Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[S:9](Cl)(=[O:11])=[O:10].[CH3:13][C:14]1([CH3:28])[C:18]([CH3:20])([CH3:19])[O:17][B:16]([C:21]2[CH:26]=[CH:25][C:24]([NH2:27])=[CH:23][CH:22]=2)[O:15]1.C(Cl)Cl>N1C=CC=CC=1>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[S:9]([NH:27][C:24]1[CH:23]=[CH:22][C:21]([B:16]2[O:17][C:18]([CH3:20])([CH3:19])[C:14]([CH3:28])([CH3:13])[O:15]2)=[CH:26][CH:25]=1)(=[O:11])=[O:10]
Reactant: CC1(C)OB(c2ccc(N)cc2)OC1(C)C
Reactant: O=S(=O)(Cl)c1cccc(Cl)c1Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC1(C)OB(c2ccc(NS(=O)(=O)c3cccc(Cl)c3Cl)cc2)OC1(C)C
Temperature: 25 °C
Reaction time: 20 h

Procedure:
The title compound was prepared by adding 2,3-dichloro-benzenesulfonyl chloride (11.2 g) and 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)phenylamine (10.0 g) to a reaction vessel containing a magnetic stirring bar, followed by 200 ml dry DCM and 4.1 ml pyridine. The reaction mixture was stirred at RT for 20 h before being cooled on an ice-bath and quenched with 1M aqueous sodium hydroxide solution. The organic phase was separated and the aqueous phase acidified with 2M aqueous hydrochloric acid and extracted three times with EtOAc. The combined organic phases were washed with brine and dried over sodium sulfate and evaporated to afford the crude product. Purification by flash chromatography on silica gel using a mixture of EtOAc and heptane as the eluent afforded 2,3-dichloro-N-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-benzenesulfonamide as a colorless solid after evaporation of the solvents under reduced pressure. Yield: 15.11 g (77%).
Reaction SMILES: Cl[C:2](Cl)(Cl)[C:3]1[NH:7][C:6]2[CH:8]=[CH:9][C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[O:18][C:19]([F:22])([F:21])[F:20])=[CH:11][C:5]=2[N:4]=1.[NH2:25][C:26]1([CH2:32][OH:33])[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1.O>O1CCOCC1>[F:20][C:19]([F:22])([F:21])[O:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[C:10]1[CH:9]=[CH:8][C:6]2[NH:7][C:3]([C:2]3[O:33][CH2:32][C:26]4([CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]4)[N:25]=3)=[N:4][C:5]=2[CH:11]=1
Reactant: FC(F)(F)Oc1ccccc1-c1ccc2[nH]c(C(Cl)(Cl)Cl)nc2c1
Reactant: NC1(CO)CCCCC1
Solvent: C1COCCO1
Solvent: O
Product: FC(F)(F)Oc1ccccc1-c1ccc2[nH]c(C3=NC4(CCCCC4)CO3)nc2c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 10 %

Procedure:
2-Trichloromethyl-5-(2-trifluoromethoxy-phenyl)-1H-benzimidazole (241 mg, 0.610 mmol, as prepared in step B of this Example) and (1-amino-cyclohexyl)-methanol (315 mg, 2.44 mmol, as prepared in the previous step) were placed in a 40 mL vial equipped with a magnetic stir bar. Water (8 mL) was added, and the mixture was cooled to 0° C. and stirred at that temperature for 1 h. Complete dissolution of starting materials did not occur, so the mixture was warmed to rt, treated with dioxane (8 mL), and stirred at rt for 14 h. The mixture was extracted three times with EtOAc (20 mL). The combined organic extracts were dried over MgSO4 and concentrated in vacuo. The crude product was purified by column chromatography using a 12-g SiO2 pre-packed column eluting with EtOAc/hexanes, 0:1 to 2:5, v/v over 30 min. The column was repeated under these conditions, yielding 24.6 mg (10%) of the desired compound. 1H-NMR (400 MHz, d6-DMSO) δ: 7.78 (br. s., 1H), 7.46-7.64 (m, 5H), 7.27-7.46 (m, 1H), 4.27 (s, 2H), 1.60-1.82 (m, 6H), 1.47-1.58 (m, 1H), 1.33-1.46 (m, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([O:13][CH3:14])[C:10]=1[O:11][CH3:12])[CH:6]=[O:7].[Br:15]Br>O.C(Cl)(Cl)Cl>[Br:15][C:8]1[C:9]([O:13][CH3:14])=[C:10]([O:11][CH3:12])[C:3]([O:2][CH3:1])=[CH:4][C:5]=1[CH:6]=[O:7]
Reactant: COc1cc(C=O)cc(OC)c1OC
Reactant: BrBr
Solvent: ClC(Cl)Cl
Solvent: O
Product: COc1cc(C=O)c(Br)c(OC)c1OC
Yield: 98.2 %

