Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CCN(C(C)C)C(C)C.[F:10][C:11]1[CH:12]=[C:13]([CH:17]=[C:18]([F:21])[C:19]=1[F:20])[C:14]([OH:16])=O.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[O:44]=[C:45]([N:62]1[CH2:67][CH2:66][NH:65][CH2:64][CH2:63]1)[CH2:46][NH:47][C:48]([C:50]1[CH:55]=[CH:54][C:53]([C:56]2[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=2)=[CH:52][CH:51]=1)=[O:49]>CN(C=O)C.O>[O:44]=[C:45]([N:62]1[CH2:67][CH2:66][N:65]([C:14](=[O:16])[C:13]2[CH:17]=[C:18]([F:21])[C:19]([F:20])=[C:11]([F:10])[CH:12]=2)[CH2:64][CH2:63]1)[CH2:46][NH:47][C:48]([C:50]1[CH:51]=[CH:52][C:53]([C:56]2[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=2)=[CH:54][CH:55]=1)=[O:49]
Reactant: O=C(NCC(=O)N1CCNCC1)c1ccc(-c2ccccc2)cc1
Reactant: O=C(O)c1cc(F)c(F)c(F)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCC(=O)N1CCN(C(=O)c2cc(F)c(F)c(F)c2)CC1)c1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 25.6 %

Procedure:
DIPEA (149.8 mg, 1.15 mmol) was added to a stirred solution of 3,4,5-trifluoro-benzoic acid (45.3 mg, 0.26 mmol) in DMF (3 mL), HOBt (38.2 mg, 0.28 mmol) and EDCI.HCl (123.4 mg, 0.64 mmol) at room temperature. After 2 minutes biphenyl-4-carboxylicacid (2-oxo-2-piperazin-1-yl-ethyl)-amide (100 mg, 0.31 mmol) was added and the resulting mixture was stirred at room temperature overnight. Cold water was then added, and the resulting precipitate was filtered. The residue was purified by column chromatography (using 60-120 mesh silica gel and 60% EtOAc in hexane as eluent) to afford 32 mg (25.8% yield) of biphenyl-4-carboxylicacid {2-oxo-2-[4-(3,4,5-trifluoro-benzoyl)-piperazin-1-yl]-ethyl}-amide, LC-MS purity: 98.04%, 1H NMR: (DMSO) δ 8.76-8.6 (bs, 1H), 8.08-7.92 (m, 2H), 7.88-7.72 (m, 4H), 7.6-7.4 (m, 4H), 4.2 (s, 2H), 3.6 (s, 5H), 3.2 (m, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:3]=1[CH2:4][NH2:5].C([N:14](CC)C(C)C)(C)C.C(N1C=CN=C1)(N1C=CN=C1)=O.C(N(CC)CC)C.FC1C=C(OC)C=C(F)C=1CN1[C:48]2[N:49]=[CH:50][CH:51]=[CH:52][C:47]=2[S:46](=[O:54])(=[O:53])[N:45]([C:55]2[CH:60]=[CH:59][C:58]([O:61][CH3:62])=[C:57]([O:63][CH3:64])C=2)[C:44]1=[O:65]>CN(C=O)C>[Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:3]=1[CH2:4][N:5]1[C:48]2[N:49]=[CH:50][CH:51]=[CH:52][C:47]=2[S:46](=[O:54])(=[O:53])[N:45]([C:55]2[CH:60]=[CH:59][C:58]([O:61][CH3:62])=[C:57]([O:63][CH3:64])[N:14]=2)[C:44]1=[O:65]
Reactant: NCc1c(F)cccc1Cl
Reactant: COc1cc(F)c(CN2C(=O)N(c3ccc(OC)c(OC)c3)S(=O)(=O)c3cccnc32)c(F)c1
Reactant: CCN(C(C)C)C(C)C
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1ccc(N2C(=O)N(Cc3c(F)cccc3Cl)c3ncccc3S2(=O)=O)nc1OC

