Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si]([O:18][C:19]1[CH:56]=[CH:55][C:22]([O:23][CH2:24][C@@H:25]([OH:54])[CH2:26][NH:27][CH2:28][CH2:29][C:30]2[CH:53]=[CH:52][C:33]([NH:34][CH:35]3[CH2:40][CH2:39][N:38]([C:41]([NH:43][CH2:44][C:45]4[CH:50]=[CH:49][CH:48]=[C:47]([F:51])[CH:46]=4)=[O:42])[CH2:37][CH2:36]3)=[CH:32][CH:31]=2)=[CH:21][CH:20]=1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1>C(Cl)(Cl)Cl.CO>[F:51][C:47]1[CH:46]=[C:45]([CH:50]=[CH:49][CH:48]=1)[CH2:44][NH:43][C:41]([N:38]1[CH2:37][CH2:36][CH:35]([NH:34][C:33]2[CH:32]=[CH:31][C:30]([CH2:29][CH2:28][NH:27][CH2:26][C@H:25]([OH:54])[CH2:24][O:23][C:22]3[CH:55]=[CH:56][C:19]([OH:18])=[CH:20][CH:21]=3)=[CH:53][CH:52]=2)[CH2:40][CH2:39]1)=[O:42]
Reactant: CC(C)(C)[Si](Oc1ccc(OC[C@@H](O)CNCCc2ccc(NC3CCN(C(=O)NCc4cccc(F)c4)CC3)cc2)cc1)(c1ccccc1)c1ccccc1
Solvent: ClC(Cl)Cl
Solvent: CO
Product: O=C(NCc1cccc(F)c1)N1CCC(Nc2ccc(CCNC[C@H](O)COc3ccc(O)cc3)cc2)CC1
Yield: 66.7 %

Procedure:
4-[4-(2-{[(2S)-3-(4-{[tert-Butyl(diphenyl)silyl]oxy}phenoxy)-2-hydroxy-propyl]amino)ethyl)anilino]-N-(3-fluorobenzyl)-1-piperidinecarboxamide (0.174 g, 0.225 mmol) was reacted according to Procedure H (eluant: 5:1 chloroform-methanol containing 1% ammonium hydroxide) to give the title compound (0.085 g, 0.15 mmol).
Reaction SMILES: O=S(Cl)[Cl:3].O=[C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:16]3[O:20][C:19]([CH:21]=[O:22])=[CH:18][CH:17]=3)[CH:14]=2)[N:9]=[CH:8][NH:7]1.CN(C=O)C.[ClH:28]>CC#N>[ClH:3].[Cl:28][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:16]3[O:20][C:19]([CH:21]=[O:22])=[CH:18][CH:17]=3)[CH:14]=2)[N:9]=[CH:8][N:7]=1
Reactant: O=S(Cl)Cl
Reactant: O=Cc1ccc(-c2ccc3nc[nH]c(=O)c3c2)o1
Agent: Cl
Solvent: CC#N
Solvent: CN(C)C=O
Product: O=Cc1ccc(-c2ccc3ncnc(Cl)c3c2)o1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Over a 1.5 hour period under an atmosphere of N2, SOCl2 (86.2 g) in MeCN (145 mL) was added dropwise into a mixture, that had been preheated at reflux for 0.5 h, of the compound of formula (IX) (29 g, 0.121 mol), MeCN (435 mL) and DMF (0.88 g) at reflux. The reaction was terminated when less than 2% (HPLC) of the compound of formula (IX) was remaining. If the reaction did not achieve complete reaction, extra SOCl2 was added. The mixture was cooled to about 25±5° C. (internal temperature), and was then filtered and washed with MeCN (58 mL) to give ca. 55 g of (Xa).HCl (moist with MeCN) with 82A % purity by HPLC. (Xa).HCl: 1H NMR (300 MHz, d6-DMSO): δ 9.68 (s, 1H), 9.17 (s, 1H), 8.57 (d, J=2.0 Hz, 1H), 8.46 (dd, J=8.6, 2.1 Hz, 1H), 8.02 (d, J=8.6 Hz, 1H), 7.74 (d, J=3.8 Hz, 1H), 7.60 (d, J=3.8 Hz, 1H). See FIG. 5 for the 1H NMR spectrum of (Xa).HCl; 13C NMR (75 MHz, d6-DMSO) δ 179.0, 159.6, 156.4, 152.9, 149.5, 141.0, 132.6, 129.2, 125.9, 123.2, 122.9, 122.7, 111.5.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][N:18]=2)[N:15]=[CH:14][CH:13]=[C:12]3[N:19]2[CH2:24][CH2:23][CH2:22][C@H:21]([NH:25]C(=O)OC(C)(C)C)[CH2:20]2)=[N:4][C:5](Cl)=[CH:6][CH:7]=1.[F:33][C:34]1[CH:39]=[CH:38][C:37](B(O)O)=[CH:36][CH:35]=1>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].C(Cl)Cl.COCCOC>[NH2:25][C@H:21]1[CH2:22][CH2:23][CH2:24][N:19]([C:12]2[C:11]3[C:16](=[CH:17][N:18]=[C:9]([C:3]4[C:2]([NH2:1])=[CH:7][CH:6]=[C:5]([C:37]5[CH:38]=[CH:39][C:34]([F:33])=[CH:35][CH:36]=5)[N:4]=4)[CH:10]=3)[N:15]=[CH:14][CH:13]=2)[CH2:20]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCN(c2ccnc3cnc(-c4nc(Cl)ccc4N)cc23)C1
Reactant: OB(O)c1ccc(F)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: COCCOC
Solvent: ClCCl
Product: Nc1ccc(-c2ccc(F)cc2)nc1-c1cc2c(N3CCC[C@H](N)C3)ccnc2cn1
Yield: 61 %

