Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:31])[C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([N:13]3[CH:22]=[CH:21][C:20]4[C:15](=[CH:16][C:17]([O:23][CH:24]5[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]5)=[CH:18][CH:19]=4)[C:14]3=[O:30])[CH:7]=2)[CH2:3][CH2:2]1.I[CH2:33][CH3:34].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[CH:1]1([NH:4][C:5](=[O:31])[C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([N:13]3[CH:22]=[CH:21][C:20]4[C:15](=[CH:16][C:17]([O:23][CH:24]5[CH2:29][CH2:28][N:27]([CH2:33][CH3:34])[CH2:26][CH2:25]5)=[CH:18][CH:19]=4)[C:14]3=[O:30])[CH:7]=2)[CH2:3][CH2:2]1
Reactant: CCI
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-n1ccc2ccc(OC3CCNCC3)cc2c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCN1CCC(Oc2ccc3ccn(-c4cc(C(=O)NC5CC5)ccc4C)c(=O)c3c2)CC1

Procedure:
N-Cyclopropyl-4-methyl-3-[1-oxo-7-(piperidin-4-yloxy)isoquinolin-2(1H)-yl]benzamide (50 mg), iodoethane (0.105 ml) and potassium carbonate (66 mg) were stirred in DMF (0.5 ml) at room temperature for 18 hours. The reaction mixture was diluted with ethyl acetate and washed with water (5×), brine, dried (magnesium sulfate) and concentrated to give N-cyclopropyl-3-[7-[(1-ethylpiperidin-4-yl)oxy]-1-oxoisoquinolin-2(1H)-yl]-4-methylbenzamide as a cream coloured foam solid (44 mg); NMR Spectrum: (DMSOd6) 0.56 (m, 2H), 0.69 (m, 2H), 1.00 (t, 3H), 1.69 (m, 2H), 1.99 (m, 2H), 2.10 (s, 3H), 2.25 (m, 2H), 2.38 (m, 2H), 2.71 (m, 2H), 2.85 (m, 1H), 4.53 (m, 1H), 6.70 (d, 1H), 7.20 (d, 1H), 7.41 (d, 1H), 7.49 (d, 1H), 7.67 (s, 1H), 7.70 (d, 1H), 7.72 (s, 1H), 7.88 (d, 1H), 8.42 (d, 1H); Mass Spectrum: M+H+ 446.
Reaction SMILES: [CH2:1]([C:8]1([N:15]([CH3:17])[CH3:16])[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH3:19][NH2:20].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>O1CCCC1.C(O)(=O)C.C(N(CC)CC)C>[CH2:1]([C:8]1([N:15]([CH3:17])[CH3:16])[CH2:13][CH2:12][CH:11]([NH:20][CH3:19])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN
Reactant: CN(C)C1(Cc2ccccc2)CCC(=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CNC1CCC(Cc2ccccc2)(N(C)C)CC1
Reaction time: 8 h
Yield: 41.7 %

Procedure:
15.0 g 4-benzyl-4-dimethylamino-cyclohexanone (see example 3) were dissolved in 225 ml analytical grade tetrahydrofuran, and 4.38 g methylamine hydrochloride, 8.9 ml triethylamine and 8.40 ml glacial acetic acid were added, while stirring in an ice-bath. 19.2 g sodium triacetoxyborohydride were then added in portions in the course of 15 minutes and the mixture was subsequently stirred overnight. For working up, 110 ml two molar sodium hydroxide solution were added dropwise (pH>10) and the mixture was extracted three times with 200 ml diethyl ether each time. The combined organic phases were washed twice with 200 ml water each time, dried over sodium sulfate and filtered and the filtrate was concentrated. The crude product obtained (15.0 g) was chromatographed over silica gel with methanol with the addition of one percent by volume of aqueous ammonia solution (25 wt. %). 11.6 g of the still significantly contaminated product were obtained, and were chromatographed again over silica gel with ethyl acetate and an addition of methanol rising from twenty-five to fifty percent by volume. 6.67 g 1-benzyl-N,N,N′-trimethyl-cyclohexane-1,4-diamine were obtained as a cis/trans mixture.
Reaction SMILES: [OH-].[Na+].[NH:3]1[CH2:10][CH2:9][CH2:8][C@H:4]1[C:5]([OH:7])=[O:6].[N+:11]([C:14]1[CH:15]=[C:16]([S:20](Cl)(=[O:22])=[O:21])[CH:17]=[CH:18][CH:19]=1)([O-:13])=[O:12].Cl>O.C(OCC)C>[N+:11]([C:14]1[CH:15]=[C:16]([S:20]([N:3]2[CH2:10][CH2:9][CH2:8][C@H:4]2[C:5]([OH:7])=[O:6])(=[O:22])=[O:21])[CH:17]=[CH:18][CH:19]=1)([O-:13])=[O:12]
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)Cl)c1
Reactant: O=C(O)[C@@H]1CCCN1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: O
Product: O=C(O)[C@@H]1CCCN1S(=O)(=O)c1cccc([N+](=O)[O-])c1
Temperature: 15 °C
Yield: 81 %

