19]2)[C:13](=[O:14])[C:11](=[O:12])[C@:9]2([OH:52])[O:10][C@@H:5]([C@@H:6]([O:54][CH3:55])[CH2:7][C@H:8]2[CH3:53])[C@@H:4]([O:56][CH3:57])[CH2:3]1>C(OCC)(=O)C.[Pd]>[OH:52][C:9]12[O:10][CH:5]([CH:6]([O:54][CH3:55])[CH2:7][CH:8]1[CH3:53])[CH:4]([O:56][CH3:57])[CH2:3][CH:2]([CH3:1])[CH2:33][C:32]([CH3:34])=[CH:31][CH:30]([CH2:35][CH2:36][CH3:37])[C:28](=[O:29])[CH2:27][CH:26]([OH:38])[CH:25]([CH3:39])[CH:24]([C:40]([CH3:51])=[CH:41][CH:42]1[CH2:43][CH2:44][CH:45]([OH:50])[CH:46]([O:48][CH3:49])[CH2:47]1)[O:23][C:21](=[O:22])[CH:20]1[N:15]([CH2:16][CH2:17][CH2:18][CH2:19]1)[C:13](=[O:14])[C:11]2=[O:12]
Reactant: C=CC[C@@H]1C=C(C)C[C@H](C)C[C@H](OC)[C@H]2O[C@@](O)(C(=O)C(=O)N3CCCC[C@H]3C(=O)O[C@H](/C(C)=C/[C@@H]3CC[C@@H](O)[C@H](OC)C3)[C@H](C)[C@@H](O)CC1=O)[C@H](C)C[C@@H]2OC
Agent: [Pd]
Agent: C=CC[C@@H]1/C=C(\C)C[C@H](C)C[C@H](OC)[C@H]2O[C@@](O)(C(=O)C(=O)N3CCCC[C@H]3C(=O)O[C@H](/C(C)=C/[C@@H]3CC[C@@H](O)[C@H](OC)C3)[C@H](C)[C@@H](O)CC1=O)[C@H](C)C[C@@H]2OC
Solvent: CCOC(C)=O
Product: CCCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(O)C(OC)C3)C(C)C(O)CC1=O)C(C)CC2OC

Procedure:
A solution of the FR-900506 substance (50 mg) in ethyl acetate (2 ml) was subjected to catalytic reduction using 10% palladium on carbon (10 mg) under atmospheric pressure at room temperature for 20 minutes. The reaction mixture was filtered and the filtrate was evaporated to dryness, which was purified on thin layer chromatography. Development with a mixture of chloroform and acetone (5:1 v/v) gave 1,14-dihydroxy-12-[2-(4-hydroxy-3-methoxycyclohexyl)-1-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-17-propyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone (50.0 mg).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH:11]2[CH:7]1[CH2:8][CH2:9][C:10]2=[O:12])=[O:5])[CH3:2].CCN(CC)CC.O([Si:28]([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:30])[CH3:29])S(C(F)(F)F)(=O)=O>ClCCl>[CH2:1]([O:3][C:4]([CH:6]1[CH:11]2[CH:7]1[CH2:8][CH:9]=[C:10]2[O:12][Si:28]([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:30])[CH3:29])=[O:5])[CH3:2]
Reactant: CCOC(=O)C1C2CCC(=O)C21
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)C1C2CC=C(O[Si](C)(C)C(C)(C)C)C21
Temperature: 22 °C

Procedure:
To a solution of (1RS,5SR,6RS)-2-oxo-bicyclo[3,1,0]hexane-6-carboxylic acid ethyl ester (28.93 g, 172 mmole) in dichloromethane (430 ml) was added at 22° C. NEt3 (36.0 ml, 258 mmole), the mixture was cooled to 0° C. and treated with tert-butyldimethylsilyl triflate (43.5 ml, 189.2 mmole) keeping the temperature below 10° C. The mixture was allowed to warm to 22° C. over 2 h, washed with saturated aqueous NaHCO3, the organic layer was dried, evaporated and the residue purified over aluminiumoxide (100 g) using cyclohexane/AcOEt (9:1) to give the title compound as a yellow oil which was used without further purification in the next step.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-:10])=[O:9])[C:3]=1[CH3:11].C1C(=O)N([Br:19])C(=O)C1>C(Cl)(Cl)(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-:10])=[O:9])[C:3]=1[CH2:11][Br:19]
Reactant: Cc1c(Br)cccc1[N+](=O)[O-]
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: O=[N+]([O-])c1cccc(Br)c1CBr

