Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][CH2:6][CH2:5][NH:4][C@H:3]1[C:8]([OH:10])=[O:9].[OH-].[Na+].[C:13](Cl)([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14]>O1CCOCC1>[CH2:16]([O:15][C:13]([N:4]1[CH2:5][CH2:6][CH2:7][C@H:2]([CH3:1])[C@@H:3]1[C:8]([OH:10])=[O:9])=[O:14])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: C[C@H]1CCCN[C@H]1C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: C[C@H]1CCCN(C(=O)OCc2ccccc2)[C@H]1C(=O)O
Reaction time: 18 h

Procedure:
(+/−)-Cis-3-methylpiperidine-2-carboxylic acid (10.4 g, 72.9 mmol) in 1,4-dioxane (200 mL) and 1 N NaOH (218 mL, 219 mmol) was treated with CBzCl (15.4 mL, 109 mmol) and stirred for 18 h. The mixture concentrated and the resulting solid was suspended in EtOAc (200 mL) and the mixture was filtered. The solids were washed with EtOAc (3 50 mL) and the solution was dried over MgSO4. The solution was concentrated to afford (+/−)-cis-1-(benzyloxycarbonyl)-3-methylpiperidine-2-carboxylic acid, which was used without further purification.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([F:8])=[CH:4][N:3]=1.[CH3:9][C:10]1[CH:11]=[C:12]([CH:14]=[C:15]([C:17]2[S:21][CH:20]=[N:19][CH:18]=2)[CH:16]=1)[NH2:13].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C(=O)([O-])[O-].[Cs+].[Cs+]>>[F:8][C:5]1[CH:4]=[N:3][C:2]([NH:13][C:12]2[CH:14]=[C:15]([C:17]3[S:21][CH:20]=[N:19][CH:18]=3)[CH:16]=[C:10]([CH3:9])[CH:11]=2)=[N:7][CH:6]=1
Reactant: Fc1cnc(Cl)nc1
Reactant: Cc1cc(N)cc(-c2cncs2)c1
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: Cc1cc(Nc2ncc(F)cn2)cc(-c2cncs2)c1
Temperature: 100 °C
Yield: 92.4 %

Procedure:
2-Chloro-5-fluoropyrimidine (0.443 ml, 3.58 mmol), 3-methyl-5-(1,3-thiazol-5-yl)aniline (682 mg, 3.58 mmol), PdOAc2 (80 mg, 0.358 mmol), Xantphos (311 mg, 0.538 mmol), and cesium carbonate (2336 mg, 7.17 mmol) were combined in a flask and degassed with Argon. Dioxane (12 mL) was added and the mixture was degassed with Argon for 5 min. The mixture was then heated to 100° C. for 2 h. The reaction was cooled to room temperature, diluted with brine and EtOAc. The layers were separated and the aqueous portion re-extracted with EtOAc. The combined organics were dried over Na2SO4, filtered and concentrated in vacuo. Purification via silica gel flash chromatography (0-40% EtOAc:CH2Cl2) afforded 5-fluoro-N-[3-methyl-5-(1,3-thiazol-5-yl)phenyl]pyrimidin-2-amine (947 mg, 92%) as a beige solid. MS ESI: [M+H]+ m/z 287. rhSYK activity=++.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([C:13]3[CH:14]=[C:15]([C:19]([O:21][CH3:22])=[S:20])[S:16][C:17]=3[CH3:18])[S:11][CH:12]=2)=[CH:4][CH:3]=1.CN1CCOCC1.CN(C1C=CC=CN=1)C.[C:39]1([S:45](Cl)(=[O:47])=[O:46])[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>ClCCl.CO>[C:39]1([S:45]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([C:8]3[N:9]=[C:10]([C:13]4[CH:14]=[C:15]([C:19]([O:21][CH3:22])=[S:20])[S:16][C:17]=4[CH3:18])[S:11][CH:12]=3)=[CH:4][CH:3]=2)(=[O:47])=[O:46])[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1
Reactant: COC(=S)c1cc(-c2nc(-c3ccc(N)cc3)cs2)c(C)s1
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Solvent: CO
Solvent: CN1CCOCC1
Product: COC(=S)c1cc(-c2nc(-c3ccc(NS(=O)(=O)c4ccccc4)cc3)cs2)c(C)s1
Temperature: 25 °C
Reaction time: 24 h
Yield: 32.3 %