Procedure:
To solution of 12.0 g of sodium hydroxide in 150 ml of water was added 15.0 g of L-proline and dissolved under water-cooling at 15° C. The solution was stirred under water-cooling at 15° C. and to the reaction mixture was added 30.0 g of 3-nitrobenzenesulfonyl chloride and 15 ml of diethyl ether under stirring for 15 minutes. After stirring at room temperature for 80 minutes, the reaction mixture was acidified at pH2 with concentrated hydrochloric acid and the separated oily substance was extracted with ethyl acetate. After the organic layer was washed with aqueous sodium chloride, the solution was filtered and the filtrate was concentrated under reduced pressure. The crystallized residue was boiled with 300 ml of hexane-ethyl acetate (1:1) and was cooled. The obtained crystals were collected by filtration to give 31.7 g of N-3-nitrobenzenesulfonyl-L-proline, melting at 155°-157° C., [α]23D =-71.3° (c=1, CHCl3)
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[CH2:4][C:5]1[C:9]2[C:10]([CH3:15])=[CH:11][C:12]([OH:14])=[CH:13][C:8]=2[S:7][CH:6]=1.CN(C=O)C.C([O-])([O-])=O.[K+].[K+].[Cl:28][C:29]1[CH:36]=[C:35]([Cl:37])[CH:34]=[CH:33][C:30]=1[CH2:31]Cl>O>[CH3:1][O:2][C:3](=[O:16])[CH2:4][C:5]1[C:9]2[C:10]([CH3:15])=[CH:11][C:12]([O:14][CH2:31][C:30]3[CH:33]=[CH:34][C:35]([Cl:37])=[CH:36][C:29]=3[Cl:28])=[CH:13][C:8]=2[S:7][CH:6]=1
Reactant: COC(=O)Cc1csc2cc(O)cc(C)c12
Reactant: ClCc1ccc(Cl)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)Cc1csc2cc(OCc3ccc(Cl)cc3Cl)cc(C)c12
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a mixture of methyl(6-hydroxy-4-methyl-1-benzothiophen-3-yl)acetate (174 mg) and DMF (dry) (2 mL) were added K2CO3 (112 mg) and 2,4-dichlorobenzyl chloride (0.113 mL) at room temperature. After stirring at room temperature for 5 h, the mixture was poured into water at room temperature and extracted with EtOAc. The organic layer was separated, washed successively with water and brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc/hexane) to give the title compound (233 mg).
Reaction SMILES: C(OC([C:6]1([OH:22])[C:14]2[C:9](=[CH:10][C:11]([CH3:20])=[C:12]([C:15](=[O:19])[CH2:16][CH2:17][CH3:18])[CH:13]=2)[NH:8]C1=O)=O)C.[OH-:23].[Na+]>CO>[C:15]([C:12]1[CH:13]=[C:14]([C:6]([OH:22])=[O:23])[C:9]([NH2:8])=[CH:10][C:11]=1[CH3:20])(=[O:19])[CH2:16][CH2:17][CH3:18]
Reactant: [OH-]
Reactant: CCCC(=O)c1cc2c(cc1C)NC(=O)C2(O)C(=O)OCC
Agent: [Na+]
Solvent: CO
Product: CCCC(=O)c1cc(C(=O)O)c(N)cc1C
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
13.0 g of 5-butyryl-3-hydroxy-6-methyloxindole-3-carboxylic acid ethyl ester are suspended in 200 ml of methanol and 85 ml of 2N sodium hydroxide solution are added. The mixture is stirred at room temperature for 90 minutes, the methanol is removed under reduced pressure, the mixture is acidified to pH 3-4 with 2N hydrochloric acid, filtered with suction, then the residue is washed with water, dissolved in ethyl acetate, dried over magnesium sulphate, concentrated to dryness by evaporation under reduced pressure, digested with a little methylene chloride and filtered with suction. 5-Butyryl-4-methylanthranilic acid having a melting point of 184°-186° is obtained.
Reaction SMILES: [F:1][C:2]([F:16])([C:6]([F:15])([F:14])[C:7]([F:13])([F:12])[C:8]([F:11])([F:10])[F:9])[CH2:3][CH2:4][OH:5].N1C=CC=CC=1.C(N(CC)CC)C.[Cl-].[C:31]([O:38][CH2:39][CH:40]([CH2:45][CH3:46])[CH2:41][CH2:42][CH2:43][CH3:44])(=[O:37])/[CH:32]=[CH:33]\[C:34]([O-])=[O:35]>C(Cl)(Cl)Cl>[C:31]([O:38][CH2:39][CH:40]([CH2:45][CH3:46])[CH2:41][CH2:42][CH2:43][CH3:44])(=[O:37])/[CH:32]=[CH:33]\[C:34]([O:5][CH2:4][CH2:3][C:2]([F:16])([F:1])[C:6]([F:14])([F:15])[C:7]([F:12])([F:13])[C:8]([F:9])([F:10])[F:11])=[O:35]
Reactant: CCCCC(CC)COC(=O)/C=C\C(=O)[O-]
Reactant: OCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Agent: [Cl-]
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: CCCCC(CC)COC(=O)/C=C\C(=O)OCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 54.9 %