Procedure:
A solution of (S)-tert-butyl 1-(6-(3-amino-6-chloropyridin-2-yl)-1,7-naphthyridin-4-yl)piperidin-3-ylcarbamate (1.0 equiv.), 4-fluorophenylboronic acid (3.0 equiv.) and Pd(dppf)Cl2—CH2Cl2 (0.15 equiv.) in 3:1 DME/2M Na2CO3 was heated in a microwave at 120° C. for 20 minutes. Upon cooling, the solution was partitioned between EtOAc and Na2CO3(sat.) washed further with NaCl(sat.), dried over MgSO4, concentrated and purified by RP HPLC. Upon lyophilization, the Boc group was deprotected by treatment with 25% TFA/CH2Cl2, concentrated, purified by RP-HPLC and lyophilized to yield (S)-2-(4-(3-aminopiperidin-1-yl)-1,7-naphthyridin-6-yl)-6-(4-fluorophenyl)pyridin-3-amine (61%). LC/MS=415.2 (M+H), LC=2.32 min.
Reaction SMILES: [CH2:1]([O:3][P:4]([SH:8])[O:5][CH2:6][CH3:7])[CH3:2].CC[O-].[Na+].[CH2:13](Br)[CH:14]=[CH2:15]>C1C=CC=CC=1.C(O)C>[CH2:1]([O:3][P:4]([CH2:15][CH:14]=[CH2:13])(=[S:8])[O:5][CH2:6][CH3:7])[CH3:2]
Reactant: C=CCBr
Reactant: CCOP(S)OCC
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Solvent: c1ccccc1
Product: C=CCP(=S)(OCC)OCC
Temperature: 40 °C
Reaction time: 3 h

