Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])(=[O:4])[NH:2][NH2:3].C(N(CC)CC)C.Br[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20]>C1(C)C=CC=CC=1>[CH2:22]([O:21][C:19](=[O:20])[CH2:18][NH:3][NH:2][C:1]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4])[CH3:23]
Reactant: CCOC(=O)CBr
Reactant: CC(C)(C)OC(=O)NN
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCOC(=O)CNNC(=O)OC(C)(C)C
Temperature: 100 °C
Yield: 43.8 %

Procedure:
A 500 mL 3-neck round bottom flask was charged with t-butyl carbazate (15.0 g, 113.5 mmol), toluene (120 mL), triethylamine (18.98 mL, 136.2 mmol) and ethyl bromoacetate (15.10 mL, 136.2 mmol). The mixture was heated in an oil bath to about 100° C. for 19 hours. The reaction mixture was allowed to cool to room temperature and was then filtered, washing the solid triethylamine bromide with ethyl acetate/hexanes. The combined organics were washed successively with saturated sodium bicarbonate, water and brine, dried over sodium sulfate, filtered, concentrated and dried in vacuo to give a crude reddish oil (20.78 g). The crude material was absorbed onto Celite® and purified on a 10×20 cm silica gel column eluting with 15% (4 L), 20% (7 L), 30% (2 L), 40% (2 L), 50% (2 L) ethyl acetate/hexanes and finally ethyl acetate (2 L). The desired fractions were combined and concentrated to give an oil (10.85 g) which solidified upon standing. The residue was concentrated with dichloro-methane/toluene and dried in vacuo to give compound A (44%) as an off-white solid. TLC: Rf =0.13, silica gel, 30% ethyl acetate/hexanes, UV and PMA detection.
Reaction SMILES: [CH3:1][C:2]1[C:3]([O:19][CH:20]([CH3:22])[CH3:21])=[CH:4][C:5]([C:13]2[CH:14]=[N:15][N:16]([CH3:18])[CH:17]=2)=[C:6]2[C:11]=1[C:10](=[O:12])[NH:9][CH2:8][CH2:7]2.[H-].[Na+].Cl[CH2:26][C:27]1[C:32]([CH3:33])=[CH:31][C:30](C)=[CH:29][C:28]=1[O:35][CH2:36][C:37]1[C:42](C2(OCC3C=CC=CC=3)C=C(C)C=C(C)C2CCl)=[CH:41][CH:40]=[CH:39][CH:38]=1.C[N:62](C=O)C>>[CH2:36]([O:35][C:28]1[C:27]([CH2:26][N:9]2[CH2:8][CH2:7][C:6]3[C:11](=[C:2]([CH3:1])[C:3]([O:19][CH:20]([CH3:22])[CH3:21])=[CH:4][C:5]=3[C:13]3[CH:14]=[N:15][N:16]([CH3:18])[CH:17]=3)[C:10]2=[O:12])=[C:32]([CH3:33])[CH:31]=[C:30]([CH3:29])[N:62]=1)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: Cc1c(OC(C)C)cc(-c2cnn(C)c2)c2c1C(=O)NCC2
Reactant: CC1=CC(OCc2ccccc2)(c2ccccc2COc2cc(C)cc(C)c2CCl)C(CCl)C(C)=C1
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Product: Cc1cc(C)c(CN2CCc3c(-c4cnn(C)c4)cc(OC(C)C)c(C)c3C2=O)c(OCc2ccccc2)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 38 %

Procedure:
To a stirred solution of 8-methyl-5-(1-methyl-1H-pyrazol-4-yl)-7-(propan-2-yloxy)-3,4-dihydroisoquinolin-1(2H)-one (108j, 60 mg, 0.2 mmol) in DMF (5 mL) was added NaH (9.6 mg, 0.4 mmol, 60% in oil) at 0° C. under N2. After 30 minutes, 1-(benzyloxy)-2-(chloromethyl)-3,5-dimethylbenzene benzyl 2-(chloromethyl)-3,5-dimethylphenyl ether (Cpd Z, 115 mg, 0.44 mmol) was added and stirred at room temperature for 14 hours. The reaction mixture was poured into ice-water (20 mL), then extracted with EtOAc (3×20 mL). The combined organic layers were washed with brine (2×10 mL), dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by column chromatography (petroleum ether/EtOAc=1:1) to give 2-{[2-(benzyloxy)-4,6-dimethylpyridin-3-yl]methyl}-8-methyl-5-(1-methyl-1H-pyrazol-4-yl)-7-(propan-2-yloxy)-3,4-dihydroisoquinolin-1(2H)-one (108k, 40 mg, 38%) as a white solid.