Procedure:
To a solution of 1-bromo-2-methyl-3-nitrobenzene (50.0 g, 0.231 mol) in CCl4(500 mL) was added NBS (41.2 g, 0.231 mol) and BPO (6.51 g, 0.0231 mol), and the mixture was stirred at reflux for 1 h. Then the mixture was washed with 1 N HCl (300 mL*3), dried over Na2SO4, concentrated in vacuo. The residue was purified via chromatography (petrol ether) to give 1-bromo-2-(bromomethyl)-3-nitrobenzene.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:32][C:33]1[C:42]([OH:43])=[CH:41][CH:40]=[C:39]2[C:34]=1[CH:35]=[CH:36][N:37]=[CH:38]2.[C:44]([N:51]1[CH2:56][CH2:55][CH:54](O)[CH2:53][CH2:52]1)([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45].C(N(CC)CC)C>ClCCl>[C:47]([O:46][C:44]([N:51]1[CH2:56][CH2:55][CH:54]([O:43][C:42]2[C:33]([Br:32])=[C:34]3[C:39](=[CH:40][CH:41]=2)[CH:38]=[N:37][CH:36]=[CH:35]3)[CH2:53][CH2:52]1)=[O:45])([CH3:50])([CH3:48])[CH3:49]
Reactant: Oc1ccc2cnccc2c1Br
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc3cnccc3c2Br)CC1
Reaction time: 0.25 h
Yield: 59 %

Procedure:
3.75 mL (4.15 g, 23.8 mmol) of diethyl azo dicarboxylate were added to 12.7 g (19.9 mmol) of polymer-bound triphenylphosphine (PS—PPh3, approx. 1.6 mmol/g, Argonaut) in 250 mL of dichloromethane at 0° C. and stirred for 15 min. 4.45 g (19.9 mmol) 5-bromo isoquinoline-6-ol (9), 4.0 g (19.9 mmol) Boc-(4-hydroxy)piperidine and 4.1 mL (3.0 g, 29.8 mmol) triethyl amine were added. The mixture was shaken for 16 h. The polymer was removed by filtration through Celite and the solvents were distilled off. 20 mL dichloromethane were added and the precipitate was isolated by filtration. The crude product (8 g) was purified by flash chromatography using ethyl acetate/n-heptane as eluent to give 4.78 g (60%) of compound 11.
Reaction SMILES: [CH2:1]1[CH2:11][C:9](=O)[C:8]2[C:3](=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:2]1.[O:12]1CCBN1.C[C@@H](N)[C@@H](O)C1C=CC=CC=1.CSC.B>C1COCC1>[CH2:1]1[CH:11]([OH:12])[CH2:9][C:8]2[C:3](=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:2]1
Reactant: B1CCON1
Reactant: O=C1CCCc2ccccc21
Agent: B
Agent: C[C@@H](N)[C@@H](O)c1ccccc1
Solvent: CSC
Solvent: C1CCOC1
Product: OC1CCc2ccccc2C1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
(1S, 2R)-(+)-Norephedrine (7.78 g, 51 mmol), toluene (150 mL), and trimethylboroxine (4.8 mL) were combined at ambient temperature and stirred for 5 days. Water, toluene and excess boroxine were distilled off until about 70 mL volume remained. The reaction was chased with toluene (3×90 mL), and the remainder of toluene removed under vacuum to afford the oxazaborolidine as a pale yellow oil (8.71 g, 98%). 1H NMR (C6D6) δ; 7.36-6.98 (m, 5H), 5.33(d, J=8 Hz, 1H), 3.43 (dq, J=8 Hz, J=6 Hz, 1H), 2.72 (bs, 1H, 0.37 (s, 3H), 0.36(d, J=6 Hz, 3H). To a solution of α-tetralone (2.92 g, 19.7 mmol), THF (80 mL), and the oxazaborolidine derived from norephedrine (218 mg, 1.2 mmol) under a nitrogen atmosphere was added borane methylsulfide complex (2M in THF, 7.0 mL, 14 mmol) over 75 min. After the addition was complete, the contents stirred for an additional 15 min, cooled to 0° C., and quenched with methanol (27 mL). After stirring the quenched reaction for 18 hrs the solvents were removed under vacuum, the residual oil was dissolved in methylene chloride (50 mL), washed with pH 4 phosphate buffer (50 mL), water (50 mL), treated with magnesium sulfate, and the solvent was removed under vacuum to give 3.16 g (80% ee) of the (S) tetralol as a colorless oil.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([O:8][S:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:18])(=[O:11])=[O:10])[CH:5]=[CH:6][CH:7]=1.[H-].[Na+].CS(O[CH2:26][CH:27]1[CH2:32][CH2:31][CH2:30][N:29]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:28]1)(=O)=O>CN(C=O)C.C(OCC)(=O)C>[C:36]([O:35][C:33]([N:29]1[CH2:30][CH2:31][CH2:32][CH:27]([CH2:26][O:1][C:2]2[CH:3]=[C:4]([O:8][S:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[Cl:18])(=[O:11])=[O:10])[CH:5]=[CH:6][CH:7]=2)[CH2:28]1)=[O:34])([CH3:39])([CH3:37])[CH3:38]
Reactant: CC(C)(C)OC(=O)N1CCCC(COS(C)(=O)=O)C1
Reactant: O=S(=O)(Oc1cccc(O)c1)c1ccccc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCCC(COc2cccc(OS(=O)(=O)c3ccccc3Cl)c2)C1
Reaction time: 0.17 h
Yield: 52.9 %