Procedure:
To a stirred refluxing solution of 3,4,5-trimethoxybenzaldehyde (17.0 g, 86.6 mmol) in water (3 mL) and chloroform (100 mL) was added a solution of bromine (14.7 g, 92 mmol) in chloroform (30 mL) dropwise. The solution was heated under reflux overnight, cooled, washed with water (2×100 mL) and saturated aqueous sodium hydrogen carbonate (50 mL), dried over MgSO4, filtered and evaporated. The residual orange oil (27 g) crystallised on standing. The solid was washed with petroleum ether, b.p. 40-60° C., to obtain 2-bromo-3,4,5-trimethoxybenzaldehyde as white crystals (23.4 g, 98%); m.p. 69° C. (literature value 69.5-71° C., see Brown, E.; Robin, J.-P.; Dhal, R. Tetrahedron 1982, 38, 2569-2579); NMR Spectrum δH (300 MHz, CDCl3) 10.40 (1H, s, 1-CHO), 7.29 (1H, s, 6-H), 4.00 (3H, s, OCH3), 3.95 (3H, s, OCH3) and 3.93 (3H, s, OCH3); NMR Spectrum δC (75 MHz, CDCl3) 56.6, 61.6, 106.9, 126.1, 128.1, 149.2, 150.3, 152.8, 189.2; νmax/cm−1 (thin film) 2940, 2843, 1685 (C═O), 1588, 1480, 1460, 1386, 1317, 1196, 1161, 1134, 1103 and 1002 (data in accordance with published values, see Brown, E.; Robin, J.-P.; Dhal, R. Tetrahedron 1982, 38, 2569-2579); Rf(hexane-ethyl acetate 4:1) 0.50.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[NH:10][CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[C:11]([O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]Br)(=[O:13])[CH3:12].C(=O)([O-])[O-].[Cs+].[Cs+].CN(C)C=O>O>[C:11]([O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][N:10]1[C:3]2[C:2]([Cl:1])=[N:7][CH:6]=[N:5][C:4]=2[CH:8]=[CH:9]1)(=[O:13])[CH3:12]
Reactant: Clc1ncnc2cc[nH]c12
Reactant: CC(=O)OCCCCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)OCCCCCn1ccc2ncnc(Cl)c21
Temperature: 40 °C
Reaction time: 96 h

Procedure:
A mixture of 4-chloro-5H-pyrrolo[3,2-d]pyrimidine (0.50 g), 5-bromopentyl acetate (0.71 mL), cesium carbonate (1.59 g) and N,N-dimethylformamide (5.0 mL) was stirred at 40° C. for 4 days. Water was added to the reaction system and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried over magnesium sulfate. After concentration under reduced pressure, the residue was separated and purified by silica gel column chromatography (eluent, ethyl acetate:hexane=1:3→6:4) to give the title compound (637 mg) as a white solid.
Reaction SMILES: [C-:1]#[N:2].[Na+].[CH2:4]([C:6]1[CH:13]=[CH:12][C:9]([CH2:10]Br)=[CH:8][CH:7]=1)[CH3:5].O>CS(C)=O>[CH2:4]([C:6]1[CH:13]=[CH:12][C:9]([CH2:10][C:1]#[N:2])=[CH:8][CH:7]=1)[CH3:5]
Reactant: CCc1ccc(CBr)cc1
Reactant: [C-]#N
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CCc1ccc(CC#N)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 93.1 %