Procedure:
3,3,4,4,5,5,6,6,6-Nonafluorohexanol (515 g, 1.95 mol), pyridine (169 g, 2.13 mol) and triethylamine (394 mL, 3.89 mol) were dissolved in chloroform (1000 mL) and added dropwise with 2-ethylhexyl maleate chloride (530 g, 2.14 mol), while the internal temperature was kept at 20° C. or lower on an ice bath. After completion of the addition, the reaction mixture was stirred at room temperature for 1 hour and then added with chloroform. The organic phase was washed with water and a saturated sodium chloride aqueous solution. Then, the organic layer was collected, and the organic solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/chloroform=10/0 to 7/3 (v/v)) to obtain the target compound (508 g, yield: 50%), which was colorless and transparent.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[N:16]([C:17]3[CH:26]=[CH:25][CH:24]=[C:23]4[C:18]=3[CH:19]=[CH:20][CH:21]=[N:22]4)[N:15]=[C:14]([CH3:27])[CH:13]=2)(=[O:10])=[O:9])=[CH:4][C:3]=1[F:28].[NH:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1.C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.OP([O-])(O)=O.[K+]>CN(C)C=O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:28][C:3]1[CH:4]=[C:5]([S:8]([NH:11][C:12]2[N:16]([C:17]3[CH:26]=[CH:25][CH:24]=[C:23]4[C:18]=3[CH:19]=[CH:20][CH:21]=[N:22]4)[N:15]=[C:14]([CH3:27])[CH:13]=2)(=[O:10])=[O:9])[CH:6]=[CH:7][C:2]=1[N:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1
Reactant: C1COCCN1
Reactant: Cc1cc(NS(=O)(=O)c2ccc(Br)c(F)c2)n(-c2cccc3ncccc23)n1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=P([O-])(O)O
Solvent: CN(C)C=O
Product: Cc1cc(NS(=O)(=O)c2ccc(N3CCOCC3)c(F)c2)n(-c2cccc3ncccc23)n1
Temperature: 90 °C
Yield: 73.3 %