Procedure:
To a solution of 2-chlorobenzenesulfonic acid 3-hydroxyphenyl ester (570 mg, 2.0 mmol), as prepared in step d of Example 1, in DMF (8 mL) was added NaH (95%, 53 mg, 2.2 mmol). The reaction mixture was stirred under nitrogen for 10 min. N-(tert-Butoxycarbonyl)-3-piperidinemethanol methanesulfonate (586 mg, 2.0 mmol), as prepared in step b, was added and the reaction mixture was stirred at 40° C. under nitrogen overnight. The reaction mixture was diluted with ethyl acetate (150 mL), washed sequentially with saturated NaHCO3 (2×50 mL) and brine (2×50 mL), dried over Na2SO4, and concentrated in vacuo. The residue was purified by flash column chromatography (2:1 hexane:ethyl acetate) to give the title compound as a colorless syrup (510 mg, 54%). 1H-NMR (300 MHz, CDCl3) δ 1.32 (m, 1H), 1.45 (s, 9H), 1.65-1.98 (m, 4H), 2.88 (m, 2H), 3.73 (m, 2H), 3.79 (d, 2H), 6.69 (m, 2H), 7.13 (t, 1H), 7.37 (t, 1H), 7.61 (m, 2H), 7.94 (d, 1H).
Reaction SMILES: [C:1]1(=[O:7])[CH:5]=[CH:4][C:3](=[O:6])[CH2:2]1.[CH:8]1[CH2:12][CH:11]=[CH:10][CH:9]=1.C(C1C=C(O)C(C(C)(C)C)=CC=1O)(C)(C)C>C1C=CC=CC=1>[CH:10]12[CH2:11][CH:12]([CH:8]=[CH:9]1)[CH:4]1[CH:5]2[C:1](=[O:7])[CH2:2][C:3]1=[O:6]
Reactant: O=C1C=CC(=O)C1
Reactant: C1=CCC=C1
Agent: CC(C)(C)c1cc(O)c(C(C)(C)C)cc1O
Solvent: c1ccccc1
Product: O=C1CC(=O)C2C3C=CC(C3)C12
Reaction time: 72 h

Procedure:
A solution of 4-cyclopentene-1,3-dione (5 84g; 0.06 mole) in anhydrous benzene (20ml) was treated with freshly distilled cyclopentadiene (7.3g; 0.122 mole) together with a few crystals of 2,5-di-t-butyl hydroquinone. An immediate reaction ensued with concommitant crystallisation of the product. After standing at room temperature for 3 days the title compound was filtered and recrystallised from methanol, m.p. 183° C.
Reaction SMILES: [Si:1]([O:8][C@H:9]1[CH2:13][N:12]([C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=2)=[O:15])[C@H:11]([CH2:27]I)[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[NH:29]1[CH:33]=[CH:32][N:31]=[CH:30]1>>[Si:1]([O:8][C@H:9]1[CH2:13][N:12]([C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=2)=[O:15])[C@:11]([CH3:27])([N:29]2[CH:33]=[CH:32][N:31]=[CH:30]2)[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: c1c[nH]cn1
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1C[C@@H](CI)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Product: CC(C)(C)[Si](C)(C)O[C@H]1CN(C(=O)OCc2ccc([N+](=O)[O-])cc2)[C@](C)(n2ccnc2)C1
Temperature: 0 °C
Reaction time: 5 h
Yield: 59.1 %