Procedure:
A mixture of 4-ethylbenzyl alcohol (2.72 g, 20 mmol, purchased from Aldrich) and 50 ml of 47% hydrobromic acid (purchased from Wako Junyaku Kogyo) was stirred vigorously for 30 minutes at room temperature. The reaction mixture was extracted with hexane to give 3.98 g of 4-ethylbenzyl bromide as a colorless oil. Then to a hot solution (50° C.) of sodium cyanide (1.96 g, 40 mmol) in 20 ml of dimethyl sulfoxide was added the above 3.98 g of 4-ethylbenzyl bromide and the mixture was stirred for 3 hours at ambient temperature. To the resultant reaction mass was added water and extracted with hexane. The solvent was removed to give 2.70 g (yield: 93.1%) of 4-ethylphenylacetonitrile as a pale yellow oil.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[Cl:11][CH2:12][CH2:13][CH2:14][C:15]#[CH:16]>O1CCCC1.C(N(CC)CC)C.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>[Cl:11][CH2:12][CH2:13][CH2:14][C:15]#[C:16][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1
Reactant: C#CCCCCl
Reactant: O=[N+]([O-])c1ccc(I)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1ccc(C#CCCCCl)cc1
Temperature: 55 °C
Reaction time: 0.5 h

Procedure:
A mixture of 4-iodonitrobenzene (25 g, 100 mmol), dichlorobis(triphenylphosphine)palladium(II) (0.30 g, 0.43 mmol) and copper (I) iodide (0.18 g, 0.95 mmol) in tetrahydrofuran (300 mL) and triethylamine (150 mL) was degassed under Argon for 10 minutes. The mixture was then heated to 55° C. and treated with 5-chloropentyne (12 mL, 110 mmol) via syringe. After 30 minutes of stirring, additional quantities of dichlorobis(triphenylphosphine)palladium(II) (0.10 g) and 5-chloropentyne (1 mL) were added. After another 30 minutes of stirring, the mixture was allowed to cool to room temperature and then was filtered through a pad of Celite diatomaceous earth. The filtrate was concentrated to dryness under reduced pressure to provide 1-(5-chloropent-1-ynyl)-4-nitrobenzene, which was carried on without further purification. ES/MS calcd. for C11H11ClNO2+ 224.1, found m/z=224.2 (M+H)+.
Reaction SMILES: C(OC([NH:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]([C:15]2[S:16][C:17]3[CH:25]=[CH:24][CH:23]=[CH:22][C:18]=3[C:19](=[O:21])[N:20]=2)[CH:10]=1)=O)(C)(C)C.C(OC(C)C)(C)C>FC(F)(F)C(O)=O>[NH2:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]([C:15]2[S:16][C:17]3[CH:25]=[CH:24][CH:23]=[CH:22][C:18]=3[C:19](=[O:21])[N:20]=2)[CH:10]=1
Reactant: CC(C)(C)OC(=O)Nc1ccnc(-c2nc(=O)c3ccccc3s2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: CC(C)OC(C)C
Product: Nc1ccnc(-c2nc(=O)c3ccccc3s2)c1
Reaction time: 5 h
Yield: 152.5 %

Procedure:
2-(4-tert-Butoxycarbonylamino-2-pyridyl)-4H-1,3-benzo thiazine-4-one (100 mg, 0.28 mmol) was dissolved in trifluoroacetic acid (2.5 ml) under ice cooling condition, and the mixture was stirred for 5 hrs. The reaction mixture was combined with diisopropyl ether to precipitate crystals, which were collected by filtration, washed with diethyl ether and dried to give the titled compound (109 mg, 60%).
Reaction SMILES: [CH3:1][C:2]1[C:17]([CH3:18])=[C:16]([O:19][CH2:20][C:21](=O)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:15]=[CH:14][C:3]=1[O:4][CH2:5][C:6](C1C=CC=CC=1)=O.BrCC([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=O.O>C1(C)C(C)=CC=CC=1>[CH3:18][C:17]1[C:16]2[O:19][CH:20]=[C:21]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:15]=2[C:14]2[C:6]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)=[CH:5][O:4][C:3]=2[C:2]=1[CH3:1]
Reactant: Cc1c(OCC(=O)c2ccccc2)ccc(OCC(=O)c2ccccc2)c1C
Reactant: O=C(CBr)c1ccccc1
Solvent: O
Solvent: Cc1ccccc1C
Product: Cc1c(C)c2occ(-c3ccccc3)c2c2c(-c3ccccc3)coc12

