Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][N:6]=[C:5]([CH2:9][N:10]([CH3:12])[CH3:11])[CH:4]=1)#[N:2].Cl.[H][H]>CO.[Pd]>[NH2:2][CH2:1][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([CH2:9][N:10]([CH3:12])[CH3:11])[CH:4]=1
Reactant: CN(C)Cc1cc(C#N)ccn1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CN(C)Cc1cc(CN)ccn1
Yield: 59.9 %

Procedure:
A mixture of 4-cyano-2-(dimethylamino)methylpyridine (800 mg, 4.97 mmol), palladium (80 mg, 10% Pd/C) and concentrated hydrochloric acid (3 mL) in methanol (30 mL) was shaken under 60 psi of hydrogen overnight. The reaction mixture was filtered through diatomaceous earth and the filter cake rinsed with water and methanol. The filtrate was concentrated under reduced pressure and the residue partitioned between water and methylene chloride. The aqueous layer was made alkaline with 1 N sodium hydroxide and extracted with methylene chloride. The organic layer was washed with saturated sodium chloride, dried (sodium sulfate), filtered, and concentrated under reduced pressure to give an orange oil. Purification by flash column chromatography (97:3 2-propanol/ammonium hydroxide) gave 4-aminomethyl-2-(dimethylamino)methylpyridine 37 (492 mg): 1H NMR (500 Hz, CDCl3) δ 8.50 (d, J=5.1 Hz, 1H), 7.37 (s, 1H), 7.15 (d, J=5.1 Hz, 1H), 3.91 (s, 2H), 3.58 (s, 2H), 2.30 (s, 6H); ESI MS m/z 166 [M+H]+.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([CH3:7])([SH:6])[CH3:5].C(N(CC)CC)C.[C:15]1(=[O:21])[O:20][C:18](=[O:19])[CH2:17][CH2:16]1>C(Cl)Cl>[CH3:5][C:4]([SH:6])([CH3:7])[CH2:3][NH:2][C:15]([CH2:16][CH2:17][C:18]([OH:20])=[O:19])=[O:21]
Reactant: CC(C)(S)CN
Reactant: O=C1CCC(=O)O1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(S)CNC(=O)CCC(=O)O
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 94.5 %

Procedure:
To an ice-cooled suspension of 1-amino-2-methylpropan2-thiol hydrochloride (5.06 g, 35.72 mmol) in methylene chloride (100 mL) was added triethylamine (5.0 mL, 35.87 mmol) followed by succinic anhydride (3.50 g, 34.96 mmol). The resulting clear solution was stirred at 0° C. or 10 minutes, then at room temperature for 2 hours. Evaporation of the volatiles under reduced pressure gave a residue which was partitioned between 2 N hydrochloric acid (100 mL) and ethyl acetate (100 mL). The aqueous layer was extracted with ethyl acetate (3×100 mL). The combined organic layers were washed with brine (5 mL), dried over sodium sulfate and evaporated to dryness. The residue was triturated with ether-hexane to afford the title compound as a white solid (6.78 g, 94.4%). Mp. 86-87° C.; 1H NMR (300 MHz, CDCl3): δ 1.34 (s, 6H), 1.55 (s, 1H), 2.59 (t, J=6.6 Hz, H), 2.70 (t, J=6.6 Hz, 2H), 3.32 (d, J=8.0 Hz, 2H), 6.58 (br t, J=5.9 Hz, 1H), 10.73 (br s, 1H); 13C NMR (75 MHz, CDCl3): δ 29.57, 29.79, 30.79, 172.50, 176.81; LCMS (m/e): 223 (M+H2O), 206 (M+1).
Reaction SMILES: [CH2:1]([N:4]1[CH:13]2[CH:8]([CH2:9][CH2:10][CH2:11][CH2:12]2)[CH2:7][CH2:6][CH2:5]1)[CH:2]=[CH2:3].[CH2:14]([Br:17])[CH:15]=[CH2:16]>C(OCC)C>[Br-:17].[CH2:1]([N+:4]1([CH2:16][CH:15]=[CH2:14])[CH:13]2[CH:8]([CH2:9][CH2:10][CH2:11][CH2:12]2)[CH2:7][CH2:6][CH2:5]1)[CH:2]=[CH2:3]
Reactant: C=CCBr
Reactant: C=CCN1CCCC2CCCCC21
Solvent: CCOCC
Product: C=CC[N+]1(CC=C)CCCC2CCCCC21
Product: [Br-]
Temperature: 5 °C
Reaction time: 24 h
Yield: 65.1 %