Reaction SMILES: [CH2:1]([NH:3][S:4]([C:7]1[CH:12]=[CH:11][C:10](I)=[CH:9][CH:8]=1)(=[O:6])=[O:5])[CH3:2].C(O)CO.C(=O)([O-])[O-].[K+].[K+].[CH3:24][O:25][C:26]1[CH:33]=[CH:32][C:29]([CH2:30][SH:31])=[CH:28][CH:27]=1>C(O)(C)C.C(Cl)(Cl)Cl>[CH2:1]([NH:3][S:4]([C:7]1[CH:12]=[CH:11][C:10]([S:31][CH2:30][C:29]2[CH:32]=[CH:33][C:26]([O:25][CH3:24])=[CH:27][CH:28]=2)=[CH:9][CH:8]=1)(=[O:6])=[O:5])[CH3:2]
Reactant: CCNS(=O)(=O)c1ccc(I)cc1
Reactant: COc1ccc(CS)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: CC(C)O
Solvent: OCCO
Product: CCNS(=O)(=O)c1ccc(SCc2ccc(OC)cc2)cc1
Temperature: 80 °C

Procedure:
To a suspension of N-ethyl-4-iodo-benzenesulfonamide 6 g in isopropanol 26 ml was added ethylene glycol 1.9 ml, potassium carbonate 4.68 g, cuprous iodide 320 mg and then 4-methoxybenzyl mercaptan 3.55 g. The mixture was heated at ˜80° C. for 16 h and then cooled, diluted with chloroform 250 ml and washed with water ×3, (any solid at the interface was filtered off). The organic solution was dried, MgSO4 and evaporated. The solid was triturated with cyclohexane ×2 and dried to give N-ethyl-4-(4-methoxy-benzylsulfanyl)-benzenesulfonamide, 5.98 g 92%. 1H NMR 7.63 (2H, d), 7.28 (2H, d), 7.18 (2H, d), 6.79 (2H, d), 4.40 (1H, m), 4.08 (1H, s), 3.72 (3H, s), 2.90 (2H, m), 1.03 (3H, t).
Reaction SMILES: [Si]([O:8][CH2:9][C@:10]1([CH3:35])[S:16][CH2:15][CH2:14][N:13]2[C:17]([C:20]3([C:23]4[CH:28]=[CH:27][C:26]([C:29]5[CH:30]=[N:31][N:32]([CH3:34])[CH:33]=5)=[CH:25][CH:24]=4)[CH2:22][CH2:21]3)=[N:18][N:19]=[C:12]2[CH2:11]1)(C(C)(C)C)(C)C.Cl>CO.O1CCOCC1>[CH3:35][C@@:10]1([CH2:9][OH:8])[S:16][CH2:15][CH2:14][N:13]2[C:17]([C:20]3([C:23]4[CH:24]=[CH:25][C:26]([C:29]5[CH:30]=[N:31][N:32]([CH3:34])[CH:33]=5)=[CH:27][CH:28]=4)[CH2:22][CH2:21]3)=[N:18][N:19]=[C:12]2[CH2:11]1
Reactant: Cn1cc(-c2ccc(C3(c4nnc5n4CCS[C@@](C)(CO[Si](C)(C)C(C)(C)C)C5)CC3)cc2)cn1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: Cn1cc(-c2ccc(C3(c4nnc5n4CCS[C@@](C)(CO)C5)CC3)cc2)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 73 %

Procedure:
The compound (403 mg, 0.79 mmol) obtained in Example 34-1) was dissolved in methanol (4 mL). A 4 N solution (1.98 mL) of hydrochloric acid in dioxane was added to the solution, and the mixture was stirred at room temperature for 1 h. The solvent was distilled off, the residue was dissolved in a mixed solvent of methylene chloride (50 mL) and methanol (2 mL), and the mixture was separated into organic and aqueous layers by the addition of saturated aqueous sodium hydrogencarbonate (20 mL). The organic layer was washed with saturated sodium chloride solution and then dried with anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (elution solvent: methanol/ethyl acetate=0% to 50%) to obtain the title compound (228 mg, 73%) in a colorless solid form.