Procedure:
The title compound (157 mg, 0.33 mmol) was prepared in two steps from (IntC3) (165 mg, 0.5 mmol), 2-chloro-6-fluorobenzylamine (75 uL, 0.6 mmol) and N,N-diisopropylethylamine (180 uL, 1.0 mmol); followed by 1,1′-carbonyldiimidazole (298 mg, 1.84 mmol), triethylamine (0.13 mL, 0.93 mmol) in DMF (1.5 mL) using the methods of (95).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:31])[C@H:4]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2C=O)=[CH:19][CH:18]=1)[NH:5][C:6](=[O:15])[C:7]1[C:12]([Cl:13])=[CH:11][CH:10]=[CH:9][C:8]=1[Cl:14].[CH3:32][O:33][C:34](=[O:55])[CH:35]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[C:56]1(C)C=CC=CC=1>>[CH3:1][O:2][C:3](=[O:31])[C@H:4]([CH2:16][C:17]1[CH:18]=[CH:19][C:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[CH:56]=[CH:35][C:34]([O:33][CH3:32])=[O:55])=[CH:21][CH:22]=1)[NH:5][C:6](=[O:15])[C:7]1[C:8]([Cl:14])=[CH:9][CH:10]=[CH:11][C:12]=1[Cl:13]
Reactant: Cc1ccccc1
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COC(=O)[C@H](Cc1ccc(-c2ccccc2C=O)cc1)NC(=O)c1c(Cl)cccc1Cl
Product: COC(=O)C=Cc1ccccc1-c1ccc(C[C@H](NC(=O)c2c(Cl)cccc2Cl)C(=O)OC)cc1
Temperature: 80 °C
Reaction time: 18 h

Procedure:
N-(2,6-Dichlorobenzoyl)-4-(2-formylphenyl)-L-phenylalanine methyl ester (51.7 mg) and (triphenylphosphoranylidene)acetic acid methyl ester (75.8 mg) were dissolved in anhydrous toluene (1 mL) and stirred at 80° C. under N2 for 18 h. The mixture was allowed to cool and purified by preparative TLC (silica gel) using hexanes/EtOAc (2:1) as eluent to give N-(2,6-dichlorobenzoyl)-4-[2-[2-(methoxycarbonyl)ethenyl]phenyl]-L-phenylalanine methyl ester (48.0 mg). ESMS: m/z 512 (MH+).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([I:9])=[CH:4][N:3]=1.Cl.C([N:14]([CH2:18][CH3:19])[CH:15]([CH3:17])C)(C)C>O1CCCC1.N1CCCC1>[Cl:1][C:2]1[N:7]=[C:6]([N:14]2[CH2:15][CH2:17][CH2:19][CH2:18]2)[C:5]([I:9])=[CH:4][N:3]=1
Reactant: Clc1ncc(I)c(Cl)n1
Reactant: CCN(C(C)C)C(C)C
Agent: Cl
Solvent: C1CCNC1
Solvent: C1CCOC1
Product: Clc1ncc(I)c(N2CCCC2)n1
Reaction time: 3 h

Procedure:
To a solution of 2,4-dichloro-5-iodopyrimidine (5.00 g) synthesized according to the method described in WO2008/155140 A1 in tetrahydrofuran (50 mL), N,N-diisopropylethylamine (3.49 mL) and pyrrolidine (1.65 mL) were added under ice cooling, and the mixture was stirred at the same temperature for 3 hours. To the reaction mixture, 1.0 mol/L aqueous hydrochloric acid was added. The solid matter was taken by filtration, washed with water, and then dried under reduced pressure to obtain 2-chloro-5-iodo-4-(pyrrolidin-1-yl)pyrimidine (H1, 4.49 g).
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]2[C:3]=1[C:4]([NH:21][C:22]1[CH:23]=[N:24][CH:25]=[C:26]([N:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)[CH:27]=1)=[C:5]([CH3:20])[C:6]([N:13]1[CH2:18][CH2:17][NH:16][C@@H:15]([CH3:19])[CH2:14]1)=[N:7]2.Cl[C:35]([O:37][CH3:38])=[O:36]>>[F:1][C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]2[C:3]=1[C:4]([NH:21][C:22]1[CH:23]=[N:24][CH:25]=[C:26]([N:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)[CH:27]=1)=[C:5]([CH3:20])[C:6]([N:13]1[CH2:18][CH2:17][N:16]([C:35]([O:37][CH3:38])=[O:36])[C@@H:15]([CH3:19])[CH2:14]1)=[N:7]2
Reactant: Cc1c(N2CCN[C@@H](C)C2)nc2cc(F)cc(F)c2c1Nc1cncc(N2CCOCC2)c1
Reactant: COC(=O)Cl
Product: COC(=O)N1CCN(c2nc3cc(F)cc(F)c3c(Nc3cncc(N4CCOCC4)c3)c2C)C[C@@H]1C

