Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]([CH:11]([CH2:19][CH2:20][C@H:21]([NH:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH2:39]([O:46][C:47]1[CH:54]=[CH:53][C:50]([CH2:51]Br)=[CH:49][CH:48]=1)[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1>CN(C)C=O>[CH2:39]([O:46][C:47]1[CH:48]=[CH:49][C:50]([CH2:51][C:11]([C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:10])([CH2:19][CH2:20][C@H:21]([NH:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[C:22]([O:24][C:25]([CH3:26])([CH3:27])[CH3:28])=[O:23])[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[CH:53][CH:54]=1)[C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=1
Reactant: BrCc1ccc(OCc2ccccc2)cc1
Reactant: CC(C)(C)OC(=O)N[C@@H](CCC(C(=O)OCc1ccccc1)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@@H](CCC(Cc1ccc(OCc2ccccc2)cc1)(C(=O)OCc1ccccc1)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 88 %

Procedure:
To a solution of 1.00 g di-tert-butyl (5S)-2-(benzyloxycarbonyl)-5-[(tert-butoxycarbonyl)-amino]hexanedioate (1.97 mmol) in NA-dimethyl formamide (20 mL) was added under argon atmosphere 71 mg of sodium hydride (60% in oil, 1.77 mmol). The resulting mixture was stirred at room temperature for 30 minutes. A solution of 546 mg 4-benzyloxybenzyl bromide (1.97 mmol; prepared according to Helv. Chim. Acta, 2002, 85, 3422) in N,N-dimethylformamide (10 mL) was added, and the mixture was stirred at 60° C. for one hour. After cooling to room temperature, the mixture was concentrated in vacuo and partitioned between water and ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and evaporated. The residue was purified by column chromatography on silica gel (2.5→20% ethyl acetate in hexane) to give 1.22 g of the title compound (88% yield).
Reaction SMILES: [CH3:1][N:2]([CH2:4][CH2:5][C:6]1[C:7]2[CH:13]=[CH:12][S:11][C:8]=2[NH:9][CH:10]=1)[CH3:3].[C:14]1([S:20](Cl)(=[O:22])=[O:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.CC([O-])(C)C.[K+]>C1COCC1>[CH3:1][N:2]([CH2:4][CH2:5][C:6]1[C:7]2[CH:13]=[CH:12][S:11][C:8]=2[N:9]([S:20]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)(=[O:22])=[O:21])[CH:10]=1)[CH3:3]
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CN(C)CCc1c[nH]c2sccc12
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CN(C)CCc1cn(S(=O)(=O)c2ccccc2)c2sccc12

Procedure:
A mixtue of N,N-dimethyl-2-(6H-thieno[2,3-b]pyrrol-4-yl)ethylamine (0.2 mmol), benzenesulfonyl chloride (0.22 mmol) and KOt-Bu (0.22 mmol) in THF is shaken at ambient temperatures for 8 h and concentrated in vacuo. The resultant residue is dissolved in a mixture of DMSO, methanol and water and purified by preparative HPLC1 to afford the title product, [M+H] 335, retention time (RT) 1.42 min. 1 Gilson Preparative HPLC conditions: Gilson Preparative HPLC system; YMC Pro C18, 20 mm×50 mm ID, 5 uM column; 2 mL injection; Solvent A: 0.02% TFA/water; Solvent B: 0.02% TFA/acetonitrile; Gradient: Time 0: 95% A; 2 min: 95% A; 14 min: 10% A, 15 min: 10% A, 16 min: 95% A; Flow rate 22.5 mL/min; Detection: 254 nm DAD.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH2:6][N:7]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:8][CH2:9][C:10]=1[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][O:20][Si:21]([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22])=[CH:13][CH:12]=1)=[O:4].Cl>CO>[CH3:1][O:2][C:3]([CH:5]1[CH:10]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][O:20][Si:21]([C:24]([CH3:27])([CH3:25])[CH3:26])([CH3:23])[CH3:22])=[CH:13][CH:12]=2)[CH2:9][CH2:8][N:7]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:6]1)=[O:4]
Reactant: COC(=O)C1=C(c2ccc(OCCO[Si](C)(C)C(C)(C)C)cc2)CCN(C(=O)OC(C)(C)C)C1
Agent: Cl
Solvent: CO
Product: COC(=O)C1CN(C(=O)OC(C)(C)C)CCC1c1ccc(OCCO[Si](C)(C)C(C)(C)C)cc1
Reaction time: 1 h
Yield: 90.6 %