Procedure:
Methyl 4-(4-(4-aminophenyl)(1,3-thiazol-2-yl))-5-methylthiothiophene-2-carboxylate (100 mg, 0.28 mmol) was dissolved in dry dichloromethane (10 mL). To this, N-methyl morpholine (46 μL, 0.42 mmol) and dimethylaminopyridine (3.4 mg, 0.028 mmol) were added, the mixture was cooled on an ice bath, and benzenesulfonyl chloride 35 μL, 0.28 mmol) was added dropwise. The mixture was then stirred for 24 h at room temperature. Workup was carried out as in Example 134, step (c). Trituration with dichloromethane and methanol gave methyl 4-(4-{4-[(phenylsulfonyl)amino]phenyl}(1,3-thiazol-2-yl))-5-methylthiothiophene-2-carboxylate (44 mg, 31%) as a crystalline solid. 1H-NMR (DMSO-d6; 300 MHz) δ10.46 (s, 1H), 8.19 (s, 1H), 8.05 (s, 1H), 7.91 and 7.19 (AB quartet, 2H, J=8.7 Hz), 7.81 (m, 2H), 7.64-7.54 (m, 3H) 3.85 (s, 3H), 2.74 (s, 3H). Mass spectrum (MALDI-TOF, CHCA matrix, m/z): Calcd. for C22H18N2O4S4 504.2 (M+H), found 504.1
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:11]2[C:12]([O:16][CH3:17])=[N:13][CH:14]=[CH:15][C:10]=2[N:9]([CH:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)[N:8]=1)(=O)=O.CC1(C)C(C)(C)OB([C:33]2[CH:34]=[C:35]([CH2:39][C:40]#[N:41])[CH:36]=[CH:37][CH:38]=2)O1.C(=O)([O-])[O-].[Na+].[Na+].O>COCCOC.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>[CH:18]1([N:9]2[C:10]3[CH:15]=[CH:14][N:13]=[C:12]([O:16][CH3:17])[C:11]=3[C:7]([C:33]3[CH:34]=[C:35]([CH2:39][C:40]#[N:41])[CH:36]=[CH:37][CH:38]=3)=[N:8]2)[CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: CC1(C)OB(c2cccc(CC#N)c2)OC1(C)C
Reactant: COc1nccc2c1c(OS(=O)(=O)C(F)(F)F)nn2C1CCCC1
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: O
Solvent: COCCOC
Product: COc1nccc2c1c(-c1cccc(CC#N)c1)nn2C1CCCC1
Yield: 87.2 %

Procedure:
A solution of 1-cyclopentyl-4-methoxy-1H-pyrazolo[4,3-c]pyridin-3-yl trifluoromethanesulfonate (160 mg) obtained in Step C of Example 12, (3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetonitrile (160 mg), tetrakis(triphenylphosphine)palladium(0) (50.6 mg) and 2M aqueous sodium carbonate solution (1.10 mL) in DME (10 mL) was heated overnight with reflux under nitrogen atmosphere. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (127 mg).
Reaction SMILES: C1C=CC=CC=1.[Cl:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[C:9]=1[CH:15]1[NH:19][CH2:18][CH2:17][S:16]1.[Cl:20][CH2:21][C:22](Cl)=[O:23]>C(N(CC)CC)C>[Cl:14][C:10]1[CH:11]=[CH:12][CH:13]=[C:8]([Cl:7])[C:9]=1[CH:15]1[N:19]([C:22](=[O:23])[CH2:21][Cl:20])[CH2:18][CH2:17][S:16]1
Reactant: O=C(Cl)CCl
Reactant: Clc1cccc(Cl)c1C1NCCS1
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: O=C(CCl)N1CCSC1c1c(Cl)cccc1Cl
Reaction time: 0.5 h