Procedure:
To a 500 mL 3-necked round-bottomed flask, was added 24.0 g of decahydroquinoline dissolved in 150 mL acetone. To this mixture was added 29.7 g of powdered anhydrous potassium carbonate. The reaction mixture was cooled to 5° C. with an ice bath. While stirring, 20.8 g of allyl bromide in 50 mL acetone was added slowly to the reaction mixture. After addition was complete, the reaction mixture was allowed to stir at room temperature for 24 hours. The reaction mixture was filtered, and the solvent was removed from the filtrate under reduced pressure using a rotary evaporator yielding 23.0 g of N-allyl decahydroquinoline as a viscous liquid. To a 500 mL 3-necked round-bottomed flask was added 22.0 g of N-allyl decahydroquinoline dissolved in 100 mL diethyl ether. After cooling to 5° C. with an ice bath, 15.5 g of allyl bromide in 20 mL diethyl ether was added slowly. After completion of addition of allyl bromide, the reaction mixture was allowed to warm to room temperature and stirred at room temperature for 24 hours. The solid residue thus formed was collected by filtration and was washed with diethyl ether (2×500 mL). The washed solid was recrystalled from acetonitrile. After removal of acetonitrile by filtration, the residue was dried under vacuum yielding 24.0 g of N,N-diallyl decahydroquinolinium bromide as a white solid.
Reaction SMILES: [N:1]1([C:6]2[CH:34]=[CH:33][C:9]([CH2:10][C:11]3[CH:19]=[C:18]4[C:14]([CH2:15][N:16](CC5C=CC(OC)=CC=5OC)[C:17]4=[O:20])=[CH:13][C:12]=3[CH3:32])=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1.C1(OC)C=CC=CC=1>FC(F)(F)C(O)=O>[N:1]1([C:6]2[CH:34]=[CH:33][C:9]([CH2:10][C:11]3[CH:19]=[C:18]4[C:14]([CH2:15][NH:16][C:17]4=[O:20])=[CH:13][C:12]=3[CH3:32])=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: COc1ccc(CN2Cc3cc(C)c(Cc4ccc(-n5cccn5)cc4)cc3C2=O)c(OC)c1
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: Cc1cc2c(cc1Cc1ccc(-n3cccn3)cc1)C(=O)NC2
Temperature: 80 °C
Reaction time: 2 h
Yield: 93.4 %

Procedure:
To a solution of 6-(4-(1H-pyrazol-1-yl)benzyl)-2-(2,4-dimethoxybenzyl)-5-methylisoindolin-1-one (0.24 g) in trifluoroacetic acid (4.34 mL) was added anisole (0.23 mL), and the mixture was stirred at 80° C. for 2 hr. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (0.15 g).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:14][CH2:13][N:12]([C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[O:16])[CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[NH2:8].[C:23](O)(=O)[CH3:24].C(=O)C=O>C(#N)C>[C:17]1([C:15]([N:12]2[CH2:11][CH2:10][N:9]([C:4]3[CH:3]=[C:2]4[C:7](=[CH:6][CH:5]=3)[N:8]=[CH:24][CH:23]=[N:1]4)[CH2:14][CH2:13]2)=[O:16])[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: CC(=O)O
Reactant: Nc1ccc(N2CCN(C(=O)c3ccccc3)CC2)cc1N
Agent: O=CC=O
Solvent: CC#N
Product: O=C(c1ccccc1)N1CCN(c2ccc3nccnc3c2)CC1
Temperature: 50 °C
Reaction time: 8 h
Yield: 28.1 %