Procedure:
A stirring mixture of 4-bromo-3-fluoro-N-(3-methyl-1-(quinolin-5-yl)-1H-pyrazol-5-yl)benzenesulfonamide (0.07 g, 0.15 mmol), morpholine (0.066 g, 0.75 mmol), tris(dibenzylideneacetone)dipalladium(0) (Pd2(dba)3, 0.007 g, 0.008 mmol), 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (BINAP, 0.014 g, 0.023 mmol), and potassium phosphate monobasic (K3PO4.H2O, 0.21 g, 0.90 mmol) in anhydrous N,N-dimethylformamide (DMF, 6 mL) was purged with nitrogen for 5 min. The reaction mixture was heated at 90° C. for 4 h. After cooling to room temperature, ethyl acetate (10 mL) was added to the reaction mixture and washed with aqueous saturated sodium bicarbonate. The organic layer was dried (Na2SO4), filtered, and concentrated in vacuo. The resulting crude material was purified by reverse phase HPLC(C18 column, acetonitrile-H2O with 0.1% TFA as eluent) to give the title compound as a white solid (0.049 g, 0.11 mmol, 70%). 1H NMR (400 MHz, CDCl3) δ 9.06 (dd, J=1.6, 4.8 Hz, 1H), 8.36 (d, J=8.4 Hz, 1H), 8.31 (d, J=8.0 Hz, 1H), 7.88 (dd, J=8.4, 9.6 Hz, 1H), 7.68 (d, J=4.8 Hz, 1H), 7.66 (d, J=6.4 Hz, 1H), 7.37 (dd, J=1.6, 8.4 Hz, 1H), 7.31 (dd, J=2.4, 12.4 Hz, 1H), 6.80 (t, J=6.8 Hz, 1H), 6.09 (s, 1H), 3.90-3.86 (m, 4H), 3.21-3.18 (m, 4H), 2.35 (s, 3H); MS: (ES) m/z calculated for C23H23FN5O3S [M+H+ 468.2. found 468.2.
Reaction SMILES: [CH3:1][N:2]([CH3:10])[C@@H:3]1[CH2:8][CH2:7][CH2:6][CH2:5][C@H:4]1[NH-:9].[F:11][C:12]([F:23])([F:22])[C:13]1[CH:14]=[C:15]([CH:19]=[CH:20][CH:21]=1)[C:16](Cl)=[O:17].[C:24]1([CH3:34])[CH:29]=[CH:28][C:27]([S:30]([OH:33])(=[O:32])=[O:31])=[CH:26][CH:25]=1>CCOCC>[C:24]1([CH3:34])[CH:25]=[CH:26][C:27]([S:30]([OH:33])(=[O:31])=[O:32])=[CH:28][CH:29]=1.[CH3:1][N:2]([CH3:10])[C@@H:3]1[CH2:8][CH2:7][CH2:6][CH2:5][C@H:4]1[NH:9][C:16](=[O:17])[C:15]1[CH:19]=[CH:20][CH:21]=[C:13]([C:12]([F:11])([F:22])[F:23])[CH:14]=1
Reactant: CN(C)[C@@H]1CCCC[C@H]1[NH-]
Reactant: O=C(Cl)c1cccc(C(F)(F)F)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOCC
Product: CN(C)[C@@H]1CCCC[C@H]1NC(=O)c1cccc(C(F)(F)F)c1
Yield: 47 %

Procedure:
This titled amide was prepared by general procedure B from trans-2-(dimethylamino)cyclohexylamide and 3-trifluoromethylbenzoyl chloride. The crude oil was converted to the salt with 1 mole of p-toluenesulfonic acid in ether, and was crystallized from MeOH-ether, 47% yield, colorless plates, m.p. 208°-209°. uv λmax 222 nm (ε 22,150); sh 227 (17,900); sh 259 (1,550); sh 266 (1,100); sh 274 (566). ir NH/N+H 3280, 3040; C=O 1660; C=C/amide II 1615, 1595, 1550, 1495; CF3 /SO3 /CN 1335, 1320, 1275, 1200,1180, 1160, 1120, 1075, 1035, 1010; aromatic/SO3- 705, 690, 680. NMR in CDCl3 (100 MHz) was in accord. Mass spectrum M+ 314.
Reaction SMILES: [CH:1]([O:4][CH2:5][CH2:6][NH:7][C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-])=O)=[CH:10][CH:9]=1)([CH3:3])[CH3:2].C1(N)C(F)=C(F)C(F)=C(N)C=1F.[ClH:29].Cl>[Zn].[Cl-].[NH4+].O.C(O)C>[ClH:29].[ClH:29].[CH:1]([O:4][CH2:5][CH2:6][NH:7][C:8]1[CH:9]=[CH:10][C:11]([NH2:14])=[CH:12][CH:13]=1)([CH3:3])[CH3:2]
Reactant: CC(C)OCCNc1ccc([N+](=O)[O-])cc1
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Agent: [Cl-]
Solvent: CCO
Solvent: O
Product: CC(C)OCCNc1ccc(N)cc1