Reaction SMILES: [F:1][C:2]1[C:26]([N+:27]([O-:29])=[O:28])=[CH:25][CH:24]=[CH:23][C:3]=1[CH2:4][C:5]1[C:6](=[O:22])[O:7][C:8]2[CH:15]=[C:14]([O:16][C:17](=[O:21])[N:18]([CH3:20])[CH3:19])[CH:13]=[CH:12][C:9]=2[C:10]=1[CH3:11].[Br:30]N1C(=O)CCC1=O.Cl>C1COCC1>[Br:30][CH2:11][C:10]1[C:9]2[CH:12]=[CH:13][C:14]([O:16][C:17](=[O:21])[N:18]([CH3:19])[CH3:20])=[CH:15][C:8]=2[O:7][C:6](=[O:22])[C:5]=1[CH2:4][C:3]1[CH:23]=[CH:24][CH:25]=[C:26]([N+:27]([O-:29])=[O:28])[C:2]=1[F:1]
Reactant: Cc1c(Cc2cccc([N+](=O)[O-])c2F)c(=O)oc2cc(OC(=O)N(C)C)ccc12
Reactant: O=C1CCC(=O)N1Br
Agent: Cl
Solvent: C1CCOC1
Product: CN(C)C(=O)Oc1ccc2c(CBr)c(Cc3cccc([N+](=O)[O-])c3F)c(=O)oc2c1
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 42.6 %

Procedure:
THF (0.9 mL) was added to dimethylcarbamic acid 3-(2-fluoro-3-nitrobenzyl)-4-methyl-2-oxo-2H-1-benzopyran-7-yl ester (compound 1g-1-4) (47.6 mg), and the resultant suspension was stirred at −78° C. for 20 minutes to yield a dark brown solution. This solution was added at 0° C. to a solution of N-bromosuccinimide (28 mg) in THF (0.8 mL) (which had been prepared in advance in a separate container), and the mixture was stirred at 0° C. for 40 minutes. This reaction solution was poured into 1N hydrochloric acid (0.119 mL) diluted with ice water (20 mL), and then extracted with ethyl acetate. The organic layer extraction liquid was washed with saturated saline, and the organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled away under reduced pressure, and the resultant residue was purified by thin layer silica gel chromatography (hexane:ethyl acetate=1:1) to yield the title compound (24.3 mg).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])[CH:4]([NH2:27])[CH2:5][NH:6][C:7]([N:9]1[CH2:26][CH2:25][C:12]2([N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:15][N:14]([CH3:23])[C:13]2=[O:24])[CH2:11][CH2:10]1)=[O:8].[C:29]([N:32]1[C@H:36]([C:37](O)=[O:38])[CH2:35][S:34][CH2:33]1)(=[O:31])[CH3:30].CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>ClCCl>[CH3:1][O:2][C:3](=[O:28])[CH:4]([NH:27][C:37]([C@@H:36]1[CH2:35][S:34][CH2:33][N:32]1[C:29](=[O:31])[CH3:30])=[O:38])[CH2:5][NH:6][C:7]([N:9]1[CH2:10][CH2:11][C:12]2([N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:15][N:14]([CH3:23])[C:13]2=[O:24])[CH2:25][CH2:26]1)=[O:8]
Reactant: CC(=O)N1CSC[C@H]1C(=O)O
Reactant: COC(=O)C(N)CNC(=O)N1CCC2(CC1)C(=O)N(C)CN2c1ccccc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)C(CNC(=O)N1CCC2(CC1)C(=O)N(C)CN2c1ccccc1)NC(=O)[C@@H]1CSCN1C(C)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.4 %

Procedure:
To a solution of 301 mg (0.77 mmol) of 2-amino-3-((3-methyl-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decane-8-carbonyl)amino)propionic acid methyl ester in 7.5 ml of dichloromethane, 135 mg (0.77 mmol) of (R)-3-acetylthiazolidin-4-carboxylic acid, 342 mg (0.77 mmol) of BOP reagent and 0.15 ml (0.86 mmol) of N,N-diisopropylethylamine were added, and the resulting mixture was stirred overnight at room temperature. To the reaction mixture, 10 ml of semi-saturated saline was added, and the resulting mixture was extracted with ethyl acetate. Organic phases were combined, washed with 0.5M hydrochloric acid, with saturated aqueous sodium hydrogen carbonate solution and with saturated saline, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (chloroform:methanol=100:1-10:1) to obtain 309 mg of 2-(((R)-3-acetylthiazolidin-4-carbonyl)amino)-3-((3-methyl-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decane-8-carbonyl)amino)propionic acid methyl ester (yield: 73%).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[C:8]([NH:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[O:21][CH3:22])[CH:7]=[CH:6]2.[F:23][C:24]1[CH:31]=[CH:30][C:27]([CH:28]=O)=[CH:26][CH:25]=1.C(O)(=O)C>ClCCCl>[F:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28][NH:1][CH2:2][C:3]2[CH:4]=[C:5]3[C:10](=[CH:11][CH:12]=2)[N:9]=[C:8]([NH:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[O:21][CH3:22])[CH:7]=[CH:6]3)=[CH:26][CH:25]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: COc1ccccc1CNc1ccc2cc(CN)ccc2n1
Solvent: ClCCCl
Solvent: CC(=O)O
Product: COc1ccccc1CNc1ccc2cc(CNCc3ccc(F)cc3)ccc2n1
Temperature: 25 °C
Reaction time: 60 h
Yield: 53.2 %

Procedure:
A solution of (6-aminomethyl-quinolin-2-yl)-(2-methoxy-benzyl)-amine (example 85, step B) (390 mg, 1.33 mmol), 4-fluorobenzaldehyde (181.5 mg, 1.46 mmol) and acetic acid (319.3 mg, 5.32 mmol) in 1,2-dichloroethane (15 ml) was stirred at room temperature for 30 min. Afterwards sodium triacetoxy-boron hydride (657 mg, 2.79 mmol) was added, the reaction mixture was allowed to stir for 60 h at room temperature, poured into ice/saturated NaHCO3 solution (30 ml) and extracted with dichloromethane (2×40 ml). The combined organic layers were washed with brine (30 ml), dried (MgSO4) and evaporated. The crude product was purified by flash chromatography (ethyl acetate/heptane) on silica gel to yield the title compound as colorless oil (284 mg, 53%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:17]=[C:18]([Cl:20])[CH:19]=1)[O:5][C:6]1[C:7](=[O:16])[NH:8][CH:9]=[CH:10][C:11]=1[C:12]([F:15])([F:14])[F:13].C(=O)([O-])[O-].[K+].[K+].Br[CH2:28][C:29]1[C:37]2[C:32](=[N:33][CH:34]=[CH:35][CH:36]=2)[N:31]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[N:30]=1>CN(C)C=O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:17]=[C:18]([Cl:20])[CH:19]=1)[O:5][C:6]1[C:7](=[O:16])[N:8]([CH2:28][C:29]2[C:37]3[C:32](=[N:33][CH:34]=[CH:35][CH:36]=3)[N:31]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[N:30]=2)[CH:9]=[CH:10][C:11]=1[C:12]([F:15])([F:13])[F:14]