Procedure:
A suspension of (4-(3-amino-4-nitrophenyl)piperazin-1-yl)(phenyl)methanone (2.0 g, 9.0 mmol), 5 ml acetic acid and palladium on carbon (100 mg, 5%) in 50 ml ethanol was stirred at room temperature under hydrogen atmosphere overnight. The mixture was filtered with the aid of celite. Crude (4-(3,4-diaminophenyl)piperazin-1-yl)(phenyl)methanone (1.2 g, 41%) was obtained after removing of solvents. A suspension of (4-(3,4-diaminophenyl)piperazin-1-yl)(phenyl)methanone (0.2 g, 0.67 mmol), acetic acid (0.23 ml, 4.0 mmol) and 40% oxalaldehyde (0.14 ml, 1.0 mmol) in 40 ml acetonitrile was stirred at 50° C. under argon atmosphere overnight. The reaction was quenched with the 5 ml water and extracted with ethyl acetate (3×40 ml). The extraction was concentrated after drying over anhydrous sodium sulfate. Phenyl(4-(quinoxalin-6-yl)piperazin-1-yl)methanone (0.060 g, 28%) was obtained by flash column chromatograph (10% acetone in ethyl acetate). 1H NMR (500 MHz, CDCl3) δ (ppm) 3.37 (d, br, 4H), 3.69 (s, br, 2H), 4.01 (s, br, 2H), 7.30 (d, J=2.7 Hz, 1H), 7.48 (m, 5H), 7.50 (dd, J=9.3, 2.7 Hz, 1H), 7.56 (d, J=9.3 Hz, 1H), 8.65 (d, J=1.9 Hz, 1H), 8.73 (d, J=1.9 Hz, 1H). 13C NMR (125 MHz, CDCl3): δ (ppm) 49.1, 49.3, 110.8, 123.0, 127.6, 29.0, 130.4, 130.5, 1135.7, 139.0, 142.6, 144.9, 151.9, 145.6, 170.9.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH3:31])=[C:5]([C:22]([O:29][CH3:30])=[C:23]([O:27][CH3:28])[C:24]=1[O:25][CH3:26])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([OH:21])=[C:11]([CH:20]=1)[C:12]([N:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)=[O:13].[N:32]1[CH:37]=[CH:36][CH:35]=[C:34](B(O)O)[CH:33]=1.C(N(CC)CC)C.N1C=CC=CC=1>C(Cl)Cl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH3:1][O:2][C:3]1[C:4]([CH3:31])=[C:5]([C:22]([O:29][CH3:30])=[C:23]([O:27][CH3:28])[C:24]=1[O:25][CH3:26])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:21][C:34]2[CH:33]=[N:32][CH:37]=[CH:36][CH:35]=2)=[C:11]([CH:20]=1)[C:12]([N:14]1[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]1)=[O:13]
Reactant: COc1c(C)c(Cc2ccc(O)c(C(=O)N3CCCCC3)c2)c(OC)c(OC)c1OC
Reactant: OB(O)c1cccnc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: COc1c(C)c(Cc2ccc(Oc3cccnc3)c(C(=O)N3CCCCC3)c2)c(OC)c(OC)c1OC
Yield: 35.7 %

Procedure:
N-[5-(3,4,5,6-Tetramethoxy-2-methylbenzyl)-2-hydroxybenzoyl]piperidine (0.150 g, 0.350 mmol) was dissolved in methylene chloride (3.5 ml) and after adding thereto in sequence copper acetate (0.064 g, 0.350 mmol), 3-pyridylboronic acid (0.114 g, 0.700 mmol), Molecular Sieves 4A (0.150 g), triethylamine (0.088 g, 0.874 mmol) and pyridine (0.069 g, 0.874 mmol), the solution was stirred at room temperature for 12 hours. The reaction solution was filtered and the filtrate was poured into water and then extracted with methylene chloride. The extract was washed with saturated brine, then dried and concentrated. The obtained residue was purified by silica gel column chromatography (chloroform:methanol=9:1) to obtain the titled compound (0.063 g, 0.125 mmol, 36%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]#[C:13]Cl)=[CH:7][CH:6]=1.[N-:16]=[N+:17]=[N-:18].[Na+]>CN(C)C=O.O>[CH3:1][O:2][C:3](=[O:15])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]#[C:13][N:16]=[N+:17]=[N-:18])=[CH:7][CH:6]=1
Reactant: [N-]=[N+]=[N-]
Reactant: COC(=O)Cc1ccc(CC#CCl)cc1
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)Cc1ccc(CC#CN=[N+]=[N-])cc1
Temperature: 25 °C
Reaction time: 14 h
Yield: 97.1 %