Procedure:
Twenty-three and five tenths ml. of a benzene solution containing 5.9 g. of 2(2',6'-dichlorophenyl) thiazolidine was combined with 25 ml. of benzene and 2.8 g. of chloroacetyl chloride and the mixture stirred in an ice bath, while 2.6 g. of triethylamine was added dropwise. After standing for about 30 minutes the mixture was washed with water, separated, dried over magnesium sulfate and the benzene stripped off under vacuum. There was obtained a yield of 8 g. of an oil, the title compound, ND30 = 1.6041.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:29]([F:32])([F:31])[F:30])[O:13][N:12]=[C:11]([C:14]3[CH:27]=[CH:26][C:17]([C:18]([NH:20][C:21]([NH:23][CH2:24][CH3:25])=[O:22])=[O:19])=[C:16]([CH3:28])[CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.C[Si](C)(C)N[Si](C)(C)C.[Li].Cl[C:44]([O:46][CH3:47])=[O:45]>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:29]([F:30])([F:32])[F:31])[O:13][N:12]=[C:11]([C:14]3[CH:27]=[CH:26][C:17]([C:18]([NH:20][C:21]([N:23]([CH2:24][CH3:25])[C:44]([O:46][CH3:47])=[O:45])=[O:22])=[O:19])=[C:16]([CH3:28])[CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: CCNC(=O)NC(=O)c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1C
Reactant: COC(=O)Cl
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: [Li]
Solvent: C1CCOC1
Product: CCN(C(=O)NC(=O)c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1C)C(=O)OC
Temperature: 25 °C
Yield: 51.8 %

Procedure:
In a solution of 0.50 g of N-[4-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-3-yl]-2-methyl benzoyl]-N′-ethyl urea synthesized similarly to Synthetic Example 26 in 4 mL of tetrahydrofuran, 4 mL of 1M tetrahydrofuran solution of lithium hexamethyl disilazane was added at −78° C. with stirring, and stirred at the same temperature for 30 minutes. Then, 0.12 g of methyl chloroformate was added in the reaction mixture at −78° C. with stirring. After the completion of the addition dropwise, it was continued to stir further for 18 hours while the temperature was slowly raised to room temperature. After the completion of the reaction, 30 mL of ice water was added, and extracted with ethyl acetate (30 mL×2). The organic phase was dehydrated with and dried over saturated sodium chloride aqueous solution and anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified with silica gel column chromatography that was eluated with ethyl acetate-hexane (gradient of 0:1 to 1:2) to obtain 0.29 g of the aimed product as colorless resinous substance.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([O:6][CH3:7])=[O:5].C(N(CC)CC)C.[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1.O>C(Cl)Cl>[CH3:15][O:16][C:17]1[CH:18]=[CH:19][C:20]([S:23]([NH:2][CH2:3][C:4]([O:6][CH3:7])=[O:5])(=[O:25])=[O:24])=[CH:21][CH:22]=1
Reactant: COC(=O)CN
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: COC(=O)CNS(=O)(=O)c1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.9 %

Procedure:
To a mixture of 12.5 g (0.1 mol) of glycine, methyl ester hydrochloride in 120 ml of CH2Cl2, cooled in an ice bath was added 41.7 ml (0.3 mol) of triethylamine, followed by the dropwise addition of a solution of 20.65 g (0.1 mol) of 4-methoxy-benzenesulfonyl chloride in 40 ml of CH2Cl2. The mixture was stirred at room temperature overnight and poured into water. The organic layer was separated and washed with 2 N citric acid, H2O, 1 N NaHCO3, brine and dried with Na2SO4. The solvent was removed under vacuum to give 24.6 g of residue which was triturated with ethyl acetate to give 19.9 g of crystals, m.p. 59°-61° C. Anal. for C10H13NSO5: Calc'd: C, 46.3; H, 5.1; N, 5.4; Found: C, 46.2; H, 5.0; N, 5.2.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:5]=[C:4]([C:14]([OH:16])=[O:15])[CH:3]=1.[S:17]1[CH:21]=[CH:20][C:19](B(O)O)=[CH:18]1>>[C:8]1([C:6]2[N:5]=[C:4]([C:14]([OH:16])=[O:15])[CH:3]=[C:2]([C:19]3[CH:20]=[CH:21][S:17][CH:18]=3)[N:7]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: OB(O)c1ccsc1
Reactant: O=C(O)c1cc(Cl)nc(-c2ccccc2)n1
Product: O=C(O)c1cc(-c2ccsc2)nc(-c2ccccc2)n1