Procedure:
A mixture of (2S,4R)-4-t-butyldimethylsilyloxy-2-iodomethyl-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (3.00 g) and imidazole (15.0 g) was fused at 100-110° C. for 5 hours with stirring. The mixture was poured into ice-water (150 ml) and extracted with chloroform (50 ml ×3). The organic layers were combined, washed with water, dried over magnesium sulfate and concentrated under reduced pressure to give a syrup. The syrup was subjected to a column chromatography on silica gel (30 g) and eluted with a mixture of methanol and chloroform (1:99, V/V) to give (2S,4R)-4-t-butyldimethylsilyloxy-2-(imidazol-1-yl)-methyl-1-(4-nitrobenzyloxycarbonyl) pyrrolidine (1.57 g).
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[CH:3]1[CH2:8][CH2:7][CH:6]([O:9][C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[NH:15][CH2:14][CH2:13]3)[CH2:5][CH2:4]1.CCN(C(C)C)C(C)C.[Cl:30][CH2:31][C:32](Cl)=[O:33]>C(Cl)Cl>[Cl:30][CH2:31][C:32]([N:15]1[C:16]2[C:12](=[CH:11][C:10]([O:9][CH:6]3[CH2:5][CH2:4][CH:3]([C:2]([F:1])([F:19])[F:20])[CH2:8][CH2:7]3)=[CH:18][CH:17]=2)[CH2:13][CH2:14]1)=[O:33]
Reactant: O=C(Cl)CCl
Reactant: FC(F)(F)C1CCC(Oc2ccc3c(c2)CCN3)CC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(CCl)N1CCc2cc(OC3CCC(C(F)(F)F)CC3)ccc21
Reaction time: 0.5 h
Yield: 77 %

Procedure:
A mixture of 5-(4-trifluoromethyl-cyclohexyloxy)-2,3-dihydro-1H-indole (130 mg, 0.46 mmol) and DIEA (103 uL) in methylene chloride (2 mL) was added chloroacetyl chloride (47 uL, 0.59 mmol) at room temperature. The black solution was stirred for 30 min. The solvent was concentrated to give crude product. The crude was used directly for next step without further purification (80 mg, yield: 77%). ESI-MS: 362.10 (M+H)+.
Reaction SMILES: [N:1]([C:4]1[CH:5]=[N:6][CH:7]=[CH:8][C:9]=1[N:10]1[CH2:15][CH2:14][CH2:13][C@H:12]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH2:11]1)=C=S.N(C1C=NC=CC=1N1CCC[C@H](NC(=O)OC(C)(C)C)C1)=[N+]=[N-].[P:47]([CH3:50])([CH3:49])[CH3:48]>C1COCC1>[CH3:48][P:47](=[N:1][C:4]1[CH:5]=[N:6][CH:7]=[CH:8][C:9]=1[N:10]1[CH2:15][CH2:14][CH2:13][C@H:12]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH2:11]1)([CH3:50])[CH3:49]
Reactant: CP(C)C
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCN(c2ccncc2N=C=S)C1
Agent: CC(C)(C)OC(=O)N[C@H]1CCCN(c2ccncc2N=[N+]=[N-])C1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@H]1CCCN(c2ccncc2N=P(C)(C)C)C1
Reaction time: 0.17 h