Procedure:
4-(3-Chloroprop-2-ynyl)phenylacetic acid methyl ester (5.3 g, 0.023M) was dissolved in dry dimethylformamide (30 ml) with sodium azide (1.7 g, 1.1 molar equivalents) and stirred at room temperature for 14 h. The reaction mixture was diluted with water (200 ml) and washed with dichloromethane (2×150 ml). The combined organic layers were washed with water (2×100 ml) and brine (1×100 ml) then dried (Na2SO4), filtered and concentrated in vacuo to give a residue which was purified by passage down a silica gel column, using as eluents 20% dichloromethane in hexane and finally neat dichloromethane, to give the required product (5.3 g) as a colourless oil. δ (360 MHz, CDCl3) 3.63 (2H, s, CH2CO2CH3), 3.70 (3H, s, CH2CO2CH3), 4.14 (2H, s, CH2N3), 7.24 (2H, d, J=8.4 Hz, ArH), 7.42 (2H, d, J=8.4 Hz, ArH); m/e 229 (M+).
Reaction SMILES: C([O-])(=O)C.[Na+].[Cl-].[CH2:7]([O:9][NH3+:10])[CH3:8].[C:11]([CH:16]1[C:21](=[O:22])[CH2:20][CH:19]([CH:23]2[CH:28]([CH3:29])[CH2:27][CH2:26][O:25][CH2:24]2)[CH2:18][C:17]1=[O:30])(=O)[CH2:12][CH2:13][CH3:14]>C(O)C>[CH2:7]([O:9][NH:10][C:11](=[C:16]1[C:17](=[O:30])[CH2:18][CH:19]([CH:23]2[CH:28]([CH3:29])[CH2:27][CH2:26][O:25][CH2:24]2)[CH2:20][C:21]1=[O:22])[CH2:12][CH2:13][CH3:14])[CH3:8]
Reactant: CCCC(=O)C1C(=O)CC(C2COCCC2C)CC1=O
Reactant: CCO[NH3+]
Agent: CC(=O)[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CCO
Product: CCCC(NOCC)=C1C(=O)CC(C2COCCC2C)CC1=O
Temperature: 25 °C
Reaction time: 20 h

Procedure:
3.69 parts by weight of sodium acetate and 3.51 parts by weight of ethoxyammonium chloride were added to 10.0 parts by weight of 2-butyryl-5-(4-methyltetrahydropyran-3-yl)-cyclohexane-1,3-dione in 100 ml of ethanol, and the mixture was stirred for 20 hours at room temperature. To work up the mixture, it was poured into ice water and extracted with methylene chloride, and the organic phase was washed with water, dried and evaporated down to give 10.7 parts by weight of 2-(1-ethoxyaminobutylidene)-5-(4-methyltetrahydropyran-3-yl)-cyclohexane-1,3-dione (active ingredient No. 1); nD22 =1.5235.
Reaction SMILES: [CH2:1]([N:4]1[C:8](=[NH:9])[C:7](=[O:10])[N:6]([CH3:11])[C:5]1=[O:12])[CH:2]=[CH2:3].O=[CH:14][C:15]([Cl:18])([Cl:17])[Cl:16].S(Cl)([Cl:21])=O>C(Cl)(Cl)Cl>[CH2:1]([N:4]1[C:8](=[N:9][CH:14]([Cl:21])[C:15]([Cl:18])([Cl:17])[Cl:16])[C:7](=[O:10])[N:6]([CH3:11])[C:5]1=[O:12])[CH:2]=[CH2:3]
Reactant: O=CC(Cl)(Cl)Cl
Reactant: C=CCN1C(=N)C(=O)N(C)C1=O
Reactant: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Product: C=CCN1C(=O)N(C)C(=O)C1=NC(Cl)C(Cl)(Cl)Cl
Temperature: 55 °C