Reactant: O=c1[nH]ccc(C(F)(F)F)c1Oc1cc(Cl)cc(Cl)c1
Reactant: CC(C)(C)OC(=O)n1nc(CBr)c2cccnc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)n1nc(Cn2ccc(C(F)(F)F)c(Oc3cc(Cl)cc(Cl)c3)c2=O)c2cccnc21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a flask charged with 3-(3,5-dichlorophenoxy)-4-(trifluoromethyl)pyridin-2(1H)-one (0.500 g, 1.54 mmol) and potassium carbonate (0.213 g, 1.54 mmol) was added dimethylformamide (5 mL). To this under N2 was added tert-butyl 3-(bromomethyl)-1H-pyrazolo[3,4-b]pyridine-1-carboxylate (0.482 g, 1.54 mmol) as a solution in dimethylformamide (2 mL). This was allowed to stir at room temperature. After 16 hours, the reaction mixture was diluted with ethyl acetate (100 mL), washed with brine (3×50 mL), dried (MgSO4), filtered and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography on a pre-packed silica gel Redi Sep 40 gram column, eluting with 0-50% ethyl acetate in hexanes to afford the title compound. 1H NMR (DMSO-d6) δ 8.72 (d, J=4.5 Hz, 1H), 8.26-8.22 (m, 1H), 8.11 (d, J=7.2 Hz, 1H), 7.43 (dd, J=8.0 Hz, J=4.6 Hz, 1H), 7.30-7.28 (m, 1H), 7.05-7.02 (m, 2H), 6.70 (d, J=7.2 Hz, 1H), 5.60 (s, 2H), 1.62 (s, 9H). HRMS (M+1)=555.0826.
Reaction SMILES: [CH2:1]([O:3][C:4]1[O:5][C@H:6]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH2:9][C@H:7]2[N:8]=1)[CH3:2].[Cl:16][C:17]1[CH:18]=[C:19]([SH:24])[CH:20]=[CH:21][C:22]=1[Cl:23].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1.C1C=CC=CC=1.C(OCC)C>[Cl:16][C:17]1[CH:18]=[C:19]([S:24][C@@H:6]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH2:9][C@H:7]2[NH:8][C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH:20]=[CH:21][C:22]=1[Cl:23]
Reactant: CCOC1=N[C@@H]2Cc3ccccc3[C@@H]2O1
Reactant: Sc1ccc(Cl)c(Cl)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: CCOC(=O)N[C@@H]1Cc2ccccc2[C@H]1Sc1ccc(Cl)c(Cl)c1
Yield: 87.2 %

Procedure:
A solution of (±) cis-2-ethoxy-3a,8b-dihydro-4H-indeno[2,1-d]oxazole (0.61 g, 3.0 mmol) in dry toluene (15 ml) was treated with 3,4-dichlorothiophenol (0.59 g, 3.3 mmol) and a catalytic amount of p-toluenesulfonic acid (0.15 ml of an anhydrous 0.1M solution of p-toluenesulfonic acid in benzene). The mixture was heated under nitrogen at 70°-75° C. for 3.5 h. The reaction was diluted with diethyl ether and washed with 5% NaOH (3×10 ml) followed by water (10 ml) and brine (10 ml). The organic phase was dried over Na2 SO4 and concentrated in vacuo to give a solid (1.0 g). Purification on a silica gel column using CHCl3 as eluant afforded the title compound as a colourless solid (0.81 g).