Procedure:
1 mole of thiophosphorous acid O,O-diethyl ester was dissolved in 600 ml of absolute benzene, and 1 mole of sodium ethylate, dissolved in absolute ethanol, was added at 0°-5° C., while cooling. 1.15 moles of allyl bromide were added dropwise to this mixture at 0°-5° C. and the mixture was stirred at 10° to 20° C. for a further 2 hours and at 40° C. for 3 hours. The NaBr which had separated out was filtered off and the filtrate was distilled.
Reaction SMILES: [F:1][C:2]([F:29])([S:25](F)(=[O:27])=[O:26])[C:3]([F:24])([F:23])[C:4]([F:22])([F:21])[C:5]([F:20])([F:19])[C:6]([F:18])([F:17])[C:7]([F:16])([F:15])[C:8]([F:14])([F:13])[C:9]([F:12])([F:11])[F:10].C[Si](C)(C)[O-:32].[Li+:35]>O1CCCC1>[F:1][C:2]([F:29])([S:25]([O-:32])(=[O:27])=[O:26])[C:3]([F:24])([F:23])[C:4]([F:22])([F:21])[C:5]([F:20])([F:19])[C:6]([F:18])([F:17])[C:7]([F:16])([F:15])[C:8]([F:14])([F:13])[C:9]([F:12])([F:11])[F:10].[Li+:35]
Reactant: C[Si](C)(C)[O-]
Reactant: O=S(=O)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Agent: [Li+]
Solvent: C1CCOC1
Product: O=S(=O)([O-])C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Yield: 55.7 %

Procedure:
The procedure of Example 1 was followed using perfluorooctanesulfonyl fluoride (11.8 g, 23.5 mmol), lithium trimethylsilanolate (2.25 g, 23.4 mmol), and dry tetrahydrofuran (150 mL). The product, lithium perfluorooctanesulfonate (6.6 g, 55% yield), was isolated as a white solid by concentrating the filtrate under vacuum: 19F NMR (tetrahydrofuran) δ -81.2 (t, J=8.5 Hz, CF3 --, 3F), -114.6 (m, --CF2CO2⊕, 2 F), -120.6 (m, --CF2, 2F), -121.7 (m, CF2, 6F), -122.7 (m, CF2, 2F), -126.2 ppm (m, CF3CF2, 2F).
Reaction SMILES: [CH2:1]([NH2:4])[CH:2]=[CH2:3].C(N(CC)CC)C.[Cl:12][C:13]([Cl:18])([Cl:17])[C:14](Cl)=[O:15]>C(Cl)Cl>[Cl:12][C:13]([Cl:18])([Cl:17])[C:14]([NH:4][CH2:1][CH:2]=[CH2:3])=[O:15]
Reactant: C=CCN
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CCNC(=O)C(Cl)(Cl)Cl
Temperature: 25 °C
Reaction time: 24 h
Yield: 95.4 %

Procedure:
To a stirred solution of allylamine (5 g, 88 mmol) and triethylamine (9.6 g, 95 mmol) in CH2Cl2 (200 mL) at -10° C. was added trichloroacetyl chloride (16.7 g, 92 mmol). The resulting solution was allowed to gradually warm to RT and stir for 24 h. The reaction solution was extracted with brine (satd., 100 mL) and dried (Na2SO4) to yield 17 g (96%) of the title compound as a white solid.
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[N:8]1([C:14]([C:16]2[CH:28]=[C:27]3[C:19]([C:20]4[CH:21]=[C:22](B5OC(C)(C)C(C)(C)O5)[CH:23]=[C:24]([C:29]([NH2:31])=[O:30])[C:25]=4[NH:26]3)=[CH:18][CH:17]=2)=[O:15])[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1.C([O-])([O-])=O.[Na+].[Na+].C1(C)C=CC=CC=1>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.CO>[N:8]1([C:14]([C:16]2[CH:28]=[C:27]3[C:19]([C:20]4[CH:21]=[C:22]([C:2]5[N:7]=[CH:6][CH:5]=[CH:4][N:3]=5)[CH:23]=[C:24]([C:29]([NH2:31])=[O:30])[C:25]=4[NH:26]3)=[CH:18][CH:17]=2)=[O:15])[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1
Reactant: CC1(C)OB(c2cc(C(N)=O)c3[nH]c4cc(C(=O)N5CCOCC5)ccc4c3c2)OC1(C)C
Reactant: Brc1ncccn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CO
Product: NC(=O)c1cc(-c2ncccn2)cc2c1[nH]c1cc(C(=O)N3CCOCC3)ccc12
Temperature: 100 °C