Procedure:
1-allyl-3-methyl-5-iminoimidazolidine-2,4-dione (20.0 g -- 0.12 mol) and 17.7 g (0.12 mol) chloral in 50 ml chloroform were stirred at 25° C. for 1/2 hour. To the resulting solution was added 28.69 (0.24 mol) thionyl chloride. The temperature rose to 35° C. and a precipitate formed. The reaction mixture was heated at 55° C. for 2 hours, cooled and filtered. The filtrate was stripped to give 24 g of 1-allyl-3-methyl-5-(1,2,2,2-tetrachloroethylimino)-imidazolidine-2,4-dione, as a yellow oil.
Reaction SMILES: CN(C)[CH:3]=[C:4]([C:10](=[O:39])[C:11]1[CH:16]=[C:15]([C:17]2[CH:18]=[N:19][C:20]([NH:32][C:33]([NH:35][CH2:36][CH3:37])=[O:34])=[CH:21][C:22]=2[C:23]2[S:24][CH:25]=[C:26]([C:28]([F:31])([F:30])[F:29])[N:27]=2)[CH:14]=[CH:13][C:12]=1F)[C:5]([O:7][CH2:8][CH3:9])=[O:6].[NH2:41][C@@H:42]([CH2:45][CH:46]([CH3:48])[CH3:47])[CH2:43][OH:44].C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>C1COCC1>[CH2:36]([NH:35][C:33](=[O:34])[NH:32][C:20]1[N:19]=[CH:18][C:17]([C:15]2[CH:16]=[C:11]3[C:12](=[CH:13][CH:14]=2)[N:41]([C@@H:42]([CH2:45][CH:46]([CH3:48])[CH3:47])[CH2:43][OH:44])[CH:3]=[C:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[C:10]3=[O:39])=[C:22]([C:23]2[S:24][CH:25]=[C:26]([C:28]([F:29])([F:31])[F:30])[N:27]=2)[CH:21]=1)[CH3:37]
Reactant: CCNC(=O)Nc1cc(-c2nc(C(F)(F)F)cs2)c(-c2ccc(F)c(C(=O)C(=CN(C)C)C(=O)OCC)c2)cn1
Reactant: CC(C)C[C@H](N)CO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CCNC(=O)Nc1cc(-c2nc(C(F)(F)F)cs2)c(-c2ccc3c(c2)c(=O)c(C(=O)OCC)cn3[C@H](CO)CC(C)C)cn1
Temperature: 60 °C
Reaction time: 8 h
Yield: 43.8 %

Procedure:
Ethyl 3-(dimethylamino)-2-(5-(6-(3-ethylureido)-4-(4-(trifluoromethyl)thiazol-2-yl)pyridin-3-yl)-2-fluorobenzoyl)acrylate (0.150 g, 0.26 mmol, Intermediate 125) and (S)-2-amino-4-methylpentan-1-ol (0.033 ml, 0.26 mmol) were taken up in THF (2 ml). The mixture was placed in an oil bath and heated to 60° C. for 2 h. Potassium carbonate (0.107 g, 0.78 mmol) was added followed by DMF (1 ml) and the mixture was stirred at 60° C. overnight. Reaction was cooled to room temperature and concentrated in vacuo. The residue was then diluted with water (0.5 mL) and cooled to 0° C. 1N HCl was added drop wise until pH˜4. A light yellow solid was collected by filtration, washed with water, and dried in vacuum oven overnight at 50° C. to give (S)-ethyl 6-(6-(3-ethylureido)-4-(4-(trifluoromethyl)thiazol-2-yl)pyridin-3-yl)-1-(1-hydroxy-4-methylpentan-2-yl)-4-oxo-1,4-dihydroquinoline-3-carboxylate (0.072 g, 44%) as a yellow solid.
Reaction SMILES: [C:1]1([PH:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:14][C:15]([CH3:20])([CH3:19])[CH2:16][CH2:17]Cl>>[CH3:14][C:15]([CH3:20])([CH3:19])[CH2:16][CH2:17][P:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CC(C)(C)CCCl
Reactant: c1ccc(Pc2ccccc2)cc1
Product: CC(C)(C)CCP(c1ccccc1)c1ccccc1