Reaction SMILES: N1[C:5]([C:6]2[CH:19]=[CH:18][C:17]3[C:8](=[C:9]4[C:14](=[CH:15][CH:16]=3)[CH:13]=[CH:12][CH:11]=[N:10]4)[N:7]=2)=[N:4][N:3]=N1.[C:20]1([C:32](Cl)=[O:33])[CH:25]=[C:24]([C:26](Cl)=[O:27])[CH:23]=[C:22]([C:29](Cl)=[O:30])[CH:21]=1>N1C=CC=CC=1>[N:7]1[C:8]2[C:17](=[CH:16][CH:15]=[C:14]3[C:9]=2[N:10]=[CH:11][CH:12]=[CH:13]3)[CH:18]=[CH:19][C:6]=1[C:5]1[O:33][C:32]([C:20]2[CH:25]=[C:24]([C:26]3[O:27][C:5]([C:6]4[CH:19]=[CH:18][C:17]5[C:8](=[C:9]6[C:14](=[CH:15][CH:16]=5)[CH:13]=[CH:12][CH:11]=[N:10]6)[N:7]=4)=[N:4][N:3]=3)[CH:23]=[C:22]([C:29]3[O:30][C:5]([C:6]4[CH:19]=[CH:18][C:17]5[C:8](=[C:9]6[C:14](=[CH:15][CH:16]=5)[CH:13]=[CH:12][CH:11]=[N:10]6)[N:7]=4)=[N:4][N:3]=3)[CH:21]=2)=[N:3][N:4]=1
Reactant: O=C(Cl)c1cc(C(=O)Cl)cc(C(=O)Cl)c1
Reactant: c1cnc2c(c1)ccc1ccc(-c3nnn[nH]3)nc12
Solvent: c1ccncc1
Product: c1cnc2c(c1)ccc1ccc(-c3nnc(-c4cc(-c5nnc(-c6ccc7ccc8cccnc8c7n6)o5)cc(-c5nnc(-c6ccc7ccc8cccnc8c7n6)o5)c4)o3)nc12
Temperature: 85 °C
Reaction time: 8 h
Yield: 44.1 %

Procedure:
To a flask was added a mixture of 15 g 2-(1H-tetrazol-5-yl)-[1,10]phenanthroline and 300 ml pyridine. The mixture was then heated to 80-90° C., and 4.86 g 1,3,5 benzene tricarbonyl chloride was added. Subsequently, the mixture solution was heated to 110° C. and stirred overnight. After completion of reaction, as shown in scheme 8, the reaction mixture was filtered to collect solids. The solids was washed by pyridine and CH2Cl2 respectively, and then dried on oven to obtain products 6.6 g (yield=44.1%). MS(m/z, FAB+), 888, 810, 521, 444, 155.
Reaction SMILES: [CH2:1]([CH:4]1[CH2:8][N:7]([CH2:9][N:10]2[CH:14]=[CH:13][CH:12]=[CH:11]2)[C:6](=[O:15])[CH2:5]1)[CH2:2][CH3:3].[Cl:16]N1C(=O)CCC1=O.C(Cl)(Cl)(Cl)Cl>C1COCC1>[Cl:16][C:14]1[N:10]([CH2:9][N:7]2[CH2:8][CH:4]([CH2:1][CH2:2][CH3:3])[CH2:5][C:6]2=[O:15])[CH:11]=[CH:12][CH:13]=1
Reactant: CCCC1CC(=O)N(Cn2cccc2)C1
Reactant: O=C1CCC(=O)N1Cl
Solvent: C1CCOC1
Solvent: ClC(Cl)(Cl)Cl
Product: CCCC1CC(=O)N(Cn2cccc2Cl)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 50 %

Procedure:
4-propyl-1-(1H-pyrrol-1-ylmethyl)pyrrolidin-2-one x264 (0.182 g, 0.88 mmol) is dissolved in absolute THF (3 ml). A solution of N-chlorosuccinimide (0.118 g, 1 eq) in absolute THF (1 ml) is added dropwise in a flow of argon at 0° C. The obtained solution is allowed to heat up slowly to room temperature in the cooling bath under stirring for 16 h. CCl4 (30 ml) is then added to the obtained solution. A small amount of a precipitate is filtered off, and the filtrate is evaporated. 1-[(2-chloro-1H-pyrrol-1-yl)methyl]-4-propylpyrrolidin-2-one 299 is isolated from the residue by reverse-phase HPLC (eluent: acetonitrile/water).