Procedure:
Essentially prepared according to Procedure N using (S)-5,7-difluoro-3-methyl-2-(3-methylpiperazin-1-yl)-N-(5-morpholinopyridin-3-yl)quinolin-4-amine (50 mg, 0.11 mmol) and methyl chloroformate to give (S)-methyl 4-(5,7-difluoro-3-methyl-4-(5-morpholinopyridin-3-ylamino)quinolin-2-yl)-2-methylpiperazine-1-carboxylate. 1H NMR (CDCl3) δ ppm 7.94 (1H, d, J=2.3 Hz), 7.69 (1H, d, J=2.2 Hz), 7.30 (1H, ddd, J=10.0, 2.6, 1.3 Hz), 6.89 (1H, d, J=12.9 Hz), 6.81 (1H, ddd, J=13.9, 8.8, 2.5 Hz), 6.58 (1H, t, J=2.4 Hz), 4.43 (1H, br. s.), 4.03 (1H, d, J=13.5 Hz), 3.86 (4H, dd, J=5.7, 3.9 Hz), 3.76 (3H, s), 3.71 (1H, d, J=9.8 Hz), 3.52-3.64 (1H, m), 3.38 (1H, td, J=12.8, 3.2 Hz), 3.17 (4H, dd, J=5.7, 4.1 Hz), 3.12 (1H, dd, J=12.8, 3.8 Hz), 2.93 (1H, td, J=12.6, 3.4 Hz), 2.10 (3H, s), 1.32 (3H, d, J=6.8 Hz). Mass Spectrum (ESI) m/e=513.3 (M+1).
Reaction SMILES: [C:1]([O-:4])(=[O:3])[CH3:2].[Na+].[Cl:6][C:7]1[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:8]=1[CH:14](O)[CH2:15][N:16]1[CH:20]=[N:19][CH:18]=[N:17]1.O>C(OC(=O)C)(=O)C>[C:1]([O:4][CH:14]([C:8]1[CH:9]=[CH:10][C:11]([Cl:13])=[CH:12][C:7]=1[Cl:6])[CH2:15][N:16]1[CH:20]=[N:19][CH:18]=[N:17]1)(=[O:3])[CH3:2]
Reactant: OC(Cn1cncn1)c1ccc(Cl)cc1Cl
Reactant: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: CC(=O)OC(Cn1cncn1)c1ccc(Cl)cc1Cl
Reaction time: 10 h
Yield: 43 %

Procedure:
A pinch of sodium acetate was added to 25.8 g (0.1 mol) of 1-(2,4-dichlorophenyl)-1-hydroxy-2-(1,2,4-triazol-1-yl)-ethane in 100 ml of acetic anhydride and the mixture was then kept for 10 hours at a temperature of 100° C. Thereafter the solution was cooled and stirred into 1,000 ml of water. A smeary, crystalline mass precipitated, which was taken up in chloroform. The chloroform solution was washed with sodium bicarbonate and water, dried over sodium sulphate and concentrated by distilling off the solvent in vacuo. The residue crystallized on adding petroleum ether. 13 g (43% of theory) of 1-acetoxy-1-(2,4-dichlorophenyl)-2-(1,2,4-triazol-1-yl)-ethane of melting point 92°-96° C. were obtained.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[Cl:10][S:11](O)(=[O:13])=[O:12].[Cl-].[NH4+]>C(Cl)Cl>[CH:1]([C:4]1[CH:9]=[CH:8][C:7]([S:11]([Cl:10])(=[O:13])=[O:12])=[CH:6][CH:5]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1ccccc1
Reactant: O=S(=O)(O)Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Product: CC(C)c1ccc(S(=O)(=O)Cl)cc1
Temperature: 5 °C
Reaction time: 1 h