Procedure:
As a known compound, t-butylethyl, (i.e., 3,3-dimethylbutyl) diphenyl phosphine was also synthesized via the known displacement approach: the reaction of lithium diphenyl phosphide with 3,3-dimethylbutyl chloride provided the compound in good yield.
Reaction SMILES: [CH2:1]([O:5][C:6]1[C:14]2[CH:13]=[C:12]([C:15]([OH:17])=O)[S:11][C:10]=2[CH:9]=[CH:8][CH:7]=1)[CH:2]([CH3:4])[CH3:3].Cl.Cl.Cl.[N:21]1([CH2:27][CH2:28][N:29]2[CH2:34][CH2:33][CH:32]([NH2:35])[CH2:31][CH2:30]2)[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1>>[N:21]1([CH2:27][CH2:28][N:29]2[CH2:30][CH2:31][CH:32]([NH:35][C:15]([C:12]3[S:11][C:10]4[CH:9]=[CH:8][CH:7]=[C:6]([O:5][CH2:1][CH:2]([CH3:3])[CH3:4])[C:14]=4[CH:13]=3)=[O:17])[CH2:33][CH2:34]2)[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: CC(C)COc1cccc2sc(C(=O)O)cc12
Reactant: NC1CCN(CCN2CCCCC2)CC1
Agent: Cl
Product: CC(C)COc1cccc2sc(C(=O)NC3CCN(CCN4CCCCC4)CC3)cc12

Procedure:
This compound is synthesized from compound 202 and amine 1 analogously to the method described in Example 178.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][C@H:6]1[CH2:10][CH2:9][C@@H:8]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[N:7]1[S:18]([C:21]1[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=1)(=[O:20])=[O:19].[NH:28]1[CH:32]=[N:31][N:30]=N1.[CH:33](Cl)(Cl)Cl>>[F:17][C:14]1[CH:15]=[CH:16][C:11]([C@H:8]2[N:7]([S:18]([C:21]3[CH:22]=[CH:23][C:24]([CH3:27])=[CH:25][CH:26]=3)(=[O:19])=[O:20])[C@@H:6]([CH2:5][CH2:4][CH2:3][CH2:2][N:31]3[CH:32]=[N:28][CH:33]=[N:30]3)[CH2:10][CH2:9]2)=[CH:12][CH:13]=1
Reactant: ClC(Cl)Cl
Reactant: Cc1ccc(S(=O)(=O)N2[C@@H](CCCCCl)CC[C@H]2c2ccc(F)cc2)cc1
Reactant: c1nnn[nH]1
Product: Cc1ccc(S(=O)(=O)N2[C@@H](CCCCn3cncn3)CC[C@H]2c2ccc(F)cc2)cc1

Procedure:
The title compound, colorless oil, MS: m/e=443.3 (M+H+) and [α]D20=−72.5° (c=0.2358 in chloroform), was prepared in accordance with the general method of example 82b from (2S,5S)-2-(4-chloro-butyl)-5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidine and 1H-tetrazole.
Reaction SMILES: [CH3:1][N:2]([CH3:18])[CH:3]1[CH2:7][CH2:6][N:5]([C:8]2[CH:17]=[CH:16][C:11]([C:12]([NH:14][NH2:15])=[O:13])=[CH:10][CH:9]=2)[CH2:4]1.[O:19]([CH2:26][CH2:27][S:28][CH2:29][C:30](O)=O)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[CH3:1][N:2]([CH3:18])[CH:3]1[CH2:7][CH2:6][N:5]([C:8]2[CH:17]=[CH:16][C:11]([C:12]3[O:13][C:30]([CH2:29][S:28][CH2:27][CH2:26][O:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[N:15][N:14]=3)=[CH:10][CH:9]=2)[CH2:4]1
Reactant: CN(C)C1CCN(c2ccc(C(=O)NN)cc2)C1
Reactant: O=C(O)CSCCOc1ccccc1
Product: CN(C)C1CCN(c2ccc(-c3nnc(CSCCOc4ccccc4)o3)cc2)C1