Procedure:
tert-butyl ((3S)-1-(3-isothiocyanato-4-pyridinyl)-3-piperidinyl)carbamate. A dry, 3 neck, 100 mL Morton flask was configured as follows: opening 1: septa/Ar inlet; opening 2 (center): septa/PTFE addition needle; opening 3: septa. The flask was charged with tert-butyl ((3S)-1-(3-azido-4-pyridinyl)-3-piperidinyl)carbamate (3.25 g, 10.22 mmol), a stirbar, and dry THF (10 mL). The slurry was stirred for 10 min, and immersed into an ice-water bath. A syringe charged with 1.0 M PMe3 in THF (10.73 mL, 10.73 mmol, Aldrich) was fitted to the PTFE addition needle and added over a 15 min period via a syringe pump. The reaction was stirred for 15 min. The solution was charged to a dry 50 mL glass syringe via the PTFE addition needle to afford (S)-tert-butyl (1-(3-((trimethylphosphoranylidene)amino)pyridin-4-yl)piperidin-3-yl)carbamate. A dry, 250 mL, one neck round bottom flask was charged with dry THF (16 mL), carbon disulfide (6.17 mL, 102 mmol) and a stirbar. The flask was fitted with a septa/Ar inlet, and immersed into an ice-water bath. The solution was stirred for 15 min. The septa was pierced with the PTFE addition needle fitted to the 50 mL glass syringe containing the solution of (S)-tert-butyl (1-(3-((trimethylphosphoranylidene)amino)pyridin-4-yl)piperidin-3-yl)carbamate and the solution (19 mL) was added via syringe pump over a 1 h period. The reaction was stirred an additional 10 min and the solvent was removed in vacuo. The residue was further dried at <1 mm Hg at RT to afford tert-butyl ((3S)-1-(3-isothiocyanato-4-pyridinyl)-3-piperidinyl)carbamate. MS (ESI, pos. ion) m/z: 335.0 [M+H].
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[NH:10][C:9]([C:11]3[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][C:12]=3[O:18][CH3:19])=[N:8][C:5]2=[N:6][CH:7]=1.[CH3:20][S:21](Cl)(=[O:23])=[O:22]>>[CH3:1][C:2]1[CH:3]=[C:4]2[NH:10][C:9]([C:11]3[CH:16]=[CH:15][C:14]([O:17][S:21]([CH3:20])(=[O:23])=[O:22])=[CH:13][C:12]=3[O:18][CH3:19])=[N:8][C:5]2=[N:6][CH:7]=1
Reactant: CS(=O)(=O)Cl
Reactant: COc1cc(O)ccc1-c1nc2ncc(C)cc2[nH]1
Product: COc1cc(OS(C)(=O)=O)ccc1-c1nc2ncc(C)cc2[nH]1

Procedure:
Prepared analogously to Example 1 from 6-methyl-2-(2'-methoxy-4'-hydroxy-phenyl)-imidazo[4,5-b]pyridine and methanesulfonic acid chloride.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([OH:12])=O)=[CH:9][C:4]=2[N:3]=[CH:2]1.[NH:13]1[CH2:18][CH2:17][CH2:16][C@@H:15]2[C:19]3[CH:20]=[CH:21][C:22]([NH2:26])=[CH:23][C:24]=3[CH2:25][C@H:14]12>>[NH2:26][C:22]1[CH:21]=[CH:20][C:19]2[C@@H:15]3[C@@H:14]([N:13]([C:10]([C:8]4[CH:7]=[CH:6][C:5]5[NH:1][CH:2]=[N:3][C:4]=5[CH:9]=4)=[O:12])[CH2:18][CH2:17][CH2:16]3)[CH2:25][C:24]=2[CH:23]=1
Reactant: Nc1ccc2c(c1)C[C@@H]1NCCC[C@H]21
Reactant: O=C(O)c1ccc2[nH]cnc2c1
Product: Nc1ccc2c(c1)C[C@H]1[C@@H]2CCCN1C(=O)c1ccc2[nH]cnc2c1
Yield: 30 %

Procedure:
The title compound is prepared from 1H-benzoimidazole-5-carboxylic acid and cis-2,3,4,4a,9,9a-hexahydro-1H-indeno[2,1-b]pyridin-7-ylamine following a procedure analogous to that described in Example 1. Yield: 30% of theory; LC (method 1): tR=0.79 min; Mass spectrum (ESI+): m/z=333 [M+H]+.
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.[O:12]1[CH:17]=[CH:16][CH2:15][CH2:14][CH2:13]1.[OH:18][C:19]1[C:24]([OH:25])=[CH:23][CH:22]=[CH:21][C:20]=1[N+:26]([O-:28])=[O:27]>C1C=CC=CC=1>[OH:18][C:19]1[C:24]([O:25][CH:17]2[CH2:16][CH2:15][CH2:14][CH2:13][O:12]2)=[CH:23][CH:22]=[CH:21][C:20]=1[N+:26]([O-:28])=[O:27]
Reactant: C1=COCCC1
Reactant: O=[N+]([O-])c1cccc(O)c1O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: O=[N+]([O-])c1cccc(OC2CCCCO2)c1O
Reaction time: 168 h

Procedure:
0.030 g of p-toluenesulphonic acid and 17.8 g of 3,4-dihydro-2H-pyrane are added to a mixture of 29.8 g of 2,3-dihydroxy-nitrobenzene in 400 ml of absolute benzene and the solution is left to stand for 7 days at 20°. It is filtered through 15 g of a silica gel formulation (Merck silica gel 60; grain size 0.063-0.200 mm) and the silica gel is rinsed with benzene. After distilling off the benzene under reduced pressure, a reddish oil is obtained which, when crystallised from hexane, gives 2-hydroxy-3-(tetrahydropyran-2-yloxy)-nitrobenzene in the form of yellow crystals; melting point 72°-73°.