Procedure:
2-Bromopyrimidine (250 g, 1.572 mmol), 7-(morpholine-4-carbonyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-9H-carbazole-1-carboxamide 429A (140 mg, 0.125 mmol), Pd(Ph3P)4 (76 mg, 0.066 mmol) and Na2CO3 (2M) (0.8 mL, 1.600 mmol) were mixed with toluene (2 mL) and MeOH (1 mL) in a sealed microwave tube. The mixture was degassed and heated at 100° C. for 12 hrs. The mixture was concentrated and purified using preparative HPLC to give titled product. MS (ESI) m/z 402.16 (M+H)+. 1H NMR (DMSO-d6) δ ppm 11.76 (s, 1H), 9.35 (s, 1H), 9.01 (d, 1H, J=1.5), 8.95 (d, 2H, J=4.9), 8.43 (s, 1H), 8.34 (d, 1H, J=7.9), 7.82 (s, 1H), 7.58 (s, 1H), 7.45 (t, 1H, J=4.7), 7.26(dd, 1H, J=8.0, 1.5), 3.7-3.5 (bm, 8 H).
Reaction SMILES: [OH:1]O.[C:3]([C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH:15]([CH3:23])[CH2:16][N:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)=[CH:10][CH:9]=1)([CH2:6][CH3:7])([CH3:5])[CH3:4]>C(O)(C)C.[Pt]>[C:3]([C:8]1[CH:9]=[CH:10][C:11]([CH2:14][CH:15]([CH3:23])[CH2:16][N+:17]2([O-:1])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]2)=[CH:12][CH:13]=1)([CH2:6][CH3:7])([CH3:4])[CH3:5]
Reactant: CCC(C)(C)c1ccc(CC(C)CN2CCCCC2)cc1
Reactant: OO
Agent: [Pt]
Solvent: CC(C)O
Product: CCC(C)(C)c1ccc(CC(C)C[N+]2([O-])CCCCC2)cc1
Temperature: 40 °C
Reaction time: 24 h

Procedure:
7.2 g of 30% hydrogen peroxide are added dropwise at 40° C. to a solution of 5.8 g of 1-[3-(p-tert.amyl-phenyl)-2-methyl-propyl]-piperidine in 20 ml of isopropanol and this addition is repeated after 24 hours. After stirring at 40° C. for 60 hours, the mixture is cooled and the excess hydrogen peroxide is decomposed by addition of platinum sponge. The solution is filtered, the filtrate is evaporated, the residue is taken up in 50 ml of water and extracted with hexane. The aqueous solution is subsequently evaporated and the residue is dried in a high vacuum. There is obtained pure 1-[3-(p-tert.amyl-phenyl)-2-methyl-propyl]-piperidine-1-oxide; nD20 =1.5180.
Reaction SMILES: [C:1]([CH:6]1[C:11](=[O:12])[CH2:10][CH:9]([CH2:13][CH:14]([S:16]([CH2:18][CH3:19])=[O:17])[CH3:15])[CH2:8][C:7]1=[O:20])(=O)[CH2:2][CH2:3][CH3:4].[CH2:21]([O:24][NH2:25])[CH:22]=[CH2:23]>C(O)C>[CH2:21]([O:24][NH:25][C:1](=[C:6]1[C:11](=[O:12])[CH2:10][CH:9]([CH2:13][CH:14]([S:16]([CH2:18][CH3:19])=[O:17])[CH3:15])[CH2:8][C:7]1=[O:20])[CH2:2][CH2:3][CH3:4])[CH:22]=[CH2:23]
Reactant: CCCC(=O)C1C(=O)CC(CC(C)S(=O)CC)CC1=O
Reactant: C=CCON
Solvent: CCO
Product: C=CCONC(CCC)=C1C(=O)CC(CC(C)S(=O)CC)CC1=O
Temperature: 25 °C
Reaction time: 15 h
Yield: 67.6 %