Procedure:
4-(3-Dimethylaminopyrrolidin-1-yl)benzohydrazide was reacted with (2-phenoxy-ethylsulfanyl)acetic acid by Method A. The product with the molecular weight of 424.57 (C23H28N4O2S) was obtained in this way; MS (ESI): 425 (M+H+).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:10]=[C:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[NH:8][N:7]=1)=[O:5])[CH3:2].[Br:16][C:17]1[CH:18]=[C:19](B(O)O)[CH:20]=[CH:21][CH:22]=1>ClCCl>[CH2:14]([O:13][C:11]([C:9]1[CH:10]=[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[N:7]([C:21]2[CH:20]=[CH:19][CH:18]=[C:17]([Br:16])[CH:22]=2)[N:8]=1)=[O:12])[CH3:15]
Reactant: CCOC(=O)c1cc(C(=O)OCC)[nH]n1
Reactant: OB(O)c1cccc(Br)c1
Solvent: ClCCl
Product: CCOC(=O)c1cc(C(=O)OCC)n(-c2cccc(Br)c2)n1
Reaction time: 36 h
Yield: 83.8 %

Procedure:
A mixture of diethyl-3,5-pyrazoledicarboxylate (1.0 g, 4.71 mmol), 3-bromophenylboronicacid (1.89 g, 9.42 mmol) and di-Micron-hydroxo-bis[(N,N,N′,N′-tetramethylethylenediamine)copper(II)]chloride (0.21 g, 0.47 mmol) in dichloromethane (22 mL) was stirred under air for 36 hours under air. It was filtered over a short silica gel pad, concentrated and purified by column chromatography (hexanes:ethyl acetate; 90:10) to yield 1.45 g (85%) of the product as a white solid.
Reaction SMILES: CN(C)[C:3]1[S:4][C:5]2[CH:28]=[C:27]([O:29][CH3:30])[CH:26]=[CH:25][C:6]=2[C:7]=1[C:8]([C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][N:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)=[CH:12][CH:11]=1)=[O:9].C1COCC1.[F:37][C:38]1[CH:39]=[C:40]([Mg]Br)[CH:41]=[CH:42][C:43]=1[O:44][CH3:45]>ClC1C=CC=CC=1>[F:37][C:38]1[CH:39]=[C:40]([C:3]2[S:4][C:5]3[CH:28]=[C:27]([O:29][CH3:30])[CH:26]=[CH:25][C:6]=3[C:7]=2[C:8]([C:10]2[CH:11]=[CH:12][C:13]([O:16][CH2:17][CH2:18][N:19]3[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)=[CH:14][CH:15]=2)=[O:9])[CH:41]=[CH:42][C:43]=1[O:44][CH3:45]
Reactant: COc1ccc([Mg]Br)cc1F
Reactant: COc1ccc2c(C(=O)c3ccc(OCCN4CCCCC4)cc3)c(N(C)C)sc2c1
Solvent: Clc1ccccc1
Solvent: C1CCOC1
Product: COc1ccc2c(C(=O)c3ccc(OCCN4CCCCC4)cc3)c(-c3ccc(OC)c(F)c3)sc2c1
Temperature: 25 °C
Yield: 42.2 %