Procedure:
Mg (1.40 g, 58 mmol) was added to a sol. of compound 4-{4-[2-(tert-Butyldimethylsilanyloxy)ethoxy]phenyl}-5,6-dihydro-2H-pyridine-1,3-dicarboxylic acid 1-tert-butyl ester 3-methyl ester (8.10 g, 17 mmol) in MeOH (40 mL) under Ar. The mixture was stirred for 1 h while maintaining the temperature below 30° C. Aq. 1M HCl (115 mL, 115 mmol) was added dropwise and the mixture was stirred for 1 h. The mixture was extracted with EtOAc (2×). The combined org. layers were washed with water, brine, dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the residue by FC (EtOAc/heptane 2:1) yielded a 2:3 trans/cis mixture of the title compound (7.6 g, 93%). LC-MS: tR=1.23 min, ES+=508.47.
Reaction SMILES: [CH3:1][C@H:2]([OH:6])[CH2:3][C:4]#[CH:5].[F:7][C:8]1[C:9](I)=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=[O:17])/[C:11]/2=[CH:18]\[C:19]1[NH:23][CH:22]=[N:21][C:20]=1[CH3:24]>CN(C=O)C.CCN(CC)CC.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.[Cu]I>[F:7][C:8]1[C:9]([C:5]#[C:4][CH2:3][C@@H:2]([OH:6])[CH3:1])=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=[O:17])/[C:11]/2=[CH:18]\[C:19]1[NH:23][CH:22]=[N:21][C:20]=1[CH3:24]
Reactant: Cc1nc[nH]c1/C=C1\C(=O)Nc2ccc(F)c(I)c21
Reactant: C#CC[C@H](C)O
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1nc[nH]c1/C=C1\C(=O)Nc2ccc(F)c(C#CC[C@H](C)O)c21

Procedure:
Using Method C above, (S)-pent-4-yn-2-ol (68 mg, 0.82 mmol) (see Example 81 below) was coupled with (Z)-1,3-dihydro-5-fluoro-4-iodo-3-[(4-methyl-1H-imidazol-5-yl)methylene]-2H-indol-2-one (100 mg, 0.27 mmol) (Starting Material 3 supra) using (Ph3P)4Pd (31 mg, 0.03 mmol) and CuI (6 mg) in a mixture of DMF (5 mL) and Et3N (5 mL) as solvent at 80° C. for 4 hrs. Upon completion, the reaction mixture was concentrated and the residue was chromatographed on a silica gel column with neat CH3CN then THF and finally MeOH as elution solvent. The resulting (S)-(Z)-1,3-Dihydro-5-fluoro-4-(4-hydroxy-1-pentynyl)-3-[(4-methyl-1H-imidazol-5-yl)methylene]-2H-indol-2-one was triturated with Et2O and then recrystalized from superheated EtOH. (Yield 57 mg, 65%).
Reaction SMILES: [C:1]1([CH:7]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:8][CH2:9][N:10]2[CH2:15][CH2:14][N:13]([C:16]3[CH:24]=[C:23]4[C:19]([CH2:20][NH:21][C:22]4=[O:25])=[CH:18][CH:17]=3)[CH2:12][CH2:11]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH:33]([CH3:35])[CH3:34]>>[C:26]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:8][CH2:9][N:10]2[CH2:11][CH2:12][N:13]([C:16]3[CH:24]=[C:23]4[C:19]([CH2:20][N:21]([CH:33]([CH3:35])[CH3:34])[C:22]4=[O:25])=[CH:18][CH:17]=3)[CH2:14][CH2:15]2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=C1NCc2ccc(N3CCN(CCC(c4ccccc4)c4ccccc4)CC3)cc21
Reactant: CC(C)Br
Product: CC(C)N1Cc2ccc(N3CCN(CCC(c4ccccc4)c4ccccc4)CC3)cc2C1=O
Yield: 58.1 %