Procedure:
A solution of 11.6 ml of isopropylbenzene in 100 ml of methylene chloride was added at 5° C. within 30 minutes to 18.3 ml of chlorosulfonic acid. The reaction mixture was stirred at 5° C. for 1 hour, poured on to 500 ml of ice-water and, after stirring for 5 minutes, treated with 100 g of ammonium chloride. After extraction with methylene chloride (1×800 ml, 1×500 ml) the organic phases were combined, dried with magnesium sulphate and the solvent was removed on a rotary evaporator. 12.3 g of 4-isopropyl-benzenesulfonyl chloride separated as a reddish oil, which was used without further purification.
Reaction SMILES: [CH3:1][CH:2]([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH3:16])[CH2:3][N:4]1[CH2:8][CH2:7][CH2:6][CH2:5]1.[CH2:17]([Br:20])[CH:18]=[CH2:19]>C(OCC)(=O)C>[Br-:20].[CH2:19]([N+:4]1([CH2:3][CH:2]([CH3:1])[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[CH3:16])[CH2:8][CH2:7][CH2:6][CH2:5]1)[CH:18]=[CH2:17]
Reactant: Cc1ccccc1CC(C)CN1CCCC1
Reactant: C=CCBr
Solvent: CCOC(C)=O
Product: C=CC[N+]1(CC(C)Cc2ccccc2C)CCCC1
Product: [Br-]

Procedure:
A solution of 51 g of N-[2-methyl-3-(o-methyl-phenyl)-propyl]-pyrrolidine and 58 g of allyl bromide in 200 ml of ethyl acetate is refluxed for 5 hours. The product precipitates as a resin. After the ethyl acetate has been decanted, the crude product is triturated several times with ethyl acetate. Supernatant solvent is decanted. Finally, the product is triturated with n-pentane and the solvent decanted. The oil which remains is freed from solvent residues in a rotary evaporator. There remains 60 g of N-allyl-N-[2-methyl-3-(o-methyl-phenyl)-propyl]-pyrrolidinium bromide as a brown resin.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5](B2OC(C)(C)C(C)(C)O2)=[N:6][CH:7]=1.Br[C:18]1[C:29]([Cl:30])=[CH:28][C:21]2[O:22][C:23]([F:27])([F:26])[CH2:24][O:25][C:20]=2[CH:19]=1>O1CCOCC1.CC#N.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.Cl[Pd]Cl>[Cl:30][C:29]1[C:18]([C:5]2[N:6]=[CH:7][C:2]([NH2:1])=[N:3][CH:4]=2)=[CH:19][C:20]2[O:25][CH2:24][C:23]([F:27])([F:26])[O:22][C:21]=2[CH:28]=1
Reactant: CC1(C)OB(c2cnc(N)cn2)OC1(C)C
Reactant: FC1(F)COc2cc(Br)c(Cl)cc2O1
Agent: Cl[Pd]Cl
Agent: CN(C)c1ccc(P(C(C)(C)C)C(C)(C)C)cc1
Solvent: C1COCCO1
Solvent: CC#N
Product: Nc1cnc(-c2cc3c(cc2Cl)OC(F)(F)CO3)cn1
Temperature: 85 °C
Yield: 8.7 %