Procedure:
6 g of 2-butyryl-5-(2-ethylsulfinylpropyl)-cyclohexane-1,3-dione was dissolved in 30 ml of ethanol. To the solution was added 1.6 g of allyloxyamine and the resulting solution was stirred at room temperature for 15 hours. After completion of the reaction, the reaction solution was treated as in Example 1 to obtain 4.8 g of the desired compound as colorless oily material.
Reaction SMILES: [BH4-].[Na+].[Br-].[CH2:4]([N+:11]1[CH:16]=[CH:15][C:14]([CH:17]([CH3:19])[CH3:18])=[CH:13][CH:12]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.O>CCO>[CH2:4]([N:11]1[CH2:12][CH:13]=[C:14]([CH:17]([CH3:19])[CH3:18])[CH2:15][CH2:16]1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: CC(C)c1cc[n+](Cc2ccccc2)cc1
Agent: [BH4-]
Agent: [Br-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CC(C)C1=CCN(Cc2ccccc2)CC1
Reaction time: 8 h
Yield: 85.2 %

Procedure:
Add sodium tetrahydroborate (1.8 g, 47.4 mmol) in portions to a solution of 1-benzyl-4-isopropyl-pyridin-1-ium bromide (11.1 g, 36.5 mmol) in EtOH (55 mL) at 0° C. Allow the reaction mixture to reach ambient temperature slowly and stir overnight. Add 10 mL of water and remove the organic solvent under vacuum. Add water and then adjust the pH with HCl (5M) to a pH of 1-2. Stir the mixture for 15 min and then add NaOH (2M) until the pH is 8-9. Extract the aqueous layer with EtOAc, combine the organic layers; and sequentially wash with NaOH (2M) then brine. Dry the organic over anhydrous sodium sulphate; filter; and concentrate the filtrate. Purify the compound by chromatography on a silica gel cartridge eluting with hexane:ethyl acetate (9:1, 7:3, 5:5, and then 100% ethyl acetate) to obtain the title compound as a pale yellow oil (6.7 g, 83%). MS (m/z): 216 (M+1).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[C:10]([OH:14])[CH:11]=[CH:12][CH:13]=2)[N:5]=[C:4]2[N:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[N:16]=[CH:17][C:3]=12.Cl.[C@H:25]12[CH2:31][C@H:28]([NH:29][CH2:30]1)[CH2:27][O:26]2.C(N(CC)CC)C>C(O)C>[C@H:25]12[CH2:31][C@H:28]([N:29]([C:2]3[N:7]=[C:6]([C:8]4[CH:9]=[C:10]([OH:14])[CH:11]=[CH:12][CH:13]=4)[N:5]=[C:4]4[N:15]([C:18]5[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=5)[N:16]=[CH:17][C:3]=34)[CH2:30]1)[CH2:27][O:26]2
Reactant: Oc1cccc(-c2nc(Br)c3cnn(-c4ccccc4)c3n2)c1
Reactant: C1O[C@@H]2CN[C@H]1C2
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: Oc1cccc(-c2nc(N3C[C@@H]4C[C@H]3CO4)c3cnn(-c4ccccc4)c3n2)c1
Temperature: 150 °C

Procedure:
A Smith process vial was charged with a suspension of 3-(4-bromo-1-phenyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)phenol (56 mg, 0.15 mmol) and (1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptane hydrochloride (22 mg, 0.16 mmol) in ethanol (4 mL). The suspension was treated with triethylamine (59 μL, 0.45 mmol) and was then heated in the microwave reactor for 15 minutes at 150° C. The reaction mixture was concentrated to dryness under reduced pressure, and the residue was purified by reverse-phase high performance liquid chromatography using a Phenomenex Prodigy 21 mm×250 mm column, running a gradient elution of 10% acetonitrile/90% of 0.1% aqueous trifluoroacetic acid to 75% acetonitrile to provide 3-{4-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl]-1-phenyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl}phenol. MS (ES+): 386.3 (M+H)+
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([Cl:12])[CH:9]=[C:8]2[C:3]=1[C:4]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:5][C:6]([C:13]([O:15]CC)=[O:14])=[N:7]2.[OH-].[Na+].Cl>CO>[C:13]([C:6]1[CH:5]=[C:4]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:3]2[C:8](=[CH:9][C:10]([Cl:12])=[CH:11][C:2]=2[Cl:1])[N:7]=1)([OH:15])=[O:14]
Reactant: CCOC(=O)c1cc(C(=O)OCC)c2c(Cl)cc(Cl)cc2n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCOC(=O)c1cc(C(=O)O)nc2cc(Cl)cc(Cl)c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.3 %