Procedure:
In the same manner as in Example 51, the title compound (32 mg) was prepared from the compound (50 mg) obtained in Example 50 and 2-bromopropane (148 mg).
Reaction SMILES: [C:1]1([S:7][C:8]2[CH:16]=[CH:15][C:11]([CH2:12][C:13]#[N:14])=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:17](Cl)[CH2:18][CH2:19][CH3:20].[OH-].[Na+]>[Br-].C([N+](CC)(CC)CC)C.O>[C:1]1([S:7][C:8]2[CH:16]=[CH:15][C:11]([CH:12]([CH2:17][CH2:18][CH2:19][CH3:20])[C:13]#[N:14])=[CH:10][CH:9]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: N#CCc1ccc(Sc2ccccc2)cc1
Reactant: CCCCCl
Agent: CC[N+](CC)(CC)CC
Agent: [Br-]
Agent: [Na+]
Solvent: O
Product: CCCCC(C#N)c1ccc(Sc2ccccc2)cc1
Reaction time: 0.5 h
Yield: 65.1 %

Procedure:
To a mixture of 41 g (0.18 mole) of 4-phenylthiobenzyl cyanide, 18 g (0.19 mole) of butyl chloride and 2 g of tetraethylammonium bromide is added 16 g (0.2 mole) of 50% sodium hydroxide solution dropwise at room temperature with stirring. The reaction mixture is heated at 85° for 1/2 hour and then an additional 16 g (0.2 mole) of 50% sodium hydroxide solution are added. Heating is continued for another 1/2 hour. The reaction mixture is poured into water and extracted with ether. The combined ether extracts are washed with water, saturated sodium chloride solution and dried over MgSO4. Solvent is evaporated to give 47 g of a crude product. Vacuum distillation (173°-180°/0.05 mm) gives 33 g of pure product.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:43])[CH:10]([C:39]([O:41]C)=[O:40])[C@H:11]([C:16](=[O:38])[NH:17][C@H:18]1[CH2:35][C:34]2=[CH:36][N:27]([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][C:33]=32)[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][NH:20][C:19]1=[O:37])[CH2:12][CH:13]([CH3:15])[CH3:14])C1C=CC=CC=1.C([O-])=O.[NH4+]>C(O)C.[Pd]>[CH3:1][O:8][C:9]([CH:10]([C@H:11]([C:16](=[O:38])[NH:17][C@H:18]1[CH2:35][C:34]2=[CH:36][N:27]([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][C:33]=32)[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][NH:20][C:19]1=[O:37])[CH2:12][CH:13]([CH3:15])[CH3:14])[C:39]([OH:41])=[O:40])=[O:43]
Reactant: COC(=O)C(C(=O)OCc1ccccc1)[C@@H](CC(C)C)C(=O)N[C@H]1Cc2cn(c3ccccc23)CCCCCCNC1=O
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: COC(=O)C(C(=O)O)[C@@H](CC(C)C)C(=O)N[C@H]1Cc2cn(c3ccccc23)CCCCCCNC1=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Alternatively, (3R,10S)-2-methoxycarbonyl-5-methyl-3-(9-oxo-1,8-diazatricyclo[10.6.1.013,18 ]nonadeca-12(19),13(18),14,16-tetraen-10-ylcarbamoyl)hexanoic acid benzyl ester was taken up in ethanol (35 mL, some heating was required) and ammonium formate 1642 mg, 3 eq) was added followed by 10% Pd on activated charcoal (100 mg). After stirring under argon at room temperature for 3 hrs. the reaction was complete. The mixture was suction-filtered through a 1 cm bed of celite, then it was concentrated, MeOH was added and it was filtered through a plug of cotton. After concentrating, CH2Cl2 was added to the residue and it was stirred vigorously and then filtered. The filtrate was concentrated and recrystallized from ethyl acetate/pet. ether to give (3R,10S)-2-methoxycarbonyl-5-methyl-3-(9-oxo-1,8-diazatricyclo[10.6.1.013,18 ]nonadeca-12(19),13(18),14,16-tetraen-10-ylcarbamoyl)hexanoic acid as a white solid (yield: 140 mg), MS: 500.3 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].[CH2:9]([S:11](Cl)(=[O:13])=[O:12])[CH3:10]>N1C=CC=CC=1.O>[Br:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH:4][S:11]([CH2:9][CH3:10])(=[O:13])=[O:12]
Reactant: Nc1ccccc1Br
Reactant: CCS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: O
Product: CCS(=O)(=O)Nc1ccccc1Br
Temperature: 25 °C
Reaction time: 16 h
Yield: 45.4 %