Procedure:
A mixture of 2-[2,3-Dimethyl-4-(2-oxo-2-phenyl-ethoxy)-phenoxy]-1-phenyl-ethanone (480 mg, 1.28 mmol) synthesized as described in Example 11, an excess of bromoacetophenone, and polyphosphoric acid (PPA, 100 mg) in xylene (10 mL) was stirred at 150° C. for 10 h. The mixture was then poured into water, extracted with EtOAc, the organic layer was washed with water and brine, dried over MgSO4 and concentrated. The residue was purified by silica gel column eluting with 10-20% EtOAc in hexane to give 190 mg of 4,5-dimethyl-1,8-diphenyl-benzo[1,2-b;4,3-b′]difuran (250 mg). 1H NMR (CDCl3, 300 MHz) δ: 7.60 (s, 2H), 7.05 (m, 4H), 6.90 (m, 2H), 6.85 (m, 4H), 2.60 (s, 6H) ppm. 13C NMR (CDCl3, 75 MHz) δ: 152.57,141.48, 133.19, 128.42, 127.52, 126.87, 124.05, 117.40, 116.29, 11.80 ppm. MS (m/z): 339 (M+H+).
Reaction SMILES: [OH:1][C:2]1[C:3]([CH:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]([CH2:20][C:21]3[CH:30]=[CH:29][CH:28]=[CH:27][C:22]=3[C:23]([O:25][CH3:26])=[O:24])[C:12]2=[O:31])=[CH:4][C:5]2[O:9][CH2:8][O:7][C:6]=2[CH:10]=1.[CH2:32]=[O:33].C([N-]C(C)C)(C)C.[Li+]>C1COCC1>[OH:1][C:2]1[C:3]([C:11]2([CH2:32][OH:33])[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]([CH2:20][C:21]3[CH:30]=[CH:29][CH:28]=[CH:27][C:22]=3[C:23]([O:25][CH3:26])=[O:24])[C:12]2=[O:31])=[CH:4][C:5]2[O:9][CH2:8][O:7][C:6]=2[CH:10]=1
Reactant: C=O
Reactant: COC(=O)c1ccccc1CN1C(=O)C(c2cc3c(cc2O)OCO3)c2ccccc21
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)c1ccccc1CN1C(=O)C(CO)(c2cc3c(cc2O)OCO3)c2ccccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.5 %

Procedure:
A solution of methyl 2-{[3-(6-hydroxy-1,3-benzodioxol-5-yl)-2-oxo-2,3-dihydro-1H-indol-1-yl]methyl}benzoate (17.1 g, 40.0 mmol) and paraformaldehyde (10.3 g, 330 mmol) in THF (500 mL) was degassed by bubbling through argon for 2 hours. To this solution was added lithium diisopropylamide solution (45.1 mL, 2 M solution, 90.0 mmol) slowly at −78° C. The mixture was stirred at ambient temperature overnight and quenched with saturated ammonium chloride solution. The mixtrue was concentrated in vacuo to remove THF followed by the addition of ethyl acetate (500 mL). The organic layer was washed with water, dried over sodium sulfate and filtered. The filtrate was concentrated in vacuo to dryness. The residue was recrystallized from ethyl acetate/hexanes to give the title compound (13.7 g, 75%): 1H NMR (300 MHz, DMSO-d6) δ 9.20 (s, 1H), 7.95 (dd, 1H), 7.53-7.33 (m, 3H), 7.08-6.82 (m, 4H), 6.53 (d, 1H), 6.25 (s, 1H), 5.93-5.86 (m, 2H), 5.31-5.07 (m, 3H), 4.26-4.17 (m, 1H), 4.00-3.92 (m, 1H), 3.88 (s, 3H); MS (ES+) m/z 448.3 (M+1).
Reaction SMILES: [CH:1]([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=O)[C:10]([OH:12])=[O:11])[N:8]=1)=[O:2].Cl.Cl.[NH2:16][O:17][CH2:18][CH2:19][NH2:20].C(=O)(O)[O-].[Na+]>C(O)C.O>[NH2:20][CH2:19][CH2:18][O:17][N:16]=[C:9]([C:7]1[N:8]=[C:4]([NH:3][CH:1]=[O:2])[S:5][CH:6]=1)[C:10]([OH:12])=[O:11]
Reactant: O=CNc1nc(C(=O)C(=O)O)cs1
Reactant: NCCON
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: NCCON=C(C(=O)O)c1csc(NC=O)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 91.6 %