Procedure:
5-Aminopyrazine-2-boronic acid pinacol ester (62 mg, 0.28 mmol) and 254 (67 mg, 0.23 mmol) were dissolved in 2 mL 1,4-dioxane and 2 mL MeCN. Next 1 ml of 2 M K3PO3 was added and the mixture was then bubbled with Ar for 2 min before bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (A-Phos, 70 mg, 0.1 mmol) was added. The reaction was then heated at 85° C. for 2 h. The reaction mixture was cooled and then worked-up with EtOAc extraction. The product was purified by flash column and afforded 256 (6 mg, 9%) as a yellow wax.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]([C:17]2[C:18](Cl)=[N:19][CH:20]=[C:21]([F:23])[CH:22]=2)=[O:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:25][C:26]1[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]([C:17]2[C:18]([O:32][C:29]3[CH:30]=[CH:31][C:26]([F:25])=[CH:27][CH:28]=3)=[N:19][CH:20]=[C:21]([F:23])[CH:22]=2)=[O:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Oc1ccc(F)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(NC(=O)c2cc(F)cnc2Cl)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(NC(=O)c2cc(F)cnc2Oc2ccc(F)cc2)CC1
Yield: 53.4 %

Procedure:
4-[(2-Chloro-5-fluoro-pyridine-3-carbonyl)-amino]-piperidine-1-carboxylic acid tert-butyl ester (4.0 g, 11.18 mmol) (see Preparation 27), 4-fluorophenol (1.378 g, 12.3 mmol) and caesium carbonate (7.29 g, 33.54 mmol) were stirred in N,N-dimethylformamide (40 ml) at 55° C. under an atmosphere of nitrogen for 18 hours. The reaction mixture was then partitioned between ethyl acetate (50 ml) and water (30 ml) and the organic layer separated. The organic layer was then washed with a saturated aqueous solution of sodium chloride (40 ml), dried over anhydrous magnesium sulphate and the solvent removed in vacuo. The residue was purified by flash column chromatography on silica gel eluting with dichloromethane. The product was finally triturated with diethylether (25 ml) giving 4-{[5-fluoro-2-(4-fluorophenoxy)-pyridine-3-carbonyl]-amino}-piperidine-1-carboxylic acid tert-butyl ester (2.59 g) as a white solid.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:13]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][C:16]=2[Cl:22])=[C:12]([F:23])[C:8]2[N:9]=[CH:10][NH:11][C:7]=2[CH:6]=1)=[O:4].[OH-].[Na+]>CCO.C(OCC)(=O)C.O.Cl>[Br:21][C:18]1[CH:19]=[CH:20][C:15]([NH:14][C:13]2[C:5]([C:3]([OH:4])=[O:2])=[CH:6][C:7]3[NH:11][CH:10]=[N:9][C:8]=3[C:12]=2[F:23])=[C:16]([Cl:22])[CH:17]=1
Reactant: COC(=O)c1cc2[nH]cnc2c(F)c1Nc1ccc(Br)cc1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCO
Product: O=C(O)c1cc2[nH]cnc2c(F)c1Nc1ccc(Br)cc1Cl
Reaction time: 16 h
Yield: 39.2 %

Procedure:
6-(4-Bromo-2-chloro-phenylamino)-7-fluoro-3H-benzoimidazole-5-carboxylic acid methyl ester 8b (58 mg, 0.146 mmol) is suspended in EtOH (2 mL) and 1 mL 2 N NaOH is added. After 16 hours, the reaction mixture is diluted with ethyl acetate, water, and 10% HCl solution. The layers are separated and the organic layer is washed with brine. The organic layer is dried (MgSO4) and concentrated under reduced pressure. Trituration with MeOH provides 22 mg (39%) pure desired product.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([Cl:17])[CH:10]=2)[N:5]=[C:4]([NH:18][CH:19]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[N:3]=1.[F:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[OH:33].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[Cl:17][C:11]1[CH:10]=[C:9]([NH:8][C:6]2[N:5]=[C:4]([NH:18][CH:19]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)[N:3]=[C:2]([O:33][C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=3[F:26])[N:7]=2)[CH:14]=[CH:13][C:12]=1[O:15][CH3:16]
Reactant: Oc1ccccc1F
Reactant: COc1ccc(Nc2nc(Cl)nc(NC3CCCCCC3)n2)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(Nc2nc(NC3CCCCCC3)nc(Oc3ccccc3F)n2)cc1Cl
Temperature: 80 °C