Procedure:
To a solution of 2-bromoaniline (344 mg, 2.0 mmol) in pyridine (5 mL) was slowly added ethyl-sulfonyl chloride (257 mg, 2.0 mmol) at rt and the mixture was stirred at rt for 16 hours. The pyridine was removed under reduced pressure and resulting residue diluted with water (30 mL) and extracted with DCM (10 mL×2). The combined organic extracts were washed with brine, dried over Na2SO4, filtered and concentrated to dryness. The residue was purified by FCC to give the title compound (240 mg, 45%). MS (ESI): mass calcd. for C8H10BrNO2S 262.96 m/z found 264.1 [M+H]+. 1H NMR (300 MHz, CDCl3) δ 7.71 (dd, J=4.8, 1.5, 1H), 7.59 (dd, J=4.8, 1.5, 1H), 7.32-7.28 (m, 1H), 7.08-7.05 (m, 1H), 6.77 (bs, 1H), 3.14 (q, J=7.2, 2H), 1.41 (t, J=7.5, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([F:12])[C:9]([N:13]2[C:18](=[O:19])[CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[N:15]=[C:14]2Cl)=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[CH3:25][CH2:26][O-:27].[Na+]>C(O)C>[CH2:26]([O:27][C:14]1[N:13]([C:9]2[C:10]([F:12])=[CH:11][C:2]([Cl:1])=[C:3]([CH:8]=2)[C:4]([O:6][CH3:7])=[O:5])[C:18](=[O:19])[CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[N:15]=1)[CH3:25]
Reactant: COC(=O)c1cc(-n2c(Cl)nc(C(F)(F)F)cc2=O)c(F)cc1Cl
Reactant: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOc1nc(C(F)(F)F)cc(=O)n1-c1cc(C(=O)OC)c(Cl)cc1F

Procedure:
using methyl 2-chloro-5-[2-chloro-6-oxo-4-trifluoromethyl-1(6H)-pyrimidinyl]-4-fluorobenzoate and sodium ethylate in ethanol there is obtained methyl 5-[2-ethoxy-6-oxo-4-trifluoromethyl -1(6H)-pyrimidinyl]-2-chloro-4-fluorobenzoate, m.p. 96°-98° C.;
Reaction SMILES: [CH3:1][C:2]([S:5]([NH:7][C:8]1([C:12]2[S:13][C:14]([C:17]3[CH:22]=[C:21]([NH:23][C:24]4[N:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[CH:26][N:25]=4)[CH:20]=[C:19]([CH3:34])[CH:18]=3)=[CH:15][N:16]=2)[CH2:11][O:10][CH2:9]1)=[O:6])([CH3:4])[CH3:3].C1C=C(Cl)C=C(C(OO)=[O:43])C=1>ClCCl>[CH3:4][C:2]([S:5]([NH:7][C:8]1([C:12]2[S:13][C:14]([C:17]3[CH:22]=[C:21]([NH:23][C:24]4[N:29]=[C:28]([C:30]([F:32])([F:33])[F:31])[CH:27]=[CH:26][N:25]=4)[CH:20]=[C:19]([CH3:34])[CH:18]=3)=[CH:15][N:16]=2)[CH2:9][O:10][CH2:11]1)(=[O:43])=[O:6])([CH3:1])[CH3:3]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnc(C3(NS(=O)C(C)(C)C)COC3)s2)c1
Solvent: ClCCl
Product: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnc(C3(NS(=O)(=O)C(C)(C)C)COC3)s2)c1
Temperature: 25 °C
Yield: 58.5 %