Procedure:
To a solution of 2-(2-formamidothiazol-4-yl)glyoxylic acid (5.5 g.) in ethanol (100 ml.) was added a solution of 2-(aminooxy)ethylamine.dihydrochloride (4.1 g.) in water (50 ml). The resulting mixture was adjusted to pH 4 with an aqueous solution of sodium bicarbonate and stirred for 3 hours at room temperature. The reaction mixture was evaporated to a volume of 100 ml. and cooled. The resulting precipitates were collected by filtration, washed successively with cold-water and ethanol to give the title compound (6.5 g.), mp 213° to 214° C. (dec.).
Reaction SMILES: F[C:2]1[C:7]([N:8]2[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH2:9]2)=[CH:6][CH:5]=[C:4]([N+:15]([O-])=O)[C:3]=1[NH2:18].Cl.CON.N1C=[CH:27][CH:26]=[CH:25][CH:24]=1>C(O)C>[CH:14]1([N:11]2[CH2:12][CH2:13][N:8]([C:7]3[CH:2]=[C:3]([NH2:18])[C:4]([NH2:15])=[CH:5][CH:6]=3)[CH2:9][CH2:10]2)[CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: CN1CCN(c2ccc([N+](=O)[O-])c(N)c2F)CC1
Reactant: c1ccncc1
Agent: CON
Agent: Cl
Solvent: CCO
Product: Nc1ccc(N2CCN(C3CCCC3)CC2)cc1N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A 25 mL round bottom flask was charged with a suspension of 1 (600 mg, 2.2 mmol), methoxyamine HCl (202 mg, 2.42 mmol), and pyridine (0.22 mL, 2.6 mmol) in ethanol (9 mL). The resulting reaction mixture was stirred at rt overnight. The crude product was concentrated, absorbed onto silica gel, and purified by flash chromatography (97:3 CH2Cl2/MeOH) to give 2 as an orange solid. LCMS m/z 303.2 (MH+), tR=2.40 min.
Reaction SMILES: Cl.[F:2][CH:3]([F:32])[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([O:14][CH:15]3[CH2:20][CH2:19][N:18]([CH:21]([CH3:23])[CH3:22])[CH2:17][CH2:16]3)=[CH:11][CH:12]=2)[CH:7]=[C:6]1[C:24]([N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)=[O:25].[CH3:33][N:34]([CH3:38])[C:35](Cl)=[O:36]>>[CH3:33][N:34]([CH3:38])[C:35]([N:29]1[CH2:28][CH2:27][N:26]([C:24]([C:6]2[N:5]([CH2:4][CH:3]([F:2])[F:32])[C:13]3[C:8]([CH:7]=2)=[CH:9][C:10]([O:14][CH:15]2[CH2:20][CH2:19][N:18]([CH:21]([CH3:23])[CH3:22])[CH2:17][CH2:16]2)=[CH:11][CH:12]=3)=[O:25])[CH2:31][CH2:30]1)=[O:36]
Reactant: CN(C)C(=O)Cl
Reactant: CC(C)N1CCC(Oc2ccc3c(c2)cc(C(=O)N2CCNCC2)n3CC(F)F)CC1
Agent: Cl
Product: CC(C)N1CCC(Oc2ccc3c(c2)cc(C(=O)N2CCN(C(=O)N(C)C)CC2)n3CC(F)F)CC1

Procedure:
The title compound was prepared in analogy to example 51, from [1-(2,2-difluoro-ethyl)-5-(1-isopropyl-piperidin-4-yloxy)-1H-indol-2-yl]-piperazin-1-yl-methanone hydrochloride and N,N-dimethylcarbamoyl chloride. Off-white solid. MS (m/z): 506.4 (M+H)+.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:15]3[S:21][CH:20]=[CH:19][C:16]=3[NH:17][N:18]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:22]C(C)([O-])C.[K+].CI.C([O-])(O)=O.[Na+]>C1COCC1>[CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:15]3[S:21][CH:20]=[CH:19][C:16]=3[N:17]([CH3:22])[N:18]=2)[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)[O-]
Reactant: c1ccc(CN2CCN(c3n[nH]c4ccsc34)CC2)cc1
Agent: O=C([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: CI
Solvent: C1CCOC1
Product: Cn1nc(N2CCN(Cc3ccccc3)CC2)c2sccc21
Temperature: -30 °C