Procedure:
This compound was prepared using a method analogous to that of Example 32, step 32.1, 6-chloro-2-phenyl-pyrimidine-4-carboxylic acid replacing intermediate 14.1 and thiophene-3-boronic acid replacing phenylboronic acid. The crude was however crystallized (EtOH/H20 2/1). LC-MS (A): tR=1.03 min; [M+H]+: 283.03.
Reaction SMILES: [C:1]([O:6][CH2:7][CH2:8][CH2:9]O)(=[O:5])[C:2]([CH3:4])=[CH2:3].[Na].C([O:24]S([O-])(=O)=O)CCCCCCCCCCC.S(OOS([O-])(=O)=O)([O-])(=O)=O.[K+].[K+]>O>[CH3:9][CH:8]([OH:24])[CH2:7][O:6][C:1]([C:2]([CH3:4])=[CH2:3])=[O:5]
Reactant: C=C(C)C(=O)OCCCO
Reactant: CCCCCCCCCCCCOS(=O)(=O)[O-]
Agent: O=S(=O)([O-])OOS(=O)(=O)[O-]
Agent: [K+]
Agent: [Na]
Solvent: O
Product: C=C(C)C(=O)OCC(C)O
Reaction time: 12 h

Procedure:
A 150 mL media bottle equipped with a stir bar was charged with 2.532 g (17.5 mmol) of hydroxypropyl methacrylate (HPMA) monomer, 52.73 mg (0.266 mmol) of ethylene glycol dimethacrylate(EGDM) crosslinker, 107.6 mg (0.3730 mmol) sodium-dodecylsulfate (SDS), and 118 mL of nitrogen degassed Milli-Q H2O. The bottle was closed and stirred to form a clear solution. In a separate vial, 83 mg of K2S2O8 was dissolved into 2 mL of Milli-Q H2O and added to the media bottle while stirring. The media bottle with clear solution was transferred into a 40° C. water bath and held at constant temperature for 12 hours. The resulting suspension of hydrogel nanoparticles had an opalescent blue color. The particles were analyzed by laser light scattering and found to have an average particle size of 21.3 nm and a size range from 14 nm to 41 nm. The suspension had approximately 1% solid polymer by mass. To date, the suspension of hydrogel nanoparticles resisted flocculation or aggregation for two years at room temperature.
Reaction SMILES: Cl[C:2]1[C:21]([C:22]2[N:26](C3CCCCO3)[N:25]=[CH:24][CH:23]=2)=[CH:20][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]([Cl:19])([F:18])[F:17])=[CH:11][CH:10]=2)=[O:7])=[CH:4][N:3]=1.[F:33][C:34]1([CH2:39][NH2:40])[CH2:38][CH2:37][NH:36][CH2:35]1>>[NH2:40][CH2:39][C:34]1([F:33])[CH2:38][CH2:37][N:36]([C:2]2[C:21]([C:22]3[NH:26][N:25]=[CH:24][CH:23]=3)=[CH:20][C:5]([C:6]([NH:8][C:9]3[CH:14]=[CH:13][C:12]([O:15][C:16]([Cl:19])([F:18])[F:17])=[CH:11][CH:10]=3)=[O:7])=[CH:4][N:3]=2)[CH2:35]1
Reactant: NCC1(F)CCNC1
Reactant: O=C(Nc1ccc(OC(F)(F)Cl)cc1)c1cnc(Cl)c(-c2ccnn2C2CCCCO2)c1
Product: NCC1(F)CCN(c2ncc(C(=O)Nc3ccc(OC(F)(F)Cl)cc3)cc2-c2ccn[nH]2)C1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 33 using 6-chloro-N-(4-(chlorodifluoromethoxy)phenyl)-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)nicotinamide (Stage 48.2) and (3-fluoropyrrolidin-3-yl)methanamine to afford an off-white powder. HPLC (Condition 4) tR=4.3 min, UPLC-MS (Condition 3) tR=0.80 min, m/z=481 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.92-2.10 (m, 2H) 3.03 (d, J=19.94 Hz, 2H) 3.11-3.67 (m, 6H) 6.41 (br. s, 1H) 7.31 (d, J=8.60 Hz, 2H) 7.79-7.91 (m, 3H) 8.08 (d, J=1.56 Hz, 1H) 8.73 (br. s, 1H) 10.23 (s, 1H) 12.90-13.16 (m, 1H).
Reaction SMILES: C([O:3][C:4](=[O:25])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][N:11]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([CH:23]=C)=[CH:19][CH:18]=1)[S:12]([CH3:15])(=[O:14])=[O:13])C.C[N+]1([O-])CC[O:30]CC1>O1CCOCC1.O.CCOC(C)=O.[Os](=O)(=O)(=O)=O>[CH:23]([C:20]1[CH:21]=[CH:22][C:17]([CH2:16][N:11]([S:12]([CH3:15])(=[O:14])=[O:13])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][C:4]([OH:3])=[O:25])=[CH:18][CH:19]=1)=[O:30]
Reactant: C[N+]1([O-])CCOCC1
Reactant: C=Cc1ccc(CN(CCCCCCC(=O)OCC)S(C)(=O)=O)cc1
Agent: O=[Os](=O)(=O)=O
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CS(=O)(=O)N(CCCCCCC(=O)O)Cc1ccc(C=O)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.7 %