Procedure:
A solution of 2-methyl-N-{3-[5-(3-methyl-5-{([4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]oxetan-3-yl}propane-2-sulfinamide (Example 59, Step 2, 75 mg, 0.147 mmol) in dichloromethane (1.5 mL) was cooled to 0° C. m-CPBA (37.8 mg, 0.219 mmol) was added and the resulting mixture was warmed to room temperature. The reaction mixture was diluted with dichloromethane, washed with 2M NaOH (2×), saturated NaHCO3 (1×), brine (1×), dried (Na2SO4), filtered and concentrated. The residue was purified by column chromatography on silica (10-100% ethyl acetate in hexanes) and lyophilized to afford 2-methyl-N-{3-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]oxetan-3-yl}propane-2-sulfonamide (45.6 mg, 0.086 mmol, 59.0% yield) as a light yellow solid. MS ESI: [M+H]+ m/z 510.1. 1H NMR (500 MHz, dmso) δ 10.29 (s, 1H), 8.83 (d, J=4.9, 1H), 8.29 (s, 1H), 8.09 (s, 1H), 7.95 (s, 1H), 7.53 (s, 1H), 7.28 (d, J=4.9, 1H), 7.18 (s, 1H), 4.90 (dd, 6.6, 33.0, 4H), 2.33 (s, 3H), 1.35 (s, 9H). rhSYK activity=+++
Reaction SMILES: [CH3:1][NH:2][CH3:3].[O:4]1[CH2:9][CH2:8][O:7][CH2:6][C:5]1=[O:10]>O1CCOCC1>[CH3:1][N:2]([CH3:3])[C:5](=[O:10])[CH2:6][O:7][CH2:8][CH2:9][OH:4]
Reactant: CNC
Reactant: O=C1COCCO1
Solvent: C1COCCO1
Product: CN(C)C(=O)COCCO
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.8 %

Procedure:
Into a round-bottom flask of the volume of 100 ml are transferred 50 ml dioxane and the solvent is cooled to 5° C. Subsequently 8.1 g (0.18 mole) dimethylamine is absorbed in the solvent at the temperature of 5-10° C. in 20 minutes. To the solution of dimethylamine, 10.2 g (0.1 mole) of [1,4]-dioxane-2-one are added at the same temperature in 5 minutes and the reaction mixture is stirred at room temperature for 2 hours. After the reaction period, the solvent is evaporated in vacuo at the temperature of 50° C. in one hour. Thus 14.1 g (95.9%) of the title product are obtained, which has the purity of 98% as determined by gas chromatography. Optionally the product can be purified by distilling in vacuo (boiling temperature 130-135° C./13 Pa). The raw product is directly suitable for the preparation of 2-chloroethoxy-acetic acid-N,N-dimethyl-amide.
Reaction SMILES: [N:1]1([C:7](=[O:20])[CH2:8][C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH:19]=[N:18][N:17]=[N:16]3)=[CH:11][CH:10]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[O:21]1[CH2:23][CH:22]1[C:24]1[CH:25]=[C:26]2[C:31](=[CH:32][CH:33]=1)[C:30](=[O:34])[O:29][CH2:28][CH2:27]2>C(O)C>[OH:21][CH:22]([C:24]1[CH:25]=[C:26]2[C:31](=[CH:32][CH:33]=1)[C:30](=[O:34])[O:29][CH2:28][CH2:27]2)[CH2:23][N:4]1[CH2:5][CH2:6][N:1]([C:7](=[O:20])[CH2:8][C:9]2[CH:10]=[CH:11][C:12]([N:15]3[CH:19]=[N:18][N:17]=[N:16]3)=[CH:13][CH:14]=2)[CH2:2][CH2:3]1
Reactant: O=C(Cc1ccc(-n2cnnn2)cc1)N1CCNCC1
Reactant: O=C1OCCc2cc(C3CO3)ccc21
Solvent: CCO
Product: O=C1OCCc2cc(C(O)CN3CCN(C(=O)Cc4ccc(-n5cnnn5)cc4)CC3)ccc21

Procedure:
A solution of 1-(piperazin-1-yl)-2-[4-(1H-tetrazol-1-yl)phenyl]ethanone (200 mg, 0.734 mmol), 6-(oxiran-2-yl)-3,4-dihydro-1H-isochromen-1-one (140 mg, 0.734 mmol) in ethanol was heated in a microwave reactor at 130° C. for 1 h. The reaction mixture was concentrated and the residue was purified by preparative TLC to afford the title compound. LC/MS: [(M+1]+=463.
Reaction SMILES: [CH3:1][N:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH2:11][S:12][CH3:13])[CH:5]=1.[BH4-].[Na+]>CCO>[CH3:1][NH:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH2:11][S:12][CH3:13])[CH:5]=1
Reactant: CN=Cc1cccc(OCSC)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CNCc1cccc(OCSC)c1
Temperature: 0 °C
Reaction time: 4 h
Yield: 57 %