Procedure:
5,7-Dichloro-2,4-diethoxycarbonylquinoline (0.5 g) was dissolved in 60% aqueous methanol (70 ml) and sodium hydroxide (0.42 g, 5 molar equivalents) added. The reaction mixture was stirred at room temperature for 1 h then heated under reflux for 4 h and the methanol was removed by rotary evaporation. The residue was diluted to give a volume of 50 ml, acidified to pH 1 with concentrated hydrochloric acid, and extracted with diethyl ether (3×50 ml). The organic layers were combined, dried (Na2SO4), filtered and the solvent was removed by evaporation to give a residue which was purified by chromatography on silica gel with 10% methanol and 1% acetic acid in dichloromethane as eluent to give, as a colourless solid, 2-carboxy-5,7-dichloro-4-ethoxycarbonyl-quinoline (0.35 g, m.p. 152°-154° C.); δ (360 MHz, DMSO) 1.35 (3H, t, J=7.1 Hz, CH3CH2), 4.45 (2H, q, J=7.1 Hz, CH3CH2), 8.16 (1H, d, J=2.0 Hz, 6-H or 8-H), 8.18 (1H, s, 3-H), 8.34 (1H, d, J=2.0 Hz, 6-H or 8-H); m/e 313 (M+), 196 (100%, M-CO2H and CO2Et); Found: C, 49.55; H, 2.93; N, 4.44. C13H9Cl2NO4 requires C, 49.71; H, 2.89; N, 4.46%.
Reaction SMILES: [F:1][CH:2]([F:22])[C:3]1[C:8]([C:9]([O:11][CH3:12])=[O:10])=[C:7]([CH2:13][CH:14]([CH3:16])[CH3:15])[C:6]([SH:17])=[C:5]([C:18]([F:21])([F:20])[F:19])[N:4]=1.[C:23]([C:27]1[CH:32]=[CH:31][C:30]([SH:33])=[CH:29][CH:28]=1)([CH3:26])([CH3:25])[CH3:24].BrBr.O>C(O)(=O)C>[C:23]([C:27]1[CH:28]=[CH:29][C:30]([S:33][S:17][C:6]2[C:7]([CH2:13][CH:14]([CH3:16])[CH3:15])=[C:8]([C:9]([O:11][CH3:12])=[O:10])[C:3]([CH:2]([F:1])[F:22])=[N:4][C:5]=2[C:18]([F:21])([F:20])[F:19])=[CH:31][CH:32]=1)([CH3:26])([CH3:24])[CH3:25]
Reactant: COC(=O)c1c(C(F)F)nc(C(F)(F)F)c(S)c1CC(C)C
Reactant: CC(C)(C)c1ccc(S)cc1
Agent: BrBr
Solvent: CC(=O)O
Solvent: O
Product: COC(=O)c1c(C(F)F)nc(C(F)(F)F)c(SSc2ccc(C(C)(C)C)cc2)c1CC(C)C
Reaction time: 1 h