Procedure:
To a stirred solution of 3-(4-benzyl-piperazin-1-yl)-1H-thieno[3,2-c]pyrazole (318.0 g, 1.07 mol) in THF (2.5 L) was added a mixture of potassium t-butoxide (134.4 g, 1.2 mol) in THF (1.5 L) dropwise over a period of 1 hour while keeping the reaction temperature below 25° C. After complete addition, the mixture was cooled to −30° C. and MeI (65.4 mL, 1.05 mol) was added dropwise over a period of 30 minutes. The mixture is then slowly warmed to room temperature overnight. To the reaction mixture is slowly added saturated NaHCO3 (1 L). The solution is then evaporated to remove the THF and the resulting aqueous mixture is taken up in EtOAc and washed with water and brine. The EtOAc extract is dried (Na2SO4), filtered and evaporated. The viscous concentrate is filtered through a silica gel plug with 1:1 EtOAc/heptane and evaporated yielding a viscous oil that is then dried under vacuum where it solidifies and yields 326.03 g (98%) as a 12:1 ratio of regioisomers in favor of the desired product.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[CH2:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:15][CH:14]=[CH:13]1>C(#N)C>[O:9]1[CH:19]2[CH:18]1[CH2:17][C:16]1[C:21]([CH2:20]2)=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C1=CCc2ccccc2C1
Solvent: CC#N
Product: c1ccc2c(c1)CC1OC1C2
Temperature: 25 °C
Reaction time: 6 h
Yield: 65.8 %

Procedure:
A solution of metachloroperbenzoic acid (55%, 22.8 g) in acetonitrile (190 ml) was added dropwise over 15 min to a solution of 1,4 dihydro naphthalene (7.86 g) in acetonitrile (100 ml) at 0° C. The resulting mixture was stirred for 6 hours at room temperature. The mixture was concentrated to about 50 ml under reduced pressure, diluted with methylene chloride and filtered. The filtrate was washed with 10% aqueous sodium sulfite, saturated aqueous sodium hydrogenocarbonate, saturated aqueous sodium chloride, dried over magnesium sulfate and concentrated in vacuo. The resulting solid (8.45 g) was chromatographed (silica gel, 150 g, elution with ethyl acetate:hexane, 1:9) to give the title compound as a solid (5.81 g).
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[CH3:15]O>>[CH3:15][NH:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[CH2:8][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: NC1CCCCC1Cc1ccccc1
Reactant: CO
Product: CNC1CCCCC1Cc1ccccc1
Temperature: 25 °C
Yield: 14 %

Procedure:
To a solution of 1-amino-2-benzylcyclohexane (an intermediate in preparation I, 0.90 gm, 4.8 mmol) and methanol (25 mL) was added RhH(Ph3P)3 (275 mg, 0.24 mmol) and the reaction mixture heated to reflux for 12 h. After cooling to room temperature, the solvent was removed under vacuum and the residue chromatographed on neutral alumina with ether and then on silica gel with triethylamine/ethyl acetate/hexane to give the title compound isolated as an oil in 14% yield.
Reaction SMILES: [CH3:1][NH:2][CH3:3].CO.[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([C:13](=[O:15])[CH3:14])=[CH:9][C:8]=1[S:16](Cl)(=[O:18])=[O:17]>O>[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([C:13](=[O:15])[CH3:14])=[CH:9][C:8]=1[S:16](=[O:17])(=[O:18])[N:2]([CH3:3])[CH3:1]
Reactant: CC(=O)c1ccc(Cl)c(S(=O)(=O)Cl)c1
Reactant: CNC
Solvent: O
Solvent: CO
Product: CC(=O)c1ccc(Cl)c(S(=O)(=O)N(C)C)c1
Temperature: 60 °C
Reaction time: 0.25 h

Procedure:
To a stirred mixture of 10 ml of 40% dimethyl amine solution and 60 ml of methanol, there were added, portionswise, 5.1 g of 4'-chloro-3'-chlorosulfonylacetophenone, so that the reaction temperature did not exceed 30° C. The reaction mixture was stirred for 3 hours at room temperature and 15 minutes at 60° C. After cooling, the reaction mixture was poured into 200 ml of water and the crystals were filtered off. Melting point: 108° C.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][NH2:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH2:12]([CH2:14][CH2:15][CH2:16][C:17](CC([O-])=O)=[O:18])[CH3:13]>>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([N:10]2[C:17](=[O:18])[CH2:16][C:15]([CH2:14][CH2:12][CH3:13])=[N:11]2)=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: CCCCCC(=O)CC(=O)[O-]
Reactant: NNc1ccc([N+](=O)[O-])cc1
Product: CCCC1=NN(c2ccc([N+](=O)[O-])cc2)C(=O)C1