Procedure:
A mixture of compound 133 (0.3 g, 0.785 mmol), 2-fluorophenol (0.106 g, 0.942 mmol) and potassium carbonate (541 mg, 3.93 mmol) in dimethylformamide (3 mL) was heated to 80° C. for 12 hours with stirring under nitrogen atmosphere. The mixture was then cooled, diluted with water (20 mL) and extracted with EtOAc (2×20 mL). The combined organic layers were washed with water (2×10 mL), dried over anhydrous sodium sulphate and concentrated under vacuum. The residue thus obtained was purified by column chromatography (10-20% EtOAc-Hexane) to afford the title compound E28 as a pale yellow solid (0.2 g, 56%). mp 98-100° C.; HPLC: Inertsil ODS 3V (250×4.6 mm) 5 microns [solvent A=0.01 M KH2PO4 (pH 7.0); solvent B=CH3CN], Gradient elution program: T/% B=0/60, 10/60, 25/80, 40/80, 45/60, 50/60; 268 nm, Rt 29.79 min, 99.82% purity; MS (CI): m/z 458 (M+H, 100).
Reaction SMILES: [SH:1][CH2:2][CH2:3][C:4]([OH:6])=[O:5].[Na].Br[CH2:9][CH2:10]Cl.[CH3:12][C:13]([C:16]1[CH:21]=[C:20]([SH:22])[CH:19]=[C:18]([C:23]([CH3:26])([CH3:25])[CH3:24])[C:17]=1[OH:27])([CH3:15])[CH3:14]>>[CH3:26][C:23]([C:18]1[CH:19]=[C:20]([S:22][CH2:9][CH2:10][S:1][CH2:2][CH2:3][C:4]([OH:6])=[O:5])[CH:21]=[C:16]([C:13]([CH3:15])([CH3:14])[CH3:12])[C:17]=1[OH:27])([CH3:24])[CH3:25]
Reactant: ClCCBr
Reactant: O=C(O)CCS
Reactant: CC(C)(C)c1cc(S)cc(C(C)(C)C)c1O
Agent: [Na]
Product: CC(C)(C)c1cc(SCCSCCC(=O)O)cc(C(C)(C)C)c1O

Procedure:
The title compound was prepared according to the method of Example 5 from 3-mercaptopropionic acid (6.1 g, 0.057 mole); sodium (3.9 g, 0.17 mole); 1-bromo-2-chloroethane (12.4 g, 0.086 mole); and 2,6-bis(1,1-dimethylethyl)-4-mercaptophenol (13.7 g, 0.057 mole), purified by chromatography on silica and recrystallized from ethyl acetate/hexane, m.p. ca. 57.5° C.
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[NH:15]1[C:23]2[C:18](=[CH:19][C:20]([C:24]3[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=3)[CH:27]=O)=[CH:21][CH:22]=2)[CH:17]=[CH:16]1.[CH2:32]([NH:39][CH2:40][CH2:41][N:42]([CH3:44])[CH3:43])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.C(O)(=O)C.C(=O)(O)[O-].[Na+]>O1CCCC1.C(OCC)(=O)C>[CH2:32]([N:39]([CH2:27][C:26]1[CH:29]=[CH:30][CH:31]=[C:24]([C:20]2[CH:19]=[C:18]3[C:23](=[CH:22][CH:21]=2)[NH:15][CH:16]=[CH:17]3)[CH:25]=1)[CH2:40][CH2:41][N:42]([CH3:44])[CH3:43])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: O=Cc1cccc(-c2ccc3[nH]ccc3c2)c1
Reactant: CN(C)CCNCc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CN(C)CCN(Cc1ccccc1)Cc1cccc(-c2ccc3[nH]ccc3c2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 68.7 %