Procedure:
A solution of ethyl-7-[(4-vinyl-benzyl)-methanesulfonyl-amino]-heptanoate (2.2 g, 6.0 mmol) in dioxane (45 mL) was added to a solution of N-methylmorpholine N-oxide (1.47 g, 12.5 mmol) in water (45 mL). Osmium tetroxide (4.6 mL, 2.5 wt % in 2-methyl-2-propanol) was added and the mixture was stirred at room temperature for 1 h. The reaction was quenched with 1N HCl (50 mL) and the aqueous solution was extracted with CH2Cl2. The organic layer was washed with water (1×) followed by brine (1×), dried over MgSO4, filtered, and concentrated in vacuo. The residue was dissolved in 35% aqueous THF (100 mL) and NaIO4 (1.41 g, 6.59 mmol) was added. The mixture was stirred at room temperature for 2 h and was diluted with EtOAc and water. The organic solution was washed with water (1×) followed by brine (1×), dried over MgSO4, filtered, and concentrated in vacuo to afford the title compound (1.9 g) which was used without further purification. 1H NMR (400 MHz, CDCl3) δ 10.0 (s, 1H), 7.82–7.90 (d, 1H), 7.50–7.59 (d, 2H), 5.30 (s, 2H), 4.45 (s, 2H), 4.05–4.18 (m, 2H), 3.12–3.22 (m, 2H), 2.86 (s, 3H), 2.19–2.30 (m, 2H), 1.42–1.62 (m, 6H), 1.18–1.30 (m, 3H); MS 387 (M+18).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[C:11]3[CH:26]=[CH:25][CH:24]=[CH:23][C:12]=3[S:13][C:14]=2[C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)=[O:9])=[CH:4][CH:3]=1.Cl.Cl[CH2:29][CH2:30][N:31]1[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1>>[N:31]1([CH2:30][CH2:29][O:1][C:2]2[CH:3]=[CH:4][C:5]([C:8]([C:10]3[C:11]4[CH:26]=[CH:25][CH:24]=[CH:23][C:12]=4[S:13][C:14]=3[C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)=[O:9])=[CH:6][CH:7]=2)[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1
Reactant: ClCCN1CCCCC1
Reactant: COc1ccc(-c2sc3ccccc3c2C(=O)c2ccc(O)cc2)cc1
Agent: Cl
Product: COc1ccc(-c2sc3ccccc3c2C(=O)c2ccc(OCCN3CCCCC3)cc2)cc1
Yield: 81 %

Procedure:
The title compound was prepared using 2-(4-methoxyphenyl)benzo[b]thiophen-3-yl 4-hydroxyphenyl ketone and 1-(2-chloroethyl)piperidine hydrochloride in 81% yield by essentially following the same procedures detailed in Example 24, Part B.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([N:15]1[CH2:20][CH2:19][N:18]([C:21]([C:23]3[CH:31]=[CH:30][C:26]([C:27]([NH2:29])=[NH:28])=[CH:25][C:24]=3C)=[O:22])[CH2:17][CH2:16]1)(=[O:14])=[O:13])[CH:6]=[CH:5]2.Cl[C:34]([O:36][CH3:37])=[O:35]>ClCCl>[CH3:37][O:36][C:34](=[O:35])[NH:29][C:27](=[NH:28])[C:26]1[CH:25]=[CH:24][C:23]([C:21]([N:18]2[CH2:17][CH2:16][N:15]([S:12]([C:7]3[CH:6]=[CH:5][C:4]4[C:9](=[CH:10][CH:11]=[C:2]([Cl:1])[CH:3]=4)[CH:8]=3)(=[O:13])=[O:14])[CH2:20][CH2:19]2)=[O:22])=[CH:31][CH:30]=1
Reactant: Cc1cc(C(=N)N)ccc1C(=O)N1CCN(S(=O)(=O)c2ccc3cc(Cl)ccc3c2)CC1
Reactant: COC(=O)Cl
Solvent: ClCCl
Product: COC(=O)NC(=N)c1ccc(C(=O)N2CCN(S(=O)(=O)c3ccc4cc(Cl)ccc4c3)CC2)cc1

Procedure:
By reaction of 4-[4-(6-chloro-2-naphthylsulphonyl)piperazine-1-carbonyl]-3-methylbenzamidine with methyl chloroformate in dichloromethane, the compound methyl(imino-{4-[4- (6-chloro-2-naphthylsulphonyl)piperazine-1-carbonyl]phenyl}methyl)carbamate is obtained after customary work-up
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][C:17](Br)=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([Sn](CCCC)(CCCC)[C:26]1[N:31]=[CH:30][CH:29]=[CH:28][N:27]=1)CCC.[F-].[Cs+]>C(PC(C)(C)C)(C)(C)C.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][C:17]([C:26]3[N:31]=[CH:30][CH:29]=[CH:28][N:27]=3)=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(Br)cc2)CC1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ncccn1
Agent: [Pd]
Agent: CC(C)(C)PC(C)(C)C
Agent: [Cs+]
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(-c3ncccn3)cc2)CC1
Temperature: 90 °C
Reaction time: 8 h

Procedure:
A mixture containing 4-(4-bromo-phenyl)-piperidine-1-carboxylic acid tert-butyl ester (100 mg, 0.29 mmol), 2-tributylstannanyl-pyrimidine (130 mg, 0.36 mmol), cesium fluoride (85 mg, 0.56 mmol) and palladium di-tert-butylphosphine was degassed three times with Ar. Dioxane was added and the formed reaction mixture was stirred at 90° C. overnight under Ar. Then the reaction mixture was filter through celite and the solvent was removed under vacuum and crude product was used directly in the next step.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][N:5]2[C:10]=1[C:9]([S:11][CH3:12])=[N:8][CH:7]=[N:6]2.C1C(=O)N(Br)C(=O)C1.CC(N=NC(C#N)(C)C)(C#N)C.[OH:33][CH:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1.CCN(C(C)C)C(C)C>C(Cl)(Cl)(Cl)Cl>[CH3:12][S:11][C:9]1[C:10]2=[C:2]([CH2:1][N:37]3[CH2:38][CH2:39][CH:34]([OH:33])[CH2:35][CH2:36]3)[CH:3]=[CH:4][N:5]2[N:6]=[CH:7][N:8]=1
Reactant: CSc1ncnn2ccc(C)c12
Reactant: OC1CCNCC1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: CSc1ncnn2ccc(CN3CCC(O)CC3)c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.4 %

Procedure:
A solution of 5-methyl-4-methylsulfanyl-pyrrolo[2,1-f][1,2,4]triazine (200 mg, 1.12 mmol), NBS (218 mg, 1.23 mmol), and AIBN (spatula tip) in carbon tetrachloride (4 mL) was heated at 80° C. for 1 h. After cooling to rt, the solution was filtered to remove succinimide. To the filtrate was added 4-hydroxypiperidine (126 mg, 1.34 mmol, Aldrich) and DIPEA (214 μL, 1.23 mmol). The reaction was stirred at rt overnight and was then concentrated in vacuo. The residue was suspended in methanol and filtered. The filtrate was concentrated and the crude product was purified by flash chromatography on silica gel (20% MeOH/EtOAc) to give the title compound (229 mg, 74%) as a colorless solid. 1H NMR (DMSO-d6) δ 8.25 (s, 1H), 7.88 (d, 1H, J=2 Hz), 6.81 (d, 1H, J=2 Hz), 4.54 (br s, 1H), 3.76 (s, 2H), 3.48–3.44 (m, 1H), 2.75–2.71 (m, 2H), 2.62 (s, 3H), 2.10–2.08 (m, 2H), 1.70–1.68 (m, 2H), 1.38–1.36 (m, 2H); MS(ESI+) m/z 279.3 (M+H)+.
Reaction SMILES: [H-].[Na+].[NH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH2:12][C:13]2[CH:14]=[C:15]([CH:28]=[CH:29][CH:30]=2)[O:16][CH2:17][C:18]2[CH:27]=[CH:26][C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[N:19]=2)=[CH:4]1.Br[CH2:32][C:33]([O:35]CC)=[O:34]>CN(C=O)C>[N:19]1[C:20]2[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:26]=[CH:27][C:18]=1[CH2:17][O:16][C:15]1[CH:14]=[C:13]([CH:30]=[CH:29][CH:28]=1)[CH2:12][C:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[N:3]([CH2:32][C:33]([OH:35])=[O:34])[CH:4]=1
Reactant: CCOC(=O)CBr
Reactant: c1cc(Cc2c[nH]c3ccccc23)cc(OCc2ccc3ccccc3n2)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(O)Cn1cc(Cc2cccc(OCc3ccc4ccccc4n3)c2)c2ccccc21
Reaction time: 2 h

Procedure:
Sodium hydride (60%, 22 mg, 0.55 mmol) is added to a solution of 2-[3-(1H-indol-3-ylmethyl)-phenoxymethyl]-quinoline (90 mg, 0.25 mmol, example 90) in DMF (2.5 mL). After stirring 5 minutes ethyl bromoacetate (0.1 mL, 0.9 mmol) is added and the reaction is allowed to stir 2 h. The reaction is partitioned between ethyl acetate and ammonium chloride and the organic phase is washed with water. The organic phase is dried over magnesium sulfate, concentrated and then the solid is titurated with ethyl ether and ethyl acetate to provide the title compound as a solid. m.p. 151–159° C.; 1H NMR (300 MHz, CDCl3) δ 8.20 (t, 2H), 7.83–7.80 (m, 1H), 7.77–7.71 (m, 1H), 7.67 (d, 1H), 7.61–7.53 (m, 1H), 7.45–7.42 (m, 1H), 7.29–7.14 (m, 3H), 7.05–6.99 (m, 2H), 6.94 (s, 1H), 6.85 (m, 2H), 5.16 (s, 2H), 4.84(s, 2H), 4.11 (s, 2H); MS (ESI) 423 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[S:12][C:11]3[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=3[CH2:9][CH:8]([N:17]3[CH2:22][CH2:21][N:20]([CH2:23][CH2:24][CH2:25][OH:26])[CH2:19][CH2:18]3)[C:7]=2[CH:27]=1.[C:28](Cl)(=[O:40])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39]>C1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[S:12][C:11]3[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=3[CH2:9][CH:8]([N:17]3[CH2:18][CH2:19][N:20]([CH2:23][CH2:24][CH2:25][O:26][C:28](=[O:40])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])[CH2:21][CH2:22]3)[C:7]=2[CH:27]=1
Reactant: COc1ccc2c(c1)C(N1CCN(CCCO)CC1)Cc1ccccc1S2
Reactant: CCCCCCCCCCCC(=O)Cl
Solvent: c1ccccc1
Product: CCCCCCCCCCCC(=O)OCCCN1CCN(C2Cc3ccccc3Sc3ccc(OC)cc32)CC1

Procedure:
In accordance with the procedure described in the foregoing Examples, 12.96 grams of 8-methoxy-10-[4-(3-hydroxypropyl)piperazino]-10,11-dihydrodibenzo[b,f]thiepin was reacted with 13.1 grams of lauroyl chloride (dodecanoyl chloride) in 50 milliliters of benzene and the resulting crude 8-methoxy-10-[4-(3-dodecanoyloxypropyl)piperazino]-10,11-dihydrodibenzo[b,f]thiepin was purified by recrystallization of the maleate from acetone and recovered in the form of its di(hydrogen maleate). The salt was recovered in a yield of 14.9 grams and had a melting point of 126-129°C. The pure ester was recovered in the form of a viscous oil by adding the salt to a dilute aqueous ammonium hydroxide solution and extracting the resulting solution with benzene. EXAMPLE 4