Procedure:
To a mixture of 100 mg of compound 7 and 48.6 mg of 4-t-butylbenzenethiol in 5 ml of acetic acid was added 23 mg of bromine. The reaction mixture was stirred for 1 h, poured into water and extracted with ether. The ether extract was washed with saturated sodium bicarbonate, dried over MgSO4 and concentrated in vacuo. The residue was purified by preparative TLC (9:1 Hexane: EtOAc) on silica gel to give the desired product.
Reaction SMILES: C(OC([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][C@H:16]([N:21]1[C:33]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[C:27]2[C:22]1=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:17]([O:19][CH3:20])=[O:18])=O)C1C=CC=CC=1.C1COCC1>[Pd].C(O)(C)C>[CH3:20][O:19][C:17](=[O:18])[C@@H:16]([N:21]1[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:27]=2[C:28]2[C:33]1=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:15][CH2:14][CH2:13][CH2:12][NH2:11]
Reactant: COC(=O)[C@H](CCCCNC(=O)OCc1ccccc1)n1c2ccccc2c2ccccc21
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CC(C)O
Product: COC(=O)[C@H](CCCCN)n1c2ccccc2c2ccccc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 83.5 %

Procedure:
10% Pd/C (0.100 g) was added in one portion to a stiffed solution of (S)-Methyl 6-benzyloxycarbonylamino-2-carbazol-9-yl-hexanoate 3 (1.06 g, 2.47 mmol) in a (1:1) mixture of THF (10 mL) and isopropanol (10 mL) under nitrogen atmosphere. The reaction mixture was subsequently stirred under hydrogen atmosphere for 4 h at room temperature. The reaction mixture was filtrated through a celite pad and the filtrate was evaporated under reduced pressure to get (S)-6-amino-2-carbazol-9-yl-hexanoic methyl ester 4 (0.640 g, 85%) as off-white solid.
Reaction SMILES: [F:1][C:2]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:3]=1[C:4]([CH:6]1[CH2:11][CH2:10][N:9](C(=O)C)[CH2:8][CH2:7]1)=[O:5].[ClH:20]>C(O)(=O)C>[ClH:20].[F:1][C:2]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:3]=1[C:4]([CH:6]1[CH2:7][CH2:8][NH:9][CH2:10][CH2:11]1)=[O:5]
Reactant: CC(=O)N1CCC(C(=O)c2ccc(F)cc2F)CC1
Agent: Cl
Solvent: CC(=O)O
Product: O=C(c1ccc(F)cc1F)C1CCNCC1
Yield: 83 %

Procedure:
The preceding ketone (40 g, 0.15 mol) was added to a mixture of 125 ml concentrated HCl and 125 ml acetic acid and refluxed for 16 hours, cooled, and concentrated in vacuo. The white residue was triturated with hot isopropanol, filtered, washed with Et2O and dried to give 32.3 g (83%) of 4-(2,4-difluorobenzoyl)piperidine hydrochloride (III), m.p. 215°-216° C.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][S:5]([N:8]([CH2:16][CH2:17][CH2:18][CH2:19][O:20][C:21]1[CH:22]=[C:23]2[C:28](=[CH:29][CH:30]=1)[NH:27][C:26](=[O:31])[CH:25]=[CH:24]2)[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)(=[O:7])=[O:6].[NH:32]1[CH:36]=[N:35][CH:34]=[N:33]1>O1CCOCC1>[N:32]1([CH2:2][CH2:3][CH2:4][S:5]([N:8]([CH2:16][CH2:17][CH2:18][CH2:19][O:20][C:21]2[CH:22]=[C:23]3[C:28](=[CH:29][CH:30]=2)[NH:27][C:26](=[O:31])[CH:25]=[CH:24]3)[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)(=[O:7])=[O:6])[CH:36]=[N:35][CH:34]=[N:33]1
Reactant: c1nc[nH]n1
Reactant: O=c1ccc2cc(OCCCCN(Cc3ccccc3)S(=O)(=O)CCCCl)ccc2[nH]1
Solvent: C1COCCO1
Product: O=c1ccc2cc(OCCCCN(Cc3ccccc3)S(=O)(=O)CCCn3cncn3)ccc2[nH]1
Yield: 30.5 %