Procedure:
The N-(2-isopropoxyethyl)-4-nitro-1-aminobenzene (7) obtained above was reduced with a boiling zinc/ammonium chloride/water/ethanol mixture. The corresponding amine was isolated in dihydrochloride form.
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2)=[C:4]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:3]=1.[F:22][C:23]1[C:28]([F:29])=[C:27]([F:30])[C:26]([F:31])=[C:25]([F:32])[C:24]=1[OH:33]>>[CH3:15][O:14][C:11]1[CH:12]=[CH:13][C:8]([C:5]2[N:6]=[N:7][C:2]([O:33][C:24]3[C:25]([F:32])=[C:26]([F:31])[C:27]([F:30])=[C:28]([F:29])[C:23]=3[F:22])=[CH:3][C:4]=2[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:9][CH:10]=1
Reactant: COc1ccc(-c2nnc(Cl)cc2-c2ccccc2)cc1
Reactant: Oc1c(F)c(F)c(F)c(F)c1F
Product: COc1ccc(-c2nnc(Oc3c(F)c(F)c(F)c(F)c3F)cc2-c2ccccc2)cc1

Procedure:
In a similar manner as in Example 2, 6-chloro-3-(4-methoxyphenyl)-4-phenylpyridazine (200 mg, 0.675 mmol) and 2,3,4,5,6-pentafluorophenol were reacted as starting materials at 150° C. for 48 hours and post-treatment was then conducted, whereby the title compound was obtained as a colorless crystalline powder (91.2 mg, 30.5%). Melting point: 133.1-133.9° C. (ethyl acetate-hexane).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:15]([O-])=O)=[C:6]([NH:8][C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)[CH:7]=1>CCOC(C)=O>[F:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)[C:5]([NH2:15])=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1Nc1cccnc1
Solvent: CCOC(C)=O
Product: Nc1ccc(F)cc1Nc1cccnc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.3 %

Procedure:
A mixture of (5-fluoro-2-nitrophenyl)pyridin-3-ylamine (1.28 g, 5.49 mmol) in EtOAc (60 mL) was degassed with a stream of nitrogen prior to addition of 10% Pd/C (107 mg) and was stirred at RT under a hydrogen atmosphere for 2 h. The resulting suspension was diluted with IMS (10 mL) and stirred under a hydrogen atmosphere for 56 h. The reaction mixture was filtered through a phase separator and the filtrate concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, gradient 0-20% MeOH in DCM) to afford the title compound as a brown solid (1.03 g, 92%). 1H NMR (CDCl3, 400 MHz): δ 8.24 (1H, d, J=2.67 Hz), 8.14 (1H, d, J=4.50 Hz), 7.20-7.05 (2H, m), 6.86 (1H, dd, J=9.62, 2.63 Hz), 6.79-6.65 (2H, m), 5.42 (1H, s), 3.50 (2H, s)
Reaction SMILES: Cl.[CH:2]1([C:8]2[C:13]([C:14]([OH:16])=[O:15])=[CH:12][N:11]=[CH:10][CH:9]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.ClC1C=CC=C(C(OO)=[O:25])C=1>C(Cl)Cl>[C:14]([C:13]1[CH:12]=[N+:11]([O-:25])[CH:10]=[CH:9][C:8]=1[CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]1)([OH:16])=[O:15]
Reactant: O=C(O)c1cnccc1C1CCCCC1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: Cl
Solvent: ClCCl
Product: O=C(O)c1c[n+]([O-])ccc1C1CCCCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-Cyclohexylnicotinic acid hydrochloride (4.5 g, 0.018 mol) is dissolved in methylene chloride (40 ml). This solution is mixed with a cold solution of metachloroperbenzoic acid (10.82 g, 0.063 mol) in CH2Cl2 (80 ml), and the resulting mixture is stirred at room temperature overnight. The precipitate obtained is filtered and the filtrate evaporated to dryness. The residue is suspended in ether. The precipitate is filtered, washed with ether and dried to yield 3-carboxy-4-cyclohexyl-pyridine N-oxide, m.p. 168°-169°. (c) To a solution of 3-carboxy-4-cyclohexyl-pyridine N-oxide (3.09 g, 0.014 mol), sodium cyanide (2.47 g, 0.05 mol) and triethylamine (7.08 g, 0.07 mol) in absolute dimethylformamide (50 ml), chlorotrimethylsilane (7.6 g, 0.07 mol) is added. The reaction mixture is then heated for 28 h at 85°. After cooling, the inorganic salts are filtered, washed with diethyl ether, and the filtrate is evaporated at 50° in vacuo. The dark residue is purified by chromatography on Florisil® (ethyl acetate/methanol 4:1) to yield 5-carboxy-2-cyano-4-cyclohexyl-pyridine; m.p. 225°-230°, Rf =0.55.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:12]=[C:11]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:10]([Br:20])=[CH:9][N:8]=1)(=O)=O.Cl.[OH:24][CH:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1.C(N(CC)CC)C>CN(C)C=O>[CH2:13]([C:11]1[C:10]([Br:20])=[CH:9][N:8]=[C:7]([N:28]2[CH2:29][CH2:30][CH:25]([OH:24])[CH2:26][CH2:27]2)[CH:12]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: OC1CCNCC1
Reactant: O=S(=O)(Oc1cc(Cc2ccccc2)c(Br)cn1)C(F)(F)F
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: OC1CCN(c2cc(Cc3ccccc3)c(Br)cn2)CC1
Reaction time: 3 h
Yield: 56 %