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]([NH:38][CH3:39])[CH2:6][S:7][CH2:8][C:9]1[C:27]([O:28][Si:29]([C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:31])[CH3:30])=[CH:26][C:25]([O:36][CH3:37])=[CH:24][C:10]=1[C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=1)=[O:12])=[O:4].[C:40]([O:59][CH2:60][CH2:61][C:62](Cl)=[O:63])([C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1)([C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1.C(N(CC)CC)C>C(Cl)Cl>[Si:29]([O:28][C:27]1[C:9]([CH2:8][S:7][CH2:6][C@H:5]([N:38]([C:62](=[O:63])[CH2:61][CH2:60][O:59][C:40]([C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)([C:41]2[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=2)[C:53]2[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=2)[CH3:39])[C:3]([O:2][CH3:1])=[O:4])=[C:10]([CH:24]=[C:25]([O:36][CH3:37])[CH:26]=1)[C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=1)=[O:12])([C:32]([CH3:34])([CH3:35])[CH3:33])([CH3:31])[CH3:30]
Reactant: CN[C@@H](CSCc1c(O[Si](C)(C)C(C)(C)C)cc(OC)cc1C(=O)OCc1ccc([N+](=O)[O-])cc1)C(=O)OC
Reactant: O=C(Cl)CCOC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)[C@H](CSCc1c(O[Si](C)(C)C(C)(C)C)cc(OC)cc1C(=O)OCc1ccc([N+](=O)[O-])cc1)N(C)C(=O)CCOC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 65.8 %

Procedure:
A solution of 0.64 g of p-nitrobenzyl (R)-2-[[[2-(methoxycarbonyl)-2-(methylamino)-ethyl]thio]methyl]-3-(tert-butyldimethylsilyloxy)-5-methoxybenzoate and 0.58 g of 3-trityloxypropionyl chloride in 6 ml of methylene chloride was treated at 0° C. with 0.17 g of triethylamine. The mixture was stirred at 0° C. for 30 minutes, then diluted with methylene chloride, and washed successively with 5% sodium bicarbonate solution and brine. The organic layer was dried over sodium sulfate, and the solvent was evaporated in vacuo. The residual oil was chromatographed on silica gel using ethyl acetate/hexane (1:2, v/v) as eluent to yield 0.65 g of p-nitrobenzyl (R)-3-(tert-butyldimethylsilyloxy)-5-methoxy-2-[[[2-(3-trityloxypropionyl-methylamino)-2-methoxycarbonyl-ethyl]thio]methyl]-benzoate as an oil.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:5]([C:6](O)=[O:7])[C:4]=1[OH:12].N1C=CC=CC=1.C(Cl)(=O)C.CC[O:25][C:26]([CH3:28])=[O:27]>C(Cl)Cl>[CH3:1][S:2][CH2:3][C:4]([C:5]1[CH:9]=[CH:10][CH:11]=[C:28]([C:26]([OH:25])=[O:27])[C:6]=1[OH:7])=[O:12]
Reactant: CCOC(C)=O
Reactant: CSc1cccc(C(=O)O)c1O
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: CC(=O)Cl
Product: CSCC(=O)c1cccc(C(=O)O)c1O
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 20 %

Procedure:
To solution of 18 (46 mg, 0.25 mmol) in 1 mL of CH2Cl2 was added dry pyridine (20 mg, 50 μL, 0.3 mmol) at 0° C. (FIG. 2C). The solution was stirred at 0° C. for 10 minutes followed by the addition of acetyl chloride (˜30 μL, 0.4 mmol). The reaction mixture was stirred overnight at 0° C. and then the solvent was removed under vacuo. The residue was partioned between water and EtOAc. The organic solution was washed with 1 M HCl (10 mL), water (50 mL), and then dried (MgSO4). The solvent was evaporated to afford a oil which was chromatographed on silica gel and eluted with hexanes:EtOAc (initially 70:30, then 50:50) to afford the desired product as a white solid (11 mg, 20% yield). 