Procedure:
Sodium triacetoxyborohydride (480 mg, 2.3 mmol) was added to a solution of 3-(1H-indol-5-yl)-benzaldehyde (250 mg, 1.1 mmol) and N′-benzyl-N,N-dimethyl-ethane-1,2-diamine (600 mg, 3.4 mmol) and acetic acid (204 mg, 3.4 mmol) in 8 mL of tetrahydrofuran. The mixture was stirred at ambient temperature overnight, and then it was diluted with ethyl acetate, and neutralized with the careful addition of saturated sodium bicarbonate solution. The layers were separated and the organic phase was treated with polystyrene supported isocyanate resin (1.49 mmol/g, 1.7 g) for 2 h. The mixture was filtered and the filtrate was washed with 1M sodium carbonate solution. The aqueous phase was extracted into ethyl acetate, and the combined organic phases were dried over magnesium sulfate, filtered and concentrated to leave 290 mg of the title compound. LC/MS (short method): retention time, 2.61 min; (M+H)=384.50.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[C:11]([CH:32]=[CH:33][CH:34]=2)[CH2:12][N:13]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:14][CH2:15][N:16]([CH3:24])C(=O)OC(C)(C)C)O1.Br[C:37]1[CH:53]=[C:52]([CH3:54])[C:40]2[NH:41][C:42]([C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][C:45]=3[O:50][CH3:51])=[N:43][C:39]=2[CH:38]=1.[C:55](=[O:58])([O-])[O-:56].[Na+].[Na+]>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:51][O:50][C:45]1[CH:46]=[CH:47][CH:48]=[CH:49][C:44]=1[C:42]1[NH:41][C:40]2[C:52]([CH3:54])=[CH:53][C:37]([C:9]3[CH:10]=[C:11]([CH:32]=[CH:33][CH:34]=3)[CH2:12][N:13]([CH2:14][CH2:15][NH:16][CH2:24][C:55]([O:56][C:11]([CH3:32])([CH3:12])[CH3:10])=[O:58])[C:25](=[O:26])[O:27][C:28]([CH3:29])([CH3:30])[CH3:31])=[CH:38][C:39]=2[N:43]=1
Reactant: CN(CCN(Cc1cccc(B2OC(C)(C)C(C)(C)O2)c1)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Reactant: O=C([O-])[O-]
Reactant: COc1ccccc1-c1nc2cc(Br)cc(C)c2[nH]1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: COc1ccccc1-c1nc2cc(-c3cccc(CN(CCNCC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c3)cc(C)c2[nH]1
Temperature: 80 °C
Yield: 97 %

Procedure:
To a solution of 158 (0.165 g, 0.336 mmol) in DME (1.5 mL) and water (0.5 mL) was added 159 (0.107 g, 0.336 mmol), sodium carbonate (0.107 g, 1.009 mmol) followed by Pd(Ph3P)4 (0.025 g, 0.022 mmol). The reaction mixture was degassed with nitrogen and heated to 80° C. for 16 hours. After the usual work-up the crude material was purified by silica gel chromatography (Biotage 25M, 20 to 30 to 50% ethyl acetate in hexanes) to give 160 (97.7 mg, 0.163 mmol, 48.3% yield) as yellow crusty solid. LRMS (ESI): (calc.) 600.7 (found) 601.5 (MH)+.
Reaction SMILES: CN([CH:4]=[O:5])C.O=P(Cl)(Cl)Cl.[F:11][CH2:12][CH2:13][N:14]1[C:18]([CH3:19])=[CH:17][C:16]([CH3:20])=[N:15]1.C(=O)([O-])[O-].[K+].[K+]>ClCCl.O>[F:11][CH2:12][CH2:13][N:14]1[C:18]([CH3:19])=[C:17]([CH:4]=[O:5])[C:16]([CH3:20])=[N:15]1
Reactant: CN(C)C=O
Reactant: Cc1cc(C)n(CCF)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1nn(CCF)c(C)c1C=O
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 24.9 %