Procedure:
A mixture of 550 mg of 4-benzyl-5-bromo-2-pyridyl trifluoromethanesulfonate (Production Example 1), 600 mg of 4-hydroxypiperidine hydrochloride, 1 ml of triethylamine and 2 ml of N,N-dimethylformamide was heated under stirring for 3 hours in an oil bath kept at 100° C. in a nitrogen atmosphere. After cooling as it was, the reaction mixture was extracted with ethyl acetate/water. The organic phase was washed with water and brine, dried over anhydrous magnesium sulfate and evaporated. The residue was subjected to silica gel column chromatography and eluted with 50% ethyl acetate/hexane, to give 270 mg of the target compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[C:6]([F:8])[CH:7]=1.[Cl:12][CH:13](Cl)[C:14]([O:16][CH2:17][CH3:18])=[O:15].CC(C)([O-])C.[K+].Cl>CN(C=O)C>[Cl:12][CH:13]([C:7]1[C:2]([F:1])=[CH:3][C:4]([N+:9]([O-:11])=[O:10])=[CH:5][C:6]=1[F:8])[C:14]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: CCOC(=O)C(Cl)Cl
Reactant: O=[N+]([O-])c1cc(F)cc(F)c1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(Cl)c1c(F)cc([N+](=O)[O-])cc1F
Temperature: -25 °C
Reaction time: 0.25 h
Yield: 96.5 %

Procedure:
A solution of 3,5-difluoronitrobenzene (20 g,126 mmol) and ethyl dichloroacetate (15.8 ml, 129 mmol) in DMF (60 ml) was added to potassium t-butoxide (31.8 g, 283 mmol) in DMF (500 ml) at −25° C. over 30 minutes. The mixture was stirred for 15 minutes at −25° C. then poured on to a mixture of ice (600 g) and 2M hydrochloric acid (500 ml). The aqueous mixture was extracted with ethyl acetate, the combined extracts were washed with water and sodium hydrogen carbonate solution and dried (MgSO4) and the solvent removed by evaporation to give ethyl 2-chloro-2-(2,6-difluoro-4-nitrophenyl)ethanoate (34 g, 97%).
Reaction SMILES: [OH:1][C@@:2]1([CH2:18][CH2:19][CH3:20])[CH2:6][CH2:5][N:4](C(OCC2C=CC=CC=2)=O)[C@H:3]1[CH3:17]>[Pd].O>[CH3:17][C@H:3]1[C@@:2]([CH2:18][CH2:19][CH3:20])([OH:1])[CH2:6][CH2:5][NH:4]1
Reactant: CCC[C@]1(O)CCN(C(=O)OCc2ccccc2)[C@H]1C
Agent: [Pd]
Solvent: O
Product: CCC[C@]1(O)CCN[C@H]1C

Procedure:
By an operation in the same manner as in Reference Example 4 and using benzyl (2S,3S)-3-hydroxy-2-methyl-3-propylpyrrolidine-1-carboxylate (2.32 g) and 50% water containing-10% Pd/C (0.10 g), the title compound was obtained as a colorless solid (yield: 1.50 g, yield: 96%).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([C:12]([OH:14])=[O:13])=[CH:7]2.[CH3:15][N:16]1[CH:20]=[C:19](B2OC(C)(C)C(C)(C)O2)[CH:18]=[N:17]1>C(O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:15][N:16]1[CH:20]=[C:19]([C:2]2[CH:11]=[CH:10][CH:9]=[C:8]3[C:3]=2[CH:4]=[CH:5][C:6]([C:12]([OH:14])=[O:13])=[CH:7]3)[CH:18]=[N:17]1
Reactant: O=C(O)c1ccc2c(Br)cccc2c1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCO
Product: Cn1cc(-c2cccc3cc(C(=O)O)ccc23)cn1
Yield: 34 %