Procedure:
1.0 g of 6-{4-[N-(3-chloropropylsulfonyl)-N-benzylamino]butoxy}carbostyril and 600 mg of 1,2,4-triazole were stirred at 140° C. for 3 hours. The reaction mixture was diluted with dioxane. The resulting crystals were collected by filtration and purified by a column chromatography (eluant: 3% methanol/chloroform). The purified crystals were recrystallized from ethyl acetate to obtain 327 mg of 6-[4-{N-[3-(1,2,4-triazol-1-yl)propylsulfonyl]-N-benzylamino}butoxy]-carbostyril.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:14]#[N:15])=[CH:10][CH:11]=[CH:12][CH:13]=2)=[CH:4][CH:3]=1.[N-:16]=[N+:17]=[N-:18].[Na+].Cl.C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:14]2[NH:18][N:17]=[N:16][N:15]=2)=[CH:6][CH:7]=1
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1ccc(-c2ccccc2C#N)cc1
Agent: Cl
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Yield: 92 %

Procedure:
Into the same device as used in Example 1 were placed 9.66 g (0.050 mole) of 4'-methylbiphenyl-2-carbonitrile, 6.50 g (0.100 mole) of sodium azide, 13.77 g (0.100 mole) of triethylamine hydrochloride and 96.6 ml of toluene. The mixture was reacted for 48 hours in the same manner as in Example 1, giving 10.85 g (0.046 mole) of 5-(4'-methylbiphenyl-2-yl)-1H-tetrazole (yield 91.9% based on 4'-methylbiphenyl-2-carbonitrile). The reaction is illustrated below with chemical formulas: ##STR26##
Reaction SMILES: [C:1]([C@@H:3]([OH:18])[C:4]1[CH:9]=[CH:8][C:7]([F:10])=[C:6]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:5]=1)#[N:2].[CH3:19][C:20]1([CH3:35])[C@@H:22](/[CH:23]=[CH:24]\[C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[C@H:21]1[C:32](O)=[O:33].C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH3:19][C:20]1([CH3:35])[C@@H:22](/[CH:23]=[CH:24]\[C:25](=[O:31])[O:26][C:27]([CH3:28])([CH3:29])[CH3:30])[C@H:21]1[C:32]([O:18][C@H:3]([C:1]#[N:2])[C:4]1[CH:9]=[CH:8][C:7]([F:10])=[C:6]([O:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:5]=1)=[O:33]
Reactant: CC(C)(C)OC(=O)/C=C\[C@H]1[C@@H](C(=O)O)C1(C)C
Reactant: N#C[C@@H](O)c1ccc(F)c(Oc2ccccc2)c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)/C=C\[C@H]1[C@@H](C(=O)O[C@H](C#N)c2ccc(F)c(Oc3ccccc3)c2)C1(C)C
Temperature: -5 °C
Yield: 87.3 %

Procedure:
A mixture of 310 g of (S)α-cyano-3-phenoxy-4-fluoro-benzyl alcohol, 310 g of (1R,cis,Z)2,2-dimethyl-3-[3-oxo-3-tert.-butoxy-1-propenyl]-cyclopropane-carboxylic acid and 1.55 liters of methylene chloride was stirred until total dissolution occured and the mixture was cooled to -5° C. and mixed with a solution of 263.5 g of dicyclohexylcarbodiimide, 3.1 g of 4-dimethylamino-pyridine and 530 ml of methylene chloride. The mixture was stirred at -5° C. for one hour and at room temperature for 3 hours and was vacuum filtered. The filtrate was washed with N hydrochloric acid and then with water, dried and evaporated to dryness under reduced pressure. The residue in 1.185 liters of isopropanol, 80 ml of water and 72 ml of triethylamine was stirred for 36 hours and was vacuum filtered. The product was washed with isopropanol to obtain 518 g of (S)α-cyano-3-phenoxy-4-fluoro-benzyl(1R,cis,Z)2,2-dimethyl-3-[3-oxo-3 -tert.-butoxy-1-propenyl]-cyclopropane-carboxylate melting at 114° C.