Procedure:
To DMF (56 g, 0.75 mol) was added POCl3 (74.55 mL, 0.8 mol) at 0° C. After 30 minutes, to the formed Vilsmaier reagent was added 1-(2-fluoroethyl)-3,5-dimethyl-1H-pyrazole (88 g, 0.62 mol), and the reaction mixture was heated for 16 h at 80° C. The reaction mixture was diluted with dichloromethane (400 mL) and treated with potassium carbonate (600 g) in water (2 L) at 0° C. The organic layer was separated, passed through silica gel (10×10 cm), and evaporated. The liquid residue was crystallized from a mixture of hexane (100 mL) and ether (200 mL), separated by filtration, and dried in vacuo using an oil pump to give 26.3 g (24.9%) of the title product. Satisfactory C,H,N-analysis was obtained. 1H NMR (400 MHz, DMSO-d6): δ 2.33 (s, 3H), 2.48 (s, 3H), 4.36 (dt, J=28 Hz, J=5 Hz, 2H), 4.74 (dt, J=44 Hz, J=5 Hz, 2H), 9.85 (s, 1H). GC-MS calcd for C8H11FN2O: 170.09, found (M+): 170 m/z.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:11])[CH3:10])=[CH:4][CH:3]=1.[Br:12][CH2:13][CH2:14][CH:15](Br)[CH3:16].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Br:12][CH2:13][CH2:14][CH2:15][CH2:16][O:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:11])[CH3:10])=[CH:6][CH:7]=1
Reactant: CC(Br)CCBr
Reactant: CC(=O)Nc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(=O)Nc1ccc(OCCCCBr)cc1

Procedure:
A solution of N-(4-hydroxyphenyl)acetamide (Paracetamol) (1) (1.50 g) and 1,3-dibromobutane (15) (10.0 ml) in acetonitrile (25.0 ml) containing potassium carbonate (5.0 g) was refluxed for 8 hrs. at room temperature. The reaction mixture was filtered and the filtrate was poured into ice cold water. The residue was filtered and washed with 5% NaOH solution (3×100 ml), water (3×50 ml), dried, filtered and crystallized from methanol to get the desired product N-[4-(4-bromobutoxy)phenyl]acetamide (17) (2.15 g, 77.06), mp 119-124° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([O:13][CH3:14])=[N:11][C:10]2[C:9]([C:15](Cl)=[O:16])=[C:8]([CH3:18])[C:7]([N+:19]([O-:21])=[O:20])=[CH:6][C:5]=2[N:4]=1.Cl.[C:23]([O:27][C:28](=[O:32])[CH2:29][NH:30][CH3:31])([CH3:26])([CH3:25])[CH3:24]>>[CH3:1][O:2][C:3]1[C:12]([O:13][CH3:14])=[N:11][C:10]2[C:9]([C:15]([N:30]([CH2:29][C:28]([O:27][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:32])[CH3:31])=[O:16])=[C:8]([CH3:18])[C:7]([N+:19]([O-:21])=[O:20])=[CH:6][C:5]=2[N:4]=1
Reactant: CNCC(=O)OC(C)(C)C
Reactant: COc1nc2cc([N+](=O)[O-])c(C)c(C(=O)Cl)c2nc1OC
Agent: Cl
Product: COc1nc2cc([N+](=O)[O-])c(C)c(C(=O)N(C)CC(=O)OC(C)(C)C)c2nc1OC
Reaction time: 24 h

Procedure:
Prepared from 2,3-dimethoxy-6-methyl-7-nitro-quinoxaline-5-carbonyl chloride (13) 200 mg (0.64 mmol) and sarcosine tert-butyl ester hydrochloride 122 mg (0.67 mmol). Reaction was continued for 24 hours, and the crude product was eluted through a flash column (4:1 hexanes:ethyl acetate), 200 mg (74%), mp 102-105° C.; 1H NMR (CDCl3): δ 8.29 (s, 1H), 4.27 (br s, 2H), 4.02 (s, 3H), 3.96 (s, 3H), 3.35 (br s, 3H), 2.54 (s, 3H), 1.41 (s, 9H); MS (APCI): m/z 421 (M+H). Anal. Calcd. for C19H24N4O7: C, 54.28; H, 5.75; N, 13.33. Found: C, 54.51; H, 5.76; N, 13.35.