Procedure:
A solution of [2-dimethylamino-6-methoxybenzothien-3-yl][4-[2-(1-piperidinyl)ethoxy]phenyl]methanone (1.5 g, 3.6 mmol)(see U.S. Pat. No. 5,420,349) in chlorobenzene (15 mL) was cooled to 0° and treated with a 0.73 M THF solution of 3-fluoro-4-methoxyphenylmagnesium bromide (16.0 mL, 11.7 mmol)(prepared from 4-bromo-2-fluoroanisole, catalytic iodine, and magnesium turnings in THF). The mixture was allowed to warm to ambient temperature and when the starting material was consumed, the reaction was quenched with water and extracted with ethyl acetate. The organic layer was washed with water (2x), and brine (2x), dried (sodium sulfate), and concentrated. The residue was purified via chromatography (silica gel, 5-10% MeOH in CH2Cl2) to provide 0.79 g (44%) of the title compound as a brown oil: 1H NMR d 1.44 (m, 2H), 1.59 (m, 4H), 2.48 (m, 4H), 2.74 (t, J=6.0 Hz, 2H), 3.83 (s, 3H), 3.88 (s, 3H), 4.09 (t, J=6.0 Hz, 2H), 6.77-6.83 (m, 3H), 6.96 (dd, J=2.3 Hz, 8.9 Hz, 1H), 7.11-7.19 (m, 2H), 7.31 (d, J=2.3 Hz, 1H), 7.50 (d, J=8.8 Hz, 1H), 7.75 (d, J=8.8 Hz, 2H); 13C NMR d 24.4, 26.1, 55.3, 55.9, 56.4, 57.9, 66.5, 104.7, 113.5, 114.6, 115.3, 116.7, 117.0, 124.4, 125.5, 126.7, 126.8, 130.5, 131.6, 132.6, 134.1, 140.4, 140.9, 148.0, 148.1, 153.8, 158.1, 163.5, 193.2; MS (FD) m/e 519 (M+); Anal. calc'd. for C30H30FNO4S: C, 69.34; H, 5.82; N, 2.69. Found: C, 69.63; H, 5.89; N, 2.64.
Reaction SMILES: II.[CH3:3][O:4][C:5]1[C:13]2[O:12][CH:11]([CH2:14][CH:15]=[CH2:16])[C:10](=O)[C:9]=2[CH:8]=[CH:7][CH:6]=1.Br[CH2:19][C:20]([O:22][CH3:23])=[O:21].C(O)(=O)C>C1COCC1.[Zn]>[CH3:3][O:4][C:5]1[C:13]2[O:12][C:11]([CH2:14][CH:15]=[CH2:16])=[C:10]([CH2:19][C:20]([O:22][CH3:23])=[O:21])[C:9]=2[CH:8]=[CH:7][CH:6]=1
Reactant: COC(=O)CBr
Reactant: C=CCC1Oc2c(OC)cccc2C1=O
Agent: II
Agent: [Zn]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: C=CCc1oc2c(OC)cccc2c1CC(=O)OC
Temperature: 0 °C
Yield: 67 %

Procedure:
THF (10 ml) was added to zinc powder (5.92 g) and then a catalytic amount of iodine was added. While vigorously stirring the resulting solution, a small amount of a solution of 7-methoxy-3-oxo-2-(2-propenyl)-2,3-dihydrobenzofuran (6.16 g) and methyl bromoacetate (8.9 ml) in THF (90 ml) was added at room temperature. After confirming generation of heat, the reaction solution was cooled to 0° C. and the remainder of the solution was added dropwise for 15 minutes. The reaction solution was stirred at 0° C. for 3 hours, cooled to room temperature and was stirred for another 2.5 hours. Acetic acid (5.5 ml) was added to the reaction solution and the resultant was filtered through Celite. After removing the solvent under reduced pressure, the residue was dissolved in toluene (100 ml) and p-toluenesulfonic acid (536 mg) was added thereto, followed by stirring the resulting mixture at room temperature for 2 hours. The reaction solution was poured into water (150 ml) and the resultant was extracted twice with ethyl acetate (50 ml). After combining the organic layers, the resultant was washed with saturated aqueous sodium hydrogen carbonate solution and with saturated brine, and dried over sodium sulfate. After removing the sodium sulfate by filtration, the solvent was removed under reduced pressure and the residue was purified by column chromatography (solvent: hexane/ethyl acetate=3/1) using a silica gel to obtain the desired compound (5.23 g, yield: 67%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].C[O-].[Na+].Br[CH2:15][CH2:16][CH2:17][CH2:18][N:19]1[C:27](=[O:28])[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:20]1=[O:29]>CN(C)C=O.O>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:15][CH2:16][CH2:17][CH2:18][N:19]2[C:27](=[O:28])[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:20]2=[O:29])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=C1c2ccccc2C(=O)N1CCCCBr
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1CCCCOc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of 14.0 g of 4-nitrophenol in 250 ml of dimethylformamide is treated with 6.0 g of sodium methoxide. After 15 minutes, 28.2 g of 2-(4-bromobutyl)-1H-isoindole-1,3(2H)-dione is added, and the mixture then stirred at room temperature for 16 hours. The reaction mixture is diluted with 1500 ml of cold water, the precipitated solid collected, washed with water, and dried. Recrystallization from ethanol gives the desired compound, m.p. 112°-114° C.