Procedure:
Compound from step 2 (3.546 g, 18.16 mmol) was dissolved in EtOH (50 mL) and cooled to 0° C. NaBH4 (859 mg, 22.70 mmol) was added and the mixture was allowed to stir for 4 h. The reaction was carefully quenched with water. The EtOH was removed in vacuo. The aqueous residue was extracted with CH2Cl2. The organic extracts were dried over Na2SO4 and concentrated in vacuo to give 2.044 g (57%) of a clear yellow oil.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][C@@H:10]([OH:13])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:14]1([CH3:24])[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=1.[OH2:25]>N1C=CC=CC=1>[CH2:1]([N:8]1[CH2:12][CH2:11][C@@H:10]([OH:13])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1.[S:20]([C:17]1[CH:18]=[CH:19][C:14]([CH3:24])=[CH:15][CH:16]=1)([O-:22])(=[O:21])=[O:25]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: O
Agent: O[C@@H]1CCN(Cc2ccccc2)C1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)[O-])cc1
Temperature: 25 °C
Reaction time: 90 h
Yield: 92 %

Procedure:
To a stirred solution of (R)-1-benzyl-3pyrrolidinol (1.77 g, 10 mmol) in pyridine(30 ml) was added p-toluenesulfonyl chloride (9.53 g, 50 mmol) by portions at 0° C. After 90 h stirring at room temperature, water was added to the reaction mixture and the mixture was extracted with ether (150 ml). The extract was washed with water, brine, dried(Na2SO4), and concentrated to give 3.06 g (92%) of brown oil.
Reaction SMILES: C(N(CC)CC)C.[CH2:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9]1.[C:17]([C:20]1[CH:21]=[C:22](I)[CH:23]=[CH:24][CH:25]=1)([OH:19])=[O:18]>CC([O-])=O.CC([O-])=O.[Pd+2].C(O)C>[C:17]([C:20]1[CH:21]=[CH:22][C:23]([C:9]2[CH2:10][C:11]3[C:16]([CH:8]=2)=[CH:15][CH:14]=[CH:13][CH:12]=3)=[CH:24][CH:25]=1)([OH:19])=[O:18]
Reactant: C1=Cc2ccccc2C1
Reactant: O=C(O)c1cccc(I)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCO
Solvent: CCN(CC)CC
Product: O=C(O)c1ccc(C2=Cc3ccccc3C2)cc1
Temperature: 25 °C
Yield: 42.3 %

Procedure:
20 ml of triethylamine, 2.2 g (20 mmole) of indene, 4.96 g (20 mmole) of meta-carboxy iodo-benzene and 0.134 g (0.6 mmole) of Pd(OAc)2 were stirred under reflux for 10 h. After that the mixture was cooled till room temperature and treated with 100 ml of ethanol. The crystalline precipitate was isolated, and dissolved in aqueous alkali. Aqueous phase was separated and treated with aqueous HCl. White precipitated was isolated washed with cooled ethanol and dried under vacuum to obtain 2 g (43%) of 2-(4-carboxy-phenyl)-indene.
Reaction SMILES: [N:1]1([CH2:6][C:7]2[CH:8]=[C:9]([NH2:14])[C:10]([NH2:13])=[CH:11][CH:12]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[C:15]1([C:21](=O)[C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=O)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C(O)C>[N:1]1([CH2:6][C:7]2[CH:8]=[C:9]3[C:10](=[CH:11][CH:12]=2)[N:13]=[C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:21]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[N:14]3)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: Nc1ccc(Cn2ccnc2)cc1N
Reactant: O=C(C(=O)c1ccccc1)c1ccccc1
Solvent: CCO
Product: c1ccc(-c2nc3ccc(Cn4ccnc4)cc3nc2-c2ccccc2)cc1
Reaction time: 4 h
Yield: 55 %