Procedure:
From the reaction of 4-nitrophenylhydrazine and ethylbutyrylacetate, 2,4-dihydro-2-(4-nitrophenyl)-5-propyl-3H-pyrazol-3-one is obtained. Subsequent reaction with 2-ethylaniline yields 4-(2-ethylanilinomethylene)-2,4-dihydro-2-(4-nitrophenyl)-5-propyl-3H-pyrazol-3-one, Mp 211° C.
Reaction SMILES: [I:1][C:2]1[CH:15]=[CH:14][C:13]2[C:12]3[C:7](=[CH:8][C:9](I)=[CH:10][CH:11]=3)[CH2:6][CH2:5][C:4]=2[CH:3]=1.B(OC(C)C)(OC(C)C)[O:18]C(C)C.C([Li])CCC.Cl>C1COCC1.CCCCCC>[I:1][C:2]1[CH:3]=[C:4]2[C:13]([C:12]3[CH:11]=[CH:10][C:9]([OH:18])=[CH:8][C:7]=3[CH2:6][CH2:5]2)=[CH:14][CH:15]=1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: Ic1ccc2c(c1)CCc1cc(I)ccc1-2
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Oc1ccc2c(c1)CCc1cc(I)ccc1-2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
8.8 g (20.4 mmol) of 2,7-diiodo-9,10-dihydrophenanthrene are dissolved in 250 ml of THF, and, after addition of 7.0 ml (30.5 mmol) of triisopropyl borate, 16.5 ml of a 15 percent soln. of n-butyllithium in hexane are added at −70° C. After 1 h, the batch is hydrolysed using 2 N hydrochloric acid and warmed to room temperature. The solution is extracted twice with MTB ether, dried over sodium sulfate, the solvent is removed in vacuo, and the resultant crude product is suspended in 80 ml of toluene and 30 ml of 2 N sodium hydroxide solution with vigorous stirring. After addition of 8 ml of 30% hydrogen peroxide, the batch is stirred at 30-40° C. for 30 min with gentle cooling, 200 ml of water are added, and the mixture is acidified using 2 N hydrochloric acid. The aqueous phase is separated off and extracted three times with ethyl acetate. The combined org. phases are washed with dil. ammonium iron(II) sulfate soln. and dried over sodium sulfate. The solvent is removed in vacuo, and the residue is filtered through silica gel with dichloromethane, giving 7-iodo-9,10-dihydrophenanthren-2-ol as colourless solid.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[NH2:8][C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[C:16]([N:18]1[CH2:22][CH:21]([OH:23])[CH:20]([N:24]2[CH2:29][CH2:28][N:27]([CH2:30][C:31]3[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=3)[CH2:26][CH2:25]2)[CH2:19]1)=[O:17].[C:38](OC(=O)C)(=[O:40])[CH3:39]>CN(C=O)C>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[Cl:15][C:13]1[CH:12]=[CH:11][C:10]([C:16]([N:18]2[CH2:22][CH:21]([OH:23])[CH:20]([N:24]3[CH2:25][CH2:26][N:27]([CH2:30][C:31]4[CH:32]=[CH:33][C:34]([Cl:37])=[CH:35][CH:36]=4)[CH2:28][CH2:29]3)[CH2:19]2)=[O:17])=[C:9]([NH:8][C:38](=[O:40])[CH3:39])[CH:14]=1
Reactant: CC(=O)OC(C)=O
Reactant: Nc1cc(Cl)ccc1C(=O)N1CC(O)C(N2CCN(Cc3ccc(Cl)cc3)CC2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: CC(=O)Nc1cc(Cl)ccc1C(=O)N1CC(O)C(N2CCN(Cc3ccc(Cl)cc3)CC2)C1
Reaction time: 1 h
Yield: 10.6 %

Procedure:
A mixture of (3R,4R; 3S,4S)-(2-Amino-4-chloro-phenyl)-{3-[4-(4-chloro-benzyl)-piperazin-1-yl]4-hydroxy-pyrrolidin-1-yl}-methanone trifluoroacetate (22 mg, 0.05 mmol) was dissolved in DMF and acetic anhydride (20 uL, 0.2 mmol) was added. The reaction mixture was shaken for 1 h and directly used for LC-MS purification, to yield 3.2 mg of the title compound as the trifluoroacetate salt. ESIMS ([M+H]+): 491.2 (100).