Procedure:
A mixture of 5-bromo-2-naphthoic acid (2.12 g, 8.44 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1.84 g, 8.86 mmol), and tetrakis(triphenylphosphine)palladium(0) (502 mg, 0.435 mmol) in a 250 mL round bottomed flask was evacuated and purged with nitrogen (in three cycles). Acetonitrile (40 mL) and 2M aqueous sodium carbonate (10 mL) were added to the mixture via syringe, and the mixture was heated under reflux under nitrogen for 22 hours. The reaction mixture was allowed to cool before the addition of 1M aqueous hydrochloric acid (30 mL) and it was then extracted with ethyl acetate (3×50 mL). The combined organic layers were dried (MgSO4), filtered, and concentrated in vacuo to provide a crude product (2.98 g after air drying). This crude material was dissolved in hot ethanol (150 mL) and filtered while hot to remove a yellow impurity (120 mg). The filtrate was concentrated in vacuo and the residue was recrystallised from dichloromethane (30 mL) to provide 5-(1-methyl-1H-pyrazol-4-yl)-2-naphthoic acid as a white solid (724 mg, 34%). A second crop of 5-(1-methyl-1H-pyrazol-4-yl)-2-naphthoic acid (527 mg, 25%) was obtained from the concentrated mother liquors by recrystallisation from dichloromethane (20 mL).
Reaction SMILES: [C:1]([O:4][C@H:5]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[C:7](=[CH:8][CH2:9][C@@H:10]3[C@@H:19]2[CH2:18][CH2:17][C@@:15]2([CH3:16])[C@H:11]3[CH2:12][CH2:13][C@@H:14]2[O:24][C:25](=[O:27])[CH3:26])[CH2:6]1)(=[O:3])[CH3:2].C(OC(=O)C)(=[O:30])C.[Cr]([O-])(OC(C)(C)C)(=O)=O.C(O)(=O)C(O)=O>C(O)(=O)C.C(Cl)(Cl)(Cl)Cl>[C:1]([O:4][C@H:5]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[C:7](=[CH:8][C:9](=[O:30])[C@@H:10]3[C@@H:19]2[CH2:18][CH2:17][C@@:15]2([CH3:16])[C@H:11]3[CH2:12][CH2:13][C@@H:14]2[O:24][C:25](=[O:27])[CH3:26])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: CC(=O)O[C@H]1CC[C@@]2(C)C(=CC[C@H]3[C@@H]4CC[C@H](OC(C)=O)[C@@]4(C)CC[C@@H]32)C1
Agent: CC(C)(C)O[Cr](=O)(=O)[O-]
Agent: O=C(O)C(=O)O
Solvent: CC(=O)O
Solvent: ClC(Cl)(Cl)Cl
Product: CC(=O)O[C@H]1CC[C@@]2(C)C(=CC(=O)[C@H]3[C@@H]4CC[C@H](OC(C)=O)[C@@]4(C)CC[C@@H]32)C1
Reaction time: 12 h
Yield: 61.66 %

Procedure:
A solution of 5-androstene-3β,17β-diol diacetate (5 g, 13.35 mmol) in a mixture of dry carbon tetrachloride (30 Ml), acetic anhydride (4.5 Ml) and glacial acetic acid (1.25 Ml) was treated while stirring with t-butyl chromate solution (35 Ml). The brown reaction mixture was brought to reflux temperature and further stirred for 12 h. The mixture was then cooled in an ice bath and treated in small portions with 10% oxalic acid solution (75 Ml). After adding a further quantity of solid oxalic acid (5.5 g), the reaction mixture was stirred for 2 h at room temperature. The organic phase was removed and the aqueous phase was extracted with carbon tetrachloride (4×50 Ml). The combined carbon tetrachloride extract was successively washed with 5% sodium carbonate solution (2×25 Ml), water and dried. Removal of solvent under reduced pressure gave a pale yellow solid, which was crystallized from methanol to afford the product 7-oxo-5-androstene-3β,17β-diol diacetate (3.2 g, 61.66%), mp 220-221° C. (lit 216-219° C.) [Singh. H., et al Indian J. Chem. 1969, 7, 1084-1087].