Procedure:
A mixture of 3.76 parts of 4-(1H-imidazol-1-ylmethyl)-1,2-benzenediamine, 4.5 parts of diphenylethanedione and 80 parts of ethanol was stirred for 4 hours at reflux temperature. The reaction mixture was concentrated and the concentrate was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (95:5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from a mixture of 1,1'-oxybisethane and ethanol. The product was filtered off and dried, yielding 4 parts (55%) of 6-(1H-imidazol-1-ylmethyl)-2,3-diphenylquinoxaline; mp. 159.3° C. (comp. 8).
Reaction SMILES: N1[CH2:5][CH2:4][C@@H:3]([NH:6][C:7](=[O:14])C2C=CN=CC=2)[CH2:2]1.NC1C=C[C:19]([S:22]([NH2:25])(=[O:24])=[O:23])=[CH:18]C=1>>[N:6]([C:3]1[CH:2]=[CH:18][C:19]([S:22]([NH2:25])(=[O:24])=[O:23])=[CH:5][CH:4]=1)=[C:7]=[O:14]
Reactant: Nc1ccc(S(N)(=O)=O)cc1
Reactant: O=C(N[C@@H]1CCNC1)c1ccncc1
Product: NS(=O)(=O)c1ccc(N=C=O)cc1

Procedure:
This compound is prepared analogously to Intermediate R by replacing 3-aminobenzenesulphonamide with 4-aminobenzenesulphonamide.
Reaction SMILES: [N+]([O-])([O-])=O.[Pd+2:5].[N+]([O-])([O-])=O.[CH2:10]([SH:22])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]>C(O)C>[CH2:10]([S-:22])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21].[Pd+2:5].[CH2:10]([S-:22])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: CCCCCCCCCCCCS
Agent: [Pd+2]
Agent: O=[N+]([O-])[O-]
Solvent: CCO
Product: CCCCCCCCCCCC[S-]

Procedure:
Palladium nitrate was dissolved in ethanol and dodecanethiol was added to the solution, while stirring. The yellow precipitate of palladium dodecanethiolate obtained was separated by centrifugation, washed several times with ethanol or acetone and finally dissolved in hot (50° C.) chloroform and re-precipitated by adding ethanol. The product was separated by centrifugation and then left to dry in the air. A solution of palladium dodecanethiolate in chloroform was then added to a solution of polystyrene in chloroform and the system, after thorough homogenization, was poured onto a glass surface and left to dry. In this way, transparent films of a deep yellow colour were produced, and these were then submitted to heat treatment at 340° C. by means of a sand bath. A thermogravimetric analysis (TGA) was carried out on the palladium dodecanethiolate, as shown in FIG. 1. The thermogram reveals two stages in degradation: the first is determined by the thermal decomposition of the palladium mercaptide which leads to the formation of the corresponding sulphide, and the second is further decomposition of the sulphide, from which the metal is obtained. The microstructure of the inclusions of Pd in polystyrene was visualized by examination by transmission electron microscopy, shown in FIG. 2.
Reaction SMILES: [H-].[K+].[CH3:3][O:4][C:5](=[O:17])[CH2:6][C:7]1[CH:16]=[CH:15][C:10]([C:11]([O:13][CH3:14])=[O:12])=[CH:9][CH:8]=1.CI.[C:20](O)(=O)C>O1CCCC1.O>[CH3:3][O:4][C:5](=[O:17])[CH:6]([CH3:20])[C:7]1[CH:16]=[CH:15][C:10]([C:11]([O:13][CH3:14])=[O:12])=[CH:9][CH:8]=1
Reactant: CC(=O)O
Reactant: COC(=O)Cc1ccc(C(=O)OC)cc1
Agent: [H-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Solvent: CI
Product: COC(=O)c1ccc(C(C)C(=O)OC)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A mixture of 35% potassium hydride in oil (6.04 g, equivalent to 2.11 g, 53 mmol of potassium hydride) in 240 mL of sieve dried tetrahydrofuran was cooled to 0° C. The cold mixture was treated with homoterephthalic acid dimethyl ester (10.0 g, 48 mmol). The mixture was stirred at 0° C. for 1 h. Methyl iodide (7.51 g, 53 mmol) was added and the mixture stirred at 0° C. for 30 min, then at room temperature for 16 h. The resulting mixture was treated with 4.8 mL of 50% acetic acid, then poured into 480 mL of water. The mixture was extracted with ether (2×250 mL). The ether extracts were combined, dried on magnesium sulfate, and concentrated to a brown oil, 15.67 g. Chromatography on 250 g of flash silica gel (10% ether in hexanes eluent) gave the product as a pale yellow oil, 7.24 g (67.9% theory). NMR (CDCl3): δ=7.56 (q, 4H, Ar); 2.78 (m, 7H, 2×CH3O+ArCH); 1.49 (d, 3H, CH3CH).