1H NMR (CDCl3) δ7.86-7.89 (d, 1 H, ArH), 7.46-7.44 (d, 1 H, ArH), 7.32-7.36 (t, 1 H, ArH), 2.45 (s, 3 H, SCH3), 2.38 (s, 3 H, CH3); FAB-MS 227 (MH+, 15) 226 (MH+ −1, 10), 167 (50), 157 (30), 102 (100).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]([CH2:19][Si](C)(C)C)[N:8]=[N:9][C:10]=1[C:11]1[CH:16]=[CH:15][C:14]([Br:17])=[CH:13][C:12]=1[F:18])=[O:5])[CH3:2].O.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>O1CCCC1>[CH2:1]([O:3][C:4]([C:6]1[N:7]([CH3:19])[N:8]=[N:9][C:10]=1[C:11]1[CH:16]=[CH:15][C:14]([Br:17])=[CH:13][C:12]=1[F:18])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(-c2ccc(Br)cc2F)nnn1C[Si](C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)c1c(-c2ccc(Br)cc2F)nnn1C
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 57.6 %

Procedure:
In a 250 mL round-bottomed flask, 5-(4-bromo-2-fluoro-phenyl)-3-trimethylsilanylmethyl-3H-[1,2,3]triazole-4-carboxylic acid ethyl ester (616 mg, 1.54 mmol) and water (55.4 mg, 55.4 μL, 3.08 mmol, Eq: 2) were combined with tetrahydrofuran (13 mL) to give a light yellow solution. The reaction was cooled to 0° C. and 1M TBAF in THF (1.85 ml, 1.85 mmol, Eq: 1.2) was added. The reaction was stirred for 20 mins at 0° C. then concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 40 g, 0% to 20% EtOAc in heptane) to afford 291 mg (58%) of the desired product as a white solid. (M+H)+=327.9/329.9 m/e; 1H NMR (DMSO-d6) δ ppm 7.73 (dq, J=9.9, 0.7 Hz, 1H), 7.50-7.62 (m, 2H), 4.29 (s, 3H), 4.25 (q, J=7.1 Hz, 2H), 1.14 (t, J=7.1 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[C:18]3[C:13](=[CH:14][C:15]([OH:19])=[CH:16][CH:17]=3)[C:12](=[O:20])[C:11]([CH3:22])([CH3:21])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].[H-].[Na+].[H][H].[CH3:27][N:28]([CH3:32])[CH2:29][CH2:30]Cl>C1(C)C=CC=CC=1>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[C:18]3[C:13](=[CH:14][C:15]([O:19][CH2:30][CH2:29][N:28]([CH3:32])[CH3:27])=[CH:16][CH:17]=3)[C:12](=[O:20])[C:11]([CH3:22])([CH3:21])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CN(C)CCCl
Reactant: [H][H]
Reactant: CC1(C)CC(c2ccc(Cl)c(Cl)c2)c2ccc(O)cc2C1=O
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CN(C)CCOc1ccc2c(c1)C(=O)C(C)(C)CC2c1ccc(Cl)c(Cl)c1
Product: Cl

Procedure:
A mixture of 4-(3,4-dichlorophenyl)-7-hydroxy-2,2-dimethyl-1-tetralone (2.3 g) and sodium hydride (0.4 g, 60% dispersion in oil) was refluxed in toluene (20 ml) until evolution of hydrogen had ceased. A solution of 2-dimethylaminoethylchloride (1.2 g) in toluene (15 ml) was added dropwise and the mixture refluxed for 3 hr. The solvent was removed and the residue shaken with ether-dilute hydrochloric acid. The aqueous layer was separated, basified, extracted with ether and the extract dried (MgSO4). Evaporation gave the product as the free base, which was converted to the hydrochloride salt. Recrystallisation from ether-ethyl acetate gave 4-(3,4-dichlorophenyl)-2,2-dimethyl-7-(2-dimethylaminoethoxy)-1-tetralone hydrochloride as white crystals, (2.2 g, 72%) m.p